Circulation-active dioxyalkylenearyl-dihydropyridines

• US 4,886,816 A
• Filed: 05/05/1988
• Issued: 12/12/1989
• Est. Priority Date: 05/19/1987
• Status: Expired due to Term

• Current Assignee: Bayer AG
• Original Assignee: Bayer AG
• Inventors: Marhold, Albrecht, Schramm, Matthias, Franckowiak, Gerhard, Bechem, Martin, Gross, Rainer, Kayser, Michael, Thomas, Gunther
• Primary Examiner(s): Fan, Jane T.
• Application Number:
  US07/190,748
• Time in Patent Office: 586 Days
• Field of Search: 546/276, 514/338, 514/253, 544/238
• US Class Current: 514/338
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Circulation-active dihydropyridines of the formula ##STR1## in which R¹ is H, CN, NO₂ or --COOR⁷,

R⁷ is H, alkyl or various other radicals,

R² and R⁴ each independently is alkyl or other radicals,

R³ is H or optionally substituted alkyl,

R⁵ completes a keto or ester group, and

R⁶ is a direct bond or --CF₂ -- or --CHF--,

and physiologically acceptable salts thereof.

Claims

1. A dioxyalkylenearyl-dihydropyridine of the formula ##STR63## in which R¹ represents hydrogen, cyano or nitro, or represents a radical of the formula --CO₂ R⁷,

wherein

R⁷ denotes hydrogen or straight-chain, branched or cyclic alkyl or alkenyl which has up to 16 carbon atoms and is optionally substituted by one or more identical or different halogen substituents,

R² and R⁴ are identical or different and in each case represent straight-chain, branched or cyclic alkyl with up to 8 carbon atoms, or represent phenyl or benzyl, or one of the substituents R² or R⁴ represents straight-chain or branched alkyl which has up to 6 carbon atoms and is substituted by halogen, C₂ -C₇ -acyloxy, hydroxyl, amino, alkoxy, dialkoxy or aminoalkoxy, with in each case up to carbon atoms per alkoxy group or represents formyl or cyano,

R³ represents hydrogen, or represents straight-chain or branched alkyl which has up to 4 carbon atoms and is optionally interrupted in the chain by an oxygen atom,

R⁵ represents straight-chain, branched or cyclic alkyl with up to 8 carbon atoms, or represents a group --OR⁸,

wherein

R⁸ denotes hydrogen or straight-chain, branched or cyclic alkyl or alkenyl which has up to 16 carbon atoms and is optionally interrupted in the chain by an oxygen atom or a sulphur atom and/or is optionally substituted by one or more identical or different substituents from the group consisting of halogen, cyano, hydroxyl, C₂ -C₇ -acyloxy and nitro, or by a group of the formula ##STR64## or by a phenyl phenoxy, phenylthio or phenylsulphonyl group which is optionally substituted by halogen, cyano, di-C₁ -C₅ -alkylamino, C₁ -C₆ -alkoxy, C₁ -C₆ -alkyl, trifluoromethyl or nitro, or by an amino group, this amino group carrying two identical or different substituents from the group consisting of C₁ -C₆ -alkyl, C₆ -C₁₄ -aryl and C₇ -C₁₄ -aralkyl, and

X denotes a direct bond or --CF₂ -- or --CHF--, or a physiologically acceptable salt thereof.

2. A compound or salt according to claim 1,

in which

R¹ represents hydrogen, nitro or a radical of the formula --CO₂ R⁷,

wherein

R⁷ denotes hydrogen or straight-chain or branched alkyl which has up to 12 carbon atoms and is optionally mono- or polysubstituted by fluorine, chlorine or bromine,

R² and R⁴ are identical or different and in each case represent straight-chain or branched alkyl with up to 6 carbon atoms, or represent phenyl or benzyl, or one of the substituents R² or R⁴ represents straight-chain or branched alkyl which has up to 4 carbon atoms and is optionally mono- or polysubstituted by fluorine, chlorine, bromine, acetoxy, benzoyloxy, methoxy, hydroxyl, amino or aminoalkoxy with in each case up to 4 carbon atoms per alkoxy group,

