JPH0581589B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel amide compound that has an excellent antiallergic effect and is useful as an antiallergic agent. (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 an amide compound with antiallergic effect, for example, The Journal of
The Journal of Allergy and Clinical
Immunology), Volume 57 (No. 5), Page 396 (1976)
tranilast [N-(3,4-dimethoxycinnamoyl)anthranilic acid], and Agents And Actions.
Actions), Vol. 1, p. 235 (1979) describes rhodoxamide ethyl [N,N'-(2-chloro-5-cyano-m-phenylene)dioxamic acid diethyl ester]. (Problems to be solved by the invention) Conventional anti-allergic agents can be used to treat various allergic symptoms,
In particular, it cannot be said that it has shown sufficient efficacy in the treatment of 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 The present invention was completed based on the discovery that the compound has excellent anti-allergic activity. That is, the compounds of the present invention have the formula:

[Formula, R ¹ is a hydrogen atom, a lower alkyl group, an acetyl group, or an alkoxyalkyl group; R ² is a hydrogen atom, a chlorine atom, a phenyl group, a lower alkoxy group, or

[Formula] (R ³ and R ⁴ are alkylene groups having 1 to 3 carbon atoms, W is an oxygen atom or methylene group); X, Y and Z are not all CH- at the same time, and each Indicates a nitrogen atom or CH-. ] It is an amide compound shown by. In the compound of formula () of the present invention, examples of the lower alkyl group in R ¹ include an alkyl group having 1 to 6 carbon atoms, preferably a methyl group and an ethyl group, and examples of the alkoxyalkyl group include a methoxyethyl group. The lower alkoxy group in R ² is an alkoxy group having 1 to 6 carbon atoms,
Preferred examples include methoxy group. (Production method) The compound of the present invention has the formula ():

[In the formula, R ² is a hydrogen atom, a chlorine atom, a phenyl group, a lower alkoxy group, or

[Formula] (R ³ and R ⁴ are alkylene groups having 1 to 3 carbon atoms, W is an oxygen atom or a methylene group); (X,
Y and Z are not all CH- at the same time, and each represents a nitrogen atom or CH-. Diamino compound () formula:

It is produced by reacting with an acid chloride represented by [Formula, R ¹ is a lower alkyl group, acetyl group, or an alkoxyalkyl group]. The reaction is carried out in an aprotic solvent such as pyridine. The reaction occurs without external application of heat, but heating may be applied to ensure completion of the reaction. A compound of formula () in which R ¹ is an acetyl group can be converted by hydrolysis into a compound of formula () in which R ¹ is a hydrogen atom. (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 intradermally injected into Wistar rats (male, weighing approximately 200 g) at 0.1 ml each on both sides of the dorsal midline at 2 points each for a total of 4 points to passively sensitize them. After 48 hours, 1 ml of ovalbumin and Evans blue mixture was administered through the tail vein.
PCA (passive cutaneous anaphylaxis) reaction was induced. After 30 minutes, cut out the blue dyed area and measure the amount of leaked dye.
Katayama et al.'s method [Microbiol. Immunol., 22
Vol., p. 89 (1978)]. The test compound was orally administered to six rats at a dose of 30 mg/Kg 30 minutes before the induction of the PCA reaction. Table 1 shows the PCA reaction inhibition rate of the compounds of the present invention.

