MXPA99011656A - Pharmaceutical composition having enhanced antitumor activity and/or reduced side effects, containing an antitumor agent and an hydroxamic acid derivative - Google Patents

Abstract

The invention refers to pharmaceutical compositions which have an enhanced antitumor activity or reduced side effect(s) comprising a known active substance having antitumor effect or a pharmaceutically acceptable salt thereof and a hydroximic acid derivative of formula (I) or a therapeutically useful acid addition salt thereof.

Description

PHARMACEUTICAL COMPOSITION THAT HAS IMPROVED ANTITUMOR ACTIVITY AND / OR SIDE EFFECTS REDUCED, WHICH CONTAINS AN ANTITUMOR AGENT AND A DERIVATIVE OF HYDROXYMIC ACID DESCRIPTION OF THE INVENTION The invention relates to a pharmaceutical composition having improved antitumor activity and / or reduced side effects. A significant portion of the antitumor agents (cytostatics) destroy the tumor cells by acting partially via the inhibition of DNA and RNA synthesis, and partially via damage to the completed DNA. The known antitumor agents can seriously damage the genes of healthy cells, causing mutations and deletions in mitochondria and nuclear genomes. Antitumor agents frequently cause general cell damage in addition to their primary antitumor effect. This leads to side effects that often make continuation of treatment impossible, and even result in the death of patients. Therefore, the most critical part of antitumor treatment is the sensitivity of the patient to the serious side effects of cytostatic drugs. Due to the problems mentioned above, it is of great significance to produce a pharmaceutical composition that possesses the anti-tumor activity of the cytostatics or increased anti-tumor activity thereof without side effects, or at least with reduced side effects. The aim of the invention is to provide a pharmaceutical composition in which the activity of a known antitumor active substance is either improved, or said activity is conserved and simultaneously the side effects of the known active substance are reduced. The hydroxyl acid derivatives of the formula (I), X R R1 / RJ-A-C-N-0-CH2-CH-CH2-N (I) \ B Rz wherein R1 is hydrogen or an alkyl group of 1 to 5 carbon atoms; R represents hydrogen; an alkyl group of 1 to 5 carbon atoms; a cycloalkyl group of 3 to 8 carbon atoms; or a phenyl group optionally substituted with a phenyl or hydroxyl group; or R1 and R2 together with the adjacent nitrogen atom form a 5- to 8-membered ring optionally containing one or more additional nitrogen, oxygen or sulfur atoms; and said ring can be condensed with another alicyclic or heterocyclic ring, preferably with benzene, naphthalene, quinoline, isoquinoline, pyridine 0 plrazoline; in addition if desired and possible, nitrogen and / or sulfur as heteroatom (s) are present in the form of an oxide or dioxide; R3 means hydrogen or a phenyl, naphthyl or pyridyl group optionally substituted with one or more halogens or alkoxy groups of 1 to 4 carbon atoms; And it's hydrogen; a hydroxyl group; an alkoxy group of 1 to 24 carbon atoms optionally substituted with an amino group; a polyalkenyloxy group of 2 to 24 carbon atoms containing 1 to 6 double bonds; an alkenoyl group of 1 to 25 carbon atoms; an alkenoyl group of 3 to 9 carbon atoms; or a group of the formula R7-COO-, wherein R7 is a polyalkenyl group of 2 to 30 carbon atoms containing from 1 to 6 double bonds; X represents halogen; an amino group; or an alkoxy group of 1 to 4 carbon atoms; or X and B together form an oxygen atom; or X and Y together with the adjacent carbon atoms and the adjacent -NR-0-CH2- group form a ring of the formula (a), z - - CH / \ C Cl (a) w / N - - 0 wherein Z is oxygen or nitrogen; R is hydrogen; or R and B together form a chemical bond; A means an alkylene group having 1 to 4 carbon atoms or a chemical bond; or a group of the formula (b), - (CH) m - (CH; (b) wherein R 4 represents a hydrogen; an alkyl group of 1 to 5 carbon atoms; a cycloalkyl group of 3 to 8 carbon atoms; or a phenyl group preferably substituted with halogen, with alkoxy of 1 to 4 carbon atoms or with an alkyl group of 1 to 5 carbon atoms; R5 means a hydrogen; an alkyl group of 1 to 4 carbon atoms; or a phenyl group; m is O, 1 OR 2; and n is 0, 1 or 2. are known in the art. US Patent No. 4,308,399 describes the compounds belonging to the scope of the hydroxyl acid derivatives of the formula (I), which are useful for the treatment of diabetic angiopathy. European Patent No. 417,210 describes hydroxyl acid halides, which also fall within the scope of the compounds of formula (I), possess a selective β-blocker effect and are useful for the treatment of diabetic angiopathy. The Hungarian Patent published under No. T / 66350 describes a number of other hydroxyl acid derivatives which are within the scope of the compound of formula (I). These known substances are useful in the therapy of vascular deformations, particularly of diabetes mellitus. It is known from the PCT Patent Application published under No. WO 97/13504 that the hydroxyl acid derivatives of the formula (I) are useful for the prevention and treatment of disorders of itochondrial origin. The object of the present invention is to provide a pharmaceutical composition which possesses the effect of the known cytostatic agent but which exerts the side effects thereof to a diminished degree. It has been found that the above objective can be achieved by the pharmaceutical composition of the invention, which comprises a known cytostatic agent or, if desired and possible, a therapeutically useful acid addition salt thereof or the therapeutically suitable salt thereof. same and a hydroxyl acid derivative of the formula (I), wherein R, R 1, R 2, R 3, A, B, X and Y are as defined above, or a therapeutically suitable acid addition salt thereof, together with one or more suitable carriers. From the point of view of the invention, the substituents defined in relation to formula (I) are as follows: alkyl of 1 to 5 carbon atoms represents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or n-pentyl, preferably a methyl or ethyl group; Cycloalkyl of 3 to 8 carbon atoms is for example a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, preferably a cyclopentyl or cyclohexyl group; - the ring of 5 to 8 members can be for example a ring of pyrrole, pyrazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, piperazine, morpholine, indole or quinoline or the like; the alkoxy group of 1 to 24 carbon atoms can be, for example, a methoxy, ethoxy, n-propoxy, tert-butoxy, n-pentoxy, decyloxy, dodecyloxy, octadecyloxy group or the like; - the alkanoyl group of 1 to 25 carbon atoms can represent, for example, a formyl, acetyl, propionyl, butyryl, caproyl, palmitoyl or stearoyl group, and the like; - the alkenoyl group of 3 to 9 carbon atoms means, for example, an acryloyl, pentenoyl, hexeenoyl, heptenoyl, octenoyl group or the like; the alkylene group of 1 to 4 carbon atoms can be, for example, a methylene, ethylene, propylene or butylene group; - halogen is, for example, fluorine, chlorine, bromine or iodine, preferably chlorine or bromine. And as the R7-COO- group, it can be, for example, a linolenoyl, linoleyl, docosahexanoyl, eicosapentanoyl or arachidonoyl group or the like. Suitable physiologically (therapeutically) acid addition salts of the compounds of the formula (I) are understood to be acid addition salts formed with therapeutically suitable inorganic acids, for example hydrochloric or sulfuric acid and the like; or with therapeutically suitable organic acids, for example acetic, fumaric or lactic acid and the like.

