JPH035465A - Optically active pyridazinone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (one of R<1> to R<3> is H and the other two are lower alkyl, CF3, halogen, CN or NO2) and its salt. EXAMPLE:(5R)-6-[4-[2-[(2S)-3-(5-chloro-2-cyanophenoxy)-2-hydroxypropyl amino]-2- methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone. USE:A hypotensor. PREPARATION:The objective compound of formula I can be produced by reacting a compound of formula II with a compound of formula III in a solvent (e.g. benzene or THF), reducing the resultant Schiff base to obtain a compound of formula N, subjecting the product to the reaction to eliminate the amino- protection group and finally reacting the product with a compound of formula V in a solvent (e.g. methanol or benzene).

Description

Detailed Description of the Invention The present invention relates to optically active pyridazinone derivatives, and more specifically, in the formula, any one of R1, R2 and R3 represents a hydrogen atom, and the remaining two each represent a lower alkyl An optically active pyridazinone derivative and a salt thereof, which represents a group, a trifluoromethyl group, a halogen atom, a cyano group, or a nitro group.

2. In the optically active pyridazinone derivative represented by formula (I) according to claim 1 or its pharmaceutically acceptable formula, any one of R1, Hz and R3 represents a hydrogen atom, and the remaining two each represents a lower alkyl group, a trifluoromethyl group, a halogen atom, a cyano group or a nitro group;
The present invention also relates to an antihypertensive agent containing an optically active pyridazinone derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present inventors previously proposed the following formula 0, in which R1 represents a hydrogen atom or a methyl group, any one of R2, R3 and R1 represents a hydrogen atom, and the remaining 2
each represents a lower alkyl group, a trifluoromethyl group, a halogen atom, a cyano group, or a nitro group.
- They discovered and proposed that it has both blocking action and vasodilatory action, and is extremely useful therapeutically as a continuous antihypertensive agent without tachycardia.
(See Publication No. 183568).

As a result of further study by the present inventors, the above formula (A)
When the asymmetric carbon of the hydroxypropylamine moiety in the compound has S-configuration, the optical activity formula (
It has been discovered that the compound A) has even more enhanced β-blocking action and vasodilatory action, and significantly reduces tachycardia as a side effect, leading to the completion of the present invention.

In the compound of formula (I) provided by the present invention, in addition to the asymmetric carbon of the hydroxypropylamino moiety, the carbon to which the methyl group of the pyridazinone ring is bonded also has an asymmetric carbon, and therefore, The compound of the present invention has the following formula (I-a)
It can exist as two diastereomers represented by and (r-b) or a mixture thereof.

In the formula, Ht, Rz and R3 have the above meanings.

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, the "lower alkyl group" used in this specification may be either linear or branched, such as methyl, ethyl, n- or isopropyl, n-1iso- 1ssc・or tert-
Mention may be made of the butyl group, among which the methyl and ethyl groups are suitable.

On the other hand, "halogen atom" refers to fluorine, chlorine, bromine and iodine atoms, with chlorine and bromine being particularly preferred.

Among the compounds of formula CI) provided by the present invention I, those particularly preferred from the viewpoint of pharmacological effects are those in which R1 represents a methyl group, a chlorine atom or a cyano group, and R1 represents a methyl group, a chlorine atom or a cyano group;
Examples include compounds of formula (1) where 2 or R3 represents a methyl group or a halogen atom.

Thus, representative examples of the pyridazinone derivatives of formula (1) provided by the present invention are as follows.

(5R)-6・[4-[2-[(2S)-3-(5-
Chlor-2-cyanophenoxy)・2-hydroxypropylamino]-2-methylglobylamino]phenyl]
-5.Methyl-4,5-dihydro-3(2H)-pyridazinone, (5R)-6-[4-[2-[(2S)-3-
(2,5-dichlorophenoxy)-2-hydroxypropylaminoco-2-methylpropylamino]phenyl]
-5-methyl-4,5.dihydro-3(2H)-pyridazinone, (5R)-6.[4-[2-[(2S)-3
-(2,3-dichlorophenoxy)2-hydroxypropylamino 1-2-methylpropylaminocophenyl]
-5-Methyl-4,5-dihydro-3(2H)-pyridazinone, (5R)-6-[4-[2-[(2S)-3
-(2,5-dimethylphenoxy)-2-hydroxypropylamino 1-2-methylpropylamino 1 phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, (5R)-6-[ 4-[2・[(2S)-
3-(5-chloro-2-methylphenoxy)・2-hydroxypropylamino]-2-methylpropylamino]
phenyl]-5-methyl-4,5-dihydro-3(2H
)・Viridazinone, (5R) ~6-[4-[2-[(2
s)-3-(2-chloro-5-methylphenoxy)-
2-hydroxypropylamino]-2-methylpropylamino1 phenyl]-5-methyl-4,5-dihydro-
3(2H)-pyridazinone, (5R)-6-[4-[2
-[(25)-3-(2-chloro-5-trifluoromethylphenoxy)-2.hydroxypropylamino]-
2-methylpropylamino]phenyl]-5-methyl-
4,5-dihydro-3(2H)-pyridazinone, (5R)-6-[4-[2-[(2S)-3-(2-
Chlor-5-cyanophenoxy)-2-hydroxypropylaminoj-2-methylpropylamino 1 phenyl]
-5-methyl-4,5-dihydro-3(2H)-pyridazinone, (5R)-6-[4-[2-[(25)-3.
(2-chloro-5-nitrophenoxy)-2-hydroxypropylamino J.2-methylpropylamino-1 phenyl]-5-methyl-4,5-dihydro-3(2H)-
Viridazinone, (55)-6-[4-[2-[(25)
-3-(3-chloro-2-cyanophenoxy)-2-hydroxypropylamino)-2-methylpropylamino 1 phenyl]-5-methyl-4,5-dihydro-3(2
H)-pyridazinone, (5S)-6·[442-[(2
s)-3-(2-methyl-3-nitrophenoxy)-
2-Hydroxypropylamino]-2-methylglobylamino1phenyl]-5-methyl-4,5-dihydro-
3(2H)-pyridazinone, (5R)-6-[4-[2
・[(2S)3-(5-ethyl-2-methylphenoxy)-2-hydroxypropylamino]-2-methylpropylamino 1 phenyl]-5-methyl 4.5-dihydro-3(2H)-pyridazinone , (5S)-6・[4-
[2-[(2S)-3-(5-bromo-2.ethylphenoxy)-2-hydroxypropylamino]-2.methylpropylaminocophenyl]-5-methyl-4,5
-dihydro-3(2H)-pyridazinone, (5S)-
6-[4-[2-[(2S)-3-(5-chloro-2
-ethylphenoxy)-2-hydroxyglopylamino]-2-methylglopylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, (
5S )-6-[4-[2-[(2S)-3・(2-
Bromo-5-methylphenoxy)-2-hydroxypropylamino 1-2 methylpropylaminocophenyl]
-5-methyl-4,5-dihydro-3(2H)-pyridazinone, (5R)-6-[4-[2-[(2'3)-3
-(2-bromo-5-nitrophenoxy)・2-hydroxypropylamino]-2・methylpropylamino 1 phenyl]-5-methyl-4,5・dihydro-3(2H)
-Viridazinone, (5R)-6-[4-[2-[(2S
)-3-(5-fluoro・2-methylphenoxy)・
2-hydroxypropylamino]-2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro
3(2H)-pyridazinone, (5R)6.[4-[2-
[(2S)-3-(5-fluoro-2-nitrophenoxy)-2-hydroxypropylamino]-2-methylpropylamino 1 phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone , (5R)-6-[
4-[2-[(2S)-3-(2-methyl-5-nitrophenoxy)-2-hydroxypropylamino]-2
-methylpropylamino]phenyl]-5-methyl-4
, 5-dihydro-3(2H)-pyridazinone, (5S
)-6=[4-[2-[(2S)-3-(2.ethyl.3-methylphenoxy)-2-hydroxypropylamino1propylamino1phenyl]-5-methyl-4,
5-dihydro-3(2H) pyridazinone, (5S)
-6-[4・[2-[(2S)-3・(3-chloro-
5-methylphenoxy)・2-hydroxypropylamino]-2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,
(5R)-6-[4-[2-[(2s)-3-, (2
-chloro-3-ditrophenoxy)-2-hydroxypropylamino]-2-methylglopylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, (5R)-6- [4-[2-[(25)-3
-(5-methyl-2-nitrophenoxy)-2-hydroxypropylamino 3-2-methylph'apylamino
phenyl]-5-methyl-4,5-dihydro-3(2H
) - pyridazinone.

