JPH04300874A - New 2,4-diamino-1,3,5-triazine derivative - Google Patents
New 2,4-diamino-1,3,5-triazine derivativeInfo
- Publication number
- JPH04300874A JPH04300874A JP6682391A JP6682391A JPH04300874A JP H04300874 A JPH04300874 A JP H04300874A JP 6682391 A JP6682391 A JP 6682391A JP 6682391 A JP6682391 A JP 6682391A JP H04300874 A JPH04300874 A JP H04300874A
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- diamino
- triazine
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- -1 2,5-difluorophenyl group Chemical group 0.000 claims description 60
- 239000000126 substance Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
Abstract
Description
【0001】0001
【産業上の利用分野】本発明は、新規2,4−ジアミノ
−1, 3,5−トリアジン誘導体に関するものである
。FIELD OF THE INVENTION This invention relates to novel 2,4-diamino-1,3,5-triazine derivatives.
【0002】0002
【従来の技術】ロイコトリエンに関しては、その生物学
的意義が広く研究され、特に新生児酸素欠乏症、肺循環
昇圧、成人性呼吸困難症候群、乾癬、脊椎関節炎、リウ
マチ性関節炎、痛風、炎症性腸炎等、種々の疾患におけ
る意義が報告されており、ロイコトリエンに対して拮抗
作用を示すロイコトリエン拮抗剤は、アレルギー性疾患
、炎症性疾患、循環器障害等の治療・予防薬として有用
である。[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.
【0003】一方、2,4−ジアミノ−1, 3, 5
−トリアジン誘導体については、抗潰瘍剤としての用途
が報告されているが (特開平2−223566号、特
公昭55−4751号) 、ロイコトリエンに対する作
用については、何ら報告されていない。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】0004
【発明が解決しようとする課題】本発明は、ロイコトリ
エンに対して拮抗作用を示す新規2,4−ジアミノ−1
, 3, 5−トリアジン誘導体を提供することを目的
とする。OBJECTS OF THE INVENTION The present invention provides novel 2,4-diamino-1
, 3,5-triazine derivatives.
【0005】[0005]
【課題を解決するための手段】本発明は、次式 (1)
:[Means for Solving the Problems] The present invention is based on the following formula (1)
:
【0006】[0006]
【化3】[Chemical formula 3]
【0007】〔式中、X及びYは、同一でも異なってい
てもよく、それぞれ水素原子又はアシル基を表し;Rは
、フェニル基、フタリジルメチル基、次式 (2) :
[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】[0008]
【化4】[C4]
【0009】(式中、 R2 及び R3 は、低級ア
ルキル基を表し、Zは、水素原子又は低級アルコキシ−
低級アルキル基を表す。)
で示される基又は次式 (3) :
−A−R1
(3)(式中、Aは、 −CH2CH2− 又は −C
H=CH−を表し; R1 は;水酸基、シアノ基、低
級アルコキシ基、低級アルコキシカルボニル基、フェニ
ル基、フェノキシ基、ベンジルオキシ基、及びトリフル
オロメチル基又は低級アルキル基で置換されたフェノキ
シ基からなる群から選ばれる少なくとも1個の置換基で
置換されたフェニル基;ナフチル基、3−ブロモフェニ
ル基、3−フルオロフェニル基、2,5−ジフルオロフ
ェニル基、2−トリフルオロメチルフェニル基、3−ト
リフルオロメチルフェニル基、4−トリフルオロメチル
フェニル基、3,5−ビス (トリフルオロメチル)
フェニル基、4−低級アルキルフェニル基、3,5−ジ
− (低級アルキル) −4−ヒドロキシフェニル基、
3−ピリジル基又は6−メチル−3−ピリジル基を表す
。)
で示される基を表すが;Rがフェニル基である場合及び
R1 が3−トリフルオロメチルフェニル基である場
合、X及び/又はYは、アシル基を表し、 R1 が3
−ピリジル基である場合、X及びYは、ニコチノイル基
又は2−トリフルオロメチルベンゾイル基を表す。〕で
示される2,4−ジアミノ−1, 3, 5−トリアジ
ン誘導体又はその塩に関するものである。(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.
【0010】前記式 (1) において、X又はYで表
されるアシル基としては、例えば、アセチル基、置換又
は非置換の、ニコチノイル基又はベンゾイル基等が挙げ
られる。本明細書において、低級アルキル基とは、炭素
数1〜6のアルキル基、例えばメチル基、エチル基、プ
ロピル基、イソプロピル基、ブチル基、tert−ブチ
ル基、 sec−ブチル基、ペンチル基、ヘキシル基等
を;低級アルコキシ基とは、炭素数1〜6のアルコキシ
基、例えばメトキシ基、エトキシ基、プロポキシ基等を
;低級アルコキシカルボニル基とは、炭素数1〜6のア
ルコキシカルボニル基、例えばメトキシカルボニル基、
エトキシカルボニル基等を;低級アルコキシ−低級アル
キル基とは、炭素数1〜6のアルコキシ−アルキル基、
例えばメトキシメチル基等をいう。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.
【0011】前記式 (1) で示される本発明の化合
物のうち、Rが−CH=CH−R1 である化合物、即
ち、次式 (4) :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】0012
【化5】[C5]
【0013】で示される化合物は、次式 (5) :The compound represented by the following formula (5):
【
0014】[
0014
【化6】[C6]
【0015】で示される化合物と式 R1−CHOで示
されるアルデヒド化合物を酸又は塩基の存在下で縮合さ
せることにより製造することができる。酸としては、例
えばメタンスルホン酸、ギ酸、硫酸が挙げられ、塩基と
しては、例えば水酸化カリウム、水酸化ナトリウム、T
riton B、ナトリウムメトキシドが挙げられる。
酸を用いる場合は、通常、無溶媒で反応を行うが、塩基
を用いる場合は、例えばメタノール、エタノール、2−
メトキシエタノールのような溶媒を用いる。反応温度は
、好ましくは60〜120℃、反応時間は通常1時間〜
7日間である。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.
【0016】前記式 (1) で示される本発明の化合
物のうち、Rが −CH2CH2−R1 である化合物
は、前記化合物 (4) を常法に従って還元すること
により製造することができる。前記式 (1) で示さ
れる本発明の化合物のうち、X及び/又はYがアシル基
である化合物は、次式 (6) :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】[0017]
【化7】[C7]
【0018】で示される化合物を、対応する酸塩化物又
は酸無水物とピリジン中で反応させることにより製造す
ることができる。反応温度は、通常80〜140℃、好
ましくは 110〜120℃、反応時間は、通常3〜
8時間である。前記式 (1) で示される本発明の化
合物のうち、Rが置換又は非置換のフェニル基である化
合物は、特公昭55−4751号公報記載の方法に従っ
て、対応するベンゾニトリル誘導体とジシアンジアミド
を塩基の存在下に反応させることにより製造することが
できる。この際、前記式 (2) においてZが水素原
子である場合は、以下に例示するように、水酸基をメト
キシメトキシ基として保護した形で環化させた後、酸で
処理して水酸基に変換する方法を用いることが好ましい
。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】[0019]
【化8】[Chemical formula 8]
【0020】(式中、 R2 及び R3 は、例えば
低級アルキルを表す。)
前記式 (1) で示される本発明の化合物のうち、R
がフタリジルメチル基である化合物、即ち、次式 (7
) :(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】[0021]
【化9】[Chemical formula 9]
【0022】で示される化合物は、前記化合物 (5)
と次式 (8) :The compound represented by the above is the compound (5)
and the following equation (8):
【0023】[0023]
【化10】[Chemical formula 10]
【0024】(式中、 R4 は、水素原子又は低級ア
ルキル基を表す。)
で示される化合物を酸の存在下に反応させることにより
製造することができる。また、次式 (9) :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】00
25]
【化11】[Chemical formula 11]
【0026】で示される化合物と次式 (10) :The compound represented by [0026] and the following formula (10):
【
0027】[
0027
【化12】[Chemical formula 12]
【0028】(式中、 R2 及び R3 は、前記と
同義である。)
で示される酸塩化物を反応させることにより、前記式
(1) で示される本発明の化合物に含まれる次式 (
11) :(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】[0029]
【化13】[Chemical formula 13]
【0030】で示される化合物を製造することができる
。本発明の化合物である前記式 (1) で示される化
合物及びその塩、例えば塩酸塩、マレイン酸塩、フマル
酸塩は、ロイコトリエンに対して拮抗作用を示すもので
あり、アレルギー性疾患、炎症性疾患、循環器障害等の
治療・予防薬として有用である。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.
【0031】次に、本発明の化合物の投与及び製剤化に
ついて説明する。一般式 (1) の化合物はそのまま
、あるいは慣用の製剤担体と共に動物及び人に投与する
ことができる。投与形態としては、特に限定がなく、必
要に応じ適宜選択して使用され、錠剤、カプセル剤、顆
粒剤、細粒剤、散剤等の経口剤、注射剤、坐剤等の非経
口剤が挙げられる。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.
