JPH0262553B2 - - Google Patents
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- Publication number
- JPH0262553B2 JPH0262553B2 JP930384A JP930384A JPH0262553B2 JP H0262553 B2 JPH0262553 B2 JP H0262553B2 JP 930384 A JP930384 A JP 930384A JP 930384 A JP930384 A JP 930384A JP H0262553 B2 JPH0262553 B2 JP H0262553B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- carbon atoms
- acid
- alkyl group
- formula
- 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.)
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- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規なチオフエン誘導体及びその製造
方法に関するものである。
更に詳しく述べれば、本発明は胃、十二指腸か
いよう治療薬として有用な、一般式
K0320
（式中のR1は水素原子、ハロゲン原子又は炭
素数１〜３のアルキル基であり、Ａ及びＢは互い
に同じでも異なつていてもよく、それぞれ炭素数
１〜３のアルキレンであり、R2は水素原子又は
炭素数１〜３のアルキル基である）で表わされる
チオフエン誘導体及びその製造方法に関するもの
である。
本発明の前記一般式(1)で表わされるチオフエン
誘導体は文献未記載の新規化合物であり、人間を
含む哺乳動物において顕著な抗かいよう作用を示
し、胃、十二指腸かいように対する治療及び予防
用医薬品として有用である。
本発明の前記一般式(1)の化合物は、一般式
K0321
（式中のＢは前記と同じ意味をもつ）で表わさ
れるフエニルアルキルカルボン酸の反応性官能的
誘導体と、一般式
K0322
（式中のR1、R2及びＡは前記と同じ意味をも
つ）で表わされるアミノアルキルチオフエン誘導
体とを反応させることによつて製造することがで
きる。
本製造方法で原料として用いられる一般式(2)の
フエニルアルキルカルボン酸は公知化合物であ
り、市販品として入手しうるか、あるいは文献記
載の方法によつて容易に製造することができる。
このような化合物として、フエニル酢酸、フエニ
ルプロピオン酸、フエニル酪酸などをあげること
ができる。
これらのカルボン酸の反応性官能的誘導体とし
ては、酸ハロゲン化物、酸無水物、混合酸無水
物、エステルなどをあげることができ、いずれも
公知の方法に従つて製造することができる。例え
ば酸ハロゲン化物は適当な溶媒中又は無溶媒で、
酸ハロゲン化剤、例えば塩化チオニル、臭化チオ
ニル等と反応させることによつて得られ、混合酸
無水物はクロル炭酸メチル、クロル炭酸エチルな
どのクロル炭酸アルキル又はベンゼンスルホニル
クロリド、ｐ−トルエンスルホニルクロリドなど
のアリールスルホニルクロリドと反応させること
により容易に得られる。
本製造方法でもう一方の原料として用いられる
一般式(3)のアミノアルキルチオフエン誘導体も公
知化合物であり、市販品として入手しうるか、あ
るいは文献記載の方法によつて容易に製造するこ
とができる。このような化合物の例としては、２
−アミノメチルチオフエン、２−メチルアミノメ
チルチオフエン、２−（２−アミノエチル）チオ
フエン、２−（３−アミノプロピル）チオフエン、
３−（２−アミノエチル）チオフエン、２−（２−
アミノエチル）−５−ブロムチオフエン、２−（２
−アミノエチル）−３−メチルチオフエン、２−
（２−アミノエチル）−５−メチルチオフエンなど
をあげることができる。
本製造方法を好適に実施するには、アミノアル
キルチオフエン誘導体(3)を適量のジオキサン−水
（１：１）混合溶媒に溶解し、氷冷下にかきまぜ
ながら、当量のフエニルアルキルカルボン酸(2)の
酸クロリドの無水ジオキサン溶液と当量ないしや
や過剰量の水酸化ナトリウム水溶液を同時に滴下
する。滴下後更に冷却下ないし室温で暫時かきま
ぜ、濃縮後適当な溶媒、例えば塩化メチレンで抽
出する。有機層を希塩酸、水、炭酸水素ナトリウ
ム水溶液及び水で順次洗い、無水硫酸マグネシウ
ム等で乾燥し、減圧下に濃縮する。残留物を常法
により精製して目的物を得る。
このようにして得られる前記一般式(1)の化合物
として、Ｎ−（２−チエニルメチル）フエニルア
セトアミド、Ｎ−メチル−Ｎ−（２−チエニルメ
チル）フエニルアセトアミド、Ｎ−〔２−（２−チ
エニル）エチル〕フエニルアセトアミド、Ｎ−
〔２−（３−メチル−２−チエニル）エチル〕フエ
ニルアセトアミド、Ｎ−〔２−（５−メチル−２−
チエニル）エチル〕フエニルアセトアミド、Ｎ−
〔２−（５−ブロム−２−チエニル）エチル〕フエ
ニルアセトアミド、Ｎ−〔２−（３−チエニル）エ
チル〕フエニルアセトアミド、３−フエニル−Ｎ
−〔２−（２−チエニル）エチル〕プロピオンアミ
ドなどをあげることができる。
本発明の前記一般式(1)で表わされる化合物は文
献未記載の新規化合物であり、種々の動物におけ
る実験かいようの発現に対して顕著な抑制作用を
示す。例えばアスピリン負荷幽門結さつラツトで
のかいよう発現に対して、体重Kg当り数＋mgない
し百数十mgで50％の抑制効果を示し、特にＮ−
〔２−（２−チエニル）エチル〕フエニルアセトア
ミドは43mg／Kgで50％の抑制効果を示す。
このように本発明の一般式１(1)で表わされるチ
オフエン誘導体は人間を含む哺乳動物において顕
著な抗かいよう作用を示し、胃、十二指腸かいよ
うの治療及び予防用医薬品として有用である。
本発明はこのように医薬品として有用な、新規
なチオフエン誘導体を提供するものであり、あわ
せてその製造方法をも提供するものである。
本発明の内容を以下の参考例及び実施例により
更に詳細に説明する。なお、各参考例及び実施例
中の化合物の融点及び沸点はすべて未補正であ
る。
参考例
２−（２−アミノエチル）チオフエン塩酸塩
10.2ｇを酢酸150ml及び水50mlの混液に溶かし、
室温でかき混ぜながら臭素10.0ｇを滴下した。30
分間かき混ぜたのち、反応液を減圧下に濃縮し、
水酸化ナトリウム水溶液を加え、PH11とし、ジエ
チルエーテルで抽出した。抽出液を無水硫酸マグ
ネシウムで乾燥したのち、活性炭で処理し、減圧
下に溶媒を留去した。残留物を減圧蒸留し、沸点
123〜126℃／11.5Torrの２−（２−アミノエチ
ル）−５−ブロムチオフエン10.5ｇを得た。
赤外線吸収スペクトル（液膜）
3375cm-1，3285cm-1
核磁気共鳴スペクトル（90MHz，CDCl3）
δ： 1.16（2H，ｓ），2.80〜3.08（4H，
ｍ），6.61（1H，ｄ），6.87（1H，ｄ）
実施例 １
２−（２−アミノエチル）チオフエン3.0ｇをジ
オキサン15ml及び水15mlの混液に溶かし、氷冷下
にかき混ぜながら、フエニルアセチルクロリド
3.7ｇを無水ジオキサン10mlに溶かした液と水酸
化ナトリウム1.0ｇを水10mlに溶かした液を同時
に滴下したのち、室温で１時間反応させた。反応
液を減圧下に濃縮し、塩酸を加え、PH１としたの
ち、塩化メチレンで抽出し、炭酸水素ナトリウム
水溶液及び水で洗つたのち、無水硫酸マグネシウ
ムで乾燥した。減圧下に溶媒を留去したのち、残
留物を塩化メチレン−フキサンより再結晶し、融
点80〜80.5℃のＮ−〔２−（２−チエニル）エチ
ル〕フエニルアセトアミド2.9ｇを得た。
元素分析値（C14H15NOSとして）
Ｃ％ Ｈ％ Ｎ％
計算値 68.54 6.16 5.71
実測値 68.63 6.17 5.70
赤外線吸収スペクトル（KBr）
3250cm-1，1625cm-1
核磁気共鳴スペクトル（90MHz，d6−DMSO）
δ： 2.95（2H，ｔ），3.15〜3.55（4H，
ｍ），6.7〜7.4（8H，ｍ），8.1（1H，
br）
実施例 ２
対応する原料を用い、実施例１に記載した方法と
同様な操作を行なつて以下の化合物を製造するこ
とができた。
The present invention relates to a novel thiophene derivative and a method for producing the same. More specifically, the present invention describes a drug useful as a therapeutic drug for gastric and duodenal ulcers, which has the general formula K0320 (wherein R 1 is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 3 carbon atoms, and A and B are mutually (which may be the same or different, and each is an alkylene having 1 to 3 carbon atoms, and R2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) and a method for producing the same. . The thiophene derivative represented by the general formula (1) of the present invention is a novel compound that has not been described in any literature, and exhibits a remarkable anti-inflammatory effect in mammals including humans, and is useful as a therapeutic and preventive drug for gastric and duodenal ulcers. It is. The compound of the general formula (1) of the present invention comprises a reactive functional derivative of phenylalkylcarboxylic acid represented by the general formula K0321 (B in the formula has the same meaning as above), and a reactive functional derivative of the phenylalkyl carboxylic acid represented by the general formula K0322 (formula R 1 , R 2 and A have the same meanings as above). The phenylalkylcarboxylic acid of general formula (2) used as a raw material in this production method is a known compound and can be obtained as a commercially available product or can be easily produced by methods described in literature.
