JP2013523846A - タンパク質チロシンキナーゼ活性の阻害剤および眼部の障害を治療するためのそれらの使用 - Google Patents
タンパク質チロシンキナーゼ活性の阻害剤および眼部の障害を治療するためのそれらの使用 Download PDFInfo
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- JP2013523846A JP2013523846A JP2013504075A JP2013504075A JP2013523846A JP 2013523846 A JP2013523846 A JP 2013523846A JP 2013504075 A JP2013504075 A JP 2013504075A JP 2013504075 A JP2013504075 A JP 2013504075A JP 2013523846 A JP2013523846 A JP 2013523846A
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Classifications
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Landscapes
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Abstract
Description
本願は米国仮出願番号第61/324,803号(2010年4月16日出願)の利益を主張する。上記出願の全体を引用により本明細書中に取り込む。
本発明は新規化合物およびその組成物を提供する。本発明はまた、かかる化合物またはその組成物による眼部の疾患、障害または病状の治療方法を提供する。本明細書中で引用される特許文献および科学文献は当業者に利用可能な知識を反映するものである。本明細書中で引用される登録された特許、刊行された特許出願および文献は、引用により組み込まれるものとして各個々の文書が具体的及び個別に示されているように、同じ範囲の引用により本明細書に組み込まれる。相違がある場合、本開示が優先される。
本発明は、構造:
本発明の化合物は当業者に周知の方法を用い、以下に記載される反応スキームまたは実施例に従い製造することができる。これらのスキームは本発明の化合物の製造に用いられ得るいくつかの製造方法を例示するものである。別の一般的な合成方法を用いることができることは当業者に自明であろう。本発明の化合物は市販の出発物質から製造することができる。本発明の化合物を得るために当業者に周知の方法による出発物質に対するあらゆる種類の置換を行うことが可能である。
スキーム1
N−[3−((6−(7−(4−(3−シクロプロピルウレイド)−2−フルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)ピリジン−3−イル)メチル)]−N−(1−エチル)−N−[3−(2−メトキシエチル)]尿素(2)
1−シクロプロピル−3−(3−フルオロ−4−(2−(5−((2−メトキシエチルアミノ)メチル)−ピリジン−2−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(1、100mg、0.197mmol)およびエチルイソシアネート(25μL、0.315mmol)のTHF(5mL)溶液を室温で終夜撹拌(しばらく超音波処理して)した。反応混合物を濃縮し、Biotage(SNAP 25 gカートリッジ;MeOH/DCM:0/100から10/90、20CV、次いで10/90で5CV)で精製した。目的のフラクションを回収し、濃縮した。残渣をAcOEt(微量のMeOHを含む)/ヘキサンで共沈し、濾取し、ヘキサンで洗浄し、風乾し、高真空下で乾燥し、表題化合物2(63mg、0.11mmol、収率56%)を白色の綿毛状の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm):8.73 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.78−7.69 (m, 2H), 7.38 (t, J = 9.0 Hz, 1H), 7.24−7.17 (m, 1H), 6.64 (bd, J = 5.4 Hz, 1H), 6.62−6.56 (m, 1H), 6.44 (t, J = 5.4 Hz, 1H), 4.53 (s, 2H), 3.44−3.34 (m, 4H), 3.23 (s, 3H), 3.12−3.03 (m, 2H), 2.59−2.52 (m, 1H), 1.02 (t, J = 7.1 Hz, 3H), 0.72−0.58 (m, 2H), 0.50−0.36 (m, 2H). MS (m/z):579.46 (M+H).
N−((6−(7−(4−(3−シクロプロピルウレイド)−2−フルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)ピリジン−3−イル)メチル)−N−(2−メトキシエチル)ホルムアミド(6)
無水酢酸(150μL、1.17mmol)のギ酸(2mL)溶液を室温で20分間隠し、1(150mg、0.296mmol)を一度に加えた。2時間後、200μLの無水酢酸(1.57mmol)を滴下して加えた。反応混合物を室温で終夜撹拌し、MeOHを加えてクエンチし、濃縮した。残渣をBiotage(SNAP 25 gカートリッジ;MeOH/DCM:0/100から10/90、20CV、次いで10/90で5CV)で精製し、表題化合物6(96mg、0.18mmol、収率76%)を灰白色の綿毛状の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :mixture of rotamers, 8.75 (s, 1H), 8.60−8.50 (m, 2H), 8.37 and 8.34 (2s, 1H), 8.32−8.23 (m, 1H), 8.15 (s, 1H), 7.90−7.77 (m, 1H), 7.73 (dd, J = 13.5, 2.5 Hz, 1H), 7.38 (t, J = 9.0 Hz, 1H), 7.20 (bd, J = 10.2 Hz, 1H), 6.67−6.58 (m, 2H), 4.60 and 4.56 (2s, 2H), 3.46−3.36 (m, 4H), 3.21 and 3.19 (2s, 3H), 2.59−2.51 (m, 1H), 0.70−0.60 (m, 2H), 0.47−0.38 (m, 2H). MS (m/z):536.4 (M+H).
N−((6−(7−(4−(3−シクロプロピルウレイド)−2,3−ジフルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)−ピリジン−3−イル)メチル)−N−(2−メトキシエチル)アセトアミド(26)
工程1.tert−ブチル (6−(7−(4−アミノ−2,3−ジフルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)ピリジン−3−イル)メチル(2−メトキシエチル)カルバメート(23)
4−アミノ−2,3−ジフルオロフェノール(1.471g、10.14mmol)のDMSO(11.5mL)撹拌溶液(室温、窒素下)にカリウムtert−ブトキシド(1.345g、11.98mmol)を加えた。30分後、tert−ブチル (6−(7−クロロチエノ[3,2−b]ピリジン−2−イル)ピリジン−3−イル)メチル(2−メトキシエチル)カルバメート(22, 4.0g、9.22mmol)を加え、反応混合物を100℃で2.5時間加熱し、室温に冷却した。反応混合物を水(90mL)に注ぎ、30分間撹拌した。飽和塩化ナトリウム水溶液を加え、混合物を室温で3日間撹拌した。固形物を濾取し、水で洗浄し、風乾し、高真空下で乾燥した。粗生成物をBiotage(40+Mカートリッジ; AcOEt/ヘキサン:50/50で3CV、50/50から100%AcOEt、6CV、次いで100%AcOEtで8CV)で精製し、得られた物質をジエチルエーテルでトリチュレートし、表題化合物23(1.94g、3.58mmol、収率38%)を灰白色の固形物として得た。
MS (m/z):543.3 (M+H).
アニリン23(500mg、0.92mmol)およびDIPEA(0.8mL、4.61mmol)のTHF(18mL)撹拌溶液(−25℃、窒素下)にトリホスゲン(273mg、0.920mmol)のTHF(2mL)を滴下して加えた。反応混合物を−25℃で撹拌し、シクロプロピルアミン(0.32mL、4.61mmol)をゆっくりと加えた。反応混合物を1.5時間かけて室温に昇温し、室温で終夜撹拌した。反応混合物をAcOEtおよび水で分液処理した。有機層を飽和塩化アンモニウム水溶液、1N NaOHおよびブラインで分液処理し、無水硫酸マグネシウムで乾燥し、濾過し、濃縮し、表題化合物24を灰白色の固形物として得た。粗物質をさらに精製することなく次工程に用いた。
MS (m/z):626.6 (M+H).
中間体24(0.92mmol)およびTFA(10mL)のDCM(50mL)溶液を室温で3時間撹拌した。反応混合物を濃縮し、最少量のMeOHで希釈し、水を加えた。4N NaOHでpHを約12に調整した。微細な懸濁液を15分間超音波処理し、濾取し、水で洗浄し、高真空下で乾燥し、表題化合物25(578mg、0.9mmol、収率98%、TFA塩)を淡アイボリー色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :8.78−8.61 (m, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.02 (t, J = 7.8 Hz, 1H), 7.90 (dd, J = 8.1, 2.1 Hz, 1H), 7.28 (td, J = 9.0, 2.1 Hz, 1H), 7.16−7.01 (m, 1H), 6.75 (d, J = 5.3 Hz, 1H), 3.78 (d, J = 6.1 Hz, 2H), 3.41 (t, J = 5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (q, J = 6.0 Hz, 2H), 2.61−2.53 (m, 1H), 2.30−2.21 (m, 1H), 0.72−0.58 (m, 2H), 0.49−0.36 (m, 2H). MS (m/z):526.6 (M+H).
化合物25(100mg、0.156mmol、TFA塩)の無水酢酸(1mL)溶液を室温で2日間撹拌した。メタノールおよび水を加えて反応混合物をクエンチした。微細な懸濁液を濾取し、水、1N NaOH、水で順に洗浄し、風乾した。粗生成物をBiotage(SNAP 25 gカートリッジ;MeOH/DCM:0/100から10/90、20CV、次いで10/90で5CV)で精製し、表題化合物26(34mg、0.06mmol、収率38%)を白色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :mixture of rotamers, 8.57−8.44 (m, 3H), 8.38 and 8.34 (2s, 1H), 8.30 and 8.24 (2d, J = 8.2 Hz, 1H), 8.04 (bt, J = 8.3 Hz, 1H), 7.82−7.75 (m, 1H), 7.32−7.25 (m, 1H), 6.87 (bd, J = 2.7 Hz, 1H), 6.79−6.74 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.54−3.40 (m, 4H), 3.24 and 3.21 (2s, 3H), 2.61−2.53 (m, 1H), 2.13 and 2.05 (2s, 3H), 0.73−0.58 (m, 2H), 0.50−0.36 (m, 2H). MS (m/z):568.6 (M+H).
1−シクロプロピル−3−(3−フルオロ−4−(2−(5−((4−(2−ヒドロキシアセチル)ピペラジン−1−イル)メチル)ピリジン−2−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(74)
工程1.tert−ブチル 4−((6−(7−(4−(3−シクロプロピルウレイド)−2−フルオロフェノキシ)チエノ[3,2−b]−ピリジン−2−イル)ピリジン−3−イル)メチル)ピペラジン−1−カルボキシレート(48)
1−シクロプロピル−3−(3−フルオロ−4−(2−(5−ホルミルピリジン−2−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(47, 3g、5.90mmol、酢酸塩)、1−boc−ピペラジン(1.65g、8.85mmol)および酢酸(675μL、11.80mmol)のNMP(50mL)懸濁液(室温、窒素下)を溶液にするために3時間超音波処理し、NaBH(OAc)3(3.95g、17.70mmol)を加えた。反応混合物を室温で3日間撹拌し、水の添加によりクエンチした。4N NaOHでpHを12−13に調整し、該懸濁液を1時間撹拌、超音波処理した。固形物を濾取し、水で洗浄し、風乾した。残渣をBiotage(SNAP 50g KP−Silカートリッジ;MeOH/DCM:1/99から10/90、20CV)で2回精製した。目的のフラクションを回収し、濃縮し、微量のメタノール/ヘキサンを含むAcOEtと共沈し、化合物48(1.511g、2.44mmol、収率41%)を白色の綿毛状の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :8.71 (s, 1H), 8.56 (bd, J = 2.0 Hz, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.73 (dd, J = 13.6, 2.4 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 7.20 (bdd, J = 8.8, 1.2 Hz, 1H), 6.65 (d, J = 5.3 Hz, 1H), 6.57 (bd, J = 2.5 Hz, 1H), 3.57 (s, 2H), 4H are hidden by water’s peak, 2.59−2.51 (m, 1H), 2.42−2.27 (m, 4H), 1.39 (s, 9H), 0.72−0.58 (m, 2H), 0.50−0.36 (m, 2H). MS (m/z):619.4 (M+H).
