KR100204381B1 - Dihydropyridazinones pyridazinones and related compounds as fungicides - Google Patents

Dihydropyridazinones pyridazinones and related compounds as fungicides Download PDF

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KR100204381B1
KR100204381B1 KR1019910016465A KR910016465A KR100204381B1 KR 100204381 B1 KR100204381 B1 KR 100204381B1 KR 1019910016465 A KR1019910016465 A KR 1019910016465A KR 910016465 A KR910016465 A KR 910016465A KR 100204381 B1 KR100204381 B1 KR 100204381B1
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리치 에건 앤
루이스 미첼로티 엔리크
로스 주니어 로날드
조우 윌슨 윌리
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마크 에스. 아들러
롬 앤드 하스 캄파니
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
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Abstract

본 발명은 다음 일반식의, 치환 디히드로피리다지논, 피리다지논과 그 관련화합물들; 그러한 화합물들을 함유하는 조성물들; 및 그들을 사용하여 균전염병들을 구제하는 방법에 관한 것이다.The present invention provides substituted dihydropyridazinone, pyridazinone and related compounds of the following general formula; Compositions containing such compounds; And methods of controlling fungal diseases using them.

상기 일반식 I에서, A는 -(CHR2)n-CHR7-Z-, -CF2-CF2-Z, -(CHR2)n-O-Z, -(CHR2)n-S-Z-, -O-CHR2-Z-, -CR2=CR7-Z-, CR2=N-Z-, CHR2-CR7=Y-, 또는 -CR2=CR2-Y=이고; D는 CR2또는 질소이고; Q는 다음 기들로 부터 선택된 방향족 기이고;In Formula I, A is-(CHR 2 ) n-CHR 7 -Z-, -CF 2 -CF 2 -Z,-(CHR 2 ) nOZ,-(CHR 2 ) nSZ-, -O-CHR 2 -Z-, -CR 2 = CR 7 -Z-, CR 2 = NZ-, CHR 2 -CR 7 = Y-, or -CR 2 = CR 2 -Y =; D is CR 2 or nitrogen; Q is an aromatic group selected from the following groups;

Z는 카보닐(C=O) 또는 티오카보닐(C=S)이고; Y는 할로, 알콕시, 알킨일티오 또는 트리아졸릴에 의해 치환된 탄소이고; R1알킬, 히드록시알킬, 시아노알킬, 히드라지달과 그 유도체, 시클로알킬알킬, 헤테로고리로고리알킬, 페닐, 페닐알킬, 페닐카보닐, 알켄일, 할로알켄일, 페닐 알켄일, 알키닐알켄일, 알킨일, 할로알킨일, 페닐알킨일, 헤테로고리, 헤테로고리알킨일, 시클로알킬알킨일, 알켄일알킨일, 히드록시알킨일, 알콕시알킨일, 알카노일옥시알킨일, 포르밀알킨일, 트리알킬실릴알킨일, 트리알킬틴 알킨일, 할로알켄일알킨일, 카르복시알킨일, 또는 알콕시 카보닐 알킨일이고; R2은 수소,(C1-C3)알킬, 페닐, 시아노 또는 할로겐이고; R7은 수소,(C1-C3)알킬, 페닐, 시아노, 할로겐, 알킨일, 알킨일알켄일, 디알킨일, 할로알킨일, 또는 알켄일알킨일이고; R3과 R6는 각각 수소, 알콕시 또는 할로겐이고; R4는 수소, 할로겐, 알콕시 또는 니트로이고; R5는 수소, 할로겐, 니트로, 알킬, 알콕시, 알킬티오, 할로알킬, 할로알콕시, 할로알킬티오, 페닐, 페녹시 또는 시아노이고; R2와 R3는 함께 (C1-C3)알킬,(C2-C3)알켄일 또는 카보닐쇄를 형성할 수 있고; R2와 R7은 함께 붙어 페닐고리 또는 (C1-C3) 시클로알킬 고리를 형성할 수 있고; X는 산소(0) 또는 황(S)이며; n은 0,1 또는 2이다.Z is carbonyl (C═O) or thiocarbonyl (C═S); Y is carbon substituted by halo, alkoxy, alkynylthio or triazolyl; R 1 alkyl, hydroxyalkyl, cyanoalkyl, hydrazide and its derivatives, cycloalkylalkyl, heterocyclic ringalkyl, phenyl, phenylalkyl, phenylcarbonyl, alkenyl, haloalkenyl, phenyl alkenyl, alkynylal Kenyl, alkynyl, haloalkynyl, phenylalkynyl, heterocyclic, heterocyclic alkynyl, cycloalkylalkynyl, alkenylalkynyl, hydroxyalkynyl, alkoxyalkynyl, alkanoyloxyalkynyl, formyl alkynyl, Trialkylsilylalkynyl, trialkyltin alkynyl, haloalkenylalkynyl, carboxyalkynyl, or alkoxy carbonyl alkynyl; R 2 is hydrogen, (C 1 -C 3 ) alkyl, phenyl, cyano or halogen; R 7 is hydrogen, (C 1 -C 3 ) alkyl, phenyl, cyano, halogen, alkynyl, alkynylalkenyl, dialkynyl, haloalkynyl, or alkenylalkynyl; R 3 and R 6 are each hydrogen, alkoxy or halogen; R 4 is hydrogen, halogen, alkoxy or nitro; R 5 is hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, phenyl, phenoxy or cyano; R 2 and R 3 together may form a (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkenyl or carbonyl chain; R 2 and R 7 may be taken together to form a phenyl ring or a (C 1 -C 3 ) cycloalkyl ring; X is oxygen (0) or sulfur (S); n is 0, 1 or 2.

Description

[발명의 명칭][Name of invention]

디히드로피리다지논, 피리다지논 화합물들, 그들을 함유하는 조성물, 및 그들의 용법Dihydropyridazinone, pyridazinone compounds, compositions containing them, and their uses

[발명의 상세한 설명]Detailed description of the invention

본 발명은 치환 디히드로피리다지논, 피리다지논 및 그 관련 화합물들, 그러한 화합물들을 함유하는 조성물, 및 살균 유효량의 그러한 화합물들을 사용하여 균류를 구제하는 방법에 관한 것이다.The present invention relates to substituted dihydropyridazinone, pyridazinone and related compounds, compositions containing such compounds, and methods of controlling fungi using bactericidal effective amounts of such compounds.

살균제, 특히 농업용 살균제의 용도로서 사용되는 많은 상이한 유형의 화합물들이 알려져 있으나, 새로운 농업용 살균제에 대한 요구가 계속되어 왔다. 특히 벼의 잔균성 병에 대해 활성적인 농업용 살균제에 대한 요구가 계속되어 왔다. 따라서, 본 발명은 농업의 진균성 병들, 특히 벼의 진균성 병들의 구제에 일종의 피리다지논, 디히드로 피리다지논 및 그 관련 화합물들을 사용하는 것에 관한 것이다.Many different types of compounds are known for use as fungicides, especially agricultural fungicides, but there is a continuing need for new agricultural fungicides. There is a continuing need for active agricultural fungicides, particularly for fungal diseases of rice. Accordingly, the present invention relates to the use of a kind of pyridazinone, dihydro pyridazinone and related compounds for the control of fungal diseases of agriculture, in particular of rice fungal diseases.

한편, 인체용 살균제의 용도로 사용되는 여러 유형의 화합물들도 알려져 있으나, 인체의 진균성 병을 치료하는데 유용한, 독성이 없으며 병원에 대하여 선택적인 새로운 화합물들이 기대되고 있다. 따라서, 본 발명은 또한 인체의 진균성 병들을 치료하는데 본 발명의 화합물을 사용하는 것에 관한 것이다.On the other hand, various types of compounds used for the use of human fungicides are also known, but new compounds that are non-toxic and selective for hospitals, which are useful for treating fungal diseases of the human body, are expected. Accordingly, the present invention also relates to the use of the compounds of the present invention in the treatment of fungal diseases of the human body.

본 발명의 화합물은 다음 일반식 I의 피리다지논계 화합물, 및 농경학적으로 수용되는 그 염들이다.The compounds of the present invention are the pyridazinone compounds of the general formula (I), and their agriculturally acceptable salts.

상기 일반식 I에서, A는 -(CHR2)n-CHR7-Z-, -CF2-CF2-Z, -(CHR2)n-O-Z, -(CHR2)n-S-Z-, -O-CHR2-Z-, -CR2=CR7-Z-, CR2=N-Z-, CHR2-CR7=Y-, 또는 -CR2=CR2-Y=이고; D는 CR8또는 질소이고; Q는 다음 기들로 부터 선택된 방향족 기이고;In Formula I, A is-(CHR 2 ) n-CHR 7 -Z-, -CF 2 -CF 2 -Z,-(CHR 2 ) nOZ,-(CHR 2 ) nSZ-, -O-CHR 2 -Z-, -CR 2 = CR 7 -Z-, CR 2 = NZ-, CHR 2 -CR 7 = Y-, or -CR 2 = CR 2 -Y =; D is CR 8 or nitrogen; Q is an aromatic group selected from the following groups;

Z는 카보닐(C=O) 또는 티오카보닐(C=S)이고 Y는 할로, 알콕시, 알킨일티오 또는 트리아졸릴에 의해 치환된 탄소이고; R1은 알킬, 히드록시알킬, 시아노알킬, 히드라지달과 그 유도체, 시클로알킬알킬, 헤테로고리알킬, 페닐, 페닐알킬, 페닐카보닐, 알켄일, 할로알켄일, 페닐 알켄일, 알키닐알켄일, 알킨일, 할로알킨일, 페닐알킨일, 헤테로고리, 헤테로 고리알킨일, 시클로알킬알킨일, 알켄일알킨일, 히드록시알킨일, 알콕시알킨일, 알카노일옥시알킨일, 포르밀알킨일, 트리알킬실릴알킨일, 트리알킬틴 알킨일, 할로알켄일알킨일, 카르복시알킨일, 또는 알콕시 카보닐 알킨일이고; R2와 R8은 각가 수소,(C1-C3)알킬, 페닐, 시아노, 또는 할로겐이고; R7은 수소,(C1-C3)알킬,알킬, 페닐, 시아노, 할로겐, 알킨일, 알킨일알켄일, 디알킨일, 할로알킨일, 또는 알켄일알킨일이고; R3과 R6는 각각 수소, 알콕시 또는 할로겐이고; R4는 수소, 할로겐, 알콕시 또는 니트로이고; R5는 수소, 할로겐, 니트로, 알킬, 알콕시, 알킬티오, 할로알킬, 할로알콕시, 할로알킬티오, 페닐, 페녹시 또는 시아노이고; R2와 R3는 함께 (C1-C3)알킬,알킬, (C2-C3)알켄일 또는 카보닐쇄를 형성할 수 있고; R2와 R7은 함께 붙어 페닐고리 또는 (C1-C3)시클로알킬 고리를 형성할 수 있고; X는 산소(O) 또는 황(S)이며; n은 0, 1 또는 2이다.Z is carbonyl (C═O) or thiocarbonyl (C═S) and Y is carbon substituted by halo, alkoxy, alkynylthio or triazolyl; R 1 is alkyl, hydroxyalkyl, cyanoalkyl, hydrazide and its derivatives, cycloalkylalkyl, heterocyclicalkyl, phenyl, phenylalkyl, phenylcarbonyl, alkenyl, haloalkenyl, phenyl alkenyl, alkynylalkenyl, Alkynyl, haloalkynyl, phenylalkynyl, heterocyclic, heterocyclic alkynyl, cycloalkylalkynyl, alkenylalkynyl, hydroxyalkynyl, alkoxyalkynyl, alkanoyloxyalkynyl, formyl alkynyl, trialkyl Silylalkynyl, trialkyltin alkynyl, haloalkenylalkynyl, carboxyalkynyl, or alkoxy carbonyl alkynyl; R 2 and R 8 are each hydrogen, (C 1 -C 3 ) alkyl, phenyl, cyano, or halogen; R 7 is hydrogen, (C 1 -C 3 ) alkyl, alkyl, phenyl, cyano, halogen, alkynyl, alkynylalkenyl, dialkynyl, haloalkynyl, or alkenylalkynyl; R 3 and R 6 are each hydrogen, alkoxy or halogen; R 4 is hydrogen, halogen, alkoxy or nitro; R 5 is hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, phenyl, phenoxy or cyano; R 2 and R 3 together can form a (C 1 -C 3 ) alkyl, alkyl, (C 2 -C 3 ) alkenyl or carbonyl chain; R 2 and R 7 may be taken together to form a phenyl ring or a (C 1 -C 3 ) cycloalkyl ring; X is oxygen (O) or sulfur (S); n is 0, 1 or 2.

상기 설명중, 할로는 브로모, 플루오로, 클로로, 및 요오도이다.In the above description, halo is bromo, fluoro, chloro, and iodo.

알킬은, 예를 들면, 메틸, 에틸, n-부틸 또는 t-부틸과 같은 (C1-C6)직쇄 또는 분지쇄알킬이다. 히드록시알킬은, 예를 들면, 1-히드록시프로필 또는 3-히드록시부틸과 같은 히드록시 (C1-C6)알킬이다. 시아노알킬은, 예를 들면, 시아노메틸과 같은 시아노(C1-C6)알킬이다. 히드라지달기는, 예를 들면, 아세틸히드라지드 같은 말단 알킬히드라이드로서, 이러한 R1치환체를 갖는 구체적인 화합물은 6-할로페닐-2-아세틸 히드라지드 4, 5-디히드로 피리다지논일 수 있다. 비말단 알킬히드라이드는 부착되는 유기기를 가질 수 있다. 그러한 화합물의 예는 6-할로페닐-2-[N-아세틸히드라지드-(N'-2,4-펜탄디온-히드라존)]-4, 5-피리다지논 또는 6-할로페닐-2-[N-아세틸히드라지드-(N'-할로페닐 히드라존)]-4, 5-디히드로피리다지논이다. 그밖에, 6-할로페닐-2-(알킬-1-피라조일메틸렌)-4,5-디히드로 피리다지논, 6-할로페닐-2-(1, 3, 4-옥사디아진-2-온-5-일-메틸렌)-4, 5-디히드로피리다지논, 또는 6-할로페닐-2-[2, 3, 4-옥사디아진-2-온-3-(2'-알키닐)-5-일-메틸렌]-4, 5-디히드로 피라다지논같은 고리화된 형태들도 포함될 수 있다. 그러한 고리 화합물에 대한 알킨일 치환체로는 2-펜틴일, 2-부틴일 및 3-할로-2-프로핀일이 포함될 수 있다. 한가지 예로서 6-(4-클로로페닐)-2-(1, 3, 4-옥사디아진-2-온-3-(3'-요오도프로파길)-5-일-메틸렌]-4, 5-디히드로피리다지논을 들 수 있다. 헤테로고리알킬 치환 화합물의 한예는 6-할로페닐-2-(알킬-4-이소옥소일알킬)-4, 5-디히드로피리다지논이다.Alkyl is, for example, (C 1 -C 6 ) straight or branched chain alkyl such as methyl, ethyl, n-butyl or t-butyl. Hydroxyalkyl is, for example, hydroxy (C 1 -C 6 ) alkyl, such as 1-hydroxypropyl or 3-hydroxybutyl. Cyanoalkyl is, for example, cyano (C 1 -C 6 ) alkyl, such as cyanomethyl. Hydrazidal groups are, for example, terminal alkylhydrides such as acetylhydrazide, and specific compounds having such R 1 substituents may be 6-halophenyl-2-acetyl hydrazide 4, 5-dihydro pyridazinone. Non-terminal alkyl hydrides may have organic groups to which they are attached. Examples of such compounds are 6-halophenyl-2- [N-acetylhydrazide- (N'-2,4-pentanedione-hydrazone)]-4, 5-pyridazinone or 6-halophenyl-2- [N-acetylhydrazide- (N'-halophenyl hydrazone)]-4, 5-dihydropyridazinone. In addition, 6-halophenyl-2- (alkyl-1-pyrazoylmethylene) -4,5-dihydro pyridazinone, 6-halophenyl-2- (1, 3, 4-oxadiazin-2-one -5-yl-methylene) -4, 5-dihydropyridazinone, or 6-halophenyl-2- [2, 3, 4-oxadiazin-2-one-3- (2'-alkynyl) Cyclized forms such as -5-yl-methylene] -4, 5-dihydro pyrazazinone can also be included. Alkynyl substituents on such ring compounds may include 2-pentynyl, 2-butynyl and 3-halo-2-propynyl. As an example 6- (4-chlorophenyl) -2- (1, 3, 4-oxadiazine-2-one-3- (3'-iodopropargyl) -5-yl-methylene] -4, 5-dihydropyridazinone One example of a heterocyclic alkyl substituted compound is 6-halophenyl-2- (alkyl-4-isooxoylalkyl) -4 and 5-dihydropyridazinone.

시클로알킬알킬은, 예를 들면, 시클로프로필메틸, 같은(C3-C6)시클로알킬-(C1-C6)알킬이다. 헤테로고리 알킬은, 예를 들면, 2, 3-에폭시프로필 또는 알킬-2-푸라닐 메틸렌 같은 헤테로고리 (C1-C6)알킬이다. 페닐알킬은, 예를 들면,벤질 또는 3-클로로벤질같은 페닐(C1-C6)알킬이다. 알켄일은, 예를 들면, 2-부텐일, 3-메틸-2-부텐일, 또는 알렌일 같은 (C3-C6)알켄일이다. 할로알켄일은, 예를 들면, 3-브로모-2-프로펜일, 3, 3-디브로모-2-프로펜일, 또는 4-브로모-2-부텐일같은 할로(C3-C6)알켄일이다. 페닐알켄일은, 예를 들면, 3-페닐-2-프로펜일같은 페닐(C3-C6)알켄일이다. 알킨일알켄일은 3-(3-메틸-2-프로핀일)-2-프로펜일 또는 3-아세틸렌일-2-프로펜일 같은 (C3-C6)알킨일(C2-C6)알켄일이다. 알킨일은, 예를 들면, 2-프로핀일, 2-부틴일, 1-메틸-2-부틴일,2-펜틴일, 1-메틸-2펜틴일, 3-비닐-2-프로핀일, 3-펜틴일, 4-메틸-2-펜틴일, 5, 5-디메틸-2-펜틴일, 2-헥신일, 펜타-2, 4-디인일, 2-옥틴일 또는 2-데신일같은 (C3-C10)알킨일 또는 디알킨일이다. 할로알킨일은, 예를 들면, 3-요오도-2-프로핀일, 4-클로로-2-부틴일, 4-브로모-2-부틴일, 4-플루오로-2-부틴일, 4, 4-디플루오로-2-부틴일, 5-플루오로-2-펜틴일 또는 4-플루오로-2-펜틴일같은 할로(C3-C6)알킨일이다. 페닐알킨일은, 예를 들면,3-페닐-2-프로핀일 또는 3-(4-클로로페닐)-2-프로핀일같은 페닐(C3-C6)알킨일이다. 헤테로고리알킨일은, 예를 들면, 3-(2-티에닐)-2-프로핀일같은 헤테로고리(C3-C6)알킨일이다. 시클로알킬알킨일은, 예를 들면, 3-시클로헥실-2-프로핀일 또는 4-시클로헥실-2-부틴일이다. 알켄일 알킨일은, 예를 들면,3-(비닐)-2-프로핀일, 3-(2-메틸비닐)-2-프로핀일 또는 3-(2-프로펜일)-2-프로핀일같은 (C3-C6)알켄일(C3-C6)알킨일이다. 히드록시알킨일은, 예를 들면, 5-히드록시-2-펜틴일 또는 4-히드록시-2-펜틴일같은 히드록시(C3-C6)알킨일이다.Cycloalkylalkyl is, for example, cyclopropylmethyl, such as (C 3 -C 6 ) cycloalkyl- (C 1 -C 6 ) alkyl. Heterocyclic alkyl is, for example, heterocyclic (C 1 -C 6 ) alkyl, such as 2, 3-epoxypropyl or alkyl-2-furanyl methylene. Phenylalkyl is, for example, phenyl (C 1 -C 6 ) alkyl, such as benzyl or 3-chlorobenzyl. Alkenyl is (C 3 -C 6 ) alkenyl, such as, for example, 2-butenyl, 3-methyl-2-butenyl, or allenyl. Haloalkenyl is, for example, halo (C 3 -C 6 ), such as 3-bromo-2-propenyl, 3, 3-dibromo-2-propenyl, or 4-bromo-2-butenyl. Alkenyl. Phenylalkenyl is, for example, phenyl (C 3 -C 6 ) alkenyl, such as 3-phenyl-2-propenyl. Alkynylalkenyl is (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, such as 3- (3-methyl-2-propynyl) -2-propenyl or 3-acetylenyl-2-propenyl to be. Alkynyl is, for example, 2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-pentynyl, 1-methyl-2pentinyl, 3-vinyl-2-propynyl, 3- Such as pentinyl, 4-methyl-2-pentinyl, 5, 5-dimethyl-2-pentinyl, 2-hexynyl, penta-2, 4-diynyl, 2-octinyl or 2-decynyl (C 3 -C 10 ) alkynyl or dialkynyl. Haloalkynyl is, for example, 3-iodo-2-propynyl, 4-chloro-2-butynyl, 4-bromo-2-butynyl, 4-fluoro-2-butynyl, 4, 4 Halo (C 3 -C 6 ) alkynyl, such as difluoro-2-butynyl, 5-fluoro-2-pentynyl or 4-fluoro-2-pentynyl. Phenylalkynyl is, for example, phenyl (C 3 -C 6 ) alkynyl, such as 3-phenyl-2-propynyl or 3- (4-chlorophenyl) -2-propynyl. Heterocyclic alkynyl is, for example, heterocyclic (C 3 -C 6 ) alkynyl, such as 3- (2-thienyl) -2-propynyl. Cycloalkylalkynyl is, for example, 3-cyclohexyl-2-propynyl or 4-cyclohexyl-2-butynyl. Alkenyl alkynyl is, for example, a (C such as 3- (vinyl) -2-propynyl, 3- (2-methylvinyl) -2-propynyl or 3- (2-propenyl) -2-propynyl) 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl. Hydroxyalkynyl is, for example, hydroxy (C 3 -C 6 ) alkynyl such as 5-hydroxy-2-pentinyl or 4-hydroxy-2-pentinyl.

알콕시알킨일은, 예를 들면, 4-메톡시-2-펜틴일 또는 4,4-디에톡시-2-부틴일같은 (C1-C6)알(C1-C6)알콕시(C3-C6)알킨일이다. 알카노일옥시알킨일은, 예를 들면, 4-아세틸옥시-2-펜틴일 같은 (C1-C6)알카노일옥시(C3-C6)알킨일이다. 포르밀 알킨일은, 예를 들면,3-포르밀-2-프로핀일같은 포르밀(C3-C6)알킨일이다. 트리알킬실릴알킨일은, 예를 들면, 3-트리메틸실릴-2-프로핀일 같은 트리(C1-C6)알킬실릴(C3-C6)알킨일이다. 트리알킬틴 알킨일은, 예를 들면, 3-(트리-n-부틸틴)-2-프로핀일같은트리(C1-C6)알킬틴(C3-C6)알킨일이다. 할로알켄일 알킨일은, 예를 들면, 3-(1, 2, 2-트리플루오로비닐)-2-프로핀일 같은 할로(C3-C6)알켄일(C3-C6)알킨일이다. 카르복시알킨일은, 예를 들면, 3-카르복시-2-프로핀일같은 카르복시(C3-C6)알킨일이다. 알콕시카보닐알킨일은, 예를 들면, 3-(메톡시카보닐)-2-프로핀일같은 (C1-C6)알콕시 카보닐(C3-C6)알킨일이다.Alkoxyalkynyl is, for example, (C 1 -C 6 ) al (C 1 -C 6 ) alkoxy (C 3- ), such as 4-methoxy-2-pentynyl or 4,4-diethoxy-2-butynyl. C 6 ) alkynyl. Alkanoyloxyalkynyl is, for example, (C 1 -C 6 ) alkanoyloxy (C 3 -C 6 ) alkynyl, such as 4-acetyloxy-2-pentynyl. Formyl alkynyl is, for example, formyl (C 3 -C 6 ) alkynyl, such as 3-formyl-2-propynyl. Trialkylsilylalkynyl is, for example, tri (C 1 -C 6 ) alkylsilyl (C 3 -C 6 ) alkynyl, such as 3-trimethylsilyl-2-propynyl. Trialkyltin alkynyl is, for example, tri (C 1 -C 6) alkyltin (C 3 -C 6 ) alkynyl, such as 3- (tri-n-butyltin) -2-propynyl. Haloalkenyl alkynyl is, for example, halo (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, such as 3- (1, 2, 2-trifluorovinyl) -2-propynyl . Carboxylkynyl is, for example, carboxy (C 3 -C 6 ) alkynyl, such as 3-carboxy-2-propynyl. Alkoxycarbonylalkynyl is, for example, (C 1 -C 6 ) alkoxy carbonyl (C 3 -C 6 ) alkynyl, such as 3- (methoxycarbonyl) -2-propynyl.

R2와 R3는 (C1-C3)알킬, (C2-C3)알킬렌 또는, 예를 들면, 4, 4a, 5, 6-테트라히드로-8-할로[h]-시놀린-2-R1-3-온 또는 그의 5, 6-디히드로형과 같은 비교적 단순한 직쇄일 수 있는 카보닐 쇄를 형성하도록 함께 연결될 수 있다. R2와 R3는 (C1-C3)알킬, (C2-C3)알킬렌 또는 8-R1-아세나프토-[1, 2c] 피리다진-3-온에서의 융합고리(fused ring)구조처럼 단순한 직쇄가 아닌 카보닐쇄를 형성하도록 함께 연결될 수도 있다.R 2 and R 3 are (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkylene or, for example, 4, 4a, 5, 6-tetrahydro-8-halo [h] -cinonoline It can be linked together to form a carbonyl chain which may be a relatively simple straight chain such as the 2-R 1-3 -one or its 5, 6-dihydro form. R 2 and R 3 are fused at (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkylene or 8-R 1 -acenaphtho- [1, 2c] pyridazin-3-one It may be linked together to form a carbonyl chain rather than a simple straight chain such as a ring structure.

R2와 R7은 융합 페닐고리를 형성하도록 함께 연결될 수 있다.R 2 and R 7 may be linked together to form a fused phenyl ring.

본 명세서에서 헤테로고리는 산소, 황 및 질소로부터 선택된 하나의 헤테로원자를 포함하여 총 10개까지의 고리 원자를 갖는, 부분포화된 또는 포화된 방향족 5- 및 6원자 단일고리 또는 이중고리 시스템들로서, 예를 들면, 에폭시, 티에닐, 벤조티에닐, 피리딜, 퀴놀일등이 포함된다. 본 발명은 또한 전술한 본 발명의 화합물들을 함유하는 조성물들을 제공한다. 본 발명에서 유용한 화합물들중 다수는 신규한 것이다. 신규화합물로는 R1이 알킨일 또는 치환알킨일인 화합물들이 포함된다.The heterocycle herein refers to partially saturated or saturated aromatic 5- and 6-membered monocyclic or bicyclic systems having up to 10 ring atoms including one heteroatom selected from oxygen, sulfur and nitrogen, For example, epoxy, thienyl, benzothienyl, pyridyl, quinolyl and the like are included. The invention also provides compositions containing the compounds of the invention described above. Many of the compounds useful in the present invention are novel. New compounds include those in which R 1 is alkynyl or substituted alkynyl.

본 발명의 한 실시태양에 있어서, 유용한 화합물은 다음 일반식 I의 화합물 및 농업적으로 허용되는 그의 염들이다.In one embodiment of the invention, useful compounds are the following compounds of Formula I and agriculturally acceptable salts thereof.

상기식에서, A는 -(CHR2)n-CHR7-Z-, -CR2=CR7-Z-, CR2=N-Z-, CHR2-CR7=Y-, 또는 -CR2=CR2-Y=이고; D는 CR8또는 질소이고; Q는 다음 기들로부터 선택된 방향족기이고;Wherein A is-(CHR 2 ) n-CHR 7 -Z-, -CR 2 = CR 7 -Z-, CR 2 = NZ-, CHR 2 -CR 7 = Y-, or -CR 2 = CR 2 -Y =; D is CR 8 or nitrogen; Q is an aromatic group selected from the following groups;

Z는 카보닐(C=O) 또는 티오카보닐 (C=S)이고; Y는 할로, (C1-C6)알콕시, (C3-C6)알킨일티오 또는 트리아졸릴에 의하여 치환된 탄소이고; R1은 (C1-C6)직쇄 또는 분지쇄 알킬, 히드록시(C1-C6)알킬, 시아노(C1-C6)알킬, (C3-C6)시클로알킬 (C1-C6)알킬, 헤테로고리(C1-C6)알킬, 페닐, 페닐(C1-C6)알킬, (C3-C6)알켄일, 할로(C3-C6)알켄일, 페닐(C3-C6)알켄일,(C3-C6)알킨일(C2-C6)알켄일,(C3-C10)알킨일, (C4-C20)디알킨일, 할로(C3-C6)알킨일, 페닐(C3-C6)알킨일, 헤테로고리(C3-C6)알킨일,(C3-C6)시클로알킬(C3-C6)알킨일, (C3-C6)알켄일(C3-C6)알킨일, 히드록시(C3-C6)알킨일, (C1-C6)알콕시(C3-C6)알킨일, (C1-C6)알카노일옥시(C3-C6)알킨일, 포르밀(C3-C6)알킨일,트리(C1-C6)알킬실릴(C3-C6)알킨일, 트리(C1-C6)알킬틴(C3-C6)알킨일, 할로(C3-C6)알켄일(C3-C6)알킨일, 카르복시(C3-C6)알킨일, 또는 (C1-C6)알콕시카보닐(C3-C6)알킨일이고; R7은 수소, (C1-C3)알킬, 페닐, 시아노, 할로겐, (C3-C10)알킨일, (C3-C6)알킨일(C2-C6)알켄일, (C4-C2)디알킨일, 할로(C3-C6)알킨일, 또는 (C3-C6)알켄일(C3-C6)알킨일이고; R8은 수소, (C1-C3) 알킬, 페닐, 시아노 또는 할로겐이고; R3와 R6는 각각 수소 또는 할로겐이고; R4는 수소, 할로겐, (C1-C6)알콕시 또는 니트로이고; R5는 수소, 할로겐, 니트로, (C1-C6)알킬, (C1-C6)알콕시, (C1-C6)알킬티오, 할로(C1-C6)알킬, 할로(C1-C6)알콕시, 할로(C1-C6)알킬티오, 페닐, 페녹시, 또는 시아노이고; R2와 R3는 함께 (C1-C3)알킬, (C2-C3)알킬렌, 또는 카보닐쇄를 형성하거나; 또는 R2와 R7은 함께 페닐고리를 형성하고; X는 산소(O) 또는 황(S)이고; n은 0, 1 또는 2이다.Z is carbonyl (C═O) or thiocarbonyl (C═S); Y is carbon substituted by halo, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) alkynylthio or triazolyl; R 1 is (C 1 -C 6 ) straight or branched chain alkyl, hydroxy (C 1 -C 6 ) alkyl, cyano (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C 1 -C 6 ) alkyl, heterocyclic (C 1 -C 6 ) alkyl, phenyl, phenyl (C 1 -C 6 ) alkyl, (C 3 -C 6 ) alkenyl, halo (C 3 -C 6 ) alkenyl, Phenyl (C 3 -C 6 ) alkenyl, (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, (C 3 -C 10 ) alkynyl, (C 4 -C 20 ) dialkynyl, Halo (C 3 -C 6 ) alkynyl, phenyl (C 3 -C 6 ) alkynyl, heterocyclic (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) Alkynyl, (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, hydroxy (C 3 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy (C 3 -C 6 ) alkyn 1 , (C 1 -C 6 ) alkanoyloxy (C 3 -C 6 ) alkynyl, formyl (C 3 -C 6 ) alkynyl, tri (C 1 -C 6 ) alkylsilyl (C 3 -C 6 Alkynyl, tri (C 1 -C 6 ) alkyltin (C 3 -C 6 ) alkynyl, halo (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, carboxy (C 3 -C 6 ) alkynyl, or (C 1 -C 6 ) alkoxycarbonyl (C 3 -C 6 ) alkynyl; R 7 is hydrogen, (C 1 -C 3 ) alkyl, phenyl, cyano, halogen, (C 3 -C 10 ) alkynyl, (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, (C 4 -C 2 ) dialkynyl, halo (C 3 -C 6 ) alkynyl, or (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl; R 8 is hydrogen, (C 1 -C 3 ) alkyl, phenyl, cyano or halogen; R 3 and R 6 are each hydrogen or halogen; R 4 is hydrogen, halogen, (C 1 -C 6 ) alkoxy or nitro; R 5 is hydrogen, halogen, nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkylthio, halo (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkoxy, halo (C 1 -C 6 ) alkylthio, phenyl, phenoxy, or cyano; R 2 and R 3 together form (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkylene, or carbonyl chain; Or R 2 and R 7 together form a phenyl ring; X is oxygen (O) or sulfur (S); n is 0, 1 or 2.

본 발명의 바람직한 실시태양에 있어서, 유용한 화합물은 다음 일반식의 화합물들 및 농경학적으로 허용되는 그의 염들이다.In a preferred embodiment of the present invention, useful compounds are compounds of the following general formula and agriculturally acceptable salts thereof.

상기 일반식에서, R1은 (C1-C6)직쇄 또는 분지쇄 알킬, 히드록시(C1-C6)알킬, 시아노(C1-C6)알킬, (C3-C6)시클로알킬 (C1-C6)알킬, 헤테로고리(C1-C6)알킬, 페닐, 페닐(C1-C6)알킬, (C3-C6)알켄일, 할로(C3-C6)알켄일, 페닐(C3-C6)알켄일,(C3-C6)알킨일(C2-C6)알켄일,(C3-C10)알킨일, (C4-C20)디알킨일, 할로(C3-C6)알킨일, 페닐(C3-C6)알킨일, 헤테로고리(C3-C6)알킨일,(C3-C6)시클로알킬(C3-C6)알킨일, (C3-C6)알켄일(C3-C6)알킨일, 히드록시(C3-C6)알킨일, (C1-C6)알콕시(C3-C6)알킨일, (C1-C6)알카노일옥시(C3-C6)알킨일, 프로밀(C3-C6)알킨일, 트리(C1-C6)알킬실릴(C3-C6)알킨일, 트리(C1-C6)알킬틴(C3-C6)알킨일, 할로(C3-C6)알켄일(C3-C6)알킨일, 카르복시(C3-C6)알킨일, 또는 (C1-C6)알콕시 카보닐(C3-C6)알킨일이고; R2는 수소 또는 (C1-C6)알킬이고; R3는 수소, 할로겐, (C1-C6)알킬 또는 (C1-C6)알콕시이거나; 또는 R2와 R3가 함께 (C1-C3)알킬, (C2-C3)알킬렌 또는 카보닐쇄를 형성하고; R4는 수소, (C1-C6)알킬, 할로겐 또는 니트로이고; R5는 수소, (C1-C6)알킬, (C1-C6)알콕시, 페녹시, 할로((C1-C6)알킬, (C1-C6)알킬티오, 시아노, 페닐, 할로(C1-C6)알콕시 또는 할로겐이고; R6는 수소 또는 할로겐이고; R7은 수소, (C1-C6)알킬, 페닐, 할로겐, (C3-C10)알킨일, (C3-C6)알킨일 (C2-C6)알켄일, (C4-C20)디알킨일, 할로(C3-C6)알킨일, 또는 (C3-C6)알켄일(C3-C6)알킨일임.Wherein R 1 is (C 1 -C 6 ) straight or branched chain alkyl, hydroxy (C 1 -C 6 ) alkyl, cyano (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cyclo Alkyl (C 1 -C 6 ) alkyl, heterocyclic (C 1 -C 6 ) alkyl, phenyl, phenyl (C 1 -C 6 ) alkyl, (C 3 -C 6 ) alkenyl, halo (C 3 -C 6 ) Alkenyl, phenyl (C 3 -C 6 ) alkenyl, (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, (C 3 -C 10 ) alkynyl, (C 4 -C 20 ) Dialkynyl, halo (C 3 -C 6 ) alkynyl, phenyl (C 3 -C 6 ) alkynyl, heterocyclic (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6) alkynyl, (C 3 -C 6) alkenyl (C 3 -C 6) alkynyl, hydroxy (C 3 -C 6) alkynyl, (C 1 -C 6) alkoxy (C 3 - C 6 ) alkynyl, (C 1 -C 6 ) alkanoyloxy (C 3 -C 6 ) alkynyl, promil (C 3 -C 6 ) alkynyl, tri (C 1 -C 6 ) alkylsilyl (C 3- C 6 ) alkynyl, tri (C 1 -C 6 ) alkyltin (C 3 -C 6 ) alkynyl, halo (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, carboxy (C 3 -C 6 ) alkynyl, or (C 1 -C 6 ) alkoxy carbonyl (C 3 -C 6 ) alkynyl; R 2 is hydrogen or (C 1 -C 6 ) alkyl; R 3 is hydrogen, halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy; Or R 2 and R 3 together form a (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkylene or carbonyl chain; R 4 is hydrogen, (C 1 -C 6 ) alkyl, halogen or nitro; R 5 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, phenoxy, halo ((C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylthio, cyano, Phenyl, halo (C 1 -C 6 ) alkoxy or halogen; R 6 is hydrogen or halogen; R 7 is hydrogen, (C 1 -C 6 ) alkyl, phenyl, halogen, (C 3 -C 10 ) alkynyl , (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, (C 4 -C 20 ) dialkynyl, halo (C 3 -C 6 ) alkynyl, or (C 3 -C 6 ) al Kenyl (C 3 -C 6 ) alkynyl.

더 바람직한 화합물들은 상기 일반식에서 R1이 (C3-C6)알킨일, (C3-C6)알켄일, (C3-C6)알켄일(C3-C6)알킨일 또는 (C3-C6)알킨일(C3-C6)알켄일이고; R2는 수소 또는 (C1-C6)알킬이고; R3는 수소, 할로 또는(C1-C6)알콕시이거나; 또는 R2와 R3가 함께 (C1-C3)알킬, (C2-C3)알킬렌 또는 카보닐쇄를 형성하며; R4는 수소, 할로 또는 (C1-C6)알킬이고; R5는 수소, 할로 또는 할로(C1-C6)알콕시이고; R6는 수소 또는 플루오로이며; R7은 수소인 화합물들이다.More preferred compounds are those in which R 1 is (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) alkenyl, (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, or ( C 3 -C 6 ) alkynyl (C 3 -C 6 ) alkenyl; R 2 is hydrogen or (C 1 -C 6 ) alkyl; R 3 is hydrogen, halo or (C 1 -C 6 ) alkoxy; Or R 2 and R 3 together form a (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkylene or carbonyl chain; R 4 is hydrogen, halo or (C 1 -C 6 ) alkyl; R 5 is hydrogen, halo or halo (C 1 -C 6 ) alkoxy; R 6 is hydrogen or fluoro; R 7 are compounds that are hydrogen.

