2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors
AssigneeAllergan Sales, Inc.
InventorsVidyasagar Vuligonda, Kwok Yin Tsang, Jayasree Vasudevan, Roshantha A. Chandraratna
Life of this patent
Estimating the term…
Abstract
Compounds of Formula 1, Formula 2 or Formula 3 where X is O, S, or (CR.sub.1 R.sub.1).sub.n where n is 0, 1 or 2; Y is a bivalent radical having Formula 4 or Formula 5 where o is an integer from 1 to 4 ##STR1## or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C.sub.1-6 alkyl or with 1 to 3 C.sub.1-6 fluoroalkyl groups; and the remaining symbols have the meaning described in the specification, have RXR selective retinoid agonist-like activity.
Claims27
A compound of Formula 1, Formula 2 or of Formula 3 ##STR26## where X is O, S, or (CR.sub.1 R.sub.1).sub.n where n is 0, 1 or 2;
- Y is a bivalent radical having Formula 4 or Formula 5 where o is an integer between 1 through 4 ##STR27## or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C.sub.1-6 alkyl or with 1 to 3 C.sub.1-6 fluoroalkyl groups with the proviso that when the compound is in accordance with Formula 2 then Y is not a 5 or 6 membered ring;
- X.sub.1 is S or NH;
- R.sub.1 is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
- R.sub.2 is independently H, lower alkyl of 1 to 6 carbons, OR.sub.1, adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R.sub.2 groups jointly represent an oxo (.dbd.O) group with the proviso that when the compound is in accordance with Formula 2 then at least one of the R.sub.2 substituents is branched-chain alkyl or adamantyl;
- R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons, OR.sub.1, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, NO.sub.2, NH.sub.2, NHCO(C.sub.1 -C.sub.6 alkyl, or NHCO(C.sub.1 -C.sub.6)alkenyl;
- A is COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, --CH.sub.2 OH, CH.sub.2 OR.sub.11, CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CH(OR.sub.13 O), --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 (OR.sub.13 O), or Si(C.sub.1-6 alkyl).sub.3, where R.sub.7 is an alky, cycloakyl or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons, and
- R.sub.14 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C.sub.1 -C.sub.10 -alkylphenyl, naphthyl, C.sub.1 -C.sub.10 -alkylnaphthyl, phenyl-C.sub.1 -C.sub.10 alkyl, naphthyl-C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 -alkenylphenyl having 1 to 3 double bonds, C.sub.1-C.sub.10 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C.sub.1 -C.sub.10 alkenyl having 1 to 3 double bonds, phenyl-C.sub.1 -C.sub.10 alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR.sub.8, or R.sub.14 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said heteroaryl group being unsubstituted or substituted with a C.sub.1 to C.sub.10 alkyl group, with a C.sub.1 to C.sub.10 fluoroalkyl group, or with halogen, and the dashed line in Formula 4 represents a bond or absence of a bond.
A compound of the formula ##STR28## wherein R is a monovalent radical of formula (i), (ii) or (iii) ##STR29## where the * shows the aromatic carbon covalently attached to the cyclopropyl ring;
- X is O, S, or CR.sub.1 R.sub.1 ;
- R.sub.1, R.sub.2, R.sub.3 and R.sub.14 are independently H, lower alkyl of 1 to 6 carbons or adamantyl, with the proviso that when R is in accordance with formula (ii) then at least one of the R.sub.2 substituents is branched-chain alkyl or adamantyl, and
- A is COOH, a pharmaceutically acceptable salt thereof, COOR.sub.8 or CONR.sub.9 R.sub.10 where R.sub.8 is lower alkyl of 1 to 6 carbons.
A compound of the formula ##STR30## where R* is H or CH.sub.3 ;
- R*.sub.1 is methyl, ethyl or n-propyl, and
- R*.sub.8 is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
A compound of the formula ##STR31## where R* is H or CH.sub.3 ;
- R*.sub.1 is methyl, ethyl or n-propyl, and
- R*.sub.8 is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
A compound of the formula ##STR32## where R* is H or CH.sub.3 ;
- R*.sub.8 is methyl, ethyl or n-propyl, and
- R*.sub.8 is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
A compound of the formula ##STR33## where R*.sub.1 is methyl, ethyl or n-propyl, and R*.sub.8 is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
Dependencies are inferred from the claim text.