JPS6330902B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel hydrazinopyridazine compound, more specifically, the compound has the following formula () In the formula, R′ is a hydrogen atom; a cyano group; a hydroxyl group; an allyloxy group; an allyl group; a halogen atom; an acetylamine group, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkylthio group, a tetrahydrofurfuryloxy group or an allyloxy group a lower alkyl group which may be substituted with; or a methoxy or ethoxy group which may be substituted with a 2-furyl group, a phenyl group or a lower alkoxy group, R ² and R ³ are each a hydrogen atom, a halogen atom, It represents a lower alkyl group or a lower alkoxy group, R ⁴ and R ⁵ each represent a hydrogen atom or a methyl group, Z represents an oxygen or sulfur atom, and Y represents -NH ₂ or

The present invention relates to a hydrazinopyridazine compound represented by the formula and a salt thereof, a method for producing the same, and an antihypertensive agent containing the hydrazinopyridazine compound of the above formula () or a salt thereof as an active ingredient. Many compounds having antihypertensive effects have been proposed in the past, and vasodilators, which have been commonly used as antihypertensive agents, generally have reliable antihypertensive effects, but have the drawback of being accompanied by tachycardia. On the other hand, sympathetic β-
Receptor blockers (hereinafter referred to as β-blockers) are also used as antihypertensive agents, and although they have the advantage of not causing tachycardia, they have the disadvantage that their antihypertensive action is slow and weak. Therefore, when treating hypertensive patients, sufficient effects cannot be expected from the use of vasodilators and β-blockers alone, and in conventional clinical treatment, vasodilators and β-blockers have not been used together.
- Parallel administration of blockers is often performed, but this parallel administration is cumbersome for patients;
This is not preferable for drug administration. Therefore, there has been a demand for the development of antihypertensive agents that combine the advantages of vasodilatory and β-blocking antihypertensive agents. A few documents have been published that suggest that it is a concomitant antihypertensive agent (see, for example, JP-A-51-13782, JP-A-54-32489, etc.); At present, there is little evidence to support that it has both effects, or even if it has been confirmed that it has both β-blocking and vasodilatory effects, their activities are currently very weak. However, in the present invention, all of the hydrazinopyridazine compounds represented by the above formula () have an excellent vasodilatory effect, and with a few exceptions, most of them have the following pharmacological data as shown in the below-mentioned pharmacological data. As a result, it was found to have both excellent β-blocking and vasodilatory effects at the same time, making it extremely suitable as an antihypertensive agent. As used herein, the term "lower" means that the group or compound to which this term is attached contains no more than 5 carbon atoms, preferably no more than 3 carbon atoms. Thus, the term "lower alkyl" as used herein may be linear or branched, for example methyl, ethyl, n- or iso-propyl, n-, iso−,
Examples include sec- or tert-butyl groups, among which methyl and ethyl groups are suitable. In addition, examples of "lower alkoxy groups" include:
Examples include methoxy, ethoxy, n-propoxy or isopropoxy groups, and "lower alkylthio groups"
Examples include methylthio and ethylthio groups. The term "halogen atom" is meant to include all four fluorine, chlorine, bromine and iodine atoms, in particular all four fluorine, chlorine and bromine atoms, in particular fluorine, chlorine and bromine atoms. . Therefore, in the above formula (), the symbol R' may be substituted with an acetylamino group, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkylthio group, a tetrahydrofurfuryloxy group, or an allyloxy group. "Lower alkyl group" includes unsubstituted lower alkyl groups, such as methyl, ethyl and n-propyl groups: one acetylamino group, hydroxyl group,
Lower alkyl groups substituted with lower alkoxy groups, lower alkylthio groups, tetrahydrofurfuryloxy groups or allyloxy groups, such as acetylaminomethyl, 2-acetylaminoethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, ethoxy Methyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, ethylthiomethyl, 2-methylthioethyl, 2-tetrahydrofurfuryloxyethyl and 2-allyloxyethyl groups: substituted with 1 to 3 halogen atoms and lower alkyl groups such as trifluoromethyl, dichloromethyl and 2-promoethyl groups. In addition, "methoxy or ethoxy group optionally substituted with a 2-furyl group, phenyl group or lower alkoxy group" includes unsubstituted methoxy and ethoxy groups: one 2-furyl group, phenyl group or lower alkoxy group. Included are methoxy or ethoxy groups substituted with groups such as furfuryloxy, benzyloxy, phenethyloxy, methoxymethoxy, 2-methoxyethoxy and 2-ethoxyethoxy groups. Preferred examples of R' in formula () include a cyano group, an allyloxy group, an allyl group, a chlorine atom, a bromine atom, a trifluoromethyl group, an ethyl group, and a 2-methoxyethyl group. On the other hand, examples of R ² and R ³ in formula () include a hydrogen atom, a chlorine or bromine atom, a methyl or ethyl group, or an ethoxy group. Accordingly, in a preferred group of hydrazinopyridazine compounds of the formula () provided by the present invention, Z represents an oxygen atom, and R ⁴
Formula () when both R 5 and R ⁵ represent a methyl group
A compound of the following formula (-a) In the formula, R ¹ , R ² , R ³ and Y have the above meanings. Other preferred groups of hydrazinopyridazine compounds of the formula () provided by the present invention include R ¹ being a cyano group, an allyloxy group, an allyl group,
represents a chlorine atom, a bromine atom, a trifluoromethyl group, an ethyl group or a 2-methoxyethyl group, and
R ² and R ³ are both hydrogen atoms, or R ¹
represents a chlorine atom, one of R ² and R ³ is a hydrogen atom, and the other represents a methyl group. Representative examples of the hydrazinopyridazine compound of formula () provided by the present invention include the following in addition to those listed in the Examples below. 1-(2-cyanophenoxy)-3-[1-methyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-allylphenoxy)-3-[1 -Methyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-promo-3-methylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-promo-5-methylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-chloro-3-methylphenoxy)-3
-[1-Methyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-methyl-5-chlorophenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-ethyl-3-chlorophenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-trifluoromethylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-ethoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-propanol, 1-[2-(3-methoxypropyl)phenoxy]-3-[1,1-dimethyl-2-(3-isopropylidenehydrazino-6-pyri dazinyloxy)ethylamino]-2-propanol, 1-[2-(2-methoxyethyl]-5-chlorophenoxy]3-[1,1-dimethyl-2-(3-
hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, 1-[2-(2-methoxyethyl)phenoxy]
-3-[1-methyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-propanol, 1-(2-methoxyphenoxy)-3-[1-methyl-2-(3-hydrazino-6-pyritazinyloxy)ethylamino]2 -propanol, 1-[2-(2-methoxyethoxy)phenoxy]-3-[1-methyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-2-
Propanol, 1-(2-ethoxymethoxyphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-propanol, 1-(2-cyanophenoxy)-3-[1,1-
Dimethyl-2-(3-isopropylidenehydrazino-6-pyridazinylthio)ethylamino]-2
-propanol, 1-(2-allylphenoxy)-3-[1-methyl-2-(3-hydrazino-6-pyridazinylthio)ethylamino]-2-propanol, 1-(2-chlorophenoxy)-3-[ 1,1-
Dimethyl-2-(3-hydrazino-6-pyridazinylthio)ethylamino]-2-propanol, 1-(2-ethylphenoxy)-3-[1,1-
Dimethyl-2-(3-hydrazino-6-pyridazinylthio)ethylamino]-2-propanol and the like. According to the present invention, acid addition salts of the hydrazinopyridazine compounds as described above are also provided. As the acid addition salt of the compound represented by the above formula (),
For example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
Inorganic acids such as phosphoric acid; as well as acetic acid, propionic acid,
Examples include salts with organic acids such as citric acid, lactic acid, and tartaric acid, among which pharmaceutically acceptable acid addition salts are advantageous. According to the present invention, the hydrazinopyridazine compound represented by the above formula () or a salt thereof is the hydrazinopyridazine compound represented by the following formula () In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the above-mentioned meanings, and X is a halogen atom, preferably chlorine,
A compound represented by a bromine or iodine atom, preferably a chlorine atom, is reacted with hydrazine or a hydrate thereof, and then, if necessary, a compound represented by the following formula (-
b) In the formula, R ¹ , R ² , R ³ .R ⁴ , R ⁵ and Z have the above meanings. It can be produced by reacting the compound represented by with acetone and further converting the reaction product into a salt if necessary. The reaction between the compound of the above formula () and hydrazine or its hydrate, preferably the latter hydrazine hydrate, can be carried out by bringing the two reaction components into contact in the absence of a solvent or in an inert solvent. can be done. Inert solvents that can be used include, for example, water; alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as dioxane and tetrahydrofuran; organic bases such as pyridine and collidine;
Examples include aromatic hydrocarbons such as benzene, toluene, and xylene. The reaction temperature is not critical and the formula used ()
Although this can vary widely depending on the nature of the starting materials, it is generally advantageous to carry out the reaction at a temperature of at least 20°C, preferably between about 50°C and the reflux temperature of the reaction mixture. The amount of hydrazine or its hydrate used relative to the compound of formula () is also not critical;
The amount of hydrazine or its hydrate can be varied widely depending on the type of compound and the reaction conditions, but in general, the amount of hydrazine or its hydrate is at least 2 moles, preferably about 10 to about 1 mole of the compound of formula (). 200 moles,
More preferably, it is advantageous to use within the range of about 50 to about 100 moles. Although the reaction time varies depending on the type of compound of formula () and the reaction temperature, the reaction can usually be completed in about 0.5 to about 5 hours. Furthermore, the above reaction may be carried out in the presence of a suitable base. Usable bases include, for example, alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; organic compounds such as pyrrolidine, piperazine, piperidine, morpholine, and 4-dimethylaminopyridine. These bases can be used in an amount of generally 1 to about 100 equivalents, preferably about 1 to about 10 equivalents, per mol of the compound of formula (). In this case, hydrazine or its hydrate may be used in large excess so that the excess hydrazine or its hydrate acts as a base. Thus, by the above reaction, the compound of the above formula () when Y represents _-NH2 , i.e. the following formula (-b) In the formula, R ¹ , R ² .R ³ .R ⁴ , R ⁵ and Z have the above-mentioned meanings, and a hydrazine derivative represented by the following is obtained. This hydrazine derivative is then reacted with acetone, if necessary, so that Y is

When [Formula] is represented, it can be changed to the compound of the above formula (). Hydrazonation of the compound of formula (b) with acetone can be carried out in the absence of a solvent or in an inert solvent such as water; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, dioxane, and tetrahydrofuran; benzene, This can be carried out by bringing the compound of formula (b) into contact with acetone among aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and tetrachloroethane. The reaction proceeds satisfactorily even at room temperature, but if necessary, the temperature may be increased up to the reflux temperature of the reaction mixture, preferably at about
The reaction may be carried out while heating to a temperature of 100°C or less. The amount of acetone used relative to the compound of formula (-b) is not critical and can vary widely depending on the type of compound of formula (-b), but generally, 1 mole of compound of formula (-b) is used. , acetone is at least 1 mole, preferably from about 2 to about
It is advantageous to use within the range of 100 moles, more preferably from about 10 to about 50 moles. This reaction proceeds extremely rapidly, usually from about 10 to about 60
It is done almost quantitatively in minutes. In this way, a hydrazinopyridazine compound represented by the above formula () is obtained, which is extracted from the reaction mixture by a method known per se, such as extraction, column chromatography, thin layer chromatography, recrystallization, etc. It can be separated and/or purified. The hydrazinopyridazine compound represented by the formula () can be further treated with, for example, hydrochloric acid, hydrobromic acid, hydrobromic acid, etc., by a method known per se, if necessary.
It can be converted into the corresponding salt by treatment with inorganic acids such as sulfuric acid, nitric acid, phosphoric acid; and organic acids such as acetic acid, propionic acid, citric acid, lactic acid, tartaric acid. The compound of formula () used as a starting material in the method of the present invention described above is a new compound that has not been described in conventional literature. I can list things. 1-(2-cyanophenoxy)-3-[1,1-
Dimethyl-2-(3-bromo-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-allylphenoxy)-3-[1-methyl-2-(3-chloro-6-pyrylamino) dadinyloxy)
ethylamino]-2-propanol, 1-(2-chloro-3-1-methylphenoxy)
-3-[1,1-dimethyl-2-(3-bromo-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-chloro-5-methylphenoxy)-3
-[1,1-dimethyl-2-(3-bromo-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-bromo-3-methylphenoxy)-3
-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-ethyl-3-chlorophenoxy)-3
-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol, 1-[2-(2-methoxyethyl)phenoxy]
-3-[1,1-dimethyl-2-(3-promo-6
-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-ethoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol, 1-[2-(2-methoxyethyl)phenoxy]
-3-[1-methyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-methoxyphenoxy)-3-[1-methyl-2 -(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol, 1-(2-cyanophenoxy)-3-[1,1-
Dimethyl-2-(3-chloro-6-pyridazinylthio)ethylamino]-2-propanol, 1-(2-allylphenoxy)-3-[1-methyl-2-(3-chloro-6-pyridazinylthio)
ethylamino]-2-propanol, 1-[2-(2-methoxyethyl)phenoxy]
-3-[1,1-dimethyl-2-(3-promo-6
-pyridazinyloxy)ethylamino]-2-propanol, etc. These compounds of formula () can be synthesized through the steps shown in reaction formula A below. In the above reaction formula A, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , Z and X have the above meanings; X' represents a halogen atom that is the same as or different from X; Q is

[Formula] or

[Formula] is represented, where B is a halogen atom. In the above reaction formula A, according to the first aspect,
Compounds of formula (), which are known per se, are reacted with compounds of formula (). The reaction between the compound of formula () and the compound of formula () is carried out by a method known per se.