【table】

[Table] The compounds of the present invention may be administered orally, parenterally or by inhalation, with oral administration being preferred. For use, they are prepared into various formulations by conventional methods using conventional pharmaceutical carriers. For example, tablets, capsules, granules, syrups, powders and the like can be used 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 provides direct contact of the lungs with the compound of the invention in the form of a dry powder. The total daily dose of the compounds of the invention is between 2 and 2000 mg. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 2,4-bis(methoxyacetylamino)-6
-Production of piperidino-pyrimidine: 2,4-diamino-6-piperidinopyrimidine
To a solution of 5.0 g dissolved in 100 ml of pyridine, 5 ml of methoxyacetyl chloride was added dropwise at room temperature. after that,
The mixture was stirred at a bath temperature of 60° C. for 1 hour and at room temperature overnight. Pyridine was distilled off under reduced pressure from the reaction mixture, and the resulting solid was suspended in water. The white crystals were collected by filtration and washed with water to obtain 6.27 g of the title compound having the following physical properties. Obtained. Melting point: 159-160℃ IR (KBr): ν=3450, 3260, 2930, 1725,
1685, 1625, 1575, 1520, 1440, 1395, 1340,
1315, 1285, 1260, 1240, 1220, 1205, 1135,
985, 940, 800 cm ^-1 NMR (DMSO-d ₆ ): δ = 9.55 (1H, s), 9.48
(1H, s), 7.05 (1H, s), 4.20 (2H, s), 4.05
(2H, s), 3.53 (4H, br.s), 3.35 (3H, s),
3.32 (3H, s), 1.60 (6H, br.s) Elemental analysis value Calculated value: C, 53.40; H, 6.87; N, 20.76 (%) Actual value: C, 53.46; H, 6.72; N, 20.81 ( %) Example 2 2,4-bis(methoxyacetylamino)-6
-Production of morpholino-pyrimidine: 2,4-diamino-6-morpholinopyrimidine
By reacting and treating 5.0g in the same manner as in Example 1, the title compound having the following physical properties was obtained.
Obtained 7.47g. Melting point: 189-191℃ IR (KBr): ν=3275, 1730, 1680, 1630,
1575, 1540, 1495, 1440, 1285, 1255, 1230,
1195, 1130, 1020, 930, 895 cm ^-1 NMR (CDCl ₃ ): δ = 8.73 (1H, br, s), 8.48
(1H, br, s), 7.22 (1H, s), 4.05 (2H, s),
3.97 (2H, s), 3.68 (8H, m), 3.47 (3H, s),
3.45 (3H, s) Elemental analysis value Calculated value: C, 49.55; H, 6.24; N, 20.64 (%) Actual value: C, 49.62; H, 6.20; N, 20.66 (%) Example 3 2,6- Production of bis(methoxyacetylamino)pyridine: 2.15 g of 2,6-diaminopyridine to 100 g of pyridine
ml of methoxyacetyl chloride was added dropwise to the solution at room temperature, and the mixture was stirred overnight at room temperature. Water is added to the residue obtained by distilling pyridine from the reaction mixture under reduced pressure, and the resulting solid is collected by filtration and washed with water to obtain crude crystals. This was recrystallized from ethanol,
1.67 g of the title compound was obtained with the following physical properties. Melting point: 146-147℃ IR (KBr): ν=3410, 1710, 1590, 1515,
1460, 1420, 1310, 1245, 1200, 1120, 990,
800, 685 cm ^-1 NMR (DMSO-d ₆ ): δ = 9.50 (2H, br, s),
7.75 (3H, s), 4.05 (4H, s), 3.37 (6H, s) Elemental analysis value Calculated value: C, 52.17; H, 5.97; N, 16.59 (%) Analysis value: C, 52.24; H, 6.03 ; N, 16.74 (%) Example 4 2,4-bis(methoxyacetylamino)-6
-Phenyl-syn-triazine 5.6 g of 2,4-diamino-6-phenyl-syn-triazine was dissolved in 80 ml of pyridine, 6.0 ml of methoxyacetyl chloride was added dropwise at room temperature, and the mixture was heated to 80°C.
Stirred for 1.5 hours. Pyridine was distilled off from the reaction mixture under reduced pressure, and water and chloroform were added to the resulting residue to separate the layers. The organic layer was dried with Glauber's salt, and the solvent was distilled off under reduced pressure to obtain crude crystals. Recrystallize this from ethanol to obtain the indicated compound with the following physical properties.
Obtained 4.9g. Melting point 171-173℃ (decomposition) IR (KBr): ν=3450, 3260, 1760, 1700,
1595, 1550, 1530, 1500, 1475, 1415, 1380,
1335, 1255, 1200, 1125, 1075, 1055, 990,
830, 785 cm ^-1 NMR (DMSO-d ₆ ): δ = 11.71 (2H, br, s),
8.42~8.15 (2H), 7.75~7.25 (3H), 4.44 (4H,
s), 3.34 (6H, s) Elemental analysis value Calculated value: C, 54.38; H, 5.17; N, 21.14 (%) Actual value: C, 54.62; H, 5.26; N, 21.15 (%) Example 5 2 ,4-bis(acetoxyacetylamino)-
Production of 6-piperidinopyrimidine: 2,4-diamino-6-piperidinopyrimidine
12 ml of acetoxyacetyl chloride was added dropwise to a solution of 9.66 g dissolved in 200 ml of pyridine at room temperature. After stirring at room temperature overnight, pyridine was distilled off from the reaction mixture under reduced pressure, and the resulting solid was washed with water and then with chloroform to obtain crude crystals. Recrystallize this from dioxane to obtain the indicated compound with the following physical properties.
Obtained 4.87g. Melting point: 248-249℃ (decomposition) IR (KBr): ν=3450, 3230, 3030, 2940,
1760, 1690, 1640, 1580, 1530, 1450, 1410,
1220, 1200, 1080, 810 cm ^-1 NMR (DMSO-d ₆ ): δ = 10.30 (1H, s),
10.00 (1H, s), 7.00 (1H, s), 5.00 (2H, s),
4.72 (2H, s), 3.55 (4H, br.s), 2.10 (6H, s),
1.60 (6H, br.s) Elemental analysis value Calculated value: C, 51.90; H, 5.89; N, 17.80 (%) Actual value: C, 51.75; H, 5.97; N, 17.73 (%) Example 6 2, 4-bis(hydroxyacetylamino)-
Preparation of 6-piperidinopyrimidine: Add 7.02 g of 2,4-bis(acetoxyacetylamino)-6-piperidinopyrimidine prepared according to Example 5 to 150 ml of a 15% ammonia methanol solution.
was added and heated under reflux at 50 to 60°C for 4 hours. After cooling, the solid was collected by filtration and washed with methanol to obtain 4.93 g of the title compound having the following physical properties. Melting point: 196-198℃ IR (KBr): ν=3400, 3300, 1735, 1680,
1620, 1565, 1540, 1480, 1455, 1380, 1310,
1240, 1215, 1105, 785 cm ^-1 NMR (DMSO-d ₆ ): δ = 7.07 (1H, s), 4.13
(2H, s), 4.00 (2H, s), 3.52 (4H, br.s),
3.48 (2H, s), 1.57 (6H, br.s) Elemental analysis value Calculated value: C, 50.48; H, 6.19; N, 22.64 (%) Actual value: C, 50.52; H, 6.24; N, 22.50 ( %) Example 7 Production of 4.6-bis(methoxyacetylamino)pyrimidine: To a solution of 4.8 g of 4.6-diaminopyrimidine 1/2 sulfate dissolved in 80 ml of pyridine, 6.0 ml of methoxyacetyl chloride was added dropwise at room temperature. Then at room temperature for 16 hours.
The mixture was then stirred at 80°C for 1 hour. After cooling, precipitated crystals were removed by filtration, and pyridine was distilled off from the filtrate under reduced pressure. Water and chloroform were added to the residue to separate the layers. The organic layer was washed with water and saturated brine, and then dried over Glauber's salt. The solvent was removed under reduced pressure to obtain crude crystals. This was recrystallized from ethyl acetate-hexane to obtain 2.9 g of the title compound having the following physical properties. Melting point: 110-112℃ IR (KBr): ν=3380, 3160, 2960, 2910,
2840, 1720, 1570, 1505, 1490, 1430, 1410,
1365, 1310, 1270, 1255, 1200, 1160, 1110,
1010, 985, 880, 830, 775, 680, 590, 555 cm ^-1 NMR (DMSO-d ₆ ): δ = 10.28 (2H, br.s),
8.73 (1H, s), 8.53 (1H, s), 4.06 (4H, s),
3.34 (6H, s) Elemental analysis value Calculated value: C, 47.24; H, 5.55: N, 22.04 (%) Actual value: C, 47.53; H, 5.55; N, 22.14 (%) Example 8 2,4- Production of bis(methoxyacetylamino)pyrimidine: 4.4g of 2,4-diaminopyrimidine was added to pyridine.
Add 8.0 ml of methoxyacetyl chloride dropwise to the 100 ml solution at room temperature. Thereafter, the mixture was stirred at room temperature for 2 hours. The precipitated crystals were removed by filtration, and the pyridine was distilled off under reduced pressure from the filtrate. Water and chloroform were added to the resulting residue to separate the layers. The organic layer was washed with water and then with saturated brine, and then dried over Glauber's salt. The solvent was distilled off under reduced pressure to obtain crude crystals. Recrystallize this from ethanol to obtain the indicated compound with the following physical properties.
Obtained 4.7g. Melting point: 168-170℃ (decomposition) IR (KBr): ν=3480, 3420, 3320, 3200,
3070, 3030, 2940, 2840, 1735, 1690, 1600,
1560, 1505, 1455, 1420, 1355, 1340, 1325,
1285, 1215, 1195, 1120, 1015, 995, 990, 940,
850, 825, 795, 755, 690, 620 cm ^-1 NMR (DMSO-d ₆ ): δ = 10.29 (1H, br.s),
10.09 (1H, br.s), 8.49 (1H, d), 7.18 (1H,
d), 4.22 (2H, s), 4.12 (2H, s), 3.35 (3H,
s), 3.32 (3H, s) Elemental analysis value Calculated value: C, 47.24; H, 5.55: N, 22.04 (%) Actual value: C, 47.01; H, 5.34; N, 21.77 (%) Example 9 2 ,4-bis(methoxyacetylamino)-6
-Production of methoxypyrimidine: 2,4-diamino-6-methoxypyrimidine
6.0 ml of methoxyacetyl chloride was added dropwise to a solution of 3.8 g dissolved in 80 ml of pyridine at room temperature. After stirring at room temperature for 2 hours, pyridine was distilled off under reduced pressure. Water and chloroform were added to the obtained residue to separate the layers. The organic layer was washed with water and then with saturated brine, and then dried over Glauber's salt. The solvent was distilled off under reduced pressure to obtain crude crystals. This was recrystallized from ethanol to obtain 3.8 g of the title compound having the following physical properties. Melting point: 168-169℃ IR (KBr) ν = 3400, 3270, 3190, 3010,
2940, 2830, 1735, 1690, 1625, 1585, 1550,
1535, 1490, 1435, 1420, 1390, 1340, 1280,
1260, 1205, 1185, 1130, 1095, 1040, 995,
960, 935, 840, 795, 780, 750, 630 cm ^-1 NMR (DMSO-d ₆ ): δ = 10.02 (2H, br.s),
7.05 (1H, s), 4.26 (2H, s), 4.06 (2H, s),
3.87 (3H, s), 3.34 (6H, s) Elemental analysis value Calculated value: C, 46.48; H, 5.67: N, 19.71 (%) Actual value: C, 46.69; H, 5.72; N, 19.98 (%) Example 10 2,6-bis(methoxyacetylamino)-4
-Manufacture of chloropyrimidine: 5.8g of 4-chloro-2,6-diaminopyrimidine
8.0 ml of methoxyacetyl chloride was added dropwise to a solution of 100 ml of pyridine at room temperature. After stirring at room temperature for 2 hours, pyridine was distilled off from the reaction mixture under reduced pressure. Water and chloroform were added to the obtained residue to separate the layers. The organic layer was washed with water and then with saturated brine, and then dried over Glauber's salt. The solvent was distilled off under reduced pressure to obtain crude crystals. This was recrystallized from ethyl acetate-hexane to obtain the indicated compound with the following physical properties.
Obtained 3.2g. Melting point: 142-144℃ (decomposition) IR (KBr): ν=3450, 3270, 1735, 1695,
1580, 1540, 1500, 1430, 1410, 1355, 1330,
1270, 1205, 1125, 1040, 985, 955, 930, 840cm
⁻¹ NMR (DMSO−d ₆ ): δ=10.62 (1H, br.s),
10.42 (1H, br.s), 7.69 (1H, s), 4.21 (2H,
s), 4.12 (2H, s), 3.32 (6H, s) Elemental analysis value Calculated value: C, 41.61; H, 4.54: N, 19.41; Cl, 12.28 (%) Actual value: C, 41.34; H, 4.36 ; N, 19.79; Cl, 12.55 (%) Example 11 2,4-bis(ethoxyacetylamino)-6
-Production of piperidinopyrimidine: 2,4-diamino-6-piperidinopyrimidine
7 ml of ethoxyacetyl chloride was added dropwise to a solution of 5.61 g dissolved in 100 ml of pyridine at room temperature. After stirring at room temperature overnight, pyridine was distilled off from the reaction mixture under reduced pressure. Water was added to this residue and the resulting solid was collected by filtration. A solution of this solid in chloroform was washed with water and dried with Glauber's salt. The crude crystals obtained by distilling off the solvent were recrystallized from ethanol-water to obtain the title compound 8.31 having the following physical properties. Melting point: 146-148℃ IR (KBr): ν=3250, 2930, 1720, 1680,
1625, 1575, 1545, 1515, 1440, 1340, 1315,
1285, 1255, 1240, 1215, 1140, 800cm ^-1 NMR (CDCl ₃ ): δ = 8.72 (1H, br.s), 8.48
(1H, br.s), 7.22 (1H, s), 4.10 (2H, s),
4.00 (2H, s), 3.62 (2H, q), 3.58 (2H, q),
3.55 (4H, br.s), 1.62 (6H, br.s), 1.30 (3H,
t), 1.28 (3H, t) Elemental analysis value Calculated value: C, 55.87; H, 7.45: N, 19.17 (%) Analysis value: C, 55.99; H, 7.52; N, 19.22 (%) Example 12 2 , 4-bis(2-methoxyethoxyacetylamino)-6-piperidinopyrimidine: 2,4-diamino-6-piperidinopyrimidine
8.0 ml of 2-methoxyethoxyacetyl chloride was added dropwise to a solution of 5.6 g dissolved in 100 ml of pyridine at room temperature. After heating and stirring at 65 to 70°C for 1 hour, the mixture was left at room temperature overnight. Pyridine was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the resulting crystals were collected by filtration to obtain 3.54 g of the title compound having the following physical properties. Melting point: 118-121℃ IR (KBr): ν=3460, 3270, 2930, 1720,
1680, 1625, 1580, 1545, 1520, 1440, 1315,
1260, 1240, 1220, 1150, 1125, 805cm ^-1 NMR (DMSO-d ₆ ): δ = 9.50 (1H, br.s),
9.40 (1H, br.s), 7.08 (1H, s), 4.22 (2H, s),
4.10 (2H, s), 3.80~3.30 (12H, m), 3.27 (3H,
s), 3.25 (3H, s), 1.56 (6H, br.s) Elemental analysis value Calculated value: C, 53.63; H, 7.34: N, 16.46 (%) Actual value: C, 53.49; H, 7.37; N ,16.76(%)

Claims (1)

[Claims] 1 Formula: [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, an acetyl group, or an alkoxyalkyl group; R ² is a hydrogen atom, a chlorine atom, a phenyl group, a lower alkoxy group, or [ A group represented by formula] (R ³ and R ⁴ are alkylene groups having 1 to 3 carbon atoms, W is an oxygen atom or a methylene group); X, Y and Z are not all CH- at the same time, and each is a nitrogen Indicates an atom or CH-. ] A novel amide compound represented by