IE64053B1 - Diaryl compounds and their use - Google Patents

Abstract

376EN 01893 Optically pure diaryl compounds of formula I (I) wherein the substituents and symbols have the meanings given in the specification are proposed as active ingredients in medicaments for the treatment of tumors.

Description

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-dihy10 dropyridines 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-methyl5-[3-(4,4-diphenyl-l-piperidinyl)-propyl]-l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, and its use for the treatment of cardiovascular diseases is claimed. - In European Patent Application 0 242 829 2-amino1,4-dihydropyridines with diaryl piperidine ester radical and their use in car20 diovascular diseases is disclosed. -zDescription of the invention The invention relates to the use of optically pure diaryl compounds of formula I wherein Ar represents a ring of the formula in which Y denotes oxygen (0), sulphur (S), vinylene (-CH=CH-), azoeethine (-CH=N-) or a group of the formula or -3R1 denotes hydrogen, I-6C-alkvl or 3-7C-al R2 denotes hydrogen, amino (NH2), l-6C-alkyl cr 3-7C-alkoxyalkyl, R3 denotes hydrogen, l-6C-alkyl or 3-7C-a1koxya,kyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, l-4C-alkyl, l-4C-alkoxy, l-4C-alkoxy which is completely or partly substituted by fluorine, l-4C-alkoxycarbonyl, 2-5C-acyl, amino, mono- or di-l-4C-alkylamino or together methylenedioxy, R6, R7, R8 and R9 are identical or different and denote hydrogen, hydroxyl, ha10 logen, l-4C-alkyl, l-4C-a1koxy or l-4C-a1koxy which is completely or partly substituted by fluorine, and A denotes 2-5C-alkylene or A1-0-A2, in which Al denotes 2-4C-alky1ene 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 20 as optically pure compounds of formula Ia with uniform configuration wherein Ar, Rl, R2, R3, R4, R5, R6, R7, R8, R9 and A have the meanings given above and which have the same configuration in the 4-position in the dihydropy ridine as the diastereomer quinchonine (+)-l-ethoxvmethyl-l,4-dihydro-5-meth25 oxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylate, which is used as a starting compound and rotates linearly polarized light of wavelength 22 o 589 nm with (e] = +101,5 (c = 1, chloroform).

D -41- 6C-alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyi, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or, in particular, ethyl or methyl radical. 3-7C-alkoxyalky1 represents, for example, a methoxyethyl, ethoxyethyl, propoxy ethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-l-methylethyl or 2- ethoxy-l-methylethyl radical.

For the purposes of the invention, halogen denotes bromine and, in particular, fluorine and chlorine. l-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. l-4C-alkoxy contains, in addition to the oxygen atom, one of the above-mentioned l-4C-alkyl radicals. The methoxy radical is preferred. l-4C-alkoxy which is completely or partially substituted by fluorine is, for example, 1,1,2,2-tetrafluoroetnoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy. 1- 4C-alkoxycarbonyl contains, in addition to the carbonyl group, one of the above-mentioned l-4C-alkoxy radicals. The methoxycarbonyl radical and the ethoxycarbonyl radical are preferred. 2-5C-acyl contains, in addition to the carbonyl group, one of the above-mentioned l-4C-a1ky1 radicals. The acetyl radical is preferred.

Mono- or di-l-4C-alkvlamino contains, in addition to the nitrogen atom, one or two of the above-mentioned l-4C-alkyl radicals. Di-l-4C-alkylamino is preferred, and in particular dimethyl-, diethyl- or di isopropyl ami no. 2-5C-a1kylen 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 (-CHj-CH,-), trimethylene (-C.Hj-C.Hj-CHX-) and tetramethylene (-C.H,-CHj-CH2 -CHj-), ethylene being preferred. -52-C-a1kyleneoxy-2C-alkylene represents ethylene which is substituted by ethyleneoxy (-CH,-CH,-O-CH,-CH,-).

Suitable salts include all salts with acids, particularly the phamacologically-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 pharmacological ly-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-tetraf1 uoroethoxy)-phenyl, 3-(1,1,2,2-tetraf 1 uoroethoxy)-phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,3-methylenedioxyphenyl, 2-tri fluoromethyl phenyl, 3-tri fluoromethyl phenyl or 2,l,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 A1-0-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 denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3-benzoxdiazol4-yl, R1 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. iu-saraeaEsa -6The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphe« nyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3-benzoxdiazol4-yl, Rl denotes methyl, R2 denotes amino, R3 denotes methyl, ethyl or methoxy5 ethyl, 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 Ar denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethyl phenyl, 2-di fluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3-benzoxdiazol10 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 de15 notes 3-nitrophenyl or 2,3-dichlorophenyl, Rl denotes methyl, R2 denotes methyl, 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 one hand.

The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, Rl denotes methyl, R2 denotes amino, 20 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.

The use, according to the invention, of compounds of formula I wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, Rl denotes methyl, R2 denotes methyl, R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen and A de25 notes A1-0-A2, Al being ethylene and A2 being ethylene, and of their salts, is preferred in addition.

