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New benzothiazolecarboxamides

A technology of benzothiazole and formamide, which is applied in the field of treatment, new intermediates, and preparation of said compounds, can solve problems such as limitations

Inactive Publication Date: 2008-02-06
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although agonists of the VR1 receptor may act as analgesics through nociceptor disruption, the use of agonists such as capsaicin and its analogs is discouraged due to their irritative, neurotoxic and induction of hypothermia effects. restricted

Method used

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  • New benzothiazolecarboxamides
  • New benzothiazolecarboxamides
  • New benzothiazolecarboxamides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] N-4-tert-butylphenyl-2-methyl-1,3-benzothiazole-5-carboxamide.

[0175] 2-Methyl-1,3-benzothiazole-5-carboxylic acid (90.0 mg, 0.400 mml) was dissolved in DMF (3.00 mL), and HATU (190 mg, 0.500 mmol), 4-tert-butylaniline (75.0 mg, 0.500mmol) and Et 3 N (0.100 mL). The mixture was stirred for 3 hours, and the solvent was evaporated. The product was purified by flash chromatography on silica gel eluting with a mixture of hexanes and EtOAc (9:1 to 4:1) to afford the product (42.0 mg, 0.129 mmol, 32.0%). 1 H NMR (400MHz, DMSO-D 6)δppm 1.27 (s, 9H) 2.83 (s, 3H) 4.90-5.18 (br s, 1H) 7.36 (d, J = 8.98Hz, 2H) 7.71 (dd, J = 8.98, 2.73Hz, 2H) 7.96 (dd , J=8.40, 1.76Hz, 1H) 8.16(d, J=8.40Hz, 1H) 8.51(d, J=1.37Hz, 1H) 10.31(s, 1H); MS[M+H] calculated value 325.0, measured Value 325.0.

Embodiment 2

[0177] N-4-cyclohexylphenyl-2-methyl-1,3-benzothiazole-5-carboxamide.

[0178] 2-Methyl-1,3-benzothiazole-5-carboxylic acid (100 mg, 0.440 mml) was dissolved in DMF (5.00 mL), and HATU (190 mg, 0.500 mmol), 4-cyclohexylaniline (88.0 mg , 0.500mmol) and Et 3 N (0.100 mL). The mixture was stirred for 3 hours, and the solvent was evaporated. The product was purified by flash chromatography on silica gel eluting with a mixture of hexanes and EtOAc (9:1 to 4:1) to give nearly pure product which was recrystallized from heptane and EtOAc to give pure product (15.1 mg, 0.043 mmol, 10.0%). 1 H NMR (400MHz, DMSO-D 6 )δppm 1.15-1.50 (m, 5H) 1.60-1.83 (m, 6H) 2.82 (s, 3H) 7.18 (d, J = 8.59Hz, 2H) 7.67 (d, J = 8.59, 2H) 7.94 (dd, J =8.40, 1.76Hz, 1H) 8.14 (d, J = 8.40Hz, 1H) 8.48 (d, J = 1.56Hz, 1H) 10.30 (s, 1H); MS [M+] calculated value 350.2, measured value 351.0.

Embodiment 3

[0180] 2-Methyl-N-[2-methyl-4-trifluoromethylphenyl]-1,3-benzothiazole-5-carboxamide.

[0181] 2-Methyl-1,3-benzothiazole-5-carboxylic acid (90.0mg, 0.470mmol) and 2-methyl-4-trifluoromethylaniline (123mg, 0.700mmol), EDC (134mg, 0.700 mmol) and DMAP (85.0 mg, 0.700 mmol) were mixed in DCM (5.00 mL) and DMF (3.00 mL) for 48 hours. The mixture was concentrated and the product was purified by flash chromatography on silica gel eluting with a mixture of heptane and EtOAc (95 / 5 to 75 / 25) to give the product (14.0 mg, 0.0400 mmol, 8.50%). 1 H NMR (600MHz, chloroform-D) δppm 2.42(s, 3H) 2.89(s, 3H) 7.50(s, 1H) 7.54(d, J=8.45Hz, 1H) 7.85-8.05(m, 3H) 8.32(d , J = 8.45 Hz, 1H) 8.41 (s, 1H); MS [M+H] calcd. 351.0, found 351.0.

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Abstract

The present invention relates to new compounds of formula I, (I) wherein R<1> to R<4>, m, n and p, are as defined as in formula I, or salts, solvates or solvated salts thereof, processes for their preparation and to a new intermediate used in the preparation thereof, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.

Description

technical field [0001] The present invention relates to novel compounds, to pharmaceutical compositions containing said compounds, and to the use of said compounds in therapy. The invention further relates to processes for the preparation of said compounds, and to novel intermediates used in their preparation. Background technique [0002] Pain perception in mammals results from the activation of terminals of specialized populations of sensory neurons called nociceptors. Capsaicin - the active ingredient in hot peppers - causes persistent activation of nociceptors and also induces dose-dependent pain sensation in humans. Cloning of the vanilloid receptor 1 (VR1 or TRPV1) revealed that VR1 is the molecular target of capsaicin and its analogues. (Caterina, M.J. et al. Nature (1997) v. 389 p 816-824). Functional studies using VR1 have shown that it is also activated by noxious heat, tissue acidification and other inflammatory mediators (Tominaga, M. et al. Neuron (1998) v. 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/62A61K31/381A61P25/00C07D277/64C07D277/68C07D277/82C07D
CPCC07D277/68C07D277/64A61P1/00A61P11/00A61P11/06A61P11/14A61P11/16A61P13/02A61P19/02A61P25/00A61P25/04A61P29/00A61P43/00
Inventor 威廉·布朗安德鲁·格里芬肖恩·约翰斯通丹尼斯·拉布雷克亚历山大·芒罗桑德赖恩·帕彻克里斯托弗·沃波尔
Owner ASTRAZENECA AB