Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

An amyloid binding compound of Formula I or a water soluble, non-toxic salt thereof:

• X is C(R″)2,
• wherein each R″ independently is H, F, Cl, Br, I, a lower alkyl group, (CH2)nOR′ wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R″, a tetrazole or oxadiazole of the form:
• wherein R′ is H or a lower alkyl group,
• or X is CR′═CR′, N═N, C═O, O, NR′, where R′ 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)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein 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 and oxadiazole of the form:
• wherein R′ is H or a lower alykl group, or a triazene of the form:
• each Q is independently selected from one or the following structures:
• IA, IB, IC, ID, IE, IF, and IG, wherein
• IA has the following structure:
• wherein:
• each of R3, R4, R5, R6, or R7 independently is defined the same as R1 above,
• provided that:
• i) if the compound of Formula I is:
• then at least one of R1-R4 or R6-R7 is independently selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph , CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• ii) if the compound of Formula I is:
• wherein R2 is a lower alkyl group, OR′ (wherein R′ is a lower alkyl group) or Cl, then at least one other of R1 -R7 is independently selected from the group consisting of F, Br, I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, (C═O) —R′, N(R′)2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, CR′═CR′—Rph, CR2, CR2′—Rph, wherein R′ is H or a lower alkyl group, unless indicated and whrein Rph represents an unsubstitutd or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from R1 and R2 above, tetrazole and oxadiazole of the form:
• wherein R′ is H or a lower alkyl group, or a traizene of the form:
• iii) if the compound of Formula I is
• wherein R3 or R7 is a lower alkyl group, CN, F, Cl, or Br, then at least one other of R1-R7 is independendtly selected from the group consisting of F, Br, I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group and wherein 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 above, tetrazole and oxadiazole of the form:
• wherein R′ is H or a lower alkyl group, or a triazene of the form:
• iv) if the compound of Formula I is
• wherein R5 is H, a lower alkyl group, CN, COOR′, (C═O)N(R′)2, F, Cl, or Br, then at least one other of R1-R7 is independently selected from the group consisting of I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2CH2—CH2F, O—CH2—CH2—CH2F, (C═O)—R′, N(R′)2, NO2, O(CO)R′, OR′, SR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group and wherein Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-pheny substituents defined from R1 and R2 above, tetrazole and oxadiazole of the form:
• wherin R′ is H or a lower alkyl group, or a triazene of the form:
• v) if the compound of Formula I is
• wherein R5 is N(R′)2 (wherein R′ is a lower alkyl group) and R1, R2, R4, and R6 are all H, then R3 and R7 are independently selected from the group consisting of F, Cl, Br, I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′ (wherein R′ is H), SR′, COOR′ (wherein R′ is H), tri-alkyl tin, Rph, CR′═CR′—Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group, unless indicated, and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• vi) if the compound of Formula I is:
• wherein R5 is H, (CH2)nOR′ (wherein n is 1 and R′ is H) or COOR′ (wherein R′ is a lower alkyl group), then at least one of R1-R4, R6 or R7 is independently selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′ (wherein R′ is H), tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group, unless indicated, and wherein Rph represents an unsubstituted or substituted phenyl group with phenyl substituents being chosen from any of the non-phenyl substituents defined from R1 and R2 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• vii) if the compound of Formula I is:
• wherein at least one of R3, R5 or R7 is a H, CN, COOR′, or (C═O)N(R′)2, then at least one other of R1-R7 is independently selected from the group consisting of F, Cl, Br, I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, (C═O)R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group and wherein 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 above, tetrazole and oxadiazole of the form:
• wherein R′ is H or a lower alkyl group, or a triazene of the form:
• viii) if the compound of Formula I is:
• wherein R5 is COOR′ (wherein R′ is H or lower alkyl), then at least one of R1-R4, R6 or R7 is independently selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ H or a lower alkyl group, unless indicated, and wherein Rph represents an unsubstituted or substituted phenyl group with phenyl substituents being chosen from any of the non-penyl substituents defined from R1 and R2 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• ix) if the compound of Formula I is:
• wherein both R5 are N(R′)2 (wherein R′ is a lower alkyl group), then at least one of R1-R4, R6 or R7 is independently selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group, unless indicated, and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• x) if the compound of Formula I is:
• wherein at least one of R3, R5 or R7 is a lower alkyl group, Cl, or OR′ (wherein R′ is a lower alkyl group), then at least one other of R2-R7 is independently selected from the other of R1-R7 is independently selected from the group consisting of F, Cl, Br, I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, C(═O)—R′, N(R′)2, NO2, O(CO)R′, OR′ (wherein R′ is H), SR′, a tri-alkyl tin, Rph, CR′═CR′Rph, CR2′—CR2′Rph, wherein R′ is H or a lower alkyl group, unless indicated, and wherein 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 above, tetrazole and oxadiazole of the form:
• wherein R′ is H or a lower alkyl group, or a triazene of the form:
• xi) if the compound of Formula I is
• wherein exactly two to R2 are OR′ (wherein R′ is a lower alkyl group), then R5 is selected from the group consisting of H, F, Cl, Br, I, or a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, tri-alkyl tin, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group, unless indicated, and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• xii) if the compound of Formula I is:
• wherein R5 is N(R′)2 (wherein R′ is a lower alkyl group) and R2, R4, R6, and R7 are all H, then R3 and R7 are independently selected from the group consisting of F, Cl, Br, I, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′ SR′, COOR′, tri-alkyl tin, Rph, Rph, CR′═CR′—Rph, CR′═CR′—Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group, unless indicated, and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• IB has the following structure:
• wherein:
• each of R10, R11, R12, R13, R14, R15, or R16 independently is defined the same as R1 above,
• provided that:
• xiii) if the compound of Formula I is:
• wherein exactly two to R2 are a lower alkyl group, then at least one of R1, R10, R11, R12, R13, R14, R15 or R16 is independently selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph, CR′═CR′Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• xiv) if the compound of Formula I is:
• wherein exactly two to R2 are a lower alkyl group, then at least one of R1, R10, R11, R12, R13, R14, R15 or R16 is independently selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′, wherein n=1, 2, or 3, CF3, CH2—CH2F, O—CH2—CH2F, CH2—CH2—CH2F, O—CH2—CH2—CH2F, CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, tri-alkyl tin, Rph, CR′═CR′Rph, CR2′—CR2′—Rph, wherein R′ is H or a lower alkyl group and wherein 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 above, tetrazole and oxadiazole of the form:
• or a triazene of the form:
• IC has the following structure:
• wherein:
• 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
• represents a heterocyclic ring of one of the six following formulas:
• IE has the following structure:
• wherein:
• each of R25, R26, or R27 independently is defined the same as R1 above
• represents a heterocyclic ring of one of the six following formulas:
• IF has the following structure:
• wherein:
• exactly one of R28, R29, R30, R31, or R32 is the
• link defined for Formula I above and each other R28, R29, R30, R31, or R32 independently is defined the same as R1 above;
• IG has the following structure:
• wherein:
• exactly one of R33, R34, R35, R36, R37, R38 or R39 is the
• link defined for Formula I above and each other R33, R34, R35, R36, R37, R38 or R39 independently is defined the same as R1 above.