Details for Patent: 4,885,363
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| Title: | 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs |
| Abstract: | Metal-chelating liquids having the formula ##STR1## wherein Y is oxygen or ##STR2## R.sub.1 is hydrogen, alkyl, arylalkyl aryl, alkoxy, hydroxyalkyl ##STR3## wherein G is ##STR4## |
| Inventor(s): | Tweedle; Michael F. (Hightstown, NJ), Gaughan; Glen T. (West Trenton, NJ), Hagan; James T. (Holmdel, NJ) |
| Assignee: | E. R. Squibb & Sons, Inc. (Princeton, NJ) |
| Filing Date: | Dec 23, 1987 |
| Application Number: | 07/137,267 |
| Claims: | 1. A compound having the formula ##STR26## or a pharmaceutically acceptable salt thereof, wherein Y is oxygen or ##STR27## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl or phenyl substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups ##STR28## wherein G is ##STR29## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR30## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl, R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having and one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and X is chloro, bromo or iodo and wherein R.sub.1 is --(CH.sub.2).sub.n G, n is one and R.sub.2 is hydrogen then G is not CO.sub.2 H, wherein the term substituted phenyl refers to phenyl groups substituted with one, two, or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups. 2. A compound in accordance with claim 1 wherein Y is oxygen. 3. A compound in accordance with claim 1 wherein Y is ##STR31## and R.sub.1 is hydrogen. 4. A compound in accordance with claim 1 wherein Y is ##STR32## and R.sub.1 is alkyl. 5. A compound in accordance with claim 4 wherein Y is ##STR33## and R.sub.1 is methyl. 6. A compound in accordance with claim 1 wherein Y is ##STR34## and R.sub.1 is phenylalkyl or substituted phenylalkyl wherein the substituted phenyl groups are those substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 7. A compound in accordance with claim 1 wherein Y is ##STR35## and R.sub.1 is benzyl. 8. A compound in accordance with claim 1 wherein Y is ##STR36## and R.sub.1 is phenyl or substituted phenyl wherein the substituted phenyl groups are those substituted with one, two or three halogen hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 9. A compound in accordance with claim 1 wherein R.sub.1 is alkoxy. 10. A compound in accordance with claim 1 wherein R.sub.1 is hydroxyalkyl. 11. A compound in accordance with claim 1 wherein R.sub.1 is hydroxyethyl. 12. A compound in accordance with claim 1 wherein R.sub.1 =2'-hydroxypropyl. 13. A compound in accordance with claim 1 wherein n is 3 and G is N.dbd.C.dbd.S. 14. A compound in accordance with claim 1 wherein n is 1 and G is N.dbd.C.dbd.S. 15. A compound in accordance with claim 1 wherein R.sub.2 is hydrogen. 16. A compound in accordance with claim 1 wherein n is 2 and G is N.dbd.C.dbd.S. 17. A compound in accordance with claim 1 wherein n is 3 and G is NH.sub.2. 18. A compound in accordance with claim 1 wherein n=1 and G is NH.sub.2. 19. A compound in accordance with claim 1 wherein n is 2 and G is CN. 20. A compound in accordance with claim 1 wherein n=1, m=0, G=NH.sub.2. 21. A compound in accordance with claim 1 wherein n=1, m=0, G=NHR.sub.4, where R.sub.4 =--CH.sub.3. 22. A compound in accordance with claim 1 wherein n=1, m=0, G=NHR.sub.4, where R.sub.4 =--CH.sub.2 --CH.sub.2 --OH. 23. A compound in accordance with claim 1 wherein R.sub.2 is alkyl. 24. A compound in accordance with claim 23 wherein R.sub.2 is methyl. 25. The compound in accordance with claim 1, 4,7,10-triscarboxymethyl-1-oxa-4,7,10-triazacyclododecane. 26. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 27. The compound in accordance with claim 1, 1-methyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 28. The compound in accordance with claim 1, 1-benzyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 29. The compound in accordance with claim 1, 1,4,7,-triscarboxymethyl-10-(2'-cyanoethyl) 1,4, 7,10-tetraazacyclododecane. 30. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-10-(2'-carboxyethyl)-1,4,7,10-tetraazacyclododecan e. 31. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl)-10-(3'-aminopropyl)-1,4,7,10-tetraazacylododecane . 