AU638205B2 - Optically pure r-(-)-niguldipine and its derivatives for treating tumorous diseases - Google Patents

Description

~OPI DATE 06/09/89 A0JP DATE 05/10/89 (51) Internationale Patentklassifikation 4 I A6 1K 31/445 APPLN. ID 30667 89 PCT NUMBER PCT/EP89/OO1LIO 'ESENS (PCT) .Al (11) Internationale Ver6ffentlichungsnummer: WO089/ 07443 (43) Internaiionales Vertiffcntlichungsdatuni: 24. August 1989 (24.08.89) (21) Internationales Aktenzeichen: PCT/EP89/00 140 (22) Internationales Anmeldedatumn: 16. Februar 1989 (16,02.89) (31) Priorititsaktenzeichen: 630/88-6 629/88-0 19. Februar 1988 (19.02.88) 19, Februar 1988 (19,02.88) (32) Priorititsdaten: D-7750 Konstanz 26 SCHUDT, Christian Hoheneggstrage 102, D-7750 Konstanz BOER, Rainer Lohrystra~e 4, D-7750 Konstanz (DE), GIETZEN, Klaus Abt. Pharmakologie und Toxikologie, Uni Ulm, Oberer Eselsberg, D-7900 Ulm (DE).

(74) Gemneinsamer Vertreter: BYK GULDEN LOMBERG CI-EMISCHE FABRIK GMBH-; Byk-Gulden-Str, 2, Postfach 6500, D-7750 Konstanz (DE).

(81) Bestimmungsstaaten: AT (europflisches Patent), AU, BE (europflisches Patent), CH (europflisehes Patent), DE (europdisches Patent), DK, FR (europtlisches Patent), GB (europtisches Patent), HU, IT (eur.jpisches Patent), JP, LU (europtiisches Patent), NL (europllisches Patent), SE (europflisches Patent).

(33) Priorititsland; CH (71) Anmelder: BYK GUILDEN LOMBERG CHEMISCHE FABRIK GMBH [DE/DEl; Byk-Gulden-Stra~e 2, D- 7750 Konstanz (DE).

(72) Erfinder. KLEMM, Kurt Im Weinberg 2, D-7753 Allensbaci(DE), ULRICH, Wolf-Rildiger ;Hebeistra~e 3, D-7750 Konstanz FOKER~r Dieter Akkerweg 26, D-7753 Allensbach (),SANDERS, Karl Felchengang 23, Di,1750 Konstanz BEL.

LER, Klaus-Dieter ,Frartz-Moser-Strake Ver~ffentlicht Mit internationalemnRecherchenlbericht C D 63 0 2 (54) Title: OPTICALLY PURE R-(-)NIGULDIPINE AND ITS DERIVATIVES FOR TREATING TUMOROUS DI-

SEASES

(54) Rezeichnung: OPTISCH REINES R-(+)NIGULDIPIN UND DESSEN DERIVATE ZUR BEHANDLUNG VON

TUMORERKRANKUNGEN

(57) Abstract Optically pure diaryl compounds of formti~a in which the substituents and symbols have the Mt-anings indicated in the description are proposed as active ingredients in medicinal preparations for treating tumorous diseases.

(57) Zusanirnenfassung Optisch relne Diarylverbindungen der Formel wormn die Substituenten und Symbole die in ,schreibung angegebenen Bedeutungen haben, werden als Wirkstoffe in Arzneimitteln zur Behandlung von Tumorer&aikungen vorgeschlagen.

0089/07,443 PCT/EP89/00140 Optically pure R-(-)-niguldipine and its derivatives for treating tumorous diseases Field of Invention The invention relates to optically pure diaryl compounds having an antineoplastic action, to their therapeutic use and to medicaments containing them. The compounds are employed in the pharmaceutical industry for the manufacture of medicaments.

Technical Background The use of calcium channel blocking compounds of the 1,4-dihydropyridine type for reducing metastasis and neoplastic growth in mammals is described in European Patent Application 0 123 850. The antineoplastic action of the 1,4-dihydropyridines investigated (like Nimodipine and Nifedipine) is said to be attached to the calcium channel blocking activity of these compounds which permits them to be used in human medicine for the treatment of vascular and cardial disorders. In European Patent Application 0 176 956 diaryl piperidine esters of 1,4-dihydropyridines and their use in cardiovascular diseases is disclosed.

In European Patent Application 0 240 828 a certain enantiomer, (+)-3-methyl- 5-[3-(4,4-dipheny1-1-piperidinyl)-propyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitroand its use for the treatment of cardiovascular diseases is claimed. In European Patent Application 0 242 829 2-amino- 1,4-dihydropyridines with diaryl piperidine ester radical and their use in cardiovascular diseases is disclosed.

I I W089/07443 W089/7 443PCT/ EP89/00 140 Description of thc- invention The invention relates to the use of optically pure diaryl compounds of formula I wherei n Ar represents a ring of the formula R4 Y R in which Y denotes oxygen sulphur vinylene azomethine or a group of the formula 0

N

S/

I-

14089/0443 PCT/EP89/00140 R1 denotes hydrogen, 1-GC-alkyl or 3-7C-alkoxyal kyl, R2 denotes hydrogen, amino 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 denotes hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or partly substituted by fluorine, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino, mono- or di-1-4C-alkylamino or together methylenedioxy, R6, R7, R8 and R9 are identical or different and denote hydrogen, hydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or partly substituted by fluorine, and A denotes 2-5C-alkylene or Al-0-A2, in which Al denotes 2-4C-alkylene and A2 denotes 2-4C-alkylene or 2C-alkyleneoxy-2C-alkylene and their salts for the manufacture of medicaments for the treatment of tumors.

The grouping of the substituents Ar and H in 4-position of the 1,4-dihydropyridine ring was accomplished on account of the publication of K. Tamazawa et al., J. Med. Chem. 29, 2504 (1986). Alternatively, compounds I can also be defined as optically pure compounds of formula Ia with uniform configuration R6 R7 Ar H R300C CO-A-N (Ia) R2 RI R8 'R9 wherein Ar, R1, R2, R3, R4, RS, R6, R7, R8, R9 and A have the meanings given above and which have the same configuration in the 4-position in the dihyd&.pyri dine as the diastereomer quinchonine k+)-1-ethoxymethyl -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl -4-(3-nitrophenyl) -pyridine-3-carboxyl ate, which is used as a starting compound and rotates linearly polarized light of wavelength 2Z 0 589 nip with [x +101,5 (c 1, chloroform).

0 W089/07443 PCT/EP89/00140 1-6C-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 particular, ethyl or methyl radical.

3-7C-alkoxyalkyl represents, for example, a methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl or 2-ethoxy-1-methylethyl radical.

For the purposes of the invention, halogen denotes bromine and, in particular, fluorine and chlorine.

1-4C-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.

1-4C-alkoxy contains, in addition to the oxygen atom, one of the above-mentioned 1-4C-alkyl radicals. The methoxy radical is preferred.

1-4C-alkoxy which is completely or partially substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy.

1-4C-alkoxycarbonyl contains, in addition to the carbonyl group, one of the above-mentioned 1-4C-alkoxy radicals. The methoxycarbonyl radical and the ethoxycarbonyl radical are preferred.

contains, in addition to the carbonyl group, one of the above-mentioned 1-4C-alkyl radicals. The acetyl radical is preferred.

Mono- or di-1-4C-alkylamino contains, in addition to the nitrogen atom, one or two of the above-mentioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred, and in particular dimethyl-, diethyl- or diisopropylamino.

2-SC-alkylen is, for example, tetramethylene, 1,2-dimethylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and, in particular, ethylene or propylene (trimethylene).

2-4C-alkylen represents ethylene (-CHz-CHz-), trimethylene (-CH.-CH 2

-CH

2 and tetramethylene (-CH -CHz-CHz-CHIz-), ethylene being preferred.

W089/07443 PCT/EP89/00140 2-C-alkyleneoxy-2C-alkylene represents ethylene which is substituted by ethy- 1 eneoxy (-CH 2

-CH

2

CH

2 -CHz-).

Suitable salts include all salts with acids, particularly the pharmacologically-acceptable salts of inorganic and organic acids customarily used in the pharmaceutical industry. Pharmacologically-unacceptable salts, which are, e.g., initially obtained as process products in preparing the compounds according to the invention on an industrial scale, are readily converted into pharmacologically-acceptable salts by conventional processes known to those skilled in the art. Examples of suitable salts are water-soluble and water-insoluble acidaddition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, metembonate, stearate, tosylate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesylate.

The use, according to the invention, of compounds of formula I wherein Ar denotes phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy)-phenyl, 3-(l,l1,2,2-tetrafluoroethoxy)-pheny 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,3-methylenedioxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or 2,1,3-benzoxdiazol-4-yl, R1 denotes methyl, R2 denotes amino or methyl, R3 denotes methyl, ethyl or methoxyethyl, R6 denotes hydrogen, R7 denotes hydrogen or methoxy, R8 denotes hydrogen, R9 denotes hydrogen or methoxy, A denotes ethylene, propylene, butylene, 1,1-dimethylethylene, 2,2-dimethylethylene or Al-0-A2, Al being ethylene and A2 being ethylene or ethyleneoxyethylene, and of their salts, has to be singled out.

The use, according to the invention, of compounds of formula I wherein Ar dernotes 3-nitrophenyl 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3-benzoxdiazol- 4-yl, RI denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R6, R7, R8 and R9 denote hydrogen and A denotes ethylene or propylene, and of their salts, has to be singled out particularly on one hand.

6 1 The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3benzoxdiazol-4-yl, R1 denotes methyl, R2 denotes amino, R3 denotes methyl, ethyl or methoxyethyl, R6, R7, R8 and R9 denote hydrogen and A denotes ethylene or propylene, and of their salts, has to be singled out particularly on the other hand.

The use, according to the invention, of compounds of formula I wherein xr denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3benzoxdiazol-4-yl, Rl denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R6, R7, R8 and R9 denote hydrogen and A denotes A1-0-A2, Al being ethylene and A2 being ethylene or ethyleneoxyethylene and of their salts, has to be singled out particularly in addition.

The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl or 2,3dichlorophenyl, R1 denotes methyl, R2 denotes methyl, R3 ^denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen 25 and A denotes ethylene or propylene, and of their salts, is preferred on one hand.

0 The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl or 2,3dichlorophenyl, R1 denotes methyl, R2 denotes amino, R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen and A denotes ethylene or propylene, and of their salts, is preferred on the other hand.

S- 6a The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl or 2,3dichlorophenyl, R1 denotes methyl, R2 denotes methyl, R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen and A denotes Al-0-A2, Al being ethylene and A2 being ethylene, and of their salts, is preferred in addition.

In an alternative aspect, the invention provides a method of treatment of a cancer in a subject in need thereof, comprising the step of administering to said subject an effective amount of a compound as defined in formula I.

Preferably the cancer is selected from the group consisting of ovarian cancer, testicular cancer, prostate cancer, cancer of the urinary bladder, oesophageal carcinoma, colon cancer, breast cancer, bronchial carcinoma, and lung carcinoma.

20 compounds has to be singled out by way of example: *0: I.o 4

A'

W089/07443 PCT/EP89/00140 -3-methyl (4,4-di phenyl -1-pi peridi nyl )-ethyl I-1,4-di hydro-2,6-dimethylI- 4- (3-nitrophenyI) -pyridine-3,5-dicarboxy Iate -3-methyl1 [3-(4,4-di ph enyl -1-piperidinyl I) -p ropyl I (3-cyanophenyl -1,4di hydro-2, 6-di met hylI pyri di ne-3 ,5-di carboxyl ate -3-methyl (4,4-di phenyl -1-piperidinyl) -2-rnethylI-propy1] -1,4 -d ihydro- 2,6 6Ai methylI (3-ni trophenyl I) -pyri di ne-3 ,5-di carboxyl ate -3 -ethyl [3-(4,4-diphenylI-1-piperidinyl )-propyl] -1,4-dihydro-?,6-dimethy]1 (3-nit-v~pheny I) -pyri di ne-3 ,5-di carboxylI ate (R)-3-methyl-5-[3-(4,4-diphenyl-1-piperidinyl)-propyl]-1,4-dihydro-2,6-dimethyl 1,2,2-tefraf 1uoroetho,,,i)-phenyl] -pyridine-3,5-dicarboxyl ate -3-methy 1-5- 2- (4,4-di phenylI-1-piperidinyl )-ethylIj -1,4-di hycdro-2,6-dimethylI- 4- (1,1,2,2-tetrafl uoroethoxi 1--henyl] (2-riethoxi ethyl [2-(4,4-di phenyl -1-pi peri di nyl )-ethyl ]-I,4-di hydro- 2,6-dimethyl (3-ni trophenyl )-pyri di ne-3,5-di carboxyl ate (2-methoxi ethyl (4,4-diphenyl -1-pi peri di nyl )-propyl] 4-di hydro- 2,6-diimethyl (3-ni trophenyl )-pyridi ne-3,5-licarboxyl ate -3-methyl 13- (4,4-di (4-methoxi phenyl -1-pi peri di nyl -propyl -1,4-di hydro- 2,6-di methyl (3-ni troplhenyl -pyri di ne-3,5-dicarboxyl cte -3-methyl (4,4-di phenyl -1-piperi di nyl -butyl -1,4-di hydro-2,6-dimethyl 4- (3-ni trophenyl -pyri di ne-3 ,5-di carboxyl ate -3-methyl 1-dimethyl (4,4-di phenyl -1-pi peridi nyl -ethyl] -1 ,4-di hydro- 2,6-dimethyl (3-ni tropheny -pyri di ne-3, 5-di carboxyl ate -3-ethy (4,4-di phenyl -1-pi peridi nyl )-propyl ]-1,4-dihydro-2,6-dimethyl 4- (2-di f I uoromethoxi phenyl -pyri di ne-3,5-di carboxyl ate -3-e-thyl (4,4-di phenyl]-1-pi peridi nyl )-propyll 4-di hydro-2,6-dimethyl 1, 2 2-tetraf Iuoroethoxi )-phenyll]-pyridi -3-ethyl (4,4-diphenyl -1-pi peridi nyl) -propyl ]-1,4-di hydro-2,6-di methyl 4- (3-di flI uoromethoxi phenyl -pyri di ne-3 ,5-di carboxyl aite -3-umethyl (4,4-di phenyl -1-piperi di nyl )-propyl -4-(2,3-dichl orophenyl) 1, 4-di hydro-2,6-dimethy] pyri di ne-3,S-di carboxyl ate -3-methyl (4,44diphenyl -1-pi peri di nyl )-propyl 1,3-benu~diazol -4y -1,4-dihydro-Z,6-dimethyl -pyri dine-3,5-di carboxyl ate (R 3mty 5 3 44d hnl--ipeid y)-rpl 14d yr-,-ie thy] (3-f]1 uorophenyl -pyri di ne-3 ,5-di carboxyl ate (R 3mty 5 3 44d hnl--ipr inl)-rpl]-,-iyr-,-ie thy] (2-tni fl1 uoromethyl phenyl -pyridi n-,5-di cairboxyl ate (R 3ehl--[-(,-ipey 1p eidnl)-rpl 4(-ynpey 14d hydro-2,6-dimethyl pyri di ne-3,5-di carboxyl1ate W089/07443 W039/7 443PCT/EP89/00140 -3-mfethyl 4-di phenylI -1-pi peridi nyl -propyl] (2-chi orophienyl -1,4di hyclro-2,6-di methyl pyri di ne-3 5-di carboxyl ate -3-methyl 4-di phenyl -1 -p1 peni di nyl -propyl] 4-di hydro-2 ,6-di *methylI (3-nitropheny I) -pyri di ne-3,5-di carboxylI ate -3 -ethyl (4,4-di phenyl -I1-pi peridinyl -ethylI] -2-ani no -I,4-di hydro-6-methylI -4-(3-nitrophen.ylI -pyri di ne-3 ,5-di carboxylI ate -3-(2-rnethoxyethyl (4,4-di phenyl- -1-pi peridinyl -propyl] -2-ami no -i 4dilhyclro-6-mfe-thyl (3-ni trophenyl -pyri di ne-3 ,5-di carboxylI ate (R)-3-ethyl-5-[4-(4,4-dipheny -l-pi peridinyl )-buty -2-amino-,4-dihydro-6-methylI (3-ni tropheny I) -pyri di ne -3 ,5-di carboxylI ate -3-methyl-5-2-(4,4-di phenyl-i-pi peridinyI) -ethy] -2-mino-,4-iihydro-6 -me thy] -4-(2-nitrophenyl -pyridine-3 ,5-di carboxyl ate [2-(4,4-dipheny -1-piperidinyl )-ethyI] -2-ami no -i,4-dihydro-6ethylI (3-ni trophenyl -pyri di ne-3 5-dicarboxyl ate -3-(propyl (4,4-di phenyl -1-pi peridi nyl -ethyl] -2-ainii no -i,4-dihydro- 6-methyl (3-ni trophenyl -pyri di ne-3, 5-di carboxylI ate -3-hexyl 4-di phenylI -1 -pi pen di nyl -ethyl] -2-ami no -di hydro-6-methylI -4-(3-nitrophenyl -pyridine-3 S -dicarboxylI ate -3-(2-n-butoxyethy 1) 4-diphenyl -1-pi peridiny I) -ethylI] -2-ami no -i,4di hyciro-6-miethylI (3-ni-tro ph enylI -pyridine-3 ,5-dic carboxy Iacte (R)-3-mfe thyl 1-5-12- [4,4-di (4-methoxypheny I) -1-piperi dinyl] -ethy I -2-ami no- -4 cli hydro-6-methyi (3-nitrophenyl -pyridi ne-3 ,5-dicarboxylI ate -3-ethyl 4-di phenylI -1-pi pen di nyl -ethyl] -2-amino-i, 4-di hydro-6-methy! -4-(2-triflIuoromethyl pheny I) -pyridine-3,5-dicay'boxy Iate -3-me-thyl (4,4-diphenyl -1-pi peridinyl -ethylI] -2-ami no -i,4-di hydro-6 -me thyl f3-(1, 1,2,2-tetrafl uoroethoxy) -phenyl] -pyri dine-3 ,5-dicarboxyl ate -3 -ethyl (4,4-di phenyl -1-pi periclinyl -ethyl] -2-amino-i ,4-di hydro-6-methylI (2-cl fl uorornethoxypheny1 -pyri di ne-3 ,5-di carboxyl ate -3-ethyl [4-(4,4-diphenylI -1-pi peridinylI) -butylI] -2-ami no -I 14-d Ihydro-6 -me thyl (2-di fl I oromethoxypheny I) -pyri di ne-3 ,5-di carboxyl ate -3 -me thylI 4-di hydroxyphenylI -1-pi pen di nyl -ethyl I -2-ami no -i,4-di hydro-6-aethvIl.4I.( -n t ropheny) -pyridi ne-3,5-dic arboxylIacte -3 -me thyl-5- (4,4-diphenyl.-el-pi peridinyl -ethyl]I -2-amino-4- (2,3-dichlI orophenyl I) -,4-dihydro-6--methyl pyri dine -3,5-di carboxyl cte -3-me-thyl [2-(4,4-diphenyl -1-piperidinyl -ethyl]. -Z-ami no i,3-benzoxdi azo I 4-y I) -1,-dihydro-6-methyl pyridine-3,5-di carboxy Iate -3-methylI 4-di phenylI -1-piperi di Ql )-~ethyl] -2-ami no-4- (3-cyanopheny I) -,44dhydro-6-metnyl pyridi ne-3,,5-dicarooxy Iate W089/07443 W089/7 443PCT/ EP89/001.40 -3-methy I-5-[2-(4,4-dipheny I--piperidinyl )-ethyl -2-amino-1,4-diydro-6-nethyl (2-methoxyphenyl -pyri di ne-3 ,5-di carboxyl ate -3-methyl -5-[2-(4,4-diphenyl -1-piperidinyl )-ethyl-2-aino -1,4-dihydro-6 -me thyl1 -4-(2",pyridyl -pyridine-3 ,5-dicarboxyl ate -3-ipethyl -5-[2-(4,4-diphenyl -1-.piperidinyl )-ethyl]-2-aniino -1,4-dihydro-6 -me thyl (5-methyl -2-thi enyl -pyri di ne-3 ,5-di carboxyl ate -3-methyl1 (4-ch I orophenyl -4-phenyl -1-pi peridi nyl I -ethyl J-2-ami no 1, 4-di hydro-6-methylI (3-nitnrophenyl -pyri di ne-3 ,5-di carboxyl cite -3-mthyl (4,4-dip ,eny I-1-piperidinyl )-propyl] -2-amino-I,4-dihydro-6methyl (2-ni trophenyl I) -pyri di ne-3 ,5-cU carboxylI ate (R)-3-methy -5-[3-(4,4-diphenyl -I piperidinyl)-propyl] -2-ai no -1,4-dihydro-6e thy l (3-ni trophenyl -pyri di ne-3 ,5-di carboxyl ate -3-(propyl 4-di phenyl -1-piperi di nyl -propyl]I -2-amfino-i ,4-dihlydro- 6-methyl (3-ni trophenyl -pyri di ne-3,5-di carboxyl ate -3-hexy 1 [3-(4,4-diphenyl -I1-piperidinyl -propylIl -2-ami no -1,4-cdihydro-6 -me thyl (3-ni trophenyl -pyri di ne-3 ,5-di carboxyl ate -3-(2-n-butoxyethy] (4,4-di phenyl -1-pi peri di nyl I) -propyl] -2-ami no -i,4di hydro-6-methyl1 (3-nitropheny I) -pyridine-3 ,5-di carboxyl at e -3-methyl 4-di (4-methoxyphenyl -1-pi peni di nyl] -propyl -2-ami no -i,4di hydro-6-methy 1 (3-ni tropheny I) -pyri di ne-3 ,5-di carboxyl ate -3-ethyl 4-di phenyl -1-piperidi nyl )-propyl]I -2-ami no-i ,4-d Ihydro-6methyl -4-(2-tri flIuoromethylphenyI) -pyridine-3,5-dic arboxyl ate -3-methyl (4,4-dipheryl -1-pi peridi nyl -propyl]I -2-ami no -1,4-dihydro-6me thyl ,2,2-tetraflIuoroethoxy) -phenyl] -pyri di ne-3,S-di carboxylIate -3 -ethyl (4,4-dipheny] -1-piperidi nyl -propyllI -2-aiino -i 4-dihydro-6methyl1 (2-di f I uoroniethoxyphenyl -pyri di ne-3,*5-di carboxylI ate (R)-3-methylI 4-di hydroxyphenyl- -1-pi peridi nyl -p ropyl I -2-amino-i, 4-di hycfro-6-imethyl -4-(3-nitropheny I) -pyridi ne-3,5-di carboxy Iacte -3-methyl -5-[(3-(4,4-dipheny I-1-piperidiny I)-propy I I 2-amino-4-(2,3-dich Iorophenyl -1 ,4-di hydro-6-methylI pyri di ne-3 ,5-di carboxylI ate -3-methy (4,4-d I phenyl -1-piperidi nyl )-propyl I-2-ami no -ben zoxdiazol -4-yl) '-t-di hydro-6-rnethyl pyridine-3,5-di carboxyl ate -3-methyl (4,4-diphenyl -1-pi peridinyl )-propyl] -2-ainlino-4-(3-cyanophienyl -1 ,4-di hydro-6-methyl pyri di ne-3 ,5-di carboxyl ate -3-niethyl [3-(4,4-diphenyl -1-piperidinyl )-prop, 1]-2-amino-1,4-dihydro-6methyl (Z-methoxyphenyl -pyri di ne-3 ,5-di carboxyl ate (R)-3-methyl-5-[3-(4,4-diphenyl-1-piperidinyl)-propyl]-2-Imino-1,4-dlihydro-6methyl (2-pyridyl -pyridi ne-3,5-di carboxyl ate W089/07443 _10- W089/7 443-.10-PCT/EP89/00 140 -3 -ethyl (4,4-di phenyl -1-pi peridi nyl -ethoxi]I -e-thyl I -l ,4-di hydro- 2,6-dimethyl (3-nitrophenyl -pyri di ne-3 ,5-di carboxyl ate -3-(2-methoxyethy) [3-(4,4-diphenyl -I-piperidi nyl )-propoxi] -propyl} 1,4-dihydro-2,6-dimethy-4- (3-nitropheny) -pyri dine (R)-3-methyl-5-2- [2-(4,4-dipheny-1-piperidinyl)-ethoxi I-ethylI}-1,4-dihydro- 2,6-dimethylI (2-iitrophenyl -pyridi ne-3 ,5-di carboxyl ate -3-methyl 2- [2-(4,4-diphenyl -I-piperidinyl )-ethoxi] -ethyl I-1,4-dihydro- 2,6di ethyl (3-ni trophenyl -pyridi ne-3 ,5-di carboxyl ate (R)-3-(propy 1 [2-(4,4-diphenyl -1-pi peridinyl -ethoxi] -ethyl 1-1,4-d lhydro-2 ,6-dimethyl1 (3-nitropheny I) -pyni di ne-3 *5-di carboxyl ate (R)-3-hexyl (4,4-diphenyl- I1-pi pe ridinyl )-ethoxi] -ethyl J-i,4-dihydro- 2, 6-di methylI (3-ni tropheny I) -pyri di ne-3 ,5-di carboxylI ate (2-n-butoxyethyl [2-(4,4-di phenyl -1-piperi (Ii nyl -ethoxi] -ethyl- 1,4-4ihiydro-2,6-dimethyl (3-ni trophenyI) -pyri dine -3 -ethyl [2-(4,4-diphenylI -I1-pi peridi nyl -ethoxi] -ethyl I-1,4-dihydro- 2,6-dIitnethyl (2-tn -fl uoroinethyl phenyl )-pyridi ne-3,5-di carboxyl ,te -3-methiy,-5- [2-(4,4-di phenyl -1-pi peridinyl -ethoxi -ethyl 1 -1 ,4-dihydro- 2,6-dIimiethyl-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyridine-3,5-cicarboxyl ate -3-ethyl 12-(2- (4,4-di phenyl -1 -pi peri di nyl )-ethox i] -ethyl 4-di hydro- 2,6di methyl (2-di f Iuoromethoxyphenyl )-pyri di ne-3, 5-di carboxylate -3-methyl 4-di phenyl I-pi peri di nyl -ethoxi -ethyl 1, 4-di hydro- 2,6di methyl (3-n itrophenyl )-pyri di ne-3,5-di carboxyl cte -3-methyl (4,4-d i phenyl -1 -pi peri di nyl -ethoxi]I -ethyl 1-4- (2,3-.di chl1 orophenyl 1, 4-di hydro-2 6-di me thyl pyri di ne-3 5-di carboxyl cite -3-methyl 12- (4,4-di phenyl -1I-pi peri di nyl -ethoxi]I -ethyl 1,3-benzoxdi cizol -4-yl 4-di hydro-2 ,6-di methyl pyri di ne-3 5-di carboxyl ate -3-metLhyl -5-12- (4,4-di phenyl -1I-pi peri di nyl -ethoxi -ethyl (3-cyanophenyl 4-di hydro-2,6-di methyl pyri di ne-3, 5-di carboxylacte -3-methyl (4,4-di pheryl p iperi di nyl )-ethox i I-ethyl I -di hydro- 2, 6di methyl (2-inethoxyphenyl -pyri di ne-3 Ii carboxyl ate -3-methyl (4,4-di phenyl -1-pi peridin,, -ethioxij -ethyl 4-dihydro- 2,6-dimethyl (2-pyri dyl )-pyri dine-3, 5-dicarboxyl ate (R)-3J-methyl [2-(4,4-cliphenyl-1-pi peridinyl )-ethoxill-e-thyl }-1,4-dihydro- 2,6-climethyl-4-(5-methyl-2-thienyl)-pyridinie-3,5-dicairboxylaite -3-methiyl (4,4-di phenyl -1-pi peridinyl )-propoxi] -propyl 4-di hydro- 2, 6-dimethyl (2-ni-trophenyl -pyri di ne-3 ,5-di carboxyl ate W089/07443 _11- W089 0 744 -11-PCT, E P89/00140 -3-methyl1 (4,4-di phenyl -1-pi pen di nyl -propoxi] -p ropy I -1,4-di hydro- 2, 6-di ethyl (3-nitrophenyl -pyridi ne-3,5-di carboxyl ate -3-(propyl phenyl-1-piperidinyl )-propoxi] -p ropy1}-1,4-di.

