JPS61268667A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 1-6C saturated or unsaturated hydrocarbon group wherein 1-2C atoms constituting the skeleton of said hydrocarbon may be substituted with O or S or 1-2H atoms of the hydrocarbon may be substituted with halogen, cyano, aryl, etc.; Ar<1> is aryl, aromatic heterocyclic group, etc.; R<2> is 1-4C saturated or unsaturated hydrocarbon group, etc.; Ar<2> is Ar<1>). EXAMPLE:Methylphenylpropargyl 4-( 3-nitrophenyl )-2,6-dimethyl-1,4-dihydropyri dine-3,5-dica-rboxylate. USE:Pharmaceuticals. It has excellent hypotensive activity, retarded time to attain the peak of blood pressure depression, and elongated time to continue the hypotensive activity. PREPARATION:The compound of formula I can be produced e.g. by reacting the compound of formula II with the compound of formula III and the compound of formula IV in an inert solvent or in the absence of solvent, preferably at 50-150 deg.C for 0.5-15hr.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel 1,4-dihydropyridine derivative having a blood pressure lowering effect.

[Conventional technology]

It is known that various 1,4-dihydropyridine derivatives exhibit blood pressure lowering effects.

4-(2-nitrophenyl) J 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester with nifedipine, U.S. Patent No. 364462
No. 7) or 4-(3-nitrophenyl)-2,6
-dimethyl-1,4-dihydropyridine-3,5-dicarzoic acid 3-methyl ester-5-[:2-(benzylmethylamino)ethyl] ester hydrochloride with calcibin,
Japanese Patent Publication No. 55-45075), etc. are used medically as antianginal drugs, cerebral circulation improving drugs, and antihypertensive drugs.

Furthermore, various compounds similar to nifedipine or nicardipine as shown below are already known (%Kokoku No. 55-29989, Japanese Patent Publication No. 55-29
990, JP-A-55-64571, etc.).

Ar In the formula, R is a methyl group, ethyl group, etc. p, Ar is 3-
For example, R may be an ethyl group, an isopropyl group, an allyl group, a glopargyl group, etc., such as a nitrophenyl group.

The present inventors have conducted intensive research to improve this 1,4-dihydropyridine derivative to develop a compound with even better antihypertensive action, and have already filed a patent application for the results (Japanese Patent Application No. 88411/1989). and patent application 1986-125
No. 379).

[Problem that the invention seeks to solve]

However, all of these had the disadvantage that the duration of their blood pressure lowering effect was short. For example, it has been reported that when nifedipine, which has a longer duration than nifedipine, is injected intravenously into a dog 1/CIOμ9, it lasts only about 30 to 40 minutes (Arzneim-Forsc.
h, vol. 22, p. 33, 1976, vol. 26, 2
172-1! - Ji, 1982, Journal of the Toho Medical Society, Volume 26, No. 2, Page 48 (1972).

Another problem was that the rate of blood pressure drop was too rapid.

[Means for solving problems]

The present invention relates to a novel 1,4-dihydropyridine derivative that solves these problems.

That is, the present invention is based on the general formula (wherein R1 is a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, or one of the carbon atoms forming the skeleton of the hydrocarbon) 1 or 2 or more are replaced by oxygen atoms or sulfur atoms, or 1 or 2
represents a derivative in which one or more hydrogen atoms are substituted with a halogen atom, a cyano group, an aryl group, an aromatic heterocyclic group, an aryloxy group, an arylthio group, or an amine group;
is an aryl group, an aromatic heterocyclic group, or one or more hydrogen atoms thereof are an alkyl group, an alkoxy group,
Halogen atom, alkylthio group, trihalomethyl group, nitro group, cyano group % Represents a derivative substituted with a sulfinyl group or a sulfonyl group, and R2 is a linear or branched saturated or unsaturated carbonized group having 1 to 4 carbon atoms. Represents a hydrogen group, which group may be optionally substituted with a substituted or unsubstituted 7-aryl group, and Ar2 has the same meaning as Ar', and Ar2 and 1 may be the same or different. It's okay. ) This relates to a 1,4-dihydropyridine derivative represented by:

The compound of the present invention is characterized in that in the above-mentioned known 1,4-dihydropyridine derivatives, R3 is an arylpropargyl group or a derivative thereof.

