JP4359817B2 - p38阻害剤としての窒素ヘテロ原子含有ヘテロアリール尿素 - Google Patents
p38阻害剤としての窒素ヘテロ原子含有ヘテロアリール尿素 Download PDFInfo
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- JP4359817B2 JP4359817B2 JP2002583386A JP2002583386A JP4359817B2 JP 4359817 B2 JP4359817 B2 JP 4359817B2 JP 2002583386 A JP2002583386 A JP 2002583386A JP 2002583386 A JP2002583386 A JP 2002583386A JP 4359817 B2 JP4359817 B2 JP 4359817B2
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- etoac
- urea
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- aniline
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/33—Heterocyclic compounds
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Description
A’−D−B’ (II)
の窒素ヘテロ原子を含むヘテロアリール尿素化合物を提供する。
そしてA’は2−(4−t−ブチル)ピリジルまたは2−(5−トリフルオロメチル)ピリジルである。
a)C1−10アルキルまたはハロゲンで置換されたフェニル、
b)ナフチル、または
c)任意にC1−10アルキル、C1−10アルコキシもしくはハロゲンで置換されたフェノキシ、ピリジルメチル、ピリジルオキシまたはピリジルチオ基を有するフェニルである。
式IおよびIIの化合物は、あるものは市販の出発原料から既知の化学反応および操作を使用して調製することができる。それにもかかわらず、当業者がこれら化合物を合成するのを助けるため以下に一般的調製法が提供される。もっと詳細な実施例は後続の実験の部に提供される。
ニトロアリールは共通してHNO3 または代りのNO2 + 源を使用して求電子性芳香族ニトロ化によって生成される。ニトロアリールは還元前にさらに手を加えてもよい。このためニトロアリールは、
ニトロアリールは遷移金属仲介クロスカップリング反応を受けることもできる。例えば、ニトロアリールブロマイド、ヨウダイドまたはトリフレートのようなニトロアリール求核試薬は、アリールボロン酸(鈴木反応、以下に例示)、アリールスズ(still反応)またはアリール亜鉛(根岸反応)のようなアリール求核試験とパラジウム仲介クロス反応を受け、ビアリール(5)を与える。
スキームIVに示すように、非対称尿素生成はアリールイソシアネート(14)とアリールアミン(13)との反応を含むことができる。ヘテロアリールイソシアネートは、ホスゲン、またはトリクロロメチルクロロホルメート(ジホスゲン)、ビス(トリクロロメチル)カーボネート(トリホスゲン)、もしくはN,N’−カルボニルジイミダゾール(CDI)のようなホスゲン均等物での処理によってヘテロアリールアミンから合成することができる。イソシアネートは、エステル、酸ハライドまたは無水物のような複素環カルボキシル酸誘導体からクルチウスタイプ転位によって得ることもできる。このように酸誘導体(16)のアジト源との反応および続いての転位はイソシアネートを与える。対応するカルボキシル酸(17)はジフェニルフォスフォリルアジト(OPPA)または類似の試薬を使用してクルチウムタイプ転位へかけることもできる。
最後に、尿素は当業者には良く知られた方法を使用してさらに処理することができる。
1999年2月25日出願No.09/257,265および
1999年10月22日出願No.09/425,229
を含む以上および以下で引用した出願、特許および発表の全体の開示を参照としてここに取入れる。
AcOH 酢酸
anh 無水
dtm 気圧
BOC t−ブトキシカルボニル
CDI 1,1’−カルボニルジイミダゾール
conc 濃縮
dec 分解
DMAC N,N−ジメチルアセタミド
DMPU 1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H )ピリミジン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
DPPA ジフェニルフォスフォリルアジド
EDCI 1−(3−ジメチルアミノプロピル)−3−エチルカルボジイ ミド
EtOAc 酢酸エチル
EtOH エタノール(100%)
Et2 O ジエチルエーテル
Et3 N トリエチルアミン
h 時
HOBT 1−ヒドロキシベンゾトリアゾール
m−CPBA 3−クロロペルオキシ安息香酸
MeOH メタノール
pet.ether 石油エーテル(沸騰範囲30〜60℃)
temp 温度
THF テトラヒドロフラン
TFA トリフルオロAcOH
Tf トリフルオロメタンスルホニル
A1.ニトロアレーンの水素化による置換アニリン生成の一般的方法
EtOH(200mL)中の4−(4−ニトロベンジル)ピリジン(7.0g,32.68mmol)の溶液へPd/C(0.7g)を加え、得られたスラリーをParrシェーカーを用いてH2 雰囲気(50psi)下で振とうした。1h後部分標本のTLCおよび 1H−NMRは完全な反応を指示した。混合物をCeliteの短いパッドを通して濾過した。濾液を減圧濃縮し、白色固体(5.4g,90%)を得た。 1H−NMR(DMSO−d6 )δ3.74(s,2H),4.91(brs,2H),6.48(d,J=8.46Hz,2H),6z86(d,J=8.09Hz,2H),7.16(d,J=5.88Hz,2H),8.40(d,J=5.88Hz,2H);EI−MSm/z184(M+ )この物質はさらに精製することなく尿素生成反応に使用した。
A2.ニトロアレーンの溶解する金属反応による置換アニリン生成の一般的方法
AcOH(5mL)中の4−(2−ピリジニルチオ)−1−ニトロベンゼン(Menai ST3355A;0.220g,0.95mmol)およびH2 O(0.5mL)の溶液へ鉄粉(0.317g,5.68mmol)を加え、得られたスラリーを室温で16h攪拌した。反応混合物をEtOAc(75mL)とH2 O(50mL)で希釈し、固体K2 CO3 を少しづつ加えて(注意:発泡)塩基性化した。有機層を飽和NaCl溶液で洗い、乾燥し(MgSO4 )、減圧濃縮した。残留固体をMPLC(30%EtOH/70%ヘキサン)によって精製し、所望の生成物を粘稠オイル(0.135g,70%)として与えた。TLC(30%EtOH/70%ヘキサン)Rf0.20
A3a.求核芳香族置換を経由するニトロアレーン生成次いで還元による置換アニリン生成のための一般的方法
DMF(100mL)中のNaH(95%,1.50g,59mmol)の室温のサスペンジョンへDMF(50mL)中の4−メトキシフェノール(7.39g,59mmol)の溶液を滴下した。反応混合物を1hかきまぜ、次にDMF(50mL)中の1−フロロ−4−ニトロベンゼン(7.0g,49mmol)の溶液を滴下し、暗緑色の溶液を得た。反応混合物を95℃へ一夜加熱し、次に室温へ冷却し、H2 Oで反応停止し、そして減圧濃縮した。残渣をEtOAc(200mL)とH2 O(200mL)との間に分配した。有機層をH2 O(2×200mL)と、飽和NaHCO3 溶液(200mL)と飽和NaCl溶液(200mL)とで順次洗い、乾燥し(Na2 SO4 )、そして減圧濃縮した。残渣をこね(Et2 O/ヘキサン)、1−メトキシ−4−(4−ニトロフェノキシ)ベンゼン(12.2g,100%)を得た。 1H−NMR(CDCl3 )δ3.83(s,3H),6.93−7.01(m,6H),8.18(d,J=9.2Hz,2H);EI−MSm/z245(M+ )
EtOAc(250mL)中の1−メトキシ−4−(4−ニトロフェノキシ)ベンゼン(12.0g,49mmol)の溶液へ5%Pd/C(1.5g)を加え、得られたスラリーをH2 雰囲気(50psi)下18h振とうした。反応混合物をEtOAcの助けによりCeliteのパッドを通して濾過し、減圧濃縮し、徐々に固化するオイル(10.6g,100%)を得た。 1H−NMR(CDCl3 )δ3.54(brs,2H),3.78(s,3H),6.65(d,J=8.8Hz,2H),6.79−6.92(m,6H);EI−MSm/z215(M+ )
A3b.求核芳香族置換を経由するニトロアレーン生成
次いで還元による置換アニリン生成のための一般的方法
無水DMF(80mL)中の4−メルカプトピリジン(2.8g,24mmol),2−フロロ−5−ニトロベンゾトリフロライド(5g,23.5mmol)および炭酸カリウム(6.1g,44.3mmol)の溶液を室温でそしてアルゴン下一夜かきまぜた。TLCは完全な反応を示した。混合物をEt2 O(100mL)と水(100mL)で希釈し、水層をEt2 O(2×100mL)で逆抽出した。有機層を飽和NaCl溶液(100mL)で洗い、乾燥し(MgSO4 )、減圧濃縮した。固体残渣をEt2 Oでこね、所望生成物を褐色固体(3.8g,54%)として得た。TLC(30%EtOAc/70%ヘキサン)Rf0.06; 1H−NMR(DMSO−d6 )δ7.33(dd,J=1.2,4.2Hz,2H),7.78(d,J=8.7Hz,1H),8.46(dd,J=2.4,8.7Hz,1H),8.54−8.56(m,3H)
3−トリフロロメチル−4−(4−ピリジニルチオ)ニトロベンゼン(3.8g,12.7mmol)、鉄粉(4.0g,71.6mmol)、酢酸(100mL)、および水(100mL)のスラリーを室温で4hかきまぜた。混合物をEt2 O(100mL)と水(100mL)で希釈した。水層を4N NaOH溶液でpH4に調節した。合併した有機層を飽和NaCl溶液(100mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。残渣をシリカのパッド(50%EtOAc/50%ヘキサンから60%EtOAc/40%ヘキサンまでの勾配)を通して濾過し、所望の生成物を得た。TLC(50%EtOAc/50%ヘキサン)Rf0.10; 1H−NMR(DMSO−d6 )δ6.21(s,2H),6.84−6.87(m,3H),7.10(d,J=2.4Hz,1H),7.39(d,J=8.4Hz,1H),8.29(d,J=6.3Hz,2H)
A3c.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリン生成のための一般的方法
DMF(40mL)中の2−メルカプト−4−フェニルチアゾール(4.0g,20.7mmol)の溶液を1−フロロ−4−ニトロベンゼン(2.3mL,21.7mmol)次いでK2 CO3 (3.18g,23mmol)で処理し、混合物を約65℃で一夜加熱した。反応混合物を次にEtOAc(100mL)で希釈し、水(100mL)と飽和NaCl溶液(100mL)で順次洗い、乾燥(MgSO4 )し、減圧濃縮した。固体残渣をEt2 O/ヘキサン溶液でこね、所望生成物を得た。TLC(25%EtOAc/ヘキサン)Rf0.49; 1H−NMR(CDCl3 )δ7.35−7.47(m,3H),7.58−7.63(m,3H),7.90(d,J=6.9Hz,2H),8.19(d,J=9.0Hz,2H)
4−(2−(4−フェニル)チアゾリル)チオ−1−ニトロベンゼンを3−(トリフロロメチル)−4−(4−ピリジニルチオ)アニリンの製造に使用したのと同様な態様で還元した。TLC(25%EtOAt/75%ヘキサン)Rf0.18; 1H−NMR(CDCl3 )δ3.89(brs,2H),6.72−6.77(m,2H),7.26−7.53(m,6H),7.85−7.89(m,2H)
A3d.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリン生成のための一般的方法
