TW201014834A - Novel ortho-aminoanilides for the treatment of cancer - Google Patents
Novel ortho-aminoanilides for the treatment of cancer Download PDFInfo
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- TW201014834A TW201014834A TW098131074A TW98131074A TW201014834A TW 201014834 A TW201014834 A TW 201014834A TW 098131074 A TW098131074 A TW 098131074A TW 98131074 A TW98131074 A TW 98131074A TW 201014834 A TW201014834 A TW 201014834A
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- Prior art keywords
- phenyl
- amino
- bromo
- vinyl
- compound
- Prior art date
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 19
- 201000011510 cancer Diseases 0.000 title claims abstract description 14
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- 125000000217 alkyl group Chemical group 0.000 claims description 18
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
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- 239000000126 substance Substances 0.000 claims description 4
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Description
201014834 六、發明說明: 【發明所屬之技術領域】 本發明係關於新穎抗腫瘤劑及其醫藥上可接受之鹽、及 製造該等新穎化合物及含有該等新穎化合物之藥劑之方 法。本發明化合物具有抗增殖及誘導分化活性從而可抑 制腫瘤細胞增殖,誘導祠亡並抑制侵襲。因此,本發明亦 係關於該等化合物用於治療諸如癌症等疾#及用於製造相 應藥劑之用途。 本發明化合物係組蛋白脫乙醯基酶(HDAC)抑制劑且因 此顯示抗增殖及誘導分化活性,從而可抑制腫瘤細胞增 殖,誘導凋亡並抑制侵襲。 【先前技術】 轉錄調節係細胞分化、增殖及凋亡中之重要事件。一組 基因之轉錄激活決定細胞目的地且因此轉錄受多種因素緊 密地調節。該過程所涉及之一種其調節機制係改變£)1^八三 級結構’從而藉由調節轉錄因子與其目標DNA片段之可接 近性來影響轉錄。核小體完整性係由核心組蛋白之乙酿化 狀態來調節。在低乙醯化狀態中,核小體緊縮且因此不允 許轉錄。另一方面’藉由乙醢化核心組蛋白使核小艘鬆 弛,從而允許轉錄。組蛋白之乙醯化狀態係由組蛋白乙醯 基轉移酶(HAT)活性與組蛋白脫乙醯基酶(HDAC)活性之平 衡來管控。近來,已發現HDAC抑制劑可阻止若干類型癌 細胞(其包括結腸癌細胞、T-細胞淋巴瘤細胞及紅白血病 細胞)之生長並可誘導其凋亡。赛於凋亡係癌症進程之關 142666.doc 201014834 鍵因素,HDAC抑制劑作為凋亡之有效誘導物係有價值之 癌症療法試劑(Koyama,Y.等人,Blood 96 (2000) 1490-1495)。 組蛋白脫乙酿基酶(HDACs)係多蛋白複合物之關鍵酶組 份’其負責使組蛋白及非組蛋白蛋白質受質中離胺酸殘基 脫乙醯化。HDACs可根據與酵母HDACs(Rpd3、Hdal及 Sir2)之序列同源性細分為三種主要類型。I類 HDACs(HDAC 1、2、3及8)與Rpd3同源,主要位於細胞核 β 中且似乎表現於大多數組織中。II類HDACs(HDAC 4、5、 6、7、9、10)與Hdal同源’視各種調節信號及細胞狀態而 定,能夠在細胞核與細胞質之間穿梭移動,並具有組織特 異性表現型。該等HDACs可進一步細分為na類(HDAC 4、 5、7、9)及 lib類(HDAC 6、10)。ΠΙ類 HDACs與 Sir2 同源, 係NAD+依賴性脫乙醯酶,在機理上有別於I類及II類 HDACs且不受典型HDAC抑制劑(例如曲古抑菌素A (trichostatin A)、曲普辛B(trapoxin B)或 SNDX-275)抑制。 W 因此,HDACs可根據序列相似性、細胞定位傾向、組織表 現型及酶機制分為三類。 - I類HDACs尤其與對抗腫瘤細胞之抗增殖作用密切相 關。舉例而言,藥理學抑制HDACs 1-3可導致誘發細胞週 期調節蛋白(cyclin)依賴性激酶抑制劑p21及伴隨細胞週期 停滯。已知Ila類HDACs與HDAC3/SMRT/N-CoR複合物及 MEF2有關,因此在調節肌肉細胞基因表現(综述於 Oncogene 2007, 26,5450-5467 中)及免疫反應(价oc/zew/ca/ 142666.doc 201014834 P/mrwaco/ogy 2007, 74,465-476)中具有重要作用。由於其 特異抗增殖功能,故選擇性抑制I類HDACs可合意地達成 抗腫瘤功效且毒性較低。 在臨床試驗中,與SNDX-275(結構上相關之HDAC抑制 劑)相比,本發明化合物顯示對I類HDACs更高的效力且對 癌細胞更高的抗增殖功效。I類HDAC抑制效力係藉由報導 基因分析評估,報導基因分析係在細胞中存在相關多蛋白 複合物情況下評估HDAC亞型活性,而在酶活性分析中通 常不存在相關多蛋白複合物。因此,本發明之化合物具有 細胞内對I類HDACs抑制效力,此與其抗癌功效較SNDX-275增進相關。 WO 2007/100657闡述了相關但結構上不同之鄰-笨二胺 衍生物作為細胞分化誘導物。WO 2007/087130之標的物亦 為同類化合物。該等申請書中所闡述之化合物僅為經苯甲 酸衍生物單醯化之鄰-伸苯基衍生物。然而,仍需要具有 經改良治療性質(僅舉幾個例子,例如更高活性、更低毒 性、更佳溶解度及/或經改良藥物代謝動力學特徵)之新穎 化合物。 單醯化鄰-苯二胺作為製備相應苯并咪唑之前體已為業 内所熟知,該等製備方法闡述於(例如)下列文獻中:DE-A2 062 265 ; FR 2 167 954 ; Rastogi, R.及 Sharma,S. ’ Indian J. Chem., Sect. B, 21B (5) (1982) 485-487 ; Moll, R. 等人,Z. Chem. 17 (1977) 133-134;及Hassan,H.等人, Indian J. Chem. 39B (2000) 764-768 ° 142666.doc 201014834 已發現本發明之化合物係HDAC抑制劑,其具有抗增殖 及誘導分化活性’從而可抑制腫瘤細胞增殖,誘導凋亡並 抑制侵襲。因此’該等化合物可用於治療諸如癌症等人類 或動物疾病。 【發明内容】 本發明係關於下式之化合物
(I) 其中 R1係氫; 鹵素; 低碳數院基,其未經取代或經鹵素取代一次或數次; 環烷基;
氰基; 低石炭數娱•氧基;
其中R3係3_10員雜環,其未經取代或經鹵素、低碳 數烧基、經基、-C(O)-低碳數烷基、=〇或 NR4R5取代一次或數次; 或 NR4R5 ; 142666.doc 201014834 r4/r5彼此獨立地係氫或低碳數烷基; η 係0、1、2、3 ’且當η=0時,R3將為藉由碳 連接之3-10員雜環; χ 係C或Ν ; 及 其醫藥活性鹽、外消旋混合物、對映異構體、光學異構體 或互變異構形式。 本發明亦涵蓋式(I)化合物之醫藥上可接受之鹽及其前藥 以及該等化合物用於製造藥劑之用途。 【實施方式】 本文所用術語「低碳數烷基」表示含有丨至8個較佳i 至6個、更佳1至4個碳原子之飽和直鏈或具支鏈烷基,例 如曱基、乙基、丙基、異丙基、卜丁基、2 丁基第三丁 基及諸如此類。較佳「Cl_C8_烷基」基團具有1、2或3個碳 原子。 本文所用術語「低碳數烷氧基」表示基團_〇·烷基,其 中「烷基」如上文所定義;例如,甲氧基、乙氧基、丙氧 基、異丙氧基、正丁氧基、異丁氧基、2-丁氧基、第三丁 氧基及諸如此類。較佳烷氧基係具有個碳原子之基 團。 本文所用術語「環烷基」意指由一個環或兩個環(其可 稠合或經由單鍵連接)組成並含有3至8個、較佳3至6個碳 原子之飽和環烴。該等3至8員環烷基環之實例係環丙基、 環丁基、環戊基、環己基、環辛基、八氫-茚、二環[2.2.1] 142666.doc 201014834 庚烧、一環己基及諸如此類。 本文所用術語「雜環基」意指如上文所定義之3至8員單 環或一環環院基,其中最多4個碳原子、較佳1個、2個或3 個碳原子係由氧、氮或硫代替。實例包括(但不限於)嗎琳 基、硫嗎琳基、六氫η比咬基、η底嗪基、四氫η比喃基、2_氧 ,雜-5-氮雜-二環[2.2.1;|庚烷基、[14]氧硫雜環己烷基、氮 雜環庚烷基、[1,4]二氮雜環庚烷基、吡咯啶基、吡唑咬 基、[1,2,3]三唾n定基、π米β坐咬基、嘆β坐咬基、氮雜環丁烧 ❿ 基。 術語「鹵素」意指氟、氣、溴或峨。 本文所用術語「經數次取代」意指最多經5次取代、較 * 佳最多經4次取代、最佳經2或3次取代。 含有一或數個對掌性中心之通式I化合物可以外消旋 物、非對映異構混合物或旋光活性單一異構體形式存在。 可根據熟知方法將外消旋物分離成異構體。較佳地,非對 . 映異構鹽係藉由使外消旋混合物與旋光活性酸(例如D-或 L-酒石酸、苦杏仁酸、蘋果酸、乳酸或樟腦磺酸)反應來 形成’其可藉由結晶來分離。 本發明之化合物可以其醫藥上可接受之鹽之形式存在。 術語「醫藥上可接受之鹽」係指習用酸加成鹽或鹼加成 鹽,其保持式I化合物之生物學有效性及性質且係自適宜 無毒有機或無機酸或有機或無機鹼形成。酸加成鹽包括 (例如)彼等衍生自諸如氫氣酸、氫溴酸、氫碘酸、硫酸、 胺基磺酸、磷酸及硝酸等無機酸者,及彼等衍生自諸如對 142666.doc 201014834 甲苯績酸、水楊酸、甲確酸、草酸、琥珀酸、擰檬酸、蘋 果酸、乳酸、富馬酸及諸如此類等有機酸者。鹼加成鹽包 括彼等衍生自氫氧化銨、氫氧化鉀、氫氧化鈉及氫氧化四 級敍(例如,氫氧化四甲基銨)者。將醫藥化合物化學修飾 成鹽係藥劑師所熟知用以獲得具有經改良物理及化學穩定 性、吸濕性、流動性及溶解度之化合物之技術。該技術闡 述於(例如)下列文獻中.Bastin R.J.等人,Organic Process
Research & Development 2000,4,427-435 ;或 Ansel, Η.等 .人,Pharmaceutical Dosage Forms and Drug Delivery
