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Heterocyclyl-substituted-tetrahydro-naphthalen derivatives as 5-ht7 receptor ligands

A technology of tetralin derivatives and heterocyclic groups, applied in the field of tetralin compounds, can solve problems such as low sequence homology

Inactive Publication Date: 2010-01-27
LAB DEL DR ESTEVE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 5-HT 7 The receptor has been cloned from rat, mouse, guinea pig, and human cDNA, showing a high degree of interspecies homology (approximately 95%), but this uniqueness lies in its low affinity to other 5-HT receptors. Sequence identity (less than 40%)

Method used

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  • Heterocyclyl-substituted-tetrahydro-naphthalen derivatives as 5-ht7 receptor ligands
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  • Heterocyclyl-substituted-tetrahydro-naphthalen derivatives as 5-ht7 receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment G

[0420] Chemical Example G: (2S)-Methyl-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-naphthalene-2 -yl]-amine

[0421]

[0422] Methyl-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amine

[0423] Example G was prepared according to the following Scheme 2

[0424]

Embodiment A

[0427] N-Benzyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amine

[0428]

[0429] To dissolve in CH 2 Cl 2 Benzylamine (23 mL, 212.80 mmol) and AcOH (0.97 mL, 17.02 mmol) were added to a solution of 5-methoxy-2-tetralone (30 g, 170.24 mmol) in (250 mL), and the mixture was heated at room temperature Stir for 4h. Then cool to 0°C and add NaB(OAc) within 20min 3 H (0.38 equiv, 13.71 g, 64.69 mmol). After stirring at 0°C for 1 h, NaB(OAc) was added within 30 min 3 H (1.07 equiv, 38.61 g, 182.16 mmol). Join CH 2 Cl 2 (100 mL), the reaction mixture was warmed to room temperature and stirred for 15 h. Then the mixture was cooled to 0 °C, and H was added slowly 2 O (200 mL). By adding saturated NaHCO 3 Aqueous solution (300 mL) was used to adjust the pH of the solution to 8.0, and the mixture was stirred at 0 °C for 15 min. After separation, the aqueous phase was washed with CH 2 Cl 2 (2 x 150 mL) extraction. All organic phases were combined and washed with anh...

Embodiment B

[0432] N-Benzyl-N-[(2S)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl]amine

[0433]

[0434] N-Benzyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amine (11.70 g, 43.76 mmol) was dissolved in Et 2 O (350 mL). The reaction mixture was heated to reflux and (S)-(+)-mandelic acid (6.66 g, 43.76 mmol) was added. Join CH 2 Cl 2 (30 mL), the mixture was refluxed for 3 h. The mixture was cooled at room temperature and stirred for 16h. The obtained solid was filtered and washed with Et 2 Washing with O (3 x 20 mL) and drying afforded 6.80 g of the diastereomeric salt as a white solid. Evaluation of the ee value in the compound (6S)-6-(dimethylamino)-5,6,7,8-tetralin-1-ol (chiral column chiralCel OD-H, 5 μm, 4.6×250mm; flow rate : 1 ml / min; mobile phase: MeOH:EtOH (1:1) / hexane 10:90). Diastereoisomeric salts from Et 2 Recrystallization in O improves ee. The salt was suspended in AcOEt (100 mL), and K 2 CO 3 Aqueous solution (20%, 80 mL). The mixture was stirred at room ...

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Abstract

The present invention relates to heterocyclyl-substituted-tetrahydro-naphthalen compounds of general formula (I) and (I prot), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans or animals, mediated by the receptor 5-HT7 affinity.

Description

technical field [0001] The present invention relates to heterocyclic-substituted tetralin compounds of general formula (I), their preparation methods, medicaments containing these compounds and their use in the preparation of medicaments for treating human or animal diseases. Background technique [0002] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of proteins and other biomolecules associated with target diseases. One important class of proteins that has been the subject of extensive study is the serotonin (serotonin, 5-HT) receptor family. 5-HT discovered in 1993 7 Receptors belong to this family and have attracted great interest as valuable new drug targets (Terrón, J.A. Idrugs, 1998, vol.1, no.3, pages 302-310: "The 5HT 7 receptor: A target for novel therapeutic venues? "). [0003] 5-HT 7 The receptor has been cloned from rat, mouse, guinea pig, and human cDNA, showing a high degree of int...

Claims

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Application Information

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IPC IPC(8): C07D231/12A61K31/415A61P25/18C07D261/08A61K31/42A61K31/4412C07D213/64
CPCC07D231/12C07D213/64C07D261/08A61P1/00A61P1/04A61P9/00A61P9/12A61P13/00A61P25/00A61P25/04A61P25/06A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/00A61P43/00
Inventor 莫妮卡·加西亚-洛佩斯安东尼奥·托伦斯-霍韦尔赫尔穆特·H·布施曼
Owner LAB DEL DR ESTEVE SA
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