JPH10231297A - New adenine-1-noxide derivative, and use of the same as medicine - Google Patents
New adenine-1-noxide derivative, and use of the same as medicineInfo
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- JPH10231297A JPH10231297A JP5112497A JP5112497A JPH10231297A JP H10231297 A JPH10231297 A JP H10231297A JP 5112497 A JP5112497 A JP 5112497A JP 5112497 A JP5112497 A JP 5112497A JP H10231297 A JPH10231297 A JP H10231297A
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- adenine
- group
- oxide
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Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、新規なアデニン−
1−N−オキシド誘導体又はその薬理的に許容される塩、
並びにそれを有効成分とする免疫性疾患治療薬に関す
る。特に、本発明の免疫性疾患治療薬は、白血球などの
炎症性細胞が患部組織細胞上に接着する免疫性疾患の進
行に不可欠な過程に関与する各種の接着分子或いはその
リガンド分子の細胞表面への発現に対し阻害・抑制作用
を有するものであり、各種の自己免疫疾患、アレルギー
性疾患、その他炎症性細胞が関与する免疫性疾患の治療
薬として利用できるものである。TECHNICAL FIELD The present invention relates to a novel adenine compound.
A 1-N-oxide derivative or a pharmaceutically acceptable salt thereof,
In addition, the present invention relates to a therapeutic drug for immunological diseases containing the same as an active ingredient. In particular, the therapeutic drug for an immune disease of the present invention is useful for the treatment of various adhesion molecules or ligand molecules involved in a process essential for the progression of an immune disease in which inflammatory cells such as leukocytes adhere to diseased tissue cells. It has an inhibitory / suppressive effect on the expression of, and can be used as a therapeutic drug for various autoimmune diseases, allergic diseases, and other immune diseases involving inflammatory cells.
【0002】[0002]
【従来の技術】リウマチ、腎炎、全身性エリテマトーデ
ス(SLE:Systemic lupus erythematosus)、多発性硬
化症、潰瘍性大腸炎などの自己免疫疾患に対する薬物治
療には、シクロオキシゲナーゼ阻害剤、ステロイド、ア
ザチオプリンなどの免疫抑制剤などが従来用いられてい
る。これらの免疫抑制剤では、対処療法的な効果しかえ
られておらず、また、例えば、インドメタシンなどのシ
クロオキシゲナーゼ阻害剤では、炎症患部のみならず消
化管のシクロオキシゲナーゼをも阻害し、高い頻度で消
化管の潰瘍を引き起こし、さらにはステロイド療法等の
如く重篤な副作用を示すものなど、治療効果と副作用の
分離が不十分であるものが大半である。2. Description of the Related Art Pharmaceutical treatments for autoimmune diseases such as rheumatism, nephritis, systemic lupus erythematosus (SLE), multiple sclerosis, ulcerative colitis and the like include immunization with cyclooxygenase inhibitors, steroids, azathioprine and the like. Inhibitors and the like are conventionally used. These immunosuppressive agents only have a cognitive effect, and, for example, cyclooxygenase inhibitors such as indomethacin inhibit not only the affected area of inflammation but also the cyclooxygenase of the gastrointestinal tract. In most cases, the therapeutic effect is not sufficiently separated from the side effects, such as those causing severe ulcers and further exhibiting serious side effects such as steroid therapy.
【0003】これらの自己免疫疾患は、その他の免疫性
疾患と同様に白血球、特には好中球、マクロファージを
初めとする炎症性細胞により引き起こされる炎症性疾患
である。即ち、これらの炎症性細胞が、ICAM−1、セレ
クチン(selectin)などの種々の接着分子を介して標的
臓器細胞へ接着した後、活性酸素やプロテアーゼなどの
起炎物質を放出して炎症を惹起・増幅する。この接着過
程を阻害・抑制すると、炎症の進行を抑えることがで
き、実際に、いくつかの接着分子に対する抗体の投与は
動物の炎症モデルにおいて有効性を示すことが報告され
ている(J. Immunology, 147, 4167−4171 (1991) など
を参照)。しかしながら、抗体は消化管吸収がほとんど
期待できないため、医薬品としては、血管内投与、例え
ば注射剤にならざるをえず、治療剤の長期かつ継続的な
投与が必要となる、自己免疫疾患のような慢性疾患の治
療薬には適さないものである。[0003] These autoimmune diseases, like other immune diseases, are inflammatory diseases caused by inflammatory cells such as leukocytes, particularly neutrophils and macrophages. That is, after these inflammatory cells adhere to target organ cells via various adhesion molecules such as ICAM-1 and selectin, they release inflammatory substances such as active oxygen and protease to induce inflammation.・ Amplify. It has been reported that inhibition and suppression of this adhesion process can suppress the progression of inflammation, and indeed, administration of antibodies to several adhesion molecules is effective in animal inflammation models (J. Immunology). , 147 , 4167-4171 (1991), etc.). However, since antibodies can hardly be expected to absorb gastrointestinal tract, as a pharmaceutical, intravenous administration, for example, inevitable injection, requires long-term and continuous administration of therapeutic agents, such as autoimmune diseases It is not suitable for the treatment of various chronic diseases.
【0004】従って、経口投与に適する消化管吸収が可
能な低分子物質で、接着分子の働きに対して阻害作用を
有する薬物の開発が待たれている。特に、患部標的細胞
の表面上の各種接着分子の発現を阻害・抑制する薬物
は、免疫系には悪影響を及ぼさず、目的とする患部での
炎症を抑制でき、特に期待されるものである。また、炎
症性細胞の標的臓器への接着を阻害する薬物は、自己免
疫疾患以外にも、喘息などのアレルギー性疾患、肝炎、
インスリン依存型糖尿病、成人呼吸切迫症、敗血症、シ
ョック、心筋梗塞後の再還流障害などの免疫性疾患、こ
れら慢性的な要因・性格を持つ免疫性疾患の治療にも効
果が期待できる。Therefore, development of a low-molecular substance suitable for oral administration and capable of absorbing gastrointestinal tract and having an inhibitory effect on the function of adhesion molecules has been desired. In particular, a drug that inhibits or suppresses the expression of various adhesion molecules on the surface of a target cell of an affected area has no adverse effect on the immune system and can suppress inflammation at a target affected area, and is particularly expected. In addition, drugs that inhibit the adhesion of inflammatory cells to target organs, besides autoimmune diseases, allergic diseases such as asthma, hepatitis,
It is also expected to be effective in the treatment of immune diseases such as insulin-dependent diabetes mellitus, adult respiratory distress, sepsis, shock, reperfusion injury after myocardial infarction, and immune diseases having these chronic factors and characteristics.
【0005】なお、これまでに、細胞接着抑制効果を有
する薬剤として、例えば、4−ヒドロキシ−N−(2−ヒ
ドロキシフェニル)安息香酸アミドに代表される置換安
息香酸アニリド類(特開平7−330595号公報を参
照)、2−クロロ−3−〔4−(1−ピロリジニル)ピペリ
ジノ〕−1,4−ナフトキノンに代表される2−アミノ−3
−ハロゲノ−1,4−ナフトキノン誘導体(特開平8−1
13555号公報を参照)等の提案があり、本発明者ら
も、6−アミノ−9−ベンジル−8−ブロモプリン(9−ベ
ンジル−8−ブロモアデニン)に代表されるプリン誘導
体を提案している(特開平7−330770号公報を参
照)が、さらなる接着阻害作用に優れた新たな化合物の
提案が要望されている。[0005] Heretofore, as agents having a cell adhesion inhibitory effect, for example, substituted benzoic anilides represented by 4-hydroxy-N- (2-hydroxyphenyl) benzoic amide (JP-A-7-330595) ), 2-amino-3- represented by 2-chloro-3- [4- (1-pyrrolidinyl) piperidino] -1,4-naphthoquinone
-Halogeno-1,4-naphthoquinone derivatives (JP-A-8-1
The present inventors have also proposed purine derivatives represented by 6-amino-9-benzyl-8-bromopurine (9-benzyl-8-bromoadenine). (See Japanese Patent Application Laid-Open No. 7-330770), however, there is a demand for a proposal of a new compound having a further excellent adhesion inhibiting action.
【0006】[0006]
【発明が解決しようとする課題】本発明は上記の課題を
解決するもので、本発明の目的は、継続的又は長期にわ
たる経口投与に適し、且つ主な薬理効果として炎症性細
胞の標的臓器細胞への接着を阻害・抑制する新規な化合
物、及びこの化合物を有効成分とする免疫性疾患治療薬
を提供することにある。DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems, and an object of the present invention is to provide continuous or long-term oral administration, and to provide a main pharmacological effect of target organ cells of inflammatory cells. It is an object of the present invention to provide a novel compound that inhibits / suppresses adhesion to a drug, and a therapeutic drug for an immune disease containing the compound as an active ingredient.
