TWI506020B - Mek雜環抑制劑及其使用方法 - Google Patents
Mek雜環抑制劑及其使用方法 Download PDFInfo
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- TWI506020B TWI506020B TW101118139A TW101118139A TWI506020B TW I506020 B TWI506020 B TW I506020B TW 101118139 A TW101118139 A TW 101118139A TW 101118139 A TW101118139 A TW 101118139A TW I506020 B TWI506020 B TW I506020B
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- Prior art keywords
- compound
- fluoro
- methyl
- dihydropyridine
- dimethyl
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Classifications
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Description
本發明申請案主張在2005年5月18日提出申請之美國臨時專利申請案第60/682,335號之優先權,將其整個內容併入本文以供參考。
本發明係關於一系列的新穎雜環化合物,其有用於治療在哺乳類中的高增殖性疾病,如癌症及發炎。本發明也關於使用這些化合物治療在哺乳類中(尤其為人類)的高增殖性疾病之方法及關於含有這些化合物之醫藥組成物。
經由生長因子受體及蛋白質激酶發信號的細胞為重要的細胞生長、增殖及分化的調節劑。在正常的細胞生長中,經由受體活化的生長因子(即PDGF或EGF及其它等)活化MAP激酶路徑。涉入正常且未受控制的細胞生長的其中一種最重要且最廣為瞭解的MAP激酶路徑為Ras/Raf激酶路徑。以活性GTP結合之Ras引起Raf激酶的活化作用及間接的磷酸化作用。接著Raf使兩種絲胺酸殘基上的MEK1與2磷酸化(就MEK1而論的S218與S222及就MEK2而論的S222與S226)(Ahn等人之Methods in Enzymology,2001,332,417-431)。接著活化之MEK使其僅知的基質(MAP激酶、ERK1與2)磷酸化。以MEK之ERK磷酸化作用發生在就ERK1而論的Y204與T202上及就ERK2而論的Y185與T183(Ahn等人之Methods in Enzymology,2001,332,
417-431)。使磷酸化之ERK二聚化及接著轉位至其積聚的核(Khokhlatchev等人之Cell,1998,93,605-615)。在核中,ERK涉入許多重要的細胞機能,包括(但不限於)核輸送、信號轉導、DNA修復、核小體組合與轉位及mRNA加工與轉譯(Ahn等人之Molecular Cell,2000,6,1343-1354)。大體上,以生長因子處理細胞導致ERK1與2活化,其引起增殖,並在一些例子中引起分化(Lewis等人之Adv.Cancer Res.,1998,74,49-139)。
在增殖性疾病中,涉入ERK激酶路徑的生長因子受體、下游信號蛋白質或蛋白質激酶之基因突變及/或過度表現導致未受控制的細胞增殖,而最終形成腫瘤。例如一些癌症包括突變,其係由於連續產生生長因子而引起該路徑的連續活化。其它的突變可導致以活化之GTP結合之Ras複合物的去活化作用有缺陷,再引起MAP激酶路徑的活化。Ras的突變性致癌型式被發現在50%之結腸癌及>90%之胰臟癌與許多其它型式的癌症中(Kohl等人之Science,1993,260,1834-1837)。最近bRaf突變被證實在超過60%之惡性黑色素瘤中(Davies,H.等人之Nature,2002,417,949-954)。在bRaf中的這些突變引起組成活性之MAP激酶梯瀑。原發腫瘤樣品及細胞株的研究也已證明在胰臟癌、結腸癌、肺癌、卵巢癌及腎癌中的MAP激酶路徑的組成或過渡活化(Hoshino,R.等人之Oncogene,1999,18,813-822)。於是在癌症與由基因突變引起的過度活性之MAP激酶路徑之間有非常大的關聯。
因為MAP激酶梯瀑的組成或過度活化在細胞增殖及分化中扮演中樞角色,故咸信該路徑的抑制作用有利於高增殖性疾病。MEK為該路徑中的關鍵角色,因為其為Ras與Raf的下游。此外其為吸引的治療標的,因為僅知為MEK磷酸化的基板為MAP激酶、ERK1與2。已在許多研究中證明MEK抑制作用具有潛在的治療效益。例如已證明小分子MEK抑制劑抑制在裸鼠異種移植中的人類腫瘤生長(Scbolt-Leopold等人之Nature-Medicine,1999,5(7),810-816;Trachet等人在2002年4月6-10日之AACR,Poster #5426;Tecel,H.在2002年9月9-10日之IBC第二屆的蛋白質激酶的國際會議(2nd
International Conference of Protein Kinase)、阻斷在動物中的靜態觸摸痛(WO 01/05390)及抑制急性骨髓性白血病細胞的生長(Milella等人之J.Clin.Invest.,2001,108(6),851-859)。
MEK之小分子抑制劑已被揭示,包括在美國專利發表案第2003/0232869號、第2004/0116710號與第2003/0216460號及美國專利申請序號第10/654,580號與第10/929,295號中,將每一個併入本文以供參考。在最近幾年出現至少15篇額外的專利申請案。參見例如:美國專利第5,525,625號、WO 98/43960、WO 99/01421、WO 99/01426、WO 00/41505、WO 00/42002、WO 00/42003、WO 00/41994、WO 00/42022、WO 00/42029、WO 00/68201、WO 01/68619、WO 02/06213、WO 03/077914及WO 03/077855。
本發明係提供新穎雜環化合物及其醫藥上可接受之鹽類與前體藥物,其有用於治療高增殖性疾病。頃發現如本文所述之具有特殊的取代基之6-側氧基-1,6-二氫嗒及6-側氧基-1,6-二氫吡啶化合物為有效的MEK酵素抑制劑。
更特定言之,本發明的一個觀點係提供化合物,包括其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化物及醫藥上可接受之鹽類,該化合物具有化學式I:
其中:R1
為Cl或F;R3
為H、Me、Et、OH、MeO-、EtO-、HOCH2
CH2
O-、HOCH2
C(Me)2
O-、(S)-MeCH(OH)CH2
O-、(R)-HOCH2
CH(OH)CH2
O-、環丙基-CH2
O-、HOCH2
CH2
-、
R7
為環丙基-CH2
-或C1
-C4
烷基,其中該烷基視需要被一或多個F取代;R8
為Br、I或SMe;及R9
為CH3
、CH2
F、CHF2
、CF3
、F或Cl。
本發明還有的另一觀點係提供化合物,包括其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化
物及醫藥上可接受之鹽類,該化合物具有化學式IV:
其中:R1
為Cl或F;R3
為H、Me、Et、OH、MeO-、EtO-、HOCH2
CH2
O-、HOCH2
C(Me)2
O-、(S)-MeCH(OH)CH2
O-、(R)-HOCH2
CH(OH)CH2
O-、環丙基-CH2
O-、HOCH2
CH2
-、
R7
為甲基或乙基,其中該甲基及乙基視需要被一或多個F取代;R8
為Br、I或SMe;及R9
為H、C1
-C4
烷基、Cl或CN,其中該烷基視需要被一或多個獨立選自F或CN之基團取代,其先決條件係:a)當R1
為F,R8
為Br,R9
為H及R3
為HOCH2
CH2
O時,則R7
不可能為Me或Et;b)當R1
為F,R8
為I,R9
為H及R3
為MeO時,則R7
不可能為Me;c)當R1
為F,R8
為Me,R9
為H及R3
為HOCH2
CH2
O時,則R7
不可能為Me;及d)當R1
為F,R8
為Br,R9
為H及R3
為環丙基-CH2
O
時,則R7
不可能為Me。
在進一步的觀點中,本發明提供兩種結晶型式之式XI化合物
其中將兩種結晶型式命名為型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺及型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
本發明也提供製備式XI化合物之型式1及型式2之方法。
在進一步的觀點中,本發明提供抑制MEK之組成物,其包含一或多種本發明的化合物。
本發明也提供製造本發明化合物之方法。
在進一步的觀點中,本發明提供一種使用本發明化合物作為治療以MEK介入之疾病或醫學症狀之醫藥的方法。例如本發明提供一種治療在哺乳類中的高增殖性疾病或發炎性症狀之方法,其包含將一或多種本發明化合物或其醫藥上可接受之鹽或前體藥物以有效治療該高增殖性疾病之量投予該哺乳類。
在進一步的觀點中,本發明提供治療或預防以MEK介入之症狀,其包含將含有本發明化合物或其醫藥上可接受
之鹽或在活體內可裂解之前體藥物的醫藥組成物以有效治療或預防以該MEK介入之症狀的量投予需要其之人類或動物。
本發明化合物可進一步有利地與其它已知的治療劑組合使用。
本發明也關於抑制MEK之醫藥組成物,其包含有效量之選自本發明的化合物或其醫藥上可接受之前體藥物、醫藥活性代謝物或醫藥上可接受之鹽類。
本發明另外的觀點為本發明化合物在製備用於治療或預防在溫血動物中(以哺乳類較佳,以人類更佳)以MEK介入之疾病或醫學症狀之醫藥中的用途,該動物承受該等疾病所苦。更特定言之,本發明包括本發明化合物在製備用於治療或預防在哺乳類中的高增殖性疾病或發炎性症狀之醫藥中的用途。
本發明另外的優點及新穎的特點部分將陳述在隨後的說明書中及部分將為那些熟諳本技藝者在檢閱下列的專利說明書時所明白,並可以本發明的實際應用而學習。本發明的優點可藉由在所附之申請專利範圍中特別指出的儀器、組合物、組成物及方法的方式明白及達成。
本發明的本發明化合物及其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化物及醫藥上可接受之鹽類與前體藥物有用於治療高增殖性疾病。總言之,本發明的一個觀點係關於當作MEK抑制劑的本發明化合物。
更特定言之,本發明的一個觀點係提供化合物,包括其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化物及醫藥上可接受之鹽類,該化合物具有化學式I:
其中:R1
為Cl或F;R3
為H、Me、Et、OH、MeO-、EtO-、HOCH2
CH2
O-、HOCH2
C(Me)2
O-、(S)-MeCH(OH)CH2
O-、(R)-HOCH2
CH(OH)CH2
O-、環丙基-CH2
O-、HOCH2
CH2
-、
R7
為環丙基-CH2
-或C1
-C4
烷基,其中該烷基視需要被一或多個F取代;R8
為Br、I或SMe;及R9
為CH3
、CH2
F、CHF2
、CF3
、F或Cl。
在一個具體實例中,本發明提供化合物,包括其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化物及醫藥上可接受之鹽類,其具有化學式IA:
其中:R1
為Cl或F;R3
為H、Me、OH、MeO、EtO、HOCH2
CH2
O、MeOCH2
CH2
O、HOCH2
CH2
CH2
、
R7
為環丙基-CH2
-或C1
-C4
烷基,其中該烷基視需要被一或多個F取代;R8
為Br、I或SMe;及R9
為CH3
、CH2
F、CHF2
、CF3
、F或Cl。
在一個具體實例中,在式I或IA化合物中,R7
為環丙基-CH2
-或Me。在另一具體實例中,R9
為CH3
、F或Cl。
在另一具體實例中,其係提供式II化合物:
或其醫藥上可接受之鹽,其中:
R3
為H、MeO、HOCH2
CH2
O、MeOCH2
CH2
O、HOCH2
CH2
CH2
、
R9
為H、CH3
、F或Cl。
在N1位置上具有甲基取代基及具有特殊的R3
與R9
基團之式II化合物為有效的MEK抑制劑。
本發明特別的新穎化合物包括下列中任一者:4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;N-(環丙基甲氧基)-4-(2-氟基-4-(甲硫基)苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-甲氧基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-(甲硫基)苯胺基)-N-甲氧基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-(甲硫基)苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;5-氟基-4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-5-氟基-4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙
氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;5-氯基-4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-5-氯基-4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-(甲硫基)苯胺基)-N-(3-羥丙基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;及(S)-N-(2,3-二羥丙基)-4-(2-氟基-4-(甲硫基)苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺。
在另一具體實例中,其係提供式III化合物:
或其醫藥上可接受之鹽,其中:R1
為Cl或F;R3
為H、Me、MeO、HOCH2
CH2
O、HOCH2
CH2
CH2
、HOCH2
CH2
、
R8
為Br或I;及R9
為CH3
、F、Cl或Br。
在N1位置上有甲基取代基及有特殊的R1
、R3
、R8
與
R9
基團之式III化合物為有效的MEK抑制劑。
本發明特別的新穎化合物包括下列中任一者:5-溴基-4-(4-溴基-2-氟基苯胺基)-N-(環丙基甲氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(R)-N-(2,3-二羥基丙氧基)-4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-碘基苯胺基)-N-甲氧基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;N-(環丙基甲氧基)-4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-4-(2-氟基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氯基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-4-(2-氯基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(4-溴基-2-氯基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-4-(4-溴基-2-氯基苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;
(R)-4-(4-溴基-2-氟基苯胺基)-N-(2,3-二羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(4-溴基-2-氟基苯胺基)-N-(1-羥基-2-甲基丙-2-氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(4-溴基-2-氟基苯胺基)-5-氟基-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-碘基苯胺基)-N,1,5-三甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;N-(環丙基甲基)-4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-碘基苯胺基)-N-(3-羥丙基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;5-氟基-4-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;4-(2-氟基-4-碘基苯胺基)-N-(2-羥乙基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;N-(2,3-二羥丙基)-4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;5-氯基-4-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-5-氯基-4-(2-氟基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;
5-氯基-4-(2-氟基-4-碘基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;5-氯基-N-(2,3-二羥丙基)-4-(2-氟基-4-碘基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;(S)-N-(2,3-二羥丙基)-4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;及(S)-5-氯基-N-(2,3-二羥丙基)-4-(2-氟基-4-碘基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺。
本發明特別的新穎化合物也包括下列化合物:4-(4-溴基-2-氟基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺;及(S)-4-(4-溴基-2-氟基苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺。
本發明還有的另一觀點係提供化合物,包括其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化物及醫藥上可接受之鹽類,該化合物具有化學式IV:
其中:R1
為Cl或F;R3
為H、Me、Er、OH、MeO-、EtO-、HOCH2
CH2
O-、HOCH2
C(Me)2
O-、(S)-MeCH(OH)CH2
O-、
(R)-HOCH2
CH(OH)CH2
O-、環丙基-CH2
O-、HOCH2
CH2
-、
R7
為甲基或乙基,其中該甲基及乙基視需要被一或多個F取代;R8
為Br、I或SMe;及R9
為H、C1
-C4
烷基、Cl或CN,其中該烷基視需要被一或多個獨立選自F或CN之基團取代,其先決條件係當:a)R1
為F,R8
為Br,R9
為H及R7
為Me或Et時,則R3
不可能為HOCH2
CH2
O;b)R1
為F,R8
為I,R9
為H及R3
為MeO時,則R7
不可能為Me;c)R1
為F,R8
為Me,R9
為H及R3
為HOCH2
CH2
O時,則R7
不可能為Me;及d)R1
為F,R8
為Br,R9
為H及R3
為環丙基-CH2
O時,則R7
不可能為Me。
在另一具體實例中,其係提供化合物,包括其互變體、代謝物、解析之鏡像異構物、非鏡像異構物、溶劑化物及醫藥上可接受之鹽類,該化合物具有化學式IVA:
其中:
R1
為Cl或F;R3
為H、Me、OH、MeO-、EtO-、HOCH2
CH2
O-、MeOCH2
CH2
O-、HOCH2
CH2
CH2
-、
R7
為甲基或乙基,其中該甲基及乙基視需要被一或多個F取代;R8
為Br、I或SMe;及R9
為H、C1
-C4
烷基、Cl或CN,其中該烷基視需要被一或多個獨立選自F或CN之基團取代,其先決條件係當:a)R1
為F,R8
為Br,R9
為H及R7
為Me或Et時,則R3
不可能為HOCH2
CH2
O;b)R1
為F,R8
為I,R9
為H及R3
為MeO時,則R7
不可能為Me;c)R1
為F,R8
為Me,R9
為H及R3
為HOCH2
CH2
O時,則R7
不可能為Me;及d)R1
為F,R8
為Br,R9
為H及R3
為環丙基-CH2
O時,則R7
不可能為Me。
在一個具體實例中,在式IV或IVA化合物中,R9
為H、Me、Et、Cl或CN。
在一個具體實例中,根據本發明的化合物具有化學式V:
或其醫藥上可接受之鹽,其中:R3
為HOCH2
CH2
O或(S)-MeCH(OH)CH2
O;及R9
為H、CH3
、F或Cl,其先決條件係當R1
為F,R8
為SMe,R9
為Cl及R7
為Me時,則R3
不可能為HOCH2
CH2
O。
其中R3
為HOCH2
CH2
O或(S)-MeCH(OH)CH2
O之式V化合物為有效的MEK抑制劑。
本發明特別的新穎化合物包括下列中任一者:2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;及
(S)-5-氯基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
在一個具體實例中,根據本發明的化合物具有化學式VI:
或其醫藥上可接受之鹽,其中:R1
為Cl或F;R3
為H、HOCH2
CH2
O或(S)-MeCH(OH)CH2
O;及R9
為H、Me、F或Cl。
其中R1
為Cl,R3
為HOCH2
CH2
O或(S)-MeCH(OH)CH2
O及R9
為H之式VI化合物為有效的MEK抑制劑。
其中R1
為F,R3
為H及R9
為Me之式VI化合物為有效的MEK抑制劑。
其中R3
為HOCH2
CH2
O或(S)-MeCH(OH)CH2
O之式VI化合物為有效的MEK抑制劑。
其中R1
為F,R3
為HOCH2
CH2
O及R9
為Me之式VI化合物為有效的MEK抑制劑及也具有好的溶解度。如本文所使用的術語〝好的溶解度〞係指具有大於50微克/毫升之溶解度的化合物,例如約50至270微克/毫升之溶解度,如實施例C之方法所測定。
根據本發明特別的新穎式VI化合物包括下列中任一者:2-(2-氯基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氯基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氟基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氟基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;2-(2-氯基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;5-氯基-2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氯基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-5-氯基-2-(2-氟基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;5-氟基-2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;
(S)-5-氟基-2-(2-氟基-4-碘基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;及2-(4-溴基-2-氟基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
