JPS6245865B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel hydrazinopyridazine derivative, more specifically, the following formula () In the formula, R represents a branched alkyl group having 3 or 4 carbon atoms; Y is -NH ₂ or

[Formula], where R ₁ and R ₂ each represent a lower alkyl group; Z is -S-, -SO ₂ -,

[Formula] -NHCO- or a direct bond, where R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group; n is an integer of 1 to 4; The present invention relates to an antihypertensive agent containing a salt thereof, and a hydrazinopyridazine derivative 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 derivatives represented by the formula () have excellent β-
It has been found that it has both blocking action and vasodilatory action 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. Therefore, in the above formula (), the lower alkyl groups represented by the symbols R ₁ , R ₂ and R ₃ may be linear or branched, such as methyl, ethyl , n- or iso-propyl, z-, iso-, sec- or
Mention may be made of the tert-butyl group, among which the methyl and ethyl groups are suitable. Furthermore, the hydroxy lower alkyl group represented by the symbol R ₃ includes, for example, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc., of which hydroxyethyl is preferred. On the other hand, the number of carbon atoms represented by the symbol R is 3
Or as the four branched alkyl groups, iso-
Propyl, iso-butyl, sec-butyl and tert-
Butyl groups are included, among them iso-propyl and
A tert-butyl group is preferred. Among the hydrazinopyridazine derivatives of the formula () provided by the present invention, preferred are those in which (i) R represents an iso-propyl or tert-butyl group; (ii) Z represents -S-,

[Formula] or one that represents a direct bond; (iii) Y is -NH ₂ ,

[Formula] or

and (iv) those in which n represents 2 or 3. Among them, the following formula (-a) In the formula, R' represents an iso-propyl group or a tert-butyl group; Y' represents -NH ₂ or

Express [formula] I; Z' is -S-,

Hydrazinopyridazine derivatives and salts thereof represented by the formula -CH ₂ - or a direct bond have very strong β-blocking and vasodilatory effects, and are a particularly preferred group of compounds in the present invention. Thus, representative examples of the hydrazinopyridazine derivatives represented by the general formula () or (-a) provided by the present invention are as follows. 1-[2-(3-hydrazino-6-pyridazinylthiomethyl)phenoxy]-3-iso-propylamino-2-propanol, 1-[2-(3-iso-propylidenehydrazino-6-pyri dazinylthiomethyl)phenoxy]-
3-tert-butylamino-2-propanol, 1-[2-[2-(3-hydrazino-6-pyridazinylthio)ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[ 2-(3-hydrazino-6-pyridazinylthio)ethyl]phenoxy]-3-tert-
Butylamino-2-propanol, 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinylthio)ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2- [2-(3-iso-propylidenehydrazino-6-pyridazinylthio)ethyl]phenoxy]-3-tert-butylamino-2-propanol, 1-[2-[2-[3-(2-butylidene)hydrazino] -6-pyridazinylthio]ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[2-[3-(3-pentylidene)hydrazino-6-pyridazinylthio]ethyl]phenoxy]-3- tert-butylamino-2-propanol, 1-[2-[3-(3-iso-propylidenehydrazino-6-pyridazinylthio)propyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[ 2-[3-(3-iso-propylidenehydrazino-6-pyridazinylthio)propyl]phenoxy]-3-tert-butylamino-2-propanol, 1-[2-[4-(3-iso-propylidene) hydrazino-6-pyridazinylthio)butyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[2-(3-hydrazino-6-pyridazinylsulfonyl)ethyl]phenoxy]-3 −
iso-propylamino-2-propanol, 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinylsulfonyl)ethyl]phenoxy]-3-iso-propylamino-2-propanol , 1-[2-[3-(3-iso-propylidenehydrazino-6-pyridazinylsulfonyl)propyl]
Phenoxy]-3-tert-butylamino-2-propanol, 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinylamino)ethyl]phenoxy]-3-iso-propyl Amino-2-propanol, 1-[2-[N-methyl-N-(3-iso-propylidenehydrazino-6-pyridazinyl)aminomethyl]phenoxy]-3-iso-propylamino-
2-propanol, 1-[2-[2-[N-methyl-N-(3-hydrazino-6-pyridazinyl)amino]ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2 -[2-[N-methyl-N-(3-iso-
Propylidenehydrazino-6-pyridazinyl)amino[ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[2-[N-methyl-N-(3-iso-
Propylidenehydrazino-6-pyridazinyl)amino[ethyl]phenoxy]-3-tert-butylamino-2-propanol, 1-[2-[3-[N-methyl-N-(3-iso-
Propylidenehydrazino-6-pyridazinyl)amino]propyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[2-[N-ethyl-N-(3-iso-
Propylidenehydrazino-6-pyridazinyl)amino[ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[2-[N-(2-hydroxyethyl)]
-N-(3-iso-propylidenehydrazino-6-
pyridazinyl)amino]ethyl]phenoxy]-
3-iso-propylamino-2-propanol, 1-[2-[2-[N-(3-hydroxypropyl)-N-(3-iso-propylidenehydrazino-
6-pyridazinyl)amino]ethyl]phenoxy]-3-iso-propylamino-2-propanol, 6-iso-propylidenehydrazino-N-[2-
[2-(3-iso-propylamino-2-hydroxypropoxy)phenyl]ethyl]-3-pyridazinecarboxamide, 6-hydrazino-N-[2-[2-(3-tert-
Butylamino-2-hydroxypropoxy)phenyl]ethyl]-3-pyridazinecarboxamide, 6-iso-propylidenehydrazino-N-[3-
[2-(3-tert-butylamino-2-hydroxypropoxy)phenyl]propyl]-3-pyridazinecarboxamide, 1-[2-(3-iso-propylidenehydrazino-6-pyridazinylmethyl)phenoxy ]-3-
iso-propylamino-2-propanol, 1-[2-(3-iso-propylidenehydrazino-6-pyridazinylmethyl)phenoxy]-3-
tert-butylamino-2-propanol, 1-[2-[2-(3-hydrazino-6-pyridazinyl)ethyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[2- (3-iso-propylidenehydrazino-6-pyridazinyl)ethyl]phenoxy]
-3-iso-propylamino-2-propanol, 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinyl)ethyl]phenoxy]
-3-tert-butylamino-2-propanol, 1-[2-[3-(3-hydrazino-6-pyridazinyl)propyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2- [3-(3-hydrazino-6-pyridazinyl)propyl]phenoxy]-3-tert-butylamino-2-propanol, 1-[2-[3-(3-iso-propylidenehydrazino-6-pyridazinyl)] Propyl]phenoxy]-3-iso-propylamino-2-propanol, 1-[2-[3-(3-iso-propylidenehydrazino-6-pyridazinyl)propyl]phenoxy]-3-tert-butylamino- 2-propanol etc. According to the present invention, acid addition salts of the hydrazinopyridazine derivatives 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 derivative represented by the formula () or a salt thereof
Although the manufacturing method differs depending on the type, the manufacturing method will be explained below for each case with reference to the reaction formula. [A] Production of compound of formula () when Z represents -S- or -SO ₂ -: (A-1) When n = 1, 2 or 3 In the above formula, R, R ₁ , R ₂ and n have the above-mentioned meanings, Hal ₁ , Hal ₂ and Hal ₃ each represent a halogen atom, especially a chlorine atom; Z ₁ is -
Represents S- or _-SO2- . In the above reaction scheme, first, a dihalopyridazine of the formula (1), which is known per se, and a 2-hydroxyphenylalkyl mercaptan of the formula (2) are reacted. The reaction is carried out in the absence of a solvent, or preferably in an inert solvent, such as aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride; dioxane,
Among ethers such as tetrahydrofuran, diethyl ether, dimethoxyethane, etc., usually in the presence of an acid binder such as sodium amide, sodium hydride, sodium alkoxide, etc., at a temperature between 0°C and the reflux temperature of the reaction mixture, preferably about The reaction can be carried out at a heating temperature between room temperature and the reflux temperature of the reaction mixture. Although the ratio of the compound of formula (1) and the compound of formula (2) to be used is not particularly limited, generally,
It is advantageous to use at least 1 mol of the compound of formula (2) per mol of the compound of formula (1), preferably in the range from about 1 to about 2 mol. A compound of formula (3) is thus obtained, which is then converted into a compound of formula (4) by reacting with epihalohydrin. The reaction can be carried out in the absence of a solvent or in an inert solvent as described above at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferably at reflux temperature. epihalohydrin,
Preferably, epichlorohydrin can be used in an amount of at least 1 mol, preferably within the range of about 4 to about 8 mol, per mol of the compound of formula (3). The resulting compound of formula (4) and the alkylamine H ₂ N
The reaction with -R can also be carried out under the same reaction conditions as used for the reaction of the compound of formula (3) above with epihalohydrin. that time,
It is preferred to react about 1 to about 10 moles of the alkylamine per mole of the compound of formula (4), thereby producing the compound of formula (5). The compound of formula (5) thus obtained can be converted into the compound of formula (6) by oxidation, if necessary. For main oxidation, the formula
The hydroxyl group and amino group in the compound (5) are protected groups that are stable against oxidation, such as formyl,
It is desirable that the protective group be protected in advance with an acyl group such as acetyl or propionyl; or an alkyloxy or aralkyloxycarbonyl group such as ethoxycarbonyl or benzyloxycarbonyl, and that the protective group be removed by a conventional method after the oxidation reaction. The above oxidation is generally carried out by treating the compound of formula (5) with an organic or inorganic peracid, such as perbenzoic acid, methachloroperbenzoic acid, peracetic acid, peracetic acid, perbenzoic acid, etc., in the absence of a solvent or in an inert solvent such as those described above. This can be carried out by treatment with formic acid, sodium periodate, preferably methachloroperbenzoic acid. The reaction temperature can generally be about 0°C to room temperature, preferably about room temperature, and the amount of the above-mentioned oxidizing agent used generally corresponds to the formula
The amount may range from about 1 to about 10 moles, preferably from about 2 to about 3 moles, per mole of compound (5). This gives a compound of formula (6). The compound of formula (5) or (6) can be converted into the compound of formula (-1), which is included within the scope of the compound of formula () of the present invention, by reacting with hydrazine or a hydrate thereof. The compound of formula (-1) thus obtained is then reacted with the dialkyl ketone of formula (7) to form the compound of formula (-2), which is also included within the scope of the compound of formula () of the present invention. ) can be obtained. The reaction between the compound of formula (5) or (6) and hydrazine or its hydrate can be carried out in the absence of a solvent or in an inert solvent such as ethanol, n-propanol, isopropanol, n-butanol,
The reaction can be carried out at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature, among alcohols such as tert-butanol and ethers such as dioxane, tetrahydrofuran and diethyl ether. In this case, it is advantageous to use hydrazine or its hydrate in a proportion of about 10 to about 50 mol per mol of the compound of formula (5) or (6). Hydrazonation of the compound of formula (-1) with the ketone of formula (7) 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; diethyl ether, dioxane, and tetrahydrofuran. Among ethers; aromatic hydrocarbons such as benzene, toluene, and xylene; and halogenated hydrocarbons such as dichloromethane, chloroform, and tetrachloroethane,
This can be carried out by bringing the compound of formula (-1) into contact with the ketone of formula (7).
Although the reaction proceeds satisfactorily even at room temperature, if necessary, the reaction may be carried out while heating the reaction mixture to the reflux temperature, preferably to a temperature of about 100° C. or lower. The amount of ketone of formula (7) used relative to the compound of formula (-1) is not critical;
Although it can vary widely depending on the type of compound, in general, the amount of the ketone of formula (7) is at least 1 mol, preferably about 2 to about 100 mol, per 1 mol of the compound of formula (-1). It is advantageous to use within the range of about 10 to about 50 moles, more preferably about 10 to about 50 moles. This reaction proceeds extremely rapidly, usually about 10 to
It takes about 60 minutes and is almost quantitative. (A-2) When n=4 In the above formula, R, R ₁ , R ₂ , Hal ₁ , Hal ₂ ,
Hal ₃ and Z ₁ have the meanings given above. In this method, first, the dihalopyridazine of formula (1) and the compound of formula (2') are reacted. This reaction is expressed by the formula in the previous section (A-1)
The reaction can be carried out in exactly the same manner as described for the reaction of dihalopyridazine (1) with the compound of formula (2). The resulting compound of formula (3') can be converted into a compound of formula (6') by oxidation, if necessary. This oxidation reaction takes place before (A-
It can be carried out in exactly the same manner as described for the oxidation of the compound of formula (5) in section 1). The compound of formula (3') or (6') thus obtained is the compound of formula (5) or
In exactly the same manner as described for the reaction of the compound (6) with hydrazine or its hydrate, it can be converted to the compound of formula (3'') by reacting it with hydrazine or its hydrate.Formula (3'')
The compound of formula (3) is then converted in a manner known per se by acid hydrolysis, for example with hydrochloric acid, into a compound of formula (3) which is then converted into a compound of formula (3) by hydrazonation with a ketone of formula (7). can be converted to a compound of formula (3). This hydrazonation can be carried out in exactly the same manner as the hydrazonation of the compound of formula (-1) with the ketone of formula (7) in the previous section (A-1). The compound of formula (3) thus obtained is:
React with epihalohydrin and alkylamine in exactly the same manner as described in the previous section (A-1) regarding the reaction of the compound of formula (3) with epihalohydrin and the reaction of the resulting compound of formula (4) with an alkylamine. Accordingly, the formula () included within the scope of the formula () of the present invention
−2′) compound is obtained. The compound of formula (-2') obtained in the above reaction is, if necessary, hydrolyzed to form a compound of formula (-1') included within the scope of the compound of formula () of the present invention. It can be changed. Note that the compound of formula (2') used as a starting material in the above reaction is a new compound that has not been described in conventional literature, for example, as described in Example 6 below.
It can be manufactured according to the method described in or a method similar thereto. [B] Z is

Production of a compound of formula () when [formula] is represented: In the above formula, R, R ₁ , R ₂ , R ₃ , n, Hal ₁ and
Hal ₂ has the meaning given above. The reaction between the dihalopyridazine of formula (1) and the compound of formula (8) can be carried out in the absence of a solvent or in the presence of an inert solvent, such as alcohols such as methanol, ethanol, isopropanol; diethyl ether, tetrahydrofuran, dioxane, etc. Among ethers, etc., the temperature is generally between about 0°C and the reflux temperature of the reaction mixture;
Preferably, it can be carried out at 50 to 100°C. Although the ratio of the compound of formula (1) and the compound of formula (8) to be used is not particularly limited, generally, the compound of formula (8) is used at least for 1 mole of the compound of formula (1). It is advantageous to use 2 moles, preferably in the range of about 2 to about 4 moles. The formula used as starting material in the above reaction
The compound (8) is a new compound that has not been described in conventional literature, such as Example 11 (when n = 1); Examples 8, 9, and 14 (when n = 2); Example 10 and
12 (when n=3); Example 13 (when n=4)
It can be manufactured according to the method described in or a method similar thereto. The compound of formula (9) obtained by the above reaction is converted into the compound of formula ( ₁₀ ) by reacting with ethyl carbazate ( _H2N -NH- _COOC2H5 ). The reaction can be carried out in the absence of a solvent or in an inert solvent such as those described above, generally at temperatures between about 80 and about 160°C, preferably between about 150 and about 160°C. The amount of ethyl carbazate used is not particularly limited, but it is generally used at a ratio of about 2 to about 20 mol, particularly about 5 to about 10 mol, per 1 mol of the compound of formula (9). It is preferable to use The resulting compound of formula (10) is then acid-hydrolyzed by a method known per se to obtain the compound of formula (10), which is included within the scope of the compounds of formula () of the present invention.
-3) is obtained, which is optionally further reacted with a ketone of formula (7) in the same manner as described above for the reaction of a compound of formula (-1) with a ketone of formula (7). Accordingly, the compound of formula (-4) can be changed to the compound of formula (-4) which is included within the scope of the compound of formula () of the present invention. [C] Formula () when Z represents -NHCO-
Production of compounds: In the above formula, R, R ₁ , R ₂ and n have the above meanings, R ₄ represents a lower alkyl group, Hal ₃ and
Each Hal ₄ represents a halogen atom. The amidation reaction between the compound of formula (11) and the compound of formula (12) can be carried out in the absence of a solvent, or preferably in an inert solvent, such as alcohols such as methanol, ethanol, isopropanol, n-butanol; ethyl The reaction can be carried out in ethers such as ether, tetrahydrofuran and dioxane at a temperature between about 0° C. and the reflux temperature of the reaction mixture, preferably at a temperature around room temperature. The ratio of the compound of formula (12) to the compound of formula (11) is not critical, but generally at least 11 moles of the compound of formula (12) to 1 mole of the compound of formula (11), preferably about Advantageously, a proportion of 2 to about 5 mol is used. The resulting compound of formula (13) is then reacted sequentially with hydrazine or its hydrate and the ketone of formula (7). This reaction is described in the previous section (A-1) regarding the reaction of hydrazine or its hydrate with the compound of formula (5) or (6) and the reaction of the ketone of formula (7) with the resulting compound of formula (-1). This can be done in the same manner as described above. Thus, a compound of formula (14) is obtained, which can then be converted into a compound of formula (15) by reacting with epihalohydrin, and the resulting compound of formula (15) can be further converted into a compound of formula (15) by reacting with an epihalohydrin.
