IE66677B1 - New Diaryl Compounds - Google Patents
New Diaryl CompoundsInfo
- Publication number
- IE66677B1 IE66677B1 IE238485A IE238485A IE66677B1 IE 66677 B1 IE66677 B1 IE 66677B1 IE 238485 A IE238485 A IE 238485A IE 238485 A IE238485 A IE 238485A IE 66677 B1 IE66677 B1 IE 66677B1
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- methyl
- ethyl
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- 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
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- 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
New diaryl compounds of the general formula I, (I) and their pharmaceutically acceptable salts are useful as vasodilators and coronary therapeutics. In a preferred compound R1, R2, and R3 are methyl, Ar is 3-nitrophenyl, A is -CH2CH2CH2 and R6, R7, R8 and R9 are each hydrogen. Processes for preparing the diaryl compounds of general formula I and pharmaceutical compositions containing them are also disclosed.
Description
Hgw, di aryl compounds Field of application of the invention The invention relates to new diaryl compounds,, processes for their preparation^ their use and medicaments ' 5 containing,, the®·» The compounds according to the invention are employed in the pharmaceutical industry for the prepara— tion of medi caaents« Known- technical background It is known· that certain 1,,4-di bydropy ri di ne deriva— tives substituted in various way®, have pharmacologically useful properties- European Patent Applications 88^903-^. 94(?,Τ59’ and 106>2.7& »ay be mentioned as examples- Surprisingly^. it has now· been· found that the new, compounds described in mare* detail belour which,, in contrast to the cos— IS pounds^ of the prior ertr carry ® piperidine ring which is di substi tilted in the 4-qpros-i tionr have particularly interesting? oha.rmaco logi ca I properties by which they differ advantageously from the compounds of the prior art.
Oescriptionr of the invention The invention relates to new diaryl compounds of the formula- I wherein Ar represents a ring of the formula in whri chr Y denotes oxygen CO),. sulphur C$)^ vinylene (-CH-CH—),. atomethine C-CH=H—5 or a group of the forffiula R-Z end R5 ers identical or different and denote hydrogen,.
Cf—ChalkyI or C5-C7—alkoxyalky 1^ R4- and RS are identical or different and denote hydrogen, hydroxyl,. halogen^ nitro, cyano,. tri f luoromethy I, £<«« I k y I Cf-C^-a Ikoxy^ C^-C^—alkoxy which is completely or partly substituted by fluorine, C^-c, alkoxycarbonyI, C^-C^-acyI, aerino or oonc- or di— C-| —Cq—a Ikylaeino^ R6^ R7, R8? and R9- are identical or different and denote· hydrogen, hydroxyl, halogen, C-j-C^-a Iky I , C-j- C4 alkoxy, aesrino, mono— or di -C.j »c ^-a I ky Iasi πσ, or —C^.—a I k 0 x y which is completely or partly substituted by fluorine-, and A denotes straight-chain or branched C^-Cj-aIkylene, and their salts..
C-j-C^-Alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, see.-butyl, t-butyl, propyl, isopropyl or, in particular, ethyl or methyl radical. propyl„ 2-aethoxy 1-methy lethyI or 2-ethoxy-1-aethyLathy I radicalHalogen denotes broBrine and,. in particular^ fluorine and chlorine·-. £-1-CX-AI fey I is straight-chain- or branched and 5 denotes^ for exaicrple>. a butyls i-butyl^ sec--buty 1,, t "butyl,, propyl^. isopropyl^ ethyl or^ in particular^, eethyl radicalIn addition to the oxygen ator^ C-j -C/_™alkoxy contains one of· the· abovewentioned —Czya Iky I radicals» The^ raethoxy radical is preferred10 C-j -C^-A Ikoxy which is completely or partly substituted by fluorine is^ for example^ 11,2^2-tetrafluoroethoxy, tri f luoroaethoxy, 2,2,2-- ri f luoroethoxy or difluoro· Bsethoxy» In addition to the carbonyl groups C^-C^-alkoxy— 15 carbonyl contains one of the abovementioned C-j-C^-alkoxy radicals. The «ethoxycarbonyl and ethoxycarbonyl radical are preferred.
In addition to the carbonyl group,, Cg-Cg-acyl contains one et the abovesentioned -C^-aIkyI radicals» The acetyl radical is preferredIn addition to ~h* nitrogen atom^ (S’ono— or di-C«C/.—a Iky I ami no .contains one or tuo of the abowenen ti oned C.j~C&—alkyl radicals» Bi—C-j—C^-alky laeino is preferred^ and especially di aethy I— diethyl— or diisapropyl-awinoStraight—chain· or branched Cg—Cg—a Iky lene is·,, for example,- tetrasrethy T,Z.-di methy lathy lener Τ,ΐ~ di iraethy lethy lene?,. Z^Z-di methy lethy lene,. i sop ropy I i dene^ ΙΙΟ methy lethy lene> 2-ethyLprdoylene- or> in particular,» ethylene or propyleneζσ Possible· salts are all salts u.ith acids. The pharsacologica I ly acceptable salts of the inorganic and organic acids usually escloyed in the pharmaceutical indus try may be mentioned in particular» Pha react) I ogi ca I ly unacceptable salts which say be obtained, for exaaple, as process products when the ccssounds according to the invention are prepared on an industrial scale are converted into pharmacologically accsstasle salts toy processes which are known to the expert» Examples of suitable salts of this type are water-soluble arc water-insoluble acid addition salts,» such as the hydro phosphate,, nitrate, s u I s benzoate, hibenzate, f e .□ride, hydrobromide,, : e , acetate, citrate, hydriodide, gluconate, :oa butyrate, sulphosalic yI a' maleate, laurate, malate, "usargts, succinate, oxalate, tartrate, aasonate, escc-ats, sstsabenate, stearate, tosylate,. 2-hy d rosy ~3 -nasi z ~ c a t» , 3-hydroxy-2-naphthoate or G> - 5 mesylate,. and also salts with bumetanide^ furoseraide^ axo« seraide,. galoseraide, besunide^. piretanide, etacrynic acid,, tienilic acid or 4-chloro-suIpharaoyl-benzoic acid.
Radicals Ar which are to be singled out are the 5 phenyl,. 3-f luoropheny I 2-ch lo ropheny 1, 3-ch loropheny I,, 4ch loropheny 1^ 2^3-dichloropheny1^ 2-cyanopheny 1,, 3-cyano— phenyl,» 2-methoxypheny 1^ S-raethoxypheny lx 2-tri f luo romethy l~ phenyl^ 3-tri f luoromethy Ipfreny 1^ 3-C1^2^2-tetrafluoro— ethoxy)-phenyl,. 2-di flue reset ho xy ph eny 1^ 3-di f luoro met ho xy — phenyl,. 2-tolyl^. p-tolyl,. L-tolyl^. 2-pyridyl,. 3-pyridyl^. 2, 1,3-iJenzoxdiazol-i-yl, 5-methyl-2~thienyl and, In particular, 2- nitrophenyl and 3-nitrophenyl radical.
Eerbodi erents. of the· invention and. preferred: and. particularly preferred embodi nsenrs. are given in the claims» Examples; which’ ©ay be mentioned, of compounds according- to the invention are: 3- ethyl 5-C2-<4^4-diphenyIpiperid-1-yI)-ethy I 3 1^4-dihydro— 2^6-di me thy l-4~l2»~ni trophenyU-pyridi ne-3^5-di ca rboxy lat ez 3- ( 2-methoxyethyl) 5-(3-(4,4-diph©nylpiperid-1-yl)-propyl) 1,420 dihydro-2„S-dimethyl*4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate „ 3-methyl 5—C4-(4^4-diphenyIpiperid-1-yI)-buty13 1r4~dihydro— 2^6-di me thy 1-4- (3-ni t rophenyI)-py ri di ne-3^5-di carboxylate·,. 3-»ethyl 5-C2-(4^4-diphenyIpiperid-1 ~y I)-ethy13 1,4-dihydro25 2,,6-di ©ethy1-4-(2-ni trophenyI)-pyri di ne-3,5-di carboxy latez 3-methyl 5"C2-C4,.4-di pheny Ipi per i d-1-y I)-ethy 13 1,4-di hydro2^6-di ethy I-4-(3-ni trophenyU-pyridi ne-3,.5-di carboxylate^ 3-(p rop-2-y I) 5-CZ-C4., 4-di pheny Ipi per i d-1 -y I) -ethy I j 1,,4-dihydro— 2,6-di me thy I-4-(3-ni trophenyU-pyridi ne-3^5-di carbo xy l~ ate, 3-hexyl 5-C2-(4^4-diphenylpiperid-1-yl)-ethyl3 1,4-dihydro2^6-di methy1-4-(3-n i t ropheny I) -p y ri di ne-3,,5 -di carboxy late , 3-( 2-n-butoxyethyl) 5-C2-4„4-diphenylpiperid-i-yl)-ethyl) 1,4dihydro-2,6-dimethyl- 4- ( 3-n I trophenyl) - pyridine-3 , S-dicarb35 oxylate, - Ο S-raethy I 5-£2-C4,4-di (i-raethoxypheny I)-pi peri d-1 ~y 13-ethy ij 1 , 4-di hy drs-2,, Ώ-ΰ i rae uh y 1-4-(3 -n i trophenyl)-pyridine-3,5— di carboxy Late, 3-ethyl 5-C2"(4,4-diphenyIpiperid-1-yL)-ethyIj 1,4-dihydro5 2,, ό-di oethy L-4— (2~tri f Luo roraethylphe nyl)-pyridin e-3 ,5 ~d i carboxy late,, 3-methyl 5-C 2-(4„ l-diphenylpiperid-1 - yl) -ethyl J. 1 , 4-dihydro-2 , 6dimetnyl-4-C3-(*,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5elcarbaxylate, S-ethyl 5—£2-^(4,4-dipheny Ipiperid—1-y l)-ethyl3 1,4—di hydro— 2.6- di oxer tty I—4-(Z—di tluo romethoxypheny L)-py ri di i'ie~5,. 5-di — carboxylate, 3-ethyl 5-C4—(4,4-diphenyIpiperid-T-yl)-butyl2 1 ,4-d i hydro— 2.6— d.i arethy 1-4—c>»di f Luora^echoxyphs-ny I) -py ri di ne-3\, 3—di — carijsxylare, -oethy I 5—C2-C4,4-di hydroxyph eny Ip i pe ri d-1 -y I) -ethry IX 1,4di hydro— 2, ©-diraethy I— 4-CX-n i tropheny I j -pyri di ne—©,5—di — carboxy late·, J-raethy I 5-C2-(4,4-di pheny Ipi peri d-1 -y I) -ethy II 4-(2,3-di ZCF oh loropheny 13 -1 ,4-di hydro-2',6"diraethy loyri di ne-o,5-di es r— boxy late·, 3-eethyl 5-C2"C4,4-diphenyIpiperid—1~yI)-ethy13 4-(2,1,3teenxexdiazol-4-yi)-t , 4-dlhydro~2 , 6-dimethylpyridine-3 , gdlcssrbaxylate·, 3-aethyL 5-C2—(4,4-diphenyIpiperid-1-yI)-ethy13 4—(3-cyano— pheny L) -T,4-di hydro-2,ό-di saethy Ipy r i di ne-3,5-di carboxylate, □"©ethyl 5-C2-(4,4"diphenyIpiperid—1-yI)-ethy13 1,4-dihydro— 2,ό-di raethy1-4-(H-raethoxyphenyL)-pyridine"5,5-dicarboxylate, 3~©ethyl S-C2-(4,4-diphenyLpiperid-1-yL)-ethyL3 1,4~dihydro30 2,6-diraethy1-4-(2-pyridyI)-pyridi ne-3,5~dicarboxy late, 3-eethyl S-C2-(4,4-diphenyLpiperid-1-yL)-ethy13 1,4-dihydro2,o-diraethyl-4-(5-®ethyI-2-thi enyI)-pyridi ne-5,5-dicarboxylate, 3-aethy I S-f2-C4-(4-chlorophenyI)-4-phenyIpiperi d-1-y1333 ethylj 1,4-dihydro-2,6-diraethyl-4"(3-nitrophenyl)-pyridine3,5-dicarboxylate, 3-raethyl 5-C3~(4,4-diphenylpiperid-1-yl)~propyl3 1,4-di— hydre-2,6-diaethyl-4-(2-ni tropheny1)-pyri di ne-3,5-di car- hy dro-2, 6-d ί e t hy I ~4~(3~n i t rophenyI)-py ri di ne-3,5-di carooxylate, 3-(p rop-2-y I ) S-C3-(4,4-di pheny Lp i pe ri d-1 -y I) -p ropy 13 1,4di hydro-2,6-di iset hy 1-4-(3-n i t roph enyI)-py ri di ne—3,5~di — carboxy late, 3-hexyl S-C3-<4(,4-di pheny lp i peri d-1 -y I) -propy 11 1,4-di hydros' 6-di methy 1-4-(3-ni tropheny I) -py ri di ne-3,5~di earboxylace,. 3- ( 2-n-butoxyethyl) 5-E3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4- S-me-thy I S-|3-C4,4-di (4-methoxypheny I) -p i peri d—1 -y I I-p ropy T^4-di hydro—2,6—di methy1-4—(3-ni trophenyI)-pyri di ne—3^3— di carboxy late> . 3—ethyl 3C3—(4,4~di pheny lp i peri d—1 -y I) -p ropy 13 1,4-dihydro— 2,6—di methy 1-4-(2-tri f luoronsethy Ipheny I) -py ri di ne— 3,5-di — carboxy late, 3-methyl. 5-C 3-(4, 4- diphenyl piper id -1 - yl) - propyl] 1 , i-dihydro-Z , B2Q dimethyl-4-£ 3-(1,1,2,£~tetrafluoroethoxy)-phenyl]-pyridine—3,ΙΟΙ lea rboxy Is t©3—ethyl S-C3—(4,4-diphenylpiperid—1-yI)-propy13 1,4-dihydro— 2,6—di roe thy l-4-(2-di fluorossethoxypheny l_)-pyridine — 3,5-di — ca rboxylate^ 3-ssefhyl 5-C3-(4,, 4-d i hydroxypheny lp i peri d-1 -y I) -propy I 3 1 ,4-di hyd ro—2,6-d imethy 1-4— (3-n itrophenyU-pyridi ne— 3,5·*· di carboxy late,. 3-methyl 5-C3—(4,4-diphenylpiperid—1-yI)-propy 13 4-(2,3-di— chlorophenyl)-1,4~dihydro-2,6-dimethylpyridine-3,5-dicar30 boxylate^ 3-raethyI 5-C3-(4,4-diphenylpiperid-1-yI)-propy I3 4-(2,1,3benzoxdiazol-t-yl)-1,4-dihydro-Z,6-dimethyIpyridin©-3,5dicarboxylate, 3-raethyl 5-C3-(4,4-diphenylpiperid-1-yU-propy13 4-(3-cyano35 phenyl)-1,4-dihydro-2,6-di methylpyridine-3,5-dicarboxylate, 3-raethyl 5-C3-(4,4-diphenylpiperid-1-yU-propy13 1,4-dihydro2,6~dimethyl-4-(2-methoxyphenyl)"pyridine-3,5-di carboxyl ate, - a 3-fsethyl 5-C3-(4Z4~d~phenyIpiperid—1-yI)-propy I] 1^4-di— hy dro-2,,6-d i methy l-4~(2~py ri dy I) -py ri di ne-3,, 5-di carboxylate, S-methyl 5-C3-(4,, d-p } ph eny Ip i pe r i d-1-y I)-p ropy I j 1,,4-di — h y dr o—2,, 6— dime thy (.-4- ( S-sset h y I-2-th ieny I)-pyridine-3„5 — di carboxy late, and ΪκΤ 3-C4-(4-chlorophenyl)-4-phenyIp i peri d-1 »y13 — propyl^ 1 z 4-di hy dro—2z0-d i we thy 1-4-(3-0 itrophenyI)-pyridine— 3z5~dicarboxylate^ and their salts» The compounds of the formula I have a chirality centre at the 4-position in the 1^4-dihydropyridine. The invention therefore includes both the enantiomers and, if a further chirality centre is present, the diastereoeers, and mixtures and racemates thereof.
The invention 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 (II) are reacted <*i th enamine derivatives of the formula II iii) o r b) cinnamic acid derivatives of the formula II are reacted 15 with ammonia andp -ketocarboxyIic acid derivatives of the formula IV - 10 (IV) ST IQ or ¢) enamines of the formula V (V) are reacted with benzy I i deneca rboxy I i c acid deriva the formula VZ o r d 3 keto compounds of the formula VII I830GC i was o (VI) (VII) are reacted with ammonia and benzylidenecarboxylic derivatives of the formula VI, or acid I (V ) e) aldehydes of Che formula VIII are reacted with enamines of the formula V andβ -ketocarboxylic acid derivatives of the formula IV, or f) aldehydes of the? formula VIII are reacted with enamine derivatives of the- formula; III and keto compounds of the formula- VII(, or g) 1 ,4— R3QQCk Λ G II c—z I (IX) k / Μ- Ι H- 10 are reacted w,i th di ary L compounds of the? formula· X 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^ Rs, R7, R8, R9, Y and A have the abovementioned meanings and I, together with the carbonyl group to which it is bonded, represents a carboxyl group or a reactive carboxylic acid derivative (tor example a carboxylic acid halide). carried - 12 The process according ¢0 variants a to f is out in suitable, preferably inert organic solvents».
Examples which may be mentioned are alcohols, such as ethanol, methanol, isopropanol or tert--butanoI, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether and glycol dimethyl ether, or other solvents, for example polar solvents, such as dimethylform— amide, dimethyl sulphoxise, acetonitrile or hexamethyIphosphoric acid triaeide, or, in particular, chlorinated hydro10 carbons, such as eethylene chloride», chloroform or tetrachloroethylene» The·' reaction temperatures can be varied within a wide range — depending1 on the reactivity of the educts» The reaction is in general carried, out at temperatures between 2Q°C and 15Q°C, preferably between 20°C and 1QQ°C and in particular at the boiling point of the solvent used· The process can be carried out under normal pressure or under increased pressure, the reaction under normal pressure- being the rule and it being possible to apply increased pressure, in particular, for reactions with ammonia.
