Patent ID: 6417178
Filing Date: 2002-07-09
Classification: A61K,A61P,C07C,C07D,G01N

Abstract:
An amyloid binding compound of Formula I or a water soluble, non-toxic salt thereof: wherein: is selected from the group consisting of N&boxH;Nâ€”Q, CRâ€²&boxH;Nâ€”Q, N&boxH;CRâ€²â€”Q, CRâ€²2â€”NRâ€²â€”Q, NRâ€²â€”CRâ€²2â€”Q, (CO)â€”NRâ€²â€”Q, NRâ€²â€”(CO)â€”Q and NRâ€²â€”NRâ€²â€”Q (where Râ€² independently represents H or a lower alkyl group); X is C(Râ€³)2, (wherein each Râ€³ independently is H, F, Cl, Br, I, a lower alkyl group, (CH2)nORâ€² where n=1, 2, or 3, CF3, CH2â€”CH2F, Oâ€”CH2â€”CH2F, CH2â€”CH2â€”CH2F, Oâ€”CH2â€”CH2â€”CH2â€”F, CN, (C&boxH;O)â€”Râ€², N(Râ€²)2, NO2, (C&boxH;O)N(Râ€²)2, O(CO)Râ€², ORâ€², SRâ€², COORâ€², Rph, CRâ€²&boxH;CRâ€²â€”Rph, CR2â€²â€”CR2â€²â€”Rph, (where Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from Râ€³), a tetrazole or oxadiazole of the form: wherein Râ€² is H or a lower alkyl group); or X is CRâ€²&boxH;CRâ€², N&boxH;N, C&boxH;O, O, NRâ€², (where Râ€² represents H or a lower alkyl group), S, or SO2; each R1 and R2 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH2)nORâ€², wherein n=1, 2, or 3, CF3, CH2â€”CH2F, Oâ€”CH2â€”CH2F, CH2â€”CH2â€”CH2F, Oâ€”CH2â€”CH2â€”CH2F, CN, (C&boxH;O)â€”Râ€², N(Râ€²)2, NO2, (C&boxH;O)N(Râ€²)2, O(CO)Râ€², ORâ€², SRâ€², COORâ€², a tri-alkyl tin, Rph, CRâ€²&boxH;CRâ€²â€”Rph, CR2â€²â€”CR2â€²â€”Rph, (where Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from R1 and R2), tetrazole or oxadiazole of the form: (wherein Râ€² is H or a lower alkyl group), or a triazene of the form: â€ƒ(wherein R8 and R9 are lower alkyl groups) or and at least one of R2 is not H, OCH3, CH3 or halogen; each Q is independently selected from one of the following structures, each of which contains a carboxylic acid or an acid like functionality selected from the group consisting of hydroxy, sulfhydryl, tetrazole, oxadiazole, isoindol-1,3 (2H)-dione, benzisoxazole, 2,3-benzodiazine-1,4 (2H,3H)-dione, 2,3-benzoxazine-1,4 (3H)-dione, (2H) 1,3-benzoxazine-2,4 (3H)-dione, (3H) 2-benzazine-1,3 (2H)-dione, and NO2; IA, IB, IC, ID, IE, IF, and IG, wherein IA has the following structure: â€ƒwherein: each of R3, R4, R5, R6, or R7 is independently defined the same as R1 above and wherein at least one of R3, R4, R5, R6, or R7 is a hydroxy, tetrazole, oxadiazole, NO2, or carboxy in both Q's; wherein R1 or R2 is not H or COORâ€² when R6 is COORâ€²; and R1 or R2 is not H when R5 or R7 is OH; and R2 is not COOH when R3=OH, R4=COORâ€²or R5=NH2 IB has the following structure: â€ƒwherein: each of R10, R11, R12, R13, R14, R15, or R16 independently is defined the same as R1 above above and, wherein at least one of R10, R11, R12, R13, R14, R15, or R16 is a hydroxy, tetrazole, oxadiazole, NO2, or carboxy in both Q's and wherein at least one of R1 or R2 is a halogen when the compound of Formula I is a 4,4â€²-diazophenyl compound; provided that if the Formula IB moiety is: then at least one of R1 or R2 is Br or I or at least one or R11-R15 is not H, bromo or methoxy; IC has the following structure: â€ƒwherein: each of R17, R18, R19, R20, or R21 independently is defined the same as R1 above; ID has the following structure: wherein each of R22, R23, or R24 independently is defined the same as R1 above and represents a heterocyclic ring of one of the six following formulas: IE has the following structure: â€ƒwherein: each of R25, R26, or R27 independently is defined the same as R1 above and represents a heterocyclic ring of one of the six following formulas: IF has the following structure: â€ƒwherein: exactly one of R28, R29, R30, R31, or R32 is the â€ƒof the â€ƒlink defined for Formula I above and each other R28, R29, R30, R31, or R32 independently is defined the same as R1 above, and wherein at least one of R28, R29, R30, R31, or R32 is a hydroxy, sulfhydryl, tetrazole, oxadiazole, NO2, or carboxy in both Q's; IG has the following structure: â€ƒwherein: exactly one of R33, R34, R35, R36, R37, R38 or R39 is the â€ƒof the â€ƒlink defined for Formula I above and each other R33, R34, R35, R36, R37, R38 or R39 independently is defined the same as R1 above and wherein at least one of R33, R34, R35, R36, R37, R38 or R39 is a hydroxy, sulfhydryl, tetrazole, oxadiazole, NO2, or carboxy in both Q's; or wherein: is NRâ€²â€”N&boxH;Q (wherein Râ€² represents H or a lower alkyl group) and each â€ƒis independently selected from one of the following structures: IIA or IIB, wherein: IIA has the following structure â€ƒwherein each of R40-R47 independently is H, F, Cl, Br, I, a lower alkyl group, (CH2)nORâ€², wherein n=1, 2, or 3, CF3, CH2â€”CH2F, Oâ€”CH2â€”CH2F, CH2â€”CH2â€”CH2F, Oâ€”CH2â€”CH2â€”CH2F, CN, (C&boxH;O)â€”Râ€², N(Râ€²)2, NO2, (C&boxH;O)N(Râ€²)2, O(CO)Râ€², ORâ€², SH, COORâ€², a tri-alkyl tin, Rph, CRâ€²&boxH;CRâ€²â€”Rph, CR2â€²â€”CR2â€²â€”Rph, (where Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R1), a tri-alkyl tin, a tetrazole or oxadiazole of the form: (wherein Râ€² is H or a lower alkyl group); IIB has the following structure: â€ƒwherein: each of R48 and R49 independently is a lower alkyl group, (CH2)nORâ€², wherein n=1, 2, or 3, CF3, CH2â€”CH2F, CH2â€”CH2â€”CH2F, CN, (C&boxH;O)â€”Râ€², NO2, (C&boxH;O)N(Râ€²)2, COORâ€², (C&boxH;O)â€”CH2)nâ€”(C6H5) where n=1, 2, or 3, Rph, CRâ€²&boxH;CRâ€²â€”Rph, CR2â€²â€”CR2â€²â€”Rph, (where Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R1), a tetrazole or oxadiazole of the form: (wherein Râ€² is H or a lower alkyl group, wherein at least one of R48 or R49 is (C&boxH;O)â€”Râ€², NO2, (C&boxH;O)N(Râ€²)2, COORâ€², CN, or a tetrazole or oxadiazole of the form: (wherein Râ€² is H or lower alkyl group) in both Q's.