CA1291137C - 1,4-dihydropyridines with diphenylpiperidylester group - Google Patents
1,4-dihydropyridines with diphenylpiperidylester groupInfo
- Publication number
- CA1291137C CA1291137C CA000491694A CA491694A CA1291137C CA 1291137 C CA1291137 C CA 1291137C CA 000491694 A CA000491694 A CA 000491694A CA 491694 A CA491694 A CA 491694A CA 1291137 C CA1291137 C CA 1291137C
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- denotes
- diphenylpiperid
- dihydro
- dimethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
Abstract New diaryl compounds of the general formula I, (I)
Description
~e~ l c o ~,~Ft~
Field of application_of the invention The invention relates to new diaryl compounds, pro-cesses for their preparation, their use and medicaments -5 containing them. The compounds according to the invention are employed in the pharmaceutical industry for the prepara-tion of medicaments.
Kno~n technical background _ It is known that certain 1,4-dihydropyridine deriva-tives subs~ituted in various ways have pharmacologically useful properties. European Patent Applications 88,903, 94,159 and 106,276 may be mentioned as examples. Surpris-ingly,`it has now been found that the new compounds des-cribed in more detail below, which, in contrast to the com-pounds of the prior art~ carry a piperidine ring which is disubstituted in the 4-position, have particularly interest-ing pharmacological properties by which they differ advan-tageously from the compounds of the prior art.
Description of the invention The invention relates to ne~ diaryl compounds of the formula I
R6 ~ R7 2) ~ ~Rl ~ 9 wherein Ar represents a ring of the formula - z ~
R~
/~
Y ~R5 \//~
;n ~hich Y denotes oxygen (0)~ sulphur (S), vinylene (-CH=CH-), azometh;ne (-CH=N-) or a group of ~he formula / N ~ ~ / N
o I or S
N ~ N ~
R1, R2 and R3 are identical or different and denote hydrogen, C1-C6-alkyl, C3-C7-alkoxyalkyl, aryl~ aryl-C1-C6-alkyl or aryloxy-C1-c6-alkyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, n;tro, cyano, tr;fluoromethyl, ~1-C4-alkyl~ C1-C4-alkoxy, C1-C4-alkoxy wh;ch is completely or partlj substituted by fluor;ne, C1-C4-alkoxycarbonyl, C2-C5-acyL, amino or mono- or di-C1-C4-alkylamino, R6, R7, R8 and R~ are identical or different and denote hydrogen, hydroxyl, halogen, C1-C4-alkyl, C1-C4-alkoxy, amino, mono- or di-C1-C4-alkylamino, or C1-C4-alkoxy ~hich is completely or partly sub-stituted by fluorine, and A denotes straight-chain or branched C2-C5-alkylene, which can be substituted by C1-c4-alkoxy or aryl, and their salts.
C1-c~6-Alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or, in par-ticular, ethyl or methyl radical.
C3-C7-Alkoxy represents, for example, a methoxyethyl, sthoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxy-propyl, 2-methoxy-1-methylethyl or 2-ethoxy-1-methylethyl radical.
Aryl ~e~7W~ represents phenyl or substituted phenyl with one or two substituents from the group compris-;ng halogen, hydroxyl, nitro, cyano~ trifluoromethyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C2-C5-acyl, amino and mono- or di-C1-C4-alkylamino.
Aryl-C1~C6-alkyl is C1-C6-alkyl which ;s sub-stituted by aryl. Aryl-C1-C6-alkYl is, for example, phen-ethyl, 3-(4-chlorophenyl)-propyl or, in particular, benzyl.
Aryloxy-C1-C6-alkyl is C1-C6-alkyl which is substituted by aryloxy. Aryloxy-c1-c6-alkyl is, for example, phenoxyethyl.
Halogen denotes bromine and, in particular, fluorine and chlorine.
C1-c4-Alkyl is straight-chain or branched and denotes, for example, a butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl or, in particular, methyl radical.
In addition to the oxygen atom, C1-C4-alkoxy con-tains one of the abovementioned C1-C4-alkyl radicals.
The methoxy radical is preferred.
C1-C4-Alkoxy which is completely or partly sub-stituted by fluorine is, for example, 1,1,2,2-tetrafluoro-ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoro-methoxy.
In addition to the carbonyl group, C1-C4-alkoxy-carbonyl contains one of the abovement;oned C1-C4-alkoxy radicals~ The methoxycarbonyl and ethoxycarbonyl radical are preferred.
In addition to the carbonyl group, C2-Cs-acyl 4~
contains one of the abovement;oned C1-C4-alkyl radicals.
The acetyl rad;cal is preferred.
In add;tion to the nitrogen atom, mono- or d;-C1-C4-alkylam;no contains one or two of the abovement;oned C1-C4-alkyl rad;cals. D;-C1-C~-alkylam;no ;s preferred, and especially dimethyl-, diethyl- or d;;sopropyl-am;no.
Straight-cha;n or branched C2-C5-alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 1,1-dimethylethylene, 2~2-dime~hylethylene, isopropyl;dene, 1-1û methylethylene, 2-ethylpropylene or, in particu~ar, ethylene or propylene.
C2-C5-Alkylene which is subst;tuted by C1-C4-alkoxy is, for example, 1-methoxy-propylene, 2-ethoxy-propylene or 1,2-dimethoxyethylene.
C2-C5-Alkylene which is substituted by aryl is, for example, 1-phenylethylene or 2-(4-chlorophenyl)-propyl-ene.
Possible salts are all salts with acids. The pharmacologically acceptable salts of the inorganic and 2û organic acids usually employed in the pharmaceutical indus-try may be mentioned i~ particular. Pharmacologically un-acceptable salts ~hich may be obtained, for example~ as pro-cess products when the compounds according to the invention are prepared on an ;ndustrial scale are converted into pharmacologically acceptable salts by processes which are known to the expert. Examples of suitable salts of this type are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosyl-ate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesylateO and also sal~s wi~h bume~anideO furos~mide, azo-sem;de, galosemide, besun;de, piretan;de, etacrynic acid, tienilic acid or 4-chloro-sulphamoyl-benzoic acid.
Radicals Ar which are to be singled out are the phenyl, 3-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-d;chlorophenyl, 2-cyanophenyl, 3-cyano-phenyl, 2-methoxyphenyl, 3~methoxyphenyl, 2-trifluorome~hyl-phenyl, 3-trifluoromethylphenyl, 3-(1,1,2,2-te~rafluoro-ethoxy)-phenyl, 2-difluorome~hoxyphenyl, 3-di~luoromethoxy~
phenyl, 2-tolyL~ 3-tolyl, 4 tolyl, 2-pyridyl, 3-pyridyl, 2,1,3-benzoxdiazol-4-yl, S-methyl-2-thienyl and, ln part~cular, 2-nitrophenyl and 3-nitrophenyl radical.
Embodiments of the invention and preferred and par-ticularly preferred embodiments are given in the claims~
Examples ~hich may be mentioned of compounds accord-ing to the invention are:
3-ethyl S-C2 (4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-~2-methoxyethyl) 5-t3-~4,~-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-~-(3-nitrophenyl)-pyridine-3,5-dicarboxy-late, 3-methyl S-C4~t4,4-diphenylpiperid-1-yl)-butyl~ 1,4-d;hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-~2-nitrophenyl~-pyridine-3,5-dicarbo%ylate, 3-methyl 5-C2-~4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6 diethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-tprop-2-yl) S-C2-(4,4-diphenylpiperid-1-yl)-ethyl~ 1,4-di-hydro-2,6-dimethyl-4-~3-nitrophenyl)-pyridine-3,5 dicarboxyl-ate,3-hexyl 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-(2-n-butoxye$hyl) 5-[2-~,4-diphenylpiperld-1-yl)-ethyl~
dihydro-2,6-dlmethyl~ 3-nitrophenyl)-pyridine-3,5-dicarb-oxylate, 3~' -- 6 --3-methyl 5-{2-C4,4-di(4-methoxyphenyl) piperid-1-yl]-ethyl~
1,4-d;hydro-2,6-dimethyl-4-(3-n;trophenyl)-pyridine-3,5-dicarboxylate, 3-ethyl 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro~
2,6-d;methyl-4-('-tr;~luoromethylphenyl)-pyr;dine-3,5-d;-carboxylate, 3-methyl 5-l2-l~,4-d1phenylpip~r~d-1-yl)-~thyl~ -d~hydro-2,~-dimethyl-~ (1,1,2t2-tetrafluoroethoxy)-ph~nyl~-pyridine-3,5-d~carboxylate, 3-ethyl S-C2-(4,4-d;phenylp;per;d-1-yl)-ethyl~ 1,4-dihydro-2,6-d;methyl-4-t2-d;fluoromethoxyphenyl)-pyr;d;ne-3,5-d;-carboxylate, 3-ethyl 5-~4-(4,4-diphenylp;perid-1-yl~-butyl~ 1,4-d;hydro-2,6-d;methyl-4-(2-d;fluoromethoxyphenyl)-pyr;d;ne-3,5-d;-carboxylate,3-methyl 5-C2-(4,4-dihydroxyphenylp;per;d-1-yl)-ethyl] 1,4-d;hydro-2,6-dimethyl-4-(3-n;trophenylj-pyr;d;ne~3,5-di-carboxylate, 3-methyl 5-~2-(4~4-d;phenylp;perid-1-yl)-ethyl~ 4-(2,3-di-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5 dicar-boxylate, 3-methyl 5-C2-~4,4-d;phenylp;per;d-1-yl)-ethyl] 4-(2,1,3-benzoxdia20l-~-yl)-1,~-dihYdro-2,6-dimethylpyridine-3,5-d~carboxylate`, 3-methyl 5-C2-~4,4-d;phenylpiperid-1-yl)-ethyl] 4-(3-cyano-phenyl) 1,4-dlhydro-2,6-dimethylpyr;d;ne-3,5-d;carboxylate, 3-methyl S-C2-(4,4-d;phenylp;perid-1-yl)-ethyl~ 1,4-d;hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-C2-(4,4-diphenylpiperid-1-yl)-ethyl~ 1,4-dihydro-2,6-dimethyl-4-(2-pyr;dyl)-pyr;d;ne-3,5-d;carboxylate, 3-methyl S-C2-(4,4-d;phenylp;perid-1-yl)-ethyl] 1,4 dihydro-2,6~d;methyl-4-(5-methyl-2-th;enyl)-pyr;dine-3,5-dicarboxy-late, 3-methyl 5-~2-C4-(4-chlorophenyl)-4-phenylpiperid-1-yl]-ethyl3 1,4-d;hydro-2,6-dimethyl-4-(3-n;trophenyl) pyr;dine-3,5-dicarboxylate, 3-methyl 5-C3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-d;-hydro-2,6-d;methyl 4-(2-n;trophenyl)-pyrid;ne-3,5-dicar-boxylate, 3-methyl 5-~3-~4,4-diphenylpiperid-1-yl)-propyl] 1,4-d;-hydro 2,6-diethyl-4-(3-n;trophenyl)-pyr;d;ne-3,5-dicar~
boxylate, 3-~prop-~-yl) 5-C3-(4,4-diphenylp;perid-1-yl)-propyl~ 1,4-dihydro-2,6-dimethyl 4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-hexyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)~pyridine-3,5-dicarboxylate, 3-(2-n-butoxysthyl) 5-~3-t~ diphenylpiperid-1-y1)-propyl~
1,~-dlhydro-2,6-dimethyl-~-(3-nitrophony1)-piperidino-3,5-dicarboxylate, 3-methyl 5-{3-C4~4-di(4-methoxyphenyl)-piperid-1-yl]-propyl3 1,4-dihydro~2,6-dimethyl~4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,3-ethyl S-C3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4 dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-di-carboxylate, 3-methyl 5-l3-l~,~-diPhenylpiPerid-1-Yl)-propYl~ -dihydro-2,6-dim~thyl-4-t3-(1,~,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate 3-ethyl S-C3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4-dihydro-2,6-dimethyl-4-(2-difluoromethoxyphenyl?-pyridine-3,5-d;
carboxylate, 3-methyL S-C3-t4,4-dihydroxyphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6~dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxyla~e, 3-methyl 5-C3-~4,4-diphenylpiperid-1-yl)-propyl] 4-t2,3-di-chlorophenyl)-1,4-dihydro-2,6 dimethylpyridine-3,5-dicar-boxylate,3-methyL 5-C3-(4,4-diphenylpiperid-1-yl)-propyl] 4-~2,1,3-benzoxdiazol-~-yl)-1,4-dihydro-2,6-dimothylpyridine-3,5-dicarboxylate, 3-methyl 5-C3~(4,4-diphenylpiperid-1-yl)-propyl~ 4-(3-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5~dicarboxylate, 3-methyl 5-C3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4-di-hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridine-3,5-di-carboxylate, ~9~
3-methyl S-C3-t4,4-diphenylpiperid-1-yl?-propyl~ 1,4-di-hydro 2,6-dimethyl-4-t2-pyridyl)-pyridine-3,5-dicarboxylate, 3-methyl S-C3-(4,4-diphenylp;perid-1-yl)-propyl~ 1,4-di-hydro-2,6-dimethyl-4-tS-methyl-2-thienyl)-pyridine-3,5-dicarboxylate, and 3-methyl 5-~3-C4-t4-chlorophenyl)-4-phenylpiper;d 1-yl~-propyl3 1,4-d;hydro-2,6-dimethyl-4-t3-nitrophenyL)-pyr;dine-3,5-dicarboxylate, and their salts.
_ 9 _ The compounds of the formula I have a chirality centre at the 4-pos;tion ;n the 1,4-dihydropyr;dine~ The invention therefore includes both ~he enant;omers and, if a further ch;rality centre ;s present, the diastereomers, and mixtures and racemates thereof~
The invent;on furthermore relates to a process for the preparation of the compounds according to the invention and their salts. The process is characterised in that a) cinnamic acid derivatives of the formula II
Ar R300c~ H ~II) R 2J~ o are reacted ~ith enamine derivatives of the formula III
R6 ~ R7 )(C--~
or b) cinnamic acid derivatives of the formula II are reacted with ammonia and~ -ketocarboxylic acid derivatives of the formula IV
._ o~ 7 ~IV~
_R8 R9 or c) enamines of the formula V
R300C~ ~H
)l (V) R2 ~NHz S are reacted ~ith benzylidenecarboxylic acid derivatives of the formula VI
~ b-- ~ (Vl) or d) keto compounds of the formula VII
R300C \
~ ~ ~VII) : R2 0 are reacted w;ith ammonia and benzylidenecarboxylic ac;d derivatives of the formula VI, or , e) aldehydes of the formula VIII
A~ ~VIII) 0~ H
are reacted ~ith enamines of the formula V and~ -ketocar-boxyl;c acid derivatives of the formula IV, or f) aldehydes of the formula VIII are reacted ~ith enamine derivatives of the formula III and keto compounds of the formula VII, or g) 1,4-dihydropyrid;nes of the formula IX
Ar 8 R2)( ~ )(t (IX) are reacted ~ith diaryl compounds of the formula X
R6 ~ R7 Ho - A__~ r ~ tX) as such or in the form of their salts, and, if desired, resulting salts are then converted into the free bases or resulting bases are converted into the salts, wherein Ar, R1, R2, R3~ R4, R5, R6, R7, R8, R9, r and A have the above-mentioned meanings and Z, together with the carbonyl group to which it is bonded, represents a carboxyl group or a reactive carboxylic acid derivative tfor example a carboxy-lic acid halide).
3~
~ 12 -The process accord;ng to var;ants a to f is carr;ed out in suitableO preferably inert organ;c solvents.
Examples which may be mentioned are alcohols, such as ethanol, methanol, isopropanol or tert.-butanol, ethers, such as dioxane, diethyl ether, tetra~ydrofuran, glycol monoethyl ether and ~lycol dimethyl ether, or other sol~
vents, for example polar solvents, such as dimethylform-amide, dimethyl sulphoxide~ acetonitrile or hexamethylphos-phoric acid triamide, or, in particular, chlorinated hydro 1û carbons, such as methylene chloride, chloroform or tetra-chloroethylene.
The reaction temperatures can be varied ~ithin a ~ide range - depending on the reactivity of the educts. The reaction is in general carried out at temperatures between 20C and 150C, preferably between 20C and 10~C and in particular at the boiling point of the solYent used~
The process can be carried out under normal pressure or under increased pressure, the reaction under normal pres-sure being the rule and ;t being possible to apply increased pressure, in particular, for reactions ~ith ammonia.
In carrying out the process according to the inven-tion in variants a to f, the substances participating in the reaction are as a rule in each case employed in molar amounts, but, if desired, an excess (for example of ammonia in variants b and d) can also be employed - depending on the reaction conditions.
In carrying out the process according to variant 9, similar reaction conditions to those for variants a to f are used, but, if appropriate, additional measures are neces-sary - depending on the nature of the substituent Z. For example, if Z represents a hydroxyl group, the reaction is preferably to be carried out in the presence of 3 condensing agent which splits off or binds water (such as, for example, dicyclohexylcarbodi;mide). If Z represents a halogen atom ~ 7 ~for example a chlorine atom~, the reaction is to be carried out, if desired, ;n the presence of a base Sfor example a tertiary organic amine, such as triethylamine, or an ;n-organic carb~nate, such as sodium carbonate).
The substances according to the invention are iso-lated and pur;fied in a manner which is knoun per se, for example by distilling off the solvent in vacuo and re-crystallising the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
Acid addit;on salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorina ted hydrocarbon, such as methylene chloride or chloroform, or a lo~ molecular weight aliphatic alcohol (ethanol or iso-propanol), conta;ning the desired acid or to which the desired ac;d is subsequently added.
The salts are obtained by filtration, reprecipita-tion, precipitation ~ith a non-soLvent for the addition salt or evaporation of the solvent.
the salts obtained can be converted into the free bases by rendering them alkaline~ for example with aqueous ammonia solution, and these bases can in turn be converted into acid addition salts. Pharmacologically unacceptable acid addition salts can in this manner be converted into pharmacologically acceptable acid addition salts.
The starting compounds are known from the literature or can be prepared by methods analogous to those known from the literature. The cinnamic acid derivatives II and the benzylidenecarboxylic acid derivatives VI can be prepared, for example, by a method analogous to that of G~ Jones ~"The Knoevenagel Condensation" in Org. Reactions, Volume ~V, 204 et seq. (1967)3. The enamine derivatives III and the enamines V are obtainable, for exampLe, by a method analogous to that of A.C. Cope ~J. Amer. Chem. Soc. 67, 1017 (1945)~ etocarboxylic acid dèrivatives IV and keto com-pounds VII can be prepared in accordance with the method of D. ~orrmann ~"Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" ("The Reaction of diketene w;th alcohols, phenols and mercaptans") in Houben-Weyl, Methoden der Organischen Chemie ~Methods of Organic Chemistry), Volume VII/4, 230 et seq. (1968)~ or Y. Oikawa et al. CJ. Org.
Chem. 43, 2087 t1978)]. The compounds IX are accessible from corresponding starting compounds by variants analogous to process variants a to f. Compounds X are obtainable by reaction of corresponding piperidines (see, for example, German Patent Specification 1,936,452) ~ith ~-halogenoaLkan-ols.
The above preparation processes are mentioned onlyfor illustration, and the preparation of the compounds of the formula I according to the invention is not restricted to these processes. Rather, any modification of these pro-2û cesses can be applied in the same manner to the preparationof the compounds according to the invention.
Preferred process variants are the variants a and c The following preparatlon examples are ~ntended to illustrate the inventlon ln more detall without lim~t1ng it m p denotec melting point and b.p. represents boiling point - 15 ~
Examples 1. 3-Meth l 5-~3-(4~4-diphenylpiperid-1-yl)-propyl] t,4-_ . . Y_ ..
dihydro-2~6-dimethyL-4-(3~ni~ro~henyl)-pyridine-3,5-dicarbo~ylate hydrochlor;de Process variant e) 4.53 9 of 3-nitrobenzaldehyde, 3.45 9 of me~hyl 3-aminocrotonate and 11.38 9 of 3-(4,4-diphenylpiperid-1-yl) propyl acetoacetate in 100 ml of 2-propanol are heated at the boiling point under reflux overnight~ The cooled solu-1û tion is concentrated to dryness and the residue whichremains is chroma~ographed over a silica gel column using ethyl acetate as the eluant. The uniform product fractions leave a solid foamed residue after concentration, the resi-due is dissolved in methanol and ethereal hydrochloric acid is added. The solution is concentrated, the solid residue ~hich remains is taken up in a little methanol and the title substance is precipitated by addition of petroleum ether.
m.p.: from 135C (decomposition); yield: ~.3 g.
The s~arting compounds are obtained as follows:
a) 3 t4~4-Diphenylpiperid-1-yl)-propyl acetoacetate 23.6 9 of 3-(4,~-diphenylpip~rid-1-yl)-propanol are dissolved in 100 ml of absolute toluene, and 16 ml of a 50X strength solution of diketene in acetone are added, with stirring. After the mixture has been left to stand at room temperature for several days (control by thin layer chroma-tography), ;t is cGncentrated and the residue is dried under a high vacuum. The pale yellow viscous o;l wh;ch rema;ns ;s employed for the next stage without further puritication.
b) ~ .4-~i~h~nv1Pi~Qrid-1-yl)-oroDa~oL
bO 9 of ~,~-dlphenylplperidine, 2~.7 g of 3-bromo-propanol, 116.4 9 of powdered potassium carbonate and about 1 9 of potassium iodide are heated at the boiling point under reflux and with vigorous stirring in SOO ml of a 1:1 mixture of d;oxane and 1-butanol for about 48 hours.
After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate and the solution is filtered again. After the filtrate has ~ 16 ~ 3~
been concentrated to dryness, the product is obta~ned as a yellowish oily residue ~hich slo~Ly ~olidifies as a wax~
Yield: 44.8 9. ~i~h ~he~eal hydrochloric ac;d, ~he hydro-chloride is obtained, and is recrystallised from 2-propanol.
m.p.: 226-7C.
Alternatively, tho startlng compound b~ i0 obtalned by heating 352 9 of 4,4-diphenylpiperidine, 128 9 of sodium hydroxide granules, 2.5 l of methylene chloride, 500 ml of water, 218 y of 3-bromo-1-propanol and cataly~ic amounts of a phase transfer catalyst (for example benzyltri~ethylammon-ium chloride) at the boiling point under reflux for 10 hours~
~he organic phase is separate~ off and washed ~ith water and the collected aqueous phases are extracted ~ith ~ethylene chloride. After the combined or~anic phases have been dried ~ith sodium sulphate, the clear brownish solution is evaporated to dryness. The resinous brown residue is taken up in 4.5 l of boiling petroleum ether (boiling range 100-140C), the insoluble residue is filtered off hot from the solution and the fi~trate is cooled. After being left to stand overnight~ the title compound is obtained as the free base in the form of colourless coarse crystals. m.p.: 97C;
yield: 303 g.
The followlng starting compounds are obtained analo-gously:
4~ diphenylpiperid-1-yl~-butanol, m p of the hydrochloride:
209-212C, 2-~4,~-diphenylpiperid-1-yl)-2-methylpropanol, m.p.: 115-116C, 3-t4,4-di-(4-methoxiphenyl)-plperld-1-yl]-propanol, m.p of the hydrochloride: 130-t34~C ~contains 1 equivalent of mathanol in the orystal), 3-(4,4-diphenylplperid-1-yl)-2-methyl-2-propanol, m.p. of the hydrochloride: 1~ 3C, 2~(4,~-diphenylpiperid-1-yl)-ethanol, ~.p of the hydrochloride:
197-199C.
3y reactlon of the above alcohol~ with a solution of di-ketene analogoulsy to Example 1a, the correspondin~ acetoacetates are obtained which are further reacted without purification.
Process var;ant c) 15~38 9 of 3-~4,4-d;phenylpiper;d-1-yl)-propyl 2-acetyl-3-(3-nitrophenyl)-acryla~e and 3.~5 9 of methyl 3-aminocrotonate ;n 100 ml of 2-propanol are heated at the boiling point under reflux overn;ght. The cooled solut;on ;s evaporated to dryness, the foamed solid residue ;s taken up in a little methylene chloride and ethereal hydrochloric acid is added. After rene~ed concentra~ion to dryness and taking up of the solid residue in a little methylene chlor-ide~ ethyl acetate is added until a slight cloudiness per-sists. After the mixture has been left to stand in a refrigerator, the title compound crystallises out overnight in the form of finè, slightly yellowish-coloured flakes (microscope)D m~p.: 230 231C (decomposition); yield:
13.6 9.
Other solvents which are ~employed for the condensa-tion reaction are: tert.-butanol, dioxane, tetrahydrofuran and chlorinated hydrocarbons~ The yields of product are 60-80X of theory.
Other salts of the title compound 1 which are pre-pared are:
hydrobromide: m.p.: 229-230C (decomposition), fine plate-lets (from ethyl acetate and diisopropyl ether);
fumarate: m.p.: 144-145C (decomposition), fine flakes (from ethyl acetate);
maleate: m.p.: 1S1-152C (decomposition), clusters of coarse needles (from ethyl acetate).
The free base of the title compound 1 is obtained when the condensation batch is concentrated to dryness and the foamed solid residue is taken up in a little methylene chloride; after addition of diisopropyl ether until a fine cloudiness remains~ the base crystallises out in the form of fine platelets, after being left to stand in a refrigera-tor. m.p.: 145 147C.
The startin~ compound 3-(4,4-diphenylpiperid-1-yl)-propyl Z-acetyl-3-(3-nitrophenyl)-acrylate (cisltrans isomer mixture) is obtained as follows:
- 18 ~
40.14 9 of 3-(4,4-d;phenylp;per;d-1-yl)-propyl acetoacetate, 15~97 9 of 3-nitrobenzaldehyde, 8.0 ml of acetic acid and 0.5 ml of piper;d;ne are heated at the boiling point in 300 ml of benzene using a water separator.
After 1.9 ml of ~ater has been separated off, the cooled solution is washed uith saturated sod;um bicarbonate solu-tion and then ~ith waterY After the organic phase has been dried uith sodium sulphate, the clear red-brown solution is concentrated to constant weight under a high vacuum. The red-brown viscous residue obtained is employed directly for the condensation, ~ithout further purif;cation. Yield: 52 9 of crude product. Other entraining agents which are suit-able are: toluene and chlorinated hydrocarbons. The yield of crude product is 90-10~% of theory.
~ y reacting the free base ~ith an equimolar amount of fumar;c acid, the fumarate of the starting compound is obtained; m.p.: from 128C (decomposition), clusters of fine needles, from ethyl acetate.
3y reaction ~ith ethereal hydrochloric acid, the hydrochloride is obtained: m.p.: 152-155~ (fine platelets, from ethyl acetate and d;ethyl ether).
Process_variant a 134.6 g of methyl 2-acetyl-3-(3-nitrophenyl)-acrylate, 204.5 9 of 3-t4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate and 4.5 ml of acetic acid in 2.7 l of anhydrous dioxane are heated at the boiling point under reflux and under a n;trogen atmosphere for 20 hours. After cooling, 45 ml of concentrated hydrochloric acid ~37X) are added to the mixture~ seed crystals of the title compound 1 are added and the mixture is left to stand at roam tempera-ture for 24 hours. The precipitate is filtered off with suction, washed with dioxane and diisopropyl ether and then dried in vacuo at 75C. The product ~270 g) is parti-tioned between 1.5 l of methylene chloride and aqueous ammonia solut;on (pH 11), the organic phase is dried over sodium sulphate and the solvent is then distilled off in i vacuo. The residue is dissolved ;n 2.5 l of d;o%aneO 35 ml of concentrated hydrochlor~c acid (37X s~rength) are added and the mixture is seeded and left to stand for 40 hours.
The product which has crystallised out ;s fil~ered off w;th suction, washed ~ith dioxane and then diisopropyl ether and dried at ~00C ;n vacuo. The t;tle substance ;s obtained as a pale yellow powder (m;croscope: small needles).
m.p~: 198-200C; yield: 246 9.
The starting compound 30(4~4-diphenylp;perid 1-yl)-propyl 3-aminocrotonate is prepared as follo~s:
260.5 9 of 3-(4,4~diphenylpiperid-1-yl)-propyl acetoacetate in 1.6 l of 2-propanol are st;rred overnight ~;th 260 ml of concentrated ammonia solution. The fine, slightly ochre coloured prec;p;tate ~h;ch has separated out is f;Ltered off ~ith suction and ~ashed with coLd 2-propanol, diethyl ether and finally petroleum ether. m.p.: 144-150C; y;eld: 225 9. After addition of a further 100 ml of concentrated ammon;a solut;on to the filtrate and after the mixture has been left to stand in a refrigerator for several days, a further 12 9 of product of identical melting point are obta;ned.
Alternatively, the starting compound is obtained if gaseous ammon;a is passed ;nto the solution of 3-(4,4-d;phenyl-p;perid-1-yl)-propyl acetoacetate in 2-propanol, with stirring, until no further precipitate separates out.
Yield: about 90% of theory.
2. 3-Methyl 5-C2-S4,4-diphenylpiperid-1-yl)-ethyl~
1,4-d;hy~dro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine--3~5 dirarboxYlate hydrochloride . _ The title compound of m.p.: from 137C (decomposi-tion); y;eld: 8.5 9, is obtained analogously to Example 1 from 4.53 9 of ~-nitrobenzaldehyde, 3.45 9 of methyl aminocrotonate and 11 9 of 2-(4,4-d;phenylpiperid-1 yl~-ethyl acetoaceta~e in 100 ml of ~-propanol.
/
/
/
/
/
/
3. 3-Methyl ~ iphenylp;per;d-1-yl?-propyl~
4-(3-cyanophenyl)-1 4-dihydro-2 6-dimethylpyridine-3 5-d;carbol~ d hlor;de The title compound of m.pr 136-146C (slow del;quescence, amorphous, precipitated ;n petroleum ether);
y;eld: 5.9 9, is obta;ned analogously to Example 1 from 3.93 9 of 3-cyanobenzaldehyde, 3.45 9 of methyl 3-am;no-crotonate and 11~38 9 of ~-(4,4~d;phenylpiperid-1-yl)-propyl acetoacetate in 80 ml of tert.-butanol.
4.
~'~
pyr ~ e h ~
The title compound of m.p. from 155C (slo~ deli-quescence, amorphous, precipitated from petroleum ether);yield: 13.6 9, ;s obtained analogously to Example 1 from 9 o~ 2-l~,4-diph~nylp1perid-l-yl)-2-m4thylpropyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 3.45 9 of methyl 3-aminocrotonate in 1ûO ml of tetrahydrofuran after a reaction time of 12 hour~.
Field of application_of the invention The invention relates to new diaryl compounds, pro-cesses for their preparation, their use and medicaments -5 containing them. The compounds according to the invention are employed in the pharmaceutical industry for the prepara-tion of medicaments.
Kno~n technical background _ It is known that certain 1,4-dihydropyridine deriva-tives subs~ituted in various ways have pharmacologically useful properties. European Patent Applications 88,903, 94,159 and 106,276 may be mentioned as examples. Surpris-ingly,`it has now been found that the new compounds des-cribed in more detail below, which, in contrast to the com-pounds of the prior art~ carry a piperidine ring which is disubstituted in the 4-position, have particularly interest-ing pharmacological properties by which they differ advan-tageously from the compounds of the prior art.
Description of the invention The invention relates to ne~ diaryl compounds of the formula I
R6 ~ R7 2) ~ ~Rl ~ 9 wherein Ar represents a ring of the formula - z ~
R~
/~
Y ~R5 \//~
;n ~hich Y denotes oxygen (0)~ sulphur (S), vinylene (-CH=CH-), azometh;ne (-CH=N-) or a group of ~he formula / N ~ ~ / N
o I or S
N ~ N ~
R1, R2 and R3 are identical or different and denote hydrogen, C1-C6-alkyl, C3-C7-alkoxyalkyl, aryl~ aryl-C1-C6-alkyl or aryloxy-C1-c6-alkyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, n;tro, cyano, tr;fluoromethyl, ~1-C4-alkyl~ C1-C4-alkoxy, C1-C4-alkoxy wh;ch is completely or partlj substituted by fluor;ne, C1-C4-alkoxycarbonyl, C2-C5-acyL, amino or mono- or di-C1-C4-alkylamino, R6, R7, R8 and R~ are identical or different and denote hydrogen, hydroxyl, halogen, C1-C4-alkyl, C1-C4-alkoxy, amino, mono- or di-C1-C4-alkylamino, or C1-C4-alkoxy ~hich is completely or partly sub-stituted by fluorine, and A denotes straight-chain or branched C2-C5-alkylene, which can be substituted by C1-c4-alkoxy or aryl, and their salts.
C1-c~6-Alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or, in par-ticular, ethyl or methyl radical.
C3-C7-Alkoxy represents, for example, a methoxyethyl, sthoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxy-propyl, 2-methoxy-1-methylethyl or 2-ethoxy-1-methylethyl radical.
Aryl ~e~7W~ represents phenyl or substituted phenyl with one or two substituents from the group compris-;ng halogen, hydroxyl, nitro, cyano~ trifluoromethyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C2-C5-acyl, amino and mono- or di-C1-C4-alkylamino.
Aryl-C1~C6-alkyl is C1-C6-alkyl which ;s sub-stituted by aryl. Aryl-C1-C6-alkYl is, for example, phen-ethyl, 3-(4-chlorophenyl)-propyl or, in particular, benzyl.
Aryloxy-C1-C6-alkyl is C1-C6-alkyl which is substituted by aryloxy. Aryloxy-c1-c6-alkyl is, for example, phenoxyethyl.
Halogen denotes bromine and, in particular, fluorine and chlorine.
C1-c4-Alkyl is straight-chain or branched and denotes, for example, a butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl or, in particular, methyl radical.
In addition to the oxygen atom, C1-C4-alkoxy con-tains one of the abovementioned C1-C4-alkyl radicals.
The methoxy radical is preferred.
C1-C4-Alkoxy which is completely or partly sub-stituted by fluorine is, for example, 1,1,2,2-tetrafluoro-ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoro-methoxy.
In addition to the carbonyl group, C1-C4-alkoxy-carbonyl contains one of the abovement;oned C1-C4-alkoxy radicals~ The methoxycarbonyl and ethoxycarbonyl radical are preferred.
In addition to the carbonyl group, C2-Cs-acyl 4~
contains one of the abovement;oned C1-C4-alkyl radicals.
The acetyl rad;cal is preferred.
In add;tion to the nitrogen atom, mono- or d;-C1-C4-alkylam;no contains one or two of the abovement;oned C1-C4-alkyl rad;cals. D;-C1-C~-alkylam;no ;s preferred, and especially dimethyl-, diethyl- or d;;sopropyl-am;no.
Straight-cha;n or branched C2-C5-alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 1,1-dimethylethylene, 2~2-dime~hylethylene, isopropyl;dene, 1-1û methylethylene, 2-ethylpropylene or, in particu~ar, ethylene or propylene.
C2-C5-Alkylene which is subst;tuted by C1-C4-alkoxy is, for example, 1-methoxy-propylene, 2-ethoxy-propylene or 1,2-dimethoxyethylene.
C2-C5-Alkylene which is substituted by aryl is, for example, 1-phenylethylene or 2-(4-chlorophenyl)-propyl-ene.
Possible salts are all salts with acids. The pharmacologically acceptable salts of the inorganic and 2û organic acids usually employed in the pharmaceutical indus-try may be mentioned i~ particular. Pharmacologically un-acceptable salts ~hich may be obtained, for example~ as pro-cess products when the compounds according to the invention are prepared on an ;ndustrial scale are converted into pharmacologically acceptable salts by processes which are known to the expert. Examples of suitable salts of this type are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosyl-ate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesylateO and also sal~s wi~h bume~anideO furos~mide, azo-sem;de, galosemide, besun;de, piretan;de, etacrynic acid, tienilic acid or 4-chloro-sulphamoyl-benzoic acid.
Radicals Ar which are to be singled out are the phenyl, 3-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-d;chlorophenyl, 2-cyanophenyl, 3-cyano-phenyl, 2-methoxyphenyl, 3~methoxyphenyl, 2-trifluorome~hyl-phenyl, 3-trifluoromethylphenyl, 3-(1,1,2,2-te~rafluoro-ethoxy)-phenyl, 2-difluorome~hoxyphenyl, 3-di~luoromethoxy~
phenyl, 2-tolyL~ 3-tolyl, 4 tolyl, 2-pyridyl, 3-pyridyl, 2,1,3-benzoxdiazol-4-yl, S-methyl-2-thienyl and, ln part~cular, 2-nitrophenyl and 3-nitrophenyl radical.
Embodiments of the invention and preferred and par-ticularly preferred embodiments are given in the claims~
Examples ~hich may be mentioned of compounds accord-ing to the invention are:
3-ethyl S-C2 (4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-~2-methoxyethyl) 5-t3-~4,~-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-~-(3-nitrophenyl)-pyridine-3,5-dicarboxy-late, 3-methyl S-C4~t4,4-diphenylpiperid-1-yl)-butyl~ 1,4-d;hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-~2-nitrophenyl~-pyridine-3,5-dicarbo%ylate, 3-methyl 5-C2-~4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6 diethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-tprop-2-yl) S-C2-(4,4-diphenylpiperid-1-yl)-ethyl~ 1,4-di-hydro-2,6-dimethyl-4-~3-nitrophenyl)-pyridine-3,5 dicarboxyl-ate,3-hexyl 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-(2-n-butoxye$hyl) 5-[2-~,4-diphenylpiperld-1-yl)-ethyl~
dihydro-2,6-dlmethyl~ 3-nitrophenyl)-pyridine-3,5-dicarb-oxylate, 3~' -- 6 --3-methyl 5-{2-C4,4-di(4-methoxyphenyl) piperid-1-yl]-ethyl~
1,4-d;hydro-2,6-dimethyl-4-(3-n;trophenyl)-pyridine-3,5-dicarboxylate, 3-ethyl 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro~
2,6-d;methyl-4-('-tr;~luoromethylphenyl)-pyr;dine-3,5-d;-carboxylate, 3-methyl 5-l2-l~,4-d1phenylpip~r~d-1-yl)-~thyl~ -d~hydro-2,~-dimethyl-~ (1,1,2t2-tetrafluoroethoxy)-ph~nyl~-pyridine-3,5-d~carboxylate, 3-ethyl S-C2-(4,4-d;phenylp;per;d-1-yl)-ethyl~ 1,4-dihydro-2,6-d;methyl-4-t2-d;fluoromethoxyphenyl)-pyr;d;ne-3,5-d;-carboxylate, 3-ethyl 5-~4-(4,4-diphenylp;perid-1-yl~-butyl~ 1,4-d;hydro-2,6-d;methyl-4-(2-d;fluoromethoxyphenyl)-pyr;d;ne-3,5-d;-carboxylate,3-methyl 5-C2-(4,4-dihydroxyphenylp;per;d-1-yl)-ethyl] 1,4-d;hydro-2,6-dimethyl-4-(3-n;trophenylj-pyr;d;ne~3,5-di-carboxylate, 3-methyl 5-~2-(4~4-d;phenylp;perid-1-yl)-ethyl~ 4-(2,3-di-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5 dicar-boxylate, 3-methyl 5-C2-~4,4-d;phenylp;per;d-1-yl)-ethyl] 4-(2,1,3-benzoxdia20l-~-yl)-1,~-dihYdro-2,6-dimethylpyridine-3,5-d~carboxylate`, 3-methyl 5-C2-~4,4-d;phenylpiperid-1-yl)-ethyl] 4-(3-cyano-phenyl) 1,4-dlhydro-2,6-dimethylpyr;d;ne-3,5-d;carboxylate, 3-methyl S-C2-(4,4-d;phenylp;perid-1-yl)-ethyl~ 1,4-d;hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-C2-(4,4-diphenylpiperid-1-yl)-ethyl~ 1,4-dihydro-2,6-dimethyl-4-(2-pyr;dyl)-pyr;d;ne-3,5-d;carboxylate, 3-methyl S-C2-(4,4-d;phenylp;perid-1-yl)-ethyl] 1,4 dihydro-2,6~d;methyl-4-(5-methyl-2-th;enyl)-pyr;dine-3,5-dicarboxy-late, 3-methyl 5-~2-C4-(4-chlorophenyl)-4-phenylpiperid-1-yl]-ethyl3 1,4-d;hydro-2,6-dimethyl-4-(3-n;trophenyl) pyr;dine-3,5-dicarboxylate, 3-methyl 5-C3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-d;-hydro-2,6-d;methyl 4-(2-n;trophenyl)-pyrid;ne-3,5-dicar-boxylate, 3-methyl 5-~3-~4,4-diphenylpiperid-1-yl)-propyl] 1,4-d;-hydro 2,6-diethyl-4-(3-n;trophenyl)-pyr;d;ne-3,5-dicar~
boxylate, 3-~prop-~-yl) 5-C3-(4,4-diphenylp;perid-1-yl)-propyl~ 1,4-dihydro-2,6-dimethyl 4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-hexyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)~pyridine-3,5-dicarboxylate, 3-(2-n-butoxysthyl) 5-~3-t~ diphenylpiperid-1-y1)-propyl~
1,~-dlhydro-2,6-dimethyl-~-(3-nitrophony1)-piperidino-3,5-dicarboxylate, 3-methyl 5-{3-C4~4-di(4-methoxyphenyl)-piperid-1-yl]-propyl3 1,4-dihydro~2,6-dimethyl~4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,3-ethyl S-C3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4 dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-di-carboxylate, 3-methyl 5-l3-l~,~-diPhenylpiPerid-1-Yl)-propYl~ -dihydro-2,6-dim~thyl-4-t3-(1,~,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate 3-ethyl S-C3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4-dihydro-2,6-dimethyl-4-(2-difluoromethoxyphenyl?-pyridine-3,5-d;
carboxylate, 3-methyL S-C3-t4,4-dihydroxyphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6~dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxyla~e, 3-methyl 5-C3-~4,4-diphenylpiperid-1-yl)-propyl] 4-t2,3-di-chlorophenyl)-1,4-dihydro-2,6 dimethylpyridine-3,5-dicar-boxylate,3-methyL 5-C3-(4,4-diphenylpiperid-1-yl)-propyl] 4-~2,1,3-benzoxdiazol-~-yl)-1,4-dihydro-2,6-dimothylpyridine-3,5-dicarboxylate, 3-methyl 5-C3~(4,4-diphenylpiperid-1-yl)-propyl~ 4-(3-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5~dicarboxylate, 3-methyl 5-C3-(4,4-diphenylpiperid-1-yl)-propyl~ 1,4-di-hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridine-3,5-di-carboxylate, ~9~
3-methyl S-C3-t4,4-diphenylpiperid-1-yl?-propyl~ 1,4-di-hydro 2,6-dimethyl-4-t2-pyridyl)-pyridine-3,5-dicarboxylate, 3-methyl S-C3-(4,4-diphenylp;perid-1-yl)-propyl~ 1,4-di-hydro-2,6-dimethyl-4-tS-methyl-2-thienyl)-pyridine-3,5-dicarboxylate, and 3-methyl 5-~3-C4-t4-chlorophenyl)-4-phenylpiper;d 1-yl~-propyl3 1,4-d;hydro-2,6-dimethyl-4-t3-nitrophenyL)-pyr;dine-3,5-dicarboxylate, and their salts.
_ 9 _ The compounds of the formula I have a chirality centre at the 4-pos;tion ;n the 1,4-dihydropyr;dine~ The invention therefore includes both ~he enant;omers and, if a further ch;rality centre ;s present, the diastereomers, and mixtures and racemates thereof~
The invent;on furthermore relates to a process for the preparation of the compounds according to the invention and their salts. The process is characterised in that a) cinnamic acid derivatives of the formula II
Ar R300c~ H ~II) R 2J~ o are reacted ~ith enamine derivatives of the formula III
R6 ~ R7 )(C--~
or b) cinnamic acid derivatives of the formula II are reacted with ammonia and~ -ketocarboxylic acid derivatives of the formula IV
._ o~ 7 ~IV~
_R8 R9 or c) enamines of the formula V
R300C~ ~H
)l (V) R2 ~NHz S are reacted ~ith benzylidenecarboxylic acid derivatives of the formula VI
~ b-- ~ (Vl) or d) keto compounds of the formula VII
R300C \
~ ~ ~VII) : R2 0 are reacted w;ith ammonia and benzylidenecarboxylic ac;d derivatives of the formula VI, or , e) aldehydes of the formula VIII
A~ ~VIII) 0~ H
are reacted ~ith enamines of the formula V and~ -ketocar-boxyl;c acid derivatives of the formula IV, or f) aldehydes of the formula VIII are reacted ~ith enamine derivatives of the formula III and keto compounds of the formula VII, or g) 1,4-dihydropyrid;nes of the formula IX
Ar 8 R2)( ~ )(t (IX) are reacted ~ith diaryl compounds of the formula X
R6 ~ R7 Ho - A__~ r ~ tX) as such or in the form of their salts, and, if desired, resulting salts are then converted into the free bases or resulting bases are converted into the salts, wherein Ar, R1, R2, R3~ R4, R5, R6, R7, R8, R9, r and A have the above-mentioned meanings and Z, together with the carbonyl group to which it is bonded, represents a carboxyl group or a reactive carboxylic acid derivative tfor example a carboxy-lic acid halide).
3~
~ 12 -The process accord;ng to var;ants a to f is carr;ed out in suitableO preferably inert organ;c solvents.
Examples which may be mentioned are alcohols, such as ethanol, methanol, isopropanol or tert.-butanol, ethers, such as dioxane, diethyl ether, tetra~ydrofuran, glycol monoethyl ether and ~lycol dimethyl ether, or other sol~
vents, for example polar solvents, such as dimethylform-amide, dimethyl sulphoxide~ acetonitrile or hexamethylphos-phoric acid triamide, or, in particular, chlorinated hydro 1û carbons, such as methylene chloride, chloroform or tetra-chloroethylene.
