O- or S-substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
View Patent ↗Compounds of the formula where the symbols have the meaning described in the application, have retinoid-like or retinoid antagonist-like biological activity.
1. A compound of the formula:
wherein X 1 is (C(R 1 ) 2 ) n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
X 2 is S or O;
Z is —CO—CR 1 ═CR 1 —;
R 2 is hydrogen, 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;
R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
R 4 is hydrogen, 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 1 -C 10 -alkylphenyl, naphthyl, C 1 -C 10 -alkylnaphthyl, phenyl-C 1 -C 10 alkyl, napthyl-C 1 -C 10 alkyl; CN, (CH 2 ) p CO 2 H or (CH 2 ) p CO 2 R 8 where p is an integer between 0 to 10;
R 5 is hydrogen, 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 1 -C 10 -alkylphenyl, naphthyl, C 1 -C 10 -alkylnaphthyl, phenyl-C 1 -C 10 alkyl, napthyl-C 1 -C 10 alkyl; Si(C 1-6 alkyl) 3 , COR 14 , camphanoyl, or 2-tetrahydropyranyl:
Y is heteroaryl selected from a group consisting of thienyl and furyl said heteroaryl groups being optionally substituted with one or two R 2 groups;
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;
B is 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, and
R 14 is hydrogen, 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 1 -C 10 -alkylphenyl, naphthyl, C 1 -C 10 -alkylnaphthyl, phenyl-C 1 -C 10 alkyl, napthyl-C 1 -C 10 alkyl.
2. A compound in accordance with claim 1 wherein Y is selected from a group consisting of thienyl.
3. A compound in accordance with claim 1 where n is 1.
4. A compound in accordance with claim 1 where A is (CH 2 ) q .
5. A compound in accordance with claim 1 where B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , or CONR 9 R 10 .
6. A compound of the formula:
where R 1 is independently H or alkyl of 1 to 6 carbons;
X 2 is S or O;
Z is —CO—CR 1 ═CR 1 —;
R 2 is hydrogen, lower alkyl of 1 to 6 carbons;
R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
Y is thienyl;
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;
B is 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 0 , —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;
R 4 is hydrogen, alkyl of 1 to 10 carbons, CH 2 COOH or CH 2 CO 2 R 8 ;
R 5 is hydrogen, alkyl of 1 to 10 carbons, 2-tetrahydropyranyl, CH 2 OCH 3 or COR 12 .
7. A compound in accordance with claim 6 where A is (CH 2 ) q , where q is 0 and where B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , or CONR 9 R 10 .
8. A compound in accordance with claim 6 where R 4 is H, CH 2 COOH or CH 2 COOR 8 .
9. A compound in accordance with claim 6 where R 5 is H, 2-tetrahydropyranyl or CH 2 OCH 3 .
10. A compound of the formula:
wherein X 1 is (C(R 1 ) 2 ) n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
X 2 is S or O;
Z is —(CR 1 ═CR 1 ) n′ —where n′is an integer having the value 1-2,
—COO—,
—OCO—;
—CSO—;
—OCS—;
—CO—CR 1 ═CR 1 —;
R 2 is hydrogen, 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;
R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
R 4 is hydrogen, 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 1 -C 10 -alkylphenyl, naphthyl, C 1 -C 10 -alkylnaphthyl, phenyl-C 1 -C 10 alkyl, napthyl-C 1 -C 10 alkyl; CN, (CH 2 ) p CO 2 H or (CH 2 ) p CO 2 R 8 where p is an integer between 0 to 10;
R 5 is hydrogen, 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 1 -C 10 -alkylphenyl, naphthyl, C 1 -C 10 -alkylnaphthyl, phenyl-C 1 -C 10 alkyl, napthyl-C 1 -C 10 alkyl; Si(C 1-6 alkyl) 3 , COR 14 , camphanoyl, or 2-tetrahydropyranyl;
Y is selected from a group consisting of thienyl and furyl, said heteroaryl groups being optionally substituted with one or two R 2 groups;
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;
B is 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, and
R 14 is hydrogen, 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 1 -C 10 -alkylphenyl, naphthyl, C 1 -C 10 -alkylnaphthyl, phenyl-C 1 -C 10 alkyl, napthyl-C 1 -C 10 alkyl.
11. A compound in accordance with claim 10 where the Z group is connected to the 2-position of the tetrahydronaphthalene ring.
12. A compound in accordance with claim 10 where the Z group is connected to the 3-position of the tetrahydronaphthalene ring.
13. A compound in accordance with claim 10 where Z is —CO—CR 1 ═CR 1 —.
14. A compound in accordance with claim 10 where R 8 is H or ethyl.