CA1328869C - Dihydropyridinamides, a process for their preparation, and their use in medicaments - Google Patents

Abstract

Dihydropyridinamides, a process for their preparation, and their use in medicaments ABSTRACT

Circulation-active novel dihydropyridinamides of the formula

Description

The present invention relates to dihydropyridlnamides, 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-4-phenylpyridine-3,5-dicarboxylate is obtained when ethyl benzylideneacetoacetate is reacted with ethyl ~-aminocrotonate or ethyl acetoacetate and ammonia [E. Knoevenagel, Ber. Dtsch. Chem.
Ges. 31, 743 (1898)].
It is furthermore known that certain l,~-dlhydro-pyridines have interesting pharmacologlcal propertie~ IF. ~ossert, W. Vater, Naturwissenschaften 58, 578 11971)1.
The present invention relates to new dihydropyridin-amlde~ of the general formula II) /~ ~-'-, ~ R 6 R3 1 / (I) RZOOC ~ \R7 H -in which l and R8 are identical or different and represent straight-chaln or branched alkyl havlng up to 4 carbon atoms, each of which ~-optionally ~ubstituted by phenyl, R2 represent~i a stralght-chain or branched, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms which ,,., ~ ' i~ - :~ .

~ ~i' ` ~ t 231~9-6707 may be interrupted in the chain by an oxygen atom and which may be substituted by fluorine, chlorine, cyano, hydroxyl or by a phenyl group or by a-, ~- Gr ~-pyridyl, R3 and ~4 are identical or different and in each case represent hydrogen, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, nitro or :.
trlfluoromethyl, R represents a group of the formula -0-(C~2)n-X11, --S-(CH2)n-R11, -0-S02-R11 or -0-C0 (CH2)n-R11, in which n denotes 0 to 3, and R11 denotes phenyl which may be monosubstituted, disubstituted or trisubstituted by identlcal or different substituents selected from the group consisting of fluorine, chlorine, nitro, trlfluoromethyl, alkyl havlng up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, amlno, alkylamlno having up to 4 carbon atoms, dialkylamino having up ~o 4 carbon :
atoms in each alkyl group, acetylamino or denotes pyridyl, and -R~ and R7 are ldentical or different and in each case ~-represent hydrogen or cycloalkyl havlnq 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, hydroxyl, alkoxy having up to 6 carbon atoms, alkylthio ~;; -having up to 6 carbon atoms, carboxyl, alkoxycarbonyl having up to ~ :-6 carbon atoms, by phenyl, or by a group of the formula -NR9R10, :
in which R9 and R10 are identical or different and in each case -:~
denote hydrogen, alkyl having up to 6 carbon atoms, benzyl, phenyl or acetyl, or :
R6 and R7 ln each case represent phenyl which may be .,"~ '"-'-'' ".

1~28869 monosubstituted, disubstituted or trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, alkyl having up to 4 carbon atom~, alkoxy having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, alkylamino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group, acetylamino and benzoylamino, or represent pyridyl, 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 diastereomeric mixtures. The racemic forms and llkewise ~he diastereomers can be resolved in a known fashion into the stereoisomerically unary components (cf.
E.L. Eliel, Stereochemlstry of Carbon Compounds, HcGraw Hill, 1962).
Physiologically acceptable salts can be salts of the compounds according to the lnvention with inorganic or organic -acids. Preferred salts are those with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphorlc acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, cltric acid, tartaric acid, lactic acid, benzoic ~-acid, or methanesulphonic acid, ethanesulphonic acid, phenyl~
sulphonic acid, toluenesulphonic acld or naphthalenedisulphonic acid.

R
.

Preferred compounds of the general formula (I) are those in which R1 and R8 are identical or different and in each case represent straight-chain or branched alkyl having up to 4 carboD
atoms which is optionally substituted by phenyl, R2 represents a straight-chain or branched, saturated or unsaturated hydrocarbon radical which has up to 8 carbon atoms and whicb may be interrupted in the chain by a oxygen atom and/or which may be substituted by fluorlne, chlorine, cyano, hydroxyl or by a phenyl, or by a-, ~- or ~-pyridyl, R3 and R4 are identical or different and in each case represent hydrogen, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, nitro or trifluoromethyl, R5 represents a group of the formula -O~(CH2)n-R
-S-(CH2)n-R11, -0-S02-R11 or -0-C0-(CH2)n-R11, in which n denotes -~
0 to 3, and R11 denotes phenyl which may be monosubstituted, disubstituted or trisubstituted by fluorine, chlorine, nitro, trifluoromethyl, 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, acetylamino or denotes pyrldyl and :- ~
R6 and R7 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, hydroxyl, alkoxy having up to 6 carbon atoms, carboxyl, .~ ,':
.;.' alkoxycarbonyl having up to 6 carbon atoms, by phenyl and/or by a group of the formula -NR9R10, in which R9 and R10 are ldentical or different and in each case denote hydrogen, alkyl having up to 6 carbon atoms, benzyl, phenyl or acetyl, or R6 and R7 in each case represent phenyl which may be mono-substituted, disubstituted or trisubstituted by nitro, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, alkylamlno having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group, acetylamino or by benzoylamino, or represent pyridyl, and the physlologically acceptable salts thereof.
Particularly preferred compounds of the general formula (I) are those in which Rl and R8 are ldentical or different and in each case represent methyl, ethyl or benzyl, R2 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 ~-pyridyl, ~ -R3 and R4 are identical or different and in each case represents hydrogen, fluorlne, chlorlne, methyl, ethyl, methoxy, ethoxy, nitro or trifluoromethyl, r ,"
R5 represents a group of the formula -0-CH2-Rll, -S-CH2-R
or -0-S02-Rll in which Rll denotes phenyl which may be monosubsti-: tuted or dlsubstituted by fluorine, chlorine, nitro, trifluoro- :~.
methyl, methyl, methoxy, amino, methylamino, dime~hylamino, f ~, :' ethylamino, diethylamino or acetylamino, the substituents belng identical or different, or denotes an a-, ~- or a ~-pyridyl group, R6 represents hydrogen or alkyl havlng up to 4 carbon atcms, :
and R7 represents hydrogen, cyclopropyl, cyclopentyl or cyclo-hexyl, or represents straight-chain or branched alkyl or alkenyl which has up to 10 carbon atoms and which may be substltuted by fluorine, chlorlne, hydroxyl, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, carboxyl, alkoxycarbonyl having up to 4 carbon atoms, phenyl and/or a group of the formula -NR9R10, in which R9 and R1~ are ldentical 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, alkylamino having up to . .

2 carbon atoms, dialkylamino having up to 2 carbon atoms in each alkyl group, acetylamino or benzoylamino, the substituents '.,, '' ' ' ' ' 132~8~9 -being identical or different, or represents a-, B- or y-pyridyl, and the physiologically acceptable salts thereof.
The compounds of the general formula (I) accord-ing to the invention in which R1 _ R8 have the abovementioned meaning, are obtained in a process in which CA] aldehydes of the general formula ~II) ~ R5 (II) R ¦
CHO
in which R3, R4 and R5 have the abovementioned meaning, and ~-ketocarboxylates of the general formuLa (III) R2OOC~ (III) R~

in which R1 and R2 have the abovementioned meaning, - are reacted ~ith B-ketocarboxamides of the general ~
formula (IV) . -.

~CON
~R7 . ( I V ) 0~ ~ 8 in which R6, R7 and R8 have the abovementioned meaning, and ammonia, if appropriate in the presence of inert solvents, .
or in a process in ~hich Le A 25 087 A ~:

~ 1328~69 ~8~ aldehydes of the general formula (II) are reacted ~;th B-ketocarboxYlates of the general formuLa (III) and enam;nocarboxam;des of the generaL formula (V) -~

,~R6 ~ CON 7 (V) in which R6, R7 and R8 have the abovementioned mean;ng, if appropriate in the presence of inert solvents, or in a process in ~h;ch CC] aldehydes of the general formula ~II) are reacted ~ith ~-ketocarboxamides of the general formula ~IV) and enaminocarboxylates of the general tormula (VI) R200C ~ (VI) in ~hich R1 and R2 have the abovementioned mean;ng, if appropriate in the presence of inert solvents, or in a process in ~hich -~ CD~ B-ketocarboxYlates of the general formuLa (III) are ~h rea~cted ~ith ammonia and y~idene-B-ketocarboxamides of the --general formula (YII) ~R4 R5 ~VII) ~- R3 ~ ,~R6 ~R8 in ~hich R3 - R8 have the abovementioned meaning, if appropriate in the presence of inert solvents, ~; or in a process in ~hich -Le A 25 087 ' 1328869 :-tE~ ~-ketocarboxamides of the general formula SIV) are reacted with ammonia and ylidene-B-ketocarboxylates of the general formula (VIII) ~ ~VIII) R200C~H
Rl~O

in wh;ch R1 _ R5 have the abovementioned meaning, if appropriate in the presence of inert solvents, or in a process in ~hich tF~ ylidene-B-ketocarboxamides of the general formuLa (VII) are reacted with enaminocarboxylates of the general formula (VI), if appropr;ate in the presence of inert solvents, or in a process in ~hich CG~ y~idene-~-ketocarboxylates of the general formula tVIII) are reacted w;th enaminocarboxamides of the general formula (V), if appropriate in the presence of inert solvents, or in a process in which ~H~ dihydropyridinemonocarboxylic acids of the general formula tIX) R ~ (IX) R2OOC~ ~ ~COOH
1~ ~N~ ~RB
H ~ -in which R1 _ R5 and R8 have the abovementioned meaning, if appropriate via a reactive acyl derivative, are reacted uith amines of the general formula tX) Le A 25 087 q d`~'. . :.
~ .
....

1328869 ~

,~R6 ::
~R7 (X) , ,' :, . . ':
in which R6 and R7 have the abovementioned meaning, .. ~1 if appropriate ;n 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 G87 /0 - : :

:

~A~ ~
~- C1~2 - C 6H5 CHO
H3COOC ~ ~ O-NSCH3)2 N~3 -:-H3COO ~ ON(CH3~2 '.-tB~ ~
~S-CH2-C6H5 CHO
HSC200 ~ X O-NH-CH3 H3 l H2 H3 -- ~:
~ : , ~S-CH2-C6H5 ~ ' 5c2oocc~o-NH-cH3 ;

Le A 25 087 A~

r,.. ~, '. ... ; ., , " , , .

` 132~69 ..........

tc~
-502-~6H5 CHO
H3COOC ~~ O-NH-C6H5 H3C H2H3 .
' .

H3COOC ~ CO-NH-C6H5 .
H3c~N~cH3 lD~ . ;

-CH~-C6H5 H3COOC~ H ~ CO-NH-C2H5 ~ :-H3C~l~O ~ CH3 - ' ' "'~ ' H3COOC~O-NH-C2H5 ~: H3C H3 :.
': ' ',.

~'` :'' Le A 25 087 1~ .

1328~69 tE~
~o-cH2-c6Hs H7C300C ~ H ~ CO-NH-C3~7 H3C~l~O CH3 , ~:

¢~0 CH2-c6Hs H7C300C ~ O-NH-C3H7 ~3 H H3 ~:

tF3 , H3COOC ~ H ~ CO-NH-CH3 H3C ~ NH2 H3 ~:~

O CH -C H

H3Co ~ O-NH-CH3 :`

H `;

Le A 25 087 1~ ~
~ ;';

~G] ~ ~-CH2-C6H5 H3COoC ~ H H ~ CO-N(CH3)2 f~O-CH2-C6H5 :, ~ , '' ~'.
H3COOC ~ O-NtCH3)2 tH~ :

¢~0- CH2 - C6H5 '~ ' H3COOC ~ OOH ~
H3 H H3 - :.
N=~ ~=N
. ~ N-C-N J
O :.~ :'-.. :

: ~ -CH ~ H5 H3COOC~CO-NJ
3C~NV^~CH3 :

H2~1 ~' .'".
~O-t H2-c6H5 H3COO ~ O-N ~ 1 ~3 H H3 ' ` :'':
~ Le A 25 087 ~ /~
' .

132~869 - Process variants A - G
_ .
Suitable solvents are water or all ;nert 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 diethylether, dioxane, tetrahydrofuran, glycoL monomethyL ether or glycoL dimethyl ether, or amides, such as dimethylform-am;de, d;methylacetam;de or hexamethyLphosphor;c tr;am;de, or glac;aL acet;c ac;d, d;methyl sulphox;de, aceton;tr;Le or pyr;d;ne.
The react;on temperatures may be var;ed w;th;n a relat;vely w;de range. In general, the process ;s carried out between +10C and ~150C, preferably between +20C
and +100C. In particular, at the boiling point~of the particular solvent.
The reaction can be carr;ed out at atmospheric pressure, but also at increased or reduced pressure. In general, the process is carr;ed out at atmospheric pressure.
When carrying out the process variants A - G
ZO accord;ng to the invention, the ratio of the substances -participating in the reaction is immaterial. In general, however, ~olar amounts of the reactants are used. The ~ -substances accord;ng to ;nvent;on are preferably ;solated --and pur;f;ed by remov;ng the solvent by d;st;llation ;n vacuo and recrystalliz;ng the residue obtained in crystalline form, if desired, only after ice cooling, from a suitab~e solvent. In some cases, it may be necessary to purify the compounds according to the invention by chromatography.
The aldehydes of the general formuLa tII) employed as starting materials are known or can be prepared by known methods ~German Offenlegungssehr;ften 2,165,260;
2,401~665; 7.D. Harr;s, G.P. Roth, J. Org. Chem. 44, 20Q4 ~1979); ~.J. Dale, H.E. Henn;s, J. Am. Chem. Soc. 78, 35 2543 ~1956); Chem. Abstr. 59, 13929 ~1963)~. ; -The B-ketocarboxYlates of the genera~ formula Le A 25 087 ~i :
~' ;

, . . . .~ . . , ... , , .. , .... . ~,. . . . .

. ~ 132~869 - (III) employed as starting materials are known or can be prepared by known methods ~D. 60rrmann in Houben ~eyl's "Methoden der organischen Chemie" ~Methods of Organic -Chemistry~ Vol. VII/4, 230 (1968); Y. Oikawa, K. Sugano, O. 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 kno~n methods CGerman Offenlegungsschrift 1,142,859].
- 10 The enaminocarboxam;des of the general formuLa (V) e~ployed as start;ng mater;als are kno~n or can be pre-pared by kno~n methods tGerman Offenlegungsschr;ft 2,ZZ8,377].
The enaminocarboxylates of the general formula tVI) employed as start;ng 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 tVII) employed as starting materials and the yl-idene-B-ketocarboxylates of the general formula (VIII) employed as starting materials are kno~n or can be pre-pared by known methods C6; Jones "The Knoevenagel Conden-sation" in Organic Reactions Vol. XV, 204 t1967)].
Process variant H according to the invention is carried out based on the literature-kno~n method of con-verting carboxylic acids into carboxamides. In thismethod, the carboxylic acid is initially converted into an activated form, such as, for example, the acyl chloride or the imidazolide, ~hich 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. Lesides 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-ylcarbodiimide or 1-cyclohexyl-3-C2-(N-methyl-morpholino)-ethyl~carbodiimide p-toluenesulphonate, or N-hydroxyphthalimide Le A 25 08? 16 ~ - .
' .. .: . . .. .. . . . : . .

or N-hydroxy-benzotriazole in the presence of dicyclohexyl-carbodiimide. Naturally, the dihydropyridinemonocarboxy-~ic acids can also be employed in the form of their salts.
CThe 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); ~.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 Synthes;s, John ~iley ~ Sons Inc. 1967, 116, 114; H.C. 8eyerman, U.O. van der ~rink, Re. Trav. 80, 1372 ~1961); C.A. ~uehler, D.E. Pearson, John Wiley ~ Sons, Volume I (1970), page 895 ff, Volume II, t1977)~.
9esides ~ater, suitable solvents for process var-iant H are all inert organic solvents ~h;ch do not react under the reaction cond;tions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyL ether, or hal-ogenated hydrocarbons, such as d;chloromethane, trichloro-methane or tetrachloromethane, or amides, such as d;methyl-tor~am;de, d;methylacetamide or hexamethylphosphoric tr;-am;de, or hydrocarbons such as benzene, toluene or xylene, or acetonitr;le, n;tromethane, pyrid;ne, d;methyl sulphox;de ~ -or ethyl acetate. M;xtures of the solvents ment;oned may l;kew;se be used. If the act;vated ;ntermed;ates of the d;hydropyr;d;nemonocarboxyl;c acids are isolated, the amines of the formula ~X) can also be used alone as d;luents.
The react;on temperatures may be varied ~ithin a -30 relat;vely w;de range. In general, the process is carried ~;~
out ;n a range from -70C to +140C, preferably from -20C
to ~100C.
The react;on can be carried out at atmospher;c pressure, but also at ;ncreased or reduced pressure. In general, the process ;s carr;ed out at atmospher;c pressure.
When carry;ng out process variant H according to ~ -Le A 25 087 ~7 A~ - ~
. ~

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 aclds of the general formula (IX) employed as starting materials are known or can be prepared by known methods [German Offenlegungs~chriften 2,847,236;
3,206,671 and 2,962,241].
The amines of the general formula (X) employed as starting materials are known or can be prepared by known methods [Houben Weyl's "Methoden der organischen Chemie" [Methods of Organic Chemistry] Vol. XI~l; Paulsen, Angewandte Chemie 78, 501 - -566 (1966)].
The compounds according to the inventlon exhibit an unforeseeable, valuable pharmacological spectrum of action. They influence the contraction power of the heart, the tone of the smooth muscles and the electrolytlc and liquid balance.
They can therefore be employed in medicaments for treatment of pathologically changed blood pre~sure and heart insufficiency, and also as coronary therapeutic agents. They can be employed to combat clrculation and cardiocirculation disorders.
In addition, the can be employed for treatment of heart rhythm disturbances, kldney insufficiency, cirrhosis of the liver, .
ascites, lung oedema, cerebral oedema, pregnancy oedema, glaucoma or diabeteq mellitus.
. ~

:- 132~869 The cardioactive effect of the compounds accordlng 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 subse-quently in each case removed from the right ventricle and fixed horizontally in an organ bath. During this procedure, one end of the muscle was held by two metallic electrodes, which simultan-eously served to stimulate the preparation, whereas the other end of the muscle ~as 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; NaC03 25; KCl 10; KH2P04 1.2; MgS04 1.2; CaC1 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 32C. The contractions of the papillary muscle were measured lsometrically 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 ~g/ml, if approprlate using a solubilizer ~DMS0 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 aæ tablets, coated tablets, pills, granules, aerosols, syrups emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In the abovementioned case, the therapeu~ically 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 sufflcient to achieve the abovementioned dosage range. The invention also extends to commercial packages containing a compound of the invention a~
active pharmaceutical ingredient, together with instructions for its use in combating circulation disorders and disorders of the electrolyte and liquid balance.
The formulations are prepared, for example, by extending the active compounds with solvents andtor excipients, if appropriate using emulsifiers and/or dispersantæ, and, for example ~ -when using water as a diluent, organic solvents can optionally be uæed as auxiliary solvents.

:~: : " ' ':: ' . - ' 132~869 Examples of auxil;ary substances which may be mentioned are: water, nontoxic organic solvents, such as paraffins (for example mineral oil fractions), veget-able 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, polyoxy-ethylene fatty alcohol ethers, alkylsulphonates and aryl-sulphonates)~ detergents (for example lignin, sulphite ~aste 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 particul-arly perlinguaLly or intravenously. In the case of oral adm;nistration, tablets can of course also contain addit-ives, 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, lubr;cants, such as magnesium stearate, sodium lauryl sul-phate and talc can be co-used for tabletting. In the case of aqueous suspensions, various flavour improvers or col-orants can be added to the active compounds in addition to the abovementioned auxiliaries.
In the case of parenteral administration, solut-ions o~ the active compounds can be employed using suit-able 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 û.5 mg/kg of body ~eight in order to achieve effective results, and in the case of oral administration, the dosage is about 0.01 ~ -e A 25 087 -~

".

, ' : ' :, . , . : . : ' ' . .: : , . , : , - , -. - , .: . -~328869 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body we;ght.
Nevertheless, it may at t;mes be necessary to deviate from the amounts ment;oned, and in particular to do so as a funct;on of the body weight and the nature of S the administration method, the indiv;dual behaviour to-wards the medicament, the nature of the formulation of the medicament and the time or interval over which admin-istration 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 ~entioned. ~hen 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, s;lica gel 60 F 254; mobile phase toluene/ethyl acetate in the volumerratio 1:2. -Example 1 Methyl 5-(dimethylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~-C~2~

COO ~ 0-N(CH3)2 H3~ H

Process variant A
2.12 9 (10 mmol) of 2-benzyloxy-benzaldehyde are boiled for 18 hours w;th 1.16 9 (10 mmol) of methyl aceto- -acetate, 1.29 9 of N,N-dimethylacetoacetamide and 1 ml of ammonia. The mixture is cooled and evaPorated. The evap-oration residue is taken up in ethyl acetate, washed tw;ce with water, dried and evaporated. It is purified over a Le A 25 087 ' ' ' i ' ' '. '.' :,` ' -~ ' : 1 . . . .

s;Lica gel column using toluene/ethyl acstate mixtures.
The pure fractions are colLected and evaporated. The product crystallizes on trituration using ether/ethyl acetate 10:1. 0.8 9 ~19% of theory) of colourless crys-tals of melting point 162 - 163C is obtained.
Process variant E
2 9 (6.45 mmol) of methyl 2-benzyloxy-benzylidene-acetoacetate are refluxed for 18 hours ~ith 0.83 9 (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 pur-ified 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 l;ttle ethyl acetate. The crystals are f;l-tered off under suction. 0.6 9 (22.9~ of theory) of a colourless substance of melting point 163 - 165C, Rf value = 0.118, is obtained.
ExampLe 2 Methyl 5-(phenylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-d;methyl-pyr;d;ne-3-carboxylate ¢~0 CH2~

H3COOC~0-N!~O
H3C H H3 . ~:

' :.
Process var;ant G
. . .
3.1 9 (10 mmol) of methyl 2-benzyloxy-benzylidene-acetoacetate are boiled for 3 hours in 20 ml of ethanol with 1.76 9 (10 mmol) of N-benzyl-3-aminocrotonamide. The mixture is cooled and evaporated. The solid evaporation Le A 25 087 . `

132~869 - residue is stirred with ether, filtered off under suction and recrystallized from acetonitrile. 2.4 9 ~51.3% of theory) of coiourless crystals of melting point 194C
are obtained.
Example 3 Methyl 5-(cyclopropylcarbamoyl)-4-(2-benzyloxy-phenylj-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~0^ CH2--O :
H3COOC~O-NH-Process variant H
.
20 9 ~45.14 mmol) of methyl 5-~imidazolylcarbamoyl~-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 90-1~0C
under argon. The mixture is cooled and evaporated. The evaporation residue is taken up in ethyl acetate, ~ashed with water, 1N hydroch~oric acid, ~ater, sodium bicarbon- ~
ate solution and again with water, dried and evaporated.
The evaporation residue is stirred with toluene, filtered off under suction and ~ashed with toluene. After recrys-tallization from about 60 ml of toluene, 14.95 9 (76~7X
of theory) of colourless crystals are obtained. Melting point: 191 - 193C.
Example 4 Z5 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2- -(3-trifluoromethyl-benzyloxy)phenyl]pyridine-3-carboxylate Le A 25 087 ' , CF
~-CH2~ :
H3COOC~O-NH-CH3 3.5 9 (6~8 mmol) of methyl S-(imidazolylcarbamoyl)-1,4-dihydro-Z,6-dimethyl-4-C2-(3-trifLuoromethyl-benzyloxy)-phenyl~pyridine-3-carboxylate (obtained from monomethyl 5 1,4-dihydro-Z,6-dimethyl-4-C2-(3-trifluoromethylbenzyloxy)- ;-~
phenyl~pyridine-3,5-dicarboxylate were reacted with carb- ~ ~
onylbisimidazoLe in tetrahydrofuran) are st;rred overnight ~ -without further purification with 40 ml of methyla~ine solution (40X strength). The preeipitaeed product is 10 filtered off under suction and washed well with water. It ~ -.
;~ is dried and recrystallized from a little toluene. 1.3 9 ~-~; (40.3Z of theory~ of a colourless product are obtained. ~ ~ -Melting point: 156 - 157C. ~-~
The~following ~ere prepared analogously to Examples ~
~;~ 15 1-~to 4: ~ `
~-~ Example 5 -~ -Methyl 5-(~cyclopropyLc~arbamoyl)-1,4-dihydro-2,6-dimethyl- ~ -- - -4-t2-(3-methyl-benzyloxy~phenyl~-pyridine-3-carboxylate CH2~ .
~ ~,, , , , . ~ : ~ ,,.
- H3COOC ~ ~ CO-NH-; H3C ~ ~ 5 Melting point: 176C

L~ A 25~087--- 25 - ~ -- 1328869 ~:
Example 6 Methyl 5-(cyclopropylcarbamoyl)-4-t2-(4-chloro-benzyloxy)-phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CH2~1 H3COOC~o-NH--a H3C ~3 ,' ' ,' ' 5 Melting point: 178C :
Example 7 Methyl 5-((2-pyridyl)carbamoyl)-4-t2-(4-chloro-benzyloxy)-phenyl~-1,4-dihydro-2,6-d;methyl-pyr;d;ne-3-carboxylate CH2~3c1 H3COOC~CO-NH~
H?C N CH3 - .
~ .
~`: 10 Melt;ng point: 201 - 204C
: Example 8 Me:thyl 5-((2-pyr;dyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-d;methyl-pyridine-3-carboxyLate ~-C~2~ .' ':: -H3COOC~O-NH~;~

15 Melting point: 164 - 165C ~ -Le A 25 087 :

`~

Exa~ple 9 1328869 Methyl 5-((2-diethyla~ino-ethyl)carbamoyl)-4-tZ-(4-chloro-benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ ' :
~ O-CH2 ~ ~C2H5 H3COOC ~ 2 2 ~C2H5 H

Melting point: from 80C
ExampLe 10 , Methyl 5-t(2-d;ethylamino-ethyl)carbamoyl)-4-(2-benzyloxy- : :
phenyl)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxylate ,- . - '-- . ' ' ~ -CH2 ~ ~ ~C2H5 ~-H3COOC ~ ~C2H5 ,:

Melting point: ~rom 95C
: Example 11 ;
.
MethyL 5-~(4-carbamoyl-phenyl)carbamoyl)-4-(2-benzyloxy~
phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~

~0 CH2--0 , : , f~
H~COOC ~ ~ CO-NH ~ ONH2 : H,C N~CH3 - --: H
Melting point: > 300C .:
~: Le A 25 087 ~
- 27 - - . -~ ,;''' ' ' ' ' Example 1Z
MethyL 5-((4-acetylaminophenyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-d1hydro-2,6-dimethyl-pyridine-3-carboxylate ¢;~ CH2--0 H3COOC ~ O-NH ~ NH-CO-CH3 H

Melting point: 298C decomposition ExampLe 13 - -Methyl 5-((4-benzoylaminophenyl)carbamoyl)-4-(2-benzyloxy- : .
phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate O-CH ~
_ ~--\ /~\ ' ' H3COOC ~ ~ CO-NH ~ NH-CO

..

: 10 Melting point: 197C : ~
~: Example 14 Methyl 5~-~(1-phenylethyl)carbamoyl)-(R,S)-4-~2-benzyloxy-phenyl)-1,4-dihydro-2:,6-dimethyl-pyridine-3-carboxylate :
~R, S mixture) 2 ~ ~ -¦ (R,S) ~;~ H3COOC ~ ~ CO-NH-IH
H3C ~ NH~^~CH3 CH3 -~ 15~ Melting point: from 162C -~
L- A a5 087 ~- :

~' . ' .

