Analogs of cocaine

• US 20030144322A1
• Filed: 10/23/2002
• Published: 07/31/2003
• Est. Priority Date: 04/07/1997
• Status: Active Grant

• Current Assignee: Georgetown University
• Original Assignee: Georgetown University
• Inventors: Araldi, Gian Luca, Kozikowski, Alan P.
• Granted Patent: US 6,806,281 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07D 211/12 with only hydrogen atoms attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/20 with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention provides a compound of formula (I):

wherein R¹, R², R³, and Y have any of the meanings defined in the specification; as well a pharmaceutical composition comprising a compound of formula I; intermediates and methods useful for preparing a compound of formula I; and therapeutic methods for treating drug addiction, Parkinson'"'"'s disease or depression comprising administering a compound of formula I, to a mammal in need of such treatment.

Claims

1. A compound of formula I:

4. The compound of claim 1 wherein R¹ is —

C(═

O)OR_a, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W; 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;

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.

5. The compound of claim 1 wherein R¹ is —

C(═

O)OR_a, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W.

6. The compound of claim 1 wherein R¹ is cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W.

7. The compound of claim 1 wherein R¹ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.

8. The compound of claim 1 wherein R¹ is —

C(═

O)OR_a; and

R_a is (C₁-C₄)alkyl.

9. The compound of claim 1, 2, or 3 wherein R² is hydrogen.

10. The compound of claim 1, 2, or 3 wherein R³ is (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, or (C₆-C₁₀)arylcarbonyl, wherein any aryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z.

11. The compound of claim 1, 2, 3, or 8 wherein R³ is 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, or 4-isopropenylphenyl.

12. The compound of claim 1 or 2 wherein Y is NR⁶;

and R⁶ is hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl.

13. The compound of claim 1 wherein Y is NR⁶;

R¹ is methoxycarbonyl, (C₁-C₆)alkyl, or acetoxymethyl;

R² is hydrogen; and

R³ is 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, or 4-isopropenylphenyl; and

R⁶ is methyl.

14. The compound of claim 1, 2, 3, or 4 wherein R¹ and R² are in a trans configuration.

15. The compound of claim 1 which is trans-1-methyl-4-(4-chlorophenyl)piperidine-3-carboxylic acid methyl ester.

16. The compound of claim 1 which is (+)-methyl 4β

-(4-chlorophenyl)-1-methylpiperidine-3α

-carboxylate.

17. The compound of claim 1 which is (−

) 4β

-(4-chlorophenyl)-1-methyl-3β

-n-propylpiperidine;

or (+) 4β

-(4-chlorophenyl)-1-methyl-3α

-n-propylpiperidine.

2. A compound of formula I:

3. A compound of formula I:

18. A pharmaceutical composition comprising a compound of formula I:

20. The method of claim 18 wherein the drug is cocaine.

22. The method of claim 20 wherein the disease is depression.

23. The method of claim 20 wherein the disease is Parkinson'"'"'s disease.

19. A method comprising treating drug addiction in a human by administering a pharmaceutically effective dose of a compound of formula I:

21. A method comprising treating a disease or condition in a mammal in which the activity of dopamine or serotonin is implicated and modulation of dopamine or serotonin reuptake is desired comprising administering a compound of formula I:

24. A radio labeled compound comprising a radionuclide and a compound of formula I:

25. A method comprising imaging the brain of a mammal by administering a radiolabeled compound comprising a radionuclide and a compound of formula I:

26. The method of claim 25 wherein the radiolabeled compound is detected using positron emission tomography or single photon emission computerized tomography.