WO1997033886A1 - Sulfonamides de biphenyl isoxazole substitues - Google Patents

Sulfonamides de biphenyl isoxazole substitues Download PDF

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Publication number
WO1997033886A1
WO1997033886A1 PCT/US1997/003670 US9703670W WO9733886A1 WO 1997033886 A1 WO1997033886 A1 WO 1997033886A1 US 9703670 W US9703670 W US 9703670W WO 9733886 A1 WO9733886 A1 WO 9733886A1
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Prior art keywords
compound
substituted
alkyl
treating
aryl
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PCT/US1997/003670
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English (en)
Inventor
Natesan Murugesan
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Bristol-Myers Squibb Company
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Priority to AU20742/97A priority Critical patent/AU2074297A/en
Publication of WO1997033886A1 publication Critical patent/WO1997033886A1/fr

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    • 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

Definitions

  • This invention relates to endothelin antagonists useful , inter alia, for the treatment of hypertension .
  • one of X and Y is N and the other is 0;
  • Q is N or NR 15 ;
  • J is O, S, N or NR 15 ;
  • the dotted line ⁇ between Q and K denotes an optional double bond when Q is N and K is CH;
  • the dotted line ⁇ between K and J denotes an optional double bond when K is CH and J is N;
  • R 1 and R 2 when present, and R 3 and R 4 , are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
  • R 3 and R 4 together may also be alkylene or
  • alkenylene either of which may be substituted with Z 1 , Z 2 and Z 3 , completing a 4- to 8- membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
  • R 5 is alkyl, alkenyl, alkynyl, cycloalkyl
  • cycloalkylalkyl cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z 1 , Z 2 and
  • R 6 , R 7 , R 8 , R 9 and R 10 are each independently
  • R 6 and R 7 together may be alkylene or alkenylene, either of which may be substituted with Z 1 , Z 2 and Z 3 , completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R 8 , R 9 and R 10 together are alkylene or alkenylene, either of which may be substituted with Z 1 , Z 2 and Z 3 , completing a 3- to 8-membered saturated or
  • R 11 , R 12 , R 13 and R 14 are each independently
  • Z 1 , Z 2 and Z 3 are each independently
  • Z 4 and Z 5 are each independently
  • Z 6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy;
  • cycloalkylalkyl cycloalkenyl; cycloalkenylalkyl; aryl;
  • Z 7 and Z 8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl or Z 7 and Z 8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
  • Z 9 and Z 10 are each independently a single bond, alkylene, alkenylene or alkynylene;
  • Z 7 , Z 8 and Z 11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
  • R 15 is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl
  • each m is independently 1 or 2;
  • each n is independently 0, 1 or 2;
  • p is 0 or an integer from 1 to 2.
  • Preferred compounds of the formula I are those having one or more (most preferably, all) of the following
  • X is O
  • Y is N
  • R 3 and R 4 are alkyl, especially lower alkyl such as methyl;
  • R 11 , R 12 , R 13 and R 14 are each independently hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide, or substituted lower alkyl, especially, R 12 , R 13 and R 14 are hydrogen and R 11 is hydrogen, hydroxy, amino,
  • heterocyclo alkenyl, alkoxy, carboxamide or substituted lower alkyl
  • R 1 and R 2 are hydrogen or are absent
  • R 15 is hydrogen, hydroxyethoxy methyl or methoxyethoxy methyl.
  • alkyl or "alk-” refers to straight or branched chain hydrocarbon groups having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms.
  • the expression “lower alkyl” refers to alkyl groups of 1 to 4 carbon atoms.
  • alkoxy refers to alkyl-O-;
  • alkylthio refers to alkyl-S-.
  • lower alkoxy refers to lower alkyl-O-.
  • aryl or "ar-" refers to phenyl, naphthyl and biphenyl.
  • aryloxy refers to aryl-O-
  • arylthio refers to aryl-S-.
  • alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10 carbon atoms having at least one double bond. Groups of two to four carbon atoms are preferred.
  • alkynyl refers to straight or branched chain groups of 2 to 10 carbon atoms having at least one triple bond. Groups of two to four carbon atoms are preferred.
  • alkylene refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., - (CH 2 ) x - wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
  • alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be
  • alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be
  • alkanoyl refers to groups of the formula -C(O) alkyl.
  • cycloalkyl and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
  • hydroxyalkyl refers to an alkyl group including one or more hydroxy radicals such as -CH 2 CH 2 OH, - CH 2 CH(OH)CH 2 OH, -CH(CH 2 OH) 2 and the like.
  • halogen and halo refer to fluorine, chlorine, bromine and iodine.
  • heterocyclo refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic or nonaromatic cyclic group for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl,
  • oxadiazolyl piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,
  • thiamorpholinyl thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.
  • bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl,
  • dihydroisoindolyl dihydroquinazolinyl (such as
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • substituted heterocyclo refers to a heterocycle substituted with 1, 2 or 3 of the following:
  • cyano (n) cyano; (o) sulfonamido (i.e., NH 2 -SO 2 -), sulfonamidoalkyl or sulfonamidodialkyl;
  • dialkylamino, halo or trihaloalkyl dialkylamino, halo or trihaloalkyl.
  • heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
  • salt(s) denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • Zwitterions are included within the term "salt(s)" as used herein, as are quaternary ammonium salts such as alkylammonium salts.
  • the compounds of formula I form salts which are also within the scope of this invention.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g. , in isolating or purifying the compounds of this invention.
  • the compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, t-butyl amine, benzathine, N-methyl-D-glueamide and hydrabamine, and with amino acids such as arginine, lysine and the like.
  • alkali metals such as sodium, potassium and lithium
  • alkaline earth metals such as calcium and magnesium
  • organic bases such as dicyclohexylamine, t-butyl amine, benzathine, N-methyl-D-glueamide and hydrabamine
  • amino acids such as arginine, lysine and the like.
  • compound I may form salts with a variety of organic and inorganic acids.
  • Such salts include those formed with hydrochloric acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, benzenesulfonate, toluenesulfonate and various other sulfonates, nitrates, phosphates, borates, acetates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, salicylates and the like.
  • Such salts may be formed by reacting
  • substituents comprise a basic moiety such as amino, zwitterions may be formed.
  • All stereoisomeric forms of the compounds of the formula I and salts thereof are contemplated in the present invention, whether present as a single enantiomer or diastereomer free of other stereoisomers, a racemic mixture, or a mixture of all other or other selected stereoisomeric forms thereof.
  • certain of the R 1 to R 4 and R 11 to R 14 substituents of compound I may contain asymmetric carbon atoms.
  • Such compounds of formula I may exist, therefore, in enantiomeric and diastereomeric forms and in racemic mixtures thereof. All are within the scope of this invention.
  • compound I may exist as enantiomers even in the absence of asymmetric carbons. All such enantiomers are within the scope of this invention.
  • the compounds of formula I are antagonists of ET-1, ET-2 and/or ET-3 and are useful in treatment of conditions associated with increased ET levels (e.g., dialysis, trauma and surgery) and of all endothelin-dependent disorders. They are thus useful as antihypertensive agents.
  • the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. They are also useful in pregnancy-induced
  • hypertension and coma preeclampsia and eclampsia
  • acute portal hypertension and hypertension secondary to treatment with erythropoietin preeclampsia and eclampsia
  • the compounds of the present invention are also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute and chronic 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 may also be 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 may also be useful as anti-arrhythmic 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.,
  • pulmonary hypertension e.g., plexogenic, embolic
  • 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 e.g., plexogenic, embolic
  • congestive heart failure including inhibition of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of hepatotoxicity and sudden death.
  • the compounds of this invention may be useful in the treatment of sickle cell disease including the
  • vasculitis such as lupus, systemic sclerosis, mixed cryoglobulinemia; and treatment of fibrosis associated with renal dysfunction and
  • the compounds of this invention may be 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;
  • psoriasis psoriasis
  • chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis (all types of dermatitis).
  • the compounds of this invention can also be formulated in combination with endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists; potassium channel openers; thrombin inhibitors (e.g., hirudin and the like); growth factor inhibitors such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; angiotensin II (All) receptor
  • ECE endothelin converting enzyme
  • PAF platelet activating factor
  • All angiotensin II
  • renin inhibitors angiotensin converting enzyme (ACE) inhibitors such as captopril, zofenopril, fosinopril, ceranapril, alacepril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds; neutral endopeptidase (NEP) inhibitors; dual NEP-ACE inhibitors; HMG CoA reductase inhibitors such as pravastatin and mevacor; squalene synthetase inhibitors; bile acid sequestrants such as questran; calcium channel blockers; potassium channel activators; beta-adrenergic agents; antiarrhythmic agents; diuretics, such as
  • chlorothiazide hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide,
  • methylchlorothiazide, trichloromethiazide, polythiazide or benzothiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds; and thrombolytic agents such as tissue
