WO2001082858A2 - Novel compounds for the treatment of inflammatory and cardiovascular diseases - Google Patents

Novel compounds for the treatment of inflammatory and cardiovascular diseases Download PDF

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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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Wolf-Georg Forssmann
Helmut Drexler
Michael Walden
Bernhard Schieffer
Boris Schmidt
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Ipf Pharmaceuticals Gmbh
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    • 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

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  • 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.

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Abstract

The invention concerns a compound having structural formula (I), wherein R1 represents H, substituted or unsubstituted alkyl or acyl groups, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl; X = halogen or OH; R2 represents H, substituted or unsubstituted alkyl or acyl groups, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, halogen or OH; R3 represents H, substituted or unsubstituted alkyl or acyl groups, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, halogen or OH; R4 represents H, substituted or unsubstituted alkyl or acyl groups, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl or is a metal radical, especially an alkali cation.

Description

Neue Verbindungen zur Behandlung inflammatorischer und kardiovaskulärer Erkrankungen New compounds for the treatment of inflammatory and cardiovascular diseases
Gegenstand der vorliegenden Erfindung ist eine Verbindung mit der in Anspruch 1 angegebenen Strukturformel, ein Arzneimittel enthaltend mindestens eine der erfindungsgemäßen Verbindungen und/oder einen analogen Metaboliten von ACE-Hemmern, ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen sowie Verwendungen der erfindungsgemäßen Verbindungen.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.
Therapeutika, die insbesondere bei rheumatischen Erkrankungen eingesetzt werden, weisen oft IMebenwirkungen auf, da sie unspezifisch die Synthese der Prostaglandine durch die unspezifische Blockierung der Cyclooxigenase (COX-1, COX-2) hemmen. Es ist mithin wünschenswert, Therapeutika bereitzustellen, die spezifischer antirheumatische und/oder entzündungshemmende Stoffwechselvorgänge beeinflussen. Ein der Erfindung zugrunde liegendes technisches Problem besteht in der Bereitstellung von chemischen Verbindungen, die spezifischer auf antirheumatische und/oder entzündungshemmende Stoffwechselvorgänge einwirken können.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.
Überraschenderweise wird dieses Problem gelöst durch eine Verbindung mit der Strukturformel
Figure imgf000002_0001
wobeiSurprisingly, this problem is solved by a connection with the structural formula
Figure imgf000002_0001
in which
R1 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, iso-Butyl-, tert.-R 1 = H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert.-
Butyl darstellt,Represents butyl,
X = Halogen oder -OH ist,X = halogen or -OH,
R2 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere 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.-
Butyl darstellt, Halogen oder -OH ist, R3 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere 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-
Butyl darstellt, Halogen oder -OH ist, R4 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere 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.-
Butyl darstellt oder ein Metallrest, insbesondere Alkalikation ist und wobei die Aldehydgruppe vorzugsweise als geschützte Aldehydgruppe, insbesondere als Acetal oder Halbacetal, insbesondere cydisches Acetal, das unter physiologischen Bedingungen die Aldehydgruppe freisetzt, vorliegt.Represents butyl or is a metal radical, in particular alkali metalation, and the aldehyde group is preferably present as a protected aldehyde group, in particular as acetal or hemiacetal, in particular cydic acetal, which releases the aldehyde group under physiological conditions.