Systems,第 6版(1995),第 196頁及第 1456-1457 頁。 在本發明之一較佳實施例中,提供如上文所定義之式⑴ 化合物,其中 R1 係_素; 低碳數烧基,其未經取代或經南素取代一次或數 次; 環烷基;且 所有其餘取代基皆具有上文中所給出之意義。 在本發明之另一較佳實施例中,提供如上文所定義之式 (I)化合物,其中 X 係C ;且 所有其餘取代基皆具有上文中所給出之意義。 在本發明之又一較佳實施例中,提供如上文所定義之式 ⑴化合物,其中 142666.doc 201014834 其中R3係吡咯啶基、嗎啉基、六氫吡啶基、硫嗎啉 基、2·氧雜-5-氮雜-二環[2.2.1]庚烷基,所有上 述環皆可未經取代或經鹵素、低碳數烷基、羥 基、-C(O)-低碳數烷基、=〇或nr4R5取代一次 或數次; 或 NR4R5 ; o r4/r5彼此獨立地係氫或低碳數烷基; 所有其餘取代基皆具有上文中所給出之意義。 根據本發明’尤佳者為下述特定化合物: 2-{4-[(Ε)·2-(2-胺基-苯基胺基甲醯基)_乙烯基]_苯基}_5_嗎 啉-4-基·戊酸(4-溴-苯基)_醯胺; 2-{4_[(Ε)-2-(2·胺基-笨基胺基甲醯基)_乙烯基]_苯基卜5_ (lS’4S)-2-氧雜_5_氮雜_二環[2 2庚_5基戊酸(4三氟曱 基-苯基)-酿胺; ® 2_{4_[(Ε)-2·(2-胺基-苯基胺基甲醯基)_乙烯基]苯基}·5_ (lS’4S)-2-氧雜·5·氮雜二環[2 2丨]庚_5-基戊酸(4溴苯 基)-醯胺; 2 {4-[(Ε)-2-(2-胺基-苯基胺基甲醯基)乙烯基]苯基卜5嗎 琳-4-基-戊酸(4_異丙基_苯基)_醯胺; 2 {4 [(Ε)-2-(2-胺基-苯基胺基曱酿基)·乙烯基]苯基卜5_ (lS,4S)-2-氧雜·5_氮雜二環[2 2庚基-戍酸(4-異丙基· 苯基)-醯胺; 142666.doc 201014834 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)_乙烯基]-苯基}-5-(3-羥基-六氫°比啶-1-基)·戊酸(4-異丙基-苯基)-醯胺; 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)_乙烯基]-苯基}_5·(3-羥基-六氫吡啶-1-基)-戊酸(4-溴-苯基)-醯胺; 2-{4-[(£)-2-(2-胺基-苯基胺基甲醯基)_乙烯基]-苯基}_>^-(4 -溴-苯基)-4 -嗎嚇>-4 -基-丁酿胺; 2·{4-[(Ε)-2-(2-胺基-苯基胺基甲醯基)_乙烯基]-苯基卜5-»比 咯啶-1-基-戊酸(4-三氟甲基-苯基)-醯胺; 2-{4-[(Ε)_2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基}_5_六 春 氫0比啶-1-基-戊酸(4-溴-苯基)-醯胺; 2-{4-[(Ε)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]•苯基}-5-«比 略咬-1-基-戊酸(4-溴-苯基)-酿胺; 2-{4-[(Ε)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基}-5-(2-氧雜-5-氮雜-二環[2.2.1]庚-5-基)-戊酸(4-氣-苯基)-醯胺; (Ε)-Ν-(2_胺基-苯基)-3-{4-[1-(4-氣-苯基胺基甲醯基)-2-(3-二乙基胺基比咯啶-1-基)-乙基]-苯基}-丙烯醯胺; 2-{4-[(E )-2-(2-胺基-苯基胺基甲酿基)-乙烤基]-苯基} -N-(4 -漠-苯基)-4-(3-經基-六氫》比咬-1-基)-丁酿胺; 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基}-N-(4-溴-苯基)-4-(1 S,4S)-2-氧雜-5-氮雜-二環[2.2.1]庚-5-基-丁醯胺; 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基}-N-(4 -漠-苯基)-4-(1-甲基-〇比洛咬-2-基)_ 丁酿胺;及 (Ε)-Ν·(2-胺基-苯基)-3-{4-[1-(4-溴-苯基胺基甲醯基)-2-(1- 142666.doc 12· 201014834 甲基-六氫n比咬-4-基)-乙基]-苯基}•丙稀酿胺。 本發明之化合物顯示頻具價值的醫藥性質,具趙而言作 為抗增殖劑或抗癌劑,更特定而言作為用於治療實體腫瘤 及血液腫瘤之試劑。 因此’在本發明之另一實施例中,提供醫藥組合物,其 •包含至少一種如上文所定義之化合物以及醫藥上可接受之 佐劑。 在本發明之另一實施例中,提供如上文所定義之化合物 β 以用作藥劑。 在本發明之又一實施例中,提供如上文所定義之化合物 以用於治療癌症’具體而言實體腫瘤及血液腫瘤、更具體 而言白也病、淋巴瘤、結腸癌、肝癌或胃癌。 在本發明之再一實施例中,提供至少一種如上文所定義 之化合物用於製造用於治療癌症(具體而言實體腫瘤及血 液腫瘤)之藥劑之用途。該等藥劑(例如呈醫藥製劑形式)可 ❹ 經口投與,例如以旋劑、糖衣鍵劑、糖衣丸、硬明膠及軟 明膠膠囊、溶液、乳液或懸浮液形式。然而,其亦可經直 腸投與(例如以栓劑形式)或非經腸投與(例如以注射溶液形 式)。 上述醫藥製劑可藉由加工本發明之化合物與醫藥上惰性 無機或有機載劑來獲得。舉例而言,可使用乳糖、玉米澱 粉或其衍生物、滑石粉、硬脂酸或其鹽及諸如此類作為旋 劑、糖衣錠劑、糖衣丸及硬明膠膠囊之載劑。舉例而言, 軟明膠膠囊之適宜載劑係植物油、蠟、脂肪、半固態及液 142666.doc -13· 201014834 態多元醇及諸如此類。然而,視活性物質之性質而定,在 軟明膠膠囊之情形下通常不需要載劑。舉例而言,用於製 造溶液及糖漿之適宜載劑係水、多元醇、甘油、植物油及 諸如此類。舉例而言,栓劑之適宜載劑係天然或硬化油、 蠟、脂肪、半液態或液態多元醇及諸如此類。 此外,醫藥製劑可含有防腐劑、增溶劑、穩定劑、潤濕 劑、乳化劑、甜味劑、著色劑、矯味劑、用於改變滲透壓
之鹽、緩衝劑、掩蔽劑或抗氧化劑。其亦可含有其他在治 療上頗具價值的物質。 劑量取決於多種因素,例如投與方式、種類、年齡及 或個體健康狀態。日投與劑量係約5_4〇〇 mg/kg、較佳麥 10-100 mg/kg,且可單次投與或分數次投與。 在本發明之另-較佳實施例中,提供治療患者癌症之2 法’其包含向該患者投與至少—種本發明之化合物。 本發明之化合物以及其起始材料可分別按照下述一般万 應圖1至8來合成。在該等反康 寻夂應圖1至8中,除非另有明確畜
明,否則所有取代基(尤其ri 5 自具有上文中所給出3 3義。此外,且除非另有明墟 格杜明’㈣所有反應、反屬 條件、縮寫及符號皆具 熟知之含義。 、有機化學之-般技術人“ 縮寫 bP : 沸點 dba : DIPEA : —亞节基丙鋼 一異丙基乙基胺 142666.doc -14- 201014834 DMEM : 達爾伯克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle Medium) DMF : 二甲基甲醯胺 DMSO : 二甲基亞颯 DNA : 脫氧核糖核酸 EDCI : 1-乙基-3-(3-二甲基胺基丙基)碳二亞胺 ELISA : 酶聯免疫吸附分析 EtOAc : 乙酸乙酯 ⑩ FBS : 胎牛血清 g : 克 GFP : 綠色螢光蛋白 GI50 : 50%生長抑制所需之濃度 GI90 : 90%生長抑制所需之濃度 h : 小時 HATU : 六氟磷酸0-(7-氮雜苯并三唑-1-基)-Ν,Ν,Ν',>Γ- 四曱基脲鏽鹽 w HDAC : 組蛋白脫乙醯基酶 HOAc : 乙酸 HOBt : 1-羥基苯并三唑 HPLC : 南效液相層析 Hz : 赫兹 MeOD : 氘代曱醇 MeOH : 曱醇 mg : 毫克 142666.doc -15- 201014834 MHz : 兆赫 mL : 毫升 mmol · 毫莫耳 MsCl : 甲確醯氯 MTS : 3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯 基)-2-(4-磺苯基)-2H-四唑鑌) MW : 分子量 nL : 毫微升 NMR : 核磁共振 O/N : 過夜 PET : 石油醚 Pybrop · 六氟磷酸溴-叁比咯啶基-鱗鹽 rt : 室溫 TBS : 第三丁基二甲基曱矽烷基 t-BuOK : :第三丁醇鉀 THF : 四氫呋喃 TLC : 薄層層析 uL : 微升 WST : 4-[3-(4-碘苯基)-2-(4-硝基苯基)-2H-5-四唑]-1,3-苯二磺酸鹽 A.合成2碳鏈接之肉桂醯胺之一般合成途徑(反應圖1) 142666.doc •16- 201014834
反應圖1 目標化合物1a可按照反應圖1來製備。自酯II(參見用於 製備II之反應圖6)開始’用氫氧化鋰水解得到酸111。使不 同苯胺與in偶合得到苯胺化物IV,冑㈤氣離子使其去保護 得到醇V。用甲續醯氣將醇V續醯化得到甲磺醯酯,隨 Φ 後可用不同胺對其實施親核取代得到化合物VII。可在酸 性條件下使化合物VII去保護以獲得目標化合物。 2 {4-[2-(2-第二丁氧基羰基胺基_苯基胺基甲醯基)_乙烯 基]-苯基}·4-羥基-丁酸乙酯(11)可按照反應圖6令所概述之 合成途徑來製備。 2 {4 [2-(2-第二丁氧基羰基胺基·苯基胺基甲醯基)_乙烯 基]-苯基L4-羥基-丁酸(m)可藉由水解„來製備。該反應 通常可利用混有適宜有機溶劑(例如甲醇或四氫呋喃)之氫 氧化鐘水溶液在室溫下實施數小時。 142666.doc •17- 201014834 笨胺化物化合物1V可藉由使不同胺與2-{4·[2-(2-第三丁 氧基幾基胺基.笨基胺基甲醯基)_乙烯基]苯基}·4·經L 丁 酸(III)偶合來製備。該反應通常係利用標準肽偶合劑⑽如 EDCI及HOBt、Pybr〇p及二異丙基乙基胺或hatu及三乙 胺)在適宜惰性溶劑(例如二氣甲燒或二甲基Μ胺或h 合物)中在室溫下實施數小時。 醇化合物v可藉由對笨胺化物化合物1¥實施氟化物調介 的去保護來製備。該反應通常係㈣氟離子源(例如四丁 基氟化銨或四丁基二氫三敗化録)在四氫南中在室溫下 實施8至12個小時。 甲磺酸醋化合物…可藉由使醇化合物v與甲績酿氣反應 來製備。該反應通常係在〇攝氏度下在二氣曱烷中利用適 宜胺鹼(例如二異丙基乙基胺或三乙胺)實施3〇分鐘至2小 時。 化合物VII可藉由用不同胺對曱磺酸酯化合物VI實施親 核取代來製備。該反應通常係在適宜惰性溶劑(例如二氣 甲烷或乙腈)中利用胺鹼(例如二異丙基乙基胺或三乙胺)在 室溫至回流間之溫度下實施數小時。 目標化合物la係藉由使化合物VII去保護來獲得。該反 應通常係在氣化氫甲醇中在室溫下實施數小時。 B,合成3碳鏈接之肉桂醯胺之一般合成途徑(反應圖2、3) 142666.doc -18 - 201014834
反應圖2 目標化合物lb可按照反應圖2來製備。自酯VIII(參見用 於製備VIII之反應圖7)開始,用氫氧化鋰水解得到酸IX。 使不同苯胺與IX偶合得到笨胺化物X,然後可用不同胺對 其實施親核取代,得到化合物Xh可在酸性條件下使化合 ⑩ 物XI去保護,獲得目標化合物Ib。 2-{4-[2-(2-第三丁氧基羰基胺基-苯基胺基曱醯基)_乙烯 基]-苯基}-5-氣-戊酸甲酯(νιπ)可按照反應圖7中所概述之 合成途徑來製備。 2-{4-[2-(2-第三丁氧基羰基胺基_笨基胺基甲醯基乙烯 基]苯基}-5-氣·戊酸(Ιχ)可藉由水解νιπ來製備。該反應 通常可利用混有適宜有機溶劑(例如甲醇或四氮咬喃)之氮 氧化鋰水溶液在室溫下實施數小時。 142666.doc •19· 201014834 苯胺化物化合物χ可藉由使不同苯胺與2_{4_[2_(2_第三 丁氧基羰基胺基-笨基胺基甲醯基)_乙烯基]_苯基}_5_氣_戊 酸(IX)偶合來製備。該反應通常係利用標準肽偶合劑(例如 EDCI及HOBt、Pybrop及二異丙基乙基胺、或HATU及三乙 胺)在適宜惰性溶劑(例如二氣甲烷或二甲基曱醯胺或其混 合物)中在室溫下實施數小時。 化合物XI可藉由用不同胺對苯胺化物化合物X實施親核 取代來製備。該反應通常係在適宜惰性溶劑(例如二甲基 甲醯胺)中在胺過量之情況下在70至80攝氏度下實施8至16 個小時。 目標化合物lb係藉由使化合物XI去保護來獲得。該反應 通常係在氯化氫甲醇中在室溫下實施數小時。
目標化合物Ic可按照反應圖3來製備。自酸χπ(參見用於 製備XII之反應圖8)開始,使不同苯胺與ΧΙΙ偶合得到苯胺 化物XIII,然後可用不同胺對其實施親核取代,得到化合 142666.doc -20· 201014834 物XIV。隨後使化合物XIV與(2-丙烯醯基胺基_苯基)_胺基 甲酸第三丁基酯發生Heck反應,得到化合物χν,可在酸 性條件下使其去保護,獲得目標化合物Ic。 2-(5-溴·吡啶-2-基)-5-氣-戊酸(χπ)可按照反應圖8中所 概述之合成途徑來製備。 苯胺化物化合物XIII可藉由使不同苯胺與2_(5_溴-吡啶_ 2-基)-5-氣-戊酸(XII)偶合來製備。該反應通常係利用標準 肽偶合劑(例如EDCI及HOBt、Pybrop及二異丙基乙基胺、 ® 或三乙胺)在適宜惰性溶劑(例如二氣曱烷或二甲 基甲醯胺或其混合物)中在室溫下實施數小時。 化合物XIV可藉由用不同胺對苯胺化物化合物ΧΙΙΙ實施 親核取代來製備。該反應通常係在適宜惰性溶劑(例如二 曱基甲醯胺)中在胺過量之情況下在70至80攝氏度下實施8 至16個小時。 化合物XV可藉由化合物χιν與(2-丙烯醯基胺基-苯基)-胺基甲酸第三丁基酯之Heck反應來製備。該反應通常係在 具有三乙胺、三-鄰-曱苯基-膦、Pd2(dba)3之脫氧二甲基甲 酿胺中在80-100攝氏度下在惰性氣氛下實施約1〇至15小 時。 目標化合物Ic係藉由使化合物χν去保護來獲得。該反應 通常係在氣化氫曱醇中在室溫下實施數小時。 C. 1或2碳鏈接之肉桂醯胺之合成(反應圖4及5) 142666.doc •21- 201014834
目標化合物Id可按照反應圖4製備。自市售腈XVI開始, 用鹼去質子化,隨後用各種烷基氣實施烷基化,得到化合 物XVII。使化合物XVII酸性水解得到酸XVIII,隨後可藉 由親核醯基取代轉化為曱酯XIX。使化合物XIX與(2-丙烯 醯基胺基-苯基)-胺基甲酸第三丁基酯發生Heck反應,得到 曱酯化合物XX,其可在鹼性條件下水解為相應酸XXI。使 各種苯胺與酸XXI偶合得到苯胺化物XXII,隨後可在酸性 條件下去保護,獲得目標化合物Id。 (4-溴-苯基)-乙腈(XVI)市面可購得。 化合物XVII可由去質子化之XVI用各種烷基氣實施烷基 化製備。該反應通常係藉由下述實施:XVI在惰性溶劑之 混合物(例如二曱基曱醯胺與曱苯)中在攝氏〇度下用強鹼 (例如氫化鈉)去質子化約1小時,隨後添加烷基氯並加熱至 約攝氏70-80度2小時。 化合物XVIII可由化合物XVII中之腈官能團酸性水解製 備。該反應通常在濃硫酸與水之混合物中於回流溫度下實 施數小時。 142666.doc -22- 201014834 化合物XIX可由化合物XVIII實施親核醯基取代製備。該 反應通常係藉由下述實施:使化合物XVIII與亞硫醯氣在 曱醇中在攝氏0度下反應,隨後加熱至回流數小時。 化合物XX可藉由化合物XIX與(2-丙烯醯基胺基-苯基)-胺基甲酸第三丁基酯之Heck反應製備。該反應通常在惰性 氣氛下在具有三乙胺、三-鄰-曱苯基-膦、Pd2(dba)3之脫氧 二甲基甲醯胺中在攝氏80-100度下實施約4至10小時。 化合物XXI可由化合物XX鹼性水解製備。該反應可利用 混有適宜有機溶劑(例如甲醇或四氫呋喃)之氫氧化鋰水溶 液在室溫下實施數小時。 苯胺化物化合物XXII可由各種苯胺與化合物XXI偶合製 備。該反應通常利用標準肽偶合試劑(例如EDCI及HOBt、 Pybrop及二異丙基乙基胺、或HATU及三乙胺)在適宜惰性 溶劑(例如二氣甲烷或二曱基甲醯胺或其混合物)中在室溫 下實施數小時。 目標化合物Id係由化合物XXII去保護獲得。該反應通常 係在甲醇-氣化氫中在室溫下實施數小時。
142666.doc -23- 201014834 目標化合物Ie可按照反應圖5來製備。自市售(4-溴-苯 基)-乙酸乙酯(XXIII)開始,使其與低聚甲醛羥醛縮合,得 到2-(4-溴-苯基)-丙烯酸乙酯(XXIV)。使不同胺與XXIV邁 克爾加成(Michael addition)得到化合物XXV,隨後在鹼性 條件下使其水解為酸XXVI。使不同苯胺與化合物XXVI偶 合得到苯胺化物XXVII。使化合物XXVII與(2-丙烯醯基胺 基-苯基)-胺基曱酸第三丁基酯發生Heck反應,得到化合物 XXVIII,然後在酸性條件下使其去保護,得到目標化合物 Ie。 參 (4-溴-苯基)-乙酸乙酯(XXIII)市面購得。 2-(4-溴-苯基)-丙烯酸乙酯(XXIV)可藉由XXIII與低聚甲 醛之羥醛縮合來製備。該反應通常係藉由使XXIV與存於 二曱基曱醯胺中之低聚曱醛及相轉移觸媒(例如四丁基氣 化銨)混合利用適宜鹼(例如碳酸鉀)來實施。然後將反應在 60-70攝氏度下加熱數小時。 化合物XXV可藉由不同胺與XXIV之邁克爾加成來製 備。該反應通常係藉由下述方式來實施:使胺與XXV在四 ® 氫呋喃中在〇攝氏度下加成,然後在室溫下加熱1至2小 時。 化合物XXVI可藉由使化合物XXV鹼性水解來製備。該 反應通常係藉由將化合物XXV與適宜鹼(例如氫氧化鋰水 溶液或氫氧化鈉水溶液)在甲醇中在40攝氏度下加熱數小 時來實施。 苯胺化物化合物XXVII可藉由不同苯胺與化合物XXVI之 142666.doc • 24- 201014834 偶合來製備。該反應通常係利用標準肽偶合劑(例如EDCI 及HOBt、Pybrop及二異丙基乙基胺、或HATU及三乙胺)在 適宜惰性溶劑(例如二氯曱烷或二甲基曱醯胺或其混合物) 中在室溫下實施數小時。 化合物XXVIII可藉由化合物XXVI與(2-丙烯醯基胺基-苯 基)-胺基曱酸第三丁基酯之Heck反應來製備。該反應通常 係在惰性氣氛下在具有三乙胺、三-鄰-曱苯基-膦、 ?(12(此3)3之脫氧二甲基曱醯胺中在80-100攝氏度下實施約 φ 4至1 0小時。 目標化合物Ie係藉由使化合物XXVIII酸性去保護來獲 得。該反應通常係在氣化氫甲醇中在室溫下實施數小時。 上文中所揭示反應圖1至5中任一圖之每一方法皆可形成 本發明之尤佳實施例。 D.關鍵結構單元之合成途徑 (五)-2-{4-[2-(2-第三丁氧基羰基胺基-笨基胺基甲醯基)-乙烯基]-苯基}-4-(第三丁基-二甲基-矽烷氧基)-丁酸乙酯 之合成(反應圖6)
142666.doc -25- 201014834 關鍵結構單元(五)-2-{4-[2-(2-第三丁氧基羰基胺基_苯基 胺基甲醯基)-乙烯基]-笨基}-4-(第三丁基_二甲基_矽烧氧 基)-丁酸乙酯(II)可按照反應圖6來製備。自市售2_溴_乙醇 (XXIX)開始,用第三丁基二甲基甲矽烷基氣實施曱矽烷基 化’得到(2-漠-乙氧基)·第三丁基-二甲基·矽烷(χχχ)。用 XXX對(4-溴-苯基)-乙酸乙酯烯醇卸實施烧基化,得到2_ (4-溴·苯基)-4-(第三丁基-二曱基_矽烷氧基)_丁酸乙酯 (XXXI)。使XXXI與(2-丙浠醯基胺基-苯基)_胺基甲酸第三 丁基酯發生Heck反應,得到關鍵結構單元2_{4-[2-(2-第三 丁氧基幾基胺基-本基胺基甲酿基)-乙烤基]-苯基}-4-經基_ 丁酸乙酯(II)。 2_溴-乙醇(XXIX)市面購得。 (2-溴·乙氧基)-第三丁基-二甲基-矽烷(XXX)可藉由用第 三丁基二甲基甲矽烷基氣對XXIX實施甲矽烷基化來製 備。該反應通常係藉由下述方式來實施:將第三丁基二甲 基甲矽烷基氣添加至存於二甲基甲醯胺中之XXIX與咪唑 之溶液中並在室溫下保持12小時。 2-(4-溴-苯基)-4-(第三丁基-二甲基-矽烷氧基)-丁酸乙酯 (XXXI)係藉由用XXX對相應烯醇鉀實施烷基化來製備。該 反應通常係藉由下述方式來實施:在二曱基曱醯胺中於室 溫下用第三丁醇鉀將(4-溴-苯基)-乙酸乙酯去質子化1小 時,然後將反應冷卻至0攝氏度並緩慢添加XXX,隨後於 室溫下攪拌12小時。 關鍵結構單元(五)-2-{4-[2-(2-第三丁氧基羰基胺基-苯基 142666.doc -26- 201014834 胺基甲醯基)-乙烯基]-苯基}-4·(第三丁基-二甲基-矽烷氧 基)-丁酸乙酯(II)可藉由XXXI與(2-丙烯醯基胺基-苯基)_胺 基甲酸第三丁基酯之Heck反應來製備。該反應通常係在惰 性氣氛下在具有三乙胺、三-鄰-甲苯基-膦、Pd2(dba)3之脫 氧二曱基甲醯胺中在90-110攝氏度下實施約4至1〇小時。 ⑹-2-{4-[2-(2-第三丁氧基幾基胺基-苯基胺基甲醯基)_ 乙烯基]-苯基}-5-氣-戊酸曱酯之合成(反應圖7)
關鍵結構單元(五)-2-{4-[2-(2-第三丁氧基羰基胺基_苯基 反應圖7 φ 胺基曱醯基)_乙烯基]-苯基卜5_氣-戊酸甲酯(VIII)可按照反 應圖7來製備。自市售4-(溴-苯基)_乙腈(χνι)開始,用強 鹼去質子化,隨後用1-溴-3-氣丙烷實施烷基化,得到2_(4_
(XXXIV),使其與(2-丙烯醯基胺基·苯基)胺基甲酸第三丁 基酯發生Heck反應,得到關鍵結構單元(£) 2_{4_[2_(2•第 142666.doc -27· 201014834 三丁氧基幾基胺基-苯基胺基曱醯基)_乙稀基]-苯基卜5-氣_ 戊酸曱酯(VIII)。 4-(溴-笨基)-乙腈(XVI)市面購得。 2-(4-演-苯基)-5-氣-戊腈(XXXII)可藉由下述方式來製 備:用強鹼將XVI去質子化,隨後用i_溴_3_氣丙烷實施烷 基化。該反應通常係藉由下述方式來實施:將XVI溶於二 甲基甲醯胺與曱苯之混合物中,使其與氫化鈉在〇攝氏度 下反應1小時,且然後在10度下添加1-溴_3_氣丙烷並保持 30分鐘。 _ 2-(4·溴-苯基)-5-氣-戊酸(XXXIII)可藉由使χχχΠ酸性水 解來製備。該反應係藉由使XXXII在濃硫酸、冰乙酸及水 之混合物中回流12小時來實施。 2-(4-溴-苯基)-5-氯-戊酸甲酯(χχχΐν)可藉由在甲醇中 用亞硫醯氣對XXXIII實施親核醯基取代來製備。該反應通 常係藉由下述方式來實施:在0攝氏度下將χχχΐΠ溶於甲 醇中,隨後添加亞硫醯氣並回流5小時。 關鍵結構單元(五)-2- {4-[2-(2-第三丁氧基羰基胺基-苯基 © 胺基甲醯基)-乙烯基]-苯基}-5-氣-戊酸甲酯(VIII)可藉由 XXXIV與(2_丙稀醯基胺基-苯基)-胺基甲酸第三丁基酯之 Heck反應來製備。該反應通常係在具有三乙胺、三_鄰-曱 苯基-膦、Pd2(dba)3之脫氧二甲基曱酿胺中在90-11〇攝氏度 下在惰性氣氛下實施約4至8小時。 2-(5-漠·°比唆-2-基)-5 -氣-戊酸之合成(反應圖8) 142666.doc • 28- 201014834 ο ο
反應圖8
關鍵結構單元2-(5-溴-吡啶-2-基)-5-氯-戊酸(XII)可按照 反應圖8來製備。自市售5-溴-2-碘-吡啶(XXXV)開始,使 其與丙二酸二乙酯發生酮催化反應,得到2-(5-溴-吡啶-2-基)-丙二酸二乙酯(XXXVI)。在鹼性條件下水解並脫羧, 得到(5-溴-吡啶-2-基)-乙酸(XXXVII),隨後可在甲醇中用 亞硫醯氣對其實施親核醯基取代,得到(5-溴-吡啶-2-基)-乙酸曱酯(XXXVIII)。用強鹼使XXXVIII去質子化,隨後 用1-溴-3-氯丙烷實施烷基化,得到2-(5-溴-吡啶-2-基)-5-氣-戊酸曱酯(XXXIX),然後可在鹼性水溶液條件下使其水 解,得到關鍵結構單元2-(5-溴-吡啶-2-基)-5-氯-戊酸 (XII)。 5-溴-2-碘-吡啶(XXXV)市面購得 2-(5-溴-吡啶-2-基)-丙二酸二乙酯(XXXVI)係藉由用丙 二酸二乙基酯酮實施催化反應來製備。該反應通常係藉由 下述方式來實施:使XXXV與丙二酸二乙基酯、碘化亞 銅、碳酸鉋及吡啶-2-曱酸於1,4-二噁烷中混合並在氮氣氛 及70攝氏度下加熱24小時。 142666.doc -29- 201014834 (5-溴·吡啶-2-基)-乙酸(XXXVII)係藉由使XXXVI鹼性水 解並脫羧來製備。該反應通常係藉由下述方式來實施:將 XXXVII溶於甲醇中並添加氫氧化納水溶液,隨後在室溫 下反應3至4小時。 (5-溴-吡啶-2-基)-乙酸甲酯(XXXVIII)可藉由在曱醇中用 亞硫醯氣對XXXVII實施親核醯基取代來製備。該反應通 常係藉由下述方式來實施:在0攝氏度下將XXXVII溶解於 甲醇中,隨後添加亞硫醯氯並在室溫下反應3小時。 2-(5-溴-吡啶-2-基)-5-氣-戊酸甲酯(XXXIX)可藉由下述 方式來製備:用強鹼將XXXVIII去質子化,隨後用1-溴-3-氣丙烷實施烷基化。該反應通常係藉由下述方式來實施: 將XXXVIII溶於二甲基甲醯胺中,使其與氫化鈉在0攝氏 度下反應1小時,且然後在10度下添加1-溴-3-氣丙烷並保 持30分鐘。 關鍵結構單元2-(5-溴-吼啶-2·基)-5-氣-戊酸(XII)可藉由 使XXXIX鹼性水解來製備。該反應通常係藉由下述方式來 實施:將XXXIX溶於四氫吱喃、甲醇及氫氧化裡水溶液之 混合物中,並於室溫下反應16小時。 上文中所提及反應圖6至8之用於獲得關鍵結構單元之每 一方法皆為本發明之又一實施例。 實例 以下實例係藉由上文反應圖中所概述之一般方法來製 備。該等實例意欲閣釋本發明之含義,而決不應代表受限 於本發明之含義: 142666.doc -30- 201014834 實例1
(幻-2-{4-【2-(2-第三丁氧基羰基胺基-苯基雎基甲醢基)-6烯基】·苯基}-4-(第三丁基-二甲基-矽烷氧基)-丁酸》向 (£)-2-{4-[2-(2-第三丁氧基羰基胺基-苯基胺基曱醯基)-乙 ❹ 烯基]-苯基}-4-(第三丁基-二甲基-矽烷氧基)· 丁酸乙酯 (2.63 g,4.52 mmol)存於MeOH/H2O(30 mL/10 mL)中之溶液 中添加Li〇H’H2〇(556 mg, 13.56 mmol),將該混合物於室 溫下攪拌約5 h,且然後蒸發以除去大部分MeOH。用濃 HC1將水性層酸化至pH 5-6。用乙酸乙酯(3x30 mL)萃取經 酸化之水性層。將合併的有機層用鹽水洗滌,用Na2S04乾 燥、過濾並蒸發,獲得2.0 g(80%)黃色固體產物。MS :計 算值係555 (MH+),實驗值係555 (MH+)。 ⑩ 實例2
(五)-【2·(3-{4-[1·(4-溴-苯基胺基甲醮基)_3_(第三丁基-二 甲基-梦烧氧基)-丙基】-苯基}_丙烯醮基胲基)_苯基】_胲基甲 酸第三丁基酶。向(五)_2·{4_[2_(2_第三丁氧基羰基胺基_苯 142666.doc •31- 201014834 基胺基甲醯基)-乙烯基]-苯基}-4-(第三丁基-二甲基-石夕貌 氧基)-丁酸(2.5 g,4.52 mmol)、EDCI(1.2 g, 4_97 mmol)及 HOBt(671 mg,4.97 mol)存於 CH2C12(50 mL)中之溶液中添 加4-漠-苯基胺(786 mg,4.57 mmol)。將該混合物於室溫下 攪拌過夜且然後用CH2C12(50 mL)稀释,用飽和NaHC03水 溶液、水及鹽水洗滌’用NajO4乾燥並蒸發,獲得黃色殘 餘物。MS :計算值係708 (MH+),實驗值係708 (MH+)。 實例3
