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36 -des (3 -methoxy-4 -hydroxycyclohexyl) 36 - (3 -hydroxycycloheptyl) derivatives of rapamycin for the treatment of cancer and other disorders

A hydroxycyclohexyl, hydroxycycloheptyl technology, applied in the field of novel 36-de-36-rapamycin derivatives, can solve the problems of immunosuppression loss and the like

Inactive Publication Date: 2009-05-27
DEBIOTECH SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hydrogenation of targeted trienes at C17, C19, and / or C21 results in retention of antifungal activity but relative loss of immunosuppression (eg, US Patent No. 5,391,730; US Patent No. 5,023,262)

Method used

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  • 36 -des (3 -methoxy-4 -hydroxycyclohexyl) 36 - (3 -hydroxycycloheptyl) derivatives of rapamycin for the treatment of cancer and other disorders
  • 36 -des (3 -methoxy-4 -hydroxycyclohexyl) 36 - (3 -hydroxycycloheptyl) derivatives of rapamycin for the treatment of cancer and other disorders
  • 36 -des (3 -methoxy-4 -hydroxycyclohexyl) 36 - (3 -hydroxycycloheptyl) derivatives of rapamycin for the treatment of cancer and other disorders

Examples

Experimental program
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example

[0183] General Methods and Materials

[0184] Material

[0185] All reagents were obtained from commercial sources and used without further purification unless otherwise stated.

[0186] to cultivate

[0187] S. hygroscopicus MG2-10 [JMNOQLhis] was maintained on Medium 1 agar plates (see below) at 28°C. Spore stocks were prepared after growth on Medium 1, kept in 20% w / v glycerol:10% w / v lactose in distilled water and stored at −80 °C. Vegetative cultures were prepared by inoculating 0.1 mL of frozen stock into 50 mL of Medium 2 (see below) in 250 mL flasks. The cultures were grown at 28°C for 36 to 48 hours at 300 rpm.

[0188] Preparation:

[0189] Vegetative cultures were inoculated into Medium 3 at 2.5-5% v / v. The culture was carried out at 26°C and 300 rpm for 6-7 days.

[0190] Feeding program:

[0191] Feeds / additions of selected carboxylic acids were performed 24-48 hours after inoculation and were fed at 1-2 mM unless otherwise stated.

[0192] Medium 1:

[...

example 1

[0245] Example 1: Fermentation and isolation of 36-des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin

[0246] 36-Des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin was prepared according to the method described in WO 04 / 007709. Briefly, cultures of S. hygroscopicus MG2-10 were transformed with appropriate expression vectors carrying the rapamycin genes rapJ, rapM, rapN, rapO, rapQ, and rapL to generate strain S. hygroscopicus MG2-10[rapJMNOQLhis]. Cultures of S. hygroscopicus MG2-10 [rapJMNOQLhis] were grown and fed cycloheptanecarboxylic acid using the method described in WO 04 / 007709. LCMS and LCMS of culture extracts n Analysis revealed that the m / z ratio of the as-prepared rapamycin analog was 16 atomic mass units less than that of rapamycin and was substituted with the 3-hydroxycycloheptyl moiety at C-36. The methoxy-4-hydroxycyclohexyl moiety is consistent.

example 2

[0247] Example 2: Synthesis of 36-des(3-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin by lipase-catalyzed esterification Methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycyclohexyl)-40-O-[2,2-bis(hydroxymethyl)propionyl]rapamycin

[0248] Under argon atmosphere, 36-des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin (10 mg, 0.011 mmol), 2,2,5- Trimethyl[1.3-dioxane]-5-vinylcarboxylate (100mg, 0.5mmol), lipase PS-C "Amano" II (100mg) and 0.5nm molecular sieves (50mg) in anhydrous tert-butyl methyl The mixture in ether (2 mL) was heated to 43°C. After 72h, LC / MS monitoring showed complete conversion of starting material. THF (10 mL) was added and the mixture was filtered through a pad of celite. The enzyme was washed with THF (2 x 10 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was dissolved in THF (7.5 mL), and H was added 2 SO 4 (2.5 mL, 0.5N). The solution was allowed to stand at room temperature for 5 h...

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Abstract

The present invention relates to novel 36-des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin derivatives, methods for their production, and uses thereof. In a further aspect the present invention provides for the use of these 36-des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin 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.

Description

technical field [0001] The present invention relates to novel 36-des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl)rapamycin derivatives, their preparation methods and their uses. In another aspect, the present invention provides that the 36-des(3-methoxy-4-hydroxycyclohexyl)-36-(3-hydroxycycloheptyl) rapamycin derivatives are effective in treating cancer and / or B cell Use in malignancy, inducing or maintaining immunosuppression, in the treatment of transplant rejection, graft-versus-host disease, autoimmune disorders, inflammatory diseases, vascular and fibrotic diseases, in stimulating neuronal regeneration or in the treatment of fungal infections. Background technique [0002] Rapamycin (sirolimus) ( figure 1 ) is produced by Streptomyceshygroscopicus NRRL 5491 (Sehgal et al., 1975; Vézina et al., 1975; U.S. Patent No. 3,929,992; U.S. Patent No. 3,993,749) with the Lipophilic macrolides with pipecolide linked 1,2,3-tricarbonyl moieties (Paiva et al., 1991). F...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/18A61K31/496A61P35/00
CPCC07D493/18A61P9/00A61P29/00A61P35/00A61P35/02A61P37/06
Inventor 巴里·威尔金森明强·张罗丝·玛丽·谢里登克里斯托夫·贝克曼
Owner DEBIOTECH SA
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