Vorzugsweise wird erfindungsgemäß eine Verbindung mit der Bezeichnung 2- Butyl-4-chlor-l-[(2'-tetrazol-5yl)biphenyl-4-yl]methyl-5- (oxomethylen)imidazol (BCT-Ox-Im) und der folgenden Strukturformel
Figure imgf000003_0001
eingesetzt.According to the invention, a compound with the name 2-butyl-4-chloro-1 - [(2'-tetrazol-5yl) biphenyl-4-yl] methyl-5- (oxomethylene) imidazole (BCT-Ox-Im) and the following structural formula
Figure imgf000003_0001
used.
Diese Verbindung ist zum Beispiel durch katalytische Oxidation von Losartan mit Ruthenium(III)chlorid erhältlich. Losartan ist Gegenstand der US-A-5 138 069 auf die hier ausdrücklich Bezug genommen wird. Losartan ist ein AT II- Rezeptorantagonist von welchem festgestellt wurde, dass die eigentliche Wirkung ausgeht von dem Metaboliten EXP 3174, welcher bei der ersten Leberpassage entsteht. Klinische Untersuchungen von Losartan haben ergeben, dass Losartan zusätzlich auch entzündungshemmend wirkt und aggregationshemmend auf Thrombozyten.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.
Eingehende Untersuchungen der Anmelderin haben ergeben, dass die entzündungshemmende und aggregationshemmende Wirkung von Losartan nicht auf den Metaboliten EXP 3174 beruhen, sondern auf dem Metaboliten EXP 3179, nämlich 2-Butyl-4-chlor-l-[(2'-tetrazol-5yl)biphenyl-4-yl]methyl-5- (oxomethylen)imidazol (BCT-Ox-Im).Detailed investigations by the applicant have shown that the anti-inflammatory and aggregation-inhibiting effect of losartan is not based on the metabolite EXP 3174, but on the metabolite EXP 3179, namely 2-butyl-4-chloro-l - [(2'-tetrazol-5yl) biphenyl-4-yl] methyl-5- (oxomethylene) imidazole (BCT-Ox-Im).
Im Rahmen der Untersuchungen wurde weiterhin festgestellt, dass dieser Metabolit synthetisch hergestellt werden kann durch katalytische Oxidation von Losartan mit Ruthenium(III)chlorid und anschließende Abtrennung weiterer Reaktionsprodukte.It was also found in the course of the investigations that this metabolite can be produced synthetically by catalytic oxidation of losartan with ruthenium (III) chloride and subsequent separation of further reaction products.
Applikationen dieses Metaboliten EXP 3179 haben gezeigt, dass dieser Metabolit starke entzündungshemmende und aggregationshemmende Wirkung hat. Überraschenderweise wurde nur eine geringfügige Beeinflussung des Blutdruckes gefunden.Applications of this metabolite EXP 3179 have shown that this metabolite has strong anti-inflammatory and anti-aggregation effects. Surprisingly, only a slight influence on blood pressure was found.
Weiterhin wurde festgestellt, dass dieser Metabolit sowohl die COX-2-Synthese wie auch die COX-2 abhängige Prostaglandinproduktionen inhibiert und dabei Wirkkonzentrationen zwischen 1 ng und 100 mg/kg Körpergewicht aufweist. Die Ergebnisse wurden bestätigt durch in vivo Studien nach oraler Gabe von Losartan, wobei im Serum ebenfalls dieser Metabolit nachgewiesen wurde. Die pharmakokinetischen Messungen haben ergeben, dass der erfindungsgemäß verwendete Metabolit nach etwa zwei Stunden ansteigt und nach drei bis fünf Stunden seinen Höhepunkt erreicht mit starker Abnahme nach etwa sechs Stunden. Demgegenüber weist der als Angiotensin II-Antagonist wirksame Metabolit EXP 3174 ein Wirkungsmaximum bei fünf Stunden auf. Die maximalen Serumkonzentrationen des erfindungsgemäß eingesetzten Metaboliten liegen bei 2.8 x 10"7 mol und entsprechen somit den Konzentrationen von Losartan selbst, welches 2.6 x 10"7 mol aufweist. Der als AT II- Rezeptorantagonist wirksame Metabolit EXP 3174 weist hingegen ein Maximum von 3.7 x 10"6 mol auf.It was also found that 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. In contrast, 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. In contrast, the metabolite EXP 3174, which acts as an AT II receptor antagonist, has a maximum of 3.7 x 10 "6 mol.
Weitere Untersuchungen haben ergeben, dass nicht nur Losartan, sondern auch die analogen Metaboliten von ACE-Hemmern wie Irbesartan und Valsartan entzündungshemmende und aggregationshemmende Wirkung aufweisen und deshalb in ähnlicher Weise eingesetzt werden können.Further studies have shown that not only losartan, but also the analogue metabolites of ACE inhibitors such as irbesartan and valsartan have anti-inflammatory and anti-aggregation effects and can therefore be used in a similar way.
