Patent EA-004632-B1 (EA)
Title: Amyloid protein aggregation inhibitors, use thereof, composition based thereon and method for imaging amyloid deposits
Inventor: ALGELLI-SZAFRAN CORINNE ELIZAB
IPC: A61K47/32
Filed: 2000-05-31
Abstract: 1. A compound of formula I wherein R<A> is hydrogen, C1-C6alkyl or alkyl; n is 0 to 5 inclusive; R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, and R<7> are independently hydrogen, halogen, -OH, -NH2, NR<B>R<C>, -CO2H, -CO2C1-C6alkyl, -NO2, -OC1-C12alkyl, -C1-C8alkyl, -CF3, -CN, -OCH2phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, R<8> is COOH, tetrazolyl, -SO2R<D>, or -CONHSO2R<D>; R<B> and R<C> are independently hydrogen, -C1-C6alkyl, -(CH2)m-phenyl, or R<B> and R<C> taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl; R<D> is hydrogen, -C1-C6alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R<1> and R<2>, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof. 2. The compounds of claim 1: 2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid; 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid; or 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid. 3. The compounds of claim 1: 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid; 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid; 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid. 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-amino-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid; or 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid. 4. The compounds of claim 1: 2-(4-Phenethyl-phenylamino)-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-terephthalic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid; 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methanesulfonyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazol-1-yl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-nitro-benzoic acid; or 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoic acid. 5. The compounds of claim 1: 5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4,6-difluoro-benzoic acid; 6-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl amino}-3-trifluoromethyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoic acid; 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-Nitrophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-Aminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(4-Aminophenyl)phenylamino}benzoic acid; 2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride monohydrate; 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid; 2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid; 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[3-(4-Dimethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-(2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[3-(4-Acetylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-(3-(4-Dibutylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoic acid; 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl} phenylamino)benzoic acid; 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Diethylaminomethylphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyl]-phenylamino}-benzoic acid; 2-{4-[3-(3-Piperidin-1-yl-phenyl)-propyl]-phenylamino}-benzoic acid; 2-{4-[3-(3,4-Dichloro-phenyl)-propyl]phenylamino}-5-methyl-benzoic acid; N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-methanesulfonamine; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitro-benzoic acid; 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid; 2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 5-Amino-2-{4-[2-(3,4-Dichloro-phenyl)-ethyl)-phenylamino}-benzoic acid; 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid; 2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; {4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-[2-(1H-tetrazol-5-yl)-phenyl]-amine; 2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-(4-Phenethyl-phenylamino)-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-nicotinic acid; 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(4-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid; 2-{4-[2-(2-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoic acid; 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-dimethylamino-benzoic acid; 2-{4-[2-(3,5-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid; 3-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 5-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4,5-dimethoxy-benzoic acid; 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-3-nitro-benzoic acid; 3-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 5-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-isophthalic acid; 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 4-(4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-5-methoxy-benzoic acid; 2-{4-[2-(3-Methoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3-Bromo-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoic acid; 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-nicotinic acid; 2-{4-[2-(3-Fluoro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoic acid. 6. Compounds of claim 1: 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-pyrrol-1-yl-benzoic acid; 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-{2-[4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid; or 2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid. 7. Compoun