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Bezothiazol derivatives as beta2 adrenoreceptor agonists

A benzothiazole and phenyl technology, applied in the field of diamine derivatives, can solve the problems of hindering rescue treatment and maintenance treatment, and slow onset of effect

Inactive Publication Date: 2009-05-27
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Salmeterol is also slow-acting, which precludes its use as rescue and maintenance therapy

Method used

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  • Bezothiazol derivatives as beta2 adrenoreceptor agonists
  • Bezothiazol derivatives as beta2 adrenoreceptor agonists
  • Bezothiazol derivatives as beta2 adrenoreceptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0401] 7-{2-[2-(3-{[2-(2,6-Dichloro-phenyl)-ethylamino]-methyl}-phenyl)-ethylamino]-1(R)- Hydroxy-ethyl}-4-hydroxy-3H-benzothiazol-2-one bis(trifluoroacetate)

[0402]

[0403] a) (3-Formyl-phenyl)-ethyl acetate

[0404] N-Bromosuccinimide (1.78 g) and 2,2'-azobis(2-methylpropionitrile) (16 mg) were added to ethyl 3-methylphenylacetate (1.76 mL) in chloroform (18 mL) solution, heated to reflux for 3 hours. After cooling the mixture was diluted with chloroform (40 mL), washed sequentially with saturated aqueous sodium bicarbonate (2 x 50 mL), brine (50 mL), dried (Na2SO4) and concentrated. The residue was dissolved in nitrogen degassed dimethyl sulfoxide (50 mL) and sodium bicarbonate (13.5 g) was added. The mixture was heated at 100 °C for 30 min under nitrogen atmosphere. The reaction mixture was cooled in an ice bath and poured into brine (300 mL). The aqueous phase was extracted with diethyl ether (3 x 300 mL). The combined organic phases were dried (sodium sulfate...

Embodiment 2

[0415] 7-[2-(2-{3-[(2,2-Diphenyl-ethylamino)-methyl]-phenyl}-ethylamino)-1(R)-hydroxy-ethyl]- 4-Hydroxy-3H-benzothiazol-2-one bis(trifluoroacetate)

[0416]

[0417] a) (3-{[tert-butoxycarbonyl-(2,2-diphenyl-ethyl)-amino]-methyl}-phenyl)-acetic acid

[0418] Prepared from (3-formyl-phenyl)-ethyl acetate (example 1, step a, 290 mg) and 2,2-diphenylethylamine (280 mg) using the method of example 1 (step b) , to give the subtitle compound as an oil (314mg).

[0419] m / z 444(M-H) - (APCI)

[0420] b) 2-{3-[(2,2-diphenyl-ethylamino)-methyl]-phenyl}-N-[2(R)-hydroxyl-2-(4-hydroxyl-2-oxo Generation-2,3-dihydro-benzothiazol-7-yl)-ethyl]-acetamide

[0421] Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (160 mg) to 7-(2-amino-1(R)-hydroxy-ethyl)-4-hydroxy -3H-Benzothiazol-2-one hydrochloride (190mg), (3-{[tert-butoxycarbonyl-(2,2-diphenyl-ethyl)-amino]-methyl}-phenyl )-acetic acid (314 mg) and 4-dimethylaminopyridine (210 mg) in dimethylformamide (10 mL) and st...

Embodiment 3

[0429] 7-[2-(2-{3-[(2-Chloro-benzylamino)-methyl]-phenyl}-ethylamino)-1(R)-hydroxy-ethyl]-4-hydroxy- 3H-Benzothiazol-2-one bis(trifluoroacetate)

[0430]

[0431] a) (2-chlorobenzyl)-[3-(2-hydroxy-ethyl)-benzyl]-tert-butyl carbamate

[0432] 2-Chlorobenzylamine (0.28 g) was added to a solution of ethyl (3-formyl-phenyl)-acetate (Example 1, step a) (0.38 g) and acetic acid (114 μL) in ethanol (10 mL). After 1 hour, sodium triacetoxyborohydride (1.27 g) was added and the reaction mixture was stirred for 18 hours. After adding a few drops of 0.880 aqueous ammonia, the reaction mixture was concentrated. The residue was dissolved in ethanol (5 mL) and loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with ethanol (3 x 20 mL) and eluted with ethanol / 0.880 ammonia solution [4:1] (2 x 15 mL). The combined eluted fractions were evaporated. The residue was dissolved in dimethylformamide (5 mL), and a solution of di-tert-butyl dicarbonate (0.48 g) in...

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Abstract

The present invention relates to compounds according to formula (I) , a process for preparing them, the intermediate compounds of the process and the use of the compounds in the manufacture of a medicament for use in treating diseases such as ARDS, pulmonary emphysema, bronchitis, bronchiectasis, COPD, asthma and rhinitis. The compounds are beta2 adrenoreceptor agonists.

Description

technical field [0001] The present invention relates to diamine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. Background technique [0002] Adrenergic receptors are a class of G protein-coupled receptors that are divided into two major subfamilies, alpha and beta. These subfamilies are further divided into subtypes, of which the β subfamily has at least 3 members: β1, β2 and β3. The β2 adrenergic receptor (hereinafter referred to as β2 receptor) is mainly expressed on smooth muscle cells. [0003] Stimulation of beta2 receptors on airway smooth muscle causes relaxation and thus bronchodilation. By this mechanism, beta2 agonists act as functional antagonists of all bronchoconstrictor substances such as the naturally occurring histamine and acetylcholine and the experimental substances methacholine and carba choline. The widespread use of beta2 agonists in the treatment of airway diseases, including asth...

Claims

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Application Information

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IPC IPC(8): C07D277/68C07D417/12A61K31/428A61K31/4439A61K31/454A61K31/55A61P11/00A61P11/06A61P11/08
Inventor 莉莲·阿尔卡拉兹安德鲁·利斯特加里·佩劳迪厄
Owner ASTRAZENECA AB
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