JPS6124566A - 1,4-dihydropyridine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to 1,4-dihydropyridine derivatives.

(Problems to be Solved by the Invention) The object of the present invention is to provide two methods useful as therapeutic agents for cardiovascular disorders.
,6-dimethyl-4-(6-nitrophenyl)-1,4
-dihydropyridine-5,5-dicarboxylic acid (2-
nidradopropyl) ester-5-(3-nitratoglovir] ester, 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-6,5-dicarboxylic acid s'-(i-nitrado- 2-propyl) ester-5-(3-nidoradopropyl) ester, 2,6
-Simethyl-4-(6-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 6-(2-nidoradoethyl diester-5-(3-nidoradopropyl)
ester and 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-5,5-dicarboxylic acid 3-(2-nidoradopropyl) ester-5-(
3-nidradopropyl) varnish, etc. [JP-A-58-
The object of the present invention is to provide a 1,4-dihydropyridine derivative which is useful as an intermediate for the combination described in Japanese Patent Publication No. 185562 and as a therapeutic agent for cardiovascular disorders.

(Means for Solving the Problems) The object compound of the present invention has a 1,4- It is a dihydropyridine derivative (hereinafter referred to as Compound I).

Compound I can be produced using methods known in the literature, for example in the following manner. [Reference: J, Org,
Ohem, Vol. 161259 (1951).

Ber,, VOl, 31 743 (1898)) (υ-
Nitrobenzaldehyde represented by the general formula and acetoacetate ester represented by the general formula CH3COCH2C02R1 (■) (wherein R1 represents a nidorado alkyl group having 2 or 3 carbon atoms or a 2-cyanethyl group). (hereinafter referred to as compound ■), and the general formula, 0H30H= CHOO2R2'
(Ill) ■ H2 (wherein, when R2rriR' is a 2-cyanoalkyl group, it represents a nidoradoalkyl group having 2 or 3 carbon atoms, and when H1 is a nidoradoalkyl group having 2 or 3 carbon atoms, 2- A 3-aminocrotosic acid ester (hereinafter referred to as compound (2)) represented by cyanethyl group is reacted by heating in an organic solvent or water. 1 At this time, a secondary amine or its inorganic or organic acid salt may also be added. Secondary amines include dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine, piperazine, N-methylpiperidine, and morpholine, and their inorganic and organic acid salts include hydrochloric acid, sulfuric acid, nitric acid, and hydrogen bromide. acids, salts of inorganic acids such as phosphoric acid, or formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid
1 p-Chlorobenzoic acid, 0-chlorobenzoic acid, p-bromobenzoic acid, 0-bromobenzoic acid, p-nitrobenzoic acid [
, 2,4-dinitrobenzoic acid, and p-toluenesulfonic acid.

Examples of organic solvents include methanol, ethanol, inglobil alcohol, dioxane, tetrahydrofuran, and benzene.
Zen, toluene, etc. can be used. The reaction temperature is preferably the boiling point of the solvent, and is suitably 70 to 100°C.

(2) Nitrobenzaldehyde and compound ■ are reacted in the presence of a basic catalyst or in the presence of a secondary amine and an inorganic or organic acid salt in an organic solvent at 0 to 150°C, and the general formula: (Formula (wherein, R has the same meaning as above), and then heated to 50 to 100°C in a solvent-free T' or an organic solvent with compound (1). , benzene, toluene, xylene/ethanol, inglobil alcohol, dioxane, tetrahydrofuran, and the like can be used. .

As the basic catalyst, alkalis such as sodium hydroxide, potassium hydroxide, and sodium ethoxide, or secondary amines such as dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine, piperazine 7, N-methylpiperidine, and morpholine are used. be able to.

In addition, as inorganic acid salts or organic acid salts of secondary amines, salts of the secondary amines and inorganic acids such as salts, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, or formic acid, acetic acid, trifluoroacetic acid, etc. ,
Propionic acid, sialic acid, benzoic acid, p-chlorobenzoic acid, 0-chlorobenzoic acid, p-brobenzoic acid, 0-
Salts of organic acids such as bromobenzoic acid, p-nitrobenzoic acid, 2,4-dinitrobenzoic acid, p-toluenesulfonic acid can be used.

In the present invention, the nidrado alkyl group represented by R1 and R2 includes a 2-nidradoethyl group, a 3-nitratoglovir group, a 2-nidradoglovir group, a 1-nidrado-2-
Gold such as propyl group.

