JPS62252774A - Phthalazine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A phthalazine derivative of formula I [R<1> is ar(lower)alkyl which may have one or more proper substituent groups; R<2> is carboxy or protected carboxy; A is O or S; Z is lower alkylene] or its salt. EXAMPLE:2-[4-(3,4-Dichlorobenzyl)-1,2-dihydro-1-oxophthalazin-2-yl]-ac etic acid ethyl ester. USE:Useful as a drug for remedy of complications of diabetes such as dysraphism in corneal damage, cataract, neuropathy, retinopathy, renal disorder, etc. It exhibits aldose reductase inhibiting activity. Administered preferably by intravenous injection, intramuscular injection or oral administration. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II or its salt with the compound of formula III or its reactive derivative at the hydroxyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel phthalazine derivatives. More specifically, the present invention provides novel phthalazine derivatives and salts thereof having aldose reductase inhibitory activity, methods for producing the same, pharmaceutical compositions containing the same,
and its use for the manufacture of drugs.

Therefore, one of the objects of this invention is to provide new and useful phthalazine derivatives and salts thereof.

Another object of the present invention is to provide a method for producing the phthalazine derivatives and salts thereof.

Yet another object of this invention is to provide a pharmaceutical composition containing the phthalazine derivative and its salts as active ingredients.

A further object of the present invention is to prepare the phthalazine derivatives and their salts for the manufacture of medicaments for the therapeutic treatment of glycosylated complications such as corneal damage union defects, cataracts, neuropathy, retinopathy, renal disorders, etc. is to provide use.

The novel phthalazine derivative of this invention can be represented by the following general formula.

[In the formula, R1 is an alkyl group which may have one or more suitable substituents, R2 is a carboxy group or a protected carboxy group, A is oxygen or sulfur, and 2 is a lower alkylene group. ] and its salts.

Suitable salts for the target compound (1) include inorganic base salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, and organic bases. Salts, such as triethylamine salts, pyridine salts, pilin salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N, N'
- Salts with bases such as organic amine salts such as dibenzylethylene diamine salts and the like.

According to this invention, the desired phthalazine derivative (I) can be produced by the production method described below.

(In the formula, R1, R2, A and 2 are respectively the preceding and Production method 1 (I-a) (I-b) or its salts or its salts Production method 3 (I-c) (I-d) or its salts R1 means that it may have one or more suitable substituents).

The raw material compounds (I[>) of the above production method include new compounds, which can be produced, for example, by the following methods or similar methods thereof, or conventional methods.

or its salts [wherein R1 and A each have the same meanings as before, =a ="-+"=1"CI:1'-"""-"'-
"--'-"""In the foregoing and following descriptions of this specification, preferred examples of the various definitions encompassed within its scope will be explained in detail below.

As used herein, "lower" shall mean 1 to 6 carbon atoms, unless otherwise specified.

Suitable 1-al(lower) alkyl groups include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl,
Mention may be made of lower alkyl groups substituted by aryl rings such as naphthylpropyl and the like; these groups include, for example, halogens such as fluorine, chlorine, bromine, iodine, e.g.
4. Lower alkoxy groups such as butoxy, pentyloxy, hexyloxy, etc., such as methyethyl, propyl, isopropylene. It may have one or more suitable substituents such as lower alkyl groups such as butyl, isobutylene, tertiary butyl, pentyl, hexyl, etc. As a particularly preferable example of the alkyl group defined in this way, the phenyl ring has one or two substituents selected from the group consisting of a halogen, an 01-C4 alkyl group, and an 01-C4 alkyl group. Phenyl optionally substituted with (C
1-C4) alkyl groups, most preferably benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 4-bromo-2-fluorobenzyl, 4
-methylbenzyl and 4-methoxybenzyl.

Suitable ``protected carboxy groups'' include, for example, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and tertiary butoxycarbonyl; examples include benzyloxycarbonyl, 4- Mono(
or di- or tri)phenyl(lower) alkoxycarbonyl groups, etc., and among them, particularly preferable examples include 01-
Examples include a C4 alkoxycarbonyl group, and the most preferred is an ethoxycarbonyl group.

Suitable lower alkylene groups include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene,
Examples include straight chain or branched ones such as propylene, among which preferable examples include 01 to C
4 alkylene, most preferably methylene.

