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Substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones, preparation and use thereof

一种二氢噁唑、基氧基甲基的技术，应用在制备这些化合物领域，能够解决无活性等问题

Inactive Publication Date: 2012-06-13
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Allosteric modulators only work when the agonist (glutamate) is present at the orthosteric binding site; thus, allosteric modulators only enhance or block the effect due to the presence of the agonist , but itself inactive

Method used

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  • Substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones, preparation and use thereof
  • Substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones, preparation and use thereof
  • Substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones, preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] (S)-2-(1,1-Dimethylindan-5-yloxymethyl)-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

[0176]

[0177] Step 1: 1,1-Dimethylindan-5-ol

[0178]The title compound was prepared in two steps following the procedure described in US Patent Application Publication No. 2006100460, using 5-methoxyindan-1-one as a starting material.

[0179] C 11 h 14 O(162.10), LCMS(ESI): 163.11(M + +H).

[0180] 1 HNMR (CDCl 3 , 300MHz), δ6.98(d, 1H), 6.66(s, 1H), 6.64(d, 1H), 4.51(s, 1H), 2.83(t, 2H), 1.92(t, 2H), 1.23( s, 6H).

[0181] Step 2: (S)-2-(1,1-Dimethylindan-5-yloxymethyl)-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

[0182] In (S)-2-toluene-4-sulfonic acidmethyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one ((S)-2-toluene-4-sulfonic acidmethyl -2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one) (0.8g, 2.48mmol) (prepared according to the operation described in WO 2008 / 112483) in acetonitrile (80ml) was added 1 , 1-Dimethylindan-5-ol (0.4 g, 2.48 mmol), then cesium carbonate (0.82 g, 2.48 ...

Embodiment 2

[0186] (S)-2-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxymethyl)-2,3-dihydrooxazolo[3,2- a] pyrimidin-7-one

[0187]

[0188] Step 1: 5,5-Dimethyl-5,6,7,8-tetralin-2-ol

[0189] The title compound was prepared in two steps following the procedure described in US Patent Application Publication No. 2006100460, using 6-methoxy-3,4-dihydro-2H-naphthalen-1-one as starting material.

[0190] C 12 h 16 O(176.12), LCMS(ES + ): 177.14 (M + +H).

[0191] 1 H NMR (CDCl 3 , 300MHz), δ7.19(d, 1H), 6.64(dd, 1H), 6.51(d, 1H), 4.46(s, 1H), 2.70(t, 2H), 1.79(m, 2H), 1.63( m, 2H), 1.26 (s, 6H).

[0192] Step 2: (S)-2-(5,5-Dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxymethyl)-2,3-dihydrooxazolo[3 , 2-a] pyrimidin-7-one

[0193] Using the procedure described in Example 1, the title compound was prepared from 5,5-dimethyl-5,6,7,8-tetralin-2-ol. [α] D 25 =-58.0 (c=0.87, CHCl 3 ).

[0194] C 19 h 22 N 2 o 3 (326.16), LCMS (ES + ): 327.16 (M + +H).

[0195] 1 H NMR (CD...

Embodiment 3

[0197] (S)-2-(5,5-Dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxymethyl)-2,3-dihydrooxa Azolo[3,2-a]pyrimidin-7-one

[0198]

[0199] Step 1: 5,5-Dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol

[0200] The title compound was prepared according to the procedure described in U.S. Patent Application Publication No. 2006100460, using 2-methoxy-6,7,8,9-tetrahydro-benzocyclohepten-5-one as a starting material, and two prepared in steps.

[0201] C 13 h 18 O(190.14), LCMS(ES + ): 191.15 (M + +H).

[0202] 1 H NMR (CDCl 3 , 300MHz), δ7.22(d, 1H), 6.59(dd, 1H), 6.57(s, 1H), 4.49(s, 1H), 2.87(m, 2H), 1.84(m, 2H), 1.64( m, 4H), 1.35 (s, 6H).

[0203] Step 2: (S)-2-(5,5-Dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxymethyl)-2,3- Dihydrooxazolo[3,2-a]pyrimidin-7-one

[0204] Using the procedure described in Example 1, the title compound was prepared from 5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol. [α] D 25 =-64.4 (c=0.68, CHCl 3 ).

...

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Abstract

The present invention relates to a series of substituted dihydro benzocycloalkyl-oxymethyl oxazolopyrimidinones of formula (I) as defined herein. This invention also relates to methods of making these compounds including novel intermediates. The compounds of this invention are modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2 receptor. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and / or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic neurodegenerative conditions, psychoses, cognition deficit disorders, convulsions, anxiety, depression, migraine, pain, sleep disorders and emesis.

Description

technical field [0001] The present invention relates to a series of substituted dihydrobenzocycloalkoxymethyloxazolopyrimidinones. More specifically, the present invention relates to a series of substituted 2-benzocycloalkoxymethyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones. The invention also relates to processes for the preparation of these compounds. The compounds of the present invention are allosteric modulators of metabotropic glutamate receptors (mGluRs), especially mGluR2. Therefore, the compounds of the present invention can be used as medicines, especially for the treatment and / or prevention of various diseases, including diseases related to the central nervous system. Background technique [0002] Recently, considerable research has been conducted involving L-glutamate, the most abundant neurotransmitter in the central nervous system (CNS). More specifically, L-glutamate mediates the major excitatory pathway in mammals and is therefore known as excitatory amino ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61K31/519A61K31/522A61P25/00
CPCA61K31/519C07D498/04A61K31/522A61P25/00A61P25/04A61P25/06A61P25/08A61P25/18A61P25/22A61P25/28A61P29/00A61P43/00A61K31/52C07D409/12
Inventor 小雷蒙德.W.科斯利R.谢尔
Owner SANOFI SA
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