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Benzimidazole-proline derivatives

A benzimidazole and phenyl technology, applied in the field of benzimidazole proline derivatives, can solve problems such as no effective therapy yet

Active Publication Date: 2015-02-04
IDORSIA PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, memory loss or impairment of memory acquisition is a prominent feature of these disorders, and no effective therapy exists to stop this deleterious process

Method used

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  • Benzimidazole-proline derivatives
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  • Benzimidazole-proline derivatives

Examples

Experimental program
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Effect test

preparation example Construction

[1106] Preparative HPLC under acidic conditions

[1107] Method E: Column: Waters XBridge (10 μm, 75×30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCOOH [eluent B]; gradient: 90% B→5% B over 6.4 minutes (flow rate: 75 mL / min). Detection: UV / Vis+MS.

[1108] Preparative HPLC under basic conditions

[1109] Method F: Column: Waters XBridge (10 μm, 75×30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH 4 OH (25% in water) [eluent B]; Gradient: 90% B→5% B over 6.5 minutes (flow rate: 75 mL / min). Detection: UV / Vis+MS.

[1110] Abbreviations (as used in context):

[1111] Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid)

[1112] AcOH acetic acid

[1113] anh. anhydrous

[1114] aq. Water-based

[1115] atm atmosphere

[1116] tBME tert-butyl methyl ether

[1117] Boc tert-butoxycarbonyl

[1118] Boc 2 O di-tert-butyl dicarbonate

[1119] BSA bovine serum albumin

[1120] Bu Butyl, such as in tBu = tert-butyl = tertiary butyl

[1121] CC silica gel colum...

Synthetic example 11

[1227]

[1228] Step 1: Mix 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (2; 12.27g, 60.4mmol) and L-proline methyl ester hydrochloride ( 1; 10.20 g, 60.4 mmol) was dissolved in DCM (250 ml), followed by the addition of DIPEA (23.42 g, 31 ml, 181 mmol) and HATU (22.95 g, 60.4 mmol). Stirring was continued at room temperature for 1 hour, DCM was evaporated under reduced pressure and EtOAc (750ml) was added. The reaction mixture was extracted with brine (3 x 300ml). The organic layer was washed with MgSO 4 Dry, filter and evaporate the solvent under reduced pressure to give (S)-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)pyrrolidine-2-carboxylic acid Methyl ester (3), which was used in the next step without further purification. LC-MS: t R = 0.66 minutes; [M+H] + = 315.09.

[1229] Step 2: Methyl (S)-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)pyrrolidine-2-carboxylate (3, 18.81 g, 60.4 mmol) was dissolved in a mixture of MeOH (180 ml) and THF (210 ml), followed by...

Synthetic example 21

[1233]

[1234]Step 1: Dissolve (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (7; 144.27mg, 0.6mmol) in a 1 / 1 mixture of DMF / DCM (1.2ml ), followed by the addition of DIPEA (0.44ml, 2.52mmol) and 4-chloro-3-methylbenzene-1,2-diamine (8; 121.95 mg, 0.6 mmol), and finally HATU (240 mg, 0.63 mmol) dissolved in DMF (1 ml) was added. The reaction mixture was stirred at room temperature for 15 hours, then passed through a PL-HCO-filled 1 / 1 mixture (4 ml) with DMF / DCM 3 filter syringe (1g). The solvent was removed under reduced pressure to afford tert-butyl (2S,4S)-2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate ( 9), which was used in the next step without further purification. LC-MS: t R = 0.79 minutes; [M+H] + = 372.26.

[1235] Step 2: (2S,4S)-2-((2-Amino-4-chloro-3-methylphenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (9; 220mg , 0.6 mmol) was dissolved in 100% AcOH (3 ml, 52.5 mmol) and ...

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Abstract

The present invention relates to compounds of the formula (I) wherein Ar1, R1, R2, R3, R4a, R4b and (R5)n are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.

Description

technical field [0001] The present invention relates to novel benzimidazole proline derivatives of formula (I) and their use as medicines. The present invention also relates to methods for the preparation of these compounds, pharmaceutical compositions containing one or more compounds of formula (I) and their use as orexin receptor antagonists, especially as orexin-1 receptor antagonists. appearance. Background technique [0002] Orexin (orexin A or OX-A and orexin B or OX-B) is a neuropeptide discovered by two research groups in 1998, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T et al., Cell, 1998, 92, 573-585). Orexin is produced in discrete neurons of the lateral hypothalamus and binds to G-protein-coupled receptors (OX 1 and OX 2 receptor) binding. Orexin-1 receptor (OX 1 ) is selective for OX-A, and the orexin-2 receptor (OX 2 ) can bind OX-A as well as OX-B. Orexin receptor antagonists are a novel class of neurological ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/4184A61K31/426A61K31/505C07D403/04C07D417/14A61P25/00
CPCC07D417/14C07D403/04C07D403/14C07D401/14A61P1/14A61P25/00A61P25/18A61P25/20A61P25/22A61P25/28A61P25/30A61P43/00A61K31/4184A61K31/505
Inventor 克里斯托弗·博斯克莉丝汀·普罗奇马库斯·古德比比安·海德曼蒂埃里·西弗朗约迪·T·威廉斯
Owner IDORSIA PHARM LTD
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