JPS5943952B2 - Method for producing alkoxyalkyl-1,4-dihydropyridine ester or salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel alkoxyalkyl-1,4 dihydropyridine ester compounds, a process for their preparation and their pharmaceutical use, in particular as drugs affecting blood vessels and in particular as coronary vasodilators.

It has already been shown that certain 1,4-dihydropyridines have important pharmacological properties (F.BO
ssert and W. ater,. IWDieNatur
Wissenschaftenlj (1971), No. 5
(Vol. 8, No. 11, p. 578). According to the research of the present inventor, in the general formula, R is a hydrogen atom or a saturated or unsaturated aliphatic group; R1 is an alkoxyalkyl group; R2 and R3 are each 1 or 2 in some cases. identical or different groups consisting of linear, molecular or cyclic saturated or unsaturated hydrocarbon chains having a hydroxyl substituent and optionally containing one or two oxygen atoms in the middle; ; R4 is hydrogen, alkyl, alkoxyalkyl or (CH2)1-COOR5 group (wherein R5 is hydrogen or an alkyl group, and n is an integer from O to 3);
; 2), phenyl, trifluoromethyl and halogen group 1
aryl radicals with one, two or three identical or different substituents; benzyl, styryl, cycloalkyl or cycloalkenyl radicals; or optionally selected from alkyl, alkoxy, dialkylamino, nitro and halogen radicals; Novel compounds which are alkoxyalkyl-1,4-dihydropyridyl esters of quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, furyl or biryl groups or salts thereof having one or more identical or different substituents are It was found to have a strong vascular influence, especially a strong coronary effect.

According to the present invention, (a) in the general formula R. (b) an enamine of the general formula, wherein R1 and R2 are as defined above, is reacted with a ylidene derivative of the general formula, or (b) an enamine of the general formula (c) with a ylidene derivative of the general formula in which R1, R2 and X are as defined above, or (c) β- of the general formula in which R3 and R4 are as defined above
The ketocarboxylic acid ester is represented by the general formula R. Rl and R2
(d) react with an enamine of the general formula in which x is as defined above and an aldehyde of the general formula in which R1 and R2 are as defined above; There is β-
The ketocarboxylic acid ester is represented by the general formula R. R3 and R4
is as defined above, and an aldehyde of the general formula in which X is as defined above, or (e) (R1 is the same as R4 and R2 is R3
2 molar parts of a β-ketocarboxylic acid ester of the general formula (where R is as defined above), where R is as defined above; There is provided a process for the preparation of the above-mentioned novel compounds, which comprises reacting 1 molar part of an amine or a salt thereof with 1 molar part of an aldehyde of the general formula in which X is as defined above.

The novel free alkoxyalkyl-1,4-dihydropyridine esters of general formula 1 and their salts can be interconverted in any suitable manner; upon such interconversion, conventional methods for interconverting free bases and their salts are used. The same method can be used.

Surprisingly, the compounds according to the invention exhibit a very strong effect on blood vessels, in particular a very strong coronary effect.

The compounds according to the invention are thus of value in the field of pharmacy. In the present specification, the term "compound in the present invention" refers to alkoxyalkyl-1,4 of the general formula
It means both dihydropyridine esters and salts thereof.

The methods (a) to (e) of the present invention described above are described below as methods (
They are referred to as a) to (e).

(A) When using, for example, 2-(3-nitrobenzylidene)-acetoacetic acid ethyl ester and 2-amino-γ-monoethoxycrotonic acid ethyl ester as starting materials, the reaction sequence for method (a) can be expressed as follows: In general formula 11, the saturated or unsaturated aliphatic group R is preferably a straight-chain or branched alkyl group of 1 to 4 carbon atoms, especially 1 to 3 carbon atoms, such as methyl, ethyl, n- and isopropyl or n-, iso- and tert-butyl) or straight-chain or branched alkenyl groups of 2 to 4, especially 2 or 3 carbon atoms (e.g. ethenyl, propene-1- IL, PROPEN-2
-yl and buten-3-yl).

In the general formula, all alkoxyalkyl groups R1 and R4 preferably represent straight-chain or branched alkylene groups (e.g. methylene, ethylene, n-propylene and isopropylene); and z is 1 to 4 carbon atoms,
Preferably one or two alkyl groups (e.g. methyl,
ethyl, n-propyl, isopropyl and n-, iso-Sec and t-butyl).

All straight-chain or branched saturated or unsaturated or cyclic groups R2 and R3 are preferably alkyl, alkenyl,
It is an alkynyl or cycloalkyl group.

All alkyl groups R2 and R3 preferably have 1 carbon atom
~6, especially 1-4.

By way of example, mention may be made of the methyl, n- and isopropyl and n-iso- and tert-butyl groups. All alkenyl groups R2 and R3 preferably have 2 to 6 carbon atoms
, especially 2 to 4. As examples, mention may be made of the ethenyl, propen-1-yl, flopen-2-yl and buten-3-yl groups. All alkynyl radicals R2 and R3 preferably have 2 to 6, especially 2 to 4 carbon atoms.

As examples, mention may be made of the ethynyl, propyn-1-yl, propyn-2-yl and buten-2-yl groups. All cycloalkyl radicals R2 and R3 can be monocyclic, bicyclic or tricyclic cycloalkyl radicals and preferably have 3 to 10 carbon atoms, especially 3, 5 or 6.

Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pingulow [2.2.1] - heptyl, pingulow [2.2.2]
-Octyl and adamantyl groups may be mentioned.
These alkyl, alkenyl, alkynyl and cycloalkyl groups R2 and R3 are 1 or 2, preferably 1
can have a human xyl group as a substituent for each hydrogen. Suitable radicals R2 and R3 consisting of a hydrocarbon chain containing 1 or 2 carbon atoms in between are preferably:
It corresponds in particular to the above-mentioned preferred alkyl, alkenyl, alkynyl and cycloalkyl groups of chains containing only one oxygen atom in the middle.

All alkyl groups R4 and R5 preferably have 1 carbon atom
~6, especially 1 to 4 straight or branched alkyl groups are preferred.

By way of example, mention may be made of methyl, ethyl, n- and isopropyl and n-, iso- and tert-butyl groups.
The optionally substituted aryl group X is preferably an aryl group having 6 or 10, especially 6, carbon atoms in the aryl part.

By way of example, optionally substituted phenyl or naphthyl groups may be mentioned. All aryl radicals X can carry one or more, preferably 1 to 3, especially 1 or 2, identical or different substituents.

Among such substituents the following may be mentioned: phenyl; preferably 1 to 4 carbon atoms, especially 1 or 2 carbon atoms;
alkyl (e.g. methyl, ethyl, n-propyl,
alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butyl); preferably having 1 to 4 carbon atoms, especially 1 or 2 carbon atoms; phthoxy); trifluoromethyl; hydroxyl;
halogens (including fluorine, chlorine, bromine and iodine, especially chlorine and bromine); nitrile; nitro; azide; amino;
Monoalkylamino and dialkylamino having preferably 1 to 4, especially 1 or 2 carbon atoms to the alkyl group (e.g. methylamino, methylethylamino,
n-propylamino, isopropylamino and methyl-
n-butylamino); preferably 2 to 4, especially 2 or 3, carbalkoxy (e.g. acetylamino and propionylamino); preferably 2 to 4 carbon atoms;
6, especially 2 to 4 acyloxys (e.g. acetoxy and propionyloxy); and S(0)Rn alkyl, where m is a number from O to 2 and "alkyl" preferably has 1 to 4 carbon atoms , especially one or two (eg methylthio, ethylthio, methylsulfoxyl, ethylsulfoxyl, methylsulfonyl and ethylsulfonyl). All cycloalkyl radicals X are preferably monocyclic, bicyclic or tricyclic cycloalkyl radicals having 3 to 10 carbon atoms, especially 3, 5 or 6 carbon atoms.
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pinlow 2,2,1-heptyl, pinlow 2,2,2-octyl and adamantyl groups. All cycloalkenyl groups X are preferably monocyclic, bicyclic or tricyclic cycloalkenyl groups of 5 to 10 carbon atoms, especially 5, 6 or 7 carbon atoms.

