Aryl or heteroaryl substituted 3,4-dihydroanthracene and aryl or heteroaryl substituted benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo [1,2-g]-1,2-dihydroquinoline derivatives having retinoid antagonist or retinoid inverse agonist type biological activity

Abstract

Compounds of the formula where the symbols have the meaning defined in the specification, have retinoid, retinoid antagonist and/or retinoid inverse-agonist-like biological activity.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
       wherein X 1  is —C(R 1 ) 2 —, —C(R 1 ) 2 —C(R 1 ) 2 —, —S—, —O—, —NR 1 —, —C(R 1 ) 2 —O—, —C(R 1 ) 2 —S—, or —C(R 1 ) 2 —NR 1 —;  
       R 1  is independently H or alkyl of 1 to 6 carbons;  
       R 2  is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;  
       m is an integer between 0 and 4;  
       n is an integer between 0 and 2;  
       o is an integer between 0 and 3;  
       R 3  is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I;  
       R 4  is (R 5 ) p -phenyl, (R 5 ) p -naphthyl, or (R 5 ) p -heteroaryl where the heteroaryl group is 5-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S and N;  
       p is an integer having the values of 0-5;  
       R 5  is optional and is defined as independently F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8  an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons;  
       Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R 2  groups, or Y is —(CR 3 ═CR 3 ) r —;  
       r is an integer between 1 and 3;  
       A is (CH 2 ) q  where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, with the proviso that when Y is —(CR 3 ═CR 3 ) r — then A is (CH 2 ) q  and q is 0.  
       B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 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 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 1  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons.  
     
   
   
       2 . A compound of  claim 1  where Y is phenyl or naphthyl.  
   
   
       3 . A compound of  claim 1  where Y is selected from pyridyl, furyl and thienyl.  
   
   
       4 . A compound of  claim 1  where Y is —CR 3 ═CR 3 ) r —.  
   
   
       5 . A compound of  claim 1  where X 1  is —C(R 1 ) 2 —C(R 1 ) 2 —.  
   
   
       6 . A compound of  claim 1  where X 1  is —C(R 1 ) 2 —O—.  
   
   
       7 . A compound of  claim 1  where X 1  is —C(R 1 ) 2 —S—.  
   
   
       8 . A compound of  claim 1  where X 1  is —C(R 1 ) 2 —NR 1 —.  
   
   
       9 . A compound of  claim 1  where A is (CH 2 ) q  and B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , or CONR 9 R 10 .  
   
   
       10 . A compound of  claim 5  where Y is phenyl or naphthyl.  
   
   
       11 . A compound of  claim 10  where R 1  is methyl.  
   
   
       12 . A compound of  claim 2  where X 1  is —C(R 1 ) 2 —O—, —C(R 1 ) 2 —S—, or —C(R 1 ) 2 —NR 1 —.  
   
   
       13 . A compound of  claim 12  where R 1  is methyl.  
   
   
       14 . A compound of the formula  
     
       
         
         
             
             
         
       
       where R 1  is independently H or alkyl of 1 to 6 carbons;  
       R 2  is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;  
       n is an integer between 0 and 2;  
       o is an integer between 0 and 3;  
       R 3  is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I;  
       R 4  is (R 5 ) p -phenyl, (R 5 ) p -naphthyl, or (R 5 ) p -heteroaryl where the heteroaryl group is pyridyl, thienyl, furyl or thiazolyl;  
       p is an integer having the values of 0-5;  
       R 5  is optional and is defined as independently F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8  an alkyl group having 1 to 10 carbons, or fluoro substituted alkyl group having 1 to 10 carbons;  
       A is (CH 2 ) q  where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and  
       B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8  CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 1 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 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 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons.  
     
   
   
       15 . A compound of  claim 14  where R 1  is H, there is no optional R 2 , R 3 , is H, A is (CH 2 ) q  and q is 0, B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , or CONR 9 R 10 .  
   
   
       16 . (canceled)  
   
   
       17 . A compound of  claim 15  where the phenyl ring is 1,4 (para) substituted by the A-B and tricyclic groups, and where B is COOH or a pharmaceutically acceptable salt thereof, or COOR 8 , where R 8  is methyl or ethyl.  
   
   
       18 . A compound of  claim 15  where R 4  is 6-methyl(3-pyridyl).  
   
   
       19 . A compound of  claim 18  where the phenyl ring is 1,4 (para) substituted by the A-B and tricyclic groups, and where B is COOH or a pharmaceutically acceptable salt thereof, or COOR 8  where R 8  is methyl or ethyl.  
   
   
       20 . A compound of  claim 15  where R 4  is 5-methyl(2-thienyl).  
   
   
       21 . A compound of  claim 20  where the phenyl ring is 1,4 (para) substituted by the A-B and tricyclic groups, and where B is COOH or a pharmaceutically acceptable salt thereof, or COOR 8  where R 8  is methyl or ethyl.  
   
   
       22 . A compound of the formula  
     
       
         
         
             
             
         
       
       where X 1  is O or S;  
       R 2  is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I. CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;  
       n is an integer between 0 and 2;  
       o is an integer between 0 and 3;  
       R 3  is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I;  
       R 4  is (R 5 ) p -phenyl, (R 5 ) p -naphthyl, or (R 5 ) p -heteroaryl where the heteroaryl group is pyridyl, thienyl, furyl or thiazolyl;  
       p is an integer having the values of 0-5;  
       R 5  is optional and is defined as independently F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8  an alkyl group having 1 to 10 carbons, or fluoro substituted alkyl group having 1 to 10 carbons;  
       A is (CH 2 ) q  where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and  
       B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 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 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons.  
     
   
   
       23 . A compound of  claim 22  where there is no optional R 2 , R 3 , is H, A is (CH 2 ) q  and q is 0, B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , or CONR 9 R 10 .  
   
   
       24 . A compound of  claim 23  where X 1  is S.  
   
   
       25 . (canceled)  
   
   
       26 . A compound of  claim 24  where the phenyl ring is 1,4 (para) substituted by the A-B and tricyclic groups, and where B is COOH or a pharmaceutically acceptable salt thereof, or COOR 8  where R 8  is methyl or ethyl.  
   
   
       27 . (canceled)  
   
   
       28 . (canceled)  
   
   
       29 . A compound of  claim 23  where X 1  is O.  
   
   
       30 . (canceled)  
   
   
       31 . A compound of  claim 29 , where the phenyl ring is 1,4 (para) substituted by the A-B and tricyclic groups, and where B is COOH or a pharmaceutically acceptable salt thereof, or COOR 8  where R 8  is methyl or ethyl.  
   
   
       32 . (canceled)  
   
   
       33 . (canceled)