Gegenstand der vorliegenden Erfindung sind somit Arzneimittel gemäß Anspruch 3.The present invention thus relates to pharmaceuticals according to claim 3.
Die Arzneimittel enthalten den Wirkstoff in galenischen Zubereitungsformen zur intravenösen intramuskulären, peroralen oder intraperitonalen Applikation in Dosierungen von 1 ng bis 100 mg/kg Körpergewicht.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.
Vorzugsweise werden die Arzneimittel auch in galenischen Zubereitungsformen mit verzögerter Freisetzung hergestellt. Dem Fachmann sind solche Zubereitungsformen aus zahlreichen pharmazeutischen Standardwerken an sich bekannt. Typische Applikationsformen der erfindungsgemäßen Verbindungen können analog der WO-A-97/49392, auf die hier ausdrücklich Bezug genommen wird, vom Fachmann leicht ermittelt werden.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.
Der erfindungsgemäß bevorzugte Wirkstoff selbst, nämlich der Metabolit EPX 3179, 2-Butyl-4-chlor-l-[(2'-tetrazol-5yl)biphenyl-4-yl]methyl-5-(oxomethy- len)imidazol (BCT-Ox-Im), kann beispielsweise durch Oxidation von Losartan mit Ruthenium(III)chlorid hergestellt werden unter Zusatz von H2O2 und Rückfluss in Acetonitril. Aus diesem Reaktionsgemisch lässt sich der gewünschte Metabolit in einer Ausbeute von ca. 25 % gewinnen. Die Reinigung ist beispielsweise möglich mit Hilfe von topographischen Methoden, insbesondere HPLC. Als stationäre Phase kommt insbesondere eine C-18 Umkehrphase in Betracht. Eine Elution erfolgt z. B. mit Acetonitril. Alternativ zur katalytischen Oxidation kommen auch Oxidationen mit folgenden Oxidationsmitteln in Betracht: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. As an alternative to catalytic oxidation, oxidations with the following oxidizing agents can also be considered:
Dess Martin, IBX und/oder Pfizer-Moffat. Dess Martin wird beschrieben in Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents. Ed. S.D. Burke, R.L. Danheiser, John Wiley & Sons 1999, S. 468 oder Organic Synteses 1999, Vol. 77, S. 141 - 152. Es wird zur Herstellung der erfindungsgemäß zu verwendenden Metabolite eingesetzt in 1,2 molarem Überschuss, beispielsweise DMSO in einer Konzentration von 0,1 bis 1 Molar. Üblicherweise betragen die Reaktionszeiten der Umsetzung der Komponenten ungefähr 6 Stunden.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.
Das Reagenz IBX ist 2-Jodoxybenzoesäure und ist beschrieben in Journal of Organic Chemistry 1999, 64, 4537-4538. Es wird in 1,2 molarem Überschuss in DMSO eingesetzt, vorzugsweise in Konzentrationen zwischen 0,1 bis 1 Molar für eine Reaktionszeit von etwa 6 Stunden. Typische Reaktionsbedingungen betreffend das Pfizer-Moffat-Reagenzes können in Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents, Herausgeber S.D. Burke, R.L., Danheiser, John Wiley & Sons 1999, S. 154 entnommen werden.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.
Die Behandlung inflammatorischer und kardiovaskulärer Erkrankungen mit Hilfe der erfindungsgemäßen Arzneimittel eröffnet interessante Aspekte, da der Wirkstoff an anderer Stelle in den Entzündungsprozess und die Thrombozytenaggregation eingreift als die bisher hierfür angewendeten Mittel. Während Acetylsalicylsäure ein unspezifischer und irreversibler COX-Inhibitor ist, klingt die Wirkung des erfindungsgemäß eingesetzten Metaboliten bereits nach sechs Stunden wieder ab. Dies kann in der Praxis von erheblicher Bedeutung sein. Es handelt sich somit um ein neues Arzneimittel mit einem anderen Wirkmechanismus, welches im Gegensatz zur Ausgangssubstanz Losartan nur einen geringfügigen Einfluss auf den Blutdruck nimmt.The treatment of inflammatory and cardiovascular diseases with the aid of the medicaments according to the invention opens up interesting aspects, since the active substance intervenes in the inflammatory process and platelet aggregation at a different point than the agents previously used for this. While 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.
Das erfindungsgemäße Arzneimittel kann bei folgenden Indikationen eingesetzt werden.
Figure imgf000007_0001
The medicament according to the invention can be used in the following indications.
Figure imgf000007_0001

