JPH02229113A - Antiallergic agent consisting of amide-based compound - Google Patents

Abstract

PURPOSE:To obtain an antiallergic agent, containing a specific amide-based compound and capable of especially powerfully suppressing immediate type allergic reaction. CONSTITUTION:An antiallergic agent containing a compound expressed by formula I [R<1> is H, lower alkyl or lower acyl; X is N or CR<2> (R<2> is H or aryl); Y is N or CR<3> (R<3> is H or lower alkyl)], e.g. 2-(methoxyacetylamino)-4- phenylthiazole. The above-mentioned pharmaceutical is useful for preventing and treating bronchial asthma, urticaria, allergic rhinitis, etc., classified as immediate type allergy. The compound expressed by formula I is obtained by reacting an amino compound expressed by formula II or an acid addition salt thereof with an acid chloride expressed by formula III (R<1>' is R<1> except H).

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an anti-allergic agent comprising an amide compound having excellent anti-allergic action.

(Prior Art) Research and development of preventive and therapeutic agents for various allergic symptoms have been carried out, and many compounds have been reported. As for amide compounds having antiallergic effects, for example, The Journal of Allergy and Clinical Immunology (The Journal of Allergy and Clinical Immunology)
Allergy and C11nical Imm
unology) +57 volumes (No. 5) 396
(1976), tranilast (, N-3,4-dimethoxycinnamoyl)anthranilic acid] was described, and also published by Agents & Actions (1976).
and Actions) vol. 1, p. 235 (1975
Lodoxamide ethyl N N'-(2-chloro-5-cyano-m-phenylene)dioxamic acid diethyl ester] was described in 2010).

(Problems to be Solved by the Invention) Conventional anti-allergic agents cannot be said to be sufficiently effective in treating various allergic symptoms, especially bronchial asthma.

(Means for Solving the Problems) The present inventors synthesized various compounds in order to obtain drugs that exhibit excellent antiallergic effects against allergic symptoms, and as a result of examining their pharmacological effects, a specific amide compound This led to the completion of the present invention based on the knowledge that the compound has excellent anti-allergic activity.

That is, the compound of the present invention has the formula: Kyl group, preferably methyl group, ethyl group, etc. The lower acyl group of R1 has 2-10 carbon atoms.
There are acyl groups, preferably an acetyl group. Examples of the aryl group for R2 include a phenyl group or a substituted phenyl group.

The lower alkyl group for R3 includes a chain alkyl group having 1 to 6 carbon atoms, preferably a methyl group.

The compound of the present invention is a group represented by formula (II): [wherein R1 is a hydrogen atom, a lower alkyl group, or a lower acyl group; ;Y is N- or -C=
(R3 is a hydrogen atom or a lower R'' alkyl group) is an anti-allergic agent comprising an amide compound represented by the following formula.

In the compound of formula (1) of the present invention, the lower alkyl group for R1 is a chain alkyl group having 1 to 6 carbon atoms [wherein, Xo is -N- or -C=(R" hydrogen R2' atom or aryl (Y' is a group represented by N- or -C- (R3° is a hydrogen atom or a lower R3'' alkyl group)) An amino compound or an acid addition salt thereof represented by the formula (■): [In the formula, RI + represents a lower alkyl group or a lower acyl group] It is produced by reacting with an acid chloride.The reaction is carried out in a solvent such as pyridine or chloroform in the presence of a base such as pyridine or triethylamine. The reaction occurs without the application of external heat, but may be heated to ensure completion of the reaction.
Like the tten-Baumann method, it can also be carried out in the presence of an alkaline aqueous solution.

A compound of formula (I) in which R1 is a lower acyl group can be converted into a compound of formula (1) in which R' is a hydrogen atom by hydrolysis.

Compounds of the present invention include 2-(methoxyacetylamino)-4-phenylthiazole, 2(cetoxyacetylamino)-4-phenylthiazole, 2-(methoxyacetylamino)thiazole, 2-(methoxyacetylamino)- 5-methyl-1,3,4-thiadiazole, 5
-(methoxyacetylamino)-3-phenyl-1,2
Examples include 4-thiadiazole, 2-(hydroxyacetylamino)-4-phenylthiazole, and 2-(isobutyroyloxyacetylamino)-4-phenylthiazole.

