JPH0251525B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is characterized in that the melting point of the hydrochloride is 196-202℃2,
6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid-
3-(1-benzyl-3-piperidyl) ester-5-methyl ester and its salts. This compound has antihypertensive effects, coronary vasodilatory effects, peripheral vasodilatory effects, etc., and is a useful compound as a circulatory organ drug such as an antihypertensive agent and a vasodilator. The present inventors have discovered that 2,6-dimethyl-4-(3-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-(1-benzyl-3
1,4-dihydropyridine derivatives including -piperidyl) ester-5-methyl ester [Japanese Patent Application No. 56937/1983
171968)]. 2,3-dimethyl-4-(3-nitrophenyl)
Since -1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl) ester-5-methyl ester has two asymmetric carbon atoms, diastereomers exist. The present inventors investigated the separation and pharmacological activity of these diastereomers. The present invention will be explained in detail below. An example of the manufacturing process of the present compound is as follows. The compound is obtained by reacting the compound with a halogenating reagent (eg, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, etc.). The reaction involves halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene, aromatic hydrocarbons such as benzene and toluene,
It is carried out in the presence or absence of ethers such as tetrahydrofuran and dioxane, aprotic polar solvents such as acetonitrile, N,N-dimethylformamide and hexamethylphosphoric triamide, and amines such as pyridine and triethylamine. Particularly preferably, thionyl chloride is used as the halogenating reagent in the presence of N,N-dimethylformamide or hexamethylphosphoric triamide, with or without the above-mentioned solvents. The molar ratio of carboxylic acid and thionyl chloride is 1.0:0.8
~1.0:2.0 range, preferably 1.0:0.9~1.0:1.2
It is. The molar ratio of thionyl chloride and N,N-dimethylformamide or hexamethylphosphoric triamide is from 1:1 to 1:100, preferably from 1:5 to
It was 1:50. The reaction is carried out at -70°C - 100°C, preferably -20°C - 50°C.
It is carried out at a temperature of °C. Next, the target compound is obtained by reacting the obtained compound (which does not need to be isolated) with a compound. As the solvent, the solvent used when producing the compound from the compound is used. The reaction takes place at a molar ratio of compound to compound: 1.0:
It is carried out in the range of 0.8 to 1.0:2.0, preferably 1.0:0.9 to 1.0:1.2, at a temperature of -70°C to 100°C, preferably -20°C to 50°C. In the reaction solution, 2,6-dimethyl-4-(3-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-(1-benzyl-3
-Piperidyl) ester-5-methyl ester compound (α form) with melting point 196-202℃ and melting point 236-242
Since there is a mixture with the compound (β-form) at °C,
The target compound, α-isomer, is isolated as follows. After conventional operations such as extraction and concentration of the reaction solution, fractional crystallization is performed from a suitable single or mixed solvent, whereby the α-isomer crystallizes and the β-isomer remains in the solution. Single or mixed solvents suitable for fractional crystallization include ethanol, chloroform, ethanol-acetone, chloroform-acetone, chloroform-ether, chloroform-ethyl acetate, etc. Especially mixed solvents of ethanol-acetone and chloroform-acetone are used. preferable. The starting material compounds are known from the literature (T. Shibanuma et al.,
Chem.Pharm.Bull., 28 , 2809 (1980)] and is obtained by the reaction formula shown below. Salts of this compound include inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, formate,
Examples include organic acid salts such as acetate, fumarate, maleate, and malate. Next, the blood pressure lowering effect of this compound will be explained. Test method Mongrel adult dogs (8-15 kg) were treated with pentobarbital.
Anesthetization was achieved by intravenous administration of sodium 30 mg/Kg. A cannula was inserted into the left femoral artery, and blood pressure was measured using a pressure transducer (Nihon Kohden) and recorded on a polygraph. The drug was dissolved in polyethylene glycol 400, and 0.1 ml per 1 kg of body weight was administered through the brachial vein. The results are shown in Table 1.

