Tropane analogs and methods for inhibition of monoamine transport

{
  "publication_number": "US6417221B1",
  "country": "US",
  "kind": "B1",
  "title": "Tropane analogs and methods for inhibition of monoamine transport",
  "abstract": "New tropane analogs that bind to monoamine transporters are described, particularly, 8-aza, 8carbo and 8-oxo tropanes having 6- or 7- substituents. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers. Certain preferred compounds of the present invention have a high selectivity for the DAT versus the SERT. Also described are pharmaceutical therapeutic compositions comprising the compounds formulated in a pharmaceutically acceptable carrier and a method for inhibiting 5-hydroxy-tryptamine reuptake of a monoamine transporter by contacting the monoamine transporter with a 5-hydroxytryptamine reuptake inhibiting amount of a compound of the present invention. Preferred monoamine transporters for the practice of the present invention include the dopamine transporter, the serotonin transporter and the norepinephrine transporter.",
  "claims": [
    "1. A compound having the structural formula: wherein: R 1 =COOCH 3, COR 3, lower alkyl, lower alkenyl, lower alkynyl, CONHR 4, or COR 6; R 2 =is a 6α, 6β, 7α or 7β substituent, which is selected from OH, OR 3, F, Cl, Br, and NHR 3; X=O, S; SO, SO 2, R 3 =H, CH 3, CH 3 CH 2, CH 3 (CH 2) n (CH 2) n C 6 H 4 Y, C 6 H 4 Y, CHCH 2, lower alkyl, lower alkenyl, or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2) n CH 3, COCH 3, or C(CH 3) 3; R 4 =CH 3, CH 2 CH 3, or CH 3 SO 2; Ar=phenyl-R 5, naphthyl-R 5, anthracenyl-R 5, phenanthrenyl-R 5, or diphenylmethoxy-R 5; R 5 =Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2)nCH 3, COCH 3, C(CH 3) 3 where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH 3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy); R 6 =morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5; and when X=O, R 2 can be H.",
    "2. The compound of claim 1 having the following structural formula: wherein X, Ar, R 2 and m have the same meaning as defined above.",
    "3. The compound of claim 2, wherein Ar is halogen substituted phenyl or halogen substituted diarylmethoxy.",
    "4. The compound of claim 2, wherein Ar is a mono- or di-halogen substituted phenyl.",
    "5. The compound of claim 2, wherein the aryl ring can be substituted with one or more halide atoms, hydroxy groups, nitro groups, amino groups, cyano groups, lower alkyl groups having from 1-8 carbon atoms, lower alkoxy groups having from 1-8 carbon atoms, lower alkenyl groups having from 2-8 carbon atoms, or lower alkynyl groups having from 2-8 carbon atoms.",
    "6. The compound of claim 5, wherein the aryl ring can be substituted with chloride or iodide.",
    "7. The compound of claim 5, wherein the amino group is a mono- or di- alkyl substituted group having from 1-8 carbon atoms.",
    "8. The compound of claim 2, wherein the aryl group has a substituent selected from the group consisting of Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, COCH 3, C(CH 3) 3, (CH 2) n CH 3 where n=0-6, allyl, isopropyl and isobutyl.",
    "9. The compound of claim 2, wherein the aryl group has a substituent selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl.",
    "10. The compound of claim 2, wherein the aryl group is substituted with a member of the group consisting of 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH 3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH and 3-F-4-OH.",
    "11. The compound of claim 1 having the following structural formula: where R is H, 4-F, 4-Cl, 4-Br, 4-I or 4-CH 3.",
    "12. The compound of claim 11, wherein the aryl group is a 3,4 dihalo substituted phenyl.",
    "13. The compound of claim 12, wherein the aryl group is 3,4-diclorophenyl.",
    "14. The compound of claim 1 having the following structural formula: where X is an oxygen, and R is a lower alkenyl or lower alkynyl group having from about 2 to about 8 carbon atoms.",
    "15. The compound of claim 14 wherein the lower alkenyl or lower alkynyl group is selected from the group consisting of ethenyl, propenyl, butenyl, propynyl and butynyl.",
    "16. The compound of claim 1 having the following structural formula: where X is an oxygen atom and Ar is 4-substituted phenyl, naphthyl, anthracenyl or phenanthrenyl.",
    "17. The compound of claim 1 having the following structural formula: where X is oxygen, R 1 is morpholinyl, piperidinyl or methoxy, Ar is phenyl, substituted phenyl, naphthyl or substituted naphthyl.",
    "18. The compound of claim 17, wherein Ar is substituted with halogen, lower alkenyl having 2-8 carbon atoms or lower alkynyl having 2-8 carbon atoms.",
    "19. The compound of claim 17, wherein Ar is substituted with 4-Cl, 4-F, 4-Br, 4-I, 3,4-Cl 2, ethenyl, propenyl, butenyl, propynyl or butynyl.",
    "20. The compound of claim 1 having the following structural formula: where X is O, R 1 is morpholinyl, piperidinyl or methoxy, R 2 is hydroxy or methoxy in the 6- or 7- position, Ar is phenyl or naphthyl either of which can be substituted with halogen, alkenyl having 2-8 carbon atoms or alkynyl having 2-8 carbon atoms.",
    "21. The compound of claim 20, wherein Ar is substituted with 4-Cl, 4-F, 4-Br, 4-I, 3,4-Cl 2, ethenyl, propenyl, butenyl, propynyl or butynyl.",
    "22. The compound of claim 1 selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)-sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; i. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; j. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; k. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; l. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; m. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ad. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicylo(3.2.1)octane; ae. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; af. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "23. The compound of claim 1 selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; and h. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.",
