WO2001049289A1 - Pharmaceutical and veterinary uses of endothelin antagonists - Google Patents

Pharmaceutical and veterinary uses of endothelin antagonists Download PDF

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Publication number
WO2001049289A1
WO2001049289A1 PCT/US2000/035280 US0035280W WO0149289A1 WO 2001049289 A1 WO2001049289 A1 WO 2001049289A1 US 0035280 W US0035280 W US 0035280W WO 0149289 A1 WO0149289 A1 WO 0149289A1
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methyl
isoxazolyl
chloro
alkyl
aryl
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PCT/US2000/035280
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French (fr)
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Thomas A. Brock
Patrick R. Ward
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Texas Biotechnology Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • methods of treatment, prevention, or amelioration of one or more symptoms of equine or bovine laminitis by administration of endothelin antagonists are provided.
  • Methods of treatment, prevention, or amelioration of one or more symptoms of menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre-eclampsia; and control and management of labor during pregnancy by administration of endothelin antagonists are also provided.
  • the vascular endothelium releases a variety of vasoactive substances, including the endothelium-derived vasoconstrictor peptide, endothelin (ET) (see, e.g., Vanhoutte et al. (1986) Annual Rev. Phvsiol. 48: 307-320; Furchgott and Zawadski (1980) Nature 288: 373-376).
  • Endothelin which was originally identified in the culture supernatant of porcine aortic endothelial cells (see, Yanagisawa et a (1988) Nature 332: 41 1-415), is a potent twenty-one amino acid peptide vasoconstrictor.
  • Endothelin is synthesized as a two hundred and three amino acid precursor preproendothelin that contains a signal sequence which is cleaved by an endogenous protease to produce a thirty-eight (human) or thirty-nine (porcine) amino acid peptide.
  • This intermediate is processed jn vivo to the mature biologically active form by a putative endothelin- converting enzyme (ECE) that appears to be a metal-dependent neutral protease (see, e.g., Kashiwabara et aL (1989) FEBS Lttrs. 247: 337-340). Cleavage is required for induction of physiological responses (see, e.g., von Geldern et aL (1991 ) Peptide Res. 4: 32-35).
  • ECE endothelin- converting enzyme
  • porcine aortic endothelial cells the thirty-nine amino acid intermediate, big endothelin, is hydrolyzed at the Trp 21 -Val 22 bond to generate endothelin-1 and a C- terminal fragment.
  • a similar cleavage occurs in human cells from a thirty-eight amino acid intermediate.
  • Three distinct endothelin isopeptides, endothelin-1 , endothelin-2 and endothelin-3, that exhibit potent vasoconstrictor activity have been identified.
  • the family of three isopeptides endothelin-1 , endothelin-2 and endothelin-3 are encoded by a family of three genes (see, Inoue et aL (1989) Proc. Natl. Acad. Sci. USA 86: 2863-2867; see, also Saida et al. (1989U. Biol. Chem. 264: 14613-14616).
  • the nucleotide sequences of the three human genes are highly conserved within the region encoding the mature 21 amino acid peptides and the C-terminal portions of the peptides are identical.
  • Endothelin-2 is (Trp 6 ,Leu 7 ) endothelin-1 and endothelin-3 is (Thr 2 ,Phe 4 ,Thr 5 ,Tyr ⁇ ,Lys 7 ,Tyr 14 ) endothelin-1 .
  • These peptides are, thus, highly conserved at the C-terminal ends. Release of endothelins from cultured endothelial cells is modulated by a variety of chemical and physical stimuli and appears to be regulated at the level of transcription and/or translation. Expression of the gene encoding endothelin-1 is increased by chemical stimuli, including adrenaline, thrombin and Ca 2+ ionophore.
  • Endothelial cells appear to secrete short-lived endothelium-derived relaxing factors (EDRF), now known to be nitric oxide, when stimulated by vasoactive agents, such as acetylcholine and bradykinin. Endothelin-induced vasoconstriction is also attenuated by atrial natriuretic peptide (ANP).
  • EDRF endothelium-derived relaxing factors
  • vasoactive agents such as acetylcholine and bradykinin. Endothelin-induced vasoconstriction is also attenuated by atrial natriuretic peptide (ANP).
  • ABP atrial natriuretic peptide
  • Laminitis Equine laminitis which is sometimes referred to as foundering, is a common disorder that was recognized and described in the earliest books of veterinary medicine. Laminitis is an inflammation of the pedal laminae that form the supportive bond between the hoof and the third
  • Laminitis is further described as a disorder of the hoof whose cause is varied. It is a complex, multi-systemic disease affecting the digestive, cardiovascular, hemic, renal, endocrine, musculoskeletal, integumentary, and immune systems. It is characterized by multi-systemic aberrations that ultimately result in reduced capillary perfusion, ischemia, and necrosis of the laminae. These results are accompanied by pain and loss of supportive function.
  • Acute laminitis is described as comprising the events leading up to and the onset of lameness.
  • Acute laminitis can progress to the chronic stage.
  • the chronic stage ensues after persistent lameness (greater than 48 hours), or when the distal phalanx deviates detectably.
  • Chronic laminitis is a consequence of some degree of loss of integrity of the supporting digital laminae.
  • the horse assumes a recumbent position in which most of the weight is placed on the hind limbs and little weight bearing pressure is exerted on the forelimbs.
  • Current therapies for equine laminitis include treatment with nitroglycerin, applied transdermally, and isoxsuprine, administered orally; and/or an anticoagulant, such as heparin, aspirin and trental (pentoxifylline) and others (see, U.S. Patent No.
  • L-Arg given intravenously, is not a particularly effective treatment.
  • veterinary uses of compounds that modulate the interaction of an endothelin peptide with an endothelin receptor are provided.
  • veterinary uses of endothelin antagonists are provided herein.
  • methods of treatment, prevention, or amelioration of one or more symptoms of laminitis, which afflict animals with hooves, particularly equine or bovine laminitis, using endothelin antagonists are provided.
  • pharmaceutical uses of endothelin antagonists are provided.
  • the pharmaceutical and veterinary methods provided herein use any compound capable of inhibiting the activity of endothelin peptides; or use any compound that is an endothelin receptor antagonist.
  • methods of using endothelin antagonists, particularly sulfonamide compounds, for the treatment of disorders involving nitric oxide, such as equine laminitis are provided.
  • Any compound, particularly any sulfonamide, known to those of skill in the art to have endothelin antagonist activity, particularly ET A antagonist activity, is contemplated for use herein.
  • Numerous such endothelin antagonists are known to those of skill in the art (see, e.g., U.S. Patent Nos.
  • TAK-044 (Masuda, Y., et al., Receptor Binding and Antagonist Properties of a Novel Endothelin Receptor Antagonist, TAK-044 ⁇ Cyclo[D- ⁇ -Aspartyl-3-[(4-Phenylpiperazin-1 -yl)Carbonyl]- L-Alanyl-L- ⁇ -Aspartyl-D-2-(2-Thienyl)Glycyl-L-Leucyl-D-Tryptophyl)Disodium Salt ⁇ , in Human Endothelin A and Endothelin B Receptors, The Journal of Pharmacology and
  • amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para- chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, alkali metal salts, such as but not limited to lithium, potassium and sodium, alkali earth metal salts, such as but not limited to barium, calcium and magnesium, transition metal salts, such as but not limited to, zinc and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate, preferably sodium salts, more preferably the sodium salt, and
  • amine salts such as but not limited to N,N'-dibenzylethylene
  • salts more preferably sodium salts, including but not limited to sodium salts and sodium hydrogen phosphate salts, most preferably the sodium salt, thereof that deliver amounts effective for the treatment, prevention,
  • the formulations are compositions suitable for administration by any desiredabnormal clotting patterns, urogenital discomfort and increased incidence of route and include solutions, suspensions, emulsions, tablets, dispersible tablets, pills, cardiovascular disease, and other disorders associated with the reduction in ovarian capsules, powders, dry powders for inhalation, sustained release formulations, aerosolsfunction in middle- aged women; pre-eclampsia; and control and management of labor for nasal and respiratory delivery, patches for transdermal delivery and any otherduring pregnancy are also provided, suitable route.
  • the compositions should be suitable for oral administration, parenteral administration by injection, including subcutaneously, intramuscularly or intravenously as an injectable aqueous or oily solution or emulsion, transdermal administration and other selected routes.
  • Methods for treatment, prevention, or amelioration of one or more symptoms of endothelin-mediated disorders including, but not limited to, laminitis, particularly equine or bovine laminitis, more particularly equine laminitis; menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease associated with menopause, and other disorders associated with the reduction in ovarian function in middle-aged and older women; pre-eclampsia; and control and management of labor during pregnancy are provided.
  • methods of treating laminitis by administering effective amounts of the compounds, or veterinarily acceptable derivatives thereof are provided.
  • laminitis particularly equine or bovine laminitis, more particularly equine laminitis
  • methods for treating laminitis, particularly equine or bovine laminitis, more particularly equine laminitis, by administering effective amounts of one or more of the compounds provided herein in veterinarily acceptable carriers are provided.
  • Preferred methods of treatment are methods for treatment of equine laminitis.
  • the formulations contain at least one compound that inhibits the interaction of endothelin-1 with ET A receptors at an IC 50 of less than about 10 ⁇ M, and preferably less than about 5 ⁇ M, more preferably less than about 1 ⁇ M, even more preferably less than 0.1 ⁇ M, and most preferably less than 0.05 ⁇ M
  • IC 50 of less than about 10 ⁇ M, and preferably less than about 5 ⁇ M, more preferably less than about 1 ⁇ M, even more preferably less than 0.1 ⁇ M, and most preferably less than 0.05 ⁇ M
  • the formulations contain pharmaceutically or veterinarily acceptable derivatives, preferably salts, of one or more compounds that is (are) ET A selective, or pharmaceutically or veterinarily acceptable derivatives, preferably salts, of one or more compounds that is (are) ET B selective.
  • the amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
  • laminitis or “foundering” refers to an inflammation of the pedal laminae that form the supportive bond between the hoof and the third phalanx. Laminitis is characterized by multi-systemic aberrations that ultimately result in reduced capillary perfusion, ischemia, and necrosis of the laminae, accompanied by pain, loss of supportive function, and ultimately lameness.
  • endothelin (ET) peptides include peptides that have substantially the amino acid sequence of endothelin-1 , endothelin-2 or endothelin-3 and that act as potent endogenous vasoconstrictor peptides.
  • an endothelin-mediated condition is a condition that is caused by abnormal endothelin activity or one in which compounds that inhibit endothelin activity have therapeutic use.
  • diseases include, but are not limited to hypertension, cardiovascular disease, asthma, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, gastroenteric disease, renal failure, pulmonary hypertension, endotoxin shock, anaphylactic shock, hemorrhagic shock, climacteric disorders, menopause, hot flushes or flashes, osteoporosis, preterm labor, pre-eclampsia, eclampsia and metabolic bone disorders.
  • Endothelin-mediated conditions also include conditions that result from therapy with agents, such as erythropoietin and immunosuppressants, that elevate endothelin levels.
  • an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
  • an endothelin agonist is a compound that potentiates or exhibits a biological activity associated with or possessed by an endothelin peptide.
  • an endothelin antagonist is a compound, such as a drug or an antibody, that inhibits endothelin-stimulated vasoconstriction and contraction and other endothelin-mediated physiological responses.
  • the antagonist may act by interfering with the interaction of the endothelin with an endothelin-specific receptor or by interfering with the physiological response to or bioactivity of an endothelin isopeptide, such as vasoconstriction.
  • an endothelin antagonist interferes with endothelin-stimulated vasoconstriction or other response or interferes with the interaction of an endothelin with an endothelin-specific receptor, such as ET A receptors, as assessed by assays known to those of skill in the art.
  • an endothelin-specific receptor such as ET A receptors
  • ET A receptors an endothelin-specific receptor
  • the effectiveness of potential agonists and antagonists can be assessed using methods known to those of skill in the art.
  • endothelin agonist activity can be identified by its ability to stimulate vasoconstriction of isolated rat thoracic aorta or portal vein ring segments (Borges et aL (1989) "Tissue selectivity of endothelin” Eur. J. Pharmacol. 165: 223-230).
  • Endothelin antagonist activity can be assessed by the ability to interfere with endothelin-induced vasoconstriction.
  • Exemplary assays are set forth in the EXAMPLES. As noted above, the preferred IC 50 concentration ranges are set forth with reference to assays in which the test compound is incubated with the ET receptor-bearing cells at 4° C. Data presented for assays in which the incubation step is performed at the less preferred 24° C are identified. It is understood that for purposes of comparison, these concentrations are somewhat higher than the concentrations determined at 4° C.
  • the biological activity or bioactivity of endothelin includes any activity induced, potentiated or influenced by endothelin vivo. It also includes the ability to bind to particular receptors and to induce a functional response, such as vasoconstriction. It may be assessed by vivo assays or by jn vitro assays, such as those exemplified herein.
  • the relevant activities include, but are not limited to, vasoconstriction, vasorelaxation and bronchodilation.
  • ET B receptors appear to be expressed in vascular endothelial cells and may mediate vasodilation and other such responses; whereas ET A receptors, which are endothelin-1 -specific, occur on smooth muscle and are linked to vasoconstriction Any assay known to those of skill in the art to measure or detect such activity may be used to assess such activity (see, e.g.. Spokes et aL (1989) J. Cardiovasc. Pharmacol. 13(Suppl. 5):S191 -S192; Spinella et aL (1991 ) Proc. Natl. Acad. Sci. USA 88: 7443-7446; Cardell et aL (1991 ) Neurochem.
  • bioavailability refers to the rate and extent of absorption. Methods for determining bioavailability are well known to those of skill in the art. For example, bioavailability of any of the compounds described herein can be determined empirically by administration of the compound to an animal, followed by taking blood samples over time and measuring the blood concentration of the compound. ]n vivo half life (t 1/2 ) is defined as the time it takes for the concentration of the compound in the blood to be reduced by one-half. Estimations of the area under the curve for intravenous administration can be used to estimate the area under the curve for oral administration, yielding bioavailability data. See, e.g., Milo Gibal (1991 ) Biopharmaceutics and Pharmacology, 4th edition (Lea and Sediger).
  • efficacy refers to the maximal effect that can be produced by a compound. Efficacy can be determined by methods known to those of skill in the art. For example, it can be determined by the properties of the compound and its receptor- effector system and is reflected in the plateau of the concentration-effect curve. ]n vivo efficacy refers to efficacy which is determined in an animal model. For example, in vivo efficacy of the compounds described herein can be determined by amelioration of hypoxia-induced pulmonary hypertension in rat. In this context, in vivo efficacy refers to the ability of a compound to restore an elevated pulmonary artery pressure to a normal value. See, e ⁇ a-., DiCarlo et aL (1995) Am.
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as binding of endothelin to tissue receptors, in an assay that measures such response.
  • EC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • a sulfonamide that is ET A selective refers to sulfonamides that exhibit an IC 50 that is at least about 10-fold lower with respect to ET A receptors than ET B receptors.
  • a sulfonamide that is ET B selective refers to sulfonamides that exhibit an IC S0 that is at least about 0-fold lower with respect to ET B receptors than ET A receptors.
  • pharmaceutically or veterinarily-acceptable salts, esters, hydrates, solvates or other derivatives of the compounds include any such salts, esters and other derivatives that may be prepared by those of skill in this art using known methods for such derivatization and that produce compounds that may be administered to animals or humans without substantial toxic effects and that either are pharmaceutically or veterinarily active or are prodrugs.
  • Pharmaceutically and veterinarily-acceptable salts include, but are not limited to, salts of alkali metals and alkaline earth metals, including but not limited to sodium salts, potassium salts, lithium salts, calcium salts and magnesium salts; transition metal salts, such as zinc salts, copper salts and aluminum salts; polycationic counter ion salts, such as but not limited ammonium and substituted ammonium salts and organic amine salts, such as hydroxyalkylamines and alkylamines; salts of mineral acids, such as but not limited to hydrochlorides and sulfates, salts of organic acids, such as but not limited acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrate, valerate and fumarates. Also contemplated herein are the corresponding esters.
  • Preferred pharmaceutically or veterinarily-acceptable salts include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin-1 '- ylmethylbenzimidazoie, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, aluminum, calcium, lithium, magnesium, potassium, sodium hydrogen phosphate, disodium phosphate, sodium, zinc, barium, gold, silver and bismuth salts.
  • Sodium salts, particularly the sodium salt of each of the compound, are most preferred herein.
  • sodium salts refers to salts of any sodium compounds in which the counter ion includes Na + and can include other ions, such as HP0 4 2" ; reference to a “sodium salt” (rather than sodium salts) refers specifically to a salt in which Na + is the counter ion.
  • treatment means any manner in which the symptoms of a conditions, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical or veterinary use of the compositions herein, such as use as contraceptive agents.
  • amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical or veterinary composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • nitric oxide "donors” or “precursors” refer to compounds such as sodium nitroprusside, nitroglycerin, sodium nitrite, hydroxylamine, sodium azide and other nitrogen-containing compounds that function as smooth muscle relaxing agents.
  • the activity of a variety of smooth muscle relaxing agents may be related to their ability to increase tissue levels of cyclic guanosine monophosphate (cGMP) or to the formation of nitric oxide (NO) (see, Katsuki, et aL (1977) J. Cyclic Nucleotide Res. 3:25-35).
  • cGMP cyclic guanosine monophosphate
  • NO nitric oxide
  • Other nitrogen-containing compounds may also function similarly, including hydroxylamine or sodium azide, and also may possess vasodilatory properties.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art.
  • a substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
  • biological activity refers to the in vivo activities of a compound or physiological responses that result upon ]n vivo administration of a compound, composition or other mixture.
  • Biological activity thus, encompasses therapeutic effects and pharmaceutical or veterinary activity of such compounds, compositions and mixtures.
  • increased stability of a formulation means that the percent of active component present in the formulation, as determined by assays known to those of skill in the art, such as high performance liquid chromatography, gas chromatography, and the like, at a given period of time following preparation of the formulation is significantly higher than the percent of active component present in another formulation at the same period of time following preparation of the formulation. In this case, the former formulation is said to possess increased stability relative to the latter formulation.
  • a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically, veterinarily or therapeutically active form of the compound.
  • the pharmaceutically or veterinarily active compound is modified such that the active compound will be regenerated by metabolic processes.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • acid isostere means a group that is significantly ionized at physiological pH.
  • suitable acid isosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl or heteroarylsulfonylcarbamoyl.
  • halo or halide refers to the halogen atoms; F, Cl, Br and I.
  • pseudohalides are compounds that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides (X " , in which X is a halogen, such as Cl or Br). Pseudohalides include, but are not limited to cyanide, cyanate, thiocyanate, selenocyanate and azide.
  • haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1 -chloro-2-f luoroethyl and the like.
  • alkyl means an aliphatic hydrocarbon group that is a straight or branched chain preferably having about 1 to 12 carbon atoms in the chain.
  • Preferred alkyl groups are loweralkyl groups which are alkyls containing 1 to about 6 carbon atoms in the chain.
  • Branched means that one or more loweralkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
  • the alkyl group may be unsubstituted or independently substituted by one or more groups, such as, but not limited to: halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino and imino.
  • Exemplary alkyl groups include methyl, ethyl, propyl, carboxymethyl, carboxyethyl, carboxypropyl, ethanesulfinic acid and ethane sulfonic acid.
  • lower describes alkyl, alkenyl and alkynyl groups containing about 6 carbon atoms or fewer. It is also used to describe aryl groups or heteroaryl groups that contain 6 or fewer atoms in the ring.
  • Loweralkyl, lower alkenyl, and lower alkynyl refer to carbon chains having less than about 6 carbons.
  • the compounds provided herein that include alkyl, alkenyl, or alkynyl portions include loweralkyl, lower alkenyl, and lower alkynyl portions.
  • alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chained having from about 2 to about 10 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more loweralkyl or lower alkenyl groups are attached to a linear alkenyl chain.
  • the alkenyl group may be unsubstituted or independently substituted by one or more groups, such as halo, carboxy, for yl, sulfo, sulfino, carbamoyl, amino and imino.
  • Exemplary alkenyl groups include ethenyl, propenyl, carboxyethenyl, carboxypropenyl, sulfinoethenyl and sulfonoethenyl.
  • alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to 10 carbon atoms in the chain. Branched means that one or more loweralkyl, alkenyl or alkynyl groups are attached to a linear alkynyl chain.
  • An exemplary alkynyl group is ethynyl.
  • aryl means an aromatic monocyclic or multicyclic hydrocarbon ring system containing from 3 to 15 or 16 carbon atoms, preferably from 5 to 10.
  • Aryl groups include, but are not limited to groups, such as phenyl, substituted phenyl, naphthyl, substituted naphthyl, in which the substituent is loweralkyl, halogen, or lower alkoxy.
  • Preferred aryl groups are lower aryl groups that contain less than 7 carbons in the ring structure.
  • the nomenclature alkyl, alkoxy, carbonyl, etc. are used as is generally understood by those of skill in this art.
  • alkyl refers to saturated carbon chains that contain one or more carbons; the chains may be straight or branched or include cyclic portions or be cyclic.
  • alicyclic refers to aryl groups that are cyclic.
  • cycloalkyl refers to saturated cyclic carbon chains; cycloalkenyl and cycloalkynyl refer to cyclic carbon chains that include at least one unsaturated double or triple bond, respectively.
  • the cyclic portions of the carbon chains may include one ring or two or more fused rings.
  • cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl or cyclohexenyl; preferred is cyclohexenyl.
  • An exemplary multicyclic cycloalkenyl ring is norbornylenyl.
  • the cycloalkenyl group may be independently substituted by one or more halo or alkyl.
  • haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1 -chloro-2-fluoroethyl and the like.
  • haloalkoxy refers to RO- in which R is a haloalkyl group.
  • Carboxamide refers to groups of formula R p CONH 2 in which R is selected from alkyl or aryl, preferably loweralkyl or lower aryl and p is 0 or 1 .
  • alkylaminocarbonyl refers to -C(0)NHR in which R is hydrogen, alkyl, preferably loweralkyl or aryl, preferably lower aryl.
  • dialkylaminocarbonyl refers to -C(0)NR ' R in which R ' and R are independently selected from alkyl or aryl, preferably loweralkyl or loweraryl;
  • carboxamide refers to. groups of formula NR ' COR.
  • alkoxycarbonyl refers to -C(0)0R in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.
  • alkoxy and thioalkoxy refer to RO- and RS-, in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.
  • haloalkoxy refers to RO- in which R is a haloalkyl group.
  • aminocarbonyl refers to -C(0)NH 2 -
  • cycloalkyl refers to saturated cyclic carbon chains
  • cycloalkyenyl and cycloalkynyl refer to cyclic carbon chains that include at least one unsaturated triple bond.
  • the cyclic portions of the carbon chains may include one ring or two or more fused rings.
  • alkylenedioxy means an -O-alkyl-0- group in which the alkyl group is as previously described.
  • a replacement analog of alkylenedioxy means an alkylenedioxy in which one or both of the oxygen atoms is replaced by a similar behaving atom or group of atoms such as, S, N, NH, Se.
  • An exemplary replacement alkylenedioxy group is ethylenebis(sulfandiyl).
  • Alkylenethioxyoxy is — S-alkylene-O— , — O-alkylene-S— and alkylenedithioxy is — S-alkylene-S — .
  • heteroaryl means an aromatic monocyclic or fused ring system in which one or more of the carbon atoms in the ring system is(are) replaced by an element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Preferred cyclic groups contain one or two fused rings and include from about 3 to about 7 members in each ring. Similar to “aryl groups", the heteroaryl groups may be unsubstituted or substituted by one or more substituents.
  • heteroaryl groups include pyrazinyl, pyrazolyl, tetrazolyl, furanyl, (2- or 3-)thienyl, (2-,3- or 4-)pyridyl, imidazoyl, pyrimidinyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl, isoquinolinyl, oxazolyl and 2,1 ,3- oxadiazolyl.
  • Preferred heteroaryl groups include 5 to 6-membered nitrogen-containing rings, such as pyrimidinyl.
  • alkoxycarbonyl means an alkyl-O-CO- group.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • carbamoyl means -CONH 2 . As with all groups described herein, these groups may be unsubstituted or substituted. Substituted carbamoyl includes groups such as -CONY 2 Y 3 in which Y 2 and Y 3 are independently hydrogen, alkyl, cyano(loweralkyl), aryalkyl, heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substituted loweralkyl), carboxy(carboxy substituted loweralkyl), carboxy(hydroxy substituted loweralkyl), carboxyfheteroaryl substituted loweralkyl), carbamoyl(loweralkyl), alkoxycarbonyl (loweralkyl) or alkoxycarbonyl (aryl substituted loweralkyl), provided that only one of Y 2 and Y 3 may be hydrogen and when one of Y 2 and Y 3 is carboxy(loweralkyl), carboxy(aryl substituted loweralkyl), carbamoy
  • Y 2 and Y 3 are independently hydrogen, alkyl, cyano(loweralkyl), aryalkyl, heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substituted loweralkyl) and carbamoyl(loweralkyl).
  • NO formerly known as endothelium derived relaxing factor
  • endothelial nitric oxide synthase eNOS
  • eNOS endothelial nitric oxide synthase
  • vascular endothelial cells synthesize nitric oxide from L-arginine (L-Arg) but not D-arginine (see, Palmer, et aL (1988) Nature 333:664-666). Release of NO from endothelial cells induced by bradykinin and the calcium ionophore A23187 is reversibly enhanced by infusions of L-Arg or L-citrulline.
  • endothelin The production and release of endothelin from the endothelium is stimulated by angiotensin II, vasopressin, endotoxin, cyclosporine and other factors (see, Brooks et al. (1991 ) Eur. J. Pharm. 194:1 15-1 17), and is inhibited by nitric oxide, which was also known as endothelin-derived releasing factor. Hence there appears to be an association between endothelin production and nitric oxide expression.
  • Laminitis As described herein, methods for treatment of laminitis are provided herein. The methods use endothelin antagonists, particularly sulfonamide compounds and related compounds. As discussed, equine laminitis is has been treated with nitric oxide (NO) NO donors, and a non-steroidal anti-inflammatory drug (NSAID) (see, U.S. Patent No. 5,891 ,472; see also, Elliott, J. (1996) Equine Vet. J. 28(1 ):1 -2). Menopause and Climacteric disorders
  • Nitric oxide synthesis and the nitric oxide effector system are thought to be regulated by steroid hormones.
  • cardiovascular diseases in women following menopause, which may be related to the decrease in sex steroids and an alteration in nitric oxide production.
  • Female steroid hormones have been shown to modulate endothelium-dependent relaxation of vascular smooth muscle by nitric oxide. Estradiol treatment of rats causes increased nitric oxide production by vascular tissues, whereas progesterone counteracts this phenomenon (see, e.g., U.S. Patent Nos. 5,906,987, 5,958,878 and 5,898,038).
  • climacterium Another symptom of climacterium in men and women is osteoporosis.
  • nitric oxide mediates steroid (estrogen and/or progestin) effects on bones.
  • treatments for climacterium, both male and female that alleviate the symptoms of progression of the disorders.
  • treatments of menopause and other disorders specific to reduction in hormone levels in postmenopausal women are also an increasing need for treatments of menopause and other disorders specific to reduction in hormone levels in postmenopausal women.
  • Spontaneous preterm labor during pregnancy remains an increasing problem confronting the medical community.
  • Preterm labor whether occurring spontaneously or the one which invariably follows any significant transuterine fetal manipulation such as needle puncture, fetoscopy, or hysterotomy for fetal surgery, presents a serious problem and is a limiting factor for all types of fetal intervention.
  • the severe forms of spontaneous preterm labor or labor induced by an incision in the gravid uterus for open fetal surgery is resistant to all known forms of tocolysis.
  • Tocolytic agents most often used to inhibit preterm labor are ?-adrenoreceptor stimulants such as epinephrine or its synthetic analogs and derivatives salbutamol, terburtaline, isoxsuprine, ritodrine, and fenoterol, magnesium sulfate, prostaglandin inhibitors such as aspirin, indomethacin and naproxen, ethanol and calcium channel- blocking agents such as nipedifine or nicardipine.
  • epinephrine or its synthetic analogs and derivatives salbutamol, terburtaline, isoxsuprine, ritodrine, and fenoterol, magnesium sulfate, prostaglandin inhibitors such as aspirin, indomethacin and naproxen, ethanol and calcium channel- blocking agents such as nipedifine or nicardipine.
  • prostaglandin inhibitors such as aspirin, indomethacin and
  • a common feature of the above-noted disorders is the involvement of nitric oxide. It appears to be involved in the etiology and/or pathology of numerous disorders, including laminitis, other inflammatory disorders, and also other disorders, such as menopausal symptoms, pregnancy-related disorders and others. It is shown herein that treatment with endothelin antagonists can ameliorate the symptoms of such disorders. Laminitis is of particular interest herein, but other disorders may be similarly treated. B. Formulation and administration of the compounds
  • compositions for use in the methods herein contain therapeutically effective amounts of one or more endothelin antagonists.
  • the compounds are preferably formulated into suitable pharmaceutical or veterinary preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • suitable compositions include parenteral compositions and transdermal patches.
  • the compounds described above are formulated into pharmaceutical or veterinary compositions using techniques and procedures known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
  • effective concentrations of one or more compounds or pharmaceutically acceptable derivatives is (are) mixed with a suitable pharmaceutical or veterinary carrier or vehicle.
  • the compounds may be derivatized as the corresponding salts, esters, acids, bases, solvates, hydrates and prodrugs prior to formulation, as described above.
  • the concentrations of the compounds in the formulations are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the endothelin-mediated disease.
  • the compositions are formulated for single dosage administration.
  • the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated.
  • Pharmaceutical and veterinary carriers or vehicles suitable for administration of the endothelin antagonists include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the compounds may be formulated as the sole pharmaceutically or veterinarily active ingredient in the composition or may be combined with other active ingredients.
  • Liposomal suspensions including tissue-targeted liposomes, may also be suitable as pharmaceutically or veterinarily acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,81 1.
  • the active compound is included in the pharmaceutically or veterinarily acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
  • the therapeutically effective concentration may be determined empirically by testing the compounds in known jn vitro and in vivo systems (see, e.g., the Examples, U.S. Patent No. 5,1 14,918 to Ishikawa et aL; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (October 7, 1991 ); Borges et aL (1989) Eur. J. Pharm. 165:223-230; Filep et aL (1991 ) Biochem. Biophys. Res. Commun. 177:171 -176) and then extrapolated therefrom for dosages for humans.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to treat the symptoms of laminitis.
  • a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 ⁇ g/ml.
  • the pharmaceutical and veterinary compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
  • Pharmaceutical and veterinary dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and preferably from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated.
  • Preferred pharmaceutically and veterinarily acceptable derivatives include acids, salts, esters, hydrates, solvates and prodrug forms.
  • the derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.
  • effective concentrations or amounts of one or more of the compounds provided herein or pharmaceutically or veterinarily acceptable derivatives thereof are mixed with a suitable pharmaceutical or veterinary carrier or vehicle for systemic, topical or local administration to form pharmaceutical or veterinary compositions.
  • Compounds are included in an amount effective for ameliorating or treating the endothelin-mediated disorder for which treatment is contemplated.
  • the concentration of active compound in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.
  • compositions are intended to be administered by an suitable route, which includes orally, parenterally, rectally and topically and locally depending upon the disorder being treated.
  • suitable route which includes orally, parenterally, rectally and topically and locally depending upon the disorder being treated.
  • capsules and tablets are presently preferred.
  • the compounds in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
  • Preferred modes of administration include parenteral, oral and topical modes of administration.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent
  • antimicrobial agents such as benzyl alcohol and methyl parabens
  • antioxidants such as ascorbic acid and sodium bisul
  • Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
  • methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO), using surfactants, such as Tween ® , or dissolution in aqueous sodium bicarbonate.
  • co-solvents such as dimethylsulfoxide (DMSO)
  • surfactants such as Tween ®
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate.
  • Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical and veterinary compositions.
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. If necessary, pharmaceutically or veterinarily acceptable salts or other derivatives of the compounds may be prepared.
  • the compound is included in the pharmaceutically or veterinarily acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. It is understood that number and degree of side effects depends upon the condition for which the compounds are administered. For example, certain toxic and undesirable side effects are tolerated when treating life- threatening illnesses, such as tumors, that would not be tolerated when treating disorders of lesser consequence.
  • the concentration of compound in the composition will depend on absorption, inactivation and excretion rates thereof, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
  • the formulations are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically or veterinarily therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical or veterinary carrier, vehicle or diluent.
  • unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
  • the composition can contain along with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and
  • Liquid pharmaceutically and veterinarily administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical or veterinary adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
  • the pharmaceutical or veterinary composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine
  • compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared.
  • a pharmaceutically or veterinarily acceptable non-toxic de ⁇ for oral administration, a pharmaceutically or veterinarily acceptable non-toxic de ⁇
  • composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • excipients such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these formulations are known to those skilled in the art.
  • the contemplated compositions may contain
  • the active compounds or pharmaceutically or veterinarily acceptable derivatives may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
  • the formulations may be include other active compounds to obtain desired combinations of properties.
  • the compounds or pharmaceutically or veterinarily acceptable derivatives thereof as described herein may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril), a diuretic (for example furosemide or hydrochlorothiazide), an endothelin converting enzyme (ECE) inhibitor (for example phosphoramidon), a neutral endopeptidase (NEP) inhibitor, an HMGCoA reduc
  • Parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously is contemplated herein.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol.
  • the pharmaceutical or veterinary compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Patent No. 3,710,795) is also contemplated herein.
  • the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
  • Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations.
  • Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
  • the solutions may be either aqueous or nonaqueous.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • Pharmaceutically or veterinarily acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically or veterinarily acceptable substances.
  • aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (Tween ® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical or veterinary carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • the concentration of the pharmaceutically or veterinarily active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect.
  • the exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
  • the unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.
  • intravenous or intra-arterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration.
  • Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.
  • Injectables are designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 % w/w up to about 90% w/w or more, preferably more than 1 % w/w of the active compound to the treated tissue(s).
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time.
  • the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.
  • the compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.
  • Topical mixtures are prepared as described for the local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • Transdermal patches are of particular interest herein (see, e.g., U.S. Patent No. 5,891 ,472).
  • the compounds or pharmaceutically or veteriarily acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma).
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the ⁇ formulation will typically diameters of less than 50 microns, preferably less than 10 microns.
  • the compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application.
  • Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.
  • Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • Oral pharmaceutical dosage forms are either solid, gel or liquid.
  • the solid dosage forms are tablets, capsules, granules, and bulk powders.
  • Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated.
  • Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
  • the formulations are solid dosage forms, preferably capsules or tablets.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
  • binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
  • Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • Glidants include, but are not limited to, colloidal silicon dioxide.
  • Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray dried flavors.
  • Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether.
  • Emetic-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the compound could be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the inte'stine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action.
  • the compound may be used with other such treatments, such as a nitric oxide donor or a nitric oxide synthase substrate.
  • the active ingredient is a compound or pharmaceutically or veterinarily acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.
  • Pharmaceutically or veterinarily acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
  • Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
  • Sugar-coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
  • Film-coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically or veterinarily acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms.
  • Flavoring and sweetening agents are used in compressed tablets, sugar-coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil. Elixirs are clear, sweetened, hydroalcoholic preparations.
  • Pharmaceutically or veterinarily acceptable carriers used in elixirs include solvents.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative.
  • An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid.
  • Pharmaceutically or veterinarily acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives.
  • Suspensions use pharmaceutically or veterinarily acceptable suspending agents and preservatives.
  • Pharmaceutically or veterinarily acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents.
  • Pharmaceutically or veterinarily acceptable substance used in effervescent granules, to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
  • Solvents include glycerin, sorbitol, ethyl alcohol and syrup.
  • preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.
  • non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Diluents include lactose and sucrose.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • Organic acids include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos 4,328,245; 4,409,239; and 4,410,545.
  • the solution e.g., in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically or veterinarily acceptable liquid carrier, e.g., water, to be easily measured for administration.
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Other useful formulations include those set forth in U.S. Patent Nos. Re 28,819 and 4,358,603.
  • tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
  • lyophilized powders which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be formulated as solids or gels.
  • compositions of salts of the active ingredients particularly sodium hydrogen phosphate or sodium, preferably sodium, salts of the sulfonamide compounds, which possess increased stability relative to formulations of the neutral sulfonamides are of interest herein.
  • Such compositions contain a sulfonamide sodium salt in a sterile, lyophilized powder. These powders are known to have increased stability relative to formulations of the neutral sulfonamides.
  • the sterile, lyophilized powder is prepared by dissolving the sodium salt in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Briefly, the lyophilized powder is prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1 -20%, preferably about 5 to 1 5%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a suitable buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a selected salt preferably the sodium salt of the sulfonamide (about 1 g of the salt per 10-100 g of the buffer solution, typically about 1 g/30 g), is added to the resulting mixture, preferably above room temperature, more preferably at about 30- 35° C, and stirred until it dissolves.
  • the resulting mixture is diluted by adding more buffer (so that the resulting concentration of the salt decreases by about 10-50%, typically about 1 5-25%).
  • the resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization.
  • Each vial will contain a single dosage (100-500 mg, preferably 250 mg) or multiple dosages of the sulfonamide salt.
  • the lyophilized powder can be stored under appropriate conditions, such as at about 4° C to room temperature.
  • Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration of sodium salts of the sulfonamides.
  • For reconstitution about 1-50 mg, preferably 5-35, more preferably about 9-30 is added per ml of sterile water or other suitable carrier. The precise amount depends upon the indication treated and selected compound. Such amount can be empirically determined.
  • rectal administration is also contemplated herein.
  • pharmaceutical and veterinary dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect.
  • Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids.
  • Agents to raise the melting point of suppositories include spermaceti and wax.
  • Rectal suppositories may be prepared either by the compressed method or by molding.
  • the typical weight of a rectal suppository is about 2 to 3 g.
  • Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
  • C. Compounds for pharmaceutical or veterinary use in treating endothelin-mediated diseases
  • inflammatory diseases particularly, laminitis, and other diseases that can be treated by increasing levels of nitric oxide.
  • the methods are practiced by administering an effective amount of an endothelin antagonist, particularly, a sulfonamide.
  • an endothelin antagonist particularly, a sulfonamide.
  • Numerous endothelin antagonists and sulfonamide endothelin antagonists are known (see, e.g., U.S. Patent Nos. 6,133,442, 6,133,263, 6,107,320, 6,083,955; 6,083,951 ; 6,080,774; 6,063,91 1
  • SB 209670 (Ohlstein, E. H., et al., SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist, Proc. Natl. Acad. Sci. USA, 57:8052-8056 (1994)); SB 217242 (Ohlstein, E. H., et al., Nonpeptide Endothelin Receptor Antagonists. VLPharmacological Characterization of SB 217242, A Potent and Highly Bioavailable Endothelin Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 275(2):609-61 5 (1996)); A-127722 (Opgenorth, T.
  • Receptor Antagonist TAK-044 ⁇ Cyclo[D-cr-Aspartyl-3-[(4-Phenylpiperazin-1 -yl)Carbonyl]- L-Alanyl-L- -Aspartyl-D-2-(2-Thienyl)Glycyl-L-Leucyl-D-TryptophyllDisodium Salt ⁇ , in Human Endothelin A and Endothelin B Receptors, The Journal of Pharmacology and Experimental Therapeutics, 275(2):675-685 (1996)); bosentan (Ro 47-0203, Clozel, M., et al., Pharmacological Characterization of Bosentan, A New Potent Orally Active Nonpeptide Endothelin Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 270(1 ):228-235 (1994)), and many are described herein.
  • the endothelin receptor antagonists for use in the methods provided herein have formula I: Ar— SO 2- N- Ar 1
  • Ar 1 is alkyl, alkenyl, or alkynyl, or is a substituted or unsubstituted aryl or heteroaryl group that, if substituted, is substituted with one or more substituents, including, but not limited to, an alkyl group, an aryl group, a substituted aryl group, a nitro group, an amino group or a halide.
  • Ar 1 is alkyl, alkenyl, or alkynyl, or is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring, including, but not limited to, isoxazolyl, including 3- or 5- isoxazolyl, pyridazinyl, thiazolyl, including 2-thiazolyl, pyrimidinyl, including 2-pyrimidinyl, pyrazolyl, isothiazolyl, including 3- or 5-isothiazolyl, pyrazinyl, or a substituted benzene group, including aryloxy substituted benzene groups or is a fused aliphatic or heteroaliphatic ring containing from 6 to about 21 carbons in the ring structure, such as bicyclic or tricyclic rings, including naphthyl groups, quinolyl groups, dibenzofuryl groups, dibenzopyrrolyl groups, dibenzothienyl groups, purines, and phenant
  • Ar 1 is, in certain embodiments, selected from groups such as:
  • R is selected from H, NH 2 , halide, pseudohalide, alkyl alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl and carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceding groups, and is unsubstituted or substituted with any of the preceding groups, and straight or branched chains of from about 1 up to about 10-1 2 carbons, preferably, 1 to about 5 or 6 carbons.
  • R is preferably H, NH 2 , halide, CH 3 , CH 3 0 or another aromatic group.
  • Ar 2 is any group such that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 100 ⁇ M.
  • Ar 2 is selected with the proviso that Ar 2 is not phenyl or naphthyl when Ar 1 is N-( ⁇ -isoxazolyl) or N-(3-isoxazolyl) unless the isoxazole is a 4-halo-isoxazole or, if enhanced ET B affinity is desired, a 4-higher alkyl-isoxazole, and when Ar 2 is phenyl it is not substituted at the para position with NH 2 , N0 2 , CH 3 , OH or a substituted amine.
  • Selected isoxazolyl-benzenesulfonamides and isoxzolyl-naphthalenesulfohamides in which the isoxazole is other than a 4-halo-isoxazole are also provided.
  • Such selected compounds including N-isoxazolylbenzenesulfonamides and N- isoxazolylnaphthalenesulfonamides in which the substituent at the 4 position on the isoxazolyl group is higher alkyl, such as C 9 H 19 to C 13 H 27 are also provided.
  • Ar 2 is selected from among alkyl, including straight and branched chains, aromatic rings, fused aromatic rings and heterocyclic rings, including, 5-membered heterocycles with one, two or more heteroatoms and fused ring analogs thereof and 6- membered rings with one, two or more heteroatoms and fused ring analogs thereof.
  • Ar 2 thus, includes, but is not limited to, alkyl, norboranyl, admantyl, phenyl, naphthyl, quinolyl, isoquinolyl, acridinyl, styryl, biphenyl, isoxazolyl, thiazolyl, oxazolyl, imidazole, dibenzofuryl, indolyl (dibenzopyrrolyl), dibenzothienyl (thianaphthalene), carbazolyl, purinyl, and phenanthryl, anthracenyl, furyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyradazinyl, morpholinyl, thiomorpholinyl, quniolzoliny
  • Ar 1 is an isoxazole and the compounds are represented by the formulae II:
  • R and R 2 are either (i), (ii) or (iii) as follows:
  • R 1 and R 2 independently selected from H, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterolaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about
  • the compounds are selected with the proviso that R 2 is not halide or pseudohalide. In other embodiments, the compounds are selected with the proviso that Ar 2 is not phenyl or naphthyl unless R 1 is a halide or a higher alkyl, particularly C 9 H 19 to C 13 H 27 .
  • R 1 is selected from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, and pseudohalide; and R 2 is selected from among lower alkyl, lower alkenyl, lower alkynyl and lower haloalkyl.
  • Ar 2 is any group such that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 100 M.
  • Ar 2 is not phenyl or naphthyl unless the compound is an N-isoxazolylsulfonamide substituted at the 4-position on the isoxazolyl group with halide or higher alkyl, particularly C 9 H 19 to C 13 H 27 .
  • Ar 1 is an isoxazolyl group
  • Ar 2 is an aliphatic straight or branched carbon chain, including alkyl, alkenyl, and alkynyl groups, heterocycle, with one or more, generally one to three rings, or is a group or isomer group selected.
  • Ar 2 is not phenyl or naphthyl, unless R 1 (the 4-substituent on the isoxazolyl group (Ar 1 )) is a halide or a higher alkyl, with greater than 8 carbons, preferably C 9 H 19 to C 13 H 27 .
  • Ar 2 is in certain embodiments selected from among groups including: alkyl.
  • n is 0 to 10, preferably 0 to 6, more preferably 0 to 3;
  • X is 0, S or NR 11 , where R 11 , which is hydrogen or contains up to about 30 carbon atoms, generally 1 to 16 carbon atoms, and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 15 and S(0) n R 16 in which n is 0-2;
  • R 15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;
  • R 11 and R 15 are are unsubstituted or are substituted with one or more substituents each selected independently from Z, which
  • R 17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R 1 , R 12 , R 15 and R 16 may be further substituted with the any of the groups set forth for Z;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each selected independently from (i)-(iv); (i) R 3 , R 4 , R 5 , R 6 and R 7 are each selected independently from among H, NHOH,
  • NH 2 , N0 2 , N 3 aminoalkyl, alkylamino, dialkylamino, carboxyl, carbonyl, hydroxyl, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heterocycle, alkoxy, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylalkoxy, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, haloalkoxy, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido in which each of the preceding groups may be unsubstituted or substituted with groups such as H,
  • R 4 and R 7 together are substituted or unsubstituted 1 , 3-butadienyl, 1 -chloro- 1 ,3-butadienyl, 4-dimethylamino-1 , 3-butadienyl, 1 -aza-1 , 3-butadienyl or 2-aza-1 ,3- butadienyl groups; and R 3 , R 5 and R 6 are as defined in (i) above; or alternatively,
  • R 7 and R 3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R 4 , R 5 and R 6 are as defined in (i) above; or alternatively,
  • R 3 , R 5 , and R 7 are H; and R 4 and R 6 are each independently selected from alkyl, alkoxy, halide, amino and aminoalkyl; and
  • R 8 , R 9 , R 10 are each independently selected as follows from (i) or (ii):
  • R 8 , R 9 and R 10 which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy.
  • R 18 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 20 , S(0) n R 20 in which n is 0-2; and R 18 and R 20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle,
  • any two of R 8 , R 9 and R 10 form an aryl, aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is unsubstituted or substituted with one or more substituents in each each substituent is independently selected from Z; and the other of R 8 , R 9 and R 10 is selected as in (i).
  • R 3 when Ar 2 is phenyl (a) at least one of R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen and (b) when Ar 1 is 3-isoxazolyl, R 3 is not NH 2 or CH 3 .
  • the alkyl, alkynyl and alkenyl portions of each listed substituent are straight or branched chains, acyclic or cyclic, and preferably have from about 1 up to about 10 carbons; in more preferred embodiments they have from 1 -6 carbons, and they can have fewer than 6 carbons.
  • the aryl, alicyclic, aromatic rings and heterocyclic groups can have from 3 to 16, generally, 3-7, more often 5-7 members in the rings, and may be single or fused rings.
  • the ring size and carbon chain length are selected up to an amount that the resulting molecule binds to retains activity as an endothelin antagonist or agonist, such that the resulting compound inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 50 ⁇ M, preferably less than about 10 ⁇ M.
  • Ar 2 is a substituted or unsubstituted group selected from among groups such as the following: naphthyl, phenyl, biphenyl, quinolyl, styryl, thienyl, furyl, isoquinolyl, pyrrolyl, benzofuranyl, benzothienyl, benzopyrrolyl, pyridinyl, thianaphthalyl, indolyl, dibenzofuranyl, dibenzopyrrolyl, dibenzothienyl, phenanthryl, thiazolyl, isoxazolyl, anthacenyl, alkenyl, alkynyl and alkyl.
  • groups such as the following: naphthyl, phenyl, biphenyl, quinolyl, styryl, thienyl, furyl, isoquinolyl, pyrrolyl, benzofuranyl, benzothienyl, benzopyrrolyl, pyr
  • Ar 1 is isoxazolyl.
  • 4-haloisoxazolyl or 4-methylisoxzaolyl are preferred, except when Ar 2 is phenyl or naphthyl, then 4-haloisoxazolyl and 4-higher alkylisoxzaolyl are preferred.
  • 4- haloisoxazolyl sulfonamides exhibit substantially enhanced activity with respect to at least one of the ET receptors (about two-fold to twenty-fold greater activity), as assessed by assays, such as those provided herein, that measure binding to ET A and/or ET B receptors, compared to corresponding sulfonamides in which the substituent at the 4 position in the isoxazolyl is other than halo, such as alkyl.
  • the IC 50 for competitive of inhibition of binding of ET-1 to ET A receptors of 2,5-dimethyl-N-(3,4- dimethyl-5-isoxazolyl)benzenesulfonamide to is 9.4 ⁇ M; whereas the IC 50 for 2,5-di- methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide is 0.19 ⁇ M and for 2,5- dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide is 0.044 ⁇ M;
  • the IC 50 of N-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfonamide for ET A receptors is about 0.008 ⁇ M, whereas, the IC 50 of N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenyl- sulfonamide is about 0.00
  • Other selected compounds include benzene and naphthalene isoxazole sulfonamides in which the 4 position on the isoxazole ring of Ar 1 is a methyl group and the 3 position is a relatively long chain (greater than about 8 carbons up to about 15 carbons, preferably about 13 carbons) alkyl group.
  • Such compounds although reportedly exhibiting a loss in affinity to ET A receptors (see, Stein et aL (1994) J.Med. Chem. 37:329-331 ), are herein shown to exhibit increased affinity to ET B receptors compared to compounds in which the group at the 3 position is a methyl group.
  • R 11 is aryl, such as phenyl, alkylphenyl, hydrogen or lower alkyl
  • R 8 , R 9 , R 10 are independently selected from hydrogen, halide, lower alkyl, lower aryl, lower heterocycle, lower aralkyl, C(0) 2 R 18 , C0 2 R 18 , N0 2 , OR 18 SR 18 , NR 18 COR 19 or C0NR 19 R 18
  • R 18 and R 19 are preferably hydrogen, lower alkyl, and lower aryl
  • Z is hydrogen, halide, pseudohalide, lower alkyl, lower alkoxy or pseudohalo- or halo(lower)alkyl.
  • R 8 and R 0 are hydrogen, halide or methyl, more preferably hydrogen or halide, and R 9 is selected independently from hydrogen, halide, aryl, pseudohalide, lower alkyl, preferably methyl or ethyl, COR 18 , CONR 18 R 19 and NR 18 COR 19 .
  • R 2 is preferably, selected from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H; and R 1 is halide, lower alkyl or lower haloalkyl, and more preferablly, R 1 is bromide, chloride, methyl or ethyl. In the most active compounds provided herein, as evidenced by in vitro binding assays, R 1 is bromide or chloride.
  • the compounds have formula II in which R 1 is halide or methyl, R 2 , Ar 2 , R 3 , R 5 , R 6 , R 8 , R 9 , R 10 and R 1 are as defined above.
  • R 1 is bromide, chloride or methyl.
  • the most preferred compounds herein, particularly with respect to ET A affinity are N-(4-bromo, chloro, or methylisoxazolyl)sulfonamides.
  • Compounds in which R 1 is methyl and Ar 2 is other than phenyl or naphthyl are also preferred.
  • Preferred compounds also include compounds that are ET B receptor selective or that bind to ET B receptors with an IC 50 of less than about 1 ⁇ M.
  • Ar 2 is 3-biphenyl, 4-biphenyl, certain compounds in which Ar 2 phenanthrene or is a 5- membered heterocyle, particularly thienyl, compounds in which Ar 2 is naphthyl and phenyl and R 1 is higher alkyl (C 9 H 19 to C 13 H 27 ).
  • R 2 is selected from among alkyl, lower haloalkyl and H; and R 1 is halide, lower alkyl or lower haloalkyl, or, when Ar 2 is phenyl or naphthyl, R 1 is higher alkyl (nine or more carbon atoms, preferably 9 to 13 carbon atoms).
  • the 5-membered heterocylic compounds that exhibit ET B affinity or selectivity are those in which R 9 and R 10 are selected independently from hydrogen, lower alkyl, preferably methyl or ethyl, and halide, and R 8 , which is the substituent at the 5-position (see, e.g., the formulae setting forth the numbering for the 5-membered heterocyclic ring compounds), is aryl or a heterocycle, particularly phenyl and isoxazolyl, which are unsubstituted or substituted with Z, which is preferably lower alkyl or halide.
  • ET A selective i.e., they interact with ET A receptors at concentrations at substantially lower concentratons (at an IC S0 at least about 10-fold lower, preferably 100-fold lower) than they interact with ET B receptors.
  • Other preferred compounds are ET B selective. These compounds interact with ET B receptors at IC 50 concentrations that are at least about 10-fold lower than the concentrations at which they interact with ET A receptors.
  • Ar 2 is a 4-biphenyl or is a single ring heterocycle, particularly a 5-membered ring, or is a fused bicyclic or tricyclic heterocycle that contains one or or more, particularly one, heteroatom selected from S, 0 and NR 42 , in the ring, where R 42 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 15 and S(0)_,R 1B in which n is 0-2; R 1 B is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkyl, cycloal
  • R 42 is aryl, such as phenyl or alkyl phenyl, hydrogen or loweralkyl.
  • Ar 2 includes thienyl, furyl and pyrrolyl, benzofuryl, benzopyrolyl, benzothienyl, benzofblfuryl, benzo[b]thienyl, and indolyl (benzo[blpyrrolyl) and 4-biphenyl
  • Ar 1 is preferably N-(5-isoxazolyl) or N-(3- isoxazolyl).
  • the sulfonamides are N-isoxazolyl sulfonamides and the compounds have have formula III:
  • X is S, O or NR 11 in which R 11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 15 and S(0) n R 15 in which n is 0-2; R 15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R 11 and R 15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl,
  • Ar 2 is thienyl, furyl, pyrrolyl or a group that is a derivative or analog, as described below, of a thienyl, furyl or pyrrolyl group, including benzo[b] derivatives such as a benzo[b]thienyl, Ar 1 is N-(5- isoxazolyl) or N-(3-isoxazolyl).
  • Ar 2 has the formula IV:
  • any two of R 8 , R 9 and R 10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R 8 , R 9 and R 10 is selected as in (i); and the heteroatoms are NR 11 , 0, or S, with the proviso that Ar 2 is not 5-haIo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl, 5- halo-3-loweralkylbenzo[b]pyrrolyl.
  • R 9 and R 10 are hydrogen, halide or methyl, more preferably hydrogen or halide
  • the compounds are selected with the proviso that if R 8 is C0 2 R 18 , (CH 2 ) r C(0)NH(CH 2 ) n R 18 , C(0)(CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r C(0)NH(CH 2 ) n R 18 or (CH 2 ) r R 18 and R 18 is phenyl, the phenyl group is substituted at at least two positions, and preferably, at least one of those positions is ortho.
  • R 18 is aryl or heteroaryl, preferably having 5 or 6 members in the ring, more preferably phenyl or pyrimidinyl, most preferably phenyl.
  • R 18 is phenyl, which is substituted at more than one position, and most preferably at least one substituent is at the ortho position
  • R 9 and R 10 are each hydrogen, halide or loweralkyl, preferably hydrogen
  • R s is C(0)NHR 18 , C(0)CH 2 R 18 , (CH 2 )R 18 , whith the proviso that if R 8 is C(0)NHR 1S , then the phenyl group must have at least two substituents, preferably one of the substituents is in the ortho positio.
  • Ar 2 is a benzofbjthieny), benzofblfuryl, or indolyl (benzo[b]pyrrolyl), with the proviso that the benzene ring is substituted and the substituents are other than 5 halo, 3-loweralkyl.
  • Preferred substituents on the benzene ring include, but are not limited to, one or more selected from alkylenedioxy, particularly methylenedioxy, preferably 3,4-methylenedioxy, ethylenedioxy, aryl, particularly phenyl, dimethylamino, diethylamino, benzyl, alkoxy, particularly lower alkoxy, such as methoxy and ethoxy, halide, and alkyl, preferably loweralkyl.
  • Preferred compounds also include compounds that are ET B receptor selective or that bind to ET B receptors with an IC S0 of less than about 1 ⁇ M.
  • ET B selective compounds interact with ET B receptors at IC 50 concentrations that are at least about 10- fold lower than the concentrations at which they interact with ET A receptors.
  • R 2 is selected from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide or H; and R 1 is halide or loweralkyl, and in preferred embodiments, R 1 is bromide or chloride, preferabaly chloride; R 9 and R 10 are selected independently from hydrogen, loweralkyl, preferably methyl or ethyl, or halide, and R 8 , which is the substituent at the 5-position (see, e.g., formulae 111 and IV), is aryl or a heterocycle, particularly phenyl and isoxazolyl, which are unsubstituted or substituted with Z, which is preferably loweralkyl or halide.
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from (i) or (ii) as follows: (i) R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from among
  • R 38 and R 39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl;
  • X is S, 0 or NR 11 , where R 11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 15 and S(0) n R 15 in which n is 0-2; R 15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R 11 and R 15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which as defined herein includes hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alky
  • R 16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHR 50 , alkylaryl, alkylheteroaryl, or — (CH 2 ) x OH;
  • R 50 is a substituent such as hydrogen, lower alkyl, or lower alkoxy;
  • R 12 which is selected independently from R 11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 17 and S(0) n R 17 in which n is 0-2;
  • R 17 is hydrogen, alkyl, alkenyl, alkynyl, aryl
  • X is preferably S, and M is preferably selected from among:
  • R 40 is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, and more preferably loweralkyl, loweralkoxy, or halo loweralkyl, and is more preferably hydrogen or loweralkyl, particularly methyl or ethyl, and is most preferably hydrogen.
  • CH 2 CH 2 C(0)(CH) 2 , CH 2 CHC(0)CH 2 , and M is most preferably selected from among:
  • Ar 2 most preferably has formula:
  • W is most preferably CH 2 or NH.
  • the preferred sulfonamides or pharmaceutically or veterinarily acceptable derivatives thereof have the formula:
  • Ar 1 is a substituted or unsubstituted monocyclic or polycyclic, preferably a monocyclic or fused bicyclic, aryl or heteroaryl group with one or more substituents, selected from, for example, H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons.
  • substituents selected from, for example, H, NH 2 , halide, pseudohalide, alkyl, alkylcarbon
  • the substituents are preferably H, NH 2 , halide, CH 3 , CH 3 0 or another aromatic group, and the sulfonamides are preferably the thiophene-3-sulfonamides.
  • R 51 - R 55 are as defined above.
  • R 56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably H, methyl or carboxymethyl.
  • X is preferably S.
  • the sulfonamides and pharmaceutically or veterinarily acceptable derivatives thereof have formula V:
  • Ar 1 , R 51 and R 53 55 are as defined above.
  • Ar 2 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5- isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl, more preferably 4-chloro-3-methyl-5-isoxazolyl or 4-chloro-5-methyl-3-isoxazolyl;
  • R B4 is selected from the group consisting of substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, 0C(0)R 16 , 0C0 2 R 16 , NR 12 R 16 and S(0) n R 16 in which n is 0-2, preferably alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, alkylsulfonylamino and aminosulfonyl.
  • R B1 , R 53 , R 54 and R 56 can be H.
  • R 51 , R 53 and R 55 are preferably alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylaikyl, or heteroarylalkyl, more preferably lower alkyl, lower alkenyl, lower alkynyl, or aryl, most preferably methyl.
  • the sulfonamides are preferably thio- phene-3-sulfonamides. In another embodiment, the sulfonamides have formulae VI:
  • Ar 1 is as defined above.
  • Ar 1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo- 2,1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl;
  • X is preferably S; each G and R is independently selected from lower alkyl, CN, -(CH 2 ) x C(0)(CH 2 ) x , -(CH 2 ) X , (CH 2 ) x N-lower alkyl, -(CH 2 ) x C(0)NH 2 , a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, — S(0) 2 NH 2 , hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, -(CH 2 ) x COOH; - ⁇ CH 2 ) x COOH-, C0 2 - lower alkyl, CN, heteroaryl, — COC(0)(CH 2 ) x CH 3 , — (CH 2 ) X N(CH 3 ) 2 , a sulfonyl chloride, S(0) 2 NHR ⁇
  • the sulfonamides have formula VII: where:
  • Ar 1 is defined as above.
  • Ar 1 is preferably benzo-2, 1 ,3-oxadiazol-5-yl or 2- methoxy-3-pyrazinyl when R 56 is H; and R 56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
  • Ar 1 is preferably benzo-2,1 ,3-oxadiazol-5- yl or 2-methoxy-3-pyrazinyl when R S6 is H and R S6 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
  • the sulfonamides have formula Vlll:
  • Ar 1 is defined as above and is preferably 4-chloro-3-methyl-5-isoxazolyl; W is NH; and R 57 is selected from the group consisting of aryl, heteroaryl, heterocycle, OH, CN, C(0)R 16 , C0 2 R 16 , SH, S(0) n R 16 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, — (CH 2 ) x 0H, NHOH, NR 12 R 16 , N0 2 , N 3 , OR 16 , R 12 NCOR 16 and CONR 12 R 16 ; R 16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R
  • Ar 1 is isoxazolyl and Ar 2 has the formula:
  • R 61 and R 62 are independently selected from the group consisting of hydrogen, halo, cyano, cyanoalkyl, C(0)R 41 , alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene;
  • W is O, NH or CH 2 ;
  • R 6B , R 6e and R 67 are each independently selected as in (i) or (ii):
  • R 66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
  • R 65 and R 67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R 41 , carbamoyloxy and alkoxycarbonyloxy; or
  • R 41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino; and R 3 is selected from hydroxy, alkoxy, alkyl and aryl, wherein
  • R 41 and R 43 are unsubstituted or substituted with one or more substituents selected from Y, which is alkoxy, halide, pseudohalide, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy.
  • the sulfonamides of these embodiments are 2-acyl-3- thiophenesulfonamides.
  • the corresponding 3-acyl-2-thiophenesulfonamides are also contemplated herein.
  • Ar 2 is a fused ring bicyclic heterocyle and Ar 1 is preferably a five or 6-membered heterocyclic ring.
  • Ar 1 is preferably an isoxazole and Ar 2 is preferably a fused ring bicyclic heterocycle containing one heteroatom in each ring and containing 5 or 6 members in each ring.
  • Ar 2 is selected from among fused bicyclic heteroaryl groups, such as those having formula:
  • Y is N or 0 + , preferably N;
  • X is S, O, NR 11 , where R 11 is as defined above;
  • R 83 , R 84 and R 85 are selected from (i), (ii), (iii) or (iv):
  • R 83 , R 84 and R 85 are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl or amido, where the alkyl, alkenyl, alkynyl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10
  • R 83 , R 84 and R 85 together are substituted or unsubstituted 1 ,3- butadienyl, 4-dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 ,3- butadienyl or 2-aza-1 , 3-butadienyl groups or form alkylenedioxy; and the others of R 83 , R 84 and R 85 are as defined in (i) above or also form substituted or unsubstituted 1 ,3- butadienyl, 4-dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 ,3- butadienyl or 2-aza-1 , 3-butadienyl groups or form alkylenedioxy; or alternatively, (iii) two of R 83 , R 84 and R 85
  • any two of R 83 , R 84 and R 85 which are each selected as in (i) form fused carbocyclic or heterocyclic rings;
  • R 87 is hydrogen or contains up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, and is selected hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, SH, S(0) n , (CH 2 ) r R 18 , C(0)R 18 , C0 2 R 18 , (CH 2 ) r C0R 18 , OR 18 , (CH 2 ) r C0(CH 2 ) s R 18 , S(0) n R 18 in which n is 0-2, and r and s are each independently 0 to 6, preferably 1 -3, HNOH, NR 18 R 19 , N0 2 , N 3 , R 19 NCOR 18 and CONR 19 R 18 , in which R 19 is
  • Ar 1 is an isoxazole and the compounds are represented by the formulae IX:
  • R 1 and R 2 are either (i), (ii) or (iii) as follows: (i) R 1 and R 2 are each independently selected from H, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, ary
  • R 1 and R 2 together form -(CH 2 ) n , where n is 3 to 6; or, (iii) R 1 and R 2 together form 1 , 3-butadienyl.
  • R 87 is (CH 2 ) r R 18 , where R 18 is aryl, preferably phenyl or pyrimidyl, more preferably phenyl, which is unsubstituted or substited with alkyl, haloalkyl, halide, or such that two adjacent positions are substituted and together form alkylenedioxy, particularly methylenedioxy and ethylenedioxy.
  • R 8 is C(0)R 27 in which R 27 is aryl, and is preferably (CH 2 ) r C(0)(CH 2 ) p -aryl, (CH 2 ) r C(0)aryl, (CH 2 ) r S(0) q (CH 2 ) p -aryl, C(0)NR 11 -aryl, NHC(0)(CH 2 ) r -aryl, NR 11 -aryl, (CH 2 ) r aryl in which p and r are each independently selected from 0-10, preferably 0-6, more preferably 0-3, most preferably 0 or 1 and q is 0-3, preferably 0-2.
  • the aryl portion is unsubstituted or is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularly methylenedioxy, N-alkyl, N-alkyoxy, amino, nitro and other such groups.
  • the alkyl substituents are preferably lower alkyl, more preferably containing 1-3 carbons.
  • the alkyl, alkynyl and alkenyl portions of each listed substituent are straight or branched chains, acyclic or cyclic, and preferably have from about 1 up to about 10 carbons; in more preferred embodiments they have from 1 -6 carbons.
  • the aryl, alicyclic, aromatic rings and heterocyclic groups can have from 3 to 16, generally, 3-7, more often 5-7 members in the rings, and may be single or fused rings.
  • the ring size and carbon chain length are selected up to an amount that the resulting molecule binds and retains activity as an endothelin antagonist or agonist, such that the resulting compound inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 100 ⁇ M.
  • IC 50 concentration determined in the ]n vitro assays is a non-linear function of incubation temperature.
  • the preferred values recited herein refer to the assays that are performed at 4° C. When the assays are performed at 24° C, somewhat higher (see, the Tables) IC 50 concentrations are observed. Accordingly, the preferred IC 50 concentrations are about 10-fold higher.
  • Ar 2 is selected from phenyl, biphenyl, and aromatic fused rings, including naphthyl, anthracenyl, phenanthryl, indenyl, azulenyl, fluorenyl, and phenazinyl.
  • Ar 2 is phenyl, biphenyl or naphthyl
  • the compounds are preferably (4- halo-isoxazolyl)sulfonamides or are (4-higher alkyl-isoxazolyl)sulfonmides, in which the alkyl group contains more than about 8, preferably 9 to 15, more preferably 9 to 13, carbon atoms.
  • n is 0 to 10, preferably 0 to 6, more preferably 0 to 3;
  • R 3 , R 4 , R 5 , R 6 , and R 7 are selected from (i), (ii), (iii) or (iv) with the proviso that: (a) when Ar 2 is phenyl, at least one of R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen, (b) when Ar 1 is 4-halo-5-methyl-3- isoxazolyl, R 3 is not NH 2 or CH 3 , and (c) when Ar 2 is phenyl, napthyl or 2-biphenyl, R 1 is halide or higher alkyl:
  • R 3 , R 4 , R 5 , R 6 , and R 7 are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10
  • R 4 and R 7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R 3 , R 5 and R 6 are as defined in (i) above; or alternatively,
  • R 7 and R 3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and n, X, R 4 , R 5 and R 6 are as defined in (i) above; or
  • R 3 , R 5 , and R 7 are H are as defined in (i); and R 4 and R 6 are each independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
  • R 2 is H, CH 3 , C 2 H 5 ;
  • R 1 is Cl, Br or CH 3 ;
  • X is O or S;
  • n is 0 or 1 ; and
  • R 3 , R 4 , R 5 , R 6 , R 7 are selected from either (i), (ii), (iii) or (iv) as follows:
  • R 5 and R ⁇ are H;
  • R 4 and R 7 are each independently selected from H, halide, NH 2 , CF 3 , Ph, CH 3 ; and
  • R 7 and R 3 together form 1 , 3-butadienyl, 3-chloro-1 , 3-butadienyl 4- dimethylamino-1 , 3-butadienyl or 1 -aza-1 , 3-butadienyl; and R 4 , R 5 and R 6 are as defined in (i) of this embodiment; or
  • R 3 , R 5 , and R 7 are H as defined in (i); and R 4 and R 6 are each independently selected from alkyl, alkoxy, halide, amino alkyl, alkylaminoalkyl or dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
  • Ar 2 is a substituted or unsubstituted phenyl or naphthyl;
  • R 1 is Br, Cl or I;
  • R 2 is H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 , cycloC 3 H 5 , and C 4 H 8 ;
  • R 3 , R ⁇ R 5 , R 6 and R 7 are either (i), (ii), (iii), (iv) or (v):
  • R 5 , R 6 and R 7 are H;
  • n is 0 and
  • R 3 is H, NH 2 , CH 3 CF 3 , halide, C 2 H 5 NH or Ph,
  • R 4 is H, CF 3 , NH 2 , R 7 is H or CF 3 , and
  • R 5 and R 6 are H; or
  • R 3 , R ⁇ and R 6 are H; n is 0 and R 4 and R 7 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, or 4-chloro-1 , 3-butadienyl; or (iii) R 4 , R 6 and R 6 are H; n is 0; and R 7 and R 3 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl; or
  • R 4 is H or NH 2 , R 5 and R 6 are H; n is 1 and R 3 is H, NH 2 and halide; CH 3 , Br, Cl, F, CF 3 , NH 2 , R 7 is H, CH 3 , Br, Cl, F, NH 2 or CF 3 , and R 5 and R 6 are H; or (v) R 3 , R B , and R 7 are H are as defined in (i); and R 4 and R 6 are each independently selected from alkyl groups that contain from 1 to 6 carbons, and are straight or branched chains, lower alkoxy, and halide.
  • the benzenesulfonamides and naphthalenesulfonamdies are N-(4-halo)-substituted N-isoxazolylsulfonamides or are 4- higher alkyl-substituted N-isoxazolylsulfonamides, in which R 2 is H, CH 3 , C 2 H 5 , C 2 F 5 or CF 3 ; and R 3 , R 4 , R 5 , R 6 and R 7 are either (i) or (ii) as follows:
  • R 4 , R s , R 6 and R 7 are each independently selected from H, halide, NH 2 , CF 3 , Ph and CH 3 ;
  • R 1 is most preferably Br
  • R 2 is CH 3 , C 2 H 5 , or CF 3
  • R 3 , R ⁇ R ⁇ and R 7 are (i) or (ii) as follows:
  • R 3 is H, NH 2 , CH 3 CF 3 , halide or C 2 H 5 NH;
  • R 4 , R 5 and R 6 are independently selected from H, CF 3 , halide, particularly Br and Cl, NH 2 ;
  • R 7 is H, CH 3 , CH 2 CH 5 , (CH 3 )CH, F or CF 3 ; or
  • R 3 , R 5 and R 7 and R 4 and R 6 are each an methyl or ethyl.
  • R 1 is most preferably Br, except in instances in which ehanced ET B affinity, compared to the corresponding compound in which R., is CH 3 , is desired, than R 1 is most preferably a higher alkyl (9 to 1 5 carbons, preferably 9 or 10 to 13 carbons).
  • R 3 , R 4 , R 5 , R 6 , and R 7 are selected from (i), (ii), (iii) or (iv) with the proviso that, (a) when Ar 2 is phenyl, at least one of R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen, (b) when Ar 2 is phenyl and Ar 1 is 3-isoxazolyl, R 3 is not NH 2 or CH 3 , and (c) when Ar 2 is napthyl, 2-biphenyl, phenyl, other than benzofuryl, dibenzothienyl and dibenzopyrrolyl, R 1 is halide or higher alkyl:
  • R 3 , R 4 , R 5 , R 6 , and R 7 are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10
  • R 3 , R ⁇ , and R 7 are H; and R 4 and R 6 are each independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, wherein the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
  • R 3 , R 5 and R 7 are each independently (a) hydrogen, except that at least one of R 3 , R 5 and R 7 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W ⁇ W 2 and W 3 , except that if one of R 3 , R 5 are R 7 is alkyl at the 4 position, at least one of the other two of R 3 , R 5 are R 7 is not hydrogen; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro, except that if one of R 3 , R 5 and R 7 is 4-N0 2 , then at least one of the other two of R 3 , R 5 and R 7 is not hydrogen; (g)
  • R 1 is halide or is higher alkyl (greater than about 8 carbons up to about 9 carbons in the chain;
  • R 2 is selected from: (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W 1 , W 2 and W 3 ; (c) hydroxyl; (d) cyano; (e) nitro; (f) -C(0)H or -C(0)R 27 ; (g) -C0 2 H or -C0 2 R 27 ; (h) -SH, -S(0) n R 27 , -S(0) m - OH, -S(0) m OR 27 , -0-S(0) m -R 27 , -
  • R 27 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W ⁇ W 2 and W 3 ;
  • R 28 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W ⁇ W 2 and W 3 ; (c) cyano; (d) hydroxyl; (e) -C(0)H or -C(0)R 27 ; (f) -C0 2 R 27 ; (g) -SH, - S(0) n R 27 , -S(0) m
  • R 32 is (a) hydrogen; (b) hydroxyl (c) -C(0)H, -C(0)R 27 or C0 2 R 27 ; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W ⁇ W 2 and W 3 ; or any two of R 30 , R 31 and R 32 together are alkylene or alkenylene (either of which may be substituted with W 1 , W 2 and W 3 ), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
  • W , W 2 and W 3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0) n W 6 , - S(0) m -OH, -S(0) m -OW 6 , -0-S(0) m -W 6 , -0-S(0) m OH, or -0-S(0) m -OW 6 ; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)W 6 ; (o) -C0 2 H or -C0 2 W 6 ; (p) -W 4 -NW 7 W 8 ; (q) W 4 -N(W 11 )- W 5 -W 6 ; or (r) -
  • W 4 and W 5 are each independently (a) a single bond; (b) -W 9 -S(0) ⁇ -W 10 -; (c) -W 9 - C(0)-W 10 -; (d) -W 9 -C(S)-W 10 -; (e) -W 9 -0-W 10 -; (f) -W 9 -S-W 10 -; or (g) -W 9 -0-C(0)-W 10 -;
  • W 6 , W 7 and W 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or W 7 and W 8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; W 9 and W 10 are each independently a single bond, alkylene, alkenylene, or alkynylene; W 11 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H, -C(0)W 6 or -C0 2 W 6 ; (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenyl
  • Preferred compounds include those in which one of R 3 , R 5 or R 7 is phenyl or phenoxy or compounds in which one of R 3 , R 5 or R 7 is hydrogen, one of the other two of R 3 , R 5 and R 7 is at the 2 position and is not hydrogen, and the other of R 3 , R 5 and R 7 is at the 5 position.
  • preferred compounds are 2-substituted benzenesulfonamides, and 2,5-substituted benzenesulfonamides.
  • R 1 is preferably halide.
  • Preferred substituents are lower alkyl, particular methyl, ethyl, and propyl, halide, amino, dimethylamino, and methoxy.
  • Ar 2 is phenyl
  • Ar 2 has the formula (Xlll):
  • R 1 is halide or higher alkyl (greater than 8 carbons);
  • R 2 selected from H, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or
  • R 3 , R 4 , R 5 , R 6 , and R 7 are selected independently from among H, NHOH, NH 2 , N0 2 , pseudohalide, including N 3 , halide, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, where the al
  • R 1 is halide or a higher alkyl selected from C 9 H 19 to C 13 H 27 ;
  • R 2 is selected independently from alkyl, lower alkenyl, lower alkynl, lower haloalkyl and H;
  • R 3 , R 4 , R 5 , R 6 , and R 7 are either (i) or (ii) as follows: (i) R 4 , R 5 , R 6 and R 7 are each independently selected from H, lower alkyl, NH 2 ,
  • R 3 is selected from H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from 1 up to 5 or 6 carbons and the aryl portions contain from
  • R 3 , R 5 , and R 7 are H; and R 4 and R 6 are each independently selected from alkyl, alkoxy, halide, aminoalkyl, and dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, and in which the alkyl and alkoxy groups contain 1 to 6 carbons, and are straight or branched chains.
  • R 1 is Cl or Br, or if greater ET B activity is preferred a higher alkyl (C 9 H 19 to C 13 H 27 ;d
  • R 2 is selected from H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n- C 3 H 7 , cyclo-C 3 H 7 , nC 13 H 27 and nC 9 H 19 ; and
  • R 3 , R ⁇ R 5 , R 6 , and R 7 are either (i) or (ii) as follows:
  • R 4 , R ⁇ , R ⁇ and R 7 are each independently selected from H, halide, NH 2 , CF 3 , Ph and CH 3 ;
  • R 3 is selected from H, NHOH, NH 2 , C 2 H B NH 2 , (CH 3 ) 2 NH, Ph-CH 2 NH, N0 2 , F, Cl, Br, I, CN, CH 3 , (CH 3 ) 3 C, C 5 H
  • R 3 , R 5 , and R 7 are H; and
  • R 4 and R 6 are each independently sleeted from alkyl and aminoalkyl in whcih the alkyl groups have from 1 to 6 carbons that may from straight or branched chains.
  • R 1 is Br, Cl or C 9 H 19 to C 13 H 27 ;
  • R 2 is H, CH 3 , C 2 H 5 , or CF 3 ;
  • R 3 , R 4 , R B , R 6 , and R 7 are either (i) or (ii) as follows: (i) R 3 is H, NH 2 , CH 3 CF 3 , halide or C 2 H 5 NH; R 4 , R 5 and R 6 are independently selected from H, CH 3 , C 2 H 5 , (CH 3 ) 2 CH, CF 3 , halide, particularly Br and Cl, NH 2 ; and R 7 is H, CH 3 , CH 2 CH 5 , (CH 3 )CH, F or CF 3 ; or
  • R 3 , R 5 , and R 7 are H; and R 4 and R 6 are each independently selected from alkyl groups in which the alkyl groups have from 1 to 3 carbons and may form straight or branched chains.
  • R 1 is preferably halide.
  • Preferred substituents are lower alkyl, particular methyl, ethyl, and propyl, halide, amino, dimethylamino, and methoxy. Other preferred substituents may be deduced from the following Table.
  • Benzene sulfonamides were synthesized and tested using the exemplified assays (see, EXAMPLES) and selected results are set forth in Table 1 (the N-(3,4-dimethyl-5- isoxazolyDbenzenesulfonamides are generlly included for comparison with the corresponding N-(4-halo-3-methyl-5-isoxazolyl)benzenesulfonamide.
  • Ar 2 is biphenyl
  • Ar 1 is N-(5-isoxazolyl) or N-(3-isoxazolyl) with R 1 and R 2 selected as described above, and Ar 2 is a substituted benzene group in which one of R 3 , R 4 , R 5 , R 6 and R 7 is selected independently from phenyl or substituted phenyl. The remaining of R 3 , R 4 , R ⁇ , R 6 and R 7 are selected as described in (1 ) above for embodiments in which Ar 2 is phenyl.
  • R 1 and R 2 are also selected as described in (1 ) above, except in instances when one of R 3 , R 4 , R 5 , R 6 and R 7 is at the 3 or 4 position so that the resulting compounds are 3- or 4-biphenyl compounds.
  • R 2 is selected as described above, but R 1 can be halide and higher alkyl, and in addition, can be any of the substituents set forth for R 2 .
  • R 1 is preferably halide, lower alkyl, particularly CH 3 , or C 9 H 19 -C 13 H 27 .
  • Ar 2 is unsubstituted or substituted biphenyl group of formula (XIV):
  • each ring may have one or more substituents each selected independently from R 26 and R 13 where:
  • R 26 and R 13 are independently selected from H, OH, OHNH, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain
  • These compounds include biphenylsulfonamides, fused tricyclic- substituted sulfonamides dibenzothiophenesulfonamides, dibenzofuransulfonamides, dibenzopyrrolefonamides (carbazolesulfonamides) and phenanthrenesulfonamides.
  • the dibenzothiophenesulfonamides, dibenzofuransulfonamides, dibenzopyrrolefonamides and phenanthrenesulfonamides are discussed separately with the compounds in which Ar 2 is a heterocycle with one heteroatom and two or more fused rings.
