KR810001502B1 - Process for preparing 4-hydroxy-2h-1 2-benzothiazine-3-carboxamide-1,1-dioxides - Google Patents

Process for preparing 4-hydroxy-2h-1 2-benzothiazine-3-carboxamide-1,1-dioxides Download PDF

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KR810001502B1
KR810001502B1 KR7803563A KR780003563A KR810001502B1 KR 810001502 B1 KR810001502 B1 KR 810001502B1 KR 7803563 A KR7803563 A KR 7803563A KR 780003563 A KR780003563 A KR 780003563A KR 810001502 B1 KR810001502 B1 KR 810001502B1
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methyl
dioxide
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트룸리츠 귄터
엥겔 볼프하르트
제거 에른스트
엥겔하르트 귄터
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쿠터, 좀머
닥터 칼토매 지엠비에이치
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

Title compds.(I; R1 = H or ethyl; R2 = methyl, ethyl or n-propyl; Y = H, methyl, methoxy, F, Cl), useful as an anti-inflammatory agent, were prepd. by the reaction of II (X = C1-8 alkoxy, C7-10 phenylalkoxy, phenyloxy, halogen, C1-8 alkylamino, anilino) and III at 20-200oC in organic solvent. Thus, 26.9 g methyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.5 g 2-amino-5-methyl-thiazole were refluxed for 24 hr in 4l xylene to give 26.0 g I.

Description

[발명의 명칭][Name of invention]

4-하이드록시-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드의 제조방법Method for preparing 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

[발명의 상세한 설명]Detailed description of the invention

본 발명은 소염제로 유용한 다음 구조식(I)의 4-하이드록시-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드 및 생리적으로 무독한 이의 염의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and its physiologically toxic salts of the following formula (I) useful as anti-inflammatory agents: .

Figure kpo00001
Figure kpo00001

상기 구조식에서 R1은 수소원자 또는 메틸 또는 에틸그룹이고, R2는 메틸, 에틸 또는 n-프로필그룹이고, Y는 수소원자, 메틸 또는 메톡시그룹 또는 불소염소원자이다.Wherein R 1 is a hydrogen atom or a methyl or ethyl group, R 2 is a methyl, ethyl or n-propyl group, and Y is a hydrogen atom, a methyl or methoxy group or a fluorine chlorine atom.

독일공개명세서 1,943,265호에는 구조식(I)화합물과 관련되어 있는 3,4-디하이드로-2H-1,2-벤조티아진-1,1-디옥사이드가 발표되어 있다. 그러나 놀랍게도 구조식(I)화합물은 이의 소염활성 및 융화성에 관하여 구조적으로 가장 유사한 상기 공고의 화합물보다도 훨씬 우수하다는 것이 발견되었다.German Publication 1,943,265 discloses 3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide associated with the compound of formula (I). Surprisingly, however, it was found that the compound of formula (I) is far superior to the compound of this publication which is most structurally similar in terms of its anti-inflammatory activity and compatibility.

구조식(I) 화합물은 다음의 공정에 따라 제조할 수 있다 :The compound of formula (I) may be prepared according to the following process:

1. 다음 구조식(II)의 4-하이드록시-2H-1,2-벤조티아진-1,1-디옥사이드-3-카복실산유도체를 다음 구조식(III)의 방향족 아민과 반응시킴으로써 구조식(I)의 모든 화합물을 제조할 수 있다.1.Reaction of formula (I) by reacting 4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid derivative of formula (II) with aromatic amine of formula (III) All compounds can be prepared.

Figure kpo00002
Figure kpo00002

상기 구조식에서 X는 친핵적으로 교환이 가능한 그룹, 특히 탄소수 1내지 8의 알콕시그룹, 총탄소수 7내지 10의 페닐알콕시그룹, 페닐옥시그룹, 할로겐원자, 유리아미노그룹, 탄소수 1내지 8의 알킬아미노그룹, 탄소수 3내지 10의 사이클로알킬아미노 그룹, 총탄소수 7내지 10의 페닐알킬아미노그룹 또는 아닐리노그룹이고 R1, R2및 Y는 상술한 바와 같다.In the above structural formula, X is a nucleophilic group, in particular an alkoxy group having 1 to 8 carbon atoms, a phenylalkoxy group having 7 to 10 carbon atoms, a phenyloxy group, a halogen atom, a free amino group, and an alkylamino having 1 to 8 carbon atoms. Group, a cycloalkylamino group having 3 to 10 carbon atoms, a phenylalkylamino group having 7 to 10 carbon atoms or an anilino group, and R 1 , R 2 and Y are as described above.

구조식(II)의 카복실레이트와 구조식(III)의 방향족 아민과의 반응은 통상의 적절한 유기용매, 예를 들어 벤젠, 톨루엔, 크실렌, 클로로벤젠, O-디클로로벤젠 또는 테트하 이드로나프탈린과 같은 방향족 탄화수소, 또는 헥사메틸포스포르산 트리아미드나 디메톡시에탄, 디에틸렌글리콜디메틸에테르 또는 디페닐에테르와 같은 에테르중에서, 또는 직접 과량의 아민중에서, 수행된다. 이 반응은 60내지 200℃의 온도에서 수행되며 구조식(II)에서 X가 알콕시그룹일 경우는 20내지 180℃에서 수행된다. 구조식(II)에서 X가 알콕시그룹, 페닐알콕시그룹 또는 페닐 옥시그룹일 경우 반응은 바람직하게 비점에서, 톨루엔 또는 크실렌중에서 수행되며 분자체에 의해 공급되는 속실레 침출기를 사용하여 공비증류시키거나 또는 환류시켜 반응중 생성된 알코올 또는 페놀을 제거한다. 생성물은 반응혼합물로부터 결정상으로 수득되거나 물과 혼화성인 용매를 사용하여 물을 가함으로써 침전시킨다. 구조식(II)에서 X가 아미노그룹이거나 상술한 바와 같은 치환된 아미노 그룹일 경우, 반응도중 촉매량의 P-톨루엔 설폰산을 가하고 방향족 아민을 과량첨가하는 것이 바람직하다. 또한 생성물은 흔히 반응혼합물으로부터 직접 석출되기도 하지만 어떤 경우에는 용매를 증발시킴으로써 수득될 수도 있으며 물을 가하면 물과 혼합되는 용매를 사용하여 침전시킬 수도 있다.The reaction of the carboxylate of formula (II) with the aromatic amine of formula (III) is carried out in conventional suitable organic solvents, for example aromatics such as benzene, toluene, xylene, chlorobenzene, O-dichlorobenzene or tetrahydronaphthalin In hydrocarbons or ethers such as hexamethylphosphoric acid triamide or dimethoxyethane, diethylene glycol dimethyl ether or diphenyl ether, or directly in an excess of amine. The reaction is carried out at a temperature of 60 to 200 ° C. and in the formula (II) when X is an alkoxy group, it is carried out at 20 to 180 ° C. When X in the formula (II) is an alkoxy group, a phenylalkoxy group or a phenyl oxy group, the reaction is preferably azeotropically distilled or refluxed using a soxylene leach machine at boiling point, in toluene or xylene and supplied by molecular sieve To remove alcohol or phenol produced during the reaction. The product is precipitated by adding water using a solvent which is obtained in the crystalline phase from the reaction mixture or is miscible with water. In the formula (II), when X is an amino group or a substituted amino group as described above, it is preferable to add a catalytic amount of P-toluene sulfonic acid and to add an aromatic amine excessively during the reaction. The product is also often precipitated directly from the reaction mixture but in some cases it may be obtained by evaporating the solvent or may be precipitated using a solvent which is mixed with water when water is added.

2. R1이 메틸 또는 에틸그룹이고 R2및 Y가 상술한 바와 같은 구조식(I) 화합물은 다음구조식(IV)의 4-하이드록시-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 염기의 존재하에서 다음구조식(V)의 알킬할로게나이드와 반응시킴으로써 수득될 수 있다.2. The compound of formula (I) wherein R 1 is a methyl or ethyl group and R 2 and Y are as described above is 4-hydroxy-2H-1,2-benzothiazine-3-carbox of formula (IV) Amide-1,1-dioxide can be obtained by reacting an alkylhalogenide of formula (V) in the presence of a base.

Figure kpo00003
Figure kpo00003

상기 구조식에서 R2및 Y는 상술한 바와 같고, Hal은 할로겐 원자이고, R11은 메틸 또는 에틸그룹이다.In the above structural formula, R 2 and Y are as described above, Hal is a halogen atom, R 11 is a methyl or ethyl group.

반응을 수성매질, 메탄올, 에탄올, n-프로판올, 이소프로판을 또는 상기 용매의 혼합물와 같은 알코올성 매질 중에서 수행할 경우 염기로서는 수산화나트륨, 수산화칼륨 또는 수산화바륨과 같은 알칼리금속 또는 알칼리토금속 수산화물, 탄산나트륨 또는 탄산칼륨과 같은 알칼리 금속 또는 알칼리토금속 탄산염, 나트륨 메틸레이트, 칼륨 에틸레이트, 칼륨-3급-부틸레이트와 같은 알칼리금속 또는 알칼리토금속 알코올 레이트 또는 트리에틸아민과 같은 3급 아민을 사용한다.When the reaction is carried out in an alcoholic medium such as aqueous medium, methanol, ethanol, n-propanol, isopropane or a mixture of the above solvents, the base is an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or barium hydroxide, sodium carbonate or carbonate. Alkali or alkaline earth metal carbonates such as potassium, alkali metal or alkaline earth metal alcoholates such as sodium methylate, potassium ethylate, potassium tert-butylate or tertiary amines such as triethylamine are used.

알킬할로게나이드, 바람직하게는 알킬브로마이드 또는 알킬요오디드는 반응혼합물에 존재하는 다른 반응물에 알코올성 용액중에서 직접가하며 메틸브로마이드를 가할 경우는 반응은 폐용기내에서 수행한다. 용매로서 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 헥사메틸포스포르산 트리아미드를 사용할 수도 있다.Alkylhalogenides, preferably alkyl bromide or alkyl iodide, are added directly to the other reactants present in the reaction mixture in alcoholic solutions and when methyl bromide is added the reaction is carried out in a waste container. Dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric acid triamide can also be used as a solvent.

알칼리금속 탄산염 또는 알칼리토금속 탄산염을 염기로 사용할 경우 아세톤과 같은 지방족 케톤을 용매로서 사용한다.When alkali metal carbonate or alkaline earth metal carbonate is used as the base, an aliphatic ketone such as acetone is used as the solvent.

반응을 벤젠과 같은 아프로틱유기용매 또는 기타 방향족 탄화수소, 테트라하이드로푸란 또는 기타 비환상 또는 환상 에테르중에서 수행할 경우 알칼리금속 수소화물 또는 알칼리 토금속 수소화물, 예를 들어 수소화나트륨이 염기로서 사용될 수 있다. 알킬할로게나이드는 알칼리금속 수소화물 또는 알칼리토금속 수소화물이 구조식(IV)의 출발화합물과 완전히 반응한 후 가하여야 한다. 반응온도는 0내지 80℃이다.Alkali metal hydrides or alkaline earth metal hydrides such as sodium hydride may be used as the base when the reaction is carried out in an aprotic organic solvent such as benzene or other aromatic hydrocarbons, tetrahydrofuran or other acyclic or cyclic ethers. Alkylhalogenide should be added after the alkali metal hydride or alkaline earth metal hydride has completely reacted with the starting compound of formula (IV). Reaction temperature is 0-80 degreeC.

어떤 경우에는 상기 공정을 수행하기전에 구조식(II) 또는 (IV)화합물에서 4-하이드록시그룹을 보호그룹에 의해 보호하고 반응을 마친 후 이 보호그룹을 제거하는 것이 바람직하다. 따라서 예를 들면 4-하이드록시 그룹의 에테르화는 유리하며 이들 하이드록시 그룹을 공지의 방법에 따라 상응하는 알콕시 또는 페닐알콕시그룹, 예를 들어 탄소수 1내지 8의 알콕시그룹 또는 총탄소수 7 내지 10의 페닐알콕시그룹으로 전환시키고 이 반응후 이들 그룹을 브롬화수소산과 같은 무기산 중에서 100℃의 온도로 가열하거나 염소화탄화수소와 같은 비활성 용매중에서 -80°내지 +80℃의 온도로하여 삼브롬화 붕소 또는 삼염화 붕소와 같은 삼할로겐붕소를 첨가하여 제거한다.In some cases, it is preferable to protect the 4-hydroxy group by a protecting group in the compound of formula (II) or (IV) before carrying out the process and to remove the protecting group after the reaction. Thus, for example, etherification of 4-hydroxy groups is advantageous and these hydroxy groups can be converted according to known methods to the corresponding alkoxy or phenylalkoxy groups, for example alkoxy groups having from 1 to 8 carbon atoms or from 7 to 10 carbon atoms in total. Converted to phenylalkoxy groups and the reaction is followed by heating these groups to a temperature of 100 ° C. in an inorganic acid such as hydrobromic acid or to a temperature of −80 ° to + 80 ° C. in an inert solvent such as chlorinated hydrocarbons. The same is removed by addition of boron trihalogen.

필요한 경우 구조식(I) 화합물은 공지의 방법에 따라 생리적으로 무득한 무기 또는 유기염기와의 염으로 전환시킬 수 있다. 염기로서는 알칼리알코올레이트, 알칼리금속 수산화물, 알칼리토금속 수산화물, 트리알킬암모늄 하이드록사이드, 알킬아민, 바람직하게는 아미노폴리알코올, 특히 N-메틸-D-글루카민 등을 사용한다.If necessary, the compound of formula (I) can be converted into salts with physiologically disadvantageous inorganic or organic bases according to known methods. Alkali alcoholates, alkali metal hydroxides, alkaline earth metal hydroxides, trialkylammonium hydroxides, alkylamines, preferably aminopolyalcohols, in particular N-methyl-D-glucamine, are used as the base.

출발물질로 사용되는 X가 알콕시, 페닐알콕시 또는 페녹시기인 구조식(II)의 에스테르는 공지의 화합물이며 독일 공개명세서 제1,943,265호(미합중국 특허 제3,591,584호 참조)에 기술되어 있는 방법에 따라 제조할 수 있다. 따라서 출발물질을 제조하기 위하여 반응을 기지의 N-(카복시메틸)-1,2-벤조이소티아졸린-3-온-1,1-디옥사이드의 에스테르[참조 : ChemReports 30, 1267(1897)]로부터 출발하여 디메틸설폭사이드 또는 디메틸포름아미드와 같은 유기극성 용매중에서 나트륨 에탄올레이트와 같은 알칼리금속 알코올 레이트를 가한다.Esters of formula (II) wherein X as the starting material is an alkoxy, phenylalkoxy or phenoxy group are known compounds and may be prepared according to the methods described in German Publication No. 1,943,265 (see US Pat. No. 3,591,584). have. Thus, to prepare starting materials, the reaction was carried out from esters of known N- (carboxymethyl) -1,2-benzoisothiazolin-3-one-1,1-dioxide (ChemReports 30, 1267 (1897)). Starting with an alkali metal alcohol rate such as sodium ethanolate in an organic polar solvent such as dimethylsulfoxide or dimethylformamide.

R1이 수소인 구조식(II)의 상응하는 에스테르의 산성화가 이루어진 후 이에 의한 전위반응이 시작된다. 2-위치에 있는 에스테르를 R1이 상술한 바와 같은 기타그룹에 가하는 것이 필요한 경우 이 반응은 알킬할로게나이드, 바람직하게는 알킬 요오디드에 의해 가장 유리하게 수행될 수 있으며 알킬화는 염기의 존재하에서 수행된다.The acidification of the corresponding ester of formula (II), wherein R 1 is hydrogen, then initiates the potential reaction. If it is necessary to add the ester in the 2-position to other groups as described above for R 1 , this reaction can be carried out most advantageously with an alkylhalogenide, preferably alkyl iodide and the alkylation is in the presence of a base Is carried out under.

X가 아미노그룹 또는 치환된 아미노그룹인 구조식(II)의 출발화합물은 문헌에 공지되어 있다. 이 화합물은 독일공개명세서 제1,943,265호(참조 : 미합중국 특허 제3,591,584호)에 기술되어 있는 방법에 따라 구조식(II)의 4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 20내지 200℃의 온도에서 디메틸설폭사이드 또는 3급-부탄올과 같은 통상의 용매중에서 구조식 NH2-R4(여기서 R4는 수소원자, 탄소수 1내지 8의 알킬그룹, 탄소수 3내지 10의 사이클로알킬그룹, 총산소수 7내지 10의 페닐알킬그룹 또는 페닐그룹이다)와 반응시켜 제조한다.Starting compounds of formula (II) wherein X is an amino group or a substituted amino group are known in the literature. This compound is prepared according to the method described in German Publication No. 1,943,265 (see US Patent No. 3,591,584), 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate- dimethyl sulfoxide or a tertiary 1,1-dioxide at a temperature of 20 to 200 ℃ - Structure in conventional solvents such as butanol, NH 2 -R 4 (wherein R 4 is an alkyl group of hydrogen atoms, having 1 to 8 carbon atoms, And a cycloalkyl group of 3 to 10, a phenylalkyl group of 7 to 10 total oxygen or a phenyl group).

X가 할로겐인 구조식(II)의 출발물질은, 예를 들어, 상응하는 4-하이드록시 또는 4-알콕시-2H-1,2-벤조티아진-3-카복실산-1,1-디옥사이드를 실온 내지 반응혼합물의 환류온도에서 벤젠 및 디메틸포름아미드와 같은 용매중에서 할로겐화 티오닐과 반응시켜 제조할 수 있다.Starting materials of the formula (II) wherein X is halogen are, for example, the corresponding 4-hydroxy or 4-alkoxy-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide from room temperature to It can be prepared by reacting with thionyl halide in a solvent such as benzene and dimethylformamide at the reflux temperature of the reaction mixture.

구조식(III) 화합물은 문헌에 공지되어 있다.Structural formula (III) compounds are known from the literature.

(참조 : 에이치. 에르렌메이어, 제트.헤르츠펠트 및 비.프리즈, Helv. chim. Acta 83, 1291 [1955] 또는 케이.디.쿨카르니 및 엠.브이.쉬르사트 J. Sci. andlnd Research (India), 18B, 411 [1959] or C.A. 54, 14230d[1960]).(See H. Erlenmeyer, J. Hertzfeld and B. Freeze, Helv. Chim. Acta 83, 1291 [1955] or K. D. Kulcarni and M. V. Sursart J. Sci. Andlnd Research) (India), 18B, 411 [1959] or CA 54, 14230d [1960]).

구조식(IV)의 출발화합물은 R1이 수소인 구조식(II)의 4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 20내지 180℃의 온도의 적절한 통상의 유기용액중에서 구조식(III)의 방향족 아민과 반응시켜 제조한다.The starting compound of formula (IV) is a temperature of 20 to 180 ° C. of 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide of formula (II) wherein R 1 is hydrogen. It is prepared by reacting with an aromatic amine of formula (III) in a suitable conventional organic solution.

상술한 바와 같이 구조식(I)의 4-하이드록시-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드 및 생리적으로 무득한 무기 또는 유기염기와의 염은 가치있는 약학적 성질을 갖고 있다. 이들 화합물은 강력한 소염작용을 가지며 염증으로 인한 고통을 덜어주고 류마티즘의 치료에 매우 적절하며 혈전증 치료작용을 나타낸다.As mentioned above, the salts of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of structural formula (I) and physiologically deficient inorganic or organic bases are valuable. Has pharmaceutical properties These compounds have a strong anti-inflammatory action, relieve pain from inflammation, are very suitable for the treatment of rheumatism, and have a therapeutic action for thrombosis.

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥시사이드(=A)는 쥐에게 경구투여하의 쥐위에 대한 궤양치료효과에 관해서는 물론, 란달-셀리토(Randal-Selitto)에 의해 규정된 시험 규칙에서의, 염증으로 인한 고통에 대한 이화합물의 효과에 관하여 관절염에 대한 소염작용에 관해 기지의 4-하이드록시-2-메틸-N-(4-메틸-2-티아졸릴)-2H-1, 2-벤조티아진-3-카복스아미드-1,1-디옥사이드(-B) 및 4-하이드록시-2-메틸-N-(2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드(수득시캄)(=C)와 비교하여 시험한다.4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxyside (= A) Anti-inflammatory for arthritis in relation to the effect of ulceration on the rat's stomach under oral administration to rats, as well as the effect of this compound on pain caused by inflammation, in the test rule defined by Randal-Selitto. 4-hydroxy-2-methyl-N- (4-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide-1,1-dioxide (- B) and 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (obtained sicam) (= C Test in comparison with).

[쥐에서의 관절염에 대한 소염작용의 측정][Measurement of Anti-inflammatory Effects on Arthritis in Rats]

시험을 시작할때 점성 파라핀오일에 M부티리쿰을 녹인 1%의 현탁액 0.1ml를 평균체중이 210g인 Chbb:THOM-숫쥐의 오른쪽뒷발의 발바닥에 주사한다. 시험물질을 1%의 메틸 셀룰로오즈(1ml/100g동물)에 마쇄시켜 M. 부티리쿰을 주사한 날로부터 20일동안 매일 한번씩 식도를 통해 투여한다.At the beginning of the test, 0.1 ml of a 1% suspension of M-butyricum in viscous paraffin oil is injected into the sole of the right hind paw of Chbb: THOM-male with a mean weight of 210 g. The test substance is ground in 1% methyl cellulose (1 ml / 100 g animals) and administered via the esophagus once daily for 20 days from the injection of M. butyricum.

관절염을 유발한 후 21일째에 시험물질로 처리한 동물의 오른쪽발(주사한곳에서의 특별하지 않은 일차반응) 및 왼쪽발(면역학적으로 유도된 특별한 이차반응)의 부피를 대조공정으로 처리한 대조동물의 발의 부피와 비교한다. 선형희귀분석법을 사용하여 피엘러(Fieller)에 따른 신뢰성한계로 ED50의 값을 대조동물균과 비교하여 발의 팽윤을 50%까지 감소시키는 용량으로서 측정한다. [참조 : Quart. J. pharm. pharma-col 17, 117(1944)]Controlled treatment of the volume of the right foot (unspecified primary response at the injection site) and the left foot (immunologically induced special secondary response) of the animals treated with the test substance 21 days after inducing arthritis Compare with the volume of the animal's foot. Using a linear analysis of rare in contrast to the value of the ED 50 with reliability limit of the multiple PLL (Fieller) is measured as the capacity to reduce the foot swelling as compared to animals, fungi by 50%. [See: Quart. J. pharm. pharma-col 17, 117 (1944)]

[쥐의 위에 대한 궤양치료 효과의 측정][Measurement of Ulcer Therapy Effect on Rat's Stomach]

시험은 평균체중이 130g인 Chbb : THOM-숫쥐를 사용하여 시작한다. 시험동물에게 표준식사(알트로민-R)를 즉흥적으로 공급한다. 시험물질을 1% 메틸 셀룰로오즈(1ml/100g 동물)에 마쇄시켜서 식도를 통해 하루에 한번씩 3일간 연속적으로 투여한다. 마지막 투여하고 4시간후 동물을 죽인다. 육안으로 측정하기 위해 위를 해부하고 정액을 물로 세척한다. 적어도 하나의 위궤양 또는 출혈성 미란을 나타내는 동물의 백분율로부터 리치필드 및 윌콕손(Litchfield and Wilcoxon)의 방법을 사용하여 ED50을 계산한다. [참조 : J. Pharmacol. exp. Therap. 96, 99(1949)]The test is started using Chbb: THOM-male with an average weight of 130 g. Improvised diet (altromine-R) is given to test animals. The test substance is ground in 1% methyl cellulose (1 ml / 100 g animals) and administered continuously for three days once a day through the esophagus. Animals are killed 4 hours after the last dose. The stomach is dissected for visual measurements and the semen is washed with water. ED 50 is calculated using the method of Litchfield and Wilcoxon from the percentage of animals exhibiting at least one gastric ulcer or hemorrhagic erosion. [Reference: J. Pharmacol. exp. Therap. 96, 99 (1949)]

[급성독성의 측정][Measurement of Acute Toxicity]

급성독성은 평균체중이 20g인 Chbb : NMRI(SPF)-암수쥐를 사용하여 측정한다. 시험물질을 1%의 메틸셀룰로오즈(0.2ml/10g 동물)에 마쇄시켜 식도를 통해 투여한다.Acute toxicity was measured using Chbb: NMRI (SPF) -male mice with an average body weight of 20 g. Test substance is ground in 1% methylcellulose (0.2ml / 10g animals) and administered via the esophagus.

LD50치의 계산은 각 시험물질을 투여한지 14일 내에 죽은 동물의 백분율로부터 리치필드 및 윌콕손의 방법에 따라 수행한다.The calculation of the LD 50 value is performed according to the method of Lichfield and Wilcoxon from the percentage of animals killed within 14 days of administration of each test substance.

[결 과][result]

상기 시험으로부터 수득한 결과를 표 1에서 3까지에 표기한다. 화합물 A는 좌약을 주사한 장소에서 일어나는 쥐의 일차 소염반응에 대한 이의 효과에 관해 활성을 나타내며 이 활성은 화합물 C의 활성보다 3배 높다. 상대측의 발(특별한 2차 반응)에서 면역학적으로 유도되는 특별한 2차 반응에 대한 효과에 관해 화합물 A는 화합물 C보다 약 5배 가량 효과가 높다. 놀랍게도 화합물 A의 위에 대한 융화성은 화합물 C에 비해 훨씬 좋다. 화합물 C는 주의 위에 대한 약한 소염 작용에도 불구하고 화합물 A보다 2배나 강력한 궤양치료효과를 나타낸다. 화합물 A의 치료범위는 화합물 C보다 7배 가량 넓다. (표 4참조)The results obtained from the above test are shown in Tables 1 to 3. Compound A shows activity on its effect on primary anti-inflammatory responses in rats that occur at the site of suppository injection, which is three times higher than that of Compound C. Compound A is about five times more effective than Compound C on the effects on immunologically induced specific secondary responses in the paw of the other side (special secondary responses). Surprisingly, the compatibility of Compound A with the stomach is much better than Compound C. Compound C exhibits twice the potent ulcer healing effect than Compound A, despite its mild anti-inflammatory effect on the stomach. The therapeutic range of Compound A is about seven times wider than Compound C. (See Table 4)

화합물 B는 화합물 A의 소염작용에 완전히 도달하지 못한다. 화합물 B의 결정적인 단점은 위에 대해 강력한 궤양치료효과를 나타내는 것이다. (화합물 A보다 6배가 강력함).Compound B does not fully reach the anti-inflammatory action of Compound A. The decisive disadvantage of Compound B is its strong ulcerative effect on the stomach. (6 times more potent than Compound A).

화합물 B의 궤양치료 작용은 이의 소염작용보다 비교적 명백하므로 화합물 B는 소염제로서 치료적으로 사용될 수 없다. 화합물 B의 치료율은 화합물 C의 치료율보다 훨씬 낮다(표 4 참조). 화합물 A의 치료범위는 화합물 B에 비하여 10배정도 넓다. 급성독성에 관해서는, 이들 3가지 화합물사이에 아무런 중요한 차이점을 관찰할 수 없다. 이것은 화합물 A에서의 소염 유효투여량과 독성유효 투여량사이의 차이점이 기타 화합물보다 명백하게 크다는 것을 의미한다. (표 5 참조). 그러나 이 결과는 그다지 중요하지 않다. 비스테로이드성 소염제가 치료적으로 사용될 수 있는 경우, 급성독성은 투여한계효과를 나타내지 않는다. 이러한 약제학적 현상에서 볼때 위장로에서의 궤양치료효과는 하루 일회씩 장기간 투여하는 것을 제한하고 있다.The ulcerative action of Compound B is relatively clearer than its anti-inflammatory action, so Compound B cannot be used therapeutically as an anti-inflammatory agent. The treatment rate of Compound B is much lower than that of Compound C (see Table 4). The therapeutic range of Compound A is about 10 times wider than Compound B. As for acute toxicity, no significant difference can be observed between these three compounds. This means that the difference between the anti-inflammatory effective dose and the toxic effective dose in Compound A is clearly greater than in other compounds. (See Table 5). But this result is not so important. If nonsteroidal anti-inflammatory agents can be used therapeutically, acute toxicity has no limiting effect. In this pharmaceutical phenomenon, the effect of treating gastric ulcers in the gastrointestinal tract is limited to long-term administration once a day.

[표 1]TABLE 1

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*1일당 투여량* Dose per day

[표 2]TABLE 2

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Figure kpo00005

[표 3]TABLE 3

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Figure kpo00006

[표 4]TABLE 4

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Figure kpo00007

[표 5]TABLE 5

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Figure kpo00008

화합물 A 및 C는 염증의 고통에 대한 이의 활성에 관해 더욱 시험한다.Compounds A and C are further tested for their activity on the pain of inflammation.

소염으로 인한 고통에 대한 활성을 체중이 100내지 130g인 Chbb : THOM -숫쥐를 사용하여 란달 및 셀리토의 방법에 따라 시험한다. [참조 : Arch. int Pharmacodyn 111, 409(1957)] 시험물질을 효모부종을 유도한지 90분후 식도를 통해 주사한다. 90분후 고통의 시작을 시험물질로 처리한 동물과 메틸셀룰로오즈 담체만으로 처리한 대조동물에서 측정하고 선형회귀분석법을 사용하여 피엘러에 따른 신뢰성 한계로 ED50의 값을 계산한다. ED50은 고통의 신작을 50% 증가시키는 투여량이다.Activity against pain caused by anti-inflammatory is tested according to the methods of Randall and Celito using Chbb: THOM-males weighing 100 to 130 g. [Reference: Arch. int Pharmacodyn 111, 409 (1957)] The test substance is injected through the esophagus 90 minutes after inducing yeast edema. After 90 minutes, the onset of pain is measured in test-treated animals and control animals treated with methylcellulose carrier only, and the value of ED 50 is calculated using the linear regression method with the limit of reliability according to Fjäller. ED 50 is a dose that increases 50% new pain.

다음의 표 6은 이 시험에서, 얻은 결과를 나타낸 것이다.Table 6 below shows the results obtained in this test.

쥐에서의 약학적 시험에서, 시험물질 A는 시험물질 C에 비하여 염증으로 유도되는 고통에 대한 증가된 효과성을 나타낸다.In the pharmaceutical test in rats, test substance A shows an increased effect on inflammation-induced pain compared to test substance C.

[표 6]TABLE 6

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다음 실시예는 본 발명을 더욱 설명한다.The following examples further illustrate the invention.

[실시예 1]Example 1

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

메틸 4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트의-1,1-디옥사이드 26.9g(0.1몰) 및/2.5g(0.11몰)의 2-아미노-5-메틸-티아졸의 혼합물을 질소압하에서 24시간동안 4ℓ의 크실렌중에서 환류시킨다. 생성된 메탄올을 속실레 침출기내에 존재하는 4Å-분자체로 제거한다. 뜨거운 반응용액을 여과한 후 냉각시키고 철야방치하면 여액으로부터 결정성 조생물이 수득된다. (32.0g, 이론치의 91%).26.9 g (0.1 mole) and / 2.5 g (0.11 mole) of 2-amino--1,1-dioxide of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate The mixture of 5-methyl-thiazole is refluxed in 4 L of xylene for 24 hours under nitrogen pressure. The resulting methanol is removed with 4'-molecular sieve present in the Soxile Leachator. The hot reaction solution is filtered, cooled and left overnight to obtain crystalline crude from the filtrate. (32.0 g, 91% of theory).

에틸렌 클로라이드에서 재결정한 후 26.0g(이론치의 74%)의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤존티아진-3-카복스아미르-1,1-디옥사이드를 수득한다.26.0 g (74% of theory) of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzonthiazine-3-car after recrystallization from ethylene chloride Obtain voxamir-1,1-dioxide.

융점 : 254℃(분해)Melting Point: 254 ℃ (Decomposition)

1H-NMR([D6]-DMSO) : δ=8.2-7.8(m, 4,5-H ∼ 8-H), 7.36(d, 1, J=0.75Hz, 4'-H), 2.90(S, 3, N-CH3), 2.36(d, 3, J=0.75Hz), 5-CH3) 및 2개의 교환가능한 양자.1 H-NMR ([D 6 ] -DMSO): δ = 8.2-7.8 (m, 4,5-H to 8-H), 7.36 (d, 1, J = 0.75 Hz, 4'-H), 2.90 ( S, 3, N-CH 3 ), 2.36 (d, 3, J = 0.75 Hz), 5-CH 3 ) and two interchangeable protons.

C14H13N3O4S2(351.40)C 14 H 13 N 3 O 4 S 2 (351.40)

계산치 : C 47.85, H 3.73, N 11.96, S 18.21Calculated Value: C 47.85, H 3.73, N 11.96, S 18.21

실측치 : 47.65, 3.72, 11.72, 18.40Found: 47.65, 3.72, 11.72, 18.40

[실시예 2]Example 2

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드의 나트륨염.Sodium salt of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

7.0g(20밀리몰)의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를, 200ml의 메탄올에 1.1g(20밀리몰)의 나트륨 메틸레이트를 녹인 용액에 가한다. 혼합물을 가열하고 생성된 황색용액을 여과한 후 진공하에서 증발 건조시킨다. 아세톤 및 에테르를 잔사에 가한 잔사를 여과하여 7.25g(이론치의 97.5%)의 4-하이드록시-2-메틸-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드 나트륨염을 수득한다.7.0 g (20 mmol) 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Was added to a solution of 1.1 g (20 mmol) of sodium methylate dissolved in 200 ml of methanol. The mixture is heated and the resulting yellow solution is filtered and evaporated to dryness in vacuo. 7.25 g (97.5% of theory) of 4-hydroxy-2-methyl- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine- filtered through the residue obtained by adding acetone and ether to the residue. 3-carboxamide-1,1-dioxide sodium salt is obtained.

융점 : 214℃(분해)Melting Point: 214 ° C (Decomposition)

[실시예 3]Example 3

4-하이드로시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드의 N-메틸-D-글로카민염.N-Methyl-D- of 4-Hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Glucamine salts.

6.0g(17.1밀리몰)의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드 및 3.33g(17.1밀리몰)의 N-메틸-D-글루카민을 1ℓ의 증류수에 녹인다. 60℃까지 가열한 후 용액을 여과하고 여액을 진공하에서 60ml로 증발시킨다. 결정으로 수득된 4-하이드록-N-메틸-D-글루코사민염을 여과하고 80℃, 진공하에서 5산화인으로 탈수시킨다. 수득량 5.2g(이론치의 56%) 융점 :11℃6.0 g (17.1 mmol) 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide And 3.33 g (17.1 mmol) of N-methyl-D-glucamine in 1 L of distilled water. After heating to 60 ° C. the solution is filtered and the filtrate is evaporated to 60 ml under vacuum. The 4-hydroxy-N-methyl-D-glucosamine salt obtained as crystals is filtered and dehydrated with phosphorus pentaoxide under vacuum at 80 ° C. Yield 5.2 g (56% of theory) Melting Point: 11 ° C

C21H20N4O9S2(546.63)C 21 H 20 N 4 O 9 S 2 (546.63)

계산치 : C 46.14, H 5.53, N 10.25, S 11.73Calculated Value: C 46.14, H 5.53, N 10.25, S 11.73

실측치 : 45.95, 5.76, 10.24. 11.98Found: 45.95, 5.76, 10.24. 11.98

[실시예 4]Example 4

4-하이드록시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-티옥사이드4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-thioxide

4-하이드록시-2H-1,2-벤조티아진-3-카복실레이드 및 2-아미노-5-메틸-티아졸로부터 실시예 1과 유사하게 제조한다.Prepared analogously to Example 1 from 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate and 2-amino-5-methyl-thiazole.

조생성물(이론치의 65%)를 클로로포름/에탄올(97:3)을 용충제로 사용하는 컬럼 크로마토그라피(메르크-실리카겔 60, 입자크기 : 0.2내지 0.5mm)로 정제하여 4-하이드로시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다.(이론치의 31%)The crude product (65% of theory) was purified by column chromatography (merc-silica gel 60, particle size: 0.2 to 0.5 mm) using chloroform / ethanol (97: 3) as a solvent. -(5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (31% of theory)

융점 : 233℃(분해) 에틸렌클로라이드Melting Point: 233 ° C (Decomposition) Ethylene Chloride

C13H11N3O4S2(337.38)C 13 H 11 N 3 O 4 S 2 (337.38)

계산치 : C 46.21, H 3.29, N 12.45, S 19.01Calculated Value: C 46.21, H 3.29, N 12.45, S 19.01

실측치 : 46.20, 3.34, 12.52, 19.12Found: 46.20, 3.34, 12.52, 19.12

[실시예 5]Example 5

2-에틸-4-하이드록시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드.2-ethyl-4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

메틸 2-에틸-4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트 및 2-아미노-5-메틸-티아졸로부터 실시예 1과 유사하게 제조된다.Prepared analogously to Example 1 from methyl 2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate and 2-amino-5-methyl-thiazole.

수득율 : 이론치의 82%Yield: 82% of theory

융 점 : 크실렌중에서 247℃(분해)Melting Point: 247 ° C (decomposition) in xylene

C15H15N3O4S2(365.43)C 15 H 15 N 3 O 4 S 2 (365.43)

계산치 : C 49.30, H 4.14, N 11.50, S 17.55Calculation: C 49.30, H 4.14, N 11.50, S 17.55

실측치 : 49.25, 4.07, 11.40, 17.72Found: 49.25, 4.07, 11.40, 17.72

[실시예 6]Example 6

N-(5-에틸-2-티아졸릴)-4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드N- (5-ethyl-2-thiazolyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

메틸 4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트의 1,1-디옥사이드 및 5-에틸-2-아미노-티아졸로부터 실시예 1과 유사하게 제조된다.Prepared analogously to Example 1 from 1,1-dioxide and 5-ethyl-2-amino-thiazole of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate .

수득율 : 이론치의 67%Yield: 67% of theory

융 점 : 크실렌에서 260℃(분해)Melting Point: 260 ° C (decomposition) in xylene

C15H15N4O2(365.43)C 15 H 15 N 4 O 2 (365.43)

계산치 : C 49.30, H 4.14, N 11.50, S 17.55Calculation: C 49.30, H 4.14, N 11.50, S 17.55

실측치 : 49.20, 4.19, 11.30, 17.63Found: 49.20, 4.19, 11.30, 17.63

[실시예 7]Example 7

4-하이드록시-2-메틸-N-(5-n-프로필-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-n-propyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

메틸 4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트의 1,1-옥사이드 및 2-아미노-5-n-프로필-티아졸을 톨루엔에 녹인 용액으로부터 실시예 1과 유사하게 제조된다.1,1-oxide and 2-amino-5-n-propyl-thiazole of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate are run from a solution of toluene Prepared similarly to Example 1.

수득율 : 이론치의 48%Yield: 48% of theory

융 점 : 디옥산 석유에테르에서 210℃(분해)Melting Point: 210 ℃ (Digest) in Dioxane Petroleum Ether

C16H17N3O4S2(379.46)C 16 H 17 N 3 O 4 S 2 (379.46)

계산치 : C 50.64, H 4.52, N 11.07, S 16.90Calculated Value: C 50.64, H 4.52, N 11.07, S 16.90

실측치 : 50.90, 4.64, 10.97, 17.00Found: 50.90, 4.64, 10.97, 17.00

[실시예 18]Example 18

2,6-디메틸-4-하이드로시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드2,6-dimethyl-4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

4-하이드록시-2,6-디메틸-2H-1,2-벤조티아진-3-카복실레이트의 1,1-디옥사이드 4.0g(14밀리몰) 및 2.0g(17밀리몰)의 2-아미노-5-메틸-티아졸을 물을 제거한 크실렌 200ml중에서 24시간동안 환류시킨다. 냉각시킨 후 결정을 여과하고 에틸렌 클로라이드에서 재결정하여 3.6g의 2,6-디메틸-4-하이드로시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다.4.0 g (14 mmol) and 2.0 g (17 mmol) 2-amino-5 of 1,1-dioxide of 4-hydroxy-2,6-dimethyl-2H-1,2-benzothiazine-3-carboxylate -Methyl-thiazole is refluxed for 24 hours in 200 ml of water removed xylene. After cooling, the crystals were filtered and recrystallized in ethylene chloride to give 3.6 g of 2,6-dimethyl-4-hydrocy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3 -Carboxamide-1,1-dioxide is obtained.

수득율 : 이론치의 70%Yield: 70% of theory

융 점 : 257℃(분해)Melting Point: 257 ℃ (Decomposition)

1H-NMR(CDCl3+TFA) : δ=7.98(brs, 1, 5-H), 7.92(d, 1, J=4Hz, 8-h), 7.7(brd, 1, J=4 Hz, 7-H), 7.47(d, 1, J=1 Hz, 4'-H), 2.96(S, 3, N-CH3) 및 2.6(br S, 6,6-CH3및 5'-CH3).1 H-NMR (CDCl 3 + TFA): δ = 7.98 (brs, 1, 5-H), 7.92 (d, 1, J = 4 Hz, 8-h), 7.7 (brd, 1, J = 4 Hz, 7 -H), 7.47 (d, 1, J = 1 Hz, 4'-H), 2.96 (S, 3, N-CH 3 ) and 2.6 (br S, 6,6-CH 3 and 5'-CH 3 ).

C15H15N3O4S2(365.45)C 15 H 15 N 3 O 4 S 2 (365.45)

계산치 : C 49.30, H 4.14, N 11.50, S 17.55Calculation: C 49.30, H 4.14, N 11.50, S 17.55

실측치 : 49.40, 4.24, 11.45, 17.35Found: 49.40, 4.24, 11.45, 17.35

용매로 크실렌대신 0-디클로로-벤젠, 테트라하이드로 나프탈린 또는 디에틸렌글리콜디메틸에테르를 사용할 경우 동일한 화합물을 각각 70, 60 또는 75%의 수득율을 얻는다. 출발 물질은 다음의 방법에 따라 제조된다 :When using 0-dichloro-benzene, tetrahydro naphthalin or diethylene glycol dimethyl ether instead of xylene, the same compounds are obtained in yields of 70, 60 or 75%, respectively. Starting materials are prepared according to the following method:

46g(0.23몰)의 5-메틸-벤즈이소티아졸로-3(2H)-온1,1-디옥사이드를 500ml의 물에 9.16g(0.23몰)의 수산화나트륨을 녹인 용액에 가하고 비등할 때까지 가열한 후 용액을 여과하고 진공하에 증발시킨다. 생성된 잔사에 톨루엔을 수차례 가한 후 톨루엔을 증류시킨다. 200ml의 디메틸설폭사이드 및 34.72g(0.32몰)의 메틸 클로로아세테이트를 상기 잔사에 가한 후 반응혼합물을 3시간동안 120℃로 가열한다. 냉각시킨 후 이 용액을, 300ml의 물에 42g의 나트륨아세테이트를 녹인 용액에 교반하면서 가하고 침전을 여과하여 물로 세척한 다음 다시 200ml의 물로 세척하고 흡인하여 제거한다. 침전을 건조시켜 메틸 5-메릴-3-옥소-벤즈 이소티아졸로-2(3H)-클로로아세테이트의 1,1-디옥사이드 48.8g(이론치의 79%)을 수득한다.46 g (0.23 mole) of 5-methyl-benzisothiazolo-3 (2H) -one1,1-dioxide was added to a solution of 9.16 g (0.23 mole) of sodium hydroxide in 500 ml of water and heated until boiling. The solution is then filtered and evaporated in vacuo. Toluene was added several times to the resulting residue, and then toluene was distilled off. 200 ml of dimethylsulfoxide and 34.72 g (0.32 mole) of methyl chloroacetate are added to the residue, and the reaction mixture is then heated to 120 ° C. for 3 hours. After cooling, the solution was added to the solution of 42 g of sodium acetate dissolved in 300 ml of water, with stirring. The precipitate was filtered, washed with water, washed again with 200 ml of water, and removed by aspiration. The precipitate is dried to give 48.8 g (79% of theory) of 1,1-dioxide of methyl 5-meryl-3-oxo-benz isothiazolo-2 (3H) -chloroacetate.

융점 : 115℃Melting Point: 115 ℃

메틸 5-메틸-3-옥소-벤즈이소티아졸로-2(3H)-클로로 아세테이트의 1,1-디옥사이드 38g(0.14몰)을 23.9g(044몰)의 나트륨메틸레이트와 혼합한 후 격렬히 교반하면서 물을 제거한 톨루엔 250ml를 먼저 가하고 다음에 물을 제거한 3급-부탄올 42ml를 가한다. 이어서 황색 반응혼합물을 1시간동안 65℃로 가열하고 냉각한 후 빙수에 붓고 에테르를 가한다. 수성상을 에테르로 2회 추출하고 진한 염산수용액으로 조심스럽게 산성화한 후 에테르로 다시 추출하고 에테르상을 물로 세척한 다음 건조 및 증발시킨다. 잔사를 에틸아세테이트에 재결정하여 27.6g(이론치의 73%)의 메틸 4-하이드록시-6-메틸-2H-1,2-벤조티아진-3-카복실레이트의 1,1-디옥사이드를 수득한다.38 g (0.14 mole) of 1,1-dioxide of methyl 5-methyl-3-oxo-benzisothiazolo-2 (3H) -chloro acetate were mixed with 23.9 g (044 mole) sodium methylate and vigorously stirred 250 ml of water-free toluene is added first, followed by 42 ml of tert-butanol without water. The yellow reaction mixture is then heated to 65 ° C. for 1 hour, cooled, poured into ice water and ether is added. The aqueous phase is extracted twice with ether, carefully acidified with concentrated aqueous hydrochloric acid solution, then extracted again with ether, the ether phase washed with water, dried and evaporated. The residue is recrystallized in ethyl acetate to give 27.6 g (73% of theory) of 1,1-dioxide of methyl 4-hydroxy-6-methyl-2H-1,2-benzothiazine-3-carboxylate.

융점 : 169℃Melting Point: 169 ℃

메틸-4-하이드록시-6-메틸-2H-1,2-벤조티아진-3-카복실레이트의 1,1-디옥사이드 25g(0.092몰) 및 메틸요오디드 36.9g(0.26몰)을 185ml의 테트라하이드로푸란에 현탁된다. 100ml의 물에 5.2g(0.092몰)의 수산화칼륨을 녹인 용액을 상기 현탁액에 가하고 24시간 후 20g의 메틸요오디드를 더욱 가한 다음 24시간 후 메틸 2,6-디메틸-4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트의 1,1-디옥사이드를 여과하여 세척 및 건조시킨다. 수득량 : 9.9g(이론치의 38%)25 g (0.092 mole) of 1,1-dioxide of methyl-4-hydroxy-6-methyl-2H-1,2-benzothiazine-3-carboxylate and 36.9 g (0.26 mole) of methyl iodide were charged with 185 ml of tetra Suspended in hydrofuran. A solution of 5.2 g (0.092 mol) of potassium hydroxide in 100 ml of water was added to the suspension, and after 24 hours, 20 g of methyliodide was further added, followed by methyl 2,6-dimethyl-4-hydroxy-2H- after 24 hours. The 1,1-dioxide of 1,2-benzothiazine-3-carboxylate is filtered off and dried. Yield: 9.9 g (38% of theory)

융점 : 186℃Melting Point: 186 ℃

[실시예 9]Example 9

2,7-디메틸-4-하이드록시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드2,7-dimethyl-4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

메틸 2,7-디메틸-4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트의 1,1-디옥사이드 2.83g(0.01몰) 및 2-아미노-5-메틸-티아졸 1.25g(0.011몰)을 크실렌중에서 실시예 8과 유사하게 반응시켜 3.1g(이론치의 84%)의 수득한다.2.83 g (0.01 mol) of 1,1-dioxide of methyl 2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate and 1.25 2-amino-5-methyl-thiazole g (0.011 mol) is reacted in xylene similarly to Example 8 to yield 3.1 g (84% of theory).

융점 : 228℃(크실렌에서)Melting Point: 228 ° C (in xylene)

반응을 톨루엔중에서 수행하여 동일한 생성물을 수득한다.The reaction is carried out in toluene to give the same product.

수득율 : 70gYield: 70 g

C15H15N304S2(365.45)C 15 H 15 N 3 0 4 S 2 (365.45)

계산치 : C 49.30, H 4.14, N 11.50, S 17.55Calculation: C 49.30, H 4.14, N 11.50, S 17.55

실측치 : 49.25, 4.08, 11.41, 17.62Found: 49.25, 4.08, 11.41, 17.62

출발물질은 다음과 같이 제조된다.Starting materials are prepared as follows.

5-메틸-벤즈이소티아졸로-3(2H)-온-1,1-디옥사이드(실시예 8참조)와 유사한 6-메틸-벤즈이소티아졸로-3(2H)-온-1,1-디옥사이드를 수산화나트륨 및 메틸 클로로아세테이트와 반응시켜 메틸 6-메틸-3-옥소-벤즈이소티아졸로-2(3H)-아세테이트(융점 : 메탄올에서 139℃)를 수득한다. 이어서 톨루엔/3급부탄올에서 나트륨메틸레이트와 재반응시켜 메틸 4-하이드록시-7-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 얻은 후 메틸요오디드와 반응시켜 메틸 2,7-디메틸 -4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한다.6-methyl-benzisothiazolo-3 (2H) -one-1,1-dioxide similar to 5-methyl-benzisothiazolo-3 (2H) -one-1,1-dioxide (see Example 8) Is reacted with sodium hydroxide and methyl chloroacetate to afford methyl 6-methyl-3-oxo-benzisothiazolo-2 (3H) -acetate (melting point: 139 ° C. in methanol). Re-reaction with sodium methylate in toluene / tert-butanol to give methyl 4-hydroxy-7-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide followed by methyliodide To react with methyl 2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide.

융점 : 183℃Melting Point: 183 ℃

[실시예 10]Example 10

4-하이드록시-6-메톡시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-6-methoxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

5.2g(0.017몰)의 메틸 4-하이드록시-6-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드 및 2.2g(0.019몰)의 2-아미노-5-메틸-티아졸을 200ml의 크실렌중에서 24시간동안 환류시킨다. 냉각시킨 후 결정을 여과하고 테트라 하이드로푸란에서 재결정하여 5.8g(이론치의 89%)의 4-1,1-디옥사이드를 수득한다.5.2 g (0.017 mole) of methyl 4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.2 g (0.019 mole) 2-amino-5-methyl-thiazole is refluxed in 200 ml of xylene for 24 hours. After cooling, the crystals are filtered and recrystallized in tetra hydrofuran to yield 5.8 g (89% of theory) of 4-1,1-dioxide.

융점 : 260℃Melting Point: 260 ℃

1H-NMR(CDCl3+TFA) : δ=7.95(d,1,J=4Hz, 8-H), 7.62(d,1,J=1,5Hz,5-H), 7.45(d,1,J=1Hz, 4'-H), 7.35(dd,1,J-4Hz 및 J'=1.5Hz, 6-H), 4.00(S,3,OCH3), 2.95(S,3,N-CH3) 및 2.55(d,3,J=1Hz, 5'-CH3).1 H-NMR (CDCl 3 + TFA): δ = 7.95 (d, 1, J = 4 Hz, 8-H), 7.62 (d, 1, J = 1,5 Hz, 5-H), 7.45 (d, 1, J = 1Hz, 4'-H), 7.35 (dd, 1, J-4Hz and J '= 1.5Hz, 6-H), 4.00 (S, 3, OCH 3 ), 2.95 (S, 3, N-CH 3 ) and 2.55 (d, 3, J = 1 Hz, 5′-CH 3 ).

C15H15N3O5S2(381.45)C 15 H 15 N 3 O 5 S 2 (381.45)

계산치 : C 47.23, H 3.96, N 11.02, S 16.81Calculated Value: C 47.23, H 3.96, N 11.02, S 16.81

실측치 : 47.50, 4.10, 10.87, 16.58Found: 47.50, 4.10, 10.87, 16.58

출발물질은 다음과 같이 제조된다.Starting materials are prepared as follows.

5-메틸-벤즈이소티아졸로-3(2H)-온-1,1-디옥사이드(실시예 8)에 상응하는 5-메톡시-벤즈 이소티아졸로-3(2H)-온-1,1-디옥사이드를 수산화나트륨 및 메틸클로로아세테이트와 반응시켜 메틸 5-메톡시-3-옥소-벤즈이소티아졸로-2(3H)-아세테이트-1,1-디옥사이드를 얻은 후 톨루엔/급 부탄올중에서 나트륨 메틸레이트와 재반응시켜 메틸 4-하이드록시-6-에톡시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 얻고 (융점 에틸아세테이트/사이클로헥산에서 183℃) 이어서 메틸화하여 메틸 4-하이드록시-6-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한다. 융점 : 164℃5-methoxy-benz isothiazolo-3 (2H) -one-1,1-equivalent to 5-methyl-benzisothiazolo-3 (2H) -one-1,1-dioxide (Example 8) The dioxide was reacted with sodium hydroxide and methylchloroacetate to give methyl 5-methoxy-3-oxo-benzisothiazolo-2 (3H) -acetate-1,1-dioxide followed by sodium methylate in toluene / grade butanol. Reaction gave methyl 4-hydroxy-6-ethoxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (183 ° C. in melting point ethyl acetate / cyclohexane) followed by methylation Obtain methyl 4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide. Melting Point: 164 ℃

[실시예 11]Example 11

6-클로로-4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2- 벤조티아진-3-카복스아미드-1,1-디옥사이드 5.0g(16.5밀리몰)의 메틸 6-클로로-4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드 및 2.1g(18.5밀리몰)의 2-아미노-5-메틸-티아졸을 4Å-분자체와 함께 공급되는 속실레장치내에서 물을 제거한 크실렌 300ml중에서 24기간동안 환류시킨다.5.0 g of 6-chloro-4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide ( 16.5 mmol) methyl 6-chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.1 g (18.5 mmol) 2-amino- 5-Methyl-thiazole is refluxed for 24 hrs in 300 ml of xylene dewatered in a Soxylene apparatus supplied with 4'-molecular sieve.

냉각시킨 후 결정상으로 수득한 조생성물을 여과하고 디옥산에서 재결정하여 4.9g(이론치의 77%)의 6-클로로 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸리)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다. 융점 : 285℃(분해)After cooling, the crude product obtained in crystalline phase was filtered and recrystallized from dioxane to give 4.9 g (77% of theory) of 6-chloro 4-hydroxy-2-methyl-N- (5-methyl-2-thiazoli) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is obtained. Melting Point: 285 ° C (Decomposition)

1H-NMR([D6]-DMSO) : δ=8.05 및 7.9(m, 3,5-H, 7-H 및 8-H) ; 7.36(d,1,J=1Hz, 4'-H)1 H-NMR ([D6] -DMSO): δ = 8.05 and 7.9 (m, 3,5-H, 7-H, and 8-H); 7.36 (d, 1, J = 1 Hz, 4'-H)

2.95(S,3,N-CH3); 2.35(d,3,J=1Hz, 5'-CH3) 및 교환가능한 2개의 양자.2.95 (S, 3, N-CH 3 ); 2.35 (d, 3, J = 1 Hz, 5′-CH 3 ) and two exchangeables.

C14H12N3O4S2(385.86)C 14 H 12 N 3 O 4 S 2 (385.86)

계산치 : C 43.58, H 3.13, Cl 9.19, N 10.89, S 16.62Calculated Value: C 43.58, H 3.13, Cl 9.19, N 10.89, S 16.62

실측치 : 43.42, 3.21, 9.28, 10.68, 16.60Found: 43.42, 3.21, 9.28, 10.68, 16.60

출발물질은 다음의 방법에 따라 제조한다.Starting materials are prepared according to the following method.

43.6g(0.18몰)의 5-클로로-벤즈이소티아졸로-3(2H)-온-1,1-디옥사이드-나트륨염(5-클로로-벤조이소티아졸로-3(2H)-온-1,1-디옥사이드 및 수산화나트륨용액으로부터 제조함) 및 35ml(0.21몰)의 메틸클로로아세테이트를 100ml의 디메틸 설폭사이드중에서 3시간동안 120℃로 가열한다. 냉각시킨 후 진공하에서 증류하여 80ml의 디메틸설폭사이드를 제거한다. 남아 있는 잔사를 100g의 나트륨아세테이트를 함유하는 700ml의 물에 교반하여며 가한 후 메틸 5-클로로-3-옥소-벤즈이소티아졸로-2(3H)-아세테이트-1,1-디옥사이드의 침전을 흡인여과하고 세척 및 건조시킨다.43.6 g (0.18 mole) of 5-chloro-benzisothiazolo-3 (2H) -one-1,1-dioxide-sodium salt (5-chloro-benzoisothiazolo-3 (2H) -one-1, Prepared from 1-dioxide and sodium hydroxide solution) and 35 ml (0.21 mol) of methylchloroacetate are heated to 120 ° C. for 3 hours in 100 ml of dimethyl sulfoxide. After cooling, distillation under vacuum removes 80 ml of dimethylsulfoxide. The remaining residue was added to 700 ml of water containing 100 g of sodium acetate, with stirring, followed by aspiration of methyl 5-chloro-3-oxo-benzisothiazolo-2 (3H) -acetate-1,1-dioxide. Filter, wash and dry.

수득량 : 31.1g(이론치의 60%)Yield: 31.1 g (60% of theory)

융 점 : 118℃Melting Point: 118 ℃

상기 화합물 24.5g(84.5밀리몰)을, 물을 제거한 톨루엔(17ml의 무수 3급부탄올을 가함으로써 물을 제거함) 190ml에 나트륨메틸레이트 13.5g(253밀리몰)을 녹인 용액과 함께 45분동안 80℃로 가열한다. 냉각시킨 반응혼합물을 교반하면서 빙수에 가한 후 에테르로 추출한다. 수성상을 염산으로 산성화한 후 백색침전을 여과하고 물로 3차례 세척한 다음 건조시켜 14.6g(이론치 60%)의 메틸 6-클로로-4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한다. 융점 : 221℃(분해)24.5 g (84.5 mmol) of the compound was added to 190 ° C. in a solution of 13.5 g (253 mmol) of sodium methylate in 190 ml of toluene (to remove water by adding 17 ml of anhydrous tert-butanol) at 80 ° C. for 45 minutes. Heat. The cooled reaction mixture is added to ice water with stirring and extracted with ether. The aqueous phase was acidified with hydrochloric acid and the white precipitate was filtered, washed three times with water and dried to give 14.6 g (60% of theory) of methyl 6-chloro-4-hydroxy-2H-1,2-benzothiazine-3 -Carboxylate-1,1-dioxide is obtained. Melting Point: 221 ° C (Decomposition)

14.5g(50밀리몰)의 메틸 6-클로로-4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 165ml의 메탄올중에서 50ml의 1N 수산화나트륨용액에 21.3g(150밀리몰)의 메틸 요오디드를 녹인 용액과 반응시켜 12.35g(이론치의 81%)의 메틸 6-클로로-4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한다. 융점 : 201℃14.5 g (50 mmol) of methyl 6-chloro-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide was dissolved in 165 ml of methanol in 50 ml of 1N sodium hydroxide solution. 12.35 g (81% of theory) of methyl 6-chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3- when reacted with a solution of g (150 mmol) methyl iodide Obtained carboxylate-1,1-dioxide. Melting Point: 201 ℃

[실시예 12]Example 12

7-플루오로-4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드7-fluoro-4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

0.29g(1밀리몰)의 메틸 7-플루오로-4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드 및 0.125g(1.1밀리몰)의 2-아미노-5-메틸-티아졸을 50ml의 크실렌중에서 24시간동안 환류시킨다. 반응혼합물을 진공하에서 증발건조시킨 후 잔사를 크실렌/사이클로헥산으로 재결정하여 0.21g(이론치의 57%)의 7-플루오로-4-하이드록시-2-메틸-N-(5-메틸-2-티아졸리)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다. 융점 : 233℃0.29 g (1 mmol) of methyl 7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 0.125 g (1.1 mmol) 2-amino-5-methyl-thiazole is refluxed in 50 ml of xylene for 24 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was recrystallized from xylene / cyclohexane to give 0.21 g (57% of theory) of 7-fluoro-4-hydroxy-2-methyl-N- (5-methyl-2- Thiazoli) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is obtained. Melting Point: 233 ℃

벤젠을 용매로 사용할 경우 30시간동안 가열하여 이와 동일한 수득율을 얻는다.When benzene is used as a solvent, the same yield is obtained by heating for 30 hours.

C14H12FN3O4S2(369.40)C 14 H 12 FN 3 O 4 S 2 (369.40)

계산치 : C 45.52, H 3.27, N 11.38, S 17.36Calculated Value: C 45.52, H 3.27, N 11.38, S 17.36

실측치 : 45.40, 3.18, 11.42, 17.18Found: 45.40, 3.18, 11.42, 17.18

출발물질은 다음과 같이 제조된다.Starting materials are prepared as follows.

5-클로로-벤즈이소티아졸로-3(2H)-온-1,1-디옥사이드(실시예 11참조)와 유사한 6-플루오로-벤즈이소티아졸로-3(2H)-온-1,1-디옥사이드를 수산화나트륨용액 및 메틸클로로아세테이트와 반응시켜 6-플루오로-3-옥소-벤즈이소티아졸로-2(3H)-아세트산-메틸에스테르-1,1-디옥사이드를 수득한다.6-fluoro-benzisothiazolo-3 (2H) -one-1,1- similar to 5-chloro-benzisothiazolo-3 (2H) -one-1,1-dioxide (see Example 11) The dioxide is reacted with sodium hydroxide solution and methylchloroacetate to give 6-fluoro-3-oxo-benzisothiazolo-2 (3H) -acetic acid-methylester-1,1-dioxide.

(융점 : 이소프로판올/석유에테르에서 86℃). 이어서 나트륨메틸레이트(융점 206℃)와 재반응시켜 메틸 7-플루오로-4-하이드록시-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한 후 메틸요오디드와 다시 반응시켜 메틸 7-플루오로-4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한다. 융점 : 에틸렌 클로라이드에서 191℃(Melting point: 86 ° C. in isopropanol / petroleum ether). Re-reaction with sodium methylate (melting point 206 ° C.) to afford methyl 7-fluoro-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide followed by methylio Reaction with died gives methyl 7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide. Melting point: 191 ° C. in ethylene chloride

[실시예 13]Example 13

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

에틸 4-하이드록시-2-메틸-2N-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드 및 2-아미노-5-메틸-티아졸으로부터 실시예 1과 유사한 방법에 따라, 단 용매로는 0-디클로로벤젠을 사용하여 제조된다.(수득율 : 이론치의 76%). 융점 : 에틸렌클로라이드에서 254℃(분해)From ethyl 4-hydroxy-2-methyl-2N-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methyl-thiazole according to a similar method as in Example 1 However, it is prepared using 0-dichlorobenzene as the solvent. (Yield: 76% of theory). Melting point: 254 ° C (decomposition) in ethylene chloride

C14H13N3O4S2(351.040)C 14 H 13 N 3 O 4 S 2 (351.040)

계산치 : C 47.85, H 3.73, N 11.96, S 18.21Calculated Value: C 47.85, H 3.73, N 11.96, S 18.21

실측치 : 47.91, 3.78, 11.80, 18.42Found: 47.91, 3.78, 11.80, 18.42

[실시예 14]Example 14

4-하이드록시-2-메틸-N-(5-메틸2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-methyl2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

1.23g(4.5밀리몰)의 4-하이드록시-2H-1,2-메틸벤조티아진-3-카복실산 클로라이드-1,1-디옥사이드를 10ml의 디메틸포름아미드에 녹인 후 1.0g(9밀리몰)의 2-아미노-5-메틸-티아졸을 소량씩 가한다.1.23 g (4.5 mmol) of 4-hydroxy-2H-1,2-methylbenzothiazine-3-carboxylic acid chloride-1,1-dioxide was dissolved in 10 ml of dimethylformamide, followed by 1.0 g (9 mmol) of 2 A small amount of -amino-5-methyl-thiazole is added.

반응 혼합물을 실온에서 24시간동안 교반한 후 40ml의 물을 가한다. 혼합물을 실온에서 20분간 더욱 교반한후 침전을 여과하고 세척 및 건조시킨다. 에틸렌클로라이드에서 재결정하여 0.4g(이론치의 25%)의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다. 융점 : 254℃(분해)The reaction mixture is stirred at rt for 24 h before 40 ml of water are added. The mixture is further stirred at room temperature for 20 minutes, after which the precipitate is filtered off, washed and dried. 0.4 g (25% of theory) of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carbox, recrystallized from ethylene chloride Obtain amide-1,1-dioxide. Melting Point: 254 ℃ (Decomposition)

C14H13N3O4S2(351.40)C 14 H 13 N 3 O 4 S 2 (351.40)

계산치 : C 47.85, H 3.73, N 11.96, S 18.21Calculated Value: C 47.85, H 3.73, N 11.96, S 18.21

실측치 : 47.75, 3.88, 11.69, 17.98Found: 47.75, 3.88, 11.69, 17.98

[실시예 15]Example 15

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

1.0g(3밀리몰)의 4-하이드록시-2-메틸-N-페닐-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 250ml의 크실렌중에서 1,15g(10밀리몰)의 2-아미노-5-메틸-티아졸 및 0.1g의 P-톨루엔 설폰산과 함께 72시간동안 환류시킨다. 냉각시킨 후 반응혼합물을 2N 염산 및 물로 세척하고 건조시킨 후 진공하에서 증발시킨다. 남아 있는 잔사를 컬럼크로마토그라피(메르크-실리카겔 60, 입자크기 : 0.2내지 0.5mm, 용출제 : 클로로포름/에탈올 95.5)로 정제하여 0.25g(이론치의 24%)의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다.1.0 g (3 mmol) of 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 250 ml of xylene 10 mmol) of 2-amino-5-methyl-thiazole and 0.1 g of P-toluene sulfonic acid at reflux for 72 hours. After cooling the reaction mixture is washed with 2N hydrochloric acid and water, dried and evaporated under vacuum. The remaining residue was purified by column chromatography (merck-silica gel 60, particle size: 0.2 to 0.5 mm, eluent: chloroform / ethanol 95.5) to 0.25 g (24% of theory) of 4-hydroxy-2-. Methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is obtained.

융점 : 에틸렌클로라이드에서 254℃(분해)Melting point: 254 ° C (decomposition) in ethylene chloride

C14H13N3O4S2(351.40)C 14 H 13 N 3 O 4 S 2 (351.40)

계산치 : C 47.85, H 3.73, N 11.96, S 18.29Calculated Value: C 47.85, H 3.73, N 11.96, S 18.29

실측치 : 47.70, 3.78, 11.86, 18.01Found: 47.70, 3.78, 11.86, 18.01

[실시예 16]Example 16

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드, 2-아미노-5-메틸-티아졸 및 P-톨루엔설폰산으로부터 실시예 15와 유사한 방법에 따라 제조된다.Example from 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-5-methyl-thiazole and P-toluenesulfonic acid It is prepared according to a method analogous to 15.

수득율 : 이론치의 48%Yield: 48% of theory

융 점 : 254℃(에틸렌 클로라이드에서)Melting Point: 254 ° C (in Ethylene Chloride)

C14H13N3O4S2(351.40)C 14 H 13 N 3 O 4 S 2 (351.40)

계산치 : C 47.85, H 3.73, N 11.96, S 18.21Calculated Value: C 47.85, H 3.73, N 11.96, S 18.21

실측치 : 47.80, 3.79, 12.00, 18.05Found: 47.80, 3.79, 12.00, 18.05

[실시예 17]Example 17

2-메틸-4-하이드록시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드2-methyl-4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

30ml의 메탄올과 2.0ml의 1N 수산화나트륨의 혼합용액에 0.7g(2밀리몰)의 4-하이드로시-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 녹인 용액에 0.94g(6밀리몰)의 에틸요오디드를 가하고 실온에서 24시간동안 교반한 후 중화시키고 진공하에서 증발시킨다. 잔사를 컬럼크로마토그라피(메르크-실리카겔 60, 입자의 크기 : 0.2내지 0.5mm, 용출제 : 클로로포름/에탄올 95:5)로 정제한 후 크실렌에서 재결정하여 0.35mg(이론치의 48%)의 2-에틸-4-하이드록시-N-(5-메틸-2-타이졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다. 융점 : 크실렌에서 247℃(분해).0.7 g (2 mmol) 4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3 in a mixed solution of 30 ml of methanol and 2.0 ml of 1N sodium hydroxide. 0.94 g (6 mmol) of ethyl iodide is added to a solution of carboxamide-1,1-dioxide, stirred at room temperature for 24 hours, neutralized and evaporated under vacuum. The residue was purified by column chromatography (merck-silica gel 60, particle size: 0.2 to 0.5 mm, eluent: chloroform / ethanol 95: 5) and recrystallized from xylene to give 0.35 mg (48% of theory) of 2- Ethyl-4-hydroxy-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is obtained. Melting point: 247 ° C. (decomposition) in xylene.

수산화나트륨용액을 수산칼륨용액, 나트륨메틸레이트 및 칼륨 -3급 부틸레이트로 치환할 경우도 상기와 유사한 수득율을 얻는다.Similar yields are obtained when the sodium hydroxide solution is replaced with potassium hydroxide solution, sodium methylate and potassium tert-butyl butyrate.

C15H15N3O4S2(365.43)C 15 H 15 N 3 O 4 S 2 (365.43)

계산치 : C 49.30, H 4.14, N 11.50, S 17.55Calculation: C 49.30, H 4.14, N 11.50, S 17.55

실측치 : 49.20, 4.24, 11.60, 17.42Found: 49.20, 4.24, 11.60, 17.42

[실시예 18]Example 18

및 메틸요오디드로부터 실시예 17과 유사한 방법에 따라 제조된다. 수득율 : 이론치의 40%에탄올을 용매로 사용할 경우에는 수득율이 30%이다.And methyliodide according to methods analogous to Example 17. Yield: When 40% of theoretical value ethanol is used as a solvent, the yield is 30%.

융점 : 에틸렌 클로라이드에서 254℃(분해)Melting point: 254 ° C (decomposition) in ethylene chloride

C14H13N3O4S2(351.40)C 14 H 13 N 3 O 4 S 2 (351.40)

계산치 : C 47.85, H 3.73, N 11.96, S 18.21Calculated Value: C 47.85, H 3.73, N 11.96, S 18.21

실측치 : 48.00, 3.69, 12.02, 18.01Found: 48.00, 3.69, 12.02, 18.01

메틸 브로마이드를 사용하여 6시간동안 메탈올성용액의 환류온도로 가열한 후 상기의 동일한 생성물을 수득한다. 반응은 또한 n-프로판올, 디메틸 포름아미드, 디메틸아세트 아미드 및 헥사메틸포스포르산 트리아미드중에서 40 내지 60℃의 온도로 수행한다. 수득율은 20%(이론치의)이다.The same product is obtained after heating to reflux temperature of the metalolic solution for 6 hours using methyl bromide. The reaction is also carried out at a temperature of 40 to 60 ° C. in n-propanol, dimethyl formamide, dimethylacetamide and hexamethylphosphoric acid triamide. Yield is 20% (of theory).

[실시예 19]Example 19

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸리)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드4-hydroxy-2-methyl-N- (5-methyl-2-thiazoli) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

0.5ml의 48% 브롬화수소산 및 1ml의 빙초산을 0.2g(0.55밀리몰)의 4-메톡시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드에 가하고 24시간동안 방치한 후 반응혼합물을 수욕상에서 가열하고 이어서 진공하에서 증발건조시킨다. 잔사를 메틸렌클로라이드에 녹이고 물로 세척한 후 건조시키고 유기상을 증발시켜 0.1g(이론치의 52%)의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다.0.2 g (0.55 mmol) of 4-methoxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine in 0.5 ml of 48% hydrobromic acid and 1 ml of glacial acetic acid After addition to -3-carboxamide-1,1-dioxide and left for 24 hours, the reaction mixture is heated in a water bath and then evaporated to dryness in vacuo. The residue was dissolved in methylene chloride, washed with water, dried and the organic phase was evaporated to 0.1 g (52% of theory) of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1 To give, 2-benzothiazine-3-carboxamide-1,1-dioxide.

융점 : 에틸렌 클로라이드에서 254℃(분해)Melting point: 254 ° C (decomposition) in ethylene chloride

C14H13N3O4S2(351.40)C 14 H 13 N 3 O 4 S 2 (351.40)

계산치 : C 47.85, H 3.73, N 11.96, S 18.21Calculated Value: C 47.85, H 3.73, N 11.96, S 18.21

실측치 : 47.82, 3.67, 11.80, 18.01Found: 47.82, 3.67, 11.80, 18.01

출발물질은 다음의 방법에 따라 제조된다.Starting materials are prepared according to the following method.

26.9g(0.1몰)의 메틸 4-하이드록시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드, 85.1g(0.616몰)의 탄산칼륨 및 71g(0.5몰)의 메틸 요오디드를 1000ml의 아세톤중에서 16시간동안 환류시키고 4시간후 14g(0.1몰)의 메틸요오디드를 상기 반응혼합물에 가한다. 이어서 혼합물을 실온에서 12시간동안 교반하고 침전을 여과한 후 아세톤으로 세척한다. 여액을 진공하에서 증발시킨 후 사염화탄소에서 재결정하여 23.5g(이론치의 83%)의 메틸 4-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 수득한다. 융점 : 78℃26.9 g (0.1 mole) of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 85.1 g (0.616 mole) of potassium carbonate and 71 g ( 0.5 mole) of methyl iodide was refluxed in 1000 ml of acetone for 16 hours and after 4 hours 14 g (0.1 mole) of methyl iodide was added to the reaction mixture. The mixture is then stirred at rt for 12 h and the precipitate is filtered off and washed with acetone. The filtrate was evaporated in vacuo and then recrystallized from carbon tetrachloride to give 23.5 g (83% of theory) of methyl 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide To obtain. Melting Point: 78 ℃

7.8g(28밀리몰)의 메틸 4-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실레이트-1,1-디옥사이드를 75ml의 에탄올에 녹인 후 42ml의 1N 수산화칼륨용액을 상기 용액에 가한다. 반응용액을 6시간동안 환류시키고 실온에서 철야교반한 후 진공하에서 증발시킨다. 잔사를 물에 녹이고 에테르화한 후 수성상을 냉각시키면서 산성화하고 침전을 여과한 다음 물로 세척하여 4-메톡시-2-메틸-2H-벤조티아진-1,2-카복실산-1,1-디옥사이드를 수득한다.Dissolve 7.8 g (28 mmol) of methyl 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide in 75 ml of ethanol and 42 ml of 1N potassium hydroxide solution. Is added to the solution. The reaction solution is refluxed for 6 hours, stirred overnight at room temperature and evaporated under vacuum. The residue was dissolved in water, etherified, acidified with cooling of the aqueous phase, the precipitate was filtered off, washed with water and then 4-methoxy-2-methyl-2H-benzothiazine-1,2-carboxylic acid-1,1-dioxide To obtain.

수득량 : 6.3g(이론치의 84%)Yield: 6.3 g (84% of theory)

융 점 : 200℃Melting Point: 200 ℃

6.2g(23밀리몰)의 4-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실산-1,1-디옥사이드를 60ml의 벤젠에 현탁시킨 후 8.2ml(0.11밀리몰)의 염화티오닐 및 물을 제거한 디메틸포름아미드 0.5ml를 상기 현탁액에 가한다. 반응혼합물을 6시간동안 환류시키고 실온에서 방해교반한 후 진공하에서 증발시킨다. 잔사를 소량의 톨루엔에 녹이고 다시 증발시켜 6.9g(이론치의 100%)의 4-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실산 클로라이드-1,1-디옥사이드를 수득한다. 융점 : 117℃6.2 g (23 mmol) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide were suspended in 60 ml of benzene followed by 8.2 ml (0.11 mmol) of 0.5 ml of dimethylformamide from which thionyl chloride and water have been removed are added to the suspension. The reaction mixture is refluxed for 6 hours, stirred at room temperature and then evaporated in vacuo. The residue was dissolved in a small amount of toluene and evaporated again to give 6.9 g (100% of theory) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide. do. Melting Point: 117 ℃

150ml의 무수벤젠에 4.7g(16밀리몰)의 4-메톡시-2-메틸-2H-1,2-벤조티아진-3-카복실산클로라이드-1,1-디옥사이드를 녹인 용액을 20내지 30℃의 온도에서 1.5시간 내에, 100ml의 무수벤젠에 1.8g(16밀리몰)의 2-아미노-5-메틸티아졸 및 1.6g(16밀리몰)의 트리에틸아민을 녹인용액에 적가한다. 이어서 반응 혼합물을 실온에서 2시간동안 교반하고 1시간동안 환류시킨다. 반응혼합물을 가열된 채로 여과한 후 여액에 석유에테르를 가한다. 냉각시켜 3.1g의 2,5-디메틸-5H,6H-티아졸로[2', 3'-2,3]-피리미도[4,5-C]-1,2-벤조티아진-5-은-7,7-디옥사이드를 결정상으로 수득한다.A solution of 4.7 g (16 mmol) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide was dissolved in 150 ml of anhydrous benzene at 20 to 30 ° C. Within 1.5 hours at temperature, 1.8 g (16 mmol) of 2-amino-5-methylthiazole and 1.6 g (16 mmol) of triethylamine are added dropwise to 100 ml of anhydrous benzene. The reaction mixture is then stirred at room temperature for 2 hours and refluxed for 1 hour. The reaction mixture is filtered while heated and petroleum ether is added to the filtrate. Cooled to 3.1 g of 2,5-dimethyl-5H, 6H-thiazolo [2 ', 3'-2,3] -pyrimido [4,5-C] -1,2-benzothiazine-5-silver -7,7-dioxide is obtained as crystalline phase.

융점 : 에틸아세테이트에서 305℃(분해)Melting Point: 305 ° C (decomposition) in ethyl acetate

모액을 증발건조시키고 에틸아세테이트에서 재결정하여 1.8g(이론치의 31%)의 4-메톡시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 수득한다.The mother liquor was evaporated to dryness and recrystallized from ethyl acetate to give 1.8 g (31% of theory) of 4-methoxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine Obtain 3-carboxamide-1,1-dioxide.

융점 : 201℃Melting Point: 201 ℃

C15H15N3O4S2(365.44)C 15 H 15 N 3 O 4 S 2 (365.44)

계산치 : C 49.30, H 4.14, N 11.50, S 17.55Calculation: C 49.30, H 4.14, N 11.50, S 17.55

실측치 : 49.45, 4.07, 11. 43, 17.70Found: 49.45, 4.07, 11. 43, 17.70

약학적으로 사용하기 위해, 구조식(I) 화합물은 통상의 약제학적 제제로 제형화 한다. 성인의 일회 투여량은 2내지 100mg, 바람직하게는 5내지 25ml이고 하루의 투여량은 5내지 20mg, 바람직하게는 10내지 50mg이다.For pharmaceutical use, the compound of formula (I) is formulated in conventional pharmaceutical formulations. The single dose of an adult is 2 to 100 mg, preferably 5 to 25 ml and the daily dose is 5 to 20 mg, preferably 10 to 50 mg.

다음 실시예는 약제학적 제제의 제조방법을 설명한다.The following examples illustrate the preparation of pharmaceutical preparations.

[실시예 1]Example 1

10mg의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 함유하는 정제.A tablet containing 10 mg of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

조성 :Furtherance :

1개의 정제는 다음의 물질을 함유한다.One tablet contains the following materials.

Figure kpo00010
Figure kpo00010

[제조방법][Manufacturing method]

유효성분과 옥수수전분과의 혼합물을, 물에 녹인 폴리비닐피롤리돈의 14% 용액과 함께 메쉬크기가 1.5mm인체를 통해 입자화한 후 45℃에서 건조시키고 다시 상기의 체를 통과시킨다. 수득한 입자를 마그네슘 스테아레이트와 혼합한 후 정제로 타정한다.The mixture of active ingredient and corn starch is granulated with a 14% solution of polyvinylpyrrolidone dissolved in water through a 1.5 mm human body, then dried at 45 ° C. and passed through the sieve again. The obtained particles are mixed with magnesium stearate and compressed into tablets.

정제의 중량 300mgWeight of tablet 300mg

직경 10mm 평평함10mm diameter flat

[실시예 2]Example 2

10mg의 하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아이드-1,1-디옥사이들 함유하는 코팅한 정제Coated tablets containing 10 mg of hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxide-1,1-dioxides

조성 :Furtherance :

1개의 코팅한 정제는 다음과 같은 물질을 함유한다.One coated tablet contains the following materials.

Figure kpo00011
Figure kpo00011

[제조방법][Manufacturing method]

유효성분과 옥수수전분과의 혼합물을 10%의 수성 젤라틴혼합물와 함께 메쉬의 크기가 1.5mm인 체를 통해 입상화한 후 45℃에서 건조시키고 다시 상기의 체를 통과시킨다. 수득한 입자를 활석 및 마그네슘 스테아레이트와 함께 혼합한 후 코팅한 정제로 타정한다.The mixture of the active ingredient and corn starch is granulated with a 10% aqueous gelatin mixture through a sieve having a size of 1.5 mm, dried at 45 ° C. and passed through the sieve again. The obtained particles are mixed with talc and magnesium stearate and then compressed into coated tablets.

핵의 중량 300.0mgWeight of nucleus 300.0mg

직경 10mm 아아치형10mm diameter arch type

코팅한 정제의 핵을 공지의 방법에 따라 주로 서당 및 활석으로 구성되는 피막으로 둘러싼다. 완성된 제피정제를 밀납으로 광택을 낸다. 코팅한 정제의 중량 : 580mgThe nucleus of the coated tablet is enclosed with a coating consisting mainly of sucrose and talc according to known methods. The finished tablet is polished with beeswax. Weight of Coated Tablets: 580mg

[실시예 3]Example 3

5mg의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 함유하는 젤라틴 캅셀Gelatin capsules containing 5 mg 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

조성 :Furtherance :

1개의 젤라틴 캅셀은 다음의 성분을 함유한다.One gelatin capsule contains the following components.

Figure kpo00012
Figure kpo00012

[제조방법][Manufacturing method]

상기 물질을 먼저 혼합한 후 크기 1의 젤라틴 캅셀에 충진시킨다.The material is first mixed and then filled into size 1 gelatin capsules.

캅셀의 함량 : 400Capsule content: 400

[실시예 4]Example 4

25mg의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2 H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 함유하는 좌약Suppositories containing 25 mg 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2 H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

조성 :Furtherance :

1개의 좌약은 다음의 물질을 함유한다.One suppository contains the following substances.

유효성분 25.0mgActive ingredient 25.0 mg

좌약덩어리 1725.0mgSuppository chunk 1725.0 mg

[예 : 위텝솔 더블유(Witepsolw)45][Example: Witepsolw 45]

1750.0mg1750.0mg

[제조방법][Manufacturing method]

미세하게 분마한 유효성분을 침액균질기를 사용하여 40℃로 냉각된 용융상태의 좌약덩어리에 교반하며 가한다. 이 혼합물을 38℃에서 미리 냉각시킨 성형틀에 붓는다.The finely powdered active ingredient is added to the suppository lump in a molten state cooled to 40 ° C. using a immersion homogenizer. The mixture is poured into a mold previously cooled at 38 ° C.

좌약의 중량 : 1.75gWeight of suppository: 1.75 g

[실시예 5]Example 5

5ml중에 25mg의 4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 함유하는 현탁액.Containing 25 mg of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 5 ml Suspension.

조성 :Furtherance :

Figure kpo00013
Figure kpo00013

[제조방법][Manufacturing method]

DONSS, 벤조산, 나트륨 사이클라메이트 및 폴리비닐 피롤리돈을 70℃로 가열하여 물에 녹인다. 여기에 글리세린 및 에어로실을 가한 후 용액을 실온으로 냉각한다. 미세하게 분마한 유효성분을 침액균질기로 현탁시키고 방향제를 첨가한 후 목적하는 용량에 도달할 때까지 유효성분을 물로 충진시킨다. 5ml의 현탁액은 25mg의 유효성분을 함유한다.DONSS, benzoic acid, sodium cyclate and polyvinyl pyrrolidone are heated to 70 ° C. and dissolved in water. Glycerine and aerosil are added thereto, and the solution is cooled to room temperature. The finely powdered active ingredient is suspended with a dipping homogenizer and the fragrance is added and the active ingredient is filled with water until the desired dose is reached. 5 ml of suspension contains 25 mg of active ingredient.

[실시예]EXAMPLE

4-하이드록시-2-메틸-N-(5-메틸-2-티아졸릴)-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드의 N-메틸-D-글루카민염을 물에 녹여 제조한 주사용 0.2% 용액.N-methyl-D- of 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 0.2% injectable solution prepared by dissolving glucamine salt in water.

조성:Furtherance:

Figure kpo00014
Figure kpo00014

[제조방법][Manufacturing method]

상기 물질을 증류수에 녹인 후 필요량의 염화나트륨을 가하여 등장성으로 만든다. 목적하는 용량에 도달할 때까지 증류수를 가한다. 이 용액을 여과막(0.2㎛)으로 여과한 후 무급조건 하에서 멸균시킨 앰플에 충진시킨다.The material is dissolved in distilled water and then isotonicized by adding the required amount of sodium chloride. Distilled water is added until the desired volume is reached. This solution is filtered through a filtration membrane (0.2 μm) and filled into ampoules sterilized under unpaid conditions.

Claims (1)

다음 구조식(II)의 4-하이드록시-2H-1,2-벤조티아진-1,1-디옥사이드-3-카복실산 유도체를 20내지 200℃의 온도에서 통상의 유기용매 또는 구조식(III)의 아민의 과잉량의 존재하에서 다음 구조식(III)의 방향족 아민과 반응시키거나 R1이 메틸 또는 에틸그룹이고 R2가 하기에 기술하는 기와 같은 구조식(I) 화합물을 제조하기 위해서는 다음 구조식(IV)의 4-하이드록시-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드를 염기의 존재하에서 0내지 80℃의 온도로하여 다음 구조식(V)의 알킬할로게나이드로 처리하거나 이들 공정을 수행하기전에 구조식(II) 또는 (IV)의 4-하이드록시그룹을 보호그룹에 의해 보호하고 반응은 종결시킨 후 이 보호그룹을 제거하거나 수득한 구조식(I) 화합물을 무기 또는 유기염기를 사용하여 이의 염으로 전환시킴을 특징으로 하여 다음 구조식(I)의 4-하이드록시-2H-1,2-벤조티아진-3-카복스아미드-1,1-디옥사이드 또는 이의 염기와의 염을 제조하는 방법.4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid derivative of the following formula (II) at a temperature of 20 to 200 ° C. in a conventional organic solvent or amine of formula (III) To react with an aromatic amine of the following formula (III) in the presence of an excess of, or to prepare a compound of formula (I) such as a group wherein R 1 is a methyl or ethyl group and R 2 is described below, Alkylhalogenide of formula (V) wherein 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is brought to a temperature of 0 to 80 캜 in the presence of a base. The 4-hydroxy group of the formula (II) or (IV) is protected by a protecting group and the reaction is terminated prior to treatment with or before these processes. Or by converting to a salt thereof using an organic base, Process for preparing a 4-hydroxy -2H-1,2- benzo salts with thiazine-3-carboxamide-1,1-dioxide or a base of breakfast (I).
Figure kpo00015
Figure kpo00015
 상기 구조식에서 R1은 수소원자, 메틸 또는 에틸그룹이고, R2는 메틸, 에틸, 또는 n-프로필그룹이고 Y는 수소원자, 메틸 또는 메톡시그룹 또는 불소 또는 염소원자이고 X는 친핵적으로 교환가능한 그룹, 특히 탄소수 1내지 8의 알콕시그룹, 총탄소수 7내지 10의 페닐알콕시그룹, 페닐옥시그룹, 할로겐원자, 유리아미노그룹, 탄소수 1내지 8의 알킬아미노그룹, 탄소수 3내지 10의 사이클로알킬아미노그룹 ,탄소수 7내지 10의 페닐알킬 아미노그룹 또는 아닐리노그룹이고 Hal은 할로겐원자이고 R11는 메틸 또는 에틸그룹이다.Wherein R 1 is a hydrogen atom, methyl or ethyl group, R 2 is methyl, ethyl, or n-propyl group, Y is hydrogen atom, methyl or methoxy group or fluorine or chlorine atom and X is nucleophilic exchange Possible groups, in particular alkoxy groups having 1 to 8 carbon atoms, phenylalkoxy groups having 7 to 10 carbon atoms, phenyloxy groups, halogen atoms, free amino groups, alkylamino groups having 1 to 8 carbon atoms, cycloalkylamino groups having 3 to 10 carbon atoms Group, a phenylalkyl amino group or an anilino group having 7 to 10 carbon atoms, Hal is a halogen atom, and R 11 is a methyl or ethyl group.
KR7803563A 1978-11-25 1978-11-25 Process for preparing 4-hydroxy-2h-1 2-benzothiazine-3-carboxamide-1,1-dioxides KR810001502B1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100353110B1 (en) * 1999-12-11 2002-09-16 두산중공업 주식회사 A Vertical Rapping Device for Electrostatic Precipitators

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100353110B1 (en) * 1999-12-11 2002-09-16 두산중공업 주식회사 A Vertical Rapping Device for Electrostatic Precipitators

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