Claims
- 1. A compound of formula (I):X—L—X1 (I) wherein X and X1 are each independently a compound of formula II wherein:Y is NR6, —C(R4)(R5)—, or —O—; R1 is —C(═O)ORa, —C(═O)N(Ra)2, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1,2,4-oxadiazol-5-yl unsubstituted or substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg; and R3 is (C6-C10)aryl, 5-10 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, 5-10 membered heteroaryl(C1-C6)alkyl, (C6-C10)arylcarbonyl, biphenyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl, biphenyl, or heteroaryl substituent is unsubstituted or substituted on carbon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg; or R1 is —CH2—, or —CH2CH2—, wherein R1 is attached to a carbon at the ortho position of R3; and R3 is (C6-C10)aryl, or 5-10 membered heteroaryl; R2 is hydrogen or (C1-C6)alkyl; R4 and R5 are independently hydrogen or (C1-C6)alkyl; R6 is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl; wherein any (C2-C6)alkyl, (C2-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted on a carbon other than the carbon attached to the piperidine nitrogen with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, and S(═O)nRg; each n is independently 0, 1 or 2; W is (C1-C6)alkyl, or aryl, unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf and S(═O)nRg; Ra is L2 hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; each Rb is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; each Rc and Rd is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; or, independently, each NRcRd together is piperidino, pyrrolidino, or morpholino; each Re and Rf is independently hydrogen, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkoxycarbonyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl; or, independently, each NReRf together is piperidino, pyrrolidino, or morpholino; each Rg is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; and L is an unbranched (C2-C12)alkylene chain, unsubstituted or substituted with one, two, or three substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, oxo, and halo; or L is an unbranched (C2-C10)alkylene chain including, within the chain, at least one divalent radical selected from the group consisting of non peroxide oxy (—O—), thio (—S—), sulfinyl, sulfonyl, —OC(═O)—, and —N(Rm)C(═O)—; or L is Ri—(C2-C10alkylene)—Rk wherein Ri and Rk are each independently —N(Rm)—, —O—, or —S—; each Rm is independently hydrogen or (C1-C4)alkyl; or a pharmaceutically acceptable salt thereof.
- 2. The compound of claim 1 wherein X and X1 each have the same structure.
- 3. The compound of claim 1 wherein X and X1 each have a different structure.
- 4. The compound of claim 2 wherein X and X1 are each a compound of formula II wherein Y is NR6.
- 5. The compound of claim 2 wherein X and X1 are each a compound of formula II wherein R1 is —C(═O)ORa.
- 6. The compound of claim 1 wherein the compound is selected from the group consisting of:(+)-5-[4′β-(4-chlorophenyl)-1-methylpiperid-3′α-ylcarbonyloxy]pentyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (+)-5-[4β-(4-chlorophenyl)-1-methyl-3α-piperidylcarbonyloxy]pentyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (+)-3-[4β-(4-chlorophenyl)-1-methyl-3α-piperidylcarbonyloxy]propyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (+)-8-[4β-(4-chlorophenyl)-1-methyl-3α-piperidylcarbonyloxy]octyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (+)-4-[4β-(4-chlorophenyl)-1-methyl-3α-piperidylcarbonyloxy]phenyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (+)-4-{4-[4β-(4-chlorophenyl)-1-methyl-3α-piperidylcarbonyloxy]phenyl}phenyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (+)-1,5-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}pentane; (−)-1,5-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}pentane; (+)-1,4-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}butane; (−)-1,4-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}butane; (+)-1,3-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}propane; (−)-1,3-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}propane; (+)-1,6-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}hexane; (−)-1,6-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}hexane; (−)-4,4′-{bis-[(4β-(4-chlorophenyl)-1-methyl-3α-piperidamido]}bispiperidine; (+)-1,5-{bis-[(4β-(4-chlorophenyl)-3α-piperidamido]}pentane; (+)-1,5-{bis-[(4β-(4-chlorophenyl)-1-(2-phenylethyl)-3α-piperidamido]}pentane; (+)-4,4′-[bis-4β-(4-chlorophenyl)-1-methyl-3β-piperidinyl)methyl]biphenyl ether hydrochloride; and (+)-4,4′-[bis-4β-(4-chlorophenyl)-1-methyl-3β-piperidinyl)methyl](1,3-adamantaneyl)diphenyl ether hydrochloride.
- 7. The compound of claim 2 wherein X and X1 are each a compound of formula II wherein R1 is (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or 1,2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg.
- 8. The compound of claim 2 wherein X and X1 are each a compound of formula II wherein R3 is (C6-C10)aryl, or biphenyl; wherein any aryl or biphenyl is unsubstituted or substituted on carbon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg.
- 9. The compound of claim 2 wherein X and X1 are each a compound of formula II wherein R2 is hydrogen.
- 10. The compound of claim 2 wherein X and X1 are each a compound of formula II wherein R6 is hydrogen, (C1-C6)alkyl, or aryl(C1-C4)alkyl; wherein any aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, and S(═O)nRg.
- 11. The compound of claim 3 wherein at least one of X and X1 is a compound of formula II wherein Y is NR6.
- 12. The compound of claim 3 wherein R1 in X is —C(═O)ORa.
- 13. The compound of claim 3 wherein at least one of X and X1 is a compound of formula II wherein R1 is (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg.