【0007】[0007]
【課題を解決するための手段】かかる背景のもと、本発
明者らは、主な薬理効果として炎症性細胞の標的臓器細
胞への接着に対して阻害・抑制作用を有する新規な化合
物を創製するべく鋭意研究を継続した結果、新規なアデ
ニン−1−N−オキシド誘導体を創製し、それらが優れた
接着阻害作用を示すこと見出し、本発明を完成するに到
った。Under these circumstances, the present inventors have created a novel compound having a main pharmacological effect of inhibiting or suppressing the adhesion of inflammatory cells to target organ cells. As a result of continued intensive studies, new adenine-1-N-oxide derivatives were created, and they were found to exhibit excellent adhesion-inhibiting effects, and the present invention was completed.
【0008】本発明の化合物は、下記一般式(I):The compound of the present invention has the following general formula (I):
【化2】 (式中、R1は、水素原子または炭素数1〜4の直鎖あるい
は分枝状のアルキル基を表わし、R2は、水素原子、炭素
数1〜4の直鎖あるいは分枝状のアルキル基又は炭素数1
〜4の直鎖あるいは分枝状のアルコキシ基を表わし、R3
は、無置換、あるいは、炭素数1〜4の直鎖あるいは分枝
状のアルキル基、炭素数1〜4の直鎖あるいは分枝状のア
ルコキシ基、アルコキシカルボニル基、トリフルオロメ
チル基、ニトロ基、フェニル基、ハロゲノ基からなる群
より選択される1以上3以下の置換基を有する置換フェ
ニル基、またはナフチル基を表わす。)で示される新規
なアデニン−1−N−オキシド誘導体又はその薬理的に許
容される塩である。また、本発明の免疫性疾患治療薬
は、この新規なアデニン−1−N−オキシド誘導体又はそ
の薬理的に許容される塩を有効成分とする医薬組成物で
ある。Embedded image (Wherein, R 1 represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and R 2 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Group or carbon number 1
It represents to 4 straight-chain or branched alkoxy group, R 3
Is an unsubstituted or straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group, a trifluoromethyl group, and a nitro group. Phenyl group, a substituted phenyl group having 1 to 3 substituents selected from the group consisting of a halogeno group, and a naphthyl group. Adenine-1-N-oxide derivative or a pharmaceutically acceptable salt thereof. The therapeutic drug for immunological diseases of the present invention is a pharmaceutical composition containing the novel adenine-1-N-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【0009】[0009]
【発明の実施の形態】先ず、本発明の新規化合物、アデ
ニン−1−N−オキシド誘導体に関して説明する。上記一
般式(I)中、炭素数1〜4の直鎖あるいは分枝状のアル
キル基は、直鎖のメチル基、エチル基、プロピル基、ブ
チル基、並びに、分枝鎖を有している、イソプロピル
基、sec−ブチル基、tert−ブチル基を意味し、炭素数1
〜4の直鎖あるいは分枝状のアルコキシ基は、前記のア
ルキル基からなるアルキルオキシ基を意味する。また、
アルコキシカルボニル基も、このアルキル基からなるア
ルキルオキシカルボニル基を意味する。ハロゲノ基と
は、フルオロ基、クロロ基、ブロモ基、ヨード基をいう
が、R3の置換フェニル基においてハロゲノ基を置換基と
して選択する際には、フルオロ基、クロロ基、ブロモ基
が好ましい。DETAILED DESCRIPTION OF THE INVENTION First, the novel compound of the present invention, an adenine-1-N-oxide derivative, will be described. In the general formula (I), the linear or branched alkyl group having 1 to 4 carbon atoms has a linear methyl group, an ethyl group, a propyl group, a butyl group, and a branched chain. , Isopropyl group, sec-butyl group, tert-butyl group, having 1 carbon atom
The straight-chain or branched alkoxy group of ~ 4 means an alkyloxy group comprising the above-mentioned alkyl group. Also,
An alkoxycarbonyl group also means an alkyloxycarbonyl group consisting of this alkyl group. The halogeno group refers to a fluoro group, a chloro group, a bromo group, and an iodo group. When a halogeno group is selected as a substituent in the substituted phenyl group of R 3 , a fluoro group, a chloro group, and a bromo group are preferable.
【0010】上記一般式(I)で示されるアデニン−1
−N−オキシド誘導体において、アデニン骨格2位の
R1、または、8位のR2の何れかに水素原子を選択すると
好ましい。更に、R1、R2を共に水素原子とするとより好
ましい。他方、R3において、置換フェニル基を選択する
際には、ハロゲノ基あるいはトリフルオロメチル基を置
換基に含むものが好ましい。更に、ハロゲノ基のうちで
は、ブロモ基がより好ましい。即ち、ブロモ基またはト
リフルオロメチル基を置換基に含む置換フェニル基がよ
り好ましい。また、置換フェニル基上の置換位置は、モ
ノ置換の場合、メタ位に置換基が存在するとより好まし
い。2以上の置換基が存在する場合、置換基数が3のも
のより、置換基数が2のものが一般に好ましい。置換基
数が2の場合、置換位置は、メタ位とオルト位の両方に
存在するものがより好ましい。Adenine-1 represented by the above general formula (I)
-N-oxide derivative, adenine skeleton at position 2
It is preferable to select a hydrogen atom for either R 1 or R 2 at the 8-position. More preferably, both R 1 and R 2 are hydrogen atoms. On the other hand, when selecting a substituted phenyl group for R 3 , a substituent containing a halogeno group or a trifluoromethyl group is preferable. Further, among the halogeno groups, a bromo group is more preferable. That is, a substituted phenyl group containing a bromo group or a trifluoromethyl group as a substituent is more preferred. In the case of mono-substitution, the substitution position on the substituted phenyl group more preferably has a substituent at the meta position. When two or more substituents are present, those having two substituents are generally preferred over those having three substituents. When the number of substituents is 2, the substitution position is more preferably present at both the meta position and the ortho position.
【0011】なお、本発明のアデニン−1−N−オキシド
誘導体において、その薬理的に許容される塩の例として
は、薬理的に許容される酸との塩である、塩酸塩、臭化
水素酸塩などの無機酸との塩、酢酸塩などのカルボン酸
との塩、メタンスルホン酸塩、p−トルエンスルホン酸
塩など有機スルホン酸との塩等を挙げることができる。In the adenine-1-N-oxide derivative of the present invention, examples of the pharmacologically acceptable salt include a salt with a pharmacologically acceptable acid such as hydrochloride and hydrogen bromide. Examples thereof include salts with inorganic acids such as acid salts, salts with carboxylic acids such as acetates, salts with organic sulfonic acids such as methanesulfonate and p-toluenesulfonate.
【0012】本発明のアデニン−1−N−オキシド誘導体
の製造法を以下に概説する。 工程1:中間原料;9−置換アデニン誘導体の調製 出発原料として、下記一般式(II):The process for producing the adenine-1-N-oxide derivative of the present invention will be outlined below. Step 1: Preparation of intermediate material; 9-substituted adenine derivative As a starting material, the following general formula (II):
【化3】 (式中、R1、R2は、それぞれ一般式(I)のR1、R2と同
義の基を表わす。)で示される、無置換あるいは2、8位
に置換基を有するアデニン誘導体を用い、塩基存在下
に、下記一般式(III):Embedded image (Wherein, R 1, R 2 are each the general formula (. Representing the R 1, R 2 group having the same meaning as in I)) represented by the adenine derivatives having substituents unsubstituted or position 2,8 In the presence of a base, the following general formula (III):
【化4】 (式中、R3は、一般式(I)のR3と同義の基を表わし、
Xは、クロロ基、ブロモ基またはヨード基を表わす。)
で示されるハロゲン化アリールメチルを反応させること
により、下記一般式(IV):Embedded image (Wherein, R 3 represents a group having the same meaning as R 3 in formula (I);
X represents a chloro, bromo or iodo group. )
By reacting an arylmethyl halide represented by the following formula (IV):
【化5】 (式中、R1、R2、R3は、それぞれ一般式(I)のR1、
R2、R3と同義の基を表わす。)で示される、9−置換ア
デニン誘導体を中間原料として合成する。用いる塩基と
しては、炭酸カリウム、水素化ナトリウム、ナトリウム
メトキシド、ナトリウムエトキシドなどのアルコキシド
などが挙げられる。反応溶媒には、ジメチルホルムアミ
ド(DMF)、テトラハイドロフラン(THF)、1,4-ジオキ
サンなどが好ましい。反応温度は、室温から溶媒が還流
する温度までの範囲から選択することができるが、特に
は、60〜80℃の範囲が好ましい。なお、この9位の窒素
原子上に置換基を導入する工程では、不純物として、7
位あるいは3位の窒素原子上に置換基が導入された7−
置換体、3−置換体も微量生成するが、次の工程後の精
製により除去されるため、この段階では特に精製する必
要はない。Embedded image (Wherein, R 1, R 2, R 3 is, R 1 in each formula (I),
Represents a group having the same meaning as R 2 and R 3 . ) Is synthesized as an intermediate material. Examples of the base used include alkoxides such as potassium carbonate, sodium hydride, sodium methoxide, and sodium ethoxide. As the reaction solvent, dimethylformamide (DMF), tetrahydrofuran (THF), 1,4-dioxane and the like are preferable. The reaction temperature can be selected from the range from room temperature to the temperature at which the solvent is refluxed, and particularly preferably in the range of 60 to 80 ° C. In the step of introducing a substituent on the nitrogen atom at the ninth position, 7
7- in which a substituent is introduced on the nitrogen atom at the 3- or 3-position
Substitutes and 3-substitutes are also produced in trace amounts, but are removed by purification after the next step, so there is no need to purify at this stage.
