KR850001352B1 - Process for preparing benzoxazole - Google Patents

Process for preparing benzoxazole Download PDF

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KR850001352B1
KR850001352B1 KR1019850000845A KR850000845A KR850001352B1 KR 850001352 B1 KR850001352 B1 KR 850001352B1 KR 1019850000845 A KR1019850000845 A KR 1019850000845A KR 850000845 A KR850000845 A KR 850000845A KR 850001352 B1 KR850001352 B1 KR 850001352B1
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methyl
dihydro
pyridazinone
group
carbon atoms
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KR1019850000845A
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하우엘 노르베르트
하이더 요하임
슈타인 헤르베르트
아우슈텔 볼크하르트
라이펜 만프레드
디데렌 빌리
하르만 발터
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닥터 칼토메 게젤샤프트 미트 베슈렝크터 하프퉁
쿠터, 좀머
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

Pyridazinylbenzoxazoles and their physiologically tolerable acid- addn. salts were prepared. Thus N-ethyl-N'-[2-hydroxy-5(5-methyl-4,5- dihydro-3(2H)-pyridazinone-6-yl)phenyl-thiourea was cyclized with dicyclohexylcarbodiimide to give 71.9% 5-methyl-6[2'-ethylamino- benzoxazole-5'-yl -4,5-dihydro-3(2H)-pyriodazinone, which at 0.1 mg/ kg i.v. in cats caused a decrease in blood pressure of 40 mm and an increase in cardiac concentration of 79%.

Description

벤즈옥사졸의 제조방법Method for preparing benzoxazole

본 발명은 심장혈관 질환의 치료에 유효한 다음 인반식(I)의 벤즈옥사졸과 벤조티아졸, 이들의 광학적으로 활성인 대장체 및 생리학적으로 무독한 이들의 유기 또는 무기산 또는 염기와의 부가염의 제조방법에 관한 것이다.The present invention is directed to the addition of the following salts of benzoxazole and benzothiazole of banban (I), their optically active colon and their physiologically nontoxic organic or inorganic acids or bases, which are effective for the treatment of cardiovascular diseases. It relates to a manufacturing method.

Figure kpo00001
Figure kpo00001

상기 일반식에서,In the above formula,

R1은 탄소수 1 내지 6의 알킬그룹 또는 탄소수 3 내지 6의 알케닐 그룹에 의해 임의로 치환된 하이드록시 또는 메르캅토그룹 ; 알킬 부위의 탄소수가 1 내지 3이고 페닐핵이 탄소수 1 내지 3의 알콕시그룹, 할로겐원자 및/또는 아미노그룹 중에서 선택된 서로 같거나 다를 수 있는 치환체로 일-, 이-또는 삼치환 될 수 있는 페닐알킬 그룹으로 치환된 하이드록시 또는 메르캅토 그룹 ; 페닐그룹에 의해 임의로 치환된 탄소수 1 내지 3의 알킬그룹 ; 메톡시 또는 시아노그룹 또는 할로겐원자에 의해 임의로 치환된 페닐그룹 ; 또는 식-

Figure kpo00002
의 그룹(여기서, R2는 수소원자 ; 탄소수 1 내지 3의 알콕시그룹에 의해 치환될 수 있는 탄소수 1 내지 7의 직쇄 또는 측쇄알킬그룹 ; 탄소수 3 내지 7의 사이클로알킬기룹 ; 탄소수 1 내지 3의 알킬 또는 알콕시그룹, 트리플루오로메틸, 니트로 또는 시아노그룹, 불소, 염소 또는 브롬원자에 의해 치환될 수 있는 페닐그룹, 이 전술한 일치환된 페닐그룹 중의 하나는 추가로 탄소수 1 내지 3의 알킬그룹 하나 또는 두 개, 탄소수 1 내지 3의 알콕시그룹 또는 불소, 염소 또는 브룸원자에 의해 치환될 수 있고 ; 또는 총탄소수 2 내지 4의 알콕시카르보닐그룹을 나타내며, R3는 수소원자 또는 탄소수 1 내지 3의 알킬그룹을 나타냄)을 나타내며, R4및 R5는 서로 같거나 다를 수 있는 그룹으로서, 수소원자 또는 탄소수 1 내지 3의 알킬그룹을 나타내며, X는 산소 또는 황원자를 나타낸다.R 1 is a hydroxy or mercapto group optionally substituted by an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 3 to 6 carbon atoms; Phenylalkyl which may be mono-, di-, or trisubstituted with substituents having 1 to 3 carbon atoms in the alkyl moiety and phenyl nuclei which may be the same or different from each other selected from alkoxy groups, halogen atoms and / or amino groups having 1 to 3 carbon atoms. Hydroxy or mercapto groups substituted with groups; An alkyl group having 1 to 3 carbon atoms optionally substituted with a phenyl group; Phenyl group optionally substituted by methoxy or cyano group or halogen atom; Or expression
Figure kpo00002
Wherein R 2 is a hydrogen atom; a straight or branched chain alkyl group having 1 to 7 carbon atoms which may be substituted by an alkoxy group having 1 to 3 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; alkyl having 1 to 3 carbon atoms Or an alkoxy group, trifluoromethyl, nitro or cyano group, a phenyl group which may be substituted by a fluorine, chlorine or bromine atom, one of the aforementioned monosubstituted phenyl groups is further an alkyl group having 1 to 3 carbon atoms. May be substituted by one or two alkoxy groups having 1 to 3 carbon atoms or fluorine, chlorine or bromine atoms; or represent alkoxycarbonyl groups having 2 to 4 carbon atoms in total, and R 3 represents a hydrogen atom or 1 to 3 carbon atoms a represents an alkyl group), represents a, R 4 and R 5 is a group that can be the same or different from each other, represents an alkyl group, a hydrogen atom or a carbon number of 1 to 3, X is oxygen or It represents an atom.

또한, 본 발명에 따른 상기 구조식(I)의 화합물에 있어서, R1은 예를 들어 하이드록시, 알릴옥시, 크로틸옥시, 펜데닐옥시, 이소프로폭시, 부톡시, 이소부톡시, 3급부톡시, 펜톡시, 네오펜톡시, 헥속시, 알릴옥시, 크로틸옥시, 펜데닐옥시, 헥세닐옥시, 벤질옥시, 메톡시-벤질옥시, 1-페닐에톡시, 2-페닐에톡시, 3-페닐프로폭시, 메르캅토, 메틸메르캅토, 에틸메르캅토, 프로필메르캅토, 이소프로필메르캅토, 부틸메르캅토, 이소부틸메르캅토, 3급부틸메르캅토, 펜틸메르캅토, 네오펜틸메르캅토, 3급 펜틸메르캅토, 헥실메르캅토, 알릴메르캅토, 크로틸메르캅토, 펜테닐 메르캅토, 헥세닐메르캅토, 벤질메르캅토, 메톡시-벤질메르캅토, 클로로벤질메르캅토, 브로모벤질-메르캅토, 디메톡시벤질메르캅토, 1-페닐에틸-메르캅토, 2-페닐에틸메르캅토, 2-(메톡시페닐)-에틸메르캅토, 2-(디메톡시페닐)-에틸메르캅토, 2-(클로로페닐)-에틸메르캅토, 2-(클로로-메톡시페닐)-에틸메르캅토, 2-(아미노-디클로로페닐)-에틸메르캅토, 3-페닐프로필메르캅토, 메틸, 에틸, 프로필, 이소프로필, 벤질, 1-페닐에틸, 2-페닐에틸, 1-페닐프로필, 2-페닐프로필, 3-페닐프로필, 페닐, 메톡시페닐, 시아노페닐, 클로로페닐, 브로모페닐, 프루오로페닐, 아미노, 메틸아미노, 에틸아미노, 프로필아미노, 이소프로필아미노, 부틸아미노, 이소부틸아미노, 3급-부틸아미노, 펜틸아미노, 이소펜틸아미노, 네오펜틸아미노, 3급-펜틸아미노, 헥실아미노, 헵틸아미노, 디메틸아미노, 디에틸아미노, 디이소프로필아미노, 메틸-에틸아미노, 메틸-프로필아미노, 에틸-이소프로필아미노, 메틸-부틸아미노, 에틸-펜틸아미노, 메틸-헵틸아미노, 메톡시 에틸아미노, 메톡시프로필아미노, 메톡시부틸아미노, 메톡시펜틸아미노, 메톡시헵틸 아미노, 에톡시 에틸아미노, 프로폭시프로필아미노, N-메틸에톡시에틸아미노, N-에틸메톡시프로필 아미노, 사이클프로필아미노, 사이클로펜틸아미노, 사이클로헥실아미노, 사이클로헵틸아미노, N-메틸-사이클로헥실아미노, N-에틸-사이클로헥실아미노, N-N프로필-사이클로헥실아미노, 페닐아미노, 메틸페닐아미노, 디메틸페닐아미노, 트리메틸페닐아미노, 에틸페닐아미노, 프로필 페닐아미노, 이소프로필페닐아미노, 메톡시 페닐아미노, 디메톡시페닐아미노, 이소프로폭시 페닐아미노, 플루오로페닐아미노, 디플루오로 페닐아미노, 클로로페닐아미노, 디클로로페닐아미노, 브로모페닐아미노, 디브로모페닐아미노, 트리플루오로메틸페닐아미노, 니트로페닐아미노, 시아노페닐아미노, 메틸플루오로페닐아미노, 메틸클로로페닐아미노, 메톡시클로로페닐아미노, 메톡시브로모페닐아미노, 메톡시시아노페닐아미노, 메톡시트리플루오로 메틸페닐아미노, 메톡시 니트로페닐아미노, 에톡시 니트로페닐아미노, 프로폭시니트로페닐아미노, 벤질아미노, 1-페닐에틸아미노, 2-페닐에틸아미노, 3-페닐프로필아미노, 메톡시벤질아미노, 디메톡시벤질아미노, 2-디메톡시페닐에틸아미노, 2-디에톡시페닐에틸아미노, 2-디프로폭시페닐에틸아미노, 2-(메톡시-에톡시-페닐)-에틸아미노, N-메틸페닐아미노, N-에틸-메틸페닐아미노. N-메틸메톡시페닐아미노, N-에틸-디메톡시-페닐아미노, N-메틸-벤질아미노, N-에틸--2-페닐에틸아미노 또는 N-메틸-메톡시벤질아미노 그룹을 나타낼 수 있으며, R4또는 R5는 각각 수소원자, 메틸, 에틸, 프로필 또는 이소프로필그룹을 나타낼 수 있다.In addition, in the compound of formula (I) according to the present invention, R 1 is, for example, hydroxy, allyloxy, crotyloxy, pendenyloxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, Pentoxy, neopentoxy, hexoxy, allyloxy, crotyloxy, pendenyloxy, hexenyloxy, benzyloxy, methoxy-benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylprop Foxy, mercapto, methyl mercapto, ethyl mercapto, propyl mercapto, isopropyl mercapto, butyl mercapto, isobutyl mercapto, tertiary butyl mercapto, pentyl mercapto, neopentyl mercapto, tertiary pentyl mer Capto, hexyl mercapto, allyl mercapto, crotyl mercapto, pentenyl mercapto, hexenyl mercapto, benzyl mercapto, methoxy-benzyl mercapto, chlorobenzyl mercapto, bromobenzyl mercapto, dimethoxy Benzyl mercapto, 1-phenylethyl-mercapto, 2-phenylethyl mercapto, 2- (methoxyfe ) -Ethyl mercapto, 2- (dimethoxyphenyl) -ethyl mercapto, 2- (chlorophenyl) -ethyl mercapto, 2- (chloro-methoxyphenyl) -ethyl mercapto, 2- (amino-dichlorophenyl ) -Ethyl mercapto, 3-phenylpropyl mercapto, methyl, ethyl, propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, phenyl , Methoxyphenyl, cyanophenyl, chlorophenyl, bromophenyl, fluorophenyl, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentyl Amino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, heptylamino, dimethylamino, diethylamino, diisopropylamino, methyl-ethylamino, methyl-propylamino, ethyl-isopropylamino, Methyl-butylamino, ethyl-pentylamino, methyl-heptylamino, methoxy ethylamino, Methoxypropylamino, methoxybutylamino, methoxypentylamino, methoxyheptyl amino, ethoxy ethylamino, propoxypropylamino, N-methylethoxyethylamino, N-ethylmethoxypropyl amino, cyclicpropylamino, Cyclopentylamino, cyclohexylamino, cycloheptylamino, N-methyl-cyclohexylamino, N-ethyl-cyclohexylamino, NNpropyl-cyclohexylamino, phenylamino, methylphenylamino, dimethylphenylamino, trimethylphenylamino, ethyl Phenylamino, propyl phenylamino, isopropylphenylamino, methoxy phenylamino, dimethoxyphenylamino, isopropoxy phenylamino, fluorophenylamino, difluoro phenylamino, chlorophenylamino, dichlorophenylamino, bromophenyl Amino, dibromophenylamino, trifluoromethylphenylamino, nitrophenylamino, cyanophenyla Furnace, methylfluorophenylamino, methylchlorophenylamino, methoxychlorophenylamino, methoxybromophenylamino, methoxycyanophenylamino, methoxytrifluoro methylphenylamino, methoxy nitrophenylamino, ethoxy nitrophenyl Amino, propoxynitrophenylamino, benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, methoxybenzylamino, dimethoxybenzylamino, 2-dimethoxyphenylethylamino, 2-die Methoxyphenylethylamino, 2-dipropoxyphenylethylamino, 2- (methoxy-ethoxy-phenyl) -ethylamino, N-methylphenylamino, N-ethyl-methylphenylamino. N-methylmethoxyphenylamino, N-ethyl-dimethoxy-phenylamino, N-methyl-benzylamino, N-ethyl--2-phenylethylamino or N-methyl-methoxybenzylamino group, R 4 or R 5 may each represent a hydrogen atom, methyl, ethyl, propyl or isopropyl group.