With the compounds of the formula (I), a preferable subgroup consists of the hydroxyl acid derivatives of the formula (II), R "R- R3- (CH) m- (CH) n-C-X R1 II II / N-0-CH2-CH-CH2-N I \ R ' wherein R1, R2, R3, R4, R5, m and n are as defined for formula (I), X means halogen or an amino group; and Y means a hydroxyl group. The compounds of the formula (II) wherein R1 and R2 together with the adjacent nitrogen atom form a piperidino group; R3 is a pyridyl group; m and n are 0; and X is as defined above, and particularly preferred of these are: 0- (3-piperidino-2-hydroxyl-1-propyl) nicotinic acid amidoxime dihydrochloride (compound * L ") is especially suitable. Preferred of the compounds of the formula (I) consists of the compounds of the formula (III), O OH R1 II I / R3-A-C-NH-0-CH2-CH-CH2-N III R ' wherein R1, R2, R3 and A are as defined for formula (I). A third preferred subgroup of the hydroxyl acid derivatives of the formula (I) includes the cyclic compounds of the formula (IV), R1 / CH2-N / \ Z - CH R '/ \ R3-A-C CH2 IV \\ N 0 wherein R1, R2, R3 and A are as defined for formula (I), and Z is oxygen or nitrogen. A further preferred subgroup of the hydroxyl acid derivatives of the formula (I) comprises the compounds of the formula (V), OR6 OH RJ R -A-C = N-0-CH2-CH-CH2-N V R < wherein R1, R2, R3 and A are as defined in formula (I), and R6 signifies an alkyl group of 1 to 4 carbon atoms. The compounds of the formula (I) can be prepared by using the known processes of U.S. Patent No. 4,308,399 and of European Patent No. 417,210; as well as the Hungarian Patent Application published No. T / 66350. From the activity point of view, a known cytostatic agent (substance) is an active agent such that it directly or indirectly inhibits the synthesis and / or transcription of DNA (RNA synthesis) and / or translation in the tumor cell; or it damages the developed DNA. A known pharmaceutical compound with antitumor activity is a compound that directly and / or indirectly inhibits synthesis and / or transcription (RNA synthesis) and / or translation of DNA, and damages completed DNA in cancer cells. In detail, the known pharmaceutical compound with antitumor activity inhibits: - adenosine-desase, biosynthesis of the purine base and transformation of nucleotides, - biosynthesis of the pyrimidine base, reduction of ribonucleotides, - synthesis of the thymidine onophosphate, RNA synthesis, DNA adduct, DNA synthesis, DNA damage, - synthesis of purine base and reduction of dihydrofolate, protein synthesis and asparagine deamination, - function of proliferation.

