JPH0449237A - Phospholipase a2 inhibitor - Google Patents

Abstract

PURPOSE:To provide a strong phospholipase A2 inhibitor not inactivated in oral administration and not causing adverse effects such as tunica mucosa disorders by compounding a dihydropyridine compound or a salt thereof as an active ingredient. CONSTITUTION:The inhibitor contains a compound of formula I {R<1> is alkyl; R<2> is (alkoxy)alkyl, CH2-X-A-R<7> [X is O, S; A is alkylene; R<7> is halogen, group of formula II (R<8>, R<9> are H, alkyl, group of formula III or IV, or forms a ring with N)]; R<3> is alkyl, R<4> is X-A-R<7> and R<5> is H, or R<4> is alkoxy and R<5> is X-A-R<7>; R<6> is NO2, aralkyloxy} or a salt thereof, such as 4-[2-(4-aminobutoxy)-5- nitrophenyl]- 2 -methyl- 6 -propyl-1,4-dihydropyridine- 3,5 -dicarboxylic acid 3,5 - diethyl ester (new compound). The compound has excellent II type phospholipase-inhibiting activity and antiinflammatory activity.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a phospholipase A2 inhibitor containing a 1,4-dihydropyridine compound or a salt thereof as an active ingredient.

(Background of the invention) Phospholipase A2 inhibition suppresses the production of arachidonic acid and lysophospholipids from in vivo cell membrane phospholipids by inhibiting the enzymatic activity of phospholipase A2, and these metabolites are used to inhibit prostaglandins involved in inflammation. The aim is to suppress the production of mediators such as leukotrienes and leukotrienes.

Among the phospholipase A2 inhibitors known so far, the one that shows the most potent inhibitory activity is a steroid anti-inflammatory agent (
glucocorticoids). However, it is well known that glucocorticoids exhibit serious side effects.

On the other hand, non-steroidal anti-inflammatory drugs such as indomethacin show anti-inflammatory activity by inhibiting cyclooxygenase of the arachidonic acid cascade and suppressing the production of prostaglandin E2.
It is also well known that it impairs the gastric mucosal protective effect of No. 2, resulting in side effects such as gastric mucosal damage.

Recent research on phospholipase A2 inhibitors has confirmed the existence of two types of phospholipase A2, namely type I and type phospholipase, which differ in their secondary structure and substrate specificity. A certain phospholipase A2 is
Identical to that of the pancreas, ■ type phospholipase A2
It has been proven that this is the case, and there is a growing belief that the enzymes involved in inflammation are type II, which are found in other tissues.

Therefore, if it shows inhibitory activity against type 2 phospholipase A2, it is considered that it can be used as an anti-inflammatory agent without side effects such as gastric mucosal damage.

Until now, various phospholipase A2 inhibitors have been known, including some that exhibit inhibitory activity against type 2 phospholipase A2. This may cause problems such as loss of efficacy or weak inhibitory activity.

Therefore, there is a strong need for the development of an orally administrable and potent 2-type phospholipase inhibitor.

On the other hand, it is known that nifedipine and nisoldipine, which are marketed as dihydropyridine calcium antagonists, exhibit inhibitory activity against phospholipase^2 [In
flammation, Vol. 11. No.3
．． 353 (1987)].

According to the research conducted by the present inventors, it has been confirmed that these drugs have weak inhibitory activity against type 1 phospholipase A2, and are not able to overcome the above-mentioned problems. In addition, as shown in this miscellaneous text, phospholipase^2 and calcium antagonistic action are independent, and even though it is a compound that has calcium antagonistic action, phospholipase^2 (II
It was also confirmed that they do not necessarily have inhibitory activity.

(Means for Solving the Problem) Based on the above state of the art, we used type II phospholipase A2 as a screening enzyme and investigated the inhibitory activity of various compounds against it, and found that the following formula (1) shows The present invention was completed by discovering that the compound has excellent phospholipase A2 inhibitory activity.

(The symbols in the formula have the following meanings.

R1, lower alkyl group.

R2: lower alkyl group, dimethoxymethyl group, lower alkoxy-substituted lower alkyl group, or a group represented by the formula -CH2-X-A-R'.

R3, alkyl group.

When R4 and R5 are hydrogen atoms, the formula -X-A-1'! ' When R5 is a group represented by the formula -X-A-R7, it is a lower alkoxy group.

When R5+R4 is a lower alkoxy group, the formula -X-A-R'
When R4 is a group represented by the formula -X-A-R', it is a hydrogen atom.

R6, nitro group, or aralkyloxy group.

X: Oxygen atom or sulfur atom Base.

R8 and R9, the same or different, hydrogen atom, lower allo3
-264459, 61-233669, etc., which have both calcium antagonistic effect and β-blocking effect (particularly cardioselective β receptor (βl) blocking effect), and have fewer side effects, such as ischemic heart disease, hypertension, etc. It is disclosed as a compound useful as a prophylactic or therapeutic agent for cardiovascular diseases such as arrhythmia, or as a compound useful as an intermediate for the production thereof.

However, these compounds have never been shown to be useful as phospholipase A2 inhibitors.

Moreover, the group shown among the compounds contained in -i formula (1).

However, R8 and R9 may be combined with the nitrogen atom to form a ring. ) Most of the above-mentioned compounds are known compounds, such as 4-[2-(4-aminobutoxy)-5- shown in Japanese Patent Publication No. 1-23463 and Japanese Patent Application Laid-Open No. 62-149659.
Nitrophenyl]-2-methyl-6-broby-1.4
-dihydropyridine-3,5-dicarboxylic acid 3,5-
The diethyl ester and the compounds produced in the examples below are new compounds that have not been described in any literature.

In the definition of general formula (1) herein, unless otherwise specified, the term "lower A" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, "lower alkyl groups include, for example, methyl group, ethyl group, propyl group, isopropyl group,
Butyl group, isobutyl group, 5ec-methyl group, ter
t-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, ■methylbutyl group,
2-methylbutyl group, ■, 2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-
Methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-
Dimethylbutyl group, 1,3-dimethylbutyl group, 2.3
-dimethylbutyl group, 3,3-dimethylbutyl group, ■-
Ethylbutyl group, 2-ethylbutyl group, 1,1.2-1
-limethylpropyl group, L2,2-)limethylpropyl group, l-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. Also, as the "lower alkoxy group" , metquine group, ethoxy group, propoxy group, isopropoquine group, butoxy group, isobutoxy group, 5ec-butoxy group, tert-
Butoxy group, hentyloxy (amyloxy) group, isopentyloxine group, tertpentyloxy group, neopentyloxy group, 2-methylbutoxy group, 2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, etc. Can be mentioned.

The aralkyloxy group represented by R6 is a hensyloxy group, a phenyloxy group, a 3-phenylpropoxy group, a 4-phenylbutoxy group, a 5-phenylpentyloxy group, or a 6-phenylbutoxy group.
The alkyl moiety is a linear or branched aromatic ring-substituted lower alkoxy group having 1 to 6 carbon atoms, such as -phenylhexyloxy group.

The lower alkoxy-substituted lower alkyl group represented by R2 means a group in which any hydrogen atom of the lower alkyl group is substituted with the lower alkoxy group.

The "alkyl group" represented by R3 includes a "lower alkyl group" and further refers to a linear or branched group having 7 to 12 carbon atoms. Therefore, specifically, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, ■-methylhexyl group, ■,2-dimethyloctyl group, 3,4-
Examples include dimethylhebutyl group, 2-ethyloctyl group, and 2=methyl-3-ethylnonyl group.