【0032】経口剤として所期の効果を発揮するために
は、患者の年令、疾患の程度により異なるが、通常成人
で一般式 (1) の化合物として1日当り0.2〜2
5mg/kg体重を数回に分けて投与するのが好ましい
。本発明の化合物は、製剤に用いられる適当な溶剤、賦
形剤、補助剤などを使用して、製剤製造の常法に従って
液剤、散剤、顆粒剤、錠剤、腸溶剤及びカプセル剤など
の製剤となし、経口又は非経口投与することができる。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】処方にあたっては、他の医療活性成分との
配合剤とすることもできる。経口投与のためには、少な
くとも一種の賦形剤、例えばデンプン、乳糖、白糖、マ
ンニット、カルボキシメチルセルロース等を用いて錠剤
、丸剤、カプセル剤、散剤、顆粒剤等に処方することが
できる。この種の製剤には、適宜前記賦形剤の他に、例
えばステアリン酸マグネシウム、ラウリル硫酸ナトリウ
ム、タルク等の滑沢剤、デキストリン、結晶セルロース
、ポリビニルピロリドン、アラビアゴム、トウモロコシ
デンプン、ゼラチン等の結合剤、繊維素グリコール酸ナ
トリウム、繊維素グリコールカルシウム、バレイショデ
ンプン、カルボキシメチルセルロース等の崩壊剤、軽質
無水ケイ酸等の流動性促進剤を使用することができる。
また、本発明の化合物を有効成分とする薬剤は、懸濁液
、エマルジョン剤、シロップ剤、エリキシル剤としても
投与することができ、これらの各種剤形には、矯味充填
剤、着色剤を含有せしめてもよい。[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】[0034]
【実施例】以下、実施例、試験例及び調剤例により、本
発明を更に詳細に説明するが、本発明の範囲はこれらに
限定されるものではない。
実施例1
2,4−ジアミノ−[E]−6−〔2− (4−メトキ
シカルボニルフェニル) エテニル〕−1, 3, 5
−トリアジン (化合物18)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】[0035]
【化14】[Chemical formula 14]
【0036】2,4−ジアミノ−6−メチル−1, 3
, 5−トリアジン5g (40mM) をギ酸50m
lに溶かし、4−ホルミル安息香酸メチル6.56g
(40mM) を加え、91時間加熱還流した。反応液
を減圧下に濃縮後、飽和炭酸水素ナトリウムを加えアル
カリ性とし、析出結晶をろ取水洗後、2−メトキシエタ
ノールとエタノールの混合溶媒から再結晶し標記化合物
(4.58g, 42.3%) を得た。
融点:258℃ (分解)
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).
実施例2及び3
実施例1と同様の方法により以下の化合物を合成した。
実施例2
2,4−ジアミノ−[E]−6−〔2− (4−シアノ
フェニル) エテニル〕−1,3,5−トリアジン (
化合物19)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】[0037]
【化15】[Chemical formula 15]
【0038】収率:17.9%
融点:>300℃ (2−メトキシエタノールから)
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).
実施例3
2,4−ジアミノ−[E]−6−〔2−(4−エトキシ
カルボニルフェニル)エテニル〕−1, 3, 5−ト
リアジン(化合物22)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】[0039]
【化16】[Chemical formula 16]
【0040】収率:15.0%
融点:229.6〜230.8℃(エタノールから)
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).MS
m/z(%)[EI]: 285(M+, 74),
284(100), 256(25), 242(2
2).
実施例4
2,4−ジアミノ−[E]−6−〔2−(4−トリフル
オロメチルフェニル)エテニル〕−1, 3, 5−ト
リアジン(化合物20)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】[0041]
【化17】[Chemical formula 17]
【0042】2,4−ジアミノ−6−メチル−1, 3
, 5−トリアジン5g (40mM) をメタンスル
ホン酸28mlに溶かし、4−トリフルオロメチルベン
ズアルデヒド5.5ml (40mM)を加え 110
℃で2時間攪拌した。冷後、反応液に希水酸化ナトリウ
ムを加えアルカリ性とし、析出結晶をろ取水洗後、エタ
ノールから再結晶し標記化合物 (6.09g, 54
.2%)を得た。
融点:274.9〜275.7℃
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).
実施例5〜13
実施例4と同様の方法により以下の化合物を合成した。
実施例5
2,4−ジアミノ−[E]−6−〔2−(2−トリフル
オロメチルフェニル)エテニル〕−1, 3, 5−ト
リアジン(化合物21)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】[0043]
【化18】[Chemical formula 18]
【0044】収率:54.0%
融点:250.0〜250.9℃(エタノールから)
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).
実施例6
2,4−ジアミノ−[E]−6−[2−〔3,5−ビス
(トリフルオロメチル)フェニル〕エテニル]−1,
3, 5−トリアジン(化合物24)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】[0045]
【化19】[Chemical formula 19]
【0046】収率:50.6%
融点:208.2〜209.0℃(エタノールから)
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).
実施例7
2,4−ジアミノ−[E]−6−〔2−(2,5−ジフ
ルオロフェニル)エテニル〕−1, 3, 5−トリア
ジン(化合物25)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】[0047]
【化20】[C20]
【0048】融点:>300℃(2−メトキシエタノー
ルから)
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).
実施例8
2,4−ジアミノ−[E]−6−〔2−(6−メチルピ
リジン−3−イル)エテニル〕−1, 3, 5−トリ
アジン(化合物26)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】[0049]
【化21】[C21]
【0050】収率:36.6%
融点:253.7〜254.3℃(エタノールから)
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).
実施例9
2,4−ジアミノ−[E]−6−〔2−(4−メトキシ
フェニル)エテニル〕−1, 3, 5−トリアジン(
化合物32)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】[0051]
【化22】[C22]
【0052】収率:27.4%
融点:244℃(分解)(メタノールから) 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).
実施例10
2,4−ジアミノ−[E]−6−〔2−(2−ナフチル
)エテニル〕−1, 3, 5−トリアジン(化合物3
3)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】[0053]
【化23】[C23]
【0054】融点:237.8〜238.4℃(メタノ
ールから) 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).
実施例11
2,4−ジアミノ−[E]−6−〔2−(3−フェノキ
シフェニル)エテニル〕−1, 3, 5−トリアジン
(化合物34)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】[0055]
【化24】[C24]
【0056】融点:167.6〜169.4℃(メタノ
ールから) 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).
