WO2004043463A2 - Sulfonamides - Google Patents

Sulfonamides Download PDF

Info

Publication number
WO2004043463A2
WO2004043463A2 PCT/US2003/035370 US0335370W WO2004043463A2 WO 2004043463 A2 WO2004043463 A2 WO 2004043463A2 US 0335370 W US0335370 W US 0335370W WO 2004043463 A2 WO2004043463 A2 WO 2004043463A2
Authority
WO
WIPO (PCT)
Prior art keywords
oxy
phenyl
chloro
bromo
methyl
Prior art date
Application number
PCT/US2003/035370
Other languages
French (fr)
Other versions
WO2004043463A3 (en
Inventor
Michael J. Neeb
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU2003287529A priority Critical patent/AU2003287529A1/en
Publication of WO2004043463A2 publication Critical patent/WO2004043463A2/en
Publication of WO2004043463A3 publication Critical patent/WO2004043463A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists
  • cardiovascular homeostasis The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
  • the principal mammalian vasoactive factors that comprise this neurohumoral axis namely angiotensin-jT, endothelin-1, norepinephrine, all function via an interaction with specific G- protein coupled receptors (GPCR).
  • GPCR G- protein coupled receptors
  • this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
  • osmoregulation effects which include the modulation of transepithelial ion (Na + , Cl ) transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
  • Urotensin-II receptor Compounds that antagonize the Urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: 131; 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction.
  • Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
  • U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, (Gartlon J. Psychopharmacology (Berl) 2001 June; 155(4):426-33), impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, parkinsons, movement disorders, sleep-wake cycle, and incentive motivation (Clark et al.Brain Research 923 (2001) 120-127. Functional U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications.
  • Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999) and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g. arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
  • diabetes Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999
  • these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
  • this invention provides for sulfonamides and pharmaceutical compositions containing them.
  • this invention provides for the use of sulfonamides as antagonists of urotensin ⁇ , and as inhibitors of urotensin ⁇ .
  • this invention provides for the use of sulfonamides for treating conditions associated with urotensin ⁇ imbalance.
  • this invention provides for the use of sulfonamides for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g.
  • pulmonary fibrosis sepsis
  • atherosclerosis dyslipidemia
  • addiction schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-IJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and c -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • Ar is phenyl substituted or unsubstituted by one or two of the following: halogen, CN, S(C!_ 6 alkyl), CF 3 , OCF 3 , SCF3, C g alkyl, C ⁇ . ⁇ alkoxy, CO ⁇ C g alkyl), or N0 2 ;
  • Y is O or S
  • Z is hydrogen, halogen, or C ⁇ . alkyl
  • R2 is hydrogen, halogen, CN, or C j.4 alkyl
  • R ⁇ is hydrogen or Cj ⁇ .g alkyl; or a pharmaceutically acceptable salt thereof.
  • alkyl includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, w ⁇ -propyl, ⁇ -butyl, sec-butyl, ⁇ o-butyl, t-butyl, n-pentyl and n-hexyl.
  • halogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.
  • Preferred substituents for Ar are halogen or C ⁇ _ alkoxy.
  • Z is preferably halogen or hydrogen.
  • R2 is preferably halogen or hydrogen.
  • Rj is preferably C ⁇ _3 alkyl.
  • Especially preferred compounds are : 5-bromo-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ phenyl)-6-[(2,3- dichlorophenyl)thio]-3-pyridinesulfonamide;
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
  • ⁇ o, s I 2 dd) phenol or thiophenol, NaH, DMF, heat; ee) phenol or thiophenol, NaH, Cs 2 C0 3 ,_DMF, heat.
