KR910001756B1

KR910001756B1 - Process for preparing hydrazynopyridazine derivatives

Info

Publication number: KR910001756B1
Application number: KR1019830000097A
Authority: KR
Inventors: 기꾸오 야스다; 리끼오 오오우찌; 도시미 세끼; 모리노부 사이또; 모또히로 고바야시
Original assignee: 데이고꾸조오끼세이야꾸 가부시끼가이샤; 야마구찌 에이이찌
Priority date: 1983-01-13
Filing date: 1983-01-13
Publication date: 1991-03-23
Also published as: KR840003241A

Abstract

내용 없음.No content.

Description

Method for preparing hydrazinopyridazine derivatives

본 발명은 뛰어난 강압작용을 갖는 히드라지노피리다진 유도체의 신규한 제조방법에 관한 것으로 더 상세하게는 하기 식 (I)The present invention relates to a novel process for preparing hydrazinopyridazine derivatives having an excellent stepping action.

[화학식 1][Formula 1]

(식중, R'은 수소원자 : 할로겐원자 : 시아노기 ; 적의 할로겐원자, 저급 알콕시지, 저급 알킬티오기, 저급 알카노일아미노기 또는 테트라히드로푸르푸릴옥시기로 치환되어 있어도 무방한 저급 알킬기, 적의 페닐기 또는 저급 알콕시기로 치환되어 있어도 무방한 저급 알콕시기 : 저급 알케닐기 : 저급 알케닐옥시기 또는 저급 알키닐기를 나타내며, R²은 수소원자 : 할로겐원자; 시아노기; 적의 할로겐원자 또는 저급 알콕시기로 치환되어 있어도 무방한 저급 알킬기 : 저급 알콕시기; 저급 알케닐기를 나타내며, R³, R⁴및 R⁵는 각각 독립하여 수소원자 : 할로겐원자; 적의 저급 알콕시기로 치환되어 있어도 무방한 저급 알킬기 또는 저급 알콕시기를 나타내며, R⁶은 수소원자 또는 메틸기를 나타냄)로 나타내는 히드라지노피리다진 유도체 및 그 산부가염의 제조방법과 이 방법에 있어의 신규한 합성 중간체에 관한 것이다.Wherein R 'is a hydrogen atom: halogen atom: cyano group; lower halogen atom, lower alkoxyl group, lower alkylthio group, lower alkanoylamino group or tetrahydrofurfuryloxy group; A lower alkoxy group which may be substituted with a lower alkoxy group: a lower alkenyl group: a lower alkenyloxy group or a lower alkynyl group, R2 may be substituted with a hydrogen atom: a halogen atom; a cyano group; an enemy halogen atom or a lower alkoxy group Lower alkyl group: Lower alkoxy group; Lower alkenyl group, R < ³ >, R ', and R <^5> represent a hydrogen atom: halogen atom independently, It may represent the lower alkyl group or lower alkoxy group which may be substituted by the lower alkoxy group, R <^6> is hydrogen Hydrazinopyridazine derivatives represented by an atom or a methyl group) and acid addition salts thereof It relates to a novel synthetic intermediate in the production method and the method.

본 발명자들은 상기식 (I)로 나타낸 히드라지노피리다진 유도체가 현저한 혈관 확장작용을 갖고 있을뿐 아니라 뛰어난 β-차단작용도 갖고 있으므로 강압제로서 극히 적합함을 발견하여 앞서 제안(일본 특개소57-108075호 공보, 동 특개소 57-106840호 명세서 참조)한 바 있다.The present inventors have found that the hydrazinopyridazine derivative represented by the formula (I) is extremely suitable as a suppressor because it has not only a significant vasodilatation effect but also an excellent β-blocking effect. 108075, the specification of Japanese Patent Application Laid-Open No. 57-106840).

금번 본 발명자들은 상기식 (I)로 나타낸 히드라지노피리다진 유도체가The present inventors have found that the hydrazinopyridazine derivative represented by the formula (I)

[화학식 2][Formula 2]

(식중 X은 염소, 브롬 또는 요오드원자를 나타내며, R¹,R²,R³,R⁴,R⁵및 R⁶은 전기의 뜻을 나타냄)로 나타내는 할로게노피리다진 유도체의 강산염을 티오요소와 반응시키고 이어서 대과잉의 히드라진 또는 그 수화물로 처리하고 그리하여 필요에 따라서 얻어지는 생성물을 산부가염으코 바꿈을 특징으로 하는 방법에 의하여 간단하게 고수율로 그리고 고순도로 제조할 수가 있음을 발견하여 본 발명을 완성하기에 이르렀다.Thiourea is a strong acid salt of the halogenopyridazine derivative represented by X (wherein X represents a chlorine, bromine or iodine atom, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the meaning of electricity). The present invention finds that it is possible to prepare the product obtained in a simple manner in high yield and in high purity by a method characterized by acid addition salt co-change, which is then treated with a large excess of hydrazine or a hydrate thereof and thus the product obtained as necessary. It was completed.

그리하여 본 발명에 의하면 상기 식 (II)로 나타내는 할로게노피리다진 유도체의 강산염을 티오요소와 반응시키고 이어서 대과잉의 히드라진 또는 그 수화물로 처리하고 그리하여 필요에 따라서 얻어지는 생성물을 산부가염으로 바꿈을 특징으로 하는 전기식 ( I )로 나타내는 히드라지노피리다진 유도체 또는 그 산부가염의 제조방법이 제공된다.Thus, according to the present invention, the strong acid salt of the halogenopyridazine derivative represented by the above formula (II) is reacted with thiourea and then treated with a large excess of hydrazine or its hydrate, thereby converting the product obtained into acid addition salt as necessary. There is provided a method for producing a hydrazinopyridazine derivative represented by the formula (I) or an acid addition salt thereof.

본 명세서에 있어 「저급」의 용어는 이 용어가 붙은 기 또는 화합물이 5개 이하, 바람직하기는 3개 이하의 탄소원자를 함유함을 뜻한다.In the present specification, the term "lower" means that the group or compound to which the term is attached contains 5 or less, preferably 3 or less, carbon atoms.

그리고 본 명세서에 있어 사용하는「저급 알킬기」의 용어는 직쇄상 또는 분지쇄상의 어느 것이어도 무방하며, 예를 들면 메틸, 에틸, n-또는 iso-프로필, n-, iso-, sec-또는 tert-부틸기등을 들수 있으며 그중에서도 메틸 및 에틸기가 적합하다.The term "lower alkyl group" used in the present specification may be linear or branched, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert. -Butyl group and the like, methyl and ethyl are suitable.

또 「저급 알콕시기」로서는 예를 들면 메톡시, 에톡시, n-프로폭시 또는 이소프로폭시기등을 들 수 있으며,「저급 알킬티오기」로서는 예를 들면 메틸티오, 에틸티오기등을 들 수 있으며, 「저급 알카노일 아미노기」로서는 예를 들면 아세틸아미노기를 들 수 있다.Moreover, as a "lower alkoxy group", a methoxy, ethoxy, n-propoxy, isopropoxy group, etc. are mentioned, for example, As a "lower alkylthio group", methylthio, an ethylthio group, etc. are mentioned, for example. As an "lower alkanoyl amino group", an acetylamino group is mentioned, for example.

또한 「저급 알케닐기」로서는 예를 들면 아릴기, 1-프로페닐기등을 들 수 있으며 그중에서도 아릴기가 바람직하며, 「저급 알케닐옥시기」는 저급 알케닐부분이 상기의 뜻을 갖는 저급 알케닐-O-기이며 그중에서도 아릴옥시기가 바람직하다.Moreover, as an "lower alkenyl group", an aryl group, 1-propenyl group, etc. are mentioned, for example, an aryl group is preferable, and a "lower alkenyloxy group" is a lower alkenyl-O whose lower alkenyl moiety has said meaning. And an aryloxy group is preferable.

「저급 알키닐기」로서는 예를 들면 에티닐, 프로팔길기등이 포함된다.Examples of the "lower alkynyl group" include ethynyl, propalyl group and the like.

「할로겐원자」의 용어는 플루오르, 염소, 브롬 및 요오드원자의 4종 모두 특히 플루오르, 염소 및 브롬원자를 포함하는 뜻이다.The term "halogen atom" means all four kinds of fluorine, chlorine, bromine and iodine atoms, especially fluorine, chlorine and bromine atoms.

그리고 상기 ( I )에 있어 「적의 할노겐원자, 히드록시기, 저급 알콕시기, 저급 알킬티오기, 저급 알카노일아미노기, 아릴옥시기 또는 테트라히드로푸르푸릴옥시기로 치환되어 있어도 무방한 저급 알킬기」, 「적의 할로겐원자 또는 저급 알콕시기로 치환되어 있으도 무방한 저급 알킬기」 및 「적의 저급 알콕시기로 치환되어있어도 무방한 저급 알킬기」에 있어의 치환된 알킬기로서는 할로겐원자 이외의 상기 치환기의 1개에 의하여치환된 저급 알킬기, 예를 들면 아세틸아미노메틸, 2-아세틸아미노에틸, 히드록시메틸, 2-히드록시에틸,3-히드록시프로필, 에톡시메틸, 2-메톡시에틸, 2-에톡시에틸, 3-메톡시프로필, 에틸티오메틸, 2-메틸티오에틸, 2-테트라히드로푸르푸릴옥시에틸 및 2-아릴옥시에틸기; 1-3개의 할로겐원자로 치환된 저급 알킬기, 예를 들면 트리플루오르메틸, 디클로로메틸 및 2-브로모에틸기등이 포함된다.또 「적의 2-프릴기, 페닐기 또는 저급 알콕시기로 치환되어 있어도 무방한 저급 알콕시기」에 있어의 치환된 저급 알콕시기로서는 1개의 2-프릴기, 페닐기 또는 저급 알콕시기로 치환된 저급 알콕시기, 예를 들면 푸르푸릴옥시, 벤질옥시, 페네틸옥시, 메톡시메톡시, 2-메톡시에톡시 및 2-에톡시에톡시기등이 포함된다.And in the above (I), "the lower alkyl group which may be substituted with an appropriate halogen halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkylthio group, a lower alkanoylamino group, an aryloxy group or a tetrahydrofurfuryloxy group", Lower alkyl group which may be substituted with halogen atom or lower alkoxy group "and lower alkyl group substituted with" lower alkyl group which may be substituted with little lower alkoxy group "as lower alkyl substituted by one of the above substituents other than halogen atom Alkyl groups such as acetylaminomethyl, 2-acetylaminoethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-meth Methoxypropyl, ethylthiomethyl, 2-methylthioethyl, 2-tetrahydrofurfuryloxyethyl and 2-aryloxyethyl groups; Lower alkyl groups substituted with 1 to 3 halogen atoms, such as trifluoromethyl, dichloromethyl, and 2-bromoethyl group, and the like. Also, "lower groups that may be substituted with an enemy 2-pryl group, a phenyl group, or a lower alkoxy group may be used. Substituted lower alkoxy group in "alkoxy group" is a lower alkoxy group substituted with one 2-pril group, phenyl group or lower alkoxy group, for example furfuryloxy, benzyloxy, phenethyloxy, methoxymethoxy, 2 -Methoxyethoxy, 2-ethoxyethoxy group and the like.

식 ( I )에 있어서의 R¹로서는 염소원자, 메틸기, 트러플루오르메틸기, 에티닐기, 에틸기, 메톡시메틸기, 메톡시에틸기, 아릴기, 시아노기등이 적합한 것으로서 예시되며 그중에서도 염소원자, 메틸기, 트리플루오르메틸기 및 티에닐기가 특히 적합하다. 또 R²로서는 메틸기, 시아노기, 염소원자, 트리플루오르메틸기등이 적합한 것으로서 예시되며 그중에서도 메틸기 및 트리플루오르메틸기가 특히 바람직하다. 또한 R³, R⁴및 R⁵로서는 메틸기 및 염소원자가 바람직하다.As R ¹ in formula (I), a chlorine atom, a methyl group, a trfluoromethyl group, an ethynyl group, an ethyl group, a methoxymethyl group, a methoxyethyl group, an aryl group, and a cyano group are exemplified as suitable ones, among which chlorine atom, methyl group and tri Fluoromethyl groups and thienyl groups are particularly suitable. Moreover, as R <^{2>, a} methyl group, a cyano group, a chlorine atom, a trifluoromethyl group, etc. are illustrated as a suitable thing, Among these, a methyl group and a trifluoromethyl group are especially preferable. Moreover, as R <^3> , R <^4> and R <^{5>, a} methyl group and a chlorine atom are preferable.

본 발명의 방법의 특징은 출발원료로서 전기 식 (II)로 나타낸 할로게노피리다진 유도체의 강산염을 사용하는 점에 있다. 즉 본 발명에 의하면 식 (II)의 할로게노피리다진 유도체를 유리염기의 형태로 티오요소와 반응시킨 경우에는 반응은 거의 진행하지 않으나 이 할로게노피리다진 유도체를 강산과의 염의 형태로 티오요소와 반응시키면 극히 원활히 반응이 진행되며 더우기 얻어지는 생성물을 달리함이 없이 그대로 대과잉의 히드라진 또는 그 수화물과 반응시키면 목적하는 전기식 (I)로 나타내는 히드라지노피리다진 유도체가 소위「원 ·폿 ·프로세스」에 의하여 고수율로 그리고 고순도로 얻어지므로 공업적으로 극히 유리함을 발견하였다.그리하여 이하의 기재에 있어 「식(II)의 화합물」이라 할 경우에는 특별히 설명하지 않는 한 전기식(II)로나타내는 할로게노피리다진 유도체의 강산염을 뜻하는 것이다.A feature of the process of the invention is the use of a strong acid salt of the halogenopyridazine derivative represented by the formula (II) as starting material. That is, according to the present invention, when the halogenopyridazine derivative of formula (II) is reacted with thiourea in the form of a free base, the reaction hardly proceeds, but the halogenopyridazine derivative is reacted with thiourea in the form of a salt with a strong acid. When reacting, the reaction proceeds extremely smoothly. Moreover, when the product obtained is reacted with a large excess of hydrazine or its hydrate without any change, the hydrazinopyridazine derivative represented by the desired electrical formula (I) is called `` one-pot-process ''. It has been found to be extremely advantageous industrially because it is obtained in high yield and with high purity. Thus, in the following description, the term "compound of formula (II)", unless otherwise specified, refers to the halogenopyri represented by the formula (II). It means a strong acid salt of the chopped derivative.

식 (II)의 화합물과 티오요소의 반응은 통상 극성용매, 특히 알콜계용매의 존재하에서 행해진다. 사용할수 있는 알콜계용매로서는 예를 들면 메탄올, 에탄올, 이소프로판올, n-프로판올, tert-부탄올, 시크로헥산올, 에틸렌글리콜, 프로필렌글리콜등을 들 수 있으며 이들은 각각 단독 또는 2종 또는 그 이상 조합하여 사용할 수가 있으며 또는 경우에 따라서는 다른 혼화할 수 있는 용매, 예를 들면 물, 아세톤, 클로로포름, 디클로로메탄, 디메틸술폭시드, 디메틸포름아미드, 2황화탄소, 벤젠, 톨루엔, 크실렌, 헥산, 시클로헥산등과 똔합하여 사용할 수도 있다.The reaction of the compound of formula (II) with thiourea is usually carried out in the presence of a polar solvent, especially an alcoholic solvent. Alcohol solvents that can be used include, for example, methanol, ethanol, isopropanol, n-propanol, tert-butanol, cyclohexanol, ethylene glycol, propylene glycol and the like, each of which may be used alone or in combination of two or more. Other miscible solvents, such as water, acetone, chloroform, dichloromethane, dimethylsulfoxide, dimethylformamide, carbon disulfide, benzene, toluene, xylene, hexane, cyclohexane, etc. It can also be used in combination with.

반응온도는 일반적으로 약 0℃ 내지 반응 혼합물의 환류온도사이의 범위, 바람직하기는 실온 내지 약60℃사이의 온도로 할 수가 있다. 또 식 (II)의 화합물에 대한 티오요소의 사용비율은 특별히 제한되는 것은 아니며 식 (II)의 화합물의 종류 등에 따라서 광범위하게 바꿀 수가 있는데 일반적으로는 식 (II)의 화합물 1몰당 적어도 1몰, 바람직하기는 1~10몰의 티오요소를 사용함이 유리하다.The reaction temperature can generally be in the range between about 0 ° C. and the reflux temperature of the reaction mixture, preferably between room temperature and about 60 ° C. In addition, the ratio of thiourea to the compound of formula (II) is not particularly limited and can be varied widely depending on the type of the compound of formula (II). Generally, at least 1 mole per mole of the compound of formula (II), It is advantageous to use 1 to 10 moles of thiourea.

상기 반응에 있어 출발원료로서 사용되는 식 (II)로 나타내는 할로게노피리다진 유도체의 강산염으로서는,예를 들면 염산염, 브롬화수소산염, 황산염, 과염소산염, 초산염, p-톨루엔술폰산염, 메탄술폰산염, 트리플루오르초산염, 트리클로로초산염등이 포함되며 그중에서도 염산염이 적합하다.As a strong acid salt of the halogenopyridazine derivative represented by formula (II) used as a starting material in the reaction, for example, hydrochloride, hydrobromide, sulfate, perchlorate, acetate, p-toluenesulfonate, methanesulfonate , Trifluoroacetate, trichloroacetate and the like, among which hydrochloride is suitable.

이와 같은 염은 식 (II)로 나타내는 유리의 할로게노피리다진 유도체를 상기와 같은 강산과 그 자체 공지의 방법에 의하여 반응시킴으로써 용이하게 제조할 수가 있다. 이 조염반응은 전술의 식 (II)의 화합물과 티오요소와의 반응에 앞서 전술한 바와 같은 용매중에 식 (II)의 할로게노피리다진 유도체를 용해하고 적어도 동당량 바람직하기는 1~5당량의 강산을 첨가함으로써 즉석에서 행할 수도 있다.Such a salt can be easily manufactured by reacting the free halogenogenpyridazine derivative represented by Formula (II) with a strong acid as described above by a method known per se. This salting reaction is carried out by dissolving the halogenopyridazine derivative of formula (II) in a solvent as described above in advance of the reaction of the compound of formula (II) with thiourea, and preferably at least 1 to 5 equivalents. It can also be performed immediately by adding a strong acid.

식 (II)의 화합물과 티오요소와의 반응에 있어 식 (II)의 할로게노피리다진 유도체는 실질적으로 모두가 강산염의 형태로 존재함이 중요하며 유리의 할로게노피리다진 유도체는 실질적으로 혼입하고 있지 않음이 바람직하다.In the reaction of the compound of formula (II) with thiourea, it is important that the halogenopyridazine derivatives of formula (II) are substantially all in the form of strong acid salts, and the free halogenopyridazine derivatives are substantially incorporated. Not preferred.

상기 조염 반응에 사용되는 식 (II)의 할로게노피리다진 유도체는 대부분 전기의 일본 특개소 57-108075호 공보에 기재된 기지의 화합물로서 신규한 것이라도 이 공보에 기재된 방법에 준하여 용이하게 제조할 수가 있다The halogenopyridazine derivatives of the formula (II) used in the salt formation reaction can be easily prepared according to the method described in this publication even though they are novel as most known compounds described in Japanese Patent Application Laid-Open No. 57-108075. have

이상 설명한 식 (II)의 화합물과 티오요소와의 반응에 의하여 하기식By the reaction of the compound of formula (II) and thiourea described above,

[화학식 3][Formula 3]

(식중R¹,R²,R³,R⁴,R⁵및 R⁶은 전기의 뜻과 같음)로 나타내는 중간체가 생성한다고 추정되는 [예를 들면 C. H. Grogan et al., J Org. Chem., 18, 728(1953) 참조] 상기 식 (Iv)의 중간체는 단리함이 없이 그대로 대과잉의 히드라진 또는 그 수화물로 처리하면 응이하게 전기식 ( I )치 히드라지노피리다진 유도체로 바뀐다. 이 히드라진 또는 그 수화물에 의한 처리는 출발원료로서 사용하는 식 (II)의 화합물 1몰당 적어도3물, 바람직하기는 10~20몰의 히드라진 또는 그 수화물을 전기의 식 (II)의 화합물과 티오요소와의 반응 혼합물에 첨가함으로써 행할 수가 있다. 이 처리는 일반적으로 약 50℃내지 반응 혼합물의 온도사이의 온도, 바람직하기는 반응 혼합물의 환류온도에 있어 행해진다.(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are synonymous with electricity), it is assumed that an intermediate is produced [see, eg, CH Grogan et al., J Org. Chem., 18, 728 (1953)] The intermediate of formula (Iv) is transformed into an electric (I) hydrazinopyridazine derivative when treated with large excess of hydrazine or its hydrate without isolation. The treatment with this hydrazine or its hydrate is carried out using at least three substances per mole of the compound of formula (II), preferably 10-20 moles of hydrazine or its hydrate, as a starting material. It can carry out by adding to the reaction mixture with. This treatment is generally carried out at a temperature between about 50 ° C. and the temperature of the reaction mixture, preferably at the reflux temperature of the reaction mixture.

이리하여 전기식( I )의 히드라지노피리다진 유도체가 고수율로 생성하며 이는 반응 혼합물로부터 자체 공지의 방법, 예를 들면 추출, 컬럼크로마토그래피, 박층 크로마토그래피, 결정화등의 방법에 의하여 단리 정제할 수가 있다.Thus, the hydrazinopyridazine derivative of the formula (I) is produced in high yield, which can be isolated and purified from the reaction mixture by a method known per se, for example, extraction, column chromatography, thin layer chromatography, crystallization, and the like. have.

또 본 발명의 별법에 의하면 상기식 (Iv)의 중간체를 염기로 처리함으로써 일단 하기식In addition, according to the alternative of the present invention, by treating the intermediate of the formula (Iv) with a base,

[화학식 4][Formula 4]

(식중R¹,R²,R³,R⁴,R⁵및 R⁶은 전기의 뜻과 같음)로 나타내는 티옥소피리다진 유도체로 바꾸고 이를 이어서 히드라진 또는 그 유도체와 반응시킴으로써 전기식( I )의 히드라지노피리다진 유도체를 제조할 수도 있다.Hydra of formula (I) by converting to a thioxopyridazine derivative represented by the formula (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as the meaning of electricity) and then reacting with hydrazine or its derivatives Zinopyridazine derivatives may also be prepared.

상기의 염기에 의한 처리는 전술한 식 (II)의 화합물과 티오요소와의 반응 혼합물에 이 염기를, 사용한 식(II)의 화합물에 대하여 적어도 등당량, 바람직하기는 5~10당량 첨가함으로써 행할 수가 있다. 사용할 수있는 염기로서는 예를 들면 탄산수소나트륨, 탄산나트룸, 탄산수소칼륨, 탄산칼륨. 수산화나트륨, 수은화칼륨등의 무기염기 : 암모니아수용액. 치드라진. 히드라진 수화물, 데틸아딘, 에틸아민, n-프로필아민, iso-프로필아민등의 유기염기를 들 수 있으며 전자의 무기염기를 사용할 경우에는 수응액의 형태로 첨가함이 적당하다. 또 이 처리의 온도는 일반적으로 약 0℃ 내지 반응 혼합물의 환류온도사이의 온도, 바람직하기는 실온 내지 반응 혼합물의 환류온도사이의 온도로 할 수가 있다.The treatment with the above base is carried out by adding the base to the reaction mixture of the compound of formula (II) and thiourea at least equally, preferably 5 to 10 equivalents, to the compound of formula (II). There is a number. Examples of the base that can be used include sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate. Inorganic bases such as sodium hydroxide and potassium hydride: aqueous ammonia solution. Crushed. Organic bases, such as hydrazine hydrate, detyladine, ethylamine, n-propylamine, and iso-propylamine, are mentioned, and when using the former inorganic base, it is suitable to add in the form of a water solution. In addition, the temperature of this treatment can generally be made into a temperature between about 0 degreeC and the reflux temperature of a reaction mixture, Preferably it is a temperature between room temperature and the reflux temperature of a reaction mixture.

이리하여 얻어지는 상기 식 (III)의 티옥소피리다진 유도체는 단리함이 없이 그대로 히드라진 또는 그 수화물과 반응시킬 수가 있는데 경우에 따라서 단리 정제한 후에 히드라진 또는 그 수화물과 반응시켜도 무방하다.The thioxopyridazine derivative of the formula (III) thus obtained can be reacted with hydrazine or its hydrate without isolation, and in some cases, it can be reacted with hydrazine or its hydrate after isolation and purification.

식(III)의 티옥소피리다진 유도체의 단리 정제는 그 자체 공지의 방법, 예를 들면 추출, 박층 크로마토그래피, 컬럼크로마토그래피, 결정화등의 방법에 의하여 행할 수가 있다.Isolation and purification of the thioxopyridazine derivative of formula (III) can be carried out by a method known per se, for example, extraction, thin layer chromatography, column chromatography, crystallization or the like.

식(III)의 티옥소피리다진 유도체는 종래의 문헌에 미재의 신규 화합물로서 그 대표적 구체예를 나타내면 다음과 같다.The thioxopyridazine derivatives of formula (III) are as follows if their representative specific examples are shown in the prior art as novel compounds.

1-(2-클노로페녹시)-3-[l, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-메틸페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노)-2-프로판올, 1-(2-에틸페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-에틸페녹시)-3-[1, 1-디메틸-2-[3 (2H )-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-시아노페녹시)-3-[l, 1-디메틸-2-[3 (2H )-피옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2, 3-디메틸페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-클로로-3-메틸페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-클로로-5-메틸페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-[2-(2-메톡시에틸) 페녹시]-3-[1, 1-디메틸-2-[3 (2H)-디옥소-6-피리다지닐옥시] 에틸아미노]-2-프로판올, 1-(2-트리플루오르메틸페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-아릴페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(3-시아노페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-시아노페녹시)-3-[1-메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올, 1-(2-메틸페녹시:-3-[1-메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올등, 이와 같은 티옥소피리다진 유도체중에서 특히 적합한 것으로서는 하기식,1- (2-clonophenoxy) -3- [l, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2 -Methylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino) -2-propanol, 1- (2-ethylphenoxy) -3- [1,1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-ethylphenoxy) -3- [1 , 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-cyanophenoxy) -3- [l, 1-dimethyl -2- [3 (2H) -Pioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2, 3-dimethylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -Tioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-chloro-3-methylphenoxy) -3- [1, 1-dimethyl-2- [ 3 (2H) -Tioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-chloro-5-methylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -Tioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- [2- (2-methoxyethyl) phen ] -3- [1, 1-dimethyl-2- [3 (2H) -dioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-trifluoromethylphenoxy)- 3- [1,1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-arylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (3-cyanophenoxy) -3- [1, 1-dimethyl- 2- [3 (2H) -Tioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-cyanophenoxy) -3- [1-methyl-2- [3 (2H ) -Tioxo-6-pyridazinyloxy] ethylamino] -2-propanol, 1- (2-methylphenoxy: -3- [1-methyl-2- [3 (2H) -thioxo-6- Particularly suitable among such thioxopyridazine derivatives such as pyridazinyloxy] ethylamino] -2-propanol, the following formula,

[화학식 5][Formula 5]

(식중 R¹¹은 할로겐원자, 시아노기, 에티닐기 또는 3개이하의 탄소원자수를 갖는 알킬기를 나타내며, R²¹및 R⁴¹은 각각 할로겐원자 또는 3개 이하의 탄소원자수를 갖는 알킬기를 나타냄)로 나타내는 것이다.Wherein R ¹¹ represents a halogen atom, a cyano group, an ethynyl group or an alkyl group having 3 or less carbon atoms, and R ²¹ and R ⁴¹ each represent a halogen atom or an alkyl group having 3 or less carbon atoms will be.

식 (III)의 티옥소피리다진은 도체와 히드라진 또는 그 수화물과의 반응은 통상 전술한 바와 같은 극성용매중에 있어 행해지며 반응온도는 일반적으로 약 50℃ 내지 반응 혼합물의 환류온도사이의 온도, 바람직하기는 반응 혼합물의 환류온도이다. 또 식 (III)의 티옥소피리다진 유도체에 대한 히드라진 또는 그 수화물의 사용량은 이 티옥소피리다진 유도체의 종류등에 따라서 광범위하게 바꿀 수가 있는데 일반적으로는 식(III)의 티옥소피리다진 유도체 1몰당 히드라진 또는 그 수하물을 적어도 3몰, 바람직하기는 10~20몰 사용함이 유리하다..The thioxopyridazine of formula (III) is usually reacted with a hydrazine or its hydrate in a polar solvent as described above and the reaction temperature is generally between about 50 ° C. and the reflux temperature of the reaction mixture, preferably Below is the reflux temperature of the reaction mixture. The amount of the hydrazine or hydrate thereof to the thioxopyridazine derivative of the formula (III) can be varied widely depending on the type of the thioxopyridazine derivative, etc. Generally, per mole of the thioxopyridazine derivative of the formula (III) It is advantageous to use at least 3 moles, preferably 10-20 moles, of hydrazine or its baggage.

이리하여 전기식 ( I )의 히드라지노피리다진 유도체가 생성하며 이것은 전술과 같은 방법에 의하여 반응혼합물로부터 단리하여 정제할 수가 있다. 얻어지는 유리의 히드라지노피리다진 유도체는 에를 들면 염화수소산, 브롬화수소산, 황산, 초산, 인산등의 무기산, 및 초산, 프로피온산, 구연산, 유산, 주석산등의 유기산등으로 처리함으로써 대응하는 산부가염으로 바꿀 수가 있다. 이들 산부가염중 특히 제약학적으로 허용할수 있는 것이 적합하다.This produces a hydrazinopyridazine derivative of the formula (I), which can be isolated and purified from the reaction mixture by the method described above. The resulting hydrazinopyridazine derivatives can be converted to the corresponding acid addition salts by treatment with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, phosphoric acid, and organic acids such as acetic acid, propionic acid, citric acid, lactic acid, tartaric acid, and the like. have. Suitable among these acid addition salts are pharmaceutically acceptable ones.

이상 설명한 본 발명의 방법에 의하면 후술의 실시예로부터 명백한 바와 같이 뛰어난 강압작용을 갖는 식 ( 1 )의 히드라지노피리다진 유도체를 고수율로 그리고 고순도로 제조할 수가 있으므로 공업적으로 극히 유용하다. 참고로 식 ( I )의 히드라지노피리다진 유도체중의 두셋의 대표적인 것의 강압작용의 시험 결과를 나타내면 다음과 같다.According to the method of the present invention described above, the hydrazinopyridazine derivative of the formula (1) having an excellent stepping action can be produced in high yield and in high purity, as is apparent from the examples below. For reference, the test results of the coercive action of the representative of two or three of the hydrazinopyridazine derivatives of formula (I) are as follows.

그리고 이하의 동물 실험에 사용한 본 발명의 화합물은 다음의 부호로 대표된다.And the compound of this invention used for the following animal experiment is represented by the following code | symbol.

화합물compound

A : 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올, B : 1-(2-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시) 에틸아미노]-2-프로판올, C : 1-(2-에티놀페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시) 에틸아미노]-2-프로판올.A: 1- (2-chlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol, B: 1- (2 -Methylphenoxy) -3- [1,1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol, C: 1- (2-ethynolphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol.

시험법Test method

펜트발비타르(60mg/kg i.p.)에 의하여 마취한 쥐(♂,Wister : 체중 300-400g)를 사용하고 혈압은 대퇴 동맥에 삽입한 카뉴레를 압과 트랜스 쥬서에 접속하여 직접적으로 측정하였다. 한편 심박수는 혈압 맥파로부터 산출하였다.Rats (♂, Wister: body weight 300-400 g) anesthetized by pentvalbitar (60 mg / kg i.p.) were used, and blood pressure was directly measured by connecting canures inserted into the femoral artery to pressure and trans juicers. Heart rate was calculated from blood pressure pulse waves.

(1) β-차단작용의 측정(1) Measurement of β-blocking action

1군 3마리의 쥐엔 이소프레나린(0.1μg/kg i.v )을 투여하고 곧 심박수를 측정 기록하였다. 이때의 심박수의 측정치를 H₁이라 한다. 다음에 피험 화합물을 생리식염수 또는 0.01N 염산수용액에 용해한 용액을 쥐의 대퇴정맥내에 카뉴테를 통하여 투여하고 3분후에 재차 이소프레나린(0.1μg/kg i,v )을 투여하고 곧 심박수를 측정 기록하였다. 이때의 심박수를 H₂로 한다. 이 측정치로부터 하기 식에 따라서 심박수의 억제율을 산출하였다.Three rats of group 1 were administered isoprenarin (0.1 μg / kg iv) and the heart rate was measured and recorded. The measured heart rate at this time is referred to as H ₁ . Next, a solution of the test compound dissolved in physiological saline or 0.01 N hydrochloric acid solution was administered to the femoral vein through the can nute, and 3 minutes later, isoprenarin (0.1 μg / kg i, v) was again administered, and the heart rate was immediately measured. Recorded. Let the heart rate at this time be H ₂ . From this measured value, the inhibition rate of heart rate was computed according to the following formula.

[수학식 1][Equation 1]

피험 화합물의 투여량을 바꾸어서 상기 조작을 반복함으로써 용량-반응 곡선을 작성하고 이 곡선으로부터 심박수의 억제율이 50%로 되었을때의 피험 화합물의 용량을 결정하였다. 그 결과를 하기 제 1표에 나타낸다.A dose-response curve was created by changing the dose of the test compound and repeating the above procedure, from which the dose of the test compound was determined when the rate of inhibition of heart rate reached 50%. The result is shown to the following 1st table | surface.

[표 1]TABLE 1

(2) 혈관 확장작용(강압작용)의 측정(2) measurement of vasodilation (coercion)

1군 3마리의 위에 피험 화합물(생리식염수 또는 0.01N염산에 용해) 1mg/kg을 정맥내 투여하고 혈압을 경시적으로 40분간 기록하였다. 그 기간 동안의 혈압 하강치의 최대치를 결정하였다. 그 결과 상기 A~C의 화합물은 모두 35mmHg이상의 혈압 강하를 나타냈다.1 mg / kg of the test compound (dissolved in physiological saline or 0.01 N hydrochloric acid) was intravenously administered to three group 1 stomachs, and blood pressure was recorded for 40 minutes over time. The maximum value of the blood pressure drop during that period was determined. As a result, all of the compounds of A to C showed a blood pressure drop of 35 mmHg or more.

이하 실시예에 의하여 본 발명을 더 설명한다.The invention is further illustrated by the following examples.

그리고 NMR의 측정은 테트라메틸실란 또는 2,2-디메틸-2-실라벤탄-5-술폰산나트륨을 내부 표준으로 사용하였다.In addition, the measurement of NMR used tetramethylsilane or 2, 2- dimethyl- 2-silabentan-5-sulfonic acid sodium as an internal standard.

[실시예 1]Example 1

(a) 3-(2-아미노-2-메틸프로폭시)-6-클로로피리다진 (25.0g)와 1-(2-클로로페녹시)-2, 3-에폭시 프로판(23.34g)의 t-부탄올(250ml)용액을 50℃에서 24시간 가온 교반하였다. 용매를 유거하고 얻어진 생성물을 벤젠(400㎖)에 용해하고 10% 염산으로 추출하였다. 이어서 벤젠으로 2회 세정한 후 클로로포름으로 추출하고 20% 탄산칼슘으로 염기성으로 한 후 물로 세정하고 황산마그네슘을 사용하여 건조하였다. 용매를 유거하고 얻어진 유상물을 알루미나 컬럼크로마토그래피 (용출액 벤젠)를 행하고 유상물의 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시) 에틸아미노]-2-프로판올 (28.4g) 을 얻었다. 이어서 이 유상물을 에탄올(280㎖)에 용해한 용액에 계산량의 20% 염산-에탄올용액을 가하였다. 용매를 감압하에서 유거하고 건조후 결정성 잔류분을 에탄올-벤젠으로부터 재결정하여 무색 프리즘정의 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염(26.5g, 융점 92.8-93.5℃)을 얻었다.(a) t- of 3- (2-amino-2-methylpropoxy) -6-chloropyridazine (25.0 g) and 1- (2-chlorophenoxy) -2,3-epoxy propane (23.34 g) The butanol (250 ml) solution was warmed and stirred at 50 ° C. for 24 hours. The solvent was distilled off and the resulting product was dissolved in benzene (400 mL) and extracted with 10% hydrochloric acid. Subsequently, the mixture was washed twice with benzene, extracted with chloroform, made basic with 20% calcium carbonate, washed with water, and dried over magnesium sulfate. The solvent was distilled off and the oily substance obtained was subjected to alumina column chromatography (eluent benzene) to give 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyrida) as an oily substance. Genyloxy) ethylamino] -2-propanol (28.4 g) was obtained. Then, a calculated amount of 20% hydrochloric acid-ethanol solution was added to the solution of this oily substance in ethanol (280 mL). The solvent was distilled off under reduced pressure, and after drying, the crystalline residue was recrystallized from ethanol-benzene to give 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-) as a colorless prism. Pyridazinyloxy) ethylamino] -2-propanol hydrochloride (26.5g, melting | fusing point 92.8-93.5 degreeC) was obtained.

(b) 상기 (a)에서 얻은 1-(2-클로로페놀시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아니노1-2-프로판올 염산염 (10.32g)과 티오요소(5.58g) 및 에탄올(51.6ml)의 혼합물을 50℃에서 5시간 가온 교반하였다. 감압하에서 용매를 일부 유거하고 5% 탄산나트륨용액(80㎖)을 가하고 이어서 황색 현탁액을 클로로포름(80㎖)으로 3회 추출하였다. 추출액을 수세후 황산마그네슘으로 건조하였다. 용매를 감압하에서 유거학고 얻어진 황색결정을 메탄올-벤젠으로부터 재결정하여 황색 침상정의 1-(2-클로로페녹시)-3-[1,1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올 (6.68g, 융점 141.2-142.2℃ )을 얻었다.(b) 1- (2-chlorophenoloxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylanino1-2-propanol obtained in (a) above. A mixture of hydrochloride (10.32 g), thiourea (5.58 g) and ethanol (51.6 ml) was stirred at 50 ° C. for 5 hours. The solvent was distilled off under reduced pressure, 5% sodium carbonate solution (80 mL) was added, and then the yellow suspension was extracted three times with chloroform (80 mL). The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained yellow crystal was recrystallized from methanol-benzene to give 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- [3 (2H) -thioxo-6 of yellow needles. -Pyridazinyloxy] ethylamino] -2-propanol (6.68 g, melting point 141.2-142.2 ° C) was obtained.

NMR(CD₃OD)δ : 1.21(6H, 단일선), 2.69-2.99(2H, 다중선), 4.05(3H, 넓은 단일선), 4.08(2H, 단일선), 6.83 (1H, 이중선, J = 9.5Hz), 6.83-7.40 (4H, 다중선), 7.50 (1H, 이중선, J=9.5Hz).NMR (CD ₃ OD) δ: 1.21 (6H, singlet), 2.69-2.99 (2H, multiplet), 4.05 (3H, wide singlet), 4.08 (2H, singlet), 6.83 (1H, doublet, J = 9.5 Hz), 6.83-7.40 (4H, multiplet), 7.50 (1H, doublet, J = 9.5Hz).

(c) 상기 (b)에서 얻은 1-(20클로로페녹시)-3-[1, 1-디메틸-2-[3(2H)-리옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올(0.5g)을 에탄올(25㎖)에 용해하고, 이어서 히드라진 수솨물(12.5ml)을 가하고 교반 환류하에 3시간 반응하였다.(c) 1- (20chlorophenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -rioxo-6-pyridazinyloxy] ethylamino] -2 obtained in (b) above. Propanol (0.5 g) was dissolved in ethanol (25 mL), and then hydrazine hydrolyzate (12.5 mL) was added and reacted under stirring under reflux for 3 hours.

용매를 감압하에서 유거후 클로로포름(50㎖)에 용해하고 수세한 후 황산마그네슘으로 건조하였다. 용매를 감압하에서 유거하고 얻어진 황색 유상물을 에탄올에 용해한후 계산량의 염산을 가하고 용매를 감압하에서 유거하였다. 얻어진 결정성 잔류분을 메탄올-에탄올(3 : 10)용액으로부터 재결정하여 담황색 침상정의1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시) 에틸아미노I-2-프로판올염산염 (3.67g, 융점 186.5-188℃)을 얻었다.The solvent was distilled off under reduced pressure, dissolved in chloroform (50 mL), washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the yellow oil obtained was dissolved in ethanol, and then a calculated amount of hydrochloric acid was added, and the solvent was distilled off under reduced pressure. The obtained crystalline residue was recrystallized from methanol-ethanol (3:10) solution to give 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-hydrazino-6-) as a pale yellow needle. Pyridazinyloxy) ethylamino I-2-propanol hydrochloride (3.67g, melting point 186.5-188 degreeC) was obtained.

NMR(D₂O)δ : 1.60(6H,단일선), 3.31~3.59(2H,다중선), 4.15~4.50(3H,다중선), 4.46(2H,단일선), 6.89~7.56 (4H, 다중선), 7.24 (2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, single line), 3.31 ~ 3.59 (2H, multiline), 4.15 ~ 4.50 (3H, multiline), 4.46 (2H, single line), 6.89 ~ 7.56 (4H, Multiplet), 7.24 (2H, singlet).

[실시예 2]Example 2

(a) 실시예 1(a)에서 얻어진 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시) 에틸아미노]-2-프로판올 염산염 대신에 1-(2-메틸페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염 (1.0g)을 사용하는 이외는 실시예 1(b)와 같이하여 담황색프리즘정의 1-(2-메틸페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올(0.573g, 융점 114.2-114.9℃)을 얻었다.(a) 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2- obtained in Example 1 (a) Replace 1- (2-methylphenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride (1.0 g) instead of propanol hydrochloride A 1- (2-methylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyrida of light yellow prismatic tablets was prepared in the same manner as in Example 1 (b) except for using. Genyloxy] ethyl amino] -2-propanol (0.573 g, melting | fusing point 114.2-114.9 degreeC) was obtained.

NMR(CD₃0D)δ : 1.21(6H,단일선), 2.19(3H,단일선), 2.58~2.95(2H,다중선), 3.99(3H,넓은 단일선), 4.07(2H,단일선), 6.62~7.35(4H,다중선), 6.81(1H,이중선, J=9.5Hz), 7.48(1H,이중선, J=9.5Hz)NMR (CD ₃ 0D) δ: 1.21 (6H, single line), 2.19 (3H, single line), 2.58 ~ 2.95 (2H, multiline), 3.99 (3H, wide single line), 4.07 (2H, single line) , 6.62 to 7.35 (4H, multiple line), 6.81 (1H, double line, J = 9.5 Hz), 7.48 (1H, double line, J = 9.5 Hz)

(b) 상기(a) 에서 얻어진 1-(2-메틸페녹시)-3-[1,1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올(0.57g)을 메탄올(3ml)에 용해한 이외는 실시예 1(c)와 같이하여 1-(2-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시) 에틸아미노3-2-프로판올 염산염을 얻었다.(b) 1- (2-methylphenoxy) -3- [1,1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino]-obtained in (a) above. Except having dissolved 2-propanol (0.57 g) in methanol (3 ml), it carried out similarly to Example 1 (c), and carrying out 1- (2-methylphenoxy) -3- [1, 1- dimethyl- 2- (3-hydra) Gino-6-pyridazinyloxy) ethylamino3-2-propanol hydrochloride was obtained.

NMR (D₂O)δ : 1.57 (6H, 단일선), 2.12 (3H, 단일선), 3.20~3.53 (2H, 다중선), 4.03~4.57 (3H, 다중선), 4.41(2H, 단일선), 6.72~7.30(4U, 다중선), 7.17(2H, 단일선)NMR (D ₂ O) δ: 1.57 (6H, singlet), 2.12 (3H, singlet), 3.20 ~ 3.53 (2H, multiplet), 4.03 ~ 4.57 (3H, multiplet), 4.41 (2H, singlet ), 6.72-7.30 (4U, multiple wire), 7.17 (2H, single wire)

[실시예 3]Example 3

(a) 실시예 1(a)에서 얻은 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염 대신에 1-(2-에틸페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염 (0.3g)을 사용하여 실시예 1(b)와 같이 티오요소와 반응하여 얻어진 조생성물을 박층 크로마토그래피 (멜크 GF₂₅₄; 클로로포름-메탄올 9:1)로써 정제하여 1-(2-에티닐페녹시)-3-[1.1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로탄올 (0.162g)을 유상물로서 얻었다.(a) 1- (2-chlorophenoxy) -3- [1, 1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2- obtained in Example 1 (a) Replace 1- (2-ethylphenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride (0.3 g) instead of propanol hydrochloride The crude product obtained by reaction with thiourea as in Example 1 (b) was purified by thin layer chromatography (melk GF ₂₅₄ ; chloroform-methanol 9: 1) to give 1- (2-ethynylphenoxy) -3- [1.1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-protanol (0.162 g) was obtained as an oil.

NMR(CDCl₃)δ : 1.24(6H,단일선), 2.74-3 21(2H,단중선), 3.28(1H,단일선), 5.90(3H,넓은 단일선), 6.72~7.55 (4H, 다중선), 6.73 (1H, 이중선, J : 9Hz). 7.52 (1H, 이중선, J : 9Hz).NMR (CDCl ₃ ) δ: 1.24 (6H, single line), 2.74-3 21 (2H, single line), 3.28 (1H, single line), 5.90 (3H, wide single line), 6.72 ~ 7.55 (4H, multiple Line), 6.73 (1H, doublet, J: 9 Hz). 7.52 (1H, doublet, J: 9 Hz).

(b) 상기 (a)에서 얻은 1-(2-에티닐페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올을 n-프로판올에 용해한 이외는 실시예 1(c)와 같이하여 담황색 분말상 정의1-(2-에티닐페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올염산염(융점 188.1~188.5℃)을 얻었다.(b) 1- (2-ethynylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] obtained in (a) above. A pale yellow powdery definition of 1- (2-ethynylphenoxy) -3- [1,1-dimethyl-2- (3-hydra) as in Example 1 (c) except that 2-propanol was dissolved in n-propanol. Zino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride (melting point 188.1-188.5 degreeC) was obtained.

NMR (CD₃OD)δ : 1.55 (6H, 단일선), 3.20~3.47(2H, 다중선), 3.64 (1H, 단일선), 3.90~4.38 (3H, 다중선), 4.42(2H, 단일선), 6.85~7.52(4H,다중선), 7.37(2H,단일선).NMR (CD ₃ OD) δ: 1.55 (6H, singlet), 3.20 ~ 3.47 (2H, multiplet), 3.64 (1H, singlet), 3.90 ~ 4.38 (3H, multiplet), 4.42 (2H, singlet ), 6.85 to 7.52 (4H, multiple line), 7.37 (2H, single line).

[실시예 4]Example 4

(a) 실시예 1(a)에서 얻어진 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시) 에틸아미노]-2-프로판올 염산염 대신에 1-(2-메톡시메틸페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 P-톨루엔술폰산염을 사용한 이외는 실시예 1(b)와 같이하여 1-(2-메톡시메틸페녹시)-3-[1, 1-디메틸-2-3(2H)-티옥소-6-피리다지닐옥시)에틸아미노]-2-프로판올을 얻었다.(a) 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2- obtained in Example 1 (a) 1- (2-methoxymethylphenoxy) -3- [1, 1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol P-toluenesulfonic acid instead of propanol hydrochloride A 1- (2-methoxymethylphenoxy) -3- [1,1-dimethyl-2-3 (2H) -thioxo-6-pyridazinyl was obtained as in Example 1 (b) except that a salt was used. Oxy) ethylamino] -2-propanol.

NMR(CDCl₃)δ: 1,24(6H, 단일선), 2.70~3.16(2H,다중선), 3.37(3H,단일선), 4.09(5H,넓은 단일선), 4.50(2H, 단일선), 6.22(3H, 넓은 단일선), 6.73~7.45(4H, 다중선), 6.75(1H, 이중선, J : 9.5Hz), 7.55(1H, 이중선, J=9.5Hz).NMR (CDCl ₃ ) δ: 1,24 (6H, single line), 2.70 ~ 3.16 (2H, multiline), 3.37 (3H, single line), 4.09 (5H, wide single line), 4.50 (2H, single line ), 6.22 (3H, wide single line), 6.73 to 7.45 (4H, multiple line), 6.75 (1H, double line, J: 9.5 Hz), 7.55 (1H, double line, J = 9.5 Hz).

(b) 상기 (a)에서 얻은 1-(2-메톡시메틸페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올을 에탄올에 용해하여 실시예 1(c)와 같이하여 1-(2-메톡시메틸페녹시)-3-[1, 1-디메틸-3-(2-히드라지노-6-피리다지닐옥시) 에틸아미노]-2-프로판올 염산염(융점 175.3~179.7℃ )을 얻었다.(b) 1- (2-methoxymethylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino obtained in (a) above. ] -2-propanol is dissolved in ethanol, and then 1- (2-methoxymethylphenoxy) -3- [1,1-dimethyl-3- (2-hydrazino-6- as in Example 1 (c). Pyridazinyloxy) ethylamino] -2-propanol hydrochloride (melting point 175.3-179.7 degreeC) was obtained.

NMR (D₂O)δ : 1.56(6H, 단일선), 3.24~3.52(2H, 다중선), 3.36(3H, 단일선), 4.05~4.60(3H, 다중선), 4.43(2H, 단일선), 4.45(2H, 단일선), 6.88~7.58(4H, 다중선), 7.30(2H, 단일선).NMR (D ₂ O) δ: 1.56 (6H, singlet), 3.24 to 3.52 (2H, multiplet), 3.36 (3H, singlet), 4.05 to 4.60 (3H, multiplet), 4.43 (2H, singlet ), 4.45 (2H, single line), 6.88 to 7.58 (4H, multiple line), 7.30 (2H, single line).

[실시예 5]Example 5

(a) 실시예 1(a)에서 얻은 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염 대신에 1-(2-아릴페녹시-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 황산염을 사용한 이외는 실시예 1(b)와 같이하여 1-(2-아릴펜녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에 틱 아미노]-2-프로판올을 얻었다.(a) 1- (2-chlorophenoxy) -3- [1, 1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2- obtained in Example 1 (a) Example except using 1- (2-arylphenoxy-3- [1, 1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol sulfate instead of propanol hydrochloride 1- (2-arylphenoxy) -3- [1,1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] etic amino] -2 as in 1 (b) -Propanol was obtained.

NMR(CDCl₃)δ : 1.24(6H,단일선), 2.70~3.20(2H,다중선), 3.35(2H,이중선, J=6Hz), 4.04(3H,넓은 단일선), 4.09(2H, 단일선), 4.79~4.96(1H, 다중선), 5.01~5.24(1H, 다중선), 5.60~6.40 (1H, 다중선), 5.79(3H,넓은 단일선), 6.68~7.35(4H,다중선), 6.73(1H,이중선, J=9Hz), 7.52(1H, 이중선, J=9Hz)NMR (CDCl ₃ ) δ: 1.24 (6H, single line), 2.70 ~ 3.20 (2H, multiline), 3.35 (2H, double line, J = 6Hz), 4.04 (3H, wide single line), 4.09 (2H, single Line), 4.79 ~ 4.96 (1H, multiple line), 5.01 ~ 5.24 (1H, multiple line), 5.60 ~ 6.40 (1H, multiple line), 5.79 (3H, wide single line), 6.68 ~ 7.35 (4H, multiple line ), 6.73 (1H, doublet, J = 9Hz), 7.52 (1H, doublet, J = 9Hz)

(b) 상기 (a)에서 얻은 1-(2-아릴페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올을 t-부탄올에 용해하여 실시예 1(c)와 같이하여 1-(2-아릴오시)-3-[1,1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염 (융점 173.5-177.1℃)을 얻었다.(b) 1- (2-arylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino]-obtained in (a) above. 2-propanol was dissolved in t-butanol and 1- (2-aryloxy) -3- [1,1-dimethyl-2- (3-hydrazino-6-pyridazinyl) was prepared as in Example 1 (c). Oxy) ethylamino] -2-propanol hydrochloride (melting point 173.5-177.1 ° C) was obtained.

NMR(D₂O)δ : 1.60(6H,단일선), 3.18~3.50(4H,다중선), 4.14(2H,이중선, J=5Hz), 4.43(3H, 넓은 단일선), 4.80~5.08(1H, 다중선), 5.15(1H, 넓은 단일선), 5.60~6.30(1H,다중선), 6.80~7.38(4H, 다중선), 7.29(2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, single line), 3.18 to 3.50 (4H, multiple line), 4.14 (2H, double line, J = 5 Hz), 4.43 (3H, wide single line), 4.80 to 5.08 ( 1H, multiplet), 5.15 (1H, wide singlet), 5.60-6.30 (1H, multiplet), 6.80-7.38 (4H, multiplet), 7.29 (2H, singlet).

실시예 1의 1-(2-플로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 대신에 하기 실시예 6-8의 화합물에 대응하는 할로게노피리다진 유도체의 강산염을 사용하여실시예 1(a.)-(c)와 같이하여 하기 실시예 6~8의 화합물을 얻었다.The following example instead of 1- (2-fluorophenoxy) -3- [1, 1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol of Example 1 Using the strong acid salt of the halogenopyridazine derivative corresponding to the compound of 6-8, the compound of Examples 6 to 8 was obtained in the same manner as in Example 1 (a.)-(C).

[실시예 6]Example 6

(a) 1-(2,3-디메틸페녹시)-3-[1, 1-디메틸-2-[3 (2H)-티옥소-6-피리다지닐옥시]에틸아미노]2-프로판올.(a) 1- (2,3-dimethylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] 2-propanol.

NMR(CD₃OD)δ : 1.21(6H,단일선), 2.10(3H,단일선), 2.22(3H,단일선), 2.65~2.91(2H,다중선), 3.95(3H, 넓은 단일선), 4.05(215, 단일선), 6.56~7.15 (3H, 다중선), 6.79 (1H, 이중선, J=9.5Hz), 7.46 (1H,이중선, J=9.5Hz).NMR (CD ₃ OD) δ: 1.21 (6H, single line), 2.10 (3H, single line), 2.22 (3H, single line), 2.65 ~ 2.91 (2H, multiline), 3.95 (3H, wide single line) , 4.05 (215, single line), 6.56 to 7.15 (3H, multiple line), 6.79 (1H, double line, J = 9.5 Hz), 7.46 (1H, double line, J = 9.5 Hz).

(b) B-(2,3-디메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.(b) B- (2,3-dimethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 189.2~190.4℃Melting Point 189.2 ~ 190.4 ℃

NMR(CD₂OD)δ : 1.55(6H,단일선), 2.00(3H,단일선), 2.19(3H,단일선), 3.27~3.55(2H,다중선), 3.98∼4.27(3H, 다중선), 4.38(2H, 단일선), 6.60~7.22(3H, 다중선), 7.04(2H, 단일선).NMR (CD ₂ OD) δ: 1.55 (6H, single line), 2.00 (3H, single line), 2.19 (3H, single line), 3.27 ~ 3.55 (2H, multiline), 3.98 ~ 4.27 (3H, multiline ), 4.38 (2H, single line), 6.60 to 7.72 (3H, multiple line), 7.04 (2H, single line).

[실시예 7]Example 7

(a) 1-(2-트리플루오르메틸페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올(a) 1- (2-trifluoromethylphenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol

융점 143.6∼144.9℃Melting Point 143.6 ~ 144.9 ℃

NMR(CDCl₃)δ : 1.24(6H,단일선), 2.60∼3.15(2H,다중선), 4.12(5H,넓은 단일선), 5.33(3H,넓은 단일선), 6.75(1H, 이중선, J=9.5Hz), 6.81∼7.73(4H, 다중선), 7.56(1H, 이중선, J=9.5Hz).NMR (CDCl ₃ ) δ: 1.24 (6H, singlet), 2.60 to 3.15 (2H, multiplet), 4.12 (5H, widet singlet), 5.33 (3H, widet singlet), 6.75 (1H, doublet, J = 9.5 Hz), 6.81-7.73 (4H, multiplet), 7.56 (1H, doublet, J = 9.5 Hz).

(b) 1-(2-트리플루오르메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.(b) 1- (2-trifluoromethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 194~196℃Melting Point 194 ~ 196 ℃

NMR(D₂O)δ : 1.57(6H,단일선), 3.20∼3.45(2H,다중선), 4.15∼4.55(3H,다중선), 4.41(2H,단일선), 6.95∼7.30(2H, 다중선), 7.34(2H, 단일선), 7.45~7.80(2H, 다중선).NMR (D ₂ O) δ: 1.57 (6H, single line), 3.20 to 3.45 (2H, multiline), 4.15 to 4.55 (3H, multiline), 4.41 (2H, single line), 6.95 to 7.30 (2H, Multiplet), 7.34 (2H, singlet), 7.45-7.80 (2H, multiplet).

[실시예 8]Example 8

(a) 1-(2-시아노페녹시)-3-[1, 1-디메틸-2-[3(2H)-티옥소-6-피리다지닐옥시]에틸아미노]-2-프로판올(a) 1- (2-cyanophenoxy) -3- [1, 1-dimethyl-2- [3 (2H) -thioxo-6-pyridazinyloxy] ethylamino] -2-propanol

NMR(CDCl₃)δ : 1.22(6H,단일선), 2.60∼3.15(2H,다중선), 3.71∼4.58(3H,다중선), 4.12(2H,단일선), 5.30(3H, 넓은 단일선), 6.78(1H, 이중선, J=9.5Hz), 6.77~7.71(4H, 다중선), 7.54(1H, 이중선, J=9.5Hz).NMR (CDCl ₃ ) δ: 1.22 (6H, single line), 2.60 to 3.15 (2H, multiline), 3.71 to 4.58 (3H, multiline), 4.12 (2H, single line), 5.30 (3H, wide single line ), 6.78 (1H, doublet, J = 9.5 Hz), 6.77 to 7.71 (4H, multiplet), 7.54 (1H, doublet, J = 9.5Hz).

(b) 1-(2-시아노페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.(b) 1- (2-cyanophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 184.1-187.6℃Melting Point 184.1-187.6 ℃

NMR(D₂O)δ : 1.59(6H,단일선), 3.30∼3.58(2H,다중선), 4.19∼4.60(3H,다중선), 4.46(2H,단일선), 6.98∼7.82(4H, 다중선), 7.33(2H, 단일선).NMR (D ₂ O) δ: 1.59 (6H, single line), 3.30-3.58 (2H, multiple line), 4.19-4.60 (3H, multiple line), 4.46 (2H, single line), 6.98-7.82 (4H, Multiplet), 7.33 (2H, singlet).

[실시예 9]Example 9

1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올염산염 (168mg), 티오요소(36mg) 및 에탄올(3ml)을 유조에서 50℃에서 3시간 가열 교반하였다. 이어서 히드라진 히드라드(1.5ml)을 가하고 3시간 환류하였다. 용매를 감압 유거후 잔류물을 끌로로포름에 용해하여 포화탄산수소나트륨수용액, 이어서 물로 세정하여 황산마그네슘으로 건조하였다. 용매를 감압 유거후 잔류물을 염화수소 포화에탄올에 용해하여 염산염으로 하였다. 용매를 감압 유거후 에탄올에 용해하여 냉장고에 하룻밤 방치후 석출한 결정을 흡입 연과하여 1-(2-클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염(96mg)을 얻었다.1- (2-chlorophenoxy) -3- [1, 1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride (168 mg), thiourea (36 mg) And ethanol (3 ml) were stirred by heating at 50 ° C. for 3 hours in an oil bath. Hydrazine hydride (1.5 ml) was then added and refluxed for 3 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, followed by water, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in saturated hydrogen chloride ethanol to obtain hydrochloride. After distilling off the solvent under reduced pressure, the solvent was dissolved in ethanol and left in the refrigerator overnight. The precipitated crystals were sucked and passed through 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-hydrazino-6). Pyridazinyloxy) ethylamino] -2-propanol hydrochloride (96 mg) was obtained.

상기 실시예 9에서 사용한 1-(2-클로로페녹시)-3-[1,1-디메틸-2-(3-클로로-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염 대신에 하기 실시예에 나타낸 화합물에 대응하는 할로게노피리다진 유도체의 강염산 사용하여 실시예 9와 같이하여 하기 실시예에 나타내는 화합물을 얻었다.Instead of 1- (2-chlorophenoxy) -3- [1,1-dimethyl-2- (3-chloro-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride used in Example 9 above The compound shown in the following Example was obtained like Example 9 using the strong hydrochloric acid of the halogenopyridazine derivative corresponding to the compound shown in the Example.

[실시예 10]Example 10

1-(2-클로로-3-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-chloro-3-methylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 192~194℃Melting Point 192 ~ 194 ℃

NMR(D₂O)δ : 1.60(6H, 단일선), 2.30(3H, 단일선), 3.35~3.61(2H, 다중선), 4.14~4.38(3H, 다중선), 4.44(2H,단일선), 6.78~7.47(3H,다중선), 7.12(2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, single line), 2.30 (3H, single line), 3.35-3.61 (2H, multiple line), 4.14-4.38 (3H, multiple line), 4.44 (2H, single line ), 6.78 to 7.47 (3H, multiline), 7.12 (2H, singlet).

[실시예 11]Example 11

융점 204.6~205.7℃Melting Point 204.6 ~ 205.7 ℃

NMR(D₂O)δ : 1.52∼155(6H, 두개의 단일선), 2.29(3H, 단일선), 3.30~3.52(2H, 다중선), 4.05~4.30(3H, 다중선), 4.40(2H, 단일선), 6.79(1H, 이중선, J=6Hz), 6.87(1H, 단일선), 7.21(1H, 이중선, J=6Hz), 7.17(2H, 다일선)NMR (D ₂ O) δ: 1.52 to 155 (6H, two single lines), 2.29 (3H, single line), 3.30 to 3.52 (2H, multiple lines), 4.05 to 4.30 (3H, multiple lines), 4.40 ( 2H, single line), 6.79 (1H, double line, J = 6 Hz), 6.87 (1H, single line), 7.21 (1H, double line, J = 6 Hz), 7.17 (2H, dill line)

[실시예 12]Example 12

1-[2-(2-메톡시에틸)페녹시]-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [2- (2-methoxyethyl) phenoxy] -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 173.3~174.1℃Melting Point 173.3 ~ 174.1 ℃

NMR(D₂O)δ : 1.58(6H, 단일선), 2.82(2H, 삼중선, J=6Hz), 3.23~3.49(2H, 다중선), 3.33(3H, 단일선), 3.65(2H, 삼중선, J=7Hz), 3.99∼4.35(3H, 다중선), 4.42(2H, 단일선), 6.80∼7.45(4H, 다중선), 7.28(2H, 단일선).NMR (D ₂ O) δ: 1.58 (6H, singlet), 2.82 (2H, triplet, J = 6Hz), 3.23-3.49 (2H, multiplet), 3.33 (3H, singlet), 3.65 (2H, Triplet, J = 7 Hz, 3.99 to 4.35 (3H, multiplet), 4.42 (2H, singlet), 6.80 to 7.45 (4H, multiplet), 7.28 (2H, singlet).

[실시예 13]Example 13

1-(2-브로모페녹스)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]2-프로판올 염산염.1- (2-bromophenox) -3- [1,1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] 2-propanol hydrochloride.

융점 181.0~184.5℃Melting Point 181.0 ~ 184.5 ℃

NMR(D₂O)δ : 1.60(6H, 단일선), 3.35∼3.65(2H, 다중선), 4.02∼4.40(3H, 다중선), 4.45(2H, 단일선), 6.82∼7.72(4H, 다중선), 7.23(2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, singlet), 3.35 to 3.65 (2H, multiplet), 4.02 to 4.40 (3H, multiplet), 4.45 (2H, singlet), 6.82 to 7.72 (4H, Multiplet), 7.23 (2H, singlet).

[실시예 14]Example 14

1-(2-에틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-ethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.10(3H, 삼중선, J=7Hz), 1.57(6H, 단일선), 2.52(2H, 사중선, J=7Hz), 3.25∼3.51(2H, 다중선), 4.00∼4.55(3H, 다중선), 4.41(2H, 단일선), 6.75∼7.41(4H, 다중선), 7.20(2H, 단일선).NMR (D ₂ O) δ: 1.10 (3H, triplet, J = 7Hz), 1.57 (6H, singlet), 2.52 (2H, quadruple, J = 7Hz), 3.25 to 3.51 (2H, multiplet), 4.00-4.45 (3H, multiplet), 4.41 (2H, singlet), 6.75-7.41 (4H, multiplet), 7.20 (2H, singlet).

[실시예 15]Example 15

1-(2-프로필페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-propylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 188.0∼189.5℃Melting Point 188.0 ~ 189.5 ℃

NMR(D₂O)δ : 0.86(3H, 삼중선, J=7Hz), 1.10∼2.00(2H, 다중선), 1.56(6H, 단일선), 2.50(2H, 삼중선, J=7Hz), 3.19∼3.51(2H, 다중선), 4.01∼4.35(3H, 다중선), 4.40(2H, 단일선), 6.73∼7.46(4H, 다중선), 7.22(2H, 단일선).NMR (D ₂ O) δ: 0.86 (3H, triplet, J = 7Hz), 1.10-2.00 (2H, multiplet), 1.56 (6H, singlet), 2.50 (2H, triplet, J = 7Hz), 3.19 to 3.51 (2H, multiple line), 4.01 to 4.35 (3H, multiple line), 4.40 (2H, single line), 6.73 to 7.46 (4H, multiple line), 7.22 (2H, single line).

[실시예 16]Example 16

1-(2-에톡시메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-ethoxymethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.20(3H, 삼중선, J=7Hz), 1.57(6H, 단일선), 3.12∼3.52(2H, 다중선), 3.60(2H, 사중선, J=7Hz), 3.99∼4.32(3H, 다중선), 4.43(2H, 단일선), 4.49(2H, 단일선), 6.86∼7.64(4H, 다중선), 7.32(2H, 단일선).NMR (D ₂ O) δ: 1.20 (3H, triplet, J = 7Hz), 1.57 (6H, singlet), 3.12 to 3.52 (2H, multiplet), 3.60 (2H, quartet, J = 7Hz), 3.99 to 4.32 (3H, multiplet), 4.43 (2H, singlet), 4.49 (2H, singlet), 6.86 to 7.74 (4H, multiplet), 7.32 (2H, singlet).

[실시예 17]Example 17

1-[2-(2-에틸티오에틸)페녹시]-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [2- (2-ethylthioethyl) phenoxy] -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 181.6∼182.5℃Melting Point 181.6-182.5 ℃

NMR(CD₃OD)δ : 1.18(3H, 삼중선, J=7Hz), 1.55(6H, 단일선), 2.49(2H, 사중선, J=7Hz), 2.52∼3.07(6H, 다중선), 3.90∼4.40(4H, 다중선), 4.42(2H, 단일선), 6.66∼7.33(4H, 다중선), 7.42(2H, 단일선).NMR (CD ₃ OD) δ: 1.18 (3H, triplet, J = 7 Hz), 1.55 (6H, singlet), 2.49 (2H, quadruple, J = 7Hz), 2.52 to 3.07 (6H, multiplet), 3.90-4.40 (4H, multiplet), 4.42 (2H, singlet), 6.66-7.33 (4H, multiplet), 7.42 (2H, singlet).

[실시예 18]Example 18

1-[2-(2-아세틸아미노에틸)페녹시]-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [2- (2-acetylaminoethyl) phenoxy] -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(CD₃OD)δ : 1.56(6H, 단일선), 2.08(3H, 단일선), 2.80(2H, 삼중선, J=8Hz), 3.18∼3.61(4H, 다중선), 3.96∼4.22(3H, 다중선), 4.44(2H, 단일선), 6.80∼7.30(4H, 다중선), 7.45(2H, 단일선).NMR (CD ₃ OD) δ: 1.56 (6H, single line), 2.08 (3H, single line), 2.80 (2H, triplet, J = 8 Hz), 3.18 to 3.61 (4H, multiplet), 3.96 to 4.22 ( 3H, multiplet), 4.44 (2H, singlet), 6.80 to 7.30 (4H, multiplet), 7.45 (2H, singlet).

[실시예 19]Example 19

1-[2-(2-테트라히드로푸르푸릴옥시에틸)페녹시]-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [2- (2-tetrahydrofurfuryloxyethyl) phenoxy] -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol Hydrochloride.

융점 168.0∼171.0℃Melting Point 168.0 ~ 171.0 ℃

NMR(D₂O)δ : 1.40∼2.20(4H, 다중선), 1.56(6H, 단일선), 2.82(2H, 삼중선, J=7Hz), 3.20∼4.01(9H, 다중선), 4.01∼4.40(3H, 다중선), 4.42(2H, 단일선), 6.65∼7.55(4H, 다중선), 7.42(2H, 단일선).NMR (D ₂ O) δ: 1.40 to 2.20 (4H, multiplet), 1.56 (6H, singlet), 2.82 (2H, triplet, J = 7Hz), 3.20 to 4.01 (9H, multiplet), 4.01 to 4.40 (3H, multiplet), 4.42 (2H, singlet), 6.65 to 7.55 (4H, multiplet), 7.42 (2H, singlet).

[실시예 20]Example 20

1-페녹시-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1-phenoxy-3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.56(6H, 단일선), 3.22∼3.50(2H, 다중선), 3.97∼4.31(3H, 다중선), 4.43(2H, 단일선), 6.78∼7.50(5H, 다중선), 7.29(2H, 단일선).NMR (D ₂ O) δ: 1.56 (6H, singlet), 3.22 to 3.50 (2H, multiplet), 3.97 to 4.31 (3H, multiplet), 4.43 (2H, singlet), 6.78 to 7.50 (5H, Multiplet), 7.29 (2H, singlet).

[실시예 21]Example 21

1-(2-에톡시페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-ethoxyphenoxy) -3- [1,1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(CD₃OD)δ : 1.38(3H, 삼중선, J=7Hz), 1.57(6H, 단일선), 3.23∼3.55(2H, 다중선), 4.07(2H, 사중선, J=7Hz), 3.98∼4.40(3H, 다중선), 4.42(2H, 단일선), 6.92(4H, 단일선), 7.38(2H, 단일선).NMR (CD ₃ OD) δ: 1.38 (3H, triplet, J = 7 Hz), 1.57 (6H, singlet), 3.23 to 3.55 (2H, multiplet), 4.07 (2H, quartet, J = 7Hz), 3.98-4.40 (3H, multiplet), 4.42 (2H, singlet), 6.92 (4H, singlet), 7.38 (2H, singlet).

[실시예 22]Example 22

1-(2-벤질옥시페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-benzyloxyphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 174∼176℃Melting Point 174 ~ 176 ℃

NMR(D₃O)δ : 1.43(6H, 단일선), 3.23∼3.50(2H, 다중선), 4.04∼4.28(3H, 다중선), 4.32(2H, 단일선), 5.09(2H, 단일선), 7.03(4H, 단일선), 7.17(2H, 단일선), 7.44(5H, 단일선).NMR (D ₃ O) δ: 1.43 (6H, singlet), 3.23 to 3.50 (2H, multiplet), 4.04 to 4.28 (3H, multiplet), 4.32 (2H, singlet), 5.09 (2H, singlet ), 7.03 (4H, singlet), 7.17 (2H, singlet), 7.44 (5H, singlet).

[실시예 23]Example 23

1-[2-(2-메톡시에톡시)페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [2- (2-methoxyethoxy) phenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₃O)δ : 1.58(6H, 단일선), 3.38(2H, 단일선), 3.45(3H, 단일선), 3.20∼3.45(2H, 다중선), 4.05∼4.32(5H, 다중선), 4.43(2H, 단일선), 7.00(4H, 단일선), 7.22(2H, 단일선).NMR (D ₃ O) δ: 1.58 (6H, singlet), 3.38 (2H, singlet), 3.45 (3H, singlet), 3.20 to 3.45 (2H, multiplet), 4.05 to 4.32 (5H, multiplet ), 4.43 (2H, single line), 7.00 (4H, single line), 7.22 (2H, single line).

[실시예 24]Example 24

1-(2-아릴옥시페녹시(-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-aryloxyphenoxy (-3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 164.8∼166.4℃Melting Point 164.8 ~ 166.4 ℃

NMR(D₂O)δ : 1.58(6H, 단일선), 3.27∼3.57(2H, 다중선), 4.02∼4.37(3H, 다중선), 4.43(2H, 단일선), 4.50∼4.70(2H, 다중선), 5.20∼5.69(2H, 다중선), 5.72∼6.50(1H, 다중선), 7.00(4H, 단일선), 7.22(2H, 단일선).NMR (D ₂ O) δ: 1.58 (6H, singlet), 3.27 to 3.57 (2H, multiplet), 4.02 to 4.37 (3H, multiplet), 4.43 (2H, singlet), 4.50 to 4.70 (2H, Multiplet), 5.20 to 5.69 (2H, multiplet), 5.72 to 6.50 (1H, multiplet), 7.00 (4H, singlet), 7.22 (2H, singlet).

[실시예 25]Example 25

1-(3-클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-chlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 150.0∼155.0℃Melting Point 150.0 ~ 155.0 ℃

NMR(D₂O)δ : 1.60(6H, 단일선), 3.27∼3.60(2H, 다중선), 4.02∼4.40(3H, 다중선), 4.46(2H, 다중선), 6.76∼7.50(4H, 단일선), 7.33(2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, single line), 3.27 to 3.60 (2H, multiple line), 4.02 to 4.40 (3H, multiple line), 4.46 (2H, multiple line), 6.76 to 7.50 (4H, Singlet), 7.33 (2H, singlet).

[실시예 26]Example 26

1-(3-브로모페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-bromophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 180.5∼183.0℃Melting Point 180.5 ~ 183.0 ℃

NMR(D₂O)δ : 1.55(6H, 단일선), 3.23∼3.55(2H, 다중선), 3.95∼4.37(3H, 다중선), 4.40(2H, 단일선), 6.70∼7.45(4H, 다중선), 7.26(2H, 단일선).NMR (D ₂ O) δ: 1.55 (6H, singlet), 3.23 to 3.55 (2H, multiplet), 3.95 to 4.37 (3H, multiplet), 4.40 (2H, singlet), 6.70 to 7.45 (4H, Multiplet), 7.26 (2H, singlet).

[실시예 27]Example 27

1-(3-플루오르페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-fluorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 173∼176℃Melting Point 173 ~ 176 ℃

NMR(D₂O)δ : 1.55(6H, 단일선), 3.22∼3.45(2H, 다중선), 4.01∼4.55(3H, 다중선), 4.42(2H, 다중선), 6.50∼7.45(4H, 다중선), 7.32(2H, 단일선).NMR (D ₂ O) δ: 1.55 (6H, singlet), 3.22 to 3.45 (2H, multiplet), 4.01 to 4.55 (3H, multiplet), 4.42 (2H, multiplet), 6.50 to 7.45 (4H, Multiplet), 7.32 (2H, singlet).

[실시예 28]Example 28

1-(3-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-methylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 168∼171℃Melting Point 168 ~ 171 ℃

NMR(D₂O)δ : 1.57(6H, 단일선), 2.30(3H, 단일선), 3.28∼4.00(2H, 다중선), 4.05∼4.55(3H, 다중선), 4.43(2H, 단일선), 6.60∼7.25(4H, 다중선), 7.27(2H, 단일선).NMR (D ₂ O) δ: 1.57 (6H, singlet), 2.30 (3H, singlet), 3.28 to 4.00 (2H, multiplet), 4.05 to 4.55 (3H, multiplet), 4.43 (2H, singlet ), 6.60 to 7.25 (4H, multiplet), 7.27 (2H, singlet).

[실시예 29]Example 29

1-(3-에틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-ethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 171.5∼173.,5℃Melting Point 171.5 ~ 173., 5 ℃

NMR(D₂O)δ : 1.19(3H, 삼중선, J=7Hz), 1.58(6H, 단일선), 2.61(3H, 사중선, J=7Hz), 3.20∼3.53(2H, 다중선), 4.-02∼4.45(3H, 다중선), 4.43(2H, 단일선), 6.60∼7.43(4H, 다중선), 7.28(2H, 단일선).NMR (D ₂ O) δ: 1.19 (3H, triplet, J = 7Hz), 1.58 (6H, singlet), 2.61 (3H, quadruple, J = 7Hz), 3.20 to 3.53 (2H, multiplet), 4.-02 to 4.45 (3H, multiplet), 4.43 (2H, singlet), 6.60 to 7.43 (4H, multiplet), 7.28 (2H, singlet).

[실시예 30]Example 30

1-(3-트리플루오르메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-trifluoromethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 181.1∼183.4℃Melting Point 181.1 ~ 183.4 ℃

NMR(D₂O)δ : 1.58(6H, 단일선), 3.20∼3.53(2H, 다중선), 4.10∼4.53(3H, 다중선), 4.44(2H, 단일선), 7.05∼7.45(4H, 다중선), 7.31(2H, 단일선).NMR (D ₂ O) δ: 1.58 (6H, singlet), 3.20 to 3.53 (2H, multiplet), 4.10 to 4.53 (3H, multiplet), 4.44 (2H, singlet), 7.05 to 7.45 (4H, Multiplet), 7.31 (2H, singlet).

[실시예 31]Example 31

1-[3-(2-메톡시에틸)페녹시]-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [3- (2-methoxyethyl) phenoxy] -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 101.0∼103.0℃Melting Point 101.0 ~ 103.0 ℃

NMR(D₂O)δ : 1.56(3H, 단일선), 2.28(3H, 삼중선, J=6Hz), 3.19∼3.48(2H, 다중선), 3.33(3H, 단일선), 3.70(2H, 삼중선, J=6Hz), 4.00∼4.28(3H, 다중선), 4.41(2H, 단일선), 6.66∼7.04(3H, 다중선)., 7.04∼7.46(1H, 다중선), 7.27(2H, 단일선).NMR (D ₂ O) δ: 1.56 (3H, singlet), 2.28 (3H, triplet, J = 6Hz), 3.19 to 3.48 (2H, multiplet), 3.33 (3H, singlet), 3.70 (2H, Triplet, J = 6 Hz, 4.00 to 4.28 (3H, multiplet), 4.41 (2H, singlet), 6.66 to 7.04 (3H, multiplet), 7.04 to 7.46 (1H, multiplet), 7.27 (2H , Singlet).

[실시예 32]Example 32

1-(3-아릴페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-arylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 181.5∼184.1℃Melting Point 181.5 ~ 184.1 ℃

NMR(D₂O)δ : 1.56(6H, 단일선), 3.20∼3.50(4H, 다중선), 4.03∼4.50(3H, 다중선), 4.42(2H, 단일선), 4.90∼5.32(2H, 다중선), 5.50∼6.30(1H, 다중선), 6.60∼7.45(4H, 다중선), 7.27(5H, 단일선).NMR (D ₂ O) δ: 1.56 (6H, single line), 3.20 to 3.50 (4H, multiple line), 4.03 to 4.50 (3H, multiple line), 4.42 (2H, single line), 4.90 to 5.32 (2H, Multiplet), 5.50 to 6.30 (1H, multiplet), 6.60 to 7.45 (4H, multiplet), 7.27 (5H, singlet).

[실시예 33]Example 33

1-(3-시아노페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-cyanophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 173.7∼176.5℃Melting Point 173.7 ~ 176.5 ℃

NMR(D₂O)δ : 1.58(6H, 단일선), 3.80∼4.05(2H, 다중선), 4.10∼4.60(3H, 다중선), 4.46(2H, 단일선), 7.23∼7.57(4H, 다중선), 7.37(2H, 단일선).NMR (D ₂ O) δ: 1.58 (6H, singlet), 3.80 to 4.05 (2H, multiplet), 4.10 to 4.60 (3H, multiplet), 4.46 (2H, singlet), 7.23 to 7.57 (4H, Multiplet), 7.37 (2H, singlet).

[실시예 34]Example 34

1-(3-에톡시페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-ethoxyphenoxy) -3- [1,1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(CD₃OD)δ : 1.34(3H, 삼중선, J=7Hz), 1.56(6H, 단일선), 3.20∼3.52(2H, 다중선), 3.97(2H, 사중선, J=7Hz), 3.92∼4.32(3H, 다중선), 4.43(2H, 단일선), 6.39∼6.69(3H, 다중선), 6.95∼7.32(1H, 다중선), 7.44(2H, 단일선).NMR (CD ₃ OD) δ: 1.34 (3H, triplet, J = 7 Hz), 1.56 (6H, singlet), 3.20 to 3.52 (2H, multiplet), 3.97 (2H, quartet, J = 7Hz), 3.92 to 4.32 (3H, multiplet), 4.43 (2H, singlet), 6.39 to 6.69 (3H, multiplet), 6.95 to 7.32 (1H, multiplet), 7.44 (2H, singlet).

[실시예 35]Example 35

1-(2-시아노-3-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-cyano-3-methylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.57(6H, 단일선), 2.41(3H, 단일선), 3.32∼3.53(2H, 다중선), 4.18∼4.50(3H, 다중선), 4.42(2H, 단일선), 6.80∼7.50(3H, 다중선), 7.22(2H, 단일선).NMR (D ₂ O) δ: 1.57 (6H, singlet), 2.41 (3H, singlet), 3.32 to 3.53 (2H, multiplet), 4.18 to 4.50 (3H, multiplet), 4.42 (2H, singlet ), 6.80 to 7.50 (3H, multiplet), 7.22 (2H, singlet).

[실시예 36]Example 36

1-(3-클로로-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3-chloro-methylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 178.0∼181.0℃Melting Point 178.0 ~ 181.0 ℃

NMR(D₂O)δ : 1.57(6H, 단일선), 2.10(3H, 단일선), 3.33∼3.57(2H, 다중선), 4.06∼4.36(3H, 다중선), 4.38(2H, 단일선), 6.75∼7.25(3H, 다중선), 7.07(2H, 단일선).NMR (D ₂ O) δ: 1.57 (6H, singlet), 2.10 (3H, singlet), 3.33-3.57 (2H, multiplet), 4.06-4.36 (3H, multiplet), 4.38 (2H, singlet ), 6.75 to 7.25 (3H, multiplet), 7.07 (2H, singlet).

[실시예 37]Example 37

1-(2, 3-디클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2, 3-dichlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(CD₃OD)δ : 1.57(6H, 단일선), 3.25∼3.50(2H, 다중선), 4.00∼4.41(3H, 다중선), 4.42(2H, 다중선), 6.92∼7.38(3H, 다중선), 7.42(2H, 단일선).NMR (CD ₃ OD) δ: 1.57 (6H, singlet), 3.25 to 3.50 (2H, multiplet), 4.00 to 4.41 (3H, multiplet), 4.42 (2H, multiplet), 6.92 to 7.38 (3H, Multiplet), 7.42 (2H, singlet).

[실시예 38]Example 38

1-[2-클로로-4-(2-메톡시에틸)페녹시]-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- [2-chloro-4- (2-methoxyethyl) phenoxy] -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2- Propanol hydrochloride.

NMR(D₂O)δ : 1.57(6H, 단일선), 2.28(2H, 삼중선, J=6Hz), 3.36(3H, 단일선), 3.47(2H, 이중선, J=4.5Hz), 3.71(2H, 삼중선, J=6Hz), 4.15∼4.34(3H, 다중선), 4.47(2H, 단일선), 6.80∼7.40(3H, 다중선), 7.28(2H, 단일선).NMR (D ₂ O) δ: 1.57 (6H, singlet), 2.28 (2H, triplet, J = 6Hz), 3.36 (3H, singlet), 3.47 (2H, doublet, J = 4.5Hz), 3.71 ( 2H, triplet, J = 6Hz), 4.15-4.34 (3H, multiplet), 4.47 (2H, singlet), 6.80-7.40 (3H, multiplet), 7.28 (2H, singlet).

[실시예 39]Example 39

1-(2-클로로-4-메톡시페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-chloro-4-methoxyphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 174.6∼175.6℃Melting Point 174.6 ~ 175.6 ℃

NMR(D₂O)δ : 1.58(6H, 단일선), 3.30∼3.55(2H, 다중선), 3.80(3H, 단일선), 4.00∼4.50(3H, 다중선), 4.44(2H, 단일선), 6.88∼7.05(3H, 다중선), 7.23(2H, 단일선).NMR (D ₂ O) δ: 1.58 (6H, singlet), 3.30 to 3.55 (2H, multiplet), 3.80 (3H, singlet), 4.00 to 4.50 (3H, multiplet), 4.44 (2H, singlet ), 6.88 to 7.05 (3H, multiplet), 7.23 (2H, singlet).

[실시예 40]Example 40

1-(2-시아노-5-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-cyano-5-methylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.59(6H, 단일선), 2.40(3H, 단일선), 3.31∼3.56(2H, 다중선), 4.15∼4.56(3H, 다중선), 4.47(2H, 단일선), 6.81∼7.08(2H, 다중선), 7.32(2H, 단일선), 7.46(1H, 이중선, J=8Hz).NMR (D ₂ O) δ: 1.59 (6H, singlet), 2.40 (3H, singlet), 3.31-3.56 (2H, multiplet), 4.15-4.56 (3H, multiplet), 4.47 (2H, singlet ), 6.81 to 7.08 (2H, multiple wire), 7.32 (2H, single wire), 7.46 (1H, double wire, J = 8 Hz).

[실시예 41]Example 41

1-(2-시아노-5-클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-cyano-5-chlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.58(6H, 단일선), 3.28∼3.55(2H, 다중선), 4.12∼4.60(3H, 다중선), 4.46(2H, 단일선), 7.14(1H, 이중선, J=8Hz), 7.21(1H, 단일선), 7.39(2H, 단일선), 7.60(1H, 이중선, J=8Hz).NMR (D ₂ O) δ: 1.58 (6H, singlet), 3.28 to 3.55 (2H, multiplet), 4.12 to 4.60 (3H, multiplet), 4.46 (2H, singlet), 7.14 (1H, doublet, J = 8 Hz), 7.21 (1H, single line), 7.39 (2H, single line), 7.60 (1H, double line, J = 8 Hz).

[실시예 42]Example 42

1-(2-클로로-5-메톡시페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-chloro-5-methoxyphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.59(6H, 단일선), 3.30∼3.57(2H, 다중선), 3.38(3H, 단일선), 4.13∼4.39(3H, 다중선), 4.46(2H, 단일선), 6.45∼6.79(2H, 다중선), 7.26(2H, 단일선), 7.30(1H, 이중선, J=9Hz).NMR (D ₂ O) δ: 1.59 (6H, singlet), 3.30-3.57 (2H, multiplet), 3.38 (3H, singlet), 4.13-4.39 (3H, multiplet), 4.46 (2H, singlet ), 6.45 to 6.69 (2H, multiple wire), 7.26 (2H, single wire), 7.30 (1H, double wire, J = 9 Hz).

[실시예 43]Example 43

1-(2, 5-디메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2, 5-dimethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.58(6H, 단일선), 2.09(3H, 단일선), 2.30(3H, 단일선), 3.30∼3.52(2H, 다중선), 3.95∼4.55(3H, 다중선), 4.40(2H, 단일선), 6.06∼7.10(3H, 다중선), 7.13(2H, 단일선).NMR (D ₂ O) δ: 1.58 (6H, singlet), 2.09 (3H, singlet), 2.30 (3H, singlet), 3.30 to 3.52 (2H, multiplet), 3.95 to 4.55 (3H, multiplet ), 4.40 (2H, single line), 6.06 to 7.10 (3H, multiple line), 7.13 (2H, single line).

[실시예 44]Example 44

1-(2, 5-디클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2, 5-dichlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(CD₃OD)δ : 1.54(6H, 단일선), 3.23∼3.50(2H, 다중선), 3.98∼4.38(3H, 다중선), 4.42(2H, 단일선), 6.94(1H, 사중선, J=8Hz, 2Hz), 7.12(1H, 이중선, J=2Hz), 7.32(1H,이중선, J=8Hz), 7.44(2H, 단일선).NMR (CD ₃ OD) δ: 1.54 (6H, singlet), 3.23 to 3.50 (2H, multiplet), 3.98 to 4.38 (3H, multiplet), 4.42 (2H, singlet), 6.94 (1H, quartet , J = 8Hz, 2Hz), 7.12 (1H, doublet, J = 2Hz), 7.32 (1H, doublet, J = 8Hz), 7.44 (2H, singlet).

[실시예 45]Example 45

1-(2-클로로-6-메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-chloro-6-methylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 187.3∼188.9℃Melting Point 187.3 ~ 188.9 ℃

NMR(D₂O)δ : 1.60(6H, 단일선), 2.31(3H, 단일선), 3.35∼3.60(2H, 다중선), 4.00∼4.50(3H, 다중선), 4.52(2H, 단일선), 6.90∼7.50(3H, 다중선), 7.38(2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, single line), 2.31 (3H, single line), 3.35 to 3.60 (2H, multiple line), 4.00 to 4.50 (3H, multiple line), 4.52 (2H, single line) ), 6.90 to 7.50 (3H, multiplet), 7.38 (2H, singlet).

[실시예 46]Example 46

1-(2, 6-디클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2, 6-dichlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 192.2∼193.2℃Melting Point 192.2-193.2 ℃

NMR(D₂O)δ : 1.60(6H, 단일선), 3.35∼3.63(2H, 다중선), 4.05∼4.50(3H, 다중선), 4.50(2H, 다중선), 6.95∼7.60(3H, 다중선), 7.40(2H, 단일선).NMR (D ₂ O) δ: 1.60 (6H, single line), 3.35 to 3.63 (2H, multiple line), 4.05 to 4.50 (3H, multiple line), 4.50 (2H, multiple line), 6.95 to 7.60 (3H, Multiplet), 7.40 (2H, singlet).

[실시예 47]Example 47

1-(4-클로로-3-메톡시페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (4-chloro-3-methoxyphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(D₂O)δ : 1.56(6H, 단일선), 3.30∼3.55(2H, 다중선), 3.84(3H, 단일선), 4.05∼4.35(3H, 다중선), 6.40∼6.62(2H, 다중선), 7.23(2H, 단일선), 7.25(1H, 이중선, J=9Hz).NMR (D ₂ O) δ: 1.56 (6H, singlet), 3.30 to 3.55 (2H, multiplet), 3.84 (3H, singlet), 4.05 to 4.35 (3H, multiplet), 6.40 to 6.62 (2H, Multiplet), 7.23 (2H, singlet), 7.25 (1H, doublet, J = 9 Hz).

[실시예 48]Example 48

1-(3, 5-디클로로페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3, 5-dichlorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

NMR(CD₃OD)δ : 1.56(6H, 단일선), 3.20∼3.50(2H, 다중선), 3.96∼4.30(3H, 다중선), 4.43(2H, 단일선), 6.95(3H, 단일선), 7.48(2H, 단일선).NMR (CD ₃ OD) δ: 1.56 (6H, singlet), 3.20 to 3.50 (2H, multiplet), 3.96 to 4.30 (3H, multiplet), 4.43 (2H, singlet), 6.95 (3H, singlet ), 7.48 (2H, singlet).

[실시예 49]Example 49

1-(3, 5-디메틸페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (3, 5-dimethylphenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 181.4∼183.0℃Melting Point 181.4 ~ 183.0 ℃

NMR(D₂O)δ : 1.55(6H, 단일선), 2.25(6H, 단일선), 3.25∼3.50(2H, 다중선), 3.98∼4.35(3H, 다중선), 4.39(2H, 단일선), 6.56(2H, 넓은 단일선), 6.68(1H, 넓은 단일선), 7.20(2H, 단일선).NMR (D ₂ O) δ: 1.55 (6H, singlet), 2.25 (6H, singlet), 3.25-3.50 (2H, multiplet), 3.98-4.35 (3H, multiplet), 4.39 (2H, singlet ), 6.56 (2H, wide single line), 6.68 (1H, wide single line), 7.20 (2H, single line).

[실시예 50]Example 50

1-(2-클로로-3-메틸페녹시)-3-[1-메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-chloro-3-methylphenoxy) -3- [1-methyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 168.0∼171.5℃Melting Point 168.0 ~ 171.5 ℃

NMR(D₂O)δ : 1.55∼1.58(3H, 두줄의 이중선, J=7Hz), 2.35(3H, 단일선), 3.48∼3.70(3H, 다중선), 4.15∼4.39(3H, 다중선), 4.40∼4.70(2H, 다중선), 6.74∼7.50(5H, 다중선).NMR (D ₂ O) δ: 1.55 to 1.58 (3H, double line, J = 7Hz), 2.35 (3H, single line), 3.48 to 3.70 (3H, multiple line), 4.15 to 4.39 (3H, multiple line) , 4.40 to 4.70 (2H, multiplet), 6.74 to 7.50 (5H, multiplet).

[실시예 51]Example 51

1-(2-플루오르페녹시)-3-[1, 1-디메틸-2-(3-히드라지노-6-피리다지닐옥시)에틸아미노]-2-프로판올 염산염.1- (2-fluorophenoxy) -3- [1, 1-dimethyl-2- (3-hydrazino-6-pyridazinyloxy) ethylamino] -2-propanol hydrochloride.

융점 178∼179.7℃Melting Point 178 ~ 179.7 ℃

NMR(D₂O)δ : 1.56(6H, 단일선), 3.27∼3.48(2H, 다중선), 4.00∼4.50(3H, 다중선), 4.43(2H, 단일선), 6.92∼7.30(4H, 다중선), 7.32(2H, 단일선).NMR (D ₂ O) δ: 1.56 (6H, singlet), 3.27 to 3.48 (2H, multiplet), 4.00 to 4.50 (3H, multiplet), 4.43 (2H, singlet), 6.92 to 7.30 (4H, Multiplet), 7.32 (2H, singlet).

Claims

The hydrazino pyridabine derivative represented by the following general formula (I) characterized by reacting a strong acid salt of the halogenopyridazine derivative represented by the following general formula (II) with thiourea and then treating it with a large excess of hydrazine or its hydrate. Or acid addition salts thereof.

(I)

(II)

Wherein R ¹ represents a hydrogen atom, a halogen atom, a cyano group: a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkanoylamino group or a tetrahydrofurfuryloxy group, or a lower alkyl group, phenyl group or lower group Lower alkoxy key which may be substituted with an alkoxy group: lower alkenyl group; lower alkenyloxy group or lower alkynyl group: R ² represents a hydrogen atom: a halogen atom; a lower group which may be substituted with a cyano group, a halogen atom or a lower alkoxy group Alkyl group: A lower alkoxy group or a lower alkenyl group, R <^3> , R <^4> and R <^5> represent a hydrogen atom; a halogen atom, a lower alkoxy group which may be substituted by the lower alkoxy group each independently, and R <^6> represents hydrogen Represents an atom or a methyl group, X represents a chlorine, bromine or iodine atom)

A zero method of a hydrazino pyridazine derivative represented by the following general formula (I) or an acid addition salt thereof characterized by reacting a thioxopyridazine derivative represented by the following general formula (III) with hydrazine or its hydrate.

Wherein R ¹ is a hydrogen atom: halogen atom: cyano group; halogen atom, lower alkoxy group, lower alkylthio group, lower alkanoylamino group or tetrahydrofurfuryloxy group, lower alkyl group: phenyl group or lower Lower alkoxy group which may be substituted with an alkoxy group: Lower alkenyl group: Lower alkenyloxy or lower alkynyl group, R ² is a hydrogen atom; a halogen atom; a cyano group; a lower group which may be substituted with a halogen atom or a lower alkoxy group Alkyl group: A lower alkoxy group or a lower alkenyl group, R <^3> , R <^4> and R <^5> represent a lower alkyl group or a lower alkoxy group which may be substituted independently by a hydrogen atom, a halogen atom, a lower alkoxy group, and R <^6> is hydrogen Atom or methyl group).