The alkylene group represented by 8 is preferably an alkylene group having 1 to 10 carbon atoms, and specifically, methylene group, ethylene group, methylmethylene group, ■-methyltrimethylene group, 2-methyl trimethylene group, 3-methyltrimethylene group, 1-ethipentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-
Methyltetramethylene group, 4-methyltetramethylene group, l-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3.3-dimethyltrimethylene group, 1.3
-dimethyltrimethylene group, 2.3-dimethyltrimethylene group, 1.2 dimethyltrimethylene group, 1-ethyltrimethylene group, 1,1.2-)limethylethylene group,
diethylmethylene group, hexamethylene group, 1-methylpentamethylene group, 1,1-dimethyltetramethylene group,
2,2-dimethyltetramethylene group, 3.3-dimethyltetramethylene group, 4,4-dimethyltetramethylene group, 1.13-trimethyltrimethylene group, Ll2-)dimethyltrimethylene group, 1,1,2. 2-tetramethylethylene group, 1.1-dimethyl-2-ethylethylene group, 1.1-diethylethylene group, heptamethylene group, ■
-Methylhexamethylene group, 1,1-dimethylpentamethylene group, 2.2-dimethylpentamethylene group, 3.3
-dimethylpentamethylene group, 4,4-dimethylpentamethylene group, 5,5-dimethylpentamethylene group, Ll
, 4-trimethyltetramethylene group, Ll2-trimethyltetramethylene group, Ll,3-)dimethyltetramethylene group, 1,1,2.2-tetramethyltrimethylene group, 1゜1.3.3-tetramethyltrimethylene group methylene group,
1,1-dimethyl-2-ethyltrimethylene group, Ll-
Dimethyl-3ethyltrimethylene group, octamethylene group, ■-methylhebutamethylene group, 1,1-dimethylhexamethylene group, nonamethylene group, ■-methyloctamethylene group, 1,1-dimethylhebutamethylene group, decamethylene group, (1)-Methylnonamethylene group, 1,1-dimethyloctamethylene group and the like.

The halogen atom represented by R7 includes chlorine, bromine, iodine, and fluorine atoms. Examples of the ring formed by combining R6 and R7 include rings such as piperidine, morpholine, thiophorphorine, piperazine, and fucurimito.

The compound represented by the general formula (1) has an asymmetric carbon atom and exists in optical isomers. The compounds of the present invention include isolated optical isomers and mixtures thereof.

Compound (1) also forms a salt. The pharmaceutical compound of the present invention (
1) includes pharmacologically acceptable salts of these, such as the above-mentioned hydrochlorides, as well as inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid, or formic acid, acetic acid, oxalic acid, malonic acid, and succinic acid. acids, organic acids such as maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, salicylic acid, gallic acid, picric acid, methanesulfonic acid, ethanesulfonic acid,
Includes acid addition salts with acidic amino acids such as glutamic acid and aspartic acid, and ammonium salts.

-a The compound represented by formula (1) is
No. 463, JP-A-62-149659, JP-A No. 63-26
It can be manufactured by the method described in each publication of No. 4459 and No. 61-233669, or according to the method.

Furthermore, in addition to the method disclosed in the above-mentioned publication, compound (1) can be synthesized by various methods taking into account the characteristics of its basic skeleton and groups.

A typical method is the application of Hantzsch's 1,4-dihydropyridine synthesis method. Hantzs
According to the application of the synthesis method of ch, compound (1) is synthesized in various combinations as shown in the following reaction formula.

H.O. / Dyed R' 0 + the law of nature\ OR2 (S2) N.H.

(S4) (S3) (wherein R1, R2, R3, R4, R5, R6 have the above-mentioned meanings, /C8 / \34.3 is a compound represented by the formula % formula %, CHCo-R 'Yo〉 / 4C\OR2 According to this reaction, when R2 is the formula -CH, -X-8-R7, or either R4 or R5 is the formula -X-A-
It is preferable to use this method when producing a compound in which R7 is not a free amino group, and when R7 is a free amino group, potassium phthalimide is added to the halogen compound produced by the above-mentioned Hantzsch synthesis method as a raw material. or Han tzsch
It can be produced by synthesizing a phthalimide compound using the synthesis method described above, and then removing the phthalic acid moiety.

For example, using a compound in which R5 is -X-A-Y (Y means a halogen atom) as a raw material, R5 is -X-A-NH
When producing a compound of 2, the above Hantzsch
A 1,4-dihydropyridine compound having a halogen side chain is obtained using one of the reactions described in the following (the method in the example corresponds to (3)), and this is reacted with potash phthalimide, and then decomposed using hydrazine or the like. Protect.

means. ) H (Ia) First, Hantzsch synthesis using a halogen compound is carried out at room temperature or under heating, preferably under heating, using a solvent that can azeotropically remove water generated by the reaction, such as Hensen, toluene, xylene, methanol, ethanol, etc. The reaction may be carried out while removing water that azeotropes downward from the reaction system. The reaction time is appropriately selected depending on the properties of the trial cutting involved in the reaction, but several hours is usually sufficient. The compound obtained here is then heated with potassium phthalimide in an aprotic solvent such as dimethylformamide or dimethyl sulfoxide, preferably at 120 to 130°C for an appropriate time to convert the halogen atom into a phthalimide group. Then, it can be converted to the desired product by the Gabriel reaction, which involves deprotection by reaction with hydrazine in a solvent such as ethanol.

R2 is -CH2-X-A-Y or R4 is -X-A-Y
It can be carried out in almost the same way when a certain compound is used as a raw material.

Further, a compound in which R1+ and R9 form a ring can be synthesized by reacting a corresponding ring amine instead of potassium phthalimide.

Isolation and purification of the target product is carried out by conventional methods such as concentration of the reaction mixture, fractionation by column chromatography, and recrystallization from single or mixed organic solvents such as methanol, chloroform, and ethyl acetate.

(Effects of the Invention) Next, the phospholipase A2 inhibitory effect of the compound of the present invention will be explained by giving experimental examples.

Measurement of phospholipase 2 inhibitory activity Journal of Biological Chemistry [J
, Biol, Chem, 261(9), 423
9-4246 (1986)], and was measured by the following method.

135mM Tris-HCl buffer '1 containing 13.5mM calcium chloride and 270μg/run of live serum albumin
m (pH 8,0) 100μ! Add 22.5 μr of rabbit platelet-derived phospholipase A to the solution and incubate in water for 30 minutes.

Next, 10μ of the compound of the present invention! , and 25μ of E. coli autoflaved specimen labeled with tritium-labeled oleic acid.
Add f (approximately 200,000 cpm) to the reaction solution and react at 6°C for 10 minutes. The reaction is stopped by adding 50 μl of 2N hydrochloric acid. After stopping the reaction, 50 μl of bovine serum albumin at 20 μ/d was added and the mixture was left on ice for 30 minutes, centrifuged, and the counts of the centrifuged supernatant were measured.

The autoflaved sample of E. coli labeled with tritium-labeled oleic acid, which was used as a substrate for the measurement of phospholipase A2 inhibitory activity, was prepared as follows. - Add night cultured E. coli culture solution to 100% tryptone medium (1% hactodryptone 0.5% sodium chloride)
In addition, incubate at 37°C until ODl, o becomes 0.4. Next, Br1j35 (surfactant)
1/]OOi and tritium-labeled oleic acid 5mC1, and further incubation was continued at 37°C for 5 hours, followed by autoflaving at 4°C for 20 minutes at 120°C. Thereafter, the bacterial cells were thoroughly washed with 0.7M Tris-HCl buffer containing 0.1% live serum albumin and 10mM calcium chloride, and then 0.7M containing 0.2% sodium azide and 10mM calcium chloride.
) Suspended in IJS hydrochloric acid buffer and stored at 4"C until use. The IC5o values of the phospholipase A2 inhibitory activity of the compounds of the present invention measured by this method are shown in the table.

