JPH03145464A - Optically active 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:An optically active 1,4-dihydropyridine derivative of formula I (R<2> is alkenyl) or its acid-added salt. EXAMPLE:(+)-3-(4-Allyl-1-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(m- nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. USE:A calcium antagonistic agent, hypotensive agent. Having strong, sustainable smooth muscle relaxative activities such as vasodepressor activity, coronary dilative activity, cerebrovascular dilative activity, peripheral vascular dilative activity, bronchial dilative activity, intraocular smooth muscle relaxative activity and nephrovascular dilative activity, platelet aggregation inhibitive activity, antiallergic activity, and carcinostatic activity; also being low toxic. PREPARATION:For example, reaction is made between compounds of formulas II, III and IV, respectively, and the resulting dihydropyridine derivatives are put to optical resolution, thus obtaining the objective compound of the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel optically active 1,4-dihydropyridine derivative and its acid addition salt useful as a medicine, particularly as an antihypertensive agent.

[Prior art]

It is known that some 1,4-dihydropyridine compounds have coronary artery dilating and blood pressure lowering effects.

However, the reality is that research on the types and pharmacological chemistry of such 1,4-dihydropyridine derivatives is still far from sufficient.

[Problem to be solved by the invention]

The present inventor has demonstrated extremely excellent pharmacological activity, particularly strong and sustained hypotensive action, coronary artery dilation action, cerebral vasodilation action,
As a result of repeated research to develop a new low-toxic 1,4-dihydropyridine derivative that has peripheral vasodilatory action, renal duct dilation action, and platelet aggregation inhibitory action, we have found that it has these excellent activities and also has low toxicity. We have discovered a new compound with low toxicity and completed the present invention.

[Means to solve the problem]

The present invention relates to an optically active 1,4-dihydropyridine derivative (hereinafter also referred to as compound (1)) represented by the general formula (1) (wherein Rt represents alkenyl) or an acid addition salt thereof.

In this specification, each abbreviation means the following.

The acid addition salt of the optically active compound (+) is not particularly limited as long as it is pharmacologically acceptable and non-toxic. phosphates, sulfates), organic acid salts (eg, acetates, succinates, maleates, fumarates, malates, tartrates, methanesulfonates), and the like.

The optically active compound (+) of the present invention and its acid addition salt have extremely strong and long-lasting pharmacological activity. In particular, compounds with an optical rotation of +, among them -
In form (1), the optically active compound (+) in which R1 is 2-propenyl and its acid addition salt have strong activity and persistence, and are particularly excellent in water solubility. Therefore, for example, it can be made into the form of eye drops, nasal drops, inhalants, etc., and can be made into an injection with a desired concentration simply by dissolving it in distilled water for injection, making it extremely easy to handle clinically. It can be easily formulated. Furthermore, even if poorly water-soluble 1,4-dihydropyridine compounds have strong activity, their absorption varies depending on the patient, and this is not desirable from a therapeutic perspective.However, the present invention Water-soluble optically active compounds (1) and their acid addition salts are particularly excellent because they have almost no variation in absorption between patients and not only provide the desired drug efficacy but also facilitate the formulation of a treatment plan tailored to each patient.

Examples of the optically active compound (N and its acid addition salt) of the present invention include the following compounds.

(+)-3-(4-AliJ-ray!-piperazinyl)~2
,2-dimethylpropylmethyl2,6-dimethyl4-(
m-nitrophenyl)-1,4-dihydropyridine-3
,5-dicarboxylate dihydrochloride (-)-3-(4-
Allyl-1-piperazinyl) 2,2-dimethylpropylmethyl 2,6-dimethyl 4 (m-nitrophenyl)-1,71-dihydropyridine-3,5-dicarboxylate dihydrochloride (+)-3-C4- (2-butenyl)
-1-piperazinyl)-2,2-dimethylpropylmethyl2,6-dimethyl-4-(m-nitrophenyl)-1
,4-dihydropyridine-3,5-dicarboxylate dihydrochloride The optically active compound (1) of the present invention and its acid addition salt are produced, for example, as follows.

Method 1 Compound (H) represented by the general formula (% formula %) (wherein RZ has the same meaning as above), compound (I[I) represented by the -form % formula %) and compound (I) represented by the -form (% formula %) A method in which three compounds (IV) are reacted and the resulting dihydropyridine derivative is subjected to optical separation.

The reaction preferably proceeds in the presence of a suitable solvent. The solvent may be any solvent as long as it does not inhibit this reaction, such as alkanols such as methanol, ethanol, propatool, isopropanol, butanol, and 5et-butanol, ethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, and ethylene glycol. Ethers such as dimethyl ether, acetic acid,
Examples include pyridine, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and the like.

The reaction temperature is usually about 10-150'C, preferably 4
It is about 0 to 120°C. In particular, the reaction time, which is preferably carried out at a temperature around the boiling point of the solvent used, is usually 0.5 to 15 hours until the reaction is completed. Compound (■)
, the usage amounts of compound (I [[) and compound (IV)] are:
Usually, it is preferable to use 1 to 1.5 mol of each of the other two compounds per 1 mol of one of the champion compounds.

The raw material compounds are known or can be produced according to known methods [for example, J, Sieve, Che++.

Soc, 67, 1017 (1945)].

Compound (I[[) and compound (TV) are both known compounds.

Compound (1) or its acid addition salt thus obtained can be optically resolved, for example, as follows.

(1) A method of fractional recrystallization using optically active acid. For example, a method of forming salt with salt and fractionating and recrystallizing it is mentioned, and a recrystallization method is preferable as a separation method.

(2) Purification method using a column using an optically active carrier: A method using a column for optical isomer separation such as Chiralcel OF (Daicel Chemical) or Ushitron ES-OVM (Shinsso Kako) is preferred. be.

Second method: A method of reacting an optically active compound '4M (X) represented by (1) or a reactive derivative thereof with a compound (■) represented by the general formula (wherein R1 has the same meaning as above).

Examples of the reactive derivative of compound (X) include acid halides (eg, acid chloride, acid bromide, etc.) and active esters (eg, tosylate, etc.).

The reaction is an esterification reaction between a carboxylic acid and an alcohol, and is carried out by means known per se.

The starting compound (X) can be prepared by a known method [for example, T.

Shibanuma, Ches+, Phars, Bul
1, 28(9), 2809 (1980)).

Compound (Vn) is a known compound (Japanese Unexamined Patent Publication No. 63-2
(See No. 25355) Since the compound produced by the second method is already in the form of an optically active substance, there is no need for optical resolution.

The optically active compound (1) and its acid addition salt thus obtained can be purified to any desired purity by using separation and purification means known per se, such as fi-condensation, extraction, chromatography, reprecipitation, and recrystallization. It can be collected as a.

Furthermore, the acid addition salt of the optically active compound (1) can be produced by means known per se, and the acid addition salt can be converted into the optically active compound (1) of J# by means known per se. can.

[Action/Effect]

The optically active compound (1) of the present invention and its acid addition salt have a strong and sustained hypotensive effect on mammals (e.g., humans, mice, rats, dogs, cats, rabbits, etc.), It has smooth muscle relaxing effects such as dilator, cerebral vasodilator, peripheral vasodilator, bronchodilator, intraocular smooth muscle relaxant and renal vasodilator, platelet aggregation inhibitory effect, antiallergic effect, and anticancer effect. , and has low toxicity.

In particular, an optically active compound with (+) optical rotation is a particularly preferred compound because it has an activity about 100 times higher than an optically active compound with (-) optical rotation.

Therefore, optically active compound (1) and its acid addition salt,
In particular, the optically active substance No. 10 can be used to treat hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral and peripheral circulation disorders (cerebral Infarction, transient ischemic attack, renal artery stenosis, etc.)
It is useful as a therapeutic/preventive drug for a-ring system diseases, as well as for allergies (asthma), cataracts, glaucoma, etc.

Furthermore, many of the optically active compounds (1) and their acid addition salts are highly water-soluble, such as eye drops, nasal drops,
Easily formulated into inhalants, injections, liniments, etc.

Optically active compound (1) and its acid addition salt can be administered orally or parenterally when used as a pharmaceutical, for example. Examples of dosage forms include oral dosage forms such as tablets, capsules, and syrups, solutions, emulsions, and more! ! , liquid injections such as 'EJ agents, ointments,
Examples include parenteral preparations such as creams, suppositories, poultices, eye drops, nasal drops, inhalants, liniments, and external preparations such as aerosols.

