JPH04300874A - New 2,4-diamino-1,3,5-triazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a treating and preventing medicine for allergic diseases, inflammatory diseases, diseases of circulatory organs, etc., having antagonism to leukotriene. CONSTITUTION:A compound shown by formula I (X and Y are H or acyl; R is phenyl, phthalidylmethyl, etc.) such as 2,4-diamino-[E]-6-[2-(4- methoxycarbonylphenyl)ethenyl]-1,3,5-triazine. The compound shown by formula I, for example, is obtained by condensing a compound shown by formula II with an aldehyde shown by the formula R<1>-CHO in the presence of an acid or a base when R is CH=CH-R<1>.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to novel 2,4-diamino-1,3,5-triazine derivatives.

0002

[Prior Art] The biological significance of leukotrienes has been widely studied, and their biological significance has been extensively studied, particularly in neonatal anoxia, pulmonary circulation pressor, adult respiratory distress syndrome, psoriasis, spondyloarthritis, rheumatoid arthritis, gout, inflammatory enteritis, etc. Leukotriene antagonists that exhibit antagonistic effects on leukotrienes are useful as therapeutic and preventive agents for allergic diseases, inflammatory diseases, circulatory disorders, etc.

On the other hand, 2,4-diamino-1,3,5
- Triazine derivatives have been reported to be used as anti-ulcer agents (JP-A-2-223566, JP-B-Sho 55-4751), but no reports have been made regarding their effects on leukotrienes.

0004

OBJECTS OF THE INVENTION The present invention provides novel 2,4-diamino-1
, 3,5-triazine derivatives.

[0005]

[Means for Solving the Problems] The present invention is based on the following formula (1)
:

[0006]

[Chemical formula 3]

[In the formula, X and Y may be the same or different and each represents a hydrogen atom or an acyl group; R is a phenyl group, a phthalidylmethyl group, and the following formula (2):

[0008]

[C4]

(In the formula, R2 and R3 represent a lower alkyl group, and Z is a hydrogen atom or a lower alkoxy group.
Represents a lower alkyl group. ) or the following formula (3): -A-R1
(3) (wherein A is -CH2CH2- or -C
H=CH-; R1 represents; hydroxyl group, cyano group, lower alkoxy group, lower alkoxycarbonyl group, phenyl group, phenoxy group, benzyloxy group, and phenoxy group substituted with trifluoromethyl group or lower alkyl group; A phenyl group substituted with at least one substituent selected from the group consisting of: naphthyl group, 3-bromophenyl group, 3-fluorophenyl group, 2,5-difluorophenyl group, 2-trifluoromethylphenyl group, 3 -trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3,5-bis (trifluoromethyl)
phenyl group, 4-lower alkylphenyl group, 3,5-di-(lower alkyl)-4-hydroxyphenyl group,
Represents a 3-pyridyl group or a 6-methyl-3-pyridyl group. ); When R is a phenyl group and when R1 is a 3-trifluoromethylphenyl group, X and/or Y represent an acyl group, and R1 is 3
-Pyridyl group, X and Y represent a nicotinoyl group or a 2-trifluoromethylbenzoyl group. ] This relates to a 2,4-diamino-1,3,5-triazine derivative or a salt thereof.

In the above formula (1), examples of the acyl group represented by X or Y include an acetyl group, a substituted or unsubstituted nicotinoyl group, or a benzoyl group. In this specification, a lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a sec-butyl group, a pentyl group, and a hexyl group. A lower alkoxy group refers to an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, etc.; a lower alkoxycarbonyl group refers to an alkoxycarbonyl group having 1 to 6 carbon atoms, such as methoxy carbonyl group,
Ethoxycarbonyl group, etc.; lower alkoxy-lower alkyl group refers to an alkoxy-alkyl group having 1 to 6 carbon atoms,
For example, it refers to a methoxymethyl group.

Among the compounds of the present invention represented by the above formula (1), compounds in which R is -CH=CH-R1, ie, the following formula (4):

0012

[C5]

The compound represented by the following formula (5):

[
0014

[C6]

It can be produced by condensing the compound represented by the formula R1-CHO with the aldehyde compound represented by the formula R1-CHO in the presence of an acid or a base. Examples of acids include methanesulfonic acid, formic acid, and sulfuric acid; examples of bases include potassium hydroxide, sodium hydroxide, T
riton B, sodium methoxide. When using an acid, the reaction is usually carried out without a solvent, but when using a base, for example, methanol, ethanol, 2-
A solvent such as methoxyethanol is used. The reaction temperature is preferably 60 to 120°C, and the reaction time is usually 1 hour to
It is 7 days.

Among the compounds of the present invention represented by the above formula (1), the compound in which R is -CH2CH2-R1 can be produced by reducing the above compound (4) according to a conventional method. Among the compounds of the present invention represented by the above formula (1), compounds in which X and/or Y are acyl groups are represented by the following formula (6):

[0017]

[C7]

The compound shown can be prepared by reacting it with the corresponding acid chloride or acid anhydride in pyridine. The reaction temperature is usually 80-140°C, preferably 110-120°C, and the reaction time is usually 3-140°C.
It is 8 hours. Among the compounds of the present invention represented by the above formula (1), compounds in which R is a substituted or unsubstituted phenyl group can be prepared by combining the corresponding benzonitrile derivative and dicyandiamide with a base according to the method described in Japanese Patent Publication No. 55-4751. It can be produced by reacting in the presence of. At this time, when Z is a hydrogen atom in the above formula (2), as illustrated below, the hydroxyl group is cyclized in a protected form as a methoxymethoxy group, and then treated with an acid to convert it into a hydroxyl group. Preferably, the method is used.

