WO1996005202A1 - Imidazoquinoline derivative - Google Patents

Imidazoquinoline derivative 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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French (fr)
Japanese (ja)
Inventor
Yasunori Niiro
Hiroki Ueda
Toshio Satoh
Hitoshi Matsumoto
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Nippon Hypox Laboratories Inc.
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Publication of WO1996005202A1 publication Critical patent/WO1996005202A1/en

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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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Abstract

An imidazoquinoline derivative represented by general formula (I) or a pharmacologically acceptable salt thereof (wherein each substituent is as defined in the specification). They have at least two types of pharmacological effects including those of inhibiting lipid peroxidation and platelet agglutination and opposing the actions of histamine and bradykinin and are efficacious for the treatment or prevention of various thromboembolic diseases, transient ischemic diseases such as coronary vascular infarction and cerebral infarction, arteriosclerosis, and reflow disturbance occurring after the recovery from the ischemic conditions, thus being useful as a remedy or preventive for these diseases.

Description

曰月糸田 » ィミダゾリキノリン誘導体 技術分野  Satsuki Tsutoda »Imidazoliquinoline Derivatives Technical Field
本発明は新規なイミダゾリキノリン誘導体およびこれを含む医薬組成物に関す る。 背景技術  The present invention relates to novel imidazoliquinoline derivatives and pharmaceutical compositions containing the same. Background art
cA Pホスホジエステラーゼ阻害剤は血小板凝集抑制作用、 末梢血管拡張作用、 及び/または陽性の強心作用を有し、 循環器障害による疾患に有効な薬剤として 知られ、 これまでに多くの化合物が報告されている。  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.
ィミダゾキノリン誘導体の中には、 cAMPホスホジエステラーゼ阻害活性を示し 血小板凝集抑制作用を有する一連の 1，3-ジヒドロ- 2H-イミダゾ [4，5-b]キノリン- 2-オン誘導体が知られている (J. Med. Chemつ 1991, 34,2906. , 同書つ 1992, 35 ，2672.， 同書， 1992, 35,2688.， 同書， 1993, 36, 3251および US-5196428， US-494 3573, DE-3717291 ) 。 また、 血小板凝集抑制作用と抗酸化作用を有する化合物と しては、 キノリン誘導体 （特開平 2— 3 1 1 4 7 9号公報及び特開平 2— 1 2 9 1 6 9号公報） が知られている。 生体の主要臓器、 特に心臓、 脳、 肝臓、 腎臓、 脬臓、 肺などにおいて、 閉塞性 の循環不全に由来する虚血状態が生じた場合、 細胞内エネルギーの消費に伴い不 可逆的な組織障害が生じる。 この循環不全状態の成立には、 生体内脂質過酸化反 応及び/又は血小板凝集が深く関与し、 活性酸素ゃフリ一ラジカルなどで誘発さ れる脂質過酸化反応により血管内皮細胞が陣害を受け、 生体内の抗血小板凝粜因 子が低下し血小板の凝集を招き、 血栓形成に伴う閉塞性の循環不全が慢性化し、 動脈硬化、 脳卒中、 心筋梗塞、 狭心症、 脳梗塞、 糸球体腎炎、 等の組織障害が生 じる。 一方、 この虚血状態の原因である血栓を血栓溶解剤や除去手術等で除去し た時、 ラジカル種が発生し再灌流障害というさらに危篤な障害を引き起こすこと が知れている。 また別に、 ブラジキニンは血管内皮細胞に作用し内皮細胞由来血 管弛緩因子 （E D R F ) を遊離させ弛緩する一方で、 ヒスタミンと同様に直接毛 細管に作用して血管透過性を上げるので浮腫の形成原因となる。 従って、 閉塞性 の循瑨陣¾による循環機能障害の治療剤および改善剤として、 抗血小板作用、 抗 酸化作用、 抗ヒスタミン作用及び抗ブラジキニン作用を併せもつ化合物が有望で あると強く期待されていたが、 現在のところこのような化合物は開発されていな い Among imidazoquinoline derivatives, a series of 1,3-dihydro-2H-imidazo [4,5-b] quinolin-2-one derivatives which exhibit cAMP phosphodiesterase inhibitory activity and have platelet aggregation inhibitory activity are known (J Med. Chem. 1991, 34, 2906., ibid. 1992, 35, 2672., ibid., 1992, 35, 2688., ibid., 1993, 36, 3251 and US-5196428, US-494 3573, DE-3717291. ). As compounds having a platelet aggregation inhibitory action and an antioxidant action, quinoline derivatives (JP-A-2-311479 and JP-A-2-129169) are known. ing. When 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. In vivo, anti-platelet coagulation factors decrease, platelet aggregation occurs, and obstructive circulatory failure associated with thrombus formation becomes chronic, arteriosclerosis, stroke, myocardial infarction, angina, cerebral infarction, glomerulonephritis Organizational obstacles such as and occur. On the other hand, when the thrombus which causes this ischemic condition is removed by a thrombolytic agent or removal surgery, radical species are generated, which may cause more serious reperfusion injury. Is known. Separately, while 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. Becomes Therefore, compounds having both antiplatelet action, antioxidant action, antihistamine action and anti-bradykinin action were expected to be promising as therapeutic and ameliorating agents for circulatory dysfunction due to obstructive circulatory activity. However, no such compound has been developed at present.
発明の開示  Disclosure of the invention
本発明者らは、 上記課題の解決のために鋭意検討を重ねた結果、 一般式  The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the general formula
X— (CH2)ni— NX— (CH 2 ) ni —N
Figure imgf000004_0001
Figure imgf000004_0001
[式中 Xは基 [Where X is a group
Figure imgf000004_0002
から選ばれる基であり、
Figure imgf000004_0002
A group selected from
基（a)中の R R2はそれそれ独立に 4アルキル基または C,〜C アルコ キシ基であり、 R R4はそれそれ独立に水素、 （^〜(^アルキル基または（^〜 C,アルコキシ ¾であり、 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) ¾,
基 (b)屮の R5, R 7はそれそれ独立に水^、 水酸基、 （^〜（：4アルキル^または Ci〜C4アルコキシ基であり、 R5, の両者が同時に水素であることはなく、 Rr., R8， R 3はそれそれ独立に水素、 水酸基、 Ci〜C4アルキル基または 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
C4アルコキシ基であり、 Rn, R«, R。の三者が同時に水素であることはなく、 基（c)中の Rlfl， Rn, R はそれそれ独立に水素、 （^〜（：4アルキル基または C,〜C4アルコキシ基であり、 R , Rn, の三者が同時に水素であること はなく、 A C 4 alkoxy group; 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,
Yは  Y is
N一 または HC一 N-one or HC-one
であり、 And
Zは基
Figure imgf000005_0001
であり、 Z is the base
Figure imgf000005_0001
And
m, n：,， r はそれぞれ独立して 1〜 6の整数である。 ]  m, n :, r are each independently an integer from 1 to 6. ]
で示されるイミダゾリキノリン誘導体またはその薬理学的に許容し得る塩が、 俊 れた脂'员 酸化抑制作川、 lilt小板凝 ½仰制作川、 ヒスタミン及び抗ブラジキニ ン作用の少なくとも 2種以上の薬理作用を併せもつこと、 又は生体内で代謝活性 化を受け前記作用の少なくとも 2種以上の活性を相加的あるいは相乗的に発現す ることにより、 生体内脂質過酸化反応、 血小板凝集、 ヒスタミン、 ブラジキニン が原因となる種々の血栓塞栓性疾患、 例えば冠血管梗塞や脳梗塞などの一過性虚 血性疾患あるいは動脈硬化症、 慢性動脈閉塞症に伴う潰瘍、 疼痛および冷感等の 虚血性諸症状、 糸球体腎炎、 糖尿病性腎症、 さらにはこの虚血状態から回復後に 生じる再灌流障害の治瘵又は子防 I1 を有することを見いだして本発明を完成 した。 発明を実施するための最良の形態 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 Various thromboembolic diseases caused by, for example, transient ischemic diseases such as coronary infarction and cerebral infarction or ischemic symptoms such as arteriosclerosis, ulcers associated with chronic arterial occlusion, pain and cold sensation, glomerulonephritis, diabetic nephropathy, further Osamu瘵又reperfusion injury occurring after recovery from the ischemic condition. the present invention has been completed found to have a Kobo I 1. BEST MODE FOR CARRYING OUT THE INVENTION
一般式 （I) で示されるイミダゾリキノリン誘導体の代表例として次の化合物 を挙げることが出来る。  The following compounds can be mentioned as typical examples of the imidazoliquinoline derivative represented by the general formula (I).
( 1) 卜 [(4-ヒドロキシ -2，3,5- トリメチルフエニル） ォキシプロビル]- 4-[4-[ (2,3- ジヒドロ- 2- ォキソ -1H-イミダゾ [4,5-b] キノリン- 7- ィル） ォキシ]-卜 ォキソプチル] ビぺラジン  (1) Tributyl [(4-hydroxy-2,3,5-trimethylphenyl) oxyprobiyl]-4- [4-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] Quinoline-7-yl) oxy] -toxosoptyl] biazine
(2) 1-(2, 3,4,5- テトラメ トキシ -6- メチルベンジル） -4-[4-[(2，3- ジヒドロ -2- ォキソ -1H-ィミダゾ [4，5-b] キノリン -7- ィル） ォキシ ]-卜ォキソプチル] ピぺラジン  (2) 1- (2,3,4,5-tetramethoxy-6-methylbenzyl) -4- [4-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] Quinoline-7-yl) oxy] -toxoptyl] piperazine
(3) 1-[(3，5，6-トリメチル - 1,4- ベンゾキノン- 2- ィル） -メチル] -4- [4-[(2，3 - ジヒドロ -2- ォキソ -1H-イミダゾ [4，5-b] キノリン- 7- ィル） ォキシ ]-1-ォキ ソブチル] ビぺラジン  (3) 1-[(3,5,6-Trimethyl-1,4-benzoquinone-2-yl) -methyl] -4- [4-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinoline-7-yl) oxy] -1-oxobutyl] biazine
(4) 卜 [(5, 6-ジメ トキシ -3- メチル - 1，4- ベンゾキノン- 2- ィル） -メチル] -4- [4-[(2,3- ジヒドロ- 2- ォキソ -1H-ィミダゾ [4，5-b] キノリ ン- 7- ィル） ォキシ ]-1-ォキソプチル] ビぺラジン  (4) [[5,6-Dimethoxy-3-methyl-1, 4-benzoquinone-2-yl) -methyl] -4- [4-[(2,3-dihydro-2-oxo-1H -Imidazo [4,5-b] quinolin-7-yl) oxy] -1-oxobutyl] biperazine
(5) 4-[5-[3-[(2，3-ジヒドロ- 2- ォキソ - 1H-ィミダゾ [4，5，-b]キノリン- 7- ィ ル） ォキシ] プロビル] -1H- テトラゾ一ル -1- ィル] -1-(2,3，4，5- テトラメ トキ シ -6- メチルベンジル） ピぺリジン  (5) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5, -b] quinolin-7-yl) oxy] provir] -1H-tetrazo-1 1-yl] -1- (2,3,4,5-tetramethoxy-6-methylbenzyl) piperidine
(6) 4-[5-[3-[(2，3-ジヒドロ- 2- ォキソ - 1H-ィミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プロビル]- 1H- テトラゾ一ル -1- ィル] -卜[(3，5，6-トリメチル -1，4 - ベンゾキノン- 2- ィル） -メチル] ピぺリジン  (6) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] propyl] -1H-tetrazol 1-yl] -tri [(3,5,6-trimethyl-1,4-benzoquinone-2-yl) -methyl] piperidine
(7) 4-[5-[3-[(2,3-ジヒドロ- 2- ォキソ -1H -ィミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プロビル] -1H- テトラゾール -1- ィル] -卜 [(5，6-ジメ トキシ -3- メ チル -1，4- ベンゾキノン- 2- ィル） -メチル] ピぺリジン (7) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] propyl] -1H-tetrazole-1 -Yl]-[[(5,6-dimethoxy-3-me Tyl-1,4-benzoquinone-2-yl) -methyl] piperidine
(8) 4- [5- [3- [(2，3-ジヒドロ- 2- ォキソ - 1H-イミダゾ [4,5_b] キノリン- 7- ィ ル） ォキシ] プロビル] -1H- テトラゾール -：!- ィル] -1-[(2，5-ジメ トキシ- 3,4,6 - リメチルフエニル） メチル] ピぺリジン  (8) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5_b] quinolin-7-yl) oxy] propyl] -1H-tetrazole-:!- Yl] -1-[(2,5-Dimethoxy-3,4,6-limethylphenyl) methyl] piperidine
(9) 4-[5-[3- [(2，3-ジヒドロ- 2- ォキソ -1H-ィミダゾ [4,5-b] キノリン- 7- ィ ル） ォキシ] プロビル] -1H- テトラゾール -1- ィル] -；1-[(3，4，5-トリメ トキシフ ェニル） メチル〗 ビぺリジン  (9) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] propyl] -1H-tetrazole-1 -Yl]-; 1-[(3,4,5-trimethoxyphenyl) methylbipyridine
上記化合物 （ 1)〜 （9) の化合物は、 後記実施例における本発明化合物 （ 1 )〜（9) に対応する。  The compounds (1) to (9) correspond to the compounds (1) to (9) of the present invention in Examples described later.
本発明化合物の具体例としてさらに次のものを例示できる。  The following can be further exemplified as specific examples of the compound of the present invention.
(a) 4-[5_[4-[(2，3-ジヒドロ- 2- ォキソ -1H-イミダゾ [4,5-b] キノ リン- 7- ィ ル） ォキシ] ブチル ]-1Η- テトラゾ一ル -1- ィル] -卜[(2,5-ジメ トキシ -3，4，6- トリメチルフエニル） メチル] ピぺリジン  (a) 4- [5_ [4-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1Η-tetrazole -1-yl] -tri [(2,5-dimethoxy-3,4,6-trimethylphenyl) methyl] piperidine
(c) 4-[5-[3- [(2，3-ジヒドロ- 2- ォキソ - 1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ〗 プロビル] -1H- テトラゾ一ル -1- ィル] -卜[(2-メチル -3,4,5- トリ メ トキシフエニル） メチル] ビぺリジン  (c) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy} propyl] -1H-tetrazol -1-yl] -tri [(2-methyl-3,4,5-trimethoxyphenyl) methyl] bipyridine
(d) 4-[5-[3-[(2，3-ジヒドロ- 2_ ォキソ -1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プロビル] -1H- テトラゾール -1- ィル] -1-[(2,4-ジヒドロキシ- 3,5 ,6- トリメチルフエニル） メチル] ビぺリジン  (d) 4- [5- [3-[(2,3-dihydro-2_oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] propyl] -1H-tetrazole-1- Yl] -1-[(2,4-dihydroxy-3,5,6-trimethylphenyl) methyl] bipyridine
(f ) 4- [5-[3-[(2,3-ジヒドロ- 2- ォキソ -1H -ィミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プロビル] -1H- テトラゾ一ル -1- ィル] -1-[(3,5-ジメ トキシ -4- ヒ ドロキシフエニル） メチル] ビぺリジン  (f) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] propyl] -1H-tetrazole -1-yl] -1-[(3,5-Dimethoxy-4-hydroxyphenyl) methyl] bipyridine
(g) 4-[5-[3-[(2，3-ジヒドロ- 2- ォキソ -1H-ィミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プロビル] _1H_ テトラゾール -1- ィル] -1-[(3，5-ジメチル -4- ヒド ロキシフエニル） メチル] ビぺリジン  (g) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] propyl] _1H_tetrazole-1- L] -1-[(3,5-Dimethyl-4-hydroxyphenyl) methyl] biperidine
(h) 4- [5- [3-[(2，3-ジヒドロ- 2- ォキソ -1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] ブロビル] -1H- テトラゾール -1- ィル] -卜 [(3,5-ジ tert- ブチル -4 - ヒドロキシフエニル） メチル] ビぺリジン  (h) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] brovir] -1H-tetrazole-1 -Yl] -tri [(3,5-ditert-butyl-4-hydroxyphenyl) methyl] biperidine
( i) 4-[5- [4- [(2，3-ジヒドロ- 2- ォキソ - 1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プチル] -1H- テトラゾール -1- ィル ]-卜[(3,5-ジ tert- ブチル - 4- ヒドロキシフエニル） メチル] ピぺリジン (i) 4- [5- [4-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinoline-7-i L) oxy] butyl] -1H-tetrazol-1-yl] -tri [(3,5-ditert-butyl-4-hydroxyphenyl) methyl] piperidine
( j ) 4-[5- [3-[(2，3-ジヒドロ- 2- ォキソ -1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プチル] -1H- テトラゾール- 1- ィル] -1-「（3，4，5-トリ トキシフエ ニル） メチル] ビぺリジン  (j) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1H-tetrazole-1 -Yl] -1-((3,4,5-tritoxylphenyl) methyl] biperidine
(k) 4-[5-[3-[(2,3-ジヒドロ- 2- ォキソ -1H-ィミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] ブチル ]-1Η- テトラゾ一ル -1- ィル] -卜 [(2-メチル -3，4，5- トリメ トキシフエニル） メチル] ピぺリジン  (k) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1Η-tetrazole -1-yl] -tri [(2-methyl-3,4,5-trimethoxyphenyl) methyl] piperidine
(1) 4- [5-[3- [(2，3-ジヒドロ- 2- ォキソ -1H-イミダゾ [4,5-b] キノリン -7- ィ ル） ォキシ] ブチル ]-1Η- テトラゾ一ル -1- ィル] -卜 [(2, 4-ジヒドロキシ -3, 5, 6 (1) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1Η-tetrazole -1-yl]-[[(2, 4-dihydroxy-3, 5, 6
- トリメチルフエニル） メチル] ビぺリジン -Trimethylphenyl) methyl] biperidine
(m) 4_[5-[3-[(2,3-ジヒドロ- 2- ォキソ - 1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プチル] -1H- テトラゾール -1- ィル]-卜[(2,4-ジヒドロ-3，5，6- ト リメ トキシフエニル） メチル] ビぺリジン  (m) 4_ [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1H-tetrazole-1- Yl] -tri [(2,4-dihydro-3,5,6-trimethoxyphenyl) methyl] bipyridine
(n) 4-[5-[3-[(2，3-ジヒドロ- 2- ォキソ -1H-ィミダゾ [4，5- b] キノリン- 7- ィ ル） ォキシ] ブチル ]-1Η- テトラゾール -1- ィル] -1-[(3，5-ジメ トキシ -4- ヒド ロキシフエニル） メチル] ビぺリジン  (n) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1Η-tetrazole-1 -Yl] -1-[(3,5-dimethoxy-4-hydroxyphenyl) methyl] bipyridine
( 0) 4-[5-[3-[(2，3-ジヒドロ- 2- ォキソ -1H-イミダゾ [4，5-b] キノリン- 7- ィ ル） ォキシ] プチル] -1H- テトラソ'一ル- 1- ィル] -卜 [(3，5-ジメチル- 4- ヒドロ キシフエニル） メチル] ビぺリジン  (0) 4- [5- [3-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] butyl] -1H-tetraso Ru-1-yl] -tri [(3,5-dimethyl-4-hydroxyphenyl) methyl] biperidine
(p) 4-[5-[4-[(2,3-ジヒドロ-2- ォキソ -1H-イミダゾ [4,5-b] キノリン -7- ィ ル） ォキシ] プロビル] -1H- テトラゾール -1- ィル] -1-[(3- (2,5- ジメ トキシ -3 ,4,6- トリメチルフエニル） プロビル] ビぺリジン  (p) 4- [5- [4-[(2,3-dihydro-2-oxo-1H-imidazo [4,5-b] quinolin-7-yl) oxy] provyl] -1H-tetrazole-1 -Yl] -1-[(3- (2,5-dimethoxy-3,4,6-trimethylphenyl) provil] bipyridine
本発明のィミダゾリキノリン誘導体は、 そのィミダゾリキノリン部分が  The imidazoliquinoline derivative of the present invention has an imidazoliquinoline moiety
Figure imgf000008_0001
で示される互変異性構造を有するが、 本発明の化合物は、 これら 2つの互変異性 体を包含するものである。
Figure imgf000008_0001
The compound of the present invention includes these two tautomers.
一般式 （I) で示される化合物は、 公知の方法で処理することにより、 酸付加 塩に変換可能である。 一般式 （I) で示される化合物の製薬上許容し得る塩とし ては、 塩酸、 臭化水素酸などのハロゲン化水素酸との塩、 酢酸、 ブロビオン酸な どのモノカルボン酸との塩、 硫酸、 メタスルホン酸、 p—トルエンスルホン酸な どのスルホン酸との塩又はシユウ酸、 マロン酸、 コハク酸等のジカルボン酸との 塩を挙げることが出来る。  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.
一般式 （I) で示される化合物のうち、 Yが基  In the compound represented by the general formula (I), Y is a group
N一 N-one
Zが基 一 C一 Z is base C-1
II  II
0 である化合物、 すなわち一般式  0, that is, the general formula
X-(CH2)nr X- (CH 2 ) n r
Figure imgf000009_0001
Figure imgf000009_0001
(式中、 X， rn, Π 2 , η3, η4は下記で定義するとおりである。 ） で示されるイミダゾリキノリン誘導体 （例えば上記化合物 （1) ~ (4) が含ま れる） は、 一般式 (Wherein, X, rn, Π 2, η 3 , and η 4 are as defined below.) The imidazoliquinoline derivatives (for example, including the above compounds (1) to (4)) include General formula
Figure imgf000009_0002
[式中 Xは基
Figure imgf000009_0002
[Where X is a group
Figure imgf000010_0001
から選ばれる基であり、
Figure imgf000010_0001
A group selected from
基 (a) 中の Ri, R2はそれぞれ独立に Ci〜C4アルキル基または（^〜〇4アル コキシ基であり、 R3， R4はそれぞれ独立に水素、 C!〜C4アルキル基または C t〜C4アルコキシ基であり、 Ri in group (a), R 2 are each independently Ci～C 4 alkyl or (^ ～〇 4 alkoxy group, R 3, R 4 are each independently hydrogen, C! -C 4 alkyl group Or a C t -C 4 alkoxy group,
基 (b) 中の R5, R 7はそれそれ独立に水素、 水酸基、 （^〜（^アルキル基また は C! C^アルコキシ基であり、 Rr R7の両者が同時に水素であることはなく 、 Rn, R«, R,】はそれそれ独立に水素、 水酸基、 （^〜（^アルキル基または d 〜C4アルコキシ基であり、 R (；， RR, の三者が同時に水素であることはなく 基（c) 中の R1D， Rn, 2はそれそれ独立に水素、 C,〜C4アルキル基また は C】〜（^アルコキシ基であり、 Ri。， R , R12の三者が同時に水素であるこ とはなく、 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 , n3はそれそれ独立して 1〜6の整数であり、 rn, r and n 3 are each independently an integer from 1 to 6,
X中の水酸基は保護基によって保護されていてもよい。 ] で示される化合物と、 一般式 The hydroxyl group in X may be protected by a protecting group. ] And a compound represented by the general formula
Figure imgf000011_0001
Figure imgf000011_0001
[式中、 n.,は 1〜6の整数である] [Where n., Is an integer from 1 to 6]
で示される化合物とを縮合反応させ、 必要ならば酸化反応に付することにより得 ることができる。 Can be obtained by subjecting the compound of the formula to a condensation reaction and subjecting it to an oxidation reaction if necessary.
縮合反応は、 ジメチルホルムアミ ド、 ジメチルスルホンアミ ド等の溶媒の存在 下に、 トリェチルァミン、 ジフエニルリン酸アジド、 ジメチルアミノビリジン、 ビリジンなどの触媒及び縮合剤を用い、 約一 10°C〜130°Cの範囲で、 0. 5 時間〜数日反応させることにより行なうことが出来る。  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. The reaction can be performed within a range of 0.5 hours to several days.
酸化反応は、 得られた一般式 （la)の化台物中の Xがハイ ドロキノンであると きに、 これをキノンにするために用いられ、 この酸化反応は、 ジメチルホルムァ ミ ド、 ジメチルスルホンアミ ド、 テトラヒドロフラン、 酢酸ェチル等の溶媒の存 在下に、 酸化鉄、 酸化亜鉛、 酸化銀、 硝酸セリウムアンモニゥム等の酸化剤を用 い約— 10° (：〜 130°Cの範囲で 0. 5時間〜数日反応させることにより行なう ことが出来る。  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. Using 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.
なお、 本発明の化合物 （la)の合成に必要な式 （III)で示される既知原料化合 物は、 前記文献 (J. Med. Chemつ 1992,35,2672 ) の方法で製^することが,1 U来 る。 また本発明化合物 （la)の合成に必要な式 （II) で示される原料化合物の 1 種は、 以下のように製造することが出来る。
Figure imgf000012_0001
Figure imgf000012_0002
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.
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0003
すなわち、 トリまたはテトラ置換ハイ ドロキノンの一方の水酸基を塩化ビバ口 ィルで保護して得た化合物を tert -プチルジメチルシリル （TBDMSi)化し た後、 ビバロイル基を除去しその水酸基を ω—ハロゲニルアルキル化してから、 ジァミン類と縮合させることにより式 （Ila)の化合物を製造することが出来る。 また、 本発明化合物 （la)の合成に必要な式 （II) で示される原料化合物の 1 称は、 以下のように ¾造することが出来る。 That is, 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 ω-halogenyl. The compound of formula (Ila) can be prepared by alkylating and then condensing with a diamine. Further, 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.
(CH2)n2ヽ (CH 2 ) n 2ヽ
NCHO  NCHO
(CH2)n3 / (CH 2 ) n 3 /
(lib)
Figure imgf000012_0004
すなわち、 原料化合物であるァリールアルキルハラィ ドを、 モノホルミルジァ ミン類と縮合させた後、 脱ホルミル化することにより式 （l ib)の化合物を製造す ることが出来る。 (lib)
Figure imgf000012_0004
That is, 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.
また， ? S¾化合物 （l a)の合成に必要な式 （II) で示される原料化合物の 1 種は、 以下のように製造することも出来る。  Also, one kind of the starting compound represented by the formula (II) required for the synthesis of the? S¾ compound (la) can be produced as follows.
Figure imgf000013_0001
Figure imgf000013_0001
(He)  (He)
すなわち、 ホルムアルデヒ ド、 置換ハイ ドロキノン類及びモノホルミルジアミ ン類を酸性条件下に加熱し反応させた後、 酸化しついで脱ホルミル化させること により式 （lie )の化合物を製造することが出来る。  That is, 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.
一般式 （I ) で示される化合物のうち、 Yが基  In the compound represented by the general formula (I), Y is a group
HC- HC-
Zが基 Z based
— N-C- 、、  — N-C- ,,
N N  N N
N である化合物、 すなわち一般式 (CH2)n4~0'
Figure imgf000014_0001
A compound of the general formula (CH 2 ) n4 ~ 0 '
Figure imgf000014_0001
(lb)  (lb)
(式中、 R「,， Ro, R7, R«, R:», n TI2, IIA, r は下記で定義するとお りである。 ） (In the formula, R “,, Ro, R 7 , R«, R: », n TI2, IIA, r are defined as follows.)
で示されるイミダゾリキノリン誘導体 （例えば上記化合物 （5) が含まれる） は 、 一般式
Figure imgf000014_0002
— Hal (IVa) The imidazoliquinoline derivative (including, for example, the above compound (5)) represented by the general formula is
Figure imgf000014_0002
— Hal (IVa)
[式中、 Rr>， R 7はそれそれ独立に水^、 水酸^、 C】〜C4アルキル^または 〇ュ〜( 4アルコキシ基であり、 R7の両者が同時に水素であることはなく、 Ro, R«， R:1はそれぞれ独立に水素、 水酸基、 C ! CAアルキル基または Ci〜 C4アルコキシ基であり、 Rc， R , R9の三者が同時に水素であることはなく、 は 1〜6の整数であり、 [Wherein 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はハロゲン原子である。 ]  Hal is a halogen atom. ]
で示される化合物と、 一般式 And a compound represented by the general formula
H— N
Figure imgf000014_0003
H—N
Figure imgf000014_0003
(式中、 n n- , r はそれそれ独立して 1〜 6の整数である。 ） (Wherein, n n- and r are each independently an integer from 1 to 6.)
で示される化合物とを縮合反応させることにより得ることができる。 縮合反応は、 メタノール又はエタノール等のアルコール系溶媒、 アセトン、 メ チルェチルケトン等のケトン系溶媒、 ジクロロメタン、 クロ口ホルム等のハロゲ ン系溶媒、 ァセトニトリル、 テトラヒドロフラン、 ジメチルホルムアミ ド、 ジメ チルスルホンアミ ド等の溶媒の存在下に、 炭酸カリウム、 炭酸水素ナトリウム等 の無機塩基、 トリェチルァミン、 メチルビペリジン等の有機塩基存在下に、 約一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. In the presence of an inorganic base such as potassium carbonate or sodium hydrogen carbonate, or an organic base such as triethylamine or methylbiperidine in the presence of
1 0 °C〜1 3 0 °Cの範囲で 0 . 5時間〜数日反応させることにより行なうことが 出来る。 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.
なお本発明化合物 （l b)の合成に必要な式 （IVa)の化合物は、 以下のようにし て製造することができる。  The compound of the formula (IVa) required for the synthesis of the compound (lb) of the present invention can be produced as follows.
OH OH
Figure imgf000015_0001
すなわち、 常法により得られるァリールアルキルアルデヒド類のホルミル基を 還元し、 水酸基としこれをハロゲン基に置換することにより式 （IVa)の化合物を 製造することが出来る。
Figure imgf000015_0001
That is, 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.
また本発明化合物 （l b)の合成に必要な式 （V) の化合物は、 前記文献 （J. M ed. Chem. 1993, 36, 3521) に記載の方法で製造することができる。  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).
一般式 （ I ) で示される化合物のうち、 Yが基  In the compound represented by the general formula (I), Y is a group
HC一 HC one
Zが基 一 N-C Z based One NC
I 、、一  I, one
N N  N N
N である化合物、 すなわち一般式  A compound of the general formula
Figure imgf000016_0001
Figure imgf000016_0001
(Ic)  (I c)
(式中、 ： , R u , R 12 , ri!, nz, n r は下記で定義するとおりであ る。 ） (Where:, R u, R 12, ri !, nz, n r are as defined below.)
で示されるイミダゾリキノリン誘導体 （例えば上記化合物 （6) ， (7) が含ま れる） は、 一般式 The imidazoliquinoline derivative represented by (including, for example, the compounds (6) and (7)) is represented by the general formula
Figure imgf000016_0002
Figure imgf000016_0002
[式中、 R 1 ()， R u , R はそれぞれ独立に水素、 （^〜（^アルキル基または[Wherein, R 1 () , R u, and R are each independently hydrogen, (^ to (^ an alkyl group or
(^〜（^アルコキシ基であり、 R R 1 1 , 2の三者が同時に水素であること はなく、 (^ ~ (^ Is an alkoxy group, and RR 11 and 2 are not hydrogen at the same time,
は 1〜6の整数であり、  Is an integer from 1 to 6,
Halはハロゲン原子である。 ]  Hal is a halogen atom. ]
で示される化合物と、 一般式 And a compound represented by the general formula
H一 N
Figure imgf000016_0003
(式中、 n 2， ii 3 , r はそれぞれ独立して 1〜6の整数である。 ） で示される化合物とを縮合反応させることにより得ることができる。 H-N
Figure imgf000016_0003
(In the formula, n 2 , ii 3, and r are each independently an integer of 1 to 6.) can be obtained by a condensation reaction.
縮合反応は、 メタノール又はエタノール等のアルコール系溶媒、 アセトン、 メ チルェチルケトン等のケトン系溶媒、 ジクロロメタン、 クロ口ホルム^のハロゲ ン系溶媒、 ァセトニトリル、 テトラヒドロフラン、 ジメチルホルムアミ ド、 ジメ チルスルホンアミ ド等の溶媒の存在下に、 炭酸カリウム、 炭酸水素ナトリウム等 の無機塩基、 トリェチルァミン、 メチルビペリジン等の有機塩基存在下に、 約一 1 0 °C〜1 3 0 °Cの範囲で 0 . 5時間〜数日反応させることにより行なうことが 出来る。  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. In the presence of an inorganic base such as potassium carbonate and sodium hydrogen carbonate, and 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.
なお本発明化合物 （l b)の合成に必要な式 （IVa)の化合物は、 以下のようにし て製造することができる。  The compound of the formula (IVa) required for the synthesis of the compound (lb) of the present invention can be produced as follows.
OH OH
Figure imgf000017_0001
Figure imgf000017_0001
(IVb)  (IVb)
すなわち、 常法により得られるァリールアルキルアルデヒド類のホルミル基を 還元し、 水酸基としこれをハロゲン基に置換することにより式 （IVb)の化合物を 製造することが出来る。  That is, 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.
また本¾明化合物 （1 13)の 成に必¾な式 （V) の化合物は、 前記文献 (J. M ed. Chem. 1993， 36, 3521) に記載の方法で製造することができる。  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).
本発明化合物 （ I ) は以下に示すように優れた脂質過酸化反応阻害作用、 血小 板凝集抑制作用、 抗ヒスタミン作用及び抗ブラゾキニン作用を有しており、 又は 生体内で代謝活性化され、 これらの作用を示し血栓症、 心、 肺、 脳、 腎、 肝、 滕 臓における動脈血管平滑筋の虚血性疾患、 すなわち、 心筋梗塞、 脳血栓、 動脈硬 化、 糸球体腎炎、 糖尿病性腎症の予防及び治療効果を示し、 さらにはこの虚血状 態が改善された後に起こるラジカル誘発性の再灌流障害についても予防及び治療 効果を有する。 また、 以下に示すように血管拡張作用及び降圧作用を有すること から、 これらが相乗的に作用し循環機能障害の予防及び治療効果を奏する。 さらに、 本発明化合物 （ I ) は抗ヒスタミ ン作用及び抗ブラジキニン作用によ る浮腫の形成抑制作用を併せもつことにより、 血管拡張作用物質に多くみられる 脳浮腫等の危篤な副作用も軽減されている。 なお、 本発明化合物 （I ) の主要薬 理作用の一部は、 cAMPホスホジエステラーゼ阻害作用に由来すると考えられ、 一 般の cAMPホスホジエステラーゼ阻害剤が示すその他の薬理作用、 例えば陽性の強 心作用も有する。 さらには、 5-リポキシゲナーゼ阻害作用も期待されることから 、 前述の抗ヒスタミン作用及び抗ブラジキニン作用と協調して、 抗炎症作用及び 抗アレルギー作用が有効な疾患の予防及び治療効果にも有用である。 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. In addition, since they have a vasodilatory effect and a hypotensive effect as shown below, they act synergistically to exert preventive and therapeutic effects on circulatory dysfunction. Furthermore, 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. I have. 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. . Furthermore, since 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. .
本発明化合物であるィミダゾリキノリン誘導体 （ I ) は任意慣用の製造方法を 用いて投与用に調製することが出来る。 したがって、 本発明の医薬組成物は少な くとも 1種以上のイミダゾリキノリン誘導体 （I ) を含有するものである。 この ような医薬組成物は、 通常汎用される製剤用担体、 賦形剤などの医薬品として許 される添加剂 を川いて ^剂化される。  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.
この医薬組成物は、 経口投与製剤として用いる場合、 錠剤、 顆粒剤、 カプセル 剤、 内服用液剤等の形態で用いることが出来るが、 消化管からの吸収に好適な形 態で提供されることが好ましい。 また、 流通性、 保存性等の理由から所望する形 態の製剤を提供する場合も従来の製剤技術をもって提供することが出来る。 また 、 非経口製剤として用いる場合、 注射剤、 坐剤、 点滴用製剤等の形態で用いるこ とが出来るが、 流通性及び保存性の理由から固形製剤を使用時に適当な溶剤で溶 解してから川いる形態をとることも可能であり、 液剤及び半 Θ形剤の形態で提供 することも従来の製剤技術で可能である。  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. In addition, when a preparation in a desired form is provided for reasons of flowability, storage stability, etc., it can be provided by conventional preparation techniques. In addition, 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.
投与量は、 目標とする治療効果、 投与方法、 年令、 体重等によって変化するので ー概的には規定できないが、 通常 1日の非経口的な投与量は、 体重当たり約 0.0 1 〜100 m であり好ましくは約 0.05 〜 10 m であり、 経口的には約 0·：！〜 300 mg、 好ましくは約 0.5 〜30 mg であり、 これを 1〜 5回に分割して投与すればよ い。 実施例 Dosage varies depending on the target therapeutic effect, administration method, age, body weight, etc.-Although it cannot be generally specified, 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. Example
以下に、 実施例及び参考例を示し、 本¾叨をさらに詳しく説明するがこれらは 本発明を何ら制限するものではない。  Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, which do not limit the present invention in any way.
製造実施例 1 (本発明化合物 （ 1 ) の製造）  Production Example 1 (Production of Compound (1) of the Present Invention)
[A] 原料化合物 （Ila ) の合成  [A] Synthesis of the starting compound (Ila)
工程（i) トリ
Figure imgf000019_0001
メチルハイ ドロキノ トリメチルハイ ドロキノン 7.61 g ( 50.0 mmol ) をビリジン 12.77 g ( 161. 3 mmol )と 50 mlの CH2C12との混合液に溶解させ、 ビバ口イルク口ライ ド 6.03 g ( 50.0 mmol )を 40 mlの CH2C12に溶解させたものを滴下し、 一昼夜攪拌させた 。 反応終了後、 反応液に AcOH 9.67 g ( 161.3 mmol ) を加え H20 で洗浄した。 苻機層を分取し、 乾燥後溶媒を^ し残杏をシリカゲルカラムに付し n- へキサ ン ： EtOAc ( 11 ： 1 ) で^出し化 Α物 （ 1 4 ) 9.0 gを ¾た。 Process (i) bird
Figure imgf000019_0001
Mechiruhai Dorokino Torimechiruhai Dorokinon 7.61 g (50.0 mmol) was dissolved in a mixture of Pyridine 12.77 g (161. 3 mmol) and of 50 ml CH 2 C1 2, Viva port Iruku port Lai de 6.03 g of (50.0 mmol) A solution dissolved in 40 ml of CH 2 C 12 was added dropwise, and the mixture was stirred overnight. After completion of the reaction, and washed with AcOH 9.67 g of (161.3 mmol) was added H 2 0 to the reaction solution. The solvent layer was separated, dried, and the solvent was removed. The residue was applied to a silica gel column, and 9.0 g of the compound (14) was obtained with n-hexane: EtOAc (11: 1).
工程 (ϋ) (14)
Figure imgf000019_0002
化合物 （ 1 4 ) 7.8 g ( 33.0 醒 ol )を DMF 30 mlに溶解させたものに tert- ブチルジメチルクロロシラン 6.64 g ( 44.0 腿 o】 ） を混合した。 これにイミダ ゾ一ル 6.62 g ( 97.0 腿 ol ) を加え、 室温で一昼夜攪拌した。 反応液を氷 50 g アンモニア水 10 mlに注ぎ EtOAc 100 ml と n- へキサン 100 mlの混合液で抽 出した。 この有機層を乾燥後濃縮しシリカゲルカラムに付し、 ベンゼンで溶出し 、 化合物 （ 1 5 ) 12.0 を得た。 0 mlの混合攪拌溶液に加えた。 3時間加熱還流した後、 ろ過した。 沈澱を EtOAc 50ml + H2050 ml に混合した後、 有機層を H20 で洗浄し、 先のろ液とこの有機 層を合わせて乾燥した。 これを濃縮し、 シリカゲルカラムに付し EtOAc ： EtOH ：Process (ϋ) (14)
Figure imgf000019_0002
6.64 g (44.0 t) of tert-butyldimethylchlorosilane was mixed with a solution of the compound (14) (7.8 g, 33.0 ol) in 30 ml of DMF. To this, 6.62 g (97.0 t) of imidazole was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into 50 g of ice and 10 ml of aqueous ammonia, and extracted with a mixture of 100 ml of EtOAc and 100 ml of n-hexane. The organic layer was dried, concentrated, applied to a silica gel column, and eluted with benzene to obtain Compound (15) 12.0. 0 ml was added to the mixed stirring solution. After heating under reflux for 3 hours, the mixture was filtered. After mixing the precipitate with 50 ml of EtOAc + 050 ml of H 2 , the organic layer was washed with H 20 and the previous filtrate and the organic layer were combined and dried. This was concentrated and applied to a silica gel column to provide EtOAc: EtOH:
NEt:! ( 20 ： 4 ： 1 )で溶出し、 ^料化 iV物 （Ila ) に相当する化合物 （ 18) NEt:! (20: 4: 1) and eluted with, ^ Ryoka iV compound (Ila) corresponding to compound (18)
0.66 g を得た。 MS: Mf 392. 0.66 g was obtained. MS: M f 392.
[B] 原料化合物 （III)の合成 [B] Synthesis of starting compound (III)
J. Med. Chem. 1992, 35， 2672に記載の方法に従って、 原料化合物 (III)に相 当する、 式
Figure imgf000020_0001
According to the method described in J. Med. Chem. 1992, 35, 2672, a compound represented by the formula
Figure imgf000020_0001
( 13) で示される化合物 （ 13) を得た c Compound (13) represented by (13) was obtained c
[C] 本発明化合物 （ 1) の合成  [C] Synthesis of compound (1) of the present invention
工程 (0Process (0
Figure imgf000020_0002
Figure imgf000020_0002
(19)  (19)
化合物 （ 13) 0.39 g ( 1.36 mmol ) 、 化合物 （ 18) 0.61 g ( 1.55膽 o 1 ) 、 トリェチルァミン 0.287 g ( 2.83 mmol )、 ジフエ二ルホスホニルアジドCompound (13) 0.39 g (1.36 mmol), Compound (18) 0.61 g (1.55 cough 1), triethylamine 0.287 g (2.83 mmol), diphenylphosphonyl azide
( DPPA ) 0.545 g ( 1.98 mmol ) 、 ジメチルアミノビリジン（ DMAP ) 0.01 g ( 0.08 mmol ) を DMF 6 ml に溶解させ、 一昼夜攪拌させた。 反応液に EtOAc 1 00 ml と H 100 ml を加え ： T卞した。 分取した有機 te1を減圧^縮しエーテル 100 ml を加え氷冷しながら攪拌した。 析出した沈澱をろ取、 乾燥させ熱 EtOAc 400 ml を加え 1時間加熱した。 不溶物を濾過し除き減圧乾燥し、 化合物 （ 19)0.545 g (1.98 mmol) of (DPPA) and 0.01 g (0.08 mmol) of dimethylaminoviridine (DMAP) were dissolved in 6 ml of DMF and stirred overnight. 100 ml of EtOAc and 100 ml of H were added to the reaction solution. The collected organic te 1 was condensed under reduced pressure, 100 ml of ether was added, and the mixture was stirred with ice cooling. The deposited precipitate was collected by filtration, dried, added with 400 ml of hot EtOAc, and heated for 1 hour. The insolubles were removed by filtration and dried under reduced pressure to give compound (19)
0.77 g を得た。 工程 (iii) (15)0.77 g was obtained. Step (iii) (15)
Figure imgf000021_0001
Figure imgf000021_0001
(16) 化合物 （ 15) 11.32 g ( 32.0誦 ol )を DMF 15 mlに溶解したものに、 窒素 雰囲気下に KOH 7.22 g ( 129.0讓 ol ) を MeOH 30 ml に溶解させたものを加え 、 室温にて一昼夜攪拌した。 反応終了後、 反応液を氷 100 gに注ぎ EtOAcで抽出 した。 分取した有機層を H20 で洗浄し、 乾燥後溶媒を留去した。 残査をシリカゲ ルカラムに付し、 ベンゼン ： EtOAc ( 20 ： 1 ) で溶出し、 油状化合物 （ 1 6) 5.3 gを得た。 (16) To a solution of 11.32 g (32.0 ol) of the compound (15) in 15 ml of DMF was added a solution of 7.22 g (129.0 benzyl) of KOH dissolved in 30 ml of MeOH under a nitrogen atmosphere. And stirred all day and night. After the completion of the reaction, the reaction solution was poured into 100 g of ice and extracted with EtOAc. The separated organic layer was washed with H 2 0, was distilled off after drying the solvent. The residue was applied to a silica gel column and eluted with benzene: EtOAc (20: 1) to obtain 5.3 g of an oily compound (16).
工程（iv) (16)Process (iv) (16)
Figure imgf000021_0002
Figure imgf000021_0002
(Π) 化合物 （ 16) 5.3 g ( 19.8腿 ol) と 1,3- ジブロモプロパン 40.2g( 198.0 腿 ol )を混合し、 窒素雰囲気下に H2035 ml に Na2C03 2.21g( 21.0廳 ol )、 テ トラプチルアンモニゥムハイ ドロゲンスルフェート 2.22 g( 6.0 mmol )と NaOH 1.28 g ( 32.0讓 ol ) を溶解したものを滴下した。 一昼夜激しく攒拌した後、 有 機層を分取し Na2C03 で乾燥し減圧濃縮した。 残査をシリカゲルカラムに付し n-へ キサン： ベンゼン （ 1 : 1) で溶出し、 油状化合物 （ 17) 4.6 gを得た。 ([Pi) Compound (16) 5.3 g (19.8 thigh ol) and 1,3-dibromopropane 40.2 g (198.0 thigh ol) were mixed, Na 2 C0 3 2.21g (21.0 Hall in H 2 035 ml under a nitrogen atmosphere ol), 2.22 g (6.0 mmol) of tetraptyl ammonium hydroxide sulphate and 1.28 g (32.0 sulol) of NaOH were added dropwise. After vigorous stirring overnight, the organic layer was separated, dried over Na 2 CO 3 and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with n-hexane: benzene (1: 1) to obtain 4.6 g of an oily compound (17).
工程 (V) (17)
Figure imgf000021_0003
Process (V) (17)
Figure imgf000021_0003
(18)  (18)
原料化合物 (lla) 化合物 （ 17 ) 0.775 g ( 2.0画 ol)、 ピぺラジン無水和物 1.72 g (19.96 m mol)を K2C03 1.38 g ( 9.9廳 ol ) 、 KI 0.01 g ( 0.06 mmol ) 、 蒸留 CH3CN 4 Starting compound (lla) Compound (17) 0.775 g (2.0 fraction ol), piperazine anhydrate 1.72 g (19.96 mmol) in K 2 C03 3 1.38 g (9.9 kanol), KI 0.01 g (0.06 mmol) , Distillation CH 3 CN 4
- 18 工程（ii) (19)-18 Step (ii) (19)
Figure imgf000022_0001
Figure imgf000022_0001
(1) (1)
化合物 （ 1 9 ) 0.52 g ( 0.79 腿 ol ) を THF 16 mlに 濁させテトラブチル アンモニゥムフルオラィ ド三水和物 0.99 g ( 3.14 mmol )を加え溶解させた。 そ の液に CH3C00H 0.57 g ( 9.49 mmol ) を加え 3時間反応させた。 反応液を約 5 ml に濃縮し、 氷冷下に 5% NaHC03 を加え pH 7 〜8 に調整し、 析出した沈澱を ろ取した。 このろ液は EtOAcで抽出し、 有機層を減圧濃縮し得た沈殿と先に得た 沈殿を合わせて乾燥した。 この沈澱をァセトン約 10 mlに懸濁させ IN HC1 3 ml と 0 5 ml を加え加熱し、 ァセトンを加え完全に溶かした。 この反応液を減圧 濃縮し、 残査にアセトンを加え び濃縮乾; ^し、 うすい J½色粉末を た。 この粉 末をァセトン ： H20 ( 9 ： 1 ) で再結晶し、 一般式 （I ) の本発明化合物に包含 される化合物 （ 1 ) の塩酸塩 0.39 g を得た。 0.52 g (0.79 tmol) of the compound (19) was turbidized in 16 ml of THF, and 0.99 g (3.14 mmol) of tetrabutylammonium fluoride trihydrate was added and dissolved. 0.57 g (9.49 mmol) of CH 3 C00H was added to the solution and reacted for 3 hours. The reaction mixture was concentrated to about 5 ml, the 5% NaHCO 3 under ice cooling was added was adjusted to pH 7 to 8, the precipitated precipitate was collected by filtration. The filtrate was extracted with EtOAc, and the precipitate obtained by concentrating the organic layer under reduced pressure and the precipitate obtained above were combined and dried. This precipitate was suspended in about 10 ml of acetone, 3 ml of IN HC1 and 0.5 ml of IN HC1 were added, heated, and acetone was added to completely dissolve the precipitate. The reaction solution was concentrated under reduced pressure, acetone was added to the residue, and the mixture was concentrated and dried; ^ to give a pale J-color powder. The powder powder Aseton: H 2 0 (9: 1 ) and recrystallized to give the hydrochloride salt 0.39 g of general formula compounds encompassed by the present invention compounds of (I) (1).
元素分析 C^H NsOs · 2HC1 · H2 O,  Elemental analysis C ^ H NsOs2HC1H2 O,
計算値 C， 56.43 %, H, 6.41 %, N， 10.97 % ,  Calculated C, 56.43%, H, 6.41%, N, 10.97%,
分析値 C， 56.51 %, H， 6.03 %, N， 10.87 %.  Analytical value C, 56.51%, H, 6.03%, N, 10.87%.
mp. 258 〜260 °C . 製造実施例 2 (本発明化合物 （2 ) の製造）  mp. 258 to 260 ° C. Production Example 2 (Production of the present compound (2))
[A] 原料化合物 （l ib)の合成  [A] Synthesis of starting compound (lib)
工程 (i)
Figure imgf000022_0002
Process (i)
Figure imgf000022_0002
3,4, 5-トリメ トキシトルエン 10.0 g ( 54.9 mmol ) を CC 30 ml に溶解し 5°C以下に冷却した。 これに臭素 4.4 g ( 27.5 mmol )を CC14 50 ml に混合し てから滴下した。 滴下終了後、 室温に戻し一昼夜攪拌した。 反応液を飽和 Na2C03 水で pH 8 〜9 に調整し CH2C12で抽出し、 有機層を乾燥した。 この有機層を減圧 下に濃縮しシリカゲルカラムに付し n- へキサン ： EtOAc ( 20 :1 )で溶出し、 化合物 （ 20 ) 4.35 g を得た。 10.0 g (54.9 mmol) of 3,4,5-trimethoxytoluene was dissolved in 30 ml of CC and cooled to 5 ° C or lower. This bromine 4.4 g of (27.5 mmol) were mixed in CC1 4 50 ml And then dropped. After completion of the dropwise addition, the mixture was returned to room temperature and stirred for 24 hours. The reaction solution was adjusted to pH 8 to 9 with saturated Na 2 C0 3 aqueous extracted with CH 2 C1 2, the organic layer was dried. The organic layer was concentrated under reduced pressure, applied to a silica gel column, and eluted with n-hexane: EtOAc (20: 1) to obtain 4.35 g of compound (20).
工程 (ϋ) (20)
Figure imgf000023_0001
化合物 （20) 2.5 g ( 9.6 mmol ) 、 CuCl 0.056 g ( 0.57塵 ol )、 NaOCH ；, ( 28 ¾ in MeOH ) 3.54 g ( 18.3删 ol ) と DMF 1.20 g を加え 125〜130。C にて 1時 f¾Jオートクレーブした。 反応液に 050 ml と EtOAc 50 mlを加えて抽 出し、 有機層を分取し乾燥した。 これを濃縮しシリカゲルカラムに付し、 n-へキ サン ： EtOAc ( 4 : 1 )で溶出し、 化合物 （21) 2.0 gを得た。 Process (ϋ) (20)
Figure imgf000023_0001
Compound (20) 2.5 g (9.6 mmol), CuCl 0.056 g (0.57 dust ol), NaOCH ;, (28 ¾ in MeOH) 3.54 g (18.3 ol ol) and DMF 1.20 g were added, and 125-130. Autoclave was performed at 1 oC at C. The reaction mixture was extracted by adding 050 ml and 50 ml of EtOAc, and the organic layer was separated and dried. This was concentrated and applied to a silica gel column, and eluted with n-hexane: EtOAc (4: 1) to obtain 2.0 g of compound (21).
工程（iii) (21)
Figure imgf000023_0002
Step (iii) (21)
Figure imgf000023_0002
(22) 化合物 （21) 1.0 g ( 4.7 mmol ) 、 ジクロロメチルメチルエーテル 1.63 g ( 14.15 mmol )を CH2C12 20 ml に溶解し 0°C以下に冷却した。 この反応液に T iCh 1.6 ml ( 14.15 mmol ) を加え 3時間攪拌した。 反応終了後、 有機層を H2 0にて洗浄し、 Na2S04 で乾燥した。 これを減圧濃縮しシリカゲルカラムに付し、 n-へキサン ： EtOAc ( 8 : 1 )で溶出し、 化合物 （22) 1.0 gを得た。 工程 (iv) (22)
Figure imgf000024_0001
化合物 （ 22 ) 6.88 g ( 28.6 mmol ) を EtOH 100 mlに溶解したものを 0°C に^却し、 そこに水酸化ホウ索ナトリウム 0.53 g ( 14.0 mmol )を加え 30 分 攪拌し、 続いて室温に戻し一昼夜攪拌した。 反応液に飽和食塩水を加え EtOAcで 抽出し、 分取した有機層を乾燥後、 濃縮し化合物 （23) 5.9 gを得た。 (22) Compound (21) 1.0 g (4.7 mmol ), dichloromethyl methyl ether 1.63 g of (14.15 mmol) was cooled to 0 ° C or below dissolved in CH 2 C1 2 20 ml. 1.6 mL (14.15 mmol) of TiCh was added to the reaction solution, and the mixture was stirred for 3 hours. After completion of the reaction, the organic layer was washed with H 2 0, dried with Na 2 S0 4. This was concentrated under reduced pressure and applied to a silica gel column, and eluted with n- hexane: EtOAc (8: 1) to obtain 1.0 g of compound (22). Process (iv) (22)
Figure imgf000024_0001
A solution of 6.88 g (28.6 mmol) of the compound (22) in 100 ml of EtOH was cooled to 0 ° C, and 0.53 g (14.0 mmol) of sodium borohydride was added thereto, followed by stirring for 30 minutes, and then at room temperature. And stirred overnight. A saturated saline solution was added to the reaction solution, and the mixture was extracted with EtOAc. The separated organic layer was dried and concentrated to obtain 5.9 g of compound (23).
工程（ (23)
Figure imgf000024_0002
Process ((23)
Figure imgf000024_0002
(24)  (twenty four)
原料化合物（IVa) 化合物 （23) 5.9 g ( 23.12 mmol ) を THF 50 mlに溶解し、 0。Cに冷却し PBr3 3.7 g ( 13.67 mmol )を加え、 、て 30 min 間攪袢した。 反応終了後、 EtOAc と 0 を加え混合し、 有機層を分取した。 この有機層を飽和 NaHCt 水、 H.0 で洗^し乾燥した。 これを ffi縮し化 ·物 （24) 6.0 gを ί た。  Starting compound (IVa) 5.9 g (23.12 mmol) of compound (23) was dissolved in 50 ml of THF. After cooling to C, 3.7 g (13.67 mmol) of PBr3 was added, and the mixture was stirred for 30 min. After completion of the reaction, EtOAc and 0 were added and mixed, and the organic layer was separated. The organic layer was washed with saturated NaHCt water and H.0 and dried. (24) 6.0 g was obtained.
工程（vi) (24)
Figure imgf000024_0003
Step (vi) (24)
Figure imgf000024_0003
(25)  (twenty five)
原料化合物 (lib) 化合物 （24) 6.0 g ( 19.7 mmol )、 ビぺラジン無水物 16.9 g ( 196 mmol )を CH3CN 100 ml に溶解させ、 窒素雰囲気下に K2C03 3.0 g ( 21. 7 mmol ) を 加え 30 分間加熱還流した。 反応終了後、 H20 100 mlを加え混合し CH3CNを減圧 下に留去し、 濃縮液を EtOAc で抽出し、 有機層を分取しこれを乾燥後減圧濃縮し た。 残査をシリカゲルカラ Aに付し EtOAc ： EtOH ： NEt3 ( 10 ： 1 ： 0.5 )で溶 出し、 原料化合物 （l ib)に相当する化合物 （ 2 5 ) 2.98 g を得た。 Starting compound (lib) Compound (24) 6.0 g (19.7 mmol), bidazine anhydride 16.9 g (196 mmol) ) Was dissolved in CH 3 CN 100 ml, and heated to reflux for K 2 C0 3 3.0 g (21. 7 mmol) was added 30 minutes under a nitrogen atmosphere. After completion of the reaction, 100 ml of H 2 O was added and mixed, and CH 3 CN was distilled off under reduced pressure. The concentrated solution was extracted with EtOAc, the organic layer was separated, dried and concentrated under reduced pressure. The residue was applied to silica gel column A and eluted with EtOAc: EtOH: NEt 3 (10: 1: 0.5) to obtain 2.98 g of compound (25) corresponding to the starting compound (lib).
MS: M+， 310. MS: M + , 310.
[ B ] 本発明化合物 （2 ) の合成 [B] Synthesis of Compound (2) of the Present Invention
Figure imgf000025_0001
Figure imgf000025_0001
(2)  (2)
化合物 （ 2 5 ) 0.535g ( 1.724 mmol )、 NEt3 0.32 g ( 3. 16 mmol )、 DPPA 0.62 g ( 2.25 mmol )、 DMAP 0.01 g ( 0.08 腿 ol ) を DMF 14 mlに混合した ものに、 製造実施例 1 [ B ] で得た化合物 （ 1 3 ) 0.431 g ( 1.5 mmol )を加え 、 一昼夜攪拌した。 反応液に H20 130 ml を加え攒拌し、 析出した沈澱をろ取し た。 沈澱を H20 で洗浄し、 次にエーテルで洗浄した。 ろ液、 洗液を併せ EtOAcで 抽, T,し乾燥後、 '減圧濃縮し、 残^に n- へキサン +エーテル混液を加え固化させ 沈澱をろ取した。 先に得た沈澱とこの沈殿と併せ、 アセトン 80 mlに溶かし活性 炭にて脱色した。 この溶液を濃縮乾燥しうす茶色の粉末を得た。 この粉末を H20 10 ml 中に懸濁させ IN HC】 3 mlを加え溶解させ、 これにァセトンを加え全量を 200 mlとした。 一夜放置し析出した結晶をろ取し乾燥し本発明化合物 （I ) に包 含される化合物 （2 ) の塩酸塩 0.49 g を得た。 Compound (25) 0.535 g (1.724 mmol), NEt 3 0.32 g (3.16 mmol), DPPA 0.62 g (2.25 mmol), DMAP 0.01 g (0.08 thigh) mixed with 14 ml of DMF to produce 0.431 g (1.5 mmol) of the compound (13) obtained in Example 1 [B] was added, and the mixture was stirred overnight. 130 ml of H 2 O was added to the reaction solution, and the mixture was stirred, and the deposited precipitate was collected by filtration. The precipitate was washed with H 2 0, then washed with ether. The filtrate and washings were combined, extracted with EtOAc, T, dried, and concentrated under reduced pressure. The residue was solidified by adding a mixture of n-hexane and ether, and the precipitate was collected by filtration. The precipitate obtained above and this precipitate were combined, dissolved in 80 ml of acetone, and decolorized with activated carbon. This solution was concentrated and dried to obtain a light brown powder. This powder was suspended in 10 ml of H 2 O, 3 ml of IN HC was added and dissolved, and acetone was added thereto to make the total volume 200 ml. The mixture was allowed to stand overnight, and the precipitated crystals were collected by filtration and dried to obtain 0.49 g of the hydrochloride of the compound (2) included in the compound (I) of the present invention.
元素分析 C3。H N507 - 2HC1 - H.0 Elemental Analysis C 3. HN 5 0 7 - 2HC1 - H.0
計算値 C， 53.73%, H, 6. 16%， N, 10.44%  Calculated value C, 53.73%, H, 6.16%, N, 10.44%
分析値 C, 53.81%, H, 6. 11¾, N, 10.35% mp. 163 〜164 °C (分解） 製造実施例 3 (本発明化合物 （3 ) の製造） Analytical value C, 53.81%, H, 6.11¾, N, 10.35% mp. 163-164 ° C (decomposition) Production Example 3 (Production of the compound (3) of the present invention)
[A] 原料化合物 （l ie )の合成  [A] Synthesis of starting compound (l ie)
工程（i)
Figure imgf000026_0001
Step (i)
Figure imgf000026_0001
(26)  (26)
N-ホルミルビぺラジン 1.5 g ( 13.1 mmol )、 ジォキサン 20 ml 、 37 %ホルマ リン 5ml、 CHaCOOH 2 ml を混合し攪拌した。 10分後、 トリメチルハイ ドロキノン 1.0 g ( 6.6 mmol ) を加え 3時問、 加熱還流した。 放冷後反応液を約 1/2に濃 縮し、 5 % NaHC03 で pH 8 〜9 に調整し EtOAcで抽出した。 有機層を H20 で洗 浄し、 乾燥後濃縮した。 残査を真空乾燥し得られた結晶性の粉末を n- へキサン で洗浄した後、 真空乾燥し化合物 （ 2 6 ) 0.66gを得た。 1.5 g (13.1 mmol) of N-formylbiazine, 20 ml of dioxane, 5 ml of 37% formalin, and 2 ml of CHaCOOH were mixed and stirred. After 10 minutes, 1.0 g (6.6 mmol) of trimethylhydroquinone was added, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated reduced to about 1/2 of the mixture was allowed to cool, with 5% NaHCO 3 was adjusted to pH 8 to 9 and extracted with EtOAc. The organic layer was wash with H 2 0, dried and concentrated. The residue was vacuum-dried, and the obtained crystalline powder was washed with n-hexane and then vacuum-dried to obtain 0.66 g of compound (26).
工程（ii) (26)
Figure imgf000026_0002
Step (ii) (26)
Figure imgf000026_0002
(26a)  (26a)
Figure imgf000026_0003
Figure imgf000026_0003
(27)  (27)
原料化合物 (He) 化合物 （ 2 6 ) 0.62 g ( 2.2 匪 o】 ）を CHCh に溶かし、 Ag20 1.0 g を加え室 温で 1時間攪拌した。 不溶物をろ過し、 ろ液を濃縮した後、 残査を真空乾燥し濃 赤色の油状化合物 （2 6 a ) 0.50 gを得た。 この化合物 （2 6 a ) にジォキサンRaw material compound (He) 0.62 g (2.2 band) of the compound (26) was dissolved in CHCh, 1.0 g of Ag 20 was added, and the mixture was stirred at room temperature for 1 hour. After filtering the insoluble matter and concentrating the filtrate, the residue was dried in vacuo to obtain 0.50 g of a dark red oily compound (26a). Dioxane is added to this compound (26a).
10 mlと IN HC1 10 ml を加え 1時間加熱還流した。 放冷し反応液に EtOAcを加 えて振とう、 分取した水層を NaHC03 にて pH 8 以上に調整し、 EtOAc 、 CHC13 で順次抽出した。 有機層を乾燥後、 減圧濃縮し、 原料化合物 （lie )に相当する油 状化合物 （2 7 ) 0.41 g を得た。 10 ml and IN HC1 (10 ml) were added, and the mixture was heated under reflux for 1 hour. Allowed to cool shaking pressurized strong point of EtOAc to the reaction solution to adjust the fractionated aqueous layer pH 8 than at NaHCO 3, and extracted sequentially with EtOAc, CHC1 3. The organic layer was dried and concentrated under reduced pressure to obtain 0.41 g of an oily compound (27) corresponding to the starting compound (lie).
[ B ] 本発明化合物 （3 ) の合成  [B] Synthesis of compound (3) of the present invention
工程（iii)
Figure imgf000027_0001
Step (iii)
Figure imgf000027_0001
(3) 化合物 （2 7 ) 0.41 g ( 1.65 腿 ol ) 、 NEt:, 0.28 g ( 2.77 mmol ) 、 DPPA(3) Compound (2 7) 0.41 g (1.65 thigh ol), NEt:, 0.28 g (2.77 mmol), DPPA
0.54 g ( 1.96 mmol ) 、 DMAP 0.02 g ( 0.16 mmol ) を DMF 14 mUこ混合し、 製造実施例 1 [ B ] で得た化合物 （ 1 3 ) 0.373 g ( 1.3 mmol ) を加え溶解さ せ、 室温で一昼夜攪拌した。 この反応液に H20 60 ml を加え攪拌し析出した沈澱 をろ取した。 この沈澱を EtOAc 100 ml に加え、 30 分加熱し攪拌した。 熱時不 溶物をろ取し乾燥した。 ろ液は濃縮し、 得られた残査をエーテルで洗浄し、 粉末 を得た。 この粉末を乾燥させ先の沈澱粉末と併せた。 この粉末 0.266 g ( 0.51 mmol )に THF 46. 16 gにドライ HC1を 4.04 g 吸収させたものを約 10.3 ml加え て 40 。(に加温し、 粉末を微細均一に混合分散させた。 室温で 30 分間攪拌した 後、 不溶物をろ取し真空乾燥し、 本発明化合物 （I ) に包含される化合物 （3 ) の塩酸塩 0.36 g を得た。 0.54 g (1.96 mmol) and DMAP 0.02 g (0.16 mmol) were mixed with 14 mU of DMF, and 0.373 g (1.3 mmol) of the compound (13) obtained in Production Example 1 [B] was added and dissolved. For 24 hours. To the reaction mixture was added H 2 60 ml, and the mixture was stirred, and the deposited precipitate was collected by filtration. This precipitate was added to 100 ml of EtOAc, heated and stirred for 30 minutes. The insolubles were collected by filtration while hot and dried. The filtrate was concentrated, and the obtained residue was washed with ether to obtain a powder. This powder was dried and combined with the precipitated powder. To 0.266 g (0.51 mmol) of this powder, about 10.3 ml of a solution obtained by absorbing 4.04 g of dry HC1 in 46.16 g of THF was added. (The powder was mixed and dispersed finely and uniformly. After stirring at room temperature for 30 minutes, the insoluble matter was collected by filtration and dried in vacuo, and hydrochloric acid of compound (3) included in compound (I) of the present invention was added. 0.36 g of salt was obtained.
元素分析 C2 8H3 1N505 · 2HC1 · H2 O Elemental analysis C 2 8 H 3 1 N 5 0 5 · 2HC1 · H2 O
計算値 C, 52.51¾, H, 5.51%, N, 10.39%  Calculated value C, 52.51¾, H, 5.51%, N, 10.39%
分析値 C, 52.43 , H, 5.37%, N, 10.74%  Analytical value C, 52.43, H, 5.37%, N, 10.74%
mp. 244 〜246 °C (分解） 製造実施例 4 (本発明化合物 （4 ) の製造） mp. 244 to 246 ° C (decomposition) Production Example 4 (Production of Compound (4) of the Present Invention)
[A] 原料化合物 （l ie )の合成  [A] Synthesis of starting compound (l ie)
Figure imgf000028_0001
Figure imgf000028_0001
2, 3-ジメ トキシ -5- メチル -1，4- ベンゾキノン 2.0 g ( 10.98 mmol ) を EtO Ac 100 ml に溶解し、 10 % Na2S204 100 mlを加え室温で 30 分間で攪拌した。 反 応終了後、 有機層を減圧濃縮し化合物 （2 8 ) 2.0 g (収率 98.9 % ) を得た。 これに、 N-ホルミルピぺラジン 2.51 g ( 21.99 匪 ol )とジォキサン 40 mlを加 え混合し、 37 % ホルマリン 10 mlと CHaCOOH 4 ml を加え、 3 時間加熱還流した 。 反応終了後、 液量が半分になるまで濃縮し、 5 % NaHCOa で pH 7 〜8 に調整 し析出した沈澱をろ取した。 これを、 i :乾燥し化合物 （ 2 9 ) 2.35 g を ί た 2, 3-dimethyl butoxy-5-methyl-1,4-benzoquinone 2.0 g of (10.98 mmol) was dissolved in EtO Ac 100 ml, and stirred at 10% Na 2 S 2 0 4 100 ml was added for 30 minutes at room temperature . After completion of the reaction, the organic layer was concentrated under reduced pressure to obtain 2.0 g of compound (28) (yield 98.9%). To this, 2.51 g (21.99 bandol) of N-formylpidazine and 40 ml of dioxane were added and mixed, 10 ml of 37% formalin and 4 ml of CHaCOOH were added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the solution was concentrated until the volume became half, adjusted to pH 7 to 8 with 5% NaHCOa, and the deposited precipitate was collected by filtration. This was dried i: 2.35 g of the compound (29) was obtained.
工程（ii) (29)Step (ii) (29)
Figure imgf000028_0002
Figure imgf000028_0002
(30)  (30)
化合物 （ 2 9 ) 2.30 g ( 7.76 mmol ) を EtOAc 50 mlと CHC13 50 ml の混合 溶液に溶解した。 この液に Ag02 3.0 g ( 12.9 mmol ) を加え室温で 1時間攪拌 した。 反応液をろ過し、 ろ液を濃縮し化合物 （ 3 0 ) 2.25 g を得た。 Compound (2 9) 2.30 g (7.76 mmol) was dissolved in a mixed solution of EtOAc 50 ml and CHC1 3 50 ml. Was stirred at room temperature for 1 hour was added to this solution Ag0 2 3.0 g (12.9 mmol) . The reaction solution was filtered, and the filtrate was concentrated to obtain 2.25 g of compound (30).
工程（iii) (30)Step (iii) (30)
Figure imgf000028_0003
Figure imgf000028_0003
(31) 化合物 （ 30 ) 2.25 g ( 7.65 mmol ) をジォキサン 70 mlに溶解し、 IN HC1 70 mlを加え 1時間加熱攪袢した。 室温にまで冷却し、 5 % NaHC03 で pH 7〜 8 に調整した。 この液を約半量まで減圧濃縮し、 濃縮液を EtOAcで抽出した。 分 取した有機層を濃縮し、 原料化合物 （lie)に相当する化合物 （31) 1.6 gを得 た。 (31) 2.25 g (7.65 mmol) of the compound (30) was dissolved in 70 ml of dioxane, and 70 ml of IN HC1 was added thereto, followed by heating and stirring for 1 hour. It cooled to room temperature and adjusted to pH. 7 to 8 with 5% NaHC0 3. This solution was concentrated under reduced pressure to about half the volume, and the concentrate was extracted with EtOAc. The separated organic layer was concentrated to obtain 1.6 g of compound (31) corresponding to the starting compound (lie).
[B] 本発明化合物 （4) の合成  [B] Synthesis of compound (4) of the present invention
Figure imgf000029_0001
Figure imgf000029_0001
(4)  (Four)
化合物 （31) 1.6 g ( 5.7 mmol )、 NEt3 1.06 g ( 10.5 mmol )、 DPPA 2 .05 g ( 7.45 mmol )、 DMAP 0.032 g ( 0.12 mmol )を DMF 30 mlに混合したも のに、 製造実施例 1 [B] で得た化合物 （ 13) 1.42 g ( 4.95 mmol ) を加え 溶解させ室温で一昼夜攪拌させた。 この反応液に H2060 ml を加え攪拌し析出し た沈澱をろ取した。 この沈澱を 0、 エーテルで順次洗浄し真空乾燥した。 この 沈澱 1.3 gを IN HC1 に溶解させァセトンを加えて再結晶し、 本発明化合物 （I ) に包含される化合物 （4) の塩酸塩 1.21 g を得た。 Compound (31) 1.6 g (5.7 mmol ), NEt 3 1.06 g (10.5 mmol), DPPA 2 .05 g (7.45 mmol), to be mixed DMAP 0.032 g of (0.12 mmol) in DMF 30 ml, Preparation 1.42 g (4.95 mmol) of the compound (13) obtained in Example 1 [B] was added and dissolved, followed by stirring at room temperature for 24 hours. To this reaction solution, 060 ml of H 2 was added, and the mixture was stirred, and the resulting precipitate was collected by filtration. The precipitate was washed sequentially with ether and dried in vacuo. 1.3 g of this precipitate was dissolved in INHC1, added with acetone, and recrystallized to obtain 1.21 g of the hydrochloride of the compound (4) included in the compound (I) of the present invention.
元素分析
Figure imgf000029_0002
Elemental analysis
Figure imgf000029_0002
計算値 C, 55.27¾, H, 5.80%， N, 11.51%  Calculated value C, 55.27¾, H, 5.80%, N, 11.51%
分析値 C, 55.13%, H, 5.92%, N, 11.48%  Analytical value C, 55.13%, H, 5.92%, N, 11.48%
mp. 213 -215 °C (分解） 製造実施例 5 [本発明化合物 （5) の製造）  mp. 213 -215 ° C (decomposition) Production Example 5 [Production of compound (5) of the present invention]
[A] 原料化合物 （V) の合成  [A] Synthesis of starting compound (V)
J. Med. Chem. 1993，36，3251に記載の方法に従って、 原料化合物 (V) に相当 する、 式
Figure imgf000030_0001
According to the method described in J. Med. Chem. 1993, 36, 3251, a compound represented by the formula
Figure imgf000030_0001
(37) (37)
で示される化合物 （37) を得た。  The compound (37) represented by was obtained.
[B] 本発明化合物 （5) の合成  [B] Synthesis of compound (5) of the present invention
Figure imgf000030_0002
Figure imgf000030_0002
(5) 化合物 （37) 1.80 g ( 4.50譲 ol ) と、 製造実施例 2 [A] (v) で得た 化合物 （24) 1.44 g ( 4.50讓 ol)を DMF 20 mlに溶解し、 I C03 0.62 g ( 4.50匪 ol) を加え、 窒素雰囲気下に 3時間加熱還流した。 反応液を濃縮し、 水を 加え不溶物をろ取し、 MeOH- エーテル混合液で洗浄し減圧下に乾燥した。 この沈 殿を乾燥 HC1で飽和した MeOH 30 mlに加え、 0.5 時間攪拌し、 エーテルを加え冷 所に放匿した。 析出した沈殿を MeOH:エーテルから再結晶し、 本発明化合物 （I ) に包含される化合物 （5) の塩酸塩 2.40 g を得た。 (5) Dissolve 1.80 g (4.50 ol) of compound (37) and 1.44 g (4.50 benzyl) of compound (24) obtained in Production Example 2 [A] (v) in 20 ml of DMF. 3 0.62 g (4.50 ol) was added, and the mixture was heated and refluxed for 3 hours under a nitrogen atmosphere. The reaction solution was concentrated, water was added, insolubles were collected by filtration, washed with a MeOH-ether mixture, and dried under reduced pressure. The precipitate was added to 30 ml of MeOH saturated with dry HC1, stirred for 0.5 hours, added with ether, and allowed to stand in a cool place. The deposited precipitate was recrystallized from MeOH: ether to obtain 2.40 g of the hydrochloride of the compound (5) included in the compound (I) of the present invention.
元素分析 C31H3sN80n · 2HC1 · HzO Elemental Analysis C 31 H 3 sN 8 0n · 2HC1 · HzO
計算値 C， 52.47%, H, 5.97%， N， 15.79%  Calculated value C, 52.47%, H, 5.97%, N, 15.79%
分析値 C， 52.28%, H, 5.76 ， N, 15.63  Analytical value C, 52.28%, H, 5.76, N, 15.63
mp. 175 〜177 °C (分解） 製造実施例 6 (本発明化合物 （6) の製造）  mp. 175-177 ° C (decomposition) Production Example 6 (Production of compound (6) of the present invention)
製造実施例 5で用いた化合物 （24) の代りに式
Figure imgf000031_0001
で示される臭化アルキルべ た以外は実施例 5と同様にして式 Instead of the compound (24) used in Production Example 5, a compound of the formula
Figure imgf000031_0001
In the same manner as in Example 5 except that the alkyl bromide represented by
Figure imgf000031_0002
Figure imgf000031_0002
(6)  (6)
で示される本発明化合物 （6) を得た。  The compound of the present invention (6) was obtained.
元素分析
Figure imgf000031_0003
* 2HC1 · H O Elemental analysis
Figure imgf000031_0003
* 2HC1HO
計算値 C， 53.79%, H， 5.60¾, N， 17.30%  Calculated value C, 53.79%, H, 5.60¾, N, 17.30%
分析値 C， 53.40%, H， 5.62 , N, 17屬  Analytical value C, 53.40%, H, 5.62, N, 17
mp. 224〜226 °C (分解） 製造実施例 7 (本発明化合物 （7) の製造）  mp. 224-226 ° C (decomposition) Production Example 7 (Production of the present compound (7))
製造実施例 5で用いた化合物 （24) の代りに式  Instead of the compound (24) used in Production Example 5, a compound of the formula
Figure imgf000031_0004
Figure imgf000031_0004
で示される臭化アルキルべンゾキノンを用いた以外は実施例 5と同様にして式 In the same manner as in Example 5 except that the alkyl benzoquinone bromide represented by
Figure imgf000031_0005
Figure imgf000031_0005
(7) で示される本発明化合物 （7) を得た。 (7) The compound of the present invention (7) was obtained.
元素分析 C23H3;iN80f · H.0 - 2HC1 Elemental analysis C2 3 H 3; i N 8 0 f · H.0 - 2HC1
計算値 C, 51.26%, H, 5.34¾, N, 16.49%  Calculated value C, 51.26%, H, 5.34¾, N, 16.49%
分析 ίιΐ( C， 51.20%, H, 5.60¾, N， 16.80¾  Analysis ίιΐ (C, 51.20%, H, 5.60¾, N, 16.80¾
mp. 208〜209 °C (分解） 製造実施例 8 (本発明化合物 （8) の製造）  mp. 208-209 ° C (decomposition) Production Example 8 (Production of compound (8) of the present invention)
製造実施例 5で用いた化合物 （24) の代りに式  Instead of the compound (24) used in Production Example 5, a compound of the formula
Figure imgf000032_0001
で示される 2，5 ジメ 卜キシ -3, 4,6- トリメチルベンジルクロライ ドを用いた以外 は実施例 5と同様にして式
Figure imgf000032_0001
In the same manner as in Example 5, except that 2,5 dimethyl-3,4,6-trimethylbenzyl chloride represented by
Figure imgf000032_0002
Figure imgf000032_0002
(8) (8)
で示される本発明化合物 （8) を得た。 The compound of the present invention (8) was obtained.
元素分析
Figure imgf000032_0003
· 2HC1 · Η,Ο Elemental analysis
Figure imgf000032_0003
· 2HC1 · Η, Ο
^ ηίή C, 54.95%, H， 6.25， N, 16.54%  ^ ηίή C, 54.95%, H, 6.25, N, 16.54%
分析値 C， 54.72¾, H， 6.55%, N， 16.32%  Analytical value C, 54.72¾, H, 6.55%, N, 16.32%
mp. 198〜200 °C (分解） 製造実施例 9 mp. 198-200 ° C (decomposition) Production Example 9
製造実施例 5で用いた化合物 （24) の代りに式  Instead of the compound (24) used in Production Example 5, a compound of the formula
Figure imgf000033_0001
で示される 3，4，5- トリメチルベンジルブ口マイ ドを用いた以外は実施例 5と同様 にして式
Figure imgf000033_0001
In the same manner as in Example 5, except that 3,4,5-trimethylbenzylbutamide represented by
Figure imgf000033_0002
Figure imgf000033_0002
(9) で示される本発明化合物 （9) を得た。  The compound (9) of the present invention represented by (9) was obtained.
元素分析 C23H34N805 · 2HC1 · H2O Elemental analysis C 2 3H 34 N 8 0 5 · 2HC1 · H2O
計算値 C， 52.33¾, H, 5.75%, N, 16.84%  Calculated value C, 52.33¾, H, 5.75%, N, 16.84%
分析値 C, 52.12¾, H， 5.89%， N, 16.51  Analytical value C, 52.12¾, H, 5.89%, N, 16.51
mp. 194〜 197 °C (分解） 薬理試験例  mp. 194 ~ 197 ° C (decomposition) Pharmacological test example
薬理試験例 1 [ラッ ト肝ミクロゾームにおける脂質過酸化反応に対する阻害作 用]  Pharmacological test example 1 [Inhibition of lipid peroxidation in rat liver microsomes]
常法に従い得たラッ ト肝臓ミクロゾームをトリス一塩酸緩衝液 （pH 7.4) に^ ^させ、 NADPH(2 mM)、 ADP(10 mM)及び FeCL (O.lmM) を加え 37°Cに加温し 20 分 反応させた。 ついで氷冷し反応を 1ヒめ、 牛-成した過酸化脂 i¾をチォバルビ ツール酸を用い求めた。 薬物を含まないコントロールに対する過酸化脂質の生成 量の減少率％を脂質過酸化反応の阻害率として表した。 結果を表 1に示す。 薬理試験例 2 [C-AMP ホスホジエステラーゼ阻害活性] 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 i¾ 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]
G . H . J o n e s (ジャーナル ォブ メディシナル ケミストリー 1987， 30, 295) 等の方法に従いヒ 卜血小板由来 C- AMPホスホジエステラーゼ懸濁液を 得た。 この酵素液を薬物、 0. 5 mM gC 、 0. 137 M NaCU 20 mM グルコース及 び 0.2 /Ci [3H] C-AMPを含むトリス塩酸緩衝液に加え 37 °Cで 10 分間加温した 。 反応液に EDTA を加え 90 °C湯浴に 60 秒間浸し反応を止め、 生成した [3H] アデノシン量を測定した。 薬物を含まないコントロールに対するアデノシンの生 成量の減少率％を C-AMP ホスホジエステラーゼの阻害率％として表した。 結果を 表 1に示す。  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.
薬理試験例 3 [ゥサギ血小板凝集抑制作用]  Pharmacological test example 3 [ゥ Egret platelet aggregation inhibitory action]
常法に従い得たラット多血小板血漿を等張緩衝液に加え、 A D P ( 5〃M ) に よる血小板凝蕖をァグリゴメータ （メバニクス製 P AM— 6 C ) を用い測定した 。 コントロール血小板の凝 率に対する ¾物による血小板凝 16率の低下率％を、 血小板凝集抑制率％として表した。 結果を表 1に示す。  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.
薬理試験例 4 [抗ブラジキニン及び抗ヒスタミン作用]  Pharmacological test example 4 [Anti-bradykinin and anti-histamine action]
常法に従い得たラット摘出子宮平滑筋を等張性トランスジューサーを設置した マグヌス管に垂直に懸垂装着し等張緩衝液を加え、 これにブラゾキニン （10_ ag / ml ) またはヒスタミン （4 x l0—8 g/ml ) を加え生じた筋収縮を圧トランスジ ユーザーにて測定した。 コントロールの平滑筋収縮に対する薬物による平滑筋収 縮の低下率％を ォ一夕:？ィ ドに対するす,1 ί抗率として表した。 結果を表 1に示す 薬理試験例 5 [血管拡張作用] Usual manner vertically suspended mounted Magnus tube were placed isotonic transducer rat excised uterine smooth muscle was obtained in accordance with an isotonic buffer was added, to which Burazokinin (10_ a g / ml) or histamine (4 x l0 - the 8 g / ml) was added resulting muscle contraction was measured by pressure Toransuji user. Percentage decrease in smooth muscle contraction by drug relative to control smooth muscle contraction It is for I de, expressed as 1 I anti rate. The results are shown in Table 1. Pharmacological test example 5 [Vasodilator action]
常法に従い得たラッ 卜摘出動脈を等張性トランスジューサーを設置したマグヌ ス管に垂直に懸垂装着し等張緩衝液を加え一定量の荷重 （0.5 g ) を懸けた。 血 管の緊張が一定してから、 これに薬物を加え緊張の弛緩する程度％を求めた。 糸 果を表 1に示す。 1 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. 1
C一 AMP  C-AMP
供試化合物 脂 K過 δδ化反応 fflS作用 ホスホジエステラーゼ 血小板; Si ί6仰制 抗ブラジキニン作用 抗ヒスタミン作用 血管拡張作 m  Test compounds Fatty acid K-over δδ conversion fflS action Phosphodiesterase platelets; Si 仰 6 Suppression Anti-bradykinin action Antihistamine action Vasodilator
\m% do M) ffl¾% (1"M) Pil害％(1 M) (30 ig/ml) (I g/ml) (lO iM) 本¾明化合物 (1) 90% >96% 87% 28% 45% 7 1% 本允 Π/j化合物 (2) >9 6% 8 C 35% 68% 64% 本 ¾明化合物 (3) 91% >96% 83% 30% 78% 96% 本允 W化 ft物 (4) 88% >96% 52% 80% 木 ¾1】化合物 (5) >96% 85% 40% 86% 68% 本 ¾1リ〗化 物 (6) 84% >96% 88% 92% c 本¾明化合物 (7) 82% >96% 87% 63% \ m% do M) ffl¾% (1 "M) Pil harm% (1 M) (30 ig / ml) (I g / ml) (lO iM) Compound of the present invention (1) 90%> 96% 87% 28% 45% 7 1% Honju Π / j compound (2)> 9 6% 8 C 35% 68% 64% Honju compound (3) 91%> 96% 83% 30% 78% 96% Honju W compound ft compound (4) 88%> 96% 52% 80% wood ¾1】 Compound (5)> 96% 85% 40% 86% 68% ¾1 compound (6) 84%> 96% 88% 92% c Compound (7) 82%> 96% 87% 63%
CO CO
本 ¾明化合物 (8) >96% 85% 80%  The present compound (8)> 96% 85% 80%
木允 Iリ 1化 r物 (9) 78% >96% 90% 75%  Kiyun Iri 1 r r (9) 78%> 96% 90% 75%
参考化 物 *h <5 *' >96% 72% 33% Reference compound * h <5 * '> 96% 72% 33%
*a ) 被験化合物の'; g媒に用いた DM SOの活性以下  * a) '' of the test compound; below the activity of DMSO used in g medium
*b ) 参考化合物： J.med.Chem. ,35,2688, 1992  * b) Reference compound: J.med.Chem., 35, 2688, 1992
Figure imgf000035_0001
Figure imgf000035_0001
薬理試験例 6 [麻酔ラッ ト血 Hi下降作用] Pharmacological test example 6 [Anesthetic rat blood Hi-lowering effect]
雄性ウィスター系ラッ トをペントノ レビタールで麻酔し、 標準第 I I誘導で心 電図をまた圧トンスジューサーを用い大腿動脈圧を記録した。 薬物を投与し血圧 と心拍数数の変化を観察した。 収縮期及び拡張期における ifn ¾の下降程度を表 2 に示す。 本発明化合物は、 心拍数には影響を与える事無く血圧下降作用を示した 表 2 麻酔ラット血圧下降作用  Male Wistar rats were anesthetized with pentonolevital and electrocardiograms were recorded on a standard lead II and femoral artery pressure was recorded using a pressure tonic juicer. The drug was administered and changes in blood pressure and heart rate were observed. Table 2 shows the degree of ifn 下降 falling during systole and diastole. The compound of the present invention showed a blood pressure lowering effect without affecting the heart rate. Table 2 Blood pressure lowering effect in anesthetized rats
d9 、 d9,
Figure imgf000036_0001
薬理試験例 7 [麻酔ラッ 卜の冠動脈閉塞—再灌流による再灌流障害性の心室性 不整脈に対する抑制作用]
Figure imgf000036_0001
Pharmacological test example 7 [Coronary artery occlusion in anesthesia rat-inhibitory effect on reperfusion-induced ventricular arrhythmia due to reperfusion]
雄性ウィスター系ラッ 卜をペントバルビタールで麻酔し、 標準第 I I誘導で心 電図をまた圧トンスジューサーを用い大腿動脈圧を記録した。 人工呼吸下に開胸 し、 左冠動脈前下行枝を 5分間結紮した後、 再灌流し生じる不整脈の発現頻度を 10分間観察した。 コントロールの不整脈の発生時間に対する不整脈発生時間の減 少率を再灌流障害抑制作用として表した。 結果を表 3に示す。 本発明化合物は 虚血一再灌流による心室性不整脈の発生を抑制し、 再灌流障害抑制作用を示した 表 3 再港流降害性心室性不整脈 薬 物 投与方法 心室性不整脈発生時間 抑制率％  Male Wistar rats were anesthetized with pentobarbital and electrocardiograms were recorded with standard lead II and femoral artery pressure was recorded using a pressure tonic juicer. After thoracotomy under artificial respiration, the left anterior descending coronary artery was ligated for 5 minutes, and the frequency of arrhythmia caused by reperfusion was observed for 10 minutes. The reduction rate of the arrhythmia occurrence time relative to the control arrhythmia occurrence time was expressed as the reperfusion injury suppressing effect. Table 3 shows the results. The compound of the present invention suppressed the occurrence of ventricular arrhythmia due to ischemia-reperfusion, and showed an inhibitory effect on reperfusion injury.Table 3 Recurrence of ventricular arrhythmia with regurgitation flow
( sec ) べ ヒ ク ノレ i . v . 5 2 6 本発明化合物（ 2 ) 1 i . v . 3 0 9 5 本発明化合物（ 5 ) 3 i . v . 2 0 9 6 本発明化合物（ 8 ) 1 i . v . 2 8 9 5 薬理試験例 8 [末梢循埙陣害仰制作用] (sec) Compound (2) 1 i.v. 309 5 Compound of the present invention (5) 3 i.v. 209 6 Compound of the present invention (8) 1 i. V. 2 8 9 5 Pharmacological test example 8 [for production of circumstance of peripheral circulation]
ddy 系雄性マウスにェピネフリン 50 g/kg及びコラーゲン 800 g/kgを静脈 内投与し、 投与 2 4時間内生存する動物数を観察した。 結果を表 4に示す。 本発 明化合物は閉塞性の末梢循環障害による死亡を抑制し、 末梢循環障害抑制作用を 示した。  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.