Xn carrying out the- process according to the invention 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 g, similar reaction conditions to those for variants a to f are used, but, if appropriate, additional measures are neces30 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 a condensing agent which splits off or binds water (such as, for example, di eyelohexyIcarbodiimide). If 7. represents a halogen atom (far example a chlorine atom), the reaction is to be carried out, if desired, in the presence of a base (for example a tertiary organic amine, such as triethylamine, or an inorganic carbonate, such as sodium carbonate). <0 ' The substances according to the invention are isolated and purified in a manner which is known per se, for example by distilling off the solvent in vacuo and rec ry sta 11 i s i ng the resulting residue fro®· a suitable solvent or subjecting it to one of the customary purification methods, such es, for example, column chromatography on a suitable carrier material» Acid addition salts, are obtained by dissolving, the free base in· a· suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, IS or a low- molecular weight aliphatic alcohol (ethanol or isopropanol), containing the desired acid or to which the desired acid is subsequently added» The salts are obtained by filtration, repreci pita — tion, precipitation with 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 pharmacologica I ly 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 6. Jones j_"The Knoevenagel Condensation" in Org. Reactions, Volume XV, 204 et seq. (1967)J. The enamine derivatives ΙΪΪ 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)3· β -KetocarboxyIic acid derivatives IV and keto compounds VII can be prepared in accordance with the method of 0» Sorrerann CUmsetzung won Oiketen sit ALkoholen, Phenolen und Kercaptanen (The Reaction of diketene with alcohols, phenols and mercaptans) in Houben-Wey I, Methoden der Organischen Chenrie- (Methods of Organic Chemistry), Volume IQ IS Vir/4·, 230 et seer» (1968)3 or Y_ Oikawa et al„ CJ - Org.
Chess·» 43, 2087 (1978)3» The- compounds ΓΧ are accessible frocr corresponding starting compounds by variants analogous to process variants a to f~ Compounds X are obtainable by reaction· of corre-spondi ng piperidines (see, for example, German· Patent Specification 1,930,452) w i th tu-ha logenoa I kan~ oli» The above preparation processes are mentioned only for illustration, and the preparation of the compounds of the· formula- £ according- to the invention is not restricted to these- processes. Rather, any modification of these pro— cesses can be applied in the same manner to the preparation of the compounds according to the invention.
PiSfetrsd process variants are- the variants a ano c.
The· following preparation examples ar® intended to illustrate the invention in more detail without limiting it. denotes meltins point and b.p. represents boiling point. m.p.
ExamoL es . 5-Methyl 5-C3-(4,4-d -j pheny La i ae ri d-1 -y I) -o r qpy I j 1,4· di byd ro-2,0~d*i methy I -4-(3-01 trophenyl)-pyridine-3,5di ea rboxylate hydrochloride Process variant e) 4.53 g of 3-ni t robenza Idehyde, 3.43 g of methyl 3-arsi nocrotonste and 11,.38 g of 3~(4-,4"di phany Ipi peri d-1 ~y I) propyl acetoacetate in 100 ml of 2-propanol are heated at the boiling point under reflux overnight· The cooled solu — tion is concentrated to dryness- and the residue which remains is chromatographed over a silica gel column using ethyl acetate as the eluant- The uniform product fractions leave & solid foamed residue after concentration, the residue is dissolved, in methanol and ethereal hydrochloric acid is added. The solution is concentrated, the solid residue which remains is taken up in a little methanol and the title substance is precipitated by addition of petroleum ether, m.p.: from 135°C (decomposition); yield: 9.3 g.
The starting compounds are obtained as follows: a) 3-(4,4-Pi phenyIpi peri d—1 -yI)-oropyI acetoacetate 23.8 g of 3-(4., 4-diphenyipiperid-1-yl)-propanol are dissolved in 100 ml of absolute- toluene, and 16 ml of a 5OX strength solution of di ketene· in acetone are added, with stirring. After the mixture· has been left to stand at room temperature for several days (control by thin layer chromatography), it is concentrated and the residue is dried under a high vacuum. The pale yellow viscous oil which remains is employed for the next stage without further purification. b ) 3-(4, A-Qiahenvlgloerid· 1 -yl) -orooanol g of 4e4-diphenyIpiperidine, 24.7 g of 3-bromopropanol, 116.4 g of powdered potassium carbonate and about 1 g of potassium iodide are heated at the boiling point under reflux and with vigorous stirring in 500 ml of a 1:1 mixture of dioxane 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 aeetst and the solution is filtered again. After the filtrate has - 16 ~ been concentrated to dryness, the product is obtained as a yellowish oily residue which slowly solidifies as a wax. Yield: 44.8 g» With ethereal hydrochloric acid, the hydrochloride is obtained, and is recrystaI lised froa 2-propanol. m.p.: 22ό-7°£» Alternatively, the starting compound o) is obtained by heating 352 g of 4,i»diphenyIpiperidine, 128 g of sodium hydroxide granules, 2.5 I of methylene chloride, 500 ml of water, 218 g of 3-b rotsa—1-p ropano I and catalytic amounts of a phase· transfer catalyst (for example bentyltrimethylaromon— ium- chloride) at the boiling point under reflux for 10 hours. The organic phase is separated off and washed with water and the collected aqueous phases are extracted with methylene chloride» After the combined organic phases have been dried with- sodium- sulphate, the clear brownish solution is evaporated to dryness- The resinous brown residue is taken up in 4--3 I of boiling petroleum ether (bailing range 10014Q°C), the insoluble residue is filtered off hot from the solution and the filtrate- is cooled- After being left stand overnight, the title compound is obtained as the base in the form of colourless coarse crystals. nr.p.: yield: 303 g. to free 97°C : The fallowing starting compounds are obtained analogously : 4-( 4s4-diphenylpiperid-1-yl)-butanol, m.p. of the hydrochloride: 2G9-2l2°C, 2~(4,4-diphenylpiperid-1-yl)-2-methylpropanal, m.p.: 115-11S°C, 3-Ctet-di-(4-methoxipheny11-piperid-1-y11-propanol, m.p. of the hydrochloride: 130-l3t°C (contains 1 equivalent of methanol in the crystal), 3~(4,t-diphenylpiperid-1-yl)-2-methyl-2-propanol, m.p. of the hydrochloride: 18i-163°C, 2-( 4 , 4-diphenylpiperid- 1 -yl)-ethanol, m.p. of the hydrochloride: 9 7 - 1 9 S ® C .
By reaction of the above alcohols with a solution of di* ketene analogoulsy to Example la, the corresponding acetoacetates are obtained which are further reacted without purification. - 17 Process variant c) .38 g of 3-(4,4*»di pheny Ip i per i d-1-y I)-p ropy I 2- acety1-3-(3-nitrophenyI)-acrylate and 3.45 g of methyl 3- aminocrotonate in 100 ml of 2-propanol are heated at the boiling point under reflux overnight. The cooled solution is evaporated to dryness, the foamed solia residue is taken up in a little- methylene chloride and ethereal hydrochloric acid is added- After renewed concentration to dryness and taking up of the solid residue in a little methylene chloride, ethyl acetate is added until a slight cloudiness persists- After the· mixture has been left to stand in a refrigerator, the title compound crystallises out overnight in the- for® of fine,. slightly yellowish-coloured flakes (microscope)» nr.p-t 23Q-231°C (decomposition); yield: 13-6 g.
Other solvents which are «employed for the condensation reaction are: tert.-butanol, dioxane, tetrahydrofuran and chlorinated hydrocarbons*. The yields of product are 60-80% of theory.
Other salts of the title compound 1 which are prepared are: hydrobromidei nr.p-: 229-230°C (decomposition), fine platelets (from- ethyl acetate and diisopropyl ether); fumarate: m.p»: 144—145°C (d®composition), fine flakes (from· ethyl acetate); maleate: m.p.: 151-152°C (decomposition), clusters of coarse needles (from ethyl acetate).
The free base of the title compound 1 is obtained when the condensation batch the foamed solid residue is chloride; after addition of is concentrated to dryness and taken up in a little methylene di isopropyl ether until a fine cloudiness remains, the base crystallises out in the for® of fine platelets, after being left to stand in a refrigera145• 7°C .
The starting compound 3-(4,4-diphenylpiperi d-1-y I) propyl 2-acetyl~5-(5-nitropheinyi)«-aerylate (cis/trans isomer mixture) is obtained as foliow,s: 40.14 g of 3(4,4-diphenyIpiperid-1-yI)-propy I acetoacetate, 15.97 g of 3-nitrobentaIdehyde, ml of acetic acid and 0.5 ml of piperidine are heated at the boiling point in 300 ml of benzene using a water separator. After 1.9 ml of water has been separate the cooled O' solution is washed with saturated sodium bicarbonate solution and than with water. After the organic phase has been dried with sodiumr 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, without further purification- Yield:. 52 g of crude· product. Other entraining agents which are suitable are: toluene and chlorinated hydrocarbons- The yield of crude product is 9Q—100S of theory.
By reacting the free base with an equimolar amount of fumaric· acid-, the fumarate of the starting compound, is obtained? er-p-t from- 128°C (decomposition), clusters of fine needles·-, from? ethyl acetate.
By reaction with ethereal hydrochloric acid, the hydrochloride is obtained: m.p.: 152~155°C (fine platelets, from ethyl acetate and diethyl ether).
