Patent EA-004476-B1 (EA)
Title: Resorcinol derivatives
Inventor: COLLINGTON ERIC WILLIAM
IPC: A61Q17/00
Filed: 2000-03-16
Abstract: 1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R<1> is a (C3-C8) cycloalkyl ring or (C5-C8) cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano; halo; (C1-C6) alkyl; aryl; (C2-C9) heterocycloalkyl; (C2 C9) heteroaryl; aryl (C1-C6) alkyl-; =O; =CHO (C1-C6) alkyl; amino; hydroxy; (C1-C6) alkoxy; aryl(C1-C6)alkoxy-; aryl(C1-C6)alkoxy-; (C1-C5)acyl; amino(C1-C6)alkyl-; aryl(C1-C6)alkylamino-; (C1-C6) alkoxy-CO-NH-; (C1-C6)alkylamino-CO-; (C2-C6)alkenyl; (C2-C6) alkynyl; hydroxy(C1-C6)alkyl; acyloxy(C1-C6)alkyl-; nitro; cyano(C1-C6)alkyl-; halo(C1-C6)alkyl-; (C1-C6)alkoxy(C1-C6)alkyl-; trifluoromethyl; trifluoromethyl(C1-C6)alkyl-; (C1-C6 halo(C1-C6)alkyl-; nitro(C1-C6)alkyl-; (C1-C6) acylamino-; (C1-C6)acylamino(C1-C6)alkyl-; (C1-C6)alkoxy(C1-C6)acylamino-; amino(C1-C6)alkylamino(C1-C6)acyl-; ((C1-C6)C6)acyl-; amino(C1-C6)acyl(C1-C6)alkyl-; alkyl)2amino(C1-C6)acyl-; -CO2R<2>; -(C1-C6)alkyl-CO2R<2>; -C(O)N(R<2>)2; -(C1-C6) alkyl-C(O)N(R<2>)2; R<2>ON=; -NR<2>(OR<2>); -(C1-C6)alkyl-NR<2>(OR<2>); -R<2>ON=CR<2>(C1-C6)alkyl-; C(O)(NR<2>OR<2>); -(C1-C6)alkyl-C(O)(NR<2>OR<2>); -S(O)mR<2>; wherein each R<2> is independently selected from hydrogen, (C1-C6) alkyl, aryl, or aryl(C1-C6)alkyl-; R<3>C(O)O-, wherein R<3> is (C1-C6) alkyl, aryl, or aryl (C1-C6) alkyl-; R<3>C(O)O-(C1-C6)alkyl-; R<4>R<5>N-C(O)-O-; R<4>R<5>NS(O)2-; R<4>R<5>NS(O)2(C1-C6) alkyl-; R<4>S(O)R<5>N-; R<4>S(O)2R<5>N(C1-C6)alkyl-; wherein m is 0,1 or 2, and R<4> and R<5> are each independently selected from hydrogen or (C1-C6)alkyl; -C (=NR<6>) (N (R<4>)2); or -(C1-C6)alkyl-C(=NR<6>) (N(R<4>)2) wherein R<6> represents OR<2> or R<2> wherein R<2> is defined as above; with the proviso that the cycloalkenyl ring is not aromatic; with the proviso that R<1> must be substituted by at least one of R<3>C(O)O-(C1-C6)alkyl-; R<2>ON=; R<2>ON=(C1-C6)alkyl-; R<2>ON=CR<2>(C1-C6)alkyl-; NR<2>(OR<2>); R<4>R<5>NS(O)2-; R<4>R<5>NS(O)2(C1-C6)alkyl-; R<4>S(O)2R<5>N-or R<4>S(O)2R<5>N(C1-C6)alkyl-; with the proviso that when R<1> is only substituted by one of R<2>ON=, then R<2> cannot be hydrogen. 2. The compound of claim 1, wherein R<1> is a cyclohexyl or cyclohexenyl ring substituted at the 3- or 4-position, or a cyclopentyl or cyclopentenyl ring substituted at the 3 position. 3. The compound of claim 1, wherein R<1> is monosubstituted. 4. The compound of claim 1, wherein R<1> is disubstituted. 5. The compound of claim 1, wherein R<1> is substituted by R<3>C(O)O-(C1-C6)alkyl-. 6. The compound of claim 1, wherein R<1> is substituted by at least one of R<2>ON=, R<2>ON=CR<2>(C1-C6)alkyl- or R<2>ON=(C1-C6)alkyl-. 7. The compound of claim 1, wherein R<1> is substituted by at least one of NR<2>(OR<2>). 8. The compound of claim 1, wherein R<1> is substituted by at least one of R<4>S(O)2R<5>N-, R<4>S(O)2R<5>N(C1-C5)alkyl-, R<4>R<5>NS(O)2- or R<4>R<5>NS(O)2(C1-C6)alkyl-. 9. The compound of claim 1, wherein R<1>is substituted by at least one of R<4>S (O)2R<5>N- or R<4>S (O)2R<5>N (C1-C6) alkyl-. 