TW201706246A - 作為選擇性組織蛋白去乙醯酶抑制劑之雜環烷基衍生物化合物及包含其之醫藥組合物 - Google Patents
作為選擇性組織蛋白去乙醯酶抑制劑之雜環烷基衍生物化合物及包含其之醫藥組合物 Download PDFInfo
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- DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
- DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 1
- ZLBJUBAPYSDNBY-UHFFFAOYSA-N tert-butyl 4-(N-(3-fluorophenyl)anilino)piperidine-1-carboxylate Chemical compound FC=1C=C(C=CC=1)N(C1CCN(CC1)C(=O)OC(C)(C)C)C1=CC=CC=C1 ZLBJUBAPYSDNBY-UHFFFAOYSA-N 0.000 description 1
- VFYGUGVUHORXSW-UHFFFAOYSA-N tert-butyl 4-(N-(4-fluorophenyl)anilino)piperidine-1-carboxylate Chemical compound FC1=CC=C(C=C1)N(C1CCN(CC1)C(=O)OC(C)(C)C)C1=CC=CC=C1 VFYGUGVUHORXSW-UHFFFAOYSA-N 0.000 description 1
- CFQHKXWKEAMLCW-UHFFFAOYSA-N tert-butyl 4-(N-[4-(trifluoromethyl)phenyl]anilino)piperidine-1-carboxylate Chemical compound C1(=CC=CC=C1)N(C1CCN(CC1)C(=O)OC(C)(C)C)C1=CC=C(C=C1)C(F)(F)F CFQHKXWKEAMLCW-UHFFFAOYSA-N 0.000 description 1
- YLLQWQAWIYVBOZ-UHFFFAOYSA-N tert-butyl 4-(n-phenylanilino)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N(C=1C=CC=CC=1)C1=CC=CC=C1 YLLQWQAWIYVBOZ-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229940061261 zolinza Drugs 0.000 description 1
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Abstract
本發明係關於具有組織蛋白去乙醯酶(HDAC)抑制活性之新穎雜環烷基衍生物、其光學異構體或其醫藥上可接受之鹽、其用於製備藥劑之用途、含有其之醫藥組合物、使用該組合物治療疾病之方法及製備該等新穎雜環烷基衍生物之方法。
本發明之該等新穎雜環烷基衍生物係選擇性組織蛋白去乙醯酶(HDAC)抑制劑,且可有效地用於治療組織蛋白去乙醯酶介導之疾病,例如細胞增殖性疾病、發炎性疾病、體染色體顯性疾病、遺傳性代謝疾病、自體免疫疾病、急性/慢性神經性疾病、肥大、心臟衰竭、眼部疾病或神經退化疾病。
Description
本發明係關於新穎雜環烷基衍生物及更特定而言具有組織蛋白去乙醯酶(HDAC)抑制活性之新穎雜環烷基衍生物、其光學異構體或其醫藥上可接受之鹽、其用以製備用於治療HDAC介導之疾病之藥劑之用途、含有其之醫藥組合物、使用該等醫藥組合物治療疾病之方法及製備該等新穎雜環烷基衍生物之方法。
細胞中之轉錄調控係複雜之生物過程。轉錄調控中之一個基本原理係基於組織蛋白(亦即形成八聚體組織蛋白核心複合物之組織蛋白H2A/B、H3及H4)之轉譯後修飾。在離胺酸殘基處藉由乙醯化或甲基化及在絲胺酸殘基處藉由磷酸化達成之複雜N-末端修飾構成所謂的「組織蛋白代碼」之一部分(參見Strahl及Ellis,Nature 403,41-45,2000)。
在簡單模型中,帶正電荷之離胺酸殘基之乙醯化降低對帶負電荷之DNA的親和力,由此可容易地進入轉錄因子中。
組織蛋白之乙醯化及去乙醯化分別係由組織蛋白乙醯基轉移酶(HAT)及組織蛋白去乙醯酶(HDAC)催化。HDAC與轉錄抑制複合物締
合,從而將染色質切換成在轉錄上惰性之沉默結構。(參見Marks等人,Nature cancer Rev.1,189-202,2001)。相反的,藉由HAT與轉錄活化複合物締合而活化。迄今為止已知三種不同種類之HDAC,亦即I類(HDAC 1-3、8;Mr=42-55kDa),其主要位於細胞核中且對於曲古抑菌素A(Trichostatin A,TSA)之抑制較為敏感;II類(HDAC 4-7、9、10;Mr=120-130kDa),其展現TSA敏感性;及III類(SIRT1~7),其可根據NAD+依賴性及TSA不敏感性進行區分。
組織蛋白去乙醯酶(HDAC)抑制劑構成具有細胞分化及細胞凋亡誘導活性之抗癌藥之新種類。藉由靶向組織蛋白去乙醯酶(HDAC),HDAC抑制劑藉由組織蛋白乙醯化來影響染色質結構,從而誘導複雜轉錄之再程式化(例如腫瘤阻抑基因之鈍化及癌基因之阻遏)。除乙醯化核心組織蛋白中之N-末端離胺酸殘基,HDAC抑制劑靶向對於癌症生物學較為重要之非組織蛋白(包括熱激蛋白90(HSP90)、微管蛋白或p53腫瘤阻抑蛋白)。因此,HDAC抑制劑可不僅用於抗癌療法中,且亦用於治療遺傳性代謝疾病、自體免疫疾病及諸如此類,此乃因已展示在發炎性疾病、類風濕性關節炎及神經退化之動物模型中之效能。
與HDAC抑制有關之組織蛋白去乙醯酶介導之疾病之實例包括細胞增殖性疾病,例如惡性腫瘤疾病,例如癌症;發炎性疾病,例如發炎性腸病、克羅恩氏病(Crohn's disease)或潰瘍性腸炎;體染色體顯性疾病,例如亨廷頓氏病(Huntington's disease)、唐氏症候群(Downs syndrome)、愛德華氏症候群(Edwards syndrome)或巴陶氏症候群(Pataus syndrome);遺傳性代謝疾病,例如糖尿病、尼曼匹克氏病(Niemann-Pick disease)、高雪氏病(Gaucher disease)、苯丙酮尿、威爾森氏症(Wilson's disease);或纖維化疾病,例如囊性纖維化、肝纖維化、腎纖維化、肺纖維化或皮膚纖維化;自體免疫疾病,例如類風濕
性關節炎、氣喘、狼瘡、牛皮癬、牛皮癬關節炎、多發性硬化、貝切特氏病(Behçet's disease)或器官移植排斥;急性/慢性神經性疾病,例如中風或多囊性腎病;肥大,例如心肥大;心臟衰竭,例如鬱血性心臟衰竭或出血性心臟衰竭;眼部疾病,例如青光眼、乾眼症候群、乾性黃斑部退化、濕性黃斑部退化、糖尿病視網膜病變或眼色素層炎;神經退化疾病,例如阿茲海默氏病(Alzheimer's disease)、肌肉萎縮性脊髓側索硬化症、恰克-馬利-杜斯氏症(Charcot Marie Tooth disease)或脊髓性肌萎縮以及由HDAC酶之異常功能引起之病狀及疾病。
迄今已知之HDAC抑制劑可根據其結構分為以下4類:1)短鏈脂肪酸(丁酸及丙戊酸);2)羥肟酸(曲古抑菌素A、SAHA及LBH-589);3)環狀肽(縮肽);及4)苯甲醯胺(MS-275及MGCD-0103)(Sonia等人,International Journal of onocology 33,637-646,2008)。該許多組織蛋白去乙醯酶(HDAC)抑制劑(SAHA、LBH-589及MS-275等)抑制細胞生長,且有效地誘導不僅在培養基且亦在動物模型中之各種轉變細胞之細胞分化及細胞凋亡(Paul A.Marks等人,Curr Opin.Oncol.13,477-483,2001)。