JPH0525131A - Indole derivative and its application to medicine - Google Patents

Abstract

PURPOSE:To provide new indole derivatives or pharmaceutically permissible salts thereof showing a PAF-antagonism and useful as an antiinflammatory agent, an antiallergic agent, etc. CONSTITUTION:Indole derivatives of formula I (R is 1-5C lower alkyl or R<1> is H or 2-10C alkoxyalkyl; R<2> is H or 1-5C lower alkyl; A and B are CH2 or CO; Z is N or NHCH; Ar is 3-pyridyl or mono-trialkoxysubstituted phenyl) or pharmaceutically permissible salts thereof, e.g. 1-[(5-methoxyindol)-2-yl- carbonyl]-4-(3,4,5-trimethoxybenzyl)-piperazine. The compounds of formula I can be obtained by reacting a carboxylic acid of formula II or its reactive derivative with a compound of formula III or its acid adduct salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel indole derivative which strongly antagonizes the action of PAF (platelet activating factor; hereinafter referred to as PAF).

[0002]

2. Description of the Related Art Platelet activating factor (PAF-Platelet A)
ctivating Factor-hereinafter referred to as PAF) has received a great deal of attention in recent years, and recently, its relevance to various diseases is becoming clear. That is, inflammation, allergic diseases, anaphylactic shock, pulmonary shock, D
IC, endotoxin shock, cardiomyopathy, asthma,
It is presumed to be involved in pulmonary edema, gastrointestinal ulcer, nephritis, hepatitis and rejection at the time of organ transplantation. [See Hyundai Kagaku Special Issue 17, Platelet Activating Factors-Biochemistry, Physiology, Pathology, edited by Keizo Waku, Keizo Inoue, Tokyo Kagaku Dojin, 1989].
Therefore, a compound that antagonizes the action of PAF is expected to have a therapeutic effect on the above-mentioned diseases or other diseases for which it is desirable to antagonize PAF.

In fact, the administration of a PAF antagonist suppressed the Alsace reaction in mice, which is a model of inflammatory reaction, indicating that PAF is involved in the inflammatory reaction (Jpn. J. Pharmacol., 46 , 55P (1988)) At present, the following are known as indole derivatives exhibiting anti-PAF action. (JP-A-62-265284)

[0004]

[Chemical 2]

Further, the following are known as indole derivatives having an inhibitory effect on platelet aggregation by arachidonic acid. (JP-A 1-132579)

[0006]

[Chemical 3]

[0007]

[PROBLEMS TO BE SOLVED BY THE INVENTION] New and useful anti-PA
Agent F is expected and required to have preventive and therapeutic effects on a wide range of diseases.

An object of the present invention is to provide a novel indole derivative having a PAF antagonistic action or a pharmacologically acceptable salt thereof, and an anti-inflammatory agent and an anti-allergic agent containing the derivative as an active ingredient.

[0009]

The inventors of the present invention synthesized various indole derivatives and searched for their PAF antagonism. As a result, the novel compound represented by the formula (I) described below was extremely potent. The present invention has been completed by discovering that it has an action.

That is, the present invention has the formula (I)

[0011]

[Chemical 4]

(Wherein R represents lower alkyl having 1 to 5 carbon atoms, R ¹ represents hydrogen or alkoxyalkyl having 2 to 10 carbon atoms, and R ² represents hydrogen or lower alkyl having 1 to 5 carbon atoms. , A and B represent CH ₂ or CO, and Z
Represents N or NHCH, Ar represents 3-pyridyl, or phenyl substituted with 1 to 3 alkoxys) and a pharmaceutically acceptable salt thereof, and the compound as an active ingredient. The present invention relates to anti-inflammatory agents, anti-allergic agents, anti-PAF agents.

In the above definition of each symbol, lower alkyl means alkyl having 1 to 5 carbon atoms, specifically methyl, ethyl, propyl and the like. Alkoxyalkyl having 2 to 10 carbon atoms means alkyl having 1 to 5 carbon atoms substituted with lower alkoxy having 1 to 5 carbon atoms such as ethoxyethyl, methoxypropyl and ethoxypropyl.
Further, Ar in the general formula (I) of the present invention is 3-pyridyl or phenyl substituted with 1 to 3 alkoxy,
This alkoxy is a lower alkoxy having 1 to 5 carbon atoms as defined above. Further, the phenyl group substituted with 1 to 3 alkoxys is specifically 4-alkoxyphenyl, 3,4-dialkoxyphenyl or 3,4,5-trialkoxyphenyl.

When Ar in the general formula (I) is 3-pyridyl, R ¹ is preferably an alkoxyalkyl group.

