Piperidinyl, indolyl, pirinidyl, morpholinyl and benzimidazolyl urea derivatives as inhibitors of soluble epoxide hydrolase for the treatment of hypertension, inflammations and other diseases

A technology of derivatives, compounds, piperidinyl, indolyl, pyridyl, morpholinyl and benzimidazolyl inhibitors of soluble epoxide hydrolase for the treatment of hypertension, inflammation and other diseases Urea derivatives field

Inactive Publication Date: 2009-04-08
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the high activity of these inhibitors, there remains a need for compounds with similar or improved activity, preferably with improved solubility and pharmacokinetic properties to facilitate formulation and delivery

Method used

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  • Piperidinyl, indolyl, pirinidyl, morpholinyl and benzimidazolyl urea derivatives as inhibitors of soluble epoxide hydrolase for the treatment of hypertension, inflammations and other diseases
  • Piperidinyl, indolyl, pirinidyl, morpholinyl and benzimidazolyl urea derivatives as inhibitors of soluble epoxide hydrolase for the treatment of hypertension, inflammations and other diseases
  • Piperidinyl, indolyl, pirinidyl, morpholinyl and benzimidazolyl urea derivatives as inhibitors of soluble epoxide hydrolase for the treatment of hypertension, inflammations and other diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0265] 4-Aminopiperidine (2.125 g, 21.2 mmol) was dissolved in toluene (50 mL). Benzaldehyde (2.16 mL, 21.2 mmol) was added. The reaction was equipped with a Dean-Stark trap and condenser and refluxed for 4 hours under nitrogen atmosphere. At this point, if no more water was formed, the reaction was cooled to 0°C and BOC anhydride (4.63 g, 21.2 mmol) was added via syringe over 10 minutes. The reaction was allowed to warm to room temperature over 1 hour and stirred for an additional 12 hours. The solvent was removed in vacuo and the resulting oil washed with KHSO 4 (aqueous) (1M, 21.2 mL) was treated. Stir for 1.5 hours. Water (25 mL) was added to the reaction, and the aqueous suspension was washed with diethyl ether (3x100 mL). The aqueous layer was then basified with KOH to pH = 10 and extracted with dichloromethane (3 x 100 mL). MgSO for organic layer 4 Drying and evaporation gave 4.76 g of a yellow oil. To this oil (1.0 g) was added THF (25 mL). Stir for 5 minutes ...

Embodiment 2

[0273] Piperidinyl urea: General procedure for the alkylation of N-(1-ethylpiperidin-4-yl)-N'-(adamantan-1-yl)urea (R=Et, 1152):

[0274]

[0275] The appropriate piperidinyl urea (0.319 mmol) was mixed with the appropriate alkyl or benzyl bromide (X=Br) (0.382 mmol) and K 2 CO 3 (132 mg, 0.96 mmol) were mixed in DMF (3.0 mL). The reaction solution was heated at 50° C. for 12 hours. At this point, the reaction was allowed to cool to room temperature and the solvent was removed in vacuo. Residues in DCM and NaHCO 3 Partition between saturated aqueous solutions, remove the organic layer and wash with Na 2 SO 4 dry. The solvent was evaporated and the residue was chromatographed on silica gel using ammonia saturated methanol / DCM as eluent (5:100). Yield = 42%. Mp.: 203-213°C dec. 1 H NMR (300MHz, CDCl 3 ): 4.15-4.05 (br, 2H), 3.63-3.47 (m, 1H), 2.91-2.81 (br m, 2H), 2.39 (q, J=7.18Hz, 2H), 2.13-1.88 (brm, 13H) , 1.66 (br, 6H), 1.40 (qd, J=8.3, 3.3Hz, 2H), 1.07 (t, J=...

Embodiment 3

[0277]

[0278] N-(1-n-propylpiperidin-4-yl)-N’-(adamantan-1-yl)urea (1155)

[0279] Yield = 60%. Mp.: 195-200°C dec. 1 H (300MHz, CDCl 3 ): 4.10-4.00(br, 2H), 3.60-3.45(m, 1H), 2.90-2.78(m, 2H), 2.32-2.22(m, 2H), 2.10-1.70(m, 13H), 1.70-1.57 (br, 6H), 1.56-1.30 (m, 4H), 0.88 (t, J=7.4Hz, 3H).

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Abstract

Compounds of the formula (I); wherein R<1> is a member selected from the group consisting of C1-C8alkyl, arylC0-C8alkyl, C3-C12cycloalkyl and heterocyclyl, Y<1> is selected from the group consisting of a bond, C(R<5>)2, NR<5> and O; Y<2> is selected from the group consisting of a bond, NR<5> and O; each R<2>, R<3> and R<5> is independently selected from the group consisting of H, alkyl and COR<6>; A is heterocyclyl, optionally substituted with from 1 to 2 R<7> substituents; L is selected from the group consisting of a direct bond, C1-C12alkylene, C1-C12heteroalkylene, C3-C6cycloalkylene, arylene, heteroarylene, -CO-, -SOin- and -Se-; R<4> is selected from the group consisting of H, C1C8alkyl, C2-C6alkenyl, C2-C6alkynyl, C1,-C8heteroalkyl, arylC0-C8alkyl, C3C,12cycloalkyl and heterocyclyl, are claimed. The compounds are inhibitors of the soluble epoxide hydrolase (sEH) and useful for the treatment of hypertension, inflammation, adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome and arthritis.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 782,172, filed March 13, 2006, the contents of which are incorporated herein by reference. [0003] Claims of Rights to Inventions Resulting from Federally Sponsored Research or Development [0004] The United States Government has certain rights in this invention under contracts ES02710 and HL078096 awarded by the National Institutes of Health. Background of the invention [0005] Epoxide hydrolases (EH, EC 3.3.2.3) catalyze the hydrolysis of epoxides or arene oxides to their corresponding diols by adding water (see, Oesch, F. et al., Xenobiotica, 1973, 3, 305-340) . Some EHs play critical roles in the metabolism of various compounds, including hormones, chemotherapeutic drugs, carcinogens, environmental pollutants, mycotoxins, and other harmful foreign compounds. [0006] Microsomal epoxide hydrolase (mEH) and soluble epoxide hydrola...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/26C07D209/08C07D211/58C07D211/96C07D213/40C07D401/06C07C275/26C07C275/28A61K31/445A61K31/4523A61P9/14A61P11/00A61P19/02C07D487/18C07D295/20
CPCC07D401/12C07D211/26C07D295/205C07D295/20C12Q1/34C07D235/30C07D401/06C07D211/96C07D211/58C07D209/08C07D487/18C07D213/40A61P11/00A61P11/06A61P13/00A61P13/12A61P15/10A61P19/02A61P29/00A61P3/00A61P9/00A61P9/12A61P9/14A61P3/10A61K31/445
Inventor B·D·哈莫克P·D·琼斯C·莫里瑟黄华章蔡幸如R·小格斯
Owner RGT UNIV OF CALIFORNIA
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