(五)-[2-(3-{4-[1-(4-溴-苯基雎基甲醢基)_3_羥基·丙基]_笨 基}_丙烯醮基按基)-苯基]-胺基甲酸第三丁基酯·向(五H2 (3-{4-[l-(4-溴-苯基胺基曱醯基)_3_(第三丁基-二甲基_石夕燒 氧基)-丙基]-笨基}-丙烯醯基胺基苯基]-胺基甲酸第三丁 基酯(1.6 g,2.26 mmol)存於THF(40 mL)中之溶液中添加四 丁基二氫三氟化敍(1.36 g,4.52 mmol)。將於室溫下該混 合物攪拌過夜且然後蒸發以除去THF。將混合物溶於水中 並用乙酸乙酯(3x30 mL)萃取。將合併的有機層用鹽水洗 滌,用NaJO4乾燥、過濾並蒸發◊藉由管柱層析 (CH2Cl2:EtOAc=10:l)來純化粗產物,得到黃色固體產物。 MS :計算值係594 (MH+),實驗值係594 (MH+)。 實例4 142666.doc •32- 201014834
(五)-甲磺酸3-(4-溴-苯基胺基甲醢基)_3-{4-[2-(2-第三丁 氧基叛基胺基-苯基胺基甲醯基)-己烯基】-苯基卜丙基篇。 於A氣氛下向已冷卻至〇攝氏度之(五)溴苯 基胺基甲醯基)-3-羥基-丙基]-苯基卜丙烯醯基胺基)_苯基]_ 胺基甲酸第三丁基酯(200 mg,0.337 mmol)及 DIPEA(81.6 mg,0.674 mmol)存於CH2C12(10 mL)中之溶液中滴加曱續 醯氣(76·8 mg,0.674 mmol)。於〇攝氏度下攪拌該反應直至 根據TLC起始材料耗盡為止(約1小時)。將混合物用cjj2c12 (10 mL)稀釋並用水(1〇 mL)及鹽水(1〇 mL)洗滌,用Na2S04 乾燥、過濾並於真空中蒸發,獲得226 mg(定量產率)淡黃 色固體,該固體未經進一步純化即使用。MS :計算值係 672 (MH+),實驗值係 672 (MH+)。 實例5
❹ (五)-[2-(3-{4_[1-(4-溴-苯基胺基甲醢基)_3_({is,4S}-2-氧 雜-5-氮雜-二環[2.2.1]庚-5-基)_丙基】-苯基卜丙烯醢基胺 基)-苯基]-脒基甲酸第三丁基酯》向(五)-甲磺酸3-(4-溴-苯 基胺基甲醯基)-3-{4-[2-(2-第三丁氧基羰基胺基-苯基胺基 甲醯基)-乙稀基]-苯基}-丙基醋(226 mg, 0.33 7 mmol)及 142666.doc -33- 201014834 DIPEA(81.6 mg,0.674 mmol)存於 CH2C12(10 mL)中之溶液 中添加(IS,4S)-2-氧雜-5-氮雜·二環[2.2.1]庚烷(430 mg, 1·685 mmol)。將反應於室溫下攪拌過夜並用ch2C12(10 mL)稀釋。將混合物用水(1() mL)及鹽水(1〇 mL)洗滌,用 NazSO4乾燥’過濾並在真空中蒸發,獲得淡黃色固體,該 固體未經進一步純化即使用。MS :計算值係675 (MH+), 實驗值係675 (MH+)。 實例6
2-{4-【(E)-2_(2-胺基-苯基胺基甲醢基)_乙烯基卜苯基卜N_ (4-溴-苯基)-4_(18,48)-2-氧離-5-氪離-二環[2.2.1】庚-5-基- 丁睡脒。將存於甲醇中之鹽酸(125]^,5 1111〇添加至(五)- [2-(3-{4-[1-(4-溴-苯基胺基曱醯基)_3_({1848}_2-氧雜-5-氮雜-二環[2.2.1]庚-5-基)-丙基]•笨基卜丙烯醯基胺基)_苯 基]-胺基曱酸第三丁基酯殘餘物中,將該混合物槐拌約4 h,且然後將NaHC〇3添加至反應系統中。濾出固體後,藉 由製備型HPLC來純化粗製混合物,獲得淡黃色固體。 MS :計算值係575 (MH+),實驗值係575 (MH+)。咕NMR (^6-DMSO, 400MHz), 10.25 (d, 1H, J=8.8 Hz), 9.40 (s, 1H), 7.59-7.45 (寬m,9H), 7.39 (d,1H, *7=8.0 Hz), 6.94-6.85 (m, 2H), 6.75 (d, 1H, /=8.0 Hz), 6.58 (t, 1H, 7=8.0 Hz), 4.95 (s, 142666.doc •34- 201014834 1H)’ 4.31 (s,1H),3.85-3.78 (寬 m,2H),3.47-3.42 (寬 m, 2H)’ 2.78 (寬 s,1H),2.43-2.20 (寬 m, 3H),1.78-1.54 (寬 m, 3H)。 下表中所述化合物係藉由與上述合成方法類似之方法來 製備,只是使用合適起始材料。 表1 實例# 結構 MW MS (MH+) 計算值 MS (MH+) 實驗值 6-2 T 0 563.50 563 563 6-3 αΗ 577.53 577 577 表2 實例# NMR數據 6-2 *H NMR (^-MeOD, 400MHz), 7.67 (d, 1H, ^15.6 Hz), 7.62 (d, 2H, 7=8.4 Hz), 7.53-7.49 (m, 4H), 7.44 (d, 2H, 7=8.4 Hz), 7.22 (d, 1H, 7=7.6 Hz), 7.06 (t, 1H, /=7.6 Hz), 6.89 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=15.6 Hz), 6.76 (t, 1H, J=7.6 Hz), 4.62 (s,1H), 3.77 (寬s,1H),3.67 (t, 3H,J=4.8 Hz), 3·37 (s,1H), 2.47-2.41 (寬m, 6H),1.97-1.95 (寬m,1H)。 6-3 *H NMR (^-DMSO, 400MHz), 10.27 (s, 1H), 9.42 (s, 1H), 7.59-7.56 (m, 4H), 7.52 (d, 1H, ^=15.6 Hz), 7.47-7.44 (m, 4H), 7.33 (d, 1H, J=7.6 Hz), 6.92 (t, 1H, J-8.0 Hz), 6.87 (d, 1H, 7=15.6 Hz), 6.75 (d, 1H, J-8.0 Hz), 6.58 (t, 1H, J=7.6 Hz), 4.95 (s, 2H), 4.57 (s, 1H), 3.76 (d, 1H, J=8.0 Hz), 2.78 (t, 1H, J=10.6 Hz), 2.65-2.57 (m, 142666.doc •35· 201014834 1H),2.25 (寬s,3H),1.82-1.68 (寬m,4H),1.56 (ts,lH),1.37-1.34(m,lH),l.〇5- 1.02 (m,2H) « 實例7
(五)-2-{4-[2-(-第三丁氧基羰基胺基-苯基胺基甲醢基)·己 缚基】-苯基}-5-氯-戍酸❶向(五)-2-{ 4-[2-(2-第三丁氧基幾基 胺基-苯基胺基甲醯基)-乙烯基]-苯基}-5-氣-戊酸甲酯(48 7 mg,10 mmol)存於Me0H/H20(4:l)(2 mL)中之溶液中添加 LiOH(24 mg,100 mmol)。將該溶液於室溫下攪拌5 h後, 用2 N HC1將溶液中和至pH 5-6。將混合物於減壓下蒸發 至乾燥,然後添加EtOAc( 10 mL)。將有機層用鹽水洗滌, 用Na2S〇4乾燥,過渡並蒸發,未經進一步純化即獲得黃色 固體產物。MS :計算值係473 (MH+),實驗值係473 (MH+)。NMR (400MHz,DMSO-d6) 12.50 〇,1H), 9.73 (s, 1H), 8.50 (s, 1H), 6.89-7.64 (m, 10H), 3.61 (m, 3H), 1.55-2.10 (m,4H),1.46 (s,9H)。 實例8
(£>【2-(3-{4-[1-(4-淡-苯基胺基甲醢基)-4_氣_丁基】_苯 基}-丙烯醮基肢基)-苯基】-肢基甲酸第三丁基酯·向(五)_2_ {4-[2-(-第三丁氧基羰基胺基-笨基胺基甲醯基)_乙烯基]_苯 142666.doc -36 - 201014834 基}-5-氯·戊酸(2.37 g, 5 mmol)、DIPEA(1.21 g,10 mmol) 及 Pybrop(4.66 g,1 〇 mmol)存於 CH2C12(30 mL)中之溶液中 添加4-溴·苯基胺(1.29 g, 7.5 mmol)。將該混合物於室溫下 攪拌過夜且然後蒸發。將混合物重新溶於40 mL EtOAc中 並用 2 N HC1(20 mLx3)、鹽水、5% NaHCO3(20 mLx3)、 鹽水洗滌’用Na2S04乾燥,過濾並蒸發。藉由在矽膠上利 . 用己烷/EtOAc實施管柱層析來純化殘餘物,得到白色固 體。MS :計算值係626 (MH+),實驗值係626 (MH+)。 ❹ 實例9
2-{4-【(Ε)-2-(2-胺基-苯基坡基甲醢基)-己烯基】-苯基}_5_ 嗎啉-4_基-戊酸(4_溴-苯基)-醢胲。向(£)-[2-(3-{4-[1-(4-溴-苯基胺基曱醯基)-4-氣-丁基]-苯基}-丙烯醯基胺基)_苯 基]-胺基甲酸第三丁基酯(187.5 mg,0.3 mmol)存於DMF(3 mL)中之溶液中添加嗎淋(261 mg,3 mmol)。然後將該溶液 於80攝氏度下攪拌過夜。將1.25 M HCl/MeOH(4 mL)溶液 添加至殘餘物中,將該溶液於周圍溫度下攪拌4 h。反應 後,用固體NaHC03中和溶液。藉由製備型HPLC來獲得最 終產物。MS :計算值係577 (MH+),實驗值係577 (MH+)。 !H NMR (J6-DMSO, 400MHz), 10.33 (s,lH),9.57 (寬 s, 2H), 7.61 (d, 1H, 7=15.6 Hz), 7.59-7.54 (m, 4H), 7.49-7.46 (m, 4H), 7.36 (d, 1H, 7=7.6 Hz), 6.99 (t, 1H, /=7.6 Hz), 142666.doc •37· 201014834 6.91-6.84 (m, 2H),6.71 (寬 s,1Η), 3·96 (d,2H, /=12.0 Hz,), 3.75 (t,1H,·7=7·2 Hz,), 3.62 (t,2H,《7=12.0 Hz), 3.40 (寬 s, 2H), 3.14 (t, 2H,J=7.6 Hz), 3·03 (寬 s,2H),2.09-2.04 (m, 1H),1.78-1.71 (m, 1H),1.67-1.57 (m, 2H)。 下表中所述化合物係藉由與上述合成方法類似之方法來 製備,只是使用合適起始材料。 表3 實例# 結構 MW MS (ΜΗ+) 計算值 MS (ΜΗ+)實驗值 9-2 YH IS? r η 589.54 589 589 9-3 、〇 575.55 575 575 9-4 V〇 552.72 553 553 9-5 V ΟΗ 591.55 591 591 9-6 545.09 545 545 142666.doc -38- 201014834
9-7 '〇 561.53 561 561 9-8 540.71 541 541 9-9 OH 554.74 555 555 9-10 $ °rNH r H αΝτ^ 578.64 579 579 9-11 σ’ 550.63 551 551 9-12 550.71 551 551 9-13 528.63 529 529 142666.doc -39- 201014834 9-14 580.66 581 581 9-15 $ 丫H 广? r η ητ^Ν^ 566.63 567 567 9-16 o’ 564.66 565 565 9-17 a: 577.53 577 577 9-18 V〇 535.65 536 536 9-19 9:/^ospBr 591.55 591 591 表4 實例# NMR數據 9-2 屮 NMR (办-DMSO, 400MHz),10.28 (s, 1H),9.42 (s, 1H),7.60-7.56 (寬m,4H), 7.52 (d, 1H, J=15.6 Hz), 7.48-7.41 (m, 4H), 7.34 (d, 1H, J=7.6 Hz), 6.93 (d, 1H, 142666.doc -40- 201014834