hydro-2,6-di met hylI (3-nitrophenylI -pyridi ne-3 ,5-dicarboxy Iate -3-hexyl-5-{3-[(3-(4,4-diphenylI-1-piperidinyl )-propoxi I-p ropy I -1,4-dihydro- 2,6-climethyl (3-ni trophenyl -pyri dine-3 ,5-dicarboxyl ate (2-n-butoxyethyl (4,4-diphenyl -1-pi peridinyl -propoxy] -propyl 3.,4-cli hydro-2 ,6-dimethyl1 (3-ni trophenyl -pyri di ne-3,5-dic arboxyl ate -3-ethyl (4,4-diphenyl -1-pi peridinyl -propoxi] -propy I -1 ,4-di hydra- 2, 6-cU methyl1 (2-tni fl1 uoromethyl pheny I) -pyri di ne-3 ,5-di carboxy I ate -3-methyl (4,4-di phenyl -1-pi peni di nyl -propoxi] -propyl -1 ,4-di hydra- 2,6-dimethyl [3-(1,,2,2-tetrafuoroethoxy) -phenyII l ate -3-ethyl 13- (4,4-di phenyl I-pi peri di nyl -propoxi] -propyl 1-1, 4-di hydro-.

2,6-ti methyl (2-di f I uoromet11hoxyphenyl -pyri di ne-3,5-di carboxyl ate -3-methyl 4-di hydroxyphenyl -1-pi peidi nyl )-propoxi I-propyl 1 1, 4di hydro-2,6-di methyl (3-ni trophenyl -pyri di ne-3 ,5-di carboxyl a te -3-methyl -5-1t3- (4,4-cii phenyl -1-pi peri di nyl -propoxi] -propyl 1 (2,3-di chl orophenyl 4-di hydro-2 ,6-di methyl pyri di ne-3 ,5-di carboxyl ate -3-methyl 13- (4,4-di phentyl -1 -pi peri di nyl -propoxi] -propyl J-4- 1,3benzoxdiazol -4-yl -1,4-di hydro-2,6-dimethyl pyri di ne-3 ,5-di carboxyl ate -3-methyl 13- (4,4-di phenyl -1I-pi peri di nyl -propoxi] -propyl J-4- (3-cyanophenyl 4-di hydro-2,6-di methyl pyri di ne-3 ,5-di carboxyl ate -3-methyl (4,4-di phenyl -1-pi peni di nyl -propoxi] -propyl 4-di hydro- 2,6di methyl (2-methoxyphenyl -pyri di ne-3 ,5-di carboxyl ate -3-methyl 13-[3- (4,4-di phenyl -pi peri di nyl )-propoxi I-propyl 1-1, 4-di hydro- 2,6-li methyl (2-pyri dyl -pyri di ne-3,5-di carboxyl cte and -3-methiyl 4-di phenyl -1-pi peridi nyl )-propoxi] -propylj-i, 4-di hydro- 2,6-dIim-ethyl (5-methyl -2-thi enyl )-pyridi ne-3,5-dicarboxyl ate and of their salts.

The use, according to the invention... of the compound -3-methyl-5-[3- (4,4-diphenyl -1-piperidi nyl )-prop/yl] .4 ,4-diihydro-Z,6-dimithyl (3-nitrophe nyl )-pyridine-3, 5-dicarboxyl ate and of itS salts is preferred particularly.

Particularly preferred subject matter of the invention is the use of 'those optically pure 1, 4-clihydropyri dines of formula I, which have in particular as FLA4. compared with their optical antipodes only a minor influence on the cardiovascular system.

12 The synthesis of compounds of formula I is disclosed, for example, in European patent application 0 242 829.

Compounds I can also be prepared by reacting optically pure dihydropyridines of formula II Ar .H

COO-A-Z

I)

with diarylpiperidines of formula III 9 9.

.9 *o 9 9 9 *9 9 *9 9 (Ill) R8' R9 as such or in the form of their salts and, if desired, the salts obtained are then converted into the free bases or the bases obtained are then converted into the salts, Ar, R1, R2, R3, R6, R7, R8 and R9 and A having the abovementioned meanings and Z representing a suitable leaving group.

A method for preparation of enantiomerically pure dihydropyridines with general formula I is set out in our earlier-filed International Application No. PCT/EP88/00239 (International Publication No. WO 88/07525).

W089/07443 -13- PCT/EP8'/001qO The reaction is carried out in suitable, preferably inert, organic solvent in the presence of water or without water. Examples of such solvents are ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether; ketones, such as acetone or ethyl methyl ketone; aromatic hydrocarbons, such as xylene or toluene; or chlorinated hydrocarbons, such as methylene chloride, chloroform, tetrachloroethylene or dichlaroethane; or polar, aprotic solvents, such as dimethylformamide, n-methylpyirlidone or dimethylsulfoxide.

Depending on the reactivity of the educts, the reaction temperatures are optionally varied within a wide range. In general, the reaction is carried out at 0 o o temperatures between 20 C and 150 C, preferably between 20 C and 100 C, in particular at the boiling point of the solvent used.

The process is conveniently carried out at atmospheric pressure or at increased pressure, work at atmospheric presssure being the rule, Depending on the leaving group Z, which is for example a tosyl group or a triflate group, preferably a halogen atom, in particular a bromine atom, the reaction can, if desired, be carried out in the presence of a base (for example of an inorganic carbonate, such as potassium carbonate) or with the use of an excess of diarylpiperidine III.

The resultant compounds I are isolated and purified in a fashion which is known per se, for example by removing the solvent by distillation in vacuo and recrystallizing the resultant residue from a suitable solvent, or by subjecting it to one of the conventional purification methods, such as column chromatography on a suitable support 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, or in a low-molecular-weight aliphatic alcohol (ethanol or isopropanol), or in an open-chain or cyclic ether, such as dioxane or tetrahydrofuran, which contains the desired acid or to which the desired acid is subsequently added.

The salts are obtained by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt, or by evaporation of the solvent.

N~&IJ

WJ089/07443 -14- PCT/EP89/00140 The salts obtained are converted into the free bases by alkalization, for example using aqueous ammonia solution; and the free bases are, in turn, converted into acid-addition salts. In this fashion, pharmacologically-unacceptable acid-addition salts are easily converted into pharmacologically-acceptable acid-addition salts.

The starting compounds II are obtained from optically pure dihydropyridine carboxylic acids IV Ar .H R300C COOH

(IV)

R2 N R1 by reaction with suitable bifunctional alkyl derivatives V Z-A-Z (V) and subsequent removal of SG, Ar, RI, R2, R3 and A having the meanings given above, Z being a suitable leaving group and SG being a protecting group.

The reaction of IV with V is carried out preferably under basic conditions in the presence of a phase-transfer catalyst.

Illustrative catalysts, besides onium salts, such as tetrabutylammonium bromide or benzyltriethylammonium chloride, are particularly crown ethers, such as dibenzo-[18]crown-6, dicyclohexyl-[18)crown-6 and, in particular, [18]crown-6.

A suitable base is employed in at least a molar amount and preferably in excess thereof. The base is, an inorganic base, such as an alkali-metal hydroxide (for example sodium hydroxide or potassium hydroxide) or, in particular, an alkali-metal carbonate (for example sodium carbonate or, preferably, potassium carbonate). When the reaction is carried out in an anhydrous solvent, the hydroxide or carbonate used is preferably in finely-powdered form.

"^S

W089/07443 -15- PCT/EP89/00140 The reaction is carried out (depending on the type of phase-transfer catalyst, the leaving group Z and the base employed) in water-containing or anhydrous organic solvent, or in a mixture of water and a water-immiscible or sparingly water-miscible organic solvent. Examples of water/solvent mixtures include mixtures of water with chloroform, dichloromethane or benzene. Examples of watercontaining or anhydrous solvents are dichloromethane, acetonitrile or acetone.

The leaving group Z is preferably a halogen atom, in particular a bromine atom.

The choice of reaction temperature in the reaction of IV with V depends on the o other reaction conditions; temperatures between 20 C and the boiling point of the solvent employed are generally preferred.

Suitable protecting groups SG are, in particular, those groups which are introduced easily and in high yield into the precursor on which the compound IV is based, which do not undergo side reactions during the reaction of IV with V, and which are removed smoothly at the end of the reaction. Examples of preferred protecting groups SG are alkoxymethyl groups or benzyloxymethyl groups, in particular the ethoxymethyl group. The removal of the protecting group is carried out in acidic medium, for example in 1 N hydrochloric acid or, preferably, in anhydrous formic acid, under reaction conditions which are known to the expert. The removal of the protecting group can also be carried out after the reaction with the diarylpiperidine III.

The solvents, bases and phase-transfer catalysts in the examples only represent an exemplary selection. Which further combinations of solvents, bases and phase-transfer catalysts are also suitable is known to the expert on the basis of his expert knowledge.

The dihydropyridine carboxylic acids IV are known from Chem. Pharm. Bull. 28(9) 2809-2812 (1980), or are prepared in an analogous fashion to that described therein. The diarylpiperidines III are known from DE-OS 19 36 452. The bifunctional.alkyl derivatives V are known or they can be prepared according to known processes.

The following preparation examples are intended to illustrate the invention in greater detail, without limiting it. M.p. denotes melting point, h represents hours, b.p. represents boiling point, and decomp. denotes decomposition.

W0809/07443 -16- PCT/EP89/00140

EXAMPLES

End Products 1. (-)-3-Methyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propyl]-1,4-dihydro-2,6dimethyl-4-(3-ni trophenyl -pyridine-3,5-dicarboxyl ate hydrochloride A mixture of 86.6 g of (-)-3-methyl-5-(3-bromopropyl)-l,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 50 g of 4,4-diphenylpiperidine hydrochloride and 69 g of finely powdered potassium carbonate is heated for 5 h 0 in 300 ml of dimethyl formamide to 100 C under a nitrogen atmosphere and with vigorous stirring. After cooling, 500 ml of ethyl acetate and 1 I ot water are added with vigorous stirring. The phases are separated; the organic phase is washed four times with water, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in 1 1 of dioxane; then 15.2 ml of concentrateu hydrochloric acid solution (12.5 M, d 1.19) are added, and about 200 ml of the solvent mixture are removed by distillation in vacuo. The product crystallizes spontaneously on standing at room temperature or after inoculation or trituration, and is filtered off by suction after 16 h, washed with dioxane and o o0 diisopropyl ether, and dried at 80 to 100 C in vacuo. For further purification the crude product is dissolved in dichloromethane. After addition of 800 ml of dioxane the dichlormethane is distilled off. The product which crystallizes after inoculation on standing at room temperature for 16 h is filtered off by 0 suction, washed with dioxane and diisopropyl ether, and dried at 100 C in vab 0 22 o cuo. 97 g of the title compound 158 C to 160 C and [a]6 39 22 o 436 (c 1, methanol) or 14,4 (c 1, methanol) are obtained.

