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WO1993015044A1 - Derives d'acide n-benzyloxamique, d'oxamate et d'oxamide et leur utilisation comme inhibiteurs du facteur de necrose tumorale (fnt) et de la phosphodiesterase iv (pde iv) - Google Patents

Derives d'acide n-benzyloxamique, d'oxamate et d'oxamide et leur utilisation comme inhibiteurs du facteur de necrose tumorale (fnt) et de la phosphodiesterase iv (pde iv) Download PDF

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Publication number
WO1993015044A1
WO1993015044A1 PCT/US1993/000552 US9300552W WO9315044A1 WO 1993015044 A1 WO1993015044 A1 WO 1993015044A1 US 9300552 W US9300552 W US 9300552W WO 9315044 A1 WO9315044 A1 WO 9315044A1
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WIPO (PCT)
Prior art keywords
substituted
hydrogen
methyl
unsubstituted
alkyl
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/US1993/000552
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English (en)
Inventor
Siegfried Benjamin Christensen, Iv
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO1993015044A1 publication Critical patent/WO1993015044A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/26—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and singly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring

Definitions

  • monokine activity such as by inhibition of TNF production
  • an HIV-infecte individual aids in enhancing the quality of life of HIV-infected patients by reducing the severity of monokine-mediated disease associated problems such as cachexia and muscle degeneration.
  • the present invention also provides a method of preventing a TNF mediated disease state in an animal in need thereof, including humans, by prophylactically administering an effective amount of a compound of Formula (I).
  • Ri is C ⁇ _2 alkyl substituted by 1 or more fluorines, CH2-cyclopropyl, CH2-cyclopentyl, cyclopentyl or cyclopentenyl;
  • R2 is methyl or fluoro substituted C ⁇ _2 alkyl;
  • A is 2-, 3- or 4-pyridyl, 4- morpholinyl, 2-thienyl, 2-imidazole or 4-thiazolyl, each of which may be substituted or unsubstituted by NR 5 R ⁇ g or N 5 C(O)R5;
  • R20 is OR5, NR5OR5 or NHCH2A.
  • Compounds of Formula (1) are prepared by reacting a compound of Formula (5) wit an appropriately activated oxamic acid derivative of a Formula (6) compound wherein X4 is activating group, well known to those skilled in the art, such as those disclosed in Bodansky 2 Peptide Synthesis, Wiley & Sons, publishers (1976) pages 99-109. More preferred X4 groups are Cl, Br, OCH2CH3, OC(O)CH 3 , OC(O)CF 3 , O-C(O)-OCH 2 CH 3 , O-C(O)- OCH2CH(CH3)2, or O-C(O)-OCH2-C6H5 in the presence of a non-nucleophilic base.
  • U-937 cells a human monocyte cell line that has been shown to contain a large amount of PDE IV.
  • nondifferentiated U-937 cells approximately 10 ⁇ cells/reaction tube
  • PDE inhibitors were incubated with various concentrations (0.01-100 mM) of PDE inhibitors for one minute and 1 mM prostaglandin E2 for an additional four minutes.
  • cells were lysed by the addition of 1M potassium carbonate and cAMP content was assessed by RIA.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne de nouvelles pyrrolidinones de la formule (I) qui inhibent le PDE IV et le FNT.
PCT/US1993/000552 1992-01-29 1993-01-19 Derives d'acide n-benzyloxamique, d'oxamate et d'oxamide et leur utilisation comme inhibiteurs du facteur de necrose tumorale (fnt) et de la phosphodiesterase iv (pde iv) Ceased WO1993015044A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US82724592A 1992-01-29 1992-01-29
US07/827,245 1992-01-29
US96800992A 1992-10-29 1992-10-29
US07/968,009 1992-10-29

Publications (1)

Publication Number Publication Date
WO1993015044A1 true WO1993015044A1 (fr) 1993-08-05

Family

ID=27125082

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/000552 Ceased WO1993015044A1 (fr) 1992-01-29 1993-01-19 Derives d'acide n-benzyloxamique, d'oxamate et d'oxamide et leur utilisation comme inhibiteurs du facteur de necrose tumorale (fnt) et de la phosphodiesterase iv (pde iv)

Country Status (2)

Country Link
AU (1) AU3588693A (fr)
WO (1) WO1993015044A1 (fr)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591776A (en) * 1994-06-24 1997-01-07 Euro-Celtique, S.A. Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV
US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
US5665737A (en) * 1994-10-12 1997-09-09 Euro-Celtique, S.A. Substituted benzoxazoles
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
WO1998056756A1 (fr) * 1997-06-12 1998-12-17 Cheil Jedang Corporation Derives acides des catecholamines et compositions pharmaceutiques les contenant
US5981599A (en) * 1996-05-01 1999-11-09 Nps Pharmaceuticals, Inc. Inorganic ion receptor active compounds
US6031003A (en) * 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US6268373B1 (en) 1995-06-07 2001-07-31 Euro-Celtique S.A. Trisubstituted thioxanthines
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
WO2002018321A3 (fr) * 2000-08-29 2003-04-10 Abbott Lab Inhibiteurs de proteine tyrosine phosphatase d'acide amino(oxo)acetique
US6627767B2 (en) 2000-08-29 2003-09-30 Abbott Laboratories Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
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
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014131024A2 (fr) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et applications associées
EP2776395A2 (fr) 2011-11-09 2014-09-17 Mylan Laboratories, Limited Procédé pour la préparation de roflumilast
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
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
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
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
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
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
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000968A1 (fr) * 1990-07-10 1992-01-23 Smithkline Beecham Corporation Oxamides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000968A1 (fr) * 1990-07-10 1992-01-23 Smithkline Beecham Corporation Oxamides

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6031003A (en) * 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
US5629285A (en) * 1993-08-23 1997-05-13 Immunex Corporation Inhibitors of TNF-α secretion
US5591776A (en) * 1994-06-24 1997-01-07 Euro-Celtique, S.A. Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV
US5665737A (en) * 1994-10-12 1997-09-09 Euro-Celtique, S.A. Substituted benzoxazoles
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
US6268373B1 (en) 1995-06-07 2001-07-31 Euro-Celtique S.A. Trisubstituted thioxanthines
US6710088B2 (en) 1996-05-01 2004-03-23 Nps Pharmaceuticals, Inc. Inorganic ion receptor-active compounds
US5981599A (en) * 1996-05-01 1999-11-09 Nps Pharmaceuticals, Inc. Inorganic ion receptor active compounds
US6342532B1 (en) 1996-05-01 2002-01-29 Nps Pharmaceuticals, Inc. Inorganic ion receptor active compounds
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
WO1998056756A1 (fr) * 1997-06-12 1998-12-17 Cheil Jedang Corporation Derives acides des catecholamines et compositions pharmaceutiques les contenant
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
WO2002018321A3 (fr) * 2000-08-29 2003-04-10 Abbott Lab Inhibiteurs de proteine tyrosine phosphatase d'acide amino(oxo)acetique
US6627767B2 (en) 2000-08-29 2003-09-30 Abbott Laboratories Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
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
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c
EP2776395A2 (fr) 2011-11-09 2014-09-17 Mylan Laboratories, Limited Procédé pour la préparation de roflumilast
EP4309673A2 (fr) 2012-03-15 2024-01-24 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
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014131024A2 (fr) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et applications associées
EP3718557A2 (fr) 2013-02-25 2020-10-07 Bausch Health Ireland Limited Agoniste du récepteur de la guanylate cyclase sp-333 à utiliser lors du nettoyage du côlon
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
EP3492106A1 (fr) 2013-08-09 2019-06-05 Ardelyx, Inc. Composés et procédés d'inhibition du transport de phosphate
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
EP3884935A1 (fr) 2013-08-09 2021-09-29 Ardelyx, Inc. Composés et procédés d'inhibition du transport de phosphate
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient

Also Published As

Publication number Publication date
AU3588693A (en) 1993-09-01

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