The use, according to the invention, of the following compounds has to be singled out by way of example: -7(R) -3-methyl -5- [2-(4,4-diphenyl -1-piperidinyl) -ethyl] -1,4-di hydro-2,6-dimethyl 4-(3-ni trophenyl) -pyridine-3,5-di carboxy late (R)-3-methyl-5-[3-(4,4-dipheny1-l-piperidiny1)-propyl]-4-(3-cyanophenyl)-l,4di hydro-2,6-dimethyl pyridine-3,5-di carboxyl ate 5 (R)-3-methyl -5-[2-(4,4-di phenyl-1-piperidinyl )-2-methyl-propyl] -1,4-dihydro2.6- dimethy1 -4-(3-ni trophenyl) -pyri di ne-3,5-di carboxy 1 ate (R)-3-ethyl -5- [3-(4,4-diphenyl-1-piperidinyl)-propyl] -1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R)-3-methyl-5- [3-(4,4-di phenyl-1-piperidinyl)-propyl ]-l, 4-di hydro-2,6-dime10 thyl -4- [3-(1,1,2,2-tetraf luoroethoxi) -phenyl] -pyridine-3,5-di carboxylate (R) -3-methyl-5-[2-(4,4-di phenyl-1-pi peridi nyl)-ethyl ] -1,4-di hydro-2,6-dimethyl4- [3-(1,1,2,2-tetraf luoroethoxi) -phenyl] -pyri di ne-3,5-di carboxy late (S) -3-(2-methoxiethyl )-5-[2- (4,4-diphenyl-1-piperidinyl) -ethyl]-1,4-di hydro2, 6-dimethy 1-4-(3-ni trophenyl) -pyridine-3,5-di carboxy late '5 (S)-3-(2-methoxiethyl )-5-(3-(4,4-diphenyl-1-piperidinyl)-propyl]-1,4-dihydro2.6- dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R)-3-methyl-5-{3-[4,4-di-(4-methoxipheny1)-l-piperidinyl]-propylf-l,4-dihydro2.6- di methyl -4-(3-ni trophenyl)-pyri di ne-3,5-di carboxy1 a te (R) -3-methyl -5- [4-(4,4-di phenyl -1-pi peridi nyl) -butyl ] -1,4-di hydro-2,6-dimethy 1 20 4-(3-ni trophenyl)-pyri di ne-3,5-di carboxy late (R) -3-methyl -5- [1,1-dimethyl -2-(4,4-diphenyl -1-piperi di nyl) -ethyl]-l,4-dihydro2.6- dimethyl-4-(3-ni trophenyl)-pyridine-3,5-dicarboxylate (R)-3-ethyl-5- [3-(4,4-di phenyl-1-piperidinyl) -propyl ]-1,4-di hydro-2,6-dimethyl4. (2.di fl uoromethoxi phenyl)-pyri di ne-3,5-di carboxyl ate (R)-3_ethy 1-5-[3-(4,4-di phenyl-1-pi peridi nyl)-propyl J-1,4-di hydro-2,6-dimethyl 4- [3- (1,1,2,2-tetraf 1 uoroethoxi) -phenyl] -pyri di ne-3,5-di carboxy 1 ate (R)-3-ethyl -5-[3-(4,4-diphenyl-1-piperidinyl) -propyl] -1,4-di hydro-2,6-dimethyl 4- (3-di f 1 uoromethoxi phenyl) -pyridine-3,5-di carboxylate (R)-3-methyl-5-[3-(4,4-di phenyl-1-pi peridi nyl)-propyl]-4-(2,3-di chlorophenyl )30 1,4-d i hydro-2,6-di methyl pyri di ne-3,5-di carboxyl ate (R) -3-methyl -5- [3- (4,4-di phenyl -1-pi peri di nyl) -propyl] -4-(2,1,3-benzoxdi azol -4yl)-l,4-dihydro-2,6-dimethyl -pyridine-3,5-di carboxyl ate (R)-3-methyl-5-[3-(4,4-di phenyl-1-pi peri di nyl)-propyl]-1,4-di hydro-2,6-dimethy 1 -4- (3- f 1 uoropheny 1) -pyri di ne-3,5-di carboxyl ate 35 (R) -3-methyl -5- [3- (4,4-diphenyl -1-pi peridi nyl) -propyl] -1,4-di hydro-2,6-dimethy 1-4-(2-tri fluoromethylphenyl)-pyridine-3,5-di carboxy late (R)-3-ethyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propy1]-4-(2-cyanophenyl)-l,4-dihydro-2,6-di methyl pyri di ne-3,5-di carboxyl ate -8(R)-3-methyl-5- [3-(4,4-di phenyl -l-piperidi nyl)-propyl]-4-(2-chlorophenyl)-1,4di hvdro-2, 6-d i me thyl pyri di ne-3, 5-dicarooxy late (8)-(+)-3-methyl-5- [3-(4,4-diphenyl-1-piperi dinyl)-propyl]-1,4-dihydro-2,6-dimethyl -4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R) -3-ethy1-5-[2-(4,4-diphenyl -l-piperidinyl)-ethyl]-2-amino-1,4-dihydro-6-methyl-4-(3-ni trophenyl)-pyridine-3,5-dicarboxylate (S) -3-(2-methoxyethy1)-5-[3-(4,4-diphenyl-1-piperi