Claims

Patentansprüche claims
1. Verbindung mit der Strukturformel
Figure imgf000008_0001
wobei1. Connection with the structural formula
Figure imgf000008_0001
in which
R1 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, iso-Butyl-, tert.- Butyl darstellt,R 1 = H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl,
X = Halogen oder -OH ist,X = halogen or -OH,
R2 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, iso-Butyl-, tert.- Butyl darstellt, Halogen oder -OH ist,R 2 = H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, halogen or -OH,
R3 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, iso-Butyl-, tert.- Butyl darstellt, Halogen oder -OH ist,R 3 = H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, halogen or -OH,
R4 = H, substituierte oder unsubstituierte Alkyl- oder Acylgruppen insbesondere Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, iso-Butyl-, tert-R 4 = H, substituted or unsubstituted alkyl or acyl groups, in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-
Butyl darstellt oder ein Metallrest, insbesondere Alkalikation ist und wobei die Aldehydgruppe vorzugsweise als geschützte Aldehydgruppe, insbesondere als Acetal oder Halbacetal, insbesondere cydisches Acetal, das unter physiologischen Bedingungen die Aldehydgruppe freisetzt, vorliegt. Represents butyl or is a metal radical, in particular alkali metalation, and the aldehyde group is preferably present as a protected aldehyde group, in particular as acetal or hemiacetal, in particular cydic acetal, which releases the aldehyde group under physiological conditions.
2. Verbindung nach Anspruch 1 mit der Bezeichnung 2-Butyl-4-chlor-l-[(2'- tetrazol-5yl)biphenyl-4-yl]methyl-5-(oxomethylen)imidazol (BCT-Ox-Im) und der folgenden Strukturformel
Figure imgf000009_0001
2. Compound according to claim 1 with the designation 2-butyl-4-chloro-l - [(2'-tetrazol-5yl) biphenyl-4-yl] methyl-5- (oxomethylene) imidazole (BCT-Ox-Im) and of the following structural formula
Figure imgf000009_0001
3. Arzneimittel enthaltend als Wirkstoff eine Verbindung nach einem der Ansprüche 1 oder 2 und/oder analoge Metaboliten von ACE-Hemmern, insbesondere Irbesartan und Valsartan.3. Medicament containing as the active ingredient a compound according to one of claims 1 or 2 and / or analogous metabolites of ACE inhibitors, in particular irbesartan and valsartan.
4. Arzneimittel gemäß Anspruch 1 enthaltend den Wirkstoff in galenischen Zubereitungsformen zur intravenösen, intramuskulären, peroralen oder intraperitonalen Applikation in Dosierungen von 1 ng bis 100 mg/kg Körpergewicht.4. Medicament according to claim 1 containing the active ingredient in galenical preparation forms for intravenous, intramuscular, peroral or intraperitoneal application in doses of 1 ng to 100 mg / kg body weight.
5. Arzneimittel gemäß Anspruch 1 oder 2 in galenischen Zubereitungsformen mit verzögerter Freisetzung.5. Medicament according to claim 1 or 2 in galenical preparation forms with delayed release.
6. Verfahren zur Herstellung der Verbindung nach Anspruch 1 oder 2 durch katalytische Oxidation der Verbindung mit der Strukturformel 6. A process for the preparation of the compound according to claim 1 or 2 by catalytic oxidation of the compound having the structural formula
Figure imgf000010_0001
mit Ruthenium(III)chlorid und anschließender Abtrennung weiterer Reaktionsprodukte, worin die Substituenten die in Anspruch 1 genannten Bedeutungen haben.
Figure imgf000010_0001
with ruthenium (III) chloride and subsequent separation of further reaction products, wherein the substituents have the meanings given in claim 1.
7. Verwendung einer Verbindung nach einem der Ansprüche 1 oder 2 und/oder analoge Metaboliten von ACE-Hemmern, insbesondere Irbesartan und Valsartan zur Herstellung eines Arzneimittels zur Behandlung von inflammatorischen und kardiovaskulären Erkrankungen.7. Use of a compound according to one of claims 1 or 2 and / or analogous metabolites of ACE inhibitors, in particular irbesartan and valsartan for the manufacture of a medicament for the treatment of inflammatory and cardiovascular diseases.
8. Verwendung nach Anspruch 7 zur Behandlung von Osteoarthritis, Synovialltis, entzündliche-rheumatische Gelenk- und Wirbelsäulenleiden, einschließlich Gicht und Reizzustände bei degenerativen Gelenk- und Wirbelsäulenleiden, Weichteilrheumatismus, schmerzhafte Schwellungen oder Entzündungen nach Verletzungen oder Operationen.8. Use according to claim 7 for the treatment of osteoarthritis, synovialltis, inflammatory rheumatic joint and spine disorders, including gout and irritation in degenerative joint and spine disorders, soft tissue rheumatism, painful swelling or inflammation after injuries or operations.
9. Verwendung nach Anspruch 7 zur Behandlung von Fieber und Schmerzen.9. Use according to claim 7 for the treatment of fever and pain.
10. Verwendung nach Anspruch 7 zur Behandlung von essentieller Hypertomie und chronischer Herzinsuffizienz.10. Use according to claim 7 for the treatment of essential hypertomy and chronic heart failure.
11. Verwendung nach Anspruch 7, zur Behandlung von Schmerzen, insbesondere Erkrankungen des rheumatischen Formenkreises. 11. Use according to claim 7, for the treatment of pain, in particular diseases of the rheumatic type.
12. Verwendung nach Anspruch 7, zur Behandlung von thrombolytischer Wirkung, wirksam bei verschiedenen Koagulopathien, Thromboseprophylaxe.12. Use according to claim 7, for the treatment of thrombolytic activity, effective in various coagulopathies, thrombosis prophylaxis.
13. Verwendung nach Anspruch 7, zur Behandlung von Dysmenorrhö und Nekrose des Endometriums bei Menstruation.13. Use according to claim 7, for the treatment of dysmenorrhea and necrosis of the endometrium during menstruation.
14. Verwendung nach Anspruch 7, zur Behandlung von Morbus Alzheimer.14. Use according to claim 7, for the treatment of Alzheimer's disease.
15. Verwendung nach Anspruch 7, zur Behandlung von Helicobacter pylori- Infektionen.15. Use according to claim 7, for the treatment of Helicobacter pylori infections.
16. Verwendung nach Anspruch 7, zur Behandlung von chronisch entzündlichen Darmerkrankungen, insbesondere Morbus Crohn, Colitis Ulcerosa sowie Zöliakie. 16. Use according to claim 7, for the treatment of inflammatory bowel diseases, in particular Crohn's disease, ulcerative colitis and celiac disease.
PCT/EP2001/005043 2000-05-04 2001-05-04 Novel compounds for the treatment of inflammatory and cardiovascular diseases WO2001082858A2 (en)