[Table] As shown in Table 1, the α-isomer exhibited a clear blood pressure lowering effect from 1 minute after administration, which lasted for more than 90 minutes. Test method: The left renal artery of a mongrel dog (9-18 kg) was stenosed under thiopental sodium anesthesia to create a dog with renal hypertension. Changes in blood pressure were measured invasively under anesthesia via a polyethylene cannula (fixed to the back of the neck) inserted into the descending artery from the left carotid artery. The drug is
A suspension in 0.3% carboxymethylcellulose was administered orally at 0.5 ml per 1 kg of body weight using an oral administration tube. The results are shown in Table 2.

【table】

[Table] Considering the pharmacological action of the compound of the present invention,
It can be used in various pharmaceutical forms for administration purposes, and is particularly preferably used in oral dosage forms such as tablets and powders. In the case of tablets, each tablet contains 5-30% of the compound of the present invention.
(w/w) If included, other ingredients (carrier)
As such, commonly used excipients, disintegrants, lubricants, binders, coating agents, etc. are used. Excipients include glucose and lactose; disintegrants include starch, carboxymethyl cellulose, and calcium; lubricants include magnesium stearate and talc; binders include syrup,
Examples of coating agents include dispersants and plasticizers such as polyvinyl alcohol, gelatin, and hydroxypropyl cellulose. Dispersants include methyl cellulose and ethyl cellulose, and plasticizers include glycerin and polyethylene glycol. Crystalline cellulose is also used as having disintegration, binding and excipient properties. In the case of powder, the compound of the present invention may be added in an amount of 1 to 20% (w/
w) It is sufficient if it is contained. As carriers, excipients such as glucose and lactose, binders such as hydroxypropyl cellulose, etc. are used. The LD ₅₀ of the compound of the present invention (α form) when administered orally to male rats was 127.
mg/Kg. The dosage is preferably in the range of 1-100 mg per day for an adult (approximately 60 kg). Example 1 2,6-dimethyl-4-(3-nitrophenyl)
10.00 g of -1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester was suspended in 70 ml of a mixed solvent of dichloromethane and N,N-dimethylformamide (4:1 v/v), and 2.43 ml of thionyl chloride was added under ice cooling. added. After stirring under ice cooling for 1 hour, 6.33 g of 1-benzyl-3-hydroxypiperidine was added, and the mixture was further stirred under ice cooling. After reacting for 2.5 hours, the reaction solution was washed with 100 ml of water and then with 100 ml of brine, and the dichloromethane layer was dried over anhydrous sodium sulfate.
It was concentrated under reduced pressure. Then add 100% acetone to the concentrate.
ml and 8 ml of ethanol to obtain yellow 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-
(1-benzyl-3-piperidylyl)ester-
7.57 g of 5-methyl ester hydrochloride (α form) was obtained. Melting point 197-198℃ (ethanol). In addition, 5.21 g of β-isomer was obtained from the crystal mother liquor. Melting point 239-240℃ (ethanol-methanol) α
The physical properties of the body are shown below. IR (KBr, cm ^-1 ): 1680, 1525, 1345 NMR (DMSO- _d6 , δ): 1.3-2.2 (4H, broad),
2.33 (6H, s), 2.7−3.4 (4H, broad), 3.57
(3H, s), 4.40 (2H, s), 4.98 (1H, s),
5.20 (1H, broad), 7.3−8.2 (9H, m), 9.47
(1H, broad) Elemental analysis value (as C ₂₈ H ₃₂ ClN ₃ O ₆ ): C H N Actual value (%) 62.16 6.01 7.76 Measured value (%) 62.04 5.96 7.75

Claims (1)

[Claims] 1 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3- whose hydrochloride has a melting point of 197-198°C
(1-benzyl-3-piperidyl)ester-5
- A therapeutic agent for cardiovascular disease containing methyl ester and its salt as an active ingredient.