dinyl)-propyl] -2-amino-l,4dihydro-6-me thy1-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (ft)-3-methyl-5-[4-(4,4-diphenyl-1-piperi dinyl)-butyl]-2-amino-1,4-dihydro-6-me thyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R)-3-methy1-5- [2-(4,4-diphenyl -1-piperi dinyl)-ethyl]-2-amino-l,4-dihydro-6-me thyl -4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (R)-3-methyl-5-[2-(4,4-diphenyl -I-pi peri dinyl)-ethyl]-2-amino-l,4-dihydro-6ethyl-4-(3-ni trophenyl )-pyridine-3,5-dicarboxylate (R)-3-(propyl-2)-5-[2-(4,4-diphenyl -1-piperidinyl) -ethyl ] -2-amino-l ,4-dihydro6-methy 1 -4-(3-ni trophenyl) -pyri di ne-3,5-di carboxyl ate (R) -3-hexyl-5- [2-(4,4-diphenyl -1-piperi diny1)-ethyl]-2-amino-l,4-dihydro-6-methyl -4-(3-ni trophenyl)-pyri di ne-3,5-di carboxy late (S) -3-(2-n-butoxyethyi)-5-[2-(4,4-diphenyl-1-piperidinyl)-ethyl]-2-amino-l,4di hydro-6-methy1-4-(3-ni trophenyl)-pyridi ne-3,5-di carboxy1 ate (R)-3-methy1-5- {2- [4,4-di - (4-methoxypheny 1) - l-piperidi nyl] -ethyl {-2-ami no-1,4di hydro-6-methyl -4- (3-ni trophenyl) -pyri di ne-3,5-di carboxyl ate (R)-3-ethy 1-5-[2-(4,4-di phenyl-l-piperidi nyl)-ethyl]-2-ami no-l,4-di hydro-e-methyl -4- (2-tri fluoromethyl phenyl) -pyri di ne-3,5-di carboxy 1 ate (R)-3-methyl-5-[2-(4,4-di phenyl-1-pi peri di nyl)-ethyl]-2-ami no-1,4-di hydro-6-me thy 1-4-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-pyri di ne-3,5-dicarboxylate (R) -3-ethyl -5- [2- (4,4-di phenyl -1-pi peri di nyl) -ethyl] -2-ami no-1,4-di hydro-6-methyl -4- (2-di f 1 uoromethoxypheny 1) -pyridi ne-3,5-di carboxy 1 ate (R)-3-ethy 1-5-(4-(4,4-di phenyl-1-pi peri di nyl)-butyl] -2-amino-l,4-dihydro-6-methy 1-4-(2-di fluoromethoxyphenyl)-pyridi ne-3,5-di carboxy late (R) -3-methyl -5- [2-(4,4-di hydroxyphenyl-l-piperidi nyl) -ethyl ] -2-ami no-1,4-di hydro-e-methyl -4-(3-ni trophenyl)-pyridi ne-3,5-dicarboxylate (R)-3-methy 1-5-[2-(4,4-di phenyl-1-pi peri di nyl)-ethyl] -2-ami no-4-(2,3-di chlorophenyl ) -1,4-di hydro-6-methyl pyri di ne-3,5-di carboxylate (R) -3-methyl -5-(2-(4,4-di phenyl -1-pi peri di nyl) -ethyl ] -2-ami no-4-(2,1,3-benzoxdi azol -4 -y 1 )-1,4-di hydro-6-methyl pyri di ne-3,5-dicarboxylate (R) -3-methyl -5- [2- (4,4-di phenyl -1-pi peri di nyl) -ethyl ] -2-ami no-4- (3-cyanophenyl) -1,4-di hydro-6-methy 1 pyri di ne-3,5-di carboxylate -9(R) -3-methyl-5- [2-(4,4-di phenyl-1-pi peri dinyl) -ethyl]-2-ami no-1,4-dihydro-6-methyl -4-(2-methoxyphenyl)-pyridine-3,5-dicarboxylate (R)-3-methyl -5-[2-(4,4-di phenyl -1-pi peri di nyl) -ethyl] -2-amino-1,4-dihydro-6-methyl-4-(2-pyridyl)-pyridi ne-3,5-dicarboxyl ate 5 (R)-3-methyl-5-[2-(4,4-di phenyl-1-pi peri di nyl)-ethyl] -2-ami no-1,4-di hydro-6-methyl-4-(5-methyl-2-thienyl)-pyridine-3,5-dicarboxylate (R) -3-methyl -5- {2- (4- (4-chl orophenyl, -4-phenyl-1-piperidinyl]-ethyl} -2-ami no1, 4-dihydro-6-methy1-4-(3-nitrophenyl)-pyri dine-3,5-dicarboxylate (R)-3-methyl-5-[3-(4,4-di phenyl-1-pi peri di nyl)-propyl]-2-ami no-1,4-dihydro-610 methy 1 -4-(2-nitrophenyl)-pyridine-3,5-dicarboxyl ate (R)-3-methyl -5-[3-(4,4-di phenyl-1-pi peri di nyl)-propyl] -2-ami no-1,4-di hydro-eethyl -4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R) -3-(propyl-2)-5-[3-(4,4-di phenyl-1-piperidinyl)-propyl]-2-ami no-1,4-dihydro6-methy1-4-(3-ni tropheny1)-pyri di ne-3,5-di