JPS63208583A - Novel (2-substituted-4-thiazolyl)oxamic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound (salt) expressed by formula I (R represents lower alkyl, phenyl, napthyl, pyridyl, etc.; R<1> represents H or lower alkyl; R<2> represents H, alkyl, pivaloyloxymethyl, 4-aryl-1-piperazyl-lower alkyl or 2,3,4,6-tetra-O- acetyl-glucopyranosyl). EXAMPLE:Ethyl(2-(2-methoxyphenyl)-4-thiazolyl)oxamate. USE:An anti-allergic agent. PREPARATION:For example, (2-substituted-4-thiazole)carboxylic acids expressed by formula II are azidated and then heated in toluene to form isocyanates. The resulting product is reacted with trimethylsilylthanol and hydrolyzed to produce a 4-amino derivative expressed by formula III. Then the resultant derivative is reacted with ethyl chloroformate to afford a compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides novel (2)
-Substituted-4-thiazolyl)oxamic acid derivatives and pharmaceutically acceptable salts thereof, more specifically, the following formula (I) (wherein R is a lower alkyl group, a phenyl group, a naphthyl group, a pyridyl group, a furyl group) or chenyl group, phenyl group, naphthyl group, pyridyl group, furyl group,
In the case of a chenyl group, the base has no substituent or a group consisting of a hydroxyl group, a lower or higher alkoxy group, an arylmethyloxy group, a lower alkyl group, a trihalomethyl group, a hegeno group, or a nitro group. It may have 1 to 3 substituents selected from among them at any position, and when it has two or more substituents, they may be the same or different.

Further, RI represents a hydrogen atom or a lower alkyl group, and R
2 is a hydrogen atom, a lower or higher alkyl group, a pivaloyloxymethyl group, a 4-aryl-1-piperazyl lower alkyl group, or a 2.3.4.6-tetra-0-7cetylglucobylanosyl group. (2-substituted-4-thiazolyl)oxamic acid derivatives represented by the following formulas and pharmaceutically acceptable salts thereof.

[Conventional technology/problems]

Conventionally, sodium cromoglycate (DSCG), rolf I niramine maleate, tranilast, etc., which are known as anti-allergic agents, have had problems in terms of oral absorption and efficacy.

[Means for Solving the Problems] In view of these facts, the present inventors conducted various studies to obtain substances with even higher pharmacological activity, and found that (2-substituted-4-thiazolyl)oxamic The present invention was completed based on the discovery that acid derivatives have extremely strong anti-allergic activity and are also useful even when administered orally.

These (2-substituted-4-thiazolyl)oxamic acid derivatives are novel compounds synthesized for the first time by the present inventors and have not been described in any literature, and the present invention
-substituted-4-thiazolyl)oxamic acid derivatives.

Hereinafter, the compounds according to the present invention will be explained in detail.

In the compound (seal) of the present invention (wherein R, R1 and R2 have the same meanings as before),
The terms used in the definition are explained in more detail as follows.

The word "lower" means carbon atoms 1 to 60 unless otherwise specified.
The term ``higher'' is used to refer to groups with a higher number of carbon atoms.

As the "aryl" of the arylmethyloxy group which is a substituent on the phenyl group, naphthyl group, pyridyl group, furyl group or chenyl group of R and the "aryl" of the 4-aryl-1-piperazyl lower alkyl of R2, for example, It includes monocyclic aryl groups such as phenyl, tolyl, xylyl, and cumenyl, and bicyclic aryl groups such as biphenyl and naphthyl, which may further have one or more substituents.

Furthermore, the "halogen" of the hexogeno group and trihalomethyl group includes fluorine, chlorine, bromine, and iodine.

The 2.3.4.6-tetra-0-fucetylglucobylanosyl group of R2 may be either D-series or L-series, and includes an α-isomer or a β-isomer.

Compound (I) of the present invention can be synthesized from a starting compound (ID), for example, roughly according to the method shown in the scheme below.

In addition, among the compounds (I), those in which R2 is a hydrogen atom (
Ia), its salt (Natsua'), and the ethyl group (I
b) , other than a hydrogen atom and an ethyl group are designated as (Ic).