The formulation of the above dosage form can be manufactured by adding additives required for formulation such as conventional carriers, excipients, binders, and stabilizers, and formulating by conventional means.

The dosage and frequency of administration may vary depending on symptoms, age, body weight, and mode of administration, but the usual dosage for adults is approximately 0.1 to 100 g per day when used as an antihypertensive agent.
Preferably, 0.5 to 50 mg can be administered once or in divided doses.

[Experiment example]

The results of pharmacological tests showing the kinetics of optically active compound (1) and its acid addition salt are shown below.

Experimental Example 1 A constant flow of nutrient solution at 37°C was perfused into the isolated rat mesenteric artery, and changes in laminar flow pressure were measured using a pressure transducer.
1:1 constant. The increase in perfusion pressure after a single administration of 3.7 mg of potassium chloride was used as an indicator, and (+)-
3-(4-allyl-1-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride The effect of a single administration of the compound on the increase in potassium chloride perfusion pressure and the increase in calcium chloride 'tM'tA pressure was investigated.

As a result, (+)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropylmethyl 2゜6-dimethyl-4-(■-nitrophenyl)-1,4-dihydropyridine-3,5- Dicarboxylate dihydrochloride is 0.
The increase in perfusion pressure caused by potassium chloride was suppressed from 1 μg.

Experimental Example 2 Three isolated dog brain and mesenteric artery spiral strip specimens were
The specimen was suspended in a Magnus device filled with nutrient solution at 7°C, and changes in tension were measured via a strain pickup. The arterial specimen was contracted by applying 20mM potassium chloride, and the test compound (+)-3-(4allyl-1-piperazinyl)-
2,2-dimethylpropylmethyl 2,6-dimethyl-4
-(m-=-trophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was used to examine the relaxing effect of cumulative application of the compound. (+)
-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(tonitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride Both specimens were relaxed from 10''M.

Experimental Example 3 Blood flow measurement probes were attached to the coronary artery, vertebral artery, and right femoral artery of an open-chest dog anesthetized with bentoparbital sodium, and the blood flow was determined by the pulsed Doppler method. A tube was placed in the left femoral artery, and blood pressure was measured via a pressure transducer. As a test compound (+)
=3-(/I-allyl-1-piperazinyl)-2,2
-dimethylpropylmethyl2,6-dimethyl-4- (
m--l-+:+phenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was used and was administered through the femoral vein.

(+)-3-(4-allyl-1-piperazinyl)-22
-dimethylpropylmethyl2,6-dimethyl4 (+
*-nitrophenyl)-1,4-dihydropyridine-3
, 5-dicarboxylate dihydrochloride lowered blood pressure and increased blood flow starting from 1 μg/kg.

Experimental Example 4 A 10-tube for measuring blood flow was implanted in the vertebral artery and the right femoral artery in advance, and a 10-tube was placed in the auricular artery of a rabbit, and blood pressure was measured via a pressure transducer. Blood flow was measured by pulsed Doppler method. As a test compound (+) -3-(4-allyl-1-piperazinyl)-
2,2-dimethylpropylmethyl 2,6-dimethyl-4
-(+m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was used and administered at 10 μs/kg through the auricular vein.

As a result, blood pressure decreased from 84 mm 11 g to 58 ma + Hg, and heart rate decreased from 220 bea Ls no sin to 270
beats/min, and the osseous blood flow is 2ml/s.
increased from in to 7a+I/win.

