JPH02212460A - Novel substituted and compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is 3-10C acyl or aryl; R<2> is cyano, trifluoromethyl, aminocarbonyl or COOR<4> (R<4> is R, alkyl or alkali metal, etc.); R<3> is H or halogen]. EXAMPLE:3,5-bis(propynyloxyacetylamino)-4-chlorobenzonitrile. USE:Useful for prevention and remedy of immediate allergy reaction of bronchial asthma, urticaria or allergic rhinitis, etc. PREPARATION:A diamino compound expressed by formula II is reacted with an acid chloride expressed by formula III to obtain the compound expressed by formula I. The reaction is performed in a solvent such as pyridine, chloroform, dichloromethane or N,N-dimethylformamide in the presence of a base such as pyridine or triethylamine.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel substituted amide compound that has excellent antiallergic activity and is useful as an antiallergic agent.

(Prior Art) Research and development of preventive and therapeutic agents for various allergic symptoms has been carried out, and many compounds have been reported. As amide compounds with antiallergic effects, for example, The Journal Off Allergy and Clinical Immunology (TI+e Journal of
Allergy and C11nical Immu
n-ology), volume 57 (floor 5), page 396 (
1976), tranilast [N-3,4, (dimethoxycinnamoyl)anthranilic acid] was introduced by Agents and Actions.
cations), Vol. 1, p. 235 (1975), lodoxamide ethyl [N,N'-(2-chloro-5-cyano-m-phanylene)dioxamic acid diethyl ester] is described.

(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 Problem) 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, it was found that certain amide compounds We found that it has excellent anti-allergic activity and completed the present invention.

That is, the compound of the present invention has the formula: 1 where R1 is an acyl group or aryl group having 3 to 10 carbon atoms, R1 is a cyano group, a trifluoromethyl group, an aminocarbonyl group, or -GOOR'(R' is hydrogen Rs is a hydrogen atom or a halogen atom].

In the compound of formula (1) of the present invention, the acyl group having 3 to 10 carbon atoms in R1 includes a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group,
Examples include pivaloyl group, hexanoyl group, heptanoyl group, octanoyl group, nonanoyl group, decanoyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, oxalyl group, malonyl group, succinyl group, benzoyl group or substituted benzoyl group, preferably propionyl group. group, butyryl group, isobutyryl group, benzoyl group, and ortho-acetoxybenzoyl group.

R''L is a cyano group, a trifluoromethyl group, an aminocarbonyl group, or a group represented by -COOR'(R' is a hydrogen atom, a lower alkyl group, an alkali metal atom or an alkaline earth metal atom).

R3 is a hydrogen atom or a halogen atom. Examples of the halogen atom for R'' include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and preferably a chlorine atom.

Examples of the lower alkyl group in R4 include alkyl groups having 1 to 6 carbon atoms, such as methyl and ethyl groups, examples of the alkali metal atoms include sodium and potassium, and examples of the alkaline earth metal atoms include magnesium and calcium. .

The compound of the present invention has the formula (n) 9! 4, where R1 is a diado group, a trifluoromethyl group, an aminocarbonyl group, or -COOR'(R' is a hydrogen atom, a lower alkyl group, an alkali metal atom or an alkaline earth metal atom), Rs is a hydrogen atom and a halogen atom] A diamino compound represented by the formula (■)
: υ In formula 1, R1 is an acyl group or aryl group having 3 to 10 carbon atoms.

The reaction involves pyridine, chloroform, dichloromethane, N,
The 8 reaction, which is carried out in a solvent such as N-dimethylformamide and in the presence of a base such as pyridine or triethylamine, occurs without the application of external heat, but can be heated to ensure completion of the reaction. good.

The reaction is also carried out in the presence of an alkaline aqueous solution like the 5-chotten Baus+an method.