carboxyl ate (R)-3-hexy 1-5-[3-(4,4-di phenyl-1-piperi dinyl)-propyl]-2-ami no-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (S) -3-(2-n-butoxyethyl)-5-[3-(4,4-diphenyl-l-piperidiny1)-propyl]-2-amino-l,4dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R)-3-methyl-5-{3-[4,4-di (4-methoxyphenyl)-1-piperidinyl] -propyl J-2-amino-1,420 dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxyl ate (R)-3-ethy 1-5-[3-(4,4-di phenyl-1-pi peri di nyl)-propyl]-2-ami no-1,4-di hydro-emethyl-4-(2-tri fluoromethylphenyl)-pyridine-3,5-dicarboxylate (R) -3-methyl -5-(3-(4,4-di phenyl -1-pi peri di nyl) -propyl] -2-ami no-1,4-dihydro-6methy 1 -4-(3-(1,1,2,2- tetraf 1 uoroethoxy) -phenyl ] -pyri di ne-3,5-di carboxyl ate (R) -3-ethy 1-5- [3-(4,4-di phenyl-1-piperidinyl) -propyl] -2-amino-1,4-dihydro-6methy1-4-(2-di fluoromethoxyphenyl)-pyri di ne-3,5-di carboxyl ate (R)-3-methyl-5-[3-(4,4-dihydroxyphenyl-l-piperidinyl)-propyl]-2-amino-l,<-dihydro-6-methy1-4-(3-nitrophenyl)-pyridine-3,5-dicarboxyl ate (R)-3-methyl-5-[3-(4,4-di phenyl-1-pi peri di nyl)-propyl]-2-ami no-4-(2,3-dichlo30 ropheny 1) -1,4-di hydro-6-methy 1 pyri di ne-3,5-di carboxy 1 ate (R)-3-methyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propyl]-2-amino-4-(2,l,3-benzoxdiazol-4-yl)-l,4-dihydro-6-methylpyridine-3,5-dicarboxylate (R)-3-methyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propy1]-2-amino-4-(3-cyanophenyl)-1,4-di hydro-6-methy1pyri di ne-3,5-di carboxyl ate (R) -3-methyl -5- [3-(4,4-di phenyl -1-piperidinyl)-propyl] -2-ami no-l,4-di hydro-emethyl-4-(2-methoxyphenyl)-pyridine-3,5-dicarboxylate (R,-3-methyl-5-[3-(4,4-di phenyl-1-piperi dinyl)-propyl]-2-amino-1,4-dihydro-6methy 1 -4-(2-pyri dy 1)-pyri d i ne-3,5-di carboxyl ate -10(R) -3-ethyl -5- {2- [2-(4,4-diphenyl-l-piperi dinyl) -ethoxi] -ethyl }-l,4-dihydro2.6- d i methyl -4-(3-nitrophenyl)-pyridine-3,5-di carboxy late (S) -3-(2-methoxyethyl) -5-{3- [3-(4,4-diphenyl -1-piperidi nyl )-propoxi] -propyl}1,4-di hydro-2,6-dimethy 1-4- (3-nitrophenyl) -pyridine-3,5-di carboxyl ate (R) -3-methyl -5- {2- (2-(4,4-di phenyl -1 -pi peri di nyl) -ethoxi] -ethyl} -1,4-di hydro2.6- dimethy 1-4-(2-nitrophenyl)-pyridine-3,5-di carboxy late (R)-3-methyl-5-}2-[2-(4,4-di phenyl-1-pi peridi nyl)-ethoxi] -ethyl }-l,4-di hydro2.6- diethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R)-3-(propyl-2)-5-{2-[2-(4,4-di phenyl-1-pi peridi nyl)-ethoxi]-ethyl }-l,4-dihy10 dro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (R) -3-hexyl -5- {2- (2-(4,4-di phenyl -1-piperidinyl) -ethoxi] -ethyl }-1,4-dihydro2.6- dimethy 1-4-(3-nitrophenyl)-pyridine-3,5-di carboxy late (R)-3-(2-n-butoxyethyl )-5-{2-(2-(4,4-di phenyl-1-pi peri di nyl)-ethoxi]-ethyl}1,4-di hydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-di carboxyl ate 15 (R)-3-ethy 1-5-{2-[2-(4,4-di phenyl-1-pi peri di nyl)-ethoxi] -ethyl {-1,4-di hydro2.6- dimethyl -4-(2-tri fluoromethyl phenyl)-pyridine-3,5-dicarboxyl ate (R)-3-methyl-5- {2-(2-(4,4-di phenyl -l-pi peri di nyl) -ethoxi] -ethyl } -1,4-dihydro2, 6-dimethy 1-4- (3-(1 ,1,2,2-tetrafl uoroethoxy) -phenyl] -pyridine-3, 5-di carboxylate (R) -3-ethy 1 -5- {2- [2- (4,4-di phenyl -1-piperidinyl) -ethoxi J -ethyl {-1,4-dihydro2.6- dimethy 1-4-(2-di fluoromethoxyphenyl)-pyridine-3,5-di carboxylate (R)-3-methyl-5-{2-(2-(4,4-di