According to the present invention, acid addition salts of optically active pyridazinone derivatives as described above are also provided. Examples of acid addition salts of the compound represented by formula (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; as well as vinegar, propionic acid, citric acid, lactic acid, Salts with organic acids such as tartaric acid may be mentioned, among which pharmaceutically acceptable acid addition salts are advantageous.

According to the present invention, the pyridazinone derivative of formula (1) can be produced by the reaction route shown in reaction formula A below.

C.I.

H3 Compound of formula (I) In the above formula, Y represents a protected amine group, RI R2 and R1 have the above meanings.

Here, the "protected amine group" refers to an amine group protected with a protecting group that can be easily removed by a normal deamination-protecting group reaction such as hydrolysis, hydrazitolysis, or hydrogenolysis.
(NHg), and examples of protecting groups for amino groups include phthaloyl group, benzyloxycarbonyl group, t-
Examples include butoxycarbonyl group and acetyl group.

In the above reaction scheme A, the reductive alkylation of the compound of formula (TI) in S-unit, R-unit or racemic form with an aldehyde of formula (I[[) is generally carried out in an inert medium, e.g.
Aromatic hydrocarbons such as toluene, benzene, and xylene; ethers such as dioxane, tetrahydrofuran, diethyl ether, and dimethoxyethane; amides such as dimethylformamide; A compound of formula (II
This can be carried out by contacting the aldehyde of I) and reducing the generated thick base.

In addition, from the racemic form of the compound of formula (II), S monolithic or R
The integral fractionation can be carried out using known methods, for example, as described in the Journal of Medicinal Chemistry (Jed.
icinal Chemistry) Volume 31, Page 352 1
This can be done by the method described in 1988.

The reduction of the thick base may be carried out simultaneously by (a) coexisting the compound of formula (If), the aldehyde of formula (III), and a reducing agent in the reaction system, or (b) the reduction of the compound of formula (I[) It can also be carried out by previously generating a Schiff base from the compound and the aldehyde of formula (III) and then reducing the Schiff base.

Examples of reducing agents that can be used in the former simultaneous method (a) include metal hydrogen complex compounds such as sodium cyanoborohydride, sodium borohydride, and lithium aluminum hydride, and formic acid. 0.25 to 10 mol, preferably 0.5 to 10 mol per mol of compound of formula (II)
It can be used in a ratio of 2 moles. The above simultaneous method is generally suitably carried out at a temperature between about 0°C and the reflux temperature of the reaction mixture, preferably between 10°C and about 100°C.

On the other hand, although the reaction for producing a ship base in the latter sequential method (b) can be carried out at room temperature, it is generally preferable to carry out the reaction while removing the water produced under heating under reflux. Reduction of the generated ship base can be carried out using the above-mentioned reducing agent, or using a reduction catalyst such as radium-attached activated carbon, palladium black, platinum-attached activated carbon, platinum oxide or Raney nickel. It can also be carried out by catalytic reduction.

In both methods (a) and (b), formula (II
The aldehyde I) is suitably used in a proportion of generally 1 to 10 mol, preferably 1 to 3 mol, per mole J of the compound of formula (f[).

The above-described reductive alkylation reaction yields a compound of formula (IV), which is then subjected to a deamination-protecting group reaction.

The deamino-protecting group reaction can be carried out by various methods depending on the type of amino-protecting group, for example, by the method described below.

(a) Removal of phthaloyl or acetyl groups can be carried out, for example, by hydrazitolysis by reaction with hydrazine in a solvent such as alconopedioxane, or by alkaline hydrolysis by heating with sodium hydroxide, potassium hydroxide in an alcohol. (b) Removal of the benzyloxycarbonyl group is carried out, for example, by hydrogenation water decomposition in alcohol in the presence of a catalyst such as palladium-coated activated carbon in a hydrogen stream, and (c) t- Removal of the butoxycarbonyl group can be carried out by acid hydrolysis, such as by reacting with hydrogen chloride or trifluoroacetic acid in an organic solvent.

The above reaction produces a compound of formula (V), which is then reacted with an optically active epoxy compound of formula (■) to obtain the desired compound of formula (I). Although the reaction between a compound of formula (v) and a compound of formula (VT) can be carried out in the absence of a solvent, it is generally carried out in an inert medium such as an alcohol such as methanol, ethanol, propatool, butanol; diethyl ether,
Ethers such as dioxane and tetrahydro-7rane; aromatic hydrocarbons such as benzene, toluene, and xylene;
It is carried out in halogenated hydrocarbons such as dichloromethane, chloroform, and tetrachloroethane.

The reaction temperature is not strictly limited, but is generally about 2
0°C to the reflux temperature of the reaction mixture, preferably 50°C
! -100°C is preferred. Furthermore, the ratio of the compound of formula (VI) to the compound of formula (V) is not critical and can be varied over a wide range; It is advantageous to use a proportion of .5 to 20 mol, preferably 1 to 5 mol.

The optically active epoxy compound of the above formula (VI) is, for example,
According to the reaction formula B below, shrimp halohydrin with R is expressed by the formula (■
) can be easily produced by reacting it with a heptanoyl derivative.

Reaction formula B (■) In the formula, Hal represents a halogen atom, and R1, R2 and R1 have the above meanings.

In this way, the target compound of formula (1) is obtained in good yield.

The compound of formula (1) produced by the method described above can be recovered and purified from the reaction mixture by a method known per se.
For example, extraction, column chromatography, thin layer chromatography, recrystallization, etc. can be used.

The optically active pyridazinone derivative represented by formula (1) produced in this way can be further treated with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. by a method known per se, if necessary. It can be converted into the corresponding salt by treatment with an inorganic acid or an organic acid such as acetic acid, propionic acid, phosphoric acid, maleic acid, citric acid, lactic acid, tartaric acid or methanesulfonic acid.

The optically active viridazinone derivative represented by formula (I) of the present invention described above has both excellent β-blocking action and vasodilatory action at the same time, and can be used as a sustained antihypertensive agent with extremely low tachycardia. It is therapeutically excellent.

The compound represented by formula (I) of the present invention has excellent β-blocking action and vasodilatory action (FE-lowering action) without causing tachycardia.
The following animal experiments demonstrate that this expression occurs.

Compound A of the present invention: (5R)-6-[4-[2-[(25)-3-
(2-cyano-5-chlorophenoxy)-2-hydroxypropylamino]-2-methyl7'apylamino7phenyl 1-5-methyl-4,5-dihydro-3(2H)
-pyridazinone As a control compound, the compound shown below was used.

B, 6-[4-[2-[3-(2-cyano-5-chlorophenoxy)-2-hydroxyglobylamino]-
2-methylpropylamino]phenyl]-5-methyl-
4,5-dihydropyridine (JP-A-63-183568
Test method (1) Measurement of β-blocking effect Bendoparbital (60 mg/kg, i
.

p,) Anesthetized rat (Wistar, male 1 body weight 350-
420 g), and blood pressure was measured by connecting a cannula inserted into the femoral artery to a pressure transducer. Heart rate was calculated from blood pressure pulse wave. Rat I isoprenaline (0.1 μg/kgi, v-) is administered and the heart rate is immediately measured and recorded. The measured value of heart rate at that time is designated as Hl. Next, a solution of the test compound suspended in 2% Tween 80/saline solution was administered through a cannula inserted into the femoral vein of the rat, and after 3 minutes, inbrenaline (0.1 μg/kg i, v) was administered again. Immediately measure and record heart rate.