(The following is a blank space) Schematic formula> R1 (IC) That is, first, a (2-substituted-4-thiazole) carboxylic acid (ID) synthesized by a known method is azidated by a conventional method to form a (2-substituted -4-thiazole)
Carbonyl azides (m) are produced. (First step) Subsequently, in an aprotic solvent such as toluene or xylene, the isocyanates are prepared by heating under reflux, and then reacted with trimethylsilylethanol (2
-Wllll-4-thiazole)carbamic acid 2-trimethylsilylethyl esters (IV) are obtained. (Second step) Compound (Iv) thus obtained in an inert solvent,
Reaction with a tetraalkylammonium fluoride, such as tetrabutylammonium fluoride, produces 2-substituted-4-7 minothiazoles 9 (V). (
3rd step) Next, this 2-11-substituted-4-aminothiazole II (V) is reacted with a halide of oxalic acid monoester such as ethyloxalyl chloride, and (
2-substituted-4-thiazolyl)oxamic acid ethyl ester II (Ib) is obtained. This reaction is preferably carried out in pyridine or in an inert solvent in the presence of an acid acceptor (step 4) followed by these ethyl esters II
The target compound (2-substituted-4-thiazolyl)oxamic acid II (Ia) can be obtained by alkaline hydrolysis of (Ib) by a conventional method.

(Sixth step) In addition, (2-substituted-4-thiazolyl)oxamic acid 1
Among 1(Ia), those in which the substituent R is an aromatic ring and has a hydroxyl group on the ring at the position ortho to the bonding position with the thiazolyl group are (2-substituted-4-thiazolyl)oxamic acids. Ethyl ester m1 (lb) can be obtained directly in good yield by reacting boron tribromide with one in which the substituent at the same position as above is a lower alkoxy group. (Step 5') The obtained (2-substituted-4-thiazolyl)oxamic acid 11 (Ia) is further treated with sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonium hydroxide, mono- , di- or tri-ethanolamine or amines having various substituents, L-arginine, L-lysine, choline, N-methylglucamine, etc., using an inorganic or organic base such as L-arginine, L-lysine, choline, N-methylglucamine, etc. (Step 6') Also, (2-@substituted-4-thiazolyl)oxamic acid 11, which can be made into an acceptable salt (Ia')
(Ia) can be easily led to various novel (2-substituted-4-thiazolyl)oxamic acid esters (Ic) by esterification using conventional methods. (
6th effect [Effect] The compound (I) according to the present invention obtained as described above is a new compound and has excellent antiallergic action not only when administered intravenously but also when administered orally. It is expected that it will be useful as a.

[Example] Hereinafter, the present invention will be explained in further detail by giving reference examples, examples, and test examples.

Reference example> 2 g of 2-(2-methoxyphenyl)-4-thiazolecarboxylic acid in 25 ml of dry tetrahydrofuran (THF)
1.19 ml of triethylamine was added dropwise, followed by 0.81 ml of ethyl chlorocarbonate in a salt bath.
was added dropwise, and the mixture was reacted for 15 minutes under the same conditions. Thereafter, a solution of 6 g of sodium azide in water (30 ml) was added to the reaction mixture under water bath conditions, and the mixture was reacted for 300 minutes under the same conditions. Water was added to the reaction mixture, extracted with ethyl acetate,
The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), and the solvent was distilled off to give 1.81 g of 2-(2-methoxyphenyl)-4-thiazolecarbonyl azide as a pale yellow solid.
I got it.

Subsequently, under an argon stream, 1.81 g of 2-(2-methoxyphenyl)-4-thiazolecarbonyl azide was suspended in 30 ml of dry toluene and reacted at 90° C. for 1 hour. Under the same conditions, 2.02 ml of 2-trimethylsilylethanol was added dropwise thereto and reacted for 2 hours. After the reaction, the solvent was distilled off from the reaction mixture, the residue was dissolved in benzene, and purified using a silica gel column. 1 (n-hexane: ethyl acetate = 4:1), the first colorless solution distilled out was collected and the solvent was distilled off to obtain 2-(2-methoxyphenyl)-4-thiazolecarbamine, which is a colorless sticky product. 1.9 g of acid 2-trimethylsilylethyl ester<13L2,1) was obtained.

(Total yield: 64%) Regarding the 2-trimethylsilylethyl ester (IV) having various other substituents, the following were synthesized by applying the method of the above-mentioned Reference Example).

2-phenyl-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (ill) 2-(2-benzyloxyphenyl)-4-thiazolecarbamic acid 2-
Trimethylsilylethyl ester (I[Additional) 2-(2-nitrophenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (-L!=1
) 2-(3-methoxyphenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (ff second base) 2-(3-)lifluoromethylphenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (I3!- 2-(4-chlorophenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (-L!Ni) 2-(4-methylphenyl)-4-thiazolecarbamate 2-trimethylsilylethyl ester (-L! !2) 2-(4-methoxyphenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (-L!Nimame) 2-(3,5-dimethoxyphenyl)-4-thiazolecarbamate 2-trimethylsilylethyl Ester 2-(3,4,5-)rimethoxyphenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (1) 2-(3-methoxy-2-naphthyl)- 4-, thiazolecarbamic acid 2-trimethylsilylethyl ester (
-L! 212) 2-(2-stearyloxyphenyl)-4-thiazolecarbamic acid 2-trimethylsilylether ester (also) 2-methyl-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (u') 2-(3 -pyridinyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (■hill j) 2-(4-methylphenyl)-゛6-methyl-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (-L!: 1 degree) 2-(4-Methoxyphenyl)-5-methyl-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (upper layer 1) 2-(2-furyl)-5-methyl-4-thiazolecarbamate 2-trimethylsilylethyl ester Ester (JEyo1) 2-(5-methyl-2-chenyl)-6-methyl-4-
Thiazolecarbamic acid 2-trimethylsilylethyl ester (No. 11) The physical properties of these compounds (IV) are summarized in Table 1.

(Left below) Example 1) 417.8 mg of 2-(2-methoxyphenyl)-4-thiazolecarbamic acid 2-trimethylsilylethyl ester (-L 22) was dissolved in 5 ml of dry THF,
After adding 4.76 ml of THFil solution of IM Citra n-butylammonium fluoride and reacting at 60° C. for 1 hour, the solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated ammonium chloride solution and saturated brine, dried (anhydrous sodium sulfate), and the solvent was distilled off to give a reddish-brown sticky substance 2-(
2-methoxyphenyl)-4-7 minothiazol 245
mg was obtained.

IR (CHCIs, cm-'): 3450.335
0'H-NMR (CDCIs, δ): 3.
93 (brs, 5H.

0CIh, N1h), 6.00 (s, 1)1. thiazole ring) 6,83-7.55 (m, 3H, Ar
-M) 8.17-8.40 (m, IH, Ar-11)
2-(2-methoxyphenyl)-4-7 obtained here
245 mg of minothiazol was dissolved in 6 ml of dry pyridine, and 0.16 ml of ethyl oxalyl chloride was dissolved under water cooling.
1 was added dropwise, the mixture was returned to room temperature and allowed to react for 1 hour.
After the reaction, the solvent was distilled off from the reaction mixture, water was added to the residue,
The mixture was then made acidic (pH 2) with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried (anhydrous sodium sulfate), the solvent was distilled off, and the residue was dissolved in chloroform and purified with a silica gel column (benzene: ethyl acetate: 9:1).
), the first pale yellow solution distilled out was collected and the solvent was distilled off to obtain pale yellow crystals of (2-(2-methoxyphenyl)-
272 mg (yield 76%) of 4-thiazolyl)oxamic acid ethyl ester (-ri422) was obtained.

mp, 90-91"C.

Ethyl ester (Ib) with various other substituents
The following compounds were synthesized by applying the method of Example 1) above.

(2-phenyl-4-thiazolyl)oxamic acid ethyl ester (Monday and 1) (2-(2-benzyloxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (l 匡二dan) (2-(2-nitro Phenyl)-4-thiazolyl)oxamic acid ethyl ester (2-(3-methoxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (iJLJL) (2-(3-)lifluoromethylphenyl)- 4-thiazolyl)oxamic acid ethyl ester (LILlf
i) (2-(4-chlorophenyl)-4-thiazolyl)oxamic acid ethyl ester (2-(4-
(methylphenyl)-4-thiazolyl)oxamic acid ethyl ester (lL=fl) (2-(4-methoxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (1) (2-(3,5-dimethoxyphenyl) )-4-thiazolyl)oxamic acid ethyl ester (IL) (2-(3,4,5-)dimethoxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (-mouth and J
",) (2-(3-methoxy-2-naphthyl)-4-thiazolyl)oxamic acid ethyl ester (I1") (2-(2-stearyloxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (L1 21]) (2-Methyl-4-thiazolyl)oxamic acid ethyl ester C#') (2-(3-pyridinyl)-4-thiazolyl)oxamic acid ethyl ester (-kuhi'1) (2-(4 -methylphenyl)-5-methyl-4-thiazolyl)oxamic acid ethyl ester (-LE: 1 degree) (2-(4-methoxyphenyl)-5-methyl-4-thiazolyl)oxamic acid ethyl ester (1υ in ■ 2-(2-furyl)-5-methyl-4-thiazolyl)
Oxamic acid ethyl ester (2-(5-methyl-2-chenyl)-5-methyl-4
-Thiazolyl) oxamic acid ethyl ester (1 box) The physical properties of these compounds (Ib) are summarized in Table 2.

