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Cyclic keto-pyridone-linked heteroaromatic ring compound as well as preparation method and application thereof

A compound, heteroaryl technology, applied in the field of medicinal chemistry, can solve problems such as unsatisfied

Pending Publication Date: 2021-05-11
JIANGXI JEMINCARE GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Plasma kininase inhibitor The macromolecular protein drug Ecallantide (Kalbitor) has been approved by the FDA for the treatment of HAE. However, no small molecule plasma kininase inhibitor has been approved for marketing so far. The development of a safe and effective small molecule inhibitor of Kallikrein may also meet the requirements. clinical unmet need

Method used

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  • Cyclic keto-pyridone-linked heteroaromatic ring compound as well as preparation method and application thereof
  • Cyclic keto-pyridone-linked heteroaromatic ring compound as well as preparation method and application thereof
  • Cyclic keto-pyridone-linked heteroaromatic ring compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Embodiment 1: the preparation of compound A1

[0092]

[0093] Step 1: Synthesis of Intermediate 1-2

[0094] 1,3 Cyclopentanedione (3.35 g, 34.15 mmol), tert-butyl glycine (2 g, 6.63 mmol) and PTSA (649 mg, 3.42 mmol) were added to toluene (100 mL). Reaction system uses N 2 Under protection, the temperature was raised to 130° C., and the reaction was carried out for 3 hours. The reaction solution was spin-dried, dissolved in 500 mL of EtOAc, and washed with saturated NaHCO 3 Washed with aqueous solution, dried, filtered, and spin-dried to obtain 5 g of the target product 1-2 as a yellow solid, yield: 69%.

[0095] Step 2: Synthesis of Intermediates 1-3

[0096]Compound 1-2 (1.7 g, 8.05 mmol) and bis(2,4,6-trichlorophenyl)malonate (3.95 g, 8.05 mmol) were added to toluene (100 mL). The reaction solution was stirred under microwave at 120°C for 2h. The reaction solution was cooled to room temperature and spin-dried to obtain a crude product, which was purified b...

Embodiment 2

[0121] Embodiment 2: the preparation of compound A2

[0122]

[0123] Wherein intermediate 2-2 is synthesized as follows.

[0124]

[0125] Compound 2-1 (domestic) (1.0g, 6.80mmol) was dissolved in 10mL DCE, at room temperature, bromoacetyl bromide (2.0g, 10.20mmol) and aluminum chloride (6g, 44.88mmol) were added, and the reaction After the solution was stirred overnight at 45°C, the reaction solution was poured into ice water, and a large amount of solids precipitated out. After the solids were filtered, the solids were washed with water and ethyl acetate. After the solids were dried, ethyl acetate was added for recrystallization and purification to obtain the intermediate 2-2, white solid, 350 mg, yield 20%. LC-MS: m / z 270.0 (M+H) + , Purity: 89% (UV254).

[0126] Example A2 was obtained from intermediates 1-10 and 2-2 by a similar synthesis procedure to A1. LC-MS: m / z 586.2 (M+H) + . 1 HNMR (400MHz, DMSO-d 6 )δ12.17(s,1H),10.05(s,1H),8.64(s,1H),7.78(dd,J=8.6,2...

Embodiment 3

[0127] Embodiment 3: the preparation of compound A3

[0128]

[0129] Wherein intermediate 3-5 is synthesized as follows:

[0130]

[0131] Step 1. Synthesis of Intermediate 3-1

[0132] Add intermediate 1-6 (1150mg, 4.98mmol), 3,3-diethoxyprop-1-yne (956mg, 7.47mmol) and toluene (10mL) into a 100mL round bottom flask, heat up to 110°C, stir Reaction 16h. LC-MS showed product formation and the reaction was complete. The reaction solution was spin-dried and purified by normal phase column (PE / EA=0-50%) to obtain 1.40 g of intermediate 3-1 as yellow oil, yield: 78%. LCMS:m / z362.0(M+H) + .

[0133] Step 2. Synthesis of Intermediate 3-2

[0134] Add HCl (20 mL) and dioxane (20 mL) into a 100 mL round bottom flask, then add compound 3-1 (1.2 g, 3.34 mmol) into the above mixed solution, heat up to 30° C., and react for 16 h. LC-MS detection showed that the product was generated, and the reaction ended. The reaction solution was diluted with water (40 mL), and extracted...

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Abstract

The invention belongs to the field of medicinal chemistry, specifically, the invention relates to a cyclic ketone and pyridone hetero-aromatic ring compound as well as a preparation method and an application of the cyclic ketone and pyridone hetero-aromatic ring compound. The structure of the compound is shown as a general formula (I). The compounds or the stereoisomers, racemes, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or / and preventing related diseases mediated by the FXIa (Factor XIa for short).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to novel compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, and The pharmaceutical composition containing them is a blood coagulation factor XIa (Factor XIa, FXIa for short) inhibitor with a new structure. Background technique [0002] Thromboembolism is a disease of humans and animals caused by abnormal blood clots that form in blood vessels during their lifetime. There are three reasons for thrombosis: damaged blood vessels, blood changes and blood stasis; it is a group of complications caused by many different diseases and different reasons. Due to the differences in various underlying diseases and the different sites of thromboembolism, thrombosis may clinically manifest as myocardial infarction, stroke, deep vein thrombosis (deep vein thrombosis, DVT), ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D471/04C07D413/14A61K31/444A61K31/4709A61K31/506A61K31/501A61K31/437A61K31/438A61P9/00A61P9/10
CPCC07D401/14C07D471/04C07D413/14A61P9/00A61P9/10
Inventor 张琼刘小斌李中尧姚虞财桓锐叶艳彭建彪郭海兵
Owner JIANGXI JEMINCARE GRP CO LTD
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