JPS63107975A - Dihydropyridine derivative and pharmaceutical composition - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R2 are H, nitro, cyano, halogen, alkyl, alkoxy, alkylmercapto, alkylsulfoxide, etc.; R3-R5 are alkyl; R6 and R7 are alkyl, aralkyl, etc., or together with N form a heterocyclic group; X is -CO- or -COO-; A is alkylene) and its non-toxic salt. EXAMPLE:2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl-4-(4-cyano-2- pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate. USE:A coronary vasodilator, cerebral blood blow increasing agent, hypotensor, preventive and remedy for thrombosis, phosphodiesterase inhibitor, etc. PREPARATION:The objective compound can be produced e.g. by reacting the compounds of formula II, III and IV in a solvent at 50-120 deg.C are reacting the resultant compound of formula V with a secondary amine.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel dihydropyridine m11 compound and its non-toxic salts useful as pharmaceuticals, and a pharmaceutical composition containing the same.

[Prior art]

Known compounds similar to the dihydropyridine derivative of the present invention include, for example, nifedipine and nicardipine. These compounds are known to be useful as antihypertensive agents, peripheral and cerebral vasodilators, and coronary artery treatment agents (angina pectoris), but it is hoped that dihydropyridine derivatives with even better effects will emerge. There is.

[Problem that the invention seeks to solve]

An object of the present invention is to provide dihydropyridine derivatives and non-toxic salts thereof that have even better pharmacological activity.

Another object of the present invention is to provide a pharmaceutical composition containing a dihydropyridine derivative with excellent pharmacological activity.

[Means for solving problems]

The present invention has excellent calcium antagonism (Ca-Anta
gonist), antihypertensive action, platelet aggregation inhibitory action, phosphogesterase inhibitory action, etc., such as coronary vasodilators, cerebral blood flow increasing agents, antihypertensive agents, thrombosis prevention or treatment agents, phosphogesterase inhibitors, etc. (General formula useful as a medicine) (In the formula, R+ and Rt are each a hydrogen atom (However, R+
, Rt are not hydrogen atoms at the same time), nitro, cyano,
Halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkylmercapto, alkyl sulfoxide or alkyl sulfone, Rs, Ra
and R1 each represents an alkyl; R6 and R7 each represent a hydrogen atom, an alkyl which may be substituted with a halogen, or an aralkyl, or may form a heterocycle together with the adjacent nitrogen atom; The present invention is a novel dihydropyridine derivative (,1) represented by a group represented by the formula COO- or a group represented by the formula COO-, where A represents an alkylene group, and a non-toxic salt thereof.

The present invention also relates to a pharmaceutical composition containing at least one selected from the dihydropyridine derivative (■) and its non-toxic salt.

The dihydropyridine derivative (1) of the present invention has a unique structure compared to conventionally specifically known dihydropyridine compounds, and has unique activity due to this structure.

That is, the dihydropyridine derivative (I) of the present invention has high organ and tissue selectivity, especially in its vasodilatory action, and can achieve excellent pharmacological effects with a relatively small dose. A major feature of this drug is that it can reduce side effects.

In this specification, halogens include fluorine, chlorine,
Mention may be made of bromine and iodine, with fluorine, chlorine and bromine being preferred. The alkyl group may be linear or branched, and examples thereof include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. Aralkyl groups include benzyl, phenethyl,
Examples include 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, etc., and the phenyl group may be substituted (as a substituent,
(For example, alkyl, halogen, etc.) The alkylene group preferably has 2 to 4 carbon atoms, and may be linear or branched, such as ethylene, trimethylene,
Examples include propylene, tetramethylene, and 1,2-dimethylethylene.

Further, in this specification, the alkyl moiety and halogen in alkoxy, alkyl halide, alkyl mercapto, alkyl sulfoxide, and alkyl sulfone are the same as the alkyl and halogen described above. Alkyl halides are those in which some of the hydrogen atoms are halogenated ((
Ch) zCHzCIlt-1CF, C11t-, etc.),
All of the hydrogen atoms may be halogenated (trifluoromethyl, etc.), and the alkoxy moiety in halogenated alkoxy is the same as the above alkoxy and halogen, and halogenated alkoxy is also a part of it. The hydrogen atoms may be halogenated or all hydrogen atoms may be substituted with halogen.

In the general formula (+), the heterocycle formed by R2 and R1 may further contain a heteroatom in addition to the adjacent nitrogen atom (such heteroatoms include, for example, an oxygen atom, a nitrogen atom, a sulfur atom, etc.). etc.