Measurement of inhibitory effect on mouse ear edema The test sample was applied to both ears of a male ICR mouse (weighing 30-35 g), and 30 minutes later, phorbol 12-myristate 13-acetite (TPA) was applied to the right ear only.
Apply 1 μg/ear. After 4 hours, cut out each ear and measure its weight. The results are shown in the table.

As is clear from the above experimental results, the pharmaceutical compound of the present invention has excellent inhibitory activity and anti-inflammatory activity, especially against type 2 phospholipase 2, and does not lose its activity upon oral administration, causing gastric mucosal disorders and other problems. It is useful as a potent phospholipase 82 inhibitor that can inhibit the biosynthesis of both arachidonic acid and lysophospholipids without any side effects.

Therefore, the phospholipase A2 inhibitor of the present invention is an anti-inflammatory agent for various inflammations, an anti-rheumatic agent, a therapeutic agent for allergic diseases such as asthma and atopic diseases, ischemic vascular disorders in which phospholipase A2 is said to be involved, It is used as a therapeutic agent for ulcers, sepsis, pancreatitis, etc.

Another advantage of the compound of the present invention is that it has low toxicity. For example, the product of Example 4, BDF, L[lS when administered intraperitoneally to mice. is 200mg/kg
That's all.

Administration method, dosage Phospholipase A containing nicardipine or its salt
2 inhibitors are particularly effective even when administered orally, so it is desirable to formulate them into oral preparations, such as tablets, capsules, powders, fine granules, granules, gunpowders, or oral spreads, etc. This does not preclude the use of parenteral preparations such as injections, suppositories, ointments, emulsions, patches, and nasal preparations, as well as sublingual preparations. Administration is preferred.

Such formulations can be prepared by conventional formulation methods in the art using commonly used pharmaceutical carriers, excipients, and other additives. Publication number 64-7047, patent application No. 2-
The formulation described in No. 66190 is suitable for reducing the burden on patients due to administration and improving compliance.

The dosage of the active ingredient of the pharmaceutical of the present invention is appropriately determined in consideration of the symptoms, weight, age, gender, etc. of the patient to whom it is applied.
Orally 5 to 500 μg per day for adults, preferably 1
The dose is 0 to 250 mg per day, 1 to 200 mg by intravenous injection, preferably 5 to 100 mg, administered once or twice a day as described above, or divided into 3 to 4 times as usual.

(Example) The manufacturing method and preparation of a new compound among the compounds of the present invention and the preparation of a preparation will be shown below as an example. In addition, the structural formula of the target compound is written at the beginning of Examples 1 to 6.

Example 1 8.92 g of 2-(4-chlorobutoxy)-5-nitrohenzaldehyde, 5.50 g of ethyl butyryl acetate
g, piperidine 0.14a1 and acetic acid 0.40d to dry benzene 80g? Understood Dean Stark (Dea)
n-5 tark)) Heat under reflux for 3 hours while removing generated water from the reaction system using plastic wrap. After cooling, the solvent was distilled off under reduced pressure, and 5.84 g of ethyl 3-aminocrotonate and 35 d of methanol were added to the resulting residue.
Heat to reflux for an hour. After cooling, the precipitated crystals were collected by filtration10.
2g diethyl 4-[2-(4-chlorobutoxy)
Crude crystals of -5-nitrophenyl]-2-methyl-6-n-propyl-1,4-dihydropyridine-3,5-dicarboxylate are obtained. 7.09 g of the present compound and 2.58 g of potassium phthalimide are suspended in 18 d of N,N-dimethylformamide and heated at 120-130°C for 2 hours. The reaction solution was poured into ice water and the precipitated solid was collected by filtration. Ethanol 180 and 7.20 g of hydrazine l hydrate (containing about 80%) are added to the solid, and the mixture is heated under reflux for 1.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, the residue was extracted with chloroform, washed with water, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography using chloroform-methanol (97:3 to 80:20 V/V
). Crystallized from methanol, diethyl 4-
2.94 g of [2-(4-aminobutoxy)-5-nitrophenyl]2-methyl-6-brobyl-1,4-dihydropyridine3.5-dicarboxylene) was obtained. This compound has the following physical and chemical properties.