Furthermore, the nitro group is present at the ortho or meta position of the benzene ring.

Compound 1 provided by the present invention is, for example, compound 1
:2,6-dimethyl-4-(6-nitrophenyl)-1
,4-dihydropyridine-3,5-dicarboxylic acid 3-(
2-cyanoethyl)ester-5-(3-nidoradopropyl)ester compound 22,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-)carboxylic acid 3-(,2- cyanethyl) Nisdel-5-(2-
Nidradocrohir) Nisder compound 3: 2,6-dimethyl-4-(5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 3-(2-cyanethyl)ester-5-(1-di)rad -2-fluoryl) Nisder compound 422,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5,5-dicarboxylic acid 3-(2-cyanoethyl) ester -5-(2-nidoradoethyl ) Ester compound 5: 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbonyl'-(2-cyanoethyl) ester-5-(
3-nidradocrohir) ester compound b: 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-cycalphone 5123-(2-cyanoethyl) ester-
5-(2-=)7)ethyl) ester.

(Effect of the invention) The present invention provides a 1,4-dihydropyridine derivative (compound 1
) provided.

Compound I of the present invention is a di-thoratoalkyl asymmetric 1,4-dihydropyridine-3,5-dicarboxylate useful as a therapeutic agent for cardiovascular diseases, as shown in Patent Applications 2 and 3 filed on the same day as the present application. ester [Unexamined Japanese Patent Publication No. 5818
No. 5562, Japanese Patent Application No. 58-197377] is useful as an intermediate for producing cedar-based products, and is not only useful as an intermediate for producing cedar-based products, but also is useful as an intermediate for producing circulatory disorders such as coronary artery blood circulation disorders, cerebral artery blood circulation disorders, and hypertension. Useful as a therapeutic agent.

(Example) Hereinafter, the present invention will be explained in more detail by giving examples showing the production of Compound 1 and test examples showing the pharmacological effects. ．．
5 f, 3-aminocrotonic acid 2-cyanoethyl ester 7.7 f, 5-nitrobenzaldehyde 7,' 6
After heating under reflux for 6 hours and 60 minutes in f'i Inglobil alcohol 76-mg, cooled on ice, collected all precipitated crystals, dried, subjected to silica gel column chromatography (developing solvent dichloromethane 9-9, and recrystallized from ethanol). Then 2,6
-Simethyl-4-(3-nitrophenyl) -1,4-
Dihydropyridine-6,5-dicarboxylic acid 5-'(2-
Cyanoethyl)nisder-5-(3-nitoratoglovir]ester [Compound 1: R6,47 was obtained.

m-p, 14Q~141°C.

Example 2 Acetoacetic acid 2-nidoradopropyl ester 2052.6
- Nidrobenzaldehyde (15.1 ml) and piperidine acetate (152 ml) were heated under reflux for 2 hours under azeotropic dehydration conditions in 74 ml of benzene, and the reaction solution was mixed with 257 ml of water. , 25rnl of 1N sodium bisulfite aqueous solution! , 25m1 of water! Wash sequentially with
After drying over anhydrous sodium sulfate, benzene was distilled off under reduced pressure. Add 15.4 f/3-aminonerotonic acid 2-cyanethyl ester to the growth and add 4 g of isopropyl alcohol.
After heating under reflux for 3 hours, cool on ice, collect the precipitated crystals, dry, subject to silica gel chromatography (developing solvent: hexane, ethyl acetate, 1=1), and recrystallize from isopropyl alcohol. 2,6-cymethyl-4-(
3-nitrophenyl) -1,4-dihydropyridine-
3,5-dicarboxylic acid 3-(2-cyanoethyl) ester-5-(2-nitratoglovir) ester [Compound 2
J31.2g was obtained.

m, p, 139-1405°C0 Example 5 Acel-acetic acid 1-nidrado-2-propyl ester 20
57.6-Aminocrotonic acid 2-cyanoethyl ester 15.41F, 151 g of 3-nitrobenzaldehyde was heated under reflux for 6 hours in 76 ml of 1-sopropyl alcohol,
The crystals were treated in the same manner as in Example 1 and subjected to silica gel chromatography (developing solvent.

