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4-(phenylmethyl and substituted phenylmethyl)-imidazole-2-thiones acting as specific alpha2 adrenergic agonists

A carbon alkyl, CH2 technology, applied in the field of 4--imidazole-2-thione, can solve the problems of adverse side effects, low blood pressure, inability to provide activity and specificity, etc.

Inactive Publication Date: 2007-09-05
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many compounds with this activity are useful in the treatment of alpha 2 Does not provide desired activity and specificity in adrenoceptor-mediated disorders
For example, many compounds found to be effective agents in the treatment of pain are often found to have adverse side effects such as hypotension and sedation at systemically effective doses

Method used

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  • 4-(phenylmethyl and substituted phenylmethyl)-imidazole-2-thiones acting as specific alpha2 adrenergic agonists
  • 4-(phenylmethyl and substituted phenylmethyl)-imidazole-2-thiones acting as specific alpha2 adrenergic agonists
  • 4-(phenylmethyl and substituted phenylmethyl)-imidazole-2-thiones acting as specific alpha2 adrenergic agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0116] Method A: Method for the preparation of 4-[1-(2,3-dichloro-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione

[0117] (compound 1)

[0118]

[0119] 4-iodo-1-trityl imidazole (see Cliff et.al. Synthesis (1994) 681, incorporated herein by reference) in dichloromethane (44 mL) at room temperature (rt) (4.4 g, 10.1 mmol ) was treated with ethylmagnesium bromide (3.40 mL, 10.2 mmol, 3M in ether) and allowed to react for 90 minutes. 2-Dichloroacetophenone (from Lancaster) (Intermediate A1 ) (1.0 g, 5.02 mmol) dissolved in dichloromethane (10 mL) was added via syringe at 20 °C and stirred for 16 h. The mixture was quenched with a saturated solution of ammonium chloride (50 mL) and washed with dichloromethane:CH 2 Cl 2 dilution. The organic material was separated by aqueous workup, followed by CH 2 Cl 2 extraction. Chromatography on silica gel with 2% MeOH:CH 2 Cl 2 Purification of the residue afforded 3.8 g of 1-(2,3-dichloro-phenyl)-1-(1-trityl-1H-imidazol-4-yl)-etha...

Embodiment A-2

[0123] Embodiment A-2 (compound 2)

[0124] 2-Fluoroacetophenone (purchased from Lancaster) was used in method A, where 10% Pd / C catalyst was used in step 4 instead of PtO 2 , 4-[1-(2,3-Difluoro-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione (compound 2) was produced. 1 H NMR (300MHz, methanol-d 4 ): δ7.19-7.06(m, 2H), 6.98-6.92(m, 1H), 6.64(d, J=1.2Hz, 1H), 4.33(q, J=7.2Hz, 1H), 1.55(d, J=7.5Hz, 3H).

Embodiment B

[0126] Method B: Process for the preparation of 4-[1-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione (compound 3)

[0127]

[0128] 2-Fluoro-3-trifluoromethylacetophenone (Intermediate B1) (purchased from Lancaster) was used in the appropriate process step of Method A (shown in the reaction scheme above) to obtain 1-(2-fluoro -3-Trifluoromethyl-phenyl)-1-(1-trityl-1H-imidazol-4-yl)-ethanol (intermediate B2).

[0129] Dissolve 1-(2-fluoro-3-trifluoromethyl-phenyl)-1-(1-trityl-1H-imidazol-4-yl) in acetic acid (13 mL) and water (3 mL) - Ethanol (Intermediate B2) (4.7 mmol) was heated to 100° C. for 1 h. The mixture was cooled to room temperature and basified with 2M NaOH. The compound was extracted with ethyl acetate and the solution was concentrated on silica gel. The product was treated with 3-5% NH 3 -MeOH:CH 2 Cl 2 Elution afforded 1-(2-fluoro-3-trifluoromethyl-phenyl)-1-(1H-imidazol-4-yl)-ethanol (intermediate B3) 1.1 g (85%).

[0130] Usi...

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PUM

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Abstract

The compound denoted in formula (1) with the meaning defined in the description is an excitant for Alpha2adrenoreceptor. The compounds disclosed in the present invention have specificity or selectivity to Alpha2B and / or Alpha2C adrenoreceptor in precedence, instead of Alpha2Aadrenoreceptor. In addition, some compounds that are claimed for protection have no or little activity to cardiovascular and / or calmness. The compound denoted in formula (1) can be used as an agent for mammals including human being to cure diseases and / or alleviate disease symptoms, which have response to therapeutic treatment with excitant for Alpha2adrenoreceptor. The compound denoted in formula (1) without noticeable activity to cardiovascular and / or calmness can be used to eliminate pain and other disease symptoms, with minimal side effect.

Description

technical field [0001] The present invention relates to 4-(benzyl and 4-substituted benzyl)-imidazole-2-thiones and to their use as agonists, preferably alpha 2 Use of a specific or selective agonist of an adrenergic receptor. More specifically, the present invention relates to the above-mentioned compounds, to pharmaceutical compositions containing these compounds, which are modulators of alpha 2 Active ingredients for adrenergic receptors, more particularly, relate to the use of these compounds and pharmaceutical compositions for the relief of chronic pain, allodynia, muscle spasticity, diarrhea, neuropathic pain and other diseases and conditions. Background technique [0002] Human adrenergic receptors are integral membrane proteins that are divided into two major classes: alpha and beta adrenergic receptors. Both types mediate peripheral sympathetic nervous system activity through binding to catecholamines, norepinephrine, and epinephrine. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/84A61K31/4174A61P1/12A61P7/12A61P9/12A61P29/00A61P37/00
CPCC07D233/84A61P1/00A61P1/04A61P1/12A61P1/14A61P13/02A61P17/00A61P19/02A61P19/08A61P21/02A61P25/00A61P25/04A61P25/18A61P25/22A61P25/24A61P25/28A61P25/36A61P27/02A61P27/06A61P27/16A61P29/00A61P37/00A61P37/02A61P7/12A61P9/04A61P9/10A61P9/12A61K31/4174
Inventor T·M·海德尔堡周健雄P·X·阮D·W·吉尔J·E·唐奈罗M·E·加斯特L·A·惠勒
Owner ALLERGAN INC
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