Prqcess var i ant a 134.6 g of methyl 2-acetyl-3-(3-nitropheny I) — acrylate, 204.5 g of 3-(4,4-diphenyIpiperid-1-yI)-p ropy I 3-aninocrotonate and 4„j si of acetic acid in 2.7 I of anhydrous dioxane are heated at the boiling point under reflux and under a nitrogen atmosphere for 20 hours. After cooling, 45 naL of concentrated hydrochloric acid (372) are added to the mixture·, seed crystals of the title compound 1 are added and the mixture is left to stand at room temperature for 24 hours. The precipitate is filtered off with suction, washed with dioxane and diisopropyl ether and then dried in vacuo at 7 50 C., The product (270 g) is partitioned between 1.5 I of ©ethylene chloride and aqueous ammonia solution (pH.11), the organic phase is dried over sodium sulphate and the solvent is then distilled off in - 1 g vacuo. The residue is dissolved in 2.5 I of dioxane, 35 ml of concentrated hydrochloric acid (37X strength) are 'added and the mixture is seeded and left to stand for 4Q hours. The product which has crystallised out is filtered off with suction, washed with dioxane- and then diisopropyl ether and dried at 100°C in vacuo. The title substance is obtained as a pale yellow powder (microscope: small needles), m.p.: 1’98"2Q0eC^ yield: 240 g.
The- starting, compound 3-(4, 4-di phenyl pi peri d-1-yI) — 10 propyl p-ami nocrotonate is prepared as follows: 260,.S g of 3—(4,4-dipheny lpiperid-1-y U-propyl acetoece-taie- in T»& I of 2-propanol are stirred overnight withr 260 ml of concentrated ammonia solution» The fine, slightly- ochre-coloured, precipitate which- has separated out is filtered off with suction and washed with cold 2-propanol, diethyl ether and finally petroleum ether. m.p_: 144— 1SQ°C,: yield: 225 gr„ After addition of a further 100 ml of concentrated' ammonia· solution to the filtrate and after the mixture has been left to stand in a 20 several days, a further 12 g of product point are obtained» refrigerator tor of identical melting Alternatively, the starting compound is obtained if gaseous ammonia is passed into the solution of 3—(4,4-diphenyI piperid—1-yI)-propy I acetoacetate in 2-propanol, with stirring, until no further precipitate separates out.
Yield: about 90X of theory. 2. 3~Wethy I 5-C2—(4, 4~q iphenyl p i per i d-1~yI)-ethy13 1,4~di hydro-2,6-di me thy I-4-(3-nit rophenyI)-py ri dine-3,5dicarboxylate hydrochloride The title compound of m.p.: from 137°C (decomposition); yield: 8.S g, is obtained analogously to Example 1 from 4.53 g of 3-nitrobenzaIdebyde, 3.45 g of methyl - 20 arai nocrotonate and 11 g ©f 2-(4,4-diphenyIpiperid-1-yI) ethyl acetoacetate in 100 el of 2-propanol. 3Γ. 3-Hethy I 5—C5—(4,4—diphenyIp i per i g—l —y I) -p ropy 13 4-(3-cyanopheny I) —1,4_-di hydro-2,6-di nethyIpyri di ne-3,55 dicarboxylate hydrpchloride The title compound of m.p.. 136-140°C (slow deliquescence, amorphous, precipitated in petroleum ether); yield: 5.9 g, is obtained analogously to example 1 from 3.93 g of 3-cyanobentaIdehyde, 3.45 g of methyl 3-ansino — 10 crotonate and 11.38 g of 3~(4,4->diphenylpiperid*1~yl)-propyl acetoacetat e in 80 sal of tert.-butanoI. 4. 3-Met hyI 5-C2-¢4,4-di phenyIpiger_i d-l-yD-Z-methylp ropy IJ 1 , 4-di hydro-^^-dj-methy 1-4-(3-011 roohenyl)pyridine-5,5~dicarboxylate hydrochloride The title compound of e„p» from 155°C (slow deli5 quescence, amorphous, precipitated froa petroleum ether); yield: 13.6 g, is obtained analogously to Example 1 from 15.8 g of 2-(4,4-dipbenylpiperid-1-yl)-2-methylpropyl 2- acetyl-3-(3-ni trophenyU-acrylate and 3.45 g. of methyl 3— aminoerotonate in 1Q0 ml of tetrahydrofuran after a reaction IQ time of 12 hours. 5_ 3-EthyI 5~—£3-(4, 4-diphenyIpi perid—1-yI)-propyl! T,4~d1hydro—2,6-dimethy1-4—(3-nitrophenyl)-pyridi ne— 3,5-dicarboxy late hydrochloride The* title compound of m.p.. 230-232°C (fine angu— lar crystals,» from· acetonitrile and diethyl ether); yield: 29.7 g, is obtained analogously to Example 1 from 13.16 g of ethyl 2-acety l-3-(3-ni tropheny I)-ac ry late- and 18.91 g of 3—¢4,4-diphenyIpiperid— 1 -yI)-propy I 3-aeinoerotonate in 100 ml of tetrahydrofuran after a reaction time of 6 hours. 6 » 5-MethyI 5-15-(4,4-di phenyIpi pgri d-1-y 1)-propyIJ T,4-dihydro-2,6-dimethy 1-4-03-(1 ,1 2,2-tet raf Luoroethoxy) phenyU-pyridine-3,5-di carboxy late hydrochloride The title compound of m.p. 189-192°C; yield: 57 g, is obtained analogously to Example 1 from 40-33 g of methyl 2-acetyI—3-C3-(1,1,2,2-t et rafluoroethoxy)-phenyl!-acrylate and 37-85 g of 3-(4,4-diphenyIpiperid-1 -y1)-propyI 3-aminocrotonate in 400 ml of tetrehydrofuran and 0.5 ml of glacial acetic acid after a reaction time of 14 hours. - 22 7. 5-MethyI 3-C2-(4,4-di gheny ip i peri d-1 -yI)-ethyl] 1,4-qjhydro-2,6-dimethyl-4~|5-Π,1,2,2-tetrafluoroethox phenyl| -py ridi ne—5,5-qicarboxylatehydrochloride The title compound of m.p- 130-140°C (slow deli3 quescence, amorphous, precipitated fro® petroleum ether and diethyl ether 1:1); yield: 6-2 g, is obtained analogously to Example 1 from 4.Q3 g of methyl 2-acetyl-3-|3-(1,1,2,2— tetrafluoroethoxy)-phenyl)-aerylate and 3-4 g of 2-(4,4diphenylpiperid-1-yI)-ethyI 3-aminocratonate in 80 ©I of 2-propanol sifter & reacti on ti me of 8 hours· · 3-(2-Kethoxveth yl ) 5 ~ ί ? r_( 4... 4 ~ d l.Ph a η V1. P±O exlri - 1 .-JtUL·. ethyl! i . 4-dlhvdro-2 S-dimethvl-e-(3-nltroj3benvJLl- -pyridine—3 , 5-dicar fe&xyl»te The title· compound of er.p· from 13O°C (slow, deli13 cuescence, fine platelets, from ethyl acetate and diethyl ether); yia-ldc 3-7 g is obtained analogously to Example- 1 froer 4-99 g of 2—(4,4-diphenyIpiperid-1-yI)-ethy I 2-acetyl— 3—(3-ni trophenyU-acrylate and 1„6 g of 2-( 2-methoxyethyl) 3-aeinocrotonate in 60 ml of tetrshydrofuran and 0„S ml of glacial acetic acid after a reaction time of 4 hours» S . 3-(g-Hetft Ο.Χ y_W-y 1 j -SrJ .31. ί4 , A- d£ahe n yJL slLqs_t 1 d -.1 - y 11 p ropy 1,3 1,4-di hydro-2,6-dimethy1-4-(3~nit ropheny I) pyri dine-3,5-dicarboxylate fumarate The title compound of m.p- 184-18S°C (angular 25 flakes, from ethyl acetate and diethyl ether); yield; 3-3 g, is obtained analogously to Example 1 from 5-12 g of 3-(4,4diphenylpiperid-1-yl)-propyl 2-acety 1-3-(3-nitrophenyI)acrylate and 1.6 g of 2-(2-methoxyethyl) 3~amln©crotonate in @0 ml o-f tert.-butanol after a reaction time of S hours. » 3-Wethy L 5-{3 - C4,4-di - C4-iaethoxyoheny I)-piperid-1-y IJpropyl); 1,4-di hydro-2,6-di methyI-4-(5-n i t rophcny I) py ri din¢-3,5-di ca rboxyI ate hydrochloride The title compound of m. ρ» fro® 138° C (slow deli5 quescence, amorphous, precipitated in petroleum ether); yield: 4.,9 g, is obtained analogously to Example 1 from 4.4 g of 3~C4,4-di -(4-methoxypheny I) -pi peri d-1 -y I3~propy I ace'oacetate, 1.-15 g of methyl 3-aminocrotonate and 1.51 g of 3nitrobenzaldehyde in 60 ml of tert.-butanoI after a reaction time of 12 hours'11» 3-Sffe-t hy I 5—04-(4-,4-di phenylpiperid-1-yl L-buty13 T,4~d i h y d r o—2 , 6 -d i me t h y I-4- ( J-ni t r o p hen y I) -p y r id i n e-3 , S— dicarboxylate fumarateThe- title· compound of m.p. 123—126° (fine needles, from· ethyl acetate and- methylene chloride); yield: 3.9 g, is obtained analogously to Example 1 from 3.94- g of 4.-(4-,4diphenyIpiperid—T~yI)-bury I acetoacetate, T.15 g of methyl -amri noc rotonate and 1 »S1 g of 3-ni trobenza Idehyde in 80 ml of tert.-butanol after a reaction time of 6 hours. 