ZN is used in the form of an alkoxide or alkyl sulfide (e.g. sodium alkoxide, potassium alkoxide, sodium alkyl sulfide) in which ZN is changed to -ZM, where M is an alkali metal, or the compound of formula () is used as a base. For example, this can be carried out by using in the presence of sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and bringing it into contact with the compound of formula (). The reaction is carried out in the absence of a solvent, or preferably in an inert solvent, e.g. aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane; amides such as dimethylformamide. The reaction can be carried out using organic bases such as pyridine, triethylamine, dimethylaniline, etc., at a temperature between 0°C and the reflux temperature of the reaction mixture, preferably at a heating temperature between about room temperature and the reflux temperature of the reaction mixture. The usage ratio of the compound of formula () and the compound of formula () is not particularly restricted, but in general,
It is advantageous to use at least 1 mol of the compound of formula () per mol of the compound of formula (), preferably in the range from about 1 to about 2 mol. Under such reaction conditions, the reaction can be completed in about 0.5 to 5 hours. In this way, the compound of formula () above is obtained in good yield. This compound is a new compound that has not been described in conventional literature, and representative examples thereof are as follows. 3-(2-amino-2-methylpropoxy)-6
-chloropyridazine, 3-(2-amino-2-methylpropylthio)-
6-chloropyridazine, 3-(2-aminopropoxy)-6-chloropyridazine, 3-(2-aminopropylthio)-6-chloropyridazine, 3-(2-aminoethoxy)-6-chloropyridazine, 3- (2-amino-2-methylpropoxy)-6
-chloropyridazine etc. The above compound of formula () can then be reacted with a compound of formula () to produce a compound of formula (). This reaction can be easily carried out by bringing the compound of formula () into contact with the compound of formula () in the presence or absence of a solvent, preferably in the presence of an inert organic solvent. The reaction temperature is not critical and can be selected as appropriate, but generally about 0°C to about 200 kg, preferably room temperature to about 100°C, and the reaction is carried out under reflux temperature conditions. is preferred. In this reaction, compound 1 of formula ()
The compound of formula () can be used in an amount ranging from about equimolar to about 2 molar based on the mole. The reaction time can be changed as appropriate depending on the type of reaction components, reaction temperature, etc., but generally a reaction time of about 1 to about 5 hours can be used. Inert solvents that can be used in the above reaction include, for example, water; lower alcohols such as methanol, ethanol, and isopropyl alcohol; aromatic hydrocarbons such as benzene, xylene, and toluene; chloroform, dichloromethane, dichloroethane, Examples include solvents such as halogenated hydrocarbons such as trichloroethane and carbon tetrachloride. In addition, in the compound of the formula () used in the first embodiment, Q is

When representing [Formula], the compound of formula () is, for example, the following formula () In the formula, R ¹ .R ² and R ³ have the above-mentioned meanings. It is obtained by reacting the compound represented by with shrimp halohydrin, and the Q obtained in this way is

Compounds of formula () when [formula] is represented, i.e., the following formula (-a) In the formula, R ¹ , R ² and R ³ have the above meanings,
Q is then treated with hydrohalic acid (HB) to cleave the epoxy group.

Compounds of formula () can be produced when [formula] is represented. The reaction of the compound of formula () with epihalohydrin can be carried out according to methods known per se, for example at room temperature to approx.
It can be produced in good yield by reacting at 100°C under alkaline conditions, preferably in the absence of a solvent or in the presence of water or an alcohol such as methanol, ethanol, propanol, etc., for about 1 to about 5 hours. . Furthermore, the cleavage reaction of the epoxy group of the compound of the above formula (-a) with hydrohalic acid is carried out according to a method known per se, for example, at a temperature ranging from 0°C to the reflux temperature of the reaction mixture, preferably using an inert organic solvent such as chloroform, In the presence of ethanol, benzene, dioxane, etc., a hydrohalic acid such as hydrochloric acid or hydrobromic acid is mixed with the compound of formula (-a),
This can be carried out by reacting for about 0.5 to 5 hours. In the reaction formula A, according to the second aspect, the compound of the formula () is reacted with the compound of the formula (). The reaction between the compound of formula () and the compound of formula () can be carried out in exactly the same manner as described above regarding the reaction between the compound of formula () and the compound of formula () in the first embodiment. Thus, the compound of formula (), i.e. In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the above meanings. A compound of formula () is obtained which is then converted into a compound of formula () by reacting with a compound of formula (). The reaction between the compound of formula () and the compound of formula () can also be carried out in exactly the same manner as described above regarding the reaction between the compound of formula () and the compound of formula () in the first embodiment. The compound of formula () produced according to the first or second embodiment described above is usually separated from the reaction mixture by a method known per se, and then subjected to the reaction with the above-mentioned hydrazine or its hydrate. Can be done. The hydrazinopyridazine compound represented by the formula () of the present invention described above generally has pharmacological characteristics in that it has both β-blocking action and vasodilatory action at the same time, and also has low toxicity. It is therapeutically excellent as a continuous antihypertensive agent without tachycardia. The following animal experiments demonstrate that the compound represented by formula () of the present invention has both excellent β-blocking action and vasodilatory action (hypertensive action). The compounds of the present invention used in the following animal experiments are represented by the following symbols. Compound A: 1-(2-cyanophenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, B: 1-(2-ethylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, C: 1-[2-(2-methoxyethyl)phenoxy]-3-[1,1-dimethyl -2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, D: 1-[2-(2-ethoxyethyl)phenoxy]-3-[1,1-dimethyl-2 -(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, E:1-[2-(3-dichlorophenoxy]-3-
[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-
2-propanol, F: 1-(2-chloro-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, G: 1-(2-chloro-5-methylphenoxy)-
3-[1,1-dimethyl-2-(3-isopropylidenehydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, H:1-(3,5-dimethylphenoxy)- 3-
[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-
2-propanol, I:1-(2-chloro-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino-6-pyridazinylthio)ethylamino]
-2-propanol, J:1-(2-cyanophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, K: 1-(2-chlorophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, L: 1-(2-propylphenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-
Propanol, M: 1-(2-allyloxyphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-
2-propanol, N:1-(2-methylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, O:1-(2-methoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-
2-propanol, P:1-(2-cyano-5-methylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, Q:1-(2-cyano-5-chlorophenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, R: 1-(2-cyano-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, S:1-(2,5-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-
2-propanol, T:1-(2-ethoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-
2-propanol, U:1-phenoxy-3-[1,1-dimethyl-
2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol. Test method Rats (〓, Wister: weight 300 ~
400g), and blood pressure is measured directly by connecting a cannula inserted into the femoral artery to a pressure transducer. On the other hand, the heart rate is calculated from the blood pressure pulse wave. (1) Measurement of β-blocking effect Isoprenaline (0.1μg/
Administer Kg iv) and immediately measure and record heart rate. The measured value of heart rate at that time is H ₁ . next,
A solution of the test compound dissolved in physiological saline or 0.01N hydrochloric acid aqueous solution was administered through a cannula into the femoral vein of the rat, and 3 minutes later, isoprenaline (0.1 μg/Kg iv) was administered again, and heart rate was immediately measured and recorded. do. The reading of the heart number at that time is H ₂ .
From this measured value, the suppression rate of heart rate is calculated according to the following formula. Suppression rate of heart rate (%) = 100−H ₂ /H ₁ ×100 Create a dose-response curve by repeating the above procedure while changing the dose of the test compound, and calculate the rate of inhibition of heart rate from this curve. Determine the dose of the test compound at which the concentration is 50%. The results are shown in Table 1 below.

【table】 (2) Measurement of vasodilatory effect (hypertensive effect) Three rats per group were given the test compound (saline or
(dissolved in 0.01N hydrochloric acid) 1 mg/Kg was administered intravenously,
Blood pressure was recorded over time for 40 minutes. blood during that period
Determine the maximum pressure drop value. The results are shown below.
It is shown in Table 2. Table 2 Compound Blood pressure lowering effect A B C D E+ F G H I + J K L M N O P Q R ± S T U ±: Blood pressure decrease of 10-14mmHg, +: Blood pressure decrease of 15-24 mmHg, : Blood pressure decrease of 25-34mmHg, : Blood pressure drop of 35mmHg or more, Toxic A group of male Wister rats (weighing 100-115g)
Five animals were used, and the test solution was 2% Twin 80 dissolved.
Suspended in saline and administered orally by probe at each dose.
The mice were administered and observed for one week. Based on the results,
Compounded by Tutsifield-Wilkoxon method
LD of objects A to U₅₀The value was calculated. As a result, the compound
LD of objects A to U₅₀The values were 700-1000 mg/Kg. Thus, the hydrogen represented by the formula () of the present invention
Radinopyridazine compounds have β-blocking and vascular
It has been used in humans as an antihypertensive agent that also has a diastolic effect.
For treatment and treatment of other warm-blooded animals,
Oral or parenteral administration (e.g. intramuscular, intravenous, subcutaneous)
administration, rectal administration, sublingual administration, etc.)
Ru. When used as a drug, the compound of the present invention may be used orally.
Formulated into various forms suitable for oral or parenteral administration
be able to. For example, the compounds of the invention may be
Non-toxic excipients and binders commonly used in seed drugs
agent, lubricant, disintegrant, preservative, tonicity agent, stabilizer
agent, dispersant, antioxidant, colorant, flavoring agent, buffer
It can be formulated using additives such as agents. Depending on the intended use, such drugs may be in solid form.
(e.g. tablets, hard capsules, soft capsules, granules)
(granules, powders, fine granules, pills, lozenges, etc.)
Semi-solid forms (e.g. suppositories) and liquid forms (notes)
(shooting agent, emulsion, suspension, syrup, etc.)
It can be prepared in the following formulation form. However,
Examples of the above-mentioned non-toxic additives that can be used include:
Starch, gelatin, glucose, lactose, fructose, mal
Toss, magnesium carbonate, talc, stearin
Magnesium acid, methyl cellulose, carboxy
Methylcellulose or its salts, gum arabic,
Polyethylene glycol, p-hydroxybenzoin
Acid alkyl ester, syrup, ethanol, syrup
Lopylene glycol, petrolatum, carboxylic
salt, glycerin, sodium chloride, sulfite
da, sodium phosphate, citric acid, etc.
Ru. the drug or other therapeutically useful drugs.
It can also contain. The content of the compound of the present invention in the drug is
depending on the dosage form, but generally solid and semi-solid
in the form of a concentration of 5 to 100% by weight, and
In liquid form, the activity is present at a concentration of 0.1 to 10% by weight.
It is desirable that the material contains a chemical compound. The dosage of the compounds of the present invention is determined to be suitable for human subjects.
Other types of warm-blooded animals, severity of symptoms, and doctors
Although it can be changed widely depending on the diagnosis, etc.,
Generally 0.02~30mg/Kg per day, preferably 0.05~
It can be 10mg/Kg. However, as above
Depending on the severity of the patient's symptoms and the doctor's diagnosis,
An amount less than the lower limit of the range or an amount greater than the upper limit
It is also possible to administer The above dosage is
Any of the above dosage forms once or several times a day
It can be administered by The present invention will be further explained below with reference to Examples. Note that NMR measurements are performed using tetramethylsilane or
2,2-dimethyl-2-silapentane-2-sul
Sodium phonate was used as an internal standard. Example 1 (a) 61% sodium hydride (1.5 g) in benzene
(20 ml) of 2-amino-2-methylpropylene into the suspension.
Panol (2.7g) was added dropwise to room temperature, then 3.
6-dichloropyridazine (4.5g) in benzene
(20ml) solution was added and refluxed for 1 hour. After cooling,
After washing the reaction solution with water and drying with magnesium sulfate,
The solvent was distilled off to give 3-(2-amino-2-methyl
(propoxy)-6-chloropyridazine
(4.33g) was obtained. NMR (CDCl)₃) δ: 1.22 (6H, singlet), 1.49
(2H, singlet), 4.23 (2H, singlet), 7.03 (1H,
double line, J=9Hz), 7.42 (1H, double line, J=
9Hz). (b) 3-(2-amino-2-methyl obtained in (a) above)
propoxy)-6-chloropyridazine (17.0g)
methanol (20 ml) solution and 1-(2-cyano
phenoxy)-2,3-epoxypropane
(14.6 g) was refluxed for 4 hours with stirring. Reduce solvent
The product obtained was distilled off under pressure and dissolved in benzene (200
ml). Add this with 10% hydrochloric acid (150ml)
After extraction, alkali with 10% sodium hydroxide
It was made into a sex. Then extracted with chloroform and sulfuric acid
Dried with sodium. The solvent was distilled off and the obtained
Column chromatography of extracted extract (Wako)
Gel C-200, 100g) and chloroform
- From the elution fraction from methanol (30:1),
1-(2-cyanophenoxy)-3-[1,1-
Dimethyl-2-(3-chloro-6-pyridazine)
ruoxy)ethylamino]-2-propanol
(24.97g, pale yellow oil) was obtained. NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.64
(2H, wide singlet), 2.73 to 2.96 (2H, multiple
line), 4.07 (3H, wide single line), 4.32 (2H, single line)
multiplet), 6.82 to 7.18 (2H, multiplet), 6.98 (1H,
Doublet, J=9Hz), 7.22-7.68 (2H, multiplet),
7.33 (H, double line, J=9Hz). (c) 1-(cyanofexy)-3- obtained in (b) above
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol (900mg), hydrazine hydrate (18
ml) and ethanol (18 ml) at 5 o'clock.
The mixture was refluxed with stirring for a while. After concentrating the solvent under reduced pressure,
The product was dissolved in chloroform, washed with water and then soaked in sulfuric acid.
After drying with magnesium chloride, the solvent was distilled off under reduced pressure.
Ta. Add acetone to the resulting oil and leave for 30 minutes
After standing at room temperature, the solvent was distilled off under reduced pressure and a thin layer was removed.
Romantography (silica gel (Merck)
GF₂₅₄):chloroform:methanol=10:1)
Separation gave a yellow oil (270 mg). this
Dissolve it in acetone and leave it to dissolve 1-(2-sia).
nophenoxy)-3-[1,1-dimethyl-2-
(3-isopropylidenehydrazine-6-pyri
dadinyloxy)ethylamino]-2-propa
Nol (150mg, yellow crystals, mp126-128℃)
Obtained. NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.91
(3H, singlet), 2.22 (3H, singlet), 2.30~
3.25 (2H, multiplet), 2.74~2.98 (2H, multiplet),
4.08 (3H, wide single line), 4.22 (2H, single line)
line), 6.82 to 7.13 (2H, multiplet line), 6.91 (1H, double
Multiple line, J=9Hz), 7.20-7.67 (2H, multiple line),
7.49 (1H, double line, J=9Hz). (d) 1-(2-cyanofexy)-3 obtained in (c) above
-[1,1-dimethyl-2-(3-isopropyli
Denhydrazino-6-pyridazinyloxy)
thylamino]-2-propanol (900 mg),
Drazine hydrate (6ml) and ethanol
(30ml) was refluxed for 2 hours. Reduce solvent
After distillation, the product was dissolved in chloroform and water
After washing, it was dried with magnesium sulfate. Remove solvent under vacuum
Dissolve the residue in ethanol and dilute with 2N-
After adding hydrochloric acid (2 ml), the solvent was distilled off under reduced pressure.
Ta. The product was then dissolved in ethanol and precipitated.
The crystals were filtered and 1-(2-cyanophyte
c)-3-[1,1-dimethyl-2-(3-hydro)
Radino-6-pyridazinyloxy)ethylamide
-2-propanol hydrochloride (684mg,
mp184.1-187.6℃) was obtained. NMR(D₂O) δ: 1.59 (6H, singlet), 3.30~
3.58 (2H, multiplet), 4.19~4.60 (3H, multiplet),
4.46 (2H, singlet) 6.98~7.82 (4H, multiplet),
7.33 (2H, singlet). Example 2 (a) 3-(2-amino-2 obtained in Example 1(a) above)
-methylpropoxy)-6-chloropyridazine
(6.04g), 1-(2-chloro-3-methylphenol)
xy)-2,3-epoxypropane (5.95g)
The methanol (120ml) solution was refluxed for 3 hours with stirring.
It flowed. After distilling off the solvent under reduced pressure, the crude product was vented.
Dissolve in ZEN and extract with 0.2N-hydrochloric acid (175ml)
did. The aqueous layer is made alkaline with potassium carbonate,
Extract with chloroform and remove the chloroform layer with sulfuric acid.
Dried with sodium. After distilling off the solvent, the obtained
The oily product (10g) was subjected to column chromatography.
