1- [(4- [benzoyl (methyl) amino] -3- (phenyl) butyl] azetidine derivatives for the treatment of gastrointestinal disorders 1

一种氮杂环丁烷、甲基的技术，应用在用于治疗胃肠疾病的1-[(4-[苯甲酰基(甲基)氨基]-3-(苯基)丁基]氮杂环丁烷衍生物领域，能够解决心血管副作用、恶化等问题

Inactive Publication Date: 2009-07-01
ALBIREO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although QT prolongation itself is not a safety concern, it carries the risk of cardiovascular side effects and in a small proportion of the population it can lead to TdP and worsen ventricular fibrillation

Method used

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  • 1- [(4- [benzoyl (methyl) amino] -3- (phenyl) butyl] azetidine derivatives for the treatment of gastrointestinal disorders 1
  • 1- [(4- [benzoyl (methyl) amino] -3- (phenyl) butyl] azetidine derivatives for the treatment of gastrointestinal disorders 1
  • 1- [(4- [benzoyl (methyl) amino] -3- (phenyl) butyl] azetidine derivatives for the treatment of gastrointestinal disorders 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] N-[(2S)-4-{3-[4-(azetidin-1-ylcarbonyl)piperidin-1-yl]azetidin-1-yl}-2-(4- Fluorophenyl)butyl]-3-bromo-N-methyl-5-(trifluoromethyl)benzamide

[0077]

[0078] 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1 ; 0.16g, 0.36mmol) and 1-azetidin-3-yl-4-(azetidin-1-ylcarbonyl)piperidine (see method 2; 0.10g, 0.47mmol) with a small amount of no Water and methanol (0.2 mL) were dissolved together in dichloromethane (10 mL). To the resulting solution was added DIPEA (0.14 g, 1.08 mmol) and sodium triacetoxyborohydride (0.15 g, 0.72 mmol). The mixture was stirred at RT under nitrogen for 4 hours. The mixture was diluted with dichloromethane and washed with saturated NaHCO 3 Wash twice with aqueous solution and then with brine. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-dichloromethane, 10:1). This...

Embodiment 2

[0081] 1-{1-[(3S)-4-[[3-bromo-5-(trifluoromethyl)benzoyl](methyl)amino]-3-(4-fluorophenyl)butyl]nitrogen Heterocyclobutan-3-yl}-N,N-dimethylpiperidine-4-carboxamide dicarboxylate

[0082]

[0083]3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1 ; 0.178g, 0.40mmol), 1-azetidin-3-yl-N, N-dimethylpiperidine-4-carboxamide (see method 3; 0.084g, 0.40mmol), acetic acid (0.3mL ), (polystyrylmethyl)trimethylammoniumcyanoborohydride (0.098 g, 0.52 mmol) and methanol was stirred at RT for 6 h. The resin was filtered off and washed with methanol. The solvent of the filtrate was removed by evaporation and the product was subjected to reverse phase chromatography (C8) using acetonitrile and ammonium formate / formic acid in water (0.1M NH 4 CO 2 H, 0.1M HCO 2 H, pH 4) was used as eluent for purification. Obtained 0.23 g (77%) of the title compound.

[0084] 1 H NMR (500MHz, CD 3 OD): δ 1.6-2.0 (cm, 6H), 2.6-4.2 (cm, 24H), 7.0-8.0 ...

Embodiment 3

[0086] 1-{1-[(3S)-4-[[3-bromo-5-(trifluoromethyl)benzoyl](methyl)amino]-3-(4-fluorophenyl)butyl]nitrogen Heterocyclobutan-3-yl}piperidine-4-carboxamide

[0087]

[0088] 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1 ; 1.00g, 2.24mmol), 1-azetidin-3-ylpiperidine-4-carboxamide (see method 4; 0.49g, 2.69mmol) and triethylamine (1.24mL, 9.0mmol) were dissolved in in dichloromethane (30 mL) and methanol (5 mL). To the resulting mixture was added sodium cyanoborohydride (0.21 g, 3.36 mmol) and the mixture was stirred at RT for 20 minutes. The solvent was removed by evaporation, and the residue was dissolved in dichloromethane and saturated NaHCO 3 Partition between aqueous solutions. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by silica gel chromatography (ammonia saturated methanol / dichloromethane, 1-20% methanol). This gave 0.24 g (17%) of...

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PUM

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Abstract

The present invention relates to new compounds of formula (I) wherein R1, R2 and X are as defined in the description, as well as salts and enantiomers thereof. The invention also relates to pharmaceutical compositions comprising said compounds, and to the use of said compounds in therapy, e.g. in the treatment of gastrointestinal disorders. The invention further relates to processes for the preparation of the compounds. The compounds are neurokinin (NK) receptor antagonists.

Description

technical field [0001] The present invention relates to novel compounds of formula I, pharmaceutical compositions containing said compounds and the use of said compounds in therapy. The invention also relates to processes for the preparation of compounds of formula I. Background technique [0002] Neurokinins (also known as tachykinins) include a class of peptide neurotransmitters found in the peripheral and central nervous systems. The three main tachykinins are substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). At least three receptor types are known for the three major tachykinins. Based on the relative selectivity of these receptor-preferred agonists SP, NKA, and NKB, they are classified as neurokinin 1 (NK 1 ) receptors, neurokinin 2 (NK 2 ) receptor and neurokinin 3 (NK 3 ) receptors. [0003] There is a need for orally active NK receptor antagonists for the treatment of eg respiratory, cardiovascular, neurological, pain, neoplastic, inflammatory and / or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/4523A61P1/00
CPCC07D401/04A61P1/00A61P1/04A61P11/00A61P25/00A61P25/04A61P29/00A61P35/00A61P43/00A61P9/00A61K31/4523
Inventor 安德斯·约翰逊约翰·约翰逊卡尔-古斯塔夫·西格弗里德逊
Owner ALBIREO
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