Enzymatic transamination of cyclopamine analogs

A cycloalkyl and aminoase technology, applied in organic chemistry, fermentation, etc., can solve the problems of low solubility and weak acid sensitivity

Inactive Publication Date: 2012-07-11
INFINITY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical development of cyclopamine as a cancer therapeutic is hampered by its low solubility, acid sensitivity, and weak potency relative to other reported small molecule Hh antagonists

Method used

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  • Enzymatic transamination of cyclopamine analogs
  • Enzymatic transamination of cyclopamine analogs
  • Enzymatic transamination of cyclopamine analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0304] In some embodiments, a method for preparing a compound of formula (R)-(II-a) or a salt thereof from a compound of formula (I-a) or a salt thereof is provided:

[0305]

[0306] in:

[0307] R 1 is H, aralkyl or -CO 2 R 16 ;

[0308] R 16 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R 20 ) 2 ] p -R 21 , where p is 0-6;

[0309] R 20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two R's present on the same substituent 20 together form an optionally substituted 4-8 membered ring;

[0310] R 21 for-OR 22 , -N(R 22 )C(=O)R 22 , -N(R 22 )C(=O)OR 22 , -N(R 22 ) SO 2 (R 22 ), -C(=O)R 22 N(R 22 ) 2 , -OC(=O)R 22 N(R 22 )(R 22 ), -SO 2 N(R 22 )(R 22 ), -N(R 22 )(R 22 ), -C(=O)OR 22 , -C(=O)N(OH)(R 22 ), -OS(O) 2 OR 22 ,-S(O) 2 OR 22 ,-OP(=O)(OR 22 )(OR 22 ), -N(R 22 )P(O)(OR 22 )(OR 22 ) or -P(=O)(OR 22 )(...

Embodiment

[0355] Having generally described the present invention, it will be more readily understood by reference to the following examples, which are given by way of illustration only and are not intended to limit the invention.

[0356] Enzymatic transamination reaction of compound of formula (I-a)

[0357]

[0358] Materials and methods

[0359] Enzymes. Amine transaminases were purchased from commercial sources, stored at -20°C, and used as received: ATA-113 (Caudex, Redwood City, Canada; Lot No. 104020902); ATA-117 (Caudex, Inc., Redwood City, Canada; Lot No. 104020902); Omega-transaminase from Vibrio riverina (Fluka; Cat. No. 08374); Glutamate-pyruvate transaminase (Fluka); Spectrum transaminase (Phloka).

[0360] Coenzymes. Coenzymes used during the study included: L-alanine dehydrogenase (LADH, Sigma, no. A7653-100U), formate dehydrogenase (FDH, Caudix, FDH -101) and pyruvate reductase mixture (PRM-102, Caudix), which is lactate dehydrogenase (LDH), glucose dehydrogenas...

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Abstract

Provided are processes for the synthesis of amino analogues from ketone starting materials.

Description

[0001] This application claims the benefit of US Provisional Patent Application 61 / 231,439, filed August 5, 2009, which is hereby incorporated by reference in its entirety. technical background [0002] Cyclopamine, a natural product isolated from Veratrum californicum, has gradually proven to be an effective pharmacological tool to validate the Hedgehog (Hh) pathway in cancer. Cyclopamine acts directly on SMO to inhibit tumor growth in several murine models of pancreatic, medulloblastoma, prostate, small cell lung and gastrointestinal cancers. However, the clinical development of cyclopamine as a cancer therapeutic has been hampered by its low solubility, acid sensitivity, and weak potency relative to other reported small molecule Hh antagonists. [0003] Considerable attention has been paid to developing new cyclopamine analogs with improved potency and improved pharmacokinetic and pharmaceutical properties relative to cyclopamine (see, e.g., U.S. Patents 7,230,004 and 7,407...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/00
CPCC07D491/10C07D491/107C12P17/18
Inventor B·奥斯塔德A·巴哈道尔J·D·贝拉尼S·加纳达南奈尔C·W·约翰内斯G·F·基尼P·L·怀特S·L·沃勒斯坦
Owner INFINITY PHARMA
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