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Claims for Patent: 6,211,244

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Claims for Patent: 6,211,244

Title: Calcium receptor-active compounds
Abstract:The present invention features compounds able to modulate one or more activities of an inorganic ion receptor and methods for treating diseases or disorders by modulating inorganic ion receptor activity. Preferably, the compound can mimic or block the effect of extracellular Ca.sup.2+ on a calcium receptor.
Inventor(s): Van Wagenen; Bradford C. (Salt Lake City, UT), Moe; Scott T. (Salt Lake City, UT), Balandrin; Manuel F. (Sandy, UT), DelMar; Eric G. (Salt Lake City, UT), Nemeth; Edward F. (Salt Lake City, UT)
Assignee: NPS Pharmaceuticals, Inc. (Salt Lake City, UT)
Application Number:08/546,998
Patent Claims: 1. A compound having the formula: ##STR15##

wherein Ar.sub.5 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH.sub.2 OH, CONH.sub.2, CN, acetoxy, benzyl, benzyloxy, .alpha.,.alpha.-dimethylbenzyl, NO.sub.2, CHO, CH.sub.3 CH(OH), acetyl, ethylene dioxy, and --CH.dbd.CH-phenyl;

Ar.sub.6 is phenyl substituted with 1 to 5 substituents each independently selected from the group consisting of acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH.sub.2 OH, CONH.sub.2, CN, carbomethoxy, OCH.sub.2 C(O)C.sub.2 H.sub.5 and OCH.sub.2 C(O)OC.sub.2 H.sub.5 and acetoxy, provided that at least one substituent is OCH.sub.2 C(O)OC.sub.2 H.sub.5 ;

R.sub.11 is hydrogen or methyl; and

R.sub.12 is hydrogen or methyl;

provided that at least one of R.sub.11 and R.sub.12 is methyl; or a pharmaceutically acceptable salt or complex thereof.

2. The compound of claim 1, wherein Ar.sub.6 is a substituted phenyl comprising a OCH.sub.2 C(O)OC.sub.2 H.sub.5 substituent in a meta position.

3. A compound selected from the group consisting of:

21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine);

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine);

21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine):

21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethyla mine);

22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine);

23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylam ine):

23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine;

24B (N-((3-methyl-4-methoxyohenyl)methyl)-1(2-(trifluoromethyl)phenyl)ethylami ne);

24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)proyl)-1-(1-naphthyl)ethylamine;

24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine );

24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine);

24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine;

25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);

25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and

25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine: or a pharmaceutically acceptable salt or complex thereof.

4. The compound of claim 3, wherein said compound is 21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethyla mine) or a pharmaceutically acceptable salt or complex thereof.

5. The compound of claim 3, wherein said compound is 22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

6. The compound of claim 3, wherein said compound is 24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine ) or a pharmaceutically acceptable salt or complex thereof.

7. The compound of claim 3, wherein said compound is 25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

8. A method of inhibiting bone resorption in a patient comprising the step of administering to said patient a therapeutically effective amount of a compound selected from the group consisting of:

21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine);

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine);

21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine);

21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethyla mine);

22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine);

23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylam ine);

23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine;

24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylam ine);

24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine;

24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine );

24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine);

24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine;

25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);

25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and

25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine; or a pharmaceutically acceptable salt or complex thereof.

9. A compound having the formula: ##STR16##

wherein Ar.sub.3 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH.sub.2 OH, CONH.sub.2, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO.sub.2, CHO, CH.sub.3 CH(OH), N(CH.sub.3).sub.2, acetyl, and ethylene dioxy;

Ar.sub.4 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH.sub.2 OH, CONH.sub.2, CN, and acetoxy;

provided that if Ar.sub.4 is 3-methoxyphenyl, then Ar.sub.3 is a substituted phenyl that is not 2-methoxy, 3-methyl, 2-methyl, 4-methyl, 2,4-dimethyl, 2,4,6-trimethyl, or 4-isopropyl; and if Ar.sub.4 is unsubstituted phenyl, then Ar.sub.3 is a substituted phenyl that is not 2-nitrophenyl, 4-nitrophenyl, or 4-dimethylaminophenyl;

R.sub.8 is either hydrogen or phenyl;

R.sub.9 is either hydrogen or methyl; and

R.sub.10 is either hydrogen, methyl, or phenyl;

or a pharmaceutically acceptable salt or complex thereof.

