JPS6051473B2 - 4-substituted phenyl phthalazine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula /゛'--1-1-0CH2CHCH which has a β-blocking effect and a blood pressure lowering effect.

NH--R＼Neihe＼／Yu<N □1-Tenichi゛T' (In the formula, R means a linear or branched lower alkyl group, and the substituents on the phenyl group are O, , m or (meaning being in the p-position) or its salts.

Examples of the compounds of the present invention include the following and their salts.

(1) 1-hydrazino 4-[2-(2-hydrocaoxy-3-isopropylaminopropoxy)phenyl]phthalazine (2) 1-hydrazino 4-[2-(2-hydro'' oxy-3-tertiary butylaminopropoxy) )
phenyl]phthalazine (3) 1-hydrazine 4-[
3-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine (4) 1-hydrazino 4-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine The compounds of the present invention can be prepared in various ways. However, the following route will be explained as a typical example.

(Y means a hydroxyl protecting group, x means a halogen atom, R' means a hydrogen atom, and R means the same as above.

) That is, 2-(methoxybenzoyl)benzoic acid (■) synthesized by a method known in the literature or a similar method is heated to react with hydrazine-hydrate in the presence or absence of an appropriate solvent. 4-(methoxyphenyl)phthalazinone (■) is synthesized by the following steps. Then (■
) is demethylated using mineral acids such as concentrated hydrobromic acid and hydriodic acid to form 4-(hydroxyphenyl)phthalazinone (■), and a suitable protecting group (acetyl group, benzoyl group, etc.) is added. to protect free hydroxyl groups. For example, when an acetyl group is used as a protecting group, a common acetylating agent such as acetic anhydride monopyridine may be used.

Next, (V) is reacted with a conventional halogenating agent such as phosphorus oxychloride to obtain a 1-halogenophthalazine derivative (■), and then the protecting group is removed by a hydrolysis reaction to form 1-
Synthesize halogeno-4-(hydroxyphenyl)phthalazine (■). The thus obtained (■) and epihalogenhydrin were reacted in an appropriate solvent in the presence of an appropriate deoxidizing agent such as potassium carbonate, and 1-halogeno-4
-[(2,3-epoxypropoxy)phenyl]phthalazine (■) is obtained. Furthermore, by reacting (■) with an amine in an appropriate solvent to form (■), and then reacting hydrazine-hydrate in the presence or absence of an appropriate solvent, 1-hydrazine 4-[ (2-Hydroxy-3-monosubstituted aminopropoxy)phenyl]phthalazine (
1) is manufactured. "Appropriate solvent" used in the above explanation
It is not necessary to refer to anything special, as long as it can dissolve the raw material even slightly and does not react with the reaction reagent.

In addition, the reaction temperature indicates the temperature range used for ordinary chemical reactions, from room temperature to about 200°C, and the reaction time is also about 3 minutes to 3 hours, and can be increased or decreased as appropriate in relation to the reaction temperature. . The Examples described below are merely illustrative and do not define the reaction reagents or reaction conditions, and the compounds of the present invention can also be produced by various other methods.

As mentioned above, the compound of the present invention has both a β-blocking action and a blood pressure lowering action, so it is an extremely useful drug in that it can lower blood pressure without causing tachycardia, which is a side effect often seen with other antihypertensive drugs. It is. 2 For example, when 1-hydrazino-4-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine was orally administered at 100m91k9 to unanesthetized spontaneously hypertensive rats (SHR), the blood pressure decreased after 3 hours. It started to appear and reached its maximum decline after 6 hours (22±4.
The pharyngeal Hgp reached 0.01), and the significant effect lasted for more than 2 hours. It should be noted that a slight increase in blood pressure (<1DI1r1nHg) was observed prior to the decrease in blood pressure until 1 hour after administration. In this case, the heart rate measured at the same time with the same SHR is almost unchanged or has a tendency to bradycardia! The results showed an extremely good separation between hypotension and tachycardia. In addition, this compound (300μYIkg,
I. v. ) in anesthetized dogs, isoproterenol (a). 21LyIkg, 1. v. ), the decrease in diastolic blood pressure and increase in heart rate and myocardial contractile force were inhibited by 30-40%, and sympathetic β-blocking activity was clearly observed. The compound of the present invention is usually used in the form of oral preparations, injection preparations, etc., and free forms or salts are used depending on the purpose.
Examples of salts include inorganic and organic acid salts such as hydrochloride, sulfate, hydrobromide, maleate, and the like. Examples of manufacturing the compounds of the present invention are shown below, but the scope of this patent is not limited thereto.

Example 1 1-Hytoradino 4-[2-(2-hydroxy-3
-isopropylaminopropoxy)phenyl]phthalazine 2-(2-methoxybenzoyl)benzoic acid 5q1 hydrazine hydrate 4q1 A mixture of 70 mL of ethanol was heated under reflux for 1 hour, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, Recrystallized from methanol, melting point 244-2
4-(2-methoxyphenyl)phthalazinone 3 at 45°C
．． 5y (68.8%) was obtained.

) Add 150 ml of concentrated hydrobromic acid to 4.75y of this methoxy compound, reflux at 170°C for 4 hours, concentrate the reaction solution to dryness, add water, and repeat the concentration to dryness three times in total.

The residue was recrystallized from water to obtain 4.50q (99%) of 4-(2-hydroxyphenyl)phthalazinone. 4.15 g of this, 1.789 acetic anhydride and 7 pyridine
The reaction mixture was stirred overnight at room temperature, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration.
y (85.7%) was obtained.

1 Acetoxy compound 3.980q1 dichloroethane 70m
Add 2.395f of t1 phosphorus oxychloride 2. After refluxing for a few seconds and the spot of the raw material disappearing at η℃, the reaction solution was poured into ice water and added to a sodium carbonate aqueous solution (20y/100y water).
Add to neutralize.

The organic layer and the aqueous layer were separated, and the organic layer was washed with water, dried, and then distilled off. The residue was purified using silica column chromatography, and a single spot of 1-chloro-4-(2-acetoxyphenyl)phthalazine was analyzed by TLC. Obtain 3.40y (80.2%). Melting point: 126-127°C. Weilstein reaction ten. e After dissolving 3.02f of this acetoxy compound in 45 ml of 95% ethanol, an equimolar amount of potassium hydroxide was added and the mixture was stirred overnight at room temperature.

Concentrate the reaction solution under reduced pressure at room temperature. Neutralize with hydrochloric acid, add water, collect the precipitated crystals by filtration, dry at 100°C under reduced pressure, and reduce the melting point to 1.
2.58y (95%) of 1-chloro-4-(2-hydroxyphenyl)phthalazine was obtained at 76.5°C. f 2.017f of this and 3.07ml of epibromohydrin
1 Potassium Carbonate 1.27y1 Methyl Ethyl Ketone 51.
Add 9 mL and reflux for 1 hour.

After the spot of the starting material disappears at L°C, the reaction solution is filtered, and the filtrate is concentrated to dryness. The residue was purified by silica gel chromatography to obtain oily 1-chloro-4-(2-(2,3-epoxypropoxy)phenyl)phthalazine 1.6y (65.1%
) was obtained. g Add 5.0ml of isopropylamine and 40mL of methanol to 1.50y of epoxy body and mix 30
Reflux. After the starting material spot disappeared on TLC, the reaction solution was concentrated, and the residue was purified using silica gel column chromatography.
Hydroxy-3-isopropylaminopropoxy)phenyl)phthalazine 1.115f (62.5%) was obtained.
Weilstein reaction +. h This thing's 1.104y
hydrazine hydrate 5.94 da and ethanol 28
．． Add 8 ml of the mixture and react at 100°C under nitrogen gas.

After the spot of the starting material almost disappeared on TLC, the reaction solution was concentrated to dryness at the lowest possible temperature. Ice water is added to the residue, extracted with chloroform, and the chloroform layer is washed with water, dried, and evaporated. The residue was recrystallized from chloroform-ether to give 1-, hydrazino-4-(
Yellow crystals of 2-(2-hydroxy-3-isopropylaminopropoxy)phenyl)phthalazine 560 m9 (51
．． 3%). Weilstein reaction. Elemental analysis C
2 Theoretical value as 2OH25O2N5: C
65.37, H6.8 sleep Nl9. O6 actual value: C65.
lO. ．． H6.8l, Nl8.78NMR spectrum (
One mountain of solvent DMSO, internal reference substance TMSlδ value (Ppm
)) Example 2 1-hydrazino 4-[3-(2-hydroxy-3
-isopropylaminopropoxy)phthalazine A4-(3-methoxyphenyl)phthalazine Example 1
, by the same method as in a, using 2-(3-methoxybenzoyl)benzoic acid 15y1 hydrazine hydrade 12y1 ethanol 150ml, the target product 10.2f (67.
4%).

Melting point 170-172'C (recrystallized from methanol). B
4-(3-methoxyphenyl)phthalazinone obtained on 4-(3-hydroxyphenyl)phthalazinone 8
．． 48y was suspended in 300ml of concentrated hydrobromic acid for 6 hours.
Heat to reflux.

After cooling, the precipitated crystals were collected by filtration, washed with water, and recrystallized from methanol to obtain the desired product 6.80f (84.9
%) was obtained. Using 4-(3-hydroxyphenyl)phthalazinone 238Tn9 obtained on C4-(3-acetoxyphenyl)phthalazinone, the same reaction as in Example 1, c was carried out to yield 208 mg (74.1%) of the target product. Obtained.

Melting point 204-206°C. 4-(3-
Using acetoxyphenyl)phthalazinone 4.72y,
The same reaction as in Example 1, d was carried out to obtain the target product 4.23y.
(84.2%) was obtained.

