AU602970B2 - Dihydropyridinamides process for their preparation, and their use in medicaments - Google Patents

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

-a r- AUSTRALIA 0 2 9 7 0 PATENTS ACT 1952 V a COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Application Number: Lodged: Sr r

I

C. It 8 8r I C Complete Specification Lodged: Accepted: Published: Priority: Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventors: BAYER AKTIENGESELLSCHAFT D-5090 LEVERKUSEN, BAYERWERK,

GERMANY

1) Jirgen StoltefuB, 2) Dr. Eckhard Schwenner, 3) Dr. Martin Bechem, 4) Dr. Claudia Hirth, Dr. Michael Kayser, 6) Dr. Matthias Schramm, 7) Dr. Johannes-Peter Stasch ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Le.rel Barrack Street SYDNEY N.S.W. 2000

AUSTRALIA

V

I

Address for Service: Complete Specification for the invention entitled -f'rd'lnao A PROCESS FOR THEIR PREPARATIONAND THEIR USE IN

MEDICAMENTS!'

The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49 ii The present invention relates to dihydropyridinamides, a process for their preparation, and their use in medicaments, in particular as circulation-influencing medicaments.

It is known that diethyl 1,4-dihydro-2,6-dimethyl- 1 4-phenylpyridin -3,5-dicarboxyLate is obtained when ethyl benzylideneacetoacetate is reacted with ethyl B-aminocrotonate or ethyl acetoacetate and ammonia CE. Knoevenagel, "Ber. Dtsch. Chem. Ges. 31, 743 (1898)3.

It is furthermore known that certain 1,4-dihydropyridines have interesting pharmacological properties CF. Bossert, W. Vater, Naturwissenschaften 58, 578 (1971)].

The present invention relates to new dihydropyridinamides of the general formula (I)

R

4 f i R3 I R 6

R

2 00C CON \R7 1 N R

H

in which 1 8 in 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,

R

2 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 Le A 25 087 1A I is optionally substituted by halogen, cyano, aLkyL having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl, 3 4 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 trifluoromethylthio, R represents a group of the formula -0-(CH2)n-R -S-(CH2)n-R 1 1 -0-S0 2

-R

1 1

-CO-(CH

2 )n-R 1 1 -0-CO-(CH2)n-R 1 1 -CO-NH-(CH2)n-R 11 r -NH-CO-(CH 2 )n-R 1 1 or -NH-SO2-(CH 2 )n-R 11 j 15 in which n denotes 0 to 4, I and

SR

1 1 denotes aryl having 6 to 12 carbon atoms which may be monosubstituted to tetrasubstituted I' 20 by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, 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 25 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group or acetylamino, the sub- I stituents 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, and

R

6 and R are identical or different and in each case represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or Le A 25 087 2 i 4 straight-chain or branched alkyl, alkenyl or SakinyL 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, alkylcarbonyl having up to 8 carbon atoms in the alkyl radical, carboxyl or alkoxycarbonyl having up to 8 carbon atoms, by phenyl which is optionally i 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 formula -NR R 10 in which 9 10 j 'iii R and R 0 are identical or different and in i 15 each case denote hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, ayl having 6 to 12 carbon atoms, acyl having up to 7 carbon atoms, alkylsulphonyl having up to 6 j carbon atoms, or arylsulphonyl having 6 to 12 20 carbon atoms, or R and R 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 25 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 j 6 carbon atoms in each alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, 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 Le A 25 087 3

L_

urx~~ w~~ nitrogen atoms, and the physiologically acceptable salts thereof.

The compounds according to the invention exist in I stereoisomeric forms which behave either as image and 5 mirror image (enantiomers) or do not behave as image and mirror image (diastereomers). The invention relates 'both Sto the antipodes and to the racemic forms and to the dir astereomeric mixtures. The racemic forms and likewise the diastereomers can be resolved in a known fashion into the I 10 stereoisomerically unary components (cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Physiologically acceptable salts can be salts of I the compounds according to the invention with inorganic S or organic acids. Preferred salts are those with inorganic acids, such as, for example, hydrochloric acid, hydro- Sbromic 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 Sacid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.

Preferred compounds of the general formula are those in which R8 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

2 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, Le A 25 087 4 hydroxyl or by a phenyL or phenoxy group which is optionally substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or by a-, B- or y-pyridyl, R and R are identical or different and in each case represent hydrogen, fluorine, chlorine, bromine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, methylthio, cyano, nitro, trifluoromethyl or trifluoromethoxy, 5 11 R represents a group of the formula -0-(CH2)n-R, S-S-(CH2)n-R 11 -0-S0 2

-R

1 1 -0-CO-(CH 2 )n-R 1 1 SI, -NH-CO-(CH2)n-R 1 1 or -NH-SO 2

-(CH

2 )n-R 1 in which S 15 n denotes 0 to 3 and R denotes phenyl or naphthyl which may be monosubstituted, disubstituted or trisubstituted by 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 carbon atoms, dialkylamino having up to 4 carbon atoms in each alkyl group, or acetylamino, the substituents being identical or different, or denote pyridyl, thienyl, furyl, pyrimidyl or l pyrazinyl, and

R

6 and R 7 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 alkenyl which has up to 14 carbon atoms and which may be substituted by fluorine, chlorine, bromine, hydroxyl, alkoxy having up to 6 carbon atoms, Le A 25 087 5 III 8aannZ~----U-~-D~.~*2I'QlllbO~omamarra alkylthio having up to 6 carbon atoms, alkylcarbonyl 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, by cyano and/or by a group of the formula -NR R 10 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 phenylsulphonyl, or represent phenyl or naphthyl which may be monosubstituted, 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, alkyli 20 amino having up to 6 carbon atoms, dialkylamino i having up to 6 carbon atoms in each alkyl group, acetylamino or by benzoylamino, the substituents Sbeing identical or different, or i i represent pyridyl, pyrimidyl, thienyl or furyl, i. 21 and the physiologically acceptable salts thereof.

Particularly preferred compounds of the general formula are those in which 1 8 R and R are identical or different and in each case represent methyl, ethyl or benzyl,

R

2 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, B- or y-pyridyl, R and R are identical or different and in each Le A 25 087 6 case represent hydrogen, fluorine, chlorine, methyL, ethyl, methoxy, ethoxy, nitro or trifluoromethyL, 5 11 R represents a group of the formula -0-CH 2

-R

1 R 11 i5 -S-CH 2

-R

1 1 or -0-S02-R in which R denotes phenyl which may be monosubstituted or disubstituted by fluorine, chlorine, nitro, trifluoromethyl, methyl, methoxy, amino, methyLamino, dimethylamino, ethylamino, diethylamino or Sacetylamino, the substituents being identical or I different, or ~denotes an B- or a y-pyridyl group, S. R 6 represents hydrogen or alkyl having up to 4 carbon atoms, and

R

7 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, i! alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, alkylcarbonyl having oxyl, alkoxycarbonyl having up to 4 carbon atoms, I 25 phenyl and/or a group of the formula -NR9R 0 in which 9 10 R and R are identical or different and denote i hydrogen, alkyl having up to 4 carbon atoms, benzyl, phenyl or acetyl, or R 7 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 Le A 25 087 7 being identical or different, or represents B- or y-pyridyl, and the physiologically acceptable salts thereof.

The compounds of the general formula according to the invention in which 1 8

R

1 R have the abovementioned meaning, are obtained in a process in which aldehydes of the general formula (II) St a R4 and 8-ketocarboxyLates of the general formuLa (III) c (III)

<CHO

1" in which R and R have the abovementioned meaning, and B-ketocarboxylates of the general formula (III)

CON

I R200C

(III)

in which R and R have the abovementioned meaning, j d are reacted with a-ketocarboxamides of the general formula (IV)

/R

6

CON

So (IV) -O 8 in which R R and R have the abovementioned meaning, and ammonia, if appropriate in the presence of inert solvents, or in a process in which Le A 25 087 8 r EB8 aldehydes of the generaL formula (II) are reacted with B-ketocarboxylates of the general formula (III) and enaminocarboxamides of the general formula (V) 6 H CON S7

V)

H2N R8 in which

R

6 R7 and R 8 have the abovementioned meaning, e if appropriate in the presence of inert solvents, or in a process in which CC] aldehydes of the general formula (II) are reacted 10 with B-ketocarboxamides of the general formula (IV) and enaminocarboxylates of the general formula (VI)

R

2 00C H (VI) R1 NH 2 in which R1 and R 2 have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which CD] 8-ketocarboxylates of the general formula (III) are o reacted with ammonia and yLidene-B-ketocarbonamides of the general formula (VII) 4

(VII)

R3 ,,6 8 CON \R 7 in which R3 8 have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which Le A 25 087 9represent cyano or phenyl, 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 /2 B-ketocarboxamides of the general formula (IV) are reacted with ammonia and ylidene-B-ketocarboxylates of the general formula (VIII) SR4 Dfi 3

~(VIII)

R

2 00C H ,i i in which 1 5 R R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which EF3 ylidene-B-ketocarboxamides of the general formula (VII) are reacted with enaminocarboxylates of the general formula if appropriate in the presence of inert solvents, or in a process in which CG] ylidene-B-ketocarboxylates of the general formula (VIII) are reacted with enaminocarboxamides of the general formula if appropriate in the presence of inert solvents, or in a process in which H]3 dihydropyridinemonocarboxylic acids of the general formula (IX)

R

4

(IX)

R3 00C CRCCOOH R1-N

R

H

in which R R and R have the abovementioned meaning, if appropriate via a reactive acyl derivative, are reacted with amines of the general formula (X) Le A 25 087 10 and an oxygen atom, a sulphur atom or two nitrogen atoms,

R

6 and R 7 are identical or different and in each case represent hydrogen, /3

HN

,,R7 in which

R

6 and R 7 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 equations: Le A 25 087 11

(A]

O-CH

2

-C

6

H

L CHO

H

3 COOC)~ 2 O-N(CH3)2 ':vNH3 H4 3 COOC ICON(CH 3 2 F

H

3 CXN

H

3

H

S. 2

-C

6

H

CHO

H

O-NH-CH

3

H

3 C-N H 2

H

4 44 4 8 4

S-CH

2

-C

6

H

5

C

2 00C CO-NH-CH 3

H

3 C IN H1 3

H

Le A 25 087 12

EC)

I::O -S0 2

-C

6

H

CHO

H~3COOCXHr

H

3 C NM 2

~O-NH-C

6

H

O+ I if '--sO 2

-C

6

H

H

3 COOC C-HCH

H

3 CN

NH

3

H

-CH

2

-C

6

H

H

3 COOC)J H CO-NH-C 2

H

H3C 0 0--kC H 3

NH

3

-CH

2

-C

6

H

H

3 COOC CO-NH-C 2

H

H

3 C) N H 3

H

Le A 25 087 13 [El I -CH 2

-C

6

H

H

7

C

3 00C -H

CO-NH-C

3

H

7

NNH

-CH

2

-C

6

H

H

7

C

3 00C ICO-NH-C 3

H

7

H

3 C N H 3

H

[F]

O-CH

2

-C

6

H

H

3 COOC)(H H .~CO-NH-C-?

H

3 C NH 2

H

3

O-CH

2

-C

6

H

H

3 COO CO-NH- CH 3

H

3 C N Hl1 3

H

Le A 25 087 14 I -CH 2

-C

6

H

H

3 CDOC I~CO-N(CH 3 2

H

3 C 0H 2 N CH 3

-O-CH

2

-C

6

H

H:

3 COOC CO-NCCH 3 2

H

3 C YDC 3

H

ftr -c 6

H

~1

IA

0 I -CH 2

-C

6

H

H

3 COOC

CO-

I 0-I Cj

H

3 C N CH 3

H

1+ H 2 N3-C 1

-CH

2

-C

6

H

H

3 C~ CH O

H

3 CC 0-nH-3

H

Le A 25 087 15 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, ethanol, propanol or isopropanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides, such as dimethylformamide, 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 0 C and +150 0 C, preferably between +20 0

C

and +100 0 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 recr'stallizing the residue obtained in crystalline form, if desired, only after ice cooling, from a 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 [German Offenlegungsschriften 2,165,260; 2,401,665; T.D. Harris, G.P. Roth, J. Org. Chem. 44, 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 formula Le A 25 087 16- (III) employed as starting materials are known or can be prepared by known methods Borrmann in Houben Weyl's "Methoden der organischen Chemie" [Methods of Organic Chemistry] Vol. VII/4, 230 (1968); Y. Oikawa, K. Sugano, 0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)3.

The B-ketocarboxamides of the general formula (IV) employed as starting materials are known or can be prepared by known methods [German Offenlegungsschrift 1,142,8593.

The enaminocarboxamides of the general formula (V) employed as starting materials are known or can be prepared by known methods [German Offenlegungsschrift 2,228,3773.

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 ylidene-B-ketocarboxylates of the general formula (VIII) employed as starting materials are known or can be prepared by known methods EG. 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 amidated 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 cyclohexylcarbodiimide or 1-cyclohexyl-3-[2-(N-methyl-morpholino)ethyl3carbodiimide p-toluenesulphonate, or N-hydroxyphthalimide Le A 25 087 17 or N-hydroxy-benzotriazole in the presence of dicycLohexylcarbodiimide. Naturally, the dihydropyridinemonocarboxy- Lic acids can also be employed in the form of their salts.

[The amidation method is described, for example: Fieser 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. 26, 254 (1961); H.A. Staab, Angew. Chemie Int. Ed. 1, 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. 1372 (1961); C.A. Buehler, D.E. Pearson, John Wiley Sons, SVolume I (1970), page 895 ff, Volume II, (1977)3.

V Besides water, suitable solvents for process variant 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 halogenated hydrocarbons, such as dichloromethane, trichloromethane or tetrachloromethane, or amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or hydrocarbons such as benzene, toluene or xylene, or acetonitrile, nitromethane, pyridine, dimethyl sulphoxide or ethyl acetate. Mixtures of the solvents mentioned may Slikewise be used. If the activated intermediates of the I dihydropyridinemonocarboxylic acids are isolated, the amines of the formula can also be used alone as diluents.

The reaction temperatures may be varied within a relatively wide range. In general, the process is carried out in a range from -70 0 C to +140 0 C, preferably from -20 0

C

to +100 0

C.

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 process variant H according to Le A 25 087 -18 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 dihydropyridinemonocarboxylic acids of the general formula (IX) employed as starting materials are known or can be prepared by known methods [German Offenlegungsschriften 2,847,236; 3,206,671 and 2,962,241].

The amines of the general formula employed as Sn starting materials are known or can be prepared by known methods [Houben Weyl's "Methoden der organischen Chemie" S[Methods of Organic Chemistry] Vol. XI/1; Paulsen, Angewandte 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 mel!itus.

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 from the right ventricle and fixed horizontally in an Le A 25 087 19 organ bath. During this procedure, one end of the muscle was held by two metallic electrodes, which simultaneously 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; NaC0 3 25; KCI

KKH

2

PO

4 1.2; MgSO 4 1.2; CaCl 2 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 isometrically 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 The dihydropyridinecarboxamides 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 dispersants, and, for example when using water as a diluent, organic solvents can optionally be used as auxiliary solvents.

Le A 25 087 20 LL- b~ 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 arylsulphonates), detergents (for example lignin, sulphite waste liquors, methylcellulose, starch and polyvinyl pyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

Administration 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 dicalcium 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 Le A 25 087 21 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 i 5 the administration method, the individual behaviour to- I wards 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.

i 15 Preparation examples SRf values: Merck TLC aluminium foil, coating thickness S0.2 mm, silica gel 60 F 254; mobile phase toluene/ethyl ii acetate in the volume ratio 1:2.

Example 1 i 20 Methyl 5-(dimethylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4dihydro-2,6-dimethyl-pyridine-3-carboxylate I H -CH 2 2

H

3 COO

CO-N(CH

3 2 H3C N H3

H

Process variant A 2.12 g (10 mmol) of 2-benzyloxy-benzaldehyde are boi'ad for 18 hours with 1.16 g (10 mmol) of methyl acetoacetate, 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 Le A 25 087 22 in which

R

3

R

8 have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in which Le A 25 087 9 i4! 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 1630C is obtained.

Process variant E 2 g (6.45 mmol) of methyl 2-benzyloxy-benzylideneacetoacetate 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 S, water, dried and evaporated. The product mixture is pur-

S

t ified over a silica gel column using a toluene/ethyl I I t acetate mixture. The pure fractions are collected and S 15 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 SMethyl 5-(phenylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4dihydro-2,6-dimethyl-pyridine-3-carboxylate t t r-CH

H

3 COOC CO-NH- 7

H

3 C N H 3 SH

H

Process variant G 3.1 g (10 mmol) of methyl 2-benzyloxy-benzylideneacetoacetate are boiled for 3 hours in 20 ml of ethanol with 1.76 g (10 mmol) of N-benzyl-B-aminocrotonamide. The mixture is cooled and evaporated. The solid evaporation Le A 25 087 23 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 1940C are obtained.

Example 3 Methyl 5-(cyclopropycarbamoyl)-4-(2-benzyoxy-phenyL)- 1,4-dihydro-2,6-dimethyl-pyridine-3-carboxyLate H3COOC1 CO-NH-j H3C N H 3

H

Process variant H 20 g (45.14 mmoL) of methyl 4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyL-pyridine-3carboxylate are dissolved in 130 mL of absoLute dimethylformamide, 5.63 mL (80.1 mmol) of cycopropyamine are added, and the mixture is stirred for 20 hours at 90-100 0

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 recrystaltization from about 60 mL of toluene, 14.95 g (76.7% of theory) of colourless crystals are obtained. Melting point: 191 193 0

C.

Example 4 Methyl 5-(methylcarbainoyl)-1,4-dihydro-2,6-dimethyL-4-E2- (3-trifluoromethyl-benzyoxy)pheny3pyridine-3-carboxyLate Le A 25 087 24 I A Le A 25 087

CF

CH 2 <C

F

H

3 COOC CO-NH-CH 3

H

3 C N H C 3

H

3.59g(6.8 mmoL) of methyL 1,4-dihydro-2,6-dimethyL-4-2-(3-trifLuoroiethyL-benzyLoxy)phenyLjpyridine-3-carboxyLate (obtained from monomethyL 1,4-dihydro-2,6-dimethyL-4-E2-(3-tr ifLuoromethyLbenzyloxy)were reacted with carbonylbisimidazole in tetrahydrofuran) are stirred overnight without further purification with 40 mL of methylamine solution (40% 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 (40.3% of theory) of a colourless product are obtained.

Melting point: 156 157 0

C.

The following were prepared analogously to Examples 1 to 4: Example Methyl 5-(cycLopropyLcarbamoyL )-1,4-dihydro-2,6-dimethyL- 4-E2-(3-methyL-benzyLoxy)phenyL )-pyr idine-3-carboxyL ate -CCH3

H

3 COOC

CO-NH--

H

3 N C 3

H

Melting point: 176 0

C

Le A 25 087 Example 6 Methyl 5-(cycLopropyLcarbamoyL )-4-[2-(4-chLoro-benzyLoxy)phenyLJ-l,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate I -CH -7 -C 1

H

3 COOC IICC)-NH-I

H

3 C N H 3

H

Melting point: 178 0

C

Example 7 Methyl 5-C (2-pyridyl)carbamoyL)-4-[2-(4-chLoro-benzyLoxy)phenyL]-1,4-dihydro-2,6--dimethyL-pyridine-3-carboxyLate

SO-CH

2 C I

H

3 COOC C0-N-

ND

H

3 C N CH' 3

H

Melting point: 201 204 0

C

ExampLe 8 Methyl 5-(CZ-pyridyL)carbamoyL)-4-(2-benzyLoxy-phenyL 1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate

H

3 CDOC CO-NH

Q,

H

3 C N 3 J

H

Melting point: 164 165 0

C

Le A 25 087 26- Le A 25 087 13 ExampLe 9 Mc lhyL 5-C (2-diethylamino-ethyL )carbamoyl )-4-E2-(4-chLoro- V benzyLoxy)phenyt)-1,4-dihydro-2,6-dimethyL-pyridine-3- V carboxylate 0 0- CH

.'C

2

H

H COOC CO-NH--(CH) 2

-N

I I

H

3 C N CH 3

H

Melting point: from 80 0

C

ExampLe Methyl 5-C (2-diethyLamino-ethyL )carbamoyL )-4-(2-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyt-pyridine-3-carboxyLate I-2-

H

3 COOC CO-NH-(CH4 2 2

-N

HC N H 3 V H Melting point: from 95 0

C

Example 11 Methyl 5-C (4-carbamoyL-phenyL )carbamoyL )-4-(2-benzyLoxyphenyL )-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate 0- CH 2 -0§

H

3 COOC c 0 -NH-G7---c

NH

2

H

Melting point: 300 0

C

Le A 25 087 -2 Le A 25 087 14 ExampLe 12 Methyl (4-acetyLaminophenyl )carbamoyl )-4-(2--benzyloxyphenyL)-1,4-dihydrco-2,6-dimethyL-pyridine-3-'carboxyLate I ~CH 2

-Q

H

3 COOC CO-NH-<C3-N CD- CH 3

H

3 C N H 3

H

MeLting point: 298 0 C decomposition ExampLe 13 Methyl 5-C C4-benzoyLaminophenyL)carbamoyL )-4-(2-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate I-O-cH 2 -KT6

H

3 COOC CO-NH NH-C D-KO H3C N CH 3

H

Melting point: 197 0

C

Example 14 Methyl 5-C(1l-phenyLethyL )carbamoyL )-(R,S)-4-C2-benzyLoxyp henyLI)-1, 4-dihy dro-2, 6-dime thy 1-pyr id ine-3-ca rboxy La te S mixture) CH 2

-KI

(R,S)

H

3 CCOC CO-NIR-CH, ,O ItII

H

3 C N H 3

CH;

3

H

Melting point: from 162 0

C

Le A 25 087 -28- Example Methyl C -phenyLethyL )carbamoyL )-(R)-4--C2-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-pyr-idine-3-carboxyLate (R f orm)

H

3 COOC CO- NH-C- I I

I

H

3 C N CH 3

CH

3

H

Melting point: 82 0

C

Example 16 Methyl 5-C (3-dimethyLaminopropyL )carbamoyL )-4-C2-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate

CH

2 D CH 3

H

3 CDDC CD-NH-(CH 2 3

-N

I I 3

H

3 C 2NH 3

H

MeLting point: 89 900C Example 17 Methyl 5-(cycLohexyLcarbamoyL )-4-(2-benzyLoxy-phenyL dihydro-2,,6-dimethyL-pyridine-3-carboxyLate I O-CH 2

KD

H

3 CDOC CO -NH KO

H

3 C N CH 3

H

Melting point: 108 111 0

C

Le A 25 087 29- Example 18 MethyL 5-(tert.butyLcarbamoyL )-4-(2-benzyLoxy-phenyL)-1,4d ihydro-2,6-dimethyL-pyridine-3-carboxyLate

CH

3 H C0OC CO-H -C--H 3

H

3 C N r1 3

CH

3

H

Melting point: 148 0

C

ExampLe 19 Methyl 5-CpropyLcarbamoyL )-4-(2-benzyLoxy-phenyL dihydr-o-2,6-dimethyL-pyr idine-3-carboxyLate

H

3 COOC CO-NH-CH -CH 2

-CH

3

H

Foam Rf 0.37 Example Methyl 5-C (2-methyL-propyL)carbamoyL)-4-(2-benzyLoxy-phenyL 1,4-dihydro-2,6-dimethyL-pyr idine-3-carboxyLate I -CHz-

D

H

3 COOC CO-NH-CH 2

CH(CH

3 2

H

3 C N H 3

H

Melting point: 134 0

C

Le A 25 087 or carbonyiimidazoLe, activating reagents which may be mentioned as examples are carbodiimides,. such as cycLohexylcarbodi imide or 1-cycLohexyL-3-E2-CN-methyL-morphoL ino)~ethyl carbodi imide p-toLuenesuLphonate, or N-hydroxyphthaL imide Le A 25 087 17 Example 21 Methyl 5-(N-benzyL-N-tert.butyLcarbamoyL )-4-(2-benzyLoxyphenyL)-1,4-dihydro-2,6dimethyL-pyridine-3carboxyLate Ci H 2KD

H

3 COOC CO-N---H2-7

H

3 u N CH 3

C(CH

3 3

H

Melting point: 128 0

C

Example 22 Methyl 5-(methyLcarbamoyL )-4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate 0 C

H

3 COOC ICO-NH-CH3

H

3 C N 3

H

Melting point: 105 0

C

Example 23 Methyl 5-(ethyLcarbamoyL )-4-(2-benzyLoxy-phenyt dihydro-2,6-dimethyL-pyridine-3-carboxyLate

H

3 COOC CO-N1- -CH 2

-CH

3

H

3 C N CMr 3

H

Melting point: 172 0

C

Le .A 25 087 31 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 process variant H according to Le A 25 087 -18- Example 24 ButyL 5-(cycLopropyLcarbamoyL )-1,4-dihydro-2,6-dimethyL- 4-E2-(2-pyridyL )methoxy-phenyLJ-pyridine-3-carboxyLate

HH

Rf C 0.1C-N 101

H

Foam R f 0 .07 ExampLe 26 ButyL~ methyLraopyL)carbamohyL)-1.4-dimhyO26dimth 1 4-(2-pyridyL )methoxy-phenyLJ-pyridine-3-carb ylate

H

9

C

4 00C CO-NH-CH-C 2

H

H

3 C N CH 3

CE

H

LexAme 2563 Butyt~ 32 -eh~poy~abaoL-.-dhdo26-iehL Foam Rf 0.25 Example 27 Methyl 5-(cycLopropyLcarbamoyL 4

-E

2 3 ,4-dichLoro-benzyloxy)phenyl 4 -dihydro-2,6--dimethyL-pyridine-3-carboxyLate Cl

-CH

2 1I

H

3 COOCy 7 CO-N Melting point: 195 0

C

Example 28 Methyl 5-(cycLopropyLcarbamoyL )-4-E2-(2,6-dichLoro-benzyLoxy)phenyL )-1,4-dihydro-2,6-dimethyL-pyrid ine-3-carboxyL ate CH2

D

H

3 Cl Melting point: 178 0

C

Example 29 Methyl -methyL-propyl )carbamoyL )-4-E2-(2,6-dichLorobenzyLoxy)phenyl J-1,4-dihydro-2,6-dimethyL-pyridine-3c arboxy late Le A 25 087 33. H3COOCCO-NH--CH-CH 2

-CH

3 3- N CH 3

LCH

3

H

Rf =0.36 Example MethyL 5-CinethyLcarbamoyL )-4-C2-(2,6-dichLoro-benzyLoxy)phenyl)-1,4-dihydro-2,6-dimethyt-pyridine-3-carboxy~ate

H

3 CO OC CO-NH-CH 3 Melting point: 133 0

C

Example 31 MethyL 5-(methyLcarbamoyL )-4-[2-C3,4-dichLoro-benzyLoxy)phenyLJ-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate

O-CH

2

H

3 CCOC CO-NH-CH3

H

3 C N -H 3

H

Melting point: 120 0

C

Le A 25 087 34 lnlOLll I ls 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 Le A 25 087 21 Example 32 Methyl 5-(cycLopropyLcarbamoyL )-4-E2-(3-fLuoro-benizyLoxy)- 3-methoxy-phenyl)-1,4-dihydro-2,6-dimethyL-pyridine-3carboxyLate 4 1 t t I I. I t t f Melting point: 202 0

C

Example 33 Methyl* 5-CcycLopropyLcarbamoyL )-4-E2-(2-chLoro-benzyLoxy)phenyl]-l',4-dihydro-2,6-dimethyL-pyr idine-3-carboxyLate C i H3COOC CC N

H

3 C N CH 3

H

I 4I~ 4 S 44(4 (I ii 4 4 4 U 4 MeLting point: 185 0

C

Example 34 Methyl 5-(methyLcarbanoyL )-4-E2-(2-chLoro-benzyLoxy)phenyLJ- 1,4-dihydro-2,6-dimethyL-'pyridine-3-carboxyLate Le A 25 087 35

H

3 COOC CO-NH-CH 3

H

3 C N Hl 3

H

Melting point: 170 0

C

Example Methyl 5-C (2-methyL-propyL)carbamoyL )-4-[2-(3-fLuorobenzyLoxy)-3-methoxy-phenyL )-1,4-dihydro-2,6-dimethyLpyridine-3-carboxyLate

CH

2 -7

H

3 COOC CO-NH-CH 2

-CH(CH-

3 2

H

3 C N r 3

H

Melting point: 98 0

C

Example 36 MethyL 5-CcycLopropyLcarbamoyL )-1,4-dihydro-2,6-dimethyL- 4-E 2-C 3-t rif Iuo romet hyL-benzy Loxy )ph enyt )-pyr idine-3carboxyL ate CF3

H

3 COOC CO-NH

H

3 C N -CH 3

H

Melting point: 148 0

C

Le A 25 087 36- 3.1 g (10 mmol) of methyl 2 -benzYLOxY-benzYLideneacetoacetate are boiled for 3 hours in 20 ml of ethanol with 1.76 g (10 mmoL) of N-benzyL-8-aminocrotonamide. rhe mixture is cooled and evaporated. The solid evaporation, Le A 25 087 23- Ii

IF

4 Example 37 Methyl -methyL-propyL )carbamoyL)-1,4-dihydro-2,6dinethyL-4-E2-(3-trifLuoromethyL--benzyLoxy)phenyL]-pyridine- 3-carboxyLate

CF

3 -CH 2

H:

3 COOC CO-NH-CH-CH 3

H

3 C N CH- 3

CH

2

-CH

3

H

Foam Rf 0.44 Example 38 Methyl isopropyLcarbanoyL )-4-E2-(3-fLuoro-benzyLoxy)- 3-methoxy-phenyl )-1,4-di hydro-2,6-dimethyL-pyr idine-3carboxyLate

-~OCH

3

F

H

3 COOC CO-NH-CH(CH 3 2 HC N CH 3

H

Melting point: 106 0

C

Example 39 1-methyL-propyL 5-(cycLopropyLcarbamoyL )-1,4-dihydro-2,6dimethyL-4-E2-(4-methyL-benzyLoxy)phenyL]-pyridine- 3 carboxy late Le A 25 087 37

-O-CH

2

-C>Q-CH

3 X~C-HC-OOc CO-NH< H.~-Zk 2 C- rH 3 C N n 3 4 Foam Rf 0.31 ExampLe MethyL 5-(cycLopropyLcarbamoyL)-4-(4-benzyLoxy-phenyL di hydro-2,6-dimethyL-pyr idine-3-carboxyLate H NCAN H 3 Melting point: 197 0

C

ExampLe 41 1-methyt-propyL 5-CC 1-methyL-propyL )carbamoyL)-1,4-dihydro- 2,6-dimethyL-4-[2-(4-methyL-benzyLoxy)phenyL J-pyridine-3carboxyL ate I -CH 2

-Q>-CH

3

H

3 C-CH-OOC CO-NH-CH-CH 3 I I I I

H

3

C-M

2 C H1 3 C N CH 3

CH

2

-CH

3

H

MeLting point: 1260 C Le A 25 087 38- Example 42 1-methyL-propyL 5-CmethylcarbamoyL )-1,4-dihydro-2,6-dimethyL- 4-E2-(4-methyL-benzyLoxy)phenyL]-pyridine-3-carboxyL ate I -CH 2 -C H 3

H

3 C-CH-OOC CO-NH-CH 3 H 3 C -H 2 C;r 3 C NJ H2 3

H

F o a m Rf 0.48 ExampLe 43 Ethyl 5-(cyclopropyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4- (3-n it ro -be n zy1o x y )p heri y IJ- p yr id in e-3- ca r b x y a te

H

5

C

2 00C CO-NH-K Hq 3 C N LCHl 3

H

Foam Rf 0.24 Example 44 Methyl 5-~(propyLcarbamoyL )-4-(4-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate Le A 25 087 -39 0- CH t H 3 CCOOC OH-HC2C3

H

3 C N H 3

H

MeLting point: 210 0

C

ExampLe Ethkl 5-C C -phenyL-ethyL )carbamoyL )-(R)-4-E2-(4-fLuorobenzyLoxy)phenyL )-1,4-dihydro-2,6-dimethyL-pyridine-3carboxyLate (R form) -C H C 2 00C CO-NH-CH-K~

H

3 C N CH 3

C

3

H

Foam Rf 0.56 lj Example 46 ~'10 Methyl 5-CC2-methyL-propyL)carbamoyL)-4-(4-benzyLoxy-phenyL)- 4 t t t 1,4-di hydro-2,6-dimethyL-pyr idine-3-carboxyL ate 0- CH 2

-Q

H

3 COO CO-NH-CH 2

-CH(CH

3 2

H

3 C N H 3

H

MeLting point: 2020 C Le A 25 087 4 FExampLe 47 Ethyl 5-(cycLopropyLcarbanoyL )-4-E2-C4-fLuoro-benzyLoxy)phenyl )-1,4-dihydro--2,6-dimethyL-pyr idine-3-carboxyL ate 0-CH 2

F

i-Sc 2 ooc C 0- NH-$ HC N C H 3

H

Melting point: 1590 C Example 48 Methyl 5-(cyc LopropyLcarbamoyL )-4-E2-(4-fLuoro-benzyLoxy)phenyL]-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate

H

3 COOC CO-NH-< Melting point: 154 0

C

it Example 49 I Methyl 5-((1-phenyLethyt )carbamoyL )-(S)-4-(4-benzyLoxyphenyL )-1,4-dihydro-2,6-diniethyL-pyridine-3-carboxyLate (S f o r m)

-CH

2 -0

(S)

H

3 COOC CO-NH-CH-CH 3

H

3 CA N L.Hl 3 Le A 25 087 -41 Melting po .int: 141 0

C

Example Methyl isopropyLcarbamoyL)-4-(4-benzyLoxy-phenyL)-1,4dihydro-2,6-dimethyL-pyridine-3-carboxyLate 0- CH 2 -07 H3C00C CO-NH-CH(CH3) 2

H

3 C N H 3

H

Melting point: 162 0

C

Example 51 Methyl 5-((1-phenyLethyL)carbamoyL )-(R)-4-(4-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyL'Ite CR form, diastereomer A)

O-CH

2

H

3 COOC o-IH-C 0 I I I

H

3 C N H' 3

CH

3

H

MeLting point: 196 0

C

ExampLe 52 Methyl 5-(cycLopropyLcarbamoyL )-4-[2-(3-chLoro-benzyLoxy)phenyl ]-1,4-dihydro-2,6-dimethyL-pyr idine-3-carboxyLate Le A 25 087 42

H

3 COOC CO-NH-'

H

3 C N Hr 3

H

V MeLting point: 174 0

C

Example 53 MethyL 5-(c-ycLopropylcarbamoyL )-4-[2-(4-fLuoro-benzyLthio)phenyL J-1,4-dihydro-2,6-dimethyL-pyr idine-3-carboxyLate I 9M H

H

3 C N CONH

H

V Melting point: 202 0

C

r ExampLe 54 I Methyl 5-C C1-phenylethyl)carbamoyL)-(R)-4-(4-benzyLoxyphenyL )-1,4-dihydro-2,6-dimethyL-pyr idine-3-carboxyLate CR form) (diastereomer 8)

(R)

H

3 COOC CO-NH-CH-

H

3 C N H 3

CH

3

H

Melting point: 202 0

C

Le A 25 087 43 ExampLe MethyL 5-C( 1-phenyLethyl )carbamoyl )-4-(4-benzyLoxyphenyl )-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate (R form, diastereomeric mixture) 0- CH 2

H

3 COOC CO- NH cH0

H

3 C N H CH-i

H

t t t t Melting point: 110 -1660 C 4 6t II tExample 56 Methyl C -phenyLethyL )carbamoyL )-(S)-4-(2--benzyLoxyphenyL )-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate (S form, diastereomer A)

H

3 COOC CO-NH-CH-4CH 3 H3C N 6S) Melting point: 172 0

C

Example 57 Methyl 5-C(1l-phenyLethyL)carbamoyL)-(S)-4-(2-benzyLoxyphenyL )-1,4-dihydro-2,6-dimethyL--pyridine-3-carboxyLate (S form, diastereomer B) Le A 25 087 44- 1' -CH2(

VH:

3 COOC H ON-C-H 6S) Foam Rf 0.53 ExampLe 58 MethyL 5-CC 1-phenyL-ethyL)carbamoyL )-(R)-4-E2-(4-fLuoroben:'yLoxy)phenyL]-1,4-dihydro2,6dimethyLpyridine3carboxylate (R form) H3COOC N CO-NH-CH-K0 1' 3 C N H C3

H

Foam Rf 0.52 Example 59 ButyL 5-CcycLopropyLcarbamoyL )-1,4-dihydro-2,6-dimethyL- 4-E2-CmethyL-benzyboxy)phenyL ]-pyridine-3-carboxyLate

H

9

C

4 00C CO-NH

H

3 C N H 3

I

Foam Rf 0.31 Le A 25 087 -mrn Example ButyL 5-(C1-phenyL-ethyL)carbamoyL )-(R)-1,4-dihydro- 2,6-dimethyL-4-C2-(3-methyL-benzyLoxy)-phenyLJ-pyridine- 3-carboxyLate CR form)

CH

3 HqC 4 00C CD-NH-CH-(j 1 3 C IN H 3

CH

3

H

Oi L Rf 0.88 Example 61 Methyl C -phenyL-ethyl )carbamoyL )-(R)-4-E2-C3-chLorobenzyLoxy)phenyL )-1,4-dihydro-2,6-dimethyL-pyr idine-3carboxyLate CR form) cl

O-CH

2 <L

H

3 COOC C0-NH-CH--K75 I I.I

I

H

3 C N H 3

CH

3

H

Foam Rf 0.73 Example 62 Methyl 5-C C -phenyL-ethyL )carbamoyL R )-4-(3-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate (R form) Le A 25 087 46- 2

-O-CH

2

Q

(R)

COOC CO-NH-CH-<:>~

H

3 C N 113 CM 3

H

Melting point: from 143 0

C

ExampLe 63 Methyl 5-CcycLopropyLcarbamoyL )-4-(3-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyr idine-3-carboxyLate i-c Io

CO-H<

H3COOCI I 1 N-

H

3 C cN

H

3

H

Melting point: 144 0

C

Example 64 MethyL 5-CC 1-phenyL-ethyL )carbamoyL)-CR)-4-E2-(4-fLuorobenzyL thio)phenyL )-1,4-di hydro-2,6-dirnethyL-pyr idine-3carboxyLate CR form)

(R)

H

3 CODC CO-NH-CMO I I I

M

3 C N CM 3

C

3

H

Foam Rf 0.47 Le A 25 087 47- Example Methyl 5-((1-phenyL--ethyL)carbamoyL )-(S)-4-E2-C4-fluorobenzyl th io)phenyL J-1,4--dihydro-2,6-dimethyL-pyridine-3carboxyLate (S form) I S-CH2~7~

(S)

H

3 COOC CO-NH-CH-CH 3

H

3 C N H 3 x t Foam Rf= 0.48 Ii Example 66 Methyl 5-CaLLyLcarbamoyL )-4-C2-(4-fLuoro-btenzyLthio)phenylj- 1,4-dihydro-2,.6-dimethyl-pyr idine-3--carboxyL ate 2 -C 73F

H

3 COOC CO-NH-CH -CHzCH 2 H 3 C N2H

H

Melting point: 177' 0

C

Example 67 Methyl 5-CaLLyLcarbanioyL)-4-C2-benzyLoxy-phenYL )-1,4-dihydro- 2,6-d imethyL-pyrnidine-3-carboxyLate

O-CH

2

-O

H

3 COOC)--, CO-NH-CH 2 -CiH=CH 2 Melting point: 148 0

C

Le A 25 087 -48 ExampLe 68 Methyl 5-CC 1-phenyL-ethyL )carbamoyL )-CR)-4-(2--benzyLoxyphenyL )-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate (R f orm)

(R

H

3 CN

CH

3

CH

3 MeLting point: 1750 C ExampLe 69 Methyl 5-CC 1-phenyl-ethyL )carbamoyL )-CR)-4-C2-benzyLoxyphenyl )-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate CR form, diastereomer 8)

(R)

H COOC CO-NH-CH--(,

H

3 C N H 3

CH

3

H

Melting point: 169 0

C

Example Methyl 5-(C2-phenyL-ethyL)carbamoyL)-4-(2-benzytoxy-phenyL)- 1 ,4-dihydro-2,6-dimethyL-pyr idine-3-carboxyLate

H

3 COOC CO-NH-CH 2

-CH

2

O

H

3 C N H 3 Le A 25 087 -49- Example 71 Methyl 5-(benzyLcarbamoyL )-4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate I -H 2

OZ

H

3 COOC co -NH -CH 2

D

H

3 C N H 3

H

Melting point: 148 -149 0

C

Example 72 Methyl 5-(ethyLcarbamoyL )-4-C2-(4-fLuoro-benzyLthio)pheflyL] 1,4-dihydro-2,6-dimethyL-pyridine3-carboxyLate I S-CH 2 -cDF

H

3 CDOC I CO-NH-CHZ-CH 3

H

3 C NIH 3

H

Melting point: 202 2040C Example 73 Methyl 5-(ethyLcarbamoyL )-4-(3-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate

H

3 CODC 60-NH-CI-i 2

-CH

3

H

3 C N CH 3

H

Melting point: 152 1540 C Le 25 087 50 Example 74 Methyl 5-(ethyLcarbanoyL )-4-(4-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyr idine-3-car-boxyLate

S-C

H3COOC

CO-NH-C

2

CH

N H 3

H

Melting point: 1838 Example 76 Methyl 5-cd iethyLcral-4-(2-benzyloxy-phenyl )-dhyr-1,dhd-2-dimethy l--pyr-idine-3-carboxylate

H

3 COOC CO-N( 2

H)

H

3 C N CH 3

H

Melting point: 1350 C ex e A 507-5 ExampLe 77 Methyl 5-C cycLopropyL carbamoyl )-1,4-dihydro-2,6-d imethyL- 4-[2-(4-methyL-phenyLsuLphonyLoxy)phenyLJ-pyr idine-3ca rboxy Late

H

3 COOC co NHI

H

3 C N H 3

H

MeLting point: 238 242 0

C

Example 78 'I Methyl 5-CethyLcarbamoyL )-1.,4-dihydro-2,6-dimethyL-4-E2- (4-methyL-phvnyL suLphonyLoxy )phenyL J-pyr idine-3-carboxyt ate -so 3 3 HCODC CO-NH-C 2

H

H

3 C N H 3

H

V Melting point: 228 0

C

Example 79 Methyl 5-CethyLcarbamoyL )-4-E2-(2,6-dichLoro-benzyLoxy)phenyL]> 1,4-dihydro--2,6-dimethyL-pyridine-3-carboxyLate

H

3 COOC C O-NH-CH 2

-CH

3

H

3 C: N H 3

H

Melting point: 174 176 0

C

Le A 25 087 52 I Example Methyl 5-(ethyLcarbamoyL )-4-[2-(3,4-dichLoro-benzyLoxy)-phenyLJ- 1,4-dihydro-2,6-dimethyL-py-idine-3-carboxyLate I~ 1l

H

3 COOC CO-NH-CH 2

-CH

3

H

MeLting point: 178 -1800 C ExampLe 81 Methyl 5-(ethyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-E2- 2-py ridyL met hyLoxy )phenyL ]-pyr id ine-3-c arboxyL ate 0-CH 2

N

H

3 COOC c0-N:A-c 2

H

3 C N H' 3

H

MeLting point: 159 161 0

C

Example 82 Methyl 5-(cycLopropyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4- E2-(2-pyridyLmethyLoxy)phenyL]-pyridine-3-carboxyLate I- -CH2-(

H-

3 COOC CO-NHK m 3 C N CH 3

H

Melting point: 168 '170 0

C

Le A 25 087 53-

H

3 CON H Melting point: 202 0

C

Le A 25 087 Example 83 Methyl 5-(methyLcarbamoyL )-1,4-dihydro-2,6-di,,nethyL-4-(2phenyLsu.lphonyLoxy-phenyL)-pyridine-3-carboxyLate I ~2

H

3 COOC ICO-NH-CH 3 I H 3 C N 3

H

Melting point: 171 -173 0

C

Example 84 -thyL 5-(ethyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-(2phenyLsuLphonyLoxy-phenyL)--pyridine-3-carboxyLate I O-S 02

H

3 CODC CO-NH-C 2

H

H *C N CH

H

Melting point: 188 -190 0

C

Example Ethyl 5-(ethyLcarbamoyL )-1,4-dihydro-4-E2-(4-fLuorobenzyLoxy)phenyL )-2,6-dimethyL-pyr idine-3-carboxyLate

H

5

C

2 00C CO-NH-C 2

H

H

3 C N H 3

H

Melting point: 147 1490 C Le A 25 087 54- Le A Z5 087 41 Example 86 Methyl 5-CethyLcarbamoyL )-1,4-dihydro-4-[2--(4-fLuorobenzyLoxy)phenyL]-2,6-dimethyL-pyridine-3-carboxyLate

H

3

COOI

Melting point: 111 113 0

C

Example 87 Methyl 5-(aLLyLca-bamoy1 )-1,4-dihydro-2,6-dimethyL-4-(2phenyLsuLphonyLoxy-phenyL)-pyridine- 3-carboxyLate

V

so 2 -0~

H

3 COOC

CO-NH-CH

2

-CH=CH

2

H

3 CN

H

3 Melting point: 154 156 0

C

Example 88 Methyl 5-((4-pyridyL )carbamoyL)-1,4-dihydro-2,6-dimethyL-4 (2-phenyLsuLphonyLoxy-phenyL)-pyridine-3-carboxyLate SD2< :0-NH _C H 2