Example 15 . .
Methyl 5-((1-phenyLethyl)carbamoyl)-(R)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr;dine-3-carboxylate (R form) :

O-CH2 ~
(R) /-='\ . :
H3COOC ~ ~ CO-NH-CIH ~ --Melt;ng point: 82C
Example 16 Methyl 5-((3-dimethylaminopropyl)carbamoyL)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate -. --.',~--CH2 ~
~3COO ~ O N 2 3 ~CH3 Melting point: 89 - 90C
Example 17 .
Methyl 5-~cyclohexylcarbamoyL)-4-(2-benzyloxy-phenyl)-1,4- . .
dihydro-2,6-dimethyl-pyridine-3-carboxylate - :
~ -.:~

~o- CH2--O .
H3COOC ~ C~-N

Melting point: 108 - 111C :
~: Le A 25 087 :-. .
' '~

' '' Example 18 , Methyl S-(tert.butylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-d;methyl-pyridine-3-carboxylate ~ - CH2~

H3COOC ~ CO-NH - C - CH3 H3C~N~CH3 CH3 Melting point: 148C
Example 19 Methyl 5-~propylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ' '~0-CH
2 ~
H3COOC ~ CO-NH-CH2-CH2-CH3 H

10~Foam Rf ~ 0.37 Examp:le:20 : ~
-~ Methyl 5~ 2-methyl-propyl)carb:amoyl)-4-(2-benzyloxy-phenyl)-1,4-d;hy~dro-2,6-dimeth~y~l-py~ridin~e-3-carboxylate : H3COOC ~ CO-NH-CN2-CH~CH3)2 H3 ~ N'~CH3 H
Me~lt;ng point: 134C
Le A 25 :087 - ~ :
.

:,~ ' '--:,:

-: ~- ~ :

132~8~9 -, :-Example 21 .
Methyl 5-(N-benzyl-N-tert.butylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ..~.....

H3COOC ~ ~ CO~ CH
H3C N CH3 C(CH3)3 Melt;ng point: 128C
Example 22 Methyl 5-(methylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4- :-dihydro-2,6-dimethyL-pyridine-3-carboxylate ~ ,, .
~- CH2--O
H3COOC~O-NH-CH3 :

H

10 MeLting point: 105C ~:
Example 23 ~;~ Methyl 5-(ethylcarbamoyl)-4-(2-benzyLoxy-phenyL)-1,4- -~
dihydro-2,6-dimethyl-pyrid;ne-3-carboxyLate ~ CH 2{~ '.
~1~ H3COOC~O-NH-CH2-CH3 ~""' H3C N H3 ~ 1 15 MeLting point: 172C :
, Le.A 25 087 . - 31 - :
~-' ,, , ,'.

132~869 Example Z4 Butyl 5-(cyc~opropylcarbamoyl)-1,4-d;hydro-2,6-dimethyl-4-C2-(2-pyridyl)methoxy-phenyl~-pyrid;ne-3-carboxylate ~ 1 2-~ -CH
H9C400C~0-NH~

Foam Rf = 0.1 Example 25 .
8utyl S-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2- :
(2-pyr;dyl)methoxy-phenyl]-pyridine-3-carboxylate ~ 'H2~ ~ ~ -H9~400C~C0-NH-CH3 ~ -H3C ~ CH3 --Foam Rf = 0.07 :~
Example 26 ~utyl 5~ methylpropyl~carbamoyl)-1.4-dihydro-2,6-dimethyl-4-C2-(2-pyridyl)methoxy-phenyl~-pyridine-3-carboxylate ~ ' ' ,'. ' --r -CH2 3 H9C400~0-NH-CI H-CH2-CH3 . .

~ Le A 25 087 : - 32 -:

Foam 1 3 2 8 8 6 9 Rf = 0.25 Example 27 .
MethyL 5-(cyclopropylcarbamoyl)-4-C2-(3,4-dichloro-benzyloxy)-S phenyl]-1,4-d;hydro-2,6-dimethyl-pyridine-3-carboxylate ~0 - CH2~ 1 !i3COOC~O-NH~
~ 3 C N H 3 . .
', . .. .
Melting point: 195C
Example 28 Methyl 5-(cyclopropylcarbamoyl)-4-C2-(2,6-dichloro-benzyL-10~ oxy)phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~-C~2~ ::

H3COO~O-NH~ .
:~ ~3 H3 -- :
'' ' Melting point: 178C
Example 29 MethyL 5-t(1-methyl-propyl)carbamoyl)-4-C2-(2,6-dichloro-benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-; carboxylate Le A 25 087 ; ~ ? ~

Cl ~ - CH
Cl H3COOC ~ ~ CO-NH-IH CH2_CH~

Rf = 0.36 Example 30 Methyl 5-tmethylcarbamoyl)-4-C2-(2,6-dichloro-benzyloxy)-phenyl]-1,4-dihydro-2,6-dimethyL-pyr;dine-3-carboxyLate ~ Cl ~-C~2~
H3COO ~ ~ O-NH-CH3 ~ -H3C H . ; ~ :.

Melting point: 133C -Example 31 Methy~ 5-(me~thyltarbamoyl)-4-C2-(3,4-dichloro-benzyloxy~-phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~; : ~ O-CH2 ~ I -~: ~: : :
H3COOC ~ ~ CO-NH-CH3 .
Melting point: 120C
Le A 25 087 _ 34 _ ~ " ,, ,,,,,, .,,~"" ,, , , ",, ,, j,", , ,,~, , ~,, , ~;~ ", ~," ~ ".,, ~ ".,; - , , "

132~8~9 Example 32 Methyl S-(cyclopropylcarbamoyl)-4-C2-(3-fluoro-benzyloxy)-3-methoxy-phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate . ~ OCH3 F
~0 CH2~ ~ ;
H3COOC~CO-NH~
H3C~N~--CH3 Melting point: Z02C -Examp(e 33 Methyl'S-~cyclopropylcarbamoyl)-4-C2-(2-chloro-benzyloxy)- -phenyl]-1',4-dihydro-2,6-d;methyl-pyridine-3-carboxylate :
"

~ c i , [I ,~o ~ .: :~ - CH2~ , . .
H3C OOC~O - NH <¦

Melting point: 1R5C
Example 34 Methyl 5-~methylcarbamoyl)-4-C2-(2-chloro-benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ .
:
~ 15 ;~
Le A 25 087 ,, .' 13288~9 CH
H3COOC ~ O-NH-CH3 .

~3C H H3 Melting po;nt: 170C
Example 35 Methyl 5-tt2-methyl-propyl)carbamoyl)-4-CZ-(3-fluoro- -~
5 benzyloxy)-3-me~hoxy-phenyl~-1,4-d;hydro-2,6-dimethyl- ~ -pyridine-3-carboxylate :~

: H3COOC ~ Co-NH-cH2-cH(cH3)2 .

3 H 3 :

Melting paint: 98C
Example 36 :-~: 10 Methyl 5-tcyclopropyl~carbamoyl)-1,4-d;hydro-2,6-dimethyl-4-CZ-(3-trifluoromethyl-benzyloxyjphenyl~-pyridine-3- :
carboxylate H3COO ~ O NH ~ ;
;~ H3 M3 ~:-Melting point: 148C :
Le A 25 087 ~ .

: : .

.~ 132886~ -Example 37 Methyl 5-t~1-methyl-propyl)carbamoyL)-1,4-dihydro-2,6-dimethyl-4-t2-(3-trifl~oromethyl-benzyloxy)phenyl~-pyridine-3-carboxylate ~ -C~2 ~
: H3COOC ~ O-~H-CH-CH3 H~C N H3 CH2-CH3 Foam Rf = 0.44 Example 38 Methyl S-~isopropylcarbamoyl)-4-C2-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CH2~
H3COOC ~ O-NH-CH(CH3)2 , ~. ' ~elting point: 106C
Example 39 1-methyl-propyl 5-(cyclopropylcarbamoyl)-1,4-dihydro-2,6-di~ethyl-4-~2-(4-methyl-benzyLoxy)phenyl]-pyridine-3-carboxylate ; Le A 25 087 ~ -:::
: ~ 37 ~

. ' ' ' .

r. ~ . ? ~

~328869 ~ O-CH2 ~ CH3 H3C-HC-OOC ~ O-NH ~ ~
H~C-H2C H3C H H3 -: .

Foam -Rf = 0.31 Example 40 Methyl 5-tcyclopropylcarbamoyl)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr;d;ne-3-carboxylate /--\ ' I - CH2~ ~

¢~
H3tOOC ~ O-NH

Melting point: 197C
-~ ~E~xample 41 ~ -1-methyl-propyl 5-((1-methyl-propyl)carbamoyl)-1,4-d;hydro-2,6-dimethyl~-4-C2-(4-met~hyl-benz~yloxy~phenyl]-pyrid;ne-3-carboxylate .