By reacting with H ₂ N-R, the formula (-
5). Above formula (14)
The reaction of the compound of formula (3) with epihalohydrin and the reaction of the resulting compound of formula (15) with the alkylamine are the same as the reaction of the compound of formula (3) with epihalohydrin and the reaction of the resulting compound of formula (15) with epihalohydrin, respectively, in the previous section (A-1).
The reaction between the compound (4) and the alkylamine can be carried out in the same manner as described above. The compound of formula (-5) obtained by the above reaction is
If necessary, by hydrolysis with hydrochloric acid,
It may be changed to a compound of formula (-6) which is included within the scope of the compound of formula () of the present invention. [D] Production of the compound of formula () when Z represents a direct bond: (D-1) When n=1 In the above formula, R, R ₁ , R ₂ and Hal ₃ have the above meanings, R ₅ represents a lower alkyl group, R ₆ represents a lower alkyl group, and Hal ₅ represents a halogen atom. The compound of formula (16) is first converted into the compound of formula (18) by reacting with the Grignard reagent of formula (17) according to the Grignard reaction known per se, and then by reacting with hydrazine or its hydrate. It can be converted into the compound of formula (19). In this reaction with hydrazine or its hydrate, about 10 to about 10 to about 1 mol of hydrazine or its hydrate is added to 1 mole of the compound of formula (18) in an organic acid such as acetic acid or propionic acid.
The reaction can be carried out at a ratio of 50 moles, usually at room temperature to the reflux temperature of the reaction mixture, preferably at the reflux temperature. The resulting compound of formula (19) is dehydrogenated in a manner known per se, for example by reaction with bromine in acetic acid, to give the compound of formula (20) and then refluxed in phosphorus pentasulphide and pyridine. The compound of formula (21) is obtained,
The compound of formula (21) is reacted with hydrazine or its hydrate in the absence of a solvent or in an inert solvent as described above at a reaction temperature of about 50 to 150° to form a compound of formula (22). Change to The compound of formula (22) thus obtained is then dealkylated in a manner known per se.
For example, the compound of formula (23) can be obtained by treatment under reflux with hydrobromic acid or hydroiodic acid. If this compound of formula (23) is reacted with the ketone of formula (7) and epihalohydrin in sequence in the same manner as described above, the compound of formula (24) will be obtained, and this compound will be reacted in the same manner as described above. By reacting an alkylamine H ₂ N-R with a compound of formula (-7), which is included within the scope of compounds of formula () of the present invention, a compound of formula (-7) can be produced. The obtained compound of formula (-7) can be converted into a compound of formula (-8), which is included within the scope of the compound of formula () of the present invention, by hydrolysis with hydrochloric acid if necessary. . (D-2) When n=2, 3 or 4 In the above formula, R, R ₁ , R ₂ and Hal ₃ have the above-mentioned meanings, R ₇ represents a lower alkyl group, and Aey represents an acyl group. In this method, first, the compound of formula (25) is reacted with the compound of formula (3) and epihalohydrin in the previous section (A-1) and the reaction of the compound of formula (4) to be produced with an alkylamine. It can be converted into the compound of formula (26) above by reacting with epihalohydrin and an alkylamine in exactly the same manner as described above. This compound of formula (26) is then cyclized by treatment with hydrazine or its hydrate. The cyclization is carried out in the absence of a solvent or in an appropriate solvent such as alcohols such as ethanol, n-propanol, and n-butanol; ethers such as dioxane, tiglyme, and tetrahydrofuran; and organic acids such as dilute acetic acid and dilute propionic acid. Among these, the reaction is achieved by reacting the compound of formula (26) with hydrazine or its hydrate at a temperature between about room temperature and the reflux temperature of the reaction mixture, particularly at the reflux temperature.
Hydrazine or its hydrate can be used generally in a ratio of 10 to 100 mol, preferably 20 to 50 mol, per 1 mol of the compound of formula (26). In this way, a compound of formula (27) is obtained, which is subjected to a dehydrogenation reaction after protecting the existing free hydroxyl group and terminal secondary amino group by acylation [compound of formula (28)]. . This dehydrogenation reaction can be carried out in the same manner as described for the dehydrogenation reaction of the compound of formula (19) in the previous section (D-1). As a result, a compound of formula (29) is obtained, and this compound of formula (29) is sequentially reacted with phosphorus pentasulfide and hydrazine or its hydrate in the same manner as described in the previous section (D-1). Therefore, the compound of the above formula (-9), which is included within the scope of the compound of the above formula () of the present invention, can be produced. Furthermore, the compound of formula (-9) obtained in this way can be reacted with the ketone of formula (7) in exactly the same manner as described above. -10). In the compound of formula (25) used as a starting material in the series of reactions described above, n=2
Compounds where R ₇ =H are known, and by converting them into lower alkyl esters by a conventional method, the compound of formula (25) where n=2 can be obtained. On the other hand, the compound of formula (25) when n=3 can be synthesized via the reaction route shown below. Reference a: KHLin et al., J.Chem.Soc., 68-72
(1937) Reference b: J.Hase, H.Ohura, Chem.Pharm.Bull.
, 2 , 368-372 (1954). In the above formula, R ₇ and Acy have the above meanings, R ₈
represents a lower alkyl group. Further, the compound of formula (25) when n=4 can be synthesized via the reaction route shown below. In the above formula, R ₇ has the above meaning, and Document b is as above. The hydrazinopyridazine derivative represented by the above formula () is produced by the methods described in [A], [B], [C], and [D] above, and can be processed by methods known per se, such as extraction and column chromatography. It can be separated and/or purified from the reaction mixture by means such as graphics, thin layer chromatography, and recrystallization. In addition, the compound of formula () when Y is -NH ₂ - is generally unstable and may be difficult to purify, but in this case, the compound may be reacted with the ketone of formula (7) above. Once Y

When represented by [Formula], it can be purified by converting it into a compound of the corresponding formula (), sufficiently purifying it, and then hydrolyzing it again with an acid or subjecting it to hydrazinolysis. The hydrazinopyridazine derivative 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 hydrazinopyridazine derivatives represented by the formula () of the present invention described above generally have pharmacological characteristics in that they have both β-blocking action and vasodilatory action at the same time, and they do not cause tachycardia. It is therapeutically excellent as a long-lasting antihypertensive agent. 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), as well as low toxicity. The compounds of the present invention used in the following animal experiments are represented by the following symbols. Compound A: 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinylthio)ethyl]phenoxy]-3-iso-propylamino-2-propanol, B: 1-[2-[2 -(3-hydrazino-6-pyridazinylthio)ethyl]phenoxy]-
3-iso-propylamino-2-propanol, C: 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinylthio)ethyl]phenoxy]-3-tert-butylamino-2-propanol , D: 1-[2-[2-(3-hydrazino-6-pyridazinylthio)ethyl]phenoxy]-
3-tert-butylamino-2-propanol, E: 1-[2-[3-(3-iso-propylidenehydrazino-6-pyridazinylthio)propyl]phenoxy]-3-iso-propylamino-2-propanol , F: 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinylsulfonyl)
Ethyl]phenoxy]-3iso-propylamino-2-propanol, G: 1-[2-[2-[N-methyl-N-(3-hydrazino-6-pyridazinyl)amino]ethyl]phenoxy]-3-iso -propylamino-2-propanol, H:1-[2-(3-hydrazino-6-pyridazinylaminomethyl)phenoxy]-3-iso
-Propylamino-2-propanol, I: 1-[2-[2-[N-ethyl-N-(3-hydrazino-6-pyridazinyl)amino]ethyl]phenoxy]-3-iso-propylamino-2- Propanol, J: 1-[2-[2-[N-(2-hydroxyethyl)-N-(3-hydrazino-6-pyridazinyl)amino]ethyl]phenoxy]-3
-iso-propylamino-2-propanol, K: 6-iso-propylidenehydrazino-N-
[3-[2-(3-iso-propylamino-2
-hydroxypropoxy)phenyl]propyl]-3-pyridazinecarboxamide, L:6-hydrazino-N-[3-[2-(3-iso
-Propylamino-2-hydroxypropoxy)phenyl]propyl]-3-pyridazinecarboxamide, M: 1-[2-[2-(3-iso-propylidenehydrazino-6-pyridazinyl)ethyl]phenoxy]-3- iso-propylamino-2
-propanol, N:1-[2-[2-(3-hydrazino-6-pyridazinyl)ethyl]phenoxy]-3-
iso-propylamino-2-propanol, Test method: Rats anesthetized with pentobarbital (60 mg/Kgi.p.) (Wistar; body weight 300-400
g), 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 Three rats per group were given isoprenaline (0.1μ
g/Kgi.v.) and immediately measure and record heart rate. Let the measured value of the heart rate at that time be _H1 . Next, a solution of the test compound dissolved in 0.1N aqueous hydrochloric acid was administered through a cannula inserted into the femoral vein of the rat, and 3 minutes later, isoprenaline (0.1μg/Kgi.v.) was administered again, and the heart rate was immediately increased. Measure and record. 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 A dose-response curve is created by repeating the above operation while cumulatively increasing the dose of the test compound, and from this curve Determine the dose of the test compound at which the number inhibition rate 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 (in 0.1N hydrochloric acid).
(dissolution) 1mg/Kg was administered intravenously, and blood pressure was measured over time.
Recorded for 40 minutes. Maximum decrease in blood pressure during that period
Determine the value. The results are shown in Table 2 below. Table 2 Compound Blood pressure lowering effect A 〓 B 〓 C 〓 D 〓 E+ F+ G 〓 H 〓 I 〓 J + K+ L+ M+ N+ +: Blood pressure decrease of 15 to 24 mmHg, 〓 : Blood pressure decrease of 25-34mmHg, 〓 : Blood pressure decrease of 35-45mmHg. (3) Toxicity Furthermore, the compound A of the present invention has low toxicity.
For example, take one ddy mouse (male: 19-22g).
The test compound was dissolved in 0.1N hydrochloric acid solution.
Each dose was administered orally using a sonde, and 72
I observed the time. As a result, the LD of compound A₅₀value is
Hydra is commercially available as a phthalazine antihypertensive agent.
Jin's LD₅₀The values were almost the same. Thus, the compound of the present invention represented by formula ()
In particular, preferred compounds represented by the above formula (-a)
The drug has both β-blocking and vasodilatory effects.
It is used as an antihypertensive agent in humans and other warm-blooded animals.
Oral or parenteral administration (e.g.
For example, intramuscular, intravenous, subcutaneous, rectal, and sublingual administration.
etc.) can be done. 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, 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 powder, 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 may also contain 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, the doctor's diagnosis may vary depending on the above.
An amount less than the lower limit of the range or an amount greater than the upper limit of the range
Of course, it is also possible to administer. Above administration
The dose can be administered once a day or in divided doses.
Wear. The present invention will be further explained below with reference to Examples. In addition, all temperatures in the examples are degrees Celsius,
NMR measurements use tetramethylsilane as an internal standard.
Deuterated chloroform solution unless otherwise specified.
I did it inside. Example 1 (a) 61% sodium hydride (oil-based) (17.63g) and
and 3,6-dichloropyridazine (34.6g).
2-(2-hydroxy) in a suspension (200 ml) of
of ethyl mercaptan (30.0g)
Benzene (200ml) solution takes 30 minutes at room temperature.
Add dropwise and stir and reflux for 30 minutes. Cool the reaction mixture
After cooling, acidify with 10% hydrochloric acid and remove the aqueous layer with chloroform.
Extract, wash with water and dry with magnesium sulfate.
After distilling off the solvent, the precipitated crude crystals were collected in chloroform.
Recrystallized from ether to give colorless needle-like 3-crystalline crystals.
Lolo-6-[2-(2-hydroxyphenyl)ethyl]
Chilthio]pyridazine (36.5 g) was obtained. mp144.5~145.6°. NMR δ; 2.75-3.60 (4H, multiplet), 6.63
~7.60 (5H, multiplet), 7.38 (2H, singlet). MS, m/e266 (M⁺). (b) The chloride obtained in (a) above (32.0g), epi
Bromohydrin (81.8g), potassium carbonate
(32.0g) and methyl ethyl ketone (320ml).
The mixture was stirred and refluxed for 8 hours, and then the insoluble materials were removed.
The residue obtained by concentrating the liquid under reduced pressure is
Column chromatography (60 to 100 meters)
Dissolved in benzene-chloroform (2:1)
3-chloro-6-[2-[2-
(2,3-epoxypropoxy)phenyl
Tiltio]pyridazine (34.5 g) was obtained.
NMR δ; 2.68~3.28 (4H, multiplet), 3.28~
3.78 (3H, multiplex), 3.80~4.40 (2H, multiplex)
line), 6.70 to 7.40 (4H, multiple line), 7.24 (2H, single line),
heavy line). MS, m/e322 (M⁺). (c) Epoxy body (27.7g) obtained in (b) above, iso
-Propylamine (40ml) and methanol
(250ml) was refluxed for 3 hours and left overnight.
Ru. After distilling off the solvent under reduced pressure, the precipitated crystals were dissolved in 3% hydrochloric acid.
and wash with benzene. chlorinate the aqueous layer
After extraction with form and washing with 5% sodium carbonate
After drying with potassium carbonate and distilling off the solvent, 1-
[2-[2-(3-chloro-6-pyridazinylthi
e) Ethyl phenoxy-3-iso-propyl
Amino-2-propanol (30.3 g) is obtained.
NMR δ; 1.07 (6H, doublet, J=6Hz),
2.36~3.32 (7H, multiplet), 3.32~3.75 (2H,
multiplet), 3.97 (3H, wide singlet), 6.70~
7.34 (4H, multiplet), 7.24 (2H, singlet). MS, m/e381 (M⁺). (d) Amine compound (30.7g) obtained in (c) above, hydride
Radine hydrate (300ml) and ethanol
(150ml) was stirred and refluxed for 8 hours, then brought to room temperature.
Cool and extract with chloroform. Chlorophor
After washing the mucus layer twice with water and drying with magnesium sulfate
Add acetone and let stand. After removing the solvent under reduced pressure
Recrystallized from acetone to give 1-[2-[2-(3
-iso-propylidenehydrazino-6-pyrida
Dinylthio)ethyl phenoxy]-3-iso-
Propylamino-2-propanol (20.34
g) is obtained. mp129.1~129.8°. NMR δ;
1.07 (6H, double line, J=6Hz), 1.95 (3H, one
double line), 2.02 (3H, single line), 2.72~3.35 (5H,
multiplet), 3.35 to 3.70 (4H, multiplet), 4.01
(4H, wide single line), 6.70~7.52 (6H, multiline)
heavy line). MS, m/e417 (M⁺). Example 2 (a) 3-chloro-6-[2-[2-(2,3-epo
xypropoxy)phenyl]ethylthio]pyri
Dazine (3.0g) and tert-butylamine (100g)
ml) in the same manner as in Example 1(c) to obtain 1-[2
-[2-(3-chloro-6-pyridazinylthio)
Ethyl]phenoxy]-3-tert-butylamide
Obtain no-2-propanol (3.0 g). NMR
δ; 1.10 (9H, singlet), 2.50-3.26 (6H,
multiplet), 3.37 to 3.72 (2H, multiplet), 4.01
(3H, wide single line), 6.69 to 7.38 (4H, multiline)
double line), 7.21 (2H, single line). MS, m/e395
(M⁺). (b) Implement the amine compound (1.2g) obtained in (a) above.