10. The compound of claim 1, wherein R<1> is a(C3-C8) cycloalkyl ring or (C5-C8) cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R<3>C(O)O-(C1-C6)alkyl-, R<2>ON=, R<2>ON=(C1-C6)alkyl-, R<2>ON=CR<2>(C1-C6)alkyl-, NR<2>(OR<2>), R<4>R<5>NS(O)2-, R<4>R<5>NS(O)2(C1-C6)alkyl-, R<4>S(O)2R<5>N- or R<4>S(O)2R<5>N(C1-C6)alkyl-. 11. The compound of claim 10, wherein R<1> is a (C3-C8)cycloalkyl ring or (C5-C8) cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R<3>C(O)O-(C1-C6) alkyl-, R<2>ON= or R<4>S(O)2R<5>N-. 12. The compound of claim 10, wherein R<1> is substituted by R<3>C(O)O-(C1-C6) alkyl-. 13. The compound of claim 10, wherein R<1> is substituted by R<2>ON=, R<2>ON= (C1- C6) alkyl-, or R<2>ON=CR<2>(C1-C6) alkyl-. 14. The compound of claim 10, wherein R<1> is substituted by R<2>ON=. 15. The compound of claim 10, wherein R<1> is substituted by -NR<2>(OR<2>). 16. The compound of claim 10, wherein R<1> is substituted by R<4>R<5>NS(O)2-, R<4>R<5>NS(O)2(C1-C6) alkyl-, R<4>S(O)2R<5>N-or R<4>S (O)2R<5>N (C1-C6) alkyl-. 17. The compound of claim 1, wherein R<1> is substituted by R<4>S(O)2R<5>N- or R<4>S(O)2R<5>N(C1-C6)alkyl-. 18. The compound of claim 1, wherein the (C2-C9)heterocycloalkyl substituent is a group of the formula: wherein m is 0,1 or 2, and Z is CH2, NR<2>, O, S, SO, or SO2. 19. The compound of claim 1 selected from the group consisting of: O-Benzyl-4-(2,4-dihydroxyphenyl) cyclohexanone oxime; (+-)-N-[3-(2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; (+-)-O-Methyl-3-(2,4-dihydroxyphenyl) cyclohexanone oxime; (+-)-O-Benzyl-3-(2,4-dihydroxyphenyl) cyclohexanone oxime; and a pharmaceutically acceptable salt thereof. 20. The compound of claim 1 selected from the group consisting of: O-Methyl-4-(2,4-dihydroxyphenyl) cyclohexanone(2,4-dihydroxyphenyl) cyclohexanone oxime; (+-)-4-[3-(Hydroxyamino) cyclohexyl]-1,3-benzenediol; cis-N-[4-(2,4-Dihydroxyphenyl) cyclohexyl]-1-butanesulfonamide; trans-N-[4-(2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; cis-N-[4-(2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl) 4-(dimethylamino) benzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 4-tert-butylbenzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 4-fluorobenzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 4-trifluoromethylbenzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 4-methoxybenzoate; trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methylbenzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 4-chlorobenzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 3,4-dimethylbenzoate; trans-4-(2,4-Dihydroxyphenyl) cyclohexyl 3,4-dichlorobenzoate; [4-(2,4-Dihydroxyphenyl) cyclohexyl] methyl propionate; cis/trans-4-[4-(hydroxyamino) cyclohexyl]-1,3-benzenediol; trans-4-[4-(methoxyamino) cyclohexyl]-1,3-benzenediol; and a pharmaceutically acceptable salt thereof. 