From the point of view of the chemical structure, the known cytostatic agents can be: alkylating agents comprising nitrogen-containing mustard derivatives, ethylene imine derivatives and methylmelamine derivatives; alkyl sulfonates; nitrosoureas; aziridines; triacenes and the like; - antimetabolites, within these folic acid analogs, pyrimidine analogs, purine analogs and the like; - native substances, including periwinkle alkaloids, podophyllotoxin, antibiotics and the like; hormones including adrenocorticosteroids, estrogens, androgens, antiestrogens and the like; and - other substances, such as complexing agents. Of the known cytostatic active agents, for example the preferred alkylating agents are the following: Chloromethine. 2-Chloro-N- (2-chloroethyl) -N-methyl-1-ethanolamine hydrochloride, Mechlorethamine oxide: 2-chloro-N- (2-chloroethyl) -N-methyl-ethanolamine N-oxide Cyclophosphamide: N, N-bis (2-chloroethyl) -tetrahydro-2H-1, 3, 2-oxazaphosphorin-2-amin-2-oxide, Isofosfamide: N, 3-bis (2-chloroethyl) -tetrahydro-2H-1,3, 2-oxazafosforin-2-amin-2-oxide, Melphalan: 4- [bis (2-chloroethyl) amino] -L-phenyl-alanine, Chlorambucil: 4- [bis (2-chloroethyl) amino] -pheni-butanoic acid, Tiotepa: triethylene-thiophosphoric acid amide, Busulfan: 1,4-butanediol dimethanesulfonate, Car thamine: 1,3-bis (2-chloroethyl) -1-nitrosourea, The usine: 1- (2-chloroethyl) -3-cyclohexyl-1-nitroso-urea, Semustin: 1 - (2-Chloroethyl) -3- (4-methylcyclohexyl) -1- nitrosourea, I prosulfan: N, N-bis (3-methylsulfonyloxy-propyl) -amine, Piposulfan: 1,4-bis (3-methanesulfonyloxy-1) -oxo-propyl) piperazine, Benzodepa: bis (l-aziridinyl) fos finylcarbamic acid phenylmethyl ester, Meturedepa: bis (2,2-dimethyl-1-aziridyl) phosphinyl-carbamic acid ethyl ester, Uredepa: ethyl ester of bis (l-aziridinyl) fos-finylcarbamic acid, Carboquone: 2- [(2-aminoarbonyloxy) -1-methoxyethyl] -3,6-bis (1-aziridinyl) -5-methyl-2, 5-cyclohexadien-1, 4 -dione, Altretamine N, N, N ', N', N ", N" -hexamethyl-l, 3, 5-tri- azin-2, 4, 6-tri amine, Triethylene phospheramide: tris (l-aziridinyl) phosphine oxide, Trimethylol elamine: 2,4,6-tris (methylolamino) -1,3,5-triazine, Clornafazine: N, N-bis (2-chloroethyl) - 2-Naphthylamine, Cyclophosphamide: N, N-bis (2-chloroethyl) -tetrahydro-2H-l, 3, 2-oxazaphosphorin-2-amine oxide, Estramustine: estra-l, 3,5- (10) -trien-3,17-diol-3- [bis (2-chloroethyl) carbamate], Nove bichin: 2-chloro-N, N-bis (2-chloroethyl) propane-amine hydrochloride, Fenesterin: ketone acetate -5-en-3β-ol-4- [bis (2-chloroethyl) -amino] phenyl, Predni ustina: 21-. { 4- [4- [bis (2-chloroethyl) amino] phenyl] -1-oxobutoxy} - 11, 17-dihydroxypropylene-1,4-dien-3, 20-dione, Trofosfamide: N, N, 3-tris (2-chloroethyl) -tetrahydro-2H-l, 3, 2-oxazaphos forin oxide -2- amine, uracil mustard: 5- [bis (2-chloroethyl) amino] -2,4 (1H, 3H) -piri idindione, Chlorozotocin: 2- [(2-chloroethyl) -nitrosoaminocarbonyl-amino] -2 -deoxy-D-glucose, Fotemustine: [l - [(2-chloroethyl) -nitrosoaminocarbonyl-amino] ethyl] phosphonic acid, diethyl ester, Ni ustin: N '- [(4-amino-2-methyl-5-pyrimidinyl) ) - methyl] -N- (2-chloroethyl) -N-nitrosourea, Ranimus t ina: 6- [(2-chloroethyl) -nitrosoamino-carbonylamino] -6-deoxy-D-glucopyranoside methyl, Manomustine: dihydrochloride of 1 , 6-bis (2-chloroethylamino) -1,6-dideoxy-D-mannitol, Mitobronitol: 1,6-dibromo-l, 6-dideoxy-D-mannitol, Mitolactol: 1,6-dibromo-l, 6- dideoxygalactitol, Pipobroman: 1,4-bis (3-bromo-l-oxopropyl) -piperazine, Decarbazine: 5- (3,3-dimethyl-1-triazene) imidazole-4-carboxamide, Preferred antimetabolites are for example the following: Methotrexate: N- [4- [(2,4-diamino-6-pteridinyl) methyl-methylamino] benzoyl] -L-glutamic acid or the sodium salt thereof, T imetrexate: 5-methyl-6- [(3,4,5-trimethoxy phenyl) -aminomethyl] -2,4-quinazolin-diamine, Fluorouracil: 5-fluoro-2,4 (1H, 3H) pyrimidinedione or the sodium salt thereof , Floxuridine: 5-fluoro-2 '-deoxyuridine, Idoxuridine: 5-iodo-2' -deoxyuridine, Doxifluridine: 5 '-deoxy-5-fluorouridine, Cytarabine: 4-amino-l-D-arabinofuranosyl-2 (1H) - pyrimidinone, Azacitidine: 4-amino-Iß-D-ribofuranosyl-1,3,3-triazin-2 (1H) -one, Gemeitabine: 2 ', 2' -difluoro-deoxycytidine, Merca topurine: 6-mercaptopurine, Thioguanine : 6-thioguanine, Fludarabine phosphate: 9β-D-arabinofurans phosphate i 1-2- fluoro- 9H-purin- 6- aa, pentostatin: (R) -3- (2-deoxy-beta-D-erythro) -pento-furans il) -3,6,7,8-tetrahydroi idazo [4, 5-d] [1, 3] diazepin-8-ol, Cladribine: 2-chloro-deoxyade nosine, Tiamiprine: 6- (l-methyl-4-nitro-lH-imidazol-5-ylthio) - lH-purin-2-amine, Ancitabine: 2, 3, 3a, 9a-tetrahydro-3-hydroxy-6- imino-6H-furo [2 ', 3': 4, 5] oxazolo [3, 2- a] pyrimidin-2-methanol, Azacytidine: 4-amino-1-beta-D-ribofuranosyl-1, 3, 5- tri-azin-2 (1H) -one, 6-azauridine: 2beta-D-ribofurans i1-1, 2,4-triazin-3, 5- (2H, 4H) -dione, Carmofur: carboxamide of 5-fluoro -N-hexyl-3, 4-dihydro-2, 4-dioxo-l (2H) -pyrimidine, Enocitabine: N- (Ibeta-D-arabinofuranosi1-1, 2-dihydro-2-oxo-4-pyrimidinyl) docosanamide , Tegafur: 5-fluoro-l- (tetrahydro-2-furanyl) -2,4 (1H, 3H) pyrimidinedione.

Of the known cytostatic active agents, for example, the following substances of natural origin are favorable: vinblastine sulphate: vincaleucoblastine sulfate, vincristine sulfate: 22-oxovincaleucoblastine sulphate, vindesine: 3- (aminocarbonyl) sulfate -0-4- deacetyl-3-de (methoxycarbonyl) -vincaleucoblastine, Paclitaxel ester [6, 12b-bis (acetyloxy) -12- benzoyloxy-2a, 3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b- dodecahydro-4, 11-dihydroxy-4a, 8, 13, 13-tetramethyl-5-oxo-7, 11-methan-lH-cyclodeca [3,4] benz [1,2- b] oxet-9- acid] [2aR, 4S, 4aS, 6R, 9S (alphaR, betaS), US, 12S, 12aR, 12bS] -beta-benzoylamino-alpha- (hydroxy phenyl) propionic, Docetaxel ester [12b-aceti 1-oxy] - 12-benzyloxy-1,2,3,4, 4a, 6,9,10,11,12,12a, 12b-dodecahydro-4,6,1-trihydroxy-4a, 8,13,13-tetramethyl-5 -oxo-7, 11-methan-5H-cyclodeca [3,4] benz [1,2-b] oxet-9-yl] of [2aR- [2a alpha, 4 beta, 4a beta, 6 beta, 9] alpha (alfaR *, betaS *), 11 beta, 1 2 alpha, 12a alpha, 12a alpha, 12b alpha]] - beta-tert-butoxycarbonylamino) -alpha- (hydroxyphenyl) propionic, Etoposide: [5R- [5 alpha, 5 alpha beta, 8a alpha, 9 beta- (R )] - [9- (4,6-0-ethylidene-beta-D-glucopyranosyloxy) -5,8,8a, 9-tetrahydro-5- (4-hydroxy-3,5-dimethoxyphenyl) -furo [3 ' , ': 6,7] naphtho [2,3-d] -l, 3-dioxol-6- (5aH) -one, Teniposide: [5R- [5 alpha, 5 alpha beta, 8 alpha, 9 beta- ( R)] - [5,8,8a, 9-tetrahydro-5- (4-hydroxy-3,5-dimethoxyphenyl) -9- [4,6-0- (2-thienylmethylene) -beta-D-glucopyranosyloxy [ furo 3 ', 4': 6, 7] naphth [2, 3-d] -1, 3-dioxol-6- (5aH) -one, Dactinomycin: actinomycin D, Daunorubicin: (8S-cis) -8-acetyl -10- (3-amino-2, 3,6-tride-oxy-alpha-L-lixo-hexopyranosyloxy) - 7,8,9,1- tetrahydro-6,8,1-trihydroxy-1-methoxy-5 , 12-naphtacendione, Doxorubicin: (8S-cis) -8- (hydroxyacet-il) -10- (3-amino-2, 3, 6-trideoxy-alpha-L-lixohexopyranosyl-oxy) -7, 8, 9, 10- tetrahydro- 6,8,11-trihydroxy-1-methoxy-5, 12-naphtha- cione, Epirubicin a: (8S-cis) -10- (3-amino-2,3,6-trideoxy-alpha-L-arabino-hexopyranosyloxy) -7,8,9, 10-tetrahydro-6,8,11-trihydroxy- 8- (hydroxy-acetyl) -1-methoxy-5, 12-naphthacenyl, Idarubicin: (7S-cis) -9-acetyl-7- (3-amino-2,3,6-tri- deoxy-alpha-L) -lixo-hexopyranosiloxi) - 7, 8, 9, 10-tetrahydro-6, 9, 11-trihydroxy-5, 12-naphtacendione, Mitoxantrone: 1,4-dihydroxy-5, 8-bis [2- (2-hydroxyethyl ) amino-ethylamino] -9, 10-anthracenedione or the dihydrochloride thereof, Bleomycin (A2, B2): mixture of isolated glycopeptide antibiotics of Streptomyces verticillus species, mainly in the form of sulfate or hydrochloride, Plicamycin: an antibiotic produced by Streptomyces argillaceus, Streptomyces tanashiensis and Streptomyces plicatus, Mitomycin: [laR- (alpha, 8 beta, 8a alpha, 8b alpha)] - 6-amino-8-aminocarbonyloxamethyl) -1, la, 2, 8, 8a, 8b-hexahydro-8a-methoxy-5 -methyl-azirino [2 ', 3': 3, 4] - pyrrolo [1,2-a] indo1-4, 7 -dione, Aclacinomycin (A and B): an antibiotic belonging to the anthracycline group, produced by Streptomyces galileus, Anthramycin: 3- (5, 10, 11, lla-tetrahydro-9, 11-dihydroxy-8-methyl-5-oxo-lH-pyrrolo [2, 1- c] [1,4] -benzodiazepin- 2-yl) -2- propenamide, Azaserin: O-diazoacetyl-L-serine, Carrubicin: 8-acetyl-10- (3-amino-2, 3, 6-tridesoxy-alpha-L-lixo-hexopyranosyloxy) -7 , 8, 9, 10- tetrahydro-1,6,8,8,1-tetrahydroxy-5,12-naphthacendione, Cactinomycin: actinomycin C, an antibiotic produced by Streptomyces chrysomallus, Carzinophilin: an antibiotic produced by Streptomyomy saha chiroi, Chromomycin: an antibiotic produced by S trept omyces gri seus, Olivomycin: an antibiotic produced by Strept omyces ol i vore ti culi, Nogalamicin : methyl ester of acid [2R- (2 alpha, 3 beta, 4 alpha, 5 beta, 6 alpha, 11 beta, 13 alpha, 14 alpha)] -11- (6-deoxy-3-C-methyl-2, 3, 4-tri-0-methyl-alpha-L-mannopyranosyloxy) -4-dimethylamino- 3, 4, 5, 6, 9, 11, 12, 13, 14, 16-decahydro-3,5,8,10 , 13-pentahydroxy-6,13-dimethyl-9,16-dioxo-2,6-epoxy-2H-naphthalene [l, 2-b] oxocin-14-carboxylic acid, Peplo-icine: amide of N '- [3 - (1-phenylethyl) aminopropyl] -bleomycin, Porphyromycin: 6-amino-8- (aminocarbonyloxymethyl) -1,1a, 2, 8, 8a, 8b-hexahydro-8a-methoxy-l, 5-dimethylazirino [2 ', 3 ': 3,4] pyrrolo [1,2- a] indole-4,7-dione, Streptonigrin: 5-amino-6- (7-amino-5,8-dihydro-6-methoxy-5,8 acid -dioxo-2-quinolinyl) -4- (2-hydroxy-3,4'-dimethoxy-phenyl) -3-methyl-2-pyridinecarboxylic acid, It is treptozocin: 2-deoxy-2- (methyl-nitrosoamino-carbonylamino) -D-glucopyranose, Tubercidin: 7beta-D-ribofuranosyl-7H-pyrrolo [2,3-d] -pyrimidin-4-amine, Ubenimex: [2S , 3R] -3-amino-2-hydroxy-4-phenyl-butanoyl] -L-leucine, Zorrubicin: [1- [4- (3-amino-2, 3, 6-trideoxy-alpha-L-lixo- hexopyranosyloxy) -l, 2,3,4,6, ll-hexahydro-2, 5, 12-trihydroxy-7-methoxy-6,1-dioxo-2-naphthacenyl] -ethylidene] - benzoic acid hydrazide, from Of the known cytostatic active agents, the hormones described herein are advantageous: Prednisolone: (ll-beta) -ll, 17, 21-trihydroxypregna-l, 4-diene-3, 20-dione, Hydroxyprogesterone: 17-hydroxypregn-4-en-3, 20-dione or the caproate thereof, Medroxyprogesterone: (6 alpha) -17-hydroxy-6- methylpregn-4-en-3, 20-dione or the acetate thereof, Megestrol: 17-hydroxy-6-met ilpregna-1,4-dien-3, 20-dione or acetate thereof, Diethylstilbestrol: (E) -4,4 '- (1,2-diethyl-l, 2-etenediyl) -bis (phenol), ethinylestradiol: (17 alpha) -19-norpregna- 1, 3, 5 (10) -trien-20-in-3, 17-diol, Ta oxyphene: (Z) -2- [4- (1,2-di-phenyl-1-butenyl) phenoxy] - N , N-dimethylethanamine or the citrate thereof, Testosterones: (17-beta) -17- (1-oxo ropoxy) -andrós t-4-en-3-one or the propionate thereof, Fluoxymesterone: (11- beta, 17 beta) -9-fluoro-11, 17-dihydroxy-17-methilandros t-4-en-3-one. * Of the known cytostatic active agents the preferred substances of other classes are for example: Cisplatin: cis-diamin-dichloroplatinum, Carboplatin: cis-diamin- [1,1-cyclobutane-dicarboxylate (2)] -platinum, L-asparaginase: an enzyme produced for example by Escherichia coli, Procarbazine: N- (1-methylethyl) -4- (2-hydrazino-methyl) benzamide, Mitotane: l-chloro-2- [2,2-dichloro-l- (4 - chlorophenyl) ethyl] benzene, Flutamide: 2-methyl-N- (4-nitro-3-trifluoromethyl-phenyl) -propane ida, Leuprorelin: 5-oxo-L-prolyl-L-histidyl-L-triptophoyl- L- seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide or the acetate thereof. The known cytostatic active agent can also be used in the form of its salt by the addition of therapeutically suitable acid, with the proviso that its chemical structure allows the preparation of a salt by addition of acid. Similarly, the known cytostatic active agent can be used as its therapeutically suitable salt, for example the metal salt, ammonium salt or salts formed with organic bases, when its chemical structure is suitable for the preparation of such salts.

