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WO1991015479A1 - Isoxazoles, isothiazoles et pyrazoles substitues - Google Patents

Isoxazoles, isothiazoles et pyrazoles substitues Download PDF

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Publication number
WO1991015479A1
WO1991015479A1 PCT/US1991/001952 US9101952W WO9115479A1 WO 1991015479 A1 WO1991015479 A1 WO 1991015479A1 US 9101952 W US9101952 W US 9101952W WO 9115479 A1 WO9115479 A1 WO 9115479A1
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WO
WIPO (PCT)
Prior art keywords
methyl
butyl
pyrazole
biphenyl
alkyl
Prior art date
Application number
PCT/US1991/001952
Other languages
English (en)
Inventor
Eric E. Allen
William J. Greenlee
Malcolm Maccoss
Wallace T. Ashton
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP91507326A priority Critical patent/JPH05505822A/ja
Publication of WO1991015479A1 publication Critical patent/WO1991015479A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings

Definitions

  • the compounds of this invention also have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
  • CNS central nervous system
  • these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia.
  • Renin-angiotensin system plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure.
  • Angiotensin II (A II), an octapeptide hormone, is produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS.
  • ACE angiotensin converting enzyme
  • a II is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
  • One of the possible modes of controlling the RAS is angiotensin II receptor antagonism.
  • non-peptide compounds have been described as A II antagonists.
  • Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; 4,582,847; and
  • novel compounds of this invention have the general formula (I):
  • K is 0, S or NR 7 ;
  • R 1 is (a) -CO 2 R 5 ,
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of -OH, -SH, -C 1 -C 4 -alkyl,
  • R 2a and R 2b are independently
  • R 4 is H, C 1 -C 6 -alkyl, aryl or -CH 2 -aryl;
  • R 5 is H, -CH-O-C-R 4a , wherein R 4a is C 1 -C 6 -alkyl, aryl, or -CH 2 -aryl;
  • E is a single bond, -NR 13 (CH 2 ) s -, -S(O) x (CH 2 ) s - where x is 0 to 2 and s is 0 to 5, -CH(OH)-, -O-, -CO-;
  • R 7 is (a) -H,
  • R 8 is (a) hydrogen
  • R 9 is H, C 1 -C 5 -alkyl, aryl or -CH 2 -aryl;
  • R 10 is H, C 1 -C 4 -alkyl
  • R 11 is H, C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 4 -alkoxy alkyl, or -CH 2 -C 6 H 4 R 20 ;
  • R 12 is -CN, -NO 2 , -CO 2 R 4 , or -CF 3 ;
  • R 1 3 is H, C 2 -C 4 -alkanoyl, C 1 -C 6 -alkyl, allyl,
  • R 14 is H, C 1 -C 8 -alkyl, C 1 -C 8 -perfluoroalkyl,
  • R 15 is H, C 1 -C 6 -alkyl
  • R 16 is H, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl or benzyl;
  • R 17 is -NR 9 R 10 , -OR 10 , -NHCONH 2 , -NHCSNH 2 ,
  • R 18 and R 19 are independently C 1 -C 4 -alkyl or taken together are -(CH 2 ) q - where q is 2 or 3;
  • R 20 is H, -NO 2 , -NH 2 , -OH or -OCH 3 ;
  • R 21 is (a) -CO-aryl
  • R 23 is (a) aryl
  • L is single bond, -CH 2 -, -O-, -S(O)p, or NR 9 ;
  • Z is 0, NR 13 or S
  • r is 1 or 2;
  • alkyl alkenyl
  • alkynyl alkynyl: and the like include both the straight chain and branched chain species of these generic terms wherein the number of carbon atoms in the species permit. Unless otherwise noted, the specific names for these generic terms shall mean the straight chain species.
  • butyl shall mean the normal butyl substituent, n-butyl.
  • halo means Cl, Br, I or F.
  • One embodiment of the compounds of formula (I) are those compounds wherein K is -O-.
  • a class of compounds within this embodiment is that wherein:
  • R 1 is -COOH -NH-SO 2 CF 3 ,
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,
  • E is a single bond, -O- or -S-;
  • X is a C-C single bond
  • E is a single bond or -S-;
  • R 2a , R 2b , R 3a and R 3b are each H;
  • R 6 is n-propyl, n-butyl, -CH 3 , -CH 2 CH 3 , or
  • R 8 is -CO 2 R 5 , -CONHSO 2 aryl, -CONHSO 2 (C 1 -C 4 -alkyl), or CONH-SO 2 -cyclopropyl, -NHSO 2 (C 1 -C 4 - polyfluoroalkyl), -S(O) x -(C 1 -C 4 -alkyl)-aryl, -NHSO 2 aryl, or -NHSO 2 -heteroaryl;
  • R 1 is -COOH, -SO 2 NH-heteroaryl, -SO 2 NH-aryl,
  • R 23 is aryl, -N(aryl) 2 , C 3 -C 7 -cycloalkyl, C 1 -C 6 alkyl, either unsubstituted or substituted with 1) C 3 -C 7 cycloalkyl, 2) polyfluoro, or 3) two aryl groups, and
  • X is a single bond.
