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Biaryl pde4 inhibitors for treating inflammatory, cardiovascular and CNS disorders

a technology of pde4 inhibitors and biaryl pde4, which is applied in the direction of respiratory disorders, cardiovascular disorders, drug compositions, etc., can solve the problems of low therapeutic ratio, severe limits on the dose that can be given, and no drug has yet reached the market, so as to improve cognition and treat or prevent a disease.

Inactive Publication Date: 2009-12-31
DECODE GENETICS EHF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0002]The present invention relates to a chemical genus of biaryl inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment and prevention of stroke, myocardial infarct, cardiovascular inflammatory diseases and central nervous system disorders.
[0012]These and other embodiments of the present invention will become apparent in conjunction with the description and claims that follow.

Problems solved by technology

Despite initial optimism, none have yet reached the market.
. . has been discontinued due to lack of efficacy.
A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given.
Many of the PDE4 inhibitors of the prior art have not reached the market because of the adverse side effect of emesis (Giembycz 2005.

Method used

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  • Biaryl pde4 inhibitors for treating inflammatory, cardiovascular and CNS disorders
  • Biaryl pde4 inhibitors for treating inflammatory, cardiovascular and CNS disorders
  • Biaryl pde4 inhibitors for treating inflammatory, cardiovascular and CNS disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of P-065

[0111]

[0112]Synthesis of 2-bromo-6-methyl-pyridin-3-ol (I-2, X═Br, Y═CH3): To 6-methyl-pyridin-3-ol (I-1, Y═CH3, 5.0 g, 45.82 mmol) in pyridine (15 mL) was added bromine (3.66 g, 22.91 mmol). The reaction was stirred at room temperature under N2 for 20 h. The crude reaction mixture was poured on to crushed ice-water (300 mL), stirred for 3 h. The mixture was extracted with ethyl acetate (5×100 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 6.3 g (73%) of 2-bromo-6-methyl-pyridin-3-ol (I-2, X═Br, Y═CH3) as light yellow solid.

[0113]Synthesis of 2-bromo-3-methoxy-6-methyl-pyridine (I-3, X═Br, Y═R1═CH3): To the 2-bromo-6-methyl-pyridin-3-ol (I-2) 6.0 g, 31.91 mmol) and K2CO3 (8.82 g, 63.82 mmol) in acetone (100 mL) was added MeI (6.79 g, 479.87 mmol). The reaction was stirred at 45° C. under N2 for 20 h. The reaction was cooled to room temperature, filtered and concentrated. The residue was purifi...

example 2

Preparation of P-176

[0118]

[0119]Synthesis of 2-bromo-3-nitro-phenol (I-8, X═Br): (Prepared by a modification of reported procedure, J. Org. Chem. 1988, 53, pp 1170-1176). To 2-amino-3-nitro-phenol (24.9 mmol, 1.0 eq.) in 24 mL of water and 12 mL of 1,4-dioxane at reflux, was added 13 mL of HBr (48% aq.) over 10 minutes. The resulting solution was refluxed for an additional 15 minutes, and cooled 0-5° C. A solution of sodium nitrite (24.4 mmol, 0.98 eq.) in 20 mL of water was added over 10 minutes, and stirred for 15 minutes. The reaction mixture was then heated to 60° C. for 15 minutes, and allowed to cool naturally to room temperature, and stirred for 16 hours. The reaction mixture was then extracted with two portions of diethyl ether, and the combined ethereal layers washed with brine, dried over magnesium sulfate, filtered through a layer of celite and concentrated. The residue was diluted with dichloromethane (with ˜0.1% MeOH), and purified via silica gel plug filtration with di...

example 3

Preparation of P-404

[0125]

