JP2838233B2 - 3,4-diphenyl isoxazole derivative - Google Patents
3,4-diphenyl isoxazole derivativeInfo
- Publication number
- JP2838233B2 JP2838233B2 JP30458390A JP30458390A JP2838233B2 JP 2838233 B2 JP2838233 B2 JP 2838233B2 JP 30458390 A JP30458390 A JP 30458390A JP 30458390 A JP30458390 A JP 30458390A JP 2838233 B2 JP2838233 B2 JP 2838233B2
- Authority
- JP
- Japan
- Prior art keywords
- isoxazole derivative
- hydrogen atom
- diphenyl isoxazole
- diphenyl
- group
- 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
Links
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は、新規な物質である3,4−ジフエニルイソキ
サゾール誘導体に関する。The present invention relates to a novel substance, a 3,4-diphenyl isoxazole derivative.
本発明の3,4−ジフエニルイソキサゾール誘導体はプ
ロスタグランジン生合成阻害作用を有しており、抗炎症
剤、鎮痛剤及び解熱剤として有用である。The 3,4-diphenyl isoxazole derivative of the present invention has a prostaglandin biosynthesis inhibitory action and is useful as an anti-inflammatory agent, an analgesic, and an antipyretic.
（従来の技術） 特開昭59−59764号公報には抗炎症、鎮痛、及び解熱
作用を有する化合物として3,4−ジアリールイソキサゾ
ール−５−酢酸類が開示されている。しかしながら上記
化合物の活性は不十分であり、より一層優れた活性を有
する化合物の開発が要望されている。(Prior Art) JP-A-59-59764 discloses 3,4-diarylisoxazole-5-acetic acids as compounds having anti-inflammatory, analgesic, and antipyretic effects. However, the activity of the above compounds is insufficient, and there is a demand for the development of compounds having even better activities.
（発明が解決しようとする課題） 本発明の目的はプロスタグランジン生合成阻害作用を
有し、抗炎症剤、鎮痛剤及び解熱剤として極めて有用な
新規な3,4−ジフエニルイソキサゾール誘導体を提供す
ることにある。(Problems to be Solved by the Invention) An object of the present invention is to provide a novel 3,4-diphenyl isoxazole derivative which has a prostaglandin biosynthesis inhibitory activity and is extremely useful as an anti-inflammatory, analgesic and antipyretic agent. To provide.
（課題を解決するための手段） 本発明は一般式 （式中、R1及びR2は同一又は相異なつて、水素原子、低
級アルコキシ基を、R3及びR4は同一又は相異なつて、水
素原子、炭素数１〜12のアルキル基を示す。又、R3とR4
は互いに結合してアルキレン鎖で環を形成してもよ
い。）で表される3,4−ジフエニルイソキサゾール誘導
体に係る。(Means for Solving the Problems) The present invention has a general formula (Wherein, R 1 and R 2 are the same or different and represent a hydrogen atom or a lower alkoxy group, and R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. Also, R 3 and R 4
May combine with each other to form a ring with an alkylene chain. The present invention relates to 3,4-diphenylisoxazole derivatives represented by the following formula:
上記式中、R1及びR2で表される低級アルコキシ基の好
ましいものは、炭素数１〜６の直鎖又は分枝状のアルコ
キシ基であり、具体的には、メトキシ、エトキシ、プロ
ポキシ、ブトキシ、tert−ブトキシ、ペンチルオクシ、
ヘキシルオキシ基等を、R3及びR4で表されるアルキル基
の好ましいものは、炭素数１〜12の直鎖又は分枝状のア
ルキル基であり、具体的には、メチル、エチル、プロピ
ル、イソプロピル、ブチル、sec−ブチル、tert−ブチ
ル、ペンチル、ヘキシル、オクチル、デシル、ドデシル
基等を例示できる。又、R3とR4が互いに結合してアルキ
レン鎖で環を形成する基としては例えば、 等を例示できる。In the above formula, preferred lower alkoxy groups represented by R 1 and R 2 are linear or branched alkoxy groups having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, propoxy, Butoxy, tert-butoxy, pentyloxy,
Hexyloxy groups and the like, preferred alkyl groups represented by R 3 and R 4 are linear or branched alkyl groups having 1 to 12 carbon atoms, specifically, methyl, ethyl, propyl Isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl groups and the like. Examples of a group in which R 3 and R 4 are bonded to each other to form a ring with an alkylene chain include, for example, Etc. can be exemplified.
