GB2036722A - 2-Methyl-dihydropyridines - Google Patents

2-Methyl-dihydropyridines Download PDF

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GB2036722A
GB2036722A GB7935022A GB7935022A GB2036722A GB 2036722 A GB2036722 A GB 2036722A GB 7935022 A GB7935022 A GB 7935022A GB 7935022 A GB7935022 A GB 7935022A GB 2036722 A GB2036722 A GB 2036722A
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methyl
dihydropyridine
carboxylic acid
compound according
ester
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Fujisawa Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

2-methyl-dihydropyridine compounds having the formula: <IMAGE> wherein R<1> is phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2- thienyl, R<2> is propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methylamino) ethyl, R<3> is lower alkyl, and R<4> is di(lower)alkoxymethyl, formyl, hydroxymethyl or cyano, provided that, when R<1> is 3-nitrophenyl, then R<2> is 2-hydroxyethyl and R<4> is cyano or formyl, or R<2> is propyl or isopropyl, and pharmaceutically acceptable salts thereof. These compounds have vasodilating and anti-hypertensive activities.

Description

SPECIFICATION 2-methyl-dihydropyridine compound, processes for preparation thereof and pharmaceutical composition comprising the same This invention relates to 2-methyl-dihydropyridiné cbri-reound and a salt thereof. More particularly, it relates to a new 2-methyl-dihydropyridine compound and a pharmaceutically acceptable salt thereof which have vasodilating and anit-hypertensive activities, to processes for the preparation thereof, and to a pharmaceutical composition comprising the same for therapeutical treatment of cardiovascular disorder and hypertension in human being.
With regard to the states of the arts in this field, for example, the following dihydropyridine compounds are
(U.S.P. 3,485,847) (Nifedipine)
(German Offenlegungsschrift 26 29 892)
(German Offenlegungsschrift 2629892 One object of this invention is to provide the new and useful 2-methyl-dihydropyridine compound and a pharmaceutically acceptable salt thereof, which are structurally characterized in the substituent at the third position of the dihydropyridine nucleus and have stronger activity as compared with the known compounds, for example, as shown above.
Another object of this invention is to provide processes for the preparation of said 2-methyldihydropyridine compound and the salt thereof.
A further object of this invention is to provide a useful pharmaceutical composition comprising, as an active ingredient, said 2-methyl dihydropyridine compound or the pharmaceutically acceptable salt thereof, which is useful, as a vasodilator and anti-hypertensive agents.
Still further object of this invention is to provide a therapeutical method for treatment of cardiovascular disorder such as coronary insufficiency, angina pectoris or myocardial infarction and hypertension.
The 2-methyl-dihydropyridine compound of this invention can be represented by the following formula:
wherein R' is phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2-thienyl, R2 is propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methyl-am ino )ethyl, R3is lower alkyl, and R4 is di(lower)alkoxymethyl, formyl, hydroxymethyl or cyano, provided that, when R1 is 3-nitrophenyl, then R2 is 2-hydroxyethyl and R4 is cyano or formyl, or R2 is propyl or isopropyl.
With regard to the object compound of the above formula (I), it is to be understood that there can be a pair of two optical isomers due to the asymmetric carbon atom at the fourth position of the dihydropyridine nucleus, and accordingly, this type of isomers are to be included within the scope of this invention and represented by the same formula (I), inclusively.
According to this invention, the object compound (I) can be prepared by the processes as illustrated by the following schemes.
(I) Construction of fundamental structure: (1) Process 1:
wherein R1 and R3 are each as defined before, Fla2 is propyl, isopropyl, 2-chloroethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N- methylamino)-ethyl and R4a is di(lower)alkoxymethyl, provided that when R' is 3-nitrophenyl, then R2 is propyl or isopropyl.
(2) Process 2
wherein R1, Fla2, R3 and Ra4 are each as defined before, provided that, when R' is 3-nitrophenyl, then Ra is propyl or isopropyl.
(11) Transformations of a functional group: (3) Process 3:
wherein Fl1, R2, R3 and Fl44 are each as defined before, provided that, when R' is 3-nitrophenyl, then R2 is propyl, isopropyl or 2-hydroxyethyl.
(4) Process 4:
wherein R1, R2 and R3 are each as defined before, provided that, when R' is 3-nitrophenyl, then R2 is propyl or isopropyl.
(5) Process 5:
wherein R' and R3 are each as defined before, and Rb is propyl, isopropyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-Nmethylamino)ethyl, provided that, when R' is 3-nitrophenyl, then Rb is propyl, isopropyl or 2-hydroxyethyl.
(6) Process 6:
wherein R1 and R3 are each as defined before, and Re is acyl.
(7) Process 7:
wherein R', R3 and Ra are each as defined before, provided that, when R' is 3-nitrophenyl, then R2 is propyl or isopropyl.
"Lower alkyl" for R3 includes C,-C6 alkyl, preferably C,-C3alkyl and more preferably normal straight ones such as methyl, ethyl, propyl or the like.
"Di(lower)alkoxymethyl" for R4 and Ra4 includes di(C,-C6 straight and branched chain lower alkoxy)-methyl, preferably C1-C3 ones such as dimethoxymethyl, diethoxymethyl, dipropoxymethyl or the like.
"Acyl" for Re includes a conventional one, preferably alkanoyl, and more preferably lower alkanoyl such as C1-C6 alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, etc.), or the like.
The starting compounds (II-1) and (11-2) used in Processes 1 and 2 include new and known ones and new ones can be prepared by reacting 4-substituted acetoacetate (IIA) or (I 1A') and aldehyde (IIB) as shown in the following reaction schemes according to a conventional manner.
wherein R1, R3 and Ra4 are each as defined before.
wherein R1 and Ra2 are each as defined before.
The other starting compounds (III-1) and (111-2) used in Processes 1 and 2 can be prepared from a 4-substituted acetoacetate compound (IIIA) or (IIIA') and ammonia or a salt thereof as shown in the following reaction schemes.
wherein Ra is as defined before.
wherein R3 and Ra4 are each as defined before.
Further, the starting compound (IIc) used in Process 6 can be prepared by the method as shown in the following reaction scheme, and the compound (1-8) can be prepared according to the similar manner to those of Process 2 and followed by the Process 3 as mentioned above.
wherein R, R and R#2 are each as definedd before.
Processes for preparation of the 2-methyl-dihydropyridine compound (1) will be explained in details below.
(1) Process 1: This process relates to a method for preparing a compound (I-I') by reacting a compound (Il-i) with an amino compound (111-1).
Each of the starting compounds (II-1) and (III-1) includes cis and trans geometrical isomers due to the double bond i their molecules, and according to this process, the compound (1-1') can be preparedd by any sequence of the reaction of either geometrical isomers of compound (Il-i) with either ones of the compound (111-1), and accordingly all isomers and optional mixtures of the isomers of these starting compounds (11-1) and (Ill-i) are to be included within the scope of this process.
The reaction can be carried out at ambient temperature or under warming or heating. The reaction can preferably be conducted in the absence of a solvent, but may be conducted in a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, or other conventional solvents. The reaction can preferably be accelerated in the presence of an agent such as an acid (e.g. acetic acid), a base (e.g. pyridine or picoline) or in a conventional buffer solution. These agents act as a reaction accelerator and may also be used as a solvent in case that they are in liquid. The reaction can also be accelerated by warming or heating. The reaction condition may vary according to the kind of the reactants, solvent and/or other agent as mentioned above to be used.
As to the reaction mode of this Process, it is to be noted that it can alternatively be conducted, for example, by reacting the 4-substituted acetoacetate compound (lIA), with the aldehyde (rib) in the presence of the amino compound (111-1).
(2) Process 2: This process relates to a method for preparing a compound (1-2) by reacting a compound (11-2) with an amino compound (1)1-2).
This process is substantially the same as Process 1, and accordingly can be conducted by reacting the compound (11-2) with (111-2) in the same manner as those for the Process 1. That is, the same reaction conditions (e.g. reaction temperature, solvent, accelerator, etc.) and the same alternative reaction procedure as mentioned in the Process 1 are also applied to this process, provided that the compound (11-2) or alternative reactants (IlA') and (IIB), and the compound (111-2) are used in this process instead of using the compound (11-1) or alternative reactants (IIA) and (IIs), and the compound (Ill-i) in the Process 1, respectively.
(3) Process 3: This process relates to a method for preparing a compound (1-3) by hydrolysing a compound (1-1).
The compound (I-i) can be prepared by the method as illustrated in the above (Processes 1 and 2).
In this process, the di(lower)alkoxymethyl group for R4 of the compound (I-i) is transformed into a formyl group.
Hydrolysis may be carried out in a conventional manner which is applicable to cleavage of a so-called acetal function into the corresponding carbonyl function, and preferably, for example, an acidic hydrolysis, i.e. in the presence of an acid such as an inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) or an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.), or an acidic ion-exchange resin.