在另一具體實例中,其係提供其中R1
為F,R3
為HOCH2
CH2
O及R9
為甲基之式VI化合物或其醫藥上可接受之鹽。
頃發現式XI化合物
可以在下列被命名為型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺及型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的兩種結晶型式存在,而且型式2可被轉換成型式1。
式XI化合物特別的結晶型式樣品係使用X-射線粉末繞射分析法與微差掃描熱量法的組合所分析,如實施例16E及16F所述。
本文所述之本發明係關於式XI化合物之結晶型式,如以X-射線粉末繞射數據所測定之結晶度適宜大於約60%,更適宜大於約80%,以大於約90%較佳及以大於約95%更佳。
根據本發明進一步的觀點,其係提供實質上具有型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物之結晶型式。
根據本發明進一步的觀點,其係提供實質上具有型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物之結晶型式。
具有型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物具有以2 θ值計在約9.5至12.6之特徵化峰波的X-射線繞射圖。根據本發明進一步的觀點,其係提供具有型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物具有以2 θ值計在約9.5、12.6、14.7及19.6之特徵化峰波的X-射線繞射圖。
型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺具有實質上如下列圖10所示之X-射線繞射圖,其具有在表A所示之大約位置上的特徵化峰波[以2 θ值計]。
具有型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧
基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物具有以2 θ值及在約9.2至13.0之特徵化峰波的X-射線繞射圖。根據本發明進一步的觀點,其係提供具有型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物具有以2 θ值計在約9.2、13.0、18.3、21.0及21.7之特徵化峰波的X-射線繞射圖。
型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺具有實質上如下列圖11或12所示之X-射線繞射圖,其具有在表B所示之大約位置上的特徵化峰波[以2 θ值計]。
如上所述,在XRPD繞射圖的峰波強度可展現一些可變性,其係依據所使用的測量條件而定。因此在表A及B中及如下列的引述,相對強度不以數字陳述。反而使用下列的強度定義:
其中相對強度係衍生自以不同的狹縫所測量的X-射線繞射圖。如所見,在圖10至13的X-射線繞射圖中出現的一些更小的峰波被從表A及表B刪除。
具有型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的
式XI化合物具有實質上如圖10所示之X-射線繞射圖。
具有型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物具有實質上如圖11或12所示之X-射線繞射圖。
在定義2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之結晶型式的X-射線粉末繞射峰波的上述段落中,在〝..以2 θ值計在約..上〞之語句中所使用的術語〝在約..上〞表示峰波的精確位置(即所敘述之2-θ角值)不應被解釋成絕對值,因為如那些熟諳本技藝者所認知之峰波的精確位置在互不相同的機器及在互不相同的樣品之間可能有些微的改變,或由於所使用的測量條件而有些微的變化。在上述段落中也陳述2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之結晶型式提供〝實質上〞與圖10至13中所示之X-射線粉末繞射圖相同的X-射線粉末繞射圖,而且實質上具有分別在表A及B中所示之最顯著的峰波(2-θ角值)。應認知的是也希望以本上下文所使用的〝實質上〞術語表示X-射線粉末繞射圖的2-θ角值可隨互不相同的機器、互不相同的樣品或由於所使用的測量條件而有些微的改變,所以在圖中或在表A及B中所引述的峰波位置再次不被解釋成絕對值。
在本文揭示用於製備或型式1或2之式XI化合物的方法。
在一個觀點中,用於製備實質上具有型式1,2-(2-氟基
-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的XI化合物的方法包含:a)使2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-乙烯氧基乙氧基)-醯胺與酸性混合物以充份的時間接觸,使化合物轉換成2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;b)允許來自步驟a)之物質從含有型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之晶種的有機溶劑溶液中結晶;及c)分離型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
在一個觀點中,在步驟a)中的酸性混合物可為無機或有機酸。在另一個觀點中,步驟a)可在兩相水性酸-醋酸乙酯溶劑系統中實行。在一個觀點中,在步驟a)中的有機溶劑為醋酸乙酯。
在另一個觀點中,用於製備具有型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物的方法包含:a)使型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺與少量的型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺在有機溶劑中攪動;及
b)分離型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
在一個觀點中,在步驟a)中所使用的型式1物質的量為約5重量/重量%。
在另一個觀點中,在步驟a)中的反應係在醋酸乙酯中及在略高於室溫的溫度下實行,如從約50至60℃。
在另一個觀點中,本發明提供一種用於製備根據申請專利範圍第1項之實質上具有型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之形式的式XI化合物的方法,其包含:a)使2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-乙烯氧基乙氧基)-醯胺與酸性混合物以充份的時間接觸,使化合物轉換成2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;b)允許來自步驟a)之物質從有機溶劑中結晶;及c)分離型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
在一個觀點中,在步驟b)中的有機溶劑包括型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之晶種。在步驟a)中的酸性混合物可為無機或有機酸,而且步驟a)可在有機溶劑中實行,如THF。在一個觀點中,在步驟a)中的有機溶劑可選自醋酸乙酯及甲基異丁酮,兩者視需要係在異己烷的存在
下。
本發明的特定化合物可以二或多種互變體型式存在。〝互變體〞為二或多種以等量存在且可輕易從一種異構型轉換成另一種的結構性異構物中之一,如在相同的分子內以氫原子從一邊移動至另一邊所形成的結構。化合物的其它互變體型式可經由例如烯醇化/去烯醇化及類似方式互相交換。因此本發明包括本發明化合物的所有互變體型式之製備。
本發明的化合物可具有一或多個不對稱中心;這些化合物因此可生成個別的(R)-或(S)-組態或成為其混合物。除非有其它另外的指示,在專利說明書及申請專利範圍中特殊的化合物的說明及命名意圖包括其兩種個別的鏡像異構物、非鏡像異構物混合物、外消旋物或其它等。因此本發明也包括所有這些異構物,包括本發明化合物的非鏡像異構物混合物及解析之鏡像異構物。非鏡像異構物混合物可藉由那些熟諳本技藝者已知的方式以彼等的物理化學差異為基準分離成彼等個別的非鏡像異構物,例如藉由色層分離法或分餾結晶法。鏡像異構物的分離可藉由與適當的旋光活性化合物(例如醇)反應而使鏡像異構物混合物轉換成非鏡像異構物混合物,分離非鏡像異構物及使個別的非鏡像異構物轉換(例如水解)成對應之純鏡像異構物。用於測定立體化學性及分離立體異構物的方法為本技藝所熟知(參見J.March,John Wiley and Sons,New York,1992年第4版〝Advanced Organic Chemistry〞的第4章中的討論)。
本發明也包含含有本發明化合物之醫藥組成物及以投予本發明化合物治療增殖性疾病或不正常的細胞生長的方法。具有自由胺基、醯胺基、羥基或羧酸基團之本發明化合物可被轉換成醫藥上可接受之前體藥物。
〝前體藥物〞為可在生理條件下或以溶劑分解而轉換成特殊的化合物或該化合物在醫藥上可接受之鹽的化合物。前體藥物包括其中胺基酸殘基或二或多個(例如2、3或4個)胺基酸殘基的多肽鏈經由醯胺或酯鍵與本發明化合物的自由胺基、羥基或羧酸基團共價連結之化合物。胺基酸殘基包括(但不限於)20個常以三個字母符號命名的天然生成之胺基酸,並也包括4-羥基脯胺酸、羥基賴胺酸、迪莫辛(demosine)、異迪莫辛(isodemosine)、3-甲基組胺酸、正纈胺酸、β-丙胺酸、γ-胺基丁酸、瓜胺酸、高半胱胺酸、高絲胺酸、鳥胺酸及蛋胺酸碸。本發明的一種較佳的前體藥物為與纈胺酸殘基共價連結的本發明化合物。
也包含另外型式的前體藥物。例如可將自由羧基衍生成醯胺或烷基酯。作為另一實例之含有自由羥基之本發明化合物可衍生成前體藥物,其係藉由使羥基轉換成磷酸酯、半琥珀酸酯二甲基胺基醋酸酯或磷醯氧基甲氧基羰基,如Advanced Drug Delivery Reviews,1996,19,115所述。也包括羥基及胺基之胺基甲酸酯前體藥物,如為碳酸酯前體藥物、磺酸酯前體藥物、羥基的磺酸酯及硫酸酯。也包含羥基之衍生物,如(醯氧基)甲基及(醯氧基)乙基醚,其中醯基可為視需要被包括(但不限於)醚、胺及羧酸官能度
之基團取代之烷基酯,或其中醯基為如上述之胺基酸酯。該型式的前體藥物說明在J.Med.Chem.,1996,39,10中。更特殊的實例包括以下列基團置換醇基之氫原子,如(C1
-C6
)烷醯氧基甲基、1-((C1
-C6
)烷醯氧基)乙基、1-甲基-((C1
-C6
)烷醯氧基)乙基、(C1
-C6
)烷氧基羰氧基甲基、N-(C1
-C6
)烷氧基羰胺基甲基、琥珀醯基、(C1
-C6
)烷醯基、α-胺基(C1
-C4
)烷醯基、芳醯基及α-胺醯基或α胺醯基-α-胺醯基(每一個α-胺醯基係獨立選自天然生成之L-胺基酸、P(O)(OH)2
、-P(O)(O(C1
-C6
)烷基)2
或糖基(從移除碳水化合物的半縮醛型式的羥基所得之基)。
自由胺也可衍生成醯胺、磺醯胺或膦醯胺。例如前體藥物可藉由以下列基團置換在胺基中的氫原子所形成,如R-羰基、RO-羰基、NRR’-羰基,其中R及R’各自獨立為(C1
-C10
)烷基、(C3
-C7
)環烷基、苯甲基,或R-羰基為天然的α-胺醯基或天然的α-胺醯基-天然的α-胺醯基、-C(OH)C(O)OY(其中Y為H、(C1
-C6
)烷基或苯甲基)、-C(OY0
)Y1
(其中Y0
為(C1
-C4
)烷基及Y1
為(C1
-C6
)烷基、羧基(C1
-C6
)烷基、胺基(C1
-C4
)烷基或單-N-或二-N,N-(C1
-C6
)烷胺基烷基)、-C(Y2
)Y3
(其中Y2
為H或甲基及Y3
為單-N-或二-N,N-(C1
-C6
)烷胺基)、嗎啉基、六氫吡啶-1-基或吡咯啶-1-基。
所有這些前體藥物部分可併入包括(但不限於)醚、胺及羧酸官能度之基團。
本發明化合物的前體藥物可使用本技藝已知的例行技
術鑑定。各種型式的前體藥物為本技藝所知。關於這些前體藥物衍生物的實例,參見例如a)由H.Bundgaard所編輯之Design of Prodrugs(Elsevier,1985)及由K.Widder等人編輯之Methods in Enzymology,Vol.42,p.309-396(Academic Press,1985);b)由Krogsgaard-Larsen與H.Bundgaard編輯之A Textbook of Drug Design and Development,H.Bundgaard的第5章”Design and Application of Prodrugs”,p.113-191(1991);c)H.Bundgaard之Advanced Drug Delivery Reviews,8,1-38(1992);d)H.Bundgaard等人之Journal of Pharmaceutical Sciences,77:285(1988);及e)N.Kakeya等人之Chem.Pharm.Bull.,32:692(1984),將每一個特別併入本文以供參考。
此外,本發明也包括本發明化合物的溶劑化物、代謝物及醫藥上可接受之鹽類。
〝溶劑化物〞術語係指分子與一或多種溶劑分子之聚集體。
〝代謝物〞為特殊的化合物或其鹽在身體內經由活體內代謝作用所產生的藥理活性產物。這些產物可由例如所投予之化合物的氧化、還原、水解、醯胺化、去醯胺化、酯化、去酯化、酵素裂解及類似作用所得。因此,本發明包括本發明化合物的代謝物,包括以含有使本發明化合物與哺乳類以充份得到其代謝產物的時間接觸之方法所產生的化合物。
代謝物的鑑定典型係藉由製備本發明化合物的放射標
記同位素(例如14
C或3
H),將其以可偵測之劑量(例如大於約0.5毫克/公斤)以非經腸方式投予哺乳類(如大鼠、小鼠、天竺鼠、猴子或人類),允許充份發生代謝作用的時間(典型係約30秒至30小時)及從尿、血液或其它生物樣品分離其轉換產物。這些產物可輕易分離,因為產物被加上標記(使用能夠結合存活在代謝物中的抗原表位的抗體分離其它產物)。代謝物結構係以慣用的方式測定,例如以MS、LC/MS或NMR分析。通常代謝物的分析係以與那些熟諳本技藝者熟知慣用的藥物代謝研究相同的方式進行。代謝物可用於以治療給予本發明化合物的診斷檢定法,只要其不以其它方式被發現在活體內即可。
如本文所使用的〝醫藥上可接受之鹽〞包括保留指定的化合物之自由酸與鹼的生物有效性及不是生物學或其它方面不希望的鹽類,除非有其它另外的指示。本發明的化合物可具有足夠的酸性、足夠的鹼性或兩種官能基團,並因此與許多無機或有機鹼及無機或有機酸中任一反應,以形成醫藥上可接受之鹽。醫藥上可接受之鹽類的實例包括藉由本發明化合物與無機或有機酸或無機鹼反應所製備的那些鹽類,這些鹽類包括硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、磷酸單氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、醋酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸鹽、甲酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、丙炔酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、辛二酸鹽、癸二酸鹽、富馬酸鹽、馬來酸鹽、
丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、苯甲酸鹽、氯基苯甲酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、羥基苯甲酸鹽、甲氧基苯甲酸鹽、苯二甲酸鹽、磺酸鹽、二甲苯磺酸鹽、苯基醋酸鹽、苯基丙酸鹽、苯基丁酸鹽、檸檬酸鹽、乳酸鹽、γ-羥基丁酸鹽、乙醇酸鹽、酒石酸鹽、甲烷磺酸鹽、丙烷磺酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽及扁桃酸鹽。因為本發明的單一化合物可包括一種以上的酸性或鹼性部分,所以本發明的化合物可包括在單一化合物中的單-、二-或三-鹽類。
如果本發明的化合物為鹼,則所欲之醫藥上可接受之鹽可藉由在本技藝中適用的任何適合的方法製備,例如以酸性化合物處理自由鹼,特別以無機酸,如鹽酸、氫溴酸、硫酸、硝酸、磷酸及類似物,或以有機酸,如醋酸、馬來酸、琥珀酸、扁桃酸、富馬酸、丙二酸、丙酮酸、草酸、乙醇酸、水楊酸、吡喃糖酸(如葡萄糖醛酸或半乳糖醛酸)、α-羥酸(如檸檬酸或酒石酸)、胺基酸(如天冬胺酸或麩胺酸)、芳香酸(如苯甲酸或肉桂酸)、磺酸(如對-甲苯磺酸或乙烷磺酸)或類似物。
如果本發明的化合物為酸,則所欲之醫藥上可接受之鹽可藉由任何適合的方法製備,例如以無機或有機鹼處理自由酸。較佳的無機鹽類為那些以鹼及鹼土金屬所形的鹽類,如以鋰、鈉、鉀、鋇及鈣。較佳的有機鹼鹽類包括例如銨、二苯甲銨、苯甲銨、2-羥乙銨、雙(2-羥乙基)銨、苯乙基苯甲胺、二苯甲基乙撐二胺及類似的鹽類。酸性部分
的其它鹽類可包括例如那些以普鹵卡因(procaine)、奎寧及N-甲基葡萄糖胺所形成的鹽類,加上以鹼性胺基酸所形成的鹽類,如以甘胺酸、鳥胺酸、組胺酸、苯基甘胺酸、賴胺酸及精胺酸。
提供用於製造本發明化合物的方法作為本發明進一步的特點。本發明的化合物可使用如以下所述之反應途徑及合成流程製備,其係使用在本技藝中適用的技術,使用可輕易取得或可使用本技藝已知的方法合成的原料。
本發明化合物的製備法圖解展示在圖1-7中。
將化合物96的製備法描述在圖1中。經取代之肼28可以兩步驟過程轉換成丙酸亞肼酯29。在第一步驟中,將肼28與丙酮酸乙酯在標準的脫水條件下(如在MgSO4
的存在下),在適合的有機溶劑中(如氯仿或二氯甲烷)及在從0℃至室溫為範圍的溫度下縮合。在第二步驟中,醯化作用係藉由以鹼在低溫下及在適合的有機溶劑中(如THF、DMF、二烷或MeCN)處理,接著加入甲基丙二醯氯而達成。在一個具體實例中,將腙在0℃下以在THF中的LiH處理,接著加入甲基丙二醯氯及溫熱至室溫。羥基嗒酮31係自丙酸亞肼酯29所製備,其係藉由在強鹼條件下的環化作用及接著以去羧基化作用。環化作用可藉由以在適合的有機溶劑中(如THF或MeCN)的強鹼(如DBU、LDA或NaH)在室溫下處理丙酸亞肼酯29而完成。在一個具體實例中,環化作用係以在MeCN中的DBU在室溫下所達成。形成羥基嗒酮31的去羧基化作用可藉由使在適合的有機溶
劑中(如二烷或十氫萘或二烷/十氫萘之混合物)的甲酯嗒酮在濃縮HCl的存在下加熱至高溫。羧酸94可自羥基嗒酮31以兩步驟過程製備,即以氯化作用及接著以氧化作用。氯化步驟可藉由以POCl3
、亞磺醯氯、草醯氯或PCl5
處理而達成。在一個具體實例中,該轉變作用可以純POCl3
在上升的溫度下(~85℃)達成。在氯化步驟之後,羧酸94可藉由在標準條件下的氧化作用製備,包括(但不限於)在水中的KMnO4
、在有機溶劑中(如二烷、二甲苯或吡啶)中的SeO2
,在水性H2
SO4
中的NaOCl/RuCl3
,CrO3
,在水中的K2
Cr2
O7
與Na2
Cr2
O7
。在一個具體實例中,該轉變作用係以K2
Cr2
O7
-H2
SO4
達成。羧酸94可以兩步驟過程轉換成嗒酮酯95,該過程包括嗒酮酸94之酯化作用,接著以鈀介入之交叉偶合反應。酯化作用可在標準條件下進行,包括(但不限於)在MeOH中的濃縮HCl,在MeOH中的TMSCl或在適合的有機溶劑中(如醚/MeOH、THF/MeOH或PhMe/MeOH)的TMSCHN2
。以鈀介入之交叉偶合反應可以標準條件達成,包括(但不限於)以在適合的有機溶劑中(如THF、DMF、PhMe、DME或MeCN)的苯胺、鈀觸媒(如Pd(OAc)2
、PdCl2
(dppf)、Pd(Ph3
P)4
或Pd2
dba3
)、膦配體及鹼在上升的溫度下處理氯基嗒酮酯。在一個具體實例中,交叉偶合反應包含以在甲苯中的Pd(OAc)2
、外消旋性-2,2-雙(二苯膦基)-1,1’-聯萘及Cs2
CO3
在70至100℃下處理酯94。在其中希望R9
=Br之化合物95的具體實例中,可在交叉偶合反應之後併入溴取代基。嗒酮的溴化作用可以在適合的有機
溶劑中(如DMF、MeCN或混合的溶劑系統)的NBS在室溫下完成。在一個具體實例中,溴化作用係在DMF中實行。羥肟酸酯96可藉由以在適合的有機溶劑中(如THF)適當的羥胺及醯胺鹼(如LDA、LiHMDS或NaHMDS)在低溫下處理嗒酮酯95所製備。在一個具體實例中,將LiHMDS溶液加入在0℃下在THF中的嗒酮酯95及羥胺之溶液中。接著將反應混合物溫熱至室溫,得到所欲之羥肟酸酯96。在一些實例中,在偶合反應中所使用的羥胺包括標準的保護基。在那些例子中,保護基可以本技藝中已知的標準條件移除。
圖2概述化合物96、100、101及102的合成法。經取代之肼28可根據兩步驟過程中之一轉換成丙二酸亞肼酯97。在一個具體實例中,在醯化作用之後的經取代之肼28的縮合作用特別有用於其中R9
為烷基或鹵素之類似物。在該具體實例中,可將肼28與2-酮基丙二酸二乙酯在使用丁史塔克(Dean-Stark)阱的標準脫水條件下,在適合的有機溶劑中(如苯或甲苯)及在從80至120℃為範圍的溫度下縮合。以輸送醯基提供丙二酸亞肼酯97的試劑之醯化作用係藉由以鹼在適當的溫度下及在適合的有機溶劑中(如THF、DMF、二烷或MeCN)處理,接著加入醯化劑而達成。醯化劑的實例為熟諳本技藝者所熟知,並包括(但不限於)醯基氯、酸酐及活化酯。在一個具體實例中,將腙以在THF中的LiH在0℃下處理,接著加入醯基氯及在25至60℃下攪拌,以提供化合物97。用於合成其中R9
不為鹵素之化合物
97的可替換方法包含以輸送醯基的試劑將肼28醯化,接著與2-酮基丙二酸二乙酯縮合,以提供丙二酸亞肼酯97。根據該方法,可將經取代之肼28以標準的醯化方法轉換成醯肼。在一個具體實例中,該轉變作用係以適當的醯基氯在二氯甲烷中及在0℃至室溫下達成。所獲得的醯肼與酮基丙二酸二乙酯在使用丁史塔克阱的標準脫水條件下,在適合的有機溶劑中(如苯或甲苯)及在從80至130℃之溫度下縮合。嗒酮99係自丙二酸亞肼酯97所製備,其係藉由在鹼性條件下的環化作用,以提供中間化酸或酯98,接著以氯化作用提供嗒酮99。環化作用可藉由以醯胺鹼(如LiHMDS、NaHMDS、KHMDS或LDA)在適合的有機溶劑中(如THF或醚)及在低溫下處理丙二酸亞肼酯7而完成。在一個具體實例中,環化作用係以在THF中的LiHMDS在低溫下(-78至-40℃),接著以濃縮的HCl處理所達成,得到98之酯衍生物(R=Et)。在另一具體實例中,98之酸衍生物(R=H)係藉由嗒酮酯98當場的皂化作用所獲得。在完成環化作用時,將反應應混合在低溫下(-78至-40℃)以水中止,接著以攪拌溫熱至室溫,接著酸化。接著嗒酮99係自嗒酮酸或酯98所製備,其係藉由以POCl3
、亞磺醯氯或PCl5
處理。在一個具體實例中,該轉變作用可以純POCl3
在上升的溫度下(~85℃)達成。當R9
不為F時,則嗒酮酸99(當R=H時)接著轉變成嗒酮101。苯胺部分的併入係藉由在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當溫度下(-78℃至室溫)
的SN
Ar反應所完成。在一個具體實例中,將苯胺加入在低溫下(-20至-80℃)在THF中的LDA或LiHMDS中。接著加入嗒酮酸99(R=H),並將反應混合物溫熱至室溫,以產生羧酸101。接著羥肟酸酯96及醯胺102可自酸101製備,其係使用標準的偶合試劑(如(但不限於)1-(3-二甲胺基丙基)-3-乙基碳二醯亞胺鹽酸鹽(EDCI)、1-羥基苯并三唑-6-磺醯胺甲基鹽酸鹽(HOBt)或六氟磷酸苯并三唑-1-基-氧基三吡咯啶鏻(PyBOP))及適當的胺或羥胺在適合的有機溶劑中(如DMF、THF或二氯甲烷)。在一些實例中,胺或羥胺包括標準的保護基。在那些例子中,保護基可以本技藝中已知的標準條件移除。另一選擇係酯嗒酮99(R=Et)可經由嗒酮酯100以圖1中所述之標準方法轉換成羥肟酸酯96。當希望R8
=Br或I時,則所欲之鹵素可使用在適合的有機溶劑或混合的溶劑系統中(如DMF、THF-MeOH或AcOH-THF)的NBS或NIS在適當的酸觸媒存在下併入。