R1 is a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms or a derivative thereof. Examples of such hydrocarbon groups include methyl group, ethyl group, n-globyl group, isobutyl group, n-butyl group, isobutyl group, tertiary group, n-pentyl group, n-hexyl group. , allyl group, 3-butenyl group, crotyl group, 3-buten-2-yl group, 2-butynyl group,
3-butynyl group, cyclohexyl group, 2-pentyl group,
3-pentyl group, 4-penten-1-yl group, 3-penten-2-yl group, 2-penten-1-yl group, 2.4
-hexagenyl group, 2-hexen-1-yl group, 1-
hexen-3-yl group, froz4rugyl group, cyclopropylmethyl group, 3-pentynyl group, 2-hexene-3-
Examples include an in-1-yl group and a 2-cyclohexenyl group.

Derivatives have one or two carbon atoms forming the skeleton.
Including those in which one or more atoms are replaced by oxygen atoms or sulfur atoms. Examples of such groups include 2-methoxyethyl group, 2-ethoxyethyl group, 2-(2-methoxyethoxy)ethyl group, 2-butoxyethyl-3,2-(2-ethoxyethoxy)ethyl group, 3 -methoxybutyl group, 4
-Methoxy-3-buten-2-yl group, 2-(2-butoxyethoxy)ethyl group, 2-Schiffa hexyloxyethyl group, 2-methylthioethyl group, 2-ethylthioethyl group, 3-methylthiobutyl group and 2-cyclohexylthioethyl group.

Furthermore, the above-mentioned hydrocarbons and derivatives include those in which one or more hydrogen atoms are substituted with a halodane atom, a cyan group, an aryl group, an aromatic heterocyclic group, an aryloxy group, an arylthio group, or an amino group. Uharon atoms include chlorine atoms, bromine atoms, fluorine atoms, etc., and aryl groups and aromatic heterocyclic groups include phenyl groups, chenyl groups, furyl groups, pyrazolyl groups, imidazolyl groups, oxacylyl groups, isoxasilyl groups, Thiazolyl group, bi-lysyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, quinoxalyl group, naphthyl group, nido-phenyl group,
Chlorophenyl group, dichlorophenyl group, cyanophenyl group, fluorophenyl group, methoxyphenyl group, methylthiophenyl group, α, α.

α-trifluorotolyl group, tolyl group, biphenyl group,
Examples include methylsulfonylphenyl group, methylsulfonylphenyl group and azidophenyl group. Aryloxy groups include phenoxy group, benzimidazolyloxy group,
Indolyloxy group, isoquinolyloxy group, pyrinolthio group, 4-methylquinolyloxy group, pyrimidinyloxy group, naphthoxy group, aminophenoxy group, nitrophenoxy group, chlorophenoxy group, cyanophenoxy group, methoxyphenoxy group, etc. be. Arylthio groups include phenylthio group, benzimidazolylthio group, benzthiazolylthio group, benzoxazolylthio group, imidazolylthio group, pyrimidinylthio group and pyridylthio group. Amino groups include diethylamino group, diethylamino group, benzylmethylamino group, piperidino group, 1-
These include pyrrolidinyl group, morpholino group, anilino group, methylamino group, ethylamino group, di-n-propylamino group, and benzylamino group.

Ar' is an aryl group, an aromatic heterocyclic group or a derivative thereof. Aryl groups and aromatic heterocyclic groups include phenyl groups, chenyl groups, furyl groups, pyrazolyl groups, imidazolyl groups, oxasilyl groups, isoxasilyl groups, thiazolyl groups, pyridyl groups, pyridazinyl groups, pyrimidyl groups,
Examples include pyrazinyl group, quinolyl group, isoquinolyl group, indolyl group, benzimidazolyl group, quinazolyl group, quinoxalyl group and naphthyl group.

