JPH058197B2 - - Google Patents
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- Publication number
- JPH058197B2 JPH058197B2 JP2065684A JP2065684A JPH058197B2 JP H058197 B2 JPH058197 B2 JP H058197B2 JP 2065684 A JP2065684 A JP 2065684A JP 2065684 A JP2065684 A JP 2065684A JP H058197 B2 JPH058197 B2 JP H058197B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- formula
- compound
- atom
- carbon atoms
- 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
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 alkali metal salt Chemical class 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 150000007979 thiazole derivatives Chemical class 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- PCLITLDOTJTVDJ-UHFFFAOYSA-N Chlormethiazole Chemical compound CC=1N=CSC=1CCCl PCLITLDOTJTVDJ-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 1
- OYELEBBISJGNHJ-UHFFFAOYSA-N 1,3-oxazinan-2-one Chemical compound O=C1NCCCO1 OYELEBBISJGNHJ-UHFFFAOYSA-N 0.000 description 1
- MHIXFTXEAYSDJY-UHFFFAOYSA-N 1,3-oxazolidine-2,4-dione;potassium Chemical compound [K].O=C1COC(=O)N1 MHIXFTXEAYSDJY-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は新奇なチアゾール誘導体に関するもの
である。更に詳しく述べれば、本発明は抗かいよ
う剤として有用な、一般式
（式中のＲは水素原子又は炭素数１〜３のアル
キル基、Ａは炭素数１〜４のアルキレン、Ｂは酸
素原子、ｌ及びｎのいずれか一方は１で、他の一
方は０又は１、ｍは１〜３の整数、但し、ｌ，ｍ
及びｎの総和が３又は４である）で表わされるチ
アゾール誘導体及びその製造方法に関するもので
ある。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel thiazole derivatives. More specifically, the present invention provides compounds of the general formula (In the formula, R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, A is an alkylene having 1 to 4 carbon atoms, B is an oxygen atom, one of l and n is 1, and the other is 0 or 1, m is an integer from 1 to 3, provided that l, m
and the sum of n is 3 or 4) and a method for producing the same.
本発明の前記一般式(1)の化合物は文献未記載の
新規化合物であり、各種実験動物を用いた実験的
かいようの発現に対して顕著な抑制作用を示す。
従つて、本発明の一般式(1)の化合物は人間を含む
哺乳動物の胃、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。 The compound of general formula (1) of the present invention is a novel compound that has not been described in any literature, and exhibits a remarkable inhibitory effect on the development of experimental ulcers using various experimental animals.
Therefore, the compound of general formula (1) of the present invention is useful as a therapeutic and preventive drug for gastric and duodenal ulcers in mammals including humans.
本発明の目的は、このように医薬品として有用
な、新規なチアゾール誘導体を提供することであ
り、更にその製造方法も併せて提供することであ
る。 The object of the present invention is to provide such novel thiazole derivatives useful as pharmaceuticals, and also to provide a method for producing the same.
本発明の前記一般式(1)の化合物は以下のように
して製造することができる。 The compound of the general formula (1) of the present invention can be produced as follows.
即ち、一般式
（式中のＲ及びＡは前記と同じ意味をもち、Ｘ
は塩素原子、臭素原子又はヨウ素原子である）で
表わされるω−ハロアルキルチアゾール誘導体
と、一般式
（式中のＢ，ｌ，ｍ及びｎは前記と同じ意味を
もつ）で表わされる化合物又はそのアルカリ金属
塩とを、塩基性物質の存在下又は非存在下に反応
させることによつて得られる。 That is, the general formula (R and A in the formula have the same meanings as above, and
is a chlorine atom, a bromine atom or an iodine atom), and a ω-haloalkylthiazole derivative represented by the general formula (In the formula, B, l, m and n have the same meanings as above) or an alkali metal salt thereof, in the presence or absence of a basic substance. .
本製造方法で出発原料として用いられる一般式
(2)及び(3)の化合物はいずれも一般に公知の化合物
であり、公知の方法に従つて容易に製造すること
ができる。 General formula used as starting material in this production method
Both compounds (2) and (3) are generally known compounds and can be easily produced according to known methods.
