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2-(1H-4(5)-imidazoyl cyclopropyl derivatives

A kind of composition and compound technology, applied in the field of treating diseases that need to block histamine H3 receptors, 1H-4-substituted imidazole derivatives and salts or solvates thereof

Inactive Publication Date: 2003-02-05
GLIATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These data support the hypothesis that histamine may have a function in modulating behavioral arousal

Method used

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  • 2-(1H-4(5)-imidazoyl cyclopropyl derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] N-(1-benzyl)-3-[(1H-imidazol-5-yl)]-2(R)-3(S)-cyclopropanamide and N-(1-benzyl)-3-[( Preparation of 1H-imidazol-5-yl)]-2(S)-3(R)-cyclopropanamide hydrochloride racemic mixture

[0136] According to Burger et al., J. Med. Chem., (1970), 13 : 3-[(1-triphenylmethyl-5-imidazolyl)]-2(R)-3(S)-cyclopropionic acid and 3-[(1-triphenyl) prepared by the method described in 33-35 The racemic mixture (0.334 g, 0.84 mM) of 2(S)-3(R)-cyclopropionic acid) was suspended in 5 mL of distilled water. Sufficient acetone (35 mL) was added throughout the solution and the homogenized solution was cooled to 0-5°C. Triethylamine (0.101 g, 1.0 mM) in 5 mL of acetone was added, followed by the dropwise addition of ethyl chloroformate (0.108 g, 1.0 mM). The reaction mixture was stirred at 0 °C for 30 minutes, then benzylamine (0.16 g, 1.5 mM) in 10 mL of acetone was added dropwise. The reaction mixture was stirred at 0-5°C for 1 hour, then cold saturated ammonium chloride solution (100 mL) wa...

Embodiment 2

[0141] N-(1-cyclohexylmethyl)-3-(1H-imidazol-5-yl)-2(R)-3(S)-cyclopropanamide and N-(1-cyclohexylmethyl)-3- Preparation of (1H-imidazol-5-yl)-2(S)-3(R)-cyclopropanamide hydrochloride racemic mixture

[0142] Except that benzylamine is replaced with cyclohexanemethylamine, the method described in Example 1 is followed to obtain N-(1-cyclohexylmethyl)-3-(1H-imidazol-5-yl)-2(R) -3(S)-cyclopropanamide and N-(1-cyclohexylmethyl)-3-(1H-imidazol-5-yl)-2(S)-3(R)-cyclopropanamide hydrochloride racemic mixture. NMR (CD 3 OD, 300MHz): d7.78(s, 1H), 6.92(s, 1H), 3.02(m, 2H), 2.30(m, 1H), 1.84(m, 1H), 1.74(m, 4H), 1.45 (m, 1H), 1.35(m, 1H), 1.22(m, 3H), 0.94(m, 2H) mass spectrum (DCl / NH 3 ): 248(M+1) + , MW=247.3422, C 14 h 21 N 3 o 1 .

Embodiment 3

[0144] N-[1-(3-aminopropyl)-2-methylpiperidine]-3-(1H-imidazol-5-yl)-2(R)-3(S)-cyclopropanamide and N-[ 1-(3-aminopropyl)-2-methylpiperidine]-3-(1H-imidazol-5-yl)-2(S)-3(R)-cyclopropanamide hydrochloride racemic mixture preparation of

[0145] Except that 1-(3-aminopropyl)-2-methylpiperidine is used instead of benzylamine, the method described in Example 1 is followed to obtain N-[1-(3-aminopropyl)-2-methylpiperidine Basepiperidine]-3-(1H-imidazol-5-yl)-2(R)-3(S)-cyclopropanamide and N-[1-(3-aminopropyl)-2-methylpiperidine ]-3-(1H-Imidazol-5-yl)-2(S)-3(R)-cyclopropanamide hydrochloride racemic mixture. NMR (CD 3 OD, 300MHz): d8.80(s, 1H), 7.38(s, 1H), 3.55(m, 1H), 3.3(m, 3H), 3.1(m, 3H), 2.44(m, 1H), 1.96 (m, 4H), 1.8(m, 2H), 1.55(m, 2H), 1.39(d, 3H, J=6Hz), 1.35(m, 4H) mass spectrum (DCl / NH 3 ): 291 (M+1) + , MW=290.4109, C 16 h 26 N 4 o 1 .

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Abstract

The present invention provides compounds having H3 histamine receptor antagonist activity of formula (1.0) wherein R2 is a hydrogen or a methyl or ethyl group; R3 is a hydrogen or a methyl or ethyl group; n is 0, 1, 2, 3, 4, 5, or 6; and R1 is selected from the group consisting of (a) C3 to C8 cycloalkyl; (b) phenyl or substituted pneyly; (c) alkyl; (d) heterocyclic; (e) decahydronaphthalene; and (f) octahydroindene; with the proviso that when X is H, A can be -CH2CH2, -COCH2-CON(CH3)-, -CH=CH-, alpha , -CH2-NH-, -CH3-N(CH3)-, -CH(OH)CH2-, -NH-CH2-, -N(CH3)-CH2-, -CH2O-, -CH2S-, and -NHCOO-; when X is NH2, HN(CH3), N(CH3)2, OH, OCH3, CH3, SH and SCH3; A can be -NHCO-, -N(CH3)-CO-, -NHCH2-, -N(CH3)-CH2-, -CH=XH-, -COCH2-, -CH2CH2-, -CH( )H)CH2-, or beta ; and when R1 and X taken together denote a 5,6 or 6,6 saturated bicyclic ring structure, X can be NH, O, or S. The pharmaceutically acceptable salts, hydrates, and individual stereoisomers of compounds of structural formula (1.0), as well as mixtures thereof, are also contemplated as falling within the scope of the present invention. The invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with an effective amount of a compound of said formula and a method of treating conditions in which antagonism of histamine H3 receptors may be of therapeutic importance.

Description

technical field [0001] The present invention relates to pharmacologically active compounds, compositions containing these compounds, and methods of treatment using these compounds and compositions. More particularly, the present invention relates to certain 1H-4(5)-substituted imidazole derivatives and salts or solvates thereof. These compounds have H 3 Histamine receptor antagonist activity. The present invention also relates to pharmaceutical compositions containing these compounds, and to treatments requiring blocking of histamine H 3 Methods of Recipient's Disease. Background of the invention [0002] Histamine is a chemical transmitter involved in a variety of complex biological effects. When released, histamine interacts with specific macromolecular receptors on the cell surface or in target cells, causing changes in various body functions. Multiple cell types, including smooth muscle, blood cells, immune system cells, endocrine and exocrine c...

Claims

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Application Information

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IPC IPC(8): C07D233/54C07D233/56C07D233/60C07D233/64
CPCC07D233/64A61P43/00A61K31/415C07D233/60
Inventor J·G·菲利浦C·E·特霍尔德A·M·汉S·L·雅特斯
Owner GLIATECH
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