Derivatives include one hydrogen atom of an aryl group and an aromatic heterocyclic group.
one or more of which are substituted with an alkyl group, an alkoxy group, a halogen atom, an alkylthio group, a trihalomethyl group, a nitro group, a cyano group, a sulfinyl group, or a sulfonyl group. Examples of the alkyl group include methyl group, ethyl group, n-7'ropyl group, 1-propyl group, n-butyl group, l-butyl group, t-butyl group, cyclohexyl group, and hycycloglovir group. Alkoxy groups include methoxy, ethoxy, n-propoxy, t-10 poxy, and t-methoxy groups, and alkylthio groups include methylthio, ethylthio, n-propylthio, i-propylthio, and t-butylthio. etc. Halodan atoms are chlorine, bromine, iodine and fluorine atoms. Examples of trihalomethyl groups include trichloromethyl and trifluoromethyl.

R2 is a linear or branched saturated or unsaturated hydrocarbon group having 1 to 4 carbon atoms or a derivative thereof. Examples of such hydrocarbon groups include methylene group, ethylene group, propylene group, trimethylene group, tetramethylene group, 2-7'ropenylene group, 2-7''ropynylene group, 1-
Methyl-2-7'OK = lene group, 3-7'' tenylene group,
3-propylene group, 1-methyl-2-fropynylene group,
Mention may be made of 1-ethylethylene group and 2-ethylethylene group.

Derivatives include hydrocarbon groups in which one or more hydrogen atoms are aryl groups, aromatic heterocyclic groups, or one or more hydrogen atoms thereof are alkyl groups,
Alkoxy groups, halogen atoms, alkylthio groups, trihalomethyl groups, nitro groups, cyano groups, and sulfinyl groups are also substituted with hasulfonyl groups. These aryl groups, aromatic heterocyclic groups and their derivatives have the same meaning as the Ar1 group described above.

Ar2 has the same meaning as Ar'. Ar2 and Ar1 may be the same or different.

Examples of such 1,4-dihydropyridine enzyme derivatives are listed below. In addition, "Phenylgurono 4 Gil" is referred to as "PP", "
"nitrophenyl" is abbreviated as rNPJ, and "2,6-dimethyl-1,4-dihydropyridine-3,5-dicardexylate" is abbreviated as "DDD".

Methyl 3-PP 4- (3-NP) -DDD
, ethyl 3-PP 4- (3-NP ) -DDD
, n-propyl 3-PP 4- (3-NP)
-DDD, innolopil 3-PP 4-(3-NP)
-DDD, n-buty, /L/3-PP 4-
(3-NP) -DDD, t-buti #3-PP
4-(3-NP)-DDD, n-hexyN3-
PP 4-(3-NP)-DDD, cyclohexyl 3
- PP 4-(3-NP)-DDD, benzyl 3-
PP4-(3-NP)-DDD, 3-butenyl 3
- PP 4-(3-NP)-DDD, 2-butenyl 3
-PP4-(3-NP)-DDD.

3-7 enyl-2-noloinyl 3-PP 4- (3
-NP)-DDD, 2,4-hexagenyl 3-P
P4-(3-NP)-DDD, 2-methoxyethyl 3-PP4-(3-NP)-DDD, 2-phenoxyethyl 3-PP4-(3-NP)-DDD,
2-Methylthioethyl 3-PP 4-(3-NP)-
DDD, 2-phenylthioethyl 3-PP 4- (
3-NP)-DDD, 2(N,N-tumethylamino)ethyl 3-PP4-(3-NP)-DDD
, 2-chloroethyl 3-PP 4- (3-NP)
-DDD, 2-cyanoethyl 3-PP 4- (
3-NP) -DDD, methyl 3-PP 4-(3
-) IJ fluoromethylphenyl) -DDD, methyl 3-PP4-(2,3-dichlorophenyl)-DD
D, methyl 3-PP 4- (2-NP) -DD
D, methyl 3-PP 4- (4-methylphenyl) -DDD, methyl 3-PP 4- (4-methoxyphenyl) -DDD.

