IE51267B1 - 1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position,their production,and their medicinal use - Google Patents

Abstract

1. Compound of the general formula I see diagramm : EP0039863,P18,F1 in which R represents a phenyl radical which optionally contains 1 or 2 identical or different substituents from the group comprising nitro, chlorine, cyano or trifluoromethyl, with the exception of a phenyl radical which is at the same time ortho- and metadichlorosubstituted, when R**2 denotes methyl and R**4 denotes alkyl with 2-3 carbon atoms, R**1 represents a saturated hydrocarbon radical with up to 6 carbon atons which is optionally interrupted by an oxygen atom, R**2 and R**4 are always different and each represents hydrogen, alkyl with 1 to 4 carbon atoms or cyclohexylmethyl, with the exception of the compound diethyl-2-methyl-6-propyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-carboxylate.

Description

The present invention relates to certain new 1,4-dihydro-pyridine compounds having different substituents in the 2-position and 6-position, to several processes for their production and to their use in agents which influence the circulation.

It has already been disclosed that l,4-dihydro-2,6-dimethyl-4phei^l-pyridine-3,5-dicarbcKylic acid diethyl esters are obtained when benzylideneacetoacetic acid ethyl ester is reacted with g-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (see E. Knoevenagel, Ber. dtsch. chan. Ges. 31, 743 (1898)).

Further, it is known that certain 1,4-dihydro-pyridines possess interesting pharmacological properties (see F. Bossert and W. Vater, Naturwissenschaften 58, 578 (1971)).

Further, dihydropyridines which carry different ester groups in the 3-position and 5-position are known (see DE-OS (German Published Specification) 2,117,571). 1,4-Oihydropyridines with identical ester groups in the 3-position and 5-position and different substituents in the 2-position and 6-position have hitherto not been disclosed.

According to the present invention we provide oanpouids which are 1,4-dihydro-pyridines of the general formula R represents a phenyl radical which optionally contains 1 or 2 identical or different substituents selected from nitro, chlorine, cyano or trifluorcmethyl, with the exception of a phenyl radical which is at the same time ortho- and metadiohloro-substituted, when 2 4 R denotes methyl and R denotes alkyl with 2-3 carbon atoms, represents.. a saturated hydrocarbon radical with up to 6 carbon atoms which is cptionally interrupted by an oxygen atom, 4 R and R are; always different and each represents a hydrogen atom, alkyl with 1 to 4 carbon atoms or cyclohexylmethyl, with the exception of the compound diethyl-2-methyl-6-propyl-4-(3-nitrophenyl)1,4-dihydropyridirie-3,5-carboxylate.

According to the present invention we further provide a process for the production of compounds of the present invention, in which A) an ylidene-e-keto-ester of the general formula (II) in which 2 R, R and R have the abovementioned meanings, is reacted with an enaminocarboxylic acid ester of the general formula R4-C=CH-COOR1 (HD NHin which z 4 R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or B) an ylidene-B-keto-ester of the general formula (II), -COR R-CH=C (II) in which COOR4· 2 R, R and R have the abovementioned meanings, is reacted with ammonia and a β-ketocarboxylic aoid ester of the general formula (V) NH3 + R4-CO-CH2-COOR1 (IV) in which 1 R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or C) an ylidene-e-keto-ester of the general formula COR (V) R-CH=C: "COOR in which 4 R, R and R have the abovementioned meanings, is reacted with an enaminocarboxylic acid ester of the general formula R2-C=CH-COOR1 nh2 (VI) in which 1 R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or D) an ylidene-B-keto-ester of the general formula (V) (V) in which 4 R, R and R have the abovementioned 15 meanings, is reacted with ammonia and a β-ketocarboxylic acid ester of the general formula (VII) ns3 + r2-co-ch2-coor1 (VII) in which 1 R and R have the abovementioned meanings, 20 optionally in the presence of an inert organic solvent, or E) an aldehyde of the general formula (VIII) in which R has the abovementioned meaning, is reacted with an enaminocarboxyllc acid ester of the general formula (III) R4-C=CH-COOR1 + R2-CO-CH,-COOR1 I 2 NH2 (III) (VII) in which 1 2 R , R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or F) an aldehyde of the general formula (VIII) in which R has the same meaning as in claim 1, is reacted with an enaminocarboxyllc acid ester of the general formula (VI) and a g-ketocarboxylic acid ester of the general formula (IV) R^C’CH-COOR1 + R4-CO-CH,-COOR1 I 2 NH2 (VI) (V) 4 in which R , R and R have the same meanings as in claim 1, optionally in the presence of an inert organic solvent.

