JPH04244081A - 1,4-dihydropyridine derivative and therapeutic agent containing the same as active ingredient for allergic or inflammatory disease - Google Patents

Abstract

PURPOSE:To obtain a 1,4-dihydropyridine derivative having various activities as an antiallergic, an anti-inflammatory agents and a therapeutic agent for cardiovascular systems. CONSTITUTION:A derivative expressed by formula I [Ar is ethynyl, nitro, (halogen-substituted) phenyl, etc.; A is lower alkoxy or lower alkylamino; R<1> is H or lower alkyl; R<2> is H or lower alkyl; R<3> is methyl or amino; X is 1,4- piperazinediyl, NH, etc.; Y is carbonyl or lower alkylene; Z is lower alkyl, halogen, etc.; (n) is 1-5] and its pharmacologically acceptable salt, e.g. 2-(4- nicotinoyl-1-piperazinyl)ethyl 4-(3-ethynyl)phenyl-2,6-dimethyl-1,4- dihydropyridine-3,5-carboxylate dihydrochloride. The compound expressed by formula I is obtained by reacting a beta-aminocrotonic acid derivative expressed by formula II with an arylaldehyde derivative expressed by formula III and a keto ester derivative expressed by formula IV in an organic solvent such as ethanol, preferably at 30-100 deg.C.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to 1,4-dihydropyridine derivatives and therapeutic agents for allergic or inflammatory diseases containing the same as an active ingredient.

0002

BACKGROUND OF THE INVENTION A large number of 1,4-dihydropyridine derivatives are known. For example, 4-(2-nitrophenyl)-2,6-
Dimethyl-1,4-dihydropyridine-dicarboxylic acid dimethyl ester (hereinafter referred to as nifedipine) is known to have strong pharmacological activities such as hypotensive action and coronary vasodilatory action (see US Pat. No. 3,644,627). . Also 4-(3-nitrophenyl)-2
, 6-dimethyl-1,4-dihydropyridine-dicarboxylate methyl 2-(N-benzyl-N-methylamino)ethyl hydrochloride (hereinafter referred to as nicardipine) (see U.S. Pat. No. 3,985,758) and 4-(
3-nitrophenyl)-2,6-dimethyl-1,4-
Dihydropyridine- Isopropyl dicarboxylate 2-
Methoxyethyl ester (hereinafter referred to as nimodipine) is widely known.

Most of the known 1,4-dihydropyridine derivatives have a nitro group or a phenyl group at the 4-position of the pyridine ring.
It is a compound substituted with a group such as halogen. There are very few examples of compounds in which the phenyl group at the 4-position is substituted with acetylene. For example, 4-(2-ethynylphenyl)-2,
6-Dialkyl-1,4-dihydropyridine-dicarboxylic acid ester is disclosed as an alkyne group in some of the patents for its production method (Japanese Patent Publication No. 126-1983).
(Refer to Publication No. 32), there is no description of Examples, so there is no specificity as a compound. That is, the physical properties and pharmacological effects of the compound are unknown. Also, 4-[2-(2-aryl)ethynyl]phenyl-2,6-dimethyl-1
, 4-dihydropyridine-3,5-dicarboxylic acid dialkyl ester is disclosed in JP-A-62-252768.
However, the detailed pharmacological action is not described and it is considered to be insufficient as a pharmaceutical invention.

[0004] Further, as a report related to a substituent at the 3-position of a 1,4-dihydropyridine ring, there is a report in JP-A-61-17562 which has a piperadylalkyl side chain. For example, in Japanese Patent Application Laid-open No. 17562/1983, “Group (1)

[0005]

[Chemical formula 3]

(Y is a C2-C5 alkylene chain, alkyleneoxyalkylene, alkylenethioalkylene or alkyleneaminoalkylene chain, and Z is one selected from lower alkyl, lower alkoxy, cyano, halo and trifluoromethyl, or phenyl, pyridinyl, or pyrimidinyl, which can be substituted with further substituents, X is O or NH).”
is disclosed. The substituents of the phenyl group substituted at the 4-position of the 1,4-dihydropyridine ring are a nitro group, a halogen atom, a cyano group, a hydroxy group, an alkoxy group, a haloalkyl group, an acetamido group, and a methylsulfonyl group. Its characteristics include both calcium antagonistic action and sympathetic α-adrenergic receptor blocking action.