This hydrolysis may be carried out in a suitable conventional solvent such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, N,N-dimethylformamide, or dimethylsulfoxide, an optional mixture thereof or a buffer solution thereof. The reaction temperature is not restrictive, and the reaction is usually conducted under cooling, at room temperature or under somewhat elevated temperature.
(4) Process 4: This process relates to a method for preparing a compound (1-4) by reducing the compound (1-3).
The reduction can be carried out in a conventional manner which can be applied to reduction of a formyl group into a hydroxymethyl group, and particularly, the reduction is conducted by using a reducing agent such as an alkali metal borohydride (e.g. lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, etc.) or by catalytic reduction for which preferable catalyst may be palladium carbon, palladium chloride or rhodium carbon and the like. The reduction is usually carried out in a conventional solvent such as water, methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran, etc., and the like. The reaction temperature is not restrictive, and the reaction is usually carried out under cooling, at room temperature or at somewhat elevated temperature.And, the method of reduction may optionally be selected according to the kind of the compound (1-3).
(5) Process 5: This process relates to a method for preparing a compound (1-5) by reacting a compound (1-3') with hydroxylamine or a salt thereof, and then reacting the resultant product with a dehydrating agent.
According to this process, the formyl group of the starting compound (1-3') may be transformed into the hydroxyiminomethyl group (the first step), and in succession said group is transformed into the cyano group (the second step).
Preferably salt of hydroxylamine may be a salt with an acid such as an inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) or an organic acid (e.g. acetic acid, etc.).
(i) The first step: The reaction of this step is carried out in a usual manner as so-called oximation reaction, for example, in the presence of an acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, silicon tetrachloride or titanium tetrachloride); in a basic condition.
brought about by a base, for example free hydroxylamine; or in an acidic or basic conventional buffer solution. The reaction is usually conducted in a suitable conventional solvent such as water, dioxane, ethanol, methanol, dimethylformamide or an optional mixture thereof, and in case that the above acid is in liquid, it can also be used as a solvent.
The reaction temperature is not restrictive, and the reaction is usually carried out under cooling, at room temperature or under somewhat elevated temperature.
The reaction product of the first step is subjected to the following second step with or without isolation and/or purification.
(ii) The second step: Suitable dehydrating agent used in this step includes conventional organic or inorganic ones such as inoganic acid (e.g. sulfuric acid, phosphoric acid, polyphosphoric acid, etc.), an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.), an organic acid anhydride (e.g. acetic anhydride, benzoic anhydride, phthalic anhydride, etc.), an organic acid halide (e.g. acetyl chloride, benzoyl chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate, phenylchloroformate, etc.); an inorganic halogen compound (e.g. thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, stannic chloride, titanium tetrachloride, etc.); a carbodiimide (e.g.N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino-ethylcarbodiimide, etc.), N,N '-carbonyldiimidazole; pentamethyleneketene-N-cyclohexylimine; ethoxyacetylene; 2-ethyl-7hydroxyisoxazolium salt; other phosphorus compound (e.g. phosphorus pentoxide, polyphosphoric acid ethyl ester, triethylphosphate or phenylphosphate) and the like or an optional mixture thereof. When an acid is used as the dehydrating agent, the reaction can also be conducted in the presence of its salt such as an alkali metal salt (e.g. sodium salt or potassium salt), or the like.
This reaction is usually carried out in a conventional solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, dioxane, and the like, and usually carried out at room temperature or under heating, but the reaction temperature is not restrictive to the above.
(6) Process 6: This process relates to a method for preparing a compound (1-6) by hydrolysing a compound (llc).
In this process, the acyl group for R2 of the compound (llc) is eliminated by hydrolysis to give the 2-hydroxyethyl compound (1-6).
Hydrolysis is carried out in a conventional manner which is conventionally applied to a cleavage of a so-called ester bond into the hydroxy function, and is preferably carried out, for example, by a basic hydrolysis, i.e. in the presence of a base such as an alkali metal hydroxide, carbonate or bicarbonate, (e.g.
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.) or by an acidic hydrolysis in the presence of an organic or inorganic acid, suitable examples thereof include those given in the above-mentioned Process 3.
This hydrolysis may preferably be carried out in a conventional solvent such as water, acetone, dioxane, methanol, ethanol, dimethylformamide, dimethylsulfoxide, or an optional mixture thereof. The reaction temperature is not restrictive, and the reaction is usually conducted at room temperature or under heating.
(7) Process 7: This process relates to a method for preparing a compound (1-7) by reacting a compound (lID) with N-methyl benzylamine.
The reaction is usually carried out in a suitable solvent such as chloroform, methylene chloride,benzene, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, methanol, ethanol, propanol, isopropanol,water and other conventional solvent or an optional mixture thereof.
This reaction can also be carried out in the presence of a base, suitable examples of which include an inorganic base such as an alkali metal hydroxide, carbonate bicarbonate, hydride or amide (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium amide, etc.) or an organic base such as an alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide, etc.), a salt of an organic acid (e.g. sodium acetate, potassium acetate, etc.), a tertiary amine or imine base (e.g. triethylamine, pyridine, picoline, N,Ndimethylaniline, N-methylpyrolidine,N-methylmorpholine, etc.) and the like.
Further, this reaction is preferably carried out in the presence of an alkali metal iodide such as iithium iodide, sodium iodide or the like in addition to the base.
The reaction temperature is not restrictive, and the reaction is usually carried out at room temperature, or under warming or heating.
According to this invention, the object reaction product can be separated and isolated from the reaction mixture and purified by methods commonly used for this purpose, for instance, extraction with suitable solvent, chromatography, precipitation, recrystallization and so on.
Suitable examples of a salt of the 2-methyl-dihydropyridine compound (I) include a pharmaceutically acceptable salt such as an inorganic acid salt (e.g. hydrochloride, hydrobromide, phosphate, sulfate, etc.) and an organic acid salt (e.g. formate, acetate, fumarate, maleate, aspartate, glutamate, etc.).
The compound (I) thus obtained frequently includes at least one pair of optical isomers due to the presence of an asymmetric carbon atom of the fourth position of the 1,4-dihydropyridine nucleus and can exist as each optical isomer or a mixture thereof. A racemic compound can be resolved into each optical isomer by a conventional method for racemic resolution, such as a chemical resolution of the salts of the diastereomer with a conventional optically active acid (e.g. tartaric acid or camphor sulfonic acid, etc.).
It is to be noted that the compound (I) and a pharmaceutically acceptable salt thereof possess a strong vasodilating and anti-hypertensive activities and useful for therapeutical treatment in cardiovascular disorder and hypertension such as coronary insufficiency, angina pectoris or myocardial infarction, and hypertension.
Particularly, the strong pharmacological activities of the compound (I) according to this invention is structurally characterized by the radical R2, specifically selected from the group consisting of propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl and 2-(N-benzyl N-methylamino)ethyl.
More particularly, the compound (I), wherein, for example, if Ra is 3-nitrophenyl or 2-chlorophenyl, R2 is isopropyl, R3 is methyl and R4 is cyano, and ii) R1 is 2-trifluoromethylphenyl, R2 is isopropyl or 2-phenoxyethyl, R3 is methyl and R4 is hydroxymethyl or cyano, possesses stronger therapeutical effects as mentioned above, as compared with the known compound as mentioned hereinbefore.
Further, the compound (I), wherein, for example, iii) Rn is 3-nitrophenyl or 2-chlorophenyl, R2 is isopropyl, R3 is methyl and R4 is dimethoxymethyl or formyl, and iv) R1 is 2-trifluoromethylphenyl, R2 is isopropyl or 2-phenoxyethyl, R3 is methyl or ethyl and R4 is dimethoxymethyl, diethoxymethyl orformyl, is useful not only as vasodilating and anti-hypertensive agents but also as an intermediate for preparing the more preferable vasodilating and anti-hypertensive agents of this invention as illustrated hereinabove.
For therapeutical purpose, the 2-methyl-dihydropyridine compound (I) is administered in daily dose of 0.1 to 500 mg, preferably 1 to 50 mg.
The pharmaceutical compositions of this invention comprise, as an active ingredient, the 2-methyldihydropyridine compound (I) or pharmaceutically acceptable salt thereof in an amount of about 0.01 mg. to about 500 mg., preferably about 0.1 mg. to about 250 mg. per dosage unit for oral and parenteral use.