Examples of such compounds include phenyl acetic acid, phenylpropionic acid, and phenylbutyric acid. Examples of the reactive functional derivatives of these carboxylic acids include acid halides, acid anhydrides, mixed acid anhydrides, and esters, all of which can be produced according to known methods. For example, an acid halide in a suitable solvent or without a solvent,
The mixed acid anhydride is obtained by reacting with an acid halogenating agent such as thionyl chloride, thionyl bromide, etc., and the mixed acid anhydride is a chloroalkyl carbonate such as methyl chlorocarbonate or ethyl chlorocarbonate, or benzenesulfonyl chloride, p-toluenesulfonyl chloride. It can be easily obtained by reacting with arylsulfonyl chloride such as. The aminoalkylthiophene derivative of general formula (3) used as the other raw material in this production method is also a known compound and can be obtained as a commercial product or easily produced by methods described in literature. Examples of such compounds include 2
-aminomethylthiophene, 2-methylaminomethylthiophene, 2-(2-aminoethyl)thiophene, 2-(3-aminopropyl)thiophene,
3-(2-aminoethyl)thiophene, 2-(2-
aminoethyl)-5-bromothiophene, 2-(2
-aminoethyl)-3-methylthiophene, 2-
Examples include (2-aminoethyl)-5-methylthiophene. To suitably carry out this production method, the aminoalkylthiophene derivative (3) is dissolved in an appropriate amount of dioxane-water (1:1) mixed solvent, and while stirring under ice-cooling, an equivalent amount of phenylalkylcarboxylic acid ( Simultaneously drop the acid chloride solution in 2) in anhydrous dioxane and an equivalent or slightly excess amount of an aqueous sodium hydroxide solution. After the dropwise addition, the mixture is stirred for a while under cooling or at room temperature, concentrated, and then extracted with a suitable solvent such as methylene chloride. The organic layer is washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, etc., and concentrated under reduced pressure. The residue is purified by a conventional method to obtain the desired product. The compounds of general formula (1) thus obtained include N-(2-thienylmethyl)phenylacetamide, N-methyl-N-(2-thienylmethyl)phenylacetamide, N-[2-( 2-thienyl)ethyl]phenylacetamide, N-
[2-(3-methyl-2-thienyl)ethyl]phenylacetamide, N-[2-(5-methyl-2-
thienyl)ethyl]phenylacetamide, N-
[2-(5-bromo-2-thienyl)ethyl]phenylacetamide, N-[2-(3-thienyl)ethyl]phenylacetamide, 3-phenyl-N
-[2-(2-thienyl)ethyl]propionamide and the like can be mentioned. The compound represented by the general formula (1) of the present invention is a novel compound that has not been described in any literature, and exhibits a remarkable suppressive effect on the development of experimental ulcers in various animals. For example, N-mg per kg of body weight to 100-odd mg showed a 50% suppressive effect on the development of canker in aspirin-loaded pylorus-ligated rats.
[2-(2-thienyl)ethyl]phenylacetamide exhibits a 50% inhibitory effect at 43 mg/Kg. As described above, the thiophene derivative represented by the general formula 1(1) of the present invention exhibits a remarkable anti-itch effect in mammals including humans, and is useful as a drug for the treatment and prevention of gastric and duodenal ulcers. The present invention thus provides a novel thiophene derivative useful as a pharmaceutical, and also provides a method for producing the same. The content of the present invention will be explained in more detail with reference to the following reference examples and examples. Note that the melting points and boiling points of the compounds in each Reference Example and Examples are all uncorrected. Reference example 2-(2-aminoethyl)thiophene hydrochloride
Dissolve 10.2g in a mixture of 150ml of acetic acid and 50ml of water,
10.0 g of bromine was added dropwise while stirring at room temperature. 30
After stirring for a minute, the reaction solution was concentrated under reduced pressure.