phenyl-1-pi peridinyl)-ethoxi]-ethyl )-1,4-di hydro2.6- dimethyl-4-(3-nitrophenyl )-pvridine-3,5-di carboxyl ate (R)-3-methyl-5-{2-[2-(4,4-di phenyl-1-pi peridi nyl)-ethoxi]-ethy 1}-4-(2,3-di25 chlorophenyl )-1,4-di hydro-2,6-dimethy1pyridine-3,5-di carboxy late (R) -3-methyl -5- {2- [2- (4,4-di phenyl -1-pi peridinyl) -ethoxi] -ethyl | -4-(2,1,3-benz oxdiazol-4-yl )-1,4-di hydro-2,6-dimethyl pyridine-3,5-di carboxyl ate (R)-3-methy 1-5-{2-[2-(4,4-di phenyl-1-pi peridi nyl)-ethoxi]-ethyl}-4-(3-cyanophenyl)-l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (R)-3-methyl-5-{2-[2-(4,4-di phenyl-1-pi peridinyl)-ethoxi]-ethyl {-1,4-dihydro2.6- dimethyl -4-(2-methoxyphenyl) -pyridine-3,5-di carboxyl ate (R)-3-methyl-5-{2-(2-(4,4-di phenyl-1-pi peridi nyl)-ethoxi]-ethyl}-1,4-di hydro2.6- dimethyl-4-(2-pyridyl)-pyridine-3,5-di carboxyl ate (R)-3-methyl-5-{2-[2-(4,4-di phenyl-1-pi peridi nyl) -ethoxi] -ethyl}-1,4-di hydro35 2,6-dimethyl-4-(5-methy1-2-thieny1) -pyridine-3,5-di carboxyl ate (R)-3-methyl-5-{3-[3-(4,4-diphenyl-1-piperidinyl )-propoxi]-propyl}-1,4-di hydro 2.6- dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate -II(R)-3-methyl-5-{3-[3-(4,4-dipheny 1-1-pi peri di nyl)-propox i]-propyl}-1,4-di hydro2.6- di ethyl -4-(3-ni trophenyl)-pyridine-3,5-dicarboxy late (R) -3-(propyl-2)-5-{3-[3-(4,4-diphenyl-1-pi peridi nyl)-propoxi] -propyl }-l, 4-di hydro-2,6-d i methy 1 -4-(3-nitrophenyl)-pyri di ne-3,5-di carboxy late (R) -3-hexyl -5- {3- (3- (4,4-di phenyl-1-pi peridi nyl) -propoxi] -propyl j -1, 4-di hydro2, 6-dimethy 1-4-(3-nitrophenyl)-pyridine-3,5-di carboxy late (S) -3-(2-n-butoxyethyl) -5-{3- (3- (4,4-di phenyl -1-pi peri di nyl) -propoxy] -propyl J 1,4-dihydro-2,6-dimethyl-4-(3-ni trophenyl)-pyridine-3,5-di carboxyl ate (R)-3-ethy 1-5-{3-[3-(4,4-di phenyl-1-pi peri di nyl)-propoxi]-propyl }-l,4-di hydro10 2,6-dimethyl-4-(2-trif1uorowethyl phenyl) -pyridine-3,5-di carboxyl ate (R) -3-methyl -5-(3-(3- (4,4-di phenyl -1-pi peri di nyl) -propoxi ] -propyl | -1,4-di hydro2.6- dimethyl-4- [3-(1, 1,2,2-tetrafluoroethoxy)-phenyl] -pyridine-3,5-dicarboxylate (R) -3-ethyl -5- (3-[3-(4,4-di phenyl-1-pi peri di nyl) -propoxi] -propyl |-1,4-di hydro15 2,6-dimethyl -4- (2-di f 1 uoronethoxypheny 1) -pyri di ne-3,5-di carboxy 1 ate (R)-3-methyl-5-{3-[3-(4,4-dihydroxyphenyl-l-piperidinyl)-propoxi]-propyl}-l,4di hydro-2,6-dimethyl-4-(3-ni trophenyl)-pyri di ne-3,5-dicarboxy late (R)-3-methyl-5-{3-[3-(4,4-diphenyl-l-piperidinyl)-propoxi]-propy1}-4-(2,3-dic.hlorophenyl)-l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (R)-3-methyl-5-(3-[3-(4,4-di phenyl-1-piperidinyl)-propoxi]-propyl}-4-(2,1,3benzoxdiazol-4-yl )-1,4-di hydro-2,6-dimethyl pyridine-3,5-dicarboxylate (R)-3-methyl-5-(3-[3-(4,4-diphenyl-l-piperidinyl)-propoxi]-propyl}-4-(3-cyanophenyl )-1,4-di hydro-2,6-dimethyl pyridine-3,5-di carboxyl ate (R)-3-methyl-5-(3-[3-(4,4-diphenyl-1-piperidinyl)-propoxi]-propyl |-1,4-di hydro25 2,6-dimethyl-4-(2-methoxyphenyl)-pyridine-3,5-dicarboxylate (R) -3-methyl -5- (3-[3-(4,4-diphenyl-1-pi peri di nyl) -propoxi] -propyl }-l,4-di hydro2, 6-dimethyl-4-(2-pyridyl)-pyridine-3,5-dicarboxylate and (R)-3-methyl-5-(3-[3-(4,4-di phenyl-1-pi peri di nyl)-propoxi]-propyl }-l,4-di hydro2.6- dimethy 1-4-(5-methyl-2-thienyl)-pyridine-3,5-di carboxy late and of their salts.