[0126]Synthesis of 3′-chloro-6-fluoro-2-methoxy-biphenyl (I-16, R1═CH3, R2═Cl, Y═F): To 2-bromo-3-fluoroanisole (1.0 g, 4.88 mmol), 3-chlorophenylboronic acid (0.91 g, 5.88 mmol), PPh3 (0.64 g, 2.44 mmol), K2CO3 (0.27 g, 1.95 mmol) and Pd(OAc)2 (0.13 g, 0.58 mmol) was added dioxane (8 mL), and EtOH—H2O (1:1, 4 mL). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was heated at 180° C. using microwave oven (Biotage Intiator II) for 20 min. The reaction was cooled to room temperature, combined with another 0.5 g scale run, concentrated. The residue was purified by silica gel column chromatography using 1:1 dichloromethane-hexanes to afford 1.33 g (77%) 3′-chloro-6-fluoro-2-methoxy-biphenyl (I-16, R1═CH3, R2═Cl, Y═F) as a viscous liquid.

[0127]Synthesis of N-[4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide (I-19, R1═CH3, R2═Cl, Y═F, R3=4-acetylaminophenyl): To a stirred suspension of 4-acetylaminobenzoic acid (Aldri...

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Abstract

The present invention relates to a genus of biaryl compounds containing at least one further ring. The compounds are PDE4 inhibitors useful for the treatment and prevention of stroke, myocardial infarct and cardiovascular inflammatory diseases and disorders. The compounds have general formula I:A particular embodiment is

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. provisional application 60 / 989,551, filed Nov. 21, 2007, the entire disclosure of which is incorporated herein by reference. The application is related to, but does not claim priority from, four other US non-provisional applications filed of even date herewith and having Jasbir Singh as a common inventor. The applications are titled “BIARYL PDE4 INHIBITORS FOR TREATING PULMONARY AND CARDIOVASCULAR DISORDERS”, “SUBSTITUTED BENZOAZOLE PDE4 INHIBITORS FOR TREATING INFLAMMATORY, CARDIOVASCULAR AND CNS DISORDERS”, “SUBSTITUTED BENZOAZOLE PDE4 INHIBITORS FOR TREATING PULMONARY AND CARDIOVASCULAR DISORDERS” and “4-(OR 5-) SUBSTITUTED CATECHOL DERIVATIVES”. Their disclosures are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to a chemical genus of biaryl inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment and prevention of stroke, myocardial infar...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/44C07D401/04C07D231/12C07D237/14C07D277/38C07D285/135C07D213/72C07D403/10C07D413/06C07D401/06A61K31/4427A61K31/5377A61K31/4439A61K31/4412A61K31/4164A61K31/4245A61K31/445A61K31/437A61K31/415A61K31/506A61K31/54A61K31/122A61K31/435A61P9/00A61P35/00A61P11/00
CPCC07B2200/05C07C65/40C07C69/94C07C275/32C07C275/62C07C305/24C07C307/10C07D207/16C07D213/38C07D213/40C07D213/64C07D213/74C07D213/75C07D213/76C07D213/79C07D213/81C07D213/84C07D213/89C07D231/12C07D233/90C07D239/42C07D257/04C07D275/06C07D285/12C07D285/135C07D401/04C07D401/06C07D403/04C07D471/04C07D473/18C07D473/40C07D205/04C07D213/65C07D213/73C07D277/42A61P1/00A61P11/00A61P11/06A61P13/10A61P19/00A61P19/08A61P19/10A61P25/00A61P25/14A61P25/22A61P25/24A61P25/28A61P29/00A61P35/00A61P43/00A61P9/00A61P9/10A61K31/4418C07D213/62A61K31/136A61K31/397A61K31/41A61K31/426A61K31/437A61K31/44A61K31/4427A61K31/5377A61K45/06C07C217/84
Inventor SINGH, JASBIRGURNEY, MARK E.BURGIN, ALEXSANDANAYAKA, VINCENTKISELYOV, ALEXANDERMOTTA, ADALIESCHILTZ, GARYHATEGAN, GEORGETAHAGEN, TIMOTHY
Owner DECODE GENETICS EHF
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