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Substituted pyridine and pyrazine compounds as pde4 inhibitors

a technology of pyridine and pyrazine, which is applied in the direction of drug compositions, immune disorders, extracellular fluid disorders, etc., can solve the problems of general association of numerous side effects, etc., and achieves limited usefulness and tolerability, greater specificity, and higher potency

Inactive Publication Date: 2016-01-14
DART NEUROSCIENCE CAYMAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a group of chemicals that can be used for various purposes such as studying how the body breaks down certain chemicals, detecting and imaging techniques, and treating different disorders. These chemicals can also be used to enhance brain function and protect nerve cells. They can also improve training for animals and humans.

Problems solved by technology

However, PDE4 inhibitors have generally been associated with numerous side effects—most notably emesis—that have typically limited their usefulness and tolerability (e.g., 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

example 1

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

[0526]

[0527]Into a 5 mL microwave vial was combined 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 (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), Pd(PPh3)4 (56.63 mg, 0.05 mmol), and aq. NaHCO3 (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. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-30%, EtOAc / hexanes) afforded the title compound as a white solid (100 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=...

example 2

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

[0528]

[0529]To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 2, 100 mg, 0.321 mmol), (2-chloropyrimidin-5-yl)boronic acid (76 mg, 0.481 mmol) in ACN (3.2 mL) was added NaHCO3 (417 mg, 1.282 mmol) and PdCl2(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 with a pipette, and the crude reaction mix was filtered thru CELITE®, and washed with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated onto silica. Purification (FCC, SiO2, 30-70% EtOAc / hexanes) afforded the title compound (61 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 3.83 (s 2H), 3.73 (s, 3H). [M+H]=346.11.

example 3

{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine

[0530]

[0531]To a solution of 2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine (Example 2, 50.00 mg, 0.14 mmol) in ACN (1.44 mL), 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 (3×). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-15% MeOH / DCM) afforded the title compound (15.6 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 8.09 (s, 1H), 7.67 (br s, 2H), 7.58 (s, 1H), 7.51-7.34 (m, 2H), 6.79 (br s, 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), 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

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS[0001]Any and all priority claims identified in the Application Data Sheet, or any correction thereto, are hereby incorporated by reference under 37 CFR 1.57. For example, this application claims priority to and the benefit of U.S. Application No. 61 / 786,288, filed on Mar. 14, 2013, the disclosure of which is incorporated herein in its entirety by reference.FIELD OF THE INVENTION[0002]The present invention relates to certain substituted pyridine and pyrazine compounds as inhibitors of PDE4 enzymes; derivatives of such compounds; compositions of such compounds; methods of making them; and their use in various methods, including detection and imaging techniques; enhancing neuronal plasticity; treating neurological disorders, including psychiatric, neurodegenerative, cerebrovascular, cognitive and motor disorders; providing neuroprotection; enhancing the efficiency of cognitive and motor training; facilitating neurorecovery and neu...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D401/06C07D239/34C07D213/64C07D405/12C07D417/06A61K51/04C07D401/14
CPCC07D403/06A61K51/0459C07D401/06C07D401/14C07D213/64C07D405/12C07D417/06C07D239/34C07D213/73C07D213/74C07D213/81C07D405/14C07D413/06C07D409/14C07D241/18A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P21/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/32A61P25/34A61P25/36A61P29/00A61P35/00A61P37/08A61P43/00A61P7/00A61P9/00A61P9/10A61P9/12A61K31/337A61K31/4178A61K31/4196A61K31/422A61K31/427A61K31/4418A61K31/444A61K31/455A61K31/4965A61K31/497A61K31/501A61K31/506C07D409/06
Inventor BOLLU, VENKATAIAHBREITENBUCHER, JAMESKAPLAN, ALANLEMUS, ROBERTLINDSTROM, ANDREWVICKERS, TROYWEINHOUSE, MICHAELWILSON, MARK EDWARDZAPF, JAMES
Owner DART NEUROSCIENCE CAYMAN LTD
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