The use, according to the invention, of the compound (R)-(+)-3-methyl-5-[3(4,4-di phenyl-1-pi peridi nyl)-propyl] -1,4-di hydro-2,6-dimethyl-4-(3-ni trophenyl)-pyridine-3,5-dicarboxylate and of its salts is preferred particularly.

Particularly preferred subject matter of the invention is the use of those op35 tically pure 1,4-dihydropyridines of formula I, which have - in particular as compared with their optical antipodes - only a minor influence on the cardiovascular system. -12The 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 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, Rl, R2, R3, R6, R7, R8, R9 and A having the above-mentioned meanings and Z representing a suitable leaving group. -13Tbe 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 dichloroethane; or polar, aprotic solvents, such as dimethylformaraide, n-methylpyrrolidone or dimethylsulfoxide.

Depending on the reactivity of the educts, the reaction temperatures are optio10 nally varied within a wide range. In general, the reaction is carried out at 0 0 0 0 . 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.

Oepenaing 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 subse30 quently added.

The salts are obtained by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt, or by evaporation of the solvent. -14The 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 di hydropyridine carboxylic acids IV (IV) by reaction with suitable bi functional alkyl derivatives V and subsequent removal of SG, Ar, Rl, 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 oniura salts, such as tetrabutyl ammonium bromide or benzyltriethylammonium chloride, are particularly crown ethers, such as dibenzo-[18] crown-6, di cyclohexyl-[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, e.g., an inorganic base, such as an alkali-metal hydroxi-° de (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. -15The 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-inmiscible or sparingly water-miscible organic solvent. Examples of water/solvent mixtures include mix5 tures 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 10 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 prefer.15 red 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 di hydropyridine 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 diaryl piperi dines III are known from DE-OS i9 36 452. The bi functional 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. -1όEXAHPLES End Products 1. (-)-3-Hethyl-5-[3-(4,4-diphenyl-1-piperidinyl)-propyl]-1,4-dihydro-2,6dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride A mixture of 86.6 g of (-)-3-methyl-5-(3-bromopropyl)-l,4-dihydro-2,6-dimethyl4-(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 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 I 1 of 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 I of dioxane; then 15.2 ml of concentrated 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 crystal15 lizes 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 o di isopropyl ether, and dried at 80 to 100 C in vacuo. For further purification the crude product is dissolved in di chloromethane. After addition of 800 ml of dioxane the dichlormethane is distilled off. The product which crystallizes af20 ter inoculation on standing at room temperature for 16 h is filtered off by o suction, washed with dioxane and di isopropyl ether, and dried at 100 C in vao o 22 o cuo. 97 g of the title compound {m.p. 158 C to 160 C and [«]. · - 39 o 436 (c = 1, methanol) or [a] = - 14,4 (c = 1, methanol)} are obtained.

