Methods and compounds for inhibiting amyloid deposits
First Claim
1. A method for inhibiting IAPP-associated amyloid deposits in a subject, comprising administering to said subject an effective amount of an IAPP-inhibiting compound, or a pharmaceutically acceptable ester, acid or salt thereof, such that said IAPP-associated amyloid deposits are inhibited, wherein said IAPP-inhibiting compound is of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or —
- NH;
n (for each individual A group) is 0 or 1;
m is 1;
l, p and q are independently 0, 1, or 2;
R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, an anionic group at physiological pH, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring.
5 Assignments
0 Petitions
Accused Products
Abstract
Methods and compositions which are useful in the treatment of amyloidosis. In particular, methods and compositions are provided for inhibiting, preventing and treating amyloid deposition, e.g., in pancreatic islets, wherein the amyloidotic deposits are islet amyloid polypeptide (IAPP)-associated amyloid deposition or deposits. The methods of the invention involve administering to a subject a therapeutic compound which inhibits IAPP-associated amyloid deposits. Accordingly, the compositions and methods of the invention are useful for inhibiting IAPP-associated amyloidosis in disorders in which such amyloid deposition occurs, such as diabetes.
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Citations
172 Claims
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1. A method for inhibiting IAPP-associated amyloid deposits in a subject, comprising administering to said subject an effective amount of an IAPP-inhibiting compound, or a pharmaceutically acceptable ester, acid or salt thereof, such that said IAPP-associated amyloid deposits are inhibited, wherein said IAPP-inhibiting compound is of the formula
wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or — - NH;
n (for each individual A group) is 0 or 1;
m is 1;
l, p and q are independently 0, 1, or 2;
R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, an anionic group at physiological pH, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring. - View Dependent Claims (3, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172)
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3. The method of claim 1, wherein said subject has IAPP-associated amyloid deposits in pancreatic islets.
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89. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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90. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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91. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(6-methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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92. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 2-(2sulfobenzoyl)-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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93. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 2-(2-sulfobenzyl)-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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94. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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95. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(3-carboxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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96. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds N-methyl-N-phenyl-3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonamide, and pharmaceutically acceptable esters, acids, and salts thereof.
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97. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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98. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 4-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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99. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 4-[2-(6methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable csters, acids, and salts thereof.
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100. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-propylthiophosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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101. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(6-methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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102. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(8-methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and phamaceutically acceptable esters, acids, and salts thereof.
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103. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydro-8-isoquinolinesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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104. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(6-dimethylamino-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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105. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(6-chloro-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable estrs, acids, and salts thereof.
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106. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 4-[2-(1,2,3,4tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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107. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydro-5-isoquinolinesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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108. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1-sulfopropyl-2-[2-(1,2,3,4-tetrahydroisoquinolinyl)methyl]-4,5-dihydroimidazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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109. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[7-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and phamaceutically acceptable esters, acids, and salts thereof.
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110. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compouads 3-[6-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts threof.
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111. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[8-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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112. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(3-methoxycarbonyl-1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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113. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[6-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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114. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[7-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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115. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds N-phosphonoacetyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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116. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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117. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds N-sulfoacetyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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118. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds N-ethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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119. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds N-propyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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120. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds N-propyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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121. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-[(1,2,3,4-tetrahydroisoquinol-2-yl)methyl]isoxazol-3-ol, and pharmaceutically acceptable esters, acids, and salts thereof.
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122. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-[(6-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)methyl]isoxazol-3-ol, and pharmaceutically acceptable esters, acids, and salts thereof.
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123. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the componnds (±
- )-laudanosoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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124. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds (−
- )-1-[5-chloro-2-(methylamino)phenyl]-1,2,3,4-tetrahydroisoquinoline (−
)-tartrate, and pharmaceutically acceptable esters, acids, and salts thereof.
- )-1-[5-chloro-2-(methylamino)phenyl]-1,2,3,4-tetrahydroisoquinoline (−
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125. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds (S)-(−
- )-(1,2,3,4-tetrahydro-3-isoquiolinecarboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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126. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds tetrahydropapaveroline hydrobromide (norlaudanosoline hydrobromide), and pharmaceutically acceptable esters, acids, and salts thereof.