  • Ar 2 is has formula (XV):
  • R 26 and R 13 are each independently selected from H, OH, OHNH, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain
  • R 13 and R 26 are preferably each selected from from H, loweralkyl, haloalkyl and halide. Again, it is understood that Ar 2 may be substituted with more than one substituent, each of which is selected independently from the selections set forth for R 26 and R 13 , and R 2 and R 1 are as defined above.
  • Ar 2 may be substituted with more than one substituent, each of which is selected independently from the selections set forth for R 26 and R 13 .
  • the sulfonamides are biphenylsulfonamides in which R 1 is halide; R 2 is selected from alkyl, lower alkenyl, lower alkynl, lower haloalkyl and H; and R 26 and R 13 are selected from H, lower alkyl, haloalkyl and halide.
  • R 1 is Cl or Br
  • R 2 is selected from H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 and cyclo-C 3 H 7
  • R 26 and R 13 are each independently selected from H, halide, NH 2 , CF 3 CH 3 , CN, CH 3 , (CH 3 ) 3 C, C 6 H
  • R 2 is H, CH 3 , C 2 H 5 , or CF 3 ;
  • R 26 and R 13 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , and halide.
  • the biphenylsulfonamides are 3- or 4- biphenylsulfonamides, in such instances R 1 is preferably, halide or methyl.
  • R 1 is preferably, halide or methyl.
  • Such compounds have a higher ET B affinity than the 2-biphenylsulfonamides. It is also preferred that the substitutent at the 2-position is hydrogen.
  • R 1 is selected from halide, CH 3 , C 2 H 6 , CF 3 , C 2 F 5 , n-C 3 H 7 and cyclo-C 3 H 7 , preferably halide or CH 3
  • R 2 is selected from H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 and cyclo-C 3 H 7
  • R 1 is halide or CH 3
  • R 2 are selected from H, CH 3 , C 2 H 5 , or CF 3
  • R 26 and R 3 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , and halide.
  • the biphenylsulfonamides are substituted 4- biphenylsulfonamides, R 13 is preferably at the para position and R 26 , if it is not hydrogen, is at any position except the 2-position.
  • R is halide or methyl or higher (C 9 -C 13 ) alkyl.
  • R 1 is selected from halide, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 and cyclo-C 3 H 7 , preferably halide or CH 3
  • R 2 is selected from H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 and cyclo-C 3 H 7 , more preferably R 1 is halide or CH 3
  • R 2 is selected from H, CH 3 , C 2 H 5 , or CF 3
  • R 1 is Cl or Br, or if greater ET B activity is preferred a higher alkyl (C 9 H 19 to C 13 H 27 ;
  • R 2 is selected from H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n- C 3 H 7 , cyclo-C 3 H 7
  • the biphenyl compounds provided herein are generally ET B active or ET B selective (see, e.g.. Table 2); Le ⁇ the compounds provided herein inhibit binding of endothelin to ET B receptors at concentrations about 10- to about 30-fold less than they inhibit binding of endothelin to ET A receptors.
  • the 4-biphenylsulfonamides are ET B selective.
  • biphenyl sulfonamides are the following and those set forth in Table 2, and include, but are not limited to: N-(3-methyl-5-isoxazolyl)-4'-methylphenyl-4-biphenylsulfonamide, N-(4-bromo-3-methyl- 5-isoxazolyl)-4'-methylphenyl-4-biphenylsulfo ⁇ amide, N-(4-chloro-3-methyl-5-isoxazolyl)- 4'-methylphenyl-4-biphenyisulfonamide, (3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4- biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsul- fonamide, (3-methyl-5-isoxazolyl)-4'-methyoxyphenyl-4-biphenylsu
  • Preferred compounds are those in which Ar 2 is a 4-biphenyl in which, referring to formula VII and at least one substitutent R 13 is at the para position.
  • Preferred substitutents are loweralkyl, halo loweralkyl and lower alkoxy. Such compounds are ET B active.
  • Ar 2 has formula (XVI):
  • R 1 and R 2 are either (i), (ii) or (iii) as follows:
  • R 1 and R 2 are each independently selected from H, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon
  • R 1 and R 2 together form -(CH 2 ) n , where n is 3 to 6; or, (iii) R 1 and R 2 together form 1 , 3-butadienyl; and
  • R 3 , R 4 , R 5 , R 6 , and R 7 are selected from (i), (ii), (iii) or (iv):
  • R 3 , R 4 , R 5 , R 6 , and R 7 are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10
  • R 4 and R 7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R 3 , R 5 and R 6 are as defined in (i) above; or alternatively, (iii) R 7 and R 3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R 4 , R 5 and R 6 are as defined in (i) above; or
  • R 3 , R 5 , and R 7 are H are as defined in (i); and R 4 and R ⁇ are each independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
  • R 2 is H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 , cyclo- C 3 H 7 and C 4 H 8 ;
  • R 1 is Br, Cl, CH 3 , or, if greater ET B affinity is desired, is higher alkyl;
  • n is 1 -3; and
  • R 3 , R ⁇ R 5 , R 6 , R 7 are selected from either (i), (ii), (iii) or (iv) as follows:
  • R 5 and R 6 are H;
  • R 4 and R 7 are each independently selected from H, halide, NH 2 , CF 3 , Ph, CH 3 ; and
  • R 7 and R 3 together form 1 , 3-butadienyl, 3-chloro-1 , 3-butadienyl 4- dimethylamino-1 , 3-butadienyl or 1-aza-1 , 3-butadienyl; and R 4 , R 5 and R ⁇ are as defined in (i) of this embodiment; or
  • R 3 , R B , and R 7 are H as defined in (i); and R 4 and R 6 are each independently selected from alkyl, alkoxy, halide, amino alkyl, alkylaminoalkyl or dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
  • R 1 is Br, Cl, I or CH 3 or, if greater ET B affinity is desired, is C 9 H 19 -C 13 H 27 ;
  • R 2 is H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7 , cyclo-C 3 H 7 and C 4 H 8 ; either R 3 , R 4 , R 5 , R 6 and R 7 are either (i), (ii), (iii), (iv) or (v): (i) R 5 , R 6 and R 7 are H; and R 3 is H, NH 2 , CH 3 CF 3 , halide, C 2 H 5 NH or Ph, R 4 is H,
  • R 3 , R 5 and R 6 are H; and R 4 and R 7 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, or 4-chloro-1 , 3-butadienyl; or (iii) R 4 , R 5 and R 6 are H; and R 7 and R 3 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl; or
  • R 4 is H or NH 2 , R 5 and R 6 are H; and R 3 is H, NH 2 and halide; CH 3 , Br, Cl, F, CF 3 , NH 2 , R 7 is H, CH 3 , Br, Cl, F, NH 2 or CF 3 , and R 5 and R 6 are H; or (v) R 3 , R 5 , and R 7 are H are as defined in (i); and R 4 and R 6 are each independently selected from alkyl groups that contain from 1 to 6 carbons, and are straight or branched chains.
  • the compounds are N-(4-halo-isoxazolyl)- sulfonamides in which R 2 is H, CH 3 , C 2 H 5 , C 2 F 5 or CF 3 ; and R 3 , R 4 , R 5 , R 6 and R 7 are either (i) or (ii) as follows:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from H, halide, NH 2 , CF 3 , Ph and CH 3 ;
  • n is 1 ;
  • R 1 is most preferably Br, Cl or CH 3 ;
  • R 2 is CH 3 , C 2 H 5 , or CF 3 ; and
  • R 3 , R ⁇ R 8 and R 7 are (i) or (ii) as follows:
  • R 3 is H, NH 2 , CH 3 CF 3 , halide or C 2 H 5 NH;
  • R 4 , R 5 and R ⁇ are independently selected from H, CF 3 , halide, particularly Br and Cl, NH 2 ;
  • R 7 is H, CH 3 , CH 2 CH 5 , (CH 3 )CH, F or CF 3 ; or
  • R 3 , R 5 and R 7 and R 4 and R 6 are independently selected from nitro, hydrogen, methyl or ethyl.
  • Ar 2 contains fused aromatic rings and is selected from naphthyl, anthracenyl and phenanthryl are provided herein.
  • Ar 2 is naphthyl
  • Ar 2 is naphthyl
  • R 1 and R 2 are as set forth above, R 2 is preferably H, lower alkyl or lower haloalkyl; R 1 is preferably halide or, if an increase in ET B affinity is desired, higher alkyl (about 8 to 15, preferably 9 to 13 carbons, which are straight or branched chains); R 3 , R 4 , R B , R 6 , and R 7 are selected from (i) or (ii):
  • R 4 and R 7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R 3 , R 5 and R 6 are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,
  • R 7 and R 3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1-aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R 4 , R 5 and R 6 are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyalkoxy, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, al
  • R 2 is H, CH 3 , C 2 H 5 or CF 3 and R 1 is halide or, in embodiments in which an increase in ET B activity is descired, R 1 is higher alkyl, in which the alkyl group contains between 8 and 15, preferably 9 and 13, carbons, which may be straight or branched chains.
  • the compounds have formulae (XVII):
  • NAPHTHYL- SO- which is substituted with R 4 , R 5 and R 6 which are selected independently: (a) hydrogen;
  • R 1 and R 2 are selected from (i) or (ii) as follows:
  • R 1 is halide or higher alkyl (greater than 8 carbons up to about 1 5); R 2 is
  • R 1 and R 2 are each independently selected from (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W ⁇ W 2 and W 3 ; (c) hydroxyl; (d) cyano; (e) nitro; (f) -C(0)H or -C(0)R 27 ; (g) -C0 2 H or -C0 2 R 27 ; (h) -SH, -S(0) n R 27 , -S(0) m - OH, -S(0) m -OR 27 , -0-S(0) m -R 27 , -0-S(0) m 0H, or -0-S(0) m -OR 27 ; (i) -W 4 -NR 28 R 27
  • R 27 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W 1 , W 2 and W 3
  • R 28 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W 1 , W 2 and W 3 ; (c) cyano; (d) hydroxyl; (e) -C(0)H or -C(0)R 27 ; (f) -C0 2 H or -C0 2 R 27 ; (g) -SH, -S(0) n R
  • R 29 is (a) hydrogen; (b) -C(0)H or -C(0)R 27 , except when W 4 is -C(O)- and R 28 is - C(0)H, -C(0)R 27 , -C0 2 H, or -C0 2 R 27 , (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W 1 , W 2 and W 3 , or
  • R 28 and R 29 together are aklylene or alkenylene (either of which may be substituted with W 1 , W 2 and W 3 ), completing 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
  • R 30 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R 27 ; (d) -C0 2 H or -C0 2 R 27 ;
  • R 31 is (a) hydrogen; (b) -C(0)H or -C(0)R 27 , except when W 6 is -C(O)- and R 30 is -
  • R 32 is (a) hydrogen; (b) hydroxyl, C0 2 R 27 or C0 2 H, except when one of R 30 and R 31 is hydroxyl, C0 2 R 27 or C0 2 H; (c) -C(0)H or -C(0)R 27 ; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W 1 , W 2 and W 3 ; or any two of R 30 , R 31 and R 32 together are alkylene or alkenylene (either of which may be substituted with W 1 , W 2 and W 3 ), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
  • W 1 , W 2 and W 3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkoxy; (e) -SH, -S(0) n W 6 , -S(0) m -OH, -S(0) m -0W 6 , -0-S(0) m -W 6 , -0-S(0) m OH, or -0- S(0) m -OW 6 ; (f) oxo; (g) nitro; (h) cyano; (i) -C(0)H or -C(0)W 6 ; (j) -C0 2 H or -C0 2 W 6 ; or (k) -NW 7 W 8 , -C(0)NW 7 W 8 , or -S(0) n W 7 W 8 ;
  • W 4 and W 5 are each independently (a) a single bond; (b) -S(0) n -; (c) -C(O)-; (d) - C(S)-; or (e) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W ⁇ W 2 and W 3 ;
  • W 6 , W 7 and W 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or W 7 and W 3 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring
  • At least one of R 4 , R 5 and R 6 is not hydrogen. In other embodiments, at least one of R 4 , R 5 and R 6 is preferably di-loweralkylamino or loweralkylamino and the others of R 4 , R B and R 6 is hydrogen or lower alkyl.
  • the sulfonamide is linked at position 1 or 2, preferably 1 , of the napthyl group and at least one of the subsituents is at position 5.
  • Naphthalenesulfonamides were synthesized and tested using the exemplified assays (see, EXAMPLES) and selected results are set forth in the Table 4 (the 4- haloisoxazole compounds are preferred).
  • R 1 and R 2 are selected as described above for the compounds in which Ar 2 is phenyl or biphenyl and n > 0.
  • the fused rings may be substiuted with one or more substituents selected from R 13 and R 26 in which R 26 and R 13 are independently selected from H, OH, OHNH, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl,
  • R 1 is halide or methyl
  • R 2 is selected from alkyl, lower alkenyl, lower alkynl, and lower haloalkyl
  • R 26 and R 13 are selected from H, lower alkyl, haloalkyl and halide.
  • R 1 is Cl, Br or CH 3 ;
  • R 2 is selected from H, CH 3 , C 2 H 5 ,CF 3 , n-C 3 H 7 , cyclo-C 3 H 7 and C 4 H 8 ; and
  • R 2 is H, CH 3 , C 2 H 5 , or CF 3 ;
  • R 26 and R 13 are independently selected from H, CH 3 , C 2 H ⁇ , CF 3 , and halide.
  • Exemplary compounds include N-(4-bromo-3-methyl-5-isoxazolyl)phenanthrene- 3-sulfonamide, N-(4-bromo-5-methyl-3-isoxazolyl)phenanthrene-3-sulfonamide and N- (3,4-dimethyl-5-isoxazolylphenanthrene-3-sulfonamide. Selected results for such componds are set forth in Table 5: TABLE 5
  • Ar 2 is a heterocycle including sulfonamides in which Ar 2 is five-membered heterocyclic ring compound with one heteroatom and fused ring analogs thereof, compounds in which Ar 2 is a five-membered heterocycle with two or more heteroatoms and fused ring analogs thereof, compounds in which Ar 2 is a six-membered heterocyclic ring compound with one heteroatom and fused ring analogs thereof, compounds in which Ar 2 is a six-membered heterocycle with two or more heteroatoms and fused ring analogs thereof are provided.
  • Ar 2 is a five-membered heterocycle with one heteroatom
  • Compounds in which Ar 2 is a is a fused ring analog of a 5-membered heterocyle with one heteroatom include, but are not limited to compounds in which Ar 2 is benzofuryl, benzothienyl (thianaphthyl), indolyl, indoliznyl, and isoindole.
  • Ar 2 is a 5-membered heterocycle with two or more heteroatoms and fused ring analogs thereof include, but are not limited to, compounds in which Ar 2 is oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl, imidaolidinyl, 1 ,3- dioxaolanyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxoxaolyl, isothiazolyl, 1 ,2,3- oxadiazolyl, 1 ,2,3-triazolyl, 1 ,3,4-thiadiazolyl, 1 H-indazolyl, benzoxazolyl, benzimidazolyl and benzothiazolyl.
  • Ar 2 is a 6-membered heterocycle with one heteroatom and fused ring analogs thereof include, but are not limited to, compounds in which Ar 2 is pyridinly, quinolinyl, isoquinolynl, acridine, 4H-quinolizine, 2H-pyran, 4H-pyran, and piperidinyl.
  • Ar 2 is a 6-membered heterocycle with two or more heteroatoms and fused ring analogs thereof include, but are not limited to, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-napthyridinyl, pterdinyl, 1 ,4-doxanyl, morpholinyl, thiomorpholinyl, morpholinyl, phenazinyl, phenythiazinyl, phenoxazinyl, quniazolinyl, quinoxalinyl, naphthyrindinyl and pteridinyl.
  • Ar 2 is thienyl, furyl and pyrrolyl
  • Ar 2 is represented by the formulae (IV):
  • R 9 , R 10 are selected as described above.
  • Ar 2 is thienyl, furyl, pyrrolyl or a group, such as benzofuryl, thianaphthyl or indolyl, that is a derivative of or analog, as described below, of a thienyl, furyl, pyrroly group
  • Ar 1 is preferably N-(5- isoxazolyl) or N-(3-isoxazolyl, and the compounds are represented by the formulae III:
  • R 1 , R 2 are either (i), (ii) or (iii) as follows:
  • R 1 and R 2 are each independently selected from H, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon
  • R 1 and R 2 together form -(CH 2 ) n , where n is 3 to 6; or, (iii) R 1 and R 2 together form 1 , 3-butadienyl; and X, R 8 , R 9 and R 10 are selected as defined above.
  • R 2 is not halide, pseudohalide or higher alkyl.
  • the more preferred compounds of formulae I and and U provided herein are compounds in which Ar 1 is N-(5-isoxazolyl) or N-(3-isoxazolyi) that can be represented by the formulae XVIII:
  • R 1 and R 2 are either (i), (ii) or (iii) as follows:
  • R 1 and R 2 are each independently selected from H, NH 2 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or
  • R 1 and R 2 together form -(CH 2 ) n , where n is 3 to 6; or, (iii) R 1 and R 2 together form 1 , 3-butadienyl;
  • X is O, S, NH or NR 11 in which R 11 , which contains up to about 30-50 atoms, generally 1 to 20 atoms, and which is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 15 , S(0) n R 15 in which n is 0-2;
  • R 15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;
  • Z which is is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R 21 , C0 2 R 21 , SH, S(0) n R 21 in which n is 0-2, NHOH, NR 22 R 21 , N0 2 , N 3 , OR 21 , R 22 NCOR 21 and CONR 22 R 21 ;
  • R 22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 23 and S(0) n R 23 in which n is 0-2; and R 21 and R 23 are
  • any two of R 8 , R 9 and R 10 form an aromatic or heteroaromatic ring or an alicyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members, and which is unsubstituted or substituted with one or more substituents in each each substituent is independently selected from Z; and the other of R 8 , R 9 and R 10 is selected as in (i).
  • X is S, O, NR 11 in which R 11 is aryl, hydrogen, or lower alkyl, preferably, a substituted or unsubstituted aryl, particularly phenyl, preferably unsubstituted or substituted with lower alkyl or halogen hydrogen or lower alkyl;
  • R 1 is hydrogen, halide, pseudohalide, lower alkyl or lower haloalkyl, most preferably halide;
  • R 2 is hydrogen, lower alkyl or lower haloalkyl; and
  • R 8 , R 9 and R 10 are each selected independently from from hydrogen, halide, pseudohalide, lower alkyl, lower aryl, lower heterocycle, lower aralkyl, S(0) n R 18 in which n is 0-2, C(0)R 18 , C0 2 R 18 , N0 2 , OR 18 or CONR 19 R 18 ;
  • R 19 is preferably hydrogen, lower alkyl, and lower aryl, C(0)R 20 , S(0) n
  • R 8 , R 9 and R 10 is selected from methyl, phenyl, pyrazolyl, isoxazolyl, carbomethoxy, carboxamide, halide, hydrogen, isopropylphenyl, pyridyl, carboxyl, phenyl, phenylaminocarbonyl, benzenesulfonyl, lower- alkylphenylaminocarbonyl, biphenylaminocarbonyl, (lower)haloalkoxyphenyl- aminocarbonyl and halophenylaminocarbonyl and, preferably, two of R 8 , R 9 and R 10 are hydrogen, halide or lower alkyl.
  • X is S.
  • R 8 , R 9 and R 10 are hydrogen, halide or lower alkyl and the other is hydrogen, halide, pseudohalide, lower alkyl, lower aryl, heterolower aryl, lower aralkyl, C(0)R 18 , C0 2 R 18 , N0 2 , OR 18 or C0NR 19 R 18 .
  • R 19 is phenyl and R 18 is hydrogen, halide or lower alkyl.
  • R 8 , R 9 and R 10 are hydrogen or lower alkyl and the other is halide, lower alkyl, C(0)R 18 , C0 2 R 18 , N0 2 , OR 18 or C0NR 19 R 18 ;
  • R 18 is hydrogen or lower alkyl.
  • R 1 is preferably halide, H, CH 3 or C 2 H 5
  • R 2 is H, CH 3 , C 2 H 5 , C 2 F 5 or CF 3 .
  • R 1 preferably Br, Cl or CH 3
  • R 2 is H, CH 3 , C 2 H ⁇ , or CF 3 .
  • R 9 and R 10 are H, halide or lower alkyl; and R 8 is any of the above listed substituents, and particularly, when a potent ET A antagonist is desired is a substituted aminocarbonyl. In other preferrred embodiments it is preferred that R 8 and R 10 are H or lower alkyl and R 9 is any of the above-listed substituents.
  • R 1 is halide, H, CH 3 or C 2 H 5
  • R 2 is H, CH 3 , C 2 H 5 , C 2 F S or CF 3 .
  • R 1 is Br, Cl or CH 3 ; and R 2 is H, CH 3 , C 2 H 5 , or CF 3 .
  • R 8 and R 10 are H or lower alkyl and R 9 is a heterocyclic or aromatic ring of preferably from 3 to 14, more preferably, 5 to 7, members in the ring.
  • R 8 and R 10 are H or lower alkyl, and R 9 , is aryl, particularly unsubstituted or substituted phenyl, such as 4-ethylphenyl.
  • R 11 is aryl, particularly! unsubstituted phenyl or substituted phenyl, such as isopropylphenyl and R 8 , R 9 and R 10 are preferably H, halide or lower alkyl.
  • the most preferred compounds provided herein have an IC 50 for ET A receptors in the assays exemplified herein between about .002 ⁇ M and 0.1 ⁇ M (see, e.g.. Table 6).
  • These compounds include: N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)- aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3- methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-bromo-5-methyl-3- isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-
  • IC B0 for ET B receptors as measured in the assays herein, of between about 0.05 ⁇ M and 1 ⁇ M.
  • These include compounds, such as N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzenesulfonylthiophene-2- sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrole-2- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-1 -(4'-isopropylphenyl)pyrrole-3- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- ⁇ 3-[1-methyl-5-(trifluoromethyl)pyra- zolyl] ⁇ thiophene-5-sulfonamide; N-(4-bromo-3
  • thienyl-, furyl- and pyrrole-sulfonamides include the following compounds: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(phenylamino- carbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-5-benzylthiophene- 2-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulf onamide; N- (4-chloro-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide; N-(4-bromo-3- methyl-5-isoxazolyi)-3-styrylthiophene-2-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyi)-3-styrylthiophene-2
  • R 10 which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
  • any two of R 8 , R 9 and R 10 form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z; the other of R 8 , R 9 and R 10 is selected as from the groups set forth for R 9 and R 10 in (i); and the heteroatoms are NR 11 , O, or S.
  • Ar 2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3- loweralkylbenzo[b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl. In other embodiments, if
  • R 8 is (CH 2 ) r C(0)NH(CH 2 ) n R 18 , C(0)(CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r R 13 , particularly if r is 0 and/or n is 0, and R 18 is aryl, particularly phenyl, then R 18 must have two or more substituents, with preferably at least one ortho substituent.
  • Ar 2 is, thus, represented by the formulae (lVA and IVB):
  • R 8 is (CH 2 ) r C(0)NH(CH 2 ) n R 18 , (CH 2 ).C(0)NH(CH 2 )-R 18 , or (CH 2 ) r R 18 , and R 18 is phenyl
  • the phenyl group is substituted at least two positions, and preferably, at least one of those positions is ortho.
  • R 18 is aryl or heteroaryl, preferably having 5 or 6 members in the ring, more preferably phenyl or pyrimidinyl, most preferably phenyl.
  • R 9 and R 10 are preferably hydrogen, halide, loweralkyl, or halo loweralkyl.
  • X is S, 0, NR 11 in which R 11 is aryl, hydrogen, or loweralkyl, preferably, a substituted or unsubstituted aryl, particularly phenyl, preferably unsubstituted or substituted with loweralkyl or halogen hydrogen or loweralkyl; R 1 is hydrogen, halide, pseudohalide, loweralkyl or lower haloalkyl, most preferably halide; R 2 is hydrogen, loweralkyl or lower haloalkyl.
  • R 9 and R 10 are hydrogen, halide or loweralkyl and R 8 is C(0)NHR 18 or C(0)CH 2 R 18 in which R 18 is a phenyl group that is substituted at least two positions, most preferably at least one substitutent at the ortho position and also 3,4 or 4,5 alkylenedioxy substituents.
  • X is S.
  • R 1 is preferably halide, H, CH 3 or C 2 H 5
  • R 2 is H, CH 3 , C 2 H 5 , C 2 F 5 or CF 3 .
  • R 1 preferably Br, Cl or CH 3 ;
  • R 2 is H, CH 3 , C 2 H 5 , or CF 3 .
  • R 8 , R 9 and R 10 form a ring so that Ar 2 is benzo[b]thienyl, benzotblfuryl, or indolyl, with the proviso that there is one or more substituents and they are other than 5-halo and 3-loweralkyl, and the other of R 8 , R 9 and R 10 is selected from aryl, (CH 2 ) r R 18 , C(0)R 18 , C0 2 R 18 , NR 18 R 19 , SH, S(0) n R 18 in which n is 0-2, HNOH, N0 2 , N 3 , OR 18 , R 19 NCOR 18 and CONR 19 R 18 .
  • Ar 2 may be further substituted with any of the groups set forth for R 8 , R 9 and R 10 , and are preferably selected from among alkyl, alkoxy, alkoxyalkyl, aryl, alkylaryl, aminoalkyl, arylamino, aryl-substituted amino, and NR 11 .
  • R 8 and R 10 are H or loweralkyl and R 9 includes heterocyclic or aromatic ring of preferably from 3 to 14, more preferably, 5 to 7, members in the ring.
  • R 8 and R 10 are H or loweralkyl, and R 9 , includes an aryl group, particularly a substituted phenyl, such as a 2-loweralkyl substituent.
  • the aryl portion is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularly methylenedioxy, amino, nitro and other such groups.
  • the alkyl substituents are preferably loweralkyl, more preferably containing 1 -3 carbons. If X is NR 11 , then R 11 is aryl, particularly unsubstituted phenyl or substituted phenyl, such as isopropylphenyl.
  • R 1 is preferably halide or loweralkyl, most preferably Br, and the compounds are, with reference to formulae IV, 2- or 3-sulfonamides, particularly thiophene sulfonamides.
  • Ar 2 is a benzo[b]thienyl, benzo[b]furyl or indolyl (benzo[b]pyrrolyl) group and the compounds provided herein are preferably benzo[b]thienyl-, benzotblfuryl- or indolylsulfonamides.
  • Benzo[b]thiophene, benzo[b]furyl and indolyl 2- or 3-sulfonamides are among the compounds preferred herein.
  • benzo[b]thiophene, benzo[b]furyl and indolyl 2- or 3-sulfonamides provided herein are selected with the proviso that the benzene group has at least one substituent and that substituent is other than 5-halo and 3-loweralkyl.
  • Compounds of particular interest include those of formula II in which Ar 2 is a phenyl-, benzothienyl, benzofuryl or indolyl [benzopyrrolyl!
  • Ar 2 is a substituted phenylaminocarbonylthienyl, substituted phenylaminocarbonylfuryl, substituted phenylaminocarbonylpyrrolyl group or Ar 2 is phenylacetylthiophene, phenyl- acetylfuran, or phenylacetylpyrrole, or is an acetoxystyrylthiophene, acetoxystyrylfuran or acetoxystyrylpyrrole.
  • Ar 2 is a substituted phenylaminocarbonylthienyl, substituted phenylaminocarbonylfuryl, substituted phenylaminocarbonylpyrrolyl group in which there are at least two substitutents on the phenyl ring.
  • the most preferred compounds provided herein have an IC 50 for ET A receptors in the assays exemplified herein less than 0.1 ⁇ M, more prefereably less than 0.01 ⁇ M, and more preferably less than 0.001 (see, e.g.. Table 6 for representative experimental results), when measured at 4° C, as described in the Examples. When measured at 24° C, the IC 50 concentrations are somewhat higher (2- to 10-fold; see, Table 1 for some comparative values).
  • Ar 2 has formula XIX:
  • R 51 , R 52 , R 53 , R 54 and R BB are each independently selected from (i) or (ii) as follows: (i) R 51 , R 52 , R 53 , R 54 and R 5B are each independently selected from among H, OH, NHR 38 , C0NR 38 R 39 , N0 2 , cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbony
  • R 5 , R 52 , R 53 , R 54 and R 55 are selected as in (i); and
  • R 38 and R 39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl.
  • M is (CH 2 ) m C(0)NH(CH 2 ) r
  • R 51 , R 52 , R 53 , R 54 and R BB are not hydrogen.
  • M is most preferably selected from
  • aryl substituent have more than one substituent or at least one substituent in the ortho position.
  • Aryl is preferably phenyl that is preferably substituted at the ortho position and, more preferably at at least one additional position, particularly 4 and 6, or adjacent positions, such as 3,4 or 4,5 when the subsitutents are linked to form an alkylenedioxy (or analog thereof in which one or both oxygens is(are) replaced with S.
  • At least one of R 51 and R 5 ⁇ is other than hydrogen.
  • M is even more preferably selected from among:
  • R 40 is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, and more preferably loweralkyl, loweralkoxy, or halo loweralkyl, and is more preferably hydrogen or loweralkyl, particularly methyl or ethyl, and is most preferably hydrogen.
  • M is most preferably:
  • R B1 , R 52 , R 53 , R 84 and R 55 are selected from (i) or (ii): (i) R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from loweralkyl, haloloweralkyl, phenyl, alkoxy, loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl, loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy lowerallkyl, acetoxy loweralkoxy or loweralkoxycarbonyl; or
  • R 52 and R 53 or R 53 and R 54 form alkylene dioxy, preferably methylenedioxy, and the others of R 51 , R 52 , R 53 , R 54 and R 55 are selected as in (i).
  • R 51 , R 83 , R 55 are other then hydrogen and are preferably loweralkyl or lower alkoxy, or R 51 or R 55 is other than hydrogen, preferably loweralkyl or lower alkoxy, and R 52 and R 53 or R 53 and R 54 form methylenedioxy.
  • Ar 1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2- pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl.
  • the sulfonamides have formula V:
  • Ar 1 is a substituted or unsubstituted monocyclic or polycyclic, preferably a monocyclic or fused bicyclic, aryl group with one or more substituents, selected from, for example, H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons.
  • substituents selected from, for example, H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formy
  • the substituents are preferably H, NH 2 , halide, CH 3 , CH 3 0 or another aromatic group.
  • Ar 2 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2- pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl, more preferably 4-chloro-3-methyl-5-isoxazolyl or 4-chloro-5-methyl-3-isoxazolyl;
  • R 54 is selected from the group consisting of substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, 0C(0)R 16 , 0C0 2 R 16 , NR 12 R 1 ⁇ and S(0) n R 16 in which n is 0-2; preferably alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, alkylsulfonylamino and aminosulfonyl.
  • R ⁇ 1 , R 53 and R 55 which are preferably alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylaikyl, or heteroarylalkyl, more preferably lower alkyl, lower alkenyl, lower alkynyl, or aryl, most preferably methyl.
  • R 54 is, in certain of these embodiments, methoxy, methoxycarbonylmethoxy, 2- (2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N- dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxy, hydroxyl, carboxyl, cyanomethyl, acetoxymethyl, hydroxymethyl, carboxylmethyl, methanesulfonylamino, N,N-dimethylaminomethyl, S0 2 NH 2 , or methoxycarbonylmethyl.
  • R 54 does not contain a cyano group and is, for example, methoxy, methoxycarbonylmethoxy, 2- ⁇ 2-methoxyethoxy)ethoxyacetoxy, 2- hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxymethyl, methoxycarbonylmethyl, hydroxy or acetoxy.
  • a cyano group is, for example, methoxy, methoxycarbonylmethoxy, 2- ⁇ 2-methoxyethoxy)ethoxyacetoxy, 2- hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxymethyl, methoxycarbonylmethyl, hydroxy or acetoxy.
  • the sulfonamides have formula XXI:
  • Ar 1 is a substituted or unsubstituted monocyclic or polycyclic, preferably a monocyclic or fused bicyclic, aryl group with one or more substituents, selected from, for example, H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons.
  • substituents selected from, for example, H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, for
  • the substituents are preferably H, NH 2 , halide, CH 3 , CH 3 0 or another aromatic group.
  • Ar 1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo-2, 1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2, 1 ,3-oxadiazol-5-yl;
  • X is S, 0 or NR 11 ; each G and R, which are selected from among the R 1 -R 5 as defined above, are preferably independently selected from lower alkyl, CN, — (CH 2 ) x C(0)(CH 2 ) x , — (CH 2 ) X , (CH 2 ) x N-lower alkyl, — (CH 2 ) x C(0)NH 2 , a
  • R, G and R' are selected where the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the heteroaryl is triazoly), and X is S are of interest.
  • Ar 1 is defined as above.
  • Ar 1 is preferably benzo-2, 1 ,3-oxadiazol-5-yl or 2-methoxy-3-pyrazinyl when R 5 ⁇ is H; and R 56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
  • Ar 1 is preferably benzo-2, 1 ,3-oxadiazol-5- yl or 2-methoxy-3-pyrazinyl when R 56 is H and
  • R 56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
  • preferred compounds of formula IV include:
  • the sulfonamides have formula XXIII: (XXIII)
  • Ar 1 is defined as above and is preferably 4-chloro-3-methy!-5-isoxazolyl; W is
  • R 57 is selected from the group consisting of aryl, heteroaryl, heterocycle, OH, CN, C(0)R 16 , C0 2 R 16 , SH, S(0) n R 16 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, — (CH 2 ) x OH, NHOH, NR 12 R 1 ⁇ , N0 2 , N 3 , OR 16 , R 12 NCOR 16 and CONR 12 R 1 ⁇ ;
  • R 16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
  • R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alky
  • Preferred embodiments of the compounds of formula XXIII are those wherein Ar 1 is 4-chloro-3-methyl-5-isoxazolyl; W is NH; and R 57 is CONH 2 , COOH, or phenyl.
  • R ⁇ 1 and R 62 are hydrogen, or are each independently selected from halo, cyano, cyanoalkyl, C(0)R 41 , alkyl, alkenyl, cycloalkyl and aryl, or R 61 and R 62 together form alkylene;
  • W is O, NH or CH 2 ;
  • R 65 , R 66 and R 67 are each independently selected as in (i) or (ii):
  • R 66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
  • R 65 and R 67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R 41 , carbamoyloxy and alkoxycarbonyloxy; or
  • R 41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, (aryD(alkyl)amino, alkylsulfonylamino, arylsulfonylamino, (alkylsulfonyl) (alkyl or aryDamino or (arylsulfonyl) (alkyl or aryDamino; and R 43 is selected from hydroxy, alkoxy, alkyl and aryl.
  • R 41 and R 43 are unsubstituted or substituted with one or more substituents selected from Y, which is defined as alkoxy, halide, pseudohalide, alkylcarbonyl, arylcarbonyl, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy. Also of interest are the corresponding 3-acyl-2- thiophenesulfonamides.
  • the aryl group is tetrasubstituted, it will preferably be substituted at the 2, 4 and 6 positions, and one of these substituents will be a polar group, such as hydroxyl, acetoxy, carboxyl and carboxamide. If the aryl group is substituted at the 2, 4 and 6 positions with nonpolar groups, such as alkyl groups, more specifically methyl groups, then the aryl group will preferably be penta- or hexasubstituted. In pentasubstituted aryl groups, the fifth substituent will be at the 3 position and will preferably be a polar group, such as hydroxyl, acetoxy, carboxyl and carboxamide.
  • Preferred compounds include those in which R 61 and R 62 are each independently hydrogen, alkyl, halo, cyano, cyanomethyl, acetyl or cycloalkyl, or together form alkylene;
  • R 65 , R 66 and R 67 are each independently selected as in (i) or (ii): (i) R 66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
  • R 65 and R 67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R 41 , carbamoyloxy or alkoxycarbonyloxy; or
  • R ⁇ 1 and R 62 are not hydrogen, then any two may form methylenedioxy, and the other is selected as in (i); x is 0 or 1 ; n is 2; R 41 is alkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino or arylsulfonylamino; and R 43 is hydroxy or alkoxy
  • Ar 1 is 4-chloro-
  • R 61 and R 62 are each independently hydrogen, methyl, cyclopropyl, fluoro, chloro, cyano, cyanomethyl or acetyl, or together form butylene;
  • R 65 , R 66 and R 67 are each independently selected from (i) or (ii):
  • R 66 is selected from hydrogen, methyl, hydroxy, methoxy, acetyl, carbamoyloxy and methoxycarbonyloxy, and
  • R 6S and R 67 are each independently hydrogen, methyl, hydroxy, acetyl, carbamoyloxy and methoxycarbonyloxy; or
  • R 61 and R 62 are not hydrogen, then R 66 and R 67 may form methylenedioxy and R 65 is selected as in (i); and R 45 is acetyl, propanoyl, 2-methylpropanoyl, cyclopropylcarbonyl, benzoyl, cyclohexylcarbonyl, methyl, 1 -hydroxy-1 -ethyl, hydroxy methyl, methoxyacetyl, fluoroacetyl, carboxyacetyl, hydroxyacetyl, oximinoacetyl or S0 2 R 41 .
  • Particularly preferred compounds of this embodiment are selected from the following: N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, N-(2-benzoyl-4,6-dimethylphenyl)-3- (((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, 3-((4-chloro- 3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-2- thiophenecarboxamide, 3-(( ⁇ 4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-propionylphenyl
  • Preferred compounds are also those where W is 0 or CH 2 .
  • the sulfonamides are thus 2-phenoxycarbonyl-3-sulfonamide, 3-phenoxycarbonyl-2-sulfonamide, 2- phenylacetyl-3-sulfonamide and 3-phenylacetyl-2-sulfonamide derivatives of the above compounds.
  • Table 6 sets forth exemplary compounds of this embodiment and demonstrates that the compounds have activity as endothelin receptor antagonists. More preferred compounds of Table 6 are those that have the highest activities, and preferred substituents are those on the compounds wiht the highest activities.
  • the data in Table 6 is intended for exemplary and comparison puroposes only and is not intended to limit the scope of this embodiment in any way.
  • the alkyl, alkynyl and alkenyl portions are straight or branched chains, acyclic or cyclic, and have from about 1 up to about 10 carbons; in certain of the more preferred embodiments they have from 1 -6 carbons, and they can have fewer than 6 carbons.
  • the aryl, homocyclic and heterocyclic groups can have from 3 to 16, generally, 3-7, more often 5-7 members in the rings, and may be single or fused rings.
  • the ring size and carbon chain length are selected such that the resulting molecule binds to exhibits activity as an endothelin antagonist or agonist as evidenced by in vitro or in vivo tests, particularly the tests exemplified herein.
  • R 1 and R 2 are preferably selected independently from alkyl, lower alkenyl, lower alkynl, lower haloalkyl, halide, pseudohalide and H. In certain embodiments, R 2 is not halide or pseudohalide or higher alkyl.
  • R 1 is preferably halide or lower alkyl, most preferably Br, and the compounds are, with reference to formulae IV, 2- or 3-sulfonamides, particularly thiophene sulfonamides.
  • results are generally the average of 2 to 5 experiments preliminary results or results in which one or more data points were only determined approximately assay performed with incubation at 24° C. As described in the Examples, incubation at the higher temperature reduces the activity by a factor of 2- to about 10-compared to the activity at 4° C data not available or measured as % inhibition @ 100 ⁇ M
  • Ar 2 is a heterocycle with one heteroatom and two or more fused rings
  • Compounds in Ar 2 is a heterocycle with one heteroatom and two or more fused rings are provided.
  • the heteroatom is O, S or N and Ar 2 is selected from among, but not limited to, quinolyl, isoquinolyl, dibenzofuryl, bibenzothienyl, and dibenzopyrrolyl compounds and other such groups.
  • the fused rings may be substituted with one or more substituents selected from among substitutents set forth for R 8 , R 9 and R 10 above. at any position.
  • the sulfonamide portion of the compounds may be linked at any . position.
  • Ar 2 is quinolyl and isoquinolyl
  • preferred compounds are quinolines, particularly, 8-quinolinesulfonamides.
  • the numbering scheme is as follows:
  • R 1 and R 2 are selected as described for the thienyl, furyl and pyrrolyl compounds, any of the rings may be substituted with one or more substituents selected from hydrogen or are selected as described above for R 26 and R 13 .
  • Ar 2 is dibenzofuryl, bibenzothienyl, and dibenzopyrrolyl
  • Ar 2 is dibenzofuryl, bibenzothienyl, and dibenzopyrrolyl and has the following formula (XXIV):
  • R 1 is halide or methyl
  • R 2 is selected from lower alkyl, lower alkenyl, lower alkynl and lower haloalkyl
  • R 26 and R 13 are selected from H, lower alkyl, haloalkyl and halide.
  • R 1 is Cl, Br or CH 3 ;
  • R 2 is selected from H, CH 3 , C 2 H 5 ,CF 3 , n-C 3 H 7 , cyclo-C 3 H 7 and C 4 H 8 ; and
  • R 2 is H, CH 3 ,
  • R 26 and R 13 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , and halide; and X is 0.
  • Exemplary compounds include those set forth in Table 8:
  • Ar 2 is a six-membered heterocycle with one heteroatom selected from S, O or NR 11
  • Prefered six-membered heterocylic rings are pyridyl rings.
  • the pyridyl groups may be substituted with one or more substituents selected from R 13 , R 8 and R 26 , as defined above and may be 2-, 3- or 4-sulfonamides.
  • R 1 and R 2 are selected as described above for the thiphenyl, furyl and pyrrolyl compounds.
  • Ar 2 is a pyridyl group
  • compounds in which Ar 2 is a pyridyl group include, but are limited to, N-(4- bromo-3-methyl-5-isoxazolyl)pyridine-2-sulf onamide, N-(4-bromo-5-methyl-3- isoxazolyl)pyridine-2-sulf onamide, N-(3,4-dimethyl-5-isoxazolyl)pyridine-2-sulf onamide, N-(4,5-dimethyl-3-isoxazolyl)pyridine-2-sulf onamide, 3-methoxycarbonyl-N-(4-bromo-5- methyl-3-isoxazolyl)pyridine-2-sulf onamide and 3-methoxycarbonyl-N-(4-bromo-5- methyl-3-isoxazolyl)pyridine-2-sulf onamide, N-(3,4-dimethyl-5-isoxazolyl)-3-(N- phen
  • Ar 2 is a heterocycle with two or more heteroatoms
  • Ar 2 is a heterocycle that contains two or more heteroatoms selected from O, S, N, and NR 11 , including, but are not limited to pyrimidinyl, purinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, benzofuryl, benzothienyl and benzopyrrolyl, are provided. These compounds may be unsubstituted or substituted with one or more substitutents selected from those set forth for R 3 R 8 or R 26 . Particular compounds that have been synthesized, include:
  • Ar 2 is a fused bicyclic heterocycle with two or more heteroatoms
  • the compounds of this embodiment have formulae IX:
  • Y is N or 0 + ;
  • X is S, 0, NR 11 , in which R 11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R 15 and S(0) n R 15 in which n is 0-2;
  • R 15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;
  • R 11 and R 15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl,
  • R 1 and R 2 together form -(CH 2 ) n , where n is 3 to 6; or, (iii) R 1 and R 2 together form 1 , 3-butadienyl;
  • R 83 , R 84 and R 85 are selected from (i), (ii), (iii) or (iv):
  • R 83 , R 84 and R 8S are each selected independently from among H, NHOH, NH 2 , N0 2 , N 3 , halide, pseudohalide, alkyl, alkenyl, alkynyl, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl or amido, where the alkyl, alkenyl, alkynyl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about
  • R 84 is H; and R 83 and R 85 are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains; or
  • any two of R 83 , R 84 and R 85 which are each selected as in (i) form fused carbocyclic or heterocyclic rings;
  • R 87 is hydrogen or contains up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, and is selected hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R 18 , C0 2 R 18 , (CH 2 ) r R 18 , (CH 2 ) r COR 18 (CH 2 ) r C0(CH 2 ) s R 18 , SH, S(0) n , (CH 2 ) r , S(0) n R 18 in which n is 0-2, and s and r are each independently 0 to 6, preferably 1 -3, HNOH, NR 18 R 19 , N0 2 , N 3 , OR 18 , R 19 NC0R 18 and C0NR 19 R
  • R 87 is preferably C(0)R 18 , C0 2 R 13 , (CH 2 ) r R 18 , (CH 2 ) r C0R 18 (CH 2 ) r CO(CH 2 ) s R 18 , NR 18 R 19 , OR 18 , R 19 NCOR 18 or CONR 19 R 18 .
  • More preferred compounds are those of formula (IX) that have formula (XXV):
  • R 87 is C(0)R 18 , C0 2 R 18 , (CH 2 ) r R 18 , (CH 2 ) r C(0)CH 2 ) s R 18 ,
  • R 87 , R 18 or R 19 is aryl, particularly phenyl, or includes an aryl group, particularly phenyl:
  • R 92 , R 93 , R 94 , R 95 and R 96 are each independently selected from (i), (ii) or (iii) as follows:
  • R 92 , R 33 , R 94 , R 95 , and R 96 are each independently selected from among H, NHR 38 , CONR 38 , N0 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl, where R 38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle
  • R 92 , R 93 , R 94 , R 96 and R 96 are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy ( e.
  • R 92 , R 93 , R 94 , R 96 and R 96 are selected as in (i); or
  • R 92 , R 93 , R 94 , R 95 and R 96 are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (he.
  • n 1 to 4, preferably 1 or 2), which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of the others of R 93 , R 94 , R 95 , and R 96 are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e.
  • R 92 , R 93 , R 94 , R 95 and R 96 is selected as in (i).
  • at least one, more preferably two, of R 92 , R 93 , R 94 , R 95 and R 96 is H and the others are selected from among (i), (ii) or (iii) as follows:
  • R 92 , R 93 , R 94 , R 94 , R 95 and R 96 are substituting adjacent carbons and together form alkylenedioxy and the others of R 92 , R 93 , R 94 , R 95 and R 96 are selected as set forth in (i); or
  • R 92 , R 93 , R 94 , R 95 and R 96 are substituting adjacent carbons and together form alkylenedioxy, and at least two of the others of R 92 , R 93 , R 94 , R 9B and R 96 are substituting adjacent carbons and together form alkylenedioxy, and the other of R 92 , R 93 , R 94 , R 95 and R 96 is H.
  • R 92 and R 96 is not hydrogen.
  • R 87 , R 18 or R 19 is pyrimidyl, it is substituted with one or more substitutents selected from (i) or (ii)
  • R 38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl, where R 38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloal
  • At least two substituents are on adjacent members of the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e. — 0-(CH 2 ) n -0-, — S-(CH 2 ) n -0-, — S-(CH 2 ) n -S-, where n is 1 to 4, preferably 1 or 2), which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others substituent(s) are selected as in (i).
  • R 87 is (CH 2 ) r R 18
  • R 18 is phenyl or pyrimidyl, preferably phenyl, in which at least two of substituents are on adjacent members of the ring and form alkylenedioxy, one or two remaining substituents are lower alkyl or lower alkoxy, preferably methyl or methoxy, more preferably methyl, and the others are hydrogen.
  • Y is preferably N
  • X is preferably S or 0, more preferably S.
  • Ar 2 alkyl
  • Ar 2 is CH 3 -(CH 2 ) n
  • n is 0 to about 30, preferably, 0 to 20, and more preferably between about 5 and about 10 and which may be substituted with halide, amino, carbonyl, nitro, and the like, and compounds in which Ar 2 is
  • R 1 and R 2 are selected as described above for the thienyl, furyl and pyrrolyl compounds.
  • the methyl groups may be replaced by other lower alkyl groups, hydrogen or halide.
  • Selected compounds have the following activities:
  • R 1 and R 2 are selected as described above for the thienyl, furyl and pyrrolyl compounds and; R 1 -R 9 are as defined above, R 8 and R 9 may be cis or trans position.
  • Compounds in which Ar 2 is styryl include, but are not limited to: N-(3,4-dimethyl-5- isoxazolyl)-jff-tra/7S-styrenesulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- / £-tra/7s-sty- renesulfonamide, N-(4-bromo-5-methyl-3-isoxazolyl)-jff-tra 7S-styrenesulfonamide, 2-nitro- N-(3,4-dimethyl-5-isoxazolyl)styrenesulf onamide, 2-nitro-N-(4-bromo-3-methyl-5- isoxazolyDstyrenesulf
  • R 1 is phenyl, substituted phenyl or heterocyclyl
  • R 2 is phenyl or substituted phenyl
  • R 3 is hydroxy, lower-alkoxy or a residue -NR 4 R 5
  • R 4 is hydrogen or a residue -R ⁇ and R 5 is hydrogen or a residue -(CH 2 ) m R 6 or R 4 and R ⁇ together with the N atom to which they are attached are in N heterocyclic residue
  • R 6 is phenyl, substituted phenyl, cycloalkyl, heterocyclyl, lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl, carboxy- lower-alkyl or lower-alkoxycarbonyl-lower-alkyl
  • R a is hydrogen, lower-alkyl or hydroxy
  • R b is hydrogen or lower-alkyl
  • X is oxygen or sulphur
  • Y is oxygen or sulphur
  • Z is hydrogen, lower
  • Preferred compounds of this embodiment are those where R 1 is phenyl; a substituted phenyl substituted by a chemical group selected from the group consisting of lower alkyl, lower alkoxy, methylenedioxy, ethylenedioxy, Iower-alkanoyl, hydroxy, amino, mono-iower-alkylamino, di-lower-alkylamino or halogen; or heterocyclyl selected from the group consisting of 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tetrazolyl-4-pyridyl, 1 ,2-diazinyl, 1 ,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl; R 2 is pheny
  • 3-thienyl isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl, wherein the heterocyclyl is substituted with lower-alkyl; m is 0, 1 , or 2; and, n is 0, 1 , or 2; and pharmaceutically acceptable salts thereof.
  • Particularly preferred compounds of this embodiment include 6-(4-tert- butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2- carboxylic acid phenylamide; (RS)-4-(4-tertButyl-phenylsulphonylamino)-6-(2,3- dihydroxy-propoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid (3-hydroxy- phenyD-amide; 4-(4-tert-Butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(3- methoxy-phenoxy)-pyrimidine-2-carboxylic acid (3-hydroxy-phenyl)-amide; 4-(4-tert- Butyl-phenylsulphonylamino)-6-(2-hydroxyethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-
  • R 1 is heterocyclyl
  • R 2 is selected from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkoxy-lower-alkyl, lower-alkylsulphonyl-lower-alkoxy, phenyl, lower alkylphenyl, lower-alkoxy-phenyl, lower-alkylenedioxyphenyl, phenyl-lower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, lower alkylenedioxyphenyl-lower alkyl, heterocyclyl and heterocycyl-lower alkyl;
  • R 3 is selected from the group consisting of lower-alkyl, lower-alkoxy, formyl, halo-lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl, -CH 2 0-A-lower-alky
  • Particularly preferred compounds of this embodiment include 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- 2,2'-bipyrimidin-4-ylamide, 5-pentyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-(2,2-dimethyl-propionyl)-thiophene- 2-sulphonic acid, 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4- ylamide, 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-thoxy)-5-2-methoxy- phenoxy)-2,2'-bipyrimidin-4-ylamide, pyridine-3-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy
  • Ring A and Ring B are a substituted or unsubstituted monocyclic, bicyclic or tricyclic hydrocarbon group, or a substituted or unsubstituted heterocyclic group
  • Q is a single bond or a group of the formula: -0-, -S-, -SO-, -S0 2 — or -CH 2 -
  • Y is a group of the formula: -O— , -S- or -NH-
  • Alk is a lower alkylene group or a lower alkenylene group
  • Z is a group of the formula: -0- or -NH-
  • R is a substituted or unsubstituted aromatic heterocyclic or aryl group
  • R 1 is a hydrogen atom, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted
  • Particularly preferred compounds of this embodiment include N-[6-[2-[(5- Bromopyrimidin-2-yl)oxy[ethoxy]-2-(4-hydroxypiperidino)-5-(2- methoxyphenyloxy)pyrimidin-4-yl]-4-tert-butylbenzenesulf onamide, N-[2-[(2- Methoxyethyl)amino]-5-(2-methoxyphenyloxy)-6-[2-[(5-methoxypyrimidin-2- yl)oxy[ethoxy[pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide, N-[6-[2-[(5- Bromopyrimidin-2-yl)oxy[ethoxy]-2-[(2-hydroxyethyl)aminol-5-(4-methylphenyl)pyrimidin- 4-yl]-4-tert-butylbenzenesulfonamide, or pharmaceutically acceptable salts thereof. d
  • Ring A and Ring B are the same or different and each is a substituted or unsubstituted benzene ring, Q is a single bond or a group of the formula: -0-, — S-,
  • Y is a group of the formula: -0-, -S- or -NH-, Alk is a lower alkylene group or a lower alkenylene group, Z is a single bond or a group of the formula: -0— or -NH-, R is a substituted or unsubstituted aromatic heterocyclic or aryl group, R is hydrogen atom, trifluoromethyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a mono- or di-lower alkylamino group, a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkynyl group, an aromatic heterocyclic group, a substituted or unsubstituted aliphatic heterocyclic
  • Ar is a phenyl group which is unsubstituted or bears 1, 2 or 3 substituents independently selected from (1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-6C)alkyl, N-K1- 4C)alkyl]amino(1-6C)alkyl, N,N-[di(1-4C)alkyl]amino(1-6C)alkyl, carboxy(1-6)alkyl, (1- 6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylcarbonyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, di-N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
  • Preferred compounds of this embodiment include 2-(4-isobutylphenyl)-N-(3- methoxy-5-methylpyrazin-2yl)pyridine-3-sulphonamide; N-(5-ch!oro-3-methoxypyrazin-2- yl)-2-(4-isobutylphenyl)pyridine-3-sulphonamide; 2-[4-(1-carboxyethoxy)phenyl]-N-(3- methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-(4-ethylphenyl)-N-(3-methoxy- 5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-(4-tert-butylphenyl)-N-(3-methoxy-5- methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N- (3-methoxy-5
  • R 1 signifies aryl or heterocyclyl
  • R 2 signifies tetrazolyl, lower-alkyl-substituted tetrazolyl, cyano, carboxy, lower-alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl, thiocarbamoly, amidino or hydroxyamidino
  • R 3 signifies a residue -0-(CR a R b ) n -OR 9
  • R -R 8 signify hydrogen, lower-alkoxy or halogen
  • R 9 signifies hydrogen, aryl, lower-aralkyl, heterocyclyl or a residue -C(0)NHR 10
  • R 10 signifies lower-alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl
  • R a and R b signify hydrogen or lower-alkyl
  • n signifies 2, 3 or 4
  • a and B signify CH; or one of the symbols
  • Preferred compounds of this embodiment include 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide, 4-tert-butyl-N- [6-(2-hydroxy-ethoxy)-5- ⁇ 2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yl]-benzenesulphonamide, 2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2- methoxy-phenoxy)-2-(2-1
  • R 1 signifies phenyl, substituted phenyl or heterocyclyl
  • R 2 signifies phenyl or substituted phenyl
  • R 3 signifies hydrogen, lower-alkyl, cyano, carboxy, esterified carboxy, phenyl, substituted phenyl, heterocyclyl or a residue -CONR 5 R 6 or -NR 5 COR 7
  • R 4 signifies hydrogen or lower-alkyl
  • R 5 signifies hydrogen or a residue R 7
  • R 6 signifies -(CH 2 ) m R 7 ; or R 5 and R 6 together with the N atom associated with them signify a heterocyclic residue
  • R 7 signifies phenyl, substituted phenyl, cycloalkyl, hetero-cyclyl, lower-alkyl, cyano-lower-alkyl, hydroxy-lower-alkyl, di-lower-alkylamino-lower-alkyl, carboxy-lower-alkyl, lower
  • Preferred compounds of this embodiment include pyridin-2-yl-carbamic acid 2-[3- (4-tert-butyl-benzene-sulphonylamino)-2-(2-methoxy-phenoxy)-5-(morpholine-4- carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-benzene- sulphonylamino-2-(2-methoxy-phenoxy)-5-(2-pyridin-2-yl-ethylcarbamoyl)-phenoxyl-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-benzene-sulphonylamino)-2-(2- methoxy-phenoxy)-5-(piperidine-1 -carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-
  • R 1 is (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy or (1 -6C)alkythio, each of which last five groups bear a substituent selected from carboxy, (1 -6C)alkoxycarbonyl, carbamoyl, N-(1 -6C)alkylcarbamoyl and N,N-di(1 - 6C)alkylcarbamoyl;
  • R 2 is an optional substituent selected from halogeno, (1 -6C)alkyl, (1 - 6C)alkoxy, carboxy, (1 -6C)alkoxycarbonyl, carbamoyl, N-(1 -6C)alkylcarbamoyl, N,N- ⁇ di(1 -6C)alkylcarbamoyl, cyano, amino, N-(1 -6C)alkylamino and N,N-di(1 -6C)
  • Preferred compounds of this embodiment include 4'-(2-carboxypropyl)-N-(3- methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide, 4'-carboxymethoxy-N-(3- methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide, 4'-(1 -carboxy)ethoxy-N-(3- methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide, 4'-(1 -carboxy)ethoxy-N-(5- chloro-3-methoxypyrazin-2-yl)-2-biphenylsulphonamide and 4'-(2-carboxy-2- methylpropyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide; or a pharmaceutically-acceptable salt thereof.
  • R 1 and R 2 are hydrogen or an optionally substituted hydrocarbon residue
  • R 3 is a alkyl group which is substituted by a C 1-6 alkoxy-carbonyl gorup or a group of the formula: -NH-S0 2 -R 5 wherein R 5 is (1 ) a C 1- ⁇ alkyl group which may optionally be substituted by halogen or (2) a C 6 . 14 aryl group
  • R 4 is an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group
  • W denotes a chemical bond or a spacer group and n denotes an integer of 1 to 3, or a salt thereof.
  • Q is a naphthyl or biphenyl group;
  • a 1 , A 2 and A 3 are attached to a phenyl or benzene ring of Q and are independently selected from hydrogen, (1 -6C)alkyl, aminod - 6C)alkyl, hydroxy(1-6C)alkyl, N-(1 -4C)alkyl]am ⁇ no(1 -6C)alkyl, N,N- [di(1 -4C)alkyllamino(1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, halogeno(1-6C)alkyl, (1 - 6C)alkoxy, dihalogeno(1 -6C)alkoxy, trihalogeno(1 -6C)alkoxy, (2-6C)alkenyloxy, (1 - 4C)alkoxy(1 -6C)alkyl, (1 -4C)alkylthio(1 -6C)alkyl
  • Preferred compounds of this embodiment include 5-dimethylamino-N-(3- methoxy-5-methyl-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-dimethylamino-N-(5- chloro-3-methoxy-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-dimethylamino-N-(5- bromo-3-methoxy-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-ethylamino-N-(5-bromo- 3methoxy-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-ethylamino-N-(6-chloro-3- pyridazinyl)-1 -naphthalenesulphonamide; 5-ethylamino-N-(5-bromo-2-pyrazinyl)-1 - naphthalenesulphonamide; 5-dimethyl
  • R 1 , R 2 and R 3 are each independently (a) hydrogen, except that R 1 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with Z ⁇ Z 2 and Z 3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R 6 ; (h) - C0 2 H or C0 2 R ⁇ ; (i) -SH, -S(0) n R 6 , -S(0) m -OH, -S(0) m -OR 6 , -0-
  • R 1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, -NZ 7 Z 8 , halo, or hydroxy
  • R 2 and R 3 are each independently hydrogen, alkyl, or -NR 7 R 8
  • R 4 and R 5 are alkyl
  • R 7 , R 8 , Z 7 and Z 8 are each independently hydrogen, alkyl, or -C(0)alkyl.
  • most preferred compounds are those wherein R 1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino or hydroxy; R 2 and R 3 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, amino, alkylamino, dialkylamino, or alkanoylamino; and R 4 and R 5 are alkyl of 1 to 4 carbon atoms, specially methyl.
  • Preferred compounds of this embodiment include N-3,4-Dimethyl-5-isoxazolyl)f1 , 1 '-biphenyl]-2-sulf onamide; N-3,4-Dimethyl-5-isoxazolyl)-2-bromobenzene-sulf onamide; N-3,4-Dimethyl-5-isoxazolyl)-2-phenoxybenzene-sulfonamide; 3'-Amino-N-(3,4-dimethyl- 5-isoxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; 2-Fluoro-N-(3,4-dimethyl- 5isoxazolyl)benzene-sulf onamide; N-[3-[[(3,4-Dimethyl-5-isoxazolyl)-2-methyl- benzenesulfonamide; 5-Amino-N-(3,4-Dimethyl-5isoxazolyl)-2-methyl-
  • R is naphthyl or naphthyl substituted with R 1 , R 2 and R 3 ;
  • R ⁇ R 2 and R 3 are each independently (a) hydrogen;
  • halo (d) hydroxyl; (e) cyano;
  • H or -C0 2 R 4 ;
  • R 6 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R 6 ; (d) -C0 2 H or -C0 2 R 6 ; (e) -SH, -S(0) R R ⁇ - S(0) m -0H, -S(0) m
  • Preferred compounds of this embodiment include 5-(Dimethylamino)-N-(3,4- dimethyl-5-isoxazolyl)-1-naphthalenesulfonaide; N-[5-[[(3,4-Dimethyl-5-isoxazolyl)amino]- sulfonylI-1 -napthalenyl]acetamide; 5-Amino-N-(3,4-dimethyl-5-isoxazolyl)-1-napthalene- sulfonamide; N-[6-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-1-naphthalenyl]acetamide; 5-Amino-N-(3,4-dimethyl-5-isoxazolyl)-2-naphthalenesulf onamide; N-[4-[[(3,4-Dimethyl- 5-isoxazolyl)amino]sulfonyl]-1
  • R 1 , R 2 and R 3 are each independently (a) hydrogen, except that R 1 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z Z 2 and Z 3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R 6 ; (h) -C0 2 H or -C0 2 R 6 ; (i) -SH, -S(0) n R 6 , -S(0) m -OH, -S(0) m -OR 6 , -0-S(0)
  • R 1 is phenyl or phenoxy, optionally substituted with one or more alkyl, alkoxy, -NZ 7 Z 8 , halo and hydroxy;
  • R 2 and R 3 are each independently hydrogen, alkyl or -NR 7 R 8 ;
  • R 4 and R 5 are alkyl;
  • R 7 , R 8 , Z 7 and Z 8 are each independently hydrogen, alkyl or -C(0)alkyl.
  • R 1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino or hydroxy;
  • R 2 and R 3 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, amino, alkylamino, dialkylamino or alkanoylamino; and
  • R 4 and R 5 are alkyl of 1 to 4 carbon atoms, especially methyl.
  • Preferred compounds of this embodiment include N-(3,4-Dimethyl-5-isoxazolyl)-
  • R 1 is hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl
  • R 2 is hydrogen, lower-alkyl, halogen, lower-alkoxy, trifluoromethyl or — OCH 2 COOR 9
  • R 3 is hydrogen, lower-alkyl, halogen, lower-alkylthio, trifluoromethyl, lower-alkoxy or trifluoromethoxy
  • R 2 and R 3 together are butadienyl, methylenedioxy, ethylene-dioxy or isopropylidenedioxy
  • R 4 is hydrogen, lower-alkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, hydroxy- lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-fower-alkoxy, alkoxy-lower-alkyl, alkoxy- lower
  • R 11 is hydrogen, C,. 4 -alkanoyl or heterocyclylcarbonyl
  • R 12 is C, ⁇ -alkyl or -(CH 2 ) 0 . 4 -aryl
  • Z is -0-, -S- or -NR 9 -
  • Het is a heterocyclic residue
  • Hal is halogen
  • n is 0 or 1 ; and salts thereof.
  • Preferred compounds of this embodiment include 4-tert-butyl-N-[6-ethoxy-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzenesulphonamide, 4-tert-butyl-N-[6- methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzenesulphonamide, 4-tert- butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-yl]- benzenesulphonamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl- 2(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-(2-chloro-5- methoxy-phenoxy)-6-hydroxy
  • R 1 represents a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a halogen atom or a trifluoromethyl group
  • R 2 represents a halogen atom, a lower alkoxyl group, a hydroxy-lower alkoxyl group or a trifluoromethyl group
  • R 3 represents a hydroxyl group, a halogen atom, an alkylthio group, a cycloalkyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, hydroxyimino-lower alkyl group, a lower alkenyl group, an oxy-lower alkyl group, a trifluoromethyl group, a trifluoromethoxyl group, a lower alkoxyl group, a lower alkoxy-lower alkoxyl group or an aryl-lower alkoxyl group, and R 2 and R 3 may form
  • R 7 represents a lower alkoxyl group or a nitro group
  • R 8 represents a halogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a nitro group, a hydroxyl group, an amino group or a trifluoromethyl group, and R 7 and R 8 may form butadienyl
  • R 9 represents a halogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkythio group or a trifluoromethyl group
  • R 10 represents a halogen atom, a lower alkyl group, a lower alkoxyl group or a lower alkylthio group
  • X and Y each represent 0, S or NH
  • n represents 2, 3 or 4.
  • "lower" means C.,. 7 .
  • R 1 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a halogen atom or a trifluoromethyl group
  • R 2 represents a hydrogen atom, a halogen atom, a lower alkoxyl group, a trifluoromethyl group or -OCH 2 COOR a
  • R 3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkylthio group, a trifluoromethyl group, a cycloalkyl group or a lower alkoxyl group, and R 2 and R 3 may form butadienyl, methylenedioxy, ethylenedioxy or isopropylidene
  • R 4 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a trifluoromethyl group, a lower alkoxyl group, a lower alkylthio group,
  • R 1 , R 2 , R 3 and R 4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z ⁇ Z 2 and Z 3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R 5 ; (h) -C0 2 H or -C0 2 R
  • R 1 and R 2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, — C0 2 R 5 or — Z 4 -NR 6 R 7 ;
  • R 3 and R 4 are each independently alkyl; and
  • R 11 , R 12 , R 13 and R 14 are each independently hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl.
  • R 1 and R 2 are each independently lower alkyl or hydrogen; R 3 and R 4 are each independently lower alkyl, especially methyl; and R 12 , R 13 and R 14 are hydrogen and R 1 is hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl.
  • Preferred compounds of this embodiment include N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2,2,2-tri- fluoroacetamide; N-(3,4-Dimethyl-5-isoxazolyl)-2',4'-bis(2-oxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide; (Z)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1 ,1 '- biphenyl]-2-sulfonamide; (E)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2- phenylethenyD
  • R 1 and R 2 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl or alkoxy; (c) hydroxyl; (d) halo; or (e) amino;
  • R 3 and R 4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z ⁇ Z 2 and Z 3 ; (c) halo; (d)
  • the heterocyclic ring containing U, T, L, K and J is a pyridine (such as a 2-or 3-pyridine), pyrimidine (such as a 2-, 4- or 5- pyrimidine), or pyrazine (such as a 2-pyrazine) ring;
  • R 1 and R 2 are each independently hydrogen, alkyl or alkoxy;
  • R 3 and R 4 are each independently alkyl;
  • R 11 , R 12 , R 13 and R 14 are each hydrogen, —CHO or substituted alkyl, especially where R 12 , R 13 and R 14 are each hydrogen and R 11 is alkyl substituted with heterocycle, substituted heterocycle or -Z 4 -N(Z 1 )-Z 5 -Z 6 ; and
  • p is 0.
  • heterocyclic ring containing U, T, L, K and J is a 2-pyrimidine ring
  • R and R 2 are each independently lower alkoxy or hydrogen
  • R 3 and R 4 are each independently lower alkyl, especially methyl.
  • Preferred compounds of this embodiment include N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino]-sulfonyl]-4-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2- thiophenebutanamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(4- methoxyphenyl)methylamino[methyl]-4'-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-2'-f ormyl-4'-(2-pyrimidinyl) [1 , 1 '-biphenyl]-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-
  • R 1 , R 2 , R 3 and R 4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z 1 , Z 2 and Z 3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R 5 ; (h) -C0 2 H or -C0
  • At least one, or most preferably all, of the substituent groups are as follows: X is 0 and Y is N; R 3 and R 4 are each independently alkyl, most preferably, methyl; R 11 and R 12 are each independently hydrogen, hydroxy, amino, alkenyl, carboxamide or substituted lower alkyl, most preferably, hydrogen; when p is 0, then J is N or NR 13 , most preferably, where R 13 is hydrogen or phenylsulfonyl, and R 1 and R 2 together are alkenylene, completing a 6-membered aromatic ring; or J is S, and R 1 and R 2 are hydrogen; and when p is 1 , then R 1 and R 2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, -C0 2 R 5 or -Z 4 -NR 6 R 7 , most preferably, hydrogen.
  • Preferred compounds of this embodiment include N-(3,4-Dimethyl-5-isoxazolyl)- 2-(2-thienyl)benzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(3- thienyljbenzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(2- pyridinyDbenzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-[1 -(phenylsulfonyD-1 H- indol-3-yl[benzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(1 H-indol-3- yDbenzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-[1 -(phenylsulfonyD-1 H-ind
  • R ⁇ R 2 , R 3 and R 4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z 1 , Z 2 and Z 3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R 5 ; (h) -C0 2 H or -C0 2 R
  • R 5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z Z 2 and Z 3 ;
  • R 6 , R 7 , R 8 , R 9 and R 10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z ⁇ Z 2 and Z 3 ; or R 6 and R 7 together may be alkylene or alkenylene, either of which may be substituted with Z ⁇ Z 2 and Z 3 , completing a 3- to 8-membered saturated or unsaturated ring together;
  • R 1 and R 2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, -C0 2 R 5 or -Z 4 -NR 6 R 7 ;
  • R 3 and R 4 are each independently alkyl; and
  • R 11 and R 12 are each independently hydrogen, hydroxy, amino or substituted lower alkyl.
  • Most preferred compounds of this embodiment are those wherein: R 1 and R 2 are each independently lower alkyl or hydrogen; R 3 and R 4 are each independently lower alkyl, especially methyl; and R 11 and R 12 are each independently hydrogen, hydroxy or substituted lower alkyl.
  • R 1 and R 2 when present, and R 3 and R 4 , are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cyc
  • Z ⁇ Z 2 and Z 3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aryl; (g) aralkyl; (h) alkoxy; (i) aryloxy; (j) aralkoxy; (k) heterocyclo, substituted heterocyclo or heterocyclooxy; (I) -SH, -S(0) n Z 6 , -S(0) m -OH, -S(0) m -OZ 6 , -0-S(0)m-Z 6 , -0-S(0) m OH or -0-S(0) m -O
  • R 1 5 is hydrogen, hydroxyethoxy methyl or methoxyethoxy methyl.
  • Preferred compounds of this embodiment include 4'-[4,5-dihydro-4-[(2- methoxyethoxy)methyl]-5-oxo-1 H-1 ,2,4-triazol-1 -yl]-N-(3,4-dimethyl-5-isoxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide; 4'-[4,5-dihydro-4-[(2-hydroxyethoxy)methyl]-5-oxo-1 H-1 ,2,4- triazol-1 -yl]-N-(3,4-dimethyl-5-isoxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl- 5-isoxazolyl)-4'-(1 ,3,4-oxadiazol-2-yl)[1 ,1 '-biphenyl]-2-sulfonamide; and salts thereof.
  • n 1 or 2;
  • A represents an optionally substituted aryl group or an optionally substituted heteroaryl group;
  • B represents an optionally substituted phenyl group;
  • R 1 represents a lower alkyl, lower alkenyl, or lower alkynyl group (these groups each being optionally substituted by one to three groups selected from the group consisting of halogen atoms and hydroxy, lower alkyl-O-, carboxyl, lower alkyl-O-CO-, and cycloalkyl groups);
  • X represents a group represented by O, S, or -NH-; and
  • Y represents 0 or S.
  • X is 0 or S
  • Hal is F, Cl, Br, or I
  • m is 1 or 2
  • n is 1 , 2, or 3.
  • Preferred compounds of this embodiment include 3-(2,1 ,3-benzothiadiazol-5- aminosulf onyl)-N-(6-acetyl-1 ,3-benzodioxol-5-yl)thiophene-2-carboxamide; 3-(2, 1 ,3- benzothiadiazol-5-aminosulfonyl)-N-(6-cyano-1 ,3-benzodioxol-5-yl)thiophene-3- carboxamide; 3-(2, 1 ,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1 ,3-benzodioxol-5- ylmethylcarbonyDthiophene; 3-(2,1 ,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1 ,3- benzodioxol-5-ylmethyl)thiophene; 3-(2, 1 ,3-benzothiadiazol-5-aminosul
  • R 1 is phenyl, substituted phenyl or heterocyclyl
  • R 2 is phenyl or substituted phenyl
  • R 3 is hydroxy, lower alkoxy, or NR R 5
  • R 4 is H or R 6
  • R 5 is H or -(CH 2 ) m R 6 ; or R 4 and R 5 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group
  • R 6 is phenyl, substituted phenyl, cycloalkyl, heterocyclyl, lower alkyl, hydroxy-lower alkyl, amino- lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl
  • R a is H, loweralkyl or hydroxy
  • R is H or lower alkyl
  • X is 0 or S
  • Y is 0 or S
  • Z is H, lower Ikyl, aryl, aryl- lower alkyl, heterocyclyl or hetero
  • Preferred compounds of this embodiment include 6-(4-tert- butylphenylsulfonylamino)-4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2- carboxylic acid; 4-(4-tert-butylphenylsulfonylamino)-5-(2-chloro-5-methoxyphenoxy)-6- (2-hydroxyehtoxy)pyrimidine-2-carboxylic acid; 4-(2-hydroxyethoxy)-5-(3- methoxyphenoxy)-6-(4-methoxyphenylsulfonylamino)pyrimidine-2-carboxylic acid; (RS)- 6-(4-tert-butylphenylsufonylamino)-4-(2,3-dihydroxypeopoxy)-5-(3- methoxyphenoxy)pyrimidine-2-carboxylic acid; 6-(4-tert-butylphenylsulfonylamino)-4-(
  • R 2 and R 3 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with Z 1 , Z 2 and Z 3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R 6 ; (h) -C0 2 H or C0 2 R 6 ; (i) -SH, -S(0) n R 6 , -S(0) m -OH, -S(0) m -OR 6 , -0-S(0) m -R 6 , -0-S-(0) m OH, or -0-S(0) m -OR 6 ; (
  • R 14 is lower alkyl substituted with 1 , 2 or 3 hlogen atoms;
  • Z 1 , Z 2 and Z 3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0) n Z 6 , -S(0) m -OH, -S(0) m -OZ 6 , -0-S(0) m -Z 6 , - 0-S(0) m OH, or -0-S(0) m -0-Z 6 ; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)Z 6 ; (o) - C0 2 H or -C0 2 Z 6 ; (p) -Z 4 -NZ 7 Z 8
  • R 2 and R 3 are each independently hydrogen or alkyl;
  • R 4 and R 5 are each independently alkyl; and
  • R 12 and R 13 together with the atoms to which they are attached, form:
  • most preferred compounds are those wherein R 2 and R 3 are each hydrogen; and R 4 and R 5 are alkyl of 1 to 4 carbon atoms, especially methyl.
  • Preferred compounds of this embodiment include N-(3,4-dimethyl-5-isoxazolyl)- 2'-(hydroxymethyl)[1 ,1 '-biphenyl]-2-sulfonamide; 4'-[(dimethylamino)methyl]-N-(3,4- dimethyl-5-isoxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-4'-[(2- hydroxyethoxy)mrthyl][1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2'- (hydroxymethyl)-4'-(2-methylpropyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'-(aminomethyl)-N- (3,4-dimethyl-5-isoxazolyl)-4'
  • Ar is an optionally substituted aryl group or optionally substituted five- to six- membered heteroaryl group
  • X is oxygen, sulfur or -NH-
  • Y is O or S
  • R. is hydrogen, optionally halogen-substituted lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted five- to six-membered heteroaryl
  • R 2 is lower alkyl lower alkenyl, lower alkynyl, and may be substituted with one to three substituent(s) selected from hydroxyl, lower alkoxy, cycloalkyl halo, carboxyl and lower alkoxycarbonyl
  • R 3 is phenyl, which may be substituted with one to four substituent(s) selected from optionally halogen-substituted lower alkyl, lower alkoxy, halo, lower alkylthio, lower alkylsulfinyl, lower alkanesulfonyl, carboxyl,
  • Nonpeptide endothelin antagonists especially sulfonamide endothelin antagonists (i.e., those containing a sulfonamide moiety -S0 2 -NH-) are preferred, particularly those described in European Patent Application EP 702012; U.S. Patent Nos. 5,612,359 and 5,594,021 ; International Patent Application Publication Nos. WO 94/27979; WO 96/31492; WO 98/13366; and WO 98/49162.
  • preferred compounds are the following compounds:
  • N-(4-chloro-3-methyl-5-isoxazolyl)-2- ⁇ [3,4-(methylenedioxy)-6-methylphenyl)- acetyl]-thiophene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulf onamide, having the structure:
  • BQ-123 (cyclo-(D-trp-D-asp-L-pro-D-val-L-leu)), BQ-1 53, BQ-238, BQ-485, BQ-610, BQ-788, BQ- 928, TAK-044, FR139317 (perhydrozaepin-1 -ylcarbonyl-L-leucyl-(1-methyl)-D- tryptophyl-[3-(2-pyridyl)]-D-alanine), RES-701 -1 , PD 142893 (acetyl-3,3-diphenyl-D- alanine)-L-leu-L-asp-L-ile-L-ile-L-trp), PD 145065, CP 170687, Ac-DBhg16-leu-asp-ile, ET-1 [Dprl-asp 1 5], Ro 61 -0612, To
  • the endothelin antagonist may, for example, be employed alone, in combination with one or more other endothelin antagonists, or with another compound useful for the prevention or treatment of endothelin-mediated disorders, such as a poly- ?-1 ⁇ 4-N-acetylglucosamine (p-GlcNAc) polysaccharide matrix; angiotensin converting enzyme (ACE) inhibitors such as captopril; dopamine receptor agonists such as apomorphine; renin inhibitors; angiotensin II (All) antagonists such as irbesartan ((2-n-butyl-4-spirocyclopentane-1 -[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2- imidazolin-5-one); dual NEP-ACE inhibitors such as [4S-[4cr(R*), la, 10a ]]-octahydro-4- (2-mer
  • Patent No. 5,508,272 [S-(R*,R*)]-hexahydro-6- [(2-mercapto-1 -oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1 H-azepine-1 -acetic acid (BMS-189921 , U.S. Patent No. 5,552,397), alatriopril, sampatrilat, MDL 100240, and CGS 30440; PDE V inhibitors such as sildenafil (see Terrett et al., Bioorg. Med. Chem.
  • alpha adrenergic blockers such as phentolamine; vasoactive intestinal peptide (VIP); nitric oxide synthase substrates such as L-arginine; nitric oxide donors such as sodium nitroprusside, nitroglycerin, glyceryl trinitrate, S1N-1 , isosorbidmononitrate or isosorbiddinitrate; and prostaglandin E acting compounds such as alprostadil.
  • Such other pharmaceutically or veterinarily active agents may be administered prior to, during or together with, or following administration of the endothelin antagonist. If formulated as a fixed dose, such combination products preferably employ the endothelin antagonists within the dosage range described above and the other pharmaceutically or veterinarily active agent within its approved dosage range. 7.
  • Pharmaceutically or veterinarily acceptable derivatives of the compounds may be administered prior to, during or together with, or following administration of the endothelin antagonist. If formulated as a fixed dose, such
  • any pharmaceutically or veterinarily acceptable derivatives including salts, esters, acids and bases, solvates, hydrates and prodrugs of the sulfonamides.
  • pharmaceutically or veterinarily-acceptable salts including, but not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para- chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, alkali metal salts, such as but not limited to lithium, potassium and sodium, alkali earth metal salts, such as but not limited to barium, calcium and magnesium, transition metal salts
  • formulations of pharmaceutically or veterinarily acceptable derivatives including salts, esters, acids and bases, solvates, hydrates and prodrugs of the sulfonamides.
  • derivatives of neutral sulfonamide compounds that yield formulations of greater stability than formulations containing the corresponding neutral compounds are provided.