12» 5-HethyI 5—Cl , T-d i methyl -2-(4, 4-di phenyIp iperid-1-yl)ethyl! 1z4-dihydro—2,6-dimethy I-4-(3-01 trophenyl)pyridine-3,5-dicarboxylate hydrochloride The title compound of m.p. from 148°C (slow deliquescence, amorphous, precipitated from petroleum ether); yield: 11.3 g, is obtained analogously to Example 1 from -8 g of 1,1~dirae£hy1-2-(4,4—diphenyIpiperid—1-yI)-ethy I 2- acety1-3-(3-nitrophenyI)-acrylate and 3.45 g of methyl 3- aminocrotonate in 120 is I of 2-propanol after a reaction time of 15 hours. - 24 13. 3-Etbyl. 5-C3- (4,4-01 ph eny La i pe r i d-1 -y I) -a roay L 3 Λ«5*β^^Β·«-βββ=-Ιβ-Μί-. — ®· ι·ιΊι·’ li*. 'W-'l.·. « ’ l^rdlhydro- 2 ^,6, dimet hvl-4^ ( 2-_d if luorome t box yphenyl ) py ridi ne-3,5-di carboxylate ftydroch loride The title compound of m.p. fro® 126°C (slow deli3 quescence, amorphous, preci pi rated froa petroleum ether and diethyl ether 1:1); yield: 2.8 g, is obtained analogously to Example 1 fro® 3.,8 g of 3-(4,4-diphenyIpiperid-1-yI)~ propyl 2-acety1—3—(2-difluorosethoxyphenyI)-acryI ate and 1.3 g of ethyl 3—©minocrotonat® in 60 ml of tert.-butanoI after a reaction time of 20 hours. 14- 1,4—0 i hydro—2,6—di methy 1-4-(3-ni t: raphenyI)-py ri dine3,5—di carboxy li e a cid 3-C3-(4,4-di phenyIpi perid-1 -y I) p r 0 p y IJ _e ate· r 6-8 gr of 3—(2-cyanoethyl) 5—C3-(4,4-diphenylpiperid After most of the 15 ml of 2 H hydrochloric The mi Ifcy/c loudy solution 1-yL)-propy 11 T,4—di hydro—2,6-dimethy1-4— (3-nitropheny I) pyridi me—3,5-dicarboxyI ate hydrochloride are stirred with 4Q ml of 0.5 M sodium· hydroxide solution and 100 ml of dioxane- at room* temperature for 3 hours dioxane has been distilled off acid are added to the residue» is extracted 4 times. with 100 ml of ch loroform/n-butanol (3:1) each time· and the combined organic phase is washed with 50 ml of saturated sodium chloride solution. The organic phase is concentrated to dryness and the solid residue is recrystallised from ch lorof orre/met hano I (1:1). m.p. 192-195°C (decomposition); yield: 5.4 g.
The starting compound 5-(2-cyanoethyl)5-(15-(4,4di pheny Ip i peri d—1-yI)-pr opy 13 1, 4-di hydro-2,ό-di met hy 1-4-(3 n i trophenyI)-pyri di ne-3,5-di carboxylate is obtained as 30 follows: 8.1 g of 2-cyanomethy I 2—a c e t y 1-3-(3-n i t r opheny j.) acrylate and 10.6 g of 3-(4,4-diphenyIpiperid-1-yI)-prepy I - 25 3~aminocrotonate are heated at the boiling point under reflux in 120 ml of 2-propanol and 0.3 ml of glacial acetic acid for 4 hours. After most of the solvent has been distilled off and 2 portions of 50 tai of toluene each have been added, the residue is concentrated to -dryness. The residue, which has foamed as a solid, is taken up in isopropanol and diethyl ether is added to the clear solution until the cloudiness first persists* After the mixture has been left to stand in a refrigerstor, the starting compound crystal— IQ Lises out in the form, of fine platelets. m.p-: 158—160°C; yield: 14.3 g.
With· ethereal hydrochloric acid, the hydrochloride of the starting compound, is obtained, and is recrystalli sed from· methylene ch lori de/tneth ano L _ m-.p·*: 184-194°C (slow deliquescence). 13* 3-£thy I 5—C3~~(4, 4-d iphenylpioerid—1-yl)~p.-opyl3 ,4-di hydro—2,6-di methy 1-4-C5—(1 ,1 ,2,2-tetrafluoraethoxy) pheny13-oyridine—3,5-diearboxylate hydrochloridg The title· compound of er.p. 196—197°C (decomposition, from «ethylene chloride and diisopropyl ether); yield: 48.9 g, is obtained analogously to Example 1 fro© 22.2 g of 3 — (1 ,1,2, 2— t e t raf luo roethoxy) -benra Idehyde, 12.9 g of ethyl -ami nocrotonate and 37.9 g of 3 —(4,4—diphenyLpiperid-1-yL) propyl acetoacetate in 28Q ml of tert.-butanol after a reaction time of 14 hours» 16» 5-£thy L 5—C3-(4,4-di oh eny Ip ipe r i d—1 -y I ) -p raoy 13 1,4-di hydro-2,67b i met hy I—4-(3-di fluoromethaxyohanyl)pyri di ne-5,5-di carboxyI ate hydroch Lori de The title compound of as. p. 197-198°C (fine plate30 lets from methylene chloride and ethyl acetate); yield: .1 g, is obtained analogously to Example 1 fro® 1.6 g of - 26 3-di f luorofsethoxybenta Idfthyde, 1.3 3 s ethyl 3-arainocrotonat® and 3.8 g of 3"(4,4-di pheny ·.□ i 9®ri p«1 ~y I) -propy l acetoacetate in 80 ml of tetrahydrofuran a*ter a reaction time of 4 hours .
IF. 3-Wethy I ?—Cp—(4,4-d ipheny (, pi per id-1-y I)-propyl j 4-(2,3-Qi ch loropheny 1)-1,4-di bydro-2,6-di methyIgyri dinegyis-di carboxylate- hydroch Lori de The title- compound of m.p. 22S«23Q°C (fine- needles from· methanol and ethyl acetate); yield: 4.2 g, is obtained analogously to Example 1 from 2.72 g of methyl 2-acetyl-3(2,3~di ch loropheny I)-aery late and 3.79 g of 5-(4,4-diphenylpiperid—1-yl)-propyI 3-aminoerotonate in 100 ml of 2-propanol after a reaction time of 7 hours. 6. 3-Msthyl 5-C3-( 4 .. 4-diphenvig_i aerid-J - vj) -aroavlj .415 12 , 4-dl^yd.rfl-2^ S,^.lm®Xh.yX--. nv £±d 1)13.-.3--.g^QXcaΓ9oxlilaxe hVdro-ch 1 ox_id e The title compound of m.p. 2Ga-2lO°C (fine lumpy crystals from ethyl acetate and methylene chloride); yield: 4.1 g, is obtained analogously to Example 1 -from· 2.5 g of methyl 2-acetyl-320 ( 2 , 1 » 3-benzoxdlazol-4-yl)-acrylate ana 3.8 g of 3-(4,4-diphenylpiperid-t-yl)-propyl 3-aminocratonate in 60 ml of tetrahydrofuran and 0.3 ml of acetic acid after 3 reaction time of 4 hours. 19. 5-HethyI 5-C5 —(4^, 4-d ipheny tpi a®r ϋ d-1-yI)-o rooyIj 1,4—d i hydro-2,6-di methy1-4-(5-fluoroph eny L)-oy ri di n&-3,325 dicarboxy late hydroch loride Th® title compound of os.p. 2t3-218°C (fin®, angular crystals from methylene chloride and diisopropyl ether); yield: 4.0 gs is obtained analogously to Example 1 from 2.44 g of methyl 2-acetyi-3-(3 - fluorophenyl)-acrylate and 4.39 g of 3-( 4,4-diphe30 nylpiperid-1-yl)-propyl 3-aminocrotonate in 30 ml of tetrahydrofuran after a reaction time of 5 hewrs. - 27 20 „ 3-Hethy I S-C3-(4,4-di pheny lai peri d-1 -y I)-proay 13 ,4-di hydro-2/.6-di wethy l-l-Cg-t r i fluoromcthylphenyl)-pyri-> di ne-5,5-di carboxy late hydroch Lori de The title compound of m.p. TS6-1S2®C (fin®, cubical 5 crystals from methvlen® chloride and diisopropyl ether); yield: 4.2 g, is obtained analogously to Example 1 from 2.7 g of methyl 2-acetyl-3-t2-trifluoromethylphenyl,-acrylate and 4.4 g of 3( 4,4-diphenylpiperid-l-yl)-propyl 3-aminocrotonate in 60 ml of tert.-butanol after a reaction time of 4 hours. „ ρ-ethyI 5-C3—¢4,4-dj phenyIpi peri d-1-yI) -propyl 3 Q 4-(2.-cy anooheny I ? -T,4-di hydro—2,6-di methy Ipy ri di ne-3,5dicarboxylate hydrochloride The· title compound of m.p. 178-161®C (fine needles from e-thyl acetate and methylene chloride); yield: 8.4 g, is, obtained analogously to Example- 1 from 3.93 g of 2-cyanobentald®hyde, 3.45- g of methyl 3-aminocrotonate and 1 1 .38 g of 3 - (4,4-diphenylpiperid-1-yl)-propyl acetoacetate in 80 ml of 2-propanol after a reaction time of 1'Q hours. 22. - 3-Hathvl_ 5-C 3-,( 4 chioroohenvl)-i . 4-diAvdro-2 ,.e-dimet.hvJjiMXlAln.e-J^£x 20 d i c.s xb o x V ia te .hydroch 1 or i a e Th® title compound of ea.p. 15Q°C (decomposition) (fine, needles from methylene chloride and diisopropyl ether); yield: 3.3 a, Is obtained analogously to Example 1 from 3.G g of methyl 2-ac®tyl-3-(2-chlorophenyl)-acrylate and 5.7 g of 3-(4,4-di25 phenylpiperid-1-yl)-propyl 3-aiminocrotonate in 60 ml of tetrahydrofuran and 0.5 ml of acetic acid after a reaction time of 8 hours .
