Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-21
1998-09-01
Lambkin, Deborah
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
562405, 562490, 560 8, 560100, 564180, 556465, 556489, C07D33308, C07C 6300, C07C 6976, C07C23300
Patent
active
058012532
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/03021 Jul. 29, 1995.
The present invention relates to novel retinoic acid X-receptor (RXR) ligands. More particularly, the present invention relates to compounds of the formula I: ##STR1## wherein the dotted bond is optional; and, when the dotted bond is present, R.sup.1 is lower alkyl and R.sup.2 is halogen, or R.sup.1 and R.sup.2 taken together with the carbon atoms to which they are attached form a 5-8 membered carbocyclic ring or a 5-8 membered heterocyclic ring containing one sulfur, oxygen or nitrogen atom, wherein, when said ring is aromatic, the dotted bond is part of the mesomeric system; or, when the dotted bond is absent, R.sup.1 and R.sup.2 taken together are methylene to form a cis-substituted cyclopropyl ring; R.sup.3 is hydroxy or lower alkoxy; R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are, independently, hydrogen or lower alkyl; X is (>CR.sup.8 R.sup.9).sub.n ; and n is 1,2 or 3; R.sup.8, R.sup.9 are, independently, hydrogen or lower alkyl; R.sup.10 is hydrogen, alkyl or alkoxy;
As used herein the term "lower" denotes groups containing 1-4 carbon atoms. Lower alkyl groups may be straight chained or branched. Preferred are methyl and ethyl. The term "halogen" includes fluorine, chlorine, bromine and iodine with bromine being preferred. Examples of 5-8 membered carbocyclic rings formed by R.sup.1 and R.sup.2 together with the carbon atoms to which they are attached are benzene, cyclopentene, cyclohexene, cycloheptene of which benzene is preferred. Examples of 5-8 membered heterocyclic rings formed by R.sup.1 and R.sup.2 together with the carbon atoms to which they are attached are thiophene, furan, dihydro furan and pyridine of which thiophene is preferred. R.sup.4 -R.sup.7 are preferably lower alkyl, most preferably methyl. X is preferably ethylene. R.sup.10 is preferably hydrogen. When the optional dotted bond is present and part of the mesomeric system of an aromatic ring, this means that the additional bond is considered to be delocalized over the ring as described in the classical model of aromaticity.
The compounds of formula I wherein R.sup.3 is hydroxy form salts with pharmaceutically acceptable bases such as alkali salts, e.g. Na and K-salts, and ammonium or substituted ammonium salts such trimethylammonium salts which are within the scope of this invention.
In one aspect the invention comprises compounds of the formula: ##STR2## wherein R.sup.1 is lower alkyl and R.sup.2 is halogen, or R.sup.1 and R.sup.2 taken together with the carbon atoms to which they are attached form a 5-8 membered carbocyclic ring or a 5-8 membered heterocyclic ring containing one sulfur, oxygen or nitrogen atom, wherein, when said ring is aromatic, the double bond between the carbon atoms adjacent to R.sup.1 and R.sup.2 is part of the mesomeric system; R.sup.3 -R.sup.7, R.sup.10 and X are as in formula I;
In another aspect the invention preferably comprises compounds of the formula: ##STR3## wherein R.sup.3 -R.sup.7, R.sup.10 and X are as in formula I; and pharmaceutically acceptable salts of carboxylic acids of formula Ib.
Especially preferred compounds of formula Ia are compounds of the formula: ##STR4## wherein R.sub.1 through R.sup.7 are as in formula Ia. Particularly preferred are compounds of formula Ia(1) in which R.sup.4 -R.sup.7 are all methyl, and R.sup.1 -R.sup.3 are as in formula Ia. Most preferred are compounds of formula Ia(1) in which R.sup.4 -R.sup.7 are all methyl and R.sup.3 is hydroxyl and R.sup.1 -R.sup.2 are as in formula Ia.
Especially preferred compounds of formula Ib are compounds of the formula: ##STR5## wherein R.sup.1 through R.sup.7 are as in formula Ib. Particularly preferred are compounds of formula Ib(1) in which R.sup.4 -R.sup.7 are all methyl, and R.sup.3 is as in formula Ib.
The invention also comprises the pharmaceutically acceptable salts of carboxylic acids of the compounds of formulas Ia(1) and Ib(1).
The compounds of this invention demonstrate a high degree of selectivity toward the RXR family of receptors. They are useful as anti pr
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Klaus Michael
Lovey Allen John
Mohr Peter
Rosenberger Michael
Hoffmann-La Roche Inc.
Johnston George W.
Lambkin Deborah
Pokras Bruce A.
Tramaloni Dennis P.
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