The cytostatic pharmaceutical composition according to the invention preferably contains cisplatin as the cytostatic active agent (antitumor) and amidoxime of 0- (3-piperidino-2-hydroxy-1-propyl) nicotinic acid or a therapeutically useful acid addition salt thereof, as a hydroxymic acid derivative of the formula (I) • The pharmaceutical composition according to the invention usually contains the active agents (ingredients) in amounts of 0.1 to 95% by weight, preferably 1 to 50% by weight, preferably 5 to 30% by weight together with the usual carrier (s) of the pharmaceutical compositions. In the pharmaceutical composition according to the invention, the proportion by weight of the two active ingredients (agents) is preferably (1 to 50): (50 to 1), particularly and preferably (1 to 10): (10 a) 1). The pharmaceutical composition of the invention may be a solid or liquid composition useful for oral, parenteral or rectal administration or for topical treatment. The solid pharmaceutical compositions useful for oral administration may be powders, capsules, tablets, film-coated tablets, microcapsules and the like; and may contain as carrier binders, for example gelatin, sorbitol, polyvinyl pyrrolidone and the like; filling materials, for example lactose, glucose, starch, calcium phosphate and the like; tabletting aids such as magnesium stearate, talc, polyethylene glycol, silicon dioxide and the like; as well as wetting agents, for example sodium lauryl sulfate and the like. Liquid pharmaceutical compositions for oral administration are solutions, suspensions or emulsions containing as carriers for example suspending agents, such as gelatin, carboxymethylcellulose and the like; emulsifying agents, for example sorbitan monooleate; solvents such as water, oils, glycerol, propylene glycol, ethanol; as well as preservatives such as methyl or propyl-p-hydroxybenzoate and the like. Pharmaceutical compositions for parenteral administration are usually the sterile solutions of the active agents. The dosage forms (dosage units) exemplified above as well as other dosage forms are per se known, see for example the manual entitled: Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing Co. Easton, USA (1990). In most cases, the pharmaceutical compositions according to the invention contain the dosage unit. For an adult person, the characteristic daily dose is 0.1 to 1000 mg of the known cytostatic active agent and 0.1 to 1000 mg of a compound of the formula (I), which can be administered once in one or more sub-doses. The effective dose depends on several factors and is determined by the attending physician. The pharmaceutical composition according to the invention is prepared by mixing the active agents (ingredients) with one or more carriers, then transforming the obtained mixture into a pharmaceutical composition in a manner known per se. Useful methods are known in the art, for example from the Remington's Pharmaceutical Sciences manual referred to.