Alternatively, the title compound is obtained as follows: 64.6 g of (±)-3-methyl -5-[3-(4,4-diphenyl-1-piperidinyl) -propyl]-1,,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl -pyri dine-3,5-di carboxyl ate hydrochloride are dissolved in 300 ml of dichloromethane. The solution is washed once with 100 ml of concentrated aqueous ammonia solution and twice with 100 ml of water. The organic phase is dried over sodium sulfate and concentrated. The obtained residue (60.91 g) and 37.63 g of L-(-)-di-0,0'-benzoyltartaric acid hydrate {ha- 22 o ving a specific rotation [al of 108.1 (c 1, methanol)} are together

D

W089/07443 -17- PCT/EP89/00140 dissolved in 400 ml of ethanol at the boil. Allowing the stirred solution to cool slowly gives a first crop of crystals (55 g of di-0,0'-benzoyltartrate of the title compound; slightly yellowish crystals) which is dissolved again at the boil in a mixture of chloroform and methanol (4 When the crystals have just dissolved, ethyl acetate (20 per cent by volume of the mixture of chloroform/methanol) is added to the boiling solution, and the mixture is allowed to cool slowly with stirring. The obtained second crop of fine crystals g) is recrystallized three times in the same way. A third (36 g with 475 fourth (33 g with 22= -49.40) and fifth {31 g with 2= 50.4 (c 1, methanol)} crop of crystals is obtained successively. The fifth crop of crystals is dissolved in 500 ml of dichloromethane. The solution is washed twice with 150 ml of concentrated aqueous ammonia solution in each case and three times with 100 ml of water in each case. The organic phase is concentrated, and the residue is worked up as described above. Yield: 19.8 g, []22 14.30 (c 1, methanol).

2. (+)-3-Ethyl-5- [3-(4,4-di phenyl piperidinyl)-propyl]-2-amino-1,4-dihydro-6-methy1-4-(3-ni trophenyl) g of (-)-3-Ethyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propyl]-2-amino-1,4dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 36,2 g of L-(-)-di-0,0'-benzoyltartaric acid hydrate {in this example having a specific rotation 108.40 (c 1, methanol)l are together dissolved in methanol/dichloromethane (9 After concentration of the solution, the solid foamed residue is taken up at the boil in 300 ml of a mixture of methyl ethyl ketone and methanol (2 and the well-stirred clear solution is then 0 allowed to cool slowly. A first crop of crystals {33 g, m.p. 165 166 C, 24 17.80 (c 1, methanol)} is obtained which yields after renewed recrystallization from methyl ethyl ketone/methanol (2 1) a second crops of crystals {22 g, []22 10.80 (c 1, methanol)}. Tie coarse yellowish needles are dissolved in 400 ml of dichloromethane. The solution is extracted with 300 ml of concncitrated aqueous ammonia solution and subsequently three times with 100 ml of water in each case. The organic phase is dried over sodium sulfate and concentrated. The obtained solid foamed residue (14.3 g) is dissolved together with 2.6 g of fumaric acid in methanol, and the solution is concentrated again. The residue is dissolved in a boiling mixture W89/07443 -18- PCT/EP89/00140 of ethyl acetate and 2-propanol (9 The solution is allowed to cool slowly, and 12.4 g of the title compound are obtained as fine needles of m.p. 151 o 22 0 152 C and [ai 42.0 (c 1, methanol).

The freee base of the title compound obtained after the extraction with ammonia can be precipitated in petroleum ether in amorphous form. A fine yellowish powder of m.p. 96 104 C (slow deliquescence) and [a] 2 2= 57.6 (c 1, methanol) is obtained.

3. (+)-3-Methyl-5- 2-[2-(4,4-diphenyl-l-piperidinyl)-ethoxy]-ethyll-1,4-dihydro-2,6-dimethyl-4-(3-nitropheny1)-pyridine-3,5-dicarboxylate hydrochloride 3 ml of oxalyl chloride are added to 997 mg of (+)-3-methyl-l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate. The mixture is stirred at room temperature until no further evolution of gas can be detected. The batch is concentrated to dryness three times with the addition of 5 ml of absolute toluene each time. The resulting brown solid residue is suspended in 3 ml of absolute methylene chloride and the suspension is added dropwise to a solution, 0 cooled to 0 C, of 1.09 g of N-[2-(2-hydroxyethoxy)-ethyl]-4,4-diphenylpiperidine and 0.6 ml of triethylamine, while gassing with Na. After the dropwise addition, the mixture is stirred at room temperature for a further 2 h and then concentrated to dryness, The brownish residue which remains is taken up in 100 ml of methylene chloride and extracted three times with 50 ml of water each time. After the organic phase has been dried over sodium sulfate, the brownish clear solution is substantially concentrated and the oily residue is chromatographed over a 2 x 30 cm silica gel column with methylene chloride/ethanol (98 2) as the eluting agent. After the chromatographically uniform product fraction has been concentrated, the yellowish residue which remains is taken up in ml of methylene chloride, and ethereal hydrochloric acid is added to the solution. After renewed concentration of the hydrochloride solution to dryness, the residue in the form of a solid foam is dissolved in 3 ml of methylene chloride and the product is precipitated as an amorphous substance by dropwise addition of the solution to 1 1 of petroleum ether/diethyl ether (2 After the precipitate has been filtered off with suction and dried, the title com- 0 pound is obtained as a fine gray powder of m.p. 118 128 C (slow deliquescence); 0.90 (c 1, methanol); yield: 490 mg.

W089/07443 PCT/EP89/00140 Starting compound (-)-3-Methyl -5-(3-bromopropyl -1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl )-pyri- 168.5 g of (+)-l-ethoxymethyl-1,4-dihydro-5-methoxycarbon1l-2,6-dimethyl-4- 22 (3-nitrophenyl)-pyridine-3-carboxylic acid/cinchonine salt o D +101.5 (c 1, chloroform)} are dissolved in 1.5 1 of dichloromethane; 1.2 1 of 0.2 N hydrochloric acid solution are added with cooling and vigorous stirring. The pH is adjusted to 2 by adding 2 N hydrochloric acid solution, and the phases are then separated. The organic phase is washed a total of four times with pH 2 hydrochloric acid solution, and then washed with water, dried over sodium sulfate and concentrated. The obtained oily residue is dissolved in 1.1 1 of acetone. 375 g of finely powdered potassium carbonate, 375 ml of 1,3dibromopropane and 1.2 g of [18]-crown-6 are subsequently added. The mixture is stirred vigorously for 24 h at room temperature and then filtered by suction; the filter caki is washed with acetone. The filtrate is concentrated under a slight vacuum in a rotary evaporator, and the excess 1,3-dibromopropane is removed by distillation at 0.02 mbar (bath temperature up to 45 690 ml of concentrated formic acid are poured onto the oily residue with ice cooling; the mixture is then stirred at room temperature until a clear solution has been produced (about 15 minutes). The formic acid is removed by distillation in vacuo. After twice adding and removing (by distillation) 200 ml of toluene in each case, the residue is dissolved in 900 ml of dichloromethane. The solution is stirred with sodium hydrogen carbonate solution (pH 8,5) and washed with water. The organic phase is dried over sodium sulfate and concentrated in vacuo. The product which crystallizes spontaneously after addition of diisopropyl ether is filtered off by suction, washed with diisopropyl ether and dried in vacuo, 102 g of the title compound 1120 to 114 C and a 13.8 (c 1, methanol)} are obtained.

4 W089/07143 PCT/EP89/00140 Commercial Applicability The compounds I and their salts possess valuable properties which make them commercially useful. They are, in particular, antineoplastic agents with an interesting cytostatic activity, They are useful for the treatment of tumors, e.g. for reducing and preventing metastasis and neoplastic growth, in mammals.

In their excellent effectiveness, which is revealed by a selective, controlled inhibition of the proliferation and which is combined with low toxicity and the absence of undesired side-effects, the compounds I and their salts differ in a surprising and advantageous manner from those 1,4-dihydropyridines the use of which is proposed for cancer chemotherapy in the art. It has to be pointed out, particularly, that up to now only those 1,4-dihydropyridines with pronounced calcium channel blocking (calcium antagonist) activity were regarded as being suitable for cancer chemotherapy, i.e. the calcium channel blocking (calciumantagonistic) activity was regarded as a prerequisite for cytostatic activity.

It has now been found, surprisingly, that compounds I and their salts, which show only minor calcium channel blocking activity, have a pronounced ability to inhibit tumor cell growth in vitro which indicates a corresponding in vivo activity.

The minor calcium channel blocking activity of compounds I is revealed by the comparatively small influence of these compounds on the cardiovascular system, e.g. on blood pressure or on heart rate. This low cardiovascular activity of cimpounds I and their sants permits them to be used in human medicine as potent antitumor and antimetastatic agents: Compounds I and their salts in contrast to the cardiovascular active calcium channel blockers hitherto known as antineoplastic agents can be administered in a therapeutically-effective amount without risk of undesired side-effects on the cardiovascular system.

