JP2559814B2 - Catechol derivative and pharmaceutical preparation containing the same - Google Patents
Catechol derivative and pharmaceutical preparation containing the sameInfo
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- JP2559814B2 JP2559814B2 JP63167064A JP16706488A JP2559814B2 JP 2559814 B2 JP2559814 B2 JP 2559814B2 JP 63167064 A JP63167064 A JP 63167064A JP 16706488 A JP16706488 A JP 16706488A JP 2559814 B2 JP2559814 B2 JP 2559814B2
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- present
- catechol derivative
- lipoxygenase
- ulcer
- action
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、新規なカテコール誘導体及びこれを含有す
る5−リポキシゲナーゼ作用阻害剤及び抗潰瘍剤に関す
る。TECHNICAL FIELD The present invention relates to a novel catechol derivative, a 5-lipoxygenase action inhibitor and an antiulcer agent containing the same.
アレルギーの発症因子であるロイコトリエンC4(LT
C4),ロイコトリエンD4(LTD4)といったロイコトリエ
ン類は生体内でアラキドン酸から5−リポキシゲナーゼ
の作用によって生合成される。Leukotriene C 4 (LT
Leukotrienes such as C 4 ) and leukotriene D 4 (LTD 4 ) are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase.
最近ロイコトリエン類はアレルギーのみでなく腎炎,
肝炎,リウマチ、胃潰瘍といった病態の発症にかかわっ
ていることが明らかにされている。Recently, leukotrienes have caused not only allergies but also nephritis,
It has been clarified that it is involved in the development of pathological conditions such as hepatitis, rheumatism, and gastric ulcer.
従って、ロイコトリエン類の生合成を抑制し、これら
疾患の治療に有効な物質を見すけ出すことが課題とされ
ていた。また、胃潰瘍などを抑制する抗潰瘍活性を持つ
物質を見つけ出すことも課題とされていた。Therefore, it has been a subject to suppress the biosynthesis of leukotrienes and to find a substance effective for treating these diseases. Further, finding a substance having an anti-ulcer activity that suppresses gastric ulcer and the like has also been an issue.
本発明者らはカテコール誘導体を種々合成し、それら
の5−リポキシゲナーゼの作用阻害活性及び抗潰瘍活性
を鋭意検討した結果、本発明に係るカテコール誘導体が
強力な5−リポキシゲナーゼの作用阻害活性及び抗潰瘍
活性を有することを見い出し本発明を完成するに至っ
た。5−リポキシゲナーゼの作用阻害活性を有する本発
明のカテコール誘導体はロイコトリエンの生合成を抑制
し、アレルギー性の疾患である喘息,鼻炎とともに腎
炎,肝炎,リウマチ,胃潰瘍の治療に有用である。The present inventors have synthesized various catechol derivatives, and as a result of diligent examination of their 5-lipoxygenase action-inhibiting activity and anti-ulcer activity. As a result, the catechol derivative of the present invention has a strong 5-lipoxygenase action-inhibiting activity and anti-ulcer. They found that they have activity and completed the present invention. The catechol derivative of the present invention having an activity of inhibiting the action of 5-lipoxygenase suppresses the biosynthesis of leukotrienes and is useful for the treatment of allergic diseases such as asthma and rhinitis, nephritis, hepatitis, rheumatism and gastric ulcer.
又、抗潰瘍活性を有する本発明のカテコール誘導体は
胃潰瘍などの潰瘍の治療にも有用である。The catechol derivative of the present invention having anti-ulcer activity is also useful for treating ulcer such as gastric ulcer.
従って、本発明は、新規なカテコール誘導体及びこれ
を含有する5−リポキシゲナーゼ作用阻害剤及び抗潰瘍
剤を提供することを目的とする。Therefore, an object of the present invention is to provide a novel catechol derivative, a 5-lipoxygenase action inhibitor containing the same, and an antiulcer agent.
上記目的に沿う本発明は、一般式 (式中Xは−CH2−CH2−又は−CH=CH−から選ばれる基
を示す。又nは4から8までの整数である。) で示されるカテコール誘導体である。The present invention in accordance with the above object is represented by the general formula (In the formula, X represents a group selected from —CH 2 —CH 2 — or —CH═CH—, and n is an integer of 4 to 8.).
