USRE38330EExpiredUtility
Preventing and reversing advanced glycosylation endproducts
Est. expiryJan 18, 2015(expired)· nominal 20-yr term from priority
A61K 31/428C07D 277/40A61Q 11/00C07D 277/22G01N 33/6842A61Q 19/08A61K 31/425A61K 8/49A61Q 19/00A61K 31/426
45
PatentIndex Score
7
Cited by
49
References
234
Claims
Abstract
The present invention relates to compositions and methods for inhibiting and reversing nonenzymatic cross-linking (protein aging). Accordingly, a composition is disclosed which comprises a thiazolium compound capable of inhibiting, and to some extent reversing, the formation of advanced glycosylation endproducts of target proteins by reacting with the carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated. A novel immunoassay for detection of the reversal of the nonenzymatic crosslinking is also disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A composition for inhibiting the advanced glycosylation of a target protein in the oral cavity comprising an effective amount of a compound one or more compounds selected from the group consisting of compounds of the formula:
wherein
R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower) alkyl, lower acyloxy(lower)alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons may be form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen, or
a group of the formula
—CH 2 C(═O)—R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group, and wherein, when R is aryl, at least one of R 1 and R 2 is other than hydrogen and R 1 and R 2 are not part of a un - substituted fused phenyl ring; or
a group of the formula —CH 2 R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and mixtures thereof, and a carrier therefor pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups; and
a pharmaceutically acceptable carrier therefor.
2. The composition of claim 1 wherein said compound has the formula wherein Y is a 2-phenyl-2-oxoethyl group R is aryl.
3. The composition of claim 2 1 wherein said compound is 3-(2-phenyl-2-oxoethyl)thiazolium bromide or another biologically acceptable salt thereofX is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
4. The composition of claim 2 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
5. The composition of claim 2 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide or another biologically acceptable salt thereof .
6. The composition of claim 2 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide or another biologically acceptable salt thereof .
7. The composition of claim 2 1 wherein said compound is 3-(2-phenyl-2-oxoethyl)-benzothiazolium bromide or another biologically acceptable salt thereofX is a halide ion.
8. The composition of claim 1 wherein Y is a 2-amino-2-oxoethyl group.
9. The composition of claim 8 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
10. The composition of claim 8 wherein said compound is a 3-(2,-amino-2-oxoethyl)benzothiazolium bromide or another biologically acceptable salt thereof .
11. The composition of claim 8 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide or another biologically acceptable salt thereof .
12. The composition of claim 1 wherein said compound is a 3-(2-methyl-2-oxoethyl)thiazolium chloride or another biologically acceptable salt thereof .
13. A pharmaceutical composition for administration to an animal to inhibit the advanced glycosylation of a target protein within said animal , comprising a pharmaceutically effective amount of a compound one or more compounds selected from the group consisting of compounds of the formula:
wherein
R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, (lower)acyloxy(lower)alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons may be form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen, or
a group of the formula —CH 2 C(═O)R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or an aryl group and wherein, when R is aryl, at least one of R 1 and R 2 is other than hydrogen and R 1 and R 2 are not part of a un - substituted fused phenyl ring; or
a group of the formula —CH 2 R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl, or aryl group; and
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and mixtures thereof, pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups: and
a pharmaceutically acceptable carrier therefor.
14. The composition of claim 13 wherein said compound has the formula wherein Y is a 2-phenyl-2-oxoethyl group R is aryl.
15. The composition of claim 14 13 wherein said compound is 3-(2-phenyl-2-oxoethyl)thiazolium bromide or another biologically acceptable salt thereofX is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
16. The composition of claim 14 wherein said compound is a 3-(2-phenyl-2-oxoethyl)4-methylthiazolium bromide or another biologically acceptable salt thereof .
17. The composition of claim 14 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide or another biologically acceptable salt thereof .
18. The composition of claim 14 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide or another biologically acceptable salt thereof .
19. The composition of claim 14 13 wherein said compound is 3-(2-phenyl-2-oxoethyl)-benzothiazolium bromide or another biologically acceptable salt thereofX is a halide ion.
20. The composition of claim 14 wherein Y is a 2-amino-2-oxoethyl group.
21. The composition of claim 20 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
22. The composition of claim 20 wherein said compound is a 3-(2-amino-2-oxoethyl)benzothiazolium bromide or another biologically acceptable salt thereof .
23. The composition of claim 20 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide or another biologically acceptable salt thereof .
24. The composition of claim 13 wherein said compound is a 3-(2-methyl-2-oxoethyl)thiazolium chloride or another biologically acceptable salt thereof .
25. A method for inhibiting the advanced glycosylation of a target protein comprising contacting the target protein with an effective amount of composition comprising a compound one or more compounds selected from the group consisting of compounds of the formula:
wherein
R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower) alkyl, lower acyloxy(lower)alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons may be form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen, or
a group of the formula
—CH 2 C(═O)—R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula —CH 2 —R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a halide, rosylate, methanesulfonate or mesitylenesulfonate ion; and mixtures thereof, and a carrier therefor pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups .
26. The method of claim 25 wherein said compound has the formula wherein Y is a 2-phenyl-2-oxoethyl group R is aryl.
27. The method of claim 26 wherein said compound is a 3-(2-phenyl-2-oxoethyl)thiazolium bromide or another biologically acceptable salt thereof .
28. The method of claim 26 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
29. The method of claim 26 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide or another biologically acceptable salt thereof .
30. The method of claim 26 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide or another biologically acceptable salt thereof .
31. The method of claim 26 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-benzothiazolium bromide, or another biologically acceptable salt thereof .
32. The method of claim 25 wherein Y is a 2-amino-2-oxoethyl group.
33. The method of claim 32 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
34. The method of claim 32 wherein said compound is a 3-(2-amino-2-oxoethyl)benzothiazolium bromide or another biologically acceptable salt thereof .
35. The method of claim 32 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide or another biologically acceptable salt thereof .
36. The method of claim 25 wherein said compound is a 3-(2-methyl-2-oxoethyl)thiazolium chloride or another biologically acceptable salt thereof .
37. A method for treating diabetes or treating or ameliorating adverse sequelae of diabetes in an animal to inhibit the formation of advanced glycosylation endproducts of a target protein within said animal , said method comprising administering an a diabetes treating or adverse sequelae of diabetes treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound one or more compounds selected from the group consisting of compounds of the formula:
wherein
R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy (lower)alkyl, lower acyloxy(lower)alkyl, or lower alkyl or R ‘ and R 2 together with their ring carbons may be form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen, or
a group of the formula
—CH 2 C(═O)—R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH 2 —R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and mixtures thereof, and a pharmaceutically acceptable carrier therefor pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups .
38. The method of claim 37 wherein said compound has the formula wherein Y is a 2-phenyl-2-oxoethyl group R is aryl.
39. The method of claim 38 wherein said compound is 3-(2-phenyl-2-oxoethyl)thiazolium bromide or another biologically acceptable has the formula wherein Y is a 2 - phenyl - 2 - oxoethyl group salt thereof .
40. The method of claim 38 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
41. The method of claim 38 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide or another biologically acceptable salt thereof .
42. The method of claim 38 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide or another biologically acceptable salt thereof .
43. The method of claim 38 wherein said compound is a 3-(2-phenyl-2-oxoethyl)-benzothiazolium bromide or another biologically acceptable salt thereof .
44. The method of claim 37 wherein Y is a 2-amino-2-oxoethyl group.
45. The method of claim 44 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
46. The method of claim 44 wherein said compound is a 3-(2-amino-2-oxoethyl)benzothiazolium bromide or another biologically acceptable salt thereof .
47. The method of claim 45 wherein said compound is a 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide or another biologically acceptable salt thereof .
48. The method of claim 37 wherein said compound is a 3-(2-methyl-2-oxoethyl)thiazolium chloride or another biologically acceptable salt thereof. .
49. A method of inhibiting the discoloration of teeth resulting from non-enzymatic browning in the oral cavity which comprises administration of an amount a teeth discloration inhibiting effective to inhibit the formation of advanced glycosylation endproducts amount of a composition comprising a compound one or more compounds selected from the group consisting of compounds of the formula:
wherein
R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, lower acyloxy(lower)alkyl, lower acyloxy(lower)alkyl, lower acyloxy(lower)alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons may be form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen, or
a group of the formula
—CH 2 C(═O)—R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH 2 —R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and mixtures thereof, and a pharmaceutically acceptable carrier therefor an anion, wherein said fused aromatic rings or aryl groups can be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di( loweralkyl ) amino groups .
50. A compound of the formula:
wherein Y and Z are both amino groups and R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, lower alkyl, or R 1 and R 2 together with their ring carbons may be an aromatic fused ring;
and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion an anion.
51. The compound according to claim 50 which is a 2,3-diaminothiazolium mesitylenesulfonate .
52. The compound according to claim 50 which is a 2,3-diaminobenzothiazolium mesitylenesulfonate .
53. A compound of the formula:
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alyl, lower acyloxy(lower)alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons may be an aromatic fused ring;
Z is hydrogen or an amino group;
Y is an alkynylmethyl group; and
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion an anion.
54. A compound of the formula:
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, lower acyloxy(lower)alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons may be form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is a 2-amino-2-oxoethyl group; and
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion an anion.
55. The compound according to claim 54 which is a 3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide or another biologically acceptable salt thereof .
56. The compound according to claim 54 which is a 3-(2-amino-2-oxoethyl)benzothiazolium bromide or another biologically acceptable salt thereof .
57. The compound according to claim 54 which is a 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide or another biologically acceptable salt thereof .
58. A method of treating or ameliorating kidney damage in an animal, said method comprising administering an kidney treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring:
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
59. The method of claim 58 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
60. The method of claim 58 wherein Z is hydrogen.
61. The method of claim 58 wherein R is aryl.
62. The method of claim 61 wherein Z is hydrogen.
63. The method of claim 61 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
64. The method of claim 61 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
65. The method of claim 61 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
66. The method of claim 61 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
67. The method of claim 58 wherein Y is a 2 - amino - 2 - oxoethyl group.
68. The method of claim 58 , comprising treating or preventing kidney damage in a human.
69. A method of treating or ameliorating damage to blood vasculature in an animal, said method comprising administering an blood vasculature treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
70. The method of claim 69 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
71. The method of claim 69 wherein Z is hydrogen.
72. The method of claim 69 wherein R is aryl.
73. The method of claim 72 wherein Z is hydrogen.
74. The method of claim 72 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
75. The method of claim 72 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
76. The method of claim 72 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
77. The method of claim 72 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
78. The method of claim 69 wherein Y is a 2 - amino - 2 - oxoethyl group.
79. The method of claim 69 , comprising treating or preventing damage to blood vasculature in a human.
80. A method of improving the elasticity or reducing wrinkles of the skin of an animal, said method comprising topically administering an skin elasticity or wrinkle reducing effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a biologically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
81. The method of claim 80 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
82. The method of claim 80 wherein Z is hydrogen.
83. The method of claim 80 wherein R is aryl.
84. The method of claim 83 wherein Z is hydrogen.
85. The method of claim 83 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
86. The method of claim 83 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
87. The method of claim 83 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
88. The method of claim 83 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
89. The method of claim 80 wherein Y is a 2 - amino - 2 - oxoethyl group.
90. The method of claim 80 comprising improving the elasticity or reducing wrinkles of the skin of a human.
91. A topical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula —CH
2
R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a biologically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups; and
a pharmaceutically acceptable carrier therefor suitable for topical administration.
92. The topical composition of claim 91 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
93. The topical composition of claim 91 wherein Z is hydrogen.
94. The topical composition of claim 91 , wherein, when R is aryl, at least one of R 1 and R 2 is other than hydrogen and R 1 and R 2 are not part of a un - substituted fused phenyl ring.
95. The topical composition of claim 94 wherein Z is hydrogen.
96. The topical composition of claim 95 wherein R is aryl.
97. The topical composition of claim 96 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl ) thiazolium.
98. The topical composition of claim 96 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
99. The topical composition of claim 96 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
100. The topical composition of claim 96 wherein said compound is 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium bromide.
101. The topical composition of claim 96 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
102. The topical composition of claim 96 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
103. The topical composition of claim 96 wherein Y is a 2 - amino - 2 - oxoethyl group.
104. The topical composition of claim 103 wherein said compound is a 3 -( 2 - amino - 2 - oxoethyl )- 4 - methylthiazolium.
105. The topical composition of claim 103 wherein said compound is a 3 -( 2 , - amino - 2 - oxoethyl ) benzothiazolium.
106. The topical composition of claim 103 wherein said compound is a 3 -( 2 - amino - 2 - oxoethyl )- 4 - methyl - 5 -( 2 - hydroxyethyl ) thiazolium.
107. A method of treating or ameliorating hypertension in an animal, said method comprising administering an hypertension treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically or biologically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
108. The method of claim 107 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
109. The method of claim 107 wherein X is a halide ion.
110. The method of claim 107 wherein Z is hydrogen.
111. The method of claim 107 wherein R is aryl.
112. The method of claim 111 wherein Z is hydrogen.
113. The method of claim 111 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
114. The method of claim 111 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
115. The method of claim 111 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
116. The method of claim 111 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
117. The method of claim 107 wherein Y is a 2 - amino - 2 - oxoethyl group.
118. The method of claim 107 , comprising treating or ameliorating hypertension in a human.
119. A method of treating or ameliorating retinopathy in an animal, said method comprising administering an retinopathy treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
120. The method of claim 119 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
121. The method of claim 119 wherein X is a halide ion.
122. The method of claim 119 wherein Z is hydrogen.
123. The method of claim 119 wherein R is aryl.
124. The method of claim 123 wherein Z is hydrogen.
125. The method of claim 123 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
126. The method of claim 123 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
127. The method of claim 123 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
128. The method of claim 123 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
129. The method of claim 120 wherein Y is a 2 - amino - 2 - oxoethyl group.
130. The method of claim 120 , comprising treating or ameliorating retinopathy in a human.
131. A method of treating damage to lens proteins in an animal, said method comprising administering an lens damage treating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
132. The method of claim 131 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
133. The method of claim 131 wherein Z is hydrogen.
134. The method of claim 131 wherein R is aryl.
135. The method of claim 134 wherein Z is hydrogen.
136. The method of claim 134 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
137. The method of claim 134 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
138. The method of claim 134 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
139. The method of claim 134 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
140. The method of claim 131 wherein Y is a 2 - amino - 2 - oxoethyl group.
141. The method of claim 131 , comprising treating damage to lens proteins in a human.
142. A method of treating or ameliorating peripheral neuropathy in an animal, said method comprising administering an neuropathy treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
143. The method of claim 142 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
144. The method of claim 142 wherein Z is hydrogen.
145. The method of claim 142 wherein R is aryl.
146. The method of claim 145 wherein Z is hydrogen.
147. The method of claim 145 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
148. The method of claim 145 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
149. The method of claim 145 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
150. The method of claim 145 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
151. The method of claim 142 wherein Y is a 2 - amino - 2 - oxoethyl group.
152. The method of claim 142 , comprising treating or ameliorating peripheral neuropathy in a human.
153. A composition adapted for ocular administration comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula —CH
2
R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups; and
a pharmaceutically acceptable carrier therefor suitable for topical administration.
154. The ocular composition of claim 153 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
155. The ocular composition of claim 153 wherein X is a halide ion.
156. The ocular composition of claim 153 wherein Z is hydrogen.
157. The ocular composition of claim 153 , wherein, when R is aryl, at least one of R 1 and R 2 is other than hydrogen and R 1 and R 2 are not part of a un - substituted fused phenyl ring.
158. The ocular composition of claim 157 wherein Z is hydrogen.
159. The ocular composition of claim 158 wherein R is aryl.
160. The ocular composition of claim 158 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl ) thiazolium.
161. The ocular composition of claim 158 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
162. The ocular composition of claim 158 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
163. The ocular composition of claim 158 wherein said compound is 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium bromide.
164. The ocular composition of claim 158 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
165. The ocular composition of claim 158 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
166. The ocular composition of claim 153 wherein Y is a 2 - amino - 2 - oxoethyl group.
167. The ocular composition of claim 166 wherein said compound is a 3 -( 2 - amino - 2 - oxoethyl )- 4 - methylthiazolium.
168. The ocular composition of claim 166 wherein said compound is a 3 -( 2 , - amino - 2 - oxoethyl ) benzothiazolium.
169. The ocular composition of claim 166 wherein said compound is a 3 -( 2 - amino - 2 - oxoethyl )- 4 - methyl - 5 -( 2 - hydroxyethyl ) thiazolium.
170. The composition of claim 1 , wherein said compounds comprise up to 10 % of the composition.
171. The composition of claim 13 wherein Z is hydrogen.
172. The composition of claim 14 wherein Z is hydrogen.
173. The composition of claim 13 wherein said compound is 3 -( 2 - phenyl - 2 - oxoethyl ) 4 - methylthiazolium bromide.
174. The composition of claim 13 wherein said compound is 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium bromide.
175. The composition of claim 13 wherein said compound is 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium bromide.
176. The composition of claim 13 wherein said compound is 3 -( 2 - amino - 2 - oxoethyl )- 4 - methylthiazolium bromide.
177. The composition of claim 13 wherein said compound is 3 -( 2 - amino - 2 - oxoethyl ) benzothiazolium bromide.
178. The composition of claim 13 wherein said compound is 3 -( 2 - amino - 2 - oxoethyl )- 4 - methyl - 5 -( 2 - hydroxyethyl ) thiazolium bromide.
179. The composition of claim 13 wherein said compound is a 3 -( 2 - methyl - 2 - oxoethyl ) thiazolium chloride.
180. The method of claim 37 , comprising treating diabetes or treating or ameliorating adverse sequelae of diabetes in a human.
181. The method of claim 37 wherein Z is hydrogen.
182. The method of claim 38 wherein Z is hydrogen.
183. A method of treating or ameliorating cataracts in an animal, said method comprising administering an lens damage treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
184. The method of claim 183 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
185. The method of claim 183 wherein Z is hydrogen.
186. The method of claim 183 wherein R is aryl.
187. The method of claim 186 wherein Z is hydrogen.
188. The method of claim 186 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
189. The method of claim 186 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
190. The method of claim 186 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
191. The method of claim 186 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
192. The method of claim 183 wherein Y is a 2 - amino - 2 - oxoethyl group.
193. The method of claim 183 , comprising treating or ameliorating damage to lens proteins in a human.
194. A method of treating or ameliorating damage to a tissue caused by contact with elevated levels of reducing sugars in an animal, said method comprising administering an treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′
is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
195. The method of claim 194 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
196. The method of claim 194 wherein Z is hydrogen.
197. The method of claim 194 wherein R is aryl.
198. The method of claim 197 wherein Z is hydrogen.
199. The method of claim 197 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
200. The method of claim 197 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
201. The method of claim 197 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
202. The method of claim 197 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
203. The method of claim 194 wherein Y is a 2 - amino - 2 - oxoethyl group.
204. The method of claim 194 , comprising administering the compound intraperitoneally.
205. A method of treating or ameliorating stroke in an animal, said method comprising administering a stroke treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
206. The method of claim 205 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
207. The method of claim 205 wherein Z is hydrogen.
208. The method of claim 205 wherein R is aryl.
209. The method of claim 208 wherein Z is hydrogen.
210. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
211. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
212. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
213. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
214. The method of claim 205 wherein Y is a 2 - amino - 2 - oxoethyl group.
215. A method of treating or ameliorating osteoarthritis in an animal, said method comprising administering a osteoarthritis treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
216. The method of claim 205 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
217. The method of claim 205 wherein Z is hydrogen.
218. The method of claim 205 wherein R is aryl.
219. The method of claim 208 wherein Z is hydrogen.
220. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
221. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
222. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
223. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
224. The method of claim 205 wherein Y is a 2 - amino - 2 - oxoethyl group.
225. A method of increasing red blood cell deformability in an animal, said method comprising administering a red blood cell deformability increasing effective amount of a pharmaceutical composition, said pharmaceutical composition comprising one or more compounds selected from compounds of the formula:
wherein
R 1 and R 2 are independently hydrogen, hydroxy ( lower ) alkyl, lower acyloxy ( lower ) alkyl, or lower alkyl, or R 1 and R 2 together with their ring carbons form an aromatic fused ring;
Z is hydrogen or an amino group;
Y is
hydrogen,
a group of the formula
—CH 2 C (═ O )— R
wherein R is a lower alkyl, lower alkoxy, hydroxy, amino or aryl group; or
a group of the formula CH
2
—R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl or aryl group; and
X is a pharmaceutically acceptable anion,
wherein the fused aromatic rings or aryl groups of R 1 , R 2 , R or R′ may be substituted with up to two groups selected from halo, hydroxy, loweralkoxy or di ( loweralkyl ) amino groups.
226. The method of claim 205 wherein X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
227. The method of claim 205 wherein Z is hydrogen.
228. The method of claim 205 wherein R is aryl.
229. The method of claim 208 wherein Z is hydrogen.
230. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 - methylthiazolium.
231. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 4 , 5 - dimethylthiazolium.
232. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- 5 - methylthiazolium.
233. The method of claim 208 wherein said compound is a 3 -( 2 - phenyl - 2 - oxoethyl )- benzothiazolium.
234. The method of claim 205 wherein Y is a 2 - amino - 2 - oxoethyl group.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.