因此,在臨床研究中評價HDAC抑制劑(例如SAHA、LBH-589及MS-275)以用於治療各種癌症(Johnstone.R.W,Nat.Rev.Drug.Discov.1,287-299,2002)。當前稱為HDAC抑制劑之代表性化合物包括SAHA(US再頒發專利第385069號,容立莎(Zolinza)、伏立諾他(Vorinostat))、PXD101(WO 02/30879,貝林司他(Belinostat))及LBH-589(WO 02/22577,帕比司他(Panobinostat))(其係氧肟酸鹽化合物)及MS-275(EP專利第0847992號,恩替諾特(Entinostat))與MGCD0103(WO 04/69823,莫賽替諾司他(Mocetinostat))(其係苯甲醯胺化合物)。在該等化合物中,SAHA批准於2006年10月且已用作用於治療CTCL(皮膚T細胞淋巴瘤)之藥劑,且其適應症已進一步擴展,但已知SAHA在效能及副效應方面不足(Paul A.Marks等人,Cancer
Res 66,5781-5789,2006)。
各種HDAC抑制劑正處於臨床前或臨床研發中,但迄今為止,僅非選擇性HDAC抑制劑已鑑別為抗癌劑。非選擇性HDAC抑制劑已知通常會在高劑量下引起諸如疲勞及噁心等副效應(Piekarz等人,Pharmaceuticals 2010,3,2751-2767)。據報導,該等副效應係由種類IHDAC之抑制所致。因該等副效應,非選擇性HDAC抑制劑在除抗癌藥外之藥物之研發中之應用受限(Witt等人,Cancer Letters,2009,277,8-21)。
同時,據報導,種類II HDAC之選擇性抑制並不展示種類I HDAC之抑制中所展示之毒性。同樣,在研發選擇性HDAC抑制劑時,可克服藉由非選擇性HDAC抑制引起之諸如毒性等副效應。因此,選擇性HDAC抑制劑可研發為有效治療各種疾病之治療劑(Matthias等人,Mol.Mol.Biol.2008,28,1688-1701)。
已知HDAC 6(種類IIb HDAC之成員)主要存在於細胞質中且涉及諸多非組織蛋白受質(HSP90、皮層蛋白等)(包括微管蛋白)之去乙醯化(Yao等人,Mol.Cell 2005,18,601-607)。此外,HDAC 6具有兩個催化結構域,且C-末端鋅指結構域其可結合至泛素化蛋白。已知HDAC 6具有許多非組織蛋白作為受質,且由此在各種疾病(例如癌症、發炎性疾病、自體免疫疾病、神經性疾病及神經退化病症)中發揮重要作用(Santo等人,Blood 2012 119:2579-258;Vishwakarma等人,International Immunopharmacology 2013,16,72-78;Hu等人,J.Neurol.Sci.2011,304,1-8)。
因此,需要研發用於治療癌症、發炎性疾病、自體免疫疾病、神經性疾病及神經退化病症且不同於非選擇性抑制劑並不引起副效應之選擇性HDAC 6抑制劑。
本發明目標係提供具有選擇性HDAC抑制活性之新穎化合物、其光學異構體或其醫藥上可接受之鹽。
本發明另一目標係提供含有具有高度選擇性HDAC抑制活性之新穎化合物、其光學異構體或其醫藥上可接受之鹽之醫藥組合物。
本發明之再一目標係提供製備新穎化合物之方法。
本發明之再一目標係提供用於治療HDAC活性相關疾病(包括癌症、發炎性疾病、自體免疫疾病、神經性疾病或神經退化病症)之含有上述化合物之醫藥組合物。
本發明之再一目標係提供化合物用以製備用於治療HDAC介導之疾病(包括癌症、發炎性疾病、自體免疫疾病、神經性疾病或神經退化病症)之藥劑之用途。
本發明之又一目標係提供治療HDAC介導之疾病(包括癌症、發炎性疾病、自體免疫疾病、神經性疾病或神經退化病症)之方法,其包含投與治療有效量之含有化合物之醫藥組合物。
發明者已發現具有HDAC抑制活性之新穎化合物,且已使用該等化合物來抑制或治療組織蛋白去乙醯酶介導之疾病,由此完成本發明。
為達成上述目標,本發明提供下文之式I化合物、其光學異構體或其醫藥上可接受之鹽。
其中X係選自由以下組成之群之雜環烷基:
{其中Z及W各自獨立地係C或N,Z及W中之至少一者係N,a、b、c及d各自獨立地係1、2或3,且R3、R4、R5及R6各自獨立地係-H或-C1-C4烷基};Y係C或N;A及B各自獨立地係-C1-C4烷基、-C6-C10芳基、-C3-C12雜芳基、-C3-C10環烷基、-C2-C10雜環烷基或-C3-C10環烯基{其中-C1-C4烷基之一或多個氫原子可經-OH或鹵素取代,且-C6-C10芳基、-C3-C12雜芳基、-C3-C10環烷基、-C2-C10雜環烷基及-C3-C10環烯基可各自獨立地未經取代或在其一或多個氫原子處經-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或鹵素取代};Q係C=O或SO2;R1係-H或-C1-C4烷基;R2係-H、-OH、-C1-C4烷基、-C1-C4烷基羥基、鹵素或不存在{限制條件係在Y係C時,R2係-H、-OH、-C1-C4烷基或-C1-C4烷基羥基,且在Y係N時,R2不存在};且n為1、2、3或4。
根據本發明之一實施例,
X係或{其中Z及W各自獨立地係C或N,且Z及W中之至少一者係N,a、b、c及d各自獨立地係1、2或3,且R3、R4、R5及R6各自獨立地係-H或-C1-C4烷基};Y係C或N;A及B各自獨立地係-C1-C4烷基、-C6-C10芳基或-C3-C12雜芳基{其中-C1-C4烷基之一或多個氫原子可經-OH或鹵素取代,且-C6-C10芳基或-C3-C12雜芳基可各自獨立地未經取代或在其一或多個氫原子處經-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或鹵素取代};Q係C=O或SO2;R1係-H或-C1-C4烷基;R2係-H、-OH、鹵素或不存在{限制條件係在Y係C時,R2係-H、-OH或鹵素,且在Y係N時,R2不存在};且n為1、2、3或4。
根據本發明之另一實施例,
X係{其中Z及W各自獨立地係C或N,Z及W中之至少一者係N,且R3及R4各自獨立地係-H或-C1-C4烷基};Y係C或N;A及B各自獨立地係-C1-C4烷基、-C6-C10芳基或-C3-C12雜芳基{其中-C1-C4烷基之一或多個氫原子可經-OH或鹵素取代,且C6-C10芳基及C3-C12雜芳基可各自獨立地未經取代或在其一或多個氫原子處經-
OH、-C1-C4烷基、-OC1-C4烷基、-CF3或鹵素取代};Q係C=O;R1係-H或-C1-C4烷基;R2係-H、-OH、鹵素或不存在{限制條件係在Y係C時,R2係-H、-OH或鹵素,且在Y係N時,R2不存在};且n為3。
由式I代表之化合物展示於下表1至3中:
在本發明中,上表1至3中所闡述之化合物或其醫藥上可接受之鹽較佳地選自由以下組成之群:化合物1102、1124、1188、1189、1190、1209、1221、1224、1241及1243,且更佳地選自以下組成之群:化合物1102、1124、1188及1209。
如本文中所使用,術語「醫藥上可接受之鹽」意指通常用於醫藥領域中之任一鹽。醫藥上可接受之鹽之實例包括(但不限於)含有無機離子(例如鈣離子、鉀離子、鈉離子或鎂離子)之鹽、使用無機酸(例如鹽酸、硝酸、磷酸、溴酸、碘酸、高氯酸或硫酸)形成之鹽、使用有機酸(例如乙酸、三氟乙酸、檸檬酸、馬來酸、琥珀酸、草酸、苯甲酸、酒石酸、富馬酸、苦杏仁酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、麩胺酸、戊二酸、葡糖醛酸、天門冬胺酸、抗壞血酸、碳酸、香草酸或氫碘酸)形成之鹽、使用磺酸(例如甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸或萘磺酸)形成之鹽、使用胺基酸(例如甘胺酸、精胺酸或離胺酸)形成之鹽及使用胺(例如三甲胺、三乙胺、氨、吡啶或甲吡啶)形成之鹽。
式I化合物可含有一或多個不對稱碳,且由此可以外消旋物、外消旋混合物、單一對映異構體、非對映異構體混合物及個別非對映異構體之形式存在。可藉由業內已知方法(例如管柱層析或HPLC)將式I化合物分離成該等異構體。或者,可藉由立體特異性合成使用具有已知構形之光學純起始材料及/或試劑來合成式I化合物之個別立體異構體。