また本発明により上記式(I)で示されるカテコール
誘導体を含有する5−リポキシゲナーゼ作用阻害剤及び
抗潰瘍剤が提供される。The present invention also provides a 5-lipoxygenase action inhibitor and an anti-ulcer agent containing the catechol derivative represented by the above formula (I).
なお、本発明において5−リポキシゲナーゼ作用阻害
剤とは5−リポキシゲナーゼの作用を抑制する作用を有
する製剤を意味する。また、本発明において抗潰瘍剤と
は、胃潰瘍などの潰瘍を抑制する作用を有する製剤を意
味する。In the present invention, the 5-lipoxygenase action inhibitor means a preparation having an action of suppressing the action of 5-lipoxygenase. Further, in the present invention, the anti-ulcer agent means a preparation having an action of suppressing ulcer such as gastric ulcer.
本発明の前記式(I)で示されるカテコール誘導体の
製造法を以下に示す。まず、下記式(II)で示されるベ
ンジリデンアセトン誘導体 (式中、(R)lは、3,4−ジメトキシメチルオキシ基
又は3,4−ジヒドロキシ基を示す)と対応するアルカン
酸イミダゾールアミドとのクライゼン反応を行い、付加
物を得る。さらに、この付加物を脱保護基反応を行うこ
とによって、本発明に係る化合物を得ることができる。
また、こうして得られた化合物をさらに、接触還元する
ことによって、本発明に係る他の化合物を得ることがで
きる。The method for producing the catechol derivative represented by the above formula (I) of the present invention is shown below. First, a benzylideneacetone derivative represented by the following formula (II) (In the formula, (R) 1 represents a 3,4-dimethoxymethyloxy group or a 3,4-dihydroxy group) and the corresponding alkanoic acid imidazole amide are subjected to Claisen reaction to obtain an adduct. Further, the compound according to the present invention can be obtained by subjecting this adduct to a deprotecting group reaction.
Further, the compound thus obtained is further subjected to catalytic reduction to obtain another compound according to the present invention.
本発明のカテコール誘導体は5−リポキシゲナーゼ作
用阻害剤及び抗潰瘍剤として使用することができ、投与
量は症状により異なるが一般に成人1日量10〜500mg、
好ましくは20〜100mgであり、症状に応じて必要により
1〜3回に分けて投与するのがよい。投与方法は投与に
適した任意の形態をとることができ、特に経口投与が望
ましいが静注も可能である。The catechol derivative of the present invention can be used as a 5-lipoxygenase action inhibitor and an anti-ulcer agent, and although the dose varies depending on the symptoms, it is generally 10 to 500 mg per day for adults.
The preferred dose is 20 to 100 mg, and it may be administered in 1 to 3 divided doses depending on the symptoms. The administration method can be any form suitable for administration, and oral administration is particularly preferable, but intravenous injection is also possible.
本発明の化合物は有効成分若しくは有効成分の1つと
して単独又は通常の方法で製剤担体あるいは賦形剤等と
混合され、錠剤,糖衣錠,散剤,カプセル剤,顆粒剤,
懸濁剤,乳剤,注射液等に製剤化された種々の形態で適
用できる。担体あるいは賦形剤の例としては炭酸カルシ
ウム,リン酸カルシウム,でんぷん,ブドウ糖,乳糖,
デキストリン,アルギン酸,マンニトール,タルク,ス
テアリン酸マグネシウム等があげられる。The compound of the present invention is used as an active ingredient or one of the active ingredients, alone or mixed with a pharmaceutical carrier or an excipient by a conventional method to give tablets, dragees, powders, capsules, granules,
It can be applied in various forms formulated into suspensions, emulsions, injections and the like. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose,
Examples include dextrin, alginic acid, mannitol, talc and magnesium stearate.
次に実施例及び試験例を示して本発明をさらに具体的
に説明するが、本発明はこれらに限定されるものではな
い。Next, the present invention will be described more specifically by showing Examples and Test Examples, but the present invention is not limited to these.
実施例1 アルゴン雰囲気下、ジイソプロピルアミン1.17gを乾
燥テトラヒドロフラン30mlに溶解し、−15℃に冷却後、
1.6M n−ブチルリチウムのヘキサン溶液7.50mlを滴下す
る。乾燥テトラヒドロフラン10mlに溶解した4−(3,4
−ジメトキシメチルオキシフェニル)−3−ブテン−2
−オン2.67gを−15℃で滴下後、同温で20分間攪拌す
る。−78℃に冷却後、乾燥テトラヒドロフラン50mlに溶
解したカプリル酸イミダゾールアミド1.95gを滴下し、
同温で3時間、室温で12時間攪拌する。反応液に飽和食
塩水を加え有機層を分離したのち、水層から酢酸エチル
で抽出する。有機層を2規定塩酸,飽和炭酸水素ナトリ
ウム水溶液,飽和食塩水で洗浄し,無水硫酸マグネシウ
ムで乾燥後、溶媒を減圧下留去する。残渣をシリカゲル
カラムクロマトグラフィーに付し塩化メチレン−ヘキサ
ン(3:1V/V)溶出画分より、1−(3,4−ジメトキシメ
チルオキシフェニル)−1−ドデセン−3,5−ジオン2.0
7gを得る。Example 1 1.17 g of diisopropylamine was dissolved in 30 ml of dry tetrahydrofuran under an argon atmosphere, and after cooling to -15 ° C,
7.50 ml of a 1.6M n-butyllithium hexane solution is added dropwise. 4- (3,4) dissolved in 10 ml of dry tetrahydrofuran
-Dimethoxymethyloxyphenyl) -3-butene-2
After adding 2.67 g of -ON at -15 ° C, stir at the same temperature for 20 minutes. After cooling to −78 ° C., 1.95 g of caprylic acid imidazole amide dissolved in 50 ml of dry tetrahydrofuran was added dropwise,
The mixture is stirred at the same temperature for 3 hours and at room temperature for 12 hours. Saturated saline is added to the reaction solution to separate the organic layer, and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction eluted with methylene chloride-hexane (3: 1 V / V), 1- (3,4-dimethoxymethyloxyphenyl) -1-dodecene-3,5-dione 2.0
Get 7g.
このクライゼン反応付加物1.15gをメタノール−テト
ラヒドロフラン(1:1V/V)20mlに溶解し、6規定塩酸2.
0mlを加え60℃で20分間攪拌する。溶媒を減圧下留去
し、析出した結晶を濾取し、水で洗浄すると1−(3,4
−ジヒドロキシフェニル)−1−ドデセン−3,5−ジオ
ン(III)0.81gを得る。このものの分光学的データは下
記式(III)の構造を支持する。1 HNMR(CDCl3)δ;0.85(3H,t,J=4.5Hz) 1.0〜1.8(10H,m) 2.34(2H,t,J=6.5Hz) 5.58(1H,s) 6.23(1H,d,J=15.5Hz) 6.5〜7.3(3H,m) 7.44(1H,d,J=15.5Hz) 実施例2 1−(3,4−ジヒドロキシフェニル)−1−ドデセン
−3,5−ジオン300mgをメタノール6mgに溶解し、5%パ
ラジウム炭素0.10gを加え、水素ガス雰囲気下で20時間
反応させた後、反応混合物を濾過し、溶媒を減圧下留去
する。残渣をシリカゲルカラムクロマトグラフィーに付
し、塩化メチレン溶出画分より、1−(3,4−ジヒドロ
キシフェニル)−3,5−ドデカンジオン(IV)157mgを得
る。このものの分光学的データは、下記式(IV)の構造
を支持する。1 HNMR(CDCl3)δ;0.86(3H,t,J=4.5Hz) 1.03〜1.95(10H,m) 2.77〜2.92(6H,m) 5.43(1H,s) 6.47〜6.97(3H,m) 実施例3 カプロン酸イミダゾールアミドを用いて実施例1と同
様に反応を行い、1−(3,4−ジヒドロキシフェニル)
−1−デセン−3,5−ジオン(V)を得る(2工程収率;
38%)。このものの分光学的データは、下記式(V)の
構造を支持する。1 HNMR(CDCl3−Methanol d4;9:1)δ; 0.89(3H,t,J=4.5Hz) 1.05〜1.83(6H,m)) 2.39(2H,t,J=6.5Hz) 6.23(1H,d,J=16Hz) 6.50〜7.15(3H,m) 7.42(1H,d,J=16Hz) 実施例4 1−(3,4−ジヒドロキシフェニル)−1−デセン−
3,5−ジオンを用いて実施例2と同様に反応を行い、1
−(3,4−ジヒドロキシフェニル)−3,5−デカンジオン
(VI)を得る(収率:54%)。このものの分光学的デー
タは下記式(VI)の構造を支持する。1 HNMR(CDCl3)δ:0.87(3H,t,J=4.5Hz) 1.0〜1.93(6H,m) 2.0〜3.0(6H,m) 5.38(1H,s) 6.23−6.79(3H,m) 実施例5 n−酪酸イミダゾールアミドを用いて、実施例1と同
様に反応を行い、1(−3,4−ジヒドロキシフェニル)
−1−オクテン−3,5−ジオン(VII)を得る(2工程収
率:43%)。このものの分光学的データは、下記式(VI
I)の構造を支持する。1 HNMR(DMSOd6)δ:0.91(3H,t,J=7Hz) 1.59(2H,sex,J=7Hz) 2.34(2H,t,J=7Hz) 5.81(1H,s) 6.40(1H,d,J=15.5Hz) 6.60−7.14(3H,m) 7.39(1H,d,J=15.5Hz) 実施例6 1−(3,4−ジヒドロキシフェニル)−1−オクテン
−3,5−ジオンを用いて実施例2と同様に反応を行い、
1−(3,4−ジヒドロキシフェニル)−3,5−オクタジオ
ン(VIII)を得る(収率:62%)。このものの分光学的
データは下記式(VIII)の構造を支持する。1 HNMR(CDCl3)δ:0.92(3H,t,J=6Hz) 1.14−3.0(8H,m) 5.46(1H,s) 6.34−6.90(3H,m) 〔試験例〕 (1) 5−リポキシゲナーゼの作用阻害活性 ラット由来好塩基性白血病細胞株RBL−1をイーグル
(Eagle)の基本培地〔ギブコラボラトリーズ(GibcoLa
boratories)社製〕に10%FCSを含む培養液中に懸濁、
5%CO2インキュベーター内で37℃にて培養した後、培
養液を4℃にて遠心分離し細胞を集める。該細胞をpH7.
4のリン酸緩衝液に再浮遊し細胞密度1.0〜3.0×107個/m
lとする。該浮遊細胞を超音波細胞破砕機で処理したあ
と、30分間15,000rpm4℃で遠心分離し、上清を5−リポ
キシゲナーゼ酵素液とする。アラキドン酸50μg及び試
験する本発明に係るカテコール誘導体をそれぞれ試験管
に入れ、これにリン酸緩衝液0.10ml、上記酵素液0.40m
l、100mM CaCl2(塩化カルシウム)溶液5μを加え、
37℃で15分間反応させる。氷冷後1N−HCl(塩酸)1drop
を加え、酢酸エチル2mlで抽出する。抽出液を濃縮乾固
後、メタノール100μを加えて試料とした。1.15 g of this Claisen reaction adduct was dissolved in 20 ml of methanol-tetrahydrofuran (1: 1V / V), and 6N hydrochloric acid was added to 2.
Add 0 ml and stir at 60 ° C. for 20 minutes. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with water to give 1- (3,4
0.81 g of -dihydroxyphenyl) -1-dodecene-3,5-dione (III) is obtained. Its spectroscopic data supports the structure of formula (III) below. 1 HNMR (CDCl 3 ) δ; 0.85 (3H, t, J = 4.5Hz) 1.0 to 1.8 (10H, m) 2.34 (2H, t, J = 6.5Hz) 5.58 (1H, s) 6.23 (1H, d, J = 15.5Hz) 6.5 to 7.3 (3H, m) 7.44 (1H, d, J = 15.5Hz) Example 2 300 mg of 1- (3,4-dihydroxyphenyl) -1-dodecene-3,5-dione was dissolved in 6 mg of methanol, 0.10 g of 5% palladium carbon was added, and the mixture was reacted for 20 hours under a hydrogen gas atmosphere. Then the reaction mixture is filtered and the solvent is evaporated under reduced pressure. The residue is subjected to silica gel column chromatography, and 1- (3,4-dihydroxyphenyl) -3,5-dodecanedione (IV) (157 mg) is obtained from the methylene chloride elution fraction. The spectroscopic data of this support the structure of formula (IV): 1 HNMR (CDCl 3 ) δ; 0.86 (3H, t, J = 4.5Hz) 1.03 to 1.95 (10H, m) 2.77 to 2.92 (6H, m) 5.43 (1H, s) 6.47 to 6.97 (3H, m) Example 3 1- (3,4-dihydroxyphenyl) was reacted using caproic acid imidazole amide in the same manner as in Example 1.
-1-decene-3,5-dione (V) is obtained (2 step yield;
38%). Its spectroscopic data supports the structure of formula (V): 1 HNMR (CDCl 3 -Methanol d 4 ; 9: 1) δ; 0.89 (3H, t, J = 4.5Hz) 1.05 to 1.83 (6H, m)) 2.39 (2H, t, J = 6.5Hz) 6.23 (1H , d, J = 16Hz) 6.50 to 7.15 (3H, m) 7.42 (1H, d, J = 16Hz) Example 4 1- (3,4-dihydroxyphenyl) -1-decene-
Reaction was carried out in the same manner as in Example 2 using 3,5-dione, and 1
-(3,4-Dihydroxyphenyl) -3,5-decanedione (VI) is obtained (yield: 54%). Its spectroscopic data supports the structure of formula (VI) below. 1 HNMR (CDCl 3 ) δ: 0.87 (3H, t, J = 4.5Hz) 1.0 to 1.93 (6H, m) 2.0 to 3.0 (6H, m) 5.38 (1H, s) 6.23-6.79 (3H, m) Example 5 Reaction was carried out in the same manner as in Example 1 using n-butyric acid imidazole amide to give 1 (-3,4-dihydroxyphenyl).
-1-Octene-3,5-dione (VII) is obtained (2 step yield: 43%). The spectroscopic data of this product is given by the following formula (VI
Support the structure of I). 1 HNMR (DMSOd 6 ) δ: 0.91 (3H, t, J = 7Hz) 1.59 (2H, sex, J = 7Hz) 2.34 (2H, t, J = 7Hz) 5.81 (1H, s) 6.40 (1H, d, J = 15.5Hz) 6.60-7.14 (3H, m) 7.39 (1H, d, J = 15.5Hz) Example 6 Using 1- (3,4-dihydroxyphenyl) -1-octene-3,5-dione, a reaction was carried out in the same manner as in Example 2,
1- (3,4-dihydroxyphenyl) -3,5-octadione (VIII) is obtained (yield: 62%). Its spectroscopic data supports the structure of formula (VIII): 1 HNMR (CDCl 3 ) δ: 0.92 (3H, t, J = 6Hz) 1.14−3.0 (8H, m) 5.46 (1H, s) 6.34−6.90 (3H, m) [Test Example] (1) 5-lipoxygenase action-inhibitory activity Rat-derived basophilic leukemia cell line RBL-1 was used as a basic medium of Eagle [Gibco Laboratories (GibcoLa
boratories)) in a culture solution containing 10% FCS,
After culturing at 37 ° C in a 5% CO 2 incubator, the culture solution is centrifuged at 4 ° C to collect cells. The cells were adjusted to pH 7.
Resuspend in 4 phosphate buffer and cell density 1.0-3.0 × 10 7 cells / m
Let l. The suspended cells are treated with an ultrasonic cell disruptor and then centrifuged for 30 minutes at 15,000 rpm at 4 ° C., and the supernatant is used as a 5-lipoxygenase enzyme solution. Arachidonic acid (50 μg) and the catechol derivative according to the present invention to be tested were placed in respective test tubes, and a phosphate buffer solution (0.10 ml) and the above enzyme solution (0.40 m) were added to the test tubes.
l, add 5μ of 100mM CaCl 2 (calcium chloride) solution,
Incubate at 37 ℃ for 15 minutes. After ice cooling 1N-HCl (hydrochloric acid) 1 drop
Is added and extracted with 2 ml of ethyl acetate. After the extract was concentrated to dryness, 100 μm of methanol was added to prepare a sample.
該試料をオクタデシルシラン(ODS)系逆相高速液体
クロマトグラフィー(HPLC)に注入し、メタノール:ア
セトニトリル:酢酸=15:45:35:0.01の溶媒で溶出さ
せ、約25分あたりに検出される5−リポキシゲナーゼ生
成物である5−HETE(5−(s)−ヒドロキシ−6,8,1
1,14−エイコサテトラエン酸)のピーク高さを測定す
る。前記5−リポキシゲナーゼ生成物のピーク高さの減
少により5−リポキシゲナーゼの作用阻害活性が確認さ
れる。試験の結果、下記の表Iに示す如く著名な5−リ
ポキシゲナーゼ作用阻害活性を見い出した。また、表I
に示さない本発明に係るカテコール誘導体についても同
様な5−リポキシゲナーゼ作用阻害活性を有することが
確認された。The sample was injected into octadecylsilane (ODS) -based reverse phase high performance liquid chromatography (HPLC) and eluted with a solvent of methanol: acetonitrile: acetic acid = 15: 45: 35: 0.01, which was detected in about 25 minutes. -The lipoxygenase product 5-HETE (5- (s) -hydroxy-6,8,1
1,14-Eicosatetraenoic acid) peak height is measured. The action-inhibiting activity of 5-lipoxygenase is confirmed by the decrease in the peak height of the 5-lipoxygenase product. As a result of the test, a prominent 5-lipoxygenase action inhibitory activity was found as shown in Table I below. Also, Table I
It was confirmed that the catechol derivative according to the present invention, which is not shown in the above, also has the similar 5-lipoxygenase action inhibitory activity.
なお、表中50%阻害濃度とは本発明に係るカテコール
誘導体を導入しない場合の5−HETEの産生量を100%と
した場合、該カテコール誘導体の導入により前記5−リ
ポキシゲナーゼ生成物の産生量を50%まで抑制する為に
要したカテコール誘導体濃度を意味する。 The 50% inhibitory concentration in the table means that when the production amount of 5-HETE when the catechol derivative according to the present invention is not introduced is 100%, the production amount of the 5-lipoxygenase product is obtained by the introduction of the catechol derivative. It means the concentration of catechol derivative required to suppress to 50%.
(2) 抗潰瘍作用 wistar系雄性ラット(体重150〜200g)を24時間絶食
後、本発明に係るカテコール誘導体を経口投与し、1時
間後エタノール−塩酸(60%エタノールに150mM塩酸を
含む)を0.5ml/100g体重の容量で経口投与した。(2) Anti-ulcer action After wistar male rats (body weight: 150 to 200 g) were fasted for 24 hours, the catechol derivative according to the present invention was orally administered, and 1 hour later, ethanol-hydrochloric acid (60% ethanol containing 150 mM hydrochloric acid) was added. It was orally administered in a volume of 0.5 ml / 100 g body weight.
1時間後にエーテル致死させ、胃を摘出しホルマリン
処理後、腺胃部に発生した損傷の長さ(mm)を測定し、
一匹あたりの損傷の総和を潰瘍係数(Ulcer Index)と
した。One hour later, lethal with ether, and the stomach was removed and treated with formalin, and the length of damage (mm) generated in the glandular stomach was measured.
The total damage per animal was taken as the Ulcer Index.
試験の結果表IIに示す如く、著名な抗潰瘍作用を見い
出した。また表IIに示さない本発明に係るカテコール誘
導体についても同様な抗潰瘍作用を有することが確認さ
れた。Results of the test As shown in Table II, a prominent antiulcer effect was found. It was also confirmed that the catechol derivatives according to the present invention, which are not shown in Table II, also have similar antiulcer action.
なお、表中の潰瘍形成阻害率(%)とは、本発明に係
るカテコール誘導体を経口投与したラットの潰瘍係数を
経口投与しないラットの潰瘍係数で除した値を1から引
いて100倍したものである。 The ulceration inhibition rate (%) in the table is the value obtained by dividing the value obtained by dividing the ulcer index of the rat to which the catechol derivative according to the present invention was orally administered by the ulcer index of the rat not to be orally administered, from 1 and multiplying by 100. Is.
ICR系雄性マウス(5週令)を用いて経口投与による
急性毒性試験を行った。本発明の化合物のLD50値はいず
れも2000mg/kg以上であり、有効量に比べて高い安全性
が確認された。An acute toxicity test by oral administration was performed using ICR male mice (5 weeks old). The LD 50 value of each of the compounds of the present invention was 2000 mg / kg or more, confirming higher safety than the effective dose.
本発明によれば、新規なカテコール誘導体及びこれを
含有する5−リポキシゲナーゼ作用阻害剤及び抗潰瘍剤
が提供される。According to the present invention, a novel catechol derivative, a 5-lipoxygenase action inhibitor and an antiulcer agent containing the same are provided.
本発明の上記化合物は、強力な5−リポキシゲナーゼ
の作用阻害活性及び抗潰瘍活性を有する。即ち、上記化
合物は5−リポキシゲナーゼの作用を阻害することによ
り、5−リポキシゲナーゼの作用によって生成されるLT
C4,LTD4といったロイコトリエン類の産生を抑制する。
従って、本発明に係るカテコール誘導体は、5−リポキ
シゲナーゼ作用阻害剤としてアレルギー性疾患である喘
息,鼻炎とともに、胃炎,肝炎,リウマチ,胃潰瘍等に
対して有効に使用することができる。The above compounds of the present invention have potent 5-lipoxygenase action inhibitory activity and anti-ulcer activity. That is, the above-mentioned compound inhibits the action of 5-lipoxygenase to produce LT produced by the action of 5-lipoxygenase.
Suppresses the production of leukotrienes such as C 4 and LTD 4 .
Therefore, the catechol derivative according to the present invention can be effectively used as a 5-lipoxygenase action inhibitor against asthma and rhinitis, which are allergic diseases, as well as against gastritis, hepatitis, rheumatism, gastric ulcer and the like.
また、本発明の化合物は潰瘍を抑制する効果があるの
で胃潰瘍などの治療薬としても有効に使用することがで
きる。Further, since the compound of the present invention has an effect of suppressing ulcer, it can be effectively used as a therapeutic agent for gastric ulcer and the like.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 FI 技術表示箇所 A61K 31/12 ACL A61K 31/12 ACL ACS ACS AED AED C07C 49/248 C07C 49/248 C12N 9/99 C12N 9/99 (72)発明者 牛島 秀人 東京都渋谷区幡ケ谷2丁目44番1号 テ ルモ株式会社内 審査官 脇村 善一Continuation of the front page (51) Int.Cl. 6 Identification number Internal reference number FI Technical display location A61K 31/12 ACL A61K 31/12 ACL ACS ACS AED AED C07C 49/248 C07C 49/248 C12N 9/99 C12N 9 / 99 (72) Hideto Ushijima 2-44-1, Hatagaya, Shibuya-ku, Tokyo Zenmo Wakimura Examiner, Terumo Corporation
Claims (3)
を示す。又、nは4から8までの整数である。) で示されるカテコール誘導体。1. A general formula (In the formula, X represents a group selected from —CH 2 —CH 2 — or —CH═CH—, and n is an integer from 4 to 8.).
る5−リポキシゲナーゼ作用阻害剤。2. A 5-lipoxygenase action inhibitor containing the catechol derivative according to claim 1.
る抗潰瘍剤。3. An anti-ulcer agent containing the catechol derivative according to claim 1.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63167064A JP2559814B2 (en) | 1988-07-05 | 1988-07-05 | Catechol derivative and pharmaceutical preparation containing the same |
EP89903276A EP0402469B1 (en) | 1988-03-02 | 1989-03-02 | Catechol compounds, process for their preparation and pharmaceutical preparation containing same |
DE68915750T DE68915750T2 (en) | 1988-03-02 | 1989-03-02 | CATHECHOL COMPOUNDS, METHOD FOR THE PRODUCTION AND PREPARATION OF MEDICINAL PRODUCTS CONTAINING THEM. |
PCT/JP1989/000217 WO1989008093A1 (en) | 1988-03-02 | 1989-03-02 | Catechol compounds, process for their preparation and pharmaceutical preparation containing same |
AU32149/89A AU624366B2 (en) | 1988-03-02 | 1989-03-02 | Catechol compounds, process for their preparation and pharmaceutical preparation containing same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63167064A JP2559814B2 (en) | 1988-07-05 | 1988-07-05 | Catechol derivative and pharmaceutical preparation containing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0217146A JPH0217146A (en) | 1990-01-22 |
JP2559814B2 true JP2559814B2 (en) | 1996-12-04 |
Family
ID=15842732
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63167064A Expired - Lifetime JP2559814B2 (en) | 1988-03-02 | 1988-07-05 | Catechol derivative and pharmaceutical preparation containing the same |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2559814B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989008093A1 (en) * | 1988-03-02 | 1989-09-08 | Terumo Kabushiki Kaisha | Catechol compounds, process for their preparation and pharmaceutical preparation containing same |
-
1988
- 1988-07-05 JP JP63167064A patent/JP2559814B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH0217146A (en) | 1990-01-22 |
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