Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto

a beta-3 adrenergic receptor and receptor technology, applied in the direction of cardiovascular disorders, organic chemistry, drug compositions, etc., can solve the problems of increased tachycardia, accelerated mortality, and initial improvement in contractility of these agents, so as to improve contractile function and hemodynamic status, inhibit the effect of contractility

Inactive Publication Date: 2019-09-19
ARENA PHARMA
View PDF0 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0060]Because increased beta-3 adrenergic receptor activity is known to inhibit contractility in the failing heart, studies were conducted to evaluate the effect of beta-3 adrenergic receptor antagonists on contractile function. As described herein, these studies demonstrat

Problems solved by technology

Acute heart failure is a rapid decline in heart function that can cause anoxia of tissues (particularly the brain), leading to death.
However, the initial improvement in contractility afforded by these agents can be foll

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto
  • Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto
  • Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto

Examples

Experimental program
Comparison scheme
Effect test

example 1

of Compounds of the Present Invention

[0584]The compounds disclosed herein and their syntheses are further illustrated by the following examples. Additional illustrated syntheses for compounds of the present invention are shown in FIGS. 1 to 24 where the symbols have the same definitions as used throughout this disclosure. The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, are named according to the AutoNom version 2.2, CS ChemDraw Ultra Version 9.0.7, or ChemBioDraw Ultra 12.0.2.1076. In certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art.

[0585]Chemistry: Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker Avance III-400 equipped with a 5 mm BBFO probe. Chemical shifts are given in parts per million (ppm) with the residual solvent signa...

example 1.1

of Benzyl 3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

Step A: Preparation of Benzyl 4-Allyl-4-hydroxypiperidine-1-carboxylate

[0587]To a mixture of benzyl 4-oxopiperidine-1-carboxylate (51 g, 218.6 mmol) in THF (36.44 mL) were added 3-bromoprop-1-ene (54.72 mL, 655.92 mmol) and saturated NH4Cl (114 mL, 218.6 mmol) aqueous solution. Then Zinc dust (31.59 g, 483.1 mmol) was added portion wise while the internal reaction temperature was kept below 40° C. The reaction was stirred at room temperature overnight. After the reaction was completed, it was quenched with H2SO4 (10%, 225 mL). The reaction mixture was filtered through a pad of Celite® and washed with MTBE (1 L). The aqueous layer was extracted with MTBE (2×) and EtOAc (lx). The combined organic layers were washed with water and brine, and then dried over MgSO4, filtered and concentrated to give the title compound (62.39 g, 104% yield). This material was used in the next step without further purificatio...

example 1.2

of (S)-3,3,3-Trifluoro-2-methoxy-N—((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamide and (R)-3,3,3-Trifluoro-2-methoxy-N—((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamide

Step A: Preparation of one Enantiomer of tert-Butyl (8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (from 1st Enantiomer)

[0614]The 1st enantiomer of benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.13 g, 2.89 mmol) from chiral HPLC in Example 1.1 was dissolved in MeOH (10 mL).

[0615]Palladium / C (30.72 mg, 0.289 mmol) and a H2 balloon were applied. The reaction was stirred at room temperature overnight at room temperature. The next day, the H2 balloon was removed. The reaction mixture was filtered through a pad of Celite®, washed with EtOAc and MeOH, and concentrated to give an enantiomer of tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (0.64 g, 86% yield) as a colorless gum which was ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Molar densityaaaaaaaaaa
Molar densityaaaaaaaaaa
Molar densityaaaaaaaaaa
Login to view more

Abstract

The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the beta-3 adrenergic receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a beta-3 adrenergic receptor-mediated disorder, such as, heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF<40% by radionuclide ventriculography; LVEF≤35% by echocardiography or ventricular contrast angiography; and conditions related thereto.

Description

FIELD OF THE INVENTION[0001]The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the beta-3 adrenergic receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a beta-3 adrenergic receptor-mediated disorder, such as, heart failure; cardiac performance in heart failure; mortality, reinfarction, and / or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and / or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ven...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D491/107A61P9/04
CPCA61K45/06C07D491/107A61P9/04A61K31/4525A61P9/10A61K31/438A61K31/4709A61K31/5383A61P9/00C07D498/04
Inventor TRAN, THUY-ANHDO, QUYEN-QUYENULLMAN, BRETTBLACKBURN, ANTHONY C.NAGURA, MAIKO
Owner ARENA PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products