32. The compound in accordance with claim 1, 1,4,7-tris(carboxymethyl)-10-(N-methylcarbamoylmethyl)-1,4,7,10-tetraazacy clododecane. 33. The compound in accordance with claim 1, 1,4,7-Triscarboxymethyl-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyclododeca ne. 34. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-10-(carbamoylmethyl)-1,4,7,10-tetraazacyclododecan e. 35. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-10-(3'-isothiocyanatopropyl)-1,4,7,10-tetraazacycl ododecane. 36. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-10-(N-hydroxyethylcarbamoyl methyl)-1,4,7,10-tetraazacyclododecane. 37. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-10-(para-aminobenzyl)-1,4,7,10-tetraazacyclododeca ne. 38. The compound in accordance with claim 1, 1,4,7-triscarboxymethyl-10-(para-isothiocyanatobenzyl)-1,4,7,10-tetraazacy clododecane. 39. The compound in accordance with claim 1, 1,4,7-triscarboxylmethyl-10-(para-nitrobenzyl)-1,4,7,10-tetraazacyclododec ane. 40. A complex, or a pharmaceutically acceptable salt of a complex, of a metal atom and a metal-chelating ligand having the formula ##STR37## wherein Y is oxygen or ##STR38## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups ##STR39## wherein G is ##STR40## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR41## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl, R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and X is chloro, bromo or iodo and wherein R.sub.1 is --(CH.sub.2).sub.n G, n is one and R.sub.2 is hydrogen then G is not CO.sub.2 H, wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxy, alkyl, alkoxy carbamoyl or carboxyl groups. 41. A complex according to claim 40 where metal atom is non-radioactive and of atomic number 56-83. 42. A complex according to claim 40 where the metal atom is a radioactive positron- or gamma-emitting nuclide. 43. A complex according to claim 40 where the metal atom is a radioactive alpha- or beta-emitting nuclide. 44. A complex according to claim 40 where the metal atom is paramagnetic. 45. A complex according to claim 40 where the metal atom is TC-99m. 46. A complex according to claim 40 where the metal atom is Indium-III. 47. A complex according to claim 40 where the metal atom is gallium-67. 48. A complex according to claim 40 where the metal atom is gallium-68. 49. A complex according to claim 40 where the metal atom is yttrium-90. 50. A complex according to claim 40 where the metal atom is rhenium-188. 51. A complex according to claim 40 where the metal atom is samarium-153. 52. A complex according to claim 40 where the metal atom is bismuth-212. 53. A complex according to claim 40 where the metal atom is gadolinium(III). 54. A complex according to claim 40 where the metal atom is chromium(III). 55. A complex according to claim 40 where the metal atom is iron(III). 56. A complex according to claim 40 where the metal atom is manganese(II). 57. A complex according to claim 40 where the metal atom is manganese(III). 58. A complex according to claim 40 where the metal atom is dysprosium(III). 59. A complex according to claim 40 where the metal atom is holmium(III). 60. A complex according to claim 40 where the metal atom is erbium(III). 61. A complex according to claim 40 where the metal atom is yterbium(III). 62. A complex according to claim 40 where the metal atom is lutetium(III). 63. A complex in accordance with claim 40 wherein Y is oxygen. 64. A complex in accordance with claim 40 wherein Y is ##STR42## and R.sub.1 is hydrogen. 65. A complex in accordance with claim 40 wherein Y is ##STR43## and R.sub.1 is alkyl. 66. A complex in accordance with claim 40 wherein Y is ##STR44## and R.sub.1 is methyl. 67. A complex in accordance with claim 40 wherein Y is ##STR45## and R.sub.1 is phenylalkyl or substituted phenylalkyl wherein the substituted phenyl groups are those substituted with one two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 68. A complex in accordance with claim 40 wherein Y is ##STR46## and R.sub.1 is benzyl. 69. A complex in accordance with claim 40 wherein Y is ##STR47## and R.sub.1 is phenyl or substituted phenyl wherein the substituted phenyl groups are those substituted with one, two or three halogen hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 70. A complex in accordance with claim 40 wherein R.sub.1 is alkoxy. 