Hexane. 2,6-dimethyl-,1(
3-nitrophenyl)-1,4-dihydropyridine-6
,5-dicarboxylic acid 3-(2-cyanoethyl) ester-5-(1-di)rad-2-propyl) ester [Compound 5) 3i, 3rl was obtained.

rn, p, 138. ．． 5-1395℃ Example 4 Acetoacetic acid 2-nidoradoethyl ester 9.7f.

5-Aminocrotonic acid 2-cyanethyl ester 7.7
9,:6-nitrobenzaldehyde 7.6 r'i
1 After heating under reflux in 76 ml of ethanol for 7 hours, the same treatment as in Example 1 was performed, and the crystals were subjected to silica gel chromatography (developing solvent: hexane:acetone = 5:3), and recrystallized from inopropyl alcohol. 2.6-dimethe-4-(6-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-/anoethyl)
Ester-5-(2-nidradoprolester [Compound 4) 14. I got sy.

m, p, 151 ~ 1'52.5 °C Example 5 6-aminocrotonic acid 3-nidoradopropyl ester 1
0.2F, acetoacetic acid 2-/anoethyl ester 7.8
f, 2-nitrobenzaldehyde 77 and isopropyl alcohol 77rnI! 98 was subjected to silica gel chromatography (developing solvent: dichloromethane) and recrystallized from dichloromethane/erthyl to give 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-5,5-dicarboxylic [ 3-(2-cyanoethyl)
Ester-5-(3-nitratoglobil) ester [compound s] 1 6. Obtained 2y.

m. I), 162-164°C.

Example 6 Ar1 nido ff+12 nido ethyl varnish 7”#9
．． 7? , 2-nitrobenozaldehyde 7.6f, and piperidine 027 were heated and poured in benzene/40 ml under azeotropic dehydration conditions for 3 hours, and then treated in the same manner as in Example 1. 2-cyanoethyl ester 7
．． 7 Process 9 to 1 soprobil alcohol 40-medium 5
After heating under reflux for an hour, inopropyl alcohol was distilled off under reduced pressure, the growth was subjected to silica gel chromatography (developing solvent: dichloromethane), and recrystallized from dichloromethane/ether. )-1,4-dihydropyridine-3,5-dicarboxylic acid 6-(2-7anoethyl)ester-5-(2-=
tra)ethylnoester [Compound 6] was obtained.

m, p, 435-1565°C.

Test example [Vasodilatory effect] One group of 7 male and female mongrel dogs (body weight 10-15 kg) were treated with bentoparbiter sodium (9.i, V at 30 my/min) u
Under anesthesia, for the coronary artery, after thoracotomy, an extracorporeal circulation path was created using heparin on the north side from the left common carotid artery to the left anterior descending artery, and for the vertebral artery, an extracorporeal circulation path was created in the right vertebral artery, and this circulation path was inserted 30 minutes after surgery. Each catheter contains 0.3 drugs.
/I9 was administered, and an electromagnetic flowmeter was inserted in the middle of the circulation path to measure blood flow while performing artificial respiration.

The drug was injected into the femoral artery through a cannula inserted into its branch, and the blood flow was measured with an electromagnetic flowmeter attached to the femoral artery.

The vasodilatory effect of Compound 1 in each artery was investigated from the ratio with the measured blood flow rate of the control drug, and the results shown in Table 1 were obtained.

The control drug was 2,6-dimethyl-4-(2-di)0phenyl)-1,4-dihydropyricino 3.5-
Dicarboxylic acid ester (generic name: nifedipine) was used.

Table 1 Vasodilation (maximum diastolic capacity) action procedure amendment (voluntary) August 28, 1980 1 Case indication 1982 Patent Application No. 145597 2 Name of the invention 1.4-Dihydropyridine derivative 3 Person making the amendment Relationship to the incident Patent applicant address: 5-24-1 Takada, Toshima-ku, Tokyo Name (281)
, 1 Taisho Pharmaceutical Co., Ltd. Representative Shoji Uehara 4, Agent Address: 6-24 Takada, Toshima-ku, Tokyo 171 @ No. 1 Taisho Pharmaceutical Co., Ltd.] 5th Assistant City Karizomei aI (no changes to the content) ] Z List of attached documents

Claims (1)

[Claims] 1,4-dihydropyridine represented by the general formula, ▲numerical formula, chemical formula, table, etc.▼ (in the formula, R represents a nitratoalkyl group consisting of 2 or 3 carbon atoms) derivative.