Hui (Florisil 50g: chloroform solution)
1-(2-chloro-3-methyl
phenoxy)-3-[1,1-dimethyl-2-
(3-chloro-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol (7.98g, colorless oil
A similar substance was obtained. NMR (CDCl)₃) δ: 1.22 (6H, singlet), 2.36
(3H, single line), 2.74 (2H, wide single line),
2.79~3,02 (2H, multiple line), 4.00 (3H, wide width)
singlet) 4.32 (2H, singlet), 6.62-7.37
(3H, multiple line) 6.90 (1H, double line, J=9Hz),
7.29 (1H, double line, J=9Hz). (b) 1-(2-chloro-3-methyl obtained in (a) above)
phenoxy)-3-[1,1-dimethyl-2-
(3-chloro-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol (1.4g), Hydra
Zin hydrate (14ml) and ethanol (14ml)
ml) was refluxed under stirring for 5 hours. solvent
After distilling off under reduced pressure, dissolve the product in chloroform.
After washing with water, it was dried with magnesium sulfate. solvent
evaporate under reduced pressure, dissolve the product in acetone, and 30
Let stand at room temperature for a minute to form hydrazone, then dilute
Layer chromatography (silica gel (Merck)
GF₂₅₄), chloroform:methanol = 10:1)
1-(2-chloro-3-methylphenylene)
noxy)-3-[1,1-dimethyl-2-(3-
Isopropylidenehydrazino-6-pyridazine
ruoxy)ethylamino]-2-propanol
(374 mg, yellow oil) was obtained. NMR (CDCl)₃) δ: 1.22 (6H, singlet), 1.92
(3H, singlet), 2.02 (3H, singlet), 2.36 (3H,
singlet), 2.70~3.20 (2H, multiplet) 2.80~3.00
(2H, multiple line), 4,03 (3H, wide single line)
line), 4.23 (2H, single line), 6.60~7.30 (3H, multiline)
double line), 6.88 (1H, double line, J=9Hz), 7.49
(1H, double line, J=9Hz). (C-1) 1-(2-chloro- obtained in (b) above)
3-methylphenoxy)-3-[1,1-dime
Chil-2-(3-isopropylidene hydrazide)
No-6-pyridazinyloxy)ethylamide
-2-propanol (1.12g), hydrazide
hydrate (12ml) and ethanol (24ml)
ml) mixture was refluxed for 1.5 hours. Reduce solvent
After distillation, the product was dissolved in chloroform,
After washing with water, it was dried with magnesium sulfate. solvent
After distilling off, the product is dissolved in ethanol,
After adding 1N hydrochloric acid (12ml), remove the solvent under reduced pressure.
I left. Then dissolve the product in ethanol
After adding 1N hydrochloric acid (12ml), reduce the solvent.
It was distilled off under pressure. The product was then dissolved in ethanol.
The precipitated crystals were filtered and 1-(2-chloro)
rho-3-methylphenoxy)-3-[1,1-
Dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-pro
Panol Hydrochloride (675mg, colorless crystals, mp192
~194°C) was obtained. NMR(D₂O) δ: 1.60 (6H, singlet), 2.30
(3H, singlet), 3.35-3.61 (2H, multiplet),
4.14~4.38 (3H, multiplet), 4.44 (2H, singlet)
line), 6.78-7.47 (3H, multiplet line) 7, 12 (2,
single line). (C-2) 1-(2-chloro- obtained in (a) above)
3-methylphenoxy)-3-[1,1-dime
Chil-2-(3-chloro-6-pyridazinyl
oxy)ethylamino]-2-propanol
(8g), hydrazine hydrate (160ml) and
and ethanol (160 ml) was stirred for 7 hours.
The mixture was refluxed under stirring. After removing the solvent under reduced pressure, the crude product
Dissolve the substance in benzene, extract with 1N hydrochloric acid,
The aqueous layer was then made alkaline with potassium carbonate.
and extracted with chloroform. chloroform layer
After drying with sodium sulfate, the solvent was distilled off under reduced pressure.
A crude product (5.7g) was obtained. This is ethanol
(50ml) and add concentrated hydrochloric acid (8g).
After converting to hydrochloride and removing the solvent under reduced pressure, add ethanol.
It was dissolved in and left in the refrigerator. Precipitated 1
-(2-chloro-3-methylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinyloxy)ethylamino]
- Take 2-propanol hydrochloride and ethanol
colorless crystals (1.03g,
mp192-194℃) was obtained. Example 3 (a) 3-(2-amino-2 obtained in Example 1(a) above)
-methylpropoxy)-6-chloropyridazine
(4.6g) and 1-(2-chloro-5-methylphthalate)
(enoxy)-2,3-epoxypropane (5.0g)
A solution of ethanol (50 ml) was refluxed for 4 hours with stirring.
It flowed. The solvent was distilled off under reduced pressure, and the resulting product
was dissolved in benzene (100ml). 10% of this
After extraction with hydrochloric acid (30ml), 10% sodium hydroxide
Make alkaline with aluminum and then with chloroform.
Extracted and dried over magnesium sulfate. solvent
Column chromatography of the oily product obtained by distillation
Perform Graphi (Florisil, 50g),
The obtained chloroform eluate was concentrated to give 1-
(2-chloro-5-methylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol (5.7 g, colorless oil) was obtained. NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.30
(3H, singlet), 2.75-3.10 (2H, multiplet),
2.92 (2H, wide single line), 4.00 (3H, wide single line)
single line), 4.32 (2H, single line), 6.68 (1H, double line)
Double line, J=6Hz), 6.72 (1H, single line), 6.92
(1H, double line, J=9Hz), 7.17 (1H, double line,
J=6Hz), 7.30 (1H, double line, J=9Hz). (b) 1-(2-chloro-5-methyl obtained in (a) above)
phenoxy)-3-[1,1-dimethyl-2-
(3-chloro-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol (740mg), Hyde
Radine hydrate (15ml) and ethanol
(15 ml) was refluxed under stirring overnight, then reduced.
The solvent was distilled off under pressure to dryness. to the obtained product
After adding acetone (90 ml) and refluxing for 15 minutes,
The solvent was distilled off. Dissolve the residue in dichloromethane.
Dissolve and wash sequentially with 5% sodium carbonate and saline.
and dried with magnesium sulfate. Distill the solvent
The product was then subjected to thin layer chromatography (silica
Gel (Merck GF₂₅₄): chloroform; methano
1-(2-chloro)
-5-methylphenoxy)-3-[1,1-dime
Chil-2-(3-isopropylidenehydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol (252 mg, pale yellow oil)
Obtained. NMR (CD₃CD) δ: 1.21 (6H, singlet),
1.94 (3H, singlet), 2.00 (3H, singlet), 2.28
(3H, singlet) 2.74 to 2.96 (2H, multiplet), 4.00
(3H, wide single line), 4.19 (2H, single line)
6.68 (1H, quartet, J=7Hz, J=1Hz), 6.81
(1H, double line, J=1Hz), 7.16 (1H, double line,
J=7Hz), 6.92 (1H, double line, J=9Hz),
7.42 (1H, double line, J=9Hz), 7.42 (1H, double line
line, J=9Hz). (c) 1-(2-chloro-5-methyl obtained in (a) above)
phenoxy)-3-[1,1-dimethyl-2-
(3-chloro-6-pyridazinyloxy)ethyl
Ruamino] 2-propanol (5.7g), Hydra
Zin hydrate (20ml) and ethanol (20ml)
ml) mixture was refluxed under stirring overnight. solvent
After distillation under reduced pressure, the product was dissolved in benzene (100ml)
and extracted with 10% hydrochloric acid (30ml). Ten%
Make alkaline with sodium hydroxide and
and dried over magnesium sulfate.
Then, the solvent was distilled off and the resulting oily product was evaporated.
Dissolved in ethanol (20ml). 1N-hydrochloric acid (57
ml), remove the solvent under reduced pressure at below 40°C.
After evaporation, the product was washed with ether (100 ml).
Cleaned and dried. Add ethanol to the oily product
After crystallization and collection, further methanol
- recrystallized from ethanol, 1-(2-chloro
-5-methylphenoxy)-3-[1,1-dime
Chil-2-(3-hydrazino-6-pyridazini)
ruoxy)ethylamino]-2-propanol
Hydrochloride (1.21g, pale yellow columnar crystals, mp204.6~
205.7℃). NMR(D₂O) δ: 1.52, 1.55 (6H, two one
double line), 2.29 (3H, single line), 3.30~3.52 (2H,
multiplet), 4.05 to 4.30 (3H, multiplet) 4.40 (2H,
singlet), 6.79 (1H, doublet, J=6Hz), 6.87
(1H, single line), 7.21 (1H, double line, J=6
Hz), 7.17 (2H, singlet). Example 4 (a) 3-(2-amino-2 obtained in Example 1(a) above)
-methylpropoxy)-6-chloropyridazine
(4.83g), 1-[2-(2-methoxyethyl)
Enoxy] 2, 3. Epoxypropane (5.0g)
and ethanol (200ml) for 4 hours.
After heating under reflux, the solvent was distilled off under reduced pressure. obtained
The crude product was dissolved in benzene and diluted with 1N hydrochloric acid.
After extraction, the hydrochloric acid extract was extracted with chloroform.
Ta. Next, wash with 5% sodium carbonate and water.
Afterwards, it was dried with magnesium sulfate and the solvent was distilled off.
1-[2-(2-methoxyethyl)phenox
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol (3.8g) was obtained. NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.30
~2.70 (2H, multiplex), 2.70~3.05 (4H, multiplex)
line), 3.30 (3H, single line), 3.57 (2H, triple line,
J=6Hz), 4.00 (3H, wide single line), 4.33
(2H, singlet), 6.70~7.24 (4H, multiplet),
6.93 (1H, double line, J=9Hz), 7.32 (1H, double line
line, J=9Hz). (b) 1-[2-(2-methoxyethyl) obtained in (a) above
phenoxy]-3-[1,1-dimethyl-2
-(3-chloro-6-pyridazinyloxy)eth
thylamino]-2-propanol (1.8g), hydro
Radine hydrate (15ml) and ethanol
The mixture (30ml) was refluxed under stirring overnight. decrease
The crude product obtained by distilling off the solvent under pressure is
(90ml) and refluxed for 15 minutes. solvent
was distilled off and the oily residue was dissolved in chloroform.
Wash with 5% sodium carbonate and saline in that order.
After that, it was dried with magnesium sulfate. Distill the solvent
The oily crude organisms are then subjected to thin-layer chromatography (silica).
Lycagel (Merck GF₂₅₄):Chloroform:Me
1-[2-(2
-methoxyethyl)phenoxy]-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
]-2-propanol (219 mg, pale yellow oil)
object) was obtained. NMR (CD₃CD) δ: 1.25 (6H, singlet),
1.94, 2.00 (6H, two single lines), 2.50~3.10
(4H, multiplet), 3.29 (3H, singlet), 3.52 (2H,
Triple line, J=6Hz), 3.98 (3H, singlet), 4.20
(3H, single line), 6.98 (1H, double line, J=9
Hz), 7.46 (1H, double line, J=9Hz), 6.66~
7.30 (4H, multiplet). (c) 1-[2-(2-methoxyethyl) obtained in (a) above
phenoxy]-3-[1,1-dimethyl-2
-(3-chloro-6-pyridazinyloxy)eth
thylamino]-2-propanol (2.0g), hydro
Radine hydrate (20ml) and ethanol
The mixture (40ml) was heated to reflux overnight. solvent
After evaporation under reduced pressure, the product was dissolved in chloroform.
Wash with water, then dry with magnesium sulfate and concentrate.
It was evaporated to dryness. Dissolve the obtained oil in ethanol.
After dissolving and adding hydrochloric acid-ether solution, at room temperature.
The solvent was distilled off under reduced pressure. The crude product obtained
Tanol (2 ml) solution in ether (20 ml)
The resulting precipitate was separated by a decanting method to obtain 1-
[2-(2-methoxyethyl)phenoxy]-3
-[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-2
−Propanol hydrochloride (1.0g, mp173.3~174.1
°C) was obtained. NMR(D₂O) δ: 1.58 (6H, singlet), 2.82
(2H, triple line, J=6Hz), 3.23-3.49 (2H, multiline
double line), 3.33 (3H, single line), 3.65 (2H, triple line,
J=7Hz), 3.99-4.35 (3H, multiplet), 4.42
(3H, singlet), 6.80~7.45 (4H, multiplet),
7.28 (2H, single line). The following compounds were prepared by the same method as in Example 2.
The products were synthesized (Example 5 to Example 36). Example 5 (a) 1-(2-chlorophenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
le NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.50
~3.04 (4H, multiplet), 4.00 (3H, wide singlet)
line), 4.33 (2H, single line), 6.70~7.45 (4H, multiline)
Double line, ), 6.90 (1H, double line J = 9Hz), 7.31
(1H, double line, 9Hz). (b) 1-(2-chlorophenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CD₃CD) δ: 1.22 (6H, singlet),
1.94 (3H, singlet), 2.01 (3H, singlet), 2.74
~2.99 (2H, multiplet), 4.04 (3H, wide singlet)
line) 4.19 (2H, single line), 6.70~7.32 (4H, multiple line)
line), 6.95 (1H, double line, J=9Hz), 7.45 (1H,
double line, J=9Hz). (c) 1-(2-chlorophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride mp186.5~188℃ NMR(D₂O) δ: 1.60 (6H, singlet), 3.31,
3.59 (2H, multiplet), 4.15~4.50 (3H, multiplet),
4.46 (2H, multiplet), 6.89~7.56 (4H, multiplet),
7.24 (2H, singlet). Example 6 (a) 1-(3-chlorophenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]2-propanol NMR (CDCl)₃) δ: 1.22 (6H, singlet), 2.48
~3.10 (2H, multiplex), 2.68~2.92 (2H, multiplex
line), 3.95 (3H, wide single line), 4.32 (2H,
singlet), 6.62 to 7.38 (4H, multiplet), 6.95 (1H,
double line, J=9Hz), 7.35 (1H, double line, J=
9Hz). (b) 1-(3-chlorophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride mp150.0~155.0℃ NMR(D₂O) δ: 1.60 (6H, singlet), 3.27~
3.60 (2H, multiplet), 4.02~4.40 (3H, multiplet),
4.46 (2H, singlet), 6.76~7.50 (4H, multiplet),
7.33 (2H singlet). Example 7 (a) 1-(2-promophenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.65
(2H, wide singlet), 2.75 to 2.98 (2H, multiple
line), 3.98 (3H, wide single line), 4.32 (2H,
singlet), 6.65-7.68 (4H, multiplet), 6.91 (1H,
double line, J=9Hz), 7.31 (1H, double line, J=
9Hz). (b) 1-(2-promophenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
2-propanol mp 132.5~134.5℃ NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.92
(3H, singlet), 2.02 (3H, singlet), 2.48~
3.25 (2H, multiplet), 2.78~3.05 (2H, multiplet),
4.00 (3H, wide single line), 4.23 (2H, single line
line), 6.65 to 7.68 (4H, multiple line), 6.88 (1H, double
Double line, J=9Hz), 7.50 (1H, double line, J=9
Hz). (c) 1-(2-promophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride mp 181.0~184.5℃ NMR(D₂O) δ: 1.60 (6H, singlet), 3.35~
3.65 (2H, multiplet), 4.02~4.40 (3H, multiplet),
4.45 (2H, singlet), 6.82~7.72 (4H, multiplet),
7.23 (2H, singlet). Example 8 (a) 1-(3-promophenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
le NMR (CDLl₃) δ: 1.20 (6H, singlet), 2.61
(2H, wide singlet), 2.60 to 2.91 (2H, multiple
line), 3.94 (3H, wide single line), 4.32 (2H,
singlet), 6.70 to 7.20 (4H, multiplet), 6.92 (1H,
double line, J=9Hz), 7.34 (1H, double line, J=
9Hz). (b) 1-(3-bromophenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
lorazino-6-pyridazinyloxy)ethylua
Mino]-2-propanol NMR (CDCl)₃) δ: 1.22 (6H, singlet), 1.92
(3H, single line), 2.02 (3H, single line), 2.60~
3.88 (2H, multiplet), 2.70~2.95 (2H, multiplet),
3.95 (3H, wide single line), 4.22 (2H, single line
line), 6.65 to 7.19 (4H, multiple line), 6.89 (1H, double
Double line, J=9Hz), 7.52 (1H, double line, J=9
Hz). (c) 1-(3-promophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]2-propano
alcohol hydrochloride mp 180.5~183.0℃ NMR(D₂O) δ: 1.55 (6H, singlet), 3.23 ~
3.55 (2H, multiplet), 3.95~4.37 (3H, multiplet),
4.40 (2H, singlet), 6.70~7.45 (4H, multiplet),
7.26 (2H, singlet). Example 9 (a) 1-(2-ethylphenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
le NMR (CDCl)₃) δ: 1.15 (3H, triple line, J=
7Hz), 1.22 (6H, singlet), 2.50~3.20 (2H,
multiplet), 2.60 (2H, quartet, J=7Hz), 2.70
~3.10 (2H, multiplet), 3.98 (3H, wide singlet)
line), 4.32 (2H, single line), 6.66 to 7.35 (4H, multiline)
double line), 6.88 (1H, double line, J=9Hz) 7.29
(1H, double line, J=9Hz). (b) 1-(2-ethylphenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
2-propanol NMR (CDCl)₃) δ: 1.14 (3H, triple line, J=
7Hz), 1.21 (6H, singlet), 1.90 (3H, singlet
line), 2.01 (3H, single line), 2.51~3.15 (2H, multiline)
Double line), 2.60 (2H, quartet, J=7Hz), 2.70~
3.10 (2H, multiple line), 3.98 (3H, wide single line)
line), 4.22 (2H, single line), 6.60~7.32 (4H, multiline)
double line), 6.84 (1H, double line, J=9Hz), 7.49
(1H, double line, J=9Hz). (c) 1-(2-ethylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride NMR(D₂O) δ: 1.10 (3H, triple line, J=7
Hz), 1.57 (6H, singlet), 2.52 (2H, quartet,
J=7Hz), 3.25~3.51 (2H, multiplet), 4.00~
4.55 (3H, multiplet), 4.41 (2H, singlet), 6.75
~7.41 (4H, multiplet), 7.20 (2H, singlet). Example 10 (a) 1-(3-ethylphenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]2-propanol NMR (CDCl)₃) δ: 1.19 (3H, triple line, J=
7Hz), 1.21 (6H, singlet), 2.55-3.10 (2H,
multiplet), 2.59 (2H, quartet, J=7Hz), 2.65
~3.95 (2H, multiplet), 3.95 (3H, wide singlet)
line), 4.32 (2H, single line), 6.53~7.35 (4H, multiline)
double line), 6.89 (1H, double line, J=9Hz), 7.30
(1H, double line, J=9Hz). (b) 1-(3-ethylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride mp 171.5~173.5℃ NMR(D₂O) δ: 1.19 (3H, triple line, J=7
Hz), 1.58 (6H, singlet), 2.61 (2H, quartet,
J=7Hz), 3.20~3.53 (2H, multiplet), 4.02~
4.45 (3H, multiplet), 4.43 (2H, singlet), 6.60
~7.43 (4H, multiplet), 7.28 (2H, singlet). Example 11 (a) 1-(2-propylphenoxy)-3-[1,
1-dimethyl-2-(3-chloro-6-pyrida
Dinyloxy)ethylamino]-2-propano
rule NMR (CDCl)₃) δ: 0.89 (3H, triple line, J=
7Hz), 1.10, 1.93 (2H, multiplet), 1.23 (6H,
singlet), 2.56 (2H, triplet, J=7Hz), 2.66
(2H, wide singlet), 2.70 to 3.10 (2H, multiple
line), 3.97 (3H, wide single line), 4.33 (2H,
singlet), 6.65 to 7.35 (4H, multiplet), 6.91 (1H,
double line, J=9Hz), 7.32 (1H, double line, J=
9Hz). (b) 1-(2-propylphenoxy)-3-[1,
1-dimethyl-2-(3-isopropylidene
Dorazino-6-pyridazinyloxy)ethyla
Mino] 2-propanol NMR (CDCl)₃) δ: 0.88 (3H, triple line, J=
7Hz), 1.10 to 1.82 (2H, multiplet), 1.20 (6H,
single line), 1.90 (3H, single line), 2.01 (3H, single line)
line), 2.56 (2H, single line, J=8Hz), 2.70~
3.35 (2H, multiplet), 2.73 to 3.10 (2H, multiplet),
3.97 (3H, wide single line), 4.23 (2H, single line)
line), 6.65 to 7.35 (4H, multiple line), 6.84 (1H, double
Double line, J=9Hz), 7.49 (1H, double line, J=9
Hz). (c) 1-(2-propylphenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride mp 188.0~189.5℃ NMR(D₂O) δ: 0.86 (3H, triple line, J=7
Hz), 1.10 to 2.00 (2H, multiplet), 1.56 (6H, one
double line), 2.50 (2H, triple line, J=7Hz), 3.19~
3.51 (2H, multiplet), 4.01~4.35 (3H, multiplet),
4.40 (2H, singlet), 6.73~7.46 (4H, multiplet),
7.22 (2H, singlet). Example 12 (a) 1-(2-allylphenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
le NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.52
(2H, wide singlet), 2.70 to 2.92 (2H, multiple
line), 3.34 (2H, double line, J=6Hz), 3.97 (3H,
wide single line), 4.32 (2H, single line), 4.77~
4.96 (1H, multiple line), 5.09 (1H, wide single line)
line), 5.60~6.30 (1H, multiple line), 6.68~7.35
(4H, multiplet), 6.92 (1H, doublet, J=9
Hz), 7.31 (1H, double line, J=9Hz). (b) 1-(2-allylphenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CDCl)₃) δ: 1.19 (6H, singlet), 1.91
(3H, singlet), 2.01 (3H, singlet), 2.47~
3.70 (2H, multiplet), 2.70~2.92 (2H, multiplet),
3.34 (2H, double line, J = 6Hz), 3.96 (3H, width
wide singlet), 4.21 (2H, singlet), 4.72~4.98
(1H, multiplet), 5.08 (1H, wide singlet),
5.60~6.30 (1H, multiple line), 6.67~7.29 (4H, multiple line)
double line), 6.86 (1H, double line, J=9Hz), 7.49
(1H, double line, J=9Hz). (c) 1-(2-allylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dazinyloxy)ethylamino]-2-propa
norl hydrochloride mp 173.5~177.1℃ NMR(D₂O) δ: 1.60 (6H, singlet), 3.18~
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, multiple line), 6.80~7.38 (4H, multiple line)
double line), 7.29 (2H, single line). Example 13 (a) 1-(2-trifluoromethylphenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinyloxy)ethylamino]-2-
propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.70
(2H, wide singlet), 2.78 to 2.96 (2H, multiple
line), 4.02 (3H, wide single line), 4.31 (2H,
Single line), 6.92 (1H, double line, J=9Hz), 6.82
~7.15 (2H, multiplet), 7.31 (1H, doublet, J=
9Hz), 7.30-7.63 (2H, multiplet). (b) 1-(2-trifluoromethylphenoxy)-
3-[1,1-dimethyl-2-(3-isopropylene)
lydenhydrazino-6-pyridazinyloxy)
ethylamino]-2-propanol mp 127~130℃ NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.91
(3H, singlet), 2.01 (3H, singlet), 2.78~
2.97 (2H, multiplet), 3.00~4.00 (2H, multiplet),
4.04 (3H, wide single line), 4.22 (2H, single line)
line), 6.87 (1H, double line, J=9Hz), 6.79~
7.15 (2H, multiplet), 7.23~7.66 (2H, multiplet),
7.49 (1H, double line, J=9Hz). (c) 1-(2-trifluoromethylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol hydrochloride mp 194~196℃ NMR(D₂O) δ: 1.57 (6H, singlet), 3.20 ~
3.45 (2H, multiplet), 4.15~4.55 (3H, multiplet),
4.41 (2H, singlet), 6.95~7.30 (2H, multiplet),
7.34 (2H, singlet), 7.45-7.80 (2H, multiplet). Example 14 (a) 1-[2-(2-ethoxyethyl) phenox
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCl)₃) δ: 1.14 (3H, triple line, J=
7Hz), 1.21 (6H, singlet), 2.57 (2H, singlet
line), 2.72~3,05 (4H, multiple line), 3.27~3.75
(4H, multiplet), 3.98 (3H, multiplet), 4.32 (2H,
singlet), 6.67 to 7.23 (4H, multiplet), 6.92 (1H,
double line, J=9Hz), 7.33(1H, double line, J=
9Hz). (b) 1-[2-(2-ethoxyethyl)phenox
[C]-3-[1,1-dimethyl-2-(3-hydro
Radino-6-pyridazinyloxy)ethylamide
-2-propanol hydrochloride NMR (CD₃OD) δ: 1.14 (3H, triple line, J
=7Hz), 1.57 (6H, singlet), 2.86 (2H, triple
line, J=6Hz), 3.10-3.78 (6H, multiple line),
3.90~4.35 (3H, multiplet), 4.44 (2H, singlet),
6.70-7.35 (4H, multiplet), 7.45 (2H, singlet). Example 15 (a) 1-[2-(2-allyloxyethyl)pheno
xy]-3-[1,1-dimethyl-2-(3-k
Lolo-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.20
~2.75 (2H, multiplex), 2.72~3.17 (4H, multiplex
line), 3.62 (2H, triple line, J=6Hz), 3.85~
4.25 (2H, multiple line), 3.98 (3H, wide single line)
line), 4.33 (2H, single line), 4.95 to 5.40 (2H, multiline)
multiplet), 5.45 to 6.40 (1H, multiplet), 6.70 to 7.37
(4H, multiplet), 6.92 (1H, doublet, J=9
Hz), 7.32 (1H, double line, J=9Hz). (b) 1-[2-(2-allyloxyethyl)pheno
xy]-3-[1,1-dimethyl-2-(3-y
Sopropylidenehydrazino-6-pyridazinyl
oxy)ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.91
(3H, single line), 2.02 (3H, single line), 2.50~
3.15 (2H, multiplet), 2.72~3.10 (4H, multiplet),
3.62 (2H, triple line, J=6Hz), 3.80-4.18
(2H, multiplet), 3.99 (3H, wide singlet),
4.23 (2H, singlet), 4.95~5.41 (2H, multiplet),
5.55 to 6.30 (1H, multiple line), 6.69 to 7.40 (4H, multiple line)
double line) 6.88 (1H, double line, J=9Hz), 7.50
(1H, double line, J=9Hz). Example 16 (a) 1-[2-(2-tetrahydrofurfuryloxy)
ethyl) phenoxy]-3-[1,1-dimethy
-2-(3-chloro-6-pyridazinyloxy)
c) Ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.38
~2.20 (4H, multiplet), 2.66 (2H, wide singlet)
line), 2.68 to 3.10 (4H, multiplet line), 3.49 (2H, double line),
Multiple line, J=5Hz), 3.60-4.23 (3H, multiple line),
3.77 (2H, triple line, J=7Hz), 3.97 (3H, width
wide singlet), 4.32 (2H, singlet), 6.65~7.35
(4H, multiplet), 6.93 (1H, doublet, J=9
Hz), 7.32 (1H, double line, J=9Hz). (b) 1-[2-(2-tetrahydrofurfuryloxy)
ethyl) phenoxy]-3-[1,1-dimethy
Ru-2-(3-isopropylidenehydrazino-
6-pyridazinyloxy)ethylamino]-2
-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.45
~2.15 (4H, multiplet), 1.91 (3H, singlet),
2.02 (3H, singlet), 2.45~3.20 (2H, multiplet),
2.60~3.14 (4H, multiplet), 3.41 (2H, doublet,
J=5Hz), 3.52-4.17 (3H, multiplet), 3.57
(2H, triple line, J=7Hz), 3.97 (3H, wide width
singlet), 4.23 (2H, singlet), 6.60-7.45
(4H, multiplet), 6.89 (1H, doublet, J=9
Hz), 7.50 (1H, double line, J=9Hz). (c) 1-[2-(2-tetrahydrofurfuryloxy)
ethyl) phenoxy]-3-[1,1-dimethy
-2-(3-hydrazino-6-pyridazinyl)
oxy)ethylamino]-2-propanol salt
acid salt mp 168.0~171.0℃ NMR(D₂O) δ: 1.40~2.20 (4H, multiplet),
1.56 (6H, single line), 2.85 (2H, triple line, J=7
Hz), 3.20~4.01 (9H, multiplet), 4.01~4.40
(3H, multiplet), 4.42 (2H, singlet), 6.65 ~
7.55 (4H, multiplet), 7.24 (2H, singlet). Example 17 (a) 1-[2-(2-hydroxyethyl) phenox
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCl)₃) δ: 1.22 (6H, singlet), 2.50
~3.28 (4H, multiplet), 3.11 (2H, singlet),
3.43 (1H, single line), 3.77 (2H, triple line, J=7
Hz), 3.98 (3H, wide single line), 4.32 (2H,
singlet), 6.63 to 7.37 (4H, multiplet), 6.95 (1H,
double line, J=9Hz), 7.32 (1H, double line, J=
9Hz). (b) 1-[2-(2-hydroxyethyl)phenox
[C]-3-[1,1-dimethyl-2-(3-iso
Propylidenehydrazino-6-pyridazinyl
xy)ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.90
(3H, singlet), 2.01 (3H, singlet), 2.43~
3.24 (3H, multiplet), 2.55~3.15 (4H, multiplet),
3.78 (2H, triple line, J=7Hz), 3.97 (3H, width
wide singlet), 4.26 (2H, singlet), 6.67~7.37
(4H, multiplet), 6.90 (1H, doublet, J=9
Hz), 7.50 (1H, double line, J=9Hz). Example 18 (a) 1-[2-(3-hydroxypropyl)pheno
xy]-3-[1,1-dimethyl-2-(3-k
Lolo-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CDCl)₃) δ: 1.22 (6H, singlet), 1.51
~2.10 (2H, multiplex), 2.50~3.10 (4H, multiplex)
line), 2.88 (3H, wide single line), 3.57 (2H,
Triple line, J=6Hz), 3.98 (3H, wide single line)
line), 4.33 (2H, single line), 6.67~7.36 (4H, multiline)
double line), 6.94 (1H, double line, J=9Hz), 7.34
(1H, double line, J=9Hz). (b) 1-[2-(3-hydroxypropyl)pheno
xy]-3-[1,1-dimethyl-2-(3-y
Sopropylidenehydrazino-6-pyridazinyl
oxy)ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.50
~2.09 (2H, multiplet), 1.91 (3H, singlet),
2.02 (3H, singlet), 2.50~3.00 (4H, multiplet),
3.00~3.45 (3H, multiplet), 3.56 (2H, triplet,
J=6Hz), 3.98 (3H, wide single line), 4.22
(2H, singlet), 6.55-7.35 (4H, multiplet),
6.88 (1H, double line, J=9Hz), 7.51 (1H, double line
line, J=9Hz). Example 19 (a) 1-[2-(4-methoxybutyl) phenox
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.35
~2.00 (4H, multiplex), 2.30~3.15 (4H, multiplex)
line), 2.87 (2H, wide single line), 3.15-3.56
(2H, multiplet), 3.29 (3H, singlet), 3.97 (3H,
wide single line), 4.32 (2H, single line), 6.60~
7.35 (4H, multiplet), 6.89 (1H, doublet, J=9
Hz), 7.30 (1H, double line, J=9Hz). (b) 1-[2-(4-methoxybutyl)phenox
[C]-3-[1,1-dimethyl-2-(3-iso
Propylidenehydrazino-6-pyridazinyl
xy)ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.28 (6H, singlet), 1.40
~1.85 (4H, multiplet), 1.92 (3H, singlet),
2.02 (3H, singlet), 2.35~3.19 (4H, multiplet),
3.20~3.83 (4H, multiplet), 3.29 (3H, singlet),
3.99 (3H, wide single line), 4.29 (2H, single line)
line), 6.65 to 7.40 (4H, multiple line), 6.95 (1H, double
Double line, J=9Hz), 7.51 (1H, double line, J=9
Hz). Example 20 (a) 1-[2-(2-methylthioethyl)phenox
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCl)₃) δ: 1.24 (6H, singlet), 2.08
(3H, singlet), 2.48~3.02 (6H, multiplet),
2.80 (2H, wide single line), 3.98 (3H, wide single line)
singlet), 4.34 (2H, singlet), 6.68-7.35
(4H, multiplet), 6.93 (1H, doublet, J=9
Hz), 7.32 (1H, double line, J=9Hz). (b) 1-[2-(2-methylthioethyl)phenoxyx
[C]-3-[1,1-dimethyl-2-(3-iso
Propylidenehydrazino-6-pyridazinyl
xy)ethylamino]-2-propanol NMR (CD₃OD) δ: 1.21 (6H, singlet),
1.92 (3H, singlet), 2.00 (3H, singlet), 2.03
(3H, singlet), 2.38-3.17 (6H, multiplet),
3.96 (3H, wide single line), 4.17 (2H, single line
line), 6.72 to 7.34 (4H, multiple line), 6.96 (1H, double
Double line, J=9Hz), 7.43 (1H, double line, J=9
Hz). (c) 1-[2-(2-methylthioethyl)phenox
[C]-3-[1,1-dimethyl-2-(3-hydro
Radino-6-pyridazinyloxy)ethylamide
-2-propanol hydrochloride NMR (CD₃CO) δ: 1.54 (6H, singlet),
2.03 (3H, singlet), 2.42~2.88 (4H, multiplet),
3.20 to 3.43 (2H, multiple line), 3.93 to 4.28 (3H, multiple line)
double line), 4.43 (2H, single line), 6.61~7.23 (4H,
multiplet), 7.27 (2H, singlet). Example 21 (a) 1-[2-(2-ethylthioethyl) phenox
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCl)₃) δ: 1.23 (3H, triple line, J=
7Hz), 1.23 (6H, singlet), 2.55 (2H, quartet,
J=7Hz), 2.56~2.72 (2H, multiplet), 2.67~
3.13 (6H, multiplet), 3.98 (3H, singlet), 4.32
(2H, singlet), 6.67-7.23 (4H, multiplet),
6.92 (1H, double line, J=9Hz), 7.32 (1H, double line
line, J=9Hz). (b) 1-[2-(2-ethylthioethyl) phenox
[C]-3-[1,1-dimethyl-2-(3-iso
Propylidenehydrazino-6-pyridazinyl
xy)ethylamino]-2-propanol NMR (CD₃OD) δ: 1.18 (3H, triple line J=
7Hz), 1.22 (6H, singlet), 1.92 (3H, singlet
line), 1.98 (3H, singlet), 2.48 (2H, quartet,
J=7Hz), 2.54-3.10 (6H, multiplet), 3.98
(3H, wide single line), 4.18 (2H, single line),
6.62~7.30 (4H, multiplet,), 6.98 (1H, doublet,
J=9Hz), 7.45 (1H, double line, J=9Hz). (c) 1-[2-(2-ethylthioethyl) phenox
[C]-3-[1,1-dimethyl-2-(3-hydro
Radino-6-pyridazinyloxy)ethylamide
-2-propanol hydrochloride mp 181.6~182.5℃ NMR (CD₃OD) δ: 1.18 (3H, triple line, J
=7Hz), 1.55 (6H, singlet), 2.49 (2H, quadruple
line, J=7Hz), 2.52-3.07 (6H, multiple line),
3.90~4.40 (4H, multiplet), 4.42 (2H, singlet),
6.66-7.33 (4H, multiplet), 7.43 (2H, singlet). Example 22 (a) 1-[2-(2-acetylaminoethyl)phene
[noxy]-3-[1,1-dimethyl-2-(3-
Chloro-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.93
(3H, singlet), 2.60~3.18 (4H, multiplet),
2.80 (2H, wide single line), 3.18~3.69 (2H,
multiplet), 4.00 (3H, wide singlet), 4.34
(2H, singlet), 5.98~6.40 (1H, multiplet),
6.69~7.38 (4H, multiplet), 6.97 (1H, doublet,
J=9Hz), 7.35 (1H, double line, J=9Hz). (b) 1-[2-(2acetylaminoethyl)pheno
xy]-3-[1,1-dimethyl-2-(3-y
Sopropylidenehydrazino-6-pyridazinyl
oxy)ethylamino]-2-propanol NMR (CD₃OD) δ: 1.25 (6H, singlet),
1.88 (3H, singlet), 1.95 (3H, singlet), 2.02
(3H, singlet), 2.60~3.04 (4H, multiplet),
3.28 to 3.42 (2H, multiple line), 4.00 (3H, wide
singlet), 4.20 (2H, singlet), 6.68~7.26 (4H,
multiplet), 6.99 (1H, doublet, J=9Hz), 7.48
(1H, double line, J=9Hz). (c) 1-[2-(2-acetylaminoethyl)phene
[noxy]-3-[1,1-dimethyl-2-(3-
hydrazino-6-pyridazinyloxy)ethyl
Amino]-2-propanol hydrochloride NMR (CD₃OD) δ: 1.56 (6H, singlet),
2.08 (3H, single line), 2.80 (2H, triple line, J=8
Hz), 3.18~3.61 (4H, multiplet), 3.96~4.22
(3H, multiplet), 4.44 (2H, singlet), 6.80 ~
7.30 (4H, multiplet), 7.45 (2H, singlet). Example 23 (a) 1-(2-ethoxyphenoxy)-3-[1,
1-dimethyl-2-(3-chloro-6-pyrida
Dinyloxy)ethylamino]-2-propano
rule NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.38
(3H, triple line, J=7Hz), 2.62~2.78 (2H, multiline
double line), 2.68 (2H, wide single line), 3.98 (3H,
wide single line), 4.04 (2H, quadruple line, J=7
Hz), 4.32 (2H, singlet), 6.88 (4H, singlet),
6.91 (1H, double line, J=9Hz), 7.31 (1H, double line
line, J=9Hz). (b) 1-(2-ethoxyphenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride NMR (CD₃OD) δ: 1.38 (3H, triple line, J
=7Hz), 1.57 (6H, singlet), 3.23~3.55 (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). Example 24 (a) 1-(3-ethoxyphenoxy)-3-[1,
1-dimethyl-2-(3-chloro-6-pyrida
Dinyloxy)ethylamino]-2-propano
rule NMR (CDCl)₃) δ: 1.19 (6H, singlet), 1.37
(3H, triple line, J=7Hz), 2.56 (2H, wide width
singlet), 2.64 to 2.92 (2H, multiplet), 3.93
(3H, wide singlet), 3.97 (2H, quartet,
J=7Hz), 4.30 (2H, singlet), 6.32-6.59
(3H, multiplet), 6.90 (1H, doublet, J=9
Hz), 6.98 to 7.22 (1H, multiplet), 7.31 (1H, double
double line, J=9Hz). (b) 1-(3-ethoxyphenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride NMR (CD₃OD) δ: 1.34 (3H, triple line, J
=7Hz), 1.56 (6H, singlet), 3.20~3.52 (2H,
multiplet), 3.97 (2H, quartet, J=7Hz), 3.92
~4.32 (3H, multiplet), 4.43 (2H, singlet),
6.39 to 6.69 (3H, multiple line), 6.95 to 7.32 (1H, multiple line)
double line), 7.44 (2H, single line). Example 25 (a) 1-(2-benzyloxyphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ: 1.15 (6H, singlet), 2.50
~3.10 (2H, multiplet), 2.80 (2H, wide singlet)
line), 4.00 (3H, wide single line), 4.28 (2H,
singlet), 5.06 (2H, singlet), 6.87 (1H, double
line, J=9Hz), 6.90 (4H, single line), 7.32 (1H,
Double line, J = 9Hz), 7.34 (5H, wide single line)
line). (b) 1-(2-benzyloxyphenoxy)-3-
[1,1-dimethyl-2-(3-isopropylide)
hydrazino-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol NMR (CDCl)₃) δ: 1.16 (6H, singlet), 1.90
(3H, single line), 2.01 (3H, single line), 2.50 ~
3.55 (2H, multiplet), 2.69~2.91 (2H, multiplet),
4.01 (3H, wide single line), 4.20 (2H, single line
line), 5.06 (2H, single line), 6.83 (1H, double line,
J=9Hz), 6.90 (4H, single line), 7.35 (5H, width
wide single line), 7.47 (1H, double line, J=9
Hz). (c) 1-(2-benzyloxyphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propanol hydrochloride mp 174~176℃ NMR(D₂O) δ: 1.43 (6H, singlet), 3.23~
3.50 (2H, multiplet), 4.04~4.28 (3H, multiplet),
4.32 (2H, singlet), 5.09 (2H, singlet), 7.03
(4H, singlet), 7.17 (2H, singlet), 7.44 (5H,
single line). Example 26 1-(2-hydroxyphenoxy)-3-[1,
1-dimethyl-2-(3-isopropylidene
Dorazino-6-pyridazinyloxy)ethyla
Mino]-2-propanol NMR (CDCl)₃) δ: 1.17 (6H, singlet), 1.89
(3H, singlet), 2.00 (3H, singlet), 2.68~3.02
(2H, multiplet), 4.00 (3H, wide singlet),
4.23 (2H, singlet), 4.94~6.03 (3H, multiplet),
6.83 (4H, wide single line), 6.87 (1H, double line,
J=9Hz), 7.50 (1H, double line, J=9Hz). Example 27 1-(2-furfuryloxyphenoxy)3-
[1,1-dimethyl-2-(3-isopropylide)
hydrazino-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol NMR (CDCl)₃) δ: 1.17 (6H, singlet), 1.90
(3H, singlet), 2.01 (3H, singlet), 2.53~3.31
(2H, multiplet), 2.70 to 2.91 (2H, multiplet), 3.99
(3H, wide single line), 4.20 (2H, single line),
4.98 (2H, singlet), 6.20~6.47 (2H, multiplet),
6.85 (1H, double line, J=9Hz), 6.92 (4H, single line
line), 7.30 to 7.56 (1H, multiple line), 7.47 (1H, double line)
line, J=9Hz). Example 28 (a) 1-(2-methoxymethoxyphenoxy)-3
-[1,1-dimethyl-2-(3-chloro-6-
pyridazinyloxy)ethylamino]-2-p
Lopanol NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.29
~2.95 (2H, multiplex), 2.50~4.00 (2H, multiplex)
line), 2.99 (2H, wide single line), 3.47 (3H,
single line), 4.00 (3H, wide single line), 4.32
(2H, singlet), 5.13 (2H, singlet), 6.71~
7.31 (4H, multiplet), 6.92 (1H, doublet, J=9
Hz), 7.32 (1H, double line, J=9Hz). (b) 1-(2-methoxymethoxyphenoxy)-3
-[1,1-dimethyl-2-(3-isopropyli
Denhydrazino-6-pyridazinyloxy)
thylamino]-2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.91
(3H, single line), 2.01 (3H, single line), 2.50 ~
4.00 (2H, multiplet), 2.70~3.10 (2H, multiplet),
3.47 (3H, single line), 4.02 (3H, wide single line)
line), 4.22 (2H, single line), 5.14 (2H, single line),
6.71~7.45 (4H, multiplet), 6.91 (1H, doublet,
J=9Hz), 7.50 (1H, two wires, J=9Hz). Example 29 (a) 1-[2-(2-methoxyethoxy) phenolium
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCI)₃) δ: 1.19 (6H, singlet), 2.50
~2.98 (2H, multiplex), 2.64~2.85 (2H, multiplex
line), 3.42 (3H, single line), 3.60 to 3.90 (2H, multiline)
multiplet), 3.90 to 4.27 (5H, multiplet), 4.31 (2H,
singlet), 6.90 (4H, singlet), 6.92 (1H, double
line, J=9Hz), 7.32 (1H, multiple line, J=9
Hz). (b) 1-[2-(2-methoxyethoxy)phenoxyx
[C]-3-[1,1-dimethyl-2-(3-iso
Propylidenehydrazino-6-pyridazinyl
xy)ethylamino]-2-propanol NMR (CD₃OD) δ: 1.23 (6H, singlet),
1.93 (3H, singlet), 2.00 (3H, singlet), 2.58
~3.08 (2H, multiplet), 3.38 (3H, singlet),
3.56 to 3.80 (2H, multiple line), 3.85 to 4.12 (5H, multiple line)
double line), 4.18 (2H, single line), 6.89 (4H, single line)
line), 6.98 (1H, double line, J=9Hz), 7.44 (1H,
double line, J=9Hz). (c) 1-[2-(2-methoxyethoxy) phenolium
[C]-3-[1,1-dimethyl-2-(3-hydro
Radino-6-pyridazinyloxy)ethylamide
-2-propanol hydrochloride NMR(D₂O) δ: 1.58 (6H, singlet), 3.38
(2H, single line), 3.45 (3H, single line), 3.20 ~
3.45 (2H, multiplet), 4.05~4.32 (5H, multiplet),
4.43 (2H, singlet), 7.00 (4H, singlet), 7.22
(2H, single line). Example 30 (a) 1-(3,5-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.28
(6H, single line), 2.48 (2H, wide single line),
2.64 to 2.88 (2H, multiplet), 3.93 (3H, wide
singlet), 4.32 (2H, singlet), 6.45~6.70 (3H,
multiplet), 6.92 (1H, doublet, J=9Hz), 7.31
(1H, double line, J=9Hz). (b) 1-(3,5-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propano Hydrochloride mp 181.4~183.0℃ NMR(D₂O) 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)
singlet), 7.20 (2H, singlet). Example 31 (a) 1-(2,3-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.08
(3H, singlet), 2.23 (3H, singlet), 2.57 (2H,
wide singlet), 2.72 to 3.05 (2H, multiplet),
3.95 (3H, wide single line), 4.32 (2H, single line
line), 6.54 to 7.18 (3H, multiple line), 6.88 (1H, double
Double line, J=9Hz), 7.30 (1H, double line, J=9
Hz). (b) 1-(2,3-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-isopropylide)
hydrazino-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol NMR (CD₃OD) δ: 1.23 (6H, singlet),
1.95 (3H, singlet), 2.02 (3H, singlet), 2.08
(3H, single line), 2.20 (3H, single line), 2.60~
3.06 (2H, multiple line), 3.95 (3H, wide single line)
line), 4.18 (2H, single line), 6.55 to 7.15 (3H, multiline)
double line), 6.88 (1H, double line, J=9Hz), 7.41
(1H, double line, J=9Hz). (c) 1-(2,3-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propanol hydrochloride mp 189.2~190.4℃ NMR(D₂O) δ: 1.55 (6H, singlet), 2.00
(3H, singlet), 2.19 (3H, singlet), 3.27~
3.55 (2H, multiplet), 3.98~4.27 (3H, multiplet),
4.38 (2H, singlet), 6.60~7.22 (3H, multiplet),
7.04 (2H, single line). Example 32 1-(3,5-dichlorophenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride NMR (CD₃OD) δ: 1.56 (6H, singlet), 3.20
~3.50 (2H, multiplet), 3.96 ~ 4.30 (3H, multiplet),
4.43 (2H, singlet), 6.95 (3H, singlet), 7.48
(2H, single line). Example 33 1-(2,3-dichlorophenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride NMR (CD₃OD) δ: 1.57 (6H, singlet), 3.25
~3.50 (2H, multiplet), 4.00 ~ 4.41 (3H, multiplet),
4.42 (2H, singlet), 6.92~7.38 (3H, multiplet),
7.42 (2H, singlet). Example 34 1-(2,5-dichlorophenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride NMR (CD₃OD) δ: 1.54 (6H, singlet), 3.23
~3.50 (2H, multiplet), 3.98 ~ 4.38 (3H, multiplet),
4.42 (2H, singlet), 6.94 (1H, quartet, J=8
Hz, 2Hz), 7.12 (1H, double line, J=2Hz), 7.32
(1H, double line, J=8Hz), 7.44 (2H, single line). Example 35 (a) 1-(3-chloro-2-methylphenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinyloxy)ethylamino]-2-
propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.22
(3H, single line), 2.60 (2H, wide single line),
2.72 to 2.96 (2H, multiple line), 3.95 (3H, wide
singlet), 4.31 (2H, singlet), 6.58~7.10 (3H,
multiplet), 6.88 (1H, doublet, J=9Hz), 7.31
(1H, double line, J=9Hz). (b) 1-(3-chloro-2-methylphenoxy)
3-[1,1-dimethyl-2-(3-isopropylene)
lydenhydrazino-6-pyridazinyloxy)
ethylamino]-2-propanol mp 117.5~120.0℃ NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.92
(3H, singlet), 2.03 (3H, singlet), 2.24 (3H,
singlet), 2.70 to 3.12 (2H, multiplet), 2.75 to 2.98
(2H, multiplet), 3.97 (3H, wide singlet),
4.23 (2H, singlet), 6.60~7.29 (3H, multiplet),
6.88 (1H, double line, J=9Hz), 7.49 (1H, double line
line, J=9Hz). (c) 1-(3-chloro-2-methylphenoxy)
3-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol hydrochloride mp 178.0~181.0℃ NMR(D₂O) 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),
6.75-7.25 (3H, multiplet), 7.07 (2H, singlet). Example 36 (a) 1-(2-allyloxyphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.68
~2.89 (2H, multiplet), 2.72 (2H, wide singlet)
line), 3.98 (3H, wide single line), 4.30 (2H,
singlet), 4.42 to 4.65 (2H, multiplet), 5.05 to 5.60
(2H, multiplet), 5.61~6.40 (1H, multiplet),
6.87 (4H, single line), 6.90 (1H, double line, J=9
Hz), 7.30 (1H, double line, J=9Hz). (b) 1-(2-allyloxyphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propanol hydrochloride mp 164.8~166.4℃ NMR(D₂O) δ: 1.58 (6H, singlet), 3.27~
3.57 (2H, multiplet), 4.02~4.37 (3H, multiplet),
4.43 (2H, singlet), 4.50~4.70 (2H, multiplet),
5.20~5.69 (2H, multiple line), 5.72~6.50 (1H, multiple line)
double line), 7.00 (4H, single line), 7.22 (2H, single line)
line). Example 37 (a) 61% sodium hydride (1.5 g) in benzene
(40ml) of 2-amino-1-propanol in the suspension.
(2.5 g) was added dropwise at room temperature, then 3,6-di
Chloropyridazine (5g) in benzene (15ml)
The solution was added and refluxed for 1 hour. After cooling, the reaction solution
It was washed with water and dried with magnesium sulfate. solvent
After distillation, the resulting product was dissolved in hydrochloric acid-ether solution.
Separate the precipitate and collect 3-(2-aminopropoxy)
-6-chloropyridazine hydrochloride (2.31g) was obtained.
Ta. NMR(D₂O) δ: 1.50 (3H, double line, J=7
Hz), 3.36 to 4.24 (1H, multiplet), 4.56 (2H, double
Double line, J=6Hz), 7.37 (1H, double line, J=9
Hz), 7.68 (1H, double line J = 9Hz). (b) 3-(2-aminopropoxy)- obtained in (a) above
6-chloropyridazine (1.3g), 1-(2-cya)
nophenoxy)-2,3-epoxypropane
(1g) in methanol (20ml) in Example 1(b)
1-(2-Cyanophenophylla)
C-3-[1-methyl-2-(3-chloro-6-
pyridazinyloxy)ethylamino]-2-p
Lopanol (1.01g) was obtained. NMR (CDCl)₃) δ: 1.20 (3H, double line, J=
6.5Hz), 2.76 (2H, wide single line), 2.87~
3.46 (3H, multiple line), 4.09 (3H, wide single line)
line), 4.41 (2H, double line, J=5Hz), 6.83~
7.70 (4H, multiple line), 6.99 (1H, double line, J=9
Hz), 7.37 (1H, double line, J=9Hz). (c) 1-(2-cyanophenoxy)- obtained in (b) above
3-[1-methyl-2-(3-chloro-6-pyri
dadinyloxy)ethylamino]-2-propa
Nol (1.05g), Hydrazine Hydrate (20
ml) and ethanol (10 ml).
The same procedure as in Example 1(c) was used to obtain 1-(2-cyanof
enoxy)-3-[1-methyl-2-(3-iso
Propylidenehydrazino-6-pyridazinyl
xy)ethylamino]-2-propanol (320
mg, mp 121-123°C). NMR (CDCl)₃) δ: 1.17 (3H, doublet, J=
6Hz), 1.90 (3H, singlet), 2.01 (3H, singlet
line), 2.60 to 3.90 (2H, multiplet line), 2.81 to 3.40
(3H, multiplet), 4.08 (3H, wide singlet),
4.29 (2H, singlet, J=6Hz), 6.70-7.70
(4H, multiplet), 6.90 (1H, doublet, J=9
Hz), 7.50 (1H, double line, J=9Hz). Example 38 The following compound was obtained in the same manner as in Example 37. (a) 1-(2-methylphenoxy)-3-[1-methyl
Chil-2-(3-chloro-6-pyridazinyl)
xy)ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.18 (3H, doublet, J=
6.5Hz), 2.20 (3H, single line), 2.58 (2H, wide
singlet), 2.80 to 3.47 (3H, multiplet), 3.99
(3H, wide single line), 4.40 (2H, double line,
J=6Hz), 6.65-7.35 (4H, multiplet), 6.90
(1H, double line, J=9Hz), 7.31 (1H, double line,
J=9Hz). (b) 1-(2-methylphenoxy)-3-[1-methyl
Chil-2-(3-isopropylidenehydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol NMR (CDCl)₃) δ: 1.16 (3H, doublet, J=
6.5Hz), 1.90 (3H, single line), 2.01 (3H, single line)
line), 2.21 (3H, single line), 2.40~3.50 (2H, multiline)
multiplet), 2.53 to 3.46 (3H, multiplet), 3.99 (3H,
wide single line), 4.30 (2H, double line, J=6
Hz), 6.65 to 7.36 (4H, multiplet), 6.85 (1H, double
Double line, J=9Hz), 7.49 (1H, double line, J=9
Hz). Example 39 The following compound was obtained in the same manner as in Example 37. (a) 1-(2-chloro-3-methylphenoxy)-
3-[1-methyl-2-(3-chloro-6-pyri
dadinyloxy)ethylamino]-2-propa
Knoll NMR (CDCl)₃) δ: 1.21 (3H, doublet, J=
7Hz), 2.38 (3H, singlet), 2.83 (2H, singlet
line), 2.89 to 3.48 (3H, multiple line), 4.04 (3H, width
wide single line), 4.42 (2H, double line, J=6
Hz), 6.60 to 7.15 (3H, multiplet), 6.93 (1H, double
Double line, J=9Hz), 7.32 (1H, double line, J=9
Hz). (b) 1-(2-chloro-3-methylphenoxy)-
3-[1-methyl-2-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
2-propanol mp 131.5~133.5℃ NMR (CDCl)₃) δ: 1.14, 1.19 (3H, two sets of
Double line, J=7Hz), 1.92 (3H, single line), 2.02
(3H, singlet), 2.38 (3H, singlet), 2.62~
3.50 (2H, multiplet), 2.88~3.78 (3H, multiplet),
4.05 (3H, wide single line), 4.34 (2H, double line)
line, J=6Hz), 6.62-7.23 (3H, multiple line),
6.88 (1H, double line, J=9Hz), 7.50 (1H, double line
line, J=9Hz). (c) 1-(2-chloro-3-methylphenoxy)-
3-[1-methyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]2-pro
Panol hydrochloride mp 168.0~171.5℃ NMR(D₂O) δ: 1.55, 1.58 (3H, two sets of two
Double line, J=7Hz), 2.35 (3H, single line), 3.48~
3.70 (3H, multiplet), 4.15~4.39 (3H, multiplet),
4.40~4.70 (2H, multiple line), 6.74~7.50 (5H, multiple line)
heavy line). Example 40 (a) 61% sodium hydride (4.2 g) in benzene
(100ml) 2-aminoethanol to the suspension
(6.2g) was added dropwise at room temperature, then 3.6-dichloro
Pyridazine (15 g) was added and the mixture was refluxed for 1 hour. cold
After that, the reaction solution was washed with water and dried with magnesium sulfate.
did. After distilling off the solvent, dissolve in hydrochloric acid-ether solution.
The crystalline 3-(2-aminoethoxy)-6-
Chloropyridazine hydrochloride (5.73g) was obtained. NMR(D₂O) δ: 3.56 (2H, triple line, J=5
Hz), 4.71 (2H, triple line, J=5Hz), 7.35 (1H,
double line, J=9Hz), 7.77 (1H, double line, J=
9Hz). (b) 3-(2-aminoenoxy)-6 obtained in (a) above
-Chloropyridazine (1.75g) and 1-(2-cya)
nophenoxy)-2,3-epoxypropane
(800 mg) in ethanol (10 ml) in Example 1
1-(2-cyanophenol) was treated in the same manner as in (b).
xy)-3-[2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
(862 mg) was obtained. NMR (CDCl)₃) δ: 2.90 (2H, wide single layer
line), 2.96 (2H, double line, J=5Hz), 3.10 (2H,
triple line, J=6Hz), 4.11 (3H, wide single line
line), 4.59 (2H, triple line, J=6Hz), 6.81~
7.70 (4H, multiple line), 6.97 (1H, double line, J=9
Hz), 7.35 (1H, double line, J=9Hz). (c) 1-(2-cyanophenoxy)- obtained in (b) above
3-[2-(3-chloro-6-pyridazinyloxy)
c) Ethylamino]-2-propanol
(1.2g), hydrazine hydrate (6ml) and
A mixture of ethanol (12 ml) was prepared from Example 1(c) and
In the same manner, 1-(2-cyanophenoxy)
-3-[2-(3-isopropylidenehydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol (201 mg) was obtained. NMR (CDCl)₃) δ: 1.59 (3H, singlet), 2.05
(3H, singlet), 2.85-3.40 (2H, multiplet),
3.03 (2H, double line, J=5Hz), 3.12 (2H, Mie
line, J=6Hz), 4.15 (3H, wide single line),
4.52 (2H, triple line, J=6Hz), 6.78-7.70
(4H, multiplet), 6.88 (1H, doublet, J=9Hz)
7.50 (1H, double line, J=9Hz). Example 41 The following compound was obtained in the same manner as in Example 40. (a) 1-(2-methylphenoxy)-3-[2-(3
-chloro-6-pyridazinyloxy)ethyl a
Mino]-2-propanol NMR (CDCl)₃) δ: 2.23 (3H, singlet), 2.60
(2H, wide single line), 2.94 (2H, double line,
J=5Hz), 3.09 (2H, triple line, J=6Hz),
4.01 (3H, wide single line), 4.60 (2H, triple line)
line, J=6Hz), 6.66-7.32 (4H, multiple line),
6.91 (1H, double line, J=9Hz), 7.32 (1H, double line
line, J=9Hz). (b) 1-(2-methylphenoxy)-3-[2-(3
-isopropylidenehydrazino-6-pyridazi
Nyloxy)ethylamino]-2-propano
le NMR (CDCl)₃) δ: 1.92 (3H, singlet), 2.03
(3H, singlet), 2.22 (3H, singlet), 2.58~
3.35 (2H, multiplet), 2.93 (2H, doublet, J=5
Hz), 3.07 (2H, double line, J=6Hz), 4.01 (3H,
wide single line), 4.50 (2H, triple line, J=6
Hz), 6.60 to 7.30 (4H, multiplet), 6.87 (1H, double
Double line, J=9Hz), 7.50 (1H, double line, J=9
Hz). Example 42 The following compound was obtained in the same manner as in Example 40. (a) 1-[2-(2-methoxyethyl) phenox
[C]-3-[2-(3-chloro-6-pyridazine
ruoxy)ethylamino]-2-propanol NMR (CDCl)₃) δ: 2.65 ~ 3.25 (6H, multiplex
line), 2.85 (2H, wide single line), 3.29 (3H,
singlet), 3.55 (2H, triplet, J=7Hz), 4.00
(3H, wide single line), 4.57 (2H, triple line,
J=6Hz), 6.60-7.33 (4H, multiplet), 6.90
(1H, double line, J=9Hz), 7.31 (1H, double line,
J=9Hz). (b) 1-[2-(2-methoxyethyl)phenox
shi]-3-[2-(3-isopropylidene hydra
Dino-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CDCl)₃) δ: 1.91 (3H, singlet), 2.02
(3H, singlet), 2.60~3.25 (2H, multiplet),
3.70~3.18 (6H, multiplet), 3.30 (3H, singlet),
3.57 (2H, triple line, J=7Hz), 4.02 (3H, width
wide single line), 4.50 (2H, triple line, J=6Hz),
6.65~7.38 (4H, multiplet), 6.88 (1H, doublet,
J=9Hz), 7.49 (1H, double line, J=9Hz). Example 43 The following compound was obtained in the same manner as in Example 40. (a) 1-phenoxy-3-[2-(3-chloro-6
-pyridazinyloxy)ethylamino]-2-
propanol NMR (CDCl)₃) δ: 2.88 (2H, doublet, J=
5Hz), 3.00 (2H, singlet), 3.08 (2H, triplet,
J=6Hz), 3.99 (3H, wide single line), 4.59
(2H, triple line, J=6Hz), 6.70~7.60 (5H, multiline
double line), 6.91 (1H, double line, J=9Hz), 7.31
(1H, double line, J=9Hz). (b) 1-phenoxy-3-[2-(3-isopropylene)
lydenhydrazino-6-pyridazinyloxy)
ethylamino]-2-propanol mp 148.0~150.0℃ NMR (CDCl)₃) δ: 1.93 (3H, singlet), 2.04
(3H, singlet), 2.70~3.30 (2H, multiplet),
2.89 (2H, double line, J=5Hz), 3.05 (2H, Mie
line, J=6Hz), 4.00 (3H, wide single line),
4.50 (2H, triple line, J=6Hz), 6.65-7.47
(5H, multiplet), 6.87 (1H, doublet, J=9
Hz), 7.49 (1H, double line, J=9Hz). Example 44 (a) 61% sodium hydride (1.32g) in benzene
(20ml) of 2-methyl-2-aminopropylene into the suspension.
Solution of panthiol (2.6g) in benzene (10ml)
was added dropwise at room temperature, then 3,6-dichloropyrida
Add a solution of gin (4.1 g) in benzene (10 ml),
It was refluxed for 6 hours. After cooling, the reaction solution was washed with water and diluted with sulfuric acid.
After drying with magnesium, the solvent was distilled off and 3-
(2-amino-2-methylpropylthio)-6-
Chloropyridazine (1.96g) was obtained. NMR (CDCl)₃) δ: 1.24 (6H, singlet), 1.42
(2H, singlet), 3.51 (2H, singlet), 7.15 (1H,
double line, J=9Hz), 7.35 (1H, double line, J=
9Hz). (b) 3-(2-amino-2-methyl obtained in (a) above)
(propylthio)-6-chloropyridazine (980
mg), 1-[2-(2-methoxyethyl)phenol
xy-2,3-epoxypropane (960mg)
A methanol (60 ml) solution was prepared in the same manner as in Example 1(b).
treatment to obtain 1-[2-(2-methoxyethyl)
enoxy]-3-[1,1-dimethyl-2-(3
-chloro-6-pyridazinylthio)ethylamide
]-2-propanol (543 mg) was obtained. NMR (CDCl)₃) δ: 1.25 (6H, singlet), 2.34
~2.75 (2H, multiplex), 2.70~3.10 (4H, multiplex)
line), 3.32 (3H, single line), 3.58 (2H, single line),
3.58 (2H, triple line, J=6Hz), 3.98 (3H, width
wide singlet), 6.69 to 7.40 (4H, multiplet), 7.21
(2H, single line). (c) 1-[2-(2-methoxyethyl) obtained in (b) above
phenoxy]-3-[1,1-dimethyl-2
-(3-chloro-6-pyridazinylthio)ethyl
Ruamino]-2-propanol (525mg), Hyde
Radine hydrate (12ml) and ethanol (12ml)
ml) was treated as in Example 1(c),
1-[2-(2-methoxyethyl)phenoxy]
-3-[1,1-dimethyl-2-(3-isopropropylene)
pyridenehydrazi)-6-pyridazinylthio)
ethylamino]-2-propanol (498mg)
Obtained. NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.89
(3H, single line), 2.01 (3H, single line), 2.10~
3.10 (2H, multiplet), 2.56~3.10 (4H, multiplet),
3.30 (3H, singlet), 3.46 (2H, singlet), 3.57
(2H, triple line, J=6Hz), 3.96 (3H, wide width
singlet), 6.65-7.35 (6H, multiplet). (d) 1-[2-(2-methoxyethyl) obtained in (c) above
phenoxy]-3-[1,1-dimethyl-2
-(3-isopropylidenehydrazino-6-pi
ridazinylthio)ethylamino]-2-propa
Nol (575mg), Hydrazine Hydrate (12
ml) and ethanol (12 ml).
1-[2-(2-meth)
xyethyl) phenoxy]-3-[1,1-dime
Chil-2-(3-hydrazino-6-pyridazini)
ruthio)ethylamino]-2-propanol salt
The acid salt (550mg) was obtained. NMR(D₂O) δ: 1.59 (6H, singlet), 2.90
(2H, triple line, J=7Hz), 3.25~3.90 (4H, multiline
double line), 3.38 (3H, single line), 3.71 (2H, single line)
line), 4.02~4.48 (3H, multiplet line), 6.82~7.53
(4H, multiplet), 7.25 (1H, doublet, J=9
Hz), 7.55 (1H, double line, J=9Hz). Example 45 In the same manner as in Example 44, the following compound was obtained. (a) 1-(2-chloro-5-methylphenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinylthio)ethylamino]2-pro
Panor NMR (CDCl)₃) δ: 1.22 (6H, singlet), 2.30
(3H, singlet), 2.40~2.79 (2H, multiplet),
2.78-2.95 (2H, singlet), 3.56 (2H, singlet),
3.98 (3H, wide single line), 6.66 (1H, double line)
line, J=8Hz), 6.72 (1H, single line), 7.15 (1H,
doublet, J=8Hz), 7.18 (2H, singlet). (b) 1-(2-chloro-5-methylphenoxy)-
3-[1,1-dimethyl-2-(3-isopropylene)
Lydenhydrazino-6-pyridazinylthio)et
thylamino]-2-propanol NMR (CDCl)₃) δ: 1.22 (6H, singlet), 1.92
(3H, singlet), 2.03 (3H, singlet), 2.30 (3H,
singlet), 2.72 to 2.90 (2H, multiplet), 2.45 to 3.15
(2H, multiplet), 3.48 (2H, singlet), 4.00 (3H,
wide single line), 6.68 (1H, double line, J=8
Hz), 6.73 (1H, singlet), 7.17 (1H, doublet,
J=8Hz), 7.25 (2H, singlet). (c) 1-(2-chloro-5-methylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinylthio)ethylamino]-2
-Propanol hydrochloride NMR(D₂O) δ: 1.61 (6H, singlet), 2.36
(3H, single line), 3.51 (2H, double line, J=5
Hz), 3.72 (2H, singlet), 4.08~4.57 (3H, multiline)
multiplet), 6.70 to 7.60 (3H, multiplet), 7.15 (1H,
double line, J=9Hz), 7.41(1H, double line, J=
9Hz). Example 46 The following compound was obtained in the same manner as in Example 44. (a) 1-(2-chloro-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinylthio)ethylamino]-2-p
Lopanol NMR (CDCl)₃) δ: 1.25 (6H, singlet), 2.37
(3H, singlet), 2.50~2.80 (2H, multiplet),
2.77~2.95 (2H, multiplet), 3.57 (2H, singlet),
4.00 (3H, wide single line), 6.62~7.15 (3H,
multiplet), 7.19 (2H, singlet). (b) 1-(2-chloro-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinylthio)ethylamino]-2
-Propanol hydrochloride NMR(D₂O) δ: 1.67 (6H, singlet), 2.40
(3H, singlet), 3.43~3.70 (2H, multiplet),
3.75 (2H, singlet), 4.10~4.65 (3H, multiplet),
6.80~7.48 (3H, multiplet), 7.19 (1H, doublet,
J=9Hz), 7.45 (1H, double line, J=9Hz). Example 47 The following compound was obtained in the same manner as in Example 44. (a) 1-(2-methylphenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nylthio)ethylamino]-2-propanol NMR (CDCl)₃) δ: 1.23 (6H, singlet), 2.19
(3H, single line), 2.56 (2H, wide single line),
2.72~2.90 (2H, multiplet), 3.56 (2H, singlet),
3.97 (3H, wide single line), 6.60-7.40 (4H,
multiplet), 7.18 (2H, singlet). (b) 1-(2-methylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinylthio)ethylamino]-2-propano
alcohol hydrochloride mp 207~210℃ NMR(D₂O) δ: 1.57 (6H, singlet), 2.20
(3H, singlet), 3.30~3.54 (2H, multiplet),
3.68 (2H, singlet), 4.04~4.50 (3H, multiplet),
6.80~7.35 (4H, multiplet), 7.14 (1H, doublet,
J=9Hz), 7.45 (1H, double line, J=9Hz). The following compounds were prepared by the same method as in Example 2.
were synthesized (Examples 48-59). Example 48 (a) 1-(2-methylphenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
le NMR (CDCl)₃) δ: 1.22 (6H, singlet), 2.18
(3H, single line), 2.40~2.70 (2H, wide single line)
line), 2.71 to 2.95 (2H, multiple line), 3.97 (3H, width
wide singlet), 4.32 (2H, singlet), 6.62~
7.20 (4H, multiplet), 6.87 (1H, doublet, J=9
Hz), 7.31 (1H, double line, J=9Hz). (b) 1-(2-methylphenoxy)-3-[1,1
-dimethyl-2-(3-isopropylidenehyde
Radino-6-pyridazinyloxy)ethylamide
-2-propanol NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.91
(3H, singlet), 2.01 (3H, singlet), 2.18
(13H, singlet), 2.70~2.98 (2H, multiplet),
3.10~4.50 (2H, wide single line), 3.97 (3H,
wide single line), 4.22 (2H, single line), 6.63~
7.20 (4H, multiple line), 6.84 (1H, double line, J=9
Hz), 7.49 (1H, double line, J=9Hz). (c) 1-(2-methylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride mp 180~183℃ NMR(D₂O) 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 (4H, multiplet), 7.17 (2H, singlet). (d) 1-(2-methylphenoxy)- obtained in (c) above
3-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol hydrochloride (200mg), acetone
(2 ml) and methanol (2 ml).
After refluxing for 6 hours, the solvent was distilled off under reduced pressure. profit
The resulting crude product was mixed with ethanol and acetone.
Crystallized from a combined solvent, 1-(2-methylphenylene)
noxy)-3-[1,1-dimethyl-2-(3-
Isopropylidenehydrazino-6-pyridazine
ruoxy)ethylamino]-2-propanol
Hydrochloride (194 mg) was obtained. mp 164.5~169.0℃ NMR (CDCl)₃) δ: 1.57 (6H, singlet), 2.16
(6H, singlet), 2.18 (3H, singlet), 3.18~
3.49 (2H, multiplet), 3.90~4.60 (3H, multiplet),
4.45 (2H, singlet), 6.70~7.27 (4H, multiplet),
7.51 (1H, double line, J=9Hz), 7.75 (1H, double line
line, J=9Hz). Example 49 (a) 1-(3-methylphenoxy)-3-[1,1
-dimethyl-2-(3-chloro-6-pyridadi
Nyloxy)ethylamino]-2-propano
le NMR (CDCl)₃) δ: 1.21 (6H, singlet), 2.30
(3H, singlet), 2.68-2.89 (2H, multiplet),
2.69 (2H, single line), 3.94 (3H, wide single line)
line), 4.32 (2H, single line), 6.52~7.21 (4H, multiline)
double line), 6.91 (1H, double line, J=9Hz), 7.31
(1H, double line, J=9Hz). (b) 1-(3-methylphenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyri
dadinyloxy)ethylamino]-2-propa
norl hydrochloride mp 168~171℃ NMR(D₂O) δ: 1.57 (6H, singlet), 2.30
(3H, singlet), 3.28~4.00 (2H, multiplet),
4.05~4.55 (3H, multiplet), 4.43 (2H, singlet),
6.60-7.25 (4H, multiplet), 7.27 (2H, singlet). Example 50 (a) 1-(3-fluorophenoxy)-3-[1,
1-dimethyl-2-(3-chloro-6-pyrida
Dinyloxy)ethylamino]-2-propano
rule NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.59
(2H, wide singlet), 2.58 to 2.92 (2H, multiple
line), 3.95 (3H, wide single line), 4.32 (2H,
singlet), 6.45-7.32 (4H, multiplet), 6.92 (1H,
double line, J=9Hz), 7.32 (1H, double line, J=
9Hz). (b) 1-(3-fluorophenoxy)-3-[1,
1-dimethyl-2-(3-isopropylidene
Dorazino-6-pyridazinyloxy)ethyla
Mino]-2-propanol NMR (CDCl)₃) δ: 1.20 (6H, singlet), 1.90
(3H, singlet), 2.01 (3H, singlet), 2.33~
3.40 (4H, multiple line), 3.94 (3H, wide single line)
line), 4.22 (2H, single line), 6.42~7.30 (4H, multiline)
double line), 6.86 (1H, double line, J=9Hz), 7.48
(1H, double line, J=9Hz). (c) 1-(3-fluorophenoxy)-3-[1,
1-dimethyl-2-(3-hydrazino-6-pi
ridazinyloxy)ethylamino]-2-pro
Panol hydrochloride mp 173~176℃ NMR(D₂O) δ: 1.55 (6H, singlet), 3.22 ~
3.45 (2H, multiplet), 4.01~4.55 (3H, multiplet),
4.42 (2H, singlet), 6.50~7.45 (4H, multiplet),
7.32 (2H, singlet). Example 51 (a) 1-(2-methoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ: 1.20 (6H, singlet), 2.67
~2.90 (2H, multiplet), 2.95 (2H, singlet),
3.33 (3H, single line), 3.98 (3H, wide single line)
line), 4.31 (2H, single line), 4.43 (2H, single line),
6.70~7.40 (4H, multiplet), 6.90 (1H, doublet,
J=9Hz), 7.30 (1H, double line, J=9Hz). (b) 1-(2-methoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propanol hydrochloride mp 175.3~179.7℃ NMR(D₂O) δ: 1.56 (6H, singlet), 3.24 ~
3.52 (2H, multiplet), 3.36 (3H, singlet), 4.05
~4.60 (3H, multiplet), 4.43 (2H, singlet),
4.45 (2H, singlet), 6.88~7.58 (4H, multiplet),
7.30 (2H, single line). Example 52 (a) 1-[2-(3-methoxypropyl) Fenoki
cy]-3-[1,1-dimethyl-2-(3-chloro
Rho-6-pyridazinyloxy)ethylamino]
-2-propanol NMR (CDCl)₃) δ: 1.21 (6H, singlet), 1.52
~2.17 (2H, multiplex), 2.42~2.92 (4H, multiplex)
line), 2.68 (2H, wide single line), 3.31 (3H,
singlet), 3.36 (2H, triplet, J=7Hz), 3.98
(3H, wide single line), 4.33 (2H, single line),
6.66~7.23 (4H, multiplet), 6.92 (1H, doublet,
J=9Hz), 7.32 (1H, double line, J=9Hz). (b) 1-[2-(3-methoxypropyl) phenox
[C]-3-[1,1-dimethyl-2-(3-hydro
Radino-6-pyridazinyloxy)ethylamide
-2-propanol hydrochloride mp 195.3~196.2℃ NMR(D₂O) δ: 1.56 (6H, singlet), 1.53~
2.17 (2H, multiplet), 2.36 to 2.78 (2H, multiplet),
3.13~3.50 (2H, multiplet), 3.33 (3H, singlet),
3.44 (2H, triple line, J=7Hz), 4.02-4.28
(3H, multiplet), 4.42 (2H, doublet), 6.58~
7.17 (4H, multiplet), 7.22 (2H, singlet). Example 53 (a) 1-(2-cyano-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinyloxy)ethylamino]2-p
Lopanol NMR (CDCl)₃) δ: 1.23 (6H, singlet), 2.38
(3H, singlet), 2.68~3.03 (2H, multiplet),
3.23 (2H, wide single line), 4.05 (3H, wide single line)
singlet), 4.33 (2H, singlet), 6.65-6.91
(2H, multiplet), 7.01 (1H, doublet, J=9.5
Hz), 7.32 (1H, double line, J=9.5Hz), 7.38
(1H, double line, J=8Hz). (b) 1-(2-cyano-5-methylphenoxy)-
3-[1,1-dimethyl-2-(3-isopropylene)
lydenhydrazino-6-pyritazinyloxy)
ethylamino]-2-propanol NMR (CDCl)₃) δ; 1.27 (6H, singlet), 1.92
(3H, singlet), 2.01 (3H, singlet), 2.37 (3H,
singlet), 2.80 to 3.12 (2H, multiplet), 3.30 to 4.50
(2H, multiplet), 4.09 (3H, wide singlet),
4.30 (2H, singlet), 6.67~6.90 (2H, multiplet),
6.92 (1H, double line, J = 9.5Hz), 7.37 (1H, double
Double line, J=8Hz), 7.49 (1H, double line, J=9.5
Hz). (c) 1-(2-cyano-5-methylphenoxy)-
3[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-2
-Propanol hydrochloride NMR(D₂O) 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),
6.81~7.09 (2H, multiplet), 7.32 (2H, singlet),
7.46 (1H, double line, J=8Hz). Example 54 (a) 1-(2-cyano-5-chlorophenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinyloxy)ethylamino]-2-
propanol NMR (CDCl)₃) δ; 1.21 (6H, singlet), 2.52
~3.15 (4H, multiplex), 4.08 (3H, wide single
line), 4.32 (2H, single line), 6.79~7.15 (2H, multiline)
double line), 6.98 (1H, double line, J=9.5Hz), 7.36
(1H, double line, J=9.5Hz), 7.45 (1H, double line,
J=8Hz). (b) 1-(2-cyano-5-chlorophenoxy)-
3-[1,1-dimethyl-2-(3-isopropylene)
lydenhydrazino-6-pyridazinyloxy)
ethylamino]-2-propanol NMR (CDCl)₃) δ; 1.21 (6H, singlet), 1.91
(3H, singlet), 2.02 (3H, singlet), 2.67~
3.35 (4H, multiple line), 4.07 (3H, wide single line)
line), 4.23 (2H, single line), 6.78~7.12 (2H, multiline)
double line), 6.90 (1H, double line, J=9.5Hz), 7.44
(1H, double line, J=8Hz), 7.49 (1H, double line,
J = 9.5Hz). (c) 1-(2-cyano-5-chlorophenoxy)-
3-[1,1-dimethyl-2-(3-hydrazino
-6-pyridazinyloxy)ethylamino]-
2-propanol hydrochloride NMR(D₂O) δ; 1.58 (6H, singlet), 3.28~
3.55 (2H, multiplet), 4.12~4.60 (3H, multiplet),
4.46 (2H, single line), 7.14 (1H, double line, J=8
Hz), 7.21 (1H, singlet), 7.39 (2H, singlet),
7.60 (1H, double line, J=8Hz). Example 55 (a) 1-(2-cyano-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-chloro-6
-pyridazinyloxy)ethylamino]-2-
propanol NMR (CDCl)₃) δ; 1.22 (6H, singlet), 2.49
(3H, singlet), 2.60~3.10 (4H, multiplet),
4.05 (3H, wide single line), 4.32 (2H, single line)
line), 6.60 to 7.51 (3H, multiplet line), 6.98 ((1H, double line)
Double line, J=9.5Hz), 7.33((1H, double line, J=
9.5Hz). (b) 1-(2-cyano-3-methylphenoxy)-
3-[1,1-dimethyl-2-(3-isopropylene)
lydenhydrazino-6-pyridazinyloxy)
ethylamino]-2-propanol NMR (CDCl)₃) δ; 1.21 (3H, singlet), 1.92
(3H, singlet), 2.02 (3H, singlet) 2.49 (3H,
singlet), 2.55 to 3.20 (4H, multiplet), 4.05 (3H,
wide single line), 4.22 (2H, single line), 6.65~
7.50 (3H, multiplet), 6.90 (1H, doublet, J=
9.5Hz), 7.47 (1H, double line, J = 9.5Hz). (c) 1-(2-cyano-3.methylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-
6-pyridazinyloxy)ethylamino]-2
-Propanol hydrochloride NMR(D₂O) δ; 1.57 (6H, singlet), 2.41
(3H, singlet), 3.32~3.53 (2H, multiplet),
4.18~4.50 (3H, multiplet), 4.42 (2H, singlet),
6.80-7.50 (3H, multiplet), 7.22 (2H, singlet). Example 56 (a) 1-(2,5-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ; 1.21 (6H, singlet), 2.13
(3H, singlet), 2.29 (3H, singlet), 2.50 (2H,
wide singlet), 2.70 to 2.90 (2H, multiplet),
3.95 (3H, wide single line), 4.32 (2H, single line)
line), 6.54 to 7.10 (3H, multiple line), 6.86 (1H, double line)
Double line, J=9.5Hz), 7.30 (1H, double line, J=9.5
Hz). (b) 1-(2,5-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-isopropylide)
hydrazino-6-pyridazinyloxy)ethyl
Ruamino]-2-propanol NMR (CDCl)₃) δ; 1.20 (6H, singlet), 1.91
(3H, singlet), 2.01 (3H, singlet), 2.13 (3H,
singlet), 2.29 (3H, singlet), 2.70~2.92 (2H,
multiplet), 3.50 to 4.45 (2H, multiplet), 3.96 (3H,
wide single line), 4.22 (2H, single line), 6.52~
7.10 (3H, multiplet), 6.83 (1H, doublet, J=
9.5Hz), 7.47 (1H, double line, J = 9.5Hz). (c) 1-(2,5-dimethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propanol hydrochloride NMR(D₂O) δ; 1.58 (6H, singlet), 2.09
(3H, singlet), 2.30 (3H, singlet), 3.30~
3.52 (2H, multiplet), 3.95~4.55 (3H, multiplet),
4.40 (2H, singlet), 6.60~7.10 (3H, multiplet),
7.13 (2H, single line). Example 57 (a) 1-(2-ethoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-chloro-6-pi
ridazinyloxy)ethylamino]-2-pro
Panor NMR (CDCl)₃) δ; 1.19 (3H, triple line, J=
7Hz), 1.20 (6H, singlet), 2.50~3.00 (4H,
multiplet), 3.50 (2H, quartet, J=7Hz), 4.00
(3H, wide single line), 4.32 (2H, single line),
4.48 (2H, singlet), 6.70~7.43 (4H, multiplet),
6.91 (1H, double line, J=9Hz), 7.31 (1H, double line
line, J=9Hz). (b) 1-(2-ethoxymethylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-
Propanol hydrochloride NMR(D₂O) δ; 1.20 (3H, triple line, J=7
Hz), 1.57 (6H, singlet), 3.12 to 3.52 (2H, multiline)
double line), 3.60 (2H, quartet, J=7Hz), 3.99~
4.32 (3H, multiplet), 4.43 (2H, singlet), 4.49
(2H, singlet), 6.86~7.64 (4H, multiplet),
7.32 (2H, single line). Example 58 (a) 1-phenoxy-3-[1,1-dimethyl-
2-(3-chloro-6-pyridazinyloxy)
ethylamino]-2-propanol NMR (CDCl)₃) δ; 1.20 (6H, singlet), 2.51
(2H, wide single line), 2.65~3.06 (2H, multiple line)
line), 3.95 (3H, wide single line), 4.32 (2H,
singlet), 6.72 to 7.50 (5H, multiplet), 6.90 (1H,
double line, J=9Hz), 7.31(1H, double line, J=
9Hz). (b) 1-phenoxy-3-[1,1-dimethyl-
2-(3-hydrazino-6-pyridazinyloxy)
c) Ethylamino]-2-propanol hydrochloride NMR(D₂O) δ; 1.56 (6H, singlet), 3.22~
3.50 (2H, multiplet), 3.97~4.31 (3H, multiplet),
4.43 (2H, singlet), 6.78~7.50 (5H, multiplet),
7.29 (2H, single line). Example 59 (a) 1-(2-chloro-5-methoxyphenoxy)
-3-[1,1-dimethyl-2-(3-chloro-
6-pyridazinyloxy)ethylamino]-2
-propanol NMR (CDCl)₃) δ; 1.23 (6H, singlet), 2.88
(4H, wide single line), 3.76 (3H, single line),
4.00 (3H, wide single line), 4.33 (2H, single line)
line), 6.40 (1H, quartet, J=8Hz, J=3
Hz), 6.46 (1H, double line, J = 3Hz), 6.93 (1H,
double line, J=9Hz), 7.13(1H, double line, J=
8Hz), 7.31 (1H, double line, J=9Hz). (b) 1-(2-chloro-5-methoxyphenoxy)
-3-[1,1-dimethyl-2-(3-hydrazi
No-6-pyridazinyloxy)ethylamino]
-2-propanol hydrochloride NMR(D₂O) δ; 1.59 (6H, singlet), 3.30~
3.57 (2H, multiplet), 3.85 (3H, singlet), 4.13
~4.39 (3H, multiplet), 4.46 (2H, singlet),
6.45~6.79 (2H, multiplet), 7.26 (2H, singlet),
7.30 (1H, double line, J=9Hz). Showing an example of manufacturing a drug containing the compound of the present invention
And, it is as follows. Example A: Tablet Tablets containing 5mg and 20mg of active ingredient per tablet
A prescription example of the agent is as follows. Prescription 1-a.5mg tabletmg/tablet 1-(2-chloro-3-methylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-pro
Panol hydrochloride 5 Lactose 137.2 Starch 44.8 Carboxymethylcellulose calcium 10 Talc 2Magnesium stearate 1 200.0mg Prescription 1-b 20mg tabletmg/tablet 1-(2-chloro-3-methylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-pro
Panol hydrochloride 20 Lactose 122.2 Starch 44.8 Carboxymethylcellulose calcium 10 Talc 2Magnesium stearate 1 200.0mg Details of the manufacturing method are as follows. 1-(2-chloro-3-methylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]2-pro
Grind the crystals of panol hydrochloride, add lactose and
Add starch and mix well. 10% starch
Add the glue to the above mixture and stir to mix to form the granules.
Manufacture. After drying, the particles are sized to a particle size of around 840 microns.
Mix talc and magnesium stearate with this.
Combine and tablet. Example B: Capsule capsule prescription Prescription 2 20mg capsulemg/capsule 1-(2-chloro-3-methylphenoxy)-3-
[1,1-dimethyl-2-(3-hydrazino-6-
pyridazinyloxy)ethylamino]-2-pro
Panol hydrochloride 20 Lactose 57.8 Starch 30Magnesium stearate 2.2 110.0mg 1-(2-chloro-3-methylphenoxy)-3
-[1,1-dimethyl-2-(3-hydrazino-6
-pyridazinyloxy)ethylamino]-2-p
Thoroughly crush the crystals of ropanol hydrochloride and make starch.
Add lactose and magnesium stearate to it.
Mix well and fill into No. 5 capsules.
do.

Claims (1)

[Claims] 1 formula In the formula, R ¹ is a hydrogen atom; cyano group; hydroxyl group; allyloxy group; allyl group; halogen atom; acetylamino group, halogen atom, hydroxyl group, lower alkoxy group, lower alkylthio group, tetrahydrofurfuryloxy group or allyloxy group a lower alkyl group which may be substituted with; or a methoxy or ethoxy group which may be substituted with a 2-furyl group, a phenyl group or a lower alkoxy group, R ² and R ³ are each a hydrogen atom, a halogen atom, A hydra represented by a lower alkyl group or a lower alkoxy group, R ⁴ and R ⁵ each represent a hydrogen atom or a methyl group, Z represents an oxygen or sulfur atom, and Y represents -NH ₂ or [Formula] Dinopyridazine compounds and salts thereof. 2. Claim 1 in which Z represents an oxygen atom
The hydrazinopyridazine compound and its salt as described in 2. 3. The hydrazinopyridazine compound and its salt according to claim 1, wherein R ⁴ and R ⁵ both represent a methyl group. 4 R ¹ is a cyano group, an allyloxy group, an allyl group,
The hydrazinopyridazine compound and its salt according to claim 1, which represents a chlorine atom, a bromine atom, a trifluoromethyl group, an ethyl group, or a 2-methoxyethyl group. 5 1-(2-cyanophenoxy)-3-[1,1
-dimethyl-2-(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol, 1-[2-(2-methoxyethyl)phenoxy]-3-[1,1-dimethyl-2 -(3-hydrazino-6-pyridazinyloxy)ethylamino]
-2-propanol, 1-(2-chloro-3-methylphenoxy)-3-[1,1-dimethyl-2-
(3-hydrazino-6-pyridazinyloxy)ethylamino]-2-propanol and 1-(2-chloro-5-methylphenoxy)-3-[1,1-dimethyl-2-(3-hydrazino-6 -pyridazinyloxy)ethylamino]-2-propanol, the hydrazinopyridazine compound and its salt according to claim 1. 6 formula In the formula, R ¹ is a hydrogen atom; cyano group; hydroxyl group; allyloxy group; allyl group; halogen atom; acetylamino group, halogen atom, hydroxyl group, lower alkoxy group, lower alkylthio group, tetrahydrofurfuryloxy group or allyloxy group a lower alkyl group which may be substituted with; or a methoxy or ethoxy group which may be substituted with a 2-furyl group, a phenyl group or a lower alkoxy group, R ² and R ³ are each a hydrogen atom, a halogen atom, represents a lower alkyl group or a lower alkoxy group, R ⁴ and R ⁵ each represent a hydrogen atom or a methyl group, Z represents an oxygen or sulfur atom, and X represents a halogen atom. , and then optionally convert the formula In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the above-mentioned meanings, and the compound represented by is reacted with acetone, and if necessary, the reaction product is converted into a salt. Featured expression In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the above-mentioned meanings, and Y represents -NH ₂ or [Formula]. Production method. 7 formula In the formula, R ¹ represents a hydrogen atom; a cyano group; a halogen atom; a lower alkyl group which may be substituted with a lower alkoxy group; or an allyloxy group,
R ² and R ³ are hydrogen atoms, halogen atoms, respectively
represents a lower alkyl group, R ⁴ and R ⁵ each represent a methyl group, Z represents an oxygen or sulfur atom, and Y represents -NH ₂ or [Formula]. Antihypertensive agent as an active ingredient.