J=8.0 Hz), 6.88 (d, 1H, J=15.6 Hz), 6.75 (d, 1H, J=8.0 Hz), 6.58 (t, 1H, 7=8.0 Hz), 4.95 (s, 2H), 4.28 (s, 1H), 3.79 (dd, 1H, J=2.8, 7.6 Hz), 3.71 (t, 1H, 7=7.6 Hz), 3.45 (d, 1H, J=6.8 Hz), 3.38 (d, 1H, /=5.6 Hz), 2.71 (d, 1H, J=9.6 Hz), 2.29 (dd, 1H, •7=2.8, 9.6 Hz), 2.10-2.05 (寬m,1H), 1.78-1.73 (寬m, 1H),1_67 (d,1H,J=9.6 Hz), 1.53 (d, 1H,《7=9.6 Hz), 1.35-1.30 (宽m,2H)。 9-3 *H NMR (JrMeOD, 400MHz), 7.76 (d, 1H, J=15.6 Hz), 7.65 (d, 2H, J=8.4 Hz), 7.54- 7.52 (m,4H),7.45 (d, 2H, <7=8.4 Hz),7.35-7.25 (寬m, 4H),6.89 (d, 1H, J=15.6 Hz), 3.78 (dd, 1H, J^6.0, 8.4 Hz), 3.51 (d, 2H, J=12.0 Hz), 3.13 (t, 2H, J=7.6 Hz),2.90 (t,2H, «7=12.0 Hz),2.22-2.19 (寬m,1H), 1.96-1.68 (寬m,8H), 1.55- 1.49(寬m, 1H)。 9-4 'H NMR (rf6-DMSO, 400MHz), 7.71 (d, 1H, J=15.6 Hz), 7.64 (d, 2H, J=1.6 Hz), 7.54 (d, 2H, 7=8.0 Hz), 7.48 (d, 2H, J=%A Hz), 7.25 (d, 1H, J=7.6 Hz), 7.21 (d, 2H, J=8.4 Hz), 7.10 (t, 1H, J=7.6 Hz), 6.94-6.86 (m, 2H), 6.79 (t, 1H, ^7.6 Hz), 4.43 (s, 1H), 4.04 (d, 1H, /=7.6 Hz), 3.75 (t, 1H, J=7.6 Hz), 3.64-3.60 (m, 2H), 2.96-2.84 (寬m,2H),2.81-2.63 (寬m, 2H),2.60 (d, 1H,《7=10.6 Hz), 2.27-2.15 (寬m, 1H), 1.91 (d, 2H, J=9.9 Hz), 1.78 (d, 1H, J=9.9 Hz), 1.66-1.53 2H), 1.27 (s, 3H), 1.25 (s,3H)。 9-5 巾 NMR (4DMSO, 400MHz),10.23 (寬s,1H),9.38 (寬s,1H),7.59-7.54 (m., 5H), 7.50-7.44 (m, 4H), 7.34 (d, 1H, J=1.6 Hz), 6.93 (d, 1H, J=7.2 Hz), 6.87 (d, 1H, ^=15.6 Hz), 6.76 (d, 1H, J=7.2 Hz), 6.58 (t, 1H, 3=7.6 Hz), 4.93 (s, 2H), 4.53 (宽s,1H),3_71 (t,1H,《7=7.6 Hz), 2.76 (d,1H, /=9.6 Hz),2.57-2.54 (m, 1H),2.27 (d,2H,/=5.2 Hz),2.06-1.98 (寬m,1H), 1.77-1.38 (寬m,5H), 1.37-1.1.26 (寬m, 3H),1.07-1.00 (m,1H)。 9-6 *H NMR (^MeOD, 400MHz), 7.78 (d, 1H, J=15.6 Hz), 7.66 (d, 2H, /=7.6 Hz), 7.59-7.52 (m, 4H), 7.39(s, 4H), 7.30 (d, 2H, 7=8.8 Hz), 6.89 (d, 1H, J=15.6 Hz), 4.68 (寬s,1H),4·40 (寬s, 1H),3.98 (寬s,1H),3.85-3.77 (m, 2H),3.64 (寬s,1H), 3.35-3.33 (s,1H),3.18-3.16 (m, 2H), 2.31-2.15 (寬m, 3H), 1.97-1.76 (m,3H)。 9-7 !H NMR (办-DMSO, 400MHz),10.37 (s,1H),9.61 (s,1H),9.47 (寬3,111),7.63-7.57 (m,4H),7.54-7.46 (m,5H),7.36 (d,1H,*7=8.0 Hz),6·99 (t,1H,/=8.0 Hz), 6.91-6.85 (m, 2H), 6.72 (t, 1H, J=72 Hz), 3.75 (t, 1H, J=7.2 Hz), 3.51 (^s, 2H), 3.17-3.13 (m, 2H), 2.95 (宽s,2H),2,10-2.08 (m,1H),1.99 (寬s, 2H), 1.85-1.75 (m, 142666.doc -41 · 201014834 3H),1.64-1.58 (m,2H)。 9-8 *H NMR (^-MeOD, 400MHz), 7.67 (d, 1H, J=15.6 Hz), 7.62 (d, 2H, J=8.0 Hz), 7.51 (d, 2H, 7=8.0 Hz), 7.44 (d, 2H, 7=8.0 Hz), 7.21 (d, 1H, 7=8.0 Hz), 7.18 (d, 2H, J=8.8 Hz), 7.06 (d, 1H, J=7.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 6.86 (d, 1H, J=15.6 Hz), 6.76 (t, 1H, J=7.6 Hz), 3.72-3.70 (m, 5 H), 2.89-2.86 (m, 1H), 2.55-2.48 (m, 6H), 2.17 (寬s,1H), 1.84 (寬s,1H),1.60 (寬s, 2H),1.24 (s, 3 H), 1.22 (s,3 H)。 9-9 !H NMR (^-MeOD, 400MHz), 7.65 (d, 1H, J=15.6 Hz), 7.58 (d, 2H, 7=8.0 Hz), 7.48 (d, 2H, J=8.0 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.20 (d, 1H, /=7.6 Hz), 7.15 (d, 2H, J=8.4 Hz), 7.04 (t, 1H, J=7.6 Hz), 6.87 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=15.6 Hz), 6.74 (d, 1H, J=1.6 Hz), 3.72-3.65 (m, 2H), 2.91-2.81 (m, 2H), 2.74-2.70 (m, 1H), 2.49-2.45 (m, 2H), 2.16-2.05 (%m, 3H), 1.96-1.72 (5tm, 3H), 1.64-1.52 (m, 3H), 1.21 (s,3H), 1.20 (s, 3H), 1.18 (寬s,1H)。 9-10 *H NMR («MSO, 400MHz), 10.47 (s, 1H), 9.37 (s, 1H), 7.81 (d, 2H, *^8.4 Hz), 7.66 (d, 2H, ^8.4 Hz), 7.59 (d, 2H, 7=8.0 Hz), 7.53 (d, 1H, J=15.6 Hz), 7.46 (d, 2H, J=8.0 Hz), 7.34 (d, 1H, J=7.6 Hz), 6.93 (d, 1H, /=8.0 Hz), 6.88 (d, 1H, ^=15.6 Hz), 6.76 (d, 1H, J=8.0 Hz), 6.58 (t, 1H, 7=7.6 Hz), 4.93 (s, 2H), 4.29 (s, 1H), 3.81-3.74 (m, 2H), 3.46 (d, 1H, J=12 Hz), 3.39 (d, 1H, J=5.6 Hz), 2.72 (d, 1H, ^=9.6 Hz), 2.31 (d, 1H, J=9.6 Hz), 2.12-2.07 (m, 1H), 1.81-1.76 (m, 1H), 1.68 (d, 1H, J=9_6 Hz), 1.53 (d, 1H, J=9.6 Hz), 1.37-1.32 (m,2H) » 9-11 NMR (山-DMSO, 400MHz),10.61 (s,1H), 9.64 (s,1H),9.48 (寬s,1H),7.82 (d, 2H, J=8.4 Hz), 7.68 (d, 2H, ^=8.4 Hz), 7.63 (d, 2H, J=8.0 Hz), 7.56 (d, 1H, J=15.6 Hz), 7.48 (d, 2H, J=8.0 Hz), 7.36 (d, 1H, J=8.0 Hz), 7.00 (t, 1H, J=7.6 Hz), 6.91-6.87 (m, 2H), 6.75-6.74 (m, 1H), 3.82-3.78 (m, 2H), 3.18-3.16 (m, 3H), 2.96 (%s, 2H),2.12-2.10 (叫 1H),1_99 (寬s,2H),1.85-1.75 (m,3H) 1.61-1.59 (m,2H)。
實例ίο
2-(5-溴-吡啶-2-基)-5-氯-戊酸(4-溴-苯基)-醯肢。向2-(5- 142666.doc • 42- 201014834 >臭-°比咬-2-基)-5-氣-戊酸(1 9 g,6.5 mmol)、Et3N(3.6 mL, 26 mmol)及 pybrop (6 g,13 mm〇l)存於 CH2C12(30 mL)中之 溶液中添加4·溴-苯基胺(1.45 g, 8.45 mmol)。將該混合物 於室溫下授拌過夜且然後蒸發。將混合物重新溶於
EtOAc(40 mL)中並用 2 N HC1(20 mL><3)、鹽水、5% NaHCO3(20 mLx3)、鹽水洗滌,用Na2S04乾燥,過濾並蒸 發。藉由在矽膠上利用己烷/Et〇Ac實施管柱層析來純化殘 餘物’得到白色固體(丨63g,兩步產率為56〇/〇)。MS :計算 值係 444 (MH+),實驗值係 444 (MH+)。4 NMR (400 MHz,CDCld) 9.65 (寬 s,1H),8.72 (d, 1H, «7=2.0 Hz),8.06 (d, 1H, J=8.4 Hz), 7.53-7.41 (m, 4H), 4.18-4.08 (m, 1H), 3.66-3.54 (m, 2H), 2.45-2.35 (m, 1H), 2.21-2.11 (m, 1H), 1.98-1.87 (m,1H),1.83-1.72 (m,1H)。 實例11
2-(5•淡-吡啶 _2·基)-5-({lS,4S}-2·氧雜 _5- |L 雜·二環 【2.2.1]庚-5-基)_戍酸(4-淡-苯基)-速按。向2-(5-;臭-0比咬-2-基)-5-氯-戊酸(4-漠-苯基)-醢胺(1.62 g, 3.63 mmol)、Et3N (2 mL,14.52 mmol)存於DMF(20 mL)中之混合物中添加 (lS,4S)-2-氧雜-5-氮雜-二環[2.2.1]庚烷(1.08 g,10.89 mmol)。然後將該溶液於80攝氏度下攪拌8 h。將混合物重 新溶於EtOAc(60 mL)中並用水(20 mL><3)、鹽水洗滌,用 142666.doc •43- 201014834
Na2S04乾燥,過濾並蒸發。藉由管柱層析來純化殘餘物, 得到白色固體(1.28 g,69%)。MS :計算值係508 (MH+), 實驗值係508 (MH+)。 實例12
Φ (£>【2-(3-{6-[1-(4-溴-苯基胺基甲醢基)_4-({lS,4S}-2-氧 雜-5-氮雜-二環[2.2.1】庚-5·基)-丁基卜吡啶-3-基}-丙烯醢基 胺基)-苯基]-胺基甲酸第三丁基酯。將2-(5-溴-吡啶-2-基)-5-(2-氧雜-5-氮雜-二環[2.2.1]庚-5-基)-戊酸(4-溴-苯基)-醯 胺(1.07 g,2.1 mmol)、(2-丙烯醯基胺基-苯基)-胺基甲酸丁 基醋(578 mg, 2.205 mmol)、Pd2(dba)3(385 mg, 0.42 mmol)、三-鄰-甲苯基膦(256 mg, 0.84 mmol)及三乙胺(636 mg,6·3 mmol)於DMF(20 mL)中之混合物於80攝氏度及N2 下攪拌15 h。將反應混合物用EtOAc(80 mL)稀釋,然後用 水(20 mLx2)、鹽水(20 mL)及Na2S04洗滌。蒸發溶液。殘 餘產物未經進一步純化即直接使用。MS :計算值係690 (MH+),實驗值係 690 (MH+)。 實例13