The heart rate reading at that time is H2. From this measurement,
Calculate the heart rate suppression rate according to the formula below.

A dose-response curve is created by cumulatively increasing the dose of the test compound and repeating the above procedure, and from this curve the dose of the test compound at which the heart rate inhibition rate reaches 50% is determined. . The doses at that time were compared with propranolol, and the results are shown in Table 1 below.

(2) Measurement of hypotensive effect and heart rate 1 group of 6 or 7 rats whose adrenal medulla was removed (Wist
ar, male (body weight 320-390 g) with 1 dose of the test compound.
It was dissolved or suspended in 0% gum arabic and distilled water and administered orally. Blood pressure and heart rate were measured by indirect method immediately before administration and 3 hours after administration, and the difference between the two was calculated to determine the antihypertensive effect of the test compound (dose that lowers blood pressure by 25 mmHg) and changes in heart rate (dose that reduces blood pressure by 25 mmHg). (heart rate increase) was determined. The results are also shown in Table 1 below.

Table 1 A 36.6 1.3
23B 57.3 2.7
44 Thus, the compound represented by formula (I) of the present invention can be used orally or parenterally as an antihypertensive agent having both β-blocking action and vasodilatory action for the treatment and treatment of humans and other warm-blooded animals. Can be administered (eg, intramuscularly, intravenously, subcutaneously, by rectal injection, sublingually, etc.).

When used as a medicament, the compounds of the invention can be formulated into a variety of forms suitable for oral or parenteral administration.

For example, the compounds of the present invention may be incorporated into non-toxic excipients, binders, lubricants, disintegrants, preservatives, etc. commonly used in such drugs.
It can be formulated using additives such as tonicity agents, stabilizers, dispersants, antioxidants, colorants, flavoring agents, and buffering agents.

Such drugs may be in solid form (e.g., tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, troches, etc.) or semi-solid forms (e.g., halved, etc.) depending on their use. and liquid forms (injections, emulsions, suspensions, syrups, etc.).

The non-toxic additives that can be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol. , p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycone petroleum jelly, carpowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The medicament may also contain therapeutically useful agents.

The content of the compound of the invention in the medicament varies depending on its dosage form, but generally in a concentration of 5 to 100% by weight for solid and semi-solid forms and o, t for liquid forms. -to% by weight of the active compound.

The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, the severity of the symptoms, the doctor's diagnosis, etc., but in general, the dosage is 0.01 per day.
-30 mg/kg, preferably 0, O1-10 mg/
kg. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range. The above dosage can be administered once a day or in divided doses.

The present invention will be further explained below with reference to Examples.

In addition, the temperature in all Examples was Celsius degree, and the NMR measurement was performed using tetramethylsilane as an internal standard.

Example 1 (1) Method for producing (2S)-(+)・1-(5-chloro-2-cyanophenoxy)-2,3-epoxypropane 5-
Chlor-2-cyanophenol (11,8 g) and R-
A mixture of (-)-epichlorohydrin (10.0 g) was stirred on an oil bath at 120° C. for 1 hour and 20 minutes.

The reaction product was dissolved in ethyl acetate, washed with saturated brine, and then the solvent was distilled off under reduced pressure. The residue was dissolved in DMF, and 60% sodium hydride (4.9 g) was added little by little while stirring while cooling with water. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing the ethyl acetate layer with saturated brine, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [benzene-ethyl acetate mixture (15:l)] to obtain (2S)-
(+)-1-(5-chloro-2-cyanophenoxy)-
2,3-epoxypropane (11.4 g) was obtained. Repeated recrystallization from ethyl acetate 2S)-(+)-1
-(5-chloro-2-cyanophenoxy)-2,3-epoxypropane (4.8 g) was obtained.

