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Improved crystalline form of compound A-348441

A technology of composition and crystalline material, applied in the direction of steroids, organic chemistry, drug combination, etc., can solve problems such as difficulty in synthesizing compound I

Inactive Publication Date: 2008-07-09
KARO BIO AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Unfortunately, the synthesis of compound I is rather difficult

Method used

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  • Improved crystalline form of compound A-348441
  • Improved crystalline form of compound A-348441
  • Improved crystalline form of compound A-348441

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 (comparison): preparation of crystal form 2 and amorphous compound I

[0031] A. Form 2

[0032] A.1 Method 1

[0033]

[0034] Compound 10

[0035] Compound 10 as shown above, the methyl ester of compound I prepared as described in WO 2004 / 000869 (17.28 g, 20.0 mmol, 91% chemical potency, therefore 15.72 g, 18.2 mmol), was added to to equipped with overhead mechanical stirrer, thermocouple and N 2 500 mL three-neck round bottom flask with static bubbler. use N 2 The reaction vessel was vacuum purged slowly 3 times. The penultimate material was then dissolved by adding EtOH (173 mL). use N 2 The solution was vacuum purged 3 times and kept under static N throughout the reaction. 2 Bubbler down. The resulting solution was cooled to +5°C and treated with 3N KOH (33.3 mL) at a rate to maintain the internal temperature at <7°C. The reaction was stirred at +5 °C until the residue of the sum of compound 10 and its ethyl ester analog was <0.6% as judged b...

Embodiment 2

[0042] Example 2: Preparation of Form 1

[0043] 100 mg of amorphous Compound I was placed in a 4 mL vial and 1.0 mL of nitromethane was added. The vial was heated briefly to 60°C and cooled to room temperature over about 5 minutes. The solid was filtered off and washed 4 times with 1 mL of nitromethane. The filtrate was allowed to stand and evaporated slowly at ambient temperature for 7 days (loss of about 2.5 mL (approximately 2-fold concentration)). Fine needles were observed on the sides of the flask. Some needles were scraped off and characterized as Form 1 by XRD and DSC.

Embodiment 3

[0044] Example 3: Preparation of Form 1 by seeding

[0045] Form 2 crystalline material (1.14 kg), prepared as in Example 1A above, was added to ethanol (5.7 L) denatured with isopropanol. The suspension was stirred at 20°C and a small amount of Form 1 (1 g) as prepared in Example 2 above was added. The suspension was stirred for 1 h, demineralized water was added over 1 h and the suspension was stirred for 2 h. The yellow suspension turned into a cream colored suspension. The product was filtered and washed with a mixture of demineralized water (1.0 L) and ethanol denatured with isopropanol (1.5 L). at T 夹套 =Dry the wet filter cake at 50°C for 63h. The yield was about 92.1% (1.05 kg). Form 1 was obtained as the hemihydrate with a purity of 98.1% as measured by HPLC.

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PUM

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Abstract

There is provided a hemihydrate of (3&bgr;,5&bgr;,7α,12α)-7,12-dihydroxy-3-{2-[{4-[17&bgr;-hydroxy-3-oxo-17α-prop-1-ynylestra-4,9-dien-11&bgr;-yl]phenyl}(methyl)amino]ethoxy}cholan-24-oic acid in a crystalline form which is characterised by an X-ray diffraction pattern having major peaks at 2&thetas;=6.58±0.2, 8.54+0.2, 12.28±0.2, and 19.68±0.2. This crystalline material is useful in the treatment of conditions associated with an excess of hepatic glucocorticoid response.

Description

technical field [0001] The present invention relates to an improved crystalline material and its use in the treatment of conditions associated with excessive hepatic glucocorticoid response. Background technique [0002] WO 2004 / 000869 relates to novel compounds which are liver selective glucocorticoid receptor antagonists. Example 1 describes (3β, 5β, 7α, 12α)-7,12-dihydroxy-3-{2-[{4-[17β-hydroxy-3-oxo-17α-prop-1-ynylestradiol- 4,9-dien-11β-yl]phenyl}(methyl)amino]ethoxy}cholan-24-oic acid (referred to in this example as (3β,5β,7α,12α)-7, 12-dihydroxy-3-{2-[{4-[11β, 17α,)-17-hydroxy-3-oxo-17-prop-1-ynylestradiol-4,9-dien-11-yl] Synthesis of phenyl}(methyl)amino]ethoxy}cholan-24-oic acid). This compound is hereinafter referred to as compound I and has the following formula: [0003] [0004] Unfortunately, the synthesis of compound I is rather difficult. The method of Example 1J of WO 2004 / 000869 leads to an amorphous material, whereas the method of Example 1S leads ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00A61P3/10A61K31/575
CPCC07J41/0083A61P3/10A61P3/04A61P3/06A61P5/46A61P5/48A61P9/12
Inventor 拉塞尔·德鲁·钦克邹道忠马文·罗伯特·莱亚纳帕斯卡尔·H·托玛米歇尔·安德烈·朗格
Owner KARO BIO AB
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