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WO1997031900A1 - Derives d'imidazole et inhibiteur d'epaississement de la paroi vasculaire - Google Patents

Derives d'imidazole et inhibiteur d'epaississement de la paroi vasculaire Download PDF

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Publication number
WO1997031900A1
WO1997031900A1 PCT/JP1997/000533 JP9700533W WO9731900A1 WO 1997031900 A1 WO1997031900 A1 WO 1997031900A1 JP 9700533 W JP9700533 W JP 9700533W WO 9731900 A1 WO9731900 A1 WO 9731900A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
pharmacologically acceptable
acceptable salt
hydrogen atom
Prior art date
Application number
PCT/JP1997/000533
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English (en)
Japanese (ja)
Inventor
Hiromu Harada
Hiroshi Kusama
Yoshinori Nonaka
Toshikazu Yazaki
Koji Kamata
Yukihiko Hotei
Kiyoshi Kasai
Original Assignee
Kissei Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to AU18113/97A priority Critical patent/AU1811397A/en
Publication of WO1997031900A1 publication Critical patent/WO1997031900A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to an imidazole derivative which has an inhibitory action on hyperproliferation of intimal cells and is useful as a pharmaceutical.
  • Atherosclerosis progresses due to the accumulation of lipids in the blood vessel wall, cell proliferation in the intima of the blood vessel, and the accumulation of collagen, etc., and the blood vessel wall becomes thickened or occluded. If such a state is left unattended, there is a risk of causing serious situations such as angina pectoris, myocardial infarction and cerebral infarction. At present, no drug has been developed to suppress the thickening or occlusion of the blood vessel wall caused by such arteriosclerosis.
  • vascular reconstruction techniques such as DCA (directional coronary atherectomy), which selectively cuts the diseased tissue at the stenotic site, are widely spread and are clinically practiced.
  • DCA directional coronary atherectomy
  • vascular wall thickening occurs again due to abnormal proliferation of vascular smooth muscle at the site damaged by the insertion of a balloon catheter.
  • the intravascular placement of DCA II stent also causes restenosis similar to that of PTCA. Therefore, a major problem remains in the above-mentioned vascular reconstruction.
  • the compound of the present invention has the general formula
  • R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acetyl group, a mono- or di-lower alkyl-substituted amino group.
  • R s may be the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group, and R ⁇ and R s may be the same or different and each is a hydrogen atom or a lower alkyl group), and the other is a group represented by the general formula
  • R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n is an integer of 2 to 6) or a rubamoyl group optionally having a tetrazolyl group
  • R e is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula
  • R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6).
  • R 7 is a hydrogen atom or a lower alkyl group which may have a carboxyl group or a lower alkoxycarbyl group as a substituent.
  • the present invention relates to a drug comprising the imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention relates to a vascular wall thickening inhibitor comprising, as an active ingredient, an imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention relates to a method for preventing or treating a disease caused by hyperproliferation of intimal cells by administering an imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. It is.
  • the present invention relates to an imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for producing a preparation for preventing or treating a disease caused by hyperproliferation of intimal cells. It is about use.
  • the present invention relates to the use of the imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as a vascular wall thickening inhibitor.
  • the present inventors have conducted intensive studies to find a compound having an inhibitory effect on abnormal proliferation of endothelial cells, and as a result, a certain imidazole derivative represented by the above general formula (I)
  • the present inventors have found that they have excellent vascular smooth muscle cell proliferation inhibitory activity and the like, and are useful as an agent for suppressing vascular wall thickening, and have accomplished the present invention.
  • the present invention provides a compound represented by the general formula:
  • R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acetyl group, a mono- or di-lower alkyl-substituted amino group Or a lower alkoxycarbonyl group
  • R 2 and R s may be the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group
  • R 5 may be the same or different and each is a hydrogen atom or a lower alkyl group), and the other is a group represented by the general formula
  • R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n is an integer of 2 to 6) or a rubamoyl group optionally having a tetrazolyl group
  • R e is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula — (CH 2 ) m -R a
  • R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6).