Alternatively, the title compound is obtained as follows: 64.6 g of (i)-3-methyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propyl]-l,4-dihydro-2,6-dimethyl-4-(3-nitrophenvl)-pvridine-3,5-dicarboxylate 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 re30 sidue (60.91 g) and 37.63 g jf (.-(-J-di-O.O’-benzoyltartaric acid hydrate [having a specific rotation [al of - 108.1 (c = 1, methanol)} are together -17dissolved 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+1). 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 (50 g) is recrystallized three times in the same way. A third (36 g with [a]22= _ 47.5°), f0urth (33 g with [a]22= - 49.4°) and fifth {31 g with [22= - 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, [e]22s - 14.3 (c - 1, methanol). 2. (-) -3-Ethyl -5- [3- (4,4-di phenyl - 1-pi peri di nyl) -propyl ] -2-amino-l ,4-dihydro-6-methyl-4-(3-ni trophenyl)-pvridine-3,5-dicarboxyl ate g of (i)-3-Ethyl-5-[3-(4,4-diphenyl-l-piperidinyl)-propyl]-2-amino-l,4dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxvlate and 36,2 g of L-(-)-di-0,0'-benzoyltartaric acid hydrate {in this example having a specific rotation [«]22= - 108.4 (c = 1, methanol)} are together dissolved in methanol/di chloromethane (9 + 1). 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*1), and the well-stirred clear solution is then o allowed to cool slowly. A first crop of crystals {33 g, m.p. 165 - 166 C, - 17.8° (c s 1, methanol)} is obtained which yields after renewed recrystallization from methyl ethyl ketone/methanol (2 ♦ 1) a second crops of crystals {22 g, [β]θ2= - 10.8 (c = 1, methanol)}. The coarse yellowish needles are dissolved in 400 ml of di chloromethane. The solu30 tion is extracted with 300 ml of concentrated aqueous anmonia 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 -18of ethyl acetate and 2-propanol (9*1). The solution is allowed to cool slowly, and 12.4 g of the title compound are obtained as fine needles of m.p. 151 152°C and [α]^2= ♦ 42.0 (c » 1, methanol).

The freee base of the title compound obtained after the extraction with ammonia 5 can be precipitated in petroleum ether in amorphous form. A fine yellowish o 22 0 powder of m.p. 96 - 104 C (slow deliquescence) and [«]0 = ♦ 57.6 (c = 1, methanol) is obtained. 3. (+)-3-Methyl-5- {2-[2-(4,4-diphenyl-l-piperidinyl)-ethoxy]-ethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydroio chloride ml of oxalyl chloride are added to 997 mg of (♦)-3-methyl-I,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, cooled to 0 C, of 1.09 g of N-[2-(2-hydroxyethoxy)-ethyl] -4,4-di phenyl piperidine and 0.6 ml of triethylamine, while gassing with N,. After the dropwise addition, the mixture is stirred at room temperature for a further 2 h and then 20 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 5 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 chlo30 ride and the product is precipitated as an amorphous substance by dropwise addition of the solution to 1 1 of petroleum ether/diethyl ether (2 ♦ 1). After the precipitate has been filtered off with suction and dried, the title compound is obtained as a fine gray powder of m.p. 113 - 128 C (slow deliquescence); [«]q2= + 0-9 (c = 1, methanol); yield: 490 mg. -19Starting compound (-)-3-Methyl-5-(3-bromopropyl)-1,4-di hydro-2,6-dimethy 1-4-(3-ni trophenyl)-pyridine-3,5-di carboxylate 168.5 g of (+)-l-ethoxymethyl-l,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-45 (3-nitrophenyl)-pyridine-3-carboxylic acid/cinchonine salt {[a] s o 0 ♦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 10 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 cake is washed with acetone. The filtrate is concentrated under a slight vacuum in a rotary evaporator, and the excess 1,3-dibromopropane is reo moved by distillation at 0.02 mbar (bath temperature up to 45 C). 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 di isopropyl ether is filtered off by suction, washed with di isopropyl ether an<^ dried in vacuo. 102 g of the title compound {m.p. 112 to 114 C and [a] O u - 13.8 (c = 1, methanol)} are obtained. -20Commercial 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 compounds I and their salts 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 the urinary bladder, oesophagal carcinomas and other malignant neoplasias, in 3q particular of colon cancer, breast cancer, bronchial carcinomas and lung carcinomas. -21The invention embraces the use of the compounds of formula I and their pharmacologicaliy-acceptable salts in the preparation of medicaments which are employed for combating said diseases.

The medicaments are prepared by processes which are in themselves known and are 5 familiar to those skilled in the art. The medicaments employed are the pharmacological ly-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, suspen10 sions, aerosols, sprays, ointments, creams, gels or solutions, the content of active compound being advantageously between 0.1 and 95 per cent by weight. -22Excipients 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, parenteral ly (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 the 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 ac25 cording 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, 30 healthy tissue regenerates more rapidly than malignant tissue is utilized therein. -23Pharmacology The antineoplastic activity of (♦)-3-methyl-5-[3-(4,4-diphenyl-l-piperidiny1)propyl]-1,4-di hydro-2,6-dimethyl -4- (3-nitrophenyl) -pyri di ne-3,5-di carboxy 1 ate 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: Cell line NCI-H 727 was seeded at a density of 5 x 10 cells/ml in 50 ml tissue 10 culture flasks. The cells were maintained in RPM1 1640 medium supplemented with L-glutamine (2 mM), fetal bovine serum (10 V/V) and gentamycih sulfate (50 pg/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: Oose-response-relationship of the anticarcinogenic effect of 1^ in the human lung carcinoid-derived cell line NCI-H 727 Treatment Seeding No. of viable cells X 10 / ml 72 hrs 144 hrs 216 hrs 20 control 5 5.7 8.9 38.3 Polyethylene glycol-control 5 7.5 28.7 72.8 1 1.0 μΜ 5 0 0 0 1 0.5 μΜ 5 1.2 1.3 1.6 25 1 0.1 μΜ 5 1.7 1.9 2.8 <4. 2. Effect of _1 on growth kinetics of the human lung adenocarcinoma-derived cell line NCI-H 322 (Clara cell) Methods and Results: Cell line NCI-H 322 was seeded at a density of 5 x 10 cells/ml in 50 ml tissue 5 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 (50 pg/ml) at 7 % CO,, 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 1 in the human lung adenocarcinoma-derived cell line NCI-H 322 (Clara cell) Treatment Seeding No. of 72 hrs viable cells X 144 hrs 10 / ml 216 hrs control 5 5.5 10.4 33.6 Polyethylene glycol-control 5 7.5 22.7 34.3 1 1.0 pM 5 0 0 0 1 0.5 pM 5 0.7 0.9 1.9 1 0.1 pM 5 1.1 1.4 2.0 -253. Effect of 1 on growth kinetics of the human lung adenocarcinoma-derived cell line NCI-.H 358 (alveolar type II cell) Methods and Results: Cell line NCI-H 358 was seeded at a density of 5 x 10 cells/ml in 50 ml tissue 5 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 (50 pg/ml) at 7 % C02, 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. io 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 X 10 / ml 144 hrs 216 hrs control 5 5.8 16.8 40.6 Polyethylene glycol-control 5 7.6 25.9 80.6 1 1.0 μΜ 5 0 0 0 1 0.5 μΜ 5 0.9 1.1 1.8 1 0.1 μΜ 5 0.9 1.2 2.0