Examples include cyclopentenyl, cyclohexenyl and cycloheptenyl groups. quinolyl,
Alkyl and alkoxy groups present as substituents on the isoquinolyl, pyridyl, pyrimidyl, diphenyl, furyl or pyryl radicals Groups are preferred.

As examples, mention may be made of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups, as well as the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy groups. . The halogen atoms present as substituents on the quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, furyl and pyryl groups X can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The dialkylamino groups present as substituents on the quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, furyl and pyryl groups X are preferably those containing 1 to 4 carbon atoms, especially 1 or 2, for the alkyl group.

Examples of alkyl groups in dialkylamino groups include methyl,
Mention may be made of the ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups. A preferred group of compounds according to the invention are: R
is a hydrogen atom; R1 is an alkoxyalkyl group having 1 or 2 carbon atoms in the alkyl portion and 1, 2 or 3 carbon atoms in the alkoxy portion; R2 and R3 each have 1 carbon atom
~4 identical or different alkyl groups (especially methyl and ethyl); R4 is an alkyl group of 1 to 4 carbon atoms (especially a methyl or ethyl group), the alkyl part has 1 or 2 carbon atoms and the alkoxy part an alkoxyalkyl group, carboxyl group or CH2-COO having 1 to 3 (preferably 1 or 2) carbon atoms in
an alkyl group, where "alkyl" is a carbon atom
4 (preferably 1 or 2) alkyl groups; and methyl, fluorine, chlorine and iodine groups, 2 to 4 carbon atoms (preferably 2 or 3)
The compound is a phenyl group having one or two substituents selected from a carbalkoxy group and an alkylsulfonyl group having 1 to 4 carbon atoms (preferably 1 or 2 carbon atoms).

Among the compounds of the invention that are salts, those that are non-toxic and physiologically well-tolerated acid addition salts are preferred.

Examples of inorganic and organic acids which form such salts with the free compounds of general formula 1 include: hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid, especially hydrochloric acid)
, phosphoric acid, sulfuric acid, nitric acid, and monofunctional and difunctional carboxylic and hydroxycarboxylic acids such as acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, zorpic acid, lactic acid and 1,5-naphthalenecarboxylic acid). These salts can generally be prepared by conventional methods, for example by dissolving the base in ether and adding the above-mentioned acids to this solution. Option a) in the present invention also involves reacting a β-ketocarboxylic acid ester of the general formula, in which R1 and R2 are as defined above, with an amine of the general formula, in which R is as defined above. The process consists of a pre-process of producing an enamine of the general formula () by

Similarly, the method (5) of the present invention is the method (5) in which R in the general formula
3 and R4 are as defined above, by reacting a β-ketocarboxylic acid ester of with an amine of the general formula, R is as defined above. Consists of processes.

Enamines () and () thus produced can be prepared by method (a)
and (b), either isolated and purified prior to reaction with ylidene derivatives of general formulas () and (), respectively, or this can be reacted in situ without intermediate isolation.

[B ．． JOhnsOn and H. C
hesnOff. J. A. C. S. 36, 1744" (
1914)].

Examples of esters of general formula () include: γ-methoxyacetoacetic acid methyl ester, γ
-Methoxyacetoacetic acid ethyl ester, γ-methoxyacetoacetic acid propyl ester, γ-methoxyacetoacetic acid isopropyl ester, γ-methoxyacetoacetic butyl ester, γ-ethoxyacetoacetic acid methyl ester, γ-ethoxyacetoacetic acid ethyl ester, γ-ethoxy Acetoacetate propyl ester, γ-propoxyacetoacetate ethyl ester, γ-propoxyacetoacetate isopropyl ester, propoxyacetoacetate t-butyl ester, isopropoxyacetoacetate methyl ester, isopropoxyacetoacetate butyl ester, butoxyacetoacetate ethyl ester, butoxyacetate Acetic acid isobutyl ester, r
-isobutoxyacetoacetic acid probyl ester, γ-methoxypropionyl acetate methyl ester, γ-methoxypropionyl acetate ethyl ester, γ-propoxypropionyl acetate propyl ester, δ-ethoxypropionyl acetate ethyl ester and δ-methoxy-γ-monoethylpropionyl acetate ethyl ester.

The amines of the general formula () which can be used as starting materials in the processes (a), (b) and (e) according to the invention are already known.

The following may be mentioned as examples of these amines: ammonia, methylamine, ethylamine, propylamine, butylamine, isopropylamine, isobutylamine and allylamine.

The enamine-β-keto-carbonyl compounds of general formula () which can be used as starting materials in the processes (a) and (c) according to the invention can be prepared from the corresponding β-diketo compounds according to generally known methods. I can [A. C. C.O.
pe. J. A. C. S. LlOl7 (1945)〕o
Examples of these enamines include: γ-methoxy-β-aminocrotonic acid methyl ester, γ-methoxy-β-aminocrotonic acid ethyl ester, γ-ethoxy-β-aminocrotonic acid propyl ester, γ-isopropoxy-β-methylaminocrotonic acid ethyl ester and γ-butoxy-γ-methyl-β-
Aminocrotonic acid ethyl ester.

The ylidene-β-ketocarboxylic acid esters of the general formula which can be used as starting materials in process a) according to the invention are known or can be prepared according to generally known methods [0rg. React10nsM,
204 et seq. (1967)] Examples of these ylidene derivatives include: ylidene-β
-ketocarboxylic acid ester ribenzylidene-γ-methoxyacetoacetic acid ethyl ester, 2'-nitrobenzylidene-γ-methoxyacetoacetic acid ethyl ester, 3'-methoxybenzylidene-γ-monoethoxyacetoacetic acid methyl ester, 3',4'-dimethoxy Benzylidene-γ-propoxyacetoacetic acid propyl ester, 2'-trifluoromethylbenzylidene-γ-methoxyacetoacetic acid ethyl ester, 2-chlorobenzylidene-γ-monoethoxyacetoacetic acid propyl ester, 3-mercaptobenzylidene-γ-butoxyacetoacetic acid ethyl ester Esters, benzylideneacetoacetic acid methyl ester, 2'-nitrobenzylideneacetoacetic acid methyl ester, 3'-nitrobenzylideneacetoacetic acid propargyl ester, 3'-nitrobenzylideneacetoacetic acid allyl ester, 3'-nitrobenzylideneacetoacetic acid β-monoethoxyethyl ester ester, 4
/-Nitrobenzylideneacetoacetic acid isopropylesal, 37-nitro-6'-chlorobenzylideneacetoacetic acid methyl ester, 2'-cyanobenzylidenepropionyl acetic acid ethyl ester, 3'-cyanobenzylideneacetoacetic acid methyl ester, 3'-nitro-4 '-chlorobenzylideneacetoacetic acid t-butyl ester, 2'-nitro-4'-methoxybenzylideneacetoacetic acid methyl ester, 27-cyano-4'-methylbenzylideneacetoacetic acid ethyl ester, 2'-azidobenzylideneacetoacetic acid ethyl ester, 2'-methylmercaptobenzylideneacetoacetic acid isopropyl ester, 2'-sulfinylmethylbenzylideneacetoacetic acid ethyl ester,
2'-sulfonylmethylbenzylideneacetoacetic acid ethyl ester, 2'-nitrobenzylidene oxalacetic acid diethyl ester, 2',4'-dioxymethylenebenzylidene oxalacetic acid dimethyl ester, 37-ethoxybenzylidene-β-ketoglutarate diethyl ester, (
21-ethoxy-V-naphthylidene)-acetoacetic acid methyl ester, (V-isoquinolyl)-methylideneacetoacetic acid methyl ester, α-pyridylmethylideneacetoacetic acid methyl ester, α-pyridylmethylideneacetoacetic acid allyl ester, α-pyridylmethylideneacetate Acetic acid cyclohexyl ester, β-pyridylmethylideneacetoacetic acid β-methoxyethyl ester, 6-methyl-α-pyridylmethylideneacetoacetic acid ethyl ester, 4'.6
'-dimethoxy-(51-pyrimidyl)-methylideneacetoacetate ethyl ester, (2'-thenyl)-methylideneacetoacetate ethyl ester (2'-furyl)-methylideneacetoacetate allyl ester, (2/-pyryl)-methylideneacetoacetate methyl ester α- Pyridylmethylidenepropionyl acetate methylesterhenol 2'-. 3'
- and 4'-methoxybenzylideneacetoacetic acid ethyl ester, 27-methoxybenzylideneacetoacetic acid propargyl ester, 2'-isopropoxybenzylideneacetoacetic acid ethyl ester, 3/-butoxybenzylideneacetoacetic acid methyl ester, 3', 4', 5' -trimethoxybenzylideneacetoacetic acid allyl ester, 2'-
Methylbenzylidenepropionyl acetic acid methyl ester 2
'-Methylbenzylideneacetoacetic acid β-propoxyethyl ester, 3',4/-dimethoxy-5/-brombenzylideneacetoacetic acid ethyl ester, 2'-, 3'-1 and 47-chloro-/bromo-1/fluoro-1/iodo −
Benzylideneacetoacetic acid ethyl ester, 3'-chlorobenzylidenepropionyl acetic acid ethyl ester, 2'.
3'- and 4! -trifluoromethylbenzylideneacetoacetic acid propyl ester, glucarboethoxybenzij
Nodenacetoacetic acid ethyl ester, and 4-carboxyisopropylbenzylideneacetoacetic acid isoprobyl ester.

The β-ketocarboxylic acid esters of the general formula and the enamino monoβ-ketocarboxylic acid esters of the general formula which can be used as starting materials in the processes (b), (c), (d) and (e) according to the invention are known. or can be produced according to a generally known method [B. JOh
nsOn and H. ChesnOff, J. A. C. S.
36, 1744 (1914); POhl and Schmi
dt, US Pat. No. 2,351,366; A.
C. COpe,. J. A. C. S. 67, 1067 (1
945)].

Examples of these esbrus and enamines include: β-dicarbonyl compounds: γ-methoxyacetoacetic acid methyl ester, γ-methoxyacetoacetic acid ethyl ester, γ-methoxyacetoacetic acid propyl ester, γ-methoxy Acetoacetic acid isopropyl ester, γ-methoxyacetoacetic acid butyl ester, γ
-Ethoxyacetoacetic acid methyl ester, γ-monoethoxyacetoacetic acid ethyl ester, γ-monoethoxyacetoacetic acid propyl ester, γ-propoxyacetoacetic acid ethyl ester, γ-propoxyacetoacetic acid isopropylesterol r-proboxyacetoacetic acid t-butyl ester, γ- Isopropoxyacetoacetic acid methyl ester, γ-isopropoxyacetoacetic acid butyl ester, γ-butoxyacetoacetic acid ethyl ester, γ-butoxyacetoacetic acid isobutyl ester, γ-isobutoxyacetoacetic acid propyl ester, γ-methoxypropionyl acetic acid methyl ester,
γ-Methoxypropionyl acetate ethyl ester, γ-propoxypropionyl acetate propyl ester, δ-ethoxypropionyl acetate ethyl ester, δ-methoxy-
γ-ethylpropionyl acetic acid ethyl ester, 3,5-
Formylacetate ethyl ester, formylacetate butyl ester, acetoacetate methyl ester, acetoacetate ethyl ester, acetoacetate isopropyl ester, acetoacetate butyl ester, acetoacetate t-butyl ester, acetoacetate α- and β-hydroxyethyl ester, acetoacetate α- and β-methoxyethyl esternoleacetoacetic acid α- and β-ethoxyethyl esternoleacetoacetic acid α- and β-n-propoxyethyl ester acetoacetic acid allyl ester, acetoacetic acid propargyl ester, propionyl acetic acid ethyl ester, butyryl ethyl acetate esters, isobutyryl acetic acid ethyl ester, oxalacetic acid dimethyl ester, oxalacetic acid diethyl ester, oxalacetic acid isopropyl ester, acetone dicarboxylic acid dimethyl ester, acetone dicarboxylic acid diethyl ester, acetone dicarboxylic acid dibutyl ester, and β-ketoadipate diethyl ester.

Enamine carboxylic acid ester: γ-methoxy-β-aminocrotonic acid methyl ester,
γ-methoxy-β-aminocrotonic acid ethyl ester,
γ-ethoxy-β-aminocrotonic acid propyl ester γ-isopropoxy-β-methylaminocrotonic acid ethyl ester, γ-butoxy-1γ-methyl-β-aminocrotonic acid ethyl ester, β-aminocrotonic acid methyl ester, β -aminocrotonic acid ethyl ester, β-aminocrotonic acid isopropyl ester, β-aminocrotonic acid butyl ester, β-aminocrotonic acid α
- and β-methoxyethyl ester, β-aminocrotonic acid β-monoethoxyethyl ester, β-aminocrotonic acid β-flopoxyethyl ester, β-aminocrotonic acid t-butyl ester, β-aminocrotonic acid cyclohexyl ester, β -Amino-β-ethyl acrylic acid ethyl ester, iminosuccinic acid dimethyl ester, iminosuccinic acid diethyl ester, iminosuccinic acid dipropyl ester, iminosuccinic acid dibutyl ester, β-iminoglutarate dimethyl ester, β-iminoglutarate diethyl ester, β-iminoadipine acid dimethyl ester, β-iminoadipate diisopropyl ester, β-methylaminocrotonic acid methyl ester,
β-1ethylaminocrotonic acid ethyl ester and β-methyliminoglutarate diethyl ester.

