PL94266B1 - - Google Patents

Description

Patent description published: December 31, 1977 94266 MKP C07d 29/40 Int. Cl1. C07D 211/82 READING ROOM I Ur7edu Pcsl ^ i ^ wego j'l temw-: Inventor: Proprietor of the patent: Bayer Aktiengesellschaft, Leverku $ en (Federal Republic of Germany) Method for the production of symmetrical alkoxyalkyl-1,4-dihydrogen pyridines The invention relates to a method for the production of new of symmetrical 1,4-dihydropyridines used as medicaments, preferably as vasodilating agents, blood vessels, especially as agents against coronary artery disease. It has been found that the process of the invention produces new e-alkoxyalkyl-dihydroxy-pyridines of the formula I, in which R is hydrogen or the group alkyl of 1-4 carbon atoms, R1 is alkoxyalkyl group of 2-6 carbon atoms, R2 and R3 are the same or different and represent an alkyl or alkoxy group of up to 4 carbon atoms, R4 is hydrogen, alkyl of 1-4 atoms carbon, 2-6 carbon alkoxyalkyl or the residue - {CH2) n-COORf where R5 is hydrogen or an alkyl group of 1-4 carbon atoms and n is from 0 to 3 and X is phenyl residue optionally substituted one or three times with nitro, cyano, azido, hydroxy, halogen, trifluoromethyl, alkyl, alkoxy, carboalkoxy, alkylthio, SOy-alkyl and / or alkylamino groups, the said alkyl and alkoxy groups having 1-2 atoms carbon, or X is a pyridyl or pyrimidyl group, optionally substituted with a dimethylamino group and salts thereof, which have a strong effect on the coronary system. The method of the invention consists in that the alkoxyalkyl dihydrogen pyridines of formula I are obtained, if a) esters of the O-keto carboxylic acids of formula 2, in which R 1 and R 2 are as defined above, will be reacted with the amines of formula 3, in which R is as defined above or their salts, optionally after separation - optionally formed from O-keto carboxylic acids and amines or salts amines, enamines of formula 4, in which R, R 1 and R 2 have the meaning given above, with the ylidene derivatives of formula 6, in which X, R 3 and R 4 have the meaning given above or If b) esters of β-ketocarboxylic acids of formula 6, in which R3 and R4 are as defined above, will be reacted with amines of formula III, in which R is as defined above, or with salts of these amines optionally after separation of - optionally formed from esters of β-keto carboxylic acids and amines or amine salts of enamines of formula 7 wherein R, R 3 and R 4 are as defined above, with the ylidene derivatives of formula 8, wherein R 1, R 2 and X have the meaning given above, or 2 94 266 c) if esters of O-keto carboxylic acids of formula B, in which R3 and R4 have the above meaning, react with enamines of formula 4, in which R, R1 and R2 are given with aldehydes of formula 9 in which X is as defined above, or if d) esters of O-ketocarboxylic acids of formula 2r in which R1 and R2 have the above meaning, will be reacted with enamines b in formula 7, in which R, R3 and R4 have the meanings given above and with aldehydes of the formula § in which X is as defined above, and if desired, that the compounds obtained according to procedure a) to d) are salt-prepared with an acid. The alkoxyalkyl-1,4-dihydrogen pyridines obtained according to the invention show unexpectedly strong potency on the vessels. If starting materials are 3,4,5-trimethoxy-benzylideneacetyl-acetic acid methyl ester, 7-isopropoxy-acetoacetic acid methyl ester and methylamine (or 0-methylamino-7-isopropoxycrotonic acid / 4), then the course of the reaction for variant a) can be represented by the scheme 1 * If the starting components are 3-chlorobenzylidene-7-methoxyacetyl-acetic acid ethyl ester, acetone dicarboxylic acid diethyl phther and ammonia (relative to methylglutarate ethyl ester) / 7), then the course of the reaction for variant b) can be represented by the scheme 2 If 3-ethylsulfones are used as starting components lobenzaldehyde, 0-amino-7-methoxycrotonic acid propyl ester and propionylacetic acid ethyl ester, then the course of the reaction for variant c) can be represented by scheme 3. If 2-formylpyridine, 7-methoxyacetyl ylethyl ethyl ester are used as starting materials and O-amrno-7-ethoxycrotonic acid ethyl ester, then the course of the reaction for variant d) can be represented by scheme 4. The salts of the compounds of formula I obtained according to the invention are non-toxic, physiologically tolerable acid addition salts. The inorganic and organic acids which form such salts with the compounds of formula I are, for example, hydrocarboxylic acids, e.g. hydrochloric and hydrobromic acid, in particular hydrochloric acid, phosphoric acids, sulfuric acid, nitric acid, mono and difunctional carboxylic acids and hydroxycarboxylic. Such as, for example, acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, sorbic, lactic and naphthalene-1,6-carboxylic acids. Soybean is prepared according to generally accepted methods, e.g. by dissolving a base in ether and applying a suitable solution to it. acid. Examples include; Methoxyacetylacetic acid methyl ester, 7-methoxyacetyl acetic acid ethyl ester, 7-methoxyacetylacetic acid propyl ester, 7-methoxyacetylacetic acid isopropyl ester, 7-methoxyacetylacetic acid butyl ester, 7-methoxyacetylacetic acid ethyl ester, 7-ethoxyacetyl acetic acid ethyl ester, 7-ethoxyacetyl acetic acid methyl ester, 7-ethoxyacetylacetic acid ethyl ester 7-ethoxyacetyl acetic acid, 7-propokiyacetyl acetic acid ethyl ester, 7-propoxyacetyl acetic acid isopropyl ester, 1-propoxy ester. 