O-CH2 ~ ~3 ;: H3C-CH-O~OC ~ O-NH-CH-CH3 3C-H2C -H3C N H3 CHz-CH3 Melting po~nt: 126C -Le A 25 087 .
~ - 38 -Example 42 . .
1-methyl-propyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-CZ-(4-methyl-benzyloxy~phenyl]-pyridine-3-carboxyLate ~ ''~
"
~O- CH2~CH3 H3C-CIH-OOC ~ 0-NH-C~3 ~3C-H2c H3C H~

Foam Rf = 0.48 Example 43 Ethyl 5-~cyclopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-~3-nitro-benzyloxy)pheny~]-pyridine-3-carboxylate ~ 1~2 ~ 0-CH
H5C200C~CO-NH~

~:~ H
~ , ''' -Foam Rf = 0.24 Example 44 Methyl 5-(prapylcarbamoyl)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ' ~ Le A 25 087 .

, :

~ .

1328~69 H3COOC ~ 0-NH-CH2-CH2-C~3 H3C H3 - .
H
Melting point: 210C
Example 45 Ethyl 5~ phenyl-ethyl)carbamoyl)-(R)-4-C2-(4-fluoro-S benzyloxy~phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R form) 0-CH2 ~ F
tR~
5C200C ~ C0-NH-CIH ~
H3~A`N CH3 CH3 : :
H ~:

Foam ~ ~
~; Rf - 0~56 ---Example 46 ~ --Methy~ 5-t~2-methyl-propyl)carbamoyl)-4-~4-benzyloxy-phenyl)-1,4-dihydro-2,6-dinethyl-pyridine-3-carboxylate ~; 0-CH2 ~ ~

H3C00 ~ 0-NH-CH2-CH(CH3)2 . - .

3 ~ H H3 Me~ting point: 202C ~-Le A 25 087 :~

.
' '`~ ''" ''i~ ~ ~ ; A ;

Example 47 EthyL 5-(cyclopropylcarbamoyl)-4-~2-(4-fluoro-benzyloxy~-phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ -.
~0- CH2~3F
H5C200C ~ O-NH

H

Melting point: 159C
Example 48 Methyl 5-(cyclopropylcarbamoyl)-4-C2-(4-fluoro-benzyloxy)-phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ -CHz ~ F :~
H3COO ~ O-NH
~` H3C H3 H
:,`~ ~ , , MeLting point: 154C
~-- E~-a~ 9 Methyl 5-(~1-phenylethyl)carbamoyl)-~S)-4-(4-benzyloxy-phenyl~-1,4-dihydro-2,6-di~ethyl-pyridine-3-carboxylate 0-CH2 ~
"
( S ) H3COOC ~ O-NH-CH-CH3 Le A 25 087 ~
- 41 - ~ -132~869 Melting point: 141C
Example S0 Methyl 5-(isopropylcarbamoyl)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate S ~ , "

H3COOC ~ O-NH-CH(CH3)2 H

Melting point: 162C
Example 51 Methyl 5-(t1-phenylethyl)carbamoyl)-(R)-4-t4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate - 10 (R form, diastereomer A) _~ ~h.::

~ ~1 .;.
H 3 C OOC~O - NH - C H~
H ~C N H3 CH 3 Melting point: 196C
Example 52 Methyl 5-(cyclopropylcarbamoyl)-4-l2-~3-chloro-benzyloxy)-phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carbsxylate .

."''', ' ''~:',''.. '' Le A 25 087 -Cl ~0- CH
~3~00 ~ 0-NH-~

Melting point: 174C
Example 53 Methyl 5-(cyclopropylcarbamoyl)-4-t2-t4-fluoro-benzylthio)-phPnyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~5 - CH2{~F
H3COOC ~ CO-NH

Melting point: 202C
ExampLe 54 Methyl 5-((1-phenylethyL)carbamoyl)-(R3-4-(4-benzyLoxy-~` 10 phenyL)-1,4-d;hydro-2,6-dimethyL-pyr;dine-3-carboxylate (R form) (diastereomer 3) ~, , .
CH f~
~: f 2 ~

~I3COOt~O-NH-C~ . "

,~
MeLting point: ZOZC
Le A 25 087 -- - 43 - ~
~' ~' , '': ' ' Example 55 Methyl 5-((1-phenyLethyl)carbamoyl)-(R)-4-(4-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyrid;ne-3-carboxylate (R form, diastereomeric mixture) ~'.

(R) ~
H3COOC~O-NH- IH~>
H3C H3 CH3 :- :

Melting point: 110 - 166C
Example 56 - -Methyl S-((1-phenylethyl)carbamoyl)-(S)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (S form, diastereomer A) : ~ ~O-CH2{~ ;
H3COO~O-NH- I ~ S ~CH3 , " , ~': ~ . ~ ' ' "' Melting point: 172C
Example 57 --5 Methyl 5-(~1-phenylethyl)carbamoyl)-~5)-4-~2-benzyloxy-15phenyL)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~S form, diastereomer 8) --~ " `,.': "
:-Le A 25 087 ~ 44 ~

13288~

~ - CH2--H3COOC ~ CO-NH-fH-CH3 H3C H `3 0 Foam Rf = 0.53 Example 58 .
Methyl S-((1-phenyl-ethyl)carbamoyl)-(R)-4-t2-~4-fluoro-benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3- -carboxylate tR form) ,.' ', O-CH2 ~ F

H3COC ~ O-NH-IH ~
H3C H~ CH3 . ~-Foam ~ 10Rf = 0.52 -j Example 59 ~ ~-`~ Butyl 5-~cyclopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(methyl-benzyloxy)phenyl~-pyridine-3-carboxylate CH2 ~ CH3 C400C ~ CO~NH ~
:~ ~3C~A~N~A~CH3 :

1~ 15 Foam ~:: R~ = 0.31 ~ : .
~ Le A ZS 087 ~ 45 ~

1~ ' .-Example 60 13288~ .
ButyL 5-((1-phenyL-ethyL)carbamoyL)-(R)-1,4-d;hydro-Z,6-dimethyL-4-CZ-(3-methyL-benzyLoxy)-phenyl~-pyr;dine-3-carboxyLate (R form) CH
tR) ~=~
HgC400C~; 3~0-NH-CI H~
H3C H H3 (:H3 Oi~ -R~ = 0.88 Example 61 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-r2-(3-chloro-10 benzyloxy)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3- ;
carboxylate (R form) ,~, C 1 : :
~0 CH2~

H3COOC~O-NH-CH~ . -~: '" `~ . '.
,~ . , .
Foam ~ Rf s 0.73 -~ 15 ExampLe 62 -Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-(3-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxylate (R form) ' , Le A 25 087 . .
' - ' .

1328869 :

/=\
¢~0 - CH2~

1 (R) /~=~\
H3COOC ~ O-NH-~
H3C ~ H3 CH3 Melting point: from 143C
Example 63 Metkyl 5-(cyclopropylcarbamoyl)-4-(3-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ¢;~0 - CH2--O

COOC ~ O-NH
~3C H3 Melting point: 144C
Example 64 Methyl 5-(~1-phenyl-ethyl)carbamoyl)-(R)-4-C2-t4-fluoro- ~ -benzyLthio)phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R for~) ~R) ~5=~
H3COO ~ ~ O-NH-H
Foa~ -Rf = 0.47 ~:: 15 - -' Le A 25 087 ~ ;,,.

~: .

132~869 . Example 65 :
Methyl 5~ phenyl-ethyl)carbamoyl)-(S)-4-C2-(4-fluoro-benzylthio)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (S form) ~
~ S-CH2 ~ F
(S) .
H3COOC ~ ~ O-NH-CH-CH3 H3C H3 ~

Foam - .
Rf = 0.48 `:~.
Example 66 .
Methyl 5-(allylcarbamoyl)-4-~2-(4-fluoro-benzylthio)phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~S - CH2~F ; .

H3COOC ~ O-NH-CH2-CH=CH2 ~;~ Melting point: 177C
Example~67 ~
Methyl 5-(allylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro- -.
2,6-dimethyl-pyridine-3-carboxylate 3COOC ~ Co-NH-cH2-cH=cH2 ~
H3C CH3 ~ .

Melting point: 148C -Le A 25 087 "~

1328~69 Example 68 Methyl 5-~(1-phenyl-ethyl)carbamoyl)-(R~-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (R form) ¢;~0 - CH2--0 ~R) f_~
H 3COOC~Co-NH- I H~;) Melting point: 175C
Example 69 Methyl 5-((1-phenyl-ethyl)carbamoyl)-(R)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~R form, diastereomer ~) ~ , ~R) H3COOC~; ;3~0-NH-CH--O :

~3C H3 CH3 :
Melting point: 169C
Example 70 Methyl 5-((2-phenyl-ethyl)carbamoyl)-4-(2-benzyloxy-phenyl)-151,4-dihydro-2,6-di~ethyL-pyridine-3-carboxyLate ~ ~-¢;~ CH2~

;~ H3coo~o-NH- CH2~ CH2~0 Le A 25 087 Example 71 Methyl 5-(benzylcarbamoyl)-4-(2-ben2yloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~0- H2--0 "

H3cooc~o-NH-cH2--O :

Melting point: 148 -149C .
Example 72 Methyl 5-(ethylcarbamoyl)-4-t2-~4-fluoro-benzylt-hio)phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ :

CH2 ~ F
~ : - .
H3COOC ~ ~ O-NH-CH2-CH3 10 Melt;ng point: 202 - 204C -~ -~ Exa~mple 73 i~: Methyl 5-~ethylcarbamoyl)-4-(3-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate .

H3Coo ~ CO-NH-CH2-cH3 15 Melting point: 152 - 154C ~: -Le Z5 087 : :
5 ~ ~:
' : ~.. ,'-' 1~2886~
Example 74 Methyl S-(ethylcarbamoyl)-~-(4-benzyloxy-phenyl)-1,4-d;hydro-2,6-dimethyl-pyridine-3-carboxylate O CH2~

H3COOC~CO-NH-CH2 -CH3 ~{3C H CH3 Melting point: 183 - 185C
Example 75 Methyl 5-carbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate -CH
H3COOC~O-NH2 Melting po;nt: 188C
`-~ Example 76 ~
Methyl 5-(diethylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4-~; dihydro-2,6-dimethyl-pyridine-3-carboxylate C~2{~
H3COO~O-N ~ C2H5 ) 2 : ':' .
Melting point: 135C
Le A 25 087 , :

13288~9 ~ Example 77 Methyl 5-(cyclopropylcarbamoyl)-1~4-dihydro-2,6-dimethyl-4-CZ-t4-methyl-phenylsulphonyloxy)phenyl~-pyrid;ne-3-carboxylate s ~ 0-502 ~ } CH~

H3COOC ~ O-NH

Xelting point: 238 - 242C
Example 78 Methyl 5-(ethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-~4-methyl-phenylsulphonyloxy)phenyl~-pyridine-3-carboxylate ~-~ '; .' ~ '' ~ -SO2 ~ H3 ~:

%3COOC ~ ~ O-NH-C2H5 -.

Melting point: 228C .
Ex-mple 79 ~ -Methyl S-(ethylcarbamoyl)-4-C2-(2,6-dichloro-benzyloxy)phenyl~
1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate : I Cl -H3COOC ~ O-NH-C~2-c~3 ~3C H3 H
Melting point: 174 - 176C
Le A 25 087 :
''~

Example 80 1328869 Methyl 5-(ethylcarbamoyl)-4-C2-(3,4-dichloro-benzyloxy)-Phenyl]
1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Cl ~O-CH2~: 1 H3t:00C~O-NH-C~2-C~3 H3C H H~

Melting point: 178 - 180C
Example 81 Methyl 5-(ethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(2-pyridylmethyloxy)phenyl~-pyridine-3-carboxylate ~ ~' ,.

H COOC3~0-NH-C2H5 ., , ~
Melting point: 159 - 161C
Example 82 ~ ~ -Meth~yl 5-(cyclopropylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-t2-(2-pyridylmethyloxy)phenyl~-pyridine-3-carboxylate ~o-CH~?
;: H ~COOC~O-NH
~: H3C H H3 ,: . ~'.,' 15 Melting point: 168 - 170C . ::
~ Le A 25 087 .~-i:~ - 53 ~ ;:

132886~
Example 83 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-(2-phenylsulphonyloxy-phenyl)-pyridine-3-carboxylate ~ '~
~ -52 H~COOC ~ O-NH-CH3 Melt;ng point: 171 - 173C :
Example 84 :-. .
Methyl 5-(ethylcarbamoyl)-1,4-dihydro-Z,6-dimethyl-4-(2-phenylsulphonyloxy-phenyl)-pyridine-3-carboxylate H

: ~ -52 H3COOC ~ O-NH-C2H5 : Hj H H3 Melting point: 188 - 190C
-~ Example 85 :
Ethyl 5-(ethylcarbamoyl)-1,4-dihydro-4-~2-~4-fluoro-benzyloxy)phenyl]-2,6-dimethyl-pyridine-3-carboxylate ~ . ~ .
1: ~- CH2~}F
1: H5C200C ~ O-NH-C2H5 ¦- H3C H H3 .
¦ 15 Melting point: 147 - 149C
¦:~ Le A 25 087 : .

1 :-1: .

Example 86 -Methyl 5-(ethylcarbamoyl)-1,4-dihydro-4-~2-(4-fluoro-benzyloxy)phenyl]-2,6-dimethyl-pyridine-3-carboxylate [~o-cH2~F " .
H3COOC~O-NH - C 2H5 Melting point~ 113C
Example 87 Methyl 5-(allylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-~Z-phenylsuLphonyloxy-phenyl)-pyridine-3-carboxylate , ` ~ ~-52-0 H3COOC~o-NH-cH2-cH=cH;2 ~: H

MeLting point: 154 - 156C
Example~ 88 Methyl 5-tt4-pyridyl)carbamoyl)-1,4-dihydro-2,6-dimethyl-4-(2-phenylsulphonyloxy-phenyl)-prridine-3-carboxylate S02~

H3COQC~CO-NH-CHz~N

H :
, ~ :
Melting point: from 240C (decompos;tion) Le A 25 087 -1328~69 : ~ -Example 89 Methyl 5-(allylcarbamoyl)-4-C2-(4-chloro-benzyloxy)phenyl~- :
1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ , ~ O-CH2--<} Cl ~, H3COOC~O-NH-CH2-CH=CH2 - '.
H3C H 3 .

Melting point: 145C
S Example 90 Methyl 5-(allylcarbamoyl)-4-(3-benzyloxy-phenyl)-1,4-dihydro- ~ :
2,6-dimethyl-pyridine-3-carboxylate - -~O-CH2--V ~
~ . , H2C=CH-HzC-NH-OC ~ OOCH3 C H H3 :~-~' . ..
;~ Melting point: 95 - 98C -Example 91 Methyl 5-~allylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-t2- : :
- (4-methyl-phenylsulphonyloxy)phenyl]pyridine-3-carboxylate -~

-52 ~ H3 -H3COOC ~ O-NH-CH2-CH-CH2 : ~ H ~ - ~
~ . . .:
Melting point: 168 - 17:0C : ~:
"' .

~ Le A 25 087 - 56 -,: ~ . .
,', . ' ' :

132~8~9 Example 92 -Methyl S-(allylcarbamoyl)-4-C2-~2,6-dichloro-benzyloxy)phenyl~- -1,4-d;hydro-2,6-dimethyl-pyridine-3-carboxylate ~O-CH
Cl H2C=HC -H2C-HN-OC~ ~COOCH3 H3C~N~CH3 Melting point: 132 - 134C
Example 93 Methyl 5-((2-hydroxyethyl)carbamoyl)-4-~2 benzyloxy-phenyl)-1,4-d;hydro-2,6-d;methyL-pyridine-3-carboxylate ¢~0 CH2--H3cooc~co-NH-cH2-cH2-~)H
11 11 .,.
H3~:~N~CH3 , 10 Melting point: 148 - 1SDC ~-~
Example 94 Methyl S-(methylcarb~moyl)-4-t2-(3-fluoro-benzyloxy)-3-methoxy-phenyl~-1,4-d;hydro-2,6-dimethyl-pyridine-3- -carboxylate ~OCH3 F -CH2~ ~ :
H3COOC~O-NH-CH3 ~' H3C H3 -.

~ ~ .,:.
Le A 25 087 - -~ 57 ~ ~

.

" " ~ - " , ,~ ;' ,~ ,,-, ~ , : ~ , ,. ., .,.

~328869 Melting point: 171 - 173C
, .... .
Example 95 Methyl 5-(2-(4-pyridyl)ethylcarbamoyl)-4-(2-benzy~oxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate S
~ -CH~ ~

H3COOC ~ ~ CO-NH-CH2-cH2 ~ N
1 11. .
H3C~ ~N ~ CH3 H
Melting po;nt:
Example 96 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(3-pyridyl)methoxy-phenyl]-pyridine-3-carboxylate , . . .
~ ~ , ' : . ~ O-CH2 ~ ::
H3COOC ~ o-NH-CH3 ` : ''' ~", ~: 10 Melting po;nt: from 210C
Example 97 :
~ Methyl 5-(ethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-;~:~ (3-pyridyl)methoxy-phenyl]-pyridine-3-carboxylate -' . ' N
H3COOC~O-NH-C2H5 '~

~ . ` :, Melting point: 122 - 125C
Le A 25 087 ,~

, Example 98 Methyl 5-(ethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(4-pyridyl)methoxy-phenyl~-pyrid;ne-3-carboxylate ~0- CH2--CN
H3COOC~o-NH- C2H5 Melting point: 95 - 100C
Example 99 Methyl 5-(methylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-C2-(4-pyridyl)methoxy-phenyl]-pyridine-3-carboxylate ~ -~O - CH 2~N
H3cooc~o-NH-cH3 , ~ "
H3C~N H3 :: ' 10 Melting point: from 203C (decomposition) Example 100 Methyl 5~((cyclopropylmethyl)-carbamoyl)-4-(2-benzyLoxy- --phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ¦~ ~ CH2--O
H3COOC ~ CO-NH-CH
H3Cf~N~CH3 H : ~:

!~ 15 Melting point: 186C
~ Le A 25 08?
3~ ~ 59 ~
~ , ' Example 101 1328869 MethyL 5-(ethylcarbamoy~ )-4-(Z-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethy~-pyridine-3-carboxylate ¢~ - CH2--0 ' H3COOC ~ O-N~-CH2^CH3 . .