[Example] Example 1 (+)-3-(4-allyl-1-piperazinyl)-2,
2-dimethylpropylmethyl 2,6-dimethyl 4-(m
-nitrophenyl)-1,4-dihydropyridine-3,
Synthesis of 5-dicarboxylate dihydrochloride 1.30 g of (-)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved in dry chloride. methylene 7
．． 2 ml and dry N,N-dimethylborumamide river,
Add 0.3 ml of thionyl chloride and suspend at -3°C.
1 ml was added and stirred at -2 to 3'C for 2 hours. 3-(4-
0.914 g of allyl-1-piperazinyl 2,2-dimethylpropanol was added dropwise, and the mixture was stirred at 0 to 5°C for 3 hours. Add methylene chloride loOm+, water-cooled 2% sodium carbonate, and 100 ml of 2% saline, and after extraction and separation, the methylene chloride layer was washed twice with 200 ml of water, dried over anhydrous magnesium sulfate, and the methylene chloride layer was vacuumed for 14 Jli!
did. The obtained residual aroma was purified using silica gel column chromatography. 1.49 g of the title compound gold compound was obtained as an oil, which was dissolved in 5.3 ml of methanol to give a 10.1N
- 0.55 ml of hydrochloric acid/ethanol solution was added, and the precipitated crystals were collected by filtration and dried to obtain 1.02 g of the title compound (yield 44%). The physical properties of the obtained compound are as follows.

Melting point 211-214°C (dec) Specific light intensity (ex) ”+71.54 (C=3.78
5. Water) I R (Nujol, am-') 3340
．． 1690.1520' +(-NMR(DMSO
-di, a value) 0.96 (6H,s, >C(
CHs)z)2.27 (3)l, s, □C-C
L) 2.37 (34s, □C-CH5) 3.60
(311,s, -COzClh)3.90 (2
H,! ! , -COzCllz-)5.00 (IH
, a, C4-I+) 7.4-8. l (411, m
, phenyl)9.19 (IH,br, >N11
)9.4-15.0 (2B, br, 211CL) Example 2 (-)-3-(4-allyl-1-piperazinyl)-2,
2-dimethylpropylmethyl 2,6-dimethyl 4-(m
-nitrophenyl) -1,4-'; Synthesis of hydropyridine-3,5-dicarboxylate dihydrochloride (+)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4 The title compound was obtained in the same manner as in Example 1 using -dihydropyridine-3-carboxylic acid as a raw material (yield 47%).

Melting point 211-213°C (dec) Specific light intensity [α) ”-68,4HG・3.844.water) [Formulation example] Formulation example 1 Nasal drop formulation example (+)-3-(4-allyl- 1-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(++-nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylate 2 Hydrochloride saline solution formulation example 2 Eye drops Prescription example (+)-3-(4-allyl-1-piperazinyl)-2,2-ditotal amount 100.0 1 0.1 mg Methylpropylmethyl 26-dimethyl-4-(tonitrophenyl 0.1 mg)
-1,4-dihydropyridine-3,5-dicarboxylate 2 hydrochloride sterile ophthalmic solution (pH 5,0) all ff1loo,
Preparation Example 3 Injection (water-soluble) Prescription 2n+1 ampoule contains (+)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-( -nitrophenyl mg)-1,
4-dihydropyridine-3,5-dicarboxylate 2 hydrochloride Distilled water for injection Total volume 2 l Formulation example 4 Injection (solid injection) prescription l vial (±)-3-(4-allyl 1-piperazinyl) )-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(-1nito-a-phenyl)-1,4-dihydropyridine 35-dicarboxylate 2 Mannitol hydrochloride formulation example 5 Tablet formulation example (+)- 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 2 Hydrochloride Lactose Stearin Magnesium acid talc mg 00mg 10111g 0g mg mg Add starch to make a total amount of 1201g.

According to the above composition, an aqueous solution of starch is added to a premixed mixture of the present compound and lactose, kneaded, and then sized by drying and pulverizing. A mixture of talc and magnesium stearate is added to and mixed with the sized bundle, and the mixture is compressed to produce tablets.

Formulation Example 6 Capsule Formulation Example (+)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropylmethyl2,6-dimethyl-4-(m-nitrophenyl 5 g) ~ 1
．． 4-dihydropyridine-3,5-dicarboxylate 2 hydrochloride milk $J! Add 100g of polyvinylpyrrolidone and 3mg of stearic acid to make a total of 110cm.

According to the above composition, an alcoholic solution of polyvinyl, lolidone, and stearic acid is added to a pre-mixed mixture of the present compound and lactose, kneaded, and then granulated to form granules. After drying, the granules are filled into No. 4 capsules to produce capsules.