本發明提供用於預防或治療組織蛋白去乙醯酶介導之疾病之醫藥組合物,其含有由下式I代表之化合物、其光學異構體或其醫藥上可接受之鹽作為活性成份。
其中R1、R2、A、B、X、Y、Q及n係如上文所定義。
組織蛋白去乙醯酶介導之疾病之實例包括細胞增殖性疾病,例如惡性腫瘤疾病,例如癌症;發炎性疾病,例如發炎性腸病、克羅恩氏病或潰瘍性腸炎;體染色體顯性疾病,例如亨廷頓氏病、唐氏症候群、愛德華氏症候群或巴陶氏症候群;遺傳性代謝疾病,例如糖尿病、尼曼匹克氏病、高雪氏病、苯丙酮尿、威爾森氏症;或纖維化疾病,例如囊性纖維化、肝纖維化、腎纖維化、肺纖維化或皮膚纖維化;自體免疫疾病,例如類風濕性關節炎、氣喘、狼瘡、牛皮癬、牛皮癬關節炎、多發性硬化、貝切特氏病或器官移植排斥;急性/慢性神經性疾病,例如中風或多囊性腎病;肥大,例如心肥大;心臟衰竭,例如鬱血性心臟衰竭或出血性心臟衰竭;眼部疾病,例如青光眼、乾眼症候群、乾性黃斑部退化、濕性黃斑部退化、糖尿病視網膜病變或眼色素層炎;神經退化疾病,例如阿茲海默氏病、肌肉萎縮性脊髓側索硬化症、恰克-馬利-杜斯氏症或脊髓性肌萎縮以及藉由HDAC酶之異常功能引起之病狀及疾病。
醫藥上可接受之鹽係如上文針對藉由本發明式I代表之化合物之醫藥上可接受之鹽所闡述。
對於投與而言,除式I化合物、其異構體或其醫藥上可接受之鹽外,本發明之醫藥組合物可進一步含有至少一種醫藥上可接受之載劑。本發明中所使用之醫藥上可接受之載劑可為生理鹽水、無菌水、林格氏溶液(Ringer solution)、緩衝鹽水、右旋糖溶液、麥芽糊精溶液、甘油、乙醇中之至少一者及其兩者或更多者之混合物。若需要,
則組合物可含有其他習用添加劑,例如抗氧化劑、緩衝劑或抑菌劑。另外,可使用稀釋劑、分散劑、表面活性劑、黏合劑及潤滑劑將組合物調配成可注射調配物,例如溶液、懸浮液、渾濁流體等、丸劑、膠囊、粒劑或錠劑。因此,本發明組合物可呈貼劑、液體、丸劑、膠囊、粒劑、錠劑、栓劑等形式。該等調配物可藉由用於業內調配物之習用方法或藉由Remington's Pharmaceutical Science(最新版),Mack Publishing Company,Easton PA中所揭示之方法來製備。
端視預期用途,本發明之醫藥組合物可經口或非經腸(例如經靜脈內、經皮下、經腹膜腔內或局部)投與。醫藥組合物之劑量端視以下因素而有所變化:患者之體重、年齡、性別、健康狀況及飲食、投與時間、投與模式、***速率、疾病嚴重程度及諸如此類。本發明之式I化合物之日劑量可約為1mg/kg至500mg/kg、較佳地5mg/kg至100mg/kg,且可每天投與一次至若干次。
除藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽外,本發明之醫藥組合物可進一步含有一或多種與其展現相同或類似醫學效能之活性成份。
本發明亦提供預防或治療組織蛋白去乙醯酶介導之疾病之方法,其包含投與治療有效量之藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽。
如本文中所使用,術語「治療有效量」係指有效預防或治療組織蛋白去乙醯酶介導之疾病之藉由式I代表之化合物之量。
本發明亦提供抑制組織蛋白去乙醯酶(HDAC)之方法,其係藉由向哺乳動物(包括人類)投與藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽來達成。
根據本發明預防或治療組織蛋白去乙醯酶介導之疾病之方法包括在症狀發作之前藉由投與藉由式I代表之化合物來抑制或防止疾病
以及解決疾病本身。在管控疾病時,特定活性成份之預防或治療劑量隨疾病或病狀之性質及嚴重程度有所變化,且亦可根據藉由投與活性成份之途徑而有所變化。該劑量及劑量頻率亦根據個別患者之年齡、體重及反應而有所變化。適宜投藥方案可易於由熟習此項技術者適當考慮該等因素來予以選擇。另外,根據本發明預防或治療組織蛋白去乙醯酶介導之疾病之方法可進一步包含投與治療有效量之有助於與藉由式I代表之化合物一起治療疾病的另一活性劑,其中另一活性劑可與式I化合物展現協同或輔助效應。
