JPH04300832A - Leukotriene antagonistic agent containing 2,4-diamino-1,3,5-triazine derivative as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a leukotriene antagonistic agent, containing a partially new 2,4-diamino-1,3,5-triazine derivative as an active ingredient and useful as a therapeutic and preventive agent for allergic, inflammatory, cardiovascular diseases, etc. CONSTITUTION:A leukotriene antagonistic agent containing a partially new compound expressed by formula I (X and Y are H or acyl; R is substituted or unsubstituted phenyl, phthalidylmethyl or AR<1>; A is CH2CH2 or CH=CH; R<1> is substituted or unsubstituted phenyl, naphthyl or pyridyl) or its pharmaceutically permissible salt, e.g. 2,4-diamino-(E)-6-[2-(3-pyridine) ethenyl]-3,5-triazine expressed by formula II as an active ingredient is obtained. The aforementioned compound can orally or parenterally be administered. In the case of the oral administration, the above-mentioned compound is normally preferably administered in a dose of 0.2-25mg/kg body weight expressed in terms of the aforementioned compound for an adult per day in several divided portions.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to leukotriene antagonists useful as therapeutic and preventive agents for allergic diseases, inflammatory diseases, circulatory disorders, etc.

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 object of the present invention is to provide new uses for 2,4-diamino-1,3,5-triazine derivatives.

[0005]

[Means for Solving the Problems] The leukotriene antagonist of the present invention has the following formula (1):

[0006]

[Case 2]

[In the formula, X and Y may be the same or different and each represents a hydrogen atom or an acyl group; R represents a substituted or unsubstituted phenyl group or phthalidylmethyl group, or The following formula (2): -A-R1
(2)(
In the formula, A is -CH2CH2- or -CH=CH
- represents; R1 represents a substituted or unsubstituted phenyl group, naphthyl group or pyridyl group. ) represents a group represented by ] 2,4-diamino-1, 3, 5
- It is characterized by containing a triazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

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. Furthermore, the phenyl group or phthalidylmethyl group represented by R may be unsubstituted or substituted with an appropriate substituent. Such suitable substituents include, for example, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxy-lower alkoxy group, a trifluoromethyl group, and the like.

Further, the phenyl group, naphthyl group or pyridyl group represented by R1 may be unsubstituted or substituted with a suitable substituent. Such suitable substituents include, for example, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxy-lower alkoxy group, a trifluoromethyl group, a phenyl group, a phenoxy group, and a benzyl group. , a benzyloxy group, and a phenoxy group substituted with a trifluoromethyl group or a lower alkyl group.

[0010] In this specification, halogen atom refers to chlorine atom, fluorine atom, bromine atom, etc.; lower alkyl group refers to alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group. group, butyl group, ter
A t-butyl group, a sec-butyl group, a pentyl group, a hexyl group, etc.; 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; a lower alkoxycarbonyl group has 1 carbon number
~6 alkoxycarbonyl groups, such as methoxycarbonyl groups, ethoxycarbonyl groups; lower alkoxy-
The lower alkoxy group refers to an alkoxy-alkoxy group having 1 to 6 carbon atoms, such as a methoxymethoxy group.

Among the compounds represented by the above formula (1), compounds in which R is -CH=CH-R1, ie, the following formula (3):

0012

[Chemical formula 3]

The compound represented by the following formula (4):

[
0014

[C4]

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 represented by the above formula (1), the compound in which R is -CH2CH2-R1 can be produced by reducing the above compound (3) according to a conventional method. Among the compounds represented by the above formula (1), compounds in which X and/or Y are acyl groups are represented by the following formula (5):

0
017]

[C5]

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 represented by the above formula (1), the compounds in which R is a substituted or unsubstituted phenyl group,
It can be produced by reacting the corresponding benzonitrile derivative with dicyandiamide in the presence of a base according to the method described in Japanese Patent Publication No. 55-4751. In this case, when R is a phenyl group substituted with a hydroxyl group, as exemplified 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. It is preferable to use

[0019]

[C6]

(In the formula, R2 and R3 represent, for example, lower alkyl.) Among the compounds represented by the above formula (1), compounds in which R is a substituted or unsubstituted phthalidylmethyl group, that is, the following formula: (6):

[0021]

[C7]

The compound represented by the formula (wherein R4 represents a hydrogen atom or an appropriate substituent) is a compound represented by the above compound (
4) and the following equation (7):

[0023]

[Chemical formula 8]

It can be produced by reacting a compound represented by the formula (wherein R5 represents a hydrogen atom or a lower alkyl group) in the presence of an acid. Also, the following formula (8):

[0025]

[Chemical formula 9]