10. The compound of claim 3, wherein said compound is 21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

11. The compound of claim 3, wherein said compound is

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

12. The compound of claim 3, wherein said compound is 21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

13. The compound of claim 3, wherein said compound is 23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylam ine) or a pharmaceutically acceptable salt or complex thereof.

14. The compound of claim 3, wherein said compound is 24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylam ine) or a pharmaceutically acceptable salt or complex thereof.

15. The compound of claim 3, wherein said compound is 23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

16. The compound of claim 3, wherein said compound is 24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

17. The compound of claim 3, wherein said compound is 24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

18. The compound of claim 3, wherein said compound is 24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine)) or a pharmaceutically acceptable salt or complex thereof.

19. The compound of claim 3, wherein said compound is 24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

20. The compound of claim 3, wherein said compound is 25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

21. A method of decreasing parathyroid hormone level in a patent to achieve a beneficial effect comprising the step of administering to said patient an effective amount of a compound selected from the group consisting of:

21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine);

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine);

21U ((R)-N-(3-(2-chlorophenyl)propyl)-1(3-isobutoxyphenyl)ethylamine);

21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethyla mine);

22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine);

23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylam ine);

23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine;

24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylam ine);

24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine;

24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

24V (N-((3-methyl-4-methoxyphenyl)methyl)-1(3-(ethylacetoxy)phenyl)ethylamine) ;

24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine);

24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine;

25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and

25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);

25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

22. The method of claim 21, wherein said compound is 21S (R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

23. The method of claim 21, wherein said compound is 21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

24. The method of claim 21, wherein said compound is 21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

25. The method of claim 21, wherein said compound is 21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethyla mine) or a pharmaceutically acceptable salt or complex thereof.

26. The method of claim 21, wherein said compound is 22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

27. The method of claim 21, wherein said compound is 23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylam ine) or a pharmaceutically acceptable salt or complex thereof.

28. The method of claim 21, wherein said compound is 23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

29. The method of claim 21, wherein said compound is 24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylam ine) or a pharmaceutically acceptable salt or complex thereof.

30. A method of treating a patient having a disease selected from the group consisting of hyperparathyroidism, Paget's disease, a hypercalcemic disorder, osteoporosis, hypertension, and renal osteodystrophy, comprising the step of administering to said patient an effective amount of the compound of any of claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 1314, 15, 16, 17, 18 or 19 or 20.

31. The method of claim 30, wherein said disease is hyperparathyroidism.

32. The method of claim 30, wherein said disease is Paget's disease.

33. The method of claim 30, wherein said disease is osteoporosis.

34. The method of claim 30, wherein said disease is hypertension.

35. The method of claim 30, wherein said disease is renal osteodystrophy.

36. The method of claim 21, wherein said compound is 24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

37. The method of claim 21, wherein said compound is 24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

38. The method of claim 21, wherein said compound is 24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine ) or a pharmaceutically acceptable salt or complex thereof.

39. The method of claim 21, wherein said compound is 24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

40. The method of claim 21, wherein said compound is 24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

41. The method of claim 21, wherein said compound is 25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

42. The method of claim 21, wherein said compound is 25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

43. The method of claim 21, wherein said compound is 25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any of claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 20 and a pharmaceutically acceptable carrier.

45. A method of treating a patient having a disease or disorder characterized by abnormal bone and mineral homeostasis comprising the step of administering to said patient a therapeutically effective amount of the compound of any of claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

46. The compound of claim 9, wherein Ar.sub.3 is either naphthyl optionally substituted with 0-5 substituents or phenyl optionally substituted with 1 to 5 substituents each independently selected from the group consisting of halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH.sub.2 OH, CONH.sub.2, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO.sub.2, CHO, CH.sub.3 CH(OH), N(CH.sub.3).sub.2, acetyl, and ethylene dioxy.
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