NZ224125A

NZ224125A - Substituted dihydropyridinamides and pharmaceutical compositions

Info

Publication number: NZ224125A
Application number: NZ224125A
Authority: NZ
Inventors: Jurgen Stoltefuss; Eckhard Schwenner; Martin Bechem; Claudia Hirth; Michael Kayser; Matthias Schramm; Johannes-Peter Stasch
Original assignee: Bayer Ag
Priority date: 1987-04-09
Filing date: 1988-04-06
Publication date: 1990-11-27
Also published as: HU204786B; NO881308D0; AU602970B2; IL85992A0; CN88101927A; JPS6419066A; ZA882449B; HUT46664A; EP0288758A2; DE3711991A1; EP0288758A3; DE3864177D1; FI881609A0; CS271486B2; ES2039267T3; CS235488A2; FI881609A; ATE66209T1; EP0288758B1; DK192988D0

Abstract

Dihydropyridine amides of the formula I <IMAGE> in which R<1> to R<8> have the meaning given in the description, are used in particular as circulation-influencing medicaments.

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £24125 WO DRAWINGS Priority Date(s): Complete Specification Filed: Class: . R>Cty Publication Date: P.O. Journal, No: . 22 4 1 2 N.Z. NO. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION DIHYDROPYRIDINAMIDES, A PROCESS FOR THEIR PREPARATION, AND THEIR USE IN MEDICAMENTS We, BAYER AKTIENGESELLSCHAFT, a Company registered under the laws of the Federal Republic of Germany of Leverkusen, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (Followed by 1A) 1 22 4 1 2 5 The present invention relates to dihydropyridin-amides, a process for their preparation, and their use in medicaments, in particular as circulation-influencing medicaments. 5 It is known that diethyl 1,4-dihydro-2,6-dimethyl- 4-phenyIpyridine-3,5-dicarboxylate is obtained when ethyl benzylideneacetoacetate is reacted with ethyl B-aminocrot-onate or ethyl acetoacetate and ammonia CE. Knoevenagel, Ber. Dtsch. Chem. Ges. 743 ( 1898)3. 10 It is furthermore known that certain 1,4-dihy- dropyridines have interesting pharmacological properties CF. Bossert, W. Vater, Natu rw i s senschaf ten j>8, 578 (1971 )]. The present invention relates to new dihydropyrid-inamides of the general formula (I) 15 r4 H in which 1 8 R and R are identical or different and represent straight-chain, branched or cyclic alkyl having up to 6 carbon atoms which is optionally 20 substituted by hydroxyl, cyano, phenyl or halogen, or represent cyano or phenyl, 2 R represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon rad-25 ical having up to 10 carbon atoms which may be interrupted in the chain by an oxygen atom or a sulphur atom and/or which may be substituted by halogen, cyano, hydroxyl, acetoxy, pyridyl or by a phenyl, phenoxy or phenylsulphonyl group which ' " V' /Jt"'«v, •, ; #■ *• 22 4 1 2 5 ~i is optionally substituted by halogen, cyano, alkyl ? ) having up to 4 carbon atoms, alkoxy having up to *t ] 4 carbon atoms or trifluoromethyl, ; /"—* 3 A '} R and R are identical or different and 5 represent hydrogen, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, cyano, i nitro, dialkylamino having up to 4 carbon atoms | (•>'; in each alkyl group, trif luoromethyl, trifluoro- i 10 methoxy, difIuoromethoxy or trifIuoromethyIthio, 5 11 | R represents a group of the formula -0-(CH2)n-R , | -S-(CH2>n-R11, -0-S02-R11, -C0-(CH2)n-R11, | -0-C0-(CH2)n-R1K -C0-NH-(CH2)n-R1 1, | -NH-C0-(CH2)n-R1 1 or -NH-S02-(CH2 ) n-R11, 15 i n w h i c h i n denotes 0 to 4, and i 11 ! R denotes aryl having 6 to 12 carbon atoms i which may be monosubstituted to tetrasubstituted I j 20 by halogen, cyano, nitro, trifluoromethyl, tri- "j f luoromethoxy, difluoromethoxy, trifluoromethyl- •| thio, alkyl having up to 6 carbon atoms, alkoxy I _ having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, amino, alkylamino having up to 25 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group or acetylamino, the sub-stituents being identical or different, or denotes a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain as hetero 30 atoms an oxygen atom, a sulphur atom or two nit rogen atoms, and R6 and R^ are identical or different and in each case 35 represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or twj i* ar a of - 2 - 22 4 i straight-chain or branched alkyl, alkenyl or alkinyl which in each case have up to 18 carbon atoms and which may be substituted by halogen, hydroxyl, alkoxy having up to 8 carbon atoms, alkylthio having up to 8 carbon atoms, alkylcar- bonyl having up to 8 carbon atoms in the alkyl radical, carboxyl or alkoxycarbonyl having up to 8 carbon atoms, by phenyl which is optionally substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms, by cyano 9 10 and/or by a group of the formula -NR R , in which 9 10 R and R are identical or different and in each case denote hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, aryl having 6 to 12 carbon atoms, acyl having up to 7 carbon atoms, alkylsulphonyl having up to 6 carbon atoms, or arylsulphonyl having 6 to 12 carbon atoms, or R^ and R^ in each case represent aryl which has 6 to 12 carbon atoms and which nay be monosubstituted, disubstituted or trisubstituted by nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, carbamoyl, dialkylcarbamoyl having up to 6 carbon atoms in each alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl-thio, amino, alkylamino having up to 8 carbon atoms, dialkylamino having up to 8 carbon atoms in each alkyl group, acetylamino or benzoylamino, the substituents being identical or different, or represent a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain as hetero atoms an oxygen atom, a sulphur atom or two 22 4 1 nitrogen atoms, and the physiologically acceptable salts thereof. The compounds according to the invention exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms and to the di-astereomeric mixtures. The racemic forms and likewise the diastereomers can be resolved in a known fashion into the stereoisomerically unary components (cf. E.L. Eliel, Stereo chemistry of Carbon Compounds, McGraw Hill, 1962). Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts are those with inorganic acids, such as, for example, hydrochloric acid, hydro-bromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic- acid or naphthalene-disulphonic acid. Preferred compounds of the general formula (I) are those in which 1 8 R and R are identical or different and in each case represent straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine or bromine, or represents cyano or phenyl, R ^ represents a straight-chain or branched, saturated or unsaturated hydrocarbon radical which has up to 8 carbon atoms and which may be interrupted in the chain by an oxygen atom and/or which may substituted by fluorine, chlorine, bromine, cyano. •ij,< $ W and 22 4 1 hydroxyl or by a phenyl or phenoxy group which is optionally substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or by a-, ! O B~ or ^-pyridyl, I 3 4 I 5 R and R are identical or different and in each I case ] represent hydrogen, fluorine, chlorine, bromine, } alkyl havingup to 4 carbon atoms, alkoxy having f UP t0 ^ carbon atoms, methylthio, cyano, nitro, I 10 trifluoromethyl or trifluoromethoxy, ? 5 11 | R represents a group of the formula -0-(CH2)n-R , -S-(CH2>n-R11, -0-S02-R11, -0-C0-(CH2)n-R11, -NH-C0-(CH2)n-R11 or -NH-S02-(CH2)n-R11, in which 15 n denotes 0 to 3 and 11 R denotes phenyl or naphthyl which may be mono-substituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, cyano, nitro, trifluoro 20 methyl, trifluoromethoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, methylthio, amino, alkylamino having up to 4 car-bon atoms, dialkylamino having up to 4 carbon atoms in each alkyl group, or acetylamino, the sub-25 stituents being identical or different, or denote pyridyl, thienyl, furyl, pyrimidyl or pyraz i ny I , R^ and R^ are identical or different and in each 30 case represent hydrogen or cycloalkyl having 3 to 7 carbon atoms, or represent straight-chain or branched alkyl or alkenyl which has up to 14 carbon atoms and which 35 may be substituted by fluorine, chlorine, bromine, hydroxyl, alkoxy having up to 6 carbon atoms, Ll A if POT - 5 - 22 4 1 2 5 alkylthio having up to 6 carbon atoms, alkylcar-bonyl having up to 6 carbon atoms in the alkyl radical, carboxyl, alkoxycarbonyl having up to 6 carbon atoms, phenyl which is optionally substituted by nitro, trifluoromethyl, methyl or methoxy, ft i n by cyano and/or by a group of the formula -NR R , in which 9 10 R and R are identical or different and in each case denote hydrogen, alkyl having up to 6 carbon atoms, benzyl, phenethyl, phenyl, acetyl, benzoyl, alkylsulphonyl having up to 4 carbon atoms or phenyl sulphonyl, or represent phenyl or naphthyl which may be mono- substituted, disubstituted or trisubstituted by nitro, fluorine, chlorine, bromine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, alkyl- amino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group, acetylamino or by benzoylamino, the substituents being identical or different, or represent pyridyl, pyrimidyl, thienyl or furyl, and the physiologically acceptable salts thereof. Particularly preferred compounds of the general formula (I) are those in which 1 8 R and R are identical or different and in each case represent methyl, ethyl or benzyl, R represents a straight-chain or branched hydrocarbon radical which has up to 6 carbon atoms, may be interrupted in the chain by an oxygen atom and/or may be substituted by fluorine, chlorine, cyano, hydroxyl, phenyl, a-, or Y~Pyr"idyl, R ^ and R ^ are identical or different and in each i , . • 22 4 1 2 5 case represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, nitro or trifluoromethyl, R^ represents a group of the formula -0-CH2~R^, -S-CH2-R11 or -0-S02-R11, in which 11 R denotes phenyl which may be monosubstituted or disubstituted by fluorine, chlorine, nitro, trifluoromethyl, methyl, methoxy, amino, methyl-ami no, dimethylamino, ethylamino, diethylaraino or acetylamino, the substituents being identical or different, or denotes an a-, B~ or a Y~Pyridyl group, represents hydrogen or alkyl having up to 4 carbon atoms, and R7 represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl or alkenyl which has up to 10 carbon atoms and which may be substituted by fluorine, chlorine, hydroxyl, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, alkylcarbonyl having up to 4 carbon atoms in the alkyl radical, carb- oxyl, alkoxycarbonyl having up to 4 carbon atoms, 9 10 phenyl and/or a group of the formula -NR R , in which 9 10 R and R are identical or different and denote hydrogen, alkyl having up to 4 carbon atoms, benzyl, phenyl or acetyl, R7 represents phenyl which may be monosubstituted or disubstituted by nitro, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino having up to 2 carbon atoms, dialkylamino having up to 2 carbon atoms in each alkyl group, acetylamino or benzoylamino, the substituents $ I 1 I I n r\ tl 4 1 25 ■8 I being identical or different, or 10 represents a-, B- or y-pyridyl, and the physiologically acceptable salts thereof. The compounds of the general formula (I) according to the invention in which 1 8 R - R have the abovementioned meaning, are obtained in a process in which [A3 aldehydes of the general formula (II) in which R- CHO R"*, R^ and R^ have the abovement ioned meaning, and B-ketocarboxylates of the general formula (III) R2000^ (III) 15 in which 1 2 R and R have the abovementioned meaning, are reacted with 8-ketocarboxamides of the general formula (IV) /R6 CON (IV) •R8 20 in which r 7 Q R , R and R have the abovementioned meaning, and ammonia, if appropriate in the presence of inert solvents, or in a process in which - 8 - 22 4 1 2 5 [B] aldehydes of the general formula (II) are reacted with 8-ketocarboxylates of the general formula (III) and enaminocarboxamides of the general formula (V) HNf'i /R6 CON W (V) R8 in wh i c h 6 7 8 R , R and R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which CC3 aldehydes of the general formula (II) are reacted with B-ketocarboxamides of the general formula (IV) and enaminocarboxylates of the general formula (VI) r200cv^h (vi) ri-^NH2 in which R^ and R^ have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which CO] 8-ketocarboxylates of the general formula (III) are reacted with ammonia and ylidene-B-ketocarboxamides of the general formula (VII) (VII) in which 3 8 R - R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which 224125 CE] B-ketocarboxamides of the general formula (IV) are reacted with ammonia and ylidene-B-ketocarboxyIates of the general formula (VIII) R4 fT%-: R5 (VIII> R2OOC-Vi^H RiAo in which - R"* have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which [ F ] ylidene-B-ketocarboxamides of the general formula (VII) are reacted with enaminocarboxylates of the general formula (VI), if appropriate in the presence of inert solvents, or in a process in which CG] yIidene-B-ketocarboxylates of the general formula (VIII) are reacted with enaminocarboxamides of the general formula (V), if appropriate in the presence of inert solvents, or in a process in which CH] dihydropyridinemonocarboxylic acids of the general formula (IX) R4 in which 15 8 R - R and R have the abovementioned meaning, if appropriate via a reactive acyl derivative, are reacted with amines of the general formula (X) - 10 - 22 4 1 2 5 /R6 hn , \r7 (X) in which and R7 have the abovementioned meaning, if appropriate in the presence of an inert organic solvent. Reactive acyl derivatives which may be mentioned as examples are: activated esters, hydroxysuccinimide esters, acyl imidazolides, acyl halides, mixed anhydrides, or the reaction in the presence of cyclohexylcarbodiimide. Depending on the type of starting materials used, the variants for the synthesis of the compounds according to the invention can be represented by the following equat i ons: 22 4 1 2 5 [A3 h3cooc\. HoC'^O ch2-c6h5 CHO + nh- /co-n(ch3)2 O^^CH-, cb] -ch2-c6h5 H3C00C H,C s-ch2-c6h5 cho h5c2ooc\ HoC^^O H^s/CO-NH-CH3 X H7N/^CH3 I h5c2ooc h3c s-ch2-c6h5 co-nh-ch3 h, h Li h ai Bin - 12 - •I 1 ccd cho -so2-c6h5 h3cooc\/h /co-nh-c6h5 H3C^-NH2 02f^CH3 1 -so2-c6h5 co-nh-c6h5 cd] h3cooc\ h3C^O nh- -ch2-c6h5 co-nh-c2h5 h3cooc ch2-c6h5 co-nh-c2h5 f o V. [e3 h7c3ooc ch2-c6h5 nh- /c0-nh-c-,h7 x„ h7c3oo -ch2-c6h5 o-nh-c3h7 cf] i V-J h3cooc OOCV-XH „x, o-ch2-c6h5 co-nh-ch3 2" 6 5 ul» * if mi? - 14 - ft I 22 4 1 2 5 . j i. CG3 q-ch2-c6h5 X0"N(CH3)O H- ch3 h3coo CO-N(CH3)2 CH2-C6H5 HoCOOCVs.X^v^COOH 1 T :h, V-C-f/ I II V 1 H3COOC' ch2-c6h5 c°-nGn 1 ♦ "zN-S^ 224125 Process variants A - G Suitable solvents are water or all inert organic solvents which do not react under the reaction conditions. These preferably include alcohols, such as methanol, eth-anol, propanol or isopropanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides, such as dimethylform-amide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulphoxide, acetonitrile or pyridine. The reaction temperatures may be varied within a relatively wide range. In general, the process is carried out between +10°C and +150°C, preferably between +20°C and +100°C. In particular, at the boiling point-of the particular solvent. The reaction can be carried out at atmospheric pressure, but also at increased or reduced pressure. In general, the process is carried out at atmospheric pressure When carrying out the process variants A - G according to the invention, the ratio of the substances participating in the reaction is immaterial. In general, however, molar amounts of the reactants are used. The substances according to invention are preferably isolated and purified by removing the solvent by distillation in vacuo and recrystallizing the residue obtained in crystalline form, if desired, only after ice cooling, from suitable solvent. In some cases, it may be necessary to purify the compounds according to the invention by chromatography. The aldehydes of the general formula (II) employed as starting materials are known or can be prepared by known methods ; "Ste- T.D. Harris, G.P. Roth, J. Org. Chem. 4_4, 2004 (1979); W.J. Dale, H.E. Hennis, J. Am. Chem. Soc. 78, 2543 ( 1956); Chem. Abstr. 59, 13929 ( 1963)]. The 8-ketocarboxylates of the general formu i n n ed oar - 16 - (III) employed as starting materials are known or can be prepared by known methods CD. Borrmann in Houben Weyl's "Methoden der organischen Cheraie" [Methods of Organic Chemistry] Vol. VII/4, 230 (1968); Y. Oikawa, K. Sugano, 0. Yonemitsu, J. Org. Chem. <43, 2087 ( 1978)]. The B-ketocarboxamides of the general formula (IV) employed as starting materials are known or can be prepared by known methods [U.K. Patent 962734]. The enaminocarboxamides of the general formula (V) employed as starting materials are known or can be prepared by known methods. The enaminocarboxylates of the general formula (VI) employed as starting materials are known or can be prepared by known methods CF.A. Glickman, A.C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)]. The ylidene-B-ketocarboxamides of the general formula (VII) employed as starting materials and the yl-idene-B-ketocarboxylates of the general formula (VIII) employed as starting materials are known or can be prepared by known methods CG." Jones "The Knoevenagel Condensation" in Organic Reactions Vol. XV, 204 (1967)]. Process variant H according to the invention is carried out based on the literature-known method of converting carboxylic acids into carboxamides. In this method, the carboxylic acid is initially converted into an activated form, such as, for example, the acyl chloride or the imidazolide, which are either isolated as such and reacted in a second reaction step, or which are ami dated directly in situ to form the compounds according to the invention. Besides inorganic halides, such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride or carbonyldiimidazole, activating reagents which may be mentioned as examples are carbodiimides, such as cyclohex-yIcarbodiimide or 1-cyclohexyl-3-C^(N-methyl-morpholino)-ethyl]carbodi imide p-toluenesulphonate, or 1*~-h,xdroxyph t h a I im - 17 - S£p/$>90 ■'M J5<:{ ?>.- (- 22 4 1 or N-hydroxy-benzotriazole in the presence of dicyclohexyl-carbodiimide. Naturally, the dihydropyridinemonocarboxy-lic acids can also be employed in the form of their salts. [The amidation method is described, for example: Fieser 5 & Fieser, Reagents for Organic Synthesis, John Wiley & Sons Inc. (1967), page 231 - 236; J.C. Shihan and G.P. Hess, J. Am. Chem. Soc. 77, 1067 ( 1955); U. Goodman, G.W. Kenner, Adv. in Protein Chem. _12:, 488 ( 1957); W.A. Bonner, P.I. McNamee, J. Org. Chem. 2^6, 254 (1961); H.A. Staab, 10 Angew. Chemie Int. Ed. 351 ( 1962); Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & Sons Inc. 1967, 116, 114; H.C. Beyerman, U.O. van der Brink, Re. Trav. 80, 1372 (1961); C.A. Buehler, D.E. Pearson, John Wiley & Sons, Volume I (1970), page 895 ff. Volume II, (1977)]. 15 Besides water, suitable solvents for process var iant H are all inert organic solvents which do not react under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or hal-20 ogenated hydrocarbons, such as dichloromethane, trichloro-methane or tetrachloromethane, or amides, such as dimethyl-formamide, dimethylacetamide or hexamethylphosphoric tri-amide, or hydrocarbons such as benzene, toluene or xylene, or acetonitrile, nitromethane, pyridine, dimethyl sulphoxide 25 or ethyl acetate. Mixtures of the solvents mentioned may likewise be used. If the activated intermediates of the dihydropyridinemonocarboxylic acids are isolated, the amines of the formula (X) can also be used alone as diluents. The reaction temperatures may be varied within a 30 relatively wide range. In general, the process is carried out in a range from -70°C to +140°C, preferably from -20°C to +100°C. The reaction can be carried out at atmospheric pressure, but also at increased or reduced pressure. In 35 general, the process is carried out at atmospheric pressure. When carrying out process variant H according to - 18 - 9 1 '1 T " t ... . the invention, the ratio of the substances participating in the reaction is immaterial. In general, however, molar amounts of the reactants are used. However, it has proven favourable to employ the amine in a 5- to 10-fold molar excess. The amine is particularly expediently employed directly as solvent in large excess. The dihydropyridinemonocarboxyIic acids of the general formula (IX) employed as starting materials are known or can be prepared by known methods [U.S. Patents A,551,467; 4,285,955 and New Zealand Patent Sepcification No. 201395], The amines of the general formula (X) employed as starting materials are known or can be prepared by known methods CHouben Weyl's "Methoden der organischen Chemie" [Methods of Organic Chemistry] Vol. XI/1; Paulsen, Ange-wandte Chemie 78, 501 - 566 (1966)]. The compounds according to the invention exhibit an unforeseeable, valuable pharmacological spectrum of action. They influence the contraction power of the heart, the tone of the smooth muscles and the electrolytic and liquid balance. They can therefore be employed in medicaments for treatment of pathologically changed bloodpressure and heart insufficiency, and also as coronary therapeutic agents. In addition, they can be employed for treatment of heart rhythm disturbances, kidney insufficiency, cirrhosis of the liver, ascites, lung oedema, cerebral oedema, pregnancy oedema, glaucoma or diabetes mellitus. The cardioactive effect of the compounds according to the invention was found on isolated, stimulated papillary muscle of the guinea pig heart. To this purpose, the experimental animals (guinea pigs of both sexes weighing 200 g) were killed, the thorax was opened, and the heart was removed. For the experiments, the smallest possible papillary muscles were subsequently in each case removed EN/* frpm the right ventricle and fixed horizontally in an'-^r cl' w ps ~ 19 ~ »~17SFPI< 22 4 1 2 5 organ bath. During this procedure, one end of the muscle was held by two metallic electrodes, which simultaneous ly served to stimulate the preparation, whereas the other end of the muscle was connected via a thread to a force transducer. The papillary muscle was stimulated above the threshold at a frequency of 1 Hz. Here Krebs-Henseleit solution (concentration in mmol: NaCl 118; NaCOj 25; KCl 10; KHgPO^ 1.2; MgSO^ 1.2; CaClj 1.8; glucose 10, pH 7.4) was passed continuously through the organ bath, which had a volume of about 2 ml, at a rate of 4 ml/min at a temperature of 32°C. The contractions of the papillary muscle were measured isometrical ly via the connected force transducer and recorded on a recorder. The substances according to the invention were dissolved in the Krebs-Henseleit solution at a concentration of 10 pg/ml, if appropriate using a solubilizer (DMSO to a concentration of 0.5%). The dihydropyridine-carboxamides according to the invention exhibited inhibition of the contractile force of the papillary muscle of more than 10% in this test, relative to the control values. The new active compounds can be converted in a known fashion into conventional formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In the abovementioned case, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient to achieve the abovementioned dosage range. The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or disper-sants, and, for example when using water as a diluent, organic solvents can optionally be used as auxiliary solvents . I11 rfl i!'fi BliU - 20 - 22 4 1 2 5 Examples of auxiliary substances which may be mentioned are: water, nontoxic organic solvents, such as paraffins (for example mineral oil fractions), vegetable oils (for example groundnut/sesame oil), alcohols (for example: ethyl alcohol, glycerol), excipients, such as, for example, ground natural minerals (for example kaolins, clays, talc and chalk), ground synthetic minerals (for example highly disperse silica and silicates), sugars (for example sucrose, lactose and glucose), emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulphonates and aryl-sulphonates), detergents (for example lignin, sulphite waste liquors, methyIcel lulose, starch and polyvinyl pyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate). Administrati on takes place in a conventional fashion, preferably orally or parenterally, in particularly perlingually or intravenously. In the case of oral administration, tablets can of course also contain additives, such as sodium citrate, calcium carbonate and dical-cium phosphate, together with various additional substances, such as starch, preferably potato starch, gelatin and the like in addition to the excipients mentioned. Furthermore, lubricants, such as magnesium stearate, sodium lauryl sulphate and talc can be co-used for tabletting. In the case of aqueous suspensions, various flavour improvers or colorants can be added to the active compounds in addition to the abovementioned auxiliaries. In the case of parenteral administration, solutions of the active compounds can be employed using suitable liquid excipient materials. In the case of intravenous administration it has generally proven expedient to administer amounts from 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight in order to achieve effective results, and in the case of oral administration, the dosage is about 0.01 hi ih qu - 21 - 22 4 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight. Nevertheless, it may at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight and the nature of the administration method, the individual behaviour towards the medicament, the nature of the formulation of the medicament and the time or interval over which administration takes place. Thus, it may in some cases be sufficient to manage with less than the abovementioned minimum amount, whereas in other cases it is necessary to exceed the upper limit mentioned. When relatively large amounts are administered, it may be advisable to divide these into several individual administrations over the course of the day. Preparation examples Rf values: Merck TLC aluminium foil, coating thickness 0.2 mm, silica gel 60 F 254; mobile phase toluene/ethyl acetate in the volume'ratio 1:2. Example 1 Methyl 5 — (d imethyl carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Process variant A 2.12 g (10 mmol) of 2-benzyloxy-benzaldehyde are boiled for 18 hours with 1.16 g (10 mmol) of methyl aceto-acetate, 1.29 g of N,N-dimethylacetoacetamide and 1 ml of ammonia. The mixture is cooled and evaporated. The evaporation residue is taken up in ethyl acetate, washed twice with water, dried and evaporated. It is purified over a teu rt if 08* H 22 22 4 silica gel column using toluene/ethyl acetate mixtures. The pure fractions are collected and evaporated. The product crystallizes on trituration using ether/ethyl acetate 10:1. 