바람직한 일반식(I)의 화합물은, R1이 탄소수- 1 내지 3의 알킬그룹 또는 알릴그룹에 의해 임의로 치환된 하이드록시 또는 메르캅토그룹 ; 헥실-메르캅토, 메톡시벤질메르캅토, 또는 2-(아미노-디클로로페닐)-에틸메르캅토그룹 ; 페닐그룹에 의해 임의로 치환된 탄소수 1 내지 3의 알킬그룹 ; 시아노페닐아미노 또는 디메틸아미노그룹 ; 메톡시그룹에 의해 치환될 수 있는 탄소수 1 내지 5의 알킬아미노그룹 ; 페닐핵이 메틸, 메톡시, 트리플루오로메틸, 시아노 또는 니트로그룹, 염소 또는 브롬원자에 의해 치환될 수 있는 페닐아미노그룹 ; 디클로로페닐아미노, 디브로모페닐아미노, 디메톡시페닐아미노, 메톡시-니트로페닐아미노, 트리메틸페닐아미노, 사이클로헥실아미노, 디메톡시페닐에틸아미노 또는 에톡시카보닐아미노 그룹을 나타내며,Preferred compounds of the general formula (I) include hydroxy or mercapto groups in which R 1 is optionally substituted by an alkyl group or an allyl group having 1 to 3 carbon atoms; Hexyl-mercapto, methoxybenzyl mercapto, or 2- (amino-dichlorophenyl) -ethyl mercapto group; An alkyl group having 1 to 3 carbon atoms optionally substituted with a phenyl group; Cyanophenylamino or dimethylamino group; An alkylamino group having 1 to 5 carbon atoms which may be substituted by a methoxy group; Phenylamino group wherein the phenyl nucleus may be substituted by methyl, methoxy, trifluoromethyl, cyano or nitro group, chlorine or bromine atom; Dichlorophenylamino, dibromophenylamino, dimethoxyphenylamino, methoxy-nitrophenylamino, trimethylphenylamino, cyclohexylamino, dimethoxyphenylethylamino or ethoxycarbonylamino group;

R4가 수소원자 또는 메틸그룹을 나타내고,R 4 represents a hydrogen atom or a methyl group,

R5가 메틸그룹을 나타내며,R 5 represents a methyl group,

X가 산소 또는 황원자를 나타내는 화합물로서, 특히 피리다지노 그룹이 5위치에 있는 화합물 및 이들의 생리학적으로 무득한 부가염이다.X is oxygen or a sulfur atom, especially a compound in which the pyridazino group is in the 5 position and their physiologically unfavorable addition salts.

특히 바람직한 일반식(I)의 화합물은 다음 일반식(Ia)의 화합물 및 이들의 생리학적으로 무독한 부가염이다.Particularly preferred compounds of formula (I) are the compounds of formula (Ia) and their physiologically toxic addition salts.

Figure kpo00003
Figure kpo00003

상기 일반식에서,In the above formula,

R1은 메르캅토, 메틸메르캅토, 하이드록시, 에톡시, 4-메톡시페닐아미노, 2-(4-아미노-3,5-디클로로페닐)-에틸메르캅토, 아미노, 디메틸아미노 또는 사이클로헥실아미노그룹 ; 탄소수 1 내지 5의 알킬아미노 그룹 ; 또는 하나 또는 두개의 메톡시그룹에 의해 임의로 치환된 페닐아미노그룹이고,R 1 is mercapto, methyl mercapto, hydroxy, ethoxy, 4-methoxyphenylamino, 2- (4-amino-3,5-dichlorophenyl) -ethylmercapto, amino, dimethylamino or cyclohexylamino group ; Alkylamino groups having 1 to 5 carbon atoms; Or a phenylamino group optionally substituted by one or two methoxy groups,

X는 산소 또는 황원자를 나타내며, 특히 X는 산소원자를 나타내는 것이 좋다.X represents oxygen or a sulfur atom, in particular X preferably represents an oxygen atom.

본 발명에 의한 일반식(I)의 신규 화합물은 다음과 같은 방법으로 제조한다.The novel compound of general formula (I) according to the present invention is prepared by the following method.

a) 반응 혼합물 중에서 임의로 제조된 다음 일반식(Ⅱ)의 화합물을 폐환시킨다.a) optionally produced in the reaction mixture and then the compound of formula (II) is closed.

Figure kpo00004
Figure kpo00004

상기 일반식에서,In the above formula,

R1, R4, R5및 X 는 상기에서 정의한 바와 같고, Y는 수소원자 또는 아실그룹을 나타내며,R 1 , R 4 , R 5 and X are as defined above, Y represents a hydrogen atom or an acyl group,

Z는 친핵성 유리기를 나타내며,Z represents a nucleophilic free group,

Y는 예를면들 아실그룹으로서 아세틸, 프로피오닐, 벤조일 또는 p-톨루엔설포닐그룹을 나타내며, Z는 예를들면 염소또는 브롬원자, 하이드록시, 메톡시, 에톡시, 벤질옥시, 메르캅토, 메틸메르캅토, 에틸-메르캅토, 프로필메르캅토, 벤질메르캅토, 페닐메르캅토 또는 이미다졸릴카보닐 그룹을 나타낸다.Y represents, for example, an acetyl, propionyl, benzoyl or p-toluenesulfonyl group as the acyl group, and Z represents, for example, a chlorine or bromine atom, hydroxy, methoxy, ethoxy, benzyloxy, mercapto, Methyl mercapto, ethyl-mercapto, propyl mercapto, benzyl mercapto, phenyl mercapto or imidazolylcarbonyl group.

이 반응은 테트라하이드로푸란, 디옥산, 벤젠, 톨루엔, 디메틸아미드, 디메틸렌글리콜 또는 설포란과 같은 용매중에 경우에 따라 N,N'-디사이클로헥실 카보디이미드, 카보닐 디이미다졸, p-톨루엔설폰산, 옥시염화인, 티오닐클로라이드, 염산, 황산, 인산 또는 폴리인산 등과 같은 축합제의 존재하에 25°내지 300℃, 바람직하게는 반응 혼합물의 비점온도, 예를들어 50°내지 285℃의 온도에서 수행하는 것이 적합하다. 그러나 이 반응은 용융 상태에서 수행할 수도 있다.This reaction is optionally carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene, dimethylamide, dimethylene glycol or sulfolane, N, N'-dicyclohexyl carbodiimide, carbonyl diimidazole, p- 25 ° to 300 ° C. in the presence of a condensing agent such as toluenesulfonic acid, phosphorus oxychloride, thionyl chloride, hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid, etc., preferably the boiling point temperature of the reaction mixture, for example 50 ° to 285 ° C. It is suitable to carry out at a temperature of. However, this reaction can also be carried out in the molten state.

b) 다음 일반식(Ⅲ)의 카본산 화합물, 또는 이들의 무수물, 에스테르, 티오에스테르, 아미드, 이미다졸리드 또는 할로겐화물을 히드라진과 반응시킨다.b) The carboxylic acid compounds of the following general formula (III), or their anhydrides, esters, thioesters, amides, imidazolides or halides are reacted with hydrazine.

Figure kpo00005
Figure kpo00005

상기 일반식에서,In the above formula,

R1, R4, R5및 X는 앞에서 정의한 바와 같다.R 1 , R 4 , R 5 and X are as defined above.

이 반응은 메탄올, 에탄올, 이소프로판올, 빙초산, 프로피온산과 같은 용매 중에서 및/또는 과량의 히드라진 또는 히드라진 수화물 중에서, 0°내지 200℃, 예를 들면 20°내지 150℃, 바람직하게는 반응 혼합물의 비점온도에서 경우에 따라 황산이나 p-톨루엔설폰산과 같은 축합제로서 산존재하에 수행하는 것이 적합하다. 그러나 이 반응은 용매없이 수행할 수도 있다.The reaction is carried out in solvents such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and / or in excess hydrazine or hydrazine hydrate, from 0 ° to 200 ° C., for example from 20 ° to 150 ° C., preferably the boiling point temperature of the reaction mixture. In some cases it is suitable to carry out in the presence of acid as a condensing agent such as sulfuric acid or p-toluenesulfonic acid. However, this reaction can also be carried out without solvent.

c) 다음 일반식(Ⅳ)의 화합물을 일반식(Ⅴ)의 화합물로 알킬화시킨다.c) The following compound of formula (IV) is alkylated with a compound of formula (V).

Figure kpo00006
Figure kpo00006

R1'-U (Ⅴ)R 1 '-U (Ⅴ)

상기 일반식에서,In the above formula,

R4, R5및 X는 앞에서 정의한 바와 같고, A는 하이드록시 또는 메르캅토그룹, 또는 식

Figure kpo00007
(여기서 R2'는 전술한 페닐기를 제외하고는 R2및 R3에서 정의한 바와 같음)의 그룹을 나타내며,R 4 , R 5 and X are as defined above and A is a hydroxy or mercapto group, or
Figure kpo00007
Wherein R 2 ′ represents a group as defined in R 2 and R 3 except for the aforementioned phenyl group,

R1'는 페닐그룹 또는 탄소수 1 내지 3의 알콕시그룹에 의해 임의로 치환된 탄소수 1 내지 3의 알킬그룹, 이때 페닐핵은 탄소수 1 내지 3의 알킬 또는 알콕시그룹, 할로겐원자 및/또는 아미노그룹에 의해 일-, 이-또는 삼치환될 수 있고 ; 탄소수 1 내지 3의 알콕시그룹에 의해 임의로 치환된 탄소수 4 내지 7의 알킬그룹 ; 탄소수 3 내지 6의 알케닐그룹 ; 또는 탄소수 3 내지 7의 사이클로알킬그룹을 나타내며, U는 할로겐원자 또는 설폰산 에스테르라디칼, 예를 들어 염소, 브롬 또는 요드원자, 메탄설포닐옥시, p-톨루엔설포닐옥시 또는 메톡시설포닐옥시그룹과 같은 친핵성 교환 가능그룹을 나타낸다.R 1 ′ is an alkyl group having 1 to 3 carbon atoms optionally substituted by a phenyl group or an alkoxy group having 1 to 3 carbon atoms, wherein the phenyl nucleus is selected from an alkyl or alkoxy group having 1 to 3 carbon atoms, a halogen atom and / or an amino group May be mono-, di-, or trisubstituted; An alkyl group having 4 to 7 carbon atoms optionally substituted with an alkoxy group having 1 to 3 carbon atoms; Alkenyl groups having 3 to 6 carbon atoms; Or a cycloalkyl group having 3 to 7 carbon atoms, U is a halogen atom or sulfonic acid ester radical, such as chlorine, bromine or iodine, methanesulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group The same nucleophilic exchangeable group.

이 알킬화 반응은 페닐알킬 할로겐화물, 알킬할로겐화물, 디알킬설페이트 또는 트리알킬옥소늄-테트라플루오로보레이트, 예를 들면 벤질클로라이드, 페닐 에틸브로마이드, 메틸 요다이드, 디메틸설페이트, 디에틸설페이트 또는 에틸 브로마이드와 같은 상응하는 알킬화제를 사용하여 적절하게는 메탄올, 에탄올, 메탄올/물, 디메틸포름아미드 또는 디옥산과 같은 용매중에서, 경우에 따라 탄산나트륨, 중탄산나트륨, 수산화나트륨, 나트륨메틸레이트 또는 탄산칼륨과 같은 염기의 존재하에, 사용된 용매의 비점 이하의 온도에서 수행한다.This alkylation reaction is carried out with phenylalkyl halides, alkylhalides, dialkylsulfates or trialkyloxonium-tetrafluoroborates, for example benzylchloride, phenyl ethylbromide, methyl iodide, dimethylsulfate, diethylsulfate or ethyl bromide Bases such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium carbonate, if appropriate, in a solvent such as methanol, ethanol, methanol / water, dimethylformamide or dioxane, as appropriate In the presence of is carried out at a temperature below the boiling point of the solvent used.

라디칼 R4및 R5가 같은 의미를 나타내지 않을 경우에는 피라다지논환의 5위치에서 광학적으로 활성인 탄소원자를 기초로 하여, 수득된 일반식(I) 화합물을 광학적으로 활성인 대장체로분리시킬 수 있다. 이 분리는 타타르산, 디벤조일 타타르산, 말산, 캄포산 또는캄포설폰산과 같은 광학적으로 활성인 산으로 상응하는 염을 분별 결정화시키거나 광학적으로 활성인 흡착제로 크로마토그라피하여 수행하는 것이 적합하다.When the radicals R 4 and R 5 do not have the same meaning, the obtained compound of general formula (I) can be separated into an optically active colon based on the optically active carbon atom at the 5-position of the pyridazinone ring. . This separation is suitably carried out by fractional crystallization of the corresponding salts with an optically active acid such as tartaric acid, dibenzoyl tartaric acid, malic acid, camphoric acid or camphorsulfonic acid or by chromatography with an optically active adsorbent.

또한 수득된 일반식(I)의 화합물은 이들의 생리학적으로 무독한 유기 또는 무기산 또는 염기와의 부가염으로 전환시킬 수 있다. 적합한 산으로는 예를 들어 염산, 브롬화수소산, 황산, 인산, 푸마르산, 숙신산, 락트산, 시트르산, 타타르산 또는 말레산이 있다.The compounds of general formula (I) obtained can also be converted to their physiologically poisonous addition salts with organic or inorganic acids or bases. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

출발 화합물로서 사용되는 인반식(I) 및 (Ⅲ)의 화합물은 간행물에 공지된 방법에 의하여 제조할 수 있다. 따라서 예를 들면 일반식(Ⅱ)의 화합물은 상응하는 3-(니트로-하이드록시벤조일)-부티르산 에스테르를 하이드라진과 반응시키고, 이어서 니트로그룹을 환원시킨 다음 수득된 화합물을 상응하는 카복실산 유도체와 반응시켜 제조할 수 있다.Compounds of Inban (I) and (III) used as starting compounds can be prepared by methods known in the publication. Thus, for example, a compound of formula (II) is reacted with the corresponding 3- (nitro-hydroxybenzoyl) -butyric ester with hydrazine, followed by reduction of the nitro group and then reaction with the corresponding carboxylic acid derivative It can manufacture.

일반식(Ⅲ)의 화합물은 다음 일반식(Ⅳ)의 화합물을 말론산 에스테르와 반응시켜 제조할 수 있다.The compound of formula (III) can be prepared by reacting the compound of formula (IV) with malonic ester.

Figure kpo00008
Figure kpo00008

수득된 화합물은 차례로 검화, 탈카르복실화시켜 염소원자를 하이드록시 또는 메르캅토그룹으로 치환시키고 니트로그룹을 환원시킨 후 수득된 아미노 화합물을 상응하는 카르복실산 유도체와 반응시킨 후 폐환시켜 원하는 벤즈옥사졸 또는 티아졸로 만든다.The obtained compound is in turn saponified and decarboxylated to replace chlorine atoms with hydroxy or mercapto groups, the nitro groups are reduced, and the resulting amino compounds are reacted with the corresponding carboxylic acid derivatives and then ring-closed to give the desired benzoxa. Made of sol or thiazole.

출발물질로 사용되는 일반식(Ⅳ)의 화합물은 상응하는 티오우레아를, 적절하게는 본 발명의 a) 방법에 의해 폐환시켜 제조할 수 있다.Compounds of formula (IV) used as starting materials can be prepared by ring closure of the corresponding thiourea, suitably by the method a) of the present invention.

앞에서 이미 언급한 바와 같이 본 발명의 일반식(I)의 신규 화합물, 이들의 광학적으로 활성인 대장체 및 이들의 생리학적으로 무독한 무기 또는 유기산과의 산부가염들은 심장혈관 질환에 대한 활성, 즉 강심작용, 혈압강하작용 및/또는 항혈전 작용이 있다. 다음과 같은 화합물을 사용하여 생물학적 특성에 관한 시험을 하였다 :As already mentioned above, the novel compounds of general formula (I) of the present invention, their optically active colon and their acid addition salts with physiologically toxic inorganic or organic acids are active against cardiovascular disease, i.e. Cardiac action, hypotensive action and / or antithrombotic action. Tests on biological properties were carried out using the following compounds:

A=5-메틸-6-[2'-에틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피라다지논,A = 5-Methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

B=5-메틸-6-[2'-사이클로헥실아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논,B = 5-Methyl-6- [2'-cyclohexylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

C=5-메틸-6-[2'-n-부틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논,C = 5-methyl-6- [2'-n-butylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone,

D=5-메틸-6-[2'-(4-메톡시페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논.D = 5-Methyl-6- [2 '-(4-methoxyphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone.

E=5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논,E = 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone,

F=5-메틸6-(2'-하이드록시-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논,F = 5-Methyl6- (2'-hydroxy-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone,

다음과 같은 시험을 수행하였다.The following tests were performed.

1. 본과 크로스의 간행물(Born and Cross, J. Pyhsiol. 170,397(1965)에 다른 혈소판 응집측정1. Measurement of Other Platelet Aggregation in Born and Cross, J. Pyhsiol. 170,397 (1965)

혈소판응집 측정은 건강한 사람의 혈소판이 풍부한 혈장에서 측정한다. ㎖ 당 1mg의 콜라겐섬유소를 함유하는 Messrs·sigma, St. Louis, U.S.A의 시판품인 콜라겐을 첨가한 후 광학 밀도의 광도계로 측정하여 기록한다. 응집속도(νmax)는 밀도 곡선의 경사각도로 측정한다. 곡선에서 빛을 대부분 투과시키는 점에서 광학 밀도(o.d.)를 측정한다. 최대응집을 유발시키기 위해 혈소판이 풍부한 혈장 1㎖에 콜라겐용액 약 0.01㎖를 첨가한다. 그 결과는 다음 표와 같다.Platelet aggregation measurements are made in platelet-rich plasma of healthy people. Messrs. Sigma, St. C., containing 1 mg of collagen fiber per ml. Add collagen, commercially available from Louis, USA, and measure and record with an optical density photometer. The aggregation rate ν max is measured by the inclination angle of the density curve. The optical density (od) is measured at the point that the light transmits most of the curve. To induce maximum aggregation, add about 0.01 ml of collagen solution to 1 ml of platelet-rich plasma. The results are shown in the following table.

Figure kpo00009
Figure kpo00009

2. 고양이의 혈압강하작용 및 수축력 증가작용의 측정2. Measurement of cat blood pressure lowering and contractile force increasing

이 시험은 펜토바비탈 나트륨(40mg/kg 복강내)으로 마취시킨 고양이를 사용하여 수행한다. 이 동물은 자발적으로 호흡한다. 동맥혈압을 복부대동맥에서 스태탐(statham) 압력전달기(P23Dc)로 측정한다. 카데테르팁마노미터(miller PC350A)를 사용하여 좌심방에서의 압력을 측정함으로써 수축력 증가효과를 측정한다. 수축성 척도 dp/dtmzx는 유추 미분 회로에 의해 기록한다. 시험 물질을 대퇴부 정맥에 주사한다. 생리학적 하이포아염산나트륨용액 또는 폴리디올 200을 용매로서 사용한다. 각 물질당 적어도 3마리의 고양이에 대하여 시험하며 용량은 0.1 또는 2.0mg/kg(정맥내)이다. 시험물질은 적어도 45분간 그 활성이 유지된다.This test is performed using cats anesthetized with pentobarbital sodium (40 mg / kg intraperitoneal). This animal breathes spontaneously. Arterial blood pressure is measured in the abdominal aorta with a statham pressure transmitter (P23D c ). The effect of increasing contractile force is measured by measuring the pressure in the left atrium using a catheter tip manometer (miller PC350A). Shrinkage scale dp / dt mzx is recorded by analogical differential circuit. Test substance is injected into the femoral vein. Physiological sodium hypochlorite solution or polydiol 200 is used as a solvent. At least three cats for each substance are tested and the dose is 0.1 or 2.0 mg / kg (intravenously). The test substance remains active for at least 45 minutes.

다음 표는 평균값을 나타낸다.The following table shows the mean values.

Figure kpo00010
Figure kpo00010

3. 급성독성3. Acute Toxicity

시험 화합물의 급성독성은 흰쥐에게 1회 용량을 경구투여한 후 측정한다(관찰기간 : 14일).Acute toxicity of the test compound is determined after oral administration to rats (observation period: 14 days).

Figure kpo00011
Figure kpo00011

본 발명에 따라 제조된 일반식(I)의 화합물, 이들의 광학적으로 활성인 대장체 및 생리학적으로 무독한 무기 또는 유기산과의 산부가염들은 그의 약제학적 특성을 기초로 하여 탄성 심부전증 또는 협심증의 치료 및/또는 동맥폐색증 및 혈전증의 예방에 적합하다.Compounds of formula (I) prepared according to the invention, their optically active colon and acid addition salts with physiologically toxic inorganic or organic acids, are based on their pharmaceutical properties to treat elastic heart failure or angina pectoris. And / or for prevention of arterial occlusion and thrombosis.

일반식(I)의 화합물 및 이들의 생리학적으로 무독한 산부 가염은 통상의 제제, 예를 들어 정제, 코팅정제, 분제, 현탁제, 좌제 또는 앰플제등으로 만들어 투여할 수 있다. 성인에 대한 1회 투여량은 10 내지 50mg(정맥내투여)으로서 1일에 1 내지 4회 투여하며 바람직하게는 20 내지 40mg이고, 경구투여시의 용량은 50 내지 150mg, 바람직하게는 75 내지 100mg이다.Compounds of general formula (I) and their physiologically toxic acid salts can be prepared and administered in conventional formulations, such as tablets, coated tablets, powders, suspensions, suppositories, or ampoules. Single dose for adults is 10 to 50 mg (intravenous), 1 to 4 times a day, preferably 20 to 40 mg, and oral dose is 50 to 150 mg, preferably 75 to 100 mg to be.

다음은 본 발명의 제조방법에 사용되는 출발물질의 제조실시예를 설명한다.The following describes a production example of the starting material used in the production method of the present invention.

제조실시예 IPreparation Example I

N-에틸-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지는-6-일)-페닐]티오우레아N-ethyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazin-6-yl) -phenyl] thiourea

10.8g(50밀리몰)의 2-아미노-4-(5-메틸-4,5-디하이드로-3(2H)-피리다지는-6-일)-페놀을 250㎖의 테트라하이드로푸란 중에 현탁시킨다. 이 현탁액을 25㎖의 테트라하이드로푸란 중에 현탁시킨다. 이 현탁액을 25㎖(0.29몰)의 에틸 이소티오시아네이트와 혼합 시키고 이 혼합물을 3.5시간 동안 환류시키면 단시간내에 맑은 용액이 형성된다. 반응시간이 지난 후 혼합물을 증발시키고 황색오일상 잔류물에 에테르를 첨가하여 결정화시킨다. 침전 생성물을 흡인여과하고 에테르로 세척한 후 실온에서 건조시킨다. 수득량 : 13.0g(이론량의 91.5%) 융점 : 137°내지 139℃10.8 g (50 mmol) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazin-6-yl) -phenol is suspended in 250 ml of tetrahydrofuran. This suspension is suspended in 25 ml of tetrahydrofuran. This suspension is mixed with 25 ml (0.29 mol) of ethyl isothiocyanate and refluxed for 3.5 hours to form a clear solution in a short time. After the reaction time, the mixture is evaporated and crystallized by adding ether to the yellow oily residue. The precipitated product is suction filtered, washed with ether and dried at room temperature. Yield: 13.0g (91.5% of theory) Melting Point: 137 ° to 139 ° C

C14H18N4O2S (306.4)C 14 H 18 N 4 O 2 S (306.4)

계산치 : C54.88 H4.92 N18.29 S10.47Calculation: C54.88 H4.92 N18.29 S10.47

실측치 : 55.10 6.10 17.90 10.30Found: 55.10 6.10 17.90 10.30

제조실시예 ⅡPreparation Example II

2-에틸아미노-5-(3-메틸-4-옥소-부티르산-4-일)-벤즈옥사졸2-ethylamino-5- (3-methyl-4-oxo-butyric acid-4-yl) -benzoxazole

3.24g(10.0밀리몰)의 N-에틸-N'-[2-하이드록시-5-(3-메틸-4-옥소-부티르산-4-일)-페닐]티오우레아를 150㎖의 테트라하이드로푸란 중에 녹인다. 이 용액을 4.17g(20.0밀리몰)의 N,N'-디사이클로헥실카보디이미드와 혼합하고 5시간 동안 환류시킨다. 환류시킨 후 용액을 1/2용량으로 증발시키고 다시 잠시 동안 가열한 후 결정이 형성될 때까지 냉각시킨다. 수득된 생성물을 흡인 여과하고 테트라하이드로푸란에서 재결정화한 후 실온에서 건조시킨다.3.24 g (10.0 mmol) of N-ethyl-N '-[2-hydroxy-5- (3-methyl-4-oxo-butyric acid-4-yl) -phenyl] thiourea in 150 ml of tetrahydrofuran Dissolve. This solution is mixed with 4.17 g (20.0 mmol) of N, N'-dicyclohexylcarbodiimide and refluxed for 5 hours. After reflux, the solution is evaporated to 1/2 volume, heated for a while and then cooled until crystals form. The product obtained is suction filtered, recrystallized in tetrahydrofuran and dried at room temperature.

수득량 : 0.71g(이론량의 24.3%)Yield: 0.71 g (24.3% of theory)

융 점 : 160°내지 162℃Melting Point: 160 ° to 162 ° C

다음 실시예를 들어 본 발명의 제조방법을 더욱 구체적으로 설명한다.The production method of the present invention will be described in more detail with reference to the following examples.

5-메틸-6-[2'-메틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-methylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

3.36g(11.5밀리몰)의 N-메틸-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐] 티오우레아를 150㎖의 테르라하이드로-푸란중에 녹인다. 이 용액을 3.13g(15 밀리몰)의 N,N'-디사이클로헥실카보디이미드와 혼합하고 5시간동안 환류시킨다. 환류시킨 후 반응 혼합물을 1/2용량까지 증발시키고 다시 잠깐동안 가열한 후 결정이 형성될 때까지 냉각시킨다. 수득된 생성물을 흡인여과하고 메탄올에서 재결정화한 후 실온에서 건조시킨다.3.36 g (11.5 mmol) N-methyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] Thiourea is dissolved in 150 ml terahydro-furan. This solution is mixed with 3.13 g (15 mmol) N, N'-dicyclohexylcarbodiimide and refluxed for 5 hours. After reflux, the reaction mixture is evaporated to 1/2 volume, heated briefly and cooled until crystals form. The product obtained is suction filtered, recrystallized in methanol and dried at room temperature.

수득량 : 0.84g(이론량의 28.3%)Yield: 0.84 g (28.3% of theory)

융 점 : 241°내지 242℃Melting Point: 241 ° to 242 ° C

C13H14N4O2(258.3)C 13 H 14 N 4 O 2 (258.3)

계산치 : C 60.46 H 5.46 N 21.69Calculated Value: C 60.46 H 5.46 N 21.69

실측치 : 60.28 5.61 21.50Found: 60.28 5.61 21.50

[실시예 2]Example 2

5-메틸-6-[2'-n-부틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-n-butylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-n-부틸-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.Nn-butyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] in a similar manner to Example 1 Prepared from thiourea.

수율 : 이론량의 39.7% 계산치 : C63.98 H6.71 N18.65Yield: 39.7% of theoretical amount Calculated: C63.98 H6.71 N18.65

융점 : 186°내지 188℃ 실측치 : C63.99 H6.96 N18.54Melting Point: 186 ° to 188 ° C. Found: C63.99 H6.96 N18.54

C16H20N4O2(300.4)C 16 H 20 N 4 O 2 (300.4)

[실시예 3]Example 3

5-메틸-6-[2'-이소프로필아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-isopropylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-이소프로필-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-isopropyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl in a similar manner to Example 1 ] From thiourea.

수율 : 이론량의 52% 계산치 : C62.92 H6.34 N19.57Yield: 52% of theoretical amount calculated: C62.92 H6.34 N19.57

융점 : 239°내지 241℃ 실측치 : 62.65 6.33 19.25Melting Point: 239 ° to 241 ° C. Found: 62.65 6.33 19.25

C15H18N4O2(286.34)C 15 H 18 N 4 O 2 (286.34)

[실시예 4]Example 4

5-메틸-6-[2'-사이클로헥실아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-cyclohexylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-사이클로헥실-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-cyclohexyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl in a similar manner to Example 1 ] From thiourea.

수율 : 이론량의 59.1% 계산치 : C66.24 H6.79 N17.16Yield: 59.1% of theoretical amount calculated: C66.24 H6.79 N17.16

융점 : 235°내지 237℃ 실측치 : 66.00 6.90 16.99Melting Point: 235 ° to 237 ° C. Found: 66.00 6.90 16.99

C18H22N4O2(326.4)C 18 H 22 N 4 O 2 (326.4)

[실시예 5]Example 5

5-메틸-6-[2'-(3,4-디메톡시펜에틸아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(3,4-dimethoxyphenethylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-3,4-디메톡시펜에틸-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐] 티오우레아로부터 제조한다.N-3,4-dimethoxyphenethyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone- in a similar manner to Example 1 6-yl) -phenyl] thiourea.

수율 : 이론량의 48.2% 계산치 ; C59.39 H5.87 N12.59 C17.99Yield: 48.2% of theoretical value calculated; C59.39 H5.87 N12.59 C17.99

융점 : 70°내지 72℃ 실측치 : 50.40 5.69 12.89 8.00Melting Point: 70 ° to 72 ° C. Found: 50.40 5.69 12.89 8.00

C22H24N4O4×염산(444.93)C 22 H 24 N 4 O 4 × hydrochloric acid (444.93)

[실시예 6]Example 6

5-메틸-6-[2'-페닐아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-phenylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

5㎖의 히드라진 수화물(99%)를 약 20℃에서 20㎖의 빙초산에 교반 및 얼음 냉각시키면서 조금씩 첨가한다. 이어서 반응 혼합물에 6.5g(20.0밀리몰)의 2-페닐아미노-5-(3-메틸-4-옥소-부티르산-4-일)-벤즈옥사졸을 첨가하고 수득된 현탁액을 환류시킨다. 1시간후 이 현탁액을 실온까지 냉각시키고 물로 희석한다. 침전된 생성물을 흡인여과하고 물로 세척한 후 80℃에서 건조시킨다.5 ml of hydrazine hydrate (99%) are added in portions to 20 ml of glacial acetic acid at about 20 ° C. with stirring and ice cooling. 6.5 g (20.0 mmol) of 2-phenylamino-5- (3-methyl-4-oxo-butyric acid-4-yl) -benzoxazole are then added to the reaction mixture and the resulting suspension is refluxed. After 1 hour the suspension is cooled to room temperature and diluted with water. The precipitated product is suction filtered, washed with water and dried at 80 ° C.

수득량 : 2.80g(이론량의 43.7%)Yield: 2.80 g (43.7% of theory)

융 점 : 214°내지 217℃Melting Point: 214 ° to 217 ° C

C18H16N4O2(320.34)C 18 H 16 N 4 O 2 (320.34)

[실시예 7]Example 7

5-메틸-6-[2'-(2-클로로아닐리노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(2-chloroanilino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-2-클로로페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-2-chlorophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) in a similar manner to Example 1 -Phenyl] thiourea.

수율 : 이론량의 33.9% 계산치 : C60.93 H4.26 N15.79 C19.99Yield: 33.9% of theoretical amount calculated: C60.93 H4.26 N15.79 C19.99

융점 : 193°내지 195℃ 실측치 : C60.90 H4.25 N16.93 C10.20Melting Point: 193 ° to 195 ° C. Found: C60.90 H4.25 N16.93 C10.20

C18H15N4O2Cl (354.8)C 18 H 15 N 4 O 2 Cl (354.8)

[실시예 8]Example 8

5-메틸-6-[2'-(4-트리플루오로 메틸페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-trifluoro methylphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-4-트리플루오로-메틸-페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-4-trifluoro-methyl-phenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone in a similar manner to Example 1 -6-yl) -phenyl] thiourea.

수율 : 이론량의 57.3% 계산치 : C58.76 H3.89 N14.42Yield: 57.3% of theoretical amount calculated: C58.76 H3.89 N14.42

융점 : 249°내지 251℃ 실측치 : C59.00 H4.13 N14.31Melting Point: 249 ° to 251 ° C. Found: C59.00 H4.13 N14.31

C19H15N4O2F3(388.36)C 19 H 15 N 4 O 2 F 3 (388.36)

[실시예 9]Example 9

5-메틸-6-[2'-(3,4-디클로로페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피다지논5-Methyl-6- [2 '-(3,4-dichlorophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pidazinone

실시예 1과 유사한 방법으로 N-3,4-디클로로 페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-3,4-dichloro phenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6- in a similar manner to Example 1 From 1) -phenyl] thiourea.

수율 : 이론량의 73.5% 계산치 : C55.54 H3.63 C118.22Yield: 73.5% of theoretical amount Calculated: C55.54 H3.63 C118.22

융점 : : 253°내지 256℃ 실측치 : C55.40 H3.83 C118.14Melting Point:: 253 ° to 256 ° C. Found: C55.40 H3.83 C118.14

C18H14N4O2Cl2(389.3)C 18 H 14 N 4 O 2 Cl 2 (389.3)

[실시예 10]Example 10

5-메틸-6-[2'-(4-브로모페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-bromophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-4-브로모페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)페닐]티오우레아로부터 제조한다.N-4-bromophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) Phenyl] thiourea.

수율 : 이론량의 65.4% 계산치 : C55.40 H3.87 N14.36 Br20.48Yield: 65.4% of theoretical amount calculated: C55.40 H3.87 N14.36 Br20.48

융점 : 243°내지 245℃ 실측치 : C55.003 H4.05 N13.95 Br20.76Melting Point: 243 ° to 245 ° C. Found: C55.003 H4.05 N13.95 Br20.76

C18H15N4O2Br (90.27)C 18 H 15 N 4 O 2 Br (90.27)

[실시예 11]Example 11

5-메틸-6-[2'-(4-메톡시페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-methoxyphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-4-메톡시페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-4-methoxyphenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

수율 : 이론량의 40.3% 계산치 : C65.13 H5.18 N15.99Yield: 40.3% of theoretical amount calculated: C65.13 H5.18 N15.99

융점 : 220°내지 222℃ 실측치 : C65.30 H5.20 N15.83Melting Point: 220 ° ~ 222 ℃ Found: C65.30 H5.20 N15.83

C19H18N4O3(350.4)C 19 H 18 N 4 O 3 (350.4)

[실시예 12]Example 12

5-메틸-6-[2'-(2-메톡시-4-니트로페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(2-methoxy-4-nitrophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-2-메톡시-4-니트로페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-2-methoxy-4-nitrophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone in a similar manner to Example 1 -6-yl) -phenyl] thiourea.

수율 : 이론량의 65.6% 계산치 : C57.82 H4.33 N17.71Yield: 65.6% of theoretical amount Calculated: C57.82 H4.33 N17.71

융점 : 223°내지 225℃ 실측치 : C58.27 H4.25 N18.17Melting Point: 223 ° to 225 ° C. Found: C58.27 H4.25 N18.17

C19H17N5O5(395.4)C 19 H 17 N 5 O 5 (395.4)

[실시예 13]Example 13

5-메틸-6-[2'-(4-메틸페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-methylphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-4-메틸페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-4-methylphenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl)-in a similar manner to Example 1 Phenyl] thiourea.

수율 : 이론량의 52.1% 계산치 : C68.25 H5.43 N16.76Yield: 52.1% of theoretical amount calculated: C68.25 H5.43 N16.76

융점 : 273°내지 275℃ 실측치 : C68.10 H5.59 N16.88Melting Point: 273 ° to 275 ° C. Found: C68.10 H5.59 N16.88

C19H18N4O2 (334.39)C 19 H 18 N 4 O 2 (334.39)

[실시예 14]Example 14

5-메틸-6-[2'-(4-트리메틸페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-trimethylphenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-2.4.6-트리메틸페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-2.4.6-trimethylphenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6- in a similar manner to Example 1 From 1) -phenyl] thiourea.

수율 : 이론량의 76.4% 계산치 : C69.59 H6.12 N15.46Yield: 76.4% of theoretical amount Calculated: C69.59 H6.12 N15.46

융점 : 225°내지 228℃ 실측치 : C69.79 H6.37 N15.65Melting Point: 225 ° to 228 ° C Found: C69.79 H6.37 N15.65

C21H22N4O2(362.4)C 21 H 22 N 4 O 2 (362.4)

[실시예 15]Example 15

5-메틸-6-[2'-(4-시아노페닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-cyanophenylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-4-시아노페닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-4-cyanophenyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

수율 : 이론량의 59.7% 계산치 : C66.08 H4.38 N20.28Yield: 59.7% of theoretical amount Calculated: C66.08 H4.38 N20.28

융점 : 318°내지 302℃ 실측치 : C66.14 H4.58 N20.03Melting Point: 318 ° to 302 ° C. Found: C66.14 H4.58 N20.03

C19H15N5O2(345.37)C 19 H 15 N 5 O 2 (345.37)

[실시예 16]Example 16

5-메틸-6-[2'-에톡시카보닐아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-ethoxycarbonylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-에톡시카보닐-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-ethoxycarbonyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) in a similar manner to Example 1 -Phenyl] thiourea.

수율 : 이론량의 19.8% 계산치 : C56.95 H5.10 N17.71Yield: 19.8% of theoretical amount calculated: C56.95 H5.10 N17.71

융점 : 235°내지 239℃ 실측치 : C55.81 H5.14 N17.08Melting Point: 235 ° to 239 ° C Found: C55.81 H5.14 N17.08

C15H16N4O4(316.33)C 15 H 16 N 4 O 4 (316.33)

[실시예 17]Example 17

5-메틸-6-[2'-n-펜틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-n-pentylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-n-펜틸-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.Nn-pentyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] in a similar manner to Example 1 Prepared from thiourea.

수율 : 이론량의 52.3% 계산치 : C64.95 H7.05 N17.82Yield: 52.3% calculated theory: C64.95 H7.05 N17.82

융점 : 154°내지 155℃ 실측치 : C65.26 H7.12 N17.88Melting Point: 154 ° to 155 ° C. Found: C65.26 H7.12 N17.88

C17H22N4O2(314.4)C 17 H 22 N 4 O 2 (314.4)

[실시예 18]Example 18

5-메틸-6-[2'-에틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-에틸-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-ethyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] in a similar manner to Example 1 Prepared from thiourea.

수율 : 이론량의 71.9% 계산치 : C61.95 H5.98 N20.85Yield: 71.9% of theoretical amount calculated: C61.95 H5.98 N20.85

융점 : 244°내지 246℃ 실측치 : C61.75 H5.92 N20.57Melting Point: 244 ° to 246 ° C. Found: C61.75 H5.92 N20.57

C14H16N4O2(272.3)C 14 H 16 N 4 O 2 (272.3)

[실시예 19]Example 19

5-메틸-6-[2'-(3-메톡시프로필아미노)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(3-methoxypropylamino) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-3-메톡시프로필-N'-[2-하이드록시-5-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.N-3-methoxypropyl-N '-[2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl in a similar manner to Example 1 ) -Phenyl] thiourea.

수율 : 이론량의 55.5% 계산치 : C60.75 H6.37 N17.71Yield: 55.5% of theoretical amount Calculated: C60.75 H6.37 N17.71

융점 : 153°내지 154℃ 실측치 : C61.00 H6.40 17.56Melting Point: 153 ° to 154 ℃ Found: C61.00 H6.40 17.56

C16H20N4O3(316.4)C 16 H 20 N 4 O 3 (316.4)

[실시예 20]Example 20

5-메틸-6-[2'-아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-amino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 1과 유사한 방법으로 N-[2-하이드록시-5-(5-메틸디하이드로-4,5-피리다지논-6-일)-페닐]티오우레아로부터 제조한다.Prepared from N- [2-hydroxy-5- (5-methyldihydro-4,5-pyridazinone-6-yl) -phenyl] thiourea in a similar manner to Example 1.

수율 : 이론량의 42.1%Yield: 42.1% of theoretical amount

융점 : 285°내지 287℃Melting Point: 285 ° to 287 ° C

[실시예 21]Example 21

5,5-디메틸-6-[2'-(α-페닐에틸)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5,5-dimethyl-6- [2 '-(α-phenylethyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4-(4-클로로페닐)-3,3-디메틸-4-옥소-부티르산a) 4- (4-chlorophenyl) -3,3-dimethyl-4-oxo-butyric acid

30g(0.688몰)의 수소화나트륨(50%오일 현탁액)을 실온에서 1,200㎖의 무수 테트라하이드로 푸란에 첨가하고 이혼합물을 15분동안 교반한다. 52g(0.228몰)의 4-(4-클로로페닐)-3-메틸-4-옥소-부티르산을 조금씩 첨가한 후 이반응 혼합물을 2시간동안 환류시킨다. 이어서 이 혼합물을 40℃까지 냉각시키고 64㎖(1.02몰)의 메틸요다이드를 적가한다. 3시간 더 환류시킨 후 실온까지 냉각시키고 이 반응 혼합물을 물에 교반시키며, 첨가하고 유기부분을 회전증발기속에서 증류시킨다. 알칼리수용액을 석유에테트로 2회 세척하고 농염산으로 산성화시킨다. 침전된 오일은 더 교반하면 결정화된다. 이 결정을 흡인 여과하여 물로 세척한 후 건조시킨다.30 g (0.688 mole) of sodium hydride (50% oil suspension) is added to 1,200 mL of anhydrous tetrahydrofuran at room temperature and the mixture is stirred for 15 minutes. 52 g (0.228 mol) of 4- (4-chlorophenyl) -3-methyl-4-oxo-butyric acid are added in portions and the reaction mixture is refluxed for 2 hours. The mixture is then cooled to 40 ° C. and 64 ml (1.02 mole) of methyl iodide are added dropwise. After refluxing for another 3 hours, the reaction mixture is cooled to room temperature, stirred in water, added and the organic portion is distilled in a rotary evaporator. The alkaline aqueous solution is washed twice with petroleum ether and acidified with concentrated hydrochloric acid. The precipitated oil crystallizes on further stirring. The crystals are suction filtered, washed with water and dried.

수득량 : 52g(이론량의 94.7%)Yield: 52 g (94.7% of theory)

융 점 : 95°내지 97℃Melting Point: 95 ° to 97 ° C

b) 4-(4-클로로-3-니트로페닐)-3,3-디메틸-4-옥소-부티르산b) 4- (4-chloro-3-nitrophenyl) -3,3-dimethyl-4-oxo-butyric acid

48g(0.2몰)의 4-(4-클로로페닐)-3,3-디메틸-4-옥소부티르산을 -15℃및 -10℃에서 500㎖의 발연질산에 교반하며 조금씩 첨가한다. -10℃에서 30분간 교반한 후 반응 혼합물을 얼음물에 붓고 침전된 생성물을 흡인여과한 후 물로 세척한여 중화하고 건조시킨다.48 g (0.2 moles) of 4- (4-chlorophenyl) -3,3-dimethyl-4-oxobutyric acid are added in portions to 500 ml of fuming nitric acid at -15 ° C and -10 ° C with stirring. After stirring at −10 ° C. for 30 minutes, the reaction mixture is poured into iced water, the precipitated product is suction filtered, washed with water, neutralized and dried.

수득량 : 47.5g(이론량의 83.1%)Yield: 47.5 g (83.1% of theory)

융 점 : 118°내지 120℃Melting Point: 118 ° ~ 120 ℃

c) 2-니트로-4-(5,5-디메틸-4,5-하이드로-3(2H)-피리다지논-6-일)-클로로벤젠c) 2-nitro-4- (5,5-dimethyl-4,5-hydro-3 (2H) -pyridazinone-6-yl) -chlorobenzene

43㎖의 히드라진 무수물(99%)을 약 20℃에서 400㎖의 빙초산에 교반 및 얼음냉각시키고 조금씩 첨가한다. 이어서 3g(0.15몰)의 4-(4-클로로-3-니트로페닐)-5,5-디메틸-4-옥소-부티르산을 첨가하고 반응 혼합물을 1시간동안 환류시킨다. 냉각시킨 후 반응 혼합물을 물로 희석하고 침전된 생성물을 흡인 여과하고 물로 다시 세척한 후 건조시킨다.43 mL of hydrazine anhydride (99%) is stirred, ice-cooled and added in portions to 400 mL of glacial acetic acid at about 20 ° C. 3 g (0.15 mole) of 4- (4-chloro-3-nitrophenyl) -5,5-dimethyl-4-oxo-butyric acid is then added and the reaction mixture is refluxed for 1 hour. After cooling the reaction mixture is diluted with water and the precipitated product is suction filtered, washed again with water and dried.

수득량 : 33g(이론량의 78.1%)Yield: 33 g (78.1% of theory)

융 점 : 193°내지 194℃Melting Point: 193 ° to 194 ° C

d) 2-니트로-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐d) 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl

28g(0.1몰)의 2-니트로-4-(5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-클로로벤젠을 750㎖의 글리콜에 현탁시키고 이 현탁액을 40g의 분말 수산화칼륨을 250㎖의 글리콜에 녹인 용액과 혼합한다. 수득된 용액을 160℃에서 2시간 동안 가열하고 실온까지 냉각시킨 후 이 용액을 약 3ℓ의 얼음물에 붓고 농염산으로 산성화시킨다. 침전된 생성물을 흡인 여과한다. 여액은 250㎖씩의 에틸아세테아트로 4회 추출하고 유기상은 황산나트륨상에서 탈수시킨 후 건조시킨다. 잔류물과 고형 생성물을 합하여 물과 함께 분쇄하고 흡인여과한 후 건조시킨다.28 g (0.1 mole) of 2-nitro-4- (5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -chlorobenzene was suspended in 750 ml of glycol and this suspension 40 g of powdered potassium hydroxide is mixed with a solution of 250 ml of glycol. The resulting solution is heated at 160 ° C. for 2 hours and cooled to room temperature, then the solution is poured into about 3 L of ice water and acidified with concentrated hydrochloric acid. The precipitated product is suction filtered. The filtrate is extracted four times with 250 ml of ethyl acetate and the organic phase is dehydrated over sodium sulfate and dried. The residue and solid product are combined, triturated with water, filtered off with suction and dried.

수득량 : 20g(이론량의 76%)Yield: 20 g (76% of theory)

융 점 : 211°내지 213℃Melting Point: 211 ° to 213 ° C

e) 2-아미노-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀e) 2-amino-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol

20g(0.076몰)의 2-니트로-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을600㎖의 디메틸포름아미드에 녹인 용액을 실온의 파르(parr)장치내에서 수소(5bar)와 2g의 Pd/c (10%)촉매를 사용하여 환원시킨다. 수소의 흡수가 중지되면 촉매를 흡인여과해내고 여액을 증발시킨다. 고형 생성물이 수득되면 에테르와 함께 분쇄한다. 흡인 여과한 후 생성물을 에테르로 세척하고 건조시킨다.20 g (0.076 mole) of 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol dissolved in 600 ml of dimethylformamide The solution is reduced using hydrogen (5 bar) and 2 g of Pd / c (10%) catalyst in a parr apparatus at room temperature. When absorption of hydrogen stops, the catalyst is aspirated off and the filtrate is evaporated. Once a solid product is obtained, it is triturated with ether. After suction filtration the product is washed with ether and dried.

수득량 : 17g(이론량의 96%)Yield: 17 g (96% of theory)

융 점 : 260°내지 263℃Melting Point: 260 ° to 263 ° C

f) 2-(2-페닐프로피오닐아미노)-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일) 페놀f) 2- (2-phenylpropionylamino) -4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) phenol

2.8g(0.012몰)의2-아미노-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)페놀 40㎖의 무수테트라하이드로푸란 40㎖의 무수 디메틸포름아미드에 현탁시킨다. 3.03g(0.018몰)의 2-페닐프로피온산 클로라이드를 실온에서 적가한다.40 mL of anhydrous tetrahydrofuran of 40 mL of 2.8 g (0.012 mol) of 2-amino-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) phenol It is suspended in anhydrous dimethylformamide. 3.03 g (0.018 mol) of 2-phenylpropionic acid chloride is added dropwise at room temperature.

1.5시간 후 반응 혼합물을 물에 교반하며 첨가하고 에틸 아세테이트로 수회 세척한다. 유기상을 황산 나트륨으로 탈수시키고 증발시킨다. 수득된 생성물을 칼럼 크로마토그라피(실리카겔, 핵의 크기 : 0.05내지 0.20mm, 용출제 : 클로로포름/에탄올 1%)로 정제한다. 수득된 생성물은 분순한 상태로 다음 반응에 사용한다.After 1.5 hours the reaction mixture is added to water with stirring and washed several times with ethyl acetate. The organic phase is dehydrated with sodium sulfate and evaporated. The obtained product is purified by column chromatography (silica gel, nucleus size: 0.05 to 0.20 mm, eluent: chloroform / ethanol 1%). The obtained product is used in the subsequent reaction in a sequential state.

수득량 : 1.7g(이론량의 38.8%)Yield: 1.7 g (38.8% of theory)

g) 5,5-디메틸-6-[2'-(α-페닐에틸)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논g) 5,5-dimethyl-6- [2 '-(α-phenylethyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

1.7g(0.0046몰)의 2-(2-페닐프로피오닐 아미노)-4-(5,5-디미틸-4,5-디하이드로-3(2H)- 피리다지논-6-일)-페놀을 12㎖의 설포란에 현탁시키고, 이 현탁액을 5시간 동안 환류시킨다. 이어서 뜨거운 반응 새성물을 얼음물에 교반하며 붓는다. 침전된 요일상 생성물을 에틸 아세테이트로 추출하고 유기상을 황산나트륨으로 탈수시킨다. 수득된 잔류물을 칼럼 크로마토그라피(실리카겔, 핵의 크기 : 0.05내지 0.20mm, 용출제 : 클로로포름/에탄올 1%)로 정제한다. 상응하는 획분을 합하여 목탄을 통해 여과시킨 후 증발시킨다. 오일상의 잔류물을 석유에테르로 결정화시킨다.1.7 g (0.0046 moles) of 2- (2-phenylpropionyl amino) -4- (5,5-dimityl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol Is suspended in 12 ml of sulfolane and the suspension is refluxed for 5 hours. The hot reaction mixture is then poured into iced water with stirring. The precipitated day phase product is extracted with ethyl acetate and the organic phase is dehydrated with sodium sulfate. The residue obtained is purified by column chromatography (silica gel, nucleus size: 0.05 to 0.20 mm, eluent: chloroform / ethanol 1%). The corresponding fractions are combined and filtered through charcoal and then evaporated. The oily residue is crystallized with petroleum ether.

수득량 : 1g(이론량의 62.5%) 계산치 : C72.61 H6.09 N12.10Yield: 1g (62.5% of theory) Calculation: C72.61 H6.09 N12.10

융 점 : 131°내지 135℃ 실측치 : C72.18 H6.30 N11.91Melting Point: 131 ° to 135 ° C Found: C72.18 H6.30 N11.91

C21H21N3O2(347.4)C 21 H 21 N 3 O 2 (347.4)

[실시예 22]Example 22

5,5-디메틸-6-(2'-아미노-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5,5-Dimethyl-6- (2'-amino-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

2.1g(0.072몰)의 N-[2-하이드록시-5-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아 {N'-벤조일-N-[2-하이드록시-5-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)페닐]-티오우레아를 알칼리성 가수분해시켜 제조}를 40㎖의 무수 테트라하이드로 푸란에 녹인다. 2.05g(0.01몰)의 N,N'-디사이클로-헥실-카보디이미드를 첨가하고 테트라하이드로 푸란으로 세척한다. 반응 생성물을 1N암모니아로 현탁시키고 30분간 교반한 후 흡인여과하고 물로 세척한후 건조시킨다.2.1 g (0.072 moles) N- [2-hydroxy-5- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] thiourea { Alkaline valence of N'-benzoyl-N- [2-hydroxy-5- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) phenyl] -thiourea Dissolution was dissolved in 40 ml of anhydrous tetrahydrofuran. 2.05 g (0.01 mol) of N, N'-dicyclo-hexyl-carbodiimide are added and washed with tetrahydrofuran. The reaction product is suspended with 1N ammonia, stirred for 30 minutes, filtered off with suction, washed with water and dried.