Methyl 3- PP 4- (4-methylphenyl) -
DDD.

Methyl 3-PP 4- (2-fluorophenyl)-D
D.D.

Methyl 3- PP 4- (2-furyl) -DDD
, methyl 3-PP 4 (1-su7thyl) -DDD
, methyl-3-PP 4- (2-pyridyl) -D
DD, methyl 3-PP4-(2-chenyl)-D
DD, methyl 3-(4-chlorophenyl)-2-propynyl 4-(3-NP)-DDD, methyl 3-(4
-NP)-2-propynyl4-(3-NP)-D
DD, methyl 3-(4-methoxyphenyl)-2-1
0 vinyl 4-(3-NP)-DDD.

Methyl 3-(4-carbomethoxyphenyl)-2-propynyl 4-(3-NP) -DDD, methyl 3-12-
chenyl)-2-propynyl 4- (3-NP) -D
D.D.

Methyl 3-(2-pyridyl)-2-propynyl 4- (
3-NP) -DDD, methyl 3-(2-naphthyl)
-2-globini/L/4- (3-NP) -DDD
, methyl 3-(4-methylthiophenyl)-2-propynyl 4-(3-NP)-DDD Such 1,4-dihydropyridine derivatives can be produced, for example, by the method shown below.

Production Example 1 A compound represented by the general formula CH3COCH2COOR1, a compound represented by the general formula Ar'-CHO, and a compound represented by the general formula CH3(NF2)C-cH-C00RC=CARr were mixed in a bath-free or reaction-inert environment. solvent,
For example, the desired derivative can be obtained by heating in methanol, ethanol, propanol, ingropanol, benzene, toluene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide. At this time, the reaction temperature is 50℃~150℃
is preferred, and a reaction time of 0.5 to 15 hours is usually sufficient.

Production method 2 A compound represented by the general formula CH, (NF2) C=CH-C0OR, a compound represented by the general formula Ar -CHO, and a general formula CH3COCH2C00R2C=CAR2
The desired derivative can be obtained by reacting the compound represented by the following under the same reaction conditions as in Production Method 1.

Manufacturing method 3 General 2〇H, (NF2)C=CHCOOR2CE=CA
A method of reacting a compound represented by r2 under the same reaction conditions as in Production Method 1.

Production Method 4 A method of reacting a general 2〇H3(NF2)C=CH-COOR' alloy under the same reaction conditions as Production Method 1.

Production method 5 A method in which a compound represented by the general formula CH3COCH2C0OR is reacted with a substance and ammonia under the same reaction conditions as in production method 1.

Production method 6 A method in which a compound represented by the general formula CH3COCH2C0ORC-CAR and ammonia are reacted under the same reaction conditions as in production method 1.

Production method 7 General formula (where z is a hydroxy group or an acid residue of an active ester, such as a halodane atom, a methylsulfonyloxy group, a paratoluenesulfonyloxy group, a benzotriazole-1
- represents an oxy group, etc., and other symbols have the same meanings as above. ) and the general formula HO-RCEiC-A
A method of reacting with an alcohol represented by r.

When 2 is a hydroxy group, this reaction is carried out in the presence of an acid such as hydrogen chloride, sulfuric acid, boron trifluoride, etc., or in the presence of a dehydration condensation agent such as dicyclohexylcarbodiimide, and optionally 4-dimethylaminopyridine. The reaction can be carried out in an inert solvent in the presence of a base. When 2 is an active ester residue, a base such as triethylamine, 4-
This can be carried out in the presence of trimethylaminopyridine, pyridine, potassium carbonate, and the like.

