JPH0647574B2 - Novel acylindole derivative and platelet aggregation inhibitor containing the compound as an active ingredient - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel acylindole derivative and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient.

(Prior Art) Recently, various thrombi, particularly cerebral thrombosis, cerebral infarction due to cerebral occlusion,
Ischemic heart disease has become a serious medical and social problem as a seriously life-threatening disease, and studies on drugs for preventing or treating it have been actively conducted.
The inventors of the present invention have searched for a drug effective for the prevention and treatment of these thrombus, embolus, and various lesions caused by these, and among them, the acylindole derivative of the present invention has an excellent inhibitory effect on platelet aggregation and is low in activity. The present invention has been completed by finding that it is toxic and useful as a medicine.

(Problems to be Solved by the Invention) An object of the present invention is to provide a novel acylindole derivative and a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition containing the compound as an active ingredient. is there.

(Means for Solving Problems) The acylindole derivative of the present invention is a compound represented by the following general formula (I).

R ₁ is hydrogen, and R ₂ is a linear or branched lower alkyl group having 1 to 5, preferably 1 to 3 carbon atoms substituted with a hydroxyl group, for example, hydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxy. It represents propyl, trihydroxypropyl, hydroxybutyl, dihydroxybutyl, trihydroxybutyl, tetrahydroxybutyl or the like.

Among the compounds of the present invention, particularly preferable compounds are as follows.

3- [P- (2-hydroxyethoxy) benzoyl] indole 3- [p- (2,3-dihydroxypropoxy) benzoyl] indole 3- [p- (3-hydroxypropoxy) benzoyl]
Indole The compound of the present invention can be synthesized by a conventional method, for example, by introducing an acyl group into indole.

When introducing an acyl group, (1) a Grignard reagent is reacted with the indole, and then an acid chloride corresponding to the acyl group of the target compound is appropriately heated in an inert solvent for 1 to several hours to react. 2) A method in which phosphorus oxychloride is used to appropriately heat an amide compound corresponding to the acyl group of the target compound for 1 to several hours for reaction.

Further, the obtained acylindole compound can be converted into another acylindole derivative of the present invention by using a usual acylation reaction, alkylation reaction, deacylation reaction and dealkylation reaction. That is, for example, (1) alcohols, anhydrous solvents such as dimethylformamide or water, inert solvents such as alcohols or mixed solvents thereof, in the presence of a base such as sodium alkoxide or sodium hydroxide, potassium hydroxide, the purpose Reaction with a halogenated alkane or halogenated hydroxyalkane corresponding to the alkyl group or hydroxyalkyl group of the compound by heating at room temperature to appropriate temperature, (2) Corresponding to the hydroxyalkyl group of the target compound in the presence of an acid in a water solvent The target compound can be obtained by carrying out a normal alkylation reaction such as a method of reacting with an aldehyde to be heated at room temperature or appropriately.

Further, the desired compound can be obtained by heating a carboxylic acid corresponding to the acyl group of the target compound or an acid anhydride thereof in the presence of a suitable acid or base catalyst in an inert solvent at room temperature to appropriate temperature.

The acylindole derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the general formula (I), and examples thereof include alkali metals such as lithium, sodium and potassium,
Examples thereof include alkaline earth metals such as calcium and magnesium, other metal salts with aluminum and the like, or salts with organic bases such as ammonia, trimethylamine, triethylamine and tris (hydroxymethyl) aminomethane.

The pharmaceutically acceptable salt contained in the present invention can be produced from the free acylindole derivative of the present invention or converted into each other by a known method.

The compound of the present invention may be administered in a free form or in the form of a suitable pharmaceutically acceptable salt, and may be used alone or in combination with other pharmaceutically active ingredients.

The compound of the present invention can be formulated by ordinary methods for oral or parenteral administration in combination with a suitable pharmaceutical carrier or diluent, for example, tablets, capsules,
It can be made into a dosage form such as powder, granules, powder, liquid, suppository, injection and the like.

As a preparation for oral administration, as it is or as a suitable additive,
For example, together with conventional excipients such as lactose, mannitol, corn starch, potato starch, etc., crystalline cellulose, cellulose derivatives, gum arabic, corn starch, binders such as gelatin, corn starch,
Tablets, powders, granules or capsules by appropriately combining disintegrating agents such as potato starch and sodium carboxymethyl cellulose, lubricants such as talc and magnesium stearate, and other fillers, wetting agents, buffers, preservatives, and flavors. It can be an agent.

