JPS606955B2 - Process for producing new thienodiazepine derivatives - Google Patents
Process for producing new thienodiazepine derivativesInfo
- Publication number
- JPS606955B2 JPS606955B2 JP50043497A JP4349775A JPS606955B2 JP S606955 B2 JPS606955 B2 JP S606955B2 JP 50043497 A JP50043497 A JP 50043497A JP 4349775 A JP4349775 A JP 4349775A JP S606955 B2 JPS606955 B2 JP S606955B2
- Authority
- JP
- Japan
- Prior art keywords
- thieno
- dihydro
- compound
- acid
- diazepine
- 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
Links
Description
【発明の詳細な説明】
本発明は一般式
で表わされる新規なチェノジアゼビン誘導体の製法に関
するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel chenodiazebin derivative represented by the general formula.
式中、Ｘはハロゲン（ＣＩ，Ｂｒ，Ｆなど）を示し、Ｒ
は水素、低級アルキル（メチル、エチル、プロピル、イ
ソプロピル、プチルなど）を示す。In the formula, X represents halogen (CI, Br, F, etc.), and R
represents hydrogen, lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, etc.).
本発明によれば、一般式（１）で表わされる化合物は、
一般式（式中、×，Ｒは前述と同義である。According to the present invention, the compound represented by general formula (1) is
General formula (wherein x and R have the same meanings as above.
）で表わされる化合物を鍵金属水素化物で還元すること
により製造される。) is produced by reducing the compound represented by the formula with a key metal hydride.
還元剤である鍔金属水素化物としては、たとえば、水素
化ホウ素ナトリウム、水素化ホウ素リチウム、水素化ア
ルミニウムリチウム、水素化アルミニウムナトリウム、
水素化モノ（又はジ又はトリ）アルコキシアルミニウム
リチウム（又はナトリウム）、或いはソジウムジヒドロ
ピス（２−メトキシェトキシ）アルミネートなどが挙げ
られる。Examples of the tsuba metal hydride which is a reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium aluminum hydride,
Examples include lithium (or sodium) mono(or di- or tri)alkoxyaluminum hydride, or sodium dihydropis(2-methoxyshethoxy)aluminate.
反応は通常溶媒中で室温ないいま溶媒の沸点下で数分な
いし数時間行われる。The reaction is usually carried out in a solvent at room temperature or below the boiling point of the solvent for several minutes to several hours.
又、必要に応じて冷却下反応させることも出来る。溶媒
としては、還元剤の種類により異なるが、たとえば、水
、アルコール（メタノール、エタノール、プロパノール
、イソプロパノールなど）、エーテル類（ジェチルェー
テル、ジブチルェーナル、テトラヒドロフラン、ジオキ
サン、モノグラィム、ジグラィムなど）、芳香族炭化水
素類（ベンゼン、トルエン、キシレンなど）、ピリジン
など或いはこれらの混合溶媒などの中から反応を阻害し
ない溶媒を適宜選択して用いられる。Moreover, the reaction can be carried out under cooling if necessary. Examples of solvents include water, alcohols (methanol, ethanol, propanol, isopropanol, etc.), ethers (dietyl ether, dibutylene, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), and aromatic hydrocarbons, although they vary depending on the type of reducing agent. A solvent that does not inhibit the reaction is appropriately selected from among (benzene, toluene, xylene, etc.), pyridine, etc., or a mixed solvent thereof.
なお、水酸化ホウ素ナトリウムなどの様な緩和な還元剤
を使用すればＣ−７位のアセチル基のみ選択的に還元さ
れるが、水酸化アルミニウムリチウムむどの様な強い還
元剤を使用する場合、Ｃ−７位のァセチル基のほかにア
ミド基も還元されるので、たとえば、低温で反応させる
など反応条件を弱くする必要がある。Note that if a mild reducing agent such as sodium boron hydroxide is used, only the acetyl group at the C-7 position is selectively reduced, but if a strong reducing agent such as lithium aluminum hydroxide is used, Since the amide group in addition to the acetyl group at the C-7 position is reduced, it is necessary to weaken the reaction conditions, for example, by conducting the reaction at a low temperature.
