WO2009158309A2

WO2009158309A2 - Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists

Info

Publication number: WO2009158309A2
Application number: PCT/US2009/048136
Authority: WO
Inventors: Andrew G. Cole; Patrick A. Jokiel; Marc-Raleigh Brescia; Lanying Qin; Ian Henderson
Original assignee: Ligand Pharmaceuticals Inc.
Priority date: 2008-06-25
Filing date: 2009-06-22
Publication date: 2009-12-30
Also published as: WO2009158309A3

Abstract

The present invention provides novel biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists useful in the treatment of conditions such as hypertension and other diseases.

Description

LIGAND.054VPC PATENT

BIPHENYL SULFONAMIDES AS DUAL ANGIOTENSIN ENDOTHELIN

RECEPTOR ANTAGONISTS

Field of the Invention

[0001] 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.

BACKGROUND OF THE INVENTION

[0002] 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. Currently, angiotensin receptor blockers (ARBs), which block the activity of Angll, are widely used as a treatment for hypertension, diabetic nephropathy and heart failure. In addition, there is a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET-I activity.

[0003] It is also known that Angll and ET-I work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of Angll at its receptor, but also limit the production of ET-I. Similarly, 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.

[0004] In well-validated rat models of human hypertension, the combination of an ARB and an ERA results in a synergistic effect. Furthermore, although ARBs are the standard of care for patients with diabetic nephropathy, improved efficacy with the coadministration of an ERA has been reported in Phase 2 clinical development.

[0005] There are preclinical and initial clinical data suggesting that compared to either mechanism alone, simultaneously blocking angiotensin II and endothelin 1 at their respective receptors, ATI and ETA, may provide an improved treatment option for several cardiovascular diseases. SUMMARY OF THE INVENTION

[0006] Disclosed herein are ompounds of general formula I, and pharmaceutically acceptable salts thereof, that are potent and selective antagonists of both angiotensin and endothelin receptors:

I

In these compounds:

R¹ is selected from the group consisting of

wherein 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 -NR⁸;

R⁴ is hydrogen or (CrC₆)alkyl;

R⁵ is hydrogen, (Ci-C₆)alkyl or halogen;

R⁶ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, hydroxyl and alkoxy;

R⁷ is a six-membered heterocycle, either unsubstitited or substituted with one or more of hydrogen, (Ci-C₆)alkyl, alkoxy carbonyl or alkoxy;

R is hydrogen or (Ci-C₆)alkyl; and

M is acyl imine or oxo, and

R is selected from the group consisting of hydrogen, (d-C₆)alkyl and alkoxyalkyl; and R³ is an optionally substituted heterocycle;

[0007] These compounds are useful as antagonists of angiotensin and endothelin receptors and, as such, are useful in indications where angiotensin or endothelin mediation is desired for the treatment of various conditions.

[0008] In another aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of general formula I₅ or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] 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.

[0010] 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.

[0011] 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.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0012] Throughout this specification the substituents are defined when introduced and retain their definitions.

[0013] In a first aspect the invention relates to biphenyl sulfonamides having general formula I, and pharmaceutically acceptable salts thereof:

I

[0014] In certain embodiments, R³ is an optionally substituted heterocycle. For instance, R³ may be an isoxazole , either unsubstituted or substutituted with one or more of (Ci-C₆) alkyl or halogen. In particular, R³ 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.

[0015] In other embodiments, R may be hydrogen, (Ci-C₆) alkyl or alkoxyalkyl. More particularly, R² may be hydrogen, propyl or ethoxymethyl.

[0016] In still other embodiments, R¹ may be

R⁴ is hydrogen or (C)-C₆) alkyl and R⁵ is hydrogen, (Ci-C₆) alkyl or halogen. In more preferred embodiments for this R¹, R⁴ is methyl and R⁵ is propyl. [0017] In yet other embodiments, R¹ may be

, A is a fused ring , either unsubstituted or substutituted with alkyl, halogen, oxo, alkoxy or acyl imine; R⁴ is hydrogen or (Ci-C₆) alkyl; and R⁵ is hydrogen, (Ci-C₆) alkyl or halogen. In still other

embodiments, R¹ is

R is methyl and R⁵ is propyl.

[0018] Some embodiments of the invention include R¹ as

R⁵ as hydrogen, (Ci-C₆)alkyl or halogen and R⁷ as a six-membered heterocycle , either unsubstituted or substutituted with one or more of hydrogen, (Ci-C₆)alkyl, alkoxycarbonyl or alkoxy. In some preferred embodiments, R⁵ is butyl and R⁷ is pyridazine, pyrimidine or pyrazine , either unsubstituted or substutituted with one or two methyls. In other embodiments, R⁵ is butyl and R⁷ is pyridine , either unsubstituted or substutituted with methoxycarbonyl or methoxy. [0019] In further embodiments of the invention, R¹ 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, R⁵ is hydrogen, (Ci-C₆)alkyl or halogen and M is acyl imine or oxo. In preferred embodiments, B is oxadiazole or thiadiazole and R⁵ is

[0020] In

yet other embodiments of the invention, R is , E is a six-membered heterocycle containing at least two heteroatoms in addition to the nitrogen attachment, R⁴ is hydrogen or (Ci-C₆)alkyl and R⁵ is hydrogen, (Ci-C₆)alkyl or halogen. In other embodiments, E is triazine and R⁴ and R⁵ are (C₁-C₆)alkyl; in particular, R⁴ is methyl and R⁵ is butyl.

[0021] In other embodiments, R¹ is

_? j _1S oxygen or -NR⁸, R⁴ is hydrogen or (d-C₆)alkyl, R⁵ is hydrogen, (C]-C₆)alkyl or halogen, R⁶ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, hydroxyl and alkoxy and R⁸ is hydrogen or (Ci-C₆)alkyl. In further embodiments, J is oxygen, NH or NCH₃, R⁴ and R⁵ are methyl and R⁶ is hydrogen or methyl. [0022] In still other embodiments, R is

, R⁴ is hydrogen or (Ci-C₆)alkyl, R⁵ is hydrogen, (Ci-C₆)alkyl or halogen and R⁶ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, hydroxyl and alkoxy. In preferred embodiments, R⁴ and R⁵ are methyl and R⁶ is hydrogen or hydroxyl.

[0023] In further embodiments, R is

G is a fused unsaturated heterocycle containing one nitrogen and R⁵ is hydrogen, (Ci-C₆)alkyl or halogen.