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127. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-phenyl-5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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128. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-methyl-5-[2-(1,2,3,4-tetrahydroisoquiolyl)methyl]isoxazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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129. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole-3-carboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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130. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-phenyl-3-[2-(1,2,3,4-tetrahydroisoquinolinyl)methyl]isoxazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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131. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole-5-carboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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132. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds (2S)-2-amino-2-[3-(2-1,2,3,4-tetrahydroisoquinolylmethyl)isoxazol-5-yl]acetic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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133. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole-5-L-alanine, and pharmaceutically acceptable esters, acids, and salts thereof.
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134. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 4-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]-L-phenylalanine, and pharmaceutically acceptable esters, acids, and salts thereof.
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135. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids and salts thereof.
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136. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-(1,2,3,4-tetrahydroisoquinol-6-yl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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137. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-[6-(1,2,3,4-tetrahydroisoquinolyl)methyl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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138. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-{2-[6-(1,2,3,4-tetrahydroisoquinolyl)]ethyl}-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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139. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-(1,2,3,4-tetrahydroisoquinol-7-yl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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140. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-[7-(1,2,3,4-tetrahydroisoquinolyl)methl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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141. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5-{2-[7-(1,2,3,4-tetrahydroisoquinolyl)]ethyl}-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
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142. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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143. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable ester, acids, and salts thereof.
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144. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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145. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, and pharmaceutically acceptable esters, acids, and salts thereof.
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146. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile, and pharmaceutically acceptable esters, acids, a salts thereof.
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147. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 6-amino-1,2,3,4-tetrahydroisoquinoline, and the pharmaceutically acceptable esters, acids, and salts thereof.
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148. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-amino-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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149. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-(3,4,5-trimethoxybenzoyl)amino-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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150. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-β
- -D-glucopyranosyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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151. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 6-β
- -D-glucopyranosyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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152. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds (1,2,3,4-tetrahydroisoquinol-1-yl)phosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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153. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 5,6,7,8-tetrahydro-2H-1,3-dioxoleno[4,5-g]isoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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154. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydrobenzo[g]isoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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155. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds (1,2,3,4-tetrahydroisoquinol-7-ylsulfonyl)aminobenzene, and pharmaceutically acceptable esters, acids, and salts thereof.
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156. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1-[(1,2,3,4-tetrahydroisoquinol-7-ylsulfonyl)amino]-3,4-dichlorobenzene, and pharmaceutically acceptable esters, acids, and salts thereof.
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157. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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158. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-benzyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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159. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-benzoyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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160. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-acetyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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161. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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162. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-carboxamide, and pharmaceutically acceptable esters, acids, and salts thereof.
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163. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-aminomethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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164. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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165. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-methyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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166. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-hydroxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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167. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-(methanesulfonyl)amino-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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168. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-(methanesulfonyl)aminomethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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169. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-nitro-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts tbereof.
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170. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, and pharmaceutically acceptable esters, acids, and salts thereof.
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171. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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172. The method of claim 1, wherein said IAPP-inhibiting compound is selected from the group consisting of the compounds 7-methylthio-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
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3. The method of claim 1, wherein said subject has IAPP-associated amyloid deposits in pancreatic islets.
- NH;
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2. A method for reducing IAPP-associated amyloid deposits in a subject having IAPP-associated amyloid deposits, the method comprising administering to said subject an effective amount of an IAPP inhibiting compound, or a pharmaceutically acceptable ester, acid or salt thereof, such that said IAPP-associated amyloid deposits are inhibited, wherein said IAPP-inhibiting compound is of the formula
wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or — - NH;
n (for each individual A group) is 0 or 1;
m is 1;
l, p and q are independently 0, 1, or 2;
R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, an anionic group at physiological pH, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring. - View Dependent Claims (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)
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4. The method of claim 2, wherein said subject has IAPP associated amyloid deposits in pancreatic islets.
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5. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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6. The method of claim 2, wherein said compound is selected from the group consisting of the comnpounds 3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
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7. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(6-methoxy-1,2,3,4-tetrahydro-isoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
8. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 2-(2-sulfobenzoyl)-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
9. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 2-(2-sulfobenzyl)-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
10. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
11. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(3-carboxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
12. The method of claim 2, wherein said compound is selected from the group consisting of the compounds N-methyl-N-phenyl-3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonamide, and pharmaceutically acceptable esters, acids, and salts thereof.