좀더 바람직한 화합물들은 상기 일반식에서 R1이 2-펜틴일, 2-헥신일, 3-비닐-2-프로핀일, 4-플루오로-2-펜틴일, 5-플루오로-2-펜틴일 또는 3-(1-프로펜일)-2-프로핀일이고; R2는 수소이고, R3는 수소이거나; 또는 R2와 R3가 함께 (C1-C3)알킬쇄를 형성하고; R4는 수소, 메틸, 클로로 또는 플루오로이고; R5는 클로로, 플루오로, 브로모 또는 트리플루오로메톡시이고; R6는 수소 또는 플루오로이며; R7은 수소인 화합물들이다.More preferred compounds are those wherein R 1 is 2-pentynyl, 2-hexynyl, 3-vinyl-2-propynyl, 4-fluoro-2-pentinyl, 5-fluoro-2-pentynyl or 3 in the above general formula. -(1-propenyl) -2-propynyl; R 2 is hydrogen and R 3 is hydrogen; Or R 2 and R 3 together form a (C 1 -C 3 ) alkyl chain; R 4 is hydrogen, methyl, chloro or fluoro; R 5 is chloro, fluoro, bromo or trifluoromethoxy; R 6 is hydrogen or fluoro; R 7 are compounds that are hydrogen.

특히 바람직한 화합물들은 상기 일반식에서 R1이 2-펜틴일이고; R2, R3, R6및 R7은 수소이고; R5는 클로로이며; R5는 수소 또는 플루오로인 것이다.Particularly preferred compounds are those in which R 1 is 2-pentynyl; R 2 , R 3 , R 6 and R 7 are hydrogen; R 5 is chloro; R 5 is hydrogen or fluoro.

본 발명의 두 번째 바람직한 실시태양에 있어서 유용한 화합물들은 다음 일반식의 화합물들 및 농경학적으로 허용되는 그의 염들이다.Compounds useful in a second preferred embodiment of the present invention are compounds of the general formulas and agriculturally acceptable salts thereof.

상기 일반식에서, R1은 (C3-C6)알킨일, (C2-C6)알킨일(C3-C6)알킨일, 할로(C3-C6)알킨일, (C2-C6)알켄일(C3-C6)알킨일 또는 트리((C1-C6)알킬)인(C3-C6)알킨일이고; R2는 수소 또는 할로겐이고; R3는 수소 또는 (C1-C6)알킬이거나 또는 R2와 R3가 함께 (C1-C3)알킬, (C2-C3)알켄일 또는 카보닐쇄를 형성하고; R4는 수소, 할로겐 또는 (C1-C6)알킬이고; R5는 수소, 할로겐, (C1-C6)알킬 또는 (C1-C6)알콕시이고; R6은 수소 또는 할로겐이며; R7은 수소 또는 할로겐이다.In the general formula, R 1 is (C 3 -C 6 ) alkynyl, (C 2 -C 6 ) alkynyl (C 3 -C 6 ) alkynyl, halo (C 3 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl or tri ((C 1 -C 6 ) alkyl) (C 3 -C 6 ) alkynyl; R 2 is hydrogen or halogen; R 3 is hydrogen or (C 1 -C 6 ) alkyl or R 2 and R 3 together form (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkenyl or carbonyl chain; R 4 is hydrogen, halogen or (C 1 -C 6 ) alkyl; R 5 is hydrogen, halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy; R 6 is hydrogen or halogen; R 7 is hydrogen or halogen.

이 실시태양에서 더 바람직한 화합물들은 상기 일반식에서 R1은 수소 또는 할로이고; R2는 R3와 함께 (C1-C3)쇄를 형성하고; R3는 수소 또는 (C1-C6)알킬이고; R4는 수소, 할로 또는 (C1-C6)알킬이고; R5는 수소, 할로, (C1-C6)알킬 또는 (C1-C6)알콕시이고; R6는 수소 또는 플루오로이며; R7은 수소 또는 플루오로인 화합물들이다.More preferred compounds in this embodiment are those in which R 1 is hydrogen or halo; R 2 together with R 3 form a (C 1 -C 3 ) chain; R 3 is hydrogen or (C 1 -C 6 ) alkyl; R 4 is hydrogen, halo or (C 1 -C 6 ) alkyl; R 5 is hydrogen, halo, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy; R 6 is hydrogen or fluoro; R 7 are compounds which are hydrogen or fluoro.

좀더 바람직한 화합물들은 R1이 2-펜틴일, 4-플루오로-2-펜틴일, 3-비닐-2-프로핀일, 또는 5-플루오로-2-펜틴일이고; R2는 수소이고 R3도 수소이거나, 또는 R2와 R3가 함께 (C1-C3) 알킬쇄를 형성하고; R4는 수소, 플루오로 또는 클로로이고; R5는 플루오로, 클로로 또는 브로모이고; R6는 수소이며; R7은 수소인 화합물들이다.More preferred compounds are those wherein R 1 is 2-pentynyl, 4-fluoro-2-pentynyl, 3-vinyl-2-propynyl, or 5-fluoro-2-pentynyl; R 2 is hydrogen and R 3 is also hydrogen, or R 2 and R 3 together form a (C 1 -C 3 ) alkyl chain; R 4 is hydrogen, fluoro or chloro; R 5 is fluoro, chloro or bromo; R 6 is hydrogen; R 7 are compounds that are hydrogen.

특히 바람직한 화합물들은 R1이 2-펜틴일이고; R2, R3, R6및 R7은 수소이고; R4는 수소 또는 플루오로이며; R5는 클로로인 것이다.Particularly preferred compounds are those in which R 1 is 2-pentynyl; R 2 , R 3 , R 6 and R 7 are hydrogen; R 4 is hydrogen or fluoro; R 5 is chloro.

본 발명의 방법에서 유용한 일종의 화합물들은 공지된 것으로서 상업적으로 구입가능하다. 그러나, 그들이 피리쿨라리아 오리자에(Pyricularia oryzae)에 대해 활성적이라는 것이 밝혀진 바 없으며, 따라서 본 발명의 방법에 활성적인 것이 밝혀진 바도 없다. 그러한 화합물들은 뒤에 나오는 표 1에 표기된 화합물 번호 (Cmpd No.) 1-5의 것들이다.A kind of compounds useful in the process of the invention are known and commercially available. However, they have not been found to be active against Pyricularia oryzae, and therefore have not been found to be active in the methods of the present invention. Such compounds are those of Compound No. (Cmpd No.) 1-5 shown in Table 1 below.

본 발명의 디히드로피리다지논 화합물들은, 예를 들면, 다음 일반식 II의 알릴케토산 또는 그 에스테르로부터 개시되는 2단계 반응에 의하여 제조된다.The dihydropyridazinone compounds of the present invention are prepared, for example, by a two step reaction initiated from the following allylketo acids of the general formula II or esters thereof.

상기 일반식 II에서 Q는 일반식 I에서 정의된 바와 같으며, Ra는 수소 또는 알킬이다.Q in Formula II is as defined in Formula I, and R a is hydrogen or alkyl.

화합물 II는 거의 동일당량의 다음 일반식 III(여기서, Rb는 수소)의 히드라진 또는 치환히드라진과 반응하여 다음 일반식 IV의 화합물을 산출한다.Compound II is reacted with approximately equal equivalents of hydrazine or substituted hydrazine of the following Formula III, wherein R b is hydrogen, to yield the compound of Formula IV:

이 반응에서 적당한 용매의 예들로는 에탄올, n-부탄올 또는 n-프로판올 같은 알코올류를 들 수 있다. 이 반응은 대기압에서 약-10˚C 내지 200˚C의 온도에서 행하여 진다. 반응온도는 바람직하게는 약 25-150˚C, 더 바람직하게는 약 50-125˚C이다.Examples of suitable solvents in this reaction include alcohols such as ethanol, n-butanol or n-propanol. The reaction is carried out at atmospheric pressure at a temperature of about -10 ° C to 200 ° C. The reaction temperature is preferably about 25-150 ° C., more preferably about 50-125 ° C.

Rb가 수소인 일반식 IV의 화합물은, 예를 들면, 디메틸 포름아미드(DMF)같은 비양성자성 극성 용매내에서 수소화 나트륨을 사용하는 표준 N-알킬화 방법에 의하여 또는 테트라부틸암모늄 하이드로겐 술페이트 같은 상전환촉매(phase transfer catalyst)의 사용에 의하여, 알킨일 메실레이트 또는 알킨일 할라이드같은 적당한 알킬화제를 사용하여 알킬화되어 본 발명의 디히드로피리다지논(Rb가 수소가 아닌 일반식 IV의 화합물)이 산출된다. 이 반응은 일반적으로 약-10˚C 내지 250˚C, 바람직하게는 약 20˚C 내지 100˚C의 온도에서 수행된다.Compounds of general formula IV wherein R b is hydrogen can be prepared by standard N-alkylation processes using sodium hydride in aprotic polar solvents such as dimethyl formamide (DMF) or by tetrabutylammonium hydrogen sulfate The dihydropyridazinones of the invention (compounds of formula IV wherein Rb is not hydrogen) are alkylated by the use of suitable alkylating agents such as alkynyl mesylates or alkynyl halides by the use of such phase transfer catalysts. Is calculated. This reaction is generally carried out at a temperature of about -10 ° C to 250 ° C, preferably about 20 ° C to 100 ° C.

Rb가 수소인 일반식 IV의 디히드로피리다지논은, 예를 들면, 브롬산화에 의하여 상응하는 본 발명의 피리다지논으로 전환될 수 있다. 반응은 일반적으로 아세트산같은 유기산 용매내에서 수행된다. 반응온도는 약 0-150˚C, 바람직하게는 약 20-100˚C, 더 바람직하게는 약 50-75˚C 범위이다.The dihydropyridazinones of formula IV wherein R b is hydrogen can be converted to the corresponding pyridazinones of the invention, for example, by bromination. The reaction is generally carried out in an organic acid solvent such as acetic acid. The reaction temperature is in the range of about 0-150 ° C., preferably about 20-100 ° C., more preferably about 50-75 ° C.

출발물질인 아릴케토산은 상업적 제품들로부터 얻을수도 있고, 또는 (1) 무수숙신산을 사용한 방향족 화합물의 프리이델-크라프트 아실화(Friedel-Crafts Acylation), (2)말론산 에스테르 축합(디-t-부틸말로네이트로부터 비스-(디-t-부틸카르복시) 에틸카르복시에탄의 제조, 방향족 아실클로라이드와의 아실화, 및 케토트리에스테르의 탈카르복시화), 또는 (3)클라이젠 축합(Claisen Condensation)같은 공지 방법들에 의하여 제조될 수도 있다.The starting material arylketo acid can be obtained from commercial products, or (1) Friedel-Crafts Acylation of aromatic compounds with succinic anhydride, (2) malonic ester condensation (di-t Preparation of bis- (di-t-butylcarboxy) ethylcarboxyethane from butylmalonate, acylation with aromatic acyl chlorides, and decarboxylation of ketotriesters, or (3) Claisen Condensation It may be prepared by the same known method.

전형적으로, 상기 반응의 알킬화단계에서 사용되는 알킨일 할라이드는, 예를 들면, 다음과 같은 선행기술에 의하여 제조된다.Typically, the alkynyl halides used in the alkylation step of the reaction are prepared, for example, by the following prior art.

(a) 알코올로부터;(a) from alcohol;

(b) 알킨으로부터;(b) from alkyne;

(c) 프로파길 클로라이드로부터;(c) from propargyl chloride;

한편, R7은 알킬, 시클로알킬등이고, R은 알킬임.On the other hand, R 7 is alkyl, cycloalkyl and the like, and R is alkyl.

알킬화 반응이 일어난 다음, 알키닐기가 변환될 수 있다. 예를 들면, 디에틸아미노설파트리플루오라이드(DAST), 무수아세트산 또는 알코올/염화수소와 함께 처리함으로써 알키닐기의 알파탄소에 불소, 아세틸 또는 알콕시기가 첨가되고 (하기 반응 a); 비스(트리페닐 포스핀) 팔라듐 디클로라이드, 요오드화구리(I) 및 트리에틸아민 존재하에서 할로알켄과 함께 처리함으로써 알킨의 알파 탄소에 알키닐기가 첨가된다.After the alkylation reaction takes place, the alkynyl group can be converted. For example, by treating with diethylaminosulfatrifluoride (DAST), acetic anhydride or alcohol / hydrogen chloride, fluorine, acetyl or alkoxy groups are added to the alpha carbon of the alkynyl group (reaction a) below; An alkynyl group is added to the alpha carbon of the alkyne by treatment with haloalkenes in the presence of bis (triphenyl phosphine) palladium dichloride, copper iodide (I) and triethylamine.

피리디논은, 예를 들면, 염기존재하에서, 2-아릴디알킬아미노프로펜알(V)과 시아노아세트아미드(VI)의 고리화에 의해 상응하는 3-시아노-5-아릴피리디논을 산출하고, 이것을 가수분해 및 탈카르복시화시켜 일반식(VIII)의 피리디논을 산출함으로써 제조된다.Pyridinone, for example, in the presence of a base, yields the corresponding 3-cyano-5-arylpyridinone by cyclization of 2-aryldialkylaminopropenal (V) and cyanoacetamide (VI). And pyridinone of the general formula (VIII) is produced by hydrolysis and decarboxylation thereof.

피리디논은 디히드로피리다지논에 대하여 기술된 바와 같이 알킬화되어 본 발명의 화합물들이 산출된다.Pyridinone is alkylated as described for dihydropyridazinone to yield the compounds of the present invention.

고리화 반응에 적당한 용매의 예로는 메탄올, 에탄올같은 알코올을 들 수 있다. 적당한 염기의 예로는 메톡시화 나트륨 및 에톡시화 나트륨을 들 수 있다. 반응은 일반적으로 대기압에서 약 25-250℃, 바람직하게는 약 50-200℃, 더 바람직하게는 약 100-150℃의 온도에서 수행된다.Examples of suitable solvents for the cyclization reaction include alcohols such as methanol and ethanol. Examples of suitable bases include sodium methoxylated and sodium ethoxylated. The reaction is generally carried out at atmospheric pressure at a temperature of about 25-250 ° C., preferably about 50-200 ° C., more preferably about 100-150 ° C.

가수분해 및 탈카르복시화 단계는 85% H3PO4또는 진한 황산 같은 강산내에서 대기압 및 약 50-200℃ (바람직하게는 100-150℃)의 온도하에서 행하여진다.The hydrolysis and decarboxylation step is carried out at atmospheric pressure and at a temperature of about 50-200 ° C. (preferably 100-150 ° C.) in a strong acid such as 85% H 3 PO 4 or concentrated sulfuric acid.

본 발명의 출발물질인 피리미디논(IX)는 산존재하에서 2-아릴디알킬아미노프로펜알(V)을 요소와 함께 고리화 시킴에 의하여 제조될 수 있다. 바람직한 산은 염산같은 무기산이다. 바람직한 용매는 극성용매로서, 예를 들면, 에탄올 같은 알코올이다.Pyrimidinone (IX), the starting material of the present invention, may be prepared by cyclizing 2-aryldialkylaminopropenal (V) with urea in the presence of acid. Preferred acids are inorganic acids such as hydrochloric acid. Preferred solvents are polar solvents, for example alcohols such as ethanol.

반응은 바람직하게는 대기압에서 20-200℃, 더욱 바람직하게는 50-150℃의 온도에서 행하여진다. 그다음, 디히드로피리다지논에 대하여 기술된 바와 같이 알킬화가 수행된다.The reaction is preferably carried out at a temperature of 20-200 ° C., more preferably 50-150 ° C. at atmospheric pressure. Then alkylation is performed as described for dihydropyridazinone.

출발물질인 옥시디아진-2-온(X)는 극성 용매(예를 들면, 에탄올 같은 알코올)내에서 α-히드록시아세토페논(XI)을 에틸 카바제이트(XIII)와 함께 0-150℃, 바람직하게는 15-70℃의 온도에서 반응시켜 얻은 화합물(XIII)을 수소화 나트륨같은 염기 존재하 극성 용매(예를 들면, 에탄올 같은 알코올)내에서 고리화시킴에 의하여 제조될 수 있다.The starting material, oxydiazin-2-one (X), reacts α-hydroxyacetophenone (XI) with ethyl carbazate (XIII) in a polar solvent (eg alcohol such as ethanol) at 0-150 ° C. Compound (XIII), preferably obtained by reaction at a temperature of 15-70 ° C., can be prepared by cyclization in a polar solvent (eg alcohol such as ethanol) in the presence of a base such as sodium hydride.

디히드로피리다지논에 관하여 전술한 바와 같이, 옥사디아진-2-온(X)을 알킬화시켜 본 발명의 화합물을 산출한다.As described above with respect to dihydropyridazinone, the oxadiazin-2-one (X) is alkylated to yield the compounds of the present invention.

출발물질인 옥사디아진-5-온(XIV)은 디옥산, 테트라하이드로푸란, 글림 또는 다른 폴리에테르 같은 반양성자성 용매내에서 치환 벤조익 하이드라지드(XV)를 할로아세틸 클로라이드(XVI)와 함께 바람직하게 0-150℃, 더욱 바람직하게는 50-100℃의 온도에서 반응시켜 화합물(XVII)을 수득하고, 이 화합물을 수산화나트룸같은 염기 존재하에서 고리화시켜 옥사디아진-5-온(XIV)을 산출함으로써 제조될 수 있다.The starting material, oxadiazine-5-one (XIV), is substituted with haloacetyl chloride (XVI) with substituted benzoic hydrazide (XV) in aprotic solvents such as dioxane, tetrahydrofuran, glim or other polyethers. Reaction is preferably carried out at a temperature of 0-150 ° C., more preferably 50-100 ° C., to afford compound (XVII), which is cyclized in the presence of a base such as sodium hydroxide to form oxadiazine-5-one (XIV). Can be prepared by calculating

디히드로피리다지논에 관하여 설명한 바와 같이, 상기 옥사디아진-5-온(XIV)을 알킬화시켜 본 발명의 화합물을 산출한다.As described for the dihydropyridazinone, the oxadiazine-5-one (XIV) is alkylated to yield the compounds of the present invention.

출발물질인 티아디아진-2-온(XVIII)은 아세토니트릴, 디메틸포름아미드 또는 알코올과 같은 극성용매내에서 펜아실 할라이드(XIV), 바람직하게는 펜아실 브로마이드를 메틸 티오카바제이트같은 알콕시티오카보닐 히드라진(XX)과 함께 바람직하게 0-150℃, 더 바람직하게는 50-100℃의 온도에 반응시킴에 의하여 제조될 수 있다.The starting material thiadiazin-2-one (XVIII) is alkoxythio, such as methyl thiocarbazate, containing phenacyl halide (XIV), preferably phenacyl bromide, in a polar solvent such as acetonitrile, dimethylformamide or alcohol. In combination with carbonyl hydrazine (XX), preferably by reacting at a temperature of 0-150 ° C, more preferably 50-100 ° C.

디히드로피리다지논에 관하여 설명한 바와 같이, 상기 티아디아진에 관하여 설명한 바와 같이, 상기 티아디아진-2-온(XVIII)을 알킬화시켜 본 발명의 화합물을 산출한다.As described for dihydropyridazinone, as described for thiadiazine, the thiadiazine-2-one (XVIII) is alkylated to yield the compounds of the present invention.

출발물질인 인데노피리다지논(XXI: 여기서 R8은 수소 또는 (C1-C6)알킬)은 수소화 나트륨같은 염기 및 디메톡시에탄같은 비양성자성 용매존재하에서 디메틸카보네이트 같은 반응제를 사용하여 적당한 인다논(XXII)을 카르복시메틸화시킨 다음, 수소화 나트륨 같은 염기 및 디메틸포름아미드 같은 비양성자성 용매 존재하에서 브로모아세테이트같은 알킬화제와 함께 알킬화시켜 하기 디에스테르 화합물(XXIII)을 산출하고 이를 후속 처리함으로써 제조될 수 있다.The starting material indenopyridazinone (XXI: wherein R 8 is hydrogen or (C 1 -C 6 ) alkyl) is reacted using a reagent such as dimethyl carbonate in the presence of a base such as sodium hydride and an aprotic solvent such as dimethoxyethane. The appropriate indanone (XXII) is carboxymethylated and then alkylated with an alkylating agent such as bromoacetate in the presence of a base such as sodium hydride and an aprotic solvent such as dimethylformamide to yield the following diester compound (XXIII) and subsequent treatment Can be prepared.

디에스테르 화합물은 표준 방법들, 바람직하게는 수성 산용액내에서의 가열, 더욱 바람직하게는 염산 수용액내에서의 환류가열에 의하여 상응하는 케토산(XXIV)으로 탈카르복시화 및 가수분해된다.The diester compound is decarboxylated and hydrolyzed to the corresponding keto acid (XXIV) by standard methods, preferably by heating in an aqueous acid solution, more preferably by reflux heating in aqueous hydrochloric acid solution.

케토산(XXIV)는 디히드로피리다지논에 관하여 설명한 바와 마찬가지로 고리화 및 알킬화되어 본 발명의 화합물이 산출된다.Keto acid (XXIV) is cyclized and alkylated as described for dihydropyridazinone to yield the compounds of the present invention.

이하 실시예들을 통하여 본 발명을 상세히 설명한다. 한편, 하기 표 1, 2 및 3에 본 발명의 화합물의 예들을 표기하였다. 신규화합물들에 대하여는, 표 4에 그 원소분석치들을 표기하고, 표 5에 양성자 NMR 데이타를 표기하였다. 화합물들의 제조 실시예들은 표 5 다음에 기술하였다.Hereinafter, the present invention will be described in detail with reference to the following examples. Meanwhile, Tables 1, 2, and 3 show examples of the compounds of the present invention. For novel compounds, their elemental analysis values are shown in Table 4 and proton NMR data in Table 5. Examples of the preparation of the compounds are described following Table 5.

[실시예들][Examples]

[실시예 6 : 6-(4-클로로페닐)-2-프로파길-4,5-디히드로피리다지논][Example 6: 6- (4-chlorophenyl) -2-propargyl-4,5-dihydropyridazinone]

a. 6-(4-클로로페닐)-4,5-디히드로피리다지논a. 6- (4-chlorophenyl) -4,5-dihydropyridazinone

10g의 3-(4-클로로벤조일)프로피온산과 100g의 에탄올의 혼합물에 2.4g의 히드라진 모노하이드레이트를 조금씩 첨가하고, 반응혼합물을 2시간 동안 환류시켰다. 냉각시 형성된 백색 결정성 고체를 여과 건조시켜 9.7g(99%)의 디히드로피리다지논을 산출하였다.To a mixture of 10 g of 3- (4-chlorobenzoyl) propionic acid and 100 g of ethanol, 2.4 g of hydrazine monohydrate was added in portions, and the reaction mixture was refluxed for 2 hours. The white crystalline solid formed upon cooling was filtered off to yield 9.7 g (99%) of dihydropyridazinone.

b. 6-(4-클로로페닐)-2-프로파길-4,5-디히드로피리다진b. 6- (4-chlorophenyl) -2-propargyl-4,5-dihydropyridazine

0.17g 의 수소화나트륨(60% in oil) 과 50ml의 무수 디메틸포름아미드(DMF)의 혼합물을 5℃로 냉각시키고, 25ml의 무수 DMF 내 0.8g의 디히드로피리다지논을 방울방울 첨가하였다. 반응혼합물을 실온에서 30℃로 승온시킨 다음 5℃로 냉각시켰다. 프로파길 클로라이드(0.31g)를 첨가하고 반응 혼합물을 상온에서 1시간 동안 교반하였다. 반응혼합물을 100ml의 물로 냉각시키고 에틸에테르 (3x100ml)로 추출하였다. 유기층들을 합하고, 물(2x100ml) 및 포화염수(1x100ml)로 세척하였다. 에테르 추출물을 무수 황산마그네슘으로 건조시키고, 여과하고 진공증발시켜 0.68g의 화합물 6을 황갈색 고체로서 산출하였다.A mixture of 0.17 g sodium hydride (60% in oil) and 50 ml of anhydrous dimethylformamide (DMF) was cooled to 5 ° C. and 0.8 g of dihydropyridazinone in 25 ml of anhydrous DMF was added dropwise. The reaction mixture was warmed from room temperature to 30 ° C. and then cooled to 5 ° C. Propargyl chloride (0.31 g) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with 100 ml of water and extracted with ethyl ether (3 × 100 ml). The organic layers were combined and washed with water (2x100ml) and saturated brine (1x100ml). The ether extract was dried over anhydrous magnesium sulfate, filtered and evaporated to yield 0.68 g of compound 6 as a tan solid.

실시예 6b에 기술된 것과 실질적으로 동일한 방법에 따라서, 적당한 디히드로피리다지논을 사용하고, 프로파길 클로라이드 대신 부틸클로라이드, 크로틸 브로마이드, 벤질 브로마이드, 벤조일 클로라이드, 클로로메틸시클로프로판, 브로모아세토니트릴, 2-클로로메틸티오펜, 브로모부틴, 1, 3-디브로모-1-프로펜, 1, 4-디브로모-2-부틴, 2-부틴-1-일-메탄술포네이트 또는 2-펜틴-1-메탄술포네이트 같은 메실레이트로부터 선택된 적당한 알킬할라이드를 사용하여 화합물들 7-10, 13, 17, 18, 19, 20, 35, 69, 71, 80, 81, 133, 141, 142 및 154가 제조되었다. 화합물 52는 프로파길 클로라이드와의 알킬화로부터 크로마토그라피(실리카겔, 30; 70 에틸아세테이트/헥산)에 의하여 분리되었다. 화합물 75는 화합물 71의 제조에서 불순물로서 분리되었다.According to the method substantially the same as that described in Example 6b, a suitable dihydropyridazinone is used and butyl chloride, crotyl bromide, benzyl bromide, benzoyl chloride, chloromethylcyclopropane, bromoacetonitrile in place of propargyl chloride , 2-chloromethylthiophene, bromobutin, 1, 3-dibromo-1-propene, 1, 4-dibromo-2-butyne, 2-butyn-1-yl-methanesulfonate or 2 Compounds 7-10, 13, 17, 18, 19, 20, 35, 69, 71, 80, 81, 133, 141, 142 using a suitable alkyl halide selected from mesylate, such as fentin-1-methanesulfonate And 154 were prepared. Compound 52 was isolated by chromatography (silica gel, 30; 70 ethyl acetate / hexanes) from alkylation with propargyl chloride. Compound 75 was isolated as an impurity in the preparation of compound 71.

[실시예 11 : 6-(4-메톡시페닐)-2-(2'-부틴일)-4,5-디히드로피리다지논]Example 11 6- (4-methoxyphenyl) -2- (2'-butynyl) -4,5-dihydropyridazinone

a. 2-부틴-1-일-메탄술포네이크a. 2-butyn-1-yl-methanesulfonake

25g의 2-부틴-1-올과 200ml의 무수디에틸에테르의 용액에 72g의 트리에틸아민을 한번에 첨가하고 반응혼합물을 0℃로 냉각시켰다. 온도를 5℃이하로 유지시키면서 메탄술포닐 클로라이드(40.8g)을 방울방울 첨가한 다음 반응 혼합물을 0-5℃에서 2시간 동안 교반하고, 트리에틸아민염을 여과하여 100ml의 에테테로 세척 하였다. 에테르부분들을 합하여 물(100ml), 염수(100ml)로 세척하고, 황산마그네슘으로 건조시키고 진공증발시켜 39.6g의 메실레이트를 황색 액체로서 수득하였다.72 g of triethylamine was added to a solution of 25 g of 2-butyn-1-ol and 200 ml of anhydrous diethyl ether at once, and the reaction mixture was cooled to 0 deg. Methanesulfonyl chloride (40.8 g) was added dropwise while maintaining the temperature below 5 ° C, and the reaction mixture was stirred at 0-5 ° C for 2 hours, and triethylamine salt was filtered and washed with 100 ml of ethete. The ether portions were combined and washed with water (100 ml), brine (100 ml), dried over magnesium sulfate and evaporated in vacuo to give 39.6 g of mesylate as a yellow liquid.

b. 6-(4-메톡시페닐)-2-(2'-부틴일)-4,5-디히드로피리다지논b. 6- (4-methoxyphenyl) -2- (2'-butynyl) -4,5-dihydropyridazinone

실시예 6a의 방법과 실질적으로 동일한 방법에 따라서 6-(4-메톡시페닐)-4,5-디히드로피리다지논이 제조되고, 실시예 6b에 기술된 것과 실질적으로 동일한 방법에 따라서 메실레이트(11a)와 함께 알킬화되었다.6- (4-methoxyphenyl) -4,5-dihydropyridazinone is prepared according to the substantially same method as that of Example 6a, and mesylate according to the method substantially the same as that described in Example 6b. Alkylated with (11a).

3-페닐-2-프로핀-1-올, 3-펜틸-1-올, 2-헥신-1-올, 3-메틸-2-부틴-1-올, 3-t-부틸프로핀-1-올, 2-데킨-1-올, 또는 2-부틴-1-올로부터 선택된 적당한 알코올을 사용하여 적당한 메실레이트를 제조하고, 적당한 치환 디히드로피리다지논을 사용하여, 실질적으로 전술한 바와 동일한 방법에 따라서 화합물들 17, 21, 22, 24, 25, 29, 84, 85, 107, 132 및 137이 제조되었다. 화합물 138은 화합물 137의 제조중 반응 혼합물로부터 분리되었다.3-phenyl-2-propyn-1-ol, 3-pentyl-1-ol, 2-hexyn-1-ol, 3-methyl-2-butyn-1-ol, 3-t-butylpropyne-1 Proper mesylate is prepared using a suitable alcohol selected from -ol, 2-dekin-1-ol, or 2-butyn-1-ol, and using the appropriate substituted dihydropyridazinone, substantially the same as described above. Compounds 17, 21, 22, 24, 25, 29, 84, 85, 107, 132 and 137 were prepared according to the method. Compound 138 was isolated from the reaction mixture during the preparation of compound 137.

[실시예 12 : 6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 12 6- (4-Chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

예. 에틸 3-비스(디-t-부틸카르복시)프로피오네이트Yes. Ethyl 3-bis (di-t-butylcarboxy) propionate

12.5g(0.11몰)의 t-부톡시칼륨과 120ml의 t-부탄올의 용액에 20g의 디-t-부틸말로네이트를 실온에서 방울방울 첨가하였다. 고체 페이스트가 형성되어 교반이 어려웠다. 15분 후 실온에서 16.7g 의 에틸 브로모아세테이트를 방울방울 첨가하고 결과의 혼합물을 실온에서 하룻밤동안 교반하였다. 알코올을 진공하 제거하고 잔류물을 150ml의 물에 취하여 결과의 혼합물 에테르(3x80ml)로 추출하였다. 에테르 층들을 합하여 황산마그네슘으로 건조시키고 탈수시켰다. 잔류물을 쇼트 비그로(Vigreux)관을 통하여 증류시켰다. 125-135℃/1mm에서 비등하는 부분들을 수집하여 14.2g(51%)의 트리에스테르를 투명한 오일로서 산출하였다.20 g of di-t-butylmalonate was added dropwise at room temperature to a solution of 12.5 g (0.11 mol) of t-butoxy potassium and 120 ml of t-butanol. Solid paste was formed, making stirring difficult. After 15 minutes 16.7 g of ethyl bromoacetate was added dropwise at room temperature and the resulting mixture was stirred overnight at room temperature. The alcohol was removed in vacuo and the residue was taken up in 150 ml of water and extracted with the resulting mixture ether (3 × 80 ml). The ether layers were combined and dried over magnesium sulfate and dehydrated. The residue was distilled through a short Vigreux tube. Fractions boiling at 125-135 ° C./1 mm were collected to yield 14.2 g (51%) of ester as clear oil.

b. 에틸 3-(4-클로로페닐)-비스(디-t-부틸카르복시) 프로피오네이트b. Ethyl 3- (4-chlorophenyl) -bis (di-t-butylcarboxy) propionate

수소화나트륨(60% in 미네랄유, 240mg, 5mmoles)을 무수 디메틸포름아미드(20ml)내에 현탁시키고 0℃로 냉각시킨 혼합물에 에틸 3-비스(디-t-부틸카르복시)-프로피오네이트 91.51g, 5mmoles)를 방울방울 첨가하였다. 10분후 0℃에서 4-클로로벤조일 클로라이드(0.88g, 5mmoles)를 방울방울 첨가하고 결과의 현탁액을 0℃에서 30분동안 교반하였다. 반응 혼합물을 포화 염화암모늄 수용액(100ml)에 붓고 에테르 (3x80ml)로 추출하였다.91.51 g of ethyl 3-bis (di-t-butylcarboxy) -propionate in a mixture suspended in sodium hydride (60% in mineral oil, 240 mg, 5 mmoles) in anhydrous dimethylformamide (20 ml) and cooled to 0 ° C., 5 mmoles) were added dropwise. After 10 minutes 4-chlorobenzoyl chloride (0.88 g, 5 mmoles) was added dropwise at 0 ° C. and the resulting suspension was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride solution (100 ml) and extracted with ether (3 × 80 ml).

유기층들을 합하여 염수(3x100ml)로 세척하고, 건조 및 증발시켜 에틸 3-(4-클로로페닐)-3-비스(t-부틸카르복시)프로피오네이트를 산출하였다.The combined organic layers were washed with brine (3 × 100 ml), dried and evaporated to yield ethyl 3- (4-chlorophenyl) -3-bis (t-butylcarboxy) propionate.

c. 3-(4-클로로벤조일) 프로피온산c. 3- (4-chlorobenzoyl) propionic acid

상기 단계 b에서 수득된 화합물을 50ml의 톨루엔에 용해시키고 100mg의 p-톨루엔술폰산을 첨가하고, 결과의 용액을 하룻밤 동안 80-85℃로 가열하였다. 실온으로 냉각시킨 후, 반응 혼합물을 2% 중탄산나트륨 수용액으로추출하고, 건조 및 증발시켜 3-(4-클로로벤조일)프로피온산을 산출하였다.The compound obtained in step b was dissolved in 50 ml of toluene and 100 mg of p-toluenesulfonic acid was added and the resulting solution was heated to 80-85 ° C. overnight. After cooling to room temperature, the reaction mixture was extracted with 2% aqueous sodium bicarbonate solution, dried and evaporated to yield 3- (4-chlorobenzoyl) propionic acid.

d. 6-(4-클로로페닐)-4,5-디히드로피리다지논d. 6- (4-chlorophenyl) -4,5-dihydropyridazinone

3-(4-클로로벤조일)프로피온산(20g)과 무수에탄올 (200ml)의 용액에 5g의 히드라진 1수화물을 첨가하였다. 형성된 고체를 가열 용해시켰다. 결과의 용액을 3시간 동안 환류시키고 냉각시킨 다음, 형성된 고체를 여과 및 건조시켜 16g(80%)의 6-(4-클로로페닐)-4,5-디히드로피리다지논을 산출하였다.To a solution of 3- (4-chlorobenzoyl) propionic acid (20 g) and ethanol anhydride (200 ml) was added 5 g of hydrazine monohydrate. The solid formed was dissolved by heating. The resulting solution was refluxed for 3 hours and cooled, then the solid formed was filtered and dried to yield 16 g (80%) of 6- (4-chlorophenyl) -4,5-dihydropyridazinone.

e. 6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논e. 6- (4-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

(방법i)(Method i)

무수 DMF 내 수소화나트륨(NaH)(210mg, 60% in 미네랄유)의 현탁액에 DMF (30ml) 내 6-(4-클로로페닐)-4,5-디히드로피리다지논(1.0g)을 0℃에서 방울방울 첨가하였다. 기체 방출이 중지될 때가지 황색혼합물을 교반하였다. 혼합물에 1-브로모펜트-2-인90.8g)을 0℃에서 첨가하고 그온도에서 30분동안 유지시켰다. 반응 혼합물을 포화 염화암모늄 수용액(100ml)에 붓고, 에테르(3x100ml)로추출하였다. 유기층들을 합하여 염수(2x50ml)로 세척하고, 건조 및 증발시켰다. 오일 잔류물을 헥산과 함께 정제하여 밝은 황색고체인 산물을 산출하였다.To a suspension of sodium hydride (NaH) (210 mg, 60% in mineral oil) in anhydrous DMF was added 6- (4-chlorophenyl) -4,5-dihydropyridazinone (1.0 g) in DMF (30 ml) at 0 ° C. Droplets were added at. The yellow mixture was stirred until gas evolution ceased. 90.8 g of 1-bromopent-2-yne) was added to the mixture at 0 ° C. and held at that temperature for 30 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride solution (100 ml) and extracted with ether (3 × 100 ml). The combined organic layers were washed with brine (2x50ml), dried and evaporated. The oil residue was purified with hexanes to give the product as a light yellow solid.

(방법 ii)(Method ii)

1-브로모펜트-2-인(1.4g), 6-(4-클로로페닐)-4,5-디히드로피리다지논(1.0g), 톨루엔(150ml) 및 테트라부틸암모늄 수소 황산염(100mg)의 교반 혼합물에 50% 수성 NaOH(1.9g)을 방울방울 첨가하였다. 반응혼합물을 50℃에서 4시간 동안 연속교반하 가열한 다음 실온으로 냉각시키고 층분리시켰다. 유기층을 물로 여러번 세척하고 건조 및 탈수시켜 1.2g(91%)의 6-(4클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논을 백색 고체로서 산출하였다.1-bromopent-2-yne (1.4 g), 6- (4-chlorophenyl) -4,5-dihydropyridazinone (1.0 g), toluene (150 ml) and tetrabutylammonium hydrogen sulphate (100 mg) To a stirred mixture of 50% aqueous NaOH (1.9 g) was added dropwise. The reaction mixture was heated under continuous stirring at 50 ° C. for 4 hours, then cooled to room temperature and separated. The organic layer was washed several times with water, dried and dehydrated to yield 1.2 g (91%) of 6- (4chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone as a white solid. .

적당한 벤조일클로라이드를 출발물질로 사용하고 본 실시예에서 기술된 것과 동일한 방법에 따라 적당한 알킬할라이드 또는 메실레이트와 함께 아실화됨으로써 화합물들 32, 40, 41, 42, 57-66, 73, 78, 79, 82, 90, 91, 96-99, 103, 104, 144, 147 및 148이 제조되었다.Compounds 32, 40, 41, 42, 57-66, 73, 78, 79 by using a suitable benzoylchloride as starting material and acylating with a suitable alkyl halide or mesylate according to the same method as described in this example , 82, 90, 91, 96-99, 103, 104, 144, 147 and 148.