In more specific embodiments, R¹ is

or

and R⁵ is (Ci-C₆)alkyl. [0024] In still other embodiments, R is

and R is hydrogen, (Q-C^alkyl or halogen. In more specific embodiments, R⁵ is halogen.

[0025] In still other embodiments, R¹ is

and R⁴ is (C _r

C₆)alkyl. In particular, R⁴ may be butyl.

[0026] The compounds described herein are useful as endothelin or angiotensin inhibitors. It may be found upon examination that species and genera not presently excluded are not patentable to the inventors in this application. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention. The invention, in a composition aspect, is all compounds of formula I except those that are in the public's possession. Definitions

[0027] For convenience and clarity certain terms employed in the specification, examples and claims are described herein.

[0028] 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 C₂₀ or below; more preferred are Cj-C₈ 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.

[0029] Ci to C₂₀ 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. Thus (C₃-Ci₀) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈-Ci₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, not otherwise limited, refers to monocycles, bicycles and polycycles.

[0030] 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.

[0031] Heteroalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by a heteroatom. For example, 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|127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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. Examples of 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. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Examples of 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, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl. A nitrogenous heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.

[0036] The term "carbocycle" is intended to include ring systems, including polycyclic structures, consisting entirely of carbon but of any oxidation state. Thus (C₃-Ci₀) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈-Ci₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.

[0037] 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.

[0038] 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, amidino, aryl, benzyl, heterocyclyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, and benzyloxy. 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. As mentioned above, two hydrogens on a single carbon may be replaced by a carbonyl to form an oxo derivative. Noteworthy oxo-substituted aryl residues include tetralone (3,4-dihydronaphthalen-l(2/f)- one) and indanone (2,3-dihydroinden-l-one).

[0039] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine. [0040] 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. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion.

[0041] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the graphic representation

indicates either, or both, of the two trans enantiomers

[0042] It will be recognized that 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 ³H, ¹⁴C, ³⁵S, ¹⁸F, ³⁶Cl and ¹²⁵I, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease in preparation and detectability. 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. Chemical Synthesis

[0043] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, 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. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.

[0044] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference.

[0045] In general, 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.

[0046] The present invention further provides pharmaceutical compositions comprising as active agents, the compounds described herein.

[0047] As used 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.

[0048] Pharmaceutical 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.

[0049] 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.

[0050] For oral administration, 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). If desired, disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0051] In addition, enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment.

[0052] Pharmaceutical 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.

[0053] In soft capsules, 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. [0054] For injection, 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. For transmucosal and transdermal administration, 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.

[0055] For administration by inhalation, 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. In the case of a pressurized aerosol, 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.

[0056] Pharmaceutical 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.

[0057] 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.

[0058] Depending on the severity and responsiveness of the condition to be treated, 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.

[0059] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound. The term "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. In general, 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.

[0060] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, 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. When the compounds contain an acidic side chain, 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.

[0061] The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an attack. The person of ordinary skill in the medical art (to which the present method claims are directed) 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.

[0062] It should be understood that in addition to the ingredients particularly mentioned above, the 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.

[0063] The compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient. Examples of 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

[0064] 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. By the administration of 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.

[0065] 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.

[0066] The compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock as well as hemorrhagic shock.

[0067] 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.

[0068] In addition, 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 of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of hepatotoxicity and sudden death.

[0069] 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).

[0070] 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.

[0071] 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. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention. [0072] The following examples will further describe the invention, and are used for the purposes of illustration only, and should not be considered as limiting the invention being disclosed. Examples

[0073] The following abbreviations and terms have the indicated meaning throughout:

Ac acetyl

ACN acetonitrile

Boc tert-butoxycarbonyl

BSA bovine serum albumin

Bu butyl

BuOH butanol

CDCl ₃ deuterated chloroform

CD₃OD deuterated methanol

NMR chemical shift referenced to tetramethylsilane

DCM dichloromethane = methylene chloride = CH₂Cl₂

DCE 1 ,2-dichloroethane

DEAD diethyl azodicarboxylate

DIC diisopropylcarbodiimide

DIEA iV,N-diisopropylethyl amine

DMAP 4-dimethylaminopyridine

DMF N,iV-dimethylformamide

DMSO dimethyl sulfoxide

EDC N-(3 -dimethylaminopropyl)-iV )ethylcarbodiimide

EDTA ethylene diamine tetraacetic acid

EtOAc ethyl acetate

EtOH ethanol

GC gas chromatography h — hours

HEPES 4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid

HMG CoA 3 -hydroxy-3-methyl-glutary 1-CoA reductase

HOAc acetic acid

HOBt hydroxybenzotriazole

K_D dissociation constant m- = meta

Me methyl

MeOH methanol = CH₃OH

MS mass spectrometry min = minutes

MOM methoxymethyl

N normal

NMR Nuclear Magnetic Resonance Na(OAc)₃BH = sodium tπacetoxy borohydπde

0- = ortho p- = para

Pd(dppf)₂Cl₂ = dichloro[l , 1 '-bis(diphenylphosphinoferrocene]palladium

PDE = phosphodiesterase

PDGF = platelet-derived growth factor

PG = protecting group

PVT = polyvinyltoluene

Ph = phenyl

PhOH = phenol

Pr = propyl

PrOH = propanol

PS = polystyrene

PS-BEMP = 2-tert-butylimino-2-diethylamino- 1 ,3 -dimethyl -perhydro

1,3,2-diazo phosphorine on polystyrene

RT = room temperature (rt) sat. = saturated

S- = secondary

SEM = trimethylsilyl ethoxymethyl

SPA = scintillation proximity assay t- = tert- = tertiary

TBAF = tetrabutyl ammonium fluoride

TBDMS = t-butyldimethylsilyl

Tf triflate

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = trimethylsilyl

[0074] Examples below describe syntheses of certain precursors and intermediates of the invention.

Compounds of formula I can be synthesized from key synthetic intermediates of formula II (Scheme 1). By way of illustration, but not limitation, the syntheses of representative compounds of formula I are detailed below.

[0075] 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, -NH₂, Hal (Cl, Br or I). X, R¹, R² and R³ are as defined within the detailed description of the invention. Conversion of compounds of formula II (X=Br) to compounds of formula II (X=NH₂) can be achieved by displacement of the bromide with phthalimide and deprotection to the primary amine with hydrazine under standard conditions.