One skilled in the art will recognize that the amount of the active ingredient in the dosage unit form may be determined by considering the activity of the ingredient as well as the size of the host human being. The active ingredient may usually be formulated in a solid form such as tablet, granule, powder, capsule, troche, lozenge or suppository, or a suspension or solution form such as syrup, injection, emulsion, lemonade, etc.
and the like. A pharmaceutical carrier or diluent includes solid or liquid non-toxic pharmaceutically acceptable substances. Examples of solid or liquid carriers or diluents are lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil or sesame oil, cacao butter, ethyleneglycol or the other conventional ones. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate, glyceryl distearate, a wax and the like.
For the purpose of showing the utility of the compound (I), the pharmacological test results of some represented compounds will be shown as follows.
Hypotensive effect: Test method; Five Wistar rats were used per group. Each animal was immobilized in a cage sized to the body. Blood pressure was measured at the femoral artery by means of a pressure transducer and recorded as electrically integrated values of mean arterial pressure, and heart rate was determined by a pulse wave detector.
Operation for the catheterization was performed under light anesthesia with ether. The test compound was administered orally 3 hours after completion of the operation.
Test compound; Compound A-1 : Nifedipine (reference compound) Compound B : Isopropyl ester of 6-cyano-5-methoxy carbonyl-2-methyl-4-(3-nitrophenyl) 1,4-dihydropyridine-3-carboxylic acid.
Compound C Isopropyl ester of 4-(2-chlorophenyl) 6-cyano-5-methoxycarbonyl-2-methyl 1,4-dihydropyridine-3-carboxylic acid.
Compound D Isopropyl ester of 6-cyano-4-(2 trifluoromethyl phenyl)-5-methoxy carbonyl-2-methyl-i ,4-dihydropyridine 3-carboxylic acid.
Compound E 2-Phenoxyethyl ester of 6-cyano-4 (2-trifluoromethylphenyl)-5-ethoxy carbonyl-2-methyl-1 ,4-dihydropyridine 3-carboxylic acid.
Compound F Isopropyl ester of 4-(2-trifluoromethyl phenyl)-6-hydroxymethyl-5-methoxy carbonyl-2-methyl-1 ,4-dihydropyridine 3-carboxylic acid.
Compound G 2-Phenoxyethyl ester of 4-(2-trifluoro methylphenyl)-5-ethoxycarbonyl-6- hydroxymethyl-2-methyl-1 ,4-dihydropyridine 3-carboxylic acid.
Test results; Mean values of A Maximum Decrease of blood pressure (mmHg) were shown in the following table.
TABLE 1 Dose 1 mg/kg 10 mg/kg Compound A-1 -25.6#1.5 -44.6#1.2 B -44.6 + 1.7 50.0 + 1.3 C -29.2#3.0 -40.6#2.2 D -34.610.9 47.4# 1.3 E -22.8#2.1 -44.2#1.5 F -18.011.9 -46.6 + 2.1 G -13.2#3.3 -47.8#2.4 Effect of coronary blood flow: Test method: Mongrel dogs, weighing 8-15 kg, were anesthetized with an intrapectoneal dose of pentobarbital sodium 35 mg/kg. After the thorax was opened under artificial respiration, a flow-meter probe was fitted to the left cicumflex branch of the coronary artery. The blood pressure was measured in the femoral artery, and the object compound of this invention were injected intravenously.The values at peak blood flow were measured.
Test results; TABLE 2 Increase of coronary blood flow (%) The value indicate percentages compared to control.
Dose Fg/kg 10 100 Test Compounds A-l 89 72 B 181 219 The following examples are given for the purpose of illustrating this invention.
Preparation of the starting compounds for processes 1 and2 Preparation 1 1) To a solution of 3-nitrobenzaldehyde (7.56 g) and methyl 4,4-dimethoxyacetoacetate (7.93 g) in dried benzene (30 ml) were added acetic acid (0.18 g) and piperidine (0.17 g), and the mixture was heated under reflux for 3.5 hours, while azeotropically removing the water formed therefrom. After adding benzene to the reaction mixture, the solution was washed successively with water, diluted aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, in turn and then dried.Removal of the solvent under reduced pressure gave an oily residue (15.74 g), which was chromatographed over silica gel (470 g) with a mixture of benzene and ethyl acetate (25:1 by volume as an eluent to give a yellow oil (8.06 g) of methyl 4,4-dimethoxy-2-(3-nitrobenzylidene)-acetoacetate (a mixture of cis and trans isomers).
N.M.R. 6 ppm (CDCt3): 3.45 (s) } (6H), 3.48 (s) 3.88 (s) 4.90 (s) } (3H) } (1 H), 3.91 (s) 5.08 (s) 7.25 - 8.4 (5H, m).
The following compounds were obtained in substantially the same manner as that of Preparation 1.
2) Methyl 4,4-dimethoxy-2-(2,methylbenzylidene)-acetoacetate (a mixture of cis and trans isomers).
N.M.R. #ppm (CDCf : 2.33 (3H, s), 3.23 (s) )(6H), 3.42 (s) 3.64 (S) 4.53 (S) # (3H), # (1H), 3.79 (S) 5.04 (S) 6.8-7.4 (4H, m), 7.97 (s) }(1H) 8.09 (s) 3) Methyl 2-(2-chlorobenzylidine)-4,4-dimethoxy- acetoacetate (a mixture of cis and trans isomers).
N.M.R. #ppm(CD#3): 3.28(s) } (6H), 3.41(s) 3.71 (s) 4.68(s) } (3H), } (1H), 3.81 (s) 5.08(s) 7-7.5 (4H, m), 8.02 (s) }(1H).
8.12 (s) 4) Methyl 4,4-dimethoxy-2-(4-pyridylmethylene)-acetoacetate (a mixture of cis and trans isomers).
N.M.R. #ppm(CDCl3): 3.41(s) } (6H), 3.48 (s) 3.82 (s) 4.82 (s) }) (3H), 3.89 (5) 5.06(s) 7.1-7.4(2H,m), 7.73 (s) } (1H), 7.83 (s) 8.5-8.8 12H, m).
5) Methyl 2-(2-trifluoromethylbenzylidene)-4,4-dimethoxyacetoacetate (a mixture of cis and trans isomers).
N.M.R. #popm(CDCl3): 3.28 (s) } (6H), 3.42 (s) 3.61 (s) 4.62 (s) } (3H), 3.84 (s) 5.06 (s) 7.2-7.8 (4H, m), 8.0-8.14(1H, m).
6) Methyl 4,4-dimethoxy-2-(2-methoxybenzylidene)-acetoacetate (a mixture of cis and trans isomers).
N.M.R. #ppm (CDCl3): 3.39 (s) } (6H), 3.47 (s) 3.78 (s) 4.77 (s) } (6H), 3.88 (s) 5.16 (s) 6.7-7.2 (m) 8.15 (s) }(4H), } (1H).
7.3-7.9 (m) 8.23 (s) 7) Methyl 2-(2-allyloxybenzylidine)-4,4-dimethoxy-acetoacetate (a mixture of cis and trans isomers).
N.M.R. #ppm(CDCl3): 3.3 (s) 3.4 (s) 3.73 (5) 4.54 (2H, m), } (3H), 3.78 (s) 4.71 (s) 5.1-5.5 (2H, m), 5.07 (s) 5.8-6.22 (1H, m), 6.7-7.0 (m) }(4H), 7.2-7.4 (m) 8.14 (s) }(lH).
8.23 (s) 8) Methyl 4,4-dimethoxy-2-(2-thenylidene)acetoacetate (a mixture of cis and trans isomers).
N.M.R. 5ppm CDCl3): 3.45 (6H, s), 3.88 (s) 3.95 (s) 5.11(s) 7-7.8 (3H, m), 5.17 (s) 7.93 (s) }(1H).] 8.06 (s) 9) Methyl 2-(2,4-dichlorobenzylidine]-4,4-dimethoxy-acetoacetate (a mixture of cis and trans isomers).
N.M.R. #ppm (CDCl3): 3.39 (s) 3.47 (s) 3.77 (5) 4.77 (s) } (3H), 3.88 (5) 5.01 (s) 7.2-7.5 (3H, m), 7.97 (s) }(1H).
8.08 (s) 10) Methyl 2-[3,4-dichlorobenzylidene]-4,4-dimethoxyacetoacetate (one of cis and trans isomers), mp 86.5-87.5 C.
11) Methyl 4,4-dimethoxy-2-(3,4-dimethoxybenzylidene)-acetoacetate (a mixture of cis and trans isomers).
N.M.R. 5ppm (CDCl3): 3.43 (s) 3.49 (s) 3.87 (s) 4.87 (s) 3.92 (s) 3.93 (s) (9H), 5.10 (s) 3.97 (s) 6.6 - 7.4 (3H, m), 7.80 (s) }(1H).
7.89 (s) 12) 2-Phenoxyethylester of 2-(2-trifluoromethyl-benzylidene)acetoacetic acid (a mixture of cis and trans isomers).