The excellent effectiveness of compounds I and of their salts makes them useful in human medicine as chemotherapeutic agents for the treatment of tumors, e.g.

ovarian tumors, testicular tumors, carcinomas of the prostate, carcinomas of oesophhse.k the urinary bladder, eeeBcarcinomas and other malignant neoplasias, in particular of colon cancer, breast cancer, bronchial carcinomas and lung carcinomas.

W089/07443 -21- PCT/EP89/00140 The invention therefore also relates to a process for treating mammals, in particular humans, suffering from one of the noted diseases. The process is characterized by administering a therapeutically-effective and pharmacologically-acceptable amount of one or more of the compounds according to the invention (and/or of pharmacologically-acceptable salts thereof) to a patient in need of such treatment.

The invention relates additionally to the compounds of formula I and their pharmacologically-acceptable salts for use in the treatment of said diseases.

The invention also embraces the use of the compounds of formula I and their pharmacologically-acceptable salts in the preparation of medicaments which are employed for combating said diseases.

The invention furthermore relates to medicaments containing one or more of the compounds of formula I and/or their pharmacologically-acceptable salts.

The medicaments are prepared by processes which are in themselves known and are familiar to those skilled in the art. The medicaments employed are the pharmacologically-active compounds of formula I and/or their salts (=active compounds), either as such or, preferably,, in combination with suitable pharmaceutical auxiliaries, in the form of.tablets, coated tablets, capsules, suppositories, patches (for transdermal drug administration), emulsions, suspensions, aerosols, sprays, ointments, creams, gels or solutions, the content of active compound being advantageously between 0.1 and 95 per cent by weight.

W089/07443 -22- PCT/EP89/00140 Excipients which are suitable for the desired medicament formulations are familiar to the skilled worker from his technical knowlege. In addition to solvents, gel formers, suppository bases, tablet excipients and other vehicles for the active ingredient, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavour improvers, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex formers (for example cyclodextrins).

The active ingredients can be administered rectally, by inhalation, parenterally (perlingually, intravenously or percutaneously) or orally.

In the case of oral administration, it has in general proved advantageous in human medicine to administer the active ingredient or ingredients in a daily dose of about 0,5 to about 30 mg/kg body weight, if desired in the form of several, preferably 1 to 4, individual doses in order to achieve the desired result. In the case of parenteral treatment, similar or (in particular in the case of intravenous administration of the active ingredients) as a rule lower doses are used.

The required optimum dose and mode of administration of the active ingredients in each case can be readily determined by anyone skilled in the art on the basis of his technical knowledge.

If the compounds according to the invention and/or their salts are used for the treatment of thp stated diseases, the pharmaceutical formulations can also contain one or more other pharmacologically active constituents from other groups of medicaments.

As is customary in internal tumor therapy, treatment with the medicaments according to the invention is optionally combined with administration of other cytostatic agents, having different action spectra, in order to reduce the risk of side-effects. it may also be appropriate to carry out treatment in accordance with the principle of cyclic cytostatic therapy. In this therapy, each treatment is followed by a recovery phase. The experience that, in most organs, healthy tissue regenerates more rapidly than malignant tissue is ,itilized therein.

WO89/07443 -23- PCT/EP89/00140 Pharmacology The antineoplastic activity of (-)-3-methyl-5-[3-(4,4-diphenyl-l-piperidinyl)propyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl hydrochloride (compound 1) was tested in a number of different in vitro assay systems. The tests are described in more detail as follows: 1. Dose-response-relationship of the anticarcinogenic effect of 1 in the human lung carcinoid derived cell line NCI-H 727 Methods and Results: 4 Cell line NCI-H 727 was seeded at a density of 5 x 10 cells/ml in 50 ml tissue culture flasks. The cells were maintained in RPM1 1640 medium supplemented with L-glutamine (2 mM), fetal bovine serum (10 V/V) and gentamycin sulfate ig/ml) at 7 C02 93 air. One day after seeding of cells the test compound was added to the tissue culture medium. The medium containing the test compound was removed on day 3 and replaced with fresh tissue culture medium.

The results are given in Table 1.

Table 1: Dose-response-relationship of the anticarcinogenic effect of 1 in the human lung carcinoid-derived cell line NCI-H 727 Treatment Seeding No.

72 hrs of viable cells 144 hrs X 10 4 ml 216 hrs control 5 5,7 8.9 38.3 Polyethylene 5 7.5 28.7 72.8 glycol-control 1 1.0 pM 5 0 0 0 1 0.5 pM 5 1,2 1.3 1.6 1 0.1 PM 5 1.7 1.9 2.8 0 W089/7443 -24- PCT/EP89/00140 2. Effect of I on growth kinetics of the human lung <.denocarcinoma-derived cell line NCI-H 322 (Clara cell) Methods and Results: 4 Cell line NCI-H 322 was seeded at a density of 5 x 10 cells/ml in 50 ml tissue culture flasks. The cells were maintained in RPMI 1640 medium supplemented with L-glutamine (2 mM), fetal bovine serum (10 V/V) and gentamycin sulfate jg/ml) at 7 COz, 93 air. One day after seeding of cells the test compound was added. Viable cells were counted after staining with trypan blue at the time intervals specified in Table 2. The results are given in Table 2.

Table 2: Dose-response-relationship of the anticarcinogenic effect of I in the human lung adenocarcinoma-derived cell line NCI-H 322 (Clara cell) Treatment Seeding No.

72 hrs of viable cells X 10 144 hrs ml 216 hrs control 5 5.5 10.4 33.6 Polyethylene 5 7.5 22.7 34.3 glycol -control 1 1.0 JM 5 0 0 0 1 0,5 pM 5 0.7 0.9 1.9 1 0.I IM 5 1.1 1.4 W089/07443 -25- PCT/EP89/00140 3. Effect of 1 on growth kinetics of the human lung adenocarcinoma-derived cell line NCI-H 358 (alveolar type II cell) Methods and Results: 4 Cell line NCI-H 358 was seeded at a density of 5 x 104 cells/ml in 50 ml tissue culture flasks. The cells were maintained in RPMI 1640 medium supplemented with L-glutamine (2 mM), fetal bovine serum (10 V/V) and gentamycin sulfate pg/ml) at 7 COz, 93 air. One day after seeding of cells the test compound was added. Viable cells were counted after staining with trypan blue at the time intervals specified in Table 3. The results are given in Table 3.

Table 3: Dose-response-relationship of the anticarcinogenic effect of 1 in the human lung adenocarcinoma-derived cell line NCI-H 358 (alveolar type II cell) Treatment Seeding No.

72 hrs of viable cells 144 hrs 4 X 10 ml 216 hrs control 5 5.8 16.8 40.6 Polyethylene 5 7.6 25.9 80.6 glycol-control 1 1.0 pM 5 0 0 0 1 0.5 pM 5 0.9 1.1 1.8 1 0. M 5 0.9 1.2

Claims (5)

1. A pharmaceutical composition kfor the treatment of tumours, comprising an optically pure diaryl compound of formula I A .H