The injection may be an aqueous solvent or a non-aqueous solvent, for example, distilled water for injection, physiological saline, Ringer's solution, vegetable oil, a synthetic fatty acid glyceride, a higher fatty acid ester, a solution or suspension of propylene glycol, etc. If necessary, commonly used additives such as a solubilizing agent and a tonicity agent may be added.

The acylindole derivative of the present invention can be appropriately used according to the target disease, administration route, etc., but usually 1 to 4000 mg for oral administration per day for an adult, or 1 to 4000 mg for parenteral administration (injection), It can be administered at a dose level of 3 to 1/10.

(Examples) Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1. To 7 g of 3- (p-hydroxybenzoyl) indole
1.44 g of sodium hydroxide was added, and this was dissolved in 200 ml of a mixed solvent of ethanol and water (ethanol: water = 1: 1). To this solution was added 2.85 g of 2-chloroethanol and refluxed in an oil bath for 3 hours. Then, the solvent was concentrated to dryness, extracted with water-ethyl acetate, and the obtained organic layer was subjected to silica gel column chromatography to obtain a crude product. This was recrystallized from ethyl acetate to give 3- [p-
White needle crystals of (2-hydroxyethoxy) benzoyl] indole (Compound 1) were obtained in a yield of 54%.

mp: 196-197 ° C IR (KBr): 3250, 2925, 1600, 1590, 1422 cm ^-1 NMR (DMSO-d ₆ ): δ = 3.76 (dt, 2H, J ₁ = 4.8Hz, J ₂ = 4.8Hz) ,
4.09 (t, 2H, J = 4.8Hz), 4.93 (t, 1H, J = 4.8Hz), 7.07 (d, 2H,
J = 8.7Hz), 7.2-7.3 (m, 2H), 7.51 (dd, 1H, J ₁ ＝ 1.5Hz, J ₂ ＝
6.8Hz), 7.79 (d, 2H, J = 8.7Hz), 7.94 (s, 1H), 8.21 (dd, 1H, J
₁ = 1.5 Hz, J ₂ = 6.8 Hz), 12.00 (brs, 1H) MS: M ⁺ ; 281 m / z; 264,236,144,116 Example 2. To 11 g of 3- (p-hydroxybenzoyl) indole
7.43 g sodium hydroxide was added and this was dissolved in 10 ml water. To this solution was added 20.51 g of 3-chloro-1,2-propanediol, and the mixture was refluxed for 3 hours in an oil bath with stirring. The reaction solution was cooled and then concentrated to dryness, and the residue was purified by silica gel column chromatography. Recrystallization using ethyl acetate gave white crystals of 3- [p- (2,3-dihydroxypropoxy) benzoyl] indole (Compound 2) in a yield of 13.8%.

mp: 178-180 ° C IR (KBr): 3350,3160,1600,1438,1244cm ^-1 NMR (DMSO-d ₆ ): δ = 3.47 (dd, 2H, J ₁ = 5.5Hz, J ₂ = 5.5Hz) ,
3.83 (m, 1H), 3.95 (dd, 1H, J ₁ = 6.2Hz, J ₂ = 10.3Hz), 4.10 (d
d, 1H, J ₁ = 4.4Hz, J ₂ = 10.3Hz), 4.72 (t, 1H, J = 5.5Hz), 5.0
2 (d, 1H, J = 5.2Hz), 7.07 (d, 2H, J = 8.7Hz), 7.1-7.3 (m, 2
H), 7.51 (dd, 1H, J ₁ = 1.5Hz, J ₂ = 6.8Hz), 7.79 (d, 2H, J = 8.
7Hz), 7.94 (s, 1H), 8.21 (dd, 1H, J ₁ = 1.5Hz, J ₂ = 6.8Hz), 1
2.01 (brs, 1H) MS: M ⁺ ; 311 m / z; 237,181,144 Example 3. 5 g of 3- (p-hydroxybenzoyl) indole was dissolved in 50 ml of dimethylformamide containing 2.28 g of sodium methoxide. To this solution was added 4.0 g of 3-chloropropanol, and the mixture was stirred in an oil bath at 110 ° C for 3 hours. After cooling, the solution was refluxed and extracted by adding 100 ml of ethyl acetate and 50 ml of water. The obtained organic layer was concentrated and purified by silica gel chromatography. Each fraction was recrystallized from ethyl acetate to give white needle crystals of 3- [p- (3-hydroxypropoxy) benzoyl] indole (compound 3). ) Was obtained with a yield of 30.5%.

mp: 184-185 ° C IR (KBr): 3460,3440,3180,2860,1602,1258cm ^-1 NMR (DMSO-d ₆ ): δ = 1.91 (tt, 2H, J ₁ = 6.2Hz, J ₁ = 6.2 Hz),
3.59 (dt, 2H, J ₁ = 6.2Hz, J ₂ = 6.2Hz), 4.14 (t, 2H, J = 6.2H
z), 4.59 (t, 1H, J = 6.2Hz), 7.06 (d, 2H, J = 8.7Hz), 7.1-7.3
(m, 2H), 7.51 (dd, 1H, J ₁ = 1.5Hz, J ₂ = 7.0Hz), 7.79 (d, 2H, J
= 8.7Hz), 7.94 (s, 1H), 8.21 (dd, 1H, J ₁ = 1.5Hz, J ₂ = 7.0H
z), 12.00 (brs, 1H) MS: M ⁺ ; 295 m / z; 236,220,144,116,89 One example of the pharmaceutical composition of the present invention is shown below.

Example 1. Tablet composition Per tablet 50 mg compound of the present invention Lactose 130 mg Corn starch 60 mg Magnesium stearate 10 mg Total 250 mg The compound of the present invention, lactose and corn starch are uniformly mixed, kneaded with water and granulated by a granulator. After drying with warm air, magnesium stearate is added and mixed, and compressed with a tablet press.

Example 2. Capsule composition: 1 compound of the present invention 200 mg Lactose 120 mg Total 320 mg The ingredients are uniformly mixed and filled into a hard capsule.

(Action) Next, the pharmacological action of the compound of the present invention will be described.

(1) Acute toxicity A group of 5 ddY male mice fasted for 18 hours was used,
The test drug was orally administered at 4000 mg / kg.

The compounds of the present invention 1, 2 and 3 were used as test drugs, but none of them died.

(2) Platelet aggregation inhibitory effect 5 male Wistar rats per group (body weight 500-700 g)
Blood samples were collected from the abdominal aorta in the presence of sodium citrate under ether anesthesia. Platelet-rich plasma (PRP) was obtained from the supernatant obtained by centrifugation at 200 xg for 8 minutes. Further, platelet-poor plasma (PPP) was obtained from the supernatant after centrifugation at 1500 xg for 15 minutes.

The platelet agglutination reaction was followed by using an aggregometer, and 5 μ of the test drug solution was added to 450 μ of the PRP at 37 ° C. constant temperature and incubated for 1 minute, and then an aggregating agent was added. Collagen (final concentration 4 μg / ml) was used as a coagulant. The test drug was dissolved in DMSO (dimethyl sulfoxide).

An example of the results is shown in Table 1.

(Effect of the invention) As is clear from the above results, the compound of the present invention has low toxicity and inhibits the aggregation of platelets by collagen.
As a preventive or therapeutic agent for various thrombosis caused by platelet aggregation, cerebrovascular disorder, arteriosclerosis, ischemic heart disease (myocardial infarction, coronary atherosclerosis), venous thrombosis, etc., or thrombotic disorder during hemodialysis It is useful as a prophylactic or therapeutic agent for, and an inhibitor of platelet aggregation on the blood vessel wall during or after surgery.

 ─────────────────────────────────────────────────── --Continued from the front page (56) Reference JP-A-57-4972 (JP, A) JP-A-56-83472 (JP, A) JP-A-56-63960 (JP, A) JP-A-60- 72861 (JP, A)

Claims (2)

[Claims] 1. An acylindole derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. [Wherein R ₁ is hydrogen and R ₂ is a hydroxyl group-substituted carbon atom 1
To 5 lower alkyl groups, and the —OR ₂ group is in the o-position or the p-position. ] 2. A platelet aggregation inhibitor containing an acylindole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. [Wherein R ₁ is hydrogen and R ₂ is a hydroxyl group-substituted carbon atom 1
To 5 lower alkyl groups, and the —OR ₂ group is in the o-position or the p-position. ]