TW201311676A - 選擇性蛋白質激酶抑制劑 - Google Patents
選擇性蛋白質激酶抑制劑 Download PDFInfo
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- TW201311676A TW201311676A TW101127351A TW101127351A TW201311676A TW 201311676 A TW201311676 A TW 201311676A TW 101127351 A TW101127351 A TW 101127351A TW 101127351 A TW101127351 A TW 101127351A TW 201311676 A TW201311676 A TW 201311676A
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
本發明係關於式I化合物或其醫藥上可接受之鹽:□其中R1、R2、R3、A、Q、W及X係如說明書中所定義。該等化合物選擇性調節、調控及/或抑制藉由某些天然及/或突變蛋白質激酶調介之信號轉導,該等天然及/或突變蛋白質激酶與各種人類及動物疾病(例如細胞增殖、代謝、過敏及退化病症)有關。更特定而言,該等化合物係強效及選擇性天然及/或突變c-kit抑制劑。
Description
本發明係關於式I化合物或其醫藥上可接受之鹽,該等物質選擇性調節、調控及/或抑制藉由某些天然及/或突變蛋白質激酶調介之信號轉導,該等天然及/或突變蛋白質激酶與各種人類及動物疾病(例如細胞增殖、代謝、過敏及退化病症)有關。更特定而言,該等化合物係強效及選擇性天然及/或突變c-kit抑制劑。
蛋白質激酶係受體型或非受體型蛋白質,其將ATP之末端磷酸酯轉移至蛋白質之胺基酸殘基(例如酪胺酸、蘇胺酸、絲胺酸殘基),藉此使信號轉導路徑活化或失活。已知該等蛋白質涉及許多細胞機制,在該等細胞機制中斷之情形下將導致諸如異常細胞增殖及遷移以及炎症等病症。
當前已知超過500種蛋白質激酶。其包含熟知之Ab1、Akt1、Akt2、Akt3、ALK、Alk5、A-Raf、Axl、B-Raf、Brk、Btk、Cdk2、Cdk4、Cdk5、Cdk6、CHK1、c-Raf-1、Csk、EGFR、EphA1、EphA2、EphB2、EphB4、Erk2、Fak、Fes、Fer、FGFR1、FGFR2、FGFR3、FGFR4、Flt-3、Fms、Frk、Fyn、Gsk3α、Gsk3β、HCK、Her2/Erbb2、Her4/Erbb4、IGF1R、IKKβ、Irak4、Itk、Jak1、Jak2、Jak3、Jnk1、Jnk2、Jnk3、KDR、Kit、Lck、Lyn、MAP2K1、MAP2K2、MAP4K4、MAPKAPK2、Met、Mer、MNK1、MLK1、mTOR、p38、PDGFRα、PDGFRβ、
PDPK1、PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ、Pim1、Pim2、Pim3、PKCα、PKCβ、PKCθ、Plk1、Pyk2、Ret、ROCK1、ROCK2、RON、Src、Stk6、Syk、TEC、Tie2、TrkA、TrkB、Tyk2、VEGFR1/Flt-1、VEGFR2/Kdr、VEGFR3/Flt-4、Yes及Zap70。
藉由蛋白質激酶調介之事件觸發之異常細胞反應會產生各種疾病。該等疾病包含自體免疫疾病、發炎性疾病、神經學及神經退化性疾病、癌症、心血管疾病、過敏及哮喘、阿茲海默氏疾病(Alzheimer's disease)及激素相關性疾病。
酪胺酸激酶係受體型或非受體型蛋白質,其將ATP之末端磷酸酯轉移至蛋白質之酪胺酸殘基,藉此使信號轉導路徑活化或失活。已知該等蛋白質涉及許多細胞機制,在該等細胞機制中斷之情形下將導致諸如異常細胞增殖及遷移以及炎症等病症。
當前已知約58種受體酪胺酸激酶。其包含熟知之VEGF受體(Kim等人,Nature 362,第841-844頁,1993)、PDGF受體、c-kit、Flt-3及FLK家族。該等受體可將信號傳輸至其他酪胺酸激酶(包含Src、Raf、Frk、Btk、Csk、Abl、Fes/Fps、Fak、Jak、Ack等)。
尤其關注酪胺酸激酶受體c-kit。實際上,c-kit係活化肥大細胞之關鍵受體,已證明肥大細胞與許多病況直接或間接有關,申請者已針對該等病況提出申請WO 03/004007、WO 03/004006、WO 03/003006、WO 03/003004、WO
03/002114、WO 03/002109、WO 03/002108、WO 03/002107、WO 03/002106、WO 03/002105、WO 03/039550、WO 03/035050、WO 03/035049、US 60/359,652、US 60/359651及US 60/449861、WO 04/080462、WO 05/039586、WO 06/135721、WO 07/089069、WO 07/124369、WO 08/137794、WO 08/063888、WO 08/011080、WO 09/109071、WO 10/096395。
發現存在於患者組織中之肥大細胞與例如以下疾病之發生有關或促成該等疾病發生:自體免疫疾病(類風濕性關節炎、發炎性腸病(IBD))、過敏性疾病、骨質流失、癌症(例如實體腫瘤、白血病及GIST)、腫瘤血管生成、發炎性疾病、間質性膀胱炎、肥大細胞增多症、移植物抗宿主疾病、感染疾病、代謝病症、纖維化、糖尿病及CNS疾病。在該等疾病中,已展示肥大細胞藉由釋放不同蛋白酶與介質(例如組胺、中性蛋白酶、脂質衍生之介質(前列腺素、促凝血素及白三烯)及各種細胞因子(IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-8、TNF-α、GM-CSF、MIP-1a、MIP-1b、MIP-2及IFN-γ))之混合物來參與組織之破壞。
亦可藉由導致異常細胞增殖且發生疾病(例如肥大細胞增多症(D816V突變)及諸如GIST(c-kit△27,近膜缺失)等各種癌症)之突變使c-kit受體組成型活化。
60%至70%之AML患者具有表現c-kit(其係幹細胞因子(SCF)之受體)胚細胞(Broudy,1997)。SCF促進造血祖細胞
之生長,並用作AML胚細胞之存活因子。在AML之一些情形(1%至2%)中,已闡述引起c-kit組成型活化之激酶結構域之保守殘基中之突變(Kit816)(Beghini等人,2000;Longley等人,2001)。已在肥大細胞白血病細胞系及源自肥大細胞增多症患者之試樣中鑑別出此獲得性功能突變(Asp至Val/Tyr之取代)(Longley等人,1996)。初步結果展示,此突變表現於大部分全身性肥大細胞增多症情形中([約60%],P Dubreuil,AFIRMM,在約300患者之進展研究中)。
因此,本發明下之主要目標係發現能夠抑制野生型及/或突變蛋白質激酶、特定而言野生型及/或突變酪胺酸激酶及更特定而言野生型及/或突變c-kit之強效及選擇性化合物。
結合本發明,我們發現式I化合物係某些蛋白質激酶(例如野生型及/或突變c-kit)之強效及選擇性抑制劑。該等化合物係用於治療諸如自體免疫疾病、發炎性疾病、癌症及肥大細胞增多症等疾病之良好候選者。
針對抑制蛋白質激酶及特定而言酪胺酸激酶及更特定而言c-Kit及/或突變c-Kit(尤其係c-Kit D816V)之能力來篩選本發明化合物。
在第一實施例中,本發明旨在式I化合物,該式I化合物可代表游離鹼形式之物質或其醫藥上可接受之鹽:
其中A係5或6員雜環;R1係氫、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基、硫代烷基或烷氧基;R2係鹵素(選自F、Cl、Br或I)、芳基、含有1至10個碳原子之鹵代烷基或烷基,該鹵代烷基或烷基視情況經至少一個雜原子(尤其係硫、氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之鹵代烷基或烷基取代;以及烷氧基、硫代烷基或鹵代烷氧基;以及-COOR、-NRR'、-NR-CO-R'、-CONRR'、-SO2NRR'或-NR-SO2-R'基團,其中R及R'各自獨立地選自氫、芳基、雜芳基、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團;R3係氫、鹵素(選自F、Cl、Br或I)、氰基、含有1至10個碳原子之烷基或烷氧基;以及CF3、-NRR'、-NR-CO-R'、-CONRR'、-SO2NRR'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係硫、氧或氮)取代,視情況經含有1至10個碳原子且視情況經增
溶基團取代之烷基取代;以及雜環基團或增溶基團;Q係O或S;W係N或CR4;R4係氫、氰基、CF3、鹵素(選自F、Cl、Br或I)、硫代烷基、含有1至10個碳原子之烷基,該烷基視情況經至少一個雜原子(尤其係硫、氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及烷氧基或鹵代烷氧基、增溶基團、雜環、-CO-NRR'、-SO2-NRR'、-NRR'、-NR-CO-R'或-NR-SO2R'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基取代;X係N或CR5;R5係氫、氰基、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基、烷氧基、-CO-OR、-CO-NRR'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係硫、氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基取代。
在一實施例中,本發明係關於式I化合物或其醫藥上可接受之鹽,其中R2係鹵素(選自F、Cl、Br或I)、芳基、含有1至10個碳原子之鹵代烷基或烷基,該鹵代烷基或烷基視情況經至少一個雜原子(尤其係硫、氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之鹵代烷基或烷基取代;以及烷氧基、硫代烷基或鹵代烷氧基;
以及-NRR'、-NR-CO-R'、-CONRR'、-SO2NRR'或-NR-SO2-R'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團。
除非另外指定,否則本文所使用之下列術語定義如下。
如本文中所使用,術語「烷基」意指具有1至10個碳原子、較佳地1至6個碳原子、更佳地1至4個碳原子之飽和直鏈或具支鏈非環狀烴。代表性飽和直鏈烷基包含甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基及正癸基;而飽和具支鏈烷基包含異丙基、第二丁基、異丁基、第三丁基、異戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基及諸如此類。本發明化合物中所包含之烷基皆可視情況經一或多個取代基取代。本發明化合物中所包含之烷基皆可視情況
經增溶基團取代。
如本文中所使用,術語「芳基」意指包括碳及氫原子之單環或多環芳族基團。適宜芳基之實例包含但不限於苯基、甲苯基、蒽基、茀基、茚基、甘菊藍基及萘基以及苯并稠合碳環部分(例如5,6,7,8-四氫萘基)。芳基可未經取代或經一或多個取代基取代。本發明化合物中所包含之芳基可視情況經增溶基團取代。
如本文中所使用,術語「烷氧基」係指藉由氧原子附接至另一部分之如上文所定義之烷基。烷氧基之實例包含甲氧基、異丙氧基、乙氧基、第三丁氧基及諸如此類。烷氧基可視情況經一或多個取代基取代。本發明化合物中所包含之烷氧基可視情況經增溶基團取代。
如本文中所使用,術語「硫代烷基」係指藉由硫原子附接至另一部分之如上文所定義之烷基。硫代烷基可視情況經一或多個取代基取代。本發明化合物中所包含之硫代烷基可視情況經增溶基團取代。
如本文中所使用,術語「雜環」共同地係指雜環烷基及雜芳基。
如本文中所使用,術語「雜環烷基」意指具有至少一個選自O、N或S之雜原子且具有2至11個碳原子之單環或多環基團,其可為飽和或不飽和,但非芳族。雜環烷基之實例包含(但不限於):六氫吡啶基、六氫吡嗪基、2-側氧基六氫吡嗪基、2-側氧基六氫吡啶基、2-側氧基吡咯啶基、4-六氫吡啶酮基、吡咯啶基、乙內醯脲基、戊內醯胺基、
環氧乙烷基、氧雜環丁基、四氫吡喃基、四氫硫代吡喃基、四氫吡啶基、四氫嘧啶基、四氫硫代吡喃基、四氫硫代吡喃基亞碸、嗎啉基、硫代嗎啉基、硫代嗎啉基亞碸、硫代嗎啉基碸、1,3-二氧雜環戊烷、四氫呋喃基、二氫呋喃基-2-酮、四氫噻吩基及四氫-1,1-二側氧基噻吩基。通常,單環雜環烷基具有3至7個成員。較佳3至7員單環雜環烷基係彼等具有5或6個環原子者。雜原子可經彼等熟習此項技術者已知之保護基團取代,舉例而言,氮上之氫可經第三丁氧基羰基取代。另外,雜環烷基可視情況經一或多個取代基取代。此外,雜環與另一基團之附接點可在雜環之碳原子或雜原子處。此定義僅涵蓋該等經取代雜環基團之穩定異構體。
如本文中所使用,術語「雜芳基」或類似術語意指包括碳原子環成員及一或多個雜原子環成員(例如,氧、硫或氮)之單環或多環雜芳族環。通常,雜芳基具有1至約5個雜原子環成員及1至約14個碳原子環成員。代表性雜芳基包含吡啶基、1-側氧基-吡啶基、呋喃基、苯并[1,3]二氧雜環戊烯基、苯并[1,4]二氧雜環己烯基、噻吩基、吡咯基、噁唑基、咪唑基、噻唑基、異噁唑基、喹啉基、吡唑基、異噻唑基、噠嗪基、嘧啶基、吡嗪基、三嗪基、三唑基、噻二唑基、異喹啉基、吲唑基、苯并噁唑基、苯并呋喃基、吲嗪基、咪唑并吡啶基、四唑基、苯并咪唑基、苯并噻唑基、苯并噻二唑基、苯并噁二唑基、吲哚基、四氫吲哚基、氮雜吲哚基、咪唑并吡啶基、喹唑啉基、嘌呤
基、吡咯并[2,3]嘧啶基、吡唑并[3,4]嘧啶基、咪唑并[1,2-a]吡啶基及苯并(b)噻吩基。雜原子可經彼等熟習此項技術者已知之保護基團取代,舉例而言,氮上之氫可經第三丁氧基羰基取代。雜芳基可視情況經一或多個取代基取代。此外,氮或硫雜原子環成員可發生氧化。在一實施例中,雜芳族環選自5-8員單環雜芳基環。雜芳族或雜芳基環與另一基團之附接點可在雜芳族或雜芳基環之碳原子或雜原子處。
如本文中所使用,術語「鹵代烷基」意指一或多個(包含所有)氫基團由鹵基代替之如上文所定義之烷基,其中每一鹵基皆獨立地選自-F、-Cl、-Br及-I。術語「鹵代甲基」意指一至三個氫基團由鹵基代替之甲基。代表性鹵代烷基包含三氟甲基、溴甲基、1,2-二氯乙基、4-碘丁基、2-氟戊基及諸如此類。鹵代烷基可視情況經一或多個取代基取代。本發明化合物中所包含之鹵代烷基可視情況經增溶基團取代。
如本文中所使用,術語「鹵代烷氧基」意指一或多個(包含所有)氫基團由鹵基代替之如上文所定義之烷氧基,其中每一鹵基皆獨立地選自-F、-Cl、-Br及-I。代表性鹵代烷氧包含三氟甲氧基、溴甲氧基、1,2-二氯乙氧基、4-碘丁氧基、2-氟戊氧基及諸如此類。鹵代烷氧基可視情況經一或多個取代基取代。本發明化合物中所包含之鹵代烷氧基可視情況經增溶基團取代。
如本文中所使用,術語「取代基」或「經取代」意指化
合物或基團上之氫基團經其未保護形式或在使用保護基團保護時對於反應條件實質上穩定之任一期望基團代替。較佳取代基之實例係彼等在本文所揭示之實例性化合物及實施例中發現者以及鹵素、如上文所定義之烷基、羥基、如上文所定義之烷氧基、硝基、硫醇、如上文所定義之硫代烷基、氰基、如上文所定義之鹵代烷基、如上文所定義之鹵代烷氧基、環烷基(其可為單環或稠合或非稠合多環(例如,環丙基、環丁基、環戊基或環己基))或增溶基團。
如本文中所使用,術語「增溶」基團意指具有足以改良或增加包含其之化合物之水溶性(與並不包含該基團之類似化合物相比)之親水性特徵的基團。可藉由任一方式達成親水性特徵,例如藉由納入在用於形成帶電部分之條件下離子化之官能基(例如,羧酸、磺酸、磷酸、胺等)、包含永久電荷之基團(例如,四級銨基團)及/或雜原子或雜原子基團(例如,O、S、N、NH、N-(CH2)zR、N-(CH2)z-C(O)R、N-(CH2)z-C(O)OR、N-(CH2)z-S(O)2R、N-(CH2)z-S(O)2OR、N-(CH2)z-C(O)NRR',其中z係介於0至6之間之整數,R及R'各自獨立地選自氫、含有1至10個碳原子且視情況經一或多個雜原子(例如鹵素(選自F、Cl、Br或I)、氧及氮)取代之烷基以及含有1至10個碳原子之烷氧基以及芳基及雜芳基)。
在一些實施例中,增溶基團係視情況包含1至5個可本身係增溶基團之取代基之雜環烷基。
在一具體實施例中,增溶基團具有下式:
其中L係選自由CH及N組成之群,M係選自由以下組成之群:-CH(R)-、-CH2-、-O-、-S-、-NH-、-N(-(CH2)z-R)-、-N(-(CH2)z-C(O)R)-、-N(-(CH2)z-C(O)OR)-、-N(-(CH2)z-S(O)2R)-、-N(-(CH2)z-S(O)2OR)-及-N(-(CH2)z-C(O)NRR')-,其中z係介於0至6之間之整數,R及R'各自獨立地選自氫、含有1至10個碳原子且視情況經一或多個雜原子(例如鹵素(選自F、Cl、Br或I)、氧及氮)取代之烷基;以及含有1至10個碳原子之烷氧基、NRR'基團(其中R及R'各自獨立地選自氫、如上文所定義之烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個視情況經取代之碳之烷基取代)以及芳基及雜芳基,前提係L及M並不同時分別為CH及CH2。
在另一具體實施例中,增溶基團係選自由以下組成之群:嗎啉基、六氫吡啶基、N-(C1-C6)烷基六氫吡啶基(特定而言係N-甲基六氫吡啶基及N-乙基六氫吡啶基)、N-(4-六氫吡啶基)六氫吡啶基、4-(1-六氫吡啶基)六氫吡啶基、1-吡咯啶基六氫吡啶基、4-嗎啉基六氫吡啶基、4-(N-甲基-1-六氫吡嗪基)六氫吡啶基、六氫吡嗪基、N-(C1-C6)烷
基六氫吡嗪基、(特定而言係N-甲基六氫吡嗪基及N-乙基六氫吡嗪基)、N-(C3-C6)環烷基六氫吡嗪基(特定而言係N-環己基六氫吡嗪基)、吡咯啶基、N-(C1-C6)烷基吡咯啶基(特定而言係N-甲基吡咯啶基及N-乙基吡咯啶基)、二氮呯基、N-(C1-C6)烷基氮呯基(特定而言係N-甲基氮呯基及N-乙基氮呯基)、高六氫吡嗪基、N-甲基高六氫吡嗪基、N-乙基高六氫吡嗪基、咪唑基及諸如此類。
在環A如上文所繪示之式I化合物中,本發明係關於下式II之化合物:
