Pyrrolopyrimidine compound, isomer or salt, and preparation method and application thereof

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

Pending 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 study of refractory cough in Europe, the end point was not reached and ended in failure. The antagonism IC50 of LY-3526318 on TRPA1 was 5-6uM, and the activity was weak

Method used

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  • Pyrrolopyrimidine compound, isomer or salt, and preparation method and application thereof
  • Pyrrolopyrimidine compound, isomer or salt, and preparation method and application thereof
  • Pyrrolopyrimidine compound, isomer or salt, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: (S)-2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrro[3,2-D]pyrimidine-5 -yl)-N-(5-(2-(S)-2-methylpyrrolidin-1-yl)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)propanamide preparation

[0070]

[0071] Step 1: (S)-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrole[3,2-D]pyrimidine-5- Preparation of methyl) propionate

[0072]

[0073] Add 1,3-dimethyl-1,5-dihydro-2h-pyrrole[3,2-d]pyrimidine-2,4(3H)-dione (743.6mg, 4.15mmol) and K into a 25ml three-necked flask 2 CO 3 (0.622 mg, 4.5 mmol), DMF (8 mL), stirred and mixed. Add (R)-methyl 2-(methylsulfonyloxy)propanoate (0.58 g, 3.2 mmol). 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

[0092] Example 2: (S)-2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrro[3,2-D]pyrimidine-5 -yl)-N-(4-(2-(S)-2-methylpyrrolidin-1-yl)pyrimidin-5-yl)thiazol-2-yl)propanamide

[0093]

[0094] Step 1: Preparation of (S)-4-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)thiazol-2-amine

[0095]

[0096] Add (S)-2-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolato) to a 25ml three-necked flask Cyclopentan-2-yl)pyrimidine (200 mg, 0.69 mmol), 4-bromothiazol-2-amine (124 mg, 0.69 mmol), Pd (Ph 3 p) 4 (80mg, 0.069mmol), potassium carbonate (286mg, 2.07mmol), dioxane (3ml), water (0.6ml), N 2 After three replacements, it was heated to 1055°C for reaction for 6h. After the reaction was completed, EA was added, extracted and washed with water, the organic phase was dried and concentrated to dryness, and passed through a silica gel column to obtain 100 mg of a yellow oily product with a yield of 55.3%.

[0097] ESI-MS: m / z = 262.1(M+H) + .

[0098] Step 2:...

Embodiment 3

[0103] Example 3: (S)-2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrro[3,2-D]pyrimidine-5 -yl)-N-(5-methyl-4-(2-(S)-2-methylpyrrolidin-1-yl)pyrimidin-5-yl)thiazole-2-propionamide

[0104]

[0105] The preparation method is the same as the preparation method of Example 2, except that 4-bromothiazol-2-amine in step 1 is replaced with equimolar 4-bromo-5-methylthiazol-2-amine, and the method in step 2 is the same to obtain a yellow solid. The title compound, the two-step reaction yield: 36.2%, the purity is 98.42%.

[0106] ESI-MS: m / z =509.2(M+H) + .

[0107] 1 HNMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 8.56 (s, 2H), 8.03-8.10 (d, 1H), 6.23 (d, 1H), 5.88 (d, 1H), 4.30 ( s, 1H), 3.59 (m, 1H), 3.46 (s, 3H), 3.19 (s, 3H), 2.48 (s, 3H), 2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d , 3H), 1.72 (s, 1H), 1.24 (d, 3H).

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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 pyrrolopyrimidine 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 diseases of the respiratory system and nervous system. 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61P11/06A61P11/14A61P29/00
CPCC07D487/04C07D519/00A61P11/06A61P11/14A61P29/00
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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