Moreover, the compound of the present invention has the formula (■): p! 1(' In the formula, R" is a cyano group, a trifluoromethyl group, an aminocarbonyl group, or -GOOR"(R' is a hydrogen atom,
lower alkyl group, alkali metal atom or alkaline earth metal atom); R3 is a hydrogen atom or a halogen atom] and a compound represented by the formula (V) RI'C1(V) [wherein R1 is the number of carbon atoms] 3-10 acyl groups] or an acid chloride represented by the formula (■);
1 is also produced by reacting with an acid anhydride represented by an acyl group having 3 to 1 O carbon atoms.

The reaction between compound (IV) and acid chloride (V) is carried out in a solvent such as pyridine, chloroform, dichloromethane, N,N-dimethylformamide, etc., in the presence of a base such as pyridine, triethylamine, etc.

The reaction occurs without external application of heat, but heating may be used to ensure completion of the reaction.

The reaction is also carried out in the presence of an alkaline aqueous solution like the 5choLLen Bauman method.

The reaction between the compound (rV) and the acid anhydride (Vl) is carried out in a solvent such as pyridine or chloroform or without a solvent in the presence of a base such as pyridine or triethylamine, an acid such as sulfuric acid, or a catalyst such as zinc chloride. The zero reaction occurs without the application of external heat, but heating may be applied to ensure completion of the reaction.

In the compound of formula (1) in which R4 is a lower alkyl group, the acid alkyl group can be converted into an alkyl group different from the alkyl group by transesterification.

In compounds of formula (1) where R4 is a hydrogen atom, the hydrogen atom can be converted to an alkali metal or alkaline earth metal atom by standard methods.

The compounds of the present invention include 3,5-bis(propionyloxyacetylamino)-4-chlorobenzonitrile,
3.5-bis(isobutyryloxyacetylamino)-
4-chlorobenzonitrile, 3.5-bis(butyryloxyacetylamino)4-chlorobenzonitrile, 3,
5-bis(propionyloxyacetylamino)-4-
Chlorobenzonylylulide, 3,5-bis(propionyloxyacetylamino)methyl benzoate quarter hydrate, 1,3-bis(propionyloxyacetylamino)benzene, 1,3-bis(benzoyloxyacetyl) Amino)benzene quarter hydrate, 3,5-bis(2-
Acetoxybenzoylacetylamino)-4-chlorobenzonitrile, ethyl 3,5-bis(phenoxyacetylamino)benzoate, 3,5-bis(propionyloxyacetylamino)-4-chlorobenzamide, 3゜5
-bis(phenoxyacetylamino)-4-chlorobenzamide and the like.

(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 serum was applied to 11 star rats (
0 on each side of the dorsal midline of a male (approximately 200 g)
．． I passively sensitized the subjects by injecting iron into 4 subjects, 2 each addressed to 1ae. After 48 hours, ovalbumin and Evans blue mixture IJI! was administered through the tail vein to induce a PCA (passive cutaneous anaphylaxis) reaction.

After 30 minutes, cut out the blue dyed area and measure the amount of leaked dye.
The method of ma et al. [Mlcrobiol, L++ muno1
．． +22 volume, page 89 (197B)].

The test compound was orally administered to six runts at a dose of 30 μg/kg 30 minutes before the induction of the pc^ reaction. Table 1 shows P of the present invention.
The CA reaction inhibition rate is shown.

Table 1 The compounds of the present invention can be administered orally, parenterally, or by inhalation, but oral administration is preferred. For oral administration, tablets, capsules, granules, syrups, powders, etc. may be mentioned. 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 allows direct contact of the compounds of the invention in dry powder form with the lungs, bronchi, etc.

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

(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 3.5-bis(propynyloxyacetylamino)-4
-Production of chlorobenzonitrile: 4-ri00-3. 5
- 1.67 g of diaminobenzonitrile was suspended in 8 (ld) chloroform, 2.77 d of triethylamine was added, and 3.0 g of propionyloxyacetyl chloride was added dropwise while cooling in a water bath. After stirring at room temperature for 6 hours, the suspension was added with 2.77 d of triethylamine. Under cooling, 0.8 g of propionyloxyacetyl chloride
was dripped.

