Thiomolybdate analogues and uses thereof
View Patent ↗The current invention provides novel thiomolybdate derivatives, methods of making novel thiomolybdate derivatives, pharmaceutical compositions of novel thiomolybdate derivatives, methods of using novel thiomolybdate derivatives to treat diseases associated with aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity or NF-κB dysregulation and methods of using pharmaceutical compositions of thiomolybdate derivatives to treat diseases associated with aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity or NF-κB dysregulation.
1. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl;
R 4 and R 8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl or are absent when N is part of an aromatic ring;
optionally, R 1 and R 2 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 5 and R 6 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 1 and R 2 taken together, R 2 and R 3 taken together and R 2 and R 4 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 5 and R 6 taken together, R 6 and R 7 taken together and R 6 and R 8 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 3 and R 7 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; and
Y −2 is (Mo 2 S 12 ) −2 , (Mo 2 S 9 ) −2 , (Mo 2 S 7 ) −2 , (Mo 2 S 8 ) −2 , (Mo 2 S 11 ) −2 , (Mo 2 S 6 ) −2 or (Mo 2 S 13 ) −2 .
2. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
R 2 , R 3 , R 5 , R 6 and R 7 are independently alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl;
R 1 is substituted alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl;
R 4 and R 8 are independently alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl or are absent when N is part of an aromatic ring;
optionally, R 1 and R 2 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 5 and R 6 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 1 and R 2 taken together, R 2 and R 3 taken together and R 2 and R 4 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
optionally, R 5 and R 6 taken together, R 6 and R 7 taken together and R 6 and R 8 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
wherein when N is part of an aromatic ring, the aromatic ring is imidazolium, pyrrolidinium or heteroalkyl substituted pyridinium; and
Y −2 is (MoS 4 ) −2 .
3. The compound of claim 1 , wherein
4. The compound of claim 2 , wherein
5. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are hydrogen, alkanyl or substituted alkanyl.
6. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are hydrogen, methyl or ethyl.
7. The compound of claim 1 or 3 , wherein R 1 and R 2 are alkanyl.
8. The compound of claim 1 or 3 , wherein R 1 and R 2 are methyl or ethyl.
9. The compound of claim 1 or 3 , wherein R 1 is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl.
10. The compound of any one of claims 1 – 4 , wherein R 1 and R 2 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
11. The compound of any one of claims 1 – 4 , wherein R 1 and R 2 taken together are alkyleno or heteroalkyleno.
12. The compound of any one of claims 1 – 4 , wherein R 1 and R 2 taken together, R 2 and R 3 taken together and R 2 and R 4 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
13. The compound of any one of claims 1 – 4 , wherein R 1 and R 2 taken together, R 2 and R 3 taken together and R 2 and R 4 taken together are alkyleno.
14. The compound of any one of claims 1 – 4 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
15. The compound of claim 1 or 3 , wherein R 3 and R 7 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
16. The compound of claim 1 or 3 , wherein R 3 and R 7 taken together are alkyleno or heteroalkyleno.
17. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are hydrogen, alkanyl or substituted alkanyl and R 3 is substituted alkyl, aryl, arylalkyl, cycloalkyl or R 3 and R 7 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
18. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are methyl or ethyl and R 3 is substituted alkyl, aryl, arylalkyl, cycloalkyl or R 3 and R 7 taken together are alkyleno or heteroalkyleno.
19. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are methyl or ethyl and R 3 is substituted alkyl, aryl, arylalkyl or cycloalkyl.
20. The compound of claim 1 or 3 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
21. The compound of any one of claims 1 – 4 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
22. The compound of claim 1 or 3 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
23. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are methyl or ethyl and R 3 and R 7 taken together are alkyleno or heteroalkyleno.
24. The compound of any one of claims 1 – 4 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
25. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are hydrogen and R 3 is substituted alkyl, cycloalkyl or substituted heteroaryl or R 3 and R 7 taken together are alkyleno.
26. The compound of claim 1 or 3 , wherein R 1 and R 2 are alkanyl and R 3 and R 4 are hydrogen, alkyl, substituted alkyl, aryl, arylalkyl or alkyleno.
27. The compound of claim 1 or 3 , wherein R 1 and R 2 are methyl or ethyl and R 3 and R 4 are hydrogen, alkyl, substituted alkyl, aryl, arylalkyl or alkyleno.
28. The compound of claim 1 or 3 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
wherein R 9 is n-C 8 H 17 , n-C 9 H 19 , n-C 10 H 21 , n-C 11 H 23 , n-C 12 H 25 , n-C 13 H 27 , n-C 14 H 29 , n-C 15 H 31 , n-C 16 H 33 , n-C 17 H 35 or n-C 18 H 37 .
29. The compound of claim 1 or 3 , wherein R 1 , R 2 and R 4 are hydrogen and R 3 is substituted alkyl, substituted heteroaryl, cycloalkyl or alkyleno.
30. The compound of claim 1 or 3 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
31. The compound of claim 1 or 3 , wherein R 1 and R 2 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno, R 3 is alkyl or substituted alkyl and R 4 is hydrogen or is absent.
32. The compound of claim 1 or 3 , wherein R 1 (R 2 )(R 3 )N or R 1 (R 2 )(R 3 )(R 4 )N has the structure:
33. A pharmaceutical composition comprising the compound of any one of claims 1 – 4 and a pharmaceutically acceptable diluent, excipient or adjuvant.
34. A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any one of claims 1 – 4 .
35. A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 33 .
36. The method of claim 34 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
37. The method of claim 35 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
38. The method of claim 34 further comprising administering to the patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
39. The method of claim 35 further comprising administering to the patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
40. The method of claim 34 , wherein the cancer is breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma.
41. A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any one of claims 1 – 4 .
42. A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 33 .
43. A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any one of claims 1 – 4 .
44. A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 33 .
45. A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any one of claims 1 – 4 .
46. A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 33 .
47. A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any one of claims 1 – 4 .
48. A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 33 .
49. The method of claim 47 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
50. The method of claim 48 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
51. A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any one of claims 1 – 4 .
52. A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 33 .
53. The method of claim 51 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease.
54. The method of claim 52 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease.
55. The method of claim 35 , wherein the cancer is breast cancer, renal cancer, brain cancer colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma.
56. The compound of claim 2 or 4 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
57. The compound of claim 2 or 4 , wherein R 1 is substituted alkyl, aryl, arylalkyl or alkenyl, R 2 and R 3 are alkanyl, and R 4 is alkyl, substituted alkyl, aryl, arylalkyl or alkenyl.
58. The compound of claim 2 or 4 , wherein R 1 is substituted alkyl, aryl, arylalkyl or alkenyl, R 2 and R 3 are methyl or ethyl, and R 4 is alkyl, substituted alkyl, aryl, arylalkyl or alkenyl.
59. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
R 1 , R 2 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, alkyl, substituted alkyl, or aryl;
R 3 and R 7 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkydiyl; and
Y −2 is (MoS 4 ) −2 .
60. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
R 1 , R 2 and R 4 are independently ethyl, propyl or butyl;
R 3 , R 5 , R 6 , R 7 and R 8 are independently alkyl; and
Y −2 is (MoS 4 ) −2 .
61. The compound of claim 60 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
62. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
R 1 and R 5 are benzyl;
R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are independently methyl and;
Y −2 is (MoS 4 ) −2 .
63. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
R 1 and R 5 are 2-hydroxyethyl;
R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are independently methyl and;
Y −2 is (MoS 4 ) −2 .
64. A pharmaceutical composition comprising i) the compound of claim 62 or 63 and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
65. A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 62 or 63 .
66. A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 64 .
67. The method of claim 65 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
68. The method of claim 66 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
69. The method of claim 65 further comprising administering to a patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
70. The method of claim 66 further comprising administering to a patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
71. The method of claim 65 , wherein the cancer is breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma.
72. The method of claim 66 , wherein the cancer is breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma.
73. A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 62 or 63 .
74. A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 64 .
75. A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 62 or 63 .
76. A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 64 .
77. A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 62 or 63 .
78. A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 64 .
79. A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 62 or 63 .
80. A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 64 .
81. The method of claim 79 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
82. The method of claim 80 further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant.
83. A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 62 or 63 .
84. A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 64 .
85. The method of claim 83 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease.
86. The method of claim 84 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease.
87. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
Y −2 is (MoS 4 ) −2 ;
R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N; and
R 1 (R 2 )(R 3 )(R 4 )N has the structure:
wherein R 9 is n-C 8 H 17 , n-C 9 H 19 , n-C 10 H 21 , n-C 11 H 23 , n-C 12 H 25 , n-C 13 H 27 , n-C 14 H 29 , n-C 15 H 31 , n-C 16 H 33 , n-C 17 H 35 or n-C 18 H 37 .
88. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
Y −2 is (MoS 4 ) −2 ;
R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N; and
wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure:
89. A compound of structural formula (I):
or a solvate or hydrate thereof wherein:
Y −2 is (MoS 4 ) −2 ; wherein
a) R 1 (R 2 )(R 3 )N═R 5 (R 6 )(R 7 )N; and R 1 (R 2 )(R 3 )N has the structure:
or
b) R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N; and R 1 (R 2 )(R 3 )(R 4 )N has the structure:
90. The method of claim 34 wherein the patient is human.
91. The method of claim 35 wherein the patient is human.
92. The method of claim 41 wherein the patient is human.
93. The method of claim 42 wherein the patient is human.
94. The method of claim 43 wherein the patient is human.
95. The method of claim 44 wherein the patient is human.
96. The method of claim 45 wherein the patient is human.
97. The method of claim 46 wherein the patient is human.
98. The method of claim 47 wherein the patient is human.
99. The method of claim 51 wherein the patient is human.
100. The method of claim 52 wherein the patient is human.
101. The method of claim 65 wherein the patient is human.
102. The method of claim 66 wherein the patient is human.
103. The method of claim 73 wherein the patient is human.
104. The method of claim 74 wherein the patient is human.
105. The method of claim 75 wherein the patient is human.
106. The method of claim 76 wherein the patient is human.
107. The method of claim 77 wherein the patient is human.
108. The method of claim 78 wherein the patient is human.
109. The method of claim 79 wherein the patient is human.
110. The method of claim 80 wherein the patient is human.
111. The method of claim 83 wherein the patient is human.
112. The method of claim 84 wherein the patient is human.