Procedural Dispute Manual (spontaneous) 21 Name of the invention Optically active 1,4-dihydropyridine derivatives and their uses 3, Person making the amendment Relationship to the case Patent applicant name (name) Kyoto Yakuhin Kogyo Co., Ltd. 4, Agent ■ 541 Address 3-3-9 Hirano-cho, Chuo-ku, Osaka (Basue Building) Aim, (06) 227-1156 Full text of the specification 6. Details of the amendment Date (correction) 1. Name of the invention Optical activity 1.4 -Dihydropyridine derivatives and uses thereof 2, Claims (1) - An optically active 1,4-dihydropyridine derivative or an acid addition salt thereof represented by the following format (wherein R1 represents alkenyl).

(2) The optically active 1,4-dihydropyridine derivative or its acid addition salt according to claim (1), which has an optical rotation of (+).

(3) A calcium antagonist comprising the optically active 1,4-dihydropyridine derivative or its acid addition salt according to claim (1) as an active ingredient.

3. Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel optically active 1,4-dihydropyridine derivative and its acid addition salt useful as a medicine, particularly as an antihypertensive agent.

[Prior art]

It is known that some 1,4-dihydropyridine compounds have coronary artery dilating and blood pressure lowering effects.

However, the reality is that research on the types and pharmacological chemistry of such 1,4-dihydropyridine derivatives is still far from sufficient.

[Problem to be solved by the invention]

The present inventor has demonstrated extremely excellent pharmacological activity, particularly strong and sustained hypotensive action, coronary artery dilation action, cerebral vasodilation action,
As a result of repeated research to develop a new 1,4-dihydropyridine derivative that has peripheral vasodilator action, renal vasodilator action, and platelet aggregation inhibitory action and is also low in toxicity, we have found a new 1,4-dihydropyridine derivative that has these excellent activities and has low toxicity. We discovered a new toxic compound and completed the present invention.

[Means to solve the problem]

The present invention relates to an optically active 1,4-dihydropyridine derivative (hereinafter also referred to as compound (1)) represented by the general formula (in which R8 represents alkenyl) or an acid addition salt thereof.

In this specification, each abbreviation means the following.

The acid addition salt of the optically active compound (1) is not particularly limited as long as it is pharmacologically acceptable and non-toxic. phosphates, sulfates), organic acid salts (eg, acetates, succinates, maleates, fumarates, malates, tartrates, methanesulfonates), and the like.

The optically active compound (1) of the present invention and its acid addition salt have extremely strong and long-lasting pharmacological activity. In particular, compounds with (+) optical rotation, especially optically active compounds (1) in the -form (1) in which R8 is 2-propenyl, and acid addition salts thereof, have strong activity and long-lasting properties. It has excellent water solubility.

Therefore, for example, it can be made into the form of eye drops, nasal drops, inhalants, etc., and can be made into an injection with a desired concentration simply by dissolving it in distilled water for injection, making it extremely easy to handle clinically. It can be easily formulated. Furthermore, even if poorly water-soluble 1,4-dihydropyridine compounds have strong activity, their absorption varies depending on the patient, and this is not desirable from a therapeutic standpoint.However, the present invention The water-soluble optically active compound (1) and its acid addition salts are particularly excellent because there is almost no variation in absorption between patients, and not only do they provide the desired drug efficacy, but they also make it easier to formulate a treatment plan tailored to each patient. be.

Examples of the optically active compound (1) of the present invention and its acid addition salt include the following compounds.

(+)-3-(4-allyl-1-piperazinyl)-2,
2-dimethylpropyl methyl 2,6-dimethyl-4
-(+*-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride (-) -3
-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(+e-
ditritrophenyl 1,4-dihydropyridine-3,5
-dicarboxylate dihydrochloride (+) -3-(4-(2
-butenyl)-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(-nitrophenyl)-1゜4-dihydropyridine-3,5-dicarboxylate dihydrochloride of the present invention Optically active compound (1) and its acid addition salt are produced, for example, as follows.

Method 1; A compound (■) represented by the general formula () (wherein R8 has the same meaning as above), a compound ([11) represented by the -form % formula % () and a compound represented by the -form ( IV) A method of reacting the king and optically resolving the obtained dihydropyridine derivative.

