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Claims for Patent: 6,031,003

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Claims for Patent: 6,031,003

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): Nemeth; Edward F. (Salt Lake City, UT), Van Wagenen; Bradford C. (Salt Lake City, UT), Balandrin; Manuel F. (Sandy, UT), DelMar; Eric G. (Salt Lake City, UT), Moe; Scott T. (Salt Lake City, UT)
Assignee: NPS Pharmaceuticals, Inc. (Salt Lake City, UT) The Brigham and Women's Hospital (Boston, MA)
Application Number:08/484,719
Patent Claims: 1. A method of treating a patient having a disease or disorder which may be treated by a compound which modulates one or more activities of a calcium receptor in vitro comprising the step of administering to said patient a therapeutically effective amount of said compound, provided that if said compound is a calcimimetic compound, then said calcimimetic 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 loaded with fura-2 using the cytosolic Ca.sup.2+ cell assay, and if said compound is a calcilytic compound, then said calcilytic compound has an IC.sub.50 less than or equal to 5 .mu.M as determined by the calcilytic bovine parathyroid cell assay, wherein said compound is not protamine.

2. The method of claim 1 wherein said patient is treated using said calcimimetic compound.

3. The method of claim 1 wherein said patient is treated using said calcilytic compound.

4. The method of claim 1 wherein said compound has the formula: ##STR16## wherein each X is independently either H, CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, I, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CF.sub.3 CH.sub.2 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, or acetoxy, or two X together is methylene dioxy;

each Ar independently is a hydrophobic entity selected from the group consisting of aromatic or cycloaliphatic ring or ring system;

each R independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, allyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, dihydroindolyl, thiodihydroindolyl, and 2-, 3-, or 4-piperid(in)yl;

Y is selected from the group consisting of CH and nitrogen; and

Z is selected from the group consisting of oxygen, nitrogen, sulfur, ##STR17## wherein n is between 1 and 4 inclusive, and each m is independently between 0 and 5 inclusive; or a pharmaceutically acceptable salt thereof.

5. The method of claim 4 wherein said hydrophobic entity is selected from the group consisting of phenyl, cyclohexyl, 2-, 3-, or 4-pyridyl, 1- or 2-naphthyl, .alpha.- or .beta.-tetrahydronaphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy.

6. The method of claim 2, wherein said calcimimetic compound is a substituted R-phenylpropyl-.alpha.-phenethylamine derivative or a substituted R-benzyl-.alpha.-1-naphthylethylamine derivative.

7. The method of claim 4, wherein said calcimimetic compound has the formula: ##STR18## and R is H, CH.sub.3, ethyl, or isopropyl; or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 wherein each X is independently selected from the group consisting of Cl, Br, F, I, CF.sub.3, CH.sub.3, CH.sub.3 O, CF.sub.3 O, CH.sub.3 S, and CF.sub.3 CH.sub.2 O.

9. The method of claim 2 wherein said calcimimetic compound has the formula: ##STR19## wherein alk is straight or branched-chain alkylene of from 0 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms or lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; and

R.sub.2 and R.sub.3 are independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein alk is n-propylene.

11. The method of claim 10 wherein R.sub.1 is methyl.

12. The method of claim 11 wherein R.sub.2 and R.sub.3 are independently selected from optionally substituted phenyl groups.

13. The method of claim 2 wherein said method reduces parathyroid hormone level in said patient.

14. The method of claim 13 wherein said patient has an elevated level of parathyroid hormone and said method reduces parathyroid hormone level to that present in a normal individual.

15. The method of claim 3, wherein said method is used to treat a patient having osteoporosis.

16. The method of claim 13 wherein said level of said parathyroid hormone is reduced to a degree sufficient to cause a decrease in plasma Ca.sup.2+.

17. The method of claim 4 wherein said method reduces parathyroid hormone level in said patient.

18. The method of claim 7 wherein said method reduces parathyroid hormone level in said patient.

19. The method of claim 9 wherein said method reduces parathyroid hormone level in said patient.

20. The method of claim wherein said method reduces parathyroid hormone level in said patient.

21. The method of claim 1 wherein said patient benefits from inhibiting bone resorption and said method inhibits bone resorption in said patient.

22. The method of claim 4 wherein said patient benefits from inhibiting bone resorption and said method inhibits bone resorption in said patient.

23. The method of claim 9 wherein said patient benefits from inhibiting bone resorption and said method inhibits bone resorption in said patient.

24. The method of claim 11 wherein said patient benefits from inhibiting bone resorption and said method inhibits bone resorption in said patient.

25. The method of claim 4 wherein said compound stimulates calcitonin secretion in vitro or in vivo.

26. The method of claim 2 wherein said calcimimetic compound is either ##STR20## or a pharmaceutically acceptable salt thereof.

27. The method of claim 2 wherein said calcimimetic compound has an EC.sub.50 less than or equal to 1 .mu.M.

28. The method of claim 27 wherein said calcimimetic compound has an EC.sub.50 less than or equal to 100 nanomolar.

29. The method of claim 28 wherein said calcimimetic compound has an EC.sub.50 less than or equal to 10 nanomolar.

30. The method claim 29 wherein said calcimimetic compound has an EC.sub.50 less than or equal to 1 nanomolar.

31. A method of treating a patient having a disease or disorder which may be treated by a compound which modulates one or more activities of a calcium receptor in vitro comprising the step of administering to said patient a therapeutically effective amount of said compound, wherein said compound has the chemical formula: ##STR21## wherein each X is independently either H, CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, I, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CF.sub.3 CH.sub.2 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, or acetoxy or two X together is methylene dioxy;

each Ar is independently selected from the group consisting of phenyl, cyclohexyl, 2-, 3-, or 4-pyridyl, 1- or 2-naphthyl, .alpha.- or .beta.-tetrahydronaphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy;

each R is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, allyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, dihydroindolyl, thiodihydroindolyl, and 2-, 3-, or 4- piperid(in)yl;

Y is selected from the group consisting of CH and nitrogen;

and Z is selected from the group consisting of oxygen, nitrogen, sulfur, ##STR22## wherein n is between 1 and 4 inclusive, and each m is independently between 0 and 5 inclusive, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein

each X is independently selected from the group consisting of H, 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 ;

each Ar is independently selected from the group consisting of phenyl, 2-, 3-, or 4-pyridyl, 1- or 2-naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy; and

each R is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, dihydroindolyl, thiodihydroindolyl, and 2-, 3-, or 4-piperid(in)yl.

33. The method of claims 31 or 32, wherein said compound is an R enantiomer having the chemical formula: ##STR23## or a pharmaceutically acceptable salt thereof.

34. The method of claims 31 or 32, wherein each Ar is independently either phenoxy, phenyl, or 1- or 2-naphthyl.

35. The method of claim 34, wherein said disease or disorder is selected from the group consisting of hyperparathyroidism, Paget's disease, and osteoporosis.

36. The method of claim 35, wherein each Ar is independently either phenyl, or 1- or 2-naphthyl.

37. The method of claim 36, wherein said disease or disorder is hyperparathyroidism.

38. The method of claim 36, wherein said disease or disorder is Paget's disease.

39. The method of claim 36, wherein said disease or disorder is osteoporosis.

40. A method of treating a patient having a disease or disorder which may be treated by a compound which modulates one or more activities of a calcium receptor in vitro comprising the step of administering to said patient a therapeutically effective amount of said compound, wherein said compound has the chemical formula: ##STR24## wherein alk is straight or branched-chain alkylene of from 0 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms or lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; and

R.sub.2 and R.sub.3 are independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents each independently selected from the group consisting of OCF.sub.3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms; and

R.sub.2 is either naphthyl or a substituted phenyl having 1 to 5 substituents, and R.sub.3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents, wherein each R.sub.2 and R.sub.3 substituent is independently selected from the group consisting of: OCF.sub.3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

42. The method of claim 40, wherein

alk is 1 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms;

R.sub.2 is either naphthyl or a substituted phenyl having 1 to 5 substituents each independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; and

R.sub.3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

43. The method of claim 42, wherein alk is an alkylene chain 1 to 3 carbon atoms in length which may be substituted with a methyl.