The pharmacologically acceptable salt of the compound represented by the formula (I) includes inorganic acid salts such as hydrochloride, hydrobromide and sulfate, acetate, maleate and fumaric acid. Examples thereof include salts, tartrate salts, succinate salts, organic acid salts such as p-toluenesulfonic acid salts, and amino acid addition salts such as lysine, glycine, and phenylalanine.

The method for producing the compound represented by the formula (I) will be described below. However, each production method is not limited thereto, and the reaction conditions in various production methods are appropriately selected from those described below.

The compound represented by the formula (I) of the present invention has the formula (II)

[0018]

[Chemical 5]

A carboxylic acid represented by the formula (wherein R, R ¹ and R ² are as defined above) or a reactive derivative thereof;
Formula (III)

[0020]

[Chemical 6]

It can be produced by reacting a compound represented by the formula (wherein B, Z and Ar are as defined above) or an acid addition salt thereof.

As the reaction conditions, amidation method, peptide synthesis method and the like known per se can be applied. For example, when the compound represented by the formula (II) is a carboxylic acid, it can be used as a condensing agent such as dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halide (for example, phosphorus oxychloride, phosphorus trichloride) and carbonyldiimidazole. By reacting in the presence of an inert solvent (dimethylformamide, tetrahydrofuran, dichloromethane, 2-butanone, etc.) at room temperature to about 150 ° C for 1 to 24 hours, the compound of formula (I)
A compound represented by can be obtained.

When an acid halide (acid chloride, acid bromide, etc.) or a mixed acid anhydride (lower alkyl carbonic acid mixed acid anhydride, etc.) is used as the reactive derivative of the compound represented by the formula (II), the reaction Is present in an inert solvent, preferably an organic base such as triethylamine or pyridine or an inorganic base such as sodium carbonate, sodium hydrogen carbonate or potassium hydroxide as a deoxidizing agent, and the temperature is about 100 ° C. from cooling. Proceed in 1-24 hours.

Further, the compound represented by the formula (I) is a compound represented by the formula (IV) obtained by the above amidation method (in the formula,
R, R ² , A, Z, B and Ar are as defined above.
Can also be obtained by reacting a compound represented by the formula (V) R ¹ X (V) (wherein R ¹ has the same meaning as defined above and X represents halogen).

[0025]

[Chemical 7]

The reaction is carried out in an inert solvent (dimethylformamide, tetrahydrofuran, etc.), sodium hydride, potassium hydride, sodium amide, potassium-t-
The reaction proceeds usually in the presence of a base such as butoxide at 0 ° C. to the boiling point of the solvent used for 10 minutes to 10 hours.

The compound represented by the formula (I) has the formula (I
A compound represented by the formula (VII) by subjecting the compound represented by the formula (I) and the compound represented by the formula (VI) (wherein Z has the same meaning as described above) to the amidation reaction described above. In the formula, R, R ¹ ,
R ² , A and Z have the same meanings as described above), and then using palladium carbon, platinum oxide or the like as a catalyst in a solvent such as acetic acid or ethanol at a temperature from room temperature to about 100 ° C. and atmospheric pressure. By carrying out catalytic hydrogenolysis under high pressure, a compound represented by the formula (VIII) (in the formula, R, R ¹ , R ² , A
And Z have the same meanings as above), and react this with a compound represented by the formula (IX) ArBX (IX) (wherein Ar and B have the same meanings as above and X represents halogen). It can also be manufactured by

[0028]

[Chemical 8]

The reaction is carried out in an inert solvent, preferably in the presence of an organic base such as triethylamine or pyridine, or an inorganic base such as sodium carbonate, sodium hydrogen carbonate or potassium hydroxide as a deoxidizing agent, and from cooling to 100 ° C.
The temperature is about 10 minutes to 24 hours.

Further, the compound represented by the formula (I) is a compound represented by the formula (X) synthesized by the above method (in the formula,
R, R ¹ , R ² , Z, Ar and B have the same meanings as described above), and can also be synthesized.
For the reaction, use alan, lithium aluminum hydride, borane, sodium hydride-bis- (2-methoxyethoxy) -aluminum, etc. in an inert solvent such as tetrahydrofuran, toluene or ether at 0 ° C. The reaction proceeds at the reflux temperature of the solvent for 10 minutes to 10 hours.

[0031]

[Chemical 9]

The compound of formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography.

The compound represented by the formula (I) can be converted into the above-mentioned pharmacologically acceptable salt by treating it with an inorganic acid or an organic acid by a conventional method.

The compound represented by the formula (II) can also be synthesized by the following method.

[0035]

[Chemical 10]

That is, the compound represented by the formula (XI) (in the formula,
R and R ² have the same meanings as described above, and R ³ represents a lower alkyl having 1 to 5 carbon atoms (methyl, ethyl, etc.) and has the formula (V) R ¹ X (V) (wherein R ¹ is It has the same meaning as described above, and X represents a halogen), and a compound represented by the formula (XI
The compound represented by formula (II) can be obtained by obtaining the compound represented by I) and then hydrolyzing it under acidic or alkaline conditions. The reaction conditions for obtaining the compound represented by formula (XII) from the compound represented by formula (XI) are the same as those for obtaining the compound represented by formula (I) from the compound represented by formula (IV). Same conditions.

The compounds represented by the formula (I) and salts thereof of the present invention show an excellent PAF antagonistic action, and are effective for inflammatory and allergic diseases (bronchial asthma, psoriasis, etc.) and other PAFs.
Diseases caused by (for example, thrombosis, stroke, myocardial infarction,
Angina, thrombophlebitis, nephritis, diabetic nephropathy, endotoxin shock, endovascular coagulation syndrome caused by endotoxin, anaphylactic shock, circulatory disorders such as hemorrhagic shock, gastrointestinal disorders such as gastric ulcer,
Pneumonia, rejection due to increased PAF production during organ transplantation,
It is useful as a prophylactic / therapeutic agent for diseases such as organ failure during organ surgery) and diseases for which PAF antagonists are effective (such as hyperendothelinosis).

Since the compound represented by the formula (I) and its acid addition salt have low toxicity, they are orally or parenterally administered to a mammal as a powder or as a pharmaceutical composition in a suitable dosage form. Can be administered to.

Specific examples of the dosage form for oral administration include tablets, pills, powders, capsules, granules, syrups, emulsions and suspensions. Such a composition is produced by a method known per se and contains a carrier or an excipient that is usually used in the field of formulation.
For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.

Examples of dosage forms for parenteral administration include ointments, injections, poultices, coatings, inhalants, suppositories,
Examples include transdermal inhalants. The injection is prepared by a method known per se, for example, by dissolving, suspending or emulsifying the compound represented by the formula (I) or a salt thereof in a sterile aqueous or oily liquid usually used for injection. Examples of the aqueous solution for injection include physiological saline and glucose solution, and examples of the oily liquid include sesame oil and soybean oil, which may be used together with a solubilizing agent. The suppository used for enteral administration is prepared by a method known per se, for example, by mixing the compound represented by the formula (I) or a salt thereof with an ordinary suppository base and molding the mixture.

The effective dose and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof depend on the administration form, the age and weight of the patient, the nature or severity of the condition to be treated. , But usually 0 per adult per day.
1-1000 mg, preferably 1-200 mg, can be administered once or in several divided doses.

Each of the above-mentioned preparations may contain other therapeutically active ingredients as long as the compound of formula (I) or a salt thereof causes no unfavorable interaction. For example, steroid drug, non-steroid anti-inflammatory drug, lipoxygenase inhibitor, leukotriene antagonist,
Phospholipase A ₂ inhibitor, interleukin 1 production inhibitor, bronchodilator, thromboxane synthesis inhibitor, thromboxane antagonist, histamine release inhibitor, cerebral circulation improver, brain protector, liver protector, anti Platelet agents, serotonin antagonists, adenosine receptor antagonists, adrenergic β receptor antagonists, immunomodulators, immunosuppressants, immunostimulants and the like can be mentioned.

The composition examples of tablets using the compound of the present invention are shown below. Formulation Example Tablet A tablet having the following composition is prepared by a conventional method . Compound of Example 8 20 mg Lactose 80 mg Corn starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Trace amount

[0044]

EXAMPLES The present invention will be specifically described below with reference to examples. The present invention is not limited to these.

Example 1 1-{(5-methoxyindole) -2-yl-carbonyl} -4
-(3,4,5-Trimethoxybenzyl) -piperazine (1)

[0046]

[Chemical 11]

5-Methoxy-indole-2-carboxylic acid 2.
Dimethylformamide (15 ml) was added to 1 g, carbonyldiimidazole (2.6 g) was added in 2 portions, and the mixture was stirred at room temperature for 1.7 hours. 1- (3,4,5-trimethoxybenzyl) -piperazine
Add 3.7 g in 2 portions and stir at 60 ° C. for 1.7 hours. The solvent was distilled off, methanol was added, the crystals were filtered and dried,
4.5 g of the title compound is obtained.

Mp: 176-177 ° C IR (KBr) cm ^-1 : 3250,1591,1524,1460,1232,1125 ¹ H NMR (DMSO-d6) δ: 11.40 (1H, s), 7.31 (1H, AB, J = 8.8),
7.06 (1H, d, J = 2.2), 6.83 (1H, ABd, J = 8.8,2.4), 6.68 (1H, d,
J = 1.5), 6.64 (2H, s), 3.77 (6H, s), 3.75 (3H, s), 3.75 (4H,
s), 3.65 (3H, s), 3.46 (2H, s), 2.46 (4H, s)

Example 2 1-{(1-ethoxyethyl-5-methoxyindol) -2-yl-carbonyl} -4- (3,4,5-trimethoxybenzyl)-
Piperazine (2)

[0050]

[Chemical 12]

To 2.8 g of the compound of Example 1 was added 20 ml of dimethylformamide and 1.1 ml of ethoxyethyl bromide.
While stirring at 60 ° C. until the compound of Example 1 disappeared 35
Add% potassium hydride and stir for 4 hours. The solvent is distilled off, water and ethyl acetate are added, the mixture is extracted, washed with water and dried.
The solvent was distilled off, and silica gel column chromatography-
Purify with (ethyl acetate: chloroform = 4: 1-ethyl acetate-ethyl acetate: methanol = 9: 1) to obtain 2.3 g of the title compound as an oil.

IR (Neat) cm ^-1 : 2940,1628,1458,1220,112
5 ¹ H NMR (CDCl3) δ: 7.33 (1H, AB, J = 9.3), 7.03 (1H, AB, J = 2.
4), 6.94 (1H, ABd, J = 9.3,2.4), 6.57 (2H, s), 6.49 (1H, s), 4.
45 (2H, t, J = 5.9), 3.87 (6H, s), 3.84 (3H, s), 3.84 (3H, s), 3.
80 (4H, brs), 3.70 (2H, t, J = 5.9), 3.48 (2H, s), 3.40 (2H, q, J
= 6.8), 2.50 (4H, brs), 1.09 (3H, t, J = 6.8) MS: 511 (M ⁺ )

Example 3 1-{(1-ethoxyethyl-5-methoxyindol) -2-yl-carbonyl} -4- (3,4,5-trimethoxybenzyl)-
Piperazine fumarate (3) To an ethanol solution of 0.52 g of the compound of Example 2 was added 0.12 g of fumaric acid in ethanol, and the mixture was concentrated and dried to give the amorphous title compound.

IR (KBr) cm ^-1 : 3424,2944,2588,1638,1462,
1125,648

Example 4 1-{(1-ethoxyethyl-5-methoxyindol) -2-yl-methyl} -4- (3,4,5-trimethoxybenzyl) -piperazine (4)

[0056]

[Chemical 13]

10 ml of tetrahydrofuran is added to 97 mg of lithium aluminum hydride and cooled in an ice water bath. Example 2
A solution prepared by dissolving 1.7 g of the compound of 1) in 15 ml of tetrahydrofuran is added dropwise over 12 minutes. After stirring at room temperature for 2 hours, 10 mg of lithium aluminum hydride is added, and the mixture is stirred at room temperature for 2.5 hours. Add ethyl acetate and aqueous ammonium chloride solution, extract, wash with water and dry. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate), 0.85 g
To obtain the title compound of.

IR (Neat) cm ^-1 : 2940,2810,1593,1485,145
6,1127,1009 ¹ HNMR (CDCl3) δ: 7.26-7.24 (1H, m), 7.01 (1H, d, J = 2.4),
6.83 (1H, dd, J = 8.8,2.4), 6.55 (2H, s), 6.27 (1H, s), 4.38 (2
H, t, J = 6.4), 3.85 (6H, s), 3.83 (6H, s), 3.72 (2H, t, J = 6.4),
3.64 (2H, s), 3.43 (2H, s), 3.43 (2H, q, J = 6.8), 2.49 (8H, m),
1.15 (3H, t, J = 6.8) MS: 497 (M ⁺ )

Example 5 1-{(1-ethoxyethyl-5-methoxyindole) -2-yl-methyl} -4- (3,4,5-trimethoxybenzyl) -piperazine.2 fumarate (5 ) 0.29 g of the compound of Example 4 was taken as an ethanol solution, 0.14 g of fumaric acid in ethanol was added, and the mixture was concentrated and recrystallized from isopropanol to give a solution of 0.
35 g of the title compound are obtained.

Mp: 177-178 ° C IR (KBr) cm ^-1 : 3400,2944,1717,1688,1454,1431,1301,11
29,646

Example 6 1-{(5-methoxyindol) -2-yl-carbonyl-4-
{(3-Pyridyl) -carbonyl} -piperazine ・ 1 / 4H ₂
O (6)

[0062]

[Chemical 14]

Compound (6) was prepared in the same manner as in Example 1 except that 1-{(3-pyridyl) -carbonyl} -piperazine was used in place of 1- (3,4,5-trimethoxybenzyl) -piperazine. obtain.

Mp: 233-233.5 ° C. Elemental analysis: Calculated as C ₂₀ H ₂₀ N ₄ O ₃ · 1/4 H ₂ O: C, 65.12; H, 5.60; N, 15.19 Measured value: C, 65.19; H , 5.57; N, 15.09 IR (KBr) cm ^-1 : 3334,1626,1531,1433,1238,1220 ¹ HNMR (DMSO-d6) δ: 11.47 (1H, s), 8.68 (2H, m), 7.90 ( 1H,
dt, J = 7.8,2.0), 7.51 (1H, dd, J = 7.8,4.9), 7.32 (1H, d, J = 8.
8), 7.06 (1H, d, J = 2.0), 6.85 (1H, dd, J = 8.8,2.4), 6.75 (1H,
s), 3.86-3.71 (6H, m), 3.75 (3H, s), 3.38 (2H, brs) MS: 364 (M ⁺ )

Example 7 1-{(5-methoxyindol) -2-yl-carbonyl} -4
-{(3-Pyridyl) -methyl} -piperazine (7)

[0066]

[Chemical 15]

Compound (7) was prepared in the same manner as in Example 1 except that 1-{(3-pyridyl) -methyl} -piperazine was used in place of 1- (3,4,5-trimethoxybenzyl) -piperazine. obtain.

IR (KBr) cm ^-1 : 1599,1526,1433,1228,804,7
58,714 ¹ HNMR (CDCl3) δ: 9.32 (1H, brs), 8.57-8.50 (2H, m), 7.70
(1H, dt, J = 7.9,2.0), 7.35-7.21 (2H, m), 7.03 (1H, m), 6.94
(1H, dd, J = 8.8,2.4), 6.68 (1H, d, J = 1.5), 3.94 (4H, t, J = 5.
1), 3.84 (3H, s), 3.57 (2H, s), 2.54 (4H, t, J = 5.1)

Example 8 1- {1-ethoxyethyl- (5-methoxyindole) -2-
Il-carbonyl} -4-{(3-pyridyl) -methyl} -piperazine ・ fumaric acid ・ 1.2 H ₂ O salt (8)

[0070]

[Chemical 16]

Compound (8) is obtained in the same manner as in Example 2 except that compound (7) is used instead of compound (1).

Mp: 146.5-147.5 ° C. Elemental analysis: C ₂₄ H ₃₀ N ₄ O ₃ .C ₄ H ₄ O ₄ .1.2 H ₂
Calculated as O: C, 60.03; H, 6.55; N, 10.00 Actual value: C, 60.06; H, 6.15; N, 9.52 IR (KBr) cm ^-1 : 2934,1638,1222,984,804,648

Example 9 1- {1-Ethoxyethyl- (5-methoxyindole) -2-yl-methyl} -4-{(3-pyridyl) -methyl} -piperazine fumarate (9)

[0074]

[Chemical 17]

5 ml of tetrahydrofuran was added to 0.12 g of lithium aluminum hydride, 0.16 g of aluminum chloride was added, and the mixture was stirred at room temperature for 10 minutes. 1- {1-ethoxyethyl-
(5-Methoxyindole) -2-yl-carbonyl} -4-
After adding a solution of 0.37 g of {(3-pyridyl) -methyl} -piperazine and 3 ml of tetrahydrofuran at room temperature for 4 minutes,
Heat to reflux for 1.2 hours. Immerse in an ice water bath, add ammonium chloride aqueous solution and sodium carbonate aqueous solution to make it alkaline, then extract with ethyl acetate, wash with water and dry. Purification by silica gel column chromatography (ethyl acetate: methanol = 20: 1 to 100: 9) gives 0.13 g of oil. This was dissolved in ethanol, 69 mg of fumaric acid in ethanol was added, concentrated and recrystallized from isopropanol to give 0.13
This gives g of the title compound.

Mp: 184-185 ° C. Elemental analysis: Calculated as C ₂₄ H ₃₂ N ₄ O ₂ .C ₄ H ₄ O ₄ : C, 64.11; H, 6.92; N, 10.68 Measured value: C, 63.95; H , 6.85; N, 10.69 IR (KBr) cm ^-1 : 3400,1678,1485,1210,1114,984,803,648

Example 10 1-Ethoxyethyl-5-methoxy-2-methyl-indole
-3-Ethylcarboxylate (10) 5-methoxy-2-methyl-indole-3- To 3.0 g of ethyl carboxylate, 20 ml of dimethylformamide was added, and 2.2 ml of ethoxyethyl bromide was added, and the temperature was 60 ° C.
At this point, add 35% potassium hydride until the starting material disappears and stir for 2.3 hours. The solvent is distilled off, water and ethyl acetate are added, the mixture is extracted, washed with water and dried. The solvent is distilled off, and the residue is purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 3.2 g of the title compound.

