US 2008/0188511 A1 · 39-Desmethoxy Derivatives of Rapamycin

Abstract

The present invention relates to novel 39-desmethoxyrapamycin derivatives, methods for their production, and uses thereof. In a further aspect the present invention provides for the use of these 39-desmethoxyrapamycin derivatives in the treatment of cancer and/or B-cell malignancies, the induction or maintenance of immunosuppression, the treatment of transplantation rejection, graft vs. host disease, autoimmune disorders, diseases of inflammation, vascular disease and fibrotic diseases, the stimulation of neuronal regeneration or the treatment of fungal infections.

Claims38

Dependent claims

A 39-desmethoxy derivative of rapamycin characterised in that the 40-hydroxy position is derivatised as a carboxylic acid ester, as an ether, as a phosphate ester, as a phosphinate ester, as an acetal or as a gycosyl.

The compound of claim 1 having the formula:
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-C4 alkyl, C2-C4 alkenyl or C2-C4 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-C4 alkyl, C2-C4 alkenyl or C2-C4 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, CF3, 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-C6 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=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-C4 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, —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;
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.

28 more elements

Dependencies are inferred from the claim text.

39-Desmethoxy Derivatives of Rapamycin

Life of this patent

39-Desmethoxy Derivatives of Rapamycin

Life of this patent

Abstract

Claims38