本發明亦意欲提供藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽用以製備用於治療組織蛋白去乙醯酶介導之疾病之藥劑的用途。為製備藥劑,可將藉由式I代表之化合物與醫藥上可接受之佐劑、稀釋劑、載劑或諸如此類混合,且與其他活性劑組合,從而該等活性成份可具有協同效應。
除非彼此抵觸,否則可適當組合本發明之用途、組合物及治療方法中所提及之特定化學物質。
本發明亦提供製備藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽之方法。現參照下列反應圖1至10來闡述該等製備方法。
如上文反應圖1中所展示,使用6-胺基己酸甲酯鹽酸鹽、7-胺基
庚酸甲酯鹽酸鹽或8-胺基辛酸甲酯鹽酸鹽(式1-2)對式1-1化合物實施脲形成反應以合成式1-3化合物。向式1-3化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1102、1240及1257。
另外,使式1-3化合物(其中引入7-胺基庚酸甲酯)與碘甲烷進行反應以合成式1-4化合物。向式1-4化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1213。
如上文反應圖2中所展示,使用7-胺基庚酸甲酯鹽酸鹽(式1-2)對式2-1化合物實施脲形成反應以合成式2-2化合物,然後與4M鹽酸溶液進行反應以去除胺基保護基團(Boc),由此合成式2-5化合物。使式2-3化合物與亞硫醯氯進行反應以合成式2-4化合物,然後使用式2-5化合物實施取代反應以合成式2-6化合物。向式2-6化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1223、1224、1647及1648。
[反應圖3]
如上文反應圖3中所展示,使用硼氫化鈉還原式3-1化合物以合成式3-2化合物,然後與甲磺醯氯進行反應以合成式3-3化合物。使用式2-5化合物對式3-3化合物實施取代反應以合成式3-4化合物。然後,向式3-4化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1222。
如上文反應圖4中所展示,使用(2S,6R)-2,6-二甲基六氫吡嗪(式4-2)對式4-1化合物實施取代反應以合成式4-3化合物,然後使用7-胺基
庚酸甲酯鹽酸鹽實施脲形成反應以合成式4-4化合物。然後,向式4-4化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1188。
另外,使式4-1化合物與A-Boc化合物進行反應,且然後使用4M鹽酸溶液進行處理以去除保護基團(Boc),由此合成式4-6化合物。使用式1-2化合物對式4-6化合物實施脲形成反應以合成式4-7化合物。然後,向式4-7化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1189、1190、1763及1764。
如反應圖5中所展示,使用(氯亞甲基)二苯(式4-1)對式5-1化合物實施取代反應以合成式5-2化合物,然後使用氫氧化鋰(LiOH)水解以合成式5-3化合物。使用6-胺基己酸甲酯鹽酸鹽、7-胺基庚酸甲酯鹽酸鹽或8-胺基辛酸甲酯鹽酸鹽對式5-3化合物實施醯胺偶合以合成式5-4化合物。然後,向式5-4化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1209、1316及1317。
另外,使式5-4化合物(其中引入7-胺基庚酸甲酯)與碘甲烷進行反
應以合成式5-5化合物。然後,向式5-5化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1256。
