Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators

A solvate and phenyl technology, which can be used in drug combinations, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as difficult reconciliation

Inactive Publication Date: 2015-05-20
SANOFI SA
View PDF2381 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Overall, these results are difficult to reconcile: very different fat diet regimens or different genetic backgrounds and so-called off-target genetic effects presumably best explain the observed differences

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
  • Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators
  • Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators
  • Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1948] Example 1: 1-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzimidazole-5-carbonyl]-amino}-cycloheptanecarboxylic acid

[1949]

[1950] a) Methyl 1-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzimidazole-5-carbonyl]-amino}-cycloheptanecarboxylate

[1951]

[1952] At 0°C, add 160 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzimidazole-5-carboxylic acid (the preparation of the intermediate is described below) in 3 ml To a solution in dry DMF was added 73 mg HOAT, 131 mg EDC and 0.16 ml DIPEA. After 15 min 100 mg of methyl 1-amino-cyclopentanecarboxylate hydrochloride and 0.16 ml of DIPEA were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then poured into water and the pH was adjusted to 3 by adding 2M aqueous hydrochloric acid. The reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate and brine, dried over m...

Embodiment 80

[1977] Example 80: (S)-2-{[1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzimidazole-5-carbonyl]- Amino}-4-methyl-pentanoic acid

[1978]

[1979] a)(S)-2-{[1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzimidazole-5-carbonyl]-amino} -4-Methyl-pentanoic acid tert-butyl ester

[1980]

[1981] At 0°C, to 55mg 1-(1-ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzimidazole-5-carboxylic acid in 1ml dry DMF 26mg HOBT, 37mg EDC and 0.05ml DIPEA were added to the solution. After 15 min 100 mg L leucine tert-butyl ester hydrochloride and 0.05 ml DIPEA were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then poured into water and the pH was adjusted to 3 by adding 2M aqueous hydrochloric acid. The reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. Ob...

Embodiment 107

[1994] Example 107: (S)-3-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzimidazole-5-carbonyl]-amino}-5- methyl-hexanoic acid

[1995]

[1996] In a 20 ml scintillation vial, to 300 mg Wang resin (NovaBioChem 70-90 mesh, loading capacity 1.3 mmol / g) in DMF was added 430 mg (S)-3-(9H-fluoren-9-ylmethoxy (carbonylamino)-5-methyl-hexanoic acid, 173 mg DIC and 14 mg DMAP. The reaction mixture was kept at room temperature for 18 h. To deprotect the Fmoc group, 50% piperidine / DMF was added and the reaction mixture was kept at room temperature for 30 min. Thereafter the resin was washed thoroughly with DMF. For amide formation, the resin was reacted with 217 mg 4-fluoro-3-nitrobenzoic acid, 185 mg HOBt and 173 mg DIC in DMF at room temperature for 18 h. In the next step, nucleophilic substitution was achieved by reacting the resin with 680 mg 1-ethyl-propylamine in DMF at room temperature for 24 h. Then pass through with 10ml 1M SnCl 2 The nitro group was reduced in DMF a...

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
optical rotationaaaaaaaaaa
optical rotationaaaaaaaaaa
Login to View More

Abstract

The present invention relates to benzoimidazole-carboxylic acid amide compounds of the formula I, in which R′, R″, R′″, R1, R2, R3, R4, R5, R6 and Z are defined as indicated below. The compounds of the formula I are APJ receptor modulators, and are useful for the treatment of diseases associated with increased blood pressure for example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

Description

technical field [0001] The present invention relates to the benzimidazole-carboxamide compound of formula I, [0002] [0003] where R', R", R"', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z are defined as shown below. Compounds of formula I are APJ receptor modulators and are useful in the treatment of diseases associated with, for example, elevated blood pressure. The present invention also relates to the use of the compounds of formula I, in particular as active ingredients of medicines, and the use of pharmaceutical compositions containing them. Background technique [0004] Apelin receptor (AplnR, also known as APJ, also known as Agtrl-1) is a G protein-coupled receptor first identified in 1993 (O'Dowd et al. Gene 1993; 136:355-60). It is expressed in several tissues, including endothelium, cardiac muscle, vascular smooth muscle, adipose tissue and throughout the brain (Farkasfalvi et al. Biochem Biophys Res Commun 2007; 357:889-95; Hosoya et al. J Biol Chem 2000;...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08C07D403/06C07D405/06C07D409/14C07D411/06C07D413/14C07D417/06C07D451/04C07D487/06A61K31/4184A61P3/10A61P9/10
CPCC07D235/08C07D403/06C07D405/06C07D409/06C07D409/14C07D411/06C07D413/06C07D417/06C07D417/14C07D451/04C07D455/02C07D487/06C07D487/08C07D413/14A61P13/12A61P27/02A61P3/00A61P43/00A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10
Inventor S·哈赫特尔P·沃尔法特J·韦斯顿M·米勒E·德福萨K·默奇J-H·翁R·A·宾尼F·阿卜杜尔-拉蒂夫W·J·博克A·沃尔泽
Owner SANOFI SA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com