【0013】なお、下記一般式(V):The following general formula (V):
【化6】 (式中、R1、R3は、それぞれ一般式(I)のR1、R3と同
義の基を表わす。)で示される中間原料は、以下の方法
で製造することもできる。下記式(VI):Embedded image (Wherein, R 1, R 3 each represents a R 1, R 3 group having the same meaning as in formula (I).) An intermediate material represented by can also be prepared by the following method. The following formula (VI):
【化7】 で示される5−アミノ−4−シアノイミダゾールと下記一
般式(VII):Embedded image 5-amino-4-cyanoimidazole represented by the following general formula (VII):
【化8】 (式中、R1は、一般式(I)のR1と同義の基を表わ
す。)で示されるアミド化合物とを閉環させ、下記一般
式(VIII):Embedded image (. In the formula, R 1, representing the R 1 group having the same meaning as in general formula (I)) in to ring closure and the amide compound represented by the following general formula (VIII):
【化9】 (式中、R1は、一般式(I)のR1と同義の基を表わ
す。)で示される2−置換アデニンを調製し、これを出
発原料として製造することができる。Embedded image (Wherein, R 1 represents a group having the same meaning as R 1 in formula (I)). The 2-substituted adenine represented by formula (I) can be prepared and used as a starting material.
【0014】或いは、下記一般式(IX):Alternatively, the following general formula (IX):
【化10】 (式中、R3は、一般式(I)のR3と同義の基を表わし、
R2は、炭素数1〜4の直鎖あるいは分枝状のアルコキシ基
を表わす。)で示される中間原料は、次の方法で製造す
ることもできる。先ず、アデニンと上述の一般式(II
I)で示されるハロゲン化アリールメチルを反応させる
ことにより、下記一般式(X):Embedded image (Wherein, R 3 represents a group having the same meaning as R 3 in formula (I);
R 2 represents a linear or branched alkoxy group having 1 to 4 carbon atoms. The intermediate raw material represented by ()) can also be produced by the following method. First, adenine and the above-mentioned general formula (II
By reacting the arylmethyl halide represented by I), the following general formula (X):
【化11】 (式中、R3は、一般式(I)のR3と同義の基を表わ
す。)で示される9−置換アデニンを調製する。次い
で、この9−置換アデニンに臭素を反応させ、8−ブロ
モ−9−置換アデニンに導き、R2のアルコキシ基に対応
しているアルコールとナトリウムを反応させ、上記一般
式(IX)で示される目的の中間原料、8−アルコキシ−9
−置換アデニン誘導体を調製することができる。Embedded image (Wherein R 3 represents a group having the same meaning as R 3 in formula (I)). Then, the 9-substituted adenine is reacted with bromine to lead to an 8-bromo-9-substituted adenine, and the alcohol corresponding to the alkoxy group of R 2 is reacted with sodium, and represented by the general formula (IX). The desired intermediate material, 8-alkoxy-9
-Substituted adenine derivatives can be prepared.
【0015】更には、下記一般式(XI):Further, the following general formula (XI):
【化12】 (式中、R3は、一般式(I)のR3と同義の基を表わし、
R2は、炭素数1〜4の直鎖あるいは分枝状のアルキル基を
表わす。)で示される中間原料は、例えば、特開平7−
330770号公報に記載の6−アミノ−9−ベンジル−
8−ブロモプリン(9−ベンジル−8−ブロモアデニン)
に代表されるプリン誘導体を製造する方法に準じて製造
することができる。先ず、式(XII):Embedded image (Wherein, R 3 represents a group having the same meaning as R 3 in formula (I);
R2 represents a linear or branched alkyl group having 1 to 4 carbon atoms. The intermediate material represented by ()) is described in, for example,
6-amino-9-benzyl- described in JP-A-330770
8-bromopurine (9-benzyl-8-bromoadenine)
Can be produced according to a method for producing a purine derivative represented by First, formula (XII):
【化13】 で示される5−アミノ−4,6−ジクロロピリミジンと下記
一般式(XIII):Embedded image 5-amino-4,6-dichloropyrimidine represented by the following general formula (XIII):
【化14】 (式中、R3は、一般式(I)のR3と同義の基を表わ
す。)で示されるアリールメチルアミン化合物を反応さ
せ、下記一般式(XIV):Embedded image (Wherein, R 3 represents a group having the same meaning as R 3 in formula (I)), and reacted with an arylmethylamine compound represented by the following formula (XIV):
【化15】 (式中、R3は、一般式(I)のR3と同義の基を表わ
す。)で示される5−アミノ−6−(アリールメチル)アミ
ノ−4−クロロピリミジン誘導体に導く。次いで、下記
一般式(XV):Embedded image (Wherein, R 3 is. Representing the R 3 group having the same meaning as in general formula (I)) lead to 5-amino-6- (aryl-methyl) amino-4-chloropyrimidine derivative represented by the. Then, the following general formula (XV):
【化16】 (式中、R2は、炭素数1〜4の直鎖あるいは分枝状のアル
キル基を表わす。)等で示されるオルトエステルを触媒
量のエタンスルホン酸の存在下で反応させ、下記一般式
(XVI):Embedded image (Wherein R 2 represents a linear or branched alkyl group having 1 to 4 carbon atoms), and an orthoester represented by the following general formula: (XVI):
【化17】 (式中、R3は、一般式(I)のR3と同義の基を表わし、
炭素数1〜4の直鎖あるいは分枝状のアルキル基を表わ
す。)で示される8−アルキル−9−アリールメチル―6
−クロロプリン誘導体とし、6位のクロロ基をアンモニ
アで置き換え、上記一般式(XI)で示される8−アルキ
ル−9−置換アデニン誘導体を調製することができる。Embedded image (Wherein, R 3 represents a group having the same meaning as R 3 in formula (I);
Represents a linear or branched alkyl group having 1 to 4 carbon atoms. 8-alkyl-9-arylmethyl-6 represented by the formula:
The 8-chloro-9-substituted adenine derivative represented by the general formula (XI) can be prepared by replacing the chloro group at the 6-position with ammonia as a -chloropurine derivative.
【0016】工程2:アデニン−1−N−オキシド誘導体
への誘導 次いで、一般式(IV)で示される中間原料の9-置換アデ
ニン誘導体に、メタクロロ過安息香酸(m−CPBA)など
の酸化剤を反応させることにより、目的とする一般式
(I)のアデニン−1−N−オキシド誘導体へ導くことが
できる。反応溶媒には、メタノール、エタノールなどの
低級アルコールの他、クロロホルム、ジクロロメタンな
どを用いることもできる。その後、必要に応じて、再結
晶等の慣用手段により精製を行うとよい。Step 2: Derivation to an Adenine-1-N-oxide Derivative Next, an oxidizing agent such as meta-chloroperbenzoic acid (m-CPBA) is added to the 9-substituted adenine derivative of the intermediate material represented by the general formula (IV). To give the desired adenine-1-N-oxide derivative of the general formula (I). As a reaction solvent, lower alcohols such as methanol and ethanol, as well as chloroform, dichloromethane and the like can be used. Thereafter, if necessary, purification may be performed by conventional means such as recrystallization.
【0017】また、本発明の免疫性疾患治療薬は、上記
するアデニン−1−N−オキシド誘導体を有効成分とする
医薬組成物であるが、以下の試験例に示すとおり、その
薬理効果は、炎症性細胞の標的臓器細胞への接着を阻害
・抑制する作用に起因するものであるので、リウマチ、
腎炎、全身性エリテマトーデス(SLE:Systemic lupus
erythematosus)、多発性硬化症、潰瘍性大腸炎などの
自己免疫疾患の治療、加えて、喘息などのアレルギー性
疾患、肝炎、インスリン依存型糖尿病、成人呼吸切迫
症、敗血症、ショック、心筋梗塞後の再還流障害などの
免疫性疾患の治療においても有効なものとなる。なお、
本発明の治療薬は、血管内投与に適する注射薬など非経
口投与剤とすることもできるが、経口投与製剤に調製す
るのが最も合目的的な形態であり、錠剤、カプセル剤、
散剤などの剤形とすることが好ましい。これら経口投与
製剤に汎用される種々の添加剤、ラクトース、グルコー
スなどの賦形剤、ステアリン酸マグネシウム、タルクな
どの滑沢剤などとともに、慣用の手段により製剤とする
ことができる。更には、経口投与に適するその他の形
態、例えば、液剤などとして投与してもよい。また、上
記のアデニン−1−N−オキシド誘導体の有効用量並びに
投与回数は、患者の体重、年齢、性別、症状に応じて、
あるいは、投与目的に応じて、適宜定めるものである
が、通常成人男子1日当たり、0.01〜100mg/kg
を1回〜数回に分けて投与することができる。The therapeutic drug for immunological diseases of the present invention is a pharmaceutical composition containing the above-mentioned adenine-1-N-oxide derivative as an active ingredient. As shown in the following Test Examples, its pharmacological effect is as follows. Because it is caused by the effect of inhibiting and suppressing the adhesion of inflammatory cells to target organ cells, rheumatism,
Nephritis, systemic lupus erythematosus (SLE: Systemic lupus)
erythematosus), treatment of autoimmune diseases such as multiple sclerosis and ulcerative colitis, as well as allergic diseases such as asthma, hepatitis, insulin-dependent diabetes mellitus, adult respiratory distress, sepsis, shock, post-myocardial infarction It is also effective in the treatment of immune diseases such as reperfusion disorder. In addition,
The therapeutic agent of the present invention can be a parenteral administration such as an injection suitable for intravascular administration, but is most suitably prepared into an oral administration preparation, tablets, capsules,
It is preferable to use a dosage form such as a powder. The preparation can be prepared by conventional means together with various additives commonly used in these preparations for oral administration, excipients such as lactose and glucose, and lubricants such as magnesium stearate and talc. Furthermore, it may be administered in another form suitable for oral administration, for example, as a liquid preparation. In addition, the effective dose and the number of administrations of the above-mentioned adenine-1-N-oxide derivative are determined according to the patient's weight, age, sex, and symptoms.
Alternatively, it is appropriately determined according to the purpose of administration, and is usually 0.01 to 100 mg / kg per day for an adult male.
Can be administered once to several times.
【0018】以下に、具体例を挙げて、本発明をより詳
しく説明する。Hereinafter, the present invention will be described in more detail with reference to specific examples.
【0019】[0019]
【実施例1】 9−(4−クロロベンジル)アデニン, 1−N
−オキシド (工程1−1;中間原料9−(4−クロロベンジル)アデニ
ンの調製)アデニン270 mg (2 mmol)、炭酸カリウム280
mg (2 mmol)、4−クロロベンジルクロリド350 mg (2.2
mmol)をDMF 20 ml に加え、80 ℃で16時間加熱撹拌し
た。溶媒を減圧留去した後、水を加えて超音波処理し
た。析出してきた固体9−(4−クロロベンジル)アデニ
ンを濾取し、トルエンで洗浄した(収量 480 mg)。Example 1 9- (4-chlorobenzyl) adenine, 1-N
-Oxide (Step 1-1; Preparation of intermediate material 9- (4-chlorobenzyl) adenine) Adenine 270 mg (2 mmol), potassium carbonate 280
mg (2 mmol), 4-chlorobenzyl chloride 350 mg (2.2
mmol) was added to 20 ml of DMF, and the mixture was heated with stirring at 80 ° C. for 16 hours. After the solvent was distilled off under reduced pressure, water was added and the mixture was subjected to ultrasonic treatment. The precipitated solid 9- (4-chlorobenzyl) adenine was collected by filtration and washed with toluene (yield 480 mg).
【0020】(工程1−2;中間原料9−(4−クロロベン
ジル)アデニンのN−オキシド化)前記工程1−1で得
られた中間原料;9−(4−クロロベンジル)アデニン190
mg(0.7 mmol) をとり、m-CPBA 270 mg (1.4 mmol) と
ともに、メタノール中で3日間撹拌した。析出した固体
を濾取し、10 % 炭酸ナトリウム溶液、次いで水で洗浄
して、標記化合物 110 mgを得た(収率:54%)。1 H-NMR (DMSO-d6) δ ppm:5.40(2H,s), 7.37(4H,dd),
8.42(1H,s), 8.61(1H,s) Mass:276 (M+)(Step 1-2: N-Oxidation of Intermediate Starting Material 9- (4-Chlorobenzyl) adenine) Intermediate Starting Material Obtained in Step 1-1; 9- (4-chlorobenzyl) adenine 190
mg (0.7 mmol) was taken and stirred with 270 mg (1.4 mmol) of m-CPBA in methanol for 3 days. The precipitated solid was collected by filtration and washed with a 10% sodium carbonate solution and then with water to obtain 110 mg of the title compound (yield: 54%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.40 (2H, s), 7.37 (4H, dd),
8.42 (1H, s), 8.61 (1H, s) Mass: 276 (M +)
【0021】[0021]
【実施例2】 9−ベンジル−8−エチルアデニン, 1−N
−オキシド 中間原料の9−ベンジル−8−エチルアデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:87%)。1 H-NMR (DMSO-d6) δ ppm:1.13(3H,m), 2.70(2H,m),
5.31(2H,d), 7.03-7.26(5H,m), 8.53(1H,s) Mass:269 (M+)Example 2 9-benzyl-8-ethyladenine, 1-N
-Oxide The title compound was synthesized in the same manner as in Example 1 using 9-benzyl-8-ethyladenine as an intermediate raw material (yield: 87%). 1 H-NMR (DMSO-d 6 ) δ ppm: 1.13 (3H, m), 2.70 (2H, m),
5.31 (2H, d), 7.03-7.26 (5H, m), 8.53 (1H, s) Mass: 269 (M +)
【0022】[0022]
【実施例3】 9−ベンジル−8−メトキシアデニン, 1
−N−オキシド 中間原料の9−ベンジル−8−メトキシアデニンを用い、
実施例1と同様の操作により標記化合物を合成した(収
率:27%)。1 H-NMR (DMSO-d6) δ ppm:4.13(3H,s), 5.15(2H,s),
7.23-7.36(5H,m), 7.90(2H,brs), 8.53(1H,s) TOF-MS:271 (M+)Example 3 9-benzyl-8-methoxyadenine, 1
-N-oxide Using 9-benzyl-8-methoxyadenine as an intermediate material,
The title compound was synthesized in the same manner as in Example 1 (yield: 27%). 1 H-NMR (DMSO-d 6 ) δ ppm: 4.13 (3H, s), 5.15 (2H, s),
7.23-7.36 (5H, m), 7.90 (2H, brs), 8.53 (1H, s) TOF-MS: 271 (M +)
【0023】[0023]
【実施例4】 9−(4−ブロモベンジル)アデニン, 1−N
−オキシド 中間原料の9−(4−ブロモベンジル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:85%)。1 H-NMR (DMSO-d6) δ ppm:5.38(2H,s), 7.27(2H,d),
7.55(2H,d), 8.42(1H,s), 8.61(1H,s) Mass:319 (M+) 元素分析:C12H10N5OBr・1H2Oとして Calcd. C:H:N=42.62:3.58:20.71 Found C:H:N=42.65:3.57:20.57Example 4 9- (4-bromobenzyl) adenine, 1-N
-Oxide Using 9- (4-bromobenzyl) adenine as an intermediate raw material, the title compound was synthesized in the same manner as in Example 1 (yield: 85%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.38 (2H, s), 7.27 (2H, d),
7.55 (2H, d), 8.42 (1H, s), 8.61 (1H, s) Mass: 319 (M +) Elemental analysis: C 12 H 10 N 5 OBr · 1H 2 O Calcd. C: H: N = 42.62 : 3.58: 20.71 Found C: H: N = 42.65: 3.57: 20.57
【0024】[0024]
【実施例5】 9−(4−メチルベンジル)アデニン, 1−N
−オキシド 中間原料の9−(4−メチルベンジル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:98%)。1 H-NMR (DMSO-d6) δ ppm:2.26(3H,s), 5.34(2H,m),
7.18(4H,dd), 8.40(1H,s), 8.61(1H,s) Mass:255 (M+)Example 5 9- (4-methylbenzyl) adenine, 1-N
-Oxide Using 9- (4-methylbenzyl) adenine as an intermediate material, the title compound was synthesized in the same manner as in Example 1 (yield: 98%). 1 H-NMR (DMSO-d 6 ) δ ppm: 2.26 (3H, s), 5.34 (2H, m),
7.18 (4H, dd), 8.40 (1H, s), 8.61 (1H, s) Mass: 255 (M +)
【0025】[0025]
【実施例6】 9−(4−メトキシベンジル)アデニン, 1
−N−オキシド 中間原料の9−(4−メトキシベンジル)アデニンを用い、
実施例1と同様の操作により標記化合物を合成した(収
率:90%)。1 H-NMR (DMSO-d6) δ ppm : 3.71(3H,s), 5.31(2H,s),
6.90(2H,d), 7.30(2H,d), 8.40(1H,s), 8.62(1H,s) Mass:271 (M+)Example 6 9- (4-methoxybenzyl) adenine, 1
Using -N-oxide intermediate material 9- (4-methoxybenzyl) adenine,
The title compound was synthesized in the same manner as in Example 1 (yield: 90%). 1 H-NMR (DMSO-d 6 ) δ ppm: 3.71 (3H, s), 5.31 (2H, s),
6.90 (2H, d), 7.30 (2H, d), 8.40 (1H, s), 8.62 (1H, s) Mass: 271 (M +)
【0026】[0026]
【実施例7】 9−(2,4−ジクロロベンジル)アデニン,
1−N−オキシド 中間原料の9−(2,4−ジクロロベンジル)アデニンを用
い、実施例1と同様の操作により標記化合物を合成した
(収率:69%)。1 H-NMR (DMSO-d6) δ ppm:5.48(2H,s), 7.10(2H,d),
7.41(2H,d), 8.35(1H,s), 8.60(1H,s) Mass:309 (M+) 元素分析:C12H9N5OCl2として Calcd. C:H:N=46.47:2.92:22.58 Found C:H:N=46.26:2.99:22.31Example 7 9- (2,4-dichlorobenzyl) adenine,
1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (2,4-dichlorobenzyl) adenine as an intermediate raw material (yield: 69%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.48 (2H, s), 7.10 (2H, d),
7.41 (2H, d), 8.35 (1H, s), 8.60 (1H, s) Mass: 309 (M +) Elemental analysis: Calcd as C 12 H 9 N 5 OCl 2 C:. H: N = 46.47: 2.92: 22.58 Found C: H: N = 46.26: 2.99: 22.31
【0027】[0027]
【実施例8】 9−(2,4,6−トリメチルベンジル)アデニ
ン, 1−N−オキシド 中間原料の9−(2,4,6−トリメチルベンジル)アデニンを
用い、実施例1と同様の操作により標記化合物を合成し
た(収率:40%)。1 H-NMR (DMSO-d6) δ ppm:2.23(3H,s), 2.26(6H,s),
5.30(2H,s), 6.92(2H,s), 7.83(1H,s), 8.64(1H,s) Mass:283 (M+)Example 8 9- (2,4,6-trimethylbenzyl) adenine, 1-N-oxide The same operation as in Example 1 using 9- (2,4,6-trimethylbenzyl) adenine as an intermediate material To synthesize the title compound (yield: 40%). 1 H-NMR (DMSO-d 6 ) δ ppm: 2.23 (3H, s), 2.26 (6H, s),
5.30 (2H, s), 6.92 (2H, s), 7.83 (1H, s), 8.64 (1H, s) Mass: 283 (M +)
【0028】[0028]
【実施例9】 9−(4−tert−ブチルベンジル)アデニ
ン, 1−N−オキシド 中間原料の9−(4−tert−ブチルベンジル)アデニンを用
い、実施例1と同様の操作により標記化合物を合成した
(収率:95%)。1 H-NMR (DMSO-d6) δ ppm:1.23(9H,s), 5.35(2H,s),
7.25(2H,d), 7.36(2H,d), 8.43(1H,s), 8.63(1H,s) Mass:297 (M+)Example 9 9- (4-tert-butylbenzyl) adenine, 1-N-oxide Using 9- (4-tert-butylbenzyl) adenine as an intermediate material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 95%). 1 H-NMR (DMSO-d 6 ) δ ppm: 1.23 (9H, s), 5.35 (2H, s),
7.25 (2H, d), 7.36 (2H, d), 8.43 (1H, s), 8.63 (1H, s) Mass: 297 (M +)
【0029】[0029]
【実施例10】 9−(4−トリフルオロメチルベンジル)
アデニン, 1−N−オキシド 中間原料の9−(4−トリフルオロメチルベンジル)アデニ
ンを用い、実施例1と同様の操作により標記化合物を合
成した(収率:79%)。1 H-NMR (DMSO-d6) δ ppm:3.18(3H,m), 4.10(1H,m),
5.52(2H,s), 7.49(2H,d), 7.72(2H,d), 8.46(1H,s), 8.
61(1H,s) Mass:309 (M+)Example 10 9- (4-trifluoromethylbenzyl)
Adenine, 1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (4-trifluoromethylbenzyl) adenine as an intermediate raw material (yield: 79%). 1 H-NMR (DMSO-d 6 ) δ ppm: 3.18 (3H, m), 4.10 (1H, m),
5.52 (2H, s), 7.49 (2H, d), 7.72 (2H, d), 8.46 (1H, s), 8.
61 (1H, s) Mass: 309 (M +)
【0030】[0030]
【実施例11】 9−(1−ナフチルメチル)アデニン, 1
−N−オキシド 中間原料の9−(1−ナフチルメチル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:59%)。1 H-NMR (DMSO-d6) δ ppm:5.89(2H,s), 7.20-8.25(7H,
m), 8.35(1H,s), 8.64(1H,s) Mass:291 (M+)Example 11 9- (1-Naphthylmethyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (1-naphthylmethyl) adenine as an intermediate raw material (yield: 59%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.89 (2H, s), 7.20-8.25 (7H,
m), 8.35 (1H, s), 8.64 (1H, s) Mass: 291 (M +)
【0031】[0031]
【実施例12】 9−(3−クロロベンジル)アデニン, 1
−N−オキシド 中間原料の9−(3−クロロベンジル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:76%)。1 H-NMR (DMSO-d6) δ ppm:5.41(2H,s), 7.27(1H,m),
7.37-7.43(3H,m), 8.45(1H,s), 8.63(1H,s) Mass:275 (M+)Example 12 9- (3-chlorobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (3-chlorobenzyl) adenine as an intermediate raw material (yield: 76%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.41 (2H, s), 7.27 (1H, m),
7.37-7.43 (3H, m), 8.45 (1H, s), 8.63 (1H, s) Mass: 275 (M +)
【0032】[0032]
【実施例13】 9−(2−クロロベンジル)アデニン, 1
−N−オキシド 中間原料の9−(2−クロロベンジル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:73%)。1 H-NMR (DMSO-d6) δ ppm:5.50(2H,s), 7.03-7.07(1H,
m), 7.30-7.42(2H,m),7.84-7.88(1H,m), 8.36(1H,s),
8.61(1H,s) Mass:275 (M+)Example 13 9- (2-chlorobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (2-chlorobenzyl) adenine as an intermediate raw material (yield: 73%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.50 (2H, s), 7.03-7.07 (1H,
m), 7.30-7.42 (2H, m), 7.84-7.88 (1H, m), 8.36 (1H, s),
8.61 (1H, s) Mass: 275 (M +)
【0033】[0033]
【実施例14】 9−(4−フルオロベンジル)アデニン, 1
−N−オキシド 中間原料の9−(4−フルオロベンジル)アデニンを用い、
実施例1と同様の操作により標記化合物を合成した(収
率:90%)。1 H-NMR (DMSO-d6) δ ppm:5.38(2H,s), 7.18(2H,m),
7.39(2H,m), 8.42(1H,s), 8.62(1H,s) Mass:259 (M+)Example 14 9- (4-Fluorobenzyl) adenine, 1
Using -N-oxide intermediate material 9- (4-fluorobenzyl) adenine,
The title compound was synthesized in the same manner as in Example 1 (yield: 90%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.38 (2H, s), 7.18 (2H, m),
7.39 (2H, m), 8.42 (1H, s), 8.62 (1H, s) Mass: 259 (M +)
【0034】[0034]
【実施例15】 9−(4−フェニルベンジル)アデニン,
1−N−オキシド 中間原料の9−(4−フェニルベンジル)アデニンを用い、
実施例1と同様の操作により標記化合物を合成した(収
率:40%)。1 H-NMR (DMSO-d6) δ ppm:5.45(2H,s), 7.36-7.48(5H,
m), 7.62-7.66(4H,m),8.48(1H,s), 8.64(1H,s) Mass:317 (M+)Example 15 9- (4-phenylbenzyl) adenine,
Using 1-N-oxide intermediate material 9- (4-phenylbenzyl) adenine,
The title compound was synthesized in the same manner as in Example 1 (yield: 40%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.45 (2H, s), 7.36-7.48 (5H,
m), 7.62-7.66 (4H, m), 8.48 (1H, s), 8.64 (1H, s) Mass: 317 (M +)
【0035】[0035]
【実施例16】 9−(4−メトキシカルボニルベンジル)
アデニン, 1−N−オキシド 中間原料の9−(4−メトキシカルボニルベンジル)アデニ
ンを用い、実施例1と同様の操作により標記化合物を合
成した(収率:44%)。1 H-NMR (DMSO-d6) δ ppm:3.83(3H,s), 5.50(2H,s),
7.41(2H,d), 7.93(2H,d), 8.45(1H,s), 8.61(1H,s) Mass:299 (M+)Example 16 9- (4-methoxycarbonylbenzyl)
Adenine, 1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (4-methoxycarbonylbenzyl) adenine as an intermediate raw material (yield: 44%). 1 H-NMR (DMSO-d 6 ) δ ppm: 3.83 (3H, s), 5.50 (2H, s),
7.41 (2H, d), 7.93 (2H, d), 8.45 (1H, s), 8.61 (1H, s) Mass: 299 (M +)
【0036】[0036]
【実施例17】 9−(4−ニトロベンジル)アデニン, 1
−N−オキシド 中間原料の9−(4−ニトロベンジル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:27%)。1 H-NMR (DMSO-d6) δ ppm:5.57(2H,s), 7.53(2H,d),
8.20(2H,d), 8.47(1H,s), 8.61(1H,s) Mass:286 (M+)Example 17 9- (4-nitrobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (4-nitrobenzyl) adenine as an intermediate raw material (yield: 27%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.57 (2H, s), 7.53 (2H, d),
8.20 (2H, d), 8.47 (1H, s), 8.61 (1H, s) Mass: 286 (M +)
【0037】[0037]
【実施例18】 9−(2−ナフチルメチル)アデニン, 1
−N−オキシド 中間原料の9−(2−ナフチルメチル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:35%)。1 H-NMR (DMSO-d6) δ ppm:5.57(2H,s), 7.49-7.89(7H,
m), 8.48(1H,s), 8.62(1H,s) Mass:291(M+)Example 18 9- (2-Naphthylmethyl) adenine, 1
—N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (2-naphthylmethyl) adenine as an intermediate raw material (yield: 35%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.57 (2H, s), 7.49-7.89 (7H,
m), 8.48 (1H, s), 8.62 (1H, s) Mass: 291 (M +)
【0038】[0038]
【実施例19】 9−(2,3−ジクロロベンジル)アデニ
ン, 1−N−オキシド 中間原料の9−(2,3−ジクロロベンジル)アデニンを用
い、実施例1と同様の操作により標記化合物を合成した
(収率:65%)。1 H-NMR (DMSO-d6) δ ppm:5.54(2H,s), 6.97-6.99(1H,
m), 7.30-7.35(1H,m),7.61-7.62(1H,m), 8.37(1H,s),
8.60(1H,s) Mass:310 (M+)Example 19 9- (2,3-Dichlorobenzyl) adenine, 1-N-oxide Using 9- (2,3-dichlorobenzyl) adenine as an intermediate material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 65%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.54 (2H, s), 6.97-6.99 (1H,
m), 7.30-7.35 (1H, m), 7.61-7.62 (1H, m), 8.37 (1H, s),
8.60 (1H, s) Mass: 310 (M +)
【0039】[0039]
【実施例20】 9−(3,4−ジクロロベンジル)アデニ
ン, 1−N−オキシド 中間原料の9−(3,4−ジクロロベンジル)アデニンを用
い、実施例1と同様の操作により標記化合物を合成した
(収率:51%)。1 H-NMR (DMSO-d6) δ ppm:5.41(2H,s), 7.26-7.30(1H,
m), 7.59-7.66(2H,m),8.43(1H,s), 8.62(1H,s) Mass:310 (M+)Example 20 9- (3,4-Dichlorobenzyl) adenine, 1-N-oxide Using 9- (3,4-dichlorobenzyl) adenine as an intermediate material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 51%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.41 (2H, s), 7.26-7.30 (1H,
m), 7.59-7.66 (2H, m), 8.43 (1H, s), 8.62 (1H, s) Mass: 310 (M +)
【0040】[0040]
【実施例21】 9−(2,6−ジクロロベンジル)アデニ
ン, 1−N−オキシド 中間原料の9−(2,6−ジクロロベンジル)アデニンを用
い、実施例1と同様の操作により標記化合物を合成した
(収率:36%)。 Mass:310(M+)Example 21 9- (2,6-Dichlorobenzyl) adenine, 1-N-oxide Using 9- (2,6-dichlorobenzyl) adenine as an intermediate starting material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 36%). Mass: 310 (M +)
【0041】[0041]
【実施例22】 9−(3,5−ジフルオロベンジル)アデニ
ン, 1−N−オキシド 中間原料の9−(3,5−ジフルオロベンジル)アデニンを用
い、実施例1と同様の操作により標記化合物を合成した
(収率:50%)。1 H-NMR (DMSO-d6) δ ppm:5.44(11H,m), 7.06-7.08(2
H,m), 7.18-7.25(2H,m), 8.44(1H,s), 8.64(1H,s) Mass:277 (M+)Example 22 9- (3,5-Difluorobenzyl) adenine, 1-N-oxide Using 9- (3,5-difluorobenzyl) adenine as an intermediate starting material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 50%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.44 (11H, m), 7.06-7.08 (2
H, m), 7.18-7.25 (2H, m), 8.44 (1H, s), 8.64 (1H, s) Mass: 277 (M +)
【0042】[0042]
【実施例23】 9−(3−ブロモベンジル)アデニン, 1
−N−オキシド 中間原料の9−(3−ブロモベンジル)アデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:83%)。1 H-NMR (DMSO-d6) δ ppm:5.40(2H,s), 7.30(2H,m),
7.49-7.57(2H,m), 8.44(1H,s), 8.62(1H,s) Mass:320 (M+)Example 23 9- (3-bromobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (3-bromobenzyl) adenine as an intermediate material (yield: 83%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.40 (2H, s), 7.30 (2H, m),
7.49-7.57 (2H, m), 8.44 (1H, s), 8.62 (1H, s) Mass: 320 (M +)
【0043】[0043]
【実施例24】 9−(3−トリフルオロメチルベンジル)
アデニン, 1−N−オキシド 中間原料の9−(3−トリフルオロメチルベンジル)アデニ
ンを用い、実施例1と同様の操作により標記化合物を合
成した(収率:41%)。1 H-NMR (DMSO-d6) δ ppm:5.51(2H,s), 7.57-7.76(4H,
m), 8.47(1H,s), 8.62(1H,s) Mass:309 (M+)Example 24 9- (3-trifluoromethylbenzyl)
Adenine, 1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (3-trifluoromethylbenzyl) adenine as an intermediate raw material (yield: 41%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.51 (2H, s), 7.57-7.76 (4H,
m), 8.47 (1H, s), 8.62 (1H, s) Mass: 309 (M +)
【0044】[0044]
【実施例25】 9−(2,3,4−トリフルオロベンジル)ア
デニン, 1−N−オキシド 中間原料の9−(2,3,4−トリフルオロベンジル)アデニン
を用い、実施例1と同様の操作により標記化合物を合成
した(収率:38%)。1 H-NMR (DMSO-d6) δ ppm:5.45(2H,s), 7.09-7.19(1H,
m), 7.25-7.35(1H,m),8.14(1H,s), 8.22(1H,s) Mass:295(M+)Example 25 9- (2,3,4-trifluorobenzyl) adenine, 1-N-oxide Same as Example 1 except for using 9- (2,3,4-trifluorobenzyl) adenine as an intermediate raw material. The title compound was synthesized by the operation described above (yield: 38%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.45 (2H, s), 7.09-7.19 (1H,
m), 7.25-7.35 (1H, m), 8.14 (1H, s), 8.22 (1H, s) Mass: 295 (M +)
【0045】[0045]
【実施例26】 9−(2,4,6−トリフルオロベンジル)ア
デニン, 1−N−オキシド 中間原料の9−(2,4,6−トリフルオロベンジル)アデニン
を用い、実施例1と同様の操作により標記化合物を合成
した(収率:97%)。1 H-NMR (DMSO-d6) δ ppm:5.43(2H,s), 7.26(2H,t),
8.34(1H,s), 8.59(1H,s) Mass:295 (M+)Example 26 9- (2,4,6-trifluorobenzyl) adenine, 1-N-oxide Same as Example 1 using 9- (2,4,6-trifluorobenzyl) adenine as an intermediate material The title compound was synthesized by the operation described above (yield: 97%). 1 H-NMR (DMSO-d 6 ) δ ppm: 5.43 (2H, s), 7.26 (2H, t),
8.34 (1H, s), 8.59 (1H, s) Mass: 295 (M +)
【0046】[0046]
【実施例27】 9−ベンジル−2−メチルアデニン, 1
−N−オキシド 中間原料の9−ベンジル−2−メチルアデニンを用い、実
施例1と同様の操作により標記化合物を合成した(収
率:63%)。1 H-NMR (DMSO-d6) δ ppm:2.57(3H,s), 5.37(2H,s),
7.26-7.33(5H,m), 8.31(1H,s) Mass:255 (M+)Example 27 9-benzyl-2-methyladenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9-benzyl-2-methyladenine as an intermediate raw material (yield: 63%). 1 H-NMR (DMSO-d 6 ) δ ppm: 2.57 (3H, s), 5.37 (2H, s),
7.26-7.33 (5H, m), 8.31 (1H, s) Mass: 255 (M +)
【0047】[0047]
【実施例28】 9−(3,4,5−トリメトキシベンジル)ア
デニン, 1−N−オキシド 中間原料の9−(3,4,5−トリメトキシベンジル)アデニン
を用い、実施例1と同様の操作により標記化合物を合成
した(収率:59%)。1 H-NMR (DMSO-d6) δ ppm:3.61(3H,s), 3.72(6H,s),
5.29(2H,s), 6.71(2H,s), 8.39(1H,s), 8.63(1H,s) Mass:331 (M+)Example 28 9- (3,4,5-trimethoxybenzyl) adenine, 1-N-oxide Same as Example 1 using 9- (3,4,5-trimethoxybenzyl) adenine as an intermediate material The title compound was synthesized by the operation described above (yield: 59%). 1 H-NMR (DMSO-d 6 ) δ ppm: 3.61 (3H, s), 3.72 (6H, s),
5.29 (2H, s), 6.71 (2H, s), 8.39 (1H, s), 8.63 (1H, s) Mass: 331 (M +)
【0048】[0048]
【実施例29】 9−(2,3−ジクロロベンジル)−2−メ
チルアデニン, 1−N−オキシド 中間原料の9−(2,3−ジクロロベンジル)−2−メチルア
デニンを用い、実施例1と同様の操作により標記化合物
を合成した(収率:89%)。1 H-NMR (DMSO-d6) δ ppm:1.90(3H,s), 5.50(2H,s),
6.88(1H,d), 7.31(1H,t), 7.62(1H,d), 8.26(1H,s) Mass:324 (M+)Example 29 9- (2,3-Dichlorobenzyl) -2-methyladenine, 1-N-oxide Example 1 was prepared using 9- (2,3-dichlorobenzyl) -2-methyladenine as an intermediate material. The title compound was synthesized in the same manner as described above (yield: 89%). 1 H-NMR (DMSO-d 6 ) δ ppm: 1.90 (3H, s), 5.50 (2H, s),
6.88 (1H, d), 7.31 (1H, t), 7.62 (1H, d), 8.26 (1H, s) Mass: 324 (M +)
【0049】[0049]
【実施例30】 ICAM−1分子発現抑制作用 本発明のアデニン N−オキシド誘導体が、優れたICAM−
1分子発現抑制作用を有することを、以下の試験により
検証した。Example 30 Inhibitory Effect of ICAM-1 Molecule Expression The adenine N-oxide derivative of the present invention has excellent ICAM-
It was verified by the following test that it had a single molecule expression suppressing effect.
【0050】試験法 96穴プレートの各ウェルにヒト臍帯静脈内皮細胞を播種
し、コンフルエントになるまで培養する。被験物質の所
定濃度およびTNF−α(100 U/ml)を添加し、24時間培養
する。細胞を0.1 %グルタルアルデヒドで固定した後、
0.1 % BSA, 0.2% gelatin, 0.75 % glysine入りPBSでブ
ロッキングを施す。マウス抗ヒトICAM−1抗体を用いたE
LISA法によって、発現しているICAM−1量を定量する。
参照群として、被験物質を添加しないとき、発現してい
るICAM−1量を定量し、その値を基準として抑制率を算
定する。Test Method Human umbilical vein endothelial cells are seeded in each well of a 96-well plate and cultured until confluent. A predetermined concentration of the test substance and TNF-α (100 U / ml) are added, and the cells are cultured for 24 hours. After fixing the cells with 0.1% glutaraldehyde,
Block with PBS containing 0.1% BSA, 0.2% gelatin, 0.75% glysine. E using mouse anti-human ICAM-1 antibody
The amount of expressed ICAM-1 is quantified by the LISA method.
As a reference group, when no test substance is added, the amount of expressed ICAM-1 is quantified, and the inhibition rate is calculated based on that value.
【0051】表1に、上記試験の結果を基に、抑制率の
被験物質添加濃度依存性から求めた抑制率が50%を超
える添加濃度、すなわち最低有効濃度を一例として示
す。Table 1 shows, by way of example, the addition concentration at which the inhibition rate obtained from the dependency of the inhibition rate on the test substance addition concentration exceeds 50%, ie, the lowest effective concentration, based on the results of the above test.
【0052】[0052]
【表1】 [Table 1]
【0053】[0053]
【実施例31】 E−selectin分子発現抑制作用 本発明のアデニン N−オキシド誘導体が、優れたE−sel
ectin分子発現抑制作用を有することを、以下の試験に
より検証した。Example 31 E-selectin Molecule Expression Inhibitory Effect The adenine N-oxide derivative of the present invention is an excellent E-sel
It was verified by the following test that it had an ectin molecule expression inhibitory effect.
【0054】試験法 96穴プレートの各ウェルにヒト臍帯静脈内皮細胞を播種
し、コンフルエントになるまで培養する。被験物質の所
定濃度およびTNF−α(100 U/ml)を添加し、3時間培養
する。細胞を0.1 % グルタルアルデヒドで固定した
後、0.1 % BSA, gelatin, 0.75 % glysine入りPBSでブ
ロッキングを施す。マウス抗ヒトE−selectin抗体を用
いたELISA法によって、発現しているE−selectin量を定
量する。参照群として、被験物質を添加しないとき、発
現しているE−selectin量を定量し、その値を基準とし
て抑制率を算定する。Test Method Human umbilical vein endothelial cells are seeded in each well of a 96-well plate and cultured until confluent. A predetermined concentration of the test substance and TNF-α (100 U / ml) are added, and the cells are cultured for 3 hours. After fixing the cells with 0.1% glutaraldehyde, perform blocking with PBS containing 0.1% BSA, gelatin and 0.75% glysine. The amount of expressed E-selectin is quantified by an ELISA method using a mouse anti-human E-selectin antibody. As a reference group, when no test substance is added, the amount of expressed E-selectin is quantified, and the inhibition rate is calculated based on that value.
【0055】表2に、上記試験の結果を基に、抑制率の
被験物質添加濃度依存性から求めた抑制率が50%を超
える添加濃度、すなわち最低有効濃度を一例として示
す。Table 2 shows, by way of example, the additive concentration at which the inhibition rate obtained from the dependence of the inhibition rate on the test substance addition concentration, based on the results of the above test, exceeds 50%, ie, the lowest effective concentration.
【0056】[0056]
【表2】 [Table 2]
【0057】[0057]
【実施例32】 細胞接着抑制作用 本発明のアデニン N−オキシド誘導体は、上記のとおり
ICAM−1分子、 E−selectin分子など接着分子の発現抑
制作用に優れるものであり、その結果炎症性細胞の接着
過程自体を抑制する作用にも優れることを、以下の試験
により検証した。Example 32 Cell Adhesion Inhibitory Effect The adenine N-oxide derivative of the present invention
It was verified by the following tests that the compound was excellent in suppressing the expression of adhesion molecules such as ICAM-1 molecule and E-selectin molecule and, as a result, also excellent in suppressing the adhesion process itself of inflammatory cells.
【0058】試験法 96穴プレートの各ウェルにヒト臍帯静脈内皮細胞を播種
し、コンフルエントになるまで培養する。被験物質の所
定濃度およびTNF−α(100 U/ml)を添加し、3時間培養
する。次いで、2',7'−bis−(2−carboxyethyl)−5,6−
dicarboxyfluoresce−acetoxymethylesterにより蛍光ラ
ベルを施したHL-60細胞の所定細胞量を添加し、30分間
培養する。未接着のHL-60細胞を吸引除去した後、接着
していたHL-60細胞を溶解して、蛍光強度を測定する
(励起:490 nm, 蛍光:530 nm)。参照群として、被験
物質を添加しないとき、接着していたHL-60細胞の細胞
数を同様にして定量し、その値を基準として抑制率を算
定する。Test Method Human umbilical vein endothelial cells are seeded in each well of a 96-well plate and cultured until confluent. A predetermined concentration of the test substance and TNF-α (100 U / ml) are added, and the cells are cultured for 3 hours. Then, 2 ', 7'-bis- (2-carboxyethyl) -5,6-
A predetermined amount of HL-60 cells fluorescently labeled with dicarboxyfluoresce-acetoxymethylester is added, and cultured for 30 minutes. After suction-removing unadhered HL-60 cells, the adhered HL-60 cells are lysed and the fluorescence intensity is measured (excitation: 490 nm, fluorescence: 530 nm). As a reference group, when no test substance is added, the number of adherent HL-60 cells is similarly quantified, and the inhibition rate is calculated based on the value.
【0059】抑制率の被験物質添加濃度依存性から、抑
制率50%となる添加濃度IC50の値を求めた。結果の一
例を示すと、実施例19および実施例23の化合物はそ
れぞれ0.179 μM、0.157 μMのIC50値を示した。From the dependence of the inhibition rate on the concentration of the test substance added, the value of the added concentration IC50 at which the inhibition rate was 50% was determined. As an example of the results, the compound of Example 19 and Example 23 were respectively 0.179 [mu] M, IC 50 values of 0.157 [mu] M.
【0060】[0060]
【実施例32】 .アジュバント関節炎モデルに対する
効果 本発明のアデニンN−オキシド誘導体は、炎症性細胞の
患部組織細胞上への接着過程自体を抑制する作用に優れ
ているため、実際の免疫性疾患における炎症症状を緩和
する効果があることを、以下のアジュバント関節炎モデ
ルにより検証した。Example 32. Effect on adjuvant arthritis model The adenine N-oxide derivative of the present invention is excellent in the action of inhibiting the process of adhesion of inflammatory cells to diseased tissue cells itself, so that it can be used in actual immune diseases. The effect of alleviating inflammatory symptoms was verified by the following adjuvant arthritis model.
【0061】試験法 8週令雄性SD系ラットの右側後肢足蹠皮下に0.6 % Myob
acterium butyricum流動パラフィン懸濁液を0.1 ml 注
射する。被験物質は、その所定用量を0.5 %CMC-Na溶液
に懸濁して、アジュバント投与日(惹起0日目)から1日
1回17日間経口投与する。惹起17日目の足容積と惹起0日
目の足容積との差;浮腫に伴う足容積の増加分の惹起0
日目の足容積に対する比を浮腫率として算定する。ま
た、最終日(惹起17日目)にエーテル麻酔下に腹大動脈
より採血し、3.2 % クエン酸:血液=1:4の割合で混合
した液のWestergren管中での血液沈降速度を測定する。Test Method 0.6% Myob was subcutaneously injected into the right hind footpad of 8-week-old male SD rats.
Inject 0.1 ml of acterium butyricum liquid paraffin suspension. The test substance is suspended at a predetermined dose in a 0.5% CMC-Na solution for one day from the day of adjuvant administration (day 0).
Oral administration once for 17 days. Difference between the paw volume on day 17 and the paw volume on day 0; increase in paw volume due to edema 0
The ratio to paw volume on day is calculated as edema rate. On the last day (17th day of induction), blood is collected from the abdominal aorta under ether anesthesia, and the blood sedimentation rate in a Westergren tube of a mixed solution of 3.2% citric acid: blood = 1: 4 is measured.
【0062】表3に、一例として、実施例19の化合物
と実施例23の化合物の結果を示す。表中には、右側後
肢の浮腫率;右足浮腫率、左側後肢の浮腫率;左足浮腫
率、並びに血液沈降速度として、採血120分後の値を併
せて示す。なお、被験物質を含まない0.5 % CMC-Na溶
液を投与した際の結果をコントロールとして示す。Table 3 shows the results of the compound of Example 19 and the compound of Example 23 as an example. In the table, the edema rate of the right hind limb; the edema rate of the right hind limb; the edema rate of the left hind limb; The results obtained when a 0.5% CMC-Na solution containing no test substance was administered are shown as controls.
【0063】[0063]
【表3】 [Table 3]
【0064】[0064]
【発明の効果】本発明のアデニンN−オキシド誘導体
は、内皮細胞上での接着分子の発現を阻害する作用に優
れるので、炎症性細胞の当該標的臓器・組織への接着を
抑制することができる。この際だった接着分子発現阻害
活性を利用して、各種の炎症性疾患すなわちリウマチ、
SLE、多発性硬化症などの自己免疫疾患、その他喘息等
のアレルギー性疾患、心筋梗塞後の再還流障害など免疫
性疾患の治療に対して有用な医薬となる。加えて、本発
明のアデニンN−オキシド誘導体は低分子化合物である
ので、経口投与が可能であり、長期又は継続的な投与に
適しており、上記の慢性疾患の治療に適する。Industrial Applicability The adenine N-oxide derivative of the present invention is excellent in inhibiting the expression of adhesion molecules on endothelial cells, so that the adhesion of inflammatory cells to the target organ / tissue can be suppressed. . Utilizing this distinctive adhesion molecule expression inhibitory activity, various inflammatory diseases, namely rheumatism,
It is a useful medicine for treating autoimmune diseases such as SLE and multiple sclerosis, other allergic diseases such as asthma, and immune diseases such as reperfusion disorder after myocardial infarction. In addition, since the adenine N-oxide derivative of the present invention is a low molecular compound, it can be administered orally, is suitable for long-term or continuous administration, and is suitable for treating the above-mentioned chronic diseases.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 FI A61K 31/52 ABS A61K 31/52 ABS ACD ACD ACE ACE ACS ACS ADP ADP ADZ ADZ ────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 6 Identification code FI A61K 31/52 ABS A61K 31/52 ABS ACD ACD ACE ACE ACS ACS ADP ADP ADZ ADZ ADZ
Claims (2)
は分枝状のアルキル基を表わし、R2は、水素原子、炭素
数1〜4の直鎖あるいは分枝状のアルキル基又は炭素数1
〜4の直鎖あるいは分枝状のアルコキシ基を表わし、R3
は、無置換、あるいは、炭素数1〜4の直鎖あるいは分枝
状のアルキル基、炭素数1〜4の直鎖あるいは分枝状のア
ルコキシ基、アルコキシカルボニル基、トリフルオロメ
チル基、ニトロ基、フェニル基、ハロゲノ基からなる群
より選択される1以上3以下の置換基を有する置換フェ
ニル基、またはナフチル基を表わす。)で示される新規
なアデニン−1−N−オキシド誘導体又はその薬理的に許
容される塩。1. The following general formula (I): (Wherein, R 1 represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and R 2 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Group or carbon number 1
It represents to 4 straight-chain or branched alkoxy group, R 3
Is an unsubstituted or straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group, a trifluoromethyl group, and a nitro group. Phenyl group, a substituted phenyl group having 1 to 3 substituents selected from the group consisting of a halogeno group, and a naphthyl group. Adenine-1-N-oxide derivative or a pharmaceutically acceptable salt thereof.
1−N−オキシド誘導体又はその薬理的に許容される塩を
有効成分として含んでなる免疫性疾患治療薬。2. The novel adenine according to claim 1,
An agent for treating an immune disease, comprising a 1-N-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
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JP5112497A JPH10231297A (en) | 1997-02-20 | 1997-02-20 | New adenine-1-noxide derivative, and use of the same as medicine |
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ID=12878070
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