DE3229169A1 - Use of 5-alkylpyrimidine nucleosides and their derivatives as cytostatics - Google Patents

Abstract

Use of 5-alkylpyrimidine nucleosides and their derivatives as cytostatics in combination with arabinonucleosides as well as pharmaceuticals of this composition.

Description

Use of 5-alkylpyrimidine nucleosides and their

Derivatives as cytostatics The present invention relates to the use of 5-alkylpyrimidine nucleosides and their derivatives as cytostatics in combating malignancies in combination with arabinonucleosides and to potentiate the cytostatic effects of arabinonucleosides and drugs with cytostatic effect, which as active ingredients aese nucleosides in combination contain.

It is known that various pyrimidine nucleosides and some of their derivatives have a cytostatic effect (DE-OS 29 18 260, DE-OS 29 20 738, DE - OS 29 30 904, Dr - OS 30 10 397, DE - OS 30 10 399, Ungar. Patient

171 306).

It is also known that some arabinonucleosides, e.g.

Cytosine arabinoside (AraC) are cytostatically effective.

However, a disadvantage of these compounds is their sometimes high toxicity, so that the therapeutic index is low and an application of the means is not without it Problems, especially when they have to be dosed in high doses. Other disadvantages are undesirable side effects, such as Mutagenicity and teratogenicity as well as unfavorable pharmacokinetic behavior.

Attempts have therefore been made again and again, by combination the known cytostatic agents with other cytostatic substances or completely other active ingredients to eliminate these disadvantages. The cytostatic effect of the Combination should be achieved through synergism (addition of effects or potentiation) with less Toxicity must be much stronger than that of the individual components.

Studies with such combinations have been described variously e.g. in medic. Forsch. 20 (6), 781 (1970), Arzneimittel. Forsch. 22 (7), 1184 (1972), 4rzneim. Fcrsch. 22 (8), 1421 (1972), Medic. Forsch. 28 (9), 1564 (1978) or are the subject of patent applications, e.g.

- OS 29 20 738, DE - OS 30 10 397 and DE - OS 20 30 904.

The known disadvantages of the cytostatic agents could however, by means of all the combinations described, it has not yet been satisfactory be eliminated. For example, the combination lotions are still too few effective. The means have to be dosed aaher high, whereby the organism through the toxic effect is heavily burdened.

Surprisingly, it has now been found that the indunksgemliche combinations of 5- «olpyrimidine nucleosides and their derivatives of the general formula I wherein R1 is a hydrogen atom, a halogen atom, a straight or branched alkyl radical with 1 to 10 carbon atoms, a straight or branched alkenyl radical with 2-6 carbon atoms, a straight-chain or branched (C2-C6) haloalkyl or (C2 - C6) haloalkenyl radical, an optionally substituted phenyl or eenzyl radical, HH or halogen, Y is -H, where R³ is - (C # - C #) - alkyl 6 n = 1 - 4, where R = H, straight or branched (C1 - C6) - alkyl, R5 and R6, which can be the same or different, a hydrogen atom, a straight or branched alkyl group with 1 to 6 carbon atoms, a phenyl, benzyl or perfluoroalkyl groups with 1 to 6 carbon atoms, n = 0 - 8, where Hal = F and Cl are, in combination with arabinonucleosides, for example

AraO (cytosine arabinoside) 5-fluoro-AraC 5-Ohloromercuri-AraC 5-chloro-AraC one have a strong cytostatic effect, which is the sum of the effects of the individual components far exceeds. The synergistic effect of the two components can be seen in in vitro, e.g. in cell culture on L-1210 mouse leukemia cells.

The compounds of the general formula I are either known or can be produced in a manner known per se, e.g. also DE-PS 1 620 185, DE - OS 30 10 397, DE - Pat. Ann. 31 41 199.

These compounds can be in the oC and / or B form. Particularly preferred compounds of formula I are: wherein R denotes an ethyl group and R2 denotes a hydrogen atom and 1. Y denotes -H - Cl stands.

The pharmaceutical preparations according to the invention with a content of at least one of the compounds according to claim 1 in combination with an arabinonucleside can be used in powder, powder, suspensions, solutions, emulsions, sprays, pastes, Ointments, creams, tablets and coated tablets are available and parenteral (intravenous, intradermal, intramuscular, intrathecal, etc.), oral, rectal, intravaginal, intranasal or local administered.

The pharmaceuticals according to the invention are prepared by mixing or dissolving the active ingredients together with or in pharmaceutically customary contractual Auxiliaries, additives and / or carriers, such as aqueous or non-aqueous solvents, Stabilizers, emulsifiers, suspending agents, dispersing agents and wetting agents and the like. as well as suitable additives and, if necessary, coloring and flavoring substances.

The medicaments according to the invention are used as cytostatics for treatment can be used advantageously for malignant diseases.

By combining the described nucleosides and their derivatives with arabinonucleosides potentiation results in a strong cytostatic Effect that far exceeds the sum of the effects of the individual components. the Exposure to the organism through toxic compounds and undesirable side effects can be reduced by a lower dosage. kuerdem can be kl give a large number of potent drugs more advantageously than larger doses weakly effective means.

Claims (4)

Claims 1. Use of 5-alkylpyrimidine nucleosides and their derivatives of the general formula I. wherein R is a hydrogen atom, a halogen atom, or a branched alkyl radical with 1 to. 10 carbon atoms, a branched or branched alkenyl radical with 2-6 carbon atoms, a straight-chain or branched (C2 - C6) haloalkyl or (C2 - C6) haloalkenyl radical, an optionally substituted phenyl or benzyl radical, R² is H or halogen, Y -H, where R³ = H (C1 -C6) -alkyl, n = 1 - 4, where R4 = H, straight or branched (C1 - C6) - alkyl, R5 and R6, which can be the same or different, a hydrogen atom, a straight or branched alkyl group with 1 to 6 carbon atoms, a phenyl, benzyl or perfluoroalkyl groups with 1 to 6 carbon atoms, n = 0 - 8, where Hal = F and Cl, mean in the fight against malignant diseases. 2. Use of 5-alkylpyrimidine nucleosides and their derivatives ndch Claim 1 for potentiating aer virkun of cytostatically active arabinonucleosides. 3. Medicines for the treatment of malignant diseases, marked by a content of at least one compound according to claim 1 4th Medicament according to Claim 3, containing at least one compound as active ingredient according to claim 1 together with an arabinonucleoside in a conventional pharmaceutical compatible carrier or diluent, optionally in conjunction with one pharmaceutically acceptable formulation agents.