[실시예 15 : 6-(4-클로로페닐)-4,5-디히드로-2-t-부틸피리다지논]Example 15 6- (4-Chlorophenyl) -4,5-dihydro-2-t-butylpyridazinone

부탄올(150ml) 내 4-클로로벤조일크로피온산(4.24g)의 용액에 무수초산나트륨(1.54g)과 t=부틸히드라진 염화수소(2.75g)를 실온에서 조금씩 첨가하였다. 결과 혼합물을 9시간 동안 환류시켜 65ml의 n-부탄올을 증류배출시켰다. 결과의 혼합물을 냉각시키고 물(500ml)에 붓고 염화메틸렌(3x150ml)으로 추출하였다. 유기층들을 합하여 2% 수산화나트륨 수용액(3x100ml), 물(2x100ml), 2% 염산 수용액(3x100ml), 및 물(1x100ml)로 세척하고, 진공하 건조 및 증발시켜 1.71g 의 목적화합물을 산출하였다.Anhydrous sodium acetate (1.54 g) and t = butylhydrazine hydrogen chloride (2.75 g) were added in portions to a solution of 4-chlorobenzoylcroponic acid (4.24 g) in butanol (150 ml) at room temperature. The resulting mixture was refluxed for 9 hours to distill 65 ml of n-butanol. The resulting mixture was cooled down, poured into water (500 ml) and extracted with methylene chloride (3 × 150 ml). The combined organic layers were washed with 2% aqueous sodium hydroxide solution (3x100 ml), water (2x100 ml), 2% aqueous hydrochloric acid solution (3x100 ml), and water (1x100 ml), dried under vacuum and evaporated to yield 1.71 g of the target compound.

t-부틸히드라진 염화수소 대신 페닐히드라진 염화수소를 사용하고 상기 실시예와 동일한 방법에 따라서 화합물 14가 제조되었다.Compound 14 was prepared according to the same method as in Example and using phenylhydrazine hydrogen chloride instead of t-butylhydrazine hydrogen chloride.

[실시예 26 : 6-(4-클로로페닐)-5-메틸-2-(2'-부틴일)-4,5-디하이드로피리다지논]Example 26 6- (4-Chlorophenyl) -5-methyl-2- (2'-butynyl) -4,5-dihydropyridazinone

a. 2-메틸-3-(4-클로로벤조일)프로피온산a. 2-Methyl-3- (4-chlorobenzoyl) propionic acid

11.4g의 무수 메틸숙신산과 38.7g의 클로로벤젠의 혼합물에 30g의 염화알루미늄을 35℃이하에서 첨가한 다음, 반응 혼합물을 2시간 동안 60-70℃로 데우고, 냉각하고 500의 얼음에 조심스럽게 부었다.혼합물을 에테르(4x100ml)로 추출하였다. 유기층들을 합하여 물(2x100ml) 및 염수(2x100ml)로 세척하고, 무수 황산마그네슘으로 건조시키고 진공증발시켜, 방치하면 결정화되는 점성오일을 산출하였다. 고체를 여과하여 12.1g의 1-메틸-3-(4-클로로벤조일)프로피온산을 산출하였다. 비결정성 물질인 잔류물은 2-메틸-3-(4-클로로벤조일)프로피온산인 것으로 확인하였다.To a mixture of 11.4 g of methylsuccinic anhydride and 38.7 g of chlorobenzene, 30 g of aluminum chloride is added below 35 ° C., then the reaction mixture is warmed to 60-70 ° C. for 2 hours, cooled and carefully poured onto 500 ice cubes. The mixture was extracted with ether (4 × 100 ml). The combined organic layers were washed with water (2x100ml) and brine (2x100ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a viscous oil that crystallized upon standing. The solid was filtered to yield 12.1 g of 1-methyl-3- (4-chlorobenzoyl) propionic acid. The residue, being amorphous, was identified as 2-methyl-3- (4-chlorobenzoyl) propionic acid.

b. 6-(4-클로로페닐)-5-메틸-2-(2'-부틴일)-4,5-디하이드로피리다지논b. 6- (4-chlorophenyl) -5-methyl-2- (2'-butynyl) -4,5-dihydropyridazinone

단계 a로부터의 1-메틸-3-(4-클로로벤조일)프로피온산을 실시예 6에 기술된 바와 마찬가지로 반응시켜 화합물 26을 산출하였다.1-Methyl-3- (4-chlorobenzoyl) propionic acid from step a was reacted as described in Example 6 to yield compound 26.

상기 단계 a로부터의 2-메틸-3-(4-클로로벤조일)프로피온산을 사용하여 동일한 방법에 따라 화합물 27이 제조되었다.Compound 27 was prepared following the same method using 2-methyl-3- (4-chlorobenzoyl) propionic acid from step a above.

상기 단계 a에서 무수 메틸숙신산 대신 무수 퍼플루오로숙신산을 사용하고 동일한 방법에 따라 화합물 106이 제조되었다.Compound 106 was prepared according to the same method using perfluorosuccinic anhydride instead of methylsuccinic anhydride in step a.

[실시예 28 : 6-(3,4-디클로로페닐)-2-(2'-펜틴일)-4,5-디하이드로피리다지논]Example 28 6- (3,4-Dichlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 3,4-디클로로벤조일크로피온산a. 3,4-dichlorobenzoylcroponic acid

1, 2-디클로로벤젠(29.4g)과 무수숙신산(10g)의 혼합물에 무수 염화알루미늄(28.0g)을 실온에서 교반하면서 조금씩 첨가하였다. 결과의 혼합물을 80℃에서 6시간동안 가열하고 실온으로 냉각하고 얼음물(600g)에 부었다.Anhydrous aluminum chloride (28.0 g) was added little by little with stirring at room temperature to the mixture of 1, 2-dichlorobenzene (29.4g) and succinic anhydride (10g). The resulting mixture was heated at 80 ° C. for 6 hours, cooled to room temperature and poured into ice water (600 g).

수성 현탁액을 에틸에테르(4x150ml)로 추출하고, 유기층들을 합하여 물(2x 150ml)로 세척하고 건조 및 탈수시켰다. 오일성 고체 잔류물을 헥산-에테르(8: 2)로 정제하여 황색고체인 산물을 산출하였다.The aqueous suspension was extracted with ethyl ether (4 × 150 ml), the combined organic layers washed with water (2 × 150 ml), dried and dehydrated. The oily solid residue was purified by hexane-ether (8: 2) to yield the product as a yellow solid.

b. 6-(3,4-디클로로페닐)-(2'-펜틴일)-4,5-디하이드로피리다지논b. 6- (3,4-dichlorophenyl)-(2'-pentynyl) -4,5-dihydropyridazinone

실시예 12d, e에 기술된 것과 실질적으로 동일한 방법을 사용하여 3, 4-디클로로벤조일프로피온산을 목적산물로 전환시켰다.3, 4-dichlorobenzoylpropionic acid was converted to the desired product using substantially the same method as described in Example 12d, e.

근본적으로 동일한 방법을 사용하여 적당한 출발물질로부터 화합물들 23,135 및 136이 제조되었다.Compounds 23,135 and 136 were prepared from suitable starting materials using essentially the same method.

[실시예 30 : 6-(4-클로로페닐)-2-(2'-펜틴일)-4-페닐-4,5-디하이드로피리다지논]Example 30 6- (4-Chlorophenyl) -2- (2'-pentynyl) -4-phenyl-4,5-dihydropyridazinone]

100ml 무수에탄올내 3-(4-클로로벤조일)-2-페닐프로피오니트릴(0.037몰)의 용액에 10ml의 진한 황산을 조심스럽게 첨가하고 혼합물을 하룻밤 동안 환류 시켰다. 에탄을 진공제거하고 잔류물을 200ml의 에틸에테르에 용해시켰다. 에테르 용액을 물(2x100ml) 및 염수(100ml)로 세척한 다음, 무수 황산마그네슘으로 건조시키고 증발시켜 9.2g(79%)의 황색오일을 산출하였다. 케토에스테르를 실시예 11b-e(i)에 기술된 방법으로 반응시켜 목적 화합물을 수득하였다.To a solution of 3- (4-chlorobenzoyl) -2-phenylpropionitrile (0.037 mol) in 100 ml anhydrous ethanol was carefully added 10 ml of concentrated sulfuric acid and the mixture was refluxed overnight. The ethane was removed in vacuo and the residue was dissolved in 200 ml of ethyl ether. The ether solution was washed with water (2 × 100 ml) and brine (100 ml), then dried over anhydrous magnesium sulfate and evaporated to yield 9.2 g (79%) of yellow oil. The ketoester was reacted in the manner described in Example 11b-e (i) to afford the desired compound.

[실시예 33 : 6-(4-페녹시페닐)-2-(2'-펜틴일)-4,5-디하이드로피리다지논]Example 33 6- (4-Phenoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 1-브로모-2-부틴a. 1-bromo-2-butyne

2-부틴-1-올의 메실레이트를 실시예 11a에 기술된 바에 따라 제조하였다. 200ml의 무수 테트라하이드로 푸란과 27g의 메실레이트의 용액에 70g의 무수 브롬화리튬을 실온에서 조금씩 첨가하였다. 혼합물을 하룻밤 동안 실온에서 교반한 다음 250ml의 무수에테르에 붓고 물(2x100ml) 및 염수(2x100ml)로 세척하였다. 에테르 추출물을 무수 황산마그네슘으로 건조시키고 탈수시켜 21g의 1-브로모-2-부틴(황색액체)을 산출하였다.Mesylate of 2-butyn-1-ol was prepared as described in Example 11a. To a solution of 200 ml of anhydrous tetrahydrofuran and 27 g of mesylate, 70 g of anhydrous lithium bromide was added little by little at room temperature. The mixture was stirred overnight at room temperature and then poured into 250 ml of anhydrous ether and washed with water (2 × 100 ml) and brine (2 × 100 ml). The ether extract was dried over anhydrous magnesium sulfate and dehydrated to yield 21 g of 1-bromo-2-butyne (yellow liquid).

b. 6-(4-페녹시페닐)-2-(2'-펜틴일)-4,5-디하이드로피리다지논b. 6- (4-phenoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 6에 기술된 바와같이 상응하는 케토산으로부터 페녹시디히드로피리다지논을 제조하고 알킬화시켜 0.7g의 화합물 33을 황색 고체로서 산출하였다.Phenoxydihydropyridazinone was prepared and alkylated from the corresponding keto acid as described in Example 6 to yield 0.7 g of compound 33 as a yellow solid.

[실시예 34 : 6-(4-클로로페닐)-2-(3'-메틸-2'-부틴일)-4,5-디하이드로피리다지논]Example 34 6- (4-Chlorophenyl) -2- (3'-methyl-2'-butynyl) -4,5-dihydropyridazinone]

a . 3-메틸-2-부틴-1-올a. 3-methyl-2-butyn-1-ol

200ml의 무수 테트라하이드로푸란(THF)내 3-메틸-2-부틴의 용액을 -78℃로 냉각시키고 n-부틸리튬(0.160몰)을 60℃ 이하에서 방울방울 첨가하였다. -78℃에서 1시간 동안 교반한 다음, 파라포름알데히드(7g)를 용융가열시키고 시스템에 정압을 적용하여 포름알데히드 기권을 형성시킴에 의하여, 반응 혼합물내에 기체 포름알데히드를 도입시켰다. 반응혼합물을 1시간 동안 교반한 다음 실온까지 승온되도록 하고 100ml의 포화 염화암모늄용액으로 냉각시키고 에테르(3x100ml)로 추출하였다. 유기층을 합하여 염수(3x100ml)로세척하고, 황산마그네슘으로 건조하고 진공증발시켜 3-메틸-2-부틴-1-올을 60% 수율로 산출하였다.A solution of 3-methyl-2-butyne in 200 ml of anhydrous tetrahydrofuran (THF) was cooled to -78 ° C and n-butyllithium (0.160 moles) was added dropwise at 60 ° C or lower. After stirring at −78 ° C. for 1 hour, gaseous formaldehyde was introduced into the reaction mixture by melting and heating paraformaldehyde (7 g) and applying a static pressure to the system to form formaldehyde gas. The reaction mixture was stirred for 1 hour and then allowed to warm up to room temperature, cooled with 100 ml of saturated ammonium chloride solution and extracted with ether (3 × 100 ml). The combined organic layers were washed with brine (3 × 100 ml), dried over magnesium sulfate and evaporated in vacuo to yield 3-methyl-2-butyn-1-ol in 60% yield.

b. 6-(4-클로로페닐)-2-(3'-메틸-2'부틴일)-4,5-디하이드로피리다지논b. 6- (4-chlorophenyl) -2- (3'-methyl-2'butynyl) -4,5-dihydropyridazinone

실시예 11a에 기술된 바와 마찬가지 방법으로알코올을 메실화시키고 실시예 6a에 기술된 바와 마찬가지 방법으로 알킬화시켜1.1g의 화합물 34를 산출하였다.Alcohol was mesylated in the same manner as described in Example 11a and alkylated in the same manner as described in Example 6a, yielding 1.1 g of Compound 34.

단계 a에서 2-메틸-1-부틴 대신 이소프로필아세틸렌 또는 3, 3-디메틸-1-부틴을 사용하여, 동일한 방법에 따라 화합물들 45 및 46이 제조되었다. 프로파길 클로라이드와 에틸렌옥사이드로부터 1-클로로-5-히드록시-2-펜틴을 제조하고, 위에서와 실질적으로 동일한 방법에 따라 화합물 50이 제조되었다.Using isopropylacetylene or 3, 3-dimethyl-1-butyne instead of 2-methyl-1-butyne in step a, compounds 45 and 46 were prepared according to the same method. 1-Chloro-5-hydroxy-2-pentine was prepared from propargyl chloride and ethylene oxide, and compound 50 was prepared following substantially the same method as above.

[실시예 36 : 6-(4-클로로페닐)-2-(2'-티에닐페닐)-4,5-디하이드로피리다지논]Example 36 6- (4-Chlorophenyl) -2- (2'-thienylphenyl) -4,5-dihydropyridazinone

a. 2-클로로메틸티오펜a. 2-chloromethylthiophene

10g의 2-티오펜메탄올, 9.3g의 트리에틸아민과 250ml의 에테르의 용액을 5℃로 냉각시키고 11g 의 티오닐클로라이드를 방울방울 첨가하였다. 반응혼합물을 5-10℃에서 30분동안 교반한 다음 실온으로 승온시켰다. 침전고체를 걸러내고 에테르용액을 100ml의 0.1M 염산으로 세척하고 이어서 100ml의 염수로 세척하였다. 에테르 추출물을 황산마그네슘으로 건조시키고 진공증발시켜 목적 염화물을 75% 수율로 수득하였다.A solution of 10 g 2-thiophenmethanol, 9.3 g triethylamine and 250 ml ether was cooled to 5 ° C. and 11 g thionyl chloride were added dropwise. The reaction mixture was stirred at 5-10 ° C. for 30 minutes and then warmed to room temperature. The precipitated solid was filtered off and the ether solution was washed with 100 ml of 0.1 M hydrochloric acid followed by 100 ml of brine. The ether extract was dried over magnesium sulfate and evaporated in vacuo to afford the desired chloride in 75% yield.

b. 6-(4-클로로페닐)-2-(2'-티에닐메틸)-4,5-디하이드로피리다지논b. 6- (4-chlorophenyl) -2- (2'-thienylmethyl) -4,5-dihydropyridazinone

실시예 6b에 기술된 바와 실질적으로 동일한 방법에 따라, 6-(4-클로로페닐)-4, 5-디히드로피리다지논을 알킬화시키는데 염화물을 사용하여 화합물 36을 산출하였다.Compound 36 was calculated using chloride to alkylate 6- (4-chlorophenyl) -4, 5-dihydropyridazinone following substantially the same method as described in Example 6b.

[실시예 37 : 6-(3-클로로페닐)-2-(2'-부틴일)-4,5-디하이드로피리다지논]Example 37 6- (3-Chlorophenyl) -2- (2'-butynyl) -4,5-dihydropyridazinone

a. 3-(3-클로로벤조일)프로피온산a. 3- (3-chlorobenzoyl) propionic acid

나트륨(11g)을 200ml의 에탄올에 교반첨가하였다. 기체 방출이 정지되었을 때, 메틸 3-클로로벤조에이트(10g, 0.057몰)와 디메틸숙시네이트(9.0g, 0.615몰)를 재빨리 첨가하고, 혼합물을 실온에서 5분동안 교반하였다. 혼합물을 로타리탈수기에서 천천히 농축시켜 녹색페이스트를 산출하고, 이것을 100ml 에테르로 슬러리화시키고 부가적인 2ml의 디메틸숙시네이트를 첨가하였다. 반응 혼합물을 페이스트로 탈수시키고 물로 냉각시키고 에테르로 추출하엿다. 에테르 추출물을 물 및 염수로 세척하고, 건조 및 진공증발시켰다.Sodium (11 g) was added to 200 ml of ethanol with stirring. When gas evolution stopped, methyl 3-chlorobenzoate (10 g, 0.057 mol) and dimethylsuccinate (9.0 g, 0.615 mol) were added quickly and the mixture was stirred at room temperature for 5 minutes. The mixture was slowly concentrated in a rotary dehydrator to yield a green paste, which was slurried with 100 ml ether and additional 2 ml of dimethylsuccinate was added. The reaction mixture was dehydrated into paste, cooled with water and extracted with ether. The ether extract was washed with water and brine, dried and evaporated in vacuo.

잔류물로부터 출발물질을 증류시키고, 남은 물질을 6N 황산내에서 2일간 환류시켜 1.6g의 목적 케토산을 산출하였다.The starting material was distilled from the residue and the remaining material was refluxed in 6N sulfuric acid for 2 days to yield 1.6 g of the desired keto acid.

b. 6-(3-클로로페닐)-2-(2'-부틴일)-4,5-디하이드로피리다지논b. 6- (3-chlorophenyl) -2- (2'-butynyl) -4,5-dihydropyridazinone

단계 a로 부터의 케토산을 실시예 6a 및 6b에 기술된 바와 마찬가지로 반응시켜 0.75g의 화합물 37을 황갈색 고체로서 산출하였다.Keto acid from step a was reacted as described in Examples 6a and 6b to yield 0.75 g of compound 37 as a tan solid.

메틸 3-클로로벤조에이트 대신 3,5-디클로로벤조에이트 또는 에틸 2-티오펜카르복실레이트를 사용하고 상기한 바와 동일한 방법을 사용하여 화합물 38 및 140이 제조되었다.Compounds 38 and 140 were prepared using 3,5-dichlorobenzoate or ethyl 2-thiophenecarboxylate instead of methyl 3-chlorobenzoate and using the same method as described above.

[실시예 39 : 6-(4-클로로-3-니트로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 39 6- (4-Chloro-3-nitrophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 4-클로로-3-니트로벤조일 프로피온산a. 4-Chloro-3-nitrobenzoyl propionic acid

발연질산(150ml)에 0℃에서 p=클로로벤조일프로피온산(20.0g)을 서서히 조금씩 첨가한 후, 결과의 혼합물을 0℃에서 30분간 교반하였다. 결과의 백색 고체를 석션 여과하고세척 액체의 pH가 중성으로 될 때까지 물로 세척한 다음 건조시켜 3-(4-클로로-3-니트로벤조일)프로피온산을 백색고체(13.0g)로서 산출하였다.P = chlorobenzoylpropionic acid (20.0 g) was gradually added to fuming nitric acid (150 ml) at 0 ° C., and the resulting mixture was stirred at 0 ° C. for 30 minutes. The resulting white solid was suction filtered, washed with water until the pH of the wash liquid became neutral and dried to yield 3- (4-chloro-3-nitrobenzoyl) propionic acid as a white solid (13.0 g).

b. 6-(4-클로로-3-니트로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (4-chloro-3-nitrophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 6a-b에서와 마찬가지 방법을 사용하여 단계 a로부터의 4-클로로-3-니트로벤조일프로피온산을 목적화합물로 전환시켰다.The same procedure as in Examples 6a-b was used to convert 4-chloro-3-nitrobenzoylpropionic acid from step a to the desired compound.

[실시예 44 : 6-(3,5-디클로로-4-메틸페닐-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 44 6- (3,5-Dichloro-4-methylphenyl-2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 3-(3,5-디클로로-4-메틸벤조일)프로피온산a. 3- (3,5-dichloro-4-methylbenzoyl) propionic acid

3-(4-메틸벤조일)프로피온산(7.5g)과 염화메틸렌(250ml)의 혼합물에 염화알루미늄(15g)을 0℃에서 서서히 조금씩 첨가하였다. 첨가완료후 염소기체가 0℃에서 서서히 포말되었다. 6시간후 반응 혼합물을 염산과 얼음의 혼합물에 붓고 염화메틸렌(3x150ml)으로 추출하였다. 유기층들을 합하여 물로 세척하고, 건조 및 진공 증발시켜 3-(3,5-디클로로-4-메틸변조일)프로피온산(황색고체, 4.5g)을 산출하였다.To the mixture of 3- (4-methylbenzoyl) propionic acid (7.5 g) and methylene chloride (250 ml) was added aluminum chloride (15 g) slowly at 0 ° C. After completion of the addition, the chlorine gas was slowly foamed at 0 ° C. After 6 hours the reaction mixture was poured into a mixture of hydrochloric acid and ice and extracted with methylene chloride (3x150 ml). The combined organic layers were washed with water, dried and evaporated in vacuo to yield 3- (3,5-dichloro-4-methylmodylyl) propionic acid (yellow solid, 4.5 g).

b. 6-(3,5-디클로로페닐-4-메틸페닐-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (3,5-dichlorophenyl-4-methylphenyl-2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 6a-b에서와 마찬가지 방법을 사용하여, 단계 a로부터의 3-(3,5-디클로로-4-메틸벤조일)프로피온산을 목적 화합물로 전환시켰다. 실질적으로 동일한 방법에 따라서 화합물 43이 제조되었다.Using the same method as in Examples 6a-b, 3- (3,5-dichloro-4-methylbenzoyl) propionic acid from step a was converted to the desired compound. Compound 43 was prepared following substantially the same method.

[실시예 47 : 6-(4-클로로페닐)-2-(4'-히드록시-2'-펜틴일)-4,5-디히드로피리다지논]Example 47 6- (4-Chlorophenyl) -2- (4'-hydroxy-2'-pentynyl) -4,5-dihydropyridazinone]

a. 2-히드록시-5-요오드-3-펜틴a. 2-hydroxy-5-iodine-3-pentine

실시예 34a에 기술된 것처럼, 프로파길 클로라이드를 아세트알데히드 및 n-부틸리듐과 함께 히드록시에틸화시켰다.As described in Example 34a, propargyl chloride was hydroxyethylated with acetaldehyde and n-butyliridium.

100ml의 무수아세톤내 2-히드록시-5-클로로-3-펜틴(2.0g)과 무수 요오드화 나트륨(12.6g)의 용액을 실온에서 하룻밤동안 교반하였다. 아세톤을 진공증발시키고 잔류물을 에테르(2x100ml)로 추출하였다. 에테르 추출물을 물(2x100ml) 및 염수(100ml)로 세척하고, 건조 및 진공증발시켜 목적요오드 화합물을 적색 액체로서 산출하였다.A solution of 2-hydroxy-5-chloro-3-pentine (2.0 g) and anhydrous sodium iodide (12.6 g) in 100 ml anhydrous acetone was stirred overnight at room temperature. Acetone was evaporated in vacuo and the residue was extracted with ether (2 × 100 ml). The ether extract was washed with water (2 × 100 ml) and brine (100 ml), dried and evaporated to yield the desired iodine compound as a red liquid.

b. 6-(4-클로로페닐)-2-(4'-히드록시-2'-펜틴일)-4,5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- (4'-hydroxy-2'-pentynyl) -4,5-dihydropyridazinone

2당량의 수소화나트륨이 사용되고 반응혼합물이 추출전 pH 5로 산성화되는 것을 제외하고는 실시예 6b에서와 마찬가지 방법을 사용하여, 요오드 화합물로부터 목적화합물을 산출하였다.The target compound was calculated from the iodine compound using the same method as in Example 6b except that 2 equivalents of sodium hydride were used and the reaction mixture was acidified to pH 5 before extraction.

[실시예 48 : 6-(4-클로로페닐)-2-(4'-메톡시-2'-펜틴일)-4,5-디히드로피리다지논]Example 48 6- (4-Chlorophenyl) -2- (4'-methoxy-2'-pentynyl) -4,5-dihydropyridazinone]

100mg의 화합물 47과 20ml의 무수에탄올의 용액에 4ml의 티오닐클로라이드를 25분간걸쳐 방울방울 첨가하였다. 첨가완료후, 메탄올 용액을 증발 건조시키고 잔류물을 100ml의 에테르에 용해시키고, 100ml의 물 및 100ml의 염수로 세척한 다음, 건조 및 진공증발시켜 100mg 의 화합물 48(황색오일)을 산출하였다.To a solution of 100 mg of compound 47 and 20 ml of anhydrous ethanol, 4 ml of thionyl chloride was added dropwise over 25 minutes. After completion of the addition, the methanol solution was evaporated to dryness and the residue was dissolved in 100 ml of ether, washed with 100 ml of water and 100 ml of brine, then dried and evaporated to yield 100 mg of compound 48 (yellow oil).

동일한 방법을 사용하여 화합물 54로부터 화합물 55를 산출하였다.Compound 55 was calculated from compound 54 using the same method.

[실시예 49 : 6-(4-클로로페닐)-2-(4'-아세톡시-2'-펜틴일)-4,5-디히드로피리다지논]Example 49 6- (4-Chlorophenyl) -2- (4'-acetoxy-2'-pentynyl) -4,5-dihydropyridazinone]

100mg의 화합물 47과 50ml 의 염화메틸렌의 용액에 54mg의 피리딘과 69mg의 무수아세트산을 첨가하였다. 반응 혼합물을 하룻밤 동안 교반하고 증발 건조시켰다. 잔류물을 200ml의 에테르에 용해시키고, 100ml의 물 및 100ml의 염수로 세척하고, 황산마그네슘으로 건조시키고 증발시켜 100mg의 화합물 49(무색오일)를 산출하였다.54 mg of pyridine and 69 mg of acetic anhydride were added to a solution of 100 mg of compound 47 and 50 ml of methylene chloride. The reaction mixture was stirred overnight and evaporated to dryness. The residue was dissolved in 200 ml of ether, washed with 100 ml of water and 100 ml of brine, dried over magnesium sulfate and evaporated to yield 100 mg of compound 49 (colorless oil).

[실시예 51 : 6-(4-클로로페닐)-2-(5'-플루오로-2'-펜틴일)-4,5-디히드로피리다지논]Example 51 6- (4-Chlorophenyl) -2- (5'-fluoro-2'-pentynyl) -4,5-dihydropyridazinone]

120mg의 화합물 50과 50ml의 염화메틸렌의 용액을 0℃로 냉각시키고 130mg의 디에틸아미노술퍼트리플루오라이드(DAST)와 15ml의 염화메틸렌의 용액을 방울방울 첨가하였다. 반응혼합물을 0-5℃에서 1시간 동안, 실온에서 하룻밤동안 교반한 다음 100ml의 염수로 냉각시키고, 염화메틸렌(2x100ml)으로 추출하였다. 유기층들을 합하고 염수로 세척하고 건조시켜 수득한 황색 오일을 50g의 실리카 상에서 크로마토그라피(50/50 에틸아세테이트/헥산)시켜 60mg의 화합물 51을 산출하였다.A solution of 120 mg of compound 50 and 50 ml of methylene chloride was cooled to 0 ° C., and a solution of 130 mg of diethylaminosulfur trifluoride (DAST) and 15 ml of methylene chloride was added dropwise. The reaction mixture was stirred at 0-5 ° C. for 1 hour at room temperature overnight and then cooled with 100 ml brine and extracted with methylene chloride (2 × 100 ml). The organic layers were combined, washed with brine and dried, and the yellow oil obtained was chromatographed (50/50 ethyl acetate / hexanes) on 50 g of silica to yield 60 mg of compound 51.

실질적으로 동일한 방법에 따라서, 화합물을 47 및 88로부터 화합물들 53 및 89를 제조하였다.According to substantially the same method, compounds 53 and 89 were prepared from 47 and 88.

[실시예 54 : 6-(4-클로로페닐)-2-(3'-카르복시-2'-프로핀일)-4,5-디히드로피리다지논]Example 54 6- (4-Chlorophenyl) -2- (3'-carboxy-2'-propynyl) -4,5-dihydropyridazinone]

a. 3-카르복시프로파길 클로라이드a. 3-carboxypropargyl chloride

10g의 프로파길 클로라이드와 200ml의 무수 에테르의 용액을 -70℃로 냉각시키고 100ml의 메틸리튬(헥산내 1.4M용액)을 30분내에 방울방울 첨가하였다. 반응 혼합물을 이산화탄소 기권하 -60℃에서 45분동안 교반한 다음 천천히 실온으로 데우고, 100ml의 염수로 냉각시키고 pH 5로 산성화시키고 에테르(3x100ml)로 추출하였다. 에테르층들을 합하여 100ml의 물 및 100ml의 염수로 세척하고 황산마그네슘으로 건조시키고 증발시켜 얻은 암갈색 액체를 분별증류(187-190℃, 0.4mmHg) 시켜 2.6g의 목적 산을 산출하였다.A solution of 10 g propargyl chloride and 200 ml of anhydrous ether was cooled to −70 ° C. and 100 ml of methyllithium (1.4M solution in hexane) were added dropwise within 30 minutes. The reaction mixture was stirred for 45 min at −60 ° C. under carbon dioxide and then slowly warmed to room temperature, cooled with 100 ml of brine, acidified to pH 5 and extracted with ether (3 × 100 ml). The ether layers were combined, washed with 100 ml of water and 100 ml of brine, dried over magnesium sulfate, and evaporated to a dark brown liquid obtained by fractional distillation (187-190 ° C., 0.4 mmHg) to yield 2.6 g of the desired acid.

b. 6-(4-클로로페닐)-2-(3'-카르복시-2'-프로펜일)-4,5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- (3'-carboxy-2'-propenyl) -4,5-dihydropyridazinone

화합물 47에 대하여 기술한 바와 실질적으로 마찬가지인 방법을 사용하여 단계 a의 산으로부터 화합물 54(황갈색고체)가 산출되었다.Compound 54 (tan solid) was obtained from the acid of step a using a method substantially the same as described for compound 47.

[실시예 56 : 6-(4-클로로페닐)-2-(3'-비닐-2'-프로핀일)-4,5-디히드로피리다지논]Example 56 6- (4-Chlorophenyl) -2- (3'-vinyl-2'-propynyl) -4,5-dihydropyridazinone]

1.0g의 화합물 6, 0.62g의 요오드화비닐 및 100ml의 트리에틸아민의 용액을 질소로 탈기시키고 50mg의 요오드화구리(I) 및 50mg의 비스-트리페닐포스핀 팔라듐 디클로라이드를 첨가하였다. 50℃에서 하룻밤동안 교반한후 트리에틸아민을 증발시키고, 잔류물을 150ml의 에테르에 용해시키고 10g의 실리카에 통과시킨후 증발시켜 1.0g의 화합물 56(황색오일)을 산출하였다.A solution of 1.0 g of compound 6, 0.62 g of vinyl iodide and 100 ml of triethylamine was degassed with nitrogen and 50 mg of copper iodide (I) and 50 mg of bis-triphenylphosphine palladium dichloride were added. After stirring at 50 ° C. overnight, triethylamine was evaporated and the residue was dissolved in 150 ml of ether, passed through 10 g of silica and evaporated to yield 1.0 g of compound 56 (yellow oil).

실질적으로 동일한 방법에 따라서, 적당한 출발물질을 사용하고 요오드화 비닐 대신 2-요오드티오펜,1-클로로-4-요오드벤젠 또는 요오드플루오로에틸렌을 사용하여, 화합물들 67, 68, 78 및 119가 제조되었다. 화합물 70은 화합물 69 및 3-메틸부틴으로부터 제조되었다.According to substantially the same method, compounds 67, 68, 78 and 119 were prepared using a suitable starting material and using 2-iodinethiophene, 1-chloro-4-iodinebenzene or iodinefluoroethylene instead of vinyl iodide. It became. Compound 70 was prepared from compound 69 and 3-methylbutyne.

[실시예 72 : 6-(4-클로로페닐)-2-(4'-클로로-2'-부틴일)-4,5-디히드로피리다지논]Example 72 6- (4-Chlorophenyl) -2- (4'-chloro-2'-butynyl) -4,5-dihydropyridazinone]

100ml의 톨루엔내 2.5g의 6-(4-클로로페닐)-4,5-디히드로피리다지논의 용액에 100mg의 테트라부틸암모늄 수소 황산염을 첨가하고, 재빨리 교반하면서 4.7g의 50% 수산화나트륨 수용액을 첨가하였다. 그 다음, 50ml의 톨루엔내 1, 4-디클로로-2-부틴(7.4g)을 방울방울 첨가하고 반응 혼합물을 4시간 동안 50-60℃로 가열하였다. 반응혼합물을 냉각시키고 200ml의 물에 부었다. 유기상을 분리하고, 수성상을 에테르(2x100ml)로 추출하였다. 유기층들을 합하여 100ml의 물 및 100ml의 염수로 건조시키고, 황산마그네슘으로 건조시키고 증발시켜 조산물(crude product)을 산출하였다. 이 조산물을 크로마토그라피시켜 1.9g의 화합물72를 산출하였다.To a solution of 2.5 g of 6- (4-chlorophenyl) -4,5-dihydropyridazinone in 100 ml of toluene was added 100 mg of tetrabutylammonium hydrogen sulfate, and 4.7 g of 50% aqueous sodium hydroxide solution was quickly stirred. Added. Then, 1, 4-dichloro-2-butyne (7.4 g) in 50 ml of toluene was added dropwise and the reaction mixture was heated to 50-60 ° C. for 4 hours. The reaction mixture was cooled down and poured into 200 ml of water. The organic phase was separated and the aqueous phase extracted with ether (2x100 ml). The combined organic layers were dried over 100 ml of water and 100 ml of brine, dried over magnesium sulfate and evaporated to yield a crude product. This crude product was chromatographed to yield 1.9 g of compound 72.

출발물질로 6(4-클로로-3-플루오로페닐)피리다지논을 사용하고 수산화나트륨 대신 분말 수산화칼륨을 사용하여, 실질적으로 동일한 방법에 따라서 화합물 128이 제조되었다. 실시예 33에 기술된 1-브로모-2-펜틴-4-엔으로부터 제조된 메실레이트를 사용하여 실질적으로 동일한 방법에 따라서 화합물 100이 제조되었다.Compound 128 was prepared following substantially the same method using 6 (4-chloro-3-fluorophenyl) pyridazinone as starting material and powdered potassium hydroxide instead of sodium hydroxide. Compound 100 was prepared following substantially the same method using mesylate prepared from 1-bromo-2-pentin-4-ene as described in Example 33.

[실시예 74 : 6-(4-클로로-3-플루오로페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논]Example 74 6- (4-Chloro-3-fluorophenyl) -2- (2'-pentynyl) -4, 5-dihydropyridazinone]

방법 AMethod A

a. 4-클로로-3-플루오로벤조산a. 4-Chloro-3-fluorobenzoic acid

(방법 i )(Method i)

0.7그램원자(17.0g)의 마그네슘 조각들을 100ml의 무수 에틸에테르로 감싸고, 0.05몰(0.95g)의 1, 2-디브로모에탄을 그것이 에테르와는 섞이지 않으나 마그네슘과는 접촉하는 방식으로 플라스크 측면에서 첨가하였다. 마그네슘 조각들 주위에 기포가 형성되고 에테르가 뿌옇게 되어질 때까지, 혼합물을 교반없이 방치시켰다. 그다음, 혼합물을 교반하고 온화하게 환류될 정도로 가열하면서 500ml의 무수에테르내 0.62몰(130.0g)의 4-클로로-3-플루오로브로모벤젠을 플라스크에 첨가하였다. 할로겐화물의 첨가 완료후 30분 동안 환류가열 및 교반을 계속하였다.Wrap 0.7 gram atoms (17.0 grams) of magnesium with 100 ml of anhydrous ethyl ether and 0.05 mole (0.95 grams) of 1,2-dibromoethane on the side of the flask in such a way that it is not mixed with ether but in contact with magnesium. Was added. The mixture was left without stirring until bubbles formed around the magnesium pieces and the ether became cloudy. Next, 0.62 mole (130.0 g) of 4-chloro-3-fluorobromobenzene in 500 ml of anhydrous ether was added to the flask while the mixture was stirred and heated to mild reflux. Reflux heating and stirring were continued for 30 minutes after the addition of the halide was completed.

반응혼합물을 -10℃로 냉각시키고 건조 CO가 -2℃이하에서 포말되었다.The reaction mixture was cooled to −10 ° C. and dry CO was bubbled below −2 ° C.

냉각 혼합물에 150ml의 25% HCl을 0℃에서 첨가하였다. 층들을 분리시키고, 수성층을 에테르(3x150ml)로 세척하였다. 유기층들을 합하여 물(2x200ml)로 세척하고, 건조 및 증발시켜 98%(91%수율)의 목적 화합물(백색고체)를 산출하였다.150 ml of 25% HCl was added at 0 ° C. to the cold mixture. The layers were separated and the aqueous layer was washed with ether (3 × 150 ml). The combined organic layers were washed with water (2 × 200 ml), dried and evaporated to yield 98% (91% yield) of the desired compound (white solid).

(방법 ii )(Method ii)

110g의 98% HSO와 192g(0.97몰)의 4-클로로-3-플루오로벤조트리플루오라이드를 교반한 다음 플라오르화 수소 방출이 개시될 때(약 130℃)까지 조심스럽게 가열하였다. 반응혼합물을 17시간 동안 130-135℃로 가열하고 1Kg의 얼음에부었다. 결과의 백색 침전을 여과하고, 세척액의 pH가 중성으로 될 때까지물로 세척한 다음, 침전을 건조시켜 165g(9.8% 수율)의 목적 산(백색고체)를 산출하였다.110 g of 98% HSO and 192 g (0.97 moles) of 4-chloro-3-fluorobenzotrifluoride were stirred and then heated carefully until hydrogen fluoride release was initiated (about 130 ° C.). The reaction mixture was heated to 130-135 ° C. for 17 hours and poured onto 1 kg of ice. The resulting white precipitate was filtered, washed with water until the pH of the wash solution became neutral, and the precipitate was dried to yield 165 g (9.8% yield) of the desired acid (white solid).

b. 6-(4-클로로-3-플루오로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (4-chloro-3-fluorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

4-클로로-3-플루오로벤조산은 표준방법들에 의하여 상응하는 산 클로라이드로 전환되었다. 목적 화합물은 실시예 11b-e에서와 마찬가지 방법에 따라 제조되었다.4-Chloro-3-fluorobenzoic acid was converted to the corresponding acid chloride by standard methods. The desired compound was prepared according to the same method as in Example 11b-e.