I. Attenuation of the side effects of cytostatics The attenuating effect of the hydroxyl acid derivative of the formula I on the side effects of the cytostatics, was investigated by the test of the hydroxylic acid derivative compound "". The experiments and results are being discussed later.

Experiments i n vi vo with ra tas. Groups of 6 Wistar rats were treated with cisplatin (50 mg / kg of body weight of daily dose), and the compound * L "(40 mg / kg of body weight of daily dose), respectively administered separately and in combination. The animals were healthy (without any tumor inoculation) at the beginning of the experiment, and the dose of the antitumor compound was provoked / unusually high, which by itself could cause tissue damage with high probability. The control group did not receive any of the active compounds. During the treatment, the cardiac function of the animals was followed by ECG, and after two weeks of treatment the enzymatic activity in the blood of the animals was determined. Concluding from the magnitude of the enzymatic activity, the degree of tissue damage caused by cisplatin was determined.

Investigation of tissue damage Tissue damage was assessed by measuring the intracellular release of the enzymes. The enzymatic activity was determined by the method of H.U. Bergmeyer (Methods in Enzymatic Analysis, 2nd edition, Academic Press (1974) .The following enzymes were measured: GOT glutamate-oxaloacetate-transamines a, GPT glutamate-pyruvate transaminase, LDH lactate dehydrogenase, CK creatine kinase, LipDH lipoamide dehydrogenase, CS citrate synthase.

The enzymatic activity is given in mUnities / ml of serum. The results are shown in Table 1.

Table 1 Enzymes Enzyme activity (mU / ml) Cisplatin Cisplatin + Control * L "GOT 273 131 94 GPT 87 47 45 LDH 5136 1950 1523 CK 9776 1445 1200 ipDH 69 41 43 CS 22 8 6 As shown in Table 1, the enzymatic activity is increased by the treatment with cisplatin indicating tissue damage. When cisplatin and compound * L "were administered in combination, the enzymatic activity correlated well with that observed in the control group, therefore, coadministration of compound * L" significantly protected against tissue damage caused by cisplatin.

Research of cardiac function The cardiac function was checked periodically by the ECG of AT-6 on all four legs. The distances QRS, RR, PR and TQ and the depressions of point J were also determined. The results are summarized in Table 2.

Table 2 Depression of point J QRS Intensity mm ms of QRS Normal 0.1 ± 0.1 67 Constant Cisplatin 2.1 ± 0.3 102 Fluctuating Cisplatin + 0.3 ± 0.3 77 Compound constant * L " As shown in Table 2, coadministration of the compound * L "and cisplatin ensures significant protection against the effect that damages the cardiac function of cisplatin It should be noted that the QRS fluctuation indicates significant cardiac damage due to the treatment with cisplatin, and this fluctuation ceased in the presence of the compound * L ".

Survival one month after treatment We investigated what percentage of animals were still alive after a two-week treatment, detailed above. The results are summarized in Table 3.

Table 3 Treatment One month survival (%) Cisplatin 25 Cisplatin + compound * L? 83 Not treated 100 As shown in Table 3, only the % of the animals were alive after one month of treatment due to the extreme toxicity of cisplatin, while all untreated animals survived. In contrast, 83% of the animals who received cisplatin in combination with the compound * L "survived, for example, the death rate was low, in vivo experiments with mice, modulation of the systemic toxicity of the known cytostatic agent cisplatin ( Platidiam, 50 La Chema, Brno) by compound * L "was studied in normal mice. (see Oncology Report (REP / O.O. I. / 1988/01)). First-generation hybrid adult male BDFi mice (female C57B1 x male DBA / 2), weighing 22 to 24 g, free of specific pathogens (SPF) were used for these experiments. The animals were kept in macrolon cages at 22-24 ° C (40-50% humidity), with an illumination regime of 12/12 hours of light / dark. The animals had free access to tap water and were fed a standard sterilized diet (pellets Altromin 1324, Altromin Ltd, Germany) ad libitum. For the toxicity test, the compound * L ", cisplatin and its mixture were dissolved in sterile physiological saline in a concentration that allowed the dose to be administered in a volume of 0.1 ml / 10 g of body weight and administered ip or po Acute toxicological effect of the compound * 1 ', cisplatin and the compound * L "+ cisplatin in combination The survival rates of BDFi male mice treated with different doses of compound * L ", cisplatin, and the compound * L" + cisplatin in combination are summarized in Table 4.

Table 4 The observation period was finished after 25 days. Of the doses of the compound * L ", the dose of 750 mg / kg of body weight, ip was lethal (Table 4) .Other treatments with the compound * L" simple had no effect on the survival of the BDF1 mice (Table 4). ). The dose-dependent toxic effect of cisplatin was also observed. The toxicity of the cytostatic agent evaluated based on survival was especially significant at higher doses and repeated treatments. The dose of 4 mg / kg, i.p., repeated 5 times (Sqd) was close to lethal (Table 4). However, cisplatin (15 mg / kg, ip) in combination with compound * L "(500 mg / kg, ip) showed considerable reduced toxicity (Table 4) When cisplatin was administered at a dose of 100 mg / kg in combination with compound * L ", all animals survived (Table 4).

II: Antitumor activity The antitumor effect of the cytostatic agents in combination with the hydroxyl acid derivative of the formula I was investigated by testing the hydroxyl-acid derivative, the compound * L. "The experiments and results are discussed below.

Experiments with cell phones. Sp-2 cells (mouse myeloma, in suspension) were plated on DMEM (Dubelso Modified Eagle Medium) in the presence of 10% FCS (fetal calf serum). Cells were plated on a 96-well plate with an initial cell number of 10/250 μl. A portion of the cells were seeded in plates without the addition of the drug, a portion of the cells was plated in the presence of 0.35 microgram / ml of cisplatin, another portion in the presence of 40 micrograms / l of compound * L ", another portion more in the presence of 0.35 microgram / ml of cisplatin + 40 micrograms / ml of compound * L "in combination. 48 hours after the treatment, for example, the addition of the compounds listed above, the cells in the wells were counted in a method of staining these with 10 microliters of trypan blue after suspension. The count was made in a Bürker chamber.

