JPS5970667A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:3-(1-Benzyl-3-piperidyl)-5-methyl-2,6-dimethyl-4-(3-nitrophen yl)- 1,4-dihydropyridine-3,5-dicarboxylate, expressed by formula I , and having 196- 202 deg.C melting point of the hydrochloride thereof and a salt thereof. USE:A drug for cardiovascular organs, e.g. a hypotensive agent, coronary vasodilator and peripheral vasodilator, etc. PROCESS:A compound expressed by formula II is reacted with a halogenating reagent, e.g. thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or phosphorus tribromide, etc. to give a compound expressed by formula III, which is then reacted with a compound expressed by formula IV to afford the aimed compound expressed by formula I .

Description

Detailed Description of the Invention The present invention provides 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1- benzyl
3-piperidyl) ester-5-methyl ester and its salt.

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 invention will be explained in detail below.

An example of the manufacturing process for the present compound is as follows.

The target compound compound ■ is a combination of a compound "and a halogenating reagent (e.g., thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride,
It is obtained by reaction with phosphorus tribromide, etc.).

The reaction is carried out with dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, etc., benzene,
Aromatic hydrocarbons such as toluene, tetrahydrofuran,
Ethers such as dioxane, acetonitrile, FbN-
It is carried out in the presence or absence of an aprotic polar solvent such as dimethylformamide or hexamethylphosphoric triamide, or an amine such as pyridine or triethylamine, but in particular using thionyl chloride as a halogenating reagent,
It is carried out 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.
A range of 8 to 1.0:2.0, preferably! ,0:0.9
~1.0:1.2.

The molar ratio of thionyl chloride and N,N-dimethylformamide or hexamethylphosphoric triamide is 1:
1 to 1:100 or preferably 1:5 to 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 desired compound is obtained by reacting the obtained compound (1) (which does not need to be isolated) with compound (2). As the solvent, the solvent used in producing compound (2) from compound (1) is used.

The reaction takes place at a molar ratio of compound (1) and compound (2) of 1.0 = 0.8.
~1.0:2.0 preferably 1.0-0.9-1.0=
1.2 in the range of -70°C to 100°C, preferably -20°C
It is carried out at a temperature of 50°C to 50°C.

In the reaction solution, 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(l-benzyl-3-piperidyl) ester-5-methyl ester A compound with a melting point of 196 to 202°C (α form) and a compound with a melting point of 236 to 242°C (β form)
Since a mixture of the α-form and the target compound exists, the α-isomer, which is the target compound, can be isolated as follows.

After the reaction solution is subjected to normal operations such as extraction, concentration, and column chromatography, hydrogen chloride gas or a hydrogen chloride solution dissolved in an appropriate solvent is added to form a hydrochloride salt, and after removing the solvent as necessary, If fractional crystallization is carried out from an appropriate single or mixed solvent, the α-isomer will crystallize and the β-isomer will remain in the solution.

Suitable single or mixed solvents 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.

In addition, the starting material compound... is known from the literature [T.

Shibanuma et al,, Chem, ph
arm, Bull, #28 e2809 (198
0)) and is obtained by the reaction formula shown below.

CH, oc　2T(.

ShiM 21JX+z tlB Compound■ Salts of this compound include hydrochloride, hydrobromide, phosphorus,
Examples include inorganic acid salts such as substitute salts and sulfates, and organic acid salts such as formates, acetates, fumarates, maleates, and malates.

Next, the blood μ-lowering effect of this compound will be explained.

Test Method Adult mongrel dogs (s-xsKp) were anesthetized by intravenous administration of bendoparbital sodium somgAg. A cannula was inserted into the left femoral artery, and blood pressure was measured using a pressure cadence juicer (Nihon Kohden) and recorded on a polygraph.

The results are shown in Table 1.

As shown in Table 1, the α form exerted a clear blood pressure lowering effect from 1 minute after administration and lasted for more than 90 minutes.

Test method A mongrel dog (9-tsKp) was anesthetized with thiobental sodium and the left renal artery was constricted to create a dog with renal hypertension. Changes in blood pressure were measured visually without anesthesia via a polyethylene cannula (fixed to the back of the neck) inserted into the descending artery from the left carotid artery.

The drug was suspended in O, A% carboxymethylcellulose at a dose of 0.5rn1.0 per kg of body weight. It was administered orally using an oral administration tube.

The results are shown in Table 2.

Table 2 Table 2 (Continued) Note) Drugs used: α-form The compound of the present invention can be used in various pharmaceutical forms for the purpose of administration, in view of its pharmacological action. It is preferable to use it as a form.

In the case of tablets, each tablet contains 5 to 30% (w/
w) It is sufficient if it is contained. Other components (carriers) include commonly used excipients, disintegrants, lubricants, binders, coating agents, and the like.

Excipients include grapes, lactose, etc. Disintegrants include Hatenbun, carboxymethyl cellulose calcium, etc. Lubricants include magnesium stearate, talc, etc. Binders include monosyrup, polyvinyl alcohol, gelatin, and hydroxypyl cellulose. Examples of coating agents include dispersants and plasticizers, and examples of dispersants include hamethyl cellulose and ethyl cellulose, and examples of plasticizers include glycerin and polyethylene glycol. Moreover, crystalline cellulose is used as having all the properties of disintegration, binding, and excipient.