  • salts particularly alkali metal salts, and more preferably sodium salts, including salts prepared from sodium compounds, including, but not limited to, sodium bicarbonate in which the resulting product is a sodium salt and disodium hydrogen phosphate in which the resulting compound is a sodium hydrogen phosphate salt.
  • the sodium salt of each compound is most preferred.
  • compositions suitable for administration by any desired route include solutions, suspensions, emulsions, tablets, dispersible tablets, pills, capsules, powders, dry powders for inhalers, sustained release formulations, aerosols for nasal and respiratory delivery, patches for transdermal delivery and any other suitable route.
  • the compositions should be suitable for oral administration, parenteral administration by injection, including subcutaneously, intramuscularly or intravenously as an injectable aqueous or oily solution or emulsion, transdermal administration and other selected routes.
  • the formulations provided herein are for administration by a selected route and contain effective concentrations of pharmaceutically or veterinarily-acceptable salts of the above-noted compounds.
  • the formulations deliver amounts effective for the treatment of laminitis, particularly equine or bovine laminitis, more particularly equine laminitis.
  • Salts, acids and other derivatives thereof can be synthesized as outlined and exemplified herein, or by other methods known to those of skill in the art.
  • the N-(alkylisoxazolyl)sulfonamides can be prepared by condensing an aminoisoxazole with a sulfonyl chloride in dry pyridine with or without the catalyst 4- (dimethylamino)pyridine.
  • the N-(3,4-dimethyl-5-isoxazolyl)sulfonamides and N-(4,5- dimethyl-3-isoxazolyl)sulfonamides can be prepared from the corresponding aminodimethylisoxazole, such as 5-amino-3,4-dimethylisoxazoIe.
  • N-(3,4- dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared from 2- methoxycarbonylthiophene-3-sulfonyl chloride and 5-amino-3,4-dimethylisoxazole in dry pyridine.
  • the N-(4-haloisoxazolyl)sulfonamides can be prepared by condensation of amino-
  • N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and thiophene-2-sulfonyl chloride in THF and sodium hydride.
  • N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfona- mide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-(3-isoxazolyl)thio- phene-2-sulfonyl chloride.
  • compounds such as those in which Ar 2 is thienyl, furyl and pyrrolyl herein, may be prepared by reacting an appropriate sulfonyl chloride with a 5- aminoisoxazole substituted at the 3 and 4 positions, such as 5-amino-4-bromo-3- methylisoxazole, in tetrahydrofuran (THF) solution containing a base, such as sodium hydride. Following the reaction, the THF is removed under reduced pressure, the residue dissolved in water, acidified and extracted with methylene chloride. The organic layer is washed and then dried over anhydrous magnesium sulfate, the solvents are evaporated and the residue is purified by recrystallization using hexanes/ethyl acetate to yield pure product.
  • THF tetrahydrofuran
  • sulfonamides also can be prepared from the corresponding sulfonyl chloride and the aminoisoxazole in pyridine with or without a catalytic amount of 4- dimethylaminopyridine (DMAP).
  • DMAP 4- dimethylaminopyridine
  • the bis-sulfonyl compound is obtained as the major or exclusive product.
  • the bis-sulfonated products can be readily hydrolyzed to the sulfonamide using aqueous sodium hydroxide and a suitable co- solvent, such as methanol or tetrahydrofuran, generally at room temperature.
  • suitable co- solvent such as methanol or tetrahydrofuran
  • N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylamino- carbonyl)thiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)- 2-carboxylthiophene-3-sulfonamide, aniline and 1 -ethyl-3'-[3-dimethylaminopropyll- carbodiimide (EDCl).
  • N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was prepared from 4- methoxyaniline, N,N'-diisopropylethylamine and N-(4-bromo-3-methy)-5-isoxazolyl)-2- carboxylthiophene-3-sulf onamide.
  • N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzylaminocar- bonyl)thiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2- carboxylthiophene-3-sulfonamide and benzylamine as described above.
  • N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfona- mide, which was prepared from the condensation of 5-amino-4-bromo-3- methylisoxazole and 2-(carbomethoxy)thiophene-3-sulfonyl chloride.
  • N-(4-bromo-3-methyl-5-isoxazolyl)-1 -(4'-isopropylphenyl)- pyrrole-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-1 -(4'- isopropylphenyl)pyrrole-3-sulfonamide were prepared from 5-amino-4-bromo-3- methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrole-2 -sulfonyl chloride and 1 - (4'-isopropylphenyl)pyrrole-3-sulfonyl chloride.
  • organic salts ' the organic base, such as N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, or tris(hydroxymethyl)aminomethane, may be mixed with an equimolar amount of the sulfonamide.
  • the organic base such as N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyr
  • the pharmaceutically or veterinarily acceptable cationic salts can be prepared by reacting the acid forms with an appropriate base.
  • Sodium salts, and other metal salts, of the compounds may be prepared by the method set forth in U.S. Patent No. 5,783,705. Briefly, a solution of the sulfonamide in an organic solvent, such as ethyl acetate, is washed with several portions (i.e., 5 or more) of a saturated solution of sodium bicarbonate or sodium carbonate, preferably sodium bicarbonate. Concentration of the organic solution provided the sodium salts of the sulfonamides. The sulfonamide sodium salts can be further purified, if required, by crystallization from an appropriate solvent, such as, for example, dichloromethane/di- ethyl ether.
  • an appropriate solvent such as, for example, dichloromethane/di- ethyl ether.
  • Further purification may optionally be performed by filtering an aqueous solution of the sulfonamide sodium salts to remove particulates, liberating the free sulfonamides by acidification with aqueous hydrochloric acid (e.g., 4 N), and repeating the ethyl acetate/aqueous sodium bicarbonate procedure. Crystallization of the sulfonamide salts from the solvent, such as dichloromethane/diethyl ether or ethanol/methyl tert- butyl ether, provides sulfonamide sodium salts of greater than 98% purity. 3.
  • aqueous hydrochloric acid e.g. 4 N
  • Prodrugs and other derivatives of the compounds suitable for administration to humans may also be designed and prepared by methods known to those of skill in the art (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
  • Compounds described herein have been synthesized and tested for activity in in vitro assays and, in some cases, in in vivo animal models.
  • Nuclear magnetic resonance spectroscopic (NMR), mass spectrometric, infrared spectroscopic and high performance liquid chromatographic analyses indicated that the synthesized compounds have structures consistent with those expected for such compounds and are generally at least about 98% pure. All of the compounds exemplified or described herein exhibited activity as endothelin antagonists.
  • NMR Nuclear magnetic resonance spectroscopic
  • mass spectrometric mass spectrometric
  • infrared spectroscopic and high performance liquid chromatographic analyses indicated that the synthesized compounds have structures consistent with those expected for such compounds and are generally at least
  • Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess any biological activities of an endothelin peptide or the ability to interfere with or inhibit endothelin peptides.
  • Compounds that exhibit in vitro activities such as the ability to bind to endothelin receptors or to compete with one or more of the endothelin peptides for binding to endothelin receptors can be used in the methods for isolation of endothelin receptors and the methods for distinguishing the specificities of endothelin receptors, and are candidates for use in the methods of treating endothelin-mediated disorders.
  • the compounds are tested for the ability to modulate the activity of endothelin-1 .
  • Numerous assays are known to those of skill in the art for evaluating the ability of compounds to modulate the activity of endothelin (see, e.g., U.S. Patent No. 5,1 14,918 to Ishikawa et aL; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD. (October 7, 1991 ); Borges et al. (1989) Eur. J. Pharm. 165: 223-230; Filep et al. (1991 ) Biochem. Biophys. Res. Commun. 177: 171 -176).
  • the properties of a potential antagonist may be assessed as a function of its ability to inhibit an endothelin induced activity jn vitro using a particular tissue, such as rat portal vein and aorta as well as rat uterus, trachea and vas deferens (see e.g., Borges, R., Von Grafenstein, H. and Knight, D.E., "Tissue selectivity of endothelin,” Eur. J. Pharmacol 165:223-230, (1989)).
  • the ability to act as an endothelin antagonist jn vivo can be tested in hypertensive rats, ddy mice or other recognized animal models (see, Kaltenbronn et aL (1990) J. Med. Chem.
  • Endothelin activity can be identified by the ability of a test compound to stimulate constriction of isolated rat thoracic aorta (Borges et aL (1989) "Tissue selectivity of endothelin” Eur. J. Pharmacol. 165: 223-230).
  • the endothelium is abraded and ring segments mounted under tension in a tissue bath and treated with endothelin in the presence of the test compound. Changes in endothelin induced tension are recorded. Dose response curves may be generated and used to provide information regarding the relative inhibitory potency of the test compound.
  • Other tissues including heart, skeletal muscle, kidney, uterus, trachea and vas deferens, may be used for evaluating the effects of a particular test compound on tissue contraction.
  • Endothelin isotype specific antagonists may be identified by the ability of a test compound to interfere with endothelin binding to different tissues or cells expressing different endothelin-receptor subtypes, or to interfere with the biological effects of endothelin or an endothelin isotype (Takayanagi et al. (1991 ) Reg. Pep. 32: 23-37, Panek et al. (1992) Biochem. Biophys. Res. Commun. 183: 566-571 ).
  • ET B receptors are expressed in vascular endothelial cells, possibly mediating the release of prostacyclin and endothelium-derived relaxing factor (De Nucci et aL (1988) Proc. Natl. Acad. Sci. USA 85:9797).
  • ET A receptors are not detected in cultured endothelial cells, which express ET B receptors.
  • the binding of compounds or inhibition of binding of endothelin to ET B receptors can be assessed by measuring the inhibition of endothelin-1 -mediated release of prostacyclin, as measured by its major stable metabolite, 6-keto PGF 1a , from cultured bovine aortic endothelial cells (see, e.g., Filep et aL (1991 ) Biochem. and Biophys Res. Commun. 177: 171-176).
  • the relative affinity of the compounds for different endothelin receptors may be evaluated by determining the inhibitory dose response curves using tissues that differ in receptor subtype.
  • the relative affinities of the compounds for ET A receptors and ET B receptors have been and can be assessed. Those that possess the desired properties, such as specific inhibition of binding of endothelin-1 , are selected. The selected compounds that exhibit desirable activities may be therapeutically useful and are tested for such uses using the above-described assays from which jn vivo effectiveness may be evaluated (see, e.g., U.S. Patent No. 5,248,807; U.S. Patent No. 5,240,910; U.S. Patent No. 5,198,548; U.S. Patent No. 5,187,195; U.S. Patent No. 5,082,838; U.S. Patent No. 5,230,999; published Canadian Application Nos.
  • endothelin antagonists Any endothelin antagonist is contemplated for use in the methods provided herein. Preferred endothelin antagonists are those described in detail herein. More preferred endothelin antagonists for use in the methods provided herein include sulfonamides disclosed in European Patent Application EP 702012; U.S. Patent Nos. 5,612,359 and 5,594,021 ; International Patent Application Publication Nos. WO 94/27979; WO 96/31492; WO 98/13366; and WO 98/49162. For example, among preferred endothelin antagonists are:
  • N-(4-chloro-3-methyl-5-isoxazolyl)-2- ⁇ [3,4-(methylenedioxy)-6-methylphenyl)- acetyl]-thiophene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[dI[1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mide, having the structure:
  • endothelin antagonists are useful for treating, preventing, or ameliorating one or more symptoms of disorders that are caused by endothelin activity or disorders in which endothelin activity is otherwise implicated.
  • endothelin-mediated disorders include, but are not limited to, menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre-eclampsia; and control and management of labor during pregnancy.
  • a medicament containing the compound is administered intravenously (IV), although treatment by local or topical administration may be tolerated in some instances.
  • the medicament containing the compound is injected into the circulatory system of a subject in order to deliver a dose to the targeted cells.
  • Targeting may be effected by linking the compound to a targeting agent specific for endothelin receptors, particularly endothelin-1 receptors. Dosages may be determined empirically, but will typically be in the range of about 0.01 mg to about 100 mg of the compound per kilogram of body weight as a daily dosage.
  • Step 1 Preparation of compound 1 :
  • Step 2A Preparation of compound 2.
  • Step 3 Preparation of compound 6.
  • Step 4B Preparation of compound 7 sodium salt.
  • 2-thiophenecarboxamide was prepared by the procedure of Example 1 except that 2- cyano-3,4,6-trimethylaniline (8) was substituted for 2-acetyl-4,6-dimethylaniline in Step 3.
  • Step 2 A Preparation of compound 11 : 3 ⁇ [(4-chloro-3-methyl-5- isoxazolyl)amino]sulfonyl ⁇ -N-methoxymethyl-2-thiophenecarboxylic acid methoxymethyl ester.
  • Compound 28 was prepared according to the procedure of Example 3 except that 5-amino-2,4,6-trimethylpyrimidine (27) was used in step 3 in the place of compound 12. Compound 28 was obtained as a white solid; mp 170-175 °C.
  • Compound 32 was prepared according to the procedure of Example 3 except that 2-cyano-3,4,6-trimethylaniline (31) was used in step 3 in the place of compound 12. Compound 32 was obtained as a white solid; mp 218-220 °C.
  • Compound 34 was prepared according to the procedure of Example 3 except that 2-chloro-4,6-dimethylaniline (33) was used in step 3 in the place of compound 12.
  • Compound 36 was prepared according to the procedure of Example 3 except that 4,6-diacetyl-3-hydroxy-2-propylaniline (35) was used in step 3 in the place of compound 12. Compound 36 was obtained as a white solid; mp 163-167 °C.
  • Compound 42 was prepared according to the procedure of Example 3 except that 2,4-dimethy)-6-(methylsulfonyl)aniline (41 ) was used in step 3 in the place of compound 12. Compound 42 was obtained as a white solid; mp 208-210 °C.
  • Compound 46 was prepared according to the procedure of Example 3 except that 2-(2-propylsulfonyl)-4,6-dimethylaniline (45) was used in step 3 in the place of compound 12. Compound 46 was obtained as a white solid; mp 190-192 °C.
  • Compound 48 was prepared according to the procedure of Example 3 except that 2,4-dimethyl-6-(propylsulfonyl)aniline (47) was used in step 3 in the place of compound 12. Compound 48 was obtained as a white solid; mp 152-155 °C.
  • Compound 52 was prepared according to the procedure of Example 3 except that 2,6-dimethyl-4-(1 ,3-oxazol-2-yl)aniline (51 ) was used in step 3 in the place of compound 12. Compound 52 was obtained as a white solid; mp 205-207 °C.
  • EXAMPLE 22 Method for testing for compounds that possess anti-laminitic activity
  • Compounds and compositions for use in the treatment, prevention, or amelioration of one or more symptoms of laminits can be and were identified by comparison with controls in foundered horses.
  • the horses are evaluated for lameness, hoof wall temperature.
  • Hoof wall temperature is used to index the digital perfusion in the experiment.
  • An increase in hoof wall temperature compared to control indicates increased digital blood flow, and that the ischemic crisis is not as severe in the developmental phase of the disorder.
  • Group A horses Eighteen healthy horses were used in the study. These horses were divided into Group A (ten horses) and Group B (eight horses). Group A horses served as placebo controls and Group B horses received treatment. All subjects used in the study were evaluated to ensure that digits were within normal limits (clinical evaluation and radiographs) and were trained to stand quietly in an instrumented stanchion containing force plates.
  • the experimental subjects were sex and age matched. Assignment to Group A or B was done randomly. Each pair was brought into the temperature (72 °F) and humidity (42%) controlled laboratory environment for a period of 24 hours. During this time, the horses were evaluated at 4-hour intervals to establish control data for each horse. At each 4-hour sampling period, the horses were brought into the measurement laboratory, which was immediately adjacent to and at the same environmental conditions as the stalls. Measurement parameters collected consisted of hoof wall temperature, mean % load, load distribution profile, and physical symptoms (presence of lameness). In addition, the horses were videotaped in their stalls during the entire 72 hours of the experiment. These tapes were reviewed to determine the horse's physical status and the amount of time that the horses were standing versus lying down.
  • the horses received a laminitis-inducing diet by nasogastric tube within 30 minutes of each other.
  • This diet is 85% cornstarch, 1 5% methyl-cellulose mix administered at 17.6 g/kg of body weight.
  • the horses were followed at 4-hour intervals using the same sampling protocol as described above.
  • the hoof wall temperature was plotted to determine the occurrence of a bilateral decrease in the hoof wall temperature relative to control temperature for each animal.
  • the temperature data was examined and separated into one of three patterns.
  • the first pattern reflected a mild, transient decrease in the hoof wall temperature that lasted less than 4 to 8 hours.
  • the second pattern was that of a decreased temperature of 4-5 °C that lasted less than 4 to 8 hours.
  • the third pattern was that of a decreased temperature of 4 to 5 °C that persisted for 10 to 12 hours.
  • the hoof wall temperature was used to index digital perfusion in this experiment, and served as the point in time when treatment with the endothelin antagonist was initiated, these three patterns index drug effectiveness in this regard.
  • the treated horses Group B
  • test compound as an antagonist or agonist of the biological tissue response of endothelin can also be assessed by measuring the effect on endothelin induced contraction of isolated rat thoracic aortic rings. The ability of the compounds to act as antagonists or agonists for
  • ET B receptors can be assessed by testing the ability of the compounds are to inhibit endothelin-1 induced prostacyclin release from cultured bovine aortic endothelial cells.
  • A. Endothelin binding inhibition - Binding Test #1 Inhibition of binding to ET A receptors

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Abstract

Pharmaceutical and veterinary uses of endothelin antagonists are provided. In particular, methods of treatment of laminitis, such as equine and bovine laminitis, by administration of one or more endothelin antagonists are provided. Methods of treatment, prevention, or amelioration of one or more symptoms of menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in women; pre-eclampsia; and control and management of labor during pregnancy by administration of endothelin antagonists are also provided.

Description

PHARMACEUTICAL AND VETERINARY USES OF ENDOTHELIN ANTAGONISTS
RELATED APPLICATIONS
For International purposes benefit of priority is claimed to U.S. provisional application No. 60/174,125, filed December 31 , 1999, to Thomas A. Brock and Patrick R. Ward, entitled "PHARMACEUTICAL AND VETERINARY USES OF ENDOTHELIN ANTAGONISTS". For U.S. purposes benefit of priority under 35 U.S.C. § 1 19(e) is claimed to U.S. provisional application No. 60/174,125. For U.S. purposes and where permitted, the above-referenced application is incorporated herein by reference in its entirety. FIELD OF THE INVENTION Provided herein are pharmaceutical and veterinary uses of endothelin antagonists. In particular, methods of treatment, prevention, or amelioration of one or more symptoms of equine or bovine laminitis by administration of endothelin antagonists are provided. Methods of treatment, prevention, or amelioration of one or more symptoms of menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre-eclampsia; and control and management of labor during pregnancy by administration of endothelin antagonists are also provided. BACKGROUND OF THE INVENTION Endothelin
The vascular endothelium releases a variety of vasoactive substances, including the endothelium-derived vasoconstrictor peptide, endothelin (ET) (see, e.g., Vanhoutte et al. (1986) Annual Rev. Phvsiol. 48: 307-320; Furchgott and Zawadski (1980) Nature 288: 373-376). Endothelin, which was originally identified in the culture supernatant of porcine aortic endothelial cells (see, Yanagisawa et a (1988) Nature 332: 41 1-415), is a potent twenty-one amino acid peptide vasoconstrictor. It is the most potent vasopressor known and is produced by numerous cell types, including the cells of the endothelium, trachea, kidney and brain. Endothelin is synthesized as a two hundred and three amino acid precursor preproendothelin that contains a signal sequence which is cleaved by an endogenous protease to produce a thirty-eight (human) or thirty-nine (porcine) amino acid peptide. This intermediate, referred to as big endothelin, is processed jn vivo to the mature biologically active form by a putative endothelin- converting enzyme (ECE) that appears to be a metal-dependent neutral protease (see, e.g., Kashiwabara et aL (1989) FEBS Lttrs. 247: 337-340). Cleavage is required for induction of physiological responses (see, e.g., von Geldern et aL (1991 ) Peptide Res. 4: 32-35). In porcine aortic endothelial cells, the thirty-nine amino acid intermediate, big endothelin, is hydrolyzed at the Trp21-Val22 bond to generate endothelin-1 and a C- terminal fragment. A similar cleavage occurs in human cells from a thirty-eight amino acid intermediate. Three distinct endothelin isopeptides, endothelin-1 , endothelin-2 and endothelin-3, that exhibit potent vasoconstrictor activity have been identified.
The family of three isopeptides endothelin-1 , endothelin-2 and endothelin-3 are encoded by a family of three genes (see, Inoue et aL (1989) Proc. Natl. Acad. Sci. USA 86: 2863-2867; see, also Saida et al. (1989U. Biol. Chem. 264: 14613-14616). The nucleotide sequences of the three human genes are highly conserved within the region encoding the mature 21 amino acid peptides and the C-terminal portions of the peptides are identical. Endothelin-2 is (Trp6,Leu7) endothelin-1 and endothelin-3 is (Thr2,Phe4,Thr5,Tyrβ,Lys7,Tyr14) endothelin-1 . These peptides are, thus, highly conserved at the C-terminal ends. Release of endothelins from cultured endothelial cells is modulated by a variety of chemical and physical stimuli and appears to be regulated at the level of transcription and/or translation. Expression of the gene encoding endothelin-1 is increased by chemical stimuli, including adrenaline, thrombin and Ca2+ ionophore. Endothelial cells appear to secrete short-lived endothelium-derived relaxing factors (EDRF), now known to be nitric oxide, when stimulated by vasoactive agents, such as acetylcholine and bradykinin. Endothelin-induced vasoconstriction is also attenuated by atrial natriuretic peptide (ANP). Laminitis Equine laminitis, which is sometimes referred to as foundering, is a common disorder that was recognized and described in the earliest books of veterinary medicine. Laminitis is an inflammation of the pedal laminae that form the supportive bond between the hoof and the third phalanx (see, Green, M. E., et aL (1991 ) Equine Medicine and Surgery, Fourth Edition, Vol. II, Colahan, P. T. et al. (Eds.), American Veterinary Publications, Inc., Chapter 12, pp. 1354-1358). Laminitis is further described as a disorder of the hoof whose cause is varied. It is a complex, multi-systemic disease affecting the digestive, cardiovascular, hemic, renal, endocrine, musculoskeletal, integumentary, and immune systems. It is characterized by multi-systemic aberrations that ultimately result in reduced capillary perfusion, ischemia, and necrosis of the laminae. These results are accompanied by pain and loss of supportive function. See, generally, equine laminitis: Katwa et aL (1999) Equine Vet. J. 31 (3):243-247; MacEachem et a (1997) Res. Vet. Sci. 62(2):147-1 52; Benamou et aL (1998) Pulm. PHarm. Ther. 1 1 :231 -235; bovine laminitis: Corder et al. (1999) J. Cardiovasc. Pharmacol. 33(4):671 -677; Desmarets et al. (1999) Biochem. Biophys. Res. Commun. 256(2):357-36Q; Acosta et al (1998) Biol. Reprod. 59(2):437-443.
Acute laminitis is described as comprising the events leading up to and the onset of lameness. Acute laminitis can progress to the chronic stage. The chronic stage ensues after persistent lameness (greater than 48 hours), or when the distal phalanx deviates detectably. Chronic laminitis is a consequence of some degree of loss of integrity of the supporting digital laminae. In the chronic phase, the horse assumes a recumbent position in which most of the weight is placed on the hind limbs and little weight bearing pressure is exerted on the forelimbs.
There are reports of evidence that equine laminitis is caused by ingestion of too much grain; colic; retained placenta; exhaustion; ingestion of black walnut shavings; ingestion of too rich grass; excessive concussion, and/or excessive cold water. Despite the gathering of voluminous information over a period exceeding 300 years, equine laminitis still remains incompletely understood and appears to be multifactorial (see, e.g., Hinckley, et aL (1994) J. Endocrinol. 143:P103, which illustrates the complexity of the aetiology of laminitis.
While it is possible that an equine with this condition can recover without intervention treatment, during the course of the disease there is substantial pain, recumbency, hoof wall deformation and even sloughing of the hooves. Several symptoms are displayed, including: a bounding digital pulse, warm feet, an abnormal gait, a shifting of weight, or some combination of some or all of these. If the animal does not recover, after the onset of lameness, the laminae deteriorate, the animal's feet are extremely painful, and the coffin bone becomes displaced.
Current therapies for equine laminitis include treatment with nitroglycerin, applied transdermally, and isoxsuprine, administered orally; and/or an anticoagulant, such as heparin, aspirin and trental (pentoxifylline) and others (see, U.S. Patent No.
5,891 ,472; see also, Elliott, J. (1996) Equine Vet. J. 28(1 ): 1 -2). All current therapies suffer from one or more drawbacks, including difficulty in the mode of administration of the active drug, lack of effectiveness, lack of compliance and lack of simplicity in the proposed treatment regimen. Another treatment for equine laminitis involves use of intravenously administered L-Arg and topically applied nitroglycerin (glyceryl trinitrate or GTN) (see, Hinckley et aL, (1996) Equine Vet. J. 28(1 ):17-28). The L-Arg is administered i.v. as a 10% aqueous solution, while the GTN is provided as a 2% ointment through a patch that is positioned, using adhesive tape, over digital vessels. In particular, a laminitic pony, weighing 250 kg, received a total dose of 120 g of L-Arg or 0.48 g/kg bwt at a rate of approximately 40 mL/min (16 mg/kg bwt/min) for 30 min. The GTN patches were also applied once daily to three limbs only, 12 hours after the L-Arg infusion. Drops in heart rates were observed, including hypotension and cardiac arrhythmia, with the i.v. infusion. Some ponies showed signs of pain, sweating and shivering. The topical application of GTN patches appeared to improve the lameness of some of the treated ponies. No improvement was observed in others. Thus, it is clear that L-Arg, given intravenously, is not a particularly effective treatment.
Thus, there is a need for an effective treatment of laminitis, particularly equine or bovine laminitis. Therefore, it is an object herein to provide methods of treating, preventing, or ameliorating one or more symptoms of laminitis, particularly equine or bovine laminitis, more particularly equine laminitis. SUMMARY OF THE INVENTION
Pharmaceutical and veterinary uses of compounds that modulate the interaction of an endothelin peptide with an endothelin receptor are provided. In certain embodiments, veterinary uses of endothelin antagonists are provided herein. In particular, methods of treatment, prevention, or amelioration of one or more symptoms of laminitis, which afflict animals with hooves, particularly equine or bovine laminitis, using endothelin antagonists are provided. In other embodiments, pharmaceutical uses of endothelin antagonists are provided.
The pharmaceutical and veterinary methods provided herein use any compound capable of inhibiting the activity of endothelin peptides; or use any compound that is an endothelin receptor antagonist. In particular, methods of using endothelin antagonists, particularly sulfonamide compounds, for the treatment of disorders involving nitric oxide, such as equine laminitis, are provided. Any compound, particularly any sulfonamide, known to those of skill in the art to have endothelin antagonist activity, particularly ETA antagonist activity, is contemplated for use herein. Numerous such endothelin antagonists are known to those of skill in the art (see, e.g., U.S. Patent Nos. 6,133,442, 6,133,263, 6, 107,320, 6,083,955; 6,083,951 ; 6,080,774; 6,063,91 1 ; 6,060,475; 6,043,265; 6,043,241; 6,030,991; 6,017,951; 6,017,916; 6,013,655 6,004,965; 5,965,732; 5,962,682; 5,958,968; 5,948,754; 5,945,448; 5,942,516 5,929,116; 5,929,106; 5,925,731; 5,922,759; 5,922,681; 5,891,892; 5,888,972 5,883,092; 5,883,090; 5,883,075; 5,866,568; 5,861,401; 5,856,484; 5,840,722 5,837,708; 5,834,469; 5,821,256; 5,817,693; 5,817,683; 5,817,653; 5,811,444 5,811,416; Re35,886; 5,780,498; 5,773,444; 5,773,414; 5,767,310; 5,767,144; 5,753,619; 5,739,333; 5,736,564; 5,731,434; 5,731,321; 5,728,706; 5,726,194, 5,719,183; 5,719,182; 5,716,985; 5,716,984; 5,714,479; 5,703,106; 5,700,807 5,691,373; 5,691,315; 5,688,974; 5,688,499; 5,686,481; 5,686,478; 5,668,176 5,668,137; 5,663,296; 5,658,943; 5,658,902; 5,656,604; 5,654,309; 5,641,793 5,641,752; 5,622,971; 5,616,684; 5,614,498; 5,614,497; 5,610,177; 5,608,078 5,599,811; 5,591,728; 5,939,446; 5,916,907; 5,856,507; 5,846,990; 5,846,985 5,827,869; 5,780,473; 5,760,038; 5,378,715; 5,514,696; 5,420,123; 5,612,359 5,543,521; 5,464,853; 5,514,691; 5,292,740; 5,334,598; 5,571,821; 5,389,620 5,541,186; 5,559,105; and 5,482,960; European Patent Application Nos. EP 959073; EP 959072; EP 929529; EP 925297; EP 924207; EP 916679; EP 915699; EP 906108 EP 904077; EP 901470; EP 888340; EP 888299; EP 888123; EP 885890; EP 885219 EP 885217; EP 885215; EP 882039; EP 882030; EP 874829; EP 873334; EP 868180 EP 863898; EP 863896; EP 861247; EP 857718; EP 854721; EP 852584; EP 852226 EP 846119; EP 844884; EP 843551 ; EP 841926; EP 841925; EP 841916; EP 838223 EP 832082; EP 830143; EP 821670; EP 817782; EP 811001; EP 805802; EP801062; EP 799221; EP 799209; EP 799206; EP 792265; EP 790993; EP 778833; EP 776324 EP 774965; EP 768878; EP 768304; EP 767801; EP 767794; EP 766684; EP 763035 EP 758650; EP 757039; EP 755934; EP 753004; EP 752986; EP 898571; EP 889894 EP 870764; EP 876364; EP 819125; EP 528312; EP 552489; EP 499266; EP 457195 EP 460679; EP 626174; EP 558258; EP 569193; EP 768305; EP 904077; EP 921800 EP 702012; EP 601386; EP 633259; EP 510526; EP 526708; EP 617001; EP 496452 EP 658548; EP 555537; EP 628569; EP 552417; EP 436189; EP 713875; EP 733626 EP 682016; and EP 743307; British Patent Application Nos. GB 2276383; GB 2275926; GB 2266890; GB 2277446; and GB 2295616; German Patent Application No. DE 4341663; Japanese Patent Application Nos.4-288099; 5-178890; 5-279390; JP 11043482A; JP 10306087A; JP 10251160A; JP 10226649A; JP 10087695A; JP 10007574A; JP 09194500A; JP 09132568A; JP 09110873A; JP 09087291A; JP 09071570A; JP 09059261A; JP 09059160A; JP 6256261; JP 6122625; JP 7330622; JP 7133254; JP 8059635; JP 7316188; and JP 7258098; International Patent Application Publication Nos. WO 99/44988; WO 99/42453; WO 99/36408; WO
99/29685 WO 99/27934 WO 99/25701 WO 99/23078 WO 99/20623; WO 99/19346 WO 99/19320 WO 99/16445 WO 99/12916 WO 99/1 1629; WO 99/06397 WO 99/05132 WO 99/02519 WO 98/58916 WO 98/57938; WO 98/57933 WO 98/41521 WO 98/41515 WO 98/41206 WO 98/27091 ; WO 98/27070 WO 98/09953 WO 98/08836 WO 97/47595 WO 97/43260; WO 97/37987 WO 97/37986 WO 97/37985 WO 97/33608 WO 97/30996; WO 97/30982 WO 97/30978 WO 97/30046 WO 97/30045 WO 97/28160; WO 97/28159 WO 97/28158 WO 97/28154 WO 97/22341 WO 97/21700; WO 97/19077 WO 97/17340 WO 97/17339 WO 97/17071 WO 97/12878; WO 97/1 1961 WO 97/1 1960 WO 97/1 1942 WO 97/10214 WO 97/08169; WO 97/071 19 WO 97/04781 WO 97/04774 WO 97/04773 WO 97/04772; WO 97/04769 WO 97/02265 WO 91 /13089 WO 92/12991 WO 97/39000; WO 92/20706 WO 93/13218 WO 93/17701 WO 98/33780 WO 98/04260; WO 97/33886 WO 97/29748 WO 97/29747 WO 94/27979 WO 97/25321 ; WO 97/35864 WO 96/06095 WO 95/08550 WO 95/26716 WO 96/1 1914; WO 95/26360 WO 93/25580 WO 93/23404 WO 96/04905 WO 94/21259; WO 95/03044 WO 95/03295 WO 95/08989 WO 94/21 590 WO 94/21259; WO 95/13262 WO 96/12706 WO 94/24084 WO 94/25013 WO 95/04534; WO 95/04530 WO 94/02474 WO 94/14434 WO 96/07653 WO 93/08799; WO 95/05376 WO 95/1261 1 WO 95/15963 WO 95/1 5944 WO 95/05374; WO 95/05372 WO 94/03483 WO 93/21219 WO 96/1 1927 WO 96/23773; WO 96/33170 WO 96/15109 WO 96/33190 WO 96/19459 WO 96/19455; WO 95/26360 WO 96/20177 WO 96/08486 WO 96/09818 WO 96/08487; WO 96/04905 WO 96/22978 WO 96/08483 WO 95/33748 WO 96/30358; WO 95/35107 WO 95/26957 WO 95/33752; and WO 96/31492; commonly owned U.S. Patent application Serial Nos. 08/721 ,183; 08/938,325; 08/938,444; 08/730,633; 09/148,643; 09/274,280; and 08/913,331 ; such as the following compounds described in the recited documents: BQ-123 (Ihara, M., et al.. Biological Profiles of Highly Potent Novel Endothelin Antagonists Selective for the ETA Receptor, Life Sciences, 50(4):247-255 (1992)); PD 156707 (Reynolds, E., et al., Pharmacological Characterization of PD 1 56707, an Orally Active ETA Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 273(3):1410-1417 (1995)); L- 754,142 (Williams, D. L., et al., Pharmacology of L-754,142, a Highly Potent, Orally Active, Nonpeptidyl Endothelin Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 275(3):1518-1526 (1995)); SB 209670 (Ohlstein, E. H., et al., SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist, Proc. Natl. Acad. Sci. USA, 57:8052-8056 (1994)); SB 217242 (Ohlstein, E. H., et al., Nonpeptide Endothelin Receptor Antagonists. V Pharmacological Characterization of SB 217242, A Potent and Highly Bioavailable Endothelin Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 276(2):609-61 5 (1996)); A-1 27722 (Opgenorth, T. J., et al., Pharmacological Characterization of A-127722: An Orally Active and Highly Potent ETA-Selective Receptor Antagonist, The Journal of
Pharmacology and Experimental Therapeutics, 276(2) :473-481 (1996)); TAK-044 (Masuda, Y., et al., Receptor Binding and Antagonist Properties of a Novel Endothelin Receptor Antagonist, TAK-044 {Cyclo[D-σ-Aspartyl-3-[(4-Phenylpiperazin-1 -yl)Carbonyl]- L-Alanyl-L-σ-Aspartyl-D-2-(2-Thienyl)Glycyl-L-Leucyl-D-Tryptophyl)Disodium Salt}, in Human EndothelinA and EndothelinB Receptors, The Journal of Pharmacology and
Experimental Therapeutics, 27S(2):675-685 (1996)); bosentan (Ro 47-0203, Clozel, M., et al., Pharmacological Characterization of Bosentan, A New Potent Orally Active Nonpeptide Endothelin Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 270(1 ):228-235 (1994)), and many are described herein. Also of interest are any pharmaceutically or veterinarily acceptable derivatives, including salts, esters, acids and bases, solvates, hydrates and prodrugs of the compounds. Preferred are pharmaceutically or vetόrinarily acceptable salts, including, but not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para- chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, alkali metal salts, such as but not limited to lithium, potassium and sodium, alkali earth metal salts, such as but not limited to barium, calcium and magnesium, transition metal salts, such as but not limited to, zinc and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate, preferably sodium salts, more preferably the sodium salt, and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates, salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates. Alkali metal salts, particularly sodium salts, are preferred herein. Most preferred salts are sodium salts.
Pharmaceutical and veterinary formulations for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein or pharmaceutically or veterinarily acceptable derivatives thereof, preferably salts, more preferably sodium salts, including but not limited to sodium salts and sodium hydrogen phosphate salts, most preferably the sodium salt, thereof that deliver amounts effective for the treatment, prevention, or amelioration of one or more symptoms of laminitis, particularly equine or bovine laminitis; menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre-eclampsia; and control and management of labor during pregnancy by administration of endothelin antagonists are also provided. The formulations are compositions suitable for administration by any desiredabnormal clotting patterns, urogenital discomfort and increased incidence of route and include solutions, suspensions, emulsions, tablets, dispersible tablets, pills, cardiovascular disease, and other disorders associated with the reduction in ovarian capsules, powders, dry powders for inhalation, sustained release formulations, aerosolsfunction in middle- aged women; pre-eclampsia; and control and management of labor for nasal and respiratory delivery, patches for transdermal delivery and any otherduring pregnancy are also provided, suitable route. The compositions should be suitable for oral administration, parenteral administration by injection, including subcutaneously, intramuscularly or intravenously as an injectable aqueous or oily solution or emulsion, transdermal administration and other selected routes.
Methods for treatment, prevention, or amelioration of one or more symptoms of endothelin-mediated disorders, including, but not limited to, laminitis, particularly equine or bovine laminitis, more particularly equine laminitis; menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease associated with menopause, and other disorders associated with the reduction in ovarian function in middle-aged and older women; pre-eclampsia; and control and management of labor during pregnancy are provided. In particular, methods of treating laminitis by administering effective amounts of the compounds, or veterinarily acceptable derivatives thereof, are provided. In particular, methods for treating laminitis, particularly equine or bovine laminitis, more particularly equine laminitis, by administering effective amounts of one or more of the compounds provided herein in veterinarily acceptable carriers are provided. Preferred methods of treatment are methods for treatment of equine laminitis.
Also provided are methods of treatment, prevention, or amelioration of one or more symptoms of menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged and older women; pre- eclampsia; and control and management of labor during pregnancy.
Of the methods of treatment, more preferred are those in which the formulations contain at least one compound that inhibits the interaction of endothelin-1 with ETA receptors at an IC50 of less than about 10 μM, and preferably less than about 5 μM, more preferably less than about 1 μM, even more preferably less than 0.1 μM, and most preferably less than 0.05 μM Other preferred methods are those in which the formulations contain pharmaceutically or veterinarily acceptable derivatives, preferably salts, of one or more compounds that is (are) ETA selective, or pharmaceutically or veterinarily acceptable derivatives, preferably salts, of one or more compounds that is (are) ETB selective.
In practicing the methods, effective amounts of formulations containing therapeutically effective concentrations of the compounds formulated for oral, intravenous, local and topical application for the treatment of laminitis, particularly equine or bovine laminitis, more particularly equine laminitis; menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre-eclampsia; and control and management of labor during pregnancy are provided are administered to an individual exhibiting the symptoms of one or more of these disorders. The amounts are effective to ameliorate or eliminate one or more symptoms of the disorders. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. Where permitted, all patents, published patent applications, patent applications and publications referred to throughout the disclosure are incorporated by reference.
As used herein, "laminitis" or "foundering" refers to an inflammation of the pedal laminae that form the supportive bond between the hoof and the third phalanx. Laminitis is characterized by multi-systemic aberrations that ultimately result in reduced capillary perfusion, ischemia, and necrosis of the laminae, accompanied by pain, loss of supportive function, and ultimately lameness.
As used herein, endothelin (ET) peptides include peptides that have substantially the amino acid sequence of endothelin-1 , endothelin-2 or endothelin-3 and that act as potent endogenous vasoconstrictor peptides.
As used herein, an endothelin-mediated condition is a condition that is caused by abnormal endothelin activity or one in which compounds that inhibit endothelin activity have therapeutic use. Such diseases include, but are not limited to hypertension, cardiovascular disease, asthma, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, gastroenteric disease, renal failure, pulmonary hypertension, endotoxin shock, anaphylactic shock, hemorrhagic shock, climacteric disorders, menopause, hot flushes or flashes, osteoporosis, preterm labor, pre-eclampsia, eclampsia and metabolic bone disorders. Endothelin-mediated conditions also include conditions that result from therapy with agents, such as erythropoietin and immunosuppressants, that elevate endothelin levels.
As used herein an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
As used herein, an endothelin agonist is a compound that potentiates or exhibits a biological activity associated with or possessed by an endothelin peptide. As used herein, an endothelin antagonist is a compound, such as a drug or an antibody, that inhibits endothelin-stimulated vasoconstriction and contraction and other endothelin-mediated physiological responses. The antagonist may act by interfering with the interaction of the endothelin with an endothelin-specific receptor or by interfering with the physiological response to or bioactivity of an endothelin isopeptide, such as vasoconstriction. Thus, as used herein, an endothelin antagonist interferes with endothelin-stimulated vasoconstriction or other response or interferes with the interaction of an endothelin with an endothelin-specific receptor, such as ETA receptors, as assessed by assays known to those of skill in the art. The effectiveness of potential agonists and antagonists can be assessed using methods known to those of skill in the art. For example, endothelin agonist activity can be identified by its ability to stimulate vasoconstriction of isolated rat thoracic aorta or portal vein ring segments (Borges et aL (1989) "Tissue selectivity of endothelin" Eur. J. Pharmacol. 165: 223-230). Endothelin antagonist activity can be assessed by the ability to interfere with endothelin-induced vasoconstriction. Exemplary assays are set forth in the EXAMPLES. As noted above, the preferred IC50 concentration ranges are set forth with reference to assays in which the test compound is incubated with the ET receptor-bearing cells at 4° C. Data presented for assays in which the incubation step is performed at the less preferred 24° C are identified. It is understood that for purposes of comparison, these concentrations are somewhat higher than the concentrations determined at 4° C.
As used herein, the biological activity or bioactivity of endothelin includes any activity induced, potentiated or influenced by endothelin vivo. It also includes the ability to bind to particular receptors and to induce a functional response, such as vasoconstriction. It may be assessed by vivo assays or by jn vitro assays, such as those exemplified herein. The relevant activities include, but are not limited to, vasoconstriction, vasorelaxation and bronchodilation. For example, ETB receptors appear to be expressed in vascular endothelial cells and may mediate vasodilation and other such responses; whereas ETA receptors, which are endothelin-1 -specific, occur on smooth muscle and are linked to vasoconstriction Any assay known to those of skill in the art to measure or detect such activity may be used to assess such activity (see, e.g.. Spokes et aL (1989) J. Cardiovasc. Pharmacol. 13(Suppl. 5):S191 -S192; Spinella et aL (1991 ) Proc. Natl. Acad. Sci. USA 88: 7443-7446; Cardell et aL (1991 ) Neurochem. Int. 18:571 -574); and the Examples herein). As used herein, bioavailability refers to the rate and extent of absorption. Methods for determining bioavailability are well known to those of skill in the art. For example, bioavailability of any of the compounds described herein can be determined empirically by administration of the compound to an animal, followed by taking blood samples over time and measuring the blood concentration of the compound. ]n vivo half life (t1/2) is defined as the time it takes for the concentration of the compound in the blood to be reduced by one-half. Estimations of the area under the curve for intravenous administration can be used to estimate the area under the curve for oral administration, yielding bioavailability data. See, e.g., Milo Gibal (1991 ) Biopharmaceutics and Pharmacology, 4th edition (Lea and Sediger).
As used herein, efficacy refers to the maximal effect that can be produced by a compound. Efficacy can be determined by methods known to those of skill in the art. For example, it can be determined by the properties of the compound and its receptor- effector system and is reflected in the plateau of the concentration-effect curve. ]n vivo efficacy refers to efficacy which is determined in an animal model. For example, in vivo efficacy of the compounds described herein can be determined by amelioration of hypoxia-induced pulmonary hypertension in rat. In this context, in vivo efficacy refers to the ability of a compound to restore an elevated pulmonary artery pressure to a normal value. See, e^a-., DiCarlo et aL (1995) Am. J. Physiol. 269:L690-L697. As used herein, the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as binding of endothelin to tissue receptors, in an assay that measures such response.
As used herein, EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
As used herein a sulfonamide that is ETA selective refers to sulfonamides that exhibit an IC50 that is at least about 10-fold lower with respect to ETA receptors than ETB receptors. As used herein, a sulfonamide that is ETB selective refers to sulfonamides that exhibit an ICS0 that is at least about 0-fold lower with respect to ETB receptors than ETA receptors.
As used herein, pharmaceutically or veterinarily-acceptable salts, esters, hydrates, solvates or other derivatives of the compounds include any such salts, esters and other derivatives that may be prepared by those of skill in this art using known methods for such derivatization and that produce compounds that may be administered to animals or humans without substantial toxic effects and that either are pharmaceutically or veterinarily active or are prodrugs. Pharmaceutically and veterinarily-acceptable salts include, but are not limited to, salts of alkali metals and alkaline earth metals, including but not limited to sodium salts, potassium salts, lithium salts, calcium salts and magnesium salts; transition metal salts, such as zinc salts, copper salts and aluminum salts; polycationic counter ion salts, such as but not limited ammonium and substituted ammonium salts and organic amine salts, such as hydroxyalkylamines and alkylamines; salts of mineral acids, such as but not limited to hydrochlorides and sulfates, salts of organic acids, such as but not limited acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrate, valerate and fumarates. Also contemplated herein are the corresponding esters.
Preferred pharmaceutically or veterinarily-acceptable salts include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin-1 '- ylmethylbenzimidazoie, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, aluminum, calcium, lithium, magnesium, potassium, sodium hydrogen phosphate, disodium phosphate, sodium, zinc, barium, gold, silver and bismuth salts. Sodium salts, particularly the sodium salt of each of the compound, are most preferred herein.
As used herein, reference to "sodium salts" refers to salts of any sodium compounds in which the counter ion includes Na+ and can include other ions, such as HP04 2"; reference to a "sodium salt" (rather than sodium salts) refers specifically to a salt in which Na+ is the counter ion.
As used herein, treatment means any manner in which the symptoms of a conditions, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical or veterinary use of the compositions herein, such as use as contraceptive agents.
As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical or veterinary composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition. As used herein, nitric oxide "donors" or "precursors" refer to compounds such as sodium nitroprusside, nitroglycerin, sodium nitrite, hydroxylamine, sodium azide and other nitrogen-containing compounds that function as smooth muscle relaxing agents. The activity of a variety of smooth muscle relaxing agents, including sodium nitroprusside, nitroglycerin and sodium nitrite, may be related to their ability to increase tissue levels of cyclic guanosine monophosphate (cGMP) or to the formation of nitric oxide (NO) (see, Katsuki, et aL (1977) J. Cyclic Nucleotide Res. 3:25-35). Other nitrogen-containing compounds may also function similarly, including hydroxylamine or sodium azide, and also may possess vasodilatory properties. As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound. As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon ]n vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmaceutical or veterinary activity of such compounds, compositions and mixtures. As used herein, increased stability of a formulation means that the percent of active component present in the formulation, as determined by assays known to those of skill in the art, such as high performance liquid chromatography, gas chromatography, and the like, at a given period of time following preparation of the formulation is significantly higher than the percent of active component present in another formulation at the same period of time following preparation of the formulation. In this case, the former formulation is said to possess increased stability relative to the latter formulation.
As used herein, a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically, veterinarily or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically or veterinarily active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically or veterinarily active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). For example, succinyl-sulfathiazole is a prodrug of 4-amino-N-(2- thiazolyDbenzenesulfonamide (sulfathiazole) that exhibits altered transport characteristics.
As used herein, acid isostere means a group that is significantly ionized at physiological pH. Examples of suitable acid isosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl or heteroarylsulfonylcarbamoyl.
As used herein, halo or halide refers to the halogen atoms; F, Cl, Br and I.
As used herein, pseudohalides are compounds that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides (X", in which X is a halogen, such as Cl or Br). Pseudohalides include, but are not limited to cyanide, cyanate, thiocyanate, selenocyanate and azide.
As used herein, haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1 -chloro-2-f luoroethyl and the like.
As used herein, alkyl means an aliphatic hydrocarbon group that is a straight or branched chain preferably having about 1 to 12 carbon atoms in the chain. Preferred alkyl groups are loweralkyl groups which are alkyls containing 1 to about 6 carbon atoms in the chain. Branched means that one or more loweralkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group may be unsubstituted or independently substituted by one or more groups, such as, but not limited to: halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino and imino.
Exemplary alkyl groups include methyl, ethyl, propyl, carboxymethyl, carboxyethyl, carboxypropyl, ethanesulfinic acid and ethane sulfonic acid.
As used herein the term lower describes alkyl, alkenyl and alkynyl groups containing about 6 carbon atoms or fewer. It is also used to describe aryl groups or heteroaryl groups that contain 6 or fewer atoms in the ring. Loweralkyl, lower alkenyl, and lower alkynyl refer to carbon chains having less than about 6 carbons. In preferred embodiments of the compounds provided herein that include alkyl, alkenyl, or alkynyl portions include loweralkyl, lower alkenyl, and lower alkynyl portions. As used herein, alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chained having from about 2 to about 10 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more loweralkyl or lower alkenyl groups are attached to a linear alkenyl chain. The alkenyl group may be unsubstituted or independently substituted by one or more groups, such as halo, carboxy, for yl, sulfo, sulfino, carbamoyl, amino and imino. Exemplary alkenyl groups include ethenyl, propenyl, carboxyethenyl, carboxypropenyl, sulfinoethenyl and sulfonoethenyl.
As used herein, alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to 10 carbon atoms in the chain. Branched means that one or more loweralkyl, alkenyl or alkynyl groups are attached to a linear alkynyl chain. An exemplary alkynyl group is ethynyl.
As used herein, aryl means an aromatic monocyclic or multicyclic hydrocarbon ring system containing from 3 to 15 or 16 carbon atoms, preferably from 5 to 10. Aryl groups include, but are not limited to groups, such as phenyl, substituted phenyl, naphthyl, substituted naphthyl, in which the substituent is loweralkyl, halogen, or lower alkoxy. Preferred aryl groups are lower aryl groups that contain less than 7 carbons in the ring structure. As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. are used as is generally understood by those of skill in this art. For example, as used herein alkyl refers to saturated carbon chains that contain one or more carbons; the chains may be straight or branched or include cyclic portions or be cyclic. As used herein, alicyclic refers to aryl groups that are cyclic. As used herein, cycloalkyl refers to saturated cyclic carbon chains; cycloalkenyl and cycloalkynyl refer to cyclic carbon chains that include at least one unsaturated double or triple bond, respectively. The cyclic portions of the carbon chains may include one ring or two or more fused rings. As used herein, cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl or cyclohexenyl; preferred is cyclohexenyl. An exemplary multicyclic cycloalkenyl ring is norbornylenyl. The cycloalkenyl group may be independently substituted by one or more halo or alkyl.
As used herein, "haloalkyl" refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1 -chloro-2-fluoroethyl and the like. As used herein, "haloalkoxy" refers to RO- in which R is a haloalkyl group.
As used herein, "carboxamide" refers to groups of formula RpCONH2 in which R is selected from alkyl or aryl, preferably loweralkyl or lower aryl and p is 0 or 1 .
As used herein, "alkylaminocarbonyl" refers to -C(0)NHR in which R is hydrogen, alkyl, preferably loweralkyl or aryl, preferably lower aryl. As used herein "dialkylaminocarbonyl" as used herein refers to -C(0)NR'R in which R' and R are independently selected from alkyl or aryl, preferably loweralkyl or loweraryl; "carboxamide" refers to. groups of formula NR'COR.
As used herein, "alkoxycarbonyl" as used herein refers to -C(0)0R in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl. As used herein, "alkoxy" and "thioalkoxy" refer to RO- and RS-, in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.
As used herein, "haloalkoxy" refers to RO- in which R is a haloalkyl group.
As used herein, "aminocarbonyl" refers to -C(0)NH2-
As used herein, cycloalkyl refers to saturated cyclic carbon chains; cycloalkyenyl and cycloalkynyl refer to cyclic carbon chains that include at least one unsaturated triple bond. The cyclic portions of the carbon chains may include one ring or two or more fused rings.
As used herein, alkylenedioxy means an -O-alkyl-0- group in which the alkyl group is as previously described. A replacement analog of alkylenedioxy means an alkylenedioxy in which one or both of the oxygen atoms is replaced by a similar behaving atom or group of atoms such as, S, N, NH, Se. An exemplary replacement alkylenedioxy group is ethylenebis(sulfandiyl). Alkylenethioxyoxy is — S-alkylene-O— , — O-alkylene-S— and alkylenedithioxy is — S-alkylene-S — . As used herein, heteroaryl means an aromatic monocyclic or fused ring system in which one or more of the carbon atoms in the ring system is(are) replaced by an element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred cyclic groups contain one or two fused rings and include from about 3 to about 7 members in each ring. Similar to "aryl groups", the heteroaryl groups may be unsubstituted or substituted by one or more substituents. Exemplary heteroaryl groups include pyrazinyl, pyrazolyl, tetrazolyl, furanyl, (2- or 3-)thienyl, (2-,3- or 4-)pyridyl, imidazoyl, pyrimidinyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl, isoquinolinyl, oxazolyl and 2,1 ,3- oxadiazolyl. Preferred heteroaryl groups include 5 to 6-membered nitrogen-containing rings, such as pyrimidinyl.
As used herein, alkoxycarbonyl means an alkyl-O-CO- group. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
As used herein, carbamoyl means -CONH2. As with all groups described herein, these groups may be unsubstituted or substituted. Substituted carbamoyl includes groups such as -CONY2Y3 in which Y2 and Y3 are independently hydrogen, alkyl, cyano(loweralkyl), aryalkyl, heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substituted loweralkyl), carboxy(carboxy substituted loweralkyl), carboxy(hydroxy substituted loweralkyl), carboxyfheteroaryl substituted loweralkyl), carbamoyl(loweralkyl), alkoxycarbonyl (loweralkyl) or alkoxycarbonyl (aryl substituted loweralkyl), provided that only one of Y2 and Y3 may be hydrogen and when one of Y2 and Y3 is carboxy(loweralkyl), carboxy(aryl substituted loweralkyl), carbamoyl(loweralkyl), alkoxycarbonyl(loweralkyl) or alkoxycarbonyl(aryl substituted loweralkyl) then the other of Y2 and Y3 is hydrogen or alkyl. Preferred for Y2 and Y3 are independently hydrogen, alkyl, cyano(loweralkyl), aryalkyl, heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substituted loweralkyl) and carbamoyl(loweralkyl).
As used herein, any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5- methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N- (4-halo-3-methyl-5-isoxazoiyl), N-(4,5-dimethyl-3-isoxazolyl) derivative thereof refers to compounds in which Ar2 is the same as the compound specifically set forth, but Ar1 is N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5- isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl), or N-(4,5- dimethyl-3-isoxazolyl) in which halo is any halide, preferably Cl or Br.
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. 1 1 :942-944). A. Nitric oxide (NO) and endothelin
NO, formerly known as endothelium derived relaxing factor, is produced continuously by the lining of blood vessels as a result of the action of an enzyme present in the endothelial cells, endothelial nitric oxide synthase or eNOS. It is thought that eNOS is activated by a rise in intracellular calcium concentration, catalyzing the conversion of L-Arg to NO and L-citrulline. The nitric oxide passes through biological membranes, binds to haem iron in the soluble enzyme guanylate cyciase (GC). The activity of GC is thus stimulated, cyclic guanosine monophosphate concentrations increase and vascular smooth muscle tone is reduced. It has been shown that vascular endothelial cells synthesize nitric oxide from L-arginine (L-Arg) but not D-arginine (see, Palmer, et aL (1988) Nature 333:664-666). Release of NO from endothelial cells induced by bradykinin and the calcium ionophore A23187 is reversibly enhanced by infusions of L-Arg or L-citrulline.
The production and release of endothelin from the endothelium is stimulated by angiotensin II, vasopressin, endotoxin, cyclosporine and other factors (see, Brooks et al. (1991 ) Eur. J. Pharm. 194:1 15-1 17), and is inhibited by nitric oxide, which was also known as endothelin-derived releasing factor. Hence there appears to be an association between endothelin production and nitric oxide expression.
By virtue of this relationship, as described herein, compounds that modulate the activity, particularly antagonize, endothelin, can be used for treatment of disorders in which NO or related factors is involved. Laminitis As described herein, methods for treatment of laminitis are provided herein. The methods use endothelin antagonists, particularly sulfonamide compounds and related compounds. As discussed, equine laminitis is has been treated with nitric oxide (NO) NO donors, and a non-steroidal anti-inflammatory drug (NSAID) (see, U.S. Patent No. 5,891 ,472; see also, Elliott, J. (1996) Equine Vet. J. 28(1 ):1 -2). Menopause and Climacteric disorders
Nitric oxide synthesis and the nitric oxide effector system (cGMP-dependent relation mechanism) are thought to be regulated by steroid hormones. There is an increase in cardiovascular diseases in women following menopause, which may be related to the decrease in sex steroids and an alteration in nitric oxide production. Female steroid hormones have been shown to modulate endothelium-dependent relaxation of vascular smooth muscle by nitric oxide. Estradiol treatment of rats causes increased nitric oxide production by vascular tissues, whereas progesterone counteracts this phenomenon (see, e.g., U.S. Patent Nos. 5,906,987, 5,958,878 and 5,898,038). It is also known that pregnancy is associated with an increase in cardiac output and a decrease in the resistance of virtually all the vascular beds in the body. Although the mechanism of this phenomenon is not known, it could be associated with changed in nitric oxide production or effects as a result of elevated steroid hormone levels. One important observation with regard to the above mechanism is that antiprogestins (RU 486) elevate blood pressure in animals and they produce hot flushes or flashes in humans, both males and females. The hot flushes or flashes may be mediated by the steroid action on the release of nitric oxide. Hot flushes or flashes are a primary symptom in menopausal and postmenopausal women and they are relieved by both estrogen and progesterone. Another symptom of climacterium in men and women is osteoporosis. There is also growing evidence that nitric oxide mediates steroid (estrogen and/or progestin) effects on bones. There is a need for treatments for climacterium, both male and female, that alleviate the symptoms of progression of the disorders. There is also an increasing need for treatments of menopause and other disorders specific to reduction in hormone levels in postmenopausal women.
Control and management of labor during pregnancy
Spontaneous preterm labor during pregnancy remains an increasing problem confronting the medical community. Preterm labor, whether occurring spontaneously or the one which invariably follows any significant transuterine fetal manipulation such as needle puncture, fetoscopy, or hysterotomy for fetal surgery, presents a serious problem and is a limiting factor for all types of fetal intervention. The severe forms of spontaneous preterm labor or labor induced by an incision in the gravid uterus for open fetal surgery is resistant to all known forms of tocolysis. The management of preterm labor after fetal surgery is particularly difficult and dangerous for mother and fetus because aggressive treatment with magnesium sulfate, betamimetics and other hemodynamically-active tocolytic agents has resulted in sequelae for both mother and fetus.
Tocolytic agents most often used to inhibit preterm labor are ?-adrenoreceptor stimulants such as epinephrine or its synthetic analogs and derivatives salbutamol, terburtaline, isoxsuprine, ritodrine, and fenoterol, magnesium sulfate, prostaglandin inhibitors such as aspirin, indomethacin and naproxen, ethanol and calcium channel- blocking agents such as nipedifine or nicardipine. However, the potential adverse effects and limited efficacy of these drugs limit their use. Other methods for controlling labor during pregnancy have been reported (see, e.g., U.S. Patent No. 5,830,848). Modulators of the activity of endothelin peptides
A common feature of the above-noted disorders is the involvement of nitric oxide. It appears to be involved in the etiology and/or pathology of numerous disorders, including laminitis, other inflammatory disorders, and also other disorders, such as menopausal symptoms, pregnancy-related disorders and others. It is shown herein that treatment with endothelin antagonists can ameliorate the symptoms of such disorders. Laminitis is of particular interest herein, but other disorders may be similarly treated. B. Formulation and administration of the compounds
Compositions for use in the methods herein contain therapeutically effective amounts of one or more endothelin antagonists. The compounds are preferably formulated into suitable pharmaceutical or veterinary preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Preferred compositions include parenteral compositions and transdermal patches. Typically the compounds described above are formulated into pharmaceutical or veterinary compositions using techniques and procedures known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
In the formulations, effective concentrations of one or more compounds or pharmaceutically acceptable derivatives is (are) mixed with a suitable pharmaceutical or veterinary carrier or vehicle. The compounds may be derivatized as the corresponding salts, esters, acids, bases, solvates, hydrates and prodrugs prior to formulation, as described above. The concentrations of the compounds in the formulations are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the endothelin-mediated disease. Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical and veterinary carriers or vehicles suitable for administration of the endothelin antagonists include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
In addition, the compounds may be formulated as the sole pharmaceutically or veterinarily active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, may also be suitable as pharmaceutically or veterinarily acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,81 1.
The active compound is included in the pharmaceutically or veterinarily acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in known jn vitro and in vivo systems (see, e.g., the Examples, U.S. Patent No. 5,1 14,918 to Ishikawa et aL; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (October 7, 1991 ); Borges et aL (1989) Eur. J. Pharm. 165:223-230; Filep et aL (1991 ) Biochem. Biophys. Res. Commun. 177:171 -176) and then extrapolated therefrom for dosages for humans.
The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to treat the symptoms of laminitis. Typically a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 μg/ml. The pharmaceutical and veterinary compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical and veterinary dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and preferably from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
Preferred pharmaceutically and veterinarily acceptable derivatives include acids, salts, esters, hydrates, solvates and prodrug forms. The derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound. Thus, effective concentrations or amounts of one or more of the compounds provided herein or pharmaceutically or veterinarily acceptable derivatives thereof are mixed with a suitable pharmaceutical or veterinary carrier or vehicle for systemic, topical or local administration to form pharmaceutical or veterinary compositions. Compounds are included in an amount effective for ameliorating or treating the endothelin-mediated disorder for which treatment is contemplated. The concentration of active compound in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.
The compositions are intended to be administered by an suitable route, which includes orally, parenterally, rectally and topically and locally depending upon the disorder being treated. For oral administration, capsules and tablets are presently preferred. The compounds in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. Preferred modes of administration include parenteral, oral and topical modes of administration. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material. ln instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO), using surfactants, such as Tween®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical and veterinary compositions.
Upon mixing or addition of the compound with the vehicle, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. If necessary, pharmaceutically or veterinarily acceptable salts or other derivatives of the compounds may be prepared.
The compound is included in the pharmaceutically or veterinarily acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. It is understood that number and degree of side effects depends upon the condition for which the compounds are administered. For example, certain toxic and undesirable side effects are tolerated when treating life- threatening illnesses, such as tumors, that would not be tolerated when treating disorders of lesser consequence. The concentration of compound in the composition will depend on absorption, inactivation and excretion rates thereof, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
The formulations are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. The pharmaceutically or veterinarily therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical or veterinary carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
The composition can contain along with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art. Liquid pharmaceutically and veterinarily administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical or veterinary adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical or veterinary composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 1 5th Edition, 1975. The composition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount sufficient to alleviate the symptoms of the treated subject.
Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically or veterinarily acceptable non-toxic de¬
composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these formulations are known to those skilled in the art. The contemplated compositions may contain 0.001 %-100% active ingredient, preferably 0.1 -85%, typically 75-95%.
The active compounds or pharmaceutically or veterinarily acceptable derivatives may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings. The formulations may be include other active compounds to obtain desired combinations of properties. The compounds or pharmaceutically or veterinarily acceptable derivatives thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril), a diuretic (for example furosemide or hydrochlorothiazide), an endothelin converting enzyme (ECE) inhibitor (for example phosphoramidon), a neutral endopeptidase (NEP) inhibitor, an HMGCoA reductase inhibitor, a nitric oxide donor, an anti-oxidant, a vasodilator, a dopamine agonist, a neuroprotective agent, a steroid, a beta-agonist, an anti-coagulant, or a thrombolytic agent. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein. 1. Injectables, solutions and emulsions
Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical or veterinary compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Patent No. 3,710,795) is also contemplated herein. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
Pharmaceutically or veterinarily acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically or veterinarily acceptable substances.
Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (Tween® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical or veterinary carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
The concentration of the pharmaceutically or veterinarily active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
The unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.
Illustratively, intravenous or intra-arterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. Injectables are designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 % w/w up to about 90% w/w or more, preferably more than 1 % w/w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations. The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. 2. Topical administration
Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. Transdermal patches are of particular interest herein (see, e.g., U.S. Patent No. 5,891 ,472). The compounds or pharmaceutically or veteriarily acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the ■ formulation will typically diameters of less than 50 microns, preferably less than 10 microns.
The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01 % - 10% isotonic solutions, pH about 5-7, with appropriate salts. 3. Formulations for oral administration
Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
In certain embodiments, the formulations are solid dosage forms, preferably capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the inte'stine. The composition may also be formulated in combination with an antacid or other such ingredient.
When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action. For example, if the compound is used for treating laminitis, it may be used with other such treatments, such as a nitric oxide donor or a nitric oxide synthase substrate. The active ingredient is a compound or pharmaceutically or veterinarily acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.
Pharmaceutically or veterinarily acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets, because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar-coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically or veterinarily acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar-coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil. Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically or veterinarily acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically or veterinarily acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically or veterinarily acceptable suspending agents and preservatives. Pharmaceutically or veterinarily acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically or veterinarily acceptable substance used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically or veterinarily acceptable liquid carrier, e.g., water, to be easily measured for administration.
Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those set forth in U.S. Patent Nos. Re 28,819 and 4,358,603.
In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
4. Lyophilized powders
Also of interest herein are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be formulated as solids or gels.
Pharmaceutical and veterinary compositions of salts of the active ingredients, particularly sodium hydrogen phosphate or sodium, preferably sodium, salts of the sulfonamide compounds, which possess increased stability relative to formulations of the neutral sulfonamides are of interest herein. Such compositions contain a sulfonamide sodium salt in a sterile, lyophilized powder. These powders are known to have increased stability relative to formulations of the neutral sulfonamides.
The sterile, lyophilized powder is prepared by dissolving the sodium salt in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Briefly, the lyophilized powder is prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1 -20%, preferably about 5 to 1 5%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
Then, a selected salt, preferably the sodium salt of the sulfonamide (about 1 g of the salt per 10-100 g of the buffer solution, typically about 1 g/30 g), is added to the resulting mixture, preferably above room temperature, more preferably at about 30- 35° C, and stirred until it dissolves. The resulting mixture is diluted by adding more buffer (so that the resulting concentration of the salt decreases by about 10-50%, typically about 1 5-25%). The resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization. Each vial will contain a single dosage (100-500 mg, preferably 250 mg) or multiple dosages of the sulfonamide salt. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C to room temperature.
Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration of sodium salts of the sulfonamides. For reconstitution about 1-50 mg, preferably 5-35, more preferably about 9-30 is added per ml of sterile water or other suitable carrier. The precise amount depends upon the indication treated and selected compound. Such amount can be empirically determined.
5. Formulations for other routes of administration
Depending upon the condition treated other routes of administration, such as rectal administration are also contemplated herein. For example, pharmaceutical and veterinary dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 g.
Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. C. Compounds for pharmaceutical or veterinary use in treating endothelin-mediated diseases
Provided herein are methods for the treatment of inflammatory diseases, particularly, laminitis, and other diseases that can be treated by increasing levels of nitric oxide. The methods are practiced by administering an effective amount of an endothelin antagonist, particularly, a sulfonamide. Numerous endothelin antagonists and sulfonamide endothelin antagonists are known (see, e.g., U.S. Patent Nos. 6,133,442, 6,133,263, 6,107,320, 6,083,955; 6,083,951 ; 6,080,774; 6,063,91 1
6,060,475 6,043,265; 6,043,241; 6,030,991; 6,017,951; 6,017,916; 6,013,655; 6,004,965 5,965,732; 5,962,682; 5,958,968; 5,948,754; 5,945,448; 5,942,516; 5,929,116 5,929,106; 5,925,731; 5,922,759; 5,922,681; 5,891,892; 5,888,972; 5,883,092 5,883,090; 5,883,075; 5,866,568; 5,861,401; 5,856,484; 5,840,722; 5,837,708 5,834,469; 5,821,256; 5,817,693; 5,817,683; 5,817,653; 5,811,444; 5,811,416 Re35,886; 5,780,498; 5,773,444; 5,773,414; 5,767,310; 5,767,144; 5,753,619 5,739,333; 5,736,564; 5,731,434; 5,731,321; 5,728,706; 5,726,194; 5,719,183 5,719,182; 5,716,985; 5,716,984; 5,714,479; 5,703,106; 5,700,807; 5,691,373 5,691,315; 5,688,974; 5,688,499; 5,686,481; 5,686,478; 5,668,176; 5,668,137 5,663,296; 5,658,943; 5,658,902; 5,656,604; 5,654,309; 5,641,793; 5,641,752 5,622,971; 5,616,684; 5,614,498; 5,614,497; 5,610,177; 5,608,078; 5,599,811 5,591,728; 5,939,446; 5,916,907; 5,856,507; 5,846,990; 5,846,985; 5,827,869 5,780,473; 5,760,038; 5,378,715; 5,514,696; 5,420,123; 5,612,359; 5,543,521 5,464,853; 5,514,691; 5,292,740; 5,334,598; 5,571,821; 5,389,620; 5,541,186 5,559,105; and 5,482,960; European Patent Application Nos. EP 959073; EP 959072 EP 929529; EP 925297; EP 924207; EP 916679; EP 915699; EP 906108; EP 904077 EP 901470; EP 888340; EP 888299; EP 888123; EP 885890; EP 885219; EP 885217 EP 885215; EP 882039; EP 882030; EP 874829; EP 873334; EP 868180; EP 863898 EP 863896; EP 861247; EP 857718; EP 854721; EP 852584; EP 852226; EP 846119 EP 844884; EP 843551; EP 841926; EP 841925; EP 841916; EP 838223; EP 832082 EP 830143; EP 821670; EP 817782; EP 811001; EP 805802; EP801062; EP 799221 EP 799209; EP 799206; EP 792265; EP 790993; EP 778833; EP 776324 EP 774965 EP 768878; EP 768304; EP 767801; EP 767794; EP 766684; EP 763035 EP 758650 EP 757039; EP 755934; EP 753004; EP 752986; EP 898571; EP 889894 EP 870764 EP 876364; EP 819125; EP 528312; EP 552489; EP 499266; EP 457195 EP 460679 EP 626174; EP 558258; EP 569193; EP 768305; EP 904077; EP 921800 EP 702012 EP 601386; EP 633259; EP 510526; EP 526708; EP 617001; EP 496452 EP 658548 EP 555537; EP 628569; EP 552417; EP 436189; EP 713875; EP 733626 EP 682016 and EP 743307; British Patent Application Nos. GB 2276383; GB
2275926; GB 2266890; GB 2277446; and GB 2295616; German Patent Application
No. DE 4341663; Japanese Patent Application Nos.4-288099; 5-178890; 5-279390; JP 1 1043482A; JP 10306087A; JP 10251 160A; JP 10226649A; JP 10087695A; JP 10007574A; JP 09194500A; JP 09132568A; JP 091 10873A; JP 09087291 A; JP 09071570A; JP 09059261 A; JP 09059160A; JP 6256261 ; JP 6122625; JP 7330622; JP 7133254; JP 8059635; JP 7316188; and JP 7258098; International Patent Application Publication Nos. WO 99/44988; WO 99/42453; WO 99/36408; WO
99/29685 WO 99/27934 WO 99/25701 WO 99/23078 WO 99/20623; WO 99/19346 WO 99/19320 WO 99/16445 WO 99/1 2916 WO 99/1 1629; WO 99/06397 WO 99/05132 WO 99/0251 9 WO 98/5891 6 WO 98/57938; WO 98/57933 WO 98/41 521 WO 98/41515 WO 98/41206 WO 98/27091 ; WO 98/27070 WO 98/09953 WO 98/08836 WO 97/47595 WO 97/43260; WO 97/37987 WO 97/37986 WO 97/37985 WO 97/33608 WO 97/30996; WO 97/30982 WO 97/30978 WO 97/30046 WO 97/30045 WO 97/28160; WO 97/281 59 WO 97/281 58 WO 97/281 54 WO 97/22341 WO 97/21700; WO 97/19077 WO 97/17340 WO 97/1 7339 WO 97/1 7071 WO 97/1 2878; WO 97/1 1 961 WO 97/1 1 960 WO 97/1 1942 WO 97/10214 WO 97/08169; WO 97/071 19 WO 97/04781 WO 97/04774 WO 97/04773 WO 97/04772; WO 97/04769 WO 97/02265 WO 91 /13089 WO 92/1 2991 WO 97/39000; WO 92/20706 WO 93/1 321 8 WO 93/1 7701 WO 98/33780 WO 98/04260; WO 97/33886 WO 97/29748 WO 97/29747 WO 94/27979 WO 97/25321 ; WO 97/35864 WO 96/06095 WO. 95/08550 WO 95/2671 6 WO 96/1 1914; WO 95/26360 WO 93/25580 WO 93/23404 WO 96/04905 WO 94/21259; WO 95/03044 WO 95/03295 WO 95/08989 WO 94/21 590 WO 94/21 259; WO 95/1.3262 WO 96/1 2706 WO 94/24084 WO 94/25013 WO 95/04534; WO 95/04530 WO 94/02474 WO 94/14434 WO 96/07653 WO 93/08799; WO 95/05376 WO 95/1261 1 WO 95/1 5963 WO 95/15944 WO 95/05374; WO 95/05372 WO 94/03483 WO 93/21219 WO 96/1 1927 WO 96/23773; WO 96/331 70 WO 96/15109 WO 96/33190 WO 96/19459 WO 96/19455; WO 95/26360 WO 96/201 77 WO 96/08486 WO 96/09818 WO 96/08487; WO 96/04905 WO 96/22978 WO 96/08483 WO 95/33748 WO 96/30358; WO 95/351 07 WO 95/26957 WO 95/33752 and WO 96/31492; commonly owned U.S.
Patent application Serial Nos. 08/721 ,183 08/938,325; 08/938,444; 08/730,633;
09/148,643; 09/274,280; and 08/913,331 ; such as the following compounds described in the recited documents: BQ-123 (Ihara, M., et al.. Biological Profiles of Highly Potent Novel Endothelin Antagonists Selective for the ETA Receptor, Life Sciences, 50(4):247-255 (1992)); PD 156707 (Reynolds, E., et al., Pharmacological Characterization of PD 1 56707, an Orally Active ETA Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 273(3):1410-1417 (1995)); L- 754,142 (Williams, D. L., et al.. Pharmacology of L-754,142, a Highly Potent, Orally Active, Nonpeptidyl Endothelin Antagonist, The Journal of Pharmacology and
Experimental Therapeutics, 275(3):1518-1526 (1995)); SB 209670 (Ohlstein, E. H., et al., SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist, Proc. Natl. Acad. Sci. USA, 57:8052-8056 (1994)); SB 217242 (Ohlstein, E. H., et al., Nonpeptide Endothelin Receptor Antagonists. VLPharmacological Characterization of SB 217242, A Potent and Highly Bioavailable Endothelin Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 275(2):609-61 5 (1996)); A-127722 (Opgenorth, T. J., et al., Pharmacological Characterization of A-127722: An Orally Active and Highly Potent ETA-Selective Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 275(2):473-481 (1996)); TAK-044 (Masuda, Y., et al., Receptor Binding and Antagonist Properties of a Novel Endothelin
Receptor Antagonist, TAK-044 {Cyclo[D-cr-Aspartyl-3-[(4-Phenylpiperazin-1 -yl)Carbonyl]- L-Alanyl-L- -Aspartyl-D-2-(2-Thienyl)Glycyl-L-Leucyl-D-TryptophyllDisodium Salt}, in Human EndothelinA and EndothelinB Receptors, The Journal of Pharmacology and Experimental Therapeutics, 275(2):675-685 (1996)); bosentan (Ro 47-0203, Clozel, M., et al., Pharmacological Characterization of Bosentan, A New Potent Orally Active Nonpeptide Endothelin Receptor Antagonist, The Journal of Pharmacology and Experimental Therapeutics, 270(1 ):228-235 (1994)), and many are described herein.
In one embodiment, the endothelin receptor antagonists for use in the methods provided herein have formula I: Ar— SO 2- N- Ar1
H d)
or a pharmaceutically or veterinarily acceptable derivative thereof, in which Ar1 is alkyl, alkenyl, or alkynyl, or is a substituted or unsubstituted aryl or heteroaryl group that, if substituted, is substituted with one or more substituents, including, but not limited to, an alkyl group, an aryl group, a substituted aryl group, a nitro group, an amino group or a halide. In particular, Ar1 is alkyl, alkenyl, or alkynyl, or is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring, including, but not limited to, isoxazolyl, including 3- or 5- isoxazolyl, pyridazinyl, thiazolyl, including 2-thiazolyl, pyrimidinyl, including 2-pyrimidinyl, pyrazolyl, isothiazolyl, including 3- or 5-isothiazolyl, pyrazinyl, or a substituted benzene group, including aryloxy substituted benzene groups or is a fused aliphatic or heteroaliphatic ring containing from 6 to about 21 carbons in the ring structure, such as bicyclic or tricyclic rings, including naphthyl groups, quinolyl groups, dibenzofuryl groups, dibenzopyrrolyl groups, dibenzothienyl groups, purines, and phenanthrenes.
Ar1 is, in certain embodiments, selected from groups such as:
Figure imgf000039_0001
that are unsubstituted or substituted with one or more substituents selected from R. R is selected from H, NH2, halide, pseudohalide, alkyl alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl and carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceding groups, and is unsubstituted or substituted with any of the preceding groups, and straight or branched chains of from about 1 up to about 10-1 2 carbons, preferably, 1 to about 5 or 6 carbons. R is preferably H, NH2, halide, CH3, CH30 or another aromatic group.
Ar2 is any group such that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 100 μM. In certain embodiments herein, Ar2 is selected with the proviso that Ar2 is not phenyl or naphthyl when Ar1 is N-(δ-isoxazolyl) or N-(3-isoxazolyl) unless the isoxazole is a 4-halo-isoxazole or, if enhanced ETB affinity is desired, a 4-higher alkyl-isoxazole, and when Ar2 is phenyl it is not substituted at the para position with NH2, N02, CH3, OH or a substituted amine. Selected isoxazolyl-benzenesulfonamides and isoxzolyl-naphthalenesulfohamides in which the isoxazole is other than a 4-halo-isoxazole are also provided. Such selected compounds, including N-isoxazolylbenzenesulfonamides and N- isoxazolylnaphthalenesulfonamides in which the substituent at the 4 position on the isoxazolyl group is higher alkyl, such as C9H19 to C13H27 are also provided. These compounds enhanced ETB affinity compared to corresponding compounds in which the substituent at the 4 position is lower alkyl or other groups, such as pseudohalide, halide, alkylaryl, aryl, lower alkyl, carboxamide, alkoxy, and others. Thus, Ar2 is selected from among alkyl, including straight and branched chains, aromatic rings, fused aromatic rings and heterocyclic rings, including, 5-membered heterocycles with one, two or more heteroatoms and fused ring analogs thereof and 6- membered rings with one, two or more heteroatoms and fused ring analogs thereof. Ar2, thus, includes, but is not limited to, alkyl, norboranyl, admantyl, phenyl, naphthyl, quinolyl, isoquinolyl, acridinyl, styryl, biphenyl, isoxazolyl, thiazolyl, oxazolyl, imidazole, dibenzofuryl, indolyl (dibenzopyrrolyl), dibenzothienyl (thianaphthalene), carbazolyl, purinyl, and phenanthryl, anthracenyl, furyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyradazinyl, morpholinyl, thiomorpholinyl, quniolzoliny, quniolxazinyl, phthalazinyl, cinnolinyl, phenazinyl, phenoxzainyl, phenothiazinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, and the like. In preferred embodiments herein, Ar2 is phenyl, naphthyl, furyl, pyrrolyl, thienyl, biphenyl, and thiadazolyl.
