JPS6233225B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an acylated indole derivative, a method for producing the same, and a platelet aggregation inhibitor containing the same as an active ingredient. The novel compound provided by the present invention, an acylated indole derivative, has an excellent anti-platelet aggregation effect, and therefore can be used to prevent occlusion in the cardiovascular system, to prevent and treat postoperative thrombosis, and to improve blood vessel function after surgery. It is an extremely useful compound for the prevention and treatment of thromboembolism, atherosclerosis, arteriosclerosis, etc., and for the prevention and treatment of myocardial infarction and recurrence after stroke. The novel acylated indole derivatives provided by the present invention are expected to have excellent anti-inflammatory and fibrinolytic activity, and are extremely useful compounds. The novel acylated indole derivative provided by the present invention has the following formula [] [In the formula, R ₁ represents a hydrogen atom, a lower alkyl group, or an acetyl group, R ₂ represents a hydrogen atom or a methyl group, and R ₃ and R ₄ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy Indicates the group. φ represents a phenyl group or thienyl group substituted with a halogen atom or a lower alkyl group, or unsubstituted. ] It is expressed as . US Pat. No. 3,557,142 describes acylated indole derivatives having low toxicity and anti-inflammatory effects, but such acylated indole derivatives have a carboxyl group or an ester group as an N-substituent. British Patent No. 959203 describes acylated indole derivatives having antiallergic effects, and these acylated indole derivatives have an aminoalkyl group as an N-substituent. As mentioned above, the acylated indole derivative of the present invention has an alcoholic hydroxyl group, ether group, or acetyloxy group in the N-substituent, and the acylated indole derivative provided by the present invention is described in the above-mentioned publications. It is clearly different from what has been described, and is a completely unknown new compound.
The aacylated indole derivative of the present invention is expected to be a compound that has a unique pharmacological action of extremely excellent platelet aggregation inhibition action, and also has anti-inflammatory action and fibrinolytic action, and is therefore extremely useful as a pharmaceutical. It is something. In the acylated indole derivative represented by the above formula [] provided by the present invention, R ₁ represents a hydrogen atom, a lower alkyl group, or an acetyl group.
Examples of such lower alkyl groups include methyl, ethyl, propyl, isopropyl, and butyl groups. Among these, especially
Acylated indole derivatives in which R ₁ is a hydrogen atom, a methyl group, or an acetyl group have excellent platelet aggregation inhibiting activity. R ₂ represents a hydrogen atom or a methyl group. R ₃ and R ₄ are the same or different, a hydrogen atom,
Indicates a halogen atom, lower alkyl group, or lower alkoxy group. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine. Examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, and butyl group. Examples of the lower alkoxy group include methoxy group, ethoxy group, propanoxy group, isopropanoxy group, and butoxy group. Among these, R ₃ and R ₄ are preferably hydrogen atoms. φ represents a phenyl group or thienyl group substituted with a halogen atom or a lower alkyl group, or unsubstituted. Examples of the halogen atom include fluorine, chlorine, and bromine atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, and butyl groups. Among these, acylated indole derivatives in which φ is a phenyl group exhibit particularly excellent platelet aggregation inhibiting activity. In the acylated indole derivative of the present invention,
When R ₂ is a methyl group, the α-carbon atom of the N-substituent is an asymmetric carbon atom, and the present invention includes not only racemic mixtures thereof but also optical isomers thereof. Specific examples of such acylated indole derivatives of the present invention include the following compounds. (1) 3-benzoyl-1-(2-hydroxyethyl)-2-methylindole, (2) 3-benzoyl-1-(1-hydroxy-2
-propyl)-2-methylindole, (3) 3-benzoyl-1-(2-methoxyethyl)-2-methylindole, (4) 3-benzoyl-1-(1-methoxy-2-
propyl)-2-methylindole, (5) 1-(2-acetoxyethyl)-3-benzoyl-2-methylindole, (6) 1-(1-acetoxy-2-propyl)-3
-benzoyl-2-methylindole, etc. Therefore, in the acylated indole derivative represented by the above formula [] provided by the present invention,
Acylated indole derivatives in which R ₁ is a lower alkyl group or an acetyl group have the following formula [] [In the formula, R ₁ ' represents a lower alkyl group or an acetyl group, and R ₂ , R ₃ , R ₄ and φ are the same as defined above. ] It is produced by subjecting the tetrahydroacylated indole derivative represented by to a dehydration reaction. Furthermore, among the acylated indole derivatives represented by the above formula [], the acylated indole derivatives in which R ₁ is a hydrogen atom are represented by the following formula [′] [In the formula, R ₁ ″ represents an acetyl group, R ₂ , R ₃ , R ₄