Aqueous sodium hydroxide solution was added to adjust the pH to 11, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, treated with activated carbon, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure and the boiling point
10.5 g of 2-(2-aminoethyl)-5-bromothiophene was obtained at 123-126°C/11.5 Torr. Infrared absorption spectrum (liquid film) 3375cm -1 , 3285cm -1 Nuclear magnetic resonance spectrum (90MHz, CDCl 3 ) δ: 1.16 (2H, s), 2.80-3.08 (4H,
m), 6.61 (1H, d), 6.87 (1H, d) Example 1 Dissolve 3.0 g of 2-(2-aminoethyl)thiophene in a mixture of 15 ml of dioxane and 15 ml of water, and while stirring under ice cooling, dissolve the phenyl acetyl chloride
A solution of 3.7 g dissolved in 10 ml of anhydrous dioxane and a solution of 1.0 g of sodium hydroxide dissolved in 10 ml of water were simultaneously added dropwise, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and hydrochloric acid was added to adjust the pH to 1, followed by extraction with methylene chloride, washing with an aqueous sodium bicarbonate solution and water, and drying over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from methylene chloride-fuxane to obtain 2.9 g of N-[2-(2-thienyl)ethyl]phenylacetamide having a melting point of 80 to 80.5°C. Elemental analysis value (as C 14 H 15 NOS) C% H% N% Calculated value 68.54 6.16 5.71 Actual value 68.63 6.17 5.70 Infrared absorption spectrum (KBr) 3250cm -1 , 1625cm -1 Nuclear magnetic resonance spectrum (90MHz, d 6 - DMSO) δ: 2.95 (2H, t), 3.15~3.55 (4H,
m), 6.7-7.4 (8H, m), 8.1 (1H,
br) Example 2 The following compound could be produced by using the corresponding raw materials and performing the same operation as described in Example 1.
【表】【table】
Claims (1)
数１〜３のアルキル基であり、Ａ及びＢは互いに
同じでも異なつていてもよく、それぞれ炭素数１
〜３のアルキレンであり、R2は水素原子又は炭
素数１〜３のアルキル基である）で表わされるチ
オフエン誘導体。 ２ 一般式 K0317 （式中のＢは炭素数１〜３のアルキレンである）
で表わされるフエニルアルキルカルボン酸の反応
性官能的誘導体と、一般式 K0318 （式中のR1は水素原子、ハロゲン原子又は炭素
数１〜３のアルキル基であり、Ａは炭素数１〜３
のアルキレンであり、R2は水素原子又は炭素数
１〜３のアルキル基である）で表わされるアミノ
アルキルチオフエン誘導体とを反応させることを
特徴とする、一般式 K0319 （式中のR1、R2、Ａ及びＢは前記と同じ意味を
もつ）で表わされるチオフエン誘導体の製造方
法。[Claims] 1 General formula K0316 (R 1 in the formula is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 3 carbon atoms, and A and B may be the same or different from each other, and each represents a carbon Number 1
-3 alkylene, and R2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. 2 General formula K0317 (B in the formula is alkylene having 1 to 3 carbon atoms)
A reactive functional derivative of phenyl alkylcarboxylic acid represented by the general formula K0318 (in the formula, R 1 is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 3 carbon atoms, and A is a
, and R 2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms). 2 , A and B have the same meanings as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP930384A JPS60152483A (en) | 1984-01-20 | 1984-01-20 | Thiophene derivative and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP930384A JPS60152483A (en) | 1984-01-20 | 1984-01-20 | Thiophene derivative and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60152483A JPS60152483A (en) | 1985-08-10 |
| JPH0262553B2 true JPH0262553B2 (en) | 1990-12-26 |
Family
ID=11716698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP930384A Granted JPS60152483A (en) | 1984-01-20 | 1984-01-20 | Thiophene derivative and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60152483A (en) |
-
1984
- 1984-01-20 JP JP930384A patent/JPS60152483A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60152483A (en) | 1985-08-10 |
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