Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-18
1997-01-21
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546285, 546340, 546342, A61K 3144, C07D21355
Patent
active
055959954
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00890 filed Apr. 29, 1993.
BACKGROUND OF THE INVENTION
1. Field of the invention
This invention relates to derivatives containing a 3- or 4-pyridyl group, namely 3- and 4-pyridylcarbinol esters of adamantanecarboxylic acid and adamantyl 2-(3- and 4-pyridyl)ethyl ketones, together with certain derivatives thereof, their preparation and use in treating prostatic cancer.
2. Description of related art
R. McCague, M. G. Rowlands, S. E. Bartie and J. Houghton, J. Med. Chem. 33, 3050-3055 (1990), have reported that certain esters of 4-pyridylacetic acid, of general formula: ##STR2##
wherein R.sup.a represents a specified alicyclic group (e.g. cyclohexyl or a terpene residue) or ##STR3##
wherein R.sup.b represents a hydrogen atom or a methyl group, inhibit the 17.alpha.-hydroxylase/C.sub.17-20 lyase enzyme complex which is essential for biosynthesis of androgens. The inhibition of androgen biosynthesis by virtue of the hydroxylase/lyase inhibition indicates that the compounds of McCague et al., supra, could be useful for the treatment of prostate cancer since many such tumours depend on androgens for growth.
The compounds of McCague et al. are also inhibitors of aromatase. Aromatase is an enzyme required in the biosynthesis of oestrogens. The ability to inhibit aromatase is considered a desirable property in compounds which are to be used to treat breast cancer. It is undesirable, however, for the treatment of prostatic cancer that a compound should be a strong inhibitor of both aromatase and hydroylase/lyase since the inhibition of aromatase would prevent the removal, by further conversion into oestrogens, of any products of the hydroxylase/lyase enzyme complex which escaped the blockade of hydroxylase/lyase. As a result, a patient could lose some of the benefits of hydroxylase/lyase inhibition. Accordingly, It is desirable to keep the lyase:aromatase inhibition ratio: ##EQU1## as low as possible. (A small numerator indicates that the compound is a powerful inhibitor of lyase. A large denominator indicates that it is a poor inhibitor of aromatase). Further prior art, the relevance of which is apparent only after knowledge of the invention, is referred to below in a separate section.
SUMMARY OF THE INVENTION
It has now surprisingly been found that compounds of formula (3) below have useful hydroxylase/lyase inhibitory activity with low IC.sub.50 lyase/aromatase ratios, and are therefore of potential value in treating androgen-dependent cancers such as prostatic cancer. These compounds have the general formula: ##STR4##
wherein each of R.sup.1 and R.sup.2 independently represents hydrogen or lower alkyl;
A represents --O--, or --CR.sup.4 R.sup.5 where R.sup.4 and R.sup.5 are defined as for R.sup.1 or R.sup.2 ;
R.sup.3 represents an adamantyl group; and
Py represents a 3- or 4-pyridyl group, as free bases or their pharmaceutically acceptable salts, especially acid addition salts. The term "lower" herein signifies that the group has 1 to 4 carbon atoms. The invention includes each of the optical isomers and mixtures thereof, especially racemic mixtures.
ADDITIONAL DESCRIPTION OF PRIOR ART
EP-A 253,681 (Farmatalia Carlo Erba) describes a class of compounds of formula ##STR5##
wherein 4-Py is the 4-pyridyl group, R is alkyl of 1-4 carbon atoms, --A--B-- has a variety of meanings including the "reverse amide" linkage --NH--CO-- and n is 1 to 5, preferably 4, i.e. the preferred cyclic group is cyclohexyl. These compounds are described as aromatase inhibitors useful, inter alia in the treatment of prostatic hyperplasia. However, applicants have found that these "reverse amides" of cyclohexanecarboxylic acid are POOR inhibitors of hydroxylase and lyase. Indeed, the reverse amide analogues of the compounds of formula (3), whereby A represents --NH-- are LESS GOOD inhibitors than the compounds of formula (3). As shown in the Table, at the end of the Examples, the cyclohexanecarboxylic acid reverse amide had an IC.sub.50 against lyase of 10 and against hydroxylase of 40, which ar
REFERENCES:
McCaque et al. "Inhibition of enzymes of estrongen . . . " Jour of Medicinal Chemistry, vol. 33 (1990), Washington, D.C. pp. 3050-3055.
D. Skwarski et al. "Sythesis of N-substituted . . . " Chemical Abstracts vol. 11 (No. 4) (14 Aug. 1989), Abstracts #57109g, p. 701. Acta Pol Pharm, 45 (4), 301-5.
CA 84(7)#43851e DE 2428294 (Merck) see formulae. (1976).
CA 79(23) #132815k & J. Med. Chem, 16(7), 865-7, see formulae. (1973).
CA 69(1) #2828z & J Med Chem. 11(2), 180-1. See formulae and anstract. (1968).
W. K. Amery et al., Drug Development Research, vol. 8, pp. 299-307, (1988).
M Ayub et al., Journal of Steroid Biochemistry, vol. 28, No. 5, pp. 521-531, (1987).
Chan Ferdinand
Jarman Michael
Potter Gerard A.
British Technology Group Limited
Rotman Alan L.
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