7-propoxyacetylacetic acid butyl ester, 7-isopropoxyacetylacetic acid methyl ester, 7-l-isopropoxyacetylacetic acid butyl ester, 7-butoxyacetylacetic acid ethyl ester, 7-butoxyacetylacetic acid isobutyl ester, 7-butoxyacetylacetic acid isobutyl ester, 7-isopropoxyacetyl acetic acid methyl ester, 7-methylacetyl acetic acid isobutyl ester 7-methylacetyl acetic acid ester * 7-isopropoxyacetylacetic acid 7-methoxypropionylacetic acid, 7-propoxypropionylacetic acid propyl ester, 7-ethoxypropionylacetic acid ethyl ester and 7-methoxy-7-ethylpropionylacetic acid ethyl ester # The amines of formula III used in the process of the invention are already known. For example, it is mentioned; ammonia, methylamine, ethylamine, propylamine, butylamine, isopropylamine, isobutylamine, allylamine. The enamine-7-ketocarbonyl compounds of the formula IV used in the process according to the invention can be prepared by generally known methods from the corresponding dicetone compounds (AC Cope, 1017 JACS67 (1945)) Examples include: 7-methoxy-7 aminocrotonic acid methyl ester, 7-methoxy-aminocrotonic acid ethyl ester, 7-ethoxy-O aminocrotonic acid propyl ester, 7-1'-propoxy-IS-methylaminocroton acid ethyl ester * 7-butoxy-7-methyl-4-aminocrotonic acid ethyl ester. The ylidene / 3-keto carboxylic acid esters of the formula 5 used in the process according to the invention are partially known and can be prepared by generally known methods (Org. Reactions XI, 204 ff. (1967)) Examples include: ylidene-O-keto carboxylic acid esters: 94266 3 benzylidene-7-methoxyacetylacetic acid ethyl ester, 2'nitrobenzylidene-7-methoxyacetylacetic acid ethyl ester, 3'-methoxybenzylidene-7-ethoxyacetylacetic acid methyl ester, 3'-4'-dimethoxybenzylidene-7-propoxyacetylacetic acid propyl ester, 2'-trifluoromethylbenzylidene-7-methylacetylacetylacetic acid ethyl ester, 2'-propylchlorobylacetylacetic acid, 2'-chloro-acetylacetylacetic acid ester , 3-mercaptobenzylidene-7-butoxyacetylacetic acid ethyl ester, benzylideneacetylacetic acid methyl ester, 2'-nitrobenzylideneacetylacetic acid methyl ester, 3'-nitrobenzylideneacetylacetic acid propargyl ester, 3'-nitrobenzylideneacetylacetic acid ethoxy-acetic acid ester-3-idoxylacetate ester-ethoxy-acetyl ester 3'-nitrobenzylideneacetylacetic acid, 4'-nitrobenzylideneacetylacetic acid isopropyl ester, 3''nitro-6'-chlorobenzylideneacetylacetic acid methyl ester, 2'cyanobenzylideneacetylacetic acid ethyl ester, 3'-Iidene-propionylacetylacetic acid ester, 3'-methylacetylacetyl acetic acid ethyl ester. -nitro-4 'chlorobenzylidene acetyl acetic acid, 2'-nitro acid methyl ester 4'-methoxybenzylideneacetylacetic acid, 2'-cyano-4 'methylbenzylideneacetylacetic acid ethyl ester, 2'-azidobenzylideneacetylacetic acid ethyl ester, 2'-methylthiobenzylidene-acetylacetic acid isopropyl ester, 2'-methylthiobenzylidene-acetylacetic acid ethyl ester 2'-ethyl-acetylacetic acid ester-ethyl-acetylacetic acid sulphonylmethylacetylacetic acid, 2'-nitrobenzylidene oxalacetic acid diethyl ester, 2'4''-dioxymethylene benzylideneacetic acid dimethyl ester, 3'ethoxybenzylidene - / α-ketoglutaric acid diethyl ester, (2'-ketoglutaric acid methyl acetylacetyl ester) methylideneacetylacetic acid, pyridylmethylacetylacetic acid methyl ester, pyridylmethylacetylacetic acid methyl ester, pyridylmethylideneacetylacetic acid aallyl ester, pyridylmethylideneacetylacetic acid cyclohexyl ester, pyridylmethylideneacetylacetic acid ester, pyridylmethylacetyl ester, pyridylmethylacetyl ester * pyridylacetylacetic acid methyl ester 4'-6'-dimethoxy76'-pyrimidyl / -methylideneacetylacetic acid ethyl ester (2'-tenyl / methyl and idenoacetylacetic acid, (2'-furyl / -methyl and ideneacetylacetic acid) methyl ester (2'-pyrrole) [beta] -methylideneacetylacetic acid, α-pyridylmethylidene I-idenopropionylacetic acid methyl ester, 2'-, 3 '- or 4'-methoxybenzylideneacetylacetic acid ethyl ester, 2'-methoxybenzylideneacetylacetic acid propargyl ester, 2'-methoxybenzylideneacetylacetic acid methyl ester 2'-ethylacetylacetyl acetic acid ester 2'-ethylacetyl acetic acid ester butoxybenzyl ideneacetyl acetic acid, 3 ', 4', 5, -trimethoxybenzylideneacetylacetic acid allyl ester, 2'-methylbenzylideneacetylacetic acid methyl ester, 2'-methylbenzyl-idenopropionylacetic acid-O-propoxyethyl ester, 3'-methyl-iobenzyl-ideno-4'-ethylacetic acid O-propoxyethyl ester -bromobenzylideneacetylacetic acid, 2 ', 3'- or 4'chloro / bromo / fluoroAiodinzylideneacetylacetic acid ethyl ester, 3'chlorobenzylidene-propionylacetic acid ethyl ester, propyl ester 2 ', 3' - or 4'-trifluoromethylbenzylideneacetylacetic acid, 2'carbetoxybenzylideneacetylacetic acid ethyl ester, 4-carboxyisopropylbenzylideneacetylacetic acid propyl ester, cyclohexyl and cyclohexenoxy esteric acids used in the invention as ester-esteroxy esters. , the tf-keto carboxyls of formula VII are known and can be prepared according to generally known methods (B. Johnson and H. Phesnoff, J.A.C.S. 36,1744 (1914); Pohl, Schmidt, US Pat. US Am. No. 2 351366; A.C. Cope, J.A.C.S. 67, 1017 (1945)) 4 94 266 Examples are O-dicarbonyl compounds: 7-methoxyacetylacetic acid methyl ester, 7-methoxyacetylacetic acid ethyl ester, 7-methoxyacetylacetic acid propyl ester, 7-methoxyacetylacetic acid isopropyl ester, 7-methoxyacetylacetic acid ester 7-Methoxyacetylacetic acid, 7-ethoxyacetylacetic acid methyl ester, 7-ethoxyacetylacetic acid ethyl ester, 7-ethoxyacetylacetic acid propyl ester, 7-propoxyacetylacetic acid ethyl ester, 7-propoxyacetyl acetic acid isopropyl ester, 7-propoxyacetyl acetic acid isopropyl ester, 7-propoxyacetyl acetic acid isopropyl ester, 7-propoxyacetyl acetic acid isopropyl ester, 7-propoxyacetyl acetic acid 7-isopropoxyacetylacetic acid methyl ester, 7-isoprocoxyacetylacetic acid butyl ester, 7-butoxyacetoacetic acid ethyl ester 7-butoxyacetoacetic acid isobutyl ester, 7-isobutoxyacetylacetic acid propyl ester, 7-isobutoxyacetylacetic acid ethyl ester, 7-propyl ethyl acetic acid methyl ester 7-propyl ester methyl ester 7-propyl ester methyl ester propoxypropion ylacetic acid, ethyl 5-ethoxyproplonylacetic acid ester, 6-metaxyβ-ethyl-propionylacetic acid ethyl ester, 3,5-formoacetic acid ethyl ester, formoacetic acid butyl ester, formoacetic acid butyl ester, methyl acetoacetic acid methyl ester, acetoacetic acid methyl ester acetoacetic acid, acetoacetic acid isopropyl ester, acetoacetic acid butyl ester, acetoacetic acid 1I butyl ester, acetoacetic