71. A complex in accordance with claim 40 wherein R.sub.1 is hydroxyalkyl. 72. A complex in accordance with claim 40 wherein R.sub.1 is hydroxyethyl. 73. A complex in accordance with claim 40 wherein R.sub.1 =2'-hydroxypropyl. 74. A complex in accordance with claim 40 wherein n is 3 and G is N.dbd.C.dbd.S. 75. A complex in accordance with claim 40 wherein n is 1 and G is N.dbd.C.dbd.S. 76. A complex in accordance with claim 40 wherein R.sub.2 is hydrogen. 77. A complex in accordance with claim 40 wherein n is 2 and G is N.dbd.C.dbd.S. 78. A complex in accordance with claim 40 wherein n is 3 and G is NH.sub.2. 79. A complex in accordance with claim 40 wherein n=1 and G is NH.sub.2. 80. A complex in accordance with claim 40 wherein n is 2 and G is CN. 81. A complex in accordance with claim 40 wherein n=1, m=0, G NH.sub.2. 82. A complex in accordance with claim 40 wherein n=1, m=0, G=NHR.sub.4, where R.sub.4 =--CH.sub.3. 83. A complex in accordance with claim 40 wherein n=1, m=0, G=NHR.sub.4, where R.sub.4 =--CH.sub.2 --CH.sub.2 --OH. 84. A complex in accordance with claim 40 wherein R.sub.2 is alkyl. 85. A complex in accordance with claim 40 wherein R.sub.2 is methyl. 86. A complex in accordance with claim 40 where the ligand is 4,7,10-triscarboxymethyl-1-oxa-4,7,10-triazacyclododecane. 87. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 88. A complex in accordance with claim 40 where the ligand is 1-methyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraacyclododecane. 89. A complex in accordance with claim 40 where the ligand is 1-benzyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 90. A complex in accordance with claim 40 where the ligand is 1,4,7,-triscarboxymethyl-10-(2'-cyanoethyl) 1,4,7,10-tetraazacyclododecane. 91. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-10-(2'-carboxyethyl)-1,4,7,10-tetraazacyclododecan e. 92. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl)-10-(3'- aminopropyl)-1,4,7,10-tetraazacyclododecane. 93. A complex in accordance with claim 40 where the ligand is 1,4,7-tris(carboxymethyl)-10-(N-methylcarbamoylmethyl)-1,4,7,10-tetraazacy clododecane. 94. A complex in accordance with claim 40 where the ligand is 1,4,7-Triscarboxymethyl-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyclododeca ne. 95. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-10-(carbamoylmethyl)-1,4,7,10-tetraazacyclododecan e. 96. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-10-(3'-isothiocyanatopropyl)-1,4,7,10-tetraazacycl ododecane. 97. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-10-(N-hydroxyethylcarbamoylmethyl)-1,4,7,10-tetraa zacyclodedecane. 98. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-10-(paraaminobenzyl)-1,4,7,10-tetraazacyclododecan e. 99. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxymethyl-10-(paraisothiocyanatobenzyl)-1,4,7,10-tetraazacyc lododecane. 100. A complex in accordance with claim 40 where the ligand is 1,4,7-triscarboxylmethyl-10-(paranitrobenzyl)-1,4,7,10-tetraazacyclododeca ne. 101. A complex in accordance with claim 40, Gadolinium (III) 4,7,10-triscarboxymethyl-1-oxa-4,7,10-triazacyclododecane. 102. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 103. A complex in accordance with claim 40, Gadolinium (III) 1-methyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 104. A complex in accordance with claim 40, Gadolinium (III) 1-benzyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 105. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(2'-cyanoethyl) 1,4,7,10-tetraazacyclododecane. 106. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(2'-carboxyethyl)-1,4,7,10-tetraazacyclododecan e. 107. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(3'-aminopropyl)-1,4,7,10-tetraazacyclododecane . 108. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-tris(carboxymethyl)-10-(N-methylcarbamoylmethyl)-1,4,7,10-tetraazacy clododecane. 109. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyclododeca ne. 110. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(carbamoylmethyl)-1,4,7,10-tetraazacyclododecan e. 111. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(3'-isothiocyanatopropyl)-1,4,7,10-tetraazacycl ododecane. 112. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(N-hydroxyethylcarbamoylmethyl)-1,4,7,10-tetraa zacyclododecane. 113. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(paraaminobenzyl)-1,4,7,10-tetraazacyclododecan e. 114. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(paraisothiocyanato)-1,4,7,10-tetraazacyclodode cane. 115. A complex in accordance with claim 40, Gadolinium (III) 1,4,7-triscarboxymethyl-10-(paranitrobenzyl)-1,4,7,10-tetraazacyclododecan e. 116. A complex in accordance with claim 40, (yttrium) 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 117. A complex in accordance with claim 40, .sup.99m Technetium(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 118. A complex in accordance with claim 40, Gallium(III)(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 119. A complex in accordance with claim 40, Bismuth(III)(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 120. A complex in accordance with claim 40, Dysprosium(III)(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 121. A complex in accordance with claim 40, Iron(III)(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 122. A complex in accordance with claim 40, Chromium(III)(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 123. A complex in accordance with claim 40, Manganese(II)(1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane)(sodi um salt). 124. A compound having the formula ##STR48## or a pharmaceutically acceptable salt thereof, wherein Y is oxygen or ##STR49## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenyl or substituted phenyl and R.sub.2 is hydrogen or alkyl and wherein the substituted phenyl groups are those substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 125. A compound in accordance with claim 124 wherein Y is oxygen. 126. A compound in accordance with claim 124 wherein Y is ##STR50## and R.sub.1 is hydrogen. 127. A compound in accordance with claim 124 wherein Y is ##STR51## and R.sub.1 is alkyl. 128. A compound in accordance with claim 124 wherein Y is ##STR52## and R.sub.1 is methyl. 129. A compound in accordance with claim 124 wherein Y is ##STR53## and R.sub.1 is arylalkyl wherein the aryl portion is phenyl or substituted phenyl and wherein the substituted phenyl groups are those substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 130. A compound in accordance with claim 124 wherein Y is ##STR54## and R.sub.1 is benzyl. 131. A compound in accordance with claim 124 wherein Y is ##STR55## and R.sub.1 is phenyl or substituted phenyl and wherein the substituted phenyl groups are those substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups. 132. A compound in accordance with claim 124 wherein R.sub.2 is hydrogen. 133. A compound in accordance with claim 124 wherein R.sub.2 is alkyl. 134. A compound in accordance with claim 124 wherein R.sub.2 is methyl. 135. A compound in accordance with claim 124, 4,7,10-triscarboxymethyl-1-oxa-4,7,10-triazacyclododecane. 136. The compound in accordance with claim 124, 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 137. The compound in accordance with claim 124, 1-methyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 138. The compound in accordance with claim 124, 1-benzyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. 139. A complex, or a pharmaceutically acceptable salt of a complex, of a metal-chelating ligand having the formula ##STR56## wherein Y is oxygen or ##STR57## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenyl or substituted phenyl wherein the substituted phenyl groups are those substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups and R.sub.2 is hydrogen or alkyl and a paramagnetic metal atom. 140. A complex in accordance with claim 139 wherein the paramagnetic metal atom is gadolinium, manganese, chromium or iron. 141. A complex in accordance with claim 139 wherein the metal chelating ligand is 4,7,10-triscarboxymethyl-1-oxa-4,7,10-triazacyclododecane. 142. A complex in accordance with claim 139 wherein the metal chelating ligand is 1,4,7-triscarboxymethyl-1,4,10-tetraazacyclododecane. 143. A complex in accordance with claim 139 wherein the chelating ligand is 1-methyl-4,7,10-triscarboxymethyl-,1,4,7,10-tetraazacyclododecane. 144. A complex in accordance with claim 139 wherein the chelating ligand is 1-benzyl-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane. |