Examples of the heterocycle include pyrrolidine, piperidine, morpholine, piperazine, 1,2,3.4-tetrahydroquinoline, 1,2,3.4-tetrahydroisoquinoline, imidazole, indole, isoindole,
Examples include benzimidazole, and the heterocycle may be substituted with alkyl, aralkyl, halogen, or the like.

-a In formula (1), Rt, the pyridyl group substituted with Rt and the 4-position of the dihydropyridine skeleton are bonded at the 2-position, 3-position or 4-position, preferably the 2-position or 3-position, of the pyridine group, and the substituent R1 and R1 can be present in ortho, meta or para positions with respect to each other. In addition, substituent R+
, Rz is preferably present at the ortho position and/or meta position with respect to the bonding site between the lysyl group and the dihydropyridine skeleton.

The dihydropyridine derivative (1) can be produced by reacting any moiety constituting the 8-dihydropyridine derivative (+) with the remaining component by a known method, particularly by subjecting it to a dehydration ring-closure reaction. For example, it is manufactured as follows.

Manufacturing method (A) (I[) (III) R4COCH
2X-AC2(IV) (V) (wherein, R3, R2, R2, R4, R1, X and A have the same meanings as defined above) (n) (I[I)Ra COCH
t
(X and A have the same meanings as defined above) Each manufacturing method will be described in detail below.

Production method (A) In this method, first, compounds (I[), (I[I) and (IV)] are reacted in an appropriate) medium to produce compound (V).
) is manufactured. This reaction is usually carried out at about 30°C to 150°C, preferably about 50°C to 120°C, and particularly if the solvent used boils within this range, it is carried out at that boiling point. Any solvent may be used as long as it is inert to the reaction, and examples thereof include alcohols such as methanol, ethanol, propatool, and isopropanol, and ethers such as tetrahydrofuran, dioxane, and dimethoxyethane. -Dimethylformamide, dimethylsulfoxide, acetonitrile, etc. The reaction usually takes 1 to 20 hours to complete. The amounts of compounds (■), (III) and (TV) used are:
This is carried out by using 1 to 1.5 moles of each of the other two compounds for 1 mole of one of the three compounds. The starting compound (■) is known or can be produced according to a known method. [For example, Journal of
American Chemical Society (J,' Aa+,
Chem, Soc, ) 6L1017 (1945
)reference〕. Compound (IV) is known or can be produced according to known methods [e.g.
Pharm, Bull, ) 27(6), 1426(
1979) Reference 30 Various substituted pyridine aldehydes (I
[[) can be obtained by synthesizing the following pyridine alcohol by a known method and oxidizing it with, for example, dimethylsulfoxide-dicyclohexylcarbodiimide-phosphoric acid.

HsP()a The thus obtained compound (V) is reacted with a secondary amine to produce the dihydropyridine derivative (I). The reaction temperature is usually 50°C to 130°C, preferably about 70°C.
It was carried out at a temperature of 110 °C to 110 °C, and the solvents used were toluene, N,
Preferred examples include N-dimethylformamide. This reaction is usually carried out by using 2 to 2.5 moles of secondary amine per 1 mole of compound (■).

It usually takes 1 to 20 hours to complete the reaction.

Production method B This can be carried out under substantially the same conditions as production method A. The raw material compound (Vl) used in the production method can be synthesized by reacting the raw material compound (TV) used in production method A with the secondary amine. That is, compound (It/) is dissolved in an appropriate solvent (e.g., ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide), and about 2.5
Add an equivalent amount of secondary amine and heat from 1 to 1 at about 30°C to 110°C
It can be easily synthesized by reacting for 18 hours.

The novel dihydropyridine derivative H) thus produced
can be collected at any purity by appropriately using known separation and purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. Furthermore, since the dihydropyridine derivative (1) has a basic group, it can also be converted into an acid addition salt by known means. Such salts are not particularly limited as long as they are pharmacologically acceptable and non-toxic, such as salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.), organic salts, etc. Salts with acids (acetate,
Succinate, maleate, fumarate, malate, tartrate), etc.

The dihydropyridine derivative (1) of the present invention and its non-toxic salts have low toxicity and have strong and sustained hypotensive and peripheral vasodilatory effects in mammals (e.g. mice, rats, rabbits, dogs, cats, humans). It has a coronary artery dilating effect, a cerebral vasodilating effect, etc., and is effective for hypertension, ischemic heart disease (angina pectoris, myocardial infarction), brain and peripheral V8 organ disorders (cerebral infarction, transient cerebral infarction, etc.) in humans. It is useful as a prophylactic and therapeutic agent for cardiovascular diseases such as ischemic attacks.