R³ represents hydrogen, or represents straight-chain or branched alkyl which has up to 4 carbon atoms and is optionally substituted by phenyl, and

R⁵ represents straight-chain or branched alkyl with up to 4 carbon atoms, or represents the group --OR⁸,

wherein

R⁸ denotes hydrogen or straight-chain or branched alkyl which has up to 12 carbon atoms and is optionally interrupted in the chain by an oxygen atom and/or is optionally substituted by one or more substituents from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl and acetyloxy, or by the group of the formula ##STR65## or by a phenyl or phenoxy group which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, nitro, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy or trifluoromethyl or by an amino group, this amino group carrying two identical or different substituents from the series C₁ -C₄ -alkyl, phenyl and benzyl.

3. A compound or salt according to claim 1,

in which

R¹ represents nitro or a group of the formula --CO₂ R⁷,

wherein

R⁷ denotes hydrogen or straight-chain or branched alkyl which has up to 8 carbon atoms and is optionally substituted by up to 15 fluorine atoms or by chlorine,

R² and R⁴ are identical or different and in each case represent straight-chain or branched alkyl with up to 4 carbon atoms, or one of the substituents R² or R⁴ represents alkyl which has up to 2 carbon atoms and is optionally substituted by up to 3 fluorine atoms or by chlorine, bromine, acetoxy, benzoyloxy, hydroxyl or aminoethoxy,

R³ represents hydrogen, and

R⁵ represents the group --OR⁸,

wherein

R⁸ denotes hydrogen or straight-chain or branched alkyl which has up to 8 carbon atoms and is optionally interrupted in the chain by an oxygen atom and/or is optionally substituted by up to 15 fluorine atoms, or by chlorine, cyano or acetoxy, or by the group of the formula ##STR66## or by phenyl or phenoxy, or by an amino group, this amino group carrying two identical or different substituents from the series C₁ -C₄ -alkyl and benzyl.

4. A compound according to claim 1, wherein such compound is methyl 4-(2,2-difluoro-1,3-benzodioxol-5-yl)-1,4-dihydro-6-methyl-5-nitro-pyridine-3-carboxylate of the formula ##STR67## or a physiologically acceptable salt thereof.

5. A compound according to claim 1, wherein such compound is diethyl 1,2,6-trimethyl-1,4-dihydro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine-3,5-dicarboxylate ##STR68## or a physiologically acceptable salt thereof.

6. A compound according to claim 1, wherein such compound is methyl 2,6-dimethyl-1,4-dihydro-5-nitro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine-3-carboxylate of the formula ##STR69## or a physiologically acceptable salt thereof.

7. A compound according to claim 1, wherein such compound is 2,6-dimethyl-3-(3-cyanopropionyl)-5-nitro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine of the formula ##STR70## or a physiologically acceptable salt thereof.

8. A compound according to claim 1, wherein such compound is 1,2,6-trimethyl-3-carboxy-5-nitro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine of the formula ##STR71## or a physiologically acceptable salt thereof.

9. A pharmaceutical composition for the treatment of cardiac insufficiency comprising an effective amount of a compound or salt according to claim 1 and a physiologically acceptable diluent.

10. A unit dose of a composition according to claim 9 in the form of a tablet, capsule or ampoule.

11. A method of treating cardiac insufficiency of a patient in need thereof which comprises administering to such patient an effective amount of a compound or salt according to claim 1.

12. The method according to claim 11, wherein such compound is

methyl 4-(2,2-difluoro-1,3-benzodioxol-5-yl)-1,4-dihydro-6-methyl-5-nitro-pyridine-3-carboxylate,

diethyl 1,2,6-trimethyl-1,4-dihydro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine-3,5-dicarboxylate,

methyl 2,6-dimethyl-1,4-dihydro-5-nitro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine-3-carboxylate,

2,6-dimethyl-3-(3-cyanopropionyl)-5-nitro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine, or

1,2,6-trimethyl-3-carboxy-5-nitro-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine.