WO1996005202A1 - Derive de l'imidazoquinoleine - Google Patents

Derive de l'imidazoquinoleine Download PDF

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Publication number
WO1996005202A1
WO1996005202A1 PCT/JP1995/001621 JP9501621W WO9605202A1 WO 1996005202 A1 WO1996005202 A1 WO 1996005202A1 JP 9501621 W JP9501621 W JP 9501621W WO 9605202 A1 WO9605202 A1 WO 9605202A1
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Prior art keywords
group
compound
hydrogen
independently
general formula
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PCT/JP1995/001621
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English (en)
Japanese (ja)
Inventor
Yasunori Niiro
Hiroki Ueda
Toshio Satoh
Hitoshi Matsumoto
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Nippon Hypox Laboratories Inc
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Nippon Hypox Laboratories Inc
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Publication of WO1996005202A1 publication Critical patent/WO1996005202A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel imidazoliquinoline derivatives and pharmaceutical compositions containing the same.
  • cAP phosphodiesterase inhibitor has platelet aggregation inhibitory action, peripheral vasodilatory action, and / or positive cardiotonic action, and is known as an effective drug for diseases caused by circulatory disorders, and many compounds have been reported so far. I have.
  • ischemic conditions resulting from obstructive circulatory failure occur in major organs of the body, especially the heart, brain, liver, kidney, kidney, lung, etc.
  • irreversible tissue damage occurs due to consumption of intracellular energy Occurs.
  • the establishment of this circulatory failure state is closely related to lipid peroxidation in vivo and / or platelet aggregation, and vascular endothelial cells are harmed by lipid peroxidation induced by active oxygen and free radicals.
  • bradykinin acts on vascular endothelial cells to release and relax endothelial cell-derived vascular relaxing factor (EDRF), it acts directly on capillaries like histamine to increase vascular permeability, thus causing edema.
  • EDRF endothelial cell-derived vascular relaxing factor
  • RR 2 in group (a) is each independently a 4 alkyl group or a C, -C alkoxy group, and RR 4 is each independently a hydrogen, ( ⁇ -( ⁇ alkyl group or ( ⁇ -C, alkoxy group) 3 ⁇ 4,
  • R 5 and R 7 of the group (b) are independently water ⁇ , hydroxyl, ( ⁇ ⁇ (: 4 alkyl ⁇ or Ci ⁇ C 4 alkoxy), and both R 5 , R 5 are hydrogen simultaneously Rr., R 8 and R 3 are each independently hydrogen, hydroxyl, Ci-C 4 alkyl or
  • Rn, R «, R are not hydrogen at the same time
  • R lfl , Rn, R in the group (c) are each independently hydrogen, ( ⁇ ⁇ (: 4 alkyl group or C, ⁇ C 4 alkoxy group, R and Rn are not hydrogen at the same time,
  • the imidazoliquinoline derivative or a pharmacologically acceptable salt thereof represented by the above is at least two or more of the following: Smooth fats; antioxidant Sakugawa, lilt platelet coagulation, Okaizumigawa, histamine and anti-bradykinin In vivo lipid peroxidation, platelet aggregation, and the like by having metabolic activation in vivo and expressing at least two or more of these activities additively or synergistically Histamine, bradykinin
  • the present invention has been completed found to have a Kobo I 1.
  • the compounds (1) to (9) correspond to the compounds (1) to (9) of the present invention in Examples described later.
  • the imidazoliquinoline derivative of the present invention has an imidazoliquinoline moiety
  • the compound of the present invention includes these two tautomers.
  • the compound represented by the general formula (I) can be converted to an acid addition salt by treating with a known method.
  • Pharmaceutically acceptable salts of the compound represented by the general formula (I) include salts with hydrohalic acids such as hydrochloric acid and hydrobromic acid, salts with monocarboxylic acids such as acetic acid and brobionic acid, and sulfuric acid. And salts with sulfonic acids such as sulfonic acid, metasulfonic acid and p-toluenesulfonic acid, and salts with dicarboxylic acids such as oxalic acid, malonic acid and succinic acid.
  • Y is a group
  • the imidazoliquinoline derivatives (for example, including the above compounds (1) to (4)) include General formula
  • R 2 are each independently Ci ⁇ C 4 alkyl or ( ⁇ ⁇ 4 alkoxy group, R 3, R 4 are each independently hydrogen, C! -C 4 alkyl group Or a C t -C 4 alkoxy group,
  • R 5 and R 7 in the group (b) are each independently hydrogen, a hydroxyl group, ( ⁇ ⁇ ( ⁇ an alkyl group or a C! C ⁇ alkoxy group, and it is possible that both Rr and R 7 are simultaneously hydrogen.
  • no,, Rn, R «, R] it independently hydrogen, hydroxyl, it is ( ⁇ - ( ⁇ alkyl or d -C 4 alkoxy group, R (; is, RR, of the three parties simultaneously hydrogen
  • R 1D , Rn, 2 in the group (c) are each independently hydrogen, a C, -C 4 alkyl group or a C]-( ⁇ alkoxy group, and Ri, R, R 12 Cannot be hydrogen at the same time,
  • rn, r and n 3 are each independently an integer from 1 to 6,
  • the condensation reaction is carried out in the presence of a solvent such as dimethylformamide or dimethylsulfonamide, using a catalyst such as triethylamine, diphenylphosphoric acid azide, dimethylaminoviridine or pyridine, and a condensing agent at about 110 ° C to 130 ° C.
  • a solvent such as dimethylformamide or dimethylsulfonamide
  • a catalyst such as triethylamine, diphenylphosphoric acid azide, dimethylaminoviridine or pyridine
  • a condensing agent at about 110 ° C to 130 ° C.
  • the reaction can be performed within a range of 0.5 hours to several days.
  • the oxidation reaction is used to convert quinone when X in the obtained compound of general formula (la) is hydroquinone, and this oxidation reaction is carried out using dimethylformamide, dimethylformamide, or dimethylformamide.
  • an oxidizing agent such as iron oxide, zinc oxide, silver oxide, or cerium ammonium nitrate in the presence of a solvent such as sulfonamide, tetrahydrofuran, or ethyl acetate, at about -10 ° (: up to 130 ° C)
  • the reaction can be performed for 0.5 hours to several days.
  • the known starting compound represented by the formula (III) required for the synthesis of the compound (la) of the present invention can be produced by the method described in the above-mentioned literature (J. Med. Chem. 1992, 35, 2672). , Comes 1 U. Further, one kind of the starting compound represented by the formula (II) required for the synthesis of the compound (la) of the present invention can be produced as follows.
  • a compound obtained by protecting one hydroxyl group of tri- or tetra-substituted hydroquinone with viva chloride is converted to tert-butyldimethylsilyl (TBDMSi), and then the vivaloyl group is removed and the hydroxyl group is converted to ⁇ -halogenyl.
  • TDMSi tert-butyldimethylsilyl
  • the compound of formula (Ila) can be prepared by alkylating and then condensing with a diamine.
  • the first name of the starting compound represented by the formula (II) necessary for the synthesis of the compound (la) of the present invention can be prepared as follows.
  • a compound of the formula (lib) can be produced by condensing an arylalkyl halide, which is a raw material compound, with monoformyldiamines and then subjecting the resultant to deformylation.
  • one kind of the starting compound represented by the formula (II) required for the synthesis of the? S3 ⁇ 4 compound (la) can be produced as follows.
  • a compound of formula (lie) can be produced by heating and reacting formaldehyde, substituted hydroquinones and monoformyldiamins under acidic conditions, and then oxidizing and then deformylating.
  • Y is a group
  • the imidazoliquinoline derivative (including, for example, the above compound (5)) represented by the general formula is — Hal (IVa)
  • R r> and R 7 are each independently a water ⁇ , a hydroxyl ⁇ , a C] -C 4 alkyl ⁇ or a ⁇ ⁇ ( 4 alkoxy group, and both R 7 are hydrogen simultaneously rather, Ro, R «, R: ! 1 are each independently hydrogen, hydroxyl, C CA alkyl group, or Ci ⁇ C 4 alkoxy group, Rc, R, that tripartite R 9 are hydrogen at the same time And is an integer from 1 to 6,
  • Hal is a halogen atom.
  • n n- and r are each independently an integer from 1 to 6.
  • Can be obtained by a condensation reaction with the compound represented by The condensation reaction is performed in an alcoholic solvent such as methanol or ethanol, a ketone solvent such as acetone or methyl ethyl ketone, a halogenated solvent such as dichloromethane or chloroform, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfonamide, etc.
  • an inorganic base such as potassium carbonate or sodium hydrogen carbonate
  • an organic base such as triethylamine or methylbiperidine in the presence of
  • the reaction can be carried out at a temperature in the range of 10 ° C. to 130 ° C. for 0.5 hours to several days.
