Substituted pyridine and pyrazine compounds as pde4 inhibitors

A technology for compounds and chemical entities, which can be used in in vivo radioactive agents, anti-inflammatory agents, drug combinations, etc., to solve problems such as limited usefulness and tolerance

Active Publication Date: 2015-12-09
다트뉴로사이언스엘엘씨
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, PDE4 inhibitors are often associated with various side effects, most notably emesis, which often limit the usefulness and tolerability of the inhibitors (eg, Giembycz, Curr. Opin. Pharm. 2005, 5, 238-244 )

Method used

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  • Substituted pyridine and pyrazine compounds as pde4 inhibitors
  • Substituted pyridine and pyrazine compounds as pde4 inhibitors
  • Substituted pyridine and pyrazine compounds as pde4 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0708] Example 1. 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile.

[0709]

[0710] Combine 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55mg, 0.54mmol), EtOH (2.45mL), Benzene (7.00mL), Pd(PPh 3 ) 4 (56.63mg, 0.05mmol) and NaHCO 3 Aqueous solution (1.38 mL, 1.15 mol / L, 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125°C under microwave conditions for 15 minutes. Use a pipette to remove water from the reaction, and via The crude reaction mixture was filtered and washed with EtOAc (3 x 5 mL). dry (Na 2 SO 4 ) combined organic layers, and the solvent was removed under reduced pressure. Purification (FCC, SiO 2 , 0-30%, EtOAc / hexanes) provided the title compound (100 mg, 53%) as a white solid. 1 HNMR (400MHz, CD 3 OD)δ8.94(s,2H),8.17(s,1H),7.95-7.90(m,1H),7.85(t,J=1.8...

Embodiment 2

[0711] Example 2. 2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine.

[0712]

[0713] To 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (intermediate 2,100mg, 0.321mmol), (2-chloropyrimidin-5-yl)boronic acid (76mg, 0.481 mmol) in ACN (3.2 mL) was added with NaHCO 3 (417mg, 1.282mmol) and PdCI 2(dppf)-DCM (23 mg, 0.032 mmol). The reaction was heated under microwave conditions at 120°C for 12 minutes. Water was removed from the reaction using a pipette, and via The crude reaction mixture was filtered and washed with EtOAc. dry (Na 2 SO 4 ) combined organics, filtered and concentrated on silica. Purification (FCC, SiO 2 , 30%-70% EtOAc / hexanes) provided the title compound (61 mg, 55%). 1 HNMR (400MHz, DMSO-d 6 )δ8.34(s, 2H), 8.11(d, J=2.0Hz, 1H), 7.70(d, J=2.0Hz, 1H), 7.58(t, J=1.8Hz, 1H), 7.53-7.36( m,3H), 3.83(s2H), 3.73(s,3H). [M+H] = 346.11.

Embodiment 3

[0714] Example 3. {2-[(5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethyl amine.

[0715]

[0716] To 2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine (Example 2, 50.00mg, 0.14mmol) in ACN (1.44mL ) was added N1,N1-dimethylethane-1,2-diamine (0.03 mL, 0.29 mmol) and DIPEA (77.13 μL, 0.43 mmol). The reaction mixture was heated at 180°C for 15 minutes. EtOAc (5 mL) was added to the reaction mixture, and the reaction mixture was extracted with water (3x). dry (Na 2 SO 4 ) combined organic layers, and the solvent was removed under reduced pressure. Purification (FCC, SiO 2 , 0-15% MeOH / DCM) provided the title compound (15.6 mg, 28%). 1 HNMR (400MHz, DMSO-d 6 )δ8.21(s,2H),8.09(s,1H),7.67(brs,2H),7.58(s,1H),7.51-7.34(m,2H),6.79(brs,1H),3.84(s ,3H), 3.72(s,2H), 2.42-2.37(m,4H), 2.17(s,6H). [M+H] = 398.20.

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Abstract

The invention provides a chemical entity of Formula (I) wherein R1, R2, R3, R4, Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.

Description

[0001] Incorporate by reference any priority application [0002] Any and all priority claims identified in the Application Data Sheet, and any amendments thereto, are hereby incorporated by reference pursuant to 37 CFR 1.57. For example, this application claims priority and benefit to US Application No. 61 / 786,288, filed March 14, 2013, the disclosure of which is incorporated herein by reference in its entirety. field of invention [0003] The present invention relates to certain substituted pyridine and substituted pyrazine compounds as PDE4 enzyme inhibitors; derivatives of such compounds; compositions of such compounds; processes for their preparation; and their use in various methods, including Detection and imaging technologies; enhance neuronal plasticity; treat neurological disorders, including psychiatric disorders, neurodegenerative diseases, cerebrovascular disorders, cognitive impairments, and movement disorders; provide neuroprotection; enhance the efficiency of c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K31/506A61K31/505A61P25/22A61P25/00
CPCC07D241/18C07D213/64C07D213/73C07D213/74C07D213/81C07D401/06C07D401/14C07D403/06C07D405/12C07D405/14C07D409/06C07D409/14C07D413/06C07D417/06A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P21/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/32A61P25/34A61P25/36A61P29/00A61P35/00A61P37/08A61P43/00A61P7/00A61P9/00A61P9/10A61P9/12A61K31/337A61K31/4178A61K31/4196A61K31/422A61K31/427A61K31/4418A61K31/444A61K31/455A61K31/4965A61K31/497A61K31/501A61K31/506A61K51/0459C07D239/34
Inventor 凡卡泰安·博鲁詹姆士·布莱特恩布什尔艾伦·卡普兰罗伯特·莱穆斯安德鲁·林德斯特洛姆特洛伊·维克斯马克·E·威尔逊詹姆士·扎普夫迈克尔·I·威豪斯
Owner 다트뉴로사이언스엘엘씨
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