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Pyrimidinecarboxamide derivative and preparation method thereof, composition, preparation and use thereof

A technology of derivatives and pharmaceutical preparations, applied in the field of medicine, can solve the problems of lowering the level of cGMP and weakening the relaxation effect of smooth muscle, and achieve the effects of reducing intake, avoiding side effects and excellent inhibitory activity

Active Publication Date: 2019-04-02
ZHENJIANG SAN AN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PDE-5 can hydrolyze cGMP to GMP, thereby reducing the level of intracellular cGMP and weakening the relaxation effect of smooth muscle

Method used

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  • Pyrimidinecarboxamide derivative and preparation method thereof, composition, preparation and use thereof
  • Pyrimidinecarboxamide derivative and preparation method thereof, composition, preparation and use thereof
  • Pyrimidinecarboxamide derivative and preparation method thereof, composition, preparation and use thereof

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preparation example Construction

[0059] The preparation of solvates and hydrates is well known in the art, a typical procedure is as follows: Dissolving the compound in the required amount of solvent (organic solvent, water or a mixture of both) at above ambient temperature In this method, the solution is cooled at a rate sufficient to form crystals, the crystals are then isolated by standard methods, and finally the presence of solvent or water in the crystals of the solvate or hydrate is confirmed by analytical techniques (eg, infrared spectroscopy, thermal analysis).

[0060] In a preferred embodiment, the above-mentioned compound represented by formula I is a single crystal or a polymorph.

[0061] Secondly, the present invention provides the above-mentioned preparation method of the compound shown in formula I, it comprises:

[0062] Step 1): Preparation of 4-bromo-2-methylthio-N-(pyrimidin-2-ylmethyl)- 5-pyrimidinecarboxamide;

[0063]

[0064] Step 2): Preparation of compound B of general formula ...

Embodiment 1

[0084] Example 1: Preparation of (S)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[5,5-dideutero-2-(hydroxymethyl)pyrrolidine-1 -yl]-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide (compound of formula II).

[0085]

[0086] The preparation of the target compound is carried out according to the process shown above, and the specific steps are as follows:

[0087] S1: Preparation of 4-bromo-2-methylthio-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide (compound 3):

[0088] Under the protection of argon, 4-bromo-2-methylthio-5-pyrimidinecarbonyl chloride (compound 1) (10mmol) was dissolved in anhydrous dichloromethane (20ml), and cooled in an ice bath (-10°C) , a solution of triethylamine (20 mmol), 4-dimethylaminopyridine (1 mmol) and 2-aminomethylpyrimidine (compound 2) (10.5 mmol) in anhydrous dichloromethane (10 ml) was added slowly, respectively. After the addition was complete, the mixture was warmed to 25 °C and stirred for 1 h.

[0089] After LC-MS and TLC showed that th...

Embodiment 2

[0102] Example 2: Preparation of (S)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2,3,3,4,4,5,5-heptadeuterio-2 -(2,2-Dideuterohydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide (compound of formula III).

[0103] The preparation of the target compound is carried out according to the process described in Example 1, the difference is that 2,3,3,4,4,5,5,6,6-nonadeutero-L-prolinol (compound 6-1 ) to replace the 5,5-dideuterio-L-prolinol (compound 6) used in S3 of Example 1 to obtain the target product. After testing, the purity of the product is greater than 97%.

[0104] LC-MS(ESI)m / z:494[M+H] + .

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Abstract

The invention belongs to the field of medicine and relates to a pyrimidinecarboxamide derivative and a preparation method thereof, a composition, a preparation and use thereof. Specifically, the present invention discloses a compound of the formula I or a derivative thereof, wherein R1, R2, R3, R4, R5 and R6 are each independently a hydrogen atom or a deuterium atom, and at least one in R1 to R6 is a helium atom. The compound or the derivative have good PDE-5 inhibitory activity, excellent pharmacokinetic properties and low toxic side effects, and is suitable for development of medicines for prevention of and / or treatment of hypertension and / or penile erectile dysfunction.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a pyrimidine carboxamide derivative used as a type 5 phosphodiesterase (PDE-5) inhibitor, a preparation method thereof, a pharmaceutical application thereof, a composition and a pharmaceutical preparation containing the same. Background technique [0002] Generally, male sexual dysfunction mainly includes loss of libido, penile erectile dysfunction, orgasm and ejaculation dysfunction, penile flaccid dysfunction, etc., among which penile erectile dysfunction (ED) is the most common. Erectile dysfunction, also known as impotence, is the persistent inability of the penis to achieve and / or maintain an erection sufficient for a satisfactory sexual life (coitus). An erection is the hydraulic effect of blood entering and retaining within the cavernous structures in the male genitalia. The erectile process is usually caused by sexual arousal, and the causes of erectile dysfunction include cardiova...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/506A61P15/10A61P11/00A61P9/12A61P9/10A61P9/04A61P3/10A61P1/00A61P9/00
CPCC07B2200/05C07D403/14
Inventor 陈兴海奥玛.派克葛均波王威琪
Owner ZHENJIANG SAN AN PHARMA
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