JPH03118319A - Antiphlogistics, agent for suppressing secretion of gastric juice or agent for suppressing production of active oxygen - Google Patents

Abstract

PURPOSE:To obtain the title suppressing agent containing a specific compound such as (R)-2-amino-3-hydroxypropaue sulfonic acid (D-cystenolic acid) as an active ingredient, having excellent antiinflammatory action, action for suppressing secretion of gastric juice and capable of orally administrating. CONSTITUTION:The aimed suppressing agent containing a compound [e.g. (R)-2- amino-3-sulfopropanoic acid (cysteic acid) or 2-aminoethanesulfonic acid (taurine), etc.] expressed by formula l (R1 is mercapto, sulfo or group expressed by formu la II; R2 is H or methyl; or a compound expressed by formula I may form a cyclic compound expressed by formula III by combining R1 with R2; R3 is H, alkyl, hydroxyalkyl or carboxyl) or salt thereof] as an active ingredient. When the suppressing agent is used, it is administered in a form of capsule, inhalant, injection, etc., using pharmaceutically acceptable ordinary carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an excellent anti-inflammatory agent, gastric juice secretion inhibitor, and active oxygen production inhibitor.

[Prior Art/Problems to be Solved by the Invention] As part of research on the utilization of marine organisms as pharmaceutical resources, D-cystenolic acid (Cys-Oll) derived from seafood has been found to have an inhibitory effect on platelet aggregation.

An object of the present invention is to provide new uses for related compounds using Cys-0)1 as a lead compound.

[Means to solve the problem]

The present inventors have repeatedly investigated the structure-activity relationship, pharmacological activity, and mechanism of this compound, and found that the following compound (1) has excellent anti-inflammatory effects, suppressive effects on gastric juice secretion, and suppressive effects on active oxygen production. The present invention was completed based on the discovery that the present invention has the following properties.

That is, the active ingredients of the anti-inflammatory agent, gastric juice secretion inhibitor, or active oxygen production inhibitor of the present invention are general 2R, -CH2-CH-
N H-R2(1)R3 (wherein, R1 is mercapto, sulfo, or the formula S-3-C
A group represented by H, -CH-NH23, R2 represents a hydrogen atom or methyl, and R and R2 are combined to form a cyclic compound represented by a compound represented by -form (1). and R3 represents a hydrogen atom, alkyl, hydroxyalkyl or carboxyl. ) [hereinafter referred to as compound (1)] or a salt thereof.

In this specification, alkyl (including alkyl in hydroxyalkyl) may be linear or branched, and is preferably C1-1 lower alkyl. Specific examples include methyl, ethyl, propyl, methyl, etc., with methyl being particularly preferred.

Note that the cyclic compound represented by formula (II) when R3 and R2 are combined corresponds to compound (1) itself.

The salts of the compound (I) of the present invention include pharmaceutically acceptable acid addition salts, such as mineral acid salts such as hydrochloride and sulfate, and organic acid salts such as acetate, citrate, and malate. etc.

Examples of the compound (1) and its salt include the following compounds.

・(R)-2-amino-3-hydroxypropanesulfonic acid (D-cystenolic acid) ・(R)-2-amino-3-sulfopropanoic acid (nesteic acid) ・2-aminoethanesulfonic acid (Clarin)・(1'1
)-2-amino-3-mercap 1-propatol (R)
-2-amino-3-mercaptopropanoic acid (cysteine) ・2-aminoethanethiol (cysteamine) (R) -
2-aminopropanethiol bis((R)-2-amino-3-hydroxypropyl)
Disulfide bisC(R)-2-amino-3-carboxyethyl]disulfide (cystine) ・Bis(2-aminoethyl)disulfide (ciscumin) ・Bis I:(R)-2-aminopropyl]disulfide ・(R) -thiazolidine-4-methanol・(R)-thiazolidine-4-carboxylic acid・thiazolidine・hydrochloride of the above compound Compound (1) and its salt, which are the active ingredients of the present invention, are substantially known compounds and are themselves Manufactured by known means.

[Action/Effect]

The compound (+) which is the active ingredient of the present invention and its salt are:
It has excellent anti-inflammatory effects, gastric juice secretion suppressing effects, and active oxygen production suppressing effects on mammals (humans, horses, dogs, mice, rats, etc.), and is an anti-inflammatory agent, gastric juice secretion suppressant, and active oxygen. It is excellent as a production inhibitor, especially as a therapeutic agent for gastrointestinal ulcers, etc.

The active ingredients of the invention are administered orally or parenterally in the form of a pharmaceutical formulation with suitable and conventional pharmaceutically acceptable carriers.

Pharmaceutical formulations may take the conventional forms such as capsules, powders, granules, syrups, tablets, injections and the like.

The dosage of Compound (1) and its salts, which are the active ingredients of the present invention, can vary depending on age, body weight, and/or the severity of the disease condition to be treated and response to treatment, and is usually administered by oral administration, for example. In the case of 1~1000m
g is administered once or over several times a day.

[Experimental example] Bis[(R)-2-aminopropyl]disulfide (Me-5S) according to the present invention was used as a sample to investigate the pharmacological activity and its mechanism on gastric juice secretion (rat pylorus ligation method) and inflammation (rat carrageenan foot). Radical scavenging (xanthine-xanthine oxidase-based cytochrome C reduction method) and active oxygen production (polymorphonuclear leukocyte luminol chemiluminescence method) Experimental gastric juice secretion suppressive effect It, 5hay, S, A, Komarov , G
astroenterology, 543 (194
The method described in 5) was followed. That is, the pyloric region of a former 5-tar male rat weighing 1.30 to 50 g, which had been fasted for 48 hours, was ligated, and the volume, total acidity, and total pepsin activity of the retained gastric fluid 4 hours later were measured. The total acidity is 0, 02 N N using phenoltskurein as an indicator.
a It was determined by OH neutralization titration, and the total Pepunun activity was 0.
It was determined according to the Anson method using 6% casein (Milk) as a substrate. Note that cystamine was used as a comparison sample. The sample was suspended in 5% gum arabic and administered intraperitoneally immediately after ligation.

Rat carrageenan footprint edema method: C, G, Vam Arman, Ha, J.
Begany, L.M., Miller H.H.
Pless, J., Pharmacol, Exp.
Ther,, 150°328 (1965):R,
Vinegar, W., 5chreiber, R.
Hug.

J, Pharmacol, Exp, Ther.
] 66, 96 (196B).

That is, the body weight after 12 hours of fasting was studied.

5D male rats weighing 120-150 g were used. Carrageenin (Picnin-A) is a 1% physiological saline solution,
This 0.1 heel was injected into the right hind paw, and at the same time, the same amount of physiological saline was injected into the left hind paw as a control. After the carrageenan injection, the volumes of the left and right paws were measured every hour until 7 hours, and the difference between them was calculated for each hour and expressed as an edema rate (%). Note that indomethacin was used as a comparison sample. Samples were suspended in 5% gum arabic and administered orally 1 hour before carrageenin injection or intraperitoneally 30 minutes before injection.

Polymorphonuclear leukocyte luminol chemiluminescence method (active oxygen production inhibition effect): M, Kudo, T, Nakamura, J,
Koyama, J., Biochem.

97, 1211 (1985): Minoru Nakano, Inflammation, 5 (4
), 277 (1985). That is, 12 hours fasted body weight 400-600 g Hartl
A 2% casein saline solution (1/10 volume of body weight) was intraperitoneally administered to Y-series male Mormonts, and the animals were bled to death 16 hours later, containing heparin (10 U/mfi) Hank's
Ba1anced 5altSolution (HB
The intraperitoneal cavity was washed with SS) to obtain a polymorphonuclear leukocyte suspension. The collected cell suspension was centrifuged at 4°C and 120 rpm for 5 minutes to precipitate the cells, and then diluted with 0.2% physiological saline for 30 minutes.
After hemolysis for a second, washing was performed to obtain a polymorphonuclear leukocyte suspension. 5 x 1067 polymorphonuclear leukocytes in a measurement cuvette
m1. IBSS (containing Luminol 20μM and analyte)
After standing at 37°C for 12 minutes, add phorbol myristate acetate (PMA) and N-formylmethionylleucylphenylalanine (FMLP) to a final concentration of 0.1 μg/mfl and 0.1 μM, respectively. Berthold MULTI-BIOLUMAT
Measured using LB9505C. Incidentally, superoxide diminutide (SOD) was used as a comparison sample.

The sample was dissolved in 1% DMSO and used.

Beef starchin-xanthine oxidase-based cytochrome C reduction method (radical scavenging action): J, M, McCord, 1. Fr1dovich
, J. Biol, Chem.

244, 6049 (1969). That is, 50 μM xanthine in the sample cell, 51! Add 50mM potassium-phosphate buffer containing M cytochrome C and the specimen - 0.1mM EDTA (pH 7,8),
After leaving at 25°C for 5 minutes, 0.025 U xanthine oxidase was added to reduce the increase in reduced cytochrome C by 55
Measured as increase in absorbance at 0 nm. Note that SOD was used as a comparison sample. The specimen was dissolved in 1% DMSO and used.

Suppressive effect on gastric juice secretion associated with acupuncture: Me-3S suppresses gastric juice secretion in pylorus-ligated rats by 10
Total pepsin activity in mg/kg, i, p, 25
mg/kg, i, p significantly suppressed gastric juice volume, total acidity, and total pepsin activity. In addition, Me
-Siscumin, the mother nucleus of 5S, is 25μ/kg, i
, p, was invalid (see Table 1).

Rat carrageenan foot P! Edema: 25 mg of Me-33 for carrageenan footprint edema
/kg, i, p, significantly suppressed edema from 2 to 5 hours. Furthermore, indomethacin used as a comparative control significantly suppressed edema from 2 to 7 hours at I Omg/kg, p, o (see Figure 1).