The reaction preferably proceeds in the presence of a suitable solvent. The solvent may be one that does not inhibit this reaction (e.g. alkanols such as methanol, ethanol, propatool, isopropanol, butanol, sec-butanol, ethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol). Examples include ethers such as dimethyl ether, acetic acid, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile.

The reaction temperature is usually about 10-150°C, preferably 4°C.
The temperature is about 0 to 120°C. In particular, the reaction time, which is preferably carried out at a temperature around the boiling point of the solvent used, is usually 0.5 to 15 hours until the reaction is completed. Compound (■),
The amount of compound (I[l) and compound (rV) to be used is usually 1 mole of one of the three compounds to 1 mole of the other two compounds.
It is preferred to use 1 to 1.5 mol of each of the two compounds.

The raw material compounds are known or can be produced according to known methods [for example, J, A+w, Chew.

Soc, 67, 1017 (1945)].

Compound (II) and compound (■) are both known compounds.

Compound (1) or its acid addition salt thus obtained can be optically resolved, for example, as follows.

(1) A method of fractional recrystallization using an optically active acid; di-0-0'-P-)luoyltartaric acid or D(+)-di0-Oo-benzoyltartaric acid-hydrate as (1) Examples include a method of forming salt and fractionating and recrystallizing, and a recrystallization method is preferable as a separation method.

(2) Purification method using a column using an optically active carrier: A method using a column for optical isomer separation such as Chiralcel OF (Daicel Chemical) or Ushitron ES-OVM (Shinsou Kako) is preferred. be.

Second method: A method of reacting an optically active compound (X) represented by (1) or a reactive derivative thereof with a compound (■) represented by the general formula (wherein Bt has the same meaning as above).

Examples of the reactive derivative of compound (X) include acid halides (eg, acid chloride, acid bromide, etc.) and active esters (eg, tosylate, etc.).

The reaction is an esterification reaction between a carboxylic acid and an alcohol, and is carried out by means known per se.

The starting compound (X) can be prepared by a known method [for example, T.

Shibanuma, Chew, Phar Shin, 8u11
．． ．． 28 (9), 2809 (1980)).

Compound (■■) is a known compound (Japanese Unexamined Patent Publication No. 63-2
(See No. 25355) Since the compound produced by the second method is already in the form of an optically active substance, there is no need for optical resolution.

The thus obtained optically active compound @rJ (1) and its acid addition salt can be separated and purified by known separation and purification means, such as am,
It can be collected with any purity by using extraction, chromatography, reprecipitation, recrystallization, or other means.

Furthermore, the acid addition salt of the optically active compound (1) can be produced by means known per se, and the acid addition salt can be converted into the free optically active compound (1) by means known per se. .

[Action/Effect] The optically active compound (1) of the present invention and its acid addition salt can be used in mammals (e.g., humans, mice, rats), dogs,
(cats, rabbits, etc.), it has strong and long-lasting hypotensive effect, coronary artery dilation effect, cerebral vasodilation effect, peripheral vasodilation effect, bronchodilator effect, intraocular smooth muscle relaxing effect, renal vasodilator effect, etc. It has smooth muscle relaxing action, platelet aggregation inhibiting action, antiallergic action, and anticancer action, and has low toxicity.

In particular, an optically active compound having an optical rotation of (+) has an activity about 100 times higher than that of an optically active compound having an optical rotation of (-), and is therefore a particularly preferable compound.

Therefore, optically active compound (1) and its acid addition salt,
In particular, the optically active substance No. 10 can be used to treat hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral and peripheral circulation disorders (cerebral Treatment and prevention drugs for cardiovascular diseases such as infarction, transient ischemic attack, renal artery stenosis, etc., as well as allergies (asthma)
It is useful as a therapeutic or preventive agent for cataracts, glaucoma, etc.

Furthermore, many of the optically active compounds (1) and their acid addition salts are highly water-soluble, such as eye drops, nasal drops,
Easily formulated into inhalants, injections, liniments, etc.

Optically active compound (1) and its acid addition salt can be administered orally or parenterally when used as a pharmaceutical, for example. Examples of dosage forms include oral dosage forms such as tablets, capsules, and syrups, liquid injections such as solutions, emulsions, and suspensions, ointments, creams, suppositories, poultices, eye drops, and drops. Examples include parenteral preparations such as nasal preparations, inhalants, liniments, and external preparations such as aerosol preparations.