  • Another embodiment of the compounds of formula (I) is that wherein K is S.
  • R 1 is -NH-SO 2 CF 3 , CO 2 H,
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 5 -C 6 - cycloalkyl, -COOCH 3 , -COOC 2 H 5 , -SO 2 -CH 3 , NH 2 , -N(C 1 -C 4 -alkyl) 2 or -NH-SO 2 CH 3 ;
  • E is a single bond, -O- or -S-;
  • X is a C-C single bond
  • E is a single bond or -S-;
  • R 2a , R 2b , R 3a and R 3b are each H;
  • R 6 is n-propyl, n-butyl, -CH 3 , -CH 2 CH 3 , or
  • R 8 is -CO 2 R 5 , -CONHSO 2 aryl, -CONHSO 2 -
  • R 1 is -COOH, SO 2 NH-heteroaryl, -SO 2 NH-aryl, -CONHSO 2 R 23
  • R 23 is aryl, polyfluoro-C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 4 alkyl(aryl) 2 ;
  • X is a single bond.
  • R 1 is -COOH, -NH-SO 2 CF 3 ,
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 5 -C 6 - cycloalkyl, -COOCH 3 , -COOC 2 H 5 , -SO 2 -CH 3 , NH 2 , -N(C 1 -C 4 -alkyl) 2 or -NH-SO 2 CH 3 ;
  • E is a single bond, -0- or -S-;
  • R 7 and R 8 are as defined above; X is a C-C single bond; and,
  • E is a single bond or -S-;
  • R 2a , R 2b , R 3a and R 3b are each H;
  • R 6 is n-propyl, n-butyl, -CH 3 , -CH 2 CH 3 , or
  • R 1 is -COOH, -SO 2 NH-heteroaryl, -SO 2 NH-aryl,
  • R 7 is H, aryl-C 1 -C 10 -alkyl, polyfluoro-C 1 -C 4 - alkyl, heteroaryl, or aryl either unsubstituted or substituted with one or two substituents selected from -Cl, -CF 3 , -CH 3 , -OCH 3 and -NO 2 ;
  • R 8 is -CO 2 R 5 , -CONHSO 2 aryl, -CONHSO 2 -
  • R 23 is aryl, -N(aryl) 2 , C 3 -C 7 -cycloalkyl, C 1 -C 6 alkyl, either unsubstituted or substituted with 1) C 3 -C 7 cycloalkyl, 2) polyfluoro, or 3) two aryl groups, and X is a single bond.
  • FAB-MS Fast atom bombardment mass spectroscopy
  • MPM (4-methoxyphenyl)methyl Pyrazoles substituted in the 1,3,4,5- positions and isothiazoles substituted in the 3,4,5- positions may be prepared as shown in Schemes 1 through 6.
  • Scheme 1 shows how the dianion of ethyl hydrogen malonate can be acylated with an R 6 acyl chloride then acidified to give the ⁇ -unsubstituted- ⁇ -ketoester shown. 1 The ⁇ -ketoester is then
  • Scheme 4 provides a route to the useful intermediate ⁇ -ketonitrile 5.
  • Cyanoacetic acid can be condensed with an R 6 acyl chloride to give the R 6 ⁇ -unsubstituted- ⁇ -ketonitrile. 2 This can then be ⁇ -alkylated using NaH in DMSO (or other suitable base and solvent) and the appropriate sidechain electrophile to afford 5.
  • Ketonitrile 5 will afford 5-aminopyrazole 6 when condensed with an R 7 hydrazine (Scheme 5).
  • 5-aminoisoxazole 7 results from the condensation of ketonitrile 5 with
  • isothiazole is shown in Schemes 7, 8, and 9.
  • Lithium acetylide displacement of the leaving group of compound 1 would give intermediate 8.
  • This material can be deprotonated with butyllithium, LDA, or other suitable base and added to ethyl chloroformate to give the ethyl propiolate derivative 9.
  • Scheme 8 provides a route to the precursor of the unstable nitrile N-sulfide. Condensation of an R 6 amide with chlorocarbonylsulfenyl chloride will give the
  • Scheme 10 gives an alternate preparation of an isoxazole via [3+2]-dipolar cycloaddition.
