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Claims for Patent: 6,313,146

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Claims for Patent: 6,313,146

Title: Calcium receptor-active molecules
Abstract:The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca.sup.2+ and the effect is on a cell having a calcium receptor; (2) inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (3) nucleic acids encoding inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (4) antibodies and fragments thereof, targeted to inorganic ion receptor proteins, preferably calcium receptor protein; and (5) uses of such molecules, proteins, nucleic acids and antibodies.
Inventor(s): Van Wagenen; Bradford C. (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:08/484,159
Patent Claims: 1. A compound having the chemical formula: ##STR15##

wherein each X.sub.1 and X.sub.2 is one or more substituents independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, or acetyl, or two of X.sub.1 are together a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy, or two of X.sub.2 are together are a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy; provided that (X.sub.2), is not 3-t-butyl;

n is between 0 and 5 inclusive, and m is between 1 and 5 inclusive; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein each said X.sub.1 and X.sub.2 is independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, i-butyl, or acetoxy, or two of X.sub.1 are together a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy, or two of X.sub.2 are together a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy.

3. The compound of claim 1, wherein each said X.sub.1 and X.sub.2 is independently selected from the group consisting of: CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2 and CH.sub.3 CH.sub.2.

4. The compound of claim 3, wherein each said X.sub.1 and X.sub.2 is independently selected from the group consisting of: CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH and CH.sub.3 CH.sub.2.

5. The compound of claim 4, wherein each said X.sub.1 and X.sub.2 is independently selected from the group consisting of: Cl, F, CF.sub.3, CH.sub.3 and CH.sub.3 O.

6. The compound of claim 5, wherein said n is 0 or 1.

7. The compound of claim 6, wherein said X.sub.1 is meta; and

said n is 0 or 1, provided that if n is 1 then X.sub.2 is either meta or ortho.

8. The compound of claim 3, wherein n is 1.

9. The compound of claim 1, wherein said X.sub.1 is meta.

10. The compound of claim 1, wherein said compound is selected from the group consisting of:

NPS R-467 which is represented by the chemical formula (R)-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine;

NPS R-568 which is represented by the chemical formula (R)-N-(3-(2-chlorophenyl)propyl)- 1-(3-methoxyphenyl)ethylamine;

R-4M which is represented be the chemical formula (R)-N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

4N which is represented by the chemical formula (R)-N-(3-(3-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

4P which is represented by the chemical formula (R)-N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

R-4V which is represented by the chemical formula (R)-N-(3-(2-trifluoromethyl)phenyl)propyl-1-(3-methoxyphenyl)ethylamine;

R-4W which is represented by the chemical formula (R)-N-(3-(3-trifluoromethyl)phenyl)propyl-1-(3-methoxyphenyl)ethylamine; and

6X which is represented by the chemical formula (R)-N-(3-(3-chlorophenyl)propyl-1-(3-methoxyphenyl)ethylamine;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10, wherein said compound is NPS R-568 which is represented by the chemical formula (R)-N-(3-(2-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10, wherein said compound is NPS R-467 which is represented by the chemical formula (R)-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

13. The compound of claim 10, wherein said compound is R-4M which is represented by the chemical formula (R)-N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

14. The compound of claim 10, wherein said compound is 4N which is represented by the chemical formula (R)-N-(3-(3- fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

15. The compound of claim 10, wherein said compound is 4P which is represented by the chemical formula (R)-N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

16. The compound of claim 10, wherein said compound is R-4V which is represented by the chemical formula (R)-N-(3-(2-trifluoromethyl)phenyl)propyl- 1 -(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

17. The compound of claim 10, wherein said compound is R-4W which is represented by the chemical formula (R)-N-(3-(3-trifluoromethyl)phenyl)propyl- 1 -(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

18. The compound of claim 10, wherein said compound is 6X which is represented by the chemical formula (R)-N-(3-(3-chlorophenyl)propyl-1-(3 -methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

19. The compound of claim 10, wherein said compound is 21M (R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(3-methoxy-phenyl)ethylamin e) or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein each X.sub.1 and X.sub.2 is one or more substituents independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, or acetyl, or two of X.sub.1 are together a fused benzene or methylene dioxy, or two of X.sub.2 are together a fused benzene or methylene dioxy: and m is at least 1.

21. The compound of claim 20, wherein each said X.sub.1 and X.sub.2 is independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, or acetoxy, or two of X.sub.1 are together a fused benzene or methylene dioxy or two of X.sub.2 are together a fused benzene or methylene dioxy.

22. The compound of claim 21, wherein each said X.sub.1 and X.sub.2 is independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2 or CH.sub.3 CH.sub.2, or two of X.sub.1 are together a fused benzene, or two of X.sub.2 are together a fused benzene.

23. The compound of claim 22, wherein n is at least 1.

24. The compound of claim 22, wherein two of X.sub.1 are together a fused benzene.

25. The compound of claim 24, wherein X.sub.2 is selected from the group consisting of Cl, F, CF.sub.3, CH.sub.3 and CH.sub.3 O.

26. The compound of claim 1, wherein said compound causes an increase in (Ca.sup.2+).sub.i with an EC.sub.50 less than or equal to 5 .mu.M as determined by measuring (Ca.sup.2+).sub.i in bovine parathyroid cells using the Cytosolic Ca.sup.2+ Cell Assay.

27. The compound of claim 26, wherein said EC.sub.50 is less than or equal to 1 .mu.M.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compound having the chemical formula: ##STR16##

wherein each X.sub.1 and X.sub.2 is one or more substituents independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, or acetyl, or two of X.sub.1 are together a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy, or two of X.sub.2 are together are a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy; provided that (X.sub.2).sub.n is not 3-t-butyl;

n is between 0 and 5 inclusive, and m is between 1 and 5 inclusive; or a pharmaceutically acceptable salt thereof.

29. The composition of claim 28, wherein each said X.sub.1 and X.sub.2 is independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, or acetoxy, or two of X.sub.1 are together a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy, or two of X.sub.2 are together a fused cycloaliphatic ring, a fused aromatic ring or methylene dioxy.

30. The composition of claim 28, wherein each said X.sub.1 and X.sub.2 is independently selected from the group consisting of: CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2 and CH.sub.3 CH.sub.2.

31. The composition of claim 30, wherein each said X.sub.1 and X.sub.2 is independently selected from the group consisting of: CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CHOH and CCH.sub.2.

32. The composition of claim 31, wherein each said X.sub.1 and X.sub.2 is independently selected from the group consisting of: Cl, F, CF.sub.3, CH.sub.3 and CH.sub.3 O.

33. The composition of claim 32, wherein said n is 0 or 1.

34. The composition of claim 33, wherein said X.sub.1 is meta; and said n is 0 or 1, provided that if n is 1 then X.sub.2 is either meta or ortho.

35. The composition of claim 30, wherein said X.sub.1 is meta.

36. The composition of claim 30, wherein n is 1.

37. The composition of claim 28, wherein said X.sub.1 is meta.

38. The composition of claim 28, wherein each X.sub.1 and X.sub.2 is one or more substituents independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, or acetyl, or two of X.sub.1 are together a fused benzene or methylene dioxy, or two of X.sub.2 are together a fused benzene or methylene dioxy.

39. The composition of claim 38 wherein each said X.sub.1 and X.sub.2 is independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CH.sub.3 CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, or acetoxy, or two of X.sub.1 are together a fused benzene or methylene dioxy, or two of X.sub.2 together a fused benzene or methylene dioxy.

40. The composition of claim 39, wherein each said X.sub.1 and X.sub.2 is independently either CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CH.sub.3 S, OH, CH.sub.2 OH, CONH.sub.2, CN, NO.sub.2 or CH.sub.3 CH.sub.2, or two of X.sub.1 are together a fused benzene, or two of X.sub.2 are together a fused benzene.

41. The composition of claim 40, wherein two of X.sub.1 are together a fused benzene.

42. The composition of claim 41, wherein X.sub.2 is selected from the group consisting of Cl, F, CF.sub.3, CH.sub.3 and CH.sub.3 O.

43. The composition of claim 40, wherein n is at least 1.

44. The composition of claim 28, wherein said compound causes an increase in (Ca.sup.2+).sub.i with an EC.sub.50 less than or equal to 5 .mu.M as determined by measuring (Ca.sup.2+).sub.i in bovine parathyroid cells using the Cytosolic Ca.sup.2+ Cell Assay.

45. The composition of claim 44, wherein said EC.sub.50 is less than or equal to 1 .mu.M.

46. The compound of claim 28, wherein said compound is NPS R-568 which is represented by the chemical formula (R)-N-(3-(2-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

47. The compound of claim 28, wherein said compound is NPS R-467 which is represented by the chemical formula (R)-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

48. The compound of claim 28, wherein said compound is R-4M which is represented by the chemical formula (R)-N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

49. The compound of claim 8, wherein said compound is 4N which is represented by the chemical formula (R)-N-(3-(3- fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

50. The compound of claim 28, wherein said compound is 4P which is represented by the chemical formula (R)-N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

51. The compound of claim 28, wherein said compound is R-4V which is represented by the chemical formula (R)-N-(3-(2-trifluoromethyl)phenyl)propyl-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

52. The compound of claim 28, wherein said compound is R-4W which is represented by the chemical formula (R)-N-(3-(3-trifluoromethyl)phenyl)propyl- 1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

53. The compound of claim 28, wherein said compound is 6X which is represented by the chemical formula (R)-N-(3-(3-chlorophenyl)propyl-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.

54. The compound of claim 28, wherein said compound is 21M which is represented by the chemical formula (R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine ) or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compound 4W which is represented by the chemical formula N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt thereof.
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