The compound represented by [0026] and the following formula (9):

0
027]

[Chemical formula 10]

By reacting the acid chloride represented by the formula (wherein R2 and R3 have the same meanings as above), one of X and Y of the compound represented by the formula (1) is substituted. or a compound in which an unsubstituted 4-(4-hydroxybenzoyloxy)benzoyl group and the other is a hydrogen atom, i.e., the following formula (10):

[0029]

[Chemical formula 11]

The compound shown below can be produced. The leukotriene antagonist of the present invention has the formula (1)
Compounds represented by or pharmaceutically acceptable salts thereof, such as hydrochloride, maleate, and fumarate, are used as active ingredients for the treatment and prevention of allergic diseases, inflammatory diseases, circulatory disorders, etc. Useful as a medicine.

Next, administration and formulation of the leukotriene antagonist 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 required, including tablets, tablets, etc.
Examples include oral preparations such as capsules, granules, fine granules, and powders, and parenteral preparations such as injections and suppositories.

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 general formula (1), which is the active ingredient of the leukotriene antagonist of the present invention, can be prepared as a solution, a powder, or a powder according to a conventional method for manufacturing a formulation using appropriate solvents, excipients, adjuvants, etc. used in formulations. It can be administered orally or parenterally in the form of formulations such as granules, tablets, enteric coated formulations, and capsules.

[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. Furthermore, the leukotriene antagonist of the present invention can be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain flavoring fillers and coloring agents. .

[0034]

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

[0035]

[Chemical formula 12]

2,4-diamino-6-methyl-1,3
, 5 g (40 mM) of 5-triazine in 50 m of formic acid.
Dissolve in 4-formylbenzoic acid methyl ester6.
56g (40mM) was added and 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). Synthesis Examples 2 and 3 The following compounds were synthesized in the same manner as in Synthesis Example 1. Synthesis Example 2 2,4-diamino-[E]-6-[2-(4-cyanophenyl) ethenyl]-1,3,5-triazine (
Compound 19)

[0037]

[Chemical formula 13]

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). Synthesis Example 3 2,4-diamino-[E]-6-[2-(4-ethoxycarbonylphenyl)ethenyl]-1, 3, 5-triazine (compound 22)

[0039]

[Chemical formula 14]

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). Synthesis example 4 2,4-diamino-[E]-6-[2-(4-trifluoromethylphenyl)ethenyl]-1, 3, 5-triazine (compound 20)

[0041]

[Chemical formula 15]

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). Synthesis Examples 5 to 13 The following compounds were synthesized in the same manner as in Synthesis Example 4. Synthesis Example 5 2,4-diamino-[E]-6-[2-(2-trifluoromethylphenyl)ethenyl]-1, 3, 5-triazine (Compound 21)

[0043]

[Chemical formula 16]

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). Synthesis Example 6 2,4-diamino-[E]-6-[2-[3,5-bis(trifluoromethyl)phenyl]ethenyl]-1,
3,5-triazine (compound 24)

[0045]

[Chemical formula 17]

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). Synthesis Example 7 2,4-diamino-[E]-6-[2-(2,5-difluorophenyl)ethenyl]-1, 3, 5-triazine (compound 25)

[0047]

[Chemical formula 18]

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). Synthesis Example 8 2,4-diamino-[E]-6-[2-(6-methylpyridin-3-yl)ethenyl]-1, 3, 5-triazine (compound 26)

[0049]

[Chemical formula 19]

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). Synthesis Example 9 2,4-diamino-[E]-6-[2-(4-methoxyphenyl)ethenyl]-1, 3, 5-triazine (
Compound 32)

[0051]

[C20]

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). Synthesis Example 10 2,4-diamino-[E]-6-[2-(2-naphthyl)ethenyl]-1, 3, 5-triazine (compound 3
3)

[0053]

[C21]

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). Synthesis Example 11 2,4-diamino-[E]-6-[2-(3-phenoxyphenyl)ethenyl]-1, 3, 5-triazine (compound 34)

[0055]

[C22]

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). Synthesis Example 12 2,4-diamino-[E]-6-[2-(3-bromophenyl)ethenyl]-1,3,5-triazine (compound 35)

[0057]

[C23]

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). Synthesis Example 13 2,4-diamino-[E]-6-[2-(3-fluorophenyl)ethenyl]-1, 3, 5-triazine (
Compound 36)

[0059]

[C24]

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). Synthesis Example 14 2,4-diamino-[E]-6-[2-(3,5-di-
t-butyl-4-hydroxyphenyl)ethenyl]-1
, 3, 5-triazine (compound 37)

[0061]

[C25]