  • Anline B Sulfonyl chlorides when not commercially available, can prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. /. Med. Chem. 1978, 21, 845; Huntress et al J. Amer. Chem. Soc. 1941, 63, 3446; Hashimoto, H. et al J. Med. Chem. 2002, 45, 1511; O'Brien, P. M. et al. J.Me ⁇ Chem. 2000, 43, 156; Brandish, D. J.Med.Chem. 1999, 22, 4584.
  • Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • sulphonamide analogs may be used for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g.
  • pulmonary fibrosis sepsis
  • atherosclerosis dyslipidemia
  • addiction schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-JJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and o -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmor 1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 niM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester. ⁇ 5j labeled
  • a microtitre plate based Ca 2+ -mobilization FLIPR assay (Molecular Devices, Sunnyvale, CA) was used for the functional identification of the ligand activating HEK-293 cells expressing (stable) recombinant GPR-14.
  • the day following transfection cells were plated in a poly-D- lysine coated 96 well black/clear plates. After 18-24 hours the media was aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (10 nM to 30 uM) of test compounds followed by h-U-II. After initiation of the assay, fluorescence was read every second for one minute and then every 3 seconds for the following one minute. The inhibitory concentration at 50% (IC50)was calculated for various test compounds.
  • Inositol phosphates assays Molecular Devices, Sunnyvale, CA
  • HEK-293-GPR14 cells in T150 flask were prelabeled overnight with 1 uCi myo-[ 3 H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C.
  • DPBS Dulbecco's phosphate-buffered saline
  • the experiment was initiated by the addition of increasing concentrations of h-U-II (1 pM to l ⁇ M ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation.
  • the supernatants were neutralized with lOOul of IM Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate.
  • Aniline B (1.2 g, 5.29 mmol) was dissolved in 11 mL of methylene chloride, 30 mL of carbon tetrachloride, and pyridine (0.428 mL, 5.29 mmol) and treated with a solution of 5-bromo-6- chloro-3-pyridinesulfonyl chloride (1.54 g, 5.29 mmol) dissolved in 4 mL of methylene chloride and 5 mL of carbon tetrachloride with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • 2,3-dichlorobenzenethiol (41.0 mg, 0.229 mmol) was dissolved in 1 mL of anhydrous 1- methyl-2-pyrrolidinone and treated with NaH (60 % dispersion in mineral oil, 10.0 mg, 0.250 mmol). After all bubbling had stopped, the reaction was stirred for an additional 30 minutes and treated with a solution of 5-bromo-6-chloro-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3- pyrrolidinyl]oxy ⁇ phenyl)-3-pyridinesulfonamide (100.0 mg, 0.208 mmol) in 1.0 mL of anhydrous l-methyl-2-pyrrolidinone.
  • Aniline B (1.2 g, 5.29 mmol) was dissolved in 11 mL of methylene chloride, 30 mL of carbon tetrachloride, and pyridine (0.428 mL, 5.29 mmol) and treated with a solution of 5-bromo-6- chloro-3-pyridinesulfonyl chloride (1.54 g, 5.29 mmol) dissolved in 4 mL of methylene chloride and 5 mL of carbon tetrachloride with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • 3,5-dichlorophenol 136.0 mg, 0.832 mmol was dissolved in 1 mL of anhydrous l-methyl-2- pynolidinone and treated with NaH (60 % dispersion in mineral oil, 35.0 mg, 0.874 mmol). After all bubbling had stopped, the reaction was stirred for an additional 30 minutes and treated with a solution of 5-bromo-6-chloro-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3- pyrrolidinyl]oxy ⁇ phenyl)-3-pyridinesulfonamide (100.0 mg, 0.208 mmol) in 1.0 mL of anhydrous l-methyl-2-pyrrolidinone.
  • Example 3- 10 The following compounds were prepared by a method similar to the one described in Examples 1 and 2 using the appropriate phenols or benzenethiols:
  • EXAMPLE 11 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form. I) 2.Corn Starch 20 mg 3.Alginic acid 20 mg 4.Sodium Alginate 20 mg 5.Mg stearate 1-3 mg 2.3 mg Procedure for tablets:
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a compound of Formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to sulfonamides, pharmaceutical compositions containing them, and their use as antagonists of urotensin II.