-
13. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
14. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 4-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
15. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 4-[2-(6-methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
16. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-propylthiophosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
17. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(6methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
18. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(8-methoxy-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
19. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydro-8-isoquinolinesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
20. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(6-dimethylamino-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
21. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(6-chloro-1,2,3,4-tetrahydroisoquinolinyl)]-1-propanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
22. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]-1-butanesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
23. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydro-5-isoquinolinesulfonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
24. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1-sulfopropyl-2-[2-(1,2,3,4-tetrahydroisoquinolinyl)methyl]-4,5-dihydroimidazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
25. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[7-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
26. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[6-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
27. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[8-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
28. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(3-methoxycarbonyl-1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
29. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[6-methoxy-2-(1,2,3,4-tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
30. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[7-methoxy-2-(1,2,3,4tetrahydroisoquinolinyl)]propylphosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
31. The method of claim 2, wherein said compound is selected from the group consisting of the compounds N-phosphonoacetyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
32. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
33. The method of claim 2, wherein said compound is selected from the group consisting of the compounds N-sulfoacetyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
34. The method of claim 2, wherein said compound is selected from the group consisting of the compounds N-ethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
35. The method of claim 2, wherein said compound is selected from the group consisting of the compounds N-propyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
36. The method of claim 2, wherein said compound is selected from the group consisting of the compounds N-propyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
37. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-[(1,2,3,4-tetrahydroisoquinol-2-yl)methyl]isoxazol-3-ol, and pharmaceutically acceptable esters, acids, and salts thereof.
-
38. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-[(6-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)methyl]isoxazol-3-ol, and pharmaceutically acceptable esters, acids, and salts thereof.
-
39. The method of claim 2, wherein said compound is selected from the group consisting of the compounds (±
- )-laudanosoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
40. The method of claim 2, wherein said compound is selected from the group consisting of the compounds (−
- )-1-[5-chloro-2-(methylamino)phenyl]-1,2,3,4-tetrahydroisoquinoline (−
)-tartrate, and pharmaceutically acceptable esters, acids, and salts thereof.
- )-1-[5-chloro-2-(methylamino)phenyl]-1,2,3,4-tetrahydroisoquinoline (−
-
41. The method of claim 2, wherein said compound is selected from the group consisting of the compounds (S)-(−
- )-1,2,3,4-tetrahydro-3-isoquiolinecarboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
42. The method of claim 2, wherein said compound is selected from the group consisting of the compounds tetrahydropapaveroline hydrobromide (norlaudanosoline hydrobromide), and pharmaceutically acceptable esters, acids, and salts thereof.
-
43. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-phenyl-5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
44. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-methyl-5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
45. The method of claim 2, wherein said compound is selected from the group consisting of the compomnds 5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole-3-carboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
46. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-phenyl-3-[2-(1,2,3,4-tetrahydroisoquinolinyl)methyl]isoxazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
47. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]isoxazole-5-carboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
48. The method of claim 2, wherein said compound is selected from the group consisting of the compounds (2S)-2-amino-2-[3-(2-1,2,3,4-tetrahydroisoquinolylmethyl)isoxazol-5-yl]acetic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
49. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 3-[2-(1,2,3,4-tetrahydroisoquinolyl)-methyl]isoxazole-5-L-alanine, and pharmaceutically acceptable esters, acids, and salts thereof.
-
50. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 4-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl]-L-phenylalanine, and pharmaceutically acceptable esters, acids, and salts thereof.
-
51. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-[2-(1,2,3,4-tetrahydroisoquinolyl)methyl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
52. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-(1,2,3,4-tetrahydroisoquinol-6-yl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
53. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-[6-(1,2,3,4-tetrahydroisoquinolyl)methyl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
54. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-{2-[6-(1,2,3,4-tetrahydroisoquinolyl)]ethyl}-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
55. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-(1,2,3,4-tetrahydroisoquinol-7yl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
56. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-[7-(1,2,3,4-tetrahydroisoquinolyl)methyl)-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
57. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5-{2-[7-(1,2,3,4-tetrahydroisoquinolyl)]ethyl}-1H-1,2,3,4-tetrazole, and pharmaceutically acceptable esters, acids, and salts thereof.
-
58. The method of claim 2, wherein said compound is selected from the group consisting of the compowuds 6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
59. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
60. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
61. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, and pharmaceutically acceptable esters, acids, and salts thereof.