The numerical values in the figure indicate mean standard errors (N=8).

Polymorphonuclear leukocyte luminol chemiluminescence method (reactive oxygen production inhibitory effect): Me-3S showed an inhibition rate of 68% at a final concentration of 50 μM and 89% at 100 μM against active oxygen production by PMA, and the activity by FMLP was inhibited by FMLP. Regarding oxygen production, the inhibition rate was 94% at a final concentration of 50 μM and 98% at a final concentration of 100 μM. In addition, SOD used as a comparison control was 100 μg for active oxygen production by PMA or FMLP.
/ m9. showed a suppression rate of approximately 90% (Figures 2 and 3).
(see figure).

xanthine-xanthine oxidase system cytochrome C1
Original method (radical scavenging action): 02 produced from the xanthine-xandine oxidase system
-, Me-33 is 10,47M and 100
No radical scavenging effect was shown at μM (see Table 2).

(Leaving space below) Table 2 Effect of Me-3S on xanthine-xanthine oxidase-based cytochrome C reduction Sample concentration Reduction of cytochrome C 8) Inhibition rate も(mmol/mln) (χ) Control Me-5S 0D 100 μm gate 10 μm 1 μg/ m1 O11μg/m1 4.71 4.35 4.71 0.76 2.39 a) Results are shown from two experiments.

ii) The inhibition rate was calculated in comparison to the cytochrome C reduction in the control group.

Jji-bis((R)-2-aminopropyl]disulfide (M
e-3S) showed anti-inflammatory and anti-gastric secretion effects at 25 mg/kg, i, p. Furthermore, although Me-3S suppressed the chemiluminescence of polymorphonuclear leukocytes, it did not show a radical scavenging effect in the cytochrome C reduction method. Therefore, Me
One of the mechanisms of action of -3S was suggested to be involved in inhibition of the active oxygen production mechanism.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained with reference to Examples, but these Examples are not intended to limit the present invention in any way.

Example 1: Tablet (1) BisC(R)-2-aminopropyl 3 1
0mg disulfide (2) Direct injection fine particles No. 209 (manufactured by Fuji Chemical Co., Ltd.)
46.6 mg Magnesium metasilicate aluminate 2
0% corn starch 30% milk tM
50% (3) Crystalline cellulose 24.0mg (4) Carboxylmethyl 4.0mg Cellulose calcium (5) Magnesium stearate 0.4mg
All of (1), (3) and (4) were passed through a 100 sieve sieve in advance. These (1), (3), (4) and (2)
After drying each to reduce the moisture content to a certain level, they are mixed using a mixer in the above weight ratio. (5) was added to the evenly mixed powder, mixed for a short time (30 seconds), and the mixed powder was compressed into tablets (punch: 6.3 mmφ, 6.0 mmR), each weighing 85 mg. .

The tablets may be coated with a commonly used gastric soluble film coating agent (eg, polyvinyl acecool diethylamine acetate) or an edible coloring agent, if necessary.

Example 2: Capsule (1) BisC(17)-2-aminopropyl disulfide 0g (2) Milk Tang
935 g (3) Magnesium stearate 15 g The above components were each weighed and mixed uniformly, and the mixed powder was filled into hard gelatin capsules in an amount of 200 squares each.

Example 3: Injection (1) BisC(R)-2-aminopropyl disulfide mg (2) Glucose 100 tng (3) Physiological saline 10 mQ After filtering the above mixed solution with a membrane filter, it was sterilized again. Perform filtration and aseptically dispense the filtrate into vials.
After filling with nitrogen gas, the container was sealed to prepare an intravenous injection.

[Brief explanation of drawings]

FIG. 1 is a graph showing the effect of the compound of the present invention on rat carrageenan footprint edema over time. FIG. 2 is a graph showing the effect of the compound of the present invention on PMA-induced polymorphonuclear leukocyte luminol chemiluminescence over time. FIG. 3 is a graph showing the effect of the compound of the present invention on polymorphonuclear leukocyte luminol chemiluminescence induced by FMLP over time. 6 Procedural amendment (voluntary) December 7, 1999 2゜3゜4゜1999 Patent Application No. 256539 Name of invention: Anti-inflammatory agent, gastric juice secretion suppressant, or active oxygen production suppressant Amendment case Relationship with Patent applicant name Midori Juji Co., Ltd.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 is mercapto, sulfo, or formula ▲ Numerical formula,
There are chemical formulas, tables, etc. ▼ The group represented by R_2 represents a hydrogen atom or methyl, and R_1 and R_2 are combined to form the general formula (I)
The compound represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (where R_3 represents a hydrogen atom, alkyl, hydroxyalkyl, or carboxyl) or its An anti-inflammatory agent, gastric juice secretion inhibitor, or active oxygen production inhibitor that contains salt as an active ingredient.