KR850000768B1 - Process for preparing thiazoline derivatives - Google Patents
Process for preparing thiazoline derivatives Download PDFInfo
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- KR850000768B1 KR850000768B1 KR1019840006150A KR840006150A KR850000768B1 KR 850000768 B1 KR850000768 B1 KR 850000768B1 KR 1019840006150 A KR1019840006150 A KR 1019840006150A KR 840006150 A KR840006150 A KR 840006150A KR 850000768 B1 KR850000768 B1 KR 850000768B1
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- 0 C*(C)*(C)(CC=N)CC=NC Chemical compound C*(C)*(C)(CC=N)CC=NC 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D277/32—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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- 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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- Thiazole And Isothizaole Compounds (AREA)
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Abstract
Description
본 발명은 다음 일반식(I)의 화합물 및 이의 약리학적으로 무독한 산부가염의 제조방법에 관한 것이다.The present invention relates to a compound of formula (I) and a pharmacologically toxic acid addition salt thereof.
상기식에서, R1은 C1-C8알킬, 탄소수 3내지 8의 사이클로알킬 또는 탄소수 3내지 4의 알케닐이고, R2,, R3및 R4는 같거나 다르며, 수소, 할로겐, 각기 탄소수 1내지 4의 알킬 또는 알콕시, 메틸렌디옥시, 에틸렌디옥시, 디메틸-또는 디에틸아미노, 또는 트리플루오로메틸이고 R5는 수소 또는 탄소수 1내지 3의 알킬이고 R6는 수소 또는 탄소수 1내지 6의 알킬이고 R7은 수소, 탄소수 1내지 12의 알킬, 탄소수 3내지 12의 사이클로알킬, 알릴, 페닐에틸 또는 벤질라디칼
상기화합물(유리형태 또는 약리학적으로 무독한 산부가염의 형태)은 중요한 약리학적 특성을 가지며 따라서 약제로서 적합하다.The compounds (in free form or in the form of pharmacologically toxic acid addition salts) have important pharmacological properties and are therefore suitable as medicaments.
본 발명에 따른 일반식(I)의 화합물은 다음과 같이 제조한다 :Compounds of formula (I) according to the invention are prepared as follows:
다음 일반식(Ⅷ)의 화합물을 산화제로 처리하고, 필요시 일반식 H-A의 유기또는 무기산을 사용하여 생성된 일반식(I)의 화합물을 이의 산부가염으로 전환시키거나, 염기를 사용하여, 생성된 일반식(I)의 화합물의 염을 일반식(I)의 유리염기성 화합물로 전환시킨다.The compound of formula (VII) is then treated with an oxidizing agent and, if necessary, the compound of formula (I) produced using an organic or inorganic acid of formula HA is converted to its acid addition salt or produced using a base. The salt of the compound of general formula (I) is converted into the free basic compound of general formula (I).
상기식에서 R1,R2,R3,R4,R5,R6,R7, 및 Y는 전술한 바와 같고, Hal은 염소 또는 브롬을 나타낸다.Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and Y are as described above, and Hal represents chlorine or bromine.
사용할 수 있는 무기산 H-A는, 예를 들어 할로겐화수소산(예 : 염산 및 브롬산), 황산, 인산 및 아미도설폰산이다.Inorganic acids H-A which can be used are, for example, hydrohalic acid (such as hydrochloric acid and bromic acid), sulfuric acid, phosphoric acid and amidosulfonic acid.
언급할 수 있는 유기산 H-A는, 예를 들어 메탄설폰산, 에탄설폰산, 벤젠설폰산 및 P-톨루엔설폰산이다.Organic acids H-A which may be mentioned are, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and P-toluenesulfonic acid.
본 발명에 따른 일반식(I)의 화합물은 또한 가능한 이성체형태로 존재할 수도 있으나, 간단히 하기 위해 특정물질의 가능한 이성체 형태중 하나만이 지적된다.The compounds of general formula (I) according to the invention may also exist in possible isomeric forms, but for simplicity only one of the possible isomeric forms of the particular substance is pointed out.
상기 방법에 따라서, 일반식(Ⅷ)의 화합물은 적당한 산화제, 바람직하게는 활성 망간-Ⅵ옥사이드를 사용하여 일반식(I)의 화합물로 전환된다. 사용되는 용매는 메틸렌클로라이드, 클로로포름 또는 테트라클로로에탄과 같은 할로겐화 탄화수소가 바람직하나, 특히 아세토니트릴이나 상기 용매와 아세토니트릴과의 혼합물이 바람직하다. 반응은 0내지 45℃, 바람직하게는 20내지 30℃의 온도에서 10내지 60시간에 걸쳐 수행한후, 산화제를 여과하고 반응을 완결시키기 위하여 반응혼합물에 메탄올, 프로판올, 이소프로판올, 부탄올 또는 빙아세트산과 같은 양자성 용매동용량을 가한 후 60내지 140℃의 온도에서 1내지 30시간동안 가열시킨다.According to this method, the compound of formula (VII) is converted to the compound of formula (I) using a suitable oxidizing agent, preferably active manganese-VI oxide. The solvent used is preferably a halogenated hydrocarbon such as methylene chloride, chloroform or tetrachloroethane, but especially acetonitrile or a mixture of the solvent and acetonitrile. The reaction is carried out over a period of 10 to 60 hours at a temperature of from 0 to 45 ° C., preferably from 20 to 30 ° C., and then filtered into the reaction mixture with methanol, propanol, isopropanol, butanol or ice acetic acid in order to filter the oxidant and complete the reaction. The same quantum solvent is added and heated for 1 to 30 hours at a temperature of 60 to 140 ℃.
일반식(Ⅷ)의 화합물은 다음 일반식(XV)의 화합물을 일반식(III)의 티오우레아와 반응시킴으로써, 독일 공개명세서 제2436263호에 기술된 것과 유사한 방법에 따라 수득된다.Compounds of formula (VII) are obtained according to a method analogous to that described in German Publication 2436263, by reacting a compound of formula (XV) with thiourea of formula (III).
상기식에서는 R1,R2,R3,R4,R5,R6,R7및 Y는 전술한 바와 같고 X는 할로겐,
일반식(I)의 화합물은 적당한 용매중에서 일반식 H-A의 산과 가역적으로 반응시킬 수 있다. 이 반응에서, 상기 산이 액체이거나 60℃보다 그다지 높지 않은 융점을 가지며 어떤 부반응도 일으키지 않는다면, 화합물(I)을 상기의 순수한 산에 바람직하게는 0°내지 60℃에서 도입시킬 수 있다.The compound of formula (I) can be reversibly reacted with the acid of formula H-A in a suitable solvent. In this reaction, if the acid is a liquid or has a melting point not higher than 60 ° C. and does not cause any side reactions, compound (I) can be introduced into the pure acid, preferably at 0 ° to 60 ° C.
그러나 반응은 물이나 디옥산, 테트라하이드로푸란, 에테르, 알킬부위의 탄소수가 1내지 4인 저급알킬아세테이트, 아세토니트릴, 니트로메탄, 아세톤, 메틸에틸케톤 등과 같은 유기용매중에서 수행하고, 탄소수 1내지 4의 저급알콜 및 탄소수 2내지 4의 카복실산이 특히 적합한 것으로 입증되었다. 화합물(I)몰당 1내지 1.5몰의 산 H-A가 사용되나 더 많은 양의 산을 사용할 수도 있다. 필요시, 반응은 0°내지 120℃, 바람직하게는 10°내지 60℃의 온도에서 수행한다. 반응은 적당히 발열적이다.However, the reaction is carried out in an organic solvent such as water, dioxane, tetrahydrofuran, ether, lower alkyl acetate having 1 to 4 carbon atoms, acetonitrile, nitromethane, acetone, methyl ethyl ketone, and the like. Lower alcohols and carboxylic acids having 2 to 4 carbon atoms have proven particularly suitable. 1 to 1.5 moles of acid H-A are used per mole of compound (I), although higher amounts of acid may be used. If necessary, the reaction is carried out at a temperature of 0 ° to 120 ° C, preferably 10 ° to 60 ° C. The reaction is moderately exothermic.
반응이 수용액중에서 수행될 경우, 일반적으로 화합물(I)은 산 H-A를 가한 후 즉시 용해하며 드문 경우에만 상응하는 산부가화합물이 침전되어 나온다. 용액이 수득되면, 본 발명에 따른 염을 완화한 조건하에 물을 증발제거시켜서, 바람직하게는 동결건조시켜서 분리시킨다. 반응을 유기용매중에서 수행할 경우 상기 산부가염은 특정상 H-A를 가하자마자 난용성 화합물로 침전되어 나온다. 용액이 얻어지면, 상기 산부가 화합물은, 필요시 먼저 용액을 농축시킨 후 적당한 침전제를 사용하여 침전시킨다. 적당한 침전제는 예를 들어 에틸 아세테이트, 디에틸 에테르, 디이소프로필 에테르, 아세톤 또는 아세토니트릴이다.When the reaction is carried out in an aqueous solution, generally compound (I) dissolves immediately after addition of acid H-A and in rare cases the corresponding acid addition compound precipitates out. Once a solution is obtained, the water according to the invention is separated off by evaporating off the water under moderate conditions, preferably by lyophilization. When the reaction is carried out in an organic solvent, the acid addition salt precipitates out as a poorly soluble compound as soon as H-A is added. Once a solution is obtained, the acid addition compound is first concentrated, if necessary, and then precipitated using a suitable precipitant. Suitable precipitants are, for example, ethyl acetate, diethyl ether, diisopropyl ether, acetone or acetonitrile.
산부가생성물은 아주 종종, 상당한 고순도에서조차 점성오일 또는 비결정성 유리상 생성물의 형태로 수득된다. 이들 비결정성 생성물은 유기용매로 처리하고, 필요시 40°내지 80℃로 가온시킴으로써 결정화시킬수 있다. 적당한 결정화-촉진 용매는, 특히 알킬부위에 1내지 4개의 탄소원자를 갖는 저급 알킬 아세테이트(예 : 메틸 아세테이트, 에틸 아세테이트 및 n-부틸 아세테이트), 저급 디알킬케톤(예 : 아세톤 또는 메틸 에틸케톤), 저급디알킬 에테르(예 : 디에틸 에테르, 디이소프로필 에테르 또는 디-n-부틸 에테르), 아세토니트릴 및 니트로메탄이며 어떤 경우에는 메탄올, 에탄올, 이소프로판을 또는 n-부탄올과 같은 저급알콜이다.Acid adducts are very often obtained in the form of viscous oils or amorphous glassy products, even at significant high purity. These amorphous products can be crystallized by treatment with an organic solvent and, if necessary, warmed to 40 ° to 80 ° C. Suitable crystallization-promoting solvents include, in particular, lower alkyl acetates (e.g. methyl acetate, ethyl acetate and n-butyl acetate) having 1 to 4 carbon atoms in the alkyl site, lower dialkyl ketones (e.g. acetone or methyl ethyl ketone), Lower dialkyl ethers (eg diethyl ether, diisopropyl ether or di-n-butyl ether), acetonitrile and nitromethane and in some cases lower alcohols such as methanol, ethanol, isopropane or n-butanol.
산부가생성물은 적당한 용매중에서 염기로 처리하여 탈양성자화시켜, 일반식(I)의 화합물을 얻을 수 있다. 사용될 수 있는 염기의 예는 수산화리튬, 수산화나트륨, 수산화칼륨, 수산화칼슘 또는 수산화바륨과 같은 무기 수산화물의 용액, 탄산나트륨, 탄산칼륨, 중탄산나트륨 또는 중탄산칼륨과 같은 탄산염 또는 중탄산염, 암모니아, 및 트리에틸아민, 디사이클로헥실아민, 피페리딘 및 메틸 디사이클로헥실아민과 같은 아민이다.The acid addition product can be deprotonated by treating with a base in a suitable solvent to obtain a compound of formula (I). Examples of bases that can be used are solutions of inorganic hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide, carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, ammonia, and triethylamine, Amines such as dicyclohexylamine, piperidine and methyl dicyclohexylamine.
반응을 수용성 매질중에서 실시할 경우, 유리염기성 화합물(I)은 난용성 화합물로 침전되고, 이는 여과하거나 유기용매, 바람직하게는 에틸아세테이트로 추출함으로써 분리시킬 수 있다. 적당한 유기반응매질은, 특히 탄소수 1내지 4의 저급알콜, 바람직하게는 메탄올 및 에탄올이나, 에틸 아세테이트, 디에틸 에테르, 테트라하이드로푸란, 디옥산, 디에틸렌글리콜 디메틸에테르, 디메틸포름아미드 등을 사용할 수도 있다. 화합물(I)을 얻는 반응은 자연발생적으로 일어난다. 반응은 -35°내지 100℃, 바람직하게는 0°내지 60℃의 온도에서 수행된다. 수-혼화성 유기용매가 사용되면, 일반식(I)의 유리 염기는, 필요시 반응 혼합물을 미리 농축시킨 후, 물을 가함으로써 침전된다. 수-불혼화성 용매가 사용되면, 사용된 공정은, 유리하게는 반응이 일어난 후 반응 혼합물을 물로 세척하고 임의로 건조시킨 후 유기 용매를 증발 제거시키는 것이다.When the reaction is carried out in an aqueous medium, the free basic compound (I) precipitates as a poorly soluble compound, which can be separated by filtration or extraction with an organic solvent, preferably ethyl acetate. Suitable organic reaction media are, in particular, lower alcohols having 1 to 4 carbon atoms, preferably methanol and ethanol, but also ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, dimethylformamide, and the like. have. The reaction to obtain compound (I) occurs spontaneously. The reaction is carried out at a temperature of -35 ° to 100 ° C, preferably 0 ° to 60 ° C. If a water-miscible organic solvent is used, the free base of formula (I) is precipitated by pre-concentrating the reaction mixture if necessary and then adding water. If a water-immiscible solvent is used, the process used is advantageously washing the reaction mixture with water after the reaction has taken place and optionally drying and then evaporating off the organic solvent.
1몰 이상의 충분히 강한 염기를 R6및/또는 R7이 수소를 나타내는 일반식(I)의 화합물에 작용시키면 설폰아미드 그룹의 탈양성자화가 일어나고 다음 일반식(XVII)의 염이 수득된다.The action of at least one mole of sufficiently strong base on a compound of formula (I) in which R 6 and / or R 7 represents hydrogen results in deprotonation of the sulfonamide group and a salt of the following formula (XVII) is obtained.
상기식에서 A는 알칼리금속 또는 알칼리토금속의 양이온이고 R1내지 R5및 Y는 진술한 바와 같고 R6또는 R7의 의미를 갖는다.Wherein A is a cation of an alkali metal or alkaline earth metal and R 1 to R 5 and Y are as stated and have the meaning of R 6 or R 7 .
사용될 수 있는 염기는, 알칼리금속 및 알칼리토금속의 수산화물(바람직하게는 NaOH 및 KOH), 알칼리금속 알콜레이트 및 알칼리토금속알콜레이트(예 : NaOCH3및 NaOCH5), NaH 나트륨 메틸설피닐메타이드 등이다.Bases that can be used are hydroxides of alkali metals and alkaline earth metals (preferably NaOH and KOH), alkali metal alcoholates and alkaline earth metal alcoholates (eg NaOCH 3 and NaOCH 5 ), NaH sodium methylsulfinylmethane, and the like. .
사용된 용매는 물이거나 메탄올, 에탄올, 이소프로판올, n-부탄올, 디메틸포름아미드, 디메틸설폭사이드 디에틸렌 글리콜 디메틸 에테르 또는 아세토니트릴과 같은 극성유기용매이다.The solvent used is water or a polar organic solvent such as methanol, ethanol, isopropanol, n-butanol, dimethylformamide, dimethylsulfoxide diethylene glycol dimethyl ether or acetonitrile.
적당한 산 H-A 1몰 부가시, 본 발명의 화합물(I)이 재차 얻어지며, 산으로 암모늄염을 사용할 수도 있다.Upon addition of 1 mole of a suitable acid H-A, compound (I) of the present invention is obtained again, and an ammonium salt may be used as the acid.
이 가역적 산/염기반응은 화합물(I)의 정제에 사용할 수 있다. 또한 상기염(XVII)은, 알킬화 반응에의 해설폰아미드 그룹에서 상응하게 전환되는 일반식(I)의 화합물을 제조하는데 사용할 수 있다.This reversible acid / base reaction can be used for the purification of compound (I). The salts (XVII) can also be used to prepare compounds of general formula (I) which are correspondingly converted in the sulfonamide group to the alkylation reaction.
다음 일반식(XVII)의 화합물은 신규이다.The compound of formula (XVII) is novel.
상기식에서 R1내지 R5및 Y는 전술한 바와같고 R은 R6또는R7의 의미를 갖고 A는 알칼리금속 또는 알칼리토금속의 양이온이다.Wherein R 1 to R 5 and Y are as defined above and R has the meaning of R 6 or R 7 and A is a cation of an alkali metal or alkaline earth metal.
이들은 특히 R6및/또는 R7이 수소인 일반식(I)의 화합물의 알킬화에 중간체로 적당하다.They are particularly suitable as intermediates for the alkylation of compounds of formula (I) wherein R 6 and / or R 7 is hydrogen.
본 발명에 따른 바람직한 화합물은 치환체가 하기 표 1에 기술된 의미를 갖는 일반식(I)의 화합물이며, 특히 바람직한 화합물은 치환체가 하기 표 2에 주어진 의미를 갖는 일반식(I)의 화합물이다.Preferred compounds according to the invention are compounds of formula (I) in which the substituents have the meanings set forth in Table 1 below, and particularly preferred compounds are compounds of formula (I) in which the substituents have the meanings given in Table 2 below.