其中:A環係5員雜環;R1係氫、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基或烷氧基;R2係鹵素(選自F、Cl、Br或I)、芳基、含有1至10個碳原子之鹵代烷基或烷基,該鹵代烷基或烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之鹵代烷基或烷基取代;以及烷氧基或鹵代烷氧基;以及-COOR、-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基團,其中R及R'各自獨立地選自
氫、芳基、雜芳基、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團;R3係氫、鹵素(選自F、Cl、Br或I)、氰基、含有1至10個碳原子之烷基或烷氧基;以及CF3、-NRR'、-NR-CO-R'、-CONRR'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團;Q係O或S;W係N或CR4;R4係氫、氰基、CF3、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及烷氧基或鹵代烷氧基、增溶基團、雜環、-CO-NRR'、-SO2-NRR'、-NRR'、-NR-CO-R'或-NR-SO2R'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基取代;X係N或CR5;R5係氫、氰基、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基、烷氧基、-CO-OR、-CO-NRR'基團,其中R及
R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基取代;M係C或N;V係CH2、CR7或NR7;R7係氫或含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基;Y係N、CR8或CR8R9;Z係N、NR8、CR8或CR8R9;R8係氫、含有1至10個碳原子之烷基或烷氧基;R9係氫或含有1至10個碳原子之烷基。
在一實施例中,本發明係關於式II化合物或其醫藥上可接受之鹽,其中R2係鹵素(選自F、Cl、Br或I)、芳基、含有1至10個碳原子之鹵代烷基或烷基,該鹵代烷基或烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之鹵代烷基或烷基取代;以及烷氧基或鹵代烷氧基;以及-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團。
上式之較佳化合物之實例繪示於下表1中:
在環A如上文所繪示之式I化合物中,本發明係關於下式III之化合物:
其中:A環係6員雜環;
R1係氫、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基或烷氧基;R2係鹵素(選自F、Cl、Br或I)、芳基、含有1至10個碳原子之鹵代烷基或烷基,該鹵代烷基或烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之鹵代烷基或烷基取代;以及烷氧基或鹵代烷氧基;以及-COOR、-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基團,其中R及R'各自獨立地選自氫、芳基、雜芳基、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團;R3係氫、鹵素(選自F、Cl、Br或I)、氰基、含有1至10個碳原子之烷基或烷氧基;以及CF3、-NRR'、-NR-CO-R'、-CONRR'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團;Q係O或S;W係N或CR4;R4係氫、氰基、CF3、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及烷氧基或鹵代烷氧基、
增溶基團、雜環、-CO-NRR'、SO2-NRR'、-NRR'、NR-CO-R'或NR-SO2R'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基取代;X係N或CR5;R5係氫、氰基、鹵素(選自F、Cl、Br或I)、含有1至10個碳原子之烷基、烷氧基、-CO-OR、-CO-NRR'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基取代;M係C或N;V係N、CH2、CR7或NR7;R7係氫、氰基或含有1至10個碳原子且視情況經增溶基團或雜環基團取代之烷基;Y係N、CR8或CR8R9;Z係N、CR8或CR8R9;T係N、C=O、CR8或CR8R9;R8係氫、鹵素(選自F、Cl、Br或I)、羥基、含有1至10個碳原子之烷基或烷氧基;R9係氫或含有1至10個碳原子之烷基。
在一實施例中,本發明係關於式III化合物或其醫藥上可接受之鹽,其中R2係鹵素(選自F、Cl、Br或I)、芳基、含有1至10個碳原子之鹵代烷基或烷基,該鹵代烷基或烷基
視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之鹵代烷基或烷基取代;以及烷氧基或鹵代烷氧基;以及-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基團,其中R及R'各自獨立地選自氫、烷基,該烷基視情況經至少一個雜原子(尤其係氧或氮)取代,視情況經含有1至10個碳原子且視情況經增溶基團取代之烷基取代;以及雜環基團或增溶基團。
上式之較佳化合物之實例繪示於下表2中:
在可與本發明之其他實施例組合之一實施例中,本發明係關於式I化合物或其醫藥上可接受之鹽,其中:R1係H或(C1-C6)烷基;R2係H;鹵素;COOH;(C1-C6)烷基,其視情況經基團-NR10R11、OH或視情況經OH取代之(C1-C4)烷氧基取代,其中R10及R11各自獨立地係H或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基取代之(C1-C4)烷基;或R10及R11與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉);(C1-C6)烷氧基,其視情況經OH、(C1-C4)烷氧基或基團-NR12R13取代,其中R12及R13各自獨立地係H或(C1-C4)烷基;或R12及R13與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉),該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-OR14,其中R14係含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉),該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-CONR15R16,其中R15及R16各自獨立地係H或視
情況經(C1-C4)烷氧基或含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係嗎啉)取代之(C1-C4)烷基;或R15及R16與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉);基團-NR17R18,其中R17係H或(C1-C4)烷基且R18係H;視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;或含有1至3個選自O、S及N之雜原子之5-或6員雜芳基(特定而言係吡啶、嘧啶及噻唑);基團-NR19COR20,其中R19係H或(C1-C4)烷基且R20係H或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基或含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉)取代之(C1-C4)烷基,該雜環烷基視情況經1至3個(C1-C4)烷基取代;或含有1或2個選自O及N之雜原子之5-或6員雜環烷基或雜芳基(特定而言係六氫吡啶及呋喃),該雜環烷基或雜芳基視情況經側氧基或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基取代之(C1-C4)烷基取代;R3係H、氰基、CF3、鹵素、(C1-C4)烷基或(C1-C4)烷氧基;Q係O或S,較佳地Q係O;
W係N或CR21,其中R21係H;鹵素;CN;CF3;OCF3;(C1-C4)烷基,其視情況經含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉)取代;(C1-C4)烷氧基;基團-O(CH2)nR22,其中n為0、1、2或3且R22係H、(C1-C4)烷氧基、基團-NR22aR22b(其中R22a及R22b各自獨立地係H或(C1-C4)烷基)或含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉),該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-NR23R24,其中R23及R24各自獨立地係H或視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;R24亦可代表基團-SO2(C1-C4)烷基;或R23及R24與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基或雜芳基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪、嗎啉及吡唑),該雜環烷基視情況經1至3個(C1-C4)烷基取代;X係N或CR25,其中R25係H、CN、(C1-C4)烷基或基團
-COO(C1-C4)烷基;且A係含有1至3個選自O及N之雜原子之5-或6員雜環烷基或雜芳基(特定而言係六氫吡啶、六氫吡嗪、吡咯啶、嗎啉、咪唑啶、二氫咪唑、三唑、二氫吡啶及四氫吡啶),該雜環烷基或雜芳基視情況經1至3個選自以下之取代基取代:側氧基;鹵素;(C1-C4)烷基,其視情況經胺基、(C1-C4)烷基胺基、二(C1-C4)烷基胺基或含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係六氫吡啶)取代;及(C1-C4)烷氧基。
在此化合物家族內,彼等R2、R3及W如下文所定義者較佳:R2係H;鹵素;(C1-C6)烷基,其視情況經基團-NR10R11或視情況經OH取代之(C1-C4)烷氧基取代,其中R10及R11各自獨立地係H或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基取代之(C1-C4)烷基;或R10及R11與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉);(C1-C6)烷氧基,其視情況經OH、(C1-C4)烷氧基或基團-NR12R13取代,其中R12及R13各自獨立地係H或(C1-C4)烷基;或R12及R13與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環
烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉),該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-OR14,其中R14係含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉),該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-CONR15R16,其中R15及R16各自獨立地係H或視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;或R15及R16與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉);基團-NR17R18,其中R17係H或(C1-C4)烷基且R18係H;視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;或含有1至3個選自O及N之雜原子之5-或6員雜芳基(特定而言係吡啶);基團-NR19COR20,其中R19係H或(C1-C4)烷基且R20係H或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基或含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉)取代之(C1-C4)烷基,該雜環烷基視情況經1至3個(C1-C4)烷基取代;或含有1或2個選自O及N之雜原子之5-或6員雜環烷基或雜芳基(特定而言係六氫吡啶及呋喃),該雜環烷基或雜芳基視情況經側氧基或視情況經胺基、(C1-C4)烷
基胺基或二(C1-C4)烷基胺基取代之(C1-C4)烷基取代;R3係H、CF3、鹵素、(C1-C4)烷基或(C1-C4)烷氧基;W係N或CR21,其中R21係H;鹵素;CN;CF3;OCF3;(C1-C4)烷基,其視情況經含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉)取代;(C1-C4)烷氧基;基團-O(CH2)nR22,其中n為0、1或2且R22係含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係吡咯啶、六氫吡啶、六氫吡嗪及嗎啉),該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-NR23R24,其中R23及R24各自獨立地係H或視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;或R23及R24與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基或雜芳基(特定而言吡咯啶、六氫吡啶、六氫吡嗪、嗎啉及吡唑),該雜環烷基視情況經1至3個(C1-C4)烷基取代。
在可與本發明之其他實施例組合之另一實施例中,涵蓋
式I化合物或其醫藥上可接受之鹽,其中:R1係H或(C1-C4)烷基;R2係H;視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;視情況經OH或基團-NR12R13取代之(C1-C4)烷氧基,其中R12及R13各自獨立地係H或(C1-C4)烷基,或R12及R13與其所鍵結之氮原子一起形成含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係嗎啉);或基團-CONR15R16,其中R15及R16各自獨立地係H或(C1-C4)烷基;R3係H或(C1-C4)烷基;Q係O;W係N或CR21,其中R21係H、OCF3、(C1-C4)烷基、(C1-C4)烷氧基或基團-O(CH2)nR22(其中n為0、1或2,較佳地n為2,且R22係含有1或2個選自O及N之雜原子之5-或6員雜環烷基(特定而言係嗎啉));X係N或CH;且A係含有1或2個氮原子之5-或6員雜環烷基或雜芳基(特定而言係咪唑啶及二氫吡啶),該雜環烷基或雜芳基視情況經1至3個(C1-C4)烷基取代。
本發明之較佳化合物選自實例1至225之彼等化合物及其醫藥上可接受之鹽。
尤佳者係下列化合物:1-{4-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-吡啶-2-基}-咪唑啶-2-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-
甲氧基-苯基}-4,4-二甲基-咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-5-甲基-苯基)-咪唑啶-2-酮;1-(4-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-(4-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-{4-[2-((5-甲氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-吡啶-2-基}-4-甲基-咪唑啶-2-酮;4-甲基-1-(4-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-(3-甲基-5-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-苯基)-咪唑啶-2-酮;1-(4-{2-[2-甲基-5-(3-嗎啉-4-基-丙氧基)-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-咪唑啶-2-酮;1-(3-甲氧基-5-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-苯基)-咪唑啶-2-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-4-甲基-咪唑啶-2-酮;1-{3-第三-丁氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-苯基}-咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-
5-甲氧基-苯基)-咪唑啶-2-酮;1-(3-甲氧基-5-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-苯基)-4-甲基-咪唑啶-2-酮;1-{3-異丙氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-苯基}-咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-5-異丙氧基-苯基)-咪唑啶-2-酮;1-(3-異丙氧基-5-{2-[5-(2-甲氧基-乙基)-2-甲基-苯基胺基]-噁唑-5-基}-苯基)-咪唑啶-2-酮;1-(3-(2-(2-甲基-5-(2-嗎啉基乙氧基)苯基胺基)噁唑-5-基)-5-(三氟甲氧基)苯基)咪唑啶-2-酮;1-(3-(2-(5-甲氧基-2-甲基苯基胺基)噁唑-5-基)-5-(三氟甲氧基)苯基)咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基甲基)-2-甲基-苯基胺基]-噁唑-5-基}-5-甲基-苯基)-咪唑啶-2-酮;3-{5-[3-異丙氧基-5-(2-側氧基-咪唑啶-1-基)-苯基]-噁唑-2-基胺基}-N-(2-甲氧基-乙基)-4-甲基-苯甲醯胺;1-(3-(2-(5-(乙氧基甲基)-2-甲基苯基胺基)噁唑-5-基)-5-(三氟甲氧基)苯基)咪唑啶-2-酮;3-{3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-三氟甲氧基-苯基}-4-甲基-1H-吡啶-2-酮;3-{3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-1H-吡啶-2-酮;3-{3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-異丙氧基-苯
基}-4-甲基-1H-吡啶-2-酮;4-[2-(5-(乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-4'-甲基-1'H-[2,3']聯吡啶-2'-酮;3-[3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-(2-嗎啉-4-基-乙氧基)-苯基]-4-甲基-1H-吡啶-2-酮;4'-甲基-4-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-1'H-[2,3']聯吡啶-2'-酮;4-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-4'-甲基-6-(2-嗎啉-4-基-乙氧基)-1'H-[2,3']聯吡啶-2'-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-異丙氧基-苯基}-咪唑啶-2-酮;4'-甲基-4-{2-[2-甲基-5-(3-嗎啉-4-基-丙氧基)-苯基胺基]-噁唑-5-基}-1'H-[2,3']聯吡啶-2'-酮;及其醫藥上可接受之鹽。
可使用如下所述之一般方案製備本發明化合物。
藉由以下方式來合成胺基噁唑衍生物:首先使用Van Leusen等人之方法(Tetrahedron Lett.,1972,23,2369)使芳族醛I與對甲苯磺醯基甲基異氰化物(TosMIC)反應以製備相應芳基取代之噁唑衍生物II(反應圖1)。使用文獻方法製備非商業醛,從而使用有機金屬試劑及DMF自相應溴化芳族化合物或根據Frey等人之方法(Tetrahedron Lett.,2001,39,6815)自相應甲苯之氧化引入醛基團。
第二,然後藉由使用適宜有機鹼對噁唑部分實施去質子化來將彼等化合物II進一步官能化,且隨後使用親電氯化
製備2-氯噁唑化合物III。藉由苯胺化合物IV(其中R'係氫)在適宜溶劑(例如醇)存在下且在升高溫度下加熱下實施直接親核置換反應通常應提供最終目標化合物V。亦可藉由使化合物IV(其中R'係乙醯基)及化合物III在氫化鈉存在下且於適宜溶劑(例如四氫呋喃或二甲基甲醯胺)中反應來獲得化合物V(WO 2007/131953)。
反應圖2繪示藉由以下方式來合成胺基噻唑衍生物VIII:首先使用由Iwao等人闡述之魏悌希反應(Wittig reaction)(J.Org.Chem.2009,74,8143)使芳族醛I與(甲氧基甲基)三苯基氯化鏻反應以製備相應芳基取代之烯醇醚衍生物VI。第二,使用Zhao等人之方法(Tetrahedron Lett.,2001,42,2101)利用烯醇醚VI、硫脲衍生物VII及N-溴琥珀醯亞胺(NBS)實施環化。
現藉由代表當前較佳實施例之實例來闡釋本發明,該等較佳實施例構成本發明之一部分,但其決不用於限制本發明範圍。
藉由參照下列製備實例來更全面地理解本發明,但該等製備實例不應理解為限制本發明範圍。
一般條件:所使用之所有化學試劑皆係商業試劑級產品。溶劑係無水商業級且未經進一步純化即使用。藉由使用預塗覆矽膠60F 254、Merck TLC板(其在UV光下可視化)之薄層層析來監測反應之進展。將1H NMR光譜中之多重性指定為單峰(s)、寬單峰(br s)、雙重峰(d)、三重峰(t)、四重峰(q)及多重峰(m)且在Bruker Avance 300、360或400 MHz光譜儀上實施NMR光譜。藉由電噴射離子化質譜(ESI MS)以正向模式或藉由大氣壓力化學離子化質譜(APCI MS)以正向模式實施質譜。
LCMS方法:方法1:此方法係在與TQD質譜儀偶合之超高效液相層析(UPLC)ACQUITY Waters儀器上運行。所用梯度係:在t=0.0 min時以5% CH3CN+0.1%甲酸水溶液+0.1%甲酸開始直至t=0.5 min時為止;然後係自t=0.5 min
至t=7.0 min達到100% CH3CN+0.1%甲酸之線性梯度;然後自t=7.0 min停留於此狀態下直至t=10.0 min為止。所用管柱係Waters HSS C18(1.8 μm,2.1×50 mm)。所用檢測儀器係使用ESI正向模式之三相四極柱質譜儀(TQD)。
方法2:此方法係在與ZMD質譜儀儀器偶合之HPLC 2695 Alliance,Waters上運行。所用梯度係:在t=0.0 min時以0% CH3CN+0.04%甲酸水溶液(10 mM)開始;然後係至t=3.1 min之達到100% CH3CN+0.04%甲酸之線性梯度;然後停留於此狀態下直至t=3.8 min並降低至0% CH3CN+0.04%甲酸水溶液直至t=4.8 min。所用管柱係Sunfire 2.1×50 mm(dp:3.5 μm)。
在惰性氣氛及0℃下,向存於無水DMF(20 mL)中之
NaH(1.89 g,47.25 mmol)之60%礦物油分散液之溶液中逐滴添加i-PrOH(3.62 mL,47.25 mmol)。將混合物在0℃下攪拌15 min。然後,在0℃下逐滴添加存於無水DMF(20 mL)中之1,3-二溴-5-氟-苯(1.98 mL,15.75 mmol)之溶液。將反應混合物在室溫下攪拌16 h。逐滴添加NaHCO3飽和溶液且使用Et2O(2次)萃取粗產物,使用NaHCO3飽和溶液(3次)洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到黃色油狀物I-a(定量產率)。1H RMN(300 MHz,CDCl3)δ7.21(t,J=1.4 Hz,1H),6.97(d,J=1.5 Hz,2H),4.61-4.40(m,1H),1.32(d,J=6.0 Hz,6H)。
在惰性氣氛及-78℃下,向存於無水Et2O(60 mL)中之I-a(4.630 g,15.75 mmol)之溶液中逐滴添加存於無水Et2O(6.3 mL,15.75 mmol)中之正丁基鋰之溶液。將反應混合物在-78℃下攪拌0.5 h。然後,在-78℃下逐滴添加無水DMF(1.35 mL)且經1.5 h使溫度達到-40℃。添加HCl溶液(3N)且Et2O(2次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到黃色油狀物I-b(產率為82%)。1H RMN(300 MHz,CDCl3)δ9.89(s,1H),7.54(m,1H),7.29(m,2H),4.60(dt,J=12.1,6.0 Hz,1H),1.36(t,J=6.0 Hz,6H)。
向存於MeOH(125 mL)中之I-b(6.925 g,28.50 mmol)之溶液中依次添加K2CO3(11.811 g,85.50 mmol)及TosMIC
(6.674 g,34.20 mmol)。將反應混合物在室溫下攪拌16 h。然後,在減壓下去除溶劑,添加水且使用EtOAc(2次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用5至30% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色油狀物I-c(產率為86%)。1H RMN(300 MHz,CDCl3)δ7.90(s,1H),7.34(m,2H),7.09(m,1H),7.00(m,1H),4.56(dt,J=12.1,6.0 Hz,1H),1.49-1.26(m,6H)。
在惰性氣氛及-78℃下,向存於無水THF(130 mL)中之I-c(6.921 g,24.50 mmol)之溶液中逐滴添加存於無水THF中之LiHMDS溶液(29 mL,29.00 mmol)。將反應混合物在-78℃下攪拌0.5小時。然後,在-78℃下添加C2Cl6(8.712 g,36.75 mmol)且將反應混合物在室溫下攪拌16 h。添加水且使用EtOAc(2次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至20% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色油狀物I-d(產率為92%)。1H NMR(300 MHz,CDCl3)δ 7.29(t,J=1.5 Hz,1H),7.27(s,1H),7.02(d,J=1.4 Hz,2H),4.57(dt,J=12.1,6.0 Hz,1H),1.36(s,3H),1.34(s,3H)。
在惰性氣氛下,向存於i-PrOH(45 mL)中之I-d(1.556 g,
4.915 mmol)及I-e(0.812 g,4.915 mmol)之溶液中逐滴添加存於無水Et2O中之HCl溶液(0.98 mL,0.98 mmol)。將反應混合物在80℃下攪拌16 h。然後,在減壓下去除溶劑且添加NaOH溶液(2.5 N)。使用EtOAc(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至30% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到白色固體I-f(產率為64%)。1H RMN(300 MHz,DMSO-d6)δ 9.30(s,1H),7.81(s,1H),7.56(s,1H),7.30(s,1H),7.16(d,J=7.7 Hz,1H),7.09(d,J=1.4 Hz,1H),7.00(d,J=1.7 Hz,1H),6.94(d,J=7.8 Hz,1H),4.69(dt,J=12.0,5.9 Hz,1H),4.41(s,2H),3.47(q,J=7.0 Hz,2H),2.27(s,3H),1.39(s,3H),1.27(d,J=6.0 Hz,6H),1.14(t,J=7.0 Hz,3H)。
在惰性氣氛下,向存於無水EtOH中之NaOEt溶液(45 mL,114.90 mmol)中添加4-氯甲基-1-甲基-2-硝基-苯(7.0 g,38.30 mmol)。將反應混合物在室溫下攪拌16小時。添加水並在減壓下去除乙醇。使用DCM(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到褐色油狀物I-g(產率為96%)。1H NMR(300 MHz,CDCl3)δ 7.95(s,1H),7.48(d,J=7.8 Hz,1H),7.31(d,J=7.9 Hz,1H),4.52(s,2H),3.56(q,J=7.0 Hz,2H),2.57(d,J=10.1 Hz,3H),1.26(t,J=7.0 Hz,3H)。
向存於EtOH(238 mL)中之I-g(7.21 g,36.93 mmol)之溶液中依次逐滴添加Pd/C(2.432 g)及(在0℃下)一水合肼(4.84 mL,99.71 mmol)。將反應混合物在80℃下攪拌2 h。然後,藉由矽藻土墊過濾熱混合物並使用EtOH洗滌。在減壓下濃縮濾液以得到黃色油狀物I-e(定量產率)。1H NMR(300 MHz,CDCl3)δ 6.99(d,J=7.6 Hz,1H),6.67(d,J=7.5 Hz,2H),4.41(s,2H),3.52(q,J=7.0 Hz,3H),2.18(s,3H),1.04(t,J=8.5 Hz,3H)。
在密封管中,向存於無水二噁烷(13 mL)中之I-f(872 mg,1.56 mmol)之溶液中依次添加咪唑啶-2-酮(674 mg,7.84 mmol)、碳酸銫(1.595 g,4.90 mmol)、Pd2(dba)3(113 mg,0.20 mmol)及XantPhos(54 mg,0.06 mmol)。將反應混合物在110℃下攪拌16 h。添加水,使用EtOAc(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用50%至100% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到白色固體化合物214(產率為50%)。1H NMR(300 MHz,DMSO-d6)δ 9.26(s,1H),7.81(s,1H),7.40(s,1H),7.29(s,1H),7.15(d,J=7.7 Hz,1H),7.11(t,J=2.0 Hz,1H),7.01(s,1H),6.92(d,J=7.7 Hz,1H),6.78(s,1H),4.62(dt,J=12.1,6.0 Hz,1H),4.41(s,2H),3.92-3.81(m,2H),3.53-3.34(m,4H),2.27(s,3H),1.29(s,3H),1.27(s,3H),1.14(t,J=7.0 Hz,3H)。
(ESI+)m/z451.2(M+H)+。
滯留時間=3.52 min(方法2)。
在惰性氣氛及-10℃下,向存於無水THF(60 mL)中之2-
溴-4-甲基吡啶(10.0 g,58.13 mmol)之溶液中依次逐滴添加亞硝酸第三丁基酯(12.5 mL,104.63 mmol)及存於無水THF中之KOtBu溶液(88 mL,87.20 mmol)。將反應混合物在-10℃下攪拌3 h。然後,添加NH4Cl飽和溶液且添加HCl溶液(4 N)直至pH=6-7為止。使用EtOAc(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到黃色油狀物II-a(產率為90%)。將粗產物直接用於下一步驟。1H NMR(300 MHz,DMSO-d6)δ 12.47(s,1H),8.49(d,J=5.1 Hz,1H),8.12(s,1H),7.90(dd,J=5.1,1.0 Hz,1H),7.55(s,1H)。
在-10℃下,向存於水(50 mL)中之II-a(10.5 g,52.23 mmol)之懸浮液中依次逐滴添加濃HCl溶液(50 mL)及甲醛(50 mL)水溶液(37% w/w)。將反應混合物在-10℃下攪拌4 h。然後,添加NaOH溶液(2 N)直至pH=6-7為止。使用EtOAc(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到淡褐色油狀物II-b(產率為97%)。1H NMR(300 MHz,DMSO-d6)δ 10.03(s,1H),8.68(d,J=4.9 Hz,1H),8.07(s,1H),7.84(d,J=4.9 Hz,1H)。
向存於MeOH(100 mL)中之II-b(9.4 g,50.53 mmol)之溶液中依次添加K2CO3(13.97 g,101.06 mmol)及TosMIC(14.80 g,75.8 mmol)。將反應混合物在室溫下攪拌16 h。
然後,在減壓下去除溶劑,添加水且使用EtOAc(2次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。在冷乙醚中研磨暗褐色固體,過濾並使用額外乙醚洗滌以得到淺褐色固體形式之最終產物II-c(產率為73%)。1H NMR(300 MHz,CDCl3)δ 8.42(d,J=5.2 Hz,1H),8.02(s,1H),7.73(s,1H),7.60(s,1H),7.48(dd,J=5.2,1.3 Hz,1H)。
向存於水(200 mL)中之2-巰基咪唑(5.0 g,49.93 mmol)之溶液中添加NaOH(2.4 g,59.91 mmol)。將反應混合物在室溫下攪拌0.5 h。然後,添加丙酮(200 mL)及MeI(3.4 mL,54.92 mmol)。將反應混合物在室溫下攪拌16 h。然後,在減壓下去除溶劑,添加水且使用EtOAc(5次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。使用石油醚將橙色固體研磨若干次並過濾以得到淺褐色固體化合物II-d(產率為88%)。1H NMR(300 MHz,DMSO-d6)δ 12.16(s,1H),7.14(s,1H),6.91(s,1H),2.50(s,3H)。
在密封管中裝填II-d(1.98 g,17.33 mmol)、II-c(3.0 g,13.33 mmol)、K2CO3(3.87 g,27.99 mmol.)、CuI(253 mg,1.33 mmol)、存於無水甲苯(19 mL)中之N,N'-二甲基環己烷-1,2-二胺(420 μL,2.66 mmol)。將反應混合物在110℃下
攪拌4天。然後,添加水且使用EtOAc(2次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。在冷乙醚中研磨褐色固體,過濾並使用額外乙醚洗滌以得到淺褐色固體形式之最終產物II-e(產率為70%)。1H NMR(300 MHz,DMSO-d6)δ 8.67(s,1H),8.60(d,J=5.2 Hz,1H),8.13(s,1H),7.97(s,1H),7.96(s,1H),7.70(dd,J=5.2,1.4 Hz,1H),7.15(d,J=1.5 Hz,1H),2.52(s,3H)。
向存於DCM(260 mg)中之II-e(2.17 g,7.83 mmol)之溶液中添加mCPBA(2.97 g,17.23 mmol)。將混合物在室溫下攪拌16 h。然後,添加NaHCO3飽和溶液且使用DCM(2次)萃取粗產物並使用NaHCO3飽和溶液(3次)洗滌有機層,使用水洗滌,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用5%至10% MeOH/EtOAc作為洗脫劑之矽膠層析純化最終產物以得到固體II-f(產率為84%)。1H NMR(300 MHz,DMSO-d6)δ 8.69(m,2H),8.14(s,1H),8.06(d,J=0.7 Hz,1H),8.00(d,J=1.2 Hz,1H),7.89(dd,J=5.2,1.5 Hz,1H),7.38(d,J=1.2 Hz,1H),3.53(s,3H)。