[0019]

[Chemical formula 8]

(In the formula, R2 and R3 represent, for example, lower alkyl.) Among the compounds of the present invention represented by the above formula (1), R
is a phthalidylmethyl group, that is, the following formula (7
) :

[0021]

[Chemical formula 9]

The compound represented by the above is the compound (5)
and the following equation (8):

[0023]

[Chemical formula 10]

It can be produced by reacting a compound represented by the following formula (wherein R4 represents a hydrogen atom or a lower alkyl group) in the presence of an acid. Also, the following formula (9):

00
25]

[Chemical formula 11]

The compound represented by [0026] and the following formula (10):

[
0027

[Chemical formula 12]

(In the formula, R2 and R3 have the same meanings as above.) By reacting the acid chloride represented by the above formula,
(1) The compound of the present invention represented by the following formula (
11) :

[0029]

[Chemical formula 13]

The compound shown below can be produced. The compound of the present invention, the compound represented by the formula (1) and its salts, such as hydrochloride, maleate, and fumarate, exhibits an antagonistic effect on leukotrienes, and is effective against allergic diseases and inflammatory diseases. It is useful as a therapeutic/preventive drug for diseases, circulatory disorders, etc.

Next, administration and formulation of the compound of the present invention will be explained. The compound of general formula (1) can be administered to animals and humans as is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be selected and used as necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to exert the desired effect as an oral agent, although it varies depending on the age of the patient and the severity of the disease, it is usually necessary for an adult to administer 0.2 to 2 ml of the compound of general formula (1) per day.
Preferably, 5 mg/kg body weight is administered in several doses. The compound of the present invention can be prepared into formulations such as solutions, powders, granules, tablets, enteric-coated formulations, and capsules according to conventional methods for manufacturing formulations using appropriate solvents, excipients, adjuvants, etc. used in formulations. None, can be administered orally or parenterally.

[0033] In formulation, it can also be combined with other medically active ingredients. For oral administration, they can be formulated into tablets, pills, capsules, powders, granules, etc. using at least one excipient such as starch, lactose, sucrose, mannitol, carboxymethyl cellulose, etc. In addition to the above-mentioned excipients, this type of preparation may contain, for example, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc, binders such as dextrin, crystalline cellulose, polyvinylpyrrolidone, gum arabic, corn starch, and gelatin. Disintegrants such as sodium cellulose glycolate, calcium cellulose glycol, potato starch, and carboxymethyl cellulose, and fluidity promoters such as light silicic anhydride can be used. In addition, drugs containing the compound of the present invention as an active ingredient can be administered as suspensions, emulsions, syrups, and elixirs, and these various dosage forms may contain flavoring fillers and coloring agents. You can force it.

[0034]

EXAMPLES The present invention will be explained in more detail with reference to Examples, Test Examples and Preparation Examples, but the scope of the present invention is not limited thereto. Example 1 2,4-diamino-[E]-6-[2-(4-methoxycarbonylphenyl)ethenyl]-1, 3, 5
-triazine (compound 18)

[0035]

[Chemical formula 14]

2,4-diamino-6-methyl-1,3
, 5 g (40 mM) of 5-triazine in 50 m of formic acid.
6.56 g of methyl 4-formylbenzoate dissolved in
(40mM) was added, and the mixture was heated under reflux for 91 hours. After concentrating the reaction solution under reduced pressure, it was made alkaline by adding saturated sodium hydrogen carbonate, and the precipitated crystals were filtered, washed with water, and recrystallized from a mixed solvent of 2-methoxyethanol and ethanol to obtain the title compound (4.58 g, 42.3%). ) obtained. Melting point: 258°C (decomposition) 1H-NMR (200MZ) δ (DMSO-d6)
:3.87(3H, s), 6.67(4H, br
s), 6.86 (1H, d, J=15.9Hz)
, 7.76 (2H, d, J=8.5Hz), 7
．． 82 (1H, d, J=15.9Hz), 7.97
(2H, d, J=8.5Hz). MS m/z (%
) [EI]: 271 (M+, 65), 270 (1
00), 228(37), 128(21). Examples 2 and 3 The following compounds were synthesized in the same manner as in Example 1. Example 2 2,4-diamino-[E]-6-[2-(4-cyanophenyl) ethenyl]-1,3,5-triazine (
Compound 19)

[0037]

[Chemical formula 15]

Yield: 17.9% Melting point: >300°C (from 2-methoxyethanol)
1H-NMR (200MZ) δ (DMSO-d6):
6.70 (4H, br s), 6.90 (1H
, d, J=15.9Hz), 7.80(1H, d
, J=15.9Hz), 7.83(4H, s). MS m/z (%) [EI]: 238 (M+, 75
), 237 (100), 195 (41), 169
(25). Example 3 2,4-diamino-[E]-6-[2-(4-ethoxycarbonylphenyl)ethenyl]-1,3,5-triazine (compound 22)

[0039]

[Chemical formula 16]

Yield: 15.0% Melting point: 229.6-230.8°C (from ethanol)
1H-NMR (200MZ) δ (DMSO-d6):
1.34 (3H, t, J=7.1Hz), 4.
33 (2H, q, J=7.1Hz), 6.68 (4
H, br s), 6.87 (1H, d, J=1
6.1Hz), 7.76 (2H, d, J=8.3
Hz), 7.82 (1H, d, J=16.1Hz)
, 7.97 (2H, d, J=8.3Hz). M.S.
m/z (%) [EI]: 285 (M+, 74),
284 (100), 256 (25), 242 (2
2). Example 4 2,4-diamino-[E]-6-[2-(4-trifluoromethylphenyl)ethenyl]-1,3,5-triazine (compound 20)

