Benzoxazolooxazinones as factor xa inhibitors

A kind of compound, the technology of phenyl, be applied in the field of new benzoxazolo oxazinone compound, can solve the problem such as no teaching, do not have coagulation factor Xa inhibition effect etc.

Active Publication Date: 2018-06-26
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, this compound does not have an inhibitory effect on blood coagulation factor Xa, and WO2011 / 147259 has no relevant teaching in this regard

Method used

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  • Benzoxazolooxazinones as factor xa inhibitors
  • Benzoxazolooxazinones as factor xa inhibitors
  • Benzoxazolooxazinones as factor xa inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] 5-chloro-N-(((3S,3aS)-1-oxo-7-(3-oxomorpholino)-1,3,3a,4-tetrahydrobenzo[b]oxazolo [3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide

[0222]

[0223] Reaction flow:

[0224]

[0225] Step A: Cool a solution of (Z)-but-2-ene-1,4-diol (39.7g, 450mmol) in dry THF (300mL) to 0°C, add sodium hydride (60% dissolved in mineral oil) in batches , 9.0 g, 225 mmol), then a dry THF solution (450 mL) of 4-bromo-2-fluoro-1-nitrobenzene (33.0 g, 150 mmol) was added dropwise at 0°C. The reaction solution was stirred at room temperature for two hours, poured into 600 mL of water, the mixture was extracted with EtOAc, the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (Z)-4-(5-bromo-2-nitrobenzene oxy)but-2-en-1-ol (45 g), yellow solid. The crude product was used in the next step without further purification.

[0226] Step B: Add zinc powder (49.0g, 750mmol) and ammonium chloride (40.0g, 750mmol) into methanol (450mL)...

Embodiment 2

[0238] 5-chloro-N-(((3S,3aS)-1-oxo-7-(2-oxopiperidin-1-yl)-1,3,3a,4-tetrahydrobenzo[b]oxa azole And[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide

[0239]

[0240] Step A: Preparation of (3R,3aS)-3-((tert-butyldimethylsilyloxy)methyl)-7-(2-oxopiperidin-1-yl)-3α according to Example 1, 4-Dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one, 7% yield, wherein the morpholin-3 in step G -one is replaced by piperidin-2-one. LCMS (ESI) m / z: 433.2 (M+1).

[0241] Step B: The title compound of Example 2 was prepared sequentially according to Example 1 Steps G, I, J, K and L as a white solid. 1 HNMR (400MHz, DMSO-d 6 )δ9.01(t, J=5.6Hz, 1H), 7.83(d, J=8.8Hz, 1H), 7.72(d, J=4.0Hz, 1H), 7.22(d, J=4.0Hz, 1H) , 6.87-6.93(m, 2H), 4.50-4.64(m, 2H), 3.99-4.13(m, 2H), 3.73(t, J=5.6Hz, 2H), 3.52-3.60(m, 2H), 2.37 (t, J=6.0Hz, 2H), 1.77-1.90 (m, 4H); LCMS (ESI) m / z: 462.1 (M+1).

Embodiment 3

[0243] 5-chloro-N-(((3S,3aS)-1-oxo-7-(5-oxo-1,4-oxazepan-4-yl)-1,3,3a, 4- Tetrahydrobenzo[b]oxazol[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide

[0244]

[0245] Step A: Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(5-oxo-1,4-oxa according to Example 1 Azepan-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one, wherein the step The morpholin-3-one in G was replaced by 1,4-oxazepan-5-one, the yield was 35%. LCMS (ESI) m / z: 449.2 (M+1).

[0246] Step B: The title compound of Example 3 was prepared sequentially according to Example 1 Steps G, I, J, K and L as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ9.01(s, 1H), 7.82(d, J=8.4Hz, 1H), 7.72(d, J=4.0Hz, 1H), 7.22(d, J=4.0Hz, 1H), 6.87-6.83( m, 2H), 4.60-4.54(m, 2H), 4.10-4.00(m, 2H), 3.80-3.65(m, 8H), 2.78(t, J=4.8Hz, 2H); LCMS (ESI) m / z: 478.1(M+1).

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Abstract

The present invention relates to a new compound of formula (I) or its solvate, hydrate, tautomer, or pharmaceutically acceptable salt, wherein R1 represents substituted or unsubstituted aryl or heteroaryl; R2 Represents an optionally substituted 3‑9 membered carbocycle or heterocycle, etc.; R3 represents H, etc.; A is selected from O, NH, N‑CH3, S, SO, SO2, and CH2; X, Y, and Z are independently selected from From CH, C-Br, C-Cl, C-F, C-I and N. The compound of the present invention can be used as an anticoagulant for treating and preventing abnormal thrombus diseases, and the present invention satisfies the actual demand for a selective and potent inhibitor of coagulation factor Xa by providing a potent inhibitor of coagulation factor Xa.

Description

technical field [0001] The present invention relates to a new benzoxazoloxazinone compound, especially a compound represented by formula (I), its preparation method, pharmaceutical composition and its use as an anticoagulant in the treatment and prevention of thromboembolic diseases. Background technique [0002] Cardiovascular disease is the leading cause of morbidity and mortality in the developed world population, with the majority of cardiovascular events primarily attributable to thrombosis. Warfarin is the first oral anticoagulant approved for marketing, and its application suffers from slow vitamin K-dependent antagonism, drug-drug interactions, and drug-food interactions, which lead to Continuous monitoring is required for accurate dosing. Other anticoagulants such as heparin and fondaparinux are only suitable for parenteral administration. The above-mentioned defects of existing anticoagulants have promoted the in-depth research of new anticoagulant drugs. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00C07D498/14C07D513/04A61K31/5383A61K31/553A61K31/5386A61K31/541A61K31/542A61P7/02A61P9/10
CPCA61P7/02A61P9/10C07D498/04C07D498/14C07D513/04
Inventor 高任龙丁照中赖光华陈曙辉颜小兵段宝玲朱秀良路新华胡军平
Owner NCPC NEW DRUG RES & DEV
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