JP2005320273A

JP2005320273A - 5-aminopyrimidine compound

Info

Publication number: JP2005320273A
Application number: JP2004138812A
Authority: JP
Inventors: Mitsuo Zakato; 光夫坂登; Hirosuke Yamazaki; 宏亮山崎; Hironari Sasahara; 宏也笹原; Toshiaki Suzuki; 敏彰鈴木; Akira Yoshimura; 朗吉村; Naoto Tadano; 尚登只野; Kazuhiko Haruta; 和彦春田
Original assignee: Zenyaku Kogyo KK
Current assignee: Zenyaku Kogyo KK
Priority date: 2004-05-07
Filing date: 2004-05-07
Publication date: 2005-11-17
Anticipated expiration: 2024-05-07
Also published as: JP4560329B2

Abstract

<P>PROBLEM TO BE SOLVED: To provide a 5-aminopyrimidine compound having both excellent TNF-α production inhibitory activity and antioxidant activity. <P>SOLUTION: This 5-aminopyrimidine compound is expressed by general formula (I) [wherein, R<SB>1</SB>is H, a 1-6C alkyl or phenyl; R<SB>2</SB>is phenyl, a phenyl 1-6C alkyl, phenyl carbamoyl, benzoyl, naphthyl, coumarinyl, a 3-7C cycloalkyl, pyridinyl or thienyl; R<SB>3</SB>is H or a 1-6C alkyl; R<SB>4</SB>is H or a 1-6C alkyl; and R<SB>5</SB>, R<SB>6</SB>bond together to form morpholino, piperidino or pyrrolidinyl]. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

本発明は一般式（Ｉ）

［式中、R₁は水素原子、C₁-C₆アルキル又はフェニル、R₂はフェニル（C₁-C₆アルキルカルボニルオキシ、1〜2個のC₁-C₆アルコキシ、C₁-C₆アルキルチオ、C₁-C₆アルキル、1〜2個のハロゲン原子、チアジアゾリル、C₁-C₆アルコキシカルボニル、フェニル又はベンジルオキシで置換されていてもよい）、フェニルC₁-C₆アルキル、フェニルカルバモイル（1〜2個のハロゲン原子で置換されていてもよい）、ベンゾイル（C₁-C₆アルコキシ、シアノ又はピペリジノで置換されていてもよい）、ナフチル、クマリニル（C₁-C₆アルコキシで置換されていてもよい）、C₃-C₇シクロアルキル、ピリジニル又はチエニル、R₃は水素原子又はC₁-C₆アルキル、R₄は水素原子又はC₁-C₆アルキル、R₅, R₆は結合してモルホリノ、ピペリジノ又はピロリジニル（ヒドロキシC₁-C₆アルキルで置換されていてもよい）を形成することを表わす。]で示される5-アミノピリミジン化合物又はその薬学的に許容される塩、並びにその5-アミノピリミジン化合物を有効成分とするTNF-α産生抑制剤および抗酸化薬に関する。 The present invention relates to general formula (I)

[Wherein R ₁ is a hydrogen atom, C ₁ -C ₆ alkyl or phenyl, R ₂ is phenyl (C ₁ -C ₆ alkylcarbonyloxy, 1 to 2 C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkyl, 1-2 halogen atoms, thiadiazolyl, C ₁ -C ₆ alkoxycarbonyl, optionally substituted phenyl or benzyloxy), phenyl C ₁ -C ₆ alkyl, phenylcarbamoyl (Optionally substituted with 1 to 2 halogen atoms), benzoyl (optionally substituted with C ₁ -C ₆ alkoxy, cyano or piperidino), naphthyl, coumarinyl (substituted with C ₁ -C ₆ alkoxy) C ₃ -C ₇ cycloalkyl, pyridinyl or thienyl, R ₃ is a hydrogen atom or C ₁ -C ₆ alkyl, R ₄ is a hydrogen atom or C ₁ -C ₆ alkyl, R ₅ , R ₆ Are bound to morpholino, piperidino or pyrrolidinyl (H Indicating the formation of a proxy C may be substituted by ₁ -C ₆ alkyl). Or a pharmaceutically acceptable salt thereof, and a TNF-α production inhibitor and antioxidant containing the 5-aminopyrimidine compound as an active ingredient.

TNF-αが関与すると考えられる疾患としては、関節リウマチやベーチェット病等の自己免疫疾患、アレルギー、気管支喘息、敗血症、炎症性腸疾患、乾癬、血栓症、肝炎、糖尿病、慢性閉塞性肺疾患、脳梗塞等が知られている。又、最近では脳において、痴呆の原因物質とされるβ-アミロイドがミクログリアや星状細胞を活性化し、炎症性サイトカインであるTNF-αやIL-1を遊離させ、最終的に細胞内に過剰にカルシウムを蓄積させることにより神経細胞死が惹起されることが報告されており（非特許文献１参照）、脳虚血再灌流により産生される多量の活性酸素が血管内皮を障害し、記憶の中枢とされる海馬錐体細胞を選択的に壊死させることが報告されている（非特許文献２参照）。又、学習をさせたマウスに純酸素を吸引させると痴呆状態になることや、ビタミンEの投与によりこの状態を防ぐ事も示されている。更に、肝臓や脳組織では活性酸素量が炎症性サイトカインの産生量に影響を及ぼすことも分かってきた（非特許文献３参照）。これらのことはTNF-α産生抑制活性と抗酸化活性を併せ持つ物質は関節リウマチ、脳梗塞等の各種炎症性疾患に有用な医薬となり得ることを示唆している。 Diseases that TNF-α may be involved in include autoimmune diseases such as rheumatoid arthritis and Behcet's disease, allergies, bronchial asthma, sepsis, inflammatory bowel disease, psoriasis, thrombosis, hepatitis, diabetes, chronic obstructive pulmonary disease, Cerebral infarction is known. Recently, β-amyloid, which is a causative agent of dementia, activates microglia and astrocytes in the brain, releasing inflammatory cytokines TNF-α and IL-1, and finally excess in the cells. It is reported that neuronal cell death is caused by accumulating calcium in the brain (see Non-Patent Document 1), and a large amount of active oxygen produced by cerebral ischemia reperfusion damages vascular endothelium, It has been reported to selectively necrotize hippocampal pyramidal cells, which are regarded as the center (see Non-Patent Document 2). It has also been shown that when pure oxygen is inhaled into a learned mouse, it becomes demented, and vitamin E administration prevents this condition. Furthermore, it has been found that the amount of active oxygen affects the amount of inflammatory cytokine produced in liver and brain tissues (see Non-Patent Document 3). These facts suggest that a substance having both TNF-α production inhibitory activity and antioxidant activity can be a useful drug for various inflammatory diseases such as rheumatoid arthritis and cerebral infarction.

従来、TNF-α産生抑制活性を有する化合物としては、ピペリジニルピリミジン誘導体（特許文献１参照）、フタラジン誘導体（特許文献２参照）等種々報告されており、又、抗酸化活性を有する化合物もビタミンE誘導体（非特許文献４参照）、フェノール誘導体等多数報告されている。更に、このような作用を併せ持つ化合物（2,4-ピリミジンジオン誘導体）も報告されている（非特許文献５参照）。
特表2001-511764号公報特開2000-191659号公報 Blasko I., Marx F., Steiner E., Hartmann T., Grubeck-Loebenstein B: TNF-α plus IFN-γ induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs, FASEB J .,13 (1), 63-68 (1999)；Viel JJ., McManus DQ., Smith SS., Brewer GJ.: Age- and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from beta-amyloid, J. Neurosci. Res., 64 (5), 454-465 (2000) Lewen A., Matz P., Chan PH.: Free radical pathways in CNS injury, J. Neurotrauma ,17 (10), 871-890 (2000) ；Nakashima M., Niwa M., Iwai T., Uematsu T.: Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral ischemia model of rat, Free Radic. Biol. Med., 26 (5-6), 722-729 (1999) Anderson MT.，Staal FJT.，Gitler C.，Herzenberg LA., Herzenberg LA.: Separation of oxidant-initiated and redox-regulated steps in the NF-κB signal transduction pathway, Proc. Natl. Acad. Sci., 91, 11527-11531 (1994) Kuribayasi Y., Yoshida K., Sakaue T., Okumura A., Arzneim.-Forsch./Drug Res., 42(II), Nr. 9, 1072-1074(1992) Goto Y., Watanabe N., Kogawa N., Tsuchiya M., etc., European Journal of Pharmacology, 438, 189-196(2002) Conventionally, various compounds such as piperidinyl pyrimidine derivatives (see Patent Document 1) and phthalazine derivatives (see Patent Document 2) have been reported as compounds having TNF-α production inhibitory activity. Many reports have been made on vitamin E derivatives (see Non-Patent Document 4), phenol derivatives and the like. Furthermore, a compound having such an action (2,4-pyrimidinedione derivative) has also been reported (see Non-Patent Document 5).
Special table 2001-511764 gazette Japanese Unexamined Patent Publication No. 2000-191659 Blasko I., Marx F., Steiner E., Hartmann T., Grubeck-Loebenstein B: TNF-α plus IFN-γ induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs, FASEB J., 13 ( 1), 63-68 (1999); Viel JJ., McManus DQ., Smith SS., Brewer GJ .: Age- and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from beta-amyloid, J. Neurosci. Res ., 64 (5), 454-465 (2000) Lewen A., Matz P., Chan PH .: Free radical pathways in CNS injury, J. Neurotrauma, 17 (10), 871-890 (2000); Nakashima M., Niwa M., Iwai T., Uematsu T. : Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral ischemia model of rat, Free Radic. Biol. Med., 26 (5-6), 722-729 (1999) Anderson MT., Staal FJT., Gitler C., Herzenberg LA., Herzenberg LA .: Separation of oxidant-initiated and redox-regulated steps in the NF-κB signal transduction pathway, Proc. Natl. Acad. Sci., 91, 11527-11531 (1994) Kuribayasi Y., Yoshida K., Sakaue T., Okumura A., Arzneim.-Forsch./Drug Res., 42 (II), Nr. 9, 1072-1074 (1992) Goto Y., Watanabe N., Kogawa N., Tsuchiya M., etc., European Journal of Pharmacology, 438, 189-196 (2002)

しかしながら、非特許文献５のようなTNF-α産生抑制活性と抗酸化活性を併せ持つ化合物の報告は少なく、その活性も満足するものではなかった。 However, there are few reports of compounds having both TNF-α production inhibitory activity and antioxidant activity as in Non-Patent Document 5, and the activity was not satisfactory.

