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Indole and indoline cyclopropyl amide derivatives as ep4 receptor antagonists

An alkyl, compound technology, applied in pain and inflammation antagonists, GE2 receptors, E2 receptor fields, can solve problems such as deterioration

Inactive Publication Date: 2010-01-06
MERCK CANADA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compounds may have the ability to degrade, thereby inducing some of the mechanism-based side effects of NSAIDs, which are non-selective cyclooxygenase inhibitors

Method used

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  • Indole and indoline cyclopropyl amide derivatives as ep4 receptor antagonists
  • Indole and indoline cyclopropyl amide derivatives as ep4 receptor antagonists
  • Indole and indoline cyclopropyl amide derivatives as ep4 receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Potassium 4-[1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)cyclopropyl]benzoate

[0132]

[0133] Step 1: 1-(tert-Butoxycarbonyl)indole-7-carboxylic acid

[0134]

[0135]Indoline-1-carboxylic acid tert-butyl ester (25 g, 114 mmol) and TMEDA (22.9 ml, 151 mmol) were added to 567 ml of diethyl ether. The resulting solution was cooled to -78°C, and s-BuLi in cyclohexane (1.2 equiv, 1.4M) was added dropwise. The mixture was stirred at the above temperature for 1 h. will CO 2 Gas was bubbled through the mixture for 5 min and the incubation was removed. After stirring for 10 min, the mixture was quenched with 1N HCl and warmed to RT, then extracted 3 times with EtOAc. The combined organic layers were washed with brine and washed over MgSO 4 Dry on top. The solvent was removed and the resulting solid was triturated with 1:1 ether / hexane.

[0136] 1 H NMR (500MHz, DMSO-d6): δ12.5(bs, 1H), 7.35(m, 2H), 7.05(t, 1H), 4.00(t, 2H), 3.00(t, 2H), ...

Embodiment 2

[0152] 1-(3,4-Dichlorobenzyl)-N-{1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}indoline-7-carboxamide

[0153]

[0154] Step 1: 4-(1-Aminocyclopropyl)benzonitrile

[0155]

[0156] Terephthalonitrile (500 mg, 390 mmol) was dissolved in 10 ml of DCM. Ti(OiPr) 4 (1.1 ml, 3.9 mmol) was added to the resulting solution, followed by a 3M solution of ethylmagnesium bromide in THF (2.3 ml, 7.0 mmol). The mixture was aged at RT for 45 min, and BF was added 3 Et 2 O (890ul, 7.0mmol). Then, the mixture was aged for another 2 h at RT. use NH 4 Cl and 3N HCl quenched the reaction. The layers were separated, and the aqueous layer was washed with ether. Then, the aqueous layer was basified with 10N NaOH (pH 9-10). EtOAc was added, and the biphasic mixture was filtered. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with MgSO 4 Dry, filter and concentrate. Yield = 15%.

[0157] Step 2: N-[1-(4-cyanophenyl)cycl...

Embodiment 3

[0169] 4-{1-[({1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]cyclopropyl}benzoic acid

[0170]

[0171] Step 1: Methyl 1-[4-(trifluoromethyl)benzyl]-1H-indole-7-carboxylate

[0172]

[0173] 1H-Indole-7-carboxylic acid methyl ester (47.8 g, 273 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (81 g, 341 mmol) were dissolved in DMF ( 1.3L). 60% w / w NaH (12 g, 300 mmol) was added in portions. The ice bath was removed, and the mixture was stirred at 0 °C for 3 hours, then at RT overnight. The reaction mixture was washed with 3 L NH 4 It was quenched with Cl(sat), and the aqueous layer was extracted 3 times with 1 L ether. The organic layers were combined and washed with water and brine. The compound was purified by flash chromatography on silica gel.

[0174] 1 H NMR (500MHz, DMSO-d6): δ8.90(d, 1H), 7.70(s, 1H), 7.60(d, 2H), 7.40(d, 1H), 7.10(t, 1H), 7.00(d , 2H), 6.70(d, 1H), 5.70(s, 2H).

[0175] Step 2: 1-[4-(Trifluoromethyl)benzyl]-1H-indole-7-...

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Abstract

The invention is directed to indole and indoline cyclopropyl amide derivatives as EP4 receptor antagonists useful for the treatment of EP4 mediated diseases or conditions, such as acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer. Pharmaceutical compositions and methods of use are also included.

Description

Background technique [0001] The present invention relates to compounds and methods, and certain pharmaceutical compositions thereof, for use in the treatment of prostaglandin E-mediated diseases. More specifically, the compounds of the present invention are structurally distinct from NSAIDs and opiates, and are antagonists of E-type prostaglandin-induced pain and inflammation. [0002] Three review articles describe the characterization and therapeutic relevance of prostanoid receptors, and the most commonly used selective agonists and antagonists (Eicosanoids: From Biotechnology to Therapeutic Applications, edited by Folco, Samuelsson, Maclouf, and Velo, Plenum Press, New York, 1996, Chapter 14, 137-154; Journal of Lipid Mediators and Cell Signaling, 1996, 14, 83-87; and Prostaglandins and Other Lipid Mediators, 2002, 69, 15557-573). [0003] Thus, selective prostaglandin ligands, agonists or antagonists (according to which subtypes of prostaglandin E receptors are considere...

Claims

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Application Information

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IPC IPC(8): C07D209/08A61K31/404A61K31/41C07D403/12
CPCC07D403/12C07D209/08C07D209/42A61P15/00A61P19/02A61P19/06A61P25/04A61P25/06A61P29/00A61P35/00A61P43/00A61P9/10
Inventor M·博伊德J·科卢奇韩永新
Owner MERCK CANADA
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