WO2001082858A2 - Nouveaux composes pour le traitement de maladies inflammatoires et cardiovasculaires - Google Patents

Nouveaux composes pour le traitement de maladies inflammatoires et cardiovasculaires Download PDF

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Publication number
WO2001082858A2
WO2001082858A2 PCT/EP2001/005043 EP0105043W WO0182858A2 WO 2001082858 A2 WO2001082858 A2 WO 2001082858A2 EP 0105043 W EP0105043 W EP 0105043W WO 0182858 A2 WO0182858 A2 WO 0182858A2
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WO
WIPO (PCT)
Prior art keywords
butyl
treatment
use according
tert
isopropyl
Prior art date
Application number
PCT/EP2001/005043
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German (de)
English (en)
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WO2001082858A3 (fr
Inventor
Wolf-Georg Forssmann
Helmut Drexler
Michael Walden
Bernhard Schieffer
Boris Schmidt
Original Assignee
Ipf Pharmaceuticals Gmbh
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 Ipf Pharmaceuticals Gmbh filed Critical Ipf Pharmaceuticals Gmbh
Priority to AU2001267404A priority Critical patent/AU2001267404A1/en
Publication of WO2001082858A2 publication Critical patent/WO2001082858A2/fr
Publication of WO2001082858A3 publication Critical patent/WO2001082858A3/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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to a compound having the structural formula given in claim 1, a medicament comprising at least one of the compounds according to the invention and / or an analogous metabolite of ACE inhibitors, a process for the preparation of the compounds according to the invention and uses of the compounds according to the invention.
  • Therapeutics which are used in particular for rheumatic diseases, often have I side effects because they unspecifically inhibit the synthesis of prostaglandins by the non-specific blocking of cyclooxygenase (COX-1, COX-2). It is therefore desirable to provide therapeutic agents that influence specific anti-rheumatic and / or anti-inflammatory metabolic processes.
  • a technical problem on which the invention is based is the provision of chemical compounds which can act more specifically on antirheumatic and / or anti-inflammatory metabolic processes.
  • R 1 H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert.-
  • R 2 H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert.-
  • Represents butyl, is halogen or -OH, R 3 H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-
  • Represents butyl, is halogen or -OH, R 4 H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert.-
  • This compound can be obtained, for example, by catalytic oxidation of losartan with ruthenium (III) chloride.
  • Losartan is the subject of US-A-5 138 069, which is expressly incorporated herein by reference.
  • Losartan is an AT II receptor antagonist which has been found to produce the actual effect from the metabolite EXP 3174, which is produced during the first passage through the liver.
  • Clinical studies of losartan have shown that losartan also has an anti-inflammatory and anti-aggregation effect on platelets.
  • this metabolite inhibits both COX-2 synthesis and COX-2 dependent prostaglandin production and has active concentrations between 1 ng and 100 mg / kg body weight.
  • the results were confirmed by in vivo studies after oral administration of losartan, whereby this metabolite was also detected in the serum.
  • the Pharmacokinetic measurements have shown that the metabolite used according to the invention increases after about two hours and peaks after three to five hours with a sharp decrease after about six hours.
  • the metabolite EXP 3174 which acts as an angiotensin II antagonist, has a maximum activity at five hours.
  • the maximum serum concentrations of the metabolite used according to the invention are 2.8 x 10 "7 mol and thus correspond to the concentrations of losartan itself, which has 2.6 x 10 " 7 mol.
  • the metabolite EXP 3174 which acts as an AT II receptor antagonist, has a maximum of 3.7 x 10 "6 mol.
  • the present invention thus relates to pharmaceuticals according to claim 3.
  • the pharmaceuticals contain the active ingredient in galenical forms for intravenous intramuscular, peroral or intraperitoneal administration in doses of 1 ng to 100 mg / kg body weight.
  • the pharmaceuticals are preferably also produced in galenical preparation forms with delayed release.
  • Such preparation forms are known per se from numerous standard pharmaceutical works to the person skilled in the art.
  • Typical forms of application of the compounds according to the invention can easily be determined by a person skilled in the art analogously to WO-A-97/49392, to which reference is expressly made here.
  • the active substance preferred according to the invention itself namely the metabolite EPX 3179, 2-butyl-4-chloro-l - [(2'-tetrazol-5yl) biphenyl-4-yl] methyl-5- (oxomethyl) len) imidazole (BCT-Ox-Im), can be prepared for example by oxidation of losartan with ruthenium (III) chloride with the addition of H 2 O 2 and reflux in acetonitrile.
  • the desired metabolite can be obtained from this reaction mixture in a yield of approximately 25%. Cleaning is possible, for example, using topographic methods, in particular HPLC.
  • a C-18 reverse phase is particularly suitable as the stationary phase.
  • An elution takes place e.g. B. with acetonitrile.
  • oxidations with the following oxidizing agents can also be considered:
  • Dess Martin, IBX and / or Pfizer-Moffat Dess Martin is described in the Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents. Ed. S.D. Burke, R.L. Danheiser, John Wiley & Sons 1999, p. 468 or Organic Synteses 1999, Vol. 77, p. 141-152. It is used to produce the metabolites to be used according to the invention in 1.2 molar excess, for example DMSO in a concentration of 0 , 1 to 1 molar. The reaction times for the reaction of the components are usually about 6 hours.
  • the reagent IBX is 2-iodoxybenzoic acid and is described in Journal of Organic Chemistry 1999, 64, 4537-4538. It is used in 1.2 molar excess in DMSO, preferably in concentrations between 0.1 to 1 molar for a reaction time of about 6 hours.
  • Typical reaction conditions regarding the Pfizer-Moffat reagent can be found in the Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents, publisher S.D. Burke, R.L., Danheiser, John Wiley & Sons 1999, p. 154.
  • acetylsalicylic acid is an unspecific and irreversible COX inhibitor the effect of the metabolite used according to the invention subsides after only six hours. In practice, this can be of considerable importance. It is a new drug with a different mechanism of action, which, in contrast to the starting substance losartan, has only a minor influence on blood pressure.
  • the medicament according to the invention can be used in the following indications.