一般式（１）で表される本発明の化合物は例えば下記
に示す方法により製造される。The compound of the present invention represented by the general formula (1) is produced, for example, by the following method.
一般式 （式中、R1及びR2は前記に同じ。）で表わされる3,4−
ジフエニルイソキサゾール−５−酢酸類を適当な溶媒
中、縮合剤及び塩基の存在下に一般式 NHR3R4 （３） （式中、R3及びR4は前記に同じ。）で表わされるアミン
類と反応させることにより得ることができる。溶媒とし
ては、本反応に関与したものであれば特に限定されない
が、例えばクロロホルム、ジクロルメタン等のハロゲン
化炭化水素類、アセトニトリル、ベンゼン、ジメチルホ
ルムアミド等の極性溶媒類、ジオキサン、テトラハイド
ロフラン等のエーテル類等が使用できる。縮合剤として
は、シアノリン酸ジエチル等の一般に酸アミドの合成に
使用されるものを用いることができる。塩基としては、
例えばピリジン、ピペラジン、ピペリジン、モルホリ
ン、トリエチルアミン等の有機塩基が挙げられる。一般
式（３）のアミン類、縮合剤及び塩基の量は、一般式
（２）の化合物に対して各々、約１〜２倍モル量の使用
するのが好ましい。反応温度は０〜100℃、好ましくは
５〜50℃である。又、反応は３〜６時間程度で完結す
る。General formula (Wherein, R 1 and R 2 are the same as above.)
Diphenyl isoxazole-5-acetic acid is represented by the general formula NHR 3 R 4 (3) (wherein R 3 and R 4 are as defined above) in a suitable solvent in the presence of a condensing agent and a base. By reacting with amines. The solvent is not particularly limited as long as it participates in the present reaction.Examples include halogenated hydrocarbons such as chloroform and dichloromethane, polar solvents such as acetonitrile, benzene and dimethylformamide, and ethers such as dioxane and tetrahydrofuran. Can be used. As the condensing agent, those generally used for the synthesis of acid amides such as diethyl cyanophosphate can be used. As the base,
For example, organic bases such as pyridine, piperazine, piperidine, morpholine, triethylamine and the like can be mentioned. The amounts of the amines, the condensing agent and the base of the general formula (3) are preferably about 1 to 2 moles per mole of the compound of the general formula (2). The reaction temperature is 0-100 ° C, preferably 5-50 ° C. The reaction is completed in about 3 to 6 hours.
かくして得られた本発明の化合物は通常公知の分離精
製手段、例えば蒸留、再結晶、シリカゲルカラムクロマ
トグラフイー等により単離精製することができる。The compound of the present invention thus obtained can be isolated and purified by generally known separation and purification means, for example, distillation, recrystallization, silica gel column chromatography and the like.
（実 施 例） 次に実施例及び実験例を挙げて本発明を具体的に説明
する。(Examples) Next, the present invention will be specifically described with reference to examples and experimental examples.
実施例１ ５−ジヘキシルアミノカルボニルメチル−3,4−ジ（ｐ
−メトキシフエニル）イソキサゾール（化合物1c）の合
成 3,4−ジ（ｐ−メトキシフエニル）イソキサゾール−
５−酢酸2.5g（7.4ミリモル）、シアノリン酸ジエチル
2.0g（11.1ミリモル）のジメチルホルムアミド10ml溶液
にジヘキシルアミン2.62ml（11.1ミリモル）を撹拌しな
がら加えた。更に、トリエチルアミン1.54ml（11.1ミリ
モル）を加え、12時間室温で撹拌した。次に溶媒を減圧
留去し、残渣に2N−塩酸30mlを加え、エーテル50mlにて
抽出し、飽和食塩水にて洗浄後、無水硫酸マグネシウム
にて乾燥した。エーテルを減圧留去し、残渣はシリカゲ
ルカラムクロマトグラフイーにて単離し、無色油状の５
−ジヘキシルアミノカルボニルメチル−3,4−ジ（ｐ−
メトキシフエニル）イソキサゾール3g（収率80％を得
た。） 1H−NMR（CDCl3,J＝HZ）及び元素分析値を第１表に示
した。Example 1 5-dihexylaminocarbonylmethyl-3,4-di (p
Synthesis of -methoxyphenyl) isoxazole (compound 1c) 3,4-di (p-methoxyphenyl) isoxazole-
2.5 g (7.4 mmol) of 5-acetic acid, diethyl cyanophosphate
To a solution of 2.0 g (11.1 mmol) in 10 ml of dimethylformamide was added 2.62 ml (11.1 mmol) of dihexylamine with stirring. Further, 1.54 ml (11.1 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 12 hours. Next, the solvent was distilled off under reduced pressure, 2N-hydrochloric acid (30 ml) was added to the residue, extracted with ether (50 ml), washed with saturated saline and dried over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain a colorless oily oil.