acid (alubjff / hydroxyethyl ester, acetoacetic acid la- or py-methoxyethyl ester, acetoacetic acid (alpha or O / ester) ester) (a- or O - / - n-propoxyethyl acetoacetic acid, acetoacetic acid allyl ester, acetoacetic acid propargyl ester, propionyl acetic acid ethyl ester, butyryl acetic acid ethyl ester, isobutyryl acetic acid ethyl ester, dimethyl acetic acid ester, dimethyl acetic acid oxy ester isopropyl acid Acetone-dicarboxylic acid dimethyl ester, acetone dicarboxylic acid diethyl ester, acetone dicarboxylic acid dibutyl ester, O-keto-adipic acid diethyl ester. Enarmecarboxylic acid esters: 7-methoxy-ethoxy-ethyl ester of 7-methoxy-ethyl ester. -O-aminocrotonic acid, 7-ethoxy-α-emphnocrotonic acid propyl ester, 7-isopropoxy-methylaminocrotonic acid ethyl ester, 7'-butoxy-methyl-amino-crotonic acid ethyl ester. Acid / Jaminacrotonic acid methyl ester, O-amlnocrotonic acid ethyl ester Aminocrotonic acid (5-aminocrotonic acid isopropyl ester, O-aminocrotonic acid butyl ester, O-aminocrotonic acid (α- or methoxystyl) ester, Ammothrotonic acid, O-ethoxyethyl ester, aminocrotonic acid, propoxyethyl ester, cyclaminohexyl ester) aminocrotonic acid, O-amino- (5-ethylacrylic acid) ethyl ester, acid dimethyl ester Iminosuccinic acid, iminosuccinic acid diethyl ester, iminosuccinic acid dipropyl ester, iminosuccinic acid dibutyl ester, O-iminoglutaric acid dimethyl ester, Mminoglutaric acid diethyl ester, iminosuccinic acid dimethyl adipyl ester, iminosuccinic acid dimethyl adipyl ester, iminosuccinic acid dimethyl ester [J-ethylaminocrotonic acid ethyl ester, [5-methylquinoglutaric acid diethyl ester. The ylidene-O-keto-carboxylic acid esters of the formula VII used in the process according to the invention are not yet known. As mentioned in the compounds of formula 5, they can be prepared by generally known methods. Examples are the esters of ylidene-O-keto carboxylic acids: methyl ester of benzylidene-2-ethoxyacetyl acetic acid methyl ester, methyl ester of 2'-nitrobenzylidene-b-propoxyacetyl acetic acid <2'-Nitrpbenzylidene-7-propoxyacetylacetic acid methyl ester, 3'-nutro-benzylidene-7-methoxyacetylacetic acid methyl ester, 3'-nitro-benzylideneacetylacetic acid propyl ester, 4'-nitro-methyl-acetyl acetic acid isopropyl ester, 4'nltribenzyl ester 6'-chlorobenzylidene-1-isopropoxyacetylacetic acid, 2'-cYJanobenzylidene-7-n-butoxyacetylacetic acid methyl ester, 94 266 5 2'-cyanobenzylidene-8-ethoxy'propionylacetic acid methyl ester, 2'-methoxy-2-nitro-nitromethyl ester 2'-Azidobenzylidene * 7-methoxyacetylacetic acid, 7-propoxyacetylacetic acid ethyl ester, 2'-methylthiobenzylidene-7-ethoxyacetylacetic acid methyl ester 3'-Methylthiobenzylidene isopropyl ester, 7-methylthoxyacetylacetic acid, 2'-sulfinylmethylbenzylideneacetylacetic acid ethyl ester, 2'-sulfonylmethylmethyl ester, 2'-methoxyacetylacetic acid ethyl ester, (2'-tethethoxy) ethyl ester methoxyacetylacetic acid, (1f-isochlnolyl / -methylidene-γ-ethoxyacetylacetic acid methyl ester, α-pyridylmethylidene-γ-propoxyacetylacetic acid ethyl ester, 4 \ 6'-dimethoxy75'-pyrimidylacetyl / ethylacetyl acetic acid ethyl ester) (2'-Tenyl), [beta] -methoxymethylideneacetylacetic acid, (2'-furyl) -7-ethoxy-methylideneacetylacetic acid, ethyl ester of 2'-, 3'- or 4'-methoxybenzylidene, γ-methoxyacetylacetic acid, ethyl ester 2'-isopropoxybenzylidene-7-isopropoxyacetylacetic acid, 3'-butoxybenzylidene-γ-methoxyacetylacetic acid methyl ester, 3 ', 4', 5'-trimethoxybenzylidene-γ-propoxyacetylacetic acid methyl ester, 2'-methylobe acetic acid ester nzylidene-2'-methoxy-propionylacetic acid, 2 ', 3' or 4'-trifluoromethylbenzylidene-7-methoxyacetylacetic acid isopropyl ester, 2'-trifluoromethylbenzylidene-methoxyacetylacetic acid ester, 3-methoxyacetylacetyl-ethylacetyl acetic acid ester-7fluoromethylacetyl acetic acid isopropyl ester 2'-carbetoxybenzylldene-γ-methoxyacetylacetic acid ethyl ester, 3'-carboxymethylbenzylidene-γ-ethoxyacetylacetic acid methyl ester, 4-carboxyisopropylbenzylidene-y-propoxyacetylacetic acid isopropyl ester, by the methods of the invention known or used in the present invention. (E. Mossetig, Org. Reactions, VIII, 218ff, (1954)) Aldehydes are mentioned as examples; benzaldehyde, 2-, 3- or 4-methoxybenzaldehyde, 2-isopropoxybenzaldehyde, 3-butoxybenzaldehyde, 3,4-dieoxymethylenebenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 2-, 3- or 4-chloro aldehyde / bromo / iodo / fluorobenzoic, 2,4- or 2,6-dichlorobenzaldehyde, 2,4-dimethylbenzaldehyde, 3,5-diisopropyl-4-methoxybenzaldehyde, 2-, 3- or 4-nitrobenzaldehyde, aldehyde 2, 4- or 2,6-dinitrobenzoic aldehyde, 2-nitro-6-br6-mobenzaldehyde, 2-nltro-3-methoxy-6-chlorobenzaldehyde, 2-nitro-4-chlorobenzaldehyde, 2-nitro-4-methoxybenzaldehyde, 2- , 3- or 4 * trifluoromethylbenzaldehyde, 2-, 3- or 4-dimethylaminobenzaldehyde, 4-dibutylaminobenzaldehyde, acetaminobenzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 2-nitro-4-cyanobenzaldehyde 3-aldehyde chloro-4-cyanobenzaldehyde, 2-, 3- or 4-methylthiobenzaldehyde, 2-methylthio-5-nitrobenzaldehyde, 2-butylthiobenzaldehyde, aldehydes d 2-, 3- or 4-methylsulfinylbenzaldehyde, 2-, 3- or 4-methylsulfonylbenzaldehyde, 2-carboethoxybenzaldehyde, 3Hzopropoxy benzaldehyde, 4-carbobutoxybenzaldehyde, 3-nitro-4-carboethoxybenzaldehyde, cinnamaldehyde, aldehyde , formylcyclohexane, 1-formylcyclohexene-3,1-formylcyclohexin-1,3, 1-formylcyclopentene-3, a-, 0- or 7-formpyridinar, 2-formyl-6 "methylpyridine, 2-formylfuran, 2-formyltlphen and 2-formylpyrrole , 2-formyl-N-methylpyrrole, 2-, 3- or 4-azido-benzaldehyde, 4-formylpyrimidine, 2-formyl-5-nitro-6-methylpyridine, 1- or 2-naphthoaldehyde, 5 * bromo-1 aldehyde -naphthoic, 2-formylquinoline, 4-formyl * 7-methoxyquinoline, 1-formylisoquinoline. In the variants of processes according to a) to d), water and all inert organic solvents are used as diluents. These preferably include alcohols, e.g. lower alkyl alcohols, preferably having 1 to 4 carbon atoms, such as