かかる状況で、本発明者らは鋭意研究を進めた結果、ピリミジン環5位にアミノ基を有する一般式(I)のピリミジン化合物が、優れたTNF-α産生抑制活性と抗酸化活性を併せ持つことを見出し本発明を完成した。 Under such circumstances, the present inventors have conducted extensive research, and as a result, the pyrimidine compound of the general formula (I) having an amino group at the 5-position of the pyrimidine ring has both excellent TNF-α production inhibitory activity and antioxidant activity. The present invention has been completed.

本発明の5-アミノピリミジン化合物は前記一般式(I)で示されるが、この式中の各記号の定義に使用する語句の意味と例を以下に説明する。 The 5-aminopyrimidine compound of the present invention is represented by the above general formula (I), and the meanings and examples of the words used for the definition of each symbol in the formula will be described below.

「C₁-C₆」とは限定がなければ炭素数１〜６個を有する基を意味する。 “C ₁ -C ₆ ” means a group having 1 to 6 carbon atoms unless otherwise specified.

「C₃-C₇」とは限定がなければ炭素数３〜７個を有する基を意味する。 “C ₃ -C ₇ ” means a group having 3 to 7 carbon atoms unless otherwise specified.

「C₁-C₆アルキル」としてはメチル、エチル、n-プロピル、iso-プロピル、n-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル等の直鎖又は分枝鎖状のアルキル基が挙げられる。 “C ₁ -C ₆ alkyl” includes a linear or branched alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Can be mentioned.

「C₃-C₇シルロアルキル」としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチルが挙げられる。 “C ₃ -C ₇ silyloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

「ヒドロキシC₁-C₆アルキル」とは、上記「C₁-C₆アルキル」で定義される基のいずれかの炭素原子にヒドロキシ基が結合した基を意味する。 “Hydroxy C ₁ -C ₆ alkyl” means a group in which a hydroxy group is bonded to any carbon atom of the group defined in the above “C ₁ -C ₆ alkyl”.

「フェニルC₁-C₆アルキル」とは、上記「C₁-C₆アルキル基」で定義される基のいずれかの炭素原子にフェニル基が結合した基を意味する。 “Phenyl C ₁ -C ₆ alkyl” means a group in which a phenyl group is bonded to any carbon atom of the group defined in the above “C ₁ -C ₆ alkyl group”.

「C₁-C₆アルキルチオ」とは、上記「C₁-C₆アルキル」で定義される基が結合したチオ基を意味する。 “C ₁ -C ₆ alkylthio” means a thio group to which a group defined by the above “C ₁ -C ₆ alkyl” is bonded.

「C₁-C₆アルコキシ」としてはメトキシ、エトキシ、n-プロポキシ、iso-プロポキシ、n-ブトキシ、tert-ブトキシ、n-ペンチルオキシ、n-ヘキシルオキシ等の直鎖又は分枝鎖状のアルコキシ基が挙げられる。 “C ₁ -C ₆ alkoxy” includes linear or branched alkoxy such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc. Groups.

「C₁-C₆アルコキシカルボニル」とは、上記「C₁-C₆アルコキシ」で定義される基が結合したカルボニル基を意味する。 “C ₁ -C ₆ alkoxycarbonyl” means a carbonyl group to which a group defined by the above “C ₁ -C ₆ alkoxy” is bonded.

「C₁-C₆アルキルカルボニルオキシ」とは、上記「C₁-C₆アルキル」で定義される基が結合したカルボニルオキシ基を意味する。 “C ₁ -C ₆ alkylcarbonyloxy” means a carbonyloxy group to which a group defined by the above “C ₁ -C ₆ alkyl” is bonded.

「ハロゲン原子」としては、フッ素、塩素、臭素、ヨウ素が挙げられる。 “Halogen atom” includes fluorine, chlorine, bromine and iodine.

本発明の化合物としては、例えば、以下の化合物を挙げることができるが、本発明はこれらの化合物に限定されるものではない。 Examples of the compound of the present invention include the following compounds, but the present invention is not limited to these compounds.

・5-アミノ-2-(4-メトキシベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (4-methoxybenzylthio) -4-methylamino-6-morpholinopyrimidine

・5-アミノ-2-(4-メチルチオベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (4-methylthiobenzylthio) -4-methylamino-6-morpholinopyrimidine

・2-(4-アセトキシベンジルチオ)-5-アミノ-4,6-ジモルホリノピリミジン 2- (4-acetoxybenzylthio) -5-amino-4,6-dimorpholinopyrimidine

・2-(4-アセトキシベンジルチオ)-5-アミノ-4-メチルアミノ-6-モルホリノピリミジン 2- (4-acetoxybenzylthio) -5-amino-4-methylamino-6-morpholinopyrimidine

・5-アミノ-2-ベンジルチオ-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2-benzylthio-4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-[2-[(S)-(+)-ヒドロキシメチル]ピロリジニル]-2-(4-メトキシベンジルチオ)-6-モルホリノピリミジン 5-amino-4- [2-[(S)-(+)-hydroxymethyl] pyrrolidinyl] -2- (4-methoxybenzylthio) -6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-2-(4-メチルベンジルチオ)-6-モルホリノピリミジン 5-amino-4-methylamino-2- (4-methylbenzylthio) -6-morpholinopyrimidine

・5-アミノ-2-(4-メトキシベンジルチオ)-4-メチルアミノ-6-ピペリジノピリミジン 5-amino-2- (4-methoxybenzylthio) -4-methylamino-6-piperidinopyrimidine

・4,5-ジアミノ-2-ベンジルチオ-6-モルホリノピリミジン 4,5-diamino-2-benzylthio-6-morpholinopyrimidine

・5-アミノ-2-シクロヘキシルメチルチオ-4-メチルアミノ-6-モルホリノピリミジン 5-Amino-2-cyclohexylmethylthio-4-methylamino-6-morpholinopyrimidine

・5-アミノ-2-(3,5-ジメトキシベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (3,5-dimethoxybenzylthio) -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(3-フェニルプロピルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (3-phenylpropylthio) pyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-フェナシルチオピリミジン 5-amino-4-methylamino-6-morpholino-2-phenacylthiopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-フェニルエチルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (2-phenylethylthio) pyrimidine

・5-アミノ-2-[N-(2,4-ジフルオロフェニル)カルバモイルメチルチオ]-4-メチルアミノ-6-モルホリノピリミジン 5-Amino-2- [N- (2,4-difluorophenyl) carbamoylmethylthio] -4-methylamino-6-morpholinopyrimidine

・5-アミノ-2-[2-(4-メトキシベンゾイル)エチルチオ]-4-メチルアミノ-6-モルホリノピリミジン・ 5-Amino-2- [2- (4-methoxybenzoyl) ethylthio] -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-ピリジニルメチルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (4-pyridinylmethylthio) pyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(1-フェニルエチルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (1-phenylethylthio) pyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-[4-(1,2,3-チアジアゾール-4-イル)ベンジルチオ]ピリミジン 5-amino-4-methylamino-6-morpholino-2- [4- (1,2,3-thiadiazol-4-yl) benzylthio] pyrimidine

・5-アミノ-2-[4-(メトキシカルボニル)ベンジルチオ]-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- [4- (methoxycarbonyl) benzylthio] -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-ピペリジノフェナシルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (4-piperidinophenacylthio) pyrimidine

・5-アミノ-2-(4-シアノフェナシルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (4-cyanophenacylthio) -4-methylamino-6-morpholinopyrimidine

・5-アミノ-2-[3-(メトキシカルボニル)ベンジルチオ]-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- [3- (methoxycarbonyl) benzylthio] -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-ジフェニルメチルチオピリミジン 5-amino-4-methylamino-6-morpholino-2-diphenylmethylthiopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-テニルチオ)ピリミジン 5-Amino-4-methylamino-6-morpholino-2- (2-enylthio) pyrimidine

・5-アミノ-2-(4-ベンジルオキシベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (4-benzyloxybenzylthio) -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-ピリジニルメチルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (2-pyridinylmethylthio) pyrimidine

・5-アミノ-2-(3-フルオロベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (3-fluorobenzylthio) -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-フェニルベンジルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (4-phenylbenzylthio) pyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(1-ナフチルメチルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (1-naphthylmethylthio) pyrimidine

・5-アミノ-2-[(7-メトキシクマリン-4-イル)メチルチオ]-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2-[(7-methoxycoumarin-4-yl) methylthio] -4-methylamino-6-morpholinopyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-ナフチルメチルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (2-naphthylmethylthio) pyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-フルオロベンジルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (4-fluorobenzylthio) pyrimidine

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-フルオロベンジルチオ)ピリミジン 5-amino-4-methylamino-6-morpholino-2- (2-fluorobenzylthio) pyrimidine

・5-アミノ-2-(2,4-ジフルオロベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン 5-amino-2- (2,4-difluorobenzylthio) -4-methylamino-6-morpholinopyrimidine

又、本発明の化合物は、その構造中に不斉炭素原子を有する場合、不斉炭素原子由来の異性体およびそれらの混合物が存在するが、それらはいずれも本発明の化合物に含まれる。 In addition, when the compound of the present invention has an asymmetric carbon atom in its structure, there are isomers derived from the asymmetric carbon atom and mixtures thereof, all of which are included in the compound of the present invention.

又、本発明の化合物は薬学的に許容される塩として酸付加塩の形体をとってもよい。適当な酸付加塩としては、無機酸塩では例えば塩酸塩、硫酸塩、臭化水素酸塩、硝酸塩、リン酸塩等、有機酸塩では例えば酢酸塩、シュウ酸塩、プロピオン酸塩、グリコール酸塩、乳酸塩、ピルビン酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、安息香酸塩、桂皮酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩、サリチル酸塩等が用いられる。 The compound of the present invention may take the form of an acid addition salt as a pharmaceutically acceptable salt. Suitable acid addition salts include, for example, hydrochlorides, sulfates, hydrobromides, nitrates, phosphates and the like for inorganic acid salts, and acetates, oxalates, propionates, glycolic acids for organic acid salts, for example. Salt, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, methanesulfonate, benzene Sulfonates, p-toluenesulfonates, salicylates and the like are used.

