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Parecoxib derivative as well as preparation method and application thereof

A technology of compounds and solvates, applied in the field of pharmaceutical compounds, can solve problems such as precipitation

Inactive Publication Date: 2021-02-26
SUZHOU INTRAGRAND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, in clinical practice, Parecoxib can only be administered through slow intramuscular injection, rapid intravenous injection or through existing intravenous access, and precipitation may occur when Parecoxib is mixed with other drugs in the solution, Parecoxib must not be mixed with other drugs during dissolution or injection
In addition, there are potential infections during the preparation and storage of parecoxib injection, and patients must be injected twice a day by hospital professionals

Method used

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  • Parecoxib derivative as well as preparation method and application thereof
  • Parecoxib derivative as well as preparation method and application thereof
  • Parecoxib derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example 1

[0085]

[0086] K 2 CO 3 (375mg, 2.7mmol, 5.0eq), methyl chloroacetate (1.16g, 10.8mmol, 20eq), the reaction was stirred at room temperature for 18 hours. with H 2 The reaction mixture was diluted with O (20 mL), extracted with EtOAc (20 mL x 2). The combined organic phases were washed with saturated brine (15 mL), washed with Na 2 SO 4 After drying, filter and concentrate in vacuo. The obtained crude product residue was purified by TLC (PE / EA=1.7:1) to obtain 50 mg of crude product, which was purified by prep-HPLC (0.1% HCOOH / H in ACN 2 O) Further purification gave white solid compound 1 (16.65 mg, yield 6%).

[0087] LCMS: (M+H)+: 443.1

[0088] 1 H-NMR (400MHz, CDCl3) δ = 8.00 (m, 2H), 7.38 (m, 7H), 5.91 (s, 2H), 2.61 (q, J = 7.2Hz, 2H), 2.52 (s, 3H), 2.08(s,3H),1.10(t,J=7.2Hz,3H).

Synthetic example 2

[0090]

[0091] K 2 CO 3 (746mg, 5.41mmol, 1.54eq), chloromethyl isopropyl carbonate (4mL), and the reaction was stirred at room temperature for 18 hours. with H 2 The reaction mixture was diluted with O (30 mL), extracted with EtOAc (40 mL×3). The combined organic phases were washed with saturated brine (30mL×3), washed with Na 2 SO 4 It was dried, filtered, and concentrated to obtain a crude residue, which was purified by TLC (EtOAc:PE=1:2) to obtain white solid Example 2 (104.4 mg, yield 33.73%). LCMS: (M+H)+: 487.2

[0092] 1 H-NMR (400MHz, DMSO-d6) δ = 8.01-7.94 (m, 2H), 7.50-7.39 (m, 5H), 7.35-7.30 (m, 2H), 5.91 (s, 2H), 4.87-4.71 ( m,1H),2.65(dd,J=7.1Hz,2H),2.49(s,3H),1.23(d,J=6.2Hz,6H),0.92(t,J=7.2Hz,3H).

[0093] Synthetic Example 3.

[0094]

[0095] DIPEA (174mg, 1.35mmol, 2.5eq), methyl chloromethyl carbonate (134.4mg, 1.08mmol, 2.0eq), the reaction was stirred at room temperature for 18 hours. Spin dry with H 2 The reaction mixture was diluted wi...

Embodiment 1

[0103] Synthesize following compound 5-28 with reference to embodiment 1

[0104] List of specific examples

[0105]

[0106]

[0107]

[0108] Also included within the scope of the present invention is a pharmaceutical combination comprising said active compound in admixture with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (hereinafter collectively referred to as "carrier" materials) substances, which may also contain other pharmaceutically active ingredients as required. The active compound of the present invention can be administered orally or externally, preferably in the form of a drug combination suitable for the administration route and at an effective dose required for treatment.

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PUM

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Abstract

The present invention relates to a parecoxib derivative represented by a formula I, a racemate, a stereoisomer, a tautomer, an isotope marker, a solvate, a polymorphic substance, an ester or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the parecoxib derivative, a preparation method thereof, and pharmaceutical and veterinary pharmaceutical uses of the parecoxib derivative, and the formula I is disclosed in the invention.

Description

technical field [0001] The invention belongs to the field of pharmaceutical compounds, and in particular relates to a parecoxib derivative, a preparation method thereof, and a medicine application. Background technique [0002] Safe and effective analgesics are still an unmet market need, especially for moderate to severe pain drugs, currently mainly opioids, narcotic analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), but The adverse reactions of these different types of drugs limit their wide clinical application. And specific cyclooxygenase-2 (COX-2) inhibitors, such as Parecoxib (Parecoxib) described in the patent US5932598 as a prodrug of Valdecoxib (Valdecoxib) that selectively inhibits cyclooxygenase-2 , its injection has active clinical application in acute moderate to severe pain, especially perioperative or postoperative analgesia. The chemical structures of parecoxib and valdecoxib are as follows: [0003] [0004] However, in clinical practice, Pa...

Claims

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Application Information

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IPC IPC(8): C07D261/08C07F9/653A61P29/00A61P1/02A61P19/02A61K31/42A61K31/675
CPCA61P1/02A61P19/02A61P29/00C07D261/08C07F9/653
Inventor 朱加望王泽根冯剑波姚瑶
Owner SUZHOU INTRAGRAND PHARMA CO LTD
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