2,6-Dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester having hypotensive properties, process for its preparation and pharmaceutical preparations containing it

Claim 2

A compound of the formula I wherein R 1 is selected from the group consisting of -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH2CH20)2CH3, R 2 is selected from the group consisting of -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH(CH 3 )CH 2 OCH 3 , -C(CH 3 ) 2 CH 2 OCH 3 , CH 2 C≡CH, and -CH 2 C(CH 3 )=CH 2 , whereby Rl and R are not the same, R is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl and methoxy.

Claim 3

A compound of claim 1, wherein R is selected from the group consisting of -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , and R 2 is selected from the group consisting of -C 2 H 5 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH(CH 3 )CH 2 OCH 3 , and C(CH 3 ) 2 CH 2 OCH 3 , R3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy.

Claim 4

A compound of claim 1, wherein R is -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R2 is selected from the group consisting of -CH 2 C = CH, -CH 2 C(CH 3 )=CH 2 , R 3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy.

Claim 5

A compound according to claims 1-3, wherein 1) 2,6-dim-4--2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarhoxylic acid-3-methylester-5-ethylester; 2) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-ethylester-5-(2-methoxyethyl- ester); 3) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-isopropylester; 4) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-(1-methylpropylester); 5) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methyl-5-tert.butylester; 6) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-(2-methoxy-l--methylethylester); 7) 2,6-dimethyl-4-(2-methoxy-3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester; 8) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-(2-methoxyethyl)ester-5-isopropylester; 9) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-(2-ethoxyethyl)ester-5-ethylester; 10) 2,6-dimethyl-4-(2,3-dichlorophenyl)-),4-dihydropyridine--3,5-dicarboxylic acid-3-[2-(2-methoxyethoxy)ethyl]-ester-5-isopropylester; 11) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-(2-isopropyloxy- ethyl)Ester; 12) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-(2-methoxy-1,1--dimethylethyl)ester; 13) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-(2-ethoxyethyl)-ester; 14) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-(2-methoxy)ethylester-5-propargyl ester; 15) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine--3,5-dicarboxylic acid-3-methylester-5-(2-methyl)allylester; 16) 2,6-dimethyl-4-(2-methoxy-3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-S-isopropylester; 17) 2,6-dimethyl-4-(2-methoxy-3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(2-methoxyethyl)ester--5-ethylester. 18) 2,6-dimethyl-4-(2-methoxy-3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(2-methoxyethyl)ester--5-isopropylester; 19) 2,6-dimethyl-4-(2-chloro-3-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-(1-methyl)-n-propylester; 20) 2,G-dimethyl-4-(2-chloro-3-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethylester-5-isopropylester; 21) 2,6-dimethyl-4-(2-chloro-3-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester; or 22) 2,6-dimethyl-4-(2-chloro-3-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester, is selected.

Claim 6

A process for preparing compounds of the formula I wherein R is selected from the group consisting of -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R 2 is selected from the group consisting of -CH 2 CH 3, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH(CH 3 )CH 2 OCH 3 , -C(CH 3 ) 2 CH 2 OCH 3 , -CH 2 C = CH, and -CH 2 C(CH 3 )=CH 2 , whereby R 1 and R2 are not the same, R3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl and methoxy, characterized in that a 1 ) a compound of formula IIa wherein R 1 , R 3 and R 4 have the meanings given above is reacted with a compound of formula IlIa wherein R 2 has the meaning given above to the formation of a compound of the formula I; a 2 ) 1 a compound of formula IIb wherein R 2 , R 3 and R 4 have the meanings given above, is reacted with a compound of formula IIIb wherein R 1 has the meaning given above, to the formation of a compound of the formula I; b 1 ) a compound of formula IV wherein R 3 and R 4 have the meanings given above, is reacted wherein R 3 and R 4 have the meanings given above, is reacted with the compounds of formules Va and IIIa wherein R 1 and R 2 have the meanings given above, to the formation of a compound of formula I; b 2 ) a compound of formula IV above, wherein R 3 and R 4 have the meanings given above, is reacted with the compounds of formulas Vb and IIIb wherein R 1 and R 2 have the meanings given above, to the formation of a compound of formula I; c 1 ) a compound of formula IIa above, wherein R 1 , R 3 , and R 4 have the meanings given above, is reacted with a compound of formula VIa wherein R 2 has the meanings given above in the presence of ammonia, to the formation of a compound of the formula 1, c 2 ) a compound of formula IIb above, wherein R 2 , R 3 , and R 4 have the meanings given above, is reacted with a compound of formula VIb wherein R has the meaning given above in the presence of ammonia to the formation of a compound of the formula I; or d) a compound of formula IV above, wherein R 3 and R 4 have the meanings given above, is reacted with the compounds of the formulas Va and Vb above, wherein R 1 and R 2 have the meanings given above in the presence of ammonia to the formation of a compound of the formula I.