III I

Scheme 2

[0076] Alternatively, compounds of formula I can be synthesized from key synthetic intermediates of formula IV and VI (Scheme 2) according to the procedures outlined in WO2000/01389, WO2001//044239, US2002/0143024, J. Med. Chem. 2002, 45, 3829, and J Med. Chem. 2005, 48, 171

General Procedure A: MOM protecting group removal (Scheme 3). To a solution of IHa in absolute ethanol was added an equal volume of 6 M HCl and the mixture heated at 80 ⁰C for 3 h. The solvent was evaporated to provide compounds of formula I.

Scheme 3

General Procedure B: SEM protecting group removal (Scheme 4). To a solution of IHb in DMF was added 2 eq. of a 1.0 M solution of TBAF in THF and the mixture heated at 80 °C for 2 h. The solvent was evaporated and the residue purified to provide compounds of formula I.

IHb

Scheme 4

[0077] Compounds of formula Ia (Examples 1 to 5 and 7 to 15 ) (Example numbers also refer to the compounds identified in Table 1, below) were synthesized according to the general synthetic route outlined in Scheme 5 with the following exceptions. Cesium carbonate was used as the base for Examples 5 and 9-15, and polystyrene bound BEMP was used as the base for Example 2.

[0078] The synthetic route outlined in Scheme 5 is exemplified by the synthesis of the following example:

iV-(4,5-dimethyl-3-isoxazolyl)-iV-(πiethoxyniethyl)-4^l-[2-butyl-imidazo[4,5-c]pyridin- 4(5H)-one-3yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (3)

[0079] To a solution of 50 mg (0.10 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyO-N-CmethoxymethyO^'-bromomethyl-l'-CethoxymethyOflJ'-biphenyl]^- sulfonamide (1) and 22 mg (0.10 mmol, 1.0 eq.) of 2-butyl-3H-imidazo[4,5-c]pyridin-4(5H)- one (2) in 4 mL of anhydrous DMF was added 33 mg (0.24 mmol, 2.5 eq.) of potassium carbonate. The resulting mixture was stirred at room temperature for 18 h. The mixture was diluted with 4 mL of water and the mixture extracted with 3 x 10 mL of EtOAc. The combined organic extracts were dried (Na₂SO₄) and the solvent removed in vacuo. The residue was purified by flash chromatography (0-10% MeOΗ/CΗ₂Cl₂) to provide 30 mg of N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[2-butyl-imidazo[4,5-c]pyridin-4(5H)- one-3yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide (3).

iY-(4,5-dimethyl-3-isoxazolyI)-4'-[2-butyl-imidazo[4,5-c]pyridin-4(5Jϊ)-one-3yl-methyl]- 2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 3)

Example 3 [0080] 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)-4¹-[2-butyl-imidazo[4,5-c]pyridin-4(5H)-one-3yl-methyl]-2^l- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 3). δ_Η (CD₃OD, 300 MHz) 0.98 (t, 3H), 1.06 (t, 3H), 1.46 (m, 2H), 1.73 (m, 5H), 2.23 (s, 3H), 3.17 (m, 2H), 3.3 (m, obscured by solvent), 4.12 (2H, q), 6.09 (s, 2H), 6.81 (d, IH), 7.11 (d, IH), 7.25 (m, 4H), 7.46 (s, IH), 7.62 (m, 3H), 8.15 (m, IH); m/z found 590.1 [M+H]⁺.

[0081] Compounds of formula Ib (Examples 16 and 17) were synthesized according to the general synthetic route outlined in Scheme 6.

IHe ^Ib

Scheme 6

[0082] The synthetic route outlined in Scheme 6 is exemplified by the synthesis of the following example:

N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[2-chloro-3-nitropyridin-4-amine- lyl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (6)

[0083] To a solution of 80 mg (0.17 mmol, 1.0 eq.) of _J/V-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-aminomethyl-2'-(ethoxymethyl)[l,r-biphenyl]-2- sulfonamide (4) and 33 mg (0.17 mmol, 1.0 eq.) of 2,4-dichloro-3-nitropyridine (5) in 4 mL of anhydrous THF was added 24 mg (0.17 mmol, 1.0 eq.) of potassium carbonate. The resulting mixture was stirred at room temperature for 40 h. The mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography (0-100% EtOAc/ Hexanes) to provide 56 mg of N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[2- chloro-3-nitropyridin-4-amine-lyl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (6).

Λ^r-(4,5-dimethyl-3-isoxazoIyl)-iV-(methoxymethyl)-4'-[2-chloro-3-aminopyridin-4- amine-lyl-methyI]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (7)

[0084] To a solution of 56 mg (0.093 mmol, 1 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[2-chloro-3-nitropyridin-4-amine-lyl-methyl]-2'- (ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (6) in 10 mL of anhydrous THF was added a catalytic amount of Raney Ni in water and the mixture was hydrogenated at 30 psi for 2 h. The mixture was filtered and the solvent was removed in vacuo to provide 52 mg of crude N- (4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[2-chloro-3-aminopyridin-4-amine-lyl- methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (7). 7V-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[2-chloro-3-(butyIamido)pyridin-4- amine-lyl-methylj-l'^ethoxymethyljl^l'-biphenylj^-sulfonamide (9)

[0085] To a solution of 48 mg (0.5 mmol, 6 eq.) of butyric acid in DCM was added 92 mg (0.5 mmol, 6 eq.) of carbonyl diimidazole. The resulting mixture was stirred for 20 min before 52 mg (0.091 mmol) of N-(4,5-dimethyl-3-isoxazolyl)-N- (methoxymethyl)-4'-[2-chloro-3-aminopyridin-4-amine-lyl-methyl]-2'-(ethoxymethyl)[l,r- biphenyl]-2-sulfonamide (7) was added. The reaction mixture was then heated at 50 °C for 5 days. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (0-100% CH₂Cl₂/Et0Ac) to provide 16 mg of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[2-chloro-3-(butylamido)pyridin-4-amine-lyl-methyl]-2'- (ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide (9).

7V-(4,5-dimethyl-3-isoxazolyl)-4'-[2-propyl-imidazo[4,5-c]pyridin-4(5H)-one-l-yI- methyl]-2'-(ethoxymethyl)[l,l'-biphenylJ-2-sulfonamide (Example 17)

Example 17

[0086] A mixture of 16 mg (0.025 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[2-chloro-3-(butylamido)pyridin-4-amine-lyl-methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide 9 in 1 :1 (v/v) EtOH/3 M aqueous NaOH was heated at 80 ⁰C for 4 hours. The reaction mixture was extracted with EtOAc (3X) and the combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. The resulting residue was purified by flash chromatography (0-100% CH₂Cl₂/Et0Ac) to provide 11 mg of the MOM protected derivative, which was then deprotected using General Procedure A to provide 4 mg of N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-propyl-imidazo[4,5-c]pyridin-4(5H)- one-l-yl-methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 17). δπ (CD₃OD, 300 MHz) 1.19 (m, 6H), 1.89 (s, 3H), 1.95 (q, 2H), 2.73 (s, 3H), 3.32 (t, 2H), 3.3 (m, obscured by solvent), 4.28 (q , 2H,), 5.88 (s, 2H), 6.97 (d, IH), 7.30 (m, 2H), 7.38 (m, IH), 7.52 (br s, IH), 7.66 (d, IH) 7.76 (m, 2H), 8.25 (m, IH); m/z found 590.1 [M+H]⁺.

