Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-19
1997-12-30
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5482674, A61K 3141, C07D24908
Patent
active
057031096
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel heterocyclic diarylalkyl compounds, their stereoisomers and their non-toxic, pharmaceutically acceptable acid addition salts, and their preparation, to pharmaceutical compositions containing the same and their use.
The compounds of the present invention have the general formula (I): ##STR1## wherein R.sub.1 is H, CH.sub.3, OCH.sub.3, NO.sub.2, NH.sub.2, CN, CF.sub.3, CHF.sub.2, CH.sub.2 F or halogen, R.sub.2 is a heterocyclyl radical selected from 1-imidazolyl, triazolyl, especially 1-1,2,4-triazolyl, tetrazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl and isothiazolyl, R.sub.3 is H or OH, R.sub.4 is H, R.sub.5 is H or OH; or R.sub.4 is H and R.sub.3 and R.sub.5 combined form a bond; or R.sub.3 is H and R.sub.4 and R.sub.5 combined form .dbd.O; R.sub.6 is methylene, ethylene, --CHOH--, --CH.sub.2 --CHOH--, --CHOH--CH.sub.2 --, --CH.dbd.CH-- or --C(.dbd.O)--; or R.sub.4 is H and R.sub.5 and R.sub.6 combined is .dbd.CH-- or .dbd.CH--CH.sub.2 --; stereoisomers thereof and non-toxic pharmaceutically acceptable acid addition salts thereof.
The compounds of formula (I) and their stereoisomers form acid addition salts with both organic and inorganic acids. They can thus form many pharmaceutically usable acid addition salts, as for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, titrates, benzoates, salicylates, ascorbates and the like.
The invention includes within its scope pharmaceutical compositions comprising at least one compound of formula (I), a stereoisomer or a non-toxic, pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier therefor. EP-A-0390558 describes diphenyl substituted 4(5)-imidazolyl derivatives which are disclosed to be aromatase inhibitors. U.S. Pat. No. 4,978,672 describes diphenyl substituted 1-1,2,4- and 1-1,3,4-triazolyl derivatives wherein the carbon chain between the phenyl groups is preferably methyl, such as Pat. No. 4,937,250 describes diphenyl substituted 1-imidazolyl derivatives, U.S. Pat. No. 5,071,861 describes diphenyl substituted 3-pyridyl derivatives and U.S. Pat. No. 5,073,574 describes diphenyl substituted 1- and 2-tetrazolyl derivatives. The derivatives of the above mentioned U.S. patents are also stated to be aromatase inhibitors.
The compounds of the present invention have selective aromatase inhibiting properties, compared with their desmolase inhibiting properties. They are therefor valuable in the treatment of estrogen dependent diseases, e.g. breast cancer or benign prostatic hyperplasia (BPH). The selectivity of the compounds of formula (I) is regulated by the stereochemical isomerism.
The absolute stereochemical configuration of the compounds of formula (I) is not experimentally determined. It is conventionally agreed to designate the stereoisomers as "a", "b" and so on, without further reference to the absolute stereochemical configuration.
Stereoisomers of the compounds of formula (I) are naturally intented to be embraced within the scope of the invention.
Compounds of formula (I) can be prepared by reacting a halogenide of the formula (II) ##STR2## wherein Hal is a halogen, preferably bromide or chloride, n is 1 or 2, R.sub.1 is as described before and R.sub.7 is CN or other functional group which may be convened to cyano group by methods that are common in preparative organic chemistry, with a heterocyclic compound R.sub.2 'H wherein R.sub.2 ' is 1-imidazolyl, 1-1,2,4-, 4-1,2,4-, 1-1,2,3- or 2-1,2,3-triazolyl or 1- or 2-tetrazolyl, in an appropriate solvent to give compounds of formula (III). ##STR3##
The heterocyclic compound is preferably in the form of its salt, preferably sodium salt. The starting compounds (II) can be prepared by conventional methods from an optionally substituted benzaldehyde and an appropriate benzene derivative.
The corresponding compounds of formula (III) wherein the R.sub.2 ' is 4-1,2,3-, 3-1,2,4-triazolyl or 5-tetrazolyl may be prepared by the method described above in the presence o
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Kalapudas Arja Marketta
Karjalainen Arto Johannes
Laine Aire Maria
Lammintausta Risto Arvo Sakari
Pelkonen Reino Olavi
Morris Patricia L.
Oy Orion-yhtyma
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