Description

SULFONAMIDES
FIELD OF THE INVENTION
The present invention relates to sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists
BACKGROUND OF THE INVENTION
The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
The principal mammalian vasoactive factors that comprise this neurohumoral axis, namely angiotensin-jT, endothelin-1, norepinephrine, all function via an interaction with specific G- protein coupled receptors (GPCR). Urotensin-II, represents a novel member of this neurohumoral axis.
In the fish, this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
• smooth muscle contraction both vascular and non- vascular in origin including smooth muscle preparations from the gastrointestinal tract and genitourinary tract. Both pressor and depressor activity has been described upon systemic administration of exogenous peptide
• osmoregulation: effects which include the modulation of transepithelial ion (Na+, Cl ) transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
• metabolism: urotensin-II influences prolactin secretion and exhibits a lipolytic effect in fish (activating triacylglycerol lipase resulting in the mobilization of non-esterified free fatty acids)
(Pearson, et. al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021; Conlon, et. al. J. Exp. Zool. 1996, 275, 226.) In studies with human Urotensin-II it was found that it:
• was an extremely potent and efficacious vasoconstrictor
• exhibited sustained contractile activity that was extremely resistant to wash out
• had detrimental effects on cardiac performance (myocardial contractility) Human Urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be the most potent contractile agonist identified to date. Based on the in vitro pharmacology and in vivo hemodynamic profile of human Urotensin-II it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et. al. Nature 1999, 401, 282; Douglas & Ohlstein (2001). Trends Cardiovasc. Med., 10: in press).
Compounds that antagonize the Urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: 131; 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
Since U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, (Gartlon J. Psychopharmacology (Berl) 2001 June; 155(4):426-33), impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, parkinsons, movement disorders, sleep-wake cycle, and incentive motivation (Clark et al.Brain Research 923 (2001) 120-127. Functional U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications. Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999) and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g. arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
SUMMARY OF THE INVENTION
In one aspect this invention provides for sulfonamides and pharmaceutical compositions containing them. In a second aspect, this invention provides for the use of sulfonamides as antagonists of urotensin π, and as inhibitors of urotensin π.
In another aspect, this invention provides for the use of sulfonamides for treating conditions associated with urotensin π imbalance. In yet another aspect, this invention provides for the use of sulfonamides for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases. The urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-IJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and c -adrenoceptor antagonists.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
DETAILED DESCREPTION OF THE INVENTION
The present invention provides for compounds of Formula (I):
Figure imgf000004_0001
Formula (I)
wherein: Ar is phenyl substituted or unsubstituted by one or two of the following: halogen, CN, S(C!_6 alkyl), CF3, OCF3, SCF3, C g alkyl, Cγ.β alkoxy, CO^C g alkyl), or N02;
Y is O or S;
Z is hydrogen, halogen, or C\. alkyl; R2 is hydrogen, halogen, CN, or C j.4 alkyl;
R\ is hydrogen or Cj^.g alkyl; or a pharmaceutically acceptable salt thereof.
When used herein, the term "alkyl" includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, wσ-propyl, π-butyl, sec-butyl, ωo-butyl, t-butyl, n-pentyl and n-hexyl.
When used herein, the terms halogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.
Preferred substituents for Ar are halogen or C\_ alkoxy. Z is preferably halogen or hydrogen.
R2 is preferably halogen or hydrogen.
Rj is preferably C^_3 alkyl.
Especially preferred compounds are : 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(2,3- dichlorophenyl)thio]-3-pyridinesulfonamide;
