WO2009158309A2 - Biphényle sulfonamides en tant que doubles antagonistes du récepteur d'angiotensine et d'endothéline - Google Patents

Biphényle sulfonamides en tant que doubles antagonistes du récepteur d'angiotensine et d'endothéline Download PDF

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WO2009158309A2
WO2009158309A2 PCT/US2009/048136 US2009048136W WO2009158309A2 WO 2009158309 A2 WO2009158309 A2 WO 2009158309A2 US 2009048136 W US2009048136 W US 2009048136W WO 2009158309 A2 WO2009158309 A2 WO 2009158309A2
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methyl
compound according
sulfonamide
biphenyl
isoxazolyl
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PCT/US2009/048136
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English (en)
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WO2009158309A3 (fr
Inventor
Andrew G. Cole
Patrick A. Jokiel
Marc-Raleigh Brescia
Lanying Qin
Ian Henderson
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Ligand Pharmaceuticals Inc.
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Publication of WO2009158309A2 publication Critical patent/WO2009158309A2/fr
Publication of WO2009158309A3 publication Critical patent/WO2009158309A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists, to methods of using such compounds in the treatment of conditions such as hypertension and other diseases, and to pharmaceutical compositions containing such compounds.
  • Angiotensin II (Angll) and endothelin- 1 (ET-I) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including hypertension, diabetic nephropathy and heart failure.
  • angiotensin receptor blockers (ARBs), which block the activity of Angll, are widely used as a treatment for hypertension, diabetic nephropathy and heart failure.
  • ET receptor antagonists ERAs
  • Angll and ET-I work together in blood pressure control and pathological tissue remodeling.
  • ARBs not only block the action of Angll at its receptor, but also limit the production of ET-I.
  • ERAs block ET-I activity and inhibit the production of Angll. Consequently, simultaneously blocking Angll and ET-I activities may offer better efficacy than blocking either substance alone.
  • R 1 is selected from the group consisting of
  • A is a fused ring, either unsubstitited or substituted with alkyl, halogen, oxo, alkoxy or acyl imine;
  • B is a five-membered heterocycle containing two heteroatoms in addition to the N attachment, with the proviso that both additional heteroatoms cannot be nitrogen;
  • E is a six-membered heterocycle containing at least two heteroatoms in addition to the nitrogen attachment;
  • G is a fused unsaturated heterocycle containing one -NH
  • J is oxygen or -NR 8 ;
  • R 4 is hydrogen or (CrC 6 )alkyl
  • R 5 is hydrogen, (Ci-C 6 )alkyl or halogen
  • R 6 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, hydroxyl and alkoxy;
  • R 7 is a six-membered heterocycle, either unsubstitited or substituted with one or more of hydrogen, (Ci-C 6 )alkyl, alkoxy carbonyl or alkoxy;
  • R is hydrogen or (Ci-C 6 )alkyl
  • M is acyl imine or oxo
  • R is selected from the group consisting of hydrogen, (d-C 6 )alkyl and alkoxyalkyl; and R 3 is an optionally substituted heterocycle;
  • the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of general formula I 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Yet another aspect of the present invention relates to a method of treating an endothelin-dependent or angiotensin II-dependent disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula I.
  • Still another aspect of the invention relates to a method of treating a disease or disorder selected from the group consisting of hypertension; pulmonary hypertension; primary pulmonary hypertension; low renin hypertension; male erectile dysfunction; male or female sexual dysfunction; heart failure; atherosclerosis; restenosis; endotoxemia; cancer; migraine; asthma; ischemia; subarachnoid hemorrhage; benign prostatic hypertrophy; diabetic nephropathy; renal, glomerular or mesangial cell disorders; or acute or chronic renal failure in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula I.
  • a disease or disorder selected from the group consisting of hypertension; pulmonary hypertension; primary pulmonary hypertension; low renin hypertension; male erectile dysfunction; male or female sexual dysfunction; heart failure; atherosclerosis; restenosis; endotoxemia; cancer; migraine; asthma; ischemia; subarachnoid hemorrhage; benign prostatic
  • Yet another aspect of the invention relates to a method of inhibiting cell growth in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula I.