無水DMF(50mL)中の5−ヒドロキシ−2−メチルピリジン(5.0g,45.8mmol)および1−フロロ−4−ニトロベンゼン(6.5g,45.8mmol)の溶液へK2 CO3 (13.0g,91.6mmol)を1度に加えた。混合物をかきまぜながら還流温度へ18h加熱し、次に室温へ冷却した。生成した混合物を水(200mL)へ注ぎ、EtOAc(3×150mL)で抽出した。合併した有機層を水(3×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮し、所望生成物(8.7g,83%)を得た。この物質はさらに精製することなく次工程に使用した。
EtOAc(150mL)中の4−(6−メチル−3−ピリジニルオキシ)−1−ニトロベンゼン(4.0g,17.3mmol)の溶液へ10%Pd/C(0.500g,0.47mmol)を加え、得られた混合物をH2 雰囲気(バルーン)下に置き、室温で18hかきまぜた。混合物を次にCeliteのパットを通して濾過し、減圧濃縮して所望生成物を褐色固体(3.2g,92%)として得た。EI−MSm/z200(M+ )
A3e.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリン生成のための一般的方法
無水DMF(20mL)中の3,4−ジメトキシフェノール(1.0g,6.4mmol)と1−フロロ−4−ニトロベンゼン(700μL,6.4mmol)の溶液へK2 CO3 (18g,12.9mmol)を1度に加えた。混合物をかきまぜながら還流温度へ18h加熱し、室温へ冷却した。混合物を次に水(100mL)へ注ぎ、EtOAc(3×100mL)で抽出した。合併した有機層を水(3×50mL)と飽和NaCl溶液(2×5mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮して所望生成物(0.8g,54%)を得た。粗生成物はさらに精製することなく次工程へ移した。
EtOAc(50mL)中の4−(3,4−ジメトキシフェノキシ)−1−ニトロベンゼン(0.8g,3.2mmol)の溶液へ10%Pd/C(0.100g)を加え、生成した混合物をH2 雰囲気(バルーン)下に置き、室温で18hかきまぜた。混合物を次にCeliteのパッドを通して濾過し、減圧濃縮して所望生成物を白色固体(0.6g,75%)として得た。EI−MSm/z245(M+ )
A3f.求核芳香族置換を経由するニトロアレーンの生成
次いて還元による置換アニリン生成のための一般的方法
無水DMF(50mL)中の3−ヒドロキシピリジン(2.8g,29.0mmol)、1−ブロモ−3−ニトロベンゼン(5.9g,29.9mmol)および臭化銅(I)(5.0g,34.8mmol)の溶液へK2 CO3 (8.0g,58.1mmol)を1度に加えた。生成した混合物をかきまぜながら還流温度へ18h加熱し、次に室温へ冷却した。混合物を水(200mL)へ注ぎ、EtOAc(3×100mL)で抽出した。合併した有機層を水(3×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮した。得られたオイルをフラッシュクロマトグラフィー(30%EtO/Ac/70%ヘキサン)で精製し、所望生成物(2.0g,32%)を得た。この物質はさらに精製することなく次工程に使用した。
EtOAc(100mL)中の3−(3−ピリジニルオキシ)−1−ニトロベンゼン(2.0g,9.2mmol)の溶液へ10%Pd/C(0.200g)を加え、得られた混合物を水素雰囲気(バルーン)下に置き、室温で18hかきまぜた。混合物を次にCeliteのパッドを通して濾過し、減圧濃縮して所望生成物を赤色オイル(1.6g,94%)として得た。EI−MSm/z186(M+ )
A3g.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリン生成のための一般的方法
無水DMF(50mL)中の3−ヒドロキシ−5−メチルピリジン(5.0g,45.8mmol)、1−ブロモ−3−ニトロベンゼン(12.0g,59.6mmol)およびヨウ化銅(I)(10.0g,73.3mmol)の溶液へK2 CO3 (13.0g,91.6mmol)を1度に加えた。混合物を還流温度へ18h加熱し、次に室温へ冷却した。混合物を次に水(200mL)へ注ぎ、EtOAc(3×150mL)で抽出した。合併した有機層を水(3×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮した。得られたオイルをフラッシュクロマトグラフィーにより精製し、所望生成物(1.2g,13%)を得た。
3−(5−メチル−3−ピリジニルオキシ)−1−ニトロベンゼン(1.2g,5.2mmol)のEtOAc(50mL)中の溶液へ10%Pd/C(0.100g)を加え、得られた混合物をH2 雰囲気(バルーン)下に置き、室温で18hかきまぜた。混合物を次にCeliteのパッドを通して濾過し、減圧濃縮して所望生成物を赤色オイルとして(0.9g,86%)得た。EI−MSm/z201(M+ )
A3h.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリンの生成のための一般的方法
DMF(200mL)中の2−クロロ−5−ニトロピリジン(6.34g,40mmol)の溶液へ4−メチルフェノール(5.4g,50mmol,1.25当量)と、K2 CO3 (8.28g,60mmol,1.5当量)を加えた。混合物を室温で一夜かきまぜた。得られた混合物を水(600mL)で処理し、沈澱を生成させた。この混合物を1hかきまぜ、固体を分離し、1N NaOH溶液(25mL)と、水(25mL)と、石油エーテル(25mL)で順次洗い、所望生成物(7.05g,76%)を得た。mp80−82℃;TLC(30%EtOAc/70%石油エーテル)Rf0.79; 1H−NMR(DMSO−d6 )δ2.31(s,3H),7.08(d,J=8.46Hz,2H),7.19(d,J=9.20Hz,1H),7.24(d,J=8.09Hz,2H),8.58(dd,J=2.94,8.82Hz,1H)、8.99(d,J=2.95Hz,1H);FAB−MSm/z(rel abundance)231(M+H+ ),100%)
EtOAc(190mL)中の5−ニトロ−2−(4−メチルフェノキシ)ピリジン(6.94g,30mmol,1当量)およびEtOH(10mL)の溶液をアルゴンでパージし、次に10%Pd/C(0.06g)で処理した。反応混合物を次にH2 雰囲気下に置き、2.5h激しくかきまぜた。反応混合物をCeliteのパッドを通して濾過した。Et2 O中のHCl溶液を濾液へ滴下した。生成する沈澱を分離し、EtOAcで洗い、所望生成物(7.56g,92%)を得た。mp208−210℃(分解);TLC(50%EtOAc/50%石油エーテル)Rf0.42; 1H−NMR(DMSO−d6 )δ2.25(s,3H),6.98(d,J=8.45Hz,2H),7.04(d,J=8.82Hz,1H),7.19(d,J=8.09Hz,2H),8.46(dd,J=2.57,8.46Hz,1H)、8.63(d,J=2.57Hz,1H);EI−MSm/z(rel abundance)(M+ ,100%)
A3i.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリンの生成のための一般的方法
無水DMF(20mL)中の4−ニトロチオフェノール(純度80%,1.2g,6.1mmol)と、3−ブロモチオフェン(1.0g,6.1mmol)と、酸化銅(II)0.5g,3.7mmol)の溶液へKOH(0.3g,6.1mmol)を加え、生成した混合物を130℃でかきまぜながら42h加熱し、次に室温へ冷却した。反応混合物を次に氷と6N HCl溶液との混合物(200mL)へ注ぎ、生成する水性混合物をEtOAc(3×100mL)で抽出した。合併した有機層を1M NaOH溶液(2×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(MgSO4 )し、減圧濃縮した。残渣をMPLC(シリカゲル、10%EtOAc/90%ヘキサンから5%EtOAc/95%ヘキサンまでの勾配)により精製し、所望生成物(0.5g,34%)を得た。GC−MSm/z237(M+ )
4−(3−チエニルチオ)−1−ニトロベンゼンを方法A1に記載した同様な方法により置換アニリンへ還元した。
A3j.求核芳香置換を経由するニトロアレーンの生成
次いで還元による置換アニリン生成のための一般的方法
4−アミノフェノール(1.0g,9.2mmol)をDMF(20mL)に溶かし、次に5−ブロモピリミジン(1.46g,9.2mmol)およびK2 CO3 (1.9g,13.7mmol)を加えた。混合物を100℃において18hそして130℃において48h加熱し、その時GC−MSはいくらかの出発物質を示した。反応混合物を室温へ冷却し、水(50mL)で希釈した。生成する溶液をEtOAc(100mL)で抽出し、有機層を飽和NaCl溶液(2×50mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。残渣の固体をMPLC(50%EtOAc/50%ヘキサン)により精製し、所望のアミン(0.650g,38%)を得た。
A3k.求核芳香族置換を経由するニトロアレーンの生成
次いで還元による置換アニリン生成のための一般的方法
MeOH(60mL)中の2,5−ジブロモピリジン(5.5g,23.2mmol)とNaOMe(3.76g,69.6mmol)の混合物を密封反応容器中で70℃で42h加熱し、次に室温へ冷却した。反応混合物を水(50mL)で処理し、EtOAc(2×100mL)で抽出した。合併した有機層を乾燥し(Na2 SO4 )、減圧濃縮して淡黄色揮発性オイル(4.1g,95%収率)を得た。TLC(10%EtOAc/90%ヘキサン)Rf0.57
−78℃においてTHF(175mL)中の5−ブロモ−2−メトキシピリジンの攪拌溶液へn−ブチルリチウム溶液(ヘキサン中2.5M,28.7mL,71.8mmol)を滴下し、得られた混合物を−78℃において45分かきまぜた。シリンジによりホウ酸トリメチル(7.06mL,62.2mmol)を加え、得られた混合物を追加の2hかきまぜた。明るいオレンジ色の反応混合物を0℃へ暖め、3N NaOH溶液(25mL,71.77mmol)と過酸化水素水(30%, 約50mL)との混合物で処理した。生成する黄色の少し濁った反応混合物を室温へ30分暖め、次に還流温度へ1h加熱した。反応混合物を次に室温へ冷却した。水層を1N HCl溶液で中和し、Et2 O(2×100mL)で抽出した。合併した有機層を乾燥(Na2 SO4 )し、減圧濃縮し、粘稠な黄色オイル(3.5g,60%)を得た。
無水DMF(100mL)中のNaH(97%,1.0g,42mmol)の攪拌溶液へDMF(100mL)中の5−ヒドロキシ−2−メトキシピリジン(3.5g,28mmol)の溶液を加えた。得られた混合物を室温で1hかきまぜ、4−フロロニトロベンゼン(3mL,28mmol)をシリンジによって加えた。反応混合物を95℃へ加熱し、水(25mL)で処理し、EtOAc(2×75mL)で抽出した。有機層を乾燥(MgSO4 )し、減圧濃縮した。残渣の褐色オイルを結晶化(EtOAc/ヘキサン)し、黄色結晶(5.23g,75%)を得た。
4−(5−(2−メトキシ)ピリジル)オキシ−1−ニトロベンゼンを方法A3d,ステップ2と同様な方法でアニリンへ還元した。
A4a.ハロピリジンを使用する求核芳香族置換による置換アニリン合成のための一般的方法
無水DMF(90mL)中の3−アミノチオフェノール(3.8mL,34mmol)の溶液へ4−クロロピリジン塩酸塩(5.4g,35.6mmol)と次いでK2 CO3 (16.7g,121mmol)を加えた。反応混合物を室温で1.5hかきまぜ、次にEtOAc(100mL)と水(100mL)で希釈した。水層をEtOAc(2×100mL)で逆抽出した。合併した有機層を飽和NaCl溶液(100mL)で洗い、乾燥し(MgSO4 )、減圧濃縮した。残渣をシリカパッド(50%EtOAc/50%ヘキサンから70%EtOAc/30%ヘキサンまでの勾配)を通して濾過し、得られる物質をEt2 O/ヘキサン溶液でこね、所望生成物(4.6g,66%)を得た。TLC(100%EtOAc)Rf0.29; 1H−NMR(DMSO−d6 )δ5.41(s,2H),6.64−6.74(m,3H),7.01(d,J=4.8Hz,2H),7.14(t,J=7.8Hz,1H),8.32(d,J=4.8,2H)