Abstract

L'invention concerne un composé de formule de structure (I), dans laquelle R1 représente H, des groupes alkyle ou acyle substitués ou non, notamment méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle ; X représente halogène ou -OH ; R2 représente H, des groupes alkyle ou acyle substitués ou non, notamment méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle, halogène ou -OH ; R3 représente H, des groupes alkyle ou acyle substitués ou non, notamment méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle, halogène ou -OH ; R4 représente H, des groupes alkyle ou acyle substitués ou non, notamment méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle ou un reste métallique, notamment un cation alcalin.
PCT/EP2001/005043 2000-05-04 2001-05-04 Nouveaux composes pour le traitement de maladies inflammatoires et cardiovasculaires WO2001082858A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001267404A AU2001267404A1 (en) 2000-05-04 2001-05-04 Novel compounds for the treatment of inflammatory and cardiovascular diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10021615.3 2000-05-04
DE10021615 2000-05-04

Publications (2)

Publication Number Publication Date
WO2001082858A2 true WO2001082858A2 (fr) 2001-11-08
WO2001082858A3 WO2001082858A3 (fr) 2002-06-27

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AU (1) AU2001267404A1 (fr)
WO (1) WO2001082858A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042443A2 (fr) * 2000-11-23 2002-05-30 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Utilisation de modulateurs de chemins de transduction de signaux eukaryotes pour traiter des infections a helicobacter
WO2002060439A1 (fr) * 2001-01-29 2002-08-08 Takeda Chemical Industries, Ltd. Medicaments analgesiques et anti-inflammatoires
WO2003094915A1 (fr) * 2002-05-14 2003-11-20 Novartis Ag Utilisation de valsartan ou de son metabolite pour inhiber l'agregation plaquettaire
EP1536785A2 (fr) * 2002-08-10 2005-06-08 Bethesda Pharmaceuticals, Inc. Nouveaux ligands ppar ne provoquant aucune retention de fluide, aucun oedeme ni aucune insuffisance cardiaque congestive
US7105557B2 (en) 2003-03-17 2006-09-12 Teva Pharmaceutical Industries, Ltd. Polymorphs of valsartan
US7199144B2 (en) 2003-04-21 2007-04-03 Teva Pharmaceuticals Industries, Ltd. Process for the preparation of valsartan and intermediates thereof
US7378531B2 (en) 2003-04-21 2008-05-27 Teva Pharmaceutical Industries Ltd Process for the preparation of valsartan
EP1950204A1 (fr) 2003-03-17 2008-07-30 Teva Pharmaceutical Industries Ltd. Forme amorphe de valsartan
WO2010029576A3 (fr) * 2008-09-02 2010-12-23 Elder Pharmaceuticals Ltd. Composés anti-inflammatoires
WO2012056294A1 (fr) 2010-10-29 2012-05-03 Jubilant Life Sciences Ltd. Procédé amélioré de préparation de n-pentanoyl-n-[[2'-(1h-tétrazol-5-yl)[1,1'-biphényl]-4-yl]méthyl]-l-valine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000977A2 (fr) * 1990-07-13 1992-01-23 E.I. Du Pont De Nemours And Company Derives de 4-alkylimidazole
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
WO1992020342A1 (fr) * 1991-05-15 1992-11-26 E.I. Du Pont De Nemours And Company Nouvelle composition contenant des antagonistes du recepteur de l'angiotensine-ii et des inhibiteurs calciques
EP0581003A1 (fr) * 1992-06-26 1994-02-02 Bayer Ag Dérivés du cyclohexane substitués par imidazole