1-[2-[2-(3
-iso-propylidenehydrazino-6-pyrida
Dinylthio)ethyl]phenoxy]-3-tert
-Butylamino-2-propanol (340mg)
get. NMR δ; 1.15 (9H, singlet), 1.98
(3H, single line), 2.01 (3H, single line), 2.70~
3.20 (4H, multiplex), 3.20~3.70 (3H, multiplex)
line), 3.80~4.60 (4H, multiple line), 6.68~7.52
(6H, multiplet). MS, m/e431 (M⁺). Example 3 (a) 61% sodium hydride (oil-based) (7.42g) and
and 3,6-dichloropyridazine (18g).
3-(2-hydroxyphenyl) in suspension (250 ml)
base of enyl)propyl mercaptan (13.5g)
(200 ml) solution was added dropwise at room temperature, then
Stir and reflux for 1 hour. The reaction mixture was prepared as Example 1(a)
3-chloro-6-[3-(2
-Hydroxyphenyl)propylthio]pyrida
Obtain gin (4.8 g). mp137.2～137.7゜.
NMR δ; 2.10 (2H, quintet, J=7Hz),
2.83 (2H, triple line, J=7Hz), 3.37 (2H, triple line, J=7Hz)
Multiple line, J=7Hz), 6.68-7.38 (5H, multiple line),
7.25 (2H, singlet). MS, m/e280 (M⁺). (b) The chloride obtained in (a) above (3.3g),
Lorohydrin (100ml) and potassium carbonate (3.4
The mixture of g) is stirred and refluxed for 2 hours. reaction mixture
The material was operated as in Example 1(b) to form a colorless oil.
3-chloro-6-[3-[2-(2,3-epoxy
cypropoxy)phenyl]propylthio]pyri
Obtain Dajin (1.6g). NMR δ；2.07
(2H, quintet, J=7Hz), 2.60-3.05 (2H,
multiplet), 2.83 (2H, triplet, J=7Hz),
3, 10~3.55 (1H, multiplet), 3.37 (2H, triplet)
line, J=7Hz), 3.80-4.40 (2H, multiple line),
6.60~7.35 (4H, multiplet), 7.23 (2H, singlet)
line). (c) Execute the epoxy body (1.4g) obtained in (b) above.
1-[2-[3-
(3-chloro-6-pyridazinylthio)propyl
phenoxy-3-iso-propylamino-
Obtain 2-propanol (1.03 g). mp72.1
~73.5°. NMR δ; 1.07 (6H, doublet, J
= 6Hz), 2.04 (2H, quintet, J = 7Hz), 2.40
~3.10 (7H, multiplet), 3.31 (2H, triplet, J
=7Hz), 3.98 (3H, wide single line), 6.69~
7.32 (4H, multiplet), 7.21 (2H, singlet). (d) Implement the amine compound (1.03g) obtained in (c) above.
1-[2-[3-(iso
-propylidenehydrazino-6-pyridazinyl
thio)propyl]phenoxy]-3-iso-pro
Obtain pyramino-2-propanol (200mg)
Ru. mp109.4～111.1゜. NMR (heavy methanol)
) δ; 1.13 (6H, double line, J=6Hz), 1.80
~2.30 (2H, multiplet), 1.99 (3H, singlet),
2.05 (3H, singlet), 2.50~3.50 (7H, multiplex)
line), 3.98 (3H, wide single line), 6.70-7.28
(4H, multiplet), 7.32 (2H, singlet). MS,
m/e431 (M⁺). Example 4 1-[2-[2-(3-iso-propylidene hydra
dino-6-pyridazinylthio)ethyl
[C]-3-iso-propylamino-2-propanol
(700 mg) and 1N hydrochloric acid (60 ml).
After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure.
Repeat this operation several times and evaporate the resulting residue.
Crystallized from nor-ether, 1-[2-[2-
(3-hydrazino-6-pyridazinylthio)ethyl
phenoxy-3-iso-propylamino-2
-Propanol hydrochloride (510 mg) is obtained. NMR
(Heavy water) δ; 1.40 (6H, double line, J = 6Hz), 2.70
~3.80 (7H, multiplex), 4.00~4.50 (3H, multiplex
line), 6.70 to 7.70 (6H, multiplet line). MS, m/e377
(M⁺). Example 5 1-[2-[2-(3-iso-propylidene hydra
dino-6-pyridazinylthio)ethyl
[C]-3-tert-butylamino-2-propanol
(870 mg) was treated in the same manner as in Example 4 to obtain 1-
[2-[2-(3-hydrazino-6-pyridazinyl
thio)ethyl phenoxy]-3-tert-butyl
Amino-2-propanol hydrochloride (610 mg) was obtained.
Ru. NMR (heavy water) δ; 1.44 (9H, singlet), 2.70
~3.80 (6H, multiplex), 4.00~4.40 (3H, multiplex
line), 6.80 to 7.60 (6H, multiplet line). MS, m/e391
(M⁺). Example 6 (a) 3-(2-benzyloxyphenyl)propyl
of carbon-1-carboxylic acid methyl ester (15g)
Hydrogen in anhydrous ether (75 ml) solution under ice-cooled stirring
Lithium aluminum chloride (4.0g) anhydrous
Add the solution (40 ml) dropwise. 30 at 0-4℃
After stirring for a minute, ethyl acetate (6 ml), ether
Add a mixed solution of 10ml (10ml) and water (8ml) dropwise.
Then add 430ml of 10% sulfuric acid. organic layer
After separating the aqueous layer, the aqueous layer is extracted with benzene. organic
Combine the layers, wash with water, and dry with magnesium sulfate.
The solvent was distilled off under reduced pressure to give 4-(2-benzyl alcohol).
xyphenyl)-1-butanol (8.5g) was obtained.
Ru. NMR δ; 1.40-1.85 (5H, multiplet),
2.48~2.85 (2H, multiplet), 3.60 (2H, triplet)
line, J=6Hz), 5.06 (2H, single line), 6.71~
7.62 (9H, multiplet). (b) The alcohol obtained in (a) above (7.2 g), dried
Dry pyridine (4 ml) and anhydrous benzene (100 ml)
Add phosphorus tribromide (9.2 ml) to a mixture of phosphorus tribromide (9.2
A solution of g) in anhydrous benzene (50 ml) is added dropwise.
After stirring and refluxing for 17 hours, the reaction mixture was poured into ice water.
The benzene layer was mixed with 5% sodium carbonate, 10% sulfuric acid and
Wash with water and dry with magnesium sulfate.
do. The oily substance obtained by distilling off the solvent is
chromatography (60 to 100 meshes,
4-(2-benzene)
oxyphenyl)-1-promobutane (31.4
g) is obtained. NMR δ; 1.50-2.13 (4H, poly
double line), 2.19 (2H, triple line, J=7Hz), 3.37
(2H, triple line, J=6Hz), 5.05 (2H, single line
line), 6.70-7.52 (9H, multiplet line). (c) Bromine compound (3.14g) obtained in (b) above, thio
of urea (4g) and 95% ethanol (40ml)
The mixed solution is stirred and refluxed for 4 hours. Remove the solvent under reduced pressure.
Distillation gives a colorless semi-solid material. Aete this
After washing with 20% sodium hydroxide (50ml) solution
and reflux for 3 hours. After cooling, acidify with concentrated hydrochloric acid.
Then extract with benzene. Wash with water and sulfuric acid
After drying with magnesium, the solvent was distilled off and 4-(2
-benzyloxyphenyl)butane-1-thio
(2.14 g) is obtained. NMR δ；1.25
(1H, triple line, J=8Hz), 1.42~2.00 (4H,
multiplet), 2.26 to 2.96 (4H, multiplet), 5.03
(2H, singlet), 6.69-7.58 (9H, multiplet). (d) The absence of the thiol compound (2.14 g) obtained in (c) above.
Dichloropyridazine (1.16
g) and 60% sodium hydride (377 mg)
A suspension in anhydrous benzene (10 ml) was stirred at room temperature for 20 minutes.
Drip in minutes. After stirring and refluxing for 1 hour, cool and insoluble.
leave things behind Magnesium sulfate after washing the solution with water.
Dry with. The solvent was distilled off to give 3-chloro-6
-[4-(2-benzyloxyphenyl)butyl
Thio]pyridazine (2.38 g) is obtained. NMR
δ; 1.52-1.96 (4H, multiplet), 2.52-2.96
(2H, multiplet), 3.10~3.54 (2H, multiplet),
5.05 (2H, singlet), 6.69~7.54 (11H, multiple
line). (e) Chlor compound (2.1 g) obtained in (d) above, ethanol
(10 ml) and hydrazine hydrate (20 ml).
The mixture is stirred and refluxed for 4 hours. Retains ethanol
After leaving, extract with chloroform, wash with water, and add potassium carbonate.
Dry with um. After distilling off the solvent under reduced pressure, ether
was added to remove the crystals and ether-n-hexane
3-hydrazino-6-[4-(2-
benzyloxyphenyl)butylthio]pyrida
Obtain gin (1.6 g). NMR (heavy methanol)
δ; 1.51-2.00 (4H, multiplet), 2.46-2.85
(2H, multiplet), 2.90~3.30 (2H, multiplet),
5.02 (2H, singlet), 6.72~7.63 (11H, multiple
line). (f) 10% of the benzylic compound (1.3g) obtained in (e) above
% hydrochloric acid (72 ml) and stirred and refluxed for 20 hours.
Add sodium carbonate to make it alkaline and remove chlorophore.
Extract with rum. Acetone in chloroform solution
(20ml) was added and left to stand for 1 hour, then the solvent was distilled off to form an oil.
get something This was performed using thin layer chromatography.
Lycagel (Merck GF₂₅₄) Chloroform-meth
(19:1)] to obtain 3-iso-pro
Pylidenehydrazino-6-[4-(2-hydroxy
Cyphenyl)butylthio]pyridazine (570
mg). NMR δ; 1.88, 2.01 (6H, di
book double line), 1.57-2.14 (4H, multiple line), 2.47
~2.89 (2H, multiplex), 3.05~3.45 (2H, multiplex
line), 3.83 (1H, single line), 6.70~7.90 (4H, multiline)
double line), 7.12 (1H, double line, J=9Hz), 7.40
(1H, double line, J=9Hz). (g) Phenol compound obtained in (f) above (450 mg), charcoal
Potassium acid (500mg), epipromohydrin
(1.0g) and methyl ethyl ketone (15ml).
The mixture is stirred and refluxed for 2 hours. Filtered liquid after cooling
After concentrating under reduced pressure, thin layer chromatography
Lycagel (Merck GF₂₅₄) Chloroform-meth
(19:1)] to obtain 3-iso-pro
Pylidenehydrazino-6-[4-[2-(2,3
-Epoxypropoxy)phenyl]butyl
Obtain pyridazine (100mg). NMR δ;
1.92, 2.04 (6H, two double lines), 1.39-2.10
(4H, multiplet), 2.45~3.00 (4H, multiplet),
3.05~3.43 (2H, multiplet), 3.71~4.17 (3H,
multiplet), 6.67-7.32 (6H, multiplet). (h) Epoxy compound obtained in (g) above (100 mg), iso
-propylamine (5 ml) and methanol (5 ml)
ml) mixture is left at room temperature for 3 days. solvent
Distill to give 1-[2-[4-(3-iso-propylene)
Denhydrazino-6-pyridazinylthio)butylene
phenoxy-3-iso-propylamino-
Obtain 2-propanol (55 mg). NMR
δ; 1.09 (6H, double line, J = 6dl), 1.95,
2.04 (6H, two double lines), 1.38~2.10 (4H,
multiplet), 2.42~3.05 (5H, multiplet), 3.09~
3.59 (2H, multiplex), 3.70~4.50 (3H, multiplex)
line), 6.70-7.52 (6H, multiplet line). Example 7 (a) 1-[2-[2-(3-chloro-6-pyridadi)
Nylthio)ethyl phenoxy]-3-iso-p
No ropylamino-2-propanol (8.0g)
Mixture of acetic acid (50ml) and pyridine (50ml)
Leave at room temperature overnight. Pour the reaction mixture into ice water.
and extract with ethyl acetate. Add 3% organic layer to
Wash in the order of monia, 10% sulfuric acid, and water, and
After drying with magnesium, the solvent was distilled off to form an oily N
-iso-propyl-N-[3-[2-[2-(3-
Chloro-6-pyridazinylthio)ethyl]fe
[Noxy]-2-acetoxypropyl]acetoa
Obtain Mido (10.0g). NMRδ; 1.20 and 1.26 (6H, 2 sets of double
line, J=6Hz), 2.08 (3H, single line), 2.16
(3H, singlet), 2.75-3.30 (2H, multiplet),
3.30~3.89 (4H, multiplet), 3.90~4.50 (3H,
multiplet), 5.20~5.60 (1H, multiplet), 6.68~
7.35 (4H, multiplet), 7.21 (2H, singlet). (b) Amide compound obtained in (a) above (800 mg), m-ku
Roroperbenzoic acid (730mg) and chloroform
Leave the mixture (30 ml) at room temperature overnight. reaction
Add the mixture to sodium bisulfite and then carbonate.
Wash with sodium hydrogen, then with magnesium sulfate.
After drying, the solvent is distilled off. Dissolve the residue in acetone and analyze with thin layer chromatography.
Roughy [Silica gel (Merck GF)₂₅₄),Black
Purified with roform-methanol (20:1)
and oily N-iso-propyl-N-[3-[2
-[2-(3-chloro-6-pyridazinylsulfonate)
nyl)ethyl]phenoxy]-2-acetoxy
Obtain [propyl]acetamide (610 mg).
NMRδ; 1.23 and 1.33 (9H, two doublets,
J=6Hz), 2.16 (3H, singlet), 2.18 (3H,
singlet), 2.90~4.60 (9H, multiplet), 5.10~
5.70 (1H, multiplex), 6.40~7.35 (4H, multiplex)
line), 7.50 (1H, double line, J=9.5Hz), 7.80
(1H, double line, J=9.5Hz). (c) The sulfonyl compound obtained in (b) above (600 mg), human
Drazine hydrate (15ml) and ethanol
(7 ml) is refluxed for 6 hours. Dissolution after reaction
The medium was distilled off and the residue was extracted with chloroform.
Ru. The chloroform layer was dissolved in 5% sodium carbonate and water.
After washing in the following order, dry with potassium carbonate. solvent
was distilled off under reduced pressure and the resulting residue was dissolved in methanol.
After solution, add acetone and perform thin layer chromatography
[Silica gel (Merck GF₂₅₄) Chloroform-mer
1-[2-
[2-(3-iso-propylidene hydrazi)-6-
pyridazinylsulfonyl)ethyl
[C]-3-iso-propylamino-2-propano
get the rules. mp116~118°. NMR (heavy methane)
) δ; 1.15 (6H, double line, J=6Hz),
2.08 (6H, singlet), 2.70~3.21 (5H, multiplex)
line), 3.58~4.32 (5H, multiple line), 6.55~7.25
(4H, multiplet), 7.38 (1H, doublet, J=9.5
Hz), 7.75 (1H, double line, J = 9.5Hz). MS,
m/e449 (M⁺). Example 8 (a) 2-benzyloxybenzaldehyde (100
g), nitromethane (57g), ammonium acetate
(15.5g) and acetic acid (200ml) for 3 hours.
After refluxing for a while, pour the reaction mixture onto ice water. The precipitated crystals
Take the sample, dissolve it in benzene, and add 5% sodium carbonate.
Wash with water and water in that order. The obtained crude product was
Floriresil chromatography (60 to 100 meters)
Dissolved in benzene-hexane (1:2)
2-benzyloxy-β-nito
Obtain Rostyrene (96 g). NMRδ; 5.19
(2H, singlet), 6.80~7.45 (4H, multiplet),
7.38 (5H, single line), 7.75 (1H, double line, J=
14Hz), 8.19 (1H, double line, J = 14Hz). (b) Hydrogen the styrene body (40g) obtained in (a) above
Ether of lithium aluminum chloride (20g)
(500 ml) added to the suspension under ice-cooling and stirring for 2 hours.
Stir. Separate the ether layer after decomposition with Rothsiel salt.
The separated aqueous layer is further extracted with ether. ether
After combining the layers and drying with magnesium sulfate, remove the solvent.
was distilled off to give 2-benzyloxyphenyl ethyl
Obtain Ruamine (30g). NMRδ; 1.15
(2H, wide single line), 2.75~3.00 (4H, multiline)
double line), 5.05 (2H, single line), 6.70~7.55 (4H,
multiplet), 7.37 (5H, singlet). (c) The amine compound (24.8g) obtained in (b) above and
Triethylamine (15g) in chloroform
(100ml) solution of ethyl chlorocarbonate (15g).