在0℃下,向存於無水MeOH/THF(1/1,6 mL)中之II-f(600 mg,2.07 mmol.)之溶液中添加存於MeOH中之NaOMe
溶液(6.2 mL,3.10 mmol)。將反應混合物在50℃下攪拌16 h。添加水且使用EtOAc(2次)萃取粗產物並使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到淺褐色固體化合物II-g(產率為98%)。1H NMR(300 MHz,DMSO-d6)δ 8.66(s,1H),8.58(d,J=5.3 Hz,1H),8.11(s,1H),8.03(s,1H),7.68(dd,J=5.2,1.4 Hz,1H),7.51(d,J=1.9 Hz,1H),6.70(d,J=1.9 Hz,1H),4.09(s,3H)。
在惰性氣氛及-78℃下,向存於無水THF(15 mL)中之中間體II-g(366 mg,1.51 mmol)之溶液中逐滴添加存於無水THF中之LiHMDS溶液(2.3 mL,2.27 mmol)。將反應混合物在-78℃下攪拌0.5 h。然後,在-78℃下添加C2Cl6(537 mg,2.27 mmol)且將反應混合物在室溫下攪拌16 h。添加水且使用EtOAc(2次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至10% MeOH/EtOAc作為洗脫劑之矽膠層析純化最終產物以得到白色固體II-h(產率為74%)。1H NMR(300 MHz,CDCl3)δ 8.51(dd,J=5.2,0.8 Hz,1H),7.95(dd,J=1.4,0.8 Hz,1H),7.55(s,1H),7.52(d,J=1.9 Hz,1H),7.33(dd,J=5.2,1.5 Hz,1H),6.75(d,J=2.0 Hz,1H),4.21(s,3H)。
在惰性氣氛下,向存於無水MeOH(40 mL)中之NaOMe
(1.6 g,29.63 mmol)之溶液中添加4-氯甲基-1-甲基-2-硝基-苯(5.0 g,26.94 mmol)。將反應混合物在室溫下攪拌16h。添加水並在減壓下去除EtOH。使用DCM(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮以得到黃色油狀物形式之中間體II-1。1H NMR(300 MHz,CDCl3)δ 7.94(s,1H),7.47(d,J=7.8 Hz,1H),7.32(d,J=7.8 Hz,1H),4.48(s,2H),3.41(s,3H),2.58(s,3H)。
向存於EtOH/H2O:9/1(150 mL)中之中間體II-1(4.77 g,26.32 mmol)之溶液中依次逐滴添加SnCl2.2H2O(29.70 g,131.60 mmol)及37%鹽酸(15 mL)。將反應混合物在室溫下攪拌16 h。在減壓下去除EtOH且向所得水溶液中添加NaOH溶液(10 N)直至pH=6-7為止。然後,使用DCM(2次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至30% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物,得到黃色油狀物形式之中間體II-m。1H NMR(300 MHz,DMSO-d6)δ 6.88(d,J=7.5 Hz,1H),6.58(s,J=17.6 Hz,1H),6.41(d,J=7.5 Hz,1H),4.80(s,2H),4.24(s,2H),3.23(s,3H),2.03(s,3H)。
向存於無水DCM(45 mL)中之II-m(2.0 g,13.23 mmol)之溶液中依次逐滴添加無水NEt3(2.3 mL,15.88 mmol)及(在
0℃下)AcCl(1.0 mL,14.55 mmol)。將反應混合物在室溫下攪拌2 h。添加水且使用DCM(2次)萃取粗產物並使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用50%至80% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物,得到淺黃色固體之中間體II-i(經3個步驟之產率為88%)。1H NMR(300 MHz,DMSO-d6)δ 9.27(s,1H),7.36(s,1H),7.16(d,J=7.7 Hz,1H),7.00(d,J=7.6 Hz,1H),4.34(s,2H),3.26(s,3H),2.18(s,3H),2.05(s,4H)。
在0℃下,向存於無水DMF(20 mL)中之NaH(237 mg,6.16 mmol)之60%礦物油分散液之溶液中逐滴添加存於無水DMF(20 mL)中之中間體II-i(595 mg,3.08 mmol)溶液。將反應混合物在室溫下攪拌1 h且在0℃下逐滴添加存於無水DMF(20 mL)中之中間體II-h(852 mg,3.08 mmol)之溶液。將反應混合物在0℃下攪拌3 h。添加水且使用EtOAc(2次)萃取粗產物,使用NaHCO3飽和溶液(3次)洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至20% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物,得到白色固體中間體II-j(產率為44%)。1H NMR(300 MHz,DMSO-d6)δ 9.65(s,1H),8.45(d,J=5.3 Hz,1H),7.86(s,1H),7.79(s,1H),7.72(s,1H),7.46(dd,J=5.1,3.6 Hz,2H),7.21(d,J=7.7 Hz,1H),7.00(d,
J=7.7 Hz,1H),6.68(d,J=1.8 Hz,1H),4.38(s,2H),4.05(s,3H),3.28(s,3H),2.29(s,3H)。
在0℃下,向存於無水二噁烷(4 mL)中之II-j(100 mg,0.26 mmol)之溶液中逐滴添加存於無水乙醚中之HCl溶液(546 μL,0.55 mmol)。將反應混合物在60℃下攪拌2 h並在室溫下攪拌16 h。然後,在減壓下去除溶劑,使用乙醚研磨粗產物並過濾以得到白色固體化合物215(產率為57%)。1H NMR(300 MHz,CD3OD)δ 10.04-9.95(m,1H),9.46(s,1H),9.15(s,1H),9.03(d,J=4.6 Hz,1H),8.95-8.87(m,1H),8.78(d,J=7.8 Hz,1H),8.19(d,J=3.2 Hz,1H),6.04(s,2H),4.97(s,3H),3.91(s,3H)。
在惰性氣氛及0℃下,向存於無水THF(13 mL)中之(甲氧基甲基)三氯化鏻(5.56 g,16.21 mmol)之溶液中逐滴添加存於無水THF中之nBuLi溶液(22 mL,21.62 mmol)。將反應混合物在室溫下攪拌1 h。然後,在0℃下逐滴添加存於無水THF(20 mL)中之3-溴苯甲醛(2.0 g;10.81 mmol)之溶液。將反應混合物在室溫下攪拌16 h。添加NH4Cl飽和溶液且使用EtOAc(2次)萃取粗產物並使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用10%至15% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色油狀物III-a(產率為66%)。1H NMR(300 MHz,CDCl3)δ 7.79(s,J=1.5 Hz,1H),7.48-7.24(m,5H),7.20-7.12(m,2H),7.06(d,J=13.0 Hz,1H),6.19(d,J=7.0 Hz,1H),5.75(d,J=13.0 Hz,1H),5.17(d,J=7.0 Hz,1H),3.82(s,3H),3.71(s,3H)。
在室溫下,向存於丙酮(10 mL)中之KSCN(780 mg,8.02 mmol)之溶液中逐滴添加存於丙酮(10 mL)中之AcCl(900 μL,8.02 mmol)之溶液。將反應混合物在50℃下攪拌15 min,然後,添加存於丙酮(10 mL)中之5-甲氧基-2-甲基苯胺(1.0 g,7.29 mmol)之溶液且將反應混合物在50℃下攪拌15 min。添加水且過濾固體,使用額外水及乙醚洗滌以得到白色固體。將該白色固體與K2CO3(2.0 g,14.58 mmol)存於MeOH(20 mL)中之溶液在室溫下攪拌3 h。在減壓下去
除MeOH且使用水及乙醚洗滌固體以得到白色固體III-b(產率為78%)。1H NMR(300 MHz,DMSO-d6)δ 9.20(s,1H),7.13(d,J=8.4 Hz,1H),6.81(d,J=2.4 Hz,1H),6.75(dd,J=8.3,2.6 Hz,1H),3.71(s,3H),2.10(s,3H)。
向存於二噁烷/水(1/1,6 mL)中之III-a(300 mg,1.41 mmol)之溶液中添加NBS(276 mg,1.55 mmol)。將反應混合物在室溫下攪拌1 h。然後,添加III-b(277 mg,1.41 mmol)且將反應混合物在80℃下攪拌16 h。依次添加水及NH4Cl飽和溶液且使用EtOAc(2次)萃取粗產物並使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至35% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到淺黃色固體III-c(產率為69%)。1H NMR(300 MHz,DMSO-d6)δ 9.48(s,1H),7.77-7.69(m,2H),7.54(d,J=2.1 Hz,1H),7.46(dd,J=7.6,0.9 Hz,1H),7.40(dd,J=7.9,1.0 Hz,1H),7.30(t,J=7.9 Hz,1H),7.11(d,J=8.3 Hz,1H),6.60(dd,J=8.3,2.5 Hz,1H),3.71(s,3H),2.19(s,3H)。
在密封管中,向存於無水二噁烷(10 mL)中之III-c(200 mg,0.53 mmol)之溶液中依次添加2-咪唑啶酮(275 mg,3.20 mmol)、碳酸銫(432 mg,1.33 mmol)、Pd2(dba)3(46 mg,
0.05 mmol)、4,5-Xantphos(61 mg,0.11 mmol)。將反應混合物在110℃下攪拌16 h。添加水,且使用EtOAc(2次)萃取粗產物並使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至30% MeOH/EtOAc作為洗脫劑之矽膠層析純化最終產物以得到黃色固體化合物216(產率為41%)。1H NMR(300 MHz,DMSO-d6)δ 9.36(s,1H),7.75(s,1H),763-7.56(m,2H),7.37(d,J=8.2 Hz,1H),7.29(t,J=7.9 Hz,1H),7.15(d,J=7.5 Hz,1H),7.11(d,J=8.4 Hz,1H),7.01(s,1H),6.59(dd,J=8.3,2.6 Hz,1H),3.93-3.83(m,2H),3.72(s,3H),3.44-3.37(m,2H),2.20(s,3H)。
向存於丙酮(21 mL)中之硫氰酸銨(1.05 g,13.85 mmol)之溶液中逐滴添加乙醯氯(0.90 mL 12.70 mmol)。將反應混合物在40℃下攪拌30 min。然後,添加存於丙酮(7 mL)中之4-甲基-3-硝基苯胺(1.76 g,11.54 mmol)之溶液且將反應混合物在室溫下攪拌4 h。將反應混合物傾倒至冰-水中且過濾沈澱物,使用額外水及環己烷洗滌以得到褐色固體化合物IV-c(產率為50%)。(300 MHz,DMSO)δ 12.45(s,1H),11.53(s,1H),8.38(d,J=2.0 Hz,1H),7.69(dd,J=8.3,2.0 Hz,1H),7.43(d,J=8.3 Hz,1H),2.44(s,3H),2.09(s,3H)。
向存於甲醇(5 mL)中之IV-c(873 mg,3.45 mmol)之溶液中添加K2CO3(953 mg,6.90 mmol)。將反應混合物在室溫下攪拌16 h。然後,在減壓下去除溶劑,添加水且使用EtOAc(兩次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥,並濃縮。藉由使用0至50% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色固體化合物IV-d(產率為60%)。(300 MHz,DMSO)δ 9.95(s,1H),8.28(d,J=2.1 Hz,1H),8.00-7.70(m,3H),7.42(d,J=8.3 Hz,1H),2.47(s,3H)。
向存於EtOH(7 mL)中之IV-d(377 mg,1.79 mmol)之懸浮液中添加氯乙醛(1.41 g,17.93 mmol)之水溶液(50% w/w)
及KHCO3(539 mg,5.37 mmol)。將反應混合物在70℃下攪拌16 h。然後,在減壓下去除溶劑,添加水且使用EtOAc(3次)萃取粗產物,使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥,並濃縮。藉由使用0至70% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色固體化合物IV-e(產率為40%)。(300 MHz,DMSO)δ 10.58(s,1H),8.55(d,J=2.4 Hz,1H),7.69(dd,J=8.4,2.4 Hz,1H),7.41(d,J=8.5 Hz,1H),7.33(d,J=3.7 Hz,1H),7.00(d,J=3.7 Hz,1H),2.45(s,3H)。
向存於EtOH/DCM:(30/13 mL)中之IV-e(737 mg,3.13 mmol)之溶液中依次逐滴添加SnCl2.2H2O(3.54 g,15.65 mmol)及37%鹽酸(3 mL)。將反應混合物在室溫下攪拌16 h。在減壓下去除EtOH且向所得水溶液中添加NaOH溶液(10 N)直至pH=6-7為止。然後,使用DCM(兩次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至30% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色油狀物中間體IV-f(產率為95%)。(300 MHz,DMSO)δ 9.74(s,1H),7.18(d,J=3.7 Hz,1H),6.90(d,J=2.0 Hz,1H),6.85-6.77(m,2H),6.66(dd,J=8.0,2.0 Hz,1H),4.83(brs,2H),1.99(s,3H)。
在0℃下,向存於無水DCE(10 mL)中之IV-f(610 mg,2.97 mmol)及NaHCO3(2.50 g,29.71 mmol)之溶液中逐滴添加乙醯氯(0.634 mL,8.91 mmol)。將反應混合物在50℃下攪拌5 h。然後,添加水且使用DCM(3次)萃取粗產物並使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用30% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到黃色固體中間體IV-a(產率為75%)。(300 MHz,DMSO)δ 9.39(s,1H),7.54(d,J=1.7 Hz,1H),7.40-7.32(m,2H),7.29(d,J=3.6 Hz,1H),7.13(dd,J=7.9,1.9 Hz,1H),2.28(s,3H),2.07(s,3H),1.99(s,3H)。
在0℃下,向存於無水DMF(3 mL)中之NaH(83 mg,2.08 mmol)之60%礦物油分散液之溶液中逐滴添加存於無水DMF(3 mL)中之中間體IV-a(300 mg,1.04 mmol)溶液。將反應混合物在室溫下攪拌1 h且在0℃下逐滴添加存於無水DMF(3 mL)中之中間體I-d(328 mg,1.04 mmol)之溶液。將反應混合物在室溫下攪拌16 h。添加水且使用EtOAc(兩次)萃取粗產物,使用NaHCO3飽和溶液(3次)洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用0至35% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到米黃色固體中間體IV-b(產率為46%)。(300 MHz,DMSO)δ 9.63(s,1H),8.08(d,J=2.1 Hz,1H),7.65
(s,1H),7.47(d,J=2.2 Hz,1H),7.45(d,J=2.5 Hz,1H),7.42-7.38(m,2H),7.19(t,J=2.0 Hz,1H),7.15(dd,J=7.9,2.2 Hz,1H),7.11(t,J=2.0 Hz,1H),4.78(七重峰,J=5.8 Hz,1H),2.49(s,3H),2.14(s,3H),1.37(d,J=6.0 Hz,6H)。
在密封管中,向存於無水二噁烷(5 mL)中之IV-b(219 mg,0.42 mmol)之溶液中依次添加咪唑啶-2-酮(286 mg,3.36 mmol)、碳酸銫(162 mg,0.50 mmol)、Pd2(dba)3(11 mg,0.01 mmol)及Xantphos(24 mg,0.04 mmol)。將反應混合物在110℃下攪拌16 h。添加水,使用EtOAc(兩次)萃取粗產物且使用水洗滌有機層,然後使用NaCl飽和溶液洗滌,藉由MgSO4乾燥並濃縮。藉由使用50%至100% EtOAc/環己烷作為洗脫劑之矽膠層析純化最終產物以得到米黃色固體化合物217(產率為49%)。(300 MHz,DMSO)δ 10.12(brs,1H),9.25(s,1H),8.04(d,J=2.1 Hz,1H),7.42(s,1H),7.38(dd,J=8.3,2.1 Hz,1H),7.25(brs,1H),7.19(d,J=3.7 Hz,1H),7.15(t,J=1.9 Hz,1H),7.10(d,J=8.4 Hz,1H),7.01(s,1H),6.85(d,J=3.6 Hz,1H),6.81(s,1H),4.61(m,1H),3.84(m,2H),3.38(m,2H),2.23(s,3H),1.27(d,J=6.0 Hz,6H)。
