IP Library › Granted Patent US 6,974,840

Granted Patent B1

US 6,974,840 · App. 10/019,802 · Granted Dec 13, 2005

Therapeutic agents

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Quick Facts

Patent No.: US 6,974,840
App. No.: 10/019,802
Granted: Dec 13, 2005
Kind: B1

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Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof in which m is 0, 1 or 2; n is 2, 3, 4 or 5; X is carbonyl or a group of formula (II) in which R 5 is H or alkyl; Y is an alkylene chain optionally substituted by one or more alkyl groups; Z is an alkylene chain containing 2 to 5 carbon atoms optionally substituted by one or more alkyl groups; R is phenyl optionally substituted by one or more halo substituents or R is naphthyl; and R 1 and R 2 , which are the same or different, are H, alkyl, or arylalkyl, provided that when R 1 is benzyl, R 2 is H or methyl; have utility in the treatment of drug misuse or other addictive disorders.

Claims (164)

1. A method of treating drug misuse or other addictive disorders comprising administering a therapeutically effective amount of a compound of formula I

and pharmaceutically acceptable salts thereof in which

m is 0, 1 or 2;

n is 2, 3, 4 or 5;

X is carbonyl or a group of formula II

in which R 5 is H or an alkyl group containing 1 to 4 carbon atoms;

Y is an alkylene chain containing 1 or 2 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

Z is an alkylene chain containing 2 to 5 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

R is phenyl optionally substituted by one or more halo substituents or R is naphthyl; and

R 1 and R 2 which are the same or different, are H, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, an arylalkyl group in which the alkyl group contains 1 to 3 carbon atoms, provided that when R 1 is benzyl, R 2 is H or methyl;

to a patient in need thereof.

2. A method according to claim 1 , wherein m is 0, 1 or 2 and n is 3 or 4.

3. A method according to claim 1 , wherein X is carbonyl or the group of formula II in which R 5 is H.

4. A method according to claim 1 , wherein Y is methylene.

5. A method according to claim 1 , wherein Z is an alkylene chain containing 2 to 4 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms.

6. A method according to claim 1 , wherein Z is an alkylene chain containing 2 to 4 carbon atoms optionally substituted by one or more methyl groups.

7. A method according to claim 1 , wherein R is phenyl substituted by one or two chloro substituents or R is naphthyl.

8. A method according to claim 1 , wherein R is 3-chlorophenyl; 3,4-dichlorophenyl; or 2-naphthyl.

9. A method according to claim 1 , wherein R 1 is an alkyl group containing 1 to 3 carbon atoms or is benzyl, and R 2 is an alkyl group containing 1 to 3 carbon atoms.

10. A method according to claim 1 , wherein R 1 and R 2 are both methyl or ethyl or R 1 is benzyl and R 2 is methyl.

11. A method of treating drug misuse or other addictive disorders comprising administering a therapeutically effective amount of a compound of formula III

and pharmaceutically acceptable salts thereof wherein:

m is 0, 1 or 2;

n is 2, 3, 4 or 5;

X is carbonyl or a group of formula II

and wherein R 5 is H or an alkyl group containing 1 to 4 carbon atoms;

Y is an alkylene chain containing 1 or 2 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

Z is an alkylene chain containing 2 to 5 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

R 1 and R 2 , which are the same or different, are H, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, an arylalkyl group in which the alkyl group contains 1 to 3 carbon atoms, provided that when R 1 is benzyl, R 2 is H or methyl; and

R 3 is halo, and R 4 is H or halo, or R 3 and R 4 together with the carbon atoms to which they are attached form a fused benzene ring;

to a patient in need thereof.

12. A method according to claim 11 , wherein R 3 is chloro and R 4 is H, R 3 and R 4 being both chloro or R 3 and R 4 together with the carbon atoms to which they are attached forming a fused benzene ring.

13. A method according to claim 11 , wherein R 3 is chloro situated in the 3-substitution position on the phenyl ring and R 4 is H, R 3 and R 4 being both chloro and situated in the 3- and 4-substitution positions on the phenyl ring respectively, or R 3 and R 4 together with the phenyl ring to which they are attached forming a 2-naphthyl group.

14. A method according to claim 1 , wherein the compound of formula I is selected from the group consisting of:

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[2-(dimethylamino)ethylthio]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[2-(dimethylamino)ethylsulphinyl]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[2-(dimethylamino)ethylsulphonyl]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[2-(diethylamino)ethylthio]ethanone;

2-[2-(N-benzyl-N-methylamino)ethylthio]-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[2-(dimethylamino)ethylthio]ethanol;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)propylthio]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)propylsulphonyl]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)propylthio]ethanol;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)-2-methylpropylthio]-ethanone;

2-[2-(dimethylamino)ethylthio]-1-(1-(2-naphthyl)cyclobutyl]ethanone;

1-[1-(3-chlorophenyl)cyclobutyl]-2-[3-(dimethylamino)propylthio]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[4-(dimethyl-amino)butylthio]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dipropyl-amino)propylthio]ethanone;

1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)-2-methylpropylthio]ethanol;

1-[1-(3,4-dichlorophenyl)cyclopentyl]-2-[3-(dimethylamino)propylthio]ethanone; and

pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates, or other mixtures of enantiomers.

15. A method of reducing cravings to an addictive substance in a mammal comprising administering an effective amount of a compound of formula I

and pharmaceutically acceptable salts thereof in which

m is 0, 1 or 2;

n is 2, 3, 4 or 5;

X is carbonyl or a group of formula II

in which R 5 is H or an alkyl group containing 1 to 4 carbon atoms;

Y is an alkylene chain containing 1 or 2 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

Z is an alkylene chain containing 2 to 5 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

R is phenyl optionally substituted by one or more halo substituents or R is naphthyl; and

to the mammal in need thereof.

16. A method according to claim 15 , wherein the addictive substance is cocaine, amphetamine, nicotine, opiates, tobacco, alcohol or ecstasy.

17. A method according to claim 15 , wherein m is 0, 1 or 2 and n is 3 or 4.

18. A method according to claim 15 , wherein X is carbonyl or the group of formula II in which R 5 is H.

19. A method according to claim 15 , wherein Y is methylene.

20. A method according to claim 15 , wherein Z is an alkylene chain containing 2 to 4 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms.

21. A method according to claim 15 , wherein Z is an alkylene chain containing 2 to 4 carbon atoms optionally substituted by one or more methyl groups.

22. A method according to claim 15 , wherein R is phenyl substituted by one or two chloro substituents or R is naphthyl.

23. A method according to claim 15 , wherein R is 3-chlorophenyl; 3,4-dichlorophenyl; or 2-naphthyl.

24. A method according to claim 15 , wherein R 1 is an alkyl group containing 1 to 3 carbon atoms or is benzyl, and R 2 is an alkyl group containing 1 to 3 carbon atoms.

25. A method according to claim 15 , wherein R 1 and R 2 are both methyl or ethyl or R 1 is benzyl and R 2 is methyl.

26. A method of reducing cravings to an addictive substance in a mammal comprising administering an effective amount of a compound of formula III

and pharmaceutically acceptable salts thereof wherein:

m is 0, 1 or 2;

n is 2, 3, 4 or 5;

X is carbonyl or a group of formula II

and wherein R 5 is H or an alkyl group containing 1 to 4 carbon atoms;

Y is an alkylene chain containing 1 or 2 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

Z is an alkylene chain containing 2 to 5 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms;

R 3 is halo, and R 4 is H or halo, or R 3 and R 4 together with the carbon atoms to which they are attached form a fused benzene ring;

to the mammal in need thereof.

27. A method according to claim 26 , wherein R 3 is chloro and R 4 is H, R 3 and R 4 being both chloro or R 3 and R 4 together with the carbon atoms to which they are attached forming a fused benzene ring.

28. A method according to claim 26 , wherein R 3 is chloro situated in the 3-substitution position on the phenyl ring and R 4 is H, R 3 and R 4 being both chloro and situated in the 3- and 4-substitution positions on the phenyl ring respectively, or R 3 and R 4 together with the phenyl ring to which they are attached forming a 2-naphthyl group.

29. A method according to claim 15 , wherein the compound of formula I is selected from the group consisting of: