JPH0251526B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1,4-dihydropyridine derivatives. More specifically, the present invention provides that the melting point of the hydrochloride is
(±)-2,6-dimethyl-4 at 196-202℃
-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl) ester-5-methyl ester, optical isomer with (+) optical rotation Concerning the body and its salts. The inventors have already determined 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 [(±)
−α body] [Japanese Patent Application No. 57-180616 (Japanese Unexamined Patent Publication No. 59-70667)]. Thereafter, the present inventors conducted various studies and found that among the above (±)-α forms, the (+)-α form has a particularly superior blood pressure lowering effect compared to the (±)-α form. An example of the method for producing this compound is shown below. Manufacturing method A compound of the formula used as a starting material (hereinafter referred to as a compound. The same applies to the formula and the compound of the formula)
As the compound, an optically active substance or racemate having a (-) optical rotation is used, and as a compound, an optically active substance or a racemate having a (+) optical rotation is used. Esterification of compounds can be carried out by, for example, (a) converting the compound into an acid halide using a halogenating reagent and then reacting it with the compound; (b) using a condensing agent such as N,N ¹ -dicyclohexylcarbodiimide (DCC). This is carried out by a method known per se, such as a method of reacting a compound with another compound in the presence of an inexpensive halogenating reagent (for example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, etc.). ) using
Particularly advantageous is method (a), in which the compound is converted into an acid halide and then reacted with the compound. Furthermore, method (a) will be explained in detail. This method is expressed by the following reaction formula when the halogenating reagent is thionyl chloride, for example. 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 and N,N- as the reaction solvent.
Dimethylformamide or hexamethylphosphoric triamide is used alone or in combination with the above solvents. The molar ratio of the compound and thionyl chloride is 1.0:0.8~
The ratio is 1.0:2.0, preferably 1.0:0.9 to 1.0:1.2. 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 to 100°C, preferably -20°C to 50°C.
It is carried out at a temperature of °C. Next, the compound is obtained by reacting the obtained compound (which may not be isolated) with the 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. The compounds and compounds used as starting materials are known compounds, and optically active compounds can be easily derived from known optically active compounds by the reaction of the following formula. The literature is shown below. Compound: T. Shibanuma et al., Chem.Pharm.
Bull., 28 , 2809 (1980) Compound V: H.Sievertsson et al., J.Med,
Chem., 15 , 1085 (1972) The target compound (+)-α form can be isolated from the reaction solution obtained in this manner as follows. When both the starting material compound and the compound are optically active forms [the compound is the (-) form and the compound is the (+) form], the product is essentially the (+)-
Since it is only the α-isomer, the target product can be isolated by operations such as extraction and concentration, but column chromatography may be performed if necessary. In addition, if either the compound or the compound is a racemate, the reaction solution contains the desired (+)-
In addition to the α form, the (+)-β form or the (-)-β form (here, the (+)-β form or the (-)-β form means the (+)-
It has the same planar structure as the α-form, and the melting point of the hydrochloride is
It is an optically active isomer of the (±)-β form that exhibits a temperature of 236 to 242°C. ), the target product can be isolated by performing column chromatography in addition to extraction and concentration. In addition, if necessary, the isolated free target product and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, fumaric acid, etc.
Salts thereof can be produced by reacting with organic acids such as maleic acid, malic acid, and tartaric acid. Next, the acute toxicity and hypotensive effect of this compound will be explained. Acute Toxicity The drug was orally administered by force to mice (ddy strain, body weight 20-24 g, male), and the survival rate 72 hours after administration was examined. The drug was prepared by suspending a small amount of Tween 80 in water and orally administering 0.1 ml per 10 g of mouse weight using a gastric tube. Acute toxicity LD ₅₀ (mg/Kg・po) (+)-α form 95 (-)-α form 918 (±)-α form 218 Hypotensive effect 1 SHR (without anesthesia) intravenous administration Spontaneous hypertensive rats (SHR ) (Okamoto
strain, 20-30 weeks old, male) treated with thiopental.
The patient is anesthetized with sodium (50 mg/Kg ip), and a cannula for blood pressure measurement is inserted into the descending aorta from the right femoral artery, and a cannula for intravenous administration is inserted into the left jugular vein, and each is secured to the back of the neck. The next day, blood pressure changes due to intravenous drug administration were measured invasively without anesthesia. The drug is polyethylene glycol
400 per 100g of rat body weight
0.1 ml was administered intravenously. The results are shown in Table 1.

【table】

[Table] 2 SHR (no anesthesia) oral administration Spontaneous hypertensive rats (SHR) (Okamoto
Changes in systolic blood pressure when the drug was orally administered to mice (Strain, 15-25 weeks old, male).
Plethysmographic tail method (Ueda Manufacturing USM
-105R). The drug was suspended in 0.3% carboxymethyl cellulose and administered orally by force using a gastric probe at 0.5 ml per 100 g of rat body weight. The results are shown in Table 2.