Commercial Usefulness The compounds of the formula I according to the invention and their salts have useful properties which render them commercially useful. In particular, they are <3 active vasodilators with properties as coronary therapeutics. The pharmacological activity of the compounds according to the invention, which is coupled with a low toxicity, manifests itself in particular in a reduction in blood pressure which starts slowly, is powerful and lasts for a long time* Moreover, the compounds according to the invention haveperipheral, coronary, cerebral and renal vasodilating properties and saIi diuretic propertiesIrr the-ir excellent activity, which is coupled with a low toxicity and the absence of substantial side effects, the- compounds according to the invention differ in a surprising and advantageous manner fro® the compounds- of the· prior art* Examples .of advantageous properties wh-'ch may be mentioned are: the- slow onset of the reduction in blood pressure, the degree of reduction in blood pressure, the long period which 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 adainistrati on, 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- excellent activity of the compounds of the formula ϊ according to the invention and their salts enables them to be used in human medicine, possible indications being, in particular, primary (essential) and secondary hypertension of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.), disturbances i n. periphera I and cerebral circulation (cerebral apoplexy, temporary - 29 disturbances in cerebral circulation, narrowing of the renal artery etc.), cardiac insufficiency and diseases ^aseti on an increased retention of water and sodium.
TO The invention also relates to the compounds of the formula· I for use in the treatment of the diseases mentioned» The- invention likewise relates to the use of compounds. of the formula I in the preparation of medicaments which are employed for combating the diseases mentioned» IS The· invenrior furthermore relates to medicaments., containing one or more compounds of the general formula I.
The- medicaments are prepared by processes which are known per se and are familiar to the expert. As medicaments, the pha rnraco logi ca I ly active compounds C~ active compounds) according to the invention are employed eitheras such or, preferably, in combination w.ith suitable pharmaceutical auxiliaries in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS ) , emulsions, suspensions or solutions, the content of active cob25 pound advantageous Iy being between 0.1 and 95Χ» The expert is familiar with what auxiliaries are suitable 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, antioxidants, dispersing agents, emulsi tiers, antifoaming agents, flavour correctants, preserva30 fives, solubilising agents, dyestuffs or, in particular, permeation promoters and complexing agents (for example eyelodext ri ns) » The active compounds can be administered orally or 5 parenterally (in particular perlingua lly, int ravenously or percutaneously)_ In general, it has proved advantageous in human medicine to administer the active coapound or compounds,. when these are adssi ni stered orally, in a daily dose of about 0»01 to about 10, preferably 0.05 to S mg/kg of body weight, if desired in the for® of several, preferably T to 4, individual doses^ to achieve the desired results,. In the ease of parenteral treatment, similar or (especially when the active compounds are administered intravenously) as a rule lower doses can be- used. With a- dosage increasing from initially smalt acounts, a lower dose- is administered at the start of the· treatment and thist 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 he mode of administration of the active compounds can easily be determined by any expert on the· basis of his expert knowledge.
If the compounds according to th® invention and/or their salts are to be employed for the treatment of the diseases mentioned, the pharmaceutical formulations can also contain on® or sore other pharmacologically active constituents. from other groups of nedilaments, such as other vasodilators, antihypertensive®„ ο-receptor blockers, 6-receptor blockers, ACE-inhibitors, nitro~cosnpounds „ cardiotonics, diuretics, saluretics, alkaloids etc., such as nifedipine, dihydralazine, prazosine, propranolol, labetaiol, captopril, isosorbide dlnitrate, digoxin, nsefruside, elopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserplne, dihydroergocristine, rescinnamine, Rauwolfia total alkaloids etc. -31 Pharisaco l θ q γ The antihypertensive activity of the cospeunds according to the invention can be demonstrated on the model of spontaneously hypertensive rats.
To determine the antihypertensi ve action, the compounds. listed below· are administered once daily, by eeans of a stomach tube, on four successive days in the doses men — »r tioned to in each case © rats, (strain SHR/H/Iber/Ber o , 250— 350 g) w»ith hypertension of genetic origin (RR > 180 mmHg). The blood pressure is in each case measured 6 and, if appropriate, 2 or 24 hours after adaiη Istrati on of the substance.
The blood pressure ceasureaent is. carried out in a heated, chamber at 3©°C in order to achieve better circula— tion In the tai I artery. For this,, the aniarals are transferred to perforated sheet metal cages and the measurement is Hade 20 — 40 minutes after warming up has been started» To measure- the systolic arterial pressure, an annular cuff with an inflatable rubber oerabrane, for suppressing circu.la— tion, and an annular piezocrystal transducer, to record pulse- waves, ar® pushed onto the tai I» When the blood stream has- been suppressed in- the tail artery, the cuff pressure is reduced centinuous ly» 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 Beasureeent in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R,., et a I . (e d s . ) , Schattauer Verlag, Stuttgart, Hew York, 1982, pages 410-413). The pulse signals and pressure course are recorded graphically for evaluation.
For acclimatisation to the measurement process, the animals are trained for 14 days before the substance is • 32 tested. In the second week of training, blood pressure prevalues are recorded. Th© groups of animals receiving th® substance are tested against a control group. £n the table which follows, the compounds investigated are labelled by serial numbers, which are allocated as follows: Serial Ho·.
Name of the compound 3-Methyl 5- £ 3- ( 4,4-diphenylpiperid- "1 - yl) - propyl] 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl5pyridlne-3,5-dlcarboxyXate hydrochloride 3-Methyl 5-E2-(4B4~dlphenyiplperid-1-yl,-ethyl] „4-dihydro-2„6-dimethyl-4-(3-nitrophenyl,pyridine-3,5-dicarboxylate hydrochloride 3-Methyl 5-C3-(4B4-diphenylpiperid-1-yl,-propyl] - ( 3-cy ano ph® nyl, - d „ 4 - di hydro - 2 , S-dime· thy ipy rid in® 3,5-dicarboxylate hydrochloride 3-Methyl 3-(2-(4,4-diphenylpip®rid-1-yl,-2-methylpropyl 3 1„A-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,S-dimethyl-4-(3-nitrophenyl)pyridine-3 „ 5-dicarboxyla te hydrochlox'ide 3-Methyl 5-(3-(4„4-diphenyIpiperid-1-yl,-propyl] , 4-dihydro-2,6-dimethyl-4 -(3-(1,1,2,2-tetra fluoro ethoxy, -phenyljl -pyridine-3 ,S-dicarboxylate hydrochloride 3-(2-Methoxyethyl, 5-(2-(4,4-diphenylpiperid-1-yl, ethyl] l,4-dihydro-2„6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate fumarate 3-(2-Methoxyethyl, 5-(3-(4,4-diphenylpiperid- 1 - yl, propyl] 1 , 4-dlhydro-2,6-dimethyl-4-(3-nitrophenyl, pyridine-3,S-dicarboxylate fumarate Serial Η© Hame of the compound 3-Methyl 5-{3-£ 4„4-di-(4-methoxyphenyl)-piperid1 - yl3-propyl} 1,4-dirtydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-d^carboxylate hydrochloride 3-Methyl 5-(4-(4,4-diphenylpiperid-ΐ-yl)-butyl] 1„4-dihydro-2 8 6-dimethyl-4-(3-nitrophenyI)pyridine-3t5-dicarboxylate fumarate 3-Methyl 5-(1,1-dimethyl-2-(4 p 4-diphenylplperidJ-yll-ethyl] lt4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -pyridine-3 ,, 5-dicarboxylate hydrochloride 3-Ethyl 3-(3-(4,4-diphenyIpiperid-1-yl)-propyl] 1„4-dihydro-2,6-dimethyl-4-(2-difluoromethoxyphenyl)-pyridin®-3,5-dlcarboxy!ate hydrochloride 3-Ethyl 5-(3-(4 B 4-diphenylplperid-1-yl) -propyl] 1p 4-dihydro-2, 6-dimethyl-4-(3-difluoromethoxyphenyl)-pyrIdine-3 e5-dicarboxylate hydrochloride 3- Methyl S - ( 3- (4 , 4-diphenylpiperid-1-yl3-propyl] 4- (2„3-dichlorophenyl)-l,4~dihydro-2,6-dimethylpyridine-3,3-dicarboxylate hydrochloride 3- Methyl 5-(3-i4,4-dlphenylpiperId-1-yl)-propyl] 4- (2,1,3-benzoxdiszol-4-ylJ - 1B4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydrochloride Serial Ho.