在圖3的化合物109、110及111合成法中,其中使用2,6-二氯基煙鹼酸作為原料。煙鹼酸103係藉由在2N水性NaOH中回流及接著以美國專利第3,682,932號所述之步驟而轉換成單氯基酸104。提供105的104烷基化作用可藉由併入烷基鹵的標準鹼性烷基化條件達成,以2當量適當的烷基鹵與鹼得到N-烷基吡啶酮酯105與位向異構物O-烷基吡啶酯之混合物,其可輕易以管柱色層分離法分離。這些條件包括(但不限於)在丙酮或DMF中的K2
CO3
在室溫或上升的溫度下或在THF中的NaH在室溫或上升的溫度下及接
著加入烷基鹵。在特定的具體實例中,該烷基化作用係以在DMF中的LiH在0℃下,接著加入烷基溴或烷基碘及溫熱至室溫而達成。吡啶酮酯105的溴化作用可以或Br2
及醋酸或在適合的有機溶劑中(如DMF)的NBS完成。在特定的具體實例中,將NBS加入在DMF中的吡啶酮酯105之溶液中,得到106。以溴化物106成為化合物107的轉換作用可使用以Pd介入之交叉偶合反應達成。當R9
=烯基或炔基時,則這些化合物可使用適當的還原劑進一步還原,以提供在R9
上的烷基取代基。通常該化學可使用廣泛不同的Pd觸媒及配體,以或不以所加入的鹼,在適合的有機溶劑中(如DMF、PhMe、DME、THF、CH3
CN)及在上升的溫度下完成。偶合伙伴將依據R9
的性質而定。例如如果希望R9
=CN時,則偶合伙伴為Zn(CN)2
。該反應可以在NMP中的Pd2
dba3
及dppf在120℃下實行。這些以鈀介入之交叉偶合為文獻中完整記錄及為熟諳本技藝這所熟知。以併入適當取代之苯胺部分提供108的作用係藉由SN
AR反應所完成。這可在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當的溫度下(-78℃至室溫)進行。在特定的具體實例中,將苯胺加入在低溫下(-20至-80℃)在THF中的LDA或LiHMDS中。接著加入吡啶酮105及將混合物在低溫下攪拌,以產生酯108。接著羧酸109可使用標準的皂化條件製備,如在標準的混合水性/有機溶劑系統中的LiOH或NaOH。羥肟酸酯110及醯胺111可使用標準的偶合步驟製備,包括(但不限於)在適合的有機溶劑中(如
DMF、THF或二氯甲烷)的EDCI、HOBt或ByBOP及適當的胺或羥胺。在特定的具體實例中,偶合係以在DMF中的HOBt及EDCI完成。在一些實例中,在偶合反應中所使用的胺或羥胺包括標準的保護基。在那些例子中,保護基可以本技藝中已知的標準條件移除。
圖4展示用於合成化合物109、110及111的可替換之反應流程。該途徑特別有用於其中R7
不等於Me或Et之類似物。在七步驟過程之後,煙鹼酸103被轉換成N-烷基吡啶酮甲酯114,其中2,6-二氯基煙鹼酸103先被轉換成甲氧基吡啶酸,將其酯化,得到甲酯,並接著去保護,得到單氯基酯112。在特定的具體實例中,成為甲氧基吡啶酸的轉化作用係藉由將第三丁醇鉀加入在MeOH中的酸103之溶液中及接著將該混合物加熱至回流數天所實行。用於得到甲酯的酯化作用可在標準的條件下實行,包括(但不限於)菲雪爾(Fisher)酯化作用(MeOH,H2
SO4
)、在MeOH中的TMSCl或在適合的有機溶劑中(如PhMe/MeOH)的TMSCHN2
。接著甲氧基吡啶的去甲基化作用係以標準的條件完成,包括(但不限於)HCl在上升的溫度下、在醋酸中的pTsOH在上升的溫度下及在MeOH中的水性HBr在上升的溫度下。得到吡啶酮112的較佳的去甲基化作用係藉由以在醋酸中的水性HBr在上升的溫度下(80至120℃)處理甲氧基吡啶所達成。112的烷基化作用可藉由併入烷基鹵的標準的鹼性烷基化條件達成,以1當量適當的烷基鹵與鹼得到N-烷基吡啶酮酯113與位向異構物O-烷基吡啶酯之混合
物,其可輕易以管柱色層分離法分離。這些條件包括(但不限於)在丙酮或DMF中的K2
CO3
在室溫或上升的溫度下或在THF中的NaH在室溫或上升的溫度下及接著加入烷基鹵。在特定的具體實例中,該烷基化作用係以在DMF中的LiH在0℃下,接著加入烷基溴或烷基碘及溫熱至室溫而達成。吡啶酮酯113的溴化作用可以或Br2
及醋酸或在適合的有機溶劑中(如DMF)的NBS完成。在特定的具體實例中,將NBS加入在DMF中的吡啶酮酯113之溶液中,得到114。以溴化物114成為化合物115的轉換作用可使用以鈀介入之交叉偶合反應達成。當R9
=烯基或炔基時,則這些化合物可使用適當的還原劑進一步還原,以提供在R9
上的烷基取代基。通常該化學可使用廣泛不同的Pd觸媒及配體,以或不以所加入的鹼,在適合的有機溶劑中(如DMF、PhMe、DME、THF、CH3
CN)及在上升的溫度下完成。偶合伙伴將依據R9
的性質而定。這些以Pd介入之交叉偶合為文獻中完整記錄且為熟諳本技藝者所熟知。以併入適當取代之苯胺部分提供116的作用係藉由SN
AR反應所完成。這可在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當的溫度下(-78℃至室溫)進行。在特定的具體實例中,將苯胺加入在低溫下(-20至-80℃)在THF中的LDA或LiHMDS中。接著加入吡啶酮115及將混合物在低溫下攪拌,以產生酯116。以116成為羧酸109與羥肟酸酯110及醯胺111的轉換作用可如圖3所述之方式完成。另一選擇係羥肟酸酯110可從在適合的有機溶劑
中(如THF)的甲酯116在適當的溫度下(-78℃至室溫)直接製備,其係使用適當的羥胺及醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)。在特定的具體實例中,將LiHMDS之溶液加入在0℃下在THF中的酯116及羥胺之溶液中。接著將反應混合物溫熱至室溫,得到所欲之羥肟酸酯110。在一些實例中,在偶合反應中所使用的羥胺包括標準的保護基。在那些例子中,保護基可以本技藝中已知的標準條件移除。
圖5展示用於合成化合物119、120及121之反應流程,其中使用N-烷基吡啶酮甲酯112作為原料。117的形成作用可藉由以SN
AR反應併入適當取代之苯胺部分而完成。這可在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當的溫度下(-78℃至室溫)進行。在特定的具體實例中,將苯胺加入在低溫下(-20至-80℃)在THF中的LDA或LiHMDS中。接著加入吡啶酮112及將混合物在低溫下攪拌,以產生酯117。這可在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當的溫度下(-78℃至室溫)進行。得到吡啶酮118的吡啶酮117之氯化作用可使用標準的條件完成,如在適合的有機溶劑中(如DMF)的NCS。以118成為羧酸119與羥肟酸酯120及醯胺121的轉換作用可如圖3及4所述之方式完成。
圖6展示用於合成化合物124及125的反應流程。4-氟基嗒酮123可自4-氯基嗒酮122製備,其係藉由在
適合的有機溶劑中(如CH3
CN、THF、DMF、NMP或DMSO)的具有或不具有鹼(如Et3
N或Me3
N)的KF或HF處理。在一個具體實例中,該轉變作用係由在DMSO中的KF在上升的溫度下(例如160℃)所達成。嗒酮酯123(當R=Et時)可被轉換成嗒酮124,其中苯胺部分的併入係以SnAr反應所完成。這可在適合的有機溶劑中(如DMF、EtOH、iPrOH、CH3
CN或THF)使用鹼(如CS2
CO3
、NaHCO3
、K2
CO3
或Na2
CO3
)在從80至160℃之溫度下進行。在一個具體實例中,將苯胺及Cs2
CO3
加入在DMF中的嗒酮123之溶液中及將反應混合物加熱至80℃。另一選擇係嗒酮酸123(R=H)可如那些在圖2中所述之標準方法轉換成嗒酮125。嗒酮124或125可如圖1或2所述之方式轉換成羥肟酸酯或醯胺。
圖7展示用於合成化合物128、129及130的反應流程,其中使用吡啶酮甲酯117作為原料。吡啶酮酯117的溴化作用可以Br2
及醋酸或在適合的有機溶劑中(如DMF)的NBS完成。較佳而言,將NBS加入在DMF中的吡啶酮酯117之溶液中,得到126。以溴化物126成為其中R9
為氰基之化合物127的轉換作用可使用以Pd介入之交叉偶合條件達成。通常該化學可使用廣泛不同的Pd觸媒及配體,以或不以所加入的鹼,在適合的有機溶劑中(如DMF、PhMe、DME、THF、CH3
CN或NMP)及在上升的溫度下完成。較佳而言,該反應係以在DMF中的Zn(CN)2
及Pd2
dba3
及dppf在120℃下實行。以127成為羧酸128與羥肟酸酯129及醯胺130
的轉換作用可如實例3及4所述之方式完成。
在圖8中描述其中R9
=H或F之式V化合物的合成法,其中使用2,6-二氯基煙鹼酸或2,6-二氯基-5-氟基煙鹼酸作為原料。該途徑特別有用於其中R7
為Me之類似物。煙鹼酸140係藉由在2N水性NaOH中回流及接著以美國專利第3682932號(1972年)所述之步驟而轉換成單氯基酸141。141的烷基化作用可藉由併入烷基鹵的標準的鹼性烷基化條件達成,以2當量適當的烷基鹵與鹼得到N-烷基吡啶酮酯與位向異構物O-烷基吡啶酯之混合物,其可輕易以管柱色層分離法分離。這些條件包括(但不限於)在丙酮或DMF中的K2
CO3
在室溫或上升的溫度下或在THF中的NaH在室溫或上升的溫度下及接著加入烷基鹵。較佳而言,該烷基化作用係以在DMF中的LiH在0℃下,接著加入烷基溴或烷基碘及溫熱至室溫而達成。以併入適當取代之苯胺部分提供143的作用係藉由SN
AR反應所完成。這可在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當的溫度下(-78℃至室溫)進行。較佳而言,將苯胺加入在低溫下(-20至-80℃)在THF中的LDA或LiHMDS中。接著加入吡啶酮及將混合物在低溫下攪拌,以產生酯143。接著羧酸144可使用標準的皂化條件製備,如在標準的混合水性/有機溶劑系統中的LiOH或NaOH。羥肟酸酯145及醯胺146可使用標準的偶合步驟製備,包括(但不限於)在適合的有機溶劑中(如DMF、THF或二氯甲烷)的EDCI、HOBt或ByBOP及適當的胺或羥胺。較佳而言,偶
合係以在DMF中的HOBt及EDCI完成。在一些實例中,在偶合反應中所使用的胺或羥胺包括標準的保護基。在那些例子中,保護基可以本技藝中已知的標準條件移除。
在圖9中描述其中R9
=H或F之式V化合物的可替換之合成法,其中使用2,6-二氯基煙鹼酸或2,6-二氯基-5-氟基煙鹼酸作為原料。在五步驟過程之後,煙鹼酸140可被轉換成N-烷基吡啶酮甲酯149,其中2,6-二氯基煙鹼酸140先被轉換成甲氧基吡啶酸,將其酯化,得到甲酯,並接著去保護,得到單氯基酯147。較佳而言,成為甲氧基吡啶酸的轉換作用係藉由將第三丁醇鉀加入在MeOH中的酸140之溶液中及接著將該混合物加熱至回流數天所實行。用於得到甲酯的酯化作用可在標準的條件下實行,包括(但不限於)菲雪爾酯化作用(MeOH,H2
SO4
)、在MeOH中的TMSCl或在適合的有機溶劑中(如PhMe/MeOH)的TMSCHN2
。接著甲氧基吡啶的去甲基化作用可以標準的條件完成,包括(但不限於)HCl在上升的溫度下、在醋酸中的pTsOH在上升的溫度下及在MeOH中的水性HBr在上升的溫度下。得到吡啶酮147的較佳的去甲基化作用係藉由以在醋酸中的水性HBr在上升的溫度下(80至120℃)處理甲氧基吡啶而達成。用於提供148的147之烷基化作用可藉由併入烷基鹵的標準的鹼性烷基化條件達成,以1當量適當的烷基鹵與鹼得到N-烷基吡啶酮酯與位向異構物O-烷基吡啶酯之混合物,其可輕易以管柱色層分離法分離。這些條件包括(但不限於)在丙酮或DMF中的K2
CO3
在室溫或上升的溫度下或在THF
中的NaH在室溫或上升的溫度下及接著加入烷基鹵。較佳而言,該烷基化作用係以在DMF中的LiH在0℃下,接著加入烷基溴或烷基碘及溫熱至室溫而達成。併入適當取代之苯胺部分係藉由SN
AR反應所完成。這可在適合的有機溶劑中(如THF)使用醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)在適當的溫度下(-78℃至室溫)進行。較佳而言,將苯胺加入在低溫下(-20至-80℃)在THF中的LDA或LiHMDS中。接著加入吡啶酮及將混合物在低溫下攪拌,以產生酯149。羥肟酸酯145可從在適合的有機溶劑中(如THF)的甲酯149在適當的溫度下(-78℃至室溫)直接製備,其係使用適當的羥胺及醯胺鹼(如LDA、LiHMDS、NaHMDS或KHMDS)。較佳而言,將LiHMDS之溶液加入在0℃下在THF中的甲酯149及羥胺之溶液中。接著將反應混合物溫熱至室溫,得到所欲之羥肟酸酯145。在一些實例中,在偶合反應中所使用的羥胺包括標準的保護基。在那些例子中,保護基可以本技藝中已知的標準條件移除。
本發明也關於一種用於治療在哺乳類中的高增殖性疾病之醫藥組成物,其包含治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物及醫藥上可接受之載體。在一個具體實例中,該醫藥組成物係用於治療癌症,如腦、肺、鱗狀細胞、膀胱、胃、胰臟、乳房、頭、頸、腎臟(renal)、腎臟(kidney)、卵巢、攝護腺、直腸、食道、睪丸、婦科或甲狀腺癌。在另一具體實例中,該醫藥組成物係用於治療非癌性高增殖性疾病,如皮膚(例如牛皮癬)、
再狹窄症或攝護腺(例如良性攝護腺肥大(BPH))的良性肥大。
本發發明也關於一種用於治療在哺乳類中的胰臟炎或腎臟疾病(包括增殖性腎絲球腎炎及以糖尿病誘發的腎臟疾病)或治療在哺乳類中的疼痛之醫藥組成物,其包含治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物及醫藥上可接受之載體。
本發明也關於一種用於預防在哺乳類中的囊胚移植之醫藥組成物,其包含治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物及醫藥上可接受之載體。
本發明也關於一種用於治療在哺乳類中與脈管生成或血管生成有關的疾病之醫藥組成物,其包含治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物及醫藥上可接受之載體。在一個具體實例中,該醫藥組成物係用於治療選自由腫瘤血管生成、慢性發炎疾病或其它發炎症狀所組成群之疾病,如類風濕性關節炎、動脈粥樣硬化症、發炎性腸道疾病、皮膚疾病(如牛皮癬、濕疹及硬皮病)、糖尿病、糖尿病視網膜病變、早產兒視網膜病變、與老化有關的黃斑病變、血管瘤、神經膠質瘤、黑色素細胞瘤、卡波西氏(Kaposi)肉瘤及卵巢、乳房、肺、胰臟、攝護腺、結腸與上皮癌。
本發明也關於一種治療在哺乳類中的高增殖性疾病之方法,其包含以治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物投予該哺乳類。在一個具體
實例中,該方法係關於治療癌症,如腦、肺、鱗狀細胞、膀胱、胃、胰臟、乳房、頭、頸、腎臟(renal)、腎臟(kidney)、卵巢、攝護腺、直腸、食道、睪丸、婦科或甲狀腺癌。在另一具體實例中,該方法係關於治療非癌性高增殖性疾病,如皮膚(例如牛皮癬)、再狹窄症或攝護腺(例如良性攝護腺肥大(BPH))的良性肥大。
本發明也關於一種治療在哺乳類中的高增殖性疾病之方法,其包含以治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物與選自由有絲分裂抑制劑、烷基化試劑、抗代謝物、嵌入抗體、生長因子抑制劑、細胞週期抑制劑、酵素抑制劑、拓撲異構酶抑制劑、生物反應改良劑、抗激素、血管生成抑制劑及抗雄激素所組成群之抗腫瘤試劑組合投予該哺乳類。
本發明也關於一種治療在哺乳類中的胰臟炎或腎臟疾病之方法,其包含以治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物投予該哺乳類。
本發明也關於一種預防在哺乳類中的囊胚移植之方法,其包含以治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物投予該哺乳類。
本發明也關於一種治療在哺乳類中與脈管生成或血管生成有關的疾病之方法,其包含以治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物投予該哺乳類。在一個具體實例中,該方法係用於治療選自由腫瘤血管生成、慢性發炎疾病所組成群之疾病,如類風濕性關
節炎、動脈粥樣硬化症、發炎性腸道疾病、皮膚疾病(如牛皮癬、濕疹及硬皮病)、糖尿病、糖尿病視網膜病變、早產兒視網膜病變、與老化有關的黃斑病變、血管瘤、神經膠質瘤、黑色素細胞瘤、卡波西氏肉瘤及卵巢、乳房、肺、胰臟、攝護腺、結腸與上皮癌。
本發明也關於一種用於治療在哺乳類中與發炎性疾病、自身免疫性疾病、毀壞性骨疾病、增殖性疾病、感染性疾病、病毒性疾病、纖維化疾病或神經退化性疾病有關的疾病或症狀之醫藥組成物,其包含治療有效量之本發明化合物或其醫藥上可接受之鹽、前體藥物或水合物及醫藥上可接受之載體。上述疾病的實例包括(但不限於)類風濕性關節炎、動脈粥樣硬化症、發炎性腸道疾病、皮膚疾病(如牛皮癬、濕疹及硬皮病)、糖尿病及糖尿病併發症、糖尿病視網膜病變、早產兒視網膜病變、與老化有關的黃斑病變、血管瘤、慢性阻塞性肺疾病、原發性肺纖維化疾病、過敏性反應(包括氣喘過敏性鼻炎及異位性皮膚炎)、腎疾病及腎衰竭、多囊性腎疾病、急性冠狀徵候群、充血性心臟衰竭、骨關節炎、神經纖維瘤病、器官移植排斥、惡體質及疼痛。
進一步提供用作治療在溫血動物中(以哺乳類較佳,以人類更佳)的上述疾病及症狀之醫藥的本發明化合物,該動物承受該等疾病所苦。也提供本發明化合物在製備用於治療在溫血動物中(以哺乳類較佳,以人類更佳)的上述疾病及症狀之醫藥中的用途,該動物承受該等疾病所苦。
可根據本發明的方法以本發明的化合物或該化合物在
醫藥上可接受之鹽類、前體藥物及水合物治療的病患包括例如被診斷患有牛皮癬、再狹窄症、動脈粥樣硬化症、BPH、肺癌、骨癌、CMML、胰臟癌、皮膚癌、頭與頸癌、皮膚或眼內黑色素瘤、子宮癌、卵巢癌、直腸癌、肛門區域癌、胃癌、結腸癌、乳房癌、睪丸癌、婦科腫瘤(例如子宮肉瘤、輸卵管肉瘤、子宮內膜肉瘤、子宮頸肉瘤、陰道肉瘤或外陰部肉瘤)、何杰金氏(Hodgkin's)病、食道癌、小腸癌、內分泌系統癌(例如甲狀腺、副甲狀腺或腎上腺癌)、軟組織肉瘤、尿道癌、陰莖癌、攝護腺癌、慢性或急性白血病、孩童固體腫瘤、淋巴細胞淋巴瘤、膀胱癌、腎或輸尿管癌(例如腎細胞肉瘤、腎盂肉瘤)或中樞神精系統腫瘤(例如原發性CNS淋巴瘤、脊髓腫瘤、腦幹神經膠質瘤或腦下垂體腺瘤)之病患。
本發明也關於一種抑制在哺乳類中不正常的細胞生長之醫藥組成物,其包含本發明化合物或其醫藥上可接受之鹽、或溶劑化物或前體藥物量與化療劑量的組合,其中化合物、鹽、溶劑化物或前體藥物量與化療劑量一起有效抑制不正常的細胞生長。許多化療劑為本技藝中目前所知。在一個具體實例中,化療劑係選自由有絲分裂抑制劑、烷基化試劑、抗代謝物、嵌入抗體、生長因子抑制劑、細胞週期抑制劑、酵素、拓撲異構酶抑制劑、生物反應改良劑、抗激素、血管生成抑制劑及抗雄激素所組成的群組。
本發明進一步關於一種抑制在哺乳類中不正常的細胞生長或治療高增殖性疾病之方法,該方法包含以本發明化
合物或其醫藥上可接受之鹽、或溶劑化物或前體藥物量與放射治療法的組合投予哺乳類,其中化合物、鹽、溶劑化物或前體藥物量與有效抑制在哺乳類中不正常的細胞生長或治療高增殖性疾病的放射治療法組合。投予放射治療法的技術為本技藝中所知,並且這些技術可用在本文所述之治療法的組合中。在該組合治療法中的本發明化合物的投藥可如本文所述予以測定。
咸信本發明的化合物可使得不正常的細胞對以殺死及/或抑制這些細胞生長為目的的放射法治療更敏感。因此本發明進一步關於使哺乳類中的不正常細胞對放射法治療敏感的方法,其包含以本發明化合物或其醫藥上可接受之鹽、或溶劑化物或前體藥物量投予該哺乳類,該量有效使不正常細胞對放射法治療敏感。在該方法中的化合物、鹽或溶劑化物量可根據確定本文所述之這些化合物的有效量的方式測定。
本發明也關於一種抑制在哺乳類中不正常的細胞生長之方法及醫藥組成物,其包含本發明化合物或其醫藥上可接受之鹽、或溶劑化物、前體藥物或以同位素標記之衍生物量及一或多種選自抗血管生成劑、信號轉導抑制劑及抗增殖劑之物質量。
可將抗血管生成劑,如MMP-2(基質金屬蛋白酶2)抑制劑、MMP-9(基質金屬蛋白酶9)抑制劑及COX-II(環氧化酶II)抑制劑與本文所述之本發明化合物及醫藥組成物結合使用。有用的COX-II抑制劑的實例包括CELEBREXTM
(阿利
寇席(alecoxib))、伐地寇席(valdecoxib)及若菲寇席(rofecoxib)。有用的基質金屬蛋白酶抑制劑的實例說明在WO 96/33172、WO 96/27583、EP 818442、EP 1004578、WO 98/07697、WO 98/03516、WO 98/34918、WO 98/34915、WO 98/33768、WO 98/30566、EP 606,046、EP 931,788、WO 90/05719、WO 99/52910、WO 99/52889、WO 99/29667、WO 99/07675、EP 945864、美國專利第5,863,949號、美國專利第5,861,510號及EP 780,386,將所有專利以其全文併入本文以供參考。更佳的MMP-2及/或MMP-9抑制劑為那些具有小的或不具任何抑制MMP-1活性之抑制劑。更佳的是那些選擇性抑制關於其它基質金屬蛋白酶(即MMP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12及MMP-13)的MMP-2及/或MMP-9之抑制劑。
〝不正常的細胞生長〞及〝高增殖性疾病〞術語在本申請案中交互使用。
如本文所使用的〝不正常的細胞生長〞係指(除非有其它另外的指示)細胞生長與正常的調節機制無關(例如喪失接觸抑制作用)。該術語包括例如不正常生長的:(1)以表現突變的酪胺酸激酶或過度表現的受體酪胺酸激酶增殖的腫瘤細胞(腫瘤)(2)其它增殖性疾病的良性及惡性細胞,其中發生畸變的的酪胺酸激酶活化作用;(3)以受體酪胺酸激酶增殖的任何腫瘤;(4)以畸變的絲胺酸/蘇胺酸激酶活化作用增殖的任何腫瘤;(5)其它增殖性疾病的良性及惡性細胞,其
中發生畸變的的絲胺酸/蘇胺酸激酶活化作用。
如本文所使用的〝治療(treating)〞術語代表(除非有其它另外的指示)逆轉、減輕、抑制該術語適用的疾病或症狀或一或多種這些疾病或症狀的症候的進展或預防該情況。如本文所使用的〝治療(treatment)〞術語係指(除非有其它另外的指示)在〝治療(treating)〞如上述直接定義時的治療行為。
對應於該量的既定試劑之量將依據一些因素而改變,如特殊的化合物、疾病症狀及其嚴重性、需藥治療的哺乳類個性(例如重量),但是仍以熟諳本技藝者依慣例測定。〝治療(treating)〞意圖代表至少緩和在受到MEK活性至少部份影響的哺乳類中(如人類)的疾病症狀,並包括(但不限於)預防在哺乳類中發生的疾病症狀,特別在發現哺乳類傾向患有疾病症狀,但是尚未診斷出已患病時;調節及/或抑制疾病症狀;及/或減輕疾病症狀。
為了使本發明的化合物或其醫藥上可接受之鹽或前體藥物用於哺乳類(包括人類)的治療(包括預防治療),故正常係根據標準的醫藥常規調配成醫藥組成物。根據本發明的該觀點,其係提供含有如上述定義之本發明化合物或其醫藥上可接受之鹽或前體藥物與醫藥上可接受之稀釋劑或載體結合的醫藥組成物。
為了製備根據本發明的一個具體實例之醫藥組成物,故將治療或預防有效量之本發明化合物或其醫藥上可接受之鹽、溶劑化物、代謝物或前體藥(單獨或與另外的治療劑
一起)與醫藥上可接受之載體根據慣用的醫藥化合物技術徹底混合,以生產一給藥量。載體可依據希望投藥之製劑形式而採取廣泛不同的形式,例如經口服或非經腸。適合的載體實例包括任何及所有溶劑、分散介質、佐劑、膜衣、抗細菌及抗霉菌劑、滲透及吸收延緩劑、甜味劑、穩定劑(促進長期貯存)、乳化劑、結合劑、增稠劑、鹽、保存劑、溶劑、分散介質、膜衣、抗細菌及抗霉菌劑、滲透及吸收延緩劑、調味劑及為了製備特殊的治療組成物可能需要的其它物質,如緩衝劑及吸收劑。這些具有醫藥活性物質之介值及試劑的使用為本技藝中所熟知。不與本發明的化合物相容的任何慣用的介質或試劑則屬例外,但是期待其在治療組成物及製劑中的用途。也可將補充的活性成分併入如本文所述之組成物及製劑中。
本發明的組成物可具有適合於經口服使用的形式(例如成為藥片、錠劑、硬或軟膠囊、水性或油性懸浮液、乳液、可分散性藥粉或藥粒、糖漿或酏劑)、局部使用的形式(例如成為乳膏、軟膏、凝膠或水性或油性溶液或懸浮液)、以吸入投藥的形式(例如成為細微藥粉或液體氣霧劑)、以吹氣投藥的形式(例如成為細微藥粉)或非經腸投藥的形式(例如成為經靜脈內、皮下或肌肉內給藥之無菌水性或油性溶液或成為結腸給藥之栓劑)。例如希望經口服使用的組成物可包括例如一或多種著色劑、甜味劑、調味劑及/或保存劑。