In the embodiments described in detail herein, Ar1 is an isoxazole and the compounds are represented by the formulae II:
Figure imgf000040_0001
or pharmaceutically or veterinarily acceptable dervatives thereof, in which R and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterolaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or, (ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 ,3-butadienyl. In certain embodiments, the compounds are selected with the proviso that R2 is not halide or pseudohalide. In other embodiments, the compounds are selected with the proviso that Ar2 is not phenyl or naphthyl unless R1 is a halide or a higher alkyl, particularly C9H19 to C13H27.
In preferred embodiments herein, R1 is selected from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, and pseudohalide; and R2 is selected from among lower alkyl, lower alkenyl, lower alkynyl and lower haloalkyl. Ar2 is any group such that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 100 M.
In certain embodiments, Ar2 is not phenyl or naphthyl unless the compound is an N-isoxazolylsulfonamide substituted at the 4-position on the isoxazolyl group with halide or higher alkyl, particularly C9H19 to C13H27.
In particular, Ar1 is an isoxazolyl group, and Ar2 is an aliphatic straight or branched carbon chain, including alkyl, alkenyl, and alkynyl groups, heterocycle, with one or more, generally one to three rings, or is a group or isomer group selected.
In other embodiments, Ar2 is not phenyl or naphthyl, unless R1 (the 4-substituent on the isoxazolyl group (Ar1)) is a halide or a higher alkyl, with greater than 8 carbons, preferably C9H19 to C13H27.
Ar2 is in certain embodiments selected from among groups including: alkyl.
Figure imgf000041_0001
in which n is 0 to 10, preferably 0 to 6, more preferably 0 to 3; X is 0, S or NR11, where R11, which is hydrogen or contains up to about 30 carbon atoms, generally 1 to 16 carbon atoms, and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR16 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and
S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R 1, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z;
R3, R4, R5, R6 and R7 are each selected independently from (i)-(iv); (i) R3, R4, R5, R6 and R7 are each selected independently from among H, NHOH,
NH2, N02, N3, aminoalkyl, alkylamino, dialkylamino, carboxyl, carbonyl, hydroxyl, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heterocycle, alkoxy, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylalkoxy, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, haloalkoxy, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido in which each of the preceding groups may be unsubstituted or substituted with groups such as H, NH2, N02, alkyl, halide, and pseudohalide; or, alternatively,
(ii) R4 and R7 together are substituted or unsubstituted 1 , 3-butadienyl, 1 -chloro- 1 ,3-butadienyl, 4-dimethylamino-1 , 3-butadienyl, 1 -aza-1 , 3-butadienyl or 2-aza-1 ,3- butadienyl groups; and R3, R5 and R6 are as defined in (i) above; or alternatively,
(iii) R7 and R3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R4, R5 and R6 are as defined in (i) above; or alternatively,
(iv) R3, R5, and R7 are H; and R4 and R6 are each independently selected from alkyl, alkoxy, halide, amino and aminoalkyl; and
R8, R9, R10 are each independently selected as follows from (i) or (ii):
(i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy. heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, C02R18, SH, S(0)nR18 in which n is 0-2, HNOH, NR18R19, N02, N3, OR18, R19NC0R18 and C0NR19R1 S, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and 10 are unsubstituted or substituted with any substituents set forth for Z, which is is halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NCOR21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R2 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is unsubstituted or substituted with one or more substituents in each each substituent is independently selected from Z; and the other of R8, R9 and R10 is selected as in (i).
In certain embodiments, when Ar2 is phenyl (a) at least one of R3, R4, R5, R6, and R7 is not hydrogen and (b) when Ar1 is 3-isoxazolyl, R3 is not NH2 or CH3. In the above embodiments, the alkyl, alkynyl and alkenyl portions of each listed substituent are straight or branched chains, acyclic or cyclic, and preferably have from about 1 up to about 10 carbons; in more preferred embodiments they have from 1 -6 carbons, and they can have fewer than 6 carbons. The aryl, alicyclic, aromatic rings and heterocyclic groups can have from 3 to 16, generally, 3-7, more often 5-7 members in the rings, and may be single or fused rings. The ring size and carbon chain length are selected up to an amount that the resulting molecule binds to retains activity as an endothelin antagonist or agonist, such that the resulting compound inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 50 μM, preferably less than about 10 μM.
Thus, Ar2 is a substituted or unsubstituted group selected from among groups such as the following: naphthyl, phenyl, biphenyl, quinolyl, styryl, thienyl, furyl, isoquinolyl, pyrrolyl, benzofuranyl, benzothienyl, benzopyrrolyl, pyridinyl, thianaphthalyl, indolyl, dibenzofuranyl, dibenzopyrrolyl, dibenzothienyl, phenanthryl, thiazolyl, isoxazolyl, anthacenyl, alkenyl, alkynyl and alkyl. It is understood that the positions indicated for substituents, including the sulfonamide groups, may be varied. Thus, for example, compounds herein encompass groups that include thiophene-3-sulfonamides and thiophene-2-sulfonamides.
In embodiments described in detail herein, Ar1 is isoxazolyl. In all embodiments, 4-haloisoxazolyl or 4-methylisoxzaolyl are preferred, except when Ar2 is phenyl or naphthyl, then 4-haloisoxazolyl and 4-higher alkylisoxzaolyl are preferred. In general, 4- haloisoxazolyl sulfonamides exhibit substantially enhanced activity with respect to at least one of the ET receptors (about two-fold to twenty-fold greater activity), as assessed by assays, such as those provided herein, that measure binding to ETA and/or ETB receptors, compared to corresponding sulfonamides in which the substituent at the 4 position in the isoxazolyl is other than halo, such as alkyl. For example: (1 ) the IC50 for competitive of inhibition of binding of ET-1 to ETA receptors of 2,5-dimethyl-N-(3,4- dimethyl-5-isoxazolyl)benzenesulfonamide to is 9.4 μM; whereas the IC50 for 2,5-di- methyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide is 0.19 μM and for 2,5- dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide is 0.044 μM; (2) the IC50 of N-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfonamide for ETA receptors is about 0.008 μM, whereas, the IC50 of N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenyl- sulfonamide is about 0.0016 μM; and (3) the IC50 of N-(3,4-dimethyl-5-isoxazolyl)-3- biphenylsulfonamide for ETB receptors is about 3.48 μM; whereas, the ICS0 of N-(4- bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ETB receptors is about 0.76 μM and the IC50 of N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ETS receptors is about 0.793 μM (see, the Tables). Other selected compounds include benzene and naphthalene isoxazole sulfonamides in which the 4 position on the isoxazole ring of Ar1 is a methyl group and the 3 position is a relatively long chain (greater than about 8 carbons up to about 15 carbons, preferably about 13 carbons) alkyl group. Such compounds, although reportedly exhibiting a loss in affinity to ETA receptors (see, Stein et aL (1994) J.Med. Chem. 37:329-331 ), are herein shown to exhibit increased affinity to ETB receptors compared to compounds in which the group at the 3 position is a methyl group.
In certain preferred embodiments herein, R11 is aryl, such as phenyl, alkylphenyl, hydrogen or lower alkyl, and R8, R9, R10 are independently selected from hydrogen, halide, lower alkyl, lower aryl, lower heterocycle, lower aralkyl, C(0)2R18, C02R18, N02, OR18 SR18, NR18COR19 or C0NR19R18; R18 and R19 are preferably hydrogen, lower alkyl, and lower aryl, and Z is hydrogen, halide, pseudohalide, lower alkyl, lower alkoxy or pseudohalo- or halo(lower)alkyl. In certain more preferred embodiments, R8 and R 0 are hydrogen, halide or methyl, more preferably hydrogen or halide, and R9 is selected independently from hydrogen, halide, aryl, pseudohalide, lower alkyl, preferably methyl or ethyl, COR18, CONR18R19 and NR18COR19.
In the preferred compounds herein, R2 is preferably, selected from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H; and R1 is halide, lower alkyl or lower haloalkyl, and more preferablly, R1 is bromide, chloride, methyl or ethyl. In the most active compounds provided herein, as evidenced by in vitro binding assays, R1 is bromide or chloride.
In preferred embodiments herein, the compounds have formula II in which R1 is halide or methyl, R2, Ar2, R3, R5, R6, R8, R9, R10 and R1 are as defined above. In most preferred embodiments, R1 is bromide, chloride or methyl. Thus, in general, the most preferred compounds herein, particularly with respect to ETA affinity, are N-(4-bromo, chloro, or methylisoxazolyl)sulfonamides. Compounds in which R1 is methyl and Ar2 is other than phenyl or naphthyl are also preferred.
Preferred compounds also include compounds that are ETB receptor selective or that bind to ETB receptors with an IC50 of less than about 1 μM. In these compounds, Ar2 is 3-biphenyl, 4-biphenyl, certain compounds in which Ar2 phenanthrene or is a 5- membered heterocyle, particularly thienyl, compounds in which Ar2 is naphthyl and phenyl and R1 is higher alkyl (C9H19 to C13H27). R2 is selected from among alkyl, lower haloalkyl and H; and R1 is halide, lower alkyl or lower haloalkyl, or, when Ar2 is phenyl or naphthyl, R1 is higher alkyl (nine or more carbon atoms, preferably 9 to 13 carbon atoms). The 5-membered heterocylic compounds that exhibit ETB affinity or selectivity are those in which R9 and R10 are selected independently from hydrogen, lower alkyl, preferably methyl or ethyl, and halide, and R8, which is the substituent at the 5-position (see, e.g., the formulae setting forth the numbering for the 5-membered heterocyclic ring compounds), is aryl or a heterocycle, particularly phenyl and isoxazolyl, which are unsubstituted or substituted with Z, which is preferably lower alkyl or halide.
Also among the most preferred compounds for use in methods provided herein, are those that are ETA selective, i.e., they interact with ETA receptors at concentrations at substantially lower concentratons (at an ICS0 at least about 10-fold lower, preferably 100-fold lower) than they interact with ETB receptors. Other preferred compounds are ETB selective. These compounds interact with ETB receptors at IC50 concentrations that are at least about 10-fold lower than the concentrations at which they interact with ETA receptors. In particular, compounds that interact with ETA with an IC50 of less than about 10 μM, preferably less than 1 μM, more preferably less than 0.1 μM, but with ETB with an ICB0 of greater than about about 10 μM or compounds that interact with ETB with an IC50 of less than about 10 μM, preferably less than 1 μM, more preferably less than 0.1 μM, but with ETA with an IC50 of greater than about 10 μM are preferred.
Among others of the preferred compounds for use in the methods herein are any compounds that interact with ETA and/or ETB receptors with an IC50 of less than about 10 μM, more preferably less than 1 μM, even more preferably less than about 0.1 μM, even more preferably less than about 0.01 μM and most preferably less than about 0.001 μM.
In certain embodiments described in detail herein, Ar2 is a 4-biphenyl or is a single ring heterocycle, particularly a 5-membered ring, or is a fused bicyclic or tricyclic heterocycle that contains one or or more, particularly one, heteroatom selected from S, 0 and NR42, in the ring, where R42 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)_,R1B in which n is 0-2; R1 B is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R42 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR1 β in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R42 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cyclo- alkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R42, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z.
In preferred embodiments herein, R42 is aryl, such as phenyl or alkyl phenyl, hydrogen or loweralkyl.
Thus, in the compounds provided herein Ar2 includes thienyl, furyl and pyrrolyl, benzofuryl, benzopyrolyl, benzothienyl, benzofblfuryl, benzo[b]thienyl, and indolyl (benzo[blpyrrolyl) and 4-biphenyl, and Ar1 is preferably N-(5-isoxazolyl) or N-(3- isoxazolyl). The sulfonamides are N-isoxazolyl sulfonamides and the compounds have have formula III:
Figure imgf000047_0001
in which X is S, O or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R1 NC0R16 and C0NR1 R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R 2, R15 and R1β may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; or the compounds are are 4-biphenylsulfonides in which Ar1 is preferably N-(5- isoxazolyl) or N-(3-isoxazolyl.
Among the embodiments described in detail herein, Ar2 is thienyl, furyl, pyrrolyl or a group that is a derivative or analog, as described below, of a thienyl, furyl or pyrrolyl group, including benzo[b] derivatives such as a benzo[b]thienyl, Ar1 is N-(5- isoxazolyl) or N-(3-isoxazolyl). Ar2 has the formula IV:
Figure imgf000048_0001
in which X is 0, S or NR11 , where R11 is as defined above; that can be substituted at any or all positions or is an analog or derivative of the groups of formula (IV) in which the substituents form fused aromatic, aliphatic or heterocyclic rings; and R8, R9 and R10 are each independently selected as follows from (i) or (ii): (i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (AcO)C = CHR18, C02R18, SH, (CH2)rC(0)(CH2)πR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)-(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)-(CH2)nR18, C = N(0H)(CH2)rR18 (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NCOR18 and C0NR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NC0R21 and C0NR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, with the proviso that if R8 is NR18R19, OR18, R19NC0R18 and CONR19R18 C02R18, (CH2)rNH(CH = CH)-(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)πR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18 or (CH2)rR18 and R18 is an aryl group containing 5 or 6 members, then the aryl group has at least two substituents, and preferably one substituent at the 2-position relative to the linkage to the thienyl, furyl or pyrrolyl;
(ii) any two of R8, R9 and R10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R8, R9 and R10 is selected as in (i); and the heteroatoms are NR11 , 0, or S, with the proviso that Ar2 is not 5-haIo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl, 5- halo-3-loweralkylbenzo[b]pyrrolyl.
In preferred embodiments of interest herein, R9 and R10 are hydrogen, halide or methyl, more preferably hydrogen or halide, and R8 is selected from C02R18, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)-(CH2)nR18, C = N(OH)(CH2)rR18, (CH2)rC(0)(CH =CH)s(CH2)nR18, (CH2)r(CH == CH)-C(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, and (CH2)rR18. In certain embodiments, the compounds are selected with the proviso that if R8 is C02R18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18 or (CH2)rR18 and R18 is phenyl, the phenyl group is substituted at at least two positions, and preferably, at least one of those positions is ortho.
In the preferred compounds, R18 is aryl or heteroaryl, preferably having 5 or 6 members in the ring, more preferably phenyl or pyrimidinyl, most preferably phenyl.
In the most preferred compounds herein, R18 is phenyl, which is substituted at more than one position, and most preferably at least one substituent is at the ortho position, R9 and R10 are each hydrogen, halide or loweralkyl, preferably hydrogen, and Rs is C(0)NHR18, C(0)CH2R18, (CH2)R18, whith the proviso that if R8 is C(0)NHR1S, then the phenyl group must have at least two substituents, preferably one of the substituents is in the ortho positio..
In other preferred embodiments, Ar2 is a benzofbjthieny), benzofblfuryl, or indolyl (benzo[b]pyrrolyl), with the proviso that the benzene ring is substituted and the substituents are other than 5 halo, 3-loweralkyl. Preferred substituents on the benzene ring, include, but are not limited to, one or more selected from alkylenedioxy, particularly methylenedioxy, preferably 3,4-methylenedioxy, ethylenedioxy, aryl, particularly phenyl, dimethylamino, diethylamino, benzyl, alkoxy, particularly lower alkoxy, such as methoxy and ethoxy, halide, and alkyl, preferably loweralkyl.
Preferred compounds also include compounds that are ETB receptor selective or that bind to ETB receptors with an ICS0 of less than about 1 μM. ETB selective compounds interact with ETB receptors at IC50 concentrations that are at least about 10- fold lower than the concentrations at which they interact with ETA receptors. In these compounds, R2 is selected from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide or H; and R1 is halide or loweralkyl, and in preferred embodiments, R1 is bromide or chloride, preferabaly chloride; R9 and R10 are selected independently from hydrogen, loweralkyl, preferably methyl or ethyl, or halide, and R8, which is the substituent at the 5-position (see, e.g., formulae 111 and IV), is aryl or a heterocycle, particularly phenyl and isoxazolyl, which are unsubstituted or substituted with Z, which is preferably loweralkyl or halide.
Among the compounds of interest herein are those in which Ar2 has the formula:
Figure imgf000050_0001
in which M is (CH2)mC(0)(CH2)r, (CH2)mC(0)NH(CH2)r, (CH2)m(CH = CH)(CH2)r, (CH2)mC(0)(CH2)sNH(CH2)r, (CH2)m(CH = CH)(CH2)r, C = N(0H)(CH2)r, (CH2)mC(0)(CH == CH)sNH(CH2)r, CH(0H)(CH2)r, CH(CH3)C(0)(CH2)r,
CH(CH3)C(0)(CH2)m(CH = CH)(CH2)r, (CH2)r, (CH2)rO, (CH2)S(0)n wherein n is 0-2, C(0)0, in which m,s and r are each independently 0 to 6, preferably 0 to 3, more preferably M is (CH2)mC(0)(CH2)r, (CH2)mC(0)NH(CH2)r, (CH2)m(CH = CH)(CH2)r, (CH2)mC(0)(CH2)sNH(CH2)r, (CH2)m(CH = CH)(CH2)r, C = N(OH)(CH2)r, CH(0H)(CH2)r, (CH2)r, (CH2)rO, (CH2)S(0)n, C(0)0;
R51 , R52, R53, R54 and R55 are each independently selected from (i) or (ii) as follows: (i) R51, R52, R53, R54 and R55 are each independently selected from among
H, OH, NHR38, C0NR38R39 , N02, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, lower alkyl, CN, -(CH2)xC(0)(CH2)x, -(CH2)X, (CH2)xN-lower alkyl, -(CH2)xC(0)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, — S(0)2NH2, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, — (CH2)xCOOH; -{CH2)xCOOH-, C02- lower alkyl, CN, heteroaryl, — COC(0)(CH2)xCH3, -(CH2)XN(CH3)2, a sulfonyl chloride, S(0)2NHR50, alkylaryl, alkylheteroaryl, C(0)NHR50, -(CH2)xOH, -C(0)N(H)N(H)M, or; (ii) at least two of Rδ1 , R52, R53, R54 and R55, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e. — 0-(CH2)π-0-, — S-(CH2)n-0-, — S-(CH2)n-S-, where n is 1 to 4, preferably 1 or 2,) which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R51, R52, R53, R54 and R55 are selected as in (i); R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl;
X is S, 0 or NR11, where R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which as defined herein includes hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, amino acids, primary and secondary amides, 0- glycosides, hexoses, riboses, alkylaryl, alkylheteroaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, OC(0)R16, C02R16, 0C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NC0R16 and
CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHR50, alkylaryl, alkylheteroaryl, or — (CH2)xOH; R50 is a substituent such as hydrogen, lower alkyl, or lower alkoxy; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12 and R16 may together form alkylene; each of R11, R12, R15 and R16 may be further substituted with the any of the appropriate groups of those set forth for Z.
X is preferably S, and M is preferably selected from among:
Figure imgf000052_0001
in which R40 is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, and more preferably loweralkyl, loweralkoxy, or halo loweralkyl, and is more preferably hydrogen or loweralkyl, particularly methyl or ethyl, and is most preferably hydrogen.
In more preferred compounds, M is C(0)CH2, C(0)NH, — CH = CH-,
CH2CH2C(0)(CH)2, CH2CHC(0)CH2, and M is most preferably selected from among:
Figure imgf000052_0002
Ar2 most preferably has formula:
Figure imgf000053_0001
in which W is most preferably CH2 or NH.
Thus, in this embodiment, the preferred sulfonamides or pharmaceutically or veterinarily acceptable derivatives thereof, have the formula:
Figure imgf000053_0002
or pharmaceutically or veterinarily acceptable derivatives thereof, where Ar1 is a substituted or unsubstituted monocyclic or polycyclic, preferably a monocyclic or fused bicyclic, aryl or heteroaryl group with one or more substituents, selected from, for example, H, NH2, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons. The substituents are preferably H, NH2, halide, CH3, CH30 or another aromatic group, and the sulfonamides are preferably the thiophene-3-sulfonamides. R51- R55 are as defined above.
In particular, Ar1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably an isoxazolyl, pyridazinyl, thiazolyl, pyrimidinyl or phenyl groups and particularly 3- or 5-isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl; W is = C(halo)2, -{CH2)X-, = N(lower alkyl), -C(0)-, = C(lower alkyl)2, -NH-, = NC0R16, -NHC(R12)(R16)-, = NC02R16 or = CHR56; x is 0-3; R51, R62, R53, R54 and R55 are each selected independently from Z, as defined above, or any two may form a ring containing two or more heteroatoms; and
R56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably H, methyl or carboxymethyl.
In all embodiments, X is preferably S.
In one embodiment, the sulfonamides and pharmaceutically or veterinarily acceptable derivatives thereof have formula V:
Figure imgf000054_0001
where Ar1, R51 and R53 55 are as defined above. In particular, Ar2 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5- isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl, more preferably 4-chloro-3-methyl-5-isoxazolyl or 4-chloro-5-methyl-3-isoxazolyl; W is -NH-, = NC0R'6, = NC02R16, -NHC(R12)(R16)- or is -CH2- when R54 is hydroxyl.
In preferred of these embodiments, RB4 is selected from the group consisting of substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, 0C(0)R16, 0C02R16, NR12R16 and S(0)nR16 in which n is 0-2, preferably alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, alkylsulfonylamino and aminosulfonyl.
In certain of these embodiments, when W is -NHC(R 2)(R16)-, then RB1, R53, R54 and R56 can be H.
R51 , R53 and R55 are preferably alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylaikyl, or heteroarylalkyl, more preferably lower alkyl, lower alkenyl, lower alkynyl, or aryl, most preferably methyl. The sulfonamides are preferably thio- phene-3-sulfonamides. In another embodiment, the sulfonamides have formulae VI:
Figure imgf000055_0001
where Ar1 is as defined above. Ar1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo- 2,1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl;
X is preferably S; each G and R is independently selected from lower alkyl, CN, -(CH2)xC(0)(CH2)x, -(CH2)X, (CH2)xN-lower alkyl, -(CH2)xC(0)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, — S(0)2NH2, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, -(CH2)xCOOH; -{CH2)xCOOH-, C02- lower alkyl, CN, heteroaryl, — COC(0)(CH2)xCH3, — (CH2)XN(CH3)2, a sulfonyl chloride, S(0)2NHRεo, alkylaryl, alkylheteroaryl, C(0)NHR50, -{CH2)x0H, -C(0)N(H)N(H)M; M is H or R50; R' is selected from hydrogen, G and R; W is = C(halo)2, =N(H), -(CH2)X-, = N(lower alkyl), -C(O) -, = C(lower alkyl)2; and x is 0-3.
In another embodiment, the sulfonamides have formula VII:
Figure imgf000056_0001
where:
Ar1 is defined as above. Ar1 is preferably benzo-2, 1 ,3-oxadiazol-5-yl or 2- methoxy-3-pyrazinyl when R56 is H; and R56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
In other embodiments of formula (IV), Ar1 is preferably benzo-2,1 ,3-oxadiazol-5- yl or 2-methoxy-3-pyrazinyl when RS6 is H and RS6 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
In another embodiment, the sulfonamides have formula Vlll:
Figure imgf000056_0002
where Ar1 is defined as above and is preferably 4-chloro-3-methyl-5-isoxazolyl; W is NH; and R57 is selected from the group consisting of aryl, heteroaryl, heterocycle, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, — (CH2)x0H, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cyclo- alkyl, cycloalkenyl or cycloalkynyl; each of R12, R15 and R16 may be further substituted with the any of the groups set forth for Z; R57 is preferably CONH2, COOH, or phenyl.
Preferred among the sulfonamide compounds are those of formula:
Ar— SO - N- Ar1 2 I H
where Ar1 is isoxazolyl and Ar2 has the formula:
Figure imgf000057_0001
or a pharmaceutically or veterinarily acceptable derivative, including alkali metal salt, particularly sodium salt, thereof, wherein:
R61 and R62 are independently selected from the group consisting of hydrogen, halo, cyano, cyanoalkyl, C(0)R41, alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene;
W is O, NH or CH2;
R6B, R6e and R67 are each independently selected as in (i) or (ii):
(i) R66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
C(0)R41, carbamoyloxy or alkoxycarbonyloxy, and
R65 and R67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R41, carbamoyloxy and alkoxycarbonyloxy; or
(ii) if at least one of R61 and R62 is not hydrogen, then any two may form alkylenedioxy, and the other is selected as in (i);
R45 is selected from the group consisting of alkyl, C(0)R41, (CH2)xOH and CH(OH)(CH2)xCH3 in which x is 0-6, S(0)nR41 in which n is 0-2 and C( *=NR43)R41;
R41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino; and R 3 is selected from hydroxy, alkoxy, alkyl and aryl, wherein
R41 and R43 are unsubstituted or substituted with one or more substituents selected from Y, which is alkoxy, halide, pseudohalide, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy.
Thus, the sulfonamides of these embodiments are 2-acyl-3- thiophenesulfonamides. The corresponding 3-acyl-2-thiophenesulfonamides are also contemplated herein.
In other embodiments described in detail herein, Ar2 is a fused ring bicyclic heterocyle and Ar1 is preferably a five or 6-membered heterocyclic ring. Ar1 is preferably an isoxazole and Ar2 is preferably a fused ring bicyclic heterocycle containing one heteroatom in each ring and containing 5 or 6 members in each ring.
In particular, Ar2 is selected from among fused bicyclic heteroaryl groups, such as those having formula:
Figure imgf000058_0001
in which Y is N or 0+, preferably N; X is S, O, NR11, where R11 is as defined above;
R83, R84 and R85 are selected from (i), (ii), (iii) or (iv):
(i) R83, R84 and R85 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl or amido, where the alkyl, alkenyl, alkynyl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons; or, alternatively,
(ii) two of R83, R84 and R85 together are substituted or unsubstituted 1 ,3- butadienyl, 4-dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 ,3- butadienyl or 2-aza-1 , 3-butadienyl groups or form alkylenedioxy; and the others of R83, R84 and R85 are as defined in (i) above or also form substituted or unsubstituted 1 ,3- butadienyl, 4-dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 ,3- butadienyl or 2-aza-1 , 3-butadienyl groups or form alkylenedioxy; or alternatively, (iii) two of R83, R84 and R85 are independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains and the other is H; or
(iv) any two of R83, R84 and R85, which are each selected as in (i) form fused carbocyclic or heterocyclic rings; and
R87 is hydrogen or contains up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, and is selected hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, SH, S(0)n, (CH2)rR18, C(0)R18, C02R18, (CH2)rC0R18, OR18, (CH2)rC0(CH2)sR18, S(0)nR18 in which n is 0-2, and r and s are each independently 0 to 6, preferably 1 -3, HNOH, NR18R19, N02, N3, R19NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R87 is unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NCOR21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl.
In more preferred embodiments Ar1 is an isoxazole and the compounds are represented by the formulae IX:
Figure imgf000059_0001
in which Y is N or 0+, preferably N; X is S, 0, NR11 , in which R11 is as defined above, and is preferably hydrogen or aryl, more preferably hydrogen or phenyl; and R1 and R2 are either (i), (ii) or (iii) as follows: (i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl.
In preferred embodiments R87 is (CH2)rR18, where R18 is aryl, preferably phenyl or pyrimidyl, more preferably phenyl, which is unsubstituted or substited with alkyl, haloalkyl, halide, or such that two adjacent positions are substituted and together form alkylenedioxy, particularly methylenedioxy and ethylenedioxy. In other preferred compounds R 8 is C(0)R27 in which R27 is aryl, and is preferably (CH2)rC(0)(CH2)p-aryl, (CH2)rC(0)aryl, (CH2)rS(0)q(CH2)p-aryl, C(0)NR11-aryl, NHC(0)(CH2)r-aryl, NR11-aryl, (CH2)raryl in which p and r are each independently selected from 0-10, preferably 0-6, more preferably 0-3, most preferably 0 or 1 and q is 0-3, preferably 0-2. The aryl portion is unsubstituted or is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularly methylenedioxy, N-alkyl, N-alkyoxy, amino, nitro and other such groups. The alkyl substituents are preferably lower alkyl, more preferably containing 1-3 carbons.
In the embodiments provided herein, the alkyl, alkynyl and alkenyl portions of each listed substituent are straight or branched chains, acyclic or cyclic, and preferably have from about 1 up to about 10 carbons; in more preferred embodiments they have from 1 -6 carbons. The aryl, alicyclic, aromatic rings and heterocyclic groups can have from 3 to 16, generally, 3-7, more often 5-7 members in the rings, and may be single or fused rings. The ring size and carbon chain length are selected up to an amount that the resulting molecule binds and retains activity as an endothelin antagonist or agonist, such that the resulting compound inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelin peptide to an endothelin receptor at a concentration of less than about 100 μM.
Of the compounds described herein, those that inhibit or increase an endothelin- mediated activity by about 50% at concentrations of less than about 10 μM are preferred. More preferred are those that inhibit or increase an endothelin-mediated activity by about 50% at concentrations of less than about 1 μM, more preferably less than about 0.1 μM, even more preferably less than about 0.01 μM, and most preferably less than about 0.001 μM. It is noted that, as described below, the IC50 concentration determined in the ]n vitro assays is a non-linear function of incubation temperature. The preferred values recited herein refer to the assays that are performed at 4° C. When the assays are performed at 24° C, somewhat higher (see, the Tables) IC50 concentrations are observed. Accordingly, the preferred IC50 concentrations are about 10-fold higher.
The compounds of the preferred embodiments are described in further detail below.
1. Isoxazolylsulfonamides in which Ar2 is phenyl, biphenyl and fused aromatic rings
Compounds in which Ar2 is selected from phenyl, biphenyl, and aromatic fused rings, including naphthyl, anthracenyl, phenanthryl, indenyl, azulenyl, fluorenyl, and phenazinyl. When Ar2 is phenyl, biphenyl or naphthyl, the compounds are preferably (4- halo-isoxazolyl)sulfonamides or are (4-higher alkyl-isoxazolyl)sulfonmides, in which the alkyl group contains more than about 8, preferably 9 to 15, more preferably 9 to 13, carbon atoms. These compounds have the formulae (X):
Figure imgf000061_0001
in which n is 0 to 10, preferably 0 to 6, more preferably 0 to 3; R3, R4, R5, R6, and R7 are selected from (i), (ii), (iii) or (iv) with the proviso that: (a) when Ar2 is phenyl, at least one of R3, R4, R5, R6, and R7 is not hydrogen, (b) when Ar1 is 4-halo-5-methyl-3- isoxazolyl, R3 is not NH2 or CH3, and (c) when Ar2 is phenyl, napthyl or 2-biphenyl, R1 is halide or higher alkyl:
(i) R3, R4, R5, R6, and R7 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably, 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons; or, alternatively,
(ii) R4 and R7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R3, R5 and R6 are as defined in (i) above; or alternatively,
(iii) R7 and R3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and n, X, R4, R5 and R6 are as defined in (i) above; or
(iv) R3, R5, and R7 are H are as defined in (i); and R4 and R6 are each independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
In more preferred embodiments, R2 is H, CH3, C2H5; R1 is Cl, Br or CH3; X is O or S; n is 0 or 1 ; and R3, R4, R5, R6, R7, are selected from either (i), (ii), (iii) or (iv) as follows:
(i) R5 and Rβ are H; R4 and R7 are each independently selected from H, halide, NH2, CF3, Ph, CH3; and R3 is selected from H, NHOH, NH2, EtNH2, (CH3)2NH, Ph-CH2NH, N02, F, Cl, Br, I, CN, CH3, (CH3)3C, CgHn, CH30, n-C4H90, CH2 = CH, Ph- CH = CH, CH sC, Ph-CH ≡≡ C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or (ii) R4 and R7 together form 1 , 3-butadienyl, 4-chloro-1 , 3-butadienyl, 4- dimethylamino-1 , 3-butadienyl or 1-aza-1 , 3-butadienyl; and R3, R5 and R6 are defined as in (i) of this embodiment; or
(iii) R7 and R3 together form 1 , 3-butadienyl, 3-chloro-1 , 3-butadienyl 4- dimethylamino-1 , 3-butadienyl or 1 -aza-1 , 3-butadienyl; and R4, R5 and R6 are as defined in (i) of this embodiment; or
(iv) R3, R5, and R7 are H as defined in (i); and R4 and R6 are each independently selected from alkyl, alkoxy, halide, amino alkyl, alkylaminoalkyl or dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains. More preferred among the above compounds are those in which Ar2 is a substituted or unsubstituted phenyl or naphthyl; R1 is Br, Cl or I; R2 is H, CH3, C2H5, CF3, C2F5, n-C3H7, cycloC3H5, and C4H8; and R3, R\ R5, R6 and R7 are either (i), (ii), (iii), (iv) or (v): (i) R5, R6 and R7 are H; n is 0 and R3 is H, NH2, CH3 CF3, halide, C2H5NH or Ph, R4 is H, CF3, NH2, R7 is H or CF3, and R5 and R6 are H; or
(ii) R3, Rε and R6 are H; n is 0 and R4 and R7 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, or 4-chloro-1 , 3-butadienyl; or (iii) R4, R6 and R6 are H; n is 0; and R7 and R3 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl; or
(iv) R4 is H or NH2, R5 and R6 are H; n is 1 and R3 is H, NH2 and halide; CH3, Br, Cl, F, CF3, NH2, R7 is H, CH3, Br, Cl, F, NH2 or CF3, and R5 and R6 are H; or (v) R3, RB, and R7 are H are as defined in (i); and R4 and R6 are each independently selected from alkyl groups that contain from 1 to 6 carbons, and are straight or branched chains, lower alkoxy, and halide.
In more preferred embodiments, the benzenesulfonamides and naphthalenesulfonamdies are N-(4-halo)-substituted N-isoxazolylsulfonamides or are 4- higher alkyl-substituted N-isoxazolylsulfonamides, in which R2 is H, CH3, C2H5, C2F5 or CF3; and R3, R4, R5, R6 and R7 are either (i) or (ii) as follows:
(i) R4, Rs, R6 and R7 are each independently selected from H, halide, NH2, CF3, Ph and CH3; R3 is selected from H, NHOH, NH2, C2H5NH2, (CH3)2NH, Ph-CH2NH, N02, F, Cl, Br, I, CN, CH3, (CH3)3C, CBH11 f CH30, n-C4H90, CH2 = CH, Ph-CH = CH, CH ≡C, Ph- CH ≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or (ii) R3, R5 and R7 are H; and R4 and R6 are each an alkyl group that contains from 1 to 3 carbons, which are straight or branched chains.
In yet more preferred embodiments, R1 is most preferably Br; R2 is CH3, C2H5, or CF3; and R3, R\ Rβ and R7 are (i) or (ii) as follows:
(i) R3 is H, NH2, CH3 CF3, halide or C2H5NH; R4, R5 and R6 are independently selected from H, CF3, halide, particularly Br and Cl, NH2; and R7 is H, CH3, CH2CH5, (CH3)CH, F or CF3; or
(ii) R3, R5 and R7 and R4 and R6 are each an methyl or ethyl. In all embodiments, R1 is most preferably Br, except in instances in which ehanced ETB affinity, compared to the corresponding compound in which R., is CH3, is desired, than R1 is most preferably a higher alkyl (9 to 1 5 carbons, preferably 9 or 10 to 13 carbons). a. Compounds in which Ar2 is phenyl and biphenyl and n is 0 Compounds in which Ar2 if phenyl or biphenyl have the following formulae (XI):
Figure imgf000064_0001
in which R3, R4, R5, R6, and R7 are selected from (i), (ii), (iii) or (iv) with the proviso that, (a) when Ar2 is phenyl, at least one of R3, R4, R5, R6, and R7 is not hydrogen, (b) when Ar2 is phenyl and Ar1 is 3-isoxazolyl, R3 is not NH2 or CH3, and (c) when Ar2 is napthyl, 2-biphenyl, phenyl, other than benzofuryl, dibenzothienyl and dibenzopyrrolyl, R1 is halide or higher alkyl:
(i) R3, R4, R5, R6, and R7 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably, 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons; are each independently selected as described above; or, alternatively,
(ii) R3, Rδ, and R7 are H; and R4 and R6 are each independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, wherein the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
Among the above phenyl and biphenyl compounds, are compounds with the following formulae (XII):
Figure imgf000064_0002
in which R3, R5 and R7 are each independently (a) hydrogen, except that at least one of R3, R5 and R7 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W\ W2 and W3, except that if one of R3, R5 are R7 is alkyl at the 4 position, at least one of the other two of R3, R5 are R7 is not hydrogen; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro, except that if one of R3, R5 and R7 is 4-N02, then at least one of the other two of R3, R5 and R7 is not hydrogen; (g) -C(0)H or -C(0)R27; (h) -C02H or -C02R27; (i) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)mOH, or -O- S(0)mOR27; (j) -W4NR28R29, except that, if one of R3, R5 and R7 is 4-W NR28R29 then at least one of the other two of R3, R5 and R7 is not hydrogen; or (k) -W4N(R32)-W5NR30R31; R1 and R2 are selected from (i) or (ii) as follows:
(i) R1 is halide or is higher alkyl (greater than about 8 carbons up to about 9 carbons in the chain; R2 is selected from: (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W1, W2 and W3; (c) hydroxyl; (d) cyano; (e) nitro; (f) -C(0)H or -C(0)R27; (g) -C02H or -C02R27; (h) -SH, -S(0)nR27, -S(0)m- OH, -S(0)mOR27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-OR27; (i) -W -NR28R29; or (j) - W4N(R32)-W5-NR30R31; or (ii) R1 and R2 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W1 , W2 and W3; (c) hydroxyl; (d) cyano; (e) nitro; (f) -C(0)H or -C(0)R27; (g) -C02H or -C02R27; (h) -SH, -S(0)nR27, -S(0)m- OH, -S(0)m0R27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-OR27; (i) -W -NR28R29; (j) - W4N(R32)-W5-NR30R31 ; or (k) halo;
R27 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; R28 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; (c) cyano; (d) hydroxyl; (e) -C(0)H or -C(0)R27; (f) -C02R27; (g) -SH, - S(0)nR27, -S(0)m-OH, -S(0)m-0R27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-OR27, except when W4 is -S(0)n-; R29 is (a) hydrogen; (b) -C(0)H or -C(0)R27, except when W4 is - C(O)- and R28 is -C(0)H, -C(0)R27, or -C02R27; (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; or R28 and R29 together are alkylene or alkenylene (either of which may be substituted with W1 , W2 and W3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; R30 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R27; (d) -C02R27; (e) -SH, - S(0)nR27, -S(0)m-OH, -S(0)m-0R27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-OR27; (f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3; R31 is (a) hydrogen; (b) -C(0)H or -C(0)R27, except when W5 is -C(O)- and R30 is -
C(0)H, -C(0)R27, or -C02R27; or (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1 , W2 and W3;
R32 is (a) hydrogen; (b) hydroxyl (c) -C(0)H, -C(0)R27 or C02R27; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; or any two of R30, R31 and R32 together are alkylene or alkenylene (either of which may be substituted with W1, W2 and W3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
W , W2 and W3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0)nW6, - S(0)m-OH, -S(0)m-OW6, -0-S(0)m-W6, -0-S(0)mOH, or -0-S(0)m-OW6; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)W6; (o) -C02H or -C02W6; (p) -W4-NW7W8; (q) W4-N(W11)- W5-W6; or (r) -W4-N(W11)-WB-NW7W8;
W4 and W5 are each independently (a) a single bond; (b) -W9-S(0)π-W10-; (c) -W9- C(0)-W10-; (d) -W9-C(S)-W10-; (e) -W9-0-W10-; (f) -W9-S-W10-; or (g) -W9-0-C(0)-W10-;
W6, W7 and W8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or W7 and W8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; W9 and W10 are each independently a single bond, alkylene, alkenylene, or alkynylene; W11 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H, -C(0)W6 or -C02W6; (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl; or any two of W7 and W8 and W11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated, or aromatic ring together with the atoms to which they are attached; m is 1 or 2; and n is 0, 1 , or 2.
Preferred compounds include those in which one of R3, R5 or R7 is phenyl or phenoxy or compounds in which one of R3, R5 or R7 is hydrogen, one of the other two of R3, R5 and R7 is at the 2 position and is not hydrogen, and the other of R3, R5 and R7 is at the 5 position. Thus, preferred compounds are 2-substituted benzenesulfonamides, and 2,5-substituted benzenesulfonamides. In addition, in preferred compounds R1 is preferably halide. Preferred substituents are lower alkyl, particular methyl, ethyl, and propyl, halide, amino, dimethylamino, and methoxy.
(1) Ar2 is phenyl In particular Ar2 has the formula (Xlll):
Figure imgf000067_0001
in which:
R1 is halide or higher alkyl (greater than 8 carbons); R2 selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon atoms, and the aryl portions contain from about 4 to about 14 carbons; and R3, R4, R5, R6, and R7 are either (i) or (ii) as follows:
(i) R3, R4, R5, R6, and R7 are selected independently from among H, NHOH, NH2, N02, pseudohalide, including N3, halide, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably, 1 to about 5 or 6 carbons, are unsubstituted or substituted with groups, such as any set forth for R8, R9, R10 and R11, above, and the aryl portions contain from 3 up to about 10 carbons, preferably 3 to 6 carbons, and, also are unsubstituted or substituted with groups, such as any set forth for R8, R9, R10 and R11,; R4 and R6 are as defined in (i); or (ii) R3, R5, and R7 are H; and R4 and R6 are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylamino, dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, and in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains. Compounds in which at least one of R3 - R7 is phenyl are discussed below with the biphenyl compounds.
In certain preferred embodiments: R1 is halide or a higher alkyl selected from C9H19 to C13H27; R2 is selected independently from alkyl, lower alkenyl, lower alkynl, lower haloalkyl and H; and R3, R4, R5, R6, and R7 are either (i) or (ii) as follows: (i) R4, R5, R6 and R7 are each independently selected from H, lower alkyl, NH2,
N02, halide, pseudohalide; R3 is selected from H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from 1 up to 5 or 6 carbons and the aryl portions contain from 4 to 14 carbons; or
(ii) R3, R5, and R7 are H; and R4 and R6 are each independently selected from alkyl, alkoxy, halide, aminoalkyl, and dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, and in which the alkyl and alkoxy groups contain 1 to 6 carbons, and are straight or branched chains.
In more preferred embodiments, R1 is Cl or Br, or if greater ETB activity is preferred a higher alkyl (C9H19 to C13H27;d R2 is selected from H, CH3, C2H5, CF3, C2F5, n- C3H7, cyclo-C3H7, nC13H27 and nC9H19; and R3, R\ R5, R6, and R7 are either (i) or (ii) as follows:
(i) R4, Rε, Rβ and R7 are each independently selected from H, halide, NH2, CF3, Ph and CH3; R3 is selected from H, NHOH, NH2, C2HBNH2, (CH3)2NH, Ph-CH2NH, N02, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H„, CH30, n-C4H90, CH2 = CH, Ph-CH = CH, CH ≡C, Ph- CH ≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or (ii) R3, R5, and R7 are H; and R4 and R6 are each independently sleeted from alkyl and aminoalkyl in whcih the alkyl groups have from 1 to 6 carbons that may from straight or branched chains.
In yet more preferred embodiments, R1 is Br, Cl or C9H19 to C13H27; R2 is H, CH3, C2H5, or CF3; and R3, R4, RB, R6, and R7 are either (i) or (ii) as follows: (i) R3 is H, NH2, CH3 CF3, halide or C2H5NH; R4, R5 and R6 are independently selected from H, CH3, C2H5, (CH3)2CH, CF3, halide, particularly Br and Cl, NH2; and R7 is H, CH3, CH2CH5, (CH3)CH, F or CF3; or
(ii) R3, R5, and R7 are H; and R4 and R6 are each independently selected from alkyl groups in which the alkyl groups have from 1 to 3 carbons and may form straight or branched chains.
Of the above compounds those with ortho and/or meta substituents or those that are substituted at positions 2 and 5 on the benzene ring are generally more preferred, except when the resulting compound is a biphenyl and ETB affinity is desired, then the corresponding para-substituted compounds are preferred. Compounds with ortho substituents are more generally more preferred than the corresponding meta- substituted compounds. This observation is particularly important when activity with respect to ETA receptors is considered. In addition, in preferred compounds R1 is preferably halide. Preferred substituents are lower alkyl, particular methyl, ethyl, and propyl, halide, amino, dimethylamino, and methoxy. Other preferred substituents may be deduced from the following Table.
Benzene sulfonamides were synthesized and tested using the exemplified assays (see, EXAMPLES) and selected results are set forth in Table 1 (the N-(3,4-dimethyl-5- isoxazolyDbenzenesulfonamides are generlly included for comparison with the corresponding N-(4-halo-3-methyl-5-isoxazolyl)benzenesulfonamide.
TABLE 1
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
* results generally from 1 , 2 or 3 experiments with the same preparation * * Two preparations
(2) Ar2 is biphenyl
In certain of the embodiments herein, Ar1 is N-(5-isoxazolyl) or N-(3-isoxazolyl) with R1 and R2 selected as described above, and Ar2 is a substituted benzene group in which one of R3, R4, R5, R6 and R7 is selected independently from phenyl or substituted phenyl. The remaining of R3, R4, Rε, R6 and R7 are selected as described in (1 ) above for embodiments in which Ar2 is phenyl. R1 and R2 are also selected as described in (1 ) above, except in instances when one of R3, R4, R5, R6 and R7 is at the 3 or 4 position so that the resulting compounds are 3- or 4-biphenyl compounds. In these instances, R2 is selected as described above, but R1 can be halide and higher alkyl, and in addition, can be any of the substituents set forth for R2. For the 3-or 4-biphenyl compounds R1 is preferably halide, lower alkyl, particularly CH3, or C9H19-C13H27.
In certain embodiments, Ar2 is unsubstituted or substituted biphenyl group of formula (XIV):
Figure imgf000076_0001
in which each ring may have one or more substituents each selected independently from R26 and R13 where:
(i) R26 and R13 are independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons; or
(ii) R26 and R13 together (see, Formula IVb) are -CH2-, -CH = CH2- O, S, NR11 in which R11 is as defined above, and is preferably, H or alkyl, particularly lower alkyl. It is understood that in either (i) or (ii) each ring of Ar2 may be unsubstituted or substituted with more than one substituent, each of which is selected independently from the selections set forth in (i) for R26 and R13. These compounds, thus, include biphenylsulfonamides, fused tricyclic- substituted sulfonamides dibenzothiophenesulfonamides, dibenzofuransulfonamides, dibenzopyrrolefonamides (carbazolesulfonamides) and phenanthrenesulfonamides. The dibenzothiophenesulfonamides, dibenzofuransulfonamides, dibenzopyrrolefonamides and phenanthrenesulfonamides are discussed separately with the compounds in which Ar2 is a heterocycle with one heteroatom and two or more fused rings.
Among preferred embodiments herein, Ar2 is has formula (XV):
Figure imgf000077_0001
in which R26 and R13 are each independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons. R13 and R26 are preferably each selected from from H, loweralkyl, haloalkyl and halide. Again, it is understood that Ar2 may be substituted with more than one substituent, each of which is selected independently from the selections set forth for R26 and R13, and R2 and R1 are as defined above.
Again, it is understood that Ar2 may be substituted with more than one substituent, each of which is selected independently from the selections set forth for R26 and R13.
In preferred embodiments, in which the sulfonamides are biphenylsulfonamides in which R1 is halide; R2 is selected from alkyl, lower alkenyl, lower alkynl, lower haloalkyl and H; and R26 and R13 are selected from H, lower alkyl, haloalkyl and halide. In preferred of these embodiments, R1 is Cl or Br, and for the 3-biphenylsulfonamides and 4-biphenylsulfonamides, R is also CH3; R2 is selected from H, CH3, C2H5, CF3, C2F5, n-C3H7 and cyclo-C3H7; and R26 and R13 are each independently selected from H, halide, NH2, CF3 CH3, CN, CH3, (CH3)3C, C6H„, CH30, n-C4H90 and CH2 = CH.
In yet more preferred embodiments, R2 is H, CH3, C2H5, or CF3; R26 and R13 are independently selected from H, CH3, C2H5, CF3, and halide.
In another preferred embodiment, the biphenylsulfonamides are 3- or 4- biphenylsulfonamides, in such instances R1 is preferably, halide or methyl. Such compounds have a higher ETB affinity than the 2-biphenylsulfonamides. It is also preferred that the substitutent at the 2-position is hydrogen. R1 is selected from halide, CH3, C2H6, CF3, C2F5, n-C3H7 and cyclo-C3H7, preferably halide or CH3, and R2 is selected from H, CH3, C2H5, CF3, C2F5, n-C3H7 and cyclo-C3H7; and R26 and R13 are each independently selected from H, halide, NH2, CF3 CH3, CN, CH3, (CH3)3C,
Figure imgf000078_0001
CH30, n- C4H90 and CH2 = CH. In more preferred of these embodiments, R1 is halide or CH3, and R2 are selected from H, CH3, C2H5, or CF3; R26 and R 3 are independently selected from H, CH3, C2H5, CF3, and halide.
In certain embodiments herein, the biphenylsulfonamides are substituted 4- biphenylsulfonamides, R13 is preferably at the para position and R26, if it is not hydrogen, is at any position except the 2-position.
In more preferred embodiments, R is halide or methyl or higher (C9-C13) alkyl. R1 is selected from halide, CH3, C2H5, CF3, C2F5, n-C3H7 and cyclo-C3H7, preferably halide or CH3, and R2 is selected from H, CH3, C2H5, CF3, C2F5, n-C3H7 and cyclo-C3H7, more preferably R1 is halide or CH3, and R2 is selected from H, CH3, C2H5, or CF3 In more preferred embodiments, R1 is Cl or Br, or if greater ETB activity is preferred a higher alkyl (C9H19 to C13H27; R2 is selected from H, CH3, C2H5, CF3, C2F5, n- C3H7, cyclo-C3H7, nC13H27 and nC9H19 In yet more preferred embodiments, R1 is Br, Cl or C9H19 to C13H27; R2 is H, CH3, C2H5, or CF3 .
The biphenyl compounds provided herein are generally ETB active or ETB selective (see, e.g.. Table 2); Le^ the compounds provided herein inhibit binding of endothelin to ETB receptors at concentrations about 10- to about 30-fold less than they inhibit binding of endothelin to ETA receptors. In particular the 4-biphenylsulfonamides are ETB selective.
Exemplary biphenyl sulfonamides are the following and those set forth in Table 2, and include, but are not limited to: N-(3-methyl-5-isoxazolyl)-4'-methylphenyl-4-biphenylsulfonamide, N-(4-bromo-3-methyl- 5-isoxazolyl)-4'-methylphenyl-4-biphenylsulfoπamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 4'-methylphenyl-4-biphenyisulfonamide, (3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4- biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsul- fonamide, (3-methyl-5-isoxazolyl)-4'-methyoxyphenyl-4-biphenylsu)fonamide, (4-bromo- 3-methyl-5-isoxazolyl)-4'-methoxyphenyl-4-biphenylsulfonamide, (4-bromo-3-methyl-5- isoxazolyl)-3'-methoxyphenyl-4-biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl)- 2'-methoxyphenyl-4-biphenylsulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3',4'- methylenedioxyphenyl-4-biphenylsulfonamide and (4-bromo-3-methyl-5-isoxazolyl)-3'- methylphenyl-4-biphenylsulfonamide. Corresponding 4-chloro and 4-fluoro isoxazolyl compounds are also encompassed herein.
Exemplary biphenyl compounds were tested using the exemplified assays (see, EXAMPLES) and the results, which are intended to be exemplary or provided for comparison with compounds provided herein, and are not limiting, are as set forth in the following table (Table 2):
TABLE 2
Figure imgf000079_0001
Figure imgf000080_0001
* results generally from 1 , 2 or 3 experiments with the same preparation ** preliminary results
Preferred compounds are those in which Ar2 is a 4-biphenyl in which, referring to formula VII and at least one substitutent R13 is at the para position. Preferred substitutents are loweralkyl, halo loweralkyl and lower alkoxy. Such compounds are ETB active. b. Compounds in which Ar2 is phenyl and biphenyl and n>0
Ar2 has formula (XVI):
Figure imgf000081_0001
These compounds include those in which n is 1 to 10, preferably 1 to 6, more preferably 1 to 3; R1 and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon atoms, and the aryl portions contain from about 4 to about 14 carbons, except the R2 is not halide or pseudohalide; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl; and
R3, R4, R5, R6, and R7 are selected from (i), (ii), (iii) or (iv):
(i) R3, R4, R5, R6, and R7 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably, 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons; or, alternatively,
(ii) R4 and R7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R3, R5 and R6 are as defined in (i) above; or alternatively, (iii) R7 and R3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R4, R5 and R6 are as defined in (i) above; or
(iv) R3, R5, and R7 are H are as defined in (i); and R4 and Rβ are each independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
In more preferred embodiments, R2 is H, CH3, C2H5, CF3, C2F5, n-C3H7, cyclo- C3H7 and C4H8; R1 is Br, Cl, CH3, or, if greater ETB affinity is desired, is higher alkyl; n is 1 -3; and R3, R\ R5, R6, R7, are selected from either (i), (ii), (iii) or (iv) as follows:
(i) R5 and R6 are H; R4 and R7 are each independently selected from H, halide, NH2, CF3, Ph, CH3; and R3 is selected from H, NHOH, NH2, EtNH2, (CH3)2NH, Ph-CH2NH, N02, F, Cl, Br, I, CN, CH3, (CH3)3C, CgH,,, CH30, n-C4H90, CH2 = CH, Ph- CH = CH, CH ≡C, Ph-CH sC, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or (ii) R4 and R7 together form 1 , 3-butadienyl, 4-chloro-1 , 3-butadienyl, 4- dimethylamino-1 , 3-butadienyl or 1 -aza-1 , 3-butadienyl; and R3, R5 and R6 are defined as in (i) of this embodiment; or
(iii) R7 and R3 together form 1 , 3-butadienyl, 3-chloro-1 , 3-butadienyl 4- dimethylamino-1 , 3-butadienyl or 1-aza-1 , 3-butadienyl; and R4, R5 and Rβ are as defined in (i) of this embodiment; or
(iv) R3, RB, and R7 are H as defined in (i); and R4 and R6 are each independently selected from alkyl, alkoxy, halide, amino alkyl, alkylaminoalkyl or dialkylaminoalkyl, which are unsubstituted or substituted with alkyl groups, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains.
More preferred among the above compounds are those in which n is 1 to 3; R1 is Br, Cl, I or CH3 or, if greater ETB affinity is desired, is C9H19 -C13H27; R2 is H, CH3, C2H5, CF3, C2F5, n-C3H7, cyclo-C3H7 and C4H8; either R3, R4, R5, R6 and R7 are either (i), (ii), (iii), (iv) or (v): (i) R5, R6 and R7 are H; and R3 is H, NH2, CH3 CF3, halide, C2H5NH or Ph, R4 is H,
CF3, NH2, R7 is H or CF3, and R5 and R6 are H; or
(ii) R3, R5 and R6 are H; and R4 and R7 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, or 4-chloro-1 , 3-butadienyl; or (iii) R4, R5 and R6 are H; and R7 and R3 together form 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl; or
(iv) R4 is H or NH2, R5 and R6 are H; and R3 is H, NH2 and halide; CH3, Br, Cl, F, CF3, NH2, R7 is H, CH3, Br, Cl, F, NH2 or CF3, and R5 and R6 are H; or (v) R3, R5, and R7 are H are as defined in (i); and R4 and R6 are each independently selected from alkyl groups that contain from 1 to 6 carbons, and are straight or branched chains.
In more preferred embodiments, the compounds are N-(4-halo-isoxazolyl)- sulfonamides in which R2 is H, CH3, C2H5, C2F5 or CF3; and R3, R4, R5, R6 and R7 are either (i) or (ii) as follows:
(i) R4, R5, R6 and R7 are each independently selected from H, halide, NH2, CF3, Ph and CH3; R3 is selected from H, NHOH, NH2, C2H5NH2, (CH3)2NH, Ph-CH2NH, N02, F, Cl, Br, I, CN, CH3, (CH3)3C, C5H , CH30, n-C4H90, CH2 = CH, Ph-CH = CH, CH = C, Ph- C = C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or (ii) R3, R5 and R7 are H; and R4 and R6 are each an alkyl group that contains from 1 to 3 carbons, which are straight or branched chains.
In yet more preferred embodiments, n is 1 ; R1 is most preferably Br, Cl or CH3; R2 is CH3, C2H5, or CF3; and R3, R\ R8 and R7 are (i) or (ii) as follows:
(i) R3 is H, NH2, CH3 CF3, halide or C2H5NH; R4, R5 and Rβ are independently selected from H, CF3, halide, particularly Br and Cl, NH2; and R7 is H, CH3, CH2CH5, (CH3)CH, F or CF3; or
(ii) R3, R5 and R7 and R4 and R6 are independently selected from nitro, hydrogen, methyl or ethyl.
The following selected compounds are among the above compounds: TABLE 3
Figure imgf000083_0001
c. Compounds in which Ar2 is a fused aromatic ring
Compounds in which Ar2 contains fused aromatic rings and is selected from naphthyl, anthracenyl and phenanthryl are provided herein.
(1 ) Ar2 is naphthyl Compounds in which Ar2 is naphthyl are provided herein.
Figure imgf000084_0001
The compounds have formulae (XI):
Figure imgf000084_0002
in which R1 and R2 are as set forth above, R2 is preferably H, lower alkyl or lower haloalkyl; R1 is preferably halide or, if an increase in ETB affinity is desired, higher alkyl (about 8 to 15, preferably 9 to 13 carbons, which are straight or branched chains); R3, R4, RB, R6, and R7 are selected from (i) or (ii):
(i) R4 and R7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R3, R5 and R6 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably, 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons; or alternatively,
(ii) R7 and R3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1-chloro-1 ,3-butadiene, 1-aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R4, R5 and R6 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyalkoxy, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably, 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons.
In preferred embodiments R2 is H, CH3, C2H5 or CF3 and R1 is halide or, in embodiments in which an increase in ETB activity is descired, R1 is higher alkyl, in which the alkyl group contains between 8 and 15, preferably 9 and 13, carbons, which may be straight or branched chains.
In certain embodiments the compounds have formulae (XVII):
NAPHTHYL- SO-
Figure imgf000085_0001
which is substituted with R4, R5 and R6 which are selected independently: (a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3;
(c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R27; (h) -C02H or -C02R27; (i) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)m-R27, -0-S(0)m0H, or -0-S(0)m-0R27; (j) -W4-NR28R29, or (k) -W -N(R32)-W5-NR30R31;
R1 and R2 are selected from (i) or (ii) as follows:
(i) R1 is halide or higher alkyl (greater than 8 carbons up to about 1 5); R2 is
(a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3; (c) hydroxyl; (d) cyano; (e) nitro; (f) -C(0)H or -C(0)R27; (g) -C02H or -C02R27; (h) -SH, - S(0)nR27, -S(0)m-0H, -S(0)m-0R27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-OR27; (i) -W4- NR28R27; or (j) -W4-N(R32)-W6-NR30R31; or
(ii) R1 and R2 are each independently selected from (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; (c) hydroxyl; (d) cyano; (e) nitro; (f) -C(0)H or -C(0)R27; (g) -C02H or -C02R27; (h) -SH, -S(0)nR27, -S(0)m- OH, -S(0)m-OR27, -0-S(0)m-R27, -0-S(0)m0H, or -0-S(0)m-OR27; (i) -W4-NR28R27; (j) -W4- N(R32)-W6-NR30R31; or (k) halo;
R27 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3, R28 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1 , W2 and W3; (c) cyano; (d) hydroxyl; (e) -C(0)H or -C(0)R27; (f) -C02H or -C02R27; (g) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-OR27, except when W4 is -S(0)π-;
R29 is (a) hydrogen; (b) -C(0)H or -C(0)R27, except when W4 is -C(O)- and R28 is - C(0)H, -C(0)R27, -C02H, or -C02R27, (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3, or
R28 and R29 together are aklylene or alkenylene (either of which may be substituted with W1, W2 and W3), completing 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
R30 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R27; (d) -C02H or -C02R27;
(e) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-0R27, -0-S(0)m-R27, -0-S(0)m0H, or -0-S(0)m-OR27;
(f) alkyl, alkynyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1 , W2 and W3; R31 is (a) hydrogen; (b) -C(0)H or -C(0)R27, except when W6 is -C(O)- and R30 is -
C(0)H, -C(0)R27, -C02H, or -C02R27; (c) alkyl, alkenyl, alkenyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3;
R32 is (a) hydrogen; (b) hydroxyl, C02R27 or C02H, except when one of R30 and R31 is hydroxyl, C02R27 or C02H; (c) -C(0)H or -C(0)R27; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3; or any two of R30, R31 and R32 together are alkylene or alkenylene (either of which may be substituted with W1, W2 and W3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
W1, W2 and W3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkoxy; (e) -SH, -S(0)nW6, -S(0)m-OH, -S(0)m-0W6, -0-S(0)m-W6, -0-S(0)mOH, or -0- S(0)m-OW6; (f) oxo; (g) nitro; (h) cyano; (i) -C(0)H or -C(0)W6; (j) -C02H or -C02W6; or (k) -NW7W8, -C(0)NW7W8, or -S(0)nW7W8;
W4 and W5 are each independently (a) a single bond; (b) -S(0)n-; (c) -C(O)-; (d) - C(S)-; or (e) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; W6, W7 and W8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or W7 and W3 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; m is 1 or 2; and n is 0, 1 , or 2.
In certain embodiments, at least one of R4, R5 and R6 is not hydrogen. In other embodiments, at least one of R4, R5 and R6 is preferably di-loweralkylamino or loweralkylamino and the others of R4, RB and R6 is hydrogen or lower alkyl.
In all preferred embodiments the sulfonamide is linked at position 1 or 2, preferably 1 , of the napthyl group and at least one of the subsituents is at position 5.
Naphthalenesulfonamides were synthesized and tested using the exemplified assays (see, EXAMPLES) and selected results are set forth in the Table 4 (the 4- haloisoxazole compounds are preferred).
TABLE 4
Figure imgf000087_0001
Figure imgf000088_0002
results generally from 1 to 4 experiments
(2) phenanthryl and anthracenyl
Isoxazolyl-sulfonamides in which Ar2 contains three fused aromatic rings are also provided herein. R1 and R2 are selected as described above for the compounds in which Ar2 is phenyl or biphenyl and n > 0. The fused rings may be substiuted with one or more substituents selected from R13 and R26 in which R26 and R13 are independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons.
More preferably R1 is halide or methyl; R2 is selected from alkyl, lower alkenyl, lower alkynl, and lower haloalkyl; and R26 and R13 are selected from H, lower alkyl, haloalkyl and halide. In more preferred embodiments, R1 is Cl, Br or CH3; R2 is selected from H, CH3, C2H5,CF3, n-C3H7, cyclo-C3H7 and C4H8; and R26 and R13 are each independently selected from H, halide, NH2, CF3 CH3, CN, CH3, (CH3)3C,
Figure imgf000088_0001
CH30, n- C4H90 and CH2 = CH. In yet more preferred embodiments, R2 is H, CH3, C2H5, or CF3; R26 and R13 are independently selected from H, CH3, C2Hε, CF3, and halide.
Exemplary compounds include N-(4-bromo-3-methyl-5-isoxazolyl)phenanthrene- 3-sulfonamide, N-(4-bromo-5-methyl-3-isoxazolyl)phenanthrene-3-sulfonamide and N- (3,4-dimethyl-5-isoxazolylphenanthrene-3-sulfonamide. Selected results for such componds are set forth in Table 5: TABLE 5
Figure imgf000089_0001
* preliminary results
2. Compounds in which Ar2 is contains a heterocyclic ring or fused rings with at least one heterocycyclic ring
Compounds in which Ar2 is a heterocycle including sulfonamides in which Ar2 is five-membered heterocyclic ring compound with one heteroatom and fused ring analogs thereof, compounds in which Ar2 is a five-membered heterocycle with two or more heteroatoms and fused ring analogs thereof, compounds in which Ar2 is a six-membered heterocyclic ring compound with one heteroatom and fused ring analogs thereof, compounds in which Ar2 is a six-membered heterocycle with two or more heteroatoms and fused ring analogs thereof are provided.
Compounds in which which Ar2 is a five-membered heterocycle with one heteroatom include, but are not limited to, compounds in which Ar2 is thienyl, furyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl and pyrrolidinyl and other such rings. Compounds in which Ar2 is a is a fused ring analog of a 5-membered heterocyle with one heteroatom, include, but are not limited to compounds in which Ar2 is benzofuryl, benzothienyl (thianaphthyl), indolyl, indoliznyl, and isoindole.
Compounds in which Ar2 is a 5-membered heterocycle with two or more heteroatoms and fused ring analogs thereof include, but are not limited to, compounds in which Ar2 is oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl, imidaolidinyl, 1 ,3- dioxaolanyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxoxaolyl, isothiazolyl, 1 ,2,3- oxadiazolyl, 1 ,2,3-triazolyl, 1 ,3,4-thiadiazolyl, 1 H-indazolyl, benzoxazolyl, benzimidazolyl and benzothiazolyl.
Compounds in which Ar2 is a 6-membered heterocycle with one heteroatom and fused ring analogs thereof include, but are not limited to, compounds in which Ar2 is pyridinly, quinolinyl, isoquinolynl, acridine, 4H-quinolizine, 2H-pyran, 4H-pyran, and piperidinyl. Compounds in which Ar2 is a 6-membered heterocycle with two or more heteroatoms and fused ring analogs thereof include, but are not limited to, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-napthyridinyl, pterdinyl, 1 ,4-doxanyl, morpholinyl, thiomorpholinyl, morpholinyl, phenazinyl, phenythiazinyl, phenoxazinyl, quniazolinyl, quinoxalinyl, naphthyrindinyl and pteridinyl. a. Ar2 is thienyl, furyl and pyrrolyl
In certain embodiments, Ar2 is represented by the formulae (IV):
Figure imgf000090_0001
that can be substituted at any or all positions or is an analog of compounds of formula
(IV) in which the substituents form fused aromatic, aliphatic or heterocyclic rings; and in which X is NR11, O, or S, and R11, which is hydrogen or contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6, and is selected as defined above. R8,
R9, R10 are selected as described above.
Thus, in certain embodiments described in detail herein, Ar2 is thienyl, furyl, pyrrolyl or a group, such as benzofuryl, thianaphthyl or indolyl, that is a derivative of or analog, as described below, of a thienyl, furyl, pyrroly group, Ar1 is preferably N-(5- isoxazolyl) or N-(3-isoxazolyl, and the compounds are represented by the formulae III:
Figure imgf000090_0002
in which R1, R2, are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon atoms, and the aryl portions contain from about 4 to about 14 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl; and X, R8, R9 and R10 are selected as defined above.
In certain embodiments, R2 is not halide, pseudohalide or higher alkyl. The more preferred compounds of formulae I and and U provided herein are compounds in which Ar1 is N-(5-isoxazolyl) or N-(3-isoxazolyi) that can be represented by the formulae XVIII:
Figure imgf000091_0001
in which: R1 and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl; X is O, S, NH or NR11 in which R11, which contains up to about 30-50 atoms, generally 1 to 20 atoms, and which is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15, S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; m is 0-2; R11 and R15, are unsubstituted or are substituted with one or more substituents each independently selected from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR1β and C0NR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R1 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12 and R16 may be further substituted with substituents selected from Z; and R8, R9, R10, which each, when not hydrogen, contain up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected as follows from (i) or (ii): (i) R8, R9 and R10 are each independently selected from hydrogen, halide pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, C02R18, SH, S(0)nR18 in which n is 0-2, HNOH, NR18R19, N02, N3, OR18, R19NCOR18 and C0NR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, which is is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; and any of the groups set forth for R8, R9 and 10 are unsubstituted or substituted with any substituents set forth for. Z, which is is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21 , C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NCOR21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl, C(0)R2B and S(0)nR25 in which n is 0-2; R24 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and R2B is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; any of the preceding groups, including R8, R9, R10, R18, R19, R20, R21, R22, R23, R24 and R25 may be unsubstituted, except as specified, or may be further substituted with substituents selected from Z, which is is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aromatic or heteroaromatic ring or an alicyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members, and which is unsubstituted or substituted with one or more substituents in each each substituent is independently selected from Z; and the other of R8, R9 and R10 is selected as in (i).
In preferred embodiments: X is S, O, NR11 in which R11 is aryl, hydrogen, or lower alkyl, preferably, a substituted or unsubstituted aryl, particularly phenyl, preferably unsubstituted or substituted with lower alkyl or halogen hydrogen or lower alkyl; R1 is hydrogen, halide, pseudohalide, lower alkyl or lower haloalkyl, most preferably halide; R2 is hydrogen, lower alkyl or lower haloalkyl; and R8, R9 and R10 are each selected independently from from hydrogen, halide, pseudohalide, lower alkyl, lower aryl, lower heterocycle, lower aralkyl, S(0)nR18 in which n is 0-2, C(0)R18, C02R18, N02, OR18 or CONR19R18; R19 is preferably hydrogen, lower alkyl, and lower aryl, C(0)R20, S(0)nR20 in which n is 0-2; R18 is preferably hydrogen, halide, lower alkyl or lower aryl, and R20 is preferably hydrogen, halide or lower alkyl; and Z is hydrogen, halide, pseudohalide, lower alkyl or lower pseudohaloalkyl or lower haloalkyl. In particular, at least one of R8, R9 and R10 is selected from methyl, phenyl, pyrazolyl, isoxazolyl, carbomethoxy, carboxamide, halide, hydrogen, isopropylphenyl, pyridyl, carboxyl, phenyl, phenylaminocarbonyl, benzenesulfonyl, lower- alkylphenylaminocarbonyl, biphenylaminocarbonyl, (lower)haloalkoxyphenyl- aminocarbonyl and halophenylaminocarbonyl and, preferably, two of R8, R9 and R10 are hydrogen, halide or lower alkyl. In more preferred of these embodiments X is S.
In more preferred embodiments, two of R8, R9 and R10 are hydrogen, halide or lower alkyl and the other is hydrogen, halide, pseudohalide, lower alkyl, lower aryl, heterolower aryl, lower aralkyl, C(0)R18, C02R18, N02, OR18 or C0NR19R18. In yet more preferred embodiments R19 is phenyl and R18 is hydrogen, halide or lower alkyl. In more preferred of these embodiments, two of R8, R9 and R10 are hydrogen or lower alkyl and the other is halide, lower alkyl, C(0)R18, C02R18, N02, OR18 or C0NR19R18; R18 is hydrogen or lower alkyl. In all embodiments, R1 is preferably halide, H, CH3 or C2H5, and R2 is H, CH3, C2H5, C2F5 or CF3. In yet more preferred embodiments, R1 preferably Br, Cl or CH3; R2 is H, CH3, C2Hε, or CF3.
In certain preferred embodiments, R9 and R10 are H, halide or lower alkyl; and R8 is any of the above listed substituents, and particularly, when a potent ETA antagonist is desired is a substituted aminocarbonyl. In other preferrred embodiments it is preferred that R8 and R10 are H or lower alkyl and R9 is any of the above-listed substituents. In the preferred of these embodiments, R1 is halide, H, CH3 or C2H5, and R2 is H, CH3, C2H5, C2FS or CF3. In yet more preferred embodiments, R1 is Br, Cl or CH3; and R2 is H, CH3, C2H5, or CF3.
In embodiments in which ETB antagonists are desired, it is preferred that R8 and R10 are H or lower alkyl and R9 is a heterocyclic or aromatic ring of preferably from 3 to 14, more preferably, 5 to 7, members in the ring. In particular, if X is S, R8 and R10 are H or lower alkyl, and R9, is aryl, particularly unsubstituted or substituted phenyl, such as 4-ethylphenyl. If X is N, then R11 is aryl, particularly! unsubstituted phenyl or substituted phenyl, such as isopropylphenyl and R8, R9 and R10 are preferably H, halide or lower alkyl.
The most preferred compounds provided herein have an IC50 for ETA receptors in the assays exemplified herein between about .002 μM and 0.1 μM (see, e.g.. Table 6). These compounds include: N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)- aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3- methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-bromo-5-methyl-3- isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5- isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- (carbomethoxy)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)ami- nocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2- methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyllthiophene-3-sulfonamide; N-(4-bromo-3- methyl-5-isoN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]- thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4- methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-3-phenylthiophene-2-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-4- phenylthiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene- 2-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methylphenyl)aminoca- rbonyl]thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropyl- phenyl)aminocarbonyl)thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N- (4-t-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxa- zolyl)-2-[N-(4-n-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide; and N-(4-bromo-3- methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide.
Other preferred compounds include those that have an ICB0 for ETB receptors, as measured in the assays herein, of between about 0.05 μM and 1 μM. These include compounds, such as N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzenesulfonylthiophene-2- sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrole-2- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-1 -(4'-isopropylphenyl)pyrrole-3- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl)pyra- zolyl]}thiophene-5-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)- aminocarbonyl]thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4- ethylphenyl)aminocarbonyl]thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)- 5-thienylthiophene-2-sulf onamide; and N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- ethylphenyl)thiophene-2-sulf onamide.
Other thienyl-, furyl- and pyrrole-sulfonamides provided herein include the following compounds: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(phenylamino- carbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-5-benzylthiophene- 2-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulf onamide; N- (4-chloro-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide; N-(4-bromo-3- methyl-5-isoxazolyi)-3-styrylthiophene-2-sulf onamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-styrylthiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- phenoxythiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- benzenesulfonylthiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- phenylthiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminothiophene-3- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamino)thiophene-3- sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide; N-(4- bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulf onamide; N-(4-bromo-3- methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-[(N-phenyl)methylaminocarbonyl]thiophene-3-sulf onamide; N-(4-bromo-3- methyl-5-isoxazolyl)-5-benzylf uran-2-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5- (phenylthio)furan-2-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5- (hydroxymethyl)furan-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5- (carbomethoxy)furan-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2,5- dimethylfuran-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropyl- phenyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- propylphenyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3- (phenylaminocarbonyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2- benzylthiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(dimethylaminocarbonyl)thiophene-3- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(di-iso-propylaminocarbonyl)thiophene- 3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethylaminocarbonyl)thiophene-3- sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-iso-butylphenyl)furan-2- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylfuran-2-sulfonamide; and N-(4- bromo-3-methyl-5-isoxazolyl)-5-styrylthiophene-2-sulf onamide. In other embodiments, the compounds are of formula XVIII, where R8, R9 and
R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
(i) R9 and R10 are selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (OAC)CH = CHR18, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NCOR18 and CONR19R18, in which R 9 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
R8 is selected from C(0)R18, (0AC)CH = CHR18, C02R18, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)nR18,
(CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, in which R18 is aryl, preferably phenyl; where any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21 , SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21 , N02, N3, OR21, R22NC0R21 and C0NR22R21 ; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z; the other of R8, R9 and R10 is selected as from the groups set forth for R9 and R10 in (i); and the heteroatoms are NR11, O, or S.
In certain embodiments, Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3- loweralkylbenzo[b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl. In other embodiments, if
R8 is (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR13, particularly if r is 0 and/or n is 0, and R18 is aryl, particularly phenyl, then R18 must have two or more substituents, with preferably at least one ortho substituent.
In these embodiments, Ar2 is, thus, represented by the formulae (lVA and IVB):
Figure imgf000098_0001
that can be substituted at any or all positions or is an analog of compounds of formula (IV) in which the substituents form fused aromatic, aliphatic or heterocyclic rings; and in which X is NR11, O, or S, and R11, which is hydrogen or contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6, and is selected as defined above. R8, R9, R 0 are selected as described above. In the embodiments provided herein, when R8, R9 and R10 are selected as in (i), above, R8 is preferably selected from among (CH2)rC(0)(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, C = N(OH)(CH2)rR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)rC{0)NH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18.
In certain of these embodiments, if R8 is (CH2)rC(0)NH(CH2)nR18, (CH2).C(0)NH(CH2)-R18, or (CH2)rR18, and R18 is phenyl, the phenyl group is substituted at least two positions, and preferably, at least one of those positions is ortho.
In preferred of these compounds, R18 is aryl or heteroaryl, preferably having 5 or 6 members in the ring, more preferably phenyl or pyrimidinyl, most preferably phenyl. R9 and R10 are preferably hydrogen, halide, loweralkyl, or halo loweralkyl.
In preferred embodiments: X is S, 0, NR11 in which R11 is aryl, hydrogen, or loweralkyl, preferably, a substituted or unsubstituted aryl, particularly phenyl, preferably unsubstituted or substituted with loweralkyl or halogen hydrogen or loweralkyl; R1 is hydrogen, halide, pseudohalide, loweralkyl or lower haloalkyl, most preferably halide; R2 is hydrogen, loweralkyl or lower haloalkyl.
In more preferred embodiments, two of R9 and R10 are hydrogen, halide or loweralkyl and R8 is C(0)NHR18 or C(0)CH2R18 in which R18 is a phenyl group that is substituted at least two positions, most preferably at least one substitutent at the ortho position and also 3,4 or 4,5 alkylenedioxy substituents. In more preferred of these embodiments X is S. In all embodiments, R1 is preferably halide, H, CH3 or C2H5, and R2 is H, CH3, C2H5, C2F5 or CF3. In yet more preferred embodiments, R1 preferably Br, Cl or CH3; R2 is H, CH3, C2H5, or CF3.
In other embodiments two of R8, R9 and R10 form a ring so that Ar2 is benzo[b]thienyl, benzotblfuryl, or indolyl, with the proviso that there is one or more substituents and they are other than 5-halo and 3-loweralkyl, and the other of R8, R9 and R10 is selected from aryl, (CH2)rR18, C(0)R18, C02R18, NR18R19, SH, S(0)nR18 in which n is 0-2, HNOH, N02, N3, OR18, R19NCOR18 and CONR19R18. Ar2 may be further substituted with any of the groups set forth for R8, R9 and R10, and are preferably selected from among alkyl, alkoxy, alkoxyalkyl, aryl, alkylaryl, aminoalkyl, arylamino, aryl-substituted amino, and NR11.
In embodiments in which ETB antagonists are desired, it is preferred that R8 and R10 are H or loweralkyl and R9 includes heterocyclic or aromatic ring of preferably from 3 to 14, more preferably, 5 to 7, members in the ring. In particular, if X is S, R8 and R10 are H or loweralkyl, and R9, includes an aryl group, particularly a substituted phenyl, such as a 2-loweralkyl substituent. The aryl portion is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularly methylenedioxy, amino, nitro and other such groups. The alkyl substituents are preferably loweralkyl, more preferably containing 1 -3 carbons. If X is NR11 , then R11 is aryl, particularly unsubstituted phenyl or substituted phenyl, such as isopropylphenyl.
Other preferred compounds, which are ETB active, are those in which Ar2 has formula IVB in which R9 is aryl or Z-substituted aryl, particularly phenyl, and Z is loweralkyl or loweralkoxy. In all embodiments of all of the compounds herein R1 is preferably halide or loweralkyl, most preferably Br, and the compounds are, with reference to formulae IV, 2- or 3-sulfonamides, particularly thiophene sulfonamides. In certain embodiments provided herein, Ar2 is a benzo[b]thienyl, benzo[b]furyl or indolyl (benzo[b]pyrrolyl) group and the compounds provided herein are preferably benzo[b]thienyl-, benzotblfuryl- or indolylsulfonamides. Benzo[b]thiophene, benzo[b]furyl and indolyl 2- or 3-sulfonamides are among the compounds preferred herein. The benzo[b]thiophene, benzo[b]furyl and indolyl 2- or 3-sulfonamides provided herein are selected with the proviso that the benzene group has at least one substituent and that substituent is other than 5-halo and 3-loweralkyl. Compounds of particular interest include those of formula II in which Ar2 is a phenyl-, benzothienyl, benzofuryl or indolyl [benzopyrrolyl! group or in which Ar2 is a substituted phenylaminocarbonylthienyl, substituted phenylaminocarbonylfuryl, substituted phenylaminocarbonylpyrrolyl group or Ar2 is phenylacetylthiophene, phenyl- acetylfuran, or phenylacetylpyrrole, or is an acetoxystyrylthiophene, acetoxystyrylfuran or acetoxystyrylpyrrole. In certain embodiments, Ar2 is a substituted phenylaminocarbonylthienyl, substituted phenylaminocarbonylfuryl, substituted phenylaminocarbonylpyrrolyl group in which there are at least two substitutents on the phenyl ring.
