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Organic amine salt of aminobenzoic acid derivative, and method for producing same

A technology of organic amine salt and manufacturing method, applied in the directions of organic chemistry, organic active ingredients, medical preparations of non-active ingredients, etc., can solve the problems such as no examples, and achieve the effect of excellent stability

Inactive Publication Date: 2013-06-12
NISSAN CHEM IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, regarding the salt of Compound A, although there are examples of alkali metal salts and the like as pharmaceutically acceptable salts, there are no examples of specific salts.

Method used

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  • Organic amine salt of aminobenzoic acid derivative, and method for producing same
  • Organic amine salt of aminobenzoic acid derivative, and method for producing same
  • Organic amine salt of aminobenzoic acid derivative, and method for producing same

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Experimental program
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Effect test

Embodiment

[0102] Hereinafter, the present invention will be described in more detail by showing synthesis examples, test examples, and formulation examples, but the present invention is not limited to these examples.

[0103] In addition, in the embodiments, LC means liquid chromatography, HPLC means high performance liquid chromatography, MS means mass spectrometry, LC / MS means liquid chromatography-mass spectrometry, LC / MS / MS means liquid chromatography-tandem mass spectrometry, TG means thermogravimetric analysis, Cmax means the maximum concentration in plasma, Tmax means the time to reach the maximum concentration in plasma, and AUC means the area under the concentration-time curve in plasma.

[0104] In addition, machine analysis was performed using the following device conditions, respectively.

[0105] 1 H-NMR was measured at 300 MHz.

[0106] TG was measured with TG8120 (manufactured by Rigaku Corporation).

[0107] Reference Synthesis Example 1

[0108] 3-{[((2E)-2-{1-[5-(4-t...

Synthetic example 1

[0114] 3-{[((2E)-2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-3-thienyl]ethylene}hydrazino)thiocarbonyl]amino} Ethanolamine Benzoate.

[0115] In 3-{[((2E)-2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)thiocarbonyl]amino A methanol solution (24.0 mL) of ethanolamine (1.47 g, 24.07 mmol) was added to an acetonitrile suspension (218 mL) of benzoic acid (10.25 g, 21.92 mmol), and stirred at room temperature for 2 hours and 50 minutes. The generated precipitate was collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain 10.88 g of the target product (94% yield).

[0116] Appearance: light yellow solid

[0117] 1 H-NMR (300MHz, DMSO-d 6 ):δ1.30(9H,s),2.39(3H,s),2.84(2H,t,J=5.0Hz),3.56(2H,t,J=5.0Hz),7.27(1H,dd,J= 8.0&7.5Hz),7.40(2H,d,J=8.5Hz),7.46(1H,d,J=7.5Hz),7.62(1H,s),7.73(2H,d,J=8.5Hz),7.91 (1H,d,J=8.0Hz),8.50(1H,s)

Synthetic example 2

[0119] 3-{[((2E)-2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-3-thienyl]ethylene}hydrazino)thiocarbonyl]amino} Benzoic acid tromethamine salt

[0120] In 3-{[((2E)-2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)thiocarbonyl]amino } To a tetrahydrofuran solution (100 mL) of benzoic acid (9.4 g, 20.1 mmol) was added tromethamine (2.7 g, 22.3 mmol) aqueous solution (20 mL), followed by acetonitrile (400 mL), and stirred at room temperature for 1 day. The generated precipitate was collected by filtration and dried under reduced pressure to obtain 11.3 g of the target product (95% yield).

[0121] Appearance: white to light yellow-green solid

[0122] 1 H-NMR (300MHz, DMSO-d 6 ):δ1.30(9H,s),2.38(3H,s),3.45(6H,s),7.29(1H,dd,J=8.0&7.5Hz),7.40(2H,d,J=8.5Hz) ,7.47(1H,d,J=7.5Hz),7.64(1H,s),7.72(2H,d,J=8.5Hz),7.89(1H,d,J=8.0Hz),8.51(1H,s)

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Abstract

The purpose of the invention is to provide a novel organic amine salt or quaternary ammonium salt of the 3-[[((2E)-2-[1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]ethylidene]hydrazino)carbonothioyl]amino] benzoic acid represented by the formula shown below. The organic amine salt or quaternary ammonium salt has excellent pharmacokinetic characteristics and stability, and possessed properties useful for a drug.

Description

technical field [0001] The present invention relates to novel thrombopoietin receptor activator 3-{[((2E)-2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-3-thienyl]ethylene The organic amine salt of base} hydrazino) thiocarbonyl] amino} benzoic acid. The compound of the present invention is particularly useful as a therapeutic agent or a thrombocytopenia agent for diseases accompanied by an abnormal platelet count. Background technique [0002] 3-{[((2E)-2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-3-thienyl]ethylene}hydrazino)thiocarbonyl]amino} Benzoic acid (hereinafter referred to as compound A) is useful as a thrombopoietin receptor activator. International Publication No. 04 / 108683 (Patent Document 1) and Japanese Patent Application Laid-Open No. 2006-527187 (Patent Document 2) disclose compound A and the tautomer of compound A in the form contained in the general formula , a prodrug or a pharmaceutically acceptable salt thereof, or a solvate thereof. In addition, Compound A is di...

Claims

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Application Information

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IPC IPC(8): C07D333/32A61K31/381A61P7/04A61P43/00
CPCA61K9/0019A61K47/14A61K9/1623A61K9/1652A61K9/2018A61K9/2059A61K9/4866C07D333/32A61P43/00A61P7/02A61P7/04A61K31/381
Inventor 岩本俊介中野智奈须麻莉子山本正雄竹内和也
Owner NISSAN CHEM IND LTD
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