-Dihexylaminocarbonylmethyl-3,4-di (p-
3 g of methoxyphenyl) isoxazole (80% yield was obtained) 1 H-NMR (CDCl 3 , J = H Z ) and elemental analysis values are shown in Table 1.
実施例２ 実施例１と同様な方法で第１表の化合物1a、1b、1dを
合成した。Example 2 Compounds 1a, 1b and 1d shown in Table 1 were synthesized in the same manner as in Example 1.
実験例１ プロスタグランジン生合成阻害作用は、プロスタグラ
ンジン生合成酵素であるシクロオキシゲナーゼに対する
阻害活性を測定することにより評価した。 Experimental Example 1 The prostaglandin biosynthesis inhibitory activity was evaluated by measuring the inhibitory activity on cyclooxygenase, which is a prostaglandin biosynthesis enzyme.
14C−アラキドン酸のヒツジ精のう腺ミクロゾーム及
び各種濃度の被験薬を一定時間反応させ、生成するプロ
スタグランジンE2を薄膜クロマトグラフイーにより分離
し、その放射活性を液体シチレンーシヨンカウンターで
測定し、対照群との放射活性の比較からIC50を算出し
た。結果を第２表に示した。 14 C-test drug sheep seminal vesicles gland microsomal and various concentrations of arachidonic acid by a predetermined time reactions, prostaglandin E 2 for generating separated by a thin film chromatography, measure its radioactivity in a liquid cytidine Ren over Chillon counter Then, the IC 50 was calculated from the comparison of the radioactivity with the control group. The results are shown in Table 2.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. 6 , DB name) CA (STN) REGISTRY (STN)
Claims (3)
級アルコキシ基を、R3及びR4は同一又は相異なつて、水
素原子、炭素数１〜12のアルキル基を示す。又、R3とR4
は互いに結合してアルキレン鎖で環を形成してもよ
い。）で表わされる3,4−ジフエニルイソキサゾール誘
導体。(1) General formula (Wherein, R 1 and R 2 are the same or different and represent a hydrogen atom or a lower alkoxy group, and R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. Also, R 3 and R 4
May combine with each other to form a ring with an alkylene chain. 3,4-Diphenyl isoxazole derivative represented by the formula:
R4は同一又は相異なつて、水素原子、炭素数１〜12のア
ルキル基、又はR3とR4は互いに結合してピペリジン環で
ある請求項１の3,4−ジフエニルイソキサゾール誘導
体。2. R 1 and R 2 are both a lower alkoxy group, R 3 and
The 3,4-diphenyl isoxazole derivative according to claim 1, wherein R 4 is the same or different and is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or R 3 and R 4 are bonded to each other to form a piperidine ring. .
子、R4はヘキシル基である請求項２の3,4−ジフエニル
イソキサゾール誘導体。3. The 3,4-diphenyl isoxazole derivative according to claim 2, wherein R 1 and R 2 are both a methoxy group, R 3 is a hydrogen atom and R 4 is a hexyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30458390A JP2838233B2 (en) | 1990-11-08 | 1990-11-08 | 3,4-diphenyl isoxazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30458390A JP2838233B2 (en) | 1990-11-08 | 1990-11-08 | 3,4-diphenyl isoxazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04173780A JPH04173780A (en) | 1992-06-22 |
| JP2838233B2 true JP2838233B2 (en) | 1998-12-16 |
Family
ID=17934745
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30458390A Expired - Lifetime JP2838233B2 (en) | 1990-11-08 | 1990-11-08 | 3,4-diphenyl isoxazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2838233B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5633272A (en) * | 1995-02-13 | 1997-05-27 | Talley; John J. | Substituted isoxazoles for the treatment of inflammation |
| RU2200158C2 (en) * | 1995-02-13 | 2003-03-10 | Джи.Ди.Сирл энд Ко. | Substituted isoxazoles, pharmaceutical composition based on thereof and method of inflammation suppression |
-
1990
- 1990-11-08 JP JP30458390A patent/JP2838233B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04173780A (en) | 1992-06-22 |
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