The ylidene-β-ketocarboxylic acid esters of the general formula which can be used in process (b) according to the invention are hitherto not known. However, as already mentioned for the compounds of the general formula, they can be produced according to generally known methods. Examples of these ylidene derivatives include: ylidene-β-
Ketocarboxylic acid ester ribenzylidene-γ-ethoxyacetoacetate methyl ester, 2'-nitrobenzylidene-γ-propoxyacetoacetate methyl ester, 3'-nitrobenzylidene-γ-methoxyacetoacetate methyl ester, 3'-nitrobenzylidene propyl acetoacetate Esters, 4'-nitrobenzylidene-r-methoxyacetoacetic acid isopropyl ester, 3/-nitro-6'-chlorobenzylidene-γ-isopropoxyacetoacetic acid methyl ester, 2/-cyanobenzylidene-γ-n-butoxyacetoacetic acid methyl ester ester, 2/-cyanobenzylidene-δ-monoethoxypropionyl acetate ethyl ester,
2'-Nitro-4'-methoxybenzylidene-γ-propoxyacetoacetic acid methyl ester, 2'-azidobenzylidene-γ-methoxyacetoacetic acid ethyl ester, 2'
-Methylmercaptobenzylidene-γ-monoethoxyacetoacetic acid methyl ester, 37-methylmercaptobenzylidene-γ-methoxyacetoacetic acid isopropyl ester,
2'-Sulfinylmethylbenzylideneacetoacetic acid ethyl ester, 2! -sulfonylmethyl-γ-methoxyacetoacetic acid ethyl ester, (2'-monoethoxy-1V-naphthylidene)-γ-methoxyacetoacetic acid methyl ester,
(1'-isoquinolyl)-methylidene-γ-1-ethoxyacetoacetic acid methyl ester, α-pyridylmethylidene-γ
-Propoxyacetoacetic acid ethyl ester, 4'/6'-
Dimethoxy-(5'-pyrimidyl)-methylidene-γ-
Methoxyacetoacetate ethyl ester (2'-tenyl)
-r-methoxymethylideneacetoacetic acid ethyl ester,
(2'-furyl)-γ-1ethoxymethylideneacetoacetic acid butyl ester, 2'-, 3'- and 4'-methoxybenzylidene-γmethoxyacetoacetic acid ethyl ester, 2
'-isopropoxybenzylidene-γ-isopropoxyacetoacetic acid ethyl ester, 3'-butoxybenzylidene-γ-methoxyacetoacetic acid methyl ester, 31.4
',5'-Trimethoxybenzylidene-γ-propoxyacetoacetic acid propyl ester, 2'-methylbenzylidene-δ-methoxypropionyl acetic acid methyl ester, 2
'-, 3'- and 4'-trifluoromethylbenzylidene-γ-methoxyacetoacetic acid propyl ester, 2'-trifluoromethylbenzylidene-γ-methoxyacetoacetic acid isopropyl ester, 3'-trifluoromethylbenzylidene-γ-ethoxy Acetoacetic acid methyl ester, 2'-carboethoxybenzylidene-gamma-methoxyacetoacetic acid ethyl ester, 3'-carboxymethylbenzylidene-gamma-1ethoxyacetoacetic acid methyl ester, and 4-carboxyisopropylbenzylidene-gammapropoxyacetoacetic acid isopropyl ester.

The aldehydes of the general formula used in processes (c), (d) and (e) according to the invention are already known or can be prepared by known methods [E
．． MOsettimg, 0rg. Reacti0ns1
, pp. 218 et seq. (1954)] Examples of these aldehydes include: benzaldehyde, 2-, 3- and 4-methoxybenzaldehyde, 2-isopropoxybenzaldehyde, 3-butoxybenzaldehyde, 3-4. -Dioxymethylenebenzaldehyde, 3.4.
5-Trimethoxybenzaldehyde, 2-, 3- and 4
-chloro-/bromo-/iodo-/fluoro-benzaldehyde, 2,4- and 2,6-dichlorobenzaldehyde, 2,4-dimethylbenzaldehyde, 3,5-diisopropyl-4-methoxybenzaldehyde, 2-,3- and 4-nitrobenzaldehyde, 2.
4-1 and 2,6-dinitrobenzaldehyde, 2-nitro-6-bromobenzaldehyde, 2-nitro-3-methoxy-6-chlorobenzaldehyde, 2-nitro-4
-Chlorbenzaldehyde, 2-nitro-4-methoxybenzaldehyde, 2- 3- and 4-trifluoromethylbenzaldehyde, 2- 3- and 4-dimethylaminobenzaldehyde, 4-dibutylaminobenzaldehyde, 4-acetaminobenzaldehyde, 2- , 3- and 4-cyanobenzaldehyde, 2-nitro-4-cyanobenzaldehyde, 3-chloro-4-cyanobenzaldehyde, 2-, 3- and 4-methylmercaptobenzaldehyde, 2-methylmercapto-5-
Nitrobenzaldehyde, 2-butylmercaptobenzaldehyde, 2-, 3- and 4-methylsulfinylbenzaldehyde, 2-, 3- and 4-methylsulfonylbenzaldehyde, benzaldehyde-2-carboxylic acid ethyl ester, benzaldehyde-3-carboxylic acid Isopropyl ester benzaldehyde-4-carboxylic acid butyl ester, 3-nitrobenzaldehyde-4-carboxylic acid ethyl ester, cinnamaldehyde, hydrocinnamaldehyde, formylcyclohexane, 1-formylcyclohexane-3, 1-formylcyclohexane-1, 3, 1 -Formylcyclobenzene-3, α-, β- and γ-pyridine aldehyde, 6-methylpyridine-2-aldehyde, furan-2-aldehyde, thiophene-2-aldehyde, pyrrole-2-aldehyde, N-methylpyrrole- 2-aldehyde, 2-3- and 4-azidobenzaldehyde, pyrimidine-4-aldehyde, 5-nitro-6-methylpyridine-2-aldehyde, 1- and 2-naphthaldehyde, 5-bromo-1-naphthaldehyde, Quinoline-2-aldehyde, 7-methoxyquinoline-4-aldehyde and isoquinoline-1-aldehyde.

Water and/or all inert organic solvents can be used as diluent in processes (a) to (e).

Among the suitable diluents are alcohols (preferably alcohols of 1 to 4 carbon atoms, such as ethanol, methanol and isopropanol), ethers (preferably di(linear) alkyl ethers of 3 to 5 carbon atoms, such as diethyl ethers or cyclic ethers such as tetrahydrofuran or dioxane), aliphatic carboxylic acids (preferably those having 2 to 5 carbon atoms, such as acetic acid and propionic acid), dialkylformamides (preferably 1 or 2 carbon atoms for the alkyl group). (e.g. dimethylformamide), alkylnitrile (
preferably having 2 to 4 carbon atoms, e.g. acetonitrile), dimethyl sulfoxide, and liquid heteroaromatic bases (e.g. pyridine), mixtures of two or more of these diluents, and water and said diluent. mixtures of one or more of these. Methods (a) to (e)
) the reaction temperature can be varied over a substantial range.

Generally this reaction is carried out between 20 and 150°C, preferably 50°C.
and 100°C, in particular at the boiling point of the diluent used. The above reaction can be carried out under normal pressure, but also under elevated pressure. Normal pressure is generally used. When carrying out processes (a) to (e) according to the invention, the starting compounds participating in the reaction are preferably each used in approximately equimolar amounts.

When using an amine () or a salt thereof, it is appropriate that it be present in a 1 to 2 molar excess.

This molar ratio can vary over a substantial range;
Does not adversely affect the results. The novel compounds can be used in medicine, in particular as active compounds acting on the blood vessels and the circulatory system.

The compounds in this invention have a wide and varied pharmacological action. In detail, this compound exhibits the following main actions: (
1) When administered parenterally, orally and sublingually, the compound causes a marked and sustained dilation of the coronary veins.

