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Oxyindole derivatives with motilin receptor agonistic activity

A hydroxyl and alkyl technology, applied in the field of novel oxindole derivatives or pharmaceutically acceptable salts thereof

Active Publication Date: 2012-01-11
RAQUALIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presence of GPR38 in the brain, while supporting the aforementioned GI and rearing utility, also suggests a broader spectrum of receptor involvement in vagal-hypothalamic function

Method used

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  • Oxyindole derivatives with motilin receptor agonistic activity
  • Oxyindole derivatives with motilin receptor agonistic activity
  • Oxyindole derivatives with motilin receptor agonistic activity

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0174] The preparation of the compounds of formula I according to the invention can be carried out in sequential or convergent synthetic routes.

[0175] Synthetic details for the preparation of the compounds of formula I of the present invention are shown in the following reaction schemes in a sequential manner.

[0176] The term "standard peptide coupling reaction conditions" is used repeatedly herein to refer to inert solvents such as DMF and methylene chloride in the presence of catalysts such as HOBT and / or such as diisopropylethylamine or triethylamine Acid activators such as EDC, DCC, HBTU, and BOP are used to couple carboxylic acids with amines in the presence of bases.

[0177] The term "PG1" used hereinafter refers to an amino-protecting group selected from typical amino-protecting groups described in the literature [Protective Groups in Organic Synthesis edited by T.W. Greene et al. (John Wiley & Sons, 1999). Typical amino-protecting groups include benzyl, CBZ, FMO...

Embodiment 1

[0263] (R)-N-((S)-1-(4-(3,3-Dimethyl-2-oxoindolane-1-yl)piperidin-1-yl) -1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide

[0264]

[0265] step 1

[0266] 1-(1-Benzylpiperidin-4-yl)-3,3-dimethylindolin-2-one

[0267] To a stirred solution of N,N-diisopropylethylamine (28.9 mL, 205 mmol) and dry tetrahydrofuran (446 mL) cooled to -78°C was added dropwise n-butyllithium (82.3 mL, 205 mmol) under nitrogen atmosphere. ). After stirring the reaction mixture for 10 minutes at -78°C, 1-(1-benzylpiperidin-4-yl)indolin-2-one (21.0 g, 68.0 mmol, Tetrahedron Communications, 2004 , 50, 8535-8537) in THF (258 mL). The reaction mixture was stirred for an additional 30 minutes and iodomethane (12.8 mL, 205 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C, and aqueous ammonium chloride solution was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (x3). The org...

Embodiment 2～16

[0300]

[0301] The following examples were prepared following a procedure similar to that described in step 5 of Example 1, using the appropriate precursor in place of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid , i.e. Examples 2-16.

[0302] {Table 4-A}

[0303]

[0304]

[0305] {Table 4-B}

[0306]

[0307]

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Abstract

The present invention relates to novel oxyindole derivatives of formula (I) or a pharmaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders which are mediated via the motilin receptor (GPR38).

Description

technical field [0001] The present invention relates to novel oxindole derivatives of chemical formula (I) or pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing them and their role in the treatment of motilin receptor (GPR38)-mediated Use in various disorders. Background technique [0002] The fact that GPR38 is a 7-transmembrane, G-protein-coupled receptor that exhibits high affinity for the polypeptide motilin [Feighner et al., Science 1999, 284, 2184] suggests that endogenous motilin acts through this Receptors exert all or most of their activity. [0003] Motilin is a polypeptide of 22 amino acids found abundantly in endocrine gland-like cells of the gastrointestinal (GI) tract and especially in the duodenum-jejunum region. The fact that this polypeptide is known to be involved in the initiation of phase III mobile complex activity in the stomach during fasting [Boivin et al., Dig. Predetermined role. Motilin ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/454A61K31/497A61P1/04A61P1/06A61P43/00C07D401/04
CPCC07D401/04C07D401/14A61P1/00A61P1/04A61P1/06A61P1/08A61P1/10A61P35/00A61P43/00A61P7/00A61P7/12A61K31/4545
Inventor 须藤正树岩田康弘新野义政甚野冈香大见仁野口洋英
Owner RAQUALIA PHARMA INC
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