The reaction temperatures can be varied ~ithin a ~ide range - depending on the reactivity of the educts. The reaction is in general carried out at temperatures between 20C and 150C, preferably between 20C and 10~C and in particular at the boiling point of the solYent used~
The process can be carried out under normal pressure or under increased pressure, the reaction under normal pres-sure being the rule and ;t being possible to apply increased pressure, in particular, for reactions ~ith ammonia.
In carrying out the process according to the inven-tion in variants a to f, the substances participating in the reaction are as a rule in each case employed in molar amounts, but, if desired, an excess (for example of ammonia in variants b and d) can also be employed - depending on the reaction conditions.
In carrying out the process according to variant 9, similar reaction conditions to those for variants a to f are used, but, if appropriate, additional measures are neces-sary - depending on the nature of the substituent Z. For example, if Z represents a hydroxyl group, the reaction is preferably to be carried out in the presence of 3 condensing agent which splits off or binds water (such as, for example, dicyclohexylcarbodi;mide). If Z represents a halogen atom ~ 7 ~for example a chlorine atom~, the reaction is to be carried out, if desired, ;n the presence of a base Sfor example a tertiary organic amine, such as triethylamine, or an ;n-organic carb~nate, such as sodium carbonate).
The substances according to the invention are iso-lated and pur;fied in a manner which is knoun per se, for example by distilling off the solvent in vacuo and re-crystallising the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
Acid addit;on salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorina ted hydrocarbon, such as methylene chloride or chloroform, or a lo~ molecular weight aliphatic alcohol (ethanol or iso-propanol), conta;ning the desired acid or to which the desired ac;d is subsequently added.
The salts are obtained by filtration, reprecipita-tion, precipitation ~ith a non-soLvent for the addition salt or evaporation of the solvent.
the salts obtained can be converted into the free bases by rendering them alkaline~ for example with aqueous ammonia solution, and these bases can in turn be converted into acid addition salts. Pharmacologically unacceptable acid addition salts can in this manner be converted into pharmacologically acceptable acid addition salts.
The starting compounds are known from the literature or can be prepared by methods analogous to those known from the literature. The cinnamic acid derivatives II and the benzylidenecarboxylic acid derivatives VI can be prepared, for example, by a method analogous to that of G~ Jones ~"The Knoevenagel Condensation" in Org. Reactions, Volume ~V, 204 et seq. (1967)3. The enamine derivatives III and the enamines V are obtainable, for exampLe, by a method analogous to that of A.C. Cope ~J. Amer. Chem. Soc. 67, 1017 (1945)~ etocarboxylic acid dèrivatives IV and keto com-pounds VII can be prepared in accordance with the method of D. ~orrmann ~"Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" ("The Reaction of diketene w;th alcohols, phenols and mercaptans") in Houben-Weyl, Methoden der Organischen Chemie ~Methods of Organic Chemistry), Volume VII/4, 230 et seq. (1968)~ or Y. Oikawa et al. CJ. Org.
Chem. 43, 2087 t1978)]. The compounds IX are accessible from corresponding starting compounds by variants analogous to process variants a to f. Compounds X are obtainable by reaction of corresponding piperidines (see, for example, German Patent Specification 1,936,452) ~ith ~-halogenoaLkan-ols.
The above preparation processes are mentioned onlyfor illustration, and the preparation of the compounds of the formula I according to the invention is not restricted to these processes. Rather, any modification of these pro-2û cesses can be applied in the same manner to the preparationof the compounds according to the invention.
Preferred process variants are the variants a and c The following preparatlon examples are ~ntended to illustrate the inventlon ln more detall without lim~t1ng it m p denotec melting point and b.p. represents boiling point - 15 ~
Examples 1. 3-Meth l 5-~3-(4~4-diphenylpiperid-1-yl)-propyl] t,4-_ . . Y_ ..
dihydro-2~6-dimethyL-4-(3~ni~ro~henyl)-pyridine-3,5-dicarbo~ylate hydrochlor;de Process variant e) 4.53 9 of 3-nitrobenzaldehyde, 3.45 9 of me~hyl 3-aminocrotonate and 11.38 9 of 3-(4,4-diphenylpiperid-1-yl) propyl acetoacetate in 100 ml of 2-propanol are heated at the boiling point under reflux overnight~ The cooled solu-1û tion is concentrated to dryness and the residue whichremains is chroma~ographed over a silica gel column using ethyl acetate as the eluant. The uniform product fractions leave a solid foamed residue after concentration, the resi-due is dissolved in methanol and ethereal hydrochloric acid is added. The solution is concentrated, the solid residue ~hich remains is taken up in a little methanol and the title substance is precipitated by addition of petroleum ether.
m.p.: from 135C (decomposition); yield: ~.3 g.
The s~arting compounds are obtained as follows:
a) 3 t4~4-Diphenylpiperid-1-yl)-propyl acetoacetate 23.6 9 of 3-(4,~-diphenylpip~rid-1-yl)-propanol are dissolved in 100 ml of absolute toluene, and 16 ml of a 50X strength solution of diketene in acetone are added, with stirring. After the mixture has been left to stand at room temperature for several days (control by thin layer chroma-tography), ;t is cGncentrated and the residue is dried under a high vacuum. The pale yellow viscous o;l wh;ch rema;ns ;s employed for the next stage without further puritication.
b) ~ .4-~i~h~nv1Pi~Qrid-1-yl)-oroDa~oL
bO 9 of ~,~-dlphenylplperidine, 2~.7 g of 3-bromo-propanol, 116.4 9 of powdered potassium carbonate and about 1 9 of potassium iodide are heated at the boiling point under reflux and with vigorous stirring in SOO ml of a 1:1 mixture of d;oxane and 1-butanol for about 48 hours.
After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate and the solution is filtered again. After the filtrate has ~ 16 ~ 3~
been concentrated to dryness, the product is obta~ned as a yellowish oily residue ~hich slo~Ly ~olidifies as a wax~
Yield: 44.8 9. ~i~h ~he~eal hydrochloric ac;d, ~he hydro-chloride is obtained, and is recrystallised from 2-propanol.
m.p.: 226-7C.
Alternatively, tho startlng compound b~ i0 obtalned by heating 352 9 of 4,4-diphenylpiperidine, 128 9 of sodium hydroxide granules, 2.5 l of methylene chloride, 500 ml of water, 218 y of 3-bromo-1-propanol and cataly~ic amounts of a phase transfer catalyst (for example benzyltri~ethylammon-ium chloride) at the boiling point under reflux for 10 hours~
~he organic phase is separate~ off and washed ~ith water and the collected aqueous phases are extracted ~ith ~ethylene chloride. After the combined or~anic phases have been dried ~ith sodium sulphate, the clear brownish solution is evaporated to dryness. The resinous brown residue is taken up in 4.5 l of boiling petroleum ether (boiling range 100-140C), the insoluble residue is filtered off hot from the solution and the fi~trate is cooled. After being left to stand overnight~ the title compound is obtained as the free base in the form of colourless coarse crystals. m.p.: 97C;
yield: 303 g.
The followlng starting compounds are obtained analo-gously:
4~ diphenylpiperid-1-yl~-butanol, m p of the hydrochloride:
209-212C, 2-~4,~-diphenylpiperid-1-yl)-2-methylpropanol, m.p.: 115-116C, 3-t4,4-di-(4-methoxiphenyl)-plperld-1-yl]-propanol, m.p of the hydrochloride: 130-t34~C ~contains 1 equivalent of mathanol in the orystal), 3-(4,4-diphenylplperid-1-yl)-2-methyl-2-propanol, m.p. of the hydrochloride: 1~ 3C, 2~(4,~-diphenylpiperid-1-yl)-ethanol, ~.p of the hydrochloride:
197-199C.
3y reactlon of the above alcohol~ with a solution of di-ketene analogoulsy to Example 1a, the correspondin~ acetoacetates are obtained which are further reacted without purification.
Process var;ant c) 15~38 9 of 3-~4,4-d;phenylpiper;d-1-yl)-propyl 2-acetyl-3-(3-nitrophenyl)-acryla~e and 3.~5 9 of methyl 3-aminocrotonate ;n 100 ml of 2-propanol are heated at the boiling point under reflux overn;ght. The cooled solut;on ;s evaporated to dryness, the foamed solid residue ;s taken up in a little methylene chloride and ethereal hydrochloric acid is added. After rene~ed concentra~ion to dryness and taking up of the solid residue in a little methylene chlor-ide~ ethyl acetate is added until a slight cloudiness per-sists. After the mixture has been left to stand in a refrigerator, the title compound crystallises out overnight in the form of finè, slightly yellowish-coloured flakes (microscope)D m~p.: 230 231C (decomposition); yield:
13.6 9.
Other solvents which are ~employed for the condensa-tion reaction are: tert.-butanol, dioxane, tetrahydrofuran and chlorinated hydrocarbons~ The yields of product are 60-80X of theory.
Other salts of the title compound 1 which are pre-pared are:
hydrobromide: m.p.: 229-230C (decomposition), fine plate-lets (from ethyl acetate and diisopropyl ether);
fumarate: m.p.: 144-145C (decomposition), fine flakes (from ethyl acetate);
maleate: m.p.: 1S1-152C (decomposition), clusters of coarse needles (from ethyl acetate).
The free base of the title compound 1 is obtained when the condensation batch is concentrated to dryness and the foamed solid residue is taken up in a little methylene chloride; after addition of diisopropyl ether until a fine cloudiness remains~ the base crystallises out in the form of fine platelets, after being left to stand in a refrigera-tor. m.p.: 145 147C.
The startin~ compound 3-(4,4-diphenylpiperid-1-yl)-propyl Z-acetyl-3-(3-nitrophenyl)-acrylate (cisltrans isomer mixture) is obtained as follows:
- 18 ~
40.14 9 of 3-(4,4-d;phenylp;per;d-1-yl)-propyl acetoacetate, 15~97 9 of 3-nitrobenzaldehyde, 8.0 ml of acetic acid and 0.5 ml of piper;d;ne are heated at the boiling point in 300 ml of benzene using a water separator.
After 1.9 ml of ~ater has been separated off, the cooled solution is washed uith saturated sod;um bicarbonate solu-tion and then ~ith waterY After the organic phase has been dried uith sodium sulphate, the clear red-brown solution is concentrated to constant weight under a high vacuum. The red-brown viscous residue obtained is employed directly for the condensation, ~ithout further purif;cation. Yield: 52 9 of crude product. Other entraining agents which are suit-able are: toluene and chlorinated hydrocarbons. The yield of crude product is 90-10~% of theory.
~ y reacting the free base ~ith an equimolar amount of fumar;c acid, the fumarate of the starting compound is obtained; m.p.: from 128C (decomposition), clusters of fine needles, from ethyl acetate.
3y reaction ~ith ethereal hydrochloric acid, the hydrochloride is obtained: m.p.: 152-155~ (fine platelets, from ethyl acetate and d;ethyl ether).
Process_variant a 134.6 g of methyl 2-acetyl-3-(3-nitrophenyl)-acrylate, 204.5 9 of 3-t4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate and 4.5 ml of acetic acid in 2.7 l of anhydrous dioxane are heated at the boiling point under reflux and under a n;trogen atmosphere for 20 hours. After cooling, 45 ml of concentrated hydrochloric acid ~37X) are added to the mixture~ seed crystals of the title compound 1 are added and the mixture is left to stand at roam tempera-ture for 24 hours. The precipitate is filtered off with suction, washed with dioxane and diisopropyl ether and then dried in vacuo at 75C. The product ~270 g) is parti-tioned between 1.5 l of methylene chloride and aqueous ammonia solut;on (pH 11), the organic phase is dried over sodium sulphate and the solvent is then distilled off in i vacuo. The residue is dissolved ;n 2.5 l of d;o%aneO 35 ml of concentrated hydrochlor~c acid (37X s~rength) are added and the mixture is seeded and left to stand for 40 hours.
The product which has crystallised out ;s fil~ered off w;th suction, washed ~ith dioxane and then diisopropyl ether and dried at ~00C ;n vacuo. The t;tle substance ;s obtained as a pale yellow powder (m;croscope: small needles).
m.p~: 198-200C; yield: 246 9.
The starting compound 30(4~4-diphenylp;perid 1-yl)-propyl 3-aminocrotonate is prepared as follo~s:
260.5 9 of 3-(4,4~diphenylpiperid-1-yl)-propyl acetoacetate in 1.6 l of 2-propanol are st;rred overnight ~;th 260 ml of concentrated ammonia solution. The fine, slightly ochre coloured prec;p;tate ~h;ch has separated out is f;Ltered off ~ith suction and ~ashed with coLd 2-propanol, diethyl ether and finally petroleum ether. m.p.: 144-150C; y;eld: 225 9. After addition of a further 100 ml of concentrated ammon;a solut;on to the filtrate and after the mixture has been left to stand in a refrigerator for several days, a further 12 9 of product of identical melting point are obta;ned.
Alternatively, the starting compound is obtained if gaseous ammon;a is passed ;nto the solution of 3-(4,4-d;phenyl-p;perid-1-yl)-propyl acetoacetate in 2-propanol, with stirring, until no further precipitate separates out.
Yield: about 90% of theory.
2. 3-Methyl 5-C2-S4,4-diphenylpiperid-1-yl)-ethyl~
1,4-d;hy~dro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine--3~5 dirarboxYlate hydrochloride . _ The title compound of m.p.: from 137C (decomposi-tion); y;eld: 8.5 9, is obtained analogously to Example 1 from 4.53 9 of ~-nitrobenzaldehyde, 3.45 9 of methyl aminocrotonate and 11 9 of 2-(4,4-d;phenylpiperid-1 yl~-ethyl acetoaceta~e in 100 ml of ~-propanol.
/
/
/
/
/
/
3. 3-Methyl ~ iphenylp;per;d-1-yl?-propyl~
4-(3-cyanophenyl)-1 4-dihydro-2 6-dimethylpyridine-3 5-d;carbol~ d hlor;de The title compound of m.pr 136-146C (slow del;quescence, amorphous, precipitated ;n petroleum ether);
y;eld: 5.9 9, is obta;ned analogously to Example 1 from 3.93 9 of 3-cyanobenzaldehyde, 3.45 9 of methyl 3-am;no-crotonate and 11~38 9 of ~-(4,4~d;phenylpiperid-1-yl)-propyl acetoacetate in 80 ml of tert.-butanol.
4.
~'~
pyr ~ e h ~
The title compound of m.p. from 155C (slo~ deli-quescence, amorphous, precipitated from petroleum ether);yield: 13.6 9, ;s obtained analogously to Example 1 from 9 o~ 2-l~,4-diph~nylp1perid-l-yl)-2-m4thylpropyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 3.45 9 of methyl 3-aminocrotonate in 1ûO ml of tetrahydrofuran after a reaction time of 12 hour~.
5. 3-Ethyl 5-C3-(4,4-diphenylpiperid-1-yl)-p-opyl]
1~4-dihydro-2~6-dimethyl-4-(3-nitrophenyl)~ eyridine-3,5 dicarboxylate hydrochlor;de The title compound of m.p. 230-232C (fine angu-lar crystals, from acetonitrile and diethyl ether); yield:29.7 9, is obtained analogously to Example 1 fron 13.16 9 of ethyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 18.91 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate in 100 ml of tetrahydrofuran after a reaction time of 6 hours.
