Azaindole compounds for treatment of central nervous system disorders

A technology of compounds and mixtures, applied in the field of pharmaceutical compounds for the treatment of central nervous system dysfunction, can solve problems such as slow onset of action

Inactive Publication Date: 2011-02-09
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Historically, first-generation drugs that increased serotonin neurotransmitters were nonselective and showed undesired side effects
In the 1980s, serotonin selective reuptake inhibitors (SSRIs) proved to have fewer side effects than their earlier counterparts, but still stimulated the serotonergic ) site
However, to date, there has been no success in showing that 5-HT reuptake inhibitors and 5-HT 1A Marketed drugs with dual mode of action of receptor agonists

Method used

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  • Azaindole compounds for treatment of central nervous system disorders
  • Azaindole compounds for treatment of central nervous system disorders
  • Azaindole compounds for treatment of central nervous system disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] 5-{4-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2- Synthesis of formamide:

[0131]

[0132] a.: Dissolve 67 g of 6-amino-nicotine nitrile in 1 L of 1,2-dichloroethane, add 125 g of silver trifluoroacetate, and reflux the mixture for 7 hours. After cooling to room temperature (RT), 143 g of iodine were added. The mixture was heated again for 12 hours. The temperature was then lowered to RT and the salts were removed by filtration. The reaction phase was treated with 1 L of water. The aqueous phase was extracted with dichloromethane, the combined organic layers were dried over magnesium sulfate, evaporated and purified by chromatography on silica gel to give 41 g of 6-amino-5-iodo-nicotinenitrile as pale yellow crystals.

[0133] [M+H] + :246

[0134] b.: 6 g of 6-chloro-1-hexyne were dissolved in 50 ml THF and cooled to -78°C. 31 ml of n-BuLi (1.6M in hexane) was added dropwise at this temperature. The reaction mixture was he...

Embodiment 2

[0154] 5-{4-[4-(5-cyano-1H-pyrrolo[3,2-b]pyridin-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2- Synthesis of formamide:

[0155]

[0156] 25 g of 5-amino-pyridine-2-carbonitrile were treated as described for 6-amino-nicotine nitrile to afford 20 g of 5-amino-6-iodo-pyridine-2-carbonitrile as light tan crystals.

[0157] HPLC: Chromolite Performance RP18-e 100-4, 6mm

[0158] Gradient: ACN / 0.05% formic acid in water

[0159] Method: Chromolith / Chromolith (Extended)

[0160] Flow rate: 3mL / min

[0161] Retention value (Rt): 1.596min

[0162] [M+H] + :246

[0163] 1 H-NMR (500MHz, d 6 -DMSO) δ 7.62 (d, 1H, J=8.3Hz), 6.97 (d, 1H, J=8.3Hz), 6.44 (br.s, 2H).

[0164] According to 5-{4-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-butyl]-piperazin-1-yl}-benzofuran- 500 mg of 5-amino-6-iodo-pyridine-2-carbonitrile and 1.2 g of 5-[4-(6-trimethylsilyl-hexyn-5-yl)-piperamide were treated as described in 2-carboxamide Azin-1-yl]-benzofuran-2-carboxamide to give 20 mg of 5-{4-[4-(5-cy...

Embodiment 3

[0175] 3-{4-[4-(2,3-dihydro-benzo[1,4]dioxane-6-yloxy)-piperidin-1 base]-butyl}-1H-pyrrole[ Synthesis of 2,3-b]pyridine-5-carbonitrile

[0176]

[0177] 10 g of 5-hexyn-1-ol was dissolved in 150 mL THF and cooled to -78°C. 187 ml (1.6M in n-hexane) of butyllithium were added dropwise. After stirring at -20°C for 1 hour, 30 ml of trimethylchlorosilane was added dropwise at the given temperature. After 12 h at RT, the mixture was worked up with 100 mL of water. After the usual extraction and purification procedure 3.3 g of 6-trimethylsilyl-hex-5-yn-1-ol were obtained as a colorless oil.

[0178] According to 5-{4-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-butyl]-piperazin-1-yl}-benzofuran- 2.9 g of 6-amino-5-iodo-nicotinenitrile and 2 g of 6-trimethylsilyl-hex-5-yn-1-ol were treated with 2-carboxamide as described to give 630 mg of 3-( 4-Hydroxy-butyl)-2-trimethylsilyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile.

[0179] HPLC: Rt: 2.370min

[0180] HPLC-MS: Rt: 1.429min ...

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Abstract

Azaindole derivative compounds are described. The compounds have an optionally substituted azaindole core linked to a carbocyclic ring having at least one nitrogen atom and further bound to an optionally substituted aryl ring. A process for preparing these compounds, compositions comprising them, and methods of using them to treat disorders of the central nervous system are described.

Description

technical field [0001] The present application is in the field of pharmaceutical compounds for the treatment of central nervous system dysfunction. Background technique [0002] Known and used to block serotonin and 5-HT 1A Compounds that inhibit the reuptake of serotonin receptors and inhibit serotonin have been used for decades to treat disease conditions such as depression, anxiety and epilepsy. In addition to their serotonin agonistic and antagonistic activities, these molecules were also found to block the binding of serotonin ligands to hippocampal receptors (Cossery et al., Bur. J. Pharmacol. 1987, 140:143) and alter DOPA Accumulation in the striatum and accumulation of 5-HT in the nuclei raphe (Seyfried et al., Eur. J. Pharmacol. 1989, 160:31-41). Administration of such compounds results in a drop in blood pressure in intubated, conscious, hypertensive rats (Strain: SHR / Okamoto / NIH-MO-CHB-Kisslegg; Methods: See Weeks and Jones, Proc. Soc. Exptl. Biol. Med .1960, 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/00C07D471/04A61K31/4353
CPCC07D471/04A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P43/00A61P9/00A61P9/12
Inventor T·海因里希M·卡特泽
Owner MERCK PATENT GMBH
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