Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-11-25
1996-11-26
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5482664, A61K 3141, C07D40506
Patent
active
055786308
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 93/01520 filed Jun. 14, 1993.
This invention relates to heterocyclic compounds which are inhibitors of the enzyme aromatase, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Oestrogens are responsible for many physiological functions in both females and males. Their action is mediated by specific intracellular hormone receptors expressed in oestrogen responsive cells. Oestradiol, the major oestrogen, is produced from oestrone which in turn is produced from androstenedione by aromatization of the A-ring. This reaction is catalysed by the predominantly ovarian enzyme aromatase although in post menopausal women aromatase located in adipose tissue is responsible for the synthesis of oestrogens (O'Neill and Miller, Br.J.Cancer (1987)).
Oestrogens are agonists in responsive tissues, such as breast, and are a major factor in the development of breast tumours. Thus, aromatase inhibitors have valuable therapeutic potential for the treatment of oestrogen responsive diseases, particularly breast cancer (Brodie, ISI Atlas of Science: Pharmacology (1987) 266-269 and Santen et al., J. Lab. Clin. Med. (1987) 109: 278-289) and have been the subject of active research world-wide, see for example, the work of Schieweck et al., Cancer Res. (1988) 48: 834-838; Wouters et al, J. Steroid Biochem., (1989) 32: 781-788; Bhatnagar et al., J. Steroid Biochem., (1990) 37: 1021-1027.
We have now found a novel group of compounds which are potent and selective aromatase inhibitors.
Thus the present invention provides a compound of general formula (I) ##STR2## wherein R.sup.1 represents a cyano or nitro group; R.sup.2 represents hydrogen or one or more halogen atoms; or a cycloalkyl group; and alkoxy groups and pharmaceutically acceptable salts and solvates thereof.
As used herein an alkyl or alkoxy group may be a straight or branched chain group, for example an alkyl group is conveniently a methyl, ethyl, propyl, isopropyl or butyl group. Halogen atom include fluorine, chlorine and bromine atoms.
The compounds of formula (I) contain at least one chiral carbon atom. It is to be understood that formula (I) is intended to encompass all enantiomers of the compounds of the invention as well as mixtures thereof, including racemic mixtures.
In a preferred group of compounds of formula (I) R.sup.2 represents hydrogen or one or more halogen atoms selected from chlorine or fluorine, preferably one or two fluorine atoms in the meta position of the benzene ring relative to substituent R.sup.1.
In a further preferred group of compounds of formula (I) R.sup.3 and R.sup.4 each independently represents a C.sub.1-6 alkyl group, especially a C.sub.1-3 alkyl group such as a methyl group.
In a further preferred group of compounds of formula (I) R.sup.5 represents hydrogen or one or more halogen atoms selected from chlorine or fluorine, preferably fluorine, or C.sub.1-3 alkoxy groups, preferably methoxy.
Compounds of formula (I) wherein R.sup.5 is other than hydrogen are preferably substituted in the 2 and/or 4-positions of the aromatic ring. However, compounds of formula (I) wherein R.sup.5 is hydrogen are particularly preferred.
In a particularly preferred group of compounds of formula (I) R.sup.1 represents a cyano or nitro group, R.sup.2 represents hydrogen or one or two fluorine atoms in the meta position of the benzene ring relative to substituent R.sup.1, R.sup.3 and R.sup.4 each represent a methyl group and R.sup.5 represents hydrogen.
Preferred compounds according to the invention include sobenzofuran-1-one; nzofuran-1-one; thyl]-3,5-difluorobenzonitrile; 1-one; thyl]-3-fluorobenzonitrile; and thyl]-benzonitrile, including individual enantiomers and racemic mixtures thereof and their pharmaceutically salts and solvates.
A particularly preferred compound according to the invention is 5-[(2,6-difluoro-4-nitrophenyl)-1,2,4-triazol-1-ylmethyl]-3,3-dimethyl-3H- isobenzofuran-1-one and its pharmaceutically acceptable salts and solvates.
Suitable pharmaceut
Cherry Peter C.
Foxton Michael W.
Merritt Andrew T.
Glaxo Group Limited
Morris Patricia L.
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