  • R 7 is a hydrogen atom or a lower alkyl group which may have a carboxyl group or a lower alkoxycarbyl group as a substituent.
  • a pharmacologically acceptable derivative thereof It is useful for preventing or treating diseases caused by intimal cell hyperproliferation.
  • the lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group.
  • a straight-chain branched or branched alkyl group having 1 to 6 carbon atoms such as tyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, and hexyl group;
  • Lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert —A linear or branched alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group and a hexyloxy group.
  • Aralkyl is a lower alkoxy group substituted with an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, and a cycloalkylalkoxy group is substituted with a 3- to 7-membered cyclic alkyl group. And the lower alkoxy group.
  • a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • a lower acetyl group refers to a straight or branched alkyl group such as an acetyl group, a propionyl group, and a butyryl group having 2 carbon atoms. ⁇ 7 alkylcarbonyl groups.
  • the mono- or di-lower alkyl-substituted amino group refers to an amino group mono-substituted with the lower alkyl group or an amino group di-substituted with the same or different lower alkyl group.
  • the compound represented by the above general formula (I) of the present invention can be produced, for example, as follows.
  • R 1 Q in the formula is a hydrogen atom, a halogen atom, a hydroxyl group having a protecting group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group having a protecting group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acryl group, A mono-lower alkyl-substituted amino group, a di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group having a group, wherein R 2 , R 3 , R ⁇ and R 5 have the same meaning as described above. Derivative or its reactive functional derivative such as acid halide, active ester, etc. (In the formula, one of P and Q is an amino group, and the other is a substituent.
  • R ° is a hydroxyl group, an amino group having a protecting group, a mono-lower alkyl-substituted amino group or a di-lower alkyl-substituted amino group having a protecting group, and n is an integer of 2 to 6).
  • R 8 is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula:
  • R e is a hydrogen atom or a lower alkyl group optionally having a lower alkoxyl group as a substituent.
  • the imidazole derivative is reacted with an imidazole derivative in an inert solvent in the presence of a base, in the presence or absence of a dehydrating agent or a condensing agent, and if necessary, an alkyl group is added to the nitrogen atom in the imidazole ring using an alkyl halide. It can be produced by introducing and, if necessary, removing a protecting group according to a conventional method, followed by hydrolysis and amidation as required.
  • [A 1 and B 1 in the formula are either general formulas.
  • the compounds represented by the general formulas (II) and (V) used as raw materials in the production method may be purchased as a commercial product, or may be produced by a known method described in a literature or a method similar thereto. it can.
  • the compound represented by the general formula (III) used as a raw material in the production method can be purchased as a commercial product, or can be produced by a known method described in a literature or a method similar thereto (J. Am. Chem. Soc., Vol. 74, pp. 2892-2894 (1952), Tetrahe dron, Vol. 42, No. 10, pp. 2625-2634 (1986)).
  • the compound represented by the general formula (IV) used as a raw material in the production method may be a reactive functional group such as a gay cinnamate derivative represented by the general formula (II) or an acid halide or an active ester thereof.
  • a reactive functional group such as a gay cinnamate derivative represented by the general formula (II) or an acid halide or an active ester thereof.
  • T and U in the formula is an amino group and the other is a lower alkoxycarbonyl group
  • an aminoimidazole derivative represented by the following formula: Or reacting in the presence or absence of a condensing agent to convert the ester group to a carboxyl group by hydrolysis,
  • R 2 , R s , R ⁇ , R 5, and R lfl have the same meanings as described above
  • the other is a carboxyl group.
  • it can be produced by ring closure in an inert solvent in the presence of a dehydrating agent such as acetic anhydride or a condensing agent, or by dehydration ring closure under heating.
  • the compound represented by the general formula (VI) used in the production method can be produced by a known method described in the literature or a method similar thereto (J. Chem. Soc., 1071). Pp. 1074 (1949), J. Chem. Soc. Perk in Tran s. I, 2310-2315 (1980), etc.).
  • the imidazole derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof by a conventional method.
  • Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid And salts with organic bases such as lysine, lysine and arginine, and salts with inorganic bases such as sodium salt and potassium salt.
