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Claims for Patent: 6,071,970

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Claims for Patent: 6,071,970

Title: Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
Abstract:Method and compositions for treating a patient having a neurological disease or disorder, such as stroke, head trauma, spinal cord injury, epilepsy, anxiety, or neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, or amyotrophic lateral sclerosis (ALS).
Inventor(s): Mueller; Alan L. (Salt Lake City, UT), Balandrin; Manuel F. (Sandy, UT), VanWagenen; Bradford C. (Salt Lake City, UT), DelMar; Eric G. (Salt Lake City, UT), Moe; Scott T. (Salt Lake City, UT), Artman; Linda D. (Salt Lake City, UT), Barmore; Robert M. (Salt Lake City, UT)
Assignee: NPS Pharmaceuticals, Inc. (Salt Lake City, UT)
Application Number:08/485,038
Patent Claims: 1. A compound having the formula: ##STR117## wherein: each X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

and R.sup.1 is methyl, and R.sup.2 is --H;

or R.sup.1 and R.sup.2 are both --H;

or R.sup.2 is methyl, and R.sup.1 is --H;

or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;

R.sup.3 is either --H or methyl; and

n is an integer from 1 to 6;

except for compounds wherein:

R.sup.3 is --H, and each X is meta-chloro, or each X is meta-fluoro, or one X is meta-fluoro and one X is meta-chloro.

2. A compound having the following formula: ##STR118## wherein: each X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

and R.sup.1 is methyl, and R.sup.2 is H;

or R.sup.1 and R.sup.2 are both --H;

or R.sup.2 is methyl, and R.sup.1 is --H;

or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;

R.sup.3 is either --H or methyl;

and n is an integer from 1 to 6.

3. A compound selected from the group consisting of: ##STR119##

4. A compound of claim 3 selected from the group consisting of

5. A compound of claim 3 selected from the group consisting of

6. A compound having a chemical structure selected from the group consisting of

7. A compound having the chemical structure

8. A compound having the chemical structure

9. A compound having the chemical structure

10. A compound having the chemical structure

11. A compound having the chemical structure

12. A pharmaceutical composition, adapted for the treatment of a neurological disease or disorder, comprising a compound having the following formula: wherein:

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl; or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;

R.sup.3 is selected from the group consisting of --H, alkyl and 2-hydroxyethyl; n is an integer from 1 to 6;

each X is independently in the meta- or ortho- position and is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, O-alkyl, and O-acyl;

m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.

13. A pharmaceutical composition of claim 12 in a pharmaceutically acceptable complex.

14. A pharmaceutical composition of claim 12 wherein NHR.sup.3 is selected from the group consisting of --NH.sub.2 and --NH-methyl;

(X)m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl; and

R.sup.1 is methyl, and R.sup.2, R.sup.5, and R.sup.6 are --H;

or R.sup.2 is methyl, and R.sup.1, R.sup.5, and R.sup.6 are --H;

or R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are --H.

15. A pharmaceutical composition of claim 12 having the following formula: ##STR120## wherein X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;

R.sup.3 is selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5.

16. A pharmaceutical composition of claim 12 having the following formula: ##STR121## wherein X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl and hydroxyalkyl;

R.sup.3 is selected from the group consisting of H and alkyl;

and m is independently an integer from 0 to 5.

17. A pharmaceutical composition of claim 12 having the following formula: ##STR122## wherein n is an integer from 1 to 6; X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sub.3 is selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5.

18. The pharmaceutical composition of claim 12 wherein said pharmaceutically acceptable salt is a hydrochloride salt.

19. A pharmaceutical composition comprising a compound selected from the group consisting of ##STR123## and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 wherein said compound is selected from the group consisting of: ##STR124## and pharmaceutically acceptable salts thereof.

21. The pharmaceutical composition of claim 19, wherein said compound is selected from the group consisting of: ##STR125## and pharmaceutically acceptable salts thereof.

22. The pharmaceutical composition of claim 19 wherein said pharmaceutically acceptable salt is a hydrochloride salt.

23. A pharmaceutical composition having the following formula: ##STR126## wherein: (X)m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

and R.sup.1 is methyl, and R.sup.2 is --H;

or R.sup.1 and R.sup.2 are both --H;

or R.sup.2 is methyl and R.sup.1 is H;

or R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;

R.sup.3 is either --H or methyl;

and n is an integer from 1 to 6, and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, adapted for the treatment of a neurological disease or disorder.