수득량 : 1.0g(이론량의 54%) 계산치 : C60.45 H5.46 N21.69Yield: 1.0 g (54% of theory) Calculated: C60.45 H5.46 N21.69

융 점 : >250℃ 실측치 : C60.67 H5.41 N21.44Melting Point:> 250 ° C Found: C60.67 H5.41 N21.44

C13H14N4O2(258.3)C 13 H 14 N 4 O 2 (258.3)

[실시예 23]Example 23

5-메틸-6-[2'-디메틸아미노-벤조티아졸-5'-일]-4,5-디하이드로-3(2H0-피리다지논5-methyl-6- [2'-dimethylamino-benzothiazol-5'-yl] -4,5-dihydro-3 (2H0-pyridazinone

a) 4-(3-아미노-4-메르캅토페닐)-3-메틸-4-옥소-부티르산a) 4- (3-amino-4-mercaptophenyl) -3-methyl-4-oxo-butyric acid

27g(0.1몰)의 4-(3-니트로-4-클로로페닐)-3-메틸-4-옥소부티르산을, 72g(0.3몰)의 나트륨 설파이드 ×9H2O를 500㎖의 물에 녹인 용액에 첨가하고 35분간 증기욕상에서 가열한다. 10℃까지 냉각시킨 후 빙초산을 사용하여 반응혼합물의 pH를 4.5로 조절한다. 이어서 반응혼합물을 에틸아세테이트로 수회 추출하고 유기상은 황산나트륨으로 탈수시킨 후 건조시킨다. 수득된 잔류물은 불순한 상태로 다음 단계의 반응에 사용한다.27 g (0.1 mole) of 4- (3-nitro-4-chlorophenyl) -3-methyl-4-oxobutyric acid and 72 g (0.3 mole) of sodium sulfide x 9 H 2 O were dissolved in 500 ml of water. Add and heat in steam bath for 35 minutes. After cooling to 10 ° C., the pH of the reaction mixture is adjusted to 4.5 using glacial acetic acid. The reaction mixture is then extracted several times with ethyl acetate and the organic phase is dehydrated with sodium sulfate and dried. The residue obtained is used for the reaction of the next step in an impure state.

수득량 : 27.5g(이론량의 약 100%)Yield: 27.5 g (about 100% of theory)

30g(0.688몰)의 수소화나트륨(50%오일 현탁액)을 실온에서 1,200㎖의 무수 테트라하이드로 푸란에 첨가하고 이혼합물을 15분동안 교반한다. 52g( 0.228몰)의 4-(4-클로로페닐)-3-메틸-4-옥소-부티르산을 조금씩 첨가한 후 이반응 혼합물을 2시간동안 환류시킨다. 이어서 이 혼합물을 40℃까지 냉각시키고 64㎖(1.02몰)의 메틸요다이드를 적가한다. 3시간 더 환류시킨 후 실온까지 냉각시키고 이 반응 혼합물을물에 교반시키며, 첨가하고 유기부분을 회전증발기속에서 증류시킨다. 알칼리수용액을 석유에테트로 2회 세척하고 농염산으로 산성화시킨다. 침전된 오일은 더 교반하면 결정화된다. 이 결정을 흡인 여과하여 물로 세척한 후 건조시킨다.30 g (0.688 mole) of sodium hydride (50% oil suspension) is added to 1,200 mL of anhydrous tetrahydrofuran at room temperature and the mixture is stirred for 15 minutes. 52 g (0.228 mol) of 4- (4-chlorophenyl) -3-methyl-4-oxo-butyric acid are added in portions and the reaction mixture is refluxed for 2 hours. The mixture is then cooled to 40 ° C. and 64 ml (1.02 mole) of methyl iodide are added dropwise. After refluxing for another 3 hours, the reaction mixture is cooled to room temperature, stirred in water, added and the organic portion is distilled in a rotary evaporator. The alkaline aqueous solution is washed twice with petroleum ether and acidified with concentrated hydrochloric acid. The precipitated oil crystallizes on further stirring. The crystals are suction filtered, washed with water and dried.

수득량 : 52g(이론량의 94.7%)Yield: 52 g (94.7% of theory)

융 점 : 95°내지 97℃Melting Point: 95 ° to 97 ° C

b) 4-(4-클로로-3-니트로페닐)-3,3-디메틸-4-옥소-부티르산b) 4- (4-chloro-3-nitrophenyl) -3,3-dimethyl-4-oxo-butyric acid

48g(0.2몰)의 4-(4-클로로페닐)-3,3-디메틸-4-옥소부티르산을 -15℃및 -10℃에서 500㎖의 발연질산에 교반하며 조금씩 첨가한다. -10℃에서 30분간 교반한 후 반응 혼합물을 얼음물에 붓고 침전된 생성물을 흡인여과한 후 물로 세척하여 중화하고 건조시킨다.48 g (0.2 moles) of 4- (4-chlorophenyl) -3,3-dimethyl-4-oxobutyric acid are added in portions to 500 ml of fuming nitric acid at -15 ° C and -10 ° C with stirring. After stirring at −10 ° C. for 30 minutes, the reaction mixture is poured into iced water, the precipitated product is suction filtered, washed with water, neutralized and dried.

수득량 : 47.5g(이론량의 83.1%)Yield: 47.5 g (83.1% of theory)

융 점 : 118°내지 120℃Melting Point: 118 ° ~ 120 ℃

c) 2-니트로-4-(5,5-디메틸-4,5-하이드로-3(2H)-피리다지논-6-일)-클로로벤젠c) 2-nitro-4- (5,5-dimethyl-4,5-hydro-3 (2H) -pyridazinone-6-yl) -chlorobenzene

43㎖의 히드라진 무수물(99%)을 약 20℃에서 400㎖의 빙초산에 교반 및 얼음냉각시키고 조금씩 첨가한다. 이어서 3g(0.15몰)의 4-(4-클로로-3-니트로페닐)-5,5-디메틸-4-옥소-부티르산을 첨가하고 반응 혼합물을 1시간동안 환류시킨다. 냉각시킨 후 반응 혼합물을 물로 희석하고 침전된 생성물을 흡인 여과하고 물로 다시 세척한 후 건조시킨다.43 mL of hydrazine anhydride (99%) is stirred, ice-cooled and added in portions to 400 mL of glacial acetic acid at about 20 ° C. 3 g (0.15 mole) of 4- (4-chloro-3-nitrophenyl) -5,5-dimethyl-4-oxo-butyric acid is then added and the reaction mixture is refluxed for 1 hour. After cooling the reaction mixture is diluted with water and the precipitated product is suction filtered, washed again with water and dried.

수득량 : 33g(이론량의 78.1%)Yield: 33 g (78.1% of theory)

융 점 : 193°내지 194℃Melting Point: 193 ° to 194 ° C

d) 2-니트로-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀d) 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol

28g(0.1몰)의 2-니트로-4-(5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일-클로로벤젠을 750㎖의 글리콜에 현탁시키고 이 현탁액을 40g의 분말 수산화칼륨을 250의 글리콜에 녹인 용액과 혼합한다. 수득된 용액을 160℃에서 2시간 동안 가열하고 실온까지 냉각시킨 후 이 용액을 약 3ℓ의 얼음물에 붓고 농염산으로 산성화시킨다. 침전된 생성물을 흡인 여과한다. 여액은 250㎖씩의 에틸아세테이트로 4회 추출하고 유기상은 황산나트륨상에서 탈수시킨 후 건조시킨다. 전류물과 고형 생성물을 합하여 물과 함께 분쇄하고 흡인여과한 후 건조시킨다.28 g (0.1 mole) of 2-nitro-4- (5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl-chlorobenzene was suspended in 750 ml of glycol and the suspension was 40 g of powdered potassium hydroxide are mixed with a solution dissolved in 250 glycol, The obtained solution is heated at 160 ° C. for 2 hours, cooled to room temperature, and then poured into about 3 L of ice water and acidified with concentrated hydrochloric acid. The product is filtered off with suction, the filtrate is extracted four times with 250 ml of ethyl acetate, and the organic phase is dehydrated over sodium sulfate and dried.The combined current and solid product are combined with water, triturated with suction, filtered and dried.

수득량 : 20g(이론량의 76%)Yield: 20 g (76% of theory)

융 점 : 211°내지 213℃Melting Point: 211 ° to 213 ° C

e) 2-아미노-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀e) 2-amino-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol

20g(0.076몰)의 2-니트로-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 600㎖의 디메틸포름아미드에 녹인 용액을 실온의 파르(parr)장치내에서 수소(5bar)와 2g의 Pd/c (10%)촉매를 사용하여 환원시킨다. 수소의 흡수가 중지되면 촉매를 흡인여과해내고 여액을 증발시킨다. 고형 생성물이 수득되면 에테르와 함께 분쇄한다. 흡인 여과한 후 생성물을 에테르로 세척하고 건조시킨다.20 g (0.076 moles) of 2-nitro-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol dissolved in 600 ml of dimethylformamide The solution is reduced using hydrogen (5 bar) and 2 g of Pd / c (10%) catalyst in a parr apparatus at room temperature. When absorption of hydrogen stops, the catalyst is aspirated off and the filtrate is evaporated. Once a solid product is obtained, it is triturated with ether. After suction filtration the product is washed with ether and dried.

수득량 : 17g(이론량의 96%)Yield: 17 g (96% of theory)

융 점 : 260°내지 263℃Melting Point: 260 ° to 263 ° C

f) 2-(2-페닐프로피오닐아미노)-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)f) 2- (2-phenylpropionylamino) -4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl)

2.8g(0.012몰)의2-아미노-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀 프로피온산 클로라이드를 실온에서 적가한다.2.8 g (0.012 mol) of 2-amino-4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol propionic acid chloride is added dropwise at room temperature.

1.5시간 후 반응 혼합물을 물에 교반하며 첨가하고 에틸 아세테이트로 수회 세척한다. 유기상을 황산 나트륨으로 탈수시키고 증발시킨다. 수득된 생성물을 칼럼 크로마토그라피(실리카겔, 핵의 크기 : 0.05 내지 0.02mm, 용출제 : 클로로포름/에탄올 1%)로 정제한다. 수득된 생성물은 분순한 상태로 다음 반응에 사용한다.After 1.5 hours the reaction mixture is added to water with stirring and washed several times with ethyl acetate. The organic phase is dehydrated with sodium sulfate and evaporated. The product obtained is purified by column chromatography (silica gel, nucleus size: 0.05-0.02 mm, eluent: chloroform / ethanol 1%). The obtained product is used in the subsequent reaction in a sequential state.

수득량 : 1.7g(이론량의 38.8%)Yield: 1.7 g (38.8% of theory)

g) 5,5-디메틸-6-[2'-(α-페닐에틸)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논g) 5,5-dimethyl-6- [2 '-(α-phenylethyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

1.7g(0.0046몰)의 2-(2-페닐프로피오닐 아미노)-4-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 12㎖의 설포란에 현탁시키고, 이 현탁액을 5시간 동안 환류시킨다. 이어서 뜨거운 반응 생성물을 얼음물에 교반하며 붓는다. 침전된 오일상 생성물을 에틸 아세테이트로 추출하고 유기상을 황산나트륨으로 탈수시킨다. 수득된 잔류물을 칼럼 크로마토그라피(실리카겔, 핵의 크기 : 0.05 내지 0.20mm 용출제 : 클로로포름/에탄올 1%)로 정제한다. 상응하는 획분을 합하여 목탄을 통해 여과시킨 후 증발시킨다. 오일상의 잔류물을 석유에테르로 결정화시킨다.1.7 g (0.0046 moles) of 2- (2-phenylpropionyl amino) -4- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol It is suspended in 12 ml of sulfolane and the suspension is refluxed for 5 hours. The hot reaction product is then poured into iced water with stirring. The precipitated oily product is extracted with ethyl acetate and the organic phase is dehydrated with sodium sulfate. The residue obtained is purified by column chromatography (silica gel, nucleus size: 0.05-0.20 mm eluent: chloroform / ethanol 1%). The corresponding fractions are combined and filtered through charcoal and then evaporated. The oily residue is crystallized with petroleum ether.

수득량 : 1g(이론량의 62.5%) 계산치 : C72.61 H6.09 N12.10Yield: 1g (62.5% of theory) Calculation: C72.61 H6.09 N12.10

융 점 : 131°내지 135℃ 실측치 : C72.18 H6.30 N11.91Melting Point: 131 ° to 135 ° C Found: C72.18 H6.30 N11.91

C21H21N3O2(347.4)C 21 H 21 N 3 O 2 (347.4)

[실시예 22]Example 22

5,5-디메틸-6-(2'-아미노-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5,5-Dimethyl-6- (2'-amino-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

2.1g(0.0072몰)의 N-[2-하이드록시-5-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]티오우레아 {N'-벤조일-N-[2-하이드록시-5-(5,5-디메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페닐]-티오우레아를 알칼리성 가수분해시켜 제조}를 40㎖의 무수 테트라하이드로 푸란에 녹인다. 2.05g(0.01몰)의 N,N'-디사이클로-헥실-카보디이미드를 첨가하고 반응혼합물을 교반상태하에 2시간 동안 환류시킨다. 실온까지 냉각시킨 후 침전된 생성물을 흡인여과하고 테트라하이드로 푸란으로 세척한다. 반응 생성물을 1N암모니아로 현탁시키고 30분간 교반한 후 흡인여과하고 물로 세척한후 건조시킨다.2.1 g (0.0072 mole) N- [2-hydroxy-5- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] thiourea { N'-benzoyl-N- [2-hydroxy-5- (5,5-dimethyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -thiourea is alkaline Hydrolyze and dissolve in 40 ml of anhydrous tetrahydrofuran. 2.05 g (0.01 mol) of N, N'-dicyclo-hexyl-carbodiimide are added and the reaction mixture is refluxed under stirring for 2 hours. After cooling to room temperature the precipitated product is suction filtered and washed with tetrahydrofuran. The reaction product is suspended with 1N ammonia, stirred for 30 minutes, filtered off with suction, washed with water and dried.