    "24. The compound of claim 1 selected from the group consisting of: a. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; d. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; e. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; f. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; v. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; w. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "25. A method for inhibiting 5-hydroxytryptamine reuptake of a monoamine transporter comprising contacting the monoamine transporter with a compound having the structural formula: wherein: R 1 =COOCH 3, COR 3, lower alkyl, lower alkenyl, lower alkynyl, CONHR 4, or COR 6; R 2 =is a 6α, 6β, 7α or 7β substituent, which can be selected from OH, OR 3, F, Cl, Br, and NHR 3; X=O, S; SO, SO 2, R 3 =H, CH 3, CH 3 CH 2, CH 3 (CH 2) n (CH 2) n C 6 H 4 Y, C 6 H 4 Y, CHCH 2, lower alkyl, lower alkenyl or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2) n CH 3, COCH 3, or C(CH 3) 3; R 4 =CH 3, CH 2 CH 3, or CH 3 SO 2; Ar=phenyl-R 5, naphthyl-R 5, anthracenyl-R 5, phenanthrenyl-R 5, or diphenylmethoxy-R 5; R 5 =Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2)nCH 3, COCH 3, C(CH 3) 3 where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH 3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy); R 6 =morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5; and when X=O, R 2 can be H.",
    "26. The method of claim 25, wherein the monoamine transporter is selected from the group consisting of a dopamine transporter, a serotonin transporter and a norepinephrine transporter.",
    "27. The method of claim 25, wherein the compound is selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; i. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo (3.2.1)octane; j. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; k. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; l. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; m. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ad. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ae. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; af. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "28. The method of claim 25, wherein the compound is selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene and h. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.",
    "29. The method of claim 25, wherein the compound is selected from the group consisting of: a. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; d. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; e. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; f. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; v. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; w. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "30. A method for inhibiting 5-hydroxytryptamine reuptake of a monoamine transporter in a mammal comprising administering to the mammal a 5-hydroxytryptamine reuptake inhibiting amount of a compound having the structural formula: wherein: R 1 =COOCH 3, COR 3, lower alkyl, lower alkenyl, lower alkynyl, CONHR 4, or COR 6; R 2 =is a 6α, 6β, 7α or 7β substituent, which can be selected from OH, OR 3, F, Cl, Br, and NHR 3; X=O, S; SO, SO 2; R 3 =H, CH 3, CH 3 CH 2, CH 3 (CH 2) n (CH 2) n C 6 H 4 Y, C 6 H 4 Y, CHCH 2, lower alkyl, lower alkenyl or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2) n CH 3, COCH 3, or C(CH 3) 3; R 4 =CH 3, CH 2 CH 3, or CH 3 SO 2; Ar=phenyl-R 5, naphthyl-R 5, anthracenyl-R 5, phenanthrenyl-R 5, or diphenylmethoxy-R 5; R 5 =Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2)nCH 3, COCH 3, C(CH 3) 3 where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH 3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy); R 6 =morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5; and when X=O, R 2 can be H.",
    "31. The method of claim 30, wherein the compound is selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; i. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; j. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; k. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; l. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; m. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ad. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ae. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; af. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "32. The method of claim 30, wherein the compound is selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene and h. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.",
    "33. The method of claim 30, wherein the compound is selected from the group consisting of: a. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b. (1R,1s)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; d. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; e. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; f. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; v. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; w. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "34. A method for inhibiting dopamine reuptake of a dopamine transporter in a mammal comprising administering to the mammal a dopamine reuptake inhibiting amount of a compound having the structural formula: wherein: R 1 =COOCH 3, COR 3, lower alkyl, lower alkenyl, lower alkynyl, CONHR 4, or COR 6; R 2 =is a 6α, 6β, 7α or 7β substituent, which can be selected from OH, OR 3, F, Cl, Br, and NHR 3; X=O, S; SO, SO 2; R 3 =H, CH 3, CH 3 CH 2, CH 3 (CH 2) n (CH 2) n C 6 H 4 Y, C 6 H 4 Y, CHCH 2, lower alkyl, lower alkenyl or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2) n CH 3, COCH 3, or C(CH 3) 3; R 4 =CH 3, CH 2 CH 3, or CH 3 SO 2; Ar=phenyl-R 5, naphthyl-R 5, anthracenyl-R 5, phenanthrenyl-R 5, or diphenylmethoxy-R 5; R 5 =Br, Cl, I, F, OH, OCH 3, CF 3, NO 2, NH 2, CN, NHCOCH 3, N(CH 3) 2, (CH 2)nCH 3, COCH 3, C(CH 3) 3 where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH 3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy); R 6 =morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5; and when X=O, R 2 can be H.",
    "35. The method of claim 34, wherein the compound is selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; i. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; j. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; k. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; l. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; m. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ad. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; ae. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; af. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.",
    "36. The method of claim 34, wherein the compound is selected from the group consisting of: a. (1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene; b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c. (1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene; d. (1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; e. (1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene; f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g. 2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene and h. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.",
    "37. The method of claim 34, wherein the compound is selected from the group consisting of: a. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b. (1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c. (1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; d. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; e. (1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; f. (1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane; g. (1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; h. (1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane; i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j. 2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k. 2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l. 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m. 2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n. 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o. 2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p. 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q. 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r. 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s. 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t. 2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; u. 2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; v. 2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane; w. 2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane and x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane."
  ],
  "description_excerpt": "This application is a division of Ser. No. 09/314,441 filed May 19, 1999, which is a division of Ser. No. 08/893,921 filed Jul. 11, 1997, now U.S. Pat. No. 5,948,933, and is a continuation-in-part of Ser. No. 08/552,584 filed Nov. 3, 1995, now U.S. Pat. No. 6,171,576.\n\nThis invention was supported by NIH Grant Nos. DA48309, DA06303 and DA09462, and Contract NO1DA 7-8081 and Grant RO1DA 11542, which are supported by the National Institute on Drug of Abuse (NIDA). The government has certain rights to this invention.\n\nThis invention relates to tropane analogs of cocaine and their use as inhibitors of monoamine reuptake.\n\nCocaine dependence is a problem of national significance. To date no cocaine pharmacotherapy has been reported. Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters, particularly the dopamine transporter (DAT). (Kennedy, L. T. and I. Hanbauer (1983), J. Neurochem. 34: 1137-1144; Kuhar, M. J., M. C. Ritz and J. W. Boja (1991), Trends Neurosci. 14: 299-302; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1990), Pharmacol Biochem. Behav. 35: 949-953; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223; Schoemaker, H., C. Pimoule, S. Arbilla, B. Scatton, F. Javoy-Agid and S. Z.",
  "cpc": [
    "C07D 451/02",
    "A61K 2123/00",
    "A61K 31/18",
    "A61K 31/198",
    "A61K 31/405",
    "A61K 38/00",
    "A61K 51/0448",
    "A61P 25/00",
    "A61P 25/30",
    "A61P 43/00",
    "C07C 2602/44",
    "C07C 69/753",
    "C07D 451/06",
    "C07D 471/08",
    "C07D 493/08"
  ],
  "ipc": [
    "A61K 31/18",
    "A61K 31/198",
    "A61K 31/35",
    "A61K 31/405",
    "A61K 31/46",
    "A61K 51/04",
    "A61P 25/00",
    "A61P 25/30",
    "A61P 43/00",
    "C07C 205/00",
    "C07C 233/00",
    "C07C 255/00",
    "C07C 33/34",
    "C07C 41/00",
    "C07C 49/105",
    "C07C 49/115",
    "C07C 69/74",
    "C07C 69/753",
    "C07D 311/00",
    "C07D 451/02",
    "C07D 451/06",
    "C07D 471/08",
    "C07D 493/08",
    "C07F 7/22"
  ],
  "assignees": [
    "Organix Inc",
    "Harvard University"
  ],
  "inventors": [
    "Peter C. Meltzer",
    "Bertha K. Madras",
    "Paul Blundell",
    "Zhengming Chen"
  ],
  "filing_date": "2000-09-27",
  "publication_date": "2002-07-09",
  "grant_date": "2002-07-09",
  "priority_date": "1995-11-03",
  "application_number": "US-67153400-A",
  "family_id": "25402344",
  "cited_by_count": 7,
  "citations": [
    "US3813404A",
    "US5736123A",
    "US5310912A",
    "US5288872A",
    "US5276211A",
    "US5374636A",
    "US5736556A"
  ]
}