  • tPA plasminogen activator
  • streptokinase urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC).
  • APSAC anisoylated plasminogen streptokinase activator complex
  • combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range.
  • the compounds of this invention may also be formulated with, or useful in conjunction with, antifungal and immunosuppressive agents such as amphotericin B, cyclosporins and the like to counteract the glomerular contraction and nephrotoxicity secondary to such compounds.
  • antifungal and immunosuppressive agents such as amphotericin B, cyclosporins and the like to counteract the glomerular contraction and nephrotoxicity secondary to such compounds.
  • the compounds of the invention can be administered orally or parenterally to various mammalian species known to be subject to such maladies, e.g., humans, in an
  • the present invention provides pharmaceutical
  • compositions for the treatment of endothelin-related disorders comprising a compound of the formula I or
  • the active substance can be utilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per unit dosage of a compound or mixture of
  • compounds of formula I or in topical form for wound healing (0.01 to 5% by weight compound of formula I, 1 to 5 treatments per day). They may be compounded in a
  • Plastibase mineral oil gelled with polyethylene
  • the compounds of the invention may also be any organic compound having the same side chain length.
  • the compounds of the invention may also be any organic compound having the same side chain length.
  • the compounds of formula I can also be formulated in compositions such as sterile solutions or suspensions for parenteral administration. About 0.1 to 500 milligrams of a compound of formula I is compounded with a
  • compositions or preparations in a unit dosage form as called for by accepted pharmaceutical practice.
  • the amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
  • the compounds of the present invention may be prepared as follows.
  • the title compounds of the formula I may be prepared by a Pd(O) catalyzed coupling of an appropriately protected
  • phenylsulfonamide-2-boronic acid intermediate 2 with a 4-heterocyclic aryl halide 1 in the presence of a suitable base, such as aqueous potassium carbonate, and solvent, such as a mixture of toluene and ethanol.
  • a suitable base such as aqueous potassium carbonate
  • solvent such as a mixture of toluene and ethanol.
  • a boronic acid intermediate 2 may be prepared from a 2-bromophenylsulfonamide 4 (preparation of which is
  • 4-Heterocyclic aryl halide intermediate 1 may be prepared by methods known in the art, for example, those methods described in Lyga, Syn . Commun . , 16(2), 163-167 (1986) and J. Het . Chem. , 26, 125 (1989).
  • a 4'-heterocyclic aryl halide 5 (see compound 1 where halo is Br) can be converted to a boronic acid intermediate 6 via the sequence shown.
  • This compound 6, upon Pd(O) catalyzed coupling with a compound 4 can provide a biaryl analog 3, which upon deprotection can lead to the title compound I.
  • the biaryl analog 3 upon deprotection can lead to the title compound I.
  • heteroatoms of the heterocyclic ring bonded directly to the group -(CH 2 ) p - may be protected to prepare the boronic acid 6, and/or to facilitate the coupling reaction to make compound 3.
  • the boronic acid 6 may be protected to prepare the boronic acid 6, and/or to facilitate the coupling reaction to make compound 3.
  • heteroatoms of this heterocyclic ring are N, one of the groups may be protected by a suitable protecting group such as t-butoxycarbonyl, etc.
  • the boronic acid may be replaced with a tin species to perform the coupling reaction.
  • R 11 - R 14 groups are chosen to be compatible with the reaction conditions shown. Additionally, specific R 11 - R 14 groups may be converted into alternative R 11 - R 14 groups, either before or after coupling of Compound 1 with Compound 2, or Compound 4 with Compound 6, using methods known in the art.
  • the compounds of the present invention may also be prepared by methods described in or analogous to those described in U.S. Patent Application Serial No.
  • Step (A) To the product of Step (A) (3.5 g, 11.76 mmol) in 100 ml toluene was added triethyl amine (1.19 g, 11.76 mmol) and diphenylphosphoryl azide (3.23 g, 11.74 mmol) and the mixture was refluxed for 1.5 hrs. The solution was then poured into 150 ml of 5% aqueous KOH and stirred for 10 min. The aqueous layer was separated and acidified to pH 1 using hydrochloric acid. The mixture was then extracted with 3 x 100 ml ethyl acetate (EtOAc). The combined organic extracts were then dried and evaporated to provide 1.1 g (39%) of the title product of this step as a light yellow solid.
  • EtOAc 3 ml ethyl acetate
  • Step (B) To the product of Step (B) (240 mg, 1.0 mmol) in 10 ml tetrahydrofuran (THF), NaH (60% in mineral oil, 54 mg, 1.35 mmol) was added. The mixture was stirred at room temperature for 15 min. Methoxyethoxy methyl chloride (156 mg, 1.25 mmol) (“MEM” denotes methoxyethoxy methyl herein) was added dropwise. The reaction was stirred at room temperature for 3 hrs., and concentrated. 50 ml EtOAc was added and the organic liquid was washed with 5 ml H 2 O and 5 ml brine, dried and concentrated. The residue was