[製造工程]
一般式(I)で表される本発明の化合物は、下記反応式に示されるように、2通りの方法で製造することができる。
（方法１） [Manufacturing process]
The compound of the present invention represented by the general formula (I) can be produced by two methods as shown in the following reaction formula.
(Method 1)

（式中、Yは塩素原子又は臭素原子を表わし、R₁, R₂, R₃, R₄, R₅, R₆は前記定義に同じ）

(In the formula, Y represents a chlorine atom or a bromine atom, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as defined above)

4,6-ジヒドロキシ-2-メルカプトピリミジン(II)を出発原料とし、溶媒中、塩化水素補足剤の存在下で、アルキルハライド(III)を反応させることで化合物(IV)が得られる。この反応で用いる塩化水素補足剤としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、トリエチルアミン又はピリジン等が挙げられ、溶媒としてはアセトン、トルエン、ヘキサン、キシレン、ジオキサン、テトラヒドロフラン又はジクロロエタン、N,N-ジメチルホルムアミド(DMF)等が挙げられる。この反応においては化合物II１モルに対して１〜1.5モルの化合物IIIを１〜1.5モルの塩化水素補足剤の存在下で室温〜100℃の温度で１〜２時間反応させる。次に化合物(IV)を過剰の塩素化剤を溶媒とし室温〜100℃の温度で１〜２時間反応させるか、或いはジメチルアニリン、ジエチルアニリン等の塩基性溶媒中で２〜３モルの塩素化剤を反応させて化合物(V)とする。 Compound (IV) is obtained by reacting 4,6-dihydroxy-2-mercaptopyrimidine (II) as a starting material and alkyl halide (III) in a solvent in the presence of a hydrogen chloride scavenger. Examples of the hydrogen chloride scavenger used in this reaction include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine or pyridine, and examples of the solvent include acetone, toluene, hexane, xylene, dioxane, tetrahydrofuran or Examples include dichloroethane, N, N-dimethylformamide (DMF), and the like. In this reaction, 1 to 1.5 mol of compound III is reacted at a temperature of room temperature to 100 ° C. for 1 to 2 hours in the presence of 1 to 1.5 mol of hydrogen chloride scavenger per 1 mol of compound II. Next, the compound (IV) is allowed to react at room temperature to 100 ° C. for 1 to 2 hours using an excess chlorinating agent as a solvent, or 2 to 3 mol of chlorination in a basic solvent such as dimethylaniline or diethylaniline. The agent is reacted to give compound (V).

次に化合物(V)を過剰のアミン(VI)と共に０℃〜室温で１〜２４時間反応させ、好ましくは室温で２４時間反応させ化合物(VII)を得る。次に過剰のアミン(VIII)と共に室温〜１００℃で１〜２４時間反応させ化合物 (IX)を得る。本反応は上述の溶媒と塩基を用いて行ってもよい。又、化合物(VIII)が低沸点の場合には加熱下封管中で行うことが好ましい。次に化合物(IX)を酢酸或いは水−酢酸の混合溶媒中０℃〜室温で１〜２モルの亜硝酸ナトリウムと5分〜5時間反応させた後還元し化合物式(I)を得る。還元剤としてパラジウム炭素を用いて水素添加する場合は、酢酸エチル、酢酸、酢酸−無水酢酸、エタノール、メタノール、DMF、メチルセロソルブを溶媒とし、室温〜１００℃、1〜5気圧で0.5〜48時間行う。還元剤としてハイドロサルファイトナトリウム、水素化ホウ素ナトリウム等を用いる場合は、メタノール、エタノール又はそれらと水の混合溶媒を使用し１〜１０モルの還元剤と室温〜１００℃で0.5〜24時間反応させる。 Next, compound (V) is reacted with excess amine (VI) at 0 ° C. to room temperature for 1 to 24 hours, preferably at room temperature for 24 hours to obtain compound (VII). Next, it is reacted with excess amine (VIII) at room temperature to 100 ° C. for 1 to 24 hours to obtain compound (IX). You may perform this reaction using the above-mentioned solvent and base. When the compound (VIII) has a low boiling point, it is preferably carried out in a sealed tube under heating. Next, the compound (IX) is reacted with 1 to 2 mol of sodium nitrite in acetic acid or a mixed solvent of water-acetic acid at 0 ° C. to room temperature for 5 minutes to 5 hours and then reduced to obtain the compound formula (I). In the case of hydrogenation using palladium carbon as a reducing agent, ethyl acetate, acetic acid, acetic acid-acetic anhydride, ethanol, methanol, DMF, methyl cellosolve are used as solvents, room temperature to 100 ° C., 1 to 5 atmospheres, 0.5 to 48 hours. Do. When using hydrosulfite sodium, sodium borohydride or the like as a reducing agent, methanol, ethanol or a mixed solvent of them and water is used and reacted with 1 to 10 moles of reducing agent at room temperature to 100 ° C. for 0.5 to 24 hours. .

（方法２）

（式中、R₁, R₂, R₃, R₄, R₅, R₆, Yは前記定義に同じ） (Method 2)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y are the same as defined above)

ピリミジン環の4位、6位にアミン類を有し2位がメトキシベンジルチオ基である化合物 (XI)をトリフルオロ酢酸中で反応させ、脱メトキシベンジル化しチオール(XII)を得る。この反応はアニソールを添加することにより円滑に進行する。通常は室温〜還流温度で0.5〜24時間反応させる。好ましくは還流温度下0.5〜１時間で行う。次に化合物(XII)を（方法１）に示した化合物(IV)の製造と同様の操作により、化合物(IX)とし、続いてニトロ化した後還元することにより、化合物(I)を製造することができる。 The compound (XI) having amines at the 4-position and 6-position of the pyrimidine ring and having the methoxybenzylthio group at the 2-position is reacted in trifluoroacetic acid to demethoxybenzylate to obtain the thiol (XII). This reaction proceeds smoothly by adding anisole. The reaction is usually carried out at room temperature to reflux temperature for 0.5 to 24 hours. Preferably, it is carried out at the reflux temperature for 0.5 to 1 hour. Next, compound (I) is produced by converting compound (XII) into compound (IX) by the same procedure as in the production of compound (IV) shown in (Method 1), followed by nitration followed by reduction. be able to.

なお、上記各工程で得られる生成物は必要に応じて通常の方法、例えば抽出、濃縮、中和、濾過、再結晶、カラムクロマトグラフィー等で分離精製することができる。 The product obtained in each of the above steps can be separated and purified by an ordinary method such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and the like, if necessary.

本発明の一般式(I)の化合物の酸付加塩は、当該技術分野で周知の各種の方法によって製造することができる。用いる適当な酸としては、無機酸では例えば塩酸、硫酸、臭化水素酸、硝酸、リン酸等、有機酸では例えば酢酸、シュウ酸、プロピオン酸、グリコール酸、乳酸、ピルビン酸、マロン酸、コハク酸、マレイン酸、フマル酸、リンゴ酸、酒石酸、クエン酸、安息香酸、桂皮酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、サリチル酸等が挙げられる。 The acid addition salts of compounds of general formula (I) of the present invention can be prepared by various methods well known in the art. Suitable acids to be used include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, oxalic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid and succinic acid. Examples include acids, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

次に、一般式(I)で表わされる本発明の化合物のTNFα産生抑制活性と抗酸化活性を説明する。なお、試験における被験化合物番号は後記実施例の化合物番号に対応する。 Next, the TNFα production inhibitory activity and antioxidant activity of the compound of the present invention represented by the general formula (I) will be described. In addition, the test compound number in a test respond | corresponds to the compound number of a postscript Example.

TNF-α産生抑制活性試験
（方法）
DMSOで段階的に希釈した被験化合物をLewis系雄性ラット末梢血単核球の培養液に加えるとともに、LPS（10 ng/ml）で細胞を刺激した。CO_２インキュベータ内で90分間培養した後、培養上清に含まれるTNF-αの含量をM. M. HoganとS. N. Vogelの方法（Current Protocols in Immunology, 2000, 6.10.1-6.10.5）に従い、測定した。すなわち、末梢血単核球の培養上清でL929細胞を18時間培養し、生存している細胞の数を測定した。細胞数の計測は、細胞をクリスタルバイオレットで染色した後、メタノールでクリスタルバイオレットを溶出し、吸光度（590nm）を測定することによりIC₅₀値を求めた。 TNF-α production inhibitory activity test (method)
The test compound diluted serially with DMSO was added to the culture medium of Lewis male rat peripheral blood mononuclear cells, and the cells were stimulated with LPS (10 ng / ml). After culturing for 90 minutes in a CO ₂ incubator, the content of TNF-α contained in the culture supernatant was measured according to the method of MM Hogan and SN Vogel (Current Protocols in Immunology, 2000, 6.10.1-6.10.5). . That is, L929 cells were cultured for 18 hours in the culture supernatant of peripheral blood mononuclear cells, and the number of surviving cells was measured. For counting the number of cells, after staining the cells with crystal violet, the crystal violet was eluted with methanol, and the absorbance (590 nm) was measured to obtain the IC ₅₀ value.