48(1.456g、2.35mmol)およびTFA(15mL)のDCM(50mL)溶液を室温で5時間撹拌した。DCMと共沸することによりTFAを除去し、残渣を水で希釈し、1N NaOHでpHを12−13に調整した。得られた懸濁液を15分間超音波処理した。固形物を濾取し、水で洗浄し、高真空下で乾燥し、化合物49(1.227g、微量のTFA)を灰白色の綿毛状の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :8.76 (bs, 1H), 8.54 (d, J = 1.4 Hz, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.1, 2.1 Hz, 1H), 7.73 (dd, J = 13.5, 2.3 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 7.20 (bd, J = 10.2 Hz, 1H), 6.64 (d, J = 5.5 Hz, 1H), 6.62 (bs, 1H), 3.58−3.48 (m, 2H), 2.73−2.64 (m, 4H), 2.59−2.52 (m, 1H), 2.38−2.25 (m, 4H), 0.69−0.62 (m, 2H), 0.46−0.40 (m, 2H), one NH is missing. MS (m/z):519.6 (M+H).
化合物49(122mg、0.235mmol、スキーム15)、グリコール酸(36mg、0.47mmol)およびDIPEA(123μL、0.71mmol)のDMF(4mL)溶液(窒素下)にHATU試薬(224mg、0.59mmol)を加え、反応混合物を室温で終夜撹拌した。次いで、水および1N NaOHを加えることにより反応混合物をクエンチし、2時間撹拌し、DCMで抽出した。合わせた有機抽出物を無水硫酸マグネシウムで乾燥し、濾過し、濃縮した。残渣をBiotage(SNAP 25 gカートリッジ;2%水酸化アンモニウム含有MeOH/DCM:0/100から10/90、20CV;次いで、SiliaFlash 40 gカートリッジ、2%水酸化アンモニウム含有MeOH/DCM:0/100から10/90、20CV、次いで10/90から15/85、20CV)で2回精製し、得られた物質をMeOHでトリチュレートし、表題化合物74(53mg、0.09mmol、収率39%)を白色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :8.77−8.69 (m, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.88 (dd, J = 8.1, 2.1 Hz, 1H), 7.73 (dd, J = 13.5, 2.3 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 7.20 (bd, J = 9.2 Hz, 1H), 6.65 (d, J = 4.9 Hz, 1H), 6.63−6.56 (m, 1H), 4.55 (t, J = 5.5 Hz, 1H), 4.07 (d, J = 5.5 Hz, 2H), 3.60 (s, 2H), 3.53−3.43 (m, 2H), 2H are hidden, 2.59−2.51 (m, 1H), 2.45−2.33 (m, 4H), 0.72−0.58 (m, 2H), 0.50−0.36 (m, 2H). MS (m/z):577.5 (M+H).
工程1.(S)−2−(4−((6−(7−(4−(3−シクロプロピルウレイド)−2−フルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)ピリジン−3−イル)メチル)ピペラジン−1−イル)−2−オキソエチル 2−(tert−ブトキシカルボニルアミノ)−3−メチルブタノエート(74−A)
74(117mg、0.20mmol)、Boc−L−バリン(132mg、0.61mmol)およびDMAP(25mg、0.20mmol)の無水DMF(4mL)撹拌溶液(窒素下)にDCC試薬(251mg、1.22mmol)を加え、反応混合物を室温で24時間撹拌した。反応混合物をAcOEtおよび飽和炭酸水素ナトリウム水溶液で分液処理した。分離後、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液およびブラインで順に洗浄し、無水硫酸マグネシウムで乾燥し、濾過し、濃縮した。残渣をBiotage(SNAP 25 gカートリッジ;MeOH/DCM:1/99から10/90、20CV、次いで10/90で5CV)で精製し、目的生成物74−A(151mg、0.195mmol、収率96%)を無色−白色の粘着性の泡状物質として得た。
MS (m/z):776.7 (M+H).
Boc−バリンエステル74−A(151mg、0.195mmol)の懸濁液およびHCl(0.49mL、1.95mmol、4M/1,4−ジオキサン)の無水DCM(10mL)溶液を室温で2.5時間撹拌した。反応混合物を濃縮し、飽和炭酸水素ナトリウム水溶液で希釈した。該水溶液を微量のメタノールを含むDCMで抽出した。有機層を合わせて無水硫酸マグネシウムで乾燥し、濾過し、濃縮した。残渣をBiotage(Silia Flash 12gカートリッジ;2%水酸化アンモニウム含有MeOH/DCM:1/99から15/85、20CV、次いで15/85から20/80、10CV)で精製し、目的生成物80(80mg、0.118mmol、収率60%)を灰白色の粘着性の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm):mixture of rotamers, 8.73 (s, 1H), 8.58 (bd, J = 1.4 Hz, 1H), 8.52 (d, J = 5.3 Hz, 1H), 8.34 (s, 1H), 8.26 (dd, J = 8.1, 0.7 Hz, 1H), 7.88 (dd, J = 8.2, 2.2 Hz, 1H), 7.73 (dd, J = 13.6, 2.4 Hz, 1H), 7.38 (t, J = 9.0 Hz, 1H), 7.20 (dd, J = 9.0, 1.4 Hz, 1H), 6.65 (dd, J = 5.3, 0.8 Hz, 1H), 6.59 (bd, J = 2.5 Hz, 1H), 4.84 (d, J = 14.7 Hz, 1H), 4.77 (d, J = 14.9 Hz, 1H), 3.63−3.58 (m, 2H), 3.50−3.37 (m, 4H), 3.20 (d, J = 5.1 Hz, 1H), 2.59−2.51 (m, 1H), 2.47−2.33 (m, 4H), 2.00−1.60 (m, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.72−0.58 (m, 2H), 0.50−0.36 (m, 2H). MS (m/z):577.6 and 676.7 (M+H).
