Tetrahydropyridopyrimidinedione derivative, preparation method thereof and application of tetrahydropyridopyrimidinedione derivative in medicine

A compound and mixture technology, applied in the field of medicine, can solve problems such as treating the symptoms but not the root cause

Pending Publication Date: 2022-03-08
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But these treatments are palliative, not permanent

Method used

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  • Tetrahydropyridopyrimidinedione derivative, preparation method thereof and application of tetrahydropyridopyrimidinedione derivative in medicine
  • Tetrahydropyridopyrimidinedione derivative, preparation method thereof and application of tetrahydropyridopyrimidinedione derivative in medicine
  • Tetrahydropyridopyrimidinedione derivative, preparation method thereof and application of tetrahydropyridopyrimidinedione derivative in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0514] (6S,7S)-7-(5-cyclopropyl-2-fluorophenyl)-6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8- Tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 1

[0515]

[0516] first step

[0517] (2R,3S)-3-(5-Bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-2-fluoropropionic acid ethyl ester 1c

[0518] (R,E)-N-(5-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide 1a (8.6g, 28.2mmol, using the literature "J.Med.Chem , 2019,62,9618-9641" prepared by known method), ethyl 2-fluoroacetate 1b (4.5g, 42.3mmol, Shanghai Titan Technology Co., Ltd.) and N,N,N',N'-tetramethyl Ethylenediamine (6.6 g, 56.4 mmol, Shanghai Aladdin Biochemical Technology Co., Ltd.) was dissolved in anhydrous THF (90 mL). After cooling to -70°C, a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (42.3 mL, 42.3 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. Under nitrogen protection, the reaction was stirred at -70°C for 3 hours. The reaction was quenched by addi...

Embodiment 2

[0546] (6S,7S)-6-fluoro-7-(2-fluoro-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)-3-(tetrahydro-2H- Pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 2

[0547]

[0548] first step

[0549] 2-Fluoro-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde 2c

[0550] 2-Fluoro-5-hydroxybenzaldehyde 2a (500 mg, 3.57 mmol, adamas) and 5-fluoro-2-(trifluoromethyl)pyridine 2b (1.2 g, 7.27 mmol, adamas) were dissolved in N,N-di Add methylformamide (10 mL), potassium carbonate (1.0 g, 7.25 mmol), and react at 110°C for 0.5 hours. Add water (50 mL), extract with ethyl acetate (20 mL×2), combine the organic phases, concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system A to obtain the title product 2c (300 mg, yield : 29.5%).

[0551] MS m / z (ESI): 285.8 [M+1].

[0552] second step

[0553] (R)-N-(2-fluoro-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzylidene)-2-methylpropane-2-sulfinamide 2e...

Embodiment 3

[0581] (6S,7S)-6-fluoro-7-(2-fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)-3-(tetrahydro-2H-pyran-4 -yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 3

[0582]

[0583]

[0584] first step

[0585] 2-Fluoro-5-((6-methylpyridin-3-yl)oxy)benzaldehyde 3c

[0586] 6-Methylpyridin-3-ol 3a (1.0g, 9.16mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) and (4-fluoro-3-formylphenyl) boronic acid 3b (2.0g, 11.9mmol, Shanghai Han Hong Chemical Technology Co., Ltd.) was dissolved in dichloromethane (10mL), added pyridine (1.5g, 18.8mmol, adamas), triethylamine (1.9g, 18.8mmol, adamas), anhydrous copper acetate (3.4g, 18.8 mmol, Shanghai Bi De Pharmaceutical Technology Co., Ltd.), reacted at room temperature for 24 hours. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3c (650 mg, yield: 30.7%).

[0587] MS m / z (ESI): 231.9 [M+1]. ...

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Abstract

The invention relates to a tetrahydropyridopyrimidinedione derivative, a preparation method thereof and application of the tetrahydropyridopyrimidinedione derivative in medicine. Specifically, the invention relates to a tetrahydropyridopyrimidinedione derivative as shown in a general formula (IM), a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent. The present invention relates to the use thereof, in particular as a myosin inhibitor and in drugs for the treatment of hypertrophic cardiomyopathy (HCM) or heart diseases having pathophysiologic characteristics associated with HCM.

Description

technical field [0001] The disclosure belongs to the field of medicine, and relates to a tetrahydropyridopyrimidinedione derivative, its preparation method and its application in medicine. In particular, the disclosure relates to tetrahydropyridopyrimidinedione derivatives represented by the general formula (IM), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as myosin (Myosin) inhibitors Use and use in a medicament for the treatment of hypertrophic cardiomyopathy (HCM) or heart disease with pathophysiological features associated with HCM. Background technique [0002] Hypertrophic cardiomyopathy (HCM) is a dominantly inherited cardiomyopathy associated with genetic mutations. With a global incidence of approximately 0.2%, it is the most important cause of sudden death in young people under the age of 35 (Tuohy, CV. et al., Eur J HeartFail, 22, 2020, 228-240). Clinically, it is characterized by asymmetrical hypertrophy o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P9/10A61P9/04A61P9/00A61P3/00C07D405/14C07D239/60
CPCC07D471/04A61P9/10A61P9/04A61P9/00A61P3/00C07D405/14C07D239/60
Inventor 张晓敏胡伟民马殿强张婷贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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