The formulation of the above dosage form can be manufactured by adding additives required for formulation such as conventional carriers, excipients, binders, and stabilizers, and formulating by conventional means.

The dosage and frequency of administration may vary depending on symptoms, age, body weight, and mode of administration, but in general, for adults, when used as an antihypertensive agent, approximately 0.1 to 100 μg/day,
Preferably, 0.5 to 50 μl can be administered once or divided into several doses.

[Experimental Examples] The results of pharmacological tests showing the effectiveness of optically active compound (1) and its acid addition salt are shown below.

Experimental Example 1 A constant flow of nutrient solution at 37°C was perfused into the isolated rat mesenteric artery, and changes in perfusion pressure were measured via a pressure transducer. The increase in perfusion pressure due to a single administration of 3.7 mg of potassium chloride was used as an indicator, and (+)-3-(4
-Allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2.6-dimethyl-4-(-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was used. The effect of a single administration of the compound on potassium chloride perfusion pressure and calcium chloride perfusion pressure was investigated.

As a result, (+)-3-(4-allyl-!-piperazinyl)-2,2-dimethylpropylmethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5- Dicarboxylate dihydrochloride is 0
．． The increase in perfusion pressure caused by potassium chloride was suppressed from 1 μg.

Experimental Example 2 Three isolated dog brain and mesenteric artery spiral strip specimens were
The specimen was suspended in a Magnus device filled with nutrient solution at 7°C, and changes in tension were measured via a strain pickup. potassium chloride 2
The arterial specimen was contracted by hM application, and the test compound (+)-3-(4-allyl-]-piperazinyl)-2,
2-dimethylpropyl methyl 2,6-dimethyl-4
-(layer-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was used to examine the relaxing effect of cumulative application of the compound. (+)−
3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(tonitrophenyl)-1,4-dihydropyridine-3,5-
Dicarboxylate dihydrochloride relaxed both specimens from 10-''M.

Experimental Example 3 Blood flow measurement probes were attached to the coronary artery, peristaltic artery, and right femoral artery of an open-chest dog anesthetized with bentoparbital sodium, and the blood flow was measured by the pulsed Doppler method. A tube was placed in the left femoral artery, and blood pressure was measured via a pressure transducer. As a test compound (+)−
3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-
Nitrophenyl)-1,4-dihydropyridine-3,5
- Dicarboxylate dihydrochloride was used, which was administered via the femoral vein.

(+)-3-(4-allyl-1-piperazinyl)-2,
2-dimethylpropyl methyl 2,6-dimethyl-4
-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride is lμg/kg
showed a decrease in blood pressure and an increase in blood flow.

Experimental Example 4 A tube was placed in the auricular artery of a rabbit in which blood flow measuring probes had been previously implanted in the vertebral artery and right femoral artery, and blood pressure was measured via a pressure transducer. Blood flow was measured by pulsed Doppler method. As a test compound (+) -3-(4-allyl-1-piperazinyl)-
Using 2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitro7enyl)-1,4-dihydropyricin-3,5-dicarboxylate dihydrochloride,
The dose of 10 μg/kg was administered through the auricular vein.

As a result, blood pressure decreased from 84smHg to 68mm11g, and heart rate decreased from 220beats/sin to 270be.
ats/win, and vertebral blood flow is 2ml/min.
It increased from 7a+l/-in.

[Example] Example 1 (+)-3-(4-allyl-1-piperazinyl)-2,
2-dimethylpro-methyl 2,6-dimethyl-4
Synthesis of -(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride (-)-5-methoxycarbonyl-2,6-dimethyl-4-cm-ditrophenyl)-1 , 1.30 g of 4-dihydropyridine-3-carboxylic acid and 7 g of dry methylene chloride.
．． 2d and dry N,N-dimethylformamide 1.
Add 0.8 d of thionyl chloride and suspend at -3°C.
1 m of the mixture was added, and the mixture was stirred at -2 to 3°C for 2 hours. 3-(4-allyl-1-
piperazinyl)-2゜2-dimethylpropanol 0.9
14 g was added dropwise and stirred for 3 hours at 0 to 5"C. 100 d of methylene chloride, water-cooled 2% sodium carbonate, and 100 d of 2% brine were added, and after extraction and separation, the methylene chloride layer was diluted with 200 ml of water. After washing twice and drying over anhydrous magnesium sulfate, the methylene chloride layer was filled under reduced pressure. The resulting residual aroma was purified by silica gel column chromatography to obtain 1.49 g of the free salt of the title compound as an oil, which was dissolved in methanol 5
．． 0.55 m of a 10.1N hydrochloric acid/ethanol solution was added to the solution, and the precipitated crystals were collected by filtration and dried to obtain 1.02 g of the title compound (yield: 44%).