1−シクロプロピル−3−(3−フルオロ−4−(2−(5−((2−(メチルスルホニル)エチルアミノ)メチル)ピリジン−2−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(100)
工程1.N−((6−(7−(2−フルオロ−4−ニトロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)ピリジン−3−イル)メチル)−2−(メチルチオ)エタンアミン(95)
化合物94(300mg、0.759mmol)のジクロロメタン(20mL)懸濁液に2−(メチルチオ)エチルアミン(141μL、1.518mmol)および酢酸(87μl)を加えた。室温で20分間撹拌後、ナトリウムトリアセトキシボロヒドリド(482mg、2.276mmol)を加えた。反応混合物を室温で16時間撹拌した。次いで、反応混合物をDCMで希釈し、1N NaOHで洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。粗生成物をBiotage(Snap 50g;MeOH/DCM:0/100から20/80、20CV)で精製し、表題化合物95(357mg、定量的収率)を得た。
MS (m/z):471.5 (M+H).
95(357mg、0.759mmol)、Boc−無水物(414mg、1.897mmol)、DMAP(93mg、0.759mmol)およびトリエチルアミン(106μL、0.61mmol)のDCM(20mL)混合物を室温で週末にかけて撹拌した。反応混合物を濃縮し、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和塩化アンモニウム水溶液で順に洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。残渣をBiotage(SNAP 100 gカートリッジ;MeOH/DCM:0/100から20/80、20CV)で精製し、表題化合物96(220mg、0.386mmol、収率50%)を得た。
MS (m/z):571.6 (M+H).
96(220mg、0.386mmol)のMeOH(29mL)および水(10mL)溶液にオキソン(登録商標)(486mg、0.790mmol)を加えた。反応混合物を終夜撹拌し、濃縮し、1N NaHSO3溶液で処理し、水相を酢酸エチルで抽出した。有機抽出物を水で洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。クルードな97(232mg、0.385mmol)をさらに精製することなく次工程に用いた。
MS (m/z):603.6 (M+H).
97(232mg、0.385mmol)のMeOH(17.5mL)および水(1.75mL)による溶液に塩化アンモニウム(62mg、1.16mmol)および鉄粉(215mg、3.85mmol)を加えた。反応混合物を2時間加熱還流し、室温に冷却した。該懸濁液をCelite(登録商標)に通して濾過し、MeOHで洗浄し、濾液を濃縮した。残渣をBiotage(SNAP 25 gカートリッジ;MeOH/DCM:0/100から20/80、20CV)で精製し、表題化合物98(241mg、定量的収率)を得た。
MS (m/z):573.7 (M+H).
98(115mg、0.20mmol)のTHF(20mL)溶液(−25℃)にDIPEA(140μL、0.80mmol)、次いでトリホスゲン(59.6mg、0.20mmol)を加えた。反応混合物を−25℃で1時間撹拌し、次いで、シクロプロピルアミン(71μL、1.00mmol)を加え、反応混合物を室温に昇温させた。終夜撹拌後、メタノールの添加により反応混合物をクエンチし、濃縮し、EtOAcおよび飽和塩化アンモニウム水溶液で分液処理した。有機相を無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。粗生成物をBiotage(Snap 25g;MeOH/DCM:0/100から20/80、20CV)で精製し、表題化合物99(120mg、0.18mmol、収率91%)を得た。
MS (m/z):656.6 (M+H).
99(120mg、0.18mmol)のDCM(20mL)溶液にTFA(5.6mL)を加えた。反応混合物を室温で終夜撹拌し、濃縮し、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。粗生成物をBiotage(SNAP 25 gカートリッジ;MeOH/DCM:0/100から20/80、20CV)で精製し、表題化合物100(90mg、0.13mmol、収率72%、TFA塩)を灰白色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :8.74 (s, 1H), 8.60 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.73 (dd, J = 13.6, 2.4 Hz, 1H), 7.38 (t, J = 8.8 Hz, 1H), 7.20 (d, J = 10.0 Hz, 1H), 6.64 (d, J = 5.2 Hz, 1H), 6.61 (s, 1H), 3.84 (s, 2H), 3.35−3.25 (m, 2H), 3.05 (s, 3H), 3.02−2.90 (m, 2H), 2.59−2.50 (m, 1H), 0.69−0.62 (m, 2H), 0.46−0.40 (m, 2H). MS (m/z):556.5 (M+H).
1−シクロプロピル−3−(3−フルオロ−4−(2−(1−(2−((2−ヒドロキシエチル)(メチル)アミノ)エチル)−1H−ピラゾール−4−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(151)
工程1:2−(1−((1,3−ジオキソラン−2−イル)メチル)−1H−ピラゾール−4−イル)−7−(2−フルオロ−4−ニトロフェノキシ)チエノ[3,2−b]ピリジン(145)
144(3.57g、8.57mmol)のDME(50mL)および水(5mL)による溶液に1−((1,3−ジオキソラン−2−イル)メチル)−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾール(2g、7.14mmol)、CsF(3.25g、21.42mmol)、NaHCO3(1.799g、36mmol)およびPd(PPh3)4(0.825g、0.714mmol)を加え、反応混合物を終夜加熱還流した。該混合物を室温に冷却し、EtOAcで希釈し、水で洗浄した。有機相を収集し、無水Na2SO4で乾燥し、濾過し、濃縮した。得られた固形物をEt2Oでトリチュレートし、表題化合物145(3g、収率95%)をベージュ色の固形物として得た。
MS (m/z) = 443.51 (M+H).