The most preferred compounds provided herein have an IC50 for ETA receptors in the assays exemplified herein less than 0.1 μM, more prefereably less than 0.01 μM, and more preferably less than 0.001 (see, e.g.. Table 6 for representative experimental results), when measured at 4° C, as described in the Examples. When measured at 24° C, the IC50 concentrations are somewhat higher (2- to 10-fold; see, Table 1 for some comparative values). Among the preferred compounds of interest herein are those in which Ar2 has formula XIX:
Figure imgf000100_0001
in which M is (CH2)mC(0)(CH2)r, (CH2)mC(0)NH(CH2)r, (CH2) CH = CH)(CH2)r,
(CH2)mC(0)(CH2)sNH(CH2)r, (CH2)m(CH = CH)(CH2)r, C = N(OH)(CH2)r, (CH2)mC(0)(CH *=CH)sNH(CH2)r, CH(0H)(CH2)r, CH(CH3)C(0)(CH2)r, CH(CH3)C(0)(CH2)m(CH = CH)(CH2)r, (CH2)r, (CH2)r0, C(0)0, in which m,s and r are each independently 0 to 6, preferably 0 to 3, more preferably M is (CH2)mC(0)(CH2)r, (CH2)mC(0)NH(CH2)r, (CH2) CH = CH)(CH2)r, (CH2)mC(0)(CH2)sNH(CH2)r, (CH2)m(CH = CH)(CH2)r C = N(0H)(CH2)r, CH(0H)(CH2)r, (CH2)r, (CH2)r0, C(0)0;
R51, R52, R53, R54 and RBB are each independently selected from (i) or (ii) as follows: (i) R51, R52, R53, R54 and R5B are each independently selected from among H, OH, NHR38, C0NR38R39 , N02, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy and formyl; or (ii) at least two of R51, R52, R53, R54 and R5B, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e. -0-(CH2)n-0-, — S-(CH2)n-0-, — S-(CH2)n-S-, where n is 1 to 4, preferably 1 or 2,) which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R5 , R52, R53, R54 and R55 are selected as in (i); and
R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl. In certain embodiments, when M is (CH2)mC(0)NH(CH2)r, then at least two of
R51 , R52, R53, R54 and RBB are not hydrogen.
M is most preferably selected from
H I \ \ \ ^ ^ o
_ , and o ' o o ■
In general, however, in all of these compounds in which Ar2 has formula V or VI or in which R8 includes an aryl group, regardless of the selection of M, it is preferred that the aryl substituent have more than one substituent or at least one substituent in the ortho position. Aryl is preferably phenyl that is preferably substituted at the ortho position and, more preferably at at least one additional position, particularly 4 and 6, or adjacent positions, such as 3,4 or 4,5 when the subsitutents are linked to form an alkylenedioxy (or analog thereof in which one or both oxygens is(are) replaced with S.
In certain compounds herein, at least one of R51 and R5δ is other than hydrogen.
In more preferred compounds, M is C(0)CH2, C(0)NH, -CH = CH— ,
CH2CH2C(0)(CH)2, CH2CHC(0)CH2, and Ar2 most preferably has formula XX:
Figure imgf000102_0001
in which W is CH, 2 or NH
M is even more preferably selected from among:
Figure imgf000102_0002
in which R40 is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, and more preferably loweralkyl, loweralkoxy, or halo loweralkyl, and is more preferably hydrogen or loweralkyl, particularly methyl or ethyl, and is most preferably hydrogen.
M is most preferably:
H I
Figure imgf000102_0003
In preferred compounds RB1, R52, R53, R84 and R55 are selected from (i) or (ii): (i) R51, R52, R53, R54 and R55 are each independently selected from loweralkyl, haloloweralkyl, phenyl, alkoxy, loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl, loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy lowerallkyl, acetoxy loweralkoxy or loweralkoxycarbonyl; or
(ii) R52 and R53 or R53 and R54 form alkylene dioxy, preferably methylenedioxy, and the others of R51, R52, R53, R54 and R55 are selected as in (i).
In preferred embodiments, R51, R83, R55 are other then hydrogen and are preferably loweralkyl or lower alkoxy, or R51 or R55 is other than hydrogen, preferably loweralkyl or lower alkoxy, and R52 and R53 or R53 and R54 form methylenedioxy. In particular, Ar1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2- pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl.
In one embodiment, the sulfonamides have formula V:
Figure imgf000103_0001
or the corresponding thiophene-2-sulfonamides as defined above. Ar1 is a substituted or unsubstituted monocyclic or polycyclic, preferably a monocyclic or fused bicyclic, aryl group with one or more substituents, selected from, for example, H, NH2, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons. The substituents are preferably H, NH2, halide, CH3, CH30 or another aromatic group. In particular, Ar2 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2- pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl, more preferably 4-chloro-3-methyl-5-isoxazolyl or 4-chloro-5-methyl-3-isoxazolyl; W is -NH-, = NC0R16, = NC02R16, -NHC(R12)(R16)- or is -CH2- when R54 is hydroxyl.
R54 is selected from the group consisting of substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, 0C(0)R16, 0C02R16, NR12R1 β and S(0)nR16 in which n is 0-2; preferably alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, alkylsulfonylamino and aminosulfonyl.
Rδ1, R53 and R55, which are preferably alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylaikyl, or heteroarylalkyl, more preferably lower alkyl, lower alkenyl, lower alkynyl, or aryl, most preferably methyl.
In preferred embodiments of the compounds of formula V, Ar1 is 3- or 5- isoxazolyl, benzo-2,1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2,1 ,3-oxadiazol-5-yl, more preferably 3-methoxy-2-pyrazinyl, 3,4-dimethyl-5-isoxazolyl, 4-chloro-3-methyl-5- isoxazolyl or 4-chloro-5-methyl-3-isoxazolyl; W is -NH-, = NC02R16, or is -CH2- when R54 is hydroxyl; R51, R53 and R55 are methyl; and R54 is selected from the group consisting of substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, OC(0)R16, 0C02R16, NR12R16 and S(0)nR16 in which n is 0-2; preferably alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, alkylsulfonylamino and aminosulfonyl.
R54 is, in certain of these embodiments, methoxy, methoxycarbonylmethoxy, 2- (2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N- dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxy, hydroxyl, carboxyl, cyanomethyl, acetoxymethyl, hydroxymethyl, carboxylmethyl, methanesulfonylamino, N,N-dimethylaminomethyl, S02NH2, or methoxycarbonylmethyl. R54, in more preferred embodiments, does not contain a cyano group and is, for example, methoxy, methoxycarbonylmethoxy, 2-{2-methoxyethoxy)ethoxyacetoxy, 2- hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxymethyl, methoxycarbonylmethyl, hydroxy or acetoxy.
Among the compounds of formula V are:
N-(4-chloro-3-methyI-5-isoxazolyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- acetoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3- methyl-5-isoxazolyl)-2-(3-pyrrolidinyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-dimethylamino- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-(N,N-dimethylthiocarbonyloxymethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N- dimethylthiocarbonyloxy)-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethoxy)-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyI-5-isoxazolyl)-2-(3-(2-(2- methoxyethoxy)ethoxy)acetoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfon- amide; N-(4-ch!oro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethoxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-methoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4- chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-dimethylaminomethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-methanesulfonylamino-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-sulfamoyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3- cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro- 5-methyl-3-isoxazolyl)-2-(3-methoxycarbonylmethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-carboxylmethyl- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-5-methyl-3- isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfona- mide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3- dimethylaminomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N- (4-chloro-5-methyl-3-isoxazolyl)-2-(3-methanesulfonylamino-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3- isoxazolyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-sulfamoyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(3,4-dimethyl-5- isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-methoxycarbonyImethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3- carboxylmethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(3,4- dimethyl-5-isoxazoiyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulfonamide; N-(3,4-dimethyI-5-isoxazolyl)-2-(3-hydroxymethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(*3,4-dimethyl-5- isoxazolyl)-2-(3-dimethylaminomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-methanesulfonylamino- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5- isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulf onamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-sulfamoyl- 2,4,6-trimethylphenylaminocarbonyl)tήiophene-3-sulfonamide; N-(benzo-2,1 ,3-thiadiazol- 5-yl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N- (benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-methoxycarbonylmethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide; N-(benzo-2, 1 ,3-thiadiazol-5-yi)-2-(3-carboxylmethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(benzo-2, 1 ,3-thiadiazol- 5-yl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyiaminocar- bonyl)thiophene-3-sulfonamide; N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3- dimethylaminomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N- (benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-methanesulfonylamino-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; N-(benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-hydroxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(benzo-2, 1 ,3-thiadiazol- 5-yl)-2-(3-carboxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-
(benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-cyano-2,4,6-trimethylphenylaminocarbonyl)thiophene- 3-sulfonamide; N-(benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-sulfamoyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-cyanomethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2- pyrazinyl)-2-(3-methoxycarbonylmethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene- 3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-acetoxymethyl- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(3-methoxy-2- pyrazinyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfona- mide; N-(3-methoxy-2-pyrazinyl)-2-(3-dimethylaminomethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3- methanesulfonylamino-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N- (3-methoxy-2-pyrazinyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(3-cyano- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(3-methoxy-2- pyrazinyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-( 1 -methyl-1 -phenyl-1 -ethylaminocarbonyDthio- phene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((R)-1 -phenyl-1 -ethylamino- carbonyl)thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-((S)-1- phenyl-1-ethylaminocarbonyl)thiophene-3-sulfonamide.
Among the more preferred compounds of formula II are: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfona- mide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-methoxycarbonylmethoxy-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-(2- methoxyethoxy)ethoxy)acetoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfon- amide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethoxy)-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N- dimethylthiocarbonyloxy)-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N-dimethylthiocarbonyloxymethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-dimethy)amino-2,4,6-trimethy)phenylaminocarbonyl)thiophene-3-sulfona- mide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-pyrrolidinyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.
In another embodiment, the sulfonamides have formula XXI:
Figure imgf000108_0001
or the corresponding thiophene-2-sulfonamides as defined above, where Ar1 is a substituted or unsubstituted monocyclic or polycyclic, preferably a monocyclic or fused bicyclic, aryl group with one or more substituents, selected from, for example, H, NH2, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons. The substituents are preferably H, NH2, halide, CH3, CH30 or another aromatic group. In particular, Ar1 is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring or a fused bicyclic substituted or unsubstituted aromatic or heteroaromatic ring, preferably 3- or 5-isoxazolyl, benzo-2, 1 ,3-thiadiazol-5-yl, 2-pyrazinyl or benzo-2, 1 ,3-oxadiazol-5-yl; X is S, 0 or NR11; each G and R, which are selected from among the R1-R5 as defined above, are preferably independently selected from lower alkyl, CN, — (CH2)xC(0)(CH2)x, — (CH2)X, (CH2)xN-lower alkyl, — (CH2)xC(0)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, — S(0)2NH2, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, -(CH2)xC00H; — (CH2)xC00H— , C02-lower alkyl, CN, heteroaryl, -C0C(0)(CH2)xCH3, -(CH2)XN(CH3)2, a sulfonyl chloride, S(0)2NHRso, alkylaryl, alkylheteroaryl, C(0)NHR50, -(CH2)x0H, -C(0)N(H)N(H)M'; R50 is hydrogen, lower alkyl, lower alkoxy; M' is H or R50; R' is selected from hydrogen, G and R; W is = C(halo)2, = N(H), -(CH2)X-, = N(lower alkyl), -C(O)-, = C(lower alkyl)2, and x is 0-3.
In particular, in these embodiments compounds where: R, G and R' are selected where the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the heteroaryl is triazoly), and X is S are of interest. Also of interest are compounds in which: W is =CH2, =NH, =NCH3, = NCH2CH3, = C(CH3)2 or CF2; and G is -CH3, -CN, -COCH3, -CH2CH3, -(CH2)xC02H. Among these compounds are: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide; N2-(3-cyanomethyl-2,4,6-trimethyiphenyl)-3-(4- chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; methyl- 2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 2,4,6-trimethylphenyl)acetate; 2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2- thienylcarboxamido)-2,4,6-trimethylphenyl)acetic acid; N2-(3-acetyloxymethyl- 2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thio- phenecarboxamide; N2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-dimethylaminomethyl-2,4,6- trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide trifluoroacetate; N2-(3-(4,5-dihydro-1 ,3-oxazol-2-yl)-2,4,6-trimethylphenyl)-3-
(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 3-(3-(4-chloro- 3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylbenzoic acid; N-[3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6- trimethylbenzoyljglutamic acid; N-[3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2- thienylcarboxamido)-2,4,6-trimethylbenzoyl]aspartic acid; N-[2-(3-(3-(4-chloro-3-methyl- 5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenyl)acetyl]glutamic acid; N-[2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6- trimethylphenyl)acetyl]aspartic acid; N2-(3-cyano-2,4,6-trimethylphenyl)-3-(4-chloro-3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 2-(3-(3-(4-chloro-3-methyl-5- isoxazoIylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenoxy)acetic acid; N2-(3- alkylsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3- ethyl-5-isoxazolylsulfamoyl)-2- thiophenecarboxamide; N2-(3-arylsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-sulfamoyl-2,4,6-trimethyl- phenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3- alkylsulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thio- phenecarboxamide; N2-(3-arylsulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-(1 H-1 ,2,3,4-tetraazol-5-ylmethyl)- 2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thio- phenecarboxamide; N2-(3-(2-pyridylmethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl- 5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-hydrazinocarbonyl-2,4,6- trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-aminomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)- -thiophenecarboxamide; N2-(3-(a-D-mannopyranosyloxymethyl)-2,4,6-trimethylphenyl)-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 5-(3-(4-chloro- 3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-cyano-6-methylbenzo[dl- [1 ,3]dioxole; 5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 6-cyano-4-methylbenzotd][1 ,3]dioxole; 2-(5-(3-(4-chloro-3-methyl-5-isoxazolyl- sulfamoyl)-2-thienylcarboxamido)-4-methylbenzo[d][1 ,31dioxole)-6-acetic acid; 5-(3-(4- chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-acetyl-6-methylbenzo- [d][1 ,3]dioxole; 5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 6-acetyl-4-methylbenzo[dlt1 ,3]dioxole; 5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2- thienylcarboxamido)-7-cyano-4,6-dimethylbenzo[d][1 ,3]dioxole; 6-(3-(4-chloro-3-methyl- 5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-5,7-dimethylbenzo[d][1 ,3]dioxole-4- carboxylic acid; 7-{3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-5,6-dimethylbenzofd][1 ,3]dioxole-4-carboxylic acid; 7-(3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-cyano-5,6-dimethylbenzo[d][1 ,3]dioxole; 7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-acetyl-5,6- dimethylbenzo[d][1 ,3]dioxole; 7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyl- carboxamido)-4-carboxamido-5,6-dimethylbenzo[d][1 ,3]dioxole; 7-(3-(4-chloro-3-methyl- 5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-aminomethyl-5,6-dimethylbenzo[d][1 ,3l- dioxole; 7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4- dimethylaminomethyl-5,6-dimethylbenzo[d][1 ,3]dioxole; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfona- mide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxymethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4- chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- methoxycarbonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide. In another embodiment, the sulfonamides have formula XXII:
Figure imgf000111_0001
or the corresponding thiophene-2-sulfonamides as defined above, and Ar1 is defined as above. Ar1 is preferably benzo-2, 1 ,3-oxadiazol-5-yl or 2-methoxy-3-pyrazinyl when R5β is H; and R56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
In other embodiments of formula (IV), Ar1 is preferably benzo-2, 1 ,3-oxadiazol-5- yl or 2-methoxy-3-pyrazinyl when R56 is H and
R56 is H, or substituted or unsubstituted alkyl or aryl, preferably H or substituted or unsubstituted lower alkyl, more preferably methyl or carboxymethyl.
Thus, preferred compounds of formula IV include:
N-(benzo-2,1 ,3-oxadizaol-5-yl)-2-(2-methyl-4,5-methylenedioxyphenylacetyl)thio- phene-3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(2-methyl-4,5- methylenedioxyphenylacetyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-(2-(2-methyl-4,5-methylenedioxyphenyl)propanoyl)thiophene-3-sulfona- mide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2-(2-methyl-4,5- methylenedioxyphenyl)propanoyl)thiophene-3-sulfonamide.
In another embodiment, the sulfonamides have formula XXIII: (XXIII)
Figure imgf000112_0001
or the corresponding thiophene-2-sulfonamides as defined above. Ar1 is defined as above and is preferably 4-chloro-3-methy!-5-isoxazolyl; W is
NH; and R57 is selected from the group consisting of aryl, heteroaryl, heterocycle, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, — (CH2)xOH, NHOH, NR12R1β, N02, N3, OR16, R12NCOR16 and CONR12R1β; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R12, R 5 and R16 may be further substituted with the any of the groups set forth for Z; R57 is preferably CONH2, COOH, or phenyl.
Preferred embodiments of the compounds of formula XXIII are those wherein Ar1 is 4-chloro-3-methyl-5-isoxazolyl; W is NH; and R57 is CONH2, COOH, or phenyl.
It is understood that 4-bromo or 4-chloro groups can be replaced by other 4-halo substituents or other suitable substituents for R1, such as alkyl. Among the preferred compounds of formula (XXIII) are:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-I(2,3/4-trimethoxy-6-cyano)phenylaminocar- bonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- methoxycarbonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-su!fonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxymethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfona- mide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,l4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- methoxycarbonylmethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-dimethylaminomethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide, trifluoroacetic acid salt, N-(4-chloro-3-methyl- 5-isoxazolyl)-2-(σ-methyl-2-methyl-4,5-(methylenedioxy)phenylacetyl)thiophene-3-sulfon- amide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(c7-carboxylmethyl-2-methyl-4,5- (methylenedioxy)phenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-methanesulfonylamino-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-carbamoyl-4,6-dimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide, N-(4-chloro-3- methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sύl- fonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-carboxyl-4,6-dimethylphenylaminocar- bonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-phenyi-4,6- dimethylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-cyano-2,4,6-trimethyIphenylaminocarbonyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide, N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-cyanomethyl- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide, N-(4-chloro-5-methyl-3- isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfona- mide, N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)-2-(3- cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide, N-(3,4- dimethyl-5-isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulf onamide, N-(3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide, and N-(4-chloro-3-methyl-5- isoxazolyl)-2-(pentamethylphenylaminocarbonyl)thiophene-3-sulfonamide. In preferred embodiments, Ar2 has the formula:
Figure imgf000114_0001
where Rβ1 and R62 are hydrogen, or are each independently selected from halo, cyano, cyanoalkyl, C(0)R41 , alkyl, alkenyl, cycloalkyl and aryl, or R61 and R62 together form alkylene; W is O, NH or CH2;
R65, R66 and R67 are each independently selected as in (i) or (ii):
(i) R66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
C(0)R41 , carbamoyloxy or alkoxycarbonyloxy, and
R65 and R67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R41, carbamoyloxy and alkoxycarbonyloxy; or
(ii) if at least one of R61 and R62 is not hydrogen, then any two may form alkylenedioxy, and the other is selected as in (i); and
R4S is selected from among alkyl, C(0)R41, (CH2)xOH and CH(OH)(CH2)xCH3 in which x is 0-6, S(0)nR41 in which n is 0-2 and C( = NR43)R41; R41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, (aryD(alkyl)amino, alkylsulfonylamino, arylsulfonylamino, (alkylsulfonyl) (alkyl or aryDamino or (arylsulfonyl) (alkyl or aryDamino; and R43 is selected from hydroxy, alkoxy, alkyl and aryl. R41 and R43 are unsubstituted or substituted with one or more substituents selected from Y, which is defined as alkoxy, halide, pseudohalide, alkylcarbonyl, arylcarbonyl, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy. Also of interest are the corresponding 3-acyl-2- thiophenesulfonamides.
If the aryl group is tetrasubstituted, it will preferably be substituted at the 2, 4 and 6 positions, and one of these substituents will be a polar group, such as hydroxyl, acetoxy, carboxyl and carboxamide. If the aryl group is substituted at the 2, 4 and 6 positions with nonpolar groups, such as alkyl groups, more specifically methyl groups, then the aryl group will preferably be penta- or hexasubstituted. In pentasubstituted aryl groups, the fifth substituent will be at the 3 position and will preferably be a polar group, such as hydroxyl, acetoxy, carboxyl and carboxamide.
Preferred compounds include those in which R61 and R62 are each independently hydrogen, alkyl, halo, cyano, cyanomethyl, acetyl or cycloalkyl, or together form alkylene;
R65, R66 and R67 are each independently selected as in (i) or (ii): (i) R66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
C(0)R41, carbamoyloxy or alkoxycarbonyloxy, and
R65 and R67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R41, carbamoyloxy or alkoxycarbonyloxy; or
(ii) if at least one of Rβ1 and R62 is not hydrogen, then any two may form methylenedioxy, and the other is selected as in (i); x is 0 or 1 ; n is 2; R41 is alkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino or arylsulfonylamino; and R43 is hydroxy or alkoxy In particular, compounds which are preferred are those in which Ar1 is 4-chloro-
3-methyl-5-isoxazolyl; R61 and R62 are each independently hydrogen, methyl, cyclopropyl, fluoro, chloro, cyano, cyanomethyl or acetyl, or together form butylene; R65, R66 and R67 are each independently selected from (i) or (ii): (i) R66 is selected from hydrogen, methyl, hydroxy, methoxy, acetyl, carbamoyloxy and methoxycarbonyloxy, and
R6S and R67 are each independently hydrogen, methyl, hydroxy, acetyl, carbamoyloxy and methoxycarbonyloxy; or
(ii) if at least one of R61 and R62 is not hydrogen, then R66 and R67 may form methylenedioxy and R65 is selected as in (i); and R45 is acetyl, propanoyl, 2-methylpropanoyl, cyclopropylcarbonyl, benzoyl, cyclohexylcarbonyl, methyl, 1 -hydroxy-1 -ethyl, hydroxy methyl, methoxyacetyl, fluoroacetyl, carboxyacetyl, hydroxyacetyl, oximinoacetyl or S02R41.
Particularly preferred compounds of this embodiment are selected from the following: N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, N-(2-benzoyl-4,6-dimethylphenyl)-3- (((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, 3-(((4-chloro- 3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-2- thiophenecarboxamide, 3-(({4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-propionylphenyl)-2-thiophenecarboxamide, 3-{((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6- dimethylphenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)- sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide, 3- (((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6- trimethylphenyl carbamate, 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thienyl)carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-3- thiophenesulf onamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2- hydroxy-1 -methylethyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6-dimethylphenyl)-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-{2-(2,6- diacetyl)-4-methylphenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-2- thiophenecarboxamide, 3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thienyl)carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoic acid, 3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-methylsulfonyl)phenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-((dimethylamino)sulfonyl)phenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)- phenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2-(2-fluoroacetyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide, N-(2-acetyi-4,6- dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2- thiophenecarboxamide, N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino_)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-5-methyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-propionylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-5-methyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclohexylcarbonyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6- dimethylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl carbamate, 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5- methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate, N-(4-chloro-3- methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-5-methyl-3- thiophenesulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6- trimethylphenyl)acetyl)-5-methyl-3-thiophenesulf onamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1 -methylethyl)-4,6-dimethylphenyl)-5-methyl- 2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2- hydroxy-ethyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-5-methyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2- methoxyacetyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(2-(((4-chloro- 3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-3,5- dimethylphenyl)-3-oxopropanoic acid, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfon- yl)-N-(2-glycolyl-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-5-methyl- 2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-((methylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sul- fonyl)phenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-5- methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2-(2-fluoroacetyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide, N-(6-acetyl-4- methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5- methyl-2-thiophenecarboxamide, N-(4-acetyl-6-methyl-1 ,3-benzodioxol-5-yl)-3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide, N-(2- acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl- 2-thiophenecarboxamide, N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino_)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-4-methyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-propionylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-4-methyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2- (cyclohexylcarbonyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6- dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-({(3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl carbamate, 3-{((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4- methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate, N-(4-chloro-3- methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-4-methyl-3- thiophenesulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6- trimethylphenyl)acetyl)-4-methyl-3-thiophenesulfonamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1 -methylethyl)-4,6-dimethylphenyl)-4-methyl- 2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2- hydroxy-ethyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyD-N-(2-(2,6-diacetyl)-4-methylphenyl)-4-methyl-2- thiophenecarboxamide, 3-({(4-chIoro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2- methoxyacetyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(2-(((4-chloro- 3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-3,5- dimethylphenyl)-3-oxopropanoic acid, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sul- fonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-4- methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide, 3- (((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)- sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-({{methylsulfonyl)amino)carbonyl)phenyl)-4- methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2-(2-fluoroacetyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, N-(6-acetyl-4- methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4- methyl-2-thiophenecarboxamide, N-(4-acetyl-6-methyl-1 ,3-benzodioxol-5-yl)-3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide, N-(2- acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methy)-5-isoxazo)yl)amino)sulfonyl)-4,5- dimethyl-2-thiophenecarboxamide, N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro- 3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyD- 4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sul- fonyl)-N-(2,4-dimethyl-6-propionylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-4,5- dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2-{cyclohexylcarbonyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3- (((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6- dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl carbamate, 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5- dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate, N-(4-chloro-3- methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-4,5-dimethyl-3- thiophenesulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6- trimethylphenyl)acetyl)-4,5-dimethyl-3-thiophenesulfonamide, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1 -methylethyl)-4,6-dimethylphenyl)-4,5- dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2-(2-hydroxy-ethyl)-4,6-dimethylphenyl)-4,5-dimethyI-2-thiophenecarboxamide, 3-(({4- chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-4,5- dimethyl-2-thiophenecarboxamide, 3-{((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- (2-(2-methoxyacetyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(2- (((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)- amino)-3,5-dimethylphenyl)-3-oxopropanoic acid, 3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-4,5-dimethyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-methylsulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro- 3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)- 4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sul- fonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-4,5-dimethyl-2- thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4- dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-4,5-dimethyl-2-thiophene- carboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyD- 4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, N-(6-acetyl-4-methyl-1 ,3- benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2- thiophenecarboxamide, and N-(4-acetyl-6-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3- methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide.
Also among the preferred compounds are those selected from the following: N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sul- fonyl)-5-cyclopropyl-2-thiophenecarboxamide, 5-acetyl-(N-(2-acetyl-4,6-dimethylphenyl)- 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, N-(2-acetyl- 4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-cyano-2- thiophenecarboxamide, N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-(cyanomethyl)-2-thiophenecarboxamide, N-(2-acetyl-4,6- dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-fluoro-2- thiophenecarboxamide, N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-chloro-2-thiophenecarboxamide, and N-2-acetyl-4,6- dimethylphenyl)-5-chloro-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5,6,7- tetrahydro-1 -benzothiophene-2-carboxamide. Preferred compounds are also those where W is 0 or CH2. The sulfonamides are thus 2-phenoxycarbonyl-3-sulfonamide, 3-phenoxycarbonyl-2-sulfonamide, 2- phenylacetyl-3-sulfonamide and 3-phenylacetyl-2-sulfonamide derivatives of the above compounds.
Table 6 sets forth exemplary compounds of this embodiment and demonstrates that the compounds have activity as endothelin receptor antagonists. More preferred compounds of Table 6 are those that have the highest activities, and preferred substituents are those on the compounds wiht the highest activities. The data in Table 6 is intended for exemplary and comparison puroposes only and is not intended to limit the scope of this embodiment in any way. In the above embodiments, the alkyl, alkynyl and alkenyl portions are straight or branched chains, acyclic or cyclic, and have from about 1 up to about 10 carbons; in certain of the more preferred embodiments they have from 1 -6 carbons, and they can have fewer than 6 carbons. The aryl, homocyclic and heterocyclic groups can have from 3 to 16, generally, 3-7, more often 5-7 members in the rings, and may be single or fused rings. The ring size and carbon chain length are selected such that the resulting molecule binds to exhibits activity as an endothelin antagonist or agonist as evidenced by in vitro or in vivo tests, particularly the tests exemplified herein.
In any of the above preferred embodiments: R1 and R2 are preferably selected independently from alkyl, lower alkenyl, lower alkynl, lower haloalkyl, halide, pseudohalide and H. In certain embodiments, R2 is not halide or pseudohalide or higher alkyl.
In all embodiments, R1 is preferably halide or lower alkyl, most preferably Br, and the compounds are, with reference to formulae IV, 2- or 3-sulfonamides, particularly thiophene sulfonamides.
TABLE 6
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
results are generally the average of 2 to 5 experiments preliminary results or results in which one or more data points were only determined approximately assay performed with incubation at 24° C. As described in the Examples, incubation at the higher temperature reduces the activity by a factor of 2- to about 10-compared to the activity at 4° C data not available or measured as % inhibition @ 100 μM
% % inhibition @ 100 μM activity relative to N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6- methylphenyl)acetyl]-thiophene-3-sulf onamide b. Ar2 is a heterocycle with one heteroatom and two or more fused rings
Compounds in Ar2 is a heterocycle with one heteroatom and two or more fused rings are provided. The heteroatom is O, S or N and Ar2 is selected from among, but not limited to, quinolyl, isoquinolyl, dibenzofuryl, bibenzothienyl, and dibenzopyrrolyl compounds and other such groups. The fused rings may be substituted with one or more substituents selected from among substitutents set forth for R8, R9 and R10 above. at any position. The sulfonamide portion of the compounds may be linked at any . position.
(1) Ar2 is quinolyl and isoquinolyl Presently, preferred compounds are quinolines, particularly, 8-quinolinesulfonamides. The numbering scheme is as follows:
Figure imgf000143_0001
QUINOLINE
R1 and R2 are selected as described for the thienyl, furyl and pyrrolyl compounds, any of the rings may be substituted with one or more substituents selected from hydrogen or are selected as described above for R26 and R13.
Exemplary quinolinesulfonamides are set forth in Table 7:
TABLE 7
Figure imgf000143_0003
(2) Ar2 is dibenzofuryl, bibenzothienyl, and dibenzopyrrolyl
In certain embodiments Ar2 is dibenzofuryl, bibenzothienyl, and dibenzopyrrolyl and has the following formula (XXIV):
Figure imgf000143_0002
which is unsubstituted or substituted with one or more substituents selected from R13 and R26. In these embodiments, R1 and R2 are selected as described above for the thienyl, furyl and pyrrolyl compounds. These compounds are substituted as described above for the biphenyl compounds in which R13 and R6; X is -CH = CH-, 0, S, NR11 , in which R11 is as set forth above (compounds in which X is -CH = CH- are phenanthrenesulfonamides, which are discussed above), and R13 and R26 are independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons.
In more preferred embodiments, R1 is halide or methyl; R2 is selected from lower alkyl, lower alkenyl, lower alkynl and lower haloalkyl; R26 and R13 are selected from H, lower alkyl, haloalkyl and halide. In more preferred embodiments R1 is Cl, Br or CH3; R2 is selected from H, CH3, C2H5,CF3, n-C3H7, cyclo-C3H7 and C4H8; and R26 and R13 are each independently selected from H, halide, NH2, CF3 CH3, CN, CH3, (CH3)3C, C5\-\„, CH30, n-C4H90 and CH2 = CH. In yet more preferred embodiments, R2 is H, CH3,
C2H5, or CF3; R26 and R13 are independently selected from H, CH3, C2H5, CF3, and halide; and X is 0.
Exemplary compounds include those set forth in Table 8:
TABLE 8
Figure imgf000144_0001
* results based on 1 to 4 experiments c. Ar2 is a six-membered heterocycle with one heteroatom selected from S, O or NR11
Prefered six-membered heterocylic rings are pyridyl rings. The pyridyl groups may be substituted with one or more substituents selected from R13, R8 and R26, as defined above and may be 2-, 3- or 4-sulfonamides. R1 and R2 are selected as described above for the thiphenyl, furyl and pyrrolyl compounds.
Compounds in which Ar2 is a pyridyl group include, but are limited to, N-(4- bromo-3-methyl-5-isoxazolyl)pyridine-2-sulf onamide, N-(4-bromo-5-methyl-3- isoxazolyl)pyridine-2-sulf onamide, N-(3,4-dimethyl-5-isoxazolyl)pyridine-2-sulf onamide, N-(4,5-dimethyl-3-isoxazolyl)pyridine-2-sulf onamide, 3-methoxycarbonyl-N-(4-bromo-5- methyl-3-isoxazolyl)pyridine-2-sulf onamide and 3-methoxycarbonyl-N-(4-bromo-5- methyl-3-isoxazolyl)pyridine-2-sulf onamide, N-(3,4-dimethyl-5-isoxazolyl)-3-(N- phenylaminocarbonyl)pyridine-2-sulf onamide, N-(4-bromo-5-methyl-3-isoxazolyl)-3-(N- phenylaminocarbonyl)pyridine-2-sulfonamide, and N-(4-bromo-3-methyl-5-isoxazolyl)-3- {N-phenylaminocarbonyl)pyridine-2-sulfonamide. These compounds appear to be ETA selective with IC50 concentrations on the order of 1-3 μM or less. d. Ar2 is a heterocycle with two or more heteroatoms Compounds in which Ar2 is a heterocycle that contains two or more heteroatoms selected from O, S, N, and NR11, including, but are not limited to pyrimidinyl, purinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, benzofuryl, benzothienyl and benzopyrrolyl, are provided. These compounds may be unsubstituted or substituted with one or more substitutents selected from those set forth for R3 R8 or R26. Particular compounds that have been synthesized, include:
TABLE 9
Figure imgf000145_0001
Figure imgf000146_0002
* results based on 1 to 4 experiments e. Ar2 is a fused bicyclic heterocycle with two or more heteroatoms The compounds of this embodiment have formulae IX:
Figure imgf000146_0001
in which Y is N or 0+; X is S, 0, NR11, in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NC0R1 β and C0NR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)πR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R1 B and R16 may be further substituted with the any of the groups set forth for Z; R1 and R2 are either (i), (ii) or (iii) as follows: (i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl;
R83, R84 and R85 are selected from (i), (ii), (iii) or (iv):
(i) R83, R84 and R8S are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl or amido, where the alkyl, alkenyl, alkynyl portions are straight or branched chains of from about 1 up to about 10 carbons, preferably 1 to about 5 or 6 carbons and the aryl portions contain from 3 up to about 10 carbons, preferably 6 carbons; or, alternatively, (ii) two of R83, R84 and R85 together are substituted or unsubstituted 1 ,3- butadienyl, 4-dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 ,3- butadienyl or 2-aza-1 , 3-butadienyl groups; and the others of R83, R84 and R85 are as defined in (i) above; or alternatively,
(iii) R84 is H; and R83 and R85 are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains; or
(iv) any two of R83, R84 and R85, which are each selected as in (i) form fused carbocyclic or heterocyclic rings; and
R87 is hydrogen or contains up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, and is selected hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, C02R18, (CH2)rR18, (CH2)rCOR18 (CH2)rC0(CH2)sR18, SH, S(0)n, (CH2)r, S(0)nR18 in which n is 0-2, and s and r are each independently 0 to 6, preferably 1 -3, HNOH, NR18R19, N02, N3, OR18, R19NC0R18 and C0NR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R87 is unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NCOR21 and CONR22R21 ; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl.
R87 is preferably C(0)R18, C02R13, (CH2)rR18, (CH2)rC0R18 (CH2)rCO(CH2)sR18, NR18R19, OR18, R19NCOR18 or CONR19R18.
More preferred compounds are those of formula (IX) that have formula (XXV):
Figure imgf000148_0001
Also of interest of compounds of formula (XXVI):
Figure imgf000148_0002
In preferred embodiments of the compounds herein, particularly the compounds of formulae (XXV) and (XXVI), R87 is C(0)R18, C02R18, (CH2)rR18, (CH2)rC(0)CH2)sR18,
NR18R19, OR18, R19NC0R18 and CONR19R18 in which r is 0 to 6, preferably 1-3,
When R87, R18 or R19 is aryl, particularly phenyl, or includes an aryl group, particularly phenyl:
Figure imgf000149_0001
it is unsubstituted or substituted at positions 2-6 with one or more of R92, R93, R94, R95 and R96, respectively, which are each independently selected from (i), (ii) or (iii) as follows:
(i) R92, R33, R94, R95, and R96 are each independently selected from among H, NHR38, CONR38, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl, where R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, lower alkyl, lower alkoxy and lower haloalkyl; or
(ii) at least two of R92, R93, R94, R96 and R96 are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy ( e. — 0-(CH2)n-O-, — S-(CH2)n-0-, — S-(CH2)n-S-, where n is 1 to 4, preferably 1 or 2), which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R92, R93, R94, R96 and R96 are selected as in (i); or
(iii) at least two of R92, R93, R94, R95 and R96 are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (he. -0-(CH2)n-0-, — S-(CH2)n-0-, -S-(CH2)n-S-, where n is 1 to 4, preferably 1 or 2), which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of the others of R93, R94, R95, and R96 are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e. — 0-(CH2)n-0-, -S-(CH2)n-0-, — S-(CH2)n-S-, where n is 1 to 4, preferably 1 or 2), which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the other of R92, R93, R94, R95 and R96 is selected as in (i). Preferably at least one, more preferably two, of R92, R93, R94, R95 and R96 is H and the others are selected from among (i), (ii) or (iii) as follows:
(i) alkoxy, halo, alkylcarbonyl, formyl, and alkyl, in which the alkyl portions or groups contain from 1 to 3 carbons, provided that at least one of R92, R93, R94, R95, and R96 is H;
(ii) at least two of R92, R93, R94, R94, R95 and R96 are substituting adjacent carbons and together form alkylenedioxy and the others of R92, R93, R94, R95 and R96 are selected as set forth in (i); or
(iii) at least two of R92, R93, R94, R95 and R96 are substituting adjacent carbons and together form alkylenedioxy, and at least two of the others of R92, R93, R94, R9B and R96 are substituting adjacent carbons and together form alkylenedioxy, and the other of R92, R93, R94, R95 and R96 is H.
More preferably, at least one of R92 and R96 is not hydrogen. When R87, R18 or R19 is pyrimidyl, it is substituted with one or more substitutents selected from (i) or (ii)
(i) H, NHR38, CONR38, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl, where R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, lower alkyl, lower alkoxy and lower haloalkyl; or
(ii) at least two substituents are on adjacent members of the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e. — 0-(CH2)n-0-, — S-(CH2)n-0-, — S-(CH2)n-S-, where n is 1 to 4, preferably 1 or 2), which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others substituent(s) are selected as in (i). In preferred compounds R87 is (CH2)rR18, and R18 is phenyl or pyrimidyl, preferably phenyl, in which at least two of substituents are on adjacent members of the ring and form alkylenedioxy, one or two remaining substituents are lower alkyl or lower alkoxy, preferably methyl or methoxy, more preferably methyl, and the others are hydrogen. In preferred compounds of all of the embodiments herein, Y is preferably N, and X is preferably S or 0, more preferably S.
Among the preferred compounds are those set forth in Table 10:
TABLE 10*
Figure imgf000151_0001
assay performed with incubation at 24° C. As described in the Examples, incubation at this higher temperature reduces the activity by a factor of 2- to about 10-compared to the activity at 4° C results are generally the average of 2 to 3 experiments - data not available or measured as % inhibition @ 100 μM % = % inhibition @ 100 μM
3. Compounds in which Ar2 is alkyl
Compounds in which Ar2 is alkyl include compounds in which Ar2 is CH3-(CH2)n, where n is 0 to about 30, preferably, 0 to 20, and more preferably between about 5 and about 10 and which may be substituted with halide, amino, carbonyl, nitro, and the like, and compounds in which Ar2 is
or isomers or substituted derivatives thereof.
Figure imgf000152_0001
R1 and R2 are selected as described above for the thienyl, furyl and pyrrolyl compounds. The methyl groups may be replaced by other lower alkyl groups, hydrogen or halide.
Selected compounds have the following activities:
TABLE 11
Figure imgf000152_0002
preliminary results 4. Compounds in which Ar2 is styryl
Compounds in which Ar2 is styryl are provided. These compounds have formulae (XXVII):
Figure imgf000153_0001
in which R1 and R2 are selected as described above for the thienyl, furyl and pyrrolyl compounds and; R1-R9 are as defined above, R8 and R9 may be cis or trans position. Compounds in which Ar2 is styryl include, but are not limited to: N-(3,4-dimethyl-5- isoxazolyl)-jff-tra/7S-styrenesulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-/£-tra/7s-sty- renesulfonamide, N-(4-bromo-5-methyl-3-isoxazolyl)-jff-tra 7S-styrenesulfonamide, 2-nitro- N-(3,4-dimethyl-5-isoxazolyl)styrenesulf onamide, 2-nitro-N-(4-bromo-3-methyl-5- isoxazolyDstyrenesulfonamide, 2-nitro-N-(4-bromo-5-methyl-3- isoxazolyDstyrenesulf onamide, 1 ,2-tra7s-dimethyl-N-(3,4-dimethyl-5-isoxazolyl)styrene- 1 -sulfonamide, 1 ,2-tra/7S-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)styrene-1 - sulfonamide, 1 ,2-tra/7s-dimethyl-N-(4-bromo-5-methyl-3-isoxazolyl)styrene-1 - sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)-2-phenylstyrene-1 -sulfonamide, N-(4-bromo- 5-methyl-3-isoxazolyl)-2-phenylstyrene-1 -sulfonamide, N-(4-bromo-3-methyl-5- isoxazolyl)-2-phenylstyrene-1 -sulfonamide, 1 ,2-c/s-dimethyl-N-(3,4-dimethyl-5- isoxazolyl)styrene-1 -sulfonamide, 1 ,2-c/s-dimethyl-N-(4-bromo-3-methyl-5- isoxazolyl)styrene-1 -sulfonamide and 1 ,2-c/s-dimethyl-N-(4-bromo-5-methyl-3- isoxazolyl)styrene-1 -sulfonamide. The activities of exemplary compounds are set forth in Table 12.
TABLE 12
Figure imgf000153_0002
Figure imgf000154_0002
* preliminary results
5. Other endothelin receptor antagonists
Any endothelin receptor antagonist, or any compound that alters or otherwise modulates endothelin activity, is intended for use in the methods provided herein. In particular, endothelin receptor antagonists disclosed in the following documents are contemplated for use in the methods provided herein. a. U.S. Patent No. 5,856,484
In particular, compounds of formula I are intended for use in the methods provided herein:
Figure imgf000154_0001
wherein R1 is phenyl, substituted phenyl or heterocyclyl; R2 is phenyl or substituted phenyl; R3 is hydroxy, lower-alkoxy or a residue -NR4R5; R4 is hydrogen or a residue -Rβ and R5 is hydrogen or a residue -(CH2)mR6 or R4 and Rδ together with the N atom to which they are attached are in N heterocyclic residue; R6 is phenyl, substituted phenyl, cycloalkyl, heterocyclyl, lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl, carboxy- lower-alkyl or lower-alkoxycarbonyl-lower-alkyl; Ra is hydrogen, lower-alkyl or hydroxy; Rb is hydrogen or lower-alkyl; X is oxygen or sulphur; Y is oxygen or sulphur; Z is hydrogen, lower-alkyl, aryl, aryl-lower-alkyl, hetero-cyclyl or heterocyclyl-lower-alkyl; m is 0, 1 or 2; and n is 0, 1 or 2; and pharmaceutically acceptable salts thereof.
Preferred compounds of this embodiment are those where R1 is phenyl; a substituted phenyl substituted by a chemical group selected from the group consisting of lower alkyl, lower alkoxy, methylenedioxy, ethylenedioxy, Iower-alkanoyl, hydroxy, amino, mono-iower-alkylamino, di-lower-alkylamino or halogen; or heterocyclyl selected from the group consisting of 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tetrazolyl-4-pyridyl, 1 ,2-diazinyl, 1 ,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl; R2 is phenyl or a substituted phenyl substituted by a chemical group selected from the group consisting of lower alkyl, lower alkoxy, methylenedioxy, ethylenedioxy, lower-alkanoyl, hydroxy, amino, mono-lower-alkylamino, di-lower-alkylamino and halogen; R3 is hydroxy, lower alkoxy or -R4 R5; R4 is hydrogen or -R6 and R5 is hydrogen or -{CH2)mR6 or R4 and R5 together are an N-heterocyclylic chosen from the group consisting of morpholino, piperidino, piperazino and N4 -lower -alkylpiperazino; R6 is phenyl; cycloalkyl; lower-alkyl; hydroxy lower alkyl; amino-lower-alkyl; carboxy-lower-alkyl; lower-alkoxycarbonyl- lower-alkyl; a substituted phenyl substituted by a chemical group selected from the group consisting of lower alkyl, lower alkoxy, methylenedioxy, ethylenedioxy, lower-alkanoyl, hydroxy, amino, mono-lower-alkylamino, di-lower-alkylamino or halogen; or heterocyclyl chosen from the group consisting of 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tetrazolyl-4-pyridyl, 1 ,2-diazinyl, 1 ,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl; Ra is hydrogen, lower-alkyl or hydroxy; Rb is hydrogen or lower alkyl; X is oxygen or sulfur; Y is oxygen or sulfur; Z is hydrogen; lower-alkyl; aryl; aryl-lower-alkyl; heterocyclyl selected from the group consisting of 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tetrazolyl-4-pyridyl, 1 ,2-diazinyl, 1 ,4-diazinyl, morpholino,
2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl; or heterocyclyl selected from the group consisting of 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tetrazolyl-4-pyridyl, 1 ,2-diazinyl, 1 ,4-diazinyl, morpholino, 2-thienyl. 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl, wherein the heterocyclyl is substituted with lower-alkyl; m is 0, 1 , or 2; and, n is 0, 1 , or 2; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of this embodiment include 6-(4-tert- butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2- carboxylic acid phenylamide; (RS)-4-(4-tertButyl-phenylsulphonylamino)-6-(2,3- dihydroxy-propoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid (3-hydroxy- phenyD-amide; 4-(4-tert-Butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(3- methoxy-phenoxy)-pyrimidine-2-carboxylic acid (3-hydroxy-phenyl)-amide; 4-(4-tert- Butyl-phenylsulphonylamino)-6-(2-hydroxyethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-c arboxylic acid (3-hydroxymethyl-phenyl)-amide; 4-(4-tert-Butyl-phenylsulphonylamino)- 6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid (2-hydroxy- methylphenyDamide; 6-{4-tert.Butyl-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-4-(2- hydroxy-ethoxy)-pyrimidine-2-carboxylic acid phenylamide; 4-(4-tert-Butyl-phenyl- sulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidine-2-car boxylic acid phenylamide; 6-(4-tert-butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)- 5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid; (RS)-6-(4-tert-butyl-phenyl- sulphonylamino)-4-(2,3-dihydroxy-propoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2- carboxylic acid; 6-(4-tert-butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-pyrimidine-2-carboxylic acid; 4-(4-tert-buty!-phenylsulphonyl- amino)-5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidine-2-carboxylic acid; 4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(3-methoxy- phenoxy)-pyrimidine-2-carboxylic acid pyridin-3-ylamide; (RS)-4-(4-tert-Butyl-phenyl- sulphonylamino)-6-(2,3-dihydroxy-propoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2- carboxylic acid pyridin-3-ylamide; 4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy- ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid (1 H-tetrazol-5-yl)amide; 6-(4-tert-butylphenylsulphonyiamino)-4-(2,3-dihydroxypropoxy)-5-(3-methoxyphenoxy)- pyrimidine-2-carboxylic acid (1 H-tetrazol-5-yl)amide; 4-tert-Butyl-N-[6-(2-hydroxy- . ethoxy)-5-(3-methoxy-phenoxy)-2-(morpholin-4-ylcarboxyl)-pyrimidin-4-yl]-benzene- sulphonamide; 4-(2-Hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-6-(4-methoxy-phenylsulpho nylamino)-pyrimidine-2-carboxylic acid phenylamide; 4-(2-Hydroxy-ethoxy)-5-(3- methoxy-phenoxy)-6-(4-methoxy-phenylsulphonylamino)-pyrimidin-2-carboxylic acid; 4-(2-Hydroxyethoxy)-5-(3-methoxyphenoxy)-6-(5-methyl-pyridin-2-ylsulphonylamino)- pyrimidine-2-carboxylic acid (1 H-tetrazol-5-yl)amide; 4-(2-hydroxy-ethoxy)-6-(5- isopropyl-pyridin-2-ylsulphonylamino)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid; (R,S)-6-(2,3-Dihydroxy-propoxy)-5-(3-methoxyphenoxy)-4-(5-methylpyridin-2-yl- sulphonylamino)-pyrimidine-2-carboxylic acid; 4-(2-hydroxy-ethoxy)-6-(5-isopropyl- pyridin-2-ylsulphonylamino)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid; and 4-(4-tert-butyl-phenylsulphonylamino)-5-(3-methoxy-phenoxy)-6-(2-pyrimidin-2-yloxy- ethoxy)-pyrimidine-2-carboxylic acid. b. U.S. Patent No. 5,837,708
Other compounds for use in the methods provided herein include sulfonamides of the formula:
Figure imgf000157_0001
wherein R1 is heterocyclyl; R2 is selected from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkoxy-lower-alkyl, lower-alkylsulphonyl-lower-alkoxy, phenyl, lower alkylphenyl, lower-alkoxy-phenyl, lower-alkylenedioxyphenyl, phenyl-lower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, lower alkylenedioxyphenyl-lower alkyl, heterocyclyl and heterocycyl-lower alkyl; R3 is selected from the group consisting of lower-alkyl, lower-alkoxy, formyl, halo-lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl, -CH20-A-lower-alkyl, -(CH2)m-0-(CRaRb) nOH, -(CH2)m -0-(CRa Rb)-n OR 9, -(CH2)m-0-(CRa Rb)n NH2 and -(CH2)m -0-(CRaRb)n-Y-R9; R4 -R8 each are selected from the group consisting of hydrogen, lower-alkoxy and halogen; R9 is selected from the group consisting of heterocyclyl; phenyl; and phenyl substituted with a group selected from the group consisting of lower-alkyl, lower-alkoxy and halogen; Ra and Rb each are hydrogen or lower-alkyl; A is a ketalized 1 ,2-dihydroxy-ethylene group; Y is selected from the group consisting of -OC(0)0-, -NH(C(0)NH- and -NHC(0)0-; n is 2, 3 or 4; and m is 0 or 1 . Particularly preferred compounds of this embodiment include 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- 2,2'-bipyrimidin-4-ylamide, 5-pentyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-(2,2-dimethyl-propionyl)-thiophene- 2-sulphonic acid, 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4- ylamide, 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-thoxy)-5-2-methoxy- phenoxy)-2,2'-bipyrimidin-4-ylamide, pyridine-3-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-tert-butyl-thiophene-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide, 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- pyrimidin-4-ylamide, N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin- 4-yl-5-isopropyl-pyridine-2-sulphonamide, 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(3-methoxy-phenyl)-pyrimidin-4-yl-pyridine-2-sulphonamide, 5- isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-methylsulphanyl-pyrimidin- 4-yl-pyridine-2-sulphonamide, N-[2-(1 , 3-benzodioxol-5-yl)-6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-pyrimidin-4-yl-5-isopropyl-pyridine-2-sulphonamide, N-[5-(2-chloro-5- methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-morpholin-4-yl-pyrimidin-4-yl-5-isopropyl- pyridine-2-sulphonamide, 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5- (2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-methyl-pyridine-2-sulphonic acid 6- (2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, 5- isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- 2-morpholin-4-yl-pyrimidin-4-ylamide, 5-tert-butylthiophene-2-sulphonic acid 6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy-2-morpholin-4-yl-pyrimidin-4-yl amide, 2,5- dichlorothiophene-3-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- 2-morpholin-4-yl-pyrimidin-4-ylamide, 3,5-dimethylisoxazole-4-sulphonic acid 6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, 2,5- dichlorothiophene-3-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'- bipyrimidin-4-ylamide, and 3,5-dimethyl-isoxazole-4-sulphonic acid 6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide; pyridin-2-ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2,2'- bipyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)- 6-(5-pentyl-thiophen-2-ylsulphonylamino)-2,2'-bipyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[6-[5-(2,2-dimethylpropionyl)-thiophen-2-ylsulphonylamino-5- (2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy-ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4- yloxy-ethyl ester, pyridin-2-ylcarbamic acid 2-[5-{2-methoxy-phenoxy)-6-pyridin-2- ylsulphonylamino)-2,2'-bipyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[5- (2-methoxy-phenoxy)-6-pyridin-3-ylsulphonylamino)-2/2'-bipyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2-ylsulphonylamino)-5-(2-chloro-5- methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl ester, pyridin-4-ylcarbamic acid 2-[6-(5-tert- butyl-thiophen-2-ylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yloxyl- ethyl ester, pyridin-2-yl-carbamic acid 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2- methoxy-phenoxy)-2-(3-methoxy-phenyl)-pyrimidin-4-yloxy]-ethyl ester, pyridin-2- ylcarbamic acid 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2- methylsulphanyl-pyrimidin-4-yloxyl-ethyl ester, pyridin-2-ylcarbamic acid 2-[2-(1 ,3- benzodioxol-5-yl)-6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)- pyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-chloro-5-methoxy- phenoxy)-6-(5-isopropyl-pyridin-2-ylsulphonylamino)-2-morpholin-4-ylpyrimidin-4-yloxy]- ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridin-2- ylsulphonylamino)-2,2'-bipyridimin-4-yloxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[5- (2-methoxy-phenoxy)-6-(5-methyl-pyridin-2-ylsulphonylamino)-2-morpholin-4-yl- pyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-chloro-5-methoxy- phenoxy)-6-(5-isopropyl-pyridin-2-sulphonylamino)-2-morpholin-4-yl-pyrimidin-4-yl- methoxyl-ethyl ester, pyridin-2-ylcarbamic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(5- isopropyl-pyridin-2-ylsulphonylamino)-2-morpholin-4-yl-pyrimidin-4-ylmethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy- phenoxy)-2-morpholin-4-ylpyrimidin-4-yloxy]ethyl ester, pyridin-2-ylcarbamic acid 2-16- (2,5-dichlorothiophen-3-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4- yloxylethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6-(3,5-dimethyl- isoxazol-4-ylsulphonylamino)-2,2'-bipyrimidin-4-yloxy]ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-tert-Butylthiophen-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-morpholin- 4-yl-pyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(2,5-dichloro-thiophen- 3-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxyl-ethyl ester, pyridin-2-ylcarbamic acid 2-16-(3,5-dimethyl-isoxazol-4-ylsulphonylamino)-5-(2- methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-ethyl ester, carboxylic acid furan- 3-ylmethyl ester 2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridin-2-sulphonylamino)-2- morpholin-4-yl-pyrimidin-4-yloxy]-ethyl ester, 5-tert-butyl-thiophene-2-sulphonic acid, 5- (2-methoxy-phenoxy)-6-[2-(3-pyridin-2-yl-ureido)-ethoxy]-2,2'-bipyrimidin-4-ylamide, 5- isopropyl-pyridine-2-sulphonic acid 5-(2-methoxy-phenoxy)-6-[2-(3-pyridin-2-yl-ureido)- ethoxy]-2,2'-bipyrimidin-4-ylamide, 5-isopropyl-pyridine-sulphonic acid [6-(2-hydroxy- ethoxy)-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, 5-isopropyl- pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy-benzyl)-5-phenoxy- pyrmidin-4-yll-amide, 5-isopropyl-pyridine-2-sulphonic acid [2-(3-hydroxy-benzyl)-6-(2- hydroxy-ethoxy)-5-phenoxy-pyrimidin-4-yl]-amide, 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]- amide, 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy- benzyl)-5-phenoxy-pyrimidin-4-yl]-amide, 5-isopropyl-pyridine-2-sulphonic acid [2-(3- hydroxy-benzyl)-6-(2-hydroxy-ethoxy)-5-phenoxy-pyrimidin-4-yl]-amide, 5-lsopropyl- pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-morpholin-4-yl- pyrimidin-4-ylamide, 5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-morpholin-4-yl- pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy- phenoxy)-6-hydroxymethyl-2-morpholin-4-yl-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2- sulphonic acid, 5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-morpholin-4-yl- pyrimidin-4-ylamide, and 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)- 2-morpholin-4-yl-pyrimidin-4-ylamide. c. U.S. Patent No. 5,739,333
Also intended for use in the methods provided herein are sulfonamides of formula:
Figure imgf000160_0001
wherein Ring A and Ring B are a substituted or unsubstituted monocyclic, bicyclic or tricyclic hydrocarbon group, or a substituted or unsubstituted heterocyclic group, Q is a single bond or a group of the formula: -0-, -S-, -SO-, -S02— or -CH2-, Y is a group of the formula: -O— , -S- or -NH-, Alk is a lower alkylene group or a lower alkenylene group, Z is a group of the formula: -0- or -NH-, R is a substituted or unsubstituted aromatic heterocyclic or aryl group, R1 is a hydrogen atom, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkoxy group, or a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof.
Particularly preferred compounds of this embodiment include N-[6-[2-[(5- Bromopyrimidin-2-yl)oxy[ethoxy]-2-(4-hydroxypiperidino)-5-(2- methoxyphenyloxy)pyrimidin-4-yl]-4-tert-butylbenzenesulf onamide, N-[2-[(2- Methoxyethyl)amino]-5-(2-methoxyphenyloxy)-6-[2-[(5-methoxypyrimidin-2- yl)oxy[ethoxy[pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide, N-[6-[2-[(5- Bromopyrimidin-2-yl)oxy[ethoxy]-2-[(2-hydroxyethyl)aminol-5-(4-methylphenyl)pyrimidin- 4-yl]-4-tert-butylbenzenesulfonamide, or pharmaceutically acceptable salts thereof. d. U.S. Patent No. 5,728,706
Other compounds for use in the methods provide herein include sulfonamides of formula:
Figure imgf000161_0001
wherein Ring A and Ring B are the same or different and each is a substituted or unsubstituted benzene ring, Q is a single bond or a group of the formula: -0-, — S-,
-SO-, -S02- or -CH2-, Y is a group of the formula: -0-, -S- or -NH-, Alk is a lower alkylene group or a lower alkenylene group, Z is a single bond or a group of the formula: -0— or -NH-, R is a substituted or unsubstituted aromatic heterocyclic or aryl group, R is hydrogen atom, trifluoromethyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a mono- or di-lower alkylamino group, a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkynyl group, an aromatic heterocyclic group, a substituted or unsubstituted aliphatic heterocyclic group or an aryl group, provided that when Z is a single bond, R is a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. e. International Patent Application Publication No. WO 96/40681
Other compounds for use in the methods provided herein include sulfonamides of formula:
Figure imgf000162_0001
wherein one of A1, A2, A3, and A4 is nitrogen and the remainder of A1, A2, A3, and A4 are CH; Ar is a phenyl group which is unsubstituted or bears 1, 2 or 3 substituents independently selected from (1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-6C)alkyl, N-K1- 4C)alkyl]amino(1-6C)alkyl, N,N-[di(1-4C)alkyl]amino(1-6C)alkyl, carboxy(1-6)alkyl, (1- 6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylcarbonyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, di-N-(1-6C)alkylcarbamoyl(1-6C)alkyl, N-(1-
6C)alkylcarbamoyloxy(1-6C)alkyl, carboxy(1-6C)alkoxy, carboxy(1-6C)alkylthio, (1- 6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxycarbonyl)1-6C)alkylthio, carbamoyl(1- 6C)alkoxy, (1 -6C)alkylcarbamoyl(1 -6C)alkoxy, di(1 -6C)alkylcarbamoyl(1 -6C)alkoxy, carbamoyl(1-6C)alkylthio, (1-6C)alkylcarbamoyi(1-6C)alkylthio, did - 6C)alkylcarbamoyl(1-6C)alkoxy,carbamoyl(1-6C)alkylthio, (106C)alkylcarbamoyl(1- 6C)alkylcarbamoyl(1-6C)alkylthio, (2-6C)alkenyl, carboxy(2-6C)alkenyl, (2-6C)alkynyl, carboxy(2-6C)alkynyl, halogen(2-6C)alkyl, trifluoromethyl, trichloromethyl, tribromomethyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihalogeno(1-6C)alkoxy, trihalogeno(1-6Calkoxy, (2-6C)alkenyloxy(1-6C)alkyl, (206C)alkenyloxy, (1-4C)alkoxy(1- 6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, carboxy(1-6Calkoxy(1-6C)alkyl, hydroxy(1-6C)alkoxy(1-6C)alkyl, (1-4C)alkylthio(1-6C)alkyl, (1-4C)alkylsulphinyl(1- 6C)alky, (1-4C)alkylsulphonyl(1-6C)alkyl, (1-4Calkylenedioxy, (3-6C)cycloalkyl, (3- 8C)cycloalkyl(1-6C)alkyl, phenyl, phenyl(1-6C)alkyl, phenoxy, phenyl(1-6C)alkoxy, pyridyl(1-6C)alkoxy(1-6C)alkyl, halogeno, hydroxy, mercapto, cyano, nitro, carboxy, (1- 6C)alkoxycarbonyl, (2-6C)alkenyloxycarbonyl, phenyloxycarbonyl, phenyld- 6C)alkoxycarbonyl, (1-6C)alkanoyl, benzoyl, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsuiphonyl, (1-6C)alkanoylamino, trifluroacetyl, trifluroacetamido, N,[(1-4C)alkyl]trifluroacetamido, benzamido, N,[(1-4C)alkyl]benzamido, carbamoyl, (1-4C)alkylcarbamoyl, di-(1- 4C)alkylcarbamoylphenylcarbamoyl, sulphamoyl, N-(1-4C)alkylsulphamoyl, N,N,-di-(1- 4C)alkylsulphamoyl, N-phenylsulphamoyl, (1-6C)alkanesu!phonamido, benezenesulphonamido, ureido, 3-(1 -6C)alkylureido, 3-phenylureido, thioureido, 3-(1 - 6C)alkylthioureido, 3-phenylthioureido, a five membered heterocyclyl group containing 1 ,2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur, a six membered heterocyclyl group containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, and a group-NRaRb in which Ra and Rb are independently selected from hydrogen, (1 -6C)alkyl, phenyl (1 -4C)alkyl and (1 -6C)alkyl bearing a carboxy, (1 -6C)alkoxycarbonyl, carbamoyl, (1 -6C)alkylcarbamoyl or di(1 - 6C)alkycarbamoyl group, or the group -NRaRb taken together complete a 1 -pyrrolidinyl, 2-oxo-1 -pyrrolidinyl, 1 -piperidinyl, 2-oxo-1 -piperidinyl, morpholino or thiamorpholino ring; B1, is an optional substituent on a carbon atom of A1, A2, A3 or A4 selected from(1 -4C)alkyl, halogeno and (1 -4C)alkoxy; m is zero, 1 , 2 or 3; the ring containing W, X, Y and Z and bearing substituent R1 is selected from: (a) a ring in which W is nitrogen; X is CH; Y is nitrogen; and Z is CRy in which Ry is hydrogen, halogeno, (1-4C)aIkyl, (1 - 4C)alkoxy or trifluoromethoxy; and substituent R1 is hydrogen, halogeno, (1 -4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethynyl; (b) a ring in which W is CRz in which Rz is hydrogen, halogeno, (1 -4C)alkyl, (1 -4C)alkoxy or trifluoromethoxy; X is nitrogen; Y is nitrogen; and Z is CH; and substituent R1 is halogeno,(1 -4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethynyl; and (c) a ring is which W and X are both nitrogen; Y is CH; and Z is CRx in which Rx is hydrogen, halogeno, (1 -4C)alkyl, (1 -4C)alkoxy or trifluoromethoxy; and substituent R1 is halogeno, (1 -4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethynyl; and wherein any of said phenyl or benzene or heterocyclyl moieties of a substituent on Ar may be unsubstituted or bear one or two substituents independently selected from (1 -4C)alkyl (1 -4C)alkoxy, halogeno, cyano, carboxy and trifluoromethyl; or an N-oxide thereof; or a pharmaceutically-acceptable salf thereof. Preferred compounds of this embodiment include 2-(4-isobutylphenyl)-N-(3- methoxy-5-methylpyrazin-2yl)pyridine-3-sulphonamide; N-(5-ch!oro-3-methoxypyrazin-2- yl)-2-(4-isobutylphenyl)pyridine-3-sulphonamide; 2-[4-(1-carboxyethoxy)phenyl]-N-(3- methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-(4-ethylphenyl)-N-(3-methoxy- 5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-(4-tert-butylphenyl)-N-(3-methoxy-5- methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N- (3-methoxy-5-methyIpyrazin-2-yl)pyridine-3-sulphonamide; 2-(4-acetylphenyl)-N-(3- methoxy-5-methylpyrazin-2yl)pyridine-3-sulphonamide; 2-[4-(1 -hydroxyethyl)phenyl]-N- (3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-(4-allyphenyl)-N-(3- methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-[4-)2-hydroxy-2- methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; N-(3- methoxy-5-methylpyrazin-2-yl)-2-(4-[3-pyridyl]pyridine-3-sulphonamide; N-(3-methoxy-5- methylpyrazin-2-yl)-2-(4-[2-pyridyl]pheyl)pyridine-3-sulphonamide; N-(3-methoxy-5- methylpyrazin-2-yl)-2-(4-[1 ,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide; N-(3- methoxy-5-methylpyrazin-2-yl)-2-(4-[ 1 ,2,4-oxadiazol-3-yl]phenyl)pyridine-3- sulphonamide; N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[pyrimidin-2-yl]phenyl)pyridine- 3-sulphonamide; 2-{4-[(2-hydroxyethoxy)methyl]phenyl}-N-(3-methoxy-5-methylpyrazin- 2-yl)pyridine-3-sulphonamide; 2-[4-(2-hydroxyethoxy)phenyl]-N-(3-methoxy-5- methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-[4-(3-acetoxy-2-methylproply)phenyl]-N- (3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-[4-(2-carboxypropyl)- phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2-[4-(2- methylpropanoyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 2- [4-(2-carboxy-2-methylpropyl)phenyl]-N.-(3-methoxy-5-methylpyrazin-2-yl_pyridine-3- sulphonamide; 2-[4-cyclopropylmethylphenyl)-N-(3-methoxy-5-methylpyrazin-2- yl)pyridine-3-sulphonamide; and 2-[4-(2-propoxycarbonyl-2-methylpropyl)phenyl]-N-(3- methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; or a pharmaceutically acceptable salt thereof. f. International Patent Application Publication No. WO 96/19459
In particular, compounds for use in the methods provided herein have the formula:
Figure imgf000164_0001
wherein R1 signifies aryl or heterocyclyl; R2 signifies tetrazolyl, lower-alkyl-substituted tetrazolyl, cyano, carboxy, lower-alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl, thiocarbamoly, amidino or hydroxyamidino; R3 signifies a residue -0-(CRaRb) n-OR9; R -R8 signify hydrogen, lower-alkoxy or halogen; R9 signifies hydrogen, aryl, lower-aralkyl, heterocyclyl or a residue -C(0)NHR10; R10 signifies lower-alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl; Ra and Rb signify hydrogen or lower-alkyl; n signifies 2, 3 or 4; and A and B signify CH; or one of the symbols A or B signifies nitrogen and the other signifies CH; or R2 signifies hydrogen and one of the symbols A or B signifies N-oxide (N→O) and the other signifies CH, and pharmaceutically usable salts of compounds of formula I.
Preferred compounds of this embodiment include 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide, 4-tert-butyl-N- [6-(2-hydroxy-ethoxy)-5-{2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yl]-benzenesulphonamide, 2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2- methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl-oxy]-ethyl pyridin-2- ylcarbamate, N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl- pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphon-amide, N-[6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzene- sulphonamide, N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl- pyridin-4-yl)-pyrimidin-4-yll-4-methoxy-benzenesulphonamide, N-[6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4- methylsulphanyl-benzenesulphonamide, 1 ,3-benzodioxol-5-sulphonic acid 6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl-pyrimidin-4-ylamide, N- [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yD- pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamide, N-[6-2(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy- benzolsulphonamide, pyridine-3-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy- phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide, 4-tert-butyl-N-[5-(2- chloro-5methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yl]-benzenesulphonamide, 1 ,3-benzodioxol-5-sulphonic acid [5-(2-chloro-5- methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2- 1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4- yl]-amide, 5-isopropyl-pyridine-2-sulphonic acid [5-(2-chloro-5-methoxy-phenoxy)-6-(2- hydroxy-ethoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-[pyrimidin-4-yl]-amide, 4-tert-butyl-N- [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[6-(1 H-tetrazol-5-yl)-pyridin-2-yll- pyrimidin-4-yl]-benzenesulphonamide, 2-[5-(2-methoxy-phenoxy)-6- phenylsulphonylamino-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl pyridin- 2-ylcarbamate, 2-[5-(2-methoxy-phenoxy)-6-(4-methyl-phenylsulphonyl-amino)-2-(2-1 H- tetrazol-5-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, 2-[5-(2-methoxy- phenoxy)-6-(4-methyI-phenylsulphonyl-amino)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yloxy]-ethyl 1 ,3-benzodioxol-5-ylcarbamate, 2-[5-(2-methoxy-phenoxy)-6-(4- methoxy-phenylsulphonyl-amino-2-(2-1 H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]- ethyl pyridin-2-ylcarbamate, 2-[5-(2-methoxy-phenoxy)-6-(4-methoxy-phenylsulphonyl- amino-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl 1 ,3-benzodioxol-5- ylcarbamate, 2-[5-(2-methoxy-phenoxy)-6-(4-methylsulphanylphenyl-sulphonylamino)-2- (2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, 2-[6-(1 ,3- benzodioxol-5-ylsulphonylamino-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4- yl)-pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, 2-[6-(1 ,3-benzodioxol-5- ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4- yloxyl-ethyl 1 ,3-benzodioxol-5-ylcarbamate, 2-[6-(3,4-dimethoxy- phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, 2-[5-{2-methoxy-phenoxy)-6-(2,5- dimethoxy-phenyl-sulphonylamino)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-2-yloxy]- ethyl pyridin-2-ylcarbamate, 2-[5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4- yl)-6-pyridin-3-ylsulphonylamino-pyrimidin4-yloxy]-ethyl pyridin-2-γlcarbamate, 2-[5-(2- methoxy-phenoxy)-6-pyridin-3-ylsulphonylamino-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yloxy]-ethyl 1 ,3-benzodioxol-5-ylcarbamate, 2-[5-(2-methoxy-phenoxy)-6-{5- methyl-pyridin-2-yl-sulphonylamino)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylox]- ethyl pyridin-2-ylcarbamate, 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy- phenoxy)-2-(2- 1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl pyridin-2- ylcarbamate, 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2- 1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl 1 ,3-benzodioxol-5-ylcarbamate, 2- [6-(4-tert-butyl-phenylsulphonylamino-5-(2-chloro-5-methoxy-phenoxy)-2-(2-1 H-tetrazol- 5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, 2-[6-(1 ,3-benzodioxol-5- ylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)- pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, 2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5- isopropyi-pyridin-2-ylsulphonylamino]-2-(2-1 H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-ylox]- ethyl pyridin-2-ylcarbamate, 2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-methoxy- phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethyl pyridin-2- ylcarbamate, N-(6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl- pyridin-4-yl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide, 5-methyl-pyridine-2- sulphonic acid [6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1 H-tetrazol-5-yl- pyridin-4-yl]-amide, 5-isopropyl-pyridine-2-sulphonic acid [6-(2-benzyloxy-ethoxy)-5-(2- methoxy-phenoxy)-2-[2-(1 H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-amide, 4-tert-butyl- N-[5-(2-methoxy-phenoxy)-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-2-(2-1 H-tetrazol-5-yl- pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[2-[2-(1 -ethyl-1 H- tetrazol-5-yl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4- yllbenzenesulphonamide, 4-tert-butyl-N-f2-(3-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1 H-tetrazol-5-yl-phenyl)-pyrimidin-4-yll- benzenesulphonamide, 2-[6-(4-tert-butyl-phenylsulphonyl)-5-(2-methoxy-phenoxy)-2-(3- 1 H-tetrazol-5-yl-phenyl)-pyrimidin-4-yloxy]-ethyl pyridin-2-ylcarbamate, N-[6-(2- benzyloxy-ethoxy)-2-(3-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert.- butyl-benzenesulphonamide, N-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1 H- tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide, 4-tert.-butyl-N-[2- (4-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene- sulphonamid, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(4-1 H- tetrazol-5-yl-phenyl)-pyrimidin-4-yll-benzenesulphonamide, N-[6-(2-benzyloxy-ethoxy)-2- (4-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert.-butyl-benzene- sulphonamide, N-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(4-1 H-tetrazol-5-yl- phenyl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide, 4-tert-butyl-N-[2-(2-cyano- pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yll- benzenesulphonamide, N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy- phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, N-[2-(2-cyano-pyridin-4-yl)-6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methyl-benzene- sulphonamide, N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- pyrimidin-4-yl]-4-methoxy-benzene-sulphonamide, N-[2-(2-cyano-pyridin-4-yl)-6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methylsulphanyl-benzene- sulphonamide, 1 ,3-benzodioxol-5-sulphonic acid 2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide, N-[2-(2-cyano-pyridin-4-yl)-6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-3,4-dimethoxy-benzene- sulphonamide, N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- pyrimidin-4-yl]-2,5-dimethoxy-benzene-sulphonamide, pyridine-3-sulphonic acid 2-(2- cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide, 5- methyl-pyridine-2-sulphonic acid 2-{2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulphonic acid 2-(2- cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide, 4- tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy- ethoxy)-pyrimidin-4-yl]-benzenesulphonamide, 1 ,3-benzodioxol-5-suiphonic acid 5-(2- chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4- ylamide, 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-2-(2- cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide, 4-tert-butyl-N-[2-(6-cyano- pyridin-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene- sulphonamide, N-[6-(2-benzyloxy-ethoxy)-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy- phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphon-amide, 5-isopropyl-pyridine-2- sulphonic acid-N-[6-(2-benzyloxy-ethoxy)-2-(2-cyanopyridin-4-yl)-5-(2-methoxyphenoxy)- pyrimidin-4-yl]-amide, 4-tert-butyl-N-[2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-6- (2-tetrahydro-pyran-2-yl)-ethoxy]-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[2- [2-(amino-imino-methyl)-pyridin-4-yll-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[2-[2-(hydroxyamino-imino-methyl)- pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]- benzenesulphonamide, ethyl 4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylate, 4-[4-{4-tert-butyl- phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]- pyridine-2-carboxylic acid, 4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1 -oxide, N-[6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2-(1 -oxy-pyridin-4-yl)-pyrimidin-4-yl]- benzenesulphonamide, N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1 -oxy-pyridin- 4-yl)-pyrimidin-4-yl]-4-methyl-benzene-sulphonamide, N-[6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(1 -oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benezene- sulphonamide, N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)- pyrimidin-4-yl]-4-methoxy-methyl-sulphonamide. 1 ,3-benzodioxol-5-sulphonic acid 6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-( 1 -oxy-pyridin-4-yl)-pyrimidin-4-ylamide, N- [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-3,4- dimethoxy-benzene-sulphonamide, N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2- (1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzene-sulphonamide, pyridine-3- sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1 -oxy-pyridin-4-yl)- pyrimidin-4-ylamide, 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2-(1 -oxy-pyridin-4-yl)-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2- sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)- pyrimidin-4-ylamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy- ethoxy)-2-(1 -oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, 1 ,3-benzodioxol-4- sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4- yl)-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy- phenoxy)-6-(2-hydroxy-ethoxy)-2-(1 -oxy-pyridin-4-yl)-pyrimidin-4-ylamide, 2-[4-(4-tert- butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2- yll-pyridine 1 -oxide. g. International Patent Application Publication No. WO 96/19455
In particular, compounds of formula I are intended for use in the methods provided herein.
Figure imgf000169_0001
wherein R1 signifies phenyl, substituted phenyl or heterocyclyl; R2 signifies phenyl or substituted phenyl; R3 signifies hydrogen, lower-alkyl, cyano, carboxy, esterified carboxy, phenyl, substituted phenyl, heterocyclyl or a residue -CONR5R6 or -NR5COR7; R4 signifies hydrogen or lower-alkyl; R5 signifies hydrogen or a residue R7, and R6 signifies -(CH2)mR7; or R5 and R6 together with the N atom associated with them signify a heterocyclic residue; R7 signifies phenyl, substituted phenyl, cycloalkyl, hetero-cyclyl, lower-alkyl, cyano-lower-alkyl, hydroxy-lower-alkyl, di-lower-alkylamino-lower-alkyl, carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl, lower-alkoxycarbonylamino- lower-alkyl or phenyl-lower-alkoxycarbonyl; Ra signifies hydrogen, lower-alkyl or hydroxy; Rb signifies hydrogen or lower-alkyl; Z signifies hydroxy, amino or a residue - OR8, -OC(0)NHR8, -OC(0)OR8, -NHC(0)NHR8 or -NHC(0)OR8; R8 signifies heterocyclyl, phenyl, substituted phenyl or lower-alkyl; A and Y each independently signify oxygen or sulphur, X signifies nitrogen or CH; m signifies 0, 1 or 2; and n signifies 0, 1 or 2; and pharmaceutically usable salts thereof.
