Pyrazolopyrimidine compound, isomer or salt as well as preparation method and application of pyrazolopyrimidine compound and isomer or salt

A technology for compounds and stereoisomers, applied in the field of medicinal chemistry, can solve problems such as weak activity, and achieve the effect of good antitussive effect and high safety

Active Publication Date: 2022-06-24
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the clinical research of refractory cough in Europe, the end point was not reached and ended in failure. The IC50 of LY-3526318’s antagonistic effect on TRPA1 was 5-6uM, and the activity was weak. TRPA1 antagonists are potential therapeutic drugs for many diseases, and There are great unmet clinical needs in the fields of pain, asthma, cough, etc. Therefore, there is a greater clinical need for antagonists with high activity of TRPA1 to provide patients with more active and safer drug options, and the development of TRPA1 antagonists has great potential. Great market value and academic value

Method used

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  • Pyrazolopyrimidine compound, isomer or salt as well as preparation method and application of pyrazolopyrimidine compound and isomer or salt
  • Pyrazolopyrimidine compound, isomer or salt as well as preparation method and application of pyrazolopyrimidine compound and isomer or salt
  • Pyrazolopyrimidine compound, isomer or salt as well as preparation method and application of pyrazolopyrimidine compound and isomer or salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: (S)-2-(4,6-Dimethyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-D]pyrimidine- 1-yl)-N-(5-(3-fluoro-4-(S)-2-methylpyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl) Preparation of propionamide:

[0081]

[0082] Step 1: (S)- 2-(4,6-dimethyl-5,7-dioxo-4,5,6,7-tetrahydro-1h-pyrazolo[4,3-d]pyrimidine-1 - preparation of methyl) propionate

[0083]

[0084] Add 1-methyl-3,4,5,7-tetrahydro-1H-purine-2,6-dione (690mg, 4.15mmol) and K into a 25ml three-necked flask 2 CO 3 (0.573 g, 4.15 mmol), DMF (7 mL), stir and mix well. Methyl (R)-2-(methylsulfonyloxy)propionate (0.58 g, 3.2 mmol) was added and the reaction was stirred at room temperature overnight, the reaction was complete, then washed with saturated NH 4 Cl (20ml) quenched. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic phases were washed with water (3 x 50 mL) and brine. Anhydrous Na for organic phase 2 SO 4 Dry and concentrated. The residue was separated and purifi...

Embodiment 2

[0107] Example 2: (S)-2-(4,6-Dimethyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-D]pyrimidine- Preparation of 1-yl)-N-(4-(3-fluoro-4-(S)-2-methylpyrrolidin-1-yl)phenyl)thiazol-2-yl)propionamide

[0108]

[0109] Step 1: Preparation of (S)-1-(3-fluoro-4-(2-methylpyrrolidin-1-yl)phenyl)ethane-1-one

[0110]

[0111] Add (S)-dimethylpyrrolidine (190mg, 2.23mmol), 3,4-difluoroacetophenone (317mg, 2.03mmol), potassium carbonate (309mg, 2.23mmol) to a 25ml reaction flask, heat to 80°C for reaction overnight. After the reaction was completed, the temperature was lowered to room temperature, water was added, extracted with EA, the layers were separated, dried and concentrated to dryness to obtain 400 mg of a yellow oily product with a yield of 88.9% and a purity of 98.16%.

[0112] ESI-MS: m / z=222.2(M+H) + .

[0113] Step 2: Preparation of (S)-2-bromo-1-(3-fluoro-4-(2-methylpyrrolidin-1-yl)phenyl)ethane-1-one

[0114]

[0115] A 25ml reaction flask was charged with (S)...

Embodiment 3

[0124]Example 3: (S)-2-(4,6-Dimethyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-D]pyrimidine- Preparation of 1-yl)-N-(2-(3-fluoro-4-(S)-2-methylpyrrolidin-1-yl)phenyl)pyrimidin-4-yl)propionamide

[0125]

[0126] Step 1: Preparation of (S)-3-fluoro-4-(2-methylpyrrolidin-1-yl)benzimidazole

[0127]

[0128] 3,4-Difluorobenzamide hydrochloride (308mg, 1.60mmol), (S)-dimethylpyrrolidine (150mg, 1.76mmol), K 2 CO 3 (664mg, 4.81mmol), DMSO (5ml), heated to 100°C with stirring for 5h. TLC monitored the reaction of the raw materials, cooled to room temperature, added water, extracted with EA, and the organic phase was concentrated to dryness. The concentrate was separated and purified by column chromatography (MeOH:DCM=2:100), the product was collected and concentrated to dryness to obtain 180 mg of the title product, yield 51%, and purity was 98.50%.

[0129] ESI-MS: m / z = 222.1(M+H) + .

[0130] Step 2: Preparation of (S)-2-(3-fluoro-4-(2-methylpyrrolidin-1-yl)phen...

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Abstract

The invention discloses a compound as shown in a formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvent compound, a metabolite and a pharmaceutically acceptable salt of the compound as shown in the formula (I). The invention also provides application of the compound, the stereoisomer or the pharmaceutically acceptable salt thereof in preparation of drugs for treating and/or preventing diseases related to TRPA1 receptors, especially application in preparation of drugs for treating and/or preventing cough, asthma, pain and sleep apnea.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to the use of novel pyrazolopyrimidine compounds or their salts, isomers, their preparation methods and their pharmaceutical compositions in the preparation, treatment and / or prevention of diseases related to TRPA1 receptors , especially in the treatment and / or prevention of respiratory diseases and neurological diseases. Background technique [0002] Transient Receptor Potential (TRP) channel is a non-selective cation channel. According to the homology of TRP sequence, TRP ion channels in mammals can be divided into 7 subfamilies, namely TRPC (7 members), TRPM (8 members), TRPV (6 members), TRPA (ankyrin, ANKTM1, only member), TRPML (3 members), TRPP (5 members), and TRPN. The TRP family is involved in a variety of cellular functions, including sensory perception and signal transduction. Among them, the TRPA1 receptor is associated with temperature, pain sensation, hyp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61P11/06A61P11/14A61P29/00A61P11/00A61P25/00A61P25/04A61K31/519A61K31/55
CPCC07D487/04C07D519/00A61P11/06A61P11/14A61P29/00A61P11/00A61P25/00A61P25/04C07B2200/07Y02P20/55
Inventor 曾燕群周广林朱绪成付海霞牟霞
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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