25. A pharmaceutical composition comprising a compound having the chemical structure: ##STR127## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a compound having the chemical structure: ##STR128## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising a compound having the chemical structure: ##STR129## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising a compound having the chemical structure: ##STR130## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising a compound having the chemical structure: ##STR131## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

30. A composition comprising a compound having a chemical structure selected from the group consisting of ##STR132## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

31. A composition comprising a compound having a chemical structure selected from the group consisting of ##STR133## or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

32. A pharmaceutical composition of any of claims 12, 14, 19, 23, or 29, wherein said pharmaceutical salt is selected from the group consisting of acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, and teoclate.

33. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is stroke.

34. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is head trauma.

35. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is spinal cord injury.

36. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is epilepsy.

37. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is anxiety.

38. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is Alzheimer's disease.

39. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is Huntington's disease.

40. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is Parkinson's disease.

41. The pharmaceutical composition of any of claims 12 or 24, wherein said neurological disease or disorder is amyotrophic lateral sclerosis.

42. The pharmaceutical composition of claim 33 wherein said stroke is global ischemic.

43. The pharmaceutical composition of claim 33 wherein said stroke is hemorrhagic.

44. The pharmaceutical composition of claim 33, wherein said stroke is focal ischemic.

45. A pharmaceutical composition adapted to provide neuroprotection to a patient, comprising a compound having the following formula: ##STR134## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl; and R.sup.1 and R.sup.2 together are --(CH.sub.2)n--;

R.sup.3 is selected from the group consisting of --H, alkyl and 2-hydroxyethyl; n is an integer from 1 to 6;

each X is independently in the meta- or ortho-3position and is independen5 tly selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, O-alkyl, and O-acyl;

m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.

46. A pharmaceutical composition of claim 45 wherein NHR.sup.3 is selected from the group consisting of --NH.sub.2 and --NH-methyl;

(X)m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl; and

R.sup.1 is methyl, and R.sup.2, R.sup.5, and R.sup.6 are --H;

or R.sup.2 is methyl, and R.sup.1, R.sup.5, and R.sup.6 are --H;

or R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are --H.

47. A pharmaceutical composition of claim 45 having the following formula: ##STR135## wherein X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;

R.sup.3 is selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5.

48. A pharmaceutical composition of claim 41 having the following formula: ##STR136## wherein X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl and hydroxyalkyl;

R.sup.3 is selected from the group consisting of H and alkyl;

and m is independently an integer from 0 to 5.

49. A pharmaceutical composition of claim 47 having the following formula: ##STR137## wherein n is an integer from 1 to 6; X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.3 is selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5.

50. A pharmaceutical composition adapted to provide neuroprotection to a patient, comprising a compound selected from the group consisting of ##STR138## and pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier.

51. The pharmaceutical composition of claim 50, wherein said compound has the formula: ##STR139##

52. The pharmaceutical composition of claim 50, wherein said compound has the formula:

53. The pharmaceutical composition of claim 50, wherein said compound has the formula:

54. The pharmaceutical composition of claim 50, wherein said compound has the formula:

55. The pharmaceutical composition of claim 50, wherein said compound has the formula:

56. The pharmaceutical composition of claim 50 wherein said pharmaceutically acceptable salt is a hydrochloride salt.

57. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula wherein:

NR.sup.3 R.sup.3 is selected from the group consisting of --NH.sub.2 and --NH-methyl;

(X)m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl; and

R.sup.1 is methyl, and R.sup.2, R.sup.5, and R.sup.6 are --H;

or R.sup.2 is methyl, and R.sup.1, R.sup.5, and R.sup.6 are --H;

or R.sup.1, R.sup.2, R.sup.5, and R.sup.6 are --H;

and pharmaceutically acceptable salts thereof.

58. The method of claim 57 where said pharmaceutically acceptable salt is a hydrochloride salt.

59. The method of claim 57, wherein the neurological disease or disorder comprises stroke.

60. The method of claim 59, wherein said stroke is global ischemic.

61. The method of claim 59, wherein said stroke is focal ischemic.

62. The method of claim 59, wherein said stroke is hemorrhagic.

63. The method of claim 57, wherein the neurological disease or disorder is a neurodegenerative disease.

64. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the structure of Formula IV or V: ##STR140## wherein n is an integer from 1 to 6; X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.3 is independently selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5 or pharmaceutically acceptable salt thereof.

