.sigma.-2 receptors as biomarkers of tumor cell proliferation

• US 6,113,877 A
• Filed: 09/17/1998
• Issued: 09/05/2000
• Est. Priority Date: 03/20/1996
• Status: Expired due to Term

• Current Assignee: Wake Forest University Health Sciences
• Original Assignee: Wake Forest University
• Inventors: Mach, Robert H., Wheeler, Kenneth T., Childers, Steven R., Yang, Biao
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/142,935
• Time in Patent Office: 719 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.85, 424/1.89, 424/108, 548/100, 546/1, 546/124, 546/125, 546/129, 546/152, 546/184, 546/249, 544/1, 540/1, 514/212
• US Class Current: 424/1.65
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: C07D 451/14 containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
• CPC Class Codes: G01N 33/574 for cancer

Abstract

The invention provides detectably-labeled compounds of formula (I): ##STR1## wherein A, B, C, D, E, F, R, X, Y and Z have any of the meanings given in the specification, and their pharmaceutically acceptable salts, are useful in competitive assays to assay for the presence of σ2 receptors. Also disclosed are pharmaceutical compositions containing such a compound of formula (I), methods for their use and intermediates useful for preparing such compounds of formula (I).

Claims

1. The compound (3-endo)-8-methyl-8-azabicyclo[3.2.1]octyl-3-N-(3'"'"',4'"'"'-dichlorophenyl)carbamate;

(3-endo)-8-methyl-8-azabicyclo[3.2.1]octyl-3-N-(2'"'"'-methoxy-5'"'"'-chlorophenyl)carbamate;

(3-endo)-9-benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(3'"'"',4'"'"'-dichlorophenyl)-carbamate;

(3-endo)-9-benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(2'"'"',5'"'"'-dimethoxyphenyl)carbamate);

(3-endo)-9-benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(5'"'"'-chloro-2'"'"',4'"'"'-dimethoxyphenyl)carbamate;

(3-endo)-9-benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(5'"'"'-chloro-2'"'"'-methoxyphenyl)carbamate;

(3-endo)-9-methyl-9-azabicyclo[3.3.1]nonanyl-3-N-(3'"'"',4'"'"'-dichlorophenyl)-carbamate;

(3-endo)-8-benzyl-8-azabicyclo[3.2.1]octyl-3-N-(2'"'"',5'"'"'-dimethoxyphenyl)-carbamate;

or

(3-endo)-8-benzyl-8-azabicyclo[3.2.1]octyl-3-N-(3'"'"',4'"'"'-dichlorophenyl)-carbamate;

or a pharmaceutically acceptable salt thereof;

or a detectably-labeled derivative thereof.

35. A pharmaceutical composition comprising a compound of any one of claims 1, 2, 3-6, 8-11, 23-26, 28, or 29 and a pharmaceutically acceptable diluent or carrier.

2. A compound which is (3-endo)-9-methyl-9-azabicyclo[3.3.1]nonanyl-3-N-(2'"'"',5'"'"'-dimethoxyphenyl)carbamate;

or a pharmaceutically acceptable salt thereof.

3. A compound which is (3-endo)-9-Benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(5'"'"'-chloro-2'"'"',4'"'"'-dimethoxyphenyl)carbamate;

or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 3-6 which is detectably labeled.

37. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable diluent or carrier.

4. A compound (3-endo)-9-methyl-9-azabicyclo [3.3.1]nonanyl-3-N-(3'"'"',4'"'"'-dichlorophenyl)-carbamate;

or a pharmaceutically acceptable salt thereof.

5. A compound (3-endo)-9-benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(2'"'"',5'"'"'-dimethoxyphenyl)-carbamate;

or a pharmaceutically acceptable salt thereof.

6. A compound (3-endo)-9-benzyl-9-azabicyclo[3.3.1]nonanyl-3-N-(2'"'"',5'"'"'-dimethoxy-5'"'"'-chlorophenyl)-carbamate;

or a pharmaceutically acceptable salt thereof.