Claim 7

A process for preparing compounds of the formula I wherein R is selected from the group consisting of -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R 2 is selected from the group consisting of -CH 2 CH 3, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH(CH 3 )CH 2 OCH 3 , -C(CH 3 ) 2 CH 2 OCH 3 , -CH 2 C = CH, and -CH 2 C(CH 3 )=CH 2 , whereby R 1 and R2 are not the same, R3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl and methoxy, characterized in that a 1 ) a compound of formula IIa wherein R 1 , R 3 and R 4 have the meanings given above is reacted with a compound of formula IlIa wherein R 2 has the meaning given above to the formation of a compound of the formula I; a 2 ) 1 a compound of formula IIb wherein R 2 , R 3 and R 4 have the meanings given above, is reacted with a compound of formula IIIb wherein R 1 has the meaning given above, to the formation of a compound of the formula I; b 1 ) a compound of formula IV wherein R 3 and R 4 have the meanings given above, is reacted wherein R 3 and R 4 have the meanings given above, is reacted with the compounds of formules Va and IIIa wherein R 1 and R 2 have the meanings given above, to the formation of a compound of formula I; b 2 ) a compound of formula IV above, wherein R 3 and R 4 have the meanings given above, is reacted with the compounds of formulas Vb and IIIb wherein R 1 and R 2 have the meanings given above, to the formation of a compound of formula I; c 1 ) a compound of formula IIa above, wherein R 1 , R 3 , and R 4 have the meanings given above, is reacted with a compound of formula VIa wherein R 2 has the meanings given above in the presence of ammonia, to the formation of a compound of the formula 1, c 2 ) a compound of formula IIb above, wherein R 2 , R 3 , and R 4 have the meanings given above, is reacted with a compound of formula VIb wherein R has the meaning given above in the presence of ammonia to the formation of a compound of the formula I; or d) a compound of formula IV above, wherein R 3 and R 4 have the meanings given above, is reacted with the compounds of the formulas Va and Vb above, wherein R 1 and R 2 have the meanings given above in the presence of ammonia to the formation of a compound of the formula I.

Claim 8

A process according to claim 5, wherein a compound of formula I is prepared, wherein R is selected from the group consisting of -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , and R 2 is selected from the group consisting of -C 2 H 5 , -CH(CH 3 ) 2 C(CH 3 ) 3 , -CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ), -CH(CH 3 )CH 2 OCH 3 , and C(CH 3 ) 2 CH 2 OCH 3 , R 3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy.

Claim 9

A process according to claim 5, wherein a compound of formula I is prepared, wherein R is -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R 2 is selected from the group consisting of -CH 2 C≡CH, -CH 2 C(CH 3 )=CH 2 , R 3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy.

Claim 10

B. Pharmaceutical preparation, which comprises as an active ingredient a therapeutically effective dose of at least one antihypertensive compound having vascular smooth muscle relaxing properties which compound has the formula I wherein R is selected from the group consisting of -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R 2 is selected from the group consisting of -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH(CH 3 )CH 2 OCH 3 , -C(CH 3 ) 2 CH2OCH 3 , -CH 2 C≡CH, and -CH 2 C(CH 3 )=CH 2 , whereby R 1 and R are not the same, R is selected from the group consisting of chloro, and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy in assocation with a pharmaceutically acceptable carrier.

Claim 11

B. Pharmaceutical preparation, which comprises as an active ingredient a therapeutically effective dose of at least one antihypertensive compound having vascular smooth muscle relaxing properties which compound has the formula I wherein R is selected from the group consisting of -CH 3 , -C 2 H 5 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R 2 is selected from the group consisting of -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , CH(CH 3 )C 2 H 5 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH(CH 3 )CH 2 OCH 3 , -C(CH 3 ) 2 CH2OCH 3 , -CH 2 C≡CH, and -CH 2 C(CH 3 )=CH 2 , whereby R 1 and R are not the same, R is selected from the group consisting of chloro, and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy in assocation with a pharmaceutically acceptable carrier.

Claim 12

A pharmaceutical preparation according to claim 8, wherein the active ingredient is a compound of formula I, wherein R 1 is selected from the group consisting of -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , and R 2 is selected from the group consisting of -C 2 H 5 , - CH ( CH 3 ) 2 , - C ( CH 3 ) 3' -CH(CH 3 )C 2 H 5 , -CH2CH20CH(CH3)2, -CH(CH 3 )CH 2 OCH 3 , and C(CH 3 ) 2 CH 2 OCH 3 , R 3 is selected from the group consisting of chloro and methoxy, and R is selected from the group consisting of chloro, methyl, and methoxy.

Claim 13

A pharmaceutical preparation according to claim 8, wherein the active ingredient is a compound of formula I, wherein R 1 is -CH 3 , -C 2 H 5 , CH 2 CH 2 OCH 3 ,- CH 2 CH 2 OC 2 H 5 , and -(CH 2 CH 2 O) 2 CH 3 , R is selected from the group consisting of -CH 2 C≡CH, -CH 2 C(CH 3 )=CH 2 , R 3 is selected from the group consisting of chloro and methoxy, and R 4 is selected from the group consisting of chloro, methyl, and methoxy.

Claim 14

A pharmaceutical preparation according to claim 8, wherein the substituted 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid-diester compound comprises 0.1 to 99 % by weight of the preparation.