A chloroform (15 ml) solution was added dropwise under ice cooling (10
minutes). After further stirring at room temperature for 30 minutes, the reaction solution was
10% sulfuric acid, water, 4% sodium hydroxide, water in that order
N-[2-(2-beta)]
oxyphenyl)ethyl]carbamic acid
Ethyl (30.8g) is obtained. NMRδ; 1.20
(3H, Mie line, J=7Hz), 2.87 (2H, Mie line
line, J=6Hz), 3.43 (2H, quartet, J=6
Hz), 4.05 (2H, quartet, J=7Hz), 4.40~
5.0 (1H, multiplet), 5.08 (2H, singlet), 6.70
~7.55 (4H, multiplet), 7.37 (5H, singlet). (d) Teeth of the urethane body (30.8g) obtained in (c) above.
Add trahydrofuran (60ml) solution to lithium hydride.
aluminum (12g) of tetrahydrofura
(60ml) suspension under ice-cooling. 10 at room temperature
After stirring for a minute, reflux for 1 hour. Then cool it on ice for 10 minutes.
% sodium hydroxide (50 ml) was added dropwise and further at room temperature.
After stirring for 30 minutes, add magnesium sulfate (30g).
Ru. After removing the insoluble matter, concentrate the solution and add benzene.
Dissolve in water (approximately 100ml) and add with 5% sulfuric acid (100ml).
Extract. The aqueous layer is made alkaline with potassium carbonate.
and extract with chloroform. with potassium carbonate
After drying, the solvent was distilled off to give N-[2-(2-benzi
oxyphenyl)ethyl]-N-methylami
(21.0g). NMRδ; 1.30 (1H, width
wide singlet), 2.43 (3H, singlet), 2.88
(4H, single line), 5.08 (2H, single line), 6.60~
7.55 (4H, multiplet), 7.36 (5H, singlet). (e) Amine compound obtained in (d) above (21.0 g), anhydrous
Mixture of acetic acid (40ml) and pyridine (50ml)
After heating on a steam bath for 1 hour, water was added to the reaction solution.
Ru. The precipitated extract was extracted with benzene and diluted with 10% sulfur.
Wash with acid, water, 4% sodium hydroxide, and water in that order.
After that, the solvent was distilled off to give N-[2-(2-benzi
(oxyphenyl)ethyl]-N-methylacetate
Toamide (22.7 g) is obtained. NMRδ; 1.79 and
and 2.01 (3H, two single lines), 2.70-3.07
(2H, multiplet), 2.76 and 2.87 (3H, two
singlet), 3.43 (2H, triplet, J=7Hz), 5.05
(2H, singlet), 6.70~7.55 (4H, multiplet),
7.35 (5H, single line). (f) The amide compound (22.7g) obtained in (e) above was evaporated.
5% palladium on carbon (2.0
g) is used as a catalyst for hydrogenation. 15 hours at room temperature
After the reaction, the catalyst is removed. The liquid distills the solvent
After leaving, dissolve in 4% sodium hydroxide and dilute with ether.
Wash with After acidifying the aqueous layer with 10% hydrochloric acid,
Extract with ether. Wash with saturated saline and remove sodium sulfate.
After drying with thorium, the solvent was distilled off and N-
[2-(2-hydroxyphenyl)ethyl]-N
-Methylacedeamide (14.7 g) is obtained.
NMRδ; 1.98 and 2.13 (3H, two singlets
line), 2.68 to 3.15 (2H, multiplet line), 2.98 and
3.04 (3H, two singlets), 3.30~3.70 (2H,
multiplet), 6.59-7.24 (4H, multiplet), 8.39
(1H, single line). (g) The phenolic compound obtained in (f) above (14.6 g),
Epichlorohydrin (100ml) and potassium carbonate
(14.6 g) was stirred and refluxed for 2 hours.
Ru. After removing the insoluble materials, distillation was carried out under reduced pressure to obtain N-[2-
[2-(2,3-epoxypropoxy)pheni
[ethyl]-N-methylacetamide (17.7
g) is obtained. bp160~170゜(0.1mmHg). NMR
δ; 1.98 and 2.06 (3H, two singlets),
2.65 to 3.10 (4H, multiplet), 2.90 and 2.95
(3H, two singlets), 3.20~4.50 (5H, multiplex)
line), 6.68-7.25 (4H, multiplet line). (h) Messenger of the epoxy body (17.7g) obtained in (g) above.
iso-propylamine in tanol (89 ml) solution
(18 ml) and reflux for 1 hour. After distilling off the solvent
An ethereal solution of hydrogen chloride dissolved in ether
In addition, by dividing the precipitate using the declination method,
N-[2-[2-(2-hydroxy-3-iso-propylene)
ropylaminopropoxy)phenyl〕ethyl〕
-N-methylacetamide hydrochloride (23g) was obtained.
Ru. NMR (heavy water) δ; 1.41 (6H, doublet, J
= 7Hz), 1.76 and 2.06 (3H, two single
line), 2.70 to 3.10 (2H, multiplet line), 2.90 and
2.96 (3H, two singlets), 3.10~3.90 (5H,
multiplet), 4.00~4.50 (3H, multiplet), 6.80~
7.50 (4H, multiplet). (i) Concentrated hydrochloric acid of the amine compound (20g) obtained in (h) above
(200ml) solution in bomberol at 120° for 15 hours.
Heat for a while. After concentrating the reaction solution, aqueous with potassium carbonate.
After making it alkali, extract it with chloroform,
1-[2-[2-(N-methylamino)ethyl]
Phenoxy]-3-iso-propylamino-2-
Propanol (16.3g) is obtained. NMRδ; 1.11
(6H, double line, J=7Hz), 2.45 (3H, single line
line), 2.65 to 3.05 (8H, multiple line), 3.32 (2H, single line),
double line), 4.02 (3H, wide single line), 6.70~
7.30 (4H, multiplet). (j) The amine compound (251 mg) obtained in (i) above and
A mixture of rolopyridazine (176 mg) was added at 100℃ for 2 hours.
Heat and stir for an hour. Thin layer chromatography of the reaction mixture
GRAPHIE [Silica gel (Merck GF)₂₅₄)Black
Purified with roform-methanol (7:1)
1-[2-[2-[N-methyl-N-(3-k
lolo-6-pyridazinyl)amino]ethyl]ph
[enoxy]-3-iso-propylamino-2-p
Obtain Ropanol Hydrochloride (220mg). NMR (heavy
Water) δ; 1.42 (6H, doublet, J=7Hz), 2.75
~3.7 (6H, multiplet), 3.25 (3H, singlet),
3.85~4.55 (4H, multiplet), 6.80~7.65 (6H,
multiplet). (k) Chlor compound (200 mg) obtained in (j) above and calcium
A mixture of ethyl bazate (500 mg) was added at 150°C.
Heat and stir for an hour. Thin layer chromatography of reaction products
GRAPHIE [Silica gel (Merck GF)₂₅₄),nine
Purified with loloform-methanol (7:3)]
, 1-[2-[2-[N-methyl-N-[3-
(2-ethoxycarbonylhydrazino)-6-pi
ridazinyl[amino]ethyl]phenoxy]-
3-iso-propylamino-2-propanol
Obtain hydrochloride (48 mg). NMR (heavy methanol)
) δ; 1.27 (3H, triple line, J=7Hz), 1.33
(6H, double line, J=7Hz), 2.70~4.50 (10H,
multiplet), 3.01 (3H, singlet), 4.15 (2H, four
Multiplet, J=7Hz), 6.75-7.25 (6H, multiplet). (l) Ethoxycarbonyl compound obtained in (k) above (45
mg) in 10% hydrochloric acid (5 ml) was refluxed for 20 hours.
After that, the solvent was distilled off under reduced pressure to give 1-[2-[2-
[N-methyl-N-(3-hydrazino-6-pyri
dadinyl)amino]ethyl]phenoxy]-3
-iso-propylamino-2-propanol salt
Obtain the acid salt (35 mg). NMR (heavy methanol)
δ; 1.44 (6H, double line, J=7Hz), 2.9-4.65
(10H, multiplet), 3.36 (3H, singlet), 6.7~
7.85 (4H, multiplet), 7.41 (1H, doublet, J=
9Hz), 7.71 (1H, double line, J=9Hz). Example 9 (a) The amine compound (30 g) obtained in Example 8(b) was
Proceeding as in Example 8(e), N-(2-benzi
oxyphenylethyl)acetamide (30.5
g) is obtained. NMRδ; 1.78 (3H, singlet),
2.86 (2H, triple line, J=6Hz), 3.48 (2H, quadruple line, J=6Hz)
Double line, J=6Hz), 5.05 (2H, single line), 5.60~
6.03 (1H, multiplex), 6.72~7.30 (4H, multiplex)
line), 7.37 (5H, single line). (b) THF of the amide compound (28g) obtained in (a) above
(400 ml) solution under ice-cooling and stirring with lithium aluminum hydride.
minium (14g) of tetrahydrofuran (200g)
ml) dropwise into the suspension and stir and reflux for 1 hour. cold
After that, the precipitate is decomposed and decanted with Rothsiel salt solution.
Excluded by law. Solvent after drying with magnesium sulfate
was distilled off to give N-[2-(2-benzyloxyphenyl)
enyl)ethyl]-N-ethylamine (26g)
get. NMRδ; 1.02 (3H, triplet, J=7
Hz), 1.75 (1H, singlet), 2.61 (2H, quadruple
line, J=7Hz), 2.87 (4H, single line), 5.00
(2H, singlet), 6.68−7.55 (4H, multiplet),
7.33 (5H, single line). (c) Implement the amine compound (7.38g) obtained in (b) above.
Proceeding as in Example 8(e), N-[2-(2-benben
Zyloxyphenyl)ethyl]-N-ethyl
Cetamide (7.5 g) is obtained. NMRδ; 1.01
(3H, triple line, 7Hz), 1.80 and 2.01 (3H,
two singlets), 2.68~3.68 (6H, multiplet),
5.01 (2H, singlet), 6.70~7.60 (4H, multiplex)
line), 7.35 (5H, single line). (d) Example of the amide compound (6g) obtained in (c) above.
8(f), N-[2-(2-hydro
xyphenyl)ethyl]-N-ethylacetoa
Mido (4.2 g) is obtained. NMRδ; 1.14 (3H, three
Heavy line, 7Hz), 2.03 and 2.10 (3H, two one
multiplet), 2.63 to 3.70 (6H, multiplet), 6.72 to 7.09
(4H, multiplet). (e) The phenol compound (2.6 g) obtained in (d) above,
Pichlorohydrin (60ml) and potassium carbonate
After stirring and refluxing a mixture of (2.6 g) for 2 hours, it became insoluble.
leave things behind After concentrating the solution under reduced pressure, chloroform
Dissolve in water, wash with water, and dry with magnesium sulfate.
Ru. The solvent was distilled off to give N-[2-[2-(2,3
-Epoxypropoxy)phenyl)ethyl]-
N-ethylacetamide (2.6 g) is obtained.
NMRδ; 1.13 (3H, triplet, 7Hz), 2.01 and
and 2.08 (3H, two single lines), 2.60 to 3.10
(4H, multiplet), 3.16 to 3.72 (5H, multiplet),
3.72~4.60 (2H, multiplet), 6.70~7.40 (4H,
multiplet). (f) Messenger of the epoxy body (2.6g) obtained in (e) above.
iso-propylamine in tanol (70ml) solution
(28 ml) and left at room temperature for 15 hours, then the solvent
N-[2-(2-(2-hydroxy)
-3-iso-propylaminopropoxy) Fe
Nyl)ethyl]-N-ethylacetamide (3.2
g) is obtained. NMRδ; 1.08 (6H, doublet, 7
Hz), 1.15 (3H, triple line, 7Hz), 1.95 and
2.09 (3H, two singlets), 2.50~4.40 (14H,
multiplet), 6.67-7.40 (4H, multiplet). (g) Implement the amine compound (2.5g) obtained in (f) above.
1-[2-[2-(N
-ethylamino)ethyl]phenoxy]-3-
iso-propylamino-2-propanol
(1.67g) is obtained. NMRδ; 1.05 (3H, Mie
line, 7Hz), 1.06 (6H, double line, 7Hz), 2.40~
3.30 (12H, multiple line), 3.98 (3H, wide line)
multiplet), 6.70-7.40 (4H, multiplet). (h) Apply the amine compound (460mg) obtained in (g) above.
In the same manner as Example 8(j), 1-[2-[2-[N
-ethyl-N-(3-chloro-6-pyridazine
)amino[ethyl]phenoxy]-3-iso-
Propylamino-2-propanol (191mg)
get. NMRδ; 1.14 (6H, doublet, J=7
Hz), 1.16 (3H, triple line, J=7Hz), 2.60~
4.02 (14H, multiplex), 6.66~7.40 (6H, multiplex
line). (i) Perform the chloride obtained in (h) above (100mg)
In the same manner as Example 8(k), 1-[2-[2-[N
-ethyl-N-[3-(2-ethoxycarbonyl
hydrazino)-6-pyridanyl]amino]ethyl
phenoxy-3-iso-propylamino-
Obtain 2-propanol (30.5 mg). NMR
(Heavy methanol) δ; 1.01 (3H, triple line, J=
7Hz), 1.20 (6H, double line, J=7Hz), 2.55~
4.42 (14H, multiplex), 6.60~7.30 (6H, multiplex
line). (j) Ethoxycarbonyl compound obtained in (h) above (84
mg) in the same manner as in Example 8(l), 1-[2
-[2-[N-ethyl-N-(3-hydrazino-
6-pyridazinyl)amino]ethyl]phoenix
[C]-3-iso-propylamino-2-propano
Obtain mol hydrochloride (74 mg). NMR (heavy water)
δ; 1.24 (3H; triple line, J=7Hz), 1.40
(6H, double line, J=7Hz), 2.75-4.60 (12H;
multiplet), 6.70-7.60 (6H, multiplet). Example 10 (a) N-[3-(2-benzyloxyphenyl)
Lopyl]-N-methylacetamide (17g)
In the same manner as in Example 8(f), N-[3-(2-
hydroxyphenyl)propyl]-N-methyl
Acetamide (11.3 g) is obtained. NMRδ; 1.70
~2.24 (2H, multiplet), 2.03 and 2.10 (3H,
two singlets), 2.48-2.80 (2H, multiplet),
2.91 and 2.95 (3H, two singlets), 3.10~
3.60 (2H, multiplex), 6.58~7.20 (4H, multiplex)
line), 7.30-8.00 (1H, multiplet line). (b) Add the phenol compound (11.3g) obtained in (a) above to
In the same manner as in Example 9(e), N-[3-(2-
(2,3-epoxypropoxy)phenyl)
ropyru]-N-methylacetamide (10.3g)
get. NMRδ; 1.60-2.18 (2H, multiplet),
2.07 and 2.08 (3H, two singlets), 2.49~
3.06 (4H, multiplet), 2.92 and 2.98 (3H, double)
book singlet), 3.06-3.59 (3H, multiplet), 3.75
~4.95 (2H, multiplex), 6.68~7.23 (4H, multiplex
line). (c) Execute the epoxy body (10.3g) obtained in (b) above.
In the same manner as in Example 9(f), N-[3-(2-hi)
Droxy-3-iso-propylamino)propo
xy)phenyl]propyl]-N-methylacetate
Toamide (12.4 g) is obtained. NMRδ; 1.10
(6H, double line), 1.60~2.25 (2H, multiple line),
2.00 and 2.05 (3H, two singlets), 2.45 ~
3.00 (7H, multiplet), 2.90 and 2.93 (3H, double
book singlet), 3.00 to 3.55 (2H, multiplet), 3.98
(3H, wide single line), 6.60~7.21 (4H, multiline)
heavy line). (d) Implement the amine compound (12.4g) obtained in (c) above.
In the same manner as Example 8(i), 1-[2-[3-(N
-methylamino)propyl]phenoxy]-3
-iso-propylamino-2-propanol
(9.6g) is obtained. NMRδ; 1.10 (6H, double
line, J=7Hz), 1.51~2.10 (2H, multiple line,
2.30~3.60 (10H, multiple line), 2.86 (3H, single line)
line), 3.98 (3H, single line), 6.70 to 7.23 (4H, multiline)
heavy line). (e) Implement the amine compound (1.99g) obtained in (d) above.