[Table] In view of its pharmacological action, this compound can be used in various pharmaceutical forms for the purpose of administration.
In particular, it is preferable to use it in oral dosage forms such as tablets and powders. In the case of tablets, each tablet contains 1 to 30% of this compound.
(w/w) may be included. Other ingredients (carriers) include commonly used excipients, disintegrants,
Lubricants, binders, coating agents, etc. are used. Excipients include glucose, lactose, etc.; disintegrants include starch, calcium carboxymethyl cellulose, etc.; lubricants include magnesium stearate and talc; binders include simple syrup, polyvinyl alcohol, gelatin, hydroxypropyl cellulose, etc. Examples of the coating agent include a dispersant and a plasticizer, and the dispersant includes methyl cellulose, ethyl cellulose, etc., and the plasticizer includes glycerin, polyethylene glycol, etc. Crystalline cellulose is also used as having disintegration, binding and excipient properties. In the case of a powder, the present compound may be contained in an amount of 1 to 20% (w/w). As carriers, excipients such as glucose and lactose, binders such as hydroxypropyl cellulose, etc. are used. This compound [(+)-α form]
The LD ₅₀ for oral administration to male mice is 95 mg/Kg. The dosage is preferably in the range of 1 to 50 mg per day for an adult (approximately 60 kg). Examples and reference examples are shown below. Example 1 (-)-2,6-dimethyl-4(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (2.50 g) was dissolved in a mixed solvent of dichloromethane and N,N-dimethylformamide (4:1v/ v) Suspend in 17 ml and add 0.57 ml of thionyl chloride while cooling on ice. After stirring for one and a half hours under ice cooling, (+)-1-benzyl- obtained in Reference Example 1
Add 1.51 g of 3-hydroxypiperidine, and stir under ice cooling. After reacting for 2 hours, the reaction solution was diluted with 25 ml of dichloromethane, diluted with 30 ml of water, and then 30 ml of brine.
Wash with ml. The dichloromethane layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography (eluent: chloroform:ethyl acetate = 1:1 v/v), and the fraction containing the target product is concentrated. Add chloroform to the concentrate.
After adding 30 ml and 10 ml of 4N hydrochloric acid and stirring vigorously,
The chloroform layer is washed twice with 20 ml of water and then dried over anhydrous sodium sulfate. The dried liquid was concentrated to dryness to obtain 4.20 g of amorphous powder. The powder is dissolved in 15 ml of acetone, added to 200 ml of ether, and stirred to form a precipitate. The precipitate was filtered and dried to give 2.72 g of (+)-2,6-dimethyl-4-(3
-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-
3-piperidyl)ester-5-methyl ester hydrochloride is obtained. [α] ²¹ _D +113.6 (c=0.50, acetone) IR (KBr, cm ^-1 ): 1680, 1525, 1350NMR
(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) Example 2 2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (2.50 g) in a mixed solvent of dichloromethane and N,N-dimethylformamide (4:
1v/v) Suspend in 17ml and add thionyl chloride under ice cooling.
Add 0.57ml. After ice-cooling and stirring for 1 hour, Reference Example 1
Add 1.51 g of (+)-1-benzyl-3-hydroxypiperidine obtained above, and stir under ice cooling. After reacting for 2 hours and 40 minutes, the reaction solution was diluted with 50 ml of dichloromethane, 50 ml of 5% sodium hydrogen carbonate,
Next, wash with 50 ml of water and 50 ml of saline. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography (eluent, chloroform: ethyl acetate: triethylamine = 50:50:1 v/v) to obtain (+)-α.
Separate the body and β body. After concentrating the fraction containing the desired (+)-α form, it was dissolved in 20 ml of acetone, 5 ml of 4N hydrochloric acid was added and stirred, and the acetone was distilled off under reduced pressure. Add 20ml of chloroform to the concentrated residue and add 20ml of water.
After washing twice with water, dry with anhydrous sodium sulfate. The dried liquid was concentrated to dryness to obtain amorphous powder (+)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-
Dicarboxylic acid-3-(1-benzyl-3-piperidyl) ester-5-methyl ester hydrochloride 1.02
get g. [α] ²¹ _D +110.7 (c=0.50, acetone) IR and NMR were consistent with the compound obtained in Example 1. Reference example 1 (-)-3-hydroxypiperidine 8.53g, benzyl chloride 7.72g and triethylamine 6.17g.
After stirring under reflux for 5.5 hours in 70 ml of toluene, it is filtered and the filtrate is concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 5.49 g of a fraction with a boiling point of 103.8°C/0.5 mmHg. [α] ²³ _D +11.9 (c=2.14, methanol) Reference example 2 (−)-2,6-dimethyl-4-(3
-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester and (+)-1-benzyl-3-hydroxypiperidine, 2.50 g each of (+)-2,6-dimethyl-4-( Amorphous powder was prepared in the same manner as in Example 1, except that 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester and 1.51 g of (-)-1-benzyl-3-hydroxypiperidine were used. (-)-2,6-
Dimethyl-4-(3-nitrophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylic acid-3-
(1-benzyl-3-piperidyl)ester-5
- 3.16 g of methyl ester hydrochloride are obtained. [α] ²² _D −110.2 (c=0.24, acetone)

Claims (1)

[Scope of Claims] 1. 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl) having the following physical and chemical properties. ) Antihypertensive agent containing ester-5-methyl ester and its salt as an active ingredient: [α] ²¹ _D +110.7 to +113.6 (C = 0.50, acetone) IR (KBr, cm ^-1 ): 1680, 1525, 1350 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))