JP2851117B2 - Indole derivatives and anti-ulcer drugs containing them as active ingredients - Google Patents

Description

The present invention relates to a novel indole derivative, an addition salt thereof with a pharmacologically acceptable acid, and an antiulcer drug containing them as an active ingredient.

(Prior art) At present, many drugs used as anti-ulcer drugs include gastric acid secretion inhibitors represented by cimetidine and drugs having a gastrointestinal cell protective action, and these include symptoms of patients. It is used according to.

(Problems to be Solved by the Invention) However, many side effects have been reported for these known drugs. For example, dimethidine, which is commonly used as a gastric acid secretion inhibitor, has problems such as gynecomastia and recurrence of ulcers after discontinuation of administration, and improvement is desired.

(Means for Solving the Problem) As described above, known drugs have a drawback such that the method of use is limited due to side effects. The present inventors have conducted intensive studies based on these findings, and as a result, have found that the following indole derivatives have a remarkable anti-ulcer effect, and have completed the present invention.

The present invention relates to a novel indole derivative represented by the following formula (I), and an addition salt thereof with a pharmacologically acceptable acid.

In the formulas, what is indicated by a wavy line means the isomer at that position, and all of these isomers are also related to the present invention.

It is shown in the test described below that the compound of the present invention represented by the formula (I) and the addition salt thereof with a pharmacologically acceptable acid show a gastric acid secretion inhibitory action. Therefore, the compound represented by the formula (I) can be expected to be useful as an anti-ulcer drug. Details of the physiological activity are described in the examples below.

The compound represented by the formula (I) of the present invention can be synthesized by any suitable method at the time of reaction condensation with the indole derivative represented by the formula (II) and the adimarin derivative represented by the formula (III). I can do it. Specific examples are as follows.

When a compound represented by the formula (II) and a compound represented by the formula (III) are bound in an organic solvent under an acid catalyst, the compound represented by the formula (I)
Is obtained.

As the acid used, an inorganic acid such as hydrochloric acid can be used, and as the solvent, an alcoholic solvent such as methanol can be used. As the reaction conditions, a temperature range of 0 to 100 ° C. can be used, but the reflux temperature of the solvent is preferable. Purification can be performed using a known method such as chromatography.

The compound represented by the formula (II) as a raw material is prepared by using a tetrahydrocarboline derivative represented by the formula (IV) as a raw material in a known manner (Pharmaceutical Magazine, 97 (3), 309-319, Shinichiro Sakai, etc.)
Can be synthesized.

On the other hand, the raw material adimarin derivative represented by the formula (III) can be obtained by the method of Sakai et al. (Chem. Pharm. Bull. 21 (8) 1783-
(1973)) from the compound of formula (V)
Methylation, for example, by reaction with chloroformate, followed by reduction with lithium aluminum hydride.

The compound represented by formula (I) of the present invention can be converted into an addition salt with a pharmacologically acceptable acid if desired, and these acid addition salts are also included in the scope of the present invention. . Examples of the acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acetic acid, succinic acid, butyric acid, oxalic acid, malic acid, fumaric acid, maleic acid, stearic acid, and citrate. Salts of organic acids such as acid, tartaric acid, lactic acid and the like can be mentioned.

When the compound represented by the general formula (I) is applied to the use as a medicine, it can be formulated into various dosage forms. That is, the formulations can be administered orally in the form of tablets, dragees, hard capsules, soft capsules, solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of an injection solution. In preparing these preparations, well-known additives for preparation such as excipients, stabilizers, preservatives, dissolving agents, wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, flavoring agents, The preparation can be prepared by adding a tonicity adjusting agent, a buffer, an antioxidant and the like.

The method of administration of the anti-ulcer drug of the present invention is not particularly limited, and is appropriately selected depending on the form of the preparation, the sex of the patient, and the degree of the disease, but the daily dose of the active ingredient is preferably 1 mg to 1 mg. 2000 mg.

The cytotoxicity (IC ₅₀ against KB cells) of the compound represented by the formula (I) is 1.5 μg / ml.

Hereinafter, the present invention will be described in more detail by way of examples, which merely illustrate the present invention.
The description of the examples does not limit the present invention in any way.

Example 1 Synthesis of Compound of Formula (I) 100 mg of an indole derivative of the formula (II) and 94 mg of an adimarin derivative of the formula (III) in 10 m of a methanol solution containing 1.5% hydrochloric acid.
The mixture was refluxed under an argon atmosphere for 1.5 hours. 40 ml of water was added to the reaction solution, neutralized with potassium carbonate, and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over sodium sulfate and evaporated. The residue was purified by an alumina column to obtain 63 mg of Compound A flowing out first and 76 mg of Compound B flowing out later.

