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Metabolites of cyclosporin analogs

A metabolite, representative technology for the manufacture and analysis of isolated ISA247 metabolites to address issues such as reducing toxic side effects

Inactive Publication Date: 2008-02-06
伊素制药公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0027] Therefore, there is a need for an immunosuppressant with pharmacological potency comparable to the naturally occurring cyclosporin A compound, but with reduced toxic side effects

Method used

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  • Metabolites of cyclosporin analogs
  • Metabolites of cyclosporin analogs
  • Metabolites of cyclosporin analogs

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0335] Metabolites of ISA247 can be produced using chemical synthesis methods. The chemical synthesis of these metabolites generally follows the following steps: 1) protection of the β-OH of the 1 amino acid side chain of cyclosporin A or ISA247; 2) epoxidation; 3) diol formation and 4) deprotection. Although the protection of β-OH is favorable for the formation of epoxide and diol metabolites, it is not suitable for the formation of cyclic metabolites. Possible protecting groups at the β-OH include acetyl, trimethylsilyl, benzoate, substituted benzoate, ether and methylsilyl ether. Under certain reaction conditions, the acetate protecting group is prone to cause undesired side reactions such as elimination and hydrolysis. Since benzoates, ethers and silyl ethers are generally more resistant to such side reactions under the same reaction conditions, it is often advantageous to use these protecting groups instead of acetates.

[0336]Under basic conditions, protected CsA or I...

Embodiment 1

[0343] Example 1. Preparation of ISA247 metabolites from whole blood

[0344] Whole blood was drawn from humans after ISA247 administration. ISA247 and its metabolites were extracted from whole blood using tert-butyl-methyl-ether (or methyl tert-butyl ether, MTBE), dried and redissolved in methanol. 2 mL of MTBE (cat. No. 7001-2; Caledon) was added to 200 uL of blood, shaken for 10 minutes, and centrifuged for 2 minutes in a desktop centrifuge. The upper MTBE layer was removed and concentrated in vacuo. The residue was redissolved in 200uL methanol. Bile and urine extractions were performed similarly.

Embodiment 2

[0345] Example 2: Chemical Synthesis of ISA247 Metabolites

[0346] Preparation of monoepoxides of OAc-E-ISA247

[0347] To prepare the diol metabolites of E-ISA247, epoxides were formed as shown in FIG. 42 . Follow the steps below. To CHCI of OAc-E-ISA247 (125 mg, 0.1 mmol) which was homogenized and cooled (0 °C) 3 (3 mL) was added potassium bicarbonate (10 mg) to the solution. Then m-chloroperbenzoic acid (23 mg, 0.1 mmol, 77%) in CHCI was added 3 (2 mL) solution. The reaction mixture was warmed to room temperature and stirring was continued for 18 hours. The reaction product was extracted with dichloroethane (25 mL). with saturated NaHCO 3 solution and brine to wash the organic layer. dry (Na 2 SO 4 ) and solvent removal gave a white solid (110 mg). MS (m / z): 1295 (M+Na+). The product is a mixture of epoxides. The same method can be used with OAc-Z-ISA247 or a mixture of ISA247 isomers, but the stereochemistry of the products will be different, as shown in Fi...

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Abstract

Isolated metabolites of the cyclosporine analog ISA247 are disclosed, including in vitro methods for their preparation. The metabolites comprise a chemical modification of ISA247, wherein the modification is at least one reaction selected from the group consisting of hydroxylation, N-demethylation, diol formation, epoxide formation, and intramolecular cyclization phosphorylation, sulfation, glucuronide formation and glycosylation. Methods of preparation include semi-synthetic methods, wherein metabolites of ISA247 are produced from the microsomal extracts of animal liver cells, or from cultures using microorganisms, and completely synthetic methods, such as chemically modifying the parent compound or isolated metabolites using organic synthetic methods.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 637,392, filed December 17, 2004, the entire teachings of which are incorporated herein by reference. technical field [0003] The present invention relates to ISA247 or ISA TX 247 (derivative of cyclosporin A) isolated metabolite. The invention also relates to methods of making and analyzing isolated ISA247 metabolites. [0004] references [0005] U.S. Patent No. 6,605,593 [0006] U.S. Patent No. 6,613,739 [0007] USA 2003 / 0212249. [0008] International Publication No. WO 99 / 18120 [0009] International Publication No. WO 03 / 033527 [0010] International Publication No. WO 2003 / 033526 [0011] International Publication No. WO 2003 / 033527 [0012] Brown, H.C. et al., J. Am. Chem. Soc. vol 110, p 1535 (1988). [0013] Christians, et al. "Cyclosporine Metabolism in Transplant Patients;" Pharmac. Ther. vol 57, pp 291-345 (19...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C12P21/04A61K38/13
CPCC07K7/645A61K38/13C07K7/64A61P37/06C12P21/02
Inventor 马克·D·亚伯罗伯特·T·福斯特迪瑞克·G·弗瑞塔格丹尼尔·J·特拉帕尼尔信·苏基亚玛斯塔尔曼·加亚拉曼兰德尔·W·亚特斯科夫
Owner 伊素制药公司
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