N.M.R. #ppm (CDCl3): 2.18(s) } (3H), 2.47 (s) 3.9-4.9 (4H, m), 6.8-8.2 |10H. m).
13) 2-Chloroethyl ester of 2-(2-trifluoro-methylbenzylidene)acetoacetic acid (a mixture of cis and trans isomers).
N.M.R. #ppm(CDCl/3): 2.18 (s) } (3H), 2.46 (s) 3.50 (t, J=6Hz) }(2H), 3.76 (t, J=6Hz) 4.34 (t,J=6Hz) 7.3-7.9(4H,m), }(2H), 4.51 (t,J=6Hz) 7.95 (q, J=2.2Hz) }(1H).
8.04 (q, J=2.2Hz) 14) 2-Ethoxyethyl ester of 2-(2-trifluoromethyl-benzylidenelacetoacetic acid (a mixture of cis and trans isomers).
N.M.R. #ppm (CC(4l : 1.10 It, J=7Hz) )(3H), 1.18 (t, J=7Hz) 2.11(s) 3.1-3.8 (4H, m), 1 (3H), 2.38 (s) 4.1-4.5 (2H, m), 7.3-8.0 (5H, m).
15) 2-Benzyloxyethyl ester of 2-(2-trifluoro-methylbenzylidene]acetoacetic acid (a mixture of cis and trans isomers).
N.M.R. #ppm(CC/4): 2.10 (s) 3.4-3.9(2H,m), )(3H), 2.37 (s) 4.1-4.7 (m) 7.2-8.0 (10H, m) 4.37 Is) (4H), 4.53 (s) Preparation of the object compounds for this invention: Example 1 1) A mixture of methyl 4,4-dimethoxy-2-(3-nitrobenzylidene)acetoacetate (8.0 9) and isopropyl 3aminocrotonate (4.07 g) was heated at 70 C for an hour with stirring, and the stirring was continued at 100 C for an hour and at 120 C for additional 2.5 hours.After dissolving the reaction mixture in ethyl acetate, the solution was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give a yellow-orange oil (11.03 g) of isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3carboxylic acid.
N.M.R. #ppm (CDC/3): 1.13(d,J=7.0Hz) )(6H) 1.27 (d, J=7.OHz) 2.40 (3H, s), 3.47 (s) }(6H1, 3.50 (s) 3.69 (3H, s), 5.0 (1H, heptet, J=7.0Hz), 5.17 (1H,s) 6.92 (1 H, broad s), 7.2-8.2 (4H, m).
2) isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-phenyl-1,4-dihydropyridine-3- carboxylic acid was prepared by reacting methyl 2-benzylidene-4,4-dimethoxyacetoacetate, which was obtained from benzaldehyde and methyl 4,4-dimethoxyacetoacetate according to the same manner as that of Preparation 1, with isopropyl 3-amino-crotonate in substantially the same manner as that of Example 1-1).
N.M.R. #ppm(CDCl3):1.11 (3H,d,J=6.5Hz), 1.23 (3H, d, J=6.5Hz),2.37 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 4.96 (1 H, heptet, J=6.5Hz),5.03 (1 H, s), 6.03 (1 H, s), 6.73 (1 H, s).7.0-7.4 (5H, m).
The following examples are prepared in substantially the same manner as that of Example 1-1).
3) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-tolyl )-1 ,4-dihydropyridine-3carboxylic acid.
N.M.R. 5ppm (CDCl3): 1.07 (3H, d, J=6.5Hz), 1.21 (3H,d,J=6.5Hz),2.32(3H,s), 2.55 (3H, s), 3.41 (3H, s), 3.44 (3H, s), 3.62 (3H, 5), 4.96 (1 H, heptet, J=6.5Hz), 5.20 (1 H, s), 5.97 (1 H, s), 6.65 (1 H, s),6.9-7.4 (4H, m).
4) Isopropyl ester of 5-methoxyca rbonyl-6-dimethoxymethyl-2-methyl-4-(4-pyridyl )-1.4-dihydropyridine- 3-carboxylic acid, mp 115-117 C.
5) Isopropyl ester of 4-(2-chlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 86-87.5 C.
6) Isopropyl ester of 4-(2-trifl uoromethylphenyl )-5-methoxywarbonyl-6-dimethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 92-94 C.
7) Isopropryl ester of 5-methoxyca rbonyl-6- dimethoxymethyl-4-(2-methoxyphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 110-111.5 C.
8) Isopropylester of 4-(2-allyloxyphenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.01 (3H,d,J=6.5Hz), 1.21 (3H, d, J=6.5Hz),2.33 (3H, s), 3.46 (6H, s), 3.63 (3H, s), 4.4- 6.3 (8H, m), 6.60 (1 H, broad s), 6.7-7.5 (4H, m).
9) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-thienyl)-1,4-dihydro- pyridine-3-carboxylic acid.
N.M.R. #ppm (CDCl3) : 1.22 (3H,d,J=6.5Hz), 1.28 (3H, d, J=6.5Hz), 2.37 (3H, s), 3.43 (3H, s),3.49 (3H, s),3.76 (3H, s), 5.07 (1 H, heptet, J=6.5Hz), 5.38 (1 H, s), 6.04(1 H, s),6.65-7.45 (4H, m).
10) Isopropyl ester of 4-(2,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. 5ppm (CDCf3):1.07 (3H, d, J=6.5Hz), 1.21 (3H, d, J=6.5Hz), 2.34 (3H, s), 3.42 (3H, s),3.46 (3H, s), 3.64 (3H, s), 4.97 (1 H, heptet, J=6.5Hz),5.39(1H, s), 5.96 (1 H, s), 6.65 (1 H, s),7.0-7.4 (3H, m).
11) Isopropyl ester of 4-(3,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3): 1.18(d,J=6.5Hz) } (6H), 1.25 (d, J=6.5Hz) 2.39 (3H,2)P,3.46 (3H, s), 3.50 (3H, s), 3.70 (3H, s), 5.00 (1 H, s), 5.00 (1H, heptet, J=6.5Hz), 6.03 (1 H, s), 6.75 (1 H, s), 7.0-7.5 (3H, m).
12) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-4(3,4-dimethoxyphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.16(3H,d,J=6.5Hz), 1.25 (3H, d, J=6.5Hz),2.37 (3H, s), 3.41 (s) 3.43 (s) 3.45 (s) (6H), 3.49(s) 3.79 (3H, s), 3.84 (6H, s),4.99 (1 H, s), 4.99 (1 H, heptet, J=6.5Hz),6.03 (1 H, s), 6.6-7.3 (4H, m).
13) Dipropyl ester of 2-methyl-4-(3-nitrophenyl)-6-dipropoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid.
N.M.R. #ppm(CDCl3):2.37 (3H,s),5.02 (1H,s), 6.21(1 H, s), 6.88 (1 H, broad s).
14) 2-( N-Benzyl-N-methylam ino)ethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethyl- phenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.1-1.3(9H,m).2.17 (3H, s), 2.33 (3H, s), 2.60 (2H, t, J=6Hz), 3.48 (2H, s),.3.4-4.4 (8H, m), 5.63 (1H,s),6.13(1H,s),6.71 (1H, s),7.1-7.6(9H,m).
15) 2-Phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl- 1,4-dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3): 1.0 to 1.5 (9H,m), 2.37 (3H, s),3.5-4.6(10H, m), 5.67 (1H, s),7.12 (1H, s),6.7-7.8 (10H, m).
16) 2-Chloroethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4dihydropyridine-3-carboxylic acid.
N.M.R. bppm (CC(4) :1.0-1.5 (6H, m), 2.39 (3H, s),3.4-4.5 (10H, m), 5.5-5.7 (1H,m),6.10(1H,s),6.55(1H,s), 7-7.6 (4H, m).
17) 2-Ethoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1 ,4dihydropyridine-3-carboxylic acid.
N.M.R. #ppm (CC(4) : 1.0-1.4(12H, m), 2.38 (3H, s),3.3-4.3 (12H, m), 5.5-5.7 (1H,m). 6.10 (1H,s), 6.47 (1 H, s), 7.2-7.7 (4H, m).
18) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl- 1,4-dihydropyridine-3-carboxylic acid.
N.M.R. 5ppm (CDCl3): 1.0-1.6 (9H, m), 2.32(3H,s),3.4-4.4(10H,m), 4.47 (2H, s), 5.6-5.7 (1H, m), 6.11(1H,s),6.6-6.8(1H,broad s), 7.2-7.7 (9H, m).