  • the ⁇ -ketonitrile 5 can be converted to the ⁇ -amino- ⁇ , ⁇ -unsaturated nitrile 16. upon treatment of 5 with concentrated ammonium hydroxide (Scheme 11). Alternatively, the ⁇ -enol triflate 6 or phosphate 7 could be treated with ammonia to give 16. Conversion of this material to the 5-aminoisothiazole 17 could be achieved using the methods described by Adams and Slack. 8
  • the 5-aminoisothiazole 12 can be a final product (after any required deprotection) or may be used as an intermediate to the carboxy derivative
  • Scheme 12 provides a route for the preparation of acyl sulfonamides 20.
  • the carboxylic acid can be activated by conversion to the acid chloride by various methods including treatment with refluxing thionyl chloride or preferably with oxalyl chloride and a catalytic amount of DMF at low
  • Activation by conversion to the acyl imidazole can be achieved upon treatment of acid 19 with carbonyldiimidazole.
  • N,N-Diphenylcarbamoyl anhydride intermediates may be prepared as activated carbonyls.
  • Treatment of the activated carbonyls with alkali metal salts of alkyl or aryl sulfonamides or with the sulfonamide and DBU will give the
  • Scheme 13 provides a route to the isomeric acyl sulfonamides 28.
  • the commerically available bromobenzenesulfonyl chloride 21 may be converted to the corresponding sulfonamide upon treatment with ammonia or ammonium carbonate. Protection with the triphenylmethyl group gives sulfonamide 23 . Palladium catalyzed cross-coupling of 23 with the aryltrimethyltin derivative 24 gives the biaryl
  • N-bromosuccinimide and catalytic AIBN in refluxing CCI 4 will give the alkylating agent 26.
  • the bromide 26 may now be used as the alkylating agent 1 shown in previous schemes to give intermediate 27.
  • the cyano group of 36 is next converted to the tetrazole 37 upon heating with trimethyltin azide in toluene 17 , the free tetrazole being obtained upon treatment with silica gel. Saponification of 37, typically by warming in a mixture of aqueous sodium hydroxide and methanol followed by acidification, provides the
  • pyrazole 41 The free sulfonamide 42 is obtained by deprotection of 41 with trifluoroacetic acid in the presence of anisole. Acylation of the sulfonamide, for example, with an acid chloride 43 in pyridine (see also Scheme 13), yields the acylsulfonamide 44, which may then be saponified to 45. Alternative acylation conditions may be employed.
  • N-acylimidazole derivative generated from the acid with 1,1'-carbonyldiimidazole
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the acid chloride in Scheme 15 may be replaced by an acid anhydride, as in the case of trifluoroacetic anhydride.
  • Scheme 16 also shows a similar route leading to pyrazolecarboxylates in which the tetrazole group of 37 or 38 is replaced by trifluoromethanesulfon- amide.
  • Alkylation of 32 from Scheme 14
  • the nitrobiphenyl species 46 gives 47, which is carried on to the pyrazole derivative 48. Hydrogenation of the nitro group of 48 in the
  • trifluoromethanesulfonyl chloride or trifluoro- methanesulfonic anhydride gives, depending on the conditions, either the mono(trifluoromethanesulfonyl) derivative 50 or the bis(trifluoromethanesulfonyl) derivative 51 as the major or exclusive product.
  • the sulfonylation may be carried out in pyridine or, alternatively, in methylene chloride in the presence of a base such as 2,6-di-t-butyl-4-methylpyridine. Under the saponification conditions, both 50 and 51 are converted to the target pyrazolecarboxylic acid 52.
  • the bromomethyl species 39 is obtained by heating 55 with N-bromosuccinimide (NBS) in carbon tetrachloride in the presence of an initiator such as
  • Schemes 18-21 illustrate transformations of the R 8 group.
  • Scheme 18, for example, shows the synthesis of a trifluoromethanesulfonamido group at R 8 .
  • compound 58 is a compound of formula I wherein R 8 is NH 2 and R 1 is
  • 60 is deprotected with methanolic HCI (or, alternatively, with aqueous acetic acid) to give
  • R 8 polyfluoroalkanesulfonamides as well as aryl or heteroaryl sulfonamides and the like, may be prepared in similar fashion. It is often
  • Scheme 20 shows a route to a reversed acylsulfonamide grouping at R 8 .
  • Compound 64 (a compound of formula I wherein R 8 is NH 2 ) may be diazotized either under aqueous conditions with nitrous acid or under nonaqueous conditions with an alkyl nitrite such as t-butyl nitrite 18 and reacted in situ with sulfur dioxide in the presence of cupric chloride in acetic acid to give the sulfonyl chloride 65. Treatment of 65 with ammonia yields the
  • sulfonamide 66 which can be acylated with an acid chloride in pyridine or an acylimidazole derivative in the presence of DBU.