Melting point: 129-130°C. 1-chloro-4-(3-acetoxyphenyl)phthalazidine obtained on 1-chloro-4-(3-hydroxyphenyl)phthalazine 4.2
3y was carried out in the same manner as in Example 1, e, and the target object was 3.55.
y (97.7%) was obtained.

Melting point: 187-188°C. 1-chlororu4-[3-(2.
1-chloro-4-(3-hydroxyphenyl)phthalazine obtained on 3-epoxypropoxy)phenyl]phthalazine 3.55y1 epibromohydrin 9.48
y10.2NKOH-83ml of 95% ethanol was added and stirred at room temperature for 2.5 days.

The precipitated crystals were collected by filtration and dissolved in chloroform, and after filtering off insoluble materials, the product was purified by silica gel column chromatography to obtain the desired product 2.43y (56%). Melting point: 142-144°C.
g11-chloro-4-[3-(2-hydroxy-3
Using 1.73f of 1-chloro-4-[3-(2,3-epoxypropoxy)phenyl)phthalazine obtained on -isopropylaminopropoxy)phenyl]phthalazine, the reaction was carried out in the same manner as in Example 1, g. 1.88q (91%) of the desired product was obtained as an oil.

h11-Hydrazino 4-[3-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine obtained on 1-chloro-4-[3-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine 1 The reaction was carried out in the same manner as in Example 1, h using .3y to give 810 mg (63.3%) of yellow crystals of 1-hydrazino-4-[3-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine.
) was obtained.

Theoretical value as elemental analysis C2Oll2, O2N: C65.37, H6.8 Mr.Nl9. O6 actual value: C65.3O. ．． H6.7th order Nl8.82 NMR spectrum (solvent CDCl3, internal reference material TMSlδ value (
Ppm)) 8-position H7.8-8.1 (1H..m) Example 3 1-hydrazino 4-[4-(2-hydroxy-3
-isopropylaminopropoxy)phenyl]phthalazine A4-(4-methoxyphenyl)phthalazinone A reaction was carried out using 840 mg of 2-(4-methoxybenzoyl)benzoic acid in the same manner as in Example 1, a, resulting in 620 mg of the desired product. (73.2%) was obtained.

Melting point 241-243'COb4-(4-hydroxyphenyl)phthalazinone 4-(4-
-methoxyphenyl)phthalazinone 7.56y,
The procedure was carried out in the same manner as in Example 1, b, and the target object was 6.4y (89.
6%).

Recrystallized from methanol, melting point 301-306°C. 4-
4-(4-hydroxyphenyl)phthalazinone obtained on (4-acetoxyphenyl)phthalazinone 4.
Using 76y, the reaction was carried out as in Example 1, c, to obtain the target product 5.06y (90.4%).

Melting point: 258°C. Using 3.42y of 4-(4-acetoxyphenyl)phthalazinone obtained on 11-chloro-4-(4-acetoxyphenyl)phthalazine, Example 1,
The reaction was carried out in the same manner as in d, and the target product was 2.96y (81.3y).
%) was obtained.

Melting point: 182-183°C. 1-chloro-4-(4-acetoxyphenyl)phthalazine obtained on 1-chloro-4-(4-hydroxyphenyl)phthalazine 2.96
Dissolve y in 50 mt of methanol and add NNaOHlOml
Add gradually.

After stirring for 3 hours at room temperature, it was neutralized with NHCl, the precipitated crystals were collected by filtration, and recrystallized from methanol, with a melting point of 300°C.
A target product 2.15y (84.4%) showing the above was obtained. 1
1-chloro-4-[1-(2●3-epoxypropoxy)phenyl]phthalazine obtained on 1-chloro-4-
(4-hydroxyphenyl)phthalazine 2.05y
was dissolved in 48 ml of 0.2NKOH-95% ethanol, 3.70 y of epichlorohydrin was added, and the mixture was stirred at room temperature overnight.

The precipitated crystals were collected by filtration, and the target product 2.04y (81.5%
) was obtained. Melting point: 167-169°C. -! 1-Chloroux 4
1- obtained on -[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine
Chloro-4-[4-(2,3 epoxypropoxy)phenyl]phthalazine. Using 37f, the reaction was carried out in the same manner as in Example 1, g) to obtain the desired product 1.10y (67.2%).

Recrystallized from methanol, melting point 158-160°C. h1
1-hydrazino 4-[4-(2-hydroxy-3
The same reaction as in Example 1, h was carried out using 600 m9 of 1-chloro-4-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine obtained on -isopropylaminopropoxy)phenyl]phthalazine. 520 m9 (87.7%) of 1-hydrazino-4-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalazine were obtained.

Melting point 127-129°C (decomposed). Elemental analysis C2OH25
As O2N5

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R means a linear or branched lower alkyl group, and the substituents on the phenyl group are o, m, or (meaning being in the p-position) and salts thereof.