After stirring for 2 hours at room temperature, triethylamine 0.73-
was added, and 0.8 g of propionyloxyacetyl chloride was added dropwise while cooling in a water bath. After stirring at room temperature for 3 hours,
40ml of diethyl ether was added. The precipitated solid was collected by filtration, washed with a mixed solvent of chloroform-diethyl ether (1:1), then with water, and recrystallized from ethanol.
1.2 g of the title compound having the following physicochemical properties were obtained.

Melting point: Gradually decomposes above 14L'C.

IR (KBr): v -3410, 3270, 22
30,1760,1690°1580, 1530.
1430. 11?0. 890. 850
．． 810cm-'NMR (DMSOdi): δ
-9,93(2H,brs), 7.97(2H,s
), 4.75 (4H, s), 2.43 (4L q
).

1.09 (6u, t) Elemental analysis value calculation value j C, 51,59i H, 4,58; N,
10.62° CI, 8.96 (%) Actual value: C, 51,62i H, 4,64; N,
], 0.53. .

c3 8.82 (%) Example 2 3.5-bis(isobutyryloxyacetylamino)-
Production of 4-chlorobenzonitrile: 35-bis(hydroxyacetylamino)4-chlorobenzonitrile 2,8
Dissolve 50ad of pyridine and add 2°3 of isobutyryl chloride at room temperature. Ii was added dropwise. After stirring at room temperature for 2 hours,
The solvent was distilled off, and water was added to the obtained oil to solidify it. The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol to obtain 2.3 g of the title compound having the following physical properties.

Melting point: 140-141"C IR (Br): v -3430,3360,30
05,2960,2260°1755,1730.15
95.1525.1480.1445.14001.3
05.1255.1195.1155.1060.88
5.765c+a-NMR (DMSOdi): δ-9
,92(214,br,s) ,7.99(211,
s).

4.75 (4B, s), 2.85-2.4
5 (2H), 1.14 (12Ld) Elemental analysis value calculation value FC, 53,84; H, 5,23i N,
9.91 (%) Actual value FC, 53,59; H, 5
,29i N, 9.92 (%) Example 3 3.5-bis(butyryloxyacetylamine)-4-
Production of chlorobenzonitrile: 2.8 g of 3.5-bis(hydroxyacetylamino)4-chlorobenzonitrile was dissolved in 50 alt of pyridine, and 1 drop of 2.3 d of butyryl chloride was added at room temperature.

After stirring at room temperature for 2 hours, the solvent was distilled off, and the resulting oil was solidified by adding water. The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol to obtain 2.8 g of the title compound having the following physical properties.

Melting point: I43-144°C IR (KBr): y = 3425.3280.29
80.2950.2880°2245, 1?55.16
85.1580.1535.1435.1260120
5, 1160.1120.10?5.965.880.
755cm-'NMR (DMSO-di): δ-9
,93(211,br,s), 7.98(2H,s)
, 4.75 (4L s), 2.10 (4H,t)
.

1.60 (4L m), 0.94 (6)1.
t) Calculated elemental analysis values: C, 53, 84, H, 5, 23i N, 9
．． 91 (%) Actual value: C, 53, 62; H, 5,
28i N, 9.88 (%) Example 4 3.5-bis(propionyloxyacetylamino)-
Production of 4-chloropenzotrifluoride 3.5-bis(
1.2 g of 4-chlorobenzotrifluoride (hydroxyacetylamino) was dissolved in pyridine 30H1, and 0.7 m of propionyl chloride was added dropwise at room temperature. After stirring at room temperature for 2 hours, the solvent was distilled off, and water was added to the obtained oil to solidify it. The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol to obtain the title compound with the following physical properties: 1. O
I got g.