C

7

N

H

3

CDOO

Melting point: from 240 0 C (decomposition) Le A 25 087 55 Example 89 Methyl 5-(aL LyLcarbamoyL )-4-C2-C4-chLoro-benzyLoxy)phenyL l,4-dihydro-2,6--dimethyL-pyridine-3-carboxyLate H3COOC CO:NH-CH2-CH=CH2

H

Melting point: 145 0

C

Example Methyl 5-(aLLyLcarbamoyL )-4-(3--benzycoxy-phenyL )-1,4--dihydro- 2,6-dimethyL-pyridine-3-carboxyLate O-CH2~

H

2

C=CH-H

2 C-NH-OC

COOCH

3

H

3 C I N H 3

H

Melting point: 95 -980 C Example 91 Methyl 5-(aLLyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-E2- 4 -methyL-phenyLsuLphonyLoxy)phenyL Jpyr idine-3-carboxyL ate 0 S0 2 3

H

3 COOCCO-NH-CH

-CH=CH

2

H

3 C N H 3

H

Melting point: 168 -170 0

C

Le A 25 087 56j Example 92 Methyl 5-CaLLyLcarbamoyL )-4-[2-(2,6-dichLoro--benzyLoxy)phenyL]- 1,4-di hydro-2,6-dirnethyL-pyr idine-3-carboxyLate 1l

-CH

2 Cl

H

2

C=HC-H

2 C-HN-OC COOCH 3

H:

3 C IN nH 3

H

MeLting point: 132 1340 C ExampLe 93 MethyL 5-C (2-hydroxyethyL )carbamoyL )-4-C2--benzyLoxy-phenyL 1,4-di hydro-2,6-d imethyL-pyr idine-3-carboxyLate

CO-CH

2 -0D

H

3 COOC CO-NH-CH 2 7CH 2

-OH

H

3 C N. H 3

H

MeLting point: 148 -150 0

C

Example 94 Methyl 5-(methyLcarbamoyL )-4-[2-C3-fLuoro-benzyLoxy)-3methoxy-phenyl )-1,4-dihydro-2,6-dirnethyL-pyridine-3carboxyLate %OCH3

F

H:

3 COOC CO-NH-CH 3

H

3 c N H 3

H

Le A 25 087 57- MeLting point: 171 -1730 C ExampLe MethyL 5-(2-(4-pyridyL)ethyLcarbamoyL )-4-(2--benzyLoxyphenyL )-1,4-dihydro-2,6-dimethyt-pyridine-3-carboxyLate L

CH

2

-Y

H

3 COOC co-NH-CH 2

-CH

2 j

H

3 C N H 3

H

MeLting point: ExampLe 96 MethyL 5-(methyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-E2- C3-pyridyL)methoxy-phenyLJ-pyr'idine-3-carboxyLate

-CHZ-C

H

3

COOCCO-NH-CH

3

H

3 C N CH H3 10 MeLting point: from 210 0

C

ExampLe 97 Methyl 5-(ethyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-E2- C3-pyridyL )methoxy-phenyL]-pyridine-3-carboxyt.ate 0: 0-C H

H

3 CODC CO NH C 2

H

3 C 1 H 3 Melting point: 122 125 0

C

Le A 25 087 58- Example 98 Methyl 5-(ethyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-E2- (4-pyridyL )methoxy-phenyL )-pyridine-3-carboxyLate I -CH 2 ~c H3CO(CCO..NHC 2 H N 1A'-CH 3 a

H

Melting point: 95 -100 0

C

v Example 99 Methyl 5-CmethyLcarbamoyL )-1,4-dihydro-2,6-dimethyL-4-E2- (4-pyridyL )methoxy-phenyLj--pyridine-3-carboxyL ate O-CHc7j H3COOCCO-NH-CM 3

H

3 C N

H

3 Melting point: from 203 0 C (decomposition) Example 100 Metyl -C CcycLopropyLmethyL)-carbamoyL)-4.-(2-benzyLoxyphenyL 4 dihydro-2,6-dmethyL-pyridine-3-carboxyLate -CH- Q:

-WH

3 COOC

CO-NH-CH

2

-<J

H 3 CX H 3

H

Melting point: 186 0

C

Le A 25 087 59- ExampLe 101 MethyL 5-(ethyLcaf bamoyL)-(+)--4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate S -CH 2 -0

H

3 COOC CO-NH--CH 2

-CH

3

H

3 C N H 3

H

MeLting point: 1470 C [a 0= 29.68

D

c 0.91 (DMF) ExampLe 102 MethyL 5-(ethytcar-bamoyi)-(-)-4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyt-pyridine-3-carboxyLate

-CH

2

Q

H

3 COOC CO-NI-CH 2

-CH

3

H

3 C N H

H

Melting point: 148 0

C

20 29.92 c 0.805 (DMF) ExampLe 103 Ethyl 5-CmethyLcarbamoyL)-4-(2-benzyLoxy-phenyL )-1,4-dihydro- 2,6-dimethyL-pyridine-3-carboxytate Le A 25 087 60 a V I CH3-~

H

5

C

2 00C

CON-H

H

3 C N 3 K H Melting point: 179 0

C

ExampLe 104 EthyL 5-(ethyLcarbamoyL)-4-(2-benzyLoxy-phenyL )-1,4-dihydro- 2,6-dimethyL-pyridn--abx~t

H

5

C

2 00C 2 CON- 2 HC N H 3

H

V MeLting point: 161 164 0

C

ExampLe 105 I Methyl 5-C (2-ethoxycarbonylethyL )carbarnoyL )-4-(2-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-rpyridine-3-carboxyLate

H

3 COOC CO-NH- (CH 2 2

-COOC

2

H

H

3 CN

H

3

H

Rf =0.35 Le A 25 087 61 Example 106 Methyl 5-C (ethoxycarbonyLmethyl )carbamoyL )-4-(2-benzyloxyphenyL)-l, 4 -dihydro-2,6-dimethyL-pyridine.3-.carboxyLate H~COOC I CO-NH-CH 2

-CODC

2

H

H

3 C N LH 3

H

Rf 0.408 Example 107 Methyl 5-(octylcarbamoyL )-4-(2-benzy~oxy-phenyL dihydro-2,6-dimethy1-pyridine-3-carboxyLate H3COOC ~yCO-NH-(CH 2 7

-CH

3

H

Rf =0.53 Example 108 Methyl 5-(nonylcarbamoyL )-4-(2-benzyloxy-phenyL dihiydro-2,6--dimethyL-pyridine-3-carboxyLate t 4 t I .CH 2 Q0

H

3 COOC >.CO-NH-(CH2)6BCH 3

H

3 C

H

3 Rf =0.55 Le A 25 087 -62 Methyl 5-(decyLcarbarnoyt)-4-(2-benzytoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate -C H

H

3 COOC CO-NH- (CH 2 9

-CH

3

H

MeLting point: 111 0

C

Example 110 Methyl 5-((2-methoxy-ethyL'icarbamoyL )-4-(2-benzyLoxy-phenyL)- 1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate 111 CH 2

Q

3coocCO-NH-CH 2

-CHZ-OCH

3 MeLting point: 145 0

C

Example 111 Methyl (3-methoxy-prcpyLcarbamoyL )-4-(2-benzyLcexy-phenyL 1,4-dihydr'o-2,6-dimethyL-pyridine--3-carboxyLate

H

3 COOC CO-Ni- (CH 2 3

-OCH

3

H

Rf 19 Le A 25 087 63- Example 112 Methyl (2-hydroxy-1-methyt-2-phenyL )ethyLcarbamoyL (R,R)-4-(2-benzyLoxy-phenyt)-1,4-dihydro-2,6-dimethyLpyridine-3-carboxyLate Process variant H (direct coupling with dicycLohexylcarbodiimidle) 1 g (2.54 mmol) of monomethyL 4-(2-benzyLoxyphenyL)-1,4-dihydro-2,6-dimethyL-pyridine-3,5-dicarboxyLate are dissolved in 5 ml of dimethyLformamide, and 0.477 (2.54 mmoL) of L-norpseudoephedrin hydrochLoride, 0.35 ml (2.54 mmoL) of triethyLamine and 0.629 g (3.05 mmoL) of dlicycLohexyL-carbodliimide (solid) are added. The mixture is stirred at room temperature for 4 hours, the urea is filtered off under suction, and the fiLtrate is evaporated.

Column chromatography: Silica gel 60, grain size 0.040- 0.063 mm using CHCI 3

/CH

3

OHINH

3 2 0 1 -0.05 Since urea is only sparingLy soluble in ether and t 120 methylene chloridle, the product is taken up several times in ether or methyLene chloride, filtered off and evaporated.

