CS245083B1 - 1,4-dihydropyridine derivatives - Google Patents

Abstract

1,4-Dihydropyridine General Derivatives of formula I wherein R, R 1 and R 2 are as defined below, are prepared by condensing the aldehyde with 4- -chloroacetate and acid ester of 3- -aminocrotone in organic medium solvent. The compounds are used for preparation drugs with a circulatory effect.

Description

The invention relates to 1,4-dihydropyridine derivatives of the general formula I

COOR 1 (where R is a phenyl group which may be substituted by halogen, methyl, methoxy or nitro; furyl or thienyl, R 1 and R 2 are methyl, ethyl and isopropyl, wherein R 1 may not be identical to R 2.

The novel compounds of formula (I) suppress the penetration of Ca ²⁺ ignites across the plasma membrane, favorably affecting the excitatory-contraction complex in smooth muscle fibers. The fact that the compounds of formula (I) favorably affect the flow in the cerebral vessels and that their action is rapid and prolonged predetermines them for the treatment of cerebrovascular ischemic diseases.

The 1,4-dihydropyridine derivatives of formula I are prepared by reacting an aldehyde of formula II

R — CHO (Π) in which R is as defined above, with a 4-chloroacetyl acetic acid ester of the general formula III

Cl-CH2-CO-CHa-COORi (III) wherein R 1 is as defined above, and a 3-aminocrotonic acid ester of formula IV

CHa-C = CH-1COOR2

The process for the preparation of the compounds of the formula I is carried out by a mixture of 1 mol of an aldehyde of the formula II in which R is as defined above, of 1 to 1.2 mol of an ester of a 4-chloroacetacetic acid of the formula III in which R 1 is as defined above and 1 to 1.2 moles of 3-aminocrotonic acid ester are reacted at a temperature of 20 to 120 ° C in an organic solvent, preferably at the boiling point of the solvent As the organic solvent, methanol, ethanol, isopropanol, chloroform, benzene, toluene and others can be used.

As reactants, for example:

benzaldehyde,

2-nitrobenzaldehyde,

3-nitrobenzaldehyde,

4-nitrobenzaldehyde,

2-methoxybenzaldehyde,

2-chlorobenzaldehyde,

3,4,5-trimethoxybenzaldehyde,

2-furaldehyde, thiophene-2-aldehyde,

Methyl 4-chloroacetate, 4-chloroacetate ethyl,

3-methyl ammonium boronate,

Ethyl 3-aminocrotonate and others.

The details of the individual preparation methods are given in the following examples without being limited to these.

Example 1

2-Chloromethyl-4- (4-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

15.1 g of 4-nitrobenzaldehyde, 15.05 g of methyl 4-chloroacetate and 11.5 g of 3-aminocrotonate are heated together in 70 ml of methanol for 3 hours at the boiling point. After standing overnight in the refrigerator, the precipitated product is filtered off with suction, washed with cold methanol and recrystallized. Light yellow needles of melting point 153 to 155% 1 are obtained.

Example 2

2-Chloromethyl-4- (2-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

15.1 g of 2-nitrobenzaldehyde, 15.05 g of methyl 4-chloroacetate and 11.5 g of methyl 3-aminocrotonate are heated together with 70 ml of benzene at reflux for 1 hour. Then, the reaction mixture is filtered and the solvent is distilled off from the reaction mixture under reduced pressure. Ethyl acetate was added to the resulting oils and the solution was allowed to stand in the refrigerator for 3 days. The precipitated pale yellow crystals are aspirated, washed on a filter! cold methanol and recrystallize. The pure product obtained has a melting point of 182-184 ° C.

Example 3

2-Chloromethyl-4-phenyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

10.6 g of freshly distilled benzal245083 dehyde, 15.05 g of methyl 4-chloroacetate and 11.5 of 3-aminocrotonate are heated together with 70 ml of chloroform at reflux for 2 hours. After cooling, the sparged aqueous layer was separated and the organic phase was dried over Na 2 SO 4. Then the solvent was distilled off from the reaction mixture and methanol was added to the residue. After standing in the refrigerator for several days, the precipitated white crystals are filtered off, washed on the filter with cold methanol and recrystallized. The product thus obtained has a melting point of 122 to 124 ° C.