  • the compound of the formula (IVa) required for the synthesis of the compound (lb) of the present invention can be produced as follows.
  • the compound of the formula (IVa) can be produced by reducing the formyl group of arylalkyl aldehydes obtained by a conventional method to obtain a hydroxyl group and substituting it with a halogen group.
  • the compound of the formula (V) necessary for the synthesis of the compound (lb) of the present invention can be produced by the method described in the above-mentioned literature (J. Med. Chem. 1993, 36, 3521).
  • Y is a group
  • the imidazoliquinoline derivative represented by (including, for example, the compounds (6) and (7)) is represented by the general formula
  • R 1 () , R u, and R are each independently hydrogen, ( ⁇ to ( ⁇ an alkyl group or
  • Hal is a halogen atom.
  • n 2 , ii 3, and r are each independently an integer of 1 to 6.
  • the condensation reaction is performed in an alcoholic solvent such as methanol or ethanol, a ketone solvent such as acetone or methyl ethyl ketone, a dichloromethane-based solvent such as dichloromethane, acetonitrile, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfonamide, etc.
  • an inorganic base such as potassium carbonate and sodium hydrogen carbonate
  • an organic base such as triethylamine and methylbiperidine in the presence of a solvent of about 110 ° C to 130 ° C for 0.5 hours to several hours.
  • the reaction can be carried out by reacting each day.
  • the compound of the formula (IVa) required for the synthesis of the compound (lb) of the present invention can be produced as follows.
  • the compound of the formula (IVb) can be produced by reducing the formyl group of arylalkyl aldehydes obtained by a conventional method to obtain a hydroxyl group and substituting it with a halogen group.
  • the compound of the formula (V) required for the synthesis of the present compound (113) can be produced by the method described in the above-mentioned reference (J. Med. Chem. 1993, 36, 3521).
  • the compound (I) of the present invention has an excellent inhibitory action on lipid peroxidation, an inhibitory action on platelet aggregation, an antihistamine action and an anti-brazokinin action as shown below, or is metabolically activated in vivo, It shows these effects and ischemic diseases of arterial vascular smooth muscle in the heart, lungs, brain, kidney, liver, and liver, including myocardial infarction, cerebral thrombosis, arterial sclerosis, glomerulonephritis, and diabetic nephropathy. Shows prophylactic and therapeutic effects, and ischemic It also has a prophylactic and therapeutic effect on radical-induced reperfusion injury that occurs after the condition has improved.
  • the compound (I) of the present invention has an antihistamine action and an anti-bradykinin action to inhibit the formation of edema, thereby reducing serious side effects such as cerebral edema, which are often observed in vasodilators.
  • a part of the main pharmacological action of the compound (I) of the present invention is considered to be derived from cAMP phosphodiesterase inhibitory action, and also has other pharmacological actions exhibited by general cAMP phosphodiesterase inhibitors, for example, a positive cardiotonic action. .
  • a 5-lipoxygenase inhibitory effect is also expected, it is also useful in preventing and treating diseases in which an anti-inflammatory effect and an anti-allergic effect are effective in cooperation with the aforementioned antihistamine and anti-bradykinin effects. .
  • the imidazoliquinoline derivative (I) which is the compound of the present invention can be prepared for administration using any conventional production method. Therefore, the pharmaceutical composition of the present invention contains at least one or more imidazoliquinoline derivatives (I). Such a pharmaceutical composition is prepared by adding commonly used pharmaceutical acceptable additives such as carriers and excipients for pharmaceuticals.
  • this pharmaceutical composition When used as a preparation for oral administration, this pharmaceutical composition can be used in the form of tablets, granules, capsules, liquids for internal use, etc., but is provided in a form suitable for absorption from the digestive tract. preferable.
  • a preparation in a desired form is provided for reasons of flowability, storage stability, etc., it can be provided by conventional preparation techniques.
  • a parenteral preparation when used as a parenteral preparation, it can be used in the form of injections, suppositories, infusion preparations, etc. It is also possible to take the form of fresh water, and it is also possible to provide in the form of liquid preparations and solid preparations by conventional preparation techniques.
  • the daily parenteral dose is usually about 0.01 to 100 per body weight. m, preferably about 0.05 to 10 m, orally about 0 :!
  • the dose is about 300 mg, preferably about 0.5 to 30 mg, which may be administered in 1 to 5 divided doses.
  • the compound of the present invention (8) was obtained.
  • Rat liver microsomes obtained according to a conventional method are made ⁇ into Tris-monohydrochloride buffer (pH 7.4), NADPH (2 mM), ADP (10 mM) and FeCL (O.lmM) are added, and the mixture is heated to 37 ° C. Then, the reaction was carried out for 20 minutes. Then, the mixture was cooled on ice and the reaction was performed for 1 h, and the bovine-peroxidized fat i3 ⁇ 4 was determined using thiobarbituric acid. The percentage reduction in the amount of lipid peroxide produced relative to the control containing no drug was expressed as the inhibition rate of the lipid peroxidation reaction. Table 1 shows the results.
  • Pharmacological test example 2 [C-AMP phosphodiesterase inhibitory activity]
  • a human platelet-derived C-AMP phosphodiesterase suspension was obtained according to the method of G. H. Johns (Journal of Medicinal Chemistry 1987, 30, 295). This enzyme solution was added to a Tris-HCl buffer containing a drug, 0.5 mM gC, 0.137 M NaCU, 20 mM glucose and 0.2 / Ci [3H] C-AMP, and the mixture was heated at 37 ° C for 10 minutes. EDTA was added to the reaction solution, the reaction was stopped by immersing in a 90 ° C water bath for 60 seconds, and the amount of [3H] adenosine produced was measured. The percentage reduction in adenosine production relative to drug-free controls was expressed as% inhibition of C-AMP phosphodiesterase. Table 1 shows the results.
  • Rat platelet-rich plasma obtained according to a conventional method was added to an isotonic buffer solution, and platelet aggregation by ADP (5 M) was measured using an agglometer (PAM-6C manufactured by Mevanix). The percent reduction in the platelet coagulation rate 16 due to the animal relative to the control platelet coagulation rate was expressed as the platelet aggregation inhibition rate%. Table 1 shows the results.
  • the rat-extracted artery obtained according to the conventional method was vertically suspended and mounted on a Magnus tube equipped with an isotonic transducer, and an isotonic buffer was added to apply a constant load (0.5 g). After the blood vessel tension became constant, a drug was added to the blood vessel to determine the degree of relaxation of the tension. Table 1 shows the results.
  • Test compounds Fatty acid K-over ⁇ conversion fflS action Phosphodiesterase platelets; Si ⁇ 6 Suppression Anti-bradykinin action Antihistamine action Vasodilator
  • Pharmacological test example 6 [Anesthetic rat blood Hi-lowering effect]
  • Pharmacological test example 7 Coronary artery occlusion in anesthesia rat-inhibitory effect on reperfusion-induced ventricular arrhythmia due to reperfusion
  • mice Male ddy mice were intravenously administered with 50 g / kg of epinephrine and 800 g / kg of collagen, and the number of surviving animals was observed within 24 hours after administration. Table 4 shows the results.
  • the compounds of the present invention suppressed death due to obstructive peripheral circulatory disorders and showed an inhibitory action on peripheral circulatory disorders.
  • the imidazoliquinoline derivative represented by the general formula (I) or a pharmacologically acceptable salt has excellent lipid peroxidation inhibitory activity, platelet aggregation inhibitory activity, anti-histamine and anti-bradykinin activity.
  • Lipid peroxidation in vivo by having at least two or more pharmacological actions combined, or by inducing metabolic activation in vivo and expressing at least two or more of these actions additively or synergistically
  • Various thromboembolic diseases caused by platelet aggregation, histamine, and bradykinin such as transient ischemic diseases such as coronary infarction and cerebral infarction or ulcers, pain and chronic arteriosclerosis.
  • ischemic symptoms such as cold sensation, glomerulonephritis, diabetic nephropathy, and reperfusion injury that occurs after recovery from this ischemic condition. It is preferably used as a medicament for treating or preventing these diseases.