9. 9** .9 i .4 4 .9 9 99 *9 9 9 99*9 9. 99 9. 9 9 9 wherein Ar represents a ring of the formula 9. 9 99 .9 9 99 09 .9 9 9 9 9. *99 999 9 99 99 99 9 9 R4 Y in which Y denotes oxygen sulphur vinylene azomethine or a group of the formula \NN Nr 27 RI denotes hydrogen, i-6C-alkyl or 3-7C-alkoxyalkyl, R2 denotes hydrogen, amino (NH 2 l-6C-alkyl or 3-7C- alkoxyalkyl, R3 denotes hydrogen, l-6C-alkyl or 3-7C-alkoxyalkyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1- 4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or partly substituted by fluorine, l-4C- alkoxycarbonyl, 2-5C-acyl, amino, mono- or di-1-4C- alkylamino or together methylenedioxy, R6, R7, RB and R9 are identical or different and denote hydrogen, hydroxyl, halogen, l-4C-alkyl, 1-4C-alkoxy or 1-4C--alkoxy which is completely or partly substituted by fluorine, and A denotes 2-5C-alkylene or A1-O-A2, in which *Al denotes 2-4C-alkylwe and A2 denotes 2-4C-alkylene or 2C-alkyleneoxy-2c- alkylene, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. A composition according to Claim I comprising a compoun~t of formula I wherein Ar denotes 3-nitrophenyl, 2- chlorophonyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluotimethoxyphenyl, 2, 3-methylenedioxyphenyl or 2,1,3- benzoxidiazol-.4-yl., RI denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R6, R7, RB a~nd R9 denote hydrogen and[ A denotes ethylene or propylene. 3. A composition accordiLng to Claim 1 comprising a compound of formula I wherein Ar denotes 3-nitrophenyl, 2- chlorophenyl, 2, 3-dichiorophenyl, 2 -trif luoromethylphenyl, 2 -difluoromethylphenyl, 2-difluoromethoxyphenyl, 2, 3- 28 methylenedioxyphenyl or 2,1,3-benzoxidiazol-4-yl, R1 denotes methyl, R2 denotes amino, R3 denotes methyl, ethyl or methoxyethyl, R6, R7, R8 and R9 denote hydrogen and A denotes ethylene or propylene. 4. A composition according to Claim 1 comprising a compound of formula I wherein Ar denotes 3-nitrophenyl, 2- chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difl1oromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3-- benzoxdiazol-4-yl, R1 denotes methyl, R2 denotes methyl, R3 denotes methyl, ethyl or methoxyethyl, R6, R7, R8 and R9 denote hydrogen and A denotes A1-O-A2, Al being ethylene and A2 being ethylene or ethyleneoxyethylene. A composition according to Claim 1 comprising a compound of formula I wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, R1 denotes methyl, R2 denotes methyl, to R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote SI hydrogen and A denotes ethylene or propylene. 6. A composition according to Claim 1 comprising a compound of formula I wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, R1 denotes methyl, R2 denotes amino, R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen and A denotes ethylene or propylene. 7. A composition according to Claim 1 compris,ing a compound of formula I wherein Ar denotes 3-nittopheyl or 2,3-dichlorophenyl, R1 denotes methyl, R2 denotes methyl, R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen and A denotes AI-0-A2, Al being ethylene and A2 being ethylene. 8. A composition according to Claim 1, wherein the compound of formula I is diphenyl-1-piperidinyl)-propyl]-1,4-dihydro-2,6-dimethyl- 4- (3-nitrophe: l) -pyridine-3,5-d'icarboxylate or a pharmaceutically acceptable salt thereof. 9. A composition when used for tumour therapy comprising one or more compounds according to any one or more of Claims 1 to 8 and/or their pharmacologically compatible salts. A method of treatment of cancer, comprising the step of administering to a subject in need of such treatment an effective amount of a compound as defined in any one of Claims 1 to 8.

11. A method according to Claim 10, wherein the cancer is "I selected from the group consisting of ovarian cancer, I testicular cancer, prostate cancer, cancer of the urinary bladder, oesophageal carcinoma, colon cancer, breast o cancer, bronchial carcinoma, and lung carcinoma. o

12. A method according to Claim 10 or Claim 11, comprising the step of administering a composition as defined in any one of Claims 1 to 9. *e DATED this 6th day of April 1993 BYK GULDEN LOMBERG CHEMISCHE FABRIK GmbH By Their Patent Attorneys: GRIFFITH HACK CO Fellows Institute of Patent Attorneys of Australia 0- 'rg^ INTERNATIONAL SEARCH REPORT International Application No PCTIEP 89/00140 I. CLASSIFICATION OF SUBJECT MATT901 (it several classification symbols apply, Indicate all) 4 'According to international Patent Classification (IPC) or to both National Classification and )PC Int.Cl.4 A 61 K 31/445 It. FIELDS SEARCHED Minimum Documentation SearcheadI Classification System IClassification Symbols Irit.CI. A 61 K 31/00 Documentation Searched other then Minimum Documentation to the Extent that such Documents are Included In the Fields Searched'I Ill. DOCUMENTS CONSIDERED TO BE RELEVANT'I Category Citation of D~ocument, I' with Indication, where appropriate, of the relevant passages Is Relevant to Claim No. 2 1 Y EP,A, 0240828 (BYK GULJDEN L 1 OMBERG) -1 14 October 1987 see page 5, lines 11-18- cited in the application Y EP,A, 0242829 (BYK GULJDEN LOMBERG) 1-10 28 October 1987 see page 11,lines; 26-28; pagel9, lines 25-28 Cited in the application Y EP,A, 0176956 (BYK GULJDEN LOMBERG) 1-10 9 April 1986 see column 6, lines 28-32 cited in the application Y IDA 3709796 (BYK GULDEN L 1 OMBERG) 1-10 1 5 November 1987 see page 7, line 68; page 8, line 3 Special categories of cited documents. so 'IT" later document published after the international fiing date document defining the general state of hs art which Is not or priority date and not in conflict with the application but cn Irdtobofprcurreeae cited t0 understand the principle or theory underlying the consdere tobe o paticuar elevnceinvention earlier document but published on or aftor the international dcmn fpriua elvne h lie neto filng atecannot be considered novel or cannot be considered to "L document which may throw doubts on diriority cialm(al, or involve an Inventive stop which Is Cited to establish the publicationo date 0f another ydouetopaiclreevnetecamdinnin cittio orothr secil raso asapei~ld)cannot be consideced to Involve en inventive step when the document referring to an oral disclosure, uge, eahibition or document Is Combined with one or more other such docu- other means ments, sucI, Combination being obvious to a person skilled document publisheod Prior to the internationak filing date but Inv %he art. later than the priority date Claimed document nmember of Ithe same patent family Dat* of the Actual Completion of the International Search Date of Maillng of this International Search Report 6 April 1989 (06.04.89) 27 April 1989 (27.0,1.89) International Searching Authority Signature of Authorized Officer European Patent officeI Form PC.TIlSA?210 (second shoot) (January Intamational Application No. PCT/EP 89/00140

111. DOCUMENTS CONSIDERED T0NE RELEVANT (CONTINUED FROM THE SECOND SHEET) category Cetation of Do-xawt WOtt Arthon, 001ar uqMr~pital Of tsVN" Wut aag Relevant to Claim No X,Y EP,A, 0123850 (BOARD OF GOVERNORS OF WAYNE 1-10 STATE UNIVERSITIY) 7 November 1984 see pages 1-6, claims 1,2,6,9,10 cited in the application Y J.Cardiovasc .Pharinacol .Vol.10, Nr 3, 1987 1-10 Raven Presse Ltd (New York, US) G.Fischer et al.: "Antihypertensive effects of niguldipine-HCI (B 844-39), a new calcium antagonist in dogs" pages 268-273 see abstract Form PCT')SA2I (oxtra asi~t) (January 1M) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 8900140 SA 26835 This annex lists the patent family members relating to the patent documents cited int the abo%e-rncntioned internatiotlal search report. The members are as contained in the European Patent Office EDP ile on 24104189 The European Patent Office is in no way liable for these particulars which are merely giv'en for the purpose of information. Patent document Publication Patent family Publication cited in search report date Member(s) date EP-A- 0240828 14-10-87 J)P-A- 62270528 24-11-87 AU-A- 7052587 10-12-87 AU-B- 5746C4 07-07-88 EP-A- 0242829 28-10-87 Wa-A- 8706579 05-11-87 AU-A- 7390187 24-11-87 EP-A- 0302871 15-02-89 JP-T- 1500118 19-01-89 EP-A- 0176956 09-04-86 jP-A- 61085362 30-04-86 AU-A- 4794885 10-04-86 US-A- 4707486 17"11-87 AU-B- 574842 14-07-88 OE-A- 3709796 05-11-87 EP-A- 0123850 07-11-84 JP-A- 60006613 14-01-85 CA-A- 1223820 07-07-87 US-A- 4690935 01-09-87 Z. For more details about this annex :see Official journal of t tie E~uropean Patent Wrfite, 12/82