JPS5852218A - Analgesic, antipyretic and anti-inflammatory agent - Google Patents

Abstract

PURPOSE:The titled drug, prepared by incorporating 1-(4-chlorobenzoyl)-5-methoxy- 2-methylindole-3-acetic acid with another specific compound having the analgesic, antipyretic and anti-inflammatory action, and capable of inhibiting the development of side effects without reducing the main action. CONSTITUTION:An analgesic, antipyretic and anti-inflammatory agent, prepared by incorporating (A) 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid with one of (B) 2-(4-isobutylphenyl)propionic acid or (C) 4-phenoxy-1-indanecarboxylic acid or (D) 5-cyclohexyl-1-indanecarboxylic acid. The component (A) has improved analgesic, antipyretic and anti-inflammatory action, but there is a difficulty in side effects, e.g. gastrointestinal disorder. The incorporation of one of the components (B)-(D) permits the inhibition of the side effects without reducing the main action. The mixing molar ratios are suitably as follows: (A):(B)=1: (0.5-15), (A):(C)=0.1-6 and (A):(D)=1:(0.1-12).

Description

[Detailed description of the invention] The present invention relates to a novel analgesic, antipyretic, and antiinflammatory agent.

Commercially available 1-(4-chlorobency A/)-5-methoxy V
-2-methymu-indo*-a-acetic acid has excellent antipyretic, antipyretic, and antiinflammatory effects, but on the other hand, it may cause gastrointestinal disorders as a side effect, which is one of the difficulties in clinical use. .

As a result of careful consideration in view of the above drawbacks, the present inventors found that 1-C
By combining other specific analgesic, antipyretic, and anti-inflammatory compounds with 4-chlorobenzoyl)-5-methoxy-2-methylindo-A/-8-acetic acid, side effects can be reduced without attenuating the main effects. The present invention was completed based on the knowledge that the expression can be significantly suppressed. In other words, the present invention is based on
&/)-5-methoxy-2-methylindole-8-acetic acid and (tl 2-(4-isobutylphenyfi/)propionic acid, 4-phenoxy-1-indanecarboxylic acid and 5-cyclohexylL/-1-indanecarboxylic acid) An analgesic agent containing a type selected from the group consisting of μ-bonic acid.
It is an antipyretic and anti-inflammatory agent.

In the present invention! -(4-chlorobenzo41k)-6-
Medoxy 2-methylindo-/I/-a-6 acid (indomethacin) (hereinafter also referred to as four components) and 2-(4-isoguti p-pheni-14/)propionic acid, 4
-Phenoxy-1-indanecarboxylic acid and 6-cyclohexS/A/-1-indanecarboxylic acid (sometimes referred to as a filling ingredient) can be used alone to provide analgesic and It is a known compound that has antipyretic and antiinflammatory effects.

In the present invention, the blending ratio of component (a) and component (a) is high, the u ratio is agh:m-1: 0.1 to 20, and the (a) component is 10 pion of 2-(4-isobutylphenyl). When using an acid, preferably Hiroga)-1-1-〇, 5~
15 (molar ratio), more preferably 1:1 to 2 (molar ratio). 4-phenokiv-1- as the nine (to) component
When indancarboxylic acid is used, it is preferable.
-1:0.1 to 6 (molar ratio), more preferably 1
:0.5 to 2 (molar ratio)〉, and when using 5y chlorohexyl A/-1,-indanecarboxylic acid as the component, preferably 2):(t)=l:0.1 to 12 (molar ratio) ratio)
, more preferably (f):(t)-1:0.2-8(
molar ratio].

The effects of the analgesic, antipyretic, and anti-inflammatory agent of the present invention (hereinafter also referred to as the combination drug of the present invention) will be shown based on experimental results.

Experiment @ J1 (Anti-inflammatory effect by carrageenan edema method) Jc
Using six lHSD rats (male, body weight 180-2201) per group, Winter et al.
) 0.05 ml of 1% cafgenin saline solution was injected subcutaneously into the leg. The hindlimb volume 8 hours after cuffgenin injection and the pre-injection volume were measured, and the edema volume was calculated from the difference. The edema volume of the non-treated group (control μ) and the treated group was compared to determine the edema suppression rate.

1) Winter, C.A., R15ley, E.
,A,andMaqs,G,-vV,,Proc
, Soc, exp, Biol.

Med, 111.544 (1962) Test compound 1-(4-chlorobenzoia 1/)-5-methoxy-2-methylindo-IV-a-acetic acid 2-(4-isobutyp)ni/L /) Propionic acid ■ 4-phenoquine-1-indanecarboxylic acid ■ 5-
Vep qHexyl-1-indankaponic acid From the above i6 table, 1-(4-chlorobenzyp)-6-medoxy2-methylindole-21-IN=acid and 2-
(4-Isoptylpheny/I/)propionic acid.

4-phenoxy-1-indanecarboxylic acid and 5
1-(4
-Chlorobenzy/I/)-5-methoxyv-g-methylindo-A/-8-# It was observed that the anti-inflammatory effect was slightly increased compared to acid alone.

Experimental Example 2 (Ulcerogenic effect) Jcl; SD flat male, weight 180-170f) 1
The sample was orally administered to a group of 6 animals. Six hours after ulcer formation reached its peak in the jejunum and ileum, the digestive tract from the stomach to the colon was removed, and the number and size of ulcers on the mucosal surface were visually measured. The ulcer area is calculated from the size and number of ulcers, and the total ulcer area per animal is expressed as g112.

From the above table, 1-(4-chlorobency-)-5-methoxy-2-methylindole-8-acetic acid and 2-(4-isobutylphenefi/)propionic acid.

When used in combination with one selected from the group consisting of 4-phenoxy-1-indanecarboxylic acid and 5-cyclohexy)v-1-indanecarboxylic acid, titP(4-rirobenzoyfi/)-6-medoxy sy-g=Methi〃Indole-8-# Formation of ulcers is less than that of acid alone, and it is clear that it has an inhibitory effect on ulcer formation.

As shown in the above experimental examples, the combination preparation of the present invention exhibits excellent anti-inflammatory effects with less ulcer formation in rats;
For example, it can be preferably used as an analgesic, antipyretic, and antiinflammatory agent for mammals such as humans, mice, rats, rabbits, dogs, monkeys, horses, and cows.

The formulation of the present invention usually combines the above-mentioned ingredients with a pharmaceutically acceptable carrier, excipient, and binder.

Mix with diluent, for example, granules, powder, 1 tablet.

Hard capsules, soft capsules, syrups, skewers.

It is administered orally or parenterally as an injection.

Even if it is a powder, 1 tablet of granules, or 7 hard turnips.

Orally administered dosage forms such as soft capsules and syrups can be prepared by known methods using carriers, excipients, binders, diluents, etc. that are conveniently used in formulations. Preferred carriers, excipients, binders, and diluents include, for example, starch, sugar, and magnesium stearate. When preparing soft capsules, for example, pharmacologically acceptable animal oils, vegetable oils, mineral oils, etc. are used as excipients, and the active ingredients (the above-mentioned ingredients) are dissolved in these oils and fats. The soft capsule/L' is filled.

Dosage forms administered parenterally include injections and skewers. Injections may be solutions or suspensions. 1-(4-chlorobency/L/)-5-methoxy-2-methylindo-/%/ used in the formulation of the present invention
-8- Acetic acid is added to water @jl! Therefore, it is recommended to use a solubilizer to prepare an aqueous injection. The skewers can be prepared by mixing the active ingredient with a crude drug base such as medium-chain or higher fatty acid triglycephyte or polyethylene glycol, and then molding the mixture.

The combination preparation of the present invention varies depending on the type of disease, symptoms, administration method, etc., but when used orally or as a skewer, it contains 1 l-(4-chlorobenzoyl) per day for an adult.
-5-methoxy-2-methylindo-μm8-# acid is 2
6-225111 preferably 5O-1251sI, 2-
(4-I V1f14yy en/l/) propionic acid is 1
5-60G”F, preferably 80-25011%F%4
-phenoxy -1-indanecarboxylic acid is 8 to 250
IIv, preferably 16-1201F%6-V chlorohexyA/-1-indanecarboxylic acid is 15-600WI/
I, preferably within the range of tiao to 260 Da.

Jcl: SD foot ← 5 weeks old 9 weight 120-160f)
The combination drug of the present invention 1-(4-chlorobency 1v)-6-medoxy 2-methylindo-1v-8- was administered to 6 animals per group.
#Acid lO drops/toge and 2-(4-isobuty~phenyfi
/) Propionic acid 201117 kQt
-Indancarboxylic acid 10 da/phantom; ■1-(4-chlorobency*)-5-methquine-2-methylindo-A/
10 Iq/kg of -8-# acid and 20 q/kg of 5-cyclohexyl-1-indanecarboxylic acid were administered orally, but no deaths were observed in either case even one week after administration.

Example 1 (Capsule) 1-(4-chlorobency A')-5-methoxy-2-
Methi μ ind-, A'-a-# acid 26 IF2
- (4-,isobutylphenyl)propionic acid 60
IF Microcrystalline Se, 4/Loin 80 ■Fuctose 57 #needle
16G Misaki The above ingredients are mixed according to a conventional method and filled into Zeftin capsules to form capsules.

Example 2 (Tablet) 1-(4-chlorobenzoyl)-6-medquin-2-methylindo-A/-8-acetic acid 26 wv4-phenoxy-1-indanecarboxylic acid 25 wjI Fuctose 44 1g starch 1106W starch (paste production ) 51q Magnesium stearate 04wg4wg
carboxymethyl cellulose sium salt itt
' 155 IIv Joki, 1st edition Combine the ingredients and make into tablets according to the usual method.

Example 8 (Soft capsule) 1-(4-chlorobenzoyl)-6-medoxy 2-methylindo-1%/-a-m acid 25 g #I5-
Cyclohexyl-1-indanka! Bonic acid: 50 Da Total: 186 Da Mix the above ingredients to make a solution, and fill it into a 7μ soft turnip according to a conventional method.

Example 4 (Skewer) l-(4-chloropensy/L')-5-methoxy-2
-Methylindo-1v-8-acetic acid 60 #2-(4-
iso1 tylphenyl A/) propionic acid 100 triglyceph needles of saturated fatty acids with a prime number of 11 to 17
1500 11' The above ingredients are mixed and shaped into skewers according to a conventional method.

Claims (1)

[Claims] 4 1-(4-chlorobency*)-5-meyxy2
-Mef~India-/L/-B-Hp acid and (t) 2-(
4-Isoguti p-pheni/L/) propionic acid, 4-phenoki V-! An analgesic, antipyretic, and anti-inflammatory agent containing 9 types selected from the group consisting of -indan-ponic acid and 5-cyclohexyl-1-indancarbonic acid.