Benzoimidazole compound capable of inhibiting prostaglandin D synthetase

A technology of benzimidazole and compound is applied in the field of medicine in which novel benzimidazole compound or its salt is an active ingredient, and can solve the problems of susceptibility to infection, insufficient drug effect, and no

Inactive Publication Date: 2008-07-16
TAIHO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these antiallergic agents are not easy to use due to their insufficient drug efficacy, central side effects such as drowsiness and sedation symptoms, gastrointestinal symptoms such as dysentery, etc., or side effects such as immunosuppression.
In addition, although steroid drugs are agents that can be used in the treatment of not only allergic diseases but also many inflammatory diseases due to their strong anti-inflammatory effects, however, due to their susceptibility to infection, effects on bones, or growth disorders Side effects such as side effects, or rebound phenomenon after discontinuation, etc., so it is not an easy-to-use drug

Method used

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  • Benzoimidazole compound capable of inhibiting prostaglandin D synthetase
  • Benzoimidazole compound capable of inhibiting prostaglandin D synthetase
  • Benzoimidazole compound capable of inhibiting prostaglandin D synthetase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0363] 5-Benzoyl-2-(2,4-dimethylfuran-3-yl)-benzimidazole (1)

[0364]

[0365] To a solution of 3,4-diaminobenzophenone (43mg, 0.19mmol) in methanol (3ml) was added 2,4-dimethylaminofuran-3-carboxylic acid (30mg, 0.21mmol) and 4-(4, 6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (65 mg, 0.23 mmol), stirred overnight, and distilled off the solvent under reduced pressure. Chloroform / methanol (7:1) and saturated aqueous sodium carbonate were added to the residue and stirred for 30 minutes, then extracted with chloroform / methanol at the same ratio, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

[0366] The residue obtained by distilling off the solvent under reduced pressure was purified by medium-pressure silica gel flash column chromatography (chloroform:methanol=99:1). The resulting condensate was dissolved in acetic acid (4 ml), stirred overnight at 80° C., then left to cool to room temperature, and the solv...

Embodiment 2

[0370] 4-(5-Benzoylbenzimidazol-2-yl)-3,5-dimethylfuran-2-carboxamide (2)

[0371] Example 2(1)

[0372] 3,5-Dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (raw material for 2)

[0373]

[0374] Dissolve ethyl 2,4-dimethyl-5-formylfuran-3-carboxylate (1.78g, 9.1mmol) known in the literature in a mixture of acetic acid (32ml) and water (8ml), add Sulfamic acid (1.19g, 12.2mmol), the mixture was cooled to 0°C with an ice bath. Sodium chlorite was added and stirred for 2 hours, then water was added to the system, and the precipitated solid was filtered to obtain 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (1.01g, 52%) , as a white solid.

[0375] 1 H-NMR (CDCl 3 ): δ (ppm) 1.38 (t, J = 7.3Hz, 3H), 2.56 (s, 3H), 2.64 (s, 3H), 4.33 (q, J = 7.3Hz, 2H).

[0376] Example 2(2)

[0377] 3,5-Dimethyl-4-ethoxycarbonylfuran-2-carboxamide (raw material for 2)

[0378]

[0379] To the 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (250mg, 1.18mmol) solution obt...

Embodiment 3

[0390] (4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethyl-2-furylcarbonyl)pyrrolidine (3)

[0391] Example 3(1)

[0392] (3,5-Dimethyl-4-ethoxycarbonyl-2-furylcarbonyl)pyrrolidine (raw material for 3)

[0393]

[0394] According to Example 2(2), by using pyrrolidine instead of 28% ammonia water, (3,5-dimethyl-4-ethoxycarbonyl-2-furylcarbonyl)pyrrolidine (89%) was obtained as a white solid .

[0395] 1 H-NMR (CDCl 3 ): δ (ppm) 1.37 (t, J = 7.3Hz, 3H), 1.92 (br, 4H), 2.49 (s, 3H), 2.57 (s, 3H), 3.62-3.73 (m, 4H), 4.31 ( q, J = 7.3 Hz, 2H).

[0396] Example 3(2)

[0397] (4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethyl-2-furylcarbonyl)pyrrolidine (3)

[0398]

[0399] According to Example 2(3), by using (3,5-dimethyl-4-ethoxycarbonyl-2-furylcarbonyl)pyrrolidine instead of 3,5-dimethyl-4-ethoxycarbonylfuran-2 -carboxamide to give (4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethyl-2-furylcarbonyl)pyrrolidine (59%) as a pale yellow solid.

[0400] Melting point: 112-114°C

[0401] ...

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Abstract

A benzoimidazole compound represented by the general formula (I) or a salt thereof: (I) wherein X<1> represents an oxygen atom or a carbonyl group; and R<1> represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents, provided that a compound represented by the general formula (I) wherein the substituent is a phosphoric acid group or a phosphate ester group is excluded. The benzoimidazole compound or salt thereof has an excellent prostaglandin D synthetase inhibitory activity, and is useful as a prophylactic and / or therapeutic agent for a disease associated with prostaglandin D2 or a metabolite thereof, such as an allergic disease or an inflammatory disease or as an inhibitor for the exacerbation of Alzheimer disease or cerebral damage.

Description

technical field [0001] The present invention relates to medicines with benzimidazole compounds or their salts as active ingredients, in particular to medicines for the prevention and / or treatment of allergic diseases, inflammatory diseases, Alzheimer's A medicine in which a novel benzimidazole compound or a salt thereof, which is useful as an inhibitor of aggravation of disease or brain injury, is an active ingredient. Background technique [0002] A series of lipid mediators collectively known as eicosanoids, such as prostaglandins and leukotrienes, are synthesized through the arachidonic acid cascade beginning with arachidonic acid cleaved from membrane phospholipids in response to various stimuli . In particular, prostaglandins are arachidonic acid metabolites synthesized in the arachidonic acid cascade using prostaglandin H2 generated by cyclooxygenase as an intermediate. It is known that prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2, thrombox...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P29/00A61K31/4184A61P37/08A61K31/422A61P43/00A61K31/428C07D403/04A61K31/4439C07D403/14A61K31/454C07D405/04A61K31/496C07D405/14A61K31/501C07D413/14A61K31/5377C07D417/14A61P25/28
Inventor 里出良博田中由起山根敬子土河三千纪
Owner TAIHO PHARMA CO LTD
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