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Inhibitors of P38 and methods of using the same

A compound, C3-C6 technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as not having oral bioavailability

Inactive Publication Date: 2006-08-23
ARQULE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as of the filing date of this application, there are no approved drugs available that are known to directly inhibit the enzyme family of p38MAP kinases, whereas those approved drugs that act by binding to cytokines to reduce or reduce cytokine levels , are generally not orally bioavailable and must therefore be administered using techniques such as injection

Method used

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  • Inhibitors of P38 and methods of using the same
  • Inhibitors of P38 and methods of using the same
  • Inhibitors of P38 and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] Example 1: 3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)- 2, Preparation of 2-dimethylpropan-1-ol

[0173] Compounds of the present invention represented by formula I (wherein X is O) are prepared according to the following representative methods.

[0174] Unless otherwise specified, the use of commercially available compounds is generally accepted.

[0175]

[0176] step 1

[0177] 2-amino-oxazole

[0178] To a solution of cyanamide (33 mL, 50% wt in water, 0.416 mol) in THF (100 mL) was added a solution of 2-hydroxyacetaldehyde (25 g, 0.416 mol) in water (40 mL), followed by dropwise addition of 2M sodium hydroxide (42 mL, 0.083 mol). Stirring was continued for a total of 24 hours. Then, the reaction mixture was concentrated in vacuo to remove most of the THF. The residual aqueous layer was extracted with ethyl acetate (4 x 200 mL). The extract was dried over sodium sulfate and the solvent was evaporated in vacuo. This gave p...

Embodiment 2

[0206] Example 2: 4-{4-[6-(4-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2-ylamino}-piperidine-1-carboxy Preparation of tert-butyl acid

[0207] Exemplary compounds of the present invention represented by formula I (X=S) were prepared according to the following representative methods.

[0208] step 1:

[0209]

[0210] Add pure ethanol (600mL ). The reaction was refluxed for 16 hours with vigorous stirring. The reaction mixture was reduced to half its original volume in vacuo. The residual liquid was poured into ice and the solution became basic after addition of ammonium hydroxide solution (30%). The resulting fine solid was filtered and washed with water. The black-yellow solid thus obtained was dried in a vacuum electric furnace at 50° C. to obtain 6-(4-fluorophenyl)-imidazo[2,1-b]thiazole (J) (43.0 g, 86%).

[0211] ESMS[M+H] + = 219;

[0212] 1 H NMR (300MHz CDCl 3 )δ8-7.6 (m, 3H), 7.38 (bs, 1H), 7.08 (bs, 2H), 6.79 (bs, 1H); 13 C75MHz (NMR CDCl 3 ...

Embodiment 3

[0234] Example 3: N'-{4-[6-(4-fluorophenyl)imidazo[2,1-b][13]thiazol-5-yl]pyrimidin-2-yl}-N,N-two Preparation of methylethane-1,2-diamine

[0235]

[0236] To 6-(4-fluorophenyl)-5-[2(methylsulfonyl)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazole (L; see Example 2 above ) (200mg, 0.53mmol) in dry dimethylsulfoxide (4mL) was added N,N-dimethylethanolamine (273mg, 3.06mmol) and potassium carbonate (365mg, 2.64mmol). The reaction mixture was stirred at 100°C for 6 hours, diluted with water (5 mL), extracted with ethyl acetate (2 x 10 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to obtain the compound N'-{4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidine-2 -yloxy}-N,N-Dimethylethylamine (N) (108 mg).

[0237] 1 H NMR (300MHz, DMSO) δ: 8.55(d, J=4.8Hz, 1H), 8.41(d, J=5.4Hz, 1H), 7.65(m, 2H), 7.52(d, J=4.5Hz, 1H ), 7.32...

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PUM

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Abstract

The present invention relates to compounds of formula I which are capable of inhibiting p38 in vivo or in vitro.

Description

[0001] Cross-references to related applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 60 / 470,735, filed May 15, 2003, and U.S. Provisional Patent Application Serial No. 60 / 512,298, filed October 17, 2003, both of which are incorporated by reference in their entirety In this article. Background of the invention [0003] Many chronic and acute conditions are associated with disturbances in the inflammatory response. A number of cytokines, including, but not limited to, IL-1, IL-6, IL-8, and TNF[alpha] participate in the response. Although these cytokines are normally expressed in response to many physiological stimuli, excessive, uncontrolled, or excessive and uncontrolled production of these cytokines often results in inflammation and tissue damage. This is one mechanism mediating the pathology of diseases such as rheumatoid arthritis (Keffer, J., et al., EMBO J., 13:4025-4031, 1991, Feldmann, M., et al., Annu. Rev. Imm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07D513/04A61K31/41A61P29/00C07D263/00C07D235/00C07D277/00
Inventor M·阿什维尔S·阿利刘继峰刘彦彬P·罗塞B·梅科宁R·塞利亚M·坦顿W·弗罗纳V·阿托科宁
Owner ARQULE INC
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