Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-11-16
1996-02-27
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142268, 5142288, 514275, 514326, 514340, 514378, 514619, 514626, 544322, 544326, 544328, 544330, 544331, 544 54, 544 55, 544 96, 546206, 546275, 548248, 564194, 564195, 564196, 564197, 564198, 564163, 564168, A61K 3141, C07D26106
Patent
active
054949114
DESCRIPTION:
BRIEF SUMMARY
A number of processes for the preparation of isoxazole-4-carboxamides have been described in the literature (DE 2,524,959; DE 2,655,009; DE 3,405,727).
It is known from European Patent Specification 13,376 that 5-methylisoxazole-4-carboxylic acid-(4-trifluoromethyl)anilide can be employed as an antirheumatic, antiinflammatory, antipyretic and analgesic owing to its pharmacological properties, and is used for the treatment of multiple sclerosis. Processes for the preparation of this compound are also described therein.
It has now been found that isoxazole-4-carboxamides of the formula I and hydroxyalkylidenecyanoacetamides of the formula Ia and their tautomeric form Ib have antitumor activity. Many of the known antitumor agents cause nausea, vomiting or diarrhea as adverse effects during treatment, which also make medical treatment in hospital necessary. In addition, these pharmaceuticals also modify the growth rate of other body cells, which then leads to symptoms such as, for example, hair loss or anemia. It was not possible to observe these symptoms in the treatment of humans and animals with the compounds of the formula I. In contrast to the cytotoxic anticancer agents known to date, these active compounds do not have the property of impairing the immune system (Bartlett, Int. J. Immunopharmac., 1986, 8: 199-204). Novel routes of tumor therapy are thus opened up as the body's defense system is not impaired, while tumor cells are prevented from growth. Surprisingly, a plurality of tumor cells are inhibited by these active compounds, while cells of the immune system, such as, for example, T lymphocytes are only inhibited at a concentration of up to 50 times higher.
The invention therefore relates to the use of at least one compound of the formula I, Ia and Ib ##STR1## its possible stereoisomeric forms and/or if appropriate at least one of its physiologically tolerable salts, in which 13 carbon atoms and 1 to 4 heteroatoms from the group comprising oxygen, sulfur and nitrogen, of which a maximum of 1 is different from nitrogen, in the ring system, unsubstituted or mono- or polysubstituted by halogen, such as fluorine, chlorine, bromine or iodine, halogen, such as fluorine, chlorine, bromine or iodine, ##STR2## in which R.sup.4, R.sup.5 and R.sup.6 can be identical or different and are halogen, such as fluorine, chlorine, bromine or iodine, phenyl ring of the formula II, form a naphthalene ring, methylenedioxy radical, halogen, such as fluorine, chlorine, bromine or iodine, halogen, such as fluorine, chlorine, bromine or iodine, chlorine, bromine or iodine, such as fluorine, chlorine, bromine or iodine, bonded, form a 4- to 9-membered ring, substituted by bonded, form a 5- to 6-membered ring of the formula IV ##STR3## in which W is 1) --CH.sub.2 --, ##STR4## 6) --CH.sub.2 --O--or such as fluorine, chlorine, bromine or iodine, pharmaceuticals for the treatment of carcinoses.
Among these pharmaceuticals, the compound 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide (compound 1) and N-(4-trifluoromethyl)-2-cyano-3-hydroxycrotonamide (compound 2) are preferred.
Suitable physiologically tolerable salts of the compound of the formula I are, for example, alkali metal, alkaline earth metal and ammonium salts including those of organic ammonium bases.
The mono-, di- or trinuclear unsaturated heterocyclic radicals having 3 to 13 carbon atoms include, for example, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, thiazolinyl, oxazolyl, thiadiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, pyrazolyl, acridinyl, indolinyl, tetrazolyl or indazolyl.
The compound of the formula I and its physiologically tolerable salts are particularly suitable for the treatment of a plurality of carcinoses. The types of cancer which are especially inhibited by these compounds include, for example, leukemia, in particular chronic leukemia of the T and B cell type, lymph node cancer, for example Hodgkin's or non-Hodgkin's lymphoma, carcinomas, sarcomas or skin cancer. The active compounds can either
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Chemotherapy of Cancer, Second Ed., Carter et al., John Wiley & Sons, pp. 364-365, 1981.
Robert R. Bartlett, "Immunopharmacological Profile of HWA 486, A Novel Isoxazol Derivative--II. In Vivo Immunomodulating Effects Differ From Those of Cyclophosphamide, Prednisolone, or Cyclosporin A," Int. J. Immunopharmac., vol. 8, No. 2, pp. 199-204, 1986.
R. R. Bartlett, et al., "Development of Autoimmunity in MRL/lpr Mice and the Effects of Drugs on This Murine Disease," Scand. J. Rheumatology 1988; Suppl. 75: 290-299.
Bartlett Robert R.
Kammerer Friedrich-Johannes
Hoechst Aktiengesellschaft
McKane Joseph K.
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