Example2 1) A mixture of 2-phenoxyethyl ester of 2-(2-trifluoromethylbenzylidene)acetoacetate (19.62 9) and ethyl 2-amino-4,4-diethoxycrotonate (11.95 g) was heated for 20 hours at 100 to 110 C and for additional 12 hours at 120 to 130 C. The resultant mixture was dissolved in ethyl acetate and washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give a crude oil (27.7 g), which was chromatographed over silica gel with a mixture of benzene and ethyl acetate (50:1 by volume) as an eluent to give 2-phenoxyethyl ester of 5-ethoxyca rbonyl-6-diethoxymethyl-4-(2-trifl uoromethylphenyl)-2methyl-14,-dihydropyridine-3-carboxylic acid (19.34 g).
N.M.R. 5ppm (CDCl3): 1.0 to 1.5 (9H, m), 2.37 (3H, s),3.5-4.6(10H, m), 5.67 (1 H, s),7.12 (1 H, s) 6.7 7.8(10H, m).
The following compounds were obtained in substantially the same manner as that of Example 2-1).
2) 2-Chloroethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CCl4): 1.0-1.5(6H,m), 2.39(3H, s), 3.4-4.5(10H,m), 5.6-5.7 (1H,m), 6.10 (1 H, s), 6.55 (1 H, s) 7-7.6 (4H, m).
3) 2-Ethoxyethyl ester of 5-ethoxyca rbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl )-2-methyl-i 4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm (CC64): 1.0-1.4(12H, m), 2.38 (3H, s),3.3-4.3 (12H, m), 5.5-5.7 (1 H, m), 6.10 (1 H, s), 6.47 (1 H, s),7.2-7.7 (4H, m).
4) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifl uoromethyl phenyl )-2-methyl- 1,4-dihydropyridine-3-carboxylic acid.
N.M.R. bppm(CDC,'3) : 1.0-1.6(9H,m), 2.32 (3H, s),3.4-4.4(10H, m), 4.47 (2H, s),5.6-5.7 (1 H, m), 6.11(1 H, s),6.6-6.8(1 H, broad s), 7.2-7.7 (9H, m) 5) 2-(N-Benzyl-N-methylamino)ethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethyl- phenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
N.M.R. bppm (CDCf3): 1.1-1.3 (9H, m), 2.17 (3H, s), 2.33 (3H, s), 2.60 (2H, t, J=6Hz), 3.48 (2H, s),3.4-4.4 (8H, m), 5.63 (1H, s), 6.13 (1H, s), 6.71 (1H,s),7.1-7.6(9H,m).
6) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-14,- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.13(d,J=7.0Hz) } (6H), 1.27 (d, J=7.0Hz) 2.40 (3H,s), 3.47(s) } (6H), 3.50 (s) 3.69 (3H, s), 5.0 (1H, heptet, J=7.0Hz), 5.17 (1 H, s), 6.04 H, s), 6.92(1 H, broad s), 7.2-8.2 (4H, m).
7) Isopropyl ester of 5-methoxycarbonyl-6- dimethoxymethyl-2-methyl-4-phenyl-1 ,4-dihydropyridine-3carboxylic acid.
N.M.R. #ppm(CDCl3): 1.11(3H,d,J=6.5Hz), 1.23 (3H, d, J=6.5Hz0,2.37 (3H, s), 3.42 (3H, s), 3.46 (3H, s),4.96 (1 H, heptet, J=6.5Hz), 5.03 (1H, s), 6.03 (1 H, s), 6.73 (1 H, s), 7.0-7.4 (5H, m).
8) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-tolyl)-1 ,4-dihydropyridine-3carboxylic acid.
N.M.R. appm (CDCl3) :1.07 (3H, d, J=6.5Hz), 1.21 (3H, d, J=6.5Hz),2.32 (3H, s), 2.55 (3H, s), 3.41 (3H, s), 3.44 (3H, s), 3.62 (3H, s), 4.96 (1H, heptet, Jd=6.5Hz), 5.20 (1 H, s), 5.97 (1 H, s), 6.65 H, M, s), 6.9-7.4 (4H, m).
9) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(4-pyridyl)-1 ,4-dihydropyridine.
3-carboxylic acid.
Nujol I.R.v 3300, 3200, 3070, 1710 (shoulder), max 1700, 1650, 1603, 1518, 1278, 1269, 1190, 1090, 960, 782 cm- 10) Isopropyl ester of 4-(2-chlorophenyl)-5-methoxy-carbonyl-6-dimethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 86-87.58C.
11) Isopropyl ester of 4-(2-trifluoromethylphenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
Nujol I.R.v 3400, 1720, 1690, 1653, 1493 max 1319, 1310, 1278, 1206, 1095, 1035, 951, 768cm-.
12) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-4-(2-methoxyphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 110-111.5 C.
13) Isopropyl ester of 4-(2-allyloxyphenyl )-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1 ,4dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.01 (3H,d,J=6.5Hz), 1.21 (3H, d, J=6.5Hz),2.33 (3H, s), 3.46(6H,s), 3.63(3H,s), 4.4-6.3 (8H, m),6.60(1H, broad s), 6.7-7.5 (4H, m) 14) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-thienyl)-1 1-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.22(3H,d,J=6.5Hz), 1.28 (3H, d, J=6.5Hz),2.37 (3H, s), 3.43 (3H, s),3.49 (3H, s), 3.76 (3H, s),5.07 (1 H, heptet, J=6.5Hz), 5.38 (1H, s),6.04 (1H, s),6.65 7.45 (4H, m).
15) Isopropyl ester of 4-(2,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.07(3H, d, J.040466.5Hz), 1.21 (3H, d, J=6.5Hz),2.34 (3H, s), 3.42 (3H, s),3.46 (3H, s), 3.64 (3H, s), 4.97 (1 H, heptet, J=6.5Hz),5.39 (1 H, s), 5.96 (1 H, s), 6.65 (1 H, s),7.0-7.4 (3H, m) 16) Isopropyl ester of 4-(3,4-dich lorophenyl )-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4dihydropyridine-3-carboxylic acid.
N.M.R. #ppm $(CDCl3): 1.18(d,J=6.5Hz) } (6H), 1.25 (d, J=6.5Hz) 2.39 (3H, s), 3.46 (3H, s), 3.50 (3H, s), 3.70 (3H, s), 5.00 (1 H, s), 5.00 (1 H, heptet, J=6.5Hz),6.03 (1 H, s), 6.75 (1 H, s),7.0-7.5 (3H, m).
17) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3):1.16(3H,d,J=6.5Hz).
1.25 (3H, d, J=6.5Hz),2.37 (3H, s), 3.41 (s) 3.43 (s) (6H), 3.45 (s) 3.49 (s) 3.79 (3H, s), 3.84 (6H, s), 4.99 (1 H, s), 4.99(1H,heptet,J=6.5Hz),6.03 (1H,s), 6.6-7.3 (4H, m).
18) Dipropyl ester of 2-methyl-4-(3-nitrophenyl)-6-dipropoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid.
N.M.R. bppm (CDC'3) : 2.37 (3H, s),5.02 (1 H, s), 6.21(1 H, s),6.88 (1 H, broad s).
Example 3 1) To a solution of 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid (15.85 g) in acetone (159 ml) was added 6N hydrochloric acid (15.85 ml) at ambient temperature with stirring and the stirring was continued for 1.5 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, and the acetone was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and then dried. Removal of the solvent gave an oil (13.56 g) of 2-phenoxyethyl ester of 5-ethoxycarbonyl-4-(2trifluoromethylpheny)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. #ppm (CDCf 3): 1.22 (3H, t, J=7.5Hz), 2.40 (3H, s),4.0-4.6 (6H, m), 5.71(1 H, s),6.7-7.7 (10H, m), 10.26 (1H, s).
The following compounds were prepared in substantially the same manner as that of Example 3-1).
2) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid.
3) Isopropyl ester of 6-formyl-5-mothoxycarbonyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylic acid,mp 143-144 C.
4) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3- carboxylic acid, mp 143-145"C.
5) Isopropyl ester of 4-(2-chlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3- carboxylic acid, mp 102-103 C.
6) Isopropyl ester of 4-(2-trifluoromethylphenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1 ,4dihydropyridine-3-carboxylic acid, mp 83-85 C.
7) Isopropyl ester of 64ormyl-5-methoxycarbonyl-4-(2-methoxyphenyl)-2-methyl-1 ,4-dihydropyridine-3- carboxylic acid, mp 142-143 C.
8) isopropyl ester of 4-(2-allyloxyphenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3carboxylic acid, mp 103-104.5 C.
9) isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3carboxylic acid, mp 114-116 C.
10) Isopropyl ester of 4-(2,4-dichlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine3-carboxylic acid.
N.M.R. #ppm(CDCl3): 1.07 (3H,d,J=6.5Hz).
1.24 (3H, d, J=6.5Hz), 2.39 (3H, s), 3.71 (3H, s),4.98 (1 H, heptet, J=6.5Hz),5.51 (1H, s), 6.93 (1H, s), 7.0-7.4(3H,m), 10.34 (1H,s).
