39-desmethoxy derivatives of rapamycin

A method of treatment of cancer or B-cell malignancies which comprises administering to a patient an effective amount of a compound of formula (I):

• wherein:
• X represents bond or CH2;
• R1 represents a keto group or (H,H);
• R2 represents OH or OMe;
• R3 represents H, OH or OMe;
• R4 and R5 each independently represent H or OH;
• R6 represents —R7, —C(O)R7, —(CH2)2—O—[CR21R22—O]a—C(O)—R23, —CR21R22—O—C(O)—R23, —POR19R20, —PO(OR19)(OR20) or Y—R15;
• R7 represents —(CR8R9)m(CR10R11)pCR12R13R14;
• R8 and R9 each independently represent C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl, any of which groups may optionally be substituted with —PO(OH)2, —CF2PO(OH)2, —OH, —COOH or —NH2;
• or R8 and R9 each independently represent H, trifluoromethyl or F;
• R10, R11, R12, R13 and R14 each independently represent C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl, any of which groups may optionally be substituted with —PO(OH)2, —CF2PO(OH)2, —OH, —COOH or —NH2;
• or R10, R11, R12, R13 and R14 may be independently selected from H, —(CR8R9)qNH2, —(CR8R9)qOH, CF6, F, COOH;
• or R10 and R11 or R12 and R13 or R13 and R14 may be taken together with the carbon to which they are joined to form a C3-6 cycloalkyl or a 3- to 6-membered heteroalkyl ring that contains one or more heteroatoms selected from N, O and S and that is optionally, substituted with up to 5 —(CR8R9)qOH, —(CR8R9)qNH2 or COOH groups;
• Y represents a bond, —C(O)—O—, —(CH2)2—O—C(O)—O—;
• R15 represents
• R16 are each independently H or OH;
• R17 is independently selected from H, OH and NH2;
• R18 is independently selected from H, —CH3, —CH2OH and —COOH;
• provided however that no more than 2 groups selected from R16, R17 and R18 represent H or CH3;
• R19 and R20 each independently represent H or C1-4 alkyl or R19 and R20 together represent ═CH2;
• R21 is independently selected from H, CH3;
• R22 is independently selected from H, —CH3, —CH═CH2, —CH2Cl, —CHCl2, —CCl3, —CH(OH)Me, —CH2OH, —CH2CH3, and —CH(Cl)Me;
• R23 is independently R7, Y—R15 or a 5- or 6-membered aryl or heteroaryl ring optionally substituted with between one and three groups selected from OH, F, Cl, Br, NO2 and NH2;
• a represents 0 or 1;
• and
• m, p and q each independently represent an integer between 0-4;
• provided however that the R7 moiety does not contain more than 12 carbon atoms and does contain at least one functional group selected from —PO(OH)2, —CF2PO(OH)2, —COOH, OH or NH2;
• or a pharmaceutically acceptable salt thereof;
• wherein the cancer is a cancer of the central nervous system, gastric cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, skin cancer, kidney cancer or uterine cancer.