Suitable "al(lower)alkylidene groups" include those substituted with an aryl ring such as benzylidene, phenethylidene, phenylpropylidene, phenylbutylidene, phenylpentylidene, phenylhexylidene, naphthylmethylene, naphdelpropylidene, etc. Examples include lower alkylidene groups, and these groups may have one or more suitable substituents such as the above-mentioned halogen, lower alkoxy group, lower alkyl group, etc. Preferred examples of alkylidene groups include halogen in the phenyl ring, 01-C4 alkoxy groups, and 01-C4 alkoxy groups.
Phenyl optionally substituted with one or two substituents selected from the group consisting of C4 alkyl groups (C1-C4
) alkylidene groups, the most preferred being benzylidene, 4-chlorobenzylidene, 3,4-dichlorobenzylidene, 4-bromo-2-fluorobenzylidene, 4-methylbenzylidene and 4-methoxybenzylidene.

The method for producing the phthalazine derivative (I) of the present invention will be explained in detail below.

(1) Compound (1) or its salts can be produced by reacting compound (Ir) or its salts with compound (III) or its reactive derivative at the hydroxyl group or its salts. .

Suitable salts for compound (If) include the same salts as for compound (I).

Suitable salts of compound (III) include salts with bases such as alkali metal salts such as lithium salts, sodium salts, and potassium salts, and alkaline earth metal salts such as calcium salts.

Suitable reactive derivatives of the hydroxy group of compound (III) include halides such as chloride, bromide, and iodide, sulfonic esters such as methanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc. Among them, halides are particularly preferred.

Preferred examples of the compound (I [ Lower alkyl esters of halo (lower) alkanoic acids such as ethyl propionate, ethyl 3-bromopropionate, ethyl 2-chloropropionate, and ethyl 2-bromopropionate;
For example, ethoxycarbonylmethyl methanesulfonate, 1-ethoxycarbonylethyl methanesulfonate, ethoxycarbonylmethyl benzenesulfonate, 1-ethoxycarbonylethyl benzenesulfonate, ethoxycarbonylmethyl toluenesulfonate, 1 toluenesulfonate.
Examples include lower alkyl dicarbonyl (lower) alkyl esters of sulfonic acids such as -ethoxycarbonylethyl.

For compound (If), 1.2 of the following formula (I[A)
-dihydro-1-oxophthalazine ring system has the formula (IIB
) is well known to have a tautomeric relationship with the 1-hydroxyphthalazine ring system, and therefore these inner ring systems are considered to be substantially the same.

(I[A) (IB) This reaction is carried out with e.g. alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium, alkali metal hydrides such as sodium hydride, alkaline earth metals such as calcium hydride, etc. hydrides, e.g. alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, e.g. sodium Alkali metal alkoxides such as methoxide, sodium ethoxide, potassium tert-butoxide, alkali metal alkanoates such as sodium acetate, trialkylamines such as triethylamine, e.g. pyridine, lutidine, pilin, 4-dimethylaminopyridine, etc. This can be carried out in the presence of an organic or inorganic base such as a pyridine compound, quinoline, etc.

This reaction is typically performed using dichloromethane, methanol, ethanol, propatool, pyridine, and N.

The reaction is carried out in a conventional solvent that does not adversely affect the reaction, such as N-dimethylformamide, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature is not particularly limited, and the reaction is usually carried out in a range from cooling to heating.

(2) 1. Compound (I-b) or its salt is compound (I-a)
Alternatively, it can be produced by reacting its salts with a thioxo-introducing agent.

Suitable salts of compounds (I-b) and (I-a) include the same salts as those of compound (I).

Suitable thioxo-introducing agents include commonly used agents capable of converting oxo groups into thioxo groups, such as phosphorus pentasulfide.

This reaction is typically performed using dichloromethane, methanol, ethanol, propatool, pyridine, and N.

It is carried out in a conventional solvent that does not adversely affect the reaction, such as N-dimethylformamide, benzene, toluene, xylene, dioxane, etc., or a mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at a temperature ranging from room temperature to heating.

(3) Production method 3 Compound (1-d) or its salt is compound (I-c)
can be produced by subjecting R2 to an elimination reaction of the carboxy protecting group.

Suitable salts of compound (I-d) include compound (I)
The same salts can be mentioned.

This elimination reaction can be carried out by conventional methods such as hydrolysis and reduction.

Hydrolysis is preferably carried out in the presence of a base or acid;
Suitable bases include inorganic bases such as those listed in the explanation of Production Method 1. Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. .

Reduction methods that can be applied to this elimination reaction include, for example, metals such as zinc and zinc amalgam, or salts of chromium compounds such as chromium chloride and chromium acetate, and acetic acid, propionic acid, etc. Reduction by combination with organic or inorganic acids such as hydrochloric acid, sulfuric acid, etc. and palladium catalysts such as e.g. palladium sponge, palladium black, palladium oxide, palladium-on-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc. Catalytic reduction in the presence of conventional metal catalysts such as nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc. Can be mentioned.

Elimination reactions are usually performed using water, acetone, dichloromethane, methanol, ethanol, propatool, and lysine, N, N
- Carry out in a commonly used solvent that does not adversely affect the reaction, such as dimethylformamide, etc., or in a mixture thereof, and if the base or acid available for this reaction is liquid, use it as the solvent. You can also.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at a temperature ranging from room temperature to heating.

The method for producing the new raw material compound (n) and its intermediate compound will be explained in detail below.

(1) Compound (VI-a) can be produced by reacting compound (IV) with compound (V) or a salt thereof.

Suitable salts for compound (V) include the same salts as for compound (II).

This reaction is preferably carried out in the presence of a base such as an alkali metal alkanoate such as sodium acetate or potassium acetate.

This reaction may be carried out in the presence or absence of conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, pyridine, N,N-dimethylformamide, etc., or mixtures thereof. can.

Although the reaction temperature is not particularly limited, the reaction is usually carried out with or without heating.

(2) Back removal 1 Compound (II) or a salt thereof can be produced by reacting compound (VI) with hydrazine or a salt thereof.

Suitable salts of hydrazine include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, such as formic acid, acetic acid,
Salts formed with acids such as organic acids such as triple oroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid are mentioned.

This reaction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, dichloromethane, methanol, ethanol, propatool, pyridine, N,N-dimethylformamide, etc., or mixtures thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out with or without heating.

The above production methods and compounds obtained by the methods can be isolated and purified by conventional methods such as extraction, precipitation, fractional chromatography, fractional crystallization, and recrystallization.

The target compound (1) thus produced can be converted into pharmaceutically acceptable salts by conventional methods, if desired.

This new phthalazine derivative! ) and its salts were found to have aldose reductase inhibitory activity and are useful in the therapeutic treatment of diabetic complications, especially cataracts and neuropathies, such as corneal wound healing defects, cataracts, neuropathy, retinopathy, and nephropathy. It is valuable as a drug for

Typical phthalazine derivatives (I) - aldose reductase inhibitory activity values are shown below.

(1) Enzyme assay method: 0.5M phosphate buffer (p) 16.2)
0.1mQ2.0M lithium sulfate
0.2% Compound of this invention (dissolved in physiological saline) 0.1ffLll enzyme solution (aldose reductase solution, prepared according to (2) below) 0.51Q6
0mMD, L-glyceraldehyde 0.05relative2, 5mM nicotinamide adenine dinucleotide phosphate (reduced form) CNADPH)
When the above reaction solution was reacted at 35°C for 2 minutes, the degree of decrease in NADPH was measured using LKB Products A, B, Ltd. (LKB).
Automatic reaction rate analyzer for Producer A, B, )
8600 (Automatic Reaction R
ateAnalyzer LKB=8600). The enzyme activity when the change in absorbance was 0.001 per minute was determined as 1 unit.

(2) Preparation of enzyme solution: Take the rabbit's eye and collect the crystalline lens from it.

The lens was homogenized with 3 times the volume of distilled water at 4°C (all subsequent operations were also performed at 4°C), then 10.000 G
The mixture was centrifuged for 60 minutes to obtain a supernatant. This supernatant was dialyzed against 0.05M saline 21 times. The dialyzed fluid thus obtained was used as an enzyme solution.

(3) Test compound: 2-[:4-(4-bromo-2-fluorobenzyl)-
1,2-dihydro-1-year-old xophthalazin-2-yl]
Acetic acid (abbreviated as Compound A) (4) Test results: The test results are shown in the table below.

The engineering C5o value (M) is the aldose reductase activity.
The concentration of the compound of the present invention for 0% inhibition is not known.

Pharmaceutical compositions may be in various forms, for example those containing the active compound of the invention, namely Compound (I) or a salt thereof, together with organic or inorganic carriers and/or excipients suitable for external, internal or topical administration. It is provided in the form of solid preparations, semi-solid preparations and liquid preparations. The active compound, together with non-toxic and pharmaceutically acceptable auxiliary ingredients, is used to provide suitable dosage forms such as tablets, pellets, capsules, shells, solutions, emulsions, suspensions, etc. be done. Such auxiliary ingredients are, for example, water, glucose, lactose, gelatin, mannitol, starch paste, magnesium trisilicate, cornstarch, keratin, colloidal silica, barley! Includes those that can be effectively used in the production of solid, semi-solid or liquid formulations such as ilR powder, urea, etc. Furthermore, stabilizers, fillers,
Adjuvants such as colorants and fragrances may also be included.

Pharmaceutical compositions according to the invention may also contain preservatives to preserve the activity of the active compounds. The composition should contain an amount of the active compound sufficient to produce the desired therapeutic effect on the associated disease process or pathology.

When this pharmaceutical composition is used in humans, it can preferably be administered intravenously, intramuscularly or orally. The effective amount of each active compound depends on the age and/or condition of the patient being treated. However, generally the pharmaceutical compositions will contain about 50 mg, 100 mg, 250 mg, 50 mg per unit dosage form.
Contains 0 mg or 1000 mg of active compound,
and 0.1 to 1 kg body weight for humans or animals.
A daily dose of oomg is administered.

The present invention will be explained in more detail below with reference to Production Examples and Examples.

4-bromo-2-fluorobenzyl (40.69g), sodium cyanide (28.8g)
6 g) and tri-n-butylamine (1.22 relative) in water (57 mm) are stirred at room temperature for 30 minutes.
Extract the reaction mixture with ethyl ether. Wash the extract sequentially with water, dilute hydrochloric acid, and brine, and then dry. The solvent was distilled off to obtain 2-(4-bromo-2-fluorophenyl)acetonitrile.

2-(4-bromo-2-fluorophenyl)acetonitrile and concentrated sulfuric acid (t7s.amu) in water (2
The mixture of 11.6 mQ) solutions is refluxed for 1 hour. After cooling, the reaction mixture is extracted with chloroform.

Wash the extract with water, dry it, and distill off the solvent to obtain a residue. The residue was recrystallized from n-hexane to give 2-(4-bromo-
2-fluorophenyl)acetic acid (23.74 g) is obtained.

mp: 124-125℃ IR 7 1695. 1605.
1575 cm-INMR (CDC13,S>
'3.67 (2H,s), 7. O3-7
-40 (3H, m), 9.27 (ILbr s)
1) 1.3-isobenzofurandione (l1g), 3.
A mixture of 4-dichlorophenylacetic acid (15 g) and sodium acetate (1.5 g) is fused at 180° C. for 1 hour. After cooling, the mixture is washed with water. This mass is recrystallized from ethanol to give 3-(3,4-dichlorobenzylidene)-1(3H)-isobenzofuranone (6.5 g).

IR (CHCL3)? 1775.1475.102
0 cm-1 HMR (CDCl2.8): 6.77
(IH,s), 7.10-8.07 (7u,m) The following compound is obtained in substantially the same manner as in Production Example 2-1).

2) 3-(4-bromo-2-fluorobenzylidene)-
1(3H)-isobenzofuranone.

mp: 149-151°C IR: 1790 am-1H
MR(CDC13,S)' 6.60 (ILs)
, 7.20-8.33 (7H, m) 3) 3-(4-chlorobenzylidene)-1(3H)-isobenzofuranone.

IR (X di m-x): 1790. 1695
cm-'4) 3-Benzylidene-1(3H)-isobenzofuranone.

IR: 1790. 1770
am-1HMR (DMSO-ds, ε): 6.9
3 (IH,s), 7.38-8.21 (9H, m>5) 3-(4-methylbenzylidene)-1(3H)-isobenzofuranone.

IR (line "-')" 1790 cm-1a
,)3-(4-methoxybenzylidene)-1(3H)-
Isobenzofuranone.

IR (71 dim-4): 1780. 1770
．． 1660. 1600 cm-'NMR (DMS
O-da, S)' 3-77 (3H1s), 6.
83 (IHLs), 7.00 (2H, d, J=8
11z), 7.73 (2H, d.

J=8Hz), 7.40J, 00 (4H, m) quantity! (1 mutual 1) 3-(3,4-dichlorobenzylidene)-1(3H
)-isobenzofuranone (4.3 g) and hydrazine hydrate (0.8 g) in ethanol (15 vol) is refluxed for 1 hour. After cooling, the precipitated crystals are collected by filtration and then recrystallized from ethanol to obtain 4-(3,4-dichlorobenzyl)-1,2-dihydro-1-oxophthalazine (1,92 g).

IR (striped gun): 3160. 1645
cm-1HMR (DMSO-ds, 8)' 4.
35 (2H9s), 7.17-8-43 (7H, m) The following compound is obtained in substantially the same manner as in Production Example 3-1).

2) 4-(4-bromo-2-fluorobenzyl)-1,
2-dihydro-1-oxophthalazine.

IR (Suji Aoi): 3160. 1645
cm-'NMR (DMSO-da, S): 4.34
(2H1s), 7.12-8,40(8H,m) 3) 4-(4-chlorobenzyl)-1,2-dihydro-
1-Oxophthalazine.

IR (Sugitar): 3170. 1665
am-'4) 4-benzyl-1,2-dihydro-1-
Oxophthalazine.

IR (Stripe 1-R)” 1660. 1610
am-1HMR (DMSO-ds, S)' 4.
30 (2H, a), 7.23 (5)t.

s), 7.67-8.30 (4H, m)5) 4-(
4-Methylbenzyl)-1,2-dihydro-1-oxophthalazine.

IR (line): 3170. 1675.
1665 am-'6) 4-(4-methoxybenzyl)-1,2-dihydro-1-oxophthalazine.

IR<String 1-R): 1660. 1605
am-'NMR (DMSO-ds, l; )' 3
-68 (3H1s), 4.23 <2)1°s),
6.80 (2H, d, J=9Hz), 7.22 (
2H,d.

J = 9 Hz), 7.67-8.30 (4H, m) Toei Yu 1> To a suspension of sodium hydride (0.35 g) in N,N-dimethylformamide (10 ffll!), 4-
(3,4-dichlorobenzyl)-1,2-'; A solution of hydro-1-oxophthalazine (1,9 animals) in N,N-dimethylformamide (511111) was added under stirring at 0°C, and the mixture was heated to room temperature. Stir for 30 minutes. To this mixture was added ethyl 2-bromoacetate (0.76 mm) at 0°C while stirring.
dropwise and the mixture is stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure is dissolved in ethyl acetate. Wash the ethyl acetate solution with water and dry. The solvent was distilled off and recrystallized from ethanol to give Z-[a-(3,4-dichlorobenzyl)-1,2-dihydro-1-oxophthalazine-2.
-yl]ethyl acetate (1.65 g) is obtained.

IR: 1740. 1640.
1220 cm-1 HMR (DMSO-ds, l;
)' 1.23 (3H1t, J=7Hz), 4.
13 (2H, q, J near Hz), 4.38 (2H,
s), 4.97 (2H, s).

7.17-8.40 (7H, m) The following compound is obtained in substantially the same manner as in Example 1-1).

2) 2-[4-(4-bromo-2-fluorobenzyl)
-1,2-dihydro-1-oxophthalazin-2-yl]ethyl acetate.

IR<streak:+-L): 1740. 1645
cm-'NMR(DMSO-da,S)' 1
．． 20 (3H1t, J=7Hz), 4.15 (2H
, q, J near Hz), 4.36 (2H,s), 4
．． 88 (2H, s).

7.03-8.37 (7H, m) 3) Ethyl 2-[4-(4-chlorobenzyl)-1,2-dihydro-1-xophthalazin-2-yl]acetate.

IR (Sujiful)' 1745. 1640
am-1HMR (CDCl2.8): 1.30 (3
H, t, J=8Hz), 2.33 (2H, s), 2
．． 35 (2H, q, J=8Hz), 4.98 (2
H,s).

7.33 (4H, s), 7.67 (3H, m),
8.43 (IH,m)4>2-[1,2-dihydro-4-(4-methylbenzyl)-1-xophthalazin-2-yl]ethyl acetate.

IR(Xdi*-L) i 1740. 1640
am-1HMR (CDCl2.l; ): 1.
27 (3H, t, J=8Hz), 2.27 (3H,
s), 4.23 (2H,s), 4.27 (
2H,q,,7=8Hz).

4.99 (2H, s), 7.10 (4H, m),
7.90 (3H, m).

