Pyridomorphinans, pyridazinomorphinans and use thereof
Compounds represented by the formula: wherein R is C 1-6 alkyl; C 4-6 cycloalkylalkyl; or C 3-6 alkenyl; R′ is H or C 1-6 alkyl; X is H or OH; Y is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or aroyl; and Z is CH or N; provided that X is H, when Z is CH and R is C 4 cycloalkylalkyl or C 4 alkenyl; prodrugs thereof; and pharmaceutically acceptable salts thereof are provided. Compounds of the above formula are useful as analgesics for treating pain; as immunomodulators, to modulate the behavioral effects of drugs of abuse and to modulate the development of tolerance and dependence to μ agonists.
1. A compound represented by the Formula:
Wherein R is selected from the group consisting of C 1-6 alkyl; C 4-6 cycloalkylalkyl; and C 3-6 alkenyl;
R′ is H or C 1-6 alkyl;
X is H or OH;
Y is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and aroyl; and
Z is CH or N; provided that when Z is CH and R is C 4-6 cycloalkylalkyl or C 3-6 alkenyl, then X is H; and
pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein R is a C 1-6 alkyl group.
3. The compound of claim 1 wherein R is methyl.
4. The compound of claim 3 wherein X is H.
5. The compound of claim 1 wherein X is H.
6. The compound of claim 1 wherein Y is aryl.
7. The compound of claim 1 being selected from the group consisting of:
6,7-Didehydro-3,14-dihydroxy-4,5α-epoxy-7-methylpyrido[2′,3′:6,7]morphinan;
6,7-Didehydro-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylpyrido[2′,3′:6,7]morphinan;
6,7-Didehydro-3,14-dihydroxy-4,5α-epoxy-17-methyl-5′-phenylpyrido[2′,3′:6,7]morphinan;
6,7-Didehydro-14-hydroxy-4,5α-epoxy-3-methoxyl-17-methyl-5′-phenylpyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-6,7-didehydro-14-hydroxy-4,5α-epoxy-3-methoxyl-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(4-Bromophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(4-Bromophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-3-methoxy-17-methylpyrido[2′,3′:6,7]morphinan;
6,7-Didehydro-4,5α-epoxy-3-hydroxy-17-methylpyrido[2′,3′:6,7]morphinan;
6,7-Didehydro-4,5α-epoxy-3-hydroxy-17-methyl-5′-phenylpyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-6,7-didehydro-4,5α-epoxy-3-hydroxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(4-Bromophenyl)-6,7-didehydro-4,5α-epoxy-3-hydroxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(3,4-Dichlorophenyl)-6,7-didehydro-4,5α-epoxy-3-hydroxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(2,4-Dichlorophenyl)-6,7-didehydro-4,5α-epoxy-3-hydroxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3-hydroxypyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3-methoxypyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-17-[(2-cyclohexyl)ethyl]-6,7-didehydro-4,5α-epoxy-3-methoxypyrido[2′,3′:6,7]morphinan;
5′-(4-Chlorophenyl)-17-[(2-cyclohexyl)ethyl]-6,7-didehydro-4,5α-epoxy-3-hydroxypyrido[2′,3′:6,7]morphinan;
5′-(Cyclohexyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxypyrido[2′,3′:6,7]morphinan;
5′-(Cyclohexyl)-6-7-didehydro-4,5α-epoxy-3-hydroxy-17-methylpyrido[2′,3′:6,7]morphinan;
5′-Benzyl-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2′,3′:6,7]morphinan;
6,7-Didehydro-4,5α-epoxy-3-hydroxy-5′-(2-hydroxybenzoyl)-17-methylpyrido[2′,3′:6,7]morphinan;
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-6′-phenylpyridazino[3′,4′:6,7]morphinan;
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-6′-(4-chlorophenyl)pyridazino[3′,4′:6,7]morphinan;
6,7-Didehydro-4,5α-epoxy-3-hydroxy-17-methyl-6′-phenylpyridazino[3′,4′:6,7]morphinan; and
6,7-Didehydro-4,5α-epoxy-3-hydroxy-17-methyl-6′-(4-chlorophenyl)pyridazino[3′,4′:6,7]morphinan.
8. The compound of claim 1 being 5′-(4chlorophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17methylpyrido[2′,3′:6,7]morphinan.
9. A method for treating a patient suffering from pain which comprises administering to the patient an effective amount of at least one compound according the claim 1 .
10. A method for treating a patient suffering from cocaine or methamphetamine abuse which comprises administering to the patient an effective amount of at least one compound according the claim 1 .
11. A method for treating a patient suffering from dependence on or tolerance to morphine which comprises administering to the patient at least one of the compounds of claim 1 in an amount effective to modulate the tolerance to or dependence on morphine.
12. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 2 .
13. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 3 .
14. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 4 .
15. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 5 .
16. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 6 .
17. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 7 .
18. A method for treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one compound according the claim 8 .
19. A method for treating a patient suffering from cocaine or methamphetamine abuse which comprises administering to the patient an effective amount of at least one compound according the claim 7 .