NiiSii of th· compound 3-Methyl 5-13-(4,4-diohenylpiperId""S-yD-prspyl] 1„ 4-dihydro-2 s6-dimethyl-4 - (3-fluorophenyl)-pyrldxne-3,5-dicarboxylate hydrochloride 3-Methyl 5-C 3- ( 4 t, 4-diphenylpipeirid-1 - yl) - propyl) 1,4-dihydro-2,5-dimethyl-A-(2-trifluoromethylphenyl)-pyridln«-3„ S-dicarboxylate hydrochloride 3- Ethyl 5-£ 3-(4 „ 4-diphenylpiperid-1-yl)-propyl] 4- ( 2-cyanophenyl) - j „ 4-dihydro-2, B-dlmethylpyridine10 3,5-dicarboxylste hydrochloride 3- Methyl 5-£ 3-(4,4-diphenylpiperid-1 -yl)-propyl] 4- {2-chlorophenyl1-1,4-dihydr©-2»6-dimethylpyridine-3„5-dicarboxylate hydrochloride Ta bis following shows the precentage oral administration to reduction rats for In blood pressure (BP) th® representatives of the compounds according to the invention. » 3S % change (0PS in genetically hypertensive rats following a single daily oral administration on four successive day® (N=6/dose); efl dose in mg/kg is calculated on the free has©. the 10 Serial E^o . Dose ΘΡ (* changes vs. control) mean values of the given of time of measurement joints 24h (1st*3rd day ) (pmol/teg ) (mg/kg) 2h (1 s t * 41 h day) Sh (1st to 4th day ) 1 S 3 , OS -47 -30 - 7 1 0 6 , 09 -so -37 -9 25 15,24 - 4 0 -45 -23 ί s 25 14,89 -51 - 3 S -2 15 "Si «s> 25 14,74 - 4 0 -4 1 -1 9 4 2 '5 13,80 -51 a a " «0 Off -25 S <9 0 S, 24 -31 •—4 1 -20 6 25 1 7 , 02 "21 -21 -10 7 23 1 5 „ 9 9 • a
Claims (6)
1. Compounds of “he general formula I in which Y denotes oxygen CO), sulphur (§),, vinylene C-CK~CH—axotaefhine (-CH-N—) or a group of the formula R1^ 22 and 83 are identical or different and denote hydrogen,. C-j-C^-a Iky I or Cg-Cy-aIkoxya Iky I, 84 and RS are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trif luoromethy I, C-j-C/.alkyl, C«j -(4.-2 Ikoxy, C-j-C^-a Ikoxy which is completely or partly substituted by fluorine, -c 4 -aIkoxycarbony I, Cj-Cg-acyI, amino or mono- or c i -C-j-C z ~a I ky I am i no, R6, Rr, R8 and R9 are identical or different and denote hydrogen, hydroxyl, halogen, C-j-C^-alkyl, C-j-C^-alkoxy, amino, mono- or di ~C., »ς 4 ~ 3 u-;y laaei no, or C-j-C^-a Ikoxy which is completely or partly substituted by fluorine, and A denotes straight-chain or branched Cj-Cj-aIkylene, and their salts. 2. Compounds of the formula I according to Claim ι, wherein Ar represent s the ring mentioned in Clai a 1 , in which Y denotes viny lene and RI, rs R3, R4, R5, Re f - R7, RS,. R9 and A have the meanings given 1 n Claim· 1, and their s a. 11 s » S’«, Compounds of the formula I according to Claim· ι , wherein Ar represents the ring mentioned in Claim· 1, in which Y denotes z*\ \ k RC and RS denote hydrogen ®nd Ri, R2 S H3, RS, R7, R8, R9 and A have the meanings given in Claim 1, and their salts. 4» Compounds according to one of Claims T to 3, wherein RT denotes C-j —C^-e Iky I, R2 denotes C-j-C^-a I ky I , R3 denotes Cf —C4—a Iky I or C5—Cj-alkoxyalkyl, R4 denotes hydrogen, chlorine, nitro, methyl or methoxy, RS denotes hydrogen, chlorine, fluorine, nitro, cyano, methyl, methoxy, difluoro— methoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethyI or acetyl, R6 denotes hydrogen or methoxy, R7 denotes hydrogen, hydroxyl, chlorine, methyl, methoxy, difluoromethoxy or 1,T,2,2-tetrsf luoroethoxy, R8 denotes hydrogen or methoxy, R9 denotes hydrogen, hydroxyl, chlorine, methyl, methoxy, di t luororsethoxy or 1,1,2,2-tetrafluoroethoxy and A denotes ethylene· or propylene, and their salts5- Compounds according to one of Claims 1 co 3, wherein RI denotes methyl, R2 denotes ©«thyl, R3 denotes methyl, ethyl or aethoxyethy I, R4 denotes hydrogen, RS denotes hydrogen, chlorine, fluorine, nitro, cyano, methyl, methoxy, di f Luo romethoxy , 1 ,1,2,2-t e t r a-f luo roe thoxy or trifluoramethyl, R6 denotes hydrogen, R7 denotes hydrogen, hydroxyl. - 38 chlorine, methyl, ©ethoxy, difluoromethoxy or 1 , T,2,2-t et ra — fluoroethoxy, R8 denotes hydrogen, R9 denotes hydrogen, hydroxyl, chlorine, eethyl, methoxy, difluoromethoxy or 1,1,2,2-tetrafluoroethoxy and A denotes ethylene or propylene, and their salts» Compounds according to Claier 2,, wherein R-1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or fsethoxye-thyI, R4 denotes hydrogen or chlorine, R5 denotes hydrogen, chlorine, fluorine, nitro, cyano, difluoromethoxy, 1,T,2f,2,-tet rafluoroethoxy or trifluoromethyl, Κό denotes hydrogen, R7 denotes, hydrogen or methoxy, RS denotes hydro™ gen, R9- denotes hydrogen or methoxy and A denotes ethylene, propylene, butylene, 1,1-dimethylethylane or 2,2-dimethyl~ ethyle-ne-, and their salts*. 7- Compounds according to Claim- 1, wherein Ar denotes phenyl, 2-ni tropheny I, 3-nitrophenyI, 2-cyanophenyI , 3cyanophenyl, 2-(1,1,2,2-tetrafluoroethoxy)-phenyI, 3— ¢1,1 ,2,2-teera fluoroethoxy)-phenyl, 2,-difluoromethoxyphenyl, 3-di f luoroeaethoxypheny I, 2-ch loropheny I, 3-ch loropheny I, 2,3-dich lorophenyI, 2—fluorophenyI, 3-f luorophenyI, 2-tri — fluoroeethyIphenyI or 3-trifluoromethyIphenyI, Rl denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyI, R6 denotes hydrogen, R7 denotes hydrogen or methoxy, R8 denotes hydrogen, R9 denotes hydrogen or methoxy •and- A denotes ethylene, propylene, butylene, 1,1-dimethy I — ethylene or 2,2-dimethylethylene, and their salts. 8. Compounds according to Claim 3, whe r-i n Rl denotes methyl, R2 denotes ©ethyl, R3 denotes methyl, ethyl or nethoxyethyI, R4 dewofces hydrogen, R5 denotes hydrogen, R© denotes hydrogen, R? denotes hydrogen or methoxy, R8 denotes hydrogen, R9 denotes hydrogen or methoxy and A denotes ethylene, propylene, butylene, 1,1-dimethylethylene or 2,2di methy lathy lene, and their salt's. 9. Compounds according to Claim 1, wherein A r denotes - 39 2-n i t ropheny I or 3-ni tropheny I, RT, R2 and P.3 are identical or different and denote C-j-C^-alkyl or Cj-Cy-aIkoxyalkyl, A represents straight-chain or branched alkylene and R6., R7, RS and R9 denote hydrogen, and their s a Its * 10- Compounds, according to Clai® T, wherein Ar denotes
2. - nitrophenyI or 3-ni tropheny I, R1 denotes oethyl, R2 denote» «ethyl, R3 denotes raethyl, ethyl or sethoxyethyI, R6 denotes hydrogen, R7 denotes- hydrogen, R8 denotes hydrogen, R^ denotes hydrogen and A denotes ethylene or propylene, and- their salts* TT- Compound selected fro® the group consisting of
3. - eethyL 5—C3—(