適合於藥片調配物的醫藥上可接受之賦形劑包括例如惰性稀釋劑,如乳糖、碳酸鈉、磷酸鈣或碳酸鈣;粒化與
崩散劑,如玉米澱粉或藻酸;結合劑,如澱粉;潤滑劑,如硬脂酸鎂、硬脂酸或滑石粉;保存劑,如對-羥基苯甲酸乙酯或丙酯;及抗氧化劑,如抗壞血酸。藥片調配物可不被包膜或被包膜,或改進彼之崩散及接著在腸胃道內吸收活性成分,或改進彼之穩定性及/或外觀,在任一例子中,使用在本技藝中熟知慣用的包膜劑及步驟。
用於經口服使用的組成物可具有硬膠囊形式,其中將活性成分與惰性固體稀釋劑混合,例如碳酸鈣、磷酸鈣或高嶺土,或具有軟膠囊形式,其中將活性成分與水或油混合,如花生油、液態石蠟或橄欖油。
水性懸浮液通常包括具有細粉末狀形式的活性成分與一起的一或多種懸浮劑,如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯基吡咯啶酮、黃蓍樹膠和阿拉伯膠;分散或濕潤劑,如卵磷脂或環氧烷羥與脂肪酸之縮合產物(例如聚氧乙烯硬脂酸酯)、或環氧烷羥與長鏈脂肪族醇之縮合產物(例如十七乙烯氧基鯨蠟醇)、或環氧烷羥與衍生自脂肪酸及己糖醇之部分酯的縮合產物(如聚氧乙烯山梨醇單油酸酯)、或環氧乙烷與衍生自脂肪酸及己糖醇酐之部分酯的縮合產物(例如聚乙烯山梨醇酐單油酸酯)。水性懸浮液也可包括一或多種保存劑(如對-羥基苯甲酸乙酯或丙酯)、抗氧化劑(如抗壞血酸)、著色劑、調味劑及/或甜味劑(如蔗糖、糖精或阿斯巴甜)。
油性懸浮液可藉由將活性成分懸浮在植物油中(如花生油、橄欖油、芝麻油或椰子油)或在礦物油中(如液態石蠟)
所調配。油性懸浮液也可包括增稠劑,如蜂蠟、硬石蠟或鯨蠟醇。可加入如那些以上所列之甜味劑及調味劑,以提供可食用之經口服製劑。這些組成物可藉由加入抗氧化劑(如抗壞血酸)而保存。
適合於藉由加入水而製備水性懸浮液之可分散性藥粉及藥粒通常包括活性成分與一起的分散或濕潤劑、懸浮劑及一或多種保存劑。適合的分散或濕潤劑及懸浮液係以上列已說明的那些試劑為實例。另外的賦形劑也可以存在,如甜味劑、調味劑及著色劑。
本發明的醫藥組成物也可具有水包油型乳液形式。油相可為植物油(如橄欖油或花生油)或礦物油(如例如液態石蠟或任何彼之混合物)。適合的乳化劑可為例如天然生成之膠(如阿拉伯膠或黃蓍樹膠)、天然生成之磷脂(如大豆、卵磷脂)、衍生自脂肪酸及己糖醇酐之酯或部分酯(例如山梨醇酐單油酸酯)及該部分酯與環氧乙烷之縮合產物(如聚氧乙烯山梨醇酐單油酸酯)。乳液也可包括甜味劑、調味劑及保存劑。
糖漿及酏劑可以甜味劑調配,如甘油、丙二醇、山梨醇、阿斯巴甜或蔗糖,並也可包括緩和劑、保存劑、調味劑及/或著色劑。
醫藥組成物也可具有無菌的可注射水性或油性懸浮液形式,其可使用一或多種已說明如上的適當的分散或濕潤劑及懸浮劑根據已知的步驟調配。無菌的可注射製劑也可為在非經腸可接受之無毒性稀釋劑或溶劑中無菌的可注射
溶液或懸浮液,例如在1,3-丁二醇中的溶液。
栓劑調配物可藉由混合活性成份與適合的無刺激性賦形劑所製備,該賦形劑在常溫下為固體,但是在直腸溫度下為液體,因此在直腸中熔融而釋放出藥物。適合的賦形劑包括例如可可脂及聚乙二醇。
局部用調配物(如乳膏、軟膏、凝膠及水性或油性溶液或懸浮液)通常可藉由以慣用且局部可接受之媒劑或稀釋劑使用在本技藝中熟知的慣用步驟調配活性成分所獲得。
以吹氣投藥之組成物可具有細微藥粉形式,其包括例如30微米或更小的平均直徑之粒子,藥粉本身包含或單獨或被一或多種生理學上可接受之載體(如乳糖)稀釋的活性成份。接著使吹氣用之藥粉適合保留在膠囊中,其包括例如1至50毫克供渦輪式吸入器裝置(如用於已知的色甘酸鈉試劑吹氣)使用的活性成分。
以吸入投藥之組成物可具有為了配置或成為含有細微固體之氣霧劑,或成為液體小滴之活性成分所安排慣用的加壓氣霧劑形式。可使用慣用的氣霧劑推進劑,如揮發性氟化烴類或烴類,並適合安排用於配置計量的活性成分量的氣霧劑裝置。
進一步的調配物資料參見第5冊Comprehensive Medicine Chemistry的第25.2章(Corwin Hansch;Chairman of Editorial Board),Pergamon Press 1990,特別將其併入本文以供參考。
與一或多種賦形劑組合以生產單一劑型之本發明化合
物的量有必要依據所治療之病患、疾病或症狀嚴重性、投藥速度、化合物的清除及配藥醫師的判斷力而改變。但是有效劑量係在約0.001至約100毫克/每公斤體重/每天之範圍內的單次或多次給藥量,以約1毫克/每公斤體重/每天至約35毫克/每公斤體重/每天較佳。就70公斤的人類而言,該劑量可等於約0.07至2.45公克/每天,以約0.05至約1.0公克/每天較佳。在一些實例中,小於上述範圍下限之劑量值可能更適當,但是在其它例子中,還可使用更大的給藥量而不會引起任何有害的副作用,其先決條件係先將這些較大的給藥量分成數份小的給藥量供整天投藥。進一步的投藥路徑及劑量攝取資料參見第5冊Comprehensive Medicine Chemistry的第25.3章(Corwin Hansch;Chairman of Editorial Board),Pergamon Press 1990,特別將其併入本文以供參考。
就治療或預防目的而言,本發明化合物的給藥量大小自然係根據症狀性質及嚴重性、動物或病患的年齡與性別及投藥路徑而改變,其係根據醫學熟知的原理。
本發明化合物可單獨與在治療疾病症狀所使用的其它藥物及治療法組合使用,其有益於MEK的抑制作用。除了本發明的化合物之外,該等治療可包含慣用的手術或放射療法或化療法。該等化療法可包括一或多種下列的抗腫瘤試劑種類:(i)如在腫瘤醫學中所使用的抗增殖/抗腫瘤藥物及其組合物,如烷基化試劑(例如順氯胺鉑(cisplatin)、奧沙利鉑
(oxaliplatin)、卡鉑(carboplatin)、環磷醯胺、氮芥、威克瘤(melphalan)、苯丁酸氮芥(chlorambucil)、馬利蘭(busulphan)、替莫唑胺(temozolamide)和亞硝脲(nitrosourea));抗代謝物(例如健擇(gemcitabine)、抗葉酸鹽,如氟基嘧啶(如5-氟嘧啶二酮(5-fluorouracil)和替加氟(tegafur))、雷替曲塞(raltitrexed)、胺甲蝶呤、胞嘧啶阿拉伯糖苷和羥基尿素)或在歐洲專利申請案第239362號所揭示的較佳的抗代謝物中之一(如N-(5-[N-(3,4-二氫-2-甲基-4-酮基喹唑啉-6-基甲基)-N-甲胺基]-2-噻吩醯基)-L-麩胺酸));抗腫瘤抗體(例如蒽環類(anthracyclines),如亞德里亞霉素(adriamycin)、博萊霉素(bleomycin)、阿霉素(doxorubicin)、道諾霉素(daunomycin)、表阿霉素(epirubicin)、去甲柔紅黴素(idarubicin)、絲裂霉素(mitomycin)-C、放線菌素(dactinomycin)和光神霉素(mithramycin));抗細胞分裂劑(例如長春花生物鹼(如長春新鹼、長春花鹼、長春地辛(vindesine)和長春花)和紫杉烷類(如紫杉醇和剋癌易(taxotere)及波羅激酶(polokinase)抑制劑));及拓樸異構酶抑制劑(例如表鬼臼毒素,如順鉑(eptoposide)和替尼泊苷(teniposide)、安吖啶(amsacrine)、拓樸替肯(topotecan)和喜樹鹼);(ii)細胞生長抑制劑,如抗雌激素(例如塔莫西芬(tamoxifen)、托密芬(toremifene)、鈣穩(raloxifene)、屈洛西芬(droloxifene)和艾朵西芬(iodoxyfene));雌激素受體向下調節劑(例如氟維斯退特(fulvestrant));抗雄激素(例如白
卡羅他邁德(bicalutamide)、氟他邁德(flutamide)、尼路他邁德(nilutamide)、醋酸環丙孕酮(cyproterone acetate)和CasodexTM
(4’-氰基-3-(4-氟苯基磺醯基)-2-羥基-2-甲基-3’-(三氟甲基)丙醯替苯胺));LHRH拮抗劑或LHRH激動劑(例如固舍端林(goserelin)、留普瑞林(leuprorelin)和布含瑞林(buserelin));孕激素類(例如醋酸甲地孕酮(megestrol acetate));芳香環抑制劑(例如安美達(anastrozole)、雷醜拙(letrozole)、伏氯唑(vorazole)和依西美坦(exemestane))及5 α-還原酶抑制劑(如柔沛(finasteride));(iii)抗癌細胞侵襲劑(例如c-Src激酶家族抑制劑及金屬蛋白酶抑制劑(如馬立馬司他(marimastat))及尿激酶血纖維蛋白溶酶原活化劑受體機能抑制劑或肝素酶抗體);(iv)生長因子機能抑制劑,如生長因子抗體、生長因子受體抗體(例如抗-erbB2抗體搓杜滋美(trastuzumab)[HerceptinTM
]、抗-EGFR抗體盤尼圖姆(panitumumab)和抗-erbB1抗體西妥昔(cetuximab)[Erbitux C225])及以Stern等人之Crritical Reviews in Oncology/Haematology,2005,vol.54,pp11-29所揭示之任何生長因子或生長因子受體抗體:這些抑制劑包括酪胺酸激酶抑制劑(例如表皮生長因子家族酪胺酸激酶之抑制劑,如N-(3-氯基-4-氟苯基)-7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-胺(吉非特尼伯(gefitinib),AZD1839)、N-(3-乙炔基苯基)-6,7-雙(2-甲氧基乙氧基)喹唑啉-4-胺(爾羅提尼伯(erlotinib),OSI-774)和6-丙烯醯胺基-N-(3-氯基-4-氟苯
基)-7-(3-嗎啉基丙氧基)喹啉-4-胺(CI 1033))、erbB2酪胺酸激酶之抑制劑(如拉帕替尼(lapatinib))、肝細胞生長因子家族之抑制劑、血小板衍生之生長因子家族之抑制劑(如伊馬替尼(imatinib))、絲胺酸/蘇胺酸激酶之抑制劑(例如Ras/Raf信號抑制劑,如法呢基轉移酶抑制劑,例如索拉非尼(sorafenib)(BAY 43-9006))、經由MEK及/或AKT激酶之細胞信號抑制劑、肝細胞生長因子家族之抑制劑、c-kit抑制劑、abl激酶抑制劑、IGF受體(似胰島素生長因子)激酶抑制劑、極光激酶抑制劑(例如AZD1152、PH73958、VX-680、MLN8054、R763、MP235、MP529、VX-528和AX39459)及週期素依賴性激抑制劑(如CDK2及/或CDK4抑制劑);(v)抗血管生成劑,如那些抑制血管內皮生長因子效應之試劑(例如抗血管內皮細胞生長因子抗體貝伐西茹麥伯(bevacizumab)[AvastinTM
]和VEGF受體酪胺酸激酶抑制劑,如4-(4-溴基-2-氟基苯胺基)-6-甲氧基-7-(1-甲基六氫吡啶-4-基甲氧基)喹唑啉(ZD6474;在WO 01/32651中的實施例2)、4-(4-氟基-2-甲基吲哚-5-氧基)-6-甲氧基-7-(3-吡咯啶-1-基丙氧基)喹唑啉(AZD2171;在WO 01/47212中的實施例240)、維它拉尼(vatalanib)(PTK787;WO 98/35985)和SU11248(舒尼替尼(sunitinib);WO 01/60814))及以其它機制作用之化合物(例如利諾邁德(linomide)、整合素α v β 3機能抑制劑、MMP抑制劑、COX-2抑制劑和癌細胞血管阻斷素(angiostatin));(vi)血管破壞劑,如康伯塔斯它汀(combretastatin)A4及
在PCT發表案第WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213所揭示之化合物;(vii)反義治療法(例如那些針對於上述所列之標的物,如ISIS 2503和抗-ras反義);(viii)基因療法,包括例如GVAXTM
、替換畸變基因之方法(如畸變的p53或畸變的BRCA1或BRCA2、GDEPT(以基因標定之酵素前體藥物治療法))、如那些使用胞嘧啶脫胺酶、胸苷激酶或細菌硝基還原酶酵素之方法及增加病患對化療法或放射療法耐受性之方法(如抗多重藥物之基因療法);(ix)干擾素;及(x)免疫治療法,包括例如增加病患腫瘤細胞免疫抗原性之活體外和活體內法(如以細胞激素轉染,如介白素2、介白素4或粒細胞巨噬細胞集落刺激因子)、降低T-細胞能量之方法、使用轉染之免疫細胞之方法(如以細胞激素轉染之樹突細胞)、使用以細胞激素轉染之腫瘤細胞株之方法及使用抗獨特型抗體之方法。
這些聯合治療法可以同時、依序或分開給予各個治療組份的方式達成。這些組合產物使用在上述給藥量範圍內的本發明化合物與在其經證實的給藥量範圍內的其它醫藥活性劑。
根據本發明的該觀點,其係提供一種含有如本文定義之本發明化合物及上述用於聯合治療癌症所定義之額外的
抗腫瘤試劑之醫藥產物。
雖然本發明的化合物主要具有作為用於溫血動物中(包括人類)的治療劑之價值,但是彼等也有用於任何需要抑制MEK效應的時候。因此彼等用作發展新的生物試驗及研究新的藥理試劑所用之藥理標準。
以本發明所包含之本發明的代表性化合物包括(但不限於)實施例的化合物及彼等在醫藥上可接受之酸或鹼加成鹽類或前體藥物。意圖由以下所提出之實施例例證本發明特殊的具體實例,並不意圖以任何方式限制說明書或申請專利範圍的範圍。
在本申請案的所有物件及參考文(包括專利)的揭示內容併入本文以供參考。
在本發明的另一具體實例中,其提供一種包括有用於治療上述疾病的物質之製品或〝套組〞。在一個具體實例中,套組包含容納本發明化合物或其調配物的容器。套組也可以包含在容器上或與容器結合的標籤或包裝插件。所使用的〝包裝插件〞術語係指在治療產品的市售包裝內習慣裝入的使用指南,其包括關於指示、用法、劑量、投藥方式、禁忌及/或關於使用這些治療產品的警語之資料。適合的容器包括例如瓶子、小瓶、針筒、膜泡包裝等。容器可以各種材料形成,如玻璃或塑膠。容器容納本發明化合物或其調配物,其有效治療症狀及可具有無菌的出入口(例如容器可為靜脈內溶液袋或具有以皮下注射針可穿通的塞子之小瓶)。標籤或包裝插件可指示用於治療選擇之症狀(如
癌症)的組成物。在一個具體實例中,標籤或包裝插件指示可使用本發明化合物或其調配物治療以MEK介入之疾病或醫學症狀。此外,標籤或包裝插件可指示欲治療之病患為一種患有以MEK介入之疾病或醫學症狀,如高增殖性疾病或發炎性症狀。標籤或包裝插件也可指示可使用組成物治療其它疾病。另一選擇或另外製品可進一步包含含有醫藥上可接受之緩衝劑的第二容器,如抑菌注射用水(BWFI)、以磷酸鹽緩衝之食鹽水、林格氏(Ringer’s)溶液及葡萄糖溶液。可進一步包括以市售及使用者為觀點所欲之其它物質,包括其它緩衝劑、稀釋劑、過濾器、針及注射器。
根據另一具體實例,套組可包含(a)第一容器,其具有容納在其中的本發明化合物或其調配物;及視需要地(b)第二容器,其具有容鈉在其中的第二種醫藥調配物,其中第二主醫藥調配物包含具有抗增殖或抗發炎活性的第二種化合物。另一選擇或另外製品可進一步包含含有醫藥上可接受之緩衝劑的第三容器,如抑菌注射用水(BWFI)、以磷酸鹽緩衝之食鹽水、林格氏溶液及葡萄糖溶液。可進一步包括以市售及使用者為觀點所欲之其它物質,包括其它緩衝劑、稀釋劑、過濾器、針及注射器。
套組可進一步包含本發明化合物或其調配物及若存在的第二種醫藥調配物投藥之指示。例如如果套組包含本發明化合物或其調配物(〝第一種調配物〞)及第二中醫藥調配物時,則套組可進一步包含使第一及第二種醫藥組成物同時、依序或分開投予需要其之病患的指示。
在另一具體實例中,套組適合輸送本發明化合物的固體口服型式,如藥片或膠囊。較佳而言,該套組包括許多單位劑量。這些套組可包括具有依彼之意圖使用的次序指導之劑量的紙卡。該套組的實例為〝膜泡包裝〞。膜泡包裝為包裝工業中所熟知且廣泛地用於包裝醫藥單位劑型。若必要時,可提供記憶輔助,例如以數字、字母或其它標記形式或以標出可投予劑量之治療時間表中的日期之月曆插件。
在其中套組包含本發明化合物或其調配物及第二種治療劑的其它特定的具體實例中,套組可包含用於容納單獨組份之容器,如分次瓶或分次之鋁箔包裝,但是單獨的組成物也可容納在單一的未分次之容器內。典型地,套組包含用於單獨組份投藥之指示。當單獨組份較佳地以不同的劑型投藥(例如經口服及非經腸),以不同的劑量間隔投藥時,或當組合物的個別組份之滴定為配藥醫師所期望時,則套組型式特別有利。
可使用下列的檢定法測量本發明化合物作為MEK抑制劑的效應。
本發明化合物的活性可藉由下列步驟測定。以N-末端6組胺酸-標記之組成活性MEK-1(2-393)表現在大腸桿菌中,並將蛋白質以慣用的方法純化(Ahn等人之Science 1994,
265,966-970)。MEK1的活性係藉由在MEK-1的存在下測量併在表現在大腸桿菌中及以慣用的方法純化之以N-末端組胺酸-標記之ERK2上來自γ-33
P-ATP之γ-33
P-磷酸鹽所評定。該檢定法係在96-井聚丙烯平盤中實行。培育混合物(100微升)包含25mM Hepes,pH7.4、10mM MgCl2
、5mM β-甘油磷酸酯、100μM釩酸鈉、5mM DTT、5nM MEK1及1μM ERK2。將抑制劑懸浮在DMSO中,並使所有反應(包括控制品)在1%DMSO之最終濃度下進行。以加入10μM ATP(具有0.5μCi γ-33
P-ATP/井)開始反應及在室溫下培育45分鐘。加入等體積的25%TCA終止反應及沉澱出蛋白質。使沉澱之蛋白質落入玻璃纖維B過濾平盤上,並將過量標記之ATP使用Tomtec MACH III收成器清除。在加入30微升/每井之Packard Microscint 20之前,允許平盤以空氣乾燥,並將平盤使用Packard TopCount計數。
本發明化合物的MEK 1/2抑制特性可藉由下列在活體外細胞檢定法中測定。基本的ERK 1/2磷酸化之抑制作用係藉由將細胞以化合物培育1小時,並定量在固定細胞上的螢光pERK信號活性及使其規範成總ERK信號所測定。
物質及方法:Malme-3M細胞可自ATCC獲得及在以10%胎牛血清補充之RPMI-1640中生長。將細胞以15,000個細胞/每井覆蓋在96-井平盤中及允許附著1-2小時。接著加入1%DMSO之最終濃度的稀釋化合物。在1小時之後,
將細胞以PBS清洗及在PBS中的3.7%甲醛中固定15分鐘。隨後在PBS/0.2% Triton X-100中清洗及在100%MeOH中透化處理15分鐘。將細胞在Odyssey阻斷緩衝液(LI-COR Biosciences)阻斷至少1小時。將磷酸化ERK 1/2(Cell Signaling #9106,單株)及總ERK 12(Santa Cruz Biotechnology #sc-94,多株)之抗體加入細胞中及培育至少1小時。在以PBS/0.2% Triton X-100清洗之後,將細胞以螢光標記之二次抗體(山羊抗兔IgG-IRDye800,Rockland及山羊抗小鼠IgG-Alexa Fluor 680,Molecular Probe)再培育1小時。接著將細胞清洗及使用Odyssey紅外線影像系統(Infrared Imaging System)(LI-COR Biosciences)在兩種波長下分析螢光。使磷酸化之ERK信號規範成總ERK信號。
化合物的熱力學水性溶解度係使用改良的振盪培養瓶法測量。每一種化合物的結晶度係使用偏光顯微鏡(Olympus BX51)確認。將每一種欲測試之化合物以約0.5毫克無水化合物稱重裝入小瓶中,用於製備標準溶液。也將約0.5毫克稱重裝入數個小瓶中,用於製備水性未知物,對每一欲測試之pH一個小瓶。
關於每一水性未知物,將具有所欲之pH的0.5毫升水性緩衝液(10mM磷酸鉀)加入0.5毫克無水化合物中(使用0.1N HCl達到pH1.2)。該檢定法的濃度上限於是為1毫克/毫升。接著將每一水性未知物在室溫下以350轉/分鐘旋轉
24小時,允許適當的時間達到平衡。在旋轉之後,檢查及確認每一樣品的最終pH。接著將整份移除及過濾至用於分析的HPLC小瓶中。
製備每一種化合物的儲備溶液,其係藉由將0.5毫克化合物溶解在1毫升總體積之甲醇中,使儲備濃度為500微克/毫升。接著將儲備溶液連續稀釋,設定從5至250微克/毫升之校正曲線。
將樣品及標準品立即以LC/UV分析。將每一種水性樣品以兩種不同的體積注射三次。將每一種標準品以兩種不同的體積注射一次。將峰波落在校正範圍之外的樣品連續稀釋及再分析。
HPLC/PDA系統係由與2996光電二極體陣列偵測器(Photodiode Array Detector)(Waters)組合之Alliance 2795分離系統(Separations System)(Waters)或Acquity UPLC分離系統(Separations System)(Waters)所組成。在Alliance系統上,分析物的色層分離係使用YMC ODS-Aq C18管柱(3.0x50毫米,3微米粒徑,120埃,Waters)與連同使用移動相A(水性,0.01%七氟丁酸(HFBA),1%異丙醇)及B(在乙腈中的0.01%HFBA及1%異丙醇)之梯度條件所達到。每單一注射的總流動時間(包括再平衡時間)為5分鐘。分析物反應係藉由監控在220奈米及254奈米下的吸收值所測量。大部分化合物在該系統上的偵測限度為約1微克/毫升。
在Acquity系統上,分析物的色層分離係使用Acquity UPLC BEH,C18管柱(2.1x50毫米,1.7微米粒徑,Waters)
與連同使用移動相A(水性,0.1%甲酸(FA),1%異丙醇)及B(在乙腈中的0.1%FA及1%異丙醇)之梯度條件所達到。每單一注射的總流動時間(包括再平衡時間)為3分鐘。分析物反應係藉由監控在220奈米及254奈米下的吸收值所測量。大部分化合物在該系統上的偵測限度為約1微克/毫升。在Acquity系統的後端上為ZQ-2000單一四極質譜儀(Waters)。使用正ESI為母體化合物的質量鑑定。
使用Waters Empower軟體取得數據及處理。校正係藉由分析物的峰波面積比為標準樣品整數濃度的函數關係繪圖所達成。校正模式係以校正曲線的線性回歸所產生。使用該模式校正所有水性樣品的濃度。
雖然式I至VI化合物的藥理特性係依據如預期之結構變化而改變,但是通常以化合物所具有的活性及/或溶解度可以下列濃度或給藥量論證:
試驗1a(酵素檢定法):IC50
≦250nM,例如≦100nM,另外的實施例≦30nM。
試驗1b(細胞檢定法):IC50
≦180nM,例如≦80nM,另外的實施例≦10nM。
試驗1a(酵素檢定法):IC50
≦250nM,例如≦50nM,另外的實施例≦20nM;及試驗1b(細胞檢定法):IC50
≦600nM,例如≦30nM,另外的實施例≦10nM。
試驗1a(酵素檢定法):IC50
≦40nM,例如≦20nM;及試驗1b(細胞檢定法):IC50
≦10nM。
試驗1a(酵素檢定法):IC50
≦35nM,另外的實施例≦15nM,而另外的實施例≦10nM。
試驗1b(細胞檢定法):IC50
≦5nM,另外的實施例≦1nM。
為了例證本發明,故納入下列的實施例。但是應瞭解這些實施例不是限制本發明,並只代表提議實際應用本發明方法。熟諳本技藝者應認知所述之化學反應可輕易被改編,以製備本發明的許多其它的MEK抑制劑,而且用於製備本發明化合物的替換方法被視為在本發明的範圍內。例如根據本發明的非例示之化合物的合成法可以那些熟諳本技藝者明白的修改法而成功地進行,例如藉由適當地保護干擾基、使用除了那些所述者之外的本技藝中已知的其它適合的試劑及/或達成慣例的反應條件修改。另一選擇係本文所揭示或在本技藝中已知的其它反應被認知為具有製備本發明的其它化合物之應用性。
在下列所述之實施例中,除非有其它另外的指示,溫度係以攝氏度數陳述。試劑係購自市場上的供應商,如Aldrich Chemical Company、Lancaster、TCI或Maybridge,並以未進一步純化予以使用,除非有其它另外的指示。四
氫呋喃(THF)、N,N-二甲基甲醯胺(DMF)、二氯甲烷、甲苯、二烷及1,2-二氟乙烷係購自Aldrich安全的密封瓶及以收到的狀態使用。
在下列所述之反應通常在正氮氣或氬氣壓下或以在無水溶劑中的乾燥試管(除非有其它另外的說明)進行,並且反應燒瓶典型係配備用於經由注射器引入基質及試劑之膠墊。將玻璃器具以烘箱乾燥及/或以加熱乾燥。
管柱色層分離法係在具有矽膠管柱之Biotage系統上(製造商:Dyax Corporation)或在二氧化矽SepPak匣上(Waters)進行。
1
H-NMR光譜係記錄在400MHz下操作的Varian儀器上。1
H-NMR光譜係以成為CDCl3
溶液使用氯仿作為參考標準(7.25ppm)所獲得(以ppm報告)。若需要時,使用其它的NMR溶劑。在報告峰波多重性時,使用下列縮寫:s(單峰)、d(雙重峰)、t(三重峰)、m(多重峰)、br(寬峰)、dd(雙二重峰)、dt(雙三重峰)。在提供偶合常數時,則以赫茲(Hz)報告。