[표 1]TABLE 1
R1=메틸, 에틸 또는 사이클로프로필R 1 = methyl, ethyl or cyclopropyl
R2=수소, 메틸, 에틸, 브롬, 염소, 불소, 트리플루오로메틸, 메톡시, 에톡시, -N(CH3)2또는 -N(C2H5)2 R 2 = hydrogen, methyl, ethyl, bromine, chlorine, fluorine, trifluoromethyl, methoxy, ethoxy, -N (CH 3 ) 2 or -N (C 2 H 5 ) 2
R3=수소, 메틸, 에틸 또는 염소R 3 = hydrogen, methyl, ethyl or chlorine
R4=수소 또는 메틸R 4 = hydrogen or methyl
R5=수소R 5 = Hydrogen
R6및 R7=수소, 메틸 또는 에틸(R6및 R7은 같거나 다르다)R 6 and R 7 = hydrogen, methyl or ethyl (R 6 and R 7 are the same or different)
Y=티아졸환의 2-,3-또는 4-위치에 있는 브롬, 염소 또는 메틸Y = bromine, chlorine or methyl in the 2-, 3- or 4-position of the thiazole ring
[표 2]TABLE 2
R1=메틸 또는 에틸 R5=수소R 1 = methyl or ethyl R 5 = hydrogen
R2=수소, 메틸, 염소, 메톡시, 불소 또는 트리플 R6및 R7=메틸 또는 에틸R 2 = hydrogen, methyl, chlorine, methoxy, fluorine or triple R 6 and R 7 = methyl or ethyl
루오로메틸 Y=티아졸환의 2-,3-또는 4-위치에 있는 염소Chlorine at the 2-, 3- or 4-position of the luoromethyl Y = thiazole ring
R3=수소 또는 메틸R 3 = hydrogen or methyl
R4=수소R 4 = Hydrogen
실시예에서 기술되는 티아졸린 유도체 이외에 하기 표 3에 열거한 일반식(I)의 화합물 및 이의 산부가생성물도 본 발명에 따라 수득될 수 있다.In addition to the thiazolin derivatives described in the examples, compounds of the general formula (I) and acid addition products thereof listed in Table 3 below can also be obtained according to the present invention.
[표 3]TABLE 3
(범례 : Me=메틸, Et=에틸, Prop=프로필, But=부틸, Pent=펜틸, Hex=헥실, i=이소, Sec=2급, c=사이클로이고, 치환체 앞에 주어진 수치는 페닐 라디칼상의 Y위치를 나타내며 이때 티아졸환은 1-위치이고 설파모일라디칼은 3-위치에 존재한다.)(Legend: Me = methyl, Et = ethyl, Prop = propyl, But = butyl, Pent = pentyl, Hex = hexyl, i = iso, Sec = secondary, c = cyclo, the value given before the substituent is Y on the phenyl radical Position, where the thiazole ring is in the 1-position and sulfamoyl radical is in the 3-position.)
본 발명에 따른 일반식(I)의 화합물은 중요한 약제이고, 혈청 지방단백질에 대한 유리한 효과로 두드러진다. 따라서 이들은 특히 혈청 지방단백질에 영향을 미치는 약제로 사용될 수 있다. 따라서, 또한 본 발명은 일반식(I)의 화합물 및 이의 약물학적으로 무독한 염에 근거한 약학적 제제, 및 약제로서의 용도에 관한 것이다.Compounds of general formula (I) according to the invention are important agents and stand out for their beneficial effects on serum lipoproteins. Thus they can be used in particular as agents which affect serum lipoproteins. Accordingly, the present invention also relates to pharmaceutical preparations based on the compounds of formula (I) and pharmacologically toxic salts thereof, and to their use as medicaments.
4-페닐-2,3-디하이드로티아졸린 유도체가 식욕감퇴, 중추신경계 흥분 및 이뇨작용을 갖는다는 사실이 문헌상에 기록되어 있고, 문헌상의 유도체들은 페닐부위에 설폰아미드 치환체를 갖지 않고 2-아미노그룹이 아릴로 치환되지 않은 화합물이다(참조 : 미합중국 특허 명세서 제3671533호 및 독일공개 명세서 제1938674호). 4-위치에 있는 페닐 라디칼이 설폰아미드 그룹을 갖지 않는 3-알킬-4-페닐-2-페닐이미노-4-티아졸린도 다음 문헌에 기술되어 있다. (참조 : Univ. Kansas Sci. Bull. 24,45-49 (1936)). 다른 치환체를 갖는 4-(3-설파모일-페닐)-3-알킬-2-이미노-4-티아졸린 및 티아졸리딘이 같은 방식으로, 특히 이뇨제로서, 문헌에 언급되어 있다(참조 : "Diuretic Agents", E.J. Cragoe, Jr., Editor: ACS-Symposium Series 83, page 24, Washington D.C., 1978).It is reported in the literature that 4-phenyl-2,3-dihydrothiazoline derivatives have anorexia, central nervous system excitability and diuresis, and derivatives in the literature do not have sulfonamide substituents at the phenyl site and are 2-amino. A group is a compound in which the group is not substituted with aryl (see US Patent Specification No. 3671533 and German Publication No. 1938674). 3-alkyl-4-phenyl-2-phenylimino-4-thiazolines in which the phenyl radical in the 4-position does not have sulfonamide groups are also described in the following documents. (See Univ. Kansas Sci. Bull. 24, 45-49 (1936)). 4- (3-Sulfamoyl-phenyl) -3-alkyl-2-imino-4-thiazoline and thiazolidine with different substituents are mentioned in the same way, in particular as diuretics, in the literature (" Diuretic Agents ", EJ Cragoe, Jr., Editor: ACS-Symposium Series 83, page 24, Washington DC, 1978).
본 발명에 따른 일반식(I)의 화합물이 혈청 지방단백질에 대한 매우 강력하고 유리한 효과를 나타내는 반면, 상기 문헌에 기술된 티아졸린 유도체는 아무런 효과가 없거나 정량적 및 정상적 관점에서 명백히 낮은 경미한 효과밖에 나타내지 못한다는 사실은 놀라운 일이었다.Whereas the compound of formula (I) according to the present invention shows a very potent and beneficial effect on serum lipoproteins, the thiazolin derivatives described in this document have no effect or only a minor effect which is clearly low in quantitative and normal terms. The fact that I could not do was surprising.
과지방단백질 혈증이, 특히 관상심장 질환에 있어서 동맥경화성 혈관 변화의 증가에 상당한 위험 요소로 된다는 것은 일반적으로 인지되어 있다. 따라서 상승된 혈청 지방단백질 수준을 낮추는 것은 동맥경화성 변화의 예방 및 회복에 매우 중요하다. 그러나 이는 여기에 관계된 혈청 지방단백질의 매우 특수한 범주인데, 왜냐하면 저밀도 지방단백질 (LDL) 및 더 낮은 밀도의 지방단백질 (VLDL)이 동백경화성 위험요소인 반면, 고밀도 지방단백질(HDL)은 관상 심장질환에 대해 보호작용을 하기 때문이다. 따라서 저지방혈증제는 혈청중의 VLDL-콜레스테롤 및 LDL-콜레스테롤의 수준을 낮추어야하며, 가능한한 HDL-콜레스테롤 농도에 아무런 영향도 주지 않거나 오히려 증가시켜야 한다. 본 발명에 따른 화합물은 중요한 치료학적 특성을 갖는다. 따라서 이들은 특히 LDL 및 VLDL의 농도를 낮추는 반면, HDL 획분을 아주 적은 정도로 감소시키거나 오히려 증가시킨다. 따라서, 이들은, 하기 시험에서 알 수 있는 바와 같이, 비교 화합물 클로피브레이트(clofibrate)와 비교시 상당한 진전을 나타낸다. 따라서, 이들은 원인적 위험 요소를 없애주기 때문에 동맥경화성 변화의 예방 및 회복에 사용될 수 있다. 이 위험 요소는 1차 과지방 단백질혈증 뿐만 아니라 당뇨병에 나타나는 2차 과지방단백질 혈증도 포함한다. 화합물(i)에 의해서는 상대적 간중량이 변하지 않는 반면, 저지방혈증 표준물질로 사용되는 클로피브레이트는 상대적 간중량의 실질적 증기를 초래시킨다.It is generally recognized that hyperlipoproteinemia poses a significant risk factor for increasing atherosclerotic vascular changes, especially in coronary heart disease. Therefore, lowering elevated serum lipoprotein levels is very important for the prevention and recovery of atherosclerotic changes. However, this is a very specific category of serum lipoproteins involved, because low density lipoproteins (LDL) and lower density lipoproteins (VLDL) are a camelliatic risk factor, while high density lipoproteins (HDL) are associated with coronary heart disease. Because it protects against. Therefore, hypolipidemic agents should lower the levels of VLDL-cholesterol and LDL-cholesterol in the serum and should increase or do not affect HDL-cholesterol concentration as much as possible. The compounds according to the invention have important therapeutic properties. They therefore, in particular, lower the concentrations of LDL and VLDL, while reducing or even increasing the HDL fraction to a very small extent. Thus, they show significant progress when compared to the comparative compound clofibrate, as can be seen in the following test. Therefore, they can be used for the prevention and recovery of atherosclerotic changes because they eliminate causal risk factors. This risk factor includes primary hyperlipoproteinemia as well as secondary hyperlipoproteinemia in diabetes. While relative liver weight does not change with compound (i), clofibrate used as a hypolipidemic standard results in substantial vapor of relative liver weight.