142666.doc • 44· 201014834 (五)-2-{5-[2-(2-鞍基-苯基胺基甲醢基)·乙烯基】-吻啶2_ 基}-5-({lS,4S}-2-氡雜_5_氮雜_二環丨2 2 j】庚·5基)戊酸(4_ 溴-苯基)-醢坡。將存於甲醇中之鹽酸(125 M,5 mL)添加 至(五)-[2-(3-{6-[1-(4-溴·苯基胺基曱醯基)4_({1S,4S卜2_氧 雜_5_氮雜-二環t1.1.1]庚-5-基)-丁基]-吼啶_3_基卜丙烯醯基 胺基)-苯基]•胺基甲酸第三丁基酯殘餘物中,將混合物於 室溫下攪拌約12 h,且然後將NaHC〇3添加至反應系統 中。濾出固體後,藉由製備型HPLC來純化粗製混合物, 獲得白色固體。MS :計算值係59〇 (MH+),實驗值係590 (MH+) H NMR (J^-MeOD, 400MHz), 8.76 (d, 1H, J=l-6 Hz), 8.09 (dd, 1H, J=2.0, 8.0 Hz), 7.70 (d, 1H, /=15.6 Hz), 7.61 (d5 1H, j=8.〇 Hz), 7.57-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.21 (d, in, J=l.6 Hz), 7.10-7.04 (m, 1H), 6.97 (d, 1H, /=15.6 Hz), 6.90 (d, 1H, /=8.0 Hz), 6.77 (t, 1H, /=8.0 Hz), 4.46 (s, 1H), 4.02 (d, 1H, 7=8.4 Hz), 3.95 (t, 1H, ^=7.6 Hz), 3.76 (^Sj 1H), 3.66 (d, 1H, /=7.3 Hz), 2.95 (d, 1H, /=10.6 Hz),2.87 (寬 S,1H), 2.77 (寬 s,2H),2.24 (寬 s,1H), 2·2 (寬 s, 1H),1.95 (d,1H,《7=10.8 Hz), 1.85 (d,1H, J=l〇.8 Hz), 1.63 (寬 s, 2H)。 實例14
-45- 1 -(4·溪·苯基)-3-(1-甲基-六氬峨啶·4·基)_丙腈。於A下 2 142666.doc 201014834 向 NaH(60%,0.44 g,11 mm〇i)分散液存*DMF(6 mL)甲苯 (12 mL)混合物中之懸浮液中添加4_溴苯乙腈(196g,1〇 mmol)。攪拌並於冰上冷卻〗^後,滴加4_氣甲基—卜曱基_ 六氫°比咬(1.48 g,1〇 mm〇i)。將混合物於7〇攝氏度下擾拌2 h,然後添加水並用EtOAc萃取混合物。將有機層乾燥 (MgSCU)並於真空中蒸發,得到油狀殘餘物,該殘餘物未 經進一步純化即使用。MS :計算值係307 (mh+),實驗值 係 307 (MH+)。 實例15
2-(4·溴-苯基)-3-(1-甲基-六氦吡啶基)_丙酸·用4 mL 濃H2S04及水(3 8:28)水解油狀殘餘物2-(4-漠·苯基)-3-(1-甲 基-六氫°比。定-4-基)-丙腈,回流2 h。用Na2C03中和混合 物,然後添加MeOH(20 mL)。濾出固體並用MeOH(3xlO mL)洗滌。蒸發合併的曱醇溶液得到油狀物。MS :計算值 係 326 (MH+),實驗值係 326 (MH+)。 實例16
2-(4-溴-苯基)-3-(1-甲基-六氩吡啶-4-基)-丙酸甲酯》於〇 攝氏度下向2-(4-溴-苯基)-3-(1-甲基-六氫。比啶-4-基)-丙酸 存於MeOH(60 mL)中之溶液中添加SOCl2(2 mL),然後將 142666.doc -46 - 201014834 混合物回流5 h。冷卻後,將溶液於減壓下蒸發至乾燥, 然後添加EtOAc ’將有機層用NaHCCh水溶液洗務,用 MgS〇4乾燥並蒸發,得到油狀物。MS :計算值係34〇 (MH+),實驗值係 340 (MH+)。 實例17 0〜ΝΗ 丫丫1 * η
❿ (Ε)-2-{4-[2-(2-第三丁氧基羰基胺基-苯基联基甲龜基)_ 乙稀基]-苯基}-3-(1-甲基-六氫咬咬-4-基)-丙酸甲磨。將2_ (4-溴·苯基)-3-(1-甲基-六氫《•比唆_4_基)-丙酸甲酯(2.27 g, 6.67 mmol)、(2-丙烯醯基胺基-苯基)_胺基曱酸第三丁基酯 (2 g,7.2 mmol)、Pd2(dba)3(160 mg,0.175 mmol)、三-鄰 _ 甲苯基膦(160 mg,0.526 mmol)及三乙胺(1_6 g,15.8 mmol) 於DMF(12 mL)中之混合物於loo攝氏度及n2下攪拌4小 時。冷卻至室溫後,將混合物倒入飽和NH4C1水溶液中, 並用乙酸乙酯(80 mL)萃取。將有機層用鹽水洗滌,經 NasSO4乾燥,過濾’於真空中濃縮並藉由急驟管柱層析來 純化,獲得淡黃色固體(1.74 g, 50%)。MS :計算值係522 (MH+),實驗值係 522 (MH+)。 實例18
142666.doc •47- 201014834 (五)-2-{4-【2-(2-第三丁氧基痕基坡基-苯基肢基甲建基)_ 2*缚基】苯基}-3-(1-甲基-六氫nfc唆-4-基)-丙酸·向(五)_2_ {4-[2-(2-第三丁氧基羰基胺基-苯基胺基甲醯基)_乙稀基]_ 苯基}-3-(1-甲基-六氫"比咬-4-基)-丙酸曱酯(521 mg,10 mmol)存於 Me0H/H20(4:l)(2 mL)甲之溶液中添加 Li〇H(24 mg,100 mmol.)。將該溶液於室溫下攪拌5 ,用2N HC1 將溶液中和至pH 5 - 6。將混合物於減壓下蒸發至乾燥,然 後添加EtOAc(10 mL)。將有機層用鹽水洗滌,用Na2s〇4乾 燥’過處並蒸發,未經進一步純化即獲得黃色固體產物。 MS :計算值係508 (MH+),實驗值係508 (MH+)。 實例19
(Ε)-Ν·(2-胺基-苯基)-3-{4-[1-(4-溴-苯基胺基甲龜基)_2_ (1-甲基-六氩吡啶-4-基)-乙基卜苯基}-丙烯醮胺。向(£)_2_ {4-[2-(2-第三丁氧基羰基胺基_苯基胺基甲酿基)_乙烯基]_ 苯基甲基-六氫吡啶-4-基)-丙酸(2.54 g,5 mmol)、 Et3N(1.21 g,10 mmol)及 HATU(3.80 g,10 mmol)存於 CH2C12(30 mL)中之溶液中添加4_溴_苯基胺(1.29 g,7.5 mmol)。將該混合物於室溫下攪拌過夜且然後蒸發。將混 合物重新溶於20 ml EtOAc中並用2 N HC1(20 mLx3)、鹽 水、5% NaHCO3(20 mLx3)、鹽水洗滌,用 Na2S04乾燥, 過濾並蒸發。藉由在矽膠上利用己烷/EtOAc實施管柱層析 142666.doc -48、 201014834 來純化殘餘物’得到白色固體。將丨·25 M HCl/MeOH(4 mL)添加至產物中。將該溶液於環境溫度下攪拌4小時。反 應後,用固體NaHC〇3中和溶液。藉由製備型HpLC來獲得 最終產物。MS :計算值係561 (MH+),實驗值係561 (MH+)。巾 NMR (‘DMSO, 400MHz),10.29 (s,1H), 9.40 (s, 1H), 7.60-7.51 (m, 5H), 7.49-7.45 (m, 4H), 7.34 (d, 1H, /=7.6 Hz), 6.94-6.85 (m, 2H), 6.75 (d, 1H, y=7.6 Hz) ❹ (t, 1H, /=7.6 Hz), 4.94 (^s, 2H), 3.84 (t, 1H> 6 Hz), 2.97 (寬 s,2H),2.36 (s,3H),2 22 (寬 s,2h),2抓2 jo (m, 1H)’ l.8〇-l.63 (m,3H),丨 3〇1 24 (m,祀)。 下表5中所述化合物係藉由與上文實例19中 法類似之方法來製備,只是使用合適起始材料述β成方 表5 ❹ 實例# 結構 --_ MW 19-2 ΌΥ 591.51 19-3 k/N 丫。 589.54 19-4 ~~—--589.54 142666.doc
Ms (MH+) 計算值
-49- 201014834 19-5 522.58 523 523 19-6 564.61 565 565 19-7 ^-Ν 531.06 531 531 19-8 V 561.53 561 561 19-9 ϊΗΐ^χαΒ, > 575.51 575 575 19-10 ο 575.51 575 575 實例20
2-(4·溴-苯基)-4-(1-甲基-吡咯啶-2·基)-丁腈。於N2下向
NaH(60%,0.44 g, 11 mmol)分散液存於 DMF(6 mL)-甲苯 142666.doc -50- 201014834 (12 mL)混合物中之懸浮液中添加4-溴苯乙腈0.94,1〇 mmol)。攪拌並於冰上冷卻1 h後,滴加2-(2-氣·乙基)_丨_甲 基-"比洛咬(1.48 g,10 mmol)。將混合物於70攝氏度下搜拌 2 h,然後添加水並用EtOAc萃取混合物。將有機層乾燥 (MgSCU)並於真空中蒸發,得到油狀殘餘物,該殘餘物未 經進一步純化即使用。MS :計算值係307 (MH+),實驗值 係 307 (MH+)。 實例21
2-(4-溴-苯基)-4-(1-甲基-吡咯啶_2_基)-丁酸❶用濃
HjO4及水(38··28)(4 mL)水解油狀殘餘物2-(4-溴-苯基)-4-(1-曱基比洛咬-2-基)-丁腈,回流2 h。用Na2C03中和混合 物,然後添加MeOH(20 mL)。濾出固體並用MeOH(3xl〇 mL)洗滌。蒸發合併的曱醇溶液,得到油狀物^ MS :計算 ❹ 值係326 (MH+),實驗值係326 (MH+)。 實例22
2-(4-溴-苯基)-4-(1-甲基-吡咯啶-2_基)-丁酸甲酯。於〇攝 氏度下向2-(4-溴-苯基)-4-(1-甲基比咯啶-2-基)-丁酸存於 MeOH(60 mL)中之溶液中添加s〇C12(2 mL),然後將該混 142666.doc -51- 201014834 合物回流5 h。冷卻後’將溶液於減壓下蒸發至乾燥,然 後添加EtOAc,將有機層用NaHC〇3水溶液洗滌,用MgS〇4 乾燥並蒸發’得到油狀物。MS :計算值係340 (MH+),實 驗值係340 (MH+)。 實例23
(五)-2·{4·丨2·(2·第三丁氧基羰基胲基-苯基胺基甲醯基)_ 乙烯基】-苯基}-4-(1-甲基-吡洛咬-2-基)-丁酸甲酯。將2-(4-溴-苯基)-4-(1-甲基-吡咯啶_2_基)-丁酸甲酯(2.27 g,6.67 mmol)、(2-丙烯醯基胺基-苯基)·胺基甲酸第三丁基酯(2 g, 7.2 mmol)、Pd2(dba)3(160 mg,0.175 mmol)、三-鄰-甲苯基 膦(160 mg, 0.526 mmol)及三乙胺(1.6 g, 15.8 mmol)存於 DMF(12 mL)中之混合物於100攝氏度及N2下攪拌4小時。 冷卻至室溫後,將混合物倒入飽和NH4C1水溶液中,並用 乙酸乙酯(80 mL)萃取。將有機層用鹽水洗滌,經Na2S04 乾燥,過濾,於真空中濃縮並藉由急驟管柱層析來純化, 獲得淡黃色固體(1.74 g, 50%)。MS :計算值係522 (MH+),實驗值係 522 (MH+)。 實例24 I42666.doc -52- 201014834
Ύ° (幻·2-{4_丨2-(2-第三丁氧基羰基胺基-苯基腚基甲醢基)_ 乙烯基】-苯基卜4_(1_甲基-吡咯啶_2_基)_丁酸β向⑺)_2{4_ [2-(2-第二丁氧基幾基胺基-苯基胺基甲醯基)·乙稀基]•苯 基}-4-(1-甲基-吡咯啶_2_基)-丁酸甲酯(52」mg,1〇 ’存於 Me〇H/H2〇(4:l)(2 mL)中之溶液中添加 Li〇H(24 mg, ❿ 100 mmo1·)。將該溶液於室溫下攪拌5 h後,用2 N HC1將 溶液中和至pH 5-6。將混合物於減壓下蒸發至乾燥然後 添加EtOAc(10 mL)。將有機層用鹽水洗滌,用Na2s〇4乾 燥,過濾並蒸發,未經進一步純化即獲得黃色固體產物。 MS :計算值係508 (MH+),實驗值係5〇8 (mh+)。 實例25
2-{4·【(Ε)-2-(2-胺基·苯基胲基甲醮基)己烯基】苯基卜Ν· (4·淡·苯基)-4-(1-甲基·他洛咬_2_基)丁鳙按。向(五)2{4_ [2-(2-第三丁氧基羰基胺基_苯基胺基甲醯基)_乙烯基]_苯 基}冰(1·曱基各啶 _2_ 基)_ 丁酸(2 54 g,$ mm〇1)、Et3N (g’ mm〇l)及 HATU(3.80 g,i〇 mm〇i)存於ch2C12(30 mL)中之溶液中添加4_溴·苯基胺〇 29 g, 75 將該 混合物於室溫下攪拌過夜且然後蒸發。將混合物重新溶於 142666.doc -53- 201014834 20 mL EtOAc 中並用 2 N HC1(20 mLx3)、鹽水、5% NaHCO3(20 mLx3)、鹽水洗滌,用Na2S04乾燥,過濾並蒸 發。藉由在矽膠上利用己烷/EtOAc實施管柱層析來純化殘 餘物,得到白色固體。將1.25 M HCl/MeOH(4 mL)添加至 產物中。將該溶液於環境溫度下攪拌4小時。反應後,用 固體NaHC03中和溶液。藉由製備型HPLC來獲得最終產 物。MS :計算值係561 (MH+),實驗值係561 (MH+)。*H NMR (d6-OMSO, 400MHz), 10.25 (d, 1H, /=8.8 Hz), 9.40 (s, 1H), 7.60-7.56 (m, 4H), 7.53 (d, 1H, /=15.6 Hz), 7.49-7.45 (m, 4H), 7.34 (d, 1H, /=8.0 Hz), 6.93 (d, 1H, 7=7.6 Hz), 6.88 (d, 1H, J=\5.6 Hz), 6.75 (d, 1H, /=7.6 Hz), 6.58 (t,1H,J=8.0 Hz), 4.95 (s,2H),3.71 (寬 s, 1H),3.07 (寬 s, 1H),2.31 (寬 s,4H),1.99 (寬 s,2H),1.69-1.46 (寬 m, 5H)。 實例26