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WO2002042443A2 (en) * 2000-11-23 2002-05-30 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Use of modulators of eukaryotic signal transduction pathways for the treatment of helicobacter infections
WO2002060439A1 (en) * 2001-01-29 2002-08-08 Takeda Chemical Industries, Ltd. Analgesic and antiinflammatory drugs
WO2003094915A1 (en) * 2002-05-14 2003-11-20 Novartis Ag Use of valsartan ot its metabolite to inhibit platelet aggregation
EP1536785A2 (en) * 2002-08-10 2005-06-08 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
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 (en) 2003-03-17 2008-07-30 Teva Pharmaceutical Industries Ltd. Amorphous form of valsartan
WO2010029576A3 (en) * 2008-09-02 2010-12-23 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
WO2012056294A1 (en) 2010-10-29 2012-05-03 Jubilant Life Sciences Ltd. An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042443A2 (en) * 2000-11-23 2002-05-30 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Use of modulators of eukaryotic signal transduction pathways for the treatment of helicobacter infections
WO2002042443A3 (en) * 2000-11-23 2003-12-18 Max Planck Gesellschaft Use of modulators of eukaryotic signal transduction pathways for the treatment of helicobacter infections
WO2002060439A1 (en) * 2001-01-29 2002-08-08 Takeda Chemical Industries, Ltd. Analgesic and antiinflammatory drugs
WO2003094915A1 (en) * 2002-05-14 2003-11-20 Novartis Ag Use of valsartan ot its metabolite to inhibit platelet aggregation
CN100408035C (en) * 2002-05-14 2008-08-06 诺瓦提斯公司 Use of valsartan or its metabolite to inhibit platelet aggregation
EP1839660A1 (en) * 2002-08-10 2007-10-03 Bethesda Pharmaceuticals, Inc. Novel PPAR ligands that do not cause fluid retention, edema or congestive heart failure
EP1536785A4 (en) * 2002-08-10 2005-11-16 Bethesda Pharmaceuticals Inc Novel ppar ligands that do not cause fluid retention, edema or congestive heart failure
EP1859799A1 (en) * 2002-08-10 2007-11-28 Bethesda Pharmaceuticals, Inc. Novel PPAR ligands that do not cause fluid retention, edema or congestive heart failure
EP1886683A1 (en) * 2002-08-10 2008-02-13 Bethesda Pharmaceuticals, Inc. Novel PPAR ligands that do not cause fluid retention edema or congestive heart failure
EP1536785A2 (en) * 2002-08-10 2005-06-08 Bethesda Pharmaceuticals, Inc. Novel ppar ligands that do not cause fluid retention, edema or congestive heart failure
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 (en) 2003-03-17 2008-07-30 Teva Pharmaceutical Industries Ltd. Amorphous form 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
WO2010029576A3 (en) * 2008-09-02 2010-12-23 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
US8236843B2 (en) 2008-09-02 2012-08-07 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
WO2012056294A1 (en) 2010-10-29 2012-05-03 Jubilant Life Sciences Ltd. An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine

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