[0007] Also, in Japanese Patent Application Laid-open No. 58-201765, “Group (2)

[0008]

[C4]

(A is alkylene, Ar is aryl or pyridyl, m is an integer from 1 to 3, R6
represents hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl).

However, the substituent of the phenyl group substituted at the 4-position of the 1,4-dihydropyridine ring is a hydrogen atom, a halogen atom, a nitro group, a trifluoromethyl group, an alkyl group,
There is no disclosure of a compound in which Ar in the compound (I) of the present invention has an ethynylphenyl group, which is a cycloalkyl group, an alkoxy group, a cyano group, an alkoxycarbonyl group, or an alkylthio group.

-X-Y- in the compound (I) of the present invention
As in Z, Y is a pyridyl group, thienyl group, pyrazinyl group, piperidinyl group, indolyl group, quinolinyl group, thiazolyl group or No compound having an imidazolyl group is known yet.

[0012] On the other hand, the pathology of inflammation and allergic diseases is complex, as not only a single mediator but also various mediators are mutually involved. especially,
Asthma is an allergic disease, and due to the diversity of pathophysiology, no definitive mediator that influences the pathophysiology has been found. The same thing has been pointed out in therapeutic agents for circulatory system diseases, particularly in therapeutic agents for circulatory system diseases induced by ischemia. Therefore, a desirable requirement for these therapeutic agents is that they have multifunctional pharmacological actions. Furthermore, the basic pathological condition of asthma is tracheal spasm during an attack, and it is essential for anti-asthmatic drugs to alleviate this.

[0013] Platelet activating factor (PAF) (1-O-alkyl-2-acetyl-
The actions of sn-acetyl-3-phosphorylcholine (sn-acetyl-3-phosphorylcholine) are wide-ranging. For example, regarding inflammation and immunity, PAF is
It induces morphological changes, strong aggregation, and release reactions in platelets, which are one of the target cells of PAF. It also has an activating effect on neutrophils, monocytes, and macrophages, and the associated production of active oxygen that damages tissues and promotes migration. Furthermore, it has a migration-promoting effect on eosinophils, a leukocyte-juvenating effect, and an arachidonic acid release-promoting effect. Furthermore, it causes edema due to its vascular permeability enhancing effect, which is 1,000 to 10,000 times more powerful than histamine. Regarding the circulatory system, it is said that vascular endothelial cells produce PAF upon stimulation by thrombin, and thrombus formation occurs when platelets and neutrophils adhere to the cells. In addition, PAF exhibits a strong blood pressure lowering effect based on the dilation effect of peripheral blood vessels. Furthermore, it exhibits a deteriorating effect on cardiac function due to a decrease in cardiac output, heart rate, and arrhythmia. The effect of PAF on the digestive system is thought to be acute gastric ulcer formation due to impaired gastric mucosal blood flow. Furthermore, it is known that PAF is involved as a mediator in the endotoxin shock caused by intracellular toxins observed in Gram-negative bacterial infections. PAF is also known to be involved as a mediator in tissue transplantation reactions. Among respiratory diseases, PAF is thought to be involved as a mediator in asthma, inducing a platelet degranulation reaction and an eosinophil migration reaction, thereby causing allergic bronchial asthma. Furthermore, it is thought to increase airway hyperresponsiveness and be involved in immediate and delayed asthma reactions. Bronchoconstriction due to anaphylactic reaction is also considered to be an effect of PAF. PA in the blood of cold urticaria, a type I allergic reaction.
The fact that F was detected suggests its involvement. With regard to skin diseases, PAF has been detected in infectious foci of inflammatory skin diseases, suggesting its involvement. Regarding renal diseases, PAF is related to glomerular function during pathological conditions, and its relationship with renal disorders is attracting attention. In the field of gynecology, the involvement of PAF in implantation of fertilized eggs, induction of labor, and induction of ovulation is attracting attention.

The object of the present invention is to provide a novel 1,4-dihydropyridine derivative that has, in addition to the anti-PAF activity described above, a bronchial relaxing effect, a vascular permeability suppressing effect, a phosphodiesterase inhibiting effect, a calcium antagonistic effect, etc. shall be. A further object of the present invention is to provide a so-called hybrid drug that has desirable multifunctional activities as an antiallergic agent, an antiinflammatory agent, and a therapeutic agent for circulatory system diseases.

[0015]

[Means for Solving the Problems] The present invention provides general formula (I)
:

[0016]

[C5]

(In the formula, Ar is an ethynyl group, an alkoxycarbonylethynyl group, a nitro group, a phenyl group optionally substituted with a halogen atom, a pyridyl group, or
, 1,3-benzoxadiazolyl group, A is lower alkoxy group or lower alkylamino group, R1 is hydrogen or lower alkyl group, R2 is hydrogen or lower alkyl group, R3 is methyl group or amino group, X is 1, 4-piperazinediyl group, 1,4-homopiperazinediyl group, -
NH-,

[0018]

[C6]

Y is substituted with a carbonyl group, thiocarbonyl group, lower alkylene group, lower alkylene carbonyl group or lower alkenylene carbonyl group, and Z is substituted with a lower alkyl group, lower alkenyl group, lower alkynyl group, halogen atom or pyridyl group. pyridyl group, thienyl group, pyrazinyl group, piperidinyl group, indolyl group, quinolinyl group, thiazolyl group or imidazolyl group, and n represents an integer of 1 to 5).
The present invention relates to a dihydropyridine derivative or a pharmacologically acceptable salt thereof and a therapeutic agent for allergic or inflammatory diseases containing the same as an active ingredient.

[0020]

[Example] In the above general formula (I), the group represented by Ar is an ethynyl group, an alkoxycarbonylethynyl group, a nitro group, a phenyl group optionally substituted with a halogen atom, a pyridyl group, or a pyridyl group, It is a 1-3-benzoxadiazolyl group, and examples of the alkoxycarbonylethynyl group include methoxycarbonylethynyl group, ethoxycarbonylethynyl group, and propoxycarbonylethynyl group, and halogen atoms include fluorine, chlorine, bromine, and iodine. Atoms can be given. Preferred groups for Ar include, for example, 3-nitrophenyl group, 3-ethynylphenyl group, 3-methoxycarbonylethynylphenyl group, 2,3-dichlorophenyl group, pyridyl group, 2
, 1,3-benzoxadiazolyl group, etc. A represents a lower alkoxy group or a lower alkylamino group, and the lower alkoxy group may be linear, branched, or cyclic, preferably having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, etc. The alkyl group of the lower alkylamino group may be linear, branched, or cyclic, and preferably has 1 to 3 carbon atoms, such as a methyl group, ethyl group, propyl group,
Examples include isopropyl group and cyclopropyl group. R1 and R2 may be the same or different and represent hydrogen or a lower alkyl group, and the lower alkyl group may be linear or branched, preferably having 1 carbon number.
-3, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, etc. R3 represents a methyl group or an amino group. X is a 1,4-piperazinediyl group, a 1,4-homopiperazinediyl group, -NH-,

[0021]

[C7]

[0022]

Y is a carbonyl group, a thiocarbonyl group, a lower alkylene group, a lower alkylene carbonyl group, a lower alkenylene carbonyl group, and examples of the lower alkylene group include a methylene group, an ethylene group, a propylene group,
Examples of the lower alkylenecarbonyl group include a methylenecarbonyl group, and examples of the lower alkenylenecarbonyl group include a vinylenecarbonyl group.

Z is a lower alkyl group, a lower alkenyl group,
A lower alkynyl group, a pyridyl group optionally substituted with a halogen atom or a pyridyl group, a thienyl group, a pyrazinyl group, a piperidinyl group, an indolyl group, a quinolinyl group, a thiazolyl group, or an imidazolyl group, and preferred examples include pyridyl. group, methylpyridyl group,
Examples include pyrazinyl group, thienyl group, chloropyridyl group, indolyl group, piperidinyl group, methylthiazolyl group, ethylthiazolyl group, pyridylthiazolyl group, and quinolinyl group.

The compound of the present invention represented by the above general formula (I) has one or two asymmetric carbon atoms in the molecule, but the present invention is directed to optical isomers or arbitrary ratios of asymmetric carbon atoms due to the asymmetric carbon atoms. It is intended to include mixtures of mixed optical isomers. Individual optical isomers or pairs of optical isomers (diastereomers) can be separated by physical means such as fractional crystallization using salts and column chromatography.

The compounds of the present invention can exist as salts, and can be converted into acid addition salts by known means. Such salts are not particularly limited as long as they are pharmacologically acceptable; examples of such salts include acid addition salts of mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid; ,
Acid addition salts of sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, or organic acids such as acetic acid, phosphoric acid, oxalic acid, maleic acid, tartaric acid, citric acid, gluconic acid, lactic acid. Examples include acid addition salts.

Tables 1-1, 1-2 and 1-3 show examples of the compounds represented by the general formula (I) obtained by the present invention.

