JPH0625163B2 - Uracil derivative - Google Patents
Uracil derivativeInfo
- Publication number
- JPH0625163B2 JPH0625163B2 JP60082016A JP8201685A JPH0625163B2 JP H0625163 B2 JPH0625163 B2 JP H0625163B2 JP 60082016 A JP60082016 A JP 60082016A JP 8201685 A JP8201685 A JP 8201685A JP H0625163 B2 JPH0625163 B2 JP H0625163B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- uracil
- uracil derivative
- group
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 （イ）産業上の利用分野 本発明は制癌剤として有用な新規なウラシル誘導体に関
するものである。DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a novel uracil derivative useful as an anticancer agent.
又、制癌作用を有する新規なウラシル誘導体を開発する
ための中間原料として、更には高分子医薬を合成するた
めの原料化合物としての有用な反応活性基を有してなる
ウラシル誘導体に関するものである。Further, the present invention relates to a uracil derivative having a useful reactive group as an intermediate raw material for developing a novel uracil derivative having an antitumor action, and as a raw material compound for synthesizing a polymer drug. .
（ロ）従来の技術 ウラシル誘導体に関しては、すでに５−フルオロウラシ
ル（５−ＦＵ）が制癌剤として有用であることは周知の
事実である。しかしながら、代謝拮抗阻害剤である５−
ＦＵは、白血球減少，血小板減少，貧血等の血液障害，
肝障害，胃腸管障害，浮腫，脱毛，味覚障害等の種々の
副作用を有して安全性の点で問題がある。この毒性を緩
和するために、５−ＦＵとフラノース環とを結合させた
フトラフール 〔特開昭50-50383号公報等〕が開発され
ている。又、５−ＦＵの１位にｎ−ヘキシルカルバモイ
ル基を有するミフロール 〔特開昭50-148365号公報〕
が開発され上市されているが、薬理活性及び副作用等が
十分改善されたとは言い難い。又、薬効の持続性の点で
も優れたものとは言い難いものである。(B) Conventional technology Regarding uracil derivatives, 5-fluorouracil has already been used.
It is well known that ru (5-FU) is useful as an anticancer agent.
It is a fact. However, 5-
FU is a leukopenia, thrombocytopenia, blood disorders such as anemia,
Various liver disorders, gastrointestinal disorders, edema, hair loss, taste disorders, etc.
It has side effects and is problematic in terms of safety. Relax this toxicity
For the purpose of conjugation, 5-FU was linked to the furanose ring
Futrafur [JP-A-50-50383] was developed.
ing. In addition, n-hexylcarbamoy was added to the 1st position of 5-FU.
Mifrole with group (Japanese Patent Laid-Open No. 50-148365)
Has been developed and put on the market, but its pharmacological activity, side effects, etc.
It is hard to say that it has been improved enough. Also, in terms of the persistence of medicinal effects
It is hard to say that it is excellent.
（ハ）発明が解決しようとする問題点 本発明は血液障害，肝障害，胃腸管障害，味覚障害等の
副作用が少なく、安全性に優れ且つ十分な薬理作用を有
し、しかも薬効の持続性の点からも充分満足し得るウラ
シル誘導体の開発を目的とするものである。(C) Problems to be Solved by the Invention The present invention has few side effects such as blood disorders, liver disorders, gastrointestinal tract disorders, and taste disorders, is excellent in safety, has a sufficient pharmacological action, and has a long-lasting medicinal effect. In view of the above, the objective is to develop a uracil derivative that is sufficiently satisfactory.
又、優れた制癌活性を有する新規ウラシル関連化合物を
合成するための中間体の開発及びラジカル重合反応又は
ビニール化合物との共重合反応によって得られる高分子
化合物は薬理活性基（５−ＦＵ）の放出コントロールを
可能にすることが考えられ、薬理活性の持続化及び副作
用の低減が期待される。Further, a polymer compound obtained by the development of an intermediate for synthesizing a novel uracil-related compound having excellent antitumor activity and a radical polymerization reaction or a copolymerization reaction with a vinyl compound has a pharmacologically active group (5-FU). It is considered that the controlled release is possible, and it is expected that the pharmacological activity is prolonged and the side effects are reduced.
