JPS60152462A - Production of indolacetic acid amide derivative - Google Patents

Abstract

PURPOSE:A thiazolidine thione derivative is used as a starting material and subjected to condensation reaction with L-glutamine to achieve high-yield production of the titled compound with anti-inflammatory action and low toxicity. CONSTITUTION:The condensation reaction between a thiazoline thion derivative of formula I and L-glutamine is conducted, preferably in aqueous tetrahydrofuran in the presence of trialkylamine to give a compound of formula II. The trialkylamine is preferably triethylamine or tibutylamine. It has remarkably reduced toxicity in comparison with a non-steroidal anti-inflammatory, indomethacin.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Background of the Invention The present invention relates to a method for producing indole acetate amide derivatives.

Indomethacin is widely used in medicine as a non-steroidal anti-inflammatory drug. However, indomethacin is known to have side effects such as ulcer formation and abdominal pain.Furthermore, indomethacin is a highly toxic compound with an LDSo value of approximately 30■/Q in an acute toxicity test in rats. Are known.

The indole acetic acid amide represented by the formula (,1) (hereinafter blank) related to the present invention is a compound known in the literature [5 out Taehakkyo Yakhak Non
munj ip) 5.67 (1980)).

The indole acetate chloride derivative represented by the following formula ([[I), which is based on this document, is easily decomposed in water. The yield of the indole acetate amide derivative represented by formula (0) is generally low. Furthermore, the anti-inflammatory effect and toxicity of the indole acetate amide derivative represented by the formula (It) have not yet been confirmed.

Under these circumstances, the present inventors have conducted intensive research on the industrial production method, anti-inflammatory effect, and toxicity of indole acetic acid amide represented by the above formula (It), and as a result, have developed a production method with a higher yield. Surprisingly, we discovered that the above formula (
The present invention was achieved by discovering that the indole acetate amide derivative represented by II) has significantly reduced toxicity compared to indomethacin.

(2) Purpose of the Invention As mentioned above, the object of the present invention is to obtain an indole acetic acid amide derivative having an anti-inflammatory effect and low toxicity in a high yield.

■ Detailed description of the invention In order to achieve this purpose, The present invention Formula (1).

A method for producing an indole acetate amide derivative represented by formula 01), which comprises condensing a thiazolidinethione derivative represented by L with L-glutamine. It is preferable to carry out the condensation reaction in the presence of a trialkylamine in order to obtain a high yield.

By condensing the thiazolidinethione derivative (1) of the present invention represented by the formula (1) with L-glutamine in the presence of a trialkylamine in aqueous tetrahydrofuran, the desired formula 1 can be obtained in an extremely high yield. ) can be obtained. As the trialkylamine, triethylamine, tributylamine, etc. are preferred.

In order to test toxicity, we conducted a 3-week daily oral administration test using rats, and found that indomethacin 10w9/K
In the case of f administration, the gold side died in 5 days, whereas in the case of the above formula 〇l
Even when the indole acetic acid amide derivative represented by ) was administered in an equimolar amount, that is, 13.5~/Kf, no gastric ulcer formation was observed at all, and it was confirmed that the safety thereof was extremely high.

The indole acetate amide derivative represented by the formula (fl) of the present invention is used as an anti-inflammatory agent, and may be administered either orally or parenterally, and the dosage is 30 to 750 per day for adults in the case of oral administration. m9, 10~ for external use
600 beats/day is preferred.

Preferred forms for oral administration of the compounds of the invention include tablets,
Examples include granules, powders, syrups, and capsules. These preparations can be mixed with a pharmaceutical carrier or excipient and prepared by a conventional method. Examples of carriers or excipients are starch, lactose, crystalline cellulose, mannitol.

Examples include magnesium stearate, Merck, etc.Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example Under an argon atmosphere, L-glutamine 176 #v (1,20 mmol) was added to a solution of 500 ml (1,09 mmol) of indomethacin thiazolidine thionamide dissolved in tetrahydrofuran (5 units) in water (5 mA).
[The dissolved solution was added at room temperature. Subsequently, 0.23 ml (1.65 mmo) of triethylamine was added, and the mixture was reacted at room temperature for 90 minutes. Add 5 m of water to this reaction mixture.
! was added and further acidified with -0.5N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water until the washing water became neutral. The precipitate collected by filtration was dried under reduced pressure in a desiccator to obtain crude product 41.
I got 0~. This crude product was recrystallized from ethanol,
The desired indomethacin L-glutamine amide (379) could be obtained in high yield. The physicochemical data of this product are shown below.

I]'E'ga; Tori: 3440.3340.174
5.1660.1600.

530'HNMR (C5DsN) δ (Ppm): 2.4
4 (3H, s), 3.82 (3H.

s) , 4.01 (2H, s) , 6.86 (IH, d
d, J-9, 0, 2, 4Hz), 7.22 (IH, d,
J=9.0Hz).

7.48 (2H, bd, J=8.3Hz),
7.69 (2H.

ba, J=8.3. H7) mass m/e: 467 (dehydration peak),
312, 139, 111 Test Examples Male Wistar-Lewis rats (Wi
ster Lewisrat) in a group of 8 animals, antigen solution was injected under the skin of the right hind paw.
um) 100 rrQ is suspended in 8.3-ml liquid paraffin and 50μ of the preparation is injected. Indomethacin L produced in the example at a rate of once a day for 20 days the next day.
- Glutaminamide 1% Tween 8Q ('l'w
een 80) It was suspended in an aqueous solution and administered orally.

The edema volume 20 days after the administration of the antigen solution was measured using a volume measuring device, and compared with the control group (1% Tween 80 aqueous solution administration group) to determine the edema suppression rate. The results are shown in Table 1.

Toxicity tests were conducted in groups of six male Wistar-Lewis rats. When indomethacin was administered at 10 μ/Ky (2s mmol/Kg) every day, all patients died due to gastric ulcer within 5 days, whereas indomethacin monoglutamine amide produced in the example was administered at 13.5 μ/Ky (28 mmol/Kg) every day. It was found that the toxicity was extremely low, with no gastric ulcers occurring even after administration for 21 days.

(2) Specific effects of the invention As described above, according to the present invention, the thiazolidinethione derivative represented by the formula (1) is converted into L-
Since it is condensed with glutamine, an indole acetic acid amide derivative having anti-inflammatory action and low toxicity can be obtained in high yield. Furthermore, by carrying out the condensation reaction in the presence of a trialkylamine, the indole acetate amide derivative can be obtained in a higher yield.

Patent applicant: Terumo Corporation

Claims (2)

[Claims] (1) A method for producing an indoleacetamide derivative represented by formula (It), which comprises condensing a thiazolidinethione derivative represented by formula (1) with L-glutamine. (2) The method for producing an indole acetate amide derivative according to claim 41, wherein the condensation reaction is carried out in the presence of a trialkylamine.