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

The compound of the present invention represented by the general formula (I) can be produced, for example, as follows.

Production method (A) General formula (I) in which R3 is a methyl group
The compound represented by a) can be obtained according to reaction formula (a).

Arylaldehyde derivative (III),
The ketoester derivative (IV) and the β-aminocrotonic acid derivative (II) are added to a suitable organic solvent, for example a lower alkanol such as ethanol.
The 1,4-dihydropyridine derivative represented by the general formula (Ia) can be produced by the 1,4-dihydropyridine derivative represented by the general formula (Ia).

[0034]

[Chemical formula 8]

(wherein A, Ar, R1, R2, n,
X, Y, and Z are the same as above. ) The organic solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, but lower alkanols such as ethanol, methanol, isopropyl alcohol, and n-propyl alcohol are preferred.

The amounts of each component used in this reaction are 1 to 1.5 equivalents of the ketoester derivative (IV) and 1 to 1.5 equivalents of the β-aminocrotonic acid derivative (II) to the aryl aldehyde derivative (III). It is preferable to use double equivalents, and it is particularly preferable to use 1 to 1.2 times equivalents of each. The reaction temperature is preferably 20 to 120°C,
The temperature is particularly preferably 30 to 100°C, and the reaction time is 1
~24 hours is preferred, and 1 to 20 hours is particularly preferred.

Production method (B) General formula (I) in which R3 is a methyl group
The compound represented by a) can also be prepared according to reaction formula (b).

Arylaldehyde derivative (III),
A 1,4-dihydropyridine derivative represented by general formula (Ia) can be obtained by adding a β-diketone derivative (V) and a β-aminocrotonic acid derivative (VI) into a suitable organic solvent, for example, a lower alkanol such as ethanol. can be manufactured.

[0039]

[Chemical formula 9]

(wherein A, Ar, R1, R2, n,
X, Y, and Z are the same as above. ) The organic solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, but lower alkanols such as ethanol, methanol, isopropyl alcohol, and n-propyl alcohol are preferred.

The amounts of each component to be used in this reaction are 1 to 1.5 equivalents of the β-diketone derivative (V) and 1 to 1 equivalent of the β-aminocrotonic acid derivative (VI) to the aryl aldehyde derivative (III). It is preferable to use .5 times equivalent, and it is particularly preferable to use 1 to 1.2 times equivalent each. The reaction temperature is preferably 20 to 120°C, particularly preferably 30 to 100°C, and the reaction time is preferably 1 to 24 hours, particularly preferably 1 to 20 hours.

Production method (C) General formula (I) in which R3 is a methyl group
The compound represented by a) can also be prepared according to reaction formula (c).

By adding the benzylidene derivative (VII) and the β-aminocrotonic acid derivative (II) to a suitable organic solvent, for example, a lower alkanol such as ethanol, 1,4-dihydropyridine of general formula (Ia) can be prepared. Derivatives can be produced.

[0044]

[Chemical formula 10]

(wherein A, Ar, R1, R2, n,
X, Y, and Z are the same as above. ) The organic solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, but lower alkanols such as ethanol, methanol, isopropyl alcohol, and n-propyl alcohol are preferred.

Regarding the amount of each component to be used in this reaction, it is preferable to use 1 to 1.5 times the equivalent of the β-aminocrotonic acid derivative (II), particularly 1 to 1.2 times the equivalent of the benzylidene derivative (VIII). It is preferable to use The reaction temperature is preferably 20 to 120°C, and 30 to 100°C.
C is particularly preferred, and the reaction time is preferably 1 to 24 hours, particularly preferably 1 to 20 hours.

Production method (D) General formula (I) in which R3 is an amino group
The compound represented by b) can be obtained according to reaction formula (d).

Amidine derivative (VIII), aryl aldehyde derivative (III), ketoester derivative (I
V) in a suitable organic solvent, for example a lower alkanol such as ethanol, the general formula (I
The 1,4-dihydropyridine derivative shown in b) can be produced.

[0049]

[Chemical formula 11]

(wherein A, Ar, R1, R2, n,
X, Y, and Z are the same as above. ) The organic solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, but lower alkanols such as ethanol, methanol, isopropyl alcohol, and n-propyl alcohol are preferred.

The amount of each component used in this reaction is 1 to 1.5 of the amidine derivative (IX) and ketoester derivative (IV) to the aryl aldehyde derivative (III).
It is preferable to use double equivalents, particularly preferably 1 to 1.2 times equivalents. The reaction temperature is 20-120℃
is preferable, 30 to 100° C. is particularly preferable, and the reaction time is preferably 1 to 24 hours, particularly preferably 1 to 20 hours.

Production method (E) General formula (I) in which R3 is an amino group
The compound represented by b) can also be prepared according to reaction formula (e).

A 1,4-dihydropyridine derivative represented by the general formula (Ib) is produced by adding the amidine derivative (VIII) and the benzylidene derivative (VII) to a suitable organic solvent, for example, a lower alkanol such as ethanol. can do.

[0054]

[Chemical formula 12]

(wherein A, Ar, R1, R2, n,
X, Y, and Z are the same as above. ) The organic solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, but lower alkanols such as ethanol, methanol, isopropyl alcohol, and n-propyl alcohol are preferred.

The amount of each component used in this reaction is as follows: benzylidene derivative (VII), amidine derivative (V
It is preferable to use 1 to 1.5 times the equivalent of III), particularly preferably 1 to 1.2 times the equivalent. The reaction temperature is preferably 20 to 120°C, particularly preferably 30 to 100°C, and the reaction time is preferably 1 to 24 hours, particularly preferably 1 to 20 hours. The products obtained by any of the above production methods can be purified and isolated by conventional processing methods such as recrystallization or chromatography.

The compound represented by the general formula (I) of the present invention has anti-PAF action, platelet aggregation inhibiting action, bronchial muscle relaxing action, phosphodiesterase inhibiting action, anti-calcium action, etc., and has anti-inflammatory, anti-allergic, and cardiovascular disease effects. It has multifunctional activities that are desirable as a therapeutic agent, especially PAF.
It is effective in the treatment and prevention of various diseases involving tissue damage, such as cardiovascular diseases caused by tissue damage, transplants, renal dysfunction, shock, skin diseases, especially various inflammatory diseases, and various allergic diseases mainly including asthma. .

The administration form of the compound represented by the general formula (I) is, for example, oral administration using tablets, capsules, granules, powders, syrups, etc., or subcutaneous injection, intravenous injection, suppository, or patch. Parenteral administration methods include drugs, creams, and sprays. These various preparations are prepared according to conventional methods, and depending on the purpose, excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents,
The formulation can be formulated using adjuvants commonly used in the field of formulation technology, such as. For example, gelatin, lactose, white sugar, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, It can be formulated with hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum acacia, propylene glycol, or polyalkylene glycol.

[0059] The dosage varies depending on symptoms, age, body weight, etc., administration method, and number of administrations, but is usually about 1 mg to 1000 mg per day for adults, and can be administered once or in several doses. Can be done.

For a typical adult patient, 2 mg to 200 mg for oral administration such as tablets and capsules.
It is formulated to contain the active ingredient. In the case of an intravenous injection, it is prepared to contain 1 mg to 10 mg. In the case of administration by inhalation using a nebulizer, aerosol, etc., the dose is adjusted as necessary in the range of 1 mg to 50 mg. Suppositories, which are used as a dosage form for infants, elderly patients, etc. for whom oral preparations are difficult to use, are prepared to contain the same amount or 1/4 of the oral dosage. External preparations used for the treatment of skin diseases, such as creams and patches, are prepared to contain one-half or the same amount as oral preparations.

The compounds of the present invention will be explained in more detail below with reference to Examples and Test Examples.

From the test examples shown below, the medicinal usefulness of the compounds of the present invention is clear. As shown in Test Example 1,
The compounds of the present invention exhibit strong antiplatelet activating factor (PAF) antagonism. During an asthma attack, the trachea is constricted, and it is essential for anti-asthmatic drugs to relax and relieve the narrowing of the airways. As shown in Test Example 2, the compound of the present invention exhibits a clear relaxing effect on isolated tracheal smooth muscle. Furthermore, as shown in Test Example 3, the compound of the present invention exhibits a clear inhibitory effect on guinea pig tracheal smooth muscle phosphodiesterase. Cyclic AMP (cAMP) in tracheal smooth muscle cells is deeply involved in cellular activities as a secondary transmitter, and it is widely known that the cAMP degrading enzyme is phosphodiesterase. Inhibiting this enzyme causes relaxation of tracheal smooth muscle,
Relieves tracheal spasm during asthma. Furthermore, as shown in Test Example 4, the compound of the present invention exhibits clear calcium antagonistic activity. One of the causes of airway hyperresponsiveness and airway spasm in asthma patients is thought to be the action of various chemical mediators released by the degranulation of respiratory system cells, especially mast cells, on the airways. It is. Calcium influx into cells is involved in this degranulation. Therefore, the effect of blocking calcium influx into cells is desirable for the treatment and prevention of asthma and allergic diseases. In addition, calcium channel blockers increase renal blood flow,
It is known that increasing glomerular filtration capacity is effective against kidney damage. Therefore, having a calcium antagonistic effect is useful for treating and preventing renal disorders. The same thing can be said about heart diseases and gastrointestinal diseases. It is known that the generation of free radicals by PAF during reperfusion at an ischemic site causes tissue damage, while calcium antagonists are known to have a coronary artery dilating effect. Therefore, calcium antagonism, anti-PA
Having both F effects is desirable for the treatment and prevention of heart diseases. Similarly, it is known that PAF causes gastric ulcer formation due to gastric mucosal blood flow disturbance, while drugs with calcium antagonistic effects have a peripheral blood vessel dilating effect. Therefore, drugs with anti-PAF and calcium antagonistic effects are effective in treating and preventing gastrointestinal diseases. Also,
As shown in Test Example 5, the acute toxicity value of the compound of the present invention shows that it is a safe compound when used as a medicine.

Test Example 1 Platelet activating factor (PAF)
Antagonistic rabbits (New Zealand White) were fixed in an upright position and treated with 0.8% citric acid, 2.2% sodium citrate,
20 with 2 ml of a solution consisting of 2.45% glucose.
18 ml of blood was drawn from the heart using a ml syringe. Centrifuge at 1200 rpm for 10 minutes and collect the supernatant.
The supernatant was further centrifuged at 1200 rpm for 5 minutes, and the resulting supernatant was used as a platelet fraction (PRP) in the experiment. PRP was prepared to contain 2.5 x 109/μl platelets. Measurement of platelet aggregation is carried out using NKK Hematoracer (manufactured by SSR).
ATRACER). That is, P.R.P.
200 μl was preincubated at 37° C. for 5 minutes, 10 μl of the test drug was added, and after further incubation for 2 minutes, 95 nM PAF was added. Subsequent platelet aggregation was recorded for 5 minutes.

A dose-dependent curve of inhibition of platelet aggregation by PAF for each test compound was determined, and the drug concentration showing 50% inhibition was defined as the IC50 value. The results are shown in Table 2.

As a positive control drug, 2-[4-(2-chlorophenyl)-9-methyl]-6H-thieno[3,2-f
][1,2,4]thiazolo [4,3-a][1,4]
Diazepin-2-yl]-ethane-1-carboxylic acid morpholide (WEB2086) was used.

[0066]

[Table 4]

Test Example 2 Relaxation effect on isolated tracheal smooth muscle After killing male Hartely guinea pigs by exsanguination, the trachea was removed and 2 mm wide tracheal smooth muscle sections were prepared, and four pieces were connected in a chain to loosen the trachea. It was used as a muscle specimen. This specimen was placed in a 2 m tube filled with Tyrode's solution.
The sample was suspended in a Magnus tank with a load of 0.3 g and tested at 37° C. under aeration of mixed gas (95% oxygen, 5% carbon dioxide). After the natural tension of the specimen became constant after being left for a while, the test drug was added to the tank, and the subsequent relaxation was measured using an isotonic transducer (manufactured by Nihon Kohden Industries, Ltd.).

A dose-dependent curve for tracheal muscle relaxation of each test compound was determined, and its 50% effective concentration (ED50) was determined. The results are shown in Table 3. WEB 20 as a positive control drug
86 was used.

[0069]

[Table 5]

Test Example 3 Guinea Pig Tracheal Smooth Muscle Phosphodiesterase Inhibition Effect Male Hartley guinea pigs were killed by exsanguination, tracheal smooth muscle was cut out, and 100 mM Tris-HCl buffer (pH 7.5) containing 1 mM dithiothreitol and 2 mM magnesium chloride was added. ) and homogenized at 0°C to prepare a phosphodiesterase sample. 2.5mM
Magnesium chloride, 2-mercaptoethanol, 1U/
ml calmodulin, 10 μM calcium chloride, 1 μM
cAMP, 2μCi/ml 3H-cAMP, 40mM
A test compound at a concentration of 10-5 and 25 μl of a phosphodiesterase preparation were mixed with 100 μl of a reaction solution consisting of Tris-HCl buffer (pH 8.0) under ice cooling, and then incubated at 37°C for 30 minutes. . After stopping the reaction by boiling for 2 minutes, 25 μl of 4 U/ml 5'-nucleotidase solution was added and further incubated at 37°C for 30 minutes.
x-1) Column chromatography was performed to measure the radioactive count of 3H-adenosine, and the phosphodiesterase activity was determined. The inhibition rate was calculated from the following formula, setting the phosphodiesterase activity in the absence of addition as 100 (control). 3-isobutyl-1-methyl-xanthine (IBMX) 10-4M was used as a positive target drug. The results are shown in Table 4.