IR (KBr) cm ^-1 : 2978,1688,1487,1203,1176,
1116 ¹ HNMR (CDCl3) δ: 7.67 (1H, d, J = 2.4), 7.20 (1H, AB, J = 8.
8), 6.85 (1H, ABd, J = 8.8,2.4), 4.39 (2H, q, J = 7.0), 4.27 (2
H, t, J = 5.9), 3.88 (3H, s), 3.68 (2H, t, J = 5.9), 3.38 (2H, q, J
= 7.0), 2.77 (3H, s), 1.53 (3H, t, J = 7.0), 1.11 (3H, t, J = 7.0)

Example 11 1-Ethoxyethyl-5-methoxy-2-methyl-indole
-3-carboxylic acid (11)

[0080]

[Chemical 18]

To 3.2 g of the compound of Example 10 were added 25 ml of 2N sodium hydroxide aqueous solution, 1 g of potassium hydroxide and 20 ml of methanol, and the mixture was heated under reflux for 8.3 hours. Add concentrated hydrochloric acid, extract with chloroform, wash with water and dry. The solvent is evaporated, hexane is added, the crystals are filtered and dried to give 2.7 g of the title compound.

IR (KBr) cm ^-1 : 2972,1655,1531,1485,1209 ¹ HNMR (CDCl3) δ: 7.78 (1H, d, J = 2.2), 7.23 (1H, AB, J = 8.
8), 6.88 (1H, ABd, J = 8.8,2.4), 4.31 (2H, t, J = 5.9), 3.94 (3
H, s), 3.72 (2H, t, J = 5.9), 3.42 (2H, q, J = 7.0), 2.84 (3H, s),
1.13 (3H, t, J = 7.0)

Example 12 1-{(1-ethoxyethyl-5-methoxy-2-methyl-indole) -3-yl-carbonyl} -4- (3,4,5-trimethoxybenzyl) -piperazine (12 )

[0084]

[Chemical 19]

To 0.36 g of the compound of Example 11 was added 5 ml of benzene and 0.2 ml of thionyl chloride, and the mixture was heated under reflux for 3 hours. The solvent is distilled off, 5 ml of toluene is added, and the mixture is placed in an ice water bath. 1- (3,
A solution of 0.42 g of 4,5-trimethoxybenzyl) -piperazine, 0.4 ml of pyridine and 5 ml of toluene was added dropwise over 8 minutes, and the mixture was stirred at room temperature for 3.5 hours. The solvent is distilled off, ethyl acetate and an aqueous solution of sodium hydroxide are added, and the mixture is extracted, washed with water and dried.
The solvent was distilled off, and silica gel column chromatography-
Purify with (ethyl acetate: methanol = 10: 1) to obtain 0.53 g of the title compound.

IR (Neat) cm ^-1 : 2940,1622,1425,1125 ¹ H NMR (CDCl3) δ: 7.19 (1H, AB, J = 8.8), 6.99 (1H, AB, J = 2.
4), 6.82 (1H, ABd, J = 8.8,2.4), 6.56 (2H, s), 4.22 (2H, t, J =
5.9), 3.86 (6H, s), 3.84 (3H, s), 3.83 (3H, s), 3.70 (4H, br
s), 3.66 (2H, t, J = 5.9), 3.47 (2H, s), 3.39 (2H, q, J = 6.8), 2.
50 (3H, s), 2.48 (4H, brs), 1.11 (3H, t, J = 6.8) MS: 525 (M ⁺ )

Example 13 1-{(1-Ethoxyethyl-5-methoxy-2-methyl-indole) -3-yl-carbonyl} -4- (3,4,5-trimethoxybenzyl) -piperazine fumar Acid salt (13) To an ethanol solution of 0.52 g of the compound of Example 12 is added an ethanol solution of 0.12 g of fumaric acid, and the mixture is concentrated and dried to give the title compound as an amorphous compound.

IR (KBr) cm ^-1 : 1702,1597,1427,1249,112
7

Example 14 1-{(1-ethoxyethyl-5-methoxy-2-methyl-indol) -3-yl-carbonyl} -4-{(3-pyridyl) -methyl} -piperazine (14)

[0090]

[Chemical 20]

Compound (14) was obtained in the same manner as in Example 12 except that 1-{(3-pyridyl) -methyl} -piperazine was used instead of 1- (3,4,5-trimethoxybenzyl) -piperazine. obtain.

IR (Neat) cm ^-1 : 2872,1618,1425,1209,111
8,752,716 ¹ HNMR (CDCl3) δ: 8.55 (1H, s), 8.51 (1H, d, J = 3.7), 7.68
(1H, d, J = 7.9), 7.27 (1H, t, J = 6.4), 7.19 (1H, d, J = 8.5), 6.9
7 (1H, d, J = 2.4), 6.82 (1H, dd, J = 8.5,2.4), 4.22 (2H, t, J = 6.
1), 3.84 (3H, s), 3.68 ((4H, brs), 3.66 (2H, t, J = 6.1), 3.55
(2H, s), 3.39 (2H, q, J = 7.3), 2.50 (3H, s), 2.49 (4H, brs), 1.
11 (3H, t, J = 7.3) MS: 436 (M ⁺ )

Example 15 1-{(1-ethoxyethyl-5-methoxy-2-methyl-indole) -3-yl-carbonyl} -4- (3-pyridyl) -methyl} -piperazine fumarate ( 15) Instead of (12) (1
(15) is obtained in the same manner as in Example 13 except that 4) is used.

IR (KBr) cm ^-1 : 1678,1620,1427,1210,804,6
48

Example 16 N- (1-benzyl-4-piperidyl)-(1-ethoxyethyl)
-5-Methoxy-2-methyl-indole) -3-carboxamide (16)

[0096]

[Chemical 21]

(16) is obtained in the same manner as in Example 12 except that 1-benzyl-4-amino-piperidine is used instead of 1- (3,4,5-trimethoxybenzyl) -piperazine.

IR (KBr) cm ^-1 : 3302,1620,1522,1485 ¹ H NMR (CDCl3) δ: 7.38-7.28 (5H, m), 7.20 (2H, AB, J = 2.
9), 6.84 (1H, ABd, J = 9.0,2.2), 5.74 (1H, d, J = 8.8), 4.24 (2
H, t, J = 5.9), 4.06 (1H, m), 3.86 (3H, s), 3.66 (2H, t, J = 5.9),
3.53 (2H, s), 3.39 (2H, q, J = 7.0), 2.93-2.80 (2H, m), 2.69 (3
H, s), 2.38-2.04 (4H, m), 1.81-1.55 (2H, m)

Example 17 N- (4-piperidyl)-(1-ethoxyethyl-5-methoxy)
-2-Methyl-indole) -3-carboxamide (17)

[0100]

[Chemical formula 22]

To 0.30 g of the compound of Example 16 were added 1 ml of acetic acid and 90 mg of platinum oxide, and the mixture was stirred at 70 ° C. for 15.7 hours. Ethyl acetate was added, the precipitate was filtered, aqueous sodium hydroxide solution was added,
It is made alkaline, extracted, washed with water and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol-1% triethylamine) to give 0.20 g of the title compound.
obtain.

IR (KBr) cm ^-1 : 3276,2934,2866,1613,1485,
1209,774 ¹ HNMR (CDCl3) δ: 7.24 (1H, AB, J = 8.6), 7.21 (1H, d, J = 2.
6), 6.84 (1H, ABd, J = 9.0,2.2), 5.75 (1H, d, J = 8.1), 4.24 (2
H, t, J = 5.9), 4.08 (1H, m), 3.86 (3H, s), 3.66 (2H, t, J = 5.9),
3.40 (2H, q, J = 7.0), 3.12 (2H, ABt, J = 9.6,3.9), 2.92-2.66
(2H, m), 2.70 (3H, s), 2.21-2.03 (2H, m), 1.66-1.35 (2H, m),
1.12 (3H, t, J = 7.0)

Example 18 N- {1- (3-pyridyl) -methyl} -4-piperidyl}-(1-
Ethoxyethyl-5-methoxy-2-methyl-indole)
-3-Carboxamide fumarate (18)

[0104]

[Chemical formula 23]

5 ml of dimethylformamide was added to 0.19 g of the compound of Example 17, 0.11 g of 3-picolyl chloride.hydrochloride and 0.23 g of potassium carbonate, and the mixture was stirred at 70 ° C. for 5.6 hours. The solvent is distilled off, ethyl acetate and water are added, and the mixture is extracted, washed with water and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 7: 1 to 5.5: 1),
0.20 g of the title compound is obtained. 0.19 g of this was dissolved in ethanol, 48 mg of fumaric acid in ethanol was added, concentrated and recrystallized from isopropanol to obtain 0.18 g of the title compound as pale yellow crystals.