다음 표에 기록된 화합물들의 혈청 지방단백질에 대한 효과는 위스타 숫쥐를 폴리에틸렌 글리콜 400중에 다음에 기록된 화합물들을 현탁시킨 액을 인후소식자로 7일간 처리하여 연구했다. 또한 이 연구에는 용매인 폴리에틸렌 글리콜 400만을 투여한 대조군이 포함되고 대부분의 시험에서 표준 저지방혈증제인 클로피브레이트를 투여한 쥐군 1군도 포함되었다. 대체로 1군당 10마리의 동물을 사용했으며 처리 후반부에 이들 쥐를 약한 에테르마취에 도입시킨 후 안와신경총으로부터 혈액을 채취하고, 이로부터 얻어진 혈청을 모아서 널리 사용되는 방법에 따라 예비 초원심분리기로 저지방단백질을 분리시킨다. 혈청지방단백질을 초원심분리기에서 다음 밀도 범주로 분리시킨다 : VLDL 1.006; LDL 1.006내지 1.04; HDL 1.04 내지 1.21The effects of the compounds listed in the following table on serum lipoproteins were studied by treating the Wistar males with polyethylene glycol 400 in suspension of the following compounds for 7 days with throat throat. The study also included a control group administered with only 4 million polyethylene glycol solvents and a group of rats that received clofibrate, the standard hypolipidemic agent in most trials. In general, 10 animals per group were used, and these rats were introduced into weak ether anesthesia at the end of the treatment, and blood was collected from the orbital plexus, and the serum obtained therefrom was collected using low-fat protein as a preliminary ultracentrifuge according to a widely used method. To separate. Serum lipoproteins are separated in the ultracentrifuge into the following density categories: VLDL 1.006; LDL 1.006 to 1.04; HDL 1.04 to 1.21
초원심분리기로 분리된 지방단백질 획분의 콜레스트롤 함량은 베링거-만하임 시험과 함께 CHOC-PAP 방법에 의해 효소적으로 완전히 측정되고, 수득된 수치를 ㎍/혈청의 ㎖로 바꿨다. 동일조건하에서, 처리 그룹의 지방단백질 콜레스테롤의 변화는 대조그룹과 비교한 것이 표에 나타나 있다. 표에서 알 수 있는 바와 같이, 클로피브레이트는 LDL 획분에 대해서 거의 같은 저하를 나타내고 HDL 획분에 대해서는 상당한 저하를 나타내는 반면, 신규 화합물들은 동맥경화성 지방단백질획분(VLDL 및 LDL)에 대해 강력한 선택적저하를 나타내고 보호성 HDL 획분에 근본적으로 영향을 미치지 않거나 오히려 이 획분을 증가시킨다.Cholesterol content of lipoprotein fractions separated by ultracentrifuge was fully enzymatically determined by the CHOC-PAP method with the Beringer-Mannheim test and the obtained values were changed to μg / ml of serum. Under the same conditions, the change in lipoprotein cholesterol of the treatment group is shown in the table compared to the control group. As can be seen from the table, clofibrate exhibits about the same degradation for LDL fraction and significant degradation for HDL fraction, while new compounds show strong selective degradation for atherosclerotic lipoprotein fraction (VLDL and LDL). It does not fundamentally affect the protective HDL fraction or rather increases this fraction.
화합물을 7일간 경구투여한 후 쥐에서의 혈청지방단백질 농도의 변화Changes in Serum Lipoprotein Concentration in Rats After Oral Administration of Compounds for 7 Days
일반식(I)의 화합물의 치료적 조성물은, 특히 정제, 당의제, 캡슐제, 좌제 또는 시럽제의 형태로 존재할 수 있다. 신규 화합물들은 단독으로 또는 약물학적으로 무독한 부형제와의 혼합물로 사용될 수 있다. 경구투여 형태가 바람직하다. 이를 위해서, 상기 활성 화합물을 공지의 물질, 및 공지의 방법에 의해 적당한 투여형태, 즉 정제, 젤라틴캡슐제, 수용성 또는 유성 현탁제, 또는 수성 또는 유성 액제로 전환되는 물질과 혼합시키는 것이 바람직하다. 사용될 수 있는 불활성 부형제는, 예를 들어 탄산마그네슘, 락토즈 또는 옥수수전분이며 마그네슘 스테아레이트와 같은 다른 물질도 부가할 수 있다. 조성물은 무수 과립 또는 습과립의 형태로 제조할 수 있다. 사용될 수 있는 유성부형제 또는 용매는 특히 식물유 및 동물유로, 예를 들어 해바라기유 또는 간유이다. 일일용량은 약 50mg내지 5g일 수 있다. 1회 용량은 250내지 500mg을 함유하는 것이 바람직하다.Therapeutic compositions of compounds of formula (I) may be present in the form of tablets, dragees, capsules, suppositories or syrups, in particular. The novel compounds can be used alone or in admixture with pharmacologically toxic excipients. Oral dosage forms are preferred. To this end, it is preferred to mix the active compound with known materials and with the methods which are converted into suitable dosage forms, ie tablets, gelatin capsules, water-soluble or oily suspensions, or aqueous or oily solutions by known methods. Inert excipients that may be used are, for example, magnesium carbonate, lactose or corn starch and may also add other materials such as magnesium stearate. The composition can be prepared in the form of anhydrous granules or wet granules. Oily excipients or solvents that can be used are especially vegetable oils and animal oils, for example sunflower oil or cod liver oil. The daily dose may be about 50 mg to 5 g. It is preferable that a single dose contains 250-500 mg.
지방대사장해 치료용으로 상기 조성물은 통상의 충진제 및 부형제 이외에, 예를 들어 염분배설제, 레셀핀, 하이드랄라진, 구아네티닌, α-메틸-도파, 클로니딘 또는 β-교감신경차단제와 같은 고혈압치료제, 항과뇨산혈증작용을 가지는 약제, 경구용 당뇨병 치료제, 노인병 증상 치료용약제, 또는 순환을 개선시키는 약제를 함유할 수도 있다.For the treatment of fat metabolism, the composition may be used in addition to conventional fillers and excipients, for example, hypertensive agents such as salinary excretion agents, reselpin, hydralazine, guanetinine, α-methyl-dopa, clonidine or β-sympathetic blockers, It may contain a medicament having an antihyperacidic action, an oral diabetic agent, a geriatric disease treatment agent, or an agent for improving circulation.
하기 실시예에 주어진 융점 및 분해온도는 변경되지 않는다.The melting point and decomposition temperature given in the examples below do not change.
[실시예 1]Example 1
4-(4-클로로-3-설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸리딘4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazolidine
a) 2-브로모-1-(4-클로로-3-설파모일페닐)-에탄올a) 2-bromo-1- (4-chloro-3-sulfamoylphenyl) -ethanol
나트륨 시아노보로하이드라이드 0.94g을 테트라하이드로푸란 20ml의 2-브로모-4'-클로로-3'-설파모일아세토페논 3.1g 및 메틸 오렌지 수용액 1ml의 빙냉 용액에 교반하면서 가하고 빙아세트산 및 2NHCl의 1 : 1 혼합물을 적가하여 pH를 신속히 3내지 4로 조절하고(지시약 적색), 때때로 상기 산혼합물을 적가하여 pH를 이 수치로 유지시킨다. 약
무색결정체 ; 융점 145℃(분해)Colorless crystals; Melting Point 145 ° C (Decomposition)
b) s-[2-(4-클로로-3-설파모일페닐)-2-하이드록시에틸]-N-메틸-N-페이소티오로늄브로마이-2-브로모-1-(4-클로로-3-설파모일페닐)-에탄올 1.6g을 아세톤 30ml중의 1-메틸-3-페닐-티오우레아 0.8g용액에 가한다. 실온에서 48시간 동안 교반한 후, 용매를 감압하에 증류 제거시키고 잔사를 디이소프로필 에테르하에 결정화시킨다. 황색고체 ; 융점 115℃(분해)b) s- [2- (4-chloro-3-sulfamoylphenyl) -2-hydroxyethyl] -N-methyl-N-phosphothioronium bromai-2-bromo-1- (4- 1.6 g of chloro-3-sulfamoylphenyl) -ethanol is added to a 0.8 g solution of 1-methyl-3-phenyl-thiourea in 30 ml of acetone. After stirring for 48 hours at room temperature, the solvent is distilled off under reduced pressure and the residue is crystallized under diisopropyl ether. Yellow solid; Melting Point 115 ° C (Decomposition)
c) 4-(4-클로로-3-설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린c) 4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline
s-[2-(4-클로로-3-설파모일페닐)-2-하이드록시에틸]-N-메틸-N-페닐이소티오로늄 브로마이드 1.5g을 메틸렌 클로라이드 70ml에 용해시키고 활성망간-Ⅳ 옥사이드 15g을 가한 후 혼합물을 실온에서 30시간 동안 교반한다. 무기 침전물을 여과한 후 유기상을 중탄산나트륨 수용액과 함께 1시간 동안 진탕시키고, 물로 1회 세척하고 빙아세트산 50ml를 가하여 생성된 혼합물을 환류 냉각기하에 1시간 동안 비등시키고 용매를 감압에 제거한다. 잔사는 실시예 73의 생성물과 동일한 박층 크로마토그램(머크 실리카겔판, 용매 에틸 아세테이트)을 나타냈고 융점은 168내지 171℃이다.1.5 g of s- [2- (4-chloro-3-sulfamoylphenyl) -2-hydroxyethyl] -N-methyl-N-phenylisothioronium bromide was dissolved in 70 ml of methylene chloride and activated manganese-IV oxide After addition of 15 g, the mixture is stirred at room temperature for 30 hours. After filtering the inorganic precipitate, the organic phase was shaken with aqueous sodium bicarbonate solution for 1 hour, washed once with water and 50 ml of glacial acetic acid was added to boil the resulting mixture under reflux condenser for 1 hour and the solvent was removed under reduced pressure. The residue showed the same thin layer chromatogram as the product of Example 73 (mercury silica gel plate, solvent ethyl acetate) and had a melting point of 168 to 171 ° C.
