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Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases

a technology of prostaglandin d2 and multiheteroaryl compounds, which is applied in the direction of immunological disorders, drug compositions, biocides, etc., can solve the problems of many existing medicines suffering from side effects, headache, sleepiness, sedation, etc., and failing to address a broader range of symptoms that affect patient quality of li

Inactive Publication Date: 2013-03-28
CAYMAN CHEMICAL COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many existing medicines suffer from side effects such as headache, sleepiness, sedation, dyspepsia, hydrodipsia, pharyngitis, and oral candidiasis.
In addition, many of these individual therapies, although treating some symptoms, may fail to address a broader range of symptoms that affect patient quality of life.
Antihistamines, for example, treat some of the most unpleasant symptoms of allergy, but have little therapeutic benefit against nasal congestion.
Immunological challenge results in the release of prostaglandin D2 (PGD2), the primary allergic and inflammatory mediator, from inflammatory cells.

Method used

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  • Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
  • Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
  • Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 2-phenyl-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

[0255]

Step A: Preparation of 5-bromo-2-phenylpyrimidine

[0256]

[0257]A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 10.0 g, 35.1 mmol), benzene boronic acid (Alfa Aesar, 4.25 g, 35.1 mmol), tetrakis(triphenylphosphine)palladium (Strem, 0.405 g, 0.351 mmol), toluene (150 mL), and a 2 M aqueous sodium carbonate solution (35 mL) was stirred at 115° C. (degrees Celsius) under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was partitioned between chloroform (250 mL) and brine (200 mL). The phases were separated and the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an orange oil (9.1 g). The crude product was purified by flash silica column chromatography. Elution through a 500-g Analogix® flash silica cartridge with 100% hexanes afforded the title intermediate as a white solid (3.15 g, 38% yield). Rf 0.69 with 9:1...

example 2

Preparation of 2-phenyl-5-(2-phenyl-1H-imidazol-5-yl)pyridine

[0265]

[0266]The title compound was prepared by the method described in Example 1, except that commercially available 2-iodo-5-bromopyridine was used instead of 2-iodo-5-bromopyrimidine in Step A; Rf 0.53 with 95:5 v / v dichloromethane-methanol; melting point 206° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.15 (s, 2H), 8.26 (dd, 2H), 8.14-7.94 (m, 5H), 7.52-7.34 (m, 5H); MS (ESI+) m / z 298.1 (M+1); H-PGDS FPBA IC50: 0.48 μM; H-PGDS inhibitor EIA IC50: 0.097 μM.

example 3

Preparation of 5-(1-methyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine

[0267]

[0268]The title compound was prepared by the method described in Example 1, Steps A-C, except that iodomethane was used instead of benzyl bromide in Step B; Rf 0.36 with 1:1 v / v ethyl acetate-hexane; melting point 211° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.17 (s, 2H), 8.41 (m, 2H), 7.75 (dd, 2H), 7.6-7.27 (m, 7H); MS (ESI+) m / z 313.2 (M+1); H-PGDS FPBA IC50: 0.625 μM; H-PGDS inhibitor EIA IC50: 0.25 μM.

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Abstract

Multiheteroaryl compounds, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the prevention and treatment of prostaglandin D2 mediated diseases and conditions that may be modulated by the inhibition of hematopoietic prostaglandin D synthase (H-PGDS).

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present invention claims priority from U.S. Provisional Application No. 61 / 098,942 filed Sep. 22, 2008 entitled “Multiheterocyclic Compounds for the Treatment of Allergy, Inflammation, and Immune Disorders.”FIELD OF THE INVENTION[0002]Multiheteroaryl compounds, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the prevention and treatment of prostaglandin D2 mediated diseases and conditions that may be modulated by the inhibition of hematopoietic prostaglandin D synthase (H-PGDS).BACKGROUND OF THE INVENTION[0003]Allergic and inflammatory disorders such as allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), allergic conjunctivitis, and atopic dermatitis affect roughly one-fifth of the world population. Symptoms arising from antigenic challenge, including bronchoconstriction, bronchial hyperactivity, sneezing, nasal discharge, and nasal congestion, have been s...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/14A61K45/06A61K31/4439
CPCC07D401/04C07D401/14C07D403/04C07D403/14C07D417/14C07D413/04C07D417/04A61K31/4439A61K45/06C07D407/14A61K31/506A61K31/5377A61P1/04A61P1/14A61P11/00A61P11/02A61P11/06A61P11/08A61P17/00A61P17/02A61P19/00A61P19/02A61P25/04A61P27/14A61P29/00A61P37/04A61P37/08A61P43/00A61P9/00
Inventor ENDRES, GREGORY W.LEE, PIL HEUIOLSON, KIURK LANGKRAMER, JAMES BERNARDCISKE, FRED LAWRENCEBARRETT, STEPHEN DOUGLAS
Owner CAYMAN CHEMICAL COMPANY
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