Manufacturing method 8 A method in which a compound represented by the general formula and a compound represented by the general formula R'-OH are reacted under the same conditions as in manufacturing method 7.

Note that the raw material compounds used in Production Methods 7 and 8 can all be produced by known methods. The 1,4-dihydropyridine derivative thus obtained is isolated and purified by ordinary chemical operations. be able to.

By formulating this in the same manner as nifedipine, nicardipine, etc., it can be used as a medicine that exhibits a blood pressure lowering effect.

[Effect]

The compounds of the present invention exhibit hypotensive effects on humans and various other warm-blooded animals.

For example, the compound of the present invention is suspended in a gum arabic bath solution, and this is injected into the duodenum of an unanaesthetized spontaneously hypertensive rat over 10 weeks of age using a cannula at 1 to 1/kl/kl. The blood pressure decrease when administered is approximately 20 W Hg or more, usually 35 W Hg or more.
m Hg or more. Also, the time to reach the maximum blood pressure is 20
It is usually 40 minutes or more. The half-life is 60 minutes or more, usually 2 hours or more.

[Example] Example 1 4-(3-nitrophenyl)-2,6-cymethyl-3
-methoxycarbonyl-1,4-dihydropyridine-5
-Carmenic acid 33211? (1mM), dicyclohexylcarbodiimide 226~(1,1mM), 4-dimethylaminopyridine 122~(1mM), and Hi'eniA, f-rollyl alcohol 158~(1,2mM)
) It was dissolved in 10IR1 of cycloethane and refluxed for 2 hours. After cooling the reaction mixture, insoluble materials were separated. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 438 methylphenyl propargyl 4.
- (3-nitrophenyl) -2,6-cymethyl-1
,4-dihydropyridine-3,5-dical? A xylate was obtained (yield 98%). Structural formula of this compound % Formula % The analysis results of the obtained compound are shown below.

Elemental analysis C25H2□N206 Theoretical value C: 67.26 H: 4.97 N: 6.
27 Actual measurement value C: 67.36 H: 4.92 N:
6.19 Melting point 127-128°C IR (crn-') NH3360ν. . 1690
SINO□1535.135O NMRδ 2.32 (s, 6H) 3.60 (s
, 3H) CDCt.

4.85 (s, 2H) 5.12 (a, IH) 6.72
(bs, IH) 7.1-8.2 (rn, 9H) Example 2 4-(3-nitrophenyl)-2,6-cymethyl-1
．． 4-dihydropyridine-3,5-dicarboxylic acid monocinnamyl ester 434# (1mM), dicyclohexylcardidiimide 226mg (1,1mM), 4-
Dimethylaminopyridine 122+f' (1mM) and phenylproA argyl alcohol 158~(1,2mM
) It was dissolved in dichloroethane at 10 m/t and refluxed for 2 hours. After cooling the reaction mixture, insoluble materials were separated. The solvent was distilled off under reduced pressure, and the residue was purified by silica dull column chromatography to obtain 510# cinnamylphenylpropargyl 4-(3-nitrophenyl)-2,6-dimethyl-1.
4-dihydropyridine-3,5-dical? A xylate was obtained (yield 93%). The structural formula of this product is shown below.

The analysis results of the obtained compound are shown below.

Elemental analysis C33H28N206 Theoretical value C near 2.25) (:5.14 N:5
．． 11 Actual value C near 2.47 H: 5.06 N
:5.02 Melting point 159.5-16ff, 5℃ rR(tM-') NH3360νco 1690
1640shiN0215201350 Hiki δcocz, 2,43(s, 6H) 4.68(d
, 2H) 4J33(a, 2H) 5.15 (s,
IH) 5.8-6.7 (rn, 3H) 7.1-8
．． 2 (m, 14H) Example 3 An experiment was conducted using a male spontaneously hypertensive rat (SHR) with a mean arterial blood pressure of 140 ya) or more. Arterial blood pressure was measured using a pressure transducer (MPU-0,5, manufactured by Nihon Kohden Co., Ltd.) via an artery into which a catheter was inserted. The catheter was inserted into the abdominal aorta via the caudal artery of the SHR under ether anesthesia. Recording was performed using a retigraph (manufactured by Sanei Sokki Co., Ltd.).