如上文反應圖6中所展示,使用苯胺對式6-1化合物實施還原胺化以合成式6-2化合物,然後實施Buckwald反應以合成式6-3化合物。使式6-3化合物與4M鹽酸溶液進行反應以去除胺基保護基團(Boc),且然後與飽和碳酸氫鈉溶液進行反應以合成式6-5化合物。使用7-胺基庚酸甲酯鹽酸鹽(式1-2)對式6-5化合物實施脲形成反應以合成式6-6化合物。然後,向式6-6化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1221、1719、1726及1734。
[反應圖7]
如反應圖7中所展示,使式7-1化合物與氯甲酸4-硝基苯基酯(式7-2)進行反應以合成式7-3化合物,然後使用7-胺基庚酸甲酯鹽酸鹽(式1-2)實施取代反應以合成式7-4化合物。然後,向式7-4化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1124。
另外,使用7-胺基庚酸甲酯鹽酸鹽(式1-2)對式7-1化合物實施脲形成反應以合成式7-4化合物,然後與二乙基胺基三氟化硫(DAST)進行反應以合成式7-5化合物。然後,向式7-5化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1649。
[反應圖8]
如上文反應圖8中所展示,使式8-1化合物與三氟甲烷磺酸甲酯(式8-2)進行反應以合成式8-3化合物。使式8-3化合物與二苯基(六氫吡啶-4-基)甲醇(式7-1)進行反應以合成式8-4化合物,然後與三氟甲烷磺酸甲酯(式8-2)進行反應以合成式8-5化合物。使式8-5化合物與7-胺基庚酸甲酯鹽酸鹽(式1-2)進行反應以合成式8-6化合物。然後,向式8-6化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1210。
如上文反應圖9中所展示,使用苯乙酮對式2-5化合物實施還原胺化以合成式9-2化合物。然後,向式9-2化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1241。
[反應圖10]
如上文反應圖10中所展示,使用苯乙酮對式10-1化合物實施還原胺化以合成式10-2化合物,然後使用氫氧化鋰(LiOH)水解以合成式10-3化合物。使用7-胺基庚酸甲酯鹽酸鹽對式10-3化合物實施醯胺偶合以合成式10-4化合物。然後,向式10-4化合物中添加氫氧化鉀(KOH)、甲醇及羥胺水溶液並在室溫下進行反應,由此合成最終化合物1243。
本發明之藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽可選擇性抑制HDAC,且由此對組織蛋白去乙醯酶介導之疾病之預防或治療展現優良效應。
圖1展示分析化合物1102對於佐劑誘導性關節炎模型中之關節炎之緩和之效應的結果。
在下文中,呈現較佳實例以有助於理解本發明。然而,該等實例僅提供用於更佳地理解本發明且並不意欲限制本發明範圍。
除非另外指定,否則下文所提及之試劑及溶劑係購自Sigma-Aldrich及TCI,且使用Waters e2695實施HPLC。對於用於管柱層析之矽膠,使用來自Merck之矽膠(230-400網目)。使用Bruker 400MHz量
測1H-NMR數據,且使用Agilent 1100系列獲得質譜。
步驟1:7-(4-二苯甲基六氫吡嗪-1-甲醯胺基)庚酸甲酯(式1-3)之合成
在室溫下,將1-二苯甲基六氫吡嗪(0.200g,0.793mmol)、7-胺基庚酸甲酯(0.151g,0.951mmol)、三光氣(0.118g,0.396mmol)及DIPEA(0.415mL,2.378mmol)溶於二氯甲烷(5mL)中,且將溶液在同一溫度下攪拌1小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(Waters,C18;1%-甲酸(formic acid、methanoic acid)水溶液/乙腈=100%至20%)純化濃縮物且藉由通過SPE柱(PL-HCO3樹脂)來進行濃縮,由此獲得淺黃色油狀物形式之式1-3之期望化合物(0.075g,21.6%)。