0.8 g (19% of theory) of colourless crystals of melting point 162 - 163°C is obtained. Process variant E acetoacetate are refluxed for 18 hours with 0.83 g (6.45 mmol) of N,N-dimethylacetoacetamide and 0.53 ml of ammonia. The mixture is cooled and evaporated. The evaporation residue is taken up in ethyl acetate, shaken twice with water, dried and evaporated. The product mixture is purified over a silica gel column using a toluene/ethyl acetate mixture. The pure fractions are collected and evaporated. The product crystallizes on trituration with ether and a little ethyl acetate. The crystals are filtered off under suction. 0.6 g (22.9% of theory) of a colourless substance of melting point 163 - 165°C, Rf value = 0.118, is obtained. Example 2 Methyl 5-(phenylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Process variant G 3.1 g (10 mmol) of methyl 2-benzyIoxy-benzyIidene-acetoacetate are boiled for 3 hours in 20 ml of ethanol with 1.76 g (10 mmol) of N-benzy1-0-aminocrotonamide. The mixture is cooled and evaporated. The solid evaporation 2 g (6.45 mmol) of methyl 2-benzyloxy-benzyI idene- H 23 22 4 residue is stirred with ether, filtered off under suction and recrystallized from acetonitrile. 2.4 g (51.3% of theory) of colourless crystals of melting point 194°C are obtained. Example 3 Methyl 5-(cyclopropylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Process variant H 20 g (45.14 mmol) of methyl 5-(imidazolyI carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate are dissolved in 130 ml of absolute dimethyl-formamide, 5.63 ml (80.1 mmol) of cyclopropylamine are added, and the mixture is stirred for 20 hours at 90-100°C under argon. The mixture is cooled and evaporated. The evaporation residue is taken up in ethyl acetate, washed with water, 1N hydrochloric acid, water, sodium bicarbonate solution and again with water, dried and evaporated. The evaporation residue is stirred with toluene, filtered off under suction and washed with toluene. After recrys-tallization from about 60 ml of toluene, 14.95 g (76.7% of theory) of colourless crystals are obtained. Melting point: 191 - 193°C. Example 4 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(3-trifluoromethyl-benzyloxy)phenyl]pyridine-3-carboxylate h3c00c h3c h ty H U 88T - 24 - 22 4 1 2 3.5 g (6.8 mmol) of methyl 5-(imidazolylcarbamoyl)-1,.4-dihydro-2,6-dimethyl-4-C2-(3-trifluoromethyl-benzyloxy)-phenyI]pyridine-3-carboxyI ate (obtained from monomethyl 1,4-dihydro-2,6-dimethyl-4-C2-(3-trifluoromethylbenzyloxy)-phenyl]pyridine-3,5-dicarboxylate were reacted with carb-onylbisimidazole in tetrahydrofuran) are stirred overnight without further purification with 40 ml of methylamine solution (40X strength). The precipitated product is filtered off under suction and washed well with water. It is dried and recrystallized from a little toluene. 1.3 g (40.3X of theory) of a colourless product are obtained. Melting point: 156 - 157°C. The following were prepared analogously to Examples 1 to 4: Example 5 Methyl 5-(cyclopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(3-methyl-benzyloxy)phenyl3-pyridine-3-carboxylate Melting point: 176°C li n es oar - 25 - r 22 4 1 2 O. Example 6 Methyl 5-(cyclopropylcarbamoyl)-4-C2-(4-chloro-benzyloxy) phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CX. CH- h ocooc^xv^co - nh-^ X JL. H 5 Melting point: 178°C Example 7 Methyl 5-((2-pyridyl)carbamoyl)-4-C2-(4-chloro-benzyIoxy) phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate -CH- CI H3C0QCV|X*Ny^C0-NH--C ^ H-C^N^CH- H 10 Melting point: 201 - 204°C Example 8 Methyl 5-((2-pyridyl)carbamoyl)-4-(2-benzyloxy-phenyl) \,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CX.ch2-o H3COOCV/\^CO-NH- v // HoC'^N-^CHg 3 h 3 15 Melting point: 164 - 165°C k» .a ar of? - 26 - a- 22 4 1 2 5 ! Example 9 Methyl 5-((2-diethylamino-ethyl)carbamoyl)-4-C2-(4-chloro-benzyloxy)phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxyI ate O h3cooc ■ch- co-nh-(ch2)2-n /c2H5 ^2*5 10 Melting point: from 80°C Example 10 Methyl 5-((2-diethylamino-ethyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate h3cooc' -ch- co-nh-(ch2)2-n ^c2H5 \C2H5 Melting point: from 95 C Example 11 Methyl 5-((4-carbamoyl-phenyl)carbamoyl)-4-(2-benzyloxy phenyl)-1,4-di hydro-2,6-di methyl-pyr id ine-3-c arboxyI ate 15 o-ch2 H 3 C 0 0 0 - NH -CH- h Melting point: > 300°C li fli IT nIT // // -onh2 27 - a- 22 4 1 2 5 Example 12 Methyl 5-((4-acetylaminophenyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CXo-CH. // h3cooctvj^yco-nh--^ ^>—nh-co-ch; H Melting point: 298 C decomposition Example 13 Methyl 5-((4-benzoylaminophenyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-diniethyl-pyridine-3-carboxylate O-CH- // H3C00CX-X\^C0-NH' H3C-^-N'^s-CH3 h nh-c 10 15 Melting point: 197 C Example 14 Methyl 5-((1-phenylethyl)carbamoyl)-(R,S)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr idine-3-carboxylate (R , S mixture) Cu-ch2-o (r»s) /=\ H3COOCV^y-CO-NH-CH-\ ) h Melting point: from 162°C - 28 - :h3 ch3 22 4 1 r^s Example 15 Methyl 5-((1-phenylethyl)carbamoyl)-(R)-4-(2-benzyloxy-phenyl)-1,4-d ihydro-2,6-dimethyl-pyr idine-3-carboxylate (R form) o-ch- // (r) h3 co0 - nk - ch' H3C-^N>^-CH3 h ch- 10 Melting point: 82 C Example 16 Methyl 5-((3-dimethylaminopropyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-d i hydro-2,6-dimethyl-pyr idine-3-carboxylate H3COO -CH- /ch3 c0-nh-(ch2)3-n Nch3 15 Melting point: 89 - 90 C Example 17 Methyl 5-(cyclohexylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 108 - 111 C - 29 - 22 4 1 2 5 n> i O Example 18 Methyl 5-(tert.butyl carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-di met hyl-pyr i di ne-3-c arboxy I ate CX. ch 2"*d) h3coocv||>\^cq-nh-H3C^\N^x:H3 h ch- CHr :h. 5 Melting point: 148°C Example 19 Methyl 5-(propylcarbamoyl)-4-(2-benzyloxy-phenyl)-1r4-dihydro-2,6-dimethyl-pyr idine-3-carboxy late *2 X y 'CO-KH-CH2-CH2-CH3 10 Foam Rf = 0.37 Example 20 Methyl 5-((2-methyl-propyl)carbamoyl)-4-(2-benzyloxy-phenyl)' 1,4-di hydro-2,6-d imethyl-pyridine-3-carboxylate 15 Melting point: 134 C hi A 0D 00? - 30 - 22 4 1 2 Example 21 Methyl 5-(N-benzyl-N-tert.butyl carbamoyl)-4-(2-benzyloxy-phenyl )-1,4-dihydro-2,6-diraethyl-pyridine-3-carboxylate 5 Melting point: 128°C Example 22 Methyl 5-(methylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 10 Melting point: 105°C Example 23 Methyl 5-(ethylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate - 31 - 22 4 1 o Example 24 Butyl 5-(cyclopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl 4-C2-(2-pyridyl)methoxy-phenyl!]-pyridine-3-carboxylate h9c4ooc 10 Foam Rf = 0.1 Example 25 Butyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2' (2-pyridyl)methoxy-phenyl]-pyridine-3-carboxylate h9c4ooc 15 Foam Rf = 0.07 Example 26 Butyl 5-((1-methylpropyl)carbamoyl)-1.4-dihydro-2,6-dimethyl' 4-C2-(2-pyridyl)me t hoxy-phenyI]-pyr i dine-3-carboxylate -ch- h9c4ooc N // c0-nh-ch-ch2-ch3 I ch, - 32 - a- 22 4 1 2 5 Foam Rf = 0.25 Example 27 Methyl 5-(cyclopropylcarbamoyl)-4-C2-(3,4-dichloro-benzyloxy)-5 phenyl 3-1,4-dihydro-2/6-dimethyl-pyridine-3-carboxylate Melting point: 195°C Example 28 Methyl 5-(cyclopropylcarbamoyl)-4-C2-(2,6-di chloro-benzyl-10, oxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 178°C Example 29 Methyl 5-((1-methyl-propyl)carbamoyl)-4-C2-(2,6-dichloro-15 benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate H H - 33 - 22 4 1 2 5 Rf = 0.36 Example 30 5 Methyl 5-(methyIcarbamoyI)-4-C2-(2,6-dichIoro-benzyI oxy)-phenyl 3-1,4—d ihydro-2,6-dimethyl-pyridine-3-carboxylate CI CH- HgCOOC^^sx'C A jC ci CO-NH-CH- H- H Melting point: 133°C Example 31 10 Methyl 5-(methylcarbamoyl)-4-C2-(3,4-dichloro-benzyloxy)-phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 120°C i i (i if nirr - 34 - 22 4 125 Example 32 Methyl 5-(eyelopropyI carbamoyl)-4-C2-(3-fluoro-benzyloxy)-3-methoxy-phenyI]-1,4-d i hydro-2,6-dimethyl-pyr id ine-3-carboxylate Melting point: 202°C Example 33 Methyl' 5-(cyclopropylcarbamoyl)-4-C2-(2-chloro-benzyloxy)-pheny I 3-1'/4-dihydro-2,6-dimethyl-pyr idine-3-carboxylate Melting point: 185°C Example 34 Methyl 5-(me thy I carbamoyl)—4— C 2—(2-c hloro-benzy loxy) phenyl 3-1,4-dihydro-2,6-dimethyl-pyr idine-3-carboxylate - 35 - =1" SftSSlWtaMaw,, -J X.. J... >5; -41 ■I I $ (Si' n i h3cooc 22 4 1 2 5 Melting point: 170°C Example 35 Methyl 5-((2-methyl-propyl)carbamoyl )-4-[2-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-1,4-di hydro-2,6-dimethyl -pyridine-3-carboxylate *0 Melting point: 98°C Example 36 10 Methyl 5-(eyelopropyI carbamoyl)-1,4-dihydro-2,6-dimethy I 4-C2-(3-trifluoromethyl-benzyloxy)phenyl]-pyridine-3-carboxylate h3cooc Melting point: 148°C a i id If B8* - 36 - c,,, ». }-> , "M -/Set1 I $ w, 1 8 i *■ & o 224125 Example 37 Methyl 5-((1-methyl-propyl)carbamoyI)-1,4-dihydro-2,6- dimethyl-4-C2-(3-trifluoromethyl-benzyloxy)phenyl]-pyridine' 3-carboxylate O h3cooc ch2-ch3 10 15 Foam Rf = 0.44 Example 38 Methyl 5-(isopropylcarbamoyl)-4-C2-(3-fluoro-benzyloxy)-3-raethoxy-phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxyI ate aCH3 / -CH2-{ ) h3c00c^y^sjrxc0-nh-ch (ch3) 2 HoC-^N^M:H3 3 H Melting point: 106°C Example 39 1-methyl-propyl 5-(cyclopropylcarbamoyL)—1,4—dihydro-2,6-dimethyl-4-C2-<4-methyl-benzyloxy)phenyl]-pyridine-3-carboxylate - 37 - 224125 H^C-HC-OOC 3 I H3C-H2C H3C °"CH2'\_ 'CO-NH rd)-0 Foam Rf = 0.31 Example 40 5 Methyl 5-(cycIopropyIcarbamoyI)-4-(4-benzyIoxy-phenyI)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 197°C Example 41 10 1-methyl-propyI 5-((1-methyl-propyl)carbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(4-methyl-benzyloxy)phenylD-pyridine-3-carboxyI ate h H,C-CH-OOC 3 I H3C-H2C H3c J Melting point: 126°C tu m lj uui 1 » • s a: v<£ ;jWL 22 4 1 2J n ,ckajp*r /~\ l > * Example 42 1-methyl-propyl 5-<methylcarbamoyl) -1 ,4-dihydro-2,6-dimethyl-4-[2-(4-methyl-benzyloxy)phenyl]-pyrid-ine-3-carboxytate h-ac-ch-ooc I II h3c-h2c h3c 5 Foam Rf = 0.48 Example 43 Ethyl 5-(eyelopropylcarbamoyl)-1,4-di hydro-2,6-dimethyl-4-C2-(3-nitro-benzyloxy)phenyl]-pyridirie-3-carboxylate 10 h5c2ooc -ch NO- co-nh 2~C^) < Foam Rf = 0.24 Example 44 Methyl 5-(propylcarbamoyl)-4-(4-benzyloxy-phenyl)-1,4-15 d ihydro-2,6-dimethyI-pyridine-3-carboxylate hi illi af OOH - 39 22 4 1 2 Melting point: 210°C Example 45 Ethyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-C2-(4-fluoro-benzyloxy)phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R form) H5C2OOC\r^\/CO-NH-CH 11 H Foam Rf = 0.56 Example 46 Methyl 5-((2-methyl-propyl)carbamoyl)-4-(4-benzyloxy-phenyl)- n Ti na*» - 40 - 22 4 Example 47 Ethyl 5-(cyclopropylcarbamoyl)-4-[2-(4-fluoro-benzyloxy)-phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 5 Melting point: 159°C Example 48 Methyl 5-(eye lopropylcarbamoyl)-4-C2-(4-fluoro-benzyloxy )-phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 10 15 Melt ing point: 154 C Example 49 Methyl 5-((1-phenylethyl)carbamoyl)-(S)-4-(4-benzyloxy-phenyl)-1/4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (S form) (s) co-nh-ch-ch3 - 41 - n O' V;:»" W S 11 4 i Melting point: 141°C | Example 50 Methyl 5-(isopropylcarbamoyl)-4-(4-benzyloxy-phenyl)-1/4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ^ 'co-nh-ch (ch3) 2 :h, h Melting point: 162°C Example 51 Methyl 5-((1-phenylethyl)carbamoyl)-(R)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 10 (R form, diastereomer A) Melting point: 196°C Example 52 Methyl 5-(eyelopropylcarbamoyl)-4-C2-(3-chloro-benzyloxy) 15 phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate % - 42 - m 22 A 1 2 5 n O h3coo Melting point: 174°C Example 53 Methyl 5-(cyclopropylcarbamoyL)-4-C2-(4-fluoro-benzylthio)' phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate h3cooc 10 Melting point: 202 C Example 54 Methyl 5-((1-phenylethyl)carbamoyl)-(R)-4~<4-benzyloxy-phenyL)-1/4-dihydro-2/6-dimethyl-pyridine-3-carboxylate (R form) (diastereomer B) H Melting point: 202°C L^T1 )H 8ff OUP - 43 - 22 4 1 2 5 Example 55 Methyl 5-((1-phenylethyl)carbamoyl)-(R)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R form, diastereomeric mixture) Melting point: 110 - 166°C Example 56 Methyl 5-((1-phenylethyl)carbamoyl)-(S)-4-(2-benzyloxy-phenyl)-1,4-di hydro-2,6-d imethy I -pyr idine-3-carboxylate 10 (S form, diastereomer A) Melting point: 172°C Example 57 Methyl 5-((1-phenylethyl)carbamoyl)-(S)-4-(2-benzyloxy-15 phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (S form, diastereomer B) fll OOP* - 44 - ■w>\ ' kp" ¥ 1 I f '% •\ I 3 <© *& o 22 4 1 2 5" •ch- co-nh-ch-ch3 ' (S) Foam Rf = 0.53 Example 58 5 Methyl 5-((1-phenyl-ethyI)carbamoyl)-(R)-4-C2-C4-f I uoro-benzyloxy)phenyl]-1,4-dihydro-2,,6-dimethyl-pyridine-3-carboxylate (r form) H3cooc>>^^yco-NH-c:H-^ ^ H Foam 10 Rf = 0.52 Example 59 Butyl 5-(cyclopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl' 4-C2-(methyl-benzyloxy)phenyl3-pyridine-3-carboxylate c? 15 Foam Rf = 0.31 H9C4°0CTYC0' ^■^°-ch2-X ) co-nh H 45 - m m $'■ # $ I 0- © o p Ttywf1 1 o I . 22 4 1 2 5 Example 60 Butyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-1,4-dihydro-2,6-diraethyl-4-C2-(3-methyI-benzyloxy)-phenyl]-pyri dine-3-carboxylate (R form) Oil Rf = 0.88 Example 61 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-C2-(3-chloro-10 benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R form) Foam Rf = 0.73 15 Example 62 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-(3-benzyloxy-phenyl)-1,4-dihydro-2,6-dime thyl-pyridine-3-carboxylate (R form) - 46 - 22 4 1 2 5 o-ch2- KD h3cooc (R) 'CO-NH-CH- '<3 H3 CH3 H Melting point: from 143°C Example 63 Methyl 5-Ceyelopropylcarbamoyl)-4-(3-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 144°C Example 64 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-C2-(4-fIuoro-benzylthio)phenyl]-1,4-dihydro-2/6-dimethyl-pyridine-3-carboxylate (R form) H,C^\N'^m:H3 3 H H Foam Rf = 0.47 - 47 - I 1 4 22 4 1 2 5 Example 65 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(S)-4-[2-(4-fluoro-^sk benzylthio)phenyl3-1,4-dihydro-2/6-dimethyl-pyridine-3- carboxylate (S form) Foam Rf = 0.48 Example 66 Methyl 5-(allylcarbamoyl )-4-C2-(4-fluoro-benzylthio)phenyl3-10 1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate H3COOC>y^\xco-NH-CH2-CH=CH2 w H Melting point: 177°C Example 67 Methyl 5-(allylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-15 2,6-dimethyl-pyridine-3-carboxylate Melting point: 148°C - 48 - 22 4 1 2 5 i ' Vw-' Example 68 Methyl 5-((1-phenyl-ethyl)carbatnoyl)-(R)-4-(2-benzyloxy phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R form) o vy 11<; y— h3coocv>^y co-nh-ch-^ } H3C-^N^CH- Melting point: 175°C Example 69 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-diniethyl-pyridine-3-carboxylate 10' (R form, diastereomer 8) H Melting point: 169°C Example 70 Methyl 5-((2-phenyl-ethyl)carbamoyl)-4-(2-benzyloxy-phenyl)' 15 1,4-dihydro-2,6-d imethyI-pyridine-3-carboxylate Oil - 49 - 22 4 1 2 5 Example 71 Methyl 5-(benzylcarbamoyl)-4-C2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 5 Melting point: 148 -149°C Example 72 Methyl 5-(ethylcarbamoyl)-4-C2-(4-fluoro-benzylthio)phenyl]-1,4-di hydro-2,6-dimethyl-pyridine-3-carboxylate 10 Melting point: 202 - 204°C Example 73 Methyl 5-(ethylcarbamoyl)-4-(3-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 15 Melting point: 152 - 154°C 22 4 1 2 5 } r* Example 74 Methyl 5-(ethylcarbamoyl)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate H3COOC rc»2-0 o-nh-ch2-ch3 Melting point: 183 - 185 C Example 75 Methyl 5-carbamoyl-4-(2-benzyloxy-phenyl)-1,4-di hydro-2,6-dimethyl-pyr idine-3-carboxylate 10 Melting point: 188 C Example 76 Methyl 5-(diethylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4* dihydro-2,6-dimethyI-pyridine-3-carboxylate H 15 Melting point: 135 C \Mt A 8f OQf - 51 - 5 10 15 22 4 1 2 5 Example 77 Methyl 5-(eyelopropylcarbamoyl) —1,4 — dihydro-2,6-dime thy I-4-[2-(4-methyl-phenylsulphonyloxy)phenyl]-pyridine-3-carboxylate ^°-S02 \ //CVi2 h 3c ooc'v^\j/c 0 - nh h,c^n^ch3 H Melting point: 238 - 242°C Example 78 Methyl 5-(ethylcarbamoyl )-1-,4-dihydro-2,6-dimethyl-4-C2-(4-methyl-phenylsulphonyloxy)phenyl3-pyridine-3-carboxylate H, Melting point: 228°C Example 79 Methyl 5-(ethylcarbamoyl)-4-C2-(2,6-dichloro-benzyloxy)phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CI o-ch2 ci H3COOC^y^sV^CO-NH-CH2-CH3 H-,C>^N^^CH3 3 H Melting point: 174 - 176°C A 15 Uil - 52 - I ft 22 4 1 2 5 i o Example 80 Methyl 5-(ethylcarbamoyl)-4-[2-(3,4-dichloro-benzyloxy)-phenyl]-1,4-d i hydro-2,6-d imethyl-pyri dine-3-carboxylate 5 Melting point: 178 - 180 C Example 81 Methyl 5-(ethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(2-pyridylmethyloxy) phenyl]-pyridine-3-carboxylate O-CH 2 v // N- H3COOC\|^n/CO-NH-C2H5 3 H 10 Melting point: 159 - 161°C Example 82 Methyl 5-(eyelopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(2-pyridylmethyloxy)phenyl]-pyridine-3-carboxylate H3COOC 15 Melting point: 168 - 170°C ■EL * LJ lilUf - 53 - 22 4 1 2 5 Example 83 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-(2-phenylsu.lphonyloxy-phenyl)-pyridine-3-carboxylate Melting point: 171 - 173°C Example 84 Methyl 5-(ethylcarbamoyl )-1/4-dihydro-2/6-dimethyl-4-(2-phenylsulphonyloxy-phenyl)-pyridine-3-carboxylate Melting point: 188 - 190°C Example 85 Ethyl 5-(ethylcarbamoyl)-1/4-dihydro-4-E2-(4-fluoro-benzyloxy)phenyl3-2,6-dimethyl-pyridine-3-carboxylate Melting point: 147 - 149°C 11 ft *ir nn» - 54 - & I 22 4 1 2 5 o Example 86 Methyl 5-(ethylcarbamoyl )-1,.4-dihydro-4-C2-(4-fluoro-benzyIoxy)phenyI 3-2,6-d i methyl-pyridine-3-carboxylate i O H3C00 5 Melting point: 111 - 113°C Example 87 Methyl 5-(allylcarbamoyl)-1/4-dihydro-2(,6-dimethyl-4-(2-phenylsulphonyloxy-phenyl)-pyridine-3-carboxylate h3cooc -SO- co-nh-ch2-ch=ch2 O' Melting point: 154 - 156°C 10 Example 88 Methyl 5-((4-pyridyl)carbamoyl)-1,4-dihydro-2,6-dimethyl-4-(2-phenylsulphonyloxy-phenyl)-pyridine-3-carboxylate ,N H Melting point: from 240°C (decomposition) - 55 - 22 4 1 2 5 Example 89 Methyl 5-(allylcarbamoyl)-4-C2-(4-chloro-benzyloxy)phenyl3-1,4-di hydro-2,6-d imethyl-pyr idine-3-carboxylate Melting point: 145°C 5 Example 90 Methyl 5-(allylcarbamoyl )-4-<3-benzyloxy-phenyl)-1/4-dihydro- Melting point: 95 - 98°C Example 91 10 Methyl 5-(allylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2- (4-methyl-phenylsulphonyloxy)phenyl3pyridine-3-carboxylate Melting point: 168 - 170°C i i n ir nnr - 56 - 22 4 1 2 5 Example 92 Methyl 5-(allylcarbamoyl)-4-C2-(2,6-dichloro-benzyloxy)phenyl]' 1,4-dihydro-2,6-dimethyl-pyr idine-3-carboxylate h2c=hc-h2c-hn- c1 -OCV^n/CO A X HrjO^N'^CH cooch- h Melting point: 132 - 134°C Example 93 Methyl 5 - ((2-hydroxyethyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr idine-3-carboxylate h3c00c -CH2" \ / co-nh-ch2-ch2-oh 10 Melting point: 148 - 150°C Example 94 Methyl 5-(methylcarbamoyl)-4-C2-(3-fluoro-benzyloxy)-3-methoxy-phenylD-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate l«e a if 88 - 57 - 22 4 Melting point: 171 - 173°C Example 95 Methyl 5-(2-(4-pyr idyDethyl carbamoyl )-4-(2-benzyl oxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: Example 96 Methyl 5-(me thy I carbamoyl)-1,.4-dihydro-2,6-dimethyl-4-[2-(3-pyridyl)methoxy-phenyl]-pyridine-3-carboxyl ate 10 Melting point: from 210°C Example 97 Methyl 5-(ethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(3-pyridyl)methoxy-phenyl]-pyridine-3-carboxylate Melting point: 122 - 125°C Ll * ilJ uui - 58 - 11 4 1 2 5 Example 98 Methyl 5-(ethylcarbamoyl)-1,4-di hydro-2,6-dimethyl-4-C2-(4-pyridyl)methoxy-phenyl3-pyridine-3-carboxylate Example 99 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(4-pyridyl)methoxy-phenyl]-pyridine-3-carboxylate 10 Melting point: from 203°C (decomposition) Example 100 Methyl 5-( (cyclopropylmethyl)-carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 15 Melting point: 186°C L'i. a air a87 - 59 - 22 4 1 2 51 Example 101 Methyl 5-(ethy IcarbamoyI)-(+)-4-(2-benzyloxy-phenyl) — 1,4 dihydro-2,6-d imethyl-pyridine-3-carboxylate 5 Melting point: 147°C [a]*0 = + 29.68 c = 0.91 (DMF) Example 102 10 Methyl 5-(ethylcarbamoyl)-(-)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 148°C Ca]J0 = - 29.92 c = 0.805 (0MF) Example 103 Ethyl 5-(methylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr id ine-3-carboxylate 22 4 1 2 5 Me Iting point: 179°C Example 104 Ethyl 5-(ethylcarbamoyl) — 4—(2—benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 161 - 164°C Example 105 Methyl 5-((2-ethoxycarbonylethyl)carbamoyl)-4-(2-benzyloxy-phenyl )—1,4—dihydro-2,6-dimethyl-pyridine-3-carboxylate - 61 - 22 4 1 2 5 Example 106 Methyl 5-((ethoxycarbonylmethyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Rf = 0.408 Example 107 Methyl 5-(octylcarbanioyl)-4-(2-benzyloxy-phenyl)-1,4-d ihydro-2,6-d ime thy I-pyr idine-3-carboxylate Rf = 0.53 Example 108 Methyl 5-(nonylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dime thyl-pyridine-3-carboxylate Rf = 0.55 - 62 - 22 4 1 2 5 Example 109 Methyl 5-(decylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 111°C Example 110 Methyl 5-((2-methoxy-ethyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-d ihydro-2,6-dimethyl-pyridine-3-carboxylate Melting point: 145°C Example 111 Methyl 5-((3-methoxy-propyI)carbamoyl)-4-(2-benzyloxy-phenyl )-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Rf = 0.19 "Li * Qfi IWf - 63 - 22 4 1 2 5 Example 112 Methyl 5-((2-hydroxy-1-methyI-2-phenyl)ethylcarbamoyl)- (R,R)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl- pyridine-3-carboxylate H^OOCV/X^CO-NH-CH CH-OH II II (R) (R) h3c^n^vch3 Process variant H (direct coupling with dicyclohexyl-carbodi imide) 1 g (2.54 mmol) of monomethyl 4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr idine-3,5-di carboxylate 10 are dissolved in 5 ml of dimethylformamide, and 0.477 a (2.54 mmol) of L-norpseudoephedrin hydrochloride, 0.35 ml (2.54 mmol) of triethylamine and 0.629 g (3.05 mmol) of dicyclohexyl-carbodiimide (solid) are added. The mixture is stirred at room temperature for 4 hours, the urea is 15 filtered off under suction, and the filtrate is evaporated. Column chromatography; Silica gel 60, grain size 0.040 - 0.063 mm using CHCI3/CH3OH/NH3 20 : 1 : 0.05 Since urea is only sparingly soluble in ether and 20 methylene chloride, the product is taken up several times in ether or methylene chloride, filtered off and evaporated. Yield: 0.9 g (67.3X of theory) Rf = 0.35 25 Co] *°: - 47.93 (CHC13) 22 A 1 25 Example 113 Methyl 5-((2-hydroxy-1-methyl-ethyl)carbamoyl)-(S)-4-(2-benzyloxy-phenyl)-1/4-dihydro-2/6-dimethyl-pyridine-3-carboxylate Rf = 0.13 Co] *°; +7.34 (CHCl3) Example 114 Methyl 5-((1-hydroxy-methyl-propyl)carbamoyl)-(S)-4-(2-10 benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ! O Rf = 0.15 Cot] *°: -9.37 (CHCI3) 15 Example 115 Methyl 5-((1-hydroxy-methyl-2-methyl-propyl )carbamoyl) (S)-4-(2-benzyloxy-phenyl)-1/4-dihydro-2/6-dimethyl-pyridine-3-carboxylate in ii ir nrrr - 65 - 22 4 1 2 5 ch2-<g> h3cooc HqC 3 H (s) co-nh-ch-ch2-oh •ch3 ch h3C^ >vmzh3 Rf = 0.19 Ca] jj°: -10.8 CCHCL3) Example 116 Methyl 5-((1-hydroxy-methyl-2-methyl-butyl)carbamoyl)-(s)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyn*dine-3-carboxylate Rf = 0.21 Ca] jj°: -17.37 (CHCI3) Example 117 Methyl 5-((3-hydroxy-propylJcarbamoyl)-4-(2-benzyloxy-phenyl)-1/4-dihydro-2,6-dimethyl-pyridine-3-carboxylate li' h lb uu? - 66 - 22 4 1 2 5 © o (T ^v^O-ch2-C > I hocoocv^v^co-nh- {ch? j -,-oh II II- H3C^S^N^NCH3 h Melting point: 205°C Example 118 Methyl 5-(3-cycloprop/lcarbamoyl)-(-) 4-(2-benzyloxy-phenyI) 5 1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Cu JCV^N^CO- HqCOOCV^Ny^CO-NH-<| II " h3C^ H h3C'^\N'^M:H3 o Melting point: 178 - 181°C Ca]589="38,28 <c=0-569' chloroform) Example 119 10 Methyl 5-(3-cyclopropylcarbanoyl)-(+) 4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate lf*i o y^-ch2^ H3COOCV.^svyx-cO-NH-<] II H -N' h H3C'^^N'^CH3 Melting point: 178 - 181°C Ca]|g^= +36.56 (c=0.52, chloroform) - 67 - 22 4 1 2 5 Example 120 Methyl 5-hexylcarbamoyl~4-(2-benzyloxy-phenyl)-1,4-di hydro-2,6-dimethyl-pyridine-3-carboxylate n o H3C00CTs^>YX0-NH-(CH2)5-CH3 „,cAXH h 5 Melting point: 133°C Example 121 Methyl 5-carbamoyl-4-C2-(4-niethyl-benzenesulphonyloxy)-phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate o ^ - s °2— >"ch 3 hocoocv^v^co - nh, II II h 10 Melting point: 205°C Example 122 ^ Methyl 5-sec.-butyIcarbamoyl-4-(2-benzyloxy-phenyI)-1,4- l*w' dihydr o-2,6-d i methyl-pyridine-2-carboxylate (X -CH2"A I — HoCOOC^v^Vy^'CO-NH-CH-CHg 3 ll II l h3o^n>'am:h3 ch2-gh3 h 15 Melting point: 135°C •trrsrw^ - 68 - © V/; Q ■i - -it' 1 f Example 123 22 4 1 2 5 Isopropyl 5-carbamoyl-4-(2-benzyloxy-phenyl)—1,4—dihydro-2,6- I dimethyl-pyridine-3-carboxylate "CH2^ __ > i h3c\ i I A CHOOC^^v/CO-NHo i m h3c/ || || I H3C^Ss»N>^CH3 I 5 Melting point: 190°C Example 124 2-Methoxy-ethyl 5-carbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-5-carboxylate I H3C-0-H2C-H2C-OOC^Y^V^CO-NH2 | O h3C-^-N'^s<;H3 1 H 10 Melting point: 165°C Example 125 Methyl 5-butylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate h3cooc\^v^'co-nh- (ch2 ) 3"ch3 J3C II 'I h 22 4 1 2 5 Melting point: 144 - 148°C Example 126 I sopropy I 5-ethylcarbamoy1-4-(2-benzyloxy-phenyI)-1,4-d ihydro-2,6-dime thyI-pyr idine-3-carboxylate 10 Melting point: 135°C Example 127 Methyl 5-(3-ethoxypropyl)carbamoyl-4-(2-benzyloxy-phenyl) 1,4-d i hydro-2,6-dimethyl-pyr i dine-3-carboxylate h^cooc^/v^co-nh- ( ch2 ) 3-0-c2h5 ii H 3 H Melting point: 115°C Example 128 Methyl 5-(5-hydroxypentyl)carbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr idi ne-3-carboxylate 15 (X. CH- ' t h3c00c'x^nn^'c0-nh- (ch2 ) 5-oh HoCX^-N 3 H 3 - 70 - m' 22 4 125 Melting point: 178°C Example 129 2-Methoxy-ethyl 5-methylcarbamoyl-4-(2-benzyloxy-phenyl) 1,4-dihydro-2/,6-dimethyl-pyridine-3-carboxylate 5 "CH2~\ H3C-0-H2C-H2C-00C^'^,J^CC)*NH"CH3 h3C^n-N'^M:H3 h Melting point: 133 - 135°C Example 130 2-Methoxy-ethyl 5-ethylcarbamoyl-4-(2-benzyloxy-phenyl )■ 1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate 10 (X, •ch2-\ I '— H3C-0-H2C-H2C-00CV^v^C0-NH-C2H5 H3c-^N-^M:H3 h 15 Melting point: 1110C r ^ Example 131 Isopropyl 5-methylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate /, \ ** »\ )-CH2-\ ) H 3 CH-OOCrv^^'CO-NH-CHa h3c^' II II 3 h - 71 - </div>

