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Cyclopenta [d] pyrimidine compound, pharmaceutically acceptable salt, solvate or prodrug thereof and application

A solvate and compound technology, applied in the field of medicine, can solve the problem of less HIF-2a inhibitors and achieve the effect of strong in vitro binding ability

Active Publication Date: 2020-06-19
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are few reports on HIF-2a inhibitors, and only one inhibitor, PT2385, is in Phase 1 clinical stage

Method used

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  • Cyclopenta [d] pyrimidine compound, pharmaceutically acceptable salt, solvate or prodrug thereof and application
  • Cyclopenta [d] pyrimidine compound, pharmaceutically acceptable salt, solvate or prodrug thereof and application
  • Cyclopenta [d] pyrimidine compound, pharmaceutically acceptable salt, solvate or prodrug thereof and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] 3-fluoro-5-((7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)benzonitrile (compound 1)

[0068]

[0069] (1) 4-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Intermediate 1-A):

[0070]

[0071] Add 1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (6.8g, 50.0mmol) into phosphorus oxychloride (60mL), raise the temperature to 110°C, and stir for 10h. TLC showed that the reaction was complete, cooled to room temperature, evaporated the solvent under reduced pressure, poured the residue into water, adjusted the pH to 7 with saturated sodium bicarbonate solution, added ethyl acetate to extract twice, washed the organic phase with saline, and Dry over sodium sulfate and concentrate to dryness to give 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (7.5 g, 98%), which is directly used in the next reaction. LCMS (ESI): m / z: 155.1 [M+1].

[0072] (2) 1-oxo-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (intermediate 1-B):

[0073]

[0074] To a solution of 4-...

Embodiment 2

[0084] 4-(3,5-Difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-7-ol (Compound 2)

[0085]

[0086] (1) 4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester:

[0087]

[0088] Using a method similar to Example 1 (4), it was prepared from 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester and 3,5-difluorophenol to produce The rate is 78.1%. 1H NMR (400MHz, CDCl3) δ8.69(s,1H),7.34(s,1H),7.29(dd,1H),7.26(dd,1H),6.16(m,1H),3.11-3.19(m, 1H), 2.94–2.99(m,1H), 2.70–2.79(m,1H), 2.11–2.17(m,4H).LCMS(ESI):m / z:307.1[M+1].

[0089] (2) 4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-7-ol (compound 2):

[0090] Using a method similar to Example 1 (5), prepared from 4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester , yield 82.5%. 1H NMR (400MHz, CDCl3) δ8.66(s,1H),6.71-6.76(m,3H),5.27(m,1H),4.78(s,1H),3.08-3.15(m,1H),2.83– 2.89 (m, 1H), 2.57–2.66 (m, 1H), 2.04–2.16 (m, 1H). LCMS (ESI): ...

Embodiment 3

[0092] 2-fluoro-5-((7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)benzonitrile (compound 3)

[0093]

[0094] (1) 4-(3-cyano-4-fluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester (Intermediate 3-A):

[0095]

[0096] Using a method similar to Example 1 (4), from 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl ethyl ester, 2-fluoro-5-hydroxybenzonitrile Preparation, yield 76.5%. LCMS (ESI): m / z: 314.1 [M+1].

[0097] (2) 2-fluoro-5-((7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)benzonitrile (compound 3):

[0098] Using a method similar to Example 1 (5), from 4-(3-cyano-4-fluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl The ester was prepared with a yield of 81.5%. 1H NMR (400MHz, CDCl3) δ8.62(s,1H),7.46(m,1H),7.40(m,1H),7.29(m,1H),5.25(m,1H),3.36(s,1H) ,3.09-3.17(m,1H),2.87–2.92(m,1H),2.60–2.69(m,1H),2.09–2.14(m,1H).LCMS(ESI):m / z:272.1[M+ 1].

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Abstract

The invention discloses a cyclopenta [d] pyrimidine compound, a pharmaceutically acceptable salt, solvate or prodrug thereof, and an application of the cyclopenta [d] pyrimidine compound, the pharmaceutically acceptable salt, the solvate or the prodrug. The compound has a structural formula which is described in the specification. The cyclopenta [d] pyrimidine compound and the pharmaceutically acceptable salt and solvate thereof disclosed by the invention can be used as an HIF-2alpha inhibitor for preparing medicines for treating and / or preventing HIF-2alpha related diseases or symptoms of mammals.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a new class of cyclopenta[d]pyrimidine compounds with antitumor activity, pharmaceutically acceptable salts, solvates or prodrugs thereof and applications thereof. Background technique [0002] Renal cancer is a malignant tumor originating from the urinary tubular epithelial system of the renal parenchyma. Renal cancer accounts for about 2% to 3% of adult malignant tumors and 80% to 90% of adult renal malignant tumors. In recent years, the rate of increase in the incidence of renal cancer ranks first among malignant tumors. Clinical treatment shows that RCC is not sensitive to radiotherapy and chemotherapy. Targeted antineoplastic drugs represented by VEGFR inhibitors Sorafenib and Sunitinib are the first-line treatment drugs for advanced RCC. Although there are as many as ten drugs approved by the FDA for the treatment of renal cancer, all of these drugs have limit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/70C07D405/12C07D401/12A61P35/00A61P29/00A61P11/00A61P1/00A61P13/12A61P19/02A61P17/02A61P3/00A61P3/04A61P3/06A61K31/517
CPCC07D239/70C07D405/12C07D401/12A61P35/00A61P29/00A61P11/00A61P1/00A61P13/12A61P19/02A61P17/02A61P3/00A61P3/04A61P3/06
Inventor 徐涛卢玲陈栋秦玉婷赵维峰
Owner OCEAN UNIV OF CHINA
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