145(900mg、2.034mmol)のTHF(20mL)溶液に3M HCl(30mL)を加え、反応混合物を24時間加熱還流した。該混合物を室温に冷却し、濃縮した。残渣の水性の溶液を固体の炭酸水素ナトリウムで処理し、DCMで抽出した。有機相を回収し、無水Na2SO4で乾燥し、濾過し、濃縮した。クルードなアルデヒド146(810mg、収率100%)をさらに精製することなく次工程に用いた。
MS (m/z) = 399.3 (M+H)
146(810mg、2.033mmol)のDCM(40mL)溶液にHOAc(0.233mL、4.07mmol)および2−(メチルアミノ)エタノール(305mg、4.07mmol)を加え、反応混合物を室温で1時間撹拌した。ナトリウムトリアセトキシボロヒドリド(1.293g、6.10mmol)を加え、混合物を室温で終夜撹拌した。該混合物を飽和NaHCO3溶液で希釈し、次いで、固体のNaHCO3を加えて酸を中和した。DCM層を回収し、無水Na2SO4で乾燥し、濾過し、濃縮し、表題化合物147(930mg、収率100%)をさらに精製することなく次工程に用いた。
MS (m/z) = 458.50 (M+H).
147(930mg、2.033mmol)のDCM(40mL)溶液にBoc2O(1.331g、6.10mmol)およびDMAP(49.7mg、0.407mmol)を加え、反応混合物を室温で終夜撹拌した。反応混合物を濃縮し、カラムクロマトグラフィー(溶出液:EtOAcから20% MeOH/EtOAc)で精製し、表題化合物148(420mg、収率37%)を茶色の油状物として得た。
(MS (m/z) = 558.49 (M+H)
148(420mg、0.753mmol)のMeOH(20mL)溶液に塩化アンモニウム(81mg、1.506mmol)/水(5mL)および亜鉛粉末(197mg、3.01mmol)を加え、反応混合物を3時間加熱還流した。該混合物を室温に冷却し、次いで濾過し、濾液を減圧濃縮した。残渣をDCMに溶解し、水で洗浄した。有機相を回収し、無水Na2SO4で乾燥し、濾過し、濃縮し、表題化合物149(397mg、収率100%)を得、さらに精製することなく次工程に用いた。
MS (m/z) = 528.49 (M+H).
149(0.397mg、0.752mmol)およびピリジン(0.183mL、2.257mmol)のDMF(20mL)撹拌溶液(0℃、窒素下)にクロロギ酸フェニル(295mg、1.881mmol)を加え、反応混合物を0℃で2時間撹拌した。シクロプロピルアミン(215mg、3.76mmol)を加え、反応混合物を55℃で5時間加熱した。反応混合物をEtOAcおよび飽和炭酸水素ナトリウム溶液で分液処理し、飽和塩化アンモニウム溶液およびブラインで洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。粗生成物をカラムクロマトグラフィー(EtOAcから30% MeOH/EtOAc)で精製し、表題化合物150(150mg、収率33%)を白色の固形物として得た。
MS (m/z) = 611.70 (M+H).
150(150mg、0.246mmol)のDCM(10mL)溶液にHCl/ジオキサン(0.307mL、1.118mmol)を加え、白色の沈殿物を室温で2時間撹拌した。該混合物を飽和NaHCO3溶液で希釈し、10分間撹拌し、層を分離した。有機相を回収し、Na2SO4で乾燥し、濾過し、濃縮した。残渣をカラムクロマトグラフィー(溶出液:EtOAcから30% MeOH/EtOAc)で精製し、表題化合物151(100mg、収率80%)を白色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm):8.43 (d, J = 5.48 Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.63 (m, 1H), 7.47 (s, 1H), 7.17 (m, 2H), 7.03 (s, 1H), 6.45 (d, J = 5.48 Hz, 1H), 4.92 (s, 1H), 4.27 (t, J = 6.26 Hz, 2H), 3.56 (t, J = 5.08 Hz, 2H), 2.95 (t, J = 6.26 Hz, 2H), 2.60 (m, 3H), 2.34 (s, 3H), 0.91 (m, 2H), 0.72 (m, 2H). MS (m/z) = 511.60 (M+H).
N−((2−(7−(4−(3−シクロプロピルウレイド)−2−フルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)−1−メチル−1H−イミダゾール−5−イル)メチル)−2−ヒドロキシ−N−(2−メトキシエチル)アセトアミド(209)
工程1:2−(((2−(7−(2−フルオロ−4−ニトロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)−1−メチル−1H−イミダゾール−5−イル)メチル)(2−メトキシエチル)アミノ)−2−オキソエチルアセテート(206)
158(423mg、0.925mmol)のDMF(18mL)溶液に2−アセトキシ酢酸(164mg、1.387mmol)、DIPEA(0.565mL、3.24mmol)およびHATU試薬(1055mg、2.77mmol)を加えた。反応混合物を室温で1時間撹拌し、次いで飽和NaHCO3溶液(200mL)およびEtOAc(300mL)を加えた。生じた白色の沈殿物を濾取し、廃棄した。濾液の有機層を回収し、無水硫酸ナトリウムで乾燥し、濃縮し、黄色がかった固形物を得、それをエーテルでトリチュレートし、表題化合物206(570mg、収率111%、クルード)をさらに精製することなく次工程に用いた。
MS:558 (MH)+.