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
WO1992000977A2 (fr) * 1990-07-13 1992-01-23 E.I. Du Pont De Nemours And Company Derives de 4-alkylimidazole
WO1992020342A1 (fr) * 1991-05-15 1992-11-26 E.I. Du Pont De Nemours And Company Nouvelle composition contenant des antagonistes du recepteur de l'angiotensine-ii et des inhibiteurs calciques
EP0581003A1 (fr) * 1992-06-26 1994-02-02 Bayer Ag Dérivés du cyclohexane substitués par imidazole

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042443A2 (fr) * 2000-11-23 2002-05-30 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Utilisation de modulateurs de chemins de transduction de signaux eukaryotes pour traiter des infections a helicobacter
WO2002042443A3 (fr) * 2000-11-23 2003-12-18 Max Planck Gesellschaft Utilisation de modulateurs de chemins de transduction de signaux eukaryotes pour traiter des infections a helicobacter
WO2002060439A1 (fr) * 2001-01-29 2002-08-08 Takeda Chemical Industries, Ltd. Medicaments analgesiques et anti-inflammatoires
WO2003094915A1 (fr) * 2002-05-14 2003-11-20 Novartis Ag Utilisation de valsartan ou de son metabolite pour inhiber l'agregation plaquettaire
CN100408035C (zh) * 2002-05-14 2008-08-06 诺瓦提斯公司 缬沙坦代谢物用于制备抑制血小板凝集药物的用途
EP1839660A1 (fr) * 2002-08-10 2007-10-03 Bethesda Pharmaceuticals, Inc. Nouveaux ligands PPAR ne provoquant aucune rétention de fluide, aucun oedème ni aucune insuffisance cardique congestive
EP1536785A4 (fr) * 2002-08-10 2005-11-16 Bethesda Pharmaceuticals Inc Nouveaux ligands ppar ne provoquant aucune retention de fluide, aucun oedeme ni aucune insuffisance cardiaque congestive
EP1859799A1 (fr) * 2002-08-10 2007-11-28 Bethesda Pharmaceuticals, Inc. Nouveaux ligands PPAR ne provoquant aucune rétention de fluide, aucun oedème ni aucune insuffisance cardique congestive
EP1886683A1 (fr) * 2002-08-10 2008-02-13 Bethesda Pharmaceuticals, Inc. Nouveaux ligands PPAR qui ne provoquent pas de rétention de liquides, d'ýdème ou d'insuffisance cardiaque congestive
EP1536785A2 (fr) * 2002-08-10 2005-06-08 Bethesda Pharmaceuticals, Inc. Nouveaux ligands ppar ne provoquant aucune retention de fluide, aucun oedeme ni aucune insuffisance cardiaque congestive
AU2003259081B2 (en) * 2002-08-10 2010-03-11 Bethesda Pharmaceuticals, Inc. Novel PPAR ligands that do not cause fluid retention, edema or congestive heart failure
US7105557B2 (en) 2003-03-17 2006-09-12 Teva Pharmaceutical Industries, Ltd. Polymorphs of valsartan
EP1950204A1 (fr) 2003-03-17 2008-07-30 Teva Pharmaceutical Industries Ltd. Forme amorphe de valsartan
US7199144B2 (en) 2003-04-21 2007-04-03 Teva Pharmaceuticals Industries, Ltd. Process for the preparation of valsartan and intermediates thereof
US7378531B2 (en) 2003-04-21 2008-05-27 Teva Pharmaceutical Industries Ltd Process for the preparation of valsartan
WO2010029576A3 (fr) * 2008-09-02 2010-12-23 Elder Pharmaceuticals Ltd. Composés anti-inflammatoires
US8236843B2 (en) 2008-09-02 2012-08-07 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
WO2012056294A1 (fr) 2010-10-29 2012-05-03 Jubilant Life Sciences Ltd. Procédé amélioré de préparation de n-pentanoyl-n-[[2'-(1h-tétrazol-5-yl)[1,1'-biphényl]-4-yl]méthyl]-l-valine

Also Published As

Publication number Publication date
WO2001082858A3 (fr) 2002-06-27
AU2001267404A1 (en) 2001-11-12

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