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Myosin inhibitor, as well as preparation method and application thereof

A technology of solvates and compounds, applied in the field of medicinal chemistry, can solve the problems of long residence time, slow elimination, inconvenient to adjust the dose quickly, etc.

Active Publication Date: 2020-01-17
SHANGHAI XIANXING PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the elimination in the body is slow, and the drug stays in the body for too long (it is estimated that the half-life of the human body is 9 days), which is not convenient for rapid dose adjustment (Mark P. Grillo et al. Xenobiotica, 2019; 49(6): 718-733)

Method used

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  • Myosin inhibitor, as well as preparation method and application thereof
  • Myosin inhibitor, as well as preparation method and application thereof
  • Myosin inhibitor, as well as preparation method and application thereof

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preparation example Construction

[0092] The second aspect of the present invention provides a method for preparing the compound provided by the first aspect of the present invention, comprising: reacting the compound of formula 4 with the compound of formula 5 to obtain the compound of formula I.

[0093]

[0094] In the preparation method provided by the present invention, the reaction can be carried out in the presence of an acid-binding agent, and those skilled in the art can select an appropriate type and amount of acid-binding agent for the above-mentioned condensation reaction. For example, the acid-binding agent can be an organic base and / or an inorganic base, specifically including but not limited to N,N-diisopropylethylamine, triethylamine, DBU, pyridine, sodium carbonate, potassium carbonate or carbonic acid One or more combinations of cesium, etc. In a preferred embodiment of the present invention, the acid-binding agent may be N,N-diisopropylethylamine and / or triethylamine. For another example...

Embodiment 1

[0112] (S)-3-isopropyl-6-((1-(1,2,3,4-tetrahydro-1-naphthyl))amino)pyrimidine-2,4(1H,3H)-dione ( I-1) Preparation

[0113]

[0114] Synthesis of isopropylurea 2a: Isopropylamine (5.13 g, 86.80 mmol) was dissolved in anhydrous CH 2 Cl 2 (25mL), cooled to 0°C, under the protection of argon, trimethylsilylisocyanate (10.01g, 86.80mmol) was added dropwise to the reaction solution. After the dropwise addition, move to room temperature and stir the reaction overnight. After the reaction was detected by LC / MS, the reaction solution was cooled to 0° C., 8 mL of anhydrous methanol was added dropwise, and stirring was continued at room temperature for 3 h. Concentrated under reduced pressure, the residue was washed with ether and filtered, and the filter cake was dried at 50°C to obtain 6.12 g of white solid, with a yield of 69.1%. LC / MS (ESI + ):m / z 103[M+H] + .

[0115]

[0116] Synthesis of 1-isopropylbarbituric acid 3a: 2a (6.12 g, 59.95 mmol) was dissolved in CH 3OH (...

Embodiment 2

[0122] (R)-3-isopropyl-6-((1-(1,2,3,4-tetrahydro-1-naphthyl))amino)pyrimidine-2,4(1H,3H)-dione ( I-2) Preparation

[0123]

[0124] Synthesis of I-2: Using compound 4a (500mg, 2.65mmol) and (R)-1,2,3,4-tetrahydro-1-naphthylamine 5b (781mg, 5.30mmol) as raw materials, the operation is the same as I-1 , 96mg of yellow solid was obtained, the yield was 12.1%. 1 H NMR (500MHz, DMSO-d 6 )δ (ppm): 9.67 (s, 1H), 7.27-7.17 (m, 3H), 7.14 (d, J = 7.4Hz, 1H), 6.39 (s, 1H), 4.99 (m, 1H), 4.78 ( s,1H),4.65-4.57(m,1H),2.83-2.66(m,2H),1.89(m,1H),1.82-1.70(m,3H),1.33(d,J=6.9Hz,6H) . 13 C NMR (126MHz, DMSO-d 6 )δ (ppm): 163.86, 151.95, 150.94, 137.67, 136.53, 129.44, 129.08, 127.83, 126.56, 73.59, 49.48, 42.78, 29.00, 28.92, 19.91, 19.51. HRMS (ESI): m / z [M+H ] + calcd for C 17 h 22 N 3 o 2 300.1712; found 300.1694

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Abstract

The invention relates to the field of medicinal chemistry, in particular to a myosin inhibitor, as well as a preparation method and application thereof. The invention provides a compound or pharmacologically acceptable salt, an isomer, a prodrug, a polymorphic substance or a solvate thereof. A chemical structural formula of the compound is as shown in a formula I. Compared with other similar medicines in the prior art, the compound or the pharmacologically acceptable salt, the isomer, the prodrug, the polymorphic substance or the solvate thereof provided by the invention have better activity and a more ideal pharmacokinetics characteristic.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a myosin inhibitor and its preparation method and application. Background technique [0002] Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by myocardial hypertrophy, mainly manifested by thickening of the left ventricular wall, obstruction of left ventricular filling and blood outflow, and decreased diastolic compliance. According to whether the left ventricular outflow tract is obstructed, it can be divided into obstructive hypertrophic cardiomyopathy and non-obstructive hypertrophic cardiomyopathy. The incidence of HCM in the population is about 1 / 500, and its clinical manifestations are diverse, including exertional dyspnea, chest tightness, palpitations, and syncope. There may be no obvious symptoms, but once symptoms appear, they can gradually worsen. It is a progressive disease with a significant accumulation of morbidity burden. The main threa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/545C07D405/04C07D401/04C07D239/553A61K31/513A61P9/00A61P9/04A61P9/10A61P9/12
CPCC07D239/545C07D405/04C07D401/04C07D239/553A61P9/00A61P9/04A61P9/10A61P9/12
Inventor 胡立宏王均伟
Owner SHANGHAI XIANXING PHARM CO LTD
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