実施例12
2,4−ジアミノ−[E]−6−〔2−(3−ブロモフ
ェニル)エテニル〕−1,3,5−トリアジン(化合物
35)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】[0057]
【化25】[C25]
【0058】収率:59.9%
融点:188.9〜189.7℃(メタノール−2−メ
トキシエタノールから)
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
r s).MS m/z(%)[EI]: 293(M
+, 77), 292(100), 291(M+,
76), 290(93),250(29), 24
8(28), 128(40).実施例13
2,4−ジアミノ−[E]−6−〔2−(3−フルオロ
フェニル)エテニル〕−1, 3, 5−トリアジン(
化合物36)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】[0059]
【化26】[C26]
【0060】融点:275.9〜276.8℃(メタノ
ール−2−メトキシエタノールから)
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).
実施例14
2,4−ジアミノ−[E]−6−〔2−(3,5−ジ−
t−ブチル−4−ヒドロキシフェニル)エテニル〕−1
, 3, 5−トリアジン(化合物37)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】[0061]
【化27】[C27]
【0062】2,4−ジアミノ−6−メチル−1, 3
, 5−トリアジン2.5g (20mM) をギ酸7
5mlに溶かし、3,5−ジ−t−ブチル−4−ヒドロ
キシベンズアルデヒド5.15g (22mM) を加
え 168時間加熱還流した。反応液を減圧下に濃縮し
、得られた残渣をシルカゲルフラッシュカラムクロマト
グラフィー(CHCl3 : MeOH=9:1) で
精製後、2−プロパノールより再結晶し、標記化合物(
0.85g, 12.5%)を得た。
融点:253.3〜255.7℃
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).実施例15
2,4−ジアミノ−[E]−6−〔2−(4−ヒドロキ
シ−3,5−ジメチルフェニル)エテニル〕−1, 3
, 5−トリアジン(化合物49)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】[0063]
【化28】[C28]
【0064】実施例14と同様の方法により標記化合物
を合成した。
収率:18.7%
融点:285.9〜288.1℃(分解)(2−プロパ
ノール−メタノールから)
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).実施例
16
2,4−ジアミノ−[E]−6−〔2−(4−イソプロ
ピルフェニル)エテニル〕−1, 3, 5−トリアジ
ン(化合物41)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】[0065]
【化29】[C29]
【0066】2,4−ジアミノ−6−メチル−1, 3
, 5−トリアジン1.25g (10mM) を2−
メトキシエタノール20mlに溶かし、Triton
B (40%メタノール溶液) 9.1ml(20mM
)及び4−イソプロピルベンズアルデヒド3ml(19
.8mM)を加え80℃で6.5時間攪拌した。冷後水
を加え、析出結晶をろ取水洗後、2−メトキシエタノー
ルとメタノールの混合溶媒から再結晶し、標記化合物
(0.91g, 35.7%)を得た。
融点:247.8〜248.8℃
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).
実施例17
2,4−ジアミノ−[E]−6−〔2−(4−ビフェニ
ル)エテニル〕−1, 3,5−トリアジン(化合物4
2)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】[0067]
【化30】[C30]
【0068】2,4−ジアミノ−6−メチル−1, 3
, 5−トリアジン1.25g(10mM)を2−メト
キシエタノール30mlに溶かし、KOH (85%)
0.66g(10mM)及び4−ビフェニルカルボキシ
アルデヒド2.91g(16mM)を加え90℃で16
時間攪拌した。冷後水を加え、析出結晶をろ取水洗後、
2−メトキシエタノールから再結晶し、標記化合物(0
.60g、20.7%)を得た。
融点:276℃(分解)(メタノール−2−メトキシエ
タノールから)
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).実施例18〜22
実施例17と同様の方法により以下の化合物を合成した
。
実施例18
2,4−ジアミノ−[E]−6−〔2−(4−ベンジル
オキシフェニル)エテニル〕−1, 3, 5−トリア
ジン(化合物44)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】[0069]
【化31】[Chemical formula 31]
【0070】収率:16.6%
融点:227.2〜227.9℃(メタノール−2−メ
トキシエタノールから)
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).
実施例19
2,4−ジアミノ−[E]−6−[2−〔3,4−ビス
(ベンジルオキシ)フェニル〕エテニル]−1, 3,
5−トリアジン(化合物45)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】[0071]
【化32】[C32]
【0072】収率:54.6%
融点:203.2 〜203.7 ℃(メタノール−2
−メトキシエタノールから)
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).実施例20
2,4−ジアミノ−[E]−6−〔2−(1−ナフチル
)エテニル〕−1, 3, 5−トリアジン(化合物4
6)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】[0073]
【化33】[Chemical formula 33]
【0074】収率:27.8%
融点:220.1〜221.2℃(2−メトキシエタノ
ール−メタノール−酢酸エチルから)
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)
.