and φ are the same as defined above. ] It is produced by subjecting the tetrahydroacylated indole derivative represented by to a dehydrogenation reaction and then hydrolyzing it. Accordingly, the present invention provides the following method for producing an acylated indole derivative. That is, the following formula ['] is characterized in that the tetrahydroacylated indole derivative represented by the above formula [] is subjected to a dehydrogenation reaction. [In the formula, R ₁ ' represents a lower alkyl group or an acetyl group, and R ₂ , R ₃ , R ₄ and φ are the same as defined above. ] A method for producing an acylated indole derivative represented by the following formula [″], which is characterized by subjecting the tetrahydroacylated indole derivative represented by the above formula [′] to a dehydrogenation reaction and then hydrolyzing it. [In the formula, R ₂ , R ₃ , R ₄ and φ are the same as defined above. ] This is a method for producing an acylated indole derivative represented by: The tetrahydroacylated indole derivative represented by the above formula [] or [''] used herein may be obtained by any method. For example, as separately proposed by the present inventors, the tetrahydroacylated indole derivative represented by the following formula [] [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. ] A tetrahydroindole derivative represented by
The following formula [] φ-COOH ... [] [In the formula, φ is the same as the above definition. ] It can be produced by condensing a carboxylic acid represented by the following with an acid anhydride or acid halide in the presence of an acid catalyst. The dehydrogenation reaction of the tetrahydroacylated indole derivative represented by the above formula [] or ['] is carried out using a commonly used dehydrogenating agent or dehydrogenating catalyst. Examples of dehydrogenating agents include sulfur, 2,3-dichloro-5,6-dicyano-p-
Benzoquinone, 2,3,5,6-tetrachlor-
Examples include p-benzoquinone, 3,4,5,6-tetrachloro-o-benzoquinone, and the like. Examples of dehydrogenation catalysts include selenium, palladium on carbon, platinum, and rhodium. The reaction proceeds even in the absence of a solvent, but in some cases an organic solvent may be used to facilitate the reaction.
As such an organic solvent, commonly used inert solvents can be used. Specific examples include tetrahydrofuran, dioxane, 1,2-
Examples include ethers such as dimethoxyethane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol, and dibutyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, naphthalene, and quinoline, and hydrocarbons such as cumene and decalin. It will be done. The dehydrogenation catalyst and dehydrogenation agent used in the present invention are used in an amount of 0.1 to 20 times, preferably 0.5 to 5 times, the mole of the raw material tetrahydroacylated indole derivative of formula []. The amount of the inert organic medium to be used is sufficient as long as the reaction proceeds smoothly, and is usually 1 to 100 times the volume of the raw materials, preferably 2 to 20 times the volume of the raw materials. The reaction temperature is carried out in the range of 0° to 500°,
Preferably it is in the range of 50 to 300°C. The end point of the reaction is determined by following the reaction using gas chromatography or thin layer chromatography.
The reaction time varies depending on the reaction temperature, dehydrogenating agent, and dehydrogenating catalyst, but the reaction is usually completed in 30 minutes to 72 hours. After the reaction, column chromatography, thin layer chromatography,
This can be carried out using purification means such as distillation and recrystallization. In this way, among the acylated indole derivatives represented by the above formula [] provided in the present invention, the acylated indole derivatives in which R ₁ is a lower alkyl group, an acetyl group, or an acetyl group, that is, the acylated indole derivatives represented by the above formula [' ] is obtained. Among the acylated indole derivatives represented by the above formula [] provided in the present invention, the acylated indole derivatives in which R ₁ is a hydrogen atom include the above-mentioned tetrahydroamylated indole derivatives represented by the above formula ['']. It is obtained by subjecting the dehydrogenation reaction to a hydrolysis reaction. This hydrolysis reaction is a reaction known per se, and is generally an alkali such as caustic soda or caustic potash, or a mineral acid such as hydrochloric acid, preferably a mineral acid such as hydrochloric acid. in an alcohol such as methanol or ethanol in the presence of an alkali,
Depending on the case, the treatment is usually carried out at a temperature of 0 to 80 DEG C. in the coexistence of an ether solvent such as tetrahydrofuran or dioxane. Isolation and purification of the target product after the reaction is carried out in the same manner as described above. Thus, among the acylated indole derivatives represented by the above formula [] provided in the present invention, an acylated indole derivative in which R ₁ is a hydrogen atom, that is, one represented by the above formula [''] is obtained. The acylated indole derivative of the invention has the following formula [] [In the formula, X is a halogen atom, and R ₁ and R ₂ are the same as defined above. ] In the presence of an acid acceptor, the compound represented by the following formula [] [In the formula, φ, R ₂ and R ₃ are the same as defined above. ] It can also be produced by reacting with a compound