8.43 (IH, m) 5) Ethyl 2-[1,2-dihydro-4-(4-methoxybenzyl)-1-xophthalazin-2-yl]acetate.

IR: 1745. 1640
am-1HMR (DMSO-da, ε): 1.2
2 (3H, t, J=7Hz>, 3.70(31(,
s), 4.23 (2Ls), 4.18
(2H, q, J=7Hz).

4.93 (2Ls>, 6.83 (2H, d, J=
9Hz>, 7.23 (2H, d, J=9Hz>, 7
．． 72-8.33 (4H, m)6)2-[4-(3,
4-dichlorobenzyl)-1,2-dihydro-1-dichlorobenzyl-2-yl]acetic acid.

IR (X Dial): 1720. 1640.
1250 am-'7)2-[4-(4-bromo-
2-fluorobenzyl)-1,2-dihydro-1-xophthalazin-2-yl]acetic acid.

mp: 190-192°C IR (streak 1-4): 1705. 1660
cm″″18) 2-[4-(4-chlorobenzyl)-
1,2-dihydro-1-year-old xophthalazin-2-yl]
Acetic acid.

IR (Xjikubo-4) 7 1705. 1640
cm-'9)2-(4-benzyl-1,2-dihydro-
1-xophthalazin-2-yl)acetic acid.

mp: 207-209°C IR (streak m-4>' 1745. 1620.
1575 cm-'10) 2-[1,2-dihydro-4-(4-methylhensyl)-1-xophthalazin-2-yl]acetic acid.

mp: 175-177°C IR: 1715. 1620
cm-111)2-[1,2-dihydro-4-(4-
methoxybenzyl)-1-xophthalazin-2-yl]acetic acid.

mp: 214°C IR (sugital): 1740. 1640.
1585 cm-' 1) 2-[4-(3,4-dichlorobenzyl)-1,2
A mixture of -dihydro-1-xophthalazin-2-yl]ethyl acetate (1.46 g) and pentasulfide (1.7 g) in toluene (120) was centrifuged for 4 hours. After cooling,
Pour the reaction mixture into a mixture of water and ethyl acetate. Separate the organic layer and wash with water.

The solvent was distilled off and recrystallized from ethanol to give 2-[4-
(3,4-dichlorobenzyl)-1,2-dihydro-1
-thioxophthalazin-2-yl]ethyl acetate (0,9
0g).

IR (line 1-le) '1740 cm''''I
NMR (DMSO-dS): 1.23 (3
1, t, J=7Hz>, 4.1.86° (2H, q, J=7Hz>, 4.48 (2) 1
．． s), 5.52 (2H, s).

7.17-8.90 (7H, m) The following compound is obtained in substantially the same manner as in Example 2-1).

2) 2-[4-(4-bromo-2-fluorobenzyl)
Ethyl-1,2-dihydro-1-thioxophthalazin-2-yl]acetate.

IR (streak rose): 1745 cm-1H
MR(DMSO-ds,S)' 1.19
(3H1t, J=7)1z), 4-13 (2H,
q, J=7)1z), 4.44 (2H,s), 5
．． 38 (2H, s).

7.13-8.90 (7H, m) J circle 1 1) 2-[4-(3,4-dichlorobenzyl)-1,2
-dihydro-1-oxophthalazin-2-yl]ethyl acetate (1,65 g) and IN aqueous sodium hydroxide solution (1
The mixture with 3ml) in methanol (40fflll) is refluxed for 2 hours. After cooling, the solvent is distilled off, the resulting residue is made acidic with dilute hydrochloric acid, and extracted with ethyl acetate. Wash the extract with water and dry. The solvent was evaporated and the residue was recrystallized from ethanol to obtain 2-[4-(3,4-dichlorobenzyl)-1,2-dihydro-1-xophthalazin-2-ylcoacetic acid (1,30 g).

IR (Streak 3-L): 1720. 1640.
1250 am-1 HMR (DMSO-da, l;
)' 4-40 (2H,s), 4゜90 (2
H.

s), 7.23-8.50 (7H, m) Example 3-
The following compound is obtained in substantially the same manner as in 1).

2) 2-[4-(4-bromo-2-fluorobenzyl)
-1,2-dihydro-1-year-old xophthalazin-2-ylcoacetic acid.

mp: 190-192°C IR: 1705. 1660
am-1HMR (DMSO-da, 8) = 4-3
3 (2H0s), 4.77 (2H1s), 7.
10-8.47 (7H, m), 12.90 (I
H, br 5) 3) 2-[4-(4-chlorobenzyl)
-1,2-dihydro-1-year-old xophthalazin-2-ylcoacetic acid.

