Orvinol and thevinol derivatives useful in the treatment of drug and alcohol abuse

1. A compound of formula 2, or a pharmaceutically acceptable salt or solvate thereof:

wherein

R is H,

R 1 is cyclopropylmethyl,

R 2 is H,

R 4 and R 5 are methyl,

R 3 is aryl or heteroaryl, either of which may be substituted or unsubstituted, and

X is a saturated bridge (—CH 2 CH 2 —) or an unsaturated bridge (—CH═CH—).

2. The compound according to claim 1 , wherein R 3 is a substituted phenyl.

3. The compound according to claim 1 , wherein R 3 is phenyl.

4. The compound according to claim 1 , wherein R 3 is heteroaryl.

5. The compound according to claim 1 , wherein X is —CH 2 CH 2 —.

6. The compound according to claim 1 , wherein X is —CH═CH—.

7. A method of synthesizing a compound of formula 2

wherein:

R is H,

R 1 is cyclopropylmethyl,

R 2 is H,

R 4 and R 5 are methyl,

R 3 is aryl or heteroaryl, either of which may be substituted or unsubstituted, and

X is a saturated bridge (—CH 2 CH 2 —) or an unsaturated bridge (—CH═CH—),

the method comprising combining N-acylnorthebaine with methacrolein in the presence of a Lewis acid catalyst.

8. A method of synthesizing a compound having structure 3:

the method comprising combining N-cyclopropylcarbonylnorthebaine with methacrolein in the presence of a Lewis acid catalyst.

9. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient or carrier.

10. A method of treating a substance abuse disorder, wherein said substance is an opiate, alcohol, or cocaine, the method comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a human with a substance abuse disorder.

11. The method according to claim 10 , wherein said treatment prevents relapse of the substance abuse disorder.

12. The compound according to claim 2 , in which R 3 has a halogen, methyl, hydroxyl or methoxy substituent.

13. A method of treating a human with a substance abuse disorder wherein said substance is an opiate, alcohol, or cocaine, the method comprising administering an effective amount of a composition according to claim 9 , or a pharmaceutically acceptable salt or solvate thereof, to a human subject with a substance abuse disorder.

14. The method according to claim 13 , wherein said treatment prevents relapse of the substance abuse disorder.

15. The composition according to claim 9 , wherein R 3 is phenyl and X is an unsaturated bridge, or a pharmaceutically acceptable salt thereof.

16. The composition according to claim 9 , wherein R 3 is phenyl and X is a saturated bridge, or a pharmaceutically acceptable salt thereof.

17. The composition according to claim 9 , wherein R 3 is m-tolyl and X is an unsaturated bridge, or a pharmaceutically acceptable salt thereof.

18. The composition according to claim 9 , wherein R 3 is 4-fluorophenyl and X is an unsaturated bridge, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 selected from the group consisting of:

(1′R, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol; and

(1′R, 5α, 6R, 7R, 14α)-1′-(5-chloro-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol,

or a pharmaceutically acceptable salt or solvate thereof.

20. A compound selected from the group consisting of:

(1′R, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol; and

(1′R, 5α, 6R, 7R, 14α)-1′(4-propylthiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol,

or a pharmaceutically acceptable salt or solvate thereof.

21. A compound selected from the group consisting of:

(1′R, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-methyl-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(5-chloro-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol; and

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methoxyphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol,

or a pharmaceutically acceptable salt or solvate thereof.