Heterocyclically substituted phenyl-cyclohexane-carboxylic acid derivatives

• US 5,395,840 A
• Filed: 02/08/1994
• Issued: 03/07/1995
• Est. Priority Date: 02/15/1993
• Status: Expired due to Fees

• Current Assignee: Bayer AG
• Original Assignee: Bayer AG
• Inventors: Kazda, Stanisiav, Kramer, Thomas, Stasch, Johannes-Peter, Knorr, Andreas, Dressel, Jurgen, Zaiss, Siegfried, Muller-Gliemann, Matthias, Hubsch, Walter, Fey, Peter, Beuck, Martin, Wohlfeil, Stefan, Muller, Ulrich E., Hanko, Rudolf H.
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US08/193,835
• Time in Patent Office: 392 Days
• Field of Search: 546/113, 546/118, 546/271, 548/252, 548/254, 548/309.7, 548/310.1, 548/503, 548/510, 514/381, 514/300, 514/303, 514/393, 514/412
• US Class Current: 514/300
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Heterocyclically substituted phenyl-cyclohexanecarboxylic acid derivatives are prepared by reacting appropriate heterocyclic compounds with cyclohexanebenzyl halides.

The compounds can be employed as active compounds in medicaments for the treatment of arterial hypertension and atherosclerosis.

Claims

1. Heterocyclically substituted phenyl-cyclohexanecarboxylic acid derivatives of the formula (I) ##STR90## in which A represents hydrogen or aryl having 6 to 10 carbon atoms, which is optionally substituted by hydroxyl, halogen or trifluoromethyl or by straight-chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms, or represents straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms,

E represents a nitrogen atom or a radical of the formula --CR¹,

in which

R¹ has the abovementioned meaning of A and is identical to or different from this,

B and D together form a radical of the formula ##STR91## in which R², R³ and R⁴ are identical or different and have the abovementioned meaning of A and are identical to or different from this, or denote halogen,

L represents hydrogen, halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, cyano or carboxyl,

T represents a radical of the formula --CO₂ R⁵, --CO--NR⁶ SO₂ R⁷ or ##STR92## in which R⁵ denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or phenyl,

R⁶ and R⁸ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R⁷ denotes trifluoromethyl or straight-chain or branched alkyl having up to 6 carbon atoms, or benzyl or phenyl, each of which is optionally substituted by straight-chain alkyl having up to 6 carbon atoms,

R⁹ denotes aryl having 6 to 10 carbon atoms, which is optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, hydroxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, carboxyl, phenoxy and C₃ -C₆ -cycloalkoxy,

R¹⁰ denotes a group of the formula --CH₂ --OR¹¹, --CO₂ R¹², --CO--NR¹³ R¹⁴ or pyridyl,

in which

R¹¹ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,

R¹² denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl or cycloalkyl having 3 to 6 carbon atoms,

R¹³ and R¹⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl,

or

T represents tetrazolyl, which is optionally substituted by triphenylmethyl or straight-chain or branched alkyl having up to 4 carbon atoms, if appropriate in an isomeric form, and their salts.

2. Heterocyclically substituted phenyl-cyclohexanecarboxylic acid derivatives according to claim 1 in which

A represents hydrogen or phenyl which is optionally substituted by hydroxyl, fluorine, chlorine, bromine or trifluoromethyl or by straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms, or represents straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,

E represents a nitrogen atom or a radical of the formula --CR¹,

in which

R¹ has the abovementioned meaning of A and is identical to or different from this,

B and D together form a radical of the formula ##STR93## in which R², R³ and R⁴ are identical or different and have the abovementioned meaning of A and are identical to or different from this, or denote fluorine, chlorine or bromine,

L represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 4 carbon atoms,

T represents a radical of the formulae --CO₂ R⁵, --CO--NR⁶ SO₂ R⁷ or ##STR94## in which R⁵ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl or phenyl,

R⁶ and R⁸ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R⁷ denotes trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, or benzyl or phenyl, each of which is optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms,

R⁹ denotes phenyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 4 carbon atoms, carboxyl or phenoxy,

R¹⁰ denotes a group of the formula --CH₂ --OR¹¹, --CO₂ R¹², --CO--NR¹³ R¹⁴ or pyridyl,

in which

R¹¹ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R¹² denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl, cyclopropyl, cyclopentyl or cyclohexyl,

R¹³ and R¹⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl or phenyl,

or

T represents tetrazolyl, which is optionally substituted by triphenylmethyl or methyl, if appropriate in an isomeric form, and their salts.