Mp: 160.5 to 161.5 ° C. Elemental analysis: calculated as C ₂₆ H ₃₄ N ₄ O ₃ .C ₄ H ₄ O ₄ : C, 63.59; H, 6.76; N, 9.89 Found: C, 63.41; H , 6.66; N, 9.91 IR (KBr) cm ^-1 : 2936,2638,1681,1620,1485,1209,984,80
4,648

Example 19 Next, the PAF antagonism of the compound represented by the formula (I) will be described.

1. In vitro PAF-induced aggregation of rabbit platelets is used to measure the platelet activating factor (PAF) antagonism of the in vitro platelet aggregation inhibition test substance. Venous blood is drawn from the rabbit ear vein into a plastic centrifuge tube containing 1.0% sodium citrate solution to obtain platelet-rich plasma (PRP). The ratio of sodium citrate solution to blood is 1:10. The citrated blood thus obtained was allowed to stand at room temperature at 70 × g (625rp
Centrifuge at m) for 20 minutes and collect the upper PRP in another plastic tube. The remaining lower layer is 1500 × g
Centrifuge at (2800 rpm) for 10 minutes to collect upper platelet-poor plasma (PPP). Platelet aggregation is measured using an aglycometer manufactured by Nikko Bioscience. PRP was dispensed into a measuring cuvette and immediately aspirin, creatinine phosphate and creatinine phosphokinase were added to a final concentration of 0.1 mM, 7 mM and
Add 45 U / ml. Subsequently, the test drug solution was added and stirred at 37 ° C for 2 minutes, and then PAF (final concentration 10
ng / ml) to induce platelet aggregation. The platelet aggregation rate is calculated from the maximum value of each agglutination curve, where the PPP permeability is the maximum agglutination (100% agglutination). The aggregation rate with the addition of physiological saline was used as the control, and the aggregation rate with the addition of each test compound was calculated as the inhibition rate for the control, and the IC ₅₀ value was determined by interpolation from the figure.

The results are shown in Table 1.

[0110]

[Table 1]

As is clear from the above test results, the compound represented by the formula (I) or a salt thereof has excellent PA.
It has an F antagonism.

2. Binding test using [ ³ H] -PAF (PAF receptor binding test) The cell membrane fraction of rabbit platelets was prepared according to the method of Hwang et al. (Biochemistry; 22; 4756, (1983)). This membrane fraction was added to 10 mM Tris buffer containing 0.25% bovine serum albumin.
(50 mg) was suspended, and tritium-labeled PAF ([[
³ H] -PAF; 0.4 nM) and test compound were added.
After keeping the temperature at 25 ° C. for 60 minutes, it was filtered through a glass fiber filter paper. The filter paper was washed 3 times with cold Tris buffer, transferred to a vial, a scintillator was added, and the radioactivity was measured with a liquid scintillation counter. The inhibition rate (binding ability) of the test compound was calculated according to the following formula, and the IC ₅₀ value was determined by interpolating from the figure.

[0113]

[Equation 1]

The total binding amount is the amount of [ ³ H] -PAF binding radioactivity in the absence of the test compound, and the nonspecific binding amount is the amount of [ ³ H] -PAF in the presence of 1 μM PAF. It is the amount of bound radioactivity. The results are shown in Table 2. WEB 2086 (Patent Document 1) disclosed as a PAF antagonist as a control drug
65-176591) was used.

[0115]

[Table 2]

As is apparent from the above test results, the compound represented by the formula (I) or a salt thereof has excellent PA.
It has an F receptor antagonistic action.

Further, since the compound of the present invention did not suppress the aggregation of platelets by ADP even when the concentration of the compound was increased up to 100 μg / ml, it has a selective antagonistic effect on PAF. Can say

[0118]

INDUSTRIAL APPLICABILITY According to the present invention, the compound represented by the formula (I) and its pharmacologically acceptable salt have a PAF antagonistic action, and various diseases thought to involve PAF. Against this, it is expected to have preventive and therapeutic effects. In particular, it can be used as an anti-asthma agent, an anti-allergic agent, an anti-inflammatory agent, an agent for relieving shock symptoms, a therapeutic agent for thrombosis and the like.

Claims (4)

[Claims] 1. Formula (I): (In the formula, R represents a lower alkyl having 1 to 5 carbon atoms, and R ¹
Represents hydrogen or alkoxyalkyl having 2 to 10 carbons, R ² represents hydrogen or lower alkyl having 1 to 5 carbons, A and B independently represent CH ₂ or CO, and Z is N.
Or NHCH, Ar is 3-pyridyl, or 1-
Represents a phenyl substituted with 3 alkoxys) or a pharmaceutically acceptable salt thereof. 2. An anti-inflammatory agent comprising the indole derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 3. An antiallergic agent comprising the indole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. An anti-PAF containing the indole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Agent.