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). Synthesis Example 15 2,4-diamino-[E]-6-[2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]-1,3
, 5-triazine (compound 49)

[0063]

[C26]

The title compound was synthesized in the same manner as in Synthesis 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). Synthesis Example 16 2,4-diamino-[E]-6-[2-(4-isopropylphenyl)ethenyl]-1, 3, 5-triazine (compound 41)

[0065]

[C27]

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). Synthesis Example 17 2,4-diamino-[E]-6-[2-(4-biphenyl)ethenyl]-1,3,5-triazine (compound 4
2)

[0067]

[C28]

2,4-diamino-6-methyl-1,3
, 1.25 g (10 mM) of 5-triazine was dissolved in 30 ml of 2-methoxyethanol, and potassium hydroxide (8
Add 0.66g (10mM) of 5%) and 2.91g (16mM) of 4-biphenylcarboxaldehyde at 90°C.
The mixture was stirred for 16 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 (0.60 g, 20.7%).
I got it. Melting point: 276°C (decomposition) 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). Synthesis Examples 18 to 22 The following compounds were synthesized in the same manner as in Synthesis Example 17. Synthesis Example 18 2,4-diamino-[E]-6-[2-(4-benzyloxyphenyl)ethenyl]-1, 3, 5-triazine (compound 44)

[0069]

[C29]

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). Synthesis Example 19 2,4-diamino-[E]-6-[2-[3,4-bis(benzyloxy)phenyl]ethenyl]-1, 3,
5-triazine (compound 45)

[0071]

[C30]

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). Synthesis Example 20 2,4-diamino-[E]-6-[2-(1-naphthyl)ethenyl]-1, 3, 5-triazine (compound 4
6)

[0073]

[Chemical formula 31]

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)
．． Synthesis Example 21 2,4-diamino-[E]-6-[2-[3-(3-trifluoromethylphenoxy)phenyl]ethenyl]-
1,3,5-triazine (compound 47)

0075
]

[C32]

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). Synthesis Example 22 2,4-diamino-[E]-6-[2-[3- (4-
t-butylphenoxy) phenyl]ethenyl]-1,
3,5-triazine (compound 48)

[0077]

[Chemical formula 33]

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). Synthesis Example 23 2,4-diamino-[E]-6-[2-(2-trifluoromethylphenyl)ethenyl]-1, 3, 5
-Triazine maleate (Compound 21 (Synthesis Example 5)
Compound) maleate salt)

[0079]

[C34]

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). Synthesis Example 24 2,4-diamino-[E]-6-[2-(2-trifluoromethylphenyl)ethenyl]-1, 3, 5
-Triazine hydrochloride (hydrochloride of compound 21 (compound of synthesis example 5))

[0081]

[C35]

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)
．． Synthesis Example 25 2,4-bis(nicotinoylamino)-[E]-6
-[2-(3-trifluoromethylphenyl) ethenyl]-1, 3, 5-triazine (Compound 23)

[
0083

[C36]

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). Synthesis Examples 26 to 29 The following compounds were synthesized in the same manner as in Synthesis Example 25. Synthesis Example 26 2-acetylamino-4-amino-[E]-6-[2-
(2-trifluoromethylphenyl) ethenyl]-
1,3,5-triazine (compound 27)

[0085]

[C37]

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

[0087]

[C38]

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). Synthesis Example 28 2,4-bis(2-trifluoromethylbenzoylamino)-[E]-6-[2-(3-pyridyl)ethenyl]-1,3,5-triazine (Compound 29
)

[0089]

[C39]

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). Synthesis 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]

[C40]

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 Synthesis Example 30 2,4-diamino-6-[2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]-1,3
, 5-triazine (compound 50)

[0093]

[C41]

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). Synthesis Example 31 (1) 3,5-di-t-butyl-4-methoxymethoxybenzonitrile

[0095]

[C42]

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]

[C43]

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). Synthesis Example 32 2,4-diamino-6- (3,5-di-t-butyl-
4-hydroxy)phenyl-1,3,5-triazine (compound 38)

[0100]

[C44]

Synthesis Example 31 Compound (5) obtained in (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°C 1H-NMR (200MZ) δ (DMSO-d6)
: 1.43 (18H, s), 6.54 (4H,
br s), 7.27 (1H, s), 8.12 (2
H, s). MS m/z (%) [EI]: 315 (
M+, 48), 301 (21), 300 (100
), 244(11). Synthesis Example 33 2,4-diamino-6-phthalidylmethyl-1, 3,
5-triazine (compound 17)

[0102]

[C45]

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).