Compounds A and B obtained as described above were epimers at the C-3 position of the broken line shown in formula (I).

Compound A UV (nm, methanol) 211, 256, 288 (sh), 294.5 IR (cm ^-1 , chloroform) 3450, 3410, 1680, 1620 MASS (m / z,%) 620 (M ⁺ , 100%), 475 (19) , 322
(5) NMR (δ, CDCl ₃ ) 8.12 (1H), 7.42 (1H, m), 7.20-6.
95 (3H, m), 6.92 (1H, s), 6.18 (1H, s), 5.20 (1H, q),
4.40−3.90 (3H, br), 3.77 (3H, s), 2.60 (3H, s), 1.60
(3H, d) [a] ^D +60.3 degrees (c = 0.625%, 26 ° C, CHCl ₃ ) Compound B Melting point 214-217 ° C (crystallized from acetone) UV (nm, methanol) 211, 256.5, 287.5 (sh) , 294 IR (cm ^-1 , chloroform) 3330,1660,1615 MASS (m / z,%) 620 (M ⁺ , 100%), 475 (17), 322
(5) NMR (δ, CDCl ₃ ) 8.28 (1H), 7.44 (1H, m), 7.20-6.
96 (3H, m), 6.92 (1H, s), 6.23 (1H, s), 5.20 (1H, d),
4.40−4.00 (3H, br), 3.81 (3H, s), 2.61 (3H, s), 1.62
(3H, d) [a] ^D -18.3 degrees (c = 0.869%, 27 ° C., CHCl ₃ ) Production Example 1 Synthesis of compound of formula (III) To a pyridine solution of 2.84 g of compound of formula (V) was added chlorocarbonic acid. 5 g of ethyl was added, and the mixture was stirred at room temperature for 6 hours. After evaporating the solvent, chloroform was added, and the mixture was washed with an aqueous ammonia solution, dried over sodium sulfate, and evaporated. Purification by a silica gel column gave 2.87 g of compound (VI).

IR (cm ^-1 , CHCl ₃ ) 1700 UV (nm, ethanol) 214,244,291,296 Lithium aluminum hydride (2.863 g) in a dry tetrahydrofuran solution of 2.86 g of compound (VI) under ice-cooling
, And the mixture was heated under reflux for 4.5 hours. After purification by a silica gel column, tetrahydrofuran and n-
Recrystallized from a mixture of hexanes to give 1.38 g of compound (III)
I got

Melting point 136-138 ° C UV (nm, ethanol) 251,298 Next, the effect of the antiulcer drug of the present invention will be described.

It was measured as follows using H ⁺ / K ⁺ ATPase were prepared from Example 2 H ⁺ / K ⁺ ATPase inhibitory activity Porcine.

H ⁺ / K ⁺ ATPase diluted solution 100μ (50μ as protein amount)
g) containing 4 mM magnesium chloride, 20 mM potassium chloride
0 mM Pipes-Tris (pH 6.2) buffer (440 μl), and a 0.1% ethanol solution of aidierythin 5
μ was added. 5 μm of dimethyl sulfoxide was added thereto, and the mixture was incubated at 37 ° C. for 30 minutes. Then 4m
10 mM Pipes-Tris buffer 4 containing disodium M ATP
The reaction was started by adding 50μ, and after 30 minutes, the reaction was stopped by adding 0.1 ml of 50% trichloroacetic acid. The amount of free phosphoric acid generated by this reaction was determined by the method of D. Lebel, G. Poirier et al. (Anal. Bio
chem.85,86~89,1978) by performing color measurement of 800nm by, was the reading of the absorbance at this time is C _1. Alternatively the absence of added potassium chloride be measured in the same manner, I was reading the absorbance at this and C _2.

Inhibition activity was measured in the above reaction by adding 5 μl of a dimethyl sulfoxide solution containing a 20 mg / ml inhibitor instead of dimethyl sulfoxide and performing the same operation, with or without potassium chloride. The absorbance readings were taken as T ₁ and T ₂ respectively.

The percent inhibition (I) of the inhibitor is calculated by the following formula:

I = [(C ₁ -C ₂ )-(T ₁ -T ₂ )] × 100 / (C ₁ -C ₂ ) Test compound H ⁺ / K ⁺ ATPase inhibition rate (%) Compound A 100 Compound B 100

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Toshihiro Takahashi 1-25-25 Kishicho, Kawagoe-shi, Saitama 53 (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 519/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. An indole derivative represented by the following formula (I) and an addition salt thereof with a pharmacologically acceptable acid. 2. An indole derivative represented by the formula (I):
Or an anti-ulcer drug comprising as an active ingredient an addition salt thereof with a pharmacologically acceptable acid.