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les composés de formule (I) inhibent l'activité de l'endothéline. Les symboles R1, R2, Q, K, J, α, β, p, R?11, R12, R13, R14¿, X, Y, R3 et R4 sont définis dans le descriptif.
PCT/US1997/003670 1996-03-12 1997-03-07 Sulfonamides de biphenyl isoxazole substitues WO1997033886A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20742/97A AU2074297A (en) 1996-03-12 1997-03-07 Substituted biphenyl isoxazole sulfonamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1349196P 1996-03-12 1996-03-12
US60/013,491 1996-03-12

Publications (1)

Publication Number Publication Date
WO1997033886A1 true WO1997033886A1 (fr) 1997-09-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1094816A1 (fr) * 1998-07-06 2001-05-02 Bristol-Myers Squibb Company Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5411980A (en) * 1989-07-28 1995-05-02 Merck & Co., Inc. Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists
US5612359A (en) * 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5411980A (en) * 1989-07-28 1995-05-02 Merck & Co., Inc. Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists
US5612359A (en) * 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1094816A1 (fr) * 1998-07-06 2001-05-02 Bristol-Myers Squibb Company Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline
EP1094816A4 (fr) * 1998-07-06 2001-12-19 Bristol Myers Squibb Co Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline
JP2002519380A (ja) * 1998-07-06 2002-07-02 ブリストル−マイヤーズ スクイブ カンパニー 二元アンギオテンシン／エンドセリン・レセプタ拮抗剤としてのビフェニルスルホンアミド化合物
EP2002837A1 (fr) * 1998-07-06 2008-12-17 Bristol-Myers Squibb Company Sulfamides biphényl en tant qu'antagonistes de récepteur d'endothéline à angiotensine double
JP2010209096A (ja) * 1998-07-06 2010-09-24 Bristol Myers Squibb Co 二元アンギオテンシン／エンドセリン・レセプタ拮抗剤としてのビフェニルスルホンアミド化合物

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