表 4 末捎循環降害抑制作用 Table 4 End-effect of circulating damage
Figure imgf000037_0001
Figure imgf000037_0001
発明の効果 The invention's effect
以上のとおり、 一般式 （I ) で示されるイミダゾリキノリン誘導体または薬理 学的に許容し得る塩は、 優れた脂質過酸化抑制作用、 血小板凝集抑制作用、 抗ヒ ス夕ミン及び抗ブラジキニン作用の少なくとも 2種以上の薬理作用を併せもつこ と、 又は生体内で代謝活性化を受け前記作用の少なくとも 2種以上の活性を相加 的あるいは相乗的に発現することにより、 生体内脂質過酸化反応、 血小板凝集、 ヒスタ ミン、 ブラジキニンが原因となる種々の血栓塞栓性疾患、 例えば冠血管梗 塞や脳梗塞などの一過性虛血性疾患あるいは動脈硬化症、 慢性動脈閉塞症に伴う 潰瘍、 疼痛および冷感等の虚血性諸症状、 糸球体腎炎、 糖尿病性腎症さらにはこ の虚血状態から回復後に生じる再灌流障害の治療又は予防効果を有するので、 れらの疾病の治療又は予防的医薬として好ましく用いられる。 As described above, 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. It has a therapeutic or preventive effect on 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.

Claims

請求の範囲 The scope of the claims
1. 一般式  1. General formula
X-(CH2)nr (I) X- (CH 2 ) n r (I)
I I
Figure imgf000039_0001
Figure imgf000039_0001
[式中 Xは基 [Where X is a group
Figure imgf000039_0002
から選ばれる基であり、
Figure imgf000039_0002
A group selected from
基 (a)中の R!， はそれそれ独立に C！〜 アルキル基または C,〜C 4アル コキシ基であり.、 R3, R 4 はそれぞれ独立に水素、 （：，〜( 4ァルキル基または。 ,〜C4アルコキシ基であり、 R! In group (a) is independently C! An alkyl group or a C, to C 4 alkoxy group. R 3 and R 4 are each independently hydrogen, (:, to ( 4 alkyl group or., To C 4 alkoxy group,
基（b)中の R5， R7 はそれぞれ独立に水素、 水酸基、 （^〜（ 4アルキル基また は アルコキシ^であり、 R5, R 7の^'者が同 に水 ¾であることはなく 、 Rn， R8 ， Rリ はそれそれ独立に水素、 水酸基、 C,〜C 4アルキル基または C ,〜C4アルコキシ基であり、 R<;， Re, R,)の三者が同時に水素であることはなく 基（c) 中の R1()， Ri., はそれそれ独立に水素、 C,〜C4アルキル基また は C ,〜（^アルコキシ基であり、 R1()， Rn, R の三者が同時に水素である とはなく、 R 5 and R 7 in the group (b) are each independently hydrogen, a hydroxyl group, (^ to ( 4 alkyl group or alkoxy ^), and the ^ ′ of R 5 and R 7 are also hydrogen. And Rn, R 8 , and R are each independently hydrogen, a hydroxyl group, a C, -C 4 alkyl group or a C, -C 4 alkoxy group, and R <;, Re, R,) R 1 () and Ri. In group (c) are independently hydrogen, C, -C4 alkyl or Is a C, ~ (^ alkoxy group, and R 1 () , Rn and R are not necessarily hydrogen at the same time,
Yは基  Y is the group
N一 または HC- であり、 N- or HC-
Zは基 COM  Z is the base COM
一 N-C  One N-C
/ 、、一  /, One
または N N  Or N N
*N  * N
であり、 And
η,, τΐ2, η:ι, η4はそれぞれ独立して 1〜 6の整数である。 ] η ,, τΐ2, η : ι , η 4 are each independently an integer of 1 to 6. ]
で示されるイミダゾリキノリン誘導体またはその薬理学的に許容し得る塩 c An imidazoliquinoline derivative represented by or a pharmacologically acceptable salt thereof c
2. 一般式 2. General formula
(Π)(Π)
Figure imgf000040_0001
Figure imgf000040_0001
[式中 Xは [Where X is
Figure imgf000040_0002
から選ばれる基であり、
Figure imgf000040_0002
A group selected from
基 (a) 中の R R 2はそれぞれ独立に C! ^アルキル基または C,〜C4アル コキシ基であり、 R3， R 4はそれぞれ独立に水素、 C,〜C4アルキル基または C 〜Γ アルコキシ基であり、 RR 2 in the group (a) is each independently a C! ^ Alkyl group or a C, to C 4 alkoxy group, and R 3 and R 4 are each independently hydrogen, a C, to C 4 alkyl group or a C to C 4 alkyl group.で an alkoxy group,
基 (b) 中の R「 R 7はそれそれ独立に水素、 水酸基、 。！〜 ^ァルキル^また は（^〜(^アルコキシ基であり、 R5， R7の両者が同時に水素であることはなく 、 Rn3 R8， はそれそれ独立に水素、 水酸基、 （^〜（ 4アルキル基または d ~C4アルコキシ基であり、 Rfi， R8， Raの三者が同時に水素であることはなく 基（c) 中の R1 ()， Rii, はそれぞれ独立に水素、 （^〜（^アルキル基また は Ct C アルコキシ基であり、 R,。， Rll, R12の三者が同時に水素であるこ とはなく、 R "R 7 is hydrogen then it independently in group (b), a hydroxyl group,.! ~ ^ Arukiru ^ or is (^ - (^ alkoxy group, both R 5, R 7 are hydrogen at the same time Rn 3 R 8 , independently of each other, is hydrogen, a hydroxyl group, (^-( 4 alkyl group or d-C4 alkoxy group, and R fi , R 8 , and Ra are not hydrogen simultaneously. no group R 1 in (c) (), Rii, are each independently hydrogen, (^ - (^ alkyl or Ct C alkoxy group, R,., RLL, tripartite hydrogen simultaneously R 12 It is not
nl5 n., n3はそれぞれ独立して 1〜6の整数であり、 n l5 n., n 3 are each independently an integer from 1 to 6,
X中の水酸基は保護基によって保護されていてもよい。 ]  The hydroxyl group in X may be protected by a protecting group. ]
で示される化合物と、 一般式 And a compound represented by the general formula
Figure imgf000041_0001
Figure imgf000041_0001
[式中、 n 4は 1〜 6の整数である] [Where n 4 is an integer from 1 to 6]
で示される化合物とを縮合反応させ、 必要ならば酸化反応に付することを特徴と する一般式 — (CH2)n]— NA compound represented by the general formula — (CH 2 ) n] — N
Figure imgf000041_0002
Figure imgf000041_0002
(式中、 X， r ， ri3， r は上 ikiで定 したとおりである。 ） で示されるィミダゾリキノリン誘導体の製造方法。 (Where X, r, ri3, and r are as defined in the above iki.) A method for producing an imidazoliquinoline derivative represented by the formula:
3. 一般式 3. General formula
Figure imgf000042_0001
Figure imgf000042_0001
[式中、 R5, R 7はそれそれ独立に水素、 水酸基、 C! C^アルキル基または (^〜( 4アルコキシ基であり、 R5， の両者が同時に水素であることはなく、 Ro, R8， R3はそれそれ独立に水素、 水酸基、 （^〜（ 4アルキル基または C!〜 C 4アルコキシ基であり、 Rc， RBj R。の三者が同時に水素であることはなく、 は 1~6の整数であり、 [Wherein, R 5 and R 7 are each independently hydrogen, a hydroxyl group, a C! C ^ alkyl group or a (^ to ( 4 alkoxy group, and both R 5 and R 5 are not hydrogen simultaneously; , R 8 , R 3 are each independently hydrogen, hydroxyl, (^ ~ ( 4 alkyl or C! ~ C 4 alkoxy, and Rc, R Bj R. And are integers from 1 to 6,
Halはハロゲン原子である。 ]  Hal is a halogen atom. ]
で示される化合物と、 一般式  And a compound represented by the general formula
Figure imgf000042_0002
Figure imgf000042_0002
(式屮、 n2， U 3 , r はそれそれ独立して 1〜6の整数である。 ） で示される化合物とを縮合反応させることを特徴とする一般式 (The formulas b, n 2 , U 3, and r are each independently an integer of 1 to 6.) A compound represented by the general formula:
Figure imgf000042_0003
Figure imgf000042_0003
(lb)  (lb)
(式中、 R5, R«, R7, R , RO, ni, n^, na, n4は上記で定義したとお りである。 ） (Where R 5 , R «, R 7 , R, RO, ni, n ^, n a , n 4 are as defined above.)
で示されるィミダゾリキノリン誘導体の製造方法。 A method for producing an imidazoliquinoline derivative represented by the formula:
4. 一般式 4. General formula
Figure imgf000043_0001
Figure imgf000043_0001
[式中、 Rn Rn, ； はそれぞれ独立に水尜、 Ci C.,アルキル基または[Wherein, Rn Rn,; are each independently hydrogen, Ci C., an alkyl group or
( ,〜。^アルコキシ基であり、 R 0 , Rii, の三者が同時に水素であること はなく、 (, ~. ^ Is an alkoxy group, and R 0 and Rii, are not hydrogen at the same time,
ηιは 1〜6の整数であり、  ηι is an integer from 1 to 6,
Halはハロゲン原子である。 ]  Hal is a halogen atom. ]
で示される化合物と、 一般式 And a compound represented by the general formula
Figure imgf000043_0002
Figure imgf000043_0002
(式中、 ri2, n3， r はそれそれ独立して 1〜6の整数である。 ） (Wherein, ri2, n 3, r is an integer of 1 to 6 which it independently.)
で示される化合物とを縮合反応させることを特徴とする一般式 Wherein a condensation reaction with the compound represented by the general formula is performed.
Figure imgf000043_0003
Figure imgf000043_0003
(Ic)  (I c)
(式中、 R1()， R 1 1 , R i 2 , ni, n2, n3, n4は上記で定義したとおりであ る。 ） (Where R 1 () , R 11, R i 2, ni, n 2 , n 3 , n 4 are as defined above)
で示されるィミダゾリキノリン誘導体の製造方法。 A method for producing an imidazoliquinoline derivative represented by the formula:
5. 請求項 1に記載のィミダゾリキノリン誘導体またはその薬理学的に許容し 得る塩を有効成分として含む医薬組成物。 5. The imidazoliquinoline derivative according to claim 1 or a pharmacologically acceptable derivative thereof. A pharmaceutical composition comprising the obtained salt as an active ingredient.
6 . 酸化反応または血小板凝集作用 （または C-AMPホスホジエステラーゼ） によ る疾病の治療剤又は改善剤である、 請求項 5記載の医薬組成物。 6. The pharmaceutical composition according to claim 5, which is a therapeutic or ameliorating agent for a disease caused by an oxidation reaction or platelet aggregation (or C-AMP phosphodiesterase).
7 . 心、 脳、 肺、 腎、 肝、 滕臓の機能障害による疾病の治療剤又は改善剤であ る、 請求項 5記載の医薬組成物。 7. The pharmaceutical composition according to claim 5, which is a therapeutic or ameliorating agent for a disease caused by impairment of the function of the heart, brain, lung, kidney, liver, and brain.
8 . 循環機能改善剤である、 請求項 5記載の医薬組成物。 8. The pharmaceutical composition according to claim 5, which is a circulatory function improving agent.
PCT/JP1995/001621 1994-08-17 1995-08-14 Imidazoquinoline derivative WO1996005202A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056790A1 (en) * 1997-06-11 1998-12-17 Glaxo Group Limited Dihydroimidazo[1,5-b]isoquinoline-1,3-diones as apoprotein b-100 inhibitors
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 (en) * 2008-10-28 2011-01-12 昆明理工大学 Method for preparing 2,3,4,5-tetramethoxytoluene
JP2016050850A (en) * 2014-08-29 2016-04-11 日立化成テクノサービス株式会社 NOx COLLECTION MATERIAL

Citations (3)

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Publication number Priority date Publication date Assignee Title
JPH03169880A (en) * 1989-11-01 1991-07-23 Bristol Myers Squibb Co Imidazo(4, 5-b)quinolinyloxyalkane acid amide improved in water-solubility
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 (en) * 1989-11-01 1991-07-23 Bristol Myers Squibb Co Imidazo(4, 5-b)quinolinyloxyalkane acid amide improved in water-solubility
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 (4)

* 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 (en) * 1997-06-11 1998-12-17 Glaxo Group Limited Dihydroimidazo[1,5-b]isoquinoline-1,3-diones as apoprotein b-100 inhibitors
CN101381291B (en) * 2008-10-28 2011-01-12 昆明理工大学 Method for preparing 2,3,4,5-tetramethoxytoluene
JP2016050850A (en) * 2014-08-29 2016-04-11 日立化成テクノサービス株式会社 NOx COLLECTION MATERIAL

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