Cyclopentene derivatives useful as antagonists of the motilin receptor

A technology of halogens and compounds, applied in the field of cyclopentene derivatives

Inactive Publication Date: 2000-12-27
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the peptide was effective in this model (IC 50 1.0nm), but its susceptibility to enzymes in the digestive tract makes this peptide hopeless as an oral drug

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Compound 1

[0102] at room temperature and N 2 A solution of 3-ethoxy-2-cyclohexen-1-one (125 g, 0.89 mol) in diethyl ether (500 mL) was added to a solution of 2M benzylmagnesium chloride (800 mL) and stirred for 6 hours. The resulting mixture was poured into 30% H 2 SO 4 solution and stirred for 5 hours. The resulting organic phase was separated and the aqueous phase was extracted several times with ether. dry (MgSO 4 ) combined organic phases and concentrated in vacuo to give compound 1 (161 g) as a colorless oil. NMR (CDCl3): 3.45 (s, 2H, benzyl proton), 5.83 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic hydrocarbon proton).

Embodiment 2

[0104] Compound 2

[0105] at 0°C and N 2 A solution of compound 1 (161 g, 0.87 mol) in diethyl ether (700 mL) was slowly added to a suspension of LAH (33 g, 0.87 mol) and diethyl ether (100 mL). The resulting mixture was stirred overnight at room temperature and cooled to 0 °C. Add saturated K 2 CO 3 The solution was quenched with excess LAH, and the mixture was filtered through Celite and washed several times with ether. dry (MgSO 4 ) and concentrated in vacuo to give compound 2 (150 g) as a colorless oil. NMR (CDCl3): 3.23 (s, 2H, benzyl proton), 4.20 (bs, 1H, CHOH), 5.52 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic hydrocarbon proton).

Embodiment 3

[0107] Compound 3

[0108] at 0°C and N 2 A solution of compound 2 (132 g, 0.7 mol) in diethyl ether (500 mL) was added to a suspension of 60% NaH (27 g, 0.7 mol) in diethyl ether (500 mL) washed with hexane and stirred for 1 hour. Trichloroacetonitrile (115 g, 0.8 mol) was added slowly and the resulting mixture was allowed to warm to room temperature and then stirred overnight. The solvent was removed in vacuo, hexane (1 L) was added and the mixture was cooled to 0 °C. Methanol (150 mL) was added and the resulting solid was filtered through Celite. The organic solvent was removed in vacuo to give the crude intermediate (215g). This intermediate was dissolved in xylene (1 L) and heated under N 2 Heating under reflux for 3 hours. The solvent was removed in vacuo, ether (3 L) was added and the solid precipitated by filtration to give compound 3 (106 g) as white crystals: mp 105-106 °C; NMR (CDCl3): 3.20 (Abq, J = 8 Hz, 2H), 5.92 (m, 2H , olefinic pr...

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PUM

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Abstract

The compounds of formula (I) are useful in treating gastrointestinal disorders associated with antagonizing the motilin receptor disorders. The compounds compete with erythromycin and motilin for the motilin receptor. In addition the compounds are antagonists of the contractile smooth muscle response to those ligands.

Description

[0001] Related applications used as cross-references [0002] This application claims priority to provisional application No. 60 / 063,669, filed October 28, 1997. field of invention [0003] The present invention relates to a series of novel cyclopentene derivatives, pharmaceutical compositions containing them and intermediates used for their preparation. The compounds of the present invention are useful as non-peptidyl antagonists of the motilin receptor. Additionally, the potency and potency of the present compounds are comparable to known motilin and erythromycin antagonists. Background of the invention [0004] Digestion of nutrients and excretion of waste in mammals is controlled by the gastrointestinal system. That said, the system is complex to say the least. A large number of natural peptides, ligands, enzymes and receptors play extremely important roles in this system and are potential targets for drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/16A61K31/167A61K31/216A61K31/40C07D295/08A61K31/4409A61K31/445A61K31/4468A61K31/5375A61K31/5377A61P1/00A61P1/06A61P1/12A61P43/00C07C233/41C07C233/78C07C323/36C07C323/42C07D211/26C07D211/58C07D213/81C07D295/092C07D295/13C07D295/22C07D295/24C07D317/68C07D333/38
CPCC07D295/24C07D211/58C07D211/26C07C233/41C07D333/38C07D295/088C07C2101/14C07C323/42C07C323/36C07D213/81C07D295/13C07C2101/10C07C233/78C07C2601/10C07C2601/14A61P1/00A61P1/06A61P1/12A61P43/00C07D295/135C07D317/68
Inventor R·H·陈M·项小J·B·莫雷M·P·比弗斯
Owner ORTHO MCNEIL PHARM INC
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