  • the invention relates to biphenyl sulfonamides having general formula I, and pharmaceutically acceptable salts thereof:
  • R 3 is an optionally substituted heterocycle.
  • R 3 may be an isoxazole , either unsubstituted or substutituted with one or more of (Ci-C 6 ) alkyl or halogen.
  • R 3 may be an isoxazole , either unsubstituted or substutituted with one or more of methyl or fluoro.
  • More particular embodiments include R as an isoxazole , either unsubstituted or substutituted with two methyls or with one methyl and one fluoro.
  • R may be hydrogen, (Ci-C 6 ) alkyl or alkoxyalkyl. More particularly, R 2 may be hydrogen, propyl or ethoxymethyl.
  • R 1 may be R 4 is hydrogen or (C)-C 6 ) alkyl and R 5 is hydrogen, (Ci-C 6 ) alkyl or halogen. In more preferred embodiments for this R 1 , R 4 is methyl and R 5 is propyl.
  • R 1 may be , A is a fused ring , either unsubstituted or substutituted with alkyl, halogen, oxo, alkoxy or acyl imine; R 4 is hydrogen or (Ci-C 6 ) alkyl; and R 5 is hydrogen, (Ci-C 6 ) alkyl or halogen. In still other
  • R 1 is R is methyl and R 5 is propyl.
  • Some embodiments of the invention include R 1 as R 5 as hydrogen, (Ci-C 6 )alkyl or halogen and R 7 as a six-membered heterocycle , either unsubstituted or substutituted with one or more of hydrogen, (Ci-C 6 )alkyl, alkoxycarbonyl or alkoxy.
  • R 5 is butyl and R 7 is pyridazine, pyrimidine or pyrazine , either unsubstituted or substutituted with one or two methyls.
  • R 5 is butyl and R 7 is pyridine , either unsubstituted or substutituted with methoxycarbonyl or methoxy.
  • R 1 is B is a five-membered heterocycle containing two heteroatoms in addition to the N attachment, with the proviso that both additional heteroatoms cannot be nitrogen
  • R 5 is hydrogen, (Ci-C 6 )alkyl or halogen and M is acyl imine or oxo.
  • B is oxadiazole or thiadiazole and R 5 is
  • R is , E is a six-membered heterocycle containing at least two heteroatoms in addition to the nitrogen attachment, R 4 is hydrogen or (Ci-C 6 )alkyl and R 5 is hydrogen, (Ci-C 6 )alkyl or halogen.
  • E is triazine and R 4 and R 5 are (C 1 -C 6 )alkyl; in particular, R 4 is methyl and R 5 is butyl.
  • R 1 is ? j 1S oxygen or -NR 8
  • R 4 is hydrogen or (d-C 6 )alkyl
  • R 5 is hydrogen, (C]-C 6 )alkyl or halogen
  • R 6 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, hydroxyl and alkoxy
  • R 8 is hydrogen or (Ci-C 6 )alkyl.
  • J is oxygen, NH or NCH 3
  • R 4 and R 5 are methyl
  • R 6 is hydrogen or methyl.
  • R is , R 4 is hydrogen or (Ci-C 6 )alkyl, R 5 is hydrogen, (Ci-C 6 )alkyl or halogen and R 6 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, hydroxyl and alkoxy. In preferred embodiments, R 4 and R 5 are methyl and R 6 is hydrogen or hydroxyl.
  • R is G is a fused unsaturated heterocycle containing one nitrogen and R 5 is hydrogen, (Ci-C 6 )alkyl or halogen.
  • R 1 is or
  • R 5 is (Ci-C 6 )alkyl.
  • R is and R is hydrogen, (Q-C ⁇ alkyl or halogen.
  • R 5 is halogen.
  • R 1 is and R 4 is (C r )
  • R 4 may be butyl.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (both n-propyl and isopropyl), butyl (including s-and t-butyl) and the like.
  • Preferred alkyl groups are those of C 20 or below; more preferred are Cj-C 8 alkyl.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.
  • Ci to C 20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • the term "carbocycle” is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • carbocycle refers to such systems as cyclopropane, benzene and cyclohexene
  • (C 8 -Ci 2 ) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • Heteroalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by a heteroatom.
  • oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing; of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, IfI 96, but without the restriction of T
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower- acyl refers to groups containing one to four carbons.
  • Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
  • the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene and naphthalene.
  • the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, indoline, thiophene, benzopyranone, thiazole, furan, benzimidazole, benzodioxole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
  • heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thia
  • carbocycle is intended to include ring systems, including polycyclic structures, consisting entirely of carbon but of any oxidation state.
  • C 3 -Ci 0 carbocycle refers to such systems as cyclopropane, benzene and cyclohexene
  • C 8 -Ci 2 carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • the terms "monocycle” and “bicycle” or “monocyclic” and “bicyclic” refer to carbocycles and heterocycles having one or two rings respectively.
  • Preferred monocycles are 3, 4, 5, 6 or 7-membered rings, which may be aromatic, saturated or partially unsaturated.
  • Non-limiting examples include cyclopropane, cyclopentane, cyclohexane, pyran, furan, tetrahydrofuran, tetrahydropyran, oxepane and phenyl.
  • Preferred bicycles are those having from 8 to 12 ring atoms in total.
  • Non-limiting examples include chroman, tetralin, naphthalene, benzofuran, indole, octahydropentalene and tetrahydrobenzo[b]oxepine.
  • a particular embodiment comprises fused 5:6 and 6:6 systems.
  • Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyloweralkyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, loweralkoxy, haloalkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), alkoxycarbonylamino, carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, acetoxy, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, sulfonylamino, acylamino,
  • the term when the parent is a heterocycle that allows such substitution, the term also includes oxides, for example pyridine-N-oxide, thiopyran sulfoxide and thiopyran-S,S-dioxide.
  • oxides for example pyridine-N-oxide, thiopyran sulfoxide and thiopyran-S,S-dioxide.
  • two hydrogens on a single carbon may be replaced by a carbonyl to form an oxo derivative.
  • oxo-substituted aryl residues include tetralone (3,4-dihydronaphthalen-l(2/f)- one) and indanone (2,3-dihydroinden-l-one).
  • halogen and “halo” refer to fluorine, chlorine, bromine or iodine.
  • Some of the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain an unnatural ratio of one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include 3 H, 14 C, 35 S, 18 F, 36 Cl and 125 I, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e.
  • Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. Because of the high affinity for the ET-I and AngII active site, radiolabeled compounds of the invention are useful for these assays.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the starting materials for example in the case of suitably substituted benzimidazole ring compounds, are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.
  • the present invention further provides pharmaceutical compositions comprising as active agents, the compounds described herein.
  • a "pharmaceutical composition” refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvates thereof, with other chemical components such as physiologically suitable carriers and excipients.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • Compounds that inhibit angiotensin or endothelin can be formulated as pharmaceutical compositions and administered to a mammalian subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal or subcutaneous routes.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
  • enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment.
  • compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
  • AU formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer.
  • physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated may be used in the composition. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.
  • the compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • the amount of a composition to be administered will, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician.
  • the compounds of the invention may be administered orally or via injection at a dose from 0.001 to 2500 mg/kg per day.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • solvate refers to a compound of Formula I or II in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent.
  • the solvate is typically dried or azeotroped under ambient conditions.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, iV,iV-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • preventing refers to administering a medicament beforehand to forestall or obtund an attack.
  • the person of ordinary skill in the medical art recognizes that the term “prevent” is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended herein.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient.
  • a packaging device include metal or plastic foil, such as a blister pack and a nebulizer for inhalation.
  • the packaging device or dispenser may be accompanied by instructions for administration.
  • Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be placed in an appropriate container and labeled for treatment of an indicated condition. Indications
  • the compounds of the present invention are antagonists of both endothelin (especially, ET-I) and angiotensin II (especially, subtype ATi) receptors ("dual angiotensin endothelin receptor antagonists") and are useful in treatment of conditions associated with increased ET levels and/or increased angiotensin II levels and of all endothelin-dependent or angiotensin II-dependent disorders. They are thus useful as antihypertensive agents.
  • a composition having one (or a combination) of the compounds of this invention the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. They are also useful in portal hypertension, hypertension secondary to treatment with erythropoietin and low renin hypertension.