~3C H H3 :

Melting point: 147C
C~D20 = ~ 29.68 c = 0~91 (DMF) Example 102 10 Methyl 5-tethylcarbamoyl)-~-)-4-~2-benzyloxy-phenyl)-1,4-~' dihydro-2,6-dimethyl-pyridine-3-carboxylate CH2'~
~ . .
: H3COO ~ ~ O-NH-CHz-CH3 Melting point: 148C
~D20 = _ 29.92 c s 0.805 tDMF~ -Exa~ple 103 Ethyl 5-~methylcarbamoyl)-4-~2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr;dine-3-carboxylate Le A 25 087 ~ .

1328~

~ -CH
H5C200C~o-NH-cH3 ~3C H H3 Melt;ng point: 179C
Example 104 .
Ethyl 5-(ethy~carbamoy~)-4-(2-benzyloxy-phenyl)-1,4-d;hydro-2,6-dimethyl-pyrid;ne-3-carboxylate ' ~
' ', 5C2QOC~O-NH-C2H5 H3C N H3 ~ :

. ''-. ': .
Melting point: 161 - 164C
Example 105 Methyl 5-~2-ethoxycarbonylethyl)carbamoyl)-4-(2-benzyloxy-;~ 10 phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ` ~ O-CH

H3COOC ~ O-NH-(cH2)2-cooc2H5 ~ H3C H H3 ,~
Rf ~ 0.35 Le A Z5 087 Example 106 MethyL 5-~(ethoxycarbonylmethyL)carbamoyl)-4-~2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyr;dine-3-carboxylate H3COOC~o-NH-cH2-cooc2Hs S Rf = 0.408 Example 107 .
Methyl 5-~octylcarbamoyl)-4-t2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxyLate ' , ~1 . '- ~ ~
~O - CH2~
H3COO~O~ CH2 ) 7 - CH3 , Rf = 0.53 ~
Example 108 ~:~ - Methyl 5-(nonylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4--~ dihydro-2,6-dimethyl-pyridine-3-carboxylate ~O-CH2--0 H3COOC~O-NH- ~ CH2 ~ 8-CH3 H
'~
Rf = 0.55 ~: Le A 25 087 - 62 - ~ .
'' 1328~69 Example 109 MethyL 5-(decylcarbamoyl)-4-(2-benzyloxy-phenyl)-1,4- .
dihydro-2,6-dimethyl-pyridine-3-carboxylate ~- CH2--O
H3COOC ~ O NH ~CH2)9 CH3 MeLting point: 111C
Example 110 Methyl 5-((2-methoxy-ethyl)carbamoyl)-4-(Z-benzyloxy-Phenyl) 1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate H3COOC ~ O-NH-CH2-CH2-0CH3 Melting point: 145C
~ , Example 111 .~:
Methyl 5-((3-methoxy-propyl)carbamoyl)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyL-pyridine-3-carboxy~ate H3COOC ~ O-NH-(CH2)~-OCH3 15 Rf = 0.19 :~
- Le A 25 087 , , .
~ ` ''' .,; .. .,-1~28869 Example 112 Methyl 5-((2-hydroxy-1-methyl-2-phenyl~ethylcarbamoyl)-(R,R)-4-~2-benzyloxy-phenyl)-1,4-dihydro-2,6-d;methyl-pyridine-3-carboxylate S .' CH3 ~
H3COOC~ ~CO-NH-Cil CH-OH
( R ) ~ R ) H3C~N--H
Process variant H (direct coupling with dicyclohexyl-carbodiimide) 1 9 (2.54 mmoL) of monomethyl 4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate 10 are dissoLved in 5 ml of dimethylformamide, and 0.477 ~ ~
(2.54 mmol) of L-norpseudoephedrin hydrochloride, 0.35 ml t2.54 mmol) of triethylamine and 0.629 9 (3.05 mmol) of dicyclohexyl-carbodiimide ~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 CHCl3/CH30H/NH3 20 : 1 : 0.05 Since urea is only sparingly soluble in ether and ~ethylene chloride, the product is taken up several times ~; in ether or methylene chloride, filtered off and evaporated.
Yield: 0.9 9 (67.3% of theory) Rf = 0.35 C~ D20 _ 47.93 (CHCl3) .~ .
~ Le A 25 û87 - 64 -. -'.
. '.

` ' ' ' ' ' . . . ... ' ' . ' . . ' . " '.. ' . " ' " .:' ~: ': ,.:. ' .' ' ' .. ' '.' :

1~288~
Example 113 Methyl 5-((2-hydroxy-1-methyl-ethyL)carbamoyl)-(S)-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6 dimethyl-pyr;dine-3-carboxylate [~0 CH2--' (S) ''.
H3COOC ~ ~ CO-NH-CH-CH20H . :
H3C CH3 CH3 . .

Rf = 0.13 ~~ D20 ~7.34 (CHCl3) Example 114 MethyL 5-((1-hydroxy-methyl-propyl)carbamoyl)-(S~-4-~2-benzyloxy-phenyl)-1,4-dihydro-2,6-d;methyl-pyridine-3-carboxylate CH
: _ I C12H5 H3COOC ~ CO-NH-CH-CH20H
: H~C~N~CH3 H
Rf = 0.15 _9.3? (CHCL3) 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 - Le A 25 0~7 -~
. .
~ 65 '-`,..

~32886~ ~
': . ' ~0 - CH2--O ' (s) , H3C9OC ~ ~ CO-NH-CH-CH2-OH

H H3C ~ ~ CH3 Rf = 0.19 C~ 20: -10.8 (CHCL3) Example 116 S Methyl 5-t~1-hydroxy-methyl-2-methyl-butyl)carbamoyl)-tS)-4-~2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate CH ~ ~
S ) H3COO ~ ~ O-NH-CIH-CH2-OH

H3C H3C i ~ ~2H5 ~ ~ .

L~ Z3; -17.37 (CHCl3 Example i17 ;~ Me~th~yL 5-tt3-hydroxy-propylScarbamoyL)-4-t2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate Le~A 25 087 :

~'^~v-CH~-~ >
H3COOC CO-N~-(CHz~3-~H
H3C~N~CH3 Melting point: 205C
xample 118 Methyl 5-t3-cyclopropylcarba~oyl)-(-) 4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ CH2 H3COOC ~ O-NH ~ ~
H3C H3 . .
- ~:
Melting point: 178 - lB1C
C~209=-38.28 (c=0.569, chloroform) ~-;
Example 119 -~ -;~ 10 Methyl 5-(3-cyclopropylcarba~oyl)-(~) 4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate -CH
- ~COOC ~ O-NH
H3cfA~N H3 :~

Melting point: 178 - 181C
ta~2589= +36.56 (c=0.52, chloroform) ~-~
Le A 25 087 - 67 '' ` ' ' 132886~
Exa~ple 120 -Methyl 5-hexylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate f ~ 2 -CH
H3COO ~ O-NH-(C~2? 5-CH3 5 Melting point 133C
Example 121 - -~
Methyl 5-carbamoyl-4-C2-(4-methyl-benzenesulphonyloxy)-phenyl]-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate .~: f~
~ S2 ~ ~'H3 -~ H~COOC ~ CO-NH2 ~; 10 Melting point: 205C ~
Example 1ZZ
~, Methyl 5-sec.-butylcarbamoyl-4-~2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-2-carboxylate . ~5eC~
H3COO ~ CO-NH-CH-CH3 H3C ~ ~ H3 CHz C~3 Melting point: 135C
Le A 25 087 .
~ - 68 -~ .~ .

Example 123 Isopropyl 5-carbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~ O-CH~-~' `j :

H3C~ ~

CHOOC ~ ~CO-NH2 ..

H3C~ ll Il, :
~l3C~1,~CH3 ,' ' . ' 5 Melting point: 190C -Example 124 -:
2-Methoxy-ethyl 5-carbamoyl-4-(2-benzyLoxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-5-carboxylate ' "' ' 3C-O-H2C-H2C-00 ~ -NH2 ~ ~
3 ~ 3 - ~ :

10 Melting point: 165C . ~:~
Example 125 ,~ Methyl 5-butylcarbamoyl-4-~2-benzyloxy-phenyl)-1,4-dihydro- :~
2,6-dimethyl-pyridine-3-carboxylate ~- -~ -CHz ~ ..

¦~: H3COO ~ O-NH-(CH2)3-CH3 ;~: H3C H3 ~
f . H ~.:~ .-~:~ Le A 25 087 .. --,~ 69 : .

Melt;ng po;nt: 144 - 148C 132886~
Example 126 Isopropyl 5-ethylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-d;hydro-2,6-dimethyl-pyridine-3-carboxylate f~
H3C~ `r -CH2--O
CH-OOC~O-NH-C2H5 Melting point: 135C
Example t27 Methyl 5-(3-ethoxypropyl)carbamoyl-4-t2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate f~o CH2~
H3COOC--C`O-NH- ( Clt2 ~ 3--C2~5 H:3C~N H3 Melting point: 115C
Example 128 ~: .
Methyl 5-(5-hydroxypentyl)carbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate H3COOC ~ O-NH- ( CH2 ) 5 OH

Le A 25 087 ' . .

Melt;ng po;nt: 178C
Example 129 2-Methoxy-ethyl 5-methylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-d;hydro-2,6-dimethyl-pyridine-3-carboxylate I CHZ~
H3C-O-H2C-HzC-OOC~CO-NH-CH3 ' ' H3C~N~--CH3 Melting point: 133 - 135C
Example 130 2-Methoxy-ethyl 5-ethylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-Z,6-dimethyl-pyridine-3-carboxy~ate ~_C~2~ ,'~
H3C O H2C HzC-OO ~ CO-NH-C2H5 , ~ - " '.'' , .
~` ' ' ':
Melting point: 111C `-Example 131 Isopropyl 5-methylcarbamoyl-4-t2-benzyloxy-phenyl~-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate H3C~ I CH2-~
I CH-OOC ~ CO-NH-CH3 H3C~
H3C~A~N ~ CH3 Le A 25 087 . .

1 328~9 Melt;ng point: 140 - 143C
Example 132 Isopropyl 5-cyclopropylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ~-CH2 7 113C~ --~_ C~l-UOC~ CO-NH~
~3C~

H3C~ ~N ~ CH3 ~' ' -' '' Melting point: 13Z - 135C
E~ample 133 Isopropyl 5-isopropylcarbamoyl-4-(2-benzyloxy-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate ` f~

~) - CH; ~
H3C~ ¦ ~CH3 H C~ 1 ,~CO NH C~CH
~: H3 H : -, ' `
Melting point: from 110C

1 ~
', '''.
¦ L2 A 25 087 -: :
I;: - 72 -1 ..
I, .

Claims (11)

1. Dihydropyridinamide of the general formula (I) (I) in which R? and R8 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms, each of which is optionally substituted by phenyl, R2 represents a straight-chain or branched, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms which may be interrupted in the chain by an oxygen atom and which may be substituted by fluorine, chlorine, cyano, hydroxyl or by a phenyl group or by .alpha.-, .beta.- or .gamma.-pyridyl, R3 and R4 are identical or different and in each case represent hydrogen, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, nitro or trifluoromethyl, R5 represents a group of the formula -O-(CH2)n-R11, -S-(CH2)n-R11, -O-SO2-R11 or -O-CO-(CH2)n-R11, in which n denotes 0 to 3, and R11 denotes phenyl which may be monosubstituted, disubstituted or trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 4 carbon atoms in each alkyl group, acetylamino or denotes pyridyl, and R6 and R7 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, hydroxyl, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, carboxyl, alkoxycarbonyl having up to 6 carbon atoms, by phenyl, or by a group of the formula -NR9R10, in which R9 and R10 are identical or different and in each case denote hydrogen, alkyl having up to 6 carbon atoms, benzyl, phenyl or acetyl, or R6 and R7 in each case represent phenyl which may be monosubstituted, disubstituted or trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, alkylamino having up to 6 carbon atoms, dialkylamino having up to 6 carbon atoms in each alkyl group, acetylamino and benzoylamino, or represent pyridyl, and the physiologically acceptable salts thereof.

2. Compounds of the general formula (I) according to claim 1, in which R11 denotes phenyl which may be monosubstituted, disubstituted or trisubstituted by identical substituents selected from the group consisting of fluorine, chlorine, nitro, trifluoro-methyl, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms and R6 and R7 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, hydroxyl, alkoxy having up to 6 carbon atoms, carboxyl, alkoxycarbonyl having up to 6 carbon atoms, by phenyl or by a group of the formula -NR9R10, in which R9 and R10 are identical or different and in each case denote hydrogen, alkyl having up to 6 carbon atoms, benzyl, phenyl or acetyl, or R6 and R7 in each case represent phenyl which may be monosubstituted, disubstituted or trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, trifluoromethyl, amino, acetylamino or by benzoylamino, or represent pyridyl, and the physiologically acceptable salts thereof.

3. Compounds of the general formula (I) according to claim 1, in which R1 and R8 are identical or different and in each case represent methyl, ethyl or benzyl, R2 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 or may be substituted by fluorine, chlorine, cyano, hydroxyl, phenyl, .alpha.-, .beta.-or -pyridyl, R3 and R4 are identical or different and in each case represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, nitro or trifluoromethyl, R5 represents a group of the formula -O-CH2-R11, -S-CH2-R11 or -O-SO2-R11 in which R11 denotes phenyl which may be monosubstituted or disubstituted by fluorine, chlorine, nitro, trifluoromethyl, methyl, methoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino or acetylamino, the substituents being identical or different, or denotes an .alpha.-, .beta.- or a -pyridyl group, R6 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, carboxyl, alkoxycarbonyl having up to 4 carbon atoms, phenyl or a group of the formula -NR9R10, in which R9 and R10 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, alkylamino 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 .alpha.-, .beta.- or .gamma.-pyridyl, and the physiolog-ically acceptable salts thereof.

4. Methyl 5-(cyclopropylcarbamoyl)-4-(2-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate in racemic form or in the form of an enantiomer or a physiologically acceptable salt thereof.

5. A process for the preparation of a dihydropyridinamide of the general formula (I) (I) in which R1 and R8 are identical or different and in each case represent straight-chain or branched alkyl having up to 4 carbon atoms, each of which is optionally substituted by phenyl, R2 represents a straight-chain or branched, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms which may be interrupted in the chain by an oxygen atom and which may be substituted by fluorine, chlorine, cyano, hydroxyl, a phenyl group or by .alpha.-, .beta.- or .gamma.-pyridyl, R3 and R4 are identical or different and in each rase represent hydrogen, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, nitro or trifluoromethyl, R5 represents a group of the formula -O-(CH2)n-R11, -S-(CH2)n-R11, -O-SO2-R11 or -O-CO-(CH2)n-R11, in which n denotes 0 to 3, and R11 denotes phenyl which may be monosubstituted, disubstituted or trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, amino, alkyl-amino having up to 4 carbon atoms, dialkylamino having up to 4 carbon atoms in each alkyl group, acetylamino or denotes pyridyl, and R6 and R7 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, hydroxyl, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, carboxyl, alkoxycarbonyl having up to

6 carbon atoms, by phenyl, or by a group of the formula -NR9R10, in which R9 and R10 are identical or different and in each case denote hydrogen, alkyl having up to 6 carbon atoms, benzyl, phenyl or acetyl, or R6 and R7 in each case represent phenyl which may be monosubstituted, disubstituted or trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, trifluoromethyl, trifluoro-methoxy, amino, alkylamino having up to 6 carbon atoms, dialkyl-amino having up to 6 carbon atoms in each alkyl group, acetylamino or by benzoylamino, or represents pyridyl, or a physiologically acceptable salt thereof, characterized in that [A] an aldehyde of the general formula (II) (II) in which R3, R4 and R5 have the abovementioned meanings, and a .beta.-ketocarhoxylate of the general formula (III) (III) in which R1 and R2 have the abovementioned meanings, are reacted with a .beta.-ketocarboxamide of the general formula (IV) (IV) in which R6, R7 and R8 have the abovementioned meanings, and ammonia, or in that [B] an aldehyde of the general formula (II) is reacted with a .beta.-ketocarboxylate of the general formula (III) above and an enaminocarboxamide of the general formula (V) (V) in which R6, R7 and R8 have the abovementioned meanings, or in that [C] an aldehyde of the general formula (II) is reacted with a .beta.-ketocarboxamide of the general formula (IV) and an enamino-carboxylate of the general formula (VI) (VI) in which R1 and R2 have the abovementioned meanings, or in that [D] a .beta.-ketocarboxylate of the general formula (III) is reacted with ammonia and an ylidene-.beta.-ketocarboxamide of the general formula (VII) (VII) in which R3 to R8 have the abovementioned meanings, [E] a .beta.-ketocarboxamide of the general formula (IV) is reacted with ammonia and an ylidene-.beta.-ketocarboxylate of the general formula (VIII) (VIII) in which R1 to R5 have the abovementioned meanings, or in that [F] an ylidene-.beta.-ketocarboxamide of the general formula (VII) defined above is reacted with an enaminocarboxylate of the general formula (VI), or in that [G] an ylidene-.beta.-ketocarboxylate of the general formula (VIII) defined above is reacted with an enaminocarboxamide of the general formula (V), or in that [H] a dihydropyridinemonocarboxylic acid of the general formula (IX) (IX) in whlch R1 to R5 and R8 have the abovementioned meanings, or a reactive acyl derivative thereof, is reacted with an amine of the general formula (X) (X) in which R6 and R7 have the abovementioned meanings, and, if required, converting an obtained compound of formula (I) into a physiologically acceptable salt thereof.

6. A process according to claim 5 wherein one of process variants [A] to [G] is used, the reaction is carried out in water or an inert solvent selected from alcohols, ethers, amides, glacial acetic acid, dimethyl sulphoxide, acetonitrile and pyridine, and the reaction is carried out at a temperature between 10 and 150°C.

7. A compound of the general formula (I) according to any one of claims 1 to 4, or a physiologically acceptable salt thereof for use in combating circulation disorders.

8. A medicament containing a compound of the general formula (I) according to any one of claims 1 to 4, or a physiolog-ically acceptable salt thereof, together with a suitable diluent or carrier.

9. A process for the production of a medicament, characterized in that a compound of the general formula (I) according to any one of claims 1 to 4 or a physiologically acceptable salt thereof, is admixed with suitable auxiliaries and excipients.

10. Use of a compound of the general formula (I) according to any one of claims 1 to 4, or a physiologically acceptable salt thereof, for combating cardiocirculation disorders and disorders of the electrolyte and liquid balance.

11. A commercial package containing as active pharmaceutical ingredient a compound of the general formula (I) according to any one of claims 1 to 4, or a physiologically acceptable salt thereof, together with instructions for the use thereof in combating circulation disorders and disorders of the electrolyte and liquid balance.