IR (Streak 8-L): 1705. 1640
am-1HMR (DMSO-ds, 8)' 4.
35 (2H1s), 4-90 (2H1s), 7.
37 (4H, s), 7.93 (3H, m), 8
．． 30 (LH.

m) 4) 2-[1,2-dihydro-4-(4-methylbenzyl)-1-xophthalazin-2-ylcoacetic acid.

mp: 175-177°C IR: 1715. 1620
cm-'NMR(DMSO-da,S)'2-
20 (31(,s), 4-25 (2)1゜s),
4.87 (2H, s), 7.15 (4H, m>
, 7.87 (3H.

m), 8.30 (IH, m) Shihenzil)-1-year-old xophthalazin-2-ylcoacetic acid.

mp: 214°C IR (line 1-le): 174G, 1640
．． 1585 am'NMR (DMSO-da, δ)
: 3.64 (3H, s), 4.22 (2H.

s), 4.85 (2H, s), 6.78 (2H
, d, J: 9Hz).

7.22 (2H, d, J=9Hz), 7.68-8
．． 32 (4H,m>Example 4 1) 2-[4-(3,4-dichlorobenzyl)-1,2
A warm mixture of ethyl -dihydro-1-thioxophthalazin-2-yl]acetate (0.9 g) and IN sodium hydroxide (4-) in methanol (301 nQ) is refluxed for 1.5 hours. After cooling, the solvent is distilled off under reduced pressure, and the resulting residue is made acidic with dilute hydrochloric acid and extracted with ethyl acetate. Separate the organic layer and wash with water. The solvent was distilled off and then recrystallized from ethanol to give 2-[4-(3,4-dichlorobenzyl)-
1,2-dihydro-1-thioxophthalazin-2-ylcoacetic acid (0,52 g) is obtained.

IR (line 1-l): 1720 cm-1N
MR(DMSO-ds,l; )=4-42(2H
1s), 5.42 (2H1,s), 7.20-9
．． 00 (7H, m) The following compound is obtained in substantially the same manner as in Example 4-1).

2) 2-[4-(4-promo-2-fluorobenzyl)
-1,2-dihydro-1-thioxophthalazin-2-yl]acetic acid.

mp 721g-220℃ IR (one line) ' 1720 cm""N
MR (DMSO-da, 6)' 4-42
(2H9s), 5.33 (2H1s), 7.
00-8.06 (6H, m), 8.67-8.93
(LH, m)
Ethyl ylcoacetate is obtained. Further, this product was prepared in Example 3.
-1), 2-(4-benzyl-1,2) was subjected to hydrolysis with an aqueous sodium hydroxide solution, and
-dihydro-1-xophthalazin-2-yl)acetic acid is obtained.

mp: 207-209℃ IR (Stripe 1-L)' 1745. 1620.
1575 am-1HMR (DMSO-d δ)
' 4.32 (2H,s), 4.88 (2
H.

6゜

Claims (1)

[Claims] 1) General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is an al (lower) alkyl group which may have one or more suitable substituents, R^2 is a carboxyl group or a protected carboxy group, A is oxygen or sulfur, and Z is a lower alkylene group] and salts thereof. 2) (a) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an alkyl group that may have one or more suitable substituents, A is oxygen or sulfur] or its salts with the general formula: HO-Z-R^2 (wherein, R^2 is a carboxyl group or a protected carboxy group, and Z is a lower alkylene group, respectively). ) or its reactive derivative at the hydroxyl group or its salts to form a compound of the general formula: ▲Which has a mathematical formula, chemical formula, table, etc.▼ (where R^1, R^2, A and or (b) general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1, R^2 and Z are (Each has the same meaning as above) or its salts are reacted with a thioxo-introducing agent to form the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and Z are (Each has the same meaning as before) or (c) General formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, A and Z each have the same meaning as before) When a compound represented by R^2_a means a protected carboxy group is subjected to an elimination reaction of the carboxy protecting group of R^2_a, the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, A and Z each have the same meaning as before)
A general formula characterized by obtaining a compound or its salts represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, A and Z each have the same meaning as before) A method for producing the compound shown in and its salts.