The new compounds of the present invention possess valuable pharmacological properties. By virtue of their circulation-influencing action they can be used as anti-hypertensive agents, as vasodilators, as cerebral therapeutic agents and as coronary therapeutic agents, and they are thus to be regarded as an enrichment of pharmacy.

The process variants (A), (B), (C), (D), (E) and (F) for the production of the compounds according to the invention are illustrated by the following equations, in which in each case, the end-product of formula (I) is 1,4-dihydro-2-ethyl-6-methyl-4-(3*-nitrophenyl) -pyridine-3,5-dicarboxylic acid diethyl ester and 1,4-dihydro-2-methyl-4-(3'-trifluoromethyl-phenyl)15 pyridine-3,5-dicarboxylic acid diethyl ester: C) 0 0 < NOg HjCgOgC. zCOgCgHj f^CgOgC> Η 1N < COg CgHj [ + 1 ---------► 1 1 H3C ' ^NHg 0 0,¾ -HgO HSC' Hk CgHs D) Hj Cg Og Cs CHZ H3CzC*0 E) Hj Cj CHj I h5c'C*o + COjjCjHs c2hs -► -2 HjO NOg COg Cg Hj CgHs F) NO, Hs Cg 02 C γ H HjC^NHg HgC Λ O C2H, COgCgH, -2 Hs O > HsCgOgCv^S-COgCgH, CgHj

Claims (11)