Claims (12)

1. Patent Claims 1. Use of optically pure diaryl compounds of formula I wherein Ar represents a ring of the formula in which Y denotes oxygen (0), sulphur (S), vinylene (-CH=CH-), azomethi (-CH=N—) or a group of the formula or -21Rl denotes hydrogen, l-6C-alkyl or 2-7C-alkoxya1kvl, R2 denotes hydrogen, amino (NH,), l-6C-alkyl or 3-7C-alkoxyalkyl, R3 denotes hydrogen, l-6C-alkyl or 3-7C-alkoxyalky1, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, ; 5 nitro, cyano, trifluoromethyl, l-4C-alky1, l-4C-alkoxy, l-4C-a1koxy which is completely or partly substituted by fluorine, 1-4C-alkoxycar- / bonyl, 2-5f-acyl, amino, mono- or di-l-4C-alkylamino or together methylenedioxy, R6, R7, R8 and R9 are identical or different and denote hydrogen, hydroxyl, halo logen, l-4C-alkyl, l-4C-alkoxy or l-4C-a1koxy which is completely or partly substituted by fluorine, and A denotes 2-5C-alky1ene or A1-0-A2, in which Al denotes 2-4C-alkylene and 15 A2 denotes 2-4C-alky1ene or 2C-a1ky1eneoxy-2C-alky1ene and their salts for the manufacture of medicaments for the treatment of tumors.

2. Use, according to claim 1, of compounds of formula I, according to claim 1, wherein Ar denotes 3-nitrophenyl, 2-chlorophenvl, 2,3-dichlorophenyl, 2-trifluoromethyl phenyl, 2-difluoromethoxyphcnyl, 2,3-methylenedioxy20 phenyl or 2,l,3-benzoxdiazol-4-y1, 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.

3. Use, according to claim 1, of compounds of formula I, according to claim 1, wherein Ar denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 25 2-tri fluoromethyl phenyl, 2-di fluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,1,3-benzoxdiazol-4-yl, RI 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.

4. Use, according to claim 1, of compounds of formula I, according to claim 30 1, wherein Ar denotes 3-nitrophenyl, 2-chlorophenvl, 2,3-dichlorophenyl, * 2-tri fluoromethyl phenyl, 2-di fluoromethoxyphenyl, 2,3-methylenedioxyphenyl or 2,l,3-benzoxdiazol-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 ethy35 leneoxyethylene, and of their salts. -1S*

5. Use, according to claim 1, of compounds of formula I, according to claim 1, wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, Rl denotes ' methyl, R2 denotes methyl, R3 denotes methyl or ethyl, R6, R7, R8 and R9 denote hydrogen and A denotes ethylene or propylene, and of their salts.

6. Use, according to claim 1, of compounds of formula I, according to claim 1, wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, Rl 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.

7. Use, according to claim 1, of compounds of formula I, according to claim 10 1, wherein Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl, Rl denotes methyl, R2 denotes methyl, R3 denotes methyl or ethyl, R6, R7, R

8. And R9 denote hydrogen and A denotes A1-0-A2, Al being ethylene and A2 being ethylene, and of their salts. 2. Use of the compound (R)-(+)-3-methy1-5-[3(4,4-cipheny1 -i-pi peri diny1) 15 propyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and of its salts for the manufacture of medicaments for the treatment of tumors.

9. A use substantially as hereinbefore described with reference to the Examples. 20

10. A method substantially as hereinbefore described with reference to the Examples.

11. A composition substantially as hereinbefore described with reference to the Examples.

12. A medicament substantially as hereinbefore described with reference 25 to the Examples.