一般式〔１〕の化合物は分子内に不整炭素原子１個を有
するので光学異性体を有し通常ラセミ体として得られる
が、必要に応じてそれぞれの光学異性体に分割すること
も出釆る。The compound of general formula [1] has one asymmetric carbon atom in the molecule, so it has optical isomers and is usually obtained as a racemate, but it can also be separated into each optical isomer if necessary. .
かくして得られた一般式〔１〕の化合物は、無機酸（た
とえば、塩酸、硫酸、臭化水素酸など）或いは有機酸（
メタンスルホン酸、パラトルェンスルホン酸、酢酸、し
ゆう酸、マレィン酸、フマール酸、クエン酸など）と処
理することにより酸付加塩とすることも出来る。The compound of the general formula [1] thus obtained can be oxidized with an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) or an organic acid (such as hydrobromic acid, hydrobromic acid, etc.).
Acid addition salts can also be obtained by treatment with methanesulfonic acid, paratoluenesulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, etc.).
一般式〔１〕の化合物及びその酸付加塩は、鎮痛、抗炎
症、鎮静、筋弛緩、抗ケィレン作用などを有しており、
医薬品として有用である。The compound of general formula [1] and its acid addition salts have analgesic, anti-inflammatory, sedative, muscle relaxing, anti-sedative effects, etc.
Useful as a medicine.
次に、本発明による化合物と既知の類似化合物との抗ケ
ィレン作用に関する薬理比較試験を示す。Next, a pharmacological comparative test regarding the anti-inflammatory effect of the compound according to the present invention and a known similar compound will be shown.
本発明による化合物は後述の実施例で得られた化合物を
用い、比較対象としては侍開昭４７−３４３９１号公報
、特関昭４７−４２７９４号公報および西独国特許出願
公開第１９６１７２７号明細書に開示されている化合物
のうち、それぞれの代表的化合物を用いた。Compounds according to the present invention are those obtained in the Examples described below, and for comparison, those disclosed in Samurai Publication No. 47-34391, Tokkoku-Kei Publication No. 47-42794, and West German Patent Application Publication No. 1961727 are used as compounds according to the present invention. Among the disclosed compounds, representative compounds were used.
方法
一群６匹からなるマウスに試験化合物を腹腔内投与し、
１５分後にベンチレンテトラゾール１５０の９／ｋｇを
皮下投与した。Method A test compound was administered intraperitoneally to a group of 6 mice,
Fifteen minutes later, 9/kg of Bentilenetetrazole 150 was administered subcutaneously.
ベンチレンテトラゾール投与３時間後、死亡したマウス
数を教え、致死率を５０％抑制するに必要な試験化合物
の投与量（ＥＤ５。Three hours after administration of ventrenetetrazole, the number of mice that died was determined and the dose of test compound required to inhibit mortality by 50% (ED5).
値）を求めて、抗ケイレン作用の指標とした。この結果
を第１表に示す。value) was determined and used as an index of anti-sedation effect. The results are shown in Table 1.
結果 第１表 試験化合物Ａ〜Ｆは、次の通りである。result Table 1 Test compounds A to F are as follows.