[0104]

[Example 1] New compound obtained in the above synthesis example and the known compound 2,4-diamino-(E)-6
-[2- (3-pyridyl) ethenyl]-1, 3,
5-triazine (compound of Example 1 of JP-A-2-223566) (compound 1), 2,4-diamino-
(E) -6-[2- (2,4-dichlorophenyl)
Ethenyl]-1, 3, 5-triazine (compound of reference example in JP-A No. 2-223566) (compound 7)
, 2,4-diamino- (E) -6-[2- (3-
trifluoromethylphenyl) ethenyl]-1, 3
, 5-triazine maleate (JP-A-2-22
Compound of Example 9 of No. 3566) (Compound 11), 2
,4-diamino-[E]-6-styryl-1, 3,
5-triazine [J. Org. Chem. ,27 17
17 (1962)] (Compound 31) and 2,4-diamino-[E]-6-[2- (4-chlorophenyl)
ethenyl]-1,3,5-triazine [J. Org
．． Chem. , 27 1717 (1962)] (Compound 39), the following tests were conducted and the results are shown in Table 1.

For reference, the structural formulas of the above-mentioned known compounds are shown below.

[0106]

[C46]

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: Hit the back of the SD rat's head, exsanguinate to death, immediately open the abdomen, and cut and remove the lower esophagus and upper duodenum with scissors and prepare in advance. Soaked in nutrient solution. The forestomach was separated and incised longitudinally along the lesser curvature, scissors were made alternately to a width of 3 mm in the fundus muscle pieces, and the pieces were further cut into muscle pieces of 3 mm in length. Magnus apparatus and measurement: 20 ml containing Tyrode's solution
Suspend the specimen in a Magnus tube, apply a load of 1 g, confirm constant isotonic contraction with 10-5 M of acetylcholine, wash, and after about 20 minutes, check the isotonic contraction of 10-8 M of leukotriene C4 as a control (100%) contraction. Contractions (A) were recorded. Approximately 30 minutes after washing, the test drug was added and the mixture was washed for 10 minutes.
After minutes, leukotriene C4 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 Removal of ileal muscle from guinea pig: The guinea pig was bled to death, the abdomen was opened, the ileum was removed, the contents were washed, and the ileum was removed from near the cecum.
As a cylindrical specimen of approximately 2 cm, except for the area near 0 cm, the sample was heated at 32°C9.
It was suspended in a Magnus tube containing Tyrode's nutrient solution with 5% O2-5% CO2 gas aeration, and a load of 1 g was applied. Magnus apparatus and measurement: After suspending the excised specimen, a 20 ml Magnus tube was filled with a nutrient solution aerated with 95% O2-5% CO2 at 32°C every 20 minutes. histamine solution
(10-5M) to confirm the measurement record of constant isotonic contraction twice, and after washing for another 20 minutes, control contraction was performed using leukotriene D4 10-8M isotonic contraction (A
) was recorded. Further, about 30 minutes after washing, the test drug was added, and 10 minutes later, leukotriene D4 10-8M was added, and the 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 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-HE without containing the compound obtained in the specific example
Peak area of TE (corrected by internal standard) S: 5-HETE when the compound obtained in the specific example was added
Peak area (corrected by internal standard)

[0110]

[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. 100 tablets containing (1) 10mg per tablet
0 pieces were manufactured. Preparation example 2 Preparation of capsules

(1) 2,4-
Diamino-[E]-6-[2- (4-hydro
xy-3,5-dimethylphenyl)ethenyl]-
1,3,5-triazine

200g (2) Lactose

150g (3) Cornstarch
100g (4) Crystalline cellulose
40g (5)
Light silicic anhydride
5g (6
) Magnesium stearate
5g ─────
──────────────────────────
─
1000 pieces
500gMix each of the above ingredients according to the usual method, make granules, fill 1000 capsules, 1
Capsules of 500 mg each were manufactured. Test Example 1 Acute toxicity test The known compounds used in Synthesis Examples 1 to 33 and Example 1 were
When administered orally to dY mice (10 doses per group)
No deaths were observed even when administered up to 1000 mg/kg, confirming that the active ingredient of the leukotriene antagonist of the present invention has low acute toxicity and high safety.

[0112]

Effects of the Invention According to the present invention, 2,4-diamino-1
, 3,5-triazine derivatives as an active ingredient can be provided.

Claims (1)

[Claims] Claim 1: The following 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 substituted or unsubstituted, It represents a phenyl group or a phthalidylmethyl group, or the following formula (2): -A-R1
(2) (wherein A is -CH2CH2- or -
CH=CH-; R1 is substituted or unsubstituted
, represents a phenyl group, a naphthyl group or a pyridyl group. )
represents a group represented by ] 2,4-diamino-
A leukotriene antagonist characterized by containing a 1,3,5-triazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.