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WO1996009818A1 - Antagonistes du recepteur d'endotheline utilises dans le traitement des vomissements - Google Patents

Antagonistes du recepteur d'endotheline utilises dans le traitement des vomissements Download PDF

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Publication number
WO1996009818A1
WO1996009818A1 PCT/US1995/012329 US9512329W WO9609818A1 WO 1996009818 A1 WO1996009818 A1 WO 1996009818A1 US 9512329 W US9512329 W US 9512329W WO 9609818 A1 WO9609818 A1 WO 9609818A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
propylphenoxy
acetamide
methylenedioxyphenyl
iso
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1995/012329
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English (en)
Inventor
Charlotte M. Harvey
Carol Sargent
Peter K. S. Siegl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and 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 and Co Inc filed Critical Merck and Co Inc
Priority to AU36427/95A priority Critical patent/AU3642795A/en
Publication of WO1996009818A1 publication Critical patent/WO1996009818A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • Endothelin is a 21-amino acid peptide produced by endothelial cells.
  • the peptide is secreted not only by endothelial cells but also by tracheal epithelial cells or from kidney cells.
  • Endothelin (ET-1) has a potent vasoconstrictor effect. The vasoconstricting effect is caused by the binding of endothelin to its receptor on the vascular smooth muscle cells. [Nature, 332, 411-415 (1988); FEBS Letters, 231 , 440-444 (1988); Biochem. Biophys. Res. Cornmun. 154, 868-875 (1988).]
  • Endothelin- 1 is one of three recently identified potent vasoconstricting peptides which also includes endothelin-2 (ET-2) and endothelin-3 (ET-3) whose sequences differ from ET-1 by two and six amino acids, respectively. [TiPS, 13, 103-108, March 1992.]
  • Endothelin was also found to control the release of many physiological substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A 2 , prostacyclin, norepinephrine, angiotensin II and substance P.
  • renin atrial natriuretic peptide
  • EDRF endothelium-derived relaxing factor
  • thromboxane A 2 prostacyclin
  • norepinephrine angiotensin II and substance P.
  • Endothelin has also been shown to promote the growth of rat vascular smooth muscle cells which would suggest a possible relevance to arterial hypertrophy. [Atherosclerosis, 78, 225-228 (1989).]
  • Endothelin receptors are present in high concentration in the peripheral tissues and also in the central nervous system, and cerebral administration of endothelin has been shown to induce behavioral changes in animals, suggesting that endothelin may play an important role in controlling neural functions. [Neuroscience Letters, 97, 276-279 (1989).]
  • Endotoxin has been shown to promote the release of endothelin. This finding has suggested that endothelin is an important mediator for endotoxin-induced diseases. [Biochem. Biophys. Res.
  • Endothelin is an endogenous substance which directly or indirectly (through the controlled release of various other endogenous substances) induces sustained contraction of vascular or non-vascular smooth muscles. Its excess production or excess secretion is believed to be one of the factors responsible for hypertension, pulmonary
  • Substances which specifically inhibit the binding of endothelin to its receptor are believed to block the physiological effects of endothelin and are useful in treating patients with endothelin related disorders.
  • novel compounds of the present invention are useful as a non-peptidic endothelin antagonists, and have not been disclosed in any issued patents or published patent applications.
  • published patent applications disclosing linear and cyclic peptidic compounds as endothelin antagonists are the following: Fujisawa in European Patent Application EP-457,195 and Patent Cooperation Treaty (PCT)
  • Fujisawa has also disclosed two nonpeptidic endothelin antagonist compounds: anthraquinone derivatives produced by a fermentation process using Streptomyces sp. No. 89009 in EP-405,421 and U.S. Patent No. 5,187,195; and a 4-phenoxyphenol derivative produced by a fermentation process using Penicillium citreonigrum F- 12880 in a UK Patent Application GB 2259450.
  • Shionogi and Co. has also disclosed nonpeptidic endothelin antagonist triterpene compounds which were produced by a fermentation process using Myrica cerifera in WO 92/12991.
  • non-peptidic endothelin antagonist compounds which are known in the patent literature are: 1) a series of substituted (1 ,4-quinolinoxy)methylbiphenylcarboxylic acids disclosed by Roussel- Uclaf in EP-498,723; 2) a series of of N-(4-pyrimidinyl)benzene- sulfonamides with different substitution patterns from Hoffmann-La Roche published in EP-510,526, EP-526,708 and EP-601,386; 3) a series of naphthalenesulfonamides and benzenesulfonamides disclosed by E.R.
  • This invention is concerned with endothelin receptor antagonists useful in the treatment of emesis.
  • This invention also concerns the use of an endothelin antagonist for the treatment of any endothelin-induced form of emesis, including acute, delayed, post- operative, last-phase, and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorder, motion, post-operative sickness, surgery, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain, migraine, opiod analgesics and variations in intercranial pressure (except quaternary salts).
  • this invention is concerned with a pharmaceutical composition for the the treatment of emesis comprising: an endothelin antagonist in combination with an NKl antagonist and/or a 5HT3 antagonist. DETAILED DESCRIPTION OF THE INVENTION.
  • This invention is concerned with a method of treatment for emesis using an endothelin receptor antagonist compound.
  • R 1 , R 2 , R 3a and R 3b are independently
  • R 1 and R 2 on adjacent carbon atoms can be joined together to form a ring structure:
  • A represents:
  • R 4 and R 5 are independently:
  • R 8 is:
  • R 9 and R 10 are independently:
  • R 9 and R 10 on adjacent carbons can join together to form a fused phenyl ring, unsubstituted or substituted with a substituent selected from the group consisting of: (C 1 -C 6 )-alkyl, (C 1 -