  • the product thus obtained is the acylsulfonamide of structure 67, wherein R is aryl, heteroaryl, alkyl, or perfluoroalkyl.
  • Compound 68 is heated with a thiol in the presence of a base, such as potassium carbonate, N,N-diisopropyl- ethylamine, or DBU, to give the thioether 69.
  • a base such as potassium carbonate, N,N-diisopropyl- ethylamine, or DBU
  • 69 may be obtained directly from 64 by nonaqueous diazotization with t-butyl nitrite in the presence of a disulfide.
  • Compound 69 can then be oxidized to either the sulfoxide 70 or the sulfone 71 using a reagent such as 30% hydrogen peroxide (aqueous) in acetic acid or an organic peracid.
  • a reagent such as 30% hydrogen peroxide (aqueous) in acetic acid or an organic peracid.
  • the choice of reagent, stoichiometry, temperature, and reaction time govern whether 70 or 71 is the major or exclusive product.
  • R is alkyl, aryl, or aralkyl.
  • a route to a carbamoylphosphinic acid R 1 group is illustrated in the pyrazolecarboxylic acid series in Scheme 22.
  • the amino intermediate 49 may be converted to the isocyanate 72 upon heating with phosgene in an inert solvent. Reaction of 72 with phenylphosphinic acid 21 in the presence of triethylamine, according to the method of Fox and
  • the phosphonite intermediate 80 may be obtained by reaction of a Grignard reagent R 23 MgBr with
  • both the carboxylate ester and the phosphinate ester 22 of 81 may be saponified by heating with sodium hydroxide in aqueous methanol to give 82. Again, this pathway can be modified for the preparation of other compounds of formula I outside the pyrazolecarboxylate series.
  • reaction conditions including reagents, solvent, temperature, and time, should be chosen so that they are consistent with the nature of the functionality present in the molecule.
  • M is Na or Li
  • the compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.
  • Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dieyelohexylamine salts, N-methyl-D-glucamine salts, salts with amino acids like arginine, lysine, and the like.
  • salts with organic and inorganic acids may be prepared;
  • non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
  • the salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze- drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
  • Angiotensin II (All) is a powerful arterial vasoconstrictor, and it exerts its action by
  • I-Sar 1 Ile 8 -angiotensin II [obtained from New England Nuclear] (10 ⁇ l; 20,000 cpm) with or without the test sample, and the mixture was incubated at 37oC for 90 minutes. The mixture was then diluted with ice-cold 50mM Tris-0.9% NaCl, pH 7.4 (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in
  • Bovine adrenal cortex was selected as the source of All receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HCl (50mM), pH 7.7 buffer and homogenized. The
  • 3H-angiotensin II was presented as a measure of the efficacy of such compounds as All antagonists.
  • mice Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p.). The trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 strokes per minute, volume - 1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37°C by a thermostatically
  • Angiotensin II was then typically given at 5, 10, 15, 30, 45 and 60 minute intervals and every half-hour thereafter for as long as the test compound showed activity. The change in the mean arterial blood pressure was recorded for each angiotensin II challenge and the percent
  • the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic
  • congestive heart failure in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis,
  • hypertension hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of vascular disorders such as migraine, Raynaud's disease, luminal hyperplasia and to minimize the
  • the compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables and the like as well as topical ocular formulations in the form of
  • intraocular pressure would typically contain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, of a compound of this invention.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral adminis- tration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the compounds of this invention can be administered to patients (animals and human) in need of such
  • the dosage range will generally be about 1 to 1000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day.
  • the compounds of this invention can also be administered in combination with other antihyper- tensives such as diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers or
  • the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine,
  • hydralazine hydrochloride hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline,
  • captopril delapril hydrochloride, enalapril,
  • felodipine nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.
  • the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
  • one of the angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the
  • hydrochlorothiazide (15-200 mg) chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),
  • nifedipine (5-60 mg), and nitrendipine (5-60 mg).
  • angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood pressure in hypertensive patients.
  • these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
  • these combinations can be formulated into pharmaceutical compositions as discussed below.
  • compositions or preparations are compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
  • a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, flavor, etc.
  • the amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as microcrystalline cellulose
  • a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint, oil of wintergreen or cherry.
  • the dosage unitform may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
  • cholinomimetics such as physostigmine and nootropic agents are known to be active.
  • rats are trained to inhibit their natural tendency to enter dark areas.
  • the test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet.
  • the test animals are pretreated with 0.2 mg/kg of the
  • muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
  • the anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay.
  • CER conditioned emotional response
  • Diazepam is a clinically useful anxiolytic which is active in this assay.