This effect on the coronary veins is enhanced by the nitrite-like effect with a simultaneous action that reduces the workload on the heart. The compounds influence or improve cardiometabolic action in the sense of energy conservation. (2) The present compound also lowers blood pressure in catatonic and hypertonic animals, and therefore can be used as an antihypertensive agent.

(3) The responsiveness of stimulus formation and excitatory transmission systems in the heart is reduced, resulting in anti-fibrillatory effects at therapeutic doses.
FibrillatiOnactiOn).

(4) The tension force (Tone) of vascular smooth muscle is significantly reduced by the action of this compound.

This vasospasmolytic effect may occur throughout the vasculature or may be more or less isolated in circumscribed vascular regions (eg, the central nervous system). (5) This compound has a strong muscle spasmolytic effect, and this effect is noticeable on the smooth muscles of the stomach, intestinal tract, genitourinary tract, and respiratory system.

(6) This compound affects the amount of cholesterol and lipids in the blood.

The coronary action of representative compounds according to the present invention is illustrated by the experimental results shown in Table 1 below.

The above-mentioned coronary vasculature was confirmed by measuring the increase in oxygen saturation in the coronary sinus in an anesthetized mongrel dog whose heart was catheterized, according to generally conventional methods known in the literature.

The compounds according to the invention are therefore suitable for the prevention, alleviation or cure of diseases in which the abovementioned effects are desired.

According to the present invention, the present invention can be used as a mixture with a liquid diluent other than a solvent, with a molecular weight of less than 200 (preferably less than 350), unless a solid or liquefied gaseous diluent or surfactant is present. Pharmaceutical compositions comprising the compound as an active ingredient are provided. The invention further provides pharmaceutical compositions comprising a compound of the invention as an active ingredient in the form of a sterile or isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprising a compound of the invention alone or in admixture with a diluent.

According to the invention, tablets (lozenges (10z
medicaments in the form of dragees, capsules, pills, ampoules or suppositories.

As used herein, "drug" refers to a tangible, discrete formulation part suitable for pharmaceutical administration.

As used herein, "drug in dosage unit form" refers to a daily dosage or multiple of a compound of the invention, respectively.
(up to 4 times) or a submultiple (up to 1/40) of a tangible, individual formulation suitable for pharmaceutical administration. Depending on whether the drug contains a daily dosage or, for example, 1/2, 1/3 or 1/4 of a daily dosage,
Each drug is administered once or e.g.
Or maybe four times. Pharmaceutical compositions according to the invention are for example ointments, gels, liniments, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders. It can take the form of

Diluents for use in pharmaceutical compositions (e.g. granules) adapted for forming into tablets, dragees, capsules and pills include: (a) fillers and extenders such as starches; , sugar, mannitol and silicic acid; (b) a binder;
(c) wetting agents, such as glycerin; (d) disintegrants, such as agar, calcium carbonate and sodium bicarbonate;
(e) dissolution retardants, such as paraffin; (f) resorption enhancers, such as quaternary ammonium compounds; (g) surfactants, such as cetyl alcohol, glycerin monostearate; (h) adsorption carriers, such as kaolin and bentonite. (1) Lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.

Tablets, dragees, capsules and pills made from the pharmaceutical compositions of the present invention may be coated with conventional coatings, envelopes.
(Op) and protective substrates, which may include opacifying agents. The formulation may be constructed so as to release the active ingredient only or preferably in a specific part of the intestinal tract, possibly for an extended period of time. Coatings, envelopes and protective matrices can be made of polymeric materials or waxes, for example. The active ingredient can also be made into microcapsules with one or more of the above diluents.

Diluents used in pharmaceutical compositions suitable for shaping into suppositories include, for example, the common water-soluble or water-insoluble diluents, such as polyethylene glycols and fats, such as cocoa oil and higher esters, such as Cl4-alcohols with C,6 fatty acids. ) or mixtures of these diluents.

Pharmaceutical compositions which are ointments, liniments, creams and gels may, for example, contain common diluents such as animal and vegetable fats, waxes, paraffin, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids. , talc and zinc oxide or mixtures of these substances.

Pharmaceutical compositions which are powders and sprays may, for example, contain the usual diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances.

Aerosol sprays can include, for example, common propellant bases such as chlorofluorohydrocarbons. Pharmaceutical compositions which are solutions and emulsions may, for example, contain the usual diluents (excluding, of course, the above-mentioned solvents with a molecular weight below 200, unless surfactants are present), such as solvents, solubilizers and emulsifiers. Specific examples of such diluents include water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil ( For example, fatty acid esters of peanut oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol, or mixtures thereof.

For parenteral administration, solutions and emulsions should be sterile and suitably blood isotonic.

For pharmaceutical compositions that are suspensions, common diluents such as water,
Liquid diluents such as ethyl alcohol, propylene glycol, surfactants (e.g. ethoxylated isostearyl alcohol, polyoxyethylene solpit and zorbitan esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth; may contain a mixture of

All pharmaceutical compositions according to the invention may also contain colorants and preservatives, as well as aroma and flavor additives (eg oil of cassava and eucalyptus) and sweetening agents (eg saccharin).

Pharmaceutical compositions according to the invention preferably contain from about 0.1 to 99.5% by weight, more preferably from about 0.5 to 95% by weight of active ingredient, based on the weight of the total composition.

In addition to the compounds of the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. The composition can also contain more than one compound of the invention. Any diluent in the medicament of the invention can be any diluent mentioned above for the medicament composition of the invention.

Such agents may contain a solvent having a molecular weight less than 200 as the sole diluent. The tangible, individual pharmaceutical parts constituting the medicament according to the invention (whether in dosage unit form or alone) can be, for example: tablets (including lozenges and granules), pills, dragees, capsules, suppositories and ampoules.

Some of these forms can provide sustained release of the active ingredient. Such capsules contain a protective envelope that renders the drug a tangible, discrete part of the dosage form. Suitable daily dosages for parenteral administration of the agents of the invention are from 0.25 to 1 y of active ingredient, especially from 1 to 500 y.
and a suitable daily dosage for oral administration is 5-5y, especially 50my-3V of active ingredient.

The above-mentioned pharmaceutical compositions and drugs can be manufactured by methods known in the art, for example, by mixing one or more active ingredients with one or more diluents to form a pharmaceutical composition (e.g., granules). , and then administering the composition to a drug (e.g. tablet)
It is done by making

The compounds of the present invention, alone or in a mixture with a diluent, or in the form of a medicament according to the present invention, can be administered to humans and non-human animals to prevent the above-mentioned diseases in the animals.
COMBAT) (including prevention, relief and treatment).

It is contemplated that the active compounds may be administered orally, parenterally (e.g. intramuscularly, intraperitoneally or intravenously) or anally, preferably orally or parenterally, in particular sublingually or intravenously. .

Suitable pharmaceutical compositions and medicaments are therefore those adapted for oral or parenteral administration, in particular sublingual or intravenous administration, such as tablets, capsules (especially oral immediate release capsules) and ampoules of injection solutions. . Administration in the method of the invention is preferably oral or parenteral, especially sublingual or intravenous. In general, to achieve the desired result, the active compound(s), at any time in various dosage forms, may be administered in doses of about 0.005 to about 10 T for parenteral (intravenous) administration.
n9/Kg body weight/24 hours, preferably 0.02-5
m9/K9 body weight/24 hours, and for oral administration, from about 0.1 to about 50 m9/K9 body weight/24 hours,
It has been found to be advantageous to administer preferably in an amount of 1 to 30 η/Kg body weight/24 hours.