  • mineral acids such as hydrochloric acid,
  • the compound represented by the general formula (I) of the present invention also includes hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.
  • the compound of the present invention represented by the general formula (I) has an unsaturated bond and thus has two geometric isomers.
  • the compound of cis form (Z form) or the trans form (Z form) Any of the compounds of the E-form) may be used.
  • a compound having an asymmetric carbon atom has two optical isomers having an R configuration and an S configuration.
  • Optical isomers may be used, and a mixture of those optical isomers may be used.
  • R 7 is preferably a hydrogen atom.
  • the compound of the present invention represented by the above general formula (I) is extremely potent in inhibiting vascular smooth muscle proliferation in an in vitro cell proliferation inhibition test using thoracic aortic vascular smooth muscle cells of spontaneously hypertensive rats. It has an action.
  • Carboxamide hydrochloride has a concentration of 46 M
  • (E) — 4 (5) Power Lubamoy Roux 5 (4)-(3, 4, 5—trimethoxycinnamoylamino) imidazole
  • the compounds of the present invention represented by the above general formula (I) and their pharmacologically acceptable salts have excellent inhibitory activity against hyperproliferation of intimal cells, It is a very useful compound as an inhibitor.
  • the compound represented by the general formula (I) of the present invention includes, for example, restenosis of a coronary artery after PTCA, restenosis after DCA, restenosis after placement of a stent in a blood vessel, autologous blood vessel and artificial blood vessel. It is effective for diseases caused by hyperproliferation of intimal cells such as restenosis and arteriosclerosis after transplantation.
  • the compound represented by the general formula (I) of the present invention is a highly safe compound.
  • (E) -5 (4) — (3,4,5) — Trimetroxycinnamoylamino) Imidazolone 4 (5) — Carboxamide hydrochloride showed no deaths and no abnormalities even after a single administration of 200 OmgZkg.
  • a suitable pharmaceutical composition such as a tablet, a powder or a granule is used. It is administered orally or parenterally as capsules, injections and the like.
  • These pharmaceutical compositions can be prepared by the pharmaceutical methods used in general preparations, by using carriers, excipients and other additives commonly used for pharmaceuticals.
  • the dosage is determined as appropriate depending on the gender, age, weight, degree of symptoms, etc. of the target patient.In the case of oral administration, it is generally 0.1 to 1000 mg per adult per day.
  • parenteral administration it is generally administered in the range of 0.01 to 10 Omg per adult per day, in one or several doses. P / 97/00
  • Acetic anhydride (369 ml) was added to a solution of 363.8 mg) in pyridine (10 ml) and reacted at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was stirred for 1.5 hours, and then extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid (E) -4- (2-acetoxethoxy) -3,5-dimethoxycinnamic acid (360.2 mg).
  • N, N-Dimethylformamide (0.1 ml) was added to a solution of 3,4,5-trimethoxycinnamic acid (10. Og) and thionyl chloride (6.1 ml) in toluene (100 ml), and the mixture was heated at 80 ° C. Stir for 3 hours.
  • the reaction solution was concentrated under reduced pressure, hexane was added to the residue, and the insoluble material was collected by filtration to obtain (E) -3,4,5-trimethoxysiloxane cinnamate chloride (10.3 g).
  • Aluminum foil (190 mg) was added to a solution of mercuric chloride (76 mg) in water (7.6 ml), and the mixture was stirred at room temperature for 1 minute. After removing the solvent, the aluminum amalgam was washed sequentially with water, methanol and getyl ether. Then, under an argon atmosphere, getyl ether (5.5 ml), tert-butyl hydroxyiminocyanoacetate (l.Og) ethyl ether (4 ml) solution and water (0.4 ml) were added sequentially.
  • SHR Spontaneously hypertensive rat
  • Thoracic aortic vascular smooth muscle cells were isolated by the EpXPant method, added to a 96-well plate at 500 cells each, and added at 37 ° C, 95% air, The cells were cultured in a DMEM culture medium containing 10% fetal bovine serum under conditions of 5% carbon dioxide for 3 days. Three days later, the culture solution of each phenyl was replaced with a DMEM culture solution containing a drug, tritiated thymidine was added, and the cells were cultured for 24 hours. After the culture, the radioactivity incorporated in the DNA fraction was measured and used as an index of the cell proliferation activity.