11) Isopropyl ester of 4-(3,4-dichlorophenyl)-6-formyl-5-methoxycarbonyl-2-mothyl-1,4-dihydropyridinc- 3-carboxylic acid, mp 95-96"C.
12) Isopropyl ester of 6-formyl-5-methoxyca rbonyl-4-(3,4-di methoxyphenyl )-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDC@3): 1.14(3H,d,J=6.5Hz), 1.26 (3H, d, J=6.5Hz), 2.40 (3H, s), 3.78 (3H, s), 3.84 (6H, s), 4.98 (1 H, heptet,J=6.5Hz),5.05(1H,s), 6.5-7.3 (4H, m), 10.44(1H,s).
13) Dipropyl ester of 6-formyl-2-methyl-4-(3-nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid.
N.M.r. #ppm (CDC@3) : 0.87 (3H, t, J=7.5Hz), 0.90 (3H, t, J=7.5Hz),1.55 (2H, sixtet, J=7.5Hz), 1.61 (2H, sixtet, J=7.5Hz),2.44 (3H, s), 4.02 (2H, t, J=7.5Hz), 4.13(2H,t,J=7.5Hz), 5.28(1H,s),7.11(1H,broad s), 7.4-8.2 (4H, m), 10.56(1 H, s).
14) 2-Hydroxyethyl ester of 5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine3-carboxylic acid.
N.M.R. bppm (CDC(3) : 5.25 (1H, s), 10.50 (1H, s).
15) 2-Ethoxyethyl ester of 5-ethoxycarbonyl-6-formyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid.
N.M.R. #ppm(CDCl3): : 1.14(t,J=7Hz) } (6H), 1.26 (t, J=7Hz) 2.43 (3H, s),3.3-3.8 (4H, m), 4.0-4.5 (4H, m),5.7-5.8 (1H, m), 6.8-7.0 (1H, m), 7.1-7.8 (4H, m), 10.27 (1H, s).
16) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-64ormyl-4-(2,trifluoromethylphenyl)-2-methyl-1 ,4dihydropyridine-3-carboxylic acid.
N.M.R. 6ppm(CCt4): 1.23 (3H, t, J=7.5Hz), 2.40 (3H, s),3.4-4.5 (6H, m), 4.41 (2H, s),5.7-5.8 (1H, m), 6.8-6.9 (1H, m),7.2-7.8 (9H, m), 10.28 (1H, s).
17) 2-[N-Benzyl-N-methylamino]ethyl ester of 5-ethoxyCarbonyl-6-formyl-4-(2-trifluoromethylphenyl)-2- methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. 6ppm (CDCt3): 1.23 (3H,t,J=7Hz), 2.19 (3H,s),2.41 (3H,s), 2.63 (2H, t, J=7Hz), 3.51 (2H, s), 4-4.4 (4H, m), 5.71 (1H, broad s), 6.91 H, broad s), 7.2-7.7 (9H, m), 10.28 (lH,s).
Example 4 A mixture of isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4- dihydropyridin-3-carboxylic acid (11.0 g) acid (11.0 g.) and 6N hydrochloric acid (11 ml.) in acetone (110 ml.) was stirred at ambient temperature for 4 hours. After removal of the acetone, water was added to the reaction mixture and adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The resultant aqueous solution was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. The removal of the solvent gave an oily residue, which was immediately solidified to provide crude yellow-orange crystals of isopropyl ester of 6-formyl-5- methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.
NMRappm(CDCI3): :1.13(3H, d, J =7Hz), 1 .28(3H, d, J=7Hz), 1 .79(3H, s),3.80)3H, s),5.02(1 H, heptet, J =7Hz), 5.27(1 H, s), 7.11(1 H, broad s), 7.4-8.2(4H, m), 10.60 (1 H, s) Example 5 1) To a solution of isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3-carboxylate (4.2 g) in ethanol (85 ml) was gradually added portionwise sodium borohydride (0.409 g) over a period of 35 minutes under cooling below 0 C with stirring. After the reaction mixture was acidified with 50% aqueous solution of acetic acid, the ethanol was removed under reduced pressure. To the resultant aqueous suspension was diluted with water and the precipitated pale-yellowish powder was collected by filtration, washed with water and dried.This powder (3.89 g) was recrystallized with ethanol to give a yellow powder (3.05 g) of isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2 methyl-4-(3-nitrophenyl)-l ,4-dihydropyridine-3-carboxylic acid, mp 164-166 C.
The following compounds were prepared in substantially the same manner as that of Example 5-1).
2) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-phenyl-1,4-di ,4-dihydropyridine-3- carboxylic acid, mp 132-133 C.
3) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-(2-tolyl )-1 ,4-dihydropyridine-3carboxylica acid,mp 134-135.5 C 4) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-(4-pyridyl)-1 )-1,4-dihydropyridine-3carboxylic acid, mp 182-183 C (dec.).
5) Isopropyl ester of 4-(2-chlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-i 4- dihydropyridine-3-carboxylic acid, mp 122-123 C.
6) Isopropyl ester of 4-(2-trifl uoromethylphenyl )-6-hydroxymethyl-5-methoxyca rbonyl-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 123-125 C.
7) Isopropyl ester of 6-hydroxymothyl-5-methoxy-carbonyl-4-(2-methoxyphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 142-1 430C.
8) Isopropyl ester of 4-(2-a I lyloxyphenyl )-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid, m p 124-125 C; 9) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3- carboxylic acid, mp 124.5-126 C.
10) Isopropyl ester of 4-(2,4-dichlorophenyl )-6-hydroxymethyl-5-methoxycarbonyl-2-methyl- 1,4- dihydro-pyridine-3-carboxylic acid, mp 150-151 C.
11) Isopropyl ester of 4-(3,4-dichlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4- dihydro-pyridine-3-carboxylic acid, mp 122-1 23"C.
12) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-4-[3,4-dimethoxyphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 123-124"C.
13) Dipropyl ester of 6-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid, mp 118-120"C.
14) 2-Phenoxyethyl ester of 5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl- 1 ,4-dihydropyridine-3-carboxylic acid, mp 148-1 49"C.
15) 2-Ethoxyethyl ester of 5-cthoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1 ,4dihydropyridine-3-carboxylic acid, mp 65-66.5 C.
16) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl- 1,4-dihydropyridine-3-carboxylic acid, mp 104-106"C.
Example 6 1) To a solution of isopropyl ester of 6-formyl-5- methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3-carboxylic acid (4.5 gin acetic acid (35 ml) were added hydroxylamine hydrochloride (0.97 g) and sodium acetate (1.43 g), and the mixture was stirred at ambient temperature for 2.5 hours. After acetic anhydride (4.14 g) was added to this reaction mixture, the mixture was stirred at ambient temperature for 1.5 hours and at 95-100 C for additional 4 hours. The acetic acid and the excess of acetic anhydride were removed in vacuo, followed by adding water to the residue and it was neutralized with a saturated aqueous solution of sodium bicarbonate.This aqueous suspension was extracted twice with ethyl acetate, and the combined extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a reddish-brown oil (4.88 g), which was chromatographed over silica gel (150 g) with a mixture of benzene and ethyl acetate (10:1 by volume) as an eluent to give a crude crystals (2.99 g). These were recrystallized from ethanol to give yellow prisms (1.89 g) of isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1 ,4-dihydropyridine-3-carboxylic acid, mp 148 1500C.
The following compounds were prepared in substantially the same manner as that of Example 6-1).
2) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, mp 130-131"C.
3) Isopropyl ester of 6-cya no-5-methoxyca rbonyl-2-methyl-4-(2,tolyl )-1 ,4-dihydropyridine-3-carboxylic acid, mp 147-149"C.
4) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(4-pyridyl)-1 ,4-dihydropyridine-3carboxylic acid, mp 192-195 C (dec.).
5) Isopropyl ester of 4-(2-chlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3- carboxylic acid, mp 176-177 C.
6) Isopropyl ester of 6-cyano-4-(2-trifluoromethyl-phenyl)-5-methoxycarbonyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 172-173"C.
7) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4-(2-methoxyphenyl)-2-methyl-1 ,4-dihydropyridine-3carboxylic acid, mp 139-140"C.
8) Isopropyl ester of 4-(2-allyloxyphenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3- carboxylic acid, mp 115-116 C.
9) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(2-thienyl)-1 ,4-dihydropyridine-3- carboxylic acid, mp 129-131 C.
10) Isopropyl ester of 4-(2,4-dichlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine- 3-carboxylic acid, mp 141-142 C.
11) Isopropyl ester of 4-(3,4-dichlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1 4-dihydropyridine- 3-carboxylic acid, mp 159-160"C.
12) Isopropyl ester of 6-cya no-5-methoxycarbonyl-4-(3,4-di methoxyphenyl )-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 124.5-125.5"C.