本製造方法を好適に実施するには、一般式(2)の
化合物及び当量の一般式(3)の化合物のアルカリ金
属塩を不活性有機溶媒中、例えばＮ，Ｎ−ジメチ
ルホルムアミド中で１〜十数時間加熱するか、又
は一般式(2)の化合物と当量の一般式(3)の化合物及
び必要量ないし過剰量の塩基性物質、例えば炭酸
カリウムを不活性有機溶媒、例えばＮ，Ｎ−ジメ
チルホルムアミド中で１〜十数時間加熱する。反
応終了後、減圧下に濃縮し、残留物に適量の水を
加え、適当な有機溶媒、例えば塩化メチレンで抽
出する。抽出液を水洗、乾燥後、減圧下に溶媒を
留去し、残留物を常法に従い精製することによつ
て目的物を得る。 To suitably carry out this production method, the compound of general formula (2) and an equivalent amount of the alkali metal salt of the compound of general formula (3) are mixed in an inert organic solvent, for example, N,N-dimethylformamide, from 1 to Either by heating for more than ten hours, or by adding an equivalent amount of the compound of general formula (3) to the compound of general formula (2) and a necessary or excess amount of a basic substance such as potassium carbonate to an inert organic solvent such as N, N- Heat in dimethylformamide for 1 to 10-odd hours. After the reaction is completed, the mixture is concentrated under reduced pressure, an appropriate amount of water is added to the residue, and the mixture is extracted with a suitable organic solvent such as methylene chloride. After washing the extract with water and drying, the solvent is distilled off under reduced pressure, and the residue is purified according to a conventional method to obtain the desired product.
本発明の一般式(1)の化合物で、ｌ及びｎが共に
ｌ，ｍが１又は２である、一般式
（式中のＲ及びＡは前記と同じ意味をもち
m′は１又は２である）で表わされる化合物は、
一般式
（式中のＲ，Ａ及びm′は前記と同じ意味をも
つ）で表わされる化合物に、ホスゲン、Ｎ，
N′−カルボニルジイミダゾールなどのカルボニ
ル化合物を反応させるか、あるいは前記一般式(4)
の化合物に、クロル炭酸メチル、クロル炭酸エチ
ルなどのハロ炭酸エステル誘導体を反応させて、
一般式
（式中のＲ，Ａ及びm′は前記と同じ意味をも
ち、R′は炭素数１〜３のアルキル基である）で
表わされる化合物を製し、これをナトリウムメト
キシドなどの塩基性物質の存在下に加熱すること
などによつても製造することができる。 A compound of the general formula (1) of the present invention, where l and n are both l and m is 1 or 2, (R and A in the formula have the same meanings as above.
m' is 1 or 2),
general formula (in the formula, R, A and m' have the same meanings as above), phosgene, N,
A carbonyl compound such as N′-carbonyldiimidazole is reacted, or the general formula (4)
By reacting the compound with a halocarbonate derivative such as methyl chlorocarbonate or ethyl chlorocarbonate,
general formula (In the formula, R, A, and m' have the same meanings as above, and R' is an alkyl group having 1 to 3 carbon atoms.) It can also be produced by heating in the presence of.
この製造方法において出発原料として用いられ
る一般式(4)の化合物は、一般式
（式中のＲ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アゾール誘導体にア
セトキシアセチルクロリドを反応させたのち加水
分解するか、又はβ−プロピオラクトンを反応さ
せることにより製造することができる。 The compound of general formula (4) used as a starting material in this production method has the general formula Produced by reacting an aminoalkylthiazole derivative represented by the formula (in which R and A have the same meanings as above) with acetoxyacetyl chloride and then hydrolyzing it, or reacting it with β-propiolactone. I can do it.
又、本発明の一般式(1)の化合物で、ｌが０、ｎ
が１、ｍが２又は３である一般式
（式中のＲ及びＡは前記と同じ意味をもち、
m″は２又は３である）で表わされる化合物は、
一般式
（式中のＲ，Ａ及びm″は前記と同じ意味をも
つ）で表わされる化合物に、ホスゲン、Ｎ，
N′−カルボニルジイミダゾールなどのカルボニ
ル化合物を反応させるか、あるいは前記一般式(7)
の化合物に、クロル炭酸メチル、クロル炭酸エチ
ルなどのハロ炭酸エステル誘導体を反応させて、
一般式
（式中のＲ，Ａ，m″及びR′は前記と同じ意味
をもつ）で表わされる化合物を製し、これをナト
リウムメトキシドなどの塩基性物質の存在下に加
熱することなどによつても製造することができ
る。 Further, in the compound of general formula (1) of the present invention, l is 0, n
General formula where is 1 and m is 2 or 3 (R and A in the formula have the same meanings as above,
m″ is 2 or 3),
general formula (in the formula, R, A and m'' have the same meanings as above), phosgene, N,
A carbonyl compound such as N′-carbonyldiimidazole is reacted, or the general formula (7)
By reacting the compound with a halocarbonate derivative such as methyl chlorocarbonate or ethyl chlorocarbonate,
general formula (In the formula, R, A, m'' and R' have the same meanings as above) and by heating it in the presence of a basic substance such as sodium methoxide. can also be manufactured.
この製造方法において出発原料として用いられ
る一般式(7)の化合物は前記一般式(4)の化合物を適
当な還元剤を用いて還元するか、又は前記一般式
(2)の化合物に、一般式
H2Ｎ−（CH2）n″−OH (9)
（式中のm″は前記と同じ意味をもつ）で表わ
される化合物を反応させることによつても容易に
製造することができる。 The compound of general formula (7) used as a starting material in this production method can be obtained by reducing the compound of general formula (4) above using an appropriate reducing agent, or by reducing the compound of general formula (4) above using a suitable reducing agent.
It is also possible to react the compound of (2) with a compound represented by the general formula H 2 N-(CH 2 ) n ''-OH (9) (m'' in the formula has the same meaning as above). Can be easily manufactured.
更に、本発明の一般式(1)の化合物で、ｌが１、
ｎが０、ｍが２又は３である、一般式
（式中のＲ，Ａ及びm″は前記と同じ意味をも
つ）で表わされる化合物は、前記一般式(6)で表わ
されるアミノアルチアゾール誘導体と、一般式
（式中のm″は前記と同じ意味をもつ）で表わ
される環状酸無水物とを加熱することによつても
製造することができる。又、この製造方法におい
て、前記一般式(6)の化合物と一般式(10)の化合物と
を、室温下に反応させて一旦、一般式
（式中のＲ，Ａ及びm″は前記と同じ意味をも
つ）で表わされる化合物を製し、次いでこれを加
熱し閉環させることによつて製造することもでき
る。 Furthermore, in the compound of general formula (1) of the present invention, l is 1,
General formula where n is 0 and m is 2 or 3 The compound represented by (R, A and m'' in the formula have the same meanings as above) is an aminoarthiazole derivative represented by the general formula (6) and the general formula It can also be produced by heating a cyclic acid anhydride represented by (m" in the formula has the same meaning as above). Also, in this production method, the above general formula (6) The compound and the compound of general formula (10) are reacted at room temperature to form the compound of general formula (10). It can also be produced by preparing a compound represented by the formula (in which R, A and m'' have the same meanings as above) and then heating and ring-closing the compound.
このようにして製造される本発明の一般式(1)の
化合物として、例えば３−〔２−（４−メチル−５
−チアゾリル）エチル〕−２，４−オキサゾリジ
ンジオン、３−〔２−（４−メチル−５−チアゾリ
ル（エチル）〕テトラヒドロ−2H−１，３−オキ
サジン−２−オン、Ｎ−｛２−（４−メチル−５−
チアゾリル）エチル〕スクシンイミドなどをあげ
ることができる。 Examples of the compound of general formula (1) of the present invention produced in this way include 3-[2-(4-methyl-5
-thiazolyl)ethyl]-2,4-oxazolidinedione, 3-[2-(4-methyl-5-thiazolyl(ethyl)]tetrahydro-2H-1,3-oxazin-2-one, N-{2-( 4-methyl-5-
Examples include thiazolyl)ethyl]succinimide.
本発明の一般式(1)の化合物の抗かいよう作用
は、各種実験動物を用いた実験的かいようの発現
に対する抑制効果によつて確認される。例えば、
アスピリン負荷幽門結さつラツトでの実験におい
ては、体重Kg当り数十mgないし百数十mg程度の投
与量で良好な抑制効果がみられ、３−〔２−（４−
メチル−５−チアゾリル）エチル〕−２，４−オ
キサゾリジンジオン及びＮ−〔２−（４−メチル−
５−チアゾリル）エチル〕スクシンイミドは30
mg／Kgの投与量で50％以上の抑制効果を発現す
る。 The anti-inflammatory action of the compound of general formula (1) of the present invention is confirmed by its inhibitory effect on the development of experimental ulcers using various experimental animals. for example,
In experiments using aspirin-loaded pylorus-ligated rats, a good suppressive effect was observed at doses ranging from several tens of mg to over 100 mg per kilogram of body weight.
Methyl-5-thiazolyl)ethyl]-2,4-oxazolidinedione and N-[2-(4-methyl-
5-thiazolyl)ethyl]succinimide is 30
It exhibits an inhibitory effect of 50% or more at a dose of mg/Kg.