[0041]

[Chemical formula 17]

2,4-diamino-6-methyl-1,3
, 5-triazine 5g (40mM) was dissolved in methanesulfonic acid 28ml, and 4-trifluoromethylbenzaldehyde 5.5ml (40mM) was added.
The mixture was stirred at ℃ for 2 hours. After cooling, dilute sodium hydroxide was added to the reaction solution to make it alkaline, and the precipitated crystals were filtered, washed with water, and recrystallized from ethanol to obtain the title compound (6.09 g, 54
．． 2%). Melting point: 274.9-275.7°C 1H-NMR (200MZ) δ (DMSO-d6)
: 6.70 (4H, br s), 6.88 (1H
, d, J=15.9Hz), 7.73(2H, d
, J=8.3Hz), 7.83(1H, d, J
=15.9Hz), 7.85(2H, d, J=8
．． 3Hz). MS m/z (%) [EI]: 281
(M+, 93), 280 (100), 238 (5
4), 212(28), 196(22), 111(
26). Examples 5 to 13 The following compounds were synthesized in the same manner as in Example 4. Example 5 2,4-diamino-[E]-6-[2-(2-trifluoromethylphenyl)ethenyl]-1,3,5-triazine (compound 21)

[0043]

[Chemical formula 18]

Yield: 54.0% Melting point: 250.0-250.9°C (from ethanol)
1H-NMR (200MZ) δ (DMSO-d6):
6.72 (4H, br s), 6.78 (1H,
d, J=15.9Hz), 7.50-8.10(4
H, m), 8.11 (1H, brd, J=15.
9Hz). MS m/z (%) [EI]: 281 (M+, 10
0), 212 (76), 170 (53), 111
(32). Example 6 2,4-diamino-[E]-6-[2-[3,5-bis(trifluoromethyl)phenyl]ethenyl]-1,
3,5-triazine (compound 24)

[0045]

[Chemical formula 19]

Yield: 50.6% Melting point: 208.2-209.0°C (from ethanol)
1H-NMR (200MZ) δ (DMSO-d6):
6.68 (4H, br s), 7.08 (1H,
d, J=15.9Hz), 7.89(1H, d,
J=15.9Hz), 8.00 (1H, br s)
, 8.33 (2H, br s). MS m/z (%
) [EI]: 349(M+, 100), 348(
56), 330 (22), 280 (27), 11
1 (60). Example 7 2,4-diamino-[E]-6-[2-(2,5-difluorophenyl)ethenyl]-1,3,5-triazine (compound 25)

[0047]

[C20]

Melting point: >300°C (from 2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 6.71 (4H, br s), 6.89 (1H
, d, J=16.1Hz), 7.20-7.40(
2H, m), 7.70-7.80 (1H, m),
7.90 (1H, br d, J=16.1Hz).
MS m/z (%) [EI]: 249 (M+, 57
), 228 (100), 188 (29), 146
(20). Example 8 2,4-diamino-[E]-6-[2-(6-methylpyridin-3-yl)ethenyl]-1,3,5-triazine (Compound 26)

[0049]

[C21]

Yield: 36.6% Melting point: 253.7-254.3°C (from ethanol)
1H-NMR (200MZ) δ (DMSO-d6):
2.49 (3H, s), 6.66 (4H, br
s), 6.80 (1H, d, J=15.9Hz),
7.28 (1H, d, J=8.3Hz), 7.
77 (1H, d, J=15.9Hz), 7.99 (
1H, dd, J=8.3, 2.2Hz), 8.
63 (1H, d, J=2.2Hz). MS m/z
(%) [EI]: 228 (M+, 45), 227
(100), 185(37), 144(23). Example 9 2,4-diamino-[E]-6-[2-(4-methoxyphenyl)ethenyl]-1, 3, 5-triazine (
Compound 32)

[0051]

[C22]

Yield: 27.4% Melting point: 244°C (decomposition) (from methanol) 1H-N
MR (200MZ) δ (DMSO-d6): 3.79
(3H, s), 6.59 (4H, br s), 6
．． 59 (1H, d, J=15.9Hz), 6.9
6 (2H, d, J=8.8Hz), 7.56 (2
H, d, J=8.8Hz), 7.75(1H, d
, J=15.9Hz). MS m/z (%) [EI
]: 243 (M+, 88), 242 (100),
200(32), 158(19). Example 10 2,4-diamino-[E]-6-[2-(2-naphthyl)ethenyl]-1,3,5-triazine (compound 3
3)

[0053]

[C23]

Melting point: 237.8-238.4°C (from methanol) 1H-NMR (200MZ) δ (DMSO
-d6): 6.82 (4H, br s), 6.
93 (1H, d, J=15.9Hz), 7.50-
7.70 (2H, m), 7.80-8.20 (5H
, m), 8.02 (1H, d, J=15.9Hz
). MS m/z (%) [EI]: 263 (M+,
100), 262 (96), 220 (44), 1
79(21), 178(36). Example 11 2,4-diamino-[E]-6-[2-(3-phenoxyphenyl)ethenyl]-1, 3, 5-triazine (compound 34)

[0055]

[C24]

Melting point: 167.6-169.4°C (from methanol) 1H-NMR (200MZ) δ (DMSO
-d6): 6.64 (4H, br s), 6.
68 (1H, d, J=15.9Hz), 6.90-
7.50 (9H, m), 7.73 (1H, d,
J=15.9Hz). MS m/z (%) [EI]: 305 (M+, 87
), 304 (100), 262 (29), 220
(23). Example 12 2,4-diamino-[E]-6-[2-(3-bromophenyl)ethenyl]-1,3,5-triazine (compound 35)

[0057]

[C25]

Yield: 59.9% Melting point: 188.9-189.7°C (from methanol-2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 6.66 (4H, br s), 6.79 (1H
, d, J=15.9Hz), 7.36(1H, d
d, J=7.8, 7.8Hz), 7.54 (1H
, br d, J=7.8Hz), 7.63(1H
, br d, J=7.8Hz), 7.72(1H,
d, J=15.9Hz), 7.82(1H, b
rs). MS m/z (%) [EI]: 293 (M
+, 77), 292 (100), 291 (M+,
76), 290 (93), 250 (29), 24
8(28), 128(40). Example 13 2,4-diamino-[E]-6-[2-(3-fluorophenyl)ethenyl]-1, 3, 5-triazine (
Compound 36)

[0059]

[C26]

Melting point: 275.9-276.8°C (from methanol-2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 6.69 (4H, br s), 6.80 (1H,
d, J=15.9Hz), 7.10-7.25(1
H, m), 7.30-7.55 (3H, m), 7
．． 76 (1H, d, J=15.9Hz). MS m
/z (%) [EI]: 231 (M+, 76), 23
0 (100), 188 (45), 162 (28),
146(22). Example 14 2,4-diamino-[E]-6-[2-(3,5-di-
t-butyl-4-hydroxyphenyl)ethenyl]-1
, 3, 5-triazine (compound 37)

[0061]

[C27]

2,4-diamino-6-methyl-1,3
, 2.5 g (20 mM) of 5-triazine in formic acid 7
5.15 g (22 mM) of 3,5-di-t-butyl-4-hydroxybenzaldehyde was added thereto, and the mixture was heated under reflux for 168 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (CHCl3:MeOH=9:1), then recrystallized from 2-propanol to give the title compound (
0.85g, 12.5%) was obtained. Melting point: 253.3-255.7°C 1H-NMR (200MZ) δ (CD3OD):
1.45 (18H, s), 6.59 (1H, d,
J=15.9Hz), 7.41(2H, s), 7
．． 85 (1H, d, J=15.9Hz). MS m
/z (%) [EI]: 342 (M++1, 24),
341 (M+, 99), 327 (23), 32
6 (100), 270 (18). Example 15 2,4-diamino-[E]-6-[2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]-1,3
, 5-triazine (compound 49)

[0063]

[C28]

The title compound was synthesized in the same manner as in Example 14. Yield: 18.7% Melting point: 285.9-288.1°C (decomposition) (from 2-propanol-methanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 2.19 (6H, s), 6.50 (1H, d
, J=15.9Hz), 6.55(4H, br s
), 7.17 (2H, s), 7.66 (1H,
d, J=15.9Hz), 8.12(1H, s)
．． MS m/z (%) [E1]: 257 (M+, 1
00), 256(70), 214(25). Example 16 2,4-diamino-[E]-6-[2-(4-isopropylphenyl)ethenyl]-1, 3, 5-triazine (compound 41)

[0065]

[C29]

2,4-diamino-6-methyl-1,3
, 1.25g (10mM) of 5-triazine was added to 2-
Dissolve Triton in 20ml of methoxyethanol.
B (40% methanol solution) 9.1ml (20mM
) and 3 ml of 4-isopropylbenzaldehyde (19
．． 8mM) and stirred at 80°C for 6.5 hours. After cooling, water was added, and the precipitated crystals were filtered, washed with water, and recrystallized from a mixed solvent of 2-methoxyethanol and methanol to obtain the title compound.
(0.91 g, 35.7%) was obtained. Melting point: 247.8-248.8°C 1H-NMR (200MZ) δ (DMSO-d6)
: 1.21 (6H, d, J=6.8Hz), 2
．． 91 (1H, m), 6.62 (4H, br s)
, 6.68 (1H, d, J=16.1Hz),
7.27 (2H, d, J=8.1Hz), 7.53
(2H, d, J=8.1Hz), 7.77 (1H
, d, J=16.1Hz). MS m/z (%) [EI]: 255 (M+, 53
), 254 (100), 240 (18), 212
(19), 156(16). Example 17 2,4-diamino-[E]-6-[2-(4-biphenyl)ethenyl]-1,3,5-triazine (compound 4
2)

[0067]

[C30]

2,4-diamino-6-methyl-1,3
, 1.25 g (10 mM) of 5-triazine was dissolved in 30 ml of 2-methoxyethanol, and KOH (85%)
Add 0.66g (10mM) and 2.91g (16mM) of 4-biphenylcarboxaldehyde and incubate at 90°C for 16 hours.
Stir for hours. After cooling, add water, filter out the precipitated crystals, wash with water,
Recrystallization from 2-methoxyethanol gave the title compound (0
．． 60g, 20.7%) was obtained. Melting point: 276°C (decomposition) (from methanol-2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 6.66 (4H, br s), 6.79 (1H
, d, J=15.9Hz), 7.35-7.75(
5H, m), 7.72 (4H, s), 7.84
(1H, d, J=15.9Hz). MS m/z (%
) [EI]: 289 (M+, 82), 288 (1
00), 246(34), 220(13), 20
5(16), 204(31). Examples 18-22 The following compounds were synthesized in the same manner as in Example 17. Example 18 2,4-diamino-[E]-6-[2-(4-benzyloxyphenyl)ethenyl]-1, 3, 5-triazine (compound 44)