  • the compounds of the present invention are also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute (such as ischemic, nephrotoxic, or glomerulonephritis) and chronic (such as diabetic, hypertensive or immune-mediated) renal failure, glomerular injury, renal damage secondary to old age or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents and to cyclosporine), renal ischemia, primary vesicoureteral reflux, glomerulosclerosis and the like.
  • the compounds of this invention are also useful in the treatment of disorders related to paracrine and endocrine function.
  • the compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock as well as hemorrhagic shock.
  • the compounds of the present invention are also useful in hypoxic and ischemic disease and as anti-ischemic agents for the treatment of, for example, cardiac, renal and cerebral ischemia and reperfusion (such as that occurring following cardiopulmonary bypass surgery), coronary and cerebral vasospasm, and the like.
  • the compounds of this invention are also useful as antiarrhythmic agents; anti-anginal agents; anti-fibrillatory agents; anti-asthmatic agents; anti- atherosclerotic and anti-arteriosclerotic agents; additives to cardioplegic solutions for cardiopulmonary bypasses; adjuncts to thrombolytic therapy; and anti-diarrheal agents.
  • the compounds of this invention may be useful in therapy for myocardial infarction; therapy for peripheral vascular disease (e.g., Raynaud's disease and Takayashu's disease); treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); treatment of primary pulmonary hypertension (e.g., plexogenic, embolic) in adults and in the newborn and pulmonary hypertension secondary to heart failure, radiation and chemotherapeutic injury, or other trauma; treatment of central nervous system vascular disorders, such as stroke, migraine and subarachnoid hemorrhage; treatment of central nervous system behavioral disorders; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn's disease, gastric mucosal damage, ulcer and ischemic bowel disease; treatment of gall bladder or bile duct- based diseases such as cholangitis; treatment of pancreatitis; regulation of cell growth; treatment of benign prostatic hypertrophy; restenosis following angioplasty or following any procedures including transplantation; therapy for congestive heart failure including inhibition
  • the compounds of this invention are useful in the treatment of sickle cell disease including the initiation and/or evolution of the pain crises of this disease; treatment of the deleterious consequences of ET-producing tumors such as hypertension resulting from hemangiopericytoma; treatment of early and advanced liver disease and injury including attendant complications (e.g., hepatotoxicity, fibrosis and cirrhosis); treatment of spastic diseases of the urinary tract and/or bladder; treatment of hepatorenal syndrome; treatment of immunological diseases involving vasculitis such as lupus, systemic sclerosis, mixed cryoglobulinemia; and treatment of fibrosis associated with renal dysfunction and hepatotoxicity.
  • the compounds of this invention are useful in therapy for metabolic and neurological disorders; cancer; insulin-dependent and non insulin-dependent diabetes mellitus; neuropathy; retinopathy; maternal respiratory distress syndrome; dysmenorrhea; epilepsy; hemorrhagic and ischemic stroke; bone remodeling; psoriasis; and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis (all types of dermatitis).
  • the compounds of this invention are also useful in the treatment of sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause) and women by improving blood flow to the genitalia, especially, the corpus cavernosum.
  • the present invention thus provides methods for the treatment of all endothelin-dependent or angiotensin II-dependent disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefor.
  • Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods.
  • such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
  • Pd(dppf) 2 Cl 2 dichloro[l , 1 '-bis(diphenylphosphinoferrocene]palladium
  • PDE phosphodiesterase
  • PDGF platelet-derived growth factor
  • PVT polyvinyltoluene
  • Ph phenyl
  • PS-BEMP 2-tert-butylimino-2-diethylamino- 1 ,3 -dimethyl -perhydro
  • TBAF tetrabutyl ammonium fluoride
  • Synthetic intermediates of formula II, incorporating a functionalized biaryl framework can be synthesized according to the synthetic procedures outlined in WO2000/01389, WO2001//044239, US2002/0143024, J Med. Chem. 2002, 45, 3829, and J Med. Chem. 2005, 48, 171.
  • PG is a suitable Nitrogen protecting group (typically MOM or SEM) and X is selected from the group consisting of -OH, -NH 2 , Hal (Cl, Br or I).