[0087] Compounds of formula Ic were synthesized according to the general synthetic route outlined in Scheme 7. Aminopyrimidine intermediates of type IHf were synthesized according to J. Med. Chem. 1981, 24, 382.

OReduction ιι) Annulation

Deprotection

Scheme 7

[0088] This is exemplified by the synthesis of Example 19: Λ^f-(4,5-dimethyl-3-isoxazolyl)-Λ^r-(methoxymethyl)-4'-[[(2,6-dimethyI-5-cyano-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (ll)

[0089] To a solution of 85 mg (0.57 mmol, 2 eq.) of 4-amino-2,6- dimethylpyrimidine-5-carbonitrile (10) in 3 mL of anhydrous DMF was added 14 mg of sodium hydride and the mixture stirred at room temperature for 30 min. A solution of 150 mg (0.29 mmol) of N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-bromomethyl-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (1) in 1 mL of DMF was added and the mixture was stirred at room temperature for a further 1 h. The mixture was diluted with 3 mL of water and the mixture extracted with 3 x 5 mL of EtOAc. The combined organic extracts were dried (Na₂SO₄) and the solvent was removed in vacuo. The residue was purified by flash chromatography (50% EtOAc/hexanes) to provide 166 mg of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[[(2,6-dimethyl-5-cyano-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (11).

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-aminomethyl-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (12)

[0090] To a solution of 150 mg (0.27 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[[(2,6-dimethyl-5-cyano-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (11) in 15 mL of 60% aqueous formic acid was added approximately 200 mg of Raney Ni in water and the mixture hydrogenated at 50 psi for 3 h. The mixture was filtered and the solvent evaporated. The components of the reaction mixture were isolated by semi-prep hplc and individually deprotected according to General procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-aminomethyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (12) 5_H (CD₃OD, 400 MHz) 1.09 (t, 3H), 1.75 (s, 3H), 2.26 (s, 3H), 2.64 (s, 3H), 2.65 (s, 3H), 3.3 (m, obscured by solvent), 4.12 (2H, ABq), 4.31 (s, 2H), 4.93 (s, 2H), 7.09 (d, IH), 7.23 (dd, IH), 7.39 (dd, IH), 7.63 (m, 4H), 8.14 (dd, IH); m/z found 551.1, [M+H]⁺ and N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimemyl-5-hydroxymethyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (13) 5_H (CD₃OD, 400 MHz) 1.07 (t, 3H), 1.73 (s, 3H), 2.25 (s, 3H), 2.50 (s, 3H), 2.59 (s, 3H), 3.3 (m, obscured by solvent), 4.13 (2H, ABq), 4.69 (s, 2H), 4.92 (s, 2H), 7.07 (d, IH), 7.27 (m, 2H), 7.62 (m, 3H), 8.15 (dd, IH); m/z found 552.1, [M+H]⁺

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5,7-dimethyl-3,4-dihydropyrimido[4,5-rf]pyrimidm-2- one-lyl-methyl]-2'-(ethoxymethyl)[l,l'-biphenyI]-2-sulfonamide (Example 18)

Example 18

[0091] To a solution of 24 mg (0.044 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-4^l-[[(2,6-dimethyl-5-aminomethyl-4-pyrimidinyl)amino] methyl]-2'-

(ethoxyniethyl)[l,l'-biphenyl]-2-sulfonamide (12) in 2 mL Of CH₂Cl₂ was added 21 mg (0.13 mmol, 3.0 eq.) of carbonyl diimidazole. The resulting reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo. The resulting residue was purified by flash chromatography (0-100% CH₂Cl₂ZEtO Ac) and then semi-prep hplc to afford 8 mg of N-(4,5-dimethyl-3-isoxazolyl)-4'-[5,7-dimethyl-3,4-dihydropyrimido[4,5-(i]pyrimidin-2-one- lyl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 18). δ_H (CDCl₃, 300 MHz) 1.07 (t, 3H), 1.75 (s, 3H), 2.22 (s, 3H), 2.29 (s, 3H), 2.58 (s, 3H), 2.74 (s, 3H), 3.34 (m, 2H), 4.14 (q, 2H), 4.43 (br s, 2H) 4.65 (s, 2H), 5.29 (s, 2H), 7.18 (d, IH), 7.24 (dd, IH), 7.36 (dd, IH), 7.53 (m, 2H), 7.67 (d, IH) 8.12 (dd, IH); m/z found 577.0, [M+H]⁺

Λ^r-(4,5-dimethyI-3-isoxazolyl)-4'-[3,5,7-trimethyl-3,4-dihydropyrimido[4,5-d]pyriiiiidin- 2-one-l-yl-methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-suIfonamide (Example 19).

Example 19

[0092] To a solution of 24 mg (0.039 mmol, 1 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[5,7-dimethyl-3,4-dihydropyrimido[4,5-i/]pyrimidin-2- one-lyl-methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (14) (an intermediate produced in the synthesis of Compound 12) in 2 mL of DMF was added 1.5 eq. of sodium hydride. The reaction mixture was stirred at room temperature for 30 min 1.0 eq methyl iodide was added. The reaction mixture was stirred at room temperature for 2 h and then 1 mL of water was added. The reaction mixture was then extracted with EtOAc (3X) and then the combined organics were dried (Na₂SO₄). The volatiles were removed in vacuo and the resulting residue was purified by semi-prep hplc to afford 9 mg of N-(4,5-dimethyl-3- isoxazolyl)-4'-[3,5,7-trimethyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2-one-l-yl-methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 19). δ_H (CD₃OD, 400 MHz) 1.08 (t, 3H), 1.72 (s, 3H), 2.26 (s, 3H), 2.53 (s, 3H), 2.74 (s, 3H), 3.15 (s, 3H), 3.3 (m, obscured by solvent), 4.10 (q, 2H), 4.65 (s, 2H), 5.40 (s, 2H), 7.02 (d, IH), 7.22 (dd, IH), 7.30 (dd, IH), 7.54 (m, IH), 7.62 (m, 2H), 8.16 (dd, IH); m/z found 591.0, [M+H]⁺.

