Heterocyclic analgesic compounds and methods of use thereof

• US 6,677,332 B1
• Filed: 05/25/2000
• Issued: 01/13/2004
• Est. Priority Date: 05/25/1999
• Status: Expired due to Term

• Current Assignee: Sepracor Incorporated (Sumitomo Chemical Company Limited)
• Original Assignee: Sepracor Incorporated (Sumitomo Chemical Company Limited)
• Inventors: Heffernan, Michele L. R., Cuny, Gregory D., Hauske, James R., Aquila, Brian M., Bannister, Thomas D., Shao, Liming, Wu, Xinhe, Wang, Fengjiang
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Liu, Hong
• Application Number:
  US09/579,398
• Time in Patent Office: 1,328 Days
• Field of Search: 546/16, 546/247, 540/610, 540/543, 514/357, 514/212.02, 514/217.12, 514/278
• US Class Current: 514/212.02
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• 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
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 221/04 Ortho- or peri-condensed ring systems
• CPC Class Codes: C07D 223/04 with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 243/08 not condensed with other rings
• CPC Class Codes: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 267/10 : not condensed with other rings
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems

Abstract

One aspect of the present invention relates to novel heterocyclic compounds. A second aspect of the present invention relates to the use of the novel heterocyclic compounds as ligands for various cellular receptors, including opiate receptors, other G-protein-coupled receptors, and ion channels. An additional aspect of the present invention relates to the use of the novel heterocyclic compounds as analgesics.

Claims

1. A compound represented by A:

wherein

m is 1, 2, 3 or 4;

n is 1 or 2;

y is 1 or 2;

R₁ represents aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

or cycloalkyl;

R₂ represents independently for each occurrence H, alkyl, fluoroalkyl, or cycloalkyl;

R₃ represents independently for each occurrence H, C₁-C₁₀ alkyl, aryl, OR₂, OC(O)R₂, CH₂OR₂, or CO₂R₂;

wherein any two instances of R₃ may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R₄ represents independently for each occurrence aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

alkenyl, or cycloalkyl;

R₅ represents independently for each occurrence H, C₁-C₁₀ alkyl, CH₂Y, aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

F, OR₂, or OC(O)R₂;

R₆ represents independently for each occurrence H, C₁-C₁₀ alkyl, CH₂Y, aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

F, OR₂, or OC(O)R₂;

Y represents independently for each occurrence OR₂, N(R₂)₂, SR₂, S(O)R₂, S(O)₂R₂, or P(O)(OR₂)₂;

X represents C(R₃)₂, or C═

O; and

the stereochemical configuration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations.

2. The compound of claim 1, wherein X is C(R₃)₂.

3. The compound of claim 1, wherein n is 2 or 3.

4. The compound of claim 1, wherein n is 1.

5. The compound of claim 1, wherein y is 1.

6. The compound of claim 1, wherein R₁ represents aryl or heteroaryl.

7. The compound of claim 1, wherein R₂ represents independently for each occurrence alkyl.

8. The compound of claim 1, wherein R₃ represents independently for each occurrence H or alkyl.

9. The compound of claim 1, wherein R₄ represents cycloalkyl, aryl, or heteroaryl.

10. The compound of claim 1, wherein R₅ represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.

11. The compound of claim 1, wherein R₆ represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.

12. The compound of claim 1, wherein X is C(R₃)₂;

and n is 1.

13. The compound of claim 1, wherein X is C(R₃)₂;

and y is 1.

14. The compound of claim 1, wherein X is C(R₃)₂;

and R₁ represents aryl or heteroaryl.

15. The compound of claim 1, wherein X is C(R₃)₂;

and R₂ represents independently for each occurrence alkyl.

16. The compound of claim 1, wherein X is C(R₃)₂;

n is 1; and

R₁ represents aryl or heteroaryl.

17. The compound of claim 1, wherein X is C(R₃)₂;

n is 1;

R₁ represents aryl or heteroaryl; and

R₂ represents independently for each occurrence alkyl.

18. The compound of claim 1, wherein X is C(R₃)₂;

n is 1;

R₁ represents aryl or heteroaryl;

R₂ represents independently for each occurrence alkyl; and

R₃ represents independently for each occurrence H or alkyl.

19. The compound of claim 1, wherein X is C(R₃)₂;

n is 1;

R₁ represents aryl or heteroaryl;

R₂ represents independently for each occurrence alkyl;

R₃ represents independently for each occurrence H or alkyl; and

R₄ represents cycloalkyl, aryl, or heteroaryl.

20. The compound of claim 1, wherein X is C(R₃)₂;

n is 1;

R₁ represents aryl or heteroaryl;

R₂ represents independently for each occurrence alkyl;

R₃ represents independently for each occurrence H or alkyl;

R₄ represents cycloalkyl, aryl, or heteroaryl; and

R₅ represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.

21. The compound of claim 1, wherein X is C(R₃)₂;

n is 1;

R₁ represents aryl or heteroaryl;

R₂ represents independently for each occurrence alkyl;

R₃ represents independently for each occurrence H or alkyl;

R₄ represents cycloalkyl, aryl, or heteroaryl;

R₅ represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and

R₆ represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.

22. The compound of claim 1, wherein X is C(R₃)₂;

m is 2;

n is 1;

R₁ represents aryl;

R₂ represents independently for each occurrence alkyl;

R₃ represents independently for each occurrence H;

R₄ represents aryl;

R₅ represents independently for each occurrence H or alkyl; and

R₆ represents independently for each occurrence H or alkyl.

23. The compound of claim 1, wherein said compound is a single stereoisomer.

24. A formulation, comprising a compound of claim 1;

and a pharmaceutically acceptable excipient.

25. A method of treating pain, drug addiction, or tinnitus in a mammal, comprising the step of:

administering to a mammal with pain, drug addiction, or tinnitus an effective amount of a formulation of claim 24.

26. The method of claim 25, wherein said mammal is a primate, equine, canine or feline.

27. The method claim 25, wherein said mammal is a human.

28. The method of claim 25, wherein said formulation is administered orally.

29. The method of claim 25, wherein said formulation is administered intravenously.

30. The method of claim 25, wherein said formulation is administered sublingually.

31. The method of claim 25, wherein said formulation is administered ocularly.

32. A compound represented by A:

wherein

m is 1, 2, 3 or 4;

n is 1 or 2;

y is 1 or 2;

R₁ represents monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

or cycloalkyl;

R₂ represents heteroaryl;

R₃ represents independently for each occurrence H, C₁-C₁₀ alkyl, aryl, OR₂, OC(O)R₂, CH₂OR₂, or CO₂R₂;

wherein any two instances of R₃ may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R₄ represents independently for each occurrence H, alkyl, aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

alkenyl, or cycloalkyl;

R₅ represents independently for each occurrence H, C₁-C₁₀ alkyl, CH₂Y, aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

F, OR₂, or OC(O)R₂;

R₆ represents independently for each occurrence H, C₁-C₁₀ alkyl, CH₂Y, aryl, monocyclic or bicyclic heteroaryl with 5-12 ring atoms, of which one to three ring atoms are selected independently from the group consisting of S, O, and N;

F, OR₂, or OC(O)R₂;

Y represents independently for each occurrence OR₂, N(R₂)₂, SR₂, S(O)R₂, S(O)₂R₂, or P(O)(OR₂)₂;

X represents C(R₃)₂, or C═

O; and

the stereochemical configuration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations.