JPH04270291A - Thiazino(6,5-b)indolizine derivative - Google Patents
Thiazino(6,5-b)indolizine derivativeInfo
- Publication number
- JPH04270291A JPH04270291A JP11419991A JP11419991A JPH04270291A JP H04270291 A JPH04270291 A JP H04270291A JP 11419991 A JP11419991 A JP 11419991A JP 11419991 A JP11419991 A JP 11419991A JP H04270291 A JPH04270291 A JP H04270291A
- Authority
- JP
- Japan
- Prior art keywords
- thiazino
- indolizine
- lower alkyl
- formula
- compound
- 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.)
- Pending
Links
- 125000003406 indolizinyl group Chemical class C=1(C=CN2C=CC=CC12)* 0.000 title description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- PNSIAWUVMZLCIM-UHFFFAOYSA-N 2h-thiazino[6,5-b]indolizine Chemical class C1=C2C=CC=CN2C2=C1SNC=C2 PNSIAWUVMZLCIM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- -1 indolizine compound Chemical class 0.000 abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 6
- 230000003266 anti-allergic effect Effects 0.000 abstract description 5
- 230000000202 analgesic effect Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical group N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000016720 allyl isothiocyanate Nutrition 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は医薬品として有用なチア
ジノ〔６，５−ｂ〕インドリジン誘導体に関するもので
ある。TECHNICAL FIELD The present invention relates to thiazino[6,5-b]indolizine derivatives useful as pharmaceuticals.
【０００２】さらに詳しく述べれば、本発明は抗アレル
ギー作用、消炎作用または鎮痛作用等の薬理作用を有し
、医薬品として有用な、一般式More specifically, the present invention provides a general formula that has pharmacological effects such as antiallergic, antiinflammatory, and analgesic effects and is useful as a pharmaceutical.
【化２】
（式中のＲ１およびＲ２は同じでも異なっていてもよく
、それぞれ水素原子または低級アルキル基であり、Ｒ３
は低級アルキル基であり、Ｒは低級アルキル基、低級ア
ルケニル基またはフェニル基であり、Ｚは酸素原子また
は硫黄原子である）で表されるチアジノ〔６，５−ｂ〕
インドリジン誘導体に関するものである。[Formula 2] (R1 and R2 may be the same or different, each is a hydrogen atom or a lower alkyl group, and R3
is a lower alkyl group, R is a lower alkyl group, lower alkenyl group, or phenyl group, and Z is an oxygen atom or a sulfur atom) Thiazino[6,5-b]
This invention relates to indolizine derivatives.
【０００３】0003
【従来の技術】本発明の一般式（Ｉ）で表されるような
チアジノ〔６，５−ｂ〕インドリジン骨格の化合物は今
まで知られておらず、全く新規な化合物である。BACKGROUND OF THE INVENTION A compound having a thiazino[6,5-b]indolizine skeleton as represented by the general formula (I) of the present invention has not been known so far and is a completely new compound.
【０００４】0004
【発明が解決しようとする課題】本発明の目的は、抗ア
レルギー作用、消炎作用または鎮痛作用等の薬理作用を
有し、医薬品として有用なチアジノ〔６，５−ｂ〕イン
ドリジン誘導体を提供することである。OBJECTS OF THE INVENTION An object of the present invention is to provide thiazino[6,5-b]indolizine derivatives that have pharmacological effects such as antiallergic, antiinflammatory, and analgesic effects and are useful as pharmaceuticals. That's true.
【０００５】[0005]
【課題を解決するための手投】本発明者らは、インドリ
ジン誘導体について鋭意研究した結果、インドリジン環
にチアジン環を縮合したある種の化合物が抗アレルギー
作用、消炎作用または鎮痛作用等、薬理作用を有するこ
とを見出し、本発明をなすに至った。[Measures to Solve the Problems] As a result of intensive research on indolizine derivatives, the present inventors found that certain compounds in which a thiazine ring is fused to an indolizine ring have anti-allergic, anti-inflammatory or analgesic effects, etc. It was discovered that it has pharmacological effects, and the present invention was completed.
【０００６】ここで、本発明の一般式（Ｉ）で表される
化合物において、低級アルキル基．は炭素数１〜６の直
鎖状または枝分かれ状のアルキル基をいい、低級アルケ
ニル基とは炭素数２〜６の直鎖状または枝分かれ状のア
ルケニル基をいう。[0006] Here, in the compound represented by the general formula (I) of the present invention, a lower alkyl group. refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and the lower alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms.
【０００７】本発明の一般式（Ｉ）で表されるチアジノ
〔６，５−ｂ〕インドリジン誘導体は新規な化合物であ
り、以下のようにして製造することができる。The thiazino[6,5-b]indolizine derivative represented by the general formula (I) of the present invention is a novel compound and can be produced as follows.
【０００８】すなわち、一般式That is, the general formula
【化３】
（式中のＲ４は低級アルキル基であり、Ｒ５は低級アル
コキシカルボニル基またはシアノ基であり、Ｒ１、Ｒ２
およびＲ３は前記と同じ意味をもつ）で表されるインド
リジン誘導体を、塩基の存在下で、一般式
Ｒ−Ｎ＝Ｃ＝Ｚ
（ＩＩＩ）
（式中のＲおよびＺは前記と同じ意味をもつ）で表され
るイソシアネートまたはイソチオシアネート化合物と反
応させることにより製造することができる。embedded image (in the formula, R4 is a lower alkyl group, R5 is a lower alkoxycarbonyl group or a cyano group, R1, R2
and R3 have the same meanings as above) in the presence of a base, the indolizine derivative represented by the general formula
RN=C=Z
(III) It can be produced by reacting with an isocyanate or an isothiocyanate compound represented by (in the formula, R and Z have the same meanings as above).
【０００９】本発明の一般式（Ｉ）で表される化合物を
製造する上述の方法は、一般に不活性溶媒中で行われる
。不活性溶媒としては、Ｎ，Ｎ−ジメチルホルムアミド
、ジメチルスルホキシド、テトラヒドロフラン、アセト
ニトリル等を用いることができる。The above-mentioned process for producing the compound of general formula (I) of the present invention is generally carried out in an inert solvent. As the inert solvent, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, etc. can be used.
【００１０】塩基としては、金属ナトリウム、水素化ナ
トリウム等の無機塩基、ｔ−ブトキシカリウム等の有機
塩基を用いることができる。As the base, inorganic bases such as metallic sodium and sodium hydride, and organic bases such as t-butoxypotassium can be used.
【００１１】本発明の製造方法は、単離が困難な中間体
である、一般式The production method of the present invention is an intermediate that is difficult to isolate, the general formula
【化４】
（式中のＹはカリウム原子またはナトリウム原子であり
、Ｒ１、Ｒ２、Ｒ３およびＲ４は前記と同じ意味である
）で表される化合物を経由するものであり、一般式（Ｉ
）におけるＳ置換基がアクリル酸エチルまたは、アクリ
ロニトリルとして脱離する。そのため、塩基の存在下で
一般式（ＩＶ）で表される化合物を形成させた後、発生
したアクリル酸エチルまたはアクリロニトリルを減圧除
去等により系外に排除するのが好ましい。また、脱離基
としては、脱離性がよく、脱離した後、反応系において
悪影響を及ぼさないような他の基を用いても構わない。[I
) is eliminated as ethyl acrylate or acrylonitrile. Therefore, after forming the compound represented by the general formula (IV) in the presence of a base, it is preferable to remove the generated ethyl acrylate or acrylonitrile from the system by removal under reduced pressure or the like. Further, as the leaving group, other groups that have good elimination properties and do not have an adverse effect on the reaction system after elimination may be used.
【００１２】本発明の製造方法において出発物質として
用いられる一般式（ＩＩ）で表される化合物は一部新規
物質が含まれるが、ブレチン オブ ザ ケミカ
ル ソサイアティー オブ ジャパン（Ｂｕｌｌ
．Ｃｈｅｍ．Ｓｏｃ．Ｊｐｎ．），６３巻、８２９〜８
３４ページ、１９９０年等の文献記載の方法またはそれ
と類似の方法により製造することができる。[0012] Some of the compounds represented by the general formula (II) used as starting materials in the production method of the present invention include new substances, but are
．． Chem. Soc. Jpn. ), vol.63, 829-8
It can be produced by the method described in the literature, such as p. 34, 1990, or a method similar thereto.
【００１３】本発明を好適に実施するには、一般式（Ｉ
Ｉ）で表される化合物を、Ｎ，Ｎ−ジメチルホルムアミ
ドまたはジメチルスルホキシド中１．５〜２．５当量の
ｔ−ブトキシカリウムの存在下、室温から１００℃で数
分から数時間反応させた後、発生した脱離生成物を減圧
除去し、これに一般式（ＩＩＩ）で表される１．０〜２
．０当量のイソシアネートまたはイソチオシアネート化
合物を加え、室温から１００℃で数時間から１日反応し
、冷却後、希塩酸等を用いて反応液を中和する。In order to suitably carry out the present invention, the general formula (I
After reacting the compound represented by I) in the presence of 1.5 to 2.5 equivalents of potassium t-butoxy in N,N-dimethylformamide or dimethyl sulfoxide at room temperature to 100°C for several minutes to several hours, The generated desorption product is removed under reduced pressure, and the 1.0 to 2
．． Add 0 equivalent of isocyanate or isothiocyanate compound, react at room temperature to 100° C. for several hours to one day, and after cooling, neutralize the reaction solution using dilute hydrochloric acid or the like.
【００１４】また、このようにして得られた反応混合物
を通常の精製方法、例えば、カラムクロマトグラフィー
あるいは分別結晶等の操作を行い目的物質を得る。Further, the reaction mixture thus obtained is subjected to a conventional purification method such as column chromatography or fractional crystallization to obtain the target substance.
【００１５】本発明の一般式（Ｉ）で表されるチアジノ
〔６，５−ｂ〕インドリジン誘導体は抗アレルギー作用
、消炎作用、鎮痛作用等を示し、医薬品として有用であ
る。本発明の一般式（Ｉ）の化合物を実際の治療に用い
る場合、種々の医薬品組成物とした後使用されるが、そ
のような医薬品組成物としては、例えば、錠剤、カプセ
ル剤、顆粒剤、注射剤、貼付剤、座剤等をあげることが
できる。The thiazino[6,5-b]indolizine derivatives represented by the general formula (I) of the present invention exhibit antiallergic, antiinflammatory, and analgesic effects, and are useful as pharmaceuticals. When the compound of general formula (I) of the present invention is used for actual treatment, it is used after being made into various pharmaceutical compositions, and such pharmaceutical compositions include, for example, tablets, capsules, granules, Examples include injections, patches, and suppositories.
【００１６】本発明の一般式（Ｉ）で表されるチアジノ
〔６，５−ｂ〕インドリジン誘導体を含有する医薬品組
成物を治療に用いる場合、その投与量は疾患の程度、患
者の性、年齢、体重等により調整されるが、経口投与で
は概ね成人１日当たり、５ｍｇ〜５０００ｍｇ、非経口
投与では１日当たり、１ｍｇ〜１０００ｍｇの範囲で投
与することができる。When the pharmaceutical composition containing the thiazino[6,5-b]indolizine derivative represented by the general formula (I) of the present invention is used for treatment, the dosage depends on the degree of the disease, the sex of the patient, Although adjusted depending on age, body weight, etc., it can be administered in the range of 5 mg to 5000 mg per day for adults for oral administration, and 1 mg to 1000 mg per day for parenteral administration.
【００１７】[0017]
【実施例】本発明の内容を以下の実施例でさらに詳細に
説明する。なお、各実施例中の化合物の融点はすべて未
補正である。
実施例 １
エチル ３−アリル−８−エチル−４−オキソ−２−
チオキソ−２Ｈ−２，３−ジヒドロ〔１，３〕チアジノ
〔６，５−ｂ〕インドリジン−１０−カルボキシラート
（化合物１）EXAMPLES The contents of the present invention will be explained in more detail in the following examples. Note that all melting points of compounds in each example are uncorrected. Example 1 Ethyl 3-allyl-8-ethyl-4-oxo-2-
Thioxo-2H-2,3-dihydro[1,3]thiazino[6,5-b]indolizine-10-carboxylate (compound 1)
【００１８】ジエチル ２−（エトキシカルボニルエ
チルチオ）−７−エチルインドリジン−１，３−ジカル
ボキシラート０．４２ｇのＮ，Ｎ−ジメチルホルムアミ
ド溶液２ｍｌにｔ−ブトキシカリウム０．２３ｇを加え
、よくかきまぜた。この反応液を６０〜７０℃の水浴上
に１５分間加熱した後、発生したアクリル酸エチルをロ
ータリーエバポレーターを用いてできる限り除去した。
これにアリルイソチオシアネート０．１２ｇを加え、こ
の反応液をさらに３時間水浴上に放置し反応させた。こ
の反応液を室温まで冷やした後、希塩酸で中和し反応生
成物を析出させた。ろ別によって分離したこの粗生成物
をクロロホルム３０ｍｌに溶解し、このクロロホルム溶
液を液相分離濾紙を通すことにより脱水後、濃縮した。
この残渣をクロロホルムを溶媒とし、アルミナカラムに
よって分離し、標題化合物０．２２ｇを得た。To 2 ml of a solution of 0.42 g of diethyl 2-(ethoxycarbonylethylthio)-7-ethylindolizine-1,3-dicarboxylate in N,N-dimethylformamide was added 0.23 g of potassium t-butoxy, and the mixture was well mixed. Stirred. After heating this reaction solution on a water bath at 60 to 70°C for 15 minutes, as much of the generated ethyl acrylate as possible was removed using a rotary evaporator. To this was added 0.12 g of allyl isothiocyanate, and the reaction solution was left on a water bath for further 3 hours to react. After cooling this reaction solution to room temperature, it was neutralized with dilute hydrochloric acid to precipitate a reaction product. The crude product separated by filtration was dissolved in 30 ml of chloroform, and the chloroform solution was dehydrated by passing through a liquid phase separation filter paper and then concentrated. This residue was separated using an alumina column using chloroform as a solvent to obtain 0.22 g of the title compound.
【００１９】融 点： １４７〜１４９℃ＩＲ（Ｋ
Ｂｒ）： ν（ＣＯ）１６９１，１６５５ｃｍ−１
ＮＭＲ（ＣＤＣｌ３）
δ：１．３２（ｔ，３Ｈ），１．４４（ｔ，３Ｈ），２
．８０（ｑ，２Ｈ），４．３８（ｑ，２Ｈ），５．０〜
５．５（ｍ．４Ｈ），５．６〜６．４（ｍ，１Ｈ），６
．９２（ｄｄ，１Ｈ），８．０７（ｂｒ−ｓ，１Ｈ），
９．５３（ｄ，１Ｈ）
元素分析値：（Ｃ１８Ｈ１８Ｎ２Ｏ３Ｓ２として）測定
値 Ｃ％５７．９２，Ｈ％５．０５， Ｎ％７．４
０
理論値 Ｃ％５７．７３，Ｈ％４．８５， Ｎ％７
．４８Melting point: 147-149°C IR (K
Br): ν (CO) 1691, 1655 cm-1 NMR (CDCl3) δ: 1.32 (t, 3H), 1.44 (t, 3H), 2
．． 80 (q, 2H), 4.38 (q, 2H), 5.0 ~
5.5 (m.4H), 5.6-6.4 (m, 1H), 6
．． 92 (dd, 1H), 8.07 (br-s, 1H),
9.53 (d, 1H) Elemental analysis value: (as C18H18N2O3S2) Measured value C%57.92, H%5.05, N%7.4
0 Theoretical value C%57.73, H%4.85, N%7
．． 48
【００２０】実施例 ２
エチル ３プロピル−８−メチル−２，４−ジオキソ
−２Ｈ−２，３−ジヒドロ〔１，３〕チアジノ〔６，５
−ｂ〕インドリジン−１０−カルボキシラート（化合物
２）Example 2 Ethyl 3propyl-8-methyl-2,4-dioxo-2H-2,3-dihydro[1,3]thiazino[6,5
-b] Indolizine-10-carboxylate (Compound 2)
【００２１】ジエチル ２−（エトキシカルボニルエ
チルチオ）−７−メチルインドリジン−１，３−ジカル
ボキシラート０．４１ｇのＮ，Ｎ−ジメチルホルムアミ
ド溶液２ｍｌにｔ−ブトキシカリウム０．２３ｇを加え
、よくかきまぜた。この反応液を６０〜７０℃の水浴上
に１５分間加熱した後、発生したアクリル酸エチルをロ
ータリーエバポレーターを用いてできる限り除去した。
これにプロピルイソシアネート０．１ｇを加え、この反
応液をさらに３時間水浴上に放置し、反応させた。この
反応液を室温まで冷やした後、希塩酸で中和し反応生成
物を析出させた。ろ別によって分離したこの粗生成物を
クロロホルム３０ｍｌに溶解し、このクロロホルム溶液
を液相分離濾紙を通すことにより脱水後、濃縮した。こ
の残渣をクロロホルムを溶媒とし、アルミナカラムによ
って分離し、標題化合物０．２３ｇを得た。Add 0.23 g of potassium t-butoxy to 2 ml of a solution of 0.41 g of diethyl 2-(ethoxycarbonylethylthio)-7-methylindolizine-1,3-dicarboxylate in N,N-dimethylformamide, and mix well. Stirred. After heating this reaction solution on a water bath at 60 to 70°C for 15 minutes, as much of the generated ethyl acrylate as possible was removed using a rotary evaporator. 0.1 g of propyl isocyanate was added to this, and the reaction solution was further left on a water bath for 3 hours to react. After cooling this reaction solution to room temperature, it was neutralized with dilute hydrochloric acid to precipitate a reaction product. The crude product separated by filtration was dissolved in 30 ml of chloroform, and the chloroform solution was dehydrated by passing through a liquid phase separation filter paper and then concentrated. This residue was separated using an alumina column using chloroform as a solvent to obtain 0.23 g of the title compound.
【００２２】融 点： １５９〜１６１℃ＩＲ（Ｋ
Ｂｒ）： ν（ＣＯ）１６８４，１６６０ｃｍ−１
ＮＭＲ（ＣＤＣｌ３）
δ：０．９６（ｔ，３Ｈ），１．３〜２．１（ｍ，２Ｈ
），１．４３（ｔ，３Ｈ），２．４７（ｓ，３Ｈ），４
．０３（ｑ．２Ｈ），４．３７（ｑ，２Ｈ），６．８４
（ｄｄ，１Ｈ），８．０３（ｂｒ−ｓ，１Ｈ），９．５
６（ｄ，１Ｈ）元素分析値：（Ｃ１７Ｈ１８Ｎ２Ｏ４Ｓ
として）
測定値 Ｃ％５９．０８，Ｈ％５．２３， Ｎ％７
．８６
理論値 Ｃ％５８．９４，Ｈ％５．２４， Ｎ％８
．０９Melting point: 159-161°C IR (K
Br): ν (CO) 1684, 1660 cm-1 NMR (CDCl3) δ: 0.96 (t, 3H), 1.3-2.1 (m, 2H
), 1.43 (t, 3H), 2.47 (s, 3H), 4
．． 03 (q.2H), 4.37 (q, 2H), 6.84
(dd, 1H), 8.03 (br-s, 1H), 9.5
6(d,1H) elemental analysis value: (C17H18N2O4S
) Measured values C%59.08, H%5.23, N%7
．． 86 Theoretical value C%58.94, H%5.24, N%8
．． 09
【００２３】実施例 ３
相当する誘導体を用いて実施例１または２と同様に操作
して以下の化合物を得た。Example 3 The following compound was obtained in the same manner as in Example 1 or 2 using the corresponding derivative.
【００２４】[0024]
【化５】[C5]
【００２５】[0025]
【表１】[Table 1]
【００２６】[0026]
【表２】[Table 2]
【００２７】[0027]
【表３】[Table 3]
【００２８】[0028]
【表４】[Table 4]
【００２９】[0029]
【表５】[Table 5]
Claims (1)
、それぞれ水素原子または低級アルキル基であり、Ｒ３
は低級アルキル基であり、Ｒは低級アルキル基、低級ア
ルケニル基またはフェニル基であり、Ｚは酸素原子また
は硫黄原子である）で表されるチアジノ〔６，５−ｂ〕
インドリジン誘導体。Claim 1: General formula:
is a lower alkyl group, R is a lower alkyl group, lower alkenyl group, or phenyl group, and Z is an oxygen atom or a sulfur atom) Thiazino[6,5-b]
Indolizine derivatives.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11419991A JPH04270291A (en) | 1991-02-25 | 1991-02-25 | Thiazino(6,5-b)indolizine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11419991A JPH04270291A (en) | 1991-02-25 | 1991-02-25 | Thiazino(6,5-b)indolizine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04270291A true JPH04270291A (en) | 1992-09-25 |
Family
ID=14631689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11419991A Pending JPH04270291A (en) | 1991-02-25 | 1991-02-25 | Thiazino(6,5-b)indolizine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04270291A (en) |
-
1991
- 1991-02-25 JP JP11419991A patent/JPH04270291A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2007302658A (en) | POLYMORPHIC FORM AND NEW CRYSTAL FORM AND AMORPHOUS FORM OF IMATINIB MESYLATE, AND METHOD FOR PREPARING FORMalpha | |
| FR2910473A1 (en) | New pyrrolopyridine derivatives e.g. useful for treating pain, inflammation, urological disorders, gynecological disorders, gastrointestinal disorders, respiratory disorders, psoriasis, pruritis | |
| MXPA01012237A (en) | Method for the production of thiazolidin. | |
| CN112778301A (en) | Tetrahydropyridopyrimidine inhibitor and preparation method and application thereof | |
| FR2846657A1 (en) | New pyridopyrimidone derivatives are kinase inhibitors and activators, useful in the treatment of cancers, hyperglycemia, dyslipidemias, diabetes and its complications, obesity, arthritis, and arterial hypertension | |
| AU636076B2 (en) | 4-desoxy-4-epipodophyllotoxin derivative or pharmaceutically acceptable salt thereof | |
| CN118076586A (en) | KIF18A inhibitors | |
| JP3040182B2 (en) | Imidazopyridazine derivatives, their uses and production methods | |
| US7776852B2 (en) | Process for producing highly pure midazolam and salts thereof | |
| JPS63310882A (en) | Polyoxygenated labdane derivative and manufacture | |
| LU86421A1 (en) | 1,4-DISUBSTITUTED PIPERAZINE DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THEM, AND PROCESS FOR OBTAINING THE SAME | |
| JPH0327534B2 (en) | ||
| FR2758329A1 (en) | New imidazole-4-butane-boronic acid derivatives | |
| JPH04270291A (en) | Thiazino(6,5-b)indolizine derivative | |
| JPS6219583A (en) | Pyridonecarboxylic acid derivative, ester and salt | |
| JPS6129959B2 (en) | ||
| JPS6183163A (en) | Antitumoral | |
| CA2584918A1 (en) | Cyanothiophenes, the production thereof and their use as medicaments | |
| JP3068175B2 (en) | Isothiazolo [5,4-b] pyridine derivatives | |
| JPH04270288A (en) | Thineno(2,3-b)indolizine derivative | |
| KR880001105B1 (en) | Process for preparing 1-benzil-4-(4-(2-pyrimidinylamino)benjil)-2,3-dioxopiperajine derivatives | |
| JPH04270289A (en) | Oxazino(6,5-b)indolizine derivative | |
| JPS62249984A (en) | D-nor-7-ergoline derivative, manufacture, drug composition and use | |
| JPS6335579A (en) | Sulfur-containing benzoxazinorifamycin derivative | |
| US4291032A (en) | Thiazolo(3,2-C)benzoxazine derivatives |