Ａ；５−（ｏ−クロロフエニル）−７−（１ーハイドロ
キシエチル）−１，３ージヒドロ−２日−チエノー〔２
，３一ｅ〕−１，４−ジアゼピンー２ーオン（本発明の
実施例１の化合物）
Ｂ：１ーメチルー５一（ｏークロロフエニル）一７一（
１−ハイドロキシエチル）−１，３−ジヒドロー２日ー
チエノー〔２，３−ｅ〕−１，４ージアゼピンー２ーオ
ン（本発明の実施例２の化合物）
Ｃ：５−ｏ−クロロフエニルー７ーエチル一２，３−ジ
ヒドローＩＨーチエノ−〔２，３一ｅ〕〔１，４〕ジア
ゼピン（特関昭４７一３４３９１号公報の化合物）Ｄ：
１−メチルカルバモイルー５一ｏ−クロロフエニルー７
ーエチル−２，３ージヒドロ−ＩＨ−チエノー〔２，３
一ｅ〕〔１，４〕ジアゼピン（特関昭４７−４２７９４
号公報の化合物）Ｅ：７ークロロー１，３−ジヒドロー
５ーフエニル−２日ーチエノ〔２，３一ｅ〕−１，４ー
ジアゼピンー２−オン（西独国特許出願公開第１９６１
７２７号明細書の化合物）Ｆ：７−クロロー１，３ージ
ヒドロー１ーメチルー５−フエニルー２Ｈ−チエノ〔２
，３一ｅ〕一１，４ージアゼピン−２−オン（西独国特
許出願公開第１９６１７２７号明細書の化合物）本発明
によって、たとえば次の様なチェノジアゼピン誘導体が
製造される。A; 5-(o-chlorophenyl)-7-(1-hydroxyethyl)-1,3-dihydro-2day-thieno [2
,31e]-1,4-diazepine-2-one (compound of Example 1 of the present invention) B:1-methyl-51(o-chlorophenyl)171(
1-hydroxyethyl)-1,3-dihydro-thieno[2,3-e]-1,4-diazepine-2-one (compound of Example 2 of the present invention) C: 5-o-chlorophenyl-7-ethyl-2, 3-dihydro IH-thieno-[2,31e][1,4]diazepine (compound disclosed in Tokokukan Sho 47-34391) D:
1-methylcarbamoyl-5-o-chlorophenyl-7
-ethyl-2,3-dihydro-IH-thieno [2,3
1e] [1,4] Diazepine (Tokukan Sho 47-42794
Compound of Publication No. 1) E: 7-chloro-1,3-dihydro-5-phenyl-2-thieno[2,31e]-1,4-diazepine-2-one (West German Patent Application Publication No. 1961)
Compound of No. 727 specification) F: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-thieno[2
, 31e] 1,4-Diazepin-2-one (Compound of German Patent Application No. 1961727) According to the present invention, for example, the following chenodiazepine derivatives are produced.
ｏ５一（ｏークロロフエニル）−７一（１ーハイドロキ
シェチル）‐１，３‐ジヒドｏ−が‐チエノ−〔２，３
一ｅ〕−１，４−ジアゼピン−２−オンｏ５一（ｏ−プ
ロモフエニル）−７一（１ーハイドロキシエチル）一１
，３ージヒドロー２Ｈ−チエノ−〔２，３−ｅ〕‐１，
４ージアゼピン−２ーオンｏ５一（〇ーフルオロフエニ
ル）−７一（１ーハィドｏキシェチル）‐１，３‐ジヒ
ドローが−チエノー〔２，３−ｅ〕−１，４−ジアゼピ
ンー２ーオンｏ１ーメチルー５−（ークロロフエニル）
一７−（１ーハイドロキシエチル）一１，３−ジヒドロ
ー２日ーチエノ〔２，３一ｅ〕一１，４ージアゼピン−
２ーオンｏ１ーメチル−５−（ｏ−ブロモフエニル）−
７一（１ーハイドロキシヱチル）−１，３ージヒドロー
２日ーチエノ〔２，３−ｅ〕−１，４ージアゼピン−，
２−オンｏ１ーメチル−５一（ｏーフルオロフエニル）
一７−（１ーハイドロキシエチル）−１，３ージヒドロ
ー２Ｈ−チエノ〔２，３−ｅ〕一１，４−ジアゼピン−
２−オン次に若干の実施例を挙げて本発明を更に具体的
に説明する。o5-(o-chlorophenyl)-7-(1-hydroxyethyl)-1,3-dihydro-thieno-[2,3
1e]-1,4-diazepin-2-one o5-(o-promophenyl)-7-(1-hydroxyethyl)-1
, 3-dihydro 2H-thieno-[2,3-e]-1,
4-Diazepin-2-one o5-(〇-fluorophenyl)-7-(1-hydroxethyl)-1,3-dihydro-thieno[2,3-e]-1,4-diazepine-2-one o1-methyl-5 -(-chlorophenyl)
-7-(1-hydroxyethyl)-1,3-dihydro-2day-thieno[2,31e]-1,4-diazepine-
2-one o1-methyl-5-(o-bromophenyl)-
7-(1-hydroxyethyl)-1,3-dihydro 2day-thieno[2,3-e]-1,4-diazepine-,
2-one o1-methyl-5-(o-fluorophenyl)
-7-(1-hydroxyethyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-
2-one Next, the present invention will be explained in more detail with reference to some examples.
