Methods and compounds for inhibiting amyloid deposits

• US 6,562,836 B1
• Filed: 05/23/2000
• Issued: 05/13/2003
• Est. Priority Date: 05/24/1999
• Status: Expired due to Fees

• Current Assignee: Bellus Health (Interational) Limited
• Original Assignee: Queen's University At Kingston
• Inventors: Gupta, Ajay, Migneault, David, Kong, Xianqi, Szarek, Walter A., Weaver, Donald F.
• Primary Examiner(s): Fay, Zohreh
• Assistant Examiner(s): KWON, YONG SOK
• Application Number:
  US09/576,677
• Time in Patent Office: 1,085 Days
• Field of Search: 514/311, 514/313, 514/314, 514/307
• US Class Current: 514/307
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4152 having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/47 : Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 : Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/472 : Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/4725 : containing further heterocyclic rings
• CPC Class Codes: A61K 31/473 : ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/4741 : condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/675 : having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/706 : containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61P 1/18 : for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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.

Claims

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.

3. The method of claim 1, wherein said subject has IAPP-associated amyloid deposits in pancreatic islets.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

4. The method of claim 2, wherein said subject has IAPP associated amyloid deposits in pancreatic islets.

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.

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.

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.

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.