  • male Sprague-Dawley rats 250-350 g are trained to press a lever on a
  • CER conditioned emotional response
  • Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, response rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice.
  • a clinically useful antidepressant which serves as a positive control in this assay is desipramine.
  • the method is based on the observations that a mouse suspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation. Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity code and to measure latency, duration and frequency of immobile periods.
  • Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced stereotypy model.
  • a clinically useful antipsychotic drug that is used as a positive control in this assay is haloperidol.
  • the assay method is based upon the observation that stimulation of the dopaminergic system in rats produces stereotyped motor behavior.
  • Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer.
  • Compounds of the invention should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the dosage range will generally be about 5 to 6000 mg. per patient per day which can be administered in single or multiple doses.
  • the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.
  • the compounds of this invention may be combined with other cognition-enhancing agents
  • acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacr idine (THA; tacrine)
  • muscarinic agonists such as oxotremorine
  • inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers and as nimodipine, and nootropic agents such as piracetam.
  • the compounds of this invention may be combined with other anxiolytic agents such as
  • alprazolam lorazepam, diazepam, and buspirone.
  • tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone
  • monoamine oxidase inhibitors such as tranylcypromine
  • the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.
  • Step A 2-cyano-4'-methylbiphenyl
  • Step B trimethyltin azide
  • the mixture was refluxed for 24 h, cooled to r.t., filtered, washed with toluene and sucked dry in a funnel.
  • the precipitate was resuspended in toluene (3.5 L) and THF (250 mL) was added.
  • Anhydrous HCI was bubbled in at a moderate rate at r.t. to give a clear solution (45 min). Addition of HCI gas was continued for another 20 min.
  • Step D N-triphenylmethyl-5- [2-(4'-methylbiphenyl)] tetrazole (Step D) (425 g, 0.89 moles) in CCI 4 (4.0 L) were added
  • 1,10-phenanthroline in 500 mL THF at -78°C was added 60 mL 2.5 M n-butyllithium in hexanes ( ⁇ one half of the total).
  • the indicator color persisted at this point.
  • the solution was warmed to -5° to +5°C after which the indicator color disappeared.
  • Another 55 mL 2.5 M n-butyllithium in hexanes was added until the indicator color again persisted.
  • the mixture was cooled to -78oC then 10.0 mL valeryl chloride was added over 3 minutes. After 10 minutes the now yellow solution was allowed to warm to room
  • Step F ethyl 3-oxoheptanenitrile
  • Step E 500 mg of N-triphenylmethyl-5-[2-(4'-bromomethylbiphenyl)]- tetrazole
  • Step E 500 mg of N-triphenylmethyl-5-[2-(4'-bromomethylbiphenyl)]- tetrazole
  • the title compound may be obtained by stirring 5-amino-3-butyl-4-[(2'-(N-triphenylmethyl- tetrazol-5-yl)biphen-4-yl)methyl] isoxazole (Step H) in methanol with excess concentrated HCI at room temperature. After 15 minutes, an indicator quantity of phenolphthalein is added followed by 10% NaOH until pink. Acetic acid is added to pH 5 and the mixture is stripped of most of its solvent in vacuo. The remainder is partitioned between brine and ether or methylene chloride. The aqueous layer is
  • Example 6 ethyl 3-butyl- 1-(2-chlorophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4- yl]methyl]-1H-pyrazole-5-carboxylate (Example 6) was converted in 96% yield to the title compound as a nearly white solid, mp > 125°C (gradual; preliminary softening); homogeneous by TLC in 9:1 CH 2 Cl 2 -MeOH. 400 MHz 1 H NMR (DMSO-d 6 ): ⁇ (ppm) 0.78 (t, 3H), 1.22 (m, 2H), 1.42 (m, 2H), 2.45 (t, 2H), 4.11 (s, 2H),
  • Step D the product from Step A (above) was converted in 69% yield to the title compound as a nearly colorless glass, mp >60°C (gradual); homogeneous by TLC in 9:1 CH 2 Cl 2 -MeOH.
  • FAB-MS m/e 521 (M+H) + .
  • Example 8 Ethyl 3-butyl-1-(2-chlorophenyl)-4-[[2'- (5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole- 5-carboxylate (Example 8) was saponified according to the procedure of Example 5 to give a 91% yield of the title compound as a white powder, mp >125°C.
  • Step D Reaction of the product from Step A with trimethyltin azide according to the method of Example 4, Step D, provided a 51% yield of the title compound as a very pale yellow-tan, stiff foam, mp >
  • Example 4 to give a 66% yield of the title compound as a golden-tan glass, mp >80°C (gradual); homogeneous by TLC in 9:1 CH 2 Cl 2 -MeOH. 400MHz 1 H NMR (CDCl 3 ): ⁇ (ppm) 0.86,0.90 (overlapping t, each 3H), 1.32 (m, 2H), 1.58 (m, 2H), 2.62 (t, 2H), 4.04 (q, 2H), 4.23 (s, 2H), 7.17 (d, 2H), 7.25 (d, 2H), 7.39 (d, 1H), 7.45 (d, 1H), 7.5-7.7 (m, 4H), 7.75 (d, 1H), 8.25 (d, 1H).
  • FAB-MS m/e 575 (M+H) + . Analysis (C 31 H 29 F 3 N 6 O 2 )
  • Example 12 The title compound was prepared from ethyl 3-butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]- 1-(2-(trifluoromethyl)phenyl]-1H-pyrazole-5- carboxylate (Example 12) by use of the procedure of Example 5. This material was obtained in 90% yield as a white powder, mp > 125°C (gradual; preliminary softening); homogeneous by TLC in 9:1 CH 2 Cl 2 -MeOH.
  • Example 4 The title compound was prepared by reaction of ethyl 3-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]- 2-methoxyimino-4-oxooctanoate (Example 4, Step B) with hydrazine hydrochloride under the conditions described in Example 4, Step C, except that only 2 equivalents of hydrazine hydrochloride were used.
  • Example 5 Step D, but in the column chromatography the solvent gradient was increased to a maximum of 7.5% MeOH in CH 2 Cl 2 .
  • the title compound was obtained in 49% yield as a cream-colored, stiff foam, mp>100° (gradual); nearly homogeneous by TLC in 9:1
  • Step B Ethyl 3-Butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]- 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate
  • the product from Step A was reacted with trimethyltin azide according to the procedure of Example 4, Step D, to give a 65% yield of the title compound as a colorless glass, mp > 45°C (gradual);
  • Example 16 Ethyl 3-butyl-4-[(2'-cyanobiphenyl-4-yl) methyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5- carboxylate (Example 16) was saponified according to the procedure of Example 5 to give an 88% yield of the title compound as a white powder, mp >95°C
  • N-Bromosuccinimide (387 mg, 2.17 mmol), ⁇ , ⁇ '-azobis(isobutyronitrile) (catalytic), 2'-(N-t- butylsulfamoyl)-4-methylbiphenyl (from Step C) (550 mg, 1.81 mmol) and carbon tetrachloride (50 ml) were heated with stirring at reflux for 3 hour. After cooling to room temperature the mixture was filtered and the filtrate evaporated to dryness. Flash chromatography (silica gel, initially 10 and then 20% ethyl acetate-hexane) afforded the title compound

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Abstract

Des isoxazoles, des isothiazoles et des pyrazoles substitués ayant la formule (I) sont des antagonistes d'angiotensine II, et sont utiles au traitement de l'hypertension, l'hypertension oculaire et certains troubles du système nerveux central.
PCT/US1991/001952 1990-03-30 1991-03-27 Isoxazoles, isothiazoles et pyrazoles substitues WO1991015479A1 (fr)

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Cited By (43)

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WO1993005025A1 (fr) * 1991-09-06 1993-03-18 Glaxo Group Limited Derives de pyrazole lies a c
AP254A (en) * 1991-09-05 1993-05-05 Glaxo Group Ltd C-Linked pyrazole derivatives.
GB2263638A (en) * 1992-01-28 1993-08-04 Merck & Co Inc Substituted pyrazoles, isoxazoles and isothiazoles as neurotensin antagonists
EP0556080A1 (fr) * 1992-01-31 1993-08-18 Roussel Uclaf Dérivés bicycliques de la pyridine, leur procédé de préparation, les intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant
WO1993017681A1 (fr) * 1992-03-02 1993-09-16 Abbott Laboratories Antagonistes du recepteur d'angiotensine ii
US5252593A (en) * 1991-05-16 1993-10-12 Glaxo Group Limited Pyrazole containing benzofuran derivatives and pharmaceutical compositions
US5262412A (en) * 1993-03-10 1993-11-16 Merck & Co., Inc. Substituted pyrazoles, compositions and use
EP0603712A3 (en) * 1992-12-22 1994-07-13 Takeda Chemical Industries Ltd Heterocyclic compounds having angiotensin ii antagonistic activity and use thereof.
JPH06239859A (ja) * 1992-09-14 1994-08-30 Takeda Chem Ind Ltd アンギオテンシンｉｉ拮抗作用を有する環状化合物およびその用途
JPH0770118A (ja) * 1992-12-22 1995-03-14 Takeda Chem Ind Ltd アンギオテンシンｉｉ拮抗作用を有する複素環化合物およびその用途
US5612359A (en) * 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
US5760038A (en) * 1995-02-06 1998-06-02 Bristol-Myers Squibb Company Substituted biphenyl sulfonamide endothelin antagonists
US5780473A (en) * 1995-02-06 1998-07-14 Bristol-Myers Squibb Company Substituted biphenyl sulfonamide endothelin antagonists
US5846990A (en) * 1995-07-24 1998-12-08 Bristol-Myers Squibb Co. Substituted biphenyl isoxazole sulfonamides
US5856507A (en) * 1997-01-21 1999-01-05 Bristol-Myers Squibb Co. Methods for the preparation of biphenyl isoxazole sulfonamides
US5916907A (en) * 1997-01-30 1999-06-29 Bristol-Myers Squibb Company Method for preventing or treating low renin hypertension by administering an endothelin antagonist
US5939446A (en) * 1996-04-09 1999-08-17 Bristol-Myers Squibb Co. Heteroaryl substituted phenyl isoxazole sulfonamide endothelin antagonists
US6043265A (en) * 1997-01-30 2000-03-28 Bristol-Myers Squibb Co. Isoxazolyl endothelin antagonists
US6080774A (en) * 1995-10-11 2000-06-27 Bristol-Myers Squibb Company Substituted biphenylsulfonamide endothelin antagonists
US6107320A (en) * 1992-05-06 2000-08-22 Bristol-Myers Squibb Co. Phenyl sulfonamide endothelin antagonists
EP1069114A3 (fr) * 1993-05-20 2001-01-31 Texas Biotechnology Corporation Sulfonamides et dérivés modulant l'activité de l'endothéline
US6297198B1 (en) 1996-05-14 2001-10-02 Syngenta Participations Ag Isoxazole derivatives and their use as herbicides
US6313308B1 (en) 1999-03-19 2001-11-06 Bristol-Myers Squibb Company Methods for the preparation of biphenyl isoxazole sulfonamides
US6331637B1 (en) 1993-10-21 2001-12-18 Texas Biotechnology Corporation N-Alkyl, N-Alkenyl, N-Alkynyl, N-Aryl and N-fused bicyclo or tricyclo thienyl-, furyl-,and Pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US6376523B1 (en) 1994-05-20 2002-04-23 Texas Biotechnology Corporation Benzenesulfonamides and the use thereof to modulate the activity of endothelin
US6515136B1 (en) 1996-02-20 2003-02-04 Bristol-Myers Squibb Company Methods for the preparation of biphenyl isoxazole sulfonamides
US6541498B2 (en) 1993-05-20 2003-04-01 Texas Biotechnology Benzenesulfonamides and the use thereof to modulate the activity of endothelin
US6639078B1 (en) 1998-12-23 2003-10-28 Smithkline Beecham Corporation Assays for ligands for nuclear receptors
US6638937B2 (en) 1998-07-06 2003-10-28 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
US6686382B2 (en) 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
US7446222B2 (en) 2002-11-01 2008-11-04 Glaxo Group Limited Phenyl compounds
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US20230233560A1 (en) * 2014-10-06 2023-07-27 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US12350262B2 (en) 2022-08-31 2025-07-08 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis

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Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5252593A (en) * 1991-05-16 1993-10-12 Glaxo Group Limited Pyrazole containing benzofuran derivatives and pharmaceutical compositions
AP254A (en) * 1991-09-05 1993-05-05 Glaxo Group Ltd C-Linked pyrazole derivatives.
WO1993005025A1 (fr) * 1991-09-06 1993-03-18 Glaxo Group Limited Derives de pyrazole lies a c
GB2263638A (en) * 1992-01-28 1993-08-04 Merck & Co Inc Substituted pyrazoles, isoxazoles and isothiazoles as neurotensin antagonists
EP0556080A1 (fr) * 1992-01-31 1993-08-18 Roussel Uclaf Dérivés bicycliques de la pyridine, leur procédé de préparation, les intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant
FR2687675A1 (fr) * 1992-01-31 1993-08-27 Roussel Uclaf Nouveaux derives bicycliques de la pyridine, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant.
WO1993017681A1 (fr) * 1992-03-02 1993-09-16 Abbott Laboratories Antagonistes du recepteur d'angiotensine ii
US5326776A (en) * 1992-03-02 1994-07-05 Abbott Laboratories Angiotensin II receptor antagonists
US6107320A (en) * 1992-05-06 2000-08-22 Bristol-Myers Squibb Co. Phenyl sulfonamide endothelin antagonists
JPH06239859A (ja) * 1992-09-14 1994-08-30 Takeda Chem Ind Ltd アンギオテンシンｉｉ拮抗作用を有する環状化合物およびその用途
EP0603712A3 (en) * 1992-12-22 1994-07-13 Takeda Chemical Industries Ltd Heterocyclic compounds having angiotensin ii antagonistic activity and use thereof.
JPH0770118A (ja) * 1992-12-22 1995-03-14 Takeda Chem Ind Ltd アンギオテンシンｉｉ拮抗作用を有する複素環化合物およびその用途
US5496835A (en) * 1992-12-22 1996-03-05 Takeda Chemical Industries, Ltd. Heterocyclic compounds having angiotensin II antagonistic activity and use thereof
US5262412A (en) * 1993-03-10 1993-11-16 Merck & Co., Inc. Substituted pyrazoles, compositions and use
US6541498B2 (en) 1993-05-20 2003-04-01 Texas Biotechnology Benzenesulfonamides and the use thereof to modulate the activity of endothelin
EP1069114A3 (fr) * 1993-05-20 2001-01-31 Texas Biotechnology Corporation Sulfonamides et dérivés modulant l'activité de l'endothéline
US6331637B1 (en) 1993-10-21 2001-12-18 Texas Biotechnology Corporation N-Alkyl, N-Alkenyl, N-Alkynyl, N-Aryl and N-fused bicyclo or tricyclo thienyl-, furyl-,and Pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US6376523B1 (en) 1994-05-20 2002-04-23 Texas Biotechnology Corporation Benzenesulfonamides and the use thereof to modulate the activity of endothelin
US5612359A (en) * 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
US5827869A (en) * 1994-08-26 1998-10-27 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
US5760038A (en) * 1995-02-06 1998-06-02 Bristol-Myers Squibb Company Substituted biphenyl sulfonamide endothelin antagonists
US5780473A (en) * 1995-02-06 1998-07-14 Bristol-Myers Squibb Company Substituted biphenyl sulfonamide endothelin antagonists
US5846990A (en) * 1995-07-24 1998-12-08 Bristol-Myers Squibb Co. Substituted biphenyl isoxazole sulfonamides
US6271248B1 (en) 1995-10-11 2001-08-07 Bristol-Myers Squibb Company Substituted biphenysulfonamide endothelin antagonists
US6080774A (en) * 1995-10-11 2000-06-27 Bristol-Myers Squibb Company Substituted biphenylsulfonamide endothelin antagonists
US6515136B1 (en) 1996-02-20 2003-02-04 Bristol-Myers Squibb Company Methods for the preparation of biphenyl isoxazole sulfonamides
US5939446A (en) * 1996-04-09 1999-08-17 Bristol-Myers Squibb Co. Heteroaryl substituted phenyl isoxazole sulfonamide endothelin antagonists
US6297198B1 (en) 1996-05-14 2001-10-02 Syngenta Participations Ag Isoxazole derivatives and their use as herbicides
US6420567B1 (en) 1996-09-27 2002-07-16 Texas Biotechnology Corporation N-heteroaryl aryl-substituted thienyl-furyl-and pyrrolyl-sulfonamides and derviatives thereof that modulate the activity of endothelin
US5856507A (en) * 1997-01-21 1999-01-05 Bristol-Myers Squibb Co. Methods for the preparation of biphenyl isoxazole sulfonamides
US5916907A (en) * 1997-01-30 1999-06-29 Bristol-Myers Squibb Company Method for preventing or treating low renin hypertension by administering an endothelin antagonist
US6043265A (en) * 1997-01-30 2000-03-28 Bristol-Myers Squibb Co. Isoxazolyl endothelin antagonists
US6638937B2 (en) 1998-07-06 2003-10-28 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
US6835741B2 (en) 1998-07-06 2004-12-28 Bristol-Myers Squibb Company Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
US6639078B1 (en) 1998-12-23 2003-10-28 Smithkline Beecham Corporation Assays for ligands for nuclear receptors
US6984650B2 (en) 1998-12-23 2006-01-10 Smithkline Beecham Corporation Use of FXR ligands
US6313308B1 (en) 1999-03-19 2001-11-06 Bristol-Myers Squibb Company Methods for the preparation of biphenyl isoxazole sulfonamides
EP2277519A2 (fr) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
US6686382B2 (en) 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
US7446222B2 (en) 2002-11-01 2008-11-04 Glaxo Group Limited Phenyl compounds
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
US20230233560A1 (en) * 2014-10-06 2023-07-27 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US12168009B2 (en) * 2014-10-06 2024-12-17 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US12350262B2 (en) 2022-08-31 2025-07-08 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis

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EP0523141A1 (fr) 1993-01-20
CA2079343A1 (fr) 1991-10-01
JPH05505822A (ja) 1993-08-26
EP0523141A4 (en) 1993-04-21

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