1~4-dihydro-2~6-dimethyl-4-(3-nitrophenyl)~ eyridine-3,5 dicarboxylate hydrochlor;de The title compound of m.p. 230-232C (fine angu-lar crystals, from acetonitrile and diethyl ether); yield:29.7 9, is obtained analogously to Example 1 fron 13.16 9 of ethyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 18.91 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate in 100 ml of tetrahydrofuran after a reaction time of 6 hours.
6. 3-Methyl 5-C3-(4,4-diphenylpiperid-1-yl)-propyl~
1,4-dihydr ~ 6-dimethyl-4-C3-(1,1~2 ~ tetrafluoroethoxy3-phenyl~-pyridine-3,5-dicarboxylate hydrochloride The title compound of m.p. 189-192C; yield: 57 9, is obtained analogously to Example 1 from 40.33 9 of methyl 2-acetyl-3-C3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-acrylate and 37.85 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-amino-crotonate in 400 ml of tetrahydrofuran and 0.5 ml of glacial acetic acid after a reaction time of 14 hours.
~ 22 - ~
1,4-dihydr ~ 6-dimethyl-4-C3-(1,1~2 ~ tetrafluoroethoxy3-phenyl~-pyridine-3,5-dicarboxylate hydrochloride The title compound of m.p. 189-192C; yield: 57 9, is obtained analogously to Example 1 from 40.33 9 of methyl 2-acetyl-3-C3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-acrylate and 37.85 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-amino-crotonate in 400 ml of tetrahydrofuran and 0.5 ml of glacial acetic acid after a reaction time of 14 hours.
~ 22 - ~
7. 3~M ~ 5-C2~(4~4-diphenyle~perid 1-yl)-ethYl~
1~d~o-2,c~-dimethyl-4~13-~ ~roethoxy)-~henyll-pyridin~o3L5-dicarboxylate hydrochloride The ~it~e co~pound o~ m.p. 130-140C (slow del;-quescence, amorphous, precipitated from petroleum ether anddiethyl ether 1:1); yield: 6.2 g, is obtained analogously to Example 1 from 4.03 9 of methyl 2-ace~yL-3-l3-(1,1,2,2-tetrafluoroethoxy)-phenyll-acrylate and 3.4 9 of 2-(4,4-diphenylpiperid-1-yl)-ethyl 3-aminocrotonate in 80 ml of 2-propanol after a reaction time of 8 hours.
1~d~o-2,c~-dimethyl-4~13-~ ~roethoxy)-~henyll-pyridin~o3L5-dicarboxylate hydrochloride The ~it~e co~pound o~ m.p. 130-140C (slow del;-quescence, amorphous, precipitated from petroleum ether anddiethyl ether 1:1); yield: 6.2 g, is obtained analogously to Example 1 from 4.03 9 of methyl 2-ace~yL-3-l3-(1,1,2,2-tetrafluoroethoxy)-phenyll-acrylate and 3.4 9 of 2-(4,4-diphenylpiperid-1-yl)-ethyl 3-aminocrotonate in 80 ml of 2-propanol after a reaction time of 8 hours.
8. 3-l2-MethoxY~thvl) 7-~2- U.~ henvl~i~erid-1-vl)-~hvlL 1~4-~ihvd~Q-2 6-di~th~ -(3-n~rop~nv~L--Dy~ldin~ r~ox~la~ ru~p~
The title compound of m~p. from 130C (slow deli-quescence, fine platelets, from ethyl acetate and diethylether); yield: 3.7 9 is obtained analogously to Example 1 from 4.99 9 of 2~(4,4-diphenylpiperid-1-yl)-ethyl 2-acetyl~
3-(3^nitrophenyl)~acrylate and 1.6 9 of 2-(2-methoxyethYl1 3-aminocrotonate ;n 6û ml of tetrahydrofuran and 0.5 0l of glacial acetic acid after a reaction time of 4 hours.
The title compound of m~p. from 130C (slow deli-quescence, fine platelets, from ethyl acetate and diethylether); yield: 3.7 9 is obtained analogously to Example 1 from 4.99 9 of 2~(4,4-diphenylpiperid-1-yl)-ethyl 2-acetyl~
3-(3^nitrophenyl)~acrylate and 1.6 9 of 2-(2-methoxyethYl1 3-aminocrotonate ;n 6û ml of tetrahydrofuran and 0.5 0l of glacial acetic acid after a reaction time of 4 hours.
9. 3-~2-Methoxveth~l~ 5-~3-(~l4-diphenvl~i~eri~-1 -Yl ) -pro_yl~ 1,4-dihydr ~ 6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarbo~ylate fumarate The title compound of m.p. 184~185C (angular flakes, from ethyl acetate and diethyl ether); yield: 5.3 9, is obtained analogously to Example 1 from 5.12 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 1.6 g of 2-(2-methoxyethyl) 3-aminocrotonate in 80 ml of tert.-butanol after a reaction time of 5 hours.
~ ~33~
~ ~33~
10. 3-MethYl 5-~3- ~4,4 d;-(4~me~hoxyphenyl)-piperid--1-yl~
~ __~_. ... _ __ ___ . ___ ~r__e 3,5-dicarboxYlate hvdrochlor;de _ _ _ . ~ _ . _ . . ~ _ _ _ The title compound of m.p. from 138C (slo~ deli-S quescence, amorphous, precipitated in petroleum ether);
yield: 4.9 9, is obtained analogously to xample 1 from 4.4 9 o-f 3-C4,4-di-t4-methoxyphenyl)-piperid-1-yl]-propyl aceto-acetate, 1.15 9 of methyl 3-aminocrotonate and 1.51 9 of 3-nitrobenzaldehyde in 60 ml of tert.-butanol after a reaction 10 time of 12 hours.
~ __~_. ... _ __ ___ . ___ ~r__e 3,5-dicarboxYlate hvdrochlor;de _ _ _ . ~ _ . _ . . ~ _ _ _ The title compound of m.p. from 138C (slo~ deli-S quescence, amorphous, precipitated in petroleum ether);
yield: 4.9 9, is obtained analogously to xample 1 from 4.4 9 o-f 3-C4,4-di-t4-methoxyphenyl)-piperid-1-yl]-propyl aceto-acetate, 1.15 9 of methyl 3-aminocrotonate and 1.51 9 of 3-nitrobenzaldehyde in 60 ml of tert.-butanol after a reaction 10 time of 12 hours.
11. 3-Methyl 5-C4-(4,4-diphenylpiperid-1-yl)-butyl~
1~4-dihydro-2~6-dimethYl-4-(3-nitrophenyl)-pyrid7ne-3~5-_ _ _ _ _ _ _ . . _ _ _ _ _ d;carboxylate fumarate The title compound of m.p. 123-126 (fine needles, 15 from ethyl acetate and methylene chloride); yield: 3.9 9, is obtained analogously to Example 1 from 3.94 9 of 4-(4,4-diphenylpiperid-1-yl)-butyl acetoacetate, 1.15 9 of methyl 3-aminocrotonate and 1.51 9 of 3-n;trobenzaldehyde in 80 ml of tert.-butanol after a reaction time of 6 hours.
20 12. 3-Methyl 5-C1,1-dimethyl-2-~4,4-diphenylpiperid-1-yl)-ethyl~ 1~4-dihydro-?,6-dimethyl-4-(3-nitrophenyl)-pyridine-3 5-dicarboxylate hydrochloride The title compound of m.p. from 148C (slow deli-quescence, amorphous, precipitated from petroleum ether);
25 yield: 11.3 9, is obtained analogously to Example 1 from 15.8 9 of 1,1-dimethyl-2-(4,4-diphenylpiperid-1-yl)-ethyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 3.45 9 of methyl 3-aminocrotonate in 120 ml of 2-propanol after a reaction time of 15 hours.
13. ~ 4 ~ -di enylpiperld-1-y ~ PX~
pyr-d e-3 ~ oxylate hydrochloride The title compound of m.p. from 126C (slow deli-S quescence, 3morphous, precipitated from petroleum ether anddiethyl ether 1:1); yield: 2.8 9, is obtained analogously to Example 1 from 3.8 g of 3-t4,4-diphenylp;perid-1-yl)-propyl 2-acetyl-3-t2-difluoromethoxyphenyl)-acrylate and 1.3 9 of ethyL 3-aminocrotonate in 60 ml of tert.-butanol after a reaction time of 20 hours.
14. 1~4-Dihydro-2,6-dimethyl-4-t3-nitrop ~ dine-3 ~ icarb_xy_lic acid 3-C3-(4c4-diphenylpiperid-1-yl~-propyl~ ester 6.8 9 of 3-(2-cyanoethyl) 5-C3-t404-diphenylpiperid-1-yl)-propyl~ 1~4~dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride are stirred with 40 ml of 0.5 N sodium hydroxide solution and 100 ml of dioxane at room temperature for 3 hours. After most of the dioxane has been distilled off, 15 ml of 2 N hydrochloric acid are added to the residue. The milky/cloudy solution is extracted 4 times with 100 ml of chloroform/n-butanol t3:1) each time and the combined organic phase is washed ~ith 50 ml of saturated sodium chloride solution. The organic phase is concentrated to dryness and the solid residue is recrystallised from chloroform/methanol t1:1).
m.p. 192-195C (decomposition); yield: 504 9.
The starting compound 3-t2-cyanoethyl) 5-~3-(4~4-diphenylpiperid-_-yl)-propy ~ -dihydro-?,6-dimethyl 4-(3-nitrophenyl)-pyr din ~ -dicarboxylate is obtained as follo~s:
8.1 g of 2-cyanomethyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 10.6 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 3~aminocrotonate are heated at the bo1Ling point under reflux in 120 ml of 2-propanol and 0.5 ml of glacial acetic acid for 4 hours. After most of the solvent has been dis-tilled off and 2 portions of 50 ml of toluene e~ch have been added, the residue is concentrated to dryness. The residue, ~hich has foamed as a sol;d, ;s taken up ;n ;sopropanol and d;ethyl ether is added to the clear solution until the cloud;ness f;rst persists. After the mixture has been left to stand in a refrigerator, the starting compound crys~al-lises out in the form of fine plateLets. mOp.: 158-160C;
y;eld: 14.3 9.
With ethereal hydrochlor;c acid, the hydrochloride of the starting compound ;s obta;ned, and is recrystallised from methylene chloride/methanol. m.p.: 184-194C (slo~
deliquescence).
15. 3-Ethyl 5-C3-(4,4-diphenylpiper;d-1-yl)-propyl~
1,4-dihydro-2,6-dimethyl-4-C3-(1,1,2,2-tetrafluoroethoxy~-phenyl~-pyr;d;ne-3~5-dicarboxylate hydrochlor;de _ _ _ . _ _ _ _ _ _ The title compound of m.p. 196-197C (decomposition, from methylene chloride and diisopropyl ether); yield: 48.9 9, is obta;ned analogously to Example 1 from 22.2 9 of 3-~1,1,2,2-tetrafluoroethoxy)-benzaldehyde, 12.9 9 of ethyl 3-aminocrotonate and 37.9 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl acetoacetate in 28û ml of tert.-butanol after a reaction t;me of 14 hours.
16. 3-Ethyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl~
1~4-dihydro-2,6-dimethyl-4-(3-difluorometho~yphenyl)-pyridine-3,5-dicarboxylate hydrochloride The tltle compound of m.p. 197-198C ~fine plate-lets from methylene chloride and ethyl acetate); yield:
5.1 9, is obtained analogously to Example 1 from 1.6 9 of 3-difluoromethoxyb~nzaldehyde, 1~3 9 of ethyl 3 aminocro~on-ate and 3.8 9 of 3-(4,4-d;phenylp;per;d-1-yl)-propyl aceto-acetate in 80 ml of tetrahydrofuran af~er a reaction t;me of 4 hours.
17. 3 Methyl 5-C3-~4~4-d;phenylp;per;d-!-yl)-propyl~
4-(2 3-dichloroDhenyl)-1~4-dihydro-2,6-dimethylpyr;d;ne-3~5-dicarboxylate h ~rochloride The ~itle compound of m.p. 228~230C (fine needLes from ~ethanol and ethyl acetate); yield: 4.2 9, is obtained analogously to Example 1 from 2~72 9 of methyl 2-acetyl-3-(2,3-dichlorophenyl)-acrylate and 3.7~ 9 of 3-~4,4-diphenyl-piperid-1-yl)-propyl 3-am;nocrotonate ;n 100 ml of 2-propanol after a reaction time of 7 hours.
18 3-M~thvl 5-r~ b~ n~erid-1-vl~-DroDv~
(2~ -benzQx~!~azol-4-v~ dihvdro-2.6-~Lim~thvl-Dvr~ e-3.5-~farboxvla~ hydrochloride The tltle compound of m p. 208-210C ~fine lumpy crystals from ethyl acetate and methylene chloride); yield: 4 1 ~, is ob-tained analogously to Example 1 from 2.5 9 o~ methyl 2-acetyl-3-t2,1,3-benzoxdiazol-~-yl)-acrylate and 3.8 g of 3-(4,4-diphenyl-piperid-l-yl)-propyl 3-aminocrotonate in 60 ml of tetrahydrofuran and 0 5 ml of acetic acid after a reaction Sime of 4 hours 19. 3-Methyl 5-~3-(4,4-d;ph~nylpiperid-1-yl)-propyl~
1,4-dihydro-2,6-dimethyl-4-(3-fluorophenyl)-pyridine 3,5-d;c~rboxylate hydrochlor;de The title compound of m p. 213-216C Ifine, angular crystals from methylene chloride and diisopropyl ether); yield:
4.8 g, iQ obtained analogously to Example 1 from 2.44 9 of methyl 2-acetyl-3-~3-fluorophenyl)-acrylate and 4.39 9 of 3-(4,~-diphe-nylpiperid-1-yl)-propyl 3-aminocrotonate in 50 ml of tetrahydro-furan after a reaction tlme of 5 hour~.
3~7 ~ 27 -.- 20.3-Me~L 5~C3~(4,4-diphenylpiper~d~ l)~roPy~
10_dihydro-2,~5-dimethyl-4-(2-tri~luorom~thylphenyl)-pyr;-d i n e -3 5-g~L~
.
Thc title compound of m.p, 158-162C [flna, cublcal crystal~ from methylene chloride ~n~ dl~sopropyl ~ther); yield:
.2 g, ls obtalned ~nalogously to Example 1 from 2.7 9 of methyl 2-acetyl-3-(2-trifluorom~thylphenyl)-~crylate and ~ of 3-~ diphenylplp~rid-l-yl)-propyl 3-aminocrotonate in ~0 ml of tert.-butanol after a reaction time of ~ hour~.
21. 3-Eth l 5-C3-~4 4-di henYl i erid-1-yl)-propyl]
. Y~ . P -... P P
104-t-2--cyanoehe~L~ro-2~6-dimethylpyridine-3~5 dicarboxyLate_hydrochloride The title compound of m.p. 178-181C (flne necdles from ethyl acetate and m~thylene chlorlde); yisld: 8.~ 9, ls obtalned analogously to Example 1 from 3.93 9 of 2-cyanobenzaldehyde, 3.~5 9 of methyl 3-amlnocrotonate and 11.38 ~ of 3~ -dlphenyl-piperid-1-yl~-propyl acetoacetate in 80 ml of Z-propanol after a reaction time of 10 hours.