5-bromo-N-(4-chloro-3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(3,5- dichlorophenyl)thio]-3-pyridinesulfonamide; 6-{ [3,4-bis(methyloxy)phenyl]thio}-5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(3,5- dichlorophenyl)oxy]-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(3,5- difluorophenyl)oxy]-3-pyridinesulfonamide; 6-{[3,4-bis(methyloxy)phenyl]oxy}-5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-3-pyridinesulfonamide;
5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-{ [3-
(methy loxy)phenyl] oxy } -3-pyridinesulf onamide ; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-{[4- (methyloxy)phenyl]oxy}-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(3,4- dichlorophenyl)oxy]-3-pyridinesulfonamide; and 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(2,3- dichlorophenyl)oxy]-3-pyridinesulfonamide.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
Compounds of Formula (I) may be prepared as outlined in Scheme 1. Starting compounds 1 may be prepared as outlined in WO 289793, incorporated by reference herein.
Scheme 1
Figure imgf000006_0001
γ = o, s I 2 dd) phenol or thiophenol, NaH, DMF, heat; ee) phenol or thiophenol, NaH, Cs2C03,_DMF, heat.
Y, Z, R! and R^ are as described in Formula I X are the substiuents listed for Ar.
Aniline B has been previously described in published application WO 2002089792 Al incorporated by reference herein.
Figure imgf000006_0002
Anline B Sulfonyl chlorides, when not commercially available, can prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. /. Med. Chem. 1978, 21, 845; Huntress et al J. Amer. Chem. Soc. 1941, 63, 3446; Hashimoto, H. et al J. Med. Chem. 2002, 45, 1511; O'Brien, P. M. et al. J.MeάChem. 2000, 43, 156; Brandish, D. J.Med.Chem. 1999, 22, 4584.
Substituted benzenesulfonyl chlorides used in the synthesis of the title compounds which were not available commercially were prepared by methods known to those practiced in the art. With appropriate manipulation, including the use of alternative nitrogen protecting group(s), the synthesis of the remaining compounds of Formula (I) was accomplished by methods analogous to those above and to those described in the Experimental section.
In order to use a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
A typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues. Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
These sulphonamide analogs may be used for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
The urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-JJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and o -adrenoceptor antagonists.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. The biological activity of the compounds of Formula (I) are demonstrated by the following tests: Radioligand binding:
HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmor1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 niM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester. ^5j labeled
U-II binding was quantitated by gamma counting. Nonspecific binding was defined by 125j u_ II binding in the presence of 100 nM of unlabeled human U-IJ. Analysis of the data was performed by nonlinear least square fitting. Ca2+-mobiIization:
A microtitre plate based Ca2+-mobilization FLIPR assay (Molecular Devices, Sunnyvale, CA) was used for the functional identification of the ligand activating HEK-293 cells expressing (stable) recombinant GPR-14. The day following transfection, cells were plated in a poly-D- lysine coated 96 well black/clear plates. After 18-24 hours the media was aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (10 nM to 30 uM) of test compounds followed by h-U-II. After initiation of the assay, fluorescence was read every second for one minute and then every 3 seconds for the following one minute. The inhibitory concentration at 50% (IC50)was calculated for various test compounds. Inositol phosphates assays:
HEK-293-GPR14 cells in T150 flask were prelabeled overnight with 1 uCi myo-[3H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C. The experiment was initiated by the addition of increasing concentrations of h-U-II (1 pM to lμM ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation. The supernatants were neutralized with lOOul of IM Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate. Combined inositol di and tris phosphate was eluted with 4ml of IM ammonium formate/ 0.1 M formic acid. Eluted fractions were counted in beta scintillation counter. Based on shift from the control curve KB was calculated. Activity for the compounds of this invention range from (radioligand binding assay): Ki = 1 nM - 1000 nM.
The following Examples are illustrative but not limiting embodiments of the present invention.