2-(4-溴-苯基)-丙烯酸乙酯。向(4-溴-苯基)-乙酸乙酯 (972.4 mg,4 mmol)、低聚甲搭(240 mg,8 mmol)及Bu4NC1 (22 mg, 0.08 mmol)存於DMF( 10 mL)中之溶液中添加 K2C03(1.32 g,9·6 mmol)。將混合物於60攝氏度下加熱2 h。然後將混合物冷卻並用EtOAc(30 mL)稀釋並用水(20 mL χ3)及鹽水洗滌,經Na2S04乾燥,過濾並蒸發。藉由在 矽膠上實施急驟管柱層析來純化殘餘物,得到白色固體 (0.74 g,73%)。MS :計算值係 255 (MH+),實驗值係 255 142666.doc •54· 201014834 (MH+)。 實例27
2-(4-溴-苯基)-3-(3-二乙基胺基-吡咯啶-1-基)-丙酸乙
酯。於0攝氏度下向二乙基-吡咯啶-3-基-胺(0.685 g, 6 mmol)存於THF(10 mL)中之溶液中滴加存於THF中之2-(4-溴-苯基)-丙烯酸乙酯(1.27 g,5 mmol)。然後將該混合物於 室溫下攪拌1小時並於真空中濃縮。將殘餘物溶於 EtOAc(30 mL)中,用水(20 mLx2)及鹽水洗滌,經Na2S04 乾燥,過濾並蒸發。所獲得之油狀物未經進一步純化即直 接使用。MS :計算值係397 (MH+),實驗值係397 (MH+)。
實例28
2-(4-淡-苯基)-3-(3-二己基肢基-"Λ洛咬-1 -基)-丙酸_。向 2-(4-溴-苯基)-3-(3-二乙基胺基-吡咯啶-1-基)-丙酸乙酯 (639 mg,1.6 mmol)存於 MeOH(4 mL)中之溶液中添加 NaOH 水溶液(2 N, 8 mmol)。將該溶液於40攝氏度下攪拌2 h,然 後於真空中濃縮。將殘餘物溶於水中並於0攝氏度下用2N HC1中和至pH 5-6。然後將混合物於減壓下蒸發至乾燥, -55- 142666.doc 201014834 未經進一步純化即獲得白色固體產物。MS :計算值係369 (MH+),實驗值係 369 。 實例29
2-(4-溴-苯基)·Ν·(4-氣-苯基)_3_(二已基胲基乂咯啶 基)-丙龜肢•向2-(4-溴-苯基)_3_(3_二乙基胺基_吡咯啶小 基)-丙酸(590 mg,1.6 mmol)、DIPEA(1.03 g,8 mmol)及 Pybrop(l_12 g,2.4 mmol)存於CH2C12(10 mL)中之溶液中添 加4-氣-苯基胺(306 mg,2.4 mmol)。將該混合物於室溫下 攪拌過夜且然後蒸發。將混合物重新溶於EtOAc(20 mL)中 並用水、鹽水洗滌,用NajCU乾燥並於真空中濃縮。藉由 急驟管柱層析來純化殘餘物,得到白色固體。MS :計算 值係478 (MH+),實驗值係478 (MH+)。 實例30
(£>【2-(3-{4-【1-(4-氯-苯基胲基甲醮基)-2-(3-二乙基胺 基咯啶-1-基)-己基I-苯基卜丙烯酿基肢基)-苯基卜坡基 甲酸第三丁基®。將2-(4-漠-笨基)-N-(4-氣-苯基)-3-(二乙 基胺基-0比洛咬-1-基)-丙醯胺(826 mg,1.72 mmol)、(2-丙 142666.doc •56- 201014834 烯醯基胺基-苯基)-胺基甲酸第三丁基酯(452 mg,1_72 mmol)、Pd2(dba)3(47.3 mg,0.051 mmol)、三-鄰-甲苯基鱗 (62.8 mg,0.017 mmol)及三乙胺(694 mg,6.88 mmol)存於 DMF(1 〇 mL)中之混合物於100攝氏度及N2下擾拌4小時β 冷卻重_室溫後,將混合物倒入飽和ΝΗβΙ水溶液中,並用 . Et〇Ac(8〇 mL)萃取。將有機層用鹽水洗滌,經Na2S〇4乾 燥,過濾並於真空中濃縮,且未經進一步純化即直接使 用。MS :計算值係660 (MH+),實驗值係660 (MH+)。 ® 實制31
胺基-苯基氯-苯基胲基甲醮基)-2-(3_二。基> 坡基_"^洛唆_ 1_基己基】-苯基}-丙焊塞胺β向 ⑹-[2-(3-{4_[1_(4_氣·苯基胺基甲醯基)-2-(3-二乙基胺基-。比咯啶基乙基]-苯基丨_丙烯醯基胺基)_苯基]-胺基甲酸 第三 τ基酯(528 mg,0.8 mmol)存於 ch2C12(10 mL)中之溶 液中添加^0001^612 uL,8 mm〇1)。將該混合物攪拌約4 h,然後將NaHC〇3添加至反應系統中。濾出固體後,藉 由製襻蜇HPLC來純化粗製混合物,獲得淡黃色固體。 MS :計算值係 560 (MH+),實驗值係 56〇 (MH+)。lH NMR ⑷-]Vie〇D,400MHz),7 66 (d’ 1H,《/=15.6 Hz), 7.60-7.57 (m,4H),7·49 (d,2H,J=8·0 Hz),7.29 (d, 2H, J=8.8 Hz), 7.22 (山 1H,·Ζ=7·6 Hz),7.06 (t,ih,/=7.6 Hz),6.89 (d,1H, -57· 142666.doc 201014834 7=8.8 Hz), 6.84 (d, 1H, J=15.6 Hz), 6.76 (t, 1H, J=7.6 Hz), 3.94 (m,1H),3.48-3.35 (m,2H), 2.82-2.53 (寬 m, 9H), 2.01-1.95 (m, 1H), 1.74-1.71 (m, 1H), 1.00 (q, 6H, /=7.0 Hz)。 下表6中所述化合物係藉由與上文實例31中所述合成方 法類似之方法來製備,只是使用合適起始材料。 表6 實例# 結構 MW MS (ΜΗ+) 計算值 MS (MH+) 實驗值 31-2 ΟΗ 538.57 539 539 31-3 φ〇 517.03 517 517 31-4 ιό 522.58 523 523 31-5 / 565.64 566 566 31-6 538.57 539 539 142666.doc -58 - 201014834
(2-溴-乙氡基)-第三丁基_二甲基_矽烷·將2溴乙醇(ι〇 〇 mL,141 mmol)添加至咪唑(125 g,184 mm〇1)與第三丁基 一甲基曱矽烷基氣(21丨g,14〇 mm〇1)存於無水DMF(25 mL)中之混合物中。將該反應混合物於室溫下攪拌12 h, 添加水及乙醚。分離各相。用二乙醚萃取水相。用水及鹽 水洗滌有機相。用NajCU乾燥溶液。蒸發溶劑得到無色液 體。MS :計算值係239 (MH+) ’實驗值係239 (MH+)。 實例33
2-(4-溴-笨基)_4_(第三丁基-二曱基矽烷氧基)丁酸乙 西曰°將(4-漢笨基)-乙酸乙酯(15 g,61.7 mmol)及t-BuOK 142666.doc -59 - 201014834 (10.3 g,92.6 mmol)存於DMF(50 mL)中之溶液於室溫下授 拌1 h。然後於〇攝氏度下向該溶液中緩慢添加溴-乙氧 基)-第三丁基-二甲基·石夕烧(26.6 g,111 mmol) »將該混合 物於室溫下攪拌過夜並倒入水(2〇〇 mL)。用EtOAc(200 mLx3)萃取水相’並將有機層用飽和nh4C1 (200 mL)、水 (100 mLx3)、鹽水(1〇〇 mL)洗滌,用Na2S04乾燥並蒸發, 得到粗產物。藉由急驟層析(EtOAc/己烷至CH2Cl2/MeOH) 來純化粗產物,獲得期望產物(12.1 g,50%)。MS :計算值 係 401 (MH+),實驗值係 401 (MH+)。 實例34
2-{4-[2-(2-第三丁氧基羰基玻基·苯基雎基甲醯基)_乙烯 基】-笨基}-4-(第三丁基-二甲基-矽烷氧基)_丁酸乙酯。將2_ (4-漠-苯基)-4-(第三丁基_二曱基·矽烷氧基丁酸乙酯(4 5 g’ II·22 mmol)、(2·丙烯醯基胺基·苯基)·胺基甲酸第三丁 基 S曰(3.1 g,11.78 mmol)、Pd2(dba)3(839 mg, 0.92 mmol)、 三-鄰-甲苯基膦(546 mg,1.79 mmol)及三乙胺(4.53 g, 44.88 mmol)存於DMF(50 mL)中之混合物於110攝氏度及N2 下搜拌4小時。冷卻至室溫後,將混合物倒入飽和nh4C1水 溶液中’並用乙酸乙酯(2〇〇 mL)萃取。將有機層用鹽水洗 滌’經NazSO4乾燥,過濾,於真空中濃縮並藉由急驟管柱 層析純化’獲得淡黃色固體(2.63 g,42%)。MS :計算值係 142666.doc •60- 201014834 583 (MH+),實驗值係 583 (MH+)。 實例35
2·(4-溴-苯基)-5-氣-戍腈。於N2下向 NaH(60%,2.2 g,55 mmol)分散液存於DMF(30 mL)-甲苯(60 mL)混合物中之懸 浮液中添加4-漠苯乙腈(9.8g, 50 mmol)。擾拌並於冰上冷 卻1 h後,滴加3-氣-1-丙基漠(7.8 7g, 50 mmol)並於10攝氏 度下繼續攪拌30 min,然後添加水並用EtOAc萃取混合 物。將有機層乾燥(MgS04)並於真空中蒸發。將油狀殘餘 物於真空中蒸餾,得到油狀物(5.4 g, 40%)。bp 155-160攝 氏度(7.5*1〇-5托)。厘8:計算值係271(^«1+),實驗值係 271 (MH+)。4 NMR (400MHz, CDC13),7.54-7.56 (2H), 7.24-7.26 (2H),3.84 (1H),3.59 (2H),1.92-2.12 (4H)。 實例36
Cl OH 2-(4-溴苯基)-5-氯-戊酸。用濃H2S04、冰乙酸及水之 3:5:3混合物(33 mL)水解2-(4-溴苯基)-5-氯戊腈(4g,14.7 mmol),回流12 h。將反應混合物冷卻至室溫,用水稀釋 並用CHC13萃取。將有機層用鹽水洗滌(3次),然後用 MgS04乾燥,將溶液於減壓下蒸發至乾燥,得到油狀物 142666.doc -61 - 201014834 (3.8 g,90%)。MS :計算值係 290 (MH+),實驗值係 290 (MH+piHNMRHOOMt^CDChPA-TMpHp.lO-7.20(2H),3.84 (1H),3.52(3H), 1.60-2.20 (4H)。 實例37
2-(4-溴-苯基)-5·氯戊酸甲酯。於0攝氏度下向2-(4-溴-苯 基)-5 -氣戊酸(3 g,10.38 mmol)存於MeOH(60 mL)中之溶液 中添加SOCl2(2 mL),然後將該混合物回流5 h。冷卻後, 將溶液於減壓下蒸發至乾燥,然後添加EtOAc並用NaHC03 水溶液洗滌混合物,將有機層用MgS04乾燥並蒸發,得到 油狀化合物(2.85 g, 90%)。MS :計算值係3 04 (MH+),實 驗值係304 (MH+)。 實例38
2-{4-[2_(_第三丁氧基羰基胺基-苯基胺基甲醮基)-已烯 基]-苯基}-5-氣-戊酸甲酯。將2-(4-溴-苯基)-5-氣戊酸甲酯 (2 g,6.67 mmol)、(2-丙烯醯基胺基-苯基)-胺基曱酸丁基 醋(2 g,7.2 mmol)、Pd2(dba)3(160 mg, 0.17 mmol)、三-鄰-甲苯基膦(160 mg, 0.53 mmol)及三乙胺(1.6 g,15.8 mmol) 存於DMF(12 mL)中之混合物於100攝氏度及N2下攪拌4小 142666.doc -62- 201014834 時。用EtOAc(80 mL)稀釋反應混合物,然後用水(2〇 mLx2)洗滌。藉助NajO4乾燥有機層。蒸發溶液。最後, 藉由急驟管柱層析來純化殘餘產物,得到產物(1.6 g,產 率為50%)。MS :計算值係487 (MH+),實驗值係487 (MH+)。
實例39
2-(5-溴-吡啶-2-基)-丙二酸二乙酯。將5_溴-2-碘-吡啶 (56.8 g,0.2 mol)、丙二酸二乙酯(64 g,0.4 mol)、Cul(3.8 经,0.02 111〇1)、€82(:〇3(195.5§,0.6 111〇1)及吡啶-2-甲酸(2.46
g,0.04 mol)存於1,4-二噁烷(400 mL)中之混合物於70攝氏 度及A下攪拌24小時。冷卻至室溫後,濾出固體並蒸發溶 劑。將殘餘物溶於乙酸乙酯(400 mL)中並用水及鹽水洗 滌’經NazS〇4乾燥,過濾,於真空中濃縮並藉由急驟層析 (石油醚:EtOAc=20:l)來純化粗產物,獲得油狀物(31.6 g, 50%) » MS :計算值係316 (MH+),實驗值係 316 (MH+)。 !H NMR (i/6-DMSO, 400MHz), 8.68 (d, 1H, J=2.4 Hz), 8.11 (dd, 1H, J=2.4, 8.4 Hz), 7.45 (d, 1H, J=8.4 Hz), 5.16 (s> 1H), 4.20_ 4.07 (m,4H), 1.18 (t, >8.4 Hz, 6H)。 實例40
142666.doc ·63· 201014834