65. The method of claim 64 wherein said pharmaceutically acceptable salt is a hydrochloride salt.

66. The method of claim 64, wherein the neurological disease or disorder comprises stroke.

67. The method of claim 66, wherein said stroke is global ischemic.

68. The method of claim 66, wherein said stroke is focal ischemic.

69. The method of claim 66, wherein said stroke is hemorrhagic.

70. The method of claim 64, wherein the neurological disease or disorder is a neurodegenerative disease.

71. A method for treating a patient having a neurological disease or disorder comprising administering a compound having the structure of Formulas VI or VII: ##STR141## wherein n is an integer from 1 to 6; X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.3 is independently selected from the group consisting of --H and alkyl;

R.sup.4 is selected from the group consisting of alkyl and cycloalkyl;

and m is independently an integer from 0 to 5.

72. A method for treating a patient having a neurological disease or disorder comprising administering a compound selected from the group consisting of ##STR142## or pharmaceutically acceptable salt thereof.

73. The method of claim 72, wherein the compound is selected from the group consisting of ##STR143##

74. The method of claim 72, wherein the compound is selected from the group consisting of or pharmaceutically acceptable salt thereof.

75. The method of claim 72, wherein the compound is ##STR144## or pharmaceutically acceptable salt thereof.

76. The method of claim 72, wherein the compound is ##STR145## or pharmaceutically acceptable salt thereof.

77. The method of claim 72, wherein the compound is ##STR146## or pharmaceutically acceptable salt thereof.

78. The method of claim 72, wherein the compound is ##STR147## or pharmaceutically acceptable salt thereof.

79. The method of claim 72 wherein said pharmaceutically acceptable salt is a hydrochloride salt.

80. The method of claim 74 where said pharmaceutically acceptable salt is a hydrochloride salt.

81. The method of claim 75 where said pharmaceutically acceptable salt is a hydrochloride salt.

82. The method of claim 76 where said pharmaceutically acceptable salt is a hydrochloride salt.

83. The method of claim 77 where said pharmaceutically acceptable salt is a hydrochloride salt.

84. The method of claim 78 where said pharmaceutically acceptable salt is a hydrochloride salt.

85. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula: ##STR148## wherein: each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;

n is an integer from 1 to 6;

each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof.

86. The method of claim 85, wherein:

each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, --OH, --O-lower-alkyl, and --O-lower-acyl;

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

and m is independently an integer from 0 to 5.

87. The method of claim 85, wherein:

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

and each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

88. The method of claim 87, wherein:

each (X).sub.m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl; and

NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2, NH-methyl, and NH-ethyl.

89. The method of claim 88, wherein:

each (X).sub.m is meta-fluoro;

and NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2 and NH-methyl.

90. The method of claim 85, wherein the compound is in a pharmaceutically acceptable complex.

91. The method of claim 85, wherein the compound is ##STR149##

92. The method of claim 85, wherein the compound is

93. The method of claim 85, wherein the neurological disease or disorder comprises stroke, head trauma, spinal cord injury, epilepsy, anxiety, Alzheimer's disease, Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis.

94. The method of claim 93, wherein the neurological disease or disorder comprises stroke.

95. The method of claim 94, wherein said stroke is global ischemic.

96. The method of claim 94, wherein said stroke is focal ischemic.

97. The method of claim 94, wherein said stroke is hemorrhagic.

98. The method of claim 93, wherein the neurological disease or disorder is a neurodegenerative disease.

99. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula: wherein n is an integer from 1 to 6;

each X is independently selected from the group consisting of--H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.3 is selected from the group consisting of --H and alkyl; and m is independently an integer from 0 to 5, and pharmaceutically acceptable salts thereof.

100. The method of claim 99, wherein:

R.sup.3 is selected from the group consisting of --H and lower alkyl;

and each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

101. The method of claim 100, wherein:

each (X).sub.m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

and NR.sup.3 is selected from the group consisting of NH, N-methyl, and N-ethyl.

102. The method of claim 101, wherein:

each (X).sub.m is meta-fluoro;

and NR.sup.3 is selected from the group consisting of NH.sub.2 and N-methyl.

103. The method of claim 99, wherein the compound is in a pharmaceutically

acceptable complex.

104. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula: ##STR150## and pharmaceutically acceptable salts thereof.

105. The method of claim 104 wherein the neurological disease or disorder is a neurodegenerative disease.

106. A method for treating a patient having Parkinson's disease, comprising administering a compound selected from the group consisting of: ##STR151## 107.

107. A method for treating stroke, comprising administering a compound having the formula:

108. The method of claim 107 wherein said stroke is global ischemic.

109. The method of claim 107 wherein said stroke is focal ischemic.

110. The method of claim 107 wherein said stroke is hemorrhagic.

111. A method for treating a patient having a neurological disease or disorder comprising administering a hydrochloride salt of a compound having the formula:

112. The method of claim 111 wherein the neurological disease or disorder is a neurodegenerative disease.

113. A method for treating a patient having Parkinson's disease, comprising administering a hydrochloride salt selected from the group consisting of:

114. A method for treating stroke, comprising administering a hydrochloride salt of a compound having the formula:

115. The method of claim 114 wherein said stroke is global ischemic.

116. The method of claim 114, wherein said stroke is focal ischemic.

117. The method of claim 114 wherein said stroke is hemorrhagic.

118. A method for treating a patient having a neurological disease or disorder, comprising administering the compound of Formula I: wherein:

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl; or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n -- or --(CH.sub.2).sub.n --N(R.sup.3)--;

R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;

n is an integer from 1 to 6;

R.sup.4 is selected from the group consisting of alkyl, cycloalkyl, and ##STR152## X is independently selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

m is independently an integer from 1 to 5; Y is --NR.sup.3 R.sup.3, except when R.sup.1 and R.sup.2 together are --(CH.sub.2)n --N(R.sup.3)--, then Y is --H;

and pharmaceutically acceptable salts thereof.

119. The method of claim 118, wherein the compounds have the structure of Formula III: ##STR153## wherein x is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 is independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 is independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;

R.sup.3 is independently selected from the group consisting of --H and alkyl;

R.sup.4 is selected from the group consisting of alkyl and cycloalkyl;

and m is independently an integer from 0 to 5.

120. The method of claim 118, wherein the compound is in a pharmaceutically acceptable complex.

121. A method for treating a patient having a neurological disease or disorder, comprising administering the compound of Formula I: ##STR154## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl; or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n -- or --(CH.sub.2).sub.n --N(R.sup.3)--;

R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;

n is an integer from 1 to 6;

R.sup.4 is selected from the group consisting of alkyl, cycloalkyl, and ##STR155## X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl, provided that at least one X is present and is not H;

m is independently an integer from 0 to 5; Y is --NR.sup.3 R.sup.3, except when R.sup.1 and R.sup.2 together are --(CH.sub.2)n--N(R.sup.3)--, then Y is --H;

and pharmaceutically acceptable salts thereof.

122. The method of claim 121, wherein the compounds have the structure of Formulas VI or VII: ##STR156## wherein n is an integer from 1 to 6; X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.3 is independently selected from the group consisting of --H and alkyl;

R.sup.4 is selected from the group consisting of alkyl and cycloalkyl;

and m is independently an integer from 0 to 5.

123. The method of claim 121, wherein the compound is in a pharmaceutically acceptable complex.

124. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula: ##STR157## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;

each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;

each X is independently selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

m is independently an integer from 1 to 5;

and pharmaceutically acceptable salts thereof.

125. The method of claim 124, wherein:

X is independently selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 is independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 is independently selected from the group consisting of --H, alkyl and hydroxyalkyl;

R.sup.3 is independently selected from the group consisting of --H and alkyl;

and m is independently an integer from 1 to 5.

126. The method of claim 124, wherein the compound is in a pharmaceutically acceptable complex.

127. The method of claim 121, wherein:

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, lower alkyl, hydroxy-lower alkyl, --OH, --O-lower alkyl, and --O-lower acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, lower alkyl, and hydroxy-lower alkyl;

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

and each X is independently selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

128. The method of claim 127, wherein:

each (X).sub.m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2, NH-methyl, and NH-ethyl;

R.sup.1 is selected from the group consisting of --H and methyl;

and R.sup.2 is selected from the group consisting of --H and methyl.

129. The method of claim 128, wherein:

each (X).sub.m is meta-fluoro;

and NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2 and NH-methyl.

130. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula: ##STR158## wherein: each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;

n is an integer from 1 to 6;

each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof.

131. The method of claim 130, wherein:

X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.1 is independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 is independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;

R.sup.3 is independently selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5.

132. The method of claim 130, wherein the compound is in a pharmaceutically acceptable complex.

133. The method of claim 130, wherein:

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, lower alkyl, hydroxy-lower alkyl, --OH, --O-lower alkyl, and --O-lower acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, lower alkyl, and hydroxy-lower alkyl;

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

and each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

134. The method of claim 133, wherein:

each (X).sub.m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2, NH-methyl, and NH-ethyl;

R.sup.1 is selected from the group consisting of --H and methyl;

and R.sup.2 is selected from the group consisting of --H and methyl.

135. The method of claim 134, wherein:

each (X).sub.m is meta-fluoro;

and NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2 and NH-methyl.

136. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula ##STR159## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl; or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n --;

each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;

n is an integer from 1 to 6;

R.sup.4 is alkyl;

X is selected from the group consisting of --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl; m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof.

137. The method of claim 136, wherein:

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, lower alkyl, hydroxy-lower alkyl, --OH, --O-lower alkyl, and O-lower acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, lower alkyl, and hydroxy-lower alkyl;

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

R.sup.4 is lower alkyl;

and X is selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

138. The method of claim 137, wherein:

(X).sub.m is selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2, NH-methyl, and NH-ethyl;

R.sup.1 is selected from the group consisting of --H and methyl;

and R.sup.2 is selected from the group consisting of --H and methyl.

139. The method of claim 138, wherein:

(X).sub.m is meta-fluoro;

and NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2 and NH-methyl.

140. The method of claim 136, wherein the compound is in a pharmaceutically acceptable complex.

141. The method of claim 136, wherein the compound is selected from the group consisting of ##STR160## 142.

142. The method of claim 136, wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, lower alkyl, hydroxy-lower alkyl, --OH, --O-lower alkyl, and O-lower acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, lower alkyl, and hydroxy-lower alkyl;

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

R.sup.4 is lower alkyl;

and X is selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

143. The method of claim 142, wherein:

(X).sub.m is selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2, NH-methyl, and NH-ethyl;

R.sup.1 is selected from the group consisting of --H and methyl;

and R.sup.2 is selected from the group consisting of --H and methyl.

144. The method of claim 143, wherein:

(X).sub.m is meta-fluoro;

and NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2 and NH-methyl.

145. The method of claim 136, wherein the compound is in a pharmaceutically acceptable complex.

146. The method of claim 136, wherein the compound is selected from the group consisting of ##STR161## 147.

147. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the formula wherein:

each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;

n is an integer from 1 to 6;

each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl; m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof.

148. A method for treating a patient having a neurological disease or disorder, comprising administering a compound having the following formula: ##STR162## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl,

each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;

n is an integer from 1 to 6;

(X)m is independently selected from the group consisting of meta-fluoro, metachloro, ortho-methoxy, and ortho-methyl;

and pharmaceutically acceptable salts thereof.

149. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises stroke.

150. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises head trauma.

151. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises spinal cord injury.

152. The method of any of claims 57, 72, 104, 89, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises epilepsy.

153. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises anxiety.

154. The method of any of claims 57, 72, 104, 89, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises Alzheimer's disease.

155. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises Huntington's disease.

156. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises Parkinson's disease.

157. The method of any of claims 57, 72, 104, 85, 99, 148, 121, 124, 130, 136, 147, or 148, wherein the neurological disease or disorder comprises amyotrophic lateral sclerosis.

158. A method for providing neuroprotection to a patient comprising administering a compound having the following formula: ##STR163## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl;

each R.sup.3 is independently selected from the group consisting of --H, alkyl and 2-hydroxyethyl;

n is an integer from 1 to 6;

each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof.

159. The method of claim 158, wherein the compound is selected from the group consisting of ##STR164## 160.

160. The method of claim 158, wherein the compound is

161. The method of claim 158, wherein the compound is

162. The method of claim 158, wherein the compound is

163. The method of claim 158, wherein the compound is

164. The method of claim 158, wherein the compound is

165. The method of claim 158, wherein said pharmaceutically acceptable salt is a hydrochloride salt.

166. The method of claim 158, wherein the compound is a hydrochloride salt of a compound selected from the group consisting of:

167. The method of claim 158, wherein the compound is a hydrochloride salt of a compound having the formula:

168. The method of claim 158, wherein the compound is a hydrochloride salt of a compound having the formula:

169. The method of claim 158, wherein the compound is a hydrochloride salt of a compound having the formula:

170. The method of claim 158 wherein the compound is a hydrochloride salt of a compound having the formula:

171. The method of claim 158, wherein the compound is a hydrochloride salt of a compound having the formula:

172. A method for providing neuroprotection to a patient comprising administering a compound having the formula: wherein:

N R.sup.3 R.sup.3 is selected from the group consisting of --NH.sub.2 and --NH-methyl;

(X)m is independently selected from the group consisting of meta-fluoro, metachloro, ortho-methoxy, and ortho-methyl; and

R.sup.1 is methyl, and R.sup.2, R.sup.5, and R.sup.6 are --H;

or R.sup.2 is methyl, and R.sup.1, R.sup.5, and R.sup.6 are --H;

or R.sup.1, R.sup.2, R.sup.5, and R.sup.6 are --H;

and pharmaceutically acceptable salts thereof.

173. The method of claim 172 wherein the patient has Parkinson's disease.

174. The method of claim 173 wherein the compound is selected from the group consisting of: ##STR165## or a hydrochloride salt thereof.

175. A method for providing neuroprotection to a patient having a neurological disease or disorder, comprising administering a compound having the formula: ##STR166## wherein: R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, alkyl, hydroxyalkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, alkyl, and hydroxyalkyl; or R.sup.1 and R.sup.2 together are --(CH.sub.2).sub.n --;

each R.sup.3 is independently selected from the group consisting of --H, alkyl, and 2-hydroxyethyl;

n is an integer from 1 to 6;

R.sup.4 is alkyl;

X is selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl; m is independently an integer from 0 to 5;

and pharmaceutically acceptable salts thereof.

176. The method of claim 175, wherein:

R.sup.1 and R.sup.5 are independently selected from the group consisting of --H, lower alkyl, hydroxy-lower alkyl, --OH, --O-lower alkyl, and O-lower acyl;

R.sup.2 and R.sup.6 are independently selected from the group consisting of --H, lower alkyl, and hydroxy-lower alkyl;

each R.sup.3 is independently selected from the group consisting of --H and lower alkyl;

R.sup.4 is lower alkyl;

and X is selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

177. The method of claim 176, wherein:

(X).sub.m is selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2, NH-methyl, and NH-ethyl;

R.sup.1 is selected from the group consisting of --H and methyl;

and R.sup.2 is selected from the group consisting of --H and methyl.

178. The method of claim 177, wherein:

(X).sub.m is meta-fluoro;

and NR.sup.3 R.sup.3 is selected from the group consisting of NH.sub.2 and NH-methyl.

179. The method of claim 175, wherein the compound is in a pharmaceutically acceptable complex.

180. The method of claim 175, wherein the compound is selected from the group consisting of ##STR167## 181.

181. A method for providing neuroprotection to a patient comprising administering a compound having the formula: wherein n is an integer from 1 to 6;

each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, alkyl, --OH, --O-alkyl, and --O-acyl;

R.sup.3 is selected from the group consisting of --H and alkyl;

and m is independently an integer from 0 to 5 or pharmaceutically acceptable salt thereof.

182. The method of claim 181, wherein:

R.sup.3 is selected from the group consisting of --H and lower alkyl;

and each X is independently selected from the group consisting of --H, --Br, --Cl, --F, --CF.sub.3, lower alkyl, and --OH.

183. The method of claim 181, wherein:

each (X).sub.m is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-methoxy, and ortho-methyl;

and NR.sup.3 is selected from the group consisting of NH, N-methyl, and N-ethyl.

184. The method of claim 183, wherein:

each (X).sub.m is meta-fluoro;

and NR.sup.3 is selected from the group consisting of NH.sub.2 and N-methyl.

185. The method of claim 181, wherein the compound is in a pharmaceutically acceptable complex.
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