[0071]

[Math 1]

[0072]

[Table 6]

Test Example 4 Calcium antagonistic effect Body weight 35
The caecal cord of a 0g male Hartley guinea pig was removed.
A 0.5 g load was suspended in a calcium-depleted high-potassium Krebs bath (32°C) with air aeration, calcium chloride was added cumulatively, and an isotonic transducer was added.
The reaction was recorded via a user (manufactured by Nihon Kohden Industries, Ltd.) to obtain a constant standard concentration reaction curve.

On the other hand, after treatment with the compound of the present invention and the positive control drug diltiazem for 30 minutes, calcium chloride was added to the reaction bath, and pA2 was determined from the concentration-response curve obtained. The results are shown in Table 5.

[0075]

[Table 7]

Test Example 5 Acute Toxicity Test A group of 4-week-old SLC (Wistar) male rats weighing 100 to 114 g consisted of 5 rats, and the compound of Example 1 was orally administered as a representative example of the test compound. administer,
The acute toxicity value was determined from the mortality rate after 7 days.

Results Rat LD50=600mg/Kg (oral administration)
Example 1 (Production method of compound 1) Methyl 2-(4-nicotinoyl-1-piperazinyl)ethyl 4-(3-ethynyl)phenyl-2
．． 6-dimethyl-1,4-dihydropyridine-3,
Method for producing 5-dicarboxylate dihydrochloride 7.8 g (0.06 mol) of 3-ethynylbenzaldehyde, 6.8 g (0.06 mol) of methyl 3-aminocrotonate
mol), 2-(4-nicotinoyl-1-piperazinyl)ethyl acetoacetate 18.0g (0.05
6 mol) was dissolved in 150 ml of ethanol and heated under reflux for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate - ethyl acetate:ethanol = 100:0
．． 5) and purification results in the free base of the target compound 18.
9 g (yield 63.0%) was obtained.

Free base 18 of the target compound obtained above
．． 9g in 300ml of ethanol and 9.0ml of concentrated hydrochloric acid
and concentrated under reduced pressure, and the residue was diluted with 150% ethanol.
ml was added and further concentrated under reduced pressure to obtain 19.4 g (yield 90.0%) of the target compound.

Melting point: 191-194°C MS (m/z)
;528 (M+), 469,422,310I
R (cm-1); 3400-3200, 3050
-2900, 2100, 1690 Examples 2 to 41 and 43 The compounds shown in Table 1 were treated in the same manner as in Example 1 or Example 42 shown later, except that the compounds shown in Tables 6-1 to 6-4 were used as starting materials. The described compound was obtained. Table 7-
1 to 7-3.

[0080]

[Table 8]

[0081]

[Table 9]

[0082]

[Table 10]

[0083]

[Table 11]

[0084]

[Table 12]

[0085]

[Table 13]

[0086]

[Table 14]

Example 42 (Production method of compound 42) Ethyl (N-nicotinoyl-2-pyrrolidinyl)methyl 2-amino-4-(3-ethynyl)phenyl-1
, 4-dihydro-6-methyl-3,5-pyridinedicarboxylate dihydrochloride production method 3-ethynylbenzaldehyde 0.96 g (7.4 mmol), (N-nicotinoyl-2-pyrrolidinyl)methyl acetoacetate 2 .14 g (7.4 mmol) was dissolved in 30 ml of ethanol and heated under reflux for 12 hours. Next, the mixture was cooled to 40° C. or lower, and 1.44 g (11.0 mmol) of ethyl 3,3-diamino-2-propenoate was added thereto and reacted at 40 to 45° C. for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: chloroform:methanol = 1).
0:0.3) and the obtained free base of the target compound was reacted and treated in the same manner as in Example 1 to obtain 1.14 g (yield 26.3%) of the target compound.