In particular, compared to conventional dihydropyridine derivatives (e.g., nifedipine, nicardipine), it has superior pharmacological action strength and duration of action. )
A stable workpiece can be obtained.

When dihydropyridine derivative (1) and its non-toxic salts are used as the above pharmaceuticals, they are mixed with pharmaceutically necessary ingredients such as appropriate pharmacologically acceptable carriers, excipients, and diluents, and prepared into powders, granules, and tablets. It can be administered orally or parenterally as a pharmaceutical composition in the form of a capsule, injection, or the like. The above formulation contains a dihydropyridine derivative (1
) is blended in an effective amount. The dosage varies depending on the administration route, symptoms, patient's weight or age, etc.
For example, when orally administered to adult hypertensive patients, 0
．． 05-20mg/kg body weight/day, preferably 0.1-20mg/kg body weight/day
It is preferable to administer 4 mg/kg body weight per day in one to several divided doses.

The results of pharmacological tests showing the efficacy of the dihydropyridine derivative (1) of the present invention and its non-toxic salts are shown below.

Blood pressure lowering effect Male spontaneously hypertensive rafts aged 10 to 11 weeks (group 1, 3 to 3)
5 animals) were used. Blood pressure measurement was performed using a non-invasive blood pressure measuring device (P E-300, Narco Bio-System).
The measurement was carried out by measuring systolic blood pressure under non-anesthetized conditions at (m).

The test compound was orally administered as a 10% HC○-60 suspension (dose: 25 mgZ kg), and blood pressure was measured at 1.4 and 7 hours after administration. Each average value (mI
IHg) are shown in Table 1.

Table 1 In addition, the blood pressure lowering effects of the compound of Example 21, the compound of Example 28, and the compound of Example 33 (all described below) were measured according to the above method, and the blood pressure values before administration were When set to 100%, each blood pressure value is
It dropped to a maximum of 61%, 67%, and 75%. In addition, this decreased blood pressure value is restored by 50% to the pre-administration blood pressure value, that is, (pre-administration blood pressure value - blood pressure value after maximum decrease)/2 = 50%.
2 to 5 The required time is 7.0 hours, 16.2 hours, respectively.
It was 1.7 hours.

Acute Toxicity When the compound of Example 28 was orally administered to mice and the acute toxicity was investigated, L D s. was 930■/kg.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example ■ fi+ 2-chloroethyl methyl, 2,6-dimethyl-4-(6-dia-2-pyridyl)-1゜4-dihydropyridine-3,5-dicarboxylate 6-cyano-2- and lysine aldehyde (1 ,613g,
12.2 mmol), chloroethyl acetoacetate (2,009 g, 12.2 mmof) and methyl 3-aminocrotonate (1,364 g, 12.2
The reaction solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography [silica gel; ethyl acetate-n-hexane (5:6 ) The crude product obtained by separation and purification by isopropyl ether
Recrystallization from methanol yielded 1.546 g of the title compound (
Yield: 34%).

! R symbol: aa-': 2225 (CN), 1695 (C,,0), 168
0(C=0)5.19 (III, s, C*-11
)4.27 (2H,t, J-6112,-COzC
IIzCIIzCi) 3.60 (311,s, -C
O, CIl, )3.60 (211,t, J-6tl
z+ -COtCIItCIItCl)2.30 (6
tl, s, Ct- and C&-CN5)+212-(
N-benzyl-N-methylamino)ethyl methyl, 2
,6-dimethyl-4- (6-dia-2-pyridyl)
-1,4-dihydropyridine-3,5-dicarboxylate (compound 1) The chloroethyl ester obtained in (1) above (1,546 g, 4.11 mmol) and N
-Methyl-benzylamine (1,047g, 8.64
The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with water, dried, and then evaporated under reduced pressure. The residue was separated and purified by column chromatography (silica gel; ethyl acetate-n-hexane (3:1)), and 449 mg of the raw material was obtained as the first fraction.
(Yield: 29%). 929 mg of Compound 1 was obtained as a second fraction. Furthermore, the crude product was purified by column chromatography [silica gel; chloroform-methanol (96:4)], and compound 1 was purified by 882 m
g (yield 47%) was obtained.