(ESI+)m/z 491(M+H)+
滯留時間=3.13 min(方法2)
使用Adger等人,J.Chem.Soc.Perkin Trans.1,1988,第2791-2796頁之方法來製備中間體V-a。使用濃H2SO4(32 mL)處理含有水(240 mL)之1 L燒瓶並冷卻至0℃,然後使
用2-胺基-4-甲基吡啶(30 g,277 mmol)一次性處理。經1 h逐滴添加存於水(40 mL)中之NaNO2(20.6 g,299 mmol)之溶液以便內部溫度不曾升至超過5℃。將反應液在0℃下攪拌1 h然後加熱至95℃,且在此溫度下保持15 min之後冷卻至室溫。使用50% NaOH水溶液使該溶液達到pH 6-7(放熱)並同時使用EtOAc(4×120 mL)萃取熱溶液。乾燥(MgSO4)合併之有機物,過濾並蒸發以提供中間體V-a之米黃色結晶固體(24.5 g,81%)。1H NMR(300 MHz,DMSO-d6)δ 11.31(s,1H),7.23(d,J=6.7 Hz,1H),6.10(s,1H),6.00(dd,J=6.7,1.2 Hz,1H),2.10(s,3H)。
使用NBS(37.4 g,210 mmol)處理存於冰乙酸(350 mL)及EtOAc(680 mL)中之4-甲基-吡啶-2-醇V-a(25 g,229 mmol)之溶液並在室溫下攪拌30 min。然後使用氨水溶液使混合物達到pH 8並使用EtOAc萃取。使用1:1 H2O/鹽水洗滌分離之有機物,然後乾燥(MgSO4),過濾並蒸發,然後藉由二氧化矽管柱層析(1-4% EtOH/DCM)純化以提供白色固體形式之期望產物V-b(8.66g)。1H NMR(300 MHz,DMSO)δ 11.90(s,1H),7.32(d,J=6.6 Hz,1H),6.19(d,J=6.6 Hz,1H),2.25(s,3H)。
使用MeI(7.29 mL,117 mmol)及Ag2CO3(6.47 g,23.5 mmol)處理存於DCM(80 mL)中之3-溴-4-甲基-2-吡啶酮V-b(2.20 g,11.7 mmol)之溶液。塞住燒瓶並在氬下攪拌6天。
過濾混合物並藉由管柱層析(SiO2,存於環己烷中之10% EtOAc)純化以提供澄清流動油狀物形式之期望產物V-c(1.83 g,80%)。1H NMR(300 MHz,CDCl3)δ 7.94(d,J=5.0 Hz,1H),6.77(d,J=5.1 Hz,1H),4.00(s,3H),2.39(s,3H)。
在氬下,向乾燥密封管中裝填3-溴-2-甲氧基-4-甲基吡啶V-c(813 mg,4.02 mmol)、雙(戊醯)二硼(1.12 g,4.41 mmol)、PdCl2(dppf):DCM(146 mg,0.20 mmol)、KOAc(1.18 g,12.0 mmol)及無水DMF(10 mL)。在100℃下保持1.5 h之後,將混合物冷卻至室溫且添加另一部分觸媒(75 mg,0.092 mmol)。將管密封並將混合物在100℃下攪拌過夜。冷卻混合物,蒸發溶劑並將混合物吸收於DCM中,然後使用水洗滌。乾燥(MgSO4)分離之有機物,過濾並蒸發,然後藉由管柱層析(SiO2,存於環己烷中之10%至20% EtOAc)純化以提供流動黃色油狀物形式之中間體V-d(2.14 g,51%)。1H NMR(300 MHz,CDCl3)δ 8.00(d,J=5.3 Hz,1H),6.65(d,J=5.3 Hz,1H),3.89(s,3H),2.33(s,3H),1.40(d,J=11.1 Hz,12H)。
在氬下,向烘乾之燒瓶中裝填2-溴-4-噁唑-5-基-吡啶(中間體II-c,461 mg,2.07 mmol)、2-甲氧基-4-甲基-3-
(4,4,5,5-四甲基-[1,3,2]二氧硼-2-基)-吡啶V-d(510 mg,2.07 mmol)、K3PO4(2.82 g,13.3 mmol)、Pd(OAc)2(51 mg,0.225 mmol)、存於iPrOH(5 mL)中之Davephos(89 mg,0.225 mmol)及水(3mL)。在100℃下保持40 min之後,將混合物冷卻至室溫,使用水稀釋並使用EtOAc萃取,然後使用鹽水洗滌。乾燥(MgSO4)有機物,過濾並蒸發,然後藉由管柱層析(SiO2,存於環己烷中之30%至100% EtOAc)純化以提供灰白色固體形式之期望產物V-e(240 mg,43%)。1H NMR(300 MHz,CDCl3)δ 8.78(d,J=4.8 Hz,1H),8.10(d,J=4.8 Hz,1H),8.01(s,1H),7.59(d,J=4.9 Hz,2H),7.51(d,J=4.9 Hz,1H),6.86(d,J=4.9 Hz,1H),3.88(s,3H),2.16(s,3H)。
如上文針對I-d所述使用LiHMDS(1 M,存於THF中,2.62 mL,2.62 mmol)及存於無水THF中之C2Cl6(496 mg,2.10 mmol)自4'-甲基-4-噁唑-5-基-1'H-[2,3']聯吡啶-2'-酮V-e(467 mg,1.74 mmol)來製備4-(2-氯-噁唑-5-基)-4'-甲基-1'H-[2,3']聯吡啶-2'-酮V-f。藉由管柱層析(SiO2;使用存於環己烷中之30%至50% EtOAc洗脫)純化粗產物以提供白色固體中間體V-f(261 mg,50%)。1H NMR(300 MHz,DMSO-d6)δ 8.76(d,J=5.3 Hz,1H),8.12(d,J=4.4 Hz,2H),7.70(s,1H),7.64(dd,J=5.2,1.7 Hz,1H),7.00(d,J=5.2 Hz,1H),3.78(s,3H),2.06(s,3H)。
使用K2CO3(0.903 g,6.53 mmol)及1,3-二溴丙烷(6.63 mL,65.3 mmol)處理存於DMF(6 mL)中之4-甲基-3-硝基苯酚(1.00 g,6.53 mmol)之溶液並加熱至100℃保持2.5 h。使用水稀釋冷卻之混合物並使用DCM萃取。乾燥(MgSO4)合併之有機物,過濾並蒸發,然後藉由管柱層析(SiO2;使用存於環己烷中之20% EtOAc洗脫)純化以提供流動黃色油狀物形式之期望產物V-h(1.05 g,59%)。1H NMR(300 MHz,CDCl3)δ 7.52(d,J=2.7 Hz,1H),7.23(d,J=8.5 Hz,1H),7.06(dd,J=8.5,2.7 Hz,1H),4.14(t,J=5.8 Hz,2H),3.60(t,J=6.4 Hz,2H),2.53(s,3H),2.40-2.24(m,2H)。
使用K2CO3(1.01 g,7.28 mmol)及嗎啉(319 μl,3.65 mmol)處理存於無水二噁烷(30 mL)中之4-(3-溴-丙氧基)-1-甲基-2-硝基-苯V-h(500 mg,1.82 mmol)之溶液並加熱至100℃保持6 h。使用水稀釋冷卻之混合物並使用DCM萃取。乾燥(MgSO4)合併之有機物,過濾並蒸發,然後藉由管柱層析(SiO2;使用存於DCM中之2% EtOH洗脫)純化以提供黃橙色油狀物形式之期望產物V-i(356 mg,70%)。1H NMR(300 MHz,CDCl3)δ 7.51(d,J=2.7 Hz,1H),7.21(d,J=8.5 Hz,1H),7.05(dd,J=8.5,2.7 Hz,1H),4.06(t,J=6.3 Hz,2H),3.79-3.66(m,4H),2.49(dt,J=9.0,5.1 Hz,9H),2.07-1.88(m,2H)。
使用SnCl2.H2O(1.58 g,6.24 mmol)及濃HCl(1.04 mL,12.5 mmol)處理存於90% EtOH(15 mL)中之4-[3-(4-甲基-3-硝基-苯氧基)-丙基]-嗎啉V-i(350 mg,1.25 mmol)之溶液並加熱至回流保持1 h。在減壓下濃縮冷卻之溶液並使用NaHCO3飽和溶液達到pH=8,然後使用EtOAc萃取。乾燥(MgSO4)組合之有機物,過濾並蒸發成黏性黃色油狀物形式之期望產物V-g(306 mg,98%)。1H NMR(300 MHz,CDCl3)δ 6.92(d,J=8.8 Hz,1H),6.30-6.24(m,2H),3.96(t,J=6.3 Hz,2H),3.76-3.69(m,4H),3.58(s,2H),2.57-2.42(m,6H),2.09(s,3H),1.93(dt,J=13.3,6.5 Hz,3H)。
使用2-甲基-5-(3-嗎啉-4-基-丙氧基)-苯基胺V-g(48 mg,0.191 mmol)及HCl(2 M,存於乙醚中,120 μL,0.240 mmol)處理存於iPrOH(4 mL)中之4-(2-氯-噁唑-5-基)-4'-甲基-1'H-[2,3']聯吡啶-2'-酮V-f(50 mg,0.159 mmol)之溶液並加熱至回流保持18 h。使用額外之150 μL HCl(2 M,存於乙醚中,150 μL,0.300 mmol)處理溶液並再加熱2 h。將混合物冷卻至室溫,然後在減壓下蒸發溶劑。使用乙醚處理殘基且過濾出白色沈澱物以提供化合物218(31 mg,39%)。1H NMR(300 MHz,DMSO)δ 11.62(s,1H),9.40(s,1H),8.55(d,J=5.3 Hz,1H),7.73(s,1H),7.55-7.48(m,2H),7.38(dd,J=5.2,1.7 Hz,1H),7.29(d,J=6.7 Hz,1H),
7.03(d,J=8.8 Hz,1H),6.52(dd,J=8.3,2.5 Hz,1H),6.13(d,J=6.7 Hz,1H),3.92(t,J=6.4 Hz,2H),3.56-3.44(m,4H),2.40-2.25(m,6H),2.16(s,3H),1.98(s,3H),1.86-1.75(m,2H)。ESI+ MS m/z 502(M+H)+;滯留時間=1.76 min(方法1)。
如針對中間體I-c所闡述使用3-溴-苯甲醛(10 g,54 mmol)、TosMIC(12.7 g,65 mmol)及存於MeOH中之K2CO3(8.97 g)來製備5-(3-溴-苯基)-噁唑VI-a以得到淡褐色固體形式之期望中間體VI-a(12.1 g,100%)。1H NMR(300 MHz,CDCl3)δ 7.92(s,1H),7.80(s,1H),7.57(d,J=7.7 Hz,1H),7.46(d,J=8.0 Hz,1H),7.37(s,1H),7.29(d,J=7.9 Hz,1H)。
將存於THF(20 mL)及水(10 mL)中之5-(3-溴-苯基)-噁唑VI-a(1.33 g,5.94 mmol)、2-甲氧基-3-吡啶基硼酸(1.00 g,6.53 mmol)、Pd(PPh3)4及K2CO3(1.81 g,13.1 mmol)之混合物加熱至回流保持4 h。冷卻混合物,然後使用水稀釋並使用EtOAc萃取。乾燥(MgSO4)合併之有機物,過濾並藉由管柱層析(SiO2;使用存於環己烷中之30% EtOAc洗脫)純化殘餘物以提供褐色油狀物形式之期望產物VI-b(其在靜置下結晶)(1.37 g,91%)。1H NMR(300 MHz,CDCl3)δ 8.18(dd,J=1.8,5.0 Hz,IH),7.91(s,1H),7.81(s,1H),7.64(d,J=6.9 Hz,2H),7.53-7.44(m,2H),7.37(s,1H),6.99(dd,J=5.0,7.2 Hz,1H),3.97(s,3H)。
如上文針對中間體I-d所述自存於2-甲氧基-3-(3-噁唑-5-基-苯基)-吡啶(1.37 g,5.43 mmol)、LiHMDS(1 M,存於THF中,5.97 mL,5.97 mmol)及無水THF(50 mL)中之C2Cl6(1.54 g,6.52 mmol)來製備3-[3-(2-氯-噁唑-5-基)-苯基]-2-甲氧基-吡啶VI-c,從而在藉由管柱層析(SiO2使用存於環己烷中之10%至30% EtOAc洗脫)純化之後得到白色固體形式之期望產物VI-c(1.24g,84%)。1H NMR(400 MHz,CDCl3)δ 8.20(dd,J=5.0,1.9 Hz,1H),7.76(t,J=1.6 Hz,1H),7.63(dd,J=7.3,2.0 Hz,1H),7.59-7.45(m,3H),7.31
(s,1H),6.99(dd,J=7.3,5.0 Hz,1H),3.99(s,3H)。
如上文針對中間體I-f所述自3-[3-(2-氯-噁唑-5-基)-苯基]-2-甲氧基-吡啶VI-c(40 mg,0.150 mmol)與3,5-二甲氧基苯胺(29 mg,0.190 mmol)及存於iPrOH(4 mL)中之HCl(2 M,存於乙醚中,120 μL,0.23 mmol)來製備3-{3-[2-(3,5-二甲氧基-苯基胺基)-噁唑-5-基]-苯基}-1H-吡啶-2-酮219。在減壓下蒸發粗製反應混合物並使用NaHCO3及EtOAc之飽和溶液處理殘餘物。自雙相混合物形成沈澱物且過濾出並乾燥以得到米黃色固體化合物219產物(19 mg,33%)。1H NMR(300 MHz,DMSO-d6)δ 11.86(s,1H),10.35(s,1H),7.96(s,1H),7.70(dd,J=2.0,6.9 Hz,1H),7.60-7.41(m,5H),6.89(d,J=2.0 Hz,2H),6.32(t,J=6.7 Hz,1H),6.13(s,1H),3.73(s,6H)。ESI+ MS m/z 390(M+H)+;滯留時間=3.45 min(方法1)。
在-10℃及氬下,使用異丙基氯化鎂(2 M,存於THF中,15.0 mL,30.0 mmol)之溶液逐滴處理存於無水THF(50 mL)中之4-溴-2-氟苯甲腈(5.00 g,25 mmol)之溶液,然後在此溫度下攪拌3 h。逐滴添加存於無水THF(15 mL)中之N-甲醯基六氫吡啶(3.89 g,35.0 mmol)之溶液並將混合物升溫至室溫,然後攪拌1.5 h。使用4 M HCl水溶液(每次250 mL)處理所得溶液並使用EtOAc萃取有機物。乾燥(MgSO4)合併之有機物,過濾並蒸發,然後藉由管柱層析(SiO2;使用存於環己烷中之30%至50% EtOAc洗脫)純化殘餘物以提供淺黃色固體形式之2-氟-4-甲醯基-苯甲腈VII-a(2.73 g,73%)。1H NMR(300 MHz,CDCl3)δ 10.07(d,J=1.7 Hz,1H),7.90-7.79(m,2H),7.74(dd,J=8.5,0.8 Hz,1H)。
如針對中間體I-c所闡述使用2-氟-4-甲醯基-苯甲腈VII-a(2 g,13.43 mmol)、TosMIC(2.85 g,14.77 mmol)及存於MeOH(40 mL)中之K2CO3(2.41 g,1.86 mmol)來製備5-(3-溴-苯基)-噁唑VII-b以得到黃色固體形式之期望中間體VII-b(1.46 g,58%)。1H NMR(300 MHz,CDCl3)δ 7.94(s,
1H),7.62(dd,J=8.0,6.5 Hz,1H),7.52-7.37(m,3H)。
使用KOH(735 mg,13.1 mmol)處理存於絕對EtOH(100 mL)中之3-甲基-1H-吡啶-2-酮(1.43 g,13.1 mmol)之溶液並在劇烈攪拌下加熱至回流保持2 h,然後冷卻至室溫並在減壓下蒸發溶劑。將橙色固體殘餘物吸收於無水DMF(100 mL)中且使用2-氟-4-噁唑-5-基-苯甲腈VII-b(2.24 g,11.9 mmol)處理並在100℃下攪拌3 h。在減壓下蒸發溶劑且使用NaHCO3飽和溶液處理殘餘物並使用DCM萃取。乾燥(MgSO4)合併之有機物,過濾並蒸發,且藉由管柱層析(SiO2,使用存於環己烷中之50% EtOAc洗脫)純化殘餘物以得到灰白色固體形式之期望中間體VII-c(2.55 g,77%)。1H NMR(300 MHz,DMSO-d6)δ 8.62(s,1H),8.15(d,J=8.1 Hz,1H),8.04(s,2H),7.99(dd,J=8.1,1.6 Hz,1H),7.62(dd,J=6.9,1.1 Hz,1H),7.49(d,J=6.6 Hz,1H),6.34(t,J=6.8 Hz,1H),2.07(s,3H)。
在-78℃及氬下,使用LiHMDS(1 M,存於THF中,11.0 mL,11.0 mmol)逐滴處理存於無水蒸餾THF(160 mL)中之2-(3-甲基-2-側氧基-2H-吡啶-1-基)-4-噁唑-5-基-苯甲腈VII-c(2.55 g,9.19 mmol)之溶液以得到不透明黃色漿液。在此溫度下保持1 h之後,一次性添加C2Cl6(3.26 g,13.8 mmol)
且將混合物升溫至室溫。使用水處理此混合物並使用DCM萃取。乾燥(MgSO4)合併之有機物,過濾並蒸發,且藉由管柱層析(SiO2;使用存於環己烷中之50% EtOAc洗脫)純化殘餘物以得到粉紅色固體形式之期望產物VII-d(1.51 g,52%)。1H NMR(300 MHz,DMSO-d6)δ 8.16(d,J=8.2 Hz,1H),8.10(s,1H),8.02(d,J=1.4 Hz,1H),7.96(dd,J=8.1,1.5 Hz,1H),7.61(d,J=6.9 Hz,1H),7.49(d,J=6.7 Hz,1H),6.35(t,J=6.8 Hz,1H),2.07(s,3H)。
如針對中間體II-i所闡述使用5-乙氧基甲基-2-甲基-苯基胺I-e(5 g,30.26 mmol)、無水三乙胺(12.23 mL)、DCM(60 mL)及AcCl(4.32 mL)來製備N-(5-乙氧基甲基-2-甲基-苯基)-乙醯胺VII-e以得到白色固體形式之期望中間體VII-e(5.39 g,86%)。1H NMR(300 MHz,CDCl3)δ 7.69(s,1H),7.15(d,J=7.7 Hz,1H),7.07(d,J=8.2 Hz,1H),4.46(s,2H),3.53(q,J=7.0 Hz,2H),2.23(s,3H),2.18(s,3H),1.23(t,J=7.0 Hz,3H)。
在氬及室溫下,將N-(5-乙氧基甲基-2-甲基-苯基)-乙醯胺VII-e(74 mg,0.361 mmol)、無水THF(3 mL)及NaH(60%,存於油中,29 mg,0.722 mmol)之混合物攪拌1 h。在0℃下,逐滴添加存於無水THF(3 mL)中之4-(2-氯-噁
唑-5-基)-2-(3-甲基-2-側氧基-2H-吡啶-1-基)-苯甲腈VII-d(75 mg,0.241 mmol)之懸浮液,然後經2 h升溫至室溫。使用水處理混合物,並使用EtOAc萃取。乾燥(MgSO4)合併之有機物,過濾並蒸發,且藉由管柱層析(SiO2;使用存於環己烷中之50% EtOAc洗脫)純化殘餘物以得到粉紅色固體形式之期望產物220(61 mg,56%)。1H NMR(300 MHz,DMSO-d6)δ 9.55(s,1H),8.05(d,J=8.0 Hz,1H),7.83-7.68(m,4H),7.61(d,J=6.7 Hz,1H),7.48(d,J=6.6 Hz,1H),7.18(d,J=7.8 Hz,1H),6.97(d,J=7.4 Hz,1H),6.33(t,J=6.8 Hz,1H),4.41(s,2H),3.46(q,J=7.0 Hz,2H),2.27(s,3H),2.06(d,J=7.1 Hz,3H),1.12(t,J=7.0 Hz,3H。
如針對中間體I-c所闡述使用2-5-溴-吡啶-3-甲醛(0.260 g,1.4 mmol)、TosMIC(0.273 g,1.54 mmol)及存於MeOH(15 mL)中之K2CO3(0.580 g,4.2 mmol)來製備5-(3-溴-苯基)-噁唑VIII-a以得到米黃色固體形式之期望中間體VIII-a(0.16 g,50%)。1H NMR(300 MHz,DMSO)δ 8.95(s,1H),8.70(s,1H),8.59(s,1H),8.43(s,1H),7.95(s,1H)。
向含有存於脫氣1,4-二噁烷(20 mL)中之3-溴-5-噁唑-5-基-吡啶VIII-a(1.00 g,4.44 mol)之溶液之烘乾密封管中添加2-羥基吡啶(507 mg,5.33 mmol)、K2CO3(1.23 g,1.78 mmol)、CuI(169 mg,0.899 mmol)及外消旋-反式-N,N'-二甲基環己烷二胺(280 μL,1.78 mmol)。使用氬沖洗管並密封,然後在120℃下於油浴中加熱過夜。在冷卻至室溫之後,過濾混合物並使用1,4-二噁烷洗滌濾餅。蒸發混合物並藉由管柱層析(存於DCM中之2%至5% EtOH)純化殘餘物以得到米黃色固體形式之期望產物VIII-b(752 mg,71%)。1H NMR(300 MHz,DMSO-d6)δ 9.06(s,1H),8.68(s,1H),8.60(s,1H),8.29(s,1H),7.95(s,1H),7.80(dd,J=6.8,1.6 Hz,1H),7.57(ddd,J=8.8,6.6,1.9 Hz,1H),6.54(d,J=9.2 Hz,1H),6.39(t,J=6.7 Hz,1H)。
如上文針對I-d所闡述使用LiHMDS(1 M,存於THF中,4.64 mL,4.64 mmol)及存於無水THF中C2Cl6(1.10 g,4.64
mmol)自5'-噁唑-5-基-[1,3']聯吡啶-2-酮VIII-d(740 mg,3.09 mmol)來製備5'-(2-氯-噁唑-5-基)-[1,3']聯吡啶-2-酮VIII-c。藉由管柱層析(SiO2;使用存於DCM中之2%至5% EtOH洗脫)純化粗產物以提供白色固體形式之期望產物VIII-c(393 mg,47%)。1H NMR(300 MHz,CDCl3)δ 8.91(s,1H),8.61(s,1H),8.06(t,J=2.2 Hz,1H),7.50-7.42(m,2H),7.35(dd,J=6.9,1.9 Hz,1H),6.70(d,J=9.3 Hz,1H),6.34(td,J=6.8,1.2 Hz,1H)。
如上文針對I-f所闡述自5'-(2-氯-噁唑-5-基)-[1,3']聯吡啶-2-酮VIII-c(68 mg,0.250 mmol)及存於iPrOH(3 mL)中之5-甲氧基-2-甲基苯胺(35 mg,0.250 mmol)來製備5'-[2-(5-甲氧基-2-甲基-苯基胺基)-噁唑-5-基]-[1,3']聯吡啶-2-酮221以在管柱層析(SiO2;使用存於DCM中之2%至5% EtOH洗脫)之後提供橙色固體形式之標題化合物221(28 mg,30%)。(300 MHz,CDCl3)δ 8.83(d,J=1.9 Hz,1H),8.45(d,J=2.3 Hz,1H),7.93(t,J=2.1 Hz,1H),7.73(d,J=2.4 Hz,1H),7.41(m,1H),7.34(m,1H),7.30(s,1H),7.07(d,J=8.3 Hz,1H),6.78(s,1H),6.68(d,J=9.3 Hz,1H),6.55(dd,J=8.3,2.5 Hz,1H),6.30(t,J=5.6 Hz,1H),3.81(s,3H),2.25(s,3H)。ESI+ MS m/z 375(M+H)+;滯留時間=2.99 min(方法1)。
將存於DMF(4 mL)中之3-{3-[2-(3,5-二甲氧基-苯基胺基)-噁唑-5-基]-苯基}-1H-吡啶-2-酮219(39 mg,0.10 mmol)、(2-氯-乙基)-二甲基-胺鹽酸鹽(17.5 mg,0.11 mmol)、K2CO3(31 mg,0.22 mmol)及碘化鉀(19 mg,0.11 mmol)之混合物在50℃下加熱16 h。在蒸發DMF之後,使用水處理混合物並使用EtOAc萃取。乾燥(MgSO4)合併之有機物,過濾並蒸發,且藉由管柱層析(Al2O3;使用存於DCM中之1% EtOH洗脫)純化殘餘物以得到黃色固體形式之期望產物222(23 mg,50%)。1H NMR(300 MHz,DMSO)δ 10.32(s,1H),7.95(s,1H),7.72(d,J=6.7 Hz,1H),7.66(dd,J=6.9,1.6 Hz,1H),7.58-7.31(m,4H),6.90(s,1H),6.89(s,1H),6.35(t,J=6.8 Hz,1H),6.13(s,1H),4.07(t,J=6.3 Hz,2H),3.73(s,6H),2.55(t,J=6.3 Hz,2H),2.20(s,6H)。ESI+ MS m/z 461(M+H)+;滯留時間=2.90 min(方法1)。
如針對實例I-d所述使用2-溴-4-噁唑-5-基-吡啶(450 mg,2 mmol)、LiHMDS(2.2 mL,2.2 mmol)及存於THF中之C2Cl6(568 mg,2.4 mmol)來製備2-溴-4-(2-氯-噁唑-5-基)-吡啶IX-a以得到黃橙色固體中間體IX-a(465 mg,90%)。1H NMR(300 MHz,CDCl3)δ 8.43(d,J=5.1 Hz,1H),7.68(s,1H),7.53(s,1H),7.46-7.36(m,1H)。
如針對實例220所述使用中間體VII-e(169 mg,0.65 mmol)、N-(5-乙氧基甲基-2-甲基-苯基)-乙醯胺(162 mg,0.78 mmol)及存於DMF中之NaH(65 mg,1.6 mmol)來製備[5-(2-溴-吡啶-4-基)-噁唑-2-基]-(5-乙氧基甲基-2-甲基-苯
基)-胺IX-b以得到黃色固體中間體IX-b(162 mg,64%)。1H NMR(300 MHz,CDCl3)δ 8.32(d,J=5.1 Hz,1H),7.94(s,1H),7.56(s,1H),7.42(s,1H),7.32(d,J=5.2 Hz,1H),7.21(d,J=7.6 Hz,1H),7.06(d,J=7.7 Hz,1H),6.91(s,1H),4.54(s,2H),3.58(q,J=7.0 Hz,2H),2.34(s,3H),1.27(t,J=7.0 Hz,3H)。
將存於二噁烷(2.5 mL)中之中間體IX-b(51 mg,0.13 mmol)、δ-戊內醯胺(16 mg,0.16 mmol)、碳酸銫(60 mg,0.18 mmol)、Pd2(dba)3(4 mg,0.004 mmol)及XantPhos(7 mg,0.012 mmol)之混合物回流1 h,直至沒有起始材料剩餘為止(藉由TLC監測反應)。然後蒸發反應混合物,且直接對粗製油狀物實施層析(SiO2,使用存於DCM中之1%至10% EtOH洗脫)以得到黃色固體形式之實例223(22 mg,42 %)。1H NMR(300 MHz,CDCl3)δ 8.39(d,J=5.3 Hz,1H),7.99(s,1H),7.94(s,1H),7.39(s,1H),7.25-7.12(m,3H),7.05(d,J=7.6 Hz,1H),4.54(s,2H),4.02-3.89(m,2H),3.57(q,J=6.9 Hz,2H),2.69-2.56(m,2H),2.34(s,3H),2.02-1.89(m,4H),1.26(t,J=7.0 Hz,3H)。ESI+ MS m/z 407(M+H)+;滯留時間=3.48 min(方法1)。
將存於二噁烷(2.5 mL)中之中間體IX-b(50 mg,0.13 mmol)、N,N'-三亞甲基脲(130 mg,1.3 mmol)、碳酸銫(46 mg,0.14 mmol)、Pd2(dba)3(4 mg,0.004 mmol)及XantPhos(7 mg,0.012 mmol)之混合物回流1小時30分鐘。然後蒸發反應混合物,溶於乙酸乙酯中,使用水洗滌若干次,藉由MgSO4乾燥,並濃縮。對粗製油狀物實施層析(SiO2,使用存於DCM中之1%至10% EtOH洗脫)以得到黃橙色固體形式之實例224(16 mg,31%)。1H NMR(300 MHz,DMSO-d6)δ 9.54(s,1H),8.28(d,J=5.2 Hz,1H),7.99(s,1H),7.79(s,1H),7.66(s,1H),7.24-7.10(m,2H),7.00-6.86(m,2H),4.41(s,2H),3.92-3.80(m,2H),3.47(q,J=6.9 Hz,2H),3.26-3.19(m,2H),2.27(s,3H),2.03-1.80(m,2H),1.14(t,J=7.0 Hz,3H)。
如針對實例I-c所述使用3-硝基苯甲醛(4 g,26 mmol)、TosMIC(5.7 g,29 mmol)及存於MeOH中之K2CO3(4.4 g,32 mmol)來製備中間體X-a以得到黃色固體中間體X-a(4.7 g,93%)。1H NMR(400 MHz,DMSO-d6)δ 8.56(s,1H),8.50(t,J=1.9 Hz,1H),8.21(ddd,J=8.2,2.3,1.0 Hz,1H),8.17(ddd,J=7.8,1.6,1.0 Hz,1H),7.99(s,1H),7.78(t,J=8.0 Hz,1H)。
如針對實例I-d所述使用中間體X-a(3.2 g,17 mmol)、LiHMDS(20.2 mL,20 mmol)及存於THF中之C2Cl6(4.78 g,
20 mmol)來製備中間體X-b以得到黃色固體形式之期望中間體X-b(3.13 g,82%)。1H NMR(400 MHz,DMSO-d6)δ 8.48(d,J=1.5 Hz,1H),8.24(d,J=8.2 Hz,1H),8.14(d,J=7.8 Hz,1H),8.09(d,J=1.9 Hz,1H),7.80(td,J=8.1,1.9 Hz,1H)。
如針對實例220所述使用中間體X-b(448 mg,2 mmol)、N-(5-胺基-2-甲基-苯基)-乙醯胺(394 mg,2.4 mmol)及存於THF中之NaH(160 mg,4 mmol)來製備中間體X-c以得到橙色固體中間體X-c(236 mg,64%)。1H NMR(300 MHz,DMSO-d6)δ 9.17(s,1H),8.32(s,1H),8.07(d,J=7.5 Hz,1H),8.00(d,J=7.7 Hz,1H),7.72(m,2H),7.11(s,1H),6.82(d,J=8.0 Hz,1H),6.24(d,J=7.4 Hz,1H),4.91(s,2H),2.11(s,3H)。
將存於DMF(15 mL)中之中間體X-c(226 mg,0.72 mmol)、1-吡咯啶基乙酸鹽酸鹽(158 mg,0.94 mmol)、1-羥基苯并三唑水合物(148 mg,1.1 mmol)、N-(3-二甲基胺基丙基)-N'-乙基-碳化二亞胺鹽酸鹽(252 mg,1.3 mmol)及NEt3(360 μL,2.6 mmol)之混合物在室溫下攪拌過夜。然後蒸發反應混合物,使用乙酸乙酯稀釋,使用水洗滌,藉由MgSO4乾燥,並濃縮至容許結晶之最小體積。然後藉由過
濾收集標題化合物以提供黃色固體中間體X-d(224 mg,72%)。1H NMR(300 MHz,DMSO-d6)δ 9.66(s,1H),9.43(s,1H),8.35(s,1H),8.03(d,J=7.3 Hz,1H),7.89(d,J=7.9 Hz,1H),7.70(m,2H),7.04(s,1H),6.89(d,J=8.1 Hz,1H),6.26(d,J=7.5 Hz,1H),3.24(s,2H),2.63-2.54(m,4H),2.22(s,3H),1.76-1.69(m,4H)。
將存於乙醇/水混合物(9 mL/1 mL)中之中間體X-d(220 mg,0.52 mmol)、SnCl2.2H2O(590 mg,2.6 mmol)及濃鹽酸(735 μL,5.2 mmol)之混合物在40℃下攪拌4 h。然後蒸發反應混合物,使用乙酸乙酯及NaOH水溶液稀釋。使用乙酸乙酯將水層萃取兩次,然後使用水洗滌合併之有機層,藉由MgSO4乾燥,並濃縮。對粗製油狀物實施層析(Al2O3,使用存於DCM中之0.5% EtOH洗脫)以得到黃色-米黃色固體中間體X-e(147 mg,72%)。1H NMR(300 MHz,DMSO-d6)δ 9.68(s,1H),9.40(s,1H),8.21(s,1H),7.95(d,J=7.8 Hz,1H),7.88(d,J=7.3 Hz,1H),7.56(s,1H),7.32(s,1H),7.05(s,1H),6.91(d,J=7.3 Hz,1H),6.19(d,J=7.6 Hz,1H),4.85(s,2H),3.28(s,2H),2.67-2.56(m,4H),2.23(s,3H),1.78-1.68(m,4H)。
在氬及0℃下,向存於無水THF(4 mL)中之中間體X-e(70 mg,0.18 mmol)之溶液中分若干份添加戊二酐(20 mg,0.18 mmol)。將混合物在環境溫度下攪拌1 h,然後回流過夜。藉由過濾收集所形成之固體,然後使用THF及二乙醚洗滌以得到白色固體(52 mg),在無水1,2-二氯乙烷(8 mL)中使用SOCl2(30 μL,0.4 mmol)處理10 min之時段。將混合物回流至少4 h直至沒有起始材料剩餘為止,然後使用DCM稀釋,使用NaHCO3水溶液及水洗滌,藉由MgSO4乾燥,並濃縮。對殘餘物實施層析(Al2O3,使用存於DCM中之0.5%至1% EtOH洗脫)以得到米黃色固體化合物225(23 mg,45%)。1H NMR(300 MHz,DMSO-d6)δ 9.96(s,1H),9.64(s,1H),9.27(d,J=12.2 Hz,1H),8.03(d,J=10.9 Hz,1H),7.94(s,1H),7.54-7.46(m,1H),7.35-7.27(m,3H),7.10(d,J=8.2 Hz,1H),3.23(s,2H),2.69(t,J=6.5 Hz,4H),2.63-2.56(m,4H),2.23(s,3H),2.12(m,2H),1.74(s,4H)。
在另一實施例中,本發明係關於包括如上文所繪示之化合物之醫藥組合物。
此一醫藥組合物可適於經口投與,且可使用業內熟知之醫藥上可接受之載劑以適宜劑量進行調配。該等載劑使得能夠將醫藥組合物調配成錠劑、丸劑、糖衣藥丸、膠囊、液體、凝膠、糖漿、漿液、懸浮液及諸如此類以用於由患者攝入。除活性成份外,該等醫藥組合物可含有有利於將活性化合物處理成可在醫藥上使用之製劑之適宜醫藥上可
接受之載劑(包括賦形劑及佐劑)。關於調配及投與之技術之其他細節可參見Remington's Pharmaceutical Sciences(Maack Publishing公司,Easton,Pa.)之最新版本。
本發明組合物亦可採用用於局部投與之醫藥或化妝品組合物之形式。
該等組合物可呈現以下形式:凝膠、膏、軟膏、乳霜、洗劑、液體水性懸浮液、水性-醇性或油性溶液或洗劑或血清型之分散液或無水或親脂性凝膠或液體或半固體稠度之牛奶類型之乳液(藉由將脂肪相分散於水相中獲得或反之亦然)或軟半固體稠度之乳霜或凝膠類型之懸浮液或乳液或(另一選擇為)微乳液、微膠囊、微粒或離子及/或非離子型之囊泡分散液。根據標準方法製備該等組合物。
本發明組合物包括常用於皮膚學及化妝品中之任一成份。其可包括至少一種選自以下之成份:親水性或親脂性膠凝劑、親水性或親脂性活性劑、防腐劑、潤膚劑、黏度增強聚合物、保濕劑、表面活性劑、防腐劑、抗氧化劑、溶劑及填充劑、抗氧化劑、溶劑、香料、填充劑、遮蔽劑、殺菌劑、去味劑及著色物質。
對於可用於本發明中之油而言,可提及礦物油(液體石蠟)、植物油(牛油樹油脂之液體部分、向日葵油)、動物油、合成油、聚矽氧油(環甲基聚矽氧)及氟化油。脂肪醇、脂肪酸(硬脂酸)及蠟(石蠟、卡瑙巴、蜂蠟)亦可用作脂肪物質。
對於乳化劑而言,在本發明中可使用甘油、聚山梨醇
酯、甘油酯及PEG。
對於親水性膠凝劑而言,可提及羧基乙烯基聚合物(卡波姆(carbomer))、丙烯酸共聚物(例如丙烯酸酯/烷基丙烯酸酯共聚物)、聚丙烯醯胺、多糖(例如羥丙基纖維素)、黏土及天然樹膠,且對於親脂性膠凝劑而言,可提及改良黏土(例如膨潤土)、脂肪酸金屬鹽(例如硬脂酸鋁)及疏水性二氧化矽或另一選擇為乙基纖維素及聚乙烯。
對於親水性活性劑而言,可使用蛋白質或蛋白質水解物、胺基酸、多元醇、尿素、尿囊素、糖及糖衍生物、維他命、澱粉及植物提取物(特定而言係蘆薈之彼等提取物)。
對於親脂性活性劑而言,可使用視黃醇(維他命A)及其衍生物、生育酚(維他命E)及其衍生物、必需脂肪酸、神經醯胺及精油。該等試劑在利用時會增加額外之潤濕或皮膚軟化特徵。
此外,表面活性劑可包含於組合物中以使得能夠空乏肥大細胞之化合物(例如酪胺酸激酶抑制劑,較佳係c-kit抑制劑)滲透地更深。
在所涵蓋成份中,本發明包含滲透增強劑,其選自(例如)由以下組成之群:礦物油、水、乙醇、甘油三乙酸酯、甘油及丙二醇;凝聚劑,其選自(例如)由聚異丁烯、聚乙酸乙烯基酯及聚乙烯醇組成之群;及增稠劑。
增強藥物之局部吸收之一般方法在業內已眾所周知。舉例而言,具有滲透增強性質之化合物包含月桂基硫酸鈉