An individual dosage form will contain the active compound or compounds in an amount of about 0.1 to about 10 WI9/Kg body weight, especially 0.2 to 5 m9/Kg body weight. However, it may be necessary to deviate from the above-mentioned dosages, depending, inter alia, on the nature and weight of the animal being treated, the nature and severity of the disease, the nature of the preparation and the method of administration of the drug and the timing or interval at which the administration is carried out. It may thus occur that in some cases it may be sufficient to use less than the abovementioned amounts of active compound, whereas in other cases the abovementioned amounts must be exceeded. Particularly required optimum dosages and methods of administration of the active compounds will be readily determined by those skilled in the art. The following examples illustrate the preparation of compounds of the invention by the methods of the invention.

Reference example 1 Benzaldehyde 10.6v in ethanol 80ml)
After heating a solution of γ-ethoxyacetoacetic acid ethyl ester 17.41 and β-aminocrotonic acid ethyl ester 131 for several hours, 2-ethoxy Methyl-6-methyl-4-phenyl-1,4-dihydropyridine-
3.5-dicarboxylic acid diethyl ester was obtained.

Reference example 2 3-iodobenzaltehyde 5 in 30 ml of ethanol
A solution of 8 v, 44 da of gamma-ethoxyacetoacetic acid ethyl ester and 3.31 da of beta-aminocrotonic acid ethyl ester was heated to boiling temperature overnight and then cooled.

After cooling, 2-ethoxymethyl-6-methyl-4-(3'-iodophenyl)-1.4- is produced in the form of pale yellow crystals that melt at 124 °C in a yield of 60% of theory.
Dihydropyridine-3.5carboxylic acid diethyl ester was obtained. Reference Example 3 Di3-nitrobenzaldehyde 157, γ-ethoxyacetoacetic acid ethyl ester 187 and β-aminocrotonic acid ethyl ester 137 were heated in 60 ml of ethanol for about 5 hours, the mixture was cooled, and the product was separated. , rinsed with cold ethanol.

Pale yellow crystalline with a melting point of 120-122°C, with a theoretical amount of 70
2-ethoxymethyl to 6methyl-4- in % yield
(3'-nitrophenyl)-1,4 dihydropyridine-
3,5-dicarboxylic acid diethyl ester was obtained. Reference example 4 2-chlorobenzaldehyde 1 in 80 ml ethanol
47, γ-ethoxyacetoacetic acid ethyl ester 17.4
A solution of t- and β-aminocrotonic acid ethyl ester 137 was heated under reflux for several hours and then cooled to give 2-ethoxymethyl-6-methyl-4(2'-chlorophenyl)-1.
4-Dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained in a yield of 55% of the theoretical amount, which was in the form of pale yellow crystals with a melting point of 115°C.

Reference Example 5 3-Fluoro-4-methoxybenzaldehyde 15,47, γ-1ethoxyacetoacetic acid ethyl ester 17.47 and β-aminocrotonic acid ethyl ester 13y in 80 ml of ethanol were heated to boiling temperature overnight, and the mixture was cooled. After filtering, filtering and rinsing with cold ethanol, 2-ethoxymethyl-6-methyl-4-(3'-fluoro-4'- methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

Reference example 6 2-nitrobenzaldehyde in ethanol 6.27,
γ-methoxyacetoacetic acid ethyl ester 6.6y and β
After heating a solution of 4.87 -aminocrotonic acid methyl ester under reflux for 6-8 hours, the mixture was cooled, the product was separated and rinsed with a small amount of cold ethanol.

2-Methoxymethyl-6-methyl-4-(2'-nitrophenyl)-1 in the form of pale yellow crystals with a melting point of 143-145°C.
4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester was obtained. Yield: 45% of theory.

7.47 ml of 2-trifluoromethylbenzaldehyde, 17.47 ml of γ-monoethoxyacetoacetic acid ethyl ester and 137 ml of β-aminocrotonic acid ethyl ester in 80 ml of ethanol were heated under reflux overnight and the mixture was cooled to a melting point of 112°C. 2-ethoxymethyl-6-methyl-4-(
2'-trifluoromethylphenyl)-1,4-dihydropyridine 3,5-dicarboxylic acid diethyl ester was obtained.

Reference Example 8 A solution of 10.4 ml of pyridine-2-aldehyde, 197 ml of γ-isopropoxyacetoacetic acid ethyl ester (boiling point 106-108°C/12 mm) and 13 V of β-aminocrotonic acid ethyl ester in 60 Tf11 of ethanol was
Hold at boiling temperature for ~8 hours, then cool, melting point 184°C
2- in the form of pale yellow crystals in a yield of 35% of theory.
Isopropoxymethyl-6-methyl-4-α-pyridyl-1,4 dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

Reference example 9 3-cyanobenzaldehyde 6 in 80 ml of ethanol
．． 57, γ-ethoxyacetoacetic acid ethyl ester 8.7
7 and β-amino-β-ethyl acrylic acid ethyl ester 7.2y were heated under reflux overnight, the mixture was cooled, filtered, and washed with cold ethanol, giving the form of pale yellow crystals with a melting point of 125°C. , 2-ethoxymethyl-6-ethyl-4-(3'-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained in a yield of 42% of theory.

Reference Example 10 2-dimethylaminopyrimidine 7.57, γ-ethoxyacetoacetic acid ethyl ester 8.
77 and β-aminocrotonic acid ethyl ester 6.57
After heating to boiling temperature overnight, cooling and filtering, 2-ethoxymethyl-6-methyl-4-(
2'-dimethylaminopyrimidine)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

Reference Example 11 Pyridine-2-aldehyde 7.57, γ-monoethoxyacetoacetic acid ethyl ester 157 and β-aminocrotonic acid ethyl ester in 60 ml of ethanol.

After heating to the boiling temperature for 5-6 hours, cooling and filtering, 2-ethoxymethyl-6-methyl -4-α-pyridyl-1,4 dihydropyridine-3.
5-dicarboxylic acid diethyl ester was obtained. Reference example 12 1 part of 2-chlorobenzaldehyde in 60 ml of ethanol
47. A solution of γ-methoxyacetoacetic acid ethyl ester 327 and 10 ml of concentrated aqueous ammonia was heated to boiling temperature overnight and, after filtration, gave a yield of 55% of theory as light yellow crystals with a melting point of 133-134°C. 2,6-dimethoxymethyl-4(2'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

Reference Example 13 8.77 g of 2-trifluoromethylbenzaldehyde, γ-methoxyacetoacetic acid ethyl ester and 5 ml of aqueous concentrated ammonia in 30 ml of ethanol are heated to boiling temperature overnight, the mixture is cooled and a Light brown crystalline, 2.6% in yield of 6.0% of theory.
-Dimethoxymethyl 4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

Reference example 14 2-nitrobenzaldehyde 1 in 80 ml ethanol
A solution of 57, gamma-ethoxyacetoacetic acid ethyl ester 35y and 11 ml of concentrated aqueous ammonia was heated to boiling temperature overnight and then cooled.