22. 3-Methvl 5- U -l4 ~4-dl~hsnvl~iDeri~- ? -~1~ -pro~vl ~-l2-~hloro~henvl~ -dihvdrQ-~6-dimethvlDvridine-3.5-dicarboxvlate hvdrochlori~
The title compound of m.p. 150C (decomposition) (fine, needles from methylene chloride and diisopropyl ether); yield:
3.3 9, is obtained analogously to Example t from 3 6 9 of methyl 2-acetyl-3-(2-chlorophenyl)-acrylate and 5.7 9 of 3-~,4-di-phenylpiperid-1-yl)-propyl 3-aminocrotonate in 60 ml of tetra-hydrofuran and 0.5 ml o~ acetic acid after a reaction time of 8 hours.
~ 3 Commercial Usefulness _~ _.A
The compounds of the formula I according to the ;nvention and their salts have useful properties which render them commerciaLly useful. In particular, they are active vasodilators with properties as coronary therapeutics.
The pharmacological activity of the compounds accordin~ to the invention, ~hich is coupled with a low toxicity, mani-fests itself ;n particu(ar in a reduction in blood pressure wh;ch starts slowly, is po~erful and lasts for a long time.
Moreover, the compounds according to the invention have peripheral, coronary, cerebral and renal vasodilating pro-perties and salidiuretic properties.
In their excellent activity, ~hich is coupled with a low toxicity and the absence of substantial s;de effects, the compounds according to the invention differ in a sur-prising and advantageous manner from the compounds of the prior art. Examples of advantageous properties ~hich may be mentioned are: the slow onset of the reduction in blood pressure, the degree of reduction in blood pressure, the long period ~hich the reduction in blood pressure lasts, the good ease of control of the reduction in blood pressure, the only slight increase in heart rate, which disappears on repeated administration, the excellent bioavailability, the wide therapeutic range, the absence of side effects on the central nervous system, the absence of kinetic interactions with other substances, the absence of-tolerance development, the balanced physical properties and the high stability.
The e~cellent activity of the compounds of the formula I according to the invention and their salts enables them to be used in human medicine, possible ind;cations being, in particular, primary (essential) and secondary hypertension of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myo-cardial ;nfarction etc.), disturbances in.peripheral and cerebral circulation (cerebral apoplexy, temporary disturbances in cerebral circulation, narrowing of the renal artery otc. ), cardi~c in~ufficl~ncy 3nd d1~eases ~asQ~ on an ln creased ret~ntlon o~ water and sodium.
The invention thus furthermore relat~s to a method for the treatment of mammals, in particular humansO suffer-ing from one of the abovement;oned d;seases. The method is character;sed in that a therapeutically effective and pharmacologically acceptable amount of one or more compounds of the formula I is administered-to the s;ck ;ndiv;dual.
The invention also relates to the compounds of the formula I for use ;n the treatment of the d;seases ment;oned.
The invention likeuise relates to the use of com-pounds of the formula ~ ;n the preparat;on of medicaments which are employed for combat;ng the d;seases ment;oned.
The invention furthermore relates to medicaments containing one or more compounds of the general formula I.
The medicaments are prepared by processes uhich are known per se and are familiar to the expert. As med;caments, ~he pharmacologically active compounds (= active compounds) according to the invention are employed either as such or, preferably, in combination with suitable pharmaceutical auxiliaries in the form of tablets, coated tablets, cap-sules, suppos;tories~ plasters (for example as TTS), emul-sions, suspensions or solutions, the content of active com-pound advantageously being between 0.1 and 95%.
The expert is famil;ar w;th what auxil;aries aresuitable for the desired medicament formulations on the basis of his expert knowledge. In addition to solvents, gelling agents, suppository bases, tabletting auxiliaries and other active compound excipients, it is possible to use, for example, antiox;dants, d;spers;ng agents, emulsi-f;ers, antifoaming agents, flavour correctants, preserva-tives, solubilising agents, dyestuffs or, in particular, permeation promoters and c~mplexing agents (for example cyclodextrins).
The active compounds can be adm;nistered orally or parenterally ~in par~icular perlingually, intravenously or percutaneously).
In general, it has proved advantageous in human medicine to administer the active compound or compounds, when these are administered orally, in a daily dose of about 0.01 to about 10, preferably û.ûS to 5 mg/kg of body weight, if desired in the form of several, preferably 1 to 4, ;ndi-vidual doses, to achieve the desired results. In the case of parenteral treatment, similar or (especially when the active compounds are administered intravenously) as a rule lo~er doses can be used. ~ith a dosage increasing from initially small amounts, a lower dose is administered at the start of the treatment and this is then slowly changed to a higher dose. When the desired therapeutic result has been achieved, the dose is reduced again to a lower dose.
The particular optimum dosage required and the mode of administration of the active compounds can easiLy be determined by any expert on the basis of his expert know-ledge.
If the compounds according to the invention and/or their salts are to be employed for the treatment of the diseases ment;oned, the pharmaceutical formulations can also contain one or more other pharmacologically active con-st;tuents from other groups of medicaments, such as other vasodilatorc, antihypertenslves, ~-receptor blockers, B-receptor blockers, ACE-inhibitors, nitro-compounds, cardiotonics, diure-tics, saluretics, alkaloids etc., such as nifedipine, dihydrala-zine, prazosine, propranolol, labetalol, captopril, isosorbide dinLtrate, digoxin, mefruside, clopamide, spironolactone, chlor-thalidone, furosemide, polythiazide, hydrochlorothiazide, reser-pine, dihydroergocristine, rescinnamine, Rauwolfia total alka-loids etc.
Pharmacology The ant;hypertensive act;vity of the compounds according to the invention can be demonstrated on the model of spontaneously hypertensive rats.
S To determ;ne the antihypertensive action, the com-pounds l;sted below are adm;nistered once daily, by means of a stomach tube, on four successive days in the doses men-tioned to in each case 6 rats (s~rain SHR/N/I~m/Bm o , 250-350 9) with hypertension of ge~et;c orig;n (RR > 180 mmHg).
The blood pressure is in each case measured 6 and, if appropriate, 2 or 24 hours after administration of the sub stance.
The blood pressure measurement is carr;ed out in a heated chamber at 36C in order to achieve better circula-t;on in the tail artery. For this, the animals are trans-ferred to perforated sheet metal cages and the measurement is made 20 - 40 minutes after warming up has been started.
To measure the systolic arterial pressure, an annular cuff with an inflatable rubber membrane, for suppressing circula-tion, and an annular piezocrystal transducer, to recordpulse waves, are pushed onto the tail. When the blood stream has been suppressed in the tail artery, the cuff pressure is reduced continuously. Return of the pulse waves as the pressure is reduced is recognised and expressed automatically as the systolic blood pressure (Buhler, R. et al.: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (eds.), Schattauer Verlag, Stuttgart, New York, 1982, pages 410-413). The pulse signals and pressure course are recorded graphicaLLy for evaluation.
For acclimatisation to the measurement process, the animals ar~ trained for 14 days before the substance is - 32 ~X~ f tested. In the second week of training, blood pressure prevalues are recorded. The groups of animals receiving the substance are tested against a control group.
In the table which follows, the compounds investigated are labelled by serial numbers, which are allocated as follows:
Serial No. Name of the compound 1 3-Methyl 5-~3-(4,4-diphenylpiperid-1-yl~-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 2 3-Methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 3 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydrochloride 4 3-Methyl 5-[2-(4,4-diphenylpiperid-1-yl)-2-methyl-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 3-Ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 6 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl~
1,4-dihydro-2,6-dimethyl-4-t3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-pyridine-3,5-dicarboxylate hydro-chloride 7 ~-(2-Methoxyethyl) 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate fumarate 8 3-(2-Methoxyethyl) 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate fumarate 33 12~
Serial No. Name of the compound . _____.
9 3-Methyl 5-{3-t4,4~di-~4-methoxyphenyl)-piperid-1-yl]-propyl} 1,4-dihydro-Z,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 1D 3-Methyl 5-[h-(4,4-diphenylpiperid-1-yl)-butyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate fumarate 11 3-Methyl 5-t1,1-dimethyl-Z-(4,4-diphenylpiPerid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-~3-nitro-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 12 3-Ethyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(2-difluoromethoxy-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 13 3-Ethyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-difluoromethoxy-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 14 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
4-(2~3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate hydrochloride 3-Methyl 5-t3-~4,4-diphenylpiperid-1-yl)-propyl]
4-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-di-methylpyridine-3,5-dicarboxylate hydrochloride - 34 - ~29~
Serial No. Name o~ the compound 16 3-Methyl 5-[3-t4,4-diphenylpiperid-t-yl)-proPYl~
1,4-dihydro-2,6-dimethyl-4-l3-~luorophenyl)-pyrl-dine-3,5-dicarboxylate hydrochloride 17 3-Methyl 5-~3-t4,4-diphenylpiperid-1-yl)-propyl~
1,~-dihydro-2,6-dimethyl-4-(2-tri~luoromethyl-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 18 3-Ethyl 5-[3-t4,~-diphenylpiperid-1-yl)-propyl]
4-t2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydrochloride 19 3-Methyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl]
4-t2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate hydrochloride Table I shows the precentage reduction in blaod pressure (~P) following oral administration to rats for the representatives of the compounds according to the invention.
Table I
X change (6P) in genetically hypertensive rats following a single daily oral administraiton on four successive days ~N=6/dose); the dose in mg/kg is calculated on the free base.
6P ~X changes vs. control) Serial Dose mean values of the given points No. of time of measurement ~mol/kg) (mg/kg) 2h 6h 24h (1st~4th (1st to 4th (1st+3rd day) day) day) 1 5 3,05 -47 -30 -7 10 6,0g -50 -37 _9 2515,24 -48 -45 -25 2 2514,89 -51 -36 -2 3 2514,74 -48 -41 -19 4 2515,60 -51 -44 -25 10 6,24 -51 -41 -20 6 2517,02 -21 -21 -10 7 2515,99 -44 -33 0 8 2516,34 -48 -2 a - 5 9 10 6,70 -53 -45 -14 10 6,24 -40 _~ -2 11 5 3,12 -54 -33 -15 12 2516,12 -31 -11 +4 13 2516,12 -41 -29 -6 14 2515,84 -49 -43 -30 2515,17 -49 -41 -16 16 2514,57 -46 -38 -7 17 2515,82 -44 -30 -17 18 2515,09 -37 -25 -1 19 2514,98 -43 -28 -2
1~4-dihydro-2~6-dimethYl-4-(3-nitrophenyl)-pyrid7ne-3~5-_ _ _ _ _ _ _ . . _ _ _ _ _ d;carboxylate fumarate The title compound of m.p. 123-126 (fine needles, 15 from ethyl acetate and methylene chloride); yield: 3.9 9, is obtained analogously to Example 1 from 3.94 9 of 4-(4,4-diphenylpiperid-1-yl)-butyl acetoacetate, 1.15 9 of methyl 3-aminocrotonate and 1.51 9 of 3-n;trobenzaldehyde in 80 ml of tert.-butanol after a reaction time of 6 hours.
20 12. 3-Methyl 5-C1,1-dimethyl-2-~4,4-diphenylpiperid-1-yl)-ethyl~ 1~4-dihydro-?,6-dimethyl-4-(3-nitrophenyl)-pyridine-3 5-dicarboxylate hydrochloride The title compound of m.p. from 148C (slow deli-quescence, amorphous, precipitated from petroleum ether);
25 yield: 11.3 9, is obtained analogously to Example 1 from 15.8 9 of 1,1-dimethyl-2-(4,4-diphenylpiperid-1-yl)-ethyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 3.45 9 of methyl 3-aminocrotonate in 120 ml of 2-propanol after a reaction time of 15 hours.
13. ~ 4 ~ -di enylpiperld-1-y ~ PX~
pyr-d e-3 ~ oxylate hydrochloride The title compound of m.p. from 126C (slow deli-S quescence, 3morphous, precipitated from petroleum ether anddiethyl ether 1:1); yield: 2.8 9, is obtained analogously to Example 1 from 3.8 g of 3-t4,4-diphenylp;perid-1-yl)-propyl 2-acetyl-3-t2-difluoromethoxyphenyl)-acrylate and 1.3 9 of ethyL 3-aminocrotonate in 60 ml of tert.-butanol after a reaction time of 20 hours.
14. 1~4-Dihydro-2,6-dimethyl-4-t3-nitrop ~ dine-3 ~ icarb_xy_lic acid 3-C3-(4c4-diphenylpiperid-1-yl~-propyl~ ester 6.8 9 of 3-(2-cyanoethyl) 5-C3-t404-diphenylpiperid-1-yl)-propyl~ 1~4~dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride are stirred with 40 ml of 0.5 N sodium hydroxide solution and 100 ml of dioxane at room temperature for 3 hours. After most of the dioxane has been distilled off, 15 ml of 2 N hydrochloric acid are added to the residue. The milky/cloudy solution is extracted 4 times with 100 ml of chloroform/n-butanol t3:1) each time and the combined organic phase is washed ~ith 50 ml of saturated sodium chloride solution. The organic phase is concentrated to dryness and the solid residue is recrystallised from chloroform/methanol t1:1).
m.p. 192-195C (decomposition); yield: 504 9.
The starting compound 3-t2-cyanoethyl) 5-~3-(4~4-diphenylpiperid-_-yl)-propy ~ -dihydro-?,6-dimethyl 4-(3-nitrophenyl)-pyr din ~ -dicarboxylate is obtained as follo~s:
8.1 g of 2-cyanomethyl 2-acetyl-3-(3-nitrophenyl)-acrylate and 10.6 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl 3~aminocrotonate are heated at the bo1Ling point under reflux in 120 ml of 2-propanol and 0.5 ml of glacial acetic acid for 4 hours. After most of the solvent has been dis-tilled off and 2 portions of 50 ml of toluene e~ch have been added, the residue is concentrated to dryness. The residue, ~hich has foamed as a sol;d, ;s taken up ;n ;sopropanol and d;ethyl ether is added to the clear solution until the cloud;ness f;rst persists. After the mixture has been left to stand in a refrigerator, the starting compound crys~al-lises out in the form of fine plateLets. mOp.: 158-160C;
y;eld: 14.3 9.
With ethereal hydrochlor;c acid, the hydrochloride of the starting compound ;s obta;ned, and is recrystallised from methylene chloride/methanol. m.p.: 184-194C (slo~
deliquescence).
15. 3-Ethyl 5-C3-(4,4-diphenylpiper;d-1-yl)-propyl~
1,4-dihydro-2,6-dimethyl-4-C3-(1,1,2,2-tetrafluoroethoxy~-phenyl~-pyr;d;ne-3~5-dicarboxylate hydrochlor;de _ _ _ . _ _ _ _ _ _ The title compound of m.p. 196-197C (decomposition, from methylene chloride and diisopropyl ether); yield: 48.9 9, is obta;ned analogously to Example 1 from 22.2 9 of 3-~1,1,2,2-tetrafluoroethoxy)-benzaldehyde, 12.9 9 of ethyl 3-aminocrotonate and 37.9 9 of 3-(4,4-diphenylpiperid-1-yl)-propyl acetoacetate in 28û ml of tert.-butanol after a reaction t;me of 14 hours.
16. 3-Ethyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl~
1~4-dihydro-2,6-dimethyl-4-(3-difluorometho~yphenyl)-pyridine-3,5-dicarboxylate hydrochloride The tltle compound of m.p. 197-198C ~fine plate-lets from methylene chloride and ethyl acetate); yield:
5.1 9, is obtained analogously to Example 1 from 1.6 9 of 3-difluoromethoxyb~nzaldehyde, 1~3 9 of ethyl 3 aminocro~on-ate and 3.8 9 of 3-(4,4-d;phenylp;per;d-1-yl)-propyl aceto-acetate in 80 ml of tetrahydrofuran af~er a reaction t;me of 4 hours.
