Heparanase inhibitors and uses thereof

A method for treatment of a disease or disorder caused by or associated with heparanase catalytic activity, said method comprising administering to a patient in need an effective amount of a heparanase inhibitor of the general formula I, II III or IV:

• wherein
• R1 is selected from the group consisting of:
• or the tautomer
• (ii) —N(R9)—CO(R10);
• (iii) —CO—N(R9)(R10);
• (iv) —SO2R11;
• (vii) —CH(OH)—CH(NH—CO—R′7)-CH2NR9R′9 R2, R3, R4, R5, R6, R′3, R′4, R′5 and R′6 each independently represents hydrogen, halogen, nitro, (C1-C32) alkyl, (C2-C32) alkenyl, (C6-C14) aryl, heteroaryl, —OR9′, —SR9′, —NR9R′9, —(CH2)n—NR9-COR′9, —COR′9, —COOR′9, —(CH2)n—CO—N(R9)(R′9);
• —SO3R′9, —SO2R′9, or —NHSO2R′9;
• or R1 and R2 together are a moiety selected from the group consisting of:
• wherein X is O, S, N(R12) or C(R′12, R″12) and X′ is O or N;
• or each pair of R2+R3, R3+R4, R4+R5 or R5+R6, together with the carbon atoms to which they are attached, form a 5- or 6-membered aromatic ring;
• R7 is selected from the group consisting of H, halogen, (C1-C32) alkyl, (C2-C32) alkenyl, (C6-C14) aryl, heteroaryl, —OR′9, —SR′9, —NR9R′9, —NR9-COR′9, —COR′9, —COOR′9, —CH(OH)—(CH2)n—O—CO—R9, —(CH2)n—NR9-COR′9, —(CH2)n—CO—N(R9)(R′9), —SO3R′9, —SO2R′9, —NHSO2R′9, —N═N—(C6-C14) aryl, and
• R′7 is (C1-C32) alkyl;
• R″7 is (C2-C32) alkenyl;
• R8 is as defined for R7;
• R9 is H or (C1-C32) alkyl and R′9 is H, (C1-C32) alkyl, (C2-C32) alkenyl or (C6-C14) aryl, or R9 and R′9 as part of the radical —NR9R′9 form together with the N atom to which they are attached a 3-7 membered saturated ring, optionally further containing one or more N, S or O atoms;
• R10 is selected from the group consisting of (C1-C32) alkyl, (C2-C32) alkenyl, —(CH2)n—CO—R17, —(CH2)n—NH—CO—R9-O—R′9, and
• R11 is OH or
• R12, R′12 and R″12 each is H or (C1-C32) alkyl, or R′12 and R″12 together are a radical
• R13 is selected from the group consisting of (C1-C32) alkyl, (C6-C14) aryl, —N═CH—(C6-C14)aryl,
• R′13 is ═O, ═NH or ═N—NH—SO2R′9;
• R14 is H, (C1-C32) alkyl, —(CH2)m—CH(OH)—CH2—NR9R′9 or —(CH2)m—CH(OH)—(C6-C14) aryl;
• R15 is H or —SO3H;
• R16 is selected from the group consisting of H, halogen, —COOH, —SO3H, —N═N—(C6-C14) aryl, and
• R17 is selected from the group consisting of (C1-C32) alkyl, (C6-C14) aryl, —NH—NH—CO—(C1-C32) alkyl, —NH—NH—CO—(C6-C14) aryl, —(CH2)n—NH—CO—C(R9)-O(C1-C32) alkyl, —(CH2)n—NH—CO—C(R9)-O(C6-C14) aryl, —(CH2)n—CO—(C1-C32) alkyl, and —(CH2)n—CO—(C6-C14) aryl;
• R18 is H or ═N—(C6-C14) aryl;
• R19 is (C6-C14) aryl;
• Y− is a counter ion selected from the group consisting of chloride, bromide, iodide, perchlorate, tosylate, mesylate, sulfate, phosphate and an organic anion;
• n is 0 or an integer from 1 to 10;
• m is an integer from 1 to 10;
• and
• any “(C1-C32) alkyl” or “(C2-C32) alkenyl” may be straight or branched and may be interrupted by one or more heteroatoms selected from O, S and/or N, and/or substituted by one or more radicals selected from the group consisting of halogen, (C3-C7) cycloalkyl, (C6-C14) aryl, nitro, OR′9, SR′9, epoxy, epithio, oxo, —COR′9, —COOR′9, —OSO3R′9, —SO3R′9, —SO2R′9, —NHSO2R′9, —NR9R′9, aziridine, ═N—OR′9, ═N—NR9R′9, —NR9-NR9R′9, —(CH2)n—NR9-COR′9, —(CH2)n—CO—NR9R′9, —OPO3R9R′9, —PO2HR′9 and —PO3R9R′9;
• “heteroaryl” means a radical derived from a mono- or poly-cyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of O, S and N;
• and any “aryl” or “heteroaryl” may be substituted by one or more radicals selected from the group consisting of halogen, (C6-C14) aryl, (C1-C32)alkyl, nitro, —OR′9, —SR′9, —COR′9, COOR′9, —OSO3R′9, —SO3R′9, —SO2R′9, —NHSO2R′9, —NR9R′9, —(CH2)n—NR9-COR′9, and —(CH2)n—CO—NR9R′9;
• or a pharmaceutically acceptable salt thereof.