Effect on tumor growth Table 6 summarizes the number of cells surviving treatment, in percent.

Table 5 % Treatment of Surviving Cells Not treated 100 Compound * L "51 ± 8 Cisplatin 12 ± 4 Cisplatin + compound * L? 10 ± 5 As shown in Table 5, all untreated cells survive. Cisplatin by itself significantly reduces the number of tumor cells, and this effect does not change when cisplatin is added in combination with the compound * L. "A similar effect was observed when the previous experiment was repeated adding fluoroacyl instead of cisplatin. case, a portion of the cells were plated without the presence of the drug, a portion of the cells was plated in the presence of 13 micrograms / ml of fluoroacyl, another portion in the presence of 13 micrograms / ml of fluoroacyl + 40 micrograms / ml of the compound * L ". The survival rate was examined 40 hours after treatment. Table 6 summarizes the number of surviving cells to treatment in percent.

Table 6 Treatment of Surviving Cells Not treated 100 Compound * L "51 + 8 Fluoroacyl 13 ± 3 Fluoroacyl + compound * L" 10 ± 4 As demonstrated in Table 6, fluoroacyl by itself significantly reduces the number of tumor cells, and this effect remains unaffected when cisplatin is added together with the compound * L. "These in vitro experiments with antitumor agents (cisplatin or fluoroacyl) by themselves or in combination with the compound * L "showed that they exerted significant reduction of tumor cells in the cell culture. Thus, under in vivo conditions, the compound * L "did not influence the antitumor capacity of the antitumor agents investigated.The above observations demonstrate that the pharmaceutical composition of the formula I reduces the side effects of the antitumor agents, while its Anti-tumor activity remains unaffected.

Experiments in vi with ra tones. Simple or repeated treatments began on day 1 after tumor transplantation P-388 or S-180. The therapeutic effectiveness was evaluated based on the survival time and the tumor volume. The experiments were finished after 45 days. The long-term survival of the mice was not followed beyond 45 days, but the endpoint was on day 46 after tumor transplantation. The comparative antitumor effect of various treatment groups on the mean survival time in days for the treated groups versus the control groups was expressed as T / C. In the case of S-180 solid tumor, the effect of the compounds, inhibitory on tumor development, was controlled 3 times a week using a digital caliper. The volume of the tumor was calculated using the following formula: V = a2 x b2 x p / 6 where * a "and * b" are the shortest and longest diameter, respectively, of a given tumor (Tomayko MM and Reynolds CP: Determination of the size of the subcutaneous tumor in nude / nude / nude mice.) Cancer Chemother. Pharmacol, 24, p 148, 1989). The mean values (X) and the standard deviations (S.D.) were also calculated. The statistically significant difference (p) was determined by Student's t-test, where appropriate.

Influence of compound * L "in vivo on the antitumor activity of the cytostatic agent cisplatin The effect of cisplatin by itself or in combination with the compound * L "+ cisplatin on the survival of BDFl mice inoculated with 1 × 10 6 leukemia cells P-388, is shown in Table 7.

Table 7 The treatments started 1 day after tumor transplantation i.p. These experiments were completed on day 45 and the number of long-term survivors is shown in Table 7. As demonstrated in Table 7, the effectiveness of cisplatin was increased in the presence of the compound * L'A Although the compound * L " It could also significantly increase the mean survival time when administered in combination with cisplatin, this combination was particularly effective after repeated administration, especially concerning long-term survival (eg, up to 45 days). term of mice bearing the P-388 tumor treated with the compound * L "-f- cisplatin was 86% relative to the control value (0%). However, the long-term survival of mice treated with cisplatin alone was only 43% for the control group (Table 7).

Influence of compound "L" on the inhibitory effect of cisplatin on tumor development, against sarcoma S-180 Based on tumor growth curves and mean tumor volumes, a significant inhibitory effect of cisplatin and the combination of compound * L "+ cisplatin was observed after simple injections (Figure 1) or repeated injections (Figure 2). inhibition of cisplatin on tumor development compared to the mixture of compound * L "plus cisplatin on day 18 after tumor transplantation is illustrated in Figure 3. The presence of compound * L" increased the inhibitory effect of cisplatin on the tumor development significantly (Figure 3) The pharmacological compound of the invention proved to be very safe (for example, unusually non-toxic even in animals that possess tumors), and can be used to increase the effectiveness and reduce the side effects of the treatment antitumor of the patient with cancer during which the patient is treated with a known antitumor compound or its salt by addition n pharmaceutically acceptable acid, supplemented by a hydroximic acid derivative of the formula I or an acid addition salt pharmaceutically acceptable acid thereof in (1-50): (1-50)% by mass.

Claims (10)

1. A pharmaceutical composition having improved antitumor activity, comprising a known active substance having an antitumor effect or, if desired and being chemically possible, a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable salt thereof and a hydroxymethyl derivative of the formula I, wherein R 1 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms, R 2 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms or a phenyl group optionally substituted by a hydroxyl group or a phenyl group, or R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 8-membered ring optionally containing one or more nitrogen atoms, additional oxygen or sulfur, and the ring may be fused with another alicyclic or heterocyclic ring, preferably a benzene ring, naphthalene, quinoline, isoquinoline, pyridine or pyrazoline, furthermore, if desired and is chemically possible, the nitrogen and / or sulfur heteroatom (s) are present in the form of an oxide or dioxide, R3 signifies a hydrogen atom, a phenyl group, a naphthyl group or a pyridyl group in which the groups may be substituted with one or more halogen atoms or alkoxy groups of 1 to 4 carbon atoms, Y is a hydrogen atom, a hydroxyl group, an alkoxy group of 1 to 24 carbon atoms optionally substituted with an amino group, a polyalkenyloxy group of 2 to 24 carbon atoms containing 1 to 6 double bonds, an alkanoyl group of 1 to 25 carbon atoms, an alkenoyl group of 3 to 9 carbon atoms or a group of the formula R7-COO- wherein R7 represents a polyalkenyl group of 2 to 30 carbon atoms containing from 1 to 6 double bonds, X means a halogen atom, an amino group, an alkoxy group of 1 to 4 Carbon atoms, or X shape with B an oxygen atom, or X and Y together with the carbon atoms to which they are attached and the group -NR-0-CH2- which is between said carbon atoms form a ring of the formula a wherein Z represents an oxygen atom or a nitrogen atom, R means a hydrogen atom or R forms a chemical bond with B, A is an alkylene group of 1 to 4 carbon atoms or a chemical bond or a group of the formula b, in where R4 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, or a phenyl group optionally substituted with a halogen atom, an alkoxy group of 1 to 4 atoms of carbon or an alkyl group of 1 to 5 carbon atoms, R5 means a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or a phenyl group, has a value of 0.1 6 2, n has a value of 0, 1 or 2, or a salt by addition of physiologically acceptable acid thereof in mixture with one or more conventional carriers.