IRν? CL3 country-': 2225 (CN), 1
685(C-Ox2)7.25 (5H,s, Ar-
II) 6.92 (LH, s, Nl+) 5.2
2 (IH, s, Ce-H) 4.14 (2H, t, J-6H2, -COtCIh
CHJko) 3.60 (3)1. s, -COtCH
s) 2.60 (2H, t, J-6Hz, -C(h
cIIzcHzNko)2.29 (6H,s, Ct-
and Ca-C1li)2.18 (311,S,
;N-Ctli) Example 2 Compound 1 (858 mg, 1.86 mmol) and fumaric acid (216 mg, 1.86 mmol) were dissolved in 25 m/25 ethanol and stirred at room temperature for 70 minutes.The reaction solvent was distilled off under reduced pressure. 1.07 g of fumarate of Compound 1 was obtained.

rRνHB C11l-': 3300 (COo+I), 2200 (CN), 1
690(C,=ox4)NM R6oMso-ah*c
Ilcts Near, 22 (5H,s, Ar-
H) 5.12 (IH, s, Ce4) 4.14 (2H, t, J=6Hz, -COxCH
tCHJ) 2.67 (2H, t, J-6Hz
, -COxCHsCHtN)2.28 (6)1
．． s, Cz- and C1-CN5)2.21 (3
1+, s, J-CHs) Example 3 (1) 2-chloroethyl methyl, 2,6-dimethyl-
4-(6-bromo-2-pyridyl)-1゜4-dihydropyridine-3,5-dicarboxylate 6-bromo-2-pyridine aldehyde (1,542 g,
8.29 mmo+), chloroethyl acetoacetate (1,388 g, 8.43 mmol) and methyl 3-aminocrotonate (984 mg-8,29 mmol)
The reaction solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [silica gel; ethyl acetate-n-hexane ( 2:3)), and the obtained crude product was recrystallized from isopropyl ether-methanol to obtain the title compound with a concentration of 1.730
g (yield 49%) was obtained.

(Melting point 152-153°C) IRν2:', Cl11-': 1705 (C-
0), 1680 (C-0) NMR δc, cjs: 5.25 (III, s, Ca-H) 4.28 (
2■, t, J-6Hz, -COzCHzCHtC
l) 3.60 (3H,s, -COtCH!>3.6
0 (211,t, J=6112.-Co□C1I□
CIhCI) 2.32.2.30 (311.s each
, c2- and Ca-C11a)+212-(N-benzyl-N-methylamino)ethyl methyl, 2,6-dimethyl-4-(6-promo-2-pyridyl)-1,4
-Dihydropyridine-3,5-dicarboxylate (compound 2) Chloroethyl ester (1,5-dicarboxylate) obtained from (1)
09g.

3,51 mmol) and N-methylbenzylamine (894 mg, 7.37 mmol) were dissolved in dimethylformamide 11- and stirred at 100 to 105°C for 15.5 hours in a nitrogen stream.The reaction solvent was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Wash the ethyl acetate layer with water,
After drying, it was distilled off under reduced pressure, and the residue was subjected to column chromatography (
Silica gel; ethyl acetate-n-hexane (5:2)
) The crude product obtained by separation and purification was recrystallized from isopropyl ether-methanol, and compound 2 was obtained by 1.
141 g (yield 63%) was obtained. (Melting point 123.5~
124.5°C) IR'W:T;t(n-': 1
695(C-Ox2)NMRδCDCL: 5.26 (IHls, Ce-H) 4.17 (2H,t, J=6Hz, -COgCI
lzGHzN) 3.60 (3H,s, C0t
CHs) 2.61 (2tl, t, J115
Hz+ -C (hcHzcIhN) 2.30 (6
8,s, Ct- and C1-CH*)2.20 (3
1,s, NCHi) Example 4 Compound 2 (1,037g, 2.02nuwol) and fumaric acid (234tl1g12.02+mol) were dissolved in ethanol 24- and stirred at room temperature for 4 hours.The reaction solvent was distilled off under reduced pressure. Then, 1.2 g of fumarate of Compound 2 was obtained.