m, p, 85-866 [α] Back +9.90 (c ” l, CzHsOH
)(2)(5R)-6'-[4-(2-methyl-2-7
Taliminoprovir) aminophenyl]-5-methyl-
Process for producing 4,5 dihydro-3(2H)-pyridazinone (5
R)-'6-(4-aminophenyl)-5-methyl-4
゜5-dihydro-3(2H)-pyridazinone (9゜55
g), 2-methyl-2-7taliminoprobanal (1
3°27g), acetic acid (4.2m0) and methanol (1
While stirring the mixture of 80-) at room temperature, a methanol solution (2
0 m12) was added dropwise. - After stirring at night, the precipitated crystals were collected in a furnace and then recrystallized from acetone, (5R)-6-'
[4-(2-methyl-2-phthaliminopropyl)aminophenyl]-5-methyl~4.5-dihydro-3(2
H)-pyridazinone (9.36 g) was obtained. m,p.

234-236° [alt? 308.4 (c-1,00, CDC1
3) NMRCDC13) Nδ; 1.18 (3H1a,
J-7Hz), 1.76 (6H,s), 2.35 (
IH.

dd, J"17Hz, '2Hz), 2.66 (IH.

dd, J=17Hz, 7Hz), 3.07-3.37(
IH, m), 3.63-3.84 (2H, b r).

4-30-4-60 (IH, b r), 6.62 (2
H.

d, J-9Hz), 7.52 (2H, d, J=9Hz)
.

7.60-7.86 (4H, m), 8.39 (IH.

S).

(3) (5R)-6-(4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4.5
-Production method of dihydro-3(2H)-pyridazinone (5R)
-6-[4-(2-methyl-2-phthaliminopropylamino)phenyl]-5-methyl-4,5-dihydro-
A mixture of 3(2H)-pyridazinone (2,81 g), hydrazine hydra-) (1,74 g), acetic acid (4,17 g) and ethanol (60 ml) was refluxed for 4 hours.

After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure.

After adding water to the residue and neutralizing it with sodium bicarbonate,
Extracted with chloroform. After drying the chloroform layer with magnesium sulfate, the solvent was distilled off under reduced pressure.

The residue was recrystallized from ethanol to give (5R)-6-14-
(2-amino-2-methylpropylamino)phenyl 1
-5-Methyl-4,5-dihydro-3(2H)-pyridazinone (1,41 g) was obtained. m, p, 186.5~1
88''[σ]111'-438,3(c -1,00,C,H
, OH) NMR (CD30D) δ; 1.15 (3H,
d, J-7Hz), 1.16 (6H,s), 2.29
(LH.

dd, J-17Hz, 2Hz), 2.69 (LH.

dd, J-17Hz, 7Hz), 3.0fr (2H.

s), 3.10-3.65 (IH, m), 6.67 (
2H, d, J=9Hz), 7.58 (2H, d.

J-9Hz).

(4) (5R)-6-[4-[2-[(2S)-3
-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamine]phenyl 1-5-methyl-4,5-dihydro-3(2H)
-Production method of pyridazinone (5R)-6-[4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4゜5-dihydro-3(2H)- obtained in the above (3) Viridazinone (87
4+ns), (2S)-1,-(obtained in (1) above)
5-chloro-2-cyanophenoxy)-2,3-epoxypropane (702■) and L-butanol (90 mf
The mixture of f) was stirred on an oil bath at 70°C for 24 hours. After removing the solvent under reduced pressure, silica gel column chromatography (
(5R)-6-[4-[2-[(25)-3-(
5-chloro-2-cyanophenoxy)-2-hydroxypropylamino 1-2-methylpropylamino 1 phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1,33 g) was obtained. . Then (5R)-6
-[4-[2-[(25)-3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino 1-
2-methylpropylamino 1 phenyl]-5-methyl-
4,5-dihydro-3(2H)-pyridazinone (1,3
Dissolve 3g) in acetone and dissolve monoethyl maleate (3g) in acetone.
96+! i+) in acetone was added. After standing at room temperature, the precipitated result was collected and maleic acid monoethyl ester salt (1.17 g) was obtained. m, p-141-144' [alU-190,1(c-1,00, EtOH)
NMR (CD, OD) δ; 1.16 (3H, d, y-
7Hz), 1.24 (3H, t, J-7Hz), l,
44 (6H, s), 1.32 (LH, dd, J=1
7Hz, 2Hz), 2. −70 (IH, dd, J=1
7Hz, 7Hz), 2.97-3.77 (3H.

m), 3.43 (2H,s), 4.13 (2H,q
.

J=7Hz), 4.13-4.50 (3H, m).

5.78 (IH, d, J-12Hz), 6-50 (I
H, d, J - 12Hz), 6.75 (H, d, J -
9Hz), 7.12 (LH, dd, J ”8Hz, 2
Hz), 7.25 (IH, d, J-2Hz), 7.4
9 (IH, d, J-8Hz), 7.49 (2H, d
.

J=9Hz).

Example 2 (5S)-6-[4-[2-[(2s)-3-(5
-Chlor-2(1)(5S)-6-[4-[2-methyl-2-phthaliminopropylamino)phenyl]-5-
(5R)-6-(4-
aminophenyl)-5-methyl-4,5-dihydro-3
(55)-6-(4 instead of (2H)-pyridazinone)
-aminophenyl)-5-methyl-4,5-dihydro-
Using 3(2H)-pyridazinone, (5S)-6-[4-(2-methyl-
2-7taliminobropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone was obtained.

m, p, 235-237' [α] dorsal +307.6° (c -1,00, CD C1
3)(2) (5S)-6-[4-[2-amino-2
-methylpropylamino)phenyl]-5-methyl-4
．． Process for producing 5-dihydro-3(2H)-pyridazinone (5S)-6-[4-(2-methyl-) obtained in (1) above
(5S)-2-phthaliminopropylamino)phenyl]-5-methyl to 4,5-dihydro-3(2H)-byridazinone in the same manner as in Example 1(3).
6-[4-(2-amino-2-methylpropylamino)
phenyl]-5-methyl-4,5-dihydro-3(2H
)-pyridazinone was obtained. m, p, 185-188° [
σJfff+422.1' (c=1.00.CtHs
OH)(3)(5S)-6-[4-[2-[(2S
)-3-(5-chloro-2-cyanophenoxy)-2-
Hydroxypropylamino-2-methylpropylamino]phenyl]5-methyl-4,5-dihydro-3(2
H)-Production method of pyridazinone (5S)-6-[4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4゜5-dihydro-3(2H )-Viridazinone (0
, 47g) and (2S)(+)- obtained in Example 1(1)
(5-chloro-2-cyanophenoxy)-2,3-epoxypropane (0.37 g) was treated in the same manner as in Example I (4) to obtain (5s)-6-[4-[2-[ (2S
)-3-(5-chloro-2-cyanophenoxy)-2
-hydroxypropylaminoco2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3
(2H)-Biridazinone maleic acid monoethyl ester salt (0.67 g) was obtained.

m, p, 141"142°[q]tr +165.1' (c = 1.00,
C, HaOH) NMR (CD, OD) δ; 1.16 (
3H%d, J-7Hz), 1.24 (3H,t,J-
7Hz), 1°44 (6H,s), 2.32 (IH
, dd, J-17Hz, 2Hz), 2.70 (IH,
dd, J=17Hz, 7Hz), 2.97-3.77
(3H.

m), 3.43 (2H,s),
4, 1 3 (2H,Q.

J-7Hz), 4.13-4.50 (3H, m).

5.78 (IH, d, J=12Hz), 6.50 (I
H, d, J-12Hz), 6.75 (2H, d, J”
"9Hz), 7-12 (IH, dd, J-8Hz.

2Hz), 7.25 (IH, d, J=2Hz), 7-
49 (IH, d, -8Hz), 7.49 (2H
.

d, J-9Hz) Example 3 6-[4-(2-EC2S)3-(5-chloro-2-
Cyano(a) 6-[4-(2-amino-2-methylpropylamino)phenyl 1-5-methyl-4,5-
Dihydro-3(2H)-pyridazinone (6.5 g) and (2 s X+ )-(5-chloro-2-cyanophenoxy)-2,3-epoxypropane (2.0 g) obtained in Example 1 (1) ) and ethanol (50 mQ) was refluxed for 3.5 hours.