13) Dipropyl ester of 6-cyano-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, mp 138-140"C.
14) 2-Phenoxyethyl ester of 6-cyano-5-ethoxyca rbonyl-4-(2-trifl uoromethyl phenyl )-2-methyl-1 4- dihydro-pyridine-3-carboxylic acid, mp 118-119"C.
15) 2-Hyd roxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl )-1,4-dihydropyridine-3carboxylic acid, mp 150.5-152"C.
16) 2-Ethoxyethyl ester of 6-cyano-5-ethoxyca rbonyl-4-(2-trifl uoromethyl phenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid, mp 104-105"C.
17) 2-Benzyl oxyethyl ester of 6-cyano-5-ethoxy-carbonyl-4-(2-trifl uoromethylphenyl )-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 146-147.5"C.
18) 2-(N-Benzyl-N-methylamino)ethyl ester of 6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2 methyl-i ,4-dihydropyridine-3-carboxylic acid hydrochloride, mp 203-204 C (dec.) Example 7 To a solution of 2-acetoxyethyl ester of 6-cya no-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1 4- dihydropyridine-3-carboxylic acid (1.119 g) in ethanol (20 ml) was added dropwise an aqueous solution (5 ml) of potassium carbonate (0.346 g) under refluxing and stirring for 2 hours.
After cooling, the ethanol was removed in vacuo from the reaction mixture, followed by neutralizing with acetic acid and extracted twice with ethyl acetate. The combined extract was washed with diluted aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and then dried.
The solvent was removed in vacuo to give an oil, which was spontaneously crystallized to obtain crystals (0.94 g) of 2-hydroxyethyl ester of 6-cya no-5-ethoxyca rbonyl-2-methyl-4-(3-nitrophenyl )-1 4- dihydropyridine-3-carboxylic acid, mp 150.5-152"C.
Example 8 A mixture of 2-chloroethyl ester of 5-ethoxy-carbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2- methyl-1,4-dihydropyridine-3-carboxylic acid (5.20 g), N-methyl benzylamine (3.63 g) and sodium iodide (0.2 g) in propyl alcohol (10 ml) was heated under reflux for 4.5 hours. After the solvent was removed in vacuo from the reaction mixture, water and ethyl acetate were added to the residue. The ethyl acetate layer was separated, washed with water and then dried. Removal of the solvent gave a residual oil (6.98 g), which was chromatographed over silica gel (210 g) with a mixture of benzene and ethyl acetate (5:1 by volume) as an eluent to give an oil (3.67 g) of 2-(N-benzyl-N-methylamino)ethyl ester of 5-ethoxycarbonyl-6 diethoxymethyl-4-(2-trifl uoromethylphenyl -2-methyl-i ,4-dihydropyridine-3-carboxylic acid.
N.M.R. á ppm(CDCI3): 1.1-1.3(9H,m), 2.17(3H,s),2.33(3H,s), 2.60(2H,t,J=6Hz),3.48 (2H,s), 3.4-4.4(8H,m), 5.63 (1 H,s),6.13(1 H,s), 6.71(1 H,s). 7.1 - 7.6 (9H,m).

Claims (53)

1. Acompound oftheformula:
wherein R1 is phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2,allyloxyphenyl, 2,4-dichiorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2-thienyl, R2 is propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methyl-amino)ethyl, R3 is lower alkyl, and R4 is di(lower)alkoxymethyl, formyl, hydroxy-methyl or cyano, provided that, when R1 is 3-nitrophenyl, then R2 is 2-hydroxyethyl and R4 is cyano orformyl, or R2 is propyl or isopropyl, and pharmaceutically acceptable salts thereof. ..
2. The compound according to claim 1, wherein R1 is phenyl,3-nitrophenyl, 2-chlorophenyl, 2 trifluommethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-dichlomphenyl, 3,4-dichlorophenyl, 3,4 dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2-thienyl, R2 is propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl,2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methyl-amino)ethyl, R3 is methyl, ethyl or propyl, and .
R4 is dimethoxymethyl, diethoxymethyl, dipropoxymethyl, formyl, hydroxymethyl or cyano.
3. The compound according to claim 2, that is isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2- methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.
4. The compound accbrding to claim 2, that is isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2- methyl-4-phenyl-1 ,4-dihydropyridine-3-carboxylic acid.
5. The, compound according to claim 2, that is isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2 methyl-4-(2-tolyl)-1 ,4-dihydropyridine-3-carboxylic acid.
6. The compound according to claim 2, that is isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2- methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylic acid.
7. The compound according to claim 2, that is isopropyl ester of 4-(2-chlorophenyl)-6-hydroxymethyl-5- methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
8. The compound according to claim 2, that is isopropyl ester of 4-(2-trifluoromethylphenyl)-6 hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
9. The compound according to claim 2, that is isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-4- (2-methoxyphenyl )-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
10. The compound according to claim 2, that is isopropyl ester of 4-(2-allyloxyphenyl)-6-hydroxymethyl- 5-methoxyCarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
11. The compound according to claim 2, that is isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl- 2-methyl-4-(2-thienyl)-1 ,4-dihydropyridine-3-carboxylic acid.
12. The compound according to claim ?, that is isopropyl ester of 4-(2,4-dichlorophenyl)-6- hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
13. The compound according to claim 2, that is isopropyl ester of 4-(3,4-dichlorophenyl)-6 hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
14. The compound according to claim 2, that is, isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl- 4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
15. The compound according to claim 2, that is dipropyl ester of 6-hydroxymethyl-2-methyl-4-(3 nitrophenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid.
16. The compound according to claim 2, that is 2-phenoxyethyl ester of 5-ethoxycarbonyl-4-(2- trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
17. The compound according to claim 2, that is 2-ethoxyethyl ester of 5-ethoxycarbonyl-4-(2- trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
18. The compound according to claim 2, that is 2-benzyloxyethyl ester of 5-ethoxycarbonyl-4-(2 triluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
19. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl 4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.
20. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl- 4-phenyl-1 ,4-dihydropyridine-3-carboxylic acid.
21. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl 4-(2-tolyl)-1 ,4-dihydropyridine-3-carboxylic acid.
22. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl- 4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylic acid.
23. The compound according to claim -2, that is isopropyl -ester of 4-(2,chlorophenyl)-6-cyano-5- methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
24. The compound according to claim 2, that is isopropyl ester of 6-cyano-4-(2-trifluoromethyl-phenyl)-5 methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
25. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-4-(2- methoxyphenyl)-2-methyl-i ,4-dihydropyridine-3-carboxylic acid.
26. The compound according to claim 2, that is isopropyl ester of 4-(2-allyloxyphenyl)-6-cyano-5 methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
27. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl- 4-(2-thienyl)-i ,4-dihydropyridine-3-carboxylic acid.
28. The compound according to claim 2, that is isopropyl ester of 4-(2,4-dichlorophenyl)-6-cyano-5- methoxycarbonyl-2-methyl-1 ,4-dihydro-pyridine-3-carboxylic acid.
29. The compound according to claim 2, that is isopropyl ester of 4-(3,4-dichlorophenyl)-6-cyano-5- methoxycarbonyl-2-methyl-l ,4-dihydro-pyridine-3-carboxylic acid.
30. The compound according to claim 2, that is isopropyl ester of 6-cyano-5-methoxycarbonyl-4-(3,4- dimethoxyphenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
31. The compound according to claim 2, that is dipropyl ester of 6-cyano-2-methyl-4-(3-nitrophenyl)-i 4.
dihydropyridine-3,5-dicarboxylic acid.
32. The compound according to claim 2, that is 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4-(2 trifluoromethylphenyl)-2-methyl-1 ,4-dihydro-pyridine-3-carboxylic acid.
33. The compound according to claim 2, that is 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2 methyl-4-(3-nitrophenyt.)-1 ,4-dihydropyridine-3-carboxylic acid.
34. The compound according to claim 2, that is 2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4-(2trifluoromethyl phenyl )-2-methyl-1 ,4-dihydro-pyridine-3-carboxylic acid.
35. The compound according to claim 2, that is 2-benzyloxyethyl ester of 6-cyano-5-ethoxy-carbonyl-4 (2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
36. The compound according to claim 2, that is 2-(N-benzyl-N-methylamino)ethyl ester of 6-cyano-5 ethoxycarbonyl-4-(2-trifluoromethylphenyl )-2-methyl-1,4-dihydropyridine-3-carboxylic acid hydrochloride.
37. The compound according to claim 2, that is isopropyl ester of 5-methoxycarbonyl-6- dimethoxymethyl-2-methyl-4-(3-nitrophenyí)-1,4-dihydropyridine-3-carboxyiic acid.