A4b.ハロピリジンを使用する求核芳香族置換による置換アニリン合成のための一般的方法
無水DMPU(50mL)中の4−アミノフェノール(3.6g,32.8mmol)と4−クロロピコリン(5.0g,39.3mmol)の溶液へカリウムt−ブトキサイド(7.4g,65.6mmol)を一度に加えた。反応混合物を水(200mL)へ注ぎ、EtOAc(3×150mL)で抽出した。合併した有機層を水(3×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮した。得られるオイルをフラッシュクロマトグラフィー(50%EtOAc/50%ヘキサン)により精製し、所望生成物を黄色オイル(0.7g,9%)として得た。CI−MSm/z201(M+H)+
A4c.ハロピリジンを使用する求核芳香族置換による置換アニリン合成のための一般的方法
DMPU(30mL)中のN−メチル−4−ニトロアニリン(2.0g,13.2mmol)とK2 CO3 (7.2g,52.2mmol)のサスペンジョンへ4−クロロピリジン塩酸塩(2.36g,15.77mmol)を加えた。反応混合物を90℃において20h加熱し、次に室温へ冷却した。生成した混合物を水(100mL)で希釈し、EtOAc(100mL)で抽出した。有機層を水(100mL)で洗い、乾燥(Na2 SO4 )し、減圧濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、80%EtOAc/20%ヘキサンから100%EtOAcまで勾配)により精製し、メチル(4−ニトロフェニル)−4−ピリジルアミン(0.42g)を得た。
メチル(4−ニトロフェニル)−4−ピリジルアミンを方法A1に記載したのと類似の方法で還元した。
A5.フェノールアルキル化次いでニトロアレーンの還元による置換アニリン合成の一般的方法
無水DMF(75mL)中の4−(4−ニトロフェニルチオ)フェノール(1.50g,6.07mmol)の溶液へNaH(鉱油中60%,0.267g,6.67mmol)を加えた。褐色のサスペンジョンをガス発生が止むまで(15分)0℃でかきまぜ、次に無水DMF(20mL)中のヨウ化ブタン(1.12g,690mL,6.07mmol)を0℃で15分にわたって滴下した。反応混合物を室温で18hかきまぜ、その時TLCは未反応フェノールを指示し、追加のヨウ化ブタン(56mg,0.035mL,0.303mmol,0.05当量)とNaH(13mg,0.334mmol)を加えた。反応混合物の追加の6h室温でかきまぜ、次に水(400mL)の添加により停止した。生成した混合物をEt2 O(2×500mL)で抽出した。合併した有機層を水(2×400mL)で洗い、乾燥(MgSO4 )し、減圧濃縮して透明な黄色オイルを取得し、これをシリカゲルクロマトグラフィー(20%EtOAc/80%ヘキサンから50%EtOAc/50%ヘキサンまでの勾配)により精製し、所望生成物を黄色固体(1.24g,67%)として得た。TLC(20%EtOAc/80%ヘキサン)Rf0.75; 1H−NMR(DMSO−d6 )δ0.92(t,J=7.5Hz,3H),1.42(app hex,J=7.5Hz,2H),1.70(m,2H),4.01(t,J=6.6Hz,2H),7.08(d,J=8.7Hz,2H),7.17(d,J=9Hz,2H),7.51(d,J=8.7Hz,2H),8.09(d,J=9Hz,2H)
4−(4−ブトキシフェニル)チオ−1−ニトロアニリンを3−(トリフロロメチル)−4−(4−ピリジニルチオ)アニリンの製造(方法A3b.ステップ2)に使用したのと類似の方法でアニリンに還元した。TLC(33%EtOAc/70%ヘキサン)Rf0.38
A6.ジアミノアレーンのアシル化による置換アニリンの合成のための一般的方法
無水THF(50mL)中の4,4’−メチリデンジアニリン(3.00g,15.1mmol)の溶液へ室温で無水THF(10mL)中のジ−t−ブチルジカーボネート(3.30g,15.1mmol)の溶液を加えた。反応混合物を還流温度で3h加熱し、その時TLCは未反応メチレンジアニリンの存在を示した。追加のジ−t−ブチルジカーボネート(0.664g,3.03mmol,0.02当量)を加え、反応混合物を還流温度で16h加熱した。生成した混合物をEt2 O(200mL)で希釈し、飽和NaHCO3 (100mL)、水(100mL)および飽和NaCl(50mL)で順次洗い、乾燥(MgSO4 )し、減圧濃縮した。生成する白色固体をシリカゲルクロマトグラフィー(33%EtOAc/67%ヘキサンから50%EtOAc/50%ヘキサンまでの勾配)により精製し、所望生成物を白色固体(2.09g,46%)として得た。TLC(50%EtOAc/50%ヘキサン)Rf0.45; 1H−NMR(DMSO−d6 )δ1.43(s,9H),3.63(s,2H),4.85(br s,2H),6.44(d,J=8.4Hz,2H),6.80(d,J=8.1Hz,2H),7.00(d,J=8.4Hz,2H),7.28(d,J=8.1Hz,2H),9.18(br s,1H);FAB−MSm/z298(M+ )
ステップ1.3−(4−ニトロシベンジル)ピリジン:
3−ベンジルピリジン(4.0g,23.6mmol)と70%硝酸(30mL)の溶液を50℃に一夜加熱した。生成する混合物を室温へ冷却し、氷水(350mL)へ注いだ。水性混合物を次に1N NaOH溶液で塩基化し、Et2 O(4×100mL)で抽出した。合併した抽出液を水(3×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮した。残渣のオイルをMPLC(シリカゲル50%EtOAc/50%ヘキサン)で精製し、再結晶(EtOAc/ヘキサン)して所望生成物(1.0g,22%)を得た。GC−MSm/z214(M+ )
3−(4−ニトロベンジル)ピリジンを方法A1に記載に類似の方法によって還元した。
A8.ニトロベンジルハライドによる還元次いで還元によるアリールアミン合成の一般的方法
無水アセトニトリル(30mL)中のインダゾール(0.5g,7.3mmol)と4−ニトロベンジルブロマイド(1.6g,7.3mmol)の溶液へK2 CO3 (1.0g,7.3mmol)を加えた。生成する混合物を室温で18hかきまぜ、次に水(200mL)へ注ぎ、生成する水溶液をEtOAc(3×50mL)で抽出した。合併した有機層を水(3×50mL)および飽和NaCl溶液(2×50mL)で順次洗い、乾燥(MgSO4 )し、減圧濃縮した。残ったオイルをMPLC(シリカゲル、25%EtOAc/75%ヘキサン)により精製し、所望の生成物(1.0g,91%)を得た。EI−MSm/z203(M+ )
4−(1−イミダゾリルメチル)−1−ニトロベンゼンを方法A2に記載のと同様な態様で還元した。
A9.ニトロベンジル化合物の酸化次いで還元による置換ヒドロキシメチルアニリンの生成
CH2 Cl2 (90mL)中の3−(4−ニトロベンジル)ピリジンのかきまぜた溶液へ10℃においてm−CPBA(5.80g,33.6mmol)を加え、混合物を室温で一夜かきまぜた。反応混合物を10%NaHSO3 溶液(50mL)と、飽和K2 CO3 溶液(50mL)と、飽和NaCl溶液(50mL)で次々に洗い、乾燥(MgSO4 )し、減圧濃縮した。生成した黄色オイル(2.68g)を無水酢酸(30mL)に溶かし、還流温度へ一夜加熱した。混合物を減圧濃縮した。残渣をMeOH(25mL)に溶かし、20%NH3 溶液(30mL)で処理した。混合物を室温で1hかきまぜ、次いで減圧濃縮した。残渣を水(50mL)とCH2 Cl2 (50mL)の混合液へ注いだ。有機層を乾燥(MgSO4 )し、減圧濃縮し、カラムクロマトグラフィー(80%EtOAc/20%ヘキサン)により精製し、白色固体として所望の生成物(0.53g,8%)を得た。mp110−118℃;TLC(80%EtOAc/20%ヘキサン)Rf0.12;FAB−MSm/z367(M+H)+ ,100%
4−(1−ヒドロキシ−1−(4−ピリジル)メチル−1−ニトロベンゼンを方法A3d,ステップ2に記載のものと類似の態様で還元した。
A10.Menisci反応による2−(N−メチルカルバモイル)−ピリジンの生成
環境温度におけるアルゴン下のN−メチルホルムアミド(250mL)中の4−クロロピリジン(10.0g)の溶液へH2 SO4 (3.55mL)を加えた(発熱)。これへH2 O2 (17mL,H2 O中30wt%)とFeSO4 ・7H2 O(0.55g)を加え、発熱反応させた。反応混合物を暗所で1h環境温度においてかきまぜ、次に45℃において4hにわたって徐々に加熱した。発泡が静まった時、混合物を60℃で16h加熱した。不透明な褐色溶液をH2 O(700mL)と次いで10%NaOH溶液(250mL)で希釈した。水性混合物をEtOAc(3×500mL)で抽出し、有機層を飽和NaCl溶液(3×150mL)で別々に洗った。合併した有機層を乾燥(MgSO4 )し、シリカゲルパッドを通して濾過し、EtOAcで溶出した。溶媒を減圧留去し、褐色残渣をシリカゲルクロマトグラフィー(50%EtOAc/50%ヘキサンから80%EtOAc/20%ヘキサンまでの勾配)により精製した。生成した黄色オイルを0℃において72hで結晶化し、2−(N−メチルカルバモイル)−4−クロロピリジン0.61g(5.3%)を得た。TLC(50%EtOAc/50%ヘキサン)Rf0.50; 1H−NMR(CDCl3 ):δ8.44(d,1H,J=5.1Hz,CHN),8.21(s,1H,CHCCO),7.96(bs,1H,NH),7.43(dd,1H,J=2.4,5.4Hz,ClCHCN),3.04(d,3H,J=5.1Hz,メチル);CI−MSm/z171((M+H)+ )
無水DMDMF(0.6mL)を40〜50℃の間でSO2 Cl(180mL)へゆっくり加えた。溶液を該温度で30分間かきまぜ、次にピコリン酸(60.0g,488mmol)を30分にわたって少しづつ加えた。反応溶液を72℃で16h加熱し(激しいSO2 発生)、黄色沈澱を生成させた。生成した混合物を室温へ冷却し、トルエン(500mL)で希釈し、200mLへ濃縮した。トルエンの添加/濃縮プロセスは2回くり返した。生成した殆んど乾燥した残渣をトルエンで洗い(2×200mL)、4h減圧乾燥して4−クロロピリジン−2−カルボニルクロライドHCl塩を黄橙色固体(92.0g,89%)として得た。
無水DMF(10.0mL)を40−48℃においてSO2 Clへゆっくり加えた。溶液をその温度範囲で10分間かきまぜ、次にピコリン酸(100g,812mmol)を30分にわたって加えた。生成した容器を72℃へ16h加熱し(激しいSO2 発生)、黄色固体を生成させた。生成した混合物を室温で冷却し、トルエン(500mL)で希釈し、200mLへ濃縮した。トルエンの添加/濃縮プロセスは2回くり返した。生成した殆んど乾燥した残渣を濾過し、固体をトルエン(50mL)で洗い、4時間高真空下乾燥して4−クロロピリジン−2−カルボニルクロライドHCl塩を灰白色固体(27.2g,16%)として得た。この物質は別に取って置いた。
MeOH(75mL)中の4−クロロピリジン−2−カルボキシル酸メチルHCl塩(89.0g,428mmol)の懸濁液を0℃において内温を5℃以下に保ってTHF(1L)中の2.0Mメチルアミン溶液で処理した。生成した混合物を3℃において5h貯え、減圧下濃縮した。生成した固体をEtOAc(1L)に懸濁し、濾過した。濾液を飽和NaCl溶液(500mL)で洗い、乾燥(Na2 SO4 )し、減圧濃縮して4−クロロ−N−メチル−2−ピリジンカルボキサマイドを淡黄色結晶(71.2g,97%)として得た。mp41−43℃; 1H−NMR(DMSO−d6 )δ2.81(s,3H),7.74(dd,J=1.22Hz,1H),8.00(d,J=2.2Hz,1H),8.61(d,J=5.1Hz,1H),8.85(brs,1H);CI−MSm/z171((M+H)+ )
