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CaMKII inhibitors and uses thereof

一种-CF3、独立地的技术，应用在CaMKII抑制剂和其用途领域，能够解决无法提供心血管症状、充分控制等问题

Active Publication Date: 2016-04-20
ALLOSTEROS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Diet and exercise, even in combination with current drug therapies, often do not provide adequate control of cardiovascular symptoms

Method used

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  • CaMKII inhibitors and uses thereof
  • CaMKII inhibitors and uses thereof
  • CaMKII inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0204] An exemplary preparation procedure for compound 9(I-7) is as follows.

[0205]

[0206] Synthesis of 1-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazole (3):

[0207] A suspension of 1H-benzo-[1,2,3]triazole (1, 40 g, 335 mmol) and 2-bromopyridine (2, 105 g, 671 mmol) in toluene (160 mL) was heated at reflux for 18 hours, The reaction mixture was then poured into EtOAc (1 L). The resulting white solid precipitate was dissolved by adding aqueous KOH (10%, 85 mL). The phases were separated and the organic layer was washed with aqueous KOH (10%, 2 x 250 mL). in anhydrous Na 2 SO 4 The organic layer was dried, filtered and concentrated to dryness. from CH 3 OH recrystallization of the isolated solid afforded compound 3 in 62% yield. 1 HNMR (500MHz, CDCl 3 )δppm: 8.65(d,1H),8.62(d,1H),8.31(d,1H),8.11(d,1H),7.94(m,1H),7.59(t,1H),7.46(t,1H ), 7.33 (m, 1H); mass (m / z): 197.2 (M+H).

[0208] Synthesis of 9H-pyrido[2,3-b]indole (4):

[0209] To compound 3 (40 g, 203 mmol) w...

example 2

[0225] Synthesis of N1-(3-(9H-pyrido[2,3-b]indol-4-yl)phenyl)propane-1,3-diamine (9a, compound 1-8):

[0226]

[0227] Compound 8a and Compound 9a were prepared from Compound 6 and Compound 7a according to the protocol described for the preparation of Compound 8 and Compound 9.

[0228] Synthesis of tert-butyl 2-(3-(9H-pyrido[2,3-b]indol-4-yl)phenylamino)propylcarbamate (8a):

[0229] According to the procedure of Compound 8 (Example 1), using Compound 6 (100 mg, 0.405 mmol), Compound 7a (228 mg, 0.60 mmol), Pd (PPh 3 ) 4 (23mg, 0.025mmol) and equivalent molar equivalents of aqueous sodium carbonate and dioxane to prepare compound 8a. 80 mg (47% yield) of compound 8a were isolated. Mass (m / z): 417.4 (M+H). Purity, 98.2%, by HPLC method.

[0230] Synthesis of N1-(3-(9H-pyrido[2,3-b]indol-4-yl)phenyl)propane-1,2-diamine (9a, compound 1-8):

[0231] Compound 9a was prepared according to the procedure of compound 9 (Example 1) using compound 8a (80 mg, 0.19 mmol) and trif...

example 3

[0240] Synthesis of 3-(9H-pyrido[2,3-b]indol-4-yl)aniline (9b, compound 1-6):

[0241]

[0242] Compound 8b and Compound 9b were prepared from Compound 6 and Compound 7b according to the protocol described for the preparation of Compound 8 and Compound 9.

[0243] Conversion of compound 6 to compound 8b

[0244] According to the procedure of Compound 8 (Example 1), using Compound 6 (100 mg, 0.405 mmol), Compound 7b (194 mg, 0.60 mmol), Pd (PPh 3 ) 4 (23mg, 0.025mmol) and equivalent molar equivalents of aqueous sodium carbonate and dioxane to prepare compound 8b. 67 mg (46% yield) of compound 8b were isolated. Mass (m / z): 360.4 (M+H). Purity: 97.12%, HPLC method.

[0245] Conversion of compound 8b to compound 9b (1-6):

[0246] Compound 9b was prepared according to the procedure of compound 9 (Example 1) using compound 8b (67 mg, 0.18 mmol) and trifluoroacetic acid (106 mg, 0.90 mmol). 22 mg (45% yield) of compound 9b were isolated. 1 HNMR (500MHz, DMSO-d 6 )δppm: 1...

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Abstract

The present invention provides compounds useful as inhibitors of Ca2+ / calmodulindependent protein kinase (CaMKII), compositions thereof, and methods of using the same. Cardiovascular disease remains the number one cause of death in developed countries. Furthermore, incidence of cardiovascular disease has increased dramatically in developing countries. Although cardiovascular disease usually affects older adults, the antecedents of cardiovascular disease, notably atherosclerosis, begin in early life, making primary prevention efforts necessary from childhood.

Description

Background technique [0001] Cardiovascular disease remains the number one cause of death in developed countries. In addition, the incidence of cardiovascular disease is significantly higher in developing countries. Although cardiovascular disease generally affects older adults, the precursors to cardiovascular disease, especially atherosclerosis, begin in early life, necessitating primary prevention starting at an early age. Therefore, prevention of atherosclerosis has received increased attention by modifying risk factors such as healthy diet, exercise and avoidance of smoking. It is estimated that 1 in 3 people die from complications caused by cardiovascular disease. "Global Atlason Cardiovascular Disease Prevention and Control," World Health Organization, January 2012. To arrest this trend and address the metastatic epidemiology of the disease, measures to prevent or reverse cardiovascular disease must be implemented. [0002] Obesity and diabetes are often associated w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/437
CPCA61K31/437A61P3/00A61P3/10A61P9/00A61P9/04A61P9/06A61P9/08A61P9/10A61P11/06A61P19/00A61P19/02A61P25/00A61P25/04A61P25/36A61P27/02A61P29/00A61P35/00A61P37/08A61P39/02A61P43/00C07D471/04
Inventor D·E·利维H·舒尔曼B·帕拉谢利E·布拉德利S·K·南古诺里B·帕拉古德I·勒胡斯
Owner ALLOSTEROS THERAPEUTICS
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