しかるに、末端にビニール基等の反応活性基を有する中
間体の開発が望まれており、本発明は係る目的を解決す
るにある。However, it is desired to develop an intermediate having a reactive active group such as a vinyl group at the terminal, and the present invention is to solve the object.
（ニ）問題を解決するための手段 本発明は一般式（Ｉ） 〔式中、R1は水素原子，ハロゲン原子又は低級アルキル
基、Ｒ2は （式中、R3は水素原子又は低級アルキル基を表わす）〕
で表わされるウラシル誘導体に関するものである。(D) Means for Solving the Problem The present invention has the general formula (I) [Wherein R 1 is a hydrogen atom, a halogen atom or a lower alkyl group, and R 2 is (In the formula, R 3 represents a hydrogen atom or a lower alkyl group.)
The present invention relates to a uracil derivative represented by
前記一般式（Ｉ）のR1，R2におけるＲ3について更に詳
しく説明すると、R1は水素原子又は塩素，臭素，弗素，
沃素等のハロゲン原子、又はメチル，エチル，ｎ−プロ
ピル，イソプロピル，ｎ−ブチル及びイソブチル等の低
級アルキル基を、Ｒ2におけるR3は、水素原子又はメチ
ル，エチル，ｎ−ブチル及びイソブチル等の低級アルキ
ル基を意味する。The R 3 in the general formula (I) R 1 and R 2 will be described in more detail. R 1 is a hydrogen atom or chlorine, bromine, fluorine,
A halogen atom such as iodine or a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, R 3 in R 2 is a hydrogen atom or a methyl, ethyl, n-butyl and isobutyl group. It means a lower alkyl group.
次に本発明の製造法について述べる。Next, the manufacturing method of the present invention will be described.
製造法 （式中、R1，R2，R3は前記と同じ、又Ｙはトリアルキル
シリル基又はトリアルキルスタニル基を、Ｚはハロゲン
原子を意味する） まず最初に５−フルオロウラシル又は５−メチルウラシ
ル（チミン）又はウラシル等にヘキサメチルジシラザン
又はトリアルキルスタニルオキシドを反応させることに
より得られる一般式（II）のウラシル誘導体と一般式
（III）で表わされるアクリル酸あるいはメタアクリル
酸等の反応性誘導体（例えば酸クロリド）を一般式（I
I）に対して１〜３倍モル使用し、アセトニトリル，テ
トラヒドロフラン，塩化メチレン，ジクロルエタン，ク
ロロホルム，四塩化炭素，ジメチルホルムアミド及びジ
メチルスルホキシド等の有機溶媒中（尚、有機溶媒は無
水のものほど好ましい）、室温又は加熱下（150℃以
下）でもって反応させることにより目的とするウラシル
誘導体を得ることができる。尚、反応時は加熱（40〜15
0℃）した方がより速く反応は進行し、しかも反応時間
は0.5〜10時間ほどで充分である。又、窒素ガスあるい
はアルゴンガス気流下のもとで反応させると収率向上に
もつながり、なるべくこれらのガス雰囲気下の状態で行
うのが望ましい。Manufacturing method (In the formula, R 1 , R 2 and R 3 are the same as above, Y is a trialkylsilyl group or a trialkylstannyl group, and Z is a halogen atom.) First, 5-fluorouracil or 5-methyl Uracil (thymine) or uracil is reacted with hexamethyldisilazane or trialkylstannyl oxide to obtain a uracil derivative of the general formula (II) and acrylic acid or methacrylic acid represented by the general formula (III). A reactive derivative (eg, acid chloride) can be represented by the general formula (I
It is used in 1 to 3 times the molar amount of I) in an organic solvent such as acetonitrile, tetrahydrofuran, methylene chloride, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide and dimethylsulfoxide (the organic solvent is preferably anhydrous). The desired uracil derivative can be obtained by reacting at room temperature or under heating (150 ° C or lower). During the reaction, heat (40-15
The reaction proceeds faster at 0 ° C), and the reaction time of about 0.5 to 10 hours is sufficient. Further, when the reaction is carried out under a nitrogen gas or argon gas flow, the yield is improved, and it is desirable to carry out the reaction under these gas atmospheres as much as possible.