実施例21
2,4−ジアミノ−[E]−6−〔2−〔3−(3−ト
リフルオロメチルフェノキシ)フェニル〕エテニル〕−
1, 3, 5−トリアジン(化合物47)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
】0075
]
【化34】[C34]
【0076】収率:42.6%
融点:204.7〜205.8℃(エタノール−2−メ
トキシエタノールから)
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).実施例22
2,4−ジアミノ−[E]−6−[2−〔3− (4−
t−ブチルフェノキシ) フェニル〕エテニル]−1,
3, 5−トリアジン (化合物48)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】[0077]
【化35】[C35]
【0078】収率:34.9%
融点:211.6〜212.2℃ (エタノールから)
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).
実施例23
2,4−ジアミノ−[E]−6−〔2− (2−トリフ
ルオロメチルフェニル) エテニル]−1, 3, 5
−トリアジン・マレイン酸塩(化合物21 (実施例5
の化合物) のマレイン酸塩)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】[0079]
【化36】[C36]
【0080】化合物21 0.5g (1.77mM)
をエタノール50mlに溶かし、マレイン酸0.25g
(2.15mM) を加え室温で0.5時間静置した。
析出した結晶を濾取後、エタノールで洗い、標記化合物
(0.60g, 85.7%) を得た。
融点:195.6〜196.2℃ (分解)(エタノー
ルから) 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).実施例24
2,4−ジアミノ−[E]−6−〔2− (2−トリフ
ルオロメチルフェニル) エテニル]−1, 3, 5
−トリアジン・塩酸塩 (化合物21 (実施例5の化
合物) の塩酸塩)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】[0081]
【化37】[C37]
【0082】化合物21 0.5g (1.77mM)
をエタノール50mlに溶かし、濃塩酸0.3gを加
え室温で0.5時間静置した。析出した結晶を濾取後、
エタノールで洗い、標記化合物 (0.38g, 67
.9%) を得た。
融点:>300℃ (エタノールから) 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)
.実施例25
2,4−ビス (ニコチノイルアミノ) −[E]−6
−〔2−(3−トリフルオロメチルフェニル) エテニ
ル〕−1, 3, 5−トリアジン (化合物23)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】[
0083
【化38】[C38]
【0084】2,4−ジアミノ−[E]−6−〔2−
(3−トリフルオロメチルフェニル) エテニル〕−1
, 3, 5−トリアジン1g (3.55mM) を
ピリジン35mlに溶かし、ニコチノイルクロリド・塩
酸塩2.01g(11.28mM) を加え4時間加熱
還流した。反応液を減圧下に濃縮後、飽和炭酸水素ナト
リウムを加えアルカリ性とし、析出結晶を濾取水洗後、
エタノールから再結晶し、標記化合物 (0.75g,
43.1%) を得た。
融点:127〜131℃
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).実施例2
6〜29
実施例25と同様の方法により以下の化合物を合成した
。
実施例26
2−アセチルアミノ−4−アミノ−[E]−6−〔2−
(2−トリフルオロメチルフェニル) エテニル〕−
1, 3, 5−トリアジン(化合物27)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】[0085]
【化39】[C39]
【0086】収率:54.7%
融点:>300℃ (2−メトキシエタノールから)M
S m/z(%)[EI]: 323(M+, 100
), 281(32), 212(30), 170(
22).
実施例27
2,4−ビス (ニコチノイルアミノ) −[E]−6
−〔2−(3−ピリジル) エテニル〕−1, 3,
5−トリアジン (化合物28)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】[0087]
【化40】[C40]
【0088】融点:242〜247℃ (2−メトキシ
エタノールから)
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
r s). MS m/z(%)[EI]: 424(
M+, 49), 319(37), 318(100
), 106(95), 78(68).実施例28
2,4−ビス (2−トリフルオロメチルベンゾイルア
ミノ) −[E]−6−〔2− (3−ピリジル) エ
テニル〕−1, 3, 5−トリアジン (化合物29
)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】[0089]
【化41】[C41]
【0090】収率:28.0%
融点:261.7〜262.3℃ (酢酸エチルから)
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,
br s). MSm/z(%)[EI]: 558(
M+, 11), 489(35), 461(43)
, 433(21), 173(100),145(6
9).
実施例29
2−アミノ−4−〔3,5−ジ−t−ブチル−4− (
3,5−ジ−t−ブチル−4−ヒドロキシベンゾイルオ
キシ) ベンゾイルアミノ〕−6−フェニル−1, 3
, 5−トリアジン (化合物43)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】[0091]
【化42】[C42]
【0092】融点:167〜170℃ (酢酸エチルか
ら) 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実施例30
2,4−ジアミノ−6−〔2− (3,5−ジ−t−ブ
チル−4−ヒドロキシフェニル) エチル〕−1, 3
, 5−トリアジン (化合物50)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】[0093]
【化43】[C43]
【0094】2,4−ジアミノ−[E]−6−〔2−
(3,5−ジ−t−ブチル−4−ヒドロキシフェニル)
エテニル〕−1, 3, 5−トリアジン (化合物
37) 0.30g (0.89mM) をエタノール
10mlと酢酸エチル5mlの混液に溶かし、5%Pd
/C 40mgを加え室温で 168時間常圧下に水添
した。触媒を濾去し減圧下に溶媒を留去後、残留物を酢
酸エチルから再結晶し、標記化合物(0.20g, 6
6.6%) を得た。
融点:205.1〜206.4℃
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).実施例
31
(1) 3,5−ジ−t−ブチル−4−メトキシメトキ
シベンゾニトリル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】[0095]
【化44】[C44]
【0096】3,5−ジ−t−ブチル−4−ヒドロキシ
ベンゾニトリル 1.9g (8.2mM)をN,N−
ジメチルホルムアミド8mlに溶かしN−エチルジイソ
プロピルアミン4.7ml(29mM) を加え冷却し
た。氷冷攪拌下にメトキシメチルクロリド (80%)
2.3ml(21.4mM) を滴下した後、室温で2
1時間攪拌した。水を加え酢酸エチルで抽出し、水洗後
、無水硫酸ナトリウムで乾燥した。減圧下に溶媒を留去
後、残留物をシルカゲルフラッシュカラムクロマトグラ
フィー (ヘキサン:酢酸エチル=40:1)で精製し
、黄色固体の標記化合物 (1.43g, 63.6%
) を得た。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.