represented by: Here, X in the above formula [] includes, for example, a bromine atom and a chlorine atom. As the acid acceptor, alkali metal hydrides such as sodium hydride and potassium hydride are preferred. Such reactions can be carried out in an inert organic solvent such as benzene, toluene, xylene, dimethylformamide, etc. at a temperature range of 20-150°C. Therefore, the acylated indole derivatives represented by the above formula [] of the present invention, especially the following formula [] [In the formula, R ₁ ′ is a hydrogen atom, a lower alkyl group, or an acetyl group, R ₂ ′ is a hydrogen atom or a lower alkyl group, and R ₃ and R ₄ are the same or different hydrogen atom, halogen atom, lower alkyl group, or lower alkoxy Indicates the group. φ' represents a phenyl group or a thienyl group. ] The acylated indole derivatives represented by these have excellent platelet aggregation inhibiting effects, and therefore these compounds are useful in mammals including humans when it is desired to inhibit platelet aggregation and inhibit or prevent thrombus formation. administered to For example, these compounds are useful for the prevention of cardiovascular occlusion, postoperative thrombosis, post-surgical vascular thromboembolism, and the prevention or treatment of atherosclerosis, arteriosclerosis, etc. It is. It is also used to prevent cerebral ischemic attacks in geriatric patients and to prevent or treat myocardial infarction and recurrence after stroke. Measurement of the platelet aggregation inhibitory effect of the acylated indole derivative of the present invention is carried out in vitro to determine the inhibitory effect of the acylated indole derivative of the present invention on the aggregation of various aggregation inducers such as arachidonic acid and collagen.
This was done by the method of quantitative determination. That is, in vitro methods require that the final concentration
Add 25 μl of acylated indole derivative solution to 200 μl of guinea pig platelet-rich plasma (PRP) in which Ca ions were chelated with sodium citrate to a concentration of 0.38%, and pre-incubate at 37°C for 2 minutes. Thereafter, 25 μl of sodium arachidonate was added, the platelet aggregation curve was recorded with an aggregometer, and the percentage of the maximum aggregation of the specimen to the maximum aggregation of Planck (PRP + saline + aggregation inducing agent) was reduced below 100. The value was determined as the aggregation inhibition rate. The acylated indole derivative of the present invention can be administered orally or parenterally, such as rectally, subcutaneously, intramuscularly, etc., but oral or rectal administration is preferred. For oral administration, it is formulated into solid or liquid preparations. Solid preparations include tablets, pills, powders, and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as the commonly used calcium carbonate, potato starch, alginic acid or lactic acid. The formulation is carried out according to conventional methods, but may contain additives other than diluents, such as lubricants such as magnesium atearate. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or xyls, containing commonly used inert diluents such as water or liquid paraffin. including. In addition to the inert diluent, this formulation contains adjuvants,
Examples include wetting agents, suspending agents, sweetening agents, flavoring agents, aromatics or preservatives. The liquid preparation may also be a capsule of absorbable material such as gelatin. Solid preparations for rectal administration include suppositories containing one or more active substances and prepared by methods known per se. Preparations for parenteral administration are sterile aqueous or nonaqueous solutions, suspensions, or emulsions. Non-aqueous solvents or suspending agents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of a sterilizing agent, or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use. The dosage of the acylated indole derivative, which is the active compound of the present invention, is 0.005 to 0.005 kg body weight per day.
Approximately 200 mg, preferably 0.01-100 mg. These dosages depend on the patient's medical condition, weight, age, or route of administration. As described above, the novel acylated indole derivatives provided by the present invention have excellent platelet aggregation inhibiting activity. EXAMPLES Hereinafter, the present invention will be illustrated in more detail with reference to Examples. Example 1 Synthesis of 3-benzoyl-1-(1-methoxy-2-propyl)-2-methylindole 4.52 g (20 mmol) of benzoic anhydride and 4,5,
6,7-tetrahydro-1-(1-methoxy-2
-propyl)-2-methylindole 2.07g (10
mmol) and 0.5 ml of 52% hydriodic acid were heated and stirred at 120°C for 2 hours under a nitrogen stream. After the reaction, add 50ml of 1N sodium hydroxide solution to the reaction mixture,
Stirred at room temperature for 2 hours. Then, the mixture was extracted twice with 50 ml each of ethyl acetate. Combine the ethyl acetate layers and add 100% water
ml and 100 ml of saturated saline in this order. After drying the ethyl acetate layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting colored oily product was subjected to column chromatography on 200 g of silica gel. Develop with ethyl acetate-benzene = 1:20 to obtain the desired 3-benzoyl-4,5,6,7-tetrahydro-1-(1-methoxy-2-propyl)-2.
-1.92 g of methyl indole was obtained as an oil.
Yield 62% Infrared absorption spectrum ν ^neat _nax 2920, 2840, 1626, 1572, 1508,
1446, 1414, 1386, 1370, 1328,
1260, 1110, 917, 730, 696 cm ^-1 Nuclear magnetic resonance absorption spectrum δ ^TMS _CDCl3 1.41 (3H.dJ=7Hz), 1.6-1
.9 (4H.
m), 2.1~2.4 (2H.m), 2.25 (3H.m)
S), 2.4-2.7 (2H.m), 3.29 (3H.m)
S), 3.63 (2H.dJ=7Hz), 4.45
(1H.sexted J=7Hz), 7.3~7.6
(3H, m), 7.6-7.9 (2H.m) 3-benzoyl-4,5,6,7-tetrahydro-1-(1-methoxy-2-propyl)-2-
Methylindole 1.55g (5 mmol) and 2,3
2.72 g (12 mmol) of -dichloro-5,6-dicyano-p-benzoquinone was dissolved in 20 ml of benzene and heated under reflux for 24 hours. After cooling to room temperature, the precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The obtained black and colored oil was subjected to column chromatography using 100 g of silica gel and developed with ethyl acetate-benzene = 1:25 to obtain the desired 3-benzoyl-1-
650 mg of (1-methoxy-2-propyl)-2-methylindole as an oil was obtained. Yield 42% Infrared absorption spectrum ν ^neat _nax 2950, 2900, 1620, 1572, 1515,
1450, 1403, 1374, 1267, 1225,
1200, 1165, 1108, 1036, 895, 744cm
^-1 Nuclear magnetic resonance absorption spectrum δ ^TMS _CDCl3 1.60 (3H.dJ=7Hz), 2.55 (
3H.S),
3.23 (3H.S), 3.6~4.1 (2H.m), 4.5
~5.1 (1H.m), 6.9~7.9 (9H.m) Example 2 1-(1-acetoxy-2-propyl)-3-
Synthesis of benzoyl-2-methylindole 1-(1-acetoxy-2-propyl)-4,
23.2 g (0.099 mol) of 5,6,7-tetrahydro-2-methylindole and 44.8 g of benzoic anhydride
(0.198 mol) and 1 ml of 52% hydriodic acid under nitrogen stream.
The mixture was heated and stirred at 145°C for 2 hours. After cooling to room temperature, the reaction mixture was dissolved in 300 ml of ethyl acetate, and washed with 100 ml of 1N caustic soda solution, 100 ml of water, and 100 ml of saturated brine in this order. After drying the organic layer with Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting black and colored oil was purified using silica gel 850.
The target 1-
29.6 g of (1-acetoxy-2-propyl)-3-benzoyl-4,5,6,7-tetrahydro-2-methylindole was obtained as an oil. Yield 88
% Nuclear magnetic resonance absorption spectrum δ ^CDCl3 _TMS 1.45 (3H.dJ=8Hz), 1.6 (4
Hm),
1.94 (3H.S), 2.2 (2H.m), 2.24
(3H.S), 2.6 (2H.m), 4.2~4.7
(3H, m), 7.3~7.6 (3H.m), 7.6~
7.8 (2H.m) 1-(1-acetoxy-2-propyl)-3-
Benzoyl-4,5,6,7-tetrahydro-2
-2.69g (7.9 mmol) of methylindole and 2,3-dichlor5,6-dicyanobenzo-
4.32 g (18.9 mmol) of 1,4-quinone was dissolved in 50 ml of dioxane and heated under reflux for 4 hours. Dioxane was distilled off under reduced pressure, and 400 ml of ethyl acetate was added to the residue to dissolve the product, which was then filtered. 200ml of water,
It was washed with 100 ml of 1N caustic soda solution, 200 ml of water, and saturated saline, and dried over anhydrous magnesium sulfate.
The black and colored oil obtained by distilling off the solvent under reduced pressure was subjected to column chromatography on 150 g of silica gel, developed with benzene:acetic acid = 20:1, and the desired 1
-(1-acetoxy-2-propyl)-3-benzoyl-2-methylindole as oil
Obtained 1.44g. Yield 25% Infrared absorption spectrum ν ^CHCl3 _nax 1736, 1625, 1521, 1461, 1613
，
1382, 1230, 1174, 1050 cm ^-1 Nuclear magnetic resonance absorption spectrum δ ^CDCl3 _TMS 1.63 (3H.dJ=8Hz), 1.87 (
3H.S),
2.52 (3H.S), 4.3~4.6 (2H.m), 4.6
~5.2 (1H.m), 6.8~7.8 (9H.m) Example 3 3-benzoyl-1-(1-hydroxy-2-
Synthesis of propyl)-2-methylindole 1-(1-acetoxy-2-propyl)-3-
Benzoyl-2-methylindole 597mg (1.78
mmol) was dissolved in 10 ml of methanol and 5 ml of 1N caustic soda solution and stirred at room temperature for 3 hours. After methanol was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, and washed with 50 ml of water and 50 ml of saturated brine. After drying the sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired 3-benzoyl-1-(1-hydroxy-2-propyl)-2.
-520 mg of methyl indole was obtained as an oil.
Yield 100% Infrared absorption spectrum ν ^CHCl3 _nax 3400, 1620, 1576, 1513, 1462
，
1412, 1390, 1273, 1230, 1163,
1056, 1131, 899 cm ^-1 Nuclear magnetic resonance absorption spectrum δ ^CDCl3 _TMS 1.60 (3H.dJ=8Hz), 2.47 (
3H.S),
2.60 (1H.br), 3.6~4.2 (2H.m) 4.2
~4.8 (1H.m), 6.9~7.8 (9H.m) Example 4 3-benzoyl-1-(2-methoxyethyl)
-Synthesis of 2-methylindole 4,5,6,7-tetrahydro-1-(2-methoxyethyl)-2-methylindole 1.2g
(6.2 mmol), 2.8 g (12.4 mmol) of benzoic anhydride, and 0.15 ml of 52% hydriodic acid under a nitrogen stream.
The mixture was heated and stirred at 130°C for 3.5 hours. After the reaction mixture was allowed to cool to room temperature, it was dissolved in 80 ml of ethyl acetate and added with saturated heavy water.
It was washed with 100 ml of water, 100 ml of water, and 100 ml of saturated saline in this order, and dried with mirabilite. The black and colored oil obtained by distilling off the solvent under reduced pressure was subjected to column chromatography using 50 g of silica gel to obtain benzene:ethyl acetate=
Developed at 20:1, oily 3-benzoyl-4,
1.05 g of 5,6,7-tetrahydro-1-(2-methoxyethyl)-2-methylindole was obtained.
Yield 57% Nuclear magnetic resonance absorption spectrum δ ^CDCl3 _TMS 1.4-1.9 (4H.m), 2.25 (3H.S
), 2.1
~2.6 (4H.m), 3.30 (3H.S), 3.17
(2H.tJ=5Hz), 3.92 (2H.tJ=5
Hz), 7.3-7.8 (5H.m) 3-benzoyl-4,5,6,7-tetrahydro-1-(2-methoxyethyl)-2-methylindole 490 mg (1.6 mmol) and 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone
900 mg (3.8 mmol) was dissolved in 10 ml of dioxane and heated under reflux for 2 hours. After the reaction, dioxane was distilled off under reduced pressure, 30 ml of ethyl acetate was added, and the mixture was dissolved and filtered. 1N solution, 20ml of caustic soda solution, 30ml of water
ml and 30 ml of saturated saline. The organic solvent was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography on 50 g of silica gel, developed with benzene:ethyl acetate = 20:1, and the oily 3-benzoyl-
264 mg of 1-(2-methoxyethyl)-2-methylindole was obtained. Yield 54% Infrared absorption spectrum ν ^CHCl3 _nax 1615, 1571, 1510, 1454, 1408
，
1230, 1167, 1120, 1026 cm ^-1 Nuclear magnetic resonance absorption spectrum δ ^CDCl3 _TMS 2.53 (3H.S), 3.23 (3H.S),
3.63
(2H.tJ=6Hz), 4.27(2H.tJ=6
Hz), 6.9-7.8 (9H.m) Example 5 Synthesis of 3-benzoyl-1-(1-ethoxy-2-propyl)-2-methylindole 1-(1-acetoxy-2-propyl)-3-
515 mg of benzoyl-2-methylindole was hydrolyzed in a conventional manner to obtain the alcohol [3-benzoyl-1-(1-hydroxy-2-propyl)].
447 mg of 2-methylindole was obtained. Dissolve 447 mg of this alcohol in 20 ml of dimethoxyethane, and while stirring under ice cooling, dissolve 90 mg of sodium hydride.
(1.2 eq.) followed by 0.5 ml of ethyl bromide and stirring continued overnight. After distilling off dimethoxyethane under reduced pressure, the reaction product was dissolved in 50 ml of ethyl acetate, washed with 50 ml of water and 50 ml of saturated brine, and dried with sodium sulfate. The oily product obtained by distilling off the solvent under reduced pressure is purified by silica gel.
