Histamine H3 receptor antagonists

An alkyl, general formula technology, applied in the field of new compounds, can solve the problem of not giving the pharmacological data of the compound and so on

Inactive Publication Date: 2008-07-09
HIGH POINT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

No pharmacological data are given for the compounds prepared

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0440] Example 1 (General Method A)

[0441] 1-[5-(4-Chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride

[0442]

[0443]2-Chloro-5-(4-chlorophenyl)pyridine (500 mg, 2.23 mmol), DMSO (2.0 mL) and 1-isopropylpiperazine (3 mL, 23.4 mmol) were stirred and heated in a 100 °C oil bath overnight. The reaction mixture was poured into water (75 mL), and the solid was isolated by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel (Kiselgel 60, 0.040-0.63 mesh), washing with a mixture of ethyl acetate and methanol (4:1). Collection of appropriate fractions afforded 600 mg (85%) of 1-[5-(4-chlorophenyl)-pyridin-2-yl]-4-isopropylpiperazine.

[0444] 1 H NMR (300MHz, CDCl 3 )δ1.10 (d, 6H), 2.63-2.68 (m, 4H), 2.75 (septet, 1H), 3.59-3.66 (m, 4H), 6.69 (d, 1H), 7.35-7.45 (m, 4H ), 7.67 (dd, 1H), 8.40 (d, 1H).

[0445] The free base was dissolved in a mixture of 0.5N hydrochloric acid solution and ethanol. A...

Embodiment 2

[0450] Embodiment 2 (general method A)

[0451] 1-Isopropyl-4-[5-(4-methoxyphenyl)pyridin-2-yl]piperazine, dihydrochloride

[0452]

[0453] 2-Chloro-5-(4-methoxyphenyl)pyridine (200 mg, 0.91 mmol), anhydrous DMSO (2.0 mL) and 1-isopropylpiperazine (500 mg, 3.9 mmol) were stirred and heated at 130° C. Heat in an oil bath overnight, then heat at 150°C for 4 hours, leave at room temperature for 2 days, and finally heat at 140°C overnight. The reaction mixture was cooled, then poured into water (100 mL). The mixture was extracted with ethyl acetate (100 mL), and the organic extract was washed with water and dried (MgSO 4 ). The solvent was evaporated to give a solid residue which was dissolved in 0.5N hydrochloric acid (20 mL). A small amount of insoluble solid was removed by filtration and the aqueous solution was evaporated to give a residue which was re-evaporated with absolute ethanol. The resulting solid was recrystallized from absolute ethanol to afford 210 mg (60%)...

Embodiment 3

[0458] Embodiment 3 (general method A)

[0459] 1-Isopropyl-4-[5-(4-trifluoromethoxyphenyl)pyridin-2-yl]piperazine, dihydrochloride

[0460]

[0461] Starting from 2-chloro-5-(4-trifluoromethoxyphenyl)pyridine and 1-isopropylpiperazine, in a similar manner to that described in Example 1, the title compound was prepared.

[0462] Mp=271-273°C.

[0463] 1 H NMR (300MHz, DMSO-d 6 )δ1.32(d, 6H), 3.05-3.21(m, 2H), 3.45-3.67(m, 5H), 4.50-4.61(m, 2H), 7.28(d, 1H), 7.46(d, 2H) , 7.82 (d, 2H), 8.17 (d, 1H), 8.46 (s, 1H), 11.4 (brs, 1H).

[0464] C 19 h 22 f 3 N 3 Microanalysis of O, 2 x HCl:

[0465] Calculated value: C: 52.06%; H: 5.52%; N: 9.59%;

[0466] Measured values: C: 52.07%; H: 5.53%, N: 9.36%.

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PUM

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Abstract

Novel compounds which interact with the histamine H3 receptor are defined. These compounds are particularly useful in the treatment of a variety of diseases or conditions in which histamine H3 interactions are beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system. The novel compounds have a core consisting of a 6 membered aromatic ring containing at least one nitrogen atom and two carbon atoms in the ring and, at the remaining positions in the ring, there is either a carbon or a nitrogen atom.

Description

field of invention [0001] The present invention relates to novel compounds, to the use of these compounds in pharmaceutical compositions, to pharmaceutical compositions comprising said compounds, and to methods of treatment using these compounds or compositions. The compounds of the present invention exhibit high and selective binding affinity to histamine H3 receptors, and exhibit histamine H3 receptor antagonistic, inverse agonistic or agonistic activities. Thus, the compounds are useful in diseases or conditions associated with histamine H3 receptors. Background of the invention [0002] The existence of the histamine H3 receptor has been known for several years, and this receptor is currently of interest for the development of new drugs. Recently, the histamine H3 receptor has been cloned. Histamine H3 receptors are presynaptic autoreceptors located in the central and peripheral nervous systems, skin and organs such as lungs, intestines, perhaps spleen and gastrointest...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/74C07D213/84C07D401/04C07D213/87C07D401/08C07D413/04C07D403/04C07D413/14C07D401/12C07D241/20C07D403/12A61P3/00C07D405/06A61K31/444C07D413/10
CPCC07D401/04C07D213/74C07D213/84C07D213/87C07D241/20C07D401/08C07D401/12C07D403/04C07D403/12C07D405/06C07D413/04C07D413/10C07D413/14
Inventor R·霍尔韦格K·E·安德森J·L·索伦森J·M·伦德贝克
Owner HIGH POINT PHARMA
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