[0093] Compounds of formula Id were synthesized according to the general synthetic route outlined in Scheme 8. i)reduction H) annulation

deprotection

IHi Id

Scheme 8

[0094] This is exemplified by the synthesis of Example 20:

iV-(4,5-dimethyl-3-isoxazolyI)-iV-(methoxymethyl)-4'-[4-chloro-imidazo[4,5-c]pyridin- ICS/O-one-lyl-methyll-Z'-CethoxymethyOf^r-biphenyll-Z-sulfonamide ClS)

IS

[0095] To a solution of 46 mg (0.08 mmol, 1.0 eq.) of _V-(4,5-dimethyl-3- isoxazoly l)-/V-(methoxymethyl)-4'- [2-chloro-3 -aminopyridin-4-amine- 1 yl-methyl] -2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (7) in 3 mL of CH₂Cl₂ was added of 17 mg (0.19 mmol, 2.4 eq.) of butyric acid and 77 mg (0.48 mmol, 6 eq.) of carbonyl diimidazole. The resulting mixture was heated at 40 °C for 16 h and then 60 °C for 24 h. The mixture was allowed to cool to rom temperature and the solvent was removed in vacuo, the residue was resuspended in 4 mL of water and extracted with EtOAc (3X). The combined organics were dried (Na₂SO₄) and the volatiles were removed in vacuo. The resulting residue was purified by flash chromatography (0-100% EtOAc/hexanes) to provide 34 mg of N-(4,5-dimethyl-3- isoxazolyl)-iV-(methoxymethyl)-4^l-[4-chloro-imidazo[4,5-c]pyridin-2(3H)-one-lyl-methyl]- 2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (15).

iV-(4,5-dimethyl-3-isoxazolyl)- -4'-[4-chloro-imidazo[4,5-c]pyridin-2(3H)-one-lyl- methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 20)

15 Example 20

[0096] To a solution of 30 mg of N-(4,5-dimethyl-3-isoxazolyl)-N- (methoxymethyl)-4'-[4-chloro-imidazo[4,5-c]pyridin-2(3H)-one-lyl-methyl]-2'- (ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (15) in 6 M HCL was added 1 mL of EtOH. The resulting reaction mixture was heated at 100 °C for 18 h. The volatiles were removed in vacuo and the resulting residue was purified by semi-prep hplc to afford 11 mg of iV-(4,5- dimethyl-3-isoxazolyl)-4'-[4-chloro-imidazo[4,5-c]pyridin-2(3H)-one-lyl-methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 20); (CD₃OD, 400 MHz) 1.03 (t, 3H), 1.62 (s, 3H), 2.21 (s, 3H), 3.26 (m, 2H), 4.07 (q, 2H), 5.19 (m, 2H), 5.40 (s, 2H), 7.03 (d, IH), 7.20 (dd, IH), 7.24 (m, 2H), 7.47 (s, IH), 7.61 (m, 2H), 8.02 (d, IH), 8.17 (dd, IH); m/z found 568.0, [M+H]⁺.

[0097] Compounds of formula Id were synthesized according to the general synthetic route outlined in Scheme 9.

Deprotection

HIk

Scheme 9

[0098] This is exemplified by the synthesis of Example 21 :

16

Λ^r-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4'-[5-(l-hydroxyethyl)-2,6 dimethylpyrimidin-4-amine-lyl-methyl]-2'-(ethoxymethyI)[l,l'-biphenyl]-2- sulfonamide (17)

Compounds 15 and 16 were synthesized using similar procedures to those outlined in J. Med. Chem. 1998, 47, 4251.

[0099] Deprotection of N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[5- ( 1 -ethoxyviny l)-2,6 dimethylpyrimidin-4-amine- 1 yl-methyl]-2'-(ethoxymethyl)[ 1 , 1 '- biphenyl]-2-sulfonamide (16) to generate the methyl ketone (17) was achieved using 1 :1 v/v 1 M HCl/acetone for 12 h. To a solution of 60 mg (0.1 mmol, 1.0 eq.) of the resulting methyl ketone in 4 mL of methanol was added 38 mg (1 mmol) of sodium borohydride and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and 3 mL of water added. The mixture was extracted with 3 x 3 mL of EtOAc and the combined organic extracted dried (Na₂SO₄) to afford N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-[5- (1 -hydroxyethyl)-2,6 dimethylpyrimidin-4-amine-l yl-methyl]-2'-(ethoxymethyl)[l , 1 '- biphenyl]-2-sulfonamide (17).

iV-(4,5-dimethyl-3-isoxazolyl)-4'-[4,5,7-trimethyl-pyrimido[4,5-d][l,3]oxazin-2(4H)-one- lyl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 21)

Example 21

[0100] To a solution of 93 mg (0.15 mmol, l.Oeq.) of N-(4,5-dimethyl-3- isoxazoly l)-jV-(methoxymethyl)-4'- [5 -( 1 -hydroxyethyl)-2,6-dimethylpyrimidin-4-amine- 1 yl- methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (17) and 0.026 mL of DEIA (0.015 mmol, 1.0 eq.) in CH₂Cl₂ was addded 35 mg (0.15 mmol. 1.0 eq.) of triphosgene. The 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. The resulting residue was purified by flash chromatography (0-100% EtOAc/hexanes then 0-10% MeOH in CH₂Cl₂) and the isolated product deprotected using General Procedure A to afford 15 mg of iV-(4,5-dimethyl-3- isoxazolyl)-4'-[4,5,7-trimethyl-pyrimido[4,5-d][l,3]oxazin-2(4H)-one-lyl-methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 21). δ_Η (CD₃OD, 300 MHz) 1.06 (t, 3H), 1.61 (m, 3H), 1.69 (m, 3H), 2.25 (m, 3H), 2.51 (s, 3H), 2.68 (d, 3H), 3.3 (m, obscured by solvent), 4.09 (m, 2H), 5.41 (m, 2H), 5.87 (q, IH), 7.03 (d, IH), 7.23 (m, IH), 7.31 (m, IH), 7.55 (m, IH), 7.62 (m, 2H), 8.17 (m, IH); m/z found 592.0, [M+H]⁺.

[0101] Compounds of formula If (Examples 22 to 41) were synthesized according to the general synthetic route outlined in Scheme 10 where Y = C or N.

