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Phenylpiperazinyl derivatives

A technology of phenylpiperazine and derivatives, applied in the field of novel substituted phenylpiperazine derivatives

Inactive Publication Date: 2003-08-20
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, dopamine D 4 Receptors are predominantly located in brain regions other than the striatum, implying that dopamine D 4 Receptor antagonism will have no extrapyramidal side effects

Method used

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  • Phenylpiperazinyl derivatives

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0107] Preparation of intermediates

[0108] A. Preparation of Arylpiperazines

[0109] Hexafluorophosphate η 6 -1,3-dichlorotoluene-η 5 -Cyclopentadienyliron(II)

[0110] Ferrocene (167 g), anhydrous aluminum trichloride (238 g) and aluminum powder (24 g) were suspended in 1,3-dichlorotoluene (500 mL) and heated to 110° C. for 5 hours under nitrogen atmosphere. The mixture was cooled to room temperature and water (1000 mL) was added very carefully in small portions while cooling on an ice bath. Heptane (500 mL) and diethyl ether (500 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with diethyl ether (3 x 300 mL). Aqueous ammonium hexafluorophosphate (60 g in 50 mL of water) was added in small portions to the remaining aqueous phase and the product was allowed to precipitate overnight at room temperature. The precipitate was filtered off and dried to give 150 g (39%) of the product as a light green powder. ...

Embodiment 1

[0139] 1-(2-Methyl-3-[3-(dimethylamino)phenoxy]phenyl)-4-[3-(1H-indol-3-yl)-propane Base] piperazine (1a)

[0140] Mix 3-(3-bromopropyl)-1H-indole (2 g), potassium carbonate (1.8 g) and 1-(3-[3-(dimethylamino)phenoxy]- 2-Methylphenyl)piperazine (2g) and boiled at reflux for 5 hours. After cooling to room temperature, silica gel (7 g) was added and the volatile solvent was evaporated in vacuo. The compound was purified by flash chromatography on silica gel (eluent ethyl acetate:heptane:triethylamine (49:49:2)). Fractions containing the compound were combined and concentrated in vacuo. Recrystallization from acetonitrile gave 2 g (66%) of the title compound as white crystals.

[0141] Mp104-105°C. 1 H-NMR (DMSO-d 6 ): 1.80-1.70(m, 2H); 2.15(s, 3H); 240(t, 2H); 2.70(t, 2H); 2.90-2.80(m, 8H); 3.35(s, 6H); 6.03( d, 1H); 6.30(s, 1H); 6.43(m, 1H); 6.55(d, 1H); 6.85(d, 1H); 7.10-6.95(m, 5H); 7.35(d, 1H); 7.50 (d, 1H); 10.75 (br.s, 1H). Analysis (C 30 h 36 N 4 O), calculate...

Embodiment 2

[0153] Example 2 1-{3-[3-(Diethylamino)phenoxy]-2-methylphenyl}-4-[3-(5-fluoro-1H-indol-3-yl)propane Base]piperazine (2a)

[0154] Suspend 2-(3-chlorobutyl)-1,3-dioxolan-4-ylmethoxymethylpolystyrene (70 g, 90.3 mmol) in anhydrous N,N-dimethylformamide (700mL). Sodium iodide (68 g, 452 mmol) was added followed by diisopropylethylamine (232 mL, 1.36 mol) and piperazine (117 g, 1.36 mol). The reaction mixture was heated with stirring at 80 °C for 12 hours. After cooling to room temperature, the resin was filtered and washed with N,N-dimethylformamide (3×500 mL), methanol (3×500 mL), tetrahydrofuran (3×500 mL), followed by methanol and tetrahydrofuran (250 mL each, 5 times) washing. Finally, the resin was washed with dichloromethane (3 x 500 mL) and dried under vacuum (25°C, 36 hours) to give an almost colorless resin (76 g).

[0155] A portion (12.8 g, 16.6 mmol) of the resulting resin was suspended in a 5:1 mixture (150 mL) of anhydrous tetrahydrofuran / N,N-dimethylformam...

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Abstract

The present invention relates to a novel class of substituted phenylpiperazinyl derivatives having the formula (I) wherein X, Z, Y, U,V, Alk, W, R<1> , R<2>, R<3>, R<11>, R<12>, R<13> n, m and the dotted line are as defined in the description. The compounds of the invention are dopamine D4 receptor ligands and are therefore useful for the treatment of certain psychiatric and neurologic disorders, including psychosis.

Description

field of invention [0001] The present invention relates to the presence of dopamine D 4 A novel class of substituted phenylpiperazinyl derivatives with receptor affinity. The compounds are useful in the treatment of certain psychiatric and neurological disorders, including psychosis. Background of the invention [0002] dopamine D 4 Receptors belong to dopamine D 2 subfamily of receptors, which are thought to be involved in the antipsychotic effects of neuroleptics. Known major classics D 2 Antagonism of receptors exhibits side effects of neuroleptic drugs due to D 2 Receptor antagonism in the striatum region of the brain. However, dopamine D 4 Receptors are predominantly located in brain regions other than the striatum, implying that dopamine D 4 Antagonism of the receptor will have no extrapyramidal side effects. This has been replaced by the antipsychotic clozapine (which is 4 with ratio to D 2 receptor higher affinity) and no extrapyramidal side effects (Van T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12A61K31/496A61K31/5377A61K31/551A61P25/18A61P25/22A61P25/24A61P25/28C07D209/14C07D403/06C07D403/12C07D405/12C07D405/14C07D413/14
CPCC07D405/14C07D403/12C07D403/06C07D405/12C07D209/14A61P25/18A61P25/22A61P25/24A61P25/28
Inventor T·鲁兰德J·凯勒K·安德森B·邦-安德森M·罗特莱恩德
Owner H LUNDBECK AS
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