(Effects of the Invention) The compounds of the present invention have the effect of strongly suppressing immediate allergic reactions, and therefore are useful for the prevention and treatment of bronchial asthma, hives, allergic rhinitis, etc., which are classified as immediate allergic reactions. be.

The antiallergic effect of the compound of the present invention was confirmed by the test examples described below.

Test Example Anti-ovalbumin rat 1-serum was applied at 0.1 ml on both sides of the dorsal midline of Wistar rats (weighing approximately 200 g).
ml.

I passively sensitized them by injecting irony into two points. After 48 hours, a mixture of ovalbumin and Evans blue was administered through the tail vein to induce PCA (passive cutaneous anaphylaxis).
provoked a reaction. After 30 minutes, the blue-stained area was cut out and the amount of leaked dye was measured using the method of Katayama et al. [formerly crobio1.
Immuno1. ．． 22, p. 89 (1978)]. The test compound was orally administered to three rats at a dose of 30 mg/kg 30 minutes before the induction of the PCA reaction. 1st
The table shows the PCA reaction inhibition rate of the present invention.

Table 1 The compounds of the invention may be administered orally, parenterally or by inhalation, with oral administration being preferred. In addition, for use, they are prepared into various formulations by conventional methods using conventional pharmaceutical carriers. Examples include tablets, capsules, granules, syrups, powders, etc. for oral administration. Examples for parenteral administration include aqueous solutions for intravenous injection, oily suspensions for intramuscular injection, and the like.

It can also be administered by an aerosol spray or by an inhaler which brings the compounds of the invention into direct contact with the lungs, bronchi, etc. in the form of a dry powder.

The total daily dose of the compounds of the invention is 2-2000
mg.

(Example) Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these.

Example 1 Production of 2-(methoxyacedelamino)-4-phenylthiazole: 2-amino-4-phenylthiazole hydrobromide 1
5.5 g of the hydrate was dissolved in 20 g of pyridine, and 2.0 mfl of methoxyacetyl chloride was added dropwise thereto. After stirring at room temperature for 2 hours, water was added to the residual aroma obtained by distilling off pyridine under reduced pressure, and the precipitated solid was collected by filtration.

The obtained solid was recrystallized from ethanol-water to obtain 4.2 g of the title compound exhibiting the following physicochemical properties.

Melting point = 113~1]5°C IR (KBr): v = 3200.1685.1
545.1450.1440.13801340.13
05, 1.285, 1205, 1130, 1080, 1
070.1025,995980.905,855,7
95,74.0.700,680,610,570cm
NMR (DMSO-d6): σ=12.05(LH
, brs), 7.95-7.20 (611°), 4.
15 (211, S), 3.35 (311, S) Elemental analysis value calculation value: C, 58° 05; If, 4.87; N, il
, 28; S, 12.91. (χ) Actual value: C, 57,
99;it, 4.89;N, 11.32;S, ], 2.
65(χ) Example 2 Production of 2-(acetoxyacetylamino)-4-phenylthiazole: 2-amino-4-phenylthiazole hydrobromide 1
Suspend the hydrate log in chlorophor, i-1-2O0,
6.2 ml of pyridine was added, and 2.1 ml of acetoxyacetyl chloride was added dropwise thereto, and the reaction was continued for 2 hours.

After filtering off the precipitated solid, the filtrate was distilled off under reduced pressure, water was added thereto, and the mixture was separated with ethyl acetate. The organic layer was dried with Glauber's salt, and the solvent was distilled off under reduced pressure to obtain crude crystals. This was recrystallized from chloroborum-n-hexane to obtain 1.6 g of the title compound having the following physical properties.

Melting point: 190-193°C IR (KBr): v = 3230.1730.1
710, 1560.1300.1.280+, 260
．． 118010801060970740cm-'NM
R(DMSO-d6): σ=10.0(11(, b
rs), 7.85-7.25(5)1゜m), 7.15
(1,11,S), 4.65 (211,S), 2.15
(3H,S) Calculated elemental analysis value: C, 56, 51; 11, 4.38. N, 10
．． 1,1. s, 11. ．． 61. (χ) Actual value: C, 5
6,36; H, 4,37; N, 10.21; S, 11.
66(χ) Example 3 Production of 2-(methoxyacedelamino)thiazole: 5 g of 2-aminothiazole to 100 mff1? Then, 5.0 g of methoxyacetyl chloride was added dropwise thereto, and the reaction was continued at room temperature for 3 hours. Water was added to the residue obtained by distilling off pyridine under reduced pressure, and the precipitated solid was collected by filtration.