Claims

<div id="claims" class="application article clearfix printTableText"> rv r\ ( J 22 A 125 Melting point: 140 - 143°C Example 132 IsopropyL 5-cycI op ropyIcarbamoyI-4-<2-benzyloxy-phenyI) 1,4-dihydro-2,6-di(nethyl-pyridine-3-carboxylate ex. -ch2-\ :> h3c\ i CH-OOCX^v^co-NH-O h3c/ ii |l ^ H3C-^v-N'XNCH3 h Melting point: 132 - 135°C Example 133 IsopropyL 5-isopropytcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dii»ethyl-pyridine-3-carboxylate O fc ^^O-ch^ _ ;> h3c\ | /ch3 ^ CH-OOC>n^^v/CO-NH-CH h3c/ ii |i nch3 h3C'Xs^N-^M:H3 h Melting point: from 110 C i > 5 \ - 72 - il S" fr 22 4 125 what we claim is: 1- D ihydropyn'dinamides of the general formula (I) R200 (I) in which 1 8 R and R are identical or different and represent straight-chain, branched or cyclic alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, cyano, phenyl or halogen, or represent cyano or phenyl, 2 R represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 10 carbon atoms which may be interrupted in the chain by an oxygen atom or a sulphur atom and/or which may be substituted by halogen, cyano, hydroxyl, acetoxy, pyridyl or by a phenyl, phenoxy or phenylsulphonyl group which is optionally substituted by halogen, cyano, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl, R"* and R^ are identical or different and : represent hydrogen, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, cyano, nitro, dialkylamino having up to 4 carbon atoms in each alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy or trif Iuoromethy11hio, 5 11 R represents a group of the formula -0-(CH2)n-R , -S-(CH2)n_Rl1* -0-S02-R11, -C0-(CH2>n-R11' -0-C0-(CH2)n-R11, -CO-NH-(CH2)n-R11, - 73 - 224125 & I l i I I? i' ® -NH-C0-(CH2)n-R11 or -NH-SOg-(CHj)n-R11, a 5 I and in which | n denotes 0 to 4, and 11 R denotes aryl having 6 to 12 carbon atoms which may be monosubstituted to tetrasubstituted by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, difIuoromethoxy, trifluoromethyl-/""N thio, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, amino, alkylamino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group or acetylamino, the substituents being identical or different, or denotes a 5- to 7-membered saturated or unsaturated hetero- 1 cyclic ring which may contain as hetero atoms -I | an oxygen atom, a sulphur atom or two nitrogen ■ 1 | atoms, R ^ and R ^ are identical or different and in each case represent hydrogen, (^) cycloalkyl having 3 to 8 carbon atoms or straight I chain or branched alkyl, alkenyl or alkinyl which in each case have up to 18 carbon atoms and which may be substituted by halogen, hydroxyl, alkoxy having up to 8 carbon atoms, 5 r~j alkylthio having up to 8 carbon atoms, alkylcar- « bonyl having up to 8 carbon atoms in the alkyl | radical, carboxyl or alkoxycarbonyl having up to j 8 carbon atoms, by phenyl which is optionally | substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms, by cyano and/or by a group of the form^V^;-7rR^ft4£*Rw._ in which hi ft IF 087. - 74 - 11 4 1 9 10 R and R are identical or different and in each case denote hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, aryl having 6 to 12 carbon atoms, acyl having up to 7 carbon atoms, alkylsulphonyl having up to 6 carbon atoms, or arylsulphonyl having 6 to 12 carbon atoms, or R^ and in each case represent aryl which has 6 to 12 carbon atoms and which may be monosubstituted, disubstituted or trisubstituted by nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, carbamoyl, dialkylcarbamoyl having up to 6 carbon atoms in each alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl-thio, amino, alkylamino having up to 8 carbon atoms, dialkylamino having up to 8 carbon atoms in each alkyl group, acetylamino or benzoyl amino, the substituents being identical or different, or represent a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain as hetero atoms an oxygen atom, a sulphur atom or two nitrogen atoms, the physiologically acceptable salts thereof- Compounds of the general formula (I) according Claim 1, in which 1 8 R and R are identical or different and in each case represent straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine or bromine, or represents cyano or phenyl, p R represents a straight-chain or branched, saturated or unsaturated hydrocarbon radical which has LI * as 09T - 75 - a? •St and 22 A 1 2 5 up to 8 carbon atoms and which may be interrupted in the chain by an oxygen atom and/or which may substituted by fluorine, chlorine, bromine, cyano, hydroxyl or by a phenyl or phenoxy group which is optionally substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or by a-, 8- or Y-pyridyl, 3 4 R and R are identical or different and in each f**) case I represent hydrogen, fluorine, chlorine, bromine, I alkyl having up to 4 carbon atoms, alkoxy having ' f | up to 4 carbon atoms, methylthio, cyano, nitro, I trifluoromethyl or trifluoromethoxy, 15 11 I R represents a group of the formula -0-(CH2)n-R , | -S-(CH2)n-R11, -0-S02-R11, -0-C0-(CH2)n-R11, | -NH-CO-CCH2>n-R11 or -NH-S02-(CH2)n"R11, | i n w h i c h I n denotes 0 to 3 I and I 11 I R denotes phenyl or naphthyl which may be mono- | substituted, disubstituted or trisubstituted by I fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 | carbon atoms, alkoxy having up to 4 carbon atoms, | methylthio, amino, alkylamino having up to 4 car- | bon atoms, dialkylamino having up to 4 carbon atoms | in each alkyl group, or acetylamino, the sub- | stituents being identical or different, or | denote pyridyl, thienyl, furyl, pyr im idyl or | pyrazinyl. R^ and R ^ are identical or different and in each case represent hydrogen or cycloalkyl having 3 to 7 carbon atoms, or represent straight-chain or branched alkyl or - 76 - I I ?: $ 11 k 1 2 5 aLkenyl which has up to 14 carbon atoms and which | may be substituted by fluorine, chlorine, bromine, I hydroxyl, alkoxy having up to 6 carbon atoms, ! alkylthio having up to 6 carbon atoms, alkylcar- | | bonyl having up to 6 carbon atoms in the alkyl I radical, carboxyl, alkoxycarbonyl having up to 6 | carbon atoms, phenyl which is optionally substit- ; uted by nitro, trifluoromethyl, methyl or methoxy, O a n | Kjs by cyano and/or by a group of the formula -NR R , | i n wh i c h | 9 10 I R and R are identical or different and in each I \ case denote hydrogen, alkyl having up to 6 carbon I | atoms, benzyl, phenethyl, phenyl, acetyl, benzoyl, | alkylsulphonyl having up to 4 carbon atoms or | phenyIsulphonyl, I or | represent phenyl or naphthyl which may be mono- ] substituted, disubstituted or trisubstituted by | nitro, fluorine, chlorine, bromine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, alkyl-amino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group, acetylamino or by benzoylamino, the substituents being identical or different, or represent pyridyl, pyrimidyl, thienyl or furyl, and the physiologically acceptable salts thereof. 