Yiel: 0.9 g (67.3% of theory) nf= 0.35 C t) 47.93 (CHCI 3 Le A 25 087 -64 Example 113 Methyl (2-hydroxy-1-methyL-ethyL )carbamoyL benzyLoxy-phenyL)-1,4-dihydro-2,6-dimethyL-pyridile-3c arbo xy late

(S)

H

3 CDoc CO-NH-CH-CH 2

O

H

3 C N CH 3

WCH

3

H

Rf =0.13 +7.34 (CHCL 3

D

Example 114 Methyl (1-hydroxy-methyL-propyL)carbamoyL)(S)4( 2 benzyLoxy-phenyL )-1,4-dihydro-2,6-dirnethyL-pyr idine-3carboxy.Late I I (S

H

Rf =0.15 ca) 20 _9.37 (CHCI 3 Example 115 Methy-l C -hydroxy-methyL-2-methyL-propyI )carbamoyL (S)-4-(2-benzyLoxy-phenyL)-1,4-dihydro-2,6-dimlethyLpyridine-3-carboxyL ate Le A 25 037

(S)

H

3 COOC CO-NH-CH-CH 2

-OH

H

3 N3

H

t Rf 0. 19 20: 10.8 CCHCL) D *3 Example 116 Methyl 5-CC 1-hydroxy-methyL-2-methYL-butyL )carbanioyL)-(S)- 4-(2-benzyLoxy-phenyL)-1,4-dihydro-2,6-dimethyL-pyr idine- 3-carboxyL ate

(S)

H

3 COOC CO-NH-CH-CH 2

-OH

I I I

H

3 C N H3 UmK 2

H

Rf 0.21 Eci) 20 -17.37 (CCL 3

D

Example 117 Methyl 5-C C3-hydroxy-propyL )carbamoyL )-4-(2-benzyLoxy-phenyL 1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate Le A 25 087 66

HCOOC-,,--NCO-NH-(CH

2

-H

H C--N-^-CH 3 3 H 3 Melting point: 205 0

C

ExampLe 118 V Met hyl 5-(3-cycLopropy Lc arbamoyL)-) 4-(2-benzyLoxy-phenyL 1,4-di hydro-2,6-dimethyL-pyr idine-3-carboxyL ate

H

3

CO-N-"COH-

H

Melting point: 178 -181 0

C

-a -38.28 (c=0.569, chloroform) Example 119 Methyl 5-C3-cycLopropyLca,-bamoyL)-C+) 4-(2-benzyLoxyr phenyL )-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate tiz H CQOC-,,

H

3

C-N---CH

3

H

Melting point: 178 181 0

C

=+36.56 (c=0.52, chloroform) 589 Le A 25 087 67 Example 120 Methyl 5-hexyLcarbamoyL-4-(2-benzyLoxy-phenyL )-1,4-dihydro- 2 ,6-d imethy 1-pyr idi ne-3-c arbox >'late C H H COOCr CTO-NH- CH 2 5

-CH

3

H

3 C- N C H 3

H

Melting point: 133 0

C

Example 121 Methyl 5-carbamoyL-4-E2-(4-methyL--benzenesuLphonyLoxy phenyL ihydro-2,6-d imethyL-pyr idi ne-3-carboxyL ate

H

3

COOC-'----CO-NH

2

H

Melting point: 205 0

C

Example 122 Methyl 5-sec.-butyLcarbamoyL-4-(2-benzyLoxy-phenyL di hydro-2,6-dimethyL-pyr idine-2-carboxyLate

H

3 C cooc-, N,-C 0-NH -C H -CH

H

3

C'-N--CH

3

C;H

2

-CH

3

H

Melting point: 135 0

C

Le A 25 087 68 ExampLe 123 11 IsopropyL 5-carbamoyL-4-(2-benzyLoxy-phenyL )-1,4-dihydro-2,6dimethyL-pyridine-3-carboxyLate

H

3

N

CHOOCN-,N,-C NH 2 H 3CC 7 II "'-H3

H

MeLting point: 190 0

C

ExampLe 124 2-Methoxy-ethyL 5-carbamoyl-4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-5-carboxyLate 00 C H

H

3 C-O-H~c-H 2 2

H

4 4 10 MeLting point: 165 0

C

ExampLe 125 Methyl 5-butyLcarbamoyL-4-(2-benzyLoxy-phenyL )-1,4-dihydro- 2,6-dimethyL-pyr idine-3-carboxyLate 1 t

H

3 COOCN- (CH 2 3

-CH

3

H

3

-H

3

H

Le A 25 087 69-

I.

I

Melting point: 144 148 0

C

Example 126 Isopi-opyL 5 -ethyLcarbamoyL-4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyt-idine-3-carboxyLate

H

3 CN., -CH2< CH-QOC-

CO-NH-C

2

H

HI 3

H

3 -N M 3

H

K

ii

'I

11 Ii

I

Melting point: 135 0

C

Example 127 Methyl 5-C3-ethoxypropyL )carbamoyL-4-C2-benzyLoxy-phenyL 1,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate ii H

H

3

C.-'N--NCH

3

H

Melting point: 115 0

C

Example 128 Methyl 5-(5--hydroxypentyL )carbamoyL-4-(2-benzyLoxy-phenyL l,4-dihydro-2,6-dimethyL-pyridine-3-carboxyLate H 3 COOCN CO-NH- (CH 2 5

-OH

H

3 3

H

Le A 25 087 70 Melting point: 178 0

C

Example 129 2-Methoxy-ethyL 5-methyLcarbamoyL-4--(2-benzyLoxy-phenyL V 1,4-di hydro-2,6-d imethyL-pyr idine-3-car-boxyLate

H

3

H

H

Melting point: 133 135 0

C

Example 130 2-Methoxy-ethyL 5-ethyLcarbamoyL-4-(2--benzyLoxy-phenyL 1, 4-d ih ydro-2 ,6-d imet hyL-pyr idin e-3-c arboxy Late

H

3

C--

2

'C-H

2 C-OOC-,- -,-CO-NH-C 2

H

Melting point: 111 0

C

Example 131 II IsopropyL 5-methyLcarbamoyL-4-C2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate H 3 C- I CH-OOC,- 'tO-CNH-CH 3

H

3

-H

3

H

Le A 25 087 -71 Melting point: .140 -143 0

C

ExampLe 132 IsopropyL 5-cycLopropyLcarbamoyl-4-(2-be-nzyLoxy-phenyL 1,,4-di hydro-2,6-dimethyt-pyr idine-3-carboxyLate CH- QOC--- ,CO -NH-<

H

3 CZ 11 11

H

3 3

H

Melting point: 132 135 0

C

ExampLe 133 IsopropyL 5-isopropyLcarbanioyL-4-(2-benzyLoxy-phenyL dihydro-2,6-dimethyL-pyridine-3-carboxyLate l C H~-CH -CH2 CH-0OCN-' -CO-NH-CH H3 c, C-,N--CH3

H

Li Melting point: from 110 0

C

Le A 25 087 -72-

Claims (2)

1. Dihydropyridinamides of the general formula (I) R 4 1 R3 /R 6 (1) R200C CON I N 8 R7 Ri: N R8 R H in which 1 n R and R 8 are identical or different and represent straight-chain, branched or cyclic aLkyl having up to 6 carbon atoms which is optionally sub- stituted by hydroxyl, cyano, phenyl or halogen, or represent cyano or phenyl, R 2 represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon rad- 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 is optionally substituted by halogen, cyano, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl, R 3 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, trifluoro- methoxy, difluoromethoxy or trifLuoromethylthio, R 5 represents a group of the formula -0-(CH 2 )n-R 1 1 11 11 -S-(CH2)n-R 1 1 -0-S0 2 -R 1 1 -CO-(CH2)n-R 1 1 -0-CO-(CH2)n-R 1 1 -CO-NH-(CH 2 )n-R 1 1 Le A 25 087