Preferred compounds of this embodiment include pyridin-2-yl-carbamic acid 2-[3- (4-tert-butyl-benzene-sulphonylamino)-2-(2-methoxy-phenoxy)-5-(morpholine-4- carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-benzene- sulphonylamino-2-(2-methoxy-phenoxy)-5-(2-pyridin-2-yl-ethylcarbamoyl)-phenoxyl-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-benzene-sulphonylamino)-2-(2- methoxy-phenoxy)-5-(piperidine-1 -carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[5-benzylcarbamoyl-3-(4-tert-butylbenzenesulphonylamino)-2-(2-methoxy- phenoxy)-phenoxy]-ethyl ester, benzyl {3-(4-tert-butyl-benzenesulphonylamino)-4-(2- methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)-ethoxy]-benzoylamino]-acetate, pyridin-2-yl-carbamic acid 2-{3-(4-tert-butylbenzene-sulphonylamino)-2-(2-methoxy- phenoxy)-5-[(pyridin-3-yl-methyl)-carbamoyl]-phenoxy}-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-benzene-sulphonylamino)-2-(2-methoxy-phenoxy)-5- phenylcarbamoyl-phenoxy]-ethyl ester, methyl 3-(benzo[1 ,3]dioxol-5-sulphonylamino)-4- (2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)-ethoxy]-benzoate, pyridin-2-yl- carbamic acid 2-[3-(benzo[1 ,3]dioxol-5-sulphonylamino)-2-(2-methoxy-phenoxy)-5- (morpholine-4-carbonyl)-phenoxy]-ethyl ester, ethyl 4-{3-(benzo[1 ,3]dioxol-5- sulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)-ethoxyl- benzoyl}-piperazine-1 -carboxylate, pyridin-2-yl-carbamic acid 2-[3-(benzo[1 ,3]dioxol-5- sulphonylamino)-5-isobutylcarbamoyl-2-(2-methoxy-phenoxy)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(benzo[1 ,3]dioxol-5-sulphonylamino)-5- isopropylcarbamoyl-2-(2-methoxy-phenoxy)-phenoxy]-ethyl ester, methyl 3-(4-methoxy- benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)- ethoxyl-benzoate, pyridin-2-yl-carbamic acid 2-[3-(4-methoxy-benzene-sulphonylamino)- 2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenoxy]-ethyl ester, ethyl 4-{4-(2- methoxy-phenoxy)-3-(4-methylsulphanyl-benzenesulphonylamino)-5-[2-(pyridin-2- ylcarbamoyloxy)-ethoxy]-benzoyl}-piperazine-1 -carboxylate, methyl 4-(2-methoxy- phenoxy)-3-t2-(pyridin-2-yl-carbamoyloxy)-ethoxy]-5-(toluene-4-sulphonylamino)- benzoate, pyridin-2-yl-carbamic acid 2-[2-(2-methoxy-phenoxy)-5-(morpholine-4- carbonyl)-3-(toluene-4-sulphonylamino)-phenoxy]-ethyl ester, 3-(4-tert-butyl- benzenesulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-N- phenyl-benzamide, methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(2-chloro-5- methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)-ethoxy)-benzoate, pyridin-2-yl- carbamic acid 2-[3-(4-tert-butyl-benzene-sulphonylamino)-2-(2-chloro-5-methoxy- phenoxy)-5-(morpholine-4-carbonyl)-phenoxy]-ethyl ester, methyl 3-(4-tert-butyl- benzenesulphonylamino)-4-(3-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)- ethoxyl-benzoate, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-benzene-sulphonylamino)- 2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl- carbamic acid 2-[3-(4-tert-butyl-benzene-sulphonylamino)-2-(3-methoxy-phenoxy)-5-(3- methoxy-phenyl-carbamoyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert- butyl-benzene-sulphonylamino)-2-(3-methoxy-phenoxy)-5-phenylcarbamoyl-phenoxyl- ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-methoxy-benzene-sulphonylamino)-2-(3- methoxy-phenoxy)-5-phenylcarbamoyl-phenoxy]-ethyl ester, {3-(4-tert-butyl- benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)- ethoxy]-benzoyl-amino}-acetic acid, pyridin-2-ylcarbamic acid 2-[3-(4-tert-butyl-phenyl- sulphonylamino)-2-(2-methoxy-phoxy)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(4-tert-butyl-phenylsulphonylamino)-2-(2-chloro-5-methoxy-phenoxy)-ethyl ester, methyl 3-(4-tert-butyl-phenylsulphonyl-amino)-5-(2-hydroxy-ethoxy)-4-(2-methoxy- phenoxy)-benzoate, 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2- methoxy-phenoxyj-benzoic acid, 4-tert-butyl-N-[3-(2-hydroxy-ethoxy)-2-(2-methoxy- phenoxy)-5-(morpho)ine-4-carbonyl)-phenyl]-benzene-sulphonamide, 4-tert-butyl-N-[3-{2- hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-5-(piperidine-1 -carbonyD-phenyll-benzene- sulphonamide, 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2- methoxy-phenoxy)-N-(2-pyridin-2-yl-ethyl)-benzamide, benzyl [3-(4-tert-butyl- benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-benzoylaminol- acetate, 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2-methoxy- phenoxy)-N-phenyl-benzamide, 3-(4-tert-butyl-benzenesulphonyl-amino)-N-cyanomethyl- 5-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-benzamide, 3-(4-tert-butyl- benzenesulphonylamino)-N-(2-dimethylamino-ethyl)-5-(2-hydroxy-ethoxy)-4-(2-methoxy- phenoxy)-benzamide, tert-butyl {2-[3-(4-tert-butyl-benzenesulphonylamino)-5-(2- hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-benzoylamino]-ethyl}-carbamate, 3-(4-tert- butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-N-pyridin-3- ylmethyl-benzamide, N-benzyl-3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy- ethoxy)-4-(2-methoxy-phenoxy)-benzamide, [3-(4-tert-butyl-benzenesulphonylamino)-5- (2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-benzoylamino]-acetic acid, methyl 3- (benzo[1 ,3]dioxol-5-sulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)- benzoate, 3-(benzo[1 ,3]dioxol-5-sulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2-methoxy- phenoxy)-benzoic acid, benzo[1 ,3]dioxol-5-sulphonic acid [3-(2-hydroxy-ethoxy)-2-(2- methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-amide, ethyl N4-[3- benzo[1 ,3]dioxol-5-sulphonylamino)-5-(2-hydroxy-ethoxy)-4-(2-methoxyphenoxy)- benzoyl]-piperazine-1 -carboxylate, 3-(benzo[1 ,3]dioxol-5-sulphonylamino)-5-(2-hydroxy- ethoxy)-N-isobutyl-4-(2-methoxy-phenoxy)-benzamide, 3-(benzof 1 ,3]dioxol-5- sulphonylamino)-5-(2-hydroxy-ethoxy)-N-isopropyl-4-(2-methoxy-phenoxy)-benzamide, 3-(benzo[1 ,3]dioxol-5-sulphonylamino)-5-(2-hydroxy-ethoxy)-N-(2-hydroxy-ethyl)-4-(2- methoxy-phenoxy)-benzamide, methyl 3-(2-hydroxy-ethoxy)-5-(4-methoxybenzene- sulphonylamino)-4-(2-methoxy-phenoxy)-benzoate, 3-(2-hydroxy-ethoxy)-5-(4-methoxy- benzenesulphonyl-amino)-4-(2-methoxy-phenoxy)-benzoic acid, N-[3-(2-hydroxy-ethoxy)- 2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyI)-phenyl]-4-methoxy-benzene- sulphonamide, methyl 3-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-5-(4- methylsulphanyl-benzenesulphonylamino)-benzoate, 3-(2-hydroxy-ethoxy)-4-(2-methoxy- phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid, N-[3-(2-hydroxy- ethoxy)-2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-4-methylsulphanyl- benzene-sulphonamide, ethyl 4-[3-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-5-(4- methylsulphanyl-benzenesulphonyl-amino)-benzoyl]-piperazine-1-carboxylate, pyridin-2- yl-carbamic acid 2-[2-(2-methoxy-phenoxy)-3-(4-methylsulphanyl- benzenesulphonylamino)-5-(morpholine-4-carbonyl)-phenoxyl]-ethyl ester, methyl 3-(2- hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-5-(toluene-4-sulphonylamino)-benzoate, 3-(2- hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-5-(toluene-4-sulphonylamino)-benzoic acid, N- [3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-4- methyl-benzenesulphonamid, methyl 3-(4-tert-butylbenzenesulphonylamino)-4-(2-chloro- 5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-benzoate, methyl 3-amino-4-(2-chloro-5- methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate, 3-(4-tert-butyl- benzenesulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-benzoic acid, 4-tert-butyl-N-[2-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5- (morpholine-4-carbonyl)-phenyl]-benzene-sulphonamide, methyl 4-(2-chloro-5-methoxy- phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-benzoate, 4-(2- chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-methoxy- benzenesulphonylamino)-benzoic acid, 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy- ethoxy)-5-(4-methoxy-benzenesulphonylamino)-N-phenyl-benzamide, methyl 3- (benzo[1 ,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy- ethoxy)-benzoate, 3-(benzo[1 ,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxy- phenoxy)-5-(2-hydroxy-ethoxy)-benzoic acid, 3-(benzo[1 ,3]dioxol-5-sulphonylamino)-4- (2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-N-phenyl-benzamide, methyl 4-(2- chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-trifluoromethyl- benzenesulphonylamino)-benzoate, 4-{2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy- ethoxy)-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoic acid, 4-(2-chloro-5- methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-N-phenyl-5-(4-trifluoromethyl- benzenesulphonylamino)-benzamide, methyl 3-(4-tert-butyl-benzenesulphonylamino)-5- (2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoate, 3-(4-tert-butyl- benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid, 4- tert-butyl-N-[3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)- phenyll-benzene-sulphonamide, 3-(4-tert-butylbenzenesulphonylamino)-5-(2-hydroxy- ethoxy)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide, N-biphenyl-2-yl-3-(4-tert-butyl- benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzamide, 3-(4- tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-N-(3- methoxy-phenyD-benzamide, methyl 2-[3-(4-tert-butyl-benzenesulphonylamino)-5-(2- hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoylamino]-4-methyl-pentanoate, N-benzo- [1 ,3]dioxol-5-yl-3-(4-tert-butylbenzene-sulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3- methoxy-phenoxy)-benzamide, 2-[3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy- ethoxy)-4-(3-methoxy-phenoxy)-benzoylamino]-4-methyl-pentanoic acid, methyl 3-(2- hydroxy-ethoxy)-5-(4-methoxy-benzene-sulphonylamino)-4-(3-methoxy-phenoxy)- benzoate, 3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonyl-amino)-4-(3-methoxy- phenoxy)-benzoic acid, 3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonyl-amino)-4- (3-methoxy-phenoxy)-N-phenyl-benzamide, methyl 3-(2-hydroxy-ethoxy)-4-(3-methoxy- phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoate, 3-(2-hydroxy- ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid, 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl- benzenesulphonyl-amino)-N-phenyl-benzamide, 4-tert-butyl-N-[3-(2-hydroxy-ethoxy)-2- (2-methoxy-phenoxy)-phenyl-benzenesulphonamide, 4-tert-butyl-N-[2-(2-chloro-5- methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-phenyl]benezesulphonamide, methyl 3-(4-tert- butylbenzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)- benzoate, 3-(4-tert-butyl-benzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3- methoxy-phenoxy)-benzoic acid, 3-(4-tert-butyl-benzenesulphonylamino)-5-(2,3- dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-N-phenyi-benzamide, methyl 3-(2,3- dihydroxy-propoxy)-5-(4-methoxy-benzene-sulphonylamino)-4-(3-methoxy-phenoxy)- benzoate, 3-(2,3-dihydroxy-propoxy)-5-(4-methoxy-benzene-sulphonylamino)-4-(3- methoxy-phenoxy)-benzoic acid, 3-{2,3-dihydroxy-propoxy)-5-(4-methoxy-benzene- sulphonylamino)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide, methyl 3-(2,3-dihydroxy- propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)- benzoate, 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl- benzenesulphonylamino)-benzoic acid, 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy- phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-N-phenyl-benzamide, 3-(4-tert.- butybenzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-N-(1 H- tetrazol-5-yl)-benzamide," ethyl 4-[3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5- (4-methylsulphanylbenzenesulphonylamino)-benzoyl]-piperazine-1-carboxylate, N-[3-(2,3- dihydroxy-propoxy)-2-(3-methoxy-phenoxy)-5-(morpholin-4-carbonyl)-phenyl]-4 methylsulphanylbenzene-sulphonamide, N-[3-(2-hydroxy-ethoxy)-2-(3-methoxy- phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-4-methylsulphanyl-benzene-sulphonamide, 4-tert-butyl-N-[5-cyano-3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-phenyl]- benzenesulphonamide, 4-tert-butyl-N-[3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-5- (1 H-tetrazol-5-yl)-phenyl]-benzenesulphonamide, 4-tert-butyl-N-[5-cyano-3-(2-hydroxy- ethoxy)-2-(3-methoxy-phenoxy)-phenyl]-benzenesulphonamide, 4-tert-butyl-N-[3-(2- hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-5-(1 H-tetrazol-5-yl)-phenyll- benzenesulphonamide, 4-tert-butyl-N-[5-cyano-3-(2,3-dihydroxy-propoxy)-2-(2-methoxy- phenoxy)-phenyl)-benzenesulphonamide, 4-tert-butyl-N-[3-(2,3-dihydroxy-propoxy)-2-(2- methoxy-phenoxy)-5-( 1 H-tetrazol-5-yl)-phenyl]-benzenesulphonamide, 4-tert-butyl-N-[5- cyano-3-(2,3-dihydroxy-propoxy)-2-(3-methoxy-phenoxy)-phenyl]-benzenesulphonamide, 4-tert-butyl-N-[3-(2,3-dihydroxy-propoxy)-2-(3-methoxy-phenoxy)-5-(1 H-tetrazoi-5-yl)- phenyll-benzenesulphonamide, pyridin-2-yl-carbamic acid 2-[3-(5-isopropyl-pyridine-2- sulphonylamino)-2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(5-isopropyl-pyridine-2-sulphonylamino)-2-(2-methoxy- phenoxy)-5-(piperidine-1 -carbonyl)-phenoxyl-ethyl ester, pyridin-2-yl-carbamic acid 2-[3- (5-isopropyl-pyridine-2-sulphonylamino)-2-(2-methoxy-phenoxy)-5-(4-methyl-piperazine- 1 -carbonyl)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[5-(2,6-dimethyl- morpholine-4-carbonyl)-3-(5-isopropyl-pyridine-2-sulphonyl-amino)-2-(2-methoxy- phenoxy)-phenoxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[3-(5-isopropyl-pyridine-2- sulphonylamino)-2-(2-methoxy-phenoxy)-5-(2-pyridin-2-ylethylcarbamoyl)-phenoxy]-ethyl ester, ethyl 4-{3-(5-isopropyl-pyridine-2-sulphonylamino)-4-(2-methoxy-phenoxy)-5-[2- (pyridin-2-ylcarbamoyloxy)-ethoxy]-benzoyl}-piperazine-1 -carboxylate, pyridin-2-yl- carbamic acid 2-[5-(4-f ormyl-piperazine-1 -carbonyl)-3-(5-isopropyl-pyridine-2- sulphonylamino)-2-(2-methoxy-phenoxy)-phenoxy)-ethyl ester, methyl 4-(2-chloro-5- methoxy-phenoxy)-3-(5-isopropyl-pyridine-2-sulphony)amino)-5-[2-(pyridin-2- ylcarbamoyloxy)-ethoxy]-benzoate, pyridin-2-yl-carbamic acid 2-[2-(2-chloro-5-methoxy- phenoxy)-3-(5-isopropyl-pyridine-2-sulphonylamino)-5-(morpholine-4-carbonyl)-phenoxy]- ethyl ester, pyridin-2-yl carbamic acid 2-[3-(5-isopropyl-2-pyridyl-sulphonylamino)~2-(2- methoxy-phenoxy)-ethyl ester, methyl 3-(2-hydroxy-ethoxy)-5-(5-isopropyl-pyridine-2- sulphonylamino)-4-(2-methoxy-phenoxy)-benzoate, 3-(2-hydroxy-ethoxy)-5-(5-isopropyl- pyridine-2-sulphonylamino)-4-(2-methoxy-phenoxy)-benzoic acid, 5-isopropyl-pyridine-2- sulphonic acid [3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyD- phenyll-amide, 5-isopropyl-pyridine-2-sulphonic acid [3-(2-hydroxy-ethoxy)-2-(2- methoxy-phenoxy)-5-(piperidine-1 -carbonyl)-phenyl]-amide, 5-isopropyl-pyridine-2- sulphonic acid [3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-5-(4-methyl-piperazine-1- carbonyD-phenyll-amide, 5-isopropyl-pyridine-2-sulphonic acid [5-(2,6-dimethyl- morpholine-4-carbonyl)-3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-phenyl]-amide, 3- (2-hydroxy-ethoxy)-5-(5-isopropyl-pyridine-2-sulphonylamino)-4-(2-methoxy-phenoxy)-N- (2-pyridin-2-yl-ethyl)-benzamide, ethyl 4-[3-(2-hydroxyethoxy)-5-(5-isopropyl-pyridine-2- sulphonylamino)-4-(2-methoxy-phenoxy)-benzoyl]-piperazine-1-carboxylate, 5-isopropyl- pyridine-2-sulphonic acid [5-(4-formyl-piperazine-1 -carbonyl)-3-(2-hydroxy-ethoxy)-2-{2- methoxy-phenoxy)-phenyl]-amide, 3-(2-hydroxy-ethoxy)-5-(5-isopropyl-pyridine-2- sulphonylamino)-4-(2-methoxy-phenoxy)-N-propylbenzamide, methyl 4-(2-chloro-5- methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(5-isopropyl-pyridine-2-sulphonylamino)- benzoate, 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(5-isopropyl-pyridine- 2-sulphonylamino)-benzoic acid, 5-isopropyl-pyridine-2-sulphonic acid [2-(2-chloro-5- methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(morpholine-4-carbonyl)-phenyl]-amide, 5- isopropyl-N-[3-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy)-phenyl-pyridyl-sulphonamide, pyridin-2-yl-carbamic acid 2[4(4-tert-butyl-benzenesulphonamino)-3-(2- methoxyphenoxy)-6-phenyl-pyridin-2-yloxy]-ethyl-ester, p-tert-butyl-N-[2-(2- hydroxyethoxy)-3-(o-methoxy-phenoxy)-6-methyl-4-pyridyl-]benzenesulphonamide, p- tert-butyl-N-[2-(2-hydroxyethoxy)-3-(3-methoxy-phenoxy)-6-methyl-4- pyridyllbenzenesulphonamide, 4-tert-butyl-N-[2-(2-hydroxyethoxy)-3-(2-methoxy- phenoxy)-6-phenyl-pyrid-4-yl]-benzenesulphonamide, Pyridin-2-yl-carbamic acid-2-[4-(5- isopropyl-pyridine-2-sulphonylamino)-3-(2-methoxy-phenoxy)-6-methyl-pyridin-2-yloxyl- ethyl ester, methyl 3-(4-tert.-butyl-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5- [2-(pyrimidin-2-yloxy)-ethoxy]-benzoate, 4-tert-butyl-N-{2-(2-methoxy-phenoxy)-5- (morpholine-4-carbonyl)-3-[2-(pyrimidin-2-yloxy)-ethoxy]-phenyl}-benzene-sulphonamide, 4-tert.-butyl-N-{2-(2-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-3-[2-(pyridin-2-yloxy)- ethoxy]-phenyl}-benzene-sulphonamide, 4-(3-methoxy-phenoxy)-3-(4-methylsulphanyl- benzene-sulphonylamino)-N-phenyl-5-[2-(pyrimidin-2-yloxy)-ethoxy]-benzamide, 4-(3- methoxy-phenoxy)-3-(4-methylsulphanyl-benzene-sulphonylamino)-N-phenyl-5-t2- (pyridin-2-yloxy)-ethoxy]-benzamide, N-{2-(3-methoxy-phenoxy)-5-(morpholine-4- carbonyl)-3-[2-(pyrimidin-2-yloxy)-ethoxy]-phenyl}-4-methylsulphanyl- benzenesulphonamide, N-{2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-3-[2- (pyridin-2-yloxy)-ethoxy]-phenyl}-4-methylsulphanyl-benzenesulphonamide. h. U.S. Patent No. 5,668,137
Other compounds for use in the methods provided herein include those of the formula:
Figure imgf000176_0001
wherein R1 is (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy or (1 -6C)alkythio, each of which last five groups bear a substituent selected from carboxy, (1 -6C)alkoxycarbonyl, carbamoyl, N-(1 -6C)alkylcarbamoyl and N,N-di(1 - 6C)alkylcarbamoyl; R2 is an optional substituent selected from halogeno, (1 -6C)alkyl, (1 - 6C)alkoxy, carboxy, (1 -6C)alkoxycarbonyl, carbamoyl, N-(1 -6C)alkylcarbamoyl, N,N- ■ di(1 -6C)alkylcarbamoyl, cyano, amino, N-(1 -6C)alkylamino and N,N-di(1 -6C)alkylamino; R3 is an optional substituent selected from (1 -6C)alkyl, amino(1 -6C)alkyl, hydroxy(1- 6C)alkyl, N-[(1-4C)alkyl[amino(1 -6C)alkyl, N,N-[di(1-4C)alkyl[amino(1 -6C)alkyl, carboxy(1 -6C)alkyl, (1 -6C)alkoxycarbonyl(1 -6C)alkyl, carbamoyl(1 -6C)alkyl, (1 - 6C)alkylcarbamoyl(1-6C)alkyl, di(1-6C)alkylcarbamoyl(1-6C)alkyl, carboxy(1-6C)alkoxy, carboxy(1-6C)alkylthio, (1 -6C)alkoxycarbonyl(1-6C)alkoxy, (1 -6C)alkoxycarbonyl(1 - 6C)alkylthio, carbamoyl(1 -6C)alkoxy, (1 -6C)alkylcarbamoyl(1 -6C)alkoxy, di(1 - 6C)alkylcarbamoyl( 1 -6C)-alkoxy, carbamoyK 1 -6C)alkylthio, ( 1 -6C)alkylcarbamoyl( 1 - 6C)alkylthio, di(1 -6C)alkylcarbamoyl(1-6C)alkylthio, (2-6C)alkenyl, carboxy{2- 6C)alkenyl, (2-6C)alkynyl, carboxy(2-6C)alkynyl, (1 -6C)alkoxycarbonyl(2-6C)alkenyl, carbamoyl(2-6C)alkenyl, carbamoyl(2-6C)alkenyl, N-(1 -6C)alkylcarbamoyl(2-6C)alkenyl, N,N-di(1 -6C)alkylcarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, carbamoyl(2-6C)alkynyl, N-(1 -6C)alkylcarbamoyl(2-6C) alkynyl, N,N-di(1- 6C)alkylcarbamoyl(2-6C)alkynyl, halogeno(2-6C)alkyl, trifluoromethyl, trichloromethyl, tribromomethyl, (1 -6C)alkoxy, dihalogeno(1 -6C)alkoxy, trihalogeno(1 -6C)alkoxy, (2- 6C)alkenyloxy, (1-4C)alkoxy(1 -6C)alkyl, (1 -4C)alkylthio(1-6C)alkyl, (1- 4C)alkylsulphinyl(1 -6C)alkyl, (1 -4C)alkylsulphonyl(1 -6C)alkyl, (1 -4C)alkylenedioxy, (3- 6C)cycloalkyl, (3-8C)cycloalkyl(1 -6C)alkyl, phenyl, phenyl(1 -6C)alkyl, phenoxy, phenyl(1-6C)alkoxy, halogeno, hydroxy, mercapto, cyano, nitro, carboxy, (1- 6C)alkoxycarbonyl, (2-6C)alkenyloxycarbonyl, phenyloxycarbonyl, phenyld - 6C)alkoxycarbonyl, (1 -6C)alkanoyl, benzoyl, (1 -6C)alkylthio, (1 -6C)alkylsulphinyl, (1 - 6C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, (1 -6C)alkanoylamino, trifluoroacetyl, trifluoroacetamido, N-[(1 -4C)alkyl]trifluoroacetamido, benzamido, N-[(1 - 4C)alkyl[benzamido, carbamoyl, (1 -4C)alkylcarbamoyl, di-(1 -4C)alkylcarbamoyl, phenylcarbamoyl, sulphamoyl, N-(1-4C)alkylsulphamoyl, N,N-di(1 -4C)alkylsulphamoyl, N- phenylsulphamoyl, (1-6C)alkanesulphonamido, benzenesulphonamido, ureido, 3-d- 6C)alkylureido, 3-phenylureido, thioureido, 3-(1 -6C)alkylthioureido, 3-phenylthioureido and a group — NRyRz in which Ry and Rz are independently selected from hydrogen, (1- 6C)alkyl, phenyl(1 -4C)alkyl and (1 -6C)alkyl bearing a carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1 -6C)alkylcarbamoyl or di(1 -6C)alkylcarbamoyl group, or the group -NRyRz taken together complete a 1 -pyrrolidinyl, 2-oxo-1 -pyrrolidinyl, 1 -piperidinyl or 2-oxo-1 - piperidinyl ring; Het is a heterocyclic ring selected from the groups of partial structural formulae lla, lib, lie, lid and lie set out hereinafter wherein Ra, Re and Re are individually selected from hydrogen, halogeno, (1 -4C)alkyl, (1 -4C)alkoxy and trifluoromethoxy; Rb is selected from hydrogen, halogeno, (1 -4C)alkyl, methoxy, ethoxy, trifluoromethyl and ethynyl; Rd and Rf are individually selected from halogeno, (1 -4C)alkyl, methoxy, ethoxy, trifluoromethyl and ethynyl; Rg is selected from methyl and bromo; Rh is methoxy or ethoxy; m is zero, 1 , 2 or 3; n is zero, 1 , 2 or 3; and wherein any of said phenyl or benzene moieties of R3 may be unsubstituted or bear one or two substituents independently selected from (1 -4C)alkyl, (1 -4C)alkoxy, halogeno, cyano and trifluoromethyl; or a pharmaceutically-acceptable salt thereof. Preferred compounds of this embodiment include 4'-(2-carboxypropyl)-N-(3- methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide, 4'-carboxymethoxy-N-(3- methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide, 4'-(1 -carboxy)ethoxy-N-(3- methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide, 4'-(1 -carboxy)ethoxy-N-(5- chloro-3-methoxypyrazin-2-yl)-2-biphenylsulphonamide and 4'-(2-carboxy-2- methylpropyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide; or a pharmaceutically-acceptable salt thereof. i. International Patent Application Publication No. WO 97/11942
In particular, compounds of the following formula and table are intended for use in the methods provided herein:
Figure imgf000178_0001
Figure imgf000178_0002
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0002
Other compounds of this embodiment include those of the following formula and table:
Figure imgf000183_0001
Figure imgf000183_0003
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
j. International Patent Application Publication No. WO 97/071 19
Of particular interest for use in the methods provided herein are compounds of the formula:
Figure imgf000189_0001
wherein each of R1 and R2 are hydrogen or an optionally substituted hydrocarbon residue, R3 is a
Figure imgf000189_0002
alkyl group which is substituted by a C1-6 alkoxy-carbonyl gorup or a group of the formula: -NH-S02-R5 wherein R5 is (1 ) a C1-β alkyl group which may optionally be substituted by halogen or (2) a C6.14 aryl group, R4 is an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, W denotes a chemical bond or a spacer group and n denotes an integer of 1 to 3, or a salt thereof.
Preferred compounds of this embodiment are shown in the following table.
Figure imgf000189_0003
Figure imgf000189_0004
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0002
k. International Patent Application Publication No. WO 95/26957
Other compounds for use in the methods provided herein have the formula:
Figure imgf000192_0001
wherein Q is a naphthyl or biphenyl group; A1 , A2 and A3 are attached to a phenyl or benzene ring of Q and are independently selected from hydrogen, (1 -6C)alkyl, aminod - 6C)alkyl, hydroxy(1-6C)alkyl, N-(1 -4C)alkyl]amιno(1 -6C)alkyl, N,N- [di(1 -4C)alkyllamino(1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, halogeno(1-6C)alkyl, (1 - 6C)alkoxy, dihalogeno(1 -6C)alkoxy, trihalogeno(1 -6C)alkoxy, (2-6C)alkenyloxy, (1 - 4C)alkoxy(1 -6C)alkyl, (1 -4C)alkylthio(1 -6C)alkyl, (1 -4C)alkylsulphinyl(1-6C)alkyl, (1-4C)alkylsulphonyl(1-6C)alkyl, (1-4C)alkylenedioxy, (3-6C)cycloalkyl,
(3-8C)cycloalkyl(1-6C)alkyl, phenyl, phenyl(1-6C)alkyl, phenoxy, phenyl(1-6C)alkoxy, halogeno, hydroxy, mercapto, cyano, nitro, carboxy, (1 -6C)alkoxycarbonyl, (2- 6C)alkenyloxycarbonyl, phenyloxycarbonyl, phenyl(1 -6C)alkoxycarbonyl, (1 -6C)alkanoyl, benzoyl, (1 -6C)alkylthio, (1 -6C)alkylsulphinyl, (1 -6C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, (1-6C)alkanoylamino, trifluoroacetyl, trifluoroacetamido, N-[(1 -4C)alkyl]trifluoroacetamido, benzamido, N-[(1 - 4C)alkyl]benzamido, carbamoyl, (1 -4C)alkylcarbamoyl, di-(1-4C)alkylcarbamoyl, phenylcarbamoyl, sulphamoyl, N-(1-4C)alkylsulphamoyl, N,N-di(1 -4C)alkylsulphamoyl, N- phenylsulphamoyl, (1-6C)alkanesulphonamido, benzenesulphonamido, ureido, 3-(1- 6C)alkylureido, 3-phenylureido, thioureido, 3-(1 -6C)alkylthioureido, 3-phenylthioureido and a group -NRaRb in which Ra and Rb are independently selected from hydrogen, (1 -6C)alkyl, phenyl(1 -4C)alkyl and (1 -6C)alkyl bearing a carboxy or (1-4C)alkoxycarbonyl group, or the group -NRaRb taken together complete a 1 - pyrrolidinyl, 2-oxo-1 -pyrrolidinyl, 1 -piperidinyl or 2-oxo-1 -piperidinyl ring; W, X, Y and Z are independently selected from nitrogen and CR2 such that two or three of W, X, Y and Z are nitrogen and the remainder are CR2, or X is nitrogen and W, Y and Z are CR2; R2 has any of the values defined above for A1, A2 or A3; R1 is selected from (1 -6C)alkyl, amino -6C)alkyl, hydroxy(1-6C)alkyl, N-[(1 -4C)alkyl]amino(1 -6C)alkyl, N,N- [di(1 -4C)alkyl]amino(1-6C)alkyl, (2-6C)alkenyl, 2-[(1 -6C)alkoxycarbonyl]ethenyl, 2- phenylethenyl, (2-6C)alkynyl, (1 -6C)alkoxycarbonylethynyl, phenylethynyl, halogeno(1 - 6C)alkyl, (1 -3C)alkoxy, dihalogeno(1 -3C)alkoxy, trihalogeno(1 -3C)alkoxy, (2-6C)alkenyloxy, (1 -4C)alkoxy(1 -6C)alkyl, (1-4C)alkylthio(1 -6C)alkyl, (1-4C)alkylsulphinyl(1 -6C)alkyl, (1 -4C)alkylsulphonyl(1 -6C)alkyl, (3-6C)cycloalkyl, (3- 8C)cycloalkyl(1-6C)alkyl, phenyl(1-6C)alkyl, phenyl(1-3C)alkoxy, halogeno, hydroxy, mercapto, nitro, carboxy, (1 -6C)alkoxycarbonyl, (2-6C) alkenyloxycarbonyl, phenyloxycarbonyl, phenyl(1 -6C)alkoxycarbonyl, (1 -6C)alkanoyl, benzoyl, (1 - 6C)alkylthio, (1-6C)alkylsulphinyl, (1 -6C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, (1-6C)alkanoylamino, trifluoroacetyl, trifluoroacetamido, N-f(1- 4C)alkyl]trifluoroacetamido, benzamido, N-[(1 -4C)alkyl]benzamido, carbamoyl, (1- 4C)alkylcarbamoyl, di-(1 -4C)alkylcarbamoyl, phenylcarbamoyl, sulphamoyl, N-(1 - 4C)alkylsulphamoyl, N,N-di(1 -4C)alkylsulphamoyl, N-phenylsulphamoyl, (1 - 6C)alkanesulphonamido, benzenesulphonamido, ureido, 3-(1 -6C)alkylureido, 3- phenylureido, thioureido, 3-(1-6C)alkylthioureido, 3-phenylthioureido and a group -NRaRb in which Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, (1 - 4C)alkyl bearing a carboxy or (1 -4C)alkoxycarbonyl group, or the group -NRaRb taken together complete a 1 -pyrrolidinyl, 2-oxo-pyrrolidinyl, -piperidinyl or 2-oxo-1 -piperidinyl ring; or when X or Y is CR2, R1 together with the adjacent R2 is (3-5C)alkylene or (3-5C)alkenylene which together with the carbon atoms to which R1 and the adjacent R2 are attached complete a 5-7 membered ring; and wherein any of said phenyl, naphthyl or benzene moieties of A1, A2, A3, R1 or R2 may be unsubstituted or bear one or two substituents independently selected from (1 -4C)alkyl, (1 -4C)alkoxy, halogeno, cyano and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.
Preferred compounds of this embodiment include 5-dimethylamino-N-(3- methoxy-5-methyl-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-dimethylamino-N-(5- chloro-3-methoxy-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-dimethylamino-N-(5- bromo-3-methoxy-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-ethylamino-N-(5-bromo- 3methoxy-2-pyrazinyl)-1 -naphthalenesulphonamide; 5-ethylamino-N-(6-chloro-3- pyridazinyl)-1 -naphthalenesulphonamide; 5-ethylamino-N-(5-bromo-2-pyrazinyl)-1 - naphthalenesulphonamide; 5-dimethylamino-N-(2-chloro-4-methoxy-5-pyrimidinyl)-1 - naphthalenesulphonamide; N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-isobutyl-2- biphenylsulphonamide; N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-methyl-2- biphenylsulphonamide; N-(5-bromo-3-methoxy-2-pyrazinyl)-2-biphenylsulphonamide; N- (5-chloro-3-methoxy-2-pyrazinyl)-2-biphenylsulphonamide; N-(3-methoxy-5-methyl-2- pyrazinyl)-2-biphenylsulphonamide; N-(2-chloro-4-methoxy-5-pyrimidinyl)-2- biphenylsulphonamide; 5-dimethylamino-N-(5-ethynyl-3-methoxy-2-pyrazinyl)-1 - naphthalenesulphonamide; N-(5-bromo-3-methoxy-2-pyrazinyl)-5-(isopropylamino)-1 - naphthalenesulphonamide; 4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-2- biphenylsulphonamide; N-(5-chloro-3-methoxy-2-pyrazinyl)-4'-isobutyl-2- biphenylsulphonamide; N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-methoxy-2- biphenylsulphonamide; 4'-methoxy-N-(3-methoxy-5-methyl-2-pyrazinyl)-2- biphenylsulphonamide; N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2- biphenylsulphonamide; 4'-chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-2- biphenylsulphonamide; 4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-3'-nitro-2- biphenylsulphonamide; and 3'-amino-4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-2- biphenylsulphonamide; or a pharmaceutically acceptable salt thereof.
I. European Patent Application Publication No. EP 0569 193 A1
Also of interest herein for use in the methods are compounds of the formula:
Figure imgf000194_0001
and pharmaceutically acceptable salts thereof, where one of X and Y is N and the other is 0; R1 , R2 and R3 are each independently (a) hydrogen, except that R1 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with Z\ Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R6; (h) - C02H or C02Rβ; (i) -SH, -S(0)nR6, -S(0)m-OH, -S(0)m-OR6, -0-S(0)m-R6, -0-S-(0)mOH, or - 0-S(0)m-OR6; (j) -Z4-NR7R8; or (k) -Z -N(R11)-ZS-NR9R10; R4 and R5 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with Z\ Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)Rβ; (h) - C02H or C02R6; (i) -SH, -S(0)nR6, -S(0)m-0H, -S(0)m-0R6, -0-S(0)m-R6, -0-S-(0)m0H, or - OS(0)m-OR6; (j) -Z4-NR7R8; or (k) -Z4-N(R11)-Z5-NR9R10; (I) R4 and R5 together are alkylene or alkenylene (either of which may be substituted with Z\ Z2 and Z3), completing a 4- to 8- membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R6 is alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; R7 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; (c) cyano; (d) hydroxyl; (e) -C(0)H or -C(0)R6; (f) -C02R6; (g) -SH, -S(0)nR6, -S(0)m-OH, -S(0)m-OR6, -0-S(0)m-R6, -0-S(0)mOH, or -0-S(O)m-0R6, except when Z4 is -S(0)n; R6 is (a) hydrogen; (b) -C(0)H or -C(0)R6, except when Z4 is - C(O)- and R7 is -C(0)H, -C(0)R6, or -C02R6; (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1 , Z2 and Z3; or R7 and R8 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; R9 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R6; (d) -C02R6; (e) -SH, -S(0)nR6, -S(0)m-OH, -S(0)m-0R6, -0-S(0)m-R6, -0-S(0)mOH, or -0- S(0)m-OR6; (f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R 0 is (a) hydrogen; (b) -C(0)H or -C(0)R6, except when ZB is -C-(0)- and R9 is -C(0)H, - C(0)R6, or -C02R6; or (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; R11 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H, -C(0)R6 or C02R6; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or any two of R9, R10 and R11 together are alkylene or alkenylene (either of which may be substituted with Z\ Z2 and Z3), completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached; Z1, Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0)nZ6, -S(0)m-OH, -S(0)m-OZ6, -0-S(0)m-Z6, - 0-S(0)mOH, or -0-S(0)m-0-Z6; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)Zβ; (o) - C02H or -C02Z6; (p) -Z -NZ7Z8; (q) Z4-N(Z11)-Z5-Z6; or (r) -Z4-N(Z11)-Z5-NZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) -Z9-S(0)n-Z10-; (c) -Z9-C(0)-Z10-; (d) -Z9- C(S)-Z10-; (e) -Z9-0-Z10-; (f) -Z9-S-Z10-; or (g) -Z9-0-C(0)-Z10-; Z6, Z7 and Z8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene, or alkynylene; Z11 is (a) hydrogen; (b) hydroxyl; (c) - C(0)H, -C(0)Z6 or -C02Z6; (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8- membered saturated, unsaturated, or aromatic ring together with the atoms to which they are attached; m is 1 or 2; and n is 0, 1 , or 2.
For this embodiment, it is preferred that R1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, -NZ7Z8, halo, or hydroxy; R2 and R3 are each independently hydrogen, alkyl, or -NR7R8; R4 and R5 are alkyl; and R7, R8, Z7 and Z8 are each independently hydrogen, alkyl, or -C(0)alkyl.
For this embodiment, most preferred compounds are those wherein R1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino or hydroxy; R2 and R3 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, amino, alkylamino, dialkylamino, or alkanoylamino; and R4 and R5 are alkyl of 1 to 4 carbon atoms, specially methyl.
Preferred compounds of this embodiment include N-3,4-Dimethyl-5-isoxazolyl)f1 , 1 '-biphenyl]-2-sulf onamide; N-3,4-Dimethyl-5-isoxazolyl)-2-bromobenzene-sulf onamide; N-3,4-Dimethyl-5-isoxazolyl)-2-phenoxybenzene-sulfonamide; 3'-Amino-N-(3,4-dimethyl- 5-isoxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; 2-Fluoro-N-(3,4-dimethyl- 5isoxazolyl)benzene-sulf onamide; N-[3-[[(3,4-Dimethyl-5-isoxazolyl)-2-methyl- benzenesulfonamide; 5-Amino-N-(3,4-Dimethyl-5isoxazolyl)-2-methyl- benzenesuif onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(1 -methylethyl)- benzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-nitro-benzenesulf onamide; 2- Amino-N-(3,4-dimethyl-5-isoxazolyl)benzene-sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)- 4'-methyl[1 ,1 '-biphenyl]-2-sulf onamide; 2'-Amino-N-(3,4-dimethyl-5-isoxazolyl)-[1 ,1 '- biphenyl]-2-sulfonamide; 3'-(Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(trifluoromethyl)- benzenesulfonamide; 2-Chloro-N-(3,4-dimethyl-5-isoxazolyl)-6-methylbenzene- sulfonamide; 4'-(Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide; N-[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl][1 ,1-biphenyl]-3- ylacetamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-propyl[1 ,1 '-biphenyl]-2-sulf onamide; 2- (Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)benzenesulf onamide; N-(3,4-Dimethyl-5- isoxazolyl)-4'-(2-methylpropyl)-[1 ,1 '-biphenyl]-2-sulfonamide; 4'-Butyl-N-(3,4-dimethyl-5- isoxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(1 - naphthalenyD-benzenesulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-3'-(2-methylpropyl)- [1 , 1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-methylpropoxy)-[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(1 -methylethoxy)-[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(phenylmethyloxy)-[1 ,1 '- biphenyl]-2-sulfonamide; 4'-(1 ,1 -Dimethylethyl)-N-(3,4-dimethyl-5-isoxazolyl)-[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-methoxy-[1 ,1 '-biphenyl]-2- sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-[(1 -methylethyl)-amino][1 ,1 '-biphenyl]-2- sulfonamide; 2-[[[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-[1 ,1 '-biphenyl]-4-yl](1 - methylethyl)amino]carbonyl]-amino]-4-methylpentanoic acid, ethyl ester; 2'-Amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methyl-propyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-[2'- [[(S^-Dimethyl-δ-isoxazolyDaminolsulfonyJll '-biphenyll^-ylU-N-fl-methylethyl)-^- phenylbenzenepropanamide; 2'-Nitro-N-(3,4-dimethyl-5-isoxazolyl)-[1 ,1 '-biphenyl]-2- sulfonamide; 5-[[(2-phenyl)phenyl]sulfonyl]amino]-3-methyl-4-isoxazolecarboxylic acid, ethyl ester; N-(3-Methyl-4-phenylmethyl-5-isoxazolyl)-4'-(2-methylpropyl)-[1 ,1 '- biphenyl]-2-sulfonamide; N-(4,5-Dimethyl-3-isoxazolyl)-4'-(2-methylpropyl)-[1 ,1 '- biphenyl)-2-sulfonamide; 4'-(2-Methylpropyl)-2'-Methoxy-N-(3,4-dimethyl-5-isoxazolyl)- [1 ,1 '-biphenyl]-2-sulfonamide; 4'-(2-Methylpropyl)-2'-hydroxy-N-(3,4-dimethyl-5- isoxazolyl)-[1 ,1 '-biphenyl]-2-sulfonamide; N-(3-Methyl-4-nitro-5-isoxazolyl)-4'-(2- methylpropyl)-[1 ,1 '-biphenyl]-2-sulf onamide; N-(4-Methyl-5-isoxazolyl)-4'-(2- methylpropyl)-[1 ,1 '-biphenyl]-2-sulf onamide; 4'-(2-Methylpropyl)-N-(4,5,6,7-tetrahydro- 2,1 -benzisoxazol-3-yl)-[1 ,1 '-biphenyl]-2-sulfonamide; 4-Amino-4'-(2-methylpropyl)-N- (3,4-dimethyl-5-isoxazolyl)-[1 ,1 '-biphenyl]-2-sulfonamide; 2'-Fluoro-4'-(2-methylpropyl)- N-(3,4-dimethyl-5-isoxazolyl)-[1 ,1 '-biphenyl]-2-sulfonamide; or 4-Methoxy-4'-(2- methyipropyl)-N-(3,4-dimethyl-5-isoxazolyl)-[1 ,1 '-biphenyl]-2-sulfonamide. m. European Patent Application Publication No. EP 0 556 258 A1
Compounds of the formula:
Figure imgf000198_0001
and pharmaceutically or veterinarily acceptable salts thereof are also intended for use in the methods provided herein. The above symbols are defined as follows: one of X and Y is N and the other is 0; R is naphthyl or naphthyl substituted with R1, R2 and R3; R\ R2 and R3 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) - C(0)H or -C(0)R6; (h) -C02H or -C02R4; (i) -SH, -S(0)„R\ -S(0)m-0H, -S(0)m-0R4, -O- S(0)m-R4, -0-S(0)mOH, or -0-S(0)m-0R4; (j) -Z -NR7R8; or (k) -Z4-N(R11)-Z6-NR9R10; R4 and R5 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z , Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or - C(0)R4; (h) -C02H or -C02R4; (i) -SH, -S(0)fiR4, -S(0)m-0H, -S(0)m-0R4, -0-S(0)m-R4, -0- S(0)mOH, or -0-S(0)m-0R4; (j) -Z -NR7R8; (k) -Z4-N(R11)-Z5-NR9R10; or (I) R4 and R5 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R4 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R7 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; (c) cyano; (d) hydroxyl; (e) -C(0)H or - C(0)R4; (f) -C02H or -C02R4; (g) -SH, -S(0)RRβ,-S(0)m-0H, S(0)m-OR6, -0-S(0)m-R6, -0- S(0)m0H, or-O-S(O)m-0R6, except when Z6 is -S(0)R-; R6 is (a) hydrogen; (b) -C(0)H or- C(0)R6, except when Z4 is -C(O)- and R7 is -C(O)- and R7 is -C(0)H, -C(0)R6, -
C02H, or-C02R6; (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or R7 and R6 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; R6 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R6; (d) -C02H or -C02R6; (e) -SH, -S(0)RR\ - S(0)m-0H, -S(0)m-OR6, -0-S(0)m-R6, -0-S(0)m-R6, -0-S(0)m-R6, -0-S(0)mOH, or -0-S(0)m- OR6; (f) alkyl, alkynyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkanyl, cycloalkenyalalkyl, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; R10 is (a) hydrogen; (b) -C(0)H or -C(0)R6, except when Z6 is -C(O)- and R9 is -C(0)R6, - C02H, or -C02R6; (c) alkyl, alkenyl, alkenyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R11 is (a) hydrogen; (b) hydroxyl, C02R6 or C02H, except when one of R9 and R10 is hydroxyl, C02R6 or C02H; (c) -C(0)H or -C(0)Re; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or any two of R9, R 0 and R11 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached; Z1, Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkoxy; (e) -SH, -S(0)RZ6, -S(0)m-OH, -S(0)m-OZ6, -0- S(0)m-Zβ, -0-S(0)mOH, or -0-S(0)m-0Z6; (f) oxo; (g) nitro; (h) cyano; (i) -C(0)H or - C(0)Z6; (j) -C02H or C02Z6; or (k) -NZ7Z8, -C(0)NZ7Z8, or -S(0)RZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) -S(0)R-; (c) -C(O)-; (d) -C(S)-; or (e) alkyl, alkanyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkengylalkyl, aryl, or aralkyl, any of which may be substituted with Z1, Z2 and Z3; Z6, Z7, and Z8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; m is 1 or 2; and n is 0, 1 , or 2.
Preferred compounds of this embodiment include 5-(Dimethylamino)-N-(3,4- dimethyl-5-isoxazolyl)-1-naphthalenesulfonaide; N-[5-[[(3,4-Dimethyl-5-isoxazolyl)amino]- sulfonylI-1 -napthalenyl]acetamide; 5-Amino-N-(3,4-dimethyl-5-isoxazolyl)-1-napthalene- sulfonamide; N-[6-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-1-naphthalenyl]acetamide; 5-Amino-N-(3,4-dimethyl-5-isoxazolyl)-2-naphthalenesulf onamide; N-[4-[[(3,4-Dimethyl- 5-isoxazolyl)amino]sulfonyl]-1 -naphthalenyllacetamide; N-[6-[[(3,4-Dimethyl-5-isoxazol- yl)amino]sulfonyl]-2-naphthalenyl]acetamide; 6-Amino-N-(3,4-dimethyl-5-isoxazolyl)-2- naphthalenesulf onamide; 4-Amino-N-(3,4-dimethyl-5-isoxazolyl)-1 -naphthalenesulfon- amide; 5-Dimethylamino-N-(4,5-dimethyl-3-isoxazolyl)-1 -naphthalenesulfonamide; N-[5- [[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-1-naphthalenyl]acetamide; N-[5-[[(3,4- dimethyl-5-isoxazolyl)amino]sulfonyl]-2-nathphthalenyl]acetamide; N-[8-[[(3,4-dimethyl- 5-isoxazolyl)amino]sulfonyl]-2-naphthalenyl]acetamide; N-[7-[[(3,4-dimethyl-5-isoxazol- yl)amino]sulfonyll-2-nathphthalenyllacetamide; N-[7-[[(3,4-dimethyl-5-isoxazolyl)aminoJ- sulfonylM -naphthalenyl]acetamide; N-(3,4-Dimethyl-5-isoxazolyl)-5-methoxy-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-1 -naphthalenesulfonamide; 5-[(1- Methylethyl)amino]-N-(3,4-dimethyl-5-isoxazolyl)-1 -naphththalenesulfonamide; N-[5- [[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-1 -naphthalenyl]-2-methylpropanamide; 5- Chloro-N-(3,4-dimethyl-5-isoxazolyl)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-5-[(phenylmethyl)amino]-1 -naphthlenesulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-5-hydroxy-1 -naphthalenesulfonamide; 7-(Dimethylamino)-N-(3,4-dimethyl-5- isoxazolyl)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-5-[methyl(1 - methylethyl)amino]-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-5-(2-oxo-1 - pyrrolldinyl)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-5-(2-oxo-1 - piperidinyl)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-5-[[(phenylamino)- thloxomethyl]amino]-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-5-(1 - pyrrolldinyl)-1 -naphthalenesulfonamide; 5-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-1 - naphthalenecarboxylic acid; 5-[[[5-(Dimethylamino)-1 -naphthalenyl]sulfonyl]aminol-3- methyl-4-isoxazolecarboxylic acid, ethyl ester; 5-[[(3,4-Dimethyl-5-isoxazolyl)aminol- sulfonylM -naphthalenecarboxylic acid, methyl ester; 5-(Dimethylamino)-N-(3-methyl-5- isoxazolyl)-1 -naphthalenesulfonamide; 5-f(Dimethylamino)methyl]-N-(3,4-dimethy)-5- isoxazolyl)-1 -naphthalenesulfonamide, trifluoroacetate (1 :1 ) salt; N-(3,4-Dimethyl-5- isoxazolyl)-5-(1 -hydroxy-1 -methylethyl)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-5-(1 -methylethenyl)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)- 5-(1 -piperidinyl)-1 -naphthalenesulfonamide; trifluoroacetate (2:1 ) salt; N-(3,4-Dimethyl- 5-isoxazolyl)-5-(methylamino)-1 -naphthalenesulfonamide; N-(3,4-Dimethyl-5-isoxazoyl)- 5-(ethylamino)-1 -naphthalenesulfonamide; N-(3-Methyl-4-phenylmethyl-5-isoxazolyl)-5- [dimethylamino]-1 -naphthalenesulfonamide; N-(3-Methyl-4-phenyl-5-isoxazolyl)-5- (dimethylamino)-l -naphthalenesulfonamide; N-(3-Ethyl-4-methyl-5-isoxazolyl)-5- (dimethylamino)-l -naphthalenesulfonamide; 5-(Dibutylamino)-N-(3,4-dimethyl-5-isoxazol- yl)-1 -naphthalenesulfonamide, monosodium salt; 4-[1 -[[(3,4-Dimethyl-5-isoxazolyl)- amino]sulfonyl]naphthalen-5-yl]amino]butanoic acid; 6-Amino-N-(3,4-dimethyl-5-isoxa- zolyl)-1 -naphthalenesulfonamide; 7-Amino-N-(3,4-dimethyl-5-isoxazolyl)-2-naphthalene- sulf onamide; 8-Amino-N-(3,4-dimethyl-5-isoxazolyl)-2-naphthalenesulf onamide; 7- Amino-N-(3,4-dimethyl-5-isoxazolyl)-1 -naphthalenesulfonamide; 7-(Dimethyiamino)-N- (3,4-dimethyl-5-isoxazolyl)-2-naphthalenesulfonamide; 8-(Dimethylamino)-N-(3,4- dimethyl-5-isoxazolyl)-2-naphthalenesulf onamide; 6-(Dimethylamino)-N-(3,4-dimethyl-5- isoxazolyl)-1 -naphthalenesulfonamide; 5-(Dimethylamino)-N-(3-methyl-4-nitro-5- isoxazolyl)-1 -naphthalenesulfonamide; 5-(Dimethylamino)-N-(4,5,6,7-tetrahydro-2,1 - benisoxazol-3-yl)-1 -naphthalenesulfonamide; 5-(Dimethylamino)-N-(4-ethyl-3-methyl-5- isoxazolyl)-1 -naphthalenesulfonamide; or 5-(Dimethylamino)-N-(4-methyl-5-isoxazolyl)-1 - naphthalenesulfonamide. n. U.S. Patent No. 5,514,696
For use in the methods provided herein are compounds of the formula:
Figure imgf000201_0001
and pharmaceutically acceptable salts thereof, where one of X and Y is N and the other is O; R1, R2 and R3 are each independently (a) hydrogen, except that R1 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R6; (h) -C02 H or -C02 R6; (i) -SH, -S(0)n R6, -S(0)m -OH, -S(0)m -OR6, -0-S(0)m -R6, -0-S(0)m OH or -0-S(0)m -OR6; (j) -Z4 -NR7 R8; or (k) -Z4 -N(R11 )-Z5 -NR9 R10; R4 and R5 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z\ Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R6; (h) -C02 H or -C02 Rδ; (i) -SH, -S(0)n R6, -S(0)m -OH, -S(0)m -OR6, -0-S(0)m -R6, -0-S(0)m OH or -0-S(0)m -OR6; (j) -Z4 -NR7R8; (k) -Z4 -N(R11 )-Z5 -NR9 R10; or (I) R4 and Rs together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 4- to 8- membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R6 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylakyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1 , Z2 and Z3; R7 is (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylakyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z Z2 and Z3; (c) cyano; (d) hydroxyl; (e) -C(0)H or -C(0)R6; (f) -C02 R6; (g) -SH, -S(0)R6, -S(0)-OH, -S(0)-OR6, -0-S(0)-R6, -0-S(0)OH or _0-S(0)-OR6, except when Z4 is -S(0)n-; R8 is (a) hydrogen; (b) -C(0)H or -C(0)R6, except when Z4 is -C(0)- and R7 is -C(0)H, -C(0)R6 or -C02R6; (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or R7 and R8 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; R9 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H or -C(0)R6; (d) -C02R6; (e) -SH, -S(0)n R6, -S(0)m -OH, -S(0)m -OR6, -O-S(0)m -R6, -0-S(0)m OH or _0-S(0)m -OR6; (f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R10 is (a) hydrogen; (b) -C(0)H or -C(0)R6, except when Z5 is -C(O)- and R9 is -C(0)H, -C(0)R6 or -C02 R6; or (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; R11 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H, -C(0)Rβ or C02 R6; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or any two of R9, R10 and R11 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached; Z\ Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0)n Z6, -S(0)m -OH, -S(0)m -OZ6, -0-S(0)m -Z6, -0-S(0)m OH or -0-S(0)m -OZ6; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)Z6; (o) -C02 H or -C02 Z6; (p) -Z4 -NZ7 Z8; (q) -Z4 -N(Z11)-Z5 -Z6; or (r) -Z4 -N(Z11)-Z5 -NZ7 Z8; Z4 and Zs are each independently (a) a single bond; (b) -Z9 -S(0)π -Z10-; (c) -Z9-C(0)-Z10; (d) -Z9 -C(S)-Z10-; (e) -Z9 -O-Z 0-; (f) -Z9 -S-Z10-; or (g) -Z9 -0-C(0)-Z10-; Z6, Z7 and Z8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene; Z 1 is (a) hydrogen; (b) hydroxyl; (c) -C(0)H, -C(0)Z6 or -C02 Z6; (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached; m is 1 or 2; and n is 0, 1 or 2.
For this embodiment, it is preferred that R1 is phenyl or phenoxy, optionally substituted with one or more alkyl, alkoxy, -NZ7 Z8, halo and hydroxy; R2 and R3 are each independently hydrogen, alkyl or -NR7 R8; R4 and R5 are alkyl; and R7, R8, Z7 and Z8 are each independently hydrogen, alkyl or -C(0)alkyl. In preferred embodiments, R1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino or hydroxy; R2 and R3 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, amino, alkylamino, dialkylamino or alkanoylamino; and R4 and R5 are alkyl of 1 to 4 carbon atoms, especially methyl. Preferred compounds of this embodiment include N-(3,4-Dimethyl-5-isoxazolyl)-
2-bromobenzene-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-phenoxybenzene- sulf onamide; 2-Fluoro-N-(3,4-dimethyl-5-isoxazolyl)benzene-sulf onamide; N-[3-[[(3,4- Dimethyl-5-isoxazolyl)aminolsulfonyl)-4-methylphenyl]acetamide; 5-Amino-N-(3,4- Dimethyl-5-isoxazolyl)-2-methyl-benzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(1 - methylethyDbenzenesulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-nitro-benzenesulf onamide; 2-Amino-N-(3,4-dimethyl-5-isoxazolyl)benzene-sulf onamide; N-(3,4-Dimethyl-5- isoxazolyl)-2-(trifluoromethyl)-benzenesulf onamide; 2-Chloro-N-(3,4-dimethyl-5- isoxazolyl)-6-methylbenzene-sulfonamide; 2-(Dimethylamino)-N-(3,4-dimethyl-5- isoxazolyDbenzenesulfonamide; and N-(3,4-Dimethyl-5-isoxazolyl)-2-( 1 -naphthalenyl)- benzenesulfonamide. o. U.S. Patent No. 5,420,129
In particular, the compounds for use in the methods provided herein are of the formula:
Figure imgf000204_0001
wherein R1 is hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl; R2 is hydrogen, lower-alkyl, halogen, lower-alkoxy, trifluoromethyl or — OCH2 COOR9; R3 is hydrogen, lower-alkyl, halogen, lower-alkylthio, trifluoromethyl, lower-alkoxy or trifluoromethoxy; R2 and R3 together are butadienyl, methylenedioxy, ethylene-dioxy or isopropylidenedioxy; R4 is hydrogen, lower-alkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, hydroxy- lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-fower-alkoxy, alkoxy-lower-alkyl, alkoxy- lower-alkyloxy, lower-alkylsulfinyl, lower-alkylsulfonyl, 2-methoxy-3-hydroxypropoxy, 2- hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl, heterocyclyl, heterocyclyl-lower-alkyl, heterocyclylamino, heterocyclylthio, heterocyclyloxy, -CHO, -CH2 OH or -CH2CI; R5 to R8 are independently hydrogen, halogen, trifluoromethyl, lower-alkoxy, lower-alkylthio or cyano; R6 and R5 or R7 together are butadienyl, methylene-dioxy, ethylenedioxy or isopropylidenedioxy; X is — O- or -S— ; Y is —CHO, C1-4 -alkyl, -(CH2).,.4 -Z— R9, -(CH2)^ -OC(0)(CH2)7.4 CH3; -(CH2)7.4OC(0)Het, -|CH2)M NHC(0)R10, -|CH2)M 0CH2CH(0H)CH20H and cyclic ketals thereof, -(CH2)1-tNR9CHaCH{OH)CH2OH, -(CH2),. 40CH2CH2SCH3, -(CH2)1JΦ0CH2CH2S(0)CH3, -(CH2)l.40(CH2)1.4-Z H, -(CH2)1.40(CH2)1.4 0C(0)R10, -(CH2)1.4NR9(CH2)1.4Z H, -(CH2)1.40(CH2)1.4OC(0)Het, -(CH2)0.3CH(OH)R10, -(CH2)0.3CH(OH)(CH2)1.4 Z H, -(CH2)0.3CH(OH)CH2SCH3, ~(CH2)0.3CH(OH)CH2S(O)CH3, -(CH2)0.3CH(OH)OCH2CH2OH, -(CH2)0.3C(O)(CH2)n.4CH3, -(CH2)0.3C(O)(CH2)1.4 Z R11, -(CH2)α3C(0)CH2Hal, -(CH2),.4Hal, -(CH2),.4CN, -(CH2)0.3C(O)OR9, -OR12 or -SR 2; R9 is hydrogen or C,^ -alkyl; R10 is C,.4 -alkyl; R11 is hydrogen, C,.4 -alkanoyl or heterocyclylcarbonyl; R12 is C,^ -alkyl or -(CH2)0.4 -aryl; Z is -0-, -S- or -NR9-; Het is a heterocyclic residue; Hal is halogen; and n is 0 or 1 ; and salts thereof. Preferred compounds of this embodiment include 4-tert-butyl-N-[6-ethoxy-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzenesulphonamide, 4-tert-butyl-N-[6- methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzenesulphonamide, 4-tert- butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-yl]- benzenesulphonamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl- 2(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-(2-chloro-5- methoxy-phenoxy)-6-hydroxymethyl-2-(morpholin-4-yl)-pyrimidin-4-ylJbenzenesulphon- amide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholin-4- yl)-pyrimidin-4-yl]benzenesulphonamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 6-(2-hydroxy-ethoxymethyl)-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesuiphonamide, 4- tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidin-4-yl]-benzenesulphon- amide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-pyrimidin-4-yll- benzenesulphonamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-hydroxy- methyl-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-chloromethyl-5-(2-chloro- 5-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-( 2-chloro- 5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy-methyl)-pyrimidin-4-yl]-benzenesulphonamide, thiophene-3-carboxylic acid 2-[6-(4-tert-butylphenylsulphonamino)-5-(2-chloro-5- methoxy-phenoxy)-2-( morpholin-4-yl)-pyrimidin-4-yl-methoxy]-ethyl ester, (R,S)-4-tert- butyl-N-[5-( 2-chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl-1 ,3-dioxolan-4-ylmethoxy- methyl)-2-morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, (R,S)-4-tert-butyl-N-[5- (2-chloro-5-methoxy-phenoxy)-6-(2,3-dihydroxy-propoxymethyl)-2-(morpholin-4-yl)- pyrimidin-4-yl]benzenesulphonamide, 4-tert-butyl-N-[5-( 2-chloro-5-methoxy-phenoxy)-6- (2-hydroxy-ethylaminomethyl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-( 2-chloro-5-methoxy-phenoxy)-6-(3-hydroxy-propoxymethyl)-pyrimidin-4-yl]-benzene- sulphonamide, (RS)-4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-dihydroxy- propylaminomethyl)-pyrimidin-4-yl]-benzenesulphonamide, (RS)-4-tert-butyl-N-[5-{2- chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl-1 ,3-dioxolan-4-ylmethoxymethyl)-pyrimidin- 4-yl]benzenesulphonamide, (RS)-4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3- dihydroxy-propoxymethyl)-pyrimidin-4-yl]-benzenesulphonamide, pyridin-3-ylacetic acid 2-[6-(4-tert-butyl-phenylsulphonyl-amino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4- ylmethoxylethyl ester, pyridin-4-ylacetic acid 2-[6-(4-tert-butyl-phenylsuIphonyl-amino)- 5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylmethoxy]ethyl ester, furan-3-carboxylic acid 2-[6-(4-tert-butyl-phenylsulphonyl-amino)-5-(2-chloro-5-methoxy-phenoxy)- pyrimidin-4-ylmethoxy]ethy) ester, thiophene-3-carboxylic 2-[6-(4-tert-butyl- phenylsulphonyl-amino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylmethoxy]ethyl ester, ethyl 6-(4-tert-butyl-phenylsulphonyl-amino)-2-chloro-5-phenoxy-pyrimidin-3- carboxylate, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2,2'-bipyrimidinyl- 4-yll-benzenesulphonamide, (S)-4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2- dimethyl-1 ,3-dioxolan-4-ylmethoxymethyl)-2-morpholin-4-yl)-pyrimidin-4-yl]- benzenesulphonamide, (R)-4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2- dimethyl-1 ,3-dioxolan-4-ylmethoxymethyl)-2-(morpholin-4-yl)-pyrimidin-4-yll- benzenesulphonamide, (S)-4-tert.-butyl-N-[5-(2-chloro-4-methoxy-phenoxy)-6-(2,3- dihydroxypropoxymethyl)-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesulphonamide, (R)-4- tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-dihydroxy-propoxymethyl)-2- (morpholin-4-yl)-pyrimidin-4-yl-benzenesulphonamide, (4S,5S)-4-tert.-butyl-N-[5-(2- chloro-5-methoxy-phenoxy)-6-(5-hydroxymethyl-2,2-dimethyl-1 ,3-dioxolan-4-ylmethoxy- methyl)-pyrimidin-4-yl]-benzenesuiphonamide, (2S,3S)-4-tert.-butyl-N-15-(2-chloro-5- methoxy-phenoxy)-6(2,3,4-trihydroxybutoxymethyl)-4-yl]benzbenzenesulphonamide, 6- (4-tert.-butyl-phenylsulphonamino )-5-(2-chloro-5-methoxy-phenoxy)-2,2'-bipyrimidinyl- 4-carboxaldehyde, 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl- 2,2'-bipyrimidin-4-yl]-benzenesulphonamide, 4-tert.-butyl-N-[5-(2-chloro-5-methoxy- phenoxy)-6-chloromethyl-2,2'-bipyrimidin-4-yl]-benzenesulphonamide, 4-tert.-butyl-N-t5- ( 2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)-2-2'-bipyrimidin-4-yl]ben- zenesulphonamide, 4-tert.-butyl-N-t5-(2-chloro-5-methoxy-phenoxy)-6-methoxy-2- methyl-pyrimidin-4-yll-benzenesulphonamide, 4-tert.-butyl-N-[5-(2-chloro-5-methoxy- phenoxy)-2-formyl-6-methoxypyrimidin-4-yl)-benzenesulphonamide, 4-tert.-butyl-N-[5-(2- chloro-5-methoxy-phenoxy)-2-hydroxymethyl-6-methoxy-pyrimidin-4-yl]-benzenesulphon- amide, 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-chloromethyl-6-methoxy- pyrimidin-4-yl]-benzenesulphonamide, 4-tert.-butyl-N-[5-( 2-chloro-5-methoxy-phenoxy)- 2-(2-hydroxy-ethoxymethyl-6-methoxy-pyrimidin-4-yl]benzenesulphonamide, (RS)-4-tert.- butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2(2,2-dimethyl-1 ,3-dioxolan-4-ylmethoxy- methyl)-6-methoxy-pyrimidin-4-ylJ-benzenesulphonamide, (RS)-4-tert.-butyl-N-[5-(2- chloro-5-methoxy-phenoxy)-2(2,3-dihydroxy-propoxy-methyl)-6-methoxy-pyrimidin-4- yljbenzenesulphonamide, 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-amino- methyl-6-methoxy-pyrimidin-4-yl]-benzenesulphonamide, N-[5-(2-chloro-5-methoxy- phenoxy)-6-(2-methoxy-ethoxy)-2-methyl-pyrimidin-4-yl]-1 ,3-benzodioxol-5-sulphon- amide, N-[5-(2-chloro-5-methoxy-phenoxy)-2-formyl-6-(2-methoxy-ethoxy)-pyrimidin-4- yl]- 1 ,3-benzodioxol-5-sulphonamide, N-[5-(2-chloro-5-methoxy-phenoxy)-2-hydroxy- methyi-6-(2-methoxy-ethoxy)-pyrimidin-4-yl]-1 ,3-benzodioxol-5-sulphonamide, N-[5-(2- chloro-5-methoxy-phenoxy)-2-chloromethyl-6-(2-methoxy-ethoxy)-pyrimidin-4-yl]- 1 ,3- benzodioxol-5-sulphonamide, N-[5-(2-ch)oro-5-methoxy-phenoxy)-2-(2-hydroxy-ethoxy- methyl)-6-(2-methoxy-ethoxy)-pyrimidin-4-yl]- 1 ,3-benzodioxol-5-sulphonamide, 4-tert.- butyl-N-[6-methoxy-5-(2-methoxy-phenylsulphanyl)-methyl-pyrimidin-4-yl]-benzene- sulphonamide, 4-tert.-butyl-N-[2-formyl-6-methoxy-5-(2-methoxy-phenylsulfanyD- pyrimidin-4-yl]-benzenesulphonamide and 4-tert.-butyl-N-[2-hydroxymethyl-6-methoxy-5- (2-methoxy-phenylsulfanyl)-pyrimidin-4-yl]-benzenesulphonamide. p. JOURNAL OF MEDICINAL CHEMISTRY 37(3):330 (1994)
Other compounds for use in the methods provided herein include those in the following tables:
— Heterocycle
Figure imgf000207_0001
Figure imgf000207_0002
Figure imgf000208_0001
Figure imgf000208_0003
q. uropean atent pplication Publication No. EP 0626 174 A2
Particular compounds for use in the methods provided herein include compounds represented by the formula:
Figure imgf000208_0002
or salts thereof, wherein R1 represents a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a halogen atom or a trifluoromethyl group; R2 represents a halogen atom, a lower alkoxyl group, a hydroxy-lower alkoxyl group or a trifluoromethyl group; R3 represents a hydroxyl group, a halogen atom, an alkylthio group, a cycloalkyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, hydroxyimino-lower alkyl group, a lower alkenyl group, an oxy-lower alkyl group, a trifluoromethyl group, a trifluoromethoxyl group, a lower alkoxyl group, a lower alkoxy-lower alkoxyl group or an aryl-lower alkoxyl group, and R2 and R3 may form butadienyl; R4 represents a lower alkyl group, an aryl group or heterocyclic aryl group; R5 represents a lower alkanoyl group, a benzoyl group, a heterocyclic carbonyl group or a tetrahydropyran-2-yl group; R6 represents
Figure imgf000209_0001
R7 represents a lower alkoxyl group or a nitro group; R8 represents a halogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a nitro group, a hydroxyl group, an amino group or a trifluoromethyl group, and R7 and R8 may form butadienyl; R9 represents a halogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkythio group or a trifluoromethyl group; R10 represents a halogen atom, a lower alkyl group, a lower alkoxyl group or a lower alkylthio group; X and Y each represent 0, S or NH; and n represents 2, 3 or 4. In the above definition, "lower" means C.,.7.
Other compounds for use in the methods provided herein include compounds represented by the formula:
Figure imgf000209_0002
wherein R1 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a halogen atom or a trifluoromethyl group; R2 represents a hydrogen atom, a halogen atom, a lower alkoxyl group, a trifluoromethyl group or -OCH2COORa; R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkylthio group, a trifluoromethyl group, a cycloalkyl group or a lower alkoxyl group, and R2 and R3 may form butadienyl, methylenedioxy, ethylenedioxy or isopropylidene; R4 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a trifluoromethyl group, a lower alkoxyl group, a lower alkylthio group, a lower alkylthio- lower alkyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a lower alkoxy-lower alkyl group, hydroxy-lower alkoxy-lower alkyl group, hydroxy-lower alkoxy- lower alkoxyl group, a lower alkylslufinyl group, a lower alkylsulfonyl group, a 2- methoxy-3-hydroxypropoxyl group, a 2-hydroxy-3-phenylpropyl group, an amino-lower alkyl group, a lower alkylamino-lower alkyl group, a di-lower alkylamino-lower alkylamino group, a lower alkylamino group, a di-lower alkylamino group, an arylamino group, an aryl group, an arylthio, an aryloxy group, an aryl-lower alkyl group or a heterocycle; R5 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a heterocyclic carbonyl group, a heterocyclic methyl group or a tetrahydropyran-2-yl group; R6 to R9 each represent hydrogen atoms, halogen atoms, trifluoromethyl groups, lower alkyl groups, lower alkoxyl groups, lower alkylthio groups, hydroxyl groups, hydroxymethyl groups, cyano groups, carboxyl groups, formyl groups, methylsulfinyl groups, methylsulfonyl gorups, methylsulfonyloxy groups or lower alkoxycarbonyloxy groups; R7 may combine with R6 or R8 to form butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Z represent -0-, -S-, ethylene, vinylene, -CO-, -OCHR10 -or -SCHR10-, wherein R10 represents a hydrogen atom or a lower alkyl group; X and Y each represent 0, S, or NH; YR5 represents a lower alkylslufinyl group or -OCH2CH(OR°)CH2-ORd; Ra, Rb, R° and Rd each represent hydrogen atoms or lower alkyl groups; Rc and Rd each represent methylene, ethylene or isopropylidine; and n represents 1 , 2 or 3. r. U.S. Patent No. 5,846,990 Compounds of the formula:
Figure imgf000211_0001
its enantiomers and diastereomers, and pharmaceutically or veterinarily acceptable salts thereof are intended for use in the methods provided herein. In this embodiment, the above symbols are defined as follows: one of X and Y is N and the other is O; R1, R2, R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z\ Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R5; (h) -C02 H or -C02RB; (i) -Z4 -NR6 R7; (j) -Z4 -N(R10)-Z5 -NR8 R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z Z2 and Z3; R6, R7, R8, R9 and R10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z\ Z2 and Z3; or R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; R1 , R12, R13 and R14 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z\ Z2 and Z3, (c) heterocycle, substituted heterocycle or heterocyclooxy; (d) halo; (e) hydroxyl; (f) cyano; (g) nitro; (h) -C(0)H or -C(0)R5; (i) -C02 H or -C02 R5; (j) -SH, -S(0)n R5, -S(0)m -OH, -S(0)m _OR5, _0-S(0)m -OR5, -0-S(0)m OH or -0-S(0)m -OR5; (k) -Z4 -NR6 R7; or (I) -Z4 -N(R10)-Z5 -NR8 R9; Z1 , Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aryl; (g) aralkyl; (h) alkoxy; (i) aryloxy; (j) aralkoxy; (k) heterocycle, substituted heterocycle or heterocyclooxy; (I) -SH, -S(0)n Z6, -S(0)m -OH, -S(0)m -OZ6, -0-S(0)m -Z6, -0-S(0)m OH or -0-S(0)m -OZ6; (m) oxo; (n) nitro; (o) cyano; (p) -C(0)H or -C(0)Z6; (q) -C02 H or -C02Z6; (r) -Z4 -NZ7 Z8; (s) -Z4 -N(Z11)-Z5 -H; (t) -Z4 -N(Z11)-Z5 -Z6; or (u) -Z4 -N(Z11)-Z5 -NZ7 Z8; Z4 and Z5 are each independently (a) a single bond; (b) -Z9 -S(0)n -Z10-; (c) -Z9 -C(0)-Z10-; (d) -Z9 _C(S)-Z10-; (e) -Z9 -O-Z10-; (f) -Z9 -S-Z10-; (g) -Z9 _0-C(0)-Z10-; or (h) -Z9 — C(0)-0-Z10-; Z6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycioalkenylalkyi; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy, trihaloalkoxy, dialkylaminocarbonyl, alkylcarbonylamino, arylalkoxy, aryloxyalkyl, alkylaryloxyalkyl and heterocycle; or heterocycle or substituted heterocycle; Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene; Z11 is (a) hydrogen; or (b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; J is 0, S, N or NR15; K and L are N or C, provided that at least one of or L is C; R15 is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl; each m is independently 1 or 2; each n is independently 0, 1 or 2; and p is 0 or an integer from 1 to 2. In this embodiment, it is preferred that at least one, or most preferably all, of the substituent groups are as follows: R1 and R2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, — C02 R5 or — Z4 -NR6 R7; R3 and R4 are each independently alkyl; and R11, R12, R13 and R14 are each independently hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl.
Most preferred compounds of this embodiment are those wherein at least one, or most preferably all, of the substituent groups are as follows: R1 and R2 are each independently lower alkyl or hydrogen; R3 and R4 are each independently lower alkyl, especially methyl; and R12, R13 and R14 are hydrogen and R1 is hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl.