3. Heterocyclically substituted phenyl-cyclohexanecarboxylic acid derivatives according to claim 1 in which

A represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents phenyl or cyclopropyl, cyclopentyl or cyclohexyl,

E represents a nitrogen atom,

B and D together form a radical of the formula ##STR95## in which R², R³ and R⁴ are identical or different and have the abovementioned meaning of A and are identical to or different from this, or denote fluorine, chlorine or bromine,

L represents hydrogen, fluorine, chlorine, trifluoromethyl or methyl,

T represents a radical of the formula --CO₂ R⁵, --CO--NR⁶ SO₂ R⁷ or ##STR96## in which R⁵ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R⁶ and R⁸ are identical or different and denote hydrogen or methyl,

R⁷ denotes trifluoromethyl or methyl, ethyl, benzyl, p-tolyl or phenyl,

R⁹ denotes phenyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 3 carbon atoms, carboxyl or phenoxy,

R¹⁰ denotes a group of the formula --CH₂ --OR¹¹, --CO₂ R¹², --CO--NR¹³ R¹⁴ or pyridyl

in which

R¹¹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R¹² denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R¹³ and R¹⁴ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

or

T represents tetrazolyl, which is optionally substituted by triphenylmethyl or methyl, if appropriate in an isomeric form, and their salts.

4. Heterocyclically substituted phenyl-cyclohexanecarboxylic acid derivatives according to claim 1

in which

A represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or represents phenyl or cyclopropyl,

E represents a nitrogen atom,

B and D together form a radical of the formula ##STR97## in which R², R³ and R⁴ are identical or different and denote methyl, hydrogen, fluorine, chlorine or bromine,

L represents hydrogen, fluorine or chlorine,

T represents a radical of the formula --CO₂ R⁵, --CO--NR⁶ SO₂ R⁷ or ##STR98## in which R⁵ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R⁶ and R⁸ are identical or different and denote hydrogen or methyl,

R⁷ denotes trifluoromethyl, methyl or p-tolyl,

R⁹ denotes phenyl which can be substituted by fluorine or chlorine, and

R¹⁰ denotes a group of the formula --CH₂ OH or --CONH₂ or pyridyl,

or

T represents tetrazolyl, which is optionally substituted by triphenylmethyl, if appropriate in an isomeric form, and their salts.

5. A heterocyclically substituted phenyl-cyclohexane-carboxylic acid derivative according to claim 1 wherein such compound is 2-{4-[(6-Cyclopropyl-imidazo[4,5-b ]pyridin)-7-yl-methyl]phenyl}-N-[(S)-phenylglycinol]-cyclohexane-1-carboxamide of the formula ##STR99## isomers and salts thereof.

6. A heterocyclically substituted phenyl-cyclohexane-carboxylic acid derivative according to claim 1 wherein such compound is 2-{4-[(6-butyl-imidazo[4,5-b]pyridin)-7-yl-methyl]phenyl}-N-[(S)-phenylglycinol]cyclohexane-1-carboxamide of the formula ##STR100## isomers and salts thereof.

7. A heterocyclically substituted phenyl-cyclohexane-carboxylic acid derivative according to claim 1 wherein such compound is 2-{4-[(6-phenyl-imidazo[4,5-b]pyridin)-7-yl-methyl]phenyl}-N-[(S)-phenylglycinol]cyclohexane-1-carboxamide of the formula ##STR101## isomers and salts thereof.

8. A heterocyclically substituted phenyl-cyclohexane-carboxylic acid derivative according to claim 1 wherein such compound is 2-{4-[(3-bromo-6-cyclopropylimidazo[4,5-b]pyridin)-7-yl-methyl]phenyl}-N-[(S)-phenylglydnoI]cyclohexane-1-carboxamide of the formula ##STR102## isomers and salts thereof.

9. A composition for the treatment of arterial hypertension and atherosclerosis comprising an amount effective therefore of a compound an isomer or a salt thereof according to claim 1 and a pharmacologically acceptable diluent.

10. The method of treating arterial hypertension and atherosclerosis in a patient in need thereof which comprises administering to such patient an amount effective therefore of a compound or salt thereof according to claim 1.