ethanol, methanol, isopropanol, an ether, e.g. lower dialkyl ethers, preferably having 3 to 5 carbon atoms, such as ethyl ether or ring ethers such as tetrahydrofuran, dioxane, lower aliphatic carboxylic acids, preferably having 2-5 carbon atoms, such as acetic acid, propionic acid, lower dialkylformamides, preferably having 1 or 2 carbon atoms in each alkyl group, such as dimethylformamide, lower alkyl nitriles, preferably having 2-4 carbon atoms, such as acetonitrile, methyl sulfoxide, liquid heterparomatic bases such as pyridine, as well as mixtures of these solvents with one another, including water.94 266 The reaction temperatures of process variants a) to d) can be varied within a fairly wide range. In general, working in the range of about 20 and about 150 ° C, preferably between 50 and 1 ° C, and especially at the boiling point of the solvent used. The reactions can be carried out under normal pressure as well as under increased pressure. In general, normal pressure is used. When carrying out the process variants according to the invention, the starting materials for the reaction are preferably used in each case in molar amounts in about a) to d). The amine or its salt to be used is preferably added in an excess of 1 to 2 mol. The molar ratios can be varied widely without affecting the result. The new active substances of the formula I prepared according to the invention include, in addition to the compounds described in the examples, the following compounds: 1-methyl-2,6-dimethoxymethyl acid dipropyl ester -4- (3 \ 5'-dioxy-4'-iodophenyl) -1,4-dihydropyridine-3,5-dicarboxylic-2-propyl-6-propoxymethyl-4 acid (3 / propyl) ester - (2'-methylsulfonylphenyl) -1,4-dihydrogen pyridine ~ 3,5-dicarboxylic acid, 1-isopropyl-2r6-dimethoxymethyl-4- (3-azidophenyl) -1,4-dihydrogen-pyridine -3,5 ester -dicarboxylic acid, 2,6-dimethoxymethyl-4V-3-carboxyphenyl (-1,4-dihydro-pyridine-3,5-d-carboxylic acid) ester (3 (methyl) (5) propyl l-benzyl) ester 1,2-Dibutyl-6-butoxyethyl-4- (pyridyl) -1,4-dihydrogen-pyridine-3,5- dibutyl ester -dupropoxymethyl-2-ZS-quinolyl / 1-dibutyl ester dicarboxylic acid, 2,6-Diethoxyethyl-4-isoquinolyl (-1,4-oN-difaoropyridine-3f5-dicarboxylic acid (3) ethyl- (5) isobutyl ester, 2f6-dimethoxymethyl-4- (5 '- [4f6n-dimethoxy] -pyrimidyl) acid diethyl ester 1-Ethyl-2-methoxyethyl-6-propyl-4- (2 '- [- nitrofuryl] - N - 1r4-dihydrogenpyridine- O-ethoxyethyl ester (N-1r4-dihydrogen-pyridinium-3,5-dicarboxylic acid) 3-carboxylic acid, 2,6-dibutoxymethyl-4- (2 '- N-propylpyrl) -1.4 "dihydrogen pyridine-3,5-dicarboxylic acid dimethyl ester, (3 (methyl) 5) isopropyl 2,6- ester dimethoxymethyl-4- (3'-nitro-4'-oxyphenyl) -1,4-dihydroxy-pyridine-3,5-dicarboxylic acid, 2-methoxymethyl-6-isopropoxyethyl- (3- (methyl-) 5) -propyl ester 4 * / 2 '- [4'-bromothienyl] / - 1,4-dihydropridine-3,5-dicarboxylic acid. The new compounds prepared according to the invention can be used as medicaments, especially as active substances acting on vessels and circulation. according to the invention, they show a broad and versatile pharmacology Specific spectrum of action. In particular, the compounds according to the invention have the following basic action: The new compounds produce clear and long-lasting dilatation of the coronary vessels when administered parenterally, orally and under the tongue. This effect on the coronary vessels is exacerbated by the concomitant cardiac relief effect similar to that of nitrite. These compounds affect relatively the metabolism of the heart in terms of energy conservation. The new compounds lower the blood pressure in animals with normal and increased blood pressure and can therefore be used against hypertension. The excitability of the system causing the sensitivity and excitement of the heart as a result there is an anti-fibrillation effect, which can be demonstrated with therapeutic doses. Under the influence of these compounds, the tension of the smooth muscle of the vessels is significantly reduced. This vasodilating effect may be vascular-wide or may appear more or less to an isolated extent including the described vascular regions (such as the central nervous system). These compounds exhibit a strong muscle relaxant effect that is pronounced with respect to smooth muscle of the stomach, intestinal tract, urogenital tract and respiratory system. These compounds affect the level of cholesterin or blood lipids.94 266 7 The new compounds according to the invention are therefore suitable for the prevention, amelioration and treatment of diseases for which the above-mentioned effects are particularly desirable. The compounds obtained with the method according to the invention can be carried out according to the invention. into pharmaceutical preparations which, in addition to suitable non-toxic and inert pharmaceutically inert carriers, contain one or more compounds of the formula I and / or their salts or also preparations containing one or more compounds of the formula I and / or their salts. The preparations are in the form of unitary elements, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, in which the active substance content corresponds to a fraction or multiple of a unit dose. Unit doses of preparations may contain, for example, 1; 2, 3, or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains an amount of active ingredient which is administered in one application and will usually correspond to 1/2 or 1/3 or 1/4 of the daily dose. Suitable nontoxic and pharmaceutically inert carriers are solid, semi-solid and liquid diluents. , fillers and any kind of molding agent. Suitable pharmaceutical preparations are tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions. Tablets, dragees, capsules, pills and granules may contain active substances or substances in addition to the usual carriers such as a) fillers, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, b) binders, e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, c) humectants, e.g. glycerin, d) disintegrating