Coupling

Scheme 10

[0102] This is exemplified by the synthesis of Example 23:

Ethyl 2-(4-bromo-3-(ethoxymethyl)benzyl)-3-oxohexanoate (Compound 22)

19 21

[0103] To a mixture of l-bromo-4-(bromomethyl)-2-(ethoxymethyl)benzene (19) (1.0 eq.) and ethyl 3-oxohexanoate (20) (1.0 eq.) in THF was added DIEA (2.0 eq.), followed by LiCl (1.0 eq.). The resulting reaction mixture was heated at refluxed for 3 days. The solvent was removed in vacuo and then redissolved EtOAc. The organic layer was washed with H₂O and then concentrated in vacuo. The resulting residue was purified by flash chromatography to give ethyl 2-(4-bromo-3-(ethoxymethyl)benzyl)-3-oxohexanoate (Compound 21).

5-(4-bromo-3-(ethoxymethyI)benzyl)-2-methyI-6-propylpyrimidin-4(3H)-one (Compound 23)

[0104] To a solution of acetamidine hydrochloride (22) (4.0 eq.) in MeOH was added NaOMe (6.0 eq.). The reaction mixture was stirred for 10 minutes at room temperature before 2-(4-bromo-3-(ethoxymethyl)benzyl)-3-oxohexanoate (21) (1.0 eq.) was added. The reaction mixture was heated to refluxed 16 h. The solvent was removed in vacuo and the residue was diluted with H₂O and adjusted the pH to 6 with acetic acid. The resulting precipitate was filtered, washed with water and dried to afford 5-(4-bromo-3- (ethoxymethyl)benzyl)-2-methyl-6-propylpyrimidin-4(3H)-one (23).

⁰C, 60mιn

23 24 25

N-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4'-[(2-methyl-6-propylpyrimidin- 4(3H)-one)-5yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Compound 25) [0105] A reaction mixture of iV-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide-2-boronic acid (1.2 eq.), 5-(4-bromo-3- (ethoxymethyl)benzyl)-2-methyl-6-propylpyrimidin-4(3H)-one (23) (1.0 eq.), Pd(PPh₃)₄ (0.1 eq.) and Na₂CO₃ (2.0 eq.) in 2 mL toluene, 2 mL TΗF and 1 mL H₂O was subjected to microwave irradiation under a nitrogen atmosphere, maintaining an internal reaction temperature of 150 ⁰C for 1 h.. After cooling to RT, the organic layer was separated and concentrated in vacuo. The residue was purified by prep. TLC to give N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[(2-methyl-6-propylpyrimidin-4(3H)-one)-5yl-methyl]-2'- (ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide (25).

iV-(4,5-dimethyl-3-isoxazoIyl)-4'-[(2-methyl-6-propylpyriniidin-4(3H)-one)-5yl-methyl]- 2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 23)

25 Example 23

[0106] 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); δ_Η (CD₃OD, 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, 2H), 4.13 (q, 2H), 6.94 (d, IH), 7.18 (d, IH), 7.22 (d, IH), 7.39 (s, IH), 7.58 (m, 2H), 8.17 (d, IH); m/z found 551.0 [M+H]⁺.

[0107] 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.

ATI receptor binding assay

[0108] Commercially-available membranes (Euroscreen) from CHO-Kl cells expressing the human angiotensin II receptor type 1 (ATI), corresponding to Genbank accession number M91464, were used to establish receptor binding assays. The K_D (180 pM) for [¹²⁵I] [Sar¹ He⁸] angiotensin II binding to ATi was determined as follows: [¹²⁵I] [Sari Ile8] Angiotensin II (PerkinElmer) was allowed to bind for one hour at 25 ⁰C, with agitation, to membrane preparations (0.125 μg/well) in a 96-well polypropylene microtiter plate, in 50 rnM Tris-HCl, pH 7.5, 5mM MgCl₂, ImM EDTA, 0.1% bovine serum albumin (BSA). 1 μM unlabeled [Sar VaI Ala ] angiotensin II (Bachem) was used to define nonspecific binding. To terminate the reaction, reaction mixtures (100 μL) 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 MgCl₂. Detection in the TriLux (PerkinElmer) was carried out in the presence of 40 μL/ well scintillation fluid.

[0109] Scintillation proximity format competition binding assays were performed in a reaction volume of 40 μL in white clear-bottom 384-well plates, in 50 mM Tris-HCl, pH 7.5, 5mM MgCl₂, 0.1% BSA, 0.5% dimethylsulfoxide (DMSO) containing 0.125 μg/well ATi membrane preparation, 30 pM [¹²⁵I] [Sar¹ He⁸] angiotensin II, 50 μg/well wheat germ agglutinin (WGA)-PVT scintillation proximity beads (Amersham/ GE Healthcare), and test compound. After five minutes of agitation, reactions were allowed to stand for 16-20 hours before detection in the TriLux (PerkinElmer). Ki values were calculated using the Cheng- Prusoff equation and the predetermined K_D value.

ET_A receptor binding assay

[0110] The K_D value (76 pM) for [¹²⁵I] endothelin-1 at ET_A was measured as follows: a 50 μL reaction containing radioligand (PerkinElmer), 0.25 μg/well membranes from mammalian cells expressing recombinant ET_A (commercially available from Chemicon, accession number S63938), 50 mM HEPES, pH 7.5, 5 mM MgCl₂, 1 mM CaCl₂, 0.2% BSA, 2 mM phosphoramidon, 0.5% DMSO, was carried out for one hour at 25 ⁰C, 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 μL/ well scintillation fluid.

[0111] Scintillation proximity format competition binding assays were performed in a reaction volume of 40 μL in white clear-bottom 384- well plates, in 50 mM Tris-HCl, pH 7.5, 5mM MgCl₂, 0.5 mM CaCl₂, 0.1% BSA, 2 mM phosphoramidon, 0.5% DMSO containing 0.25 μg/well ET_A membrane preparation, 35 pM [ ⁵I] endothelin-1, 50 μg/well wheat germ agglutinin (WGA)-PVT scintillation proximity beads (Amersham/ GE Healthcare), and test compound. After five minutes of agitation, reactions were allowed to stand for 16-20 hours before detection in the TriLux (PerkinElmer). Ki values were calculated using the Cheng-Prusoff equation and the predetermined K_D value.