抗酸化活性試験（ラット脳ホモジネート自動酸化試験）
（方法）
Wistar系雄性ラット（300〜380 g前後）から大脳を摘出し、生理的食塩液を加え、20% 脳ホモジネートを作製した。脳ホモジネート200μl、PBS (−) 200μlおよびDMSOに溶解した被験化合物の4μlを混和し（100倍希釈）、160回／分の振盪数で37℃、2時間インキュベートして過酸化脂質を生成させた。5分間冷却した後、生成された過酸化脂質をチオバルビツール酸法によってTBARSとして測定した。すなわち、 8.1%ドデシル硫酸100μl、pH3.5に調整した20%酢酸750μl、0.8% チオバルビツール酸750μlを加えて60分間煮沸し、冷却後、蒸留水500μl、N-ブタノール・ピリジン（15:1）2.5 mlを加えて5分間振盪後、3000 rpmで10分間遠心分離した上清の吸光度を532nmにて測定した。例数は2例とした。 Antioxidant activity test (rat brain homogenate auto-oxidation test)
(Method)
The cerebrum was removed from Wistar male rats (about 300 to 380 g), and physiological saline was added to prepare a 20% brain homogenate. 200 μl of brain homogenate, 200 μl of PBS (−) and 4 μl of test compound dissolved in DMSO were mixed (diluted 100 times), and incubated at 37 ° C. for 2 hours at a shaking rate of 160 times / minute to generate lipid peroxide. . After cooling for 5 minutes, the produced lipid peroxide was measured as TBARS by the thiobarbituric acid method. That is, 8.1% dodecyl sulfate 100 μl, 20% acetic acid 750 μl adjusted to pH 3.5, 0.8% thiobarbituric acid 750 μl was added and boiled for 60 minutes. After cooling, 500 μl distilled water, N-butanol pyridine (15: 1 ) After adding 2.5 ml and shaking for 5 minutes, the absorbance of the supernatant centrifuged at 3000 rpm for 10 minutes was measured at 532 nm. The number of cases was 2.

各被験化合物の過酸化脂質生成抑制効果：各濃度における吸光度/溶媒対照の吸光度ｘ100で算出した結果からsigmoid曲線を描き、ロジット変換した上でIC₅₀値を算出した。 Lipid peroxide production inhibitory effect of each test compound: A sigmoid curve was drawn from the results calculated by absorbance at each concentration / absorbance of solvent control × 100, and logit converted to calculate IC ₅₀ value.

TNF-α産生抑制活性および抗酸化活性結果を以下の表１に示す。 The results of TNF-α production inhibitory activity and antioxidant activity are shown in Table 1 below.

上記表１の試験結果から、本発明の化合物が優れたTNF-α産生抑制活性および抗酸化活性を有することは明らかである。 From the test results of Table 1 above, it is clear that the compounds of the present invention have excellent TNF-α production inhibitory activity and antioxidant activity.

次に、本発明の化合物を哺乳類とりわけヒトに適用する場合の投与方法、剤型、投与量について説明する。 Next, the administration method, dosage form, and dosage when the compound of the present invention is applied to mammals, particularly humans, will be described.

本発明の化合物は経口又は非経口で投与可能であり、経口投与の剤型としては錠剤、コーティング錠剤、散剤、顆粒剤、カプセル剤、マイクロカプセル剤、シロップ剤等が、又非経口投与の剤型としては注射剤（用時溶解して用いる注射用凍結乾燥剤を含む）、坐剤等が使用できる。これらの剤型の調製は薬学的に許容される賦形剤、結合剤、滑沢剤、崩壊剤、懸濁化剤、乳化剤、防腐剤、安定化剤および分散剤、例えば乳糖、白糖、でんぷん、デキストリン、結晶セルロース、カオリン、炭酸カルシウム、タルク、ステアリン酸マグネシウム、蒸溜水又は生理食塩水を用いて行われる。 The compound of the present invention can be administered orally or parenterally. Tablets, coated tablets, powders, granules, capsules, microcapsules, syrups and the like are given as oral dosage forms. As the mold, an injection (including an injectable lyophilizer used by dissolving at the time of use), a suppository and the like can be used. The preparation of these dosage forms is pharmaceutically acceptable excipients, binders, lubricants, disintegrants, suspending agents, emulsifiers, preservatives, stabilizers and dispersants such as lactose, sucrose, starch. , Dextrin, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate, distilled water or physiological saline.

投与量は患者の症状、年齢、体重等に応じて異なるが、成人に対する一日量として10〜300mgを１回或いは分割して投与することができる。 The dose varies depending on the symptoms, age, weight, etc. of the patient, but 10 to 300 mg as a daily dose for an adult can be administered once or divided.

本発明の化合物は、優れたTNF-α産生抑制活性と抗酸化活性を併せて発揮する効果がある。 The compound of the present invention has an effect of exhibiting both excellent TNF-α production inhibitory activity and antioxidant activity.

次に、本発明化合物の実施例を示し更に具体的に説明するが、本発明はこれに限定されるものではない。 Next, examples of the compound of the present invention will be shown and described more specifically, but the present invention is not limited thereto.

実施例１）
5-アミノ-2-(4-メトキシベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン(化合物１)

Example 1)
5-Amino-2- (4-methoxybenzylthio) -4-methylamino-6-morpholinopyrimidine (Compound 1)

（１-１）4,6-ジヒドロキシ-2-メルカプトピリミジン(i)（50g, 346mmol）、Et₃N(62.7ml, 450mmol)、4-メトキシベンジルクロライド（52.8ml, 381mmol）のDMF（500ml）溶液を100℃で1時間45分加熱撹拌した。反応液を水にあけしばらく撹拌し、析出した結晶を濾取し、風乾して4,6-ジヒドロキシ-2-（4-メトキシベンジルチオ）ピリミジン（ii）を75.2g（収率82％）得た。
NMR(CDCl₃+CD₃OD)δ: 3.80(3H, s), 4.39(2H, s), 6.85(2H, m), 7.31(2H, m) (1-1) 4,6-dihydroxy-2-mercaptopyrimidine (i) (50 g, 346 mmol), Et ₃ N (62.7 ml, 450 mmol), 4-methoxybenzyl chloride (52.8 ml, 381 mmol) in DMF (500 ml) The solution was heated and stirred at 100 ° C. for 1 hour and 45 minutes. The reaction mixture was poured into water and stirred for a while. The precipitated crystals were collected by filtration and air-dried to obtain 75.2 g (yield 82%) of 4,6-dihydroxy-2- (4-methoxybenzylthio) pyrimidine (ii). It was.
NMR (CDCl ₃ + CD ₃ OD) δ: 3.80 (3H, s), 4.39 (2H, s), 6.85 (2H, m), 7.31 (2H, m)

（１-２）この化合物（ii）（21.4g、81mmol）にPOCl₃(45.5ml, 487mmol)、ジメチルアニリン（20ml, 162mmol）を加え、100℃で1.5時間加熱撹拌した。反応液を氷水に注ぎ酢酸エチルで2回抽出した。酢酸エチル層を合わせ飽和食塩水で洗浄後MgSO₄で乾燥し溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝20：1）で分離精製し、4,6-ジクロロ-2-（4-メトキシベンジルチオ）ピリミジン（iii）を15.4g（収率63％）得た。 (1-2) POCl ₃ (45.5 ml, 487 mmol) and dimethylaniline (20 ml, 162 mmol) were added to this compound (ii) (21.4 g, 81 mmol), and the mixture was heated and stirred at 100 ° C. for 1.5 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, dried over MgSO ₄ , and the solvent was evaporated under reduced pressure. Separation and purification by silica gel column chromatography (hexane: ethyl acetate = 20: 1) gave 15.4 g (yield 63%) of 4,6-dichloro-2- (4-methoxybenzylthio) pyrimidine (iii).

（１-３）この化合物（iii）（3.0g、10mmol)を40%メチルアミン-メタノール溶液（20ml）に溶解し、室温で終夜撹拌した。溶媒を減圧留去し、水を加え酢酸エチルで２回抽出した。有機層を合わせ飽和食塩水で洗浄後MgSO₄で乾燥し、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(酢酸エチル：ヘキサン=1：2)で分離精製し4-クロロ-2-(4-メトキシベンジルチオ)-6-メチルアミノピリミジン（iv）を1.64g(収率56%)得た。
NMR(CDCl₃)δ：2.93(3H, d, J=5.2Hz), 3.79(3H, s), 4.30(2H, s), 6.04(1H, s), 6.83(2H, d, J=8.8Hz), 7.33(2H, d, J=8.8Hz) (1-3) This compound (iii) (3.0 g, 10 mmol) was dissolved in a 40% methylamine-methanol solution (20 ml) and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water was added and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over MgSO ₄ , and the solvent was evaporated under reduced pressure. Separation and purification by silica gel column chromatography (ethyl acetate: hexane = 1: 2) gave 1.64 g (yield 56%) of 4-chloro-2- (4-methoxybenzylthio) -6-methylaminopyrimidine (iv). It was.
NMR (CDCl ₃ ) δ: 2.93 (3H, d, J = 5.2Hz), 3.79 (3H, s), 4.30 (2H, s), 6.04 (1H, s), 6.83 (2H, d, J = 8.8Hz ), 7.33 (2H, d, J = 8.8Hz)

（１-４）この化合物(iv)（10.3g, 35mmol)をモルホリン（50ml, 0.57mol)に溶かし、80℃で終夜加熱撹拌した。室温まで放冷しモルホリンを減圧留去した後水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水洗し、MgSO₄で乾燥後、溶媒を減圧留去した。残渣をエタノールより再結晶し2-(4-メトキシベンジルチオ)-4-メチルアミノ- 6-モルホリノピリミジン(v)を10.2g(収率84%)得た。
NMR(CDCl₃)δ：2.86(3H, d, J=5.2Hz), 3.52-3.56(4H, m), 3.73-3.77(4H, m), 3.78(3H, s), 4.29(2H, s), 4.66-4.69(1H, m), 5.12(1H, s), 6.81(2H, d, J=8.6Hz), 7.31(2H, d, J=8.6Hz), 6.82(2H, d, J=8.6Hz), 7.31(2H, d, J=8.6Hz) (1-4) This compound (iv) (10.3 g, 35 mmol) was dissolved in morpholine (50 ml, 0.57 mol) and stirred with heating at 80 ° C. overnight. The mixture was allowed to cool to room temperature, morpholine was distilled off under reduced pressure, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and dried over MgSO ₄ , and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 10.2 g (yield 84%) of 2- (4-methoxybenzylthio) -4-methylamino-6-morpholinopyrimidine (v).
NMR (CDCl ₃ ) δ: 2.86 (3H, d, J = 5.2Hz), 3.52-3.56 (4H, m), 3.73-3.77 (4H, m), 3.78 (3H, s), 4.29 (2H, s) , 4.66-4.69 (1H, m), 5.12 (1H, s), 6.81 (2H, d, J = 8.6Hz), 7.31 (2H, d, J = 8.6Hz), 6.82 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.6Hz)