本発明の一般式(1)の化合物はこのように強い抗
かいよう作用を有しており、人間を含む哺乳動物
の胃、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。 The compound of general formula (1) of the present invention thus has a strong anti-inflammatory effect and is useful as a therapeutic and preventive drug for gastric and duodenal ulcers in mammals including humans.
本発明の内容を、以下に示す実施例によつて更
に詳細に説明する。なお各実施例における化合物
の融点はすべて未補正である。 The content of the present invention will be explained in more detail by the following examples. Note that all melting points of compounds in each example are uncorrected.
実施例 １
５−（２−クロルエチル）−４−メチルチアゾー
ル5.00ｇと２，４−オキサゾリジンジオンカリウ
ム塩4.30ｇを乾燥Ｎ，Ｎ−ジメチルホルムアミド
150ml中、100℃で17時間反応させた。反応液を減
圧下に濃縮し、塩化メチレンを加え、水洗したの
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、残留結晶をエタノールより
再結晶し、融点104〜105℃の３−〔２−（４−メチ
ル−５−チアゾリル）エチル〕−２，４−オキサ
ゾリジンジオン5.54ｇを得た。Example 1 5.00 g of 5-(2-chloroethyl)-4-methylthiazole and 4.30 g of 2,4-oxazolidinedione potassium salt were dissolved in dry N,N-dimethylformamide.
The reaction was carried out in 150 ml at 100°C for 17 hours. The reaction solution was concentrated under reduced pressure, diluted with methylene chloride, washed with water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from ethanol to obtain 5.54 g of 3-[2-(4-methyl-5-thiazolyl)ethyl]-2,4-oxazolidinedione with a melting point of 104-105°C. I got it.
元素分析値（C9H10N2O3Ｓとして）
Ｃ％ Ｈ％ Ｎ％
計算値 47.77 4.46 12.38
実測値 47.77 4.37 12.30
赤外線吸収スペクトル（KBr）
1815cm-1，1720cm-1
核磁気共鳴スペクトル（90MHz，CDCl3）
δ：2.31（ｓ，3H），3.08（ｔ，2H），
3.69（ｔ，2H），4.60（ｓ，2H），
８，54（ｓ，1H）
実施例 ２
５−（２−クロルエチル）−４−メチルチアゾー
ル8.1ｇ、３−アミノ−１−プロパノール11.2ｇ、
トリエチルアミン25.2ｇ及び１−ブタノール150
mlの混合物を64時間加熱還流させた。反応液を減
圧下に濃縮したのち、水と水酸化ナトリウム3.0
グラムを加え、減圧下に濃縮し、残留物に塩化メ
チレンを加え、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、残留油状物にベンゼ
ンを加え、活性炭で処理をしたのち、減圧下に溶
媒を留去し、油状物として、３−〔２−（４−メチ
ル−５−チアゾリル）エチルアミノ〕−１−プロ
パノールと３−アミノ−１−プロパノールの約
２：１の混合物8.3ｇを得た。 Elemental analysis value (as C 9 H 10 N 2 O 3 S) C% H% N% Calculated value 47.77 4.46 12.38 Actual value 47.77 4.37 12.30 Infrared absorption spectrum (KBr) 1815cm -1 , 1720cm -1 Nuclear magnetic resonance spectrum (90MHz , CDCl 3 ) δ: 2.31 (s, 3H), 3.08 (t, 2H), 3.69 (t, 2H), 4.60 (s, 2H), 8,54 (s, 1H) Example 2 5-(2- chloroethyl)-4-methylthiazole 8.1g, 3-amino-1-propanol 11.2g,
25.2 g of triethylamine and 150 g of 1-butanol
ml of the mixture was heated to reflux for 64 hours. After concentrating the reaction solution under reduced pressure, water and sodium hydroxide 3.0
gram and concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, benzene was added to the residual oil, and treated with activated carbon.The solvent was distilled off under reduced pressure to obtain 3-[2-(4-methyl-5-thiazolyl) ) 8.3 g of an approximately 2:1 mixture of ethylamino]-1-propanol and 3-amino-1-propanol were obtained.
このものをジオキサン80mlと水80mlの混液に溶
かし、水冷下にかき混ぜながら、クロル炭酸エチ
ル7.3ｇを乾燥ジオキサン40mlに溶かした液と1N
水素化ナトリウム水溶液70mlを滴下したのち、室
温で１時間反応させた。反応液を減圧下に濃縮し
たのち、ジエチルエーテルで抽出した。有機層を
希塩酸で抽出し、水層に炭酸水素ナトリウムを加
え中和したのち、塩化メチレンで抽出し、水洗後
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、油状物として、Ｎ−（３−ヒドロキシ
プロピル）−Ｎ−〔２−（４−メチル−５−チアゾ
リル）エチル〕カルバミン酸エチル4.5ｇを得た。 Dissolve this in a mixture of 80 ml of dioxane and 80 ml of water, and mix with a solution of 7.3 g of ethyl chlorocarbonate dissolved in 40 ml of dry dioxane while stirring while cooling with water.
After dropping 70 ml of an aqueous sodium hydride solution, the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then extracted with diethyl ether. The organic layer was extracted with diluted hydrochloric acid, and the aqueous layer was neutralized by adding sodium bicarbonate, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.5 g of ethyl N-(3-hydroxypropyl)-N-[2-(4-methyl-5-thiazolyl)ethyl]carbamate as an oil.
赤外線吸収スペクトル（液膜）
3400cm-1，1690cm-1
核磁気共鳴スペクトル（90MHz，CDCl3）
δ：1.27（ｔ，3H），1.72（quint，2H），
2.43（ｓ，3H），2.9〜3.8（ｍ，9H），
4.18（ｑ，2H），8.60（ｓ，1H）
Ｎ−（３−ヒドロキシプロピル）−Ｎ−〔２−（４
−メチル−５−チアゾリル）エチル〕カルバミン
酸エチル4.4ｇ、ナトリウムメトキシド0.3ｇ及び
トルエン100mlの混合物を還流液中のエタノール
を塩化カルシウムで除去しながら、48時間加熱還
流させた。反応液を減圧下に濃縮したのち、残留
物を塩化メチレンに溶かし、水洗後無水硫酸マグ
ネシウムで乾燥した。減圧下に溶媒を留去したの
ち、残留物をベンゼン−ヘキサンより再結晶し、
融点104〜105℃の３−〔２−（４−メチル−５−チ
アゾリル）エチル〕テトラヒドロ−2H−１，３
−オキサジン−２−オン2.6ｇを得た。 Infrared absorption spectrum (liquid film) 3400cm -1 , 1690cm -1 Nuclear magnetic resonance spectrum (90MHz, CDCl 3 ) δ: 1.27 (t, 3H), 1.72 (quint, 2H), 2.43 (s, 3H), 2.9-3.8 (m, 9H), 4.18 (q, 2H), 8.60 (s, 1H) N-(3-hydroxypropyl)-N-[2-(4
-Methyl-5-thiazolyl)ethyl] A mixture of 4.4 g of ethyl carbamate, 0.3 g of sodium methoxide, and 100 ml of toluene was heated under reflux for 48 hours while removing ethanol in the reflux liquid with calcium chloride. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from benzene-hexane.
3-[2-(4-methyl-5-thiazolyl)ethyl]tetrahydro-2H-1,3 with melting point 104-105°C
2.6 g of -oxazin-2-one were obtained.
元素分析値（C10H14N2O2Ｓとして）
Ｃ％ Ｈ％ Ｎ％
計算値 53.08 6.24 12.38
実測値 52.91 6.24 12.31
赤外線吸収スペクトル（KBr）
1680cm-1
核磁気共鳴スペクトル（90MHz，CDCl3）
δ：1.85〜2.15（ｍ，2H），2.45（ｓ，3H），
3.13（ｔ，2H），3.21（ｔ，2H），
3.53（ｔ，2H），4.24（ｔ，2H），
8.61（ｓ，1H）
実施例 ３
５−（２−クロルエチル）−４−メチルチア
ゾール4.85ｇ、スクシンイミド4.50ｇ、炭酸
カリウム6.20ｇ及びＮ，Ｎ−ジメチルホルム
アミド100mlの混合物を室温で１時間かき混
ぜたのち、100℃で２時間加熱した。反応液
を減圧下に濃縮したのち、残留物に水を加
え、クロロホルムで抽出し、水洗後無水硫酸
マグネシウムで乾燥した。減圧下に溶媒を留
去し、残留物をベンゼンより再結晶し、融点
106〜107℃のＮ−〔２−（４−メチル−５−チ
アゾリル）エチル〕スクシンイミド3.90ｇを
得た。 Elemental analysis value (as C 10 H 14 N 2 O 2 S) C% H% N% Calculated value 53.08 6.24 12.38 Actual value 52.91 6.24 12.31 Infrared absorption spectrum (KBr) 1680cm -1 Nuclear magnetic resonance spectrum (90MHz, CDCl 3 ) δ: 1.85-2.15 (m, 2H), 2.45 (s, 3H), 3.13 (t, 2H), 3.21 (t, 2H), 3.53 (t, 2H), 4.24 (t, 2H), 8.61 (s, 1H) Example 3 A mixture of 4.85 g of 5-(2-chloroethyl)-4-methylthiazole, 4.50 g of succinimide, 6.20 g of potassium carbonate and 100 ml of N,N-dimethylformamide was stirred at room temperature for 1 hour and then heated at 100°C. Heated for 2 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was recrystallized from benzene, and the melting point
3.90 g of N-[2-(4-methyl-5-thiazolyl)ethyl]succinimide at 106-107°C was obtained.
元素分析値（C10H14N2O2Ｓとして） Ｃ％ Ｈ％ Ｎ％ 計算値 53.55 5.39 12.49 実測値 53.47 5.35 12.54 赤外線吸収スペクトル（KBr） 1770cm-1，1690cm-1 核磁気共鳴スペクトル（90MHz，CDCl3） δ：2.41（ｓ，3H），2.68（ｓ，4H）， 3.08（ｔ，2H），3.75（ｔ，2H）， 8.61（ｓ，1H） Elemental analysis value (as C 10 H 14 N 2 O 2 S) C% H% N% Calculated value 53.55 5.39 12.49 Actual value 53.47 5.35 12.54 Infrared absorption spectrum (KBr) 1770cm -1 , 1690cm -1 Nuclear magnetic resonance spectrum (90MHz , CDCl 3 ) δ: 2.41 (s, 3H), 2.68 (s, 4H), 3.08 (t, 2H), 3.75 (t, 2H), 8.61 (s, 1H)
Claims (1)
キル基、Ａは炭素数１〜４のアルキレン、Ｂは酸
素原子、ｌ及びｎのいずれか一方は１で、他の一
方は０又は１、ｍは１〜３の整数、但し、ｌ，ｍ
及びｎの総和が３又は４である）で表わされるチ
アゾール誘導体。 ２ 一般式 （式中のＲは水素原子又は炭素数１〜３のアル
キル基、Ａは炭素数１〜４のアルキレン、Ｘは塩
素原子、臭素原子又はヨウ素原子である）で表わ
されるω−ハロアルキルチアゾール誘導体と、一
般式 （式中のＢは酸素原子、ｌ及びｎのいずれか一
方は１で、他の一方は０又は１、ｍは１〜３の整
数、但し、ｌ，ｍ及びｎの総和が３又は４であ
る）で表わされる化合物又はそのアルカリ金属塩
とを、塩基性物質の存在下又は非存在下に反応さ
せることを特徴とする、一般式 （式中のＲ，Ａ，Ｂ，ｌ，ｍ及びｎは前記と同
じ意味をもつ）で表わされるチアゾール誘導体の
製造方法。[Claims] 1. General formula (In the formula, R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, A is an alkylene having 1 to 4 carbon atoms, B is an oxygen atom, one of l and n is 1, and the other is 0 or 1, m is an integer from 1 to 3, provided that l, m
and the sum of n is 3 or 4). 2 General formula (In the formula, R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, A is an alkylene having 1 to 4 carbon atoms, and X is a chlorine atom, a bromine atom, or an iodine atom.) , general formula (In the formula, B is an oxygen atom, one of l and n is 1, the other is 0 or 1, m is an integer from 1 to 3, provided that the sum of l, m and n is 3 or 4. A general formula characterized by reacting a compound represented by (a) or an alkali metal salt thereof in the presence or absence of a basic substance. A method for producing a thiazole derivative represented by the formula (R, A, B, l, m and n have the same meanings as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2065684A JPS60163881A (en) | 1984-02-06 | 1984-02-06 | Thiazole derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2065684A JPS60163881A (en) | 1984-02-06 | 1984-02-06 | Thiazole derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60163881A JPS60163881A (en) | 1985-08-26 |
| JPH058197B2 true JPH058197B2 (en) | 1993-02-01 |
Family
ID=12033254
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2065684A Granted JPS60163881A (en) | 1984-02-06 | 1984-02-06 | Thiazole derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60163881A (en) |
-
1984
- 1984-02-06 JP JP2065684A patent/JPS60163881A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60163881A (en) | 1985-08-26 |
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