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

Abstract

Dérivé de l'imidazoquinoléine représenté par la formule générale (I), ou son sel pharmacologiquement acceptable, formule dans laquelle chaque substituant se présente tel qu'il est précisé dans la description. Ces substances ont au moins deux sortes d'effets pharmacologiques, notamment d'inhiber la peroxydation lipidique et l'agglutination plaquettaire et de combattre l'action de l'histamine et de la bradykinine. Elles sont efficaces pour le traitement ou la prévention de diverses maladies thromboemboliques, d'accès ischémiques transitoires comme l'infarctus du myocarde et l'infarctus cérébral, de l'artériosclérose, et en cas de troubles dus aux reperfusions survenant après des affections ischémiques, et constituent donc des remèdes utiles pour traiter ou prévenir ces maladies.
PCT/JP1995/001621 1994-08-17 1995-08-14 Derive de l'imidazoquinoleine Ceased WO1996005202A1 (fr)

Applications Claiming Priority (2)

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JP19336194 1994-08-17
JP6/193361 1994-08-17

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WO1996005202A1 true WO1996005202A1 (fr) 1996-02-22

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056790A1 (fr) * 1997-06-11 1998-12-17 Glaxo Group Limited Dihydroimidazo[1,5-b]isoquinoline-1,3-diones utilises comme inhibiteurs de l'apoproteine b-100
US5859025A (en) * 1996-03-19 1999-01-12 Hoechst Aktiengesellschaft Fluoroalkyl- and fluoroalkoxy-substituted heterocyclic bradykinin antagonists, process for their preparation, and their use
CN101381291B (zh) * 2008-10-28 2011-01-12 昆明理工大学 一种制备2,3,4,5-四甲氧基甲苯的方法
JP2016050850A (ja) * 2014-08-29 2016-04-11 日立化成テクノサービス株式会社 ＮＯｘ捕集材
WO2024149378A1 (fr) * 2023-01-13 2024-07-18 上海超阳药业有限公司 Composé quinolinone et composé naphtyridinone et leur utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03169880A (ja) * 1989-11-01 1991-07-23 Bristol Myers Squibb Co 水溶性の高められたイミダゾ〔４，５―ｂ〕キノリニルオキシアルカン酸アミド
US5196428A (en) * 1992-04-03 1993-03-23 Bristol-Myers Squibb Company Imidazo[4,5-b]qinolinyl oxy alkyl ureas
US5208237A (en) * 1992-04-03 1993-05-04 Bristol-Meyers Squibb Company 7-oxypropylsulfonamido-imidazo[4,5-b]quinolin-2-ones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03169880A (ja) * 1989-11-01 1991-07-23 Bristol Myers Squibb Co 水溶性の高められたイミダゾ〔４，５―ｂ〕キノリニルオキシアルカン酸アミド
US5196428A (en) * 1992-04-03 1993-03-23 Bristol-Myers Squibb Company Imidazo[4,5-b]qinolinyl oxy alkyl ureas
US5208237A (en) * 1992-04-03 1993-05-04 Bristol-Meyers Squibb Company 7-oxypropylsulfonamido-imidazo[4,5-b]quinolin-2-ones

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859025A (en) * 1996-03-19 1999-01-12 Hoechst Aktiengesellschaft Fluoroalkyl- and fluoroalkoxy-substituted heterocyclic bradykinin antagonists, process for their preparation, and their use
WO1998056790A1 (fr) * 1997-06-11 1998-12-17 Glaxo Group Limited Dihydroimidazo[1,5-b]isoquinoline-1,3-diones utilises comme inhibiteurs de l'apoproteine b-100
CN101381291B (zh) * 2008-10-28 2011-01-12 昆明理工大学 一种制备2,3,4,5-四甲氧基甲苯的方法
JP2016050850A (ja) * 2014-08-29 2016-04-11 日立化成テクノサービス株式会社 ＮＯｘ捕集材
WO2024149378A1 (fr) * 2023-01-13 2024-07-18 上海超阳药业有限公司 Composé quinolinone et composé naphtyridinone et leur utilisation

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