（１-５）この化合物(v)（5.0g, 14.4mmol)を酢酸（50ml）に溶解し、亜硝酸ナトリウム（1.49g, 21.6mmol)の水（10ml）溶液を水冷下滴下し、室温で５時間撹拌した。酢酸を減圧留去し酢酸エチルに溶解したのち、2N NaOH, 水の順で洗浄後MgSO₄で乾燥し溶媒を減圧留去した。残渣を酢酸エチル（100ml）に溶解し、Pd/C 1.0gを加え常圧で４時間接触還元に付した。セライトを用いてPd/Cを濾過し、濾液を減圧留去した。シリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン=２：１)により分離精製し、題記化合物を1.28g(収率25%)得た。
融点：79.5-84℃
MS m/z: 361(M⁺)
NMR(CDCl₃)δ：2.82(2H, brs), 3.02(3H, d, J=5.1Hz), 3.11-3.16(4H, m), 3.78(3H, s), 3.79-3.83(4H, m), 4.33(2H, s), 4.52-4.55(1H, m), 6.81(2H, d, J=8.6Hz), 7.35(2H, d, J=8.6Hz) (1-5) This compound (v) (5.0 g, 14.4 mmol) was dissolved in acetic acid (50 ml), and a solution of sodium nitrite (1.49 g, 21.6 mmol) in water (10 ml) was added dropwise under water cooling at room temperature. Stir for 5 hours. Acetic acid was distilled off under reduced pressure and dissolved in ethyl acetate, washed with 2N NaOH and water in that order, dried over MgSO ₄ and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), 1.0 g of Pd / C was added, and catalytic reduction was performed for 4 hours at normal pressure. Pd / C was filtered using Celite, and the filtrate was distilled off under reduced pressure. Separation and purification by silica gel column chromatography (ethyl acetate / hexane = 2: 1) gave 1.28 g (yield 25%) of the title compound.
Melting point: 79.5-84 ℃
MS m / z: 361 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.82 (2H, brs), 3.02 (3H, d, J = 5.1Hz), 3.11-3.16 (4H, m), 3.78 (3H, s), 3.79-3.83 (4H, m) , 4.33 (2H, s), 4.52-4.55 (1H, m), 6.81 (2H, d, J = 8.6Hz), 7.35 (2H, d, J = 8.6Hz)

実施例１と同様の方法で相当する出発原料から下記化合物を製造した。 The following compound was produced from the corresponding starting material in the same manner as in Example 1.

・5-アミノ-2-(4-メチルチオベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン（化合物２）
融点:112-113℃
MS m/z: 377(M⁺)
NMR(CDCl₃)δ：2.50(3H, s), 2.72(2H, brs), 3.01(3H, d, J=4.9Hz), 3.12(4H, m), 3.80(4H, m), 4.30(2H, s), 4.50(1H, m), 7.20(2H, d, J=8.2Hz), 7.35(2H, d, J=8.2Hz) ・ 5-Amino-2- (4-methylthiobenzylthio) -4-methylamino-6-morpholinopyrimidine (Compound 2)
Melting point: 112-113 ℃
MS m / z: 377 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.50 (3H, s), 2.72 (2H, brs), 3.01 (3H, d, J = 4.9Hz), 3.12 (4H, m), 3.80 (4H, m), 4.30 (2H , s), 4.50 (1H, m), 7.20 (2H, d, J = 8.2Hz), 7.35 (2H, d, J = 8.2Hz)

・2-(4-アセトキシベンジルチオ)-5-アミノ-4-メチルアミノ-6-モルホリノピリミジン（化合物３）
oil
MS m/z: 389(M⁺)
NMR(CDCl₃)δ:2.27(3H, s), 2.82(2H, brs), 3.00(3H, d, J=4.9Hz), 3.11(4H, m), 3.80(4H, m), 4.35(2H, m), 4.55(1H, brs), 6.98(2H, d, J=8.6Hz), 7.42(2H, d, J=8.6Hz) 2- (4-acetoxybenzylthio) -5-amino-4-methylamino-6-morpholinopyrimidine (Compound 3)
oil
MS m / z: 389 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.27 (3H, s), 2.82 (2H, brs), 3.00 (3H, d, J = 4.9Hz), 3.11 (4H, m), 3.80 (4H, m), 4.35 (2H , m), 4.55 (1H, brs), 6.98 (2H, d, J = 8.6Hz), 7.42 (2H, d, J = 8.6Hz)

・5-アミノ-2-ベンジルチオ-4-メチルアミノ-6-モルホリノピリミジン（化合物４）
融点:87-92℃
MS m/z: 331(M⁺)
NMR(CDCl₃)δ:2.82(2H, brs), 3.02(3H, d, J=5.0Hz), 3.10-3.15(4H, m), 3.78-3.83(4H, m), 4.38(2H, s), 4.5-4.6(1H, m), 7.20-7.31(3H, m), 7.42-7.45(2H, m) 5-amino-2-benzylthio-4-methylamino-6-morpholinopyrimidine (compound 4)
Melting point: 87-92 ℃
MS m / z: 331 (M ⁺ )
_{NMR (CDCl 3) δ: 2.82} (2H, brs), 3.02 (3H, d, J = 5.0Hz), 3.10-3.15 (4H, m), 3.78-3.83 (4H, m), 4.38 (2H, s) , 4.5-4.6 (1H, m), 7.20-7.31 (3H, m), 7.42-7.45 (2H, m)

・5-アミノ-4-[2-[(S)-(+)-ヒドロキシメチル]ピロリジニル]-2-(4-メトキシベンジルチオ)-6-モルホリノピリミジン（化合物５）
MS m/z: 375(M⁺)
NMR(CDCl₃)δ:1.50-2.00(5H, m), 2.44(2H, brs), 3.00(3H, d, J=4.9Hz), 3.48-3.84(4H, m), 3.80(3H, s), 4.44(2H, s), 4.50(1H, m), 5.26(1H, m), 6.80(2H, d, J=8.6Hz), 7.32(2H, d, J=8.6Hz) 5-amino-4- [2-[(S)-(+)-hydroxymethyl] pyrrolidinyl] -2- (4-methoxybenzylthio) -6-morpholinopyrimidine (Compound 5)
MS m / z: 375 (M ⁺ )
NMR (CDCl ₃ ) δ: 1.50-2.00 (5H, m), 2.44 (2H, brs), 3.00 (3H, d, J = 4.9Hz), 3.48-3.84 (4H, m), 3.80 (3H, s) , 4.44 (2H, s), 4.50 (1H, m), 5.26 (1H, m), 6.80 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6Hz)

・5-アミノ-4-メチルアミノ-2-(4-メチルベンジルチオ)-6-モルホリノピリミジン（化合物６）
oil
MS m/z: 345(M⁺)
NMR(CDCl₃)δ:2.31(3H, s), 3.01(3H, d, J=4.1Hz), 3.13(4H, m), 3.80(4H, m), 4.33(2H, s), 4.54(1H, brs), 7.07(2H, d, J=7.9Hz), 7.31(2H, d, J=7.9Hz) -5-amino-4-methylamino-2- (4-methylbenzylthio) -6-morpholinopyrimidine (Compound 6)
oil
MS m / z: 345 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.01 (3H, d, J = 4.1Hz), 3.13 (4H, m), 3.80 (4H, m), 4.33 (2H, s), 4.54 (1H , brs), 7.07 (2H, d, J = 7.9Hz), 7.31 (2H, d, J = 7.9Hz)

・5-アミノ-2-(4-メトキシベンジルチオ)-4-メチルアミノ-6-ピペリジノピリミジン（化合物７）
oil
MS m/z: 359(M⁺)
NMR(CDCl₃)δ:1.70(6H, m), 2.70(3H, brs), 3.00(3H, d, 4.9Hz), 3.05(4H, m), 3.78(3H, s), 4.30(2H, s), 4.55(1H, m), 6.80(2H, d, J=8.7Hz), 7.40(2H, d, J=8.7Hz) ・ 5-Amino-2- (4-methoxybenzylthio) -4-methylamino-6-piperidinopyrimidine (Compound 7)
oil
MS m / z: 359 (M ⁺ )
NMR (CDCl ₃ ) δ: 1.70 (6H, m), 2.70 (3H, brs), 3.00 (3H, d, 4.9Hz), 3.05 (4H, m), 3.78 (3H, s), 4.30 (2H, s ), 4.55 (1H, m), 6.80 (2H, d, J = 8.7Hz), 7.40 (2H, d, J = 8.7Hz)

・4,5-ジアミノ-2-ベンジルチオ-6-モルホリノピリミジン（化合物８）
融点:188-191℃
MS m/z: 317(M⁺)
NMR(CDCl₃)δ:3.19(4H, t, J=4.8Hz), 3.80(4H, t, J=4.8Hz), 4.34(2H, s), 7.17-7.43(5H, m) ・ 4,5-Diamino-2-benzylthio-6-morpholinopyrimidine (Compound 8)
Melting point: 188-191 ° C
MS m / z: 317 (M ⁺ )
_{NMR (CDCl 3) δ: 3.19} (4H, t, J = 4.8Hz), 3.80 (4H, t, J = 4.8Hz), 4.34 (2H, s), 7.17-7.43 (5H, m)

実施例２）
5-アミノ-2-シクロヘキシルメチルチオ-4-メチルアミノ-6-モルホリノピリミジン（化合物9）

Example 2)
5-Amino-2-cyclohexylmethylthio-4-methylamino-6-morpholinopyrimidine (Compound 9)

（２-１）実施例１-４で得た2-(4-メトキシベンジルチオ)-6-メチルアミノ- 4-モルホリノピリミジン（5.41g, 15.6mmol）とアニソール(2.0ml, 18.7mmol)をトリフルオロ酢酸(50ml)に加え0.5時間加熱環流した。減圧下トリフルオロ酢酸を留去し、残渣に2N水酸化ナトリウム水溶液を加えpH8〜9とし、析出した沈殿物を濾取し、水洗後更にエーテルで洗浄し2-メルカプト-6-メチルアミノ-4-モルホリノピリミジン(vii)を3.41g(収率97%)得た。
NMR(DMSO-d₆)δ：2.81(3H, d, J=3.9Hz), 3.61(8H, m), 5.38(1H, s), 7.06(1H, brs) (2-1) 2- (4-Methoxybenzylthio) -6-methylamino-4-morpholinopyrimidine (5.41 g, 15.6 mmol) obtained in Example 1-4 and anisole (2.0 ml, 18.7 mmol) were trimethylated. The mixture was added with fluoroacetic acid (50 ml) and heated to reflux for 0.5 hours. Trifluoroacetic acid was distilled off under reduced pressure, and 2N aqueous sodium hydroxide solution was added to the residue to adjust the pH to 8-9. The deposited precipitate was collected by filtration, washed with water and further washed with ether to give 2-mercapto-6-methylamino-4. -3.41 g (97% yield) of morpholinopyrimidine (vii) was obtained.
NMR (DMSO-d ₆ ) δ: 2.81 (3H, d, J = 3.9Hz), 3.61 (8H, m), 5.38 (1H, s), 7.06 (1H, brs)

（２-２）この化合物（vii）(300mg, 1.33mmol)を脱水DMF(5ml)に溶かし、0℃冷却下60%水素化ナトリウム(60mg, 1.46mmol)を加え0.5時間撹拌した。同温度でシクロヘキシルメチルブロミド (0.2ml, 1.46mmol)を滴下し、室温に戻し更に2時間撹拌した。反応液に水を加え酢酸エチルで抽出した後、水洗し、MgSO₄で乾燥後減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル-ヘキサン＝1：1）にて分離精製し2-シクロヘキシルメチルチオ-6-メチルアミノ-2-モルホリノピリミジン（viii）を235mg(収率55%)得た。
NMR(CDCl₃)δ： 0.90-1.90(11H, m), 2.85(3H, d, J=5.3Hz), 2.95(2H, d, J=6.8Hz), 3.54(4H, m), 3.76(4H, m), 4.65(1H, m), 5.10(1H, s). (2-2) This compound (vii) (300 mg, 1.33 mmol) was dissolved in dehydrated DMF (5 ml), 60% sodium hydride (60 mg, 1.46 mmol) was added with cooling at 0 ° C., and the mixture was stirred for 0.5 hours. At the same temperature, cyclohexylmethyl bromide (0.2 ml, 1.46 mmol) was added dropwise, and the mixture was returned to room temperature and further stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, dried over MgSO ₄ and evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate-hexane = 1: 1) to obtain 235 mg (yield 55%) of 2-cyclohexylmethylthio-6-methylamino-2-morpholinopyrimidine (viii).
NMR (CDCl ₃ ) δ: 0.90-1.90 (11H, m), 2.85 (3H, d, J = 5.3Hz), 2.95 (2H, d, J = 6.8Hz), 3.54 (4H, m), 3.76 (4H , m), 4.65 (1H, m), 5.10 (1H, s).

（２-３）この化合物（viii）(200mg, 0.62mmol)、亜硝酸ナトリウム(64mg, 0.93mmol)、酢酸(3ml)およびPd/C(50mg)を用い、実施例１-５と同様の方法により題記化合物を176mg（収率84%）得た。
融点：74-76.5℃
MS m/z: 337(M⁺)
NMR(CDCl₃)δ：0.90-2.00(11H, m), 2.80(2H, brs), 3.00(5H, m), 3.14(4H, m), 3.81(4H, m), 4.50(1H, m) (2-3) Using this compound (viii) (200 mg, 0.62 mmol), sodium nitrite (64 mg, 0.93 mmol), acetic acid (3 ml) and Pd / C (50 mg), the same method as in Example 1-5 Gave 176 mg (84% yield) of the title compound.
Melting point: 74-76.5 ℃
MS m / z: 337 (M ⁺ )
NMR (CDCl ₃ ) δ: 0.90-2.00 (11H, m), 2.80 (2H, brs), 3.00 (5H, m), 3.14 (4H, m), 3.81 (4H, m), 4.50 (1H, m)

実施例２と同様の方法で、相当する出発原料から下記化合物を製造した。 In the same manner as in Example 2, the following compound was produced from the corresponding starting material.

・5-アミノ-2-(3,5-ジメトキシベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン（化合物10）
oil
MS m/z: 391(M⁺)
NMR(CDCl₃)δ:2.86(2H, brs), 3.02(2H, d, J=4.9Hz), 3.13(4H, m), 3.76(6H, s), 3.80(4H, m), 4.31(2H, s), 4.55(1H, brs), 6.32(1H, m), 6.60(1H, m) ・ 5-Amino-2- (3,5-dimethoxybenzylthio) -4-methylamino-6-morpholinopyrimidine (Compound 10)
oil
MS m / z: 391 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.86 (2H, brs), 3.02 (2H, d, J = 4.9Hz), 3.13 (4H, m), 3.76 (6H, s), 3.80 (4H, m), 4.31 (2H , s), 4.55 (1H, brs), 6.32 (1H, m), 6.60 (1H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(3-フェニルプロピルチオ)ピリミジン（化合物11）
融点:131-134℃
MS m/z: 359(M⁺)
NMR(CDCl₃)δ:2.06(2H, m), 2.74-2.79(4H, m), 2.98(3H, d, J=4.8Hz), 3.08-3.13(6H, m), 3.80(4H, m), 4.53(1H, brs), 7.17-7.27(5H, m) ・ 5-Amino-4-methylamino-6-morpholino-2- (3-phenylpropylthio) pyrimidine (Compound 11)
Melting point: 131-134 ° C
MS m / z: 359 (M ⁺ )
_{NMR (CDCl 3) δ: 2.06} (2H, m), 2.74-2.79 (4H, m), 2.98 (3H, d, J = 4.8Hz), 3.08-3.13 (6H, m), 3.80 (4H, m) , 4.53 (1H, brs), 7.17-7.27 (5H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-フェナシルチオピリミジン（化合物12）
融点:113-120℃
MS m/z: 359(M⁺)
NMR(CDCl₃) δ:2.79(2H, brs), 2.87(3H, d, J=4.8Hz), 2.98(4H, m), 3.70(4H, m), 4.52(1H, brs), 4.55(2H, s), 7.47-7.61(3H, m), 8.05-8.08(2H, m) ・ 5-Amino-4-methylamino-6-morpholino-2-phenacylthiopyrimidine (Compound 12)
Melting point: 113-120 ° C
MS m / z: 359 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.79 (2H, brs), 2.87 (3H, d, J = 4.8Hz), 2.98 (4H, m), 3.70 (4H, m), 4.52 (1H, brs), 4.55 (2H , s), 7.47-7.61 (3H, m), 8.05-8.08 (2H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-フェニルエチルチオ)ピリミジン（化合物13）
oil
MS m/z: 345(M⁺)
NMR(CDCl₃)δ:3.03-3.09(7H, m), 3.15(4H, m), 3.32(2H, m), 3.82(4H, m), 4.56(1H, brs), 7.21-7.33(5H, m) ・ 5-Amino-4-methylamino-6-morpholino-2- (2-phenylethylthio) pyrimidine (Compound 13)
oil
MS m / z: 345 (M ⁺ )
_{NMR (CDCl 3) δ: 3.03-3.09} (7H, m), 3.15 (4H, m), 3.32 (2H, m), 3.82 (4H, m), 4.56 (1H, brs), 7.21-7.33 (5H, m)

・5-アミノ-2-[N-(2,4-ジフルオロフェニル)カルバモイルメチルチオ]-4-メチルアミノ-6-モルホリノピリミジン（化合物14）
融点:102℃
MS m/z: 410(M⁺)
NMR(CDCl₃)δ:2.85(2H, brs), 3.02(3H, d, J=4.9Hz), 3.16(4H, m), 3.80(4H, m), 3.87(2H, s), 4.68(1H, brs), 6.74-6.89(2H, m), 8.22-8.29(1H, m) ・ 5-Amino-2- [N- (2,4-difluorophenyl) carbamoylmethylthio] -4-methylamino-6-morpholinopyrimidine (Compound 14)
Melting point: 102 ° C
MS m / z: 410 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.85 (2H, brs), 3.02 (3H, d, J = 4.9Hz), 3.16 (4H, m), 3.80 (4H, m), 3.87 (2H, s), 4.68 (1H , brs), 6.74-6.89 (2H, m), 8.22-8.29 (1H, m)

・5-アミノ-2-[2-(4-メトキシベンゾイル)エチルチオ]-4-メチルアミノ-6-モルホリノピリミジン（化合物15）
oil
MS m/z: 403(M⁺)
NMR(CDCl₃)δ:2.83(2H, brs), 2.97(3H, d, J=4.9Hz), 3.11(4H, m), 3.44(4H, s), 3.78(4H, m), 3.86(3H, s), 4.54(1H, brs), 6.92(2H, d, J=9.0Hz), 7.93(2H, d, J=9.0Hz) -5-Amino-2- [2- (4-methoxybenzoyl) ethylthio] -4-methylamino-6-morpholinopyrimidine (Compound 15)
oil
MS m / z: 403 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.83 (2H, brs), 2.97 (3H, d, J = 4.9Hz), 3.11 (4H, m), 3.44 (4H, s), 3.78 (4H, m), 3.86 (3H , s), 4.54 (1H, brs), 6.92 (2H, d, J = 9.0Hz), 7.93 (2H, d, J = 9.0Hz)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-ピリジニルメチルチオ)ピリミジン（化合物16）
融点:182-184℃
MS m/z: 332(M⁺)
NMR(CDCl₃)δ:2.80(2H, brs), 3.00(3H, d, J=4.8Hz), 3.10(4H, m), 3.80(4H, m), 4.30(2H, s), 4.60(1H, m), 7.40(2H, d, J=6.1Hz), 8.50(2H, d, J=6.1Hz) ・ 5-Amino-4-methylamino-6-morpholino-2- (4-pyridinylmethylthio) pyrimidine (Compound 16)
Melting point: 182-184 ° C
MS m / z: 332 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.80 (2H, brs), 3.00 (3H, d, J = 4.8Hz), 3.10 (4H, m), 3.80 (4H, m), 4.30 (2H, s), 4.60 (1H , m), 7.40 (2H, d, J = 6.1Hz), 8.50 (2H, d, J = 6.1Hz)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(1-フェニルエチルチオ)ピリミジン（化合物17）
融点:127-129℃
MS m/z: 345(M⁺)
NMR(CDCl₃)δ:1.80(3H, d, J=9.0Hz), 2.80(2H, brs), 3.00(3H, d, J=5.0Hz), 3.10-3.20(4H, m), 3.80-3.90(4H, m), 4.50-4.60(1H, m), 5.00(1H, q, J=9.0Hz), 7.20-7.30(3H, m), 7.40-7.50(2H, m) ・ 5-Amino-4-methylamino-6-morpholino-2- (1-phenylethylthio) pyrimidine (Compound 17)
Melting point: 127-129 ° C
MS m / z: 345 (M ⁺ )
NMR (CDCl ₃ ) δ: 1.80 (3H, d, J = 9.0Hz), 2.80 (2H, brs), 3.00 (3H, d, J = 5.0Hz), 3.10-3.20 (4H, m), 3.80-3.90 (4H, m), 4.50-4.60 (1H, m), 5.00 (1H, q, J = 9.0Hz), 7.20-7.30 (3H, m), 7.40-7.50 (2H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-[4-(1,2,3-チアジアゾール-4-イル)ベンジルチオ]ピリミジン（化合物18）
融点:188-195℃
MS m/z: 415(M⁺)
NMR(CDCl₃)δ:2.80(2H, brs), 3.00(3H, d, J=5.0Hz), 3.10-3.20(4H, m), 3.80-3.90(4H, m), 4.40(2H, s), 4.50-4.60(1H, m), 7.60(2H, d, J=9.0Hz), 8.00(2H, d, J=9.0Hz), 8.60(1H, s) 5-amino-4-methylamino-6-morpholino-2- [4- (1,2,3-thiadiazol-4-yl) benzylthio] pyrimidine (Compound 18)
Melting point: 188-195 ° C
MS m / z: 415 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.80 (2H, brs), 3.00 (3H, d, J = 5.0Hz), 3.10-3.20 (4H, m), 3.80-3.90 (4H, m), 4.40 (2H, s) , 4.50-4.60 (1H, m), 7.60 (2H, d, J = 9.0Hz), 8.00 (2H, d, J = 9.0Hz), 8.60 (1H, s)