The mixture was subjected to column chromatography on 15 g and developed with benzene:ethyl acetate: 20:1, and 10 ml of each fraction was collected to obtain 270 ml of the desired ethyl ether compound as an oil in fractions 7 to 14. The physical property data of this product with a yield of 56% were as follows. IR; ν ^CHCl3 _npy 2960, 2850, 1620, 1572,
1516, 1459, 1445, 1407, 1381,
1254, 1268, 1210―1230, 1168,
1100, 1070, 1025, 896, 696 cm ^-1 NMR ^COil3 _TMS 1.03 (3H.tJ=6.5), 1.60 (
3H.dJ
=7), 2.53 (3H.S), 3.1~3.6 (2H.
m), 3.7-4.2 (2H.m), 4.67 (1H.m)
6.9-7.9 (9H.m) Example 6 Synthesis of 3-benzoyl-5-chloro-1-(1-methoxy-2-propyl)-2-methylindole 3-benzoyl-5-chloro-4, 5, 6, 7
From -tetrahydro-1-(1-methoxy-2-propyl)-2-methylindole, 3-benzoyl-5-chloro-1-
(1-methoxy-2-propyl)-2-methylindole was obtained. NMR (CDCl ₃ , δ (ppm)): 1.59 (3H.dJ=
7Hz), 2.47 (3H.s), 3.21 (3H.s),
3.5−4.1 (2H.m), 4.67 (1H.m),
7.05 (1H.dd.J=2.9Hz), 7.25−7.9
(7H.m). IR (CHCl ₃ ) cm ^-1 : 1626, 1600, 1580, 1522,
1452, 1412, 1168, 1114, 940, 898. Example 7 Synthesis of 3-benzoyl-1-(1-ethoxy-2-propyl)-2,5-dimethylindole 3-benzoyl-4,5,6,7 -tetrahydro-1-(1-methoxy-2-propyl)-2,
From 5-dimethylindole, 3-benzoyl-1-(1-ethoxy-2
-propyl)-2,5-dimethylindole was obtained. Melting point: 84-85℃ (cyclohexane) NMR (CDCl ₃ , δ (ppm)): 1.06 (3H.tJ=
7Hz), 1.61 (3H.dJ=7Hz), 2.27
(3H.s), 2.47 (3H.s), 3.1−3.6 (2H.s)
m), 3.82 (2H.dd.J=2.7Hz), 4.4−
4.93 (1H.m), 6.82−7.9 (8H.m). IR (KBr) cm ^-1 : 1628, 1600, 1580, 1520,
1486, 1470, 1444, 1410, 1386,
1376, 1360, 1274, 1238, 1194,
1176, 1110, 1078, 1050, 900, 878,
792, 736, 708. Example 8 Synthesis of 1-(1-methoxy-2-propyl)-2-methyl-3-thienoylindole 4,5,6,7-tetrahydro-1-(1-methoxy-2 -propyl)-2-methyl-3-thienoylindole, in the same manner as in Example 1,
1-(1-methoxy-2-propyl)-2-methyl-3-thienoylindole was obtained. IR (CHCl ₃ ) cm ^-1 : 1605, 1514, 1460, 1413,
1390, 1351, 1267, 1220, 1165,
1106, 1082, 834. NMR (CDCl ₃ , δ (ppm)): 1.60 (3H.dJ=
6Hz), 2.55 (3H.s), 3.18 (3H.s),
3.5−4.1 (2H.m), 4.70 (1H.sexted.J
= 6Hz), 6.9-7.75 (7H.m). Example 9 1-(1-hydroxy-2-propyl)-2-
Synthesis of methyl-3-(0-tolyl)indole 4,5,6,7-tetrahydro-1-(1-acetoxy-2-propyl)-2-methyl-3-
From (0-tolyl)indole, 1-(1-hydroxy-2-propyl) was prepared in the same manner as in Example 3.
-2-methyl-3-(0-tolyl)indole was obtained. NMR (CDCl ₃ , δ (ppm)): 1.46 (3H.dJ=
7Hz), 2.21 (3H.s), 2.40 (3H.s),
3.33 (1H.bs), 3.45−4.20 (2H.m). IR (CHCl ₃ ) cm ^-1 : 3400, 3040, 2920, 1600,
1565, 1510, 1480, 1455, 1400,
1260, 1255, 1165, 1050, 920, 895,
760, 740. Example 10 Synthesis of 3-benzoyl-5-methoxy-1-(1-methoxy-2-propyl)-2-methylindole 3-benzoyl-5-methoxy-4,5,6,
From 7-tetrahydro-1-(1-methoxy-2-propyl)-2-methylindole, Example 1
Similarly, 3-benzoyl-5-methoxy-
1-(1-methoxy-2-propyl)-2-methylindole was obtained. IR (CHCl ₃ ) cm ^-1 : 2960, 2900, 1610, 1572,
1474, 1440, 1410, 1388, 1275,
1160, 1144, 1106, 1032, 905. NMR (CDCl ₃ , δ (ppm)): 1.57 (3H.dJ=
7Hz), 2.47 (3H.s), 3.20 (3H.s),
3.59 (3H.s), 3.60 (2H.m), 4.63
(1H.sextet, J=7Hz), 6.6−6.9
(2H.m), 7.2−7.8 (6H.m). Example 11 Synthesis of 3-(p-chlorobenzoyl)-1-(1-methoxy-2-propyl)-2-methylindole 3-(p-chlorobenzoyl)-4,5,6,
From 7-tetrahydro-1-(1-methoxy-2-propyl)-2-methylindole, Example 1
Similarly, 3-(p-chlorobenzoyl)-
1-(1-methoxy-2-propyl)-2-methylindole was obtained. IR (liquid film) cm ^-1 : 2850, 1618, 1593, 1460,
1408, 1105, 1089, 898, 837. NMR (CDCl ₃ , δ (ppm)): 1.62 (3H.dJ=
7Hz), 2.58 (3H.s), 3.26 (3H.s),
3.8 (2H.m), 4.76 (1H.sextet.J=7
Hz), 6.9−7.8 (8H.m). Example 12 In vitro platelet aggregation inhibition effect of the acylated indole derivative of the present invention
The platelet aggregation inhibitory effect was measured using Guinea pig PRP. The results were expressed as 50% inhibitory concentration (IC ₅₀ ) of platelet aggregation. Sodium arachidonic acid was used as the flocculant. [Preparation of PRP, drugs, and aggregating agents] (1) Preparation of PRP (platelet-rich plasma) Citrated blood (3.8%
1 volume of sodium citrate to 9 volumes of blood) was collected. The obtained citrate blood was centrifuged at 1000 rpm for 10 minutes at room temperature, and the supernatant (PRP) was separated. The obtained PRP was stored at room temperature and used as soon as possible, and was not used after 4 hours had passed after conditioning. (2) Preparation of drug The test drug is generally dissolved in dimethyl sulfoxide to a concentration of 10 mg/ml and diluted with physiological saline to 2500 μg/ml, 1000 μg/ml, and 750 μg/ml.
μg/ml, 500μg/ml, 250μg/ml, 100μ
1 ml of each solution was prepared. However, a compound having a free carboxyl group was dissolved in 0.1M NaHCO ₃ to obtain a 10 mg/ml sodium salt solution, and similarly diluted with physiological saline to prepare a test drug solution. Platelet aggregation inhibition test result: 100μg/ml
If the drug completely suppresses platelet aggregation even at a final concentration of 10 μg/ml, dilute the drug solution with physiological saline (75 μg/ml, 50 μg/ml). ,25μg/ml,10
Platelet inhibition tests were also performed on each dilution (μg/ml). (3) Adjustment of flocculant Arachidonic acid (99% pure) manufactured by Sigma
Prepare 3.3mM arachidonic acid sodium salt solution by dissolving in _0.1M NaHCO3. This was diluted with physiological saline to 1mM and used in the experiment. The 3.3mM solution was stored in the refrigerator as a stock mother solution, and the 1mM solution was newly prepared from this mother solution each time it was used. [Platelet aggregation inhibition test] (1) Blank platelet aggregation 25μ
of physiological saline and a 25μ agglutinant solution were added to aggregate the platelets, and the aggregation curve was recorded for 3 minutes using a Bryston aggregometer. The maximum aggregation degree in this platelet aggregation was defined as the maximum aggregation degree of the blank. (2) Adjustment of coagulation strength of arachidonic acid sodium salt Add 25μ of ibuprofen solution (250μg/ml or 100μg/ml) to 200μ of PRP,
Pre-incubation was carried out in an aggregometer cuvette while stirring with a stirrer for 2 minutes in the same manner as in (1) above, and then 25μ
Add 1mM sodium arachidonic acid solution to the above
A platelet aggregation curve was recorded in the same manner as in (1), the maximum degree of aggregation was calculated from the curve, and the aggregation inhibition rate was calculated using the following formula. Inhibition rate (%) = 100 - maximum aggregation degree of ibuprofen-added system / Planck's maximum aggregation degree x 100 At this time, the inhibition rate was 50% or more in the system with ibuprofen added at 250 μg/ml, and the inhibition rate was over 50% in the system added with ibuprofen at 100 μg/ml. It was confirmed that the inhibition rate was below 50%, and if it was not, the sodium arachidonic acid salt solution was not at an appropriate concentration, so the concentration was readjusted and the test was performed again to match the conditions. (3) Platelet aggregation inhibition test Add 25μ of the test drug solution to 200μ of PRP, pre-incubate at 37°C for 2 minutes in the same manner as in (2) above, and then add sodium arachidonate to which the concentration was adjusted in (2) above. 25μ of the solution was added, an aggregation curve was recorded for 3 minutes, the maximum degree of platelet aggregation within that time was measured, and the inhibition rate was calculated using the following formula. The lowest concentration of the drug where the inhibition rate exceeds 50%
Expressed as IC ₅₀ value. Inhibition rate (%) = 100 - (maximum aggregation degree of test drug added system/Maximum aggregation degree of Planck x 100) The results are shown in Table 1. In addition, an acute toxicity test was conducted using mice by oral administration of the test drug. LD ₅₀ value is 3000~
It was over 1000mg/Kg. As a subacute toxicity test, 20, 100, and 500 mg/Kg were continuously orally administered to rats for 7 days, and no abnormalities were observed up to 100 mg/Kg.