206(300mg、0.538mmol)、塩化アンモニウム(24.75mg、0.463mmol)および鉄粉(255mg、4.57mmol)/エタノール(6mL)/水(3.0mL)からなる反応混合物を1時間加熱還流した。反応混合物を温濾過し、濃縮した。残渣をBiotage(MeOH/DCM、0−20%、SNAP 25 gカートリッジ)で精製し、表題化合物207(133mg、0.252mmol、収率47%)を白色の固形物として得た。
MS:528(MH)+.
207(130mg、0.246mmol)のTHF(20mL)溶液(0℃)にDIPEA(0.172mL、0.986mmol)およびトリホスゲン(43.9mg、0.148mmol)を加えた。反応混合物を0℃で1時間撹拌し、シクロプロピルアミン(70.3mg、1.232mmol)を加えた。反応混合物を室温に昇温し、1時間撹拌し、濃縮した。残渣をBiotage(MeO/DCM、0−20%、SNAP 25 gカートリッジ)で精製し、表題化合物208(104mg、0.170mmol、収率69%)を白色の固形物として得た。
MS:611 (MH)+.
208(104mg、0.170mmol)のTHF(18mL)溶液にLiOH(32.6mg、1.362mmol)の水(6mL)溶液を加え、該混合物を室温で2時間撹拌し、濃縮した。残渣をBiotage(MeOH/DCM、0−20%、SNAP 25 gカートリッジ)で精製し、表題化合物209(40mg、0.070mmol、収率41%)を白色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) d (ppm):8.75 (s, 1H), 8.55 (d, 1H, J=5.3Hz), 7.94 (s, 1H), 7.75 (dd, 1H, J1=2.3Hz, J2=13.5Hz), 7.41 (t, 1H, J=9.0Hz), 7.24−7.22 (m, 1H), 7.09 (s, 1H), 6.70 (d, 1H, J=5.5Hz), 6,60 (m, 1H), 4.74 (s, 2H), 4.68−4.66 (m,1H), 4.24 (d, 2H, J=5.7Hz), 3.87 (s, 3H), 3.45 (m, 2H), 3.35 (s, 3H), 3.28 (m, 2H), 2.60−2.57 (m, 1H), 0.71−0.67 (m, 2H), 0.48−0.45 (m, 2H). MS:569.6 (MH)+
1−((2−(7−(4−イソプロピルアミノカルボニルアミノ−2−フルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)−1−メチル−1H−イミダゾール−5−イル)メチル)−3−イソプロピル−1−(2−メトキシエチル)尿素(192)
化合物192は、化合物209の合成のスキーム7で用いられたものと同様の方法により、工程1のDIPEAおよびHATU試薬の存在下における2−アセトキシ酢酸をトリホスゲン、次いでイソプロピルアミンで、工程3のシクロプロピルアミンをイソプロピルアミンで置き換えることにより得られた。
1H NMR (400 MHz, DMSO−d6) d (ppm):8.67 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 7.89 (s, 1H), 7.68 (dd, J1=2.6 Hz, J2=13.5 Hz, 1H), 7.34 (t, J=9.0 Hz, 1H), 7.12−7.09 (m, 1H), 6.94 (s, 1H), 6.64 (d, J=5.5 Hz, 1H), 6.14−6.09 (m, 2H), 4.55 (s, 2H), 3.83 (s, 3H), 3.80−3.74 (m, 2H), 3.38−3.27 (m, 4H), 3.21 (s, 3H), 2.06−1.04 (m, 12H). MS (m/z) = 598.6 (M+H).
1−シクロプロピル−3−(3−フルオロ−4−(2−(5−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−カルボニル)ピリジン−2−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(234)
工程1:6−(7−(4−(3−シクロプロピルウレイド)−2−フルオロフェノキシ)チエノ[3,2−b]ピリジン−2−イル)ニコチン酸(225)
アルデヒド47(200mg、0.446mmol)のDMF(10mL)懸濁液にオキソン(登録商標)(330mg、0.535mmol)を室温で加え、反応混合物を50℃で16時間撹拌した。反応混合物を0℃に冷却し、1N HCl水溶液(20mL)で処理し、室温でさらに1時間撹拌した。生じた沈殿物を濾取し、水(30mL)で洗浄し、乾燥した。粗生成物をMeOHでトリチュレートし、表題化合物225(165mg、収率80%)をベージュ色の固形物として得た。
NMR (400 MHz, CD3OD) δ (ppm):9.66 (bs, 1H), 8.98 (dd, J = 1.9, 0.9 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J = 8.1, 1.9 Hz, 1H), 8.17 (dd, J = 8.1, 0.9 Hz, 1H), 7.77 (dd, J = 13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J = 9.1 Hz, 1H), 7.26 (dd, J = 8.9, 1.5 Hz, 1H), 6.62 (d, J = 5.3, 0.8 Hz, 1H), 2.60−2.52 (m, 1H), 0.69−0.56 (m, 2H), 0.50−0.37 (m, 2H). [Carboxylic OH is not seen]. MS:465.3 (MH)+
酸225(300mg、0.646mmol)のDMF(10mL)撹拌溶液(0℃)にHOBT(198mg、1.292mmol)、EDC(248mg、1.292mmol)および1−メチル−4−(ピペリジン−4−イル)ピペラジン(118mg、0.646mmol)を加えた。反応混合物を室温で終夜撹拌し、飽和NaHCO3溶液で洗浄し、EtOAcで抽出した。抽出物を無水Na2SO4で乾燥し、減圧濃縮した。残渣をBiotage(MeOH/EtOAc、0−50%、25gカラム)で3回、次いでGilson[MeOH/H2O、50−95%、HCOOH(0.05%)]で精製し、表題化合物234(50mg、0.079mmol、収率12.29%)を一ギ酸塩として得た。
