Thienodibenzoazulene compounds as tumor necrosis factor inhibitors

A technology of compounds and solvates, applied in the field of 1-thiadibenzoazulene derivatives

Inactive Publication Date: 2005-03-30
PLIVA ISTRAZIVACKI INST D O O
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, none of the compounds representing the subject of the present invention have been described as anti-inflammatory substances or inhibitors of TNF-alpha and IL-1 secretion or analgesics

Method used

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  • Thienodibenzoazulene compounds as tumor necrosis factor inhibitors
  • Thienodibenzoazulene compounds as tumor necrosis factor inhibitors
  • Thienodibenzoazulene compounds as tumor necrosis factor inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0068] Preparation of Alcohol

[0069] To LiAlH 4 A suspension in anhydrous diethyl ether (10mmol / 15ml anhydrous diethyl ether) was added dropwise to a solution of ester in diethyl ether (2mmol / 15ml anhydrous diethyl ether). The reaction mixture was stirred at room temperature for 4 hours. Subsequently, when all esters were consumed in the reaction (reaction progress monitored by TLC), diethyl ether and water were added to decompose the excess LiAlH 4 . The resulting white precipitate was filtered off and washed with anhydrous Na 2 SO 4 After drying, the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography.

[0070] According to the method of Example A, starting from the corresponding ester, prepare dibenzoazulene alcohol represented by formula I, wherein R 1 , R 5 , R 6 , R 7 , R 8 and R 9 = H, R 2 , R 3 , R 4 and X have the meanings described in Table 1.

[0071] compound

Embodiment 1

[0074] Dimethyl-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine hydrochloride

[0075] Benzyltriethylammonium chloride (0.1 g, 0.44 mmol) and alcohol 1 (0.28 g , 0.001mol) toluene solution. The reaction mixture was heated to reflux for 4 hours with vigorous stirring. It was then cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography, the oily product (0.25 g) was isolated. Concentrated hydrochloric acid was added to a cold ethanol solution of the amine to give a crystalline product, m.p. 162-165°C.

[0076] C, H, N, S analysis: C 65.45 (calculated 65.74); H 6.12 (calculated 6.02); N 3.89 (calculated 3.48); S8.52 (calculated 7.98)

[0077] 1 H NMR (ppm, CDCl 3 ): 2.18(m, 2H); 2.79(d, 6H); 3.15(m, 2H); 3.68(t, 2H); 4.71(s, 2H); 1H).

Embodiment 2

[0079] Dimethyl-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride

[0080] Reaction of alcohol 1 (0.45 g, 0.0015 mol) with 2-dimethylaminoethyl chloride hydrochloride (3.05 g, 0.021 mol) gave an oily product (0.3 g), converted to hydrochloride, m.p. 203°C .

[0081] C, H, N analysis: C 64.85 (calculated 65.02); H 5.80 (calculated 5.72); N 3.48 (calculated 3.61).

[0082] 1 H NMR (ppm, CDCl 3 ): 2.89(s, 6H); 3.27(m, 2H); 4.07(m, 2H); 4.78(s, 2H); 7.16-7.47(m, 9H); 12.5(s, 1H).

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Abstract

The present invention relates to the dibenzoazulene compounds represented by formula I as well as to their pharmaceutical preparations for the inhibition of tumor necrosis factor alpha (TNF-alpha) and interleukine 1 (IL-1) in mammals at all diseases and conditions where these mediators are excessively secreted. The compounds of the present invention also demonstrate an analgetic action and can be used to relieve pain.

Description

technical field [0001] The present invention relates to novel 1-thiadibenzoazulene derivatives, their pharmacologically acceptable salts, solvates and prodrug forms, their preparation and their anti-inflammatory effects, in particular tumor necrosis factor Inhibition of the production of -α (TNF-α) and interleukin-1 (IL-1) and their analgesic effects. Background technique [0002] So far, 1-thiadibenzoazulenes substituted at the 2-position by methyl, methylketone, nitro or carboxyl derivatives have been described in the literature (Cagniant P. and Kirsch G., C.R. Hebd. Sceances Acad. Sci., 1976, 283:638-686). However, to the best of our knowledge and available literature data, neither the 1-thiadibenzoazulene derivatives of the general formula I nor any possible process for their preparation have hitherto been described. 1-Thiadibenzoazulene is also not known to have anti-inflammatory properties. [0003] In 1975, TNF-α was defined as an endotoxin-induced serum factor (Ca...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/381A61K31/55A61P1/04A61P11/06A61P17/00A61P17/02A61P17/06A61P19/02A61P27/02A61P29/00A61P35/00A61P37/02A61P43/00C07B61/00C07D495/04
CPCC07D495/04A61P1/04A61P11/06A61P17/00A61P17/02A61P17/06A61P19/02A61P27/02A61P29/00A61P35/00A61P37/02A61P43/00
Inventor M·默塞普M·梅斯奇D·佩斯奇Z·祖帕诺维奇B·哈瓦科奇
Owner PLIVA ISTRAZIVACKI INST D O O
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