[0069]

[Chemical formula 31]

Yield: 16.6% Melting point: 227.2-227.9°C (from methanol-2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
:5.15(2H, s), 6.58(4H, br
s), 6.59 (1H, d, J=15.9Hz)
, 7.03 (2H, d, J=8.8Hz), 7
．． 30-7.50 (5H, m), 7.56 (2H,
d, J=8.8Hz), 7.74(1H, d,
J=15.9Hz). MS m/z (%) [EI]: 319 (M+, 11
), 228 (39), 91 (100), 78 (2
2). Example 19 2,4-diamino-[E]-6-[2-[3,4-bis(benzyloxy)phenyl]ethenyl]-1, 3,
5-triazine (compound 45)

[0071]

[C32]

Yield: 54.6% Melting point: 203.2-203.7°C (methanol-2
- from methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 5.18 (2H, s), 5.22 (2H, s
), 6.56 (4H, br s), 6.61 (1H
, d, J=15.9Hz), 7.00-7.15
(2H, m), 7.25-7.55 (11H, m
), 7.69 (1H, d, J=15.9Hz). M
S m/z (%) [EI]: 425 (M+, 5),
334(17), 91(100). Example 20 2,4-diamino-[E]-6-[2-(1-naphthyl)ethenyl]-1,3,5-triazine (compound 4
6)

[0073]

[Chemical formula 33]

Yield: 27.8% Melting point: 220.1-221.2°C (from 2-methoxyethanol-methanol-ethyl acetate) 1H-NMR (200MZ) δ (DMSO-d6)
: 6.72 (4H, br s), 6.81 (1H
, d, J=15.9Hz), 7.50-7.70(
3H, m), 7.90-8.05 (3H, m),
8.18 (1H, br d, J=7.8Hz), 8
．． 64 (1H, d, J=15.9Hz). MS m
/z (%) [EI]: 263 (M+, 100),
262 (68), 220 (22), 178 (28)
．． Example 21 2,4-diamino-[E]-6-[2-[3-(3-trifluoromethylphenoxy)phenyl]ethenyl]-
1,3,5-triazine (compound 47)

0075
]

[C34]

Yield: 42.6% Melting point: 204.7-205.8°C (from ethanol-2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 6.63 (4H, br s), 6.72 (1H
, d, J=15.9Hz), 7.00-7.70(
8H, m), 7.76 (1H, d, J=15.
9Hz). MS m/z (%) [EI]: 374 (M++1,
92), 373 (M+, 100), 330 (34
), 289(15), 112(12). Example 22 2,4-diamino-[E]-6-[2-[3- (4-
t-butylphenoxy) phenyl]ethenyl]-1,
3,5-triazine (compound 48)

[0077]

[C35]

Yield: 34.9% Melting point: 211.6-212.2°C (from ethanol)
1H-NMR (200MZ) δ (DMSO-d6)
:1.30 (9H, s), 6.64 (4H, br
s), 6.69 (1H, d, J=15.9Hz)
, 6.90-7.00 (3H, m), 7.20 (
1H, br s), 7.30-7.50 (4H, m
), 7.73 (1H, d, J=15.9Hz). MS m/z (%) [EI]: 361 (M+, 64
), 360(38), 347(25), 346(
100). Example 23 2,4-diamino-[E]-6-[2-(2-trifluoromethylphenyl)ethenyl]-1, 3, 5
-Triazine maleate (Compound 21 (Example 5)
Compound) maleate salt)

[0079]

[C36]

Compound 21 0.5g (1.77mM)
Dissolve in 50 ml of ethanol and add 0.25 g of maleic acid.
(2.15mM) and allowed to stand at room temperature for 0.5 hours. The precipitated crystals were collected by filtration and washed with ethanol to obtain the title compound (0.60 g, 85.7%). Melting point: 195.6-196.2°C (decomposition) (from ethanol) 1H-NMR (200MZ) δ (DMSO-
d6): 6.21 (2H, s), 6.83 (1
H, d, J=15.9Hz), 7.09(4H,
br s), 7.55-7.85 (3H, m),
7.99 (1H, d, J=7.6Hz), 8.15
(1H, brd, J=15.6Hz). Example 24 2,4-diamino-[E]-6-[2-(2-trifluoromethylphenyl)ethenyl]-1, 3, 5
-Triazine hydrochloride (hydrochloride of compound 21 (compound of Example 5))

[0081]

[C37]

Compound 21 0.5g (1.77mM)
was dissolved in 50 ml of ethanol, 0.3 g of concentrated hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 0.5 hour. After filtering the precipitated crystals,
Wash with ethanol and extract the title compound (0.38g, 67
．． 9%). Melting point: >300℃ (from ethanol) 1H-NMR
(200MZ)δ(DMSO-d6): 7.01(
1H, d, J=15.6Hz), 7.60-7.
90 (3H, m), 7.99 (1H, d, J=7
．． 6Hz), 8.00-8.60(4H, br),
8.29 (1H, br d, J=15.6Hz)
．． Example 25 2,4-bis(nicotinoylamino)-[E]-6
-[2-(3-trifluoromethylphenyl) ethenyl]-1, 3, 5-triazine (Compound 23)

[
0083

[C38]