The physical properties of the obtained compound are as follows.

Melting point 211-214℃ (dec) i1i luminous intensity (α) a'+71.54 (C-3,785,
Water) I R (Nujol, cab-') 3340
．． 1690. 1520'H-NMR (min.5o-d6
．． δ value) 0.96 (611,s, >C(
CHi)z)2.27 (311,s, =C-C
1h) 2.37 (311,s, =C-C84)
3.60 (311,s, -COzCIh)3.
90 (211,s, -COiCIlz-)5.
00 (Ill, S, C4-I+) 7.4~
8.1 (411, ■, phenyl) 9.19 (IL
hr, >NH) 9.4 ~ 15.0 (211,
br, 2HCL) Example 2 (-)-3-(4-allyl-1-piperazinyl)-2,
2-dimethylpropyl methyl 2,6-dimethyl-4
Synthesis of -(*-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride (+)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1 , 4-dihydropyridine-3-carboxylic acid as a raw material and the same method as in Example 1 to obtain a mu compound (yield: 47%).

Melting point 211-213°C (dec) Specific light intensity [α] -68.41 (C・3.844.
water) [Formulation example] Formulation example 1 Nasal drop formulation example (+) -3-(4-allyl-1-piperazinyl)-2,2-dimethyl 10 pyru Methyl 2.6 Dimethyl-4-(tonitrof 0.1 ■Enyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride physiological saline solution Total 1100.0d Formulation example 2 Eye drops prescription example (+)-3-(4-allyl 1-piperazinyl)- 2,2-dimethylpropyl methyl 2.6 monodimethyl-4-(-nitroso 0.1Benyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride sterile ophthalmic solution (pl!5. 0) All it 100
．． OIn1 Formulation Example 3 Injection (Water-Soluble) Formulation 2I1 In ampule (+)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6 monodimethyl-4-(-nitroso lag enil)
-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride Distilled water for injection Total amount 21111 Formulation example 4 Injection (solid injection) formulation (+)-3-(4-allyl-1) in 1 vial -piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(-1-ditrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride mannitol formulation example 5 Tablet formulation example (+)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2.6 Monocymethyl-4-(tonitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 2 Add hydrochloride lactose magnesium stearate talc starch to make a total amount of 1 mg 100■ 0-g 80■ 2■ 4■ 120■.

According to the above composition, an aqueous solution of starch is added to a premixed mixture of the present compound and lactose, kneaded, and then sized by drying and pulverizing. A mixture of talc and magnesium stearate is added to and mixed with the sized bundle, and the mixture is compressed to produce tablets.

Formulation example 6 Capsule formulation example (+)-3-(4-allyl-■-piperazinyl)-2,2-dimethylpropyl methyl 2.6-dimethyl-4-(s+-nitroso 5+*g-enyl)-1, 4-dihydropyridine-3,5-dicarboxylate dihydrochloride milk 1! Add 100■ polyvinylpyrrolidone 3I1g stearic acid to make a total ffl of 110■.

According to the above composition, an alcohol solution of polyvinylpyrrolidone and stearic acid is added to a pre-mixed mixture of the present compound and lactose, kneaded, and then granulated to form granules. After drying, the granules are filled into No. 4 capsules to produce capsules.

Claims (3)

[Claims] (1) Optically active 1,4-dihydropyridine derivative or its acid addition salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^2 represents alkenyl). (2) The optically active 1,4-dihydropyridine derivative or its acid addition salt according to claim (1), which has an optical rotation of (+). (3) A calcium antagonist comprising the optically active 1,4-dihydropyridine derivative or its acid addition salt according to claim (1) as an active ingredient.