NMR (400 MHz, CD3OD) δ (ppm):8.67 (dd, J1=0.8 Hz, J2=2.1 Hz, 1H,), 8.48 (s, 1H), 8.47 (s, 1H), 8.19 (dd, J1=0.8 Hz, J2=8.3 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J1=2.2Hz, J2=8.2Hz, 1H), 7.65 (dd, J1=2.4Hz, J2=13.1Hz, 1H), 7.29 (t, 1H, J=8.8 Hz, H), 7.20−7.18 (m, 1H), 6.65 (dd, J1=0.8 Hz, J2=5.5 Hz, 1H), 3.83 (br. s, 1H), 3.24 (br s, 1H), 3.01 (br. s, 6H), 2.85 (br. s, 3H), 2.76−2.70 (m, 2H), 2.67 (s, 3H), 2.61−2.57(m, 1H), 2.02 (br. s, 1H), 1.91−1.85 (br. s, 1H), 1.56−1.49 (br. s, 2H), 0.78−0.74 (m, 2H), 0.55−0.51(m, 2H). MS:630.4 (MH)+
1−シクロプロピル−3−(3−フルオロ−4−(2−(1−(2−モルホリノエチル)−1H−イミダゾール−4−イル)チエノ[3,2−b]ピリジン−7−イルオキシ)フェニル)尿素(265)
工程1.1−(2,2−ジエトキシエチル)−4−ヨード−1H−イミダゾール(260)
4−ヨードイミダゾール(10g、51.6mmol)およびブロモアセトアルデヒドジエチルアセタール(9.31mL)のDMSO(30mL)撹拌溶液にK2CO3(10.69g、77mmol)を加えた。反応混合物を110℃で16時間加熱した。室温に冷却後、反応混合物を水で希釈し、AcOEtで抽出した。有機抽出物をブラインで洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。残渣をBiotage(SNAP 80 gカートリッジ;AcOEt/ヘキサン:0/100から50/50、20CV)で精製した。目的のフラクションを回収し、濃縮し、表題化合物260(11.29g、36.4mmol、収率71%)を黄色の油状物として得た。
MS (m/z):310.97 (M+H).
7−クロロチエノ[3,2−b]ピリジン(9.26g、54.6mmol)のTHF(88mL)撹拌溶液(−15℃)にn−BuLi(21.84mL、54.6mmol)を加えた。30分後、0.5M ZnCl2/THF溶液(109mL、54.6mmol)を−15℃で加え、反応混合物を45分間かけて室温に昇温した。パラジウムテトラキスフェニルホスフィン(0.841g、0.73mmol)およびヨージド260(11.29g、36.4mmol)のTHF(33mL)溶液を加え、該混合物を3時間加熱還流し、次いで濃縮した。残渣を水および水酸化アンモニウムで希釈し、DCMで抽出した。有機抽出物をブラインで洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。残渣をBiotage(SNAP 80 gカートリッジ; AcOEt/ヘキサン:0/100から100/0、20CV)で精製し、得られた物質をMTBEでトリチュレートし、表題化合物261(1.2g、3.41mmol、収率9%)を薄茶色の固形物として得た。
MS (m/z):437.45 (M+H).
4−アミノ−2−フルオロフェノール 塩酸塩(1.39g、8.53mmol)のDMSO(20mL)撹拌溶液にt−BuOK(1.99g、17.76mmol)を加えた。30分後、塩化物261(2.5g、7.11mmol)を加え、反応混合物を100℃で1時間加熱した。
別のフラスコで4−アミノ−2−フルオロフェノール 塩酸塩(1.39g、8.53mmol)のDMSO(20mL)溶液をt−BuOK(1.99g、17.76mmol)で処理し、得られたフェノレートの溶液を上の反応混合物に100℃で加えた。30分後、該混合物を水(300mL)に注ぎ、生じた沈殿物を濾取し、高真空下で乾燥し、表題化合物262(2.86g、6.46mmol、収率91%)を薄茶色の固形物として得た。
MS (m/z):443.44 (M+H).
アミン262(2.86g、6.46mmol)およびピリジン(1.04mL、12.93mmol)のDMF(50mL)撹拌溶液(0℃)にクロロギ酸フェニル(973μL、7.76mmol)を加えた。30分後、シクロプロピルアミン(1.14mL、16.16mmol)を0℃で加え、反応混合物を60℃で45分間加熱した。さらなるシクロプロピルアミン(1mL、14.18mmol)を加え、反応混合物を60℃でさらに10分間加熱した。室温に冷却後、水を加えて反応混合物をクエンチすると沈殿物が生じた。その固形物を濾取し、水で洗浄し、2時間減圧乾燥した。残渣をBiotage(SNAP 80 gカートリッジ;MeOH/DCM:0/100から10/90、20CV)で精製した。目的のフラクションを回収し、濃縮し、MTBEでトリチュレートし、高真空下で乾燥し、表題化合物263(2.95g、5.61mmol、収率87%)をピンク色の固形物として得た。
MS (m/z):526.60 (M+H).
アセタール263(2.95g、5.61mmol)のAcOH/H2O(20/20mL)溶液に濃HCl(2mL)を加え、反応混合物を90℃で1時間加熱した。反応混合物を濃縮し、水で希釈し、4M NaOHでpH10に調整して生じた沈殿物を濾取し、水で希釈し、減圧乾燥した。次いで、該物質をBiotage(SNAP 100 gカートリッジ;2%水酸化アンモニウム含有MeOH/DCM:0/100から15/85、20CV)で精製し、表題化合物264(1.2g、2.66mmol、収率47%)を茶色の固形物として得た。
MS (m/z):484.51 (M+H).
