JPS6217998B2 - - Google Patents
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- Publication number
- JPS6217998B2 JPS6217998B2 JP58104639A JP10463983A JPS6217998B2 JP S6217998 B2 JPS6217998 B2 JP S6217998B2 JP 58104639 A JP58104639 A JP 58104639A JP 10463983 A JP10463983 A JP 10463983A JP S6217998 B2 JPS6217998 B2 JP S6217998B2
- Authority
- JP
- Japan
- Prior art keywords
- benzylazetidin
- diphenyl
- oxygen species
- general formula
- active oxygen
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は一般式（）
で示される３・４−ジフエニル−１−ベンジルア
ゼチジン−２−オンの製造法に関する。従来アゼ
チジン−２−オンの骨格を持つ化合物については
抗生物質を除くとその薬理作用は殆んど知られて
いない。本発明者らはアゼチジン−２−オンと同
様な環状アミド構造を有するバルビツールやヒダ
ントインが各々催眠、鎮静作用などの中枢神経作
用や抗てんかん作用を有することからアゼチジン
−２−オンの薬理作用について種々検討の結果本
発明に到達した。[Detailed Description of the Invention] The present invention relates to the general formula () The present invention relates to a method for producing 3,4-diphenyl-1-benzylazetidin-2-one shown in the following. Conventionally, little is known about the pharmacological effects of compounds having an azetidin-2-one skeleton, except for antibiotics. The present inventors have investigated the pharmacological effects of azetidin-2-one because barbiturates and hydantoins, which have a cyclic amide structure similar to azetidin-2-one, have central nervous effects such as hypnosis and sedation, and antiepileptic effects, respectively. As a result of various studies, we have arrived at the present invention.
上記（）式に示される３・４−ジフエニル−
１−ベンジルアゼチジン−２−オンは抗炎症剤と
して有用性を持つ化合物である。 3,4-diphenyl- shown in the above formula ()
1-Benzylazetidin-2-one is a compound that has utility as an anti-inflammatory agent.
炎症作用には活性酸素種が深く関与しているこ
とは周知である。したがつて抗炎症作用を判定す
るにあたつて薬剤の活性酸素種に対する抑制効果
をみることは非常に有効な手段である。しかしな
がらこの抑制効果の判定には技術的な困難さがあ
りこれまで信頼性のあるデータを得る手段がなか
つた。最近化学発光法により活性酸素種の濃度を
精度、再現性ともによく検出する方法が確立さ
れ、この方法が薬剤の活性酸素種抑制効果を伴定
する一手段となつた。この方法により一般式
（Ｉ）化合物と従来の抗炎症剤との作用を比較す
ると、たとえば活性酸素種を70％抑制する薬剤の
濃度は従来の抗炎症剤インドメタシンやジクロロ
フエナツクナトリウムが10-3mol／あるいはそ
れ以上に対し一般式（）化合物は10-4mol／
以下であり10倍以上強い活性酸素種抑制効果をも
つ（第１図、第２図参照）。 It is well known that reactive oxygen species are deeply involved in inflammatory effects. Therefore, observing the inhibitory effect of a drug on active oxygen species is a very effective means for determining the anti-inflammatory effect. However, there are technical difficulties in determining this inhibitory effect, and until now there has been no means to obtain reliable data. Recently, a method for detecting the concentration of active oxygen species with good accuracy and reproducibility using chemiluminescence has been established, and this method has become a means of determining the active oxygen species suppressing effect of drugs. Comparing the effects of the compound of general formula (I) and conventional anti-inflammatory drugs using this method, it was found that, for example, the concentration of the drug that suppresses active oxygen species by 70% was 10 -3 compared with the conventional anti-inflammatory drugs indomethacin and dichlorofenac sodium. mol/or more, whereas the compound of general formula () is 10 -4 mol/
It has a more than 10 times stronger active oxygen species suppression effect (see Figures 1 and 2).
一般式（）化合物はケテンをイミンと環化付
加させる一般的な方法やアミノカルボン酸からの
閉環反応等でも合成可能である。しかしケテンは
不安定な化合物で取扱いに非常な注意を要する
し、アミノカルボン酸を用いる方法では原料の合
成に数段階を要し、しかも適応範囲は広いと言い
難い。本発明者らは種々検討の結果これらの一般
法に比較して工業的に有用なアゼチジン−２−オ
ンの製法についての発明を完成した。 The compound of the general formula () can be synthesized by a general method of cycloaddition of ketene with an imine, or by a ring-closing reaction from an aminocarboxylic acid. However, ketene is an unstable compound and must be handled with great care, and the method using aminocarboxylic acids requires several steps to synthesize the raw materials, and it cannot be said that the range of application is wide. As a result of various studies, the present inventors have completed the invention of a method for producing azetidin-2-one, which is industrially more useful than these general methods.