In the case of a powder, the compound of the present invention may be contained in an amount of 1 to 20% (w/w). As carriers, excipients such as glucose and lactose, binders such as hydroxyglobil cellulose, etc. are used. LD in oral administration of the compound of the present invention (α form) to male rats.

is 127 gin. The dosage is preferably in the range of #) t-10011F per day for adults (approximately 60 Ky).

Example 1 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester io, oor in a mixed solvent of dichloromethane and N,N-dimethylformamide (4: IV/V)
Add 1 m of ml to 70 rnl and add 2 ml of thionyl dichloride under water cooling.
．． 43 ml was added. After stirring under water cooling for 1 hour, 6.331 g of 1-benzyl-3-hydroxypiperidine was added, and the mixture was further stirred under water cooling. After reacting for 2.5 hours, the reaction solution was diluted with 10 ml of water.
The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, acetone 100*/ and ethanol 8 alt#n were added to the concentrated solution, and yellow 2,6-dimethyl-4-(3
-nitrophenyl)-'1,4-cyhydrohyricin-3
, 5-dicarboxylic acid-3-(1-benzyl-3-piperidyl) ester-5-methyl ester hydrochloride (α form)
Got 7.57 ty. Melting point 197-198°C (ethanol).

Further, β-isomer 5.21f was obtained from the crystal mother liquor.

Melting point 239-240℃ (ethanol-methanol) The physical properties of the α-form are shown below.

IR (KBr, cm crab 1680.152511345
NMR (DMSO-δ): 1.3-12 (4H,
broad, ), 2.33 (6H.

s), 2.7-3.4()L broad)*
L57 (3L 8) + 4.40 (2H* 8) 14
．． 98 (IHI S) 15.20 (IHy 8% 7.3
-8.2 (9H+m)*9.47 (I H,
broad) Calculated value C%) 62.04 5.9
6 7.75 Patent Applicant (102) wJJ Wafunko Kogyo Co., Ltd. Representative Honshita Ikube H't:, 1:i'
;::Nl:” B Procedural Amendment January 2q, 1982 1, Description of the case 1982 Patent Application No. 180616 2, Title of the invention 1, 4-dihydropyridine derivative 3, Person making the amendment Related Patent applicant postal code 100 Address 6-1 Otemachi, Chiyoda-ku, Tokyo Name
(102) VIJfI+Hakko Kogyo Co., Ltd. (Location: 03
-201-7211 extension 2751) Representative Kinoshita
Celebration Part 7 Part □・1-9H+1 View, ゛,・1,.

4. Target of correction ,,+:
,,T,,,5:,7/Specific claims and detailed description of the invention "The present invention corrects the melting point of the hydrochloride to -1.

(3) Same book @ page 4, line 6 11.0-0.9" is corrected to rt, o:o, 9".

(4) Ibid.￥J, page 4, bottom line 4 - page 5, line 1 In addition, after converting into a hydrochloride salt and removing the solvent if necessary, correct the appropriate single-1 to ``After the reaction solution is subjected to normal operations such as extraction and concentration, an appropriate single''.

(5) Add the following sentence between the first and second lines of the bottom of page 6 of the city.

"The drug is dissolved in polyethylene glycol 400,
1 ml of Q per body weight I KP was administered into the brachial vein. ” Claims 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 Procedural amendment February 22, 1980 Commissioner of the Japan Patent Office 1. Indication of the case 1980 Patent Application No. 180616 2. Title of the invention 1, 4- Dihydropyridine Derivatives 3, Relationship with the Person Making Amendment Case Patent Applicant Postal Code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name (
102) Kyowa Hakko Kogyo Co., Ltd. (Location: 03-201
-7211 extension 2751) Detailed description of the invention in the specification.

5. Contents of correction (1) Page 4, line 13 of the specification Correct "melting point of" to "melting point of hydrochloride of".

-→F Zokuin City I] 3 Y 1 no j 1 September 1958 t 6 Usutoku S7 Director h゛ 1 ~ 1 Incident display 1! (Japanese 57) Mouth, Stomach 1 Period 1 No. 180616 2 Name of the invention 1, /l-dihydro[]pyridine derivative 3 Correlation between amendments 1gJ r Applicant postal code 100 fJ Office Higashi Qil Chiyoda Ward Sencho - J number 6 number 1 name
<102) Kyowa Hakko Kogyo Co., Ltd. (]] Ichikawa-:03-
201-7211 extension 27!11>5 Correction details i) ITJJlrnm line 12L412 INM1
<(DMSO-6) J f N M R (DtvlS
Correct it to O-(16, δ)j.

2) Same book No. 12, line 14, 15, 20 (1N, s) J to I'5.20 (11
-1, broad) Corrected to J.

Claims (1)

[Claims] 2,6-dimethyl-4- having a melting point of 196-202°C
(3-nitrophenyl)-1,4-dihydropyridi, /
-3,5-dicarboxylic acid-3-(1-isosyl-3-
piperidyl) ester-5-methyl ester and its salts.