In the same manner as Example 8(j), 1-[2-[3-[N
-Methyl-N-(3-chloro-6-pyridazine
)amino[propyl]phenoxy]-3-iso
-Propylamino-2-propanol hydrochloride
(890 mg). NMRδ; 1.48 (6H, double
line, J=7Hz), 1.60-2.20 (2H, multiple line),
2.45~4.72 (12H, multiplet), 3.06 (3H, singlet)
line), 6.45 to 7.22 (4H, multiplet line), 6.78 (1H, double line),
Double line, J=9Hz), 7.18 (1H, double line). (f) Apply the chloride obtained in (e) above (600mg)
-[2-[3-[N-memory]
Chil-N-[3-(2-ethoxycarbonylhydride)
radino)-6-pyridazinyl]amino]propyl
phenoxy-3-iso-propylamino-
Obtain 2-propanol hydrochloride (240 mg).
NMRδ; 1.22 (3H, triplet, J=7Hz), 1.41
(6H, double line, J=7Hz), 1.72~2.23 (2H,
multiplet), 2.28-4.49 (16H, multiplet), 2.99
(3H, singlet), 6.21-7.20 (6H, multiplet). (g) Ethoxycarbonyl compound obtained in (f) above
(200 mg) was treated in the same manner as in Example 8(l) to obtain 1-
[2-[3-[N-methyl-N-[3-hydrazino
-6-pyridazinyl]amino]propyl]fe
[noxy]-3-iso-propylamino-2-pro
Obtain panol hydrochloride (160 mg). NMR (heavy
Water) δ; 1.42 (6H, doublet), 1.75-4.55
(12H, multiplet), 3.18 (3H, singlet), 6.85~
7.78 (6H, multiplet). Example 11 (a) 2-hydroxyphenylmethylamine (12.3
g) in acetic anhydride (20 ml) and pyridine (20 ml).
ml) at room temperature overnight, then evaporate the solvent.
, N-(2-hydroxyphenylmethyl)a
Cetamide (12.6 g) is obtained. NMRδ；2.00
(3H, single line), 4.28 (2H, double line, J=6
Hz), 6.50 to 7.40 (5H, multiplet), 9.31 (1H, width
wide single line). (b) Example of the amide compound (14g) obtained in (a) above.
9(e), N-[2-(2,3-E)
poxypropoxy)phenylmethyl]acetoa
Obtain mido (15 g). NMRδ; 2.00 (3H, -
multiplet), 2.75 to 3.00 (2H, multiplet), 3.20 to 3.60
(1H, multiplet), 3.80~4.55 (4H, multiplet),
6.12~6.50 (1H, multiplet), 6.70~7.40 (4H,
multiplet). (c) Apply the epoxy body (5g) obtained in (b) above.
In the same manner as in Example 8(h), N-[2-(2-hydro
Roxy-3-iso-propylaminopropoxy
c) Phenylmethylacetamide hydrochloride
(5.9g) is obtained. NMR (heavy water) δ; 1.41
(6H, double line, J=7Hz), 2.05 (3H, single line
line), 3.20 to 3.90 (3H, multiplet line), 4.00 to 4.50
(3H, multiplet), 4.38 (2H, singlet), 6.85~
7.60 (4H, multiplet). (d) Implement the amine compound (2.4g) obtained in (c) above.
Proceeding as in Example 8(i), the 1-(2-aminomethyl
tylphenoxy)-3-iso-propylamino-
Obtain 2-propanol (2.1 g). NMRδ;
1.08 (6H, double line, J=7Hz), 2.40-3.20
(7H, multiplet), 3.60~4.25 (5H, multiplet),
6.70-7.40 (4H, multiplet). (e) Implement the amine compound (345 mg) obtained in (d) above.
In the same manner as Example 8(j), 1-[2-[N-(3
-chloro-6-pyridazinyl)aminomethyl]
Phenoxy]-3-iso-propylamino-2-
Obtain propanol hydrochloride (412 mg). NMR
δ; 1.35 (6H, double line, J=7Hz), 2.90~
3.60 (3H, multiplex), 3.88~4.70 (5H, multiplex)
line), 5.70 (3H, wide single line), 6.50 to 7.50
(6H, multiplet). (f) Apply the chloride (400 mg) obtained in (e) above.
In the same manner as Example 8(k), 1-[2-[N-[3
-(2-ethoxycarbonylhydrazino)-6-
Pyridazinyl]aminomethyl]phenoxy]-
3-iso-propylamino-2-propanol
Obtain hydrochloride (300 mg). NMR (heavy methanol)
) δ; 1.21 (3H, triple line, J=7Hz), 1.30
(6H, double line, J=7Hz), 3.00~3.25 (3H,
multiplet), 3.90 to 4.41 (5H, multiplet), 4.52
(2H, singlet), 6.70-7.43 (6H, multiplet). (g) Implement the ethoxycarbonyl compound obtained in (f) above.
In the same manner as in Example 8(l), 1-[2-[N-
(3-hydrazino-6-pyridazinyl)amino
Methyl]phenoxy]-3-iso-propylamide
No-2-propanol hydrochloride is obtained. Example 12 (a) 3-(2-hydroxyphenyl)propyla
Min (11 g) was treated as in Example 11(a),
N-(2-hydroxyphenylpropyl)acetate
Toamide (11 g) is obtained. NMR (heavy methanol)
) δ; 1.50 to 2.10 (2H, multiplet), 1.95
(3H, singlet), 2.48~2.80 (2H, multiplet),
3.05~3.40 (2H, multiplet), 6.52~7.18 (4H,
multiplet). (b) Example of the amide compound (12g) obtained in (a) above.
9(e) to obtain N-[3-(2-(2,
3-Epoxypropoxy)phenyl)propyl
] Acetamide (13 g) was obtained. NMRδ;
1.50~2.10 (2H, multiplet), 1.99 (3H, singlet)
line), 2.50~3.00 (4H, multiple line), 3.00~3.50
(3H, multiplet), 3.75~4.50 (2H, multiplet),
6.70-7.30 (5H, multiplet). (c) Apply the epoxy body (13g) obtained in (b) above.
In the same manner as Example 9(f), N-[3-[2-(2
-Hydroxy-3-iso-propylaminopro
poxy)phenyl]propyl]acetamide
(14 g) is obtained. NMRδ; 1.08 (6H, doublet,
J=7Hz), 1.50-2.07 (2H, multiplet), 1.96
(3H, singlet), 2.07~3.00 (7H, multiplet),
3.00 to 3.68 (2H, multiple line), 3.98 (3H, wide width)
singlet), 6.10-7.28 (5H, multiplet). (d) Example of the amine compound (13g) obtained in (c) above.
8(i), 1-[2-(3-amino
propyl) phenoxy]-3-iso-propyla
Mino-2-propanol (12 g) is obtained.
NMRδ; 1.08 (6H, doublet, J=7Hz), 1.50
~2.00 (2H, multiplex), 2.00~2.50 (4H, multiplex)
line), 2.50 to 3.10 (7H, multiple line), 3.98 (3H, width
wide singlet), 6.70 to 7.30 (4H, multiplet). (e) Implement the amine compound (1.2g) obtained in (d) above.
In the same manner as Example 8(j), 1-[2-[3-[N
-(3-chloro-6-pyridazinyl)amino]
Propyl phenoxy-3-iso-propyla
Obtained mino-2-propanol hydrochloride (870mg)
Ru. NMR (heavy methanol) δ; 1.39 (6H, di
Multiple line, J=7Hz), 1.70-2.28 (2H, multiple line),
2.55~2.94 (2H, multiplet), 3.05~3.65 (5H,
multiplet), 3.80~4.50 (3H, multiplet), 6.70~
7.31 (4H, multiplet), 6.90 (1H, doublet, J=
9Hz), 7.27 (1H, double line, J=9Hz). (f) Apply the chloride (500 mg) obtained in (e) above.
In the same manner as Example 8(k), 1-[2-[3-[N
-[3-(2-ethoxycarbonylhydrazino)
-6-pyridazinyl]amino]propyl]fe
[noxy]-3-iso-propylamino-2-pro
Obtain panol hydrochloride (300 mg). NMR (heavy media)
Tanol) δ; 1.25 (3H, triple line, J=7
Hz), 1.35 (6H, double line, J=7Hz), 1.55~
2.25 (2H, multiplex), 2.40~3.00 (2H, multiplex)
line), 3.00~3.70 (5H, multiple line), 3.80~4.60
(5H, multiplet), 6.60-7.27 (6H, multiplet). (g) Ethoxycarbonyl compound obtained in (f) above
(300 mg) was treated in the same manner as in Example 8(l) to obtain 1-
[2-[3-[N-(3-hydrazino-6-pyrida
di(dinyl)amino[propyl]phenoxy]-3
-iso-propylamino-2-propanol salt
Obtain the acid salt (225 mg). NMR (heavy methanol)
δ; 1.42 (6H, double line, J=7Hz), 1.70~
2.50 (2H, multiplex), 2.65~3.01 (2H, multiplex)
line), 3.01~3.85 (5H, multiple line), 3.90~4.60
(3H, multiplet), 6.61-7.86 (6H, multiplet).
MS, m/e374 (M⁺). Example 13 (a) 3-(2-acetoxyphenyl)-1-prope
(50g) in chloroform solution (250ml) -
Passes ozone at 60° to -70°C. Obtained ozo
After adding acetic acid (50 ml) to the nitride solution, the temperature of the solution was lowered to 18
Add zinc powder (40g) while keeping the temperature between ° and 25℃.
Ru. After reacting for 2 hours, remove insoluble materials and chlorinate.
Wash the loform solution in the order of 5% baking soda and water, and
Dry with magnesium acid. By distilling off the solvent,
2-acetoxyphenylacetaldehyde (48
g) is obtained. NMRδ; 2.28 (3H, singlet),
3.56 (2H, double line, J=3Hz), 7.25 (4H, width
wide single line), 9.61 (1H, triple line, J=3
Hz). (b) The aldehyde obtained in (a) above (47.9g),
Methoxycarbonylmethylenetriphenylphos
Horan (91.0g) and anhydrous toluene (500g)
ml) is stirred and refluxed for 5 hours. Insoluble after cooling
The solvent was distilled off under reduced pressure. Remove residue
5% sodium carbonate, 10% sulfur
Wash with acid and water in that order and dry with magnesium sulfate.
After that, the solvent was distilled off to give 3-(2-acetoxyphenate).
Methyl(enyl)-1-propene-1-carboxylate
ester (58.0 g) is obtained. NMRδ; 2.30 and above
and 2.33 (3H, two singlets), 3.20-3.52
(2H, multiplet), 3.71 (3H, singlet), 5.64~
7.65 (6H, multiplet). (c) Ester of the ester (40g) obtained in (b) above
5% palladium on charcoal.
Hydrogenation is carried out using 4g of hydrogen as a catalyst. anti
After the reaction, the catalyst is removed, the solvent is distilled off, and then distilled under reduced pressure.
3-(2-acetoxyphenyl)propane-1
-Carboxylic acid methyl ester (35.1g) was obtained.
Ru. bp139-141゜(3mmHg). NMRδ; 1.58
~2.10 (2H, multiplet), 2.31 (3H, singlet),
2.45 (2H, triple line, J=7Hz), 2.57 (2H, triple line, J=7Hz)
Double line, J=7Hz), 3.64 (3H, single line), 6.80~
7.30 (5H, multiplet). (d) Ester obtained in (c) above (10g), meta
Mixture of nol (100ml) and 10% hydrochloric acid (6ml)
After refluxing the liquid for 1 hour, add baking soda to make it alkaline.
and evaporate the solvent. Dissolve the residue in benzene
After washing with water, dry with magnesium sulfate.
The solvent was distilled off to give 3-(2-hydroxyphenylene)
) Propane-1-carboxylic acid methyl ester
(7.86g) is obtained. NMRδ; 1.60-2.17 (2H,
multiplet), 2.39 (2H, triplet, J=6Hz), 2.67
(2H, triple line, J=7Hz), 3.69 (3H, single line
line), 6.30 (1H, wide single line), 6.60 to 7.25
(4H, multiplet). (e) The phenol obtained in (d) above (18g),
Tanol (90ml) and potassium carbonate (40g)
After adding benzyl chloride (13.5g) to the mixture of
Stir and reflux for 4 hours. Remove insoluble matter and remove solvent
To leave. Dissolve the residue in benzene and add 4% hydroxy acid.
Wash with sodium chloride and water in that order, and rinse with magnesium sulfate.
The solvent was distilled off to give 3-(2-
benzyloxyphenyl)propane-1-cal
Obtain boronic acid ethyl ester (27.3g).
NMRδ; 1.20 (3H, triplet, J=7Hz), 1.70
~2.50 (4H, multiplet), 2.72 (2H, triplet, J
= 6Hz), 4.06 (2H, quartet, J = 6Hz), 5.05
(2H, singlet), 6.68-7.57 (9H, multiplet). (f) The benzyl ether compound obtained in (e) above (10
g), ethanol (100ml) and 10% sodium hydroxide
Reflux the mixture of thorium aqueous solution (20ml) for 30 minutes.
do. After distilling off the solvent and washing with benzene, remove the aqueous layer.
Acidify with 10% sulfuric acid and extract with benzene. ben
After washing the Zen layer with water, dry it with magnesium sulfate and dissolve it.
The solvent was distilled off to give 3-(2-benzyloxyphene).
)propane-1-carboxylic acid (8.4g)
obtain. NMRδ; 1.80-2.55 (4H, multiplet),
2.75 (2H, triple line, J=7Hz), 5.04 (2H, one
multiplet), 6.70~7.50 (9H, multiplet), 9.70~
10.30 (1H, wide single line). (g) Carboxylic acid (20g) obtained in (f) above and
Stir and heat thionyl chloride (30ml) at 50℃ for 3 hours.
do. Ether of oil obtained by distilling off the solvent
(60ml) solution under ice-cooling, concentrated ammonia (28%)
in a mixture of aqueous solution and ether (100ml)
After adding dropwise with stirring, stir at room temperature for 30 minutes. anti
Separate the ether layer from the reaction mixture and add 1% hydroxy acid.
sodium chloride, 5% sulfuric acid and water in this order.
Clean the layer. Magnesium sulfate ether layer
After drying with a vacuum cleaner, the solvent was distilled off to give 4-(2-
Benzyloxyphenyl)butanamide (13.2
g) is obtained. NMRδ; 1.70-2.40 (4H, multiplex
line), 2.70 (2H, triple line, J=6Hz), 5.02
(2H, single line), 5.45 (2H, wide single line),
6.70~7.55 (4H, multiplet), 7.33 (5H, singlet)
line). (h) Perform the acid amide compound (12g) obtained in (g) above.
Working similarly to Example 8(b), 4-(2-benzyl
Oxyphenyl)-1-butylamine (10.8
g) is obtained. NMR (heavy methanol) δ; 1.50
~1.90 (4H, multiplex), 2.50−3.05 (4H, multiplex)
line), 5.06 (2H, single line), 6.70~7.60 (9H, multiline)
heavy line). (i) Conduct the amine compound (10.0g) obtained in (h) above.
Proceeding as in Example 8(e), N-[4-(2-benzene)
Zyloxyphenyl)butyl]acetamide
(10.1g) is obtained. NMRδ; 1.35-2.30 (4H,
multiplet), 1.91 (3H, singlet), 2.40~2.91
(2H, multiplet), 3.00~3.50 (2H, multiplet),
5.08 (2H, singlet), 6.70~7.60 (4H, multiplex)
line), 7.40 (5H, single line). (j) Execute the acetyl compound (10.0g) obtained in (i) above.
In the same manner as in Example 8(f), N-[4-(2-hi)
Droxyphenyl)butyl]acetamide
(5.2g) is obtained. NMR (deuterium dimethyl sulfochloride)
Sid) δ; 1.12-2.00 (4H, multiplet), 1.80
(3H, singlet), 2.30~2.80 (2H, multiplet),
2.80~3.30 (2H, multiplet), 6.50~7.20 (5H,
multiplet), 7.75 (1H, wide singlet). (k) Add the phenol compound (4.5g) obtained in (j) above to
In the same manner as in Example 8(g), N-[4-[2-
(2,3-epoxypropoxy)phenyl]butylene
] Acetamide (3.6 g) was obtained. NMRδ;
1.30~1.82 (4H, multiplet), 1.95 (3H, singlet)
line), 2.45~3.00 (4H, multiple line), 3.03~3.50
(3H, multiplet), 3.70~4.45 (2H, multiplet),
6.30 (1H, wide single line), 6.60-7.30
(4H, multiplet). (l) Epoxy compound (3.5g) obtained in (k) above, iso
-propylamine (10ml) and methanol
(10 ml) is refluxed for 1 hour. Retain the solvent
to give N-[4-[2-(2-hydroxy-3
-iso-propylaminopropoxy)pheni
[butyl]acetamide (3.8 g) is obtained.