Each test compound was administered using a catheter previously inserted into the tail vein or duodenum.

The test compound was dissolved in a 1.5% pvp/ethanol solution and administered by diluting it with 0.9% physiological saline for intravenous injection (30 μg/+?). On the other hand, when administering to the duodenum (1 da/kg), the drug was suspended in a solution of 5 thiarabic gum and administered. The results obtained are shown in the table below.

For intravenous administration Compound Maximum blood pressure reduction Time to reach maximum blood pressure reduction Duration Example 1 55 2 90 (Example 2
20 20 - Nifedipine 18
．． 7 0.9 35.6±6.5 Nicardipine 58.3 0.6
45-90 When administered into the duodenum Compound Maximum hypotension EI3 warming time Half-life Example 1
45 60 240<nifedipine
48.3 6.0 20.0 Nicardipine 35 10.7
The results of measuring 46.7 acute toxicity are shown below. The measurement was performed using a male ddy mouse weighing 15 to 30 g using an up-and-down method. Each compound was dissolved in a 1.54 PVP/ethanol solution, diluted with saline, and injected into the tail vein of a given carcass. The results obtained are shown in the table below.

Compound LD5゜Example 1 60〈 Nifedipine 5 Nicardipine 9.7 Example 4 An experiment was conducted using a male SHR with a systolic blood pressure of 160 w) 1 g or more under no anesthesia. Systolic collapse pressure was measured by the tail cuff method using a non-invasive blood pressure measuring device (PE-300, manufactured by Nalco). The test compound was suspended in a 5% gum arabic solution, and 3 Da/kg was orally administered.

The results obtained are shown in the table below.

Compound Blood Pressure Lowering (mHg) Duration Example 1 -65-75 phenopine at 24
-45-22,0 (7 dicardipine -27-4,
5 (3 [Effects of the Invention]) The compound of the present invention is characterized by a large blood pressure lowering effect, a slow time to reach the maximum blood pressure lowering, and a long duration of the blood pressure lowering effect.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, or One or more carbon atoms forming the skeleton are replaced by oxygen atoms or sulfur atoms, or one or more hydrogen atoms are halogen atoms, cyano groups, aryl groups, aromatic heterocyclic groups, Represents a derivative substituted with an aryloxy group, an arylthio group, or an amino group, and Ar^1 is an aryl group, an aromatic heterocyclic group, or one or more of these hydrogen atoms is an alkyl group, an alkoxy group, or a halogen group. Represents a derivative substituted with an atom, an alkylthio group, a trihalomethyl group, a nitro group, a cyano group, a sulfinyl group, or a sulfonyl group, and R^2 is a linear or branched saturated or unsaturated carbonized group having 1 to 4 carbon atoms. A hydrogen group, or one or more of its hydrogen atoms is an aryl group, an aromatic heterocyclic group, or one or more of these hydrogen atoms is an alkyl group,
It represents a derivative substituted with an alkoxy group, a halogen atom, an alkylthio group, a trihalomethyl group, a nitro group, a cyano group, a sulfinyl group, or a sulfonyl group, and Ar^2 has the same meaning as Ar^1, and Ar^2 and Ar^
1 may be the same or different. ) 1,4-dihydropyridine derivative represented by (2) R^1 is a methyl group or a cinnamyl group, and Ar
Claim 1, wherein ^1 is a 3-nitrophenyl group, 2-nitrophenyl group, or 2,3-dichlorophenyl group, R^2 is a methylene group, and Ar^2 is a phenyl group. 1,4-dihydropyridine derivatives described in section (3) 1,4-dihydropyridine derivative according to claim 2, wherein Ar^1 is a 3-nitrophenyl group