방법 BMethod B

a. 4-클로로-3-플루오로벤조일프로피온산a. 4-Chloro-3-fluorobenzoylpropionic acid

테트라하이드로푸란(60ml) 내 무수숙신산(6.0g)의 용액에, 상기 단계 a의 방법을 사용하여 1.5g(0.062몰)의 마그네슘 조각들 및 10.5g(0.05몰)의 1-브로모-4-클로로-3-플루오로벤젠으로부터 제조된 Grignard를 방울방울 첨가하였다. 첨가가 완료되었을 때, 결과의 현탁액을 45℃에서 2시간동안 교반한 후 물(100ml)을 천천히 첨가하고, 결과의 혼합물을 진한 염산을사용하여 pH=1로 산성화시켰다. 에테르층을 분리하고 5% 수산화나트륨 수용액(3x100ml)로 추출하였다. 수용액들을 합하여 에테르(1x100ml)로 세척하고, 염기성 수성층들을 합하여 진한 황산으로 산성화(pH=1)시키고 에틸아세테이트(3x150ml)로 추출하였다. 유기추출물을 합하여 물(1x150ml) 및 염수(1x150ml)로 세척하고, 무수황산마그네슘으로 건조시키고 진공증발시켜 7.1g(62%수율)의 목적산물(황색 오렌지색고체)을 수득하였다. 결과 산출된 산을 실시예 11d-e의 방법을 사용하여 목적화합물로 전환시켰다.To a solution of succinic anhydride (6.0 g) in tetrahydrofuran (60 ml), 1.5 g (0.062 mole) magnesium pieces and 10.5 g (0.05 mole) 1-bromo-4- using the method of step a above Droplets of Grignard prepared from chloro-3-fluorobenzene were added. When the addition was complete, the resulting suspension was stirred at 45 ° C. for 2 hours, then water (100 ml) was added slowly and the resulting mixture was acidified to pH = 1 with concentrated hydrochloric acid. The ether layer was separated and extracted with 5% aqueous sodium hydroxide solution (3 × 100 ml). The combined aqueous solutions were washed with ether (1 × 100 ml), the combined basic aqueous layers were acidified with concentrated sulfuric acid (pH = 1) and extracted with ethyl acetate (3 × 150 ml). The combined organic extracts were washed with water (1x150ml) and brine (1x150ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 7.1 g (62% yield) of the desired product (yellow orange solid). The resulting acid was converted to the target compound using the method of Example 11d-e.

실질적으로 동일한 방법에 따라 화합물 83이 제조되었다.Compound 83 was prepared following substantially the same method.

[실시예 76 : 6-(4-클로로페닐)-2-(4'-플루오로-2'-부틴일)-4,5-디히드로피리다지논]Example 76 6- (4-Chlorophenyl) -2- (4'-fluoro-2'-butynyl) -4,5-dihydropyridazinone]

a. 4-테트라히드로피란옥시-2-부틴-1-올a. 4-tetrahydropyranoxy-2-butyn-1-ol

5.0g의 2-부틴-1,4-디올,10mg의 p-톨루엔술폰산 및 150ml의 무수에테르의 혼합물에 4.9g의 3, 4-디히드로-2H-피란을 실온에서 방울방울 교반첨가하였다. 상온에서 하룻밤동안 교반한 다음 에테르를 증발시키고 잔류물을 200ml의 물에 부었다. 수용액을 헥산(2x100ml)으로 추출한다음 에테르(3x100ml)로 재추출하였다. 에테르 추출물을 합하여 100ml 의 염수로 세척하고, 황산 마그네슘으로 건조시키고 증발시켜 6.8g의 4-테트라히드로피란옥시-2-부틴-1-올을 산출하였다.To a mixture of 5.0 g of 2-butyne-1,4-diol, 10 mg of p-toluenesulfonic acid and 150 ml of anhydrous ether, 4.9 g of 3,4-dihydro-2H-pyran was added dropwise with stirring at room temperature. After stirring overnight at room temperature, the ether was evaporated and the residue was poured into 200 ml of water. The aqueous solution was extracted with hexane (2x100ml) and then reextracted with ether (3x100ml). The combined ether extracts were washed with 100 ml brine, dried over magnesium sulfate and evaporated to yield 6.8 g of 4-tetrahydropyranoxy-2-butyn-1-ol.

b. 6-(4-클로로페닐)-2-(4'-히드록시-2'-부틴일)-4,5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- (4'-hydroxy-2'-butynyl) -4,5-dihydropyridazinone

실시예 11a에서와 마찬가지 방법을 사용하여 알코올을 메실레이트로 전환시키고, 실시예 6a에서와 마찬가지 방법에 따라서 메실레이트가 알킬화에 사용되었다. 결과의 화합물을 100ml의 메탄올에 용해시켰다. Amberlite IR20(2.0g)수지를 10ml의 메탄올로 세척하고 반응혼합물에 첨가하였다. 1시간동안 교반후, 수지를 걸러내고 메탄올을 증발시켰다. 오일상 잔류물을 헥산으로 정제하여 1.3g의 목적알코올을 황갈색 고체로서 수득하였다.The alcohol was converted to mesylate using the same method as in Example 11a and mesylate was used for alkylation according to the same method as in Example 6a. The resulting compound was dissolved in 100 ml of methanol. Amberlite IR20 (2.0 g) The resin was washed with 10 ml of methanol and added to the reaction mixture. After stirring for 1 hour, the resin was filtered off and the methanol was evaporated. The oily residue was purified with hexane to give 1.3 g of the desired alcohol as a tan solid.

c. 6-(4-클로로페닐)-2-(4'-플루오로-2'-부틴일)-4,5-디히드로피리다지논c. 6- (4-chlorophenyl) -2- (4'-fluoro-2'-butynyl) -4,5-dihydropyridazinone

상기 단계 b로부터의 알코올을 실시예 51에서와 마찬가지 방법에 따라 DAST와 함께 처리하였다. 비정제산물을 실리카겔 크로마토그라피(50: 50헥산/에틸아세테이트)로 처리하여 300mg의 화합물 76을 담황색 고체로서 수득하였다.The alcohol from step b was treated with DAST according to the same method as in Example 51. The crude product was treated with silica gel chromatography (50: 50 hexanes / ethyl acetate) to afford 300 mg of compound 76 as a pale yellow solid.

[실시예 77 : 6-(4-클로로페닐)-2-에폭시메틸-4,5-디히드로피리다지논]Example 77 6- (4-Chlorophenyl) -2-epoxymethyl-4,5-dihydropyridazinone]

1.0g의 화합물 56과 50ml의 염화메틸렌의 혼합물에 1.3g의 m-클로로벤조산을 실온에서 조금씩 첨가하였다. 반응 혼합물을 상온에서 밤새 교반하고 100ml의 염화 메틸렌에 부은 다음, 포화 아황산수소나트륨(2x100ml), 염수(100ml)로 세척하고, 황산마그네슘으로 건조시키고 증발시켜 얻은 잔류물을 실리카 상에서 크로마토그라피 50 : 50 에틸아세테이트/헥산)시켜 350mg의 화합물 77(백색고체)을 산출하였다.To a mixture of 1.0 g of compound 56 and 50 ml of methylene chloride was added 1.3 g of m-chlorobenzoic acid in portions at room temperature. The reaction mixture was stirred at room temperature overnight and poured into 100 ml of methylene chloride, washed with saturated sodium hydrogen sulfite (2x100 ml), brine (100 ml), dried over magnesium sulfate and evaporated to give a residue on silica 50:50. Ethyl acetate / hexane) yielded 350 mg of compound 77 (white solid).

[실시예 86 : 6-(4-클로로페닐)-2-(4'-트리메틸실릴-2'-부틴일)-4,5-디히드로피리다지논]Example 86 6- (4-Chlorophenyl) -2- (4'-trimethylsilyl-2'-butynyl) -4,5-dihydropyridazinone]

실시예 11a 및 33a에서와 마찬가지 방법에 따라서 트리메틸실릴 프로파길 알코올의 브로마이드가 제조되었다. 300ml의 무수테트라하이드로푸란과 4.8g의 수소화나트륨(60% in oil)의 혼합물에 200ml의 테트라하이드로푸란에 용해된 25g의 6-(4-클로로페닐)-4, 5-디히드로피리다지논을 첨가하였다. 수소기체방출이 정지되었을 때, 용매를 진공제거시켰다. 결과의 고체를 헥산내에 슬러리화시키고 여과시켜 27.4g의 나트륨염을 백색의 비흡습고체로서 산출하였다.A bromide of trimethylsilyl propargyl alcohol was prepared according to the same method as in Examples 11a and 33a. In a mixture of 300 ml of anhydrous tetrahydrofuran and 4.8 g of sodium hydride (60% in oil), 25 g of 6- (4-chlorophenyl) -4, 5-dihydropyridazinone dissolved in 200 ml of tetrahydrofuran was added. Added. When hydrogen gas evolution stopped, the solvent was removed in vacuo. The resulting solid was slurried in hexane and filtered to yield 27.4 g of sodium salt as a white, non-hygroscopic solid.

50ml의 디메틸포름아미드내 1.0g의 나트륨염의 용액을 5℃로 냉각시키고 0.9g의 1-브로모-3-트리메틸실릴-2-프로핀을 방울방울 첨가하였다. 5℃에서 30분간 교반한 후 반응 혼합물을 실온으로 데우고, 100ml의 물로 냉각시키고 에테르(3x100ml)로 추출하였다. 에테르 추출물을 합하여 100ml의 물 및 100ml의 염수로 세척하고 황산마그네슘으로 건조시키고 증발시켜 비정제 산물을 수득하였다. 이 비정제 산물을 실리카겔크로마토그라피(30: 70 에틸아세테이트/헥산) 처리하여 0.5g의 화합물86(백색고체)을 산출하였다.A solution of 1.0 g sodium salt in 50 ml of dimethylformamide was cooled to 5 ° C. and 0.9 g of 1-bromo-3-trimethylsilyl-2-propine was added dropwise. After 30 min stirring at 5 ° C., the reaction mixture was warmed to rt, cooled with 100 ml of water and extracted with ether (3 × 100 ml). The combined ether extracts were washed with 100 ml of water and 100 ml of brine, dried over magnesium sulfate and evaporated to afford the crude product. This crude product was treated with silica gel chromatography (30: 70 ethyl acetate / hexane) to yield 0.5 g of Compound 86 (white solid).

실질적으로 동일한 알킬화 방법 및 2-옥틴-1-올의 메실레이트 또는 2, 4-펜타디인-1-올(실시예 93)의 메실레이트를 사용하여 화합물 96 및 124가 제조되었다.Compounds 96 and 124 were prepared using substantially the same alkylation method and mesylate of 2-octin-1-ol or mesylate of 2,4-pentadiin-1-ol (Example 93).

3-클로로벤질 브로마이드와 함께 알킬화되는 6-(4-클로로페닐)피리다지논의 나트륨염을 형성하는 것과 실질적으로 동일한 방법에 따라 화합물105가 제조되었다.Compound 105 was prepared according to substantially the same method as the forming a sodium salt of 6- (4-chlorophenyl) pyridazinone which is alkylated with 3-chlorobenzyl bromide.

프로파길알코올과 1-브로모-1-프로펜으로부터 실시예 56에 기술된 바와 실질적으로 마찬가지 방법에 따라 제조되는 2-헥신-4-엔-1-올의 메실레이트를 사용하고 동일한 방법에 따라 화합물 101이 제조되었다.Using the mesylate of 2-hexyn-4-en-1-ol prepared from propargyl alcohol and 1-bromo-1-propene in substantially the same manner as described in Example 56 and according to the same method Compound 101 was prepared.

1: 3 에틸아세테이트/헵탄으로 용출되는 HPLC 세미프레프 실리카관상에서의 크로마토그라피에 의하여 화합물 101로부터 화합물 102 및 103이 제조되었다.Compounds 102 and 103 were prepared from compound 101 by chromatography on HPLC semiprep silica tubes eluting with 1: 3 ethylacetate / heptane.

[실시예 87 : 6-(4-클로로페닐)-2-(4'-알데히도-2'-부틴일)-4,5-디히드로피리다지논, 디에틸 아세탈]Example 87 6- (4-Chlorophenyl) -2- (4'-aldehyde-2'-butynyl) -4,5-dihydropyridazinone, diethyl acetal

a. 4-히드록시-2-부틴일알데히드 디에틸아세탈a. 4-hydroxy-2-butynylaldehyde diethylacetal

마그네슘 조각들(18.5g)과 무수 테트라 하이드로푸란(350ml)의 혼합물에 브로모에탄(83g)을 50℃이하에서 방울방울 첨가하였다. 모든 마그네슘이 반응된후, 100ml의 테트라하이드로푸란내 프로파길알코올(20g, 0.356몰)의 용액을 방울방울 첨가하였다. 혼합물을 1시간동안 환류시킨 다음, 50ml의 테트라하이드로푸란내 에틸오르도포르메이트(53g, 0.356몰)를 가능한한 빨리 방울방울 첨가하였다. 혼합물을 8시간동안 환류시키고 실온에서 하룻밤동안 교반하였다. 혼합물을 얼음 냉각된 20% 암모늄 아세테이트 수용액(500ml)에 붓고 에틸에테르(3x100ml)로 추출하였다. 에테르 추출물을 물(2x100ml) 및 염수(100ml)로 세척하고 무수 MgSO4로 건조시키고 탈수시켜 42g의 비정제산물을 수득하였다. 이것을 115-120℃(3mmHg)에서 증류시켜 31g의 순수한 산물(56%수율)을 분리하였다.To a mixture of magnesium pieces (18.5 g) and anhydrous tetrahydrofuran (350 ml), bromoethane (83 g) was added dropwise below 50 ° C. After all magnesium had reacted, a drop of a solution of propargyl alcohol (20 g, 0.356 mol) in 100 ml of tetrahydrofuran was added. The mixture was refluxed for 1 hour, and then 50 ml of ethylordoformate (53 g, 0.356 mol) in tetrahydrofuran were added dropwise as soon as possible. The mixture was refluxed for 8 hours and stirred overnight at room temperature. The mixture was poured into an ice cooled 20% ammonium acetate aqueous solution (500 ml) and extracted with ethyl ether (3 × 100 ml). The ether extract was washed with water (2 × 100 ml) and brine (100 ml), dried over anhydrous MgSO 4 and dehydrated to afford 42 g of crude product. It was distilled at 115-120 ° C. (3 mmHg) to separate 31 g of pure product (56% yield).

b. 6-(4-클로로페닐)-2-(4'-알데히도-2'-부틴일)-4,5-디히드로피리다지논, 디에틸 아세탈b. 6- (4-chlorophenyl) -2- (4'-aldehyde-2'-butynyl) -4,5-dihydropyridazinone, diethyl acetal

히드록시 화합물은 상응하는 메실레이트로 전환된 다음 실시예 11a 및 6b(i)에 각각 기술된 바와 같이 6-(4-클로로페닐)-4, 5-디히드로피리다진을 알킬화시키는데 사용되었다.The hydroxy compound was converted to the corresponding mesylate and then used to alkylate 6- (4-chlorophenyl) -4, 5-dihydropyridazine as described in Examples 11a and 6b (i), respectively.

[실시예 88 : 6-(4-클로로페닐)-2-(4'-알데히도-2'-부틴일)-4,5-디히드로피리다지논]Example 88 6- (4-Chlorophenyl) -2- (4'-aldehyde-2'-butynyl) -4,5-dihydropyridazinone]

디에틸디아세탈(화합물 86)(4.0g), 포름산(10ml) 및 물(20ml)의혼합물을 3시간 동안 교반하면서 40℃로 가열하였다. 혼합물을 100ml의 물에 붓고 에틸에테르 (3x100ml)로 추출하고 100ml의 포화 중탄산나트륨 및 100ml의 염수로 세척하였다. 에테르 추출물을 무수 MgSO4로 건조시키고 탈수시켜 알데히드로 특정되는 황갈색 고체 2.2g(80% 수율)을 산출하였다.A mixture of diethyldiacetal (compound 86) (4.0 g), formic acid (10 ml) and water (20 ml) was heated to 40 ° C with stirring for 3 hours. The mixture was poured into 100 ml of water, extracted with ethyl ether (3 × 100 ml) and washed with 100 ml of saturated sodium bicarbonate and 100 ml of brine. The ether extract was dried over anhydrous MgSO 4 and dehydrated to yield 2.2 g (80% yield) of an aldehyde specific tan solid.

[실시예 93 : 6-(4-클로로페닐)-2-(2', 4'-펜타디인일)-4,5-디히드로피리다지논]Example 93 6- (4-Chlorophenyl) -2- (2 ', 4'-pentadiynyl) -4,5-dihydropyridazinone]

a. 2, 4-펜타디인-1-올a. 2,4-pentadiin-1-ol

소다이미드의 현탁액(20.5g(0.89 그람원자)의 나트륨과 500ml의 액체 암모니아로부터 제조된 것)에 1, 4-디클로로-2-부틴(37g, 0.3몰)을 -40℃에서 방울방울 첨가하였다.1, 4-dichloro-2-butyne (37 g, 0.3 mol) was added dropwise at -40 ° C to a suspension of sodimid (made from 20.5 g (0.89 gram atom) of sodium and 500 ml of liquid ammonia).

-40℃에서 30분동안 교반한 후, 무수 포름알데히드(9g)의현탁액을 100ml의 무수 디에틸에테르(Et2O)에 조금씩 첨가하였다. -40℃에서 1시간동안 교반한 후, 염화암모늄(40g, 0.75몰)을 고체로서 조금씩 첨가하고 이어서 200ml의 Et2O를 첨가하였다. 암모니아를 밤새 증발시키고 용액을 Celite를 통하여 여과시켰다. 고체를 Et2 O(100ml)로세척하고에테르 층을 염수로 세척하였다. 에테르 층을 무수 MgSO4로 건조시키고 탈수시켜 16g의 2,4-펜타디인-1-올을 적색 오일(67%수율)로서 산출하였다.After stirring at −40 ° C. for 30 minutes, a suspension of anhydrous formaldehyde (9 g) was added portionwise to 100 ml of anhydrous diethyl ether (Et 2 O). After stirring at −40 ° C. for 1 hour, ammonium chloride (40 g, 0.75 mol) was added portionwise as a solid followed by 200 ml of Et 2 O. Ammonia was evaporated overnight and the solution was It was filtered through. The solid was washed with Et 2 O (100 ml) and the ether layer was washed with brine. The ether layer was dried over anhydrous MgSO 4 and dehydrated to yield 16 g of 2,4-pentadiin-1-ol as a red oil (67% yield).

b. 6-(4-클로로페닐)-2-(2'4'-펜타디인일)-4, 5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- (2'4'-pentadiynyl) -4, 5-dihydropyridazinone

실시예 11a에 기술된 바와 마찬가지 방법에 따라서 알코올을 메실레이트로 전환시키고, 메실레이트를 실시예 86에 기술된 바와같이 알킬화에 사용하여 목적화합물을 산출하였다.The alcohol was converted to mesylate according to the same method as described in Example 11a and mesylate was used for alkylation as described in Example 86 to yield the desired compound.

적당한 피리다지논을 사용하여 실질적으로 동일한 방법에 따라 화합물 125가 제조되었다.Compound 125 was prepared following substantially the same method using an appropriate pyridazinone.

[실시예 94 : 6-(4-클로로페닐)-2-(3'-시클로헥실-2'-프로펜일)피리다지논]Example 94 6- (4-Chlorophenyl) -2- (3'-cyclohexyl-2'-propenyl) pyridazinone

a. 3-시클로헥실-2-프로핀일-1-올a. 3-cyclohexyl-2-propynyl-1-ol

에틸 마그네슘 브로마이드(2.5g의 마그네슘과 11.3g의 브로모에탄으로부터 제조된 것)와 에테르의 용액에 10.2g의 시클로헥실아세틸렌과 에테르의 용액을 방울방울 첨가하고 반응 혼합물을 2시간 동안 환류시켰다 반응혼합물을 상온으로 냉각시키고 무수 포름알데히드(50g의 파라포름 알데히드를 20분 동안 열분해시켜 제조한 것)를 첨가하였다. 냉각후, 반응혼합물을 포화염화암모늄으로 냉각시키고 에테르(2x100㎖)로 추출하였다. 에테르 추출물들을 합하여 염수로 세척하고 황산마그네슘으로 건조시키고 증발시켜 수득한 산출물을 68-74℃에서 고진공하 증류시켜 6.4g의 목적화합물(무색액체)을 산출하였다.To a solution of ethyl magnesium bromide (prepared from 2.5 g magnesium and 11.3 g bromoethane) and ether was added dropwise a solution of 10.2 g of cyclohexylacetylene and ether and the reaction mixture was refluxed for 2 hours. Was cooled to room temperature and anhydrous formaldehyde (prepared by pyrolysis of 50 g of paraformaldehyde for 20 minutes) was added. After cooling, the reaction mixture was cooled with saturated ammonium chloride and extracted with ether (2 × 100 mL). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated, and the resulting product was distilled under high vacuum at 68-74 ° C. to yield 6.4 g of the target compound (colorless liquid).

b. 6-(4-클로로페닐)-2-(3'-시클로헥실-2'-프로핀일)피리다지논b. 6- (4-chlorophenyl) -2- (3'-cyclohexyl-2'-propynyl) pyridazinone

상기 단계 a로부터의 알코올을 사용하고, 실시예 11 및 86에기술된 바와 실질적으로동일한 방법에 따라 화합물 94가 제조되었다.Using the alcohol from step a above, compound 94 was prepared according to substantially the same method as described in Examples 11 and 86.

1-시클로헥실-2-프로핀을 출발물질로하여 실질적으로 동일한 방법에 따라서 화합물 95가 제조되었다.Compound 95 was prepared following substantially the same method using 1-cyclohexyl-2-propine as starting material.

[실시예 109 : 6-(4-클로로페닐)-2-(2'-펜틴일)피리다지노]Example 109 6- (4-chlorophenyl) -2- (2'-pentynyl) pyridazino

a. 6-(4-클로로페닐)피리다지논a. 6- (4-chlorophenyl) pyridazinone

6-(4-클로로페닐)-4,5-디히드로피리다지논(11.75g)과 빙초산(100㎖)의 용액에 3㎖의 브롬을 방울방울 첨가하고 혼합물을 60-70℃에서 3시간동안 가열하였다. 결과의 혼합물을 냉각시키고 400㎖의 냉수에 천천히 부었다. 결과의 백색고체를 여과하고 건조시켜 10.83g(89%)의 6-(4-클로로페닐)피리다지논을 산출하였다.To a solution of 6- (4-chlorophenyl) -4,5-dihydropyridazinone (11.75 g) and glacial acetic acid (100 ml) were added dropwise 3 ml of bromine and the mixture was stirred at 60-70 ° C. for 3 hours. Heated. The resulting mixture was cooled and poured slowly into 400 ml of cold water. The resulting white solid was filtered and dried to yield 10.83 g (89%) of 6- (4-chlorophenyl) pyridazinone.

b. 6-(4-클로로페닐)-2-(2'-펜틴일)피리다지논b. 6- (4-chlorophenyl) -2- (2'-pentynyl) pyridazinone

상기 단계 a에서 수득한 피리다지논을 실시예 6에서처럼 알킬화시켜 6-(4-클로로페닐)-2-(2'-펜틴일)피라다지논을 산출하였다. 적당한 디히드로피리다지논 및 알킬화제를 출발물질로 하여 동일한 방법에 따라 화합물들 108, 110-118, 120, 121, 127 및 129-131 이 제조되었다.The pyridazinone obtained in step a was alkylated as in Example 6 to yield 6- (4-chlorophenyl) -2- (2'-pentynyl) pyradazinone. Compounds 108, 110-118, 120, 121, 127 and 129-131 were prepared according to the same method with suitable dihydropyridazinone and alkylating agents as starting materials.

[실시예 122 : 6-(4-클로로페닐)-4,5-디플루오로-2-(2'-펜틴일)피리다지논]Example 122 6- (4-Chlorophenyl) -4,5-difluoro-2- (2'-pentynyl) pyridazinone]

a. 1, 4-디클로로-1,2,2-트리플루오로시클로부트-3-엔a. 1, 4-dichloro-1,2,2-trifluorocyclobut-3-ene

100ml의 무수에테르내 1,1,2-트리클로로-2,3,3-트리플루오로시클로부탄(55.5g)의 용액에 트리에틸아민(40ml)을 실온에서 30분간에 걸쳐 방울방울 첨가하고, 혼합물을 상온에서 하룻밤동안 교반하였다. 혼합물을 120ml의 물 및 7.5ml의 진한염산과 함께 교반한 다음 에테르층을 물(100ml) 및 염수(100ml)로 세척시키고, 무수 MgSO4로 건조시키고 진공증발시켰다. 잔류물을 분별증류(64-68℃,대기압)시켜 36g(79%)의 순수한 산물(무색액체)를 산출하였다.To a solution of 1,1,2-trichloro-2,3,3-trifluorocyclobutane (55.5 g) in 100 ml of anhydrous ether was added dropwise triethylamine (40 ml) at room temperature over 30 minutes, The mixture was stirred at room temperature overnight. The mixture was stirred with 120 ml of water and 7.5 ml of concentrated hydrochloric acid, then the ether layer was washed with water (100 ml) and brine (100 ml), dried over anhydrous MgSO 4 and evaporated in vacuo. The residue was fractionated (64-68 ° C., atmospheric pressure) to yield 36 g (79%) of pure product (colorless liquid).

b. 2-클로로-2,3,3-트리플루오로숙신산b. 2-Chloro-2,3,3-trifluorosuccinic acid

250ml H2O 내 수산화칼륨(11.3g)에 과망간산칼륨(56g)을 한번에 첨가하고, 모든 것이 용액으로 될 때까지 혼합물을 교반한 다음 1,4-디클로1,2,2-트리플루오로부텐-3-엔(31.3g)을 15-20℃에서 30분간 걸쳐 방울방울 첨가하였다. 혼합물을 실온에서 12시간동안 교반한 후 Celite를 통하여 여과시키고 물로 세척하였다. 수용액을 23ml의 진한황산(4x100ml)로 산성화시켰다. 산용액을 에테르로 추출하고 무수 MgSO4로 건조시켰다. 에테르층을 증발시켜 26g(71%)의 무색액체로서 목적산물을 회수하였다.Potassium permanganate (56 g) is added to potassium hydroxide (11.3 g) in 250 ml H 2 O at once, and the mixture is stirred until everything is in solution, then 1,4-dichloro1,2,2-trifluorobutene -3-ene (31.3 g) was added dropwise at 15-20 ° C. over 30 minutes. The mixture was stirred at rt for 12 h and then Celite Filter through and wash with water. The aqueous solution was acidified with 23 ml of concentrated sulfuric acid (4 × 100 ml). The acid solution was extracted with ether and dried over anhydrous MgSO 4 . The ether layer was evaporated to recover the desired product as 26 g (71%) colorless liquid.

c. 2,2,3-트리플루오로숙신산c. 2,2,3-trifluorosuccinic acid

200ml 디옥산과 클로로트리플루오로숙신산(24.5g: 단계 b의 산물)의 교반용액에 아연금속(85g)을 조금씩 첨가하고, 혼합물을 상온에서 10시간동안 교반하고 미반응 아연을 분리하여 점성액체를 산출하였다. 대부분의 디옥산을 진공증발시키고, 잔류물을 100ml H2O에 용해시키고, 7.7ml의 진한황산과 25ml의 물의 용액을 첨가하였다. 용액을 에테르(3x100ml)로 추출하고 무수 MgSO4로 건조시켰다. 유기층을 증발시켜 8.3g(32% 수율)의 목적산물을 결정성 고체로서 수득하였다.To a stirring solution of 200 ml dioxane and chlorotrifluorosuccinic acid (24.5 g: product of step b), zinc metal (85 g) was added little by little, the mixture was stirred at room temperature for 10 hours, and unreacted zinc was separated to obtain a viscous liquid. Calculated. Most of the dioxane was evaporated in vacuo and the residue was dissolved in 100 ml H 2 O and a solution of 7.7 ml of concentrated sulfuric acid and 25 ml of water was added. The solution was extracted with ether (3 × 100 ml) and dried over anhydrous MgSO 4 . The organic layer was evaporated to give 8.3 g (32% yield) of the desired product as a crystalline solid.

d. 무수 2,2,3-트리플루오로숙신산d. 2,2,3-trifluorosuccinic anhydride

숙신산(단계 c의 산물, 8.0g)과 오산화인(14.7g)의 슬러리를 가열하고, 무수물을 15㎝ 비그로우관을 통하여 증류(15㎜Hg)시켰다. 60-68℃에서 무색액체가 수집 목적산물은 53% 수율(3.0g)로 분리되었다.A slurry of succinic acid (product of step c, 8.0 g) and phosphorus pentoxide (14.7 g) was heated and the anhydride was distilled (15 mm Hg) through a 15 cm non-grown tube. At 60-68 ° C, the product was collected as colorless liquid. The product was isolated in 53% yield (3.0 g).

e. 6-(4-클로로페닐)-4,5-디플루오로-2-(2'-펜틴일)-피리다지논e. 6- (4-Chlorophenyl) -4,5-difluoro-2- (2'-pentynyl) -pyridazinone

단계 d의 무수산을 실시예 26a에서 처럼 클로로벤젠과 반응시켜 플루오르화 케토산들의 혼합물을 산출하였다. 히드라진과 함께 고리화시켜 단일 디플루오로디히드로피리다지논을 수득하고, 이것을 1-브로모-2-펜틴과 함께 알킬화시켜 6-(4-클로로페닐)-4,5-디플루오로-2-(2'-펜틴일)피리다지논을 산출하였다.The anhydrous acid of step d was reacted with chlorobenzene as in Example 26a to yield a mixture of fluorinated keto acids. Cyclization with hydrazine yields a single difluorodihydropyridazinone, which is alkylated with 1-bromo-2-pentin to give 6- (4-chlorophenyl) -4,5-difluoro-2- (2'-pentynyl) pyridazinone was calculated.

[실시예 124 : 6-(4-클로로페닐)-2-(3'-트리-n-부틸틴-2'-프로핀일)-4,5-디히드로피리다지논]Example 124 6- (4-Chlorophenyl) -2- (3'-tri-n-butyltin-2'-propynyl) -4,5-dihydropyridazinone]

6.0g의 화합물 118과 50ml의 무수테트라하이드로푸란 용액을 -78℃로 냉각시키고 17.4ml의 1.6M n-부틸리튬/헥산용액을 방울방울 첨가하였다. 용액을 -78℃에서 30분동안 교반한 다음 8.0g 트리부틸틴클로라이드/30ml 무수테트라하이드로푸란의 용액을 방울방울 첨가하였다 반응혼합물을 실온으로 데우고 하룻밤동안 교반한 다음 100ml의 염수로 냉각시키고 에테르(3x100ml)로 추출하였다. 에테르 추출물을 합하여 100ml의 물, 100ml의 염수로 세척하고 건조 및 증발시켜 수득한 잔류물을 실리카상에서 크로마토그라피(50:50에틸아세테이트/헥산)시켜 2.1g의 화합물124(황색오일)을 산출하였다.6.0 g of Compound 118 and 50 ml of anhydrous tetrahydrofuran solution were cooled to -78 ° C and 17.4 ml of 1.6M n-butyllithium / hexane solution was added dropwise. The solution was stirred at −78 ° C. for 30 minutes and then a dropwise solution of 8.0 g tributyltin chloride / 30 ml anhydrous tetrahydrofuran was added dropwise. The reaction mixture was warmed to room temperature, stirred overnight, cooled with 100 ml of brine and ether ( 3 × 100 ml). The combined ether extracts were washed with 100 ml of water, 100 ml of brine, dried and evaporated and the resulting residue was chromatographed on silica (50:50 ethyl acetate / hexanes) to yield 2.1 g of Compound 124 (yellow oil).

[실시예 134 : 6-(1-나피틸)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 134 6- (1-naphthyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 3-(1-나프틸)프로피온산a. 3- (1-naphthyl) propionic acid

나프탈렌(40g)과 무수숙신산(20g)의 혼합물에 잘교반된 삼염화알루미늄(55g)/니트로벤젠(140ml)이 현탄액을 첨가하고, 결과의 혼합물을 실온에서 하룻밤동안 교반하였다. 혼합물을 얼음물(600g)에 서서히 붓고 6N염산으로 산성화시켰다. 비정제산을 여과하고, 세척액이 중성으로 될 때까지 물로 세척한 다음 에탄올로 재결정화시켜 목적산물(m.p. 170-172℃)을 산출하였다.To a mixture of naphthalene (40 g) and succinic anhydride (20 g) was added a suspension of aluminum trichloride (55 g) / nitrobenzene (140 ml), and the resulting mixture was stirred at room temperature overnight. The mixture was poured slowly into ice water (600 g) and acidified with 6N hydrochloric acid. The crude acid was filtered off, washed with water until the wash solution became neutral and recrystallized with ethanol to yield the desired product (m. P. 170-172 ° C.).

b. 6-(1-나피틸)-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (1-naphthyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

상기 단계 a로 부터의 프로피온산을 실시예 6a-b에서와 마찬가지로 반응시켜 목적화합물을 산출하였다.Propionic acid from step a was reacted in the same manner as in Example 6a-b to yield the target compound.

[실시예 139 : 2-(2-부틴일)-7-페닐-1,2-디아자핀-3-온]Example 139 2- (2-butynyl) -7-phenyl-1,2-diaza-3-one

a. 7-페닐-1, 2-디아자핀-3-온a. 7-phenyl-1, 2-diaza-3-one

10g(0.052몰)의 4-벤조일부티르산과 300ml의 톨루엔 혼합물에 히드라진을 한번에 첨가하고, 모든 물이 공비를 중지할 때까지 반응혼합물을 환류가열시켰다. 반응혼합물을 냉각시키고 톨루엔을 진공증발시켰다. 잔류물을 200ml Et2O에 용해시키고 물(10ml) 및 염수(100ml)로 세척하였다. 에테르 추출물을 무수 MgSO4로 건조시키고 여과 및 증발시켜 수득한 오렌지색 반고체를 에테르로 정제시켜 3.8g(39% 수율)의목적산물을 황색고체로서 수득하였다.Hydrazine was added to 10 g (0.052 mol) of 4-benzoylbutyric acid and 300 ml of toluene mixture at once, and the reaction mixture was heated to reflux until all water stopped azeotroping. The reaction mixture was cooled and toluene was evaporated in vacuo. The residue was dissolved in 200 ml Et 2 O and washed with water (10 ml) and brine (100 ml). The ether extract was dried over anhydrous MgSO 4 , filtered and evaporated and the orange semisolid obtained was purified with ether to yield 3.8 g (39% yield) of the desired product as a yellow solid.

b. 2-(2-부틴일)-7-페닐-1,2-디아자핀-3-온b. 2- (2-butynyl) -7-phenyl-1,2-diaza-3-one

단계 a로부터의 산출물을 실시예 6b에서와 마찬가지로 알킬화시켜 1.1g의 목적화합물을 황색오일로서 수득하였다.The output from step a was alkylated as in Example 6b to afford 1.1 g of the desired compound as a yellow oil.

[실시예 143 : 7-클로로-2,4,4a,5-테트라히드로-2-(2-펜틴-1-일)-인테노[1,2-c]피리다진-3-온]Example 143 7-chloro-2,4,4a, 5-tetrahydro-2- (2-pentyn-1-yl) -intheno [1,2-c] pyridazin-3-one

a. 2-카보메톡시-5-클로로인다논a. 2-carbomethoxy-5-chloroindanone

수소화나트륨(2.4g, 60% in 미네랄유, 0.06몰)과 50ml 무수 디메톡시에탄의 혼합물에 5-클로로인다논(50g, 0.03몰)과 50ml 디메톡시에탄을 혼합물을 실온에서 방울방울 첨가하고, 수소방출이 그칠 때까지 반응혼합물을 실온에서 교반하였다. 디메틸카보네이트(27g, 0.3몰)를 방울방울 첨가한 다음 반응 혼합물을 60℃에서 1시간동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고 100ml의 물에 붓고 진한염산으로 산성화시키고 에틸에테르(3x100ml)로 추출하였다. 에테르 추출물을 염수로 세척하고 무수 MgSO4로 건조시키고 증발시켜 3.0g(45%수율)의 목적산물(황갈색고체)를 산출하였다.To a mixture of sodium hydride (2.4 g, 60% in mineral oil, 0.06 mol) and 50 ml anhydrous dimethoxyethane, 5-chloro indone (50 g, 0.03 mol) and 50 ml dimethoxyethane were added dropwise at room temperature, The reaction mixture was stirred at room temperature until hydrogen evolution ceased. Dimethyl carbonate (27 g, 0.3 mol) was added dropwise and the reaction mixture was heated at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into 100 ml of water, acidified with concentrated hydrochloric acid and extracted with ethyl ether (3 × 100 ml). The ether extract was washed with brine, dried over anhydrous MgSO 4 and evaporated to yield 3.0 g (45% yield) of the desired product (brown solid).

b. 2-카보메톡시-2-카보메톡시메틸-5-클로로인다논b. 2-carbomethoxy-2-carbomethoxymethyl-5-chloroindanone

수소화나트륨(0.44g, 60% in 미네랄유 0.0111몰 )과 50ml 무수 디메틸포름아미드(DMF)의 혼합물에 상기 단계 a의 인다논에스테르(2.5g, 0.0111몰)과 50ml DMF의 혼합물을 냉각하 방울방울 첨가하고, 수소방출이 그칠때까지 반응혼합물을 10℃에서 교반한 다음 25ml DMF에 용해된 메틸브로모아세테이트(1.9g, 0.0122몰)를 10℃에서 방울방울 첨가하였다. 반응 혼합물을 5-10℃에서 1시간 및 상온에서 하룻밤동안 교반한 다음 물(100ml)로 냉각시키고 에테르(3x100ml)로 추출하였다. 유기층들을 합하여 물(100ml) 및 염수(100ml)로 세척하고, 무수 MgSO4로 건조시키고 탈수시켜 3.0g의 황갈색 고체를 산출하였다.To a mixture of sodium hydride (0.44 g, 60% in mineral oil 0.0111 mole) and 50 ml anhydrous dimethylformamide (DMF), the mixture of indanone ester (2.5 g, 0.0111 mole) and 50 ml DMF of step a was cooled and dropped. The reaction mixture was stirred at 10 ° C. until hydrogen evolution ceased, and then methyl bromoacetate (1.9 g, 0.0122 mol) dissolved in 25 ml DMF was added dropwise at 10 ° C. The reaction mixture was stirred at 5-10 ° C. for 1 hour and at room temperature overnight, then cooled with water (100 ml) and extracted with ether (3 × 100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous MgSO 4 and dehydrated to yield 3.0 g of a tan solid.

c. 7-클로로-2,4,4a,5-테트라히드로-인데노[1,2-c]-피리다진-3-온c. 7-chloro-2,4,4a, 5-tetrahydro-indeno [1,2-c] -pyridazin-3-one

상기 단계에서 산출된 디에스테르(2.5g, 0.0084몰)와 100ml의 6NHCl의 혼합물을 출발물질이 TLC에 의해 검출되지 않을 때까지 약 2시간 동안 환류시킨다음, 반응혼합물을 실온으로 냉각시키고 200ml의 얼음물에 부었다. 형성된 침전을 진공여과에 의하여 수집하고 200ml의 물로 세척하였다. 침전물을 밤새 감압건조시켜 1.8g(95% 수율)의 백색고체를 산출하였다.The mixture of diester (2.5 g, 0.0084 mol) and 100 ml of 6NHCl obtained in the above step was refluxed for about 2 hours until the starting material was not detected by TLC, and then the reaction mixture was cooled to room temperature and 200 ml of ice water. Poured into. The precipitate formed was collected by vacuum filtration and washed with 200 ml of water. The precipitate was dried under reduced pressure overnight to yield 1.8 g (95% yield) of white solid.

d. 7-클로로-2,4,4a,5-테트라히드로-2-(2-펜틴-1-일)-인데노[1,2-c]피리다진-3-온d. 7-chloro-2,4,4a, 5-tetrahydro-2- (2-pentyn-1-yl) -indeno [1,2-c] pyridazin-3-one

케토산을 실시예 6a-b에서 처럼 반응시켜 화합물 143을 산출하였다. 5-클로로-3-메틸인다논을 출발물질로하여 실질적으로 동일한 방법에 따라서 화합물 155가 제조되었다.Keto acid was reacted as in Examples 6a-b to yield Compound 143. Compound 155 was prepared according to substantially the same method using 5-chloro-3-methylindanon as starting material.

[실시예 145와 146 : 5-(4-클로로페닐)-1-(2-펜틴-1-일)-2-피리다지논 및 5-(4-클로로페닐)-3-시아노-1-(2-펜틴-1-일)-2-피리다지논]Examples 145 and 146: 5- (4-Chlorophenyl) -1- (2-pentyn-1-yl) -2-pyridazinone and 5- (4-chlorophenyl) -3-cyano-1- (2-pentin-1-yl) -2-pyridazinone]

a. 2-(4-클로로페닐)-3-디메틸아미노프로펜알a. 2- (4-chlorophenyl) -3-dimethylaminopropenal

10-15℃에서 산화염화인(92g)을 교반하는 DMF(78ml)에 방울방울 첨가하고, 결과의 슬러리에 4-클로로페닐아세트산(34.12g)을 첨가하였다. 혼합물을 실온에서 1.5시간동안 교반한 다음 70-80℃에서 5.5시간동안 가열하였는데, 그동안 거품이 일어났다. 반응혼합물을 냉각시키고 얼음에 천천히 부었다. 결과의 현탁액을 고체 탄산칼륨을 사용하여 pH 10으로 조절하되, 그동안 얼음을 첨가하여 온도를 15℃ 이하로 유지시켰다. 톨루엔(150ml)을 첨가하고 혼합물을 한시간동안 100℃로 가열하였다. 혼합물을 냉각시키고 하룻밤동안 세워둔 다음, 형성된 두층들을 분리하고 수성층을 톨루엔(2x100ml)으로 추출하였다. 유기층들을 합하여 물(5x100ml)로 세척하고 무수 황산나트륨으로 건조시켰다. 용매를 진공증발시키고 결과의 황색고체를 헥산으로 정제시켜 26g의 2-(4-클로로페닐)-3-디메틸아미노프로펜알을 황갈색고체(mp. 120-125℃)로서 수득하였다.Droplets were added to DMF (78 ml) with stirring phosphorus oxychloride (92 g) at 10-15 ° C., and 4-chlorophenylacetic acid (34.12 g) was added to the resulting slurry. The mixture was stirred at room temperature for 1.5 hours and then heated at 70-80 ° C. for 5.5 hours, during which time bubbles occurred. The reaction mixture was cooled down and poured slowly onto ice. The resulting suspension was adjusted to pH 10 with solid potassium carbonate, while ice was added to keep the temperature below 15 ° C. Toluene (150 ml) was added and the mixture was heated to 100 ° C. for one hour. The mixture was cooled and left overnight, then the two layers formed were separated and the aqueous layer was extracted with toluene (2x100 ml). The combined organic layers were washed with water (5x100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the resulting yellow solid was purified with hexane to give 26 g of 2- (4-chlorophenyl) -3-dimethylaminopropenal as a tan solid (mp. 120-125 ° C.).

b. 3-시아노-5-(4-클로로페닐)-2-피리디논b. 3-cyano-5- (4-chlorophenyl) -2-pyridinone

메톡시화나트륨(7.52g)과 메탄올(130ml)의 용액에 시아노아세트아미드(5.84g)을 첨가하고 이어서 2-(4-클로로페닐)-3-디메틸아미노프로펜알을 첨가하고, 결과의 현탁액을 밤새 환류시켰다. 이동안 황색고체가 형성되었다. 혼합물을 실온으로 냉각시키고 빙초산 (50ml)을 첨가하고 이어서 물(100ml)을 첨가하였다. 결과의 오렌지색 고체를 걸러내어 물로 여러번 세척하고 건조시켜 8.1g의 3-시아노-5-(4-클로로페닐)-2-피리다논을 산출하였다.To a solution of sodium methoxide (7.52 g) and methanol (130 ml) is added cyanoacetamide (5.84 g) followed by 2- (4-chlorophenyl) -3-dimethylaminopropane, and the resulting suspension is added. It was refluxed overnight. Yellow solids formed during this time. The mixture was cooled to room temperature and glacial acetic acid (50 ml) was added followed by water (100 ml). The resulting orange solid was filtered off, washed several times with water and dried to yield 8.1 g of 3-cyano-5- (4-chlorophenyl) -2-pyridanone.

c. 5-(4-클로로페닐)-2-피리디논c. 5- (4-chlorophenyl) -2-pyridinone

3-시아노-5-(4-클로로페닐)-2-피리디논(4.6g)과 83%인산(60ml)의 혼합물을 6시간동안 환류가열시켰다. 결과의 혼합물을 실온으로 냉각시키고, 얼음물에 붓고 여과하여 3.1g의 5-(4-클로로페닐)-2-피리디논을 황색고체로서 수득하였다.A mixture of 3-cyano-5- (4-chlorophenyl) -2-pyridinone (4.6 g) and 83% phosphoric acid (60 ml) was heated to reflux for 6 hours. The resulting mixture was cooled to room temperature, poured into ice water and filtered to yield 3.1 g of 5- (4-chlorophenyl) -2-pyridinone as a yellow solid.

d. 5-(4-클로로페닐)-1-(2-펜틴-1-일)-2-피리디논d. 5- (4-chlorophenyl) -1- (2-pentyn-1-yl) -2-pyridinone

NaH(60% in 미네랄유, 200mg)과 무수 DMF(50ml)의 현탁액에 피리미딘(단계 c의 산물)을 0℃에서 첨가하고 혼합물을 0℃에서 1.5시간동안 교반하였다. 결과의현탁액에서 1-브로모-2-펜틴을 방울방울 첨가하고, 혼합물을 0℃에서 1.5시간동안 유지시킨 다음 포화 수성염화암모늄(200ml)에 부었다. 수성현탁액을 에테르(3x100ml)로 추출하고, 에테르층들을 합하여 염수로 세척하고 건조시켜 비정제산물을 수득하였다. 이것을 크로마토그라피(실리카겔관, 헥산: 에틸아세테이트 8: 2)시켜 목적화합물(백색비정질고체)를 수득하였다.Pyrimidine (product of step c) was added to a suspension of NaH (60% in mineral oil, 200 mg) and anhydrous DMF (50 ml) at 0 ° C. and the mixture was stirred at 0 ° C. for 1.5 h. Droplets of 1-bromo-2-pentine were added in the resulting suspension and the mixture was kept at 0 ° C. for 1.5 hours and then poured into saturated aqueous ammonium chloride (200 ml). The aqueous suspension was extracted with ether (3 × 100 ml), the ether layers combined and washed with brine and dried to afford the crude product. This was chromatographed (silica gel tube, hexane: ethyl acetate 8: 2) to obtain the target compound (white amorphous solid).

3. 5-(4-클로로페닐)-3-시아노-1-(2-펜틴-1-일)-2-피리디논3. 5- (4-Chlorophenyl) -3-cyano-1- (2-pentin-1-yl) -2-pyridinone

3-시아노-5-(4-클로로페닐)-2-피리디논을 전술한 바와 유사하게 알킬화시켜 5-(4-클로로페닐)-3-시아노-1-(2-펜틴-1-일)-2-피리디논(화합물146)을 산출하였다.3-Cyano-5- (4-chlorophenyl) -2-pyridinone is alkylated similarly to that described above to give 5- (4-chlorophenyl) -3-cyano-1- (2-pentyn-1-yl ) -2-pyridinone (Compound 146) was calculated.

[실시예 149 : 5-클로로-1-(2-펜틴-1-일)-2-퀴놀린]Example 149 5-Chloro-1- (2-pentyn-1-yl) -2-quinoline]

a. N-(4-클로로페닐)신남아미드a. N- (4-chlorophenyl) cinnamamide

4-클로로아닐린(16.2g), 톨루엔(120ml) 및 피리딘(11ml)의 혼합물에 신나모일클로라이드(20.0g)/톨루엔(120ml)을 0℃에서 방울방울 첨가하고, 0℃에서 15분간 교반한 다음 반응혼합물을 에틸아세테이트(250ml)/물(250ml)의 혼합물에 부었다. 유기층을 분리하여 5% 염산수(3x250ml), 물(1x250ml), 및 5% 중탄산나트륨수용액(3x250ml)로 추출하고, 무수황산나트륨으로 건조시키고 탈수시켜 목적아미드를 백색고체로서 수득하였다.To a mixture of 4-chloroaniline (16.2 g), toluene (120 ml) and pyridine (11 ml), cinnamoyl chloride (20.0 g) / toluene (120 ml) was added dropwise at 0 ° C. and stirred at 0 ° C. for 15 minutes. The reaction mixture was poured into a mixture of ethyl acetate (250 ml) / water (250 ml). The organic layer was separated and extracted with 5% aqueous hydrochloric acid (3x250ml), water (1x250ml), and 5% aqueous sodium bicarbonate solution (3x250ml), dried over anhydrous sodium sulfate and dehydrated to give the desired amide as a white solid.

b. 5-클로로-2-퀴놀리논b. 5-chloro-2-quinolinone

질소기권하 실온에서, N-(4-클로로페닐)신남아미드(8.3g)과 클로로벤젠(60ml)의 혼합물에 염화암모늄(21.4g)을 조금씩 첨가하고 반응혼합물을 125℃까지 천천히 승온시킨 다음 그 온도에서 3시간동안 유지시켰다. 반응혼합물을 냉각시키고 400g의 얼음에 부었다. 분홍색 고체로서 결정화 산출되는 산물을 여과 및 건조시켜 목적 산물을 수득하였다.At room temperature under a nitrogen atmosphere, ammonium chloride (21.4 g) was added little by little to a mixture of N- (4-chlorophenyl) cinnaamide (8.3 g) and chlorobenzene (60 ml), and the reaction mixture was slowly heated to 125 占 폚. The temperature was kept for 3 hours. The reaction mixture was cooled down and poured onto 400 g of ice. Crystallization as a pink solid The resulting product was filtered and dried to afford the desired product.

c. 5-클로로-1-(2-펜틴-1-일)-2-퀴놀리논c. 5-chloro-1- (2-pentyn-1-yl) -2-quinolinone

무수 DMF(100ml)so NaH(60% in 미네랄유, 700mg)의현탁액에 전단계의 퀴놀리논(2.05g)을 첨가하고 혼합물을 0℃에서 1.5시간동안 교반하였다. 결과의 현탁액에 1-브로모-2-펜틴(1.6g)을 방울방울 첨가하고, 혼합물을 0℃에서 1.5시간동안 유지시킨 후 포화염화 암모늄 수용액(200ml)에 부었다. 수성현탁액을 에테르(3x100ml)로 추출하고 에테르층들을 합하여 염수로 세척하고 건조시켜 비정제산물을 산출하였다. 이것을 헥산으로 정제시켜 목적산물을 황색고체(1g)로서 수득하였다.To a suspension of anhydrous DMF (100 ml) so NaH (60% in mineral oil, 700 mg) was added quinolinone (2.05 g) in the previous step and the mixture was stirred at 0 ° C. for 1.5 h. Droplets of 1-bromo-2-pentine (1.6 g) were added to the resulting suspension, and the mixture was kept at 0 ° C. for 1.5 hours and then poured into saturated aqueous ammonium chloride solution (200 ml). The aqueous suspension was extracted with ether (3 × 100 ml) and the ether layers combined, washed with brine and dried to yield the crude product. This was purified by hexane to give the desired product as a yellow solid (1 g).

[실시예 150 : 5-(4-클로로페닐)-1-(2-펜틴-1일)-2-피리미디논]Example 150 5- (4-Chlorophenyl) -1- (2-pentyn-1 yl) -2-pyrimidinone]

a. 5-(4-클로로페닐)-2-피리미디논a. 5- (4-chlorophenyl) -2-pyrimidinone

2-(4-클로로페닐)디메틸아미노프로펜알(실시예 145a: 5.13g), 요소(2.4g), 진한염산(10ml), 물(4ml) 및 에탄올(150ml)의 혼합물을 4시간동안 환류가열시켰다.A mixture of 2- (4-chlorophenyl) dimethylaminopropenal (Example 145a: 5.13 g), urea (2.4 g), concentrated hydrochloric acid (10 ml), water (4 ml) and ethanol (150 ml) was heated to reflux for 4 hours. I was.

실온으로 냉각시킨후 pH 7이 될 때까지 진한 염화암모늄을 첨가하였다. 결과의 황색고체를 여과 및 건조시켜 1.5g의 5-(4-클로로페닐)-2-피리미디논을 산출하였다.After cooling to room temperature, concentrated ammonium chloride was added until pH 7. The resulting yellow solid was filtered and dried to yield 1.5 g of 5- (4-chlorophenyl) -2-pyrimidinone.

b. 5-(4-클로로페닐)-1-(2-펜틴-1-일)-2-피리미디논b. 5- (4-chlorophenyl) -1- (2-pentyn-1-yl) -2-pyrimidinone

무수 DMF(75ml) 내 NaH(60% in 미네랄유, 340mg)의 현탁액에 전단계의 피리미디논(1.0g)을 0℃에서 첨가하고 혼합물을 0℃에서 1.5시간동안 교반하였다. 결과의 현탁액에 1-브로모-2-펜틴(750mg)을 방울방울 첨가하였다. 결과의 혼합물을 0℃에서 1.5시간동안 유지시키고 포화 암모늄 수용액(200ml)에 부었다. 수성현탁액을 에테르(3x100ml)로추출하고, 에테르층들을 합하여 염수로 세척하고 건조시켜 비정제산물을 산출하였다. 이것을 헥산으로 정제하여 황색고체로서 목적화합물을 수득하였다.To a suspension of NaH (60% in mineral oil, 340 mg) in anhydrous DMF (75 ml) was added pyrimidinone (1.0 g) at 0 ° C. and the mixture was stirred at 0 ° C. for 1.5 h. To the resulting suspension was added dropwise 1-bromo-2-pentin (750 mg). The resulting mixture was kept at 0 ° C. for 1.5 hours and poured into saturated aqueous ammonium solution (200 ml). The aqueous suspension was extracted with ether (3 × 100 ml), the ether layers combined and washed with brine and dried to yield the crude product. This was purified by hexane to give the target compound as a yellow solid.

[실시예 151 : 5,5'-[비스(펜트-2-인-1-일)]-7-클로로-2,5-디히드로인데노-[1,2-c]-(2H)-피리다진-3-온]Example 151 5,5 ′-[bis (pent-2-yn-1-yl)]-7-chloro-2,5-dihydroindeno- [1,2-c]-(2H)- Pyridazin-3-one]

a. 7-클로로-2, 5-디히드로인데노-[1,2-c]-(2H)-피리다진-3-온 2,4,4a,5-테트라히드로인데노-[1,2-c]-피리다진-3-온(4.5g, 실시예 143c)과 빙초산(100ml)의 혼합물에 브롬(3.3g)을 실온에서 교반하여 방울방울 첨가하고 반응혼합물을 3시간동안 환류시켰다. 반응혼합물을 실온을 냉각시키고 200ml의 물에 부어 백색침전을 산출하고, 이것을 진공여과에 의하여 수집하여 물로 세척하고 40℃에서 건조시켜 3.3g의 황갈색고체를 산출하였다.a. 7-chloro-2, 5-dihydroindeno- [1,2-c]-(2H) -pyridazin-3-one 2,4,4a, 5-tetrahydroindeno- [1,2-c To the mixture of] -pyridazin-3-one (4.5 g, Example 143c) and glacial acetic acid (100 ml) were added dropwise bromine (3.3 g) at room temperature and the reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into 200 ml of water to yield a white precipitate which was collected by vacuum filtration, washed with water and dried at 40 ° C. to yield 3.3 g of a tan solid.

b. 5,5'-[비스)펜트-2-인-1-일)]-7-클로로-2,5-디히드로인데노-[1,2-c]-(2H)-피리다진-3-온b. 5,5 '-[bis) pent-2-yn-1-yl)]-7-chloro-2,5-dihydroindeno- [1,2-c]-(2H) -pyridazine-3- On

상기 단계 a의 산출물을 실시예 6b에서와 유사하게 1-브로모-2-펜틴으로 알킬화시켜 수득한 산출물과 출발물질의 혼합물을 칼럼 크로마토그라피(실리카 ; 60%에틸아세테이트/ 40%/헥산)에 의하여 분리정제시켜 목적화합물을 산출하였다.Similarly as in Example 6b, the output of step a was obtained by alkylation with 1-bromo-2-pentine, and the mixture of the output and the starting material was subjected to column chromatography (silica; 60% ethyl acetate / 40% / hexane). The purification was carried out to obtain the target compound.

[실시예 152 : 6-(4-클로로페닐)-3-(2-펜틴-1-티오)피리다진]Example 152 6- (4-chlorophenyl) -3- (2-pentin-1-thio) pyridazine

a. 6-(4-클로로페닐)-피리다진티온a. 6- (4-chlorophenyl) -pyridazinethione

3.0g의 6-(4-클로로페닐)-피리다지논, 50ml의 무수피리딘 및 3.2g 오황화인의 혼합물을 1시간동안 환류시키고, 증발건조시키고 에테르(200ml)로 추출하였다. 에테르 추출물을 물(3x100ml) 및 염수(100ml)로 세척하고 황산마그네슘으로 건조시키고 증발시켜 3.0g의 6-(4-클로로페닐)-피리다진티온을 황색고체로서 수득하였다.A mixture of 3.0 g of 6- (4-chlorophenyl) -pyridazinone, 50 ml of anhydropyridine and 3.2 g of phosphorus pentasulphide was refluxed for 1 hour, evaporated to dryness and extracted with ether (200 ml). The ether extract was washed with water (3 × 100 ml) and brine (100 ml), dried over magnesium sulfate and evaporated to yield 3.0 g of 6- (4-chlorophenyl) -pyridazinethione as a yellow solid.

b. 6-(4-클로로페닐)-3-(2-펜틴-1-티오)피리다진b. 6- (4-chlorophenyl) -3- (2-pentin-1-thio) pyridazine

상기 단계 a의 6-(4-클로로페닐)-피리다진티온을 실시예 6b에 기술된 바와 유사한 방법에 따라 1-브로모-2-펜틴으로 알킬화시켜 1.1g 의 화합물 152를 백색고체로서 수득하였다.The 6- (4-chlorophenyl) -pyridazinethione of step a was alkylated with 1-bromo-2-pentin according to a similar method as described in Example 6b to give 1.1 g of compound 152 as a white solid. .

[실시예 153 : 6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다진티온]Example 153 6- (4-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinthione]

6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논(3.0g, 0.011몰), 무수피리딘(50㎖) 및 오황화인(2.5g, 0.011몰)의 혼합물을 1시간동안 환류시키고 냉각시킨후, 피리딘을 진공증발시켰다. 잔류물을 200㎖의 에틸에테르에 용해시키고 물(3x100㎖) 및 염수(100㎖)로 세척하였다. 에테르 추출물을 무수 MgSO4로 건조시키고 증발시켜 2.6g(82% 수율)의 목적화합물을 황색고체로서 수득하였다.6- (4-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone (3.0 g, 0.011 mol), anhydrous pyridine (50 mL) and phosphorus sulphide (2.5 g, 0.011 mole) of the mixture was refluxed for 1 hour and cooled, and then pyridine was evaporated in vacuo. The residue was dissolved in 200 mL of ethyl ether and washed with water (3 × 100 mL) and brine (100 mL). The ether extract was dried over anhydrous MgSO 4 and evaporated to afford 2.6 g (82% yield) of the title compound as a yellow solid.

[실시예 156 : 7-클로로-2,4,4a,5-테트라히드로-2-(2-펜틴-4-엔-1-일)-인데노[1,2-c]-피리다진-3-온]Example 156 7-Chloro-2,4,4a, 5-tetrahydro-2- (2-pentyn-4-en-1-yl) -indeno [1,2-c] -pyridazine-3 -On]

a. 3-비닐-2-프로핀-1-올a. 3-vinyl-2-propyn-1-ol

수산화칼륨(1.7g, 87%,분말), FeCl3(0.1g), 디메틸술폭시드(100㎖) 및 에테르(100㎖)의 혼합물에 크실렌 비함유 비닐아세테이트(17g)과 에테르(25㎖)의 용액을 15℃에서 첨가하고 반응혼합물을 10-15℃에서 1시간동안 교반하고 파라포름알데히드(4.5g)을 한번에 첨가한다음, 혼합물을 다시 1시간동안 교반하고 포화염수(100㎖)로 냉각시키고 에테르(2x100㎖)로 추출하였다. 에테르 추출물을 염수(100㎖)로 세척하고 황산마그네슘으로 건조시키고 증발시켜 20g의 알코올을 무색액체로서 수득하였다.To a mixture of potassium hydroxide (1.7 g, 87%, powder), FeCl 3 (0.1 g), dimethyl sulfoxide (100 mL) and ether (100 mL), a mixture of vinyl acetate (17 g) and ether (25 mL) without xylene was added. The solution was added at 15 ° C. and the reaction mixture was stirred at 10-15 ° C. for 1 hour and paraformaldehyde (4.5 g) was added at once, then the mixture was stirred for 1 hour again and cooled with saturated brine (100 mL) Extracted with ether (2x100 mL). The ether extract was washed with brine (100 mL), dried over magnesium sulfate and evaporated to give 20 g of alcohol as a colorless liquid.

b. 7-클로로-2,4,4a,5-테트라히드로-2-(2-펜틴-4-엔-1-일)-인데노[1,2-c]-피리다진-3-온b. 7-chloro-2,4,4a, 5-tetrahydro-2- (2-pentyn-4-en-1-yl) -indeno [1,2-c] -pyridazin-3-one

상기 단계 a의 알코올로부터, 실시예 11a 및 6b에 기술된 바와 유사한 방법에 따라서, 목적화합물을 산출하였다.From the alcohol of step a above, the desired compound was calculated according to a similar method as described in Examples 11a and 6b.

[실시예 157 : 6-(4-클로로페닐)-3-클로로-2-(2'펜틴-1-일)-2,5-디히드로피리다진]Example 157 6- (4-chlorophenyl) -3-chloro-2- (2'pentyn-1-yl) -2,5-dihydropyridazine]

무수 DMF(100㎖)내 6-(4-클로로페닐)-2-(2'펜틴일)피리다지논화합물(109, 3.0g, 0.011몰)의 용액을 5℃로 냉각시키고 포스포릴클로라이드(4.2g, 0.0275몰)를 방울방울 첨가하였다. 용액이 즉시 당황색으로 변하였다. 16시간 교반후, 반응혼합물을 200㎖의 냉수에 붓고 교반하여 솜털같은 황색고체를 산출하였다. 이것을 걸러내어 진공건조시켜 3.0g(93% 수율)의 목적화합물을 황색고체로서 수득하였다.A solution of 6- (4-chlorophenyl) -2- (2'pentynyl) pyridazinone compound (109, 3.0 g, 0.011 mol) in anhydrous DMF (100 mL) was cooled to 5 ° C and phosphoryl chloride (4.2 g, 0.0275 mole) was added dropwise. The solution immediately turned embarrassed. After stirring for 16 hours, the reaction mixture was poured into 200 ml of cold water and stirred to give a fluffy yellow solid. It was filtered and dried in vacuo to yield 3.0 g (93% yield) of the title compound as a yellow solid.

산화염화인 대신에 염화브롬화인을 사용하고동일한 방법에 따라서 화합물 160이 제조되었다.Compound 160 was prepared according to the same method using phosphorus chloride instead of phosphorus oxychloride.

[실시예 158 : 6-(4-클로로페닐)-3-메톡시-2-(2'-펜틴-1-일)2,5-디히드로피리다진]Example 158 6- (4-chlorophenyl) -3-methoxy-2- (2'-pentyn-1-yl) 2,5-dihydropyridazine

화합물 157(1.0g, 0.00342몰), 나트륨금속(0.08g, 0.00342 그람원자), 및 무수메탄올(25㎖)의 혼합물을 모든 나트륨금속이 반응될 때까지 실온에서 교반하고, 반응혼합물을 다시 하룻밤동안 교반하였다. 메탄올을 진공증발시키고 잔류물을 에틸에테르(100㎖)에 넣었다. 에테르 용액을 염수(100㎖)로 세척하고 무수 MgSO4로 건조시켜 0.45g의 목적화합물을 황색고체로서 수득(45% 수율)하였다.A mixture of compound 157 (1.0 g, 0.00342 mole), sodium metal (0.08 g, 0.00342 gram atom), and anhydrous methanol (25 mL) was stirred at room temperature until all sodium metal reacted, and the reaction mixture was again overnight. Stirred. Methanol was evaporated in vacuo and the residue was taken up in ethylether (100 mL). The ether solution was washed with brine (100 mL) and dried over anhydrous MgSO 4 to afford 0.45 g of the desired compound as a yellow solid (45% yield).

메톡시화나트륨대신 칼륨트리아졸을 사용하여 유사한 방법으로 화합물 159가 제조되었다.Compound 159 was prepared in a similar manner using potassium triazole instead of sodium methoxide.

[실시예 161 : 2-(4-클로로페닐)-4-(-펜틴-1-일)-4H,6H-1,3,4-옥사디아진-5-온]Example 161 2- (4-Chlorophenyl) -4-(-pentyn-1-yl) -4H, 6H-1,3,4-oxadiazine-5-one]

a. N'-클로로아세틸-4-클로로벤조익히드라지드a. N'-chloroacetyl-4-chlorobenzoichydrazide

p-클로로벤조익히드라지드(11.2g)과 디옥산(100㎖)의 용액에 클로로아세틸클로라이드(6㎖)를 첨가하였다. 결과의 혼합물을 3시간동안 환류시키고 실온으로 냉각시키고 여과하였다. 결과 산출된 고체를 에틸에테르로 세척하고 건조시켜 N'-클로로아세틸-2-클로로벤조익히드라지드를 백색고체로서 수득하였다.Chloroacetyl chloride (6 mL) was added to a solution of p-chlorobenzoichydrazide (11.2 g) and dioxane (100 mL). The resulting mixture was refluxed for 3 hours, cooled to room temperature and filtered. The resulting solid was washed with ethyl ether and dried to give N'-chloroacetyl-2-chlorobenzoichydrazide as a white solid.

b. 5,6-디히드로-2-(4-클로로페닐)-4H-1,3,4-옥사디아진-3-온b. 5,6-dihydro-2- (4-chlorophenyl) -4H-1,3,4-oxadiazin-3-one

단계 a에서 산출된 화합물(6g), 수산화나트륨(1.5g)과 DMF(75㎖)의 혼합물을 130℃에서 2시간동안 교반하면서 가열하였다. 냉각된 반응혼합물을 물에 붓고, 결과 형성된 침전물을 여과하고 에탄올/물로 재결정시켜 5,6-디히드로-2-(4-클로로페닐)-4H -1,3,4-옥시디아진-3-온(3g)을 산출하였다.The mixture of compound (6 g), sodium hydroxide (1.5 g) and DMF (75 mL) calculated in step a was heated with stirring at 130 ° C. for 2 hours. The cooled reaction mixture was poured into water, the resulting precipitate was filtered and recrystallized from ethanol / water to give 5,6-dihydro-2- (4-chlorophenyl) -4H-1,3,4-oxydiazine-3- On (3 g) was calculated.

c. 2-(4-클로로페닐)-4-(2-펜틴-1-일)-4H,6H-1,3,4-옥사디아진-3-온c. 2- (4-chlorophenyl) -4- (2-pentyn-1-yl) -4H, 6H-1,3,4-oxadiazin-3-one

단계b에서 산출된 화합물(1.8g)을 수소화나트륨(1.3g, 60%in 미네랄유)과 DMF(75㎖)의 혼합물에 질소기권하 0℃에서 교반하면서 혼합하였다. 결과의 혼합물을 0℃에서 30분동안 교반하고 1-브로모-2-펜티(1.45g)을 0℃에서 교반하면서 방울방울 첨가하였다. 반응혼합물을 0℃에서 1시간동안 교반하고 얼음물(150g)에 붓고 여과하여 황색고체로서 목적화합물을 수득하였다.The compound (1.8 g) produced in step b was mixed with a mixture of sodium hydride (1.3 g, 60% in mineral oil) and DMF (75 mL) with stirring at 0 ° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C. for 30 minutes and 1-bromo-2-penti (1.45 g) was added dropwise with stirring at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour, poured into ice water (150 g) and filtered to afford the target compound as a yellow solid.

[실시예 162 : 2-(4-클로로페닐)-3-(2'-펜틴-1-일)-3H,6H-1,3,4-옥사디아진-3-온]Example 162 2- (4-Chlorophenyl) -3- (2'-pentyn-1-yl) -3H, 6H-1,3,4-oxadiazin-3-one]

a. 4-클로로-α-히드록시-아세토페논a. 4-Chloro-α-hydroxy-acetophenone

p-클로로아세토페논(32.2g), 수산화칼륨(68.5g)과 메탄올(400㎖)의 교반용액을 -℃로 유지시키면서 요오도벤젠 디아세테이트(67.33g)를 15분간에 걸쳐서 첨가하고, 혼합물을 신온으로 승온시키고 3시간동안 교반한 다음 감압하에서 증발건조시켰다. 잔류물을 물(300㎖) 및 에틸에테르(300㎖)와 함께 섞고, 에테르용액을 분리하여 황산마그네숨으로 건조시키고 증발건조시켰다. 잔류물, 에탄올(70㎖)과 수성 2N염산(70㎖)의 혼합물을 실온에서 하룻밤동안 교반한 다음 여과하고, 고체산물을 메탄올로 재결정시켜 4-클로로-α-히드록시-아세토페논(17.5g)을 산출하였다.Iodobenzene diacetate (67.33 g) was added over 15 minutes while maintaining a stirred solution of p-chloroacetophenone (32.2 g), potassium hydroxide (68.5 g) and methanol (400 mL) at-° C, and the mixture was The temperature was raised to new temperature, stirred for 3 hours, and evaporated to dryness under reduced pressure. The residue was mixed with water (300 mL) and ethyl ether (300 mL), the ether solution was separated, dried over magnesium sulfate and evaporated to dryness. The residue, a mixture of ethanol (70 mL) and aqueous 2N hydrochloric acid (70 mL) was stirred overnight at room temperature and then filtered, and the solid product was recrystallized from methanol to give 4-chloro-α-hydroxy-acetophenone (17.5 g). ) Was calculated.

b. 4-클로로아세토페논 에톡시카보닐히드라존b. 4-chloroacetophenone ethoxycarbonylhydrazone

단계 a에서 산출된 화합물(16.4g), 에틸카바제이트(10.5g) 및 에탄올(400㎖)의 혼합물을 실온에서 5일동안 교반한 다음 증발시켜 작은 부피로 농축시켰다. 맑은 용액이 수득될 때까지 잔류물을 가열하고, 냉각 및 여과시켜 4-클로로아세토페논 에톡시카보닐 히드라존을 백색고체(16.0g)로서 산출하였다.A mixture of compound (16.4 g), ethyl carbazate (10.5 g) and ethanol (400 mL), calculated in step a, was stirred at room temperature for 5 days and then evaporated to concentrated to a small volume. The residue was heated, cooled and filtered until a clear solution was obtained, yielding 4-chloroacetophenone ethoxycarbonyl hydrazone as a white solid (16.0 g).

c. 5-(4클로로페닐)-3H, 6H-1,3,4-옥시디아진-2-온c. 5- (4chlorophenyl) -3H, 6H-1,3,4-oxydiazin-2-one

단계 b에서 산출된 화합물(11.4g)과 에탄올(250㎖)의 교반용액에 수소화나트륨(0.5g, 60% in미네랄유)을 첨가하고, 혼합물을 실온에서 하룻밤동안 교반한 다음 여과 하였다. 형성된 고체산물을 여과 및 건조시켜 5-(4-클로로페닐)-3H,6H-1,3,4-옥사디아진-2-온을 백색고첼(8.2g)로서 수득하였다.Sodium hydride (0.5 g, 60% in mineral oil) was added to the stirred solution of compound (11.4 g) and ethanol (250 mL), which was then produced, and the mixture was stirred at room temperature overnight and then filtered. The solid product formed was filtered and dried to give 5- (4-chlorophenyl) -3H, 6H-1,3,4-oxadiazin-2-one as a white gochelle (8.2 g).

d. 5-(4-클로로페닐)-3H,6H-1,3,4-옥시디아진-2-온의 나트륨염d. Sodium salt of 5- (4-chlorophenyl) -3H, 6H-1,3,4-oxydiazin-2-one

단계 c에서 산출된 화합물(8.2g)과 테트라하이드로푸란(300㎖)의 교반용액에 수소화나트륨(2.0g, 60%in 미네랄유)을 첨가 하였다. 결과의 혼합물을 기체 방출이 정지될 때까지 실온에서 교반하고, 용매를 진공증발시키고 잔류물을 헥산으로 정제시켜 5-(4-클로로페닐)-3H,6H-1,3,4-옥사디아진-2-온의 나트륨염을 백색고체(10.4g)로서 수득하였다.Sodium hydride (2.0 g, 60% in mineral oil) was added to the stirred solution of compound (8.2 g) and tetrahydrofuran (300 mL) produced in step c. The resulting mixture was stirred at room temperature until gas evolution ceased, the solvent was evaporated in vacuo and the residue was purified with hexane to give 5- (4-chlorophenyl) -3H, 6H-1,3,4-oxadiazine Sodium salt of 2-one was obtained as a white solid (10.4 g).

e. 2-(4-클로로페닐)-3-(2-펜틴-1-일)-3H,6H-1,3,4-옥시디아진-2-온e. 2- (4-chlorophenyl) -3- (2-pentyn-1-yl) -3H, 6H-1,3,4-oxydiazin-2-one

단계 d에서 산출된 화합물(2.0g)을 질소기권하 0℃에서 DMF(75㎖)내에 교반하면서 용해시키고, 결과의 혼합물에 1-브로모-2-펜틴(1.5g)을 0℃에서 방울방울 첨가하였다. 반응혼합물을 0℃에서 1시간동안 교반하고 얼음물(150g)에 붓고 여과하여 목적화합물을 황색고체(2.5g)로서 수득하였다.The compound (2.0 g) obtained in step d was dissolved in DMF (75 mL) at 0 ° C. under nitrogen atmosphere, and 1-bromo-2-pentin (1.5 g) was added dropwise at 0 ° C. to the resulting mixture. Added. The reaction mixture was stirred at 0 ° C. for 1 hour, poured into ice water (150 g) and filtered to afford the desired compound as a yellow solid (2.5 g).

실질적으로 동일한 방법에 따라서 화합물 163과 164가 제조되었다.Compounds 163 and 164 were prepared following substantially the same method.

[실시예 165 : 5-(4-클로로페닐)-3-(2-펜틴-1-일)-3H,6H-1,3,4-티아디아진-2-온]Example 165 5- (4-Chlorophenyl) -3- (2-pentyn-1-yl) -3H, 6H-1,3,4-thiadiazin-2-one]

a. 5-(4-클로로페닐)-3H,6H-1,3,4-티아디아진-2-온a. 5- (4-chlorophenyl) -3H, 6H-1,3,4-thiadiazin-2-one

2-브로모-p-클로로아세토페논(9.16g), 메톡시티오카보닐히드라진(13.0g)과 아세토니트릴(75㎖)의 혼합물을 하룻밤동안 환류시킨다음 냉각 및 여과시켰다. 담황색고체를 헥산으로 세척하고 건조시켜 4.2g의 5-(4-클로로페닐)-3H,6H-1,3,4-티아디아진-2-온을 산출하였다.A mixture of 2-bromo-p-chloroacetophenone (9.16 g), methoxythiocarbonylhydrazine (13.0 g) and acetonitrile (75 mL) was refluxed overnight, then cooled and filtered. The pale yellow solid was washed with hexane and dried to yield 4.2 g of 5- (4-chlorophenyl) -3H, 6H-1,3,4-thiadiazin-2-one.

b. 5-(4-클로로페닐)-3H,6H-1,3,4-티아디아진-2-온의 나트륨염b. Sodium salt of 5- (4-chlorophenyl) -3H, 6H-1,3,4-thiadiazin-2-one

단계 a에서 산출된 화합물(2.0g)과 THF(100㎖)의 교반용액에 수소화나트륨 (0.5g, 60% in 미네랄유)을 첨가하였다. 결과의 혼합물을 기체방출이 중지될때까지 실온에서 교반하고, 용매를 진공증발시키고 잔류물을 헥산으로 정제하여 5-(4-클로로페닐)-3H,6H-1,3,4-티아디아진-2-온의 나트륨염을 산출하였다.Sodium hydride (0.5 g, 60% in mineral oil) was added to the stirred solution of the compound (2.0 g) and THF (100 mL) obtained in step a. The resulting mixture was stirred at room temperature until gas evolution ceased, the solvent was evaporated in vacuo and the residue was purified with hexane to give 5- (4-chlorophenyl) -3H, 6H-1,3,4-thiadiazine- The sodium salt of 2-one was calculated.

c. 5-(4-클로로페닐)-3-(2-펜틴-1-일)-3H,6H-1,3,4-티아디아진-2-온c. 5- (4-chlorophenyl) -3- (2-pentyn-1-yl) -3H, 6H-1,3,4-thiadiazin-2-one

단계 b에서 산출된 화합물을 질소기권하 0℃에서 DMF (75㎖)내에 교반하면서 용해시켰다. 결과의 혼합물에 1-브로모-2-펜틴(1.5g)을 0℃에서 교반첨가하였다. 반응혼합물을 0℃에서 2시간동안 교반하고 얼음물(150g)에 붓고 여과하여 황색고체로서 목적화합물을 수득하였다.The compound produced in step b was dissolved with stirring in DMF (75 mL) at 0 ° C. under a nitrogen atmosphere. To the resulting mixture was added 1-bromo-2-pentin (1.5 g) by stirring at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours, poured into ice water (150 g), and filtered to obtain the target compound as a yellow solid.

[실시예 200 : 4,4a,5,6-테트라히드로-8-클로로[h]-시놀린-2-(2'-펜틴일)-3-온]Example 200 4,4a, 5,6-Tetrahydro-8-chloro [h] -shinolin-2- (2'-pentynyl) -3-one]

a. 4-(3-클로로페닐)부티르산a. 4- (3-chlorophenyl) butyric acid

자석교반기 및 환류냉각기가 장착된 300㎖들이 둥근바닥 플라스크에 23.7g의 87% 수산화칼륨과 150㎖의 디에틸렌글리콜을 채우고, 교반하면서, 23g의 3-(3-클로로벤조일)프로파온산 및 24g의 85% 히드라진을 첨가하였다. 혼합물을 2시간동안 환류가열시켰으며, 50㎖의 용매가 딘-스타크트랩내로 공비배출되었다. 반응혼합물을 2시간동안 더 환류시키고, 냉각시킨후 500g의 얼음과 50㎖의 진한 염산의 혼합물에 부었다. 형성된 백색침전물을 400㎖의 에틸에테르로 추출하고 물(100㎖) 및 포화염수(10ml)로 세척하였다. 에테르 추출물을 무수황산마그네슘으로 건조시키고 여과 및 증발시켜 19.5g의 목적산물을 백색고체로서 수득하였다.A 300 ml round bottom flask equipped with a magnetic stirrer and reflux cooler was charged with 23.7 g of 87% potassium hydroxide and 150 ml of diethylene glycol and stirred, 23 g of 3- (3-chlorobenzoyl) propanoic acid and 24 g 85% hydrazine of was added. The mixture was heated to reflux for 2 hours, and 50 mL of solvent was azeotrope into the Dean-Stark trap. The reaction mixture was further refluxed for 2 hours, cooled and poured into a mixture of 500 g ice and 50 mL concentrated hydrochloric acid. The white precipitate formed was extracted with 400 ml of ethyl ether and washed with water (100 ml) and saturated brine (10 ml). The ether extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give 19.5 g of the desired product as a white solid.

b. 4-(3-클로로페닐)-부티릴클로라이드b. 4- (3-chlorophenyl) -butyryl chloride

자석교반기 및 환류냉각기가 장착된 100㎖의 건조된 플라스크에 단계 a에서 산출된 화합물 및 티오닐클로라이드(20㎖)를 채우고, 결과의 용액을 2시간동안 환류시키고, 냉각 및 증발시켜 18g의 목적산물을 황색오일로서 수득하였다.A 100 ml dried flask equipped with a magnetic stirrer and a reflux condenser was charged with the compound obtained in step a and thionyl chloride (20 ml), and the resulting solution was refluxed for 2 hours, cooled and evaporated to 18 g of the desired product. Was obtained as a yellow oil.

c. 6-클로로테트라론c. 6-chlorotetraron

사이드암 첨가깔대기, 온도계, 질소주입구, 및 자석교반기가 장착된 500㎖들이 플라스크에 33g의 무수염화알루미늄 및 200㎖의 무수 아황화탄소를 채우고, 그 혼합물에 단계b의 산출물(18g)을 방울방울 첨가한후 반응혼합물을 2.5시간동안 환류시켰다.반응혼합물을 냉각시키고 300g의 얼음물에 붓고 에틸에테르(3x100㎖)로 추출하였다. 에테르 추출물을 100㎖의 포화염수로 세척하고 무수 황산마그네슘으로 건조시키고 여과 및 증발시켜 7.5g의 목적산물을 황색액체로서 수득하였다.Fill a 500 ml flask equipped with sidearm funnel, thermometer, nitrogen inlet, and magnetic stirrer with 33 g of anhydrous aluminum chloride and 200 ml of anhydrous sulfite, and drop the product of step b (18 g) into the mixture. After the addition, the reaction mixture was refluxed for 2.5 hours. The reaction mixture was cooled, poured into 300 g of ice water, and extracted with ethyl ether (3 × 100 mL). The ether extract was washed with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 7.5 g of the desired product as a yellow liquid.

d. 6-클로로-2-(카르복시메틸인덴)-테트라론d. 6-chloro-2- (carboxymethylindene) -tetrarone

사이드암 첨가깔대기, 온도계 및 자석교반기가 장착된 250㎖들이 건조 플라스크에 6.7g의 메타퍼요오드산 나트륨과 40㎖의 물을 넣고, 그 용액을 5℃로 냉각시키고 0.6㎖의 진한 황산으로 처리한 다음 D-타타르산(4.7g)과 물(9㎖)의 용액 및 20㎖의 무수에탄올을 첨가하였다. 혼합물을 실온에서 16시간동안 교반하고 10분동안 80℃로 가열한 다음 냉각시키고 150㎖의 물로 희석시켰다. 염기성 용액을 100㎖의 에틸에테르로 한번 세척하고, 1N염산을 사용하여 pH 4로 산성화시켰다. 결과 형성된 침전물을 진공여과에 의하여 수집하고 30℃에서 하룻밤동안 진공건조시켜 7.2g의 목적산물(백색고체)를 산출하였다.In a 250 ml dry flask equipped with a sidearm funnel, thermometer and magnetic stirrer, 6.7 g of sodium metaperiodate and 40 ml of water were cooled, and the solution was cooled to 5 ° C. and treated with 0.6 ml of concentrated sulfuric acid. Then a solution of D-tartaric acid (4.7 g) and water (9 mL) and 20 mL of ethanol anhydride were added. The mixture was stirred at rt for 16 h, heated to 80 ° C. for 10 min, then cooled and diluted with 150 mL of water. The basic solution was washed once with 100 ml of ethyl ether and acidified to pH 4 with 1N hydrochloric acid. The resulting precipitate was collected by vacuum filtration and vacuum dried overnight at 30 ° C. to yield 7.2 g of the desired product (white solid).

e. 6-클로로-2-(카르복시메틸렌)-테트라론e. 6-chloro-2- (carboxymethylene) -tetrarone

자속교반기가 장착된 100㎖들이 건조플라스크에 단계 d 에서의 산출물(7.2g), 물(20㎖), 빙초산(50㎖), 및 아연분말(3.8g)을 채우고, 반응혼합물을 1시간동안 50℃로 가열하고 상온에서 하룻밤동안 교반하였다. 반응혼합물을 100㎖의 에틸아세테이트에 붓고 여과하고, 물(100㎖) 및 포화염수(100㎖)로 세척하였다. 에틸 아세테이트 추출물을 무수 황산마그네슘으로 건조시키고, 여과 및 탈수시켜 6.0g의 목적산물(백색고체)을 산출하였다.A 100 ml dry flask equipped with a magnetic flux stirrer was charged with the output (7.2 g), water (20 ml), glacial acetic acid (50 ml) and zinc powder (3.8 g) in step d. Heat to C and stir overnight at room temperature. The reaction mixture was poured into 100 ml of ethyl acetate, filtered, and washed with water (100 ml) and saturated brine (100 ml). The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and dehydrated to yield 6.0 g of the desired product (white solid).

f. 4,4a,5,6-테트라히드로-8-클로로벤조[h]시놀린-3-(2H)-온f. 4,4a, 5,6-tetrahydro-8-chlorobenzo [h] cinonoline-3- (2H) -one

실시예 12d에 기술된 바와 유사한 방법을 사용하여, 상기 단계 e의 산출물을 히드라진과 함께 처리하여 5.7g의 목적산물을 황갈색고체로서 수득하였다.Using a method similar to that described in Example 12d, the output of step e was treated with hydrazine to yield 5.7 g of the desired product as a tan solid.

g. 4,4a,5,6-테트라히드로-8-클로로벤조[h]시눌린-2-(2'-펜틴일)-3-온g. 4,4a, 5,6-tetrahydro-8-chlorobenzo [h] syninin-2- (2'-pentynyl) -3-one

실시예 12e에 기술된 바와 실질적으로 동일한 방법을 사용하여 상기단계 e의 산출물로부터 목적화합물이 제조되었따.The desired compound was prepared from the output of step e using substantially the same method as described in Example 12e.

[실시예 201 : 6-(4-클로로페닐)-2-메틸-4,5-디히드로피리다지논]Example 201 6- (4-Chlorophenyl) -2-methyl-4,5-dihydropyridazinone

자석교반기 및 환류냉각기가 장착된 250㎖들이 플라스크에 10g의 3-(4-클로로벤조일) 프로피온산, 250㎖의 무수에탄올, 및 2.5㎖의 메틸히드라진을 채우고, 반응혼합물을 3시간동안 환류시키고 냉각시켜 수득한고체를 진공여과에 의하여 수집하고 50㎖의 헥산으로 세척하고 공기건조시켰다. 9.5g의 목적화합물이 백색고체로서 수득되었다.A 250 ml flask equipped with a magnetic stirrer and reflux cooler was charged with 10 g of 3- (4-chlorobenzoyl) propionic acid, 250 ml of ethanol anhydride, and 2.5 ml of methylhydrazine, and the reaction mixture was refluxed and cooled for 3 hours. The solid obtained was collected by vacuum filtration, washed with 50 ml of hexane and air dried. 9.5 g of the desired compound were obtained as a white solid.

[실시예 202 : 5,6-디히드로-8-클로로벤조[h]시놀린-3-(2'-펜틴일)-온]Example 202 5,6-dihydro-8-chlorobenzo [h] cinonoline-3- (2'-pentynyl) -one]

실시예 200의 단계 f로부터의 산출물을 실시예 109a, b에 기술된 바와 실질적으로 동일한 방법을 사용하여 산화 및 알킬화 시켜 목적화합물을 산출하였다.The output from step f of Example 200 was oxidized and alkylated using substantially the same method as described in Examples 109a and b to yield the desired compound.

[실시예 203 : 6-(4-클로로페닐)-4-(2'-펜틴일)-2-메틸-4,5-다하드로피리다지논]Example 203 6- (4-Chlorophenyl) -4- (2'-pentynyl) -2-methyl-4,5-dahydropyridazinone]

질소주입구, 사이드암 첨가깔대기, 온도계, 및 자석교반기가 구비된 250㎖들이 건조플라스크에 3.0g의 화합물 201 및 75㎖의 무수에틸에테르를 넣고, 그 용액을 드라이아이스-아세톤 조내에서 -78℃로 냉각시키고 8.4㎖의 1.6M n-부틸리튬을 방울방울 첨가하였다. 반응혼합물을 -78℃에서 30분동안 교반한다음 1.98g의 펜틴일브로마이드와 25㎖의 에테르를 방울방울 첨가하였다. 반응혼합물을 -70℃에서 1시간교반하고 이어서 상온에서 하룻밤동안 교반한 다음 100㎖의 물로 냉각시키고 에틸에테르(3x100㎖)로 추출하였다. 에테르 추출물을 물(100㎖) 및 포화염수(100㎖)로 세척하고 무수황산마그네슘으로 건조시키고 여과 및 증발시켜 수득한 황색오일을 실리카겔상에서 크로마토그라피(30:70, 에틸아세테이드/헥산)시켜 0.7g의 목적화합물(백색고체)를 산출하였다.Into a 250 ml dry flask equipped with a nitrogen inlet, sidearm funnel, thermometer, and magnetic stirrer, 3.0 g of compound 201 and 75 ml of anhydrous ethyl ether were added and the solution was brought to -78 ° C in a dry ice-acetone bath. Cool and 8.4 ml of 1.6 M n-butyllithium were added dropwise. The reaction mixture was stirred at −78 ° C. for 30 minutes, followed by dropwise addition of 1.98 g of pentynyl bromide and 25 mL of ether. The reaction mixture was stirred at −70 ° C. for 1 hour and then stirred overnight at room temperature, cooled with 100 mL of water and extracted with ethyl ether (3 × 100 mL). The ether extract was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated, and the yellow oil was chromatographed (30:70, ethyl acetate / hexane) on silica gel. 0.7 g of the target compound (white solid) was calculated.

[실시예 204 : 6-(4-클로로페닐)-2-(5-메틸-2-푸라닐메틸렌)-피리다지논]Example 204 6- (4-Chlorophenyl) -2- (5-methyl-2-furanylmethylene) -pyridazinone]

a. 2-클로로메틸-5-메틸푸란a. 2-chloromethyl-5-methylfuran

환류냉각기, 자석교반기, 질소주입구 및 사이드암 첨가 깔대기가 구비된 200㎖들이 건조플라스크에 10g의 2-디메틸아미노메틸-5-메틸푸란 및 50㎖의 헥산을 넣고, 실온에서 7.8g의 에틸클로로포르메이트를 방울방울 첨가하고 결과의 용액을 2시간동안 환류시켰다. 혼합물을 진공증류 (60-65℃, 0.5mmHg)시켜 1g의 순수한 목적산물을 수득하였다.In a 200 ml dry flask equipped with a reflux cooler, a magnetic stirrer, a nitrogen inlet, and a sidearm addition funnel, 10 g of 2-dimethylaminomethyl-5-methylfuran and 50 ml of hexane were added and 7.8 g of ethylchloroform at room temperature. The mate was added dropwise and the resulting solution was refluxed for 2 hours. The mixture was vacuum distilled (60-65 ° C., 0.5 mm Hg) to afford 1 g of pure desired product.

b. 6-(4-클로로페닐)-2-(5-메틸-2-푸라닐메틸렌)피리다지논b. 6- (4-chlorophenyl) -2- (5-methyl-2-furanylmethylene) pyridazinone

실시예 12e에 기술된 바와 실질적으로 동일한 방법을 사용하여 상기 단계 a의 산출물로부터 목적화합물이 제조되었다.The desired compound was prepared from the output of step a using substantially the same method as described in Example 12e.

[실시예 205 : 6-(4-클로로스티릴)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 205 6- (4-Chlorostyryl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 3-(4-클로로신나모일)-프로피온산a. 3- (4-Chlorocinnamoyl) -propionic acid

자석교반기, 딘-스타크트햅 및 환류냉각기가 구비된 250㎖들이 건조플라스크에 15g의 4-클로로벤즈알데히드, 12.4g의 레블렌산, 5.7㎖의 피페리딘, 및 100㎖의 톨루엔을 넣고 반응혼합물을 3시간동안 환류시켰다.In a 250 ml dry flask equipped with a magnetic stirrer, Dean-Starkhap and reflux cooler, 15 g of 4-chlorobenzaldehyde, 12.4 g of leblenic acid, 5.7 ml of piperidine, and 100 ml of toluene were added to the reaction mixture. It was refluxed for time.

용액으로부터 공비되는 물이 더 이상 관찰되지 않았다. 혼합물을 냉각시키고 증발시켜 수득한 적갈색 액체를 헥산으로 정제시켜 11.2g의 목적산물을 황색고체로서 산출하였다.Azeotropic water from the solution was no longer observed. The mixture was cooled and evaporated to give a reddish brown liquid which was purified by hexane to yield 11.2 g of the desired product as a yellow solid.

b. 6-(4-클로로스티릴)-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (4-chlorostyryl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 12d-e에서와 실질적으로 동일한 방법을 사용하여, 상기 단계 a의 산출물을 히드라진과 함께 고리화시키고 펜틴일 메실레이트와 함께 알킬화 시켜서 목적화합물을 산출하였다.Using the substantially same method as in Example 12d-e, the output of step a was cyclized with hydrazine and alkylated with pentynyl mesylate to yield the desired compound.

[실시예 206 : 6-(4-클로로스티릴)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 206 6- (4-Chlorostyryl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

4.5g의 6-(4-클로로스티릴)-2(H)-디히드로피리다지논을 200㎖의 메톡시에탄올에 용해시키고 500㎖ Parr수소화 병에 넣었다. 탄소상의 10% 팔라듐(1g)을 메톡시에탄올내의 슬러리로서 첨가하고 반응혼합물을 50Psi, 상온에서 Parr 기구내에서 수소로 처리하였다. 이론적인 양의 수소가 소비되었을 때 (약 35분), 수소화를 멈추고 촉매를 걸러냈다. 유기용매를 제거하고 잔류물을 크로마토그라피(실리카겔, 50/50 에틸아세테이트/헥산)시켜서 3.4g의 목전산물을 황색고체로서 수득하였다.4.5 g of 6- (4-chlorostyryl) -2 (H) -dihydropyridazinone was dissolved in 200 ml of methoxyethanol and 500 ml Parr Placed in a hydrogenation bottle. 10% palladium on carbon (1 g) was added as a slurry in methoxyethanol and the reaction mixture was treated with hydrogen in a Parr apparatus at 50 Psi, room temperature. When the theoretical amount of hydrogen was consumed (about 35 minutes), the hydrogenation was stopped and the catalyst was filtered off. The organic solvent was removed and the residue was chromatographed (silica gel, 50/50 ethyl acetate / hexanes) to afford 3.4 g of the crude product as a yellow solid.

b. 6-(4-클로로페네틸)-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (4-chlorophenethyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 12d에 기술된 바와 실질적으로 동일한 방법을 사용하여 상기 단계 a의 산출물을 펜티닐 메실레이트와 함계 알킬화시켜 목적화합물을 산출하였다.The output of step a was alkylated with pentynyl mesylate using substantially the same method as described in Example 12d to yield the desired compound.

[실시예 207 : 6-(3,4-메틸렌디옥시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 207 6- (3,4-methylenedioxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12 b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 피페로닐산으로부터 목적화합물이 제조되었다.The desired compound was prepared from piperonylic acid using substantially the same method as described in Example 12 b-e.

[실시예 208 : 6-(4-클로로페닐)-2-(1-메틸-2-펜틴일)-4,5-디히드로피리다지논]Example 208 6- (4-Chlorophenyl) -2- (1-methyl-2-pentynyl) -4,5-dihydropyridazinone]

a. 3-헥신-2-일-메틸 술포네이트a. 3-hexyn-2-yl-methyl sulfonate

실시예 11a에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-헥신-2올의 메실레이트가 제조되었다.Mesylate of 3-hexyn-2ol was prepared using substantially the same method as described in Example 11a.

b. 6-(4-클로로페닐)-2-(1-메틸-2-펜틴일)-4,5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- (1-methyl-2-pentynyl) -4,5-dihydropyridazinone

실시예 6b에 기술된 바와 실질적으로 동일한 방법을 사용하여 6-(4-클로로페닐)-4,5-디히드로피리다지논을 상기 단계 a로 부터의 산출물과 함께 알킬화 시켜서 몰적화합물을 산출하였다.Using the same method as described in Example 6b, 6- (4-chlorophenyl) -4,5-dihydropyridazinone was alkylated with the output from step a above to yield the molar compound.

[실시예 209 : 6-(2-플루오로페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논]Example 209 6- (2-fluorophenyl) -2- (2'-pentynyl) -4, 5-dihydropyridazinone]

실시예 12b-e에 기술된바와 실질적으로 동일한 방법을 사용하여 2-플루오로벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 2-fluorobenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 210 : 6-(2-메틸페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논]Example 210 6- (2-methylphenyl) -2- (2'-pentynyl) -4, 5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 2-메틸벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 2-methylbenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 211 : 6-(2-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 211 6- (2-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 2-클로벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 2-clobenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 212 : 6-(2-메톡시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 212 6- (2-methoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된바와 실질적으로 동일한 방법을 사용하여 2-메톡시벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 2-methoxybenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 213 : 6-(3-트리플루오로메틸페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 213 6- (3-trifluoromethylphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된바와 실질적으로 동일한 방법을 사용하여 3-트리플루오로메틸벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-trifluoromethylbenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 214 : 6-(3-플루오로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 214 6- (3-fluorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-플루오로벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-fluorobenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 215 : 6-(3-메틸페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 215 6- (3-methylphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-메틸벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-methylbenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 216 : 6-(3-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 216 6- (3-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-클로로벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-chlorobenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 217 : 6-(3-시아노페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 217 6- (3-cyanophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-시아노벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-cyanobenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 218 : 6-(3-니트로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 218 6- (3-nitrophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-니트로벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-nitrobenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 219 : 6-(3-메톡시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 219 6- (3-methoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-메톡시벤조일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-methoxybenzoyl chloride using substantially the same method as described in Example 12b-e.

[실시예 220 : 6-(3-메톡시-4-메틸페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 220 6- (3-methoxy-4-methylphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-메톡시-4-메틸벤조산 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-methoxy-4-methylbenzoic acid chloride using substantially the same method as described in Example 12b-e.

[실시예 221 : 6-(3-클로로-4-메톡시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 221 6- (3-chloro-4-methoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-클로로-4-메톡시벤조산 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-chloro-4-methoxybenzoic acid chloride using substantially the same method as described in Example 12b-e.

[실시예 222 : 6-(3-브로모-4-플루오로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 222 6- (3-bromo-4-fluorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-브로모-4-플루오로벤조산 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-bromo-4-fluorobenzoic acid chloride using substantially the same method as described in Example 12b-e.

[실시예 223 : 6-(3-니트로-4-메톡시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 223 6- (3-nitro-4-methoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-니트로-4-메톡시벤조산으로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-nitro-4-methoxybenzoic acid using substantially the same method as described in Example 12b-e.

[실시예 224 : 6-(3,4-디플루오로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 224 6- (3,4-difluorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된바와 실질적으로 동일한 방법을 사용하여 3,4-디플루오로벤조산으로부터 목적화합물이 제조되었다.The desired compound was prepared from 3,4-difluorobenzoic acid using substantially the same method as described in Example 12b-e.

[실시예 225 : 6-(3-플루오로-4-메틸페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 225 6- (3-fluoro-4-methylphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 3-플루오로-4-메틸벤조산 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 3-fluoro-4-methylbenzoic acid chloride using substantially the same method as described in Example 12b-e.

[실시예 226 : 6-(3-니트로-4-메톡시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 226 6- (3-nitro-4-methoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 3-니트로-4-메톡시벤조산a. 3-nitro-4-methoxybenzoic acid

자석교반기가 구비된 500㎖들이 엘렌메이어 플라스크에 10.3g의 3-니트로-4-메톡시메틸벤조에이트, 400㎖의 테트라하이드로푸란, 및 3.2g의 86% 수산화칼륨을 채우고, 반응혼합물을 상온에서 12시간동안 교반한후, 결과산출된 고체를 진공여과에 의하여 수집하고 에틸에테르(2x100㎖)로 세척하였다. 고체를 200㎖의 물에 용해 시키고 6N 염산을 사용하여 pH 4로 산성화시켰다. 결과 형성된 침전물을 진공여과에 의하여 수집하고 200㎖의 물로 세척하고 30℃에서 하룻밤동안 진공건조시켜 7.4g의 목전산물을 백색고체로서 수득하였다.Fill a 500 ml Elenmeyer flask with a magnetic stirrer with 10.3 g of 3-nitro-4-methoxymethylbenzoate, 400 ml of tetrahydrofuran, and 3.2 g of 86% potassium hydroxide, and the reaction mixture at room temperature. After stirring for 12 hours, the resulting solid was collected by vacuum filtration and washed with ethyl ether (2x100 mL). The solid was dissolved in 200 mL of water and acidified to pH 4 with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with 200 ml of water and dried in vacuo at 30 ° C. overnight to yield 7.4 g of a crude product as a white solid.

b. 6-(3-니트로-4-메톡시페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논b. 6- (3-nitro-4-methoxyphenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 12b-e에 기술된 바와 실질적으로 동일한 방법을 사용하여 상기 단계 a의 산출물을 목적화합물로 전환시켰다.The output of step a was converted to the target compound using substantially the same method as described in Example 12b-e.

[실시예 227 : 6-(9,10-디히드로-2-페나프탈렌)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 227 6- (9,10-dihydro-2-phenaphthalene) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 6a-b에 기술된바와 실질적으로 동일한 방법을 사용하여 9,10-디히드로-오메가-옥소-2-페나프탈렌부티르산부터 목적화합물이 제조되었다.The desired compound was prepared from 9,10-dihydro-omega-oxo-2-phennaphthalenebutyric acid using substantially the same method as described in Examples 6a-b.

[실시예 228 : 5,6-디페닐-4-시아노-2-(2'-펜틴일)-4,5-피리다지논]Example 228 5,6-diphenyl-4-cyano-2- (2'-pentynyl) -4,5-pyridazinone

실시예 12e에 기술된바와 실질적으로 동일한 방법을 사용하여 2,3-디히드로-3-옥소-5,6-디페닐-4-피리다진 카보니트릴로부터 목적화합물이 제조되었다.The desired compound was prepared from 2,3-dihydro-3-oxo-5,6-diphenyl-4-pyridazine carbonitrile using substantially the same method as described in Example 12e.

[실시예 229 : 6-(2-퀴놀린)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 229 6- (2-Quinoline) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된바와 실질적으로 동일한 방법을 사용하여 2-퀴놀린 카르복시산으로부터 목적화합물이 제조되었다.The desired compound was prepared from 2-quinoline carboxylic acid using substantially the same method as described in Example 12b-e.

[실시예 230 : 6-(2-퀴녹살린)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 230 6- (2-quinoxaline) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

실시예 12b-e에 기술된바와 실질적으로 동일한 방법을 사용하여 2-퀴녹살로일 클로라이드로부터 목적화합물이 제조되었다.The desired compound was prepared from 2-quinoxaloyl chloride using substantially the same method as described in Example 12b-e.

[실시예 231 : 6-(4-클로로페닐)-2-(3,5-디메틸-4-이소옥소일메틸)-디히드로피리다지논]Example 231 6- (4-chlorophenyl) -2- (3,5-dimethyl-4-isooxoylmethyl) -dihydropyridazinone]

실시예 6b에 기술된바와 실질적으로 동일한 방법을 사용하여 4-(클로로메틸)-3,5-디메틸이소옥소졸로부터 목적화합물이 제조되었다.The desired compound was prepared from 4- (chloromethyl) -3,5-dimethylisoxosol using substantially the same method as described in Example 6b.

[실시예 232 : 8-(2'-펜틴일)아세나프토[1,2c]피리다진-9-온]Example 232: 8- (2'-pentynyl) acenaphtho [1,2c] pyridazine-9-one

a. 메틸(Z)-(1,2-디히드로-2-옥소-1-아세나프탈렌일리덴)-아세테이트a. Methyl (Z)-(1,2-dihydro-2-oxo-1-acenaphthalenylidene) -acetate

자석교반기, 온도계, 질소주입구, 및 사이드암 첨가 깔대기가 구비되 500㎖들이 플라스크에 8.4g의 메틸-(트리페닐포스포르아닐리덴)아세테이트 및 200㎖의 무수에탄올을 채웠다. 즉시 침전이 형성되었다. 반응혼합물을 상온에서 2시간동안 교반한 다음, 침전을 진공여과에 의해 수집하였다. 4.4g의 목적산물이 황색고체로서 수득되었다.A 500 ml flask was equipped with 8.4 g of methyl- (triphenylphosphoranilidene) acetate and 200 ml of anhydrous ethanol equipped with a magnetic stirrer, thermometer, nitrogen inlet, and sidearm addition funnel. A precipitate formed immediately. The reaction mixture was stirred at room temperature for 2 hours, and then the precipitate was collected by vacuum filtration. 4.4 g of the desired product were obtained as a yellow solid.

b. 8-(H)-아세나프토[1,2c]피리다진-9-온b. 8- (H) -acenaphtho [1,2c] pyridazine-9-one

자석교반기 및 환류냉각기가 구비된 200㎖들이 플라스크에 단계 a로부터의 산출물(2.5g) 및 클로로포롬(100㎖)을 채우고, 실온에서 0.45㎖의 85% 히드라진을 첨가한 후 반응혼합물을 총 2시간동안 환류시켰다. 냉각시 형성된 침전물을 진공여과에 의하여 수집하였다. 0.5g의 목적산물이 황색고체로서 수득되었다.Fill a 200 ml flask equipped with a magnetic stirrer and reflux cooler with the output from step a (2.5 g) and chloroform (100 ml), add 0.45 ml of 85% hydrazine at room temperature and then add the reaction mixture to the mixture for 2 hours. Reflux for a while. The precipitate formed upon cooling was collected by vacuum filtration. 0.5 g of the desired product were obtained as a yellow solid.

c. 8-(2'-펜틴일)아세나프토[1.2c]피리다진-9-온c. 8- (2'-pentynyl) acenaphtho [1.2c] pyridazine-9-one

실시예 12e에 기술된 바와 실질적으로 동일한 조건들을 사용하여 상기 단계 b의 산출물을 펜틴일 메실레이트와 함께 알킬화시켜서 목적화합물을 산출하였다.The product of step b was alkylated with fentinyl mesylate using substantially the same conditions as described in Example 12e to yield the desired compound.

[실시예 233 : 6-(4-클로로페닐)-2-(아세틸히드라지드)-4,5-디히드로피리다지논]Example 233 6- (4-chlorophenyl) -2- (acetylhydrazide) -4,5-dihydropyridazinone]

a. 6-(4-클로로페닐)-2-(에틸아세틸)-4,5-디히드로피리다지논a. 6- (4-chlorophenyl) -2- (ethylacetyl) -4,5-dihydropyridazinone

자석교반기와 환루냉각기가 구비된 100㎖들이 건조 플라스크에 10g의 (4-클로로벤조일)-프로피온산, 50㎖의 무수에탄올, 및 5.3g의 트리에틸아민을 채우고, 교반하면서, 7.3g의 에틸 히드라지노아세테이트 하이드로클로라이드를 방울방울 첨가하고 반응혼합물을 3시간동안 환류시켰다.A 100 ml dry flask equipped with a magnetic stirrer and an annulus cooler was charged with 10 g of (4-chlorobenzoyl) -propionic acid, 50 ml of ethanol anhydride, and 5.3 g of triethylamine, and stirred, 7.3 g of ethyl hydrazino Droplets of acetate hydrochloride were added and the reaction mixture was refluxed for 3 hours.

냉각후 형성된 백색결정성 고체를 진공여과에 의하여 수집하고 헥산으로 세척하였다. 13.3g의 목적산물이 백색고체로서 수득되었다.The white crystalline solid formed after cooling was collected by vacuum filtration and washed with hexane. 13.3 g of the desired product were obtained as a white solid.

b. 6-(4-클로로페닐)-2-(아세틸히드라지드)-4,5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- (acetylhydrazide) -4,5-dihydropyridazinone

자석교반기와 환류냉각기가 구비된 100㎖들이 플라스크에 산출물(10.2g), 물(10㎖), 및 80%의 히드라진(6.1㎖)을 채우고, 반응 혼합물을 70℃로 6시간동안 가열한 후 냉각시키고 200㎖의 냉수로 희석시켰다.Fill a 100 ml flask with a magnetic stirrer and reflux cooler with output (10.2 g), water (10 ml) and 80% hydrazine (6.1 ml) and heat the reaction mixture to 70 ° C. for 6 hours and then cool. And diluted with 200 ml of cold water.

결과 형성된 고체를 진공여과에 의하여 수집하고 40℃에서 하룻밤동안 진공건조시켜 9.6g의 목적산물을 백색고체로서 수득하였다.The resulting solid was collected by vacuum filtration and dried in vacuo at 40 ° C. overnight to yield 9.6 g of the desired product as a white solid.

[실시예 234 : 6-(4-클로로페닐)-2-[N-아세틸히드라지드-(N'-2,4-펜탄디온-히드라졸)]-4,5-디히드로피리다지논]Example 234 6- (4-Chlorophenyl) -2- [N-acetylhydrazide- (N'-2,4-pentanedione-hydrazole)]-4,5-dihydropyridazinone]

자석교반기와 환류냉각기가 구비된 100㎖들이 건조플라스크에 화합물 233(1g),무수에탄올(30㎖), 및 2,4-펜탄디온(0.4㎖)을 채우고 1시간동안 환류시킨후, 용매를 제거하고 잔류물을 헥산으로 정제시켜 0.7g의 목적화합물을 담화색 고체로서 수득하였다.A 100 ml dry flask equipped with a magnetic stirrer and a reflux condenser was charged with compound 233 (1 g), ethanol anhydride (30 ml), and 2,4-pentanedione (0.4 ml), refluxed for 1 hour, and then the solvent was removed. The residue was purified by hexane to afford 0.7 g of the desired compound as a pale solid.

[실시예 235 : 6-(3-티아나프탈렌)-2-(2'-펜틴일)-4,5-디히드로피리다지논]Example 235 6- (3-thianaphthalene) -2- (2'-pentynyl) -4,5-dihydropyridazinone]

a. 3-티아나프탈렌오일 아크릴산a. 3-thianaphthalen oil acrylic acid

단-스타크트랩과 환류냉각기 및 자석교반기가 구비된 250㎖들이 플라스트에 5g의 3-아세틸 티아나프탈렌, 100㎖의 톨루엔, 및 3.9g의 수화 글리옥실산을 채우고 반응혼합물을 2.5시간동안 환류 및 공비시킨 후 진공증류에 의하여 톨루엔을 제거하였다. 결과의 잔류물을 헥산으로 세척하고 진공여과에 의하여 고체를 수집하여 6g의 목적산물을 황색고체로서 수득하였다.A 250 ml flask equipped with a single-star trap, reflux cooler and a magnetic stirrer was charged with 5 g of 3-acetyl thianaphthalene, 100 ml of toluene, and 3.9 g of hydrated glyoxylic acid and the reaction mixture was refluxed for 2.5 hours and After azeotropy, toluene was removed by vacuum distillation. The resulting residue was washed with hexane and the solid collected by vacuum filtration to give 6 g of the desired product as a yellow solid.

b. 6-(3-티아나프탈렌)-2[H]-4,5-디히드로피리다지논b. 6- (3-thianaphthalene) -2 [H] -4,5-dihydropyridazinone

자석교반기와 환류냉각기가 구비된 100㎖들이 플라스크에 단계 a의 산출물을 채우고 60㎖의 빙초산 및 20㎖의 물을 첨가하고 이어서 2.5g의 아연분말을 첨가하였다. 반응 혼합물을 50℃에서 2시간동안 가열한 후 냉각시키고 150㎖의 에틸아세테이트에 부었다. 불용물질을 걸러내고 에틸아세테이드 추출물을 100㎖의 물 및 100㎖의 포화염수로 세척하고 무수황산마그네슘으로 건조시키고 여과 및 탈수시켰다. 잔류물을 50㎖의 무수에틴올에 재용해시키고 0.75㎖의 85% 히드라진으로 처리하였다. 3시간 환류시킨후, 반응 혼합물을 냉각시키고 진공여과에 의하여 고체를 수집하여, 3.7g의 목적산물을 황색고체로서 수득하였다.The 100 mL flask equipped with the magnetic stirrer and the reflux cooler was charged with the output of step a, 60 mL of glacial acetic acid and 20 mL of water were added followed by 2.5 g of zinc powder. The reaction mixture was heated at 50 ° C. for 2 hours, then cooled and poured into 150 ml of ethyl acetate. The insoluble material was filtered off and the ethyl acetate extract was washed with 100 ml of water and 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and dehydrated. The residue was redissolved in 50 mL of anhydrous ethanol and treated with 0.75 mL of 85% hydrazine. After refluxing for 3 hours, the reaction mixture was cooled and the solid collected by vacuum filtration to give 3.7 g of the desired product as a yellow solid.

c. 6-(3-티아나프탈렌)-2-(2'-펜틴일)-4,5-디히드로피리다지논c. 6- (3-thianaphthalene) -2- (2'-pentynyl) -4,5-dihydropyridazinone

실시예 12e에 기술된 바와 실질적으로 동일한 방법을 사용하여 단계 b의 산출물을 펜틴일 메실레이트와 함께 알킬화시켜 목적화합물을 산출하였다.The output of step b was alkylated with fentinyl mesylate using substantially the same method as described in Example 12e to yield the desired compound.

[실시예 236 : 6-(3-티아나프탈렌)-2-(2'-펜틴일)-4,5-피리다지논]Example 236 6- (3-thianaphthalene) -2- (2'-pentynyl) -4,5-pyridazinone]

화합물 235로부터의 비정제산물을 크로마토그라피(실리카겔관, 30/70에틸아세테이트, 헥산)시켜서 목적화합물을 산출하였다.The crude product from compound 235 was chromatographed (silica gel tube, 30/70 ethyl acetate, hexane) to yield the target compound.

[실시예 237 : 6-(4-클로로페닐)-2-(3,5-디메틸-1-피라조일메틸렌)-4,5-디히드로피리다지논]Example 237 6- (4-chlorophenyl) -2- (3,5-dimethyl-1-pyrazoylmethylene) -4,5-dihydropyridazinone]

화합물 234를 제조하는데 사용된 것과 실질적으로 동일한 방법을 사용하여 0.5㎖의 6N 염산물 촉매로 하여 화합물 233으로부터 목적화합물이 제조되었다. 0.9g의 목적화합물이 백색고체로서 수득되었다.The desired compound was prepared from compound 233 using 0.5 ml of 6N hydrochloride catalyst using substantially the same method used to prepare compound 234. 0.9 g of the desired compound was obtained as a white solid.

[실시예 238 : 6-(4-클로로페닐)-2-(1,3,4-옥사디아진-2-온-5-일-메틸렌)-4,5-디히드로피리다지논]Example 238 6- (4-Chlorophenyl) -2- (1,3,4-oxadiazin-2-one-5-yl-methylene) -4,5-dihydropyridazinone]

자석교반기, 사이드암 첨가 깔대기, 온도계, 및 질소주입구가 구비된 100㎖들이 플라스크에 1.5g의 화합물 233 및 30㎖의 염화메틸렌을 채우고, 실온에서 트리포스겐(0.54g)과 염화 메틸렌(30g)의 용액을 방울방울 첨가하였다. 반응혼합물을 1시간동안 환류시키고 냉각시킨 다음 헥산내에 슬러리화시키고 진공여과에 의하여 백색고체를 수집하였다. 1.55g의 목적화합물의 백색고체로서 수득되었다.A 100 ml flask equipped with a magnetic stirrer, sidearm funnel, thermometer, and nitrogen inlet was charged with 1.5 g of compound 233 and 30 ml of methylene chloride, and the mixture of triphosgene (0.54 g) and methylene chloride (30 g) was added at room temperature. The solution was added dropwise. The reaction mixture was refluxed for 1 hour, cooled, slurried in hexane and the white solid collected by vacuum filtration. 1.55 g of the desired compound was obtained as a white solid.

[실시예 239 : 6-(4-클로로페닐)-2-[1,3,4-옥사디아진-2-온-3-(2'-펜틴일)-5-일-메틸렌]-4,5-디히드로피리다지논][Example 239: 6- (4-chlorophenyl) -2- [1,3,4-oxadiazin-2-one-3- (2'-pentynyl) -5-yl-methylene] -4, 5-dihydropyridazinone]

자석교반기, 사이드암 첨가깔대기, 온도계, 및 환류냉각기가 구비된 100㎖들이 건조플라스크에 0.5g의 화합물 238, 0.45g의 탄산칼륨, 및 50㎖의 무수아세톤을 채우고 반응 혼합물을 실온에서 1시간동안 교반한 다음 0.3g의 펜틴일 메실레이트와 5㎖의 아세톤을 방울방울 첨가하였다. 반응 혼합물을 1시간동안 환류시킨 후 냉각시키고 여과시켰다. 여과물을 증발시켜 수득한 황색고체를 100㎖의 에틸아세테이트에 용해시키고 100ml의 물 및 100ml 포화염수로 세척 하였다. 에틸아세테이트 추출물을 무수 황산마그네슘으로 건조시키고 여과 및 증발시켜 0.6g의 목적화합물을 백색고체로서 수득하였다.A 100 ml dry flask equipped with a magnetic stirrer, sidearm funnel, thermometer, and reflux cooler was charged with 0.5 g of Compound 238, 0.45 g of potassium carbonate, and 50 ml of anhydrous acetone and the reaction mixture was allowed to stand at room temperature for 1 hour. After stirring, 0.3 g of pentynyl mesylate and 5 ml of acetone were added dropwise. The reaction mixture was refluxed for 1 hour, then cooled and filtered. The yellow solid obtained by evaporation of the filtrate was dissolved in 100 ml of ethyl acetate and washed with 100 ml of water and 100 ml of saturated brine. The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and evaporated to yield 0.6 g of the target compound as a white solid.

[실시예 240 : 6-(4-클로로페닐)-2-[N-아세틸히드라지드-(N'-3,5-디클로로-2-히드록시-페닐히드리존]-4,5-디히드로피리다지논]Example 240 6- (4-Chlorophenyl) -2- [N-acetylhydrazide- (N′-3,5-dichloro-2-hydroxy-phenylhydrridone] -4,5-dihydro Pyridazinone]

100㎖들이 얼렌메이어 플라스크에 0.65g의 화합물 233, 25㎖의 에탄올, 및 0.45g의 3,5-디클로로살리실알데히드를 채우고 교반하면서 용액에 5방울의 빙초산을 첨가하였다. 반응 혼합물을 실온에서 2시간동안 교반한 후 결과의 침전물을 여과 수집하고 핵산(50㎖)으로 세척하여 0.9g의 목적화합물을 황색고체로서 수득하였다.Into a 100 ml Erlenmeyer flask was charged 0.65 g of compound 233, 25 ml of ethanol, and 0.45 g of 3,5-dichlorosalicylaldehyde and 5 drops of glacial acetic acid were added to the solution while stirring. The reaction mixture was stirred at room temperature for 2 hours and the resulting precipitate was collected by filtration and washed with nucleic acid (50 mL) to yield 0.9 g of the desired compound as a yellow solid.

[실시예 241 : 6-(4-클로로페닐)-2-[1,3,4-옥사디아진-2-온-3-(3'-요오도프로파길)-5-일-메틸렌]-4,5-디히드로피리다지논]Example 241 6- (4-chlorophenyl) -2- [1,3,4-oxadiazin-2-one-3- (3'-iodopropargyl) -5-yl-methylene]- 4,5-dihydropyridazinone]

a. 6-(4-클로로페닐)-2-[1,3,4-옥사디아진-2-온-3-(프로파길)-5-일-메틸렌]-4,5-디히드로피리다지논a. 6- (4-chlorophenyl) -2- [1,3,4-oxadiazin-2-one-3- (propargyl) -5-yl-methylene] -4,5-dihydropyridazinone

화합물 239를 제조하는데 사용된 것과 실질적으로 동일한 방법을 사용하여 화합물 238을 프로파길브로마이드와 함께 알킬화시켜 목적화합물을 산출하였다.Compound 238 was alkylated with propargyl bromide using substantially the same method used to prepare compound 239 to yield the desired compound.

b. 6-(4-클로로페닐)-2-[1,3,4-옥사디아진-2-온-3-(3'-요오도프로파길)-5-일-메틸렌]-4,5-디히드로피리다지논b. 6- (4-chlorophenyl) -2- [1,3,4-oxadiazin-2-one-3- (3'-iodopropargyl) -5-yl-methylene] -4,5-di Hydropyridazinone

자석교반기와 환류냉각기가 구비된 100㎖들이 건조플라스크에 상기 단계 a의 산출물(0.5g), N-요오드숙신아미드(0.4g), 질산은(10㎎), 및 무수아세톤(40㎖)을 채우고, 반응혼합물을 상온에서 16시간동안 교반하고 100㎖의 아세톤에 붓고 여과하여 고체를 분리하였다. 아세톤 여과액을 증발시키고 잔류물을 150㎖의 에틸아세테이트에 재용해지시켰다. 에틸아세테이트 추출물을 100㎖의 물 및 100㎖의 포화 염수로 세척하고, 무수황산마그네슘으로 건조시키고 여과 및 증발시켜 0.5g의 목적화합물을 황색 점성액체로서 수득하였다.A 100 ml dry flask equipped with a magnetic stirrer and a reflux condenser was charged with the output of step a (0.5 g), N-iodine succinamide (0.4 g), silver nitrate (10 mg), and anhydrous acetone (40 ml). The reaction mixture was stirred at room temperature for 16 hours, poured into 100 ml of acetone and filtered to separate solids. The acetone filtrate was evaporated and the residue was redissolved in 150 ml of ethyl acetate. The ethyl acetate extract was washed with 100 ml of water and 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 0.5 g of the target compound as a yellow viscous liquid.

본 발명의 화합물들은 살균활성, 특히 식물성 균류에 대한 살균활성을 갖는다. 그들은 튜테로미세테스(편지임페르펙티), 바시디오미세테스 및 아스코미세테스를 포함하여 많은 종류의 균들에 대하여 활성적이다. 특히, 본 발명은 피리큘라리아 오리자에, 피레노포라 트리코스토마, 푸사리움스페시스, 에리시페 그라미니스, 푸치니아 레콘디타, 알사 류코스토마, 콜레토트리쿰 라게나리움, 넥트리아 갈리게나, 코클리오블루스 미야베아누스, 티나테포루스 쿠쿠메리스, 슈우도세르코스페렐라 헤르포트리카오이데스, 헬민토스포리움 스페시스, 모니리니아 푸룩티콜라, 스크레로티움 롤프시이. 벤투리아 이네쿠알리스, 보토리오티니아 푸켈리아나. 디아포르테시트리, 리조푸스 스톨로니페르, 베리시리움 알보-아트룸, 피토파토라 캅시키, 알테르나리아 솔라니, 우스틸라고 마이디스, 피티움 울티움, 렙토스파에리아 노도룸, 클레로티니아 스페시스, 스파에로테카 풀리기네아, 짐노스포란기움 아시아티쿰, 알테르나리아 알테르나타, 운시눌라 네카토르, 및 포도스파에라 류코트리카를 포함한 유기물에 대한 활성을 제공한다. 벼에 대한 병해가 본 발명의 방법에 의하여 구제될 수 있다. 그러한 벼 병해를 예로들면 코클리오볼루스 미야베아누스 및 피리쿨라리아 오리자에등에 의하여 유도되는 종자전염병, 푸사리움 스페시스, 리조토니아 스페시스 및 리조푸스 스페스스와 같은 토양전염병, 및 피리쿨라리아 오리자에, 타나테포루스 쿠쿠메리스 및 코클리오볼루스 미야베아누스에 의하여 유도되는 것과 같은 파종박스 및 필드전염병을 들 수 있다. 기타의 전염병들로는 스프에로테카 풀리기네아(예 : 호리병박 흰가루병), 운시눌라 네카토르 (예: 포도흰가루병), 및 포도스파에라 류코트라(예 : 사과 흰가루병)에 의한 흰가루병들이 포함된다.The compounds of the present invention have bactericidal activity, in particular against bacterium. They are active against many types of bacteria, including tuteromycetes (letter imperfecti), bacidiomycetes and ascomycetes. Particularly, the present invention relates to Pyrricularia orizae, Pyrenophora trichostomae, Fusarium spesis, erycife graminis, Puccinia recondita, Alsa leucostoma, Colletotricum lagenarium, Neck Tria Galligana, Cocclio Blues Miyabeanus, Tinatteporus Cucumis, Pseudocercosferella Herpotricaides, Helmintosporiium spesis, Monyrronia Fruticola, Screrotium Rolfsey. Venturia Inequialis, Botoritonia Pukeliana. Diafortecitri, Rizopus Stolonifer, Veririum Albo-Artrum, Phytopatora Capsiki, Alternaria Solani, Urtila Madidis, Pitium Ultium, Leptosperia Nodorum, Klotini Spope It provides activity against organics including cis, spaeroteca pulliginea, jimnosporangium asiaticum, alternaria alternata, uncinula necator, and grapespaera leukotrica. Diseases against rice can be controlled by the method of the present invention. Examples of such rice pests include seed infectious diseases induced by Cocliobolus Miyabeanus and Pycurularia orizae, soil infectious diseases such as Fusarium spesis, risottonia spesis and lycopus spess, and pyricularia Orizae, seeding boxes and field epidemics, such as those induced by Tanateporus kucumeris and Cocliobolus Miyabeanus. Other infectious diseases include powdery mildew caused by Sproteca pulliginea (such as Calabash white powder), Uncinula necator (such as Grape powdery mildew), and Grapespaera leukotra (such as apple powdery mildew).

본발명의 화합물은 글레오필름 트라베움, 피알로포라 무타빌리스, 포리아 팔센타 및 트라메테스 베르시콜로르 같은 목재부식균을 구제하는데도 유용하다. 따라서, 본발명은 목재 보존제로서의 화합물 사용도 포함한다.The compounds of the present invention are also useful for controlling wood erosion bacteria, such as Gleofilm Trabeum, Pialophora mutabilis, Poria palsenta and Tramethes versichol. Thus, the present invention also encompasses the use of compounds as wood preservatives.

본 발명의 화합물은 대용량 고압스프레이, 저용량 스프레이, 에어-블래스트, 공기 스프레이 및 더스트 같은 통상적으로 사용되는 방법들에 의하여 살균 스프레이(fungicidal sprays)로서 적용될 수 있다. 그러한 용법은 야채, 과일, 풍치림, 종자, 잔디, 곡물 및 덩굴식물등과 같은 작물들에서 균병해를 편리하게 처리하는 것을 가능케 하여 준다.The compounds of the present invention can be applied as fungicidal sprays by commonly used methods such as high volume high pressure spray, low volume spray, air-blast, air spray and dust. Such usage makes it possible to conveniently treat fungal diseases in crops such as vegetables, fruits, saplings, seeds, grasses, grains and vines.

적용양 및 희석율은 사용되는 장비의 형태, 소망되는 적용방법 및 회수, 및 구제되어질 전염병에 좌우될 것이나, 유효량은 일반적으로 핵타르당 약 0.01-20kg의 활성성분(a.i.)이다. 잎적용 살균제로서의 경우, 피리다지논은 헥타르당 약 0.1-5kg, 바람직하게는 약 0.125-0.5kg의 비율로 성장식물에 적용된다.The application amount and dilution rate will depend on the type of equipment used, the desired application and recovery, and the infectious disease to be rescued, but the effective amount is generally about 0.01-20 kg of active ingredient (a.i.) per hectare. As a leaf application fungicide, pyridazinone is applied to the growing plant at a rate of about 0.1-5 kg, preferably about 0.125-0.5 kg, per hectare.

종자 보호제로서의 경우, 종자에 도포되는 살균제의 양은 일반적으로 종자 50kg당 약 10-250g, 바람직하게는 약 20-60g의 투여량이다. 토양적용살균제로서의 경우, 화합물은 헥타르당 약 0.5-20kg, 바람직하게는 약 1-5kg의 비율로 토양내에 또는 토양표면에 적용될 수 있다.As a seed protectant, the amount of fungicide applied to the seed is generally in a dosage of about 10-250 g, preferably about 20-60 g per 50 kg of seed. As a soil application disinfectant, the compounds may be applied in the soil or on the soil surface at a rate of about 0.5-20 kg, preferably about 1-5 kg, per hectare.

본 발명의 화합물들은 균류의 구제에 유용하며, 종자, 수표면, 토양 또는 잎과 같은 다양한 영역에 사용될 수 있다. 그러한 목적들에 있어서. 본 화합물들은 제조된 순수물로서, 용액으로서 또는 조성물로서 사용될 수 있다. 화합물들은 통상적으로 담체에 혼합되거나 또는 살균제로서 연속사용에 적합하도록 배합된다. 예를 들면, 그들은 습성분말, 건성분말, 유화가능한 농축물, 재, 과립배합물, 에어로졸, 유동성 에멀션농축물로서 조성될 수 있다. 그러한 조성물들에 있어서, 화합물들은 액체 또는 고체담체와 함께 처리되며, 필요한 경우 적당한 계면활성제가 혼합될 수 있다. 농경실제에 따라서, 일반적으로, 특히 잎적용 스프레이 조성물의 경우, 습윤제, 확장제, 분산제, 점착제, 접착제등과 같은 보조제를 포함하는 것이 바람직하다,The compounds of the present invention are useful for controlling fungi and can be used in a variety of areas such as seeds, water surfaces, soil or leaves. For such purposes. The compounds can be used as pure water produced, as a solution or as a composition. The compounds are usually mixed in a carrier or formulated to be suitable for continuous use as a fungicide. For example, they can be formulated as wet powder, dry powder, emulsifiable concentrate, ash, granule blend, aerosol, flowable emulsion concentrate. In such compositions, the compounds are treated with a liquid or solid carrier, and a suitable surfactant can be mixed if necessary. Depending on the agricultural practice, it is generally preferred to include auxiliaries such as wetting agents, dilators, dispersants, tackifiers, adhesives and the like, in particular in the case of leaf application spray compositions.

본 분야에서 사용될 수 있는 그러한 보조제들은 엠시출판사(뉴저지)의 맥커천디비전에 의하여 매년 발간된 McCutcheon's Emulsifiers and Detergents, McCutcheon's Emulsifiers and Detergents/ Functional Materials, 및 McCutcheon's Functional Materials 에 개시되었다.Such auxiliaries that can be used in this field are disclosed in McCutcheon's Emulsifiers and Detergents, McCutcheon's Emulsifiers and Detergents / Functional Materials, and McCutcheon's Functional Materials, which are published annually by McCorcheon Division of MC Publishing (New Jersey).

일반적으로, 본 발명에서 유용한 화합물들은 아세통, 메탄올, 에탄올, 디메틸포름아미드 또는 디메틸술폭시드 등과 같은 적당한 용매류에 용해될 수 있으며, 그러한 용액들은 물로 희석된다. 용액의 농도는 약 1-90%, 바람직하게는 5-50% 범위에서 변화될 수 있다.In general, compounds useful in the present invention can be dissolved in suitable solvents such as aceton, methanol, ethanol, dimethylformamide or dimethyl sulfoxide, and such solutions are diluted with water. The concentration of the solution may vary in the range of about 1-90%, preferably 5-50%.

유화가능한 농축물의 제조에 있어서, 본 발명의 화합물들은, 물속에서 살균제의 분산을 허용하는 유화제와 함께, 적당한 유기용매 또는 용매혼합물에 용해될 수 있다. 유화가능한 농축물내의 활성성분 농도는 통상 10-90%이고, 유통성 에멀션 농축물에 있어서는 75%정도로 높을수 있다. 스프레이용 습성분말(wettable powders)은 점토, 무기실리케이트, 무기카보네이트 및 실리카 같은 미세분쇄고체와 함께 화합물을 혼합하고 그러한 혼합물에 습윤제, 점착제, 및/또는 분산제를 넣음으로써 제조될수 있다. 그러나 조성물내의 활성성분 농도는 일반적으로 20-98%, 바람직하게는 40-75%이다. 전형적인 예로서, 습성분말은 50부의 6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논, 45부의 합성석출된 수화 이산화규소(Hi-Sil로 판매됨), 및 5부의 리그노술폰산나트륨 (MarasperseN-22)를 혼합하여 제조된다. Kaolin 유형의 제조에 있어서는 Hi-Sil 대신 (바덴)점토가 사용되며, 다른 유형의 제조에 있어서는 25%의 Hi-Sil이 합성 실리콘알루민산나트륨(Zeolex7)으로 대체된다.In the preparation of emulsifiable concentrates, the compounds of the present invention can be dissolved in a suitable organic solvent or solvent mixture, together with emulsifiers which allow dispersion of the fungicide in water. The active ingredient concentration in emulsifiable concentrates is typically 10-90% and can be as high as 75% for flowable emulsion concentrates. Wettable powders for spraying can be prepared by mixing the compound with finely divided solids such as clays, inorganic silicates, inorganic carbonates and silica and adding a wetting agent, a tackifier, and / or a dispersant to such a mixture. However, the active ingredient concentration in the composition is generally 20-98%, preferably 40-75%. As a typical example, the wet component powder is 50 parts 6- (4-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone, 45 parts synthetic precipitated hydrous silicon dioxide (Hi-Sil). Sold), and 5 parts sodium lignosulfonate (Marasperse N-22) is prepared by mixing. In the manufacture of Kaolin type (baden) clay is used instead of Hi-Sil, and in other types of production 25% of Hi-Sil is synthetic sodium aluminate (Zeolex). Replaced by 7).

재(Dusts)는 본 발명의 화합물을 미세분쇄된 유기 또는 무기 불활성고체들과 혼합함에 의하여 제조된다. 이러한 목적에 유용한 물질들로는 식물성분말, 실리카, 실리케이트, 카보네이트 및 점토가 포함된다. 재를 제조하는 한가지 편리한 방법은 습성분말을 미세분쇄한 담체로 희석시키는 것이다. 20-80%의 활성성분을 함유하는 재농축물이 통상제조되며, 이것은 추후 약 1-10%의 사용농도에 희석된다.Dusts are prepared by mixing the compounds of the present invention with finely divided organic or inorganic inert solids. Materials useful for this purpose include plant powders, silica, silicates, carbonates and clays. One convenient way to make ash is to dilute the wet powder with a finely ground carrier. Reconcentrates containing 20-80% of the active ingredient are usually prepared, which is then diluted to a concentration of about 1-10%.

본 발명의 화합물은 다음과 같은 기타 살균제들과 혼합하여 사용될 수 있다.The compounds of the present invention can be used in admixture with other fungicides, such as:

(a) 디티오카바메이트 및 유도체들 :(a) dithiocarbamate and derivatives:

파아밤, 지람, 마네브, 만코제브, 지네브, 프로피네브, 메탐, 티람, 지네브와 폴리에틸렌 티우람 디술파이드의 착물, 다조메트, 및 이들과 구리염들의 혼합물.Pabam, ziram, maneb, mancozeb, zineb, propineb, metham, tiram, zineb and polyethylene thiuram disulfide complexes, dazomet, and mixtures of these and copper salts.

(b) 니트로페놀 유도체들 :(b) nitrophenol derivatives:

디노캅, 비나파크릴, 및 2-sec-부틸-4,6-디니트로페놀 이소프로필 카보네이트.Dinocap, vinapacryl, and 2-sec-butyl-4,6-dinitrophenol isopropyl carbonate.

(c) 헤테로고리 화합물들 :(c) heterocyclic compounds:

캡탄, 폴페트, 글리오딘, 아닐라진, 디타림포스, 4-부틸-1,2,4-트리아졸, 5-아미노-1-[비스(디메틸아미노)포스피닐]-3-페닐-1,2,4-트리아졸, 에트라디아졸, 디티아논, 티아퀴녹스, 베노밀, 티아벤다졸, 4-(2-클로로페닐히드라조노)-3-메틸-5-이소옥사졸론, 빈클로졸린, 이프로디온, 프로시미돈, 트리아디메놀, 트리아디메폰, 비테르타놀, 프로클로라조, 페나리몰, 비스-(p-클로로페닐)-3-피리딘 메탄올, 비스(p-클로페닐)-5-피리미딘메탄올, 트리아리몰, 플루트리아폴, 플루실라졸, 프로피코나졸, 엑타코나졸, 미크로부타닐, 펜부코나졸(즉, 알파-[2-(4-클로로페닐)에틸]-알파-페닐-1H-1,2,4-트리아졸-1-프로판니트릴), 헥사코나졸, 시프로코나졸, 테르부코나졸, 디니코나졸, 플루오로이미드, 피리딘-2-티올-1-옥사이드, 8-히드록시퀴놀린 술페이트 및 그의 금속염들, 2,3디히드로-5-카르복사닐리도-6-메틸-1,4-옥사티인-4,4-디옥사이드, 2,3-디히드로-5-카르복사닐리도-6-메틸-1,4-옥사티인, 시스-N-[(1,1,2,2-테트라클로로에틸)티올]-시클로헥센-1,2-디카르복시미드, 시클로헥시미드, 디히미드로아세트산, 캅타폴, 에티리몰, 퀴노메티오네이트, D,L-메틸-N-(2,6-디메틸페닐)-N-(2'-메톡시아세틸)아닐린 메틸에스테르, D,L-메틸-N-(2,6-디메틸페닐)-N-(클로로아세틸-D,L-2-아미노부티로락톤, D,L-N-(2,6-디메틸페닐)-N-(페닐아세틸)아닐린 메틸에스테르, 5-메틸-5-비닐-3-(3,5-디클로로페닐)-2,4-디옥소-1,3-옥사졸리딘, 3-(3,5-디클로로페닐)-5-메틸-5-(메톡시메틸)-1,3-옥사졸리디-2,4-디온, 3-(3,5-디클로로페닐)-1-이소프로필카바모일히단티온, 2-시아노-[N-(에틸아미노카보닐)2-메톡시마노]아세트아미드, 펜프로피모르프, 펜프로피딘, 2,6-디메틸-N-트리데실 모로폴린, 도데모르프, 및 트르포린.Captan, polpet, gliodine, anilazine, dithalimfoss, 4-butyl-1,2,4-triazole, 5-amino-1- [bis (dimethylamino) phosphinyl] -3-phenyl-1, 2,4-triazole, etradiazole, dithianon, thiaquinox, benomyl, thibendazole, 4- (2-chlorophenylhydrazono) -3-methyl-5-isoxazolone, vinclozoline, if Rodione, procmidone, triadimenol, triadimefon, vitertanol, prochlorazo, phenarimol, bis- (p-chlorophenyl) -3-pyridine methanol, bis (p-chlorophenyl) -5- Pyrimidinmethanol, triarimol, flutriafol, flusilazole, propiconazole, ecconazole, microbutanyl, fenbuconazole (ie alpha- [2- (4-chlorophenyl) ethyl] -alpha- Phenyl-1H-1,2,4-triazole-1-propanenitrile), hexaconazole, ciproconazole, terbuconazole, diconazole, fluoroimide, pyridine-2-thiol-1-oxide, 8 Hydroxyquinoline sulfate and metal salts thereof, 2,3 dihydrate -5-Carboxylinido-6-methyl-1,4-oxathiine-4,4-dioxide, 2,3-dihydro-5-carboxanilideo-6-methyl-1,4-oxati Phosphorus, cis-N-[(1,1,2,2-tetrachloroethyl) thiol] -cyclohexene-1,2-dicarboximide, cycloheximide, dihimidoacetic acid, captapol, etirimol, Quinomethionate, D, L-methyl-N- (2,6-dimethylphenyl) -N- (2'-methoxyacetyl) aniline methylester, D, L-methyl-N- (2,6-dimethyl Phenyl) -N- (chloroacetyl-D, L-2-aminobutyrolactone, D, LN- (2,6-dimethylphenyl) -N- (phenylacetyl) aniline methylester, 5-methyl-5-vinyl -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3-oxazolidine, 3- (3,5-dichlorophenyl) -5-methyl-5- (methoxymethyl)- 1,3-oxazolidi-2,4-dione, 3- (3,5-dichlorophenyl) -1-isopropylcarbamoylhyddanone, 2-cyano- [N- (ethylaminocarbonyl) 2- Methoxymano] acetamide, fenpropimorph, fenpropidine, 2,6-dimethyl-N-tridecyl morpholine, Know programs, and reportage bit lean.

(d) 할로겐화 살균제들 :(d) Halogenated fungicides:

클로로탈로닐, 디클론, 클로로네브, 트리캄바, TCPN, 디클로란, 2-클로로-1-니트로프로판, 펜타클로로니트로벤젠(PCNB)같은 폴리클로로니트로벤젠류, 및 테트라플루오로디클로로아세톤.Polychloronitrobenzenes such as chlorothalonil, diclones, chloroneve, tricamba, TCPN, dichloran, 2-chloro-1-nitropropane, pentachloronitrobenzene (PCNB), and tetrafluorodichloroacetone.

(e) 살균성 항생물질들 :(e) Bactericidal antibiotics:

그리세오풀빈, 카수가마이신, 폴리옥신, 발리드마이신, 및 스트렙토마이신.Griseofulvin, kasugamycin, polyoxin, validmycin, and streptomycin.

(f) 구리계 살균제들 :(f) Copper fungicides:

수산화구리, 산화구리, 염기성 염화구리, 염기성 탄산구리, 테레프탈산구리, 나트텐산구리, 및 Bordeaux 혼합물.Copper hydroxide, copper oxide, basic copper chloride, basic copper carbonate, copper terephthalate, copper nitrate, and Bordeaux mixture.

(g) 기타의 살균제들 :(g) Other fungicides:

도딘, 페닐머큐릭아세테이트, N-에틸머큐리-1., 2, 3, 6-테트라히드로-3, 6-엔도메타노-3, 4, 5, 6, 7, 7-헥사클로로프탈이미드, 페닐모큐릭 모노에탄올 암모늄 락테이트, p-디메틸아미노벤젠, 술폰산나트륨, 메틸 이소티오시아네이트, 1-티오시아노-2, 4-디니트로벤젠, 1-페닐티오-세미카바지드, 함니켈 화합물들, 칼슘시아나미드, 라임설파, 티오파네이트-메틸, 플루토라닐, 에디펜포스, 이소프로티올란, 프로베나졸, 이프로벤포스, 트리시클라졸, 및 피로퀼론.Dodine, phenyl mercury acetate, N-ethyl mercury-1., 2, 3, 6-tetrahydro-3, 6-endomethano-3, 4, 5, 6, 7, 7-hexachlorophthalimide , Phenylmocuric monoethanol ammonium lactate, p-dimethylaminobenzene, sodium sulfonate, methyl isothiocyanate, 1-thiocyano-2, 4-dinitrobenzene, 1-phenylthio-semicarbazide, nickel Compounds, calcium cyanamide, limesulfa, thiophanate-methyl, flutoranyl, edifene, isoprothiolane, probenazole, ifprobenfos, tricyclazole, and pyroquilon.

증진된 비조균류 구제를 위하여는, 디티오카바메이트(예: 만코네브 또는 마네브)와 함께 본 발명 화합물을 사용하는 것이 특히 바람직하다.For enhanced non-fungal control, it is particularly preferred to use the compounds of the present invention in combination with dithiocarbamates such as manconeb or maneb.

실시예 1-165 및 200-241 의 화합물들을 그들의 살균활성에 대하여 시험하였다. 화합물들은 다음 유기물들에 대하여 하기 생체내시험(in vivo test) 및/ 또는 생체외 시험(in vitro test)되었다.The compounds of Examples 1-165 and 200-241 were tested for their bactericidal activity. Compounds were tested in vivo and / or in vitro for the following organics.

시험유기물들 : 피라큘라리아 오리자에, 피레노포라 트리코스토마, 푸사리움 스페시스, 에리시페 그라미니스, 푸치니아 레콘디타, 알사 류코스토마, 콜레토트리쿰 라게나리움, 넥트리아 갈리게나, 코클리오볼루스 미야베아누스, 티나테포루스 쿠쿠메리스, 슈우도세르코스페렐라 헤르포트리키오이데스, 헬민토스포리움 스페시스, 모니리니아 푸룩티콜라, 스크레로티움 롤프시이, 벤투리아 이네쿠알리스, 보트리오티니아 푸켈리아나, 디아포르테 시트리, 지조푸스 스톨로니페르, 베리시리움 알보-아트룸, 피토파토라 캅시키, 알테르나리아 솔라니, 우스틸라고 마이디스, 피티움 울티뭄, 렙토스파에리아 노도룸, 클레로티니아 스페시스, 스파에로테카 폴리기네아 짐노스포란기움 아시아티쿰, 알테르나리아 라테르나타, 운시눌라 네카토르, 및 포도스파에라 류코트리카.Tested Organics: Pyracularia Orizae, Pyrenopora Trichostoma, Fusarium spesis, Eriche Graminis, Puccinia Recondita, Alsa Ryukostoma, Colletotricum Lagenarium, Nectria Galiguena, Cochliobolus Miyabeanus, Tinateforus Cucumis, Schudocercosperella herforriquiides, Helmintosporiium spesis, Monyrrini furucticola, Screrotium rolfsi, Venturia Inecualis, Boliotinia Puchelliana, Diaforte Citri, Gizopus Stolonifer, Veririum Albo-Artroom, Phytopatora Capsiki, Alterna Solani, Urtilia Midis, Pitti Umm Ultimum, Leptospaeria Nodorum, Clotinispesis, Spaeroteca Polygineia Jimnosporangium Asiaticum, Alternaria Laternata, Uncinula Necator, and Grape Spae La leukotrica.

I. 생체외 시험-균독성 분석(Fungitoxicity Assay)I. In Vitro Test-Fungitoxicity Assay

화합물들은 육즙희석방법(BD) 또는 한천희석방법(AD)에 의하여 그 활성에 대하여 분석되었다. 한천희석방법에 있어서는 감자 덱스트로즈 한천이 시험화합물의 용액으로 보정되고 표 6에 표기된 농도로서 디메틸술폭시드 또는 유사용매에 용해된 다음, 6mm 플러그 균사체(fungal mycelium)로 접종되었다. 각 시료에 대하여 방사성장(radial growth)이 측정되고 종균크기(inoculum size)에 대해 수정되었다. 성장억제퍼센트(%)는, 다음 식에서와 같이, 표준시료(A)의 방사성장에서 시험시료(B)의 방사성장을 뺀값을 표준시료(A)의 방사성장으로 나누고 거기에 100을 곱한 값에 해당한다.The compounds were analyzed for their activity by the juice dilution method (BD) or agar dilution method (AD). In the agar dilution method, potato dextrose agar was calibrated with a solution of the test compound, dissolved in dimethyl sulfoxide or a similar solvent at the concentrations indicated in Table 6, and then inoculated with 6 mm plug mycelium (fungal mycelium). Radial growth was measured for each sample and corrected for inoculum size. Percent growth inhibition (%) is obtained by dividing the radial growth of the standard sample (A) by the radial growth of the standard sample (A) and subtracting it by 100. Corresponding.

육즙희석방법에 있어서는, 디메틸술폭시드에 용해된 시험화합물이 표 6에 표기된 농도로 YD 육즙(2% 덱스트로즈, 0.4% 이스트추출물)에 첨가되고 200rpm의 주변교반기내에서 48시간동안 28℃에서 균사체로 접종되었다. 성장억제 %는 다음 방정식에 따라 건조중량 측정치로부터 평가 되었다.In the juice dilution method, test compounds dissolved in dimethyl sulfoxide were added to YD juice (2% dextrose, 0.4% yeast extract) at the concentrations shown in Table 6 and at 28 ° C for 48 hours in an ambient stirrer at 200 rpm. Inoculated with mycelium. % Growth inhibition was evaluated from dry weight measurements according to the following equation.

생체외시험 결과들을 하기 표 6에 표기하였다.In vitro test results are shown in Table 6 below.

II. 생체내시험II. In vivo test

시험화합물들은 접종전 24시간예비적용 예방보호제 시험으로서 200ppm농도에서 시험되었다.The test compounds were tested at 200 ppm concentration as a 24 hour preapplied prophylactic test before inoculation.

(a) 도열병(RB) 피리큘라리아 오리자에(a) RB pyricuria orizae

2주일자란 M201 벼작물을, 분무기로 잎 및 줄기에 분무함에 의하여, 마그나포르테 그리지아 (피라큘라리아 오리자에)의 포트당 250,000 포자들로서 접종시켰다. 접종된 작물을 약 27℃(80℉)에서 48시간동안 미스트 캐비넷내에서 배양시킨 다음 약 22-27℃(70-80℉)의 온실환경에 놓아두었다. 접종 6일후, 표준영역 전염병 다이어그램(standard area disease diagrams)을 참고하여, 체크작물과 비교된 전염병구제율(%)에 대하여 작물들을 평가하였다.Two week old M201 rice crops were inoculated as 250,000 spores per port of Magnaporte grigia (Pyracularia orissa) by spraying leaves and stems with a nebulizer. Inoculated crops were incubated in a mist cabinet for 48 hours at about 27 ° C. (80 ° F.) and then placed in a greenhouse environment at about 22-27 ° C. (70-80 ° F.). Six days after inoculation, the crops were evaluated for percent infectious disease control compared to the check crop, referring to standard area disease diagrams.

(b) 벼얼룩병(RSB)(b) rice blot (RSB)

교반배양기내의 감자 텍스트로즈 육즙내에서 타나테포루스 쿠쿠메리스(리조토니아 솔라니)균사체를 6일간 생장시켰다. 건져낸 균사체 매트를 거의 동일 중량의 쌀가루 및 5부의 물과 함께 혼합하였다. 이 슬러리를 시험화합물로 미리 처리된 벼종자들을 포함한 포트들의 토양표면상에 분포시켰다. 작물들을 25-28℃에서 48시간동안 미스트 챔버내에 놓아두었다.Tanateporus Cucumis (Rizonia solani) mycelium was grown for 6 days in the potato Textose broth in a stirred incubator. The harvested mycelium mat was mixed with nearly equal weight of rice flour and 5 parts of water. This slurry was distributed on the soil surface of the pots containing rice seeds pretreated with the test compound. Crops were placed in the mist chamber at 25-28 ° C. for 48 hours.

25℃ 및 70-90% 상대습도에서 2일간 더 놓아둔 후, 체크작물과 비교된 전염병구제율(%)에 대하여 작물들을 평가하였다.After two more days at 25 ° C. and 70-90% relative humidity, the crops were evaluated for percent infectious disease control compared to the check crop.

생체내시험 결과들을 하기 표 7에 표기하였다.In vivo test results are shown in Table 7 below.

본 발명의 화합물은 칸디다 알비칸즈에 대하여서도 활성적이다. 따라서 본 발명의 화합물은, 당 기술분야에서 알려진 방법들, 예를 들면, 공지의 의학적으로 허용되는 담체내에서의 적용에 의하여, 칸디다 알비칸즈 및 인체내 피부생균류(예 : 트리코피톤 스페시스)를 구제하는데 사용될 수 있다. 다음 시험법을 사용하여 칸디다 알비칸즈에 대한 활성을 평가하였다.The compounds of the present invention are also active against Candida albicans. Thus, the compounds of the present invention can be prepared by methods known in the art, for example, by application in known medically acceptable carriers, to Candida albicans and to dermatological fungi in humans (e.g., trichophyton spesis). It can be used to rescue. The following assays were used to assess activity against Candida albicans.

1. 접종원준비(inoculum preparation)1. inoculum preparation

대부분의 분생자(conidia)가 접종원으로서 사용되도록, 감자 덱스트로즈 한천 플레이트상에서 부양된 칸디다 알칸비즈 배양균으로부터 분생자 및 균사체를 이스트 추출물-덱스트로즈 육즙(YDB)내로 살짝 긁어내었다. 분생자 현탁액을 치즈클로드(cheesecloth)의 이중층을 통하여 걸러 내어 균사체 덩어리를 제거하였다. 접종원 혼합물을 12-팁 피펫을 사용하여 마이크로티터 플레이트들 상에 놓았다. 마이크로티터 플레이트들의 각 정(well)내에 175㎖를 넣고 플레이트들을 하룻밤 동안 냉장고내에 넣어두었다. 두 번의 복제가 있었다.Conidia and mycelium were scraped lightly into yeast extract-dextrose juice (YDB) from Candida alkanes cultures grown on potato dextrose agar plates so that most conidia were used as inoculum. The conidia suspension was filtered through a bilayer of cheesecloth to remove the mycelium mass. The inoculum mixture was placed on microtiter plates using a 12-tip pipette. 175 ml were placed in each well of the microtiter plates and the plates were placed in the refrigerator overnight. There were two clones.

2. 화합물의 첨가2. Addition of Compound

시험될 화합물을 1:1 아세톤: 메탄올내에 용해시키고, 100ppm의 화합물 용액을 앞서 준비된 마이크로티터 플레이트들의 정내에 놓았다.The compound to be tested was dissolved in 1: 1 acetone: methanol and 100 ppm of the compound solution was placed in the tablets of the microtiter plates prepared previously.

3. 배양 및 평가3. Culture and Evaluation

화합물 첨가 후 마이크로티터 플레이트들을 실온에서 7일간 배양시켰다. 구제율(%)을 마이크로티터 플레이트 리딩미러를 사용하여 시각적으로 측정하였다. 측정은 처리후 1, 2, 3 및/또는 7일에 행하여졌다. 결과를 하기 표 8에 표기하였다.Microtiter plates were incubated at room temperature for 7 days after compound addition. % Rescue was measured visually using a microtiter plate reading mirror. Measurements were made on 1, 2, 3 and / or 7 days after treatment. The results are shown in Table 8 below.

공지의 소정 살균성 화합물과 함께 본 발명의 소정 화합물을 포함하는 조성물들이 그 조성물의 각 성분들의 예상활성의 합계치보다 더 큰 향상된 살균활성을 갖는 것으로 밝혀졌다. 살균활성성분들의 주어진 조합에 대한 예상활성(E)는 콜비방정식에 따라 계산될 수있다.It has been found that compositions comprising certain compounds of the present invention, together with known certain bactericidal compounds, have improved bactericidal activity that is greater than the sum of the expected activities of the respective components of the composition. The expected activity (E) for a given combination of bactericidal active ingredients can be calculated according to Colby's equation.

E=X ＋ Y - (X * Y / 100)E = X + Y-(X * Y / 100)

여기서, X=제1살균제의 전염병 구제활성(%); Y=제2살균제의 전염병 구제활성(%); E=혼합물에서의 제1 및 제2살균제의 예상활성.Where X = infectious disease control activity (%) of the first fungicide; Y = infectious disease control activity (%) of the second fungicide; E = expected activity of the first and second fungicides in the mixture.

참조문헌 : 콜비 엘, 알 Caculating Synergistic and Antagonistic Responses of Herbicide CombinationsReferences: Colbiel, Al Caculating Synergistic and Antagonistic Responses of Herbicide Combinations

Weeds, 15. pp 20-22(1967) 및 림펠등, weeds Control by... Certain Combinations, Proc. NEWCL, 16, pp. 48-53(1962)Weeds, 15. pp 20-22 (1967) and Limpel et al., Weeds Control by ... Certain Combinations, Proc. NEWCL, 16, pp. 48-53 (1962)

그러한 향상된 성질을 갖는 조성물의 살균성분들의 비(ratio)는 특정성분들 및 사용조건들에 따라 광범위한 범위에서 변화될 수 있다. 일반적으로, 그러한 조성물은 조성물의 각성분들의 예상활성의 합계치보다 더 큰 조성물 살균활성을 산출하기에 효과적인 비율로 충분한 양의 각 성분을 함유할 것이다 조성물의 각 성분들의 예상활성의합계치보다 조성물의 실측 살균활성이 바람직하게는 최소 0.5%, 더욱 바람직하게는 5% 이상크다. 적절히 측정될 때, 실측활성(E)이 콜비방정식으로 계산된 예상활성(E)보다 크다. 즉, 실측E/예상E가 1이상, 바람직하게는 1.005이상, 더욱 바람직하게는 1.05이상이다.The ratio of bactericidal components of the composition with such improved properties can vary over a wide range depending on the specific components and conditions of use. Generally, such a composition will contain a sufficient amount of each component in a proportion effective to yield a composition bactericidal activity that is greater than the sum of the expected activities of the individual components of the composition. The bactericidal activity is preferably at least 0.5%, more preferably at least 5%. When properly measured, the measured activity (E) is greater than the expected activity (E) calculated by Colby's equation. That is, the measured E / expected E is at least 1, preferably at least 1.005, more preferably at least 1.05.

따라서, 본 발명은 향상된 살균활성을 가지며 다음 성분(i) 및 (ii)를 포함하는 살균제 조성물들을 제공한다.Accordingly, the present invention provides fungicide compositions having improved bactericidal activity and comprising the following components (i) and (ii).

(I) 식 6-(3-A-4-B-페닐)-2-(C)-피리다지논 (여기서, A는 수소 또는 플루오로치환기; B는 수소, 클로로 또는 브로모 치환기이고, C는 2'-펜틴일, 3'-비닐-2-프로핀일, 4'-플루오로-2'-펜틴일, 또는 5'-플루오로-2'-펜틴일 치환기임), 또는 식 6-(3-A'-4-B'-페닐)-2-(C')-4, 5-디히드로피리다지논(여기서, A는 수소 또는 플루오로 치환기 ; B'는 수소, 브로모, 또는 클로로 치환기이며; C'는 2'-펜틴일, 3'-비닐-2'프로핀일, 4'-플루오로-2'-펜틴일 또는 5'-플루오로-2'펜틴일 치환기임)으로 표현되는 하나이상의 화합물; (II) 만코제브, 마네브, 이프로디온, 클로로탈로닐, 프로베나졸, 피로퀼론 및 펜부코나졸로 구성된 군으로부터 선택된 하나이상의 살균제 화합물.(I) Formula 6- (3-A-4-B-phenyl) -2- (C) -pyridazinone, wherein A is hydrogen or fluorosubstituted group; B is hydrogen, chloro or bromo substituent, and C Is a 2'-pentynyl, 3'-vinyl-2-propynyl, 4'-fluoro-2'-pentynyl, or 5'-fluoro-2'-pentynyl substituent), or formula 6- ( 3-A'-4-B'-phenyl) -2- (C ')-4, 5-dihydropyridazinone, wherein A is hydrogen or a fluoro substituent; B' is hydrogen, bromo, or chloro C 'is a 2'-pentynyl, 3'-vinyl-2'propynyl, 4'-fluoro-2'-pentynyl or 5'-fluoro-2'pentynyl substituent) One or more compounds; (II) at least one fungicide compound selected from the group consisting of mancozeb, maneb, iprodione, chlorotalonyl, probenazole, pyroquilon and fenbuconazole.

향상된 살균활성을 갖는 조성물에서 바람직한 6-(3-A-4-B-페닐)-2-(C)-피리다지논은 A가 수소 또는 플루오로이고, B는 클로로이며, C는 2'-펜틴일 또는 3'-비닐-2'-프로핀일인 화합물들이다. 더욱 바람직한 것은 6-(4-클로로페닐)-2-(2'-펜틴일)-피리다지논, 6-(3-플루오로-4-클로로페닐)-2-(2'-펜틴일)피리다지논, 6-(4-클로로페닐)-2-(3'-비닐-2'-프로핀일)-피리다지논, 또는 6-(3-플루오로-4-클로로페닐)-2-(3'-비닐-2'-프로핀일)-피리다지논이다.Preferred 6- (3-A-4-B-phenyl) -2- (C) -pyridazinone in compositions with improved bactericidal activity is A is hydrogen or fluoro, B is chloro and C is 2'- Phentinyl or 3'-vinyl-2'-propynyl. More preferred are 6- (4-chlorophenyl) -2- (2'-pentynyl) -pyridazinone, 6- (3-fluoro-4-chlorophenyl) -2- (2'-pentynyl) pyridine Dazinone, 6- (4-chlorophenyl) -2- (3'-vinyl-2'-propynyl) -pyridazinone, or 6- (3-fluoro-4-chlorophenyl) -2- (3 '-Vinyl-2'-propynyl) -pyridazinone.

향상된 살균활성을 갖는 바람직한 조성물에서 바람직한 6-(3-A'-4-B'-페닐)-2-(C')-4, 5-디히드로피리다지논 화합물은A'가 수소 또는 플루오로이고, B'가 클로로이며, C'는 2'-펜틴일 또는 3'-비닐-2'-프로핀일인 화합물들이다. 더욱 바람직한 것은 6-(4-크로로페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논, 6-(3-플루오로-4-클로로페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논, 6-(4-클로로페닐)-2-(3'-비닐-2'-프로핀일)-4, 5-디히드로피리다지논, 또는 6-(3-플루오로-4-클로로페닐)-2-(3'-비닐-2'-프로핀일)-4, 5-디히드로피리다지논이다.Preferred 6- (3-A'-4-B'-phenyl) -2- (C ')-4, 5-dihydropyridazinone compounds in preferred compositions with improved bactericidal activity are those in which A' is hydrogen or fluoro And B 'is chloro and C' is 2'-pentynyl or 3'-vinyl-2'-propynyl. More preferred are 6- (4-chlorophenyl) -2- (2'-pentynyl) -4, 5-dihydropyridazinone, 6- (3-fluoro-4-chlorophenyl) -2- ( 2'-pentynyl) -4, 5-dihydropyridazinone, 6- (4-chlorophenyl) -2- (3'-vinyl-2'-propynyl) -4, 5-dihydropyridazinone Or 6- (3-fluoro-4-chlorophenyl) -2- (3'-vinyl-2'-propynyl) -4,5-dihydropyridazinone.

향상된 물성을 갖는 바람직한 조성물들은 (I) 6-(4-클로로페닐)-2-(2'-펜틴일)-피리다지논, 6-(3-플루오로-4-클로로페닐)-2-(2'-펜틴일)-피리다지논, 또는 6-(4-클로로페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논 및; (II) 만코제브, 프로베나졸, 피로퀼론, 이프로디온, 펜부코나졸 또는 클로로탈로닐의 조합이다.Preferred compositions with improved physical properties are (I) 6- (4-chlorophenyl) -2- (2'-pentynyl) -pyridazinone, 6- (3-fluoro-4-chlorophenyl) -2- ( 2'-pentynyl) -pyridazinone, or 6- (4-chlorophenyl) -2- (2'-pentynyl) -4, 5-dihydropyridazinone and; (II) mancozeb, probenazole, pyroquilon, iprodione, fenbuconazole or chlorothalonil.

더욱 바람직한 조성물들은 6-(4-클로로페닐)-2-(2'-펜틴일)-피리다지논과 만코제브, 프로베나졸, 피로퀼론, 이프로디온 또는 펜부코나졸의 조합; 및 6-(4-클로로페닐)-2-(2'-펜틴일)-4, 5-디히드로피리다지논과 클로로탈로닐의 조합이다.More preferred compositions include a combination of 6- (4-chlorophenyl) -2- (2'-pentynyl) -pyridazinone with mancozeb, probenazole, pyroquilon, iprodione or fenbuconazole; And 6- (4-chlorophenyl) -2- (2'-pentynyl) -4, 5-dihydropyridazinone and chlorotalonyl.

바람직하게, 그러한 향상된 물성을 갖는 조성물들에 있어서, 피리다지논 또는 디히드로피리다지논과 기타의 살균제 화합물의 비는 약 25/1 내지 1/25 일수 있다. 바람직한 근사 비들(approximate ratios)은 다음과 같다.Preferably, in compositions having such improved physical properties, the ratio of pyridazinone or dihydropyridazinone and other fungicide compounds may be about 25/1 to 1/25. Preferred approximate ratios are as follows.

(i) 성분 I이 6-(4-클로로페닐)-2-(2'-펜틴일)피리다지논인 경우:(i) when component I is 6- (4-chlorophenyl) -2- (2'-pentynyl) pyridazinone:

(ii) 성분 I이 6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논이고 성분 II가 클로로탈로닐인 경우, 바람직한 비(I/II)는 20/1 내지 1/20이고, 더욱 바람직한 비는 4/1 내지 1/4이다.(ii) where component I is 6- (4-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone and component II is chlorothalonyl, the preferred ratio (I / II ) Is 20/1 to 1/20, and more preferably 4/1 to 1/4.

향상된 활성을 갖는 본 발명의 조성물들은 화합물이 단독살균제로 사용되는 경우에 대하여 전술한 바와 마찬가지 방법들에 따라서 사용될 수 있다. 각각의 화합물 단독사용시에 비하여 특정적용에서 살균제 화합물의 사용량을 줄일 수 있고, 향상된 활성을 갖지 않는 조합들에 비하여 동일 내지 더 적은 농도 수준에서도 더 광범위하고 지속적인 활성을 나타내므로, 그러한 향상된 활성을 갖는 조성물들을 사용하는 것이 매우 유리하다.Compositions of the invention having improved activity can be used according to the same methods as described above for the case where the compound is used as a disinfectant alone. Compositions having such enhanced activity can reduce the amount of fungicide compound used in a particular application as compared to the use of each compound and exhibit more extensive and sustained activity at the same to less concentration levels than combinations that do not have enhanced activity. It is very advantageous to use them.

다음의 실험예는 향상된 활성을 갖는 본 발명의 조성물 및 그 활성을 설명하는 것이다.The following experimental example illustrates the composition of the present invention with improved activity and its activity.

[실험과정][Experimental process]

시험화합물들 및 통상적인 살균제들을 탱크내에서 혼합되고 아세톤/메탄올/물(1/1/2)의 혼합물내에 여러농도로서 기계식 분무되었다. 예방보호제 스프레이는 포자접종 1일후 적용되었다. 치료제 또는 전염후 스프레이는 포자접종 1일후 적용되었다. 스프레이시스템은 헥타르당 1458리터의 속도에서 200ppm 투여수준이 되도록 하였다. 다음 질병들에 대하여 시험평가하였다.Test compounds and conventional fungicides were mixed in a tank and mechanically sprayed at various concentrations into a mixture of acetone / methanol / water (1/1/2). A prophylactic spray was applied 1 day after spore inoculation. Therapeutic or post-infective sprays were applied one day after spore inoculation. The spray system was brought to a 200 ppm dose level at a rate of 1458 liters per hectare. Trials were evaluated for the following diseases.

[도열병, 피리큘라리아][The Plague, Pycurularia]

M-201 벼작물들을 피리큘라리아 오리자에 분생자로 접종시켰다. 포자농도는 1㎖물당 300,000-500,000 분생자이었다. 플랫당 20개의 작물에 20㎖의 접종원이 적용되도록 분무기가 사용되었다. 접종된 작물들을 100%상대습도의 습한 캐비넷내에 48시간 놓아둔후 온실에 놓아두었다. 접종후 7-8일에 평가를 행하였다.M-201 rice crops were inoculated into pyricularia oriza as conidia. Spore concentration was 300,000-500,000 conidia per ml of water. A nebulizer was used to apply 20 ml of inoculum to 20 crops per flat. Inoculated crops were placed in a greenhouse in a humid cabinet at 100% relative humidity for 48 hours. Evaluation was performed 7-8 days after inoculation.

[밀셉토리아][Milfstoria]

필터 밀작물들을 셉토리아 노도룸 분생자로 접종시켰다. 포자농도는 1㎖물당 약 3,000,000 분생자이었다. 플랫당 20개의 작물에 20㎖의 접종원이 적용되도록 분무기가 사용되었다. 접종된 작물들을 100% 상대습도의 습한 캐비넷에 72시간 놓아둔 후, 온실에 놓아두었다. 접종후 10일에 평가를 행하였다.Filter crops were inoculated with Septoria nodorum conidia. Spore concentration was about 3,000,000 conidia per ml of water. A nebulizer was used to apply 20 ml of inoculum to 20 crops per flat. Inoculated crops were placed in a humid cabinet at 100% relative humidity for 72 hours and then in a greenhouse. Evaluation was performed 10 days after inoculation.

[토마토 보트리티스][Tomato Botrytis]

3주자란 픽시(Pixie)토마토 작물들을 보트리티스 시네레아 분생자로 접종시켰다. 작물들은 접종 전 2일간 희미한 빛에서 유지되었다. 포자농도는 덱스트로즈 용액 1㎖ 당 500,000-650,000 분생자이었다. 작물의 잎상하 양면 및 줄기에 분생자 현탁액이 짙게 도포되어 흘러내릴 정도로 분무기가 사용되었다. 접종된 작물들을 20℃에서 5일간 미스트 챔버내에서 유지시켰다.Pixie tomato crops were inoculated with Botrytis cinerea conidia. Crops were kept in dim light for two days before inoculation. Spore concentration was 500,000-650,000 conidia per ml of dextrose solution. Atomizers were used so that the conidia suspension was densely applied and dripping down both the upper and lower leaves and the stems of the crop. Inoculated crops were maintained in a mist chamber at 20 ° C. for 5 days.

전염병 구제율은 조성물이 스프레이 되지 않은 접종대조 표준들과 조성물 처리된 접종작물들의 비교에 기초한 퍼센트 구제율로서 기록되었다. 결과를 다음 표들에 표기하였다.Infectious disease control rates were reported as percent rescue based on the comparison of inoculum control compositions with inoculated control compositions and inoculated crops treated with the composition. The results are shown in the following tables.

Claims (19)

다음 일반식의 화합물, 및 농경학적으로 허용되는 그 염A compound of the general formula and an agriculturally acceptable salt thereof 상기 일반식에서, A는 -(CHR2)n-CHR7-Z-, -CF2-CF2-Z, -(CHR2)n-O-Z, -(CHR2)n-S-Z-, -O-CHR2-Z-, -CR2=CR7-Z-, CR2=N-Z-, CHR2-CR7=Y-, 또는 -CR2=CR2-Y=이고; D는 CR2또는 질소이고; Q는 다음 기들로부터 선택된 방향족 기이고;In the above general formula, A is-(CHR 2 ) n-CHR 7 -Z-, -CF 2 -CF 2 -Z,-(CHR 2 ) nOZ,-(CHR 2 ) nSZ-, -O-CHR 2 -Z -, -CR 2 = CR 7 -Z-, CR 2 = NZ-, CHR 2 -CR 7 = Y-, or -CR 2 = CR 2 -Y =; D is CR 2 or nitrogen; Q is an aromatic group selected from the following groups; Z는 카보닐(C=0) 또는 티오카보닐(C=S)이고; Y는 할로, 알콕시, 알킨일티오 또는 트리아졸릴에 의해 치환된 탄소이고; X는 산소(O) 혹은 황(S)이며, (i) R1은 시아노알킬, 시클로알킬알킬, 페닐카보닐, 할로알켄일, 알키닐알켄일, 알킨일, 할로알킨일, 페닐알킨일, 헤테로시클릴, 디알키닐, 헤테로시클릴알킨일, 시클로알킬알킨일, 알켄일알킨일, 히드록시알킨일, 알콕시알킨일, 알카노일옥시알킨일, 포르밀알킨일, 트리알킬실릴알킨일, 트리알킬틴알킨일, 할로알켄일알킨일, 카르복시알킨일, 또는 알콕시 카보닐 알킨일이고; R6은 수소, 알콕시 또는 할로겐이고; R2는 수소, (C1-C6)알킬, 페닐, 시아노 도는 할로겐이고; R7은 수소, (C1-C3)알킬, 페닐, 할로겐 또는 시아노이고; R6는 수소, 알콕시 또는 할로겐이고; R3는 수소, (C1-C6)알킬, 알콕시 또는 할로겐이고; R4는 수소, 할로겐, (C1-C6)알킬, 알콕시 또는 니트로이고; R5는 수소, 할로겐, 니트로, 알킬, 알콕시, 알킬티오, 할로알킬, 할로알콕시, 페닐, 페녹시 또는 시아노이고; 헤테로시크릴이란 산소, 황 혹은 질소로 구성되는 구룹으로부터 선택된 하나의 헤테로 원자를 포함하여 최고 10개의 원자를 갖는 부분 포화된 또는 포화된 5- 및 6-원자 방향족 고리 혹은 이중고리(bicyclic ring)이며; 혹은 (ii) R2와 R3는 함께(C1-C3) 알킬렌을 형성하고 R1, R4, R5, R6및 R7은 상기한 바와 같으며; A가 -CH2-CH2-(C=O)-이고 Q가 4-클로로페닐이면, R1은 CH2C≡CH3가 아님.Z is carbonyl (C = 0) or thiocarbonyl (C = S); Y is carbon substituted by halo, alkoxy, alkynylthio or triazolyl; X is oxygen (O) or sulfur (S), (i) R 1 is cyanoalkyl, cycloalkylalkyl, phenylcarbonyl, haloalkenyl, alkynylalkenyl, alkynyl, haloalkynyl, phenylalkynyl, Heterocyclyl, dialkyl, heterocyclylalkynyl, cycloalkylalkynyl, alkenylalkynyl, hydroxyalkynyl, alkoxyalkynyl, alkanoyloxyalkynyl, formyl alkynyl, trialkylsilylalkynyl, trialkyl Tinalkynyl, haloalkenylalkynyl, carboxyalkynyl, or alkoxy carbonyl alkynyl; R 6 is hydrogen, alkoxy or halogen; R 2 is hydrogen, (C 1 -C 6 ) alkyl, phenyl, cyano or halogen; R 7 is hydrogen, (C 1 -C 3 ) alkyl, phenyl, halogen or cyano; R 6 is hydrogen, alkoxy or halogen; R 3 is hydrogen, (C 1 -C 6 ) alkyl, alkoxy or halogen; R 4 is hydrogen, halogen, (C 1 -C 6 ) alkyl, alkoxy or nitro; R 5 is hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, phenyl, phenoxy or cyano; Heterocyclyl is a partially saturated or saturated 5- and 6-membered aromatic ring or bicyclic ring having up to 10 atoms, including one hetero atom selected from a group consisting of oxygen, sulfur or nitrogen. ; Or (ii) R 2 and R 3 together form a (C 1 -C 3 ) alkylene and R 1 , R 4 , R 5 , R 6 and R 7 are as described above; When A is —CH 2 —CH 2 — (C═O) — and Q is 4-chlorophenyl, then R 1 is not CH 2 C≡CH 3 ; 제1항에 있어서, 치환기가 다음과 같은 화합물 및 농경학적으로 수용가능한 그 염 A는 -CHR2-CHR7-Z-, -CR2=CR7-Z-, -CR2=N-Z-, 또는 -CHR2-CR7=X-이고 D는 DR2또는 질소이고, Q는 다음 기들로부터 선택된 방향족 기이고;A compound according to claim 1, wherein the substituent is agrochemically acceptable and salt A is -CHR 2 -CHR 7 -Z-, -CR 2 = CR 7 -Z-, -CR 2 = NZ-, or -CHR 2 -CR 7 = X- and D is DR 2 or nitrogen and Q is an aromatic group selected from the following groups; Z는 카보닐(C=O) 또는 티오카보닐(C=S)이고; Y는 할로, (C1-C6)알콕시, (C3-C6)알킨일티오 또는 트리아졸릴에 의하여 치환된 탄소이고; X는 산소 혹은 황이며; (i) R1은 시아노 (C1-C6)알킬, (C3-C6)시클로알킬알킬, 할로(C3-C6)알켄일,(C3-C6)알킨일(C2-C6)알켄일, (C3-C10)알킨일, (C4-C20)디알킨일, 할로(C3-C6)알킨일, 페닐(C3-C6)알킨일, 헤테로시클릴(C3-C6)알킨일, (C3-C6)시클로알킬(C3-C6)알킨일, (C3-C6)알켄일(C3-C6)알킨일, 히드록시(C3-C6)알킨일, (C1-C6)알콕시 (C3-C6)알킨일, (C1-C6)알카노일옥시(C3-C6)알킨일, 포르밀(C3-C6)알킨일, 트리(C1-C6)알킬실릴(C3-C6)알킨일, 트리(C1-C6)알킬틴(C3-C6)알킨일, 할로(C3-C6)알켄일 (C3-C6)알킨일, 카르복시(C3-C6)알킨일, 또는 (C1-C6)알콕시카보닐 (C3-C6)알킨일이고; R2는 수소, (C1-C6)알킬, 페닐, 또는 할로겐이고; R6은 수소, 혹은 할로겐이고; R3은 수소, 또는 할로겐, (C1-C6)알킬 또는 (C1-C6)알콕시이고; R4는 수소, 할로겐, (C1-C6)알킬, (C1-C6)알콕시 또는 니트로이고; R5는 수소, 할로겐, 니트로, (C1-C6)알킬, (C1-C6)알콕시, (C1-C6)알킬티오, 할로(C1-C6)알킬, 할로(C1-C6)알콕시, 페닐, 페녹시 또는 시아노이고; R7은 수소, (C1-C3)알킬, 페닐 또는 할로겐이며; 혹은 (ii) R2와 R3은 함께, (C1-C3)알킬렌을 형성하고; R1, R4, R5, R6및 R7은 상기한 바와 같음.Z is carbonyl (C═O) or thiocarbonyl (C═S); Y is carbon substituted by halo, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) alkynylthio or triazolyl; X is oxygen or sulfur; (i) R 1 is cyano (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkylalkyl, halo (C 3 -C 6 ) alkenyl, (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, (C 3 -C 10 ) alkynyl, (C 4 -C 20 ) dialkynyl, halo (C 3 -C 6 ) alkynyl, phenyl (C 3 -C 6 ) alkynyl, Heterocyclyl (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl , Hydroxy (C 3 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy (C 3 -C 6 ) alkynyl, (C 1 -C 6 ) alkanoyloxy (C 3 -C 6 ) alkynyl , Formyl (C 3 -C 6 ) alkynyl, tri (C 1 -C 6 ) alkylsilyl (C 3 -C 6 ) alkynyl, tri (C 1 -C 6 ) alkyltin (C 3 -C 6 ) Alkynyl, halo (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, carboxy (C 3 -C 6 ) alkynyl, or (C 1 -C 6 ) alkoxycarbonyl (C 3 -C 6 ) alkynyl; R 2 is hydrogen, (C 1 -C 6 ) alkyl, phenyl, or halogen; R 6 is hydrogen or halogen; R 3 is hydrogen or halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy; R 4 is hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy or nitro; R 5 is hydrogen, halogen, nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkylthio, halo (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkoxy, phenyl, phenoxy or cyano; R 7 is hydrogen, (C 1 -C 3 ) alkyl, phenyl or halogen; Or (ii) R 2 and R 3 together form (C 1 -C 3 ) alkylene; R 1 , R 4 , R 5 , R 6 and R 7 are as described above. 제2항에 있어서, 다음 일반식을 갖는 화합물 및 농경학적으로 수용가능한 그 염.The compound according to claim 2, and an agriculturally acceptable salt thereof having the general formula 상기 일반식에서, R1은 시아노(C1-C6)알킬, (C3-C6)시클로알킬(C1-C6)알킬, 할로(C3-C6)알켄일, (C3-C6)알킨일(C2-C6)알켄일, (C3-C10)알킨일, (C4-C10)디알킨일, 할로(C3-C6)알킨일, 페닐(C3-C6)알킨일, 헤테로시클릴(C3-C6)알킨일, (C3-C6)시클로알킬(C3-C6)알킨일, (C3-C6)알켄일(C3-C6)알킨일, 히드록시(C3-C6)알킨일, (C1-C6)알콕시(C3-C6)알킨일, (C1-C6)알카노일옥시(C3-C6)알킨일, 포르밀(C3-C6) 알킨일, 트리(C1-C6)알킬실릴(C3-C6)알킨일, 트리(C1-C6)알킬틴(C3-C6)알킨일, 할로(C3-C6)알켄일(C3-C6)알킨일, 카르복시(C3-C6)알킨일, 또는 (C1-C6)알콕시카보닐(C3-C6)알킨일이고; R2는 수소, 플루오로 또는 (C1-C6)알킬이고; R3는 수소, 할로겐, (C1-C6)알킬 또는 (C1-C6)알콕시이거나; 또는 R2는 R3가 함께 (C1-C3) 알킬렌을 형성하고; R4는 수소, (C1-C6)알킬, 할로겐 또는 니트로이고; R5는 수소, (C1-C6)알킬, (C1-C6)알콕시, 페녹시, 할로(C1-C6)알킬, (C1-C6)알킬티오, 시아노, 페닐, 할로(C1-C6)알콕시 또는 할로겐이고; R6는 수소 또는 할로겐이고; R7은 수소,(C1-C3) 알킬, 페닐, 할로겐임.Wherein R 1 is cyano (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C 1 -C 6 ) alkyl, halo (C 3 -C 6 ) alkenyl, (C 3 -C 6 ) alkynyl (C 2 -C 6 ) alkenyl, (C 3 -C 10 ) alkynyl, (C 4 -C 10 ) dialkynyl, halo (C 3 -C 6 ) alkynyl, phenyl (C 3 -C 6 ) alkynyl, heterocyclyl (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) alkynyl, (C 3 -C 6 ) alkenyl ( C 3 -C 6 ) alkynyl, hydroxy (C 3 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy (C 3 -C 6 ) alkynyl, (C 1 -C 6 ) alkanoyloxy ( C 3 -C 6 ) alkynyl, formyl (C 3 -C 6 ) alkynyl, tri (C 1 -C 6 ) alkylsilyl (C 3 -C 6 ) alkynyl, tri (C 1 -C 6 ) alkyl Tin (C 3 -C 6 ) alkynyl, halo (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl, carboxy (C 3 -C 6 ) alkynyl, or (C 1 -C 6 ) Alkoxycarbonyl (C 3 -C 6 ) alkynyl; R 2 is hydrogen, fluoro or (C 1 -C 6 ) alkyl; R 3 is hydrogen, halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy; Or R 2 together with R 3 form (C 1 -C 3 ) alkylene; R 4 is hydrogen, (C 1 -C 6 ) alkyl, halogen or nitro; R 5 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, phenoxy, halo (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylthio, cyano, phenyl , Halo (C 1 -C 6 ) alkoxy or halogen; R 6 is hydrogen or halogen; R 7 is hydrogen, (C 1 -C 3 ) alkyl, phenyl, halogen. 제3항에 있어서, 상기 일반식에서 R1이 할로(C3-C6)알킨일, (C3-C10)알킨일, (C3-C6)알켄일(C3-C6)알킨일 또는 (C3-C6)알킨일(C3-C6)알켄일이고; R2는 수소 또는(C1-C6)알킬이고, R3는 수소, 할로 또는 (C1-C6)알콕시이거나, 또는 R2와 R3가 함께(C1-C3)알킬렌을 형성하며; R4는 수소, 할로 또는(C1-C6)알킬이고; R5는 수소, 할로 또는 할로(C1-C6)알콕시이고, R6는 수소 또는 플루오로이며; R7은 수소인 화합물.According to claim 3, wherein in the general formula R 1 is halo (C 3 -C 6 ) alkynyl, (C 3 -C 10 ) alkynyl, (C 3 -C 6 ) alkenyl (C 3 -C 6 ) alkyn One or (C 3 -C 6 ) alkynyl (C 3 -C 6 ) alkenyl; R 2 is hydrogen or (C 1 -C 6 ) alkyl, R 3 is hydrogen, halo or (C 1 -C 6 ) alkoxy, or R 2 and R 3 together (C 1 -C 3 ) alkylene Form; R 4 is hydrogen, halo or (C 1 -C 6 ) alkyl; R 5 is hydrogen, halo or halo (C 1 -C 6 ) alkoxy, and R 6 is hydrogen or fluoro; R 7 is hydrogen. 제4항에 있어서, R1은 2-펜틴일, 2-헥신일, 3-비닐-2-프로핀일, 4-플루오로-2-펜틴일, 5-플루오로-2-펜틴일, 또는 3-(1프로펜일)-2-프로핀일이고; R2는 수소이고 R3도 수소이거나, 또는 R2와 R3가 함께(C1-C3)알킬렌쇄를 형성하고; R4는 수소, 메틸, 클로로 또는 플루오로이고; R5는 클로로, 플루오로, 브로모, 또는 트리플루오로메톡시이고; R6는 수소 또는 플루오로이며; R7은 수소인 화합물.The compound of claim 4, wherein R 1 is 2-pentynyl, 2-hexynyl, 3-vinyl-2-propynyl, 4-fluoro-2-pentinyl, 5-fluoro-2-pentinyl, or 3 -(1propenyl) -2-propynyl; R 2 is hydrogen and R 3 is also hydrogen, or R 2 and R 3 together form a (C 1 -C 3 ) alkylene chain; R 4 is hydrogen, methyl, chloro or fluoro; R 5 is chloro, fluoro, bromo, or trifluoromethoxy; R 6 is hydrogen or fluoro; R 7 is hydrogen. 제5항에 있어서, R1은 2-펜틴일이고; (i) R4는 수소, 플루오로, 클로로 또는 메틸이고; R5는 클로로, 플루오로, 브로모 또는 트리플루오로메톡시이며; R6는 수소 또는 플루오로이며; 혹은 (ii) R2, R3, R6및 R7은 수소이며; R5는 클로로이며 R4는 수소 또는 플루오로인 화합물.The compound of claim 5, wherein R 1 is 2-pentynyl; (i) R 4 is hydrogen, fluoro, chloro or methyl; R 5 is chloro, fluoro, bromo or trifluoromethoxy; R 6 is hydrogen or fluoro; Or (ii) R 2 , R 3 , R 6 and R 7 are hydrogen; R 5 is chloro and R 4 is hydrogen or fluoro. 제5항에 있어서, 상기 R1은 2-펜틴일 혹은 3-비닐-2-프로핀일이고; R2와 R3는 함께 (C1-C3)알킬렌쇄를 형성하고; R4는 수소 또는 플루오로이고; R5는 클로로, 플루오로 또는 브로모인 화합물.The compound of claim 5, wherein R 1 is 2-pentynyl or 3-vinyl-2-propynyl; R 2 and R 3 together form a (C 1 -C 3 ) alkylene chain; R 4 is hydrogen or fluoro; R 5 is chloro, fluoro or bromo. 제5항에 있어서, R1은 2-헥신일이고; R4는 수소 또는 플루오로이고; R5는 클로로이고; R6는 수소인 화합물.The compound of claim 5, wherein R 1 is 2-hexynyl; R 4 is hydrogen or fluoro; R 5 is chloro; R 6 is hydrogen. 제2항에 있어서, 다음 일반식의 화합물 및 농경학적으로 수용가능한 그 염3. A compound according to claim 2, wherein the compound of formula 상기 일반식에서, R1은 (C3-C6)알킨일, (C2-C6)알킨일(C3-C6)알킨일, 할로(C3-C6)알킨일, (C2-C6)알켄일(C3-C6)알킨일 또는 트리 (C1-C6)알킬틴(C3-C6)알킨일이고; R2는 수소 또는 할로겐이고; R3는 수소 또는 (C1-C6)알킬이거나 또는 R2와 R3가 함께 (C1-C3)알킬렌을 형성하고; R4는 수소, 할로겐 또는 (C1-C6)알킬이고; R5는 수소, 할로겐, (C1-C6)알킬 또는 (C1-C6)알콕시이고; R6은 수소 또는 할로겐이며; R7은 수소 또는 할로겐이다.In the general formula, R 1 is (C 3 -C 6 ) alkynyl, (C 2 -C 6 ) alkynyl (C 3 -C 6 ) alkynyl, halo (C 3 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl (C 3 -C 6 ) alkynyl or tri (C 1 -C 6 ) alkyltin (C 3 -C 6 ) alkynyl; R 2 is hydrogen or halogen; R 3 is hydrogen or (C 1 -C 6 ) alkyl or R 2 and R 3 together form (C 1 -C 3 ) alkylene; R 4 is hydrogen, halogen or (C 1 -C 6 ) alkyl; R 5 is hydrogen, halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy; R 6 is hydrogen or halogen; R 7 is hydrogen or halogen. 제9항에 있어서, R1은 2-펜틴일, 3-비닐-2-프로핀일, 4-플루오로-2-펜틴일, 또는 5-플루오로-2-펜틴일; R2와 R3는 각각 수소이거나 또는 함께(C1-C3)알킬렌쇄를 형성하고; R4는 수소, 플루오로 또는 클\로로이고; R5는 플루오로, 클로로 또는 브로모이고; R6는 수소이며; R7은 수소인 화합물.The compound of claim 9, wherein R 1 is 2-pentynyl, 3-vinyl-2-propynyl, 4-fluoro-2-pentinyl, or 5-fluoro-2-pentinyl; R 2 and R 3 are each hydrogen or together form a (C 1 -C 3 ) alkylene chain; R 4 is hydrogen, fluoro or chloro; R 5 is fluoro, chloro or bromo; R 6 is hydrogen; R 7 is hydrogen. 농경학적으로 또는 의학적으로 허용되는 담체 및 살균활성적인 양의 청구항 1의 화합물로 구성되는 살균제 조성물.A fungicide composition comprising an agriculturally or medically acceptable carrier and a bactericidal active amount of the compound of claim 1. 다음 성분(I) 및 (II)로 구성되는 살균제 조성물A fungicide composition consisting of the following components (I) and (II) (I) 제1성분으로 식 6-(3-A-4-B-페닐)-2-(C)-피리다지논 또는 식 6-(3-A'-4-B'-페닐)-2-(C')-4,5-디히드로피리다지논(여기서, A 혹은 A'는 수소 또는 플루오로치환기; B 혹은 B'는 수소, 브로모, 또는 클로로치환기이며; C 혹은 C'는 2-펜틴일, 3-비닐-2-프로핀일, 4-플루오로-2-펜틴일 또는 5-플루오로-2-펜틴일치환기임);를 갖는 하나 이상의 화합물; 및 (II) 제2성분으로 만코제브, 마네브, 이프로디온, 클로로탈로닐, 프로베나졸, 피로퀼론 및 펜부코나졸로 구성되는 그룹으로부터 선택된 하나 이상의 화합물.(I) Formula 6- (3-A-4-B-phenyl) -2- (C) -pyridazinone or formula 6- (3-A'-4-B'-phenyl) -2 as the first component -(C ')-4,5-dihydropyridazinone, wherein A or A' is hydrogen or fluorosubstituted group; B or B 'is hydrogen, bromo, or chlorosubstituted group; C or C' is 2 At least one compound having: -pentynyl, 3-vinyl-2-propynyl, 4-fluoro-2-pentynyl or 5-fluoro-2-pentynyl substituent; And (II) at least one compound selected from the group consisting of mancozeb, maneb, iprodione, chlorothalonyl, probenazole, pyroquilon and fenbuconazole as a second component. 제12항에 있어서, 상기 제1성분은 식-6-(3-A-4-클로로페닐)-2-(C)-피리다지논이며, 이때 A는 수소 혹은 플루오로 치환기이고, C는 2-펜틴일 또는 3-비닐-2-프로핀일 치환체임을 특징으로 하는 조성물.13. The compound of claim 12, wherein the first component is formula-6- (3-A-4-chlorophenyl) -2- (C) -pyridazinone, wherein A is hydrogen or a fluoro substituent, and C is 2 A pentynyl or 3-vinyl-2-propynyl substituent. 제12항에 있어서, 상기 제1성분은 식 6-(3-A' -4-클로로페닐)-2-(C')-4,5-디히드로피리다지논이며, 이때 A'는 수소 또는 플루오로 치환기이고, C'는 2-펜틴일 또는 3-비닐-2-프로핀일 치환체임을 특징으로 하는 조성물13. The method of claim 12 wherein the first component is formula 6- (3-A'-4-chlorophenyl) -2- (C ')-4,5-dihydropyridazinone, wherein A' is hydrogen or A fluoro substituent and C 'is a 2-pentynyl or 3-vinyl-2-propynyl substituent 6-(4-클로로페닐)-2-(2'-펜틴일)피리다지논, 6-(3-플루오로-4-클로로페닐)-2-(2'-펜틴일)피리다지논, 및 6-(4-클로로페닐)-2-(2'-펜틴일)-4,5-디히드로피리다지논으로 구성되는 그룹으로부터 선택된 제1성분; 및 만코제브, 프로베나졸, 피로퀼론, 이프로디온, 펜부코나졸, 및 클로로탈로닐로 구성되는 그룹으로부터 선택된 제2성분으로 구성되며, 상기 제1성분 및 제2성분은 조성물의 제1성분과 제2성분 각각의 살균활성의 합계치보다 조성물의 살균활성이 더 크도록 하기에 유효한 비율로 존재하는 살균제 조성물.6- (4-chlorophenyl) -2- (2'-pentynyl) pyridazinone, 6- (3-fluoro-4-chlorophenyl) -2- (2'-pentynyl) pyridazinone, and A first component selected from the group consisting of 6- (4-chlorophenyl) -2- (2'-pentynyl) -4,5-dihydropyridazinone; And a second component selected from the group consisting of mancozeb, probenazole, pyroquilon, iprodione, fenbuconazole, and chlorotalonyl, wherein the first component and the second component are combined with the first component of the composition. A fungicide composition present in an effective ratio so that the bactericidal activity of the composition is greater than the sum of the bactericidal activities of each of the second components. 제15항에 있어서, 제1성분은 6-(4-클로로페닐)-2-(2'-펜틴일)피리다지논이고, 제2성분은 만코제브, 프로베나졸, 피로퀼론, 이프로디온 또는 펜부코나졸인 조성물.16. The composition of claim 15 wherein the first component is 6- (4-chlorophenyl) -2- (2'-pentynyl) pyridazinone and the second component is mancozeb, probenazole, pyroquilon, iprodione or The composition is fenbuconazole. 제16항에 있어서, 제2성분은 만코제브이고, 제1성분과 제2성분의 비는 20/1 내지 1/20인 조성물.The composition of claim 16 wherein the second component is mancozeb and the ratio of the first component to the second component is between 20/1 and 1/20. A가 CH2-CH2-(C=O)-이고 Q가 4-클로로페닐, R1은 CH2C≡CCH3인 살균유효량의 청구범위 1항의 화합물을 균류 또는 그 서식처에 적용함을 포함하는 초식성균류 구제방법.Applying a compound of claim 1 to a fungus or habitat thereof, wherein A is CH 2 -CH 2- (C = O)-, Q is 4-chlorophenyl, and R 1 is CH 2 C≡CCH 3 Herbivorous fungal control method. 제3항에 있어서, 상기 Q는혹은가 아니며, R7은 수소, (C1-C3)알킬, 페닐 혹은 할로겐임을 특징으로 하는 화합물.The method of claim 3, wherein Q is or And R 7 is hydrogen, (C 1 -C 3 ) alkyl, phenyl or halogen.
KR1019910016465A 1990-09-21 1991-09-20 Dihydropyridazinones pyridazinones and related compounds as fungicides KR100204381B1 (en)

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