2,4-diamino-[E]-6-[2-
(3-trifluoromethylphenyl) ethenyl]-1
, 1g (3.55mM) of 3,5-triazine was dissolved in 35ml of pyridine, 2.01g (11.28mM) of nicotinoyl chloride hydrochloride was added, and the mixture was heated under reflux for 4 hours. After concentrating the reaction solution under reduced pressure, saturated sodium hydrogen carbonate was added to make it alkaline, and the precipitated crystals were filtered and washed with water.
Recrystallized from ethanol to obtain the title compound (0.75g,
43.1%) was obtained. Melting point: 127-131°C 1H-NMR (200MZ) δ (DMSO-d6)
: 7.21 (1H, d, J=15.9Hz),
7.56 (2H, dd, J=8.1, 4.9Hz),
7.60-7.80 (2H, m), 7.90-8
．． 10 (2H, m), 7.94 (1H, d, J
=15.9Hz), 8.29(2H, br d, J
=8.1Hz), 8.78(2H, dd, J=4
．． 9, 1.7Hz), 9.08 (2H, d, J=
1.7Hz). MS m/z (%) [EI]: 491 (M+, 11
), 386(93), 385(65), 357(
67), 106 (66), 78 (100). Example 2
6-29 The following compounds were synthesized by the same method as in Example 25. Example 26 2-acetylamino-4-amino-[E]-6-[2-
(2-trifluoromethylphenyl) ethenyl]-
1,3,5-triazine (compound 27)

[0085]

[C39]

Yield: 54.7% Melting point: >300°C (from 2-methoxyethanol) M
S m/z (%) [EI]: 323 (M+, 100
), 281(32), 212(30), 170(
22). Example 27 2,4-bis(nicotinoylamino)-[E]-6
-[2-(3-pyridyl) ethenyl]-1, 3,
5-triazine (compound 28)

[0087]

[C40]

Melting point: 242-247°C (from 2-methoxyethanol) 1H-NMR (200MZ) δ (DMSO-d6)
: 7.18 (1H, d, J=15.9Hz),
7.48 (1H, dd, J=8.1, 4.9Hz),
7.56 (2H, dd, J=8.1, 4.9H
z), 7.91 (1H, d, J=15.9Hz)
, 8.20 (1H, br d, J=8.1Hz),
8.29 (2H, br d, J=8.1Hz),
8.60 (1H, br d, J=4.9Hz),
8.78 (2H, br d, J=4.9Hz),
8.85 (1H, brs), 9.08 (2H, b
rs). MS m/z (%) [EI]: 424 (
M+, 49), 319 (37), 318 (100
), 106(95), 78(68). Example 28 2,4-bis(2-trifluoromethylbenzoylamino)-[E]-6-[2-(3-pyridyl)ethenyl]-1,3,5-triazine (Compound 29
)

[0089]

[C41]

Yield: 28.0% Melting point: 261.7-262.3°C (from ethyl acetate)
1H-NMR (200MZ) δ (DMSO-d6)
: 6.83 (1H, d, J=16.1Hz),
7.03 (1H, d, J=16.1Hz), 7.4
5 (1H, dd, J=8.1, 4.4Hz),
7.60-7.90 (8H, m), 8.01 (1H,
br d, J=8.1Hz), 8.58(1H,
br d, J=4.4Hz), 8.64(1H,
brs). MSm/z (%) [EI]: 558 (
M+, 11), 489 (35), 461 (43)
, 433 (21), 173 (100), 145 (6
9). Example 29 2-Amino-4-[3,5-di-t-butyl-4- (
3,5-di-t-butyl-4-hydroxybenzoyloxy)benzoylamino]-6-phenyl-1,3
, 5-triazine (compound 43)

[0091]

[C42]

Melting point: 167-170°C (from ethyl acetate) 1H-NMR (200MZ) δ (DMSO-d6
): 1.32 (18H, s), 1.44 (18H
, s), 7.30-7.60 (6H, m), 7.
89 (2H, s), 7.99 (2H, s), 8.
24-8.32 (2H, m). MS m/z (%) [+FAB]: 652.4 (M+
+1), 233.2[-FAB]: 650.3(M
+-1), 418.2 Example 30 2,4-diamino-6-[2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]-1,3
, 5-triazine (compound 50)

[0093]

[C43]

2,4-diamino-[E]-6-[2-
(3,5-di-t-butyl-4-hydroxyphenyl)
Ethenyl]-1,3,5-triazine (Compound 37) 0.30g (0.89mM) was dissolved in a mixture of 10ml of ethanol and 5ml of ethyl acetate, and 5% Pd was added.
40 mg of /C was added and hydrogenated at room temperature under normal pressure for 168 hours. After removing the catalyst by filtration and distilling off the solvent under reduced pressure, the residue was recrystallized from ethyl acetate to give the title compound (0.20 g, 6
6.6%) was obtained. Melting point: 205.1-206.4°C 1H-NMR (200MZ) δ (DMSO-d6)
: 1.35 (18H, s), 2.45-2.60 (
2H, m), 2.75-2.85 (2H, m),
6.55 (4H, br s), 6.64 (1H,
s), 6.88 (2H, s). MS m/z (%) [EI]: 343 (M+, 92
), 328(64), 272(65), 219(
54), 126(44), 125(100). Example 31 (1) 3,5-di-t-butyl-4-methoxymethoxybenzonitrile

[0095]

[C44]

1.9 g (8.2 mM) of 3,5-di-t-butyl-4-hydroxybenzonitrile was dissolved in N,N-
4.7 ml (29 mM) of N-ethyldiisopropylamine was dissolved in 8 ml of dimethylformamide and cooled. Methoxymethyl chloride (80%) under stirring on ice.
After dropping 2.3ml (21.4mM),
Stirred for 1 hour. Water was added, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 40:1) to obtain the title compound (1.43 g, 63.6%) as a yellow solid.
) obtained.