【0097】MS m/z : 276, 275(M
−), 230, 228, 188, 172, 4
5
(2) 2,4−ジアミノ−6− (3,5−ジ−t−
ブチル−4−メトキシメトキシフェニル) −1, 3
, 5−トリアジン (化合物5)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】[0098]
【化45】[C45]
【0099】3,5−ジ−t−ブチル−4−メトキシメ
トキシベンゾニトリル 1.41g (5.1mM)を
2−メトキシエタノール8mlに溶かし、ジシアンジア
ミド (90%) 及び水酸化カリウム (85%)
0.40g (6.1mM) を加え20時間加熱還流
した。冷後、水を加え、析出結晶をろ取した後、水洗し
、標記化合物 (1.5g, 82.0%) を得た。
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).実施例32
2,4−ジアミノ−6− (3,5−ジ−t−ブチル−
4−ヒドロキシ)フェニル)−1, 3, 5−トリア
ジン (化合物38)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】[0100]
【化46】[C46]
【0101】実施例31 (2) で得た化合物 (5
) 1.45g (4mM) をエタノール50mlと
メタノール10mlの混液に溶かし、p−トルエンスル
ホン酸−水和物1.52g(8mM) を加え1.5時
間加熱還流した。反応液を減圧下に濃縮後、飽和炭酸水
素ナトリウムを加えアルカリ性とし、析出結晶を濾取後
、水及びヘキサンで洗い、標記化合物(1.12g,
89.0%) を得た。融点:>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).
実施例33
2,4−ジアミノ−6−フタリジルメチル−1, 3,
5−トリアジン (化合物17)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】[0102]
【化47】[C47]
【0103】2,4−ジアミノ−6−メチル−1, 3
, 5−トリアジン 0.5g (4mM) をメタン
スルホン酸 2.5mlに溶かし、2−ホルミル安息香
酸 0.6g (4mM) を加え 110℃で3時間
攪拌した。冷後、反応液に希水酸化ナトリウムを加えア
ルカリ性とし、析出結晶をろ取水洗後、エタノールから
再結晶し、標記化合物 (0.10g, 9.8%)を
得た。融点:257.0〜258.0℃ (分解)(エ
タノールから) 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).試験例1
前述の実施例で得られた化合物について、以下の試験を
行い、結果を表1に示した。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.
【0104】ロイコトリエンC4 拮抗試験試薬:ロイ
コトリエンC4 (和光純薬工業)二塩酸ヒスタミン
(和光純薬工業)
実験動物:体重 250g前後のSD系雄性ラット (
日本チャールスリバー) の胃底条件を用いた。
栄養液:タイロード液
NaCl 137.9mM, KCl 2.7mM,
MgCl2・6H2O 0.5mM, NaH2PO4
・2H2O 1.1mM, CaCl2・2H2O 1
.8mM, NaHCO3 11.9mM, グルコー
ス 5.6mM
ラット胃底条片標本の作成:
SDラットの後頭部を殴打し、放血致死後直ちに開腹し
食道下部及び十二指腸上部をそれぞれハサミで切断し摘
出し、予め用意してある栄養液に浸した。前胃部を切り
離し小彎に沿って縦方向に切り開き、胃底部筋片に幅3
mmに交互にハサミ目を入れ、更にそれを筋長3mmに
切った。
マグヌス装置及び測定:
タイロード液の入った20mlのマグヌス管に標本を懸
垂し1gの負荷をかけアセチルコリン10−5Mで一定
の等張性収縮を確認、洗浄し約20分後、コントロール
(100%) 収縮としてロイコトリエンC4 10−
8Mの等張性収縮 (A) を記録した。更に洗浄後約
30分して被験薬を加え、10分後にロイコトリエンC
4 10−8Mを加えてその等張性収縮 (B) を記
録した。
活性の判定:
ロイコトリエンD4 拮抗試験
試薬:ロイコトリエンD4 (和光純薬工業)二塩酸ヒ
スタミン (和光純薬工業)
実験動物:体重 300g前後の Hartley系雄
性モルモット(紀和動物) の回腸を用いた。
栄養液:タイロード液
NaCl 137.9mM, KCl 2.7mM,
MgCl2・6H2O 0.5mM, NaH2PO4
・2H2O 1.1mM, CaCl2・2H2O 1
.8mM, NaHCO3 11.9mM, グルコー
ス5.6mM
モルモットからの回腸筋摘出:
モルモットを脱血致死させ、開腹し回腸を摘出し内容物
を洗浄、盲腸近くより10cm近くは除き、約2cmの
筒状標本として32℃95% O2−5% CO2 ガ
ス通気のタイロード栄養液の入ったマグヌス管に懸垂し
1gの負荷をかけた。マグヌス装置及び測定:
摘出標本を懸垂後、約20分おき32℃95% O2−
5% CO2 を通気した栄養液を20mlマグヌス管
に満たした。ヒスタミン溶液 (10−5M) で2度
一定の等張性収縮を測定記録確認し、洗浄して更に約2
0分後、コントロール収縮としてロイコトリエンD4
10−8Mの等張性収縮 (A) を記録した。更に洗
浄後約30分して被験薬を加え、10分後にロイコトリ
エンD4 10−8Mを加えてその等張性収縮 (B)
を記録した。
活性の判定:
5−リポキシゲナーゼ阻害試験
RBL1培養細胞を5×106 細胞/mlとなるよう
に1mMエチレンジアミン四酢酸(EDTA)および1
0%エチレングリコールを含む50mMリン酸緩衝液(
pH7.4)に浮遊し、超音波処理後、10,000×
Gで10分間、さらに105,000 ×Gで60分間
遠心分離した上清を5−リポキシゲナーゼ酵素標品とし
た。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.
【0105】基質として、10μM アラキドン酸、上
記のように調製して得た酵素標品および具体例で得た化
合物のDMSOを終濃度10μM となるように試験管
