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Claims for Patent: 6,011,068

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Claims for Patent: 6,011,068

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:08/353,784
Patent Claims: 1. A compound having the chemical formula: ##STR15## wherein alk is selected from the group consisting of n-propylene, 2,4-butylene and 1,3-butylene;

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 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 hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; provided that if R.sub.2 is phenyl, then said phenyl R.sub.2 has at least one substituent and is not 4-OH-phenyl; or a pharmaceutically acceptable acid addition salt or complex thereof.

2. The compound of claim 1 wherein alk is n-propylene.

3. The compound of claim 2 wherein R.sub.1 is methyl.

4. The compound of claim 3 wherein R.sub.2 is a substituted phenyl and R.sub.3 is an optionally substituted phenyl.

5. A compound having the chemical formula: ##STR16## wherein alk is either n-propylene, 2,4-butylene, or 1,3-butylene; R.sub.1 is a lower alkyl of from 1 to 3 carbon atoms;

R.sub.2 is either naphthyl or a phenyl substituted with 1 to 5 substituents, and R.sub.3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents; wherein each of said R.sub.2 substituents and each of said R.sub.3 substituents are 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 hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms;

provided that R.sub.2 is not 4-OH-phenyl; or

a pharmaceutically acceptable acid addition salt or complex thereof.

6. The compound of claim 5, wherein

R.sub.1 is methyl; and

each of said R.sub.2 substituents and each of said R.sub.3 substituents are 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, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

7. The compound of claim 6, wherein

R.sub.2 is either naphthyl or said phenyl having 1 to 5 substituents; and

R.sub.3 is either naphthyl or said phenyl optionally substituted with 1 to 5 substituents.

8. The compound of claim 7, wherein alk is 2,4-butylene.

9. The compound of claim 7, wherein alk is 1,3-butylene.

10. The compound of any one of claims 8 or 9, wherein R.sub.3 is naphthyl.

11. The compound of any one of claims 8 or 9, wherein R.sub.3 is said optionally substituted phenyl.

12. The compound of claim 11, wherein R.sub.2 is naphthyl.

13. The compound of claim 11, wherein R.sub.2 is said substituted phenyl.

14. The compound of claim 13, wherein said R.sub.2 substituted phenyl is a meta-substituted phenyl.

15. The compound of claim 14, wherein said R.sub.2 metasubstituted 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.

16. The compound of claim 15, wherein said R.sub.2 meta substituent is methoxy.

17. The compound of claim 15, wherein said R.sub.2 meta substituent is trihalomethyl.

18. The compound of claim 15, wherein said R.sub.2 meta substituent is lower thioalkyl of 1 to 3 carbon atoms.

19. The compound of claim 16, 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.

20. The compound of claim 19, wherein said R.sub.3 substituted phenyl is an ortho-substituted phenyl having either a chloro or fluoro substituent.

21. The compound of any one of claims 5-7, wherein said compound is an R enantiomer having the following chemical structure: ##STR17## or a pharmaceutically acceptable acid addition salt or complex thereof.

22. The compound of claim 11, wherein said compound is an R enantiomer having the following chemical structure: ##STR18## or a pharmaceutically acceptable acid addition salt or complex thereof.

23. The compound of claim 15, wherein said compound is an R enantiomer having the following chemical structure: ##STR19## or a pharmaceutically acceptable acid addition salt or complex thereof.

24. The compound of claim 5, wherein said compound ##STR20## or a pharmaceutically acceptable acid addition salt or complex thereof.

25. compound of claim 5, wherein said compound ##STR21## or a pharmaceutically acceptable acid addition salt or complex thereof.

26. A compound represented by a formula selected from the group consisting of ##STR22## wherein m is independently an integer of 0 to 5 for naphthyl rings and m is independently an integer of 1 to 5 for phenyl rings;

x is independently selected from the group consisting of --Br, --C1, --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; provided that the X substituent on the phenyl ring of the Ph-CHR-group is other than hydroxy, 4-OCH.sub.3, or 4-CH.sub.3 ; 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; provided that if said compound has the chemical formula: ##STR23## wherein the naphthyl is either unsubstitued or substituted with a lower alkyl or halogen and only one substituent is present on the phenyl, then said one substituent is not lower alkyl or halogen; or a pharmaceutically acceptable acid addition salt or complex thereof.

27. The compound of claim 26, wherein each R is independently C.sub.1 -C.sub.3 alkyl.

28. The compound of claim 26, represented by a formula selected from the group consisting of: ##STR24## wherein each m is independently an integer of 1 to 5; each X is independently selected from the group consisting of --C1, --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 acid addition salt or complex thereof.

29. The compound of claim 28, wherein each m is independently an integer of 1 or 2;

X is independently selected from the group consisting of --C1, --F, --CF.sub.3, --SCH.sub.3, methyl and methoxy radicals, and

R is a hydrogen or methyl radical.

30. The compound of claim 29, wherein said compound has the following formula: ##STR25## or a pharmaceutically acceptable acid addition salt or complex thereof.

31. The compound of claim 29, wherein said compound has the following formula: ##STR26## or a pharmaceutically acceptable acid addition salt or complex thereof.

32. The compound of claim 29, wherein said compound has the following formula: ##STR27## or a pharmaceutically acceptable acid addition salt or complex thereof.

33. The compound of claim 29, wherein said compound has the following formula: ##STR28## or a pharmaceutically acceptable acid addition salt or complex thereof.

34. The compound of claim 29, wherein said compound has the following formula: ##STR29## or a pharmaceutically acceptable acid addition salt or complex thereof.

35. The compound of claim 29, wherein said compound has the following formula: ##STR30## or a pharmaceutically acceptable acid addition salt or complex thereof.

36. The compound of claim 26, wherein said compound has a chemical structure selected from the group consisting of: ##STR31## or a pharmaceutically acceptable acid addition salt or complex thereof.

37. A pharmaceutical composition comprising the compound of any one of claims 26-29 and 30-36, and a pharmaceutically acceptable carrier.

38. A compound having the chemical formula: ##STR32## wherein alk is 1,1-ethylidine or methylene; 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 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 hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms;

provided that R.sub.2 is not and unsubstituted phenyl and R.sub.3 is not an unsubstituted phenyl;

further provided that if alk is methylene then either, R.sub.2 and R.sub.3 are both substituted phenyls, R.sub.3 does not contain a OH substituent, and R.sub.3 is not 4-OCH.sub.3 -phenyl, or 4-CH.sub.3 -phenyl, or R.sub.2 is an optionally substituted naphthyl and R.sub.3 is a substituted phenyl not containing an OH substituent; and

further provided that if one of R.sub.2 or R.sub.3 is naphthyl or naphthyl substituted with a lower alkyl of 1 to 3 carbons or halogen and the other of R.sub.2 or R.sub.3 is phenyl, then the phenyl has 1-5 substituents and if one substituent is present, then the one substituent is other than 2-OH, lower alkyl of 1 to 3 carbons or halogen; or a pharmaceutically acceptable acid addition salt or complex thereof.

39. The compound of claim 38, wherein R.sub.2 is either naphthyl or a substituted phenyl having 1 to 5 substituents; and

R.sub.3 is either naphthyl or a substituted phenyl having 1 to 5 substituents.

40. The compound of claim 39, wherein each of said substituents are 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, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

41. The compound of claim 40, wherein R.sub.3 is substituted phenyl.

42. The compound of claim 41, wherein R.sub.2 is naphthyl.

43. The compound of claim 41, wherein R.sub.2 is substituted phenyl.

44. The compound of claim 43, wherein said R.sub.3 substituted phenyl is substituted with 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.

45. The compound of any one of claims 38-44, wherein said compound is an R enantiomer having the chemical formula: ##STR33## or a pharmaceutically acceptable acid addition salt or complex thereof.

46. The compound of claim 45, 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 loaded with fura-2 using the Cytosolic Ca.sup.2+ Cell Assay.

47. The compound of any one of claims 38-44, wherein alk is methylene.

48. The compound of any one of claims 38-44, wherein alk is 1,1-ethylidine.

49. A compound selected from the group consisting of: ##STR34## or a pharmaceutically acceptable acid addition salt or complex thereof.

50. The compound of claim 49, wherein said compound is selected from group consisting of: ##STR35## or a pharmaceutically acceptable acid addition salt or complex thereof.

51. The compound of claim 50, wherein said compound is selecced from the group consistirng of; ##STR36## or a pharmaceutically acceptable acid addition salt or complex thereof.

52. The compound of claim 49, wherein said compound is ##STR37## or a pharmaceutically acceptable acid addition salt or complex thereof.

53. The compound of claim 49, wherein said compound is ##STR38## or a pharmaceutically acceptable acid addition salt or complex thereof.

54. The compound of claim 49, wherein said compound is ##STR39## or a pharmaceutically acceptable acid addition salt or complex thereof.

55. The compound of claim 49, wherein said compound is ##STR40## or a pharmaceutically acceptable acid addition salt or complex thereof.

56. The compound of claim 49, wherein said compound is ##STR41## or a pharmaceutically acceptable acid addition salt or complex thereof.

57. The compound of claim 49, wherein said compound is ##STR42## or a pharmaceutically acceptable acid addition salt or complex thereof.

58. The compound of claim 49, wherein said compound is ##STR43## or a pharmaceutically acceptable acid addition salt or complex thereof.

59. The compound of claim 49, wherein said compound is selected from the group consisting of: ##STR44## or a pharmaceutically acceptable acid addition salt or complex thereof.

60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of claims 49-59.

61. The compound of claim 5, wherein

R.sub.1 is methyl; and

each of said R.sub.2 substituents and each of said R.sub.3 substituents are 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, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

62. The compound of claim 61, wherein alk is n-propylene.

63. The compound of claim 61, wherein alk is 1,1-ethylidine.

64. The compound of claim 61, wherein alk is 274-butylene.

65. The compound of claim 61, wherein alk is 1,3-butylene.

66. The compound of any one of claims 61-65, wherein R.sub.3 is naphthyl.

67. The compound of any one of claims 61-65, wherein R.sub.3 is said optionally substituted phenyl.

68. The compound of claim 67, wherein R.sub.2 is naphthyl.

69. The compound of claim 67, wherein R.sub.2 is said substituted phenyl.

70. The compound of claim 69, wherein said R.sub.2 substituted phenyl is a meta-substituted phenyl.

71. The comnpound of claimn 70, 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.

72. The compound of claim 71, wherein said R.sub.2 meta substituent is methoxy.

73. The compound of any one of claims 61-65, wherein said compound is an a enantiomer having the following chemical structure: ##STR45## or a pharmaceutically acceptable acid addition salt or complex thereof.

74. The compound of claim 73, 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 loaded with fura-2 using the Cytosolic Ca.sup.2+ Cell Assay.

75. The pharmaceutical composition of claim 100, 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 loaded with fura-2 using the Cytosolic Ca.sup.2+ Cell assay.

76. The pharmaceutical composition of claim 101, 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 loaded with fura-2 using the cytosolic Ca.sup.2+ cell assay.

77. The compound of claim 21, 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 loaded with fura-2 using the Cytosolic Ca.sup.2+ Cell Assay.

78. The compound of claim 23, 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 loaded with fura-2 using the Cytosolic Ca.sup.2+ Cell Assay.

79. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the chemical formula: ##STR46## wherein alk is a straight- or branched-chain alkylene of from 0 to 6 carbon atoms;

R.sub.1 is a lower alkyl of from 1 to 3 carbon atoms or a 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 each 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 hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; provided that if R.sub.2 is phenyl, then R.sub.2 is substituted with 1 to 5 substituents; further provided that if R.sub.3 is cycloalk and alk is --CH.sub.2 --, then R.sub.2 is not 4 aminophenyl; or a pharmaceutically acceptable acid addition salt or complex thereof.

80. The pharmaceutical composition of claim 79, wherein alk is 1 to 6 carbon atoms;

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 hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

81. The pharmaceutical composition of claim 79, 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 hydroxyalkyl 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 hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms.

82. The pharmaceutical composition of claim 81, wherein alk is an alkylene chain 1 to 3 carbon atoms in length which may be substituted with a methyl.

83. The pharmaceutical composition of claim 81, wherein R.sub.1 is methyl.

84. The pharmaceutical composition of claim 83, wherein alk is n-propylene.

85. The pharmaceutical composition of claim 83, wherein alk is 1,1-ethylidine.

86. The pharmaceutical composition of claim 83, wherein alk is 2,4-butylene.

87. The pharmaceutical composition of claim 83, wherein alk is 1,3-butylene.

88. The pharmaceutical composition of claim 83, wherein alk is methylene.

89. The pharmaceutical composition of any one of claims 84-88, wherein R.sub.3 is naphthyl.

90. The pharmaceutical composition of any one of claims 84 -88, wherein R.sub.3 is said optionally substituted phenyl.

91. The pharmaceutical composition of claim 90, wherein R.sub.2 is naphthyl.

92. The pharmaceutical composition of claim 90, wherein R.sub.2 is said substituted phenyl.

93. The pharmaceutical composition of claim 92, wherein said R.sub.2 substituted phenyl is a meta-substituted phenyl.

94. The pharmaceutical composition of claim 93, 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.

95. The pharmaceutical composition of claim 94, wherein said R.sub.2 meta substituent is methoxy.

96. The pharmaceutical composition of claim 94, wherein said R.sub.2 meta substituent is trihalomethyl.

97. The pharmaceutical composition of claim 94, wherein said R.sub.2 meta substituent is a lower thioalkyl of 1 to 3 carbon atoms.

98. The pharmaceutical composition of claim 94, 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.

99. The pharmaceutical composition of claim 98, wherein said R.sub.3 substituted phenyl is an ortho-substituted phenyl having either a chloro or fluoro substituent.

100. The pharmaceutical composition of any one of claims 80 -83, wherein said compound is an R enantiomer having the following chemical structure: ##STR47## or a pharmaceutically acceptable acid addition salt or complex thereof.

101. The pharmaceutical composition of claim 94, wherein said compound is an R enantiomer having the following chemical structure: ##STR48## or a pharmaceutically acceptable acid addition salt or complex thereof.

102. The pharmaceutical composition of claim 95, wherein said compound is an R enantiomer having the following chemical structure: ##STR49## or a pharmaceutically acceptable acid addition salt or complex thereof.

103. The pharmaceutical composition of claim 79, wherein said compound is ##STR50## or a pharmaceutically acceptable acid addition salt or complex thereof.
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