  • R 1 1 is
  • aryl wherein aryl is defined as phenyl or
  • naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
  • Q is O, S or -NR 7 ;
  • R 12 is
  • amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro and Val and which can be further substituted as a (C 1 -C 6 )- alkyl ester or an amide, or
  • aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
  • heteroaryl is defined as carbazolyl, ftiryl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl,
  • pyrimidyl purinyl or quinolinyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: i) (C 1 -C 4 )-alkyl,
  • R 13 is:
  • R 14 and R 15 independently are (C 1 -C 6 )-alkyl or phenyl; and R 16 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkylphenyl.
  • R 1 , R 2 , R 3a and R 3b are independently:
  • R 1 and R 2 on adjacent carbon atoms can be joined together to form a ring structure:
  • A represents:
  • R 8 is:
  • R 9 and R 10 on adjacent carbons can join together to form a fused phenyl ring, unsubstituted or substituted with a substituent selected from the group consisting of: (C 1 -C 6 )-alkyl, (C 1 - C 6 )-alkoxy , (C 3 -C 7 )-cycloalkyl and (C 1 -C 6 )-alkyl-(C 3 -
  • R 1 1 is
  • aryl wherein aryl is defined as phenyl or
  • naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
  • amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lie, Phe, Asp, Pro and Val and which can be further substituted as a (C 1 -C 6 )- alkyl ester or an amide, or
  • phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: i) (C 1 -C 4 )-alkyl,
  • heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl,
  • pyrimidyl purinyl or quinolinyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: i) (C 1 -C 4 )-alkyl,
  • R 14 and R 15 independently are (C 1 -C 6 )-alkyl or phenyl; and R 16 is H, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkylphenyl.
  • R 1 , R 2 , R 3a and R 3b are independently:
  • A represents:
  • Y is -O-, -S- and NR 7 R 4 and R 5 are independently:
  • R8 is:
  • R 9 and R 10 are independently:
  • aryl wherein aryl is defined as phenyl or
  • naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
  • Q is O, S or -NR 7 ;
  • R 12 is
  • amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro and Val and which can be further substituted as a (C 1 -C 6 )- alkyl ester or an amide, or
  • phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: i) (C 1 -C 4 )-alkyl,
  • R 4 (b) unsubstituted or substituted as defined in R 4 (b), (g) -CONHSO 2 -heteroa ⁇ yl, wherein heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl,
  • R 13 is: (C 1 -C 4 )-alkyl
  • R 16 is H, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkylphenyl.
  • a subclass of this method treatment is the endothelin antagonist of Formula IV:
  • A represents:
  • Y is -O-
  • R 3a is:
  • R 4 and R 5 are independently:
  • R 8 is:
  • R 9 is:
  • aryl wherein aryl is defined as phenyl or
  • naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
  • Q is O, S or -NR 7 ;
  • R 12 is (a) H,
  • amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro and Val and which can be further substituted as a (C 1 -C 6 )- alkyl ester or an amide, or
  • aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
  • heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl, or quinolinyl, which is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of:
  • R 13 is: (C 1 -C 4 )-alkyl
  • R 16 is H, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkylphenyl.
  • a second embodiment of this method of treatment is the endothelin antagonist of Formula V:
  • R 1 , R 2 , R 3a and R 3b are independently
  • aryl wherein aryl is defined as phenyl or
  • naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
  • R 12 is
  • amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro and Val and which can be further substituted as a (C 1 -C 6 )- alkyl ester or an amide, or
  • phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: i) (C 1 -C 4 )-alkyl,
  • heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl,
  • R 16 is H, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkylphenyl.
  • R 1 and R 2 are represented by the following ring structure:
  • A represents:
  • R 3a and R 3b are independently:
  • R 8 is:
  • R 9 and R 10 are independently:
  • aryl wherein aryl is defined as phenyl or
  • naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
  • Q is O, S or -NR 7 ;
  • R 12 is
  • amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro and Val and which can be further substituted as a (C 1 -C 6 )- alkyl ester or an amide, or
  • phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: i) (C 1 -C 4 )-alkyl,
  • R 4 (b) unsubstituted or substituted as defined in R 4 (b), (g) -CONHSO 2 -heteroaryl, wherein heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl,
  • R 13 is: (C 1 -C 4 )-alkyl
  • R 16 is H, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkylphenyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un procédé de traitement des vomissements consistant à utiliser une quantité thérapeutiquement efficace d'un antagoniste du récepteur de l'endothéline. Cette invention se rapporte également à l'utilisation d'un antagoniste de l'endothéline dans le traitement de n'importe quelle forme de vomissement induite par l'endothéline, y compris les vomissements aigus, tardifs, post-opératoires, en phase finale et d'anticipation, par exemple, des vomissements induits par la chimiothérapie, les rayonnements, les toxines, la grossesse, les troubles des vestibules, le mal des transports, les interventions chirurgicales, les obstructions gastro-intestinales, la motilité gastro-intestinale réduite, les douleurs viscérales, les migraines, les analgésiques opioïdes et les variations de pression intercrânienne (excepté les sels quaternaires). Cette invention se rapporte de plus à une composition pharmaceutique utilisée dans le traitement des vomissements et comprenant: un antagoniste de l'endothéline associé à un antagoniste NK1 et/ou un antagoniste 5HT3.
PCT/US1995/012329 1994-09-27 1995-09-22 Antagonistes du recepteur d'endotheline utilises dans le traitement des vomissements Ceased WO1996009818A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36427/95A AU3642795A (en) 1994-09-27 1995-09-22 Endothelin receptor antagonists for the treatment of emesis

