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5-HT7 receptor antagonosts

A technology of isomers and solvates, applied in the field of 5-HT7 receptor antagonists, can solve problems such as low sequence homology and unreported activity

Inactive Publication Date: 2007-08-01
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 and shows a high degree of interspecies homology (approximately 95%), but is unique in that it has low sequence identity with other 5-HT receptors Source (less than 40%)
[0014] EP 21580 and EP 76072 describe compounds corresponding to the general formula R with antiarrhythmic activity 2 N(CH 2 ) n -NH-SO 2 R 1 The sulfonamide compound, 5-HT 7 activity not mentioned

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0123] The starting materials of general formula (IV) are prepared by conventional methods of organic chemistry well known to those skilled in the art.

[0124] The synthesis of general formula (IV) compound

[0125] 7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride

[0126] This compound is described in J. Med. Chem. 2003, 46, 831-837 by Buolamwini et al., which is hereby incorporated by reference and forms part of the present disclosure.

[0127]

[0128] A cold solution of 1,2,3,4-tetrahydroisoquinoline (13.3 g, 0.1 mol) in concentrated sulfuric acid (50 mL) was treated in small portions with potassium nitrate (11.12 g, 1.1 mol) maintaining the temperature at 5 below ℃. The reaction was left overnight at room temperature and poured onto ice. The resulting solution was basified with ammonium hydroxide and washed with CH 2 Cl 2 Extracted, dried and evaporated to dryness in vacuo. The crude product was dissolved in 100 mL of ethanol. Then 2.8M hydrochloric acid in...

Embodiment B

[0133] Synthesis of compounds of general formula (II)

[0134]

[0135] a) 2-(4-N-phthalimidobutyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline

[0136] At room temperature, 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (9.87 g, 0.046 mol), N- A mixture of (4-bromobutyl)phthalimide (12.97 g, 0.046 mol), potassium carbonate (25.43 g, 0.184 mol) was stirred overnight. The mixture was concentrated in vacuo and the residue was dissolved in water (150 mL), extracted with ethyl acetate (3 x 50 mL), washed with water, the organic layer was dried and evaporated to give the product (16.58 g, 95% yield), This product was used without further purification.

[0137] 1 H NMR (300MHz, DMSO-D6) d ppm 1.64(m, 2H), 1.79(m, 2H), 2.60(m, 2H), 2.78(m, 2H), 2.96(m, 2H), 3.72(m, 4H), 7.23 (m, 1H), 7.71 (m, 2H), 7.79 (m, 3H), 8.01 (m, 1H).

[0138] b) 2-(4-aminobutyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline dihydrochloride

[0139]2-(4-N-phthalimidobutyl)-7-nitro-1,2,3,4-tetrahydroisoquino...

Embodiment C

[0144] Compounds of general formula (I) are prepared by coupling compounds of general formula (II) with compounds of general formula (III) according to conventional methods of organic chemistry known to those skilled in the art.

[0145] Naphthalene-1-sulfonic acid [4-(3,4-dihydro-1H-isoquinolin-2-yl)-butyl]amide hydrochloride

[0146]

[0147] Naphthalene-1-sulfonyl chloride (238 mg, 1.05 mmol) was added to 2-(4-aminobutyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (272 mg, 1 mmol), N, CH of N-diisopropylethylamine (517mg, 4mmol) 2 Cl 2 (10 mL) solution and stirred overnight at room temperature. The resulting solution was washed with water (3×15 mL), washed with Na 2 SO 4 The organic layer was dried and evaporated to dryness. The free base was dissolved in 2-propanol (5 mL). Then 2.8 M ethanolic hydrogen chloride solution (0.40 mL) was added. The product crystallized and collected by filtration and dried in vacuo to give a white solid (310 mg, 72%).

[0148] M...

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Abstract

The invention relates to compounds of formula (I) having pharmacological activity towards the 5-HT7 receptor, and more particularly to some tetrahydroisoquinoline substituted sulfonamide compounds, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which 5-HT is involved, such as CNS disorders.

Description

field of invention [0001] The present invention relates to compounds having pharmacological activity on 5-HT7 receptors, and more particularly to certain tetrahydroisoquinoline substituted sulfonamide compounds, to processes for the preparation of such compounds, and to pharmaceutical compositions comprising said compounds , and their therapeutic use, especially for the treatment and / or prevention of 5-HT such as CNS disorders 7 disease involved. Background of the invention [0002] In recent years, the search for new therapeutic agents has been greatly assisted by a better understanding of the structures of proteins and other biomolecules associated with target diseases. An important class of proteins that has been the subject of extensive research is the serotonin (serotonin, 5-HT) receptor family. 5-HT discovered in 1993 7 Receptors belong to this family and have attracted great attention as valuable new drug targets (Terrón, J.A. Idrugs, 1998, vol.1, no.3, pages 302-3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04C07D413/14C07D409/12C07D401/12C07D513/04C07D413/12C07D417/12A61K31/47A61K31/4725A61P25/00
CPCC07D401/12C07D217/04
Inventor 安东尼·托伦斯霍维尔何塞普·马斯普里奥苏珊娜·耶内斯明格斯莫妮卡·加希尔洛佩斯埃尔伯特·多达尔卓尔拉斯卢斯·罗麦罗阿隆索赫尔穆特·H·布施曼
Owner LAB DEL DR ESTEVE SA
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