JP2574357B2 - 5-Alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound and method for producing the same - Google Patents
5-Alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound and method for producing the sameInfo
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- JP2574357B2 JP2574357B2 JP1078988A JP1078988A JP2574357B2 JP 2574357 B2 JP2574357 B2 JP 2574357B2 JP 1078988 A JP1078988 A JP 1078988A JP 1078988 A JP1078988 A JP 1078988A JP 2574357 B2 JP2574357 B2 JP 2574357B2
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- alkoxy
- mercaptoimidazo
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Description
【発明の詳細な説明】 産業上の利用分野 本発明は式[I]で示される5−アルコキシ−2−メ
ルカプトイミダゾ[4,5−b]ピリジン化合物(以下、
本発明化合物と言う。)及びその製造法に関する。The present invention relates to a 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula [I]
It is referred to as the compound of the present invention. ) And its manufacturing method.
(式中、R1は環状アルキル基で置換されていてもよい炭
素数1〜8個の直鎖状もしくは分岐状のアルキル基又は
炭素数2〜4個のフルオロアルキル基を表わす。) 本発明化合物は下記式[II]で示される新規な抗潰瘍
活性化合物であるイミダゾ[4,5−b]ピリジン誘導体
の製造中間体として有用である。 (In the formula, R 1 represents a linear or branched alkyl group having 1 to 8 carbon atoms or a fluoroalkyl group having 2 to 4 carbon atoms which may be substituted with a cyclic alkyl group.) The compound is useful as an intermediate for producing an imidazo [4,5-b] pyridine derivative which is a novel anti-ulcer active compound represented by the following formula [II].
(式中、R1は環状アルキル基で置換されていてもよい炭
素数1〜8個の直鎖状もしくは分岐状のアルキル基又は
炭素数2〜4個のフルオロアルキル基を表わし、R2は水
素原子、メチル基又はメトキシ基を表わし、R3及びR4は
同一又は異なって夫々水素原子又はメチル基を表わ
す。) 従来の技術 胃又は十二指腸潰瘍における近年の病態生理の研究で
は、胃小胞体ベシクル内での塩酸産生に関与するカリウ
ムイオン依存性アデノシントリホスファターゼ[以下
(H++K+)ATPアーゼと略す。]の挙動が注目され、こ
の酸素の活性阻害の有無が抗潰瘍剤の一つの指標とされ
るに至って来た[ガストロエンテロロジィー(Gastroen
tero−logy)1巻420頁1943年;同73巻921頁1977年]。
無置換乃至三置換ピリジルメチルスルフィニル基を側鎖
に有する化合物において、かかる観点から、現在、抗潰
瘍剤として開発が進められている代表的なものとして
は、ベンズイミダゾール骨格を持つオメプラゾール[特
開昭54−141783号公報;ブリティッシュ・メディカル・
ジヤーナル(British Medical Journal)287巻12頁1983
年]が知られている。一方、イミダゾピリジン化合物に
おいて、当該酵素の阻害作用が確認又は示唆されている
代表的なものとしては、下記一般式 (式中、XおよびYは、一方が=CH−基で他方が=N−
基を示し、R1′およびR2′は、同一または異なっ
て、それぞれ水素原子、低級アルコキシカルボニル基、
ハロゲン原子、低級アルキル基、アミノ基または水酸
基、R3′、R4′およびR5′は、同一または異なっ
て、それぞれ水素原子、低級アルコキシ基または低級ア
ルキル基、Aは低級アルキレン基、lは0または1を示
す。ただし、Yが=CH−基、Xが=N−基、lが0の場
合は、R3′、R4′およびR5′は同時に水素原子で
あることはない)で表わされる化合物(以下公知イミダ
ゾピリジン誘導体と仮称する。)が報告されている(特
開昭61−145182号公報)。 (Wherein, R 1 represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a cyclic alkyl group or a fluoroalkyl group having 2 to 4 carbon atoms, and R 2 represents A hydrogen atom, a methyl group or a methoxy group is represented, and R 3 and R 4 are the same or different and represent a hydrogen atom or a methyl group, respectively.) Prior art In recent studies on pathophysiology of gastric or duodenal ulcer, gastric endoplasmic reticulum Potassium ion-dependent adenosine triphosphatase (hereinafter abbreviated as (H + + K + ) ATPase involved in hydrochloric acid production in vesicles. ], And the presence or absence of this oxygen activity inhibition has been used as one indicator of anti-ulcer agents [Gastroentrophy (Gastroen)
tero-logy) 1: 420, 1943; 73: 921, 1977].
From such a viewpoint, as a compound having an unsubstituted or trisubstituted pyridylmethylsulfinyl group in the side chain, a representative one currently being developed as an anti-ulcer agent is omeprazole having a benzimidazole skeleton from this viewpoint [ No. 54-141783; British Medical
Journal (British Medical Journal) 287: 12 1983
Year] is known. On the other hand, in the imidazopyridine compound, a typical one whose inhibitory action of the enzyme has been confirmed or suggested is represented by the following general formula: (Wherein one of X and Y is = CH— and the other is NN-
R 1 ′ and R 2 ′ are the same or different and each represents a hydrogen atom, a lower alkoxycarbonyl group,
A halogen atom, a lower alkyl group, an amino group or a hydroxyl group, R 3 ′ , R 4 ′ and R 5 ′ are the same or different and are each a hydrogen atom, a lower alkoxy group or a lower alkyl group, A is a lower alkylene group, l is Indicates 0 or 1. However, when Y is a = CH- group, X is a = N- group, and l is 0, a compound represented by R 3 ' , R 4' and R 5 ' is not a hydrogen atom at the same time (hereinafter referred to as a compound). A known imidazopyridine derivative is tentatively reported) (JP-A-61-145182).
発明が解決しようとする問題点 本発明者らは、オメプラゾール及び前記の公知イミダ
ゾピリジン誘導体よりも貯蔵時安定性、インビトロ(in
vitro)での(H++K+)ATPアーゼ阻害作用、インビボ
(in vivo)での胃酸分泌抑制作用及び各種実験潰瘍に
対する抑制作用において優れた効果を示す前記式[II]
の化合物を見出し、先に特許出願を行った(特開昭62−
133534号)。SUMMARY OF THE INVENTION The present inventors have found that storage stability, in vitro (in vitro) compared to omeprazole and the above-mentioned known imidazopyridine derivatives.
The above-mentioned formula [II] showing excellent effects in (H + + K + ) ATPase inhibitory effect in vitro, gastric acid secretion inhibitory effect in vivo and inhibitory effect on various experimental ulcers.
Was found, and a patent application was filed earlier (Japanese Patent Application Laid-Open No. Sho 62-62).
133534).
問題点を解決するための手段 本発明は前記式[II]で示されるイミダゾ[4,5−
b]ピリジン誘導体のうち、R1O−(R1は前記と同意義
である。)がイミダゾ[4,5−b]ピリジン環の5位に
置換した化合物の製造中間体として有用である式[I]
で示される5−アルコキシ−2−メルカプトイミダゾ
[4,5−b]ピリジン化合物及びその製造法を提供する
ものである。Means for Solving the Problems The present invention provides an imidazo [4,5-
b] a pyridine derivative which is useful as an intermediate for producing a compound in which R 1 O- (R 1 has the same meaning as described above) is substituted at the 5-position of the imidazo [4,5-b] pyridine ring; [I]
A 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula: and a method for producing the same.
式[I]で示される5−アルコキシ−2−メルカプト
イミダゾ[4,5−b]ピリジン化合物には下記式
[I′]、[I″]及び[I]で示される互変異性体
も包含される。The 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula [I] also includes tautomers represented by the following formulas [I '], [I "] and [I]. Is done.
(各式中、R1は前記と同意義である。) 本発明化合物[I]は次の反応式に従って製造でき
る。 (In each formula, R 1 has the same meaning as described above.) The compound [I] of the present invention can be produced according to the following reaction formula.
(式中、R1は前記と同意義である。) 2−アミノ−6−クロロ−3−ニトロピリジン[II
I]とR1OH(式中、R1は前記と同意義である。)で示さ
れるアルコール類とを塩基の存在下反応させることによ
り6−アルコキシイ−2−アミノ−3−ニトロピリジン
化合物[IV]を得る。塩基としてはt−ブトキシカリウ
ム、ナトリウム、水素化ナトリウム、水酸化カリウム、
炭酸カリウムなどが用いられ、反応溶媒としてはR1OHで
示されるアルコール類のほか、ジオキサン、アセトン、
ジメチルホルムアミド、ヘキサメチルリン酸トリアミド
又はこれらと水との混合溶媒等が用いられる。反応温度
は−10〜120℃、反応時間は1分〜10時間で行なう。次
いで、化合物[IV]をラネーニッケル、パラジウム等の
触媒の存在下で接触還元するか、または、アルカリ存在
下、ハイドロサルファイトナトリウムを用いて還元を行
うことにより6−アルコキシ2,3−ジアミノピリジン化
合物[V]を得る。次いで、この化合物[V]とエチル
キサントゲン酸カリウム又は二硫化炭素とを反応させて
本発明化合物[I]を得る。反応溶媒としてはメタノー
ル、エタノール、イソプロパノール等のアルコール類又
は含水アルコール類が好ましく、加熱還流下、2〜8時
間反応を行う。二硫化炭素を使用する場合は、水酸化ナ
トリウム、水酸化カリウム等のアルカリ存在下が好まし
い。 (Wherein, R 1 has the same meaning as described above.) 2-amino-6-chloro-3-nitropyridine [II
I] and an alcohol represented by R 1 OH (where R 1 is as defined above) in the presence of a base to give a 6-alkoxyi-2-amino-3-nitropyridine compound [IV] is obtained. As the base, potassium t-butoxide, sodium, sodium hydride, potassium hydroxide,
Potassium carbonate and the like are used, and as a reaction solvent, in addition to alcohols represented by R 1 OH, dioxane, acetone,
Dimethylformamide, hexamethylphosphoric triamide or a mixed solvent thereof with water is used. The reaction is carried out at a temperature of -10 to 120 ° C and a reaction time of 1 minute to 10 hours. Then, the compound [IV] is catalytically reduced in the presence of a catalyst such as Raney nickel, palladium or the like, or is reduced with sodium hydrosulfite in the presence of an alkali to give a 6-alkoxy 2,3-diaminopyridine compound [V] is obtained. Next, the compound [V] is reacted with potassium ethyl xanthate or carbon disulfide to obtain the compound [I] of the present invention. As the reaction solvent, alcohols such as methanol, ethanol and isopropanol or hydrous alcohols are preferable, and the reaction is carried out under heating and refluxing for 2 to 8 hours. When carbon disulfide is used, it is preferably in the presence of an alkali such as sodium hydroxide or potassium hydroxide.
本発明化合物[I]を式 (式中、R2、R3及びR4は前記と同意義である。)で示さ
れるピリジン化合物と縮合させて、式 (式中、R1、R2、R3及びR4は前記と同意義である。)で
示されるスルフィド化合物とし、次いで、この化合物を
m−クロロ過安息香酸、過安息香酸、過酢酸などで酸化
することにより、前記式[II]のイミダゾ[4,5−b]
ピリジン誘導体へ導くことができる。これらの誘導体は
貯蔵時安定性に優れているとともに、優れた抗潰瘍活性
を有する。The compound of the present invention [I] is represented by the formula (Wherein R 2 , R 3 and R 4 have the same meanings as described above). (Wherein R 1 , R 2 , R 3 and R 4 are as defined above), and then this compound is treated with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, etc. By oxidizing with the above, the imidazo [4,5-b] of the formula [II]
It can lead to pyridine derivatives. These derivatives have excellent storage stability and excellent anti-ulcer activity.
次に、本発明化合物[I]の製造例を実施例をもって
説明する。Next, Production Examples of the compound [I] of the present invention will be described with reference to Examples.
実施例1 (a)2−アミノ−6−クロロ−3−ニトロピリジン3
0.0g(0.173モル)、シクロプロピルカルビノール18.7g
(0.259モル)及びt−ブトキシカリウム(純度90%)2
3.7g(0.190モル)をジオキサン50mlへ加え、50℃で8
時間撹拌した。放冷後、ジオキサン100mlを加え、この
混合液を5℃の水1.5中へ撹拌しながら加えたところ
結晶が析出した。この析出結晶を取し、水洗し、乾燥
して2−アミノ−6−シクロプロピルメチルオキシ−3
−ニトロピリジン33.4g(92.5%)を得た。Example 1 (a) 2-amino-6-chloro-3-nitropyridine3
0.0 g (0.173 mol), 18.7 g of cyclopropyl carbinol
(0.259 mol) and potassium t-butoxide (purity 90%) 2
3.7 g (0.190 mol) is added to 50 ml of dioxane,
Stirred for hours. After allowing to cool, 100 ml of dioxane was added, and the mixture was added into 1.5 of water at 5 ° C. with stirring to precipitate crystals. The precipitated crystals are collected, washed with water and dried to give 2-amino-6-cyclopropylmethyloxy-3.
-33.4 g (92.5%) of nitropyridine were obtained.
(b)上記で得た2−アミノ−6−シクロプロピルメチ
ルオキシ−3−ニトロピリジン33.0g(0.158モル)をエ
タノール500mlに懸濁し、ラネーニッケルを加え、常温
常圧下で接触還元を行った。反応終了後、ラネーニッケ
ルを別し、液にエチルキサントゲン酸カリウム50.6
g(0.316モル)及び水100mlを加え、3時間加熱還流し
た。反応液に活性炭3.0gを加え、熱時過し、液に水
500mlを加え、60〜70℃に加熱した。この溶液中に、撹
拌しながら酢酸を加えてpH3〜4としたのち、氷冷下で
撹拌した。析出した結晶を取し、水洗し、乾燥し、次
いで50%含水メタノールから再結晶して5−シクロプロ
ピルメチルオキシ−2−メルカプトイミダゾ[4,5−
b]ピリジンの無色結晶を29.5g(84.5%)得た。(B) 33.0 g (0.158 mol) of 2-amino-6-cyclopropylmethyloxy-3-nitropyridine obtained above was suspended in 500 ml of ethanol, Raney nickel was added, and catalytic reduction was performed at room temperature and normal pressure. After completion of the reaction, Raney nickel was separated and the solution was added with potassium ethyl xanthate (50.6).
g (0.316 mol) and 100 ml of water were added, and the mixture was heated under reflux for 3 hours. Add 3.0 g of activated carbon to the reaction solution, heat, and add water to the solution.
500 ml was added and heated to 60-70 ° C. Acetic acid was added to this solution with stirring to adjust the pH to 3 to 4, and then the mixture was stirred under ice cooling. The precipitated crystals were collected, washed with water, dried and then recrystallized from 50% aqueous methanol to give 5-cyclopropylmethyloxy-2-mercaptoimidazo [4,5-
b] 29.5 g (84.5%) of colorless crystals of pyridine were obtained.
融点 247〜248℃ 元素分析値(C10H11N3OSとして): 理論値(%);C,54.28H,5.01N,18.99 実測値(%);C,54.14H,5.16N,18.78 実施例2〜17 実施例1の(a)のシクロプロピルカルビノールを対
応するアルコール類に、t−ブトキシカリウムをナトリ
ウム、水素化ナトリウム、水酸化カリウム等から適宜選
択した塩基に、ジオキサンをアルコール類、ジメチルホ
ルムアミド、ヘキサメチルリン酸トリアミド等から適宜
選択した溶媒にそれぞれ変更し、反応温度、反応時間等
を若干変更した以外は実施例1の(a)とほぼ同様に処
理して6−アルコキシ−2−アミノ−3−ニトロピリジ
ン化合物[IV]を得た。次いで、この化合物[IV]を実
施例1の(b)とほぼ同様の方法で処理することによ
り、第1表に示す化合物を得た。Mp two hundred forty-seven to two hundred forty-eight ° C. Elemental analysis (as C 10 H 11 N 3 OS) : theory (%); C, 54.28H, 5.01N, 18.99 Found (%); C, 54.14H, 5.16N, 18.78 performed Examples 2 to 17 The cyclopropylcarbinol of Example 1 (a) was used as a corresponding alcohol, t-butoxy potassium was used as a base appropriately selected from sodium, sodium hydride, potassium hydroxide, and the like, and dioxane was used as an alcohol. 6-Alkoxy-2 was treated in substantially the same manner as in Example 1 (a) except that the solvent was appropriately selected from dimethylformamide, hexamethylphosphoric triamide, etc., and the reaction temperature, reaction time, etc. were slightly changed. -Amino-3-nitropyridine compound [IV] was obtained. Next, the compound [IV] was treated in substantially the same manner as in Example 1 (b) to give the compounds shown in Table 1.
Claims (2)
素数1〜8個の直鎖状もしくは分岐状のアルキル基又は
炭素数2〜4個のフルオロアルキル基を表わす。)で示
される5−アルコキシ−2−メルカプトイミダゾ[4,5
−b]ピリジン化合物。(1) Expression (In the formula, R 1 represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a cyclic alkyl group or a fluoroalkyl group having 2 to 4 carbon atoms.) 5-alkoxy-2-mercaptoimidazo [4,5
-B] pyridine compounds.
ンと式 R1OH (式中、R1は前記と同意義である。)で示されるアルコ
ール類を塩基の存在下で反応させることにより式 (式中、Rは前記と同意義である。)で示される6−ア
ルコキシ−2−アミノ−3−ニトロピリジン化合物を
得、次いで還元し、得られた6−アルコキシ−2,3−ジ
アミノピリジン化合物とエチルキサントゲン酸カリウム
又は二硫化炭素とを反応させることを特徴とする式 (式中、R1は前記と同意義である。)で示される5−ア
ルコキシ−2−メルカプトイミダゾ[4,5−b]ピリジ
ン化合物の製造法。(2) By reacting 2-amino-6-chloro-3-nitropyridine represented by the formula with an alcohol represented by the formula R 1 OH (wherein R 1 is as defined above) in the presence of a base. formula (Wherein R is as defined above), and then reduced to give the obtained 6-alkoxy-2,3-diaminopyridine. A compound characterized by reacting a compound with potassium ethyl xanthate or carbon disulfide (Wherein, R 1 has the same meaning as described above.) A method for producing a 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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JP1078988A JP2574357B2 (en) | 1988-01-22 | 1988-01-22 | 5-Alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound and method for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1078988A JP2574357B2 (en) | 1988-01-22 | 1988-01-22 | 5-Alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound and method for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH01190683A JPH01190683A (en) | 1989-07-31 |
JP2574357B2 true JP2574357B2 (en) | 1997-01-22 |
Family
ID=11760108
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JP1078988A Expired - Fee Related JP2574357B2 (en) | 1988-01-22 | 1988-01-22 | 5-Alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound and method for producing the same |
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JP (1) | JP2574357B2 (en) |
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JP4738763B2 (en) * | 2004-06-18 | 2011-08-03 | 日本曹達株式会社 | Method for producing 3,7 (9) -dihydro-1H-purine-2,6-dithione compound |
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