After evaporating the solvent under reduced pressure, the residue was treated in the same manner as in Example 1 (4) to give 6-[4-[2-[(2S)-3-(5-chloro-2-cyanophenoxy)-2- Hydroxypropylaminoco-2-methylpropylamino]phenyl]-5
-Methyl-4,5-dihydro-3(2H)-pyridazinone (4.30 g) was obtained.

[σl& +2.37°(c −1,00, C2HsO
trC2H50tr)N,)δ; 1.20(6H,S
), 1°22 (3H, d, J-7Hz)
1.97-3.45 (9H, m), 3.85-4.
30 (3H, br).

3.85-4.30 (3H,br), 4.
30-4゜57 (IH, br), 6.60 (2
H, d, J=9Hz), 6-89 (LH, d,
J = 2Hz), 7゜00 (IH, dd, J
-6Hz, 2Hz), 7.44(l H, d, J=
6Hz), 7.55 (2H, d.

J-9H2), 8-53 (IH, s).

(b) 6-[4-[(2S)- obtained in (a) above
3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylaminoco-2-methylpropylamino 1
7enyl 1-5-methyl-4,5-dihydro-3(2H
)-pyridazinone in acetate, 6-[4-[2-[(2s)] in the same manner as in Example 1 (4).
-3-(5-chloro2-cyanophenoxy)-2-hydroxypropylamino-2-methylpropylamino]
phenyl]-5-methyl-4,5-dihydro-3(2H
)-pyridazinone maleic acid monoethyl ester salt I
f-0m, p, 153-156' NMR (CD30D) δ; 1.16 (3H, d, J'
-7Hz), 1.24 (3H, t, J=7Hz), l
.

'44 (6H, s), 2.32 (IH, dd, J
-17Hz, 2Hz), 2.70 (IH, dd,
J -17Hz, 7Hz), 2.97-3.77 (3
H, m).

3.43 (2H, s), 4.1 3 (H, q,
J = 7H2), 4.1 3-4.50 (
3H, m), 5.78 (IH, d, J-12Hz)
, 6.50 (IH, d.

J-12Hz), 6.75 (2H, d, J-9Hz).

7.1 2 (LH, dd, J=8Hz, 2Hz
), 7°25 (LH, d, J=2Hz), 7-49
(LH, d.

J-8Hz), 7.49 (IH, d, J=9Hz)
.

An example of manufacturing a drug containing the compound of the present invention is as follows.

Example A Two Tablets An example formulation of a tablet containing 5'LyJ and 20 μm of active ingredient per tablet is as follows.

starch talc Magnesium stearate lactose starch 44.8 200.0 22.2 44.8 talc lactose 137.2 Magnesium stearate 1200.0 Details of the manufacturing method are as follows.

(5R)-6-[4-[2-[(2S)-3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylami/]・2-methylglobylamino J phenyl]-
The crystals of 5-methyl-4,5-dihydro-3(2H)-pyridazinone maleate are ground, and lactose and starch are added thereto and mixed well. Add 10% starch paste to the above mixed powder and mix with stirring to produce granules.

After drying, the particles are sized to a particle size of around 840 microns, mixed with talc and magnesium stearate, and tableted.

Example B: Injection xypropylamine rho2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)
Viridazinone is suspended in a solvent containing prescribed amounts of macrogol 4000, polysorbate 20, and sodium chloride, and after adjusting the pH to around 7.0, it is filled into ampoules and melt-sealed.

Macrogol 4000 30 ■ Polysorbate 20 4 mg Sodium chloride 9 ■ Add distilled water for injection to make the whole 1-.

Details of the manufacturing method are as follows.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, any one of R^1, R^2 and R^3 represents a hydrogen atom, and the remaining An optically active pyridazinone derivative and a salt thereof, each of which represents a lower alkyl group, a trifluoromethyl group, a halogen atom, a cyano group, or a nitro group. 2. An antihypertensive agent containing an optically active pyridazinone derivative represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.