agents, e.g. agar-agar, calcium carbonate, sodium bicarbonate, e) dissolution retarders e.g. paraffin and f) resorption accelerators e.g. quaternary ammonium compounds, g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, h) adsorbing agents, e.g. kaolin and bentonite ii) anti-adhesives, e.g. talc, calcium and magnesium stearate and permanent polyethylene glycol U) mixtures of the listed substances - (i) The tablets, dragees, capsules, pills and granules may be provided with the usual coatings or shells, possibly containing opaque agents, and may be arranged such that they may release the active substances or substances with a delay only or primarily within a specified period of time. parts of the intestinal tract, whereby polymeric substances and waxes are used as the coating mass. The active substance or substances may be present, optionally with one or more of the above-mentioned carriers, also in the form of microcapsules. Suppositories may contain, in addition to or in addition to the active substances, usually water-soluble or insoluble carriers, e.g. polyethylene glycols, fats, e.g. cocoa butter and higher esters (e.g. C1A alcohol; fatty acid - C, 6) or mixtures of these Solutions and emulsions may contain, in addition to or in addition to the active substances, the usual carriers, such as solvents, dissolving agents and emulsifiers, e.g. water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butanediol -1,3, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor and sesame oil, glycerin, glyceraldehyde, tetrahydrofuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan, or mixtures of these substances. parenteral solution and emulsions may also be sterile and isotonic with blood. In addition to the active substance or substances, they usually contain carriers, such as liquid diluents, e.g. water, ethanol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene oxide and sorbitan esters, microcrystalline cellulose, aluminum methoxide, bentonite, agar-agar-agar-agar-agar-agar-agar. and traganthus or mixtures of these substances. The mentioned preparation forms may also contain coloring agents, preservatives, as well as additives improving the aroma and taste, e.g. peppermint and eucalyptus oil, and sweetening agents, such as saccharin. The therapeutically active compounds in the above-mentioned preparations should be present in the concentration approx. 0.1-99.5, preferably about 0.5-0594, by weight, based on the total mixture. The pharmaceutical preparations listed above may contain, in addition to the compounds of formula I and / or their salts, also other pharmaceutically active substances. takes place in the usual way according to known methods, n p. by mixing the active ingredient or the active ingredients with a carrier or carriers. 8 94 266 The active ingredients or pharmaceutical preparations can be administered, preferably orally, parenterally and / or rectally, preferably orally and parenterally, in particular by the tongue and intravenously. In order to obtain the desired results, it has proven advantageous to administer the active ingredient or the active ingredients in parenteral (intravenous) application amounts of about 0.005 to about 10, preferably 0.02-5 mg / kg body weight for 24 hours and for oral application in amounts of about 0, 1 to about 50, preferably 1-30 mg / kg body weight every 24 hours, optionally as several single doses. A single dose contains the active substances or substances preferably in an amount of 0.1-10, in particular 0.2-5 mg / kg body weight. However, it may be necessary to deviate from the above-mentioned doses, depending on the type and weight of the treated object, the type and severity of the disease, the type of preparation and drug application as well as the time or intervals in which the drug is administered. Thus, in some cases it is sufficient to administer the drug in amounts less than the above-mentioned amounts, while in other cases the above-mentioned amount of active ingredient should be exceeded. Any person skilled in the art can easily determine the required optimal dosage and type of application of the active substances on the basis of his expert knowledge. The effect of several characteristic compounds according to the invention on the coronary system is illustrated by the experimental results presented in Table 1. Table 1 Clearly recognizable increase in saturation oxygen in the coronary bay Dose Action time (mg / kg - iv) «(minutes) 1 II III IV VII viii X XII XIII XIV XV XVI UD¬ O / I 0.1 003 0.3 /) 10j0. 0 2J0 120 45 180 45 eo 150 30 45 45 iv «* Intravenously Effects on the coronary system were found according to generally accepted methods from the literature, by measuring the increase in oxygen saturation in the coronary sinus by cardiac catheterization in drug-treated bastard dogs. "The preparation of new compounds according to the invention is explained on the basis of the following examples. Example I. Preparation of the compound of formula 10 After heating a solution of 10.6 g of benzyl aldehyde, 17.4 g of ethyl 7-ethoxyacetyl acetic acid, 113 g of ethyl ester of acid for several hours 2-ethoxymethyl-6-methyl-4-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester in 80 ml of ethanol was obtained in 65% of the theoretical yield in the form of yellow crystals of melting point 112 ° C. Example II. Preparation of the compound of formula 11. A solution of 5.8 g of 3-iodobenzaldehyde, 4.4 g of 7-ethoxyacetylacetic acid ethyl ester and 3.3 g of O-aminocrotonic acid ethyl ester in 30 ml of ethanol is heated to reflux overnight and then After cooling, 2-ethoxymethyl-6-methyl-4- (3'-iodophenyl) -1,4-dihydrogen-pyridine-3,5-dicarboxylic acid diethyl ester is obtained with a yield of 60% of theory, form Pale yellow crystals which melt at 124 ° C. Example III. Preparation of the compound of formula 12. g of 3-nitrobenzaldehyde, 16 g of 7-ethoxyacetylacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester are heated for about 5 hours in 60 ml of ethanol, cooled, filtered under vacuum and washed with cold ethanol. 