実施例 １
５−（ｏークロロフエニル）一７−アセチルー１，３ー
ジヒドロー２日ーチヱノ〔２，３一ｅ〕一１，４ージア
ゼピンー２−オン ６．３夕をエタノール４０の‘に溶
解し、これに水素化ホウ素ナトリウム０．８夕を加えて
室温で４時間燈杵する。Example 1 5-(o-chlorophenyl)-17-acetyl-1,3-dihydro-2-thieno[2,31e]-1,4-diazepine-2-one 6.3 days was dissolved in 40 parts of ethanol and added to it. Add 0.8 g of sodium borohydride and heat at room temperature for 4 hours.
次にこれを氷水に注ぎクロロホルムで抽出する。水洗、
無水硫酸マグネシウムで乾燥後、クロロホルムを減圧留
去する。残査を酢酸エチルで再結晶すると、５一（ｏ−
クロロフエニル）一７−（１−ハイドロキシエチル）−
１，３ージヒドロー２日ーチエノー〔２，３−ｅ〕−１
，４ージアゼピンー２−オンを白色結晶として得る。融
点２１５午○実施例 ２水素化ホウ素ナトリウム０．７
９をエタノール３０ｗ‘及び水１の‘に溶解し、これに
１ーメチルー５−（ｏークロロフエニル）一７ーアセチ
ル−１，３−ジヒドロ−２日ーチエノ〔２，３−ｅ〕１
，４−ジアゼピン−２ーオン６９をエタノール２０の【
に溶解した液を室温で滴下する。Next, pour this into ice water and extract with chloroform. washing with water,
After drying over anhydrous magnesium sulfate, chloroform is distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give 5-(o-
chlorophenyl)-7-(1-hydroxyethyl)-
1,3-dihydro 2 days-thieno [2,3-e]-1
, 4-diazepine-2-one is obtained as white crystals. Melting point 215 pm ○Example Sodium diborohydride 0.7
9 was dissolved in 30w' of ethanol and 1 part' of water, and 1-methyl-5-(o-chlorophenyl)-7-acetyl-1,3-dihydro-2day-thieno[2,3-e]1
, 4-diazepin-2-one 69 in ethanol 20 [
Add the solution dissolved in the solution dropwise at room temperature.
Claims (1)
特徴とする、一般式▲数式、化学式、表等があります▼ で表わされるチエノジアゼピン誘導体の製法。 （上記式中、Ｒは水素、低級アルキルを、Ｘはハロゲン
を示す。）[Claims] 1 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ which is characterized by reducing a compound represented by the following with a complex metal hydride. A method for producing the expressed thienodiazepine derivatives. (In the above formula, R represents hydrogen or lower alkyl, and X represents halogen.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50043497A JPS606955B2 (en) | 1975-04-09 | 1975-04-09 | Process for producing new thienodiazepine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50043497A JPS606955B2 (en) | 1975-04-09 | 1975-04-09 | Process for producing new thienodiazepine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS51118785A JPS51118785A (en) | 1976-10-18 |
| JPS606955B2 true JPS606955B2 (en) | 1985-02-21 |
Family
ID=12665338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50043497A Expired JPS606955B2 (en) | 1975-04-09 | 1975-04-09 | Process for producing new thienodiazepine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS606955B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008109856A2 (en) * | 2007-03-07 | 2008-09-12 | Xenon Pharmaceuticals Inc. | Methods of using diazepinone compounds in treating sodium channel-mediated diseases or conditions |
-
1975
- 1975-04-09 JP JP50043497A patent/JPS606955B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51118785A (en) | 1976-10-18 |
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