MS m/z: 276, 275 (M
-), 230, 228, 188, 172, 4
5 (2) 2,4-diamino-6- (3,5-di-t-
butyl-4-methoxymethoxyphenyl) -1, 3
, 5-triazine (compound 5)

[0098]

[C45]

Dissolve 1.41 g (5.1 mM) of 3,5-di-t-butyl-4-methoxymethoxybenzonitrile in 8 ml of 2-methoxyethanol, and add dicyandiamide (90%) and potassium hydroxide (85%).
0.40g (6.1mM) was added and heated under reflux for 20 hours. After cooling, water was added, and the precipitated crystals were collected by filtration and washed with water to obtain the title compound (1.5 g, 82.0%). 1H-NMR (DMSO-d6) δ: 1.44 (
18H, s), 3.57 (3H, s), 4.8
9 (2H, s), 6.65 (4H, br s),
8.23 (2H, s). Example 32 2,4-diamino-6- (3,5-di-t-butyl-
4-hydroxy)phenyl)-1,3,5-triazine (compound 38)

[0100]

[C46]

Compound (5) obtained in Example 31 (2)
) was dissolved in a mixture of 50 ml of ethanol and 10 ml of methanol, 1.52 g (8 mM) of p-toluenesulfonic acid hydrate was added, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction solution under reduced pressure, it was made alkaline by adding saturated sodium hydrogen carbonate, and the precipitated crystals were collected by filtration and washed with water and hexane to obtain the title compound (1.12 g,
89.0%) was obtained. Melting point: >300℃ 1H-NM
R(200MZ)δ(DMSO-d6): 1.43
(18H, s), 6.54 (4H, br s),
7.27 (1H, s), 8.12 (2H, s).
MS m/z (%) [EI]: 315 (M+, 48
), 301(21), 300(100), 244
(11). Example 33 2,4-diamino-6-phthalidylmethyl-1, 3,
5-triazine (compound 17)

[0102]

[C47]

2,4-diamino-6-methyl-1,3
, 0.5g (4mM) of 5-triazine was dissolved in 2.5ml of methanesulfonic acid, 0.6g (4mM) of 2-formylbenzoic acid was added, and the mixture was stirred at 110°C for 3 hours. After cooling, the reaction solution was made alkaline by adding diluted sodium hydroxide, and the precipitated crystals were filtered, washed with water, and then recrystallized from ethanol to obtain the title compound (0.10 g, 9.8%). Melting point: 257.0-258.0°C (decomposition) (from ethanol) 1H-NMR (200MZ) δ (DM
SO-d6): 2.71 (1H, dd, J=8
．． 8Hz), 3.12 (1H, dd, J=15.1
, 4.9Hz), 6.10(1H, dd, J=
8.8, 4.9Hz), 6.72(4H, br
s), 7.60-7.90 (4H, m). MS m/
z (%) [EI]: 258 (17), 257 (M+
, 100), 229(59), 212(58),
152 (59), 133 (92), 105 (55)
, 77(62). Test Example 1 The following tests were conducted on the compounds obtained in the above examples, and the results are shown in Table 1.

Leukotriene C4 antagonistic test reagent: Leukotriene C4 (Wako Pure Chemical Industries) histamine dihydrochloride
(Wako Pure Chemical Industries) Experimental animal: SD male rat weighing around 250g (
The gastric fundus conditions of Charles River (Japanese) were used. Nutrient solution: Tyrode's solution NaCl 137.9mM, KCl 2.7mM,
MgCl2・6H2O 0.5mM, NaH2PO4
・2H2O 1.1mM, CaCl2・2H2O 1
．． 8mM, NaHCO3 11.9mM, Glucose 5.6mM Preparation of rat gastric fundus strip specimen: The back of the SD rat's head was hit, the abdomen was opened immediately after exsanguination, and the lower esophagus and upper duodenum were cut and removed with scissors and prepared in advance. Soaked in nutrient solution. Separate the forestomach, incise longitudinally along the lesser curvature, and cut a 3-width incision into the fundus muscle piece.
Scissors were cut alternately into the strips, and the strips were further cut into 3 mm strips. Magnus apparatus and measurement: Suspend the specimen in a 20 ml Magnus tube containing Tyrode's solution, apply a load of 1 g, confirm constant isotonic contraction with acetylcholine 10-5M, wash, and after about 20 minutes, control (100% ) Leukotriene C4 10- as contraction
An isotonic contraction (A) of 8M was recorded. Approximately 30 minutes after washing, test drug was added, and leukotriene C was added 10 minutes later.
4 10-8 M was added and the isotonic contraction (B) was recorded. Determination of activity: Leukotriene D4 Antagonism test reagent: Leukotriene D4 (Wako Pure Chemical Industries) Histamine dihydrochloride (Wako Pure Chemical Industries) Experimental animal: The ileum of a Hartley male guinea pig (Kiwa Animals) weighing approximately 300 g was used. Nutrient solution: Tyrode's solution NaCl 137.9mM, KCl 2.7mM,
MgCl2・6H2O 0.5mM, NaH2PO4
・2H2O 1.1mM, CaCl2・2H2O 1
．． 8mM, NaHCO3 11.9mM, Glucose 5.6mM Ileal muscle removal from a guinea pig: The guinea pig was bled to death, the abdomen was opened, the ileum was removed and the contents were washed, the 10cm from the cecum was removed, and a 2cm cylindrical specimen was prepared. The tube was suspended in a Magnus tube containing Tyrode's nutrient solution at 32°C, 95% O2-5% CO2 gas aeration, and a load of 1 g was applied. Magnus apparatus and measurement: After suspending the excised specimen, heat the specimen at 32°C, 95% O2- every 20 minutes.
A 20 ml Magnus tube was filled with nutrient solution aerated with 5% CO2. Confirm the measurement record of constant isotonic contraction twice with histamine solution (10-5M), wash it, and then
After 0 minutes, leukotriene D4 was added as a control contraction.
An isotonic contraction (A) of 10-8 M was recorded. Furthermore, approximately 30 minutes after washing, the test drug was added, and 10 minutes later, leukotriene D4 10-8M was added to induce isotonic contraction (B).
was recorded. Determination of activity: 5-lipoxygenase inhibition test RBL1 cultured cells were diluted with 1 mM ethylenediaminetetraacetic acid (EDTA) and 1
50mM phosphate buffer containing 0% ethylene glycol (
pH 7.4) and after sonication, 10,000×
The supernatant obtained by centrifugation at G for 10 minutes and then at 105,000 x G for 60 minutes was used as a 5-lipoxygenase enzyme preparation.