-
62. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile, and pharmaceutically acceptable esters, acids, and salts thereof.
-
63. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 6-amino-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
64. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-amino-1,2.3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
65. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-(3,4,5-trimethoxybenzoyl)amino-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
66. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-β
- -D-glucopyranosyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
67. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 6-β
- -D-glucopyranosyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
68. The method of claim 2, wherein said compound is selected from the group consisting of the compounds (1,2,3,4-tetrahydroisoquinol-1-yl)phosphonic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
69. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 5,6,7,8-tetrahydro-2H-1,3-dioxoleno[4,5-g]isoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
70. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydrobenzo[g]isoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
71. The method of claim 2, wherein said compound is selected from the group consisting of the compounds (1,2 3,4-tetrahydroisoquinol-7-ylsulfonyl)aminobenzene, and pharmaceutically acceptable esters, acids, and salts thereof.
-
72. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1-[(1,2,3,4-tetrahydroisoquinol-7-ylsulfonyl)amino]-3,4-dichlorobenzene, and pharmaceutically acceptable esters, acids, and salts thereof.
-
73. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
74. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-benzyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
75. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-benzoyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
76. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-acetyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
77. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquoline-7-carboxylic acid, and pharmaceutically acceptable esters, acids, and salts thereof.
-
78. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-carboxamide, and pharmaceutically acceptable esters, acids, and salts thereof.
-
79. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-aminomethyl-1,2,3,4-tetrahydroisoquinoline;
- and pharmaceutically acceptable esters, acids, and salts thereof.
-
80. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
81. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-methyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
82. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-hydroxy-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
83. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-(methanesulfonyl)amino-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
84. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-(methanesulfonyl)aminomethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
85. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-nitro-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and sats thereof.
-
86. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, and pharmaceutically acceptable esters, acids, and salts thereof.
-
87. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, and pharmaceutically acceptable esters, acids, and salts thereof.
-
88. The method of claim 2, wherein said compound is selected from the group consisting of the compounds 7-methylthio-1,2,3,4-tetrahydroisoquinoline, an pharmaceutically acceptable esters, acids, and salts thereof.
-
4. The method of claim 2, wherein said subject has IAPP associated amyloid deposits in pancreatic islets.
- NH;
Specification
- Resources
-
Current AssigneeBellus Health (Interational) Limited (GSK plc)
-
Original AssigneeQueen's University At Kingston
-
InventorsGupta, Ajay, Migneault, David, Kong, Xianqi, Szarek, Walter A., Weaver, Donald F.
-
Primary Examiner(s)Fay, Zohreh
-
Assistant Examiner(s)KWON, YONG SOK
-
Application NumberUS09/576,677Time in Patent Office1,085 DaysField of Search514/311, 514/313, 514/314, 514/307US Class Current514/307CPC Class CodesA61K 31/00 Medicinal preparations cont...A61K 31/185 Acids; Anhydrides, halides ...A61K 31/192 having aromatic groups, e.g...A61K 31/194 having two or more carboxyl...A61K 31/198 Alpha-amino acids, e.g. ala...A61K 31/205 Amine addition salts of org...A61K 31/4015 having oxo groups directly ...A61K 31/403 condensed with carbocyclic ...A61K 31/4035 Isoindoles, e.g. phthalimideA61K 31/404 Indoles, e.g. pindololA61K 31/4152 having oxo groups directly ...A61K 31/428 condensed with carbocyclic ...A61K 31/437 the heterocyclic ring syste...A61K 31/44 Non condensed pyridines; Hy...A61K 31/4409 only substituted in positio...A61K 31/4418 having a carbocyclic group ...A61K 31/4439 containing a five-membered ...A61K 31/445 Non condensed piperidines, ...A61K 31/4453 only substituted in positio...A61K 31/465 Nicotine; Derivatives thereofA61K 31/47 : Quinolines; IsoquinolinesA61K 31/4709 : Non-condensed quinolines an...A61K 31/472 : Non-condensed isoquinolines...A61K 31/4725 : containing further heterocy...A61K 31/473 : ortho- or peri-condensed wi...A61K 31/4741 : condensed with ring systems...A61K 31/675 : having nitrogen as a ring h...A61K 31/706 : containing six-membered rin...A61P 1/18 : for pancreatic disorders, e...A61P 25/28 : for treating neurodegenerat...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 43/00 : Drugs for specific purposes...