Preferred compounds of this embodiment include N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2,2,2-tri- fluoroacetamide; N-(3,4-Dimethyl-5-isoxazolyl)-2',4'-bis(2-oxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide; (Z)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2-phenylethenyl)[1 ,1 '- biphenyl]-2-sulfonamide; (E)-N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2- phenylethenyDd ,1 '-biphenyl]-2-sulfonamide; 4-Chloro-N-[[2'-[[(3,4-dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)-[1 ,1 '-biphenyl]-2-yl[methyl[phenylacetamide; N- (3, 4-Dimethyl-5-isoxazolyl)-2'-oxazolyl-5-yl-4'-oxazol-2-yl-[1 ,1 '-biphenyl]-2-sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1 -methylethyl)-5-oxazolyl]-4'-(2-oxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-oxazolyl)-4'-(2- oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[2-(1 - methylethyl)-4-oxazolyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-4'-(2-oxazolyl)-2'-[[5-(1-methylethyl)-2-oxazolyl]-methyl][1 ,1 '-biphenyl]-2- sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[4-(1 -methylethyl)-2- oxazolyll-methylld ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2- oxazolyl)-2'-[[(2,2,2-trifluoroethyl)amino[methyl][1 ,1 '-biphenyll-2-sulfonamide; N-(3,4- Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[(2,2,2-trifluoroethyl)amino[methyl][1 ,1 '- biphenyl]-2-sulf onamide, monohydrochloride; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-(2,2,2- trifluoroethyl)-2,2-dimethylpropanamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'- (2-oxazolylmethyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'- [[methyl(2,2,2-trifluoroethyl)amino[methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide, -trifluoroacetate (1 :1 ); N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-3,3,3-trifluoro-N-methylpropanamide; N-[[2'- [[{3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-4- fluoro-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfony)]-4-(2- oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-2-fluoro-N-methy)benzamide; N-[[2'-[[(3,4-Dimethyl- 5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-3-fluoro-N- methylbenzamide; 4-Chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl[-4-(2- oxazolyl) [1 ,1 '-biphenyl]-2-yl[methyl]-N-methylbenzamide; N-(3,4-Dimethyl-5-isoxazolyl)- 2'-[[ethyl(2,2,2-trifluoroethyl)aminotmethyl[-4'-(2-oxazolyl)[1 ,1 '-biphenyl)-2-sulfonamide; 2-Chloro-N-[[2'-t[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl) [1 ,1 '- biphenyl]-2-yl[methyl]-N-methylbenzamide; 2,4-Dichloro-N-[[2'-[[(3,4-dimethyl-5- isoxazolyl)amino[sulfonyll-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)aminotsulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yltmethyl]-3,4-difluoro-N-methylbenzamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)- 2'-[[(phenylmethyl)(2,2,2-trifluoroethyl)amino[methyl][1 ,1 '-biphenyl]-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1 -pyrrolidinyl)methyl]-4'-(2- oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(4- methoxyphenyl)methylamino[methyl]-4'-2-oxazolyl)[1 ,1 '-biphenyl]-2-sulf onamide, monohydrochloride; 2'-[(3,3-Difluoro-1 -pyrrolidinyl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)- 4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide, monohydrochloride; N-[[2'-[[(3,4-Dimethyl- 5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2- pyrazinecarboxamide; N-[t2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,3-dimethyl-2-thiophenecarboxamide; 3-Cyano-N- [[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl]-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyll-2-yl[methyl]-2-methoxy-N-methylbenzamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2-fluoro- N-methylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 ,3-benzodioxole-5-carboxamide; (R)-N- [t2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]-sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl]-α-methoxy-N-methylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyll-N-methyl-2- thiophenebutanamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-3,4,5-trifluoro-N-methylbenzamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyll-4-(2-oxazolyl)[1 , T-biphenyl]-2-yl[methyl]-2,4,6- trifluoro-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-4-methoxy-N-methylbenzenepropanamide; 4-(1 ,1 - Dimethylethyl)-N-[t2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)d ,1 '- biphenyl]-2-yl[methyl]-N-methylcyclohexanecarboxamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-4- (trifluoromethyD-benzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-4-(trifluoromethoxy)benzamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl[tetrahydro-N-methyl-2-furancarboxamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-4- pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-{2- oxazolyDd ,1 '-biphenyl]-2-yl[methyl]-N-methyl-3-pyridinecarboxamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N- methyl-2-pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonylJ-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 ,2,3-thiadiazole-4-carboxamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)f1 , r-biphenyl)-2-yl[methyll- N,1 ,5-trimethyl-1 H-pyrazole-3-carboxamide; N-t[2'-[[(3,4-Dimethyl-5- isoxazolyl)aminotsulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,3,5-trimethyl-4- isoxazolecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-{2- oxazolyl)I1 ,1 '-biphenyl]-2-yl[methyl]-N-methylbicyclo[4,2,0[octa-1 ,3,5-triene-7- carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyll-2-yl[methyll-3-methoxy-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2,5-difluoro-N- methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-3,5-difluoro-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 - phenylcyclopropanecarboxamide; 3-(Dimethylamino)-N-[[2'-[[(3,4-dimethyl-5- isoxazolyl)aminotsulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyll-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulf onyl]-4-(2-oxazolyl) , 1 '-biphenyl]-2- yl[methyl]-N,2,2-trimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxamide; N-[[2'- t[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N- methyl-2-pyridineacetamide, trifluoroacetate (1 :1 ); N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyll-N-methyl-4- pyridineacetamide, trifluoroacetate (1 : 1 ); N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-3-pyridineacetamide, trifluoroacetate (1 :1 ); N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yltmethyl]-N,1 -dimethyl-1 H-indole-2-carboxamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]- 2,3,6-trifluoro-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4- (2-oxazolyl)[1 ,1 -biphenyl]-2-yl[methylM ,2,3,4-tetrahydro-N-methyl-2-naphthalene- carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N,2,4,6-tetramethylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 ,3- benzodioxole-5-acetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyDd ,1 '-biphenyll-2-yl[methyl]-N-methyl-4-(1-methylethoxy)benzamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)t1 ,1 '-biphenyl]-2-yl[methyll- 2,3-dimethoxy-N-methylbenzamide; 1 -(1 ,1 -Dimethyl)-N-[[2'-[[(3,4-dimethyl-5-isoxazoIyl)- amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,3-dimethyl-1 H-pyrazole-5- carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N-methyl-3-(trifluoromethyl)benzamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-4-fluoro-N-methyl-1 - naphthalenecarboxamide; 3,5-Dichloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyll-2-yltmethyl]-N-methylbenzamide; 3,4-Dichloro-N- [[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl]-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyll-2-yl[methyl]-1 -(4-methoxyphenyl)-N-methylcyclopropane- carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyll-2-yl[methyll-2,3,5,6-tetrafluoro-N-methylbenzamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-4- (trifluoromethyl)benzene-acetamide; 2,6-Dichloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)- amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methylbenzeneacetamide; N- [[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyD [1 ,1 '-biphenyl]-2- yl[methyl]-3-fluoro-N-methyl-5-(trifluoromethyl)benzamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-4-fluoro-N-methyl-2- (trifluoromethyl) benzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyDd ,1 '-biphenyl]-2-yltmethyl]-N-ethyl-σ-phenylbenzeneacetamide; 2-(2- Chlorophenoxy)-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N,2-dimethylpropanamide; 2-Chloro-N-[[2'-[[(3,4-dimethyl-5- isoxazolyl)amino[sulfonyll-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-3,4-dimethoxy-N- methylbenzamide; 2-(2,4-Dichlorophenoxy)-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino- [sulfonyl[-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methylacetamide; 2-Chloro-N-[[2'- [[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 "-biphenyl]-2-yl[methyl]-N- methyl-5-(trifluoromethyl)benzamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[hydroxy(5- phenyl-2-oxazolyl)methyl]-4'-(2-oxazolyl)([1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl- 5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(5-phenyl-2-oxazolyl)methyl][1 , 1 '-biphenyl]-2- sulf onamide; 2'-[[(2,2-Difluoro-2-phenylethyl)amino[methyl)-N-(3,4-dimethyl-5- isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide, monohydrochloride; N-(3,4- Dimethyl-5-isoxazolyl)-2'-( 1 H-imidazol- 1 -ylmethyl)-4'-(2-oxazolyl) [1 ,1 '-biphenyl]-2- sulfonamide, monohydrochloride; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(4- phenyl-1 -piperazinyl)methyl][1 ,1 '-biphenyl]-2-sulfonamide; N-[(2,3-Dihydro-1 H-indol-1 - yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulf onamide, monohydrochloride; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(2-phenyl-1 H- imidazol-1 -yl)methyll[1 ,1 '-biphenyl]-2-sulfonamide, -monohydrochloride; 2'-[(1 ,3- Dihydro-1 ,3-dioxo-2H-isoindol-2-yl)methyll-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2- oxazolyOd , 1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)- 2'[(1 ,2,3,4-tetrahydro-1-quinolinyl)methyll[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4- Dimethyl-5-isoxazolyl)-2'-[[(1 -methylethyl)(2,2,2-trifiuoroethyl)amino[methyl]-4'-(2- oxazolyDd ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'- [[[1 -(trifluoromethyl)ethyl[amino[methyl]-[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl- 5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(3-phenyl-1 H-pyrazol-1 -yl)methyl][1 ,1 '-biphenyl]-2- sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-( 1 H-pyrazol-1 -ylmethyl)- [1 ,1 '-biphenyl]-2-sulfonamide; 2'-[(1 ,3-Dihydro-1 -oxo-2H-isoindol-2-yl)methyl]-N-(3,4- dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-2'-[[(3,4-dimethyl-5-isoxazolyl)amino[methyl[-4'-[2-oxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-(2H-1 ,2,3-triazol-2- ylmethyUπ ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'- (1 H-1 ,2,3-triazoM -ylmethyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1 -piperidinyl)methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyll-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N-methyl-2-phenoxyacetamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'- f(4,4-dimethy)-3-oxo-2-isoxazolidinyl)methyl]-4'-(2-oxazoly))[1 , 1 '-biphenyl]-2- sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[2-(1-methylethyl)-1 H-imidazol-1 - yI[methyl]-4'-(2-oxazolyl)d ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'- (2-oxazolyl)-2'-[(5-phenyl-2H-tetrazol-2-yl)methyl][l,1 '-biphenyl]-2-sulfonamide; N-(3,4- Dimethyl-5-isoxazolyl)-2'-[(5-methyl-1 H-tetrazol-1 -yl)methyl]-4'-(2-oxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(5-methyl-2H-tetrazol-2- yl)methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'- (2-oxazolyl)-2'-[(5-phenyl-2H-1 ,2,4-triazol-2-yl)methyl][1 ,1 '-biphenyll-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[3-(trifluoromethyl)-1 H-pyrazol-1- yl[methyl][1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[3-(3-methyl- 2-pyrazinyl)-1 H-pyrazol-1 -yl[methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4- Dimethyl-5-isoxazolyl)-2'-[[3-(2-methyl-5-pyridinyl)-1 H-pyrazol-1 -yl[methyl]-4'-(2- oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'-(1 H-Benzotriazol-1 -ylmethyl)-N-(3,4-dimethyl- 5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)- 4'-(2-oxazolyl)-2'-[(1 ,2,3-triazolo[4,5-b[pyridinyl)methyl][1 ,1 '-biphenyl]-2-sulfonamide, Isomers A and B; 2'-[(3,4-Dihydro-2H-pyrido[3,2-b]-1 ,4-oxazin-4-yl)methyll-N-(3,4- dimethyl-5-isoxazolyl)-4'-(2-oxazolyi)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5- isoxazolyl)-4'-(2-oxazolyl)-2'-[(imidazolo[4,5b]-pyridinyl)methyl]-[1 ,1 '-biphenyl]-2- sulfonamide, Isomers A and(B; 2'-[(3,3-Difluoro-2,3-dihydro-2-oxo-1 H-indol-1 -yl)methyl]- N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyll-2-sulfonamide; N-(3,4- Dimethyl-5-isoxazolyl)-2'-[(4-pyrimidinylamino)methyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyI]-2- sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-(4-morpholinylmethyl)-4'-(2-oxazolyl)[1 ,1 '- biphenyl)-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(4-methyl-1 -piperazinyl)- methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyll-2-sulfonamide; 1-Acetyl-4-[[2'-[[(3,4-dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl[piperazine; N-(3,4- Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[4-(2,2,2-trifluoroethyl)-1 -piperazinyl- [methyl][1 ,1 '-biphenyl]-2-sulfonamide dihydrochloride; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 H-indole- 2-carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-2,3-dihydro-N-methyl-1 H-indene-2-carboxamide; N-(3,4-Dimethyl- 5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(1 ,2,3,4-tetrahydro-1 -oxo-2-isoquinolinyl)methyl][1 ,1 '- biphenyl]-2-sulfonamide; 2'-(1 H-Benzimidazol-1 -ylmethyl)-N-(3,4-dimethyl-5-isoxazolyl)- 4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'-[(2,3-Dihydro-2-oxo-3-benzoxazolyl)- methyI]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'- [(2,3-Dihydro-2-oxo-1 H-indol-1 -yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2- oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2'-[(4,4-dimethyl-2- oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,1 ,3- trimethyl- 1 H-pyrazole-5-carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyll-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-N,2-dimethylbenzeneacetamide; N- [[2'-[[{3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2- yl [methyl] -1 -ethyl-N,3-dimethyl-1 H-pyrazole-5-carboxamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,1 ,3,5-tetramethyl- 1 H-pyrazole-4-carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2,6-difluoro-N-methylbenzamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2- methoxy-N-methylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyi)amino[sulfonyl]- 4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-3-methoxy-N-methylbenzeneacetamide; N-[[2'- f[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-4- methoxy-N-methylbenzeneacetamide; 4-Chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyD[1 ,1 '-biphenyl]-2-yl[methyl]-N-methylbenzeneacetamide; 2- Chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyll-2- yl[methyl]-N-methylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2,6-difluoro-N-methylbenzene- acetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-3,5-difluoro-N-methylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyll-2-yl[methyl]-2,5-difluoro-N- methylbenzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyll-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2,4-difluoro-N-methylbenzeneacetamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N- methyl-4-quinolinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-6-benzothiazolecarboxamide; 3-(1 ,1 - Dimethylethyl)-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N,1 -dimethyl-1 H-pyrazole-5-carboxamide; 4-Chloro-N-[[2'-[[(3,4- dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2- methoxy-N-methylbenzamide; 3-(1 ,1 -Dimethylethyl)-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)- amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 -phenyl-1 H-1 ,2,3- triazole-5-carboxamide; 2,3-Dihydro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]- 4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,4-dimethyl-2-thioxo-3-thiazoleacetamide; N- [[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyi]-2- yl[methyl]-N,3-dimethyl-5-(trifluoromethyl)-4-isoxazolecarboxamide; 3-( 1 ,1 -Dimethyl- ethyl)-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl [methyl]- 1 -ethyl-N-methyl-1 H-pyrazole-5-carboxamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-5-(1- pyrrolidinyl)-2H-tetrazole-2-acetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-3-(trifluoromethyD- benzeneacetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)- [1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2-(trif luoromethyDbenzeneacetamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,1 - dimethyl-1 H-benzimidazole-2-propanamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,2-dimethyl-4-(trifluoromethyl)-3- pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-5-(2-pyridinyl)-2-thiophenecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2- yl[methyl]-N-methyl-4-phenyl-1 ,2,3-thiadiazole-5-carboxamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-4-(1 ,2,3- thiadiazol-4-yl)benzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2-oxo-3(2H)-benzoxazolepropanamide; N- [[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl]-N,5-dimethyl-2-phenyl-4-oxazoleacetamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-N-methyl-1 ,4- dithiaspiro[4.5[decane-8-carboxamide; 4-Chloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)- amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,1 ,3-trimethyl-1 H- pyrazolo[3,4-b[pyridine-5-carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 -phenyl-5-propyl-1 H- pyrazole-4-acetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-3-[(4-methylphenoxy)methyl[benzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2- yl[methyl]-N-methyl-5-[3-(trifluoromethyl)phenyl]-2H-tetrazole-2-acetamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N- methyl-5-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-2-thiophenecarboxamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]- N,4-dimethyl-5-[3-(trifluoromethyl)phenyl]-5-thiazoleacetamide; 1 -(4-Chlorophenyl)-N- [[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl]-N-methyl-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,6- dimethyl-2-pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2-thiopheneacetamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N- methyl-2-(phenylmethoxy)benzeneacetamide; 3-(2-Chloro-6-fluorophenyl)-N-[[2'-[[(3,4- dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,5- dimethyl-4-isoxazolecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4- (2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,1 -dimethyl-1 H-pyrazole-4-carboxamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]- N,5-dimethyl-1 H-pyrazole-3-carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2-thiophenecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2- yl[methyl]-N-methyl-3-thiophenecarboxamide; 6-Chloro-N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-3- pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-1 H-indole-5-carboxamide; 2-Chloro-N-[: 2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]- N,6-dimethyl-4-pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]- 4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-4-cinnolinecarboxamide; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N- methyl-1 H-indole-1 -acetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 , 1 '-biphenyl]-2-yl[methyl]-N-methyl-1 H-indole-3-acetamide; 2,3-Dihydro-N- [[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl) [ 1 , 1 '-biphenyl]-2- yl[methyl]-N-methyl-1 H-indene-2-acetamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-5-fluoro-N-methyl-1 H-indole-2- carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1- biphenyl]-2-yl[methyl]-3,5-dimethoxy-N-methylbenzamide; 5-Chloro-N-[[2'-[[(3,4- dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-2- methoxy-N-methylbenzamide; 2,6-Dichloro-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-3-pyridinecarboxamide; 3- (Acetylamino)-N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N,4-dimethylbenzamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino- [sulfonyl]-4-(2-oxazoiyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,5-dimethyl-1 -phenyl-1 H-pyrazole- 4-carboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '- biphenyl]-2-yl[methyl]-4-methoxy-N-methyl-2-quinolinecarboxamide; N-[[2'-[[(3,4- Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,5- dimethyl-2-phenyl-2H-1 ,2,3-triazole-4-carboxamide; N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino[sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2- phenoxy-3-pyridinecarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N',N'-diethyl-N-methyl-1 ,2-benzenedicarboxamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-oxazolyi)[1 ,1 '-biphenyl]-2- yl[methyl]-N-methyl-9H-fluorene-9-propanamide; 2'-[[[1-(1 ,1-Dimethylethyl)-3-methyl- 1 H-pyrazol-5-yl[amino[methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(1 H-pyrazol-3- ylamino)methyl][1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2- oxazolyl)-2'-[(1 H-1 ,2,4-triazol-3-ylamino)methyl][1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4- Dimethyl-5-isoxazolyl)-2'-[[(5-methyl-3-oxazolyl)amino[methyl]-4'-(2-oxazolyl)[1 , 1 '- biphenyl]-2-sulfonamide; 2'-[[(4-Cyano-1 H-pyrazol-3-yl)amino[methyl]-N-(3,4-dimethyl-5- isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'- [[(3,5-dimethyl-2-pyrazinyl)amino[methyl]-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(3,5-dimethyl-2-pyrimidinyl)amino[methyl]-4'-(2- oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(5-ethyl- 1 ,3,4- thiadiazol-2-yl)amino[methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'-[(2- Benzothiazolylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]- 2-sulfonamide; 2'-[[(4-Bromo-1 H-pyrazol-3-yl)amino[methyl]-N-(3,4-dimethyl-5- isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'- (2-oxazolyl)-2'-[[[5-(2-thienyl)-1 H-pyrazol-3-yl[amino[methyl][1 ,1 '-biphenyl]-2- sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(6-methoxy-2-benzothiazolyl)amino- [methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'-[[[4-(4-Chlorophenyl)-6-ethoxy- 2-pyrimidinyl[amino[methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 ,1 '-biphenyl]- 2-sulf onamide; and N-(4,5-dimethyl-3-isoxazolyl)-4'-(2-oxazolyl)-2'-[[3-(trifluoromethyl)- 1 H-pyrazol-1 -yl[methyl][1 ,1 '-biphenyl]-2-sulfonamide. s. U.S. Patent No. 5,760,038 Other compounds for use in the methods provided herein include N-(3,4-
Dimethyl-5-isoxazolyl)-4'-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl- 5-isoxazolyl)-4'-(2-pyridinyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)- 4'-(3-pyridinyl)[1 ,1 '-biphenyl]-2-sulfonamide; 4'-(4,6-Dimethoxy-2-pyrimidinyl)-N-(3,4- dimethyl-5-isoxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(4- pyrimidinyl) [1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-{2- pyrazinyl)[1 ,1 '-biphenyl]-2-sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-{5- pyrimidinyl)[1 , 1 '-biphenyl]-2-sulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2- pyridinyl)[1 ,1 '-biphenyl]-2-sulfonamide, N4'-oxide; and N-(3,4-Dimethyl-5-isoxazolyl)-4'- (6-methoxy-2-pyridinyl)[1 ,1 '-biphenyl]-2-sulf onamide. t. U.S. Patent No. 5,780,473
Compounds of the formula:
Figure imgf000223_0001
its enantiomers and diastereomers, and pharmaceutically or veterinarily acceptable salts thereof are also intended for use in the methods provided herein. In this embodiment, the above symbols are defined as follows: one of X and Y is N and the other is 0; R1 and R2 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl or alkoxy; (c) hydroxyl; (d) halo; or (e) amino; R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z\ Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R5; (h) -C02 H or -C02 R5; (j) _z4 -NR6 R7; or (j) -Z4 -N(R10)-Z5 -NR8 R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R6, R7, R8, R9 and R10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; R 1, R12, R13 and R14 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1 , Z2 and Z3, (c) heterocycle, substituted heterocycle or heterocyclooxy; (d) halo; (e) hydroxyl; (f) cyano; (g) nitro; (h) -C(0)H or -C(0)R5; (i) -C02 H or -C02 R5; (j) -SH, -S(0)n R5, -S(0)m -OH, -S(0)m -OR5, -0-S(0)m -OR5, -0-S(0)m OH or -0-S(0)m -OR5; (k) -Z4 -NR6 R7; or (I) -Z4 -N(R10)-Z5 -NR8 R9; Z\ Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aryl; (g) aralkyl; (h) alkoxy; (i) aryloxy; (j) aralkoxy; (k) heterocycle, substituted heterocycle or heterocyclooxy; (I) -SH, -S(0)nZβ, -S(0)m-0H, -S(0)m-OZ6, -0-S(0)m-Z6, -0-S(0)mOH or _0-S(0)m-OZ6; (m) oxo; (n) nitro; (o) cyano; (p) -C(0)H or -C(0)Z6; (q) -C02 H or -C02Z6; (r) -Z -NZ7Z8; (s) -Z -N(Z11)-ZB-H; (t) -Z4-N(Z11)-Z5-Z6; or (u) -Z4-N(Z11)-Z5-NZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) _Z9-S(0)n-Z10-; (c) _Z9-C(0)-Z10-; (d) _Z9-C(S)-Z10-; (e) _Z9-0-Z10-; (f) _Z9-S-Z10-; (g) -Z9-0-C(0)-Z10-; or (h)
-Z9— C(0)-0-Z10-; Z6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycioalkenylalkyi; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocyclo or substituted heterocyclo; Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene; Z11 is (a) hydrogen; or (b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; J, K, L, T and U are each independently N or C, provided that at least one is N, and at most two are N; and when only one of J, K, L, T and U is N, the N may be substituted with -0Θ so that an N-oxide is formed; each m is independently 1 or 2; each n is independently 0, 1 or 2; and p is 0 or an integer from 1 to 2.
In this embodiment, it is preferred that the heterocyclic ring containing U, T, L, K and J is a pyridine (such as a 2-or 3-pyridine), pyrimidine (such as a 2-, 4- or 5- pyrimidine), or pyrazine (such as a 2-pyrazine) ring; R1 and R2 are each independently hydrogen, alkyl or alkoxy; R3 and R4 are each independently alkyl; R11, R12, R13 and R14 are each hydrogen, —CHO or substituted alkyl, especially where R12, R13 and R14 are each hydrogen and R11 is alkyl substituted with heterocycle, substituted heterocycle or -Z4-N(Z1 )-Z5-Z6; and p is 0.
Most preferred compounds of this embodiment are those wherein: the heterocyclic ring containing U, T, L, K and J is a 2-pyrimidine ring; R and R2 are each independently lower alkoxy or hydrogen; and R3 and R4 are each independently lower alkyl, especially methyl.
Preferred compounds of this embodiment include N-[[2'-[[(3,4-Dimethyl-5- isoxazolyl)amino]-sulfonyl]-4-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N-methyl-2- thiophenebutanamide; N-(3,4-Dimethyl-5-isoxazolyl)-2'-[[(4- methoxyphenyl)methylamino[methyl]-4'-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-2'-f ormyl-4'-(2-pyrimidinyl) [1 , 1 '-biphenyl]-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2- sulfonamide; N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino[sulfonyl]-4-(2-pyridinyl)[1 ,1 '- biphenyl]-2-yl[methyl]-N,3,3-trimethylbutanamide; N-(4,5-Dimethyl-3-isoxazolyl)-2'-[(3,3- dimethyl-2-oxo-1 pyrrolidinyl)methyl[-4'-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-sulfonamide; N- (3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1 pyrrolidinyl)methyl[-4'-(2- pyrimidinyDd ,1 '-biphenyl]-2-sulfonamide; N-[[2'-[[(4,5-Dimethyl-3-isoxazolyl)amino]- sulfonyl]-4'-(2-pyrimidinyl)[1 ,1 '-biphenyl]-2-yl[methyl]-N,3,3-trimethylbutanamide; N- (4,5-Dimethyl-3-isoxazolyl)-4'-(2-pyrimidinyl)-2'-[[3-(trifluoromethyl)-1 H-pyrazol-1- yl[methy!][1 , 1 '- biphenyl]-2-sulfonamide; and N-(3,4-Dimethyl-5-isoxazolyl)-41-(2- pyrimidinyl)-2'-[[3-(trifluoromethyl)-1 H-pyrazol-1-yl[methyl][1 , 1 '- biphenyl]-2- sulfonamide. u. U.S. Patent No. 5,939,446
Compounds of the formula:
Figure imgf000226_0001
its enantiomers and diastereomers, and pharmaceutically or veterinarily acceptable salts thereof are intended for use in the methods provided herein. In this embodiment, the above symbols are defined as follows: one of X and Y is N and the other is O; R1, R2, R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R5; (h) -C02H or -C02R5; (i) -Z4-NR6R7; (j) -Z4-N(R10)-Z5-NR8R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R6, R7, R8, R9 and R10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3 ; or R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z\ Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z\ Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; R11 and R12 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1 , Z2 and Z3, (c) heterocycle, substituted heterocycle or heterocyclooxy; (d) halo; (e) hydroxyl; (f) cyano; (g) nitro; (h) -C(0)H or -C(0)R6; (i) -C02H or -C02R5; (j) -SH, -S(0)nR5, -S(0)m-OH, -S(0)m-OR5, -0-S(0)m-ORB, -0-S(0)mOH or -0-S(0)m-OR5; (k) -Z4-NR6R7; or (I) -Z4-N(R10)-Z5- NR8R9; Z1 , Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aryl; (g) aralkyl; (h) alkoxy; (i) aryloxy; (j) aralkoxy; (k) heterocycle, substituted heterocycle or heterocyclooxy; (I) -SH, -S(0)nZ6, -S(0)m-OH, -S(0)m-OZ6, -0-S(0)m-Z6, -0-S(0)mOH or -0-S(0)m-OZ6; (m) oxo; (n) nitro; (o) cyano; (p) -C(0)H or -C(0)Z6; (q) -C02H or -C02Z6; (r) -Z -NZ7Z8; (s) -Z -N(Z11)-Z5-H; (t) -Z4-N(Z11)-Z5-Z6; or (u) -Z -N(Z11)-Z5-NZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) -Z9- S(0)n-Z10-; (c) -Z9-C(0)-Z10-; (d) -Z9-C(S)-Z10-; (e) -Z9-0-Z10-; (f) -Z9-S-Z10-; (g) -Z9-0-C(0)- Z10-; or (h) -Z9-C(0)-0-Z10-; Z6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycioalkenylalkyi; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle; Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8- membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; Z9 and Z'° are each independently a single bond, alkylene, alkenylene or alkynylene; Z11 is (a) hydrogen; or (b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; each m is independently 1 or 2; each n is independently 0, 1 or 2; p is 0 or 1 ; and when p is 0, then J is N, NR13 or S; K and L are each -C; R13 is H, alkyl or -S02R14 ; and R14 is aryl; and R1 and R2 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached; or when p is 1 , then J, K and L are each, independently, -C or N, provided that at least one of J, K and L is -C and at least one of J, K and L is N.
In this embodiment, it is preferred that at least one, or most preferably all, of the substituent groups are as follows: X is 0 and Y is N; R3 and R4 are each independently alkyl, most preferably, methyl; R11 and R12 are each independently hydrogen, hydroxy, amino, alkenyl, carboxamide or substituted lower alkyl, most preferably, hydrogen; when p is 0, then J is N or NR13, most preferably, where R13 is hydrogen or phenylsulfonyl, and R1 and R2 together are alkenylene, completing a 6-membered aromatic ring; or J is S, and R1 and R2 are hydrogen; and when p is 1 , then R1 and R2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, -C02 R5 or -Z4 -NR6 R7, most preferably, hydrogen.
Preferred compounds of this embodiment include N-(3,4-Dimethyl-5-isoxazolyl)- 2-(2-thienyl)benzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(3- thienyljbenzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(2- pyridinyDbenzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-[1 -(phenylsulfonyD-1 H- indol-3-yl[benzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(1 H-indol-3- yDbenzenesulfonamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-[1 -(phenylsulfonyD-1 H-indol-2- yl[benzenesulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-(2- pyrimidinyDbenzenesulf onamide; N-(3,4-Dimethyl-5-isoxazolyl)-2-{3- pyridinyDbenzenesulfonamide; and N-(3,4-Dimethyl-5-isoxazolyl)-2-(1 H-indol-2- yDbenzenesulfonamide. v. U.S. Patent No. 5,827,869
Compounds of the formula:
Figure imgf000229_0001
its enantiomers and diastereomers, and pharmaceutically or veterinarily acceptable salts thereof are intended for use in the methods provided herein. In this embodiment, the above symbols are defined as follows: one of X and Y is N and the other is O; R\ R2, R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R5; (h) -C02H or -C02R5; (i) -Z -NR6R7; (j) -Z4-N(R10)-ZB-NR8R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to
8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z Z2 and Z3; R6, R7, R8, R9 and R10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z\ Z2 and Z3; or R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z\ Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z\ Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; R11, R12, R13 and R14 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3, (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R6; (h) -C2H or -C02R5; (i) -SH, -S(0)nRB, -S(0)m-OH, -S(0)m-0R5, -0-S(0)m-OR5, -0-S(0)mOH or _0-S(0)m-OR5; (j) -Z4-NR6R7; or (k) -Z -N(R10)-Z5-NR8R9; Z1, Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0)nZ6, -S(0)m-OH, -S(0)m-OZ6, -0-S(0)m-Zβ, -0-S(0)mOH or -0-S(0)m-OZ6; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)Z6; (o) -C02H or -C02Z6; (p) -Z -NZ7Z8; (q) -Z -N(Z1 )-Z5-H; (r) -Z -N(Z11)-Z5-Z6; or (s) -Z -N(Z11)-ZB-NZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) -Z9-S(0)n-Z10-; (c) -Z9-C(0)-Z10-; (d) _Z9-C(S)-Z10-; (e) -Z9-0-Z10-; (f) -Z9-S-Z10-; (g) -Z9-0-C(0)-Z10-; or (h) _Z9-C(0)-0-Z10-; Z6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl; Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8- membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; Z9 and Z 0 are each independently a single bond, alkylene, alkenylene or alkynylene; Z11 is (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl; or any two of Z7, Z8 and Z1 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; J is O, S, N or NR15; K and L are N or C, provided that at least one of K or L is C; R15 is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl; each m is independently 1 or 2; each n is independently 0, 1 or 2; and p is 0 or an integer from 1 to 2.
In this embodiment, it is preferred that: R1 and R2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, -C02R5 or -Z4-NR6R7; R3 and R4 are each independently alkyl; and R11 and R12 are each independently hydrogen, hydroxy, amino or substituted lower alkyl. Most preferred compounds of this embodiment are those wherein: R1 and R2 are each independently lower alkyl or hydrogen; R3 and R4 are each independently lower alkyl, especially methyl; and R11 and R12 are each independently hydrogen, hydroxy or substituted lower alkyl. w. U.S. Patent No. 5,846,985
Compounds of the formula:
Figure imgf000231_0001
its enantiomers and diastereomers, and pharmaceutically or veterinarily acceptable salts thereof are intended for use in the methods provided herein. In this embodiment, the above symbols are defined as follows: one of X and Y is N and the other is 0; Q is N or NR15; J is O, S, N or NR15; K is G=0 or CH; the dotted line α between Q and K denotes an optional double bond when Q is N and K is CH; the dotted line β between K and J denotes an optional double bond when K is CH and J is N; with the proviso that said α and β double bonds may not simultaneously be present; R1 and R2, when present, and R3 and R4, are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z\ Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R5; (h) -C02H or -C02RB; (i) -Z4-NR6R7; or (j) -Z -N(R10)-Z5-NR8R9; and (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; R6, R7, R8, R9 and R10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z\ Z2 and Z3; or R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; R11 , R12, R13 and R14 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z\ Z2 and Z3, (c) heterocyclo, substituted heterocyclo or heterocyclooxy; (d) halo; (e) hydroxyl; (f) cyano; (g) nitro; (h) -C(0)H or -C(0)R5; (i) -C02H or -C02R5; (j) -SH, -S(0)nR5, -S(0)m-OH,
-S(0)m-OR5, -0-S(0)m-ORB, -0-S(0)mOH or -0-S(0)m-0R5; (k) -Z4-NR6R7; or (I) -Z4-N(R10)-Z5-NR8R9; Z\ Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aryl; (g) aralkyl; (h) alkoxy; (i) aryloxy; (j) aralkoxy; (k) heterocyclo, substituted heterocyclo or heterocyclooxy; (I) -SH, -S(0)nZ6, -S(0)m-OH, -S(0)m-OZ6, -0-S(0)m-Z6, -0-S(0)mOH or -0-S(0)m-OZ6; (m) oxo; (n) nitro; (o) cyano; (p) -C(0)H or -C(0)Z6; (q) -C02H or -C02Z6; (r) -Z -NZ7Z8; (s) -Z4-N(Z11)-Z5-H; (t) -Z -N(Z11)-Z6-Z6; or (u) -Z4-N(Z11)-Z5-NZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) -Z9-S(0)n-Z10-; (c) _Z9-C(0)-Z10-; (d) _Z9_C(S)-Z10-; (e) -Z9-0-Z10-; (f) -Z9-S-Z10-; (g) _z9-0-C(0)-Z10-; or (h) -Z9— C(O)— Z10— ; Z6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycioalkenylalkyi; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocyclo or substituted heterocyclo; Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8- membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene; Z11 is (a) hydrogen; or (b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl; or any two of Z7, Z8 and Z1 1 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; R15 is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl; each m is independently 1 or 2; each n is independently 0, 1 or 2; and p is 0 or an integer from 1 to 2.
Preferred compounds of this embodiment are those having one or more (most preferably, all) of the following preferred substituent definitions: X is O; Y is N; R3 and R4 are alkyl, especially lower alkyl such as methyl; R1 , R12, R13 and R14 are each independently hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide, or substituted lower alkyl, especially, R12, R 3 and R14 are hydrogen and R11 is hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl; p is zero; R1 and R2 are hydrogen or are absent; Q is N; K is CH, J is 0 and the double bond α is present or K is C=0, J is
NR15 and neither of the double bonds α or β is present; R15 is hydrogen, hydroxyethoxy methyl or methoxyethoxy methyl.
Preferred compounds of this embodiment include 4'-[4,5-dihydro-4-[(2- methoxyethoxy)methyl]-5-oxo-1 H-1 ,2,4-triazol-1 -yl]-N-(3,4-dimethyl-5-isoxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide; 4'-[4,5-dihydro-4-[(2-hydroxyethoxy)methyl]-5-oxo-1 H-1 ,2,4- triazol-1 -yl]-N-(3,4-dimethyl-5-isoxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl- 5-isoxazolyl)-4'-(1 ,3,4-oxadiazol-2-yl)[1 ,1 '-biphenyl]-2-sulfonamide; and salts thereof. x. International Patent Application Publication No. WO 98/57938
Also intended for use in the methods provided herein are compounds of formula:
Figure imgf000233_0001
and pharmaceutically acceptable salts thereof, where n is 1 or 2; A represents an optionally substituted aryl group or an optionally substituted heteroaryl group; B represents an optionally substituted phenyl group; R1 represents a lower alkyl, lower alkenyl, or lower alkynyl group (these groups each being optionally substituted by one to three groups selected from the group consisting of halogen atoms and hydroxy, lower alkyl-O-, carboxyl, lower alkyl-O-CO-, and cycloalkyl groups); X represents a group represented by O, S, or -NH-; and Y represents 0 or S.
Preferred compounds of this embodiment are those shown in the following tables:
Figure imgf000234_0001
Figure imgf000234_0003
Figure imgf000234_0002
Figure imgf000235_0002
y. International Patent Application Publication No. WO 97/30996
Compounds of formula:
Figure imgf000235_0001
and their salts, are intended for use in the methods provided herein. In this embodiment, -A = B = C = D- is a -CH = CH-CH = CH- group in which 1 or 2 of the CH groups may be replaced with N; Het is an unsubstituted or -Z-R6 substituted mono- or bicyclic saturated, unsaturated or aromatic heterocycle containing from 1 to 4 N, 0 and/or S atoms; R , R2 and R3 are each independently H, Hal, A, CF3, N02, NR4R5, CN, COOR4 or NHCOR4; R4 and R5 are each independently H or A, or together form -CH2- (CH2)n-CH2-; R6 is an unsubstituted or a mono, di or trisubstituted phenyl, benzothiadiazol-5-yl or benzoxadiazol-5-yl group, where the substituents are R7, R8 and/or R9; R7, R8 and R9 are each independently A, O-A, CN, COOH, COOA, Hal, formyl, -CO-A, benzothiadiazol-5yl or benzoxadiazol-5-yi, or R7 and R8 together form -0-(CH2)m- 0-; A is C,.6alkyl; X is 0 or S; Z is -CO-, -CONH-, -CO-(CH2)n-, -CH = CH-, -(CH2)n-, - CONHCO-, -NHCONH-, -NHCOO-, -0-CONH-, -CO-O- or -0-C0-; Hal is F, Cl, Br, or I; m is 1 or 2; and n is 1 , 2, or 3.
Preferred compounds of this embodiment include 3-(2,1 ,3-benzothiadiazol-5- aminosulf onyl)-N-(6-acetyl-1 ,3-benzodioxol-5-yl)thiophene-2-carboxamide; 3-(2, 1 ,3- benzothiadiazol-5-aminosulfonyl)-N-(6-cyano-1 ,3-benzodioxol-5-yl)thiophene-3- carboxamide; 3-(2, 1 ,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1 ,3-benzodioxol-5- ylmethylcarbonyDthiophene; 3-(2,1 ,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1 ,3- benzodioxol-5-ylmethyl)thiophene; 3-(2, 1 ,3-benzothiadiazol-5-aminosulf onyl)-2-(6- methyl-1 ,3-benzodioxol-5-ylethyl)thiophene; 3-(2,1 ,3-benzothiadiazol-5-aminosulfonyl)- N-(4-tolyl)thiophene-2-carboxamide; 3-{2, 1 ,3-benzothiadiazol-5-aminosulfonyl)-N-(4- methoxyphenyl)thiophene-2-carboxamide; 3-(2, 1 ,3-benzothiadiazol-5-aminosulfonyl)-N- (4-cyanophenyl)thiophene-2-carboxamide; 3-(2, 1 ,3-benzothiadiazol-5-aminosulf onyD-N- (4-methoxycarbonylphenyl)thiophene-2-carboxamide; 3-(2, 1 ,3-benzothiadiazol-5- aminosulf onyl)-N-(4-chlorophenyl)thiophene-2-carboxamide; 3-(2,1 ,3-benzothiadiazol-5- aminosulfonyl)-2-(6-methyl-1 ,3-benzodioxol-5-ylcarbonyl)thiophene; 3-(2,1 ,3- benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1 ,3-benzodioxol-5- yloxycarbonyl)thiophene; 3-(2,1 ,3-benzothiadiazol-5-aminosulfonyl)-2-(6-methyl-1 ,3- benzodioxol-5-ylvinyl)thiophene; 3-(2, 1 ,3-benzothiadiazol-5-aminosulf onyl)-N-(6-acetyl- 1 ,3-benzodioxol-5-ylcarbonyl)thiophene-2-carboxamide; and 3-([1 ,2,5]-thiadiazolo-[3,4- b]-pyridin-5-aminosulfonyl)-N-(6-methyl-1 ,3-benzodioxol-5-yl)thiophene-2-carboxamide. z. European Patent Application Publication No. EP 768 304
In particular, compounds for use in the methods provided herein have the formula:
Figure imgf000237_0001
or pharmaceutically acceptable salts thereof, where R1 is phenyl, substituted phenyl or heterocyclyl; R2 is phenyl or substituted phenyl; R3 is hydroxy, lower alkoxy, or NR R5; R4 is H or R6; R5 is H or -(CH2)mR6; or R4 and R5 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group; R6 is phenyl, substituted phenyl, cycloalkyl, heterocyclyl, lower alkyl, hydroxy-lower alkyl, amino- lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl; Ra is H, loweralkyl or hydroxy; R is H or lower alkyl; X is 0 or S; Y is 0 or S; Z is H, lower Ikyl, aryl, aryl- lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; m is 0, 1 or 2; and n is 0, 1 or 2.
Preferred compounds of this embodiment include 6-(4-tert- butylphenylsulfonylamino)-4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2- carboxylic acid; 4-(4-tert-butylphenylsulfonylamino)-5-(2-chloro-5-methoxyphenoxy)-6- (2-hydroxyehtoxy)pyrimidine-2-carboxylic acid; 4-(2-hydroxyethoxy)-5-(3- methoxyphenoxy)-6-(4-methoxyphenylsulfonylamino)pyrimidine-2-carboxylic acid; (RS)- 6-(4-tert-butylphenylsufonylamino)-4-(2,3-dihydroxypeopoxy)-5-(3- methoxyphenoxy)pyrimidine-2-carboxylic acid; 6-(4-tert-butylphenylsulfonylamino)-4-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-2-carboxylic acid; N-phenyl 6-(4-tert- butylphenylsulfonylamino)-4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2- carboxamide; N-phenyl 4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)-6-(4- methoxyphenylsulfonylamino)pyrimidine-2-carboxamide; N-phenyl 6-(4-tert- butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-4-(2-hydroxyethoxy)pyrimidine-2- carboxamide; N-phenyl 4-(4-tert-butylphenylsulfonylamino)-5-(2-chloro-5- methoxyphenyolxy)-6-(2-hydroxyethoxy)pyrimidine-2-carboxamide; N-( 1 H-tetrazoly-5-yl) 4-(4-tert~butylpheny!su!fonylamino)-6-(2-hydroxyethoxy)-5-(3- methoxyphenoxy)pyrimidine-2-carboxamide; and 4-(2-hydroxyethoxy)-6-(5- isopropylpyridin-2-ylsufonaylamino)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid. aa. U.S. Patent No. 6,043,265
The compounds N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide, N-(4,5-dimethyl-3- isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2- sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1 - pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3- isoxazolyl)-2'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1 ,1 '- biphenyl]-2-sulfonamide, 2'-(bromomethyl)-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2- methoxyethoxy)methyl]-4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3- isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1 -pyrrolidinyl)methyl]-N-[(2-methoxyethoxy)methyl]- 4'-(2-oxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide, and 4-[[[2'-[[{4,5-dimethyl-3- isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1 , 1 '-biphenyl]-2-yl]methyl]amino]-2,2- dimethylbutanoic acid, and salts thereof, are intended for use in the methods provided herein. bb. U.S. Patent No. 6,080,774 Certain of the compounds for use in the methods provided herein include those having the formula:
Figure imgf000238_0001
and pharmaceutically acceptable salts thereof, where one of X and Y is N and the other is 0; R is:
Figure imgf000238_0002
R2 and R3 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R6; (h) -C02H or C02R6; (i) -SH, -S(0)nR6, -S(0)m-OH, -S(0)m-OR6, -0-S(0)m-R6, -0-S-(0)mOH, or -0-S(0)m-OR6; (j) -Z -NR7R8; or (k) -Z -N(R11)- Z5-NR9R10; R4 and R5 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(0)H or -C(0)R6; (h) -C02H or C02R6; (i) -SH, -S(0)nR6, -S(0)m- OH, -S(0)m-OR6, -0-S(0)m-R6, -0-S-(0)mOH, or -0S(0)m-0Rβ; (j) -Z4-NR7R8; or (k) -Z4- N(R11)-Z5-NR9R10; (I) R4 and R5 together are alkylene or alkenylene (either of which may be substituted with Z\ Z2 and Z3), completing a 4- to 8- membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R6 is alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z1 , Z2 and Z3; R7, R8, R9, R10 and R1 are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with Z\ Z2 and Z3; R7 and R8 together may be alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; any two of R9, R10 and R11 together may be alkylene or alkenylene (either of which may be substituted with Z\ Z2 and Z3), completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached; G1 is (a) hydrogen; or (b)alkyl; G2 is (a) hydroxyalkyl; (b) -(CH2)mOR6; or (c) -(CH2)m-NR12R13; (d) mono-to-hexa-halo substituted alkyl (i.e., alkyl substituted with one, two, three, four, five or six halogen atoms); or (e) -(CH2)nOR14; R12 and R13 are each independently (a) hydrogen; or (b) alkyl, cyclocalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or R12 and R13 together may be alkylene or alkenylene (either of which may be substituted with Z\ Z2 and Z3), completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached, or, together with the nitrogen atom to which they are attached form:
Figure imgf000239_0001
R14 is lower alkyl substituted with 1 , 2 or 3 hlogen atoms; Z1, Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aralkyl; (g) alkoxy; (h) aryloxy; (i) aralkoxy; (j) -SH, -S(0)nZ6, -S(0)m-OH, -S(0)m-OZ6, -0-S(0)m-Z6, - 0-S(0)mOH, or -0-S(0)m-0-Z6; (k) oxo; (I) nitro; (m) cyano; (n) -C(0)H or -C(0)Z6; (o) - C02H or -C02Z6; (p) -Z4-NZ7Z8; (q) Z4-N(Z11)-Z5-H; (r) Z4-N(Z11)-ZB-Z6; or (s) -Z4-N(Z11)-ZB- NZ7Z8; Z4 and ZB are each independently (a) a single bond; (b) -Z9-S(0)n-Z10-; (c) -Z9- C(0)-Z10-; (d) -Z9-C(S)-Z10-; (e) -Z9-0-Z10-; (f) -Z9-S-Z10-; (g) -Z9-0-C(0)-Z10-; or (h) -Z9- C(0)-0-Z10-; Z6 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl; Z7 and Z8 are each independenly hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8- membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene, or alkynylene; Z11 is (a) hydrogen; (b) alkyl, cycloalkyl, cycloalkylalkyl, cycioalkenylalkyi, aryl, or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8- membered saturated, unsaturated, or aromatic ring together with the atoms to which they are attached; each m is independently 1 or 2; and each n is independently 0, 1 , or 2.
For this embodiment, it is preferred that R2 and R3 are each independently hydrogen or alkyl; R4 and R5 are each independently alkyl; and R12 and R13, together with the atoms to which they are attached, form:
Figure imgf000240_0001
For this embodiment, most preferred compounds are those wherein R2 and R3 are each hydrogen; and R4 and R5 are alkyl of 1 to 4 carbon atoms, especially methyl.
Preferred compounds of this embodiment include N-(3,4-dimethyl-5-isoxazolyl)- 2'-(hydroxymethyl)[1 ,1 '-biphenyl]-2-sulfonamide; 4'-[(dimethylamino)methyl]-N-(3,4- dimethyl-5-isoxazolyl)[1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-4'-[(2- hydroxyethoxy)mrthyl][1 ,1 '-biphenyl]-2-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2'- (hydroxymethyl)-4'-(2-methylpropyl)[1 ,1 '-biphenyl]-2-sulfonamide; 2'-(aminomethyl)-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1 ,1 '-biphenyl]-2-su)fonamide; N-(3,4- dimethyl-5-isoxazolyl)-4'-(1 -hydroxy-2-methylpropyl)[1 ,1 '-biphenyl]-2-sulfonamide; N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-hydroxy-2-methylpropyl)[1 ,1 '-biphenyl]-2-sulf onamide; N-(3,4-dimethyl-5-isoxazolyl)-4'-(3-hydroxy-2-methylpropyl)[1 ,1 '-biphenyl]~2- sulfonamide; and N-(3,4-dimethyl-5-isoxazolyl)-2'-[(formylamino)methyl]-4'-(2- methylpropyl)[1 , 1 '-biphenyl]-2-sulfonamide. cc. U.S. Patent No. 6,083,955 Other compounds for use in the methods provided herein include those having the formula:
Figure imgf000241_0001
where Ar is an optionally substituted aryl group or optionally substituted five- to six- membered heteroaryl group; X is oxygen, sulfur or -NH-; Y is O or S; R., is hydrogen, optionally halogen-substituted lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted five- to six-membered heteroaryl; R2 is lower alkyl lower alkenyl, lower alkynyl, and may be substituted with one to three substituent(s) selected from hydroxyl, lower alkoxy, cycloalkyl halo, carboxyl and lower alkoxycarbonyl; R3 is phenyl, which may be substituted with one to four substituent(s) selected from optionally halogen-substituted lower alkyl, lower alkoxy, halo, lower alkylthio, lower alkylsulfinyl, lower alkanesulfonyl, carboxyl, lower alkoxycarbonyl and carbamoyl; R4 and R5 are each independently hydrogen or lower alkyl. Preferred compounds of this embodiment include:
N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2- phenylethenesulfonamide; N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyl]-2-phenylethenesulfonamide; N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2- (2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide; N-[6-(2-propynyloxy)-5-(2- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulf onamide; N-[6- methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-methyl-2- phenylethenesulf onamide; N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyl]-1 -ethyl-2-phenylethenesulfonamide; and N-[6-methoxy-5-(2- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-thienyl)ethenesulf onamide. dd. Preferred compounds
Nonpeptide endothelin antagonists, especially sulfonamide endothelin antagonists (i.e., those containing a sulfonamide moiety -S02-NH-) are preferred, particularly those described in European Patent Application EP 702012; U.S. Patent Nos. 5,612,359 and 5,594,021 ; International Patent Application Publication Nos. WO 94/27979; WO 96/31492; WO 98/13366; and WO 98/49162. For example, among preferred compounds are the following compounds:
N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide, having the structure:
Figure imgf000242_0001
N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2- oxazolyl)[1 , 1 '-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide, having the structure:
Figure imgf000242_0002
N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)- acetyl]-thiophene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulf onamide, having the structure:
Figure imgf000243_0001
N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, having the structure:
Figure imgf000243_0002
N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide, having the structure:
Figure imgf000244_0001
N-{2-acetyl-4,6-dimethylphenyl)-3-({(3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide, having the structure:
Figure imgf000244_0002
5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2-[2-(1 H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]amide sodium salt (1 :2) (also referred to as Ro61 ), having the structure:
Figure imgf000245_0001
and pharmaceutically or veterinarily acceptable derivatives thereof.
Other compounds for use in the methods provided herein include BQ-123, (cyclo-(D-trp-D-asp-L-pro-D-val-L-leu)), BQ-1 53, BQ-238, BQ-485, BQ-610, BQ-788, BQ- 928, TAK-044, FR139317 (perhydrozaepin-1 -ylcarbonyl-L-leucyl-(1-methyl)-D- tryptophyl-[3-(2-pyridyl)]-D-alanine), RES-701 -1 , PD 142893 (acetyl-3,3-diphenyl-D- alanine)-L-leu-L-asp-L-ile-L-ile-L-trp), PD 145065, CP 170687, Ac-DBhg16-leu-asp-ile, ET-1 [Dprl-asp 1 5], Ro 61 -0612, To 61 -1790, To 42-2005, Ro 46-2005, Ro 46-8443, Ro 47-0203 (also known as bosentan), PD 155080, PD 156707, SB 209670, SB 217242, L-744,453, L-749,329, L-754,142, CGS 27830, BMS 182874, LU 135252, S-1039, mA386, A-127722, Nz-arg-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamide and EQ 1 23.
6. Combination Therapy
In the methods provided herein, the endothelin antagonist may, for example, be employed alone, in combination with one or more other endothelin antagonists, or with another compound useful for the prevention or treatment of endothelin-mediated disorders, such as a poly- ?-1→4-N-acetylglucosamine (p-GlcNAc) polysaccharide matrix; angiotensin converting enzyme (ACE) inhibitors such as captopril; dopamine receptor agonists such as apomorphine; renin inhibitors; angiotensin II (All) antagonists such as irbesartan ((2-n-butyl-4-spirocyclopentane-1 -[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2- imidazolin-5-one); dual NEP-ACE inhibitors such as [4S-[4cr(R*), la, 10a ]]-octahydro-4- (2-mercapto-1 -oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2, 1-b][1 ,3]thiazepine-7- carboyxlic acid (BMS-186716, U.S. Patent No. 5,508,272), [S-(R*,R*)]-hexahydro-6- [(2-mercapto-1 -oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1 H-azepine-1 -acetic acid (BMS-189921 , U.S. Patent No. 5,552,397), alatriopril, sampatrilat, MDL 100240, and CGS 30440; PDE V inhibitors such as sildenafil (see Terrett et al., Bioorg. Med. Chem. Ltrs., 6:1819-1824 (1996)), GF 196960 and IC-351 ; alpha adrenergic blockers such as phentolamine; vasoactive intestinal peptide (VIP); nitric oxide synthase substrates such as L-arginine; nitric oxide donors such as sodium nitroprusside, nitroglycerin, glyceryl trinitrate, S1N-1 , isosorbidmononitrate or isosorbiddinitrate; and prostaglandin E acting compounds such as alprostadil. Such other pharmaceutically or veterinarily active agents may be administered prior to, during or together with, or following administration of the endothelin antagonist. If formulated as a fixed dose, such combination products preferably employ the endothelin antagonists within the dosage range described above and the other pharmaceutically or veterinarily active agent within its approved dosage range. 7. Pharmaceutically or veterinarily acceptable derivatives of the compounds
Also of interest are any pharmaceutically or veterinarily acceptable derivatives, including salts, esters, acids and bases, solvates, hydrates and prodrugs of the sulfonamides. Preferred are pharmaceutically or veterinarily-acceptable salts, including, but not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para- chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, alkali metal salts, such as but not limited to lithium, potassium and sodium, alkali earth metal salts, such as but not limited to barium, calcium and magnesium, transition metal salts, such as but not limited to zinc and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate, preferably sodium salts, more preferably the sodium salt, and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates, salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates. Alkali metal salts, particularly sodium salts, are preferred herein. Most preferred salts are sodium salts.
Of interest are formulations of pharmaceutically or veterinarily acceptable derivatives, including salts, esters, acids and bases, solvates, hydrates and prodrugs of the sulfonamides. In particular, derivatives of neutral sulfonamide compounds that yield formulations of greater stability than formulations containing the corresponding neutral compounds are provided. Preferred are salts, particularly alkali metal salts, and more preferably sodium salts, including salts prepared from sodium compounds, including, but not limited to, sodium bicarbonate in which the resulting product is a sodium salt and disodium hydrogen phosphate in which the resulting compound is a sodium hydrogen phosphate salt. The sodium salt of each compound is most preferred.
The formulations are compositions suitable for administration by any desired route and include solutions, suspensions, emulsions, tablets, dispersible tablets, pills, capsules, powders, dry powders for inhalers, sustained release formulations, aerosols for nasal and respiratory delivery, patches for transdermal delivery and any other suitable route. The compositions should be suitable for oral administration, parenteral administration by injection, including subcutaneously, intramuscularly or intravenously as an injectable aqueous or oily solution or emulsion, transdermal administration and other selected routes.
The formulations provided herein are for administration by a selected route and contain effective concentrations of pharmaceutically or veterinarily-acceptable salts of the above-noted compounds. The formulations deliver amounts effective for the treatment of laminitis, particularly equine or bovine laminitis, more particularly equine laminitis.
D. Preparation of the compounds
The preparation of the neutral (i.e., free) sulfonamide compounds that possess the requisite activities are set forth in U.S. Patent Nos. 5,464,853, 5,594,021 , 5,591 ,761 , 5,571 ,821 , 5,514,691 , 5,464,853, commonly owned copending U.S. application Serial Nos. 08/721 ,183 and 08/847,797, and commonly owned published International PCT application Nos. WO 96/31492 and WO 97/27979. Representative syntheses are set forth the Examples. Compounds whose synthesis is not explicitly exemplified herein or in the above-listed patents and published International PCT applications can be synthesized by routine modification of one or more methods described in detail in the Examples by substituting appropriate readily available reagents.
Salts, acids and other derivatives thereof can be synthesized as outlined and exemplified herein, or by other methods known to those of skill in the art.
1. Neutral compounds In general, most of the syntheses involve the condensation of a sulfonyl chloride with an aminoisoxazole in dry pryridine or in tetrahydrofuran (THF) and sodium hydride. The sulfonyl chlorides and aminoisoxazoles either can be obtained commercially or synthesized according to methods described in the Examples or using other methods available to those of skill in this art (see, e.g., U.S. Patent Nos. 4,659,369, 4,861 ,366 and 4,753,672).
The N-(alkylisoxazolyl)sulfonamides can be prepared by condensing an aminoisoxazole with a sulfonyl chloride in dry pyridine with or without the catalyst 4- (dimethylamino)pyridine. The N-(3,4-dimethyl-5-isoxazolyl)sulfonamides and N-(4,5- dimethyl-3-isoxazolyl)sulfonamides can be prepared from the corresponding aminodimethylisoxazole, such as 5-amino-3,4-dimethylisoxazoIe. For example, N-(3,4- dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared from 2- methoxycarbonylthiophene-3-sulfonyl chloride and 5-amino-3,4-dimethylisoxazole in dry pyridine. The N-(4-haloisoxazolyl)sulfonamides can be prepared by condensation of amino-
4-haloisoxazole with a sulfonyl chloride in THF with sodium hydride as a base. For example, N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and thiophene-2-sulfonyl chloride in THF and sodium hydride. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfona- mide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-(3-isoxazolyl)thio- phene-2-sulfonyl chloride.
Alternatively, compounds, such as those in which Ar2 is thienyl, furyl and pyrrolyl herein, may be prepared by reacting an appropriate sulfonyl chloride with a 5- aminoisoxazole substituted at the 3 and 4 positions, such as 5-amino-4-bromo-3- methylisoxazole, in tetrahydrofuran (THF) solution containing a base, such as sodium hydride. Following the reaction, the THF is removed under reduced pressure, the residue dissolved in water, acidified and extracted with methylene chloride. The organic layer is washed and then dried over anhydrous magnesium sulfate, the solvents are evaporated and the residue is purified by recrystallization using hexanes/ethyl acetate to yield pure product.
These sulfonamides also can be prepared from the corresponding sulfonyl chloride and the aminoisoxazole in pyridine with or without a catalytic amount of 4- dimethylaminopyridine (DMAP). In some cases, the bis-sulfonyl compound is obtained as the major or exclusive product. The bis-sulfonated products can be readily hydrolyzed to the sulfonamide using aqueous sodium hydroxide and a suitable co- solvent, such as methanol or tetrahydrofuran, generally at room temperature. Other examples include:
(a) N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylamino- carbonyl)thiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)- 2-carboxylthiophene-3-sulfonamide, aniline and 1 -ethyl-3'-[3-dimethylaminopropyll- carbodiimide (EDCl). N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was prepared from 4- methoxyaniline, N,N'-diisopropylethylamine and N-(4-bromo-3-methy)-5-isoxazolyl)-2- carboxylthiophene-3-sulf onamide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzylaminocar- bonyl)thiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2- carboxylthiophene-3-sulfonamide and benzylamine as described above.
N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfona- mide, which was prepared from the condensation of 5-amino-4-bromo-3- methylisoxazole and 2-(carbomethoxy)thiophene-3-sulfonyl chloride.
(b) N-(4-bromo-3-methyl-5-isoxazolyl)-1 -(4'-isopropylphenyl)- pyrrole-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-1 -(4'- isopropylphenyl)pyrrole-3-sulfonamide were prepared from 5-amino-4-bromo-3- methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrole-2 -sulfonyl chloride and 1 - (4'-isopropylphenyl)pyrrole-3-sulfonyl chloride. These sulfonyl chlorides were prepared from 1 -(4'-isopropylphenyl)pyrrole-2-sulfonic acid, phosphorus oxychloride and phosphorus pentachloride. 1 -(4'-isopropylphenyl)pyrrole-2-sulfonic acid was prepared from 1 -(4'-isopropylphenyl)pyrrole and chlorosulfonic acid. 1 -(4'-isopropylphenyl)pyrrole was prepared from 4-isopropylaniline and 2,5-dimethoxytetrahydrofuran. 2. Salts of the neutral compounds
Pharmaceutically or veterinarily-acceptable salts of the compounds may be prepared by the exemplified method or any other method known to those of skill in the art. As exemplified herein, in the case of organic salts', the organic base, such as N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, or tris(hydroxymethyl)aminomethane, may be mixed with an equimolar amount of the sulfonamide. Subsequent recovery of the salt by crystallization, precipitation, concentration of the solution, lyophilization, spray-drying, chromatography, including, but not limited to, normal- and reverse-phase chromatography or resin chromatography, or any other method known to those of skill in the art would provide the desired salts. The pharmaceutically or veterinarily acceptable cationic salts can be prepared by reacting the acid forms with an appropriate base.
Sodium salts, and other metal salts, of the compounds may be prepared by the method set forth in U.S. Patent No. 5,783,705. Briefly, a solution of the sulfonamide in an organic solvent, such as ethyl acetate, is washed with several portions (i.e., 5 or more) of a saturated solution of sodium bicarbonate or sodium carbonate, preferably sodium bicarbonate. Concentration of the organic solution provided the sodium salts of the sulfonamides. The sulfonamide sodium salts can be further purified, if required, by crystallization from an appropriate solvent, such as, for example, dichloromethane/di- ethyl ether. Further purification may optionally be performed by filtering an aqueous solution of the sulfonamide sodium salts to remove particulates, liberating the free sulfonamides by acidification with aqueous hydrochloric acid (e.g., 4 N), and repeating the ethyl acetate/aqueous sodium bicarbonate procedure. Crystallization of the sulfonamide salts from the solvent, such as dichloromethane/diethyl ether or ethanol/methyl tert- butyl ether, provides sulfonamide sodium salts of greater than 98% purity. 3. Other derivatives
Prodrugs and other derivatives of the compounds suitable for administration to humans may also be designed and prepared by methods known to those of skill in the art (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). Compounds described herein have been synthesized and tested for activity in in vitro assays and, in some cases, in in vivo animal models. Nuclear magnetic resonance spectroscopic (NMR), mass spectrometric, infrared spectroscopic and high performance liquid chromatographic analyses indicated that the synthesized compounds have structures consistent with those expected for such compounds and are generally at least about 98% pure. All of the compounds exemplified or described herein exhibited activity as endothelin antagonists. E. Evaluation of the bioactivity of the compounds
Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess any biological activities of an endothelin peptide or the ability to interfere with or inhibit endothelin peptides. Compounds that exhibit in vitro activities, such as the ability to bind to endothelin receptors or to compete with one or more of the endothelin peptides for binding to endothelin receptors can be used in the methods for isolation of endothelin receptors and the methods for distinguishing the specificities of endothelin receptors, and are candidates for use in the methods of treating endothelin-mediated disorders.
Thus, other preferred compounds of formulae l-XXVII, in addition to those specifically identified herein, that are endothelin antagonists or agonists may be identified using such screening assays. Identifying compounds that modulate the activity of an endothelin peptide
The compounds are tested for the ability to modulate the activity of endothelin-1 . Numerous assays are known to those of skill in the art for evaluating the ability of compounds to modulate the activity of endothelin (see, e.g., U.S. Patent No. 5,1 14,918 to Ishikawa et aL; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD. (October 7, 1991 ); Borges et al. (1989) Eur. J. Pharm. 165: 223-230; Filep et al. (1991 ) Biochem. Biophys. Res. Commun. 177: 171 -176). In vitro studies may be corroborated with in vivo studies (see, e.g., U.S. Patent No. 5,1 14,918 to Ishikawa et aL; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD. (October 7, 1991 )) and pharmaceutical or veterinary activity thereby evaluated. Such assays are described in the Examples herein and include the ability to compete for binding to ETA and ETB receptors present on membranes isolated from cell lines that have been genetically engineered to express either ETA or ETB receptors on their cell surfaces.
The properties of a potential antagonist may be assessed as a function of its ability to inhibit an endothelin induced activity jn vitro using a particular tissue, such as rat portal vein and aorta as well as rat uterus, trachea and vas deferens (see e.g., Borges, R., Von Grafenstein, H. and Knight, D.E., "Tissue selectivity of endothelin," Eur. J. Pharmacol 165:223-230, (1989)). The ability to act as an endothelin antagonist jn vivo can be tested in hypertensive rats, ddy mice or other recognized animal models (see, Kaltenbronn et aL (1990) J. Med. Chem. 33:838-845, see, also, U.S. Patent No. 5,1 14,918 to Ishikawa et aL; and EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (October 7, 1991 ); see, also Bolger et aL (1983) J. Pharmacol. Exp. Ther. 225291 -309). Using the results of such animal studies, pharmaceutical or veterinary effectiveness may be evaluated and pharmaceutically or veterinarily effective dosages determined. A potential agonist may also be evaluated using in vitro and in vivo assays known to those of skill in the art.
Endothelin activity can be identified by the ability of a test compound to stimulate constriction of isolated rat thoracic aorta (Borges et aL (1989) "Tissue selectivity of endothelin" Eur. J. Pharmacol. 165: 223-230). To perform the assay, the endothelium is abraded and ring segments mounted under tension in a tissue bath and treated with endothelin in the presence of the test compound. Changes in endothelin induced tension are recorded. Dose response curves may be generated and used to provide information regarding the relative inhibitory potency of the test compound. Other tissues, including heart, skeletal muscle, kidney, uterus, trachea and vas deferens, may be used for evaluating the effects of a particular test compound on tissue contraction.
Endothelin isotype specific antagonists may be identified by the ability of a test compound to interfere with endothelin binding to different tissues or cells expressing different endothelin-receptor subtypes, or to interfere with the biological effects of endothelin or an endothelin isotype (Takayanagi et al. (1991 ) Reg. Pep. 32: 23-37, Panek et al. (1992) Biochem. Biophys. Res. Commun. 183: 566-571 ). For example, ETB receptors are expressed in vascular endothelial cells, possibly mediating the release of prostacyclin and endothelium-derived relaxing factor (De Nucci et aL (1988) Proc. Natl. Acad. Sci. USA 85:9797). ETA receptors are not detected in cultured endothelial cells, which express ETB receptors.
The binding of compounds or inhibition of binding of endothelin to ETB receptors can be assessed by measuring the inhibition of endothelin-1 -mediated release of prostacyclin, as measured by its major stable metabolite, 6-keto PGF1a, from cultured bovine aortic endothelial cells (see, e.g., Filep et aL (1991 ) Biochem. and Biophys Res. Commun. 177: 171-176). Thus, the relative affinity of the compounds for different endothelin receptors may be evaluated by determining the inhibitory dose response curves using tissues that differ in receptor subtype.
Using such assays, the relative affinities of the compounds for ETA receptors and ETB receptors have been and can be assessed. Those that possess the desired properties, such as specific inhibition of binding of endothelin-1 , are selected. The selected compounds that exhibit desirable activities may be therapeutically useful and are tested for such uses using the above-described assays from which jn vivo effectiveness may be evaluated (see, e.g., U.S. Patent No. 5,248,807; U.S. Patent No. 5,240,910; U.S. Patent No. 5,198,548; U.S. Patent No. 5,187,195; U.S. Patent No. 5,082,838; U.S. Patent No. 5,230,999; published Canadian Application Nos. 2,067,288 and 2071 193; published Great Britain Application No. 2,259,450; Published International PCT Application No. WO 93/08799; Benigi et aL (1993) Kidney International 44:440-444; and Nirei et aL (1993) Life Sciences 52:1869-1874). Compounds that exhibit in vitro activities that correlate with jn vivo effectiveness will then be formulated in suitable pharmaceutical or veterinary compositions and used as therapeutics. F. Methods of Use
Methods of use of endothelin antagonists are provided. Any endothelin antagonist is contemplated for use in the methods provided herein. Preferred endothelin antagonists are those described in detail herein. More preferred endothelin antagonists for use in the methods provided herein include sulfonamides disclosed in European Patent Application EP 702012; U.S. Patent Nos. 5,612,359 and 5,594,021 ; International Patent Application Publication Nos. WO 94/27979; WO 96/31492; WO 98/13366; and WO 98/49162. For example, among preferred endothelin antagonists are:
N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide, having the structure:
Figure imgf000253_0001
N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide, having the structure:
Figure imgf000254_0001
N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)- acetyl]-thiophene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[dI[1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mide, having the structure:
Figure imgf000254_0002
N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, having the structure:
Figure imgf000255_0001
N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide, having the structure:
Figure imgf000255_0002
N-(2-acetyl-4,6-dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide, having the structure:
Figure imgf000256_0001
and pharmaceutically or veterinarily acceptable derivatives thereof. The endothelin antagonists are useful for treating, preventing, or ameliorating one or more symptoms of disorders that are caused by endothelin activity or disorders in which endothelin activity is otherwise implicated. Such endothelin-mediated disorders include, but are not limited to, menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre-eclampsia; and control and management of labor during pregnancy.
Preferably, a medicament containing the compound is administered intravenously (IV), although treatment by local or topical administration may be tolerated in some instances. Generally, the medicament containing the compound is injected into the circulatory system of a subject in order to deliver a dose to the targeted cells. Targeting may be effected by linking the compound to a targeting agent specific for endothelin receptors, particularly endothelin-1 receptors. Dosages may be determined empirically, but will typically be in the range of about 0.01 mg to about 100 mg of the compound per kilogram of body weight as a daily dosage.
The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. EXAMPLE 1
Preparation of compound 7: N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4 dimethyl-5- isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide
Step 1 : Preparation of compound 1 :
Figure imgf000257_0001
To a 250 mL round-bottom flask equipped with a magnetic stir bar was added 20.0 gm of 5-amino-3,4-dimethylisoxazole, 50 mL of pyridine, and 2.0 gm (catalytic amount) of dimethylaminopyridine. The mixture was cooled in an ice bath as 21 .5 gm of 2-carboxymethyl-3-thiophenesulfonyl chloride was added in portions. The flask was sealed, the ice bath removed, and the reaction stirred at room temperature overnight. The majority of the pyridine was removed by rotary evaporation and the residual materials partitioned between ethyl acetate and 2N HCI. The layers were separated and the aqueous layer extracted with ethyl acetate (2X). The combined extracts were washed with dilute HCL (2X), brine (2X), and then dried over magnesium sulfate.
Filtration and condensation by rotary evaporation yielded 23.2 gm of compound 1 as an oil.
Step 2A: Preparation of compound 2.
Figure imgf000257_0002
To a 1 L round-bottom flask equipped with a magnetic stir bar and dropping funnel was added 23.1 gm of compound 1 , 500 mL of methylene chloride, and 28.4 gm of diisopropylamine. The reaction was cooled in an ice bath and 6.0 mL of bromomethylmethyl ether was added dropwise. The ice bath was removed and the reaction stirred at room temperature overnight. At this point, 200 mL of water was added and the reaction stirred for 30 min. The layers were separated and the aqueous layer extracted (2X) with methylene chloride. The combined organic layers were then washed with 0.5 N HCI, water, saturated sodium bicarbonate, brine, and finally dried over magnesium sulfate. Filtration and rotary evaporation yielded an oil which was further purified by silica gel chromatography using 25 - 30% ethyl acetate/hexane as the eluant to afford 21 .5 gm of compound 2 as an oil. Step 2B: Preparation of compound 3.
Figure imgf000258_0001
To a 500 mL round bottom flask equipped with a magnetic stir bar was added 21 .4 gm of compound 2, 1 20 ,mL of tetrahydrofuran, and 120 mL of 1 N sodium hydroxide. The reaction was rapidly stirred until complete reaction (approximately 3 - 4 hr). The majority of the tetrahydrofuran was removed by rotary evaporation and the residual materials mixed with 50 mL of water. This mixture was then acidified by the addition of 130 mL of 1 N HCI and then extracted with 200 mL (2X) of ethyl acetate. The combined extracts were washed with water (50 mL), then brine (50mL), and finally dried with magnesium sulfate. Filtration and condensation by rotary evaporation yielded 20.1 gm of compound 3 as a yellow oil which solidified upon standing. Step 2C: Preparation of compound 4.
Figure imgf000259_0001
To a 1 L round bottom flask equipped with a magnetic stir bar and dropping funnel was added 19.7 gm of compound 3,200 mL of methylene chloride, and 5 drops of pyridine. A solution of 128 mL of oxalyl chloride in 100 mL of methylene chloride was added dropwise. The dropping funnel was then replaced with a reflux condenser and the reaction heated to gentle reflux for 3 hr. after which it was condensed by rotary evaporation to yield 20.9 gm of compound 4 as a brown solid. This material was used directly in Step 3 without further purification. Step 3: Preparation of compound 6.
Figure imgf000259_0002
To a 1 -L round bottom flask equipped with a magnetic stir bar and dropping funnel was added 18.5 gm of 2-acetyl-4,6-dimethylaniline (5) and 1 50 mL of methylene chloride. To this was added dropwise a solution of 20.7 gm of compound 4 dissolved in 350 mL of methylene chloride. The reaction was stirred at room temperature for 3 hr. and then condensed by rotary evaporation. To the residual materials was added 200 mL of ether and the mixture was filtered. The filter cake was washed with 3X 100 mL of ether. The combined filtrates were washed with 3X 100mL of 1 HCI followed by 100 mL each with water, sat. sodium bicarbonate, and brine. The solution was then dried with magnesium sulfate, filtered, and condensed by rotary evaporation to yield a semi-crystalline material. This material was triturated with 200 mL of ether to yield 23.7 gm of compound 6 as a white solid.
Step 4A: Preparation of compound 7.
Figure imgf000260_0001
To a 500 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser was added 23.7 gm of compound 6, 180 mL of methanol, and 90 mL of cone. HCI. The mixture was heated to reflux for 4 hr. Heating was discontinued and the mixture stirred and cooled with an ice bath. After approximately 30 min. the mixture was filtered and the filter cake washed with a mixture of water and methanol to yield 18.3 gm of compound 7. This material was recrystallized from ethyl acetate/hexane to give 16.8 gm of material as a white solid: mp 158 - 160 °C.
Step 4B: Preparation of compound 7 sodium salt.
Figure imgf000261_0001
To 1 6.8 gm of compound 7 solubilized in 800 mL of ethyl acetate and 200 mL of tetrahydrofuran was added 100 mL of saturated sodium bicarbonate. The layers were separated and the organic layer washed with an additional 2X 100 mL of sat. sodium bicarbonate. The combined bicarbonate washes were back extracted with ethyl acetate and the combined organic solutions dried over magnesium sulfate, filtered, and condensed by rotary evaporation to yield a foam. This material was solubilized in 300 mL of water and the resulting solution filtered and lyophilized to yield 1 5.5 gm of compound 7 sodium salt as a white solid.
EXAMPLE 2
Preparation of compound 9: N-(2-cyano-3,4,6-trimethylphenyl)-3-{f(3,4-dimethyl-5- isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide
Figure imgf000262_0001
N-(2-cyano-3,4,6-trimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl}-
2-thiophenecarboxamide, was prepared by the procedure of Example 1 except that 2- cyano-3,4,6-trimethylaniline (8) was substituted for 2-acetyl-4,6-dimethylaniline in Step 3.
EXAMPLE 3
Preparation of compound 16: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino] sulfonyl}-N- (3,4,6-trimethyl-2-propanoylphenyl)-2-thiophenecarboxamide Step 1 : Preparation of compound 10: 3{[(4-chloro-3-methyl-5- isoxazolyl)amino]suIfonyl}-2-thiophenecarboxylic acid
Figure imgf000262_0002
To a 500 mL round bottom flask containing 46.5 g of 3-{[(4-chloro-3-methyl-5- isoxazolyl)amino]sulfonyl}-2-thiophenecarboxylic acid methyl ester was added 250 mL of 1 N sodium hydroxide. The mixture was stirred until no starting material remained. The reaction solution was acidified with 2 N hydrochloric acid, ethyl acetate extracted (3 x 100 mL). The combined extracts were dried (MgS04), filterred and condensed by rotary evaporation to yield 42.5 g of compound 10 as a solid.
Step 2 A: Preparation of compound 11 : 3{[(4-chloro-3-methyl-5- isoxazolyl)amino]sulfonyl}-N-methoxymethyl-2-thiophenecarboxylic acid methoxymethyl ester.
Figure imgf000263_0001
To a 2-L round bottom flask equipped with a magnetic stir bar and dropping funnel was added 42.5 gm of compound 10, 500 mL of methylene chloride, and 40.1 gm of diisopropylethylamine. The reaction mixture was cooled with an ice bath and 21 .5 mL of bromomethylmethyl ether was added dropwise. The ice bath was removed and the reaction stirred at room temperature overnight. 200 mL of water was added and the reaction mixture stirred for 30 min. The layers were separated and the aqueous layer washed with 100 mL of methylene chloride. The combined organic layers were washed with 50 mL each of 0.5 N HCI, water, sat. sodium bicarbonate, brine and then finally dried with magnesium sulfate. The mixture was filtered and the filtrate condensed by rotary evaporation to yield an oil that was further purified by silica gel chromatography using 25 - 30% ethyl acetate/hexane as the eluant to yield 38.1 gm of compound 1 1 as an oil.
Step 2B: Preparation of compound 12.
Figure imgf000263_0002
To a 1-L round bottom flask equipped with a magnetic stir bar was added 38 gm of compound 11 , 250 mL of tetrahydrofuran, and 250 mL of 1 N sodium hydroxide. The reaction was rapidly stirred until complete reaction (approximately 4 hr). The majority of the tetrahydrofuran was removed by rotary evaporation and the residual materials were mixed with 50 mL of water. This solution was then acidified by the addition of 260 mL of 1 N HCI. This mixture was then twice extracted with 200 mL of ethyl acetate. The combined extracts were washed with 50 mL each of water and brine and then dried with magnesium sulfate. Filtration and condensation by rotary evaporation yielded 30.8 gm of compound 12 as a yellow oil which solidified upon standing. Step 2C: Preparation of compound 13.
Figure imgf000264_0001
To a 1 -L round bottom flask equipped with a magnetic stir bar and dropping funnel was added 30 gm of compound 12, 200 mL of methylene chloride, and 5 drops of pyridine. A solution of 29.2 gm of thionyl chloride in 200 mL of methylene chloride was added dropwise. The dropping funnel was then replaced with a reflux condenser and the reaction heated to gentle reflux for 4 hr. The reaction was then condensed by rotary evaporation to yield 31 .4 gm of compound 13 as a brown solid. This material was used directly in Step 3 without additional purification. Step 3: Preparation of compound 15.
Figure imgf000265_0001
15
To a 1-L round bottom flask equipped with a magnetic stir bar and dropping funnel was added 19.8 gm of compound (14) and 150 mL of methylene chloride. To this was added dropwise a solution of 20.0 gm of compound 13 dissolved in 350 mL of methylene chloride. The reaction was stirred at room temperature for 3 hr and then condensed by rotary evaporation. To the residual materials was added 200 mL of ether and the mixture was filtered. The filter cake was washed with 100 mL of ether followed by 2X 200 mL of hot ethyl acetate. The combined washings were washed with 3X 100mL of 1 N HCI followed by 100 mL each with water, sat. sodium bicarbonate, and brine. The solution was then dried with magnesium sulfate, filtered, and condensed by rotary evaporation to yield a semi-crystalline material. This material was triturated with 100 mL of ether to yield 20.1 gm of compound 15 as a white solid.
Step 4: Preparation of compound 16.
Figure imgf000266_0001
By the procedure of Example 1 , Step 4A, compound 15 was converted to compound 16, a solid, mp 166-170 °C.
EXAMPLE 4
Preparation of compound 18: 3-{f(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-[2- (1 -hydroxyethyl)-4,6-dimethylphenyl]-2-thiophene carboxamide
Figure imgf000266_0002
To a solution of 100 mg of compound 17 (sodium salt) in water was added 100 mg of sodium borohydride. After 3 h, an additional 100 mg of sodium borohydrode was added and the solution stirred at room temperature overnight. The reaction was mixed with excess saturated ammonium chloride solution, extracted with ethyl acetate (3 x 50 mL). The extracts were washed with saturated sodium bicarbonate solution and evaporated to give compound 18 (Na salt) as a solid, mp 147-154 °C.
EXAMPLE 5
Preparation of compound 20: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino] sulfonyl}-N-{2- [(dimethylamino)carbonyl]-4,6-dimethylphenyl)-2-thiophene carboxamide
Figure imgf000267_0001
H3C CH3
Compound 20 was prepared according to the procedure of Example 3 except that 2-[(dimethylamino)carbonyl]-4,6-dimethylaniline (19) was used in step 3 in the place of compound 12. Compound 20 was obtained as a white solid. EXAMPLE 6
Preparation of compound 22: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N- {2,4-dimethyl-6-[(methyloxy)ethanimidoyl]phenyl}-2-thiophene carboxamide
Figure imgf000268_0001
Compound 17 was reacted with methoxyamine (21) in ethanol solution to yield compound 22 as a white solid; mp 140-145 °C.
EXAMPLE 7
Preparation of compound 24: 3-{[(3-{I(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}- 2-thiophenyl)carbonyl]amino}-2,4,6-trimethylphenyl-N,N-dimethylsulfamate
Figure imgf000268_0002
24
23
To an ice-cold solution of 700 mg of 3-{[(4-chloro-3-methy)-5- isoxazolyl)amino]sulfonyl}-N-{3-hydroxy-2,4,6-trimethylphenyl}-2-thiophenecarboxamide (23) in 1 5 mL of dimethylformamide was added 247 mg of potassium t-butoxide. After a short period, 317 mg of dimethylaminosulfonyl chloride was added. When the reaction was judged complete, it was diluted with water, acidified with 1 N hydrochloric acid. This mixture was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were dried (MgS04), filtered, and evaporated to yield compound 24 as a white solid; mp 169-174 °C.
EXAMPLE 8
Preparation of compound 26: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-{3- [(cyclopropylmethyl)oxy]-2,4,6-trimethylphenyl}-2-thiophenecarboxamide
Figure imgf000269_0001
To an ice-cold solution of 700 mg of 3-{[(4-chloro-3-methyl-5- isoxazolyl)amino]sulfonyl}-N-{3-hydroxy-2,4,6-trimethylphenyl}-2-thiophenecarboxamide (23) in 15 mL of dimethylformamide was added 247 mg of potassium t-butoxide. After a short period, 135 mg of cyclopropylmethylbromide (25) was added. When the reaction was judged complete, it was diluted with water, acidified with 1 N hydrochloric acid. This mixture was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were dried (MgS04), filtered, and evaporated to yield compound 26 as a white solid; mp 1 55-1 58 °C.
EXAMPLE 9
Preparation of compound 28: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N- (2,4,6-trimethyl-5-pyrimidinyl)-2-thiophenecarboxamide
Figure imgf000270_0001
Compound 28 was prepared according to the procedure of Example 3 except that 5-amino-2,4,6-trimethylpyrimidine (27) was used in step 3 in the place of compound 12. Compound 28 was obtained as a white solid; mp 170-175 °C.
EXAMPLE 10
Preparation of compound 30: N-(2-acetyl-3,4,6-trimethylphenyl)-3-{[(4-chloro-3-methyl- 5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide
Figure imgf000270_0002
Compound 30 was prepared according to the procedure of Example 3 except that 2-acetyl-3,4,6-trimethylaniline (29) was used in step 3 in the place of compound
12. Compound 30 was obtained as a white solid; mp 223-225 °C.
EXAMPLE 11
Preparation of compound 32: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2- eyano-3,4,6-trϊmethylphenyl)-2-thiophenecarboxamide
Figure imgf000271_0001
Compound 32 was prepared according to the procedure of Example 3 except that 2-cyano-3,4,6-trimethylaniline (31) was used in step 3 in the place of compound 12. Compound 32 was obtained as a white solid; mp 218-220 °C.
EXAMPLE 12
Preparation of compound 34: N-(2-chloro-4,6-dJmethylphenyl)-3-{[(4-chloro-3-rnethyl-5- isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide
Figure imgf000272_0001
Compound 34 was prepared according to the procedure of Example 3 except that 2-chloro-4,6-dimethylaniline (33) was used in step 3 in the place of compound 12.
Compound 34 was obtained as a white solid; mp 174-176 °C.
EXAMPLE 13
Preparation of compound 36: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N- (4,6-diacetyl-3-hydroxy-2-propylphenyl-2-thϊophenecarboxamide
Figure imgf000272_0002
Compound 36 was prepared according to the procedure of Example 3 except that 4,6-diacetyl-3-hydroxy-2-propylaniline (35) was used in step 3 in the place of compound 12. Compound 36 was obtained as a white solid; mp 163-167 °C.
EXAMPLE 14
Preparation of compound 38: 3-{[(4-chIoro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N- (2,4-dimethyl-6-[2-(methylsulfonyl)acetyl]phenyI}-2-thiophenecarboxamide
Figure imgf000273_0001
Intermediate compound 53 was prepared according to the procedure of Example 3 except that 2,4-dimethyl-6-(2-chloroacetyl)aniline (37) was used in step 3 in the place of compound 12. A solution of 400 mg of compound 53 and 1.2 g of sodium methanesulfonate in
10 mL of dimethylformamide was stirred at room temperature. When the reation was judged complete, the reaction was diluted with water, acidified with 2 N hydrochloric acid and extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried (MgS04), filtered, and condensed by rotary evaporation to yield compound 38 as a solid; mp 172-175 °C.
EXAMPLE 15
Preparation of compound 40: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-
(2,4-dimethyl-6-{[methyl(2,2-dimethylpropyl)amino]carbonyl}phenyl)-2- thiophenecarboxamide
Figure imgf000274_0001
Compound 40 was prepared according to the procedure of Example 3 except that 2-{[methyl-(2,2-dimethylpropyl)amino]carbonyl}-4,6-dimethylaniline (39) was used in step 3 in the place of compound 12. Compound 40 was obtained as a white solid; mp 174-176 °C. EXAMPLE 16
Preparation of compound 42: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl)-N- [2,4-dimethyl-6-(methylsulfonyl)phenyl]-2-thiophenecarboxamide
Figure imgf000275_0001
Compound 42 was prepared according to the procedure of Example 3 except that 2,4-dimethy)-6-(methylsulfonyl)aniline (41 ) was used in step 3 in the place of compound 12. Compound 42 was obtained as a white solid; mp 208-210 °C.
EXAMPLE 17 Preparation of compound 44: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N- [2,4-dimethyl-6-(1 ,3-oxazol-2-yl)phenyl]-2-thiophenecarboxamide
Figure imgf000275_0002
Compound 44 was prepared according to the procedure of Example 3 except that 2,4-dimethyl-6-(1 ,3-oxazol-2-yl)aniline (43) was used in step 3 in the place of compound 12. Compound 44 was obtained as a white solid; mp 176-178 °C.
EXAMPLE 18
Preparation of compound 46: 3-{[{4-chloro-5-isoxazolyl)amino]sulfonyl}-N-[2-(2- propylsulfonyl)-4,6-dϊmethylphenyl]-2-thiophenecarboxamide
Figure imgf000276_0001
Compound 46 was prepared according to the procedure of Example 3 except that 2-(2-propylsulfonyl)-4,6-dimethylaniline (45) was used in step 3 in the place of compound 12. Compound 46 was obtained as a white solid; mp 190-192 °C.
EXAMPLE 19 Preparation of compound 48: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amϊno]sulfonyl)-N- [2,4-dimethyl-6-(propylsulfonyl)phenyl]-2-thiophenecarboxamide
Figure imgf000277_0001
Compound 48 was prepared according to the procedure of Example 3 except that 2,4-dimethyl-6-(propylsulfonyl)aniline (47) was used in step 3 in the place of compound 12. Compound 48 was obtained as a white solid; mp 152-155 °C.
EXAMPLE 20
Preparation of compound 50: 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2- ethyl-4,6-dimethylphenyl)-2-thiophenecarboxamide
Figure imgf000277_0002
Compound 50 was prepared according to the procedure of Example 3 except that 2-ethyl-4,6-dimethylaniline (49) was used in step 3 in the place of compound 12. Compound 50 was obtained as a white solid; mp 1 52-1 54 °C. EXAMPLE 21
Preparation of compound 52: 3-{[(4-chloro-3-rnethyl-5-isoxazolyl)amino]sulfonyl}-N- [2,6-dimethyl-4-(1,3-oxazol-2-yl)phenyl]-2-thiophenecarboxamide
Figure imgf000278_0001
Compound 52 was prepared according to the procedure of Example 3 except that 2,6-dimethyl-4-(1 ,3-oxazol-2-yl)aniline (51 ) was used in step 3 in the place of compound 12. Compound 52 was obtained as a white solid; mp 205-207 °C.
EXAMPLE 22 Method for testing for compounds that possess anti-laminitic activity Compounds and compositions for use in the treatment, prevention, or amelioration of one or more symptoms of laminits can be and were identified by comparison with controls in foundered horses. The horses are evaluated for lameness, hoof wall temperature. Hoof wall temperature is used to index the digital perfusion in the experiment. An increase in hoof wall temperature compared to control indicates increased digital blood flow, and that the ischemic crisis is not as severe in the developmental phase of the disorder. Material and methods
Eighteen healthy horses were used in the study. These horses were divided into Group A (ten horses) and Group B (eight horses). Group A horses served as placebo controls and Group B horses received treatment. All subjects used in the study were evaluated to ensure that digits were within normal limits (clinical evaluation and radiographs) and were trained to stand quietly in an instrumented stanchion containing force plates.
At the initiation of the experiment, the fore digits of the subjects were instrumented with skin surface thermistors and the hoof wall temperature and force plate loading parameters were collected. Force plate data was recorded for 5 minutes at a 0.01 -second interval. The force plates were used to record the load voluntarily placed on each digit. These individual digital loads were summated to determine the weight of the horse, and the percentage of the total load on each digit was calculated. The mean percent of the total load placed on each digit (% load) and one standard deviation of the percent load (load distribution profile) were recorded and used as parameters in the study.
The experimental subjects were sex and age matched. Assignment to Group A or B was done randomly. Each pair was brought into the temperature (72 °F) and humidity (42%) controlled laboratory environment for a period of 24 hours. During this time, the horses were evaluated at 4-hour intervals to establish control data for each horse. At each 4-hour sampling period, the horses were brought into the measurement laboratory, which was immediately adjacent to and at the same environmental conditions as the stalls. Measurement parameters collected consisted of hoof wall temperature, mean % load, load distribution profile, and physical symptoms (presence of lameness). In addition, the horses were videotaped in their stalls during the entire 72 hours of the experiment. These tapes were reviewed to determine the horse's physical status and the amount of time that the horses were standing versus lying down.
The horses (one treated and one placebo) received a laminitis-inducing diet by nasogastric tube within 30 minutes of each other. This diet is 85% cornstarch, 1 5% methyl-cellulose mix administered at 17.6 g/kg of body weight. Following administration of the diet the horses were followed at 4-hour intervals using the same sampling protocol as described above. At each sampling period the hoof wall temperature was plotted to determine the occurrence of a bilateral decrease in the hoof wall temperature relative to control temperature for each animal. At this point the horses in Group A received a placebo and the Group B horses received the endothelin antagonist N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyD- acetyl]-thiophene-3-sulfonamide, also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mide, via an intravenous catheter at a dose of 10 mg/kg, SID for the next 48 hours. Following treatment the subjects were returned to their stalls and monitoring was continuted at the same 4-hour intervals described above. At the end of the 72 hours the horses were evaluated for lameness and returned to their stalls. Similarly, each horse was examined for lameness once a day for three additional days. The severity of lameness was determined subjectively (Obel Grading) and by force plate evaluation. Eight hours following onset of lameness, or eight hours from the termination of the experiment if the horse did not develop lameness, a dorsal submural biopsy was obtained. This was completed under local anesthesia. Samples were stained and examined for the integrity of the laminar epithelium and basal cell/basement membrane. At the termination of the experiment the horses were placed on systemic analgesics (phenylbutazone 2.2 mg/kg) if necessary and allowed to recover. Data analysis and interpretation Digital temperature data was plotted and used to grade the severity of the digital ischemia. The force plate parameters (mean % load and load distribution profile) were used to grade the severity of lameness if present. Digital temperatures and force plate parameters from treated, placebo, and non-treated control horses were compared statistically (one way AVOVA). Results
Clinical status and recovery following treatment Five of the placebo treated horses (Group A) were clinically recovered from their lamenesses by 72 hours, 2 were still lame, and 3 demonstrated a persistent lameness. In the treated horses (Group B), 6 were fully recovered at 72 hours, 2 demonstrated lameness at 72 hours, and none demonstrated persistent lameness. These data indicate a strong trend that the endothelin antagonist enhanced the recovery from the acute insult (p = 0.0608).
Digital Blood Flow The temperature data was examined and separated into one of three patterns. The first pattern reflected a mild, transient decrease in the hoof wall temperature that lasted less than 4 to 8 hours. The second pattern was that of a decreased temperature of 4-5 °C that lasted less than 4 to 8 hours. The third pattern was that of a decreased temperature of 4 to 5 °C that persisted for 10 to 12 hours. As the hoof wall temperature was used to index digital perfusion in this experiment, and served as the point in time when treatment with the endothelin antagonist was initiated, these three patterns index drug effectiveness in this regard. In the treated horses (Group B), five
(62.5%) demonstrated the first pattern, 2 (25%) demonstrated pattern 2, and only 1
(12.5%) deomonstrated pattern 3. In the placebo treated horses (Group A), only 1 (12.5%) demonstrated pattern one, 3 (37.5%) demonstrated the second pattern, and 4
(50%) demonstrated a significant and prolonged decrease in digital perfusion (pattern
3). Statistical comparisons (Wilcoxon rank-sum) beween the treated (Group B) and placebo (Group A) horses indicated that they were different (p = 0.0039).
EXAMPLE 23 Assays for identifying compounds that exhibit endothelin antagonistic and/or agonist activity
Compounds that are potential endothelin antagonists are identified by testing their ability to compete with 126I-labeled ET-1 for binding to human ETA receptors or ETB receptors present on isolated cell membranes. The effectiveness of the test compound as an antagonist or agonist of the biological tissue response of endothelin can also be assessed by measuring the effect on endothelin induced contraction of isolated rat thoracic aortic rings. The ability of the compounds to act as antagonists or agonists for
ETB receptors can be assessed by testing the ability of the compounds are to inhibit endothelin-1 induced prostacyclin release from cultured bovine aortic endothelial cells. A. Endothelin binding inhibition - Binding Test #1 : Inhibition of binding to ETA receptors
TE 671 cells (ATCC Accession No. HTB 139) express ETA receptors. These cells were grown to confluence in T-175 flasks. Cells from multiple flasks were collected by scraping, pooled and centrifuged for 10 min at 190 X g. The cells were re- suspended in phosphate buffered saline (PBS) containing 10 mM EDTA using a
Tenbroeck homogenizer. The suspension was centrifuged at 4° C at 57,800 X g for 15 min, the pellet was resuspended in 5 ml of buffer A (5 mM HEPES buffer, pH 7.4 containing aprotinin (100 KIU/mD) and then frozen and thawed once. 5 ml of Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCI2 and 0.001 % deoxyribonuclease Type 1 ) was added, the suspension mixed by inversion and then incubated at 37° C for 30 minutes. The mixture was centrifuged at 57,800 X g as described above, the pellet washed twice with buffer A and then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containing aprotinin (100 KlU/ml) to give a final protein concentration of 2 mg/ml and stored at -70° C until use. The membrane suspension was diluted with binding buffer (30 mM HEPES buffer, pH 7.4 containing 150 mM NaCl, 5mM MgCI2, 0.5% Bacitracin) to a concentration of 8 /g/50 μl. 125l-endothelin-1 (3,000 cpm, 50 mL) was added to 50 μL of either: (A) endothelin-1 (for non specific binding) to give a final concentration 80 nM); (B) binding buffer (for total binding); or (C) a test compound (final concentration 1 nM to 100 μM). The membrane suspension (50 μL), containing up to 8 μg of membrane protein, was added to each of (A), (B), or (C). Mixtures were shaken, and incubated at 4° C for 16-18 hours, and then centrifuged at 4° C for 25 min at 2,500 X g. Alternatively, the incubation was conducted at 24° C. When incubated at 24° C, the ICB0 concentrations are 2- to 10-fold higher than when the incubation is conducted at 4° C. This, must be kept in mind when comparing IC50 concentrations among compounds provided herein.
The supernatant, containing unbound radioactivity, was decanted and the pellet counted on a Genesys multiwell gamma counter. The degree of inhibition of binding (D) was calculated according to the following equation:
(C) - (A)
% D = 100 - X 100
(B) - (A)
Each test was generally performed in triplicate. B. Endothelin binding inhibition - Binding Test #2: Inhibition of binding to ETB receptors
COS7 cells were transfected with DNA encoding the ETB receptor. The resulting cells, which express the human ETB receptor, were grown to confluence in T-1 50 flasks.
Membrane was prepared as described above. The binding assay was performed as described above using the membrane preparation diluted with binding buffer to a concentration of 1 //g/50 μl.
Briefly, the COS7 cells, described above, that had been transfected with DNA encoding the ETB receptor and express the human ETB receptor on their surfaces were grown to confluence in T-175 flasks. Cells from multiple flasks were collected by scraping, pooled and centrifuged for 10 min at 190 X g. The cells were resuspended in phosphate buffered saline (PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. The suspension was centrifuged at 4° C 57,800 X g for 1 5 min, the pellet was resuspended in 5 ml of buffer A (5mM HEPES buffer, pH 7.4 containing aprotinin (100 KlU/ml)) and then frozen and thawed once. Five ml of Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCI2 and 0.001 % deoxyribonuclease Type 1 ) was added, the suspension mixed by inversion and then incubated at 37° C for 30 minutes. The mixture was centrifuged at 57,800 X g as described above, the pellet washed twice with buffer A and then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containing aprotinin (100 KlU/ml) to give a final protein concentration of 2 mg/ml. The binding assay was performed as described above using the membrane preparation diluted to give 1 μg/50 μl of binding buffer.
C. Test for activity against endothelin-induced contraction of isolated rat thoracic aortic rings
The effectiveness of the test compound as an antagonist or agonist of the biological tissue response of endothelin also is assessed by measuring the effect on endothelin induced contraction of isolated rat thoracic aortic rings (see, e.g., Borges et aL (1989) Eur. J. Pharmacol. 165:223-230) or by measuring the ability to contract the tissue when added alone.
Compounds to be tested are prepared as 100 μM stocks. If necessary to effect dissolution, the compounds are first dissolved in a minimum amount of DMSO and diluted with 150 mM NaCl. Because DMSO can cause relaxation of the aortic ring, control solutions containing varying concentrations of DMSO were tested.
The thoracic portion of the adult rat aorta is excised, the endothelium abraded by gentle rubbing and then cut into 3 mm ring segments. Segments are suspended under a 2 g preload in a 10 ml organ bath filled with Krebs'- Henseleit solution saturated with a gas mixture of 95% 02 and 5% C02 (1 18 mM NaCl, 4.7 mM KCI, 1 .2 mM
MgS04, 1 .2 mM KH2P04, 25 mM NaHC03, 2.5 mM CaCI2, 10 mM D-glucose).
There is a correlation between activity as an antagonist of endothelin-induced thoracic aortic ring contraction and activity as an inhibitor of binding of endothelin to endothelin receptors. The pA2 is a linear function of the log of the IC50.
D. Assay for identifying compounds that have agonist and/or antagonistic activity against ETB receptors
1. Stimulation of prostacyclin release
Since endothelin-1 stimulates the release of prostacyclin from cultured bovine aortic endothelial cells, the compounds that have agonist or antagonist activity are identified by their ability to inhibit endothelin-1 induced prostacyclin release from such endothelial cells by measuring 6-keto PGF1 O substantially as described by (Filep et al. (1991 ) Biochem. Biophys. Res. Commun. 177 171 -176. Bovine aortic cells are obtained from collagenase-treated bovine aorta, seeded into culture plates, grown in Medium 199 supplemented with heat inactivated 15% fetal calf serum, and L-glutamine (2 mM), penicillin, streptomycin and fungizone, and subcultured at least four times. The cells are then seeded in six-well plates in the same medium. Eight hours before the assay, after the cells reach confluence, the medium is replaced. The cells are then incubated with a) medium alone, b) medium containing endothelin-1 (10 nM), c) test compound alone, and d) test compound + endothelin-1 (10 nM).
After a 15 min incubation, the medium is removed from each well and the concentrations of 6-keto PGF1σ are measured by a direct immunoassay. Prostacyclin production is calculated as the difference between the amount of 6-keto PGF1σ released by the cells challenged with the endothelin-1 minus the amount released by identically treated unchallenged cells. Compounds that stimulate 6-keto PGF1O release possess agonist activity and those which inhibit endothelin-1 6-keto PGFlσ release possess antagonist activity.
2. Inhibition of sarafotoxin 6c induced contraction Sarafotoxin 6c is a specific ETB antagonist that contracts rat fundal stomach strips. The effectiveness of tests compounds to inhibit this sarafotoxin 6c-induced contraction of rat fundal stomach strips is used as a measure ETB antagonist activity. Two isolated rat fundal stomach strips are suspended under a 1 g load in a 10 ml organ bath filled with Krebs'-Henseleit solution containing 10 μM cyclo(D-Asp-Pro-D-Val-Leu- D-Trp) (BQ-123; see, U.S. Patent No. 5,1 14,918 to Ishikawa et aL), 5 μM indomethacin, and saturated with a gas mixture of 95% 02/5% C02. Changes in tension are measured isometrically and recorded using a Grass Polygraph coupled to a force transducer. Sarafotoxin 6c is added cumulatively to one strip while the second strip is preincubated for 1 5 min with a test compound prior to addition of cumulative doses of sarafotoxin 6c. The effects of the test compounds on the concentration- response curve for sarafotoxin 6c are examined.
E. Deoxγcorticosterone acetate (DOCA)-salt hypertensive rat model for assessing jn vivo activity of selected compounds
Selected compounds disclosed herein have been tested for activity in the deoxy- corticosterone acetate (DOCA)-salt hypertensive rat model. To perform these tests, silastic MDX4-4210 elastomer implants containing 47 mg (DOCA) were prepared according to the method of Ornmsbee et aL ((1973) the J. Pharm. Sci. 62:255-257).
Briefly, DOCA is incorporated into silicon rubber implants for sustained release. To prepare the implants the DOCA is incorporated into unpolymerized silicone rubber, catalyst is added and the mixture is cast in a hemicylindrical shape. Sprague Dawley rats (7-8 weeks old) were unilaterally nephrectomized under ketamine anesthesia and a DOCA-implant was placed on the left lateral dorsal abdomen of the animal. The rats were allowed to recover for three weeks. During recovery they were permitted free access to normal rat chow and 0.9% NaCl drinking solution in place of drinking water. The rats develop hypertension within 3 weeks.
All animals were used in the tests between 21 and 30 days post surgery. The mean arterial blood pressure in these animals ranged from 165-200 mm Hg.
On the day of experimentation, catheters were inserted under brevital anesthesia into the right femoral artery for measurement of blood pressure, and into the right femoral vein for administration of a selected compound. The animals were placed in a restrainer and allowed to recover for a minimum of 60 min or until a steady mean arterial blood pressure was recorded. At that time, the selected compound or control vehicle was administered either intravenously, as a 60 minute infusion, or orally by oral gavage. Blood pressure was recorded continuously for a further 10 hrs. F. Effect of Intravenous administration on ET-1 -induced pressor responses in conscious, autonomically blocked rats; a model for assessing in vivo activity of selected compounds
Male Sprague Dawley rats (250-450 g) were anesthetized (Brevital 50 mg/kg,
IP) and cannulae were placed in the femoral artery to measure mean arterial pressure (MAP) and in the femoral vein for intravenous drug administration. Animals were placed in a restrainer and allowed to regain consciousness. Thirty minutes later autonomic blockade was administered (atropine methyl nitrate, 3 mg/kg, IV, followed by propranalol, 2 mg/kg, IV). An hour later animals received a bolus injection of vehicle
(0.5 ml) followed thirty minutes later by intravenous bolus administration of ET-1 (Control, 1 μg/kg). Following recovery from this challenge, test -compounds were administered by intravenous bolus administration (0.5 ml) and then re-challenged with
ET-1 thirty minutes later. Results are expressed as the percent inhibition of the ET-1 - induced pressor response after administration of the test compound compared to the pressor response induced by the control ET-1 challenge. In some cases a third ET-1 challenge was administered ninety minutes after administration of the test compound.
G. Results
1. In vitro
The IC50 for each of the compounds of the preceding Examples for ETA and ETB receptors has been measured. Almost all of the compounds have an IC50 of less than 10 μM for either or both of the ETA and ETB receptors. Many of the compounds have an IC50 less than about 10 μM, others have an IC50 less than about 1 μM and some of the compounds have an IC50 less than about 0.1 μM. A number of the compounds have an IC50 for ETA receptors that is substantially less (10 to 100-fold or more) than for ETB receptors, and, thus are selective for ETA receptors. Others of the compounds are ETB selective.
2. In vivo a. Selected compounds, such as N-(4-chloro-3-methyl-5- isoxazolyl)-2-(N-(4-methyl-phenyl)aminocarbonyl)thiophene-3-sulf onamide, N-(4-bromo- 3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4,-methylenedioxy)benzyl)benzo[b]thiophene-3- sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[j#-hydroxy(3,4-methylenedioxy)- phenylethyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamideand N-(4-chloro-3-methyl- 5-isoxazolyl)-2-(3,4-methylenedioxybenzylcarbonyl)thiophene-3-sulf onamide, have been tested in the hypertensive rat model, and were effective in decreasing blood pressure. b. Selected compounds, such as N-(4-chloro-3-methyl-5- isoxazolyl)-2-{[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulf onamide, N-(4-chloro- 3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thio- phene-3-sulf onamide, N-(4-chIoro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methyl- phenyl)aminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazoly))-2-[2- cyano-4, 5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide, and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mide have been tested in the autonomically blocked, normotensive rat model and shown to have substantial activity, reducing pressure about 30% in 30 min at dosages as low as 30 mg/kg, and more than 50% at dosages of 60 mg/kg. On the average dosages of 30-60 mg/kg of the test compound resulted in a 40-60% inhibition of pressor response.
Since modifications will be apparent to those of skill in this art, it is intended that this invention be limited only by the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A method of treating, preventing, or ameliorating one or more symptoms of laminitis, comprising administering to a hooved animal an effective amount of an endothelin receptor antagonist or a veterinarily acceptable derivative thereof.
2. The method of claim 1 , wherein the laminitis is equine or bovine laminitis.
3. The method of claim 1 or claim 2, further comprising administering an effective amount of (i) a nitric oxide synthase substrate; or (ii) a nitric oxide donor.
4. The method of claim 3, wherein: the nitric oxide synthase substrate is L-arginine; and the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1 , isosorbidmononitrate or isosorbiddinitrate.
5. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is a sulfonamide or a veterinarily acceptable derivative thereof.
6. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is a sulfonamide compound of formula II:
Figure imgf000287_0001
or a veterinarily acceptable derivative thereof, wherein, R1 and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or, (ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl; Ar2 selected from: alkyl.
Figure imgf000288_0001
wherein n is 0 to 10, X is 0, S or NR11, where R11, which is hydrogen or contains up to about 30 carbon atoms, and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11 , R12, R15 and R16 are optionally further substituted with the any of the groups set forth for Z; R3, R4, R5, R6 and R7 are each selected independently from (i)-(iv):
(i) R3, R4, R5, R6 and R7 are each selected independently from among H, NHOH, NH2, N02, N3, aminoalkyl, alkylamino, dialkylamino, carboxyl, carbonyl, hydroxyl, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heterocycle, alkoxy, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylalkoxy, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, haloalkoxy, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido in which each of the preceding groups are unsubstituted or substituted with groups such as H, NH2, N02, alkyl, halide, and pseudohalide; or, alternatively, (ii) R4 and R7 together are substituted or unsubstituted 1 , 3-butadienyl, 1-chloro- 1 , 3-butadienyl, 4-dimethylamino-1 , 3-butadienyl, 1 -aza-1 , 3-butadienyl or 2-aza-1 ,3- butadienyl groups; and R3, R5 and Rδ are as defined in (i) above; or alternatively, (iii) R7 and R3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadienyl, 1 -chloro-1 , 3-butadienyl, 1 -aza-1 ,3-butadienyi or 2-aza- 1 , 3-butadienyl groups; and R4, R5 and R6 are as defined in (i) above; or alternatively, (iv) R3, R5, and R7 are H; and R4 and R6 are each independently selected from alkyl, alkoxy, halide, amino and aminoalkyl; and
R8, R9, R10 are each independently selected as follows from (i) or (ii): (i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, C02R18, SH, S(0)nR18 in which n is 0-2, HNOH, NR1SR19, N02, N3, OR18, R19NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is is halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R2\ N02, N3, OR21, R22NC0R21 and C0NR 2R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, that is unsubstituted or substituted with one or more substituents in each each substituent is independently selected from Z; and the other of R8, R9 and R10 is selected as in (i).
7. The method of claim 6 in which Ar2 is selected from alkyl, naphthyl, biphenyl, and phenyl.
8. The method of claim 6 in which Ar2 is selected from thienyl, furyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl and pyrrolidinyl.
9. The method of claim 6 or claim 7, wherein Ar2 is naphthyl, phenyl or biphenyl, and the compounds have the formulae:
Figure imgf000290_0001
in which n is 0 to 10; R3, R4, R5, R6, and R7 are selected from (i), (ii), (iii) or (iv):
(i) R3, R4, R5, R6, and R7 are each selected independently from among H, NHOH, NH2, N02, N3, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, and the aryl portions contain from 3 up to about 10 carbons; or, alternatively,
(ii) R4 and R7 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R3, R5 and R6 are as defined in (i) above; or alternatively,
(iii) R7 and R3 together are substituted or unsubstituted 1 , 3-butadienyl, 4- dimethylamino-1 ,3 butadiene, 1 -chloro-1 ,3-butadiene, 1 -aza-1 , 3-butadienyl or 2-aza- 1 , 3-butadienyl groups; and R4, R5 and R6 are as defined in (i) above; or
(iv) R3, R5, and R7 are H; and R4 and R6 are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, and are straight or branched chains.
10. The method of any one of claims 6, 7 or 9 in which Ar2 is phenyl and biphenyl and the compound has the formulae (XII):
Figure imgf000290_0002
wherein:
R3, R5 and R7 are each independently (a) hydrogen, except that at least one of R3, RB and R7 is other than hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W1, W2 and W3, except that if one of R3, RB are R7 is alkyl at the 4 position, at least one of the other two of R3, R5 are R7 is not hydrogen;
(c) halo;
(d) hydroxyl; (e) cyano;
(f) nitro, except that if one of R3, R5 and R7 is 4-N02, then at least one of the other two of R3, R5 and R7 is not hydrogen;
(g) -C(0)H or -C(0)R27; (h) -C02H or -C02R27; (i) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-0R27, -0-S(0)m0H, or -O-
S(0)m0R27; (j) -W4NR28R29, except that, if one of R3, RB and R7 is 4-W NR28R29 then at least one of the other two of R3, RB and R7 is not hydrogen; or (k) -W4N(R32)-WBNR30R31;
R1 and R2 are selected from (i) or (ii) as follows: (i) R1 is halide or is higher alkyl;
R2 is selected from: (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W\ W2 and W3;
(c) hydroxyl;
(d) cyano; (e) nitro;
(f) -C(0)H or -C(0)R27;
(g) -C02H or -C02R27;
(h) -SH, -S(0)nR27, -S(0)m-0H, -S(0)m0R27, -0-S(0)m-R27, -0-S(0)m0H, or -0-S(0)m-0R27; (i) -W4-NR28R29; or
(j) -W4N(R32)-WB-NR30R31; or
(ii) R1 and R2 are each independently selected from:
(a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, aryloxy, aralkyl, or aralkoxy, any of which may be substituted with W\ W2 and W3;
(c) hydroxyl;
(d) cyano; (e) nitro;
(f) -C(0)H or -C(0)R27;
(g) -C02H or -C02R27;
(h) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m0R27, -0-S(0)m-R27, -0-S(0)mOH, or -0-S(0)m-0R27; (i) -W -NR28R29;
(j) -W4N(R32)-W5-NR30R31; or
(k) halo;
R27 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3; R28 is
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W , W2 and W3; (c) cyano;
(d) hydroxyl;
(e) -C(0)H or -C(0)R27;
(f) -C02R27;
(g) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)m-R27, -Q-S(0)mOH, or -0-S(0)m-QR27, except when W4 is -S(0)n-;
R29 is
(a) hydrogen;
(b) -C(0)H or -C(0)R27, except when W4 is -C(O)- and R28 is -C(0)H, C(0)R27, or -C02R27; (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; or R28 and R29 together are alkylene or alkenylene (either of which may be substituted with W1, W2 and W3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
R30 is
(a) hydrogen; (b) hydroxyl;
(c) -C(0)H or -C(0)R27;
(d) -C02R27;
(e) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)m-R27, -0-S(0)m0H, or -0-S(0)m-0R27; (f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; R31 is
(a) hydrogen; (b) -C(0)H or -C(0)R27, except when W5 is -C(O)- and R30 is -C(0)H, -
C(0)R27, or -C02R27; or (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3; R32 is
(a) hydrogen;
(b) hydroxyl
(c) -C(0)H, -C(0)R27 or C02R27; or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; or any two of R30, R31 and R32 together are alkylene or alkenylene (either of which may be substituted with W\ W2 and W3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
W\ W2 and W3 are each independently (a) hydrogen; (b) halo;
(c) hydroxy;
(d) alkyl;
(e) alkenyl;
(f) aralkyl; (g) alkoxy;
(h) aryloxy;
(i) aralkoxy;
(j) -SH, -S(0)nW6, -S(0)m-OH, -S(0)m-OW6, -0-S(0)m-W6,
-0-S(0)mOH, or -0-S(0)m-OW6; (k) oxo;
(I) nitro;
(m) cyano;
(n) -C(0)H or -C(0)W6;
(o) -C02H or -C02W6; (p) -W4-NW7W8;
(q) W4-N(W11)-W5-W6; or
(r) -W4-N(W1 )-W5-NW7W8;
W4 and W5 are each independently
(a) a single bond; (b) -W9-S(0)n-W10-;
(c) -W9-C(0)-W10-;
(d) -W9-C(S)-W10-;
(e) -W9-0-W10-;
(f) -W9-S-W10-; or (g) -W9-0-C(0)-W10-;
W6, W7 and W8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or W7 and W8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
W9 and W10 are each independently a single bond, alkylene, alkenylene, or alkynylene; W11 is
(a) hydrogen;
(b) hydroxyl;
(c) -C(0)H, -C(0)W6 or -C02W6;
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl; or any two of W7 and W8 and W11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated, or aromatic ring together with the atoms to which they are attached; m is 1 or 2; and n is 0, 1 , or 2.
1 1 . The method of any one of claims 6, 7, 9 or 10 in which Ar2 is unsubstituted or substituted biphenyl group of formula (XIV):
Figure imgf000295_0001
in which each ring has one or more substituents each selected independently from R26 and R13 where:
(i) R26 and R13 are independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or
(ii) R26 and R13 together are -CH2-, -CH = CH-, O, S, NR11.
12. The method of claim 6, wherein the compound has formulae (XI):
Figure imgf000296_0001
which is substituted with R4, RB and R6 which are selected independently, with the proviso that at least one of R4, R5 and R6 is not hydrogen:
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3; (c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) -C(0)H or -C(0)R27; (h) -C02H or -C02R27;
(i) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-0R27, -0-S(0)m-R27, -O-
S(0)mOH, or -0-S(0)m-OR27; (j) -W4-NR28R29, or
(k) -W4-N(R32)-WB-NR30R31 ; R1 and R2 are selected from (i) or (ii) as follows:
(i) R1 is halide or higher alkyl;
R2 is
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3;
(c) hydroxyl;
(d) cyano; (e) nitro;
(f) -C(0)H or -C(0)R27;
(g) -C02H or -C02R27;
(h) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)m-R27, -O- S(0)mOH, or -0-S(0)m-OR27;
(i) -W4-NR28R27; or
(j) -W -N(R32)-W6-NR30R31; or
(ii) R1 and R2 are each independently selected from
(a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3;
(c) hydroxyl;
(d) cyano; (e) nitro;
(f) -C(0)H or -C(0)R27;
(g) -C02H or -C02R27;
(h) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-S(0)m-R27, -0-
S(0)m0H, or -0-S(0)m-0R27; (i) -W4-NR23R27;
(j) -W -N(R32)-W6-NR30R31; or
(k) halo;
R27 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3, R28 is
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; (c) cyano;
(d) hydroxyl;
(e) -C(0)H or -C(0)R27;
(f) -C02H or -C02R27; (g) -SH, -S(0)nR27, -S(0)m-0H, -S(0)m-OR27, -0-S(0)m-R27, -O-
S(0)mOH, or -0-S(0)m-OR27, except when W4 is -S(0)n-; R29 is
(a) hydrogen; (b) -C(0)H or -C(0)R27, except when W4 is -C(O)- and R28 is -C(0)H, -
C(0)R27, -C02H, or -C02R27, (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3, or R28 and R29 together are aklylene or alkenylene (either of which may be substituted with W\ W2 and W3), completing 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; R30 is
(a) hydrogen; (b) hydroxyl;
(c) -C(0)H or -C(0)R27;
(d) -C02H or -C02R27;
(e) -SH, -S(0)nR27, -S(0)m-OH, -S(0)m-OR27, -0-:S(0)m-R27, -O- S(0)m0H, or -0-S(0)m-0R27; (f) alkyl, alkynyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; R31 is
(a) hydrogen; (b) -C(0)H or -C(0)R27, except when W6 is -C(0)- and R30 is -C(0)H, -
C(0)R27, -C02H, or -C02R27; (c) alkyl, alkenyl, alkenyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W1, W2 and W3;
R3 is
(a) hydrogen;
(b) hydroxyl, C02R27 or C02H, except when one of R30 and R31 is hydroxyl, C02R27 or C02H;
(c) -C(0)H or -C(Q)R27; or (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; or any two of R30, R31 and R32 together are alkylene or alkenylene (either of which may be substituted with W1, W2 and W3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
W1, W2 and W3 are each independently (a) hydrogen; (b) halo;
(c) hydroxy;
(d) alkoxy;
(e) -SH, -S(0)nW6, -S(0)m-OH, -S(0)m-OW6, -0-S(0)m-W6, -0-S(0)mOH, or -0-S(0)m-OW6; (f) oxo;
(g) nitro;
(h) cyano;
(i) -C(0)H or -C(0)W6;
(j) -C02H or -C02Wβ; or (k) -NW7W8, -C(0)NW7W8, or -S(0)nW7W8;
W4 and W5 are each independently
(a) a single bond;
(b) -S(0)n-; (0 -C(O)-; (d) -C(S)-; or
(e) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, any of which may be substituted with W\ W2 and W3; W6, W7 and W8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycioalkenylalkyi, aryl, or aralkyl, or W7 and W8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached; m is 1 or 2; and n is 0, 1 , or 2.
13. The method of claim 6 or claim 8, wherein the compound has formulae III:
Figure imgf000300_0001
in which R1, R2, are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon atoms, and the aryl portions contain from about 4 to about 14 carbons, except the R2 is not halide, pseudohalide or higher alkyl; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl; and X is O, S, N or NR11, where R11, which is hydrogen or contains up to about 30 carbon atoms, preferably 1 to 16 carbon atoms, and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R1B and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R1 and R 5 are are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z; and
R8, R9, R10 are each independently selected as follows from (i) or (ii): (i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, C02R18, SH, S(0)nR18 in which n is 0-2, HNOH, NR18R19, N02, N3, OR18, R 9NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl or ureido; and any of the groups set forth for R8, R9 and 10 are unsubstituted or substituted with any substituents set forth for Z, which is is halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21 , R22NCOR21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is unsubstituted or substituted with one or more substituents in each each substituent is independently selected from Z; and the other of R8, R9 and R10 is selected as in (i).
14. The method of claim 13, wherein X is S.
1 5. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is a sulfonamide of formula I: Ar2— SO N- Ar1
H (D or a veterinarily acceptable derivative thereof, wherein:
Ar1 is a five or six membered aromatic or heteroaromatic ring, or is a bicyclic or tricyclic carbon or heterocyclic ring;
Ar2 is either (i) or (ii):
(i) Ar2 has formula (XIV):
Figure imgf000302_0001
wherein: Ar2 is substituted with one or more than one substituent, each of which is selected independently from the selections set forth for R26 and R13, in which R26 and R13 are each independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons, with the proviso that if there is only one R13, it is not hydrogen; or
(ii) Ar2 has formula IV:
Figure imgf000302_0002
in which X is S, 0 or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NC0R16 and C0NR 2R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R 1 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R1 B and R16 may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and R8, R9 and R10 are each independently selected as follows from (i) or (ii):
(i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, acetoxy-(CH = CH)-, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R2\ C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR2 R21 , N02, N3, OR21, R22NCOR21 and CONR22R21 ; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, with the proviso that if R8 is NR 8R19, OR18, R19NCOR18 and CONR19R18 C02R18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C{0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18 or (CH2)rR18 and R18 is an aryl group containing 5 or 6 members, then the aryl group has at least two substituents, and preferably one substituent at the 2- position relative to the linkage to the thienyl, furyl or pyrrolyl, or
(ii) any two of R8, R9 and R10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R8, R9 and R10 is selected as in (i); and the heteroatoms are NR11, O, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl, 5- halo-3-loweralkylbenzo[b]pyrrolyl.
16. The method of claim 1 5, wherein the compound has any of formulae
XVII:
Figure imgf000304_0001
wherein: X is S, O or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R B are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NC0R16 and C0NR 2R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R1 1, R12, R1B and R16 may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and
R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
(i) R9 and R10 are selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (OAC)CH = CHR18, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH *■*■= CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C *= N(OH)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)πR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R 9NC0R18 and C0NR 9R18, in which R 9 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R8 is selected from C(0)R18, (OAC)CH = CHR18, C02R18, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)-(CH2)nR18, C = N(OH)(CH2)rR18, (CH2)r(CH = CH)-NH(CH2)nR18, (CH2)rC(0)NH{CH2)nR18, C(0)(CH2)rNH(CH2)πR18, (CH2)rNH(CH2)nR18, (CH2)rR18, in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, in which R18 is aryl, preferably phenyl, with the proviso that, if R8 is (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, particularly if r is 0 and/or n is 0, and R18 is aryl, particularly phenyl, then R18 must have two or more substituents, with preferably at least one ortho substituent; where any of the groups set forth for R8, Rs and R'° are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21 , N02, N3, OR21 , R22NCOR21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z; the other of R8, R9 and R10 is selected as from the groups set forth for R9 and R10 in (i); and the heteroatoms are NR11, O, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkyl- benzo[b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl; and R1 and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or,
(iii) R and R2 together form 1 , 3-butadienyl.
17. The method of claim 1 5, wherein Ar1 is an isoxazolyl, a thiazolyl, a pyrimidinyl, a pyridazinyl or a phenyl group.
18. The method of any one of claims 15 to 17, in which Ar2 formula IVA or IVB:
Figure imgf000307_0001
wherein:
X is NR11, O, or S; R8 is selected from among (CH2)rC(0)(CH2)nR18, (CH2)rNH(CH2)nR18,
(CH2)rNH(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)r(CH *= CH)sNH(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, with the proviso that if R8 is (CH2)rC(0)NH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, or (CH2)rR18, and R18 is phenyl, the phenyl group is substituted at least two positions; and R9 and R10 are independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (0AC)CH = CHR18, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)r(CH = CH)-NH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NC0R18 and C0NR 9R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl.
19. The method of any one of claims 1 5 to 18, wherein Ar2 is phenylamino- carbonylthienyl, phenylaminocarbonylfuryl, phenylaminocarbonylpyrrolyl, phenyl- acetylthiophene, phenylacetylfuran, phenylacetylpyrrole, acetoxystyrylthiophene, acetoxystyrylfuran or acetoxystyrylpyrrole, with the proviso that, when Ar2 is a phenylaminocarbonylthienyl, phenylaminocarbonylfuryl, aminocarbonylpyrrolyl, the phenyl group is substituted with at least two substitutents selected from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NC0R21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl.
20. The method of any one of claims 1 5 to 19, wherein Ar2 has formula XIX:
Figure imgf000308_0001
wherein:
M is (CH2)mC(0)(CH2)r, (CH2)mC(0)NH(CH2)r, CH(OH)(CH2)r,
(CH2)m(CH = CH)(CH2)r, (CH2)mC(0)(CH2)sNH(CH2)r, (CH2)m(CH = CH)(CH2)r, C = N(OH)(CH2)r, (CH2)mC(0)(CH = CH)sNH(CH2)r, CH(CH3)C(0)(CH2)r,
CH(CH3)C(0)(CH2) CH = CH)(CH2)r, (CH2)r, (CH2)r0, C(0)0, in which m,s and r are each independently 0 to 6, preferably 0 to 3;
R81 , R52, R53, R54 and R55 are each independently selected from
(i) or (ii) as follows: (i) R51, R52, R53, R54 and R55 are each independently selected from among H, OH, NHR38, C0NR38R39 , N02, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy and formyl; or 5 (ii) at least two of R51, R52, R53, R54 and R55, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R51, R52, R53, R54 and R55 are selected as in (i); and
10 R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl, with the proviso that when M is (CH2)mC(0)NH(CH2)r, then at least two of R51, R52, R53, R54 and R55 are not hydrogen.
15 21 . The method of any one of claims 15 to 20, wherein Ar2 has formula XX:
Figure imgf000309_0001
25 in which W is CH2 or NH.
22. The method of claim 20, wherein M is selected from
Figure imgf000309_0002
23. The method of any one of claims 15 to 18, wherein R9 and R10 form a 35 ring so that Ar2 is benzo[b]thienyl, benzo[b]furyl, or indolyl, with the proviso that there is one or more substituent and they are other than 5-halo and 3-loweralkyl, and the other of R8, R9 and R10 is selected from aryl, (CH2)rR18, C(0)R18, C02R18, NR18R19, SH, S(0)nR18 in which n is 0-2, HNOH, N02, N3, OR18, R 9NC0R18 and C0NR19R18.
24. The method of claim 23, wherein the compound is selected from among N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-benzylbenzo[b]thiophene-3-sulfonamide; N-(4- bromo-3-methyl-5-isoxazolyl)-2-butylbenzo[b]thiophene-3-sulfonamide; N-(4-bromo-3- methyl-5-isoxazolyl)-2-/-propylbenzo[b]thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5- isoxazolyl)-2-(4-ethylbenzyl)benzo[b]thiophene-3-sulfonamide;
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3- sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]- thiophene-3-sulf onamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5- methylbenzo[b]thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazoly))-2-[(3,4- methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide; N-(4-bromo~3-methyl-5- isoxazolyl)-2-(3,4-dimethoxybenzyl)benzo[b]thiophene-3-sulf onamide; N-(4-bromo-3- methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamide; N-(4-bromo-3- methyl-5-isoxazolyl)-2-(4-methoxybenzyl)benzo[b]thiophene-3-sulf onamide; N-(4-bromo- 3-methyl-5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide; N-(3,4- dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)benzo[b]thiophene-3-sul- f onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3-sulfonamide; N-(4- chloro-3-methyl-5-isoxazolyl)-2-phenylbenzo[b]thiophene sulfonamide; N-(4-chloro-3- methyI-5-isoxazolyl)-6-methoxy-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sul- f onamide; and N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]- benzo[b]thiophene-3-sulf onamide.
25. The method of claim 15, wherein Ar2 is thienyl.
26. The method of claim 15, wherein Ar2 is furyl.
27. The method of claim 15, wherein Ar2 is pyrrolyl.
28. The method of claim 1 5, wherein Ar2 is biphenyl.
29. The method of claim 28, wherein the compound has formula XV:
Figure imgf000310_0001
wherein Ar2 is substituted with one or more than one substituent, each of which is selected independently from the selections set forth for R26 and R13, and R26 and R13 are each independently selected from H, loweralkyl, haloalkyl and halide.
30. The method of claim 28, wherein the compound is selected from among N-(4-bromo-3-methyl-5-isoxazolyl)-4'-methylphenyl-4-biphenylsulf onamide, (4-bromo-3- methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsulfonamide, N-(4-bromo-3-methyl-5- isoxazolyl)-4'-methoxyphenyl-4-biphenylsulf onamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 3'-methoxyphenyl-4-biphenylsulf onamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2'- methoxyphenyl-4-biphenylsulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-3',4'- methylenedioxyphenyl-4-biphenylsulf onamide.
31 . The method of claim 28 or claim 29, wherein the compound is N-(4- bromo-3-methyl-5-isoxazolyl)-4'-methylphenyl-4-biphenylsulfonamide or N-(4-bromo-3- methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsulfonamide.
32. The method of claim 1 5, wherein the compound is a (phenyl- acetyDthiophenesulfonamide.
33. The method of claim 15, wherein the compound is selected from among N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene- 3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)phenoxycarbonyl]thiophene-3-sulf onamide, N-(4-bromo-3-methyl-5- isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3- methyl-5-isoxazolyl)-{2-[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulf onamide oxime, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocar- bonyl]thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylphenyl)- thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hydroxy-4- methylphenyl)aminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-{[2-cyano-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenyl- aminocarbonyl]thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4- dimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (2,4-dimethylphenylacetyl)thiophene-3-sulf onamide, N-(4-bromo-3-methyl-5-isoxazolyD- 2-(2,4-dimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)]phenylaminocarbonyl-3-thiophenesulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxy- ethyl)phenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3- sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethylphenylacetyl)thiophene- 3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methanesulfonylaminomethyl)- 4,5-(methylenedioxy)phenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-cyanomethyl-4,5-(methylenedioxy)-6-cyanomethyl]- phenylaminocarbonyl-3-thiophenesulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- hyroxyproyl-4,5-(methylenedioxy)phenylaminocarbonyl]thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-{2-[(dimethylamino)carbonylmethyl]-4,5-(methylene- dioxy)phenylaminocarbonyl}thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[^-acetoxy-2-methyl-4,5-(methylenedioxy)styryl]thiophene-3-sulf onamide, N-(4-chloro- 3-methyl-5-isoxazolyl)-2-[(2,3,4-trimethoxy-6-cyano)phenylaminocarbonyl]thiophene-3- sulf onamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-propylphenyl)thiophene-2- sulf onamide, N-(3,4-dimethyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)- phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6- trimethylphenylaminocarbonyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(2,4,6-trimethylphenylacetyl)thiophene-3-sulf onamide, N-(4-chloro-5- methyl-3-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3- sulf onamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)cinnamyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)- 2-(2,4-dimethylphenethyl)thiophene-3-sulfonamide and N-(4-chloro-3-methyl-5-isoxa- zolyl)-2-[(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl]thiophene-3- sulfonamide or any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl- 3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo- 3-methyl-5-isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivative of any of these compounds.
34. The method of claim 1 5, wherien the compound is selected from among N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenylamino- carbonyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2,3,4- trimethoxy-6-acetylphenylaminocarbonyl)thiophene-3-sulf onamide,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methoxycarbonyl- phenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (2, 3,4-trimethoxy-6-carboxylphenylaminocarbonyl)thiophene-3-sulf onamide, N-(4-chloro- 3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methanesulfonylphenylaminocarbonyl)thio- phene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6- (cyanomethyl)phenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulf- onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6- methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-acetylphenylaminocarbonyl]thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6- methoxycarbonylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylaminocarbonyl]thio- phene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2- methoxy-6-methanesulfonylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro- 3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-cyanophenylamino- carbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-2-methoxy-6-cyanomethylphenylaminocarbonyl]thiophene-3-sulfona- mide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(2- hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulf- onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2- methylphenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxycarbonyl-2- methylphenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-6-carboxyl-2-methylphenylaminocarbonyl]thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2- methylphenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonyl-2-methylphenyl- aminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-cyano-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(cyanomethyl)-2-methylphenyl- aminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-cyano-6- methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-cyanophenylaminocarbonyl]thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyI)-2-[3,4-(methylenedioxy)-2-acetyl-6- methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-acetylphenylaminocarbonyl]thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazoIyl)-2-(3-cyano-2,4,6-trimethyl- phenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- carboxyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3- methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene- 3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6- trimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfona- mide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6- trimethylphenyiaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[3-(carboxylmethyl)-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulf- onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6-dimethylphenylaminocar- bonyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6- dimethylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-[4-(hydroxymethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl)-2,6-dimethylphenylamino- carbonyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4- (cyanomethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulf onamide, N-(4-chloro- 3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2,6-dimethylphenylaminocarbonyl]thio- phene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6- dimethylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenylacetyl)thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-acetylphenylacetyl)thiophene-3-sulf- onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6- methoxycarbonylphenylacetyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5- isoxazolyl)-2-(2, 3, 4-trimethoxy-6-carboxylphenylacetyl)thiophene-3-sulf onamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methanesulfonylphenylacetyl)thio- phene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6- (cyanomethyl)phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)- 2-[2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6- methylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-2-methoxy-6-acetylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro- 3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonyl- phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-2-methoxy-6-carboxylphenylacetyl]thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy-2-methoxy-6-methane- sulfonyl)phenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- [3,4-{methylenedioxy)-2-methoxy-6-(cyano)phenylacetyl]thiophene-3-sulf onamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(cyanomethyl- phenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2,6- dimethylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- [3, 4-(methylenedioxy)-6-acetyl-2-methylphenylacetyl]thiophene-3-sulf onamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxycarbonyl-2- methylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-carboxyl-2-methylphenylacetyl]thiophene-3-sulfonamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2- methylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-methanesulfonyl-2-methylphenylacetyl]thiophene-3-sulf onamide, N- (4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano-2- methylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-(cyanomethyl)-2-methylphenylacetyl]thiophene-3-sulf onamide, N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2- methylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-2-cyano-6-methylphenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3- methyi-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-cyanophenylacetyl]thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-acetyl-6- methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- (methylenedioxy)-6-methoxy-2-acetylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro- 3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylacetyl)thiophene- 3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6- trimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- methanesulfonyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3- methyl-5-isoxazolyl)-2-[3-(cyanomethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfon- amide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6-trimethylphenyl- acetyl]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3- (carboxylmethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3- methyl-5-isoxazolyl)-2-(4-cyano-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6-dimethylphenylacetyl)thiophene-3-sul- f onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-hydroxymethyl-2,6- dimethylphenylacetyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4- (2-hydroxyethyl)-2,6-(dimethyl)phenylacetyl]thiophene-3-sulf onamide, N-(4-chloro-3- methyl-5-isoxazolyl)-2-[4-cyanomethyl-2,6-(dimethyl)phenylacetyl]thiophene-3-sulfona- mide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2,6- dimethylphenylacetyl]thiophene-3-sulf onamide, and
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6-dimethylphenylacetyl)thio- phene-3-sulfonamide or any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5- methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N- (4-halo-3-methyl-5-isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivative of any of these compounds.
35. The method of claim 15, wherein the compound is selected from among N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-(4-methyl-phenyl)aminocarbonyl)thiophene-3-sul- f onamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]ben- zo[b]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4,-methylene- dioxy)benzyl)benzo[b]thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[ ?- hydroxy(3,4-methylenedioxy)phenylethyl]thiophene-3-sulfonamide and N-(4-chloro-3- methyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzylcarbonyl)thiophene-3-sulfonamide or any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N- (3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5- isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivative thereof.
36. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is a sulfonamide of formula (V):
Figure imgf000317_0001
or the corresponding 2-sulfonamides, or a veterinarily acceptable derivative thereof, wherein:
Ar1 is a substituted or unsubstituted monocyclic or polycyclic aryl group with one or more substituents, selected from the group consisting of H, NH2, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons;
R51, R53, R54 and R5B are each independently selected from (i) or (ii) as follows: (i) R5 , R53, R54 and R55 are each independently selected from among H, OH,
NHR38, CONR38R39 , NOz, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (aikyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, lower alkyl, CN, — (CH2)xC(0)(CH2)x, -(CH2)X, (CH2)XN- lower alkyl, — (CH2)xC(0)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, — S(0)2NH2, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, -(CH2)xCOOH; -(CH2)xCOOH-, C02-lower alkyl, CN, heteroaryl, -COC(0)(CH2)xCH3, -(CH2)XN(CH3)2, a sulfonyl chloride, S(0)2NHR50, alkylaryl, alkylheteroaryl, C(O)NHRB0, -(CH2)xOH, -C(0)N(H)N(H)M, or; (ii) at least two of R51, R53, R54 and RδS, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R51, R53, R54 and R55 are selected as in (i); R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl.
37. The method of claim 36, wherein:
Ar1 is benzo-2, 1 ,3-thiadiazol-5-yl, benzo-2, 1 ,3-oxadiazol-5-yl, 3-methoxy-2- pyrazinyl, 3,4-dimethyl-5-isoxazolyl, 4-chloro-3-methyl-5-isoxazolyl or 4-chloro-5-methyl- 3-isoxazolyl;
W is -NH-, =NC02R16, or is -CH2- when R9 is hydroxyl; RB1, R53 and R65 are methyl; and
RB4 is selected from the group consisting of Z-substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, OC(0)R16, 0C02R16, NR12R16 and S(0)nR16 in which n is 0-2.
38. The method of claim 36 or claim 37, wherein R54 is selected from the group consisting of methoxy, methoxycarbonylmethoxy, 2-(2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxy, hydroxy, cyanomethyl, acetoxymethyl, hydroxymethyl, carboxylmethyl, methanesulfonylamino, N,N-dimethylaminomethyl, S02NH2, and methoxycarbonylmethyl.
39. The method of any one of claims 36 to 38, wherein the sulfonamide or veterinarily acceptable derivative thereof is selected from the group consisting of: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-pyrrolidinyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-dimethylamino-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N-dimethylthiocarbonyloxymethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N-dimethylthiocarbonyloxy)- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethoxy)-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-(2-methoxyethoxy)ethoxy)acetoxy-
2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyImethoxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethyl- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-dimethylaminomethyl- 2,4, 6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonylamino- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulf onamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-methoxycarbonylmethyl-
2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-dimethylaminomethyl- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-methanesulfonylamino- 2, 4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-methoxycarbonylmethyl- 2,4, 6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulf onamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulf onamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-dimethylaminomethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-methanesulfonylamino-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3,4-dimethyl-5-isoxazolyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-(benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-methoxycarbonylmethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;
N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-carboxylmethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulf onamide; N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide;
N-(benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide;
N-(benzo-2, 1 ,3-thiadiazol-5-yl)-2-{3-dimethylaminomethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide;
N-(benzo-2, 1 ,3-thiadiazol-5-yl)-2-(3-methanesulfonylamino- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide;
N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-carboxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-cyano-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(benzo-2,1 ,3-thiadiazol-5-yl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-methoxycarbonylmethyl-2,4,6-trimethyIphenyl- aminocarbonyl)thiophene-3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-dimethylaminomethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-methanesulfonylamino-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(3-cyano-2,4,6-trimethylphenylaminocarbonyl)thio- phene-3-sulf onamide;
N-(3-methoxy-2-pyrazinyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulf onamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(1 -methyl-1 -phenyl-1 -ethylaminocar- bonyl)thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-((R)-1 -phenyl-1 -ethylaminocarbonyDthio- phene-3-sulf onamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-((S)-1 -phenyl-1 -ethylaminocarbonyDthio- phene-3-sulfonamide; and veterinarily acceptable derivatives thereof.
40. The method of any one of claims 36 to 38, wherein the sulfonamide or veterinarily acceptable derivative thereof has formula VI:
Figure imgf000322_0001
wherein: X is S, 0 or NR11 ; each G and R is independently selected from lower alkyl, CN, -(CH2)xC(0)(CH2)x, -(CH2)X, (CH2)xN-lower alkyl, -(CH2)xC(0)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, — S(0)2NH2, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, — (CH2)xCOOH; — (CH2)xCOOH-, C02- lower alkyl, CN, heteroaryl, -COC(0)(CH2)xCH3, -(CH2)XN(CH3)2, a sulfonyl chloride, S(0)2NHR60, alkylaryl, alkylheteroaryl, C(O)NHRB0, -(CH2)xOH, -C(0)N(H)N(H)M;
R50 is hydrogen, lower alkyl, or lower alkoxy;
M is H or R50; R' is independently! selected from hydrogen, G and R;
W is = C(halo)2, = N(H), -(CH2)X-, =N(lower alkyl), -C(O)-, =C(lower alkyl)2; and each x is independently is 0-3.
41 . The method of claim 40, wherein Ar1 is isoxazolyl.
42. The method of claim 40 or claim 41 , wherein:
W is = CH2, = NH, = NCH3, = NCH2CH3, = C(CH3)2 or CF2; and
G is -CH3, -CN, -C0CH3, -CH2CH3, -(CH2)xC02H.
43. The method of any one of claims 40 to 42, wherein the sulfonamide or veterinarily acceptable derivative thereof is selected from the group consisting of: N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfa- moyl)-2-thiophenecarboxamide; methyl-2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfa- moyl)-2-thienylcarboxamido)-2,4,6-trimethyiphenyl)acetate;
2-{3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6- trimethylphenyDacetic acid;
N2-(3-acetyloxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxa- zolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-dimethylaminomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-
3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide trifluoroacetate;
N2-(3-(4,5-dihydro-1 ,3-oxazol-2-yl)-2,4,6-trimethylphenyl)-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyl- carboxamido)-2,4,6-trimethylbenzoic acid;
N-[3-(3-(4-ch)oro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-2,4,6-trimethylbenzoyl]glutamic acid; N-[3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-2,4,6-trimethylbenzoyl]aspartic acid;
N-[2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 2,4,6-trimethylphenyl)acetyl]glutamic acid;
N-[2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-2,4,6-trimethylphenyl)acetyl]aspartic acid;
N2-(3-cyano-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thio- phenecarboxamide;
2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcar- boxamido)-2,4,6-trimethylphenoxy)acetic acid; N2-(3-alkyIsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-arylsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N -(3-sulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl- 5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-alkylsulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-arylsulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-(1 H-1 ,2,3,4-tetraazol-5-ylmethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-
3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-(2-pyridylmethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-hydrazinocarbonyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxa- zolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-aminomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide;
N2-(3-(a-D-mannopyranosyloxymethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4- cyano-6-methylbenzo[d][1 ,3]dioxole;
5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 6-cyano-4-methylbenzo[d][1 ,3]dioxole; 2-(5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-
4-methylbenzo[d][1 ,3]dioxole)-6-acetic acid;
5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcar- boxamido)-4-acetyl-6-methylbenzo[d][1 ,3]dioxole;
5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 6-acetyl-4-methylbenzo[d][1 ,3]dioxole;
5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-7-cyano- 4,6-dimethylbenzo[d][1 ,3]dioxole;
6-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-5,7-dimethylbenzo[d][1 ,3]dioxole-4-carboxylic acid; 7-(3-(4-chloro-3-methyl-5-isoxazo!y!sulfamoyl)-2-thienylcarbox- amido)-5,6-dimethylbenzo[d][1 ,3]dioxole-4-carboxylic acid;
7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4- cyano-5,6-dimethylbenzo[d][1 ,3]dioxole;
7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-4-acetyl-5,6-dimethylbenzo[d][1 ,3]dioxole;
7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4- carboxamido-5,6-dimethylbenzo[d][1 ,3]dioxole;
7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcar- boxamido)-4-aminomethyl-5,6-dimethylbenzo[d][1 ,3]dioxole; 7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-4-dimethylaminomethyl-5,6-dimethylbenzo[d][1 ,3]dioxole;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulf onamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- carboxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulf onamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulf onamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; and veterinarily acceptable derivatives thereof.
44. The method of claim 36 or claim 37, wherein the sulfonamide or veterinarily acceptable derivative thereof is of formula (VIII):
Figure imgf000326_0001
wherein:
W is -NH-; and
R57 is selected from the group consisting of aryl, heteroaryl, heterocycle, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, — (CH2)x0H, NHOH, NR 2R16, N02, N3, OR16, R12NCOR16 and CONR 2R1β;
R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
R12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2;
R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and each of R 2, R15 and R16 may be further substituted with the any of the groups set forth for Z.
45. The method of any one of claims 36 to 44, wherein Ar1 has formula:
Figure imgf000326_0002
in which RA and RB are either (i), (ii) or (iii) as follows:
(i) RA and RB are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, except that R2 is not halide or pseudohalide; or,
(ii) RA and RB together form -(CH2)n, where n is 3 to 6; or,
(iii) RA and RB together form 1 , 3-butadienyl.
46. The method of claim 36, wherein the compound is N2-(3-hydroxy-2,4,6- trimethyl)phenyl-3-(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl-2-thiophenecarboxamide or a veterinarily acceptable derivative thereof.
47. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is a sulfonamide of formula (I):
Ar— SOr- M- Ar1
I
H (D
where Ar1 is isoxazolyl and Ar2 has the formula:
Figure imgf000327_0001
or a veterinarily acceptable derivative thereof, wherein:
R61 and R62 are independently selected from the group consisting of hydrogen, halo, cyano, cyanoalkyl, C(0)R41, alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene; W is O, NH or CH2;
R65, R66 and R67 are each independently selected as in (i) or (ii):
(i) R66 is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,
C(0)R41, carbamoyloxy or alkoxycarbonyloxy, and R65 and R67 are each independently selected from hydrogen, unsubstituted alkyl, hydroxy, C(0)R41, carbamoyloxy and alkoxycarbonyloxy; or
(ii) if at least one of R61 and R62 is not hydrogen, then any two may form alkylenedioxy, and the other is selected as in (i);
R4B is selected from the group consisting of alkyl, C(0)R41 , (CH2)xOH and CH(OH)(CH2)xCH3 in which x is 0-6, S(0)nR41 in which n is 0-2 and C( = NR43)R41;
R41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino; and R43 is selected from hydroxy, alkoxy, alkyl and aryl, wherein
R41 and R43 are unsubstituted or substituted with one or more substituents selected from Y, which is alkoxy, halide, pseudohalide, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy.
48. The method of claim 47, wherein the sulfonamide is selected from the group consisting of:
N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,
N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyD-
4,6-dimethylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- propionylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6- dimethylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)- 4,6-dimethylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)- 4, 6-dimethylphenyl)-2 -thiophenecarboxamide, 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thienyl)carbonyl)amino)-2,4,6-trimethylphenyl carbamate,
3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thienyl)carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6- trimethylphenyl)acetyl)-3-thiophenesulf onamide,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)- 3-thiophenesulf onamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1 - methylethyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6- dimethylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4- methylphenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6- dimethylphenyl)-2-thiophenecarboxamide,
3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)- 3,5-dimethylphenyl)-3-oxopropanoic acid,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6- dimethylphenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- methylsulfonyl)phenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- ((methylamino)sulfonyl)phenyl)-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-
((dimethylamino)sulfonyl)phenyl)-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- (((methylsulfonyl)amino)carbonyl)phenyl)-2-thiophenecarboxamide,
3-({(4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6- dimethylphenyl)-2-thiophenecarboxamide,
N-(2-acetyl-4, 6-dimethylphenyl)-3-( ( (4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,
N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino sulfonyl)-N-(2-hydroxyethanimidoyl)- 4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- propionylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6- dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyD- 4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropyfcarbonyl)- 4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5- methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl carbamate,
3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5- methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6- trimethylphenyl)acetyl)-5-methyl-3-thiophenesulf onamide,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)- 5-methyl-3-thiophenesulfonamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1 - methylethyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6- dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4- methylphenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6- dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-{5- methylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoic acid,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6- dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- methylsulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- ((methylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- ((dimethylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- (((methylsulfonyDamino)carbonyl)phenyl)-5-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6- dimethylphenyl)-5-methyl-2-thiophenecarboxamide,
N-(6-acetyl-4-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,
N-(4-acetyl-6-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,
N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,
N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino_)sulfonyl)-N-(2-hydroxyethanimidoyl)-
4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- propionylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6- dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)- 4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)- 4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4- methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl carbamate,
3-({(3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4- methylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6- trimethylphenyl)acetyl)-4-methyl-3-thiophenesulf onamide,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyD- 4-methyl-3-thiophenesulf onamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1- methylethyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6- dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4- methylphenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6- dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4- methylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoic acid,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6- dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- methylsulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- ((methylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-
((dimethylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- (((methylsulfonyl)amino)carbonyl)phenyl)-4-methyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6- dimethylphenyl)-4-methyl-2-thiophenecarboxamide,
N-(6-acetyl-4-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,
N-(4-acetyl-6-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide, N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,
N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino_)sulfonyl)-N-(2-hydroxyethanimidoyD- 4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- propionylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6- dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyD- 4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)- 4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(({3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5- dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl carbamate,
3-(((3-{((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5- dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6- trimethylphenyl)acetyl)-4,5-dimethyl-3-thiophenesulf onamide,
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyD- 4,5-dimethyl-3-thiophenesulf onamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1 - methylethyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6- dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4- methylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6- dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5- dimethylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoic acid,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6- dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- methylsulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethy)-6- ((methylamino)sulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- ((dimethylamino)sulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,
3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6- (((methylsulfonyl)amino)carbonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide, 3-
(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6- dimethylphenyl)-4,5-dimethyi-2-thiophenecarboxamide, N-(6-acetyl-4-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,
N-(4-acetyl-6-methyl-1 ,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide, N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-cyclopropyl-2-thiophenecarboxamide,
5-acetyl-(N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,
N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-cyano-2-thiophenecarboxamide,
N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-(cyanomethyl)-2-thiophenecarboxamide,
N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-fluoro-2-thiophenecarboxamide, N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-chloro-2-thiophenecarboxamide, and
N-2-acetyl-4,6-dimethylphenyl)-5-chloro-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-4,5,6,7-tetrahydro-1 -benzothiophene-2-carboxamide.
49. The method of claim 47, wherein the compound is selected from the group consisting of N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide and N-(2-acetyl-4,6-dimethylphenyD- 3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide.
50. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is the sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4- (methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulfonamide also designated 4- chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulf onamide.
51. The method of any one of claims 1 to 5, wherein the endothelin receptor antagonist is selected from the group consisting of:
N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide, having the structure:
Figure imgf000335_0001
N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide, having the structure:
Figure imgf000335_0002
N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)- acetyl]-thiophene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mide, having the structure:
Figure imgf000336_0001
N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide, having the structure:
Figure imgf000336_0002
N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide, having the structure:
Figure imgf000337_0001
N-(2-acetyl-4,6-dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide, having the structure:
Figure imgf000337_0002
and veterinarily acceptable derivatives thereof.
52. The method of any one of claims 1 to 51 , wherein the endothelin receptor antagonist is a sulfonamide that is a sodium salt.
53. A method of treating, preventing, or ameliorating one or more symptoms of climacterium (climacteric symptoms), comprising administering an effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable derivative thereof.
54. The method of claim 53, further comprising administering an effective amount of a compound selected from an estrogen, a progestin and an androgen.
55. The method of claim 53, further comprising administering an effective amount of (i) a nitric oxide synthase substrate; or (ii) a nitric oxide donor.
56. The method of claim 53, further comprising administering
(i) an effective amount of a compound selected from an estrogen, a progestin and an androgen; and
(ii) an effective amount of (a) a nitric oxide synthase substrate; or (b) a nitric oxide donor.
57. The method of claim 53, wherein the climacteric symptoms are associated with menopause, osteoporosis, metabolic bone disorders, hot flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women.
58. The method of claim 53, wherein the endothelin receptor antagonist is a sulfonamide or a pharmaceutically acceptable derivative thereof.
59. The method of any one of claims 53 to 58, wherein the endothelin receptor antagonist is a sulfonamide that has formula I:
Ar2— SO N- Ar1
H (I)
or a pharmaceutically acceptable derivative thereof, wherein:
Ar1 is a five or six membered aromatic or heteroaromatic ring, or is a bicyclic or tricyclic carbon or heterocyclic ring;
Ar2 is either (i) or (ii):
(i) Ar2 has formula (XIV):
Figure imgf000338_0001
wherein: Ar2 is substituted with one or more than one substituent, each of which is selected independently from the selections set forth for R26 and R13, in which R26 and R13 are each independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons, with the proviso that if there is only one R13, it is not hydrogen; or (ii) Ar2 has formula IV:
Figure imgf000339_0001
in which X is S, O or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and C0NR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cyclo- alkyl, cycloalkenyl or cycloalkynyl; each of R11, R.12, R15 and R16 may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and R8, R9 and R 0 are each independently selected as follows from (i) or (ii): (i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, acetoxy-(CH = CH)-, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)πR18, C(0)(CH2)rNH{CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NC0R18 and C0NR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21 , C02R21 , SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21 , N02, N3, OR21, R22NC0R21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, with the proviso that if R8 is NR18R19, OR18, Rl9NCOR18 and CONR19R18 C02R18, (CH2)rNH(CH = CH)-(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18,
(CH2)rNH(CH2)nR18 or (CH2)rR18 and R18 is an aryl group containing 5 or 6 members, then the aryl group has at least two substituents, and preferably one substituent at the 2- position relative to the linkage to the thienyl, furyl or pyrrolyl, or
(ii) any two of R8, R9 and R10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R8, R9 and R10 is selected as in (i); and the heteroatoms are NR11, O, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl, 5- halo-3-loweralkylbenzo[b]pyrrolyl.
60. The method of claim 59, wherein the compound has any of formulae XVII:
Figure imgf000341_0001
wherein: X is S, 0 or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR1 B in which n is 0-2; R1B is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R B are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R 2NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl', aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R1B and R16 may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
(i) R9 and R10 are selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (OAC)CH = CHR18, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NCOR18 and CONRl9R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
R8 is selected from C(0)R18, (0AC)CH = CHR18, C02R18, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(OH)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, in which R18 is aryl, preferably phenyl, with the proviso that, if R8 is (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, particularly if r is 0 and/or n is 0, and R18 is aryl, particularly phenyl, then R18 must have two or more substituents, with preferably at least one ortho substituent; where any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21 , N02, N3, OR21 , R22NC0R21 and C0NR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or (ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z; the other of R8, R9 and R10 is selected as from the groups set forth for R9 and R10 in (i); and the heteroatoms are NR11 , 0, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkyl- benzo[b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl; and R and R2 are either (i), (ii) or (iii) as follows: (i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R and R2 together form 1 , 3-butadienyl.
61 . The method of claim 60, wherein Ar2 is thienyl.
62. The method of claim 60, wherein the compound is a (phenyl- acetyDthiophenesulfonamide.
63. The method of claim 60, wherein the compound is N-(4-chloro-3-methyl-5- isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulfonamide.
64. The method of claim 63, wherein the compound is a sodium salt.
65. The method of claim 60, wherein the compound is selected from the group consisting of:
N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; N- [[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1 ,1 '-biphenyl]-2-yl]- methyl]-N,3,3-trimethylbutanamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4- (methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulfonamide also designated 4- chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulf onamide; N-(2-acetyl-4,6- dimethylphenyl)3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide;N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide; and N-(2-acetyl-4,6- dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)suifonyl)-2-thiophenecarboxamide; and pharmaceutically acceptable derivatives thereof.
66. A method for control and management of preterm labor during pregnancy, comprising administering an effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable derivative thereof.
67. The method of claim 66, further comprising administering an effective amount of a compound that augment an inducible nitric oxide synthase (iNOS) production.
68. The method of claim 66, wherein the endothelin receptor antagonist is a sulfonamide or a pharmaceutically acceptable derivative thereof.
69. The method of any one of claims 66 to 68, wherein the endothelin receptor antagonist is a sulfonamide of formula I:
Ar— SO,- N- Ar1
I
H (I)
or a pharmaceutically acceptable derivative thereof, wherein:
Ar1 is a five or six membered aromatic or heteroaromatic ring, or is a bicyclic or tricyclic carbon or heterocyclic ring;
Ar2 is either (i) or (ii):
(i) Ar2 has formula (XIV):
Figure imgf000344_0001
wherein: Ar2 is substituted with one or more than one substituent, each of which is selected independently from the selections set forth for R26 and R13, in which R26 and R 3 are each independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons, with the proviso that if there is only one R13, it is not hydrogen; or
(ii) Ar2 has formula IV:
Figure imgf000345_0001
in which X is S, 0 or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and CONR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and R8, R9 and R10 are each independently selected as follows from (i) or (ii):
(i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, acetoxy-(CH = CH)-, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)-(CH2)nR18, (CH2)r(CH = CH)-C(0){CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, Rl9NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NC0R21 and CONR22R21 ; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, with the proviso that if R8 is NR18R19, OR18, R19NCOR18 and CONR19R18 C02R18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18 or (CH2)rR18 and R18 is an aryl group containing 5 or 6 members, then the aryl group has at least two substituents, and preferably one substituent at the 2- position relative to the linkage to the thienyl, furyl or pyrrolyl, or
(ii) any two of R8, R9 and R10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R8, R9 and R10 is selected as in (i); and the heteroatoms are NR11, 0, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl, 5- halo-3-loweralkylbenzo[b]pyrrolyl.
70. The method of claim 69, wherein the compound has any of formulae
XVII:
Figure imgf000347_0001
wherein: X is S, O or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR1 B in which n is 0-2, NHOH, NR1 R16, N02, N3, OR16, R12NC0R16 and C0NR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z, and R11 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and
R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
(i) R9 and R 0 are selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (OAC)CH = CHR18, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(OH)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)πR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR18R19, N02, N3, OR18, R19NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R 8 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R8 is selected from C(0)R18, (OAC)CH = CHR18, C02R'8, (CH2)rC(0)(CH2)nR18,
(CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)πR18, (CH2)rNH(CH = CH)-(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, in which R18 is aryl, preferably phenyl, with the proviso that, if R8 is (CH2)rC(0)NH(CH2)nR18,
C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, particularly if r is 0 and/or n is 0, and R18 is aryl, particularly phenyl, then R18 must have two or more substituents, with preferably at least one ortho substituent; where any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21 , SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21 , N02, N3, OR21, R22NC0R21 and C0NR 2R21 ; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy. cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z; the other of R8, R9 and R10 is selected as from the groups set forth for R9 and R10 in (i); and the heteroatoms are NR11, O, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkyl- benzo[b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl; and R1 and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl.
71 . The method of claim 70, wherein Ar2 is thienyl.
72. The method of claim 70, wherein the compound is a (phenyl- acetyDthiophenesulfonamide.
73. The method of claim 70, wherein the compound is N-(4-chloro-3-methyl- 5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulf onamide also designated 4-ch oro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulf onamide.
74. The method of claim 73, wherein the compound is a sodium salt.
75. The method of claim 70, wherein the compound is selected from the group consisting of N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2- sulf onamide; N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2- oxazolyl)[1 , -biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulf onamide also designated 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methy!-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-su)fonamide; N-(2-acetyl-4,6- dimethylphenyl)3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide; N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide; and N-(2-acetyl-4,6- dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide; and pharmaceutically acceptable derivatives thereof.
76. Use of an endothelin receptor antagonist for treatment, prevention, or amelioration of one or more symptoms of laminitis.
77. The use of claim 76, wherein the laminitis is equine or bovine laminitis.
78. The use of claim 76 or claim 77, further comprising use of (i) a nitric oxide synthase substrate; or (ii) a nitric oxide donor.
79. The use of claim 78, wherein: the nitric oxide synthase substrate is L-arginine; and the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1 , isosorbidmononitrate or isosorbiddinitrate.
80. The use of any one of claims 76 to 79, wherein the endothelin receptor antagonist is a sulfonamide or a veterinarily acceptable derivative thereof.
81 . The use of any one of claims 76 to 80, wherein the endothelin receptor antagonist is a sulfonamide of formula I: Ar— SO N- Ar1
Η (') or a pharmaceutically acceptable derivative thereof, wherein: Ar1 is a five or six membered aromatic or heteroaromatic ring, or is a bicyclic or tricyclic carbon or heterocyclic ring;
Ar2 is either (i) or (ii):
(i) Ar2 has formula (XIV):
Figure imgf000351_0001
wherein: Ar2 is substituted with one or more than one substituent, each of which is selected independently from the selections set forth for R26 and R13, in which R26 and R13 are each independently selected from H, OH, OHNH, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons, with the proviso that if there is only one R13, it is not hydrogen; or
(ii) Ar2 has formula IV:
Figure imgf000351_0002
in which X is S, O or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more sub- stituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl. cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and C0NR12R16; R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z, and R is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and R8, R9 and R10 are each independently selected as follows from (i) or (ii):
(i) R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, acetoxy-(CH = CH)-, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)-(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR1SR19, N02, N3, OR18, R19NC0R18 and C0NR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R10 are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NC0R21 and C0NR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, with the proviso that if R8 is NR 8R19, OR18, R 9NC0R18 and C0NR19R18 C02R18, (CH2)rNH(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sNH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18 or (CH2)rR18 and R18 is an aryl group containing 5 or 6 members, then the aryl group has at least two substituents, and preferably one substituent at the 2- position relative to the linkage to the thienyl, furyl or pyrrolyl, or
(ii) any two of R8, R9 and R10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R8, R9 and R 0 is selected as in (i); and the heteroatoms are NR11, 0, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl, 5- halo-3-loweralkylbenzo[b]pyrrolyl.
81. The use of claim 80, wherein the compound has any of formulae XVII:
Figure imgf000353_0001
wherein: X is S, 0 or NR11 in which R11 contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R15 and S(0)nR15 in which n is 0-2; R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R16, C02R16, SH, S(0)nR16 in which n is 0-2, NHOH, NR12R16, N02, N3, OR16, R12NCOR16 and C0NR12R16; R1β is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R17 and S(0)nR17 in which n is 0-2; and R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R11, R12, R15 and R16 may be further substituted with the any of the groups set forth for Z, and R1 is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and
R8, R9 and R10, which each contain hydrogen or up to about 50 carbon atoms, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
(i) R9 and R10 are selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R18, (0AC)CH = CHR18, C02R18, SH, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR13, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2)rNH(CH = CH)s(CH2)nR18, C = N(0H)(CH2)rR18, (CH2)r(CH = CH)sNH{CH2)πR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, S(0)mR18 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR 8R19, N02, N3, OR18, R19NCOR18 and CONR19R18, in which R19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R20, S(0)nR20 in which n is 0-2; and R18 and R2Q are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
R8 is selected from C(0)R18, (OAC)CH = CHR18, C02R18, (CH2)rC(0)(CH2)nR18, (CH2)r(CH = CH)s(CH2)nR18, (CH2)rC(0)(CH = CH)s(CH2)nR18, (CH2)r(CH = CH)sC(0)(CH2)nR18, (CH2).NH(CH = CH)s(CH2)nR18, C = N(OH)(CH2)rR18, (CH2)r(CH =CH)-NH(CH2)nR18, (CH2)rC(0)NH(CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, in which R18 is aryl, preferably phenyl, with the proviso that, if RB is (CH2)rC(0)NH{CH2)nR18, C(0)(CH2)rNH(CH2)nR18, (CH2)rNH(CH2)nR18, (CH2)rR18, particularly if r is 0 and/or n is 0, and R18 is aryl, particularly phenyl, then R18 must have two or more substituents, with preferably at least one ortho substituent; where any of the groups set forth for R8, R9 and R 0 eare unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R21, C02R21, SH, S(0)nR21 in which n is 0-2, NHOH, NR22R21, N02, N3, OR21, R22NCOR21 and CONR22R21; R22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R23 and S(0)nR23 in which n is 0-2; and R21 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or
(ii) any two of R8, R9 and R10 form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z; the other of R8, R9 and R10 is selected as from the groups set forth for R9 and R10 in (i); and the heteroatoms are NR11, O, or S, with the proviso that Ar2 is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkyl- benzo[b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl; and R1 and R2 are either (i), (ii) or (iii) as follows:
(i) R1 and R2 are each independently selected from H, NH2, N02, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylaikyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons; or,
(ii) R1 and R2 together form -(CH2)n, where n is 3 to 6; or, (iii) R1 and R2 together form 1 , 3-butadienyl.
82. The use of claim 81 , wherein Ar2 is thienyl.
83. The use of claim 81 , wherein the compound is a (phenyl- acetyl)thiophenesulfonamide.
84. The use of any one of claims 80 to 83, wherein the compound is N-(4- chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thio- phene-3-sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6- methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3- methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulf onamide.
85. The use of claim 84, wherein the compound is a sodium salt.
86. The use of claim 81 , wherein the compound is selected from the group consisting of N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2-sulfonamide; N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-{2- oxazolyl)[1 ,1 '-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulf onamide also designated 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulfonamide; N-(2-acetyl-4,6- dimethylphenyl)3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide; N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide; and N-(2-acetyl-4,6- dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide; and pharmaceutically acceptable derivatives thereof.
87. Use of an endothelin receptor antagonist for preparation of a medicament for treatment, prevention, or amelioration of one or more symptoms of laminitis.
88. The use of claim 87, wherein the laminitis is equine or bovine laminitis.
89. The use of claim 87 or claim 88, wherein the compound is N-(4-chloro-3- methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3- sulfonamide also designated 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5- yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide.
90. The use of claim 89, wherein the compound is a sodium salt.
91 . The use of claim 87 or claim 88, wherein the compound is selected from the group consisting of N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1 , 1 '-biphenyl]-2- sulfonamide; N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2- oxazolyl)[1 ,1 '-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide; N-(4-chloro-3-methyl-5- isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulf onamide also designated 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1 ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methγl-4,5- (methylenedioxy)phenylacetyl]thiophene-3-sulfonamide; N-(2-acetyl-4,6- dimethylphenyl)3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide; N-(2-acetyl-4,6-dimethylphenyl)3-(((4-chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide; and N-(2-acetyl-4,6- dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide; and pharmaceutically acceptable derivatives thereof.
92. Use of an endothelin antagonist for the treatment of menopausal conditions or symptoms or for treatement of preganancy-related disorders.
93. Use of an endothelin antagonist for the formulation of a medicament for the treatment of menopausal conditions or symptoms or for the treatment of preganancy-related disorders.
94. The use of claim 92 or claim 93, wherein the symptoms are one or more of osteoporosis, metabolic bone disorders, hot flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women; pre- eclampsia; and control and management of labor during pregnancy.
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