After cooling, 2,6-(diethoxymethyl) appeared in the form of yellow crystals with a melting point of 138-140°C, in a yield of 50% of theory.
-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained. Reference example 15 Pyridine-2-aldehyde 5 in 40 ml of ethanol,
2 ml γ-ethoxyacetoacetic acid ethyl ester and 5 ml aqueous concentrated ammonia were heated to boiling temperature overnight, the mixture was cooled, the product was separated and the crystals obtained (melting point 1
10°C) was dissolved in ether and the HCl salt was precipitated with ethereal hydrogen chloride.

2,6-(diethoxymethyl) with a melting point of 168-170°C
-4-α-pyridyl-1,4-dihydropyridine-3.
The hydrochloride of 5-dicarboxylic acid diethyl ester was obtained. Yield: 45% of theory.

Reference Example 16 4-methylsulfonylbenzaldehyde 9.27, γ-methoxyacetoacetic acid ethyl ester 87 and β-aminocrotonic acid ethyl ester 6.
The solution of No. 57 was heated to boiling temperature, and after cooling, the melting point was 156 ~
2methoxymethyl-6-methyl-4-(4'-methylsulfonylphenyl)-1,4- in the form of yellow crystals at 158°C.
Dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

Yield: 65% of theory.

Reference Example 17 After heating a solution of 3-carboethoxybenzaldehyde 8.97, γ-methoxyacetoacetic acid ethyl ester 87 and β-aminocrotonic acid mesal ester 67 in 30 ml of ethanol for several hours, light yellow crystals with a melting point of 108-110°C were obtained. 2-methoxymethyl-6-methyl-4-(3
'-carboethoxyphenyl)-1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid ethyl ester was obtained.

Yield: 60% o of theory Reference example 18 7.6y of 4-methylmercaptobenzaldehyde, 167y of γ-methoxyacetoacetic acid ethyl ester and 6ml of aqueous concentrated ammonia in 30ml of ethanol are heated to boiling temperature for 6-8 hours to reduce the melting point. 2,6-dimethoxymethyl-4-(4'-methylmercaptophenyl)1,4-dihydropyridine-3,5- in the form of grayish brown crystals at 136-138°C.
Dicarboxylic acid diethyl ester was obtained.

Yield: 50% of theory.

(a) When 4-methylmercaptobenzaldehyde 7.67 and β-amino-γ methoxycrotonic acid ethyl ester 167 in 40 me of ethanol were heated to boiling temperature overnight, a similar compound with a melting point of 137-138°C was obtained.

Reference Example 19 3-Methoxy-4-hydroxybenzaldehyde 7,67, γ-methoxymethylacetic acid ethyl ester 16y and 12 ml of aqueous concentrated ammonia in 30 ml of ethanol were heated to boiling temperature overnight and after cooling, the melting point was 140-142.
2 in pale yellow crystalline form at a yield of 40% of theory.
・6-dimethoxymethyl-4-(3/-methoxy-47
-Hydroxyphenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid diethyl ester was obtained.

Example 1 1 part of 3-nitrobenzaldehyde in 60 ml of ethanol
5.17, β-amino-γ-methoxycrotonic acid ethyl ester 167 and oxalacetic acid diethyl ester 19
After heating a solution of 1 under reflux for 12 hours, the mixture was evaporated under vacuum to give 2-methoxymethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5 in an almost quantitative yield. - 6-tricarboxylic acid triethyl ester was obtained as a yellow oil (N5O-1.5353).

Reference Example 20 A solution of 1.157 sodium in 25 ml of ethanol was added to the triester 237 obtained according to example 20, which was then heated to boiling temperature overnight in a total volume of 200 ml of ethanol and then this mixture was concentrated under vacuum, the residue was taken up in water and after filtration the product was precipitated with dilute sulfuric acid.

2-Methoxymethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester-6-carboxylic acid in the form of yellow crystals with a melting point of 146°C in a yield of 50% of theory. Acid was obtained. Reference example 21 10 pyridine-3-aldehyde in 40 ml ethanol
．． 2ml, γ-methoxyacetoacetic acid ethyl ester 16
A solution of 7 and β-iminoglutarate ethyl ester 207 was heated to boiling temperature overnight, then it was cooled.

After cooling, 2-methoxymethyl-4-(
(β-pyridyl)1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester-6 monoacetic acid ethyl ester was obtained. Example 2 Pyridine-2-aldehyde in 40 ml of ethanol 5.
2m11 isobutyroyl acetic acid ethyl ester 87 and β
A solution of -amino-γ-methoxycrotonic acid ethyl ester (boiling point 112-116°C/10 mm) 87 was heated to boiling temperature overnight and concentrated, the residue was taken up in ether and converted into the hydrochloride salt using ethereal hydrochloric acid. -methoxymethyl-6-isopropyl-4-(α-pyridyl)-1
- 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was precipitated.

Pale yellow crystals with a melting point of 198-200°C.

Yield: 60% Reference Example 22 3-Nitrobenzaldehyde in 40 ml of pyridine 7.
57, γ-methoxyacetoacetic acid ethyl ester 16y and methylamine hydrochloride 57 were heated to 90-100°C for 5-6 hours, the mixture was concentrated under vacuum, the residue was taken up in ether, and the ether solution was diluted with dilute hydrochloric acid and water. Wash with
Dry and evaporate.

1-Methyl-2,6-dimethoxymethyl-4(3'-nitroJyanyl)-1,4-dihydropyridine-3,5-
Dicarboxylic acid diethyl ester was obtained as a brown oil in 90% yield.

Example 3 0.1 mol of 2-(3-nitrobenzylidene)acetoacetic acid ethyl ester and 0.1 mol of 2-amino-γ monoethoxycrotonic acid ethyl ester were heated under reflux for 15 hours in 150 ml of ethanol. , the solvent is evaporated to obtain 2-ethoxymethyl-6-methyl 4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.

Yellow crystals with a melting point of 120-122°C, yield 78% of theory Example 4 0.1 mol of 2-(2-chlorobenzylidene)acetoacetic acid ethyl ester and 0.1 mol of 2-amino- 2-γ monoethoxy-crotonic acid ethyl ester was heated under reflux in 180 ml of ethanol for 12 hours.

After distilling off the solvent, 2-ethoxymethyl-6methyl-4-(
2'-chlorophenyl)-1.4dihydropyridine-3
- 5-dicarboxylic acid diethyl ester was obtained. Melting point 114-116° C. yield 63% of theory Example 5 According to Example 25, 0.1 mol of 2-(2-trifluoromethylbenzylidene)-acetoacetic acid ethyl ester and 0.1 mol of 2- Amino-γ-ethoxycrotonic acid ethyl ester was reacted to form 2-ethoxymethyl-6-methyl-4-(2'-trifluoromethylphenyl-1,4
-Dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained.

The melting point was 112° C., and the yield was 62% of theory.The main embodiments and related matters of the present invention are as follows. 1
．． In the general formula, R is a hydrogen atom or a saturated or unsaturated aliphatic group; R1 is an alkoxyalkyl group; R2 and R5 each optionally have one or two hydroxy substituents, and R4 is hydrogen, alkyl , alkoxyalkyl or -(CH2)n-COOR5 group, where R5 is hydrogen or an alkyl group and n is an integer from O to 3; X is optionally nitro, nitrile, azide, Alkyl, alkoxy, hydroxyl, acyloxy, carbalkoxy, amino, acylamino, monoalkylamino, dialkylamino, S(0)ml-alkyl(
where m is 011 or 2), phenyl, trifluoromethyl, and an aryl group having one, two, or three identical or different substituents selected from the group consisting of a halogen group; benzyl, styryl; , cycloalkyl or cycloalkenyl; or quinolyl, isoquinolyl, pyridyl, pyrimidyl, optionally with one or more identical or different substituents selected from alkyl, alkoxy, dialkylamino, nitro and halogen groups; , a diphenyl, furyl or pyryl group, or a salt thereof.