步驟A:2-(2-甲基亞肼基)丙酸乙酯的製備:將在CHCl3
(100毫升)中的甲肼(18.0毫升,332毫莫耳)之溶液在0℃下加入在CHCl3
(500毫升)中的丙酮酸乙酯(37.8毫升,338毫莫耳)及MgSO4
(40.8公克,339毫莫耳)之懸浮液中。將反應混合物溫熱至室溫。在室溫下攪拌24小時之後,將反應混合物過濾。將過濾物在減壓下濃縮,得到44公克(94%)所欲產物,直接使用未進一步純化之該產物。
步驟B:3-(2-(1-乙氧基-1-酮基亞丙-2-基)-1-甲肼基)-3-酮基丙酸甲酯的製備:將LiH(2.02公克,241毫莫耳)加入在0℃下在THF(500毫升)中的2-(2-甲基亞肼基)丙酸乙酯(25.0毫升,186毫莫耳)之溶液中。將所得混合物在0℃下攪拌10分鐘,溫熱至室溫及攪拌6小時。在0℃下加入在THF(20毫升)中的甲基丙二醯氯(26.7毫升,242毫莫耳)。將反應溫熱至室溫及攪拌16小時。將反應在0℃下以1N水性HCl小心中止,在減壓下濃縮及以EtOAc稀釋。將有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到46公克(99%)所欲產物,直接使用未進一步純化之該產物。
步驟C:5-羥基-2,6-二甲基-3-側氧基-2,3-二氫嗒-4-羧酸甲酯的製備:將DBU(2.0毫升,13毫莫耳)加入在0℃下在MeCN(10毫升)中的2-(2-甲基-2-(甲基-3-酮基丙醯基)亞肼基)丙酸乙酯(1.02公克,4.09毫莫耳)之溶液中。將反應混合物溫熱至室溫及攪拌3小時。將反應混合物在減壓下濃縮及以EtOAc稀釋。將有機層以10%水性HCl清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到0.39公克(48%)
粗產物,直接使用未進一步純化之該產物。
步驟D:5-羥基-2,6-二甲基嗒-3(2H)-酮的製備:將在二烷(25毫升)中的5-羥基-2,6-二甲基-3-側氧基-2,3-二氫嗒-4-羧酸甲酯(3.00公克,15.1毫莫耳)與6N水性HCl(25毫升,150毫莫耳)之混合物回流48小時。將反應混合物冷卻至室溫及在減壓下濃縮,得到粗物質,將其以EtOAc稀釋。將有機層以水及食鹽水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到0.74公克(35%)所欲產物。將水層在減壓下濃縮。將所得固體以水及EtOAc-THF稀釋。將有機層分開。將水層以EtOAc(2x)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到0.80公克(37%)額外的所欲產物。獲得總共1.54公克(72%)所欲產物,直接使用未進一步純化之該產物。
步驟E:5-氯基-2,6-二甲基嗒-3(2H)-酮的製備:將5-羥基-2,6-二甲基嗒-3(2H)-酮(736毫克,5.25毫莫耳)與POCl3
(4.5毫升)之混合物在85℃下攪拌2小時。將反應混合物在減壓下濃縮,得到粗物質,將其以飽和水性Na2
CO3
中止。將所得混合物攪拌2小時及以EtOAc(3x)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到587毫克(70%)所欲產物,直接使用未進一步純化之該產物。
步驟F:4-氯基-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸的製備:將K2
Cr2
O7
(3.33公克,11.2毫莫耳)以攪拌緩慢加入在0℃下在發煙H2
SO4
(25毫升)中的5-氯基-2,6-二甲基嗒-3(2H)-酮(780毫克4.67毫莫耳)之溶液中。在加完
K2
Cr2
O7
之後,移除冰浴及允許反應混合物溫熱至室溫。當反應開始進展太快時,則再放回冰浴及加入其餘的K2
Cr2
O7
。將反應混合物在60℃下攪拌16小時。將反應混合物冷卻至室溫,倒入冰中及以EtOAc(x3)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到649毫克(74%)所欲產物,直接使用未進一步純化之該產物。
步驟G:4-氯基-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯的製備:將在MeOH(6毫升)中的4-氯基-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸(390毫克,2.07毫莫耳)及濃縮HCl(0.10毫升)之溶液回流8小時。將反應混合物冷卻至室溫及在減壓下濃縮,得到粗物質,將其再溶解在EtOAc中。將有機層以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%己烷至在己烷中的10至20至30至50%EtOAc)純化,供應72毫克(17%)所欲產物。
步驟H:4-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯的製備:將在甲苯(1.5毫升)中的4-氯基-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯(72毫克,0.35毫莫耳)、2-氟基-4-甲硫基苯胺(69毫克,0.44毫莫耳)、Pd(OAc)2
(10毫克,0.044毫莫耳)、BINAP(40毫克,0.064毫莫耳)與CS2
CO3
(197毫克,0.60毫莫耳)之混合物溶液密封在N2
氣下的小瓶中。將其在室溫下攪拌10分鐘及接著在80℃下以攪拌加熱16小時。將反應混合物冷卻至室溫及以EtOAc稀釋。將沉澱物過濾及以EtOAc清洗。將過濾
物以水清洗。將有機層分開及將水層以EtOAc萃取。將合併的有機層經MgSO4
乾燥,過濾及濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%CH2
Cl2
至在CH2
Cl2
中的1%MeOH)純化,接著以額外的矽膠快速管柱色層分離法(在CH2
Cl2
中的10至15至20%EtOAc)純化,供應48毫克(42%)所欲產物。
步驟I:4-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫嗒-3-甲醯胺的製備:將LiHMDS(0.54毫升,0.54毫莫耳,在THF中的1M溶液)加入在0℃下在THF(2毫升)中的4-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯(25毫克,0.077毫莫耳)及O-(2-乙烯氧基-乙基)-羥胺(24毫克,0.23毫莫耳)之溶液中。將反應混合物溫熱至室溫及攪拌1小時。將反應混合物以飽和水性NaHCO3
中止及以EtOAc稀釋。將有機層以食鹽水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%CH2
Cl2
至在CH2
Cl2
中的1.5%MeOH)純化,供應30毫克(99%)所欲產物。
步驟J:4-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺的製備:將1N水性HCl(0.15毫升,0.15毫莫耳,1N水溶液)在室溫下加入在EtOH/THF(2毫升/2毫升)中的4-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫嗒-3-甲醯胺(30毫克,0.077毫莫耳)之溶液中。將反應混
合物在室溫下攪拌1小時。將反應混合物中和至pH7,以EtOAc(3x)稀釋,以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%EtOAc至100%CH2
Cl2
至在CH2
Cl2
中的2.5至3至5%MeOH)純化,供應6毫克(22%)所欲產物。偵測出MS APCI(-)m/z 367(M-1);1
H NMR(400MHz,CD3
OD)δ 7.35(t,1H),7.18(dd,1H),7.14(dd,1H),5.92(s,1H),4.06(t,2H),3.79(t,2H),3.74(s,3H),2.51(s,3H)。
步驟A:4-(2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯的製備:該標題化合物係以先前實施例1(步驟H)所述之步驟製備,得到61%產量,其係使用4-氯基-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯(109毫克,0.54毫莫耳,如以先前所述之實施例1(步驟A-G)所製備)及2-氟基苯胺(0.053毫升,0.54毫莫耳)。
步驟B:5-溴基-4-(4-溴基-2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯的製備:將在DMF(1.5毫升)
中的4-(2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯(88毫克,0.32毫莫耳)與NBS(59毫克,0.33毫莫耳)之混合物在室溫下攪拌2小時。將反應混合物以EtOAc稀釋及以水(2x)清洗。將有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%CH2
Cl2
至在CH2
Cl2
中的0.5%MeOH)純化,接著以額外的矽膠快速管柱色層分離法(在CH2
Cl2
中的30%EtOAc)純化,得到5-溴基-4-(2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯與5-溴基-4-(4-溴基-2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯之80毫克混合物。將該混合物再進行溴化作用。將DMF(1.5毫升)在室溫下加入該混合物中,接著加入NBS(29毫克,0.22毫莫耳)。將反應混合物在室溫下攪拌2.5小時。再加入15毫克NBS及將反應混合物在室溫下再攪拌20小時。將反應混合物以EtOAc稀釋及以水(2x)清洗。將有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(在CH2
Cl2
中的30%EtOAc)純化,供應62毫克(64%)所欲產物。
步驟C:5-溴基-4-(4-溴基-2-氟基苯胺基)-N-(環丙基甲氧基)-1-甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺的製備:該標題化合物係以實施例1(步驟I)所述之步驟製備,得到40%產量,其係使用5-溴基-4-(4-溴基-2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫嗒-3-羧酸甲酯(31毫克,0.071毫莫耳)及O-環丙基甲基羥胺(20毫克,0.23毫莫耳)。偵測出MS
APCI(-)m/z 487,489,491(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.38(dd,1H),7.31(dd,1H),7.05(t,1H),3.82(s,3H),3.65(d,2H),1.13(m,1H),0.58(q,2H),0.31(q,2H)。
步驟A:N-甲基丙醯肼的製備:將在CH2
Cl2
(30毫升)中的乙醯氯(15.0毫升,169毫莫耳)之溶液加入在0℃下在CH2
Cl2
(130毫升)中的甲肼(27.6毫升,508毫莫耳)及催化量之DMAP的溶液中。將反應混合物溫熱至室溫及攪拌16小時。將白色固體過濾及將過濾物在減壓下濃縮,得到粗物質,將其以真空蒸餾法純化,供應8.25公克(48%)所欲產物(在0.14毫米Hg下63-66℃)。
步驟B:2-(2-甲基-2-丙醯基亞肼基)丙二酸二乙酯的製備:將在甲苯(136毫升)中的N-甲基丙醯肼(18.78公克,183.9毫莫耳)及酮基丙二酸二乙酯(56.1毫升,368毫莫耳)之溶液以丁史塔克阱回流4小時。將反應混合物在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%
己烷至在己烷中的5至10%EtOAc)純化,供應23公克(49%)所欲產物。
步驟C:4-羥基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯的製備:將在THF(1毫升)中的2-(2-甲基-2-丙醯基亞肼基)丙二酸二乙酯(50毫克,0.19毫莫耳)之溶液加入在-78℃下在THF(1毫升)中的LiHMDS(0.78毫升,0.78毫莫耳,在THF中的1M溶液)之溶液中。將所得混合物緩慢溫熱至-40℃及在-40℃下攪拌1.5小時。將反應混合物以10%水性HCl中止及以水稀釋。將所得混合物以EtOAc(2x)萃取。將合併的有機層以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%己烷至在己烷中的20%EtOAc)純化,供應25毫克(61%)所欲產物。
步驟D:4-氯基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯的製備:將4-羥基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯(1.85公克,8.72毫莫耳)與POCl3
(9毫升)之混合物在85℃下加熱16小時。在減壓下移除POCl3
。接著將粗物質以冰水中止。將混合物以飽和水性NaHCO3
中和(~pH6至7)及以EtOAc(3x)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%己烷至在己烷中的5至10至20%EtOAc)純化,供應1.72公克(86%)所欲產物。
步驟E:4-(2-氟基-4-(甲硫基)苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯的製備:該標題化合物係以
實施例1(步驟H)所述之步驟製備,得到81%產量,其係使用4-氯基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯(500毫克,2.17毫莫耳)及2-氟基-4-甲硫基苯胺(375毫克,2.38毫莫耳)。
步驟F:4-(2-氟基-4-(甲硫基(苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺的製備:該標題化合物係以實施例1(步驟I及J)所述之步驟製備,得到78%產量(2個步驟),其係使用4-(2-氟基-4-(甲硫基)苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯(50毫克,0.14毫莫耳)及O-(2-乙烯氧基-乙基)-羥胺(44毫克,0.43毫莫耳)。偵測出MS APCI(-)m/z 381(M-1);1
H NMR(400MHz,CD3
OD)δ 7.10(dd,1H),7.03(dd,1H),6.84(t,1H),3.99(t,2H),3.79(s,3H),3.74(t,2H),2.47(s,3H),1.74(s,1H)。
下列化合物係藉由實施例1(步驟I)所述之步驟製備,其係使用4-(2-氟基-4-(甲硫基)苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸乙酯及適當的羥胺。
偵測出MS APCI(-)m/z 391(M-1);1
H NMR(400MHz,CD3
OD)δ 7.09(dd,1H),7.03(dd,1H),6.86(t,1H),3.78(s,3H),3.71(d,2H),2.47(s,3H),1.75(s,3H),1.16(m,1H),0.58(m,2H),0.31(m,2H)。
偵測出MS APCI(-)m/z395 (M-1);1
H NMR(400MHz,CD3
OD)δ 7.10(dd,1H),7.03(d,1H),6.87(t,1H),4.05(t,2H),3.78(s,3H),3.64(t,2H),3.37(s,3H),2.47(s,3H),1.74(s,3H)。
偵測出MS APCI(-)m/z 351(M-1);1
H NMR(400MHz,CD3
OD)δ 7.10(d,1H),7.04(d,1H),6.87(t,1H),3.78(s,3H),3.76(s,3H),2.47(s,3H),1.74(s,3H)。
步驟A:4-羥基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸的製備:將在THF(10毫升)中以實施例3(步驟B)所述之步驟所製備的2-(2-甲基-2-丙醯基亞肼基)丙二酸二乙酯(21.40公克,82.86毫莫耳)之溶液加入在-78℃下在THF(430毫升)中的LiHMDS(331毫升,331毫莫耳,在THF中的1M溶液)之溶液中。將所得混合物經1小時緩慢溫熱至-40℃及在-40℃下攪拌1.5小時。將水(500毫升)加入-40℃之反應混合物中。將反應混合物溫熱至室溫及攪拌3小時。將反應混合物在減壓下濃縮,以移除THF。將所得水性混合物在0℃下以6N水性HCl中止及酸化成pH1至2。將所得混合物在室溫下攪拌16小時。將沉澱物過濾及以CH2
Cl2
濕磨,供應7.21公克(47%)所欲產物。將過濾物以EtOAc(3x)
萃取。將合併的有機層以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以CH2
Cl2
濕磨,供應3.56公克(23%)額外的所欲產物。將水層再以EtOAc(3x)萃取。將合併的有機層以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以CH2
Cl2
濕磨,供應1.32公克(9%)額外的所欲產物。獲得總共12.09公克(79%)所欲產物。
步驟B:4-氯基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸的製備:將4-羥基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸(876毫克,4.76毫莫耳)與POCl3
(4.5毫升)之混合物在85℃下加熱24小時。在減壓下移除POCl3
。將粗物質以冰中止。將反應混合物在室溫下攪拌1小時。在以過濾移除固體之後,將水性過濾物以EtOAc(3x)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質。將回收的物質與先前分離的固體合併及以醚濕磨,供應577毫克(60%)所欲產物。
步驟C:4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸的製備:將LiHMDS(3.00毫升,3.00毫莫耳,在THF中的1M溶液)緩慢加入在-78℃下在THF(6.5毫升)中的4-氯基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸(200毫克,0.99毫莫耳)及2-氟基-4-碘基苯胺(478毫克,1.97毫莫耳)之懸浮液中。在加完之後,將所得混合物緩慢溫熱至室溫及攪拌4小時。將反應混合物在0℃下以6N水性HCl(8毫升)中止,溫熱至室溫及攪拌1.5小時。將沉澱物過濾,以水及醚清洗及以醚濕磨,供應158毫克(38%)所
欲產物。
步驟D:4-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺的製備:將EDCI(40毫克,0.21毫莫耳)在室溫下加入在DMF(1.5毫升)中的4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸(41毫克,0.10毫莫耳)及HOBt(28毫克,0.21毫莫耳)之懸浮液中。將所得混合物攪拌1.5小時。將O-(2-乙烯氧基-乙基)-羥胺(21毫克,0.20毫莫耳)及TEA(0.030毫升,0.22毫莫耳)加入在室溫下的活化酯中。在攪拌1.5小時之後,將反應混合物以EtOAc稀釋及以水飽和水性NH4
Cl、食鹽水、飽和NaHCO3
(2x)及食鹽水清洗。將有機層分開,經MgSO4
乾燥,過濾及在減壓下濃縮,得到4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫嗒-3-甲醯胺,直接使用未進一步純化。該標題化合物係以先前實施例1(步驟J)所述之步驟製備,其係使用粗4-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫嗒-3-甲醯胺(經兩個步驟得到40%產量)。偵測出MS APCI(-)m/z 461(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(d,1H),6.63(t,1H),3.98(t,2H),3.80(s,3H),3.74(t,2H),1.78(s,3H)。
下列化合物係藉由先前實施例7(步驟C及D)所述之步驟製備,其係使用適當的苯胺及羥胺。在一些實例中,可能需要最終的去保護步驟。這些去保護作用可藉由標準的文獻方法完成。
偵測出MS APCI(-)m/z 491(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(d,1H),6.63(t,1H),4.02(m,1H),3.88(m,2H),3.80(s,3H),3.59(m,2H),1.77(s,3H)。
偵測出MS APCI(-)m/z 431(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(d,1H),6.63(t,1H),3.79(s,3H),3.75(s,3H),1.77(s,3H)。
偵測出MS APCI(-)m/z 471(M-1);1
H NMR(400MHz,CD3
OD)δ 7.51(dd,1H),7.44(d,1H),6.62(t,1H),3.79(s,3H),3.70(d,2H),1.78(s,3H),1.15(m,1H),0.57(q,2H),0.30(q,2H)。
步驟A:2-(2-甲基亞肼基)丙二酸二乙酯的製備:將MeNHNH2
(32毫升,600毫莫耳)在室溫下以一份加入在EtOH(600毫升)中的酮基丙二酸二乙酯(95公克,546毫莫耳)之溶液中(配備熱電偶、N2
管線、濃縮器及機械攪拌器之2公升3-頸燒瓶)。將反應混合物溫熱至60℃(內溫,以加熱
包加熱)及攪拌6小時。將反應混合物冷卻至室溫及攪拌隔夜。將反應混合物在減壓下濃縮,得到粗物質與一起的固體沉澱物,將其以矽膠塞(3:2之己烷:EtOAc)純化,供應81公克(74%)所欲產物。
步驟B:2-(2-甲基-2-丙醯基亞肼基)丙二酸二乙酯的製備:將LiHMDS(643毫克,643毫莫耳)以加料漏斗經45分鐘加入在0℃下在THF(1公升)中的2-(2-甲基亞肼基)丙二酸二乙酯(100公克,494毫莫耳)之溶液中。將反應混合物在0℃下攪拌45分鐘。加入一份丙醯氯(51.6毫升,593毫莫耳)。將所得混合物溫熱至室溫及攪拌20小時。將反應混合物以飽和水性NH4
Cl(85毫升)及水(85毫升)中止。將反應混合物在減壓下濃縮,並再加入水(300毫升)。將所得混合物以EtOAc(3x250毫升)萃取。將合併的有機層以飽和水性NaHCO3
(2x250毫升)及接著以食鹽水(250毫升)清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到112公克(88%)粗產物,在下一步驟中直接使用未進一步純化之該產物。
步驟C:4-羥基-1,5-二甲基-6-側氧基-1,6-二氫嗒-2-羧酸的製備:將在THF(10毫升)中的2-(2-甲基-2-丙醯基亞肼基)丙二酸二乙酯(21.40公克,82.86毫莫耳)之溶劑加入在-78℃下在THF(430毫升)中的LiHMDS(331毫升,331毫莫耳,在THF中的1M溶液)之溶液中。將所得混合物經1小時緩慢溫熱至-40℃及在-40℃下攪拌1.5小時。將水(500毫升)在-40℃下加入反應混合物中。將反應混合物溫熱至室溫及攪拌3小時。將反應混合物在減壓下濃縮,在0℃下以
6N水性HCl中止及酸化成pH 1至2。將所得混合物在室溫下攪拌16小時。將沉澱物過濾及以CH2
Cl2