にとり、37℃で10分間反応させた。内部標準として
0.25M のブチル3,5 ジニトロベンゾエート
10μl を添加し、ヘキサン1.8ml で抽出した
。この中の5−HETEの量を高速液体クロマトグラフ
ィー〔カラム、TSKgel ODS−80TM(TO
YO SODA)移動相、アセトニトリル:水:酢酸=
60:40:0.02 流速、1ml/分;検出、紫
外線(235nm) 〕により測定した。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)].
【0106】この結果から、5−リポキシゲナーゼ阻害
率を次式により算出した。
C:具体例で得た化合物を含まない場合の5−HETE
のピーク面積(内部標準により補正)
S:具体例で得た化合物を添加した場合の5−HETE
のピーク面積(内部標準により補正)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】[0107]
【表1】[Table 1]
【0108】調剤例1
錠剤の調製
(1) 2,4−ジアミノ−[E]−6−〔2−
(3,5−ジ− t−ブチル−4−ヒドロキ
シフェニル) エテニル〕 −1, 3,
5−トリアジン
10g (2) 乳 糖
90g (3)
コーンスターチ
29g (
4) ステアリン酸マグネシウム
1g ────
─────────────────────────
─
1000 錠
130g(1), (2)及び17gのコー
ンスターチを混和し、7gのコーンスターチから作った
ペーストとともに顆粒化、この顆粒に5gのコーンスタ
ーチと(4) を加え、混合物を圧縮錠剤機で圧縮して
錠剤1錠当り(1) 10mgを含有する錠剤1000
個を製造した。
調剤例2
カプセルの調製
(1) 2,4−ジアミノ−[E]−6−〔2−
(4−ヒドロ キシ−3,5−ジメチルフェ
ニル) エテニル〕−1, 3, 5−ト
リアジン
200g (2) 乳
糖
150g
(3) コーンスターチ
10
0g (4) 結晶セルロース
40g (5) 軽質無水ケイ酸
5g (6) ステアリン酸マグネシウム
5g ────────────────────
──────────
1000 個
500g常法に従って、
上記各成分を混和し、顆粒状としたものをカプセル10
00個に充填し、1個500mgのカプセル剤を製造し
た。
試験例2
急性毒性試験
実施例1〜33で得た化合物を ddY系マウスに経口
投与したところ (各用量1群10匹) 、1000m
g/kgまで投与しても死亡例は認められず、本発明の
化合物は、急性毒性が低く、安全性が高いことが確認さ
れた。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】[0109]
【発明の効果】本発明によれば、ロイコトリエン拮抗剤
として有用な新規2,4−ジアミノ−1,3, 5−ト
リアジン誘導体を提供することができる。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)
れぞれ水素原子又はアシル基を表し;Rは、フェニル基
、フタリジルメチル基、次式 (2) :【化2】 (式中、 R2 及び R3 は、低級アルキル基を表
し、Zは、水素原子又は低級アルコキシ−低級アルキル
基を表す。) で示される基又は次式 (3) : −A−R1
(3)(式中、Aは、 −CH2CH2− 又は −C
H=CH−を表し; R1 は;水酸基、シアノ基、低
級アルコキシ基、低級アルコキシカルボニル基、フェニ
ル基、フェノキシ基、ベンジルオキシ基、及びトリフル
オロメチル基又は低級アルキル基で置換されたフェノキ
シ基からなる群から選ばれる少なくとも1個の置換基で
置換されたフェニル基;ナフチル基、3−ブロモフェニ
ル基、3−フルオロフェニル基、2,5−ジフルオロフ
ェニル基、2−トリフルオロメチルフェニル基、3−ト
リフルオロメチルフェニル基、4−トリフルオロメチル
フェニル基、3,5−ビス (トリフルオロメチル)
フェニル基、4−低級アルキルフェニル基、3,5−ジ
− (低級アルキル) −4−ヒドロキシフェニル基、
3−ピリジル基又は6−メチル−3−ピリジル基を表す
。) で示される基を表すが;Rがフェニル基である場合及び
R1 が3−トリフルオロメチルフェニル基である場
合、X及び/又はYは、アシル基を表し、 R1 が3
−ピリジル基である場合、X及びYは、ニコチノイル基
又は2−トリフルオロメチルベンゾイル基を表す。〕で
示される2,4−ジアミノ−1, 3, 5−トリアジ
ン誘導体又はその塩。[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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6682391A JPH04300874A (en) | 1991-03-29 | 1991-03-29 | New 2,4-diamino-1,3,5-triazine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6682391A JPH04300874A (en) | 1991-03-29 | 1991-03-29 | New 2,4-diamino-1,3,5-triazine derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH04300874A true JPH04300874A (en) | 1992-10-23 |
Family
ID=13326950
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6682391A Pending JPH04300874A (en) | 1991-03-29 | 1991-03-29 | New 2,4-diamino-1,3,5-triazine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH04300874A (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999011633A1 (en) * | 1997-08-18 | 1999-03-11 | Boehringer Ingelheim Pharma Kg | Triazines with an adenosine antagonistic effect |
