US 5,859,244 A · 1,4-dihydropyridine derivatives and methods of producing the same

Abstract

1,4-dihydropyridine derivatives and optically active 1,4-dihydropyridine derivatives with the following formula, having vasodilating activity based on calcium antagonism, and PAF antaognism, and methods of producing the same are disclosed: ##STR1## wherein (*) indicates a chiral center in the case of the optically active 1,4-dihydropyridine derivatives.

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Claims2

Dependent claims

A method of producing a compound of formula (XIII), comprising:

(a) reacting a keto-ester derivative of formula (X) with an optically active enamine derivative of formula (XI), and then reacting a product of this reaction with ammonia or an ammonium salt to produce an optically active cyanoethylester of formula (XII);
and
(b) reacting said optically active cyanoethylester of formula (XII) with a basic compound to obtain the compound of formula (XIII), ##STR141## wherein R.sup.1 represents hydrogen, a straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted aromatic hydrocarbon group selected from the group consisting of phenyl and naphthyl, or an unsubstituted or substituted aromatic heterocyclic group selected from the group consisting of pyridyl, quinolyl, isoquinolyl, furyl, thienyl, benzoxazolyl, benzthiazolyl, pyridazinyl, pyrazinyl, pyrimidyl, indolyl, benzoxadiazolyl and benzthiadiazolyl;
R.sup.2 represents hydrogen, a straight chain, branched chain or cyclic alkyl group, and R.sup.1 and R.sup.2 in combination may form a saturated or unsaturated hydrocarbon ring selected from the group consisting of cyclopentane, cyclohexane and tetrahydronaphthalene;
R.sup.4 and R.sup.5 each represent hydrogen, an unsubstituted or substituted straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted amino group, an unsubstituted or substituted aromatic hydrocarbon group selected from the group consisting of phenyl and naphthyl, or an unsubstituted or substituted aromatic heterocyclic group as defined in R.sup.1 above;
R.sup.3 represents hydrogen, cyano, nitro, --COR.sup.8, an unsubstituted or substituted aromatic hydrocarbon group as defined in R.sup.1 above or an unsubstituted or substituted aromatic heterocyclic group as defined in R.sup.1 above, in which R.sup.1 represents an unsubstituted or substituted straight chain, branched chain or cyclic alkoxyl group, an alkenyloxy group, an alkynyloxy group, or --N(R.sup.61)--B.sup.1 --COR.sup.71, wherein R.sup.61 represents hydrogen, a straight chain, branched chain or cyclic alkyl group, or a trialkylsilyl group;
B.sup.1 represents an unsubstituted or substituted alkylene group, an unsubstituted or substituted aromatic hydrocarbon group, an unsubstituted or substituted aromatic heterocyclic group, an unsubstituted or substituted cycloalkylidene group;
R.sup.71 represents an unsubstituted or substituted straight chain, branched chain or cyclic alkoxyl group, an unsubstituted or substituted amino group, or an unsubstituted or substituted cyclic amino group;
R.sup.17 and R.sup.18 are each different and independently represent an unsubstituted or substituted straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted aromatic hydrocarbon group, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted straight chain, branched chain or cyclic alkoxycarbonyl group, or an unsubstituted or substituted straight chain, branched chain or cyclic aminocarbonyl group, and an * indicates a chiral center.

6 more elements

A method of producing an optically active cyanoethylester of formula (XII), comprising:

reacting a keto-ester derivative of formula (X) with an optically active enamine derivative of formula (XI), and then reacting a product of this reaction with ammonia or an ammonium salt to produce an optically active cyanoethylester of formula (XII) ##STR142## wherein R.sup.1 represents hydrogen, a straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted aromatic hydrocarbon group selected from the group consisting of phenyl and naphthyl, or an unsubstituted or substituted aromatic heterocyclic group selected from the group consisting of pyridyl, quinolyl, isoquinolyl, furyl, thienyl, benzoxazolyl, benzthiazolyl, pyridazinyl, pyrazinyl, pyrimidyl, indolyl, benzoxadiazolyl and benzthiadiazolyl;
R.sup.2 represents hydrogen, a straight chain, branched chain or cyclic alkyl group, and R.sup.1 and R.sup.2 in combination may form a saturated or unsaturated hydrocarbon ring selected from the group consisting of cyclopentane, cyclohexane and tetrahydronaphthalene;
R.sup.4 and R.sup.5 each represent hydrogen, an unsubstituted or substituted straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted amino group, an unsubstituted or substituted aromatic hydrocarbon group selected from the group consisting of phenyl and naphthyl, or an unsubstituted or substituted aromatic heterocyclic group as defined in R.sup.1 above;
R.sup.3 represents hydrogen, cyano, nitro, --COR.sup.8, an unsubstituted or substituted aromatic hydrocarbon group as defined in R.sup.1 above or an unsubstituted or substituted aromatic heterocyclic group as defined in R.sup.1 above, in which R.sup.8 represents an unsubstituted or substituted straight chain, branched chain or cyclic alkoxyl group, an alkenyloxy group, an alkynyloxy group, or --N(R.sup.61)--B.sup.1 --COR.sup.71, wherein R.sup.61 represents hydrogen, a straight chain, branched chain or cyclic alkyl group, or a trialkylsilyl group;
B.sup.1 represents an unsubstituted or substituted alkylene group, an unsubstituted or substituted aromatic hydrocarbon group, an unsubstituted or substituted aromatic heterocyclic group, an unsubstituted or substituted cycloalkylidene group;
R.sup.71 represents an unsubstituted or substituted straight chain, branched chain or cyclic alkoxyl group, an unsubstituted or substituted amino group, or an unsubstituted or substituted cyclic amino group,
R.sup.17 and R.sup.18 are each different and independently represent an unsubstituted or substituted straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted aromatic hydrocarbon group, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted straight chain, branched chain or cyclic alkoxycarbonyl group, or an unsubstituted or substituted straight chain, branched chain or cyclic aminocarbonyl group, and an * indicates a chiral center.