すなわち本発明は２・３−ジフエニルシクロプ
ロペノン又は１・３−ジハロ−１・３−ジフエニ
ルプロパノンとベンジルアミンを反応させること
を特徴とする上記一般式（）で示される３・４
−ジフエニル−１−ベンジルアゼチジン−２−オ
ンの製法である。 That is, the present invention is characterized in that 2,3-diphenylcyclopropenone or 1,3-dihalo-1,3-diphenylpropanone and benzylamine are reacted.
This is a method for producing -diphenyl-1-benzylazetidin-2-one.
これらの反応は不活性有機溶剤中において室温
もしくは室温より低温で反応させることが好まし
い。また１・３−ジハロ−１・３−ジフエニルプ
ロパノンを用いる方法においては生成するハロゲ
ン化水素の受酸剤の存在下で行うことが望まし
い。不活性有機溶剤としてはベンゼン、トルエ
ン、ジオキサン、テトラヒドロフラン、ジエチル
エーテル、アセトニトリル、トリエチルアミン等
が挙げられる。また受酸剤としてはアルカリ金属
の炭酸塩、アルカリ土類金属の炭酸塩、トリエチ
ルアミン、ピリジン等のアミン類が挙げられる。
この反応溶液は減圧濃縮しクロマト分離すること
により３・４−ジフエニル−１−ベンジルアゼチ
ジン−２−オンが得られる。本発明法によれば原
料も容易に合成できまた安定であり、操作も簡単
で反応条件も調節し易い等多くの利点を有する。 These reactions are preferably carried out in an inert organic solvent at room temperature or a temperature lower than room temperature. Further, in the method using 1,3-dihalo-1,3-diphenylpropanone, it is desirable to carry out the reaction in the presence of an acid acceptor for the hydrogen halide produced. Examples of the inert organic solvent include benzene, toluene, dioxane, tetrahydrofuran, diethyl ether, acetonitrile, and triethylamine. Examples of acid acceptors include carbonates of alkali metals, carbonates of alkaline earth metals, and amines such as triethylamine and pyridine.
This reaction solution is concentrated under reduced pressure and subjected to chromatographic separation to obtain 3,4-diphenyl-1-benzylazetidin-2-one. The method of the present invention has many advantages, such as the raw materials can be easily synthesized and is stable, the operation is simple, and the reaction conditions are easy to adjust.
一般式（）化合物は解熱鎮痛消炎剤、抗アレ
ルギー剤、免疫調整剤などの用途が期待できる。 Compounds of general formula () can be expected to have uses such as antipyretic, analgesic, and antiinflammatory agents, antiallergic agents, and immunomodulators.
実施例 １
２・３−ジフエニルシクロプロペノン水和物10
ｇ（44.6ミリモル）を減圧下60℃で加熱乾燥した
後、無水テトラヒドロフラン100mlを加えて溶液
とし、ベンジルアミン9.54ｇ（89.2ミリモル）を
この溶液に加え、一晝夜室温で反応させる。この
反応溶液を減圧濃縮しアルミナを用いてカラムク
ログラフイーで分離し、３・４−ジフエニル−１
−ベンジルアゼチジン−２−オンのシス体3.20ｇ
（収率23％）、トランス体6.00ｇ（収率43％）を
各々無色プリズム状結晶、油状物質として得た。Example 1 2,3-diphenylcyclopropenone hydrate 10
g (44.6 mmol) was dried by heating at 60° C. under reduced pressure, 100 ml of anhydrous tetrahydrofuran was added to form a solution, and 9.54 g (89.2 mmol) of benzylamine was added to this solution, followed by reaction overnight at room temperature. This reaction solution was concentrated under reduced pressure and separated by column chromatography using alumina, and 3,4-diphenyl-1
-3.20g of cis isomer of benzylazetidin-2-one
(Yield: 23%) and trans isomer (6.00 g: Yield: 43%) were obtained as colorless prismatic crystals and an oily substance, respectively.
シス体；融点144−145℃、IR1750（Ｃ＝Ｏ）
cm-1、NMRδ3.78（ｄ、1H）、4.88（ｄ、1H）、
4.69（ｓ、2H）、6.94（ｓ、10H）、7.20（ｓ、
5H）、Massｍ／e313（M+）。 Cis form; melting point 144-145℃, IR1750 (C=O)
cm -1 , NMRδ3.78 (d, 1H), 4.88 (d, 1H),
4.69 (s, 2H), 6.94 (s, 10H), 7.20 (s,
5H), Massm/e313 (M + ).
元素分析 C22H19NO 測定値 Ｃ 84.11％、Ｈ 6.05％、 計算値 Ｃ 84.31％、Ｈ 6.11％。Elemental analysis C 22 H 19 NO Measured values C 84.11%, H 6.05%, calculated values C 84.31%, H 6.11%.