(Space below) Example 2) 247 mg of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (formerly Ni2) was dissolved in 15 ml of methanol, and 4.05 ml of IN sodium hydroxide was added thereto. After gradually adding
The reaction was allowed to proceed for 0 minutes.

After the reaction, methanol was distilled off from the reaction mixture, water was added to the residue, and the mixture was made acidic (pH 2) with 2N hydrochloric acid under water cooling, and then returned to room temperature and stirred for 30 minutes. The precipitated solid was collected by suction filtration, thoroughly washed with water, and dried to obtain ocher crystals (2-(2-
185 mg (yield: 82%) of methoxyphenyl)-4-thiazolyl)oxamic acid (LL, 1) was obtained.

mp, 178-180°C.

Example 3) 0.19 ml of boron tribromide (BBr3) was dissolved in 6 ml of dry methylene chloride under cooling with water, and under the same conditions, (2-(
A solution of 250 mg of 2-methoxyphenyl)-4-thiazolyl)oxamic acid ethyl ester (-Rini 2) in dry methylene chloride (6 ml) was added dropwise. After dropping, the mixture was returned to room temperature and reacted for 1.6 hours. After the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), the solvent was distilled off, and the residue was recrystallized from water-dioxane to give yellow crystals of (2-(2-hydroxyphenyl)-4-thiazolyl). Oxamic acid (100mg) 140mg
(yield: 65%). mp, 210-212℃
.

IR (KBr+ cm-re: 3700-210
0, 17801730.1680'H-NMR (DMSO-da, δ): 6.58
~8.05 (m, 5H+ Ar -M + thiazole ring) 11, 22 ~ 11.78 (brs, IH, -
COOII) 11, 60 (brs, IH, -NHC
O-)m/Z=264 (M◆) Example 4) After dissolving 80 mg of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid (I-i, iL) in 10 ml of methanol, IN sodium hydroxide J4
0.29 ml was added and allowed to react at 50'C for 30 minutes. After the reaction, the solvent was distilled off from the reaction mixture, and the residue was crystallized with acetone to obtain 75 mg (yield) of (2-(methoxyphenyl)-4-thiazolyl)oxamic acid sodium salt (b2) as a pale yellow solid. 86%).

mp, 287-269°C.

Summer R (KBr, cm-1): 3450.
3400. 1880 Example 5) 1-j(2-(2-
1) Dissolve 100 mg of methoxyphenyl)-4-thiazolyl) oxamic acid in 5 ml of dry methanol, and add 0.024% of monoethanolamine to this solution.
ml was added and allowed to react at room temperature for 30 minutes. After the reaction, the precipitated solid in the reaction mixture is collected by suction filtration, dried,
53 mg of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid monoethanolamine salt (Len and 21-) as a white solid was obtained.

The solvent of the filtrate was distilled off, and the remaining residue was crystallized by adding dry ether, collected by suction filtration, and dried to obtain 30 m of the same objective product.
I got g. Combined with the solid obtained earlier, the yield is 8
3 mg (yield 68%), mp, 174~
177℃.

Regarding the compounds of the present invention (Ia) and their salts (Ia') having various other substituents, the following compounds were synthesized by applying the methods of Examples 2) to 5) above.

(2-phenyl-4-thiazolyl)oxamic acid (
L1) (2-(2-benzyloxyphenyl)-4-thiazolyl)oxamic acid K-1) (2-(2-nitrophenyl)-4-thiazolyl)oxamic acid (lx
21) (2-(3-methoxyphenyl)-4-thiazolyl)oxamic acid (L-1) (2-(3-)lifluoromethylphenyl)-4-thiazolyl)oxamic acid (I-i bipod) (2-(4-
Chlorophenyl)-4-thiazolyl)oxamic acid
(]-Lniヱ)(2-(4-methylphenyl)-4-thiazolyl)oxamic acid (-Lnidan) (2-(4-methoxyphenyl)-4-thiazolyl)oxamic acid (I-i di foot) (2-(3,5-dimethoxyphenyl)-4-thiazolyl)oxamic acid (
LL21) (2-(3,4,5-)dimethoxyphenyl)-4-thiazolyl)oxamic acid (I) (
2-(3-Methoxy-2-naphthyl)-4-thiazolyl)oxamic acid
(LLJJll) (2-Methyl-4-thiazolyl)oxamic acid (I company ff1) (2-(3-pyridyl)-4-thiazolyl)oxamic acid (I Beni'1) (2-(4-methylphenyl)- 5-Methyl-4-thiazolyl)oxamic acid (-LL21) (2-(4-
methoxyphenyl)-5-methyl-4-thiazolyl)oxamic acid (2-(2-furyl)-6-methyl-4-thiazolyl)
Oxamic acid (2-(5-methyl-2)
Table 3 summarizes the physical properties of these compounds (!a) and (Ia').

(Space below) Example 6) 200 mg of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid (1 in L) was dissolved in 115 ml of dry acetone, and 0.1 ml of triethylamine was added thereto.
2ml and 0.0ml of pivaloyloxymethyl chloride.
After dropping 128 ml of sodium iodide 1
28.8 mg was added thereto, and the reaction was stirred for 19.6 hours under heating and reflux. After the reaction, the precipitated solid in the reaction mixture was filtered off under suction, the filtrate was evaporated, and the residue was dissolved in ethyl acetate. This was washed with water and dried (anhydrous sodium sulfate), and after distilling off the solvent, the residue was crystallized from isopropyl ether to give pale yellow crystals of pivaloyloxymethyl (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid. Ester (O=1) 126 mg (yield 4
5%).

mp, 148-149°C.

Example 7) 150 mg of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid (L-1) was dissolved in 7 ml of dry acetone, and 0.09 m of triethylamine was dissolved therein.
1 and 0.225 ml of octadecyl bromide were added dropwise in this order, and the mixture was allowed to react under heating under reflux for 9 hours. After the reaction, the solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried (anhydrous sodium sulfate), the solvent was distilled off, the residue was dissolved in ben7ane, and silica gel column purification (n-hexane: ethyl acetate = 7:3) was carried out. The pale yellow solution distilled out first was collected and the solvent was distilled off to give pale yellow crystals of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid octadecyl ester (I), 255 mg (yield: 89
%) obtained m mp, 57-63°C.

Example 8> After suspending 8 mg of (2-(2-methoxyphenyl)-4-thiazolyl)oxamic acid (LLJl) 105 in 5 ml of dry toluene, 0.064 ml of triethylamine was added thereto.

Then, 127 mg of 2-(4-(3-)lifluoromethylphenyl)-1-piperazinyl)ethyl bromide
A solution of dry toluene (2 ml) was added dropwise thereto, and the mixture was reacted under heating under reflux for 3 hours.

After the reaction, the solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. After dispersing the organic layer, washing with water, drying (anhydrous sodium sulfate), and distilling off the solvent, the residue was dissolved in 8 ml of dry acetone, and concentrated hydrochloric acid was added to acidify (pH 2).
).

The whole precipitated surface was collected by suction filtration, and the filtered material was washed with acetone and dried to obtain a yellow solid (2-(2-methoxyphenyl)-
4-thiazolyl)oxamic acid 2- (4-(3-)
(Lifluoromethylphenyl)-1-piperazinyl) ethyl ester hydrochloride (-LL bipod 144 mg
(yield 49%).

mp, 192-196°C.

Example 9) After suspending 200 mg of (2-(4-methoxyphenyl)-4-thiazolyl)oxamic acid (-LL) in 12 ml of dry toluene, triethylamine 0,15
1 ml and a solution of 444.1 mg of a-D-2,3,4,6-tetra-0-tetra-0-fucetylglucobylanosyl bromide in dry toluene (2 ml) were added in order, and the mixture was heated under reflux for 1 ml.
The reaction was allowed to proceed for 5 hours. After the reaction, the solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate.

The organic layer was separated, washed with water, dried (anhydrous sodium sulfate), treated with activated carbon, and the solvent was distilled off.

After dissolving the residue in ether at room temperature, n-hexane was added until it no longer became cloudy, and the mixture was left closed for 1 hour in a cool place. The precipitated solid was collected by filtration and a pale yellow solid (2-(4-methoxyphenyl) -4-thiazolyl)oxamic acid D-2,3,
4,6-tetra-0-fucetyl glucobylanosyl ester (-LLdim) 209 mg (yield 48%)
I got it.

mp, 66-70°C.

Regarding the ester compound (Ic) which is a compound of the present invention having various other substituents, the following compounds were synthesized by applying any of the methods of Examples 6) to 9) above.

(2-(4-methylphenyl)-4-thiazolyl)oxamic FIID-2,3,4,6-tetra-0-acetyl-glucopyranosyl ester (bji1) (2-(3,5-dimethoxyphenyl) )-4-thiazolyl)oxamic acid D-2,3,4゜6-Chitler O-
Acetyl glucopyranosyl ester (1 in L) (2-phenyl-4-thiazolyl)oxamic acid D-
2,3,4,6-Chitler O-acetyl gluco and lanosyl ester (L-niji) (2-(4-chlorophenyl)
-4-thiazolyl)oxamic acid D-2,3,4,6
-Citler O-acetyl gluco and lanosyl ester (
, lx1) The physical property values of these compounds (Ic) are summarized in Table 4.

(Leaving space below) Test Example) Experimental Materials and Methods i) Animals Used Male Wistar rats (age 6) were purchased from the Shizuoka Experimental Animal Agricultural Cooperative, and used in the experiment after one week of preliminary breeding.

ii) Preparation of antiserum Journal of Φ or Immunology (J, 1mm-un
ol, ), 1lli, 1002-1011
(I971).

Ascaris suum extract was dinitrophenylated and DNP-As was administered subcutaneously to the heel of Wistar female rats together with killed Bacillus pertussis, and 1 mg of NP-As was administered to the back muscle of female Wistar rats. Sensitized. Three days later, the blood was collected and the serum was separated to obtain anti-DNP-As serum. The titer of the antiserum was determined by rat 48 hour PCA and was 1:200.

1ii) 48-hour PCA A 35-fold dilution of anti-DNP-As serum was administered to two sites on the right side of the rat's back, which had been shaved in advance, for sensitization. After 48 hours, 1 ml of a 0.5% Evans blue saline solution containing 500 μg of DNP-As was administered into the tail vein to induce a reaction. After 30 minutes, the head was decapitated, the back skin was peeled off, the sensitized site 2tlfI and the control site lfi were cut out, and microbiological immunology (Micrb-io
l, 1mmuno1. ) +22+ 89~10
1 (I97B), the amount of Evans blue leached out, which was used as a reaction index, was determined. That is, 1 ml of IN potassium hydroxide was added to the excised skin, and 1 ml of IN potassium hydroxide was added to the excised skin.
The skin tissue was lysed by incubation for 6 hours.

After adding and mixing 9mK of 0.6N phosphoric acid-acetone (5:13) mixture, centrifuge at 3000r, p, m for 15 minutes, measure the absorbance of the supernatant at 620nm, and quantify the leached Evans blue. did. In addition, compound (I)
was administered intravenously into the tail vein 5 minutes before the initiation of the reaction, or suspended in 0.5% tragacanth and administered orally 1 o'clock before the initiation of the reaction.

Results Table 5 shows the results of tail vein administration, and Table 6 shows the results of oral administration. From these results, it was found that the compound of the present invention significantly inhibited the reaction and had a strong anti-PCA effect.

Table 6> Table 6> (that's all)

Claims (1)

[Claims] The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R is a lower alkyl group, a phenyl group, a naphthyl group, a pyridyl group, a furyl group, or a thienyl group. Indicates one of phenyl group, naphthyl group, pyridyl group, furyl group,
In the case of a thienyl group, it has no substituent or is selected from the group consisting of a hydroxyl group, a lower or higher alkoxy group, an arylmethyloxy group, a lower alkyl group, a trihalomethyl group, a halogeno group, and a nitro group. It may have 1 to 3 selected substituents at any position, and when it has 2 or more substituents, they may be the same or different. Further, R^1 represents a hydrogen atom or a lower alkyl group,
R^2 is a hydrogen atom, a lower or higher alkyl group, a pivaloyloxymethyl group, a 4-aryl-1-piperazyl lower alkyl group, or a 2,3,4,6-tetra-O-acetyl-glucopyranosyl group shows. ) A (2-substituted-4-thiazolyl)oxamic acid derivative and a pharmaceutically acceptable salt thereof.