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Benzothiophenecarboxamide derivatives and PGD2 antagonists comprising them

A technology of antagonists and compounds, which is applied in the field of benzothiophene amide derivatives and their intermediates, can solve the problems such as the great influence on prostaglandin synthesis

Inactive Publication Date: 2000-01-05
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But PGD 2 Biosynthesis inhibitors may have a great influence on prostaglandin synthesis in other parts of the body, so it is expected to develop PGD 2 Receptor-specific antagonists (blockers)

Method used

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  • Benzothiophenecarboxamide derivatives and PGD2 antagonists comprising them
  • Benzothiophenecarboxamide derivatives and PGD2 antagonists comprising them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0069] Preparation of (1R, 2S, 3S, 5S)-2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol (IVA-b-1) and (IR, 2R , 3S, 5S)-2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol (IVA-c-1)

[0070] According to the literature method, compound (6) (Chem.Pharm.Bull.Vol.37, No. 6 1524-1533 (1989)) can be reduced with sodium, and compound (IVA-a-1) can be removed by filtration as benzoate. The mother liquor (79 g) was suspended in 150 ml of ethyl acetate, 260 ml of 1N HCl was added and stirred. The aqueous phase separated from the two phases was basified with 65 ml of 4N NaOH solution and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily residue (6.7 g out of 30 g) was dissolved in 40 ml of 90% methanol and washed with 500 ml of ion exchange resin-Amberlite CG-50 (NH 4 + ) type I absorption and was eluted with a gradient of 2.2 liters of water and 2.2 lit...

Embodiment 1

[0074] Preparation of (5Z)-7-{(1R,2R,3S,5S)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylamino)-6,6-dimethylbicyclo[3.1.1 Sodium ]hept-3-yl}-5-heptenoate (IVA-a-6) (step 1)

[0075] To a solution of 1.450 mg (5.2 mmol) of compound (IIA-a-1) (see Japanese Patent Publication (Kokoku) No. 23170 / 1994) in 25 ml of tetrahydrofuran, 2.6 ml (18.7 mmol) of triethylamine and 1.454 mg (1.1 mmol) of ) 5-acetoxybenzo[b]thiophene-3-carbonyl chloride (5) (prepared by Reference Example 2) was stirred for 1.5 hours, and the mixture was diluted with water and extracted with toluene. The organic phase was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (eluent toluene:ethyl acetate=9:1) to obtain 2.481 mg of compound IA-a-10). Yield 96.1%. [α] D 23 =+48.0° (c=1.01%, CH 3 OH) elemental analysis (C 28 h 35 NO 5 S·0.1H 2 O) Theoretical (%): C, 67.34; H, 7.10; N, 2.80...

Embodiment 2

[0078] Preparation of (5Z)-7-[(1R,2S,3R,5S)-2-(5-Hydroxybenzo[b]thiophen-3-yl-carbonylamino)-6,6-dimethyl-bicyclo[3.1 .1]hept-3-yl]-5-heptenoic acid (IA-b-1) (step 1)

[0079] To 916mg (3mmol) (1R, 2S, 3S, 5S)-2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol benzoate in 3ml of water 3.1 ml of 1N HCl was added to the suspension. The precipitated benzoic acid was extracted with ethyl acetate. The aqueous phase was adjusted to pH 10.5 with 700 mg of anhydrous sodium carbonate, and a solution of 1.06 g (3 mmol) of 5-benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (3) in 6 ml of tetrahydrofuran was added dropwise thereto. After 1.5 hours, the mixture was diluted with water and extracted with toluene. The organic phase was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue (1.5 g) was subjected to silica gel chromatography (eluent: hexane: ethyl acetate = 1:1) to obtain 1.497 g of compound (VA-...

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Abstract

The present invention provides a compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof having PGD2-antagonistic activities, inhibitory activities against infiltration of eosinophils, and being useful as a drug for treating diseases, such as systemic mastocytosis and disorder of systemic mast cell activation, as well as tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, ischemic reperfusion injury, inflammation and atopic dermatitis, which is shown by the following formula (I).

Description

field of invention [0001] The present invention relates to benzothiophene amide derivatives and intermediates thereof, as well as pharmaceutical compositions containing them and PGD containing them 2 (prostaglandin D 2 ) antagonists and medications for nasal congestion. Background of the invention [0002] It is reported that some bicyclic amide derivatives similar to the compounds of the present invention can be used as thromboxane A 2 Antagonists (see Japanese Patent Laid-Open (Kokoku) No. 53295 / 1991). But the patent only shows that this type of compound can be used as Thromboxane A 2 (TXA 2 ) antagonists without introducing such compounds as found in the present invention as PGD 2 Use of antagonists. On the other hand, documents such as Japanese Patent Publication (Kokoku) No.79060 / 1993, No.23170 / 1994 and Chem.Pharm.Bull.Vol.37, No.6, 1524-1533 (1989) have also reported bicyclic amides Derivatives, which are intermediates of bicyclic sulfamoamide derivatives. Howe...

Claims

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Application Information

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IPC IPC(8): A61K31/381A61P9/00A61P11/00A61P29/00A61P37/08A61P43/00C07D333/38C07D333/68C07D333/70
CPCC07D333/68C07D333/38A61P11/00A61P11/02A61P11/06A61P27/14A61P29/00A61P37/00A61P37/08A61P43/00A61P9/00A61P9/02
Inventor 本摩恒利平松义春有村昭典
Owner SHIONOGI & CO LTD
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