3- Compounds of the general formula (I) according to Claim 1, in which 1 8 R and R are identical or different and in each | case represent methyl, ethyl or benzyl, R represents a straight-chain or branched hydrocarbon radical which has up to 6 carbon atoms, may be interrupted in the chain by an oxygen atom and/or - 77 - 11h 125 o n may be substituted by fluorine, chlorine, cyano, hydroxyl, phenyl, a-, &- or y-pyridyl, R 3 and R ^ are identical or different and in each case represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, nitro or trifluoromethyl, 5 11 R represents a group of the formula -0-CH2-R , -S-CH2-R 11 or -0-S02-R11, in which 11 R denotes phenyl which may be monosubstituted or disubstituted by fluorine, chlorine, nitro, trifluoromethyl, methyl, methoxy, amino, methyl-ami no, dimethylamino, ethylamino, diethylamino or acetylamino, the substituents being identical or different, or denotes an a-, B~ or a y-pyr idyl group, R^ represents hydrogen or alkyl having up to 4 carbon atoms, and R7 represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl or alkenyl which has up to 10 carbon atoms and which may be substituted by fluorine, chlorine, hydroxyl, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, alkylcarbonyl having up to 4 carbon atoms in the alkyl radical, carb- ^ oxyl, alkoxycarbonyl having up to 4 carbon atoms, ^ phenyl and/or a group of the formula -NR9R1^, in which 9 10 R and R are identical or different and denote hydrogen, alkyl having up to 4 carbon atoms, benzyl, phenyl or acetyl, or R7 represents phenyl which may be monosubstituted or disubstituted by nitro, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, - 78 - ?24 125 r\ alkylanino having up to 2 carbon atoms, dialkylamino having up to 2 carbon atoms in each alkyl group, acetylamino or benzoylamino, the substituents being identical or different, or represents a-, B- or Y~Pyridyl, and the physiologically acceptable salts thereof. 4. Compounds of the general formula I according to claim 1 r>. R2OOC R3 (I) G 5. 6. in which Rj and Rg each represent methyl R2 represents alky! with up to 4 carbon atoms1 R3 and R4 each represent hydrogen R5 rcprcscnis °"CH2 optionally substituted by 1 fluoro, and R6 and R7 arc identical or different and in each case represent hydrogen or straight-chain or branched alkyl, cycloalkyi or alkeny! with up to 4 carbon atoms, and the physiologically acceptable salts thereof. A compound according to claim A wherein R2 is methyl. Methyl 5-(cyclopropylcarbamoyl)-A-(2-benzyloxy-phenyl)-1,A dihydro-2, 6-dimethyl-pyridine-3-carboxylate. - 79 / 7. Methyl 5-(3-cyclopropylcarbamoyl)-(+) <i-(2-b0nzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridlne-3-carboxylate. 8. Process for the preparation of dihydropyridinamides of the general formula (1) R2OOC (I) in which 1 8 R and R are identical or different and represent straight-chain/ branched or cyclic alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, cyano, phenyl or halogen, or represent cyano or phenyl, 2 R represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 10 carbon atoms which may be interrupted in the chain by an oxygen atom or a sulphur atom and/or which may be substituted by halogen, cyano, hydroxyl, acetoxy, pyridyl or by a phenyl, phenoxy or phenyIsulphonyl group which is optionally substituted by halogen, cyano, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl, R ^ and R ^ are identical or different and represent hydrogen, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, »r «»er i «■. alkylthio having up to 4 carbon atoms, cyano. IT frfff - 79A- 1!7 5EP?95$'-'"V L. * i 3®; 1 224125 ■i n and W nitro, dialkylamino having up to 4 carbon atoms in each alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy or trifluoromethy 11hio, 5 11 R represents a group of the formula -0-(CH2)n-R / -S-(CH2)n-R11/ -0-S02-R11, -0-C0-<CH2)n-R11/ -NH-CO-(CH2)n-R11 in which n denotes and 11 -C0-(CH2)n~R 11 11 -C0-NH-(CH2)n-R or -NH-S02-(CH2)n-« 11 0 to 4, R'1 denotes aryl having 6 to 12 carbon atoms which may be monosubstituted to tetrasubstituted by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl-thio, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, amino, alkylamino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group or acetylamino, the substituents being identical or different, or denotes a 5- to 7-membered saturated or unsaturated heterocyclic ring, which may contain as hetero atoms an oxygen atom, a sulphur atom or two nitrogen atoms, R^ and R7 are identical or different and case represent hydrogen, cycloalkyi having 3 to 8 carbon atoms or straight-chain or branched alkyl, alkenyl or alkinyl which in each case have up to 18 carbon atoms and which may be substituted by halogen, hydroxyl, alkoxy having up to 8 carbon atoms, alkylthio having up to 8 carbon atoms, alkylcar-bonyl having up to 8 carbon atoms in the alkyl radical, carboxyl or alkoxycarbonyl having up to - 80 - 22 4 1 25 8 carbon atoms, by phenyl which is optionally substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms or alkoxy having up to A carbon atoms, by cyano g in and/or by a group of the formula -NR R , in which 9 10 R and R are identical or different and in each case denote hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, aryl having 6 to 12 carbon atoms, acyl having up to 7 carbon atoms, alkyIsulphonyl having up to 6 carbon atoms, or aryIsuIphonyI having 6 to 12 carbon atoms, or R ^ and R 7 in each case represent aryl which has 6 to 12 carbon atoms and which may be monosubstituted, disubstituted or trisubstituted by nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, carbamoyl, dialkylcarbamoyl having up to 6 carbon atoms in each alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl-thio, amino, alkylamino having up to 8 carbon atoms, dialkylamino having up to 8 carbon atoms in each alkyl group, acetylamino or benzoylamino, the substituents being identical or different, or represent a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain as hetero atoms an oxygen atom, a sulphur atom or two n i trogen atoms, characterized in that CA] aldehydes of the general formula (II) ku ft if BOf - 81 - 22 4 1 2 5 in which and 0-ketocarboxylates of the general formula (III) 3 4 5 R , R and R have the abovementioned meaning, R2OOC\ (III) in which 1 2 R and R have the abovementioned meaning, are reacted with B-ketocarboxamides of the general formula (IV) (IV) in which 6 7 8 R , R and R have the abovementioned meaning, and ammonia, if appropriate in the presence of inert solvents, or in that CB] aldehydes of the general formula (II) are reacted with 8-ketocarboxylates of the general formula (III) and enaminocarboxamides of the general formula (V) /R6 HV^CON I 2N^R8 in which 6 7 8 R , R and R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in that CCJ aldehydes of the general formula (II) are reacted with B-ketocarboxamides of the general formula (IV) and ft * DP 00* - 82 - 22 4 1 25 enaminocarboxylates of the general formula (VI) R2OOCvvXH (VI) Rl^—-NH2 in which 1 2 R and R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in that CD] 6-ketocarboxylates of the general formula (III) are reacted with ammonia and ylidene-B-ketocarboxamides of the general formula (VII) (VII) in which 3 8 R - R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in that CE] B-ketocarboxamides of the general formula (IV) are reacted with ammonia and ylidene-B-ketocarboxylates of the general formula (VIII) (VIII) r200c> in which R^ - R^ have the abovementioned meaning, if appropriate in the presence of inert solvents, PT? ft DI? OPT* - 83 - 224125 or in that CF] ylidene-fl-ketocarboxamides of the general formula (VII) are reacted with enaminocarboxylates of the general formula (VI), if appropriate in the presence of inert solvents, or in that C63 ylidene-0-ketocarboxylates of the general formula (VIII) are reacted with enaminocarboxamides of the general formula (V), if appropriate in the presence of inert solvents, or in that CH] dihydropyridineraonocarboxylic acids of the general formula (IX) (IX) in which 15 8 R - R and R have the abovementioned meaning, if appropriate via a reactive acyl derivative, are^eacted with amines of the general formula (X) /Rb HN _ in which t A R and R have the abovementioned meaning, if appropriate in the presence of an inert organic solvent. Jf 9. Process for the preparation of compounds of the general formula (I) according to Claim 8'by process variants CA]-CG], characterized in that the solvent employed is water and inert- solvents and the reaction is carried out at temperatures between 10 and 150°C. . 10. A process according to claim 9 wherein the inert solvent is ' chosen from alcohols, ethers, amides, glacial acetic acid, dimethyl sulphoxide, acetonitrile and pyridine. '■ --• 224125 11. Compounds of the general, formula (I) according to Claim 1 for use in combating circulation disorders. 12. Medicaments containing at least one compound of the general formula (I) according to Claim 1. 13. Process for the production of medicaments/ characterized in that compounds of the general formula (I) according to Claim 1 are converted into a suitable form of administration, if appropriate using conventional auxiliaries and excipients. 14. Use of compounds of the general formula'(I) according to Claim 1 in the production of medicaments. 15. Dihydropyridinamides according to claim 1 substantially as herein described or exemplified. 16. A process according to claim 8 substantially as herein described or exemplified. BAYER AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LTD By La A 05 Off - 85 - t C'.'l! ''-L' ''<> ' ^->-vVO it. </div>