2-ethoxymethyl-6-methyl-4- (3'-nitrophenes) diethyl ester is obtained. Compound of Example No. * 94 266 9 l / -1,4-dihydrogen-pyridine-3,5-dicarboxylic acid in the form of pale yellow crystals at a temperature mp 120-122 ° C., with a yield of 70% of theory. • Example IV. Preparation of the compound of formula 13. ¦ After heating for several hours under reflux, a solution of 14 g of 2-chlorobenzaldehyde, 17.4 g of 7-ethoxyacetylacetic acid ethyl ester and 13 g of O-aminocrotonic acid ethyl ester in 80 ml of ethanol, the ester is obtained after cooling 2-ethoxymethyl-6-methyl-4- (2'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl in the form of yellow crystals, mp 115 ° C, yield 55% Theoretical yield. Example 5 Preparation of the compound of formula 14, 4 g of 3-fluoro-4-methoxybenzaldehyde, 17.4 g of 7-ethoxyacetylacetic acid ethyl ester, 13 g of aminocrotonic acid ethyl ester in 60 ml of ethanol is heated to reflux overnight, cooled, and after suction draining and washing with cold ethanol, 2-ethoxymethyl-10-6-methyl-4- (3'-fluoro-4'-methoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained with the efficiency of 35% of theoretical efficiency in the form of white crystals with a temperature of melting temperature 12 ° C. Example VI. Preparation of the Compound of Formula 15 A solution of 6.2 g of 2-nitrobenzaldehyde, 6.6 g of 7-methoxyacetylacetic acid ethyl ester and 4.8 g of O-aminocrotonic acid methyl ester in ethanol is heated for 6 ~ 8 hours under reflux, filtered under suction. vacuum {rinsed with a small amount of ethanol. There is obtained (3 (ethyl) (5) methyl ester of 2-methoxymethyl-6-methyl-4 (2'-n -trophenyl) -1 # 4-dihydrogen pyridine-3,5-dicarboxylic acid as light yellow crystals, m.p. 143 -145 ° C. Yield: 45% of theoretical yield. Example VII. Preparation of the compound of formula 16. 7.4 g of 2-trifluoromethylbenzaldehyde, 17.4 g of 7-ethyl acetoacetic acid ethyl ester and 13 g of O-aminocrotonic acid ethyl ester in 80 ml of ethanol heated overnight under reflux, chilled to give 2-ethoxymethyl-6H-nethyl-4- (2'-trifluoromethylphenyl) -1,4-dihydrogen-pyridine-3,5-dicarboxylic acid diethyl ester as yellow-white crystals at a temperature of mp 112 ° C in 55% of theory Example 8 Preparation of the compound of formula 17. Solution 10.4 ml of 2-formylpyridine, 19 g of 7-isopropoxyacetylacetic acid ethyl ester (Kp 106-106 ° C / 12 mm) and 13 g of O-aminocrotonic acid ethyl ester in 60 ml of ethanol is boiled for 6-8 hours, then it is cooled to give 2-isopropoxymethyl-6-methyl-4-α-pyridyl-1,4-dihydroxy-pyridyl-3,5-dicarboxylic acid diethyl ester in the form of light yellow crystals, m.p. 184 ° C, on a yield of 35% of the theoretical value. Example IX. Preparation of the compound of formula 16. 6.5 g of 3-cyanobenzaldehyde, 8.7 g of 7-ethoxyacetylacetic acid ethyl ester and 7.2 g of ethylacetic acid ethyl ester in 80 ml of ethanol are heated overnight under reflux, cooled and cooled. after draining under vacuum and washing with cold ethanol, there is obtained 2-ethoxymethyl-6-ethyl- '4- (3'-cyanophenyl) -1,4-dihydrogen-pyridine-3,5-dicarboxylic acid diethyl ester in the form of light yellow crystals with a melting point of 12E ° C, 42% of theoretical yield. Example X. Preparation of the compound of formula 19. 7.5 g of 5-form-2-dimethylammonopyridine, 8.7 g of 7-ethoxyacetylacetic acid ethyl ester and 6.5 g of p-aminocrotonic acid ethyl ester in 40 ml of ethanol is boiled overnight, and after cooling and suction filtration, 2-ethoxymethyl-6-methyl-4- (2'-dimethylaminopyrimidyl) -1,4-dihydrogen-pyridine-3,5-dicarboxylic acid diethyl ester is obtained in pale yellow crystals with a melting point Efficiency 124 ° C, with the efficiency of 40% of the theoretical efficiency. P r y k l a d XI. Preparation of the compound of formula 20. 7.5 g of 2-formylpyridine, 15 g of 7-ethoxyacetyl acetic acid ethyl ester (9.1 g of ethyl 1-aminocrotonic acid are boiled in 60 ml of ethanol for 5-6 hours, and then cooling and vacuum filtration gives 2-ethoxymethyl-6-methyl-4-α-pyridyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester in the form of light yellow crystals, m.p. 135 ° C, Yield 35% of theoretical yield. Example XII Preparation of the compound of formula 21 A solution of 14 g of 2-chlorobenzaldehyde, 32 g of 7-methoxyacetylacetic acid ethyl ester and 10 ml of concentrated aqueous ammonia solution is heated overnight to boiling in 60 ml of ethanol and then drained. under vacuum, 2,6-dimethoxymethyl-4- (2'-chlorophenyl) -1,4-dihydro-pyridine-3,5-dicarboxylic acid ethyl ester is obtained in the form of pale yellow crystals, mp 133-134 ° C, yield 55% theoretical yield. 10 94 266 Example XI11. Preparation of the compound of formula 22. • 8R7 g of 2-trifluoromethylbenzaldehyde, 16 g of 7-methoxyacetylacetic acid ethyl ester and 5 ml of concentrated aqueous ammonia solution in 30 ml of ethanol, heated overnight to boiling, cooled, to obtain 2,6 carboxylic acid diethyl ester in The form of light brown crystals with a melting point of 133 ~ 1346C, with a yield of 60% of theoretical yield. <Example XIV. Preparation of the compound of formula 23. A solution of 15 g of 2-nitrobenzaldehyde, 36 g of ethyl ester of? -Ethoxyacetyl acetic acid and 11 ml of a concentrated aqueous ammonia solution in 60 ml of ethanol is heated to reflux overnight and then cooled. After suction filtration, the diethyl 2,6V-diethoxyethyl (-4- (2'-nitrophenyl) -1,4-dihydro-pyridine-3,5-dicarboxylic acid) is obtained in the form of yellow crystals, m.p. 138-140 ° C, yield 50% of the theoretical value. Example XV. Preparation of the compound of formula 24. 