Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Patent
1995-01-31
1996-10-22
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
A61K 3112
Patent
active
055677380
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/9B93/01669 filed Aug. 6, 1993.
The present invention relates to the treatment of cancer. More particularly, the invention is concerned with the use of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone and physiologically acceptable salts and physiologically functional derivatives thereof as anti-tumour agents, and the use of said compound for the manufacture of medicaments for the treatment of cancer.
Research in the area of cancer chemotherapy has produced a variety of anti-tumour agents, which have differing degrees of efficacy. Standard clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cis-platinum, vincristine and vinblastine. However, these presently available anti-tumour agents are known to have various disadvantages, such as toxicity to healthy cells, and common side effects of anti-tumour drugs include alopecia and skin toxicity.
The compound 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy- 1,4-naphthoquinone has previously been disclosed, for example in European Patent No. 123,238 which relates to 2-substituted-3-hydroxy-1,4-naphthoquinones of formula (I) ##STR1## wherein either R.sup.1 is hydrogen and R.sup.2 is selected from C.sub.1-6 alkoxy, aralkoxy, C.sub.1-6 alkyl-C.sub.1-6 alkoxy, phenyl substituted by one or two groups selected from halogen and C.sub.1-6 alkyl, halogen and perhalo-C.sub.1-6 alkyl or R.sup.1 and R.sup.2 are both C.sub.1-6 alkyl or phenyl, and n is zero or 1, and physiologically acceptable salts thereof. The compounds are said to have antiprotozoal activity. Specifically, compounds of formula (I) wherein n is zero are said to be active against the human malaria parasite Plasmodium falciparum and also against Eimeria species such as E.tenella and E.acervulina, which are causative organisms of coccidiosis and compounds of formula (I) where n is 1 are said to be active against protozoa of the genus Theileria, in particular T.annulata or T.parva. Amongst the compounds specifically named and exemplified is the compound of formula (I) wherein n is zero, R.sup.1 is hydrogen and R.sup.2 is 4-chlorophenyl, i.e. 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone.
It has now surprisingly been found that 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, represented in this specification by formula (II): ##STR2## exhibits activity against tumour cells, more specifically against carcinoma, adenocarcinoma and fibrosarcoma cells.
Thus, in a first aspect the present invention provides the use of the compound of formula (II) and physiologically acceptable salts and other physiologically functional derivatives thereof for the manufacture of a medicament for the treatment of tumours in mammals (including humans).
According to a further aspect the present invention provides a method for the treatment of tumours in mammals, including humans which comprises the administration of an effective amount of a compound of formula (II), or a physiologically acceptable salt or other physiologically functional derivative thereof.
Treatment is particularly important for immunocompromised individuals, such as people with AIDS, who are more susceptible to certain types of tumour than people with a normally functioning immune system.
The hydroxyl group in the compound of formula (II) may form salts with appropriate bases, and physiologically acceptable salts of the compound (II) include inorganic base salts such as alkali metal (e.g. sodium and potassium) salts and alkaline earth metal (e.g. calcium salts; organic base salts e.g. phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine and diethanolamine salts; and amino acid salts e.g. lysine and arginine.
Physiologically functional derivatives of formula (II) are derivatives which are converted in vivo to a compound of formula (II). Such derivatives include those described in EPO362996 and EPO537947.
It will be appreciated that the compound of formula (II) may exist as the cis or trans isomer, that is to say that the cyclohexyl ring may be cis or trans s
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Glaxo Wellcome Inc.
Goldberg Jerome D.
Neuner George W.
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