THF(100mL)およびMeOH(20mL)中の2.0Mメチルアミン溶液へ0℃において4−クロロピリジン−2−カルボニルHCl塩(7.0g,32.95mmol)を少しづつ加えた。生成した混合物を3℃において4h貯え、減圧濃縮した。生成した殆んど乾燥した固体をEtOAc(100mL)に懸濁し、濾過した。濾液を飽和NaCl溶液で洗い(2×100mL)、乾燥(Na2 SO4 )し、減圧濃縮して4−クロロ−N−メチル−2−ピリジンカルボキサマイドを黄色結晶性固体(4.95g,88%)として得た。mp37−40℃
無水DMF(150mL)中の4−アミノフェノール(9.60g,88.0mmol)の溶液をカリウムt−ブトキサイド(10.29g,91.7mmol)で処理し、赤褐色混合物を室温で2hかきまぜた。中味を4−クロロ−N−メチル−2−ピリジンカルボキサマイド(15.0g,87.9mmol)とK2 CO3 (6.50g,47.0mmol)で処理し、次に80℃へ8h加熱した。混合物を室温へ冷却し、EtOAc(500mL)と飽和NaCl溶液(500ml)の間に分配した。水相をEtOAc(300mL)で逆抽出した。合併した有機層を飽和NaCl溶液で洗い(4×1000mL)、乾燥(Na2 SO4 )し、減圧濃縮した。生成した固体を35℃において3h減圧乾燥し、4−(2−(N−メチルカルバモイル)−4−ピリジルオキシ)アニリンを明るい褐色固体(17.9g,84%)として得た。 1H−NMR(DMSO−d6 )δ2.77(d,J=4.8Hz,3H),5.17(brs,2H),6.64,6.86(AA’BB’カルテット、J=8.4Hz,4H),7.06(dd,J=5.5,2.5Hz,1H),7.33(d,J=2.5Hz,1H),8.44(d,J=5.5Hz,1H),8.73(brd,1H);HPLC ES−MSm/z244((M+H)+ )
A11.5−(4−アミノフェノキシ)イソインドリン−1,3−ジオンの合成のための一般方法
濃AcOH(25mL)中の炭酸アンモニウム(5.28g,54.9mmol)の混合物へ4−ヒドロキシフタル酸(5.0g,27.45mmol)をゆっくり加えた。生成した混合物を120℃へ45分加熱し、次に透明な明るい黄色混合物を160℃で2h加熱した。生成した混合物を160℃に保ち、約15mLへ濃縮し、室温へ冷却し、そして1N NaOH溶液でpH10へ調節した。この混合物を0℃へ冷却し、1N HCl溶液を用いてゆっくりpH5へ酸性化した。生成した沈澱を濾過によって集め、減圧乾燥して淡黄色粉末(3.24g,72%)として5−ヒドロキシイソインドリン−1,3−ジオンを得た。 1H−NMR(DMSO−d6 )δ7.00−7.03(m,2H),7.56(d,J=9.3Hz,1H)
DMF(40mL)中のNaH(1.1g,44.9mmol)のかきまぜスラリーへ、0℃においてDMF(40mL)中の5−ヒドロキシイソインドリン−1,3−ジオン(3.2g,19.6mmol)の溶液を滴下した。明るい黄緑色混合物を室温へ戻し、1hかきまぜ、次に1−フロロ−4−ニトロベンゼン(2.67g,18.7mmol)をシリンジから3〜4回に分けて加えた。生成した混合物を一夜70℃で加熱し、室温へ冷却し、水(150mL)でゆっくり希釈し、EtOAc(2×100mL)で抽出した。合併した有機層を乾燥(MgSO4 )し、減圧濃縮して5−(4−ニトロフェノキシ)イソインドリン−1,3−ジオンを黄色固体(3.3g,62%)として得た。TLC(30%EtOAc/70%ヘキサン)Rf0.28; 1H−NMR(DMSO−d6 )δ7.32(d,J=(2Hz,2H),2H),7.52−7.57(m,2H),7.89(d,J=7.8Hz,1H),8.29(d,J=9Hz,2H),11.43(brs,1H);CI−MSm/z285((M+H)+ ,100%)
濃AcOH(12mL)と水(0.1mL)中の5−(4−ニトロフェノキシ)イソインドリン−1,3−ジオン(0.6g,2.11mmol)の溶液を鉄粉(0.59g,55.9mmol)をゆっくり加えながらアルゴン気流下かきまぜた。この混合物を室温で72hかきまぜ、次に水(25mL)で希釈し、EtOAc(3×50mL)で抽出した。合併した有機層を乾燥(MgSO4 )し、減圧濃縮して茶褐色固体として5−(4−アミノフェノキシ)イソインドリン−1,3−ジオン(0.4g,75%)を得た。TLC(50%EtOAc/50%ヘキサン)Rf0.27; 1H−NMR(DMSO−d6 )δ5.14(brs,2H),6.62(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,2H),7.03(d,J=2.1Hz,1H),7.23(dd,1H),7.75(d,J=8.4Hz,1H),11.02(s,1H);HPLC ES−MSm/z255((M+H)+ ,100%)
A12.δ−スルホニルフェニルアニリンの合成のための一般的方法
0℃におけるCH2 Cl2 (75mL)中の4−(4−メチルチオフェノキシ)−1−ニトロベンゼン(2g,7.66mmol)の溶液へmCPBA(57−86%,4g)をゆっくり加え、反応混合物を室温で5hかきまぜた。反応混合物を1N NaOH溶液(25mL)で処理した。有機層を水(25mL)と飽和NaCl溶液(25mL)で順次洗い、乾燥(MgSO4 )し、減圧濃縮し、4−(4−メチルスルホニルフェノキシ)−1−ニトロベンゼンを固体(2.1g)として得た。
ステップ2.4−(4−メチルスルホニルフェノキシ)−1−アニリン:
4−(4−メチルスルホニルフェノシキ)−1−ニトロベンゼンを方法A3d,ステップ2に記載したのと類似の態様で還元した。
A13.δ−アルコキシ−δ−カルボキシフェニルアニリンの合成のための一般的方法
アセトン(50mL)中のδ−(3−カルボキシ−4−ヒドロキシフェノキシ)−1−ニトロベンゼン(方法A3a,ステップ1に記載した方法と類似の方法により調製、1.12mmol)の溶液へ、K2 CO3 (5g)とジメチル硫酸(3.5mL)を加えた。生成した混合物を還流温度で一夜加熱し、室温へ冷却し、Celiteのパッドで濾過した。得られた溶液を減圧濃縮し、シリカゲルへ吸収させ、カラムクロマトグラフィー(50%EtOAc/50%ヘキサン)により精製し、黄色粉末(3g)として4−(3−メトキシカルボニル−4−メトキシフェノキシ)−1−ニトロベンゼンを得た。mp115−118℃
MeOH(45mL)中の4−(3−メトキシカルボニル−4−メトキシフェノキシ)−1−ニトロベンゼン(1.2g)と、KOH(0.33g)と、水(5mL)の混合物を室温で一夜かきまぜ、次に還流温度で4h加熱した。得られた混合物を室温で冷却し、減圧濃縮した。残渣を水(50mL)に溶かし、水性混合物を1N HClで酸性とした。得られた混合物をEtOAc(50mL)で抽出した。有機層を乾燥(MgSO4 )し、減圧濃縮して4−(3−カルボキシ−4−メトキシフェノキシ)−1−ニトロベンゼン(1.04g)を得た。
CH2 Cl2 (12mL)中の4−(3−カルボキシ−4−メトキシフェノキシ)−1−ニトロベンゼン(0.50g,1.75mmol)の溶液へSO2 Cl2 (0.64mL,8.77mmol)を少しづつ加えた。生成した溶液を還流温度で18h加熱し、室温へ冷却して減圧濃縮した。生成した黄色固体をCH2 Cl2 (3mL)に溶かし、生成した溶液をメチルアミン溶液(THF中2.0M,3.5mL,7.02mmol)で少しづつ処理し(注意:ガス発生)、室温で4hかきまぜた。生成した混合物を1N NaOH溶液で処理し、次にCH2 Cl2 (25mL)で抽出した。有機層を乾燥(Na2 SO4 )し、減圧濃縮して黄色固体(0.50g,95%)として4−(3−(N−メチルカルバモイル)−4−メトキシフェノキシ)−1−ニトロベンゼンを得た。
EtOH(55mL)中の4−(3−(N−メチルカルバモイル)−4−メトキシフェノキシ)−1−ニトロベンゼン(0.78g,2.60mmol)と10%Pd/C(0.20g)のスラリーを1気圧H2 (バルーン)下2.5日かきまぜ、次にCeliteのパッドを通して濾過した。生成した溶液を減圧濃縮し、灰白色固体(0.68g,96%)として4−(3−(N−メチルカルバモイル)−4−メトキシフェノキシ)アニリンを得た。TLC(0.1%Et3 N/99.9%EtOAc)Rf0.36
A14.4−(3−N−メチルカルバモイルフェノキシ)アニリンの合成のための一般的方法
DMF(125mL)中の4−フロロ−1−ニトロベンゼン(16mL,150mmol)と、3−ヒドロキシ安息香酸エチル(25g,150mmol)と、K2 CO3 (41g,300mmol)の混合物を還流温度で一夜加熱し、室温へ冷却し、水(250mL)で処理した。得られた混合物をEtOAc(3×150mL)で抽出した。合併した有機層を水(3×100mL)と飽和NaCl溶液(2×100mL)で順次洗い、乾燥(Na2 SO4 )し、減圧濃縮した。残渣をカラムクロマトグラフィー(10%EtOAc/90%ヘキサン)により精製し、4−(3−エトキシカルボニルフェノキシ)−1−ニトロベンゼンをオイル(38g)として得た。
3:1 THF/水溶液(75mL)中の4−(3−エトキシカルボニルフェノキシ)−1−ニトロベンゼン(5.14g,17.9mmol)の激しくかきまぜた混合物へ水(36mL)中のLiOH・H2 O(1.50g,35.8mmol)の溶液を加えた。生成する溶液を50℃で一夜加熱し、室温へ冷却し、減圧濃縮し、1M HCl溶液でpH2へ調節した。生成した明るい黄色固体を濾過により回収し、ヘキサンで洗い、4−(3−カルボキシフェノキシ)−1−ニトロベンゼン(4.4g,95%)を得た。
CH2 Cl2 (45mL)中の4−(3−カルボキシフェノキシ)−1−ニトロベンゼン(3.72g,14.4mmol)と、EDCI・HCl(3.63g,18.6mmol)と、N−メチルモルホリン(1.6mL,14.5mmol)と、メチルアミン(THF中2.0M,8mL,16mmol)の混合物を室温で3日間かきまぜ、次に減圧濃縮した。残渣をEtOAc(50mL)に溶かし、生成する混合物を1M HCl溶液(50mL)で抽出した。水層をEtOAc(2×50mL)で逆抽出し、合併した有機層を減圧濃縮し、4−(3−(N−メチルカルバモイル)フェノキシ)−1−ニトロベンゼンをオイル(1.89g)として得た。
EtOAc(20mL)中の4−(3−(N−メチルカルバモイル)フェノキシ)−1−ニトロベンゼン(1.89g,6.95mmol)と5%Pd/C(0.24g)のスラリーをH2 雰囲気(バルーン)下一夜かきまぜた。生成した混合物をCeliteのパッドを通して濾過し、減圧濃縮した。残渣をカラムクロマトグラフィー(5%MeOH/95%CH2 Cl2 )により精製した。得られたオイルを真空下一夜固化させ、4−(3−(N−メチルカルバモイル)フェノキシ)アニリンを黄色固体(0.95g,56%)として得た。
B. 尿素生成の一般的方法
B1.複素環アミンとアリールイソシアネートの反応
無水トルエン(15mL)中の2−アミノ−4−t−ブチルピリジン(192mg)と2,3−ジクロロフェニルイソシアネート(240mg)の溶液をアルゴン下70℃で24h加熱した。反応混合物をEtOAc(200mL)で希釈し、次に水(125mL)で洗った。有機層を乾燥(MgSO4 )し、減圧濃縮してガムを得た。このガムをヘキサンとこね、N−(4−t−ブチルピリジル)−N’−(2,3−ジクロロフェニル)尿素を白色固体(394mg,91%)として得た。TLC(2:1ヘキサン/EtOAc)Rf0.40;FAB−MSm/z338((M+H)+ )
B2a.複素環アミンとN,N’−カルボニルジイミダゾールとの反応次いて置換アニリンとの反応
無水CH2 Cl2 (15mL)中の4−t−ブチル−2−アミノピリジン(192mg)のかきまぜ溶液へ、アルゴン下0℃においてCDI(207mg)を加えた。生成した溶液を2hにわたって環境温度へ暖めた。この混合物へ4−(4−ピリジニルメチル)アニリン(方法A1に従って調製、235mg)を加えた。生成した溶液を室温で24hかきまぜ、水(125mL)で反応停止した。得られた混合物をEtOAc(200mL)で抽出し、有機層を水(100mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。残渣をクロマトグラフィー(SiO2 ,EtOAc)により精製し、N−(4−t−ブチルピリジル)−N’−(4−(4−ピリジニルメチル)フェニル尿素を白色固体(200mg,43%)として得た。TLC(EtOAc)Rf0.43;FAB−MSm/z361((M+H)+ )
B2b.複素環アミンとN,N’−カルボニルジイミダゾールの反応次いで置換アニリンとの反応
無水CH2 Cl(15mL)中の3−アミノー2−メトキシキノリン(138mg)のかきまぜ溶液へ、アルゴン下0℃においてCDI(128mg)を加えた。得られた溶液を1hにわたって室温へ温めた。16h後4−(2−N−メチルカルバモイル−4−ピリジルキシ)アニリン(175mg)を加え、生成した黄色溶液をアルゴン下室温で72hかきまぜた。この溶液を水(125mL)で処理し、得られた混合物をEtOAc(2×150mL)で抽出した。合併した有機層を飽和NaCl溶液(100mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。残渣を10%ヘキサン/90%EtOAcでこねた。得られた白色結晶をEtOAcで洗った。濾液をクロマトグラフィー(SiO2 ,50%EtOAc/50%ヘキサン)により精製し、N,N’−(ビス(3−(2−メトキシキノリニル)尿素(30mg,20%収率)を得た。TLC(50%EtOAc/ヘキサン)Rf0.45;HPLC ES−MSm/z375((M+H)+ )
B2c.複素環アミンとN,N’−カルボニルジイミダゾールの反応次いで置換アニリンとの反応
無水CH2 Cl2 (1.2mL)中の4−t−ブチル−2−アミノピリジン(0.177g,1.18mmol,1当量)の溶液をCDI(0.200g,1.24mmol,1.05当量)へ加え、混合物をアルゴン下室温で1日かきまぜた。得られた溶液へ4−(4−クロロフェノキシ)アニリン(0.259g,1.18mmol,1当量)を一度に加えた。得られた混合物を室温で1日かきまぜ、次に10%クエン酸溶液(2mL)で処理し、1hかきまぜた。有機層をEtOAc(3×5mL)で抽出し、合併した有機層を乾燥(MgSO4 )し、減圧濃縮した。残渣をCH2 Cl2 (10mL)と1N NaOH水溶液で処理した。この混合物を一夜かきまぜた。得られた有機層をCH2 Cl2 (3×5mL)で抽出し、合併した有機層を乾燥(MgSO4 )し、減圧濃縮した。得られた固体をジエチルエーテル(10mL)に懸濁し、15分間超音波処理した。得られた白色固体を乾燥し、N−(4−t−ブチルピリジル)−N’−(4−(4−クロロフェノキシ)フェニル)尿素(42mg,9%)を得た。mp198−199℃
B3.置換アニリンとN,N’−カルボニルジイミダゾールの反応次いで複素環アミンとの反応
CH2 Cl2 (12mL)中の3−(4−ピリジルチオ)アニリン(300mg,1.48mmol)の溶液をCDI(253mg,1.56mmol)で処理した。この溶液をアルゴン下室温で2hかきまぜた。得られた溶液を2−アミノ−5−(トリフロロメチル)ピリジン(238mg,1.47mmol)で処理し、40℃で一夜加熱した。次に反応混合物をEtOAc(25mL)で希釈し、水(10mL)および飽和NaCl溶液(25mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。残渣をカラムクロマトグラフィー(SiO2 ,70%EtOAc/30%CH2 Cl2 から100%EtOAcまでの勾配)により精製し、N−(2−(5−トリフロロメチル)ピリジル)−N’−(3−(4−ピリジルチオ)フェニル)尿素(103mg)を得た。TLC(50%EtOAc/50%CH2 Cl2 )Rf0.33; 1H−NMR(DMSO−d6 ):δ6.06(d,1H,J=6Hz,2H),7.25(dt,J=1.2,7.8Hz,1H),7.48(t,J=8.1Hz,1H),7.50−7.63(m,1H),7.77(d,J=8.7Hz,1H),7.86(t,J=1.8Hz,1H),8.12(dd,J=2.7,9.3Hz,1H),8.37(d,J=6.3Hz,2H),8.67(bs,1H),9.88(s,1H),10.26(s,1H);FAB−MSm/z391((M+H)+ )
B4.複素環アミンとホスゲンの反応次いで置換アニリンとの反応
CH2 Cl2 (20mL)中のホスゲン(トルエン中20%、1.38mL)のかきまぜ溶液へ、アルゴン下0℃で無水ピリジン(207mg)続いて3−アミノ−2−メトキシキノリン(456mg)を加えた。得られた溶液を1hにわたって環境温度へ暖め、白色固体を得た。この固体を減圧下15分乾燥し、次に無水トルエン(20mL)に懸濁した。得られたスラリーへ4−(4−(2−(メチルカルバモイル)ピリジルオキシ)アニリン(方法A2により調製、300mg)を加え、反応混合物をアルゴン下80℃において20h加熱した。得られた混合物を水(200mL)で希釈し、飽和NaHCO3 溶液(10mL)で処理し、EtOAc(2×300mL)で抽出した。合併した有機層を飽和NaCl溶液(100mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。固体の黄色残渣をクロマトグラフィー(SiO2 ,50%EtOAc/50%ヘキサンから100%EtOAcまでの勾配)により精製し、次いでジエチルエーテルとヘキサンから再結晶し、N−(3−(2−メトキシキノリニル)−N’−(4−(4−(2−N−メチルカルバミル−4−ピリジルオキシ)フェニル)尿素を白色固体(140mg,25%)として得た。TLC(EtOAc)Rf0.52;FAB−MSm/z430((M+H)+ )B5a.アニリンとN,N’−カルボニルジイミダゾールとの反応次いで第2のアニリンの付加:
無水CH2 Cl2 (15mL)中の3−アミノ−2−メトキシキノリン(0.14g)のかきまぜ溶液へ0℃においてCDI(0.13g)を加えた。生成した溶液を1時間にわたって室温へ暖め、室温で16hかきまぜた。生成した混合物を4−(2−(N−メチルカルバモイル)−4−ピリジルオキシ)アニリン(0.18g)で処理した。生成した黄色溶液を室温で72hかきまぜ、次に水(125mL)で処理した。生成した水性混合物をEtOAc(2×150mL)で抽出し、合併した有機層を飽和NaCl溶液(100mL)で洗い、乾燥(MgSO4 )し、そして減圧濃縮し、残渣をこねた(90%EtOAc/10%ヘキサン)。生成した白色固体を濾過により集め、EtOAcで洗い、ビス(4−(2−(N−メチルカルバモイル)−4−ピリジルオキシ)フェニル)尿素(0.081g,44%)を得た。
TLC(100%EtOAc)Rf0.50; 1H−NMR(DMSO−d6 ):δ2.76(d,1H,J=5.1Hz,6H),7.1−7.6(m,12H),8.48(d,J=5.4Hz,1H),8.75(d,J=4.8Hz,2H),8.86(s,2H);HPLC ES−MSm/z513((M+H)+ )
B5b.イソシアネートとアニリンの反応
CH2 Cl2 (1.5mL)中の2−メトキシ−5−(トリフロロメチル)フェニルイソシアネート(0.10g,0.47mmol)のかきまぜ溶液へ5−(4−アミノフェノキシ)イソインドリン−1,3−ジオン(方法A3,ステップ3;0.12g,0.47mmol)を一度に加えた。生成した混合物を12hかきまぜ、次にCH2 Cl2 (10mL)とMeOH(5mL)で処理し、1N HCl溶液(15mL)と飽和NaCl溶液(15mL)で順次洗い、乾燥(MgSO4 )し、減圧濃縮した。白色固体としてN−(2−メトキシ−5−(トリフロロメチル)フェニル−N’−(4−(1,3−ジオキソイソインドリン−5−イルオキシ)フェニル)尿素(0.1g,96%)が得られた。TLC(70%EtOAc/30%ヘキサン)Rf0.50; 1H−NMR(DMSO−d6 ):δ3.95(s,3H),7.31−7.10(m,6H),7.57(d,J=9.3Hz,2H),7.80(d,J=8.7Hz,1H),8.53(brs,2H),9.57(s,1H),11.27(brs,1H);HPLC ES−MSm/z472.0((M+H)+ ,100%)
B6.アニリンとホスゲンの反応次いで第2のアニリンの付加
CH2 Cl2 (20mL)中のホスゲン(トルエン中20%,1.38mL)溶液へ0℃においてアルゴン下無水ピリジン(207mg)次いで3−アミノ−2−メトキシキノリン(456mg)を加えた。得られた溶液を1時間を要して環境温度へ得め、環境温度において減圧濃縮し、白色固体を得た。この固体を減圧下15分乾燥し、トルエン(20mL)に懸濁した。得られたスラリーへ4−(4−(2−メチルカルバモイル)アニリン(方法A2によって調製,300mg)を加え、アルゴン下80℃で20h加熱した。生成した混合物を水(200mL)で希釈し、飽和NaHCO3 溶液(10mL)で処理し、EtOAc(2×300mL)で抽出した。合併した有機層を飽和NaCl溶液(100mL)で洗い、乾燥(MgSO4 )し、減圧濃縮した。固体の黄色残渣をクロマトグラフィー(SiO2 ,50%EtOAc/50%ヘキサンから100%EtOAcまでの勾配)より精製し、次いでジエチルエーテルとヘキサンから再結晶し、白色固体としてN−(3−(2−メトキシキノリニル)−N’−(4−(4−(2−N−メチルカルバモイル−4−ピリジルオキシ)フェニル)尿素(140mg,25%)を得た。TLC(EtOAc)Rf0.52;FAB−MSm/z430((M+H)+ )
表1−8に掲げた特定化合物を製造するために使用した詳細な製造ステップの記載が以下に与えられる。表に掲げた化合物の多数は種々の方法に従って合成することができる。それ故以下の特定実施例は例証のみとして与えられ、本発明の範囲を限定すると考えるべきではない。
エントリー2:4−t−ブチル−2−アミノピリジンを4−フロロフェニルイソシアネートと反応させ、尿素を得た。
エントリー3:方法B1に従ってN−(4−t−ブチルピリジニル)−N’−(2,3−ジクロロフェニル)尿素を製造した。
エントリー4:4−t−ブチル−2−アミノピリジンを1−ナフチルイソシアネートと方法B1に従って反応させ、尿素を得た。
エントリー5:方法B2aに従ってN−(4−t−ブチルピリジル)−N’−(4−(4−ピリジニルメチル)フェニル尿素を製造した。
エントリー6:方法B2cに従って4−t−ブチルー2−アミノピリジンを4−フェノキシアニリンと反応させ、尿素を得た。
エントリー7:方法B2cに従って4−t−ブチル−2−アミノピリジンを4−(4−メトキシフェノキシ)アニリンと反応させ、尿素を得た。
エントリー8:方法B2cに従ってN−(4−t−ブチルピリジル)−N’(4−(4−クロロフェノキシ)フェニル)尿素を製造した。
エントリー9:方法B2cに従って4−t−ブチル−2−アミノピリジンを4−(4−メトキシフェノキシ)アリニンと反応させ、尿素を得た。
エントリー10:方法A3fに従って4−(4−アミノフェノキシ)ピリジンを4−ヒドロキシピリジンと1−ブロモ−3−ニトロベンゼンから出発して製造した。方法B2aに従って4−t−ブチルー2−アミノピリジンを4−(4−アミノフェノキシ)ピリジンと反応させ、尿素を得た。
エントリー11:方法A4aに従って4−アミノチオフェノールと4−クロロピリジンから出発して4−(4−ピリジルチオ)アニリンを製造した。方法B2cに従って4−t−ブチル−2−アミノピリジンを4−(4−ピリジルチオ)アニリンと反応させ、尿素を得た。
エントリー12:方法A4aに従って4−アミノチオフェノールと4−クロロピリジン塩酸塩から出発して4−(4−ピリジルチオ)アニリンを製造した。方法B2cに従って4−t−ブチル−2−アミノピリジンを3−(4−ピリジルチオ)アニリンと反応させ、尿素を得た。
エントリー13:方法B3に従って2−アミノー5−(トリフロロメチル)ピリジンと4−(4−ピリジルメチル)アニリンを反応させ、尿素を得た。
エントリー14:方法B3に従ってN−(2−(5−トリフロロメチル)ピリジルオキシ)−N’−(3−(4−ピリジルチオ)フェニル)尿素を製造した。
エントリー15:方法B1に従って3−アミノイソキノリンを4−トリルイソシアネートと反応させ、尿素を得た。
エントリー16:方法B1に従って3−アミノイソキノリンを4−フロロフェニルイソシアネートと反応させ、尿素を得た。
エントリー17:方法B1に従って3−アミノイソキノリンを2,3−ジクロロイソシアネートと反応させ、尿素を得た。
エントリー18:方法B1に従って3−アミノイソキノリンを1−ナフチルイソシアネートと反応させ、尿素を得た。
エントリー19:方法B2aに従って3−アミノイソキノリンを4−(4−ピリジンメチル)アニリンと反応させ、尿素を得た。
エントリー20:方法A3fに従って4−ヒドロキシピリジンと1−ブロモ−3−ニトロベンゼンから出発して4−(4−アミノフェノキシ)ピリジンを製造した。方法B2aに従って3−アミノイソキノリンを4−(4−アミノフェノキシ)ピリジンと反応させ、尿素を得た。
エントリー21:方法B3に従って3−アミノイソキノリンを4−(4−ピリジルメチル)アニリンと反応させ、尿素を得た。
エントリー22:方法B2bに従ってN,N’−(ビス(3−(2−メトキシキノリニル)尿素)を製造した。
エントリー23:方法B3に従って3−アミノ−2−メトキシキノリンを4−(4−ピリジルメチル)アニリンと反応させ、尿素を得た。
エントリー24:方法B4に従って3−アミノ−2−メトキシキノリンを4−(4−ピリジルカルボニル)アニリンと反応させ、尿素を得た。
エントリー25:方法A3dに従って4−ヒドロキシピリジンと1−フロロ−4−ベンゼンから出発して4−(4−ピリジルオキシ)アニリンを製造した。方法B2cに従って3−アミノ−2−メトキシキノリンを4−(4−ピリジルオキシ)アニリンと反応させ、尿素を得た。
エントリー26:方法B4に従って3−アミノ−2−メトキシキノリンを4−((4−メトキシフェニル)メチルアミノ)アニリンと反応させ、尿素を得た。
エントリー27:方法A2aに従って3−(4−ピリジルチオ)アニリンを製造した。方法B3に従って3−アミノ−2−メトキシキノリンと3−(4−ピリジルメチル)アニリンを反応させ、尿素を得た。
エントリー28:方法A3dに従って4−ヒドロキシピリジンと1−フロロ−4−ニトロベンゼンから出発して4−(4−ピリジルオキシ)アニリンを製造した。方法B2aに従って1−(4−メチルピペラジニル)−3−アミノイソキノリンを4−(4−アミノフェノキシ)ピリジンと反応させ、尿素を得た。
エントリー104:方法A10に従って4−(4−(2−(N−メチルカルバモイル)ピリジルオキシ)アニリンを製造した。方法B4に従って3−アミノ−2−メトキシキノリンを4−(4−(2−(N−メチルカルバモイル)ピリジルオキシ)アニリンと反応させ、尿素を得た。
エントリー105:方法A14に従って4−(3−N−メチルカルバモイルフェノキシ)アニリンを製造した。方法B4に従って3−アミノ−2−メトキシキノリンを4−(3−N−メチルカルバモイルフェノキシ)アニリンと反応させ、尿素を得た。
エントリー106:方法A10, ステップ3bに従って4−クロロピリジン−2−カルボニルクロライドをイソプロピルアミンと反応させた。得られた4−クロロ−N−イソプロピル−2−ピリジンカルボキサマイドを方法A10,ステップ4に従って4−アミノフェノールと反応させ、4−(2−(N−イソプロピルカルバモイル)−4−ピリジルオキシ)アニリンを得た。方法B5bに従って3−アミノ−2−メトキシキノリンを4−(2−(N−イソプロピルカルバモイル)−4−ピリジルオキシ)アニリンと反応させ、尿素を得た。
エントリー107:方法A10, ステップ3bに従って4−クロロピリジン−2−カルボニルクロライドHCl塩をアンモニアと反応させ、4−クロロ−2−ピリジンカルボキサマイドを得た。方法A10に従い、DMFの代りにDMACを使用して4−クロロ−2−ピリジンカルボキサマイドを4−アミノフェノールと反応させ、4−(2−カルバモイル−4−ピリジルオキシ)アニリンを得た。方法B6に従って4−(2−カルバモイル−4−ピリジルオキシ)アニリンを4−(2−(N−イソプロピルカルバモイル)−4−ピリジルオキシ)アニリンと反応させ、尿素を得た。
エントリー108:方法A10, ステップ3bに従って4−クロロ−N−メチル−2−ピリジンカルボキサマイドを合成した。方法A10,ステップ4に従い、DMFの代りにDMACを使用して4−クロロ−N−メチル−2−ピリジンカルボキサマイドを4−アミノフェノールと反応させ、4−(2−(N−メチルカルバモイル)−4−ピリジルオキシ)アニリンを得た。方法B6に従って3−アミノ−2−メトキシキノリンを4−(2−(N−メチルカルバモイル)−4−ピリジルオキシ)アニリンと反応させ、尿素を得た。
エントリー109:方法A10, ステップ3bに従って4−クロロピリジン−2−エルボニルクロライドHCl塩をアンモニアと反応させ、4−クロロ−2−ピリジンカルボキサマイドを得た。方法A10,ステップ4に従い、DMFの代りにDMACを使用して4−クロロ−2−ピリジンカルボキサマイドを3−アミノフェノールと反応させ、3−(2−カルバモイル−4−ピリジルオキシ)アニリンを得た。方法B6に従って3−アミノ−2−メトキシキノリンを3−(2−カルバモイル−4−ピリジルオキシ)アニリンを反応させ、尿素を得た。
エントリー110:方法A10, ステップ3aに従って合成した4−クロロ−N−メチル−2−ピリジンカルボキサマイドを方法A10、ステップ4に従い、DMFの代りにDMACを使用して3−アミノフェノールと反応させ、3−(2−(N−メチルカルバモイル)−4−ピリジル)アニリンを得た。方法B6に従って3−アミノ−2−メトキシキノリンを3−(2−(N−メチルカルバモイル)−4−ピリジルオキシ)アニリンと反応させ、尿素を得た。
エントリー111:方法A13に従って4−(4−(3−(N−メチルカルバモイル)−2−メトキシフェノキシ)アニリンを製造した。方法B6に従って3−アミノ−2−メトキシキノリンを4−(4−(3−(N−メチルカルバモイル)−2−メトキシフェノキシ)アニリンと反応させ、尿素を得た。
エントリー112:方法A11に従って5−(4−アミノフェノキシ)イソインドリン−1,3−ジオンを製造した。3−アミノ−2−メトキシキノリンを方法B5aに従って5−(4−アミノフェノキシ)イソインドリン−1, 3−ジオンと反応させ、尿素を得た。
4−t−ブチルー2−ピリジル尿素
p38キナーゼアッセイ:
化合物のインビトロ阻害性はp38キナーゼ阻害アッセイを使用して決定された。p38活性は96ウエルマイクロタイタープレート中で行われたインビトロキナーゼアッセイを用いて検出された。組替えヒトp38(0.5μg/mL)をキナーゼバッファー(25mM Hepes,20mM MgCl2 および150mM NaCl)中の基質(ミエリン塩基性タンパク)および化合物と混合した。33P標識ATP(10μM)の1μCi/ウエルを最終容積100μLへ加えた。反応は32℃で30分実施され、1M HCl溶液で停止された。基質に取込まれた放射活性の量が1%リン酸溶液を用いて負に帯電したガラス繊維ペーパー上に標識基質をトラップし、そしてシンチレーションカウンターで読み取ることによって決定された。陰性対照は基質プラスATP単独を含んでいる。
例示したすべての化合物は1nMないし10μMのp38 IC50を示した。
選んだ化合物のインビボ阻害性は、インビボモデルにおけるネズミLPS誘発TNFα生産を用いて決定された。1群10匹のBALB/cマウス(Charles River Breeding Laboratories;Kingston,NY)が記載したルートによってビヒクルのみまたは化合物で処理された。1時間後、エンドトキシン(E.coliリポポリサッカライド(LPS)100μg)が腹腔内(i.p.)投与された。90分後動物を二酸化炭素窒息により安楽死させ、そして血漿を個々の動物からヘパリン処理チューブへ心臓穿刺によって得た。サンプルを4℃において12, 500×g5分間遠心することによって清澄化した。上清を新しいチューブへ傾しゃし、必要に応じ−20℃で貯蔵した。血清中のTNFαレベルを市販のネズミELISAキット(Genzyme)を用いて測定した。
Claims (2)
- 式A’−D−B’ (II)
の化合物またはその薬学的に許容し得る塩:
ここでDは−NH−C(O)−NH−であり;
A’は2−(4−t−ブチル)ピリジルまたは2−(5−トリフルオロメチル)ピリジルであり;
B’は、
a)C1−10アルキルまたはハロゲン
で置換されたフェニル、
b)ナフチル、または
c)任意にC1−10アルキル、C1−10アルコキシもしくはハロゲン置換されたフェノキシ、ピリジルオキシまたはピリジルチオ基を有するフェニルである。 - N−(2−(4−t−ブチル)ピリジル)−N’−(4−メチルフェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−フルオロフェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(2,3−ジクロフェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(1−ナフチル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−(4−ピリジルメチル)フェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−フェノキシフェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−(4−メチルフェノキシ)フェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−(4−クロロフェノキシ)フェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−(4−メトキシフェノキシ)フェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−(4−ピリジルオキシ)フェニル)尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(4−(4−ピリジルチオ)フェニル尿素、
N−(2−(4−t−ブチル)ピリジル)−N’−(3−(4−ピリジルチオ)フェニル)尿素、
N−(2−(5−トリフルオロメチル)ピリジル)−N’−(4−(4−ピリジルメチル)フェニル)尿素、または
N−(2−(5−トリフルオロメチル)ピリジル)−N’−(3−(4−ピリジルチオ)フェニル)尿素
から選ばれる請求項1の化合物またはその薬学的許容し得る塩。
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Families Citing this family (64)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7141244B1 (en) * | 1992-03-02 | 2006-11-28 | Chiron Srl | Helicobacter pylori proteins useful for vaccines and diagnostics |
DE69529219T2 (de) * | 1994-07-01 | 2003-11-06 | Chiron Corp. (N.D.Ges.D. Staates Delaware), Emeryville | Helicobacter proteine und impstoffe |
PT909323E (pt) * | 1996-01-04 | 2007-06-04 | Novartis Vaccines & Diagnostic | ''bacterioferritina de helicobacter pilori'' |
US7517880B2 (en) * | 1997-12-22 | 2009-04-14 | Bayer Pharmaceuticals Corporation | Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas |
EP1158985B1 (en) | 1999-01-13 | 2011-12-28 | Bayer HealthCare LLC | OMEGA-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS |
RU2319693C9 (ru) * | 1999-01-13 | 2008-08-20 | Байер Копэрейшн | Производные мочевины (варианты), фармацевтическая композиция (варианты) и способ лечения заболевания, связанного с ростом раковых клеток (варианты) |
US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
WO2000042012A1 (en) * | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
ATE355272T1 (de) * | 2001-04-20 | 2006-03-15 | Bayer Pharmaceuticals Corp | Inhibierung der raf-kinase durch chinolin-, isochinolin- oder pyridin-harnstoffe |
US7371763B2 (en) * | 2001-04-20 | 2008-05-13 | Bayer Pharmaceuticals Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
US20050175629A1 (en) * | 2001-08-31 | 2005-08-11 | Giuseppe Del Giudice | Helicobacter pylori vaccination |
ES2275931T5 (es) * | 2001-12-03 | 2018-10-23 | Bayer Healthcare Llc | Compuestos de aril-urea en combinación con otros agentes citostáticos o citotóxicos para tratamiento de cánceres humanos |
WO2003068228A1 (en) | 2002-02-11 | 2003-08-21 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
AU2003209119A1 (en) | 2002-02-11 | 2003-09-04 | Bayer Pharmaceuticals Corporation | Pyridine, quinoline, and isoquinoline n-oxides as kinase inhibitors |
ATE529406T1 (de) | 2002-02-11 | 2011-11-15 | Bayer Healthcare Llc | Aryl-harnstoffe als kinase inhibitoren |
EP1549621A1 (en) * | 2002-08-08 | 2005-07-06 | Boehringer Ingelheim Pharmaceuticals Inc. | Fluorinated phenyl-naphthalenyl-urea compounds as inhibitors of cytokines involved in inflammatory processes |
JP4927533B2 (ja) * | 2003-02-28 | 2012-05-09 | ニッポネックス インコーポレイテッド | 癌その他の疾患の治療に有用な置換ピリジン誘導体 |
CA2516931C (en) | 2003-02-28 | 2014-09-09 | Bayer Pharmaceuticals Corporation | Novel bicyclic urea derivatives useful in the treatment of cancer and other disorders |
UY28213A1 (es) | 2003-02-28 | 2004-09-30 | Bayer Pharmaceuticals Corp | Nuevos derivados de cianopiridina útiles en el tratamiento de cáncer y otros trastornos. |
MXPA05012486A (es) | 2003-05-20 | 2006-07-03 | Bayer Pharmaceuticals Corp | Diaril ureas para enfermedades mediadas por pdgfr. |
UA84156C2 (ru) * | 2003-07-23 | 2008-09-25 | Байер Фармасьютикалс Корпорейшн | Фторозамещённая омега-карбоксиарилдифенилмочевина для лечения и профилактики болезней и состояний |
MXPA06002853A (es) | 2003-09-11 | 2006-06-14 | Kemia Inc | Inhibidores citoquina. |
DE10342503A1 (de) | 2003-09-12 | 2005-04-14 | Merck Patent Gmbh | Benzyl-Benzimidazolylderivate |
DE10356579A1 (de) | 2003-12-04 | 2005-07-07 | Merck Patent Gmbh | Aminderivate |
JP2007523923A (ja) * | 2004-02-26 | 2007-08-23 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | イソキノリン誘導体 |
US7459562B2 (en) | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
TW200538453A (en) | 2004-04-26 | 2005-12-01 | Bristol Myers Squibb Co | Bicyclic heterocycles as kinase inhibitors |
EP2295426A1 (en) | 2004-04-30 | 2011-03-16 | Bayer HealthCare, LLC | Substituted pyrazolyl urea derivatives useful in the treatment of cancer |
US20050288290A1 (en) | 2004-06-28 | 2005-12-29 | Borzilleri Robert M | Fused heterocyclic kinase inhibitors |
US7432373B2 (en) | 2004-06-28 | 2008-10-07 | Bristol-Meyers Squibb Company | Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors |
US7439246B2 (en) | 2004-06-28 | 2008-10-21 | Bristol-Myers Squibb Company | Fused heterocyclic kinase inhibitors |
BRPI0514150A (pt) * | 2004-08-06 | 2007-11-27 | Otsuka Pharma Co Ltd | composto aromático ou um sal do mesmo, método para produzir o mesmo, e, composição farmacêutica para tratar a fibrose |
US20080051416A1 (en) * | 2004-10-05 | 2008-02-28 | Smithkline Beecham Corporation | Novel Compounds |
EP1828169A2 (en) | 2004-12-07 | 2007-09-05 | Locus Pharmaceuticals, Inc. | Urea inhibitors of map kinases |
JP2008523072A (ja) | 2004-12-07 | 2008-07-03 | ルーカス ファーマシューティカルズ, インコーポレイテッド | タンパク質キナーゼの阻害剤 |
NZ561178A (en) * | 2005-03-07 | 2010-11-26 | Bayer Schering Pharma Ag | Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer |
DE102005015253A1 (de) * | 2005-04-04 | 2006-10-05 | Merck Patent Gmbh | Pyrazolderivate |
ES2580108T3 (es) | 2005-07-11 | 2016-08-19 | Aerie Pharmaceuticals, Inc | Compuestos de isoquinolina |
EP1968589A2 (en) | 2005-10-31 | 2008-09-17 | Bayer Pharmaceuticals Corporation | Combinations comprising sorafenib and interferon for the treatment of cancer |
NZ568031A (en) * | 2005-11-10 | 2011-06-30 | Bayer Schering Pharma Ag | Use of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide (BAY 43-9006) for treating pulmonary hypertension |
WO2007064872A2 (en) * | 2005-12-01 | 2007-06-07 | Bayer Healthcare Llc | Urea compounds useful in the treatment of cancer |
US8236826B2 (en) * | 2005-12-05 | 2012-08-07 | Otsuka Pharmaceutical Co., Ltd. | Diarylether derivatives as antitumor agents |
WO2007075650A2 (en) * | 2005-12-21 | 2007-07-05 | Bayer Healthcare Ag | Substituted pyrimidine derivatives useful in the treatment of cancer and other disorders |
CA2652926A1 (en) | 2006-05-26 | 2007-12-06 | Bayer Healthcare Llc | Drug combinations with substituted diaryl ureas for the treatment of cancer |
CA2664335C (en) | 2006-09-20 | 2014-12-02 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
UA95978C2 (ru) * | 2006-10-02 | 2011-09-26 | Оцука Фармас'Ютікел Ко., Лтд. | Ингибитор активации stat3/5 |
EP2134677B1 (en) | 2006-12-20 | 2011-10-12 | Bayer HealthCare LLC | 4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1h-pyrazol-5-yl}carbamoyl)-amino]-3-chlorophenoxy}-n-methylpyridine-2-carboxamide as an inhibitor of the vegfr kinase for the treatment of cancer |
US8455513B2 (en) * | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
EP3354643B1 (en) | 2009-05-01 | 2020-10-28 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
US20130183268A1 (en) | 2010-07-19 | 2013-07-18 | Bayer Healthcare Llc | Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
EP3461484B9 (en) | 2013-03-15 | 2021-06-09 | Aerie Pharmaceuticals, Inc. | Dimesylate salts of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl, their combinations with prostaglandins and the use thereof in the treatment of ocular disorders |
CN105659085B (zh) | 2013-08-28 | 2018-12-07 | 中美冠科生物技术(太仓)有限公司 | 预测受试者对多激酶抑制剂的反应的基因表达标志及其使用方法 |
ES2738695T3 (es) | 2014-05-28 | 2020-01-24 | Novartis Ag | Nuevos Derivados de Pirazolo Pirimidina y su uso como inhibidores de MALT1 |
US9638690B2 (en) | 2014-11-07 | 2017-05-02 | The University Of British Columbia | Compounds and compositions for use as alkylating agent sensors and methods of use thereof |
WO2017086941A1 (en) | 2015-11-17 | 2017-05-26 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
WO2017151409A1 (en) | 2016-02-29 | 2017-09-08 | University Of Florida Research Foundation, Incorporated | Chemotherapeutic methods |
MX2019002396A (es) | 2016-08-31 | 2019-07-08 | Aerie Pharmaceuticals Inc | Composiciones oftalmicas. |
EP3609871A4 (en) | 2017-03-31 | 2021-01-06 | Aerie Pharmaceuticals, Inc. | ARYL CYCLOPROPYL-AMINO-ISOQUINOLINYL AMIDE COMPOUNDS |
WO2019191032A1 (en) | 2018-03-26 | 2019-10-03 | Clear Creek Bio, Inc. | Compositions and methods for inhibiting dihydroorotate dehydrogenase |
AU2019337703B2 (en) | 2018-09-14 | 2023-02-02 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
WO2023091679A1 (en) * | 2021-11-18 | 2023-05-25 | Board Of Regents Of The University Of Nebraska | Novel inhibitors of claudin-1 for therapeutic intervention |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1935388A1 (de) | 1968-07-12 | 1970-01-22 | Kyowa Hakko Kogyo Kk | Derivate von Mitomycin B |
US3755406A (en) | 1969-07-07 | 1973-08-28 | Ciba Geigy Corp | Isothiocyano diphenylamines |
US3839582A (en) | 1969-07-07 | 1974-10-01 | Ciba Geigy Corp | Control of helminths with 4-isothiocyano-diphenylamines |
CH575208A5 (ja) | 1973-07-30 | 1976-05-14 | Ciba Geigy Ag | |
JPS5562066A (en) * | 1978-11-03 | 1980-05-10 | Toshihiko Okamoto | N-(2-substituted-4-pyridyl)-urea and thio urea, their preparation and plant growth regulator |
DE59107782D1 (de) | 1990-04-03 | 1996-06-13 | Ciba Geigy Ag | Konzentrierte Farbstofflösungen |
FR2683818B1 (fr) | 1991-11-14 | 1993-12-31 | Adir Cie | Nouveaux derives de 3-sulfonylamino-2-(1h)-quinoleinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
DE4227989A1 (de) | 1992-08-21 | 1994-06-09 | Schering Ag | Mittel zur transdermalen Applikation enthaltend 3-Keto-desogestrel |
IL110296A (en) | 1993-07-16 | 1999-12-31 | Smithkline Beecham Corp | Imidazole compounds process for their preparation and pharmaceutical compositions containing them |
JP3377529B2 (ja) | 1993-09-17 | 2003-02-17 | スミスクライン・ビーチャム・コーポレイション | 薬物結合タンパク質 |
WO1995013067A1 (en) | 1993-11-08 | 1995-05-18 | Smithkline Beecham Corporation | Oxazoles for treating cytokine mediated diseases |
US5559137A (en) | 1994-05-16 | 1996-09-24 | Smithkline Beecham Corp. | Compounds |
WO1996018616A1 (en) | 1994-12-12 | 1996-06-20 | Merck & Co., Inc. | Substituted 2-aminopyridines as inhibitors of nitric oxide synthase |
PL325341A1 (en) | 1996-06-29 | 1998-07-20 | Samjin Pharmaceutical Co | Derivatives od piperazine and method of obtaining them |
US6093742A (en) * | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
ES2154253T3 (es) * | 1997-12-22 | 2012-01-27 | Bayer Healthcare Llc | Inhibición de la actividad de p38 cinasa usando ureas heterocíclicas sustituidas. |
DE69830513T2 (de) * | 1997-12-22 | 2006-03-16 | Bayer Pharmaceuticals Corp., West Haven | HEMMUNG DER p38 KINASE UNTER VERWENDUNG VON SYMMETRISCHEN UND ASYMMETRISCHEN DIPHENYLHARNSTOFFEN |
EP1158985B1 (en) * | 1999-01-13 | 2011-12-28 | Bayer HealthCare LLC | OMEGA-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS |
DE60036726T2 (de) * | 1999-11-16 | 2008-02-07 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Harnstoff derivate als entzündungshemmende mittel |
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2001
- 2001-04-20 US US09/838,286 patent/US20020065296A1/en not_active Abandoned
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- 2002-04-17 JP JP2002583386A patent/JP4359817B2/ja not_active Expired - Fee Related
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- 2002-04-17 EP EP02725709A patent/EP1379507B1/en not_active Expired - Lifetime
- 2002-04-17 EP EP11170364A patent/EP2386545A1/en not_active Withdrawn
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HK1062440A1 (en) | 2004-11-05 |
CA2443952C (en) | 2011-05-24 |
ES2372020T3 (es) | 2012-01-13 |
WO2002085859A1 (en) | 2002-10-31 |
ATE520663T1 (de) | 2011-09-15 |
EP2386545A1 (en) | 2011-11-16 |
US20020065296A1 (en) | 2002-05-30 |
JP2004537511A (ja) | 2004-12-16 |
EP1379507A1 (en) | 2004-01-14 |
CA2443952A1 (en) | 2002-10-31 |
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