[0112] Analytical hplc data was acquired using a Millenium 2690/996PDA separations system employing a Phenomenex Columbus 5u cl8 column 50 x 4.60 mm analytical column. The aqueous acetonitrile based solvent gradient involves;

0 - 0.5 min - Isocratic 10% of (0.05% TFA/ acetonitrile);

0.5 min - 5.5 min - Linear gradient of 10 - 90% of (0.05% TFA/acetonitrile):

5.5 min - 7.5 min - Isocratic 90% of (0.05% TFA/acetonitrile);

7.5 min - 8 min - Linear gradient of 90 - 10% of (0.05% TFA/acetonitrile);

8 min - 10 min - Isocratic 10% of (0.05% TFA/acetonitrile).

Flow rate = 0.4 mL/min. Mass Spectroscopy was conducted using Thermo-electron LCQ classic. Liquid Chromatography Mass Spectroscopy was conducted using a Waters Millenium

2690/996PDA linked Thermo-electron LCQ classic.

Alternatively, LCMS data was acquired for Examples 16, 25, and 34 using a Micromass ZQ

LCMS equipped with a 2996 PDA using the same gradient and column above.

¹H NMR spectroscopy was conducted using a Varian 300 MHz Gemini 2000 NMR or a

Bruker 400 MHz Ultrashield Avance II NMR.

[0113] Some comparative examples are shown below. All of the Ki's for ATI and ETA are below 2μM.

Table 1.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I, and pharmaceutically acceptable salts thereof

I wherein R¹ is selected from the group consisting of

wherein A is a fused ring, , either unsubstituted or substutituted with alkyl, halogen, oxo, alkoxy or acyl imine;

G is a fused unsaturated heterocycle containing one -NH;

J is oxygen or -NR8;

R4 is hydrogen or (Cl-Cό)alkyl;

R5 is hydrogen, (Cl-Cό)alkyl or halogen; R is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, hydroxyl and alkoxy;

R⁷ is a six-membered heterocycle , either unsubstituted or substutituted with one or more of hydrogen, (CrC₆)alkyl, alkoxycarbonyl or alkoxy;

R⁸ is hydrogen or (C]-C₆)alkyl; and

M is acyl imine or oxo, and

R2 is selected from the group consisting of hydrogen, (Cl-Cό)alkyl and alkoxy alky 1; and

R3 is an optionally substituted heterocycle;

2. A compound according to claim 1 wherein R³ is isoxazole , either unsubstituted or substutituted with one or more of (Ci-C₆)alkyl or halogen.

3. A compound according to claim 2 wherein R³ is isoxazole , either unsubstituted or substutituted with one or more of methyl or fluoro.

4. A compound according to claim 1 wherein R is chosen from hydrogen, propyl and ethoxymethyl.

5. A compound according to claim 1 wherein R¹ is

6. A compound according to claim 5 wherein R⁵ is chosen from hydrogen and (d-C₆)alkyl.

7. A compound according to claim 1 wherein R¹ is

8. A compound according to claim 7 wherein A is a triazole , either unsubstituted or substutituted with oxo and R⁵ is hydrogen or (Ci-C6)alkyl.

9. A compound according to claim 8 wherein R is

, R⁴ is methyl and R⁵ is propyl.

10. A compound according to claim 1 wherein R¹ is

11. A compound according to claim 10 wherein R⁵ is hydrogen or (Ci-C₆)alkyl and R⁷ is a carbon-attached, six-membered heterocycle containing one or two nitrogens.

12. A compound according to claim 11 wherein R⁵ is butyl and R⁷ is a pyrazine, pyridazine or pyrimidine , either unsubstituted or substutituted with one or two methyl groups.

13. A compound according to claim 11 wherein R⁵ is butyl and R⁷ is a pyridine , either unsubstituted or substutituted with methoxy or methoxycarbonyl.

14. A compound according to claim 1 wherein R¹ is

15. A compound according to claim 14 wherein B is oxadiazole or thiadiazole and R⁵ is (C)-C₆)alkyl or hydrogen.

16. A compound according to claim 1 wherein R¹ is

17. A compound according to claim 16 wherein E is triazine and R and R⁵ are both hydrogen or (Ci-C₆)alkyl.

18. A compound according to claim 17 wherein R⁴ is methyl and R⁵ is butyl.

19. A compound according to claim 1 wherein R¹ is

20. A compound according to claim 19 wherein J is oxygen, NH or NCH₃; R⁴ and R⁵ are (Ci-C₆)alkyl or hydrogen; and

R⁶ is selected from the group consisting of hydrogen and (Ci-C₆)alkyl.

21. A compound according to claim 20 wherein R⁴ and R⁵ are methyl and R⁶ is hydrogen or methyl.

22. A compound according to claim 1 wherein R¹ is

23. A compound according to claim 22 wherein R⁵ is chosen from hydrogen and (Ci-C₆)alkyl; and R⁶ is hydrogen or hydroxyl.

24. A compound according to claim 23 wherein R⁴ and R⁵ are each methyl and R⁶ is hydrogen or hydroxyl.

25. A compound according to claim 1 wherein R¹ is

26. A compound according to claim 25 wherein R¹ is

R⁵ is (Ci-C₆)alkyl.

27. A compound according to claim 1 wherein R¹ is

28. A compound according to claim 27 wherein R⁵ is halogen.

29. A compound according to claim 1 wherein R¹ is

30. A compound according to claim 29 wherein R⁴ is (C)-C₆)alkyl.

31. A compound according to claim 1 selected from the group consisting of N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-propyl-imidazo[4,5-c]pyridm-4(5H)-one-

3yl-methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(3-butyl-6-methyl-l,2,4-triazin-5-one-4yl)- methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-imidazo[4,5-c]pyridin-4(5H)-one- 3yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

Λf-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-2,3-diazaspiro[4.4]nonane-l,4- dione-3yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[3-butyl-l,2,4-oxadiazol-5-one-4yl-methyl]- 2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(N-(5-ethyl-l,3,4-thiadiazol-2- ylidene)acetamide)-3yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide; N-(4,5-dimethyl-3-isoxazolyl)-4'-[(3-butyl-6-methyl-l,2,4-triazin-5-one-2yl)- methyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[(3-butyl-6-methyl-l,2,4-triazin-5-one- 2yl)-methyl]-[l , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(3-butyl-6-methyl-l,2,4-triazin-5-one-2yl)- methyl]-[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(3-butyl-6-methyl-l,2,4-triazin-5-one-2yl)- methyl]-2'-propyl[l , 1 '-biphenyl]-2-sulfonamide;