[실시예 2]Example 2
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline
10ml의 트리에틸아민을 20ml의 메탄올중의 9.8g(0.02몰)의 4-(4-클로로-3-디메틸설파모일-페닐)-3-메틸-2-페닐이미노-4-티아졸린 하이드로브로마이드(융점 258내지 260℃)현탁액에 가한다. 혼합물을 약 20내지 30℃에서 3시간동안 교반시키고 용매를 감압하에 제거시킨다. 잔사를 100ml의 물에서 2시간동안 교반하고 결정을 여과해낸다. 융점 179내지 181℃10 ml of triethylamine was added to 9.8 g (0.02 mol) of 4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-2-phenylimino-4-thiazoline hydrobromide in 20 ml of methanol. (Melting point 258 to 260 ° C) is added to the suspension. The mixture is stirred at about 20-30 ° C. for 3 hours and the solvent is removed under reduced pressure. The residue is stirred in 100 ml of water for 2 hours and the crystals are filtered off. Melting Point 179 ~ 181 ℃
[실시예 3]Example 3
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린 하이드로클로라이드 150ml의 메탄올 중의 8.9g(0.02몰)의 4-(4-클로로-3-디메틸-설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린 염화수소의 포화에테르용액으로 산성화시키고, 용매를 증류 제거시키고 잔사를 에탄올로부터 재결정화시킨다. 융점 229내지 233℃(분해)4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrochloride 8.9 g (0.02 moles) of 4- (4-chloro-3 in 150 ml of methanol Acidify with a saturated ether solution of -dimethyl-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrogen chloride, distill off the solvent and recrystallize the residue from ethanol. Melting Point 229-233 ℃ (Decomposition)
[실시예 4]Example 4
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린 메탄설포네이트 4-(4-클로로-3-디메틸-설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린 및 0.02몰의 메탄설폰산으로부터, 실시예 3과 유사한 방법에 따라 수득된다. 무색결정체 ; 융점 198내지 199℃4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline methanesulfonate 4- (4-chloro-3-dimethyl-sulfamoylphenyl) -3- From methyl-2-phenylimino-4-thiazoline and 0.02 moles of methanesulfonic acid are obtained according to a method analogous to Example 3. Colorless crystals; Melting Point 198 ~ 199 ℃
[실시예 5]Example 5
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린-P-톡루엔설포네이트 4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린 및 0.02몰의 P-톨루엔설폰산으로부터, 실시예 3과 유사한 방법에 따라 수득된다. 무색결정체 ; 융점 196℃4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline-P-toluenesulfonate 4- (4-chloro-3-dimethylsulfamoylphenyl) From -3-methyl-2-phenylimino-4-thiazoline and 0.02 moles of P-toluenesulfonic acid, it is obtained according to a similar method as in Example 3. Colorless crystals; Melting Point 196 ℃
[실시예 6]Example 6
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2-메틸페닐이미노)-4-티아졸린 메탄올중의 4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2-메틸페닐이미노)-4-티아졸린 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득한다. 메탄올/에틸 아세테이로부터의 무색결정체 ; 158내지 162℃4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2-methylphenylimino) -4-thiazoline methanol 4- (4-chloro-3-dimethylsulfamoylphenyl) From 3-methyl-2- (2-methylphenylimino) -4-thiazoline hydrobromide and triethylamine, it is obtained according to a method similar to that of Example 2. Colorless crystals from methanol / ethyl acetate; 158-162 ℃
[실시예 7]Example 7
4-(4-클로로-3-디메틸설파모일페닐)-2-(4-플루로오페닐이미노)-3-메틸-4-티아졸린 4-(4-클로로-3-디메틸-설파모일페닐)-2-(4-플루로오페닐이미노)-3-메틸-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득된다. 무색 내지 담황색 결정체 ; 융점 144내지 145℃4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-fluophenylimino) -3-methyl-4-thiazoline 4- (4-chloro-3-dimethyl-sulfamoylphenyl ))-2- (4-Fluorophenylimino) -3-methyl-4-thiazoline hydrobromide, obtained according to a method analogous to Example 2. Colorless to pale yellow crystals; Melting Point 144-145 ℃
[실시예 8]Example 8
2-(4-디에틸아미노페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린 메탄올중의 2-(4-디에틸아미노페닐아미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린 하이드로브로마이드 및 트리에틸아민으로부터 실온에서, 실시예 2와 유사한 방법에 따라 수득된다. 융점 184내지 185℃2- (4-diethylaminophenylamino in 2- (4-diethylaminophenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline methanol ) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine are obtained according to a method analogous to Example 2 at room temperature. Melting Point 184 ~ 185 ℃
[실시예 9]Example 9
4-(4-클로로-3-디메틸설파모일페닐)-2-(2-클로로페닐-아미노)-3--메틸-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-chlorophenyl-amino) -3--methyl-4-thiazoline
표제화합물의 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법으로 따라 수득한다.From hydrobromide and triethylamine of the title compound, it is obtained in a similar manner to Example 2.
무색결정체 ; 융점 152내지 154℃(에탄올로부터)Colorless crystals; Melting point 152-154 ° C (from ethanol)
[실시예 10]Example 10
4-(4-클로로-3-디메틸설파모일페닐)-2-(4-메톡시페닐-이미노)-3-메틸-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline
에탄올중의 표제화합물의 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득한다. 무색결정체 ; 융점 198내지 199℃From hydrobromide and triethylamine of the title compound in ethanol, it is obtained according to a method similar to that of Example 2. Colorless crystals; Melting Point 198 ~ 199 ℃
[실시예 11]Example 11
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(4-트리플루오로메틸페닐-이미노)-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (4-trifluoromethylphenyl-imino) -4-thiazoline
표제화합물의 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득한다.From hydrobromide and triethylamine of the title compound, it is obtained according to a method analogous to Example 2.
융점 147내지 151℃Melting Point 147-151 ℃
[실시예 12]Example 12
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2,4-디메틸페닐-이미노)-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2,4-디메틸페닐-이미노)-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득한다. 무색결정체 ; 융점 152내지 154℃From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 2 do. Colorless crystals; Melting Point 152-154 ℃
[실시예 13]Example 13
2-(4-클로로-2-메틸페닐-이미노)-4-(4-클로로-3-디메틸설파모일-페닐)-3-메틸-4-티아졸린2- (4-Chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline
2-(4-클로로-2-메틸페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득한다. 융점 137내지 141℃From 2- (4-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine Obtained according to a similar method. Melting Point 137-141 ℃
[실시예 14]Example 14
4-(4-클로로-3-디메틸설파모일페닐)-2-(4-클로로페닐-이미노)-3-메틸-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-chlorophenyl-imino) -3-methyl-4-thiazoline
표제화합물의 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득한다.From hydrobromide and triethylamine of the title compound, it is obtained according to a method analogous to Example 2.
무색결정체 ; 융점 184℃Colorless crystals; Melting point 184 ℃
[실시예 15]Example 15
4-(4-클로로-3-디메틸설파모일)-3-메틸-2-(2,3-디메틸페닐-이미노)-4-티아졸린4- (4-chloro-3-dimethylsulfamoyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline
메탄올중의 4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2,3-디메틸페닐-이미노)-4-티아졸린 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득한다. 융점 226℃Example from 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline hydrobromide and triethylamine in methanol Obtained according to a method analogous to 2. Melting point 226 ℃
[실시예 16]Example 16
2-(3-클로로-2-메틸페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린2- (3-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline
메탄올의 2-(3-클로로-2-메틸페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐-이미노)-3-메틸-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득되는데, 반응혼합물은 트리에틸아민 대신에 20%메탄올성 암모니아용액을 사용하여 알칼리성으로 만들고 실시예 2에서처럼 끝처리시킨다.Example 2 from 2- (3-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl-imino) -3-methyl-4-thiazoline hydrobromide of methanol Obtained according to a similar method, the reaction mixture is made alkaline using 20% methanolic ammonia solution instead of triethylamine and is finished as in Example 2.