1. Specific details of the various process variants are as follows; Process variant A The ylidene-8-keto-esters of the formula (II) 5 used as the starting material are known from the literature or can be prepared according to methods known from the literature (see, for example, G. Jones The Knoevenagel Condensation in Org. Reactions, Vol. XV, 204 et seq. (1967)). 10 The enaminocarboxylic acid esters of the formula (III) used as starting materials ate known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J Amer. Chem. Soc. 67, 1017 (1945)). 15 Suitable diluents are any of the inert organic solvents. These include as preferences alcohols (such as ethanol, methanol and isopropanol), ethers (such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether and glycol dimethyl 20 ether), glacial acetic acid, dimethylformamide, dimethylsulphoxide, acetonitrile, pyridine and hexamethylphosphorotriamide. The reaction temperatures can be varied within a substantial range. In general, the reaction is 25 carried out at between 20 and 150°C, preferably between 20 and 1OO°C, especially at the boiling point of the particular solvent. The reaction can be carried out under normal pressure but also under elevated pressure. In general, 30 it is carried out under normal pressure. In carrying out the process according to the invention, one mole of an ylidene-β-keto-ester of the formula (II) is reacted with one mole of an enaminocarboxylic acid ester of the formula (II) in a suitable 35 solvent. The substances according to the invention are preferably isolated and purified by distilling off the solvent ln vacuo and recrystallising the residue which may only be obtained in a crystalline form after cooling with ice - from a suitable solvent. Process variant B The B-ketocarboxylic acid esters of the formula (IV) used as starting materials are known from the literature and can be prepared in accordance with methods known from the literature (see example, D. Borrmann Umsetzung Von Diketen mit Alkoholen, Phenolen und Mercaptanen (Reaction of Oiketene with Alcohols, Phenols and Mercaptans), in Houben-Weyl, Methoden der organischen chemie (Methods of Organic Chemistry), Vol. VII/4, 230 et seq. (1968); and Y. Oikawa, K. Sugano and 0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)). Suitable diluents are any of the inert organic solvent. These include, as preferences, those mentioned for reaction variant A. The reaction temperatures can be varied within a substantial range. In general, the reaction is carried out at between 20 and 150°C, but preferably at the boiling point of the particular solvent. The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure. In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae (II) and (IV), are each employed in molar amounts. The ammonia used is advantageously added in an excess of 1 to 2 moles. The compounds according to the invention can easily be purified by recrystallisation from a suitable solvent. Process variant C The ylidene-B-keto-esters of the formula (V), used as starting materials, are known from the literature or can be prepared in accordance with methods known from the literature (see, for example, G. Jones (The Knoevenagel Condensation in Org. Reactions, Vol. XV, 204 et seq. (1967)). The enaminocarboxylic acid esters of the formula (VI) used as starting materials are known from 5 the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J. Amer. Chem. Soo. 67, 1017 (1945)). Suitable diluents are any of the inert organic solvents. These include, as preferences, those 10 mentioned for reaction variant A. The reaction temperatures can be varied within a substantial range. In general, the reaction is carried out at between 20 and 150°C, preferably between 20 and 100°C, especially at the boiling point 15 of the particular solvent. The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure. In carrying out the process according to the 20 invention, one mole of the ylidene-g-keto-ester Of the formula (V) is reacted with one mole of enaminocarboxylic acid ester of the formula (VI) in a suitable solvent. Process variant D 25 The g-ketocarboxylic acid esters of the formula (VII) used as starting materials are known from the literature or can be prepared in accordance with methods known from the literature (see for example, D. Borrmann Umsetzung von Diketen mit Alkoholen, 30 Phenolen und Mercaptanen (Reaction of Diketene with Alcohols, Phenols and Hercaptans), in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vol. VII/4, 230 et seq. (1968); and Y. Oikawa, K. Sugano and 0. Yonemitsu, J. Org. Chem. 35 43, 2087 (1978)). S1267 Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A. The reaction temperatures can be varied within a substantial range. In general, the reaction is carried out at between 20 and 150°C, but preferably at the boiling point of the particular solvent. The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure. In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae (V) and (VII), are each employed in molar amounts. The ammonia used is advantageously added in an excess of 1 to 2 moles. Process variant E The aldehydes of the formula (VIII), used as starting materials, are known from the literature or can be prepared in accordance with methods known from the literature (see, for example, E. Mosettig, Org. Reactions VIII, 218 et seq. (1954)). Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A. The reaction temperatures can be varied within a substantial range. In general, the reaction is carried out at between 20 and 15o°C, but preferably at the boiling point of the particular solvent. The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure. In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae (VIII), (III) and (VII) , are each employed in molar amounts. 5 Process variant F Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A. The reaction temperatures can be varied 10 within a substantial range. In general, the reaction is carried out at between 20 and 150°C, but preferably at the boiling point of the particular solvent. The reaction can be carried out under normal pressure but also under elevated pressure. In general, 15 it is carried out under normal pressure. In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae (VIII), (VI) and (IV), are each employed in molar amounts. Depending on the choice of the starting substances, the compounds according to the invention may exist in stereoisaneric forms, which either are related to one another like an image and its mirror image (enantiomers) or are not related to one another like an image and its mirror image (diastereomers). Both the antipodes and the racemic forms, and also the diastereomer mixtures, form a subject of the present invention. The racemic forms, like the diastereomers, can be separated in a known manner into the individual stereoisomer components (see for example, E.L. Eliel, Stereo-chemistry of Carbon Compounds, McGraw Hill, 1962). In addition to those mentioned in the preparative Examples, the following active compounds according to the invention may be mentioned; 1,4dihydro-2-ethyl-6-methyl-4-(2'-nitrophenyl)-pyridine3, 5-dicarboxylic acid diethyl ester, l,4-dihydro-2ethyl-6-methyl-4-(2 1 -nitro-phenyl)-pyridine-3,5dicarboxylic acid di-n-butyl ester, 1,4-dihydro-2ethyl-6-methyl-4-(2'-nitrophenyl)-pyridine-3,5dicarboxylic acid diisobutyl ester, l,4-dihydro-2ethyl-6-methyl-4-(2'-nitrophenyl)-pyridine-3,5dicarboxylio acid bis-(2-methoxyethyl) ester, 1,4dihydro-2-ethyl-6-methyl-4-(2’-cyanophenyl)-pyridine3, 5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2ethyl-6-methyl-4-(2'-cyanophenyl)-pyridine-3,5-dicarboxylic acid dipropyl ester, l,4-dihydro-2-ethyl6-methyl-4-(2'-cyanophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester, l,4-dihydro-2-ethyl-6-methyl4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester, l,4-dihydro-2-ethyl-6-methyl-451267 (2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid dipropyl ester, 1,4-dihydro-2-ethyl-6-methyl-4(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, l,4-dihydro-2-ethyl-6-methyl-4-(3'5 nitrophenyl)-pyridine-3,5-dicarboxylic acid dipropyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(3'-nitrophenyl)pyridine-3,5-dicarboxylic acid dicyclopentyl ester, 1,4 -dihydro-2-ethyl-6-methyl-4-(3'-nitrophenyl)pyridine-3,5-dicarboxylic acid bis-(2-propoxyethyl) 10 ester, l,4-dihydro-2-ethyl-6-methyl-4-(2’-chlorophenyl) pyridine-3,5-dicarboxylio acid diethyl ester, 1,4dihydro-2-propyl-6-methy1-4-(2'-nitrophenyl)-pyridine3,5-dicarboxylic acid dimethyl ester, 1,4-dihydro2-isopropyl-6-methyl-4-(2'-nitrophenyl)-pyridine-3,515 dicarboxylic acid dimethyl ester, l,4-dihydro-2-propyl6-methyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester, l,4-dihydro-2-propyl-6-methyl4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid dicyclopentyl ester and 1,4-dihydro-2-propyl-6-methyl20 4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid bis(2-propoxyethyl) ester. The new compounds have a broad and diverse pharmacological action spectrum. In detail, the following main actions, can be demonstrated in animal experiments;