Example 4

2-Chloromethyl-4- (4-tolyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester g 4-tolualdehyde, 16.05 g ethyl 4-chloroacetate and 13 g ethyl 3-aminocrotonate together with 70 ml of methanol are allowed to stand at 20 ^DEG C. for 7 days, after which time the precipitated crystals are filtered off and recrystallized. The pure product obtained has a melting point of 108-110 ° C.

Examples 5 to 20

The following compounds were prepared in an analogous manner:

5. 2-Chloromethyl-4-phenyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 98-101 ° C.

6. 2-Chloromethyl-4- (2-chlorophenyl) -6-methyl-1,1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 120-122 ° C.

7. 2-Chloromethyl-4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 105-106 ° C.

8. 2-Chloromethyl-4- (2-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 100-102 ° C.

9. 2-Chloromethyl-4- (3-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 174-177 ° C.

10. 2-Chloromethyl-4- (3-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-isopropyl ester, m.p. 144-146 ° C.

2-Chloromethyl-4- (3-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 121-122 ° C.

12. 2-Chloromethyl-4- (4-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid tert-5-methyl ester, m.p. 140-142 ° C.

13. 2-Chloromethyl-4- (4-nitrophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 142-144 ° C.

14th dimethyl ester of 2-chloromethyl-4- (3,4,5-trimethoxyphenyl) -6-methyl-l, 4-dihydropyridine-3,5-dicarboxylate of melting point 171-173 C. ^Q

15. 2-Chloromethyl-4- (2-furyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 111-112 ° C.

16. 2-Chloromethyl-4- (2-thienyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 124-126 ° C.

17. 2-Chloromethyl-4- (2-thienyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 143-145 ° C.

18. 2-Chloromethyl-4- (2-methoxyphenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 142-145 ° C.

19. Diethyl ester of an acid. 2-chloromethyl-4- (2-methoxyphenyl j -6-methyl-l, 4-dihydropyridine-3,5-dicarboxylate of melting point 125-126 ^C. C.

20. 2-Chloromethyl-4- (3-bromophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 18-9 ° C.

Example 21

The example illustrates the hemodynamic properties of the compounds of the invention.

For example, the compound of Example 11 at a dose of 10 µg. kg ^-1 1st v. in an experiment on dogs with unopened chest under pentobarbital anesthesia, increased blood flow in the vertebral artery from 31.8 to 92.4 ml. min ^-1 , ie 190 percent, while ¹ or nifedipine at the same dose increased blood flow by 106%. The effect of the substance was demonstrated as early as 30 seconds after administration, with a peak at 1 minute and lasted for 25 minutes similar to the compared nifedipine. Following administration of the compound of Example 11 at 30 µg ^/ kg, blood flow increased from 28.2 to 96 ml. min-i, ie by 240%.

When investigating the effect of the substance of Example 11 on a 10 μζ pressure drop. kg ^-1 after iv administration, systolic pressure returned to control values after 2 minutes. The diastolic BP decreased from 15 kPa to 9 kPa, ie by 6 kPa. The maximum decrease in blood pressure was recorded 30 seconds after administration and lasted for more than 15 minutes. Nifedipine at the same dose showed a decrease in blood pressure consistent with the compound of Example 11.

The fact that the compounds of formula (I) favorably affect arterial flow and significantly lower blood pressure, and that their effect is rapid, is a prerequisite for their clinical use in ischemic disease.

Claims (3)

1. 1,4-Dihydropyridine derivatives of the general formula I COOR ₁ CH 2 (i) wherein R represents a phenyl group which may be substituted by halogen, methyl, methoxy or nitro; furyl or thienyl, R 1 and R 2 are the same or different and represent! methyl, ethyl or isopropyl. 2. A process for the preparation of 1,4-dihydropyridine derivatives of the formula I as defined in claim 1, wherein R, R1 and R2 are as defined above, characterized in that the aldehyde of the formula II is reacted. R — CHO (Π) in which R is as defined above, with a 4-chloroacetoacetic acid ester of the general formula III C1-CH2-CO-CHa-COORi (III) wherein R 1 is as defined above and a 3-aminocrotonic acid ester of formula IV CH ·, —C = CH — COOR ₂ I NH 2 (IV) wherein R 2 is as defined above in an organic solvent at a temperature of 20 to 120 ° C, preferably at the boiling point of the solvent. 3. The method of claim 2, wherein the organic solvent is methanol, ethanol, isopropanol, chloroform, benzene, toluene or a mixture thereof. Severography, n. P., Plant 7, Most Price 2,40 Kčs