17. 3 Methyl 5-C3-~4~4-d;phenylp;per;d-!-yl)-propyl~
4-(2 3-dichloroDhenyl)-1~4-dihydro-2,6-dimethylpyr;d;ne-3~5-dicarboxylate h ~rochloride The ~itle compound of m.p. 228~230C (fine needLes from ~ethanol and ethyl acetate); yield: 4.2 9, is obtained analogously to Example 1 from 2~72 9 of methyl 2-acetyl-3-(2,3-dichlorophenyl)-acrylate and 3.7~ 9 of 3-~4,4-diphenyl-piperid-1-yl)-propyl 3-am;nocrotonate ;n 100 ml of 2-propanol after a reaction time of 7 hours.
18 3-M~thvl 5-r~ b~ n~erid-1-vl~-DroDv~
(2~ -benzQx~!~azol-4-v~ dihvdro-2.6-~Lim~thvl-Dvr~ e-3.5-~farboxvla~ hydrochloride The tltle compound of m p. 208-210C ~fine lumpy crystals from ethyl acetate and methylene chloride); yield: 4 1 ~, is ob-tained analogously to Example 1 from 2.5 9 o~ methyl 2-acetyl-3-t2,1,3-benzoxdiazol-~-yl)-acrylate and 3.8 g of 3-(4,4-diphenyl-piperid-l-yl)-propyl 3-aminocrotonate in 60 ml of tetrahydrofuran and 0 5 ml of acetic acid after a reaction Sime of 4 hours 19. 3-Methyl 5-~3-(4,4-d;ph~nylpiperid-1-yl)-propyl~
1,4-dihydro-2,6-dimethyl-4-(3-fluorophenyl)-pyridine 3,5-d;c~rboxylate hydrochlor;de The title compound of m p. 213-216C Ifine, angular crystals from methylene chloride and diisopropyl ether); yield:
4.8 g, iQ obtained analogously to Example 1 from 2.44 9 of methyl 2-acetyl-3-~3-fluorophenyl)-acrylate and 4.39 9 of 3-(4,~-diphe-nylpiperid-1-yl)-propyl 3-aminocrotonate in 50 ml of tetrahydro-furan after a reaction tlme of 5 hour~.
3~7 ~ 27 -.- 20.3-Me~L 5~C3~(4,4-diphenylpiper~d~ l)~roPy~
10_dihydro-2,~5-dimethyl-4-(2-tri~luorom~thylphenyl)-pyr;-d i n e -3 5-g~L~
.
Thc title compound of m.p, 158-162C [flna, cublcal crystal~ from methylene chloride ~n~ dl~sopropyl ~ther); yield:
.2 g, ls obtalned ~nalogously to Example 1 from 2.7 9 of methyl 2-acetyl-3-(2-trifluorom~thylphenyl)-~crylate and ~ of 3-~ diphenylplp~rid-l-yl)-propyl 3-aminocrotonate in ~0 ml of tert.-butanol after a reaction time of ~ hour~.
21. 3-Eth l 5-C3-~4 4-di henYl i erid-1-yl)-propyl]
. Y~ . P -... P P
104-t-2--cyanoehe~L~ro-2~6-dimethylpyridine-3~5 dicarboxyLate_hydrochloride The title compound of m.p. 178-181C (flne necdles from ethyl acetate and m~thylene chlorlde); yisld: 8.~ 9, ls obtalned analogously to Example 1 from 3.93 9 of 2-cyanobenzaldehyde, 3.~5 9 of methyl 3-amlnocrotonate and 11.38 ~ of 3~ -dlphenyl-piperid-1-yl~-propyl acetoacetate in 80 ml of Z-propanol after a reaction time of 10 hours.
22. 3-Methvl 5- U -l4 ~4-dl~hsnvl~iDeri~- ? -~1~ -pro~vl ~-l2-~hloro~henvl~ -dihvdrQ-~6-dimethvlDvridine-3.5-dicarboxvlate hvdrochlori~
The title compound of m.p. 150C (decomposition) (fine, needles from methylene chloride and diisopropyl ether); yield:
3.3 9, is obtained analogously to Example t from 3 6 9 of methyl 2-acetyl-3-(2-chlorophenyl)-acrylate and 5.7 9 of 3-~,4-di-phenylpiperid-1-yl)-propyl 3-aminocrotonate in 60 ml of tetra-hydrofuran and 0.5 ml o~ acetic acid after a reaction time of 8 hours.
~ 3 Commercial Usefulness _~ _.A
The compounds of the formula I according to the ;nvention and their salts have useful properties which render them commerciaLly useful. In particular, they are active vasodilators with properties as coronary therapeutics.
The pharmacological activity of the compounds accordin~ to the invention, ~hich is coupled with a low toxicity, mani-fests itself ;n particu(ar in a reduction in blood pressure wh;ch starts slowly, is po~erful and lasts for a long time.
Moreover, the compounds according to the invention have peripheral, coronary, cerebral and renal vasodilating pro-perties and salidiuretic properties.
In their excellent activity, ~hich is coupled with a low toxicity and the absence of substantial s;de effects, the compounds according to the invention differ in a sur-prising and advantageous manner from the compounds of the prior art. Examples of advantageous properties ~hich may be mentioned are: the slow onset of the reduction in blood pressure, the degree of reduction in blood pressure, the long period ~hich the reduction in blood pressure lasts, the good ease of control of the reduction in blood pressure, the only slight increase in heart rate, which disappears on repeated administration, the excellent bioavailability, the wide therapeutic range, the absence of side effects on the central nervous system, the absence of kinetic interactions with other substances, the absence of-tolerance development, the balanced physical properties and the high stability.
The e~cellent activity of the compounds of the formula I according to the invention and their salts enables them to be used in human medicine, possible ind;cations being, in particular, primary (essential) and secondary hypertension of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myo-cardial ;nfarction etc.), disturbances in.peripheral and cerebral circulation (cerebral apoplexy, temporary disturbances in cerebral circulation, narrowing of the renal artery otc. ), cardi~c in~ufficl~ncy 3nd d1~eases ~asQ~ on an ln creased ret~ntlon o~ water and sodium.
The invention thus furthermore relat~s to a method for the treatment of mammals, in particular humansO suffer-ing from one of the abovement;oned d;seases. The method is character;sed in that a therapeutically effective and pharmacologically acceptable amount of one or more compounds of the formula I is administered-to the s;ck ;ndiv;dual.
The invention also relates to the compounds of the formula I for use ;n the treatment of the d;seases ment;oned.
The invention likeuise relates to the use of com-pounds of the formula ~ ;n the preparat;on of medicaments which are employed for combat;ng the d;seases ment;oned.
The invention furthermore relates to medicaments containing one or more compounds of the general formula I.
The medicaments are prepared by processes uhich are known per se and are familiar to the expert. As med;caments, ~he pharmacologically active compounds (= active compounds) according to the invention are employed either as such or, preferably, in combination with suitable pharmaceutical auxiliaries in the form of tablets, coated tablets, cap-sules, suppos;tories~ plasters (for example as TTS), emul-sions, suspensions or solutions, the content of active com-pound advantageously being between 0.1 and 95%.
The expert is famil;ar w;th what auxil;aries aresuitable for the desired medicament formulations on the basis of his expert knowledge. In addition to solvents, gelling agents, suppository bases, tabletting auxiliaries and other active compound excipients, it is possible to use, for example, antiox;dants, d;spers;ng agents, emulsi-f;ers, antifoaming agents, flavour correctants, preserva-tives, solubilising agents, dyestuffs or, in particular, permeation promoters and c~mplexing agents (for example cyclodextrins).
The active compounds can be adm;nistered orally or parenterally ~in par~icular perlingually, intravenously or percutaneously).
In general, it has proved advantageous in human medicine to administer the active compound or compounds, when these are administered orally, in a daily dose of about 0.01 to about 10, preferably û.ûS to 5 mg/kg of body weight, if desired in the form of several, preferably 1 to 4, ;ndi-vidual doses, to achieve the desired results. In the case of parenteral treatment, similar or (especially when the active compounds are administered intravenously) as a rule lo~er doses can be used. ~ith a dosage increasing from initially small amounts, a lower dose is administered at the start of the treatment and this is then slowly changed to a higher dose. When the desired therapeutic result has been achieved, the dose is reduced again to a lower dose.
The particular optimum dosage required and the mode of administration of the active compounds can easiLy be determined by any expert on the basis of his expert know-ledge.
If the compounds according to the invention and/or their salts are to be employed for the treatment of the diseases ment;oned, the pharmaceutical formulations can also contain one or more other pharmacologically active con-st;tuents from other groups of medicaments, such as other vasodilatorc, antihypertenslves, ~-receptor blockers, B-receptor blockers, ACE-inhibitors, nitro-compounds, cardiotonics, diure-tics, saluretics, alkaloids etc., such as nifedipine, dihydrala-zine, prazosine, propranolol, labetalol, captopril, isosorbide dinLtrate, digoxin, mefruside, clopamide, spironolactone, chlor-thalidone, furosemide, polythiazide, hydrochlorothiazide, reser-pine, dihydroergocristine, rescinnamine, Rauwolfia total alka-loids etc.
Pharmacology The ant;hypertensive act;vity of the compounds according to the invention can be demonstrated on the model of spontaneously hypertensive rats.
S To determ;ne the antihypertensive action, the com-pounds l;sted below are adm;nistered once daily, by means of a stomach tube, on four successive days in the doses men-tioned to in each case 6 rats (s~rain SHR/N/I~m/Bm o , 250-350 9) with hypertension of ge~et;c orig;n (RR > 180 mmHg).
The blood pressure is in each case measured 6 and, if appropriate, 2 or 24 hours after administration of the sub stance.
The blood pressure measurement is carr;ed out in a heated chamber at 36C in order to achieve better circula-t;on in the tail artery. For this, the animals are trans-ferred to perforated sheet metal cages and the measurement is made 20 - 40 minutes after warming up has been started.
To measure the systolic arterial pressure, an annular cuff with an inflatable rubber membrane, for suppressing circula-tion, and an annular piezocrystal transducer, to recordpulse waves, are pushed onto the tail. When the blood stream has been suppressed in the tail artery, the cuff pressure is reduced continuously. Return of the pulse waves as the pressure is reduced is recognised and expressed automatically as the systolic blood pressure (Buhler, R. et al.: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (eds.), Schattauer Verlag, Stuttgart, New York, 1982, pages 410-413). The pulse signals and pressure course are recorded graphicaLLy for evaluation.
For acclimatisation to the measurement process, the animals ar~ trained for 14 days before the substance is - 32 ~X~ f tested. In the second week of training, blood pressure prevalues are recorded. The groups of animals receiving the substance are tested against a control group.
In the table which follows, the compounds investigated are labelled by serial numbers, which are allocated as follows:
Serial No. Name of the compound 1 3-Methyl 5-~3-(4,4-diphenylpiperid-1-yl~-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 2 3-Methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 3 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydrochloride 4 3-Methyl 5-[2-(4,4-diphenylpiperid-1-yl)-2-methyl-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 3-Ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride 6 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl~
1,4-dihydro-2,6-dimethyl-4-t3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-pyridine-3,5-dicarboxylate hydro-chloride 7 ~-(2-Methoxyethyl) 5-~2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate fumarate 8 3-(2-Methoxyethyl) 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate fumarate 33 12~
Serial No. Name of the compound . _____.
9 3-Methyl 5-{3-t4,4~di-~4-methoxyphenyl)-piperid-1-yl]-propyl} 1,4-dihydro-Z,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 1D 3-Methyl 5-[h-(4,4-diphenylpiperid-1-yl)-butyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate fumarate 11 3-Methyl 5-t1,1-dimethyl-Z-(4,4-diphenylpiPerid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-~3-nitro-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 12 3-Ethyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(2-difluoromethoxy-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 13 3-Ethyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-difluoromethoxy-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 14 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
4-(2~3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate hydrochloride 3-Methyl 5-t3-~4,4-diphenylpiperid-1-yl)-propyl]
4-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-di-methylpyridine-3,5-dicarboxylate hydrochloride - 34 - ~29~
Serial No. Name o~ the compound 16 3-Methyl 5-[3-t4,4-diphenylpiperid-t-yl)-proPYl~
1,4-dihydro-2,6-dimethyl-4-l3-~luorophenyl)-pyrl-dine-3,5-dicarboxylate hydrochloride 17 3-Methyl 5-~3-t4,4-diphenylpiperid-1-yl)-propyl~
1,~-dihydro-2,6-dimethyl-4-(2-tri~luoromethyl-phenyl)-pyridine-3,5-dicarboxylate hydrochloride 18 3-Ethyl 5-[3-t4,~-diphenylpiperid-1-yl)-propyl]
4-t2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydrochloride 19 3-Methyl 5-~3-(4,4-diphenylpiperid-1-yl)-propyl]
4-t2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate hydrochloride Table I shows the precentage reduction in blaod pressure (~P) following oral administration to rats for the representatives of the compounds according to the invention.
Table I
X change (6P) in genetically hypertensive rats following a single daily oral administraiton on four successive days ~N=6/dose); the dose in mg/kg is calculated on the free base.
6P ~X changes vs. control) Serial Dose mean values of the given points No. of time of measurement ~mol/kg) (mg/kg) 2h 6h 24h (1st~4th (1st to 4th (1st+3rd day) day) day) 1 5 3,05 -47 -30 -7 10 6,0g -50 -37 _9 2515,24 -48 -45 -25 2 2514,89 -51 -36 -2 3 2514,74 -48 -41 -19 4 2515,60 -51 -44 -25 10 6,24 -51 -41 -20 6 2517,02 -21 -21 -10 7 2515,99 -44 -33 0 8 2516,34 -48 -2 a - 5 9 10 6,70 -53 -45 -14 10 6,24 -40 _~ -2 11 5 3,12 -54 -33 -15 12 2516,12 -31 -11 +4 13 2516,12 -41 -29 -6 14 2515,84 -49 -43 -30 2515,17 -49 -41 -16 16 2514,57 -46 -38 -7 17 2515,82 -44 -30 -17 18 2515,09 -37 -25 -1 19 2514,98 -43 -28 -2
Claims (17)
1. A compound of the general formula I, (I) wherein Ar represents a ring of the formula in which Y denotes oxygen (O), sulphur (S), vinylene (-CH=CH-), azomethine (-CH=N-) or a group of the formula or Rl, R2 and R3 are identical or different and denote hydrogen, Cl-C6-alkyl, C3-C7-alkoxyalkyl, aryl, aryl-Cl-C6-alkyl or aryloxy-Cl-C6 alkyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, cl-C4-alkyl, Cl-C4-alkoxy, C1-C4-alkoxy which is completely or partly substitu-ted by fluorine, C1-C4-alkoxycarbonyl, C2-C5-acyl, amino or mono-or di-C1-C4-alklylamino, R6, R7, R8 and R9 are identical or different and denote hydrogen, hydroxyl, halogen, C1-C4-alkyl, C1-C4-alkoxy, amino, mono- or di-C1-C4-alkylamino, or C1-C4-alkoxy which is completely or partly substituted by fluorine, and A denotes straight-chain or branched C2-C5-alkylene, which can be substituted by C1-C4-alkoxy or aryl, or a pharmaceutically acceptable salt thereof wherein aryl represents phenyl or phenyl substituted by halogen, hydroxyl, nitro, cyano, trifluoromethyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C2-C5-acyl, amino or mono- or di-C1-C4-alkylamino.