WO1999031088A1 (en) * | 1997-12-12 | 1999-06-24 | Abbott Laboratories | Triazine angiogenesis inhibitors |
US6150362A (en) * | 1997-12-12 | 2000-11-21 | Henkin; Jack | Triazine angiogenesis inhibitors |
US7390908B2 (en) | 2001-08-17 | 2008-06-24 | Astrazeneca Ab | Compounds effecting glucokinase |
US7642263B2 (en) | 2005-07-09 | 2010-01-05 | Astrazeneca Ab | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
US7696191B2 (en) | 2006-12-21 | 2010-04-13 | Astrazeneca Ab | Crystalline compound |
US7700640B2 (en) | 2004-10-16 | 2010-04-20 | Astrazeneca Ab | Process for making phenoxy benzamide compounds |
US7709505B2 (en) | 2002-11-19 | 2010-05-04 | Astrazeneca Ab | Benzofuran derivatives, process for their preparation and intermediates thereof |
US7902200B2 (en) | 2006-10-23 | 2011-03-08 | Astrazeneca Ab | Chemical compounds |
US7973178B2 (en) | 2005-11-28 | 2011-07-05 | Astrazeneca Ab | Chemical process for the preparation of an amido-phenoxybenzoic acid compound |
US8071608B2 (en) | 2009-04-09 | 2011-12-06 | Astrazeneca Ab | Therapeutic agents |
-
1991
- 1991-03-29 JP JP6682391A patent/JPH04300874A/en active Pending
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999011633A1 (en) * | 1997-08-18 | 1999-03-11 | Boehringer Ingelheim Pharma Kg | Triazines with an adenosine antagonistic effect |
WO1999031088A1 (en) * | 1997-12-12 | 1999-06-24 | Abbott Laboratories | Triazine angiogenesis inhibitors |
US6150362A (en) * | 1997-12-12 | 2000-11-21 | Henkin; Jack | Triazine angiogenesis inhibitors |
US7390908B2 (en) | 2001-08-17 | 2008-06-24 | Astrazeneca Ab | Compounds effecting glucokinase |
US7524957B2 (en) | 2001-08-17 | 2009-04-28 | Astrazeneca Ab | Compounds effecting glucokinase |
US7951830B2 (en) | 2001-08-17 | 2011-05-31 | Astrazeneca Ab | Compounds effecting glucokinase |
US7709505B2 (en) | 2002-11-19 | 2010-05-04 | Astrazeneca Ab | Benzofuran derivatives, process for their preparation and intermediates thereof |
US7700640B2 (en) | 2004-10-16 | 2010-04-20 | Astrazeneca Ab | Process for making phenoxy benzamide compounds |
US7642259B2 (en) | 2005-07-09 | 2010-01-05 | Astrazeneca Ab | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
US7642263B2 (en) | 2005-07-09 | 2010-01-05 | Astrazeneca Ab | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
US7973178B2 (en) | 2005-11-28 | 2011-07-05 | Astrazeneca Ab | Chemical process for the preparation of an amido-phenoxybenzoic acid compound |
US7902200B2 (en) | 2006-10-23 | 2011-03-08 | Astrazeneca Ab | Chemical compounds |
US7696191B2 (en) | 2006-12-21 | 2010-04-13 | Astrazeneca Ab | Crystalline compound |
US8071608B2 (en) | 2009-04-09 | 2011-12-06 | Astrazeneca Ab | Therapeutic agents |
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