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Pyrimidine carboxamide derivatives and preparation method, composition, formulation and use thereof

A technology of pyrimidine carboxamide and derivatives, applied in the field of medicine, can solve the problems of weakening smooth muscle relaxation, lowering cGMP levels, etc., and achieve the effects of avoiding side effects, reducing intake, and reducing the frequency of medication

Active Publication Date: 2020-09-01
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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  • Pyrimidine carboxamide derivatives and preparation method, composition, formulation and use thereof
  • Pyrimidine carboxamide derivatives and preparation method, composition, formulation and use thereof
  • Pyrimidine carboxamide derivatives and preparation method, composition, formulation and use thereof

Examples

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preparation example Construction

[0059] The preparation methods of solvates and hydrates are well known in the art. The typical method is as follows: Dissolve the compound in the required amount of solvent (organic solvent, water or a mixture of the two) at a temperature higher than ambient temperature In the process, the solution is cooled at a speed sufficient to form crystals, then the crystals are separated by standard methods, and finally the presence of solvent or water in the solvate or hydrate crystals is confirmed by analytical techniques (such as 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 a preparation method of the above-mentioned compound represented by formula I, which comprises:

[0062] Step 1): Prepare 4-bromo-2-methylthio-N-(pyrimidin-2-ylmethyl)- from 4-bromo-2-methylthio-5-pyrimidinecarbonyl chloride and 2-aminomethylpyrimidi...

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] Follow the procedure shown above to prepare the target compound, 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, dissolve 4-bromo-2-methylthio-5-pyrimidinecarbonyl chloride (Compound 1) (10mmol) in anhydrous dichloromethane (20ml), and cool down in an ice bath (-10℃) , Slowly add triethylamine (20mmol), 4-dimethylaminopyridine (1mmol) and 2-aminomethylpyrimidine (compound 2) (10.5mmol) in dry dichloromethane (10ml) respectively. After the addition was complete, the mixture was heated to 25°C and stirred for 1 hour.

[0089] After LC-MS and TLC showed that the intermediate reaction was basically completed, water was added to ter...

Embodiment 2

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

[0103] The target compound was prepared according to the procedure described in Example 1, except that 2,3,3,4,4,5,5,6,6-nonadeutero-L-prolinol (Compound 6-1 ) Replace the 5,5-dideutero-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, its preparation method, its pharmaceutical use, and compositions and pharmaceutical preparations containing the same. Background technique [0002] Generally, male sexual dysfunction mainly includes loss of libido, erectile dysfunction, orgasm and ejaculation dysfunction, and weak penile dysfunction, among which erectile dysfunction (ED) is the most common. Penile erectile dysfunction, also known as impotence, refers to the symptom that the penis is continuously unable to achieve and / or maintain a sufficient erection and therefore cannot obtain a satisfactory sex life (sexual intercourse). Erection refers to the hydraulic effect produced by blood entering and remaining in the cavernous structure of the male genitalia. The erectile process is usually caused by sexual arousal, and the main causes of penile e...

Claims

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Application Information

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Patent Type & Authority Patents(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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