2. A compound according to Claim 1, wherein Ar represents the ring mentioned in Claim 1, in which Y denotes vinylene (-CH=CH-), and R1, R2, R3, R4, R5, R6, R7, R8, R9 and A have the meanings given in Claim 1.
3. A compound according to Claim 1, wherein Ar represents the ring mentioned in Claim 1, in which Y denotes R4 and R5 denote hydrogen and R1, R2, R3, R6, R7, R8, R9 and A have the meanings given in Claim 1.
37a 25458-65
37a 25458-65
4. A compound according to Claim 1, 2 or 3, wherein R1 denotes C1-C4-alkyl, R2 denote.s C1-C4-alkyl, R3 denotes C1-C4-alkyl or C3-C5-alkoxyalkyl, R4 denotes hydrogen, chlorine, nitro, methyl or methoxy, R5 denotes hydrogen, chlorine, fluorine, nitro, cyano, methyl, methoxy, difluoromethoxy, 1,1,2,2-tetrafluoro-ethoxy, trifluoromethyl or acetyl, R6 denotes hydrogen or methoxy, R7 denotes hydrogen, hydroxyl, chlorine, methyl, methoxy, di-fluoromethoxy or 1,1,2,2-tetrafluoroethoxy, R8 denotes hydrogen or methoxy, R9 denotes hydrogen, hydroxyl, chlorine, methyl, methoxy, difluoromethoxy or 1,1,2,2 tetrafluoroethoxy and A denotes ethylene or propylene.
5. A compound according to Claim 1, 2 or 3, wherein R1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R4 denotes hydrogen, R5 denotes hydrogen, chlorine, fluorine, nitro, cyano, methyl, methoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy or trifluoromethyl, R6 denotes hydrogen, R7 denotes hydrogen, hydroxyl chlorine, methyl, methoxy, difluoro-methoxy or 1,1,2,2-tetrafluoroethoxy, R8 denotes hydrogen, R9 denotes hydrogen, hydroxyl, chlorine, methyl, methoxy, difluoro-methoxy or 1,1,2,2-tetrafluoroethoxy and A denotes ethylene or propylene.
6. A compound according to Claim 2, wherein R1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxy-ethyl, R4 denotes hydrogen or chlorine, R5 denotes hydrogen, chlorine, fluorine, nitro, cyano, difluoromethoxy, 1,1,2,2-tetra-fluoroethoxy or trifluoromethyl, R6 denotes hydrogen, R7 denotes hydrogen or methoxy, R8 denotes hydrogen, R9 denotes hydrogen or methoxy and A denotes ethylene, propylene, butylene, 1,1-dimethyl-ethylene or 2,2-dimethylethylene.
7. A compound according to Claim 1, wherein Ar denotes phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyano-phenyl, 2-(1,1,2,2-tetrafluoroethoxy)-phenyl, 3-(1,1,2,2-tetra-fluoroethoxy)-phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxy-phenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl or 3-tri-fluoromethylphenyl, R1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R6 denotes hydrogen, R7 denotes hydrogen or methoxy, R8 denotes hydrogen, R9 denotes hydrogen or methoxy and A denotes ethylene, propylene, butylene, 1,1-dimethylethylene or 2,2-dimethylethylene.
8. A compound according to Claim 3, wherein R1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxy-ethyl, R4 denotes hydrogen, R5 denotes hydrogen, R6 denotes hydrogen, R7 denotes hydrogen or methoxy, R8 denotes hydrogen, R9 denotes hydrogen or methoxy and A denotes ethylene, propylene, butylene, 1,1-dimethylethylene or 2,2-dimethylethylene.
9. A compound according to Claim 1, wherein Ar denotes 2-nitrophenyl or 3-nitrophenyl, R1, R2 and R3 are identical or different and denote C1-C6-alkyl or C3-C7-alkoxyalkyl, A repre-sents straight-chain or branched C2-C5-alkylene and R6, R7, R8 and R9 denote hydrogen.
10. A compound according to Claim 1, wherein Ar denotes 2-nitrophenyl or 3-nitrophenyl, R1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R6 denotes hydrogen, R7 denotes hydrogen, R8 denotes hydrogen, R9 denotes hydrogen and A denotes ethylene or propylene.
11. A compound selected from the group consisting of 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(3-cyano-phenyl)-1,4 dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, 3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-2-methyl-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxyate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate, 3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate, 3-(2-methoxyethyl) 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-(2-methoxyethyl) 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-methyl 5-{3-[4,4-di(4-methoxyphenyl)-piperid-1-yl]-propyl}
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-methyl 5-[4-(4,4-diphenylpiperid-1-yl)-butyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[1,1-dimethyl-2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(2-difluoromethoxyphenyl)-pyridine-3,5-dicarboxyl-ate, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylic acid 3-[3-(4,4-diphenylpiperid-1-yl)-propyl ester]
3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro 2,6-dimethyl-4-(3-difluoromethoxyphenyl)-pyridine-3,5-dicarboxyl-ate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxyl-ate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine-3,5-di-carboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-fluorophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxyl-ate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine,-3,5-dicarboxylate and 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2-chloro-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydro-chloride, or a pharmaceutically acceptable salt thereof.
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxyate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate, 3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate, 3-(2-methoxyethyl) 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-(2-methoxyethyl) 5-[3-(4,4-diphenylpiperid-1-yl)-propyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-methyl 5-{3-[4,4-di(4-methoxyphenyl)-piperid-1-yl]-propyl}
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylate, 3-methyl 5-[4-(4,4-diphenylpiperid-1-yl)-butyl]
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[1,1-dimethyl-2-(4,4-diphenylpiperid-1-yl)-ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(2-difluoromethoxyphenyl)-pyridine-3,5-dicarboxyl-ate, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylic acid 3-[3-(4,4-diphenylpiperid-1-yl)-propyl ester]
3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-dicarboxylate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro 2,6-dimethyl-4-(3-difluoromethoxyphenyl)-pyridine-3,5-dicarboxyl-ate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxyl-ate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine-3,5-di-carboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-fluorophenyl)-pyridine-3,5-dicarboxylate, 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxyl-ate, 3-ethyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine,-3,5-dicarboxylate and 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 4-(2-chloro-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydro-chloride, or a pharmaceutically acceptable salt thereof.
12. 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, or a pharmaceutically acceptable salt thereof.
13. A process for preparing a compound of the general formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises:
a) reacting cinnamic acid derivative of the formula II, (II) wherein Ar, R2 and R3 are as defined in claim 1, with an enamine derivative of the formula III
(III) wherein A, R1, R6, R7, R8 and R9 are as defined in claim 1 or b) reacting a cinnamic acid derivative of the formula II as defined above with ammonia and a .beta.-ketocarboxylic acid derivative of the formula IV
(IV) wherein A, R1, R6, R7, R8 and R9 are as defined in claim 1 or c) reacting an enamine of the formula V
(V) wherein R2 and R3 are as defined in claim 1, with a benzylidenecarboxylic acid derivative of the formula VI
(VI) wherein A, Ar, R1, R6, R7, R8 and R9 are as defined in claim 1, or d) reacting a keto compound of the formula VII
(VII) wherein R2 and R3 are as defined in claim 1, with ammonia and a benzylidenecarboxylic acid derivative of the formula VI, as defined above, or e) reacting an aldehyde of the formula VIII
(VIII) wherein Ar is as defined in claim 1, with an enamine of the formula V, as defined above, and a .beta.-ketocarboxylic acid derivative of the formula IV, as defined above, or f) reacting an aldehyde of the formula VIII, as defined above, with an enamine derivative of the formula III, as defined above, and a keto compound of the formula VII as defined above, or g) reacting a 1,4-dihydropyridine of the formula IX
(IX) wherein Ar, R1, R2 and R3 are as defined in claim 1 and 2, together with the carbonyl group to which it is bonded, represents a carboxyl group or a reactive derivative thereof, with a diaryl compound of the formula X
(X) wherein A, R6, R7, R8 and R9 are as defined in claim 1 as such or in the form of its salt, and, if required, converting a resulting salt into the free base or converting a resulting base into a pharmaceutically acceptable salt.
a) reacting cinnamic acid derivative of the formula II, (II) wherein Ar, R2 and R3 are as defined in claim 1, with an enamine derivative of the formula III
(III) wherein A, R1, R6, R7, R8 and R9 are as defined in claim 1 or b) reacting a cinnamic acid derivative of the formula II as defined above with ammonia and a .beta.-ketocarboxylic acid derivative of the formula IV
(IV) wherein A, R1, R6, R7, R8 and R9 are as defined in claim 1 or c) reacting an enamine of the formula V
(V) wherein R2 and R3 are as defined in claim 1, with a benzylidenecarboxylic acid derivative of the formula VI
(VI) wherein A, Ar, R1, R6, R7, R8 and R9 are as defined in claim 1, or d) reacting a keto compound of the formula VII
(VII) wherein R2 and R3 are as defined in claim 1, with ammonia and a benzylidenecarboxylic acid derivative of the formula VI, as defined above, or e) reacting an aldehyde of the formula VIII
(VIII) wherein Ar is as defined in claim 1, with an enamine of the formula V, as defined above, and a .beta.-ketocarboxylic acid derivative of the formula IV, as defined above, or f) reacting an aldehyde of the formula VIII, as defined above, with an enamine derivative of the formula III, as defined above, and a keto compound of the formula VII as defined above, or g) reacting a 1,4-dihydropyridine of the formula IX
(IX) wherein Ar, R1, R2 and R3 are as defined in claim 1 and 2, together with the carbonyl group to which it is bonded, represents a carboxyl group or a reactive derivative thereof, with a diaryl compound of the formula X
(X) wherein A, R6, R7, R8 and R9 are as defined in claim 1 as such or in the form of its salt, and, if required, converting a resulting salt into the free base or converting a resulting base into a pharmaceutically acceptable salt.
14. A pharmaceutical composition for use as a vasodilator or coronary therapeutic which comprises a compound as claimed in any one of claims 1 to 12, together with a suitable diluent or carrier.
15. A process for preparing a pharmaceutical composition for use as a vasodilator or coronary therapeutic, which process comprises incorporating a compound as claimed in any one of claims 1 to 12 as active ingredient in the composition, together with a suitable diluent or carrier.
16. The use of a compound as claimed in any one of claims 1 to 12 as a vasodilator or coronary therapeutic.
17. A commercial package containing as active pharmaceutical ingredient a compound as claimed in any one of claims 1 to 12, together with instructions for the use thereof as a vasodilator or coronary therapeutic.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH465284 | 1984-09-28 | ||
| CH4652/84-8 | 1984-09-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1291137C true CA1291137C (en) | 1991-10-22 |
Family
ID=4280111
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000491694A Expired CA1291137C (en) | 1984-09-28 | 1985-09-27 | 1,4-dihydropyridines with diphenylpiperidylester group |
Country Status (14)
| Country | Link |
|---|---|
| KR (1) | KR930001404B1 (en) |
| AU (1) | AU574842B2 (en) |
| CA (1) | CA1291137C (en) |
| DK (1) | DK440885A (en) |
| ES (3) | ES8703148A1 (en) |
| FI (1) | FI83957C (en) |
| GR (1) | GR852364B (en) |
| HU (1) | HU194210B (en) |
| IE (1) | IE66677B1 (en) |
| IL (1) | IL76511A (en) |
| NO (1) | NO169586C (en) |
| NZ (1) | NZ213629A (en) |
| PT (1) | PT81209B (en) |
| ZA (1) | ZA857477B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK704488D0 (en) * | 1988-12-19 | 1988-12-19 | Novo Industri As | NEW N-SUBSTITUTED AZAHETEROCYCLIC CARBOXYLIC ACIDS |
| DK142287A (en) * | 1986-03-27 | 1987-09-28 | Byk Gulden Lomberg Chem Fab | OPTIC ACTIVE 1,4-DIHYDROPYRIDINE DERIVATIVES |
| HU206181B (en) * | 1988-02-19 | 1992-09-28 | Byk Gulden Lomberg Chem Fab | Process for producing pharmaceutical compositions comprising optically pure r-(+)-niguldipin and its derivatives and suitable for treating tumoros diseases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK525179A (en) * | 1978-12-18 | 1980-06-19 | Sandoz Ag | PROCEDURE FOR PREPARING BENZOXADIAZOLES AND BENZOTHIAZOLES |
-
1985
- 1985-09-06 FI FI853415A patent/FI83957C/en not_active IP Right Cessation
- 1985-09-25 HU HU853602A patent/HU194210B/en unknown
- 1985-09-26 KR KR1019850007105A patent/KR930001404B1/en not_active IP Right Cessation
- 1985-09-27 IL IL76511A patent/IL76511A/en not_active IP Right Cessation
- 1985-09-27 PT PT81209A patent/PT81209B/en not_active IP Right Cessation
- 1985-09-27 AU AU47948/85A patent/AU574842B2/en not_active Ceased
- 1985-09-27 ES ES547385A patent/ES8703148A1/en not_active Expired
- 1985-09-27 NO NO853833A patent/NO169586C/en unknown
- 1985-09-27 ZA ZA857477A patent/ZA857477B/en unknown
- 1985-09-27 IE IE238485A patent/IE66677B1/en not_active IP Right Cessation
- 1985-09-27 DK DK440885A patent/DK440885A/en not_active Application Discontinuation
- 1985-09-27 CA CA000491694A patent/CA1291137C/en not_active Expired
- 1985-09-27 GR GR852364A patent/GR852364B/el unknown
- 1985-09-27 NZ NZ213629A patent/NZ213629A/en unknown
-
1986
- 1986-04-16 ES ES554067A patent/ES8800201A1/en not_active Expired
- 1986-04-16 ES ES554068A patent/ES8708135A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FI853415L (en) | 1986-03-29 |
| FI83957B (en) | 1991-06-14 |
| AU574842B2 (en) | 1988-07-14 |
| ES8800201A1 (en) | 1987-11-01 |
| PT81209A (en) | 1985-10-01 |
| KR930001404B1 (en) | 1993-02-27 |
| ES8708135A1 (en) | 1987-10-16 |
| NO853833L (en) | 1986-04-01 |
| PT81209B (en) | 1988-01-22 |
| ES8703148A1 (en) | 1987-02-16 |
| ES554067A0 (en) | 1987-11-01 |
| IE852384L (en) | 1986-03-28 |
| NO169586B (en) | 1992-04-06 |
| ZA857477B (en) | 1986-05-28 |
| AU4794885A (en) | 1986-04-10 |
| FI83957C (en) | 1991-09-25 |
| DK440885D0 (en) | 1985-09-27 |
| NO169586C (en) | 1992-07-15 |
| DK440885A (en) | 1986-03-29 |
| GR852364B (en) | 1985-12-13 |
| IE66677B1 (en) | 1996-01-24 |
| ES547385A0 (en) | 1987-02-16 |
| HUT38627A (en) | 1986-06-30 |
| KR860002497A (en) | 1986-04-26 |
| ES554068A0 (en) | 1987-10-16 |
| IL76511A (en) | 1990-06-10 |
| NZ213629A (en) | 1989-07-27 |
| HU194210B (en) | 1988-01-28 |
| FI853415A0 (en) | 1985-09-06 |
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