5.2 ml of 2-formylpyridine, 17.4 g of 7-ethoxyacetylacetic acid ethyl ester and 5 ml of a concentrated aqueous ammonia solution in 40 ml of ethanol is heated overnight to boiling, cooled, and vacuum-filtered. the obtained crystals (mp. 110 ° C) are dissolved in ether and the salt is trapped in the form of the hydrochloride with ethereal hydrochloric acid. This gives 2,6- (diethoxymethyl) -4-L-pyridyl-1-4-dihydro-3,5-dicarboxylic acid diethyl ester hydrochloride, m.p. 168-170 ° C. Yield: 45% of the theoretical amount. Example XVI. Preparation of the compound of formula 25 A solution of 9.2 g of 4-methoxysulfonylbenzaldehyde, 8 g of 7-methoxyacetylacetic acid ethyl ester and 6.5 g of O-ammonocrotonic acid ethyl ester in 40 ml of ethanol is heated to boiling and cooling to obtain the acid diethyl ester 2-methoxymethyl-6-methyl-4- (4'-methylsulfonylphenyl) -1,4-dihydrogen-pyridine-3,5-dicarboxylic acid as yellow crystals, mp 156-158 ° C. Yield: 65% of theory. • Example XVI I. Preparation of the compound of formula 26 After heating a solution of 6.9 g of 3-carbetoxybenzaldehyde, 8 g of 7-methoxyacetylacetic acid ethyl ester and 6 g of O-aminocrotonic acid methyl ester in 30 ml of ethanol, the ester (3 2 * methoxymethyl-6-methyl-4- (3'-carbetoxyphenyl) -1,4-dihydro-pyridine-3,5-dicarbqxyl / methyl-5 / ethyl acid in the form of light yellow crystals, m.p. 108-110 ° C. Yield: 60% of theoretical yield. Example XVI 11. Preparation of the compound of formula 27. 7.6 g of 4-methylthiobenzaldehyde, 16 g of Y-methoxyacetylacetic acid ethyl ester and 6 ml of aqueous ammonia solution in 30 ml of ethanol, The mixture is heated to reflux for 6-8 hours and the diethyl ester of 2,6-dimethoxymefy-4-4'-methylthiophenyl acid is obtained in the form of beige crystals, mp 136-138 ° C. Yield: 60% of theoretical yield. mp 137-138 ° C on heating to reflux overnight 7.6 g of 4-methylthiobenzaldehyde and 16 g of ethyl (3-amino-7-methoxycrotonic acid) in 40 ml of ethanol. <p r z y k l a d XIX. Preparation of Compound of Formula 2B. 7.6 g of 3-methoxy-4-hydroxybenzaldehyde, 16 g of 7-methoxymethylacetylacetic acid ethyl ester 112 ml of concentrated aqueous ammonia solution in 30 ml of ethanol are boiled overnight, and after cooling, the 2,6-dimethoxymethyl acid diethyl ester is obtained. 4- (3'-methoxy-4'-hydroxyphenyl) -1,4-dihydrogen pyridine-3,5-dicarboxylic acid in the form of light yellow crystals, m.p. 140-142 ° C, yield 40% of theoretical yield. Example XX. Preparation of the compound of formula 29 After heating the solution for 12 hours, 15.1 g of 3-n-tobenzaldehyde, 16 g of β-amimimo-7-methoxycrotonic acid ethyl ester, 19 g of oxaloacetic acid diethyl ester under reflux, in 60 ml of ethanol, was evaporated under Pf. obtains almost quantitative yield 2-metp * ksymeta [o-4- / 3'-nitrophenyi / 1,4-dihydrogen-pyridine-3,5,6-tricarboxylic acid triethyl ester in the form of a yellow oil (n ^ * 11.6353. XXI. Preparation of the compound of formula 30. • 23 g of trout, obtained according to example XX, are boiled overnight after the addition of a solution, 1.15 g of sodium in 25 ml of ethanol in a total amount of ethanol of 200 ml, then concentrated under vacuum , water is added and, after draining in a vacuum, it is eliminated with dilute sulfuric acid to give ester 94 266 11 (3,5 (2-methoxylmethyl4V3'-nitrophenyl) -1f4-dihydrogen-pyridine-3 # 5,6-tricarboxylic acid diethyl ester in the form of yellow crystals at temperature melting 146 ° Cr with an efficiency of 50% theoretical yields). • P r z y k l a d XXII. Preparation of the compound of formula 31 A solution of 10.2 ml of 3-formylpyridine, 16 g of 7-methoxyacetylacetic acid ethyl ester and 20 g of O-iminoglutaric acid ethyl ester in 40 ml of ethanol is heated to boiling overnight and then cooled. After cooling, 2-methoxymethyl-4- (O-pyridyl) -1,4-dihydro-pyridine-6-methylcarboxyethyl-3,5-dicarboxylic acid diethyl ester is obtained as pale pink crystals, m.p. 104-106 ° C, yield 65% of the theoretical amount. ¦ Example XXIII. Preparation of the compound of formula 32 A solution of 6.2 ml of 2-formylpyridine, 8 g of isobutyl acetic acid ethyl ester and 8 g of p-aminine-methylxycrotonic acid ethyl ester (Kp. 112-116 ° / 10 mm) in 40 cm3 of ethanol is heated by to boil overnight, concentrate, add ether and reduce the 2-methoxymethyl-6-isopropyl-4- (α-pyridyl) -1,4-dihydrogen-pyridine-3,5-dwL 'diethyl ester hydrochloride with hydrochloric acid solution etc carboxylic acid. Pale yellow crystals, mp 198-200 °. Yield: 60%. Example XXIV. Preparation of the compound of formula 33. 7.6 g of 3-nitrobenzaldehyde, 16 g of 7-methoxyacetylacetic acid ethyl ester and 5 g of methylamine hydrochloride in 40 cm3 of pyridine are heated for 5-6 hours to the temperature of 90-100 °, concentrated in a vacuum, extracted with ether, washed with dilute hydrochloric acid and water, and after drying the ethereal solution is evaporated. 1-Methyl-2,6-dimethoxymethyl-4V3'-nitrophenyl) -1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of a brown oil with a yield of 90%. PL

Claims (4)

Claims 1. A process for the preparation of alkoxyalkyl dihydrogen pyridine esters of formula 1, wherein R is hydrogen or an alkyl group of 1-4 carbon atoms, R1 is an alkoxyalkyl group of 2-6 carbon atoms, R2 and R3 are the same or different and represent an alkyl group or alkoxyalkyl (with up to 4 carbon atoms, R4 is hydrogen, 1-4 carbon alkyl, 2-6 carbon alkoxyalkyl or a residue (CH2) n-COOR ', where R5 is hydrogen or 1-4 alkyl group) carbon atoms, and n- is a number from 0 to 3 and X is a phenyl residue optionally substituted one to three times with nitro, cyano, azido, hydroxy, halogen, trifluoromethyl, alkyl, alkoxy, carboa Ikoxy, alkylthio, SO2-alkyl and / or alkylamino, the said alkyl and alkoxy groups having 1-2 carbon atoms, or X represents a pyridyl or pyrimidyl group optionally substituted by dimethylamino, or their salts, characterized in that The O-keto carboxylic acid esters of formula 2, in which R 1 and R 2 are as defined above, are reacted with the amines of formula 3, in which R is as defined above, or with their salts, optionally after separation of any esters formed from O-keto carboxylic acids and amines or