(1) Melting point 156.5-157.5°C (11) Nuclear magnetic resonance spectrum (CDCfi 3) δ (ppm);
0.9B (3H, t) 1.16 (6tl, t)
2.84 (2tl, t) 5.28 (IH, s)
Example 2 υ 9.24 g of 2-(4-bromobutoxy)-5-nitrohenzaldehyde, 9.79 g of ethyl 4-(2-phthalimidoethoxy)acetoacetate, 0 piperidine
．． 1M and acetic acid 0.35- dried Hensen 5011!
l! Dean-Stark
)) Heat under reflux for 3 hours while removing produced water from the reaction system using a lamp. After cooling, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and 7 mL was added with Hensen-ethyl acetate (92:8 V/V).
Volume: 139 g of amorphous ethyl 2-12-(4-bromobutoxy)-5-nitrophenyl 1 methylene-4
-(2-phthalimidoethoxy)acetoacetate is obtained. 8 g of the present compound 1:J and 2.96 g of ethyl 3-aminocrotonate were dissolved in Metatsuru 40I11 and heated under reflux for 15 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized with a mixed solvent of methanol and chloroform to obtain diethyl 4-[2-(4-bromobutoxy)-5-
nitrophenyl]2-methyl-6-(2-phthalimidoethoxy)methyl 1,4-dihydropyridine-3,5-
5.04 g of dicarboxylate was obtained. This compound has the following physical and chemical properties.

(1) Melting point 170.5-172"C (11) Nuclear magnetic resonance spectrum (CDCffi 3) δ
(ppm) ;1.12(3)1. t) 1.1
6 (38, t) 2.42 (3H, s) 4.66 (
2H,s) 5.24 (IH,s) Example 3 H 5-benzyloxy-2-(4-bromobutoxy)benzaldehyde 38.3g, methylacetoacetate 12
．． 2g.

0.4 M of piperidine and 1.40 m of acetic acid were dissolved in 220 d of dry benzene and
The reaction system is heated under reflux for 3.5 hours while removing generated water from the reaction system using a t-ark trap. After cooling, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and benzene-ethyl acetate (98:2V
/V) to obtain 44.1 g of an amorphous intermediate. 40.1 g of this intermediate and 9.99 g of methyl 3-aminocrotonate were dissolved in 2-propatool 200- and heated under reflux for 9 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was crystallized from ether to obtain crude crystals, and recrystallized from a mixed solvent of ethyl acetate and ether to give dimethyl 4-[5-hensyloxy-
23.5 g of 2-(4-bromobutoxy)phenyl 1-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate was obtained. This compound has the following physical and chemical properties.

(i) Melting point 136.5-139°C (11) Nuclear magnetic resonance spectrum (cnc i,) δ(
ppm); 2.24 (6H, s) 3.55 (6)
1. s) 3.92 (2H, t) 4.95 (2H,
s) 5.23 (IH, s) Example 4 7.60 g of 2-(4-chlorobutoxy)-5-nitrohenzaldehyde and 5.46 g of potassium phthalimide
was suspended in N,N-dimethylformamide 35 and 120
Heat at °C for 3.5 hours. The reaction solution was poured onto ice water and extracted with chloroform. After washing with saturated brine and drying over anhydrous sulfuric acid, the l8 medium was distilled off under reduced pressure. By crystallizing the resulting residue from methanol, 2-(4-
7.74 g of crude crystals of (phthalimidobutoxy)-5-nitrohenzaldehyde are obtained. This compound 5.34g, methylacetoacetate 1.78g, piperidine 0.06
mj! and acetic acid 0.17- dried benzene 50! Dean Stark (Dean-5tark)
2 while removing the water produced from the reaction system using a lamp.
Heat to reflux for an hour. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
Hensen-ethyl acetate (95:5 to 90:10V/V
). Obtained 6,46. amorphous methyl
2-[5nitro-2-(4-phthalimidobutoxy)phenyl]methyleneacetoacetate and methyl 3-
Amino-4,4-dimethoxycrotony) 2.38g
was dissolved in 40 liters of methanol and heated under reflux for 62 hours.