以上の製造法で得られたウラシル誘導体は、有機溶媒に
よる再結晶又はカラムクロマトグラフィー等の精製手段
によって高純度な化合物となすことができる。The uracil derivative obtained by the above production method can be made into a highly pure compound by a purification means such as recrystallization with an organic solvent or column chromatography.
以上の如くして得られた本発明の化合物は通常の製剤処
方、あるいは各種賦形剤との処方でもってカプセル剤，
錠剤，細粒剤，シロップ剤，軟膏剤，坐剤及び注射剤等
の各種医薬製剤とすることができる。The compound of the present invention obtained as described above is prepared into a capsule formulation by a conventional pharmaceutical formulation or a formulation with various excipients.
Various pharmaceutical preparations such as tablets, fine granules, syrups, ointments, suppositories and injections can be prepared.
（ホ）作用 本発明の化合物は制癌作用を有し、医薬品としての有用
性を充分に期待しうるものである。(E) Action The compound of the present invention has a carcinostatic action and can be expected to be sufficiently useful as a drug.
又、本発明の化合物はウラシル骨格の１位の置換基にお
いて反応性に優れているビニール基の官能基を有する為
に顕著な制癌作用が期待できる多くのウラシル誘導体、
あるいはラジカル重合又はビニール化合物と共重合させ
て得られる高分子化合物の中間体としての有用性が示唆
されるものである。Further, since the compound of the present invention has a vinyl group functional group having excellent reactivity at the substituent at the 1-position of the uracil skeleton, many uracil derivatives which can be expected to have a remarkable antitumor effect,
Alternatively, it is suggested that the polymer compound obtained by radical polymerization or copolymerization with a vinyl compound is useful as an intermediate.
（ヘ）実施例 以下に実施例を示し本発明をより具体的に説明するが、
勿論、本発明はこれらの実施例にのみ限定されるもので
はない。(F) Examples The present invention will be described more specifically with reference to Examples below.
Of course, the invention is not limited to these examples.
実施例１ 2,4−ビス（トリメチルシリル）−５−メチルウラシル
1.36ｇをアセトニトリル50mlに溶解させ、室温下でメタ
アクリロイルクロリド1.04ｇを徐々に滴加し、終了後、
還流下３時間反応させる。次に溶媒を減圧下に留去し、
残渣を無水エタノールにて再結晶すると無色透明針状晶
の１−メタアクリロイル−５−メチルウラシル0.92ｇ
（収率95％）を得た。Example 1 2,4-bis (trimethylsilyl) -5-methyluracil
Dissolve 1.36 g in 50 ml of acetonitrile, gradually add 1.04 g of methacryloyl chloride at room temperature, and after completion,
React under reflux for 3 hours. Then the solvent is distilled off under reduced pressure,
The residue was recrystallized from absolute ethanol to give colorless needle-like 1-methacryloyl-5-methyluracil 0.92 g.
(Yield 95%) was obtained.
この物質の物理化学的データは下記の通りである。The physicochemical data of this substance are as follows.
融点 141.5〜142.5℃ IR(KBr,cm-1)1725,1680 1640 NMR（δ，DMSO-d6,ppm） 11.58(br,1H,3-NH) 7.70(s,1H,6-CH) 5.80〜5.52(d,2H,C＝CH2,J＝4Hz) 1.94(s,3H,-CH3) 1.82(s,3H,5-CH3) Mass(m/e)194(M+) UV(MeOH)〔λ，nm〕264.8,208.0 実施例２ 2,4−ビス（トリメチルシリル）−５−フルオロウラシ
ル1.38ｇをアセトニトリル50mlに溶解させ、室温下でア
クリロイルクロリド0.90ｇを徐々に滴加し、終了後、室
温にて６時間攪拌する。次に溶媒を留去し、残渣をベン
ゼン−ｎ−ヘキサンの混合溶媒にて再結晶すると無色透
明針状晶の１−アクリロイル−５−フルオロウラシル0.
12ｇ（収率13％）を得た。Melting point 141.5〜142.5 ℃ IR (KBr, cm -1 ) 1725,1680 1640 NMR (δ, DMSO-d 6 , ppm) 11.58 (br, 1H, 3-NH) 7.70 (s, 1H, 6-CH) 5.80-5.52 (d, 2H, C = CH 2 , J = 4Hz) 1.94 ( s, 3H, -CH 3) 1.82 (s, 3H, 5-CH 3) Mass (m / e) 194 (M +) UV (MeOH) [lambda, nm] 264.8,208.0 example 2 2,4-bis (Trimethylsilyl) -5-fluorouracil (1.38 g) is dissolved in acetonitrile (50 ml), and acryloyl chloride (0.90 g) is gradually added dropwise at room temperature. After completion, the mixture is stirred at room temperature for 6 hours. Next, the solvent was distilled off, and the residue was recrystallized with a mixed solvent of benzene-n-hexane to give 1-acryloyl-5-fluorouracil as colorless transparent needle crystals.
12 g (yield 13%) was obtained.
この物質の物理化学的データは下記の通りである。The physicochemical data of this substance are as follows.
実施例３ 2,4−ビス（トリメチルシリル）−５−メチルウラシル
1.36ｇをアセトニトリル50mlに溶解させ、室温下でアク
リロイルクロリド0.90ｇを徐々に滴加し、終了後、還流
下３時間反応させる。次に、反応液を冷却放置し、析出
する結晶を濾取後、更に無水アセトニトリルにて再結晶
すると無色透明針状晶の１−アクリロイル−５−メチル
ウラシル0.32ｇ（収率36％）を得た。 Example 3 2,4-bis (trimethylsilyl) -5-methyluracil
1.36 g is dissolved in 50 ml of acetonitrile, 0.90 g of acryloyl chloride is gradually added dropwise at room temperature, and after completion, the mixture is reacted under reflux for 3 hours. Next, the reaction solution was left to cool and the precipitated crystals were collected by filtration and recrystallized with anhydrous acetonitrile to obtain 0.32 g (yield 36%) of 1-acryloyl-5-methyluracil as colorless transparent needle crystals. It was
この物質の物理化学的データは下記の通りである。The physicochemical data of this substance are as follows.
実施例４ 2,4−ビス（トリメチルシリル）−５−フルオロウラシ
ル1.38ｇをアセトニトリル50mlに溶解させ、室温下でメ
タアクリロイルクロリド1.04ｇを徐々に滴加し、滴加終
了後、還流下３時間反応させる。次に溶媒を減圧下に留
去し、残渣をベンゼン−ｎ−ヘキサンの混合溶媒にて再
結晶すると無色透明針状晶の１−メタアクリロイル−５
−フルオロウラシル0.23ｇ（収率27％）を得た。 Example 4 1.38 g of 2,4-bis (trimethylsilyl) -5-fluorouracil was dissolved in 50 ml of acetonitrile, 1.04 g of methacryloyl chloride was gradually added dropwise at room temperature, and after completion of the addition, the mixture was reacted for 3 hours under reflux. . Next, the solvent was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of benzene-n-hexane to give 1-methacryloyl-5 as colorless transparent needle crystals.