乙酯(16.6 g,52·5 mmol)存於Me〇H(2〇〇 mL)中之溶液中添 加NaOH水溶液(2N, 105 mL,210 mmol)。將該溶液於室溫 將攪拌3小時,然後於真空中濃縮。將殘餘物溶於水中並 用2 N HC1中和至pH 3-4。然後將固體濾出並用水及醚洗 滌,乾燥,未經進一步純化即得到白色固體產物(9 〇 g, 80%)。MS ··計算值係 215 (MH+),實驗值係 215 (MH+)。 實例41
(5-溴-吡啶-2-基)-乙酸甲職β於〇攝氏度下向(溴-吡啶· 2-基)-乙酸(9 g,41.7 mmol)存於Me〇H(80 mL)中之溶液中 添加Social0 g,83.4 mmol),然後將該混合物於室溫下攪 拌3 h。冷卻後,將溶液於減壓下蒸發至乾燥,然後添加 EtOAc並用NaHC03水溶液洗滌混合物,將有機層用MgS04 乾燥並蒸發,得到油狀化合物(8.6 g,90%)。MS :計算值 係 229 (MH+),實驗值係 229 (MH+)。 實例42
2-(5-溴-吡啶-2-基)-5-氯-戊酸甲酯。於N2下向NaH (60%,1.8 g, 44.9 mmol)分散液存於DMF混合物(60 mL)中 之懸浮液中添加(5-溴-吡啶-2-基)-乙酸甲酯(8.6 g,37.4 142666.doc -64· 201014834 mmol)。授拌並於冰上冷卻1 h後,滴加3-氯-1-丙基溴 (7.07g, 44.9 mmol)並於10攝氏度下繼續攪拌30 min,然後 添加水並用EtOAc萃取混合物。將有機層乾燥(MgS04)並 於真空中蒸發。藉由層析(石油謎:EtOAc= 15:1)來純化油 狀殘餘物,得到油狀物(6.87 g, 60%)。MS :計算值係305 (MH+),實驗值係 305 (]\^+)。11^]^11(40〇]^沿,00(:13-d) 8.64 (d, 1H, J=2.4 Hz), 7.84 (dd, 1H, 7=2.4, 8.4 Hz), 7.28 (s,lH), 3.90-3.84 (m, 1H), 3.71 (s, 3H), 3.55 (t, 2H, ® J=6A Hz), 2.32-2.20 (m, 1H), 2.14-2.05 (m, 1H), 1.88-1.67 (m,2H)。 實例43
2-(5-漢-"tb咬-2-基)-5-氣-戍酸。向2-(5-漠-°比咬-2-基)-5-氯-戊酸甲酯(2.0 g,6.5 mmol)存於 THF/MeOH(5/l) 30 mL Q 中之溶液中添加υ〇ΗΉ2〇 (1.092 g,26 mmol.)。將溶液於 室溫下攪拌16 h後,用2 N HC1將溶液中和至pH 5-6。將混 合物於減壓下蒸發至乾燥,然後添加EtOAc(50 mL)。將有 機層用鹽水洗滌,用Na2S04乾燥,過濾並蒸發,未經進一 步純化即獲得油狀產物。MS :計算值係291 (MH+),實驗 值係 291(MH+)。 實例44 新穎化合物對HDAC之抑制:HeLa提取物HDAC螢光 142666.doc -65- 201014834 * 分析 利用體外脫乙醯化分析來測試新穎化合物抑制組蛋白脫 乙醯基酶之能力。用於該分析之酶源係HeLa細胞核提取 物。受質由含有乙醯化離胺酸側鏈之市售產品組成(HeLa 提取物與受質二者皆係購自BIOMOL Research Laboratories有限公司,Plymouth Meeting, PA)。藉由用 HeLa細胞核提取物培育使受質脫乙醢化後,接著將受質暴 露於顯影劑以產生螢光團,螢光團正比於脫乙醯化程度。 使用等於HeLa細胞核提取物Km的受質濃度,在30微莫耳 © 新穎化合物存在下實施脫乙醢化分析,並測定相對於習知 參考HDAC抑制劑(SNDX-275)之酶抑制百分比。上文實例 及表中所述之本發明化合物展示相對於習知參考化合物在 約75%至1 90%範圍内的組蛋白脫乙醯基酶抑制活性。特定 代表性化合物之抑制活性可見於表7中。 實例45 新穎化合物對p21報導基因之誘導 利用報導基因分析測試本發明之新穎化合物誘導p21基 ® 因表現之能力,該報導基因分析涉及用p21啟動子-螢光素 酶構建體來轉染HeLa細胞。p21啟動子含有的Spl/Sp3結合 位點而非上游p53結合位點結合HDAC。簡言之,轉染前一 天,將HeLa細胞以11,000個細胞/孔接種於96孔培養板中 並於37攝氏度下在5% C02中培育過夜。轉染時,除去培養 基並用100微升/孔轉染培養基來代替,其係先前以如下方 式製備··將5微升無血清DMEM、0.15微升Fugene 6試劑、 142666.doc -66 - 201014834 40 ng p2 1 -螢光素酶、10 ng GFP輕輕混合並於室溫下培育 30分鐘;然後將98微升DMEM(具有10% FBS、1%青黴素 及鏈黴素)添加至DNA:Fugene 6試劑複合物中並輕輕混 合。將細胞於37攝氏度下在5% C02中培育24小時後,向各 孔中添加新鮮培養基及測試化合物並再次將細胞於3 7攝氏 度下在5% C02中培育15小時。藉由添加80微升/孔的細胞 培養裂解劑(Promega)使細胞裂解。每一裂解物均取50微 升用以GFP檢測,採用486 nm激發波長並於527 nm處檢 ® 測。然後向每20微升細胞裂解物中添加100微升螢光素酶 分析試劑(Promega)以實施光度計檢測。在濃度為3微莫耳 時,上文實例及表中所述之本發明化合物展示相對於習知 HDAC抑制劑(SNDX-275)在約25%至300%範圍内的p21誘 導活性。特定代表性化合物之誘導活性可見於表7中。 實例46 新穎化合物對癌細胞系之抗增殖活性 利用下述體外生長抑制分析測試了本發明之新穎化合物 抑制不同癌細胞系生長之能力。 ΜΓ51分析 將細胞接種於96孔培養板中(200微升/孔,端視細胞類型 採用不同接種濃度)並於37攝氏度下在5% C02中培育過 夜。向細胞中添加化合物稀釋液後(DMSO濃度保持在0.5% 以下),將細胞於37攝氏度下在5% C02中培育72小時。對 增殖的作用係藉由下述方式來測定:按照廠商說明書添加 MTS試劑(Promega),隨後於37攝氏度下在5% C02中培育2 142666.doc •67- 201014834 小時,且最後使用ELISA平板讀數器記錄49〇 nm處的吸光 率。 WST分析 其類似於MTS分析’只是顯影劑係CCK-8試劑(Dojindo) 且平板讀數器設置為450 11111吸光率。 上文實例及表中所述之本發明化合物可抑制癌細胞系生 長,其中72小時GIso值在約400毫微莫耳至大於6微莫耳範 圍内。特定代表性化合物抗SMMC-7721肝癌細胞之GIso及 GI9〇值可見於表7中。 表7 實例 HD (RP30) p21 (RP3) GIW毫微莫耳)SMMC_ 7721 GI9o(毫微莫耳)SMMC-7721 SNDX-275 100% 100% 3.5 10.5 6 151% 212% 0.8 2.7 25 170% 199% 0.8 2.5 6-2 134% 233% 1.0 3.1 9-2 173% 74% 0.7 1.5 9-3 139% 305% 0.8 2.1 31 184% 243% 0.9 3.3 9-4 163% 155% 1.4 4.9 9-5 179% 127% U 3.2 9 187% 253% 1.3 2.9 表7·本發明所選實例之生物活性數據。HDAC(RP30)係在 30微莫耳時與SNDX-275相比之相對抑制效力;p21 (RP3) 係在3微莫耳時與SNDX-275相比之相對誘導效力。 142666.doc -68 -
Claims (1)
- 201014834 七、申請專利範園: 1. 一種下通式之化合物其中 β R1係氫; 鹵素; 低碳數烷基,其未經取代或經自素取代一次或數 次; 環烷基; 氰基; 低碳數烷氧基; ❹ R2 係(VR3, 其中R3係3-10員雜環,其未經取代或經鹵素、低碳 數烷基、羥基、-C(O)-低碳數烷基、=〇或 NR4R5取代一次或數次; 或 NR4R5 ; R4/R5 彼此獨立地係氫或低碳數炫基; η 係〇、1、2、3,當η=0時,R3為由破連接之3-10 員雜環; 142666.doc 201014834 X 係C或N ;及 其醫藥活性鹽、外消旋混合物、對映異構體、光學異構 體或互變異構形式。 如請求項1之式(I)化合物,其中 R1係鹵素; 低碳數烷基,其未經取代或經鹵素取代一次或數 次; 環烷基; 所有其餘取代基具有S青求項1中所給之意義。 3. 4. 如請求項1或2之式(I)化合物,其中 X 係C ; 所有其餘取代基具有請求項1或2中所給之意義》 如請求項1或2之式(I)化合物,其中其中R3係吡咯啶基、嗎啉基、六氫吡啶基、硫嗎啉 基、2_氧雜_5-氮雜二環[2.2.1]庚烷基,所有 上述環可未經取代或經函素、低碳數烷基、 經基、_C(0)-低碳數烷基、=0或NR4R5取代 一次或數次; 或 NR4R5 ; R4/R5彼此獨立地係氫或低碳數烷基; 所有其餘取代基具有請求項i、2或3中所給之意義。 如請求項1之式(I)化合物,該化合物係 142666.doc 201014834 2-{4-[(E)-2-(2-胺基-笨基胺基甲醯基)_ 乙烯基]-苯基}-5- 嗎啉-4-基_戊酸(4_溴_苯基)_醯胺; 2-{4-[(Ε)-2-(2·胺基-笨基胺基甲醯基)乙烯基]苯基卜5_ (lS,4S)-2-氧雜-5_氮雜二環[2 2丨]庚·5_基-戊酸(4•三氟 甲基-苯基)-酿胺; 2-{4-[(Ε)-2-(2-胺基笨基胺基甲醯基)乙烯基]_苯基卜5_ (lS,4S)-2-氧雜_5_氮雜_二環[2 2 ”庚^基戊酸(4溴苯 基)-醯胺; 2-{4-[(E)-2-(2-胺基-笨基胺基曱醯基)_乙烯基]_苯基卜5_ 嗎啉-4-基-戊酸(4-異丙基·笨基醯胺; 2-{4-[(E)-2-(2-胺基-苯基胺基曱醯基)·乙烯基卜苯基卜5_ (lS,4S)-2-氧雜-5-氮雜-二環[2 2 ”庚_5_基_戊酸(4_異丙 基-本基)·酿胺; 2-{4-[(E)-2-(2-胺基-笨基胺基甲醯基)乙烯基]_苯基卜5_ (3-羥基-六氫吼啶-1-基)_戊酸(4_異丙基_苯基)醯胺; 2-{4-[(E)-2-(2-胺基-笨基胺基曱醯基)乙烯基]•苯基} 5_ (3-羥基-六氫吡啶-1-基)_戊酸(4_溴_苯基)_醯胺; 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)_乙烯基]•苯基卜义 (4-演-苯基)-4-嗎琳-4-基-丁酿胺; 2-{4-[(E)-2-(2-胺基-笨基胺基曱醯基)_乙烯基卜苯基卜5_ 0比洛'>定-1-基-戊酸(4-三氟曱基·笨基)_醯胺; 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)_乙烯基卜苯基丨_5_ 六氫°比咬-1-基-戊酸(4-溴-笨基)_醯胺; 2-{4-[(E)-2-(2-胺基_笨基胺基甲醯基)_乙烯基]_苯基卜5_ 142666.doc 201014834 吡咯啶-1-基-戊酸(4-溴-苯基)-醯胺; 2-{4-[(£)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基}_5-(2-氧雜-5-氮雜-二環[2.2· 1]庚-5-基)-戊酸(4-氣-苯基)-醯 胺; (E)-N-(2-胺基-苯基)-3-{4-[1-(4-氯-苯基胺基甲醯基)-2-(3-二乙基胺基比略啶-1-基)-乙基l·苯基}-丙烯醯胺; 2-{4-[(E)-2-(2-胺基-苯基胺基甲醯基)·乙烯基]-苯基卜N-(4-溴-苯基)-4-(3-羥基-六氫β比啶-1-基)-丁醯胺; 2-{4-[(Ε)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基卜Ν- _ (4-溴-苯基)-4-(18,48)-2-氧雜-5-氮雜-二環[2.2.1]庚-5- 基-丁酿胺; 2-{4-[(Ε)-2-(2-胺基-苯基胺基甲醯基)-乙烯基]-苯基卜Ν-(4-溴-笨基)-4-(1-甲基-η比咯啶_2_基)-丁醯胺;及 (Ε)-Ν-(2-胺基-苯基)-3-{4-[1-(4-溴-苯基胺基甲醯基)_2_ (1-甲基-六氫咐>啶-4-基)-乙基]-苯基}_丙烯醯胺。 6. 如請求項1、2及5中任一項之化合物’其用作藥劑。 7. 一種醫藥組合物,其包含至少一種如請求項中任— _ 項之化合物以及醫藥上可接受之佐劑。 8. 如請求項丨、2及5中任一項之化合物其用於治療癌 症、尤其實體腫瘤及血液腫瘤。 9. 種如晴求項1至5中任-項之化合物的用途,其用以製 造用於治療癌症、尤其實體腫瘤及血液腫瘤之藥劑。 142666.doc -4· 201014834 四、指定代表圓: (一) 本案指定代表圖為:(無) (二) 本代表圖之元件符號簡單說明: 五、本案若有化學式時,請揭示最能顯示發明特徵的化學式:142666.doc
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