METHOD OF INHIBITING AMYLOID PROTEIN AGGREGATION AND IMAGING AMYLOID DEPOSITS USING ISOINDOLINE DERIVATIVES

摘要

1. Compounds having the Formula 1: or the pharmaceutically acceptable salts thereof, wherein X is phenyl or substituted phenyl; Y is phenyl, substituted phenyl, pyridyl, or substituted pyridyl; wherein substituted phenyl and substituted pyridyl can have from 1 to 4 substituents, each independently selected from -OC1-C12alkyl, halogen-C1-C6alkyl, phenyl, -CO2H, -CO2R<1>, -NO2, -CF3, -CN, -NR<1>R<2>, -(CH2)nCO2H, -(CH2)nCO2R<1>, -SO2NR<1>R<2>, tetrazole, -(CH2)n-tetrazole, decahydroisoquinoline, imidazole, -(CH2)n imidazole, -CH=CH tetrazole, -CH=CH-imidazole, or phenyl; R<1> and R<2> independently are hydrogen or C1-C6alkyl; and each n is independently 0 to 5 inclusive. R" is hydrogen, C1-C6alkyl, or phenyl; and R' is hydrogen, C1-C6alkyl, -CF3, or phenyl. 2. A compound in accordance with Claim 1, having formula or the pharmaceutically acceptable salts thereof, wherein X is phenyl or substituted phenyl; when X is substituted phenyl and the substituted phenyl has from 1 to 4 substituents independently selected from -OC1-C6alkyl, halogen, C1-C6alkyl, -CF3, or phenyl. Y is substituted phenyl and the substituted phenyl has from 1 to 4 substituents independently selected from -CO2H, -NO2, -OC1-C12 alkyl, -CN, -CF3, -(CH2)nCO2H, -SO2NR<1>R<2>, tetrazole, -(CH2)n-tetrazole, imidazole, (CH2)n imidazole, -CH=CH-tetrazole, or -CH=CH-imidazole. 3. The compounds according to claim 1: 2-[2-(2,3,4-Trimethoxy-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-benzoic acid; 5-Nitro-2-[2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 4-Methoxy-5-nitro-2-[2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 2-[2-(3,4-Dichlorophenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 2-[2-(3,4-Dichlorophenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid; 2-[2-(3,4-dichlorophenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-4-methoxy-5-nitro-benzoic acid; 2-[2-(3-Chlorophenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 2-[2-(4-Chlorophenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 2-[2-(3,4-Dimethylphenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 2-[2-(4-Chloro-3-trifluoromethylphenyl)-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; 2-[2-Biphenyl-4-yl-2,3-dihydro-1H-isoindol-5-ylamino] benzoic acid; or 2-[2-(3-Chlorophenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid. 4. The compounds according to claim 1: 2-[2-(3,4-Dimehtyl-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino] 5-nitro-benzoic acid; 2-(2-Phenyl-2,3-dihydro-1H-isoindol-5-ylamino)-benzoic acid. 2-[2-(3-Chloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid; 2-[2-(4-Chloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5 nitro-benzoic acid [2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-yl]-[2-(1 tetrazol-5-yl)-phenyl]-amine; 5-Amino-2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-yl-amino]-benzoic acid; 5-Nitro-2-(2-phenyl-2,3-dihydro-1H-isoindol-5-ylamino)-benzoic acid; 2-[2-(4-Chloro-3-trifluoromethyl-phenyl)-2,3-dihydro-1H-isoindol-5-yl-amino]-5-nitro-benzoic acid; 2-[2-(3-Fluoro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid; 2-[2-(3-Methoxy-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid; 2-[2-(3-Fluoro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-benzoic acid; 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-fluoro-benzoic acid; and 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid. 5. The compounds according to claim 1: 2-[2-(3,4,5-Trimethoxy-phenyl)-2,3-dihydro-1H-isoindol 5-ylamino]-benzoic acid; or 2-[2-(3-Methoxy-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid; 6. A pharmaceutical composition comprising a compound of Claim 1 together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. 7. Use of compound according to claim 1 for producing of pharmaceutical treatment for treating Alzheimer's disease. 8. Use of compound according to claim 1 for producing of pharmaceutical treatment for inhibiting the aggregation of amyloid proteins to form amyloid deposits. 9. A method of imaging amyloid deposits, the method comprising the steps of: a) introducing into a patient a detectable quantity of a labeled compound of Formula 1; b) allowing sufficient time for the labeled compound to become associated with amyloid deposits; and c) detecting the labeled compound associated with the amyloid deposits.