). R is a hydrogen atom; R1 is an alkoxyalkyl group having 1 or 2 carbon atoms in the alkyl portion and 1, 2 or 3 carbon atoms in the alkoxy portion; R2 and R3 each have 1 carbon atom;
~4 identical or different alkyl groups; R4
is an alkyl group of 1 to 4 carbon atoms, the alkyl part has 1 or 2 carbon atoms, and the alkoxy part has 1 to 4 carbon atoms.
an alkoxyalkyl group having 3, a carboxyl group,
or CH2-COOalkyl or -COOalkyl, where [alkyl] is alkyl of 1 to 4 carbon atoms; and X is phenyl, or alkoxy and alkylthio groups each of 1 or 2 carbon atoms. , nitrile, nitro, hydroxyl, trifluoromethyl, fluorine, chlorine and iodine groups, and from 2 to carbon atoms
phenyl with one or two substituents selected from four carbalkoxy groups, or pyridyl or 2-
The compound in 1 above, which is a dimethylaminopyrimidyl group.

{． 2-Ethoxymethyl-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and its salt. 1,2-ethoxymethyl-
6-Methyl-4-(3'iodophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and its salt.

]． 2-Ethoxymethyl-6-methyl-4-(3'nitrophenyl)-1,4-dihydropyridine-3,5-
Dicarboxylic acid diethyl ester and its salts.

6, 2-ethoxymethyl-6-methyl-4-(2'chlorophenyl)-1,4-dihydropyridine-3,5-
Dicarboxylic acid diethyl ester and its salts.

7.2-Ethoxymethyl-6-methyl-4-(21 trifluoromethylphenyl)-1,4-dihydroxypyridine-3,5-dicarboxylic acid diethyl ester and its salt.

8, 2-isopropoxymethyl-6-methyl-4α-
Pyridyl-1,4-dihydropyridine 3,5-dicarboxylic acid diethyl ester and its salt.

9.2-Ethoxymethyl-6-methyl-4-('2/dimethylaminopyrimidyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and its salt.

10.2,6-dimethoxymethyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and its salt.

11.

2,6-dimethoxymethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5
-Dicarboxylic acid diethyl ester and its salt.

12,2,6-(diethoxymethyl)-4-(2'nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylic acid diethyl ester and its salt.

13.2.6-(diethoxymethyl)-4-α-pyridyl-1.4-dihydropyridine-3.5 dicarboxylic acid diethyl ester and its salt.

14.2-Methoxymethyl-6-methyl-4-(37carboethoxyphenyl)-1,4-dihydropyridine-
3-carboxylic acid methyl ester 5-carboxylic acid ethyl ester and its salt.

15. Compounds according to 1 above as specified above other than compounds according to 3 to 14 above.

16. (a) Reacting the enamine of the general formula with the ylidene derivative of the general formula, or c) Reacting the enamine of the general formula with the ylidene derivative of the general formula, c) Reacting the β-ketocarboxylic acid ester of the general formula with the enamine of the general formula and (d) a β ketocarboxylic acid ester of the general formula is reacted with an enamine of the general formula and an aldehyde of the general formula; or (e) (R1 is the same as R4 and R2 is R3
), 2 mole parts of a β-ketocarboxylic acid ester of the general formula are reacted with 1 mole part of an amine of the general formula or its salt and 1 mole part of an aldehyde of the general formula, provided that the general formulas () to () 16. The method for producing a compound according to any one of 1 to 15 above, wherein R, R1, R2, R3, R4 and X are as defined in 1 or 2 above.

17. A β-ketocarboxylic acid ester of general formula is reacted with an amine of general formula, where in general formulas () and () R, R1 and R2 are as defined in 16 above, optionally an enamine of general formula (). The method according to 16(a) above, comprising a pre-step of manufacturing.

18. a β-ketocarboxylic acid ester of the general formula is reacted with an amine of the general formula, where in the general formulas () and () R, R3 and R4 are as defined in 16 above, optionally an enamine of the general formula (); The method according to 16(b) above, comprising a pre-step of manufacturing.

19. The method according to 17 or 18 above, when the enamine of general formula () or (), respectively, is not isolated before the reaction with the ylidene derivative of general formula () or (), respectively.

20. The reaction is carried out using alcohol, ether, aliphatic carboxylic acid, dialkylformamide, alkyl nitrile, dimethyl sulfoxide, liquid heteroaromatic base, as a diluent,
or a mixture of two or more thereof, or a mixture of water and one or more of these, according to any one of 16 to 19 above.

21. 16-2 above when carrying out the reaction at 50-100°C
0 method.

22. A method for producing the compound according to 1 above, as exemplified in any of the Examples substantially as described herein.

23. The compound in 1 above when produced by the method according to any one of 16 to 22 above.

24. Compounds according to any of 1 to 15 or 23 above as a mixture with a solid or liquefied gaseous diluent or with a liquid diluent other than a solvent with a molecular weight of less than 200, unless a surfactant is present. A pharmaceutical composition comprising as an active ingredient.

25. A pharmaceutical composition comprising as an active ingredient a compound according to any of 1 to 15 or 23 above in the form of a sterile or isotonic aqueous solution.

26. The composition according to 24 or 25 above, containing 0.5 to 95% by weight of active ingredient.

27. A composition according to 24, 25 or 26 above substantially as described herein.

28. A medicament in dosage unit form consisting of a compound according to any of 1 to 15 or 23 above, alone or in a mixture with a diluent.

29. A tablet or pill consisting of a compound according to any one of the above 1 to 15 or 23 (.) alone or in a mixture with a diluent;
Drugs in the form of dragees, capsules, ampoules or suppositories.

30. A medicament in dosage unit form substantially as described herein.

31, consisting of administering to humans and non-human animals an active compound according to any of 1 to 15 and 23 above, either alone or in a mixture with a diluent, or in the form of a medicament according to 28, 29 or 30 above. A method for preventing blood circulatory system disorders in the animal.

32. 32. The method according to 31 above, wherein the active compound is administered parenterally.

33. 0.005 to 10 active compounds/Kg body weight/2
The method according to 32 above, when administered in a 4 hour dose.

34. The method according to 31 above, wherein the active compound is administered orally.

35. Active compound from 0.1 to 50 m9/K9 body weight/24
35. The method according to 34 above, when administered in hourly amounts.

36. 36. A method according to any of 31-35 above, substantially as described herein.

Claims (1)

[Claims] 1. Reacting the enamine of the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) with the ylidene derivative of the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V), provided that the general formula In (IV) and (V, R, R^1, R^
2. A general formula characterized by the fact that R^3, R^4 and ^1 is an alkoxyalkyl group;
R^2 and R^3 are the same or different groups consisting of linear saturated hydrocarbon chains; R^4 is alkyl or -
(CH_2)_n-COOR^5 groups (here R^
5 is an alkyl group and n is 0); X is an aryl group optionally having one substituent selected from the group consisting of nitro, trifluoromethyl, and halogen groups;
A method for producing a compound which is an alkoxyalkyl-1,4-dihydropyridine ester or a salt thereof having a pyridyl group.