-0.23 g (27% yield) of fluorouracil was obtained.
この物質の物理化学的データは下記の通りである。The physicochemical data of this substance are as follows.
融点 147.0〜148.0℃ NMR（δ，DMSO-d6,ppm） 12.12(br,1H,3-NH) 8.22〜8.14(d,1H,6-CH,J＝8Hz) 5.92〜5.60(d,2H,C＝CH2) 1.96(s,3H,-CH3) Mass(m/e)198(M+) UV(E+OH)〔λ，nm〕265.8,205.8 （ト）効果 本発明は制癌作用を有する新規ウラシル誘導体を提供す
るものである。Melting point 147.0-148.0 ° C NMR (δ, DMSO-d 6 , ppm) 12.12 (br, 1H, 3-NH) 8.22-8.14 (d, 1H, 6-CH, J = 8Hz) 5.92-5.60 (d, 2H, C = CH 2) 1.96 (s , 3H, -CH 3) Mass (m / e) 198 (M +) UV (E + OH) [lambda, nm] 265.8,205.8 (g) effect invention carcinostatic action The present invention provides a novel uracil derivative having
又、本発明は反応性に富む活性基、つまりビニール基か
ら成る活性基を有する化合物を提供されるものである。
尚、これらの活性基を利用して、更により優れた制癌作
用を有する新規ウラシル誘導体の合成が可能となる。
又、高分子化合物とすることによって薬理活性基（５−
ＦＵ）の放出コントロールが可能となり、薬理活性の持
続化及び副作用の低減が期待できる。The present invention also provides a compound having an active group having a high reactivity, that is, an active group consisting of a vinyl group.
By utilizing these active groups, it becomes possible to synthesize a novel uracil derivative having an even more excellent antitumor effect.
In addition, by using a high molecular compound, the pharmacologically active group (5-
It is possible to control the release of FU), and it is expected that the pharmacological activity is sustained and side effects are reduced.
このように本発明は制癌作用を有する化合物を合成する
ための貴重な中間化合物として極めて重要な化合物であ
る。Thus, the present invention is a very important compound as a valuable intermediate compound for synthesizing a compound having an antitumor effect.
Claims (1)
ル基、Ｒ2は （式中、Ｒ3は水素原子又は低級アルキル基を表わ
す）〕で表わされるウラシル誘導体。1. A general formula (I) [In the formula, R 1 is a hydrogen atom, a halogen atom or a lower alkyl group, and R 2 is (In the formula, R 3 represents a hydrogen atom or a lower alkyl group)].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60082016A JPH0625163B2 (en) | 1985-04-16 | 1985-04-16 | Uracil derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60082016A JPH0625163B2 (en) | 1985-04-16 | 1985-04-16 | Uracil derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61246169A JPS61246169A (en) | 1986-11-01 |
| JPH0625163B2 true JPH0625163B2 (en) | 1994-04-06 |
Family
ID=13762722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60082016A Expired - Lifetime JPH0625163B2 (en) | 1985-04-16 | 1985-04-16 | Uracil derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0625163B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08230965A (en) * | 1995-02-22 | 1996-09-10 | Yasui Kk | Fish container made of foamed synthetic resin |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1307786B1 (en) * | 1999-07-22 | 2001-11-19 | Bracco Spa | CERAMID ANALOGS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ANTI-TUMORAL. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5946234B2 (en) * | 1975-11-10 | 1984-11-10 | 旭化成株式会社 | Pyrimidine Luino Seizouhouhou |
| JPS606944B2 (en) * | 1975-11-10 | 1985-02-21 | 旭化成工業株式会社 | Method for producing new uracil derivatives |
-
1985
- 1985-04-16 JP JP60082016A patent/JPH0625163B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08230965A (en) * | 1995-02-22 | 1996-09-10 | Yasui Kk | Fish container made of foamed synthetic resin |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61246169A (en) | 1986-11-01 |
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