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Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists

A technology of pyridazine and piperidine is applied in the field of compounds that rapidly dissociate dopamine 2 receptor antagonists, and can solve the problems of lack of dopamine receptor blocker properties and the like

Active Publication Date: 2013-04-10
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since none of the compounds tested antagonized the stereotyped behavior induced by subsequent doses of demorphine, they were also considered to lack the properties of dopamine receptor blockers

Method used

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  • Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists
  • Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists
  • Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0111] N-[1-(3,4-difluorobenzyl)hexahydropyridin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E1)

[0112]

[0113] 3,4-Difluorobenzaldehyde (1.52 g , 10.6 mmol) and sodium triacetoxyborohydride (2.24 g, 10.6 mmol). After stirring for 18 hours, the reaction mixture was quenched with 1N sodium hydroxide, the organic layer was removed, dried and the solvent was evaporated in vacuo. The crude product was purified by chromatography (silica; 2%-5% ammonia in methanol (7M) / dichloromethane) to afford E1 (2.39 g, 61%). C 17 h 17 f 5 N 4 The required value is 372; the measured value is 373 (MH + ); melting point: 167.7-168.9°C. 1 H NMR (DMSO-D6) δ1.50 (qd, J=11.5, 3.7Hz, 1H), 1.96 (br.d, J=12.4Hz, 2H), 2.12 (td, J=11.4, 2.6Hz, 2H) , 2.78(br.d, J=11.3Hz, 2H), 3.48(s, 2H), 3.90(br.s, 1H), 6.94(d, J=9.4Hz, 1H), 7.13-7.19(m, 1H ), 7.32-742 (m, 2H), 7.53 (br.d, J=7.3Hz, 1H), 7.63 (d, J=9.4Hz, 1H).

example 2

[0115] N-[1-(4-fluorobenzyl)hexahydropyridin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (E2)

[0116]

[0117] A mixture containing D2 (1.7 g, 5.32 mmol), 4-fluorobenzaldehyde (0.66 g, 5.32 mmol), di-isopropylethylamine (1.37 g, 10.6 mmol) and triacetoxy borohydride (On resin) (Aguno Technologies; 2.2 mmol / g; 3 equiv) in dichloroethane (10 mL) was stirred at room temperature for 18 hours. After this period, the reaction mixture was filtered and the solvent was evaporated in vacuo. The crude product was purified by chromatography (silica; 2%-6% ammonia in methanol (7M) / dichloromethane) to afford E2 (0.79 g, 42%). C 17 h 18 f 4 N 4 The required value is 354; the measured value is 355 (MH + ); melting point: 163.3-165.3°C. 1 H NMR (DMSO-D6) δ1.48(q, J=10.8Hz, 2H), 1.95(br.d, J=12.5Hz, 2H), 2.09(t, J=11.1Hz, 2H), 2.78(br .d, J=11.3Hz, 2H), 3.47(s, 2H), 3.89(br.s, 1H), 6.94(d, J=9.4Hz, 1H), 7.15(t, J=8.8Hz, 2H) , 7.34 (dd, J=8.3, 5.7Hz, 2H), 7.53 (br.d, J=7.3Hz, 1H), 7....

example 12

[0119] N-[1-(3,4-difluorobenzyl)hexahydropyridin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine (E12)

[0120]

[0121] Containing D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in normal - A solution in butanol (4 mL) was heated at 190° C. for 2 hours in a microwave reactor (Emrys Optimizer; 0-9 bar). After this period, the reaction mixture was evaporated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, dried (MgSO 4 ) and the solvent was evaporated in vacuo. Purification was performed by reverse phase HPLC (conditions as described previously) to afford E12 (210 mg, 54%). C 18 h 19 f 5 N 4 The required value is 386; the measured value is 387 (MH + ). 1 H NMR (CDCl 3 )δ1.74(br.d, J=12.0Hz, 2H), 1.88(qd, J=12.0, 3.9Hz, 2H), 2.17(td, J=11.8, 2.5Hz, 2H), 2.96(br.d , J=11.6Hz, 2H), 3.00(s, 3H), 3.47(s, 2H), 4...

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Abstract

The present invention relates to compounds that are fast dissociating dopamine 2 receptor antagonists, processes for preparing these compounds, pharmaceutical compositions comprising these compounds as an active ingredient. The compounds find utility as medicines for treating or preventing central nervous system disorders, for example schizophrenia, by exerting an antipsychotic effect without motor side effects.

Description

technical field [0001] The present invention relates to a compound which is a fast-dissociating dopamine 2 receptor antagonist, a process for preparing the compound, and a pharmaceutical composition containing the compound as an active ingredient. The compound finds utility as a medicine for the treatment or prevention of central nervous system disorders, such as schizophrenia, by exerting an antipsychotic effect without motor side effects. Background technique [0002] Journal of Medicinal Chemistry (1999), 42 (4), 730-741 discloses 6-phenyl-N-[1-(phenylmethyl)-4-hexahydropyridyl]-3-pyridazinamine and similar compounds as Acetylcholinesterase inhibitors. [0003] Pharmacology, Vol. 35, No. 11, 1980, pp. 951-964 Discloses substituted N-[4-hexahydropyridyl]-2-aminopyrimidines having dopaminergic activity, ie the disclosed compounds Most are agonists at dopamine 2 receptors. Since none of the compounds tested antagonized stereotyped behavior induced by subsequent doses of d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D409/14A61K31/501A61P25/00
CPCC07D409/14C07D401/12A61K31/501A61P25/00A61P25/02A61P25/14A61P25/18A61P25/22A61P25/24A61P25/28A61P43/00
Inventor M·F·L·德布鲁恩G·J·麦克唐纳L·E·J·肯尼斯X·J·M·兰洛伊斯F·A·M·范登基巴斯Y·E·M·范鲁斯布罗克
Owner JANSSEN PHARMA NV
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