aminenamine salts of formula 4, wherein R, R 1 and R2 are as defined above, with the ylidene derivatives of formula 5 wherein X, R3 and R4 are as defined above, and optionally compounds obtained are converted into salts by treatment with an acid. • 2. Process for the preparation of alkoxyalkyl dihydrogen pyridine esters of formula I, in which R is hydrogen or an alkyl group of 1-4 carbon atoms, R1 is an alkoxyalkyl group of 2-6 carbon atoms, R2 and R3 are the same or different and represent an alkyl or alkoxyalkyl group, containing up to 4 carbon atoms, R4 is hydrogen, 1-4 carbon alkyl, 2-6 carbon alkoxyalkyl or a residue (CH2) n-COOR5, where R5 is hydrogen or 1-4 carbon alkyl group, and n is a number from 0 to 3, aX is a phenyl residue optionally substituted one or three times with nitro, cyano, azido, hydroxyl, halogen, trifluoromethyl, alkyl, alkoxy, carboalkoxy, alkylthio, SO2-alkyl and / or alkylamino , said alkyl and alkoxy groups having 1-2 carbon atoms, or X is a pyridyl or pyrimidyl group, optionally substituted with dimethylamino, or their salts, characterized in that the esters of O-ketocarb oxyl compounds of formula 6, in which R 3 and R 4 are as defined above, are reacted with the amines of formula 3, in which R is as defined above, or with their salts, optionally after separation - optionally formed from O-keto carboxylic acids and amines or amine salts of enamines of formula 7 in which R, R3 and R4 are as defined above, with the ylidene derivatives of formula 8 in which R1, R2 and X have the above meaning, and the compounds optionally obtained are converted into salts by treatment with an acid . ' 3. A process for the preparation of alkoxyalkyl dihydrogen pyridine esters of formula I, wherein R is hydrogen or an alkyl group of 1-4 atoms, R 1 represents an alkoxyalkyl group of 2-6 carbon atoms R2 and R3 are identical or different and represent an alkyl or alkoxyalkyl group of up to 4 carbon atoms, R412 94 266 is hydrogen, alkyl of 1-4 carbon atoms, alkoxyalkyl of 2-6 atoms carbon or a residue (CH2) n-COOR5, whereby R5 is hydrogen or an alkyl group of 1-4 carbon atoms, n is a number from 0 to 3 and X is a phenyl residue optionally substituted one to three times with a nitro, cyano group, azide, hydroxy, halogen, trifluoromethyl, alkyl, alkoxy, carboaIkoxy, alkylthio, SO2 -alkyl and / or alkylamino, said alkyl and aalkyl groups having 1-2 carbon atoms, or X being a pyridyl or pyrimidyl group, optionally substituted with e, dimethylamino or their salts, characterized in that esters of O-keto carboxylic acids in the formula 6, in which R3 and R4 are as defined above, are reacted with zenamines of formula 4, in which R, R1 and R2 are as defined above, and with aldehydes of formula 9 in which X is as defined above, and the compounds obtained are optionally salified by treatment with an acid. - 4. Process for the preparation of alkoxyalkyl dihydrogen pyridine esters of formula I, wherein R is hydrogen or an alkyl group of 1-4 carbon atoms, R1 is an alkoxyalkyl group of 2-6 carbon atoms, R2 and R3 are the same or different and represent an alkyl or alkoxyalkyl group, with up to 4 carbon atoms, R4 is hydrogen, 1-4 carbon alkyl, 2-6 carbon alkoxyalkyl or a residue (CH2) ncOOR5, where Rs is hydrogen or 1-4 carbon alkyl group, and n is a number from 0 to 3, and X is a phenyl residue optionally substituted one to three times with a nitro, cyano, azido, hydroxyl, halogen, trifluoromethyl, alkyl, alkoxy, carbon, carbon, carbon, alkylthio, SO2-alkyl and / or alkylamino group, the said alkyl and alkoxy groups having 1-2 carbon atoms, or X represents a pyridyl or pyrimidyl group, optionally substituted with dimethylamino, or their salts, characterized in that the esters of the O-ketocar acids the aldehydes of formula 2, in which R1 and R2 are as defined above, are reacted with enamines of formula 7, in which R, R3 and R4 are as defined above, and with aldehydes of the chip 9 in which X is as defined above, and the compounds obtained are optionally salified by treatment with an acid. 94 266 H. COOCH3 o " OHN &lt; XH20CH3 &quot; H, < 2 &gt; CH3 OCH-COOCH, CH2N CH2N CH2CH AND CH / CH3H Scheme 1 H5C200C H K5C200CCH2 NM C00C2H5 H5C200C C00C2H5 0 CH20CH3 H5C200CCf ^ hr "CH20CH3 H Scheme 294 266 H H5C2O0CJ / H OU / -j C / pn» CH ° HvC00C3H7 + 1 H2W '^ CH20CH3 S02C2H3 H3C2H3 H3C2H3 H3C200Cg Scheme 3 H5C20CH2 NH, HH COOCH '3 O ^^ CHgOCH ^ H5C200C COOCH, H5C20CH2 N ^ CHoOCh- Scheme A94 266 H R300C ^ X.C00R r4 n r1 "^ ° r'2 R1-C0-CHo-C00R2 R Formula 1 Formula 2 H2N-R Formula 3 NH-R! 1-i = CH- COOR 'Formula A X-CH = CC-R4 R4-C0-CH2-C00R3 ir ^ n3: oor Formula 5 Formula 6 NH-R R4-C = CH-C00R3 Formula 7 X-CH0 Formula 9 X-CH = C-C0-R1 i00R 'Formula 8 H H5C200CV / rC00C2H5 CH3 N CH2 ~ 0C2H5 H Formula 1094 266 | h H5C20OC / ^ COOCgHg CH, ^ N ^ CH2-0C2H5 H Formula 11 NO, C00C2H5 H ^ 2 in Formula 12 Formula 13 OCH, C2H5 0OCn / V'COOC2N5 CH3N CH20C2H5 CH ^ OOC ^ Ay ° H 2 C00C2H5 CH20CH3 Formula 15 Formula 14 H5C20OC CH CR C00C2H5 CH2 ~ 0CP .u Formula 1694 266 v 2n * CH3 H5C200C H2-0CH ^ C00C2H5 m Formula V CH3 \ / H3 N H5C200Cy ^ YC00C2H5 CH3N CH2-0C2H5 C2H5H CH2- ° C2H5 Formula 18 C00C2H5 3 H CH20C2H5 Formula 20 C00 CH2H5 Formula 20 Formula 19 H2C2003G - ^ N-CH2-OCH5 H H5C200C CF3 C00C2H5 CH30CH2 ^ N CH20CH »H Formula 21 Formula 2294 266 ^ S NO, H H5C200CX ^ C00C2H5 C2H30CH2 ^ N ^ CH20G2H5 H Formula 23 S02-CH3 H5C200C C00C2H3 H3 N CH2H3 H3 N CH200 H5C20CH2 N CH20C2H5 H Formula 24 CH300C C00C2H5 C00C2H5 CH "N ^ CH2-0CH3 5 H Formula 25 Formula 26 S-CH- H5C200C C00C2H5 CH.OCH2N CH2-0CH3 H Formula 27 H5C200C C00G2H5 CH3OCH2 N CHOC6 H3 Formula 2894gO 26 CH3OCH2 N CHOC6 H3 Formula 2894g C00C2H5 H5C200C N CH20CH3 H3C200CVv / HOOC ^ N ^ CH-OCH, H 2 3 Formula 29 Formula 30 H5C200C C00C2H5 H5C200C CH2 N ^^ CH20-CH3 Formula 31 VN H3C200C ^ C00C2H3 CH ~ .XX CH '3 \ CH' V CH9OCH - H "¦ 'Formula 32 H3C200Cv \ ^ C00C2H3 CH30CH2 ^ N ^^ CH20CH3 I CH- Formula 3394 266 Works . 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