N-(4-fluoro-5 -methyl-3 -isoxazolyl)-4'- [(3 -butyl-6-methyl- 1 ,2,4-triazin-5-one- 2yl)-methyl]-2'-propyl[l , 1 '-biphenyl]-2-sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[(2,4-dimethylpyrido[2,3-i/|pyrimidin- 7-one-8yl)-methyl]-2'-propyl[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(2,4-dimethylpyrido[2,3-d]pyrimidin-7-one- 8yl)-methyl]-2'-(ethoxymethyl) [l,l'-biphenyl]-2-sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[(2,4-dimethylpyrido[2,3-(/]pyrimidin- 7-one-8yl)-methyl]-2'-(ethoxymethyl) [l,l'-biphenyl]-2-sulfonamide;

7V-(4,5-dimethyl-3-isoxazolyl)-4'-[2-propyl-imidazo[4,5-c]pyridin-4(5H)-one- 1 -yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4^l-[2-butyl-imidazo[4,5-c]pyridin-4(5H)-one-l- yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5,7-dimethyl-3,4-dihydropyrimido[4,5- <i]pyrimidin-2-one- 1 yl-methyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[3,5,7-trimethyl-3,4-dihydropyrimido[4,5- i/]pyriniidin-2-one- 1 -yl-methyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)- -4'-[4-chloro-imidazo[4,5-c]pyridin-2(3H)- one-lyl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[4,5,7-trimethyl-pyrimido[4,5-d][l,3]oxazin- 2(4H)-one-l yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(2-methyl-6-propylpyrimidin-4(3H)-one)- 5yl-methyl]-[l,r-biphenyl]-2-sulfonamide; N-(4,5-dimethyl-3-isoxazolyl)-4'-[(2-methyl-6-propylpyrimidin-4(3H)-one)- 5yl-methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl-[l,2,4]triazolo[l,5- c]pyrimidine)-8yl-methyl]-2'-(ethoxymethyl)[ 1 , l'-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl-[l,2,4]triazolo[l,5- c]pyrimidine)-8yl-methyl]-[l , 1 '-biphenyl]-2-sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4^l-[(5-methyl-7-propyl- [1 ,2,4]triazolo[l ,5-c]pyrimidine)-8yl-methyl]-[l ,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl-[l,2,4]triazolo[l,5- c]pyrimidine)-8yl-methyl]-2'-(propyl)[l,r-biphenyl]-2-sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl- [ 1 ,2,4] triazolo [ 1 ,5 -c]pyrimidine)-8yl-methyl] -2'-(propyl) [1,1 '-biphenyl] -2- sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl-

[l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one)-8yl-methyl]-2'-(propyl)[l,r-biphenyl]-2- sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl-[l,2,4]triazolo[l,5- c]pyrimidin-2(3H)-one)-8yl-methyl]-2'-(propyl)[l ,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[(5-methyl-7-propyl-[l,2,4]triazolo[l,5- c]pyrimidin-2(3H)-one)-8yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3 -isoxazolyl)-4'- [(5 -Ηydroxy-2,4-dimethyl-pyrido [2,3 - t/]pyriniidin-7-one)-8yl-methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide;

N-(4-fluoro,5-methyl-3-isoxazolyl)-4'-[(5-Hydroxy-2,4-dimethyl-pyrido[2,3- </]pyrimidin-7-one)-8yl-methyl]-[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(2,5-dimethylpyrazin-3yl)- imidazo- 1 yl-methyl]-2'-(propyl) [1,1 '-biphenyl] -2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(3-methylpyridazin-6yl)-imidazo- lyl-methyl]-2'-(propyl)[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(3-methylpyridazin-6yl)-imidazo- 1 yl-methyl]-[ 1 , 1 '-biphenyl]-2-sulfonamide; N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(2,5-dimethylpyrazin-3yl)- imidazo- lyl-methyl]-[l , 1 '-biphenyl]-2-sulfonamide;

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[2-butyl-4-(3-methylpyridazin-6yl)- imidazo- 1 yl-methy I]- [ 1 , 1 '-bipheny l]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(2-methoxypyridin-6yl)-imidazo- lyl-methyl]-2'-(propyl)[l,r-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(nicotinic acid methyl ester-6yl)- imidazo- 1 yl-methy l]-[ 1 , 1 '-biphenyl]-2-sulfonamide;

N-(4,5-dimethyl-3-isoxazolyl)-4'-[2-butyl-4-(nicotinic acid methyl ester-6yl)- imidazo-lyl-methyl]-2'-(propyl)[l,r-biphenyl]-2-sulfonamide; and the harmaceutically acceptable salts thereof.

32. Use of at least one compound according to any of claims 1-31 for the treatment of an endothelin-dependent or angiotensin II-dependent disorder.

33. Use of at least one compound according to any of claims 1-31 for the treatment of hypertension.

34. Use of at least one compound according to any of claims 1-31 for the treatment of pulmonary hypertension.

35. Use of at least one compound according to any of claims 1-31 for the treatment of primary pulmonary hypertension.

36. Use of at least one compound according to any of claims 1-31 for the treatment of low renin hypertension.

37. Use of at least one compound according to any of claims 1-31 for the treatment of male erectile dysfunction.

38. Use of at least one compound according to any of claims 1-31 for the treatment of male or female sexual dysfunction.

39. Use of at least one compound according to any of claims 1-31 for the treatment of heart failure.

40. Use of at least one compound according to any of claims 1-31 for the treatment of atherosclerosis.

41. Use of at least one compound according to any of claims 1-31 for the treatment of restenosis.

42. Use of at least one compound according to any of claims 1-31 for the treatment of endotoxemia.

43. Use of at least one compound according to any of claims 1-31 for the inhibition of cell growth.

44. Use of at least one compound according to any of claims 1-31 for the treatment of cancer.

45. Use of at least one compound according to any of claims 1-31 for the treatment of migraine.

46. Use of at least one compound according to any of claims 1-31 for the treatment of asthma.

47. Use of at least one compound according to any of claims 1-31 for the treatment of ischemia.

48. Use of at least one compound according to any of claims 1-31 for the treatment of subarachnoid hemorrhage.

49. Use of at least one compound according to any of claims 1-31 for the treatment of benign prostatic hypertrophy.

50. Use of at least one compound according to any of claims 1-31 for the treatment of a disorder selected from the group consisting of renal, glomerular and mesangial cell disorders.

51. Use of at least one compound according to any of claims 1-31 for the treatment of acute or chronic renal failure 1.

52. Use of at least one compound according to any of claims 1-31 for the treatment of diabetic nephropathy.

53. A pharmaceutical composition for the treatment of an endothelin-dependent or angiotensin II-dependent disorder, comprising a pharmaceutically acceptable vehicle or diluent and at least one compound according to any of claims 1-31 in an amount effective therefor.