Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1992-11-24
1996-05-07
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514218, 514283, 514318, 424114, A61K 3170, A61K 3155, A61K 3144, A61K 3500, A61K 31445
Patent
active
055146643
DESCRIPTION:
BRIEF SUMMARY
FIELD OF USE OF THE INVENTION
The invention relates to a new use of known dihydropyridines. The dihydropyridines can be employed in the pharmaceutical industry for the preparation of new medicaments.
KNOWN TECHNICAL BACKGROUND
The development of resistances to one or more active compounds (drug resistance, multidrug resistance =MDR) is an ever increasing problem in the therapy of certain diseases, thus, for example, in the chemotherapy of tumour diseases or in the treatment of malaria.
The use of so-called calcium antagonists, and in this context in particular 1,4-dihydropyridines, for overcoming "drug resistance" or "multidrug resistance (MDR)" has thus been under discussion for a few years see e.g. EP-A-0 221 382; EP-A-0 353 692; M. Kamiwatari et al., Cancer Research 49, 3190 (1989); I. Nogae et al., Biochem. Pharm. 38, 519 (1989) or D. J. Krogstad et al., Science 238, 1283 (1987)!. Because of the marked influence which many of the calcium antagonists investigated have on the cardiovascular system, the search for suitable "MDR blockers" has concentrated on those 1,4-dihydropyridines which display only a mild calcium-antagonistic activity T. Yoshinari et al., Cancer Chemother. Pharmacol. 24, 367 (1989)!.
The use of certain optically pure 1,4-dihydropyridines, which have a comparatively small influence on the cardiovascular system, for the preparation of medicaments for the treatment of tumour disease is claimed in International Patent Application WO 89/07443, which corresponds to application Ser. No. 07/881,319, filed on May 7, 1992.
DESCRIPTION OF THE INVENTION
It has now been found that the 1,4-dihydropyridines described in more detail below are outstandingly capable of increasing the activity of cytostatics against tumour cells (synergism) and of overcoming the resistance of tumour cells to certain cytostatics. Surprisingly, it has also been found that overcoming of resistance is not limited to resistances to cytostatics, but that resistances to other therapeutics (e.g. for the treatment of malaria) are also overcome.
The invention therefore relates to the use of optically pure 1,4-dihydropyridines of the formula I ##STR2## wherein R1 denotes 1-6C-alkyl or 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or partly substituted by fluorine, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylamino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or partly substituted by fluorine, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylamino, (--CH.sub.2).sub.m --E--(CH.sub.2).sub.n -- or the grouping --A1--O--A2--, bonded, represent a radical of the formula ##STR3## wherein A denotes --CH.sub.2 --CH.sub.2 --C(R7)R8--CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CHR9--CH.sub.2 --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --CHR10--, ##STR4## wherein R11 and R12 are identical or different and denote hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl, trifluoromethyl or, together, methylenedioxy, medicaments which are to be used for improving the action of antibiotics and/or cytostatics and/or for overcoming resistances to antibiotics and/or cytostatics.
1-6C-Alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl or, in particular, ethyl or methyl radical.
1-4C-Alkyl is straight-chained or branched and denotes, for example, a butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl or, in particular, methyl radical.
1-4C-Alkoxy contains, in addition to the oxygen atom, one of the abovementioned 1-4C-alkyl radicals. The methoxy and the ethoxy radical are preferred.
1-4C-Alkoxy-2-4C-alkyl represents a butyl, propyl or, in particular, ethyl radical which is substituted by one of the abovementioned 1-4C-alkoxy radicals. The methoxyethyl radical is preferred.
Halogen in the context of the invention denotes bromine, fluorine and, in particular, chlorine.
1-4C-Alkoxy which is completely or partly substituted by fluorine
REFERENCES:
Cancer Research, vol. 50, No. 5, Mar. 1, 1990, pp. 1645-1649.
Naunyn-Schmiedeberg's Arch Pharmacol. vol. 341 (Suppl.) 1990, p. R45, abstract No. 177.
Nature, vol. 345, May 17, 1990, pp. 253-256.
Nature, vol. 345, May 17, 1990, pp. 202-203.
International Journal of Cancer, vol. 47, No. 6, Apr. 1, 1991, pp. 870-874.
Proc. Natl. Acad. Sci., vol. 84, pp. 7310-7314, Oct. 1987.
Am. J. Trop. Med Hyg. 39(1), 1988, pp. 15-20.
Cell, vol. 57, Jun. 16, 1989, pp. 921-930.
Proceedings of 81st annual meeting of the Amer. Assoc. for Cancer Research, vol. 31, Mar. 1990, p. 350 abstract only.
Carter et al., Chemotherapy of Cancer, 2nd Ed, John Wiley & Sons, N.Y., N.Y. 1981, pp. 84 & 85.
ByK Gulden Lomberg Chemische Fabrik GmbH
Goldberg Jerome D.
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