  • the growth inhibitory activity of the compound was represented by a concentration (IC 50 ) showing 50 % inhibition with respect to the untreated group. The results are shown in the table below.
  • mice Male 7-week-old ICR mice consisted of 5 mice per group, fasted for 4 hours and suspended in 0.5% sodium carboxymethylcellulose ( ⁇ ) -5 (4) 1-2 (3,4,5- Trimethoxycinnamoylamino) imidazole-4 (5) monocarboxamide hydrochloride was administered orally at 100, 300, 100, 200 mg Okg / kg to examine the presence or absence of death. No deaths were observed in the group administered with 200 mg OkgZkg, and no abnormalities occurred.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés d'imidazole représentés par la formule générale (I) et leurs sels pharmacologiquement acceptables (formule dans laquelle A ou B représentent un groupe représenté par la formule générale (II) et l'autre représente un groupe carbamoyle), présentant une activité inhibant la croissance excessive des cellules de l'intima, utiles en tant qu'inhibiteur d'épaississement de la paroi vasculaire.
PCT/JP1997/000533 1996-02-29 1997-02-26 Derives d'imidazole et inhibiteur d'epaississement de la paroi vasculaire WO1997031900A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU18113/97A AU1811397A (en) 1996-02-29 1997-02-26 Imidazole derivatives and vascular wall thickening inhibitor

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP8/82966 1996-02-29
JP8296696 1996-02-29
JP35423896 1996-11-28
JP35423796 1996-11-28
JP8/354238 1996-11-28
JP8/354237 1996-11-28

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046573A1 (fr) * 1997-04-15 1998-10-22 Kissei Pharmaceutical Co., Ltd. Derives d'acide 2-substitue carbamoylimidazolecarboxylique et inhibiteur de l'epaississement de la paroi vasculaire
WO2001025190A1 (fr) * 1999-10-01 2001-04-12 Japan Energy Corporation Nouveaux derives de diarylamide et utilisation de ces composes comme medicaments
WO2006001750A1 (fr) * 2004-06-24 2006-01-05 Astrazeneca Ab Variants d'imidazole utilises comme modulateurs du recepteur gaba pour le traitement de troubles gastro-intestinaux
FR2889190A1 (fr) * 2005-08-01 2007-02-02 Merck Sante Soc Par Actions Si Nouveaux derives d'imidazoles carboxamides comme inhibiteurs de fructose -1,6-biphosphatase et compositions pharmaceutiques les contenant
CN100473661C (zh) * 2001-07-24 2009-04-01 博新药业股份有限公司 达玛烷皂苷配基,它们作为抗癌剂的应用和生产它们的方法
US7745474B2 (en) 2005-12-23 2010-06-29 Astrazeneca Ab Imidazole derivatives for the treatment of gastrointestinal disorders
US7812026B2 (en) 2005-12-23 2010-10-12 Astrazeneca Ab Imidazole derivatives having a positive allosteric GABAB receptor modulator effect and methods of use
JP2012506852A (ja) * 2008-10-27 2012-03-22 コンジェニア・エッセエッレエッレ ミトコンドリアの膜透過性遷移の阻害剤として有用なアクリルアミド誘導体
US10821096B1 (en) 2019-04-15 2020-11-03 King Abdulaziz University Compounds for inhibiting NS3 and compositions containing the inhibited protein

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04154720A (ja) * 1990-10-16 1992-05-27 Terumo Corp カテコール誘導体及びこれを含有する血管壁肥厚防止薬
JPH0789938A (ja) * 1993-07-31 1995-04-04 Hoechst Ag 置換ベンゾイルグアニジン類、それらの製造方法、医薬または診断剤としてのそれらの使用およびそれらを含有する医薬