무색결정체 ; 융점 144내지 146℃Colorless crystals; Melting Point 144-146 ℃
[실시예 17]Example 17
2-(4-클로로-2-메톡시페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸 4-티아졸린2- (4-chloro-2-methoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl 4-thiazoline
2-(4-클로로-2-메톡시페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸 4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득한다. 무색결정체 ; 융점 148내지 150℃From 2- (4-chloro-2-methoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl 4-thiazoline hydrobromide, in a similar manner to Example 2 Obtained accordingly. Colorless crystals; Melting Point 148-150 ℃
[실시예 18]Example 18
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(3,4-메틸렌디옥시페닐-이미노)-4-티아졸린4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4-methylenedioxyphenyl-imino) -4-thiazoline
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(3,4-메틸렌디옥시페닐-이미노)-4-티아졸린 하이드로브로마이드로부터, 실시예 16와 유사한 방법에 따라 수득한다. 융점 171내지 173℃인 결정체.From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4-methylenedioxyphenyl-imino) -4-thiazoline hydrobromide, in a similar manner to Example 16 Obtained accordingly. Crystal with melting point of 171-173 ° C.
[실시예 19]Example 19
2-(3,4-에틸렌디옥시페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린2- (3,4-ethylenedioxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline
2-(3,4-에틸렌디옥시페닐-이미노)-4-(클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득한다. 융점 200내지 203℃From 2- (3,4-ethylenedioxyphenyl-imino) -4- (chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide, obtained in a similar manner to Example 2 do. Melting Point 200 ~ 203 ℃
[실시예 20]Example 20
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(3,4,5-트리메톡시페닐-이미노)-4-티아졸린4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4,5-trimethoxyphenyl-imino) -4-thiazoline
a) 메탄올중의 4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(3,4,5-트리메톡시페닐-이미노)-4-티아졸린 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 수득하거나,a) 4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4,5-trimethoxyphenyl-imino) -4-thiazoline hydrobromide and tri From ethylamine, following a method analogous to Example 2, or
b) 100ml의 에틸 아세테이트/50ml의톨루엔 및 100ml의 중탄산나트륨 수용액 (pH 8내지 8.5)의 혼합물중에서 교반시켜 수득한다. 유기상을 4시간후 분리해내고 용매를 워터펌프 진공하에서 증류 제거시키고 잔사를 디이소프로필 에테르 또는 물로 처리하여 결정체를 여과해낼 수 있다. 융점 110내지 122℃b) obtained by stirring in a mixture of 100 ml of ethyl acetate / 50 ml of toluene and 100 ml of aqueous sodium bicarbonate solution (pH 8-8.5). The organic phase can be separated off after 4 hours and the solvent can be distilled off under water pump vacuum and the residue can be filtered off with diisopropyl ether or water to filter off the crystals. Melting Point 110 ~ 122 ℃
[실시예 21]Example 21
3-에틸-4-(4-클로로-3-디메틸설파모일페닐)-2-(2-메틸페닐-이미노)-4-티아졸린3-ethyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline
3-에틸-4-(4-클로로-3-디메틸설파모일)-2-(2-메틸페닐-이미노)-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득한다. 무색결정체 ; 융점 164내지 166℃From 3-ethyl-4- (4-chloro-3-dimethylsulfamoyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a similar method as in Example 2. Colorless crystals; Melting Point 164 ~ 166 ℃
[실시예 22]Example 22
4-(4-클로로-3-디메틸설파모일페닐)-3-사이클로프로필-2-페닐-이미노)-4-티아졸린4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl-2-phenyl-imino) -4-thiazoline
4-(4-클로로-3-디메틸설파모일페닐)-3-사이클로프로필-2-페닐이미노-4-티아졸린하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득한다. 융점 156내지 159℃From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl-2-phenylimino-4-thiazolinehydrobromide, obtained according to a method analogous to Example 2. Melting Point 156-159 ℃
[실시예 23]Example 23
3-2급-부틸-4-(4-클로로-3-디메틸설파모일페닐)-2-페닐-아미노-4-티아졸린3-tert-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2-phenyl-amino-4-thiazoline
3-2급-부틸-4-(4-클로로-3-디메틸설파모일페닐)-2-페닐-4-아미노-티아졸린 하이드로브로마이드로부터, 실시예 2 또는 20 b)와 유사한 방법에 따라 수득한다. 무색결정체 ; 융점 138℃From 3-tert-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2-phenyl-4-amino-thiazoline hydrobromide, obtained according to methods analogous to Example 2 or 20 b) . Colorless crystals; Melting point 138 ℃
[실시예 24]Example 24
4-(4-클로로-3-디메틸설파모일페닐)-3-n-헥실-2-페닐이미노-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n-hexyl-2-phenylimino-4-thiazoline
4-(4-클로로-3-디메틸설파모일페닐)-3-n-헥실-2-페닐이미노-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 수득한다. 융점 86℃From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n-hexyl-2-phenylimino-4-thiazoline hydrobromide, obtained according to a similar method as in Example 2. Melting point 86 ℃
[실시예 25]Example 25
4-(4-클로로-3-디메틸설파모일페닐)-3-사이클로헥실-2-페닐이미노-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclohexyl-2-phenylimino-4-thiazoline
4-(4-클로로-3-디메틸설파모일페닐)-3-사이클로헥실-2-페닐이미노-4-티아졸린 하이드로브로마이드로부터, 실시예 2 또는 20 b)와 유사한 방법에 따라 제조된다. 무색결정체 ; 융점 148℃From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclohexyl-2-phenylimino-4-thiazoline hydrobromide, prepared according to a method analogous to Example 2 or 20 b). Colorless crystals; Melting point 148 ℃
[실시예 26]Example 26
3-n-부틸-4-(4-클로로-3-디메틸설파모일페닐)-2-(2-메틸페닐-이미노)-4-티아졸린3-n-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline
3-n-부틸-4-(4-클로로-3-디메틸설파모일페닐)-2-(2-메틸페닐-이미노)-4-티아졸린 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 얻어진다. 결정체 ; 융점 104℃From 3-n-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 2 . Crystal; Melting point 104 ℃
[실시예 27]Example 27
4-(3-디에 틸설파모일-4-클로로페닐-2-(4-클로로페닐-이미노)-3-메틸-4-티아졸린4- (3-Diethylsulfamoyl-4-chlorophenyl-2- (4-chlorophenyl-imino) -3-methyl-4-thiazoline
상응하는 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 얻어진다. 무색결정체 ; 융점 108℃From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting point 108 ℃
[실시예 28]Example 28
4-(3-디에틸설파모일-4-클로로페닐)-3-메틸-2-(2-메틸페닐-이미노)-4-티아졸린4- (3-Diethylsulfamoyl-4-chlorophenyl) -3-methyl-2- (2-methylphenyl-imino) -4-thiazoline
상응하는 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 얻어진다. 무색결정체 ; 융점 166℃From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting point 166 ℃
[실시예 29]Example 29
4-(3-N-부틸-N-메틸설파모일-4-클로로페닐-3-메틸-2-페닐이미노-4-티아졸린 하이드로브로마이드4- (3-N-butyl-N-methylsulfamoyl-4-chlorophenyl-3-methyl-2-phenylimino-4-thiazoline hydrobromide
상응하는 티아졸린으로부터, 실시예 3와 유사한 방법에 따라 얻어진다.From the corresponding thiazolin, it is obtained according to a method analogous to Example 3.
무색고체 ; 융점 84내지 87℃(분해)Colorless solid; Melting Point 84 ~ 87 ℃ (Decomposition)
[실시예 30]Example 30
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2-메틸페닐-이미노)-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2-methylphenyl-imino) -4-thiazoline
상응하는 하이드로브로마이드 및 트리에틸아민으로부터, 실시예 2와 유사한 방법에 따라 얻어진다. 융점 114내지 116℃From the corresponding hydrobromide and triethylamine, it is obtained according to a method analogous to Example 2. Melting Point 114-116 ℃
[실시예 31]Example 31
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2,4-디메틸페닐-이미노)-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline
상응하는 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 얻어진다.From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2.
무색결정체 ; 융점 136내지 141℃Colorless crystals; Melting Point 136-141 ℃
[실시예 32]Example 32
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2,3-디메틸페닐-이미노)-4-티아졸린4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline
표제화합물의 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 얻어진다. 무색결정체 ; 융점 184내지 187℃From hydrobromide of the title compound, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting Point 184 ~ 187 ℃
[실시예 33]Example 33
2-(5-클로로-2,4-디메톡시페닐-이미노)-4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-4-티아졸린2- (5-chloro-2,4-dimethoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline
상응하는 하이드로브로마이드로부터, 실시예 2와 유사한 방법에 따라 얻어진다.From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2.
무색결정체 ; 융점 173내지 175℃Colorless crystals; Melting Point 173 ~ 175 ℃
다음 실시예에 기술된 일반식(I)의 염기성 화합물은 일반식(I)의 화합물의 산부가염에 염기를 작용시킴으로써, 실시예 2, 16 및 20 b)와 유사한 방법에 따라 얻어질 수 있다.The basic compounds of formula (I) described in the following examples can be obtained according to methods analogous to Examples 2, 16 and 20 b) by acting a base on the acid addition salts of compounds of formula (I).