The resulting solid was recrystallized from ethanol to yield 6.3 g of the title chemical having the following physical properties.

Melting point = 105 ~ 107"C IR (KBr): v -3180, 2920, 16
95, 1575, 1455, 14451375, 133
0,12so, 1190.1170.1125.10
65.1015.96093082077573063
0cm NMR (DMSO-d6): a -11,91 (L
H, brs) 7.44 (IHd) 7.18 (111,
d), 4.11 (2+1.S), 3.33 (3113'
) Calculated elemental analysis values: C, 41,85; H, 4,68, N, 16.
27. S, 18.62 (χ) Actual value: C, 41,74
,l(,4,74,N, 16.35;S, 18.6
8(χ) Example 4 2-(methoxyacetylamino)-5-methyl 1.3.
Production of 4-thiadiazole: 9.2 g of 2-amino-5-1,3,4-thiadiazole
was dissolved in 100 d of pyridine, 5.0 d of methoxyacetyl chloride was added dropwise thereto, and stirring was continued at room temperature for 2 hours. Pyridine was distilled off, water was added to the residual aroma, and the precipitated solid was collected by filtration. The resulting solid was recrystallized from ethanol to yield 11.5 g of the title compound with the following physical properties.

Melting point: 219-220°C ■R: Sea 3470.3200, 2930, 2830
,2760171015801450,1420.13
90, 1325.1275, 1215. l 20
0.1135.1090°955.930,810,7
40cm-'NMR (DMSO-da): o-1
2,21 (LH, brs), 4.16 (2H, S).

3.35 (3H,S), 2.10 (3+1.S) Calculated elemental analysis value: C, 3111,49,1+, 4.89. N,
22.44. S, 17.12 (χ) Actual value: C, 38
,34;H,5,00;N,22.75;S,17.2
2(χ) Example 5 5-(methoxyacetylamino)-3-phenyl-1,
Production of 2,4-thiadiazole = 4.4 g of 5-amino-3-phenyl-1,24-thiadiazole was added to pyridine 5
Methoxyacetyl chloride 3,4 in a solution dissolved in 0ml
mfl was added dropwise. After stirring at room temperature for 2 hours, pyridine was distilled off from the reaction mixture under reduced pressure to obtain a solid. This was recrystallized from ethanol-water to give 3.6 g of the title compound having the following physical properties.

Melting point: 113-116°C IR (KBr): p = 3260.1710.1
540.1340.1310.1290°1200, 1
110.720 cm-' NMR (CDCe 3): a-10,15 (IH
, brs), 8.30-7.35 (51(.

m), 4.15 (211, S), 3.45 (3H, S)
Calculated elemental analysis values: C, 53,00, H, 4,45, N, 16.
86. S, 12.86 (actual value: C, 53,12;
II, 4.72; N, 16.86. S, 12.81
(χ) Example 6 Production of 2-(hydroxyacetylamino)-4-phenylthiazole: 2-(acetoxyacetylamino) produced in Example 3
To a solution of 1.6 g of -4-phenylthiazole dissolved in 70 parts of methanol, 1 part of concentrated ammonia water was added dropwise at room temperature. After stirring at room temperature for 3 hours, methanol was distilled off under reduced pressure and the resulting residue was recrystallized from ethanol-water to obtain 1.3 g of the title compound having the following physical properties.

Melting point: 183-187°C IR (KBr): v = 3280.1700,155
0,1490,1450,13801350.1300
,1230,1210,1080,990,910,7
80,750,720°690.550,450cm-
' NMR (DMSO-da): a = 11.80 (I
H, brs), 7.25-8.00 (6Hm), 5.4
5 (IH, brS), 4.15 (2H, brS) Elemental analysis calculated values: C, 56,40; H, 4,30; N, 11.
96; S, 13.69 (X) Actual value: C, 56, 52
;H,4,26;N,11.91;S,13.55(X
) Example 7 Production of 2-(isobutyroyloxyacetylamino)4-phenylthiazole; 2-amino-4-phenylthiazole hydrobromide -
Suspend 5.5 g of hydrate in 100 mF of chloroform and add 2.8 mj of triethylamine! 2.2 g of isobutyroyloxyacetyl chloride was added thereto, and stirring was continued for 2 hours. After water was added thereto to separate the layers, the molar layer was dried with Glauber's salt, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from ethanol to obtain the indicated compound 1 having the following physical properties.
．． 99g was obtained.

Melting point: 99-100°C IR (KBr): v = 3300.3250,
3100.3000,1730.17101570.1
490 1480, 1465, 1435. ], 400.
1370, 1335.13001280, 121.0.
1185.1170.1.100.1080.1,06
5.1030.970905.855,850,780
, 740, 690, 680, 550 cm NMR (DMS
O-dJ: ty = 12.52 (IH, br
s), 7.75-7.28 (6Hm), 4.82 (2H
, S, ), 2.69 (q, LH), 1.15 (d, 6
Calculated tD elemental analysis value: C, 59,19; H, 5,30; N, 9.2
0; S, 10.54 (χ> Actual value: C, 59, 16;
II, 5.25; N, 9.22; S, lO, 50 (χ)
Patent applicant Toyobo Co., Ltd. Procedural amendment (voluntary) September 8, 1999 rN-3,4-J is corrected to rN-(3,4-J).

(2) Page 2, line 13 Correct rN, N'-J to r[:N, N'-J.

(3) 5th line from the bottom of page 3 1゜ 2゜ 3゜ Display of incidents 1999 Patent Application No. 49197 name of invention A person who corrects anti-allergic drugs consisting of Ami-V compounds Relationship to the case Patent applicant 2-2-8 Dojimahama, Kita-ku, Osaka “Detailed description of the invention” column in the specification (2) Page 5, line 14 ``(Correct cetoxyj to ``(acetoxy.'')

(5)　Page 6, line 1 ``Correct butyroyl j to ``butyryl.''

(6) Page 6, line 12 ro, in++" is corrected to "0.1m1J each.

■ Correct "butyroyl" to "butyryl" in the test compound column (bottom row) of Table 1 on page 7.

(8) Page 9, line 3 Correct "lingering scent" to "residue".

(9) Page 9, line 5 Correct "physicochemical properties" to "physical properties."

(10) Page 9, line 10 Correct "σ" to "δ".

(11) Page 9, line 11 (2 places) rsJ
Correct.

(12) Page 10, line 11 Correct "σ" to "δ".

(13) Page 10, line 12 (3 places) "S" is replaced by "s"
” is corrected.

(I4) 10th page, line 19 Correct rloOmlJ to ``Pyridine 100mlJ.

(I5) Page 11, line 9 Correct "σ" to "δ".

(16) Page 11, line 10 (2 places) rsJ to rs
Correct to J.

(17) Page 11, line 17 Correct "5-" to "5-methyl-".

(18) End of page 11 Correct "residual scent" to "residual liquid".

(19) Page 12, line 8 Correct "σ" to "δ".

(20) rsJ page 12, line 9 (2 places) “S”
Correct.

(21) Page 13, line 6 Correct "σ" to "δ".

(22) Page 13, line 7 (2 places) “S” is rsJ
Correct.

(23) Page 14, line 5 Correct "σ" to "δ".

(24) Page 14, line 6 (2 places) "S" is replaced by "sj"
Correct.

(25) On page 14, lines 11 and 16, "butyroyl" is corrected to "butyryl."

(26) Page 15, line 6 Correct "σ" to "δ".

(27) Page 15, line 7 Correct rsJ to rsJ.

(28) Page 15, line 7 r (q, III) Correct J to r (IH, q).

(29) Page 15, line 7 rd, 6H) J to rf38. Correct d).

Claims (1)

[Claims] Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a hydrogen atom, a lower alkyl group, or a lower acyl group; , tables, etc. ▼ (R^2 is a hydrogen atom or an aryl group); Y is -N= or ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (R^3 is a hydrogen atom or lower alkyl group) An anti-allergic agent comprising an amide compound represented by the following group.