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

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- Number: US 2008/0188511 A1
- Document ID: US20080188511A1
- Status: Published application
- Kind: A1
- Application number: 11/908,250
- Filed: 2006-03-10
- Published: 2008-08-07
- Earliest claimed: 2005-03-11
- Assignees: Biotica Technology Limited
- Inventors: Christoph Hendrik Beckmann; Steven James Moss; Rose Mary Sheridan; Mingqiang Zhang; Barrie Wilkinson
- Web page: https://patentgrep.com/patent/US20080188511A1

## CPC

- C07D 498/18: Bridged systems
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/10: Antimycotics
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim at position 1

1: 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.

### Claim at position 2 (depends on 1)

2: 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.

### Claim at position 3 (depends on 2)

3: A compound according to claim 2 where R6 is selected from the group consisting of —R7, —C(O)R7, and —(CH2)2—O—[CR21R22—O]a—C(O)—R23.

### Claim 4

(canceled)

### Claim 5

(canceled)

### Claim at position 6 (depends on 3)

6: A compound according to claim 3 where R23 R7 or Y—R15.

### Claim 7

(canceled)

### Claim at position 8 (depends on 2)

8: A compound according to claim 2 where R7 satisfies at least one feature selected from the group consisting of:
a) R7 contains 7 or fewer carbon atoms;
b) R7 contains 5 or fewer carbon atoms;
c) R7 contains two groups selected from —PO(OH)2, —CF2PO(OH)2, —OH, —COOH and —NH2; and
d) R7 contains at least one functional group selected from —COOH, OH and NH2.

### Claim at position 9

9-11. (canceled)

### Claim at position 10 (depends on 2)

12: A compound according to claim 2 wherein p, m, or both represents 0 or 1.

### Claim 13

(canceled)

### Claim at position 12 (depends on 2)

14: A compound according to claim 2 wherein q represents 0, 1 or 2.

### Claim at position 13 (depends on 2)

15: A compound according to claim 2 wherein R11, R12, or both represents H.

### Claim 16

(canceled)

### Claim at position 15 (depends on 2)

17: A compound according to claim 2, wherein R13 represents H or OH.

### Claim at position 16 (depends on 2)

18: A compound according to claim 2 where p represents 1, and R10 represents Me, OH or CH2OH; R11 represents Me, H or CH2OH; or both R10 and R11 represent Me, OH or CH2OH.

### Claim 19

(canceled)

### Claim at position 18 (depends on 2)

20: A compound according to claim 2 where m and p both represent 0; R12 and R13 both represent H and R14 represents —(CR8R9)q—OH where q=0 or 1 and R8 and R9 both represent H.

### Claim at position 19 (depends on 2)

21: A compound according to claim 2 where p represents 1 and m represents 0, R10 and R11 both represent H, R12 represents H, R13 represents H, OH or NH2 and R14 represents —(CR8R9)q—OH where q=0 or 1 and R8 and R9 both represent H.

### Claim at position 20 (depends on 2)

22: A compound according to claim 2 wherein R6 represents the residue derived from forming an ester with hydroxyacetic acid, 3-hydroxy-2,2-dimethylpropionic acid, 2,3-dihydroxypropionic acid, 3-hydroxy-2-hydroxymethylpropionic acid or 2,2-bis(hydroxymethyl)propionic acid.

### Claim 23

(canceled)

### Claim at position 22 (depends on 2)

24: A compound according to claim 2 which is selected from the group consisting of 39-desmethoxy-40-O—[2,2-bis(hydroxymethyl)propionyl]rapamycin, 39-desmethoxy-40-O-(2-hydroxy)ethyl rapamycin, 39-desmethoxy-40-O—[2-hydroxyethyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin, 27-O-desmethyl-39-desmethoxy-40-O-[2,2-bis(hydroxymethyl)propionyl]rapamycin, and or a pharmaceutically acceptable salts thereof.

### Claim at position 23

25-27. (canceled)

### Claim at position 24 (depends on 2)

28: A compound according to claim 2 where R6 represents —POR19R20 or —PO(OR19) (OR20).

### Claim 29

(canceled)

### Claim at position 26 (depends on 28)

30: A compound according to claim 28 where R19 and R20 both represent CH3 or both represent CH2CH3.

### Claim at position 27 (depends on 2)

31: A compound according to claim 2 where R6 represents Y—R15.

### Claim 32

(canceled)

### Claim at position 29 (depends on 31)

33: A compound according to claim 31 wherein R15 is a moiety either (i) formed by forming an acetal with glucose, glucosamine, glucuronic acid, fructose or arabinose or (ii) formed by forming an ester with glucuronic acid.

### Claim at position 30

34-46. (canceled)

### Claim at position 31 (depends on 1)

47: A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable diluents or carriers.

### Claim at position 32 (depends on 1)

48: A method for 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 which comprises administering to a patient an effective amount of a compound according to claim 1.

### Claim at position 33 (depends on 1)

49: A method of treatment of cancer or B-cell malignancies which comprises administering to a patient an effective amount of a compound according to claim 1.

### Claim 50

(canceled)

### Claim 51

(canceled)

### Claim at position 36 (depends on 2)

52: A process for preparation of a compound of formula (I) according to claim 2 which comprises:
(a) reacting a compound of formula (II):
where RA represents H or (CH2)2—OH or a protected derivative thereof with a compound of formula (III):
HO—R6 (III)
or an activated derivative thereof wherein the group R6 is as defined above for compounds of formula (I) or a protected derivative thereof; or
(b) converting a compound of formula (I) or a salt thereof to another compound of formula (I) or another pharmaceutically acceptable salt thereof; or
(c) deprotecting a protected compound of formula (I).

### Claim at position 37 (depends on 1)

53: A composition or kit of parts comprising (i) a compound according to claim 1 and (ii) one or more other therapeutically effective agent(s).

### Claim at position 38 (depends on 53)

54: The composition or kit of parts of claim 53 wherein the one or more other therapeutically effective agent(s) are selected from the group of methotrexate, leukovorin, adriamycin, prenisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors, VEGF inhibitors, proteasome inhibitors, hsp90 inhibitors, azathioprine, corticosteroids, cyclophosphamide, cyclosporin A, FK506, Mycophenolate Mofetil, OKT-3, ATG, amphotericin B, flucytosine, echinocandins, griseofulvin, an imidazole and a triazole antifungal agent.