- 14. The compound of claim 3 wherein at least one of X and X1 is a compound of formula II wherein R3 is (C6-C10)aryl, or biphenyl; wherein any aryl or biphenyl is unsubstituted or substituted on carbon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg.
- 15. The compound of claim 3 wherein at least one of X and X1 is a compound of formula II wherein R2 is hydrogen.
- 16. The compound of claim 3 wherein at least one of X and X1 is a compound of formula II wherein R6 is hydrogen, (C1-C6)alkyl, or aryl(C1-C4)alkyl; wherein any aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, and S(═O)nRg.
- 17. The compound of claim 1 wherein L is an unbranched (C2-C12)alkylene chain.
- 18. The compound of claim 1 wherein L is an unbranched (C2-C10)alkylene chain comprising within the chain, 1 or 2 divalent radicals selected from the group consisting of non peroxide oxy (—O—), thio (—S—), sulfinyl, sulfonyl, —OC(═O)—, and —NHC(═O)—.
- 19. The compound of claim 1 wherein L is Ri—(C2-C10)—Rk, wherein Ri and Rk are each independently —N(Rm)—, —O—, or —S—; and Rm is hydrogen or (C1-C4)alkyl.
- 20. The compound of claim 1 wherein L is attached to X and X1 through R1.
- 21. The compound of claim 12 wherein each R1 is —C(═O)ORa and each Ra is L.
- 22. The compound of claim 1 wherein each R1 is —C(═O)N(Ra)2 and each Ra is L.
- 23. The compound of claim 1 wherein each Y is NR6, and L is attached to X and X1 by replacing each R6 with a bond to L.
- 24. The compound of claim 1 wherein L is attached to X and X1 through a ring carbon of R3.
- 25. The compound of claim 21 or 22 wherein X and X1 are each (−)-methyl 4β-(4-vinylphenyl)-1-methylpiperidine-3β-carboxylate.
- 26. The compound of claim 1 wherein X and X1 are each individually selected from (−)-Methyl 4β-(4-bromophenyl)-1-ethylpiperidine-3β-carboxylate; (−)-Methyl 4β-(4-vinylphenyl)-1-methylpiperidine-3β-carboxylate; (±)-Methyl 4β-(2-naphthyl)-1-methylpiperidine-3β-carboxylate; and (±)-Methyl 4-(2-naphthyl)-1-methylpiperidine-3-carboxylate; or a pharmaceutically acceptable salt thereof.
- 27. The compound of claim 1 wherein X and X1 are each (+) 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate.
- 28. The compound of claim 27 wherein L is an unbranched (C2-C12)alkylene chain.
- 29. The compound of claim 1 wherein X and X1 are each (−)-methyl 4β-(4-vinylphenyl)-1-methylpiperidine-3β-carboxylate.
- 30. The compound of claim 29 wherein L is an unbranched (C2-C12)alkylene chain that forms ester bonds with the 3β-carboxylate groups on X and X1.
- 31. A pharmaceutical composition comprising a compound of claim 1; and a pharmaceutically acceptable diluent or carrier.
- 32. A method of treating drug addiction in a human comprising administering to said human a pharmaceutically effective dose of a compound of claim 1.
- 33. The method of claim 32 wherein the drug is cocaine.
- 34. A compound selected from the group consisting of:(+)-methyl (2-E)-3-[4(-(4-chlorophenyl)-1-methyl-3(-piperidyl)]prop-2-enoate; (+)-methyl 3-[4(-(4-chlorophenyl)-1-methyl-3(-piperidyl]propanoate; (+)-3-[4(-(4-chlorophenyl)-1-methyl-3)-piperidyl]propan-1-ol; (+)-5-[4β-(4-chlorophenyl)-1-methyl-3-piperidyl]-3-methyl-1,2,4-oxadiazole; (+)-5-[4β-(4-chlorophenyl)-1-methyl-3-piperidyl]-3-phenyl-1,2,4-oxadiazole; (+)-1-[4(-(4-chlorophenyl)-1-methyl-3-piperidyl]propan-1-one; (+)-5-hydroxypentyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; (−)-1-[9-fluorenyl-methoxycarbonyl]-5-[4β-(4-chlorophenyl)-1-methylpiperidine-3α-amido]pentyl-1-amine; (−)-1-(benzamido)-5-[4β-(4-chlorophenyl)-1-methylpiperidine-3α-amido]pentane; (−)-1-(1-adamantaneamido)-5-[4β-(4-chlorophenyl)-1-methylpiperidine-3α-amido]pentane; (−)-1-(4-chlorocinnamido)-5-[4β-(4-chlorophenyl)-1-methylpiperidine-3α-amido]pentane; and (−)-1-[4β-(4-chlorophenyl)-1-methylpiperidine-3α-amido]-5-[(+)-3β-(4-chlorophenyl)tropane-2α-amido)pentane.
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Patent Application No. 60/103,460, filed Oct. 7, 1998, the specification of which is hereby incorporated by reference; and U.S. Provisional Patent Application No. 60/103,423, filed Oct. 7, 1998, the specification of which is hereby incorporated by reference.
GOVERNMENT FUNDING
The invention described herein was made with U.S. Government support under grant DA11546, awarded by the National Institutes of Health, National Institute on Drug Abuse.
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Provisional Applications (2)
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Number |
Date |
Country |
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60/103460 |
Oct 1998 |
US |
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60/103423 |
Oct 1998 |
US |