264(200mg、0.443mmol)、モルホリン(46μL、0.532mmol)およびAcOH(51μL、0.886mmol)のNMP(10mL)溶液にナトリウムトリアセトキシボロヒドリド(282mg、1.329mmol)を加え、反応混合物を室温で18時間撹拌した。水で反応混合物をクエンチし、DCMで抽出した。有機抽出物を飽和塩化アンモニウム溶液およびブラインで順に洗浄し、無水硫酸ナトリウムで乾燥し、濾過し、濃縮した。残渣をBiotage(SNAP 40 gカートリッジ;2%水酸化アンモニウム含有MeOH/DCM:0/100から15/85、20CV)、およびGilson(Phenomenex, Luna 15μ,C18(2)100A,250x50.0mm,15μm;共に0.05%ギ酸を含むMeOH/水:20/80から95/5、60分間;流速:30mL/分)で精製し、表題化合物265(30mg、0.057mmol、収率13%、ギ酸塩)を白色の固形物として得た。
1H NMR (400 MHz, DMSO−d6) δ (ppm) :9.52 (bs, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.36 (bs, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.71 (dd, J = 2.4 and 14.0 Hz, 1H), 7.65 (s, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.32 (bs, 1H), 7.22 (dd, J = 1.6 and 8.8 Hz, 1H), 6.54 (d, J = 5.6 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.57 (t, J = 4.4 Hz, 4H), 2.66 (t, J = 6.4 Hz, 2H), 2.58−2.51 (m, 1H), 2.49−2.40 (m, 4H), 0.64−0.59 (m, 2H), 0.43−0.39 (m, 2H). MS (m/z):523.55 (M+H).
いくつかの実施態様において、本発明は、本発明の化合物ならびに医薬的に許容される担体、賦形剤または希釈剤を含む医薬組成物を提供する。本発明の組成物は技術分野で周知のいずれの方法により製剤化されてもよく、様々な経路、例えば、局所、硝子体内、眼窩周囲、眼球内、といった経路、ならびに眼球、眼部および/または眼部周囲への別の局所投与方法(送達装置によるものを含む)で投与されるよう製造されてもよい。いくつかの実施態様において、投与は経口経路によるものでもよい。
VEGF活性の阻害
以下のプロトコルが本発明の化合物のアッセイに用いられた。
インビトロ受容体型チロシンキナーゼアッセイ(VEGF受容体 KDR)
この試験は本発明の化合物のヒト組み換えVEGF受容体酵素活性阻害能を評価するものである。
VEGF依存的Erkリン酸化
細胞および増殖因子:HUVEC細胞をCambrex Bio Science Walkersville, Incから購入し、販売者の説明書に従って培養した。Sf9におけるバキュロウィルスによる発現用にGateway Cloning Technology (Invitrogen)を用いてVEGF165の全長をコードする配列をクローニングした。NaClmpグラジエント溶出を用いたHiTrapヘパリンカラム(GE Healthcare Life Sciences)、次いでイミダゾールグラジエント溶出を用いたHiTrap Chelatingカラム(GE Healthcare Life Sciences)でVEGF165を培養培地から精製し、0.1%BSA含有PBSバッファー中で保存し、濾過滅菌した。
インビボ脈絡叢新血管新生(CNV)モデル
この試験は、化合物のCNV進行阻害能を評価するものである。CNVは加齢性黄斑変性症(AMD)患者における重篤な失明の主な原因である。
ウサギにおけるVEGF誘発性網膜血管透過性亢進
資料と方法
この試験は化合物のVEGF誘発性網膜血管透過性亢進の阻害能を評価するものである。血管透過性の亢進は加齢性黄斑変性症(AMD)患者における重篤な失明の主な原因である。メスダッチウサギ(〜2kg;Kitayama LABES CO., LTD、長野県、日本)をペントバルビタールで麻酔し、0.4%オキシブプロカイン塩酸塩で局所麻酔した。0.5%トロピカミド点眼液で瞳孔を散大させた後、試験化合物またはベヒクルを硝子体腔に注射した。ヒト組み換えVEGF165(500ng;Sigma−Aldrich Co., St Louis, MO)を硝子体フルオレセイン濃度測定の48時間前に硝子体内に注射した。ウサギをペントバルビタールで麻酔し、次いで、フルオレセインナトリウム(2mg/kg)を耳静脈から注入した。0.5%トロピカミド点眼液で瞳孔を散大させ、フルオレセイン注入の30分後、眼球のフルオレセイン量をFM−2 Fluorotron Master(Ocumetrics, Mountain View, CA)で測定した。硝子体内のフルオレセイン濃度は光軸に沿って後端から0.25mm離れたデータポイントにおいて得た。硝子体内のフルオレセイン濃度は網膜血管から漏出したフルオレセインであると見做される。試験化合物処理群における平均フルオレセインピークをベヒクル処理群のものと比較した。化合物26および74は、ベヒクル処理群と比べてフルオレセイン漏出の有意な阻害を示した。
Claims (15)
- 請求項1から11のいずれかに記載の化合物および医薬的に許容される担体を含む組成物。
- 治療上の有効量の請求項1から12のいずれかに記載の化合物またはその組成物を患者に投与することを特徴とする眼部の疾患、病状または障害の治療方法であって、眼部の該疾患、病状または障害が(a)脈絡叢の血管新生により引き起こされる疾患、障害または病状、(b)糖尿病網膜症および(c)網膜浮腫からなる群より選択される方法。
- 眼部の疾患、障害または病状が加齢性黄斑変性症である請求項14に記載の方法.
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