Example 1 5-bromo-N-(4-chloro-3-{r(3R)-l-methyl-3-pyrrolidinylloxylphenyl)-6-r(2,3- dichlorophenyl)thiol-3-pyridinesulfonamide
Figure imgf000010_0001
la) 5-bromo-6-chloro-N-(4-chloro-3-ir(3R)-l-methyl-3-pyrrolidinyll oxy|phenyl)-3- pyridinesulfonamide
Figure imgf000010_0002
Aniline B (1.2 g, 5.29 mmol) was dissolved in 11 mL of methylene chloride, 30 mL of carbon tetrachloride, and pyridine (0.428 mL, 5.29 mmol) and treated with a solution of 5-bromo-6- chloro-3-pyridinesulfonyl chloride (1.54 g, 5.29 mmol) dissolved in 4 mL of methylene chloride and 5 mL of carbon tetrachloride with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 A, 35 mL/min, A: MeOH, B: CH2C12, A: 0% for 20 min, 0% to 10% over 10 min, 10% for 20 min, 10% to 30% over 20 min, 30% for 15 min, 30% to 50% over 2 min, 50% for 10 min; detection at 214 nm) to give 1.14 g (45%) of the title compound as an orange solid. MS
(ES) m/e 480 [M+H]+
lb1 5-bromo-N-(4-chloro-3-i r(3R -l-methyl-3-pyrrolidinvnoxylphenylV6-r(2.3- dichlorophenyr)thio1-3-pyridinesulfonarrude
2,3-dichlorobenzenethiol (41.0 mg, 0.229 mmol) was dissolved in 1 mL of anhydrous 1- methyl-2-pyrrolidinone and treated with NaH (60 % dispersion in mineral oil, 10.0 mg, 0.250 mmol). After all bubbling had stopped, the reaction was stirred for an additional 30 minutes and treated with a solution of 5-bromo-6-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-3-pyridinesulfonamide (100.0 mg, 0.208 mmol) in 1.0 mL of anhydrous l-methyl-2-pyrrolidinone. The reaction was heated at 125 °C for eighteen hours, cooled to room temperature, filtered through a 0.2 micron Acrodisk, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UV detection at 214 nm) to give 92.5 mg (71 %) of the title compound as a brown solid. MS (ES) m/e 624 [M+H]+
Example 2 5-bromo-N-(4-chloro-3-{r(3R)-l-methyl-3-pyrrolidinynoxy)phenyl)-6-r(3.5- dichlorophenyl)oxyl-3-pyridinesulfonamide
Figure imgf000011_0001
2a) 5-bromo-6-chloro-N-(4-chloro-3-{ r(3R)-l-methyl-3-pyrrolidinyn oxylphenvD-3- pyridinesulfonamide
Figure imgf000011_0002
Aniline B (1.2 g, 5.29 mmol) was dissolved in 11 mL of methylene chloride, 30 mL of carbon tetrachloride, and pyridine (0.428 mL, 5.29 mmol) and treated with a solution of 5-bromo-6- chloro-3-pyridinesulfonyl chloride (1.54 g, 5.29 mmol) dissolved in 4 mL of methylene chloride and 5 mL of carbon tetrachloride with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 A, 35 mL/min, A: MeOH, B: CH2C12, A: 0% for 20 min, 0% to 10% over 10 min, 10% for 20 min, 10% to 30% over 20 min, 30% for 15 min, 30% to 50% over 2 min, 50% for 10 min; detection at 214 nm) to give 1.14 g (45%) of the title compound as an orange solid. MS (ES) m e 480 [M+H]+
2b 5-bromo-N-(4-chloro-3-i r(3R -l-methyl-3-pynolidinylloxylphenyl)-6-r(3.5- dichlorophenyl")oxy1-3-pyridinesulfonamide
3,5-dichlorophenol (136.0 mg, 0.832 mmol) was dissolved in 1 mL of anhydrous l-methyl-2- pynolidinone and treated with NaH (60 % dispersion in mineral oil, 35.0 mg, 0.874 mmol). After all bubbling had stopped, the reaction was stirred for an additional 30 minutes and treated with a solution of 5-bromo-6-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-3-pyridinesulfonamide (100.0 mg, 0.208 mmol) in 1.0 mL of anhydrous l-methyl-2-pyrrolidinone. The reaction was heated at 125 °C for eighteen hours, cooled to room temperature, filtered through a 0.2 micron Acrodisk, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UV detection at 214 nm) to give 19.4 mg (15 %) of the title compound as a brown solid. MS (ES) m/e 606 [M+H]+
Example 3- 10 The following compounds were prepared by a method similar to the one described in Examples 1 and 2 using the appropriate phenols or benzenethiols:
Figure imgf000012_0001
Figure imgf000013_0001
EXAMPLE 11 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form. I) 2.Corn Starch 20 mg 3.Alginic acid 20 mg 4.Sodium Alginate 20 mg 5.Mg stearate 1-3 mg 2.3 mg Procedure for tablets:
Step 1: Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. Step 2: Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
Step 3: The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
Step 4: The wet granules are then dried in an oven at 140°F (60°C) until dry. Step 5: The dry granules are lubricated with ingredient No. 5. Step 6: The lubricated granules are compressed on a suitable tablet press.
Inhalant Formulation
A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use. Parenteral Formulation
A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers. The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims

What is claimed is:
1. A compound of Formula (I) :
Figure imgf000015_0001
Formula (I)
wherein:
Ar is phenyl substituted or unsubstituted by one or two of the following: halogen, CN,
S(Cι_6 alkyl), CF3, OCF , SCF3, Cι_6 alkyl, C g alkoxy, C02(Cι_6 alkyl), or N02;
Y is O or S;
Z is hydrogen, halogen, or Cι_g alkyl
R2 is hydrogen, halogen, CN, or Cι_4 alkyl;
Rl is hydrogen or C\_ alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein Ar is substituted with one or two halogen or
C _g alkoxy; Z is halogen or hydrogen; R2 is halogen or hydrogen; and Ri is C .3 alkyl.
3. A compound of claim 1 chosen from:
5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(2,3- dichlorophenyl)thio]-3-pyridinesulfonamide;
5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pynolidinyl]oxy}phenyl)-6-[(3,5- dichlorophenyl)thio]-3-pyridinesulfonamide; 6-{[3,4-bis(methyloxy)phenyl]thio}-5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3- pynolidinyl]oxy}phenyl)-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pynolidinyl]oxy}phenyl)-6-[(3,5- dichlorophenyl)oxy]-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(3,5- difluorophenyl)oxy]-3-pyridinesulfonamide; 6-{ [3,4-bis(methyloxy)phenyl]oxy}-5-bromo-N-(4-chloro-3-{ [(3R)-l-methyl-3- pyrrolidinyl]oxy }phenyl)-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-{[3-
(methyloxy)phenyl]oxy}-3-pyridinesulfonamide; 5-bromo-N-(4-chloro-3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-{[4-
(methy loxy)pheny 1] oxy } -3 -pyridinesulf onamide ; 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-6-[(3,4- dichlorophenyl)oxy]-3-pyridinesulfonamide; and 5-bromo-N-(4-chloro-3-{[(3R)-l-methyl-3-ρyrrolidinyl]oxy}phenyl)-6-[(2,3- dichlorophenyl)oxy]-3-pyridinesulfonamide.
4. A pharmaceutical composition comprising a compound of formula (I) of claim
1 and a pharmaceutically acceptable carrier or excipient.
5. A method of treating conditions associated with Urotensin-II imbalance by antagonizing the Urotensin-JJ. receptor which comprises administering to a patient in need thereof, a compound of Formula I of claim 1.
6. A method according to Claim 5 wherein the disease is congestive heart failure, stroke, ischemic heart disease , angina, myocardial ischemia, cardiac arrhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemonhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
7. A method of treating conditions associated with Urotensin-JJ imbalance by antagonizing the Urotensin-II receptor which comprises administering to a patient in need thereof, a compound of Formula I of claim 3.
8. A method according to Claim 7 wherein the disease is congestive heart failure, stroke, ischemic heart disease , angina, myocardial ischemia, cardiac anhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemonhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
9. A pharmaceutical composition comprising a compound of formula (I) of claim
3 and a pharmaceutically acceptable carrier or excipient.
PCT/US2003/035370 2002-11-06 2003-11-06 Sulfonamides WO2004043463A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003287529A AU2003287529A1 (en) 2002-11-06 2003-11-06 Sulfonamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42416202P 2002-11-06 2002-11-06
US60/424,162 2002-11-06