As a substrate, 10 μM arachidonic acid, the enzyme preparation prepared as described above, and the compound obtained in the specific example in DMSO were placed in a test tube at a final concentration of 10 μM, and reacted at 37° C. for 10 minutes. Ta. 0.25M butyl 3,5 dinitrobenzoate as internal standard
10 μl was added and extracted with 1.8 ml hexane. The amount of 5-HETE in this was measured by high performance liquid chromatography [column, TSKgel ODS-80TM (TO
YO SODA) Mobile phase, acetonitrile: water: acetic acid =
60:40:0.02 flow rate, 1 ml/min; detection, ultraviolet light (235 nm)].

From this result, the 5-lipoxygenase inhibition rate was calculated using the following formula. C: 5-HETE without the compound obtained in the specific example
Peak area (corrected by internal standard) S: 5-HETE when the compound obtained in the specific example was added
Peak area (corrected by internal standard)

[0107]

[Table 1]

Preparation Example 1 Preparation of tablets (1) 2,4-diamino-[E]-6-[2-
(3,5-di-t-butyl-4-hydroxyphenyl) ethenyl] -1, 3,
5-triazine
10g (2) Lactose
90g (3)
corn starch
29g (
4) Magnesium stearate
1g ────
──────────────────────────
─
1000 tablets
Mix 130g (1), (2) and 17g of cornstarch, granulate it with a paste made from 7g of cornstarch, add 5g of cornstarch and (4) to the granules, and compress the mixture with a compression tablet machine to form tablets. 1000 tablets containing (1) 10mg per tablet
manufactured. Preparation Example 2 Preparation of capsules (1) 2,4-diamino-[E]-6-[2-
(4-hydroxy-3,5-dimethylphenyl)ethenyl]-1,3,5-triazine
200g (2) Lactose
150g
(3) Cornstarch
10
0g (4) Crystalline cellulose

40g (5) Light silicic anhydride

5g (6) Magnesium stearate

5g ────────────────────
──────────
1000 pieces
500g according to the usual method,
10 capsules of the above ingredients mixed and made into granules
00 capsules each weighing 500 mg were produced. Test Example 2 Acute toxicity test When the compounds obtained in Examples 1 to 33 were orally administered to ddY mice (10 mice per group at each dose), 1000 m
No deaths were observed even when administered up to 100 g/kg, confirming that the compound of the present invention has low acute toxicity and high safety.

[0109]

According to the present invention, a novel 2,4-diamino-1,3,5-triazine derivative useful as a leukotriene antagonist can be provided.

Claims (1)

[Claims] [Claim 1] The following formula (1): [Formula 1] [In the formula, X and Y may be the same or different and each represents a hydrogen atom or an acyl group; R is a phenyl group, phthalidylmethyl A group represented by the following formula (2): [Chemical formula 2] (wherein, R2 and R3 represent a lower alkyl group, and Z represents a hydrogen atom or a lower alkoxy-lower alkyl group) or a group represented by the following formula: (3): -A-R1
(3) (wherein A is -CH2CH2- or -C
H=CH-; R1 represents; hydroxyl group, cyano group, lower alkoxy group, lower alkoxycarbonyl group, phenyl group, phenoxy group, benzyloxy group, and phenoxy group substituted with trifluoromethyl group or lower alkyl group; A phenyl group substituted with at least one substituent selected from the group consisting of: naphthyl group, 3-bromophenyl group, 3-fluorophenyl group, 2,5-difluorophenyl group, 2-trifluoromethylphenyl group, 3 -trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3,5-bis (trifluoromethyl)
phenyl group, 4-lower alkylphenyl group, 3,5-di-(lower alkyl)-4-hydroxyphenyl group,
Represents a 3-pyridyl group or a 6-methyl-3-pyridyl group. ); When R is a phenyl group and when R1 is a 3-trifluoromethylphenyl group, X and/or Y represent an acyl group, and R1 is 3
-Pyridyl group, X and Y represent a nicotinoyl group or a 2-trifluoromethylbenzoyl group. ] A 2,4-diamino-1,3,5-triazine derivative or a salt thereof.