수득량 : 1.0g(이론량의 54%) 계산치 : C60.45 H5.46 N21.69Yield: 1.0 g (54% of theory) Calculated: C60.45 H5.46 N21.69

융 점 : >250℃ 실측치 : C60.67 H5.41 N21.44Melting Point:> 250 ° C Found: C60.67 H5.41 N21.44

C13H14N4O2(258.3)C 13 H 14 N 4 O 2 (258.3)

[실시예 23]Example 23

5-메틸-6-[2'-디메틸아미노-벤조티아졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2'-dimethylamino-benzothiazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4-(3-아미노-4-메르캅토페닐)-3-메틸-4-옥소-부티르산a) 4- (3-amino-4-mercaptophenyl) -3-methyl-4-oxo-butyric acid

27g(0.1몰)의 4-(3-니트로-4-클로로페닐)-3-메틸-4-옥소부티르산을, 72g(0.3몰)의 나트륨 설파이드×9H2O를 500㎖의 물에 녹인 용액에 첨가하고 35분간 증기욕상에서 가열한다. 10℃까지 냉각시킨 후 빙초산을 사용하여 반응혼합물의 pH를 4.5로 조절한다. 이어서 반응혼합물을 에틸아세테이트로 수회 추출하고 유기상은 황산나트륨으로 탈수시킨 후 건조시킨다. 수득된 잔류물은 불순한 상태로 다음 단계의 반응에 사용한다.To a solution of 27 g (0.1 mole) of 4- (3-nitro-4-chlorophenyl) -3-methyl-4-oxobutyric acid and 72 g (0.3 mole) of sodium sulfide x 9H 2 O in 500 ml of water Add and heat in steam bath for 35 minutes. After cooling to 10 ° C., the pH of the reaction mixture is adjusted to 4.5 using glacial acetic acid. The reaction mixture is then extracted several times with ethyl acetate and the organic phase is dehydrated with sodium sulfate and dried. The residue obtained is used for the reaction of the next step in an impure state.

수득량 : 27.5g(이론량의 약 100%)Yield: 27.5 g (about 100% of theory)

b) 5-메틸-6-[2'-디메틸아미노벤조티아졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논b) 5-methyl-6- [2'-dimethylaminobenzothiazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.2g(0.018몰)의 디메틸티오 카바모일 클로라이드를 실온에서, 2.8g(0.012몰)의 -2-아미노-4-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-티오페놀 [4-(3-아미노-4-메르캅토페닐)-3-메틸-4-옥소-부티르산과 하이드라진을 반응시켜 제조]을 40㎖의 무수 테트라하이드로푸란에 녹인 용액에 교반하며 첨가한다. 20시간 후 침전된 생성물을 여과한다. 여액을 물로 희석하고 에틸 아세테이트로 2회 추출한다. 이어서 수성상은 2N수산화나트륨 용액을 첨가하여 알칼리성화하고 클로로포름으로 추출한다. 유기상을 황산나트륨으로 탈수시키고 증발시킨다. 오일상의 생성물이 수득되며 이것은 하룻밤 방치하면 결정화된다. 수득된 조생성물(1g)을 칼럼크로마토 그라피로 정제한다(실리카겔, 핵의 크기 : 0.05 내지 0.20mm, 용출제 : 클로로포름/에탄올 1%).2.2 g (0.018 mole) of dimethylthio carbamoyl chloride at room temperature, 2.8 g (0.012 mole) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone -6-yl) -thiophenol [prepared by reacting 4- (3-amino-4-mercaptophenyl) -3-methyl-4-oxo-butyric acid with hydrazine] in 40 ml of anhydrous tetrahydrofuran Add to stirring. After 20 hours the precipitated product is filtered off. The filtrate is diluted with water and extracted twice with ethyl acetate. The aqueous phase is then alkalined by addition of 2N sodium hydroxide solution and extracted with chloroform. The organic phase is dehydrated with sodium sulfate and evaporated. An oily product is obtained which crystallizes when left overnight. The crude product (1 g) obtained is purified by column chromatography (silica gel, nucleus size: 0.05-0.20 mm, eluent: chloroform / ethanol 1%).

수득량 : 550mg(이론량의 16%) 계산치 : C58.31 H5,59 N19.43 S11.12Yield: 550 mg (16% of theory) Calculated: C58.31 H5,59 N19.43 S11.12

융 점 : 177°내지 184℃ 실측치 : C58.41 H5.69 N19.12 S11.02Melting Point: 177 ° to 184 ° C. Found: C58.41 H5.69 N19.12 S11.02

C14H16N4OS (288.4)C 14 H 16 N 4 OS (288.4)

[실시예 24]Example 24

5-메틸-6-[2'-(4-시아노페닐)-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- [2 '-(4-cyanophenyl) -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

2.07g(5.3밀리몰)의 1-아세톡시-2-(4'-시아노-벤조일아미노)-4-(5-메틸-4,5-디하이드로-(2H)피리다지논-6-일)-벤젠을 50㎖의 설포란에 녹인 용액을 0.5㎖의 10%염산과 혼합한다. 240℃에서 4시간 동안 가열한 후 이혼합물을 150㎖의 물에 교반하며 첨가하고 수득된 침전물을 흡인여과한다. 생성물을 칼럼크로마토그라피(실리카겔, 클로로포름 1%에탄올)로 정제한다.2.07 g (5.3 mmol) 1-acetoxy-2- (4'-cyano-benzoylamino) -4- (5-methyl-4,5-dihydro- (2H) pyridazinone-6-yl) -A solution of benzene in 50 ml of sulfolane is mixed with 0.5 ml of 10% hydrochloric acid. After heating at 240 ° C. for 4 hours, the di-mixture is added with stirring to 150 ml of water and the precipitate obtained is suction filtered. The product is purified by column chromatography (silica gel, chloroform 1% ethanol).

수득량 : 145mg(이론량의 8.3%) 계산치 : C69.08 H4.27 N16.96Yield: 145 mg (8.3% of theory) calculated: C69.08 H4.27 N16.96

융 점 : 278°내지 280℃ 실측치 : C68.24 H4.34 N16.86Melting Point: 278 ° to 280 ° C. Found: C68.24 H4.34 N16.86

C19H14N4O2(330.35)C 19 H 14 N 4 O 2 (330.35)

[실시예 25]Example 25

5-메틸-6-(2'-하이드록시-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-hydroxy-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

1.08g(0.005몰)의 2-아미노-4-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 50㎖의 무수 테트라하이드로푸탄에 현탁시키고 이 현탁액을 1g(0.006몰)의 N,N'-카보닐디이미다졸과 교반하며 혼합한다. 45분간 환류시킨 후 반응혼합물을 증발시키고 잔류물을 물과 함께 교반한다. 수득된 결정을 흡인여과하고 물로 세척한 후 탈수시킨다. 이어서 이 조생성물을 클로로포름 : 메탄올=9 : 1에 녹이고 뜨거울대 활성탄을 통과시켜 여과하고 여액은 결정이 형성될때까지 증발시킨다. 반응 생성물을 얼음욕에 냉각시키고 침전된 생성물을 흡인여과하고 에테르로 세척하여 건조시킨다.Suspend 1.08 g (0.005 mol) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol in 50 ml of anhydrous tetrahydroputan. The suspension is mixed with 1 g (0.006 mole) of N, N'-carbonyldiimidazole with stirring. After refluxing for 45 minutes, the reaction mixture is evaporated and the residue is stirred with water. The crystals obtained are suction filtered, washed with water and then dehydrated. This crude product is then dissolved in chloroform: methanol = 9: 1 and filtered through hot carbon activated carbon and the filtrate is evaporated until crystals are formed. The reaction product is cooled in an ice bath and the precipitated product is suction filtered, washed with ether and dried.

수득량 : 0.55g(이론량의 44.7%) 계산치 : C58.77 H4.52 N17.13Yield: 0.55 g (44.7% of theory) Calculation: C58.77 H4.52 N17.13

융 점 : 250°내지 253℃ 실측치 : C58.77 H4.46 N17.22Melting Point: 250 ° to 253 ° C. Found: C58.77 H4.46 N17.22

C12H11N3O3(245.2)C 12 H 11 N 3 O 3 (245.2)

[실시예 26]Example 26

5-메틸-6-(2'-에톡시-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-ethoxy-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

2.19g(0.01몰)의 2-아미노-4-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 10㎖의 테트라에틸 카보네이트에 현탁시키고 3㎖의 디메틸포름아미드를 첨가한다. 180℃(오일욕)에서 1시간 동안 가열한 후 반응혼합물을 실온까지 냉각시키고 침전된 생성물을 흡인여과한 후 에테르로 세척한다. 이어서 반응생성물을 100㎖씩의 에탄올에서 활성탄을 첨가하여 2회 재결정화한다.2.19 g (0.01 mol) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was suspended in 10 ml of tetraethyl carbonate and 3 ml of dimethylformamide is added. After heating at 180 ° C. (oil bath) for 1 hour, the reaction mixture is cooled to room temperature, the precipitated product is suction filtered and washed with ether. The reaction product is then recrystallized twice by adding activated charcoal in 100 mL of ethanol.

수득량 : 900mg(이론량의 33%) 계산치 : C61.53 H5.53 N15.38Yield: 900 mg (33% of theory) Calculated: C61.53 H5.53 N15.38

융 점 : 193°내지 194℃ 실측치 : C61.59 H5.52 N15.65Melting Point: 193 ° to 194 ° C. Found: C61.59 H5.52 N15.65

C14H15N3O3(273.3)C 14 H 15 N 3 O 3 (273.3)

[실시예 27]Example 27

5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

22g(0.1몰)의 2-아미노-4-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 500㎖의 에탄올에 현탁시키고 24g(0.15몰)의 칼륨 에틸 크산투게네이트를 교반하며 첨가한다. 3시간동안 환류시킨 후 반응혼합물을 실온까지 냉각시키고 침전된 생성물을 흡인 여과하고 냉에탄올과 에테르로 세척한다. 수득된 칼륨염을 1,000㎖의 물에 녹이고 활성탄을 통과시켜 여과하고 여액은 2N 아세트산으로 중화시킨다. 침전된 생성물은 흡인여과하고 진공건조기로 건조시킨다.22 g (0.1 mole) of 2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was suspended in 500 ml of ethanol and 24 g (0.15) Mole) potassium ethyl xanthogenate is added with stirring. After refluxing for 3 hours, the reaction mixture was cooled to room temperature, the precipitated product was suction filtered and washed with cold ethanol and ether. The potassium salt obtained is dissolved in 1,000 ml of water, filtered through activated carbon and the filtrate is neutralized with 2N acetic acid. The precipitated product is suction filtered and dried by vacuum dryer.

수득량 : 15g(이론량의 57.7%) 계산치 : C55.16 H4.24 N16.08 S12.27Yield: 15 g (57.7% of theory) Calculated: C55.16 H4.24 N16.08 S12.27

융 점 : >250℃ 실측치 : C55.09 H4.16 N15.93 S12.10Melting Point:> 250 ° C Found: C55.09 H4.16 N15.93 S12.10

C12H11N3OS(261.3)C 12 H 11 N 3 OS (261.3)

[실시예 28]Example 28

5-메틸-6-(2'-메틸메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-methylmercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

653mg(0.0025몰)의 5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논을 10㎖의 무수 디메틸포름아미드에 녹이고 이용액을 210mg(0.0025몰)의 중탄산나트륨과 혼합한다. 2㎖의 메틸 요다이드를 첨가한 후 이 반응혼합물을 40℃에서 15분간 교반한다. 이 반응혼합물을 물에 교반하며 첨가하고 에틸 아세테이트로 추출한다. 유기상을 황산나트륨으로 탈수시키고 증발시킨다. 수득된 고체 잔류물을 에탄올에서 재결정화 한다.653 mg (0.0025 mol) of 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone in 10 ml of anhydrous dimethyl Dissolve in formamide and mix with 210 mg (0.0025 mol) of sodium bicarbonate. After addition of 2 ml of methyl iodide, the reaction mixture is stirred at 40 ° C for 15 minutes. The reaction mixture is added to water with stirring and extracted with ethyl acetate. The organic phase is dehydrated with sodium sulfate and evaporated. The solid residue obtained is recrystallized in ethanol.

수득량 : 340mg(이론량의 49.4% 계산치 : C56.71 H4.76 N15.26 S11.65Yield: 340 mg (49.4% of theory) Calculated: C56.71 H4.76 N15.26 S11.65

융 점 : 178°내지 180℃ 실측치 : C56.20 H4.78 N15.41 S11.57Melting Point: 178 ° to 180 ° C. Found: C56.20 H4.78 N15.41 S11.57

C13H13N3O2S (275.3)C 13 H 13 N 3 O 2 S (275.3)

[실시예 29]Example 29

5-메틸-6-(2'-n-헥실메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-n-hexylmercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

2.99g(0.01몰)의 5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논-칼륨염을 20㎖의 무수 디메틸포름아미드에 녹인다. 1.5㎖의 n-헥실 브로마이드를 교반하며 첨가하고 반응혼합물을 40℃에서 1시간 동안 교반한다. 이어서 반응혼합물을 물에 교반하며 붓고 에틸 아세테이트로 추출한다. 유기상을 황산나트륨으로 탈수시킨 후 증발시킨다. 수득된 잔류물을 에탄올로부터 재결정화한다.2.99 g (0.01 mol) of 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone-potassium salt Dissolve in ml of anhydrous dimethylformamide. 1.5 ml of n-hexyl bromide is added with stirring and the reaction mixture is stirred at 40 ° C. for 1 hour. The reaction mixture is then poured into water with stirring and extracted with ethyl acetate. The organic phase is dehydrated with sodium sulfate and then evaporated. The residue obtained is recrystallized from ethanol.

수득량 : 2.4g(이론량의 69.6%) 계산치 : C62.57 H6.71 N12.16 S9.28Yield: 2.4 g (69.6% of theory) Calculated: C62.57 H6.71 N12.16 S9.28

융 점 : 119°내지 121℃ 실측치 : C62.65 H6.79 N12.17 S9.05Melting Point: 119 ° to 121 ° C Found: C62.65 H6.79 N12.17 S9.05

C18H23O2S (345.5)C 18 H 23 O 2 S (345.5)

[실시예 30]Example 30

5-메틸-6-(2'-알릴메르캅토-벤즈옥사졸-5'-일-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-allylmercapto-benzoxazol-5'-yl-4,5-dihydro-3 (2H) -pyridazinone

실시예 29와 유사한 방법으로 5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논-칼륨염과 알릴 브로마이드로부터 제조한다.5-Methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone-potassium salt with allyl in a similar manner to Example 29 Prepared from bromide.

수 율 : 이론량의 73% 계산치 : C59.78 H5.02 N13.94 S10.63Yield: 73% of theoretical amount calculated: C59.78 H5.02 N13.94 S10.63

융 점 : 113°내지 114℃ 실측치 : C60.01 H5.21 N14.28 S10.50Melting Point: 113 ° to 114 ° C Found: C60.01 H5.21 N14.28 S10.50

C15H15N3O2S(301.4)C 15 H 15 N 3 O 2 S (301.4)

[실시예 31]Example 31

5-메틸-6-(2'-p-메톡시벤질메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논5-Methyl-6- (2'-p-methoxybenzylmercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone

실시예 29와 유사한 방법으로 5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논-칼륨염과-p-메톡시 벤질 브로마이드로부터 제조한다.5-Methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone-potassium salt with a method similar to Example 29- Prepared from p-methoxy benzyl bromide.

수 율 : 이론량의 66.6% 계산치 : C62.97 H5.02 N11.02 S8.41Yield: 66.6% of theoretical amount calculated: C62.97 H5.02 N11.02 S8.41

융 점 : 174°내지 176℃ 실측치 : C63.47 H5.02 N11.34 S8.63Melting Point: 174 ° to 176 ° C. Found: C63.47 H5.02 N11.34 S8.63

C20H19N3O3S (381.5)C 20 H 19 N 3 O 3 S (381.5)

[실시예 32]Example 32

5-메틸-[2'-[2-(4-아미노-3,5-디클로로페닐)-에틸메르캅토]-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl- [2 '-[2- (4-amino-3,5-dichlorophenyl) -ethylmercapto] -benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -Pyridazinone

실시예 29와 유사한 방법으로 5-메틸-6-(2'-메르캅토-벤즈옥사졸-5'-일)-4,5-디하이드로-3(2H)-피리다지논-칼륨염과 2-(4-아미노-3,5-디클로로페닐)-에틸브로마이드로부터 제조한다.In a similar manner as in Example 29, 5-methyl-6- (2'-mercapto-benzoxazol-5'-yl) -4,5-dihydro-3 (2H) -pyridazinone-potassium salt and 2 Prepared from-(4-amino-3,5-dichlorophenyl) -ethylbromide.

수 율 : 이론량의 52% 융 점 : 205°내지 208℃Yield: 52% of theoretical amount Melting point: 205 ° to 208 ° C

[실시예 33]Example 33

5-메틸-[2'-메틸벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl- [2'-methylbenzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 21(g)와 유사한 방법으로 2-아세틸-아미노 4-(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 설포란중에 가열하여 제조한다.In a manner similar to Example 21 (g), 2-acetyl-amino 4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was heated in sulfolane Manufacture.

수 율 : 이론량의 75.3% 융 점 : 210°내지 213℃Yield: 75.3% of theoretical amount Melting point: 210 ° to 213 ° C

[실시예 34]Example 34

5-메틸-[2'-이소프로필벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논5-Methyl- [2'-isopropylbenzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

실시예 21(g)와 유사한 방법으로 2-이소부티릴아미노-4(5-메틸-4,5-디하이드로-3(2H)-피리다지논-6-일)-페놀을 설포란중에 가열하여 제조한다.2-isobutyrylamino-4 (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenol was heated in sulfolane in a similar manner to Example 21 (g) To prepare.

수 율 : 이론량의 52.5% 융 점 : 160°내지 162℃Yield: 52.5% of theoretical amount Melting point: 160 ° to 162 ° C

[실시예 A]Example A

100mg의 5-메틸-6-[2'-에틸아미노벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논을 함유하는 정제.A tablet containing 100 mg of 5-methyl-6- [2'-ethylaminobenzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone.

조성 : 1정제당 함량 :Composition: content per tablet:

활성성분 100.0mg 카복시메틸 셀룰로오즈 19.0mgActive Ingredient 100.0mg Carboxymethyl Cellulose 19.0mg

락토오즈 50.0mg 마그네슘 스테아테이트 1.0mgLactose 50.0mg Magnesium Stearate 1.0mg

폴리비닐피롤리돈 5.0mg 175.0mgPolyvinylpyrrolidone 5.0mg 175.0mg

활성성분과 락토오즈를 리비폴닐피롤리돈 수용액으로 균질하게 가습시킨다.The active ingredient and lactose are homogenized with an aqueous solution of ribipolylpyrrolidone.

습식스크리닝 ; 1.5mm 건조 : 50℃의 회전 공기전조기중에서 건식 스크리닝 : 1mmWet screening; 1.5mm drying: Dry screening in rotary air rolling machine at 50 ℃: 1mm

이 과립과 나머지 보조제들을 혼합하여 정제로 압축한다.The granules and the remaining auxiliaries are mixed and compressed into tablets.

정제중량 : 175mg 펀치 : 8mm

Figure kpo00012
Tablet weight: 175mg Punch: 8mm
Figure kpo00012

[실시예 B]Example B

50mg의 5-메틸-6-[2'-에틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논을 함유하는 코팅정제Coating tablet containing 50 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

1코팅정제당 함량 ;Content per 1 coated tablet;

Figure kpo00013
Figure kpo00013

활성성분과 전분을 가용성전분 수용액으로 균질하게 가습시킨다.The active ingredient and starch are homogenized with an aqueous solution of soluble starch.

습식 스크리닝 : 1.0mmWet Screening: 1.0mm

건식 스크리닝 : 1.0mmDry Screening: 1.0mm

건 조 : 50℃의 회전 공기전기전조기중에 과립과 나머지 보조제를 혼합하여 정제로 압축한다.Drying: Granules and remaining auxiliaries are mixed and compressed into tablets in a 50 ° C rotary air electroformer.

나정의 중량 : 80mgUncoated tablet weight: 80mg

펀 치 : 6mmPunch: 6mm

곡률반경 : 5mmBending radius: 5mm

이 정제를 통상의 방법으로 설탕코팅제로 코팅한다.This tablet is coated with a sugar coating agent in a conventional manner.

코팅정제의 중량 ; 120mgWeight of coated tablet; 120mg

[실시예 C]Example C

75mg의 5-메틸-6-[2'-에틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논을 함유하는 좌제Suppositories containing 75 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

1좌제당 함량 :Content per suppository:

Figure kpo00014
Figure kpo00014

[제조방법][Manufacturing method]

좌제기재를 용융시킨다. 38℃에서 분쇄된 활성성분을 이 용융물내에 균질하게 분산시킨다. 이 좌제기재를 35℃까지 식히고 미리 냉각시킨 틀에 붓는다.Melt the suppository base. The active ingredient ground at 38 ° C. is dispersed homogeneously in this melt. The suppository base is cooled to 35 ° C and poured into a pre-cooled mold.

좌제중량 : 1.7gSuppository weight: 1.7 g

[실시예 D]Example D

25mg의 5-메틸-6-[2'-에틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논을 함유하는 앰플제Ampoules Containing 25 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone

조성 : 1앰플당 함유 :Composition: Per Ampoule:

활성성분 25.0mg 용해매체(예 : 하이드록시 -25.0 mg of active ingredient

염화나트륨 45.0mg 에틸화 수화피마자유) 0.5㎖0.5 ml of sodium chloride 45.0 mg ethylated hydrated castor oil)

폴리에틸렌글리클 600 1.0㎖ 주사용수 5.0㎖까지 첨가Polyethyleneglycol 600 1.0 ml Water for injection up to 5.0 ml

[제조방법][Manufacturing method]

활성성분을 폴리에틸렌글리콜, 용해매체 및 약 1/2양의 물의 혼합물에 용량 눈금이 있는 적절한 용기속에서 교반하며 녹인다. 이 용액을 염화나트륨의 등장액과 혼합하고 물로 원하는 용량으로 만든다.The active ingredient is dissolved in a mixture of polyethylene glycol, a dissolution medium and about 1/2 amount of water in a suitable vessel with a volumetric scale. This solution is mixed with an isotonic solution of sodium chloride and made to the desired volume with water.

[실시예 E]Example E

5㎖당 75mg의 5-메틸-6-[2'-에틸아미노-벤즈옥사졸-5'-일]-4,5-디하이드로-3(2H)-피리다지논을 함유하는 현탁제Suspending agent containing 75 mg of 5-methyl-6- [2'-ethylamino-benzoxazol-5'-yl] -4,5-dihydro-3 (2H) -pyridazinone per 5 ml

현탁제 : 100㎖ 당함량 :Suspension: 100 ml

활성성분 1.5g 사탕수수 설탕 10.0gActive Ingredients 1.5g Sugar Cane Sugar 10.0g

카복시메틸 셀룰로오즈 1.0g 글리세린 5.0gCarboxymethyl Cellulose 1.0g Glycerin 5.0g

메틸 p-하이드록시 벤조에이트 0.05g 소르비트용액 70% 20.0gMethyl p-hydroxy benzoate 0.05 g Sorbite solution 70% 20.0 g

프로필 p-하이드록시 벤조에이트 0.03g 향 료 0.3gPropyl p-hydroxy benzoate 0.03 g Perfume 0.3 g

증류수 100.0㎖100.0ml of distilled water

[제조방법][Manufacturing method]

증류수를 70℃까지 가열하고 교반시키면서 메틸 p-하이드록시벤조에이트, 프로필 p-하이드록시 벤조에이트, 글리세린 및 카복시메틸셀룰로우즈를 용해시킨다. 이 용액은 실온까지 냉각시키고 활성성분을 교반하며 첨가하여 균질하게 분산시킨다. 이어서 설탕, 소르비트용액 및 향료를 첨가하고 용해시켜 진공상태에서 교반하며 현탁제를 증발시킨다.Methyl p-hydroxybenzoate, propyl p-hydroxy benzoate, glycerin and carboxymethylcellulose are dissolved while distilled water is heated to 70 ° C. and stirred. The solution is cooled to room temperature and the homogeneously dispersed by adding the active ingredient with stirring. Sugar, sorbet solution and flavorings are then added, dissolved, stirred in vacuo and the suspending agent is evaporated.

Claims (1)

다음 일반식(Ⅳ)의 화합물을 다음 일반식(Ⅴ)의 화합물로 알킬화시킴을 특징으로 하여 다음 일반식(I)의 벤즈옥사졸을 제조하는 방법.A process for preparing benzoxazoles of the following general formula (I), characterized by alkylating a compound of the following general formula (IV) with a compound of the following general formula (V).
Figure kpo00015
Figure kpo00015
R1'-U (Ⅴ)R 1 '-U (Ⅴ) 상기 일반식에서,In the above formula, R1은 탄소수 1 내지 7의 알킬그룹 또는 탄소수 3내지 6의 알케닐그룹에 의해 치환된 메르캅토그룹 ; 알킬부위의 탄소수가 1 내지 3개이고 페닐핵이 탄소수 1내지 3의 알콕시그룹, 할로겐원자 및 아미노그룹중에서 선택된 서로 같거나 다를 수 있는 치환체로 일-, 이-또는 삼치환될 수 있는 페닐알킬 그룹으로 치환된 메르캅토그룹을 나타내며, R4및 R5는 서로 같거나 다를 수 있는 그룹으로서, 수소원자 또는 탄소수 1내지 3의 알킬그룹을 나타내고R 1 is a mercapto group substituted with an alkyl group having 1 to 7 carbon atoms or an alkenyl group having 3 to 6 carbon atoms; A phenylalkyl group which may be mono-, di-, or trisubstituted with a substituent having 1 to 3 carbon atoms in the alkyl moiety and a phenyl nucleus having the same or different substituents selected from alkoxy groups having 1 to 3 carbon atoms, halogen atoms and amino groups. A substituted mercapto group, R 4 and R 5, which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. X는 산소원자를 나타내며,X represents an oxygen atom, A는 메르캅토 그룹을 나타내며,A represents a mercapto group, R1'는 페닐그룹에 의해 임의로 치환된 탄소수 1내지 3의 알킬그룹, 이때 페닐핵은 탄소수 1내지 3의 알콕시그룹, 할로겐원자 및 아미노그룹에 의해 일-, 이-또는 삼치환될 수 있고 ; 탄소수 4내지 7의 알킬그룹 ; 탄소수 3내지 6의 알케닐 그룹을 나타내며,R 1 ′ is an alkyl group of 1 to 3 carbon atoms optionally substituted by a phenyl group, wherein the phenyl nucleus may be mono-, di- or trisubstituted by an alkoxy group, a halogen atom and an amino group of 1 to 3 carbon atoms; Alkyl groups of 4 to 7 carbon atoms; An alkenyl group having 3 to 6 carbon atoms, U는 할로겐원자를 나타낸다.U represents a halogen atom.
KR1019850000845A 1981-02-21 1985-02-11 Process for preparing benzoxazole KR850001352B1 (en)

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