2. A pharmaceutical composition having an antitumor activity with reduced side effects, comprising a known active substance having an antitumor effect or, if desired and being chemically possible, a pharmaceutically suitable acid addition salt or a pharmaceutically suitable salt thereof and a hydroxyl acid derivative of the formula I, wherein R 1 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms, R 2 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a group cycloalkyl of 3 to 8 carbon atoms or a phenyl group optionally substituted by a hydroxyl group or a phenyl group, or R1 and R2 together with the nitrogen atom to which they are attached form a ring of 5 to 8 members optionally containing one or further nitrogen, oxygen or sulfur atoms, and the ring may be fused with another alicyclic or heterocyclic ring, preferably a benzene ring, naphthalene, quinoline, isoquinoline, pyridine or pyrazoline, furthermore, if desired and is chemically possible, the nitrogen and / or sulfur heteroatom (s) are present in the form of an oxide or dioxide, R3 signifies a hydrogen atom, a phenyl group , a naphthyl group or a pyridyl group in which the groups may be substituted with one or more halogen atoms or alkoxy groups of 1 to 4 carbon atoms, Y is a hydrogen atom, a hydroxyl group, an alkoxy group of 1 to 24 carbon atoms optionally substituted with an amino group, a polyalkenyloxy group of 2 to 24 carbon atoms containing 1 to 6 double bonds, an alkanoyl group of 1 to 25 carbon atoms, an alkenoyl group of 3 to 9 carbon atoms or a group of the formula R7-COO- wherein R7 represents a polyalkenyl group of 2 to 30 carbon atoms containing from 1 to 6 double bonds, X means a halogen atom, an amino group, an alkoxy group of 1 to 4 carbon atoms, or X for ma with B an oxygen atom, or X and Y together with the carbon atoms to which they are attached and the group -NR-0-CH2- which is between said carbon atoms form a ring of the formula a_ wherein Z represents an oxygen atom or a nitrogen atom, R means a hydrogen atom or R forms a chemical bond with B, A is an alkylene group of 1 to 4 carbon atoms or a chemical bond or a group of the formula b, wherein R 4 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, or a phenyl group optionally substituted with a halogen atom, an alkoxy group of 1 to 4 carbon atoms or an alkyl group of 1 to 5 carbon atoms, R5 means a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or a phenyl group, m has a value of 0, 1 or 2, n has a value of 0,16 2, or a salt by addition of physiologically acceptable acid of the ism in admixture with one or more conventional carriers.

3. A pharmaceutical composition according to claim 1 or 2, comprising an o-oxime O- (3-piperidino-2-hydroxy-l-propyl) nicotinic acid or a salt by addition of physiologically acceptable acid thereof as the acid derivative hydroxymetric of formula I.

4. A pharmaceutical composition according to any of claims 1 to 3, comprising cisplatin as the active substance having an antitumor activity.

5. A process for the treatment of a tumor state with increased effectiveness in which, in addition to a known active substance having antitumor activity or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable salt thereof, also an effective non-toxic amount of a hydroxyl acid derivative of the formula I, wherein R1, R2, R3, R, X, Y, A and B are as defined according to claim 1, or a pharmaceutically acceptable acid addition salt thereof, it is administered to the patient suffering from said condition.

6. A process for reducing the side effects of the treatment of a tumor state with an active substance having antitumor activity, which, in addition to a known active substance having antitumor activity or a pharmaceutically suitable acid addition salt or a pharmaceutically suitable salt thereof, Also, an effective non-toxic amount of a hydroxy acid derivative of the formula I is administered, wherein R 1, R 2, R 3, R, X, Y, A and B are as defined in claim 2, or a salt by adding pharmaceutically acceptable acid thereof, to the patient suffering from said condition.

7. A process according to claim 5 or 6, in which the known active substance having an antitumor effect is cisplatin, the hydroxyimic acid derivative of the formula I is the amidoxime of O- (3-piperidino-2-hydroxy) acid. 1-propyl) -nicotinic acid or a pharmaceutically acceptable acid addition salt thereof.

8. The use of a known active substance that has an antitumor effect or, if desired and is chemically possible, a pharmaceutically acceptable acid addition salt or a pharmaceutically suitable salt thereof and a hydroxyl acid derivative of the formula I, wherein R 1 , R2, R3, R, X, Y, A and B are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a pharmaceutical composition having improved antitumor activity.

9. The use of a known active substance which has an antitumor effect or, if desired and is chemically possible, a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable salt thereof and a hydroxyl acid derivative of the formula I, wherein R 1 , R 2, R 3, R, X, Y, A and B are as defined in claim 2, or a salt by addition of suitable pharmaceutically acceptable acid thereof for the preparation of a pharmaceutical composition having antitumor activity with reduced side effects.

10. The use of a hydroxyl acid derivative of the formula I, wherein R 1, R 2, R 3, R, X, Y, A and B are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof , to reduce the side effects that appear in the treatment of a tumor state with a known active agent that has antitumor activity.