JPH07109251A (ja) * 1993-08-27 1995-04-25 Hoechst Ag オルト置換ベンゾイルグアニジン、それらの製法、医薬または診断剤としてのそれらの使用およびそれらを含有する医薬

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04154720A (ja) * 1990-10-16 1992-05-27 Terumo Corp カテコール誘導体及びこれを含有する血管壁肥厚防止薬
JPH0789938A (ja) * 1993-07-31 1995-04-04 Hoechst Ag 置換ベンゾイルグアニジン類、それらの製造方法、医薬または診断剤としてのそれらの使用およびそれらを含有する医薬
JPH07109251A (ja) * 1993-08-27 1995-04-25 Hoechst Ag オルト置換ベンゾイルグアニジン、それらの製法、医薬または診断剤としてのそれらの使用およびそれらを含有する医薬

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Title
TETRAHEDRON, Vol. 38, No. 10, (1982), F.E. NIELSEN et al., "Phosphorus Pentoxide in Organic Synthesis. I. Phosphorus Pentoxide-Amine Hydrochloride Mixtures as Reagents in a New Synthesis of Hypoxanthines", pages 1435-1441. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046573A1 (fr) * 1997-04-15 1998-10-22 Kissei Pharmaceutical Co., Ltd. Derives d'acide 2-substitue carbamoylimidazolecarboxylique et inhibiteur de l'epaississement de la paroi vasculaire
WO2001025190A1 (fr) * 1999-10-01 2001-04-12 Japan Energy Corporation Nouveaux derives de diarylamide et utilisation de ces composes comme medicaments
CN100473661C (zh) * 2001-07-24 2009-04-01 博新药业股份有限公司 达玛烷皂苷配基,它们作为抗癌剂的应用和生产它们的方法
WO2006001750A1 (fr) * 2004-06-24 2006-01-05 Astrazeneca Ab Variants d'imidazole utilises comme modulateurs du recepteur gaba pour le traitement de troubles gastro-intestinaux
US7718686B2 (en) 2004-06-24 2010-05-18 Astrazeneca Ab Imidazole variants as modulators of GABA receptor for the treatment of GI disorders
FR2889190A1 (fr) * 2005-08-01 2007-02-02 Merck Sante Soc Par Actions Si Nouveaux derives d'imidazoles carboxamides comme inhibiteurs de fructose -1,6-biphosphatase et compositions pharmaceutiques les contenant
JP2009502992A (ja) * 2005-08-01 2009-01-29 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング フルクトース−１，６−ビスホスファターゼ阻害剤としての新規イミダゾールカルボキサミド誘導体、およびそれを含む医薬組成物
WO2007014619A1 (fr) * 2005-08-01 2007-02-08 Merck Patent Gmbh Nouveaux dérivés d’imidazole carboxamide comme inhibiteurs de la fructose-1,6-bisphosphatase, et compositions pharmaceutiques qui les contiennent
AU2006275172B2 (en) * 2005-08-01 2011-11-24 Merck Patent Gmbh Novelimidazolecarboxamide derivatives as fructose-1,6-bisphosphatase inhibitors, and pharmaceutical compositions comprising same
US8362057B2 (en) 2005-08-01 2013-01-29 MERCK Patent Gesellschaft mit beschränkter Haftung Imidazolecarboxamide derivatives as fructose-1,6-bisphosphatase inhibitors, and pharmaceutical compositions comprising same
US7745474B2 (en) 2005-12-23 2010-06-29 Astrazeneca Ab Imidazole derivatives for the treatment of gastrointestinal disorders
US7812026B2 (en) 2005-12-23 2010-10-12 Astrazeneca Ab Imidazole derivatives having a positive allosteric GABAB receptor modulator effect and methods of use
JP2012506852A (ja) * 2008-10-27 2012-03-22 コンジェニア・エッセエッレエッレ ミトコンドリアの膜透過性遷移の阻害剤として有用なアクリルアミド誘導体
US10821096B1 (en) 2019-04-15 2020-11-03 King Abdulaziz University Compounds for inhibiting NS3 and compositions containing the inhibited protein
US10959987B2 (en) 2019-04-15 2021-03-30 King Abdulaziz University Imidazole-based compounds as hepatitis C virus inhibitors

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