  • Example 3 N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[2-butyl- imidazo[4,5-c]pyridin-4(5H)-one-3yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2- sulfonamide (3) was deprotected using General Procedure A to provide 24 mg of N-(4,5- dimethyl-3-isoxazolyl)-4 1 -[2-butyl-imidazo[4,5-c]pyridin-4(5H)-one-3yl-methyl]-2 l - (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 3).
  • reaction mixture was stirred at room temperature for 16 h and then recharged with DIEA and triphosgene and stirred an additional 6 h.
  • the reaction mixture was then recharged again with DIEA and triphosgene and stirred 16 h.
  • the reaction was then quenched with 2 mL of MeOH and the volatiles were removed in vacuo.
  • N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[(2-methyl-6- propylpyrimidin-4(3H)-one)-5yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (25) was deprotected using General Procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)- 4'-[(2-methyl-6-propylpyrimidin-4(3H)-one)-5yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]- 2-sulfonamide (Example 23); ⁇ ⁇ (CD 3 OD, 400 MHz) 0.95 (t, 3H), 1.06 (t, 3H), 1.68 (m, 5H), 2.23 (s, 3H), 2.50 (s, 3H), 2.61 (t, 2H), 3.27 (m, obscured by solvent), 3.95 (s
  • Examples 24 to 31 were synthesized from Compound 23 using the literature procedures in J. Med. Chem. 1994, 37 2371.
  • Examples 32 and 33 were sythesized from Compound IV using the literature procedures in J. Med. Chem., 1998, 41 4251.
  • Examples 34 to 41 were sythesized from Compound IV using the literature procedures in J. Med. Chem. 1995; 55(15) 2925.
  • reaction mixtures 100 ⁇ L were filtered through 0.3% polyethyleneimine-blocked MAFCNOB filter plates (Millipore) and washed three times with ice-cold 50 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 . Detection in the TriLux (PerkinElmer) was carried out in the presence of 40 ⁇ L/ well scintillation fluid.
  • the K D value (76 pM) for [ 125 I] endothelin-1 at ET A was measured as follows: a 50 ⁇ L reaction containing radioligand (PerkinElmer), 0.25 ⁇ g/well membranes from mammalian cells expressing recombinant ET A (commercially available from Chemicon, accession number S63938), 50 mM HEPES, pH 7.5, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.2% BSA, 2 mM phosphoramidon, 0.5% DMSO, was carried out for one hour at 25 0 C, with agitation.
  • Reaction mixtures were then filtered through 0.3% polyethyleneimine-blocked MAFCNOB filter plates (Millipore) and washed four times with ice-cold 50 mM HEPES, pH 7.5, 0.5 M NaCl, 0.1% BSA. Detection in the TriLux (PerkinElmer) was carried out in the presence of 40 ⁇ L/ well scintillation fluid.

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Abstract

L'invention concerne de nouveaux composés biphényle sulfonamides qui sont des antagonistes combinés du récepteur d'angiotensine et d'endothéline et qui sont utiles dans le traitement d'états tels que l'hypertension ou d'autres maladies.
PCT/US2009/048136 2008-06-25 2009-06-22 Biphényle sulfonamides en tant que doubles antagonistes du récepteur d'angiotensine et d'endothéline WO2009158309A2 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN112876424A (zh) * 2019-11-29 2021-06-01 上海拓界生物医药科技有限公司 血管紧张素ii受体及内皮素受体双重拮抗剂
WO2022266370A1 (fr) 2021-06-17 2022-12-22 Aria Pharmaceuticals, Inc. Sparsentan pour le traitement de la fibrose pulmonaire idiopathique

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112876424A (zh) * 2019-11-29 2021-06-01 上海拓界生物医药科技有限公司 血管紧张素ii受体及内皮素受体双重拮抗剂
CN112876424B (zh) * 2019-11-29 2023-06-30 上海拓界生物医药科技有限公司 血管紧张素ii受体及内皮素受体双重拮抗剂
WO2022266370A1 (fr) 2021-06-17 2022-12-22 Aria Pharmaceuticals, Inc. Sparsentan pour le traitement de la fibrose pulmonaire idiopathique

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