Therapeutic benzothiazole compounds

a technology of benzothiazole and compound, which is applied in the field of ligands, can solve problems such as limiting its us

Inactive Publication Date: 2006-05-25
BARLAAM BERNARD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ERT shows detrimental uterine and breast side effects that limit its use.

Method used

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  • Therapeutic benzothiazole compounds
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  • Therapeutic benzothiazole compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-Chloro-6-hydroxy-2-(4-hydroxyphenyl)benzoxazole

1) Synthetic method A: Synthesis of 2-amino-3-chloro-5-methoxyphenol

[0098] A solution of 3-chloro-5-methoxy-2-nitrophenol [1] (450 mg) and tin(II) chloride dihydrate (2 g, 4 eq.) in ethyl acetate (30 mL) was heated under reflux for 4 h. The mixture was cooled, diluted with ethyl acetate and aqueous potassium fluoride. The mixture was filtered through celite. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent afforded the title compound (280 mg) as a pale solid. NMR (DMSO-d6): 9.74 (m, 1H), 6.33 (d, 1H, J=2.4 Hz), 6.30 (d, 1H, J=2.4 Hz), 4.19 (m, 2H), 3.60 (s, 3H).

[0099] Reference 1: Hodgson, Wignall, J. Chem. Soc., 1928, 330. Prepared from 1-chloro-3,5-dimethoxybenzene by nitration with concentrated nitric acid in acetic anhydride below 10° C. to give 1-chloro-3,5-dimethoxy-2-nitrobenzene, and subsequent reaction with boron tribromide (1 eq.) in dichloromethane from −78° C. to 0° C.

2) Synthe...

example 2

[0100] A solution of 2-amino-3-chloro-5-methoxyphenol (270 mg) and ethyl 4-hydroxybenzimidate hydrochloride (376 mg, 1.2 eq.) in absolute ethanol (5 mL) was heated under reflux for 4 h. The mixture was cooled, partitioned between ethyl acetate and water. The organic layer was dried over MgSO4. After evaporation of the solvent, the residue was triturated with methanol to give the title compound (130 mg) as a light orange solid. NMR (DMSO-d6): 10.35 (s, 1H), 8.00 (d, 2H, J=8.7 Hz), 7.39 (d, 1H, J=2.1 Hz), 7.10 (d, 1H, J=2.1 Hz), 6.96 (d, 2H, J=8.7 Hz), 3.85 (s, 3H); MS: 276 (MH+).

3) Synthetic method C: Synthesis of 4-chloro-6-hydroxy-2-(4-hydroxyphenyl)benzoxazole

[0101] To a suspension of 4-chloro-2-(4-hydroxyphenyl)-6-methoxybenzoxazole (240 mg) in dichloromethane (5 mL) cooled at −78° C. was added boron tribromide (5 mL, 1M solution in dichloromethane, 5.7 eq.). The mixture was stirred at −78° C. for 10 min, warmed to room temperature and stirred for 3 h. The mixture was poured o...

example 3

6-Hydroxy-2-(4-hydroxyphenyl)-4-methylbenzoxazole

1) Synthesis of 2-(4-hydroxyphenyl)-6-methoxy-4-methylbenzoxazole (Example 4)

According to synthetic method B, from 2-amino-5-methoxy-3-methylphenol [2] (440 mg) was obtained the title compound (340 mg) as a light orange solid. MS: 256 (MH+).

[0102] Reference 2: Musso H; Beecken H, Chem. Ber. 1961, 94, 585; made from 3,5-dimethoxytoluene by nitration and monodeprotection of the 3-methoxy with BBr3 similarly to Ref. 1 followed by reduction of the nitro group to the amino by hydrogenation with palladium on charcoal.

[0103] 2) According to synthetic method C, the above compound (220 mg) was converted to 6-hydroxy-2-(4-hydroxyphenyl)-4-methylbenzoxazole (112 mg) as a light pinkish powder. NMR (DMSO-d6): 10.14 (s, 1H), 9.58 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 6.84 (s, 1H), 6.63 (s, 1H), 2.46 (s, 3H); MS: 242 (MH+).

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Abstract

Compounds of the formula (I) for use as an estrogen receptor -β-selective ligand are described wherein: X is O or S; and R1, R3-R6 are as described in the specification. The use of these compounds in treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis and prostate cancer is described; as are processes for making them.

Description

[0001] This application is a divisional of U.S. application Ser. No. 10 / 450,927, which is the National Stage of International Application No. PCT / SE01 / 02855, filed Dec. 19, 2001.TECHNICAL FIELD [0002] The present invention is directed to a series of ligands, and more particularly to estrogen receptor-β ligands which have better selectivity than estrogen for the estrogen receptor-β over the estrogen receptor-α, as well as to methods for their production and use in the treatment of diseases related to the estrogen receptor-β, specifically, Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis, or prostate cancer. BACKGROUND [0003] Estrogen-replacement therapy (“ERT”) reduces the incidence of Alzheimer's disease and improves cognitive function in Alzheimer's disease patients (Nikolov et al. Drugs of Today, 34(11), 927-933 (1998)). ERT also exhibits beneficial effects in osteoporosis and cardiovascular disease, and may h...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/428C07D417/02C07D277/60A61K31/423C07D277/64A61P5/30A61P9/02A61P19/02A61P19/10A61P25/22A61P25/24A61P25/28A61P29/00A61P35/00C07D263/56C07D263/57C07D277/66C07D413/04C07D417/04
CPCC07D263/57C07D277/66C07D413/04C07D417/04A61P19/02A61P19/10A61P25/00A61P25/22A61P25/24A61P25/28A61P29/00A61P35/00A61P5/30A61P9/02
Inventor BARLAAM, BERNARDBERNSTEIN, PETERDANTZMAN, CATHYWARWICK, PAUL
Owner BARLAAM BERNARD
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