After cooling, the solvent was distilled off under reduced pressure and the residue was extracted with chloroform.

(2) Wash with normal hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution and dry with anhydrous magnesium sulfate.

Dimethyl-2-dimethoxymethyl-6 was obtained by distilling off the solvent under reduced pressure and crystallizing the resulting residue with ethyl acetate.
-Methyl-4-[5-nitro-2-(4-phthalimidobutoxy)phenyl]-1,4-dihydropyridine-3
2.73 g of 5-dicarboxylate was obtained. This compound has the following physical and chemical properties.

(1) Melting point 144.5-146.5"C (11) Nuclear magnetic resonance spectrum (CDCI!, 3) δ (ppm);
2.35 (3H, s) 3.35 (3H, s) 3.
43(31(,s) 3.56(3H,s)3.
58 (3H, s) 5.35 (IH, s) 5.92
(1)1. s) The following compound was obtained in the same manner as in Example 1.

Example 5 Example 6 Dimethyl 4-[2-(6-aminohexyloxy)
-5nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Physical and chemical properties (i) Melting point 168-171''C (ii) Nuclear magnetic resonance spectrum (DMSO-d6) δ (
ppm); 2.24 (6) 1. s) 3.48 (6
H, s) 4.08 (2H, t) 5.21 (18,
s) ■ Dimethyl 4- [2-(8-aminooctyloxy)
-5-nitrophenyl]-2,6-dimethyl-1,4-
Dihydropyridine-3,5-dicarboxylate Physical and chemical properties (i) Melting point 178-181°C (ii) Nuclear magnetic resonance spectrum (DMSO-d6) δ (
ppm);2.22(61(,s) 3.48(6
8, s) 4.08 (2H, t) 5.20 (IH,
s) Example 7 (Formulation example) An example of a tablet formulation is shown.

Prescription example (tablet) Compound of Example 1 100g starch
185g Lactose 25g Magnesium Stearate 1.5g The above bones were granulated using Scooch Paste as a binder and compressed into tablets by a conventional method.
1,000 100 mg tablets were prepared.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (Symbols in the formula have the following meanings. R^1: Lower alkyl group. R^2: Lower alkyl group , a lower alkoxy-substituted lower alkyl group, or a group represented by the formula -CH_2-X-A-R^7. R^3: Alkyl group. R^4: When R^5 is a hydrogen atom, the formula -X-A- When the group represented by R^7 and R^5 is a group represented by the formula -X-A-R^7, it is a lower alkoxy group. When R^5: R^4 is a lower alkoxy group, -X-A-R
When R^4 is a group represented by the formula -X-A-R^7, it is a hydrogen atom. R^6: Nitro group or aralkyloxy group. X: oxygen atom or sulfur atom A: alkylene group. R^7: A halogen atom or a group represented by ▲ where there are numerical formulas, chemical formulas, tables, etc. ▼. R^8 and R^9: Same or different, a hydrogen atom, a lower alkyl group, a group represented by the formula ▲There is a mathematical formula, chemical formula, table, etc.▼, or a group represented by the formula ▲There is a mathematical formula, chemical formula, table, etc.▼ Group shown. However, R^8 and R^9 may be combined with the nitrogen atom to form a ring. ) A phospholipase A_2 inhibitor containing a dihydropyridine compound or a salt thereof as an active ingredient. 2,4-[2-(4-aminobutoxy)-5-nitrophenyl]-2-methyl-6-propyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-diethyl ester or salt thereof