Phenoxypropylpiperidines and -pyrrolidines and their use as histamine h3-receptor ligands

An Alkyl, Alkenyl Technology Applied in the Field of New H3-Receptor Ligands

Active Publication Date: 2008-09-03
BIOPROJET
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] However, the inventors found that compounds exhibiting para-substituted phenyl groups in WO 00 / 06254 generally inhibit cytochrome 2D6 or cytochrome 3A4

Method used

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  • Phenoxypropylpiperidines and -pyrrolidines and their use as histamine h3-receptor ligands
  • Phenoxypropylpiperidines and -pyrrolidines and their use as histamine h3-receptor ligands
  • Phenoxypropylpiperidines and -pyrrolidines and their use as histamine h3-receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0358]

[0359] trans-1-{3-[4-(N,N-Dimethylcarbamoyl)phenoxy]propyl}-3,5-dimethylpiperidine oxalate

[0360]

[0361] 4-[3-(cis and trans-3,5-dimethylpiperidinyl)propoxy]benzoyl chloride hydrochloride (866 mg), 2M dimethylamine in tetrahydrofuran (3.75 mL) and tetrahydrofuran ( 10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by chromatography using silica gel and a mixture of diethyl ether / naphtha / triethylamine (80 / 20 / 1) as eluent. Fractions containing the expected product were collected, concentrated under reduced pressure and salified with 20 mg oxalic acid to give 37 mg trans-1-{3-[4-(N,N-dimethylcarbamoyl)-phenoxy] Propyl}-3,5-dimethylpiperidine oxalate, which is a pink powder.

[0362] 1 H NMR: Base (CDCl 3 )

[0363] 7.38(d, J=8.7Hz, 2H, arm), 6.90(d, J=8.7Hz, 2H, arm), 4.05(t, J=6.0Hz, 2H, CH 2 O), 3.05(br s, 6H, 2CH 3 NCO), 2.5-1.8(m, 10H, 3CH 2 N, CH 2 , 2CH), 1.25 (dd, J=5.8Hz, J=5.8Hz...

Embodiment 2

[0381]

[0382] trans-1-{3-[4-(N,N-tetramethylenecarbamoyl)phenoxy]propyl}-3,5-dimethylpiperidine, oxalate

[0383] Following the procedure described in Example 1§A, but starting from 4-[3-(cis and trans-3,5-dimethylpiperidinyl)propoxy]benzoyl chloride hydrochloride (700 mg) and A solution of pyrrolidine (500 μL) in dichloromethane (10 mL) gave 24 mg of trans-1-{3-[4-(N,N-tetramethylenecarbamoyl)phenoxy]propyl}-3,5 -Dimethylpiperidine oxalate as a white powder.

[0384] 1 H NMR: Base (CDCl 3 )

[0385] 7.51(d, J=8.7Hz, 2H, arm), 6.90(d, J=8.7Hz, 2H, arm), 4.06(t, J=6.0Hz, 2H, CH 2 O), 3.55(m, 4H, 2CH 2 NCO), 2.5-1.8(m, 14H, 3CH 2 N,3CH 2 , 2CH), 1.25 (dd, J=5.8Hz, J=5.8Hz, 2H, CH 2 ), 0.95 (2d, J=6.8Hz, J=6.8Hz, 6H, 2CH 3 )

Embodiment 3

[0387]

[0388] 1-[3-(4-Benzoylphenyl)propoxy]piperidine oxalate

[0389]A Following the procedure described in Example 1§D, but starting with 4-(3-chloropropoxy)benzophenone (1.37 g), piperidine (1 mL), potassium carbonate (2.07 g) and catalyst Quantitative potassium iodide in N,N-dimethyl-formamide (25 mL) gave 239 mg of 1-[3-(4-benzoylphenyl) after generating the salt with oxalic acid (55 mg) in acetone (0.6 mL) ) Propoxy]piperidine oxalate, which is a white powder.

[0390] 1 H NMR: Oxalate (DMSO)

[0391] 7.73 (d, J = 8.8Hz, 2H, aroma), 7.67-7.53 (m, 5H, Ph), 7.07 (d, J = 8.8Hz, 2H, aroma), 4.15 (t, J = 6.0Hz, 2H, CH 2 O), 3.09(m, 6H, 3CH 2 N), 2.15(m, 2H, CH 2 ), 1.70 (m, 4H, 2CH 2 ), 1.50 (m, 2H, CH 2 )

[0392] B 4-(3-chloropropoxy)benzophenone can be prepared as follows:

[0393] Following the procedure described in Example 1§E, but starting with N of 4-hydroxybenzophenone (0.99 g), potassium carbonate (3.45 g) and 1-bromo-3-chloropropane (2.5 mL), A sol...

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Abstract

The present patent application concerns compounds of formula (I) with R1 and R2 taken together with the nitrogen atom to which they are attached, form a mono or bicyclic saturated nitrogen-containing ring; their preparation and their use as a H3 receptor ligand for treating e.g. CNS disorders like Alzheimer's disease.

Description

technical field [0001] This patent application relates to the new H 3 - Receptor ligands, processes for their preparation, and their therapeutic use. Background technique [0002] known histamine H 3 - Receptor antagonists in particular increase the synthesis and release of histamine in the brain. Through this mechanism, it results in prolonged wakefulness, improved cognitive processes, decreased food intake and normalized vestibular reflexes (Schwartz et al., Physiol. Rev., 1991, 71: 1-51). [0003] known histamine H 3 - Agonists inhibit the release of several neurotransmitters, including histamine, monoamine, and neuropeptides, thereby exerting a calming and sleep-promoting effect in the brain. In peripheral tissues, H 3 - Receptor agonists exert anti-inflammatory, analgesic, gastrointestinal inhibitory secretory smooth muscle relaxation activity. [0004] previously known H 3 Receptor antagonist or agonist compounds are similar to histamine in having a 4(5)-monosub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/088C07D213/30C07D211/68C07D333/16C07D211/14C07D401/10A61K31/40A61K31/44A61K31/381A61K31/5377A61P25/00
CPCC07D207/20C07D207/30C07D207/335C07D211/22C07D211/42C07D211/46C07D211/68C07D211/70C07D213/30C07D213/61C07D213/64C07D213/89C07D231/12C07D295/088C07D295/192C07D333/16C07D333/20C07D401/12C07D401/14C07D409/12C07D413/12A61P11/00A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/20A61P25/22A61P25/24A61P25/28A61P3/10A61P3/04A61P43/00A61P5/02A61K31/44
Inventor 伊莎贝尔·贝特朗马克·卡佩让娜-玛丽·勒孔特尼古拉·勒沃恩哈维尔·利尼奥奥利维娅·普帕尔丹-奥利维耶菲利普·罗贝尔让-夏尔·施瓦茨奥利维耶·拉比尤
Owner BIOPROJET
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