21. A topical pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R<1> is a (C3-C8) cycloalkyl ring or (C5-C8) cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano; halo; (C1-C6)alkyl; aryl; (C2-C9)heterocycloalkyl; (C2-C9)heteroaryl; aryl(C1-C6)alkyl-; =O; =CHO(C1-C6)alkyl; amino; hydroxy; (C1-C6)alkoxy; aryl(C1-C6)alkoxy-; aryl(C1-C6)alkoxy-; (C1-C5)acyl; amino(C1-C6)alkyl-; aryl(C1-C6)alkylamino-; (C1-C6)alkoxy-CO-NH-; (C1-C6)alkylamino-CO-; (C2-C6)alkenyl; (C2-C6)alkynyl; hydroxy(C1-C6)alkyl; acyloxy(C1-C6)alkyl-; nitro; cyano(C1-C6)alkyl-; halo(C1-C6)alkyl-; (C1-C6)alkoxy(C1-C6)alkyl-; trifluoromethyl; trifluoromethyl(C1-C6)alkyl-; (C1-C6)halo(C1-C6)alkyl-; nitro(C1-C6)alkyl-; (C1-C6)acylamino-; (C1-C6)acylamino(C1-C6)alkyl-; (C1-C6)alkoxy(C1-C6)acylamino-; amino(C1-C6)alkylamino(C1-C6)acyl-; ((C1-C6)C6)acyl-; amino(C1-C6)acyl(C1-C6)alkyl-; alkyl2amino(C1-C6)acyl-; -CO2R<2>; -(C1-C6)alkyl-CO2R<2>; -C(O)N(R<2>)2; -(C1-C6)alkyl-C(O)N(R<2>)2; R<2>ON=; -NR<2>(OR<2>); -(C1-C6)alkyl-NR<2>(OR<2>); -R<2>ON=CR<2>(C1-C6)alkyl-; C(O)(NR<2>OR<2>); -(C1-C6)alkyl-C(O)(NR<2>OR<2>); -S(O)mR<2>; wherein each R<2> is independently selected from hydrogen, (C1-C6)alkyl, aryl, or aryl(C1-C6)alkyl-; R<3>C(O)O-, wherein R<3> is (C1-C6)alkyl, aryl, or aryl(C1-C6)alkyl-; R<3>C(O)O-(C1-C6)alkyl-; R<4>R<5>N-C(O)-O-; R<4>R<5>NS(O)2-; R<4>R<5>NS(O)2(C1-C6)alkyl-; R<4>S(O)R<5>N-; R<4>S(O)2R<5>N(C1-C6)alkyl-; wherein m is 0,1 or 2, and R<4> and R<5> are each independently selected from hydrogen or (C1-C6)alkyl; -C (=NR<6>)(N(R<4>)2); or -(C1-C6)alkyl-C(=NR<6>)(N(R<4>)2) wherein R<6> represents OR<2> or R<2> wherein R<2> is defined as above; with the proviso that the cycloalkenyl ring is not aromatic; with the proviso that R<1> must be substituted by at least one of R<3>C(O)O-(C1-C6)alkyl-; R<2>ON=; R<2>ON=(C1-C6)alkyl-; R<2>ON=CR<2>(C1-C6)alkyl-; NR<2>(OR<2>); R<4>R<5>NS(O)2-; R<4>R<5>NS (O)2(C1-C6)alkyl-; R<4>S(O)2R<5>N- or R<4>S(O)2R<5>N(C1-C6) alkyl-. 22. The composition of claim 21, wherein R<1> of the compound is a cyclohexyl or cyclohexenyl ring substituted at the 3- or 4-position, or a cyclopentyl or cyclopentenyl ring substituted at the 3-position. 23. The composition of claim 21, wherein R<1> of the compound is monosubstituted. 24. The composition of claim 21, wherein R<1> of the compound is disubstituted. 25. The composition of claim 21, wherein R<1> of the compound is substituted by at least R<3>C(O)O-(C1-C6)alkyl-. 26. The composition of claim 1, wherein R<1> is substituted by at least one of R<2>ON=, R<2>ON=CR<2>(C1-C6)alkyl- or R<2>ON=(C1-C6)alkyl-. 27. The composition of claim 21, wherein R<1> is substituted by at least one of NR<2>(OR<2>). 28. The composition of claim 21, wherein R<1> is substituted by at least one of R<4>S(O)2R<5>N-, R<4>S(O)2R<5>N(C1-C5)alkyl-, R<4>R<5>NS(O)2- or R<4>R<5>NS(O)2(C1-C6)alkyl-. 29. The composition of claim 21, wherein R<1>is substituted by at least one of R<4>S(O)2R<5>N- or R<4>S (O)2R<5>N (C1-C6) alkyl-. 30. The composition of claim 21, wherein R<1> is a (C3-C8) cycloalkyl ring or (C5-C8) cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R<3>C(O)O-(C1-C6)alkyl-, R<2>ON=, R<2>ON=(C1-C6)alkyl-, R<2>ON=CR<2>(C1-C6)alkyl-, NR<2>(OR<2>), R<4>R<5>NS(O)2-, R<4>R<5>NS(O)2(C1-C6)alkyl-, R<4>S(O)2R<5>N- or R<4>S(O)2R<5>N(C1-C6)alkyl-. 31. The composition of claim 10, wherein R<1> is a (C3-C8)cycloalkyl ring or (C5-C8) cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R<3>C(O)O-(C1-C6)alkyl-, R<2>ON=