I Ry ::: Cm −' : 3375(CO
O1'l) + 1695 (C song o x4) N M R
6Il, 5o-ab*cochs: 5.08 (1
111slCe-11)4.15 (2H,t, J-
6Hz, -COtCHtCIIJ/-)/M&3.56 (58,s, -COgCIls and -N-C
IItPh)2',66 (2H,t, J-6Hz,
-COtCHtCHtN”)2.27 (6L s
, Ct- and C1-CHz)2.19 (3H,s
, ::NC11s) Example 5 2-(N-benzyl-N-methylamino)ethyl methyl, 2,6-dimethyl-4-(4-nitro-2-pyridyl)-1,4-dihydropyridine-3,5 -Dicarboxylate (Compound 3) Proceed as in Example 1.3;
Compound 3 was obtained using -nitro-2-pyridine aldehyde (yield 25%), (melting point 163°C, methanol) I
Rν=:Deaf cffi-1= 3070, 2950.1700.1670.1640.
1620.15805.2 (LH5s, Ce-H) 4.1 (211,t+ J-611z, -C(hc
lItclh-)3.6 (3tl, s, -COtC
Hs) 2.60 (2H,t, J-6Hz, -C0
wC11zCH*”)2.30 (6H,s, Ct-
and C6-CO2)2.2 (3H,s, N-
CH5) Example 6 2-(N-benzyl-N-methylamino)ethyl methyl, 2,6-dimethyl-4-(,2-)lifluoromethyl-4-pyridyl)-1,4-dihydropyridine-3,
5-Dicarboxylate (Compound 4) In the same manner as in Examples 1 and 3, an oily Compound 4 was obtained using 2-trifluoromethyl-4-pyridine aldehyde. (Yield 55%) IR(Neat)am-': 3350, 2950.2800.1690(broad
), 1460 (broad)5.06 (111,s
, Ce-II) 4.13 (211,t, J'=6
11z, -0CIhC1h-)'3.60 (3H
,s, -0C1h)3.47 (2H,s,
-CI, φ) 2.63 (2H, t, J=6Hz,
-0CHZC1L! -)2.31 (6H,s, Ct
- and C, -CHl, )2,17 (3H1s,
> N-CHl)” F-NMRφcnct3:
-67,5(s) Examples 7 to 45 The compounds shown in Tables 2 to 7 were obtained in the same manner as in Examples 1 to 6.

Margin below C] Table 5 Table 6 Table 7 Examples 14.18 to 21.27.28 in Tables 2 to 7.
The physical properties of compounds Nos. 31 and 38 to 45 and their respective phthalates or hydrochlorides were investigated, and the results are shown in Table 8.

[Margin below]

Formulation Example 1 Compound 1.2.3 or 4' 10mg Magnesium Stearate 2mg Hydroxypropylcellulose 2mg Starch added to give a total of 130
The amount shall be 0 mg.

A tablet consisting of the following was prepared in a conventional manner.

Claims (8)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are each a hydrogen atom (However, R
_1 and R_2 are not hydrogen atoms at the same time), nitro, cyano, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkylmercapto,
Alkyl sulfoxide or alkyl sulfone, R_
3, R_4 and R_5 each represent alkyl, R_6
and R_7 each represents a hydrogen atom, alkyl optionally substituted with halogen, or aralkyl, or may form a heterocycle together with the adjacent nitrogen atom, X is a group represented by the formula -CO- or the formula A dihydropyridine derivative represented by -COO-, A represents an alkylene group, or a non-toxic salt thereof. (2) The pyridyl group having R_1 and R_2 in general formula (I) and the 4-position of the dihydropyridine skeleton are bonded at the 2- or 3-position of the pyridyl group.
The dihydropyridine derivative or non-toxic salt thereof according to item 1). (3) Claim (1) in which the substituents R_1 and R_2 in general formula (I) are present at the ortho position and/or meta position with respect to the bonding site between the pyridyl group and the dihydropyridine skeleton. or the dihydropyridine derivative or non-toxic salt thereof according to item (2). (4) Substituents R_1 and R_2 in general formula (I)
The dihydropyridine derivative or non-toxic salt thereof according to any one of claims (1) to (3), wherein either one is cyano or trifluoromethyl. (5) [1] 2-(N-benzyl-N-methylamino)
Ethylmethyl, 2,6-dimethyl-4-(4-cyano-
2-pyridyl)-1,4-dihydropyridine-3,5-
dicarboxylate or [2]2-(N-benzyl-
N-methylamino)ethylmethyl, 2,6-dimethyl-
4-(2-trifluoromethyl-3-pyridyl)-1,
The dihydropyridine derivative or non-toxic salt thereof according to claim (1), which is 4-dihydropyridine-3,5-dicarboxylate. (6) The non-toxic salt of the dihydropyridine derivative according to claim (5), which is in the form of a hydrochloride. (7) The non-toxic salt of the dihydropyridine derivative according to claim (6), which is in the form of a dihydrochloride. (8) A pharmaceutical composition comprising at least one selected from the dihydropyridine derivatives or non-toxic salts thereof defined in claims (1) to (7) and components necessary for pharmaceuticals.