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4-substituted-2-phenoxy-phenylamine delta opioid receptor modulators

A Substitute, Phenyl Technology, Applied in the Field of Novel Opioid Receptor Modulators

Inactive Publication Date: 2012-10-17
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when selected pain-relieving doses of morphine are given to pain-free individuals, the experience is not always pleasant; nausea is common, and vomiting may also occur

Method used

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  • 4-substituted-2-phenoxy-phenylamine delta opioid receptor modulators
  • 4-substituted-2-phenoxy-phenylamine delta opioid receptor modulators
  • 4-substituted-2-phenoxy-phenylamine delta opioid receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0373]

[0374] A. 4-Bromo-2-(4-methoxy-phenoxy)nitrobenzene (1c). Compound 1a (2.20g, 10.0mmol), 4-methoxyphenol (compound 1b, 1.32g, 10.5mmol), K 2 CO 3 (1.52 g, 11.0 mmol) and 6 mL of DMF were stirred at 75°C for 3 hours. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was sequentially washed with 2N NaOH aqueous solution, 2N HCl aqueous solution, saturated NaHCO 3 aqueous and brine washes, with Na 2 SO 4 Dried, then concentrated to give compound 1c (2.95 g, 91%) as a brown gel. 1 H NMR (300MHz, CDCl 3 ): δ7.11-7.84 (d, 1H), 7.24-7.27 (m, 1H), 7.01-7.06 (m, 3H), 6.93-6.97 (m, 2H), 3.71 (s, 3H).

[0375] B. 4-Bromo-2-(4-methoxy-phenoxy)-aniline (1d). A mixture of compound 1c (1.64 g, 5.06 mmol), zinc (1.98 g, 30.4 mmol), 15 mL of HOAc and 50 mL of MeOH was stirred at 20 °C for 20 hours. After removal of solvent, the residue was partitioned between EtOAc and 3N aqueous NaOH. The organic phase was wa...

example 2

[0382]

[0383] A. 2-(S)-{[4-(2-Diethylcarbamoyl-ethyl)-2-(4-methoxy-phenoxy)-anilino]-methyl}-pyrrolidine - tert-butyl 1-carboxylate (2a). A mixture of compound Ik (0.050 g, 1.0 mmol) and 10% palladium on carbon in MeOH was shaken at 20 °C for 4 hours under a hydrogen atmosphere (34 psi). The catalyst was filtered off and the solvent was removed by evaporation to give compound 2a. MS: m / z526.3 (M+H) + .

[0384] B. Compound 2: N,N-diethyl-3-[3-(4-methoxyphenoxy)-4-{[(2S)-pyrrolidin-2-ylmethyl]amino}phenyl ] Propionamide. Compound 2a (0.050g, 0.095mmol), TFA and CH 2 Cl 2 The mixture was stirred at 20 °C for 4 hours. After concentration, the residue was purified by reverse phase HPLC to give compound 2 (0.022 g, 36% yield) as TFA salt. 1 H NMR (300MHz, CD 3 OD): δ6.87-6.91(m, 5H), 6.78(d, 1H), 6.60(d, 1H), 3.90(m, 1H), 3.79(s, 3H), 3.42-3.48(m, 2H) 3.24-3.34(m, 6H), 2.77(t, 2H), 2.53(t, 2H), 2.18-2.28(m, 1H), 2.00-2.14(m, 2H), 1.73-1.86(m, 1H), 1.03-1.08 (m, 6H);...

example 3

[0386]

[0387] A. 4-Chloro-2-(4-methoxy-phenoxy)nitrobenzene (3b). 4-chloro-2-fluoronitrobenzene (compound 3a, 1.76g, 10mmol), compound 1b (1.30g, 10.5mmol) and K 2 CO 3 (1.52 g, 11 mmol) was heated in 6 mL of DMF at 75 °C for 3 hours. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was sequentially washed with 1N NaOH aqueous solution, 1N HCl aqueous solution, saturated NaHCO 3 aqueous and brine washes, followed by NaXSO 4 dry. Flash column chromatography (SiO 2 ) was concentrated and purified to obtain compound 3b (2.75 g, 98% yield) as a yellow solid. MS: m / z 279.9 (M+H) + .

[0388] B. 4-Chloro-2-(4-methoxy-phenoxy)-aniline (3c). A mixture of compound 3b (2.47 g, 8.83 mmol), zinc (3.46 g, 53 mmol), 60 mL HOAc, 5 mL THF and 36 mL MeOH was stirred at 20° C. for 20 hours. The solid material was filtered and washed with MeOH. The filtrate was partitioned between EtOAc and 1N aqueous NaOH. The orga...

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Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein R1, R2, R3, Ra, and Y are defined herein.

Description

[0001] Cross references to related patent applications [0002] This application claims the benefit of US Provisional Patent Application 61 / 256,412, filed October 30, 2009, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to novel opioid receptor modulators of formula (I). The invention also relates to the preparation of such compounds, pharmaceutical compositions containing said compounds and their use in the treatment of opioid regulated disorders. Background technique [0004] The term "opioid" has been used to refer to pharmaceutically active alkaloids derived from opium, such as morphine, codeine, and the many semi-synthetic congeners of morphine. After the isolation of peptide compounds with morphine-like effects, the term opioid was introduced to generally refer to all drugs with morphine-like effects. Opioids include various peptides (eg, endorphins, enkephalins, and dynorphins) that exhibit morphine-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04C07D207/09C07D211/56C07D401/12C07D405/12C07D409/12C07D413/12C07D451/04C07D453/02C07C217/90A61K31/397A61K31/40A61K31/444A61K31/4245A61K31/4025
CPCC07D453/02C07D401/12C07C233/11C07C233/08C07C211/50C07D451/04C07D409/12C07C233/65C07D405/12C07D205/04C07C255/50C07D207/09C07D413/12C07D211/56C07C211/48A61P1/00A61P1/02A61P1/04A61P1/12A61P1/16A61P3/10A61P9/00A61P11/00A61P11/02A61P11/04A61P11/12A61P13/00A61P13/02A61P13/08A61P13/10A61P15/00A61P15/08A61P17/00A61P17/02A61P17/04A61P19/02A61P21/00A61P25/00A61P25/02A61P25/04A61P25/06A61P25/16A61P25/24A61P25/30A61P25/32A61P25/36A61P27/02A61P27/16A61P29/00A61P29/02A61P35/00A61P43/00
Inventor S.J.科亚茨H.卞蔡潮钟B.L.德科特L.刘M.J.马切莱格S.L.达克斯P.M.皮蒂斯P.J.康诺利W.何
Owner JANSSEN PHARMA NV
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