Agents for use in the treatment of amyloidosis

Agent for stabilising the native tetrameric form of transthyretin and thereby protecting it from proteolytic cleavage, which comprises a compound of the general formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

• A-L-B (I)
• wherein:
• A is a group of formula (II):
• or of formula (III):
• or of formula (IV):
• or of formula (V):
• wherein:
• Y is independently a direct bond or a C1-C4 alkylene group which may be linear, branched, or may include a cyclopropyl group;
• W is —COOH or a tetrazole group;
• Q1, Q2, Q3 and Q4 are independently CH or N, provided that no more than two of Q1, Q2, Q3 and Q4 are N;
• X is independently —NH—, —O—, —S—, —CH2—, —NR—, —CO—, —CONH—, —CONR—, —C═N—O—, —NHCO—, —NRCO—, —O—N═C—, —SO—, —SO2— or a direct bond, wherein R is C1-C3 alkyl optionally substituted by one or more halogen atoms;
• each of R1, R2 and R4 is independently selected from H, F, Cl, Br, I, CN, CF3, OCF3, R′, OR′, NR′R′, SOR′ or SO2R′, wherein R′ are each independently C1-C3 alkyl optionally substituted by one or more halogen atoms;
• R5 is selected from C1-C3 alkyl or C1-C3 alkoxy optionally substituted by one or more halogen atoms or —OH groups;
• and
• T is selected from groups of the following formulas (IVa) to (IVf):
• wherein R3 is selected from C1-C3 alkyl or C1-C3 alkoxy optionally substituted by one or more halogen atoms or —OH groups;
• B is a group of formula (III), (IV) or (V), or a group of formula (VI):
• or a group of formula —R10Z,
• wherein:
• Q5 is N or CR7;
• each of R6 and R7 is independently selected from H, F, Cl, Br, I, CF3, CN, OCF3, R′, OR′, NR′R′, SOR′ or SO2R′, wherein R and R′ are each independently C1-C3 alkyl optionally substituted by one or more halogen atoms, and provided that R6 and R7 are not both H;
• R8 is -Alk-, —CONH(Alk)-, or —COO(Alk)-, where Alk is a C1-C4 alkylene or alkenylene group which may be linear or branched or may include a cyclopropyl group, or Re is a group of formula (VII):
• wherein Q6 is selected from O or S and R9 is C1-C4 alkyl or alkoxy;
• Z is selected from —CO2R′, —CONR′R″, —SO2R′ wherein R′ and R″ are independently H or C1-C4 alkyl;
• and
• R10 is a C1-C4 alkylene or alkenylene group;
• and
• L represents a linker group which is a saturated or unsaturated chain of 5 to 13 carbon atoms in which optionally from one to three of the carbon atoms are replaced by O, S, NR′, SO, SO2, or CONR′, wherein R′ is H or C1-C3 alkyl, and wherein the said chain is unsubstituted or substituted by one or more groups comprising halogen, OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C1-C3 alkoxy.