Publications (2)

Publication Number Publication Date
WO2004043463A2 true WO2004043463A2 (en) 2004-05-27
WO2004043463A3 WO2004043463A3 (en) 2004-06-17

Family

ID=32312762

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2003/035369 WO2004043948A1 (en) 2002-11-06 2003-11-06 Sulfonamides
PCT/US2003/035370 WO2004043463A2 (en) 2002-11-06 2003-11-06 Sulfonamides

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2003/035369 WO2004043948A1 (en) 2002-11-06 2003-11-06 Sulfonamides

Country Status (4)

Country Link
AR (1) AR041885A1 (en)
AU (2) AU2003291264A1 (en)
TW (1) TW200418831A (en)
WO (2) WO2004043948A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7432258B2 (en) 2006-07-20 2008-10-07 Smithkline Beecham Corporation Morpholinyl and pyrrolidinyl analogs
US7750161B2 (en) 2003-09-26 2010-07-06 Daniel Bur Pyridine derivatives
US8067601B2 (en) 2004-10-12 2011-11-29 Actelion Pharmaceticals Ltd. 1-[2-(4-benzyl-4-hydroxy-piperidin-1 -yl )-ethyl]-3-(2-methyl-quinolin- 4-yl)- urea as crystalline sulfate salt

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3378565A (en) * 1966-04-25 1968-04-16 Dow Chemical Co Sulfamoylpyridyl phosphorothioates and intermediates therefor
US5869428A (en) * 1995-03-13 1999-02-09 Ishihara Sangyo Kaisha Ltd. Pyridonesulfonylurea compounds, process for their production and herbicides containing them

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5338739A (en) * 1994-03-10 1994-08-16 Hoechst-Roussel Pharmaceuticals Inc. (Pyrrolidinyl)phenyl carbamates, compositions and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3378565A (en) * 1966-04-25 1968-04-16 Dow Chemical Co Sulfamoylpyridyl phosphorothioates and intermediates therefor
US5869428A (en) * 1995-03-13 1999-02-09 Ishihara Sangyo Kaisha Ltd. Pyridonesulfonylurea compounds, process for their production and herbicides containing them

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7750161B2 (en) 2003-09-26 2010-07-06 Daniel Bur Pyridine derivatives
US8067601B2 (en) 2004-10-12 2011-11-29 Actelion Pharmaceticals Ltd. 1-[2-(4-benzyl-4-hydroxy-piperidin-1 -yl )-ethyl]-3-(2-methyl-quinolin- 4-yl)- urea as crystalline sulfate salt
US7432258B2 (en) 2006-07-20 2008-10-07 Smithkline Beecham Corporation Morpholinyl and pyrrolidinyl analogs
US7749998B2 (en) 2006-07-20 2010-07-06 Glaxosmithkline Llc Morpholinyl and pyrrolidinyl analogs

Also Published As

Publication number Publication date
WO2004043463A3 (en) 2004-06-17
TW200418831A (en) 2004-10-01
WO2004043948A1 (en) 2004-05-27
AU2003287529A1 (en) 2004-06-03
AR041885A1 (en) 2005-06-01
AU2003291264A1 (en) 2004-06-03

Similar Documents

Publication Publication Date Title
US20040198979A1 (en) Sulfonamides
EP1385840B1 (en) Sulfonamides
US20040152893A1 (en) Sulfonamides
US20040152692A1 (en) Pyrrolidine sulfonamides
EP1244452A1 (en) Urotensin-ii receptor antagonists
WO2001045694A1 (en) Urotensin-ii receptor antagonists
US7019008B2 (en) Pyrrolidine sulfonamides
EP1351687A2 (en) Urotensin-ii receptor antagonists
WO2004043463A2 (en) Sulfonamides
EP1385841A1 (en) Sulfonamides
WO2002089740A2 (en) Sulfonamides
EP1385830A1 (en) Sulfonamides
WO2004043369A2 (en) Sulfonamides
US20040082566A1 (en) Pyrrolidine sulfonamides
US20040142923A1 (en) Pyrrolidine sulfonamides
WO2002078707A1 (en) Pyrrolidine sulfonamides
US20040142948A1 (en) Sulfonamides
US20040152895A1 (en) Sulfonamides
AU2002303678A1 (en) Sulfonamides

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AU BA BB BR BZ CA CN CO CR CU DM DZ EC EG GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MA MG MK MN MX NO NZ OM PH PL RO SC SG TN TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP