Source: https://insight.rpxcorp.com/pat/US20050107398A1
Timestamp: 2020-08-07 03:57:43
Document Index: 800823832

Matched Legal Cases: ['art2', 'art1', 'art 3', 'art 0', 'art\u20022', 'art\u20020', 'art 2', 'art 1']

Patent US 20050107398A1
1. A benzamide compound having a structure shown in the structure in Formula (I):
Novel benzamide compounds of Formula (I), Formula (II) and Formula (III, salts, water soluble salts, analogs and radiolabeled counterparts thereof as sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors. A method for diagnosing a mammal for the presence of a mammalian tumor therein comprises administering to the mammal a diagnostic imaging detectable effective amount of a benzamide compound having a structure illustrated in Formula (I), Formula (II) and Formula (III) and detecting binding of the compound to a tumor in the mammal. A method for diagnostic imaging of a mammalian tissue having cell surface sigma-2 receptors comprising administering to a mammal a diagnostic imaging amount of a compound having a structure illustrated in Formula (I) Formula (II) and Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors.
US 10,005,792 B2
CTxT Pty. Ltd.
US 10,421,743 B2
US 10,494,376 B2
3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies
US 10,519,167 B2
US 10,550,096 B2
US 10,647,708 B2
View Dependent Claims (2, 3, 4, 5, 6, 7, 156, 157, 158, 159, 160)
2. A compound in accordance with claim 1 having a structure of at least one of:
3. A compound in accordance with claim 2 wherein the compound has a structure depicted in the structure of compound 6.
4. A compound in accordance with claim 3 wherein the compound is radiolabeled with 76Br.
5. A compound in accordance with claim 3 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
6. A compound in accordance with claim 3 wherein the compound has a structure depicted in the structure of compound 10.
7. A compound in accordance with claim 6 wherein the compound is labeled with 11C.
156. A compound in accordance with claim 1 having 123 iodine associated therewith as a radiolabel.
157. A compound in accordance with claim 1 having 124 Iodine associated therewith as a radiolabel.
158. A compound in accordance with claim 1 having 125 Iodine associate therewith as a radiolabel.
159. A compound in accordance with claim 1 having Carbon 11 associated therewith as a radiolabel.
160. A compound in accordance with claim 1 having tritium associated therewith as a radiolabel.
8. A process for the preparation of a compound selected from one of compounds 1, 2, 3, 4, 5 and 6 of FIG. 4 which comprises respectively reacting a compound having a formula wherein R is hydrogen or methoxy
9. A process in accordance with claim 8 wherein the compound is Compound 1.
10. A process in accordance with claim 8 wherein the compound is Compound 2.
11. A process in accordance with claim 8 wherein the compound is Compound 3.
12. A process in accordance with claim 8 wherein the compound is Compound 4.
13. A process in accordance with claim 8 wherein the compound is Compound 5.
14. A process in accordance with claim 8 wherein the compound is Compound 6.
15. A process for the preparation of a compound 7, 8, 9 and 10 of FIG. 5 which comprises reacting a compound of the formula
17. A process in accordance with claim 15 wherein the compound is Compound 7.
18. A process in accordance with claim 15 wherein the compound is Compound 8.
19. A process in accordance with claim 15 wherein the compound is Compound 9.
20. A process in accordance with claim 15 wherein the compound is Compound 10.
22. A process in accordance with claim 15 wherein the compound is Compound 11.
23. A process in accordance with claim 15 wherein the compound is Compound 12.
16. In an aspect X comprises at least one of methyl and bromide.
21. A process for the preparation of a compound depicted as 11 and 12 which comprises:
(c) reacting a compound of the formula (d) with bromoacetonitrile to produce a compound of the formula (d) hydrogenating that compound over palladium on charcoal to provide a compound of the formula and condensing that compound with either one of 2-methoxy-5-bromonaphthoyl chloride or 5-bromo-2,3-dimethoxybenzoic acid respectively to produce compound 11 and compound 12.
24. A method for diagnosing a mammal for the presence of a cancer comprises administering to the mammal a diagnostic imaging detectable effective amount of a novel benzamide detectably labeled compound having a structure selected from at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 structurally depicted in Formula (II) and compound 14 structurally depicted in Formula (III) and detecting binding of the at least one benzamide compound to a tumor in the mammal;
25. A compound in accordance with claim 24 wherein the compound has a structure depicted in the structure of compound 6.
26. A compound in accordance with claim 25 wherein compound 6 is radiolabeled with 76Br.
27. A compound in accordance with claim 25 wherein compound 6 is radiolabeled with at least one of 123I, 124I and 125I.
28. A compound in accordance with claim 24 wherein the compound has a structure depicted in the structure of compound 10.
29. A compound in accordance with claim 28 wherein compound 10 is labeled with 11C.
30. A method in accordance with claim 24 which comprises determining that a mammalian tumor is present upon detecting binding.
31. A method in accordance with claim 24 which further comprises producing an acquisition of the detection.
32. A marker for cancer comprising a detectably-labeled benzamide compound having a structure of at least one of the structures illustratively depicted of benzamide compounds illustratively depicted in Formula (I) including compound 23, compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and having an explicit provocative binding efficacy to a tumor in a living mammal and in an aspect the detectably labeled benzamide compound is a highly selective σ
2 radioligand having the aforementioned structure appended with a radioactive ligand;
View Dependent Claims (33, 34, 35, 36, 37, 39, 40)
33. A compound in accordance with claim 32 wherein the compound has a structure depicted in the structure of compound 6.
34. A compound in accordance with claim 33 wherein compound 6 is radiolabeled with 76Br.
35. A compound in accordance with claim 32 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
36. A compound in accordance with claim 32 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and iodine 125 for invitro measurement of sigma-2 receptors in tumors and normal tissue.
37. A compound in accordance with claim 32 wherein the compound is radiolabled with at least one of tritium and iodine 125.
39. A compound in accordance with claim 32 wherein the compound has a structure depicted in the structure of compound 10.
40. A compound in accordance with claim 36 wherein compound 10 is labeled with 11C.
38. Radiolabel compounds of Formula (I), Formula (II) and Formula (III) including compound 23 having at least one of tritium and/or iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the invitro detection of sigma 2 receptors in tumors and normal tissue.
41. A pharmaceutical composition comprising a benzamide compound having as a structure at least one of structures shown for novel benzamide compounds illustratively depicted in Formula (I) compound, 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and a pharmaceutically acceptable diluent or carrier;
conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
42. A compound in accordance with claim 41 wherein the compound has a structure depicted in the structure of compound 6.
43. A compound in accordance with claim 42 wherein the compound is radiolabeled with 76Br.
44. A compound in accordance with claim 42 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and/or tritium.
45. A compound in accordance with claim 41 wherein the compound has a structure depicted in the structure of compound 10.
46. A compound in accordance with claim 45 wherein the compound is labeled with 11C.
47. A bezamide composition comprising a detectably labeled benzamide compound further comprising a highly selective σ
2 radioligand.
48. A pharmaceutical composition effective for treating human or non-human neoplastic disorder comprises a detectably labeled pharmaceutically effective amount of at least one compound having a structure of at least one of the structures illustratively depicted in one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) in a composition including a pharmaceutically acceptable carrier.
49. A composition in accordance with claim 48 when the detectably labeled benzamide compound is a highly selective σ
wherein the benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
50. A compound in accordance with claim 49 wherein the compound has a structure depicted in the structure of compound 6.
51. A compound in accordance with claim 50 wherein the compound is radiolabeled with 76Br.
52. A compound in accordance with claim 50 wherein the compound is radiolabeled with at least one of 123I, 124I and/or 125I.
53. A compound in accordance with claim 49 wherein the compound has a structure depicted in the structure of compound 10.
54. A compound in accordance with claim 53 wherein the compound is labeled with 11C.
55. A method for determining the proliferative status of a cancer cell in a living mammal comprises administering to a living mammal afflicted with a solid malignant tumor, an effective amount of a detectably-labeled benzamide compound having a structure of at least of at least one of the one of the benzamide compounds illustratively depicted in Formula (I) compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and determining the extent to which the detectably-labeled benzamide compound binds to cells of a tumor in the mammal, the extent providing a measure of the proliferative status of the cells.
View Dependent Claims (56, 57, 58, 59, 60, 61, 63, 64, 65)
56. A method in accordance with claim 55 wherein the living mammal is a human and benzamide compounds include those compounds having a structure shown in the structure in Formula (I):
57. A method in accordance with claim 56 wherein the benzamide compound has a structure depicted in the structure of compound 6.
58. A method in accordance with claim 57 wherein the benzamide compound is radiolabeled with 76Br.
59. A method in accordance with claim 57 wherein the benzamide compound is radiolabeled with at least one of 123I, 124I, 125I and/or tritium.
60. A method in accordance with claim 55 wherein the benzamide compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and/or iodine 125 for invitro measurement of these receptors in tumors and normal tissue.
61. A method in accordance with claim 60 wherein the benzamide compound is radiolabled with at least one of tritium and/or iodine 125.
63. A compound in accordance with claim 55 wherein the compound has a structure depicted in the structure of compound 10.
64. A compound in accordance with claim 63 wherein the compound is labeled with 11C.
65. A method in accordance with claim 64 when determining the proliferative status includes assessing the proliferative status of a breast cancerous tumor.
62. Radiolabel compounds and compositions of Formula (I), Formula (II) and Formula (III) including compound 23 wherein at least one benzamide compound(s) is radiolabeled with at least one of tritium and/or iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the invitro detection of sigma 2 receptors in tumors and normal tissue.
66. A method for pharmacologically treating a mammalian tumor as a disorder in a mammal comprises administering to a mammal having a tumor a composition including a tumor-inhibiting amount of at least one detectably-labeled benzamide compound having a structure of the structure shown of at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) In an aspect the mammal is a human;
novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
67. A compound in accordance with claim 66 wherein the compound has a structure depicted in the structure of compound 6.
68. A compound in accordance with claim 67 wherein the compound is radiolabeled with 76Br.
69. A compound in accordance with claim 67 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
70. A compound in accordance with claim 66 wherein the compound has a structure depicted in the structure of compound 10.
71. A compound in accordance with claim 70 wherein the compound is labeled with 11C.
72. A method for diagnostic imaging of a mammalian tissue having ample cell surface sigma-2 receptors comprising administering to the tissue of the mammal a diagnostic imaging amount of at least one compound having a structure of at least one benzamide compound illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors and including those compounds having a structure shown in the structure in Formula (I):
73. A compound in accordance with claim 72 wherein the compound has a structure depicted in the structure of compound 6.
74. A compound in accordance with claim 73 wherein the compound is radiolabeled with 76Br.
75. A compound in accordance with claim 73 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium
76. A compound in accordance with claim 72 wherein the compound has a structure depicted in the structure of compound 10.
77. A compound in accordance with claim 76 wherein the compound is labeled with 11C.
78. A method for in vitro detection of a cancer cell in living mammalian tissue sample comprising contacting a mammalian tissue sample comprising a cell with an in vitro diagnostic imaging amount of at least one detectably labeled benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) for a time and under conditions sufficient and effective for binding of the compound to the cell and detecting such binding indicative of an association with the present of cancer.
79. A method in accordance with claim 78 wherein the mammal is a living human.
80. A method in accordance with claim 79 wherein the detecting is by image acquisition.
81. A method in accordance with claim 80 wherein the compound is selected from novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I):
82. A method for in vitro detection of a cancer cell in a living mammalian tissue sample comprising contacting a mammalian tissue sample with an in vitro diagnostic imaging detectable and acquisitionable amount of at least one detectably labeled benzamide compound having as a structure a structure of at least one of the benzamide compounds including compound 23 illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) for a time and under cellular conditions functionally sufficient and effective for binding of the compound to the cancer cell and detecting such binding.
83. A compound in accordance with claim 82 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and/or iodine 125 for in vitro measurement of these receptors in tumors and normal tissue.
84. A compound in accordance with claim 82 wherein the compound is radiolabled with at least one of tritium and/or iodine 125.
85. Radiolabel compounds of Formula (I), Formula (II) and Formula (III) including compound 23 are radiolabeled with at least one of tritium and iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the in vitro detection of sigma 2 receptors in tumors and normal tissue.
86. Benzamide compounds having a structure shown in the structure in Formula (I):
87. A compound in accordance with claim 86 wherein the compound has a structure depicted in the structure of compound 6.
88. A compound in accordance with claim 87 wherein the compound is radiolabeled with 76Br.
89. A compound in accordance with claim 87 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
90. A compound in accordance with claim 86 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and iodine 125 for in vitro measurement of these receptors in tumors and normal tissue.
91. A compound in accordance with claim 86 wherein the compound is radiolabled with at least one of tritium and iodine 125.
92. A compound in accordance with claim 86 wherein the compound has a structure depicted in the structure of compound 10.
93. A compound in accordance with claim 92 wherein the compound is labeled with 11C.
94. A method in accordance with claim 93 wherein the mammal is a human.
95. A method for determining proliferation and progression of a cancer as a disorder in a living mammal comprising administering to a living mammal a diagnostic imaging detectable amount of at least one detectably-labeled benzamide compound having as a structure a structure of at least one of the benzamide compounds illustratively structurally depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first selected time, detecting an image of a tissue having ample cells with sigma-2 receptors at a second selected (later) time respectively detecting an image of a tissue having ample cells with sigma-2 receptors at both times, comparing the images and determining if the detected image at the later time is smaller than the detected image at the first time;
View Dependent Claims (96, 97, 98, 99, 100, 101, 102, 103, 104)
96. A compound in accordance with claim 95 wherein the compound has a structure depicted in the structure of compound 6.
97. A compound in accordance with claim 96 wherein the compound is radiolabeled with 76Br.
98. A compound in accordance with claim 96 wherein the compound is radiolabeled with at least one of 123I, 124I and 125I.
99. A compound in accordance with claim 96 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and/or iodine 125 for in vitro measurement of these receptors in tumors and normal tissue.
100. A compound in accordance with claim 96 wherein the compound is radiolabled with at least one of tritium and/or iodine 125.
101. A compound in accordance with claim 96 wherein the compound has a structure depicted in the structure of compound 10.
102. A compound in accordance with claim 101 wherein the compound is labeled with 11C.
103. A method in accordance with claim 102 wherein the elapsed time between the first time and second time is selected to be a time duration significant amount.
104. A method in accordance with claim 103 wherein the mammal is a living human.
105. A method for identifying a modulating effect (and regression effect) of a cancer in a living mammal with a disorder, comprising administering to the mammal a diagnostic imaging detectable amount of at least one detectably-labeled benzamide compound having a structure of at least one of the structures illustrated in Formula (I) Formula (II) and Formula (III) at a first time, detecting and acquisitioning an image of a tissue having ample available cells with sigma-2 receptors, administering a detectably-labeled benzamide compound having a structure of at least one of the compound structures illustrated in Formula (I), Formula (II) and Formula (III) to the mammal and at a second (later) time respectively detecting and acquisitioning an image of a tissue having an abundance of cells with sigma receptors, comparing the respective images and determining that there has been an prophylactic effect and/or regression.;
View Dependent Claims (106, 107, 109, 110, 111, 112, 113, 114, 115, 116)
106. A compound in accordance with claim 105 wherein the compound has a structure depicted in the structure of compound 6.
107. A compound in accordance with claim 106 wherein the compound is radiolabeled with 76Br.
109. A compound in accordance with claim 106 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and iodine 125 for invitro measurement of these receptors in tumors and normal tissue.
110. A compound in accordance with claim 106 wherein the compound is radiolabled with at least one of tritium and/or iodine 125.
111. A compound in accordance with claim 106 wherein the compound has a structure depicted in the structure of compound 10.
112. A compound in accordance with claim 111 wherein the compound is labeled with 11C.
113. A method in accordance with claim 112 wherein the comparison shows the amount of regression over time.
114. A method in accordance with claim 113 wherein the mammal is a living human.
115. A method in accordance with claim 114 wherein the comparison shows the prophylactic effect of the compound and its toxicity to cancer.
116. A method in accordance with claim 114 wherein the comparison shows the efficacy of the compound towards killing cancer in a living mammal and wherein the detectably-labeled benzamide compound is tagged with a radioactive ligand.
108. A compound in accordance with claim 108 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
117. A method for diagnosing and determining the response of a mammalian patient(s) with a disorder to tailored drug therapy comprising administering to a mammal a diagnostic imaging detectable amount of at least one detectably labeled benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first and second (later) times respectively, detecting an image of a tissue having an abundance of cells with sigma receptors at both times, comparing the images and determining if the image at a later time is larger than the image at the first time that there has been a proliferative effect and progression of cancer;
novel conformationally flexible benzamide compounds including those compounds having a structure shown in the structure in Formula (I);
View Dependent Claims (118, 119, 120, 121, 122, 123, 124, 125, 126)
118. A compound in accordance with claim 117 wherein the compound has a structure depicted in the structure of compound 6.
119. A compound in accordance with claim 118 wherein the compound is radiolabeled with 76Br.
120. A compound in accordance with claim 118 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
121. A compound in accordance with claim 117 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and/or iodine 125 for in vitro measurement of these receptors in tumors and normal tissue.
122. A compound in accordance with claim 117 wherein the compound is radiolabled with at least one of tritium and/or iodine 125.
123. A compound in accordance with claim 117 wherein the compound has a structure depicted in the structure shown for compound 10.
124. A compound in accordance with claim 123 wherein the compound is labeled with 11C.
125. A method in accordance with claim 117 where the dynamic comparison shows the proliferation and progression of the cancer over elapsed time. In an aspect the mammal is a living human.
126. A method in accordance with claim 125 where a method for diagnosis and determining the response is a determination of a prophylaxis or management of a disorder associated with neoplastic cells.
127. A method of screening candidate chemicals for toxicity/lethality to cancer comprising administering to a mammal a diagnostic imaging detectable amount of at least one detectably labeled benzamide compound selected from the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first time, detecting and acquisitioning an image of a tissue having ample cells with sigma-2 receptors, administering to the mammal a candidate chemical, detecting and acquisitioning an image of tissue having ample cells with sigma-2 receptors, comparing the detected images and making a determination as to whether there has been a proliferative effect and progression of the cancer;
View Dependent Claims (128, 129, 130, 131, 132, 133, 134, 135)
128. A compound in accordance with claim 127 wherein the compound has a structure depicted in the structure of compound 6.
129. A compound in accordance with claim 128 wherein the compound is radiolabeled with 76Br.
130. A compound in accordance with claim 128 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
131. A compound in accordance with claim 128 wherein the compound has a structure depicted in the structure (depicted in the structure depictied for compound 10) and is radiolabeled with at least one of tritium and/or iodine 125 for invitro measurement of these receptors in tumors and normal tissue.
132. A compound in accordance with claim 128 wherein the compound is radiolabled with at least one of tritium and/or iodine 125.
133. A compound in accordance with claim 128 wherein the compound has a structure depicted in the structure of compound 10.
134. A compound in accordance with claim 133 wherein the compound is labeled with 11C.
135. A method in accordance with claim 134 wherein the mammal is a human.
136. A medical treatment for a mammal and a method of medically treating a mammal comprising administering to a mammal a diagnostic imaging detectable amount of at least one benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I) compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first and second (later) time respectively, detecting an image of a tissue having ample cells with sigma receptors at the first and second times, comparing the images taken respectively and determining if the image at the later time is larger than the image at the first time that there has been a proliferative effect and progression of the cancer;
wherein benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
137. A compound in accordance with claim 136 wherein the compound has a structure depicted in the structure of compound 6.
138. A compound in accordance with claim 137 wherein the compound is radiolabeled with 76Br.
139. A compound in accordance with claim 137 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
140. A compound in accordance with claim 136 wherein the compound has a structure depicted in the structure depicted for compound 10.
141. A compound in accordance with the compound of claim 136 wherein the compound is labeled with 11C.
142. A method in accordance with claim 141 wherein the mammal is a human.
143. A method in accordance with claim 142 wherein the treatment is a cancer treatment.
144. A method in accordance with claim 143 wherein medical treatment includes a method of retarding, preventing, and ameliorating disease or a medical affliction in a mammal.
145. A method of customizing drug therapy for a living mammalian subject comprising administering to the subject to the mammal undergoing drug therapy a diagnostic imaging detectable amount of at least benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I) compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) detecting an image of a tumor having ample sigma-2 receptors and making a determination regarding the drug therapy based on the captured images;
having conformationally flexible benzamide compounds including those compounds having a structure shown in the structure in Formula (I);
View Dependent Claims (146, 147, 148, 149, 150, 151, 152)
146. A compound in accordance with claim 145 wherein the compound has a structure depicted in the structure of compound 6.
147. A compound in accordance with claim 146 wherein the compound is radiolabeled with 76Br.
148. A compound in accordance with claim 146 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium
149. A compound in accordance with claim 146 wherein the compound has a structure depicted in the structure (depicted in compound 10) and is radiolabeled with at least one of tritium and/or iodine 125 for invitro measurement of these receptors in tumors and normal tissue.
150. A compound in accordance with claim 149 wherein the compound is radiolabled with at least one of tritium and/or iodine 125.
151. A compound in accordance with claim 146 wherein the compound has a structure depicted in the structure of compound 10.
152. A compound in accordance with claim 151 wherein the compound is labeled with 11C.
153. A compound having a structure depicted as
View Dependent Claims (154)
154. A compound in accordance with claim 153 wherein the compound is radiolabeled.
155. A process for the preparation of a compound having a structure depicted as compound 23, which comprises reacting the corresponding phenol with 1-bromo-2-fluoroethane.
This application claims the benefit of U.S. Provisional Patent Application, Ser. No. 60/491,582, filed Jul. 31, 2003 which is incorporated herein in its entirety by reference.
This research was funded by grants DA 12647, CA86307 and CA102869 awarded by the National Institutes of Health and grant DAMD17-01-1-0446 awarded by the Department of Defense Breast Cancer Research Program of the US Army Medical Research and Material Command Office. The Government has certain rights in the invention.
(a) having a formula wherein R is hydrogen or methoxy
(b) bromoacetonitrile to produce a compound having the structure shown in the formula
FIG. 9 shows a comparison of [18F]FLT ((18)F-3′-fluoro-3′-deoxy-L-thymidine PET (FLT PET) ) and [11C]10. Although [18F]FLT has a high uptake in tumors (top graph), the high uptake of radioactivity in normal tissues results in a lower tumor:background radio of [18F]FLT relative to [11C]10, particularly the tumor:muscle, tumor:blood, and tumor:heart ratios (bottom graph).
As used herein the phrase “benzamide compound” illustratively depicted in Formula (I) including compound 23, compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III)″ includes any moiety derived from or of the benzamide compound in any form including pharmaceutically effective and acceptable water soluble salt form, radical, analogs, ionic form, ion, conformational form, radiolabeled conformational form, radiolabeled ion and mammalian and metabolic derivatives thereof. Acceptable salts include but are not limited to tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Suitable inorganic salts include hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
As used herein the term “fluoroalkyl” includes fluoro C1 to C4″ and includes fluormethyl, fluoroethyl, fluoropropyl and fluorobutyl.
As used in the specification, claims and drawings, for convenience numbers 1-12 refer respectively to various structures of novel benzamide compounds of Formula (I) structurally depicted respectively in FIGS. 1, 2 and 3., Formula (II) and Formula (III) of FIG. 7.
(c) condensing said amine product with either 2-methoxy-5-bromonaphtholy chloride or 5-bromo-2,3-dimethoxybenzoic acid to produce a compound selected from one of compounds 1, 2, 3, 4, 5 and 6.
and condensing that compound with either of 2-methoxy-5-bromonaphthoyl chloride or 5-bromo-2,3-dimethoxybenzoic acid to provide compound 11 and compound 12.
A noninvasive novel method using novel benzamide compounds of Formula (I) Formula (II) and Formula (III) and their radiolabeled nuclides is provided to detect cancer cells and to assess the proliferative status of cancer cells which express sigma-2 (sigma.2) receptors, such as cells of solid tumors, in vitro and in vivo.
In an aspect, a method of detecting cancer comprises administering to a human patient afflicted with a solid tumor, such as breast cancer, a functionally effective amount of a detectably labeled conformationally-flexible benzamide compound having a structure of at least one of the structures illustrated in Formula (I) Formula (II) and Formula (III) and determining the extent to which the compound binds to cells of the cancer, the extent providing a measure of the presence and/or proliferative status of the cells, which status correlates to the extent of sigma-2 receptor expression by said cells. The method is based on the ability of the compounds illustratively depicted in FIGS. 1, 2, 3, and 7 to selectively bind to sigma-2 (sigma.2) receptors versus sigma.1 receptors.
Generally, the concentration of the benzamide compound(s) of Formula (I) Formula (II) and Formula (III) in a liquid composition, such as a lotion, will be from about 0.1- about 25 wt-%, preferably from about 0.5- about 10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-about 5 wt-%, preferably about 0.5- about 2.5 wt-%. Single dosages for injection, infusion or ingestion will generally vary between 50-1500 mg, and may be administered, i.e., 1-3 times daily, to yield levels of about 0.5-50 mg/kg, for adult humans.
Additionally, a benzamide compound of Formula (I), Formula (II) and Formula (III) can be labeled with a metal chelating group optionally comprising a radionuclide, such as a metallic radioisotope. Such chelating groups are well known in the art and include polycarboxylic acids such as for example diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, and the like, or analogs or homologs thereof, as well as the chelating groups disclosed in Anderson and Welch (Chem Rev. 99: 2219-2234, 1999) and Jurisson and Lydon (Chem. Rev. 99: 2205-2218, 1999).
The chelating group or the radionuclide therein may be attached directly to a compound of Formula (I), Formula (II) and Formula (III) or may be attached to a compound of Formula (I), Formula (II) and Formula (III) by means of a divalent or bifunctional organic linker group. Such bifunctional organic linker groups are well known in the art and are preferably less than about 50 angstroms in length. Examples of suitable bifunctional linker groups include 2-carboxymethyl, 3-carboxypropyl, 4-carboxybutyl, and the like. Preferably, the bifunctional linker group is attached to a compound of Formula (I) at the amino nitrogen which is substituted by the group, NRR′ in Formula (I). The linker group may also be attached at any synthetically feasible position. For example, FIG. 7 shows two compounds of the invention (compounds II and IIII) which are compounds of Formula (I), labeled with a metal chelating group comprising a radionuclide (M).
Suitable nonlimiting examples of useful radionuclides include: Actinium-225, Astatine-211, Bismuth-212, Bismuth-213, Bromine-75, Bromine-76, Carbon-11, Cerium-141, Chromium-51, Copper-60, Copper-61, Copper-62, Copper-64, Copper-67, Dysprosium-166, Fluorine-18, Gadolinium-152, Gadolinium-153, Gold-195m, Holmium-166, Indium-111, Indium-113m, Iodine-123, Iodine-124, Iodine-121, Iron-55, Iron-59, Lutetium-177, Nitrogen-13, Oxygen-15, Palladium-103, Radium-223, Radium-224, Rhenium-186, Rhenium-188, Rubidium-81, Rubidium-82, Rubidium-86, Ruthenium-103, Ruthenium-106, Samarium-153, Scandium-46, Tantalum-178, Technetium-94m, Technetium-99m, Thallium-201, Titanium-45, Ytterbium-169, Yttrium-86, Yttrium-90, and Zirconium-89, In an aspect technetium-99m is used for SPECT imaging studies, and rhenium-188, rhenium-186, copper-64 and yitrium-90 are useful for radiotherapy of breast tumors. In an aspect the compounds of Formula (I), Formula (II) and Formula (III) including compound 23 are radiolabeled with at least one of tritium and iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the invitro detection of sigma 2 receptors in tumors and normal tissue.
In an aspect, single photon emission computed tomography (“SPECT imaging”) comprises a collimation of gamma rays emitted by a radiopharmaceutical distribution such as detectable radioactivity emitting a benzamide compound of the invention or a pharmaceutical composition comprising a novel benzamide compound within the mammalian body undergoing treatment and analysis. Generally collimators for SPECT imaging are lead and comprise thousands of various shaped parallel channels through which—and only through which—gamma rays are allowed to pass. Generally such collimators are positioned over a single crystal of NaI contained in the Gamma camera in an arrangement referred to as an Anger camera, http://www.amershamhealth.com/medcyclopaedia/Volume%20I/Anger%20camera). The image or acquisition from the camera is the captured image which is presented to a human operator as part of a viewable image. This may be a screen shot or a captured digital image, which may be stored in a computer storage. In an aspect multi-acquisition is used. In an aspect a multi-acquisition is carried out over an elapsed time interval.
Physical data for Compound 23. 1H-NMR (CDCl3) δ 1.60-1.70 (m, 4H), 2.33(s, 3H), 2.51-2.56 (t, 2H), 2.67-2.72 (t, 2H), 2.78-2.83 (t, 2H), 3.48-3.54 (m, 4H), 3.82-3.83 (s, 6H), 4.21-4.25 (t, 1H), 4.30-4.34 (t, 1H), 4.68-4.72 (t, 1H), 4.84-4.88 (t, 1H), 6.49 (s, 1H), 6.57 (s, 1H), 6.99-6.83 (d, 1H), 7.19-7.30 (d, 1H), 7.95 (s, 1H), 7.99 (d, 1H).
The IC50 values at sigma sites were generally determined in triplicate from non-linear regression of binding data as analyzed by JMP (SAS InstituteIncv., JMP Software, SAS Campus Drive; Cary, N.C. 27513), using 8 concentrations of each compound. Ki values were calculated using the method of Cheng-Prusoff (Biochem. Pharmacol. 1973, 22, 3099-4022) and represent mean values±SEM. All curves were best fit to a one site fit and gave Hill coefficients of 0.8-1.0. The Kd value used for [3H]DTG in rat liver was 17.9 nM and was 4.8 nM for [3H](+)-pentazocine in guinea pig brain.11,12
This compound was studied in mature Balb/C mice that were implanted with EMT-6 mammary tumors. The mice were implanted in the nape of the neck 7 days prior to the study. The biodistribution study consisted of three groups: 1 hr low dose (˜6 μCi), 4 hr low dos and a 4 hr high dose (˜150 μCi). The % ID/g at 1 hr for tumor, brain, fat, blood and liver were 4.0±0.4, 0.25±0.02, 1.1±0.4, 2.1±0.3 and 5.4±0.4, respectively. At 4 hr for the low dose animals the values decreased to 1.2±0.2, 0.15±0.02, 0.3±0.2, 0.82±0.08 and 1.3±0.2, respectively. The % ID/g for the 4 hr high dose animals was not significantly different. The activity injected into the high dose animals was enough to perform microPET® imaging studies. At 1 and 2 hr the tumors were clearly identified in the three animals that were injected. This initial study has shown that this σ2 receptor compound has a high uptake into EMT-6 mammary tumors and can be imaged non-invasively. (MicroPET® is a dedicated PET scanner designed for high resolution imaging of small laboratory animals. It is available from Concorde Microsystems, Inc. 10427 Cogdill Rd, Suite 500 Knoxville, Tenn. 37932 USA.)
Specificσ1:σ2Activity#XRnσ1σ2Ratio% Yield(EOB) 9HCH3210,41213.3 78360-75˜5,000mCi/μmol10HCH34 3,07810.3 30060-75˜4,000mCi/μmol 8HBr2 5,48412.2 44210-15˜1,000mCi/μmol 6OCH3Br412,900 8.21,57330-40˜4,000mCi/μmol
% ID per gram5 min30 min1 hourblood5.89 ± 0.292.62 ± 0.221.98 ± 0.35lung5.69 ± 0.701.42 ± 0.151.39 ± 0.67liver18.49 ± 2.87 3.87 ± 0.671.70 ± 0.23kidney44.07 ± 1.67 2.77 ± 0.421.01 ± 0.12muscle1.75 ± 0.210.56 ± 0.190.41 ± 0.22fat3.07 ± 0.400.38 ± 0.120.26 ± 0.09heart2.89 ± 0.360.76 ± 0.060.76 ± 0.46brain1.63 ± 0.300.11 ± 0.010.10 ± 0.04tumor3.10 ± 0.251.08 ± 0.080.85 ± 0.14ratioTumor:blood0.53 ± 0.040.41 ± 0.020.44 ± 0.06Tumor:lung0.55 ± 0.070.77 ± 0.140.68 ± 0.19Tumor:muscle1.79 ± 0.202.08 ± 0.592.40 ± 0.84Tumor:fat1.03 ± 0.213.10 ± 1.213.46 ± 0.91Tumor:heart1.08 ± 0.101.43 ± 0.141.32 ± 0.45
% ID per gram 5 min 30 min 1 hour blood 7.12 ± 1.01 0.99 ± 0.15 0.45 ± 0.04 lung 6.01 ± 0.77 1.34 ± 0.23 0.70 ± 0.26 liver(all) 25.02 ± 3.70 2.48 ± 0.52 1.19 ± 0.17 kidney 19.48 ± 1.46 2.57 ± 0.78 1.34 ± 0.19 muscle 1.94 ± 0.13 1.67 ± 0.14 0.26 ± 0.07 fat 1.66 ± 0.41 0.46 ± 0.19 0.20 ± 0.08 heart 3.54 ± 0.31 0.68 ± 0.12 0.29 ± 0.10 brain 0.33 ± 0.09 0.10 ± 0.00 0.03 ± 0.00 tumor 2.82 ± 0.36 0.92 ± 0.10 0.50 ± 0.09 ratio Tumor:blood 0.40 ± 0.01 0.94 ± 0.05 1.10 ± 0.11 Tumor:lung 0.47 ± 0.04 0.69 ± 0.08 0.79 ± 0.30 Tumor:muscle 1.46 ± 0.19 0.59 ± 0.05 1.84 ± 0.25 Tumor:fat 1.82 ± 0.45 2.05 ± 0.57 2.77 ± 0.82 Tumor:heart 0.80 ± 0.07 1.36 ± 0.12 1.86 ± 0.64
% IDper gram5 min.30 min.1 hour2 hourblood 4.55 ± 0.59 2.55 ± 0.062.08 ± 0.693.46 ± 0.66lung 5.52 ± 0.73 1.59 ± 0.101.20 ± 0.271.75 ± 0.20liver(all)17.85 ± 3.17 5.57 ± 1.313.09 ± 0.483.77 ± 0.80spleen 3.22 ± 0.75 0.92 ± 0.260.59 ± 0.060.72 ± 0.05kidney50.08 ± 2.0932.24 ± 4.6415.60 ± 2.01 3.61 ± 0.52muscle 1.42 ± 0.05 0.57 ± 0.070.56 ± 0.260.45 ± 0.02fat 2.61 ± 0.45 0.80 ± 0.050.66 ± 0.110.69 ± 0.18heart 2.44 ± 0.43 0.99 ± 0.130.78 ± 0.141.23 ± 0.18brain 1.69 ± 0.18 0.24 ± 0.050.15 ± 0.010.21 ± 0.01bone 1.55 ± 0.20 0.52 ± 0.020.50 ± 0.170.49 ± 0.17tumor 2.28 ± 0.14 1.30 ± 0.081.12 ± 0.201.19 ± 0.13ratioTumor:blood 0.50 ± 0.04 0.51 ± 0.020.58 ± 0.220.35 ± 0.21Tumor:lung 0.42 ± 0.05 0.82 ± 0.050.98 ± 0.340.68 ± 0.10Tumor: 1.61 ± 0.05 2.31 ± 0.402.47 ± 1.532.63 ± 2.47muscleTumor:fat 0.90 ± 0.20 1.63 ± 0.021.71 ± 0.291.82 ± 2.22Tumor:heart 0.95 ± 0.13 1.32 ± 0.191.50 ± 0.490.98 ± 0.13
% ID per gram 5 min. 30 min. 1 hour 2 hour blood 6.90 ± 1.29 2.44 ± 0.65 1.17 ± 0.29 3.37 ± 1.23 lung 5.95 ± 1.30 1.39 ± 0.29 0.81 ± 0.20 1.27 ± 0.37 liver(all) 41.37 ± 7.23 8.20 ± 1.05 2.87 ± 0.34 3.47 ± 1.05 kidney 54.77 ± 8.42 38.59 ± 2.05 18.07 ± 2.07 8.46 ± 1.26 muscle 1.47 ± 0.20 0.70 ± 0.25 0.37 ± 0.23 0.38 ± 0.06 fat 3.46 ± 0.59 1.03 ± 0.44 0.77 ± 0.66 0.37 ± 0.13 heart 2.79 ± 0.35 0.94 ± 0.19 0.40 ± 0.02 0.86 ± 0.26 brain 1.42 ± 0.33 0.20 ± 0.06 0.06 ± 0.02 0.09 ± 0.03 tumor 2.91 ± 0.40 1.33 ± 0.13 0.71 ± 0.12 0.82 ± 0.09 ratio Tumor:blood 0.42 ± 0.03 0.57 ± 0.12 0.62 ± 0.09 0.26 ± 0.08 Tumor:lung 0.50 ± 0.07 0.98 ± 0.16 0.91 ± 0.24 0.67 ± 0.14 Tumor: 2.00 ± 0.37 2.06 ± 0.69 2.14 ± 0.99 2.17 ± 0.23 muscle Tumor:fat 0.84 ± 0.06 1.49 ± 0.65 1.93 ± 1.87 2.44 ± 0.77 Tumor:heart 1.04 ± 0.08 1.44 ± 0.18 1.81 ± 0.32 1.00 ± 0.27
E. Blocking studies. The results of the above biodistribution studies in tumor bearing rodents (mice) showed the utility that [11C]10, [76Br]6, and [125I]6i as potential candidates for further evaluation.
F. Comparison with [18F]FLT. One of the specific aims of the project was to compare the σ2 receptor imaging approach with the nucleoside analog, [18F]FLT. These studies were conducted and the results are summarized in FIGS. 3-5. In this study, the uptake of [18F]FLT at 1 hr was compared with the one hr data for [11C]Compound 10. For studies comparing [18F]FLT with [76Br]6 and [125I]6i, the two hr post-i.v. injection time point was used.
G. MicroPET® Imaging Studies—The inventors conducted microPET® imaging studies with [76Br]6 in Balb-c mice bearing EMT-6 breast tumor xenografts to model a living mammal afflicted with cancer. The results of the imaging studies are shown in FIG. 6. Note the high uptake of the radiotracer in the NCA study (left image), which can be blocked with a known sigma receptor ligand (right image). These data show that [76Br] Compound 6 is a potential radiotracer for imaging the σ2 receptor status of breast tumors.
H. Log P Calculations. The lipophilicity of each compound was calculated using the program Clog P (Advanced Chemistry Development, Inc.; Toronto, Canada). The results of the log P calculations are shown in Table X. The log P values ranged from 2.31 to 3.43.
TABLE X#Log P
92.31102.84 83.17 73.33 63.43 6i3.24
The relationship between the uptake of the radiolabeled benzamide analogs (% I.D. at 5 min post-i.v. injection) and log P is shown in Figure X. There was no clear trend with respect to log P and tumor uptake (top graph) and tumor:fat ration (bottom graph). The higher tumor:fat ratio of [76Br]6 and [125I]6i was due to the later time point that can be imaged because of the longer half-life of Br-76 and I-125 versus that of C-11.
3. [125I]6i , which has a similar tumor:fat ratio as [18F]FLT and exceeds [18F]FLT in all other tumor:background ratios.
Mach R H, Huang Y, Buchheimer N, Kuhner R, Wu L, Morton T E, Wang L-M, Ehrenkaufer R L, Wallen C A, Wheeler K T. [18F]N-4′-fluorobenzyl-4-(3-bromophenyl)acetamide for imaging the sigma receptor status of shown tumors: comparison with [18F]FDG and [125I]IUDR. Nucl Med Biol 2001; 28:451-458.
Douglas J. Rowland Jr, Michael J. Welch, Robert H. Mach, Zhude Tu
Tu, Zhude, Welch, Michael J., Mach, Robert H., Rowland, Douglas J. Jr.
514/255.30