濕磨,供應7.21公克(47%)所欲產物。將過濾物以EtOAc(3x)萃取。將合併的有機層以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以CH2
Cl2
濕磨,供應額外的3.56公克(23%)所欲產物。將水層再以EtOAc(3x)萃取。將合併的有機層以水清洗,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以CH2
Cl2
濕磨,供應額外的1.32公克(9%)所欲產物。獲得總共12.09公克(79%)所欲產物。
步驟D:4-氯基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸的製備:將4-羥基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸(35.4公克,192毫莫耳)、催化量之DMF(3滴)與POCl3
(178毫升,1.92莫耳)之混合物在90℃下加熱2天,並接著在減壓下移除POCl3
。將粗物質以冰中止,並將反應混合物在室溫下攪拌2小時。將從溶液所形成的沉澱物過濾及以醚清洗。將所收集的沉澱物以醚濕膜,供應11.7公克(30%)所欲產物。將過濾物以EtOAc(2x)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗產物,將其以醚濕磨及在減壓下乾燥,供應額外的9.56公克(24%)所欲產物。獲得總共21.29公克(55%)所欲產物。
步驟E:4-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸的製備:將LiHMDS(174毫升,174毫莫耳,在THF中的1M溶液)緩慢加入在-78℃下在THF(165毫升)中的4-溴基-2-氟基苯胺(22.6公克,116毫莫
耳)之溶液中。將所得混合物在-78℃下攪拌1小時。將在-78℃下成為固體的4-氯基-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸(11.0公克,54.4毫莫耳)加入該混合物中。將反應混合物緩慢溫熱至室溫及攪拌21小時。將反應在0℃下以10%水性HCl(250毫升)中止及酸化。將水(100毫升)、EtOAc(350毫升)及食鹽水(50毫升)加入該混合物中。將反應混合物溫熱至室溫及攪拌30分鐘。將有機層分開及將酸性水層以EtOAc(2x300毫升)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以醚(5x)濕磨,過濾,以醚清洗及在減壓下乾燥,供應14.51公克(75%)所欲產物。
步驟F:4-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫嗒-3-甲醯胺的製備:將EDCI(15.62公克,81.48毫莫耳)在室溫下加入在DMF(165毫升)中的4-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-羧酸(14.51公克,40.74毫莫耳)及HOBt(11.01公克,81.48毫莫耳)之懸浮液中。將所得混合物攪拌1.5小時。將O-(2-(乙烯氧基)乙基)羥胺(8.36毫升,81.48毫莫耳)及TEA(11.36毫升,81.48毫莫耳)加入在室溫下的活化酯中。在攪拌1.5小時之後,將反應混合物以EtOAc稀釋及以水飽和水性NH4
Cl、食鹽水、飽和NaHCO3
(2x)及食鹽水清洗。將有機層分開,經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗產物,直接使用未進一步純化之該產物。
步驟G:4-(4-溴基-2-氟基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫嗒-3-甲醯胺的製備:將在EtOH/THF(50毫升/50毫升)中的4-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫嗒-3-甲醯胺(17.98公克,40.75毫莫耳)與6N水性HCl(13.58毫升,81.50毫莫耳)之混合物在室溫下攪拌3小時。將反應混合物在減壓下濃縮及以水(50毫升)稀釋。將所得混合物以EtOAc(2x)萃取。將合併的有機層經MgSO4
乾燥,過濾及在減壓下濃縮,得到粗物質,將其以矽膠快速管柱色層分離法(100%CH2
Cl2
至在CH2
Cl2
中的2.5%MeOH)純化,供應9.41公克(以兩個步驟得到56%)所欲產物。偵測出MS APCI(-)m/z 413,415(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.38(dd,1H),7.27(d,1H),6.79(t,1H),3.99(t,2H),3.80(s,3H),3.74(t,2H),1.77(s,3H)。
偵測出MS APCI(-)m/z 413,415(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.38(dd,1H),7.27(d,1H),6.79(t,1H),3.99(t,2H),3.80(s,3H),3.74(t,2H),1.77(s,3H)。
偵測出MS APCI(-)m/z 427,429(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.39(dd,1H),7.27(dd,1H),6.79(t,1H),3.98(m,1H),3.84(dd,1H),3.80(s,3H),3.72(dd,1H),1.78(s,3H),1.15(d,3H)。
步驟A:2-氯基-6-側氧基-1,6-二氫吡啶-3-羧酸的製備:2-氯基-6-側氧基-1,6-二氫吡啶-3-羧酸係自二氯基煙鹼酸(3.00公克,15.6毫莫耳,Aldrich)所製備,其係根據美國專利第3,682,932號所述之步驟,得到1.31公克(48%)所欲產物。
步驟B:2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將氫化鋰(95%,0.078公克,9.28毫莫耳)加入在DMF(20毫升)中的2-氯基-6-側氧基-1,6-二氫吡啶-3-羧酸(0.644公克,3.71毫莫耳)之溶液中,並將反應混合物在N2
下攪拌40分鐘。接著加入甲基碘(0.508毫升,1.16公克,8.16毫莫耳)及將反應混合物再攪拌45分鐘。將反應混合物以2M HCl中止,直到pH為6-7為止。將反應混合
物以EtOAc及飽和NaCl稀釋,並將層分開。將水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮,得到黃色粗固體。HPLC分析顯示兩種以4:1之比的產物,將其以快速管柱色層分離法(15:1至10:1之二氯甲烷/EtOAc)分開,得到成為白色結晶固體的0.466公克(62%)純的所欲產物。也分離出成為淡黃色結晶固體的少量產物,並鑑定為2-氯基-6-甲氧基煙鹼酸甲酯之位向異構物。
步驟C:5-溴基-2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將N-溴基琥珀醯亞胺(0.177公克,0.992毫莫耳)加入在DMF(5毫升)中的2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.100公克,0.496毫莫耳)之溶液中,並將反應混合物在室溫及N2
下攪拌4小時。將反應混合物以飽和亞硫酸氫鈉中止,接著以EtOAc及H2
O稀釋,並將層分開。將水層以EtOAc(2x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮,得到定量產量之黃色固體。
步驟D:2-氯基-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將二甲鋅(0.713毫升,1.43毫莫耳,在甲苯中的2M溶液)加入在0℃及N2
下在二烷(8毫升)中的5-溴基-2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.400公克,1.43毫莫耳)及1,1’-雙(二苯膦基)二茂鐵二氯鈀(II)(0.0587公克,0.0713毫莫耳)之懸浮液中。將反應混合物立即加熱至100℃經30分鐘。將反應混合物冷卻至0℃及以MeOH(0.800毫升)中止。將反應混合物以EtOAc稀
釋及以1M HCl清洗。將水層以EtOAc(1x)反萃取。將合併的有機層以飽和NaCl清洗,乾燥(Na2
SO4
)及在減壓下濃縮成深黃色膠。以快速管柱色層分離法(15:1之二氯甲烷/EtOAc)純化,得到成為黃色結晶固體的0.164公克(53%)純的所欲產物。
步驟E:2-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將雙(三甲基矽烷基)醯胺鋰(0.56毫升,0.56毫莫耳,在己烷中的1M溶液)逐滴加入在-78℃及N2
下在THF(2毫升)中的4-溴基-2-氟苯胺(0.058公克,0.31毫莫耳)之溶液中。將反應混合物在-78℃下攪拌1小時。接著逐滴加入在THF(1毫升)中成為溶液之2-氯基-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.060公克,0.28毫莫耳)及將反應混合物在-78℃下攪拌25分鐘。將反應混合物以加入H2
O中止及將pH以0.1M HCl調整,接著以EtOAc及飽和NaCl稀釋,並將層分開。將水層以EtOAc(1x)反萃取。將合併的EtOAc層乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(20:1之二氯甲烷/EtOAc)純化,得到成為白色結晶固體的0.086公克(84%)純的所欲產物。偵測出MS ESI(+)m/z 371,373(M+,Br圖案);1
H NMR(400MHz,CDCl3
)δ 9.57(s,1H),7.79(s,1H),7.32(d,1H),7.18(d,1H),6.58(t,1H),3.85(s,3H),3.29(s,3H),2.14(s,3H)。
步驟A:2-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫吡啶-3-甲醯胺的製備:將O-(2-乙烯氧基-乙基)-羥胺(0.042毫升,0.41毫莫耳)加入在THF(2毫升)中的2-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.060公克,0.16毫莫耳)之溶液中。將溶液冷卻至0℃及逐滴加入雙(三甲基矽烷基)醯胺鋰(0.81毫升,0.81毫莫耳,在己烷中的1M溶液)。將反應混合物溫熱至室溫。在攪拌35分鐘之後,將反應混合物以加入飽和NaHCO3
中止,並分溶在EtOAc與飽和NaCl之間。將層分開,並將有機層乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(20:1之二氯甲烷/MeOH)純化,得到成為灰白色結晶固體的0.067公克(94%)純的所欲產物。
步驟B:2-(4-溴基-2-氟基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將水性2M HCl(0.380毫升,0.760毫莫耳)加入在乙醇(2毫升)中的2-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫吡啶-3-甲醯胺(0.067公克,0.150毫莫耳)之溶液中。將反應混合物在室溫下攪拌
16小時。將反應混合物的pH以1M NaOH調整。將反應混合物以EtOAc及H2
O稀釋。將有機層分開及以飽和NaCl清洗。將合併的水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮,得到成為灰白色結晶固體的0.060公克(94%)純的所欲產物。偵測出MS ESI(+)m/z 414,416(M+,Bt圖案);1
H NMR(400MHz,CDCl3
)δ 9.80(s,1H),8.44(s,1H),7.31(d,1H),7.19(d,1H),6.59(t,1H),4.05(m,2H),3.85(m,1H),3.75(m,2H),3.29(s,3H),2.15(s,3H)。
下列化合物係使用如實施例13及14所述之方法製備。在一些實施例中,如實施例14,可能需要最終的去保護步驟。這些去保護作用可藉由標準的文獻方法完成。
將2-氯基-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯轉換成2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯,其係依照實施例13的步驟E之步驟,使用2-氟基-4-碘苯胺,得到成為白色結晶固體的所欲產物。偵測出MS ESI(+)m/z 417(M+1);1
H NMR(400MHz,CDCl3
)δ 9.56(s,1H),7.79(s,1H),7.49(d,1H),
7.36(d,1H),6.43(t,1H),3.85(s,3H),3.30(s,3H),2.15(s,3H)。
步驟A:2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫吡啶-3-甲醯胺的製備:將O-(2-乙烯氧基-乙基)-羥胺(0.149公克,1.44毫莫耳)加入在THF(60毫升)中的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.500公克,1.20毫莫耳)之溶液中。將溶液冷卻至0℃及逐滴加入雙(三甲基矽烷基)醯胺鋰(4.81毫升,4.81毫莫耳)(在己烷中的1M溶液)。將反應混合物溫熱至室溫。在攪拌10分鐘之後,將反應混合物以加入1M HCl中止,並分溶在EtOAc與飽和NaCl之間。將層分開,並將有機層乾燥(Na2
SO4
)及在減壓下濃縮,得到粗黃色固體,在下一步驟中使用未純化之該固體。
步驟B:2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將水性2M HCl(3毫升)加入在乙醇(10毫升)中的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧
基)-1,6-二氫吡啶-3-甲醯胺(0.585公克,1.20毫莫耳)之溶液中。將反應混合物在室溫下攪拌45分鐘。將反應混合物的pH以1M NaOH調整至pH7。將反應混合物以EtOAc及H2
O稀釋。將有機層分開及以飽和NaCl清洗。將合併的水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮。以矽膠快速管柱色層分離法(15:1之二氯甲烷/MeOH)純化,得到成為淡黃色固體的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫吡啶-3-甲醯胺(0.421公克;經兩個步驟得到76%)。偵測出MS ESI(+)m/z 462(M+1)圖案;1
H NMR(400MHz,CDCl3
)δ 9.77(s,1H),8.50(s,1H),7.47(d,1H),7.36(d,1H),6.43(t,1H),4.04(brs,2H),3.85(brs,1H),3.74(brs,2H),3.29(s,3H),2.14(s,3H)。偵測出MS ESI(+)m/z 462(M+1)圖案。
步驟1:2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將在己烷中的1M雙(三甲基矽烷基)醯胺鋰(120公克)在-43至-41.6℃下經28分鐘
加入在-45℃及氮氣下在THF(5.25公升)中的2-氟基-4-碘基苯胺(182公克,0.77莫耳)之攪拌溶液中。在1小時之後,經43分鐘加入在THF(1.05公升)中的2-氯基-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(155公克,0.72莫耳)。將混合物在-46℃下維持1小時55分鐘,接著允許溫熱至-13℃及以水(186毫升,10.3莫耳)經5分鐘中止,使溫度維持在-13℃至-11℃之間。接著允許混合物經30分鐘溫熱至0℃。接著經1小時加入2M H2
O,直到達成pH 7-8為止(加入1855毫升)。在放置隔夜之後,允許混合物溫熱至室溫及加入氯化鈉溶液(1公升,15重量/體積%)。將下層(水層)棄置及將THF層以蒸餾濃縮成約1.4公升。將異己醇(4.65公升)在約52℃下經1小時15分鐘加入混合物中,並接著將混合物經3小時冷卻至20℃。在20℃下1小時之後,將混合物冷卻至0℃及在該溫度下維持隔夜。接著將反應混合物過濾及將固體以冷凝的異己醇(5℃)(2x1.25公升)清洗。將固體在45℃之真空烘箱中乾燥,提供2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(248公克,0.60莫耳,83%產量)。1
H MMR(D6
-DMSO)δ:7.75(d,1H,J1Hz,ArH),7.68(dd,1H,J11,2Hz,ArH),7.42(d,1H,J8.5Hz,ArH),6.62(~t,1H,J8.5Hz,ArH),3.69(s,3H,OCH3
),3.22(s,3H,NCH3
),2.03(s,3H,ArCH3
)。
步驟2:2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-乙烯氧基-乙氧基)-醯胺的製備:將在己烷中的1M雙(三甲基矽烷基醯胺)鋰溶液(2.85公升)經
55分鐘加入在氮氣下在THF(2.85公升)中的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(221公克,0.53莫耳)及O-(2-乙烯氧基乙基)-羥胺(63公克,0.61莫耳)之攪拌溶液中,使溫度維持在-14.7至-12.4℃之間。在-15℃下2小時之後,將水(165毫升,9.2莫耳)加入混合物中,接著經20分鐘加入2M HCl溶液(1.98公升)。接著允許混合物溫熱至22℃,並將下層水相(2.25公升)分開及棄置。將有機相以氯化鈉溶液(15重量/重量%,1100毫升)清洗及將體積在室溫下以蒸餾2.25公升溶劑縮減成約1.75公升。將異己醇(3.35公升)以維持在約58℃之溫度下經2.5小時加入混合物中。在室溫下再1小時之後,將混合物冷卻至20℃,維持1小時,並接著冷卻至0℃及在該溫度下維持隔夜。加入更多的異己醇量(500毫升)及將混合物維持1小時,接著加入更多異己醇(500毫升)。在0℃下45分鐘之後,將漿料過濾及將固體以冷凝的異己醇(1.1公升)清洗,接著在30℃之真空烘箱中乾燥,提供2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-乙烯氧基乙氧基)-醯胺(190公克,0.39莫耳,74%產量)。1
H MMR(D6
-DMSO):δ 7.63(dd,1H,J11,2Hz,ArH),7.52(s,1H,ArH),7.38(d,1H,J8.5Hz,ArH),6.55-6.46(m,2H,ArH/OCH=CH2
),4.18(dd,1H,J14,2Hz,OCH=CH2
),3.99(dd,1H,J7,2Hz,OCH=CH2
),3.90-3.88(m,2H,OCH2
),3.81-3.79(m,2H,OCH2
),3.25(s,3H,NCH3
),
2.02(s,3H,ArCH3
)。
步驟3:型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將2M HCl(318毫升)在17-22℃下經15分鐘加入在氮氣下在THF(850毫升)中的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-乙烯氧基乙氧基)-醯胺(170公克,0.35莫耳)之攪拌溶液中。在1小時之後反應完成(以HPLC顯示),並經10分鐘加入2M氫氧化鈉溶液(318毫升),使溫度維持在約22℃。混合物的pH約8。接著將混合物以MIBK(1.02公升)分溶,並將下水層分開及棄置。接著將有機溶液體積在室溫下及以85-95℃之夾套溫度蒸餾縮減。在移除750毫升溶劑之後,蒸餾速度明顯變慢,並將混合物冷卻至約22℃。將結晶2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺型式2(1公克,如實施例16C所述之方式製備的晶種)加入混合物中,接著加入醋酸乙酯(170毫升)。在5分鐘之後,混合物開始結晶及在23-25℃下經50分鐘加入異己醇(1.7公升)。將漿料維持在25℃下80分鐘及接著過濾。將固體以異己醇(680毫升)清洗及接著在30℃之真空烘箱中乾燥,提供標題物質(147公克,0.31莫耳,89%產量)。1
H MMR(D6
-DMSO):δ 7.63(dd,1H,J11,2Hz,ArH),7.55(s,1H,ArH),7.38(d,1H,J8.5Hz,ArH),6.52(~t,1H,J8.5Hz,ArH),4.91-4.35(bs,1H,OH),3.74(~t,2H,J5Hz,OCH2
),3.51(~t,2H,J5Hz,OCH2
),
3.25(s,3H,NCH3
),2.02(s,3H,ArCH3
)。MS(ESI)(+)m/z 484(27%,[M+Na]+
),462(100%,[M+H]+
),385(8%),100(26%)。
步驟4:型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(4.9公克)(如步驟5所述之方式製備)加入在50℃下在醋酸乙酯(2.0公升)中來自步驟3之產物的攪拌漿料(123公克)中,並將殘餘物質以醋酸乙酯(0.45公升)清洗至容器中。將混合物在該溫度下維持64小時。以樣品的分析顯示物質主要為型式2。在再1小時之後,使混合物溫度增加至60℃,並在該溫度下6小時之後,再加入3.25公克型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(如實施例16D所述之方式製備)及以醋酸乙酯(100毫升)清洗。在60℃下再持續攪拌16小時,然後分析顯示留有一些型式2。接著將混合物體積在52℃之批組溫度及400毫巴下以蒸餾溶劑縮減(移除780毫升)。接著在60℃下持續攪拌隔夜,並再分析混合物,但是分析顯示仍留有一些型式2。在再7小時之後,將外加的折流板放入反應器中及持續攪拌,直到隔天為止。接著加入更多醋酸乙酯(0.5公升),幫助攪動效率,並將混合物在60℃下再維持2小時。發現在該點取出的樣品為型式1。從型式2轉變成型式1所花的全部時間為143小時。將物質在50℃
下維持隔夜,接著冷卻至12℃及過濾。將濾塊在12℃下以醋酸乙酯(400毫升)清洗,接著在35℃之真空烘箱中經一週末(68小時)乾燥,提供型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(109公克)。
將氯化氫(17.05毫升,17.0493公克,17.05毫莫耳)加入在醋酸乙酯(126.00毫升)中上述的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-羥基乙氧基)-醯胺(4.2公克,8.52毫莫耳)(根據實施例16A,步驟2所製備)之快速攪拌的混合物中。在2小時之後,仍有小於1%原料(以HPLC分析),並允許相沉積。將下層水相分開及棄置,並將有機相以氯化鈉(42毫升,15重量/體積%,接著2x25毫升,9重量/體積%)清洗。接著將體積在大氣壓力下(65℃蒸餾頭溫度)以蒸餾溶劑(44毫升)縮減。接著將溶液冷卻至70℃,並加入根據實施例16A,步驟4所製得的型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(40.3265毫克)。將混合物在70℃下攪拌20小時。將溫度經4小時15分鐘減低至24℃及經1小時降低至1℃。接著將漿料過濾,將濾塊以冷醋酸乙酯(17毫升)清洗及將固體在45℃之真空烘箱中乾燥,提供2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基
-6-側氧基-1,6-二氫吡啶-3-甲醯胺型式1(3.15公克,76%)