・5-アミノ-2-[4-(メトキシカルボニル)ベンジルチオ]-4-メチルアミノ-6-モルホリノピリミジン（化合物19）
融点:88-90℃
MS m/z: 389(M⁺)
NMR(CDCl₃)δ:2.80(2H, brs), 3.00(3H, d, J=5.0Hz), 3.10-3.20(4H, m), 3.70-3.80(4H, m), 3.90(3H, s), 4.40(2H, s), 4.50-4.60(1H, m), 7.50(2H, d, J=9.0Hz), 8.00(2H, d, J=9.0Hz) 5-amino-2- [4- (methoxycarbonyl) benzylthio] -4-methylamino-6-morpholinopyrimidine (Compound 19)
Melting point: 88-90 ℃
MS m / z: 389 (M ⁺ )
_{NMR (CDCl 3) δ: 2.80} (2H, brs), 3.00 (3H, d, J = 5.0Hz), 3.10-3.20 (4H, m), 3.70-3.80 (4H, m), 3.90 (3H, s) , 4.40 (2H, s), 4.50-4.60 (1H, m), 7.50 (2H, d, J = 9.0Hz), 8.00 (2H, d, J = 9.0Hz)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-ピペリジノフェナシルチオ)ピリミジン（化合物20）
融点:99-100℃
MS m/z: 442(M⁺)
NMR(CDCl₃)δ:1.50-1.70(6H, m), 2.80(2H, brs), 2.90(3H, d, J=4.9Hz), 3.02(4H, m), 3.71(4H, m), 4.50(2H, s), 6.83(2H, d, J=9.0Hz), 7.95(2H, d, J=9.0Hz) ・ 5-amino-4-methylamino-6-morpholino-2- (4-piperidinophenacylthio) pyrimidine (Compound 20)
Melting point: 99-100 ° C
MS m / z: 442 (M ⁺ )
NMR (CDCl ₃ ) δ: 1.50-1.70 (6H, m), 2.80 (2H, brs), 2.90 (3H, d, J = 4.9Hz), 3.02 (4H, m), 3.71 (4H, m), 4.50 (2H, s), 6.83 (2H, d, J = 9.0Hz), 7.95 (2H, d, J = 9.0Hz)

・5-アミノ-2-(4-シアノフェナシルチオ)-4-メチルアミノ-6-モルホリノピリミジン（化合物21）
融点:132-137℃
MS m/z: 384(M⁺)
NMR(CDCl₃)δ:2.80(2H, brs), 2.89(3H, d, J=4.6Hz), 3.02(4H, m), 3.75(4H, m), 4.52(2H, s), 7.75(2H, d, J=7.9Hz), 8.14(2H, d, J=7.9Hz) ・ 5-Amino-2- (4-cyanophenacylthio) -4-methylamino-6-morpholinopyrimidine (Compound 21)
Melting point: 132-137 ° C
MS m / z: 384 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.80 (2H, brs), 2.89 (3H, d, J = 4.6Hz), 3.02 (4H, m), 3.75 (4H, m), 4.52 (2H, s), 7.75 (2H , d, J = 7.9Hz), 8.14 (2H, d, J = 7.9Hz)

・5-アミノ-2-[3-(メトキシカルボニル)ベンジルチオ]-4-メチルアミノ-6-モルホリノピリミジン (化合物22)
融点:106-110℃
MS m/z: 389(M⁺)
NMR(CDCl₃)δ:2.83(2H, brs), 3.02(3H, d, J=4.9Hz), 3.10-3.14(4H, m), 3.78-3.83(4H, m), 3.90(3H, s), 4.39(2H, s), 4.53-4.56(1H, m), 7.35(1H, t, J=7.7Hz), 7.65(1H, d, J=7.7Hz), 7.88(1H, d, J=7.7Hz), 8.15(1H, s) 5-amino-2- [3- (methoxycarbonyl) benzylthio] -4-methylamino-6-morpholinopyrimidine (Compound 22)
Melting point: 106-110 ° C
MS m / z: 389 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.83 (2H, brs), 3.02 (3H, d, J = 4.9Hz), 3.10-3.14 (4H, m), 3.78-3.83 (4H, m), 3.90 (3H, s) , 4.39 (2H, s), 4.53-4.56 (1H, m), 7.35 (1H, t, J = 7.7Hz), 7.65 (1H, d, J = 7.7Hz), 7.88 (1H, d, J = 7.7 Hz), 8.15 (1H, s)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-ジフェニルメチルチオピリミジン (化合物23)
融点:168℃
MS m/z: 407(M⁺)
NMR(CDCl₃)δ:2.76(2H, brs), 2.92(3H, d), 3.00(4H, m), 3.76(4H, m), 4.46(1H, m), 6.20(1H, s), 7.10-7.50(10H, m) 5-amino-4-methylamino-6-morpholino-2-diphenylmethylthiopyrimidine (Compound 23)
Melting point: 168 ° C
MS m / z: 407 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.76 (2H, brs), 2.92 (3H, d), 3.00 (4H, m), 3.76 (4H, m), 4.46 (1H, m), 6.20 (1H, s), 7.10 -7.50 (10H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-テニルチオ)ピリミジン（化合物24）
融点:88-90℃
MS m/z: 337(M⁺)
NMR(CDCl₃)δ:2.84(2H, brs), 3.03(3H, d, J=5.1Hz), 3.14-3.18(4H, m), 3.79-3.84(4H, m), 4.56-4.58(3H, m), 6.88(1H, dd, J=5.3Hz, 3.5Hz), 7.01(1H, dd, J=3.5Hz, 1.3Hz), 7.12 (1H, dd, J=5.3Hz, 1.3Hz) ・ 5-Amino-4-methylamino-6-morpholino-2- (2-enylthio) pyrimidine (Compound 24)
Melting point: 88-90 ℃
MS m / z: 337 (M ⁺ )
_{NMR (CDCl 3) δ: 2.84} (2H, brs), 3.03 (3H, d, J = 5.1Hz), 3.14-3.18 (4H, m), 3.79-3.84 (4H, m), 4.56-4.58 (3H, m), 6.88 (1H, dd, J = 5.3Hz, 3.5Hz), 7.01 (1H, dd, J = 3.5Hz, 1.3Hz), 7.12 (1H, dd, J = 5.3Hz, 1.3Hz)

・5-アミノ-2-(4-ベンジルオキシベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン（化合物25）
oil
MS m/z: 437(M⁺)
NMR(CDCl₃)δ:2.82(2H, brs), 3.01(3H, d, J=4.8Hz), 3.12(4H, m), 3.80(4H, m), 4.32(2H, s), 4.50(1H, m), 5.03(2H, s), 6.88(2H, d, J=8.7Hz), 7.30-7.45(7H, m) ・ 5-Amino-2- (4-benzyloxybenzylthio) -4-methylamino-6-morpholinopyrimidine (Compound 25)
oil
MS m / z: 437 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.82 (2H, brs), 3.01 (3H, d, J = 4.8Hz), 3.12 (4H, m), 3.80 (4H, m), 4.32 (2H, s), 4.50 (1H , m), 5.03 (2H, s), 6.88 (2H, d, J = 8.7Hz), 7.30-7.45 (7H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-ピリジニルメチルチオ)ピリミジン（化合物26）
融点:135-137℃
MS m/z: 332(M⁺)
NMR(CDCl₃)δ:2.81(2H, brs), 2.95(3H, d J=5.0Hz), 3.07(4H, m), 3.78(4H, m), 4.51(2H, s), 4.55(1H, m), 7.11(1H, m), 7.55(2H, m), 8.51(1H, m) ・ 5-Amino-4-methylamino-6-morpholino-2- (2-pyridinylmethylthio) pyrimidine (Compound 26)
Melting point: 135-137 ° C
MS m / z: 332 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.81 (2H, brs), 2.95 (3H, d J = 5.0Hz), 3.07 (4H, m), 3.78 (4H, m), 4.51 (2H, s), 4.55 (1H, m), 7.11 (1H, m), 7.55 (2H, m), 8.51 (1H, m)