Applications Claiming Priority (2)

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US31349594A 1994-09-27 1994-09-27
US313,495 1994-09-27

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0758650A1 (fr) * 1995-08-16 1997-02-19 MERCK PATENT GmbH Antagonistes du récepteur de l'endothéline
WO1999061410A1 (fr) * 1998-05-12 1999-12-02 American Home Products Corporation Diphenyles 2,3,5-substitues utiles pour le traitement de la resistance insulinique et de l'hyperglycemie
US6017918A (en) * 1998-08-06 2000-01-25 Warner-Lambert Company Phenyl glycine compounds and methods of treating atherosclerosis and restenosis
US6110963A (en) * 1998-05-12 2000-08-29 American Home Products Corporation Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6166069A (en) * 1998-05-12 2000-12-26 American Home Products Corporation Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6221902B1 (en) 1998-05-12 2001-04-24 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6232322B1 (en) 1998-05-12 2001-05-15 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6284795B1 (en) 1998-09-04 2001-09-04 Warner-Lambert Company Sulfonamide compounds and methods of treating atherosclerosis and restenosis
US6310081B1 (en) 1999-05-10 2001-10-30 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6451827B2 (en) 1998-05-12 2002-09-17 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
WO2001091736A3 (fr) * 2000-05-31 2002-10-17 Warner Lambert Co Combinaisons d"un antagoniste de recepteur d"endotheline et compose anti-epileptique presentant des proprietes analgesiques ou de soulagement de la douleur
US6699896B1 (en) 1998-05-12 2004-03-02 Wyeth Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6908935B2 (en) 2002-05-23 2005-06-21 Amgen Inc. Calcium receptor modulating agents
US7091230B2 (en) 2001-02-09 2006-08-15 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US7176322B2 (en) 2002-05-23 2007-02-13 Amgen Inc. Calcium receptor modulating agents
US7482462B2 (en) 2001-10-05 2009-01-27 Amarylla Horvath Acylsulfonamides as inhibitors of steroid sulfatase
US7626020B2 (en) 2004-02-20 2009-12-01 Astrazeneca Ab Protected forms of N-(3-methoxy-5-methylpiperazin-2-yl)-2-(4-[1,3,4,-oxadiazol-2-yl]phenyl)-pyridine-3-sulphonamide
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7820679B2 (en) 2002-08-23 2010-10-26 Astrazeneca Ab N-(-3-methoxy-5-methylpyrazin-2-yl)-2-(4-′1,3,4-oxadiazol-2-yl-phenyl)pyridine-3 sulphonamide as an anticancer agent
US8592629B2 (en) 2010-07-12 2013-11-26 Pfizer Limited Sulfonamide derivatives as Nav 1.7 inhibitors
US8685977B2 (en) 2010-07-12 2014-04-01 Pfizer Limited Chemical compounds
US8772343B2 (en) 2010-07-12 2014-07-08 Pfizer Limited Chemical compounds
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US9085517B2 (en) 2011-12-15 2015-07-21 Pfizer Limited Sulfonamide derivatives
US9096500B2 (en) 2010-07-12 2015-08-04 Pfizer Limited Acyl sulfonamide compounds
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US10450273B2 (en) 2016-08-29 2019-10-22 Novartis Ag N-(pyridin-2-yl)pyridine-sulfonamide derivatives and their use in the treatment of disease
WO2021118826A1 (fr) * 2019-12-12 2021-06-17 Daljit Dhanoa Acides phénoxyphényl acétiques substitués enrichis en deutérium et acylsulfonamides

Citations (1)

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Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0758650A1 (fr) * 1995-08-16 1997-02-19 MERCK PATENT GmbH Antagonistes du récepteur de l'endothéline
US5821256A (en) * 1995-08-16 1998-10-13 Merck Patent Gesellschaft Mit Beschrankter Haftung Endothelin receptor antagonists
US7008636B2 (en) 1998-05-12 2006-03-07 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US7141672B2 (en) 1998-05-12 2006-11-28 Wyeth Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6110963A (en) * 1998-05-12 2000-08-29 American Home Products Corporation Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6166069A (en) * 1998-05-12 2000-12-26 American Home Products Corporation Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6214877B1 (en) 1998-05-12 2001-04-10 John A. Butera 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6221902B1 (en) 1998-05-12 2001-04-24 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6232322B1 (en) 1998-05-12 2001-05-15 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6765021B2 (en) 1998-05-12 2004-07-20 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6509360B1 (en) 1998-05-12 2003-01-21 Wyeth Penyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6369072B2 (en) 1998-05-12 2002-04-09 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6391897B2 (en) 1998-05-12 2002-05-21 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6451827B2 (en) 1998-05-12 2002-09-17 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6699896B1 (en) 1998-05-12 2004-03-02 Wyeth Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
WO1999061410A1 (fr) * 1998-05-12 1999-12-02 American Home Products Corporation Diphenyles 2,3,5-substitues utiles pour le traitement de la resistance insulinique et de l'hyperglycemie
US6844358B2 (en) 1998-05-12 2005-01-18 Wyeth Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6017918A (en) * 1998-08-06 2000-01-25 Warner-Lambert Company Phenyl glycine compounds and methods of treating atherosclerosis and restenosis
US6284795B1 (en) 1998-09-04 2001-09-04 Warner-Lambert Company Sulfonamide compounds and methods of treating atherosclerosis and restenosis
US6458815B2 (en) 1998-09-04 2002-10-01 Warner-Lambert Company Sulfonamide compounds and methods of treating atherosclerosis and restenosis
US6310081B1 (en) 1999-05-10 2001-10-30 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
WO2001091736A3 (fr) * 2000-05-31 2002-10-17 Warner Lambert Co Combinaisons d"un antagoniste de recepteur d"endotheline et compose anti-epileptique presentant des proprietes analgesiques ou de soulagement de la douleur
US8536184B2 (en) 2000-11-01 2013-09-17 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
USRE43098E1 (en) 2000-11-01 2012-01-10 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7091230B2 (en) 2001-02-09 2006-08-15 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US7495020B2 (en) 2001-02-09 2009-02-24 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US7482462B2 (en) 2001-10-05 2009-01-27 Amarylla Horvath Acylsulfonamides as inhibitors of steroid sulfatase
US7176322B2 (en) 2002-05-23 2007-02-13 Amgen Inc. Calcium receptor modulating agents
US7196102B2 (en) 2002-05-23 2007-03-27 Amgen Inc. Calcium receptor modulating agents
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