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Modulators of the g protein-coupled mas receptor and the treatment of disorders related thereto

A solvate, selected technology, used in sexual diseases, anti-inflammatory agents, metabolic diseases, etc., can solve problems such as weak binding

Inactive Publication Date: 2014-10-15
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although it was shown in early studies that Mas is an angiotensin II (Ang II) receptor (Jackson T.R., et al. Nature 335:437-440, (1988)), later studies confirmed that Ang II in Mas-transfected cells -mediated intracellular signaling only by endogenously expressed AT 1 Observed in receptor cells (Ambroz C., et al. Biochim Biophys Acta1133:107-111, (1991))
Dong et al. reported that the Mas receptor does not bind angiotensin I and II, but binds a peptide called NPFF, but the binding is rather weak (EC 50 About 400nM) (Dong, et al., Cell106:619-632(2001))

Method used

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  • Modulators of the g protein-coupled mas receptor and the treatment of disorders related thereto
  • Modulators of the g protein-coupled mas receptor and the treatment of disorders related thereto
  • Modulators of the g protein-coupled mas receptor and the treatment of disorders related thereto

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Experimental program
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Embodiment approach

[0355] Some Embodiments: Compositions and Methods Related to Compounds of the Invention

[0356] One aspect of the invention pertains to compositions comprising a compound of the invention. One aspect of the present invention pertains to a pharmaceutical product selected from the group consisting of pharmaceutical compositions, formulations, unit dosage forms and kits, each comprising a compound of the present invention. One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier. One aspect of the present invention pertains to a process for the preparation of a pharmaceutical composition comprising the step of admixing a compound of the present invention and a pharmaceutically acceptable carrier; some embodiments pertain to a pharmaceutical composition obtainable by any of the methods described herein. One aspect of the invention pertains to compositions comprising a comp...

Embodiment 1

[0625] Embodiment 1: the synthesis of compound of the present invention

[0626] Exemplary syntheses for compounds of the invention are shown in Figures 1 to 4C , where the variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and "X" have the same definition used throughout this disclosure.

[0627] The compounds of the present invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the invention without limiting the invention to the specifics of these examples. The compounds described in the context of this application were named according to AutoNom Version 2.2, AutoNom 2000, CS ChemDraw Ultra Version 7.0.1 or CS ChemDraw Ultra Version 9.0.7. In some instances, common names are used and it is understood that such common names will be known to those skilled in the art.

[0628] Proton NMR ( 1 H NMR) spectra were recorded with a Bruker Avance-400 equipped with QNP (Quadruple Probe) or BBI (B...

Embodiment 11

[0630] Example 1.1: Preparation of N-(4-chloro-2-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)phenyl)-4-((diethylamino)methyl base) benzamide (compound 2).

[0631] Step A: Preparation of 4-chloro-2-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)aniline.

[0632] Piperazine (36.8 g, 427 mmol) was dissolved in IPA (150 mL) and cooled in an ice bath. 4-Chloro-2-fluoro-1-nitrobenzene (25 g, 142 mmol) previously dissolved in IPA (100 mL) was slowly added to the reaction mixture via a drop funnel (the solution turned yellow-orange over time). After the addition was complete, the reaction mixture was warmed to room temperature and stirred at this temperature overnight. The next day, the solvent was evaporated and the product extracted (H 2 200 mL each of O and EtOAc). The aqueous layer was extracted twice with EtOAc (200 mL). The organic layers were combined and washed with H 2 O / brine (500 mL) back extracted once. The organic layer was washed with MgSO 4 Drying and concentration gave...

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PUM

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Abstract

The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof that are useful in methods of treatment and alleviation of diseases and disorders of the heart, brain, kidney, immune, and reproductive system resulting from ischemia, or reperfusion subsequent to ischemia, and any downstream complication(s) related thereto. The present invention further relates to methods of treatment and alleviation of diseases and disorders of the vasculature resulting from vasoconstriction or hypertension and any downstream complication(s) resulting from elevated blood pressure and / or reduced tissue perfusion.

Description

technical field [0001] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof, which regulate the activity of Mas receptors and can be used to treat and alleviate heart, brain, Diseases and disorders of the kidney, immune system and reproductive system and any downstream complications associated therewith. The present invention also relates to methods of treating and alleviating vasculature diseases and disorders resulting from vasoconstriction or hypertension and any downstream complications resulting from elevated blood pressure and / or decreased tissue perfusion. These diseases and disorders include, for example, vascular disorders such as: coronary heart disease, atherosclerosis, ischemia, reperfusion injury, angina, myocardial infarction, no-reflux phenomenon, hypertension, anxiety, transient ischemic attack, erectile dysfunction, Ischemic colitis, mesenteric ischemia, acute extremity ischemia, skin d...

Claims

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Application Information

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IPC IPC(8): C07D241/04A61K31/496A61P9/00
CPCC07F9/650958C07D241/24C07D241/08C07D205/04C07D265/30C07D213/82C07D335/02C07D241/04C07D295/135C07D207/08C07D207/12C07D207/16C07D209/44C07D211/22C07D249/10C07D295/15C07F9/650952C07F9/65583A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P13/02A61P13/12A61P15/08A61P15/10A61P17/00A61P17/02A61P17/06A61P19/02A61P19/10A61P25/00A61P25/22A61P25/28A61P27/02A61P29/00A61P31/04A61P31/14A61P33/06A61P35/00A61P35/02A61P37/04A61P37/06A61P37/08A61P43/00A61P7/00A61P7/02A61P9/00A61P9/06A61P9/10A61P9/12A61P3/10
Inventor T-A.特兰A.C.布莱克伯恩B.A.克拉默M.纳古拉C.R.萨格Y-J.申N.邹
Owner ARENA PHARMA
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