8. A compound of formula (I):

##STR5## wherein R is C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O, or S;

C is O or S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O; and

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

9. A compound of formula (I):

##STR6## wherein R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is O or S;

C is O or S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O; and

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I):

##STR7## wherein R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O, or S;

C is S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O; and

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

11. A compound of formula (I):

##STR8## wherein R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O or S;

C is O or S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O;

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof;

which is detectably-labeled with a radionuclide.

12. A compound of claim 11 wherein E, D and F are CH.

13. A compound of claim 11 wherein B is NH and A is O.

14. A compound of claim 11 wherein Y and Z are halo.

15. A compound of claim 11 wherein Y and Z are OCH₃.

16. A compound of claim 11 wherein R is benzyl or CH₃.

17. A method to determine the proliferative status of a cancer cell comprising

(a) administering to a human afflicted with a solid tumor, an effective amount of a detectably-labeled compound of formula (I):

##STR9## wherein R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O, or S;

C is O or S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O;

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof; and

(b) determining the extent to which the compound of formula (I) binds to cells of said tumor, said extent providing a measure of the proliferative status of said cells.

18. The method of claim 17 wherein E, D and F are CH.

19. The method of claim 17 wherein B is NH and A is O.

20. The method of claim 17 wherein Y and Z are halo.

21. The method of claim 17 wherein Y and Z are OCH₃.

22. The method of claim 17 wherein R is benzyl or CH₃.

23. A compound of formula (I):

##STR10## wherein R is C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O, or S;

C is O or S;

D is N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O;

X is (CH₂)₂, (CH)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 23-26 which is detectably labeled.

38. A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable diluent or carrier.

24. A compound of formula (I):

##STR11## wherein R is C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O, or S;

C is O or S;

D is CH or N;

E is N;

F is CH or N;

Y and Z are individually H, halo, OH (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O;

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

25. A compound of formula (I):

##STR12## wherein R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O, or S;

C is O or S;

D is CH or N;

E is CH or N;

F is N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O;

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

26. A compound of formula (I):

##STR13## wherein R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is NH, O or S;

B is NH, O or S;

C is O or S;

D is CH or N;

E is CH or N;

F is N;

Y and Z are H;

or a pharmaceutically acceptable salt thereof.

28. A compound of compound of formula (I):

##STR14## wherein;

R is (C₁ -C₄)alkyl, C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH₂ or H;

A is S;

B is NH, O, or S;

C is O or S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, halo, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O;

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 28 or 29 which is detectably labeled.

39. A pharmaceutical composition comprising a compound of claim 36 and a pharmaceutically acceptable diluent or carrier.

29. A compound of formula (I):

##STR15## wherein R is (C₁ -C₄)alkyl C₆ F₅ CH₂, and T--C₆ H₄ CH₂ wherein T is halo, CH₃ S, CH₃ O, NH or H;

A is NH, O or S;

B is NH, O, or S;

C is O or S;

D is CH or N;

E is CH or N;

F is CH or N;

Y and Z are individually H, OH, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂ or together are OCH₂ O; and

X is (CH₂)₂, (CH₂)₃ or CH═

CH;

provided when B is NH, the ring comprising D, E, and F is not substituted at a position ortho to B with OH, (C₁ -C₄)alkoxy, (C₁ -C₄)C(O), (C₁ -C₄)alkylS, NH₂, SH, N(R)₂, or a position ortho to B and a position meta to B together are not OCH₂ O;

or a pharmaceutically acceptable salt thereof.

30. A compound of claim 29 wherein E, D and F are CH.

31. A compound of claim 29 wherein B is NH and A is O.

32. A compound of claim 29 wherein Y and Z are halo.

33. A compound of claim 29 wherein Y and Z are OCH₃.

34. A compound of claim 29 wherein R is benzyl or CH₃.