トランス体；油状物質IR1750（Ｃ＝Ｏ）cm-1、
NMRδ3.77（ｄ、1H）、4.88（ｄ、1H）、4.09
（ｄ、1H）、4.21（ｄ、1H）、7.14（ｓ、10H）、
7.29（ｓ、5H）、Massｍ／e313（M+）。 Trans form; oily substance IR1750 (C=O) cm -1 ,
NMRδ3.77 (d, 1H), 4.88 (d, 1H), 4.09
(d, 1H), 4.21 (d, 1H), 7.14 (s, 10H),
7.29 (s, 5H), Massm/e313 (M + ).
元素分析 C22H19NO 測定値 Ｃ 83.98％、Ｈ 6.09％、 計算値 Ｃ 84.31％、Ｈ 6.11％。Elemental analysis C 22 H 19 NO Measured values C 83.98%, H 6.09%, calculated values C 84.31%, H 6.11%.
実施例 ２
１・３−ジブロモ−１・３−ジフエニルプロパ
ノン−２、8.15ｇのテトラヒドロフラン100ml溶
液を氷冷下撹拌しながらトリエチルアミン８mlを
含むテトラヒドロフラン50ml中に滴下した後、反
応液にさらにベンジルアミン4.7ｇを滴下し、一
晝液室温で反応させる。反応混合物を濾別して臭
化水素酸塩を除き、濾液を減圧濃縮しアルミナを
用いてカラムクロマトグラフイーで分離し実施例
１と同様の３・４−ジフエニル−１−ベンジルア
ゼチジン−２−オンのシス体1.45ｇ、トランス体
2.42ｇを得た。Example 2 A solution of 8.15 g of 1,3-dibromo-1,3-diphenylpropanone-2 in 100 ml of tetrahydrofuran was added dropwise to 50 ml of tetrahydrofuran containing 8 ml of triethylamine while stirring under ice cooling, and then benzyl was added to the reaction solution. Add 4.7 g of amine dropwise and allow to react at room temperature overnight. The reaction mixture was filtered to remove hydrobromide, and the filtrate was concentrated under reduced pressure and separated by column chromatography using alumina to obtain 3,4-diphenyl-1-benzylazetidin-2-one as in Example 1. 1.45g of cis form, trans form of
2.42g was obtained.
第１図、第２図は本発明法による化合物と従来
品とを用いた場合の活性酸素種に対する薬剤の抑
制作用（化学発光法による）を表わすグラフで第
１図の試料は全血液細胞、第２図の試料は腹腔膜
マクロフアージである。
〇……３・４−ジフエニル−１−ベンジルアゼ
チジン−２−オン、●……インドメタシン、△…
…ジクロフエナツクナトリウム。
Figures 1 and 2 are graphs showing the inhibitory effect of drugs on active oxygen species (by chemiluminescence method) when using the compound according to the present invention and the conventional product.The samples in Figure 1 are whole blood cells, The sample in Figure 2 is a peritoneal macrophage. 〇...3,4-diphenyl-1-benzylazetidin-2-one, ●...Indomethacin, △...
...Diclofenuc sodium.
Claims (1)
１・３−ジハロ−１・３−ジフエニルプロパノン
とベンジルアミンとを反応させることを特徴とす
る一般式（） で示される３・４−ジフエニル−１−ベンジルア
ゼチジン−２−オンの製法。[Claims] 1 General formula () characterized by reacting 2,3-diphenylcyclopropenone or 1,3-dihalo-1,3-diphenylpropanone with benzylamine A method for producing 3,4-diphenyl-1-benzylazetidin-2-one shown by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58104639A JPS6075457A (en) | 1983-06-11 | 1983-06-11 | 3,4-diphenyl-1-benzylaztidin-2-one and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58104639A JPS6075457A (en) | 1983-06-11 | 1983-06-11 | 3,4-diphenyl-1-benzylaztidin-2-one and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6075457A JPS6075457A (en) | 1985-04-27 |
| JPS6217998B2 true JPS6217998B2 (en) | 1987-04-21 |
Family
ID=14386016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58104639A Granted JPS6075457A (en) | 1983-06-11 | 1983-06-11 | 3,4-diphenyl-1-benzylaztidin-2-one and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6075457A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101541805A (en) | 2006-09-15 | 2009-09-23 | 先灵公司 | Azetidine and azetidinone derivatives for the treatment of pain and disorders of lipid metabolism |
| CA2663500A1 (en) | 2006-09-15 | 2008-03-20 | Schering Corporation | Spiro-condensed azetidine derivatives useful in treating pain, diabetes and disorders of lipid metabolism |
-
1983
- 1983-06-11 JP JP58104639A patent/JPS6075457A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6075457A (en) | 1985-04-27 |
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