將在四氫呋喃(5毫升)中的2-(2-氟基-4-碘基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-羧酸(2-乙烯氧基-乙氧基)-醯胺(500毫克,915微莫耳)與氯化氫(1毫升)之混合物攪拌隔夜。接著加入氫氧化鈉(1M,2.00毫升),並於再10分鐘之後,將甲基異丁酮(3毫升)及醋酸乙酯(3毫升)加入混合物中。將層分開及將有機溶液以50%食鹽水(4毫升)清洗,接著蒸發(以溢出損失約一半的物質)。將殘餘物溶解在甲基異丁酮(3毫升)及醋酸乙酯(1毫升)中,並將混合物加熱至回流。一旦冷卻至50℃時,混合物變混濁及加入異己烷(5毫升)。其引起固體結晶,並將混合物冷卻至20℃,接著再加入異己烷(5毫升)。接著將固體過濾,以異己烷(1毫升)清洗及在40℃之真空烘箱中乾燥,提供140毫克標題化合物。
將來自實施例16的最終產物(25毫克)放入具有磁攪拌器一起的Syn 10(Radleys)反應試管中,並以攪拌加入預加熱至50℃之一份(1毫升)甲醇,使物質溶解在甲醇中。再將5毫升甲醇加入反應試管中,確保在冷卻時產生超飽和溶
液。當大部分固體溶解時,將所得溶液在50℃下經由Pall 0.45微米PTFE Acrodisc CR13過濾器過濾至Syn 10的第二個試管中。接著將試管以3℃/分鐘之速度冷卻至0℃及維持在0℃,直到物質結晶為止。將樣品過濾,以抽氣乾燥,接著放置在室內條件下。將固體小心地自濾紙移除及以XRPD檢查。
2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的型式1及型式2之X-射線粉末繞射圖的測定係藉由將結晶物質樣品架設在Siemens單矽晶片(SSC)架上及將樣品以顯微鏡片的幫助展開成薄層。使樣品在30轉/分鐘下旋轉(以改進計數統計學),並使用Bruker D5000動力X-射線繞射儀(Bruker AXS,Banner Lane Coventry CV4 9GH)在40kV與40毫安培下以1.5406埃之波長操作的銅製細長的聚焦管操作的X-射線照射。使平行的X-射線源通過設定在V20之自動化可變式發射狹縫,並使反射的輻射直接經由2毫米防散射狹縫及0.2毫米偵測器狹縫。將樣品在2度至40度2-θ範圍之θ-θ模式中曝露1秒/每增量0.02度2-θ(連續掃描模式)。儀器配備作為偵測器之閃爍計數器。控制及數據獲取係藉由以Diffract+軟體操作的Dell Optiplex 686 NT 4.0 Workstation之方式。收集在以0.02度2-θ增量之2-40度2-θ範圍內的數據,以4秒/每一增量。
熟諳本技藝者熟知可獲得X-射線粉末繞射圖,其具有依據測量條件而定的一或多個測量誤差(如所使用的設備、樣品分離或機器)。特定言之,通常已知在X-射線粉末繞射圖中的強度可依據測量條件及樣品製備而波動。例如熟諳本技藝者明白峰波的相對強度可受到例如大於約30微米尺寸之顆粒及非單一性縱橫比的影響,其可影響樣品的分析。熟諳本技藝者也明白反射位置可受到樣品位於繞射儀中的確切高度及繞射儀的零點校正的影響。樣品的表面平坦性也可具有小的影響。於是熟諳本技藝者應認知本文所提出的繞射圖數據不被解釋成絕對值(進一步的資料參見Jenkins,R & Snyder,R.L.‘Introduction to X-Ray Powder Diffractometry’John Wiley & Sons,1996)。因此應瞭解2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的結晶型式不被限制成提供與在圖10至12所示之X-射線粉末繞射圖相同的X-射線粉末繞射圖之晶體,而提供實質上與圖10至12所示之繞射圖相同的X-射線粉末繞射圖的任何晶體係落在本發明的範圍內。熟諳X-射線粉末繞射技藝者能夠判斷具有實質同一性的X-射線粉末繞射圖。
微差掃描熱量法(DSC)分析係使用Mettler DSC820e在2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺型式1及2上進行。將內含
在配備穿孔蓋之40微升鋁盤中的典型小於5毫克物質之樣品以每分鐘10℃之固定的加熱速度在25℃至325℃之溫度範圍內加熱。以每分鐘100毫升之流速使用沖洗氣體,該氣體係使用氮氣。
結果顯示型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺由於熔融的169.7℃之起始溫度而顯現大且突然的放熱現象(圖14),但是型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺由於熔融的154.3℃之起始溫度而具有大且突然的放熱現象(圖13)。在熔融之後,由於降解而觀察到大的放熱事件。應瞭解DSC之起始及/或峰波溫度值從互不相同的機器、互不相同的方法及在互不相同的樣品可有些微的改變,所以不被引述成絕對值。
步驟A:依照實施例14之步驟A所述之步驟,將2-(4-溴基-2-氟基苯胺基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-
羧酸甲酯轉換成(S)-2-(4-溴基-2-氟基苯胺基)-N-(2-(第三丁基二甲基矽烷氧基)丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
步驟B:將1M HCl(0.682毫升,0.682毫莫耳)加入在THF(1.00毫升)中的(S)-2-(4-溴基-2-氟基苯胺基)-N-(2-(第三丁基二甲基矽烷氧基)丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(0.037公克,0.0682毫莫耳)之溶液中。將反應混合物在室溫下攪拌1小時。將反應混合物以EtOAc稀釋及以飽和NaHCO3
(3x)、飽和NaCl(1x)清洗,乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(30:1之二氯甲烷/甲醇)純化,得到成為黃色固體的0.020公克(69%)純的所欲產物。偵測出MS ESI(+)m/z 428,430(M+,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.55(s,1H),7.40(d,1H),7.24(d,1H),6.68(t,1H),3.86(m,1H),3.71(m,1H),3.58(m,1H),3.40(s,3H),2.12(s,3H),1.10(d,3H)。
步驟A:2-氯基-5-乙基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:如實施例13之步驟D所述,將5-溴
基-2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯轉換成2-氯基-5-乙基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯,其係使用二乙鋅(在己烷中的1M溶液),得到成為黃色結晶固體的所欲產物。
步驟B:2-(4-溴基-2-氟基苯胺基)-5-乙基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:如實施例13之步驟E所述,將2-氯基-5-乙基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯轉換成2-(4-溴基-2-氟基苯胺基)-5-乙基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯。偵測出MS ESI(+)m/z 383,385(M+,Br圖案);1
H NMR(400MHz,CDCl3
)δ 9.59(s,1H),7.76(s,1H),7.32(d,1H),7.18(d,1H),6.59(t,1H),3.86(s,3H),3.28(s,3H),2.56(q,2H),1.22(t,2H)。
如實施例14所述,將2-(4-溴基-2-氟基苯胺基)-5-乙基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯偶合及去保護,得到成為黃色固體的所欲產物。偵測出MS APCI(+)m/z 428,430(M+,Br圖案);1
H NMR(400MHz,DMSO-d6
)δ
11.51(brs,1H),9.54(brs,1H),7.57(d,1H),7.47(s,1H),7.25(d,1H),6.69(t,1H),4.67(brs,1H),3.74(m,2H),3.50(m,2H),3.24(s,3H),2.43(q,2H),1.14(t,3H)。
將N-氯基琥珀醯亞胺加入在DMF中的2-(4-溴基-2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯之溶液中。將反應混合物在室溫下攪拌25分鐘及接著以飽和亞硫酸氫鈉中止。將反應混合物以H2
O稀釋及分溶在EtOAc/二乙醚與飽和NaCl之間。將層分開及將水層以EtOAc(1x)再萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(15:1之二氯甲烷/EtOAc)純化,得到成為白色固體的所欲產物。偵測出MS ESI(+)m/z 389,391,393(M+,Cl,Br圖案);1
H NMR(400MHz,CDCl3
)δ 9.88(s,1H),8.13(s,1H),7.34(d,1H),7.24(d,1H),6.69(t,1H),3.87(s,3H),3.29(s,3H)。
如實施例14所述,將2-(4-溴基-2-氟基苯胺基)-5-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯偶合及去保護,得到成為淡黃色固體的所欲產物。偵測出MS APCI(+)m/z 434,436,438(M+,Cl,Br圖案);1
H NMR(400MHz,DMSO-d6
)δ 11.56(brs,1H),9.75(brs,1H),7.91(s,1H),7.57(d,1H),7.26(d,1H),6.89(t,1H),4.68(brs,1H),3.70(m,2H),3.50(m,2H),3.28(s,3H)。
步驟A:2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將雙(三甲基矽烷基)醯胺鋰(在己烷中的1M溶液)逐滴加入在-78℃及N2
下在THF(5毫升)中自2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-
羧酸甲酯及2-氟基-4-(甲硫基)苯胺所製備的溶液中。將反應混合物在-78℃下攪拌1小時。接著逐滴加入在THF中成為溶液的2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯及將反應混合物在-78℃下攪拌1小時。將反應混合物以加入H2
O中止及將pH以飽和NH4
Cl調整至pH7,並接著以EtOAc稀釋。將有機層分開及以飽和NaCl清洗,乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(15:1之二氯甲烷/EtOAc)純化,得到所欲產物。
步驟B:5-溴基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將N-氯基琥珀醯亞胺加入2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧.基-1,6-二氫吡啶-3-羧酸甲酯之溶液中。將反應混合物在室溫下攪拌25分鐘及接著以飽和亞硫酸氫鈉中止。將反應混合物以H2
O稀釋及分溶在EtOAc/二乙醚與飽和NaCl之間。將層分開及將水層以EtOAc(1x)再萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(15:1之二氯甲烷/EtOAc)純化,得到5-溴基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯。
步驟C:5-氰基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將5-溴基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.020公克,0.050毫莫耳)、參(二亞苯甲基丙酮)-二鈀(0)(0.046公克,0.050毫莫耳)、1,1’-雙(二苯膦基)-二茂鐵(0.055公克,0.100毫莫耳)與Zn(CN)2
(0.006公克,0.055
毫莫耳)之混合物在120℃下加熱2小時。將反應混合物以EtOAc及H2
O稀釋,並將層分開。將EtOAc層以飽和NH4
Cl及飽和NaCl清洗,乾燥(Na2
SO4
)及在減壓下濃縮成深黃色膠。以快速管柱色層分離法(10:1之二氯甲烷/EtOAc)純化,得到成為黃色固體的0.005公克(29%)純的所欲產物。偵測出MS APCI(-)m/z 346(M-1);1
H NMR(400MHz,CDCl3
)δ 10.84(s,1H),8.39(s,1H),6.95-7.06(m,3H),3.90(s,3H),3.17(s,3H),2.50(s,3H)。
下列化合物係如先前以上述實施例所述之步驟製備,除非有其它另外的指示。
步驟A:2-氯基-6-側氧基-1,6-二氫吡啶-3-羧酸的製備:根據美國專利第3,682,932號(1972年)所述之步驟,2-氯基-6-側氧基-1,6-二氫吡啶-3-羧酸係自二氯基煙鹼酸(3.00公克,15.6毫莫耳,Aldrich)所製備,得到1.31公克(48%)所欲產物。
步驟B:2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸
甲酯的製備:將氫化鋰(95%,0.078公克,9.28毫莫耳)加入在DMF(20毫升)中的2-氯基-6-側氧基-1,6-二氫吡啶-3-羧酸(0.644公克,3.71毫莫耳)之溶液中及將反應混合物在N2
下攪拌40分鐘。接著加入甲基碘(0.508毫升,1.16公克,8.16毫莫耳)及將反應混合物再攪拌45分鐘。將反應混合物以2M HCl中止,直到pH為6-7為止。將反應混合物以EtOAc與飽和NaCl稀釋,並將層分開。將水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮,得到黃色粗固體。HPLC分析顯示兩種以4:1比的產物,將其以快速管柱色層分離法(15:1至10:1之二氯甲烷/EtOAc)分開,得到成為白色結晶固體的0.466公克(62%)純的所欲產物。也分離出成為淡黃色結晶固體的少量產物,並鑑定為位向異構物2-氯基-6-甲氧基煙鹼酸甲酯。
步驟C:2-(4-溴基-2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將雙(三甲基矽烷基)醯胺鋰(1.50毫升,1.50毫莫耳,在己烷中的1M溶液)逐滴加入在-78℃及在N2
下在THF(5毫升)中的4-溴基-2-氟基苯胺(0.192公克,1.01毫莫耳)之溶液中。將反應混合物在-78℃下攪拌1小時。接著逐滴加入在THF(5毫升)中成為溶液的2-氯基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.202公克,1.00毫莫耳)及將反應混合物在-78℃下攪拌1小時。將反應混合物以加入H2
O中止,並將pH以飽和NH4
Cl調整至pH7及接著以EtOAc稀釋。將有機層分開及以飽和NaCl清洗,乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離
法(15:1之二氯甲烷/EtOAc)純化,得到成為白色結晶固體的0.232公克(65%)純的所欲產物。
步驟D:(S)-2-(4-溴基-2-氟基苯胺基)-N-(2-(第三丁基二甲基矽烷氧基)丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將雙(三甲基矽烷基)醯胺鋰(0.70毫升,0.70毫莫耳)緩慢加入在0℃下在THF(1.50毫升)中的2-(4-溴基-2-氟基苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.050公克,0.14毫莫耳)及(S)-O-(2-(第三丁基二甲基矽烷氧基)丙基)羥胺(0.072公克,0.35毫莫耳)之溶液中。在加完之後,將反應混合物在室溫下攪拌1小時及接著以飽和NaHCO3
中止。將反應混合物分溶在EtOAc與飽和NaCl之間。將層分開及將水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
),過濾及在減壓下濃縮,得到棕色粗固體,在下一步驟中使用未進一步純化之該固體。
步驟E:(S)-2-(4-溴基-2-氟基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將1M水性HCl(1.4毫升,1.4毫莫耳)加入在THF(1.50毫升)中的(S)-2-(4-溴基-2-氟基苯胺基)-N-(2-(第三丁基二甲基矽烷氧基)丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(0.074公克,0.14毫莫耳)之溶液中。將反應在室溫下攪拌16小時。將反應混合物以EtOAc稀釋,並以飽和水性NaHCO3
(3x)及飽和水性NaCl清洗。將有機層乾燥(Na2
SO4
),過濾及在減壓下濃縮,得到白色粗固體。以Et2
O濕磨予以純化粗產物,並將所得固體分離,提供成為白色
固體的(S)-2-(4-溴基-2-氟基苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(經兩個步驟得到0.030公克,52%)。偵測出MS ESI(+)m/z 414,416(M+)Br圖案;1
H NMR(400MHz,CD3
OD)δ 7.65(d,1H),7.42(dd,1H),7.28(m,1H),6.81(t,1H),6.28(d,1H),3.88(m,1H),3.70(dd,1H),3.58(dd,1H),3.38(s,3H),1.11(d,3H)。
偵測出MS ESI(+)m/z 388(M+1)Br圖案;1
H NMR(400MHz,CDCl3
)δ 10.8(s,1H),7.47(d,2H),7.39(d,1H),6.54(t,1H),6.26(d,1H),5.59(brs,2H),3.24(s,3H)。
偵測出MS ESI(+)m/z 432(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.4(brs,1H),9.83(brs,1H),7.66(dd,1H),7.58(d,1H),7.43(d,1H),6.65(t,1H),6.18(d,1H),3.70(q,2H),3.21(s,3H),1.10(t,3H)。
偵測出MS ESI(+)m/z 448(M+1)圖案;1
H NMR(400MHz,CD3
OD)δ 7.66(d,1H),7.56(m,1H),7.46(m,1H),6.65(t,1H),6.28(d,1H),3.85(t,2H),3.67(t,2H),3.36(s,3H)。
偵測出MS ESI(+)m/z 462(M+1)圖案;1
H NMR(400MHz,CD3
OD)δ 7.66(d,1H),7.56(d,1H),7.46(d,1H),6.65(t,1H),6.28(d,1H),3.85(m,1H),3.67(m,1H),3.57(m,1H),3.38(s,3H),1.11(d,3H)。
偵測出MS APCI(+)m/z 352(M+1)圖案;1
H NMR(400MHz,CD3
OD)δ 7.64(d,1H),7.12(dd,1H),7.05(m,1H),6.86(t,1H),6.21(d,1H),3.85(q,2H),3.32(s,3H),2.47(s,3H),1.22(t,3H)。
偵測出MS ESI(+)m/z 368(M+1)圖案;1
H NMR(400MHz,CDCl3
)δ 10.28(s,1H),8.48(s,1H),7.38(d,1H),7.00(m,1H),6.96(m,1H),6.79(t,1H),6.19(d,1H),4.04(m,2H),3.88(m,1H),3.75(m,2H),3.22(s,3H),2.48(s,3H)。
偵測出MS ESI(+)m/z 382(M+1)圖案;1
H NMR(400MHz,CD3
OD)δ 7.64(d,1H),7.12(d,1H),7.04(d,1H),6.85(t,1H),6.21(d,1H),4.01(m,1H),3.90(m,1H),3.71(m,1H),3.60(m,1H),3.32(s,3H),2.47(s,3H),1.10(d,3H)。
偵測出MS APCI(+)m/z 464,466(M+,Cl圖案);1
H NMR(400MHz,DMSO-d6
)δ 11.59(brs,1H),10.06(brs,1H),7.86(d,1H),7.64(d,1H),7.54(dd,1H),6.53(d,1H),6.21(d,1H),4.67(t,1H),3.78(t,2H),3.52(m,2H),3.13(s,3H)。
偵測出MS APCI(+)m/z 478,480(M+,Cl圖案);1
H NMR(400MHz,DMSO-d6
)δ 11.59(s,1H),9.99(s,1H),7.86(d,1H),7.64(d,1H),7.54(dd,1H),6.53(d,1H),6.21(d,1H),4.73(m,1H),3.75(m,1H),3.58(m,2H),3.14(s,3H),1.02(d,3H)。
偵測出MS ESI(+)m/z 476(M+1)圖案;1
H
NMR(400MHz,CDCl3
)δ 9.79(s,1H),8.53(s,1H),7.46(d,1H),7.35(m,1H),6.44(t,1H),4.15(m,1H),3.92(dd,1H),3.69(dd,1H),3.28(s,3H),2.14(s,3H),1.14(d,3H)。
偵測出MS APCI(-)m/z 395(M-1);1
H NMR(400MHz,CD3
OD)δ 7.10(dd,1H),7.03(d,1H),6.87(t,1H),4.00(m,1H),3.85(dd,1H),3.79(s,3H),3.72(dd,1H),2.47(s,3H),1.75(s,3H),1.16(d,3H)。
偵測出MS APCI(-)m/z 475(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(dd,1H),
6.63(t,1H),3.98(m,1H),3.84(dd,1H),3.79(s,3H),3.72(dd,1H),1.78(s,3H),1.16(d,3H)。
下列化合物係如先前以上述實施例所述之步驟製備。
偵測出MS APCI(+)m/z 366(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.38(brs,1H),9.79(brs,1H),7.54(s,1H),7.23(dd,1H),6.99(dd,1H),6.73(t,1H),3.76(q,2H),3.19(s,3H),2.46(s,3H),2.01(s,3H),1.12(t,3H)。
偵測出MS APCI(+)m/z 382(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.48(brs,1H),9.78(brs,1H),7.56(s,1H),7.23(dd,1H),6.99(m,1H),6.73(t,1H),4.68(brs,1H),3.76(t,2H),3.51(t,2H),3.19(s,3H),2.46(s,3H),2.01(s,3H)。
偵測出MS APCI(+)m/z 396(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.48(brs,1H),9.68(brs,1H),7.55(s,1H),7.23(dd,1H),6.99(dd,1H),6.73(t,1H),
4.73(d,1H),3.74(m,1H),3.56(d,2H),3.20(s,3H),2.46(s,3H),2.01(s,3H),1.02(d,3H)。