NMRδ; 1.07 (6H, doublet, J=7Hz), 1.30
~1.80 (4H, multiplet), 1.96 (3H, singlet),
2.30 to 3.50 (10H, multiple line), 3.97 (3H, wide width)
wide single line), 5.85 (1H, wide single line), 6.65
~7.30 (4H, multiplet). (m) 10% of the amine compound (2 g) obtained in (l) above
A solution of hydrochloric acid (40ml) is refluxed for 16 hours. reaction solution
After making alkaline with potassium carbonate, chlorophore
1-[2-(4-aminobutylene)
phenoxy]-3-iso-propylamino-
Obtain 2-propanol (1.5 g). the compound
(580 mg) was treated in the same manner as in Example 8(j) to obtain 1-
[2-[4-[N-(3-chloro-6-pyridazine
)amino[butyl]phenoxy]-3-iso-
Propylamino-2-propanol hydrochloride
(506 mg). NMRδ; 1.20-2.00 (4H,
multiplet line), 1.45 (6H, double line, J=7Hz), 2.40
~2.90 (2H, multiplex), 3.10~3.70 (5H, multiplex)
line), 4.04 (2H, wide single line), 4.60
(1H, wide single line), 6.60~7.20 (6H, multiline)
heavy line). (n) The chloride obtained in (m) above (500mg)
1-[2-[4-
[N-3-(2-ethoxycarbonyl hydrazide
-6-pyridazinyl[amino]butyl]
[enoxy]-3-iso-propylamino-2-p
Obtain Ropanol Hydrochloride (350mg). NMR (heavy
methanol) δ; 1.25 (3H, triple line, J=7
Hz), 1.35 (6H, double line, J=7Hz), 1.50~
2.00 (4H, multiplex), 2.48~3.00 (2H, multiplex)
line), 3.00 to 3.60 (5H, multiple line), 3.80 to 4.40
(3H, multiplet), 4.14 (2H, quartet, J=7
Hz), 6.75-7.40 (6H, multiplet). (o) Ethoxycarbonyl obtained in (n) above
body (200 mg) in 10% hydrochloric acid (10 ml) for 18 hours.
Stir and reflux. The solvent was distilled off under reduced pressure and dried.
1-[2-[4-(3-hydrazino-6-pyrida
Dinyl]amino]butyl]phenoxy]-3-
iso-propylamino-2-propanol hydrochloride
Obtain salt (50 mg). NMR (heavy methanol);
1.40 (6H, double line, J=6Hz), 1.52-2.00
(4H, multiplet), 2.52~3.00 (2H, multiplet),
3.00~3.80 (5H, multiplet), 3.90~4.60 (3H,
multiplet), 6.64-7.20 (6H, multiplet). Ms,
m/e386 (M⁺). Example 14 (a) 2-benzyloxyphenylacetic acid (2.42g)
Add thionyl chloride (8.5 ml) dropwise to the solution while stirring on ice.
down. After stirring at 50℃ for 3 hours, it was distilled off under reduced pressure.
2-benzyloxyphenyl acetate chloride
Add ethanol to a dichloromethane (50ml) solution of
Amine (1.83g) dissolved in dichloromethane (50ml)
Drop the solution under ice cooling. After stirring for 1 hour at room temperature
4% sodium hydroxide solution, then washed with water and sulfuric acid.
Dry with magnesium acid. The solvent was distilled off to give N-(2-hydroxyethyl
)-2-benzyloxyphenylacetamide
Obtain (2.36 g). NMRδ; 2.40~2.99 (1H, multiplet), 3.05~
3.71 (4H, multiplet), 3.57 (2H, singlet), 5.07
(2H, singlet), 5.90~6.41 (1H, multiplet),
6.75-7.50 (9H, multiplet). (b) Perform the amide compound (2.0g) obtained in (a) above.
Proceeding as in Example 8(f), N-(2-hydroxy
ethyl)-2-hydroxyphenylacetoa
Obtain Mido (1.60 g). NMRδ; 3.05-3.70
(6H, multiplet), 3.53 (2H, singlet), 6.52~
7.20 (4H, multiplex), 9.20~9.50 (1H, multiplex)
line). (c) Add the phenol compound (1.6g) obtained in (b) above to
In the same manner as in Example 9(e), N-(2-hydro
(oxyethyl)-2-(2,3-epoxypropo
xy) phenylacetamide (1.75 g) was obtained.
Ru. NMRδ; 1.95 (1H, singlet), 2.79-3.00
(2H, multiplet), 3.00~4.55 (9H, multiplet),
3.56 (2H, singlet), 6.05~6.70 (1H, multiple
line), 6.70-7.42 (4H, multiplet line). (d) Execute the epoxy body (1.75g) obtained in (c) above.
Working as in Example 9(f), N-(2-hydro
xyethyl)-2-(2-hydroxy-3-iso
Propylaminopropoxy) Phenylacetoa
Mido (2.06 g) is obtained. NMRδ; 1.08 (6H,
Double line, J=7Hz), 2.46-3.80 (10H, multiplex
line), 3.53 (2H, single line), 4.01 (3H, wide width)
singlet), 6.60-7.43 (5H, multiplet). (e) Tet of the amine (2.0g) obtained in (d) above
Add ice-cooled, stirred sewage water to a solution of lahydrofuran (50 ml).
Add a small amount of lithium aluminum oxide (3.0g)
After addition, the mixture was stirred and refluxed for 2 hours. Lotuse after cooling
Digest with a salt solution and remove the precipitate using a decanting method. After drying with magnesium sulfate, the solvent was distilled off.
Then dissolve the residue in 10% hydrochloric acid and wash with ether.
Ru. Neutralize the hydrochloric acid solution with 4% sodium hydroxide
After that, extract with ether and wash with water. sulfuric acid mug
After drying with nesium, the solvent was distilled off and N-
(2-hydroxyethyl)-N-[2-[2-(2
-Hydroxy-3-iso-propylaminopro
poxy)phenyl]ethyl]amine (1.8g)
get. NMRδ; 1.07 (6H, doublet J = 7Hz), 2.45
~3.06 (8H, multiplex), 3.06~3.80 (7H, multiplex)
line), 3.98 (3H, wide single line), 6.70-7.28
(4H, multiplet). (f) Conduct the amine compound (1.66g) obtained in (e) above.
In the same manner as Example 8(j), 1-[2-[2-[N
-(2-hydroxyethyl)-N-[3-chloro
-6-pyridazinyl]amino]ethyl]pheno
xy]-3-iso-propylamino-2-propa
Obtain nol hydrochloride (686 mg). NMRδ; 1.35 (6H, doublet J = 7Hz), 2.35
~5.00 (17H, multiplex), 6.65~7.22 (6H, multiplex
line). MS, m/e408 (M⁺). (g) Execute the chloride obtained in (f) above (500mg)
In the same manner as Example 8(k), 1-[2-[2-[N
-(2-hydroxyethyl)-N-[3-(2-ethyl)
Toxicarbonylhydrazino)-6-pyridazi
Nyl]amino]ethyl]phenoxy]-3-iso
Propylamino-2-propanol hydrochloride
(275 mg). NMR (heavy methanol) δ;
1.32 (6H, double line, J=7Hz), 1.28 (3H, three
Double line, J=7Hz), 2.65-4.50 (16H, multiplex
line), 6.70-7.30 (6H, multiplet line). (h) Ethoxycarbonyl compound obtained in (g) above
(250 mg) was treated in the same manner as in Example 8(l) to obtain 1-
[2-[2-[N-(2-hydroxyethyl)-N
-[3-hydrazino-6-pyridazinyl]ami
[ethyl]phenoxy]-3-iso-propyl
Amino-2-propanol hydrochloride (260mg)
obtain. NMR (heavy water) δ; 1.41 (6H, doublet,
J=7Hz), 2.75-5.50 (14H, multiplet), 6.80
~7.45 (6H, multiplet). Example 15 (a) 3-chloro-6-ethoxycarbonylpyrida
Gin (9.30g), 2-hydroxyphenylethyl
of Ruamine (6.60g) and Ethanol (50ml)
The mixture is stirred at room temperature overnight. After distilling off the solvent,
Thin layer chromatography of the residue [silica gel
(Merck GF254), purified with chloroform],
6-chloro-N-[2-(2-hydroxyphenylene)
)ethyl]-3-pyridazinecarboxamide
(6.12g) is obtained. NMR (heavy methanol) δ;
2.94 (2H, triple line, J=7Hz), 3.68 (2H, triple line)
Multiple line, J=7Hz), 6.50-7.20 (4H, multiple line),
7.87 (1H, double line, J=9Hz), 8.20 (1H, double line)
double line, J=9Hz). (b) The chloride obtained in (a) above (2.04g) and
Hydrazine hydrate (1.50g) in ethanol
(100 ml) for 2 hours. Cool the reaction mixture
After cooling, the solvent is distilled off and water is added to remove the precipitated crystals.
and 6-hydrazino-N-[2-(2-hydro
Roxyphenyl)ethyl]-3-pyridazinca
Ruboxamide (1.68 g) is obtained. This hydrazi
A suspension of the compound (1.68 g) in acetone (200 ml)
After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure.
6-iso-propylidenehydrazino-N-
[2-(2-hydroxyphenyl)ethyl]-3
- Obtained pyridazine carboxamide (1.63 g)
Ru. NMRδ; 1.94 (3H, singlet), 2.09
(3H, single line), 2.98 (2H, triple line, J=7
Hz), 3.60 (2H, triple line, J=7Hz), 6.60~
7.50 (5H, multiplet), 7.51 (1H, doublet, J=
9Hz), 8.10 (1H, double line, J=9Hz), 8.20~
8.60 (1H, wide single line). MS, m/e313
(M⁺). (c) The phenolic compound obtained in (b) above (1.26 g),
Epipromohydrin (3.52g) and ethanol
(10ml) of 0.1N sodium ethyl alcohol.
Add oxide (40 ml) and reflux for 30 minutes. Then
The solvent was distilled off, water was added to the residue, and chloroform was added.
Extract with Magnesium sulfate removes the chloroform layer
The crude product obtained by distilling off the solvent after drying with a
Thin layer chromatography [Silica gel (Merck
GF254), chloroform-methanol (30:
1)] to produce 6-iso-propylidenehyde.
Radino-N-[2-[2-(2,3-epoxyp
Ropoxy)phenyl]ethyl]-3-pyridazi
Obtain carboxamide (300 mg). NMRδ;
1.98 (3H, singlet), 2.09 (3H, singlet), 2.70
~3.20 (4H, multiplex), 3.25~4.42 (5H, multiplex)
line), 6.70 to 7.40 (4H, multiple line), 7.53 (1H, double
Double line, J=9Hz), 8.10 (1H, double line, J=9
Hz), 8.30-8.70 (1H, wide singlet).
MS, m/e369 (M⁺). (d) Messenger of the epoxy compound (210 mg) obtained in (c) above.
iso-propylamine in tanol (10ml) solution
(10ml) in methanol (50ml) for 30 minutes.
Reflux for a while. Then, the solvent was distilled off to give 6-iso
-Propylidenehydrazino-N-[2-[2-
(2-hydroxy-3-iso-propylaminopropylene)
Ropoxy)phenyl]ethyl]-3-pyridazi
obtain carboxamide (170mg). NMRδ; 1.17 (6H, doublet, J=6Hz),
1.99 (3H, singlet), 2.07 (3H, singlet), 2.65
~3.30 (7H, multiplet), 3.65 (2H, wide four
Multiple line, J=6Hz), 3.90-4.50 (3H, multiple line),
6.60~7.35 (4H, multiplet), 7.49 (1H, doublet)
line, J=9Hz), 8.04 (1H, double line, J=9
Hz), 8.23 (1H, wide triple line, J=6
Hz). MS, m/e428 (M⁺). Example 16 6-iso-propylidenehydrazino-N-[2-
[2-(2-hydroxy-3-iso-propylamide
nopropoxy)phenyl]ethyl]-3-pyrida
Zincarboxamide (410 mg) was added as in Example 4.
6-hydrazino-N-[2-[2-
(2-hydroxy-3-iso-propylaminopro
poxy)phenyl]ethyl]-3-pyridazinka
Obtain Ruboxamide Hydrochloride (270mg). NMR (heavy
methanol) δ; 1.43 (6H, doublet, J=6
Hz), 2.70~3.90 (7H, multiplet), 3.90~4.60
(3H, multiplet), 6.70 to 7.40 (4H, multiplet), 7.56
(1H, double line, J=9Hz), 8.14 (1H, double line,
J=9Hz). Example 17 (a) 2-hydroxybenzylamine (695mg)
Working similarly to Example 15(a), 6-chloro-N
-(2-hydroxyphenylmethyl)-3-pyri
Obtain Dazine carboxamide (800mg). NMR
(Heavy methanol) δ; 4.60 (2H, singlet), 6.60
~7.40 (4H, multiplet), 7.80 (1H, doublet, J
= 9Hz), 8.24 (1H, double line, J = 9Hz). (b) Apply the chloride obtained in (a) above (600mg)
Proceeding as in Example 15(b), the 6-iso-propyl
Denhydrazino-N-(2-hydroxyphenylene)
methyl)-3-pyridazinecarboxamide
(599 mg). NMR (heavy methanol) δ;
2.20 (3H, singlet), 2.22 (3H, singlet), 4.56
(2H, singlet), 6.60~7.40 (4H, multiplet),
7.89 (1H, double line, J=9Hz), 8.30 (1H, double line, J=9Hz)
double line, J=9Hz). (c) Add the phenolic compound (500 mg) obtained in (b) above to
Proceed as in Example 15(c) to prepare 6-iso-propylene.
Pylidenehydrazino-N-[2-(2,3-epo
xypropoxy)phenylmethyl]-3-pyri
Obtain Dazine carboxamide (150 mg). NMRδ; 1.97 (3H, singlet), 2.08 (3H, singlet)
multiplet), 2.70 to 3.10 (2H, multiplet), 3.20 to 3.55
(1H, multiplet), 3.70~4.45 (2H, multiplet),
4.68 (2H, double line, J=6Hz), 6.65-7.45
(4H, multiplet), 7.50 (1H, doublet, J=9
Hz), 8.10 (1H, double line, J=9Hz), 8.10~
8.60 (2H, wide single line). (d) Execute the epoxy compound (300 mg) obtained in (c) above.
Proceeding as in Example 15(d), 6-iso-propylene
Lydenhydrazino-N-[2-(2-hydroxy
-3-iso-propylaminopropoxy) Fe
Nylmethyl]-3-pyridazinecarboxamide
(300 mg). NMR (heavy methanol) δ;
1.06 (6H, double line, J=6Hz), 2.00 (3H, one
double line), 2.07 (3H, single line), 2.40~3.15 (3H,
multiplet), 4.02 (3H, wide singlet), 4.62
(2H, singlet), 6.70~7.40 (4H, multiplet),
7.44 (1H, double line, J=9Hz), 7.97 (1H, double line)
heavy line, J=9Hz). Example 18 6-iso-propylidenehydrazino-N-[2-
(2-hydroxy-3-iso-propylaminopro
poxy)phenylmethyl]-3-pyridazinecal
Boxamide (150mg) was treated as in Example 4.
and 6-hydrazino-N-[2-(2-hydroxy
-3-iso-propylaminopropoxy)pheni
methyl]-3-pyridazinecarboxamide hydrochloride
Obtain salt (95 mg). NMR (heavy water) δ; 1.39 (3H, doublet, J=6
Hz), 1.42 (3H, double line, J=6Hz), 3.10-3.80
(3H, multiplet), 4.00 to 4.60 (3H, multiplet), 6.70
~7.60 (4H, multiplet), 7.58 (1H, doublet, J=
9Hz), 8.15 (1H, double line, J=9Hz). Example 19 (a) 3-(2-hydroxyphenyl)propyla
Min (1.35 g) was treated as in Example 15(a).
6-chloro-N-[3-(2-hydroxyph)
enyl)propyl]-3-pyridazinecarboxy
Obtain samide (1.34 g). NMRδ; 1.70-2.40
(2H, multiplet), 2.77 (2H, triplet, J=7
Hz), 3.53 (2H, quartet, J=7Hz), 6.55~
7.40 (5H, multiplet), 7.64 (1H, doublet, J=
9Hz), 8.27 (1H, double line, J=9Hz), 8.30~
8.70 (1H, multiplet). (b) Perform the chloride (1.16g) obtained in (a) above.
Proceeding as in Example 15(b), the 6-iso-propyl
Denhydrazino-N-[3-(2-hydroxyph)
enyl)propyl]-3-pyridazinecarboxy
Obtain samide (807 mg). NMRδ; 1.70-2.20
(2H, multiplet), 1.92 (3H, singlet), 2.07
(3H, single line), 2.77 (2H, triple line, J=7
Hz), 3.47 (2H, quartet, J=7Hz), 6.60~
7.30 (5H, multiplet), 7.48 (1H, doublet, J=
9Hz), 8.08 (1H, double line, J=9Hz), 8.00~
8.45 (1H, multiplet). (c) Add the phenol compound (740 mg) obtained in (b) above to
Proceed as in Example 15(c) to prepare 6-iso-propylene.
Pylidenehydrazino-N-[3-[2-[2,3
-Epoxypropoxy)phenyl]propyl]
-3-pyridazinecarboxamide (220mg)
obtain. NMRδ; 1.70-2.30 (2H, multiplet),
1.97 (3H, singlet), 2.08 (3H, singlet), 2.55
~3.00 (4H, multiplex), 3.20~3.70 (3H, multiplex)
line), 3.80~4.40 (2H, multiple line), 6.70~7.30
(4H, multiplet), 7.50 (1H, doublet, 9Hz),
8.08 (1H, double line, J=9Hz), 8.45 (1H, width
wide single line). (d) Add the epoxide (200mg) obtained in (c) above to
Using the same procedure as in Example 15(d), the 6-iso-propylene
Pylidenehydrazino-N-[3-[2-(2-H
Droxy-3-iso-propylamide) propoxy
Cyphenylspropyl-3-pyridazinecal
Get boxamide. NMRδ; 1.38 (3H, double
line, J=7Hz}, 1.46 (3H, double line, J=7
Hz), 1.70 to 2.30 (2H, multiplet), 2.07 (3H, one
double line), 2.17 (3H, single line), 2.40~5.00
(12H, multiplet), 6.40~7.40 (4H, multiplet),
7.63 (1H, double line, J=9Hz), 8.00 (1H, width
wide single line), 8.08 (1H, double line, J=9
Hz). MS, m/e442 (M⁺). Example 20 6-iso-propylidenehydrazino-N-[3-
[2-(2-hydroxy-3-iso-propylamide
nopropoxy)phenyl]propyl]-3-pyri
Dazine carboxamide (50 mg) as in Example 4.
6-hydrazino-N-[3-[2-
(2-hydroxy-3-iso-propylaminopro
poxy)phenyl]propyl]-3-pyridazine
Obtain carboxamide hydrochloride (32 mg). NMR
(Heavy water) δ; 1.43 (6H, doublet, J=7Hz), 1.97
(2H, quintet, J=7Hz), 2.76 (2H, triplet,
J=7Hz), 3.10~3.85 (5H, multiplet), 4.00~
4.50 (3H, multiplet), 6.70~7.40 (4H, multiplet),
7.54 (1H, double line, J=9Hz), 8.06 (1H, double line
line, J=9Hz). MS, m/e402 (M⁺). Example 21 (a) 2-methoxybenzyl bromide (18 g)
A solution of magnesium in dry ether (100ml)
(2.08 g) in dry ether (5 ml).
Gradually add dropwise while stirring warmly. Mostly magnesium
After the water has disappeared, the reaction mixture obtained above is
Chirsuccinimide (4g) in benzene (30
ml) into the solution gradually at 15-18°C while stirring.
After the dropwise addition was completed, stirring was continued for an additional 17 hours at room temperature. cold
Separate the organic layer after decomposition with warmed ammonium solution
Then, the aqueous layer is further extracted with ether. organic layer
The mixture was dried with magnesium sulfate, and the solvent was distilled off.
Florisil Column Bear Sparrowfish After Leaving
(60-100 meshes, chloroform elution)
and N-methyl-3-(2-methoxybendi
2-pyrrolidone (2.35 g) is obtained.
NMRδ; 2.32~2.75 (2H, multiplet), 2.75~
3.20 (2H, multiplet), 3.09 (3H, singlet), 3.83
(3H, single line), 5.93 (1H, wide single line),
6.70-7.40 (4H, multiplet). MS, m/e217 (M
⁺). (b) The pyrrolidone compound (4.3g) obtained in (a) above,
Drazine hydrate (10ml) and 50% acetic acid solution
The mixture of liquid (250 ml) is refluxed for 1 hour. melt
After removing the solvent under reduced pressure, 5% sodium carbonate solution was added.
Extract with methylene chloride. with magnesium sulfate
After drying, the solvent was distilled off to give 6-(2-methoxyphenyl)
enylmethyl)-4,5-dihydro-3(2H)
- Obtain pyridazinone (3.9 g). NMRδ;
2.40 (4H, singlet), 3.63 (2H, singlet), 3.81
(3H, singlet), 6.70~7.50 (4H, multiplet),
8.75 (1H, wide single line). MS, m/e218
(M⁺). (c) Dihydropyridazinone compound obtained in (b) above
(1.52 g) in acetic acid (15 ml) and kept at 75℃.
While adding a solution of bromine (270 mg) in acetic acid (10 ml) to 30
The mixture was added dropwise over a period of 30 minutes, and the mixture was further stirred at the same temperature for 30 minutes. solvent
After distilling off the salt, add 5% sodium carbonate solution.
Extract with methylene chloride. Dry with magnesium sulfate
After drying, remove the solvent and perform thin layer chromatography.
[Silica gel (Merck GF254) Chloroform-
methanol (10:1)] to obtain 6-(2-methane)
Toxyphenylmethyl)-3(2H)-pyridazi
Obtain Non (840mg). NMR (heavy methanol)
δ; 3.80 (3H, singlet), 3.91 (2H, singlet
line), 6.71 to 7.47 (4H, multiple line), 6.81 (1H, double
Double line, J=9Hz), 7.29 (1H, double line, J=9
Hz). MS, m/e216 (M⁺). (d) Pyridazinone compound obtained in (c) above (1.0 g),
Phosphorus pentasulfide (6.5g) and pyridine (80ml)
The mixture was stirred and refluxed for 1 hour. Remove the solvent under reduced pressure
After removing, dissolve in methylene chloride and add dilute hydrochloric acid.
Wash with water and dry with magnesium sulfate.
After distilling off the solvent, use a Florisil column chromatograph.
Roughy (60-100 mesh, dissolved in chloroform)
6-(2-methoxyphenyl)
Methyl)-3(2H)-pyridazinethione (750
mg). NMRδ; 3.78 (3H, singlet),
3.97 (2H, singlet), 6.60~7.57 (5H, multiple
line), 6.93 (1H, double line, J=9Hz), 7.58
(1H, double line, J=9Hz). MS, m/e232 (M
⁺). (e) Thione compound (1.3g) obtained in (d) above and
Nitrogenize the mixture of hydrazine hydrate (50ml)
Reflux under atmosphere for 2.5 hours. The solvent was removed under reduced pressure and the residue was dissolved in dry ethanol.
Dissolve in a solution of hydrogen chloride and add a mixture of dry hydrogen chloride and ether.
When heated, crystals will precipitate. Take this ethanol
6-(2-methoxy)
Cyphenylmethyl)-3-hydrazinopyridadi
Obtain 940 mg of ion hydrochloride. NMR (heavy methanol)
) δ; 3.77 (3H, singlet), 4.35 (2H, singlet)
line), 6.73 to 7.63 (4H, multiplet line), 7.77 (1H, double line),
Double line, J=9Hz), 8.00 (1H, double line, J=9
Hz), MS, m/e230 (M⁺). (f) Hydrochloride (1.0g) obtained in (e) above and 48
After stirring and refluxing % hydrobromic acid (5 ml) for 2 hours.
Concentrate under reduced pressure. 10% potassium carbonate water to the residue
Solution (10ml) and acetone (1ml)
Extract with loloform. chloroform layer with sulfuric acid
After drying with magnesium, the solvent was distilled off to give 6-
(2-hydroxyphenylmethyl)-3-iso-
Propylidenehydrazinopyridazine (700g)
get. NMRδ; 1.90 (3H, singlet), 2.03
(H, singlet), 4.07 (2H, singlet), 6,63~
7.67 (5H, multiplet), 7.28 (1H, doublet, J=
9Hz), 7.51 (1H, double line, J=9Hz). MS,
m/e256 (M⁺). (g) The phenol compound (1.75g) obtained in (f) above,
Pipromohydrin (10ml), potassium carbonate (20ml)
g) and methyl ethyl ketone (200 ml).
The mixture is stirred and refluxed for 4 hours. removed insoluble matter
Afterwards, the solvent is distilled off. The residue was dissolved in methanol (10
ml) and iso-propylamine (5 ml).
Add and leave at room temperature for 17 hours. After distilling off the solvent
Thin layer chromatography [Silica gel (Merck
GF254) Chloroform-methanol (5:
1)] to obtain 1-[2-(3-iso-propylene)
lydenhydrazino-6-pyridazinylmethyl)
Phenoxy]-3-iso-propylamino-2-
Obtain propanol (213 mg). NMRδ; 1.07
(6H, double line, J=7Hz), 1.90 (3H, single line
line), 2.00 (3H, single line), 2.45 to 3.20 (3H, multiline)
multiplet), 3.55 to 4.4 (5H, multiplet), 4.14 (2H,
singlet), 6.68-7.50 (6H, multiplet). MS,
m/e371 (M⁺). Example 22 (a) 5-(2-hydroxyphenyl)-3-oxo
Methane of pentane-1-carboxylic acid (2.5g)
(75 ml) solution and concentrated sulfuric acid (2.5 ml).
The combined solution is refluxed for 1 hour. Distill methanol under reduced pressure
After that, dilute with water, extract with chloroform, and wash with water.
After drying with magnesium sulfate. Distill the solvent
After that, Florisil column chromatography [60
-100 mesh, eluted with chloroform]
and 5-(2-hydroxyphenyl)-2-o
Xopentane-1-carboxylic acid methyl ester
(2.6g) is obtained. NMRδ; 2.50-2.76 (4H,
multiplet), 2.86 (4H, singlet), 3.62 (3H, singlet)
multiplet), 6.60 to 7.26 (4H, multiplet), 7.32 (1H,
wide single line). MS, m/e236 (M⁺). (b) The methyl ester obtained in (a) above (850
mg), epibromohydrin (4.25g), potassium carbonate
(850 mg) and methyl ethyl ketone (25
ml) mixture was stirred and refluxed for 10 hours, and then the insoluble matter was removed.
and evaporate the solvent. Thin layer chromatography of the residue
Graphie [Silica gel (Merck GF254) Ben]
purified with zene-methanol (50:1)],
- [2(2,3-epoxypropoxy)pheni
]-3-oxopentane-1-carboxylic acid
The thyl ester (585 mg) is obtained. NMRδ; 2.50
~3.10 (10H, multiplex), 3.15~3.65 (1H, multiplex)
line), 3.65 (3H, single line), 3.75 to 4.45 (2H, multiline)
multiplet), 6.68-7.50 (4H, multiplet). MS, m/
e292(M⁺). (c) Messenger of the epoxy compound (560 mg) obtained in (b) above.
iso-propylamine in tanol (10ml) solvent
(5 ml) and reflux for 45 minutes. distill off the solvent
5-[2-(2-hydroxy-3-isopropropylene)
pyraminopropoxy)phenyl]-3-oxy
Sopentane-1-carboxylic acid methyl ester
(672 mg). NMRδ; 1.08 (6H, double
line, J=7Hz), 2.30-3.20 (13H, multiple line),
3.68 (3H, single line), 3.99 (3H, wide single line)
line), 6.69-7.45 (4H, multiplet line). MSm/e351
(M⁺). (d) Amine compound (600 mg) obtained in (c) above, hydra
Zine hydrade (1.0g) and ethanol
(25ml) was refluxed for 1 hour and then dissolved under reduced pressure.
Distill the medium. Thin layer chromatography of residue
− [Silica gel (Merck GF254) Chloroform
-methanol (4:1)] and purified with 1-[2
-[2-(3(2H)-oxo-4,5-dihydro
-6-pyridazinyl)ethyl)phenoxy]-
3-iso-propylamino-2-propanol
(540 mg). NMRδ; 1.08 (6H, double
line, J=7Hz), 2.10~3.30 (13H, multiple line),
4.02 (3H, wide single line), 6.70-7.50
(4H, multiplet). MSm/e333 (M⁺). (e) Dihydropyridazinone compound obtained in (d) above
(500mg), acetic acid (2.5ml), acetic anhydride (2.5ml) and
and pyridine (2 drops) at 70°C for 45 minutes.
While stirring and maintaining the same temperature, add bromine (260
mg) in acetic acid (10 ml) was added dropwise over 40 minutes.
After removing the solvent under reduced pressure, the residue was subjected to thin layer chromatography.
Tography - [Silica gel (Merck GF₂₅₄)Black
Roform-acetone-methanol (20:5:
1)] to obtain 1-[2-[2-(3(2H)-
Oxo-6-pyridazinyl)ethyl
[C]-3-N-acetyl-iso-propylamino
-2-acetoxypropanol (255 mg) was obtained.
Ru. NMRδ; 1.18, 1.25 (6H, 2 sets of double
line, J=6Hz), 2.04, 2.17 (3H, two single
line), 2.17 (3H, single line), 2.90 (4H, wide width)
singlet), 3.00~4.40 (5H, multiplet), 5.65~
6.05 (1H, multiple line), 6.70~7.40 (6H, multiple line)
line). MS, m/e415 (M⁺). (f) Pyridazinone compound obtained in (e) above (800 mg),
Phosphorus pentasulfide (800mg) and pyridine (50ml)
The mixture was stirred and refluxed for 1 hour, and then the solvent was removed under reduced pressure.
To leave. Solvent the residue in methylene chloride and dilute
Washed with hydrochloric acid and then dried with magnesium sulfate.
and evaporate the solvent. Thin layer chromatography of the residue
Roughy [Silica gel (Merck GF)₂₅₄)benzene
- methanol = 10:1] and purified with Rf = 0.4 parts
minutes, 1-[2-[2-(3(2H)-thioxo
-6-pyridazinyl)ethyl]phenoxy]-
3-N-thioacetyl-iso-propylamino
-2-acetoxypropanol (310 mg) was obtained.
Ru. NMRδ; 1.25, 1.30 (6H, two sets of double
line, J=6Hz), 2.05 (3H, single line), 2.74
(3H, single line), 2.94 (4H, single line), 3.40~
4.55 (5H, multiplex), 5.65~6.05 (1H, multiplex)
line), 6.60 to 7.40 (5H, multiple line), 7.60 (1H, double
double line, J=9Hz). MS, m/e447 (M⁺). Rf
From the =05 part 1-[2-[2-(3(2H)-chi)
Oxo-6-pyridazinyl)ethyl
[C]-3-N-acetyl-iso-propylamino
-2-acetoxypropanol (310 mg) was obtained.
Ru. NMRδ; 1.19, 1.25 (6H, two sets of double
line, J=6Hz), 2.04, 2.18 (3H, two single
line), 2.18 (3H, single line), 2.93 (4H, single line)
line), 3.00~4.30 (5H, multiple line), 5.30~5.75
(1H, multiplet), 6.76~. 43 (5H, multiplet),
7.57 (1H, double line, J=9Hz). MSm/e431
(M⁺). (g) (i) Thioxo-N-thioa obtained in (f) above
Cetyl compound (310mg), 1N sodium hydroxide
(10ml) and methanol (150ml) mixture
After refluxing for 1.5 hours, the solvent was distilled off under reduced pressure.
Ru. Dissolve the residue in chloroform, wash with water, and remove with sulfuric acid.
After drying with magnesium acid and evaporating the solvent, the remaining
Thin layer chromatography of substances - [Silica gel
(Merck GF₂₅₄) Benzene-methanol (15:
1)] and purified with 1-[2-[2-(3(2H)-
Thioxo-6-pyridazinyl)ethyl]fe
[Noxy]-3-iso-propylamino-2-p
Obtain Lopanol (170mg). NMRδ; 1.23
(6H, double line, J=7Hz), 2.60-3.52
(5H, multiplet), 22.91 (4H, singlet), 3.80
~4.06 (2H, multiplet), 4.06~4.51 (1H, multiplet)
multiplet), 6.60 to 7.37 (5H, multiplet), 7.50
(1H, double line, J=9Hz). MSm/e347 (M
⁺). (ii) Thioxo-N-acetyl obtained in (f) above
body (310 mg) in the same manner as in (g)(i) above.
1-[2-[2-(3(2H)-thioxo-6-
pyridazinyl)ethyl]phenoxy]-3-
iso-propylamino-2-propanol
(40 mg). (h) The amino compound obtained in (g) above (200 mg) and
Nitrogenize the mixture of hydrazine hydrate (20ml)
Reflux under atmosphere for 2.5 hours. excess hydrazi
The hydrate was distilled off under reduced pressure to give 1-[2-[2-
(3-hydrazino-6-pyridazinyl)ethyl
phenoxy-3-iso-propylamino-
Obtain 2-propanol (191 mg). NMR (heavy
methanol) δ; 1.22 (6H, doublet, J=7
Hz), 2..70~3.45 (3H, multiplet), 3.01 (4H,
singlet), 3.80~4.40 (3H, multiplet), 6.60~
7.39 (6H, multiplet). MSm/e345 (M⁺). The above compound is treated with ethanol-hydrochloric acid to form a salt.
Obtain the acid salt. NMR (heavy water) δ; 1.42 (6H, di
Multiple line, J=7Hz), 2.40-3.90 (7H, multiple line),
3.95~4.56 (3H, multiplet), 6.81~7.56 (4H,
multiplet), 7.68 (1H, doublet, J=9Hz), 7.94
(1H, double line, J=9Hz). MSm/e345 (M
⁺). Example 23 1-[2-[2-(3-hydrazino-6-pyrida
(dinyl)ethyl]phenoxy]-3-iso-propylene
Ruamino-2-propanol was treated with acetone.
, 1-[2-[2-(3-iso-propylidenehyde
Radino-6-pyridazinyl)ethyl phenoxy
-3-iso-propylamino-2-propanol
get. NMRδ; 1.24 (6H, doublet, J=7
Hz), 1.96 (3H, singlet), 2.00 (3H, singlet),
2.60 to 3.70 (9H, multiple line), 3.79 to 4.50 (3H, multiple line)
multiplet), 6.65 to 7.37 (5H, multiplet), 7.38 (1H, double
double line, J=9Hz). MS, m/e385 (M⁺). Example 24 (a) Carboxylic acid obtained in Example 13 (f) (5.0
g) and thionyl chloride (15 ml) at 50°C for 3 hours.
Heat while stirring. Oily substance obtained by distilling off the solvent
of diazomethane in anhydrous ether (50 ml)
Add dropwise into ether solvent (150 ml) at 0°C.
Leave for 1 hour. 40% cold in this ether solution
Add the hydrogen bromide-containing ether solution dropwise. 0℃,
After standing for 1 hour, the solvent was distilled off and the resulting oil was filtered.
Loridil column chromatography (60-100
Purify with mesh, benzene elution) and 1 bronch.
mo-2-oxo-5-[2-benzyloxif
[enyl]pentane (6.11 g) was obtained. NMR
δ; 1.70 to 2.30 (2H, multiplet), 2.60 (2H, triplet)
double line, J=7Hz), 2.70 (2H, triple line, J=7
Hz), 3.71 (2H, singlet), 5.02 (2H, singlet)
line), 6.70-7.50 (9H, multiplet line). (b) Bromoketone body obtained in (a) above (6.11g)
Anhydrous benzene (20ml) solution of methoxycarboxylate
Nilmethylenetriphenylphosphorane (11.76
Add dropwise to a solution of g) in anhydrous benzene (20 ml) under reflux.
Then, the mixture was stirred and refluxed for 2 hours. Precipitation after cooling
Remove the precipitate and add ethyl bromoacetate to the solution.
Add 2.69 g and stir and reflux for an additional 2 hours. After cooling
After removing the precipitated crystals and washing the liquid with water, add sulfuric acid.
Dry over magnesium and evaporate the solvent. residue
Florisil column chromatography (60~
100 mesh, benzene elution) and purify with 6
-(2-benzyloxyphenyl)-3-oxo
-1-hexene-1-carboxylic acid methyl ester
(5.57 g). NMRδ; 1.60-2.25
(2H, multiplet), 2.62 (2H, triplet, J=7
Hz), 2.73 (2H, triple line, J=7Hz), 3.78
(3H, singlet), 5.05 (2H, singlet), 6.53
(1H, double line, J=16Hz), 7.19 (1H, double line
line, J=16Hz), 6.80-7.55 (9H, multiplet line). (c) δ-ketoester obtained in (b) above (4.1
g) in ethanol (150 ml) with 5% paradia.
Hydrogen for 3 hours using um-carbon (1.2g) as a catalyst
Added. The catalyst is removed and the solvent is distilled off. residual
Thin layer chromatography (silica gel)
Luc GF₂₅₄) Benzene-methanol (5:1)]
6-(2-benzyloxyphenylene)
)-3-oxo-hexane-1-carboxylic acid
Methyl ester 4 (1.67 g) is obtained. NMR
δ; 1.60-2.20 (2H, multiplet), 2.30-2.86
(8H, multiplet), 3.65 (3H, singlet), 5.06
(2H, singlet), 6.70-7.60 (9H, multiplet). (d) δ-ketoester obtained in (c) above (1.6
g), acetic acid (20 ml) and concentrated hydrochloric acid (10 ml).
After refluxing the combined solution for 2 hours, the solvent was distilled off under reduced pressure.
Ru. The obtained 6-(2-hydroxyphenylene)
)-3-oxohexane-1-carboxylic acid
(1.4 g) was treated in the same manner as in Example 22(a) to obtain 6-
(2-hydroxyphenyl)-3-oxohexa
N-1-carboxylic acid methyl ester (1.2g)
get. NMRδ; 1.80-2.15 (2H, multiplet),
2.40~3.00 (8H, multiple line), 3.68 (3H, single line)
line), 6.60 to 7.25 (5H, multiplet line). (e) The methyl ester obtained in (d) above (1.2
g) in the same manner as in Example 22(b) to obtain 6-[2
-(2,3-epoxypropoxy)phenyl]-
3-oxohexane-1-carboxylic acid methyl ester
Obtain stell (1.3 g). NMRδ; 1.32-2.05
(2H, multiplet), 2.30~3.00 (10H, multiplet),
3, 20 to 3.50 (1H, multiple line), 3.65 (3H, single line)
line), 3.75~4.40 (2H, multiple line), 6.70~7.40
(4H, multiplet). (f) Execute the epoxy body (1.28g) obtained in (e) above.
6-[2-(2-hi) was prepared in the same manner as in Example 22(c).
Droxy-3-isopropylaminopropoxy
c) Phenyl]-3-oxohexane-1-ka
Rubonic acid methyl ester (1.52 g) is obtained.
NMRδ; 1.08 (6H, doublet, J=7Hz), 1.60
~2.15 (2H, multiplex), 2.80~3.10 (15H, multiplex)
line), 3.67 (3H, single line), 3.98 (3H, wide
singlet), 6.70-7.35 (4H, multiplet). (g) Implement the amine compound (1.36g) obtained in (f) above.
1-[2-[3-(3
(2H)-oxo-4,5-dihydro-6-pyri
dadinyl)propyl]phenoxy]-3-iso-
Propylamino-2-propanol (846mg)
get. NMRδ; 1.12 (6H, doublet, J=6Hz),
1.50~2.14 (2H, multiplet), 2.14~3.10 (12H,
multiplet), 3.84 to 4.30 (4H, wide singlet),
6.68-7.23 (4H, multiplet). (h) Dihydropyridazinone compound obtained in (g) above
(1.0 g) was treated in the same manner as in Example 22(e) to obtain 1-
[2-[3-(3(2H)-oxo-6-pyridasi]
(propyl) phenoxy]-3-N-acetate
thyl-iso-propylamino-2-acetoxy
Propanol and 1-[2-[3-(3(2H)
-oxo-6-pyridacinyl)propyl-4-
Bromo]phenoxy]3-N-acetyl-iso
-propylamino-2-acetoxypropanol
(320 mg) of the mixture. NMRδ; 1.22 and
and 1.25 (6H, two double lines, J=7Hz), 1.50
~3.02 (6H, multiplet), 2.08 (3H, singlet),
2.19 (3H, singlet), 3.05~4.50 (5H, multiplex)
line), 5.20 to 5.60 (1H, wide single line), 6.68
(1H, double line, J=10Hz), 7.15 (1H, double line
line, J = 10Hz). 6.62-7.40 (4H, multiplet). (i) Pyridazinone compound obtained in (h) above (320 mg)
was operated in the same manner as in Example 22(f) to produce the following two types.
to obtain a mixture of 1-[2-[3-(3(2H)-thioxo-6-
Pyridazinyl]propyl]phenoxy]-3-
N-thioacetyl-iso-propylamino-2
-acetoxypropanol and 1-[2-[3
-(3(2H)-thioxo-6-pyridazinyl)
Propyl-4-bromo]phenoxy]-3-N
-thioacetyl-iso-propylamino-2-
Mixture of acetoxypropanol (166mg).
NMRδ: 1.27 and 1.33 (6H, two doublets,
J=7Hz), 1.60-2.30 (2H, multiplet), 2.08
(3H, singlet), 2.19 (3H, singlet), 2.45~
3.00 (5H, multiplex), 3.40~4.75 (4H, multiplex)
line), 5.70 to 6.10 (1H, wide single line), 6.55
~7.40 (4H, multiplet), 6.96 (1H, doublet, J
= 9Hz), 7.66 (1H, double line, J = 9Hz). 1-[2-[3-3(2H)-thioxo-6-pi]
ridazinyl)propyl]phenoxy]-3-N
-acetyl-iso-propylamino-2-acetyl
Toxypropanol and 1-[2-[3-3
(2H)-thioxo-6-pyridazinyl)propyl
Le-4-bromo]phenoxy]3-N-acety
-iso-propylamino-2-acetoxyp
Ropanol mixture (76 mg). NMRδ; 1.22 and 1.25 (6H, two double
line, J=7Hz), 1.55-2.38 (2H, multiplet line),
2.06 (3H, singlet), 2.20 (3H, singlet), 2.40
~2.95 (4H, multiplex), 2.50~4.50 (5H, multiplex)
line), 5,25-5.75 (1H, wide single line),
6.65~7.40 (4H, multiplet), 6.90 (1H, doublet)
line, J=9Hz), 7.57 (1H, double line, J=9
Hz). (j) (i) Thioxo-N-thioa obtained in (i) above
Cetyl derivative (166 mg) was added in the same manner as in Example 22(g)(i).
By operation, 1-[2-[3-(3(2H)-thio
xo-6-pyridazinyl)propyl]pheno
xy]-3-iso-propylamino-2-pro
Panol and 1-[2-[3-(3(2H)-
Thioxo-4-pyridazinyl)propyl-4
-bromo]phenoxy]-3-iso-propyl
Mixture of amino-2-propanol (90mg)
get. NMRδ: 1.23 (6H, doublet, J=
7Hz), 1.70~2.30 (2H, multiplex), 2.40~
3.40 (9H, multiplex), 3.80~4.50 (3H, multiplex)
line), 6.57~7.40 (4H, multiple line), 6.90 (1H,
double line, J = 9Hz), 7.57 (1H, double line, J
=9Hz). (j) (ii) Thioxo-N-acetyl obtained in (i) above
The compound (76 mg) was treated in the same manner as in Example 22(g)(i).
to obtain the same product (34 mg) as in (j)(i) above.
Ru. (k) The amine compound (90 mg) obtained in (j) above and the
A mixture of drazine hydrate (5 ml) was placed in a nitrogen atmosphere.
Reflux for 2.5 hours under ambient air. excess hydrazine
After hydrate is distilled off under reduced pressure, it is treated with acetone.
Then 1-[2-[3-(3-iso-propylidene
hydrazino-6-pyridazinylpropyl
[enoxy]-3-iso-propylamino-2-p
Lopanol and 1-[2-[3-(3-iso-propylene)
(ropylidenehydrazino-6-pyridazinyl)
Lopyl-4-bromo]phenoxy]-3-iso-
Mixture of propylamino-2-propanol
(68 mg). NMRδ; 1.23 (6H, doublet,
J=7Hz), 1.98, 2.03 (6H, two single lines),
1.70~2.30 (2H, multiplet), 2.40~3.40 (9H,
multiplet), 3.80~4.50 (3H, multiplet), 6.57~
9.40 (4H, multiplet), 7.12 (1H, doublet, J=
9Hz), 7.44 (1H, double line, J=9Hz). (l) Mixed product obtained in (k) above (68 mg), 5%
Palladium on carbon (68mg), triethylamine
(1.0ml) and ethanol (30ml) in water
Stir in bare gas and liquid for 40 hours. I removed the catalyst
Then, the liquid is distilled off under reduced pressure. acetone on the residue
was added, refluxed for 15 minutes, and the solvent was distilled off. residue
Thin layer chromatography [silica gel (mel)]
GF₂₅₄) Benzene - methanol - concentrated ammonia
a water (80:20:1)] and purified with 1-[2-
[3-(3-iso-propylidenehydrazino-6
-pyridazinyl)propyl]phenoxy]-3
-iso-propylamino-2-propanol
(12 mg). NMRδ; 1.07 (6H, doublet, J=6Hz),
2.00 (6H, singlet), 1.52−3.20 (11H, multiplex)
line), 4.00 (3H, wide single line), 6.70−7.23
(6H, multiplet). MSm/e: 399 (M⁺). 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-[2-(3-iso -Propylidenehydrazino-6 -pyridazinylthio)ethyl] Phenoxy]-3-iso-pro Pyramino-2-propanol 5 Lactose 137.2 Starch 44.8 carboxymethyl cellulose Calcium 10 Talk 12Magnesium stearate 1 200.0 Prescription 1-b.20mg tabletmg/tablet -[2-[2-(3-iso -Propylidenehydrazino-6 -pyridazinylthio)ethyl] Phenoxy]-3-iso-Pro Pyramino-2-propanol 20 Lactose 122.2 Starch 44.8 carboxymethyl cellulose Calcium 10 Talk 2Magnesium stearate 1 200.0 Details of the manufacturing method are as follows. 1-[2-[2-(3-iso-propylidene hydra
dino-6-pyridazinylthio)ethyl
[C]-3-iso-propylamino-2-propanol
Grind the crystals and add lactose and starch to it.
Mix well. 10% starch paste above
Add to mixed powder and mix with stirring to produce granules.
After drying, the particles are sized to a particle size of around 840 microns, and then
Mix Luk and Magnesium Stearate and
Lock it. Example B: Injection solution 1-[2-[2-(3-iso-propylidene hydra
Dino-6-pyridazinylthio)ethylpheno
xy]-3-iso-propylamino-2-propa
Nor hydrochloride 5mg Methyl p-hydroxybenzoate 1.8mg Sodium chloride 6.0mg Manufacturing method by adding distilled water for injection to make a total volume of 1 ml
The details are as follows. Methyl p-hydroxybenzoate in distilled water for injection
Stir and dissolve, then 1-[2-[2-(3-iso-propylene)]
(ropylidenehydrazino-6-pyridazinylthio)
Ethyl phenoxy-3-iso-propylamino
-Dissolve 2-propanol hydrochloride and sodium chloride.
Let me understand. After dissolving, add dilute sodium hydroxide to adjust the pH.
Adjust to around 7.0. Apply this solution to the membrane filter.
Pass sterile with a router (0.2 micron) and ampoule
Fill and seal.

Claims (1)

[Claims] 1 formula In the formula, R represents a branched alkyl group having 3 or 4 carbon atoms; Y represents -NH ₂ or [Formula], where R ₁ and R ₂ each represent a lower alkyl group; Z represents -S-, -SO ₂ -, [Formula] -NHCO- or a direct bond, where R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group; n is an integer of 1 to 4; A compound which is a hydrazinopyridazine derivative and a salt thereof represented by the following. 2. A compound according to claim 1, wherein R represents an iso-propyl or tert-butyl group. 3. The compound according to claim 1, wherein Z represents -S-, [Formula] or a direct bond. 4. The compound according to claim 1, wherein Y represents -NH ₂ , [Formula] or [Formula]. 5. The compound according to claim 1, wherein n is 2 or 3. 6 formula In the formula, R represents a branched alkyl group having 3 or 4 carbon atoms; Y represents -NH ₂ or [Formula], where R ₁ and R ₂ each represent a lower alkyl group; Z represents -S-, -SO ₂ -, [Formula] -NHCO- or a direct bond, where R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group; n is an integer of 1 to 4; An antihypertensive agent containing a hydrazinopyridazine derivative and a salt thereof as active ingredients.