44. The method of claim 42, wherein R.sub.1 is methyl.

45. The method of claim 44, wherein alk is n-propylene.

46. The method of claim 44, wherein alk is 1,1-ethylidine.

47. The method of claim 44, wherein alk is 2,4-butylene.

48. The method of claim 44, wherein alk is 1,3-butylene.

49. The method of claim 44, wherein alk is methylene.

50. The method of claim 44, wherein R.sub.3 is naphthyl.

51. The method of claim 44, wherein R.sub.3 is said optionally substituted phenyl.

52. The method of claim 51, wherein R.sub.2 is naphthyl.

53. The method of claim 51, wherein R.sub.2 is said substituted phenyl.

54. The method of claim 53, wherein said R.sub.2 substituted phenyl is a meta-substituted phenyl.

55. The method of claim 54, wherein said R.sub.2 meta-substituted phenyl has a meta substituent selected from the group consisting of: halogen, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

56. The method of claim 55, wherein said R.sub.2 meta substituent is methoxy.

57. The method of claim 55, wherein said R.sub.2 meta substituent is trihalomethyl.

58. The method of claim 55, wherein said R.sub.2 meta substituent is a lower thioalkyl of 1 to 3 carbon atoms.

59. The method of claim 55, wherein said R.sub.3 optionally substituted phenyl is a substituted phenyl having one or more substituents each independently selected from the group consisting of: halogen, CF.sub.3, alkoxy of 1 to 3 carbon atoms, and lower alkyl of 1 to 3 carbon atoms.

60. The method of claim 59, wherein said R.sub.3 substituted phenyl is an ortho-substituted phenyl having either a chloro or fluoro substituent.

61. The method of claim 52, wherein alk is 1,1 ethylidine.

62. The method of claim 54, wherein alk is n-propylene.

63. The method of claim 54, wherein alk is 2,4 butylene.

64. The method of claim 40, wherein said compound is selected from the group consisting of:

NPS 467 (N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine);

NPS 568 (N-(3-(2-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4M (N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4N/40) (N-(3-(3-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4P/4Q (N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4V (N-(3-(2-(trifluoromethyl)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4W (N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine); and

6X/6Y (N-(3-(3-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

or a pharmaceutically acceptable salt thereof.

65. The method of claim 64, wherein said compound is NPS R-568 ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

66. The method of claim 64, wherein said compound is NPS R-467 ((R)-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

67. The method of claim 64, wherein said compound is 4M (N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

68. The method of claim 67, wherein said compound is R-4M ((R)-N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

69. The method of claim 64, wherein said compound is 4N/4O (N-(3-(3-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

70. The method of claim 69, wherein said compound is 4N ((R)-N-(3-(3-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

71. The method of claim 64, wherein said compound is 4P/4Q (N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

72. The method of claim 71, wherein said compound is 4P ((R)-N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

73. The method of claim 64, wherein said compound is 4V (N-(3-(2-tri(fluoromethyl)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein said compound is R-4V ((R)-N-(3-(2-tri(fluoromethylphenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

75. The method of claim 64, wherein said compound is 4W (N-(3-(3-tri(fluoromethylphenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

76. The method of claim 75, wherein said compound is R-4W ((R)-N-(3-(3-tri(fluoromethylphenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

77. The method of claim 64, wherein said compound is 6X/6Y (N-(3-(3-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

78. The method of claim 77, wherein said compound is 6X ((R)-N-(3-(3-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt thereof.

79. The method of claim 40, wherein said compound is 21M ((R-)-N-(3-(3-tri(fluoromethoxy)phenyl)propyl)-1-(3-methoxyphenyl)ethylami ne) or a pharmaceutically acceptable salt thereof.

80. The method of any one of claims 40 or 41-63, wherein said compound is an R enantiomer having the following absolute configuration: ##STR25## or a pharmaceutically acceptable salt thereof.

81. The method of claim 80 wherein said patient is a human.

82. A method of modulating parathyroid hormone secretion in a patient who would benefit from such treatment comprising administering an effective amount of a compound of the formula: ##STR26## wherein alk is a straight or branched chain alkylene of 0-6 carbon atoms: R.sub.1 is an alkyl radical of 1-3 carbon atoms or a haloalkyl radical of 1-3 carbon atoms substituted with 1-7 halogen atoms:

R.sub.2 and R.sub.3 are each independently monocyclic or bicyclic aryl or cycloalkyl radicals of 5-7 ring member carbon atoms, which are optionally substituted with 1-5 radicals of alkyl of 1-3 carbon atoms, haloalkyl of 1-3 carbon atoms substituted with 1-7 halogen atoms, alkoxy of 1-3 carbon atoms, halogen, nitro, amino, alkylamino of 1-3 carbon atoms, amido, alkylamido of 1-3 carbon atoms, cyano, hydroxy, acyl of 2-4 carbon atoms, hydroxyalkyl of 1-3 carbon atoms, or thioalkyl of 1-3 carbon atoms; or a pharmaceutically acceptable salt thereof.