(Dugard,P.H.及Sheuplein,R.J.,「Effects of Ionic Surfactants on the Permeability of Human Epidermis:An Electrometric Study」,J.Ivest.Dermatol.,第60卷,第263-69頁,1973)、月桂基氧化胺(Johnson等人,US 4,411,893)、氮酮(Rajadhyaksha,US 4,405,616及3,989,816)及癸基甲基亞碸(Sekura,D.L.及Scala,J.,「The Percutaneous Absorption of Alkylmethyl Sulfides」,Pharmacology of the Skin,Advances In Biolocy of Skin,(Appleton-Century Craft)第12卷,第257-69頁,1972)。已觀察到,增加兩性分子中之首基之極性會增加其滲透增強性質,但代價係增加其皮膚刺激性質(Cooper,E.R.及Berner,B.,「Interaction of Surfactants with Epidermal Tissues:Physiochemical Aspects」,Surfactant Science Series,第16卷,Reiger,M.M.編輯(Marcel Dekker公司)第195-210頁,1987)。
第二類化學增強劑通常稱為共溶劑。該等材料相對容易地經局部吸收,且藉由各種機制達成一些藥物之滲透增強。乙醇(Gale等人,美國專利第4,615,699號及Campbell等人,美國專利第4,460,372號及第4,379,454號)、二甲基亞碸(US 3,740,420及3,743,727及US 4,575,515)及甘油衍生物(US 4,322,433)係已展示增強各種化合物之吸收之能力之少數化合物實例。
本發明之醫藥組合物亦可意欲以氣溶膠化調配物形式投與患者呼吸道之目標區域。
用於遞送藥物調配物之氣溶膠化突發劑(burst)之裝置及方法揭示於US 5,906,202中。調配物較佳係溶液(例如水溶液、乙醇溶液、水/乙醇溶液、鹽水溶液)、膠態懸浮液及微晶懸浮液。舉例而言,氣溶膠化顆粒包括上文所提及之活性成份及載劑(例如,醫藥活性呼吸道藥物及載劑),其係在迫使調配物穿過噴嘴(該噴嘴較佳地呈撓性多孔膜之形式)時形成。顆粒之大小足夠小,從而在形成顆粒時其保持懸浮於空氣中足量時間從而患者可將顆粒吸入患者之肺中。
本發明涵蓋US 5,556,611中所闡述之系統:- 液-氣系統(將液化氣體用作壓力容器中之推進劑氣體(例如低沸點FCHC或丙烷、丁烷)),- 懸浮液氣溶膠(將活性物質顆粒以固體形式懸浮於液體推進劑相中),- 增壓氣體系統(使用壓縮氣體,例如氮、二氧化碳、一氧化二氮、空氣)。
因此,根據本發明,製備醫藥製劑,其中將活性物質溶解或分散於適宜無毒介質中且將該溶液或分散液霧化成氣溶膠,亦即極精細地分佈於載氣中。此在技術上可能(例如)呈以下形式:氣溶膠推進劑氣體包裝、幫浦氣溶膠或本身已知用於液體造霧及固體霧化且特定而言允許確切個別劑量之其他裝置。
因此,本發明亦係關於包括如上文所定義之化合物及此一調配物且較佳地具有計量劑量閥之氣溶膠裝置。
本發明醫藥組合物亦可意欲鼻內投與。
就此而言,普通技術人員易於瞭解用於將化合物投與鼻黏膜表面之醫藥上可接受之載劑。該等載劑闡述於「Remington's Pharmaceutical Sciences」(第16版,1980,Arthur Osol編輯)中,其揭示內容以引用方式併入本文中。
適當載劑之選擇取決於預計之特定投與類型。為經由上呼吸道進行投與,可將組合物調配成溶液(例如,緩衝或未緩衝水或等滲鹽水)或懸浮液以用於以液滴或噴霧形式進行鼻內投與。較佳地,該等溶液或懸浮液相對於鼻分泌物等滲且具有介於(例如)約PH 4.0至約PH 7.4或PH 6.0至PH 7.0之間之大致相同pH。緩衝劑應在生理上相容且包含(僅舉例而言)磷酸鹽緩衝劑。舉例而言,據闡述,將代表性鼻去充血劑緩衝至約6.2之pH(Remington's,Id.,第1445頁)。當然,普通技術人員可易於確定關於用於經鼻及/或上呼吸道投與之無害水載劑之適宜鹽水含量及pH。
常見鼻內載劑包含黏度為(例如)約10 cp至約3000 cp或約2500 cp至6500 cp或更大之鼻凝膠、乳霜、膏或軟膏,其亦可用於提供與鼻黏膜表面之更持久接觸。該等載劑黏性調配物可基於(僅舉例而言)業內熟知之高黏度烷基纖維素及/或其他生物相容載劑(例如參見上文所引用之Remington's)。較佳烷基纖維素係(例如)濃度介於約5 mg至約1000 mg或更高/100 ml載劑之間之甲基纖維素。甲基纖維素之更佳濃度為(僅舉例而言)約25 mg資至約mg/100 ml
載劑。
亦可包含其他成份(例如業內已知之防腐劑、著色劑、潤滑或黏性礦物油或植物油、香料、天然或合成植物提取物(例如芳族油)及保濕劑及黏度增強劑(例如,甘油))以提供用於調配物之額外黏度、保濕性及舒適質地及氣味。為經鼻投與本發明之溶液或懸浮液,在業內可利用各種裝置生成液滴、微滴及噴霧。
製備含有一或多個劑量之擬投與藥物之預量測單位劑量分配器(包含含有用於以液滴或噴霧遞送之溶液或懸浮液之滴管或裝置裝置)且係本發明之另一目標。本發明亦包含套組,其含有化合物之一或多個單位脫水劑量以及任一所需鹽及/或緩衝劑、防腐劑、著色劑及諸如此類以準備用於藉由添加適宜量水來製備溶液或懸浮液。
本發明之另一態樣係關於該化合物在製造藥劑中之用途。換言之,本發明包含治療與未調控c-kit轉導有關之疾病之方法,其包括向需要該治療之哺乳動物投與有效量之如上文所定義之化合物。
更特定而言,本發明旨在治療選自以下之疾病之方法:自體免疫疾病、過敏性疾病、骨質流失、癌症(例如白血病及GIST)、腫瘤血管生成、發炎性疾病、發炎性腸病(IBD)、間質性膀胱炎、肥大細胞增多症、感染疾病、代謝病症、纖維化、糖尿病及CNS病症,其包括向需要該治療之哺乳動物投與有效量之上文所繪示之化合物。
上述化合物可用以製造用於治療與未調控c-kit轉導有關
之疾病之藥劑,該等疾病包含但不限於:
- 腫瘤疾病,例如肥大細胞增多症、犬肥大細胞瘤、實體腫瘤、人類胃腸道間質瘤(「GIST」)、小細胞肺癌、非小細胞肺癌、急性髓細胞性白血病、急性淋巴細胞性白血病、脊髓發育不良症候群、慢性骨髓性白血病、結直腸癌、胃癌、胃腸道間質瘤、睾丸癌、膠質母細胞瘤、實體腫瘤及星形細胞瘤。
- 腫瘤血管生成。
- 代謝疾病,例如糖尿病及其慢性併發症、肥胖症、II型糖尿病、高脂血症及脂質代謝障礙、動脈粥樣硬化、高血壓及心血管疾病。
- 過敏性疾病,例如哮喘、過敏性鼻炎、過敏性鼻竇炎、過敏症候群、蕁麻疹、血管性水腫、異位性皮炎、過敏性接觸性皮炎、結節性紅斑、多形性紅斑、皮膚壞死性靜脈炎及昆蟲咬傷皮膚發炎及吸血寄生蟲感染。
- 間質性膀胱炎。
- 骨質流失(骨質疏鬆)。
- 發炎性疾病,例如類風濕性關節炎、結膜炎、類風濕性脊柱炎、骨關節炎、痛風性關節炎及其他關節炎病狀。
- 自體免疫疾病,例如多發性硬化、乾癬、腸發炎性疾病、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、類風濕性關節炎及多關節炎、局部及全身性硬皮病、全身性紅斑狼瘡、盤狀紅斑狼瘡、皮膚狼瘡、皮肌炎、多發性肌炎、薛格連氏症候群(Sjogren's syndrome)、結節性全
身動脈炎、自體免疫腸病以及增殖性腎小球腎炎。
- 任一器官移植(包含腎、胰腺、肝、心、肺及骨髓)中之移植物抗宿主疾病或移植物排斥。
- 本發明所包含之其他自體免疫疾病:慢性活動性肝炎及慢性疲勞症候群。
- 皮下起泡病症,例如天皰瘡。
- 血管炎。
- HIV感染。
- 與黑素細胞功能障礙有關之疾病,例如自黑素細胞功能障礙引起之黑素增多病且包含著色斑、日光性及老年性著色斑、杜百威黑變病(Dubreuilh melanosis)、痣以及惡性黑素瘤。就此而言,本發明包含如上文所定義之化合物在製造用於使人類皮膚增白之藥劑或化妝品組合物中之用途。
- CNS病症,例如精神病症、偏頭痛、疼痛、記憶力喪失及神經細胞退化。更特定而言,本發明方法可用於治療下列病症:抑鬱症,包含情緒惡劣性病症、循環性情感病症、雙相性抑鬱症、嚴重或「憂鬱型」抑鬱症、典型型抑鬱症、難治性抑鬱症、季節性抑鬱症、厭食症、貪食症、經前症候群、絕經後症候群、其他症候群(例如智力下降及注意力喪失)、悲觀煩惱、精神激動、自我貶低、性欲降低;疼痛,包含急性疼痛、術後疼痛、慢性疼痛、傷害性疼痛、癌症疼痛、神經性疼痛、精神性疼痛症候群;焦慮病症,包含與換氣過度及心律失常有
關之焦慮、恐懼症、強迫症、創傷後應激病症、急性應急病症、廣泛性焦慮病症;精神病急症,例如恐慌發作,包含精神病、妄想病症、轉換病症、恐怖症、狂躁、譫妄症;分離性事件,包含分離性遺忘症、分離性漫遊及分離性認同病症;人格解體、緊張症、癲癇發作;嚴重精神病急症,包含自殺行為、自我忽略、強烈或攻擊性行為、創傷、邊緣性人格及急性精神病;精神分裂症,包含偏執型精神分裂症、錯亂型精神分裂症、緊張型精神分裂症及未分化型精神分裂症,
- 神經退化性疾病,包含阿茲海默氏病、帕金森氏病(Parkinson's disease)、亨廷頓氏病(Huntington's disease)、朊病毒病、運動神經元疾病(MND)及肌萎縮側索硬化(ALS)。
- 如本文所提及之物質使用病症,包含但不限於藥物成癮、藥物濫用、藥物習慣、藥物依賴、戒斷症候群及超劑量。
- 腦缺血。
- 纖維化。
- 迪謝內肌營養不良(Duchenne muscular dystrophy)。
對於肥大細胞增多症而言,本發明涵蓋如上文所定義之化合物在治療可如下分類之不同種類中之用途:種類I係由兩個子類(IA及IB)構成。種類IA係肥大細胞滲入嚴格侷限於皮膚中之疾病。此種類代表最常見形式之疾病且包含:i)色素性蕁麻疹,最常見形式之皮膚肥大細胞
增多症,尤其係在兒童中所遇到者;ii)彌漫性皮膚肥大細胞增多症;iii)孤立性肥大細胞瘤;及iv)一些稀有子型,例如大皰性肥大細胞增多症、紅皮性肥大細胞增多症及毛細管擴張性肥大細胞增多症。該等形式之特徵在於其具有極佳預後,且在兒童中具有自發性復原並在成人中具有極惰性過程。此疾病形式之長期存活通常與正常群體相當,且很少轉變成另一形式之肥大細胞增多症。種類IB係由涉及皮膚或並不涉及皮膚之惰性全身性疾病(SM)代表。與兒童相比,該等形式更常見於成人中。該疾病之過程通常係惰性的,但有時可發生攻擊性或惡性肥大細胞增多症之體徵,從而引起進行性受損器官功能。
種類II包含具有相關血液學病症(例如骨髓增殖性或骨髓發育不良症候群或急性白血病)之肥大細胞增多症。該等惡性肥大細胞增多症通常並不涉及皮膚。該疾病之進展通常取決於決定預後之相關血液學病症之類型。
種類III係由攻擊性全身性肥大細胞增多症代表,其中通常藉由異常肥大細胞引起多器官巨大滲入。在患有此類攻擊性臨床過程之患者中,指示骨髓增殖性病症之周邊血特徵較為明顯。類似於急性白血病,該疾病之進展可極其迅速,或一些患者可展示較長存活時間。
最後,肥大細胞增多症之種類IV包含肥大細胞白血病,其特徵在於存在代表10%以上之白血細胞之循環肥大細胞及肥大細胞祖細胞。此實體可能代表最稀有類型之人類白血病,且類似於惡性肥大細胞增多症之快速進展變體具有
極差預後。肥大細胞白血病可重新發生或在色素性蕁麻疹或全身性肥大細胞增多症之末期發生。
本發明亦涵蓋所述用於治療復發性細菌感染、無症狀時段之後之複生性感染(例如細菌膀胱炎)之方法。更特定而言,可實踐本發明以用於治療表現FimH之細菌感染,例如格蘭氏陰性腸細菌(Gram-negative enterobacteria),包含大腸桿菌(E.coli)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、黏質沙雷菌(Serratia marcescens)、弗氏檸檬酸菌(Citrobactor freudii)及鼠傷寒沙門氏菌(Salmonella typhimurium)。
在治療細菌感染之此方法中,較為關注單獨、依序或同時投與至少一種選自以下之抗生素:桿菌肽(bacitracin)、頭孢菌素(cephalosporin)、青黴素(penicillin)、胺基糖苷、四環素(tetracycline)、鏈黴素(streptomycin)及大環內酯抗生素(例如紅黴素(erythromycin))、氟喹諾酮(fluoroquinolone)、放線菌素(actinomycin)、磺醯胺及甲氧苄胺嘧啶(trimethoprim)。
在一較佳實施例中,本發明係關於治療例如以下腫瘤疾病之方法:肥大細胞增多症、犬肥大細胞瘤、實體腫瘤、人類胃腸道間質瘤(「GIST」)、小細胞肺癌、非小細胞肺癌、急性髓細胞性白血病、急性淋巴細胞性白血病、脊髓發育不良症候群、慢性骨髓性白血病、結直腸癌、胃癌、胃腸道間質瘤、睾丸癌、膠質母細胞瘤及星形細胞瘤,其包括向需要該治療之人類或哺乳動物(尤其係狗及貓)投與
如本文所定義之化合物。
在一其他較佳實施例中,本發明係關於治療例如以下過敏性疾病之方法:哮喘、過敏性鼻炎、過敏性鼻竇炎、過敏症候群、蕁麻疹、血管性水腫、異位性皮炎、過敏性接觸性皮炎、結節性紅斑、多形性紅斑、皮膚壞死性靜脈炎及昆蟲咬傷皮膚發炎及吸血寄生蟲感染,其包括向需要該治療之人類或哺乳動物(尤其係狗及貓)投與如本文所定義之化合物。
在另一較佳實施例中,本發明係關於治療例如以下發炎性疾病之方法:類風濕性關節炎、結膜炎、類風濕性脊柱炎、骨關節炎、痛風性關節炎及其他關節炎病狀,其包括向需要該治療之人類投與如本文所定義之化合物。
在另一較佳實施例中,本發明係關於治療例如以下自體免疫疾病之方法:多發性硬化、乾癬、腸發炎性疾病、潰瘍性結腸炎、克羅恩氏病、類風濕性關節炎及多關節炎、局部及全身性硬皮病、全身性紅斑狼瘡、盤狀紅斑狼瘡、皮膚狼瘡、皮肌炎、多發性肌炎、薛格連氏症候群、結節性全身動脈炎、自體免疫腸病以及增殖性腎小球腎炎,其包括向需要該治療之人類投與如本文所定義之化合物。
在另一較佳實施例中,本發明係關於治療任一器官移植(包含腎、胰腺、肝、心、肺及骨髓)中之移植物抗宿主疾病或移植物排斥之方法,其包括向需要該治療之人類投與如本文所定義之化合物。
在另一實施例中,本發明化合物或其醫藥上可接受之鹽
可與一或多種其他活性醫藥藥劑以足以提供治療效應之量組合投與。在一實施方案中,同時共投與本發明化合物及其他藥劑。在另一實施方案中,依序共投與本發明化合物及其他藥劑。在另一實施方案中,共同投與本發明化合物及其他藥劑歷經一段時間。
在BaF3 Kit WT或Kit D816細胞系上以及人類及鼠類肥大細胞瘤及肥大細胞白血病細胞系上實施比色細胞增殖及活力分析(CellTiter-Blue購自Promega編號N°G8081)。
在96孔板之每個孔中接種總共2.104個細胞/50 μl。藉由添加介於0至10 μM之間之½連續稀釋液之2×藥物溶液來開始處理。在37℃下培育48小時之後,向每一孔中添加10 μl CellTiter-Blue試劑之½稀釋液且將板放回培育器中再保持4小時。CellTiter-Blue試劑之螢光強度與活細胞數量成正比,且使用POLARstar OMEGA微量板讀數儀(BMG LabteckSarl)記錄數據(544Ex/590Em)。將沒有細胞之背景對照用作空白對照。分析之陽性對照對應於在沒有藥物處理下獲得之細胞增殖(100%增殖)。一式三份對每一試樣進行實驗。結果係以相對於沒有處理下所獲得增殖之百分比表示。
所有藥物皆於DMSO中製成20 mM儲備溶液,並儲存於-80℃下。在每一實驗之前,於介質中新鮮製備藥物稀釋
液。在每一實驗中包含DMSO對照。
人類Kit WT及人類Kit D816V係源於鼠類IL-3依賴性Ba/F3 proB淋巴樣細胞。在使用250 ng/ml重組鼠類SCF刺激Ba/F3 Kit WT時,表現Kit D816V之細胞不依賴細胞因子即可生長。FMA3及P815細胞系係表現Kit之內源性突變形式(亦即,受體-密碼子573至579之鼠類近膜編碼區域中之框架缺失)(FMA3)及活化激酶結構域中之D814Y突變(P815)之肥大細胞瘤細胞。人類白血病MC系HMC-1表現c-Kit基因中之兩種單一點突變,即近膜結構域中之V560G及激酶結構域中之D816V。
對於每一分析而言,如本文中所述,將5.106個表現各種c-kit突變之Ba/F3細胞及Ba/F3衍生細胞裂解並實施免疫沈澱(Beslu等人,1996)。簡言之,使用針對抗鼠類KIT(Rottapel等人,1991)或抗人類KIT(Santa Cruz)之胞質結構域之兔免疫血清來對細胞裂解物實施免疫沈澱。將西方印跡與4G10抗磷酸化酪胺酸抗體(UBI)(針對信號傳導分子之相應兔免疫血清抗KIT或抗體)雜交。然後將膜與HRP偶聯之山羊抗小鼠IgG抗體或HRP偶聯之山羊抗兔IgG抗體(Immunotech)一起培育,然後藉由與ECL試劑(Amersham)一起培育來使所關注蛋白質可視化。
使用上述方案之本發明各種化合物之實驗結果闡述於表
3中:
發明者觀察到,本發明之式I類化合物可極其有效地抑制蛋白質激酶及更特定而言天然及/或突變c-kit。表3中所列示之化合物充分代表了式I化合物之種類。
Claims (27)
- 一種化合物,其具有式I:
- 如請求項1之化合物,其具有式II:
- 如請求項1之化合物,其具有式III:
- 如請求項1之化合物或其醫藥上可接受之鹽,其中:R1係H或(C1-C6)烷基;R2係H;鹵素;COOH;(C1-C6)烷基,其視情況經基團-NR10R11、OH或視情況經OH取代之(C1-C4)烷氧基取代,其中R10及R11各自獨立地係H或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基取代之(C1-C4)烷基;或R10及R11與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基;(C1-C6)烷氧基,其視情況經OH、(C1-C4)烷氧基或基團-NR12R13取代,其中R12及R13各自獨立地係H或(C1-C4)烷基;或R12及R13與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基,該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-OR14,其中R14係含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基,該雜環烷基視情況經1 至3個(C1-C4)沈基取代;基團-CONR15R16,其中R15及R16各自獨立地係H或視情況經(C1-C4)烷氧基或含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基取代之(C1-C4)烷基;或R15及R16與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基;基團-NR17R18,其中R17係H或(C1-C4)烷基且R18係H;視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;或含有1至3個選自O、S及N之雜原子之5-或6員雜芳基;基團-NR19COR20,其中R19係H或(C1-C4)烷基且R20係H或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基或含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基取代之(C1-C4)烷基,該雜環烷基視情況經1至3個(C1-C4)烷基取代;或含有1或2個選自O及N之雜原子之5-或6員雜環烷基或雜芳基,該雜環烷基或雜芳基視情況經側氧基或視情況經胺基、(C1-C4)烷基胺基或二(C1-C4)烷基胺基取代之(C1-C4)烷基取代;R3係H、氰基、CF3、鹵素、(C1-C4)烷基或(C1-C4)烷氧基;Q係O或S,較佳地Q係O;W係N或CR21,其中R21係 H;鹵素;CN;CF3;OCF3;(C1-C4)烷基,其視情況經含有1或2個選自O及N之雜原子之5-或6員雜環烷基取代;(C1-C4)烷氧基;基團-O(CH2)nR22,其中n為0、1、2或3且R22係H;(C1-C4)烷氧基;基團-NR22aR22b,其中R22a及R22b各自獨立地係H或(C1-C4)烷基;或含有1或2個選自O及N之雜原子之5-或6員雜環烷基,該雜環烷基視情況經1至3個(C1-C4)烷基取代;基團-NR23R24,其中R23及R24各自獨立地係H或視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;R24亦可代表基團-SO2(C1-C4)烷基;或R23及R24與其所鍵結之氮原子一起形成含有1或2個選自O、S及N之雜原子之5-或6員雜環烷基或雜芳基,該雜環烷基視情況經1至3個(C1-C4)烷基取代;X係N或CR25,其中R25係H、CN、(C1-C4)烷基或基團-COO(C1-C4)烷基;且A係含有1至3個選自O及N之雜原子之5-或6員雜環烷基或雜芳基,該雜環烷基或雜芳基視情況經1至3個選自以下之取代基取代:側氧基;鹵素;(C1-C4)烷基,其視情況 經胺基、(C1-C4)烷基胺基、二(C1-C4)烷基胺基或含有1或2個選自O及N之雜原子之5-或6員雜環烷基取代;及(C1-C4)烷氧基。
- 如請求項1之化合物或其醫藥上可接受之鹽,其中:R1係H或(C1-C4)烷基;R2係H;視情況經(C1-C4)烷氧基取代之(C1-C4)烷基;視情況經OH或基團-NR12R13取代之(C1-C4)烷氧基,其中R12及R13各自獨立地係H或(C1-C4)烷基,或R12及R13與其所鍵結之氮原子一起形成含有1或2個選自O及N之雜原子之5-或6員雜環烷基;或基團-CONR15R16,其中R15及R16各自獨立地係H或(C1-C4)烷基;R3係H或(C1-C4)烷基;Q係O;W係N或CR21,其中R21係H;OCF3;(C1-C4)烷基;(C1-C4)烷氧基;或基團-O(CH2)nR22,其中n為0、1或2,且R22係含有1或2個選自O及N之雜原子之5-或6員雜環烷基;X係N或CH;且A係含有1或2個氮原子之5-或6員雜環烷基或雜芳基,該雜環烷基或雜芳基視情況經1至3個(C1-C4)烷基取代。
- 如請求項1至3中任一項之化合物,其中該增溶基團係選自嗎啉基、六氫吡啶基、N-(C1-C6)烷基六氫吡啶基、N-(4-六氫吡啶基)六氫吡啶基、4-(1-六氫吡啶基)六氫吡啶基、1-吡咯啶基六氫吡啶基、4-嗎啉基六氫吡啶基、4- (N-甲基-1-六氫吡嗪基)六氫吡啶基、六氫吡嗪基、N-(C1-C6)烷基六氫吡嗪基、N-(C3-C6)環烷基六氫吡嗪基、吡咯啶基、N-(C1-C6)烷基吡咯啶基、二氮呯基、N-(C1-C6)烷基氮呯基、高六氫吡嗪基、N-甲基高六氫吡嗪基、N-乙基高六氫吡嗪基及咪唑基。
- 如請求項1之化合物或其醫藥上可接受之鹽,其選自:1-{4-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-吡啶-2-基}-咪唑啶-2-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-4,4-二甲基-咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-5-甲基-苯基)-咪唑啶-2-酮;1-(4-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-(4-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-{4-[2-((5-甲氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-吡啶-2-基}-4-甲基-咪唑啶-2-酮;4-甲基-1-(4-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮;1-(3-甲基-5-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-苯基)-咪唑啶-2-酮;1-(4-{2-[2-甲基-5-(3-嗎啉-4-基-丙氧基)-苯基胺基]-噁唑-5-基}-吡啶-2-基)-咪唑啶-2-酮; 1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-咪唑啶-2-酮;1-(3-甲氧基-5-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-苯基)-咪唑啶-2-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-4-甲基-咪唑啶-2-酮;1-{3-第三-丁氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-苯基}-咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-5-甲氧基-苯基)-咪唑啶-2-酮;1-(3-甲氧基-5-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-苯基)-4-甲基-咪唑啶-2-酮;1-{3-異丙氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-苯基}-咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基)-2-甲基-苯基胺基]-噁唑-5-基}-5-異丙氧基-苯基)-咪唑啶-2-酮;1-(3-異丙氧基-5-{2-[5-(2-甲氧基-乙基)-2-甲基-苯基胺基]-噁唑-5-基}-苯基)-咪唑啶-2-酮;1-(3-(2-(2-甲基-5-(2-嗎啉基乙氧基)苯基胺基)噁唑-5-基)-5-(三氟甲氧基)苯基)咪唑啶-2-酮;1-(3-(2-(5-甲氧基-2-甲基苯基胺基)噁唑-5-基)-5-(三氟甲氧基)苯基)咪唑啶-2-酮;1-(3-{2-[5-(2-羥基-乙氧基甲基)-2-甲基-苯基胺基]-噁唑-5-基}-5-甲基-苯基)-咪唑啶-2-酮; 3-{5-[3-異丙氧基-5-(2-側氧基-咪唑啶-1-基)-苯基]-噁唑-2-基胺基}-N-(2-甲氧基-乙基)-4-甲基-苯甲醯胺;1-(3-(2-(5-(乙氧基甲基)-2-甲基苯基胺基)噁唑-5-基)-5-(三氟甲氧基)苯基)咪唑啶-2-酮;3-{3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-三氟甲氧基-苯基}-4-甲基-1H-吡啶-2-酮;3-{3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-甲氧基-苯基}-1H-吡啶-2-酮;3-{3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-異丙氧基-苯基}-4-甲基-1H-吡啶-2-酮;4-[2-(5-(乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-4'-甲基-1'H-[2,3']聯吡啶-2'-酮;3-[3-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-5-(2-嗎啉-4-基-乙氧基)-苯基]-4-甲基-1H-吡啶-2-酮;4'-甲基-4-{2-[2-甲基-5-(2-嗎啉-4-基-乙氧基)-苯基胺基]-噁唑-5-基}-1'H-[2,3']聯吡啶-2'-酮;4-[2-(3,5-二甲基-苯基胺基)-噁唑-5-基]-4'-甲基-6-(2-嗎啉-4-基-乙氧基)-1'H-[2,3']聯吡啶-2'-酮;1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基胺基)-噁唑-5-基]-5-異丙氧基-苯基}-咪唑啶-2-酮;4'-甲基-4-{2-[2-甲基-5-(3-嗎啉-4-基-丙氧基)-苯基胺基]-噁唑-5-基}-1'H-[2,3']聯吡啶-2'-酮;及其醫藥上可接受之鹽。
- 一種醫藥組合物,其包括如請求項1至7中任一項之化合 物或其醫藥上可接受之鹽。
- 一種用於局部投與之化妝品組合物,其包含如請求項1至7中任一項之化合物或其醫藥上可接受之鹽。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽,其係用作藥劑。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽,其係用於治療肥大細胞增多症。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽,其係用於治療血液惡性病、骨髓增殖性病症、其他增殖性病症、自體免疫病症、發炎性疾病、過敏性疾病或神經學疾病。
- 如請求項12之化合物,其中該血液惡性病係急性髓性白血病(AML)、脊髓發育不良症候群(MDS)、急性淋巴母細胞白血病(ALL)、慢性髓性白血病(CML)或嗜伊紅性白血球增多症候群(HES)。
- 如請求項12之化合物,其中該增殖性病症係癌症。
- 如請求項12之化合物,其中該自體免疫病症係多發性硬化、乾癬、腸發炎性疾病、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、類風濕性關節炎及多關節炎、局部及全身性硬皮病、全身性紅斑狼瘡、盤狀紅斑狼瘡、皮膚狼瘡、皮肌炎、多發性肌炎、薛格連氏症候群(Sjogren's syndrome)、結節性全身動脈炎、自體免疫腸病、異位性皮炎或增殖性腎小球腎炎。
- 如請求項12之化合物,其中該過敏性疾病係哮喘、過敏 性鼻炎、過敏性鼻竇炎、過敏症候群、蕁麻疹、血管性水腫、異位性皮炎、過敏性接觸性皮炎、結節性紅斑、多形性紅斑、皮膚壞死性靜脈炎及昆蟲咬傷皮膚發炎或吸血寄生蟲感染。
- 如請求項12之化合物,其中該神經學疾病係亨廷頓氏病(Huntington's disease)、精神分裂症、帕金森氏病(Parkinson's disease)或阿茲海默氏疾病(Alzheimer's disease)。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽,其係用作蛋白質激酶之抑制劑。
- 如請求項18之化合物,其中該蛋白質激酶係天然及/或突變c-kit。
- 如請求項8之醫藥組合物,其進一步包括另一活性醫藥藥劑。
- 如請求項10至19中任一項之化合物,其係與另一活性醫藥藥劑組合使用。
- 一種如請求項1至7中任一項之化合物或其醫藥上可接受之鹽之用途,其係用以製造用於治療或預防蛋白質激酶相關性疾病或病症之藥劑。
- 如請求項22之用途,其中該蛋白質激酶係酪胺酸激酶。
- 如請求項23之用途,其中該酪胺酸激酶係c-kit。
- 一種如請求項1至7中任一項之化合物或其醫藥上可接受之鹽之用途,其係用以製造用於治療血液惡性病、骨髓增殖性病症、另一增殖性病症、自體免疫病症或皮膚病 症之藥劑。
- 如請求項25之用途,其中該藥劑與另一活性醫藥藥劑同時或依序使用。
- 一種如請求項1至7中任一項之化合物或其醫藥上可接受之鹽之用途,其係用以製造意欲用於治療下列疾病或病症中之一者之藥劑:肥大細胞增多症、血液惡性病、骨髓增殖性病症、另一增殖性病症、自體免疫病症、發炎性疾病、過敏性疾病或神經學疾病。
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WO2009054332A1 (ja) * | 2007-10-23 | 2009-04-30 | Banyu Pharmaceutical Co., Ltd. | ピリドン置換ジヒドロピラゾロピリミジノン誘導体 |
CN101239978A (zh) | 2008-03-05 | 2008-08-13 | 南方医科大学 | 一种咪唑并吡啶类化合物 |
WO2010096395A1 (en) | 2009-02-18 | 2010-08-26 | Syntech Solution Llc | Amides as kinase inhibitors |
EP2512246B1 (en) * | 2009-12-17 | 2015-09-30 | Merck Sharp & Dohme Corp. | Aminopyrimidines as syk inhibitors |
-
2012
- 2012-07-24 RU RU2014107463A patent/RU2612972C2/ru active
- 2012-07-24 CA CA2840029A patent/CA2840029C/en not_active Expired - Fee Related
- 2012-07-24 WO PCT/EP2012/064539 patent/WO2013014170A1/en active Application Filing
- 2012-07-24 US US14/234,935 patent/US9168245B2/en not_active Expired - Fee Related
- 2012-07-24 CN CN201280037457.9A patent/CN103717591B/zh not_active Expired - Fee Related
- 2012-07-24 JP JP2014522071A patent/JP5944503B2/ja not_active Expired - Fee Related
- 2012-07-24 BR BR112014001977A patent/BR112014001977A2/pt not_active IP Right Cessation
- 2012-07-24 MX MX2014001079A patent/MX2014001079A/es not_active Application Discontinuation
- 2012-07-24 EP EP12741307.8A patent/EP2736904B1/en not_active Not-in-force
- 2012-07-24 ES ES12741307.8T patent/ES2573831T3/es active Active
- 2012-07-24 AU AU2012288900A patent/AU2012288900B2/en not_active Ceased
- 2012-07-24 KR KR1020137034946A patent/KR101924247B1/ko active IP Right Grant
- 2012-07-27 TW TW101127351A patent/TW201311676A/zh unknown
- 2012-07-27 AR ARP120102736A patent/AR087354A1/es unknown
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2014
- 2014-01-03 CL CL2014000007A patent/CL2014000007A1/es unknown
- 2014-01-16 IL IL230504A patent/IL230504A0/en active IP Right Grant
- 2014-01-20 ZA ZA2014/00465A patent/ZA201400465B/en unknown
Also Published As
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AR087354A1 (es) | 2014-03-19 |
EP2736904A1 (en) | 2014-06-04 |
US9168245B2 (en) | 2015-10-27 |
AU2012288900B2 (en) | 2016-10-06 |
ES2573831T3 (es) | 2016-06-10 |
CA2840029A1 (en) | 2013-01-31 |
JP2014521624A (ja) | 2014-08-28 |
RU2014107463A (ru) | 2015-09-10 |
CN103717591B (zh) | 2016-08-24 |
ZA201400465B (en) | 2015-04-29 |
AU2012288900A1 (en) | 2014-01-16 |
IL230504A0 (en) | 2014-03-31 |
BR112014001977A2 (pt) | 2017-02-21 |
RU2612972C2 (ru) | 2017-03-14 |
CL2014000007A1 (es) | 2014-09-05 |
CA2840029C (en) | 2021-07-20 |
KR20140041609A (ko) | 2014-04-04 |
MX2014001079A (es) | 2014-09-12 |
JP5944503B2 (ja) | 2016-07-05 |
NZ618953A (en) | 2015-05-29 |
US20140179698A1 (en) | 2014-06-26 |
EP2736904B1 (en) | 2016-03-16 |
CN103717591A (zh) | 2014-04-09 |
WO2013014170A1 (en) | 2013-01-31 |
KR101924247B1 (ko) | 2019-02-22 |
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