Melting point: 116-118°C IR (KBr): y = 3440.3300.17
60.1705.1610゜1560, 1535.15
44.1435.1375.1275.1180°11
30, 980.925.885 cm-'NMR (DMS
O-di): δ-9,92 (2B, br, s),
7.93 (2H, s), 4.76 (4H, s), 2.
44 (4H, q) 1.09 (61 (, t) Elemental analysis value calculation value: C, 46, 53; H, 4, t3; N,
6.38 (%) Actual value: C, 46,79; H, 4
, 22; N, 6.38 (%) Example 5 Production of methyl 3.5-bis(propionyloxyacetylamino)benzoate quarter hydrate: 3.5-bis(hydroxyacetylamino)benzoic acid 2.1 g of methyl quarter hydrate was suspended in 5+d propionic anhydride, 1 drop of concentrated sulfuric acid was added, and the mixture was stirred at room temperature for 6 hours. 20 ml of diethyl ether was added, and the precipitated solid was collected by filtration and washed with water. After drying, the solid was recrystallized from ethanol to yield 3.0 g of the title compound with the following physical properties.

Melting point 167-168℃ IR (KBr): y = 3470.3380.30
20.2980.1?40°1720, 1620.15
65.1475.1445.1395.1350°12
65, 1240.1190.1100.1005.88
0.780cmNMR (DMSOdi): δ-10,
26 (2tl, br, s), 8.12 (LH, t)
, 7.91 (2H, d), 4.72 (4H, s).

3.87 (38,s), 2.41
(4H, q), 1.06 (6H, writing,
) Elemental analysis value calculation value F C, 54, 20; H, 5, 68; N,
7.02 (%) Actual value: C, 54,41; H, 5
, 47; N, 7.13 C%) Example 6 Production of 1.3-bis(propionyloxyacetylamino)benzene: 1.3-bis(hydroxyacetylamino)benzene 2
．． 2 g was dissolved in 50 ad of pyridine, and 1.9 d of propionyl chloride was added dropwise. After stirring at room temperature for 3 hours, the solvent was distilled off, and water was added to the obtained oil to solidify it. The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol to obtain 3.0 g of the title compound having the following physical properties.

Melting point: 130-132°C IR (War): v -3470,3370,33
15,3005,2960°1750,1?10.16
90.1620.1570.1555.1500゜14
35, 1370.1315.1290.1195.11
? 5.1095°870,790.7QOC1-' N? lR(DMSO-di): δ-10,01
(2H, br, s), 7.88 (1B, s),
7.35-7.15 (3H, m), 4.60 (
4Hs), 2.40 (4H, q), 1.05 (6H, t
) Calculated elemental analysis values: C, 57, 14i H, 5, 99, N, 8
．． 33 (%) Actual value: C, 57,04; H, 6,
01; N, 8.35 (%) Example 7 Production of 1.3-bis(benzoyloxyacetylamino)benzene quarter hydrate: 1.3-bis(hydroxyacetylamino)benzene 2
．． Dissolve 2g in 50ml of pyridine and add 2g of benzoyl chloride.
．． 6d was added dropwise. After stirring at room temperature for 10 hours, the solvent was distilled off, and water was added to the resulting oil to solidify it. The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol.
4.2 g of the title compound were obtained having the following physical properties.

Melting point; 193-197°C IR (KBr): v = 3460.1730.17
05.1680.1615°1550, 1495.14
55.1435.1320.1275゜1230゜11
80, 1125. LO75,1025,715C11
-'NMR (DMSOdi): δ-10,18 (2H
,br,s), 8.227.05 (14B), 4
．． 89 (4H,s) Elemental analysis value calculation value: C265,97; H, 4,73i N,
6.41 (%) Actual value: C, 66,09; H, 4
, 71; N, 6.61 (%) Example day 3. Production of 5-bis(2-acetoxybenzoylacetylamino)-4-chlorobenzonitrile 3.5-bis(
2.8 g of hydroxyacetylamino)-4-chlorobenzonitrile to 50 aj of pyridine! 4.4 g of acetylsalicyloyl chloride was added at room temperature. After stirring at room temperature for 2 hours, the solvent was distilled off, and water was added to the obtained oil to solidify it.

The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol to obtain 2.6 g of the title compound having the following physical properties.

Melting point: Decomposition from 166°C fR (lfBr): y -3440,2240,1
770,1740,161015B5 1515.14
90.1455.1435.1375.1295°! 2
55. 1205. 1180. 1!55. 108
5. 1010.915,880°760.705cm
-' NMR (DMSOdh): δ -10,08 (2L
br, s), 8.25-7°10 (IOH), 5.
00 (411,s), 2.27 (611,s)
Calculated elemental analysis value: C, 57,29i H, 3,65; N,
6.91 (%) Actual value: C, 57,01; H, 3
,63,N, 6°89 (%) Example 9 Production of ethyl 3.5-bis(phenoxyacetylamino)benzoate: 1.8 g of ethyl 3.5-diaminobenzoate was dissolved in pyridine 5
Phenoxyacetyl chloride 3.0 dissolved in 0+d at room temperature
m was added dropwise. After stirring at room temperature for 2 hours, the solvent was distilled off. Water was added, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, a small amount of ethanol was added to the resulting oil,
Solidified. The solid was collected by filtration, washed with diethyl ether, dried and recrystallized from ethanol to yield 2.1 g of the title compound with the following physical properties.

Melting point: 140-141''C IR (Br): v = 3480.3440.17
35.1700,1620゜1600.1560.15
05,1470,1445,1380,1345゜13
20.1240. 1185. 1120,1095.
1065. 1035°890, 855. 7
80. 765. 700c So -1N old? (DM
SOdi) : δ-10,32(2H,br,s
), 8.31 (1, o, t ), 8. ol
(2H,d), 7.95-6.75 (
108).

4.69 (411, s), 4.29 (2H, q), 1.
30 (3H, t) elemental analysis calculated value: C, 66,95; H, 5,39; N,
6.25 (%) Actual value: C, 66,97; H, 5
,38; N, 6.25 (%) Example 10 3.5-bis(propionyloxyacetylamide/)-
Production of 4-chlorobenzamide: 0.6 g of 3.5-bis(hydroxyacetylamino)4-chlorobenzamide
was dissolved in pyridine 15d, and propionyl chloride was added dropwise at room temperature. After stirring at room temperature for 2 hours, the solvent was distilled off, and the resulting oil was solidified by adding water. Filter the solid,
After washing with water and drying, it was recrystallized with ethanol to obtain 0.6 g of the title compound having the following physical properties.

Melting point: 195-198°C IR (KBr): y -3420, 3270, 29
90,2950,1?45°1615,1585.14
65.1460.1430.13B0.1290°12
60, 1175.1090.1050.970.890
．． 840.805.770C1l-' NMR (DMSOdi): δ-9,79 (2tl
, br, s), 7.99(IN, br, s),
7.96 (2H,s), 7.39 (!H,
br,s) 4.72(4H,s,), 2.4.2(
4L q), 1.08 (6H, t) Elemental analysis value calculation value j C, 49,34i H, 4,87i N,
10.15 (%) Actual value: C, 49, 10, H2S
, 00; N, 10.03 (%) Example 11 Production of 3.5-bis(phenoxyacetylamino)4-chlorobenzamide: 2.4 g of 4-chloro-3,5-diaminobenzamide was dissolved in 100 m of pyridine, Phenoxyacetyl chloride at room temperature4. OJd was added dropwise. After stirring at room temperature for 2 hours,
The solvent was distilled off, and water was added to the obtained oil to solidify it. The solid was collected by filtration, washed with water, dried, and then recrystallized with ethanol to obtain 3.6 g of the title compound having the following physical properties.

Melting point: 250-251°C IR (XBr): v -3500,3400,17
15,1705,1690°1600,1595.15
20.1500.1440.1390.1305゜13
05, 1245.1235.1175.1085.10
60.840.755CI''' NMR (DMSO-di): δ -9,89 (2H
, br, s), 8.08 (2H, s).

7.99 (IH, br, s), 7.60-0.80
(IIH), 4.78 (4H, s) elemental analysis value

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 is an acyl group or aryl group having 3 to 10 carbon atoms; R^2 is a cyano group, trifluoro methyl group,
A new substitution represented by an aminocarbonyl group or a group represented by -COOR^4 (R^4 is a hydrogen atom, a lower alkyl group, an alkali metal atom or an alkaline earth metal atom); R^3 is a hydrogen atom or a halogen atom] amide compound.