38. The compound according to claim 2, that is isopropyl ester of 4-(2-chlorophenyl)-5-methoxycarbonyl- 6-dimethoxymethyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
39. The compound according to claim 2, that is isopropyl ester of 4-(2-trifluoromethylphenyl)-5 methoxycarbonyl-6-di methoxymethyl-2-methyl-i ,4-dihydropyridine-3-carboxylic acid.
40. The compound according to claim 2, that is dipropyl ester of 2-methyl-4-(3-nitrophenyl)-6 dipropoxymethyl-1 ,4-di hydropyridine-3,5-dicarboxylic acid.
41. The compound according to claim 2, that is 2-(N-benzyl-N-methylamino)ethyl ester of 5 ethoxycarbonyl-6-diethoxymethyl-4-(2-trifl uoromethylphenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
42. The compound according to claim 2, that is 2-phenoxyethyl ester of 5-ethoxycarbonyl-6 diethoxymethyl-4-(2-trifluoromethylphenyl 1-2-methyl-i ,4-dihydropyridine-3-carboxylic acid.
43. The compound according to claim 2, that is 2-ethoxyethyl ester of 5-ethoxycarbonyl-6diethoxymethyl-4-(2-trifl uoromethyl phenyl )-2-methyl-l ,4-dihydropyridine-3-carboxylic acid.
44. The compound according to claim 2, that is 2-benzyloxyethyl ester of 5-ethoxycarbonyl-6 diethoxymethyl-4-(2-trifl uoromethylphenyl )-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
45. The compound according to claim 2, that is isopropyl ester of 5-methoxycarbonyl-6-formyl-2-methyl4-(3-nitrophenyl)-1 ,4-dihydropyridine-3-carboxylic acid.
46. The compound according to claim 2, that is isopropyl ester of 4-(2-chlorophenyl)-5-methoxy carbonyl-6-formyl-2-methyl-l ,4-dihydropyridine3-carboxylic acid.
47. The compound according to claim 2, that is isopropyl ester of 4-(2-trifluoromethylphenyl)-5 methoxycarbonyl-64ormyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
48. The compound according to claim 2, that is dipropyl ester of 2-methyl-4-(3-nitrophenyl)-6-formyl-1 4dihydropyridine-3,5-dicarboxylic acid.
49. The compound according to claim 2, that is 2-(N-benzyl-N-methylamino)ethyl ester of 5 ethoxycarbonyl-6-formyl-4-(2-trifl uoromethyl-phenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
50. The compound according to claim 2, that is 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-formyl-4-(2trifluoromethylphenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
51. The compound according to claim 2, that is 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-formyl-4-(2trifluoromethylphenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
52. The compound according to claim 2, that is 2-benzyloxyethyl ester of 5-ethoxycarbonyl-6-formyl-4-(2 trifluoromethylphenyl)-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid.
53. A pharmaceutical composition which comprises, as an active ingredient, the compound claimed in claim 1 in association with pharmaceutically acceptable carrier or diluent.
GB7935022A 1978-10-10 1979-10-09 2-methyl-dihydropyridines Expired GB2036722B (en)

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DE (1) DE2940833A1 (en)
FR (1) FR2438654A1 (en)
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GB2196631A (en) * 1986-10-31 1988-05-05 Nippon Shinyaku Co Ltd 2-substituted 1,4-dihydropyridine derivatives
EP0323604A2 (en) * 1987-12-29 1989-07-12 Fujisawa Pharmaceutical Co., Ltd. A venous extensibility improving and cardiac hypertrophy suppressant agent containing a dihydropyridine compound
CN101987833A (en) * 2009-08-04 2011-03-23 北京利乐生制药科技有限公司 Novel nilvaldipine crystal types and preparation method thereof

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SE7910521L (en) * 1979-12-20 1981-06-21 Haessle Ab NEW 2-METHYL-6-SUBSTITUTED-4- (2,3-DISUBSTITUTED PHENYL) -1,4-DIHYDROPYRIDINE-3,5-DIESTERS WITH HYPOTHESIVE PROPERTIES, AND PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION
JPS57175164A (en) * 1981-04-18 1982-10-28 Banyu Pharmaceut Co Ltd 1,4-dihydropyridine derivative and its preparation
EP0080220B1 (en) * 1981-11-17 1986-02-19 FISONS plc Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals
ZA83959B (en) * 1982-03-10 1984-09-26 Sandoz Ltd 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them
CH655110A5 (en) * 1982-09-03 1986-03-27 Otsuka Pharma Co Ltd CARBOSTYRILE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM.
DE3312216A1 (en) * 1983-04-05 1984-10-11 Bayer Ag, 5090 Leverkusen METHOD FOR PRODUCING SYMMETRIC 1,4-DIHYDROPYRIDINE CARBONIC ACID ESTERS
JPS6038322A (en) * 1983-08-11 1985-02-27 Fujisawa Pharmaceut Co Ltd Easily soluble solid preparation containing dihydropyridine-a substance
GB8412208D0 (en) * 1984-05-12 1984-06-20 Pfizer Ltd Quinolone inotropic agents
GB8431119D0 (en) * 1984-12-10 1985-01-16 Fujisawa Pharmaceutical Co Anti-arteriosclerotic composition
GB8602518D0 (en) * 1986-02-01 1986-03-05 Wyeth John & Brother Ltd 1 4-dihydropyridines
EP0294601B1 (en) * 1987-06-12 1993-01-20 American Cyanamid Company Transdermal delivery of pharmaceuticals
US5114946A (en) * 1987-06-12 1992-05-19 American Cyanamid Company Transdermal delivery of pharmaceuticals
US5045553A (en) * 1987-06-24 1991-09-03 Fujisawa Pharmaceutical Company, Ltd. Pharmaceutical composition for percutaneous drug absorption and percutaneous drug absorption promoter
EP0322747B1 (en) * 1987-12-29 1994-03-02 Fujisawa Pharmaceutical Co., Ltd. A brain neuron protecting agent containing a dihydropyridine compound
JP2007230869A (en) * 2004-04-05 2007-09-13 Takeda Chem Ind Ltd Aldosterone receptor antagonist

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GB1552911A (en) * 1975-07-02 1979-09-19 Fujisawa Pharmaceutical Co 1,4 dihydropyridine derivatives and the preparation thereof
GB1591089A (en) * 1976-12-17 1981-06-10 Fujisawa Pharmaceutical Co 1,4-dihydropyridine derivatives and process for preparation thereof
DE2658183A1 (en) * 1976-12-22 1978-07-06 Bayer Ag 2-POSITION SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT

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Publication number Priority date Publication date Assignee Title
GB2196631A (en) * 1986-10-31 1988-05-05 Nippon Shinyaku Co Ltd 2-substituted 1,4-dihydropyridine derivatives
GB2196631B (en) * 1986-10-31 1990-07-11 Nippon Shinyaku Co Ltd 2-substituted 1,4-dihydropyridine derivatives
EP0323604A2 (en) * 1987-12-29 1989-07-12 Fujisawa Pharmaceutical Co., Ltd. A venous extensibility improving and cardiac hypertrophy suppressant agent containing a dihydropyridine compound
EP0323604A3 (en) * 1987-12-29 1991-07-31 Fujisawa Pharmaceutical Co., Ltd. A venous extensibility improving and cardiac hypertrophy suppressant agent containing a dihydropyridine compound
CN101987833A (en) * 2009-08-04 2011-03-23 北京利乐生制药科技有限公司 Novel nilvaldipine crystal types and preparation method thereof
CN103951608A (en) * 2009-08-04 2014-07-30 北京利乐生制药科技有限公司 Nilvadipine crystal forms and preparation method thereof
CN101987833B (en) * 2009-08-04 2014-07-30 北京利乐生制药科技有限公司 Novel nilvaldipine crystal types and preparation method thereof
CN103951608B (en) * 2009-08-04 2016-04-27 喜德生（苏州）医药科技有限公司 Nilvadipine crystal formation and preparation method thereof

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NL7907482A (en) 1980-04-14
SE7908367L (en) 1980-04-11
JPS61118366A (en) 1986-06-05
JPS5562065A (en) 1980-05-10
FR2438654A1 (en) 1980-05-09
DE2940833C2 (en) 1989-01-26
SE446265B (en) 1986-08-25
GB2036722B (en) 1982-12-01
SE446096B (en) 1986-08-11
SE8400689D0 (en) 1984-02-09
IT1125469B (en) 1986-05-14
DE2940833A1 (en) 1980-04-30
CA1117117A (en) 1982-01-26
FR2438654B1 (en) 1983-01-14
SE8400689L (en) 1984-02-09
BE879263A (en) 1980-04-08
JPS6143343B2 (en) 1986-09-26
IT7926362A0 (en) 1979-10-09
CH642353A5 (en) 1984-04-13
JPS6125711B2 (en) 1986-06-17

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