[실시예 34]Example 34
4-(4-클로로-3-설파모일페닐)-3,5-디메틸-2-페닐-이미노-4-티아졸린, 117℃이상에서 분해4- (4-chloro-3-sulfamoylphenyl) -3,5-dimethyl-2-phenyl-imino-4-thiazoline, decomposed at above 117 ° C
[실시예 35]Example 35
4-(4-브로모-3-설파모일페닐)-2-(4-메톡시페닐-이미노)-4-티아졸린,4- (4-bromo-3-sulfamoylphenyl) -2- (4-methoxyphenyl-imino) -4-thiazoline,
융점 197℃(알콜로부터)Melting point 197 degrees Celsius (from alcohol)
[실시예 36]Example 36
2-(2-에틸페닐-이미노)-4-(4-클로로-3-설파모일페닐)-3-메틸-4-티아졸린,2- (2-ethylphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline,
융점 161내지 163℃Melting Point 161-163 ℃
[실시예 37]Example 37
4-(4-클로로-3-설파모일페닐)-3-메틸-2-(4-메틸-페닐-이미노)-4-티아졸린, 융점 267℃4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (4-methyl-phenyl-imino) -4-thiazoline, melting point 267 ° C
[실시예 38]Example 38
4-[4-클로로-3-(1-피페리딜닐설포닐)페닐]-3-메틸-2-페닐이미노-4-티아졸린, 융점 189내지 195℃4- [4-chloro-3- (1-piperidylylsulfonyl) phenyl] -3-methyl-2-phenylimino-4-thiazoline, melting point 189-195 ° C.
[실시예 39]Example 39
4-[4-클로로-3-(1-피롤리디닐설포닐)-페닐]-3-메틸-2-페닐-이미노-4-티아졸린, 융점 191내지 194℃4- [4-Chloro-3- (1-pyrrolidinylsulfonyl) -phenyl] -3-methyl-2-phenyl-imino-4-thiazoline, melting point 191-194 ° C.
[실시예 40]Example 40
4-(4-클로로-3-설파모일페닐)-2-페닐이미노-3-프로필-4-티아졸린, 융점 165내지 170℃4- (4-chloro-3-sulfamoylphenyl) -2-phenylimino-3-propyl-4-thiazoline, melting point 165 to 170 ° C
[실시예 41]Example 41
3-2급-부틸-4-(4-클로로-3-설파모일페닐페닐)-2-이미노-4-티아졸린, 융점 80℃3-tert-butyl-4- (4-chloro-3-sulfamoylphenylphenyl) -2-imino-4-thiazoline, melting point 80 占 폚
[실시예 42]Example 42
4-[3-(1-부틸설파모일)4-페닐클로로페닐]3-메틸-2-페닐이미노-4-티아졸린, 융점 80℃4- [3- (1-butylsulfamoyl) 4-phenylchlorophenyl] 3-methyl-2-phenylimino-4-thiazoline, melting point 80 deg.
[실시예 43]Example 43
4-(3-디에틸설파모일-4-클로로페닐)-3-메틸-2-페닐-이미노-4-티아졸린, 융점 173내지 175℃4- (3-Diethylsulfamoyl-4-chlorophenyl) -3-methyl-2-phenyl-imino-4-thiazoline with melting point 173 to 175 ° C
[실시예 44]Example 44
4-(4-클로로-3-설파모일페닐)-3-메틸-2-(3,4,5-트리메톡시-페닐-이미노)-4-티아졸린, 융점 187내지 189℃4- (4-Chloro-3-sulfamoylphenyl) -3-methyl-2- (3,4,5-trimethoxy-phenyl-imino) -4-thiazoline, melting point 187-189 ° C.
[실시예 45]Example 45
2-(3,4-에틸렌디옥시페닐-이미노)-4-(4-클로로-3-설파모일페닐)-3-메틸-4-티아졸린, 융점 247내지 249℃2- (3,4-ethylenedioxyphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point 247-249 ° C.
[실시예 46]Example 46
4-(4-클로로-3-설파모일페닐)-2-(3,4-메틸렌디옥시-페닐-이미노)-3-메틸-4-티아졸린, 융점 187내지 189℃4- (4-Chloro-3-sulfamoylphenyl) -2- (3,4-methylenedioxy-phenyl-imino) -3-methyl-4-thiazoline, melting point 187-189 ° C.
[실시예 47]Example 47
4-(4-클로로-3-설파모일페닐)-2-(4-메톡시페닐-이미노)-3-메틸-4-티아졸린, 융점 210내지 214℃4- (4-chloro-3-sulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline, melting point 210 to 214 ° C
[실시예 48]Example 48
4-(4-클로로-3-설파모일페닐)-2-(4-플루오로페닐이미노)-3-메틸-4-티아졸린, 융점 234내지 236℃4- (4-chloro-3-sulfamoylphenyl) -2- (4-fluorophenylimino) -3-methyl-4-thiazoline, melting point 234-236 ° C
[실시예 49]Example 49
2-(4-에톡시페닐-이미노)-3-메틸-4-(4-클로로-3-설파모일페닐)-4-티아졸린, 융점 233℃2- (4-ethoxyphenyl-imino) -3-methyl-4- (4-chloro-3-sulfamoylphenyl) -4-thiazoline, melting point 233 ° C
[실시예 50]Example 50
4-(4-클로로-3-설파모일페닐)-3-메틸-2-(3-메틸-페닐-이미노)-4-티아졸린, 융점 193내지 194℃(메탄올로부터)4- (4-Chloro-3-sulfamoylphenyl) -3-methyl-2- (3-methyl-phenyl-imino) -4-thiazoline, melting point 193-194 ° C. (from methanol)
[실시예 51]Example 51
2-(5-클로로-2,4-디메톡시페닐-이미노)-4-(4-클로로-3-설파모일페닐)-3-메틸-4-티아졸린, 융점 204내지 206℃2- (5-chloro-2,4-dimethoxyphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point 204 to 206 캜
[실시예 52]Example 52
4-(4-클로로-3-설파모일페닐메틸)-3-메틸-2-(3-(디메틸이미노페닐-이미노)-4-티아졸린, 융점 134내지 140℃4- (4-chloro-3-sulfamoylphenylmethyl) -3-methyl-2- (3- (dimethyliminophenyl-imino) -4-thiazoline, melting point 134-140 ° C.
[실시예 53]Example 53
4-(4-클로로-3-설파모일페닐)-3-메틸-2-(2,4-디메틸-페닐-이미노)-4-티아졸린, 융점 270내지 275℃4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (2,4-dimethyl-phenyl-imino) -4-thiazoline, melting point 270 to 275 ° C
[실시예 54]Example 54
2-(2-에톡시-5-메틸페닐-이미노)-4-(4-클로로-3-설파모일페닐)-3-메틸-4-티아졸린, 융점 194내지 197℃2- (2-ethoxy-5-methylphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point 194-197 ° C.
다음 실시예에 기술된 일반식(I)의 산부가염은 실시예 3과 유사한 방법에 따라 일반식 HA의 양성자산을 일반식(I)의 염기성 화합물에 작용시킴으로써 얻어진다.The acid addition salts of general formula (I) described in the following examples are obtained by acting on the basic compounds of general formula (I) the positive asset of general formula HA according to a method analogous to Example 3.
[실시예 55]Example 55
4-(4-클로로-3-설파모일페닐)-3-메틸-2-(3-트리플루오로메틸페닐-이미노)-4-티아졸린 하이드로브로마이드, 융점 222℃4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (3-trifluoromethylphenyl-imino) -4-thiazoline hydrobromide, melting point 222 ° C
[실시예 56]Example 56
4-(4-클로로-3-n-프로필설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린 하이드로브로브로마이드, 융점 239℃4- (4-chloro-3-n-propylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrobrobromide, melting point 239 ° C
[실시예 57]Example 57
4-[4-클로로-3-(4-메틸벤질설파모일)-페닐]-3-메틸-2-페닐-이미노-4-티아졸린, 융점 92내지 100℃4- [4-Chloro-3- (4-methylbenzylsulfamoyl) -phenyl] -3-methyl-2-phenyl-imino-4-thiazoline, melting point 92 to 100 ° C
[실시예 58]Example 58
4-(4-클로로-3-설파모일페닐)-2-(4-메톡시페닐-이미노)-3-메틸-4-티아졸린 하이드로브로마이드, 융점 276℃4- (4-chloro-3-sulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline hydrobromide, melting point 276 ° C
[실시예 59]Example 59
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐-이미노-4-티아졸린 아미도설포네이트.4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline amidosulfonate.
융점 296내지 298℃Melting Point 296 ~ 298 ℃
[실시예 60]Example 60
3-메틸-4-(3-디메틸설파모일페닐)-2-페닐이미노-4-티아졸린, 융점 254℃3-methyl-4- (3-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 254 ° C
[실시예 61]Example 61
2-(4-메톡시페닐이미노)-3-메틸-4-(3-디메틸설파모일페닐)-4-티아졸린, 융점 234℃2- (4-methoxyphenylimino) -3-methyl-4- (3-dimethylsulfamoylphenyl) -4-thiazoline, melting point 234 ° C
[실시예 62]Example 62
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(3-트리플루오로메틸페닐-이미노)-4-티아졸린, 융점 226℃4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3-trifluoromethylphenyl-imino) -4-thiazoline, melting point 226 DEG C
[실시예 63]Example 63
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-페닐-이미노-4-티아졸린,융점274℃4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, melting point 274 ° C
[실시예 64]Example 64
2-(4-브로모페닐이미노)-4-(4-클로로-3-디메틸설파모일-페닐)-3-메틸-4-티아졸린, 융점 185내지 188℃2- (4-bromophenylimino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline, melting point 185-188 ° C.
