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2-aminothiazole derivatives or salts thereof

A technology of amino and thiazole, applied in the field of active ingredients of therapeutic pharmaceutical compositions, can solve problems such as unclear effectiveness of urination disorder and the like

Active Publication Date: 2020-04-14
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, adrenaline alpha 1 The effectiveness of receptor antagonists against voiding disorders not caused by benign prostatic hyperplasia is unclear (Journal of Pharmacological Sciences, 112:pp.121-127(2010))

Method used

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  • 2-aminothiazole derivatives or salts thereof
  • 2-aminothiazole derivatives or salts thereof
  • 2-aminothiazole derivatives or salts thereof

Examples

Experimental program
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Effect test

Embodiment

[0382] Hereinafter, the production method of the compound of formula (I) is demonstrated in more detail based on an Example. It should be noted that the present invention is not limited to the compounds described in the following examples. In addition, the production method of the raw material compound is shown in the production example. In addition, the production method of the compound of formula (I) is not limited to the production method of the specific examples shown below, and the compound of formula (I) can also be obtained by a combination of these production methods, or those skilled in the art method manufacturing.

[0383] In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used for naming compounds.

[0384] In addition, the following abbreviations may be used in Examples, Production Examples, and Tables described later.

[0385]PEx: Production example number, Ex: Example number, PSyn: Produ...

manufacture example 1

[0388] Sodium hydride (90 mg, 60% oil dispersion) was added to 5-{[(2R,5R)-2,5-dimethylpyrrolidin-1-yl under argon atmosphere with ice-methanol bath cooling ]methyl}-4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (300mg), 4,6-dichloro-5-fluoro-2- A mixture of methylpyrimidine (175 mg) and dehydrated tetrahydrofuran (6.0 mL) was stirred at 0°C for 30 minutes. Ice water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6-chloro-N-(5-{[(2R,5R)-2,5-dimethylpyrrolidine-1 -yl]methyl}-4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl)-5-fluoro-2-methylpyrimidin-4-amine (407 mg).

manufacture example 2

[0390] At room temperature, N,N-diisopropylethylamine (1.2 mL) was added to N 2 -(6-Chloro-2-methylpyrimidin-4-yl)-4-[3-fluoro-5-(trifluoromethyl)phenyl]-N 5 -Isopropyl-N 5 -(2-methoxyethyl)-1,3-thiazole-2,5-diamine (279mg), 3-(piperazin-1-yl) ethyl propionate dihydrochloride (440mg) and 1 - in a mixture of methylpyrrolidin-2-one (NMP) (6.0 mL). The reaction mixture was stirred at 80°C for 12 hours. Ethyl acetate and water were added to the reaction mixture, whereby the organic layer was separated. After drying the organic layer over anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-{4-[6-({4-[3-fluoro-5-(trifluoromethyl)phenyl]] as a solid -5-[isopropyl(2-methoxyethyl)amino]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]piperazin-1-yl}propyl ethyl acetate (303mg).

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Abstract

[Problem] To provide a compound that can be used as an active ingredient of a pharmaceutical composition for treating urinary storage disorders, voiding disorders, and lower urinary tract diseases. [Solution] The inventors have found that 2-aminothiazole derivatives have excellent muscarinic M 3 receptor positive allosteric modulator activity, and is expected to act as a 3 A prophylactic or therapeutic agent for bladder / urological diseases related to receptor-mediated bladder contraction, thereby completing the present invention. The 2-aminothiazole derivatives or salts thereof of the present invention are expected to act as 3 A prophylactic or therapeutic agent for bladder / urological diseases related to receptor-mediated bladder contraction (such as voiding disorders such as hypoactive bladder).

Description

technical field [0001] The present invention relates to a 2-aminothiazole derivative or a salt thereof expected as a pharmaceutical composition, particularly a pharmaceutical composition for the treatment of bladder / urological diseases associated with muscarinic M3 receptor-mediated bladder contraction active ingredients. Background technique [0002] The important functions of the lower urinary tract are urine storage and voiding, which are regulated by the synergistic action of the bladder and urethra. In other words, bladder smooth muscle relaxes during urine storage, and urethral sphincter contracts, thereby maintaining a high state of urethral resistance, thereby maintaining urinary continence. On the other hand, the bladder smooth muscle contracts during urination, and at the same time the urethral smooth muscle relaxes, and the contraction of the external urethral sphincter is also inhibited. Disorders of the lower urinary tract include urinary storage disorders suc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14A61K31/4439A61K31/496A61K31/506A61P13/02A61P13/10A61P43/00C07D417/12
CPCA61K31/496A61K31/4439A61K31/506A61P13/02A61P13/10A61P43/00C07D417/12C07D417/14
Inventor 高桥泰辅田中宏明赤岩路则根来贤二三原久史藤秀义高松肇
Owner ASTELLAS PHARMA INC
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