4 more elements

Dependencies are inferred from the claim text.

Description23,083 words

Summary4,312 words

#The present invention relates to 1,4-dihydropyridine derivatives and optically active 1,4-dihydropyridine derivatives having (a) vasodilating activity based on calcium antagonism and (b) PAF antaognism, and methods of producing the optically active 1,4-dihydropyridine derivatives.

#Generally it is known that 1,4-dihydropyridine derivatives are useful as remedies for diseases of circulatory system such as remedies for ischemic heart disease, cerebral circulatory disease and hypertension, since the 1,4-dihydropyridine derivatives have vasodilating activity based on the calcium antagonism thereof.

#It has been reported that it is essential that the 1,4-dihydropyridine derivatives have a 3,5-diester structure in order that the 1,4-dihydropyridine derivatives exhibit the above-mentioned actions.

Detailed description18,771 words

#A mixture of 11.2 g (45 mmol) of methyl 2-(3-nitrobenzylidene)acetoacetate and 11.53 g (45 mmol) of (s)-t-butyl 2-(S)-N-(3-amino-2-butenoyl)amino!-3-methylbutylate was heated at 100.degree. C. for 20 minutes. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 14.7 g (67.5%) of a diastereo mixture was obtained. The diastereo mixture was recrystallized from acetonitrile, so that 8.9 g (40.7%) of Compound a of the captioned compound was obtained. The mother liquor was distilled away under reduced pressure and the residue was recrystallized from methanol, whereby 5.8 g (27%) of Compound b of the captioned compound was obtained.

#______________________________________ (Compound a) ______________________________________ Melting point (.degree.C.) 194 (dec.) IR (.nu.KBr, cm.sup.-1) 3308, 1716, 1690, 1530, 1354 Mass spectrometry Based on Formula C.sub.25 H.sub.33 N.sub.3 O.sub.7 Calcd. 487.23180 Found 487.23146 NMR (.delta.,CDCl.sub.3) 0.72 (3H, d, J=7Hz), 0.75 (3H, d, J=7Hz), 1.40 (9H, s), 1.98-2.01 (1H, m), 2.22 (1H, s), 2.35 (3H, s), 3.62 (3H, s), 4.39 (1H, dd, J=8Hz, 4Hz), 4.99 (1H, s), 5.58 (1H, s), 5.76 (1H, d, J=8Hz), 7.41 (1H, dd, J=8Hz, 8Hz), 7.66 (1H, d, J= 8Hz), 8.03 (1H, d, J=8Hz), 8.13 (1H, s) Optical rotation .alpha.!.sup.20.sub.D = +60.9.degree. (C = 1.00, ethanol) (Compound b) Melting point (.degree.C.) 157 (dec.) IR (.nu.KBr, cm.sup.-1) 3330, 1732, 1714, 1676, 1530, 1352 Mass spectrometry Based on Formula C.sub.25 H.sub.33 N.sub.3 O.sub.7 Calcd. 487.23180 Found 487.23299 NMR (.delta., CDC13) 0.698 (3H, d, J=7Hz), 0.703 (3H; d, J=7Hz), 1.45 (9H, s), 1.96-2.01 (1H, m), 2.30 (3H, s), 2.33 (3H, s), 3.66 (3H, s); 4.42 (1H, dd, J=8Hz, 4Hz), 4.96 (1H, s), 5.59 (1H, s), 5.90 (1H, d, J=8Hz), 7.42 (1H, dd, J=8Hz, 8Hz), 7.70 (1H, d, J.=8Hz), 8.03 (1H, d, J=8Hz), 8.15 (1H, s) Optical rotation .alpha.!.sup.D.sub.20 = +31.4.degree. (c = 1.00, ethanol) ______________________________________

#1.65 g (5 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-car boxylic acid was suspended in 20 ml of dichloromethane. 1.054 g (5.5 mmol) of hydrochloric acid 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to the above suspension in an ice-cooled condition and the mixture was stirred for one hour.

Facts

Application

08/855,500Filed 13 May 1997 · continuation

Priority

JP 2-33000530 Nov 1990

Granted

12 Jan 1999

Term ended

29 Nov 2011

Estimated · how

20 years from earliest known nonprovisional domestic filing. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination. Patent term adjustment is unavailable; no adjustment was added.

Classification13 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/08
Drugs for disorders of the cardiovascular system: vasodilators for multiple indications
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives

1,4-dihydropyridine derivatives and methods of producing the same

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1,4-dihydropyridine derivatives and methods of producing the same

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Abstract

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Claims2

Description23,083 words

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Classification13 codes

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Description23,083 words