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Substituted 7H-pyrrolo[2,3-d]pyrimidine derivative and preparation method and application thereof

A technology of metabolites and compounds, applied in the field of medicine

Active Publication Date: 2019-10-22
WUHAN YUXIANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

JAK1, JAK2 and TYK2 can repress the expression of multiple genes, whereas JAK3 only functions in granulocytes

Method used

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  • Substituted 7H-pyrrolo[2,3-d]pyrimidine derivative and preparation method and application thereof
  • Substituted 7H-pyrrolo[2,3-d]pyrimidine derivative and preparation method and application thereof
  • Substituted 7H-pyrrolo[2,3-d]pyrimidine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Preparation of the compound represented by formula I-1

[0064]

[0065] The synthetic route is as follows:

[0066]

[0067] Preparation Process:

[0068] Step 1: Synthesis of compound 1B

[0069] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (7.00g, 45.6mmol) was added to 58% hydroiodic acid (51.1g, 228mmol) to obtain a turbid suspension. Stir under the atmosphere for 80 hours. The suspension was then neutralized with 50% sodium hydroxide solution, and the solid was collected by filtration. The filter cake was washed with cold water and dried in vacuum. The filtrate was extracted with dichloromethane (3×50 ml). The combined organic phase was dried with sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure. The obtained solid and the precipitate were combined to obtain the target compound 1B (10.9 g, light yellow solid) with a yield of 98%. MS m / z(ESI): 246.1[M+1].

[0070] Step 2: Synthesis of compound 1C

[0071] Will K 2 CO 3 (2g, 14.6m...

Embodiment 2

[0101] Example 2: Preparation of the compound represented by formula I-2

[0102]

[0103] The compound of Example 2 was synthesized according to the procedure of synthesis I-1 in Example 1, but in the tenth step, methylsulfonyl chloride was used to replace ethylsulfonyl chloride.

[0104] MS m / z(ESI): 359[M+1].

[0105] 1 H NMR(400MHz, DMSO-d 6 )ppm 12.12(s,1H),8.95(s,1H),8.74(s,1H),7.56(s,1H),7.13(s,1H),4.61(d,J=8.8Hz,2H),4.22 (d,J=9.2Hz,2H), 3.68(s, 2H), 3.01(s, 3H).

Embodiment 3

[0106] Example 3: Preparation of the compound represented by formula I-3

[0107]

[0108] The compound of Example 3 was synthesized according to the procedure of Synthesis I-1 in Example 1, but in the tenth step, ethylsulfonyl chloride was replaced by isopropylsulfonyl chloride.

[0109] MS m / z(ESI):387[M+1].

[0110] 1 H NMR(400MHz, DMSO-d 6 )ppm 12.05(s,1H),8.97(s,1H),7.83(s,1H),7.33(s,1H),7.05(s,1H),4.50(d,J=8.0Hz,2H),4.23 (d,J=8.0Hz,2H), 3.68(s,2H), 3.12(m,1H), 1.33(d,J=6.8Hz,6H).

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Abstract

The invention provides a substituted 7H-pyrrolo[2,3-d]pyrimidine derivative and a preparation method and application thereof, and specifically provides a compound as shown in a formula I, or pharmaceutically-acceptable salts thereof, or a racemate thereof, or a stereoisomer thereof, or a geometrical isomer thereof, or a tautomer thereof, or nitric oxides thereof, or a hydrate thereof, or a solvatethereof, or an active metabolite thereof or a pro-drug thereof. The medicine can be used for preventing and / or treating proliferative diseases, auto-immunization diseases, allergic diseases, inflammatory diseases or transplant rejection diseases of mammals (including the human being).

Description

Technical field [0001] The present invention belongs to the technical field of medicine, and relates to substituted 7H-pyrrolo[2,3-d]pyrimidine derivatives and preparation methods and uses thereof. Specifically, the present invention relates to a class of JAK inhibitors with JAK inhibitory activity Compounds of substituted 7H-pyrrolo[2,3-d]pyrimidine derivatives, pharmaceutical compositions, preparation methods and uses thereof. Background technique [0002] Janus kinase (JAK) belongs to the tyrosine kinase family and consists of JAK1, JAK2, JAK3 and TYK2. JAK plays an important role in cytokine signaling. The downstream substrates of JAK family kinases include transcription signal sensing and activation (STAT) proteins. JAK / STAT signaling has been implicated in the mediation of many abnormal immune responses, such as allergies, asthma, autoimmune diseases, such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and Solid and h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/02A61P35/00A61P37/00A61P29/00A61P37/06A61P13/12A61P9/10A61P3/10A61P17/06A61P11/00A61P11/06A61P27/02A61P37/02A61P19/02A61P19/10A61P1/00
CPCC07D487/04A61P35/02A61P35/00A61P37/00A61P29/00A61P37/06A61P13/12A61P9/10A61P3/10A61P17/06A61P11/00A61P11/06A61P27/02A61P37/02A61P19/02A61P19/10A61P1/00
Inventor 方华祥余斌李芳芳张晓林车鹏许勇
Owner WUHAN YUXIANG PHARM TECH CO LTD