1. On parenteral, oral and perlingual administration the compounds produce a distinct and long-lasting dilation of the coronary vessels. This action on the coronary vessels is intensified by a simultaneous nitrite-like effect of reducing the load on the heart. They influence or modify the heart metabolism in the sense of an energy saving.

2. The excitability of the stimulus formation and excitation conduction system within the heart is lowered, so that an anti-fibrillation action demonstrable at therapeutic doses results.

3. The tone of the smooth muscle of the vessels is greatly reduced under the action of the compounds. This vascular-spasmolytic action can take place in the entire vascular system or can manifest itself more or less isolated in circumscribed vascular regions (such as, for example, the central nervous system). The compounds are therefore particularly suitable as cerebral therapeutic agents.

4. The compounds lower the blood pressure of normotonic and hypertonic 'animals and can thus be used as anti-hypertensive agents.

5. The compounds have strongly muscular-spasmolytic actions which manifest themselves on the smooth muscle of the stomach, the intestinal tract, the urogenital tract and the respiratory system. On the basis of these properties, the compounds according to the invention are particularly suitable for the prophylaxis and therapy of acute and chronic ischaemic heart disease in the broadest sense, for the therapy of hypertension and for the treatment of cerebral and peripheral circulation disorders. As stated above, the invention also relates tc the use in human and veterinary medicine of the compounds of the invention. The present invention provides a pharmaceutical 5 composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the

6. 10 presence of a surface active agent. The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile and/or physiologically isotonic aqueous solution.

7. 15 The invention also provides a medicament in dosage unit form comprising a compound of the invention. The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories

8. 20 comprising a compound of the invention. Medicament as used in this Specification means physically discrete coherent portions suitable for medical administration. Medicament in dosage unit form as used in this Specification means physically

9. 25 discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed

10. 30 within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day

11. 35 respectively. The pharmaceutical composition according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders. The diluente to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, ar.d silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycolB. The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances dr waxes. The ingredient canalso be made up in microencapsulated form together with one or several of the above-mentioned diluents. The diluente to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g. C 11( -alcohol with C-^g-fatty acid)) or mixtures of these diluents. The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose 5 derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances. The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, 10 e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons . 15 The pharmaceutical compositions which are solutions and emulsions can, for example,, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), 20 such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, 25 oils (for example ground nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof. For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, 30 blood-isotonic. The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl 35 alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.