4. ,4-diphenylpip*rid—1-yI)-propyll 1,4-di— hydro—2,6-disethy l-4-(3-ni tropheny15-py r i di ne—3,5-d icarboxylate> 3-erethyl 5—C2—(4,4-diphenyIpiperid~1~yI)-sthyll 1,4-dihydro2.6— di methy I— 4—(3-n it ro phenyl)-pyridine-3,5-dicarboxylate, 3-®ethyl 5-C3-(4,4-diphenyIpiperid—1-yI)-propy 11 4-(3-cyanopheny 15 —1,4-di hy dr o-2,6-di methy Ipyri di ne-3,5~di carboxy late, p-tcet hy I S-C2.— <4, 4-di pheny lpi peri d—1 -y 15 -2-(5 ethy I-propyl! 1 ,4—d i hydro— 2,6—di sethy 1-4—(3-n i t roph eny I) -py r i di ne—3,5-d i — carboxy late, 3—ethyl 5—C3 —(4,4~d i pheny Ip i peri d—1-y 15-p ropy 11 1,4-dihydro— 2.6— di me thy l-4-(3-ni tropheny I) -pyri di ne-3,5~di carboxylate, 3-sethyl 5-C3—(4,4-diphenylpiperid-1-yl5-propy13 1,4-di-; hydro—2,6-diraethyl -4-C3- (1,1,2,2-tetrafluoroethaxy5-phenyl3pyridine—3,5-dicarboxy late, 3-raethyl 5-C2 —(4,4-diphenylpiperid—1-yl)-ethyll 1,4-dihydro2.6— dimethyl -4-C3- ζ 1,1,2,2-tetrafluaroethoxy) -phenyl! -p yr i di ns-3,5-di carboxy late, 3- ( 2-fflethoxyetthyl) 5-(2-(4,4-diphenylpiperid-1-yl)-ethyl3 1.4- d ihydro-2,6-dime“hyl~4-(3“nitrophenyl)-pyridine-3,5d icarboxylate, 3 - ( 2-methoxyethyl, 5-(3-(4,4-dxphenyXpiperid-l-ylJ-propyl] 1.4- dihyd ro-2,6-di methy1-4-(3-niTrophenyl)-pyridine-3,5dicarboxylate. - 40 3-®ethyl 5- {3-C4, 4-d i -( 4-iae t ho xy ph eny I) -p i per 1 d-Ί -y 13 — propyl} 1,4-di hydro-2,6~di «ethy1-4-(3-nitrophenyI)-pyridi ne3,5-d i carboxylate, 3ieethy I 5-C4-14,4-di pheny Ipi peri d-1 -y I) -buty II 1,4-di hydro2,o~d i methy I-4-(3-ni trophenyI) -pyridine~ 3,5-dicarboxylate, 3-eethy I 5-C1,1-di©ethy1-2-(4,4-diphenyIpiperid-1 -yI)-ethyU 1.4- di hydro-2,6-di®ethyt~4-C3-nftrophenyI) -pyridi ne-3,5di carboxy late, 3-ethyl 5-C3-(4,4-dipheny lpiperid-1—yl)-propy 13 1,4-d.ihydro— 2, ό-di thy I—4-(2-di f luo raise thoxy pheny I) -py ri di ne-3, 5-d i — carboxylat e^ 1.4- dihydro-2,6-dimethyI—4—(3-nitrophenyl)-pyri di ne—3,5— dicarboxylic acid 3-C3—(4.,4-di pheny Ipi peri d-Ί-y 13 ~p ropy I esterT 3-ethyl 5-C3-C4,4-diphenyIp i per i d-1-y I)-p ropy IJ 1,4-dihydro2, 6.-di me thy1-4-(3-(1,1,2,2-tet raf Luo roethoxy)-phenyl3-pyrid i ne-3,5—di carboxylate, 3—ethyl 5-C3~<4,4-diphenyIpi per i d-1—y I)-propy 13 1,4-dihydro2, ό—di met hy I-4-(3-di fluoromethoxyphenyD-pyridine—3,5-dica rboxy late, 3-taethyl 5-C3-C4,4-di pheny Ip i pe ri d-1-y I)-propy 13 4-(2,3-dichlorophenyI)—1 ,4-dihydro—2,ό—di ©ethy Lpyri di ne-3,5-dicarboxy— late, 3-sethyl 5~C3-(4,4-di ph eny Ip i peri d-1-y U ~p ropy L3 4— (2.1 , 3-benz0xdiarzol-4-yl) - i „ 4-dihyero-2 „ 6~dirc»ethylpyridine-3 „ 5dicarboxylste „ 3-raethyl 5-C3~C4,4-diphenyIpiperid-1-yI)-propy13 1,4-dihydro-2,ό-dimethyl-4-(3-fluoropheny I)-pyridi ne-3,5-dicarboxylate, 3-aethyl S-C3-(4,4-ciph any Ipiperid-1-yI)-propy Ij 1,4-dihydro-2,ό-di ©ethy1-4-(2-t rifluoromethyIphenyl)-pyridi ne-3,5di ca rboxy late, 3-ethyl 5-C3-(4,4-diphenyIpiperip-1-y()-propy 13 4-(2-cyanopnenyI)~1,4-dihydro-2,6-diaethylpy ri di ne-3,S-di carboxy late and 3-methyl 5-C3-(4,4-diohenylpipe3rid-1 -yi)-propyl] 4-(2~chXoro~ phenyl)- 1 a 4-dihydro-2,S-dimethyipyrieine-S,S-flicarboxylate hydrochloride and their salts. -41 12« 3-*Methyl 5“C3 (4,4-d i ph eny Ip i pe r i d~1 -y I) ”P cop y I j 1,4d i h y d r o~2,6-d i me t h y 1-4-(3-0 itrophenyI) -pyridine-3,5-01carboxylate and its salts» 13. Process far the preparation of compounds of the formula I according to Claim 1 and their salts, chargeterisedinthat a) cinnamic acid derivatives of the for«ula XI (II) b) cinnamic acid derivatives of the formula II are reacted w.ith ammon formula IV w.ith ammonia and p> -ketocarboxy li c acid derivatives of the (IV) (V) are reacted with benzyIidene carboxy Iie acid derivatives o the formula VI CVI) d) keto compounds of the formula VII R300C CHx GT CVII) are reacted with ammonia and benzy I i denecarboxy li c acid, derivatives of the formula VI^ sr e) aldehydes of the formula VIII ΑΓ CVIII) are reacted with enamines of the formula V and ^-ketocarboxylic acid derivatives of the f orau la IV, or f) aldehydes of the formula Mill are reacted with enamine derivatives of the formula III and keto coaoounds of the formula. VII, or g) 1,4-dihydropyridines of the formula IX as such or in- the- fora of their salts, and, if desired,
5. Resulting salts, are then converted into the- free· bases or resulting bases are converted into the salts, wherein Ar, RT, R2T, Ro, R4-, R5, R6, RF, R8, R9, Y and A have the meanings- given in Claim- 1 and. 2, together with the carbonyl group to which it is bonded, represents a carboxyl group or to a reactive- carboxylic acid, derivative. 1 Medicaments containing one or more compounds according to one or more of Claims 1 to 12 and/or their pharmacologically acceptable salts. 15» Compounds according to one or more of Claims 1 ta 12 15 and their pharmacologically acceptable salts for use in the treatment and/or prophylaxis of hypertension, coronary heart diseases, disturbances in peripheral and cerebral circulation and/or diseases based on an increased retention of water or sodium. - 44 16. Use of compounds according to one or more of Claims 1 to 12 and their pharmacologically acceptable salts for the manufacture of medicaments for the treatment and/or prophylaxis of hypertension, coronary heart diseases, disturbances in peripheral and cerebral circulation and/or 5 diseases based on an increased retention of water or sodium. 17. A compound substantially as hereinbefore described with reference to the Examples. 18. A process substantially as hereinbefore described with reference to the Examples.
6. 10 19. A medicament substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH465284 | 1984-09-28 |
Publications (2)
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| IE852384L IE852384L (en) | 1986-03-28 |
| IE66677B1 true IE66677B1 (en) | 1996-01-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| IE238485A IE66677B1 (en) | 1984-09-28 | 1985-09-27 | New Diaryl Compounds |
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| 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) |
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| 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 |
| WO1989007443A1 (en) * | 1988-02-19 | 1989-08-24 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Optically pure r-(-)-niguldipine and its derivatives for treating tumorous diseases |
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1985
- 1985-09-06 FI FI853415A patent/FI83957C/en not_active IP Right Cessation
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- 1985-09-26 KR KR1019850007105A patent/KR930001404B1/en not_active IP Right Cessation
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- 1985-09-27 CA CA000491694A patent/CA1291137C/en not_active Expired
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1986
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| GR852364B (en) | 1985-12-13 |
| ES554068A0 (en) | 1987-10-16 |
| ES554067A0 (en) | 1987-11-01 |
| FI83957B (en) | 1991-06-14 |
| FI83957C (en) | 1991-09-25 |
| AU4794885A (en) | 1986-04-10 |
| DK440885A (en) | 1986-03-29 |
| AU574842B2 (en) | 1988-07-14 |
| KR860002497A (en) | 1986-04-26 |
| FI853415A0 (en) | 1985-09-06 |
| ES8703148A1 (en) | 1987-02-16 |
| HUT38627A (en) | 1986-06-30 |
| ZA857477B (en) | 1986-05-28 |
| HU194210B (en) | 1988-01-28 |
| FI853415L (en) | 1986-03-29 |
| ES8800201A1 (en) | 1987-11-01 |
| PT81209A (en) | 1985-10-01 |
| NO853833L (en) | 1986-04-01 |
| KR930001404B1 (en) | 1993-02-27 |
| PT81209B (en) | 1988-01-22 |
| IL76511A (en) | 1990-06-10 |
| ES8708135A1 (en) | 1987-10-16 |
| ES547385A0 (en) | 1987-02-16 |
| IE852384L (en) | 1986-03-28 |
| CA1291137C (en) | 1991-10-22 |
| NZ213629A (en) | 1989-07-27 |
| NO169586C (en) | 1992-07-15 |
| NO169586B (en) | 1992-04-06 |
| DK440885D0 (en) | 1985-09-27 |
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| MM4A | Patent lapsed |