偵測出MS APCI(+)m/z 478,480(M+,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.79(d,1H),7.59(s,1H),7.52(dd,1H),6.39(d,1H),3.89(t,2H),3.67(t,2H),3.34(s,3H),2.13(s,3H)。
偵測出MS ESI(+)m/z 482,484(M+,Cl圖案);1
H NMR(400MHz,DMSO-d6
)δ 11.56(brs,1H),9.69(brs,1H),7.89(s,1H),7.64(dd,1H),7.40(dd,1H),6.72(t,1H),4.66(t,1H),3.67(t,2H),3.49(m,2H),3.28(s,3H)。
偵測出MS APCI(-)m/z 477,479(M-1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.77(d,1H),7.54(dd,1H),6.51(d,1H),4.01(t,2H),3.81(s,3H),3.75(t,2H),1.74(s,3H)。
偵測出MS APCI(-)m/z 491,493(M-1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.77(d,1H),7.54(dd,1H),6.51(d,1H),4.00(m,1H),3.87(dd,1H),3.80(s,3H),3.75(dd,1H),1.74(s,3H),1.16(d,3H)。
偵測出MS APCI(-)m/z 429,431,433(M-1,Br,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.62(d,1H),7.38(dd,1H),6.67(d,1H),4.02(t,2H),3.81(s,3H),3.75(t,2H),1.73(s,3H)。
本發明額外的化合物包括如下列表1-8所示之通式Ia、IVa、IVb、IVc、IVd、IVe、IVf及IVg化合物:
本發明額外的化合物包括下列可以上述方法所製得的化合物,除非有其它另外的指示。
偵測出MS APCI(-)m/z 321(M-1);1
H NMR(400MHz,CD3
OD)δ 7.09(dd,1H),7.04(d,1H),6.87(t,1H),3.81(s,3H),2.48(s,3H),1.70(s,3H)。
偵測出MS APCI(-)m/z 385(M-1);1
H NMR(400MHz,CD3
OD)δ 7.14(td,1H),7.07(m,2H),4.05(t,2H),3.79(s,3H),3.78(t,2H),2.94(s,3H)。
偵測出MS APCI(-)m/z 399(M-1);1
H NMR(400MHz,CD3
OD)δ 7.14(td,1H),7.07(m,2H),4.04(m,1H),3.93(dd,1H),3.81(m,1H),3.80(s,3H),2.49(s,3H),1.18(d,3H)。
偵測出MS APCI(-)m/z 401,403(M-1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.06(m,3H),3.94(t,2H),3.81(s,3H),3.73(t,2H),2.49(s,3H)。
偵測出MS APCI(-)m/z 415,417(M-1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.06(m,3H),3.98(m,1H),3.81(m,1H),3.80(s,3H),3.69(dd,1H),2.49(s,3H),1.16(d,3H)。
偵測出MSAPCI(-)m/z 379(M-1);1
H NMR(400MHz,CD3
OD)δ 7.09(dd,1H),7.03(d,1H),6.86(t,1H),3.81(s,3H),3.64(t,2H),3.43(t,2H),2.47(s,3H),1.80(m,2H),1.71(s,3H)。
偵測出MSAPCI(-)m/z 395(M-1);1
H NMR(400MHz,CD3
OD)δ 7.10(dd,1H),7.03(dd,1H),6.86(t,1H),3.81(s,3H),3.80(m,1H),3.51(m,3H),3.37(dd,1H),2.47(s,3H),1.71(s,3H)。
偵測出MS APCI(-)m/z 353,355(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.38(dd,1H),7.27(m,1H),6.80(t,1H),3.82(s,3H),1.72(s,3H)。
偵測出MS APCI(-)m/z 443,445(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.39(dd,1H),7.27(m,1H),6.79(t,1H),4.03(m,1H),3.89(m,2H),3.80(s,3H),3.59(m,2H),1.77(s,3H)。
偵測出MS APCI(-)m/z 441,443(M-1,Br圖案);1
H NMR(400MHz,CD3
OD)δ 7.38(dd,1H),7.27(d,1H),6.79(t,1H),3.81(s,3H),3.38(s,2H),1.78(s,3H),1.25(s,6H)。
偵測出MS APCI(-)m/z 401(M-1);1
H NMR(400MHz,DMSO-d6
)δ 9.75(s,1H),8.25(s,1H),7.90(s,1H),7.65(s,1H),7.43(s,1H),6.63(t,1H),3.71(s,3H),1.63(s,3H)。
偵測出MS APCI(-)m/z 417,419(M-1,Br圖案);1
H NMR(400MHz,CDCl3
)δ 9.66(brs,1H),9.30(brs,1H),7.28(m,2H),6.97(td,1H),4.11(t,2H),3.84(t,2H),3.82(s,3H),3.51(t,1H)。
偵測出MS APCI(-)m/z 415(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(m,1H),6.61(t,1H),3.81(s,3H),2.87(s,3H),1.74(s,3H)。
偵測出MS APCI(-)m/z 445(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(dd,1H),6.62(t,1H),3.83(s,3H),3.18(d,2H),1.75(s,3H),1.06(m,1H),0.51(dd,2H),0.27(dd,2H)。
偵測出MS APCI(-)m/z 459(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(dd,1H),6.62(t,1H),3.81(s,3H),3.63(t,2H),3.43(t,2H),1.79(m,2H),1.74(s,3H)。
偵測出MS APCI(-)m/z 465(M-1);1
H NMR(400MHz,CD3
OD)δ 7.55(dd,1H),7.50(d,1H),6.95(td,1H),4.05(t,2H),3.80(s,3H),3.78(t,2H)。
偵測出MS APCI(-)m/z 445(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(dd,1H),6.62(t,1H),3.82(s,3H),3.68(t,2H),3.64(t,2H),1.74(s,3H)。
偵測出MS APCI(-)m/z 475(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(dd,1H),6.62(t,1H),3.82(s,3H),3.80(m,1H),3.52(m,3H),3.36(dd,1H),1.74(s,3H)。
偵測出MS APCI(-)m/z 481,483(M-1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.53(dd,1H),7.49(d,1H),6.88(t,1H),3.97(t,2H),3.81(s,3H),3.74(t,2H)。
偵測出MS APCI(-)m/z 495,496(M-1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.53(dd,1H),7.49(d,1H),6.88(t,1H),3.99(m,1H),3.83(m,1H),3.81(s,3H),3.71(dd,1H),1.17(d,3H)。
偵測出MS APCI(-)m/z 421,423(M-1,Cl圖案);1
H NMR(400MHz,CDCl3
/CD3
OD)δ 7.56(td,1H),7.46(m,1H),6.82(t,1H),3.87(s,3H)。
偵測出MS APCI(+)m/z 497,499(M+1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.53(dd,1H),7.49(d,1H),6.86(t,1H),3.84(s,3H),3.80(m,1H),3.55(d,2H),3.50(m,1H),3.37(dd,1H)。
偵測出MS APCI(-)m/z 475(M-1);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.44(d,1H),6.62(t,1H),3.82(s,3H),3.80(m,1H),3.52(m,3H),3.36(dd,1H),1.74(s,3H)。
偵測出MS APCI(+)m/z 497,499(M+1,Cl圖案);1
H NMR(400MHz,CD3
OD)δ 7.52(dd,1H),7.48(d,1H),6.86(t,1H),3.84(s,3H),3.80(m,1H),3.55(d,2H),3.51(d,1H),3.37(dd,1H)。
偵測出MS APCI(+)m/z 308(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.38(s,1H),7.92(brs,1H),7.89(d,1H),7.45(brs,1H),7.25(dd,1H),7.04(dd,1H),6.88(t,1H),6.09(d,1H),3.07(s,3H),2.48(s,3H)。
步驟A:2-氯基-5-氟基-6-側氧基-1,6-二氫吡啶-3-羧酸的製備:將2,6-二氯基-5-氟基煙鹼酸(15.00公克,71.43毫莫耳,Lancaster Synthesis)與2N NaOH(178.6毫升,357.2毫莫耳)之混合物在回流下攪拌2小時及接著在室溫下16小時。將反應混合物冷卻至0℃及以12N HCl(32.74毫升,
392.9毫莫耳)酸化。將混合物在冰浴中冷卻30分鐘,將固體過濾及以H2
O清洗。將分離的固體在溫EtOH中漿化,過濾及接著以溫EtOH清洗。收集固體及在真空下乾燥隔夜,得到成為米黃色固體的所欲產物(6.4公克,47%)。
步驟B:2-氯基-5-氟基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將LiH(95%,0.661公克,83.14毫莫耳)加入在0℃下在DMF(250毫升)中的2-氯基-5-氟基-6-側氧基-1,6-二氫吡啶-3-羧酸(6.37公克,33.26毫莫耳)之溶液中。將反應混合物攪拌45分鐘及接著加入碘基甲烷(4.56毫升,73.16毫莫耳)。將反應混合物在室溫下攪拌2小時及接著以2M HCl中止,直到反應混合物的pH為6-7為止。將反應混合物以EtOAc及飽和NaCl稀釋,並將層分開。將水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮,得到黃色粗油。HPLC分析顯示兩種以5:1之比的產物,將其以快速管柱色層分離法(15:1之二氯甲烷/EtOAc)分開,得到成為淡黃色固體的所欲產物(5.40公克,74%)。也分離出成為淡黃色結晶固體的少量產物,並鑑定為2-氯基-5-氟基-6-甲氧基煙鹼酸甲酯之位向異構物。
步驟C:5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯的製備:將雙(三甲基矽烷基)醯胺鋰(3.42毫升,3.42毫莫耳,在己烷中的1M溶液)逐滴加入在-78℃及N2
下在THF(10毫升)中的2-氟基-4-(甲硫基)苯胺(0.236公克,1.50毫莫耳)之溶液中。在加完之後,將反應混合物在-78℃下攪拌1小時。接著逐滴加入在THF(5
毫升)中成為溶液的2-氯基-5-氟基-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.300公克,1.37毫莫耳)及將反應混合物在-78℃下攪拌30分鐘。將反應以加入1M HCl中止,直到反應混合物的pH為5為止,並接著以EtOAc及飽和NaCl稀釋。將有機層分開,乾燥(Na2
SO4
)及在減壓下濃縮。以快速管柱色層分離法(15:1之二氯甲烷/EtOAc)純化,得到成為白色固體的所欲純產物(0.359公克,75%)。
步驟D:5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫吡啶-3-甲醯胺的製備:將雙(三甲基矽烷基)醯胺鋰(1.18毫升,1.18毫莫耳,在己烷中的1M溶液)逐滴加入在0℃下在THF(2毫升)中的5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-羧酸甲酯(0.100公克,0.294毫莫耳)與O-(2-(乙烯氧基)乙基)羥胺(0.045毫升,0.441毫莫耳)之混合物中。將反應混合物溫攪拌20分鐘,以1M HCl中止及接著分溶在EtOAc與飽和NaCl之間。將層分開及將水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
),過濾及在減壓下濃縮,得到黃色粗固體,在下一步驟中使用未進一步純化之該固體。
步驟E:5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺的製備:將2M HCl(0.75毫升)加入在EtOH(3毫升)中的5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-1-甲基-6-側氧基-N-(2-(乙烯氧基)乙氧基)-1,6-二氫吡啶-3-甲醯胺(0.121公克,0.294毫
莫耳)之溶液中。將反應混合物在室溫下攪拌16小時。將反應混合物的pH以1M NaOH調整至pH7。將反應混合物以EtOAc及H2
O稀釋。將有機層分開及以飽和NaCl清洗。將合併的水層以EtOAc(1x)反萃取。將合併的有機層乾燥(Na2
SO4
)及在減壓下濃縮。以矽膠快速管柱色層分離法(15:1之二氯甲烷/MeOH)純化,得到成為白色固體的5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺(經兩個步驟得到0.079公克,70%)。偵測出MS ESI(+)m/z 386(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.54(brs,1H),9.65(brs,1H),7.65(d,1H),7.23(dd,1H),6.99(dd,1H),6.81(t,1H),4.67(t,1H),3.74(t,2H),3.51(q,2H),3.25(s,3H),2.46(s,3H)。
偵測出MS ESI(+)m/z 402,404(M+,Cl圖案);1
H NMR(400MHz,DMSO-d6
)δ 11.59(brs,1H),10.00(brs,1H),7.93(s,1H),7.23(dd,1H),7.01(dd,1H),6.93(t,1H),4.66(t,1H),3.73(t,2H),3.51(m,2H),3.24(s,3H),2.47(s,3H)。
偵測出MS APCI(+)m/z 400(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.54(brs,1H),9.61(brs,1H),7.64(d,1H),7.22(dd,1H),6.99(dd,1H),6.81(t,1H),4.73(s,1H),3.73(m,1H),3.54(d,2H),3.25(s,3H),2.46(s,3H),1.01(d,3H)。
偵測出MS APCI(+)m/z 416,418(M+,Cl圖案);1
H NMR(400MHz,DMSO-d6
)δ 11.59(brs,1H),9.94(brs,1H),
7.92(s,1H),7.23(dd,1H),7.01(dd,1H),6.94(t,1H),4.71(d,1H),3.75(m,1H),3.54(d,2H),3.24(s,3H),2.47(s,3H),1.02(d,3H)。
偵測出MS ESI(+)m/z 338(M+1)圖案;1
H NMR(400MHz,CDCl3
)δ 10.33(s,1H),8.39(s,1H),7.40(d,1H),7.02(dd,1H),6.96(dd,1H),6.75(t,1H),6.20(d,1H),3.83(s,3H),3.23(s,3H),2.47(s,3H)。
偵測出MS ESI(+)m/z 402(M+1)圖案;1
H
NMR(400MHz,DMSO-d6
)δ 10.75(s,1H),7.85(brs,1H),7.78(s,1H),7.66(d,1H),7.40(m,2H),6.54(t,1H),3.13(s,3H),2.00(s,3H)。
偵測出MS ESI(+)m/z 460(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 10.34(s,1H),8.27(t,1H),7.72(s,1H),7.64(dd,1H),7.38(dd,1H),6.50(t,1H),4.41(t,1H),3.17(s,5H),2.01(s,3H),1.55(s,2H)。
偵測出MS APCI(+)m/z 460(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.54(brs,1H),9.62(brs,1H),7.86(s,1H),7.62(dd,1H),7.38(dd,1H),6.69(t,1H),4.69(m,1H),3.46(m,2H),3.27(s,3H),0.99(d,3H)。
偵測出MS APCI(+)m/z 492(M+1)圖案;1
H NMR(400MHz,CD3
OD)δ 7.79(d,1H),7.58(m,1H),7.52(dd,1H),6.39(d,1H),3.87(m,1H),3.73(dd,1H),3.62(dd,1H),3.35(s,3H),2.13(s,3H),1.10(d,3H)。
偵測出MS ESI(+)m/z 466(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.53(brs,1H),9.37(brs,1H),7.64(dd,1H),7.62(d,1H),7.37(dd,1H),6.61(t,1H),4.68(t,1H),3.69(t,2H),3.49(q,2H),3.30(s,3H)。
偵測出MS APCI(+)m/z 480(M+1)圖案;1
H NMR(400MHz,DMSO-d6
)δ 11.49(brs,1H),9.48(brs,1H),7.61(m,2H),7.36(m,1H),6.59(t,1H),4.77(brs,1H),3.69(m,1H),3.49(s,1H),3.48(d,1H),3.29(s,3H),0.99(d,3H)。
上述說明被認為只是本發明原理的論證。再者因為許多修改及變化可為那些熟諳本技藝者輕易明白,所以不希望將本發明限制成如上述所示之實際結構及方法。因此所有適合的修改及同等物被認為落在如隨後的申請專利範圍所定義之本發明的範圍內。
當在本專利說明書及以下的申請專利範圍中使用〝包含(comprise)〞、〝包含(comprising)〞、〝包括(include)〞、
〝包括(including)〞及〝包括(includes)〞用字時,則意圖指明所述特點、整數、組份或步驟的存在,但是彼等不排除一或多種彼之其它特點、整數、組份、步驟或群組的存在或加入。
以併入本文及構成一部分專利說明書的所附之圖形圖解本發明的非限制性具體實例,並與說明書一起幫助解釋本發明的原理。
在圖形中:圖1展示用於合成化合物96的反應流程。
圖2展示用於合成化合物96、100、101及102的反應流程。
圖3展示用於合成化合物109、110及111的反應流程。
圖4展示用於合成化合物109、110及111的可替換之反應流程。
圖5展示用於合成化合物119、120及121的反應流程。
圖6展示用於合成化合物124及125的反應流程。
圖7展示用於合成化合物128、129及130的反應流程。
圖8展示用於合成化合物145及146的反應流程。
圖9展示用於合成化合物145的可替換之反應流程。
圖10展示根據實施例16A之步驟3所製備的型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之X-射線粉末繞射圖。
圖11展示根據實施例16A之步驟4所製備的型式1,
2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之X-射線粉末繞射圖。
圖12展示根據實施例16B所製備的型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之X-射線粉末繞射圖。
圖13展示根據實施例16D所製備的型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之X-射線粉末繞射圖。
圖14展示型式2,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之DSC溫度記錄圖。
圖15展示型式1,2-(2-氟基-4-碘基苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺之DSC溫度記錄圖。
Claims (11)
- 一種具有化學式V之化合物,
- 根據申請專利範圍第1項之化合物,其中化合物係選自:2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基乙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;(S)-5-氟基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙 氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;及(S)-5-氯基-2-(2-氟基-4-(甲硫基)苯胺基)-N-(2-羥基丙氧基)-1-甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺。
- 根據申請專利範圍第1至2項中任一項之化合物,其係用作醫藥。
- 根據申請專利範圍第1至2項中任一項之化合物,其係用作治療高增殖性疾病或發炎性症狀之醫藥。
- 一種根據申請專利範圍第1至2項中任一項之化合物的用途,其供製造用於治療高增殖性疾病或發炎性症狀之醫藥。
- 一種根據申請專利範圍第1至2項中任一項之化合物的用途,其供製造在需要該治療之溫血動物產生MEK酵素抑制效應之醫藥。
- 一種醫藥組成物,其包含與醫藥上可接受之載體結合的根據申請專利範圍第1至2項中任一項之化合物。
- 一種製備申請專利範圍第1項之化合物的方法,其中R9 為CH3 ,該方法包含:(a)將具有化學式105之化合物溴化
- 一種製備申請專利範圍第1項之化合物的方法,其中R9 為Cl,該方法包含:(a)將式112化合物
- 一種製備申請專利範圍第1項之化合物的方法,其中R9 為H或F,該方法包含:(a)將式140化合物
- 根據申請專利範圍第8-10項中任一項之方法,其中該偶合試劑為1-(3-二甲胺基丙基)-3-乙基碳二醯亞胺鹽酸鹽、1-羥基苯并三唑-6-磺醯胺基甲基鹽酸鹽或六氟磷酸苯并三唑-1-基-氧基三吡咯啶鏻。
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