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Heterocyclic compounds

A compound and drug technology, applied in drug combination, organic chemistry, cardiovascular system diseases, etc., can solve problems such as deterioration of heart function, insufficient interpretation of parathyroid hormone, and insufficient explanation of improvement in survival rate

Active Publication Date: 2019-12-17
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Regarding heart failure, although non-patent documents 1 and 2 describe that parathyroid hormone treatment can improve cardiac function, non-patent document 3 describes that cardiac function deteriorates due to parathyroid hormone treatment
Therefore, the relationship between parathyroid hormone therapy and improved cardiac function has not been fully elucidated
[0013] In addition, although it is described in Non-Patent Document 4 that Calhex231, which is a CaSR inhibitor, improves cardiac hypertrophy in the aortic artery ligation (TAC) model, it does not explain the effect on cardiac function reduction.
Non-Patent Document 5 shows that the administration of Calhex231 results in an increase in cardiac load, so its administration does not improve the decrease in cardiac function
Also, Non-Patent Document 6 describes that CaSR antagonists cause loss of cardioprotective effect in an ischemic preconditioning model
Thus, the relationship between improved cardiac function decline and improved survival due to CaSR inhibition has not been fully elucidated

Method used

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  • Heterocyclic compounds
  • Heterocyclic compounds
  • Heterocyclic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0627] (5R)-N-((2R)-1-(((2S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-ethylphenyl)-1-oxo Butan-2-yl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide

[0628] A) Methyl (2R)-2-amino-2-(4-ethylphenyl)butanoate

[0629] 2-amino-2-(4-ethylphenyl)butanoic acid methyl ester (44.9g) with SFC (CHIRALPAK IC (trade name), 30mmID * 250mmL), mobile phase: carbon dioxide / (methanol / diethylamine= 1000 / 3)=900 / 100 (v / v)) fractionation, and the fraction with shorter retention time was concentrated. Ethyl acetate and water were added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (18.2 g).

[0630] Optical purity: >99.9% enantiomeric excess

[0631] The shorter retention time under the following optical analysis conditions

[0632] Column: CHIRALPAK IC (trade name) ...

Embodiment 2

[0646] (5R)-N-(1-(((2S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-ethylphenyl)-1-oxobutan-2 -yl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide

[0647] A) 2-((((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl) Carbonyl)amino)-2-(4-ethylphenyl)butanoic acid methyl ester

[0648] (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (1.655g) was stirred at room temperature , a mixture of HATU (2.78g), DIPEA (0.946g) and DMF (15ml) for 5 minutes. Then a mixture of methyl 2-amino-2-(4-ethylphenyl)butanoate (1.35 g) and DMF (5 ml) was added, and the mixture was stirred at 80° C. overnight. Water was added to the mixture, and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the tit...

Embodiment 3

[0656] (5R)-N-((2S)-1-(((2S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-ethylphenyl)-1-oxo Butan-2-yl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide

[0657] A) 2-(4-ethylphenyl)-2-((((5R)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a]pyridin-3-yl)carbonyl)amino)butanoic acid methyl ester

[0658] (5R)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (516mg ), HATU (825 mg), a mixture of DIPEA (280 mg) and DMA (5 ml) for 5 minutes. Then, a mixture of methyl 2-amino-2-(4-ethylphenyl)butanoate (400 mg) and DMA (2 ml) was added, and the resulting mixture was stirred at 80° C. for 2 days. Water was added to the mixture, and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title com...

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Abstract

The present invention provides a compound or a salt thereof that has calcium-sensitive receptor antagonistic activity and is expected to be useful as a preventive or therapeutic agent for heart failure, pulmonary hypertension, and the like. The compound represented by formula (I) or a salt thereof has calcium-sensitive receptor antagonistic activity, and is expected to be useful as a preventive or therapeutic agent for heart failure, pulmonary hypertension, and the like. Each symbol in the formula is as described in the description.

Description

technical field [0001] The present invention relates to a heterocyclic compound having a calcium-sensitive receptor antagonistic action and useful as a preventive or therapeutic agent for heart failure, pulmonary hypertension, and the like. Background technique [0002] Heart failure refers to a disease characterized by a disease state in which cardiac output is reduced due to insufficiency of cardiomyocytes, and a disease state in which the cardiac output maintenance mechanism places a burden on the body. The function of cardiomyocytes is contraction and relaxation, and for contraction and relaxation, Ca 2+ ions are necessary. The contraction of cardiomyocytes is produced by the propagation of the action potential to the transverse tubule, the stage of depolarization of the transverse tubule membrane, Ca 2+ Potential-dependent L-type Ca of ions from transverse tubules 2+ The stage of channel influx into the cell, and, the influx of Ca 2+ Ca ion bound to sarcoplasmic ret...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P9/04A61P9/12A61P11/00
CPCA61K31/519A61P9/04A61P9/12A61P11/00C07D487/04A61K31/4184A61K2300/00A61K9/2013A61K9/2018A61K9/2054A61K9/2059A61K9/4858A61K9/4866A61K47/38
Inventor 北村周治池田善一生驹实渡部浩史广濑英喜汤川猛史森本幸惠西泽直城浅见泰司
Owner TAKEDA PHARMA CO LTD
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