・5-アミノ-2-(3-フルオロベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン（化合物27）
融点:82-85℃
MS m/z: 349(M⁺)
NMR(CDCl₃)δ:2.83(2H, brs), 3.01(3H, d, J=5.1Hz), 3.09-3.14(4H, m), 3.78-3.83(4H, m), 4.35(2H, s), 4.55-4.58(1H, m), 6.85-6.94(1H, m), 7.15-7.26(3H, m) ・ 5-Amino-2- (3-fluorobenzylthio) -4-methylamino-6-morpholinopyrimidine (Compound 27)
Melting point: 82-85 ℃
MS m / z: 349 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.83 (2H, brs), 3.01 (3H, d, J = 5.1Hz), 3.09-3.14 (4H, m), 3.78-3.83 (4H, m), 4.35 (2H, s) , 4.55-4.58 (1H, m), 6.85-6.94 (1H, m), 7.15-7.26 (3H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-フェニルベンジルチオ)ピリミジン（化合物28）
融点:148-149℃
MS m/z: 407(M⁺)
NMR(CDCl₃)δ:2.83(2H, brs), 3.03(3H, d, J=5.1Hz), 3.12-3.16(4H, m), 3.79-3.83(4H, m), 4.42(2H, s), 4.53-4.56(1H, m), 7.28-7.48(3H, m), 7.50-7.59(6H, m) ・ 5-Amino-4-methylamino-6-morpholino-2- (4-phenylbenzylthio) pyrimidine (Compound 28)
Melting point: 148-149 ℃
MS m / z: 407 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.83 (2H, brs), 3.03 (3H, d, J = 5.1Hz), 3.12-3.16 (4H, m), 3.79-3.83 (4H, m), 4.42 (2H, s) , 4.53-4.56 (1H, m), 7.28-7.48 (3H, m), 7.50-7.59 (6H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(1-ナフチルメチルチオ)ピリミジン（化合物29）
融点:133-134℃
MS m/z: 381(M⁺)
NMR(CDCl₃)δ:2.84(2H, brs), 3.03(3H, d, J=4.3Hz), 3.13-3.18(4H, m), 3.78-3.82(4H, m), 4.87(2H, s), 7.38(1H, dd, J=8.4Hz, 7.0Hz), 7.47-7.53(2H, m), 7.62(1H, d, J=7.0Hz), 7.75 (1H, d, J=8.1Hz), 7.85(1H, dd, J=9.2Hz, 2.4Hz), 8.21(1H, d, J=7.3Hz) ・ 5-Amino-4-methylamino-6-morpholino-2- (1-naphthylmethylthio) pyrimidine (Compound 29)
Melting point: 133-134 ° C
MS m / z: 381 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.84 (2H, brs), 3.03 (3H, d, J = 4.3Hz), 3.13-3.18 (4H, m), 3.78-3.82 (4H, m), 4.87 (2H, s) , 7.38 (1H, dd, J = 8.4Hz, 7.0Hz), 7.47-7.53 (2H, m), 7.62 (1H, d, J = 7.0Hz), 7.75 (1H, d, J = 8.1Hz), 7.85 (1H, dd, J = 9.2Hz, 2.4Hz), 8.21 (1H, d, J = 7.3Hz)

・5-アミノ-2-[(7-メトキシクマリン-4-イル)メチルチオ]-4-メチルアミノ-6-モルホリノピリミジン（化合物30）
融点:190-195℃
MS m/z: 429(M⁺)
NMR(CDCl₃)δ:2.88(2H, brs), 2.95(3H, d, J=4.9Hz), 3.07(4H, m), 3.77(4H, m), 3.87(3H, s), 4.43(2H, s), 4.58(1H, m), 6.49(1H, s), 6.83(2H, s), 7.65(1H, m) ・ 5-Amino-2-[(7-methoxycoumarin-4-yl) methylthio] -4-methylamino-6-morpholinopyrimidine (Compound 30)
Melting point: 190-195 ° C
MS m / z: 429 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.88 (2H, brs), 2.95 (3H, d, J = 4.9Hz), 3.07 (4H, m), 3.77 (4H, m), 3.87 (3H, s), 4.43 (2H , s), 4.58 (1H, m), 6.49 (1H, s), 6.83 (2H, s), 7.65 (1H, m)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-ナフチルメチルチオ)ピリミジン（化合物31）
融点:113-115℃
MS m/z: 381(M⁺)
NMR(CDCl₃)δ:2.82(2H, brs), 3.03(3H, d, J=4.3Hz), 3.11-3.15(4H, m), 3.78-3.83(4H, m), 4.50-4.54(3H, m), 7.40-7.47(2H, m), 7.58(1H, dd, J=8.4Hz, 1.9Hz), 7.77-7.81(3H, m), 7.89(1H, brs) ・ 5-Amino-4-methylamino-6-morpholino-2- (2-naphthylmethylthio) pyrimidine (Compound 31)
Melting point: 113-115 ° C
MS m / z: 381 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.82 (2H, brs), 3.03 (3H, d, J = 4.3Hz), 3.11-3.15 (4H, m), 3.78-3.83 (4H, m), 4.50-4.54 (3H, m), 7.40-7.47 (2H, m), 7.58 (1H, dd, J = 8.4Hz, 1.9Hz), 7.77-7.81 (3H, m), 7.89 (1H, brs)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(4-フルオロベンジルチオ)ピリミジン（化合物32）
融点:75-80℃
MS m/z: 349(M⁺)
NMR(CDCl₃)δ:2.83(2H, brs), 3.01(3H, d, J=4.9Hz), 3.10-3.14(4H, m), 3.78-3.83(4H, m), 4.33(2H, s), 4.55-4.57(1H, m), 6.95(2H, t, J=8.6Hz), 7.39(2H, dd, J=8.6Hz, 5.4Hz) ・ 5-Amino-4-methylamino-6-morpholino-2- (4-fluorobenzylthio) pyrimidine (Compound 32)
Melting point: 75-80 ℃
MS m / z: 349 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.83 (2H, brs), 3.01 (3H, d, J = 4.9Hz), 3.10-3.14 (4H, m), 3.78-3.83 (4H, m), 4.33 (2H, s) , 4.55-4.57 (1H, m), 6.95 (2H, t, J = 8.6Hz), 7.39 (2H, dd, J = 8.6Hz, 5.4Hz)

・5-アミノ-4-メチルアミノ-6-モルホリノ-2-(2-フルオロベンジルチオ)ピリミジン（化合物33）
融点:128℃
MS m/z: 349(M⁺)
NMR(CDCl₃)δ:2.82(2H, brs), 3.01(3H, d, J=5.1Hz), 3.10-3.14(4H, m), 3.78-3.82(4H, m), 4.42(2H, s), 4.55-4.56(1H, m), 6.97-7.07(2H, m), 7.14-7.23(1H, m), 7.52(1H, dt, J=7.7Hz, 1.8Hz) 5-amino-4-methylamino-6-morpholino-2- (2-fluorobenzylthio) pyrimidine (compound 33)
Melting point: 128 ° C
MS m / z: 349 (M ⁺ )
NMR (CDCl ₃ ) δ: 2.82 (2H, brs), 3.01 (3H, d, J = 5.1Hz), 3.10-3.14 (4H, m), 3.78-3.82 (4H, m), 4.42 (2H, s) , 4.55-4.56 (1H, m), 6.97-7.07 (2H, m), 7.14-7.23 (1H, m), 7.52 (1H, dt, J = 7.7Hz, 1.8Hz)

・5-アミノ-2-(2,4-ジフルオロベンジルチオ)-4-メチルアミノ-6-モルホリノピリミジン（化合物34）
融点:87-93℃
MS m/z: 367(M⁺)
NMR(CDCl₃)δ:2.83(2H, brs), 3.01(3H, d, J=5.0Hz), 3.10-3.14(4H, m), 3.78-3.83(4H, m), 4.36(2H, s), 4.55-4.56(1H, m), 6.74-6.81(2H, m), 7.48-7.51(1H, m) ・ 5-Amino-2- (2,4-difluorobenzylthio) -4-methylamino-6-morpholinopyrimidine (Compound 34)
Melting point: 87-93 ℃
MS m / z: 367 (M ⁺ )
_{NMR (CDCl 3) δ: 2.83} (2H, brs), 3.01 (3H, d, J = 5.0Hz), 3.10-3.14 (4H, m), 3.78-3.83 (4H, m), 4.36 (2H, s) , 4.55-4.56 (1H, m), 6.74-6.81 (2H, m), 7.48-7.51 (1H, m)

Claims

Formula (I)

[Wherein, R ₁ is a hydrogen atom, C ₁ -C ₆ alkyl or phenyl, R ₂ is phenyl (C ₁ -C ₆ alkylcarbonyloxy, 1 to 2 C ₁ -C ₆ alkoxy, C ₁ -C ₆ Alkylthio, C ₁ -C ₆ alkyl, 1 to 2 halogen atoms, thiadiazolyl, C ₁ -C ₆ alkoxycarbonyl, optionally substituted with phenyl or benzyloxy), phenyl C ₁ -C ₆ alkyl, phenylcarbamoyl (Optionally substituted with 1 to 2 halogen atoms), benzoyl (optionally substituted with C ₁ -C ₆ alkoxy, cyano or piperidino), naphthyl, coumarinyl (substituted with C ₁ -C ₆ alkoxy) C ₃ -C ₇ cycloalkyl, pyridinyl or thienyl, R ₃ is a hydrogen atom or C ₁ -C ₆ alkyl, R ₄ is a hydrogen atom or C ₁ -C ₆ alkyl, R ₅ , R ₆ Are combined to form morpholino, piperidino or pyrrolidinyl ( Which may be substituted with hydroxy C ₁ -C ₆ alkyl). Or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein R ₃ is methyl and R ₄ is a hydrogen atom.

The compound according to claim 1, wherein R ₃ is methyl, R ₄ is a hydrogen atom, and R ₅ and R ₆ are combined to form a morpholino.

A TNF-α production inhibitor comprising at least one compound according to claim 1 as an active ingredient.

The antioxidant which uses the at least 1 compound of Claims 1-3 as an active ingredient.

A pharmaceutical composition comprising at least one compound according to claims 1 to 3 as a TNF-α production inhibitory component together with a pharmaceutically acceptable diluent or carrier.

A pharmaceutical composition comprising at least one compound according to claims 1 to 3 as an antioxidant component together with a pharmaceutically acceptable diluent or carrier.