【table】

[Table] Example 13 Preparation of tablets Tablets were manufactured, each having the following composition. Active ingredient 200mg Lactose 280mg Dimeat starch 80mg Polyvinylpyrrolidone 11mg Magnesium stearate 5mg 576mg The active ingredients, lactose and Dimonia starch were mixed, evenly moistened with a 20% ethanol solution of polyvinylpyrrolidone, and passed through a 20mm mesh sieve. It was dried at 45°C and passed through a 1.5 mm mesh sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets. As an active ingredient, typically 3-benzoyl-
1-(1-methoxy-2-propyl)-2-methylindole was used. Example 14 Capsule Tablets Hard gelatin capsules were prepared, one capsule containing the following composition: Active ingredient 200mg Microcrystalline cellulose 195mg Amorphous silicic acid 5mg 400mg The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard gelatin capsules. As an active ingredient, typically 3-benzoyl-1
-(1-methoxy-2-propyl)-2-methylindole was used. Example 15 Preparation of ampoule An ampoule containing the following composition in one ampoule (5 ml volume) was manufactured. Active ingredient 200 mg Polyethylene glycol 600 200 mg Distilled water Total volume 5.0 ml Polyethylene glycol and active ingredient were dissolved in water under nitrogen, which was boiled, cooled under nitrogen and distilled. The solution was made up to the given volume with pretreated water and filtered under sterile conditions. This production is carried out under diffused light. Filling was carried out in a nitrogen stream and sterilization was carried out at 121°C for 20 minutes. In addition, as an active ingredient, 3-benzoyl-1-
(1-methoxy-2-propyl)-2-methylindole was used.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ₁ is a hydrogen atom, a lower alkyl group or an acetyl group, R ₂ is a hydrogen atom or a methyl group, R ₃ and R ₄ are the same or different hydrogen atoms,
Indicates a halogen atom, lower alkyl group, or lower alkoxy group. φ represents a phenyl group or thienyl group substituted with a halogen atom or a lower alkyl group or unsubstituted. ] An acylated indole derivative represented by 2. The acylated indole derivative according to claim 1, wherein R ₃ and R ₄ are hydrogen atoms. 3. The acylated indole derivative according to claim 1 or 2, wherein φ is a phenyl group. 4 The following formula [] [In the formula, R ₁ ' represents a lower alkyl group or an acetyl group, R ₂ represents a hydrogen atom or a methyl group, and R ₃
and R ₄ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. φ is substituted with a halogen atom or a lower alkyl group, or an unsubstituted phenyl group,
Represents a thienyl group. ] The following formula [′] is characterized by subjecting the tetrahydroacylated indole derivative represented by to a dehydrogenation reaction. [In the formula, R ₁ ′, R ₂ , R ₃ , R ₄ and φ are the same as defined in the above formula []. ] A method for producing an acylated indole derivative represented by: 5 The following formula [′] [In the formula, R ₁ ″ represents an acetyl group, R ₂ represents a hydrogen atom or a methyl group, and R ₃ and R ₄ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group. φ represents a phenyl group or thienyl group substituted with a halogen atom or a lower alkyl group, or unsubstituted.] The tetrahydroacylated indole derivative represented by is subjected to a dehydrogenation reaction, and then hydrolyzed. The following formula [″] [In the formula, R ₂ , R ₃ , R ₄ and φ are the same as defined in the above formula [′]. ] A method for producing an acylated indole derivative represented by: 6 The following formula [] [In the formula, R ₁ ′ is a hydrogen atom, a lower alkyl group, or an acetyl group, R ₂ ′ is a hydrogen atom or a methyl group, R ₃ ,
R ₄ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. φ' represents a phenyl group or a thienyl group. ] A platelet aggregation inhibitor comprising an effective amount of an acylated indole derivative represented by the following formula and a pharmaceutically acceptable carrier.