Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-05-09
1996-09-24
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514396, 5483361, A61K 31415, C07D23364
Patent
active
055591418
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to substituted imidazole derivatives, their stereoisomers and their non-toxic, pharmaceutically acceptable acid addition salts, and their preparation, to pharmaceutical compositions containing the same and their use.
The imidazole derivatives of the present invention have the general formulae (Ia) or (Ib): ##STR2## wherein one of R.sub.1 and R.sub.2 is CN and the other 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' is H or ##STR3## where R.sub.3 is H, CH.sub.3 or halogen; R.sub.4 is H and R.sub.5 is H or R.sub.4 and R.sub.5 together form a bond, n is 1 or 2 and y is 0, 1 or 2.
The compounds of formulae (Ia) and (Ib) are preferably para-substituted and preferably R' is H. For compounds of formula (Ia) preferably R.sub.1 is CN and R.sub.2 is H, CN, CF.sub.3, OCH.sub.3 or halogen; especially CN or F. For compounds of formula (Ib) preferably R.sub.1 and R.sub.2 are both CN or the substituent that is not CN is H or halogen; especially F; more preferably R.sub.1 is CN and R.sub.2 is H or halogen, especially F. Preferably y is 1 or 2.
The stereoisomers and the non-toxic pharmaceutically acceptable acid addition salts of these compounds are also within the scope of the invention.
The compounds of formulae (Ia) and (Ib) 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, surfaces, nitrates, phosphates, suffonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
The invention includes within its scope pharmaceutical compositions comprising at least some of the compounds of formula (Ia) and (Ib), their stereoisomers or a non-toxic, pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier therefor.
EP-A-0311447 describes diphenyl substituted imidazole derivatives which are stated to be aromatase inhibitors. Compounds in which a phenyl ring is substituted by a cyano group are not disclosed. EP-A-0390558 describes diphenyl substituted imidazole derivatives which are stated to be aromatase inhibitors. Compounds in which a phenyl ring is substituted by a cyano group are not specifically disclosed or exemplified; nor are any test data given for such compounds.
The compounds of the present invention possess selective aromatase inhibiting properties, compared with their desmolase inhibiting properties, and are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer or benign prostatic hyperplasia (BPH). Moreover the compounds of the present invention are unexpectedly more potent aromatase inhibitors than corresponding compounds having no CN substituent(s) in the phenyl ring(s). Interestingly the selectivity of the unsaturated compounds of formulae (Ia) and (Ib) seems to be regulated by the geometric isomerism so that the selectivity ratio of certain configurations is more than one thousand.
Compounds of formula (Ia) can be prepared by reacting a ketone of the formula (IIa) ##STR4## wherein R' is a protecting benzyl group, n is 1 to 2 and R'.sub.2 is H, CH.sub.3, OCH.sub.3, CF.sub.3, CHF.sub.2, CH.sub.2 F or halogen, with an appropriate reagent of the formula (IIIa) ##STR5## wherein Hal is halogen, especially bromide, and Z is a protecting group, such as a tenbutylaminocarbonyl group, --CONHC(CH.sub.3).sub.3, or an oxazoline group, in an appropriate solvent, e.g. tetrahydrofuran, in the presence of an alkyl lithium, for example n-butyl lithium, or magnesium to give compounds of formula (IVa) ##STR6## wherein Z, R'.sub.2, R' and n are as defined for formulae (II) and (IIIa). Compounds of formula (IVa) are further dehydrated by refluxing with e.g. SOCl.sub.2, POCl.sub.3 or PCl.sub.5 optionally in an appropriate solvent such as acetonitrile. The protecting group Z reacts at the same time to form compounds of formula (Va) ##STR7## wherein R', n and R'.sub.2 are as defined for formula (IIa). The unsaturated comp
REFERENCES:
patent: 5439928 (1995-08-01), Karjalainen et al.
Kalapudas Arja M.
Karjalainen Arto J.
Laine Aire M.
Lammintausta Risto A.
Pelkonen Reino O.
Kubovcik Ronald J.
Morris Patricia L.
Orion-yhtyma Oy
LandOfFree
Selective aromatase inhibiting 4(5)-imidazoles does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Selective aromatase inhibiting 4(5)-imidazoles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Selective aromatase inhibiting 4(5)-imidazoles will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1928719