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Motilide compounds

A compound and prodrug technology, applied in the field of prokinetic preparations, can solve problems such as the decline in the efficacy of kinetolactones

Inactive Publication Date: 2005-09-07
菲塞股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This desensitization may herald a decreased response to multiple doses of kinetolide

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] This example describes the manufacture of 15-methyl-6-deoxyerythromycin B (also known as 13-propyl-6-dEB or 15-methyl-6-dEB), which was used to synthesize the Intermediates for specific compounds. (Other erythromycins are similarly named; for example, erythromycin with a methyl group replaced by a fluorine atom at position 15 is called 15-fluoro-6-dEB).

[0093] 15-Methyl-6-deoxyerythromycin B

[0094] Thaw the CH999 / pJRJ2 (Streptomyces coelicolor, which contains PKS in which the ketone synthase domain of module 1 is inactivated by mutation) working cell bank (working cell bank) in the 1 ml vial, and the contents of the vial Add to 50 mL of Medium 1 in a 250 mL stoppered flask.

[0095] Medium 1 contains 45 g / L cornstarch, 10 g / L corn steep liquor, 10 g / L dry, inactivated S. cerevisiae, and 1 g / L CaCO 3 . The solution was sterilized in an autoclave at 121°C for 90 minutes. After sterilization, add 1 mL / L sterile-filtered 50 mg / mL thiostrepton in 100% DMSO and 1 m...

Embodiment 2

[0103] This example describes the conversion of 15-methyl-6-deoxyerythromycin B into 15-methylerythromycin A (formula II, R 1 =-CH 2 CH 2 CH 3 ; 3 =R 4 =OH). Transformation techniques are also found in Carreras et al., J. Biotechnology, 92, pp. 217-228 (2002), the entire contents of which are hereby incorporated by reference.

[0104] Thaw working cell bank K39-14V (an eryA mutant of S. rubrum that cannot produce 6-dEB) in a 1 ml vial and add the contents of the vial to 50 ml of a 250 ml stoppered flask Medium 2.

[0105] Medium 2 consisted of 16 g / L cornstarch, 10 g / L corn dextrin, 15 g / L soy meal, 4 g / L CaCO 3 , 5 g / L corn steep liquor, 6 g / L soybean oil, 2.5 g / L NaCl, and 1 g / L (NH 4 ) 2 SO 4 . The solution was autoclaved at 121°C for 60 minutes, and 1 ml / L of autoclaved 100% Foam B Silicone Emulsion was added just before use.

[0106]Place the flask containing thawed cells and Medium 2 in an incubator / mixer at 34±1°C and 175±25 RPM for 48±10 hours. Then, 50 ml...

Embodiment 3

[0115] This example describes a conventional method for preparing (9S)-9-dihydroerythromycin (Formula II), see Scheme 1 for details.

[0116] A solution of erythromycin (0.36 mmol) in 1:3 ethanol / ether (20 mL) was cooled to -15°C and treated with sodium borohydride (0.9 mmol). The reaction was allowed to warm slowly to ambient temperature over 4 hours. Excess borohydride was removed by adding pH 6 phosphate buffer, and 10 mL of triethanolamine was added. After 1 h, the mixture was extracted with ethyl acetate and washed with MgSO 4 Dry, filter, and concentrate to dryness under reduced pressure. The product was purified by silica gel chromatography using 1:1 acetone-hexane and 1% triethylamine. The following compounds were prepared using this procedure:

[0117] (9S)-9-dihydroerythromycin A;

[0118] (9S)-9-dihydro-15-methylerythromycin A; and

[0119] (9S)-9-dihydro-15-fluoroerythromycin A.

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PUM

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Abstract

Motilide compounds having the formula (I), wherein R1, R2, R3, and R4 are as defined herein, and methods for their preparation and use in the treatment of diseases or conditions characterized by impaired gastric motility.

Description

technical field [0001] The present invention provides prokinetic agents having supra-pharmacological and pharmacogenetic properties, which can be used to treat gastrointestinal motility disorders. The present invention relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology and pharmacology. Background technique [0002] Gastrointestinal ("GI") motility regulates the orderly movement of digested material through the intestinal tract to ensure adequate absorption of nutrients, electrolytes, and fluids. Proper transit through the esophagus, stomach, small intestine, and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement of GI contents and prevent reflux. Normal GI movement patterns can be compromised by many environmental factors, including disease and surgery. [0003] Gastrointestinal motility disorders include, for example, gastroparesis and gastroesophageal ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/35A61K31/7048A61P1/00C07D313/00C07H17/08C12N1/21C12N15/52C12P19/62
CPCC07H17/08C12P19/62C12N15/52A61P1/00A61P1/04A61P1/06A61P1/08A61P1/14A61P1/16C07D407/14
Inventor D·圣B·梅特卡夫C·卡雷拉斯Y·刘R·麦克丹尼尔斯E·J·罗德里格斯
Owner 菲塞股份有限公司
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