[실시예 65]Example 65
2-(4-브로모페닐-이미노)-4-(4-클로로-3-디메틸설파모일-페닐)-3-메틸-4-티아졸린, 융점 155℃2- (4-Bromophenyl-imino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline, melting point 155 ° C.
[실시예 66]Example 66
3-메틸-4-(4-메틸-3-디메틸설파모일페닐)-2-페닐이미노-4-티아졸린, 융점 155℃3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 155 deg.
[실시예 67]Example 67
2-(4-메톡시페닐-이미노)-3-메틸-4-(4-메틸-3-디메틸설파모일페닐)-4-티아졸린, 융점 180℃2- (4-methoxyphenyl-imino) -3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -4-thiazoline, melting point 180 deg.
[실시예 68]Example 68
2-(4-클로로페닐-이미노)-3-메틸-4-(4-메틸-3-디메틸설파모일페닐)-4-티아졸린, 융점 172℃2- (4-Chlorophenyl-imino) -3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -4-thiazoline, melting point 172 ° C
[실시예 69]Example 69
3-에틸-4-(4-메틸-디메틸설파모일페닐)-2-페닐-이미노)-4-티아졸린, 융점175℃3-ethyl-4- (4-methyl-dimethylsulfamoylphenyl) -2-phenyl-imino) -4-thiazoline, melting point 175 ° C
[실시예 70]Example 70
4-(4-클로로-3-디메틸설파모일페닐)-3-메틸-2-(2,6-디메틸페닐-이미노)-4-티아졸린, 융점 180℃4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,6-dimethylphenyl-imino) -4-thiazoline, melting point 180 deg.
다음 실시예에 기술된 일반식(I)의 염기성 화합물은 일반식(I)의 화합물의 상응하는 산부가염에 염기를 작용시킴으로써, 실시예 2,16 및 20 b 와 유사한 방법에 따라 얻을 수 있다.The basic compounds of general formula (I) described in the following examples can be obtained according to methods analogous to Examples 2,16 and 20 b, by acting a base on the corresponding acid addition salt of the compound of general formula (I).
[실시예 71]Example 71
3-메틸-4-(2-메틸-5-디메틸설파모일페닐)-2-페닐이미노-4-티아졸린, 융점190℃3-methyl-4- (2-methyl-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 190 ° C
[실시예 72]Example 72
3-메틸-4-(3-메틸-5-디메틸설파모일페닐)-2-페닐이미노-4-티아졸린, 융점166℃3-methyl-4- (3-methyl-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 166 ° C
[실시예 73]Example 73
4-(2-클로로-5-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린, 융점197℃4- (2-chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline, melting point 197 ° C
[실시예 74]Example 74
4-(3-클로로-5-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린, 융점167℃4- (3-chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline, melting point 167 ° C
[실시예 75]Example 75
4-(2-클로로-5-디메틸설파모일페닐)-2-(2-클로로페닐이미노)-3-메틸4-티아졸린, 융점 227℃4- (2-chloro-5-dimethylsulfamoylphenyl) -2- (2-chlorophenylimino) -3-methyl4-thiazoline, melting point 227 ° C
[실시예 76]Example 76
3-에틸-4-(2-클로로-5-디메틸설파모일페닐)-2-페닐이미노-4-티아졸린,융점 201℃(분해)3-ethyl-4- (2-chloro-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 201 ° C. (decomposition)
[실시예 77]Example 77
4-(3-클로로-5-디메틸설파모일페닐)-2-(2-클로로페닐이미노)-3-메틸-4-티아졸린, 융점 163℃4- (3-chloro-5-dimethylsulfamoylphenyl) -2- (2-chlorophenylimino) -3-methyl-4-thiazoline, melting point 163 deg.
[실시예 78]Example 78
3-메틸-4-(2-메틸-5-설파모일페닐)-2-페닐이미노-4-티아졸린,융점 188내지 191℃3-methyl-4- (2-methyl-5-sulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 188-191 ° C.
[실시예 79]Example 79
3-메틸-4-(3-메틸-5-설파모일페닐)-2-페닐이미노-4-티아졸린, 융점 201내지 212℃3-methyl-4- (3-methyl-5-sulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 201-212 ° C
[실시예 80]Example 80
4-(2-클로로-5-설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린, 융점 198내지 200℃4- (2-chloro-5-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline, melting point 198 to 200 ° C
[실시예 81]Example 81
4-(2-브로모-5-디메틸설파모일페닐)-3-메틸-2-페닐이미노-4-티아졸린, 융점 204℃4- (2-bromo-5-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline, melting point 204 deg.
[실시예 82]Example 82
4-(2-브로모-5-디메틸설파모일페닐)-3-메틸-2-(2-클로로페닐이미노)-4-티아졸린, 융점 242℃(분해)4- (2-Bromo-5-dimethylsulfamoylphenyl) -3-methyl-2- (2-chlorophenylimino) -4-thiazoline, melting point 242 ° C. (decomposition)
[실시예 83]Example 83
4-(2-브로모-5-디메틸설파모일페닐)-3-메틸-2-(2,4-디메틸페닐-이미노)-4-티아졸린, 융점 260℃(분해)4- (2-Bromo-5-dimethylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline, melting point 260 ° C. (decomposition)
[실시예 84]Example 84
3-에틸-4-(2-브로모-5-디메틸설파모일페닐)-2-(2-메틸페닐-이미노)-4-티아졸린, 융점 209내지 210℃(분해)3-ethyl-4- (2-bromo-5-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline, melting point 209-210 ° C. (decomposition)
[실시예 85]Example 85
2-(4-메톡시페닐-아미노)-3-메틸-4-(2-메틸-5-디메틸설파모일페닐)-4-티아졸린, 융점 186내지 189℃2- (4-methoxyphenyl-amino) -3-methyl-4- (2-methyl-5-dimethylsulfamoylphenyl) -4-thiazoline, melting point 186-189 ° C.
[실시예 86]Example 86
3-에틸-4-(3-메틸-5-디메틸설파모일페닐)-2-(2-메틸페닐이미노)-4-티아졸린, 융점 155℃3-ethyl-4- (3-methyl-5-dimethylsulfamoylphenyl) -2- (2-methylphenylimino) -4-thiazoline, melting point 155 deg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019840006150A KR850000768B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019800002608A KR850000757B1 (en) | 1980-07-01 | 1980-07-01 | Process for preparing thiazoline derivatives |
| KR1019840006150A KR850000768B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019800002608A Division KR850000757B1 (en) | 1980-07-01 | 1980-07-01 | Process for preparing thiazoline derivatives |
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| Publication Number | Publication Date |
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| KR850000768B1 true KR850000768B1 (en) | 1985-05-29 |
| KR850003297A KR850003297A (en) | 1985-06-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019800002608A KR850000757B1 (en) | 1980-07-01 | 1980-07-01 | Process for preparing thiazoline derivatives |
| KR1019840006151A KR850000758B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006152A KR850000742B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006146A KR850000765B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006150A KR850000768B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006149A KR850000767B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006148A KR850000766B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
Family Applications Before (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019800002608A KR850000757B1 (en) | 1980-07-01 | 1980-07-01 | Process for preparing thiazoline derivatives |
| KR1019840006151A KR850000758B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006152A KR850000742B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006146A KR850000765B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019840006149A KR850000767B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
| KR1019840006148A KR850000766B1 (en) | 1980-07-01 | 1984-10-05 | Process for preparing thiazoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| KR (7) | KR850000757B1 (en) |
-
1980
- 1980-07-01 KR KR1019800002608A patent/KR850000757B1/en active IP Right Grant
-
1984
- 1984-10-05 KR KR1019840006151A patent/KR850000758B1/en active IP Right Grant
- 1984-10-05 KR KR1019840006152A patent/KR850000742B1/en active IP Right Grant
- 1984-10-05 KR KR1019840006146A patent/KR850000765B1/en active IP Right Grant
- 1984-10-05 KR KR1019840006150A patent/KR850000768B1/en active IP Right Grant
- 1984-10-05 KR KR1019840006149A patent/KR850000767B1/en active IP Right Grant
- 1984-10-05 KR KR1019840006148A patent/KR850000766B1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| KR850000758B1 (en) | 1985-05-25 |
| KR850003295A (en) | 1985-06-13 |
| KR850003298A (en) | 1985-06-13 |
| KR850000767B1 (en) | 1985-05-29 |
| KR850000766B1 (en) | 1985-05-29 |
| KR850000765B1 (en) | 1985-05-29 |
| KR850003297A (en) | 1985-06-13 |
| KR850003299A (en) | 1985-06-13 |
| KR850003296A (en) | 1985-06-13 |
| KR850000757B1 (en) | 1985-05-25 |
| KR850003293A (en) | 1985-06-13 |
| KR830003453A (en) | 1983-06-20 |
| KR850000742B1 (en) | 1985-05-24 |
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| Date | Code | Title | Description |
|---|---|---|---|
| G160 | Decision to publish patent application | ||
| E701 | Decision to grant or registration of patent right |