73- -NH-CO-(CH 2 )n-R 1 1 or -NH-S02-(CH2)n-R 1 1 in which n denotes 0 to 4, and R 11 denotes aryL having 6 to 12 carbon atoms which may be monosubstituted to tetrasubstituted by halogen, cyano, nitro, trifluoromethyl, tri- fluoromethoxy, 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 sub- stituents being identical or different, or denotes a 5- to 7-membered saturated or unsaturated hetero- cyclic ring which may contain as hetero atoms an oxygen atom, a sulphur atom or two nitrogen atoms, and R 6 and R 7 are identical or different and in each case represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or staight- chain or branched alkyl, alkenyL or alkinyL which in each case have up to 18 carbon atoms S' and which may be substituted by halogen, hy- i t droxyl, alkoxy having up to 8 carbon atoms, alkylthio having up to 8 carbon atoms, alkylcar- Sbonyl 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 and/or by a group of the formula -NR R 10 in which Le A 25 087 -74 I ~ium~xclr~-l; r 0 I 0, 9 10 R 9 and R 10 are identical or different and in each case denote hydrogen, alkyl having up to 8 carbon atoms, aralkyl havin 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 6 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 un- saturated heterocyclic ring which may contain as hetero atoms an oxygen atom, a sulphur atom or two nitrogen atoms, and the physiologically acceptable salts thereof. 2. Compounds of the general formula according to Claim 1, in which 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 substit- uted by hydroxyl, phenyL, fluorine, chlorine or bromine, or represents cyano or phenyl, R 2 represents a straight-chain or branched, satur- ated or unsaturated hydrocarbon radical which has Le A 25 087 75 I: jii; is II% ;;i i: 1 i i tk~ Y1 r~ I a ky LCz rr*- 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 c-, 8- or y-pyridyl, R 3 and R 4 are identical or different and in each case represent hydrogen, fluorine, chlorine, bromine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, methylthio, cyano, nitro, trifluoromethyl or trifluoromethoxy, R represents a group of the formula -O-(CH2)n-R 1 1 -S-(CH2)n-R 1 1 -0-S0 2 -R 1 1 CO-(CH2)n-R 1 1 -NH-CO-(CH 2 )n-R 1 1 or -NH-S02-(CH 2 )n-R 1 1 in which n denotes 0 to 3 and R 1 denotes phenyl or naphthyl which may be mono- substituted, disubstituted or trisubstituted by fluorine, chlorine, bromine, cyano, nitro, trifluoro- 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- stituents being identical or different, or denote pyridyl, thienyl, furyl, pyrimidyl or pyrazinyl, and R 6 and R 7 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 Le A 25 087 76 SalkenyL which has up to 14 carbon atoms and which may be substituted by fluorine, chlorine, bromine, 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 radical, carboxyl, alkoxycarbonyl having up to 6 carbon atoms, phenyl which is optionally substit- uted by nitro, trifluoromethyl, methyl or methoxy, by cyano and/or by a group of the formula -NR 9 R 1 0 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 phenylsulphonyl, or represent phenyl or naphthyl which may be mono- substituted, disubstituted or trisubstituted by i 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, i trifluoromethyl, trifluoromethoxy, amino, alkyl- amino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group, Sacetylamino or by benzoylamino, the substituents v being identical or different, or represent pyridyl, pyrimidyl, thienyl or furyl, V and the physiologically acceptable salts thereof. 3. Compounds of the general formula according to Claim 1, in which R 1 and R 8 are identical or different and in each case represent methyl, ethyl or benzyl, 2 i R represents a straight-chain or branched hydro- carbon radical which has up to 6 carbon atoms, may be interrupted in the chain by an oxygen atom and/or Le A 25 087 77 i may be substituted by fluorine, chlorine, cyano, hydroxyL, phenyl, B- or y-pyridyl, 3- 4 R and R are identical or different and in each case represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, nitro or trifluoromethyl, R represents a group of the formula -O-CH2-R 11 11 S-S-CH2-R 1 or -0-S02-R 1 in which R denotes phenyl which may be monosubstituted or disubstituted by fluorine, chlorine, nitro, trifluoromethyl, methyl, methoxy, amino, methyl- amino, dimethylamino, ethylamino, diethylamino or acetylamino, the substituents being identical or S different, or denotes an B- or a y-pyridyl group, R 6 represents hydrogen or alkyl having up to 4 carbon atoms, and S7 R represents hydrogen, cyclopropyl, cyclopentyl S.or cyclohexyl, or represents straight-chain or branched alkyl or I alkenyl which has up to 10 carbon atoms and which may be substituted by fluorine, chlorine, hydroxyl, Salkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, alkylcarbonyl having S1 rup to 4 carbon atoms in the alkyl radical, carb- I oxyl, alkoxycarbonyl having up to 4 carbon atoms, phenyl and/or a group of the formula -NR R 0 Sin which SR and R 10 are identical or different and denote hydrogen, alkyl having up to 4 carbon atoms, benzyl, phenyl or acetyl, or R represents phenyl which may be monosubstituted or disubstituted by nitro, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, Le A 25 087 78 alkylamino having up to 2 carbon atoms, dialkyl- amino having up to 2 carbon atoms in each alkyl group, acetylamino or benzoylamino, the substituents being identical or different, or represents a- or y-pyridyl, and the physio- logically acceptable salts thereof. 4. Process for the preparation of dihydropyridinamides of the general formula (I) R 4 R R R3 /,B 6 (I) R2OOC Y CON I I R 7 H in which 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, R 2 represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon rad- 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 is optionally substituted by halogen, cyano, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl, R 3 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, Le A 25 087 79 I 4 nitro, dialkylamino having up to 4 carbon atoms in each alkyl group, trifLuoromethyL, trifluoro- methoxy, difluoromethoxy or trifluoromethyLthio, R 5 represents a group of the formula -O-(CH 2 )n-R 1 1 -S-(CH2)n-R 1 1 -0-S 2 -R 11 -CO-(CH2)n-R 1 1 -CO-(CH2)n-R 1 1, -CO-NH-(CH 2 )n-R 1 1 -NH-CO-(CH 2 )n-R 1 1 or -NH-SO2-(CH2)n-R 1 1, in which n denotes 0 to 4, and R denotes aryl having 6 to 12 carbon atoms which may be monosubstituted to tetrasubstituted by halogen, cyano, nitro, trifluoromethyL, tri- fluoromethoxy, 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 stituents being identical or different, or denotes a 5- to 7-membered saturated or unsatur- ated heterocyclic ring, which may contain as hetero atoms an oxygen atom, a sulphur atom or two nit- rogen atoms, and R 6 and R 7 are identical or different and in each 1 c case represent hydrogen, cycloalkyl 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, carbo)yl or alkoxycarbonyl having up to Le A 25 087 80 F r 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 formula -NR R 10 in which R 9 and R 10 are identical or different and in each case denote hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, (e\ky I,a l or ro\ ky carbo-/ 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 6 and R 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 Srepresent a 5- to 7-membered saturated or un- saturated heterocyclic ring which may contain as hetero atoms an oxygen atom, a sulphur atom or two nitrogen atoms, characterized in that EAD aldehydes of the general formula (II) R 4 '3 5 (II) R3 CHO Le A 25 087 81 t in which R R and R have the abovementioned meaning, and B-ketocarboxyLates of the general formula (III) R200C (III) RI,- in which R and R have the abovementioned meaning, Sare reacted with B-ketocarboxamides of the general formula (IV) CON IR 7 (IV) i oR 8 in which j 6 7 8 R R and R have the abovementioned meaning, Sand ammonia, if appropriate in the presence of inert Ssolvents, or in that B3 aldehydes of the general formula (II) are reacted Swith B-ketocarboxylates of the general formula (III) and enaminocarboxamides of the general formula (V) S-co .R 6 CON (V) SH2 N R8 in which R 6 R 7 and R 8 have the abovementioned meaning, if appropriate in the presence of inert solvents, or in that aldehydes of the general formula (II) are reacted with 8-ketocarboxamides of the general formula (IV) and Le A 25 087 82 r tz enaminocarboxylates of the general formula (VI) R200Cr PO C (VI) P1 NH 2 in which 1 2 R and R have the abovementioned meaning, if appropriate in the presence of inert solvents, or in that CD] 8-ketocarboxylates of the general formula (III) are reacted with ammonia and ylidene-B-ketocarboxamides of the general formula (VII) R4 (VII) IR3 6 Hj CON R 8 in which R- R 8 have the abovementioned meaning, if appropriate in the presence of inert solvents, or in that EEl B-ketocarboxamides of the general formula (IV) are reacted with ammonia and ylidene-B-ketocarboxylates of the general formula (VIII) t t 3 (VIII) R 2 00C H R 1 0 in which RI R5 have the abovementioned meaning, if appropriate in the presence of inert solvents, Le A 25 087 83 Fe I or in that ylidene-B-ketocarboxamides of the general formula (VII) are reacted with enaminocarboxylates of the general formuLa if appropriate in the presence of inert solvents, or in that ylidene-B-ketocarboxylates of the generaL formula (VIII) are reacted with enaminocarboxamides of the general formula if appropriate in the presence of inert solvents, or in that CH] dihydropyridinemonocarboxylic acids of the general formula (IX) R 4 I R 5 (IX) R R200C COOH I I N R H i in which 1 5 8 R R and R have the abovementioned meaning, i if appropriate via a reactive acyl derivative, are reacted iI .with amines of the general formula (X) /R HN (X) in which R and R have the abovementioned meaning, if appropriate in the presence of an inert organic solvent. Process for the preparation of compounds of the general formula according to Claim 4 by process var- iants [A]-EG3, characterized in that the solvent employed is water and inert solvents such as alcohols, ethers, amides, glacial acetic acid, dimethyl sulphoxide, aceto- nitrile or pyridine, and the reaction is carried out at Le A 25 087 84 temperatures between 10 and 150 0 C. 6. Methyl 5-(cyclopropylcarbamoyl)-4-(2-benzyloxy-phenyl)- 1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate. 7. Methyl 5-(3-cyclopropylcarbamoyl)-(+) 4-(2-benzyloxy- phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate. 8. A dihydropyridinamide compound of general formula as shown in claim 1, said compound substantially as herein described with reference to any one of the Examples. 9. A pharmaceutical composition comprising at least one compound defined in any one of claims 1 to 3 or 6 to 8 together with a pharmaceutically suitable excipient or solvent. A process for producing a pharmaceutical composition which comprises admixing at least one compound defined in any V one of claims 1 to 3 or 6 to 8 with a pharmaceutically suitable excipient or solvent. 11. A method for the treatment or prophylaxis, of a circulation disorder in a subject which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. h 12. A method for the lowering of high blood pressure in a subject, which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. 13. A method for the treatment of heart insufficiency in a subject, which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. 2- 85 0210e/AC 14. A method for the treatment, as a coronary therapeutic agent, of a subject requiring said treatment which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. A method for the treatment of kidney insufficiency in a subject, which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. 16. A method for the treatment of heart rhythm disturbances in a subject, which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. 17. A method for the treatment or prophylaxis of a condition selected from cirrhosis of the liver, ascites, lung oedema, U cerebral oedema, pregnancy, oedema, glaucoma of diabetes melitus, in a subject, which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. 18. A method for the treatment or prophylaxis of cardiocirculation disorders, or disorders of the electrolyte or liquid balance in a subject which comprises administering to said subject an effective amount of a compound defined in any one of claims 1 to 3 or 6 to 8. DATED this 2nd day of May, 1990. BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys ARTHUR S. CAVE CO. 86