Melting point: 186-189°C MS (m/z
); 514 (M+), 408, 311IR
(cm-1); 3350-3150, 3050-29
00, 2100, 1710-1690 Example 44 Methyl 2-(4-nicotinoyl-1-piperazinyl)ethyl 4-(3-ethynyl)phenyl-2
．． 6-dimethyl-1,4-dihydropyridine-3,
5- Method for producing dicarboxylate dihydrochloride (Example 1)
(alternative method) 4.3 g (10 mmol) of 2-(4-nicotinoyl-1-piperazinyl)ethyl 3-ethynylphenylbenzylidene acetoacetate in 50 ml of ethanol
1.7 g of methyl 3-aminocrotonate dissolved in
(15 mmol) was added and heated under reflux for 12 hours. After cooling, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography in the same manner as in Example 1 to obtain 3.94 g (yield: 74.7%) of the free base of the target compound. 3.9 g of the free base of the target compound obtained above was reacted and treated in the same manner as in Example 1 to obtain 4.1 g (yield 92.5%) of the target compound.

Alternatively, 2.3 g (10 m
mol) in 50 ml of ethanol, 2-(4
- Nicotinoyl-1-piperazinyl)ethyl 3
4.8 g (15 mmol) of -aminocrotonate was added and heated under reflux for 15 hours, followed by reaction, treatment and purification in the same manner as in Example 1 to obtain 3.7 g (yield 70.5%) of the free base of the target compound. Ta.

Example 45 1620 g of lactose was placed in a centrifugal fluid coating device, and 1000 ml of ethanol/methylene chloride (1:1, V/V) in which 300 g of Compound 1 and 310 g of hydroxypropyl methylcellulose were completely dissolved was sprayed onto it. It was coated and made into granules. This product was dried at 40° C. for 4 hours and then granulated to obtain granules.

Example 46 After dissolving 30 g of Compound 1 and 33 g of polyvinylpyrrolidone in 200 ml of ethanol, the ethanol was distilled off by drying under reduced pressure. The residue was crushed into powder, and 22 g of lactose and 21 g of carboxymethylcellulose calcium were added to the powder.
g and 1 g of magnesium stearate were added, and the mixture was compressed into tablets by a conventional method to obtain tablets containing 30 mg of Compound 1 per tablet.

Example 47 180 g of compound 33 was added to 150 ml of 90% ethanol.
Dissolve this in 150ml of propylene glycol,
Trisodium citrate 2g, and citric acid 0.3g
was added to distilled water for injection to make a total volume of 600 ml. The solution was filtered through a sterile filter and aseptically filled into sterile vials, which were then closed with sterile rubber stoppers. Each vial contained 5 ml of 3 mg/ml injection solution.

[0093]

[Effects of the Invention] As is clear from the above, the compound of the present invention is a compound that has multifunctional activities such as PAF antagonistic activity, tracheal and branch muscle relaxing activity, vascular permeability suppressing activity, phosphodiesterase inhibitory activity, and anticalcium activity. Yes, PA
Treatment of various diseases related to F, such as circulatory diseases caused by tissue damage, transplants, renal dysfunction, shock, skin diseases, especially various inflammatory diseases, various allergic diseases mainly including asthma, and circulatory system diseases. Effective for prevention.

Claims (2)

[Claims] Claim 1 General formula (I): [Formula 1] (wherein, Ar is an ethynyl group, an alkoxycarbonylethynyl group, a nitro group, or a phenyl group optionally substituted with a halogen atom, a pyridyl group, or 2, 1,3-benzoxadiazolyl group, A is lower alkoxy group or lower alkylamino group, R1 is hydrogen or lower alkyl group, R2 is hydrogen or lower alkyl group, R3 is methyl group or amino group, X is 1,4 -piperazinediyl group, 1,4-homopiperazinediyl group, -NH-, [Formula 2] Y is a carbonyl group, thiocarbonyl group, lower alkylene group, lower alkylenecarbonyl group, lower alkenylenecarbonyl group or vinylenecarbonyl group, Z is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a pyridyl group optionally substituted with a halogen atom or a pyridyl group, a thienyl group, a pyrazinyl group, a piperidinyl group,
A 1,4-dihydropyridine derivative represented by an indolyl group, a quinolinyl group, a thiazolyl group, or an imidazolyl group, and n represents an integer of 1 to 5, or a pharmacologically acceptable salt thereof. 2. A therapeutic agent for allergic or inflammatory diseases comprising the 1,4-dihydropyridine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.