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Use of phosphodiesterase inhibitor

A phosphodiesterase and inhibitor technology, applied in the field of medicine, can solve the problems of weakened myocardial protection ability and increased expression level, etc.

Active Publication Date: 2020-09-15
TRANSTHERA SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, the expression of PDE9 is significantly increased in heart failure, especially in HFpEF, so the ability to protect the myocardium is greatly weakened

Method used

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  • Use of phosphodiesterase inhibitor
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  • Use of phosphodiesterase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0250] Preparation Example 1: Synthesis of intermediate 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0251] Step 1: Synthesis of 6-chloro-2H-pyrido[3,4-d][1,3]oxazine-2,4(1H)-dione

[0252]

[0253] Dissolve 5-amino-2-chloroisonicotinic acid (30g, 0.1738mol, 1.0eq) in N,N-dimethylformamide (300mL), and add N,N'-carbonyl di Imidazole (48g, 0.2955mol, 1.7eq), slowly warmed to room temperature overnight. LC-MS showed that the reaction was complete, cooled to room temperature, and proceeded directly to the next step without treatment.

[0254] Step 2: Synthesis of 6-chloro-4-hydroxy-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0255]

[0256] Add triethylamine (35.182g, 0.3478mol, 2eq) and ethyl cyanoacetate (19.665g, 0.1738mol) to the above reaction solution, react at 150°C for 3h, LC-MS monitors that the reaction is complete, the reaction solution is cooled to room temperature, and Concentrate under reduced pressure, add water (200mL), adjus...

preparation example 2

[0260] Preparation Example 2: Intermediate 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile and 2,4-dichloro-6-ethane Synthesis of 1,7-naphthyridine-3-carbonitrile

[0261] Step 1: Synthesis of methyl 6-ethyl-3-(cyanoacetamido)-1-pyridine-4-carboxylate

[0262]

[0263] The intermediate 6-ethyl-3-amino-1-pyridine-4-carboxylic acid methyl ester (131g, 727.13mmol, 1.0eq) was dissolved in dichloromethane (1.31L), and cyanoacetic acid ( 74.22g, 872.56mmol, 1.2eq), EDCI (209.07g, 1090.70mmol, 1.5eq) was added in batches, and reacted at 25°C for 2 hours. LC-MS detected that the reaction was complete. Add H to the reaction solution 2 O (1.5L), liquid separation, organic phase with H 2 O (2×800mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the crude product was slurried with methyl tert-butyl ether (500mL) to obtain the product (165g, yield: 91.78%).

[0264] Step 2: Synthesis of 6-ethyl-4-hydroxy-2-oxo-1,2-dihydr...

Embodiment 1

[0271] Example 1: 6-isopropyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazepine Synthesis of Naphthalene-3-carbonitrile (Compound 91)

[0272] Step 1: Synthesis of 6-chloro-2H-pyrido[3,4-d][1,3]oxazine-2,4(1H)-dione

[0273]

[0274] Dissolve 5-amino-2-chloroisonicotinic acid (30g, 0.1738mol, 1.0eq) in N,N-dimethylformamide (300mL), and add N,N'-carbonyl di Imidazole (48g, 0.2955mol, 1.7eq), slowly warmed to room temperature overnight. LC-MS showed that the reaction was complete, cooled to room temperature, and proceeded directly to the next step without treatment.

[0275] Step 2: Synthesis of 6-chloro-4-hydroxy-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0276]

[0277] Add triethylamine (35.182g, 0.3478mol, 2eq) and ethyl cyanoacetate (19.665g, 0.1738mol) to the above reaction solution, react at 150°C for 3h, LC-MS monitors that the reaction is complete, the reaction solution is cooled to room temperature, and Concentrate under reduced ...

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Abstract

The invention belongs to the technical field of medicines, and relates to use of a phosphodiesterase inhibitor, in particular to use of a compound as shown in a general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof in preparation of medicines for treating heart failure diseases. X<1>, X<2>, X<3>, X<4>, R<1>, R<2>, L, m and ring A are as defined in thespecification. Experiments prove that the compound in the invention can improve the cardiac function of heart failure rats, reverse myocardial remodelling caused by heart failure of the rats and reduce fibrosis of infarction marginal areas, and has clinical application potential for treating heart failure.

Description

technical field [0001] The invention belongs to the field of medical technology, in particular to phosphodiesterase 9 (PDE9) inhibitor compounds represented by general formula (I) and pharmaceutically acceptable salts, isomers, and deuterated compounds thereof in the preparation and treatment of mammalian heart disease. Use in medicine for aging diseases. Background technique [0002] Heart failure (Heat Failure, referred to as heart failure) is a clinical syndrome characterized by abnormal cardiac structure and / or function, resulting in reduced cardiac output and / or increased intracardiac pressure at rest or under load, resulting in Pathophysiological states, such as dyspnea, ankle edema, and fatigue, may also be accompanied by signs, such as elevated jugular venous pressure, pulmonary rales, and peripheral edema. According to the measurement of left ventricular ejection fraction (LVEF), the level of natriuretic peptide, and abnormal cardiac function, it can be divided int...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/55A61K31/4545A61K31/438A61K31/4375A61K31/5377A61K31/496A61P9/04
CPCA61K31/55A61K31/4545A61K31/438A61K31/4375A61K31/5377A61K31/496A61P9/04A61K45/06A61K2300/00C07D471/04
Inventor 盛泽娟吴永谦
Owner TRANSTHERA SCIENCES (NANJING) INC
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