83. A method of modulating parathyroid hormone secretion in a patient who would benefit from such treatment comprising administering an effective amount of a compound of the formula: ##STR27## wherein m is independently an integer of 0-5; X is independently selected from the group consisting of --Br, --Cl, --F, --I, --CN, NO.sub.2, OR, NR.sub.2, CF.sub.3, --SR, --S(O)R, --S(O).sub.2 R, --C(O)R, --OC(O)R, --C(O)OR, --NRC(O)R, --C(O)NR.sub.2, methyl and isopropyl radicals; and

each R is independently either a hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.10 cycloalkyl, --CF.sub.3, CF.sub.2 H, --CFH.sub.2, --CH.sub.2 CF.sub.3 or phenyl radical; or a pharmaceutically acceptable salt thereof.

84. The method of claim 83, wherein R is independently C.sub.1 -C.sub.3 alkyl or hydrogen.

85. The method of claim 84, comprising administering an effective amount of a compound of the formula: ##STR28## wherein m is independently an integer of 1 to 5; X is independently selected from the group consisting of --Cl, --F, --I, --CF.sub.3, --OCF.sub.3 --OCH.sub.2 CF.sub.3, --SCH.sub.3, methyl, isopropyl and methoxy radicals; and

R is a hydrogen, methyl, ethyl, or isopropyl radical; or a pharmaceutically acceptable salt thereof.

86. The method of claim 85, wherein

m is independently an integer of 1 or 2;

X is independently selected from the group consisting of --Cl, --F, CF.sub.3, --SCH.sub.3, methyl and methoxy radicals; and

R is a hydrogen or methyl radical.

87. The method of claim 83, wherein said compound is selected from the group consisting of:

NPS R-568 ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

NPS R-467 ((R)-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine);

R-4M ((R)-N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4N ((R)-N-(3-(3-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

4P ((R)-N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine);

R-4V ((R)-N-(3-(2-tri(fluoromethyl)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine );

R-4W ((R)-N-(3-(3-tri(fluoromethyl)phenyl)propyl)-1-(3-methoxyphenyl)ethylamine ); and

6X ((R)-N-(3-(3-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine); or a pharmaceutically acceptable salt thereof.

88. The method of claim 83, wherein said compound is 21M ((R-)-N-(3-(3-tri(fluoromethoxy)phenyl)propyl)-1-(3-methoxyphenyl)ethylami ne or a pharmaceutically acceptable salt thereof.

89. A method of treating hyperparathyroidism comprising the step of administering to a patient an effective amount of a compound of the formula: ##STR29## wherein alk is a straight or branched chain alkylene of 0-6 carbon atoms: R.sub.1 is an alkyl radical of 1-3 carbon atoms or a haloalkyl radical of 1-3 carbon atoms substituted with 1-7 halogen atoms:

R.sub.2 and R.sub.3 are each independently monocyclic or bicyclic aryl or cycloalkyl radicals of 5-7 ring member carbon atoms, which are optionally substituted with 1-5 radicals of alkyl of 1-3 carbon atoms, haloalkyl of 1-3 carbon atoms substituted with 1-7 halogen atoms, alkoxy of 1-3 carbon atoms, halogen, nitro, amino, alkylamino of 1-3 carbon atoms, amido, alkylamido of 1-3 carbon atoms, cyano, hydroxy, acyl of 2-4 carbon atoms, hydroxyalkyl of 1-3 carbon atoms, or thioalkyl of 1-3 carbon atoms; or a pharmaceutically acceptable salt thereof.

90. A method of treating hyperparathyroidism comprising the step of administering to a patient an effective amount of a compound of the formula: ##STR30## wherein m is independently an integer of 0-5; X is independently selected from the group consisting of --Br, --Cl, --F, --I, --CN, NO.sub.2, OR, NR.sub.2, CF.sub.3, --SR, --S(O)R, --S(O).sub.2 R, --C(O)R, --OC(O)R, --C(O)OR, --NRC(O)R, --C(O)NR.sub.2, methyl and isopropyl radicals; and

each R is independently either a hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.10 cycloalkyl, --CF.sub.3, CF.sub.2 H, --CFH.sub.2, --CH.sub.2 CF.sub.3 or phenyl radical; or a pharmaceutically acceptable salt thereof.

91. The method of claim 90, wherein R is independently C.sub.1 -C.sub.3 alkyl or hydrogen.

92. The method of claim 91, comprising administering an effective amount of a compound of the formula: ##STR31## wherein m is independently an integer of 1 to 5; X is independently selected from the group consisting of --Cl, --F, --I, --CF.sub.3, --OCF.sub.3 --OCH.sub.2 CF.sub.3, --SCH.sub.3, methyl, isopropyl and methoxy radicals; and

R is a hydrogen, methyl, ethyl, or isopropyl radical; or a pharmaceutically acceptable salt thereof.

93. The method of claim 92, wherein

m is independently an integer of 1 or 2;

X is independently selected from the group consisting of --Cl, --F, --CF.sub.3, --SCH.sub.3, methyl and methoxy radicals; and

R is a hydrogen or methyl radical.

94. The method of claim 83, wherein said compound is either ##STR32## or a pharmaceutically acceptable salt thereof.

95. A method of enhancing bone formation in a patient in need of such treatment by causing an increase in parathyroid hormone levels comprising the step of administering to said patient an effective amount of a calcilytic compound to cause an increase in parathyroid hormone, wherein said calcilytic compound decreases one or more activities of a calcium receptor in vitro.

96. A method of treating a patient having a disease or disorder which may be treated by a calcilytic compound which decreases one or more activities of a calcium receptor in vitro comprising the step of administering to said patient a therapeutically effective amount of said compound, provided that said patient has Paget's disease or osteoporosis.

97. The method of claim 96, wherein said disease or disorder is Paget's disease.

98. The method of claim 96, wherein said disease or disorder is osteoporosis.

99. A method of decreasing parathyroid hormone level in a patient who would benefit from such treatment comprising the step of administering to said patient an effective amount of a compound having the chemical formula: ##STR33## wherein each X is independently either H, CH.sub.3, CH.sub.3 O, CH.sub.3 CH.sub.2 O, Br, Cl, F, I, CF.sub.3, CHF.sub.2, CH.sub.2 F, CF.sub.3 O, CF.sub.3 CH.sub.2 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, or acetoxy, or two X together make up methylene dioxy;

each Ar is independently selected from the group consisting of phenyl, cyclohexyl, 2-, 3-, or 4-pyridyl, 1- or 2-naphthyl, .alpha.- or .beta.-tetrahydronaphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy;

each R is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, allyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, dihydroindolyl, thiodihydroindolyl, and 2-, 3-, or 4-piperid(in)yl;

Y is selected from the group consisting of CH and nitrogen; and Z is selected from the group consisting of oxygen, nitrogen, sulfur, ##STR34## wherein n is between 1 and 4 inclusive, and each m is independently between 0 and 5 inclusive, or a pharmaceutically acceptable salt thereof.

100. The method of claim 99, wherein

each X is independently selected from the group consisting of H, 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 ;

each Ar is independently selected from the group consisting of phenyl, 2-, 3-, or 4-pyridyl, 1- or 2-naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy; and

each R is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, dihydroindolyl, thiodihydroindolyl, and 2-, 3-, or 4-piperid(in)yl.

101. The method of claims 99 or 100, wherein said chemical formula is: ##STR35## or a pharmaceutically acceptable salt thereof.

102. The method of claim 101, wherein each Ar is independently either phenoxy, phenyl, or 1- or 2-naphthyl.

103. The method of claim 102, wherein said compound is an R enantiomer having the chemical formula: ##STR36## or a pharmaceutically acceptable salt thereof; and said patient is a human.

104. A method to decrease parathyroid hormone level in a patient who would benefit from such treatment comprising the step of administering to said patient an effective amount of a compound having the chemical formula: ##STR37## wherein alk is straight or branched-chain alkylene of from 0 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms or lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; and

R.sub.2 and R.sub.3 are independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents each independently selected from the group consisting of OCF.sub.3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof.

105. The method of claim 104, wherein

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms; and

R.sub.2 is either naphthyl or a substituted phenyl having 1 to 5 substituents, and R.sub.3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents, wherein each R.sub.2 and R.sub.3 substituent is independently selected from the group consisting of: OCF.sub.3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

106. The method of claim 104, wherein

alk is 1 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms;

R.sub.2 is either naphthyl or a substituted phenyl having 1 to 5 substituents each independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; and

R.sub.3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

107. The method of claim 106, wherein alk is an alkylene chain 1 to 3 carbon atoms in length which may be substituted with a methyl.

108. The method of claim 106, wherein R.sub.1 is methyl.

109. The method of claim 108, wherein alk is n-propylene.

110. The method of claim 108, wherein alk is 1,1-ethylidine.

111. The method of claim 108, wherein alk is 2,4-butylene.

112. The method of claim 108, wherein alk is 1,3-butylene.

113. The method of claim 108, wherein alk is methylene.

114. The method of claim 108, wherein R.sub.3 is naphthyl.

115. The method of claim 108, wherein R.sub.3 is said optionally substituted phenyl.

116. The method of claim 109, wherein R.sub.2 is naphthyl.

117. The method of claim 109, wherein R.sub.2 is said substituted phenyl.

118. The method of claim 117, wherein said R.sub.2 substituted phenyl is a meta-substituted phenyl.

119. The method of claim 104, wherein said compound is selected from the group consisting of: ##STR38## or a pharmaceutically acceptable salt thereof.

120. The method of claim 119, wherein said compound is selected from the group consisting of: ##STR39## or a pharmaceutically acceptable salt thereof.

121. The method of claim 119, wherein said compound is selected from the group consisting of: ##STR40## or a pharmaceutically acceptable salt thereof.

122. The method of claim 104, wherein said compound is ##STR41## or a pharmaceutically salt thereof.

123. The method of claim 104, wherein said compound is ##STR42## or a pharmaceutically acceptable salt thereof.

124. The method of claim 104, wherein said compound is ##STR43## or a pharmaceutically acceptable salt thereof.

125. The method of claim 104, wherein said compound is ##STR44## or a pharmaceutically acceptable salt thereof.

126. The method of claim 104, wherein said compound is ##STR45## or a pharmaceutically acceptable salt thereof.

127. The method of claim 104, wherein said compound is ##STR46## or a pharmaceutically acceptable salt thereof.

128. The method of claim 104, wherein said compound is ##STR47## or a pharmaceutically acceptable salt thereof.

129. The method of claim 104, wherein said compound is ##STR48## or a pharmaceutically acceptable salt thereof.

130. The method of claim 104, wherein said compound is either ##STR49## or a pharmaceutically acceptable salt thereof.

131. The method any one of claims 104-130, wherein said patient is a human patient.

132. The method of any one of claims 40 and 41-79, wherein said patient is a human patient.

133. The method claim 132, wherein said patient is a human patient.

134. The method of any one of claims 1-3, 4-12, 17-28, and 30-34, wherein said patient is a human patient.

135. The method of any one of claims 1-3, 4-12, and 31-34, wherein said patient is a human patient and said disease or disorder is hyperparathyroidism.

136. The method of any one of claims 1-3, 4-12, and 27-30, wherein said patient is a human patient and said disease or disorder is Paget's disease.

137. The method of any one of claims 1-3, 4-12, and 27-30, wherein said patient is a human patient and said disease or disorder is osteoporosis.

138. The method of claim 132, wherein said disease or disorder is hyperparathyroidism.

139. The method of claim 132, wherein said disease or disorder is Paget's disease.

140. The method of claim 132, wherein said disease or disorder is osteoporosis.

141. The method of claim 2 wherein said calcimimetic compound has 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 loaded with fura-2 using the cytosolic Ca.sup.2+ cell assay, and an EC.sub.50 greater than 5 .mu.M at a bone osteoclast as measured using the molecule screening assay with rat osteoclasts.

142. A method of reducing serum ionized calcium in a patient who would benefit from such treatment comprising the step of administering to said patient an effective amount of a calcimimetic compound to reduce serum ionized calcium, wherein said calcimimetic compound increases one or more activities of a calcium receptor in vitro.

143. A method of reducing serum ionized calcium in a patient who would benefit from such treatment comprising the step of administering to said patient an effective amount of a calcimimetic compound to reduce serum ionized calcium, wherein said calcimimetic compound has the chemical formula: ##STR50## wherein alk is straight or branched-chain alkylene of from 0 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbon atoms or lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; and

R.sub.2 and R.sub.3 are independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents each independently selected from the group consisting of OCF.sub.3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof.

144. The method of claim 143,

wherein alk is straight or branched-chain alkylene of from 1 to 6 carbon atoms;

R.sub.1 is lower alkyl of from 1 to 3 carbons;

R.sub.2 and R.sub.3 are independently either naphthyl, or phenyl optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxylalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

145. The method of claim 144, wherein R.sub.1 is methyl.
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