步驟2:4-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡嗪-1-甲醯胺(化合物1102)之合成
在室溫下,將式1-3化合物(0.075g,0.171mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.210mL,3.428mmol)及氫氧化鉀(0.096g,1.714mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌30分鐘。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫
鈉飽和水溶液(20mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥,由此獲得黃色固體形式之期望化合物1102(0.047g,62.5%)。
1H NMR(400MHz,DMSO-d6)δ 9.39(brs,1 H),7.42(d,4 H,J=7.2Hz),7.29(t,4 H,J=7.5Hz),7.18(t,2 H,J=7.3Hz),6.40(t,1 H,J=5.3Hz),4.28(s,1 H),3.27(s,4 H),2.98-2.93(m,2 H),2.08(s,4 H),1.89(t,2 H,J=7.3Hz),1.44-1.43(m,2 H),1.34-1.33(m,2 H),1.20(s,4 H);MS(ESI)m/z 439.6(M++H)。
步驟1:4-(羥基二苯基甲基)六氫吡啶-1-甲酸4-硝基苯基酯(式7-3)之合成
在0℃下,將二苯基(六氫吡啶-4-基)甲醇(0.100g,0.374mmol)及三乙胺(0.104mL,0.748mmol)溶於二氯甲烷(5mL)中,且向溶液中添加氯甲酸4-硝基苯基酯(0.083g,0.411mmol),隨後在同一溫度下攪拌1小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=0%至20%)純化濃縮物並濃縮,由此獲得無色油狀物形式之式7-3之期望化合物(0.152g,94.0%)。
步驟2:7-(4-(羥基二苯基甲基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式7-4)之合成
在室溫下,將式7-3化合物(0.152g,0.351mmol,在步驟1中製得)、7-胺基庚酸甲酯鹽酸鹽(0.280g,1.757mmol)及碳酸鉀(0.097g,0.703mmol)溶於N,N-二甲基甲醯胺(5mL)中,且將溶液在100℃下攪拌17小時。然後,將溫度降至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑,且藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=10%至40%)純化濃縮物並濃縮,由此獲得橙色油狀物形式之式7-4化合物(0.075g,39.4%)。
步驟3:N-(7-(羥基胺基)-7-側氧基庚基)-4-(羥基二苯基甲基)六氫吡啶-1-甲醯胺(化合物1124)
在室溫下,將式7-4化合物(0.075g,0.166mmol,在步驟2中製得)、羥胺(50.00%水溶液,0.203mL,3.314mmol)及氫氧化鉀(0.093g,1.657mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。過濾沈澱之固體,使用己烷洗滌,並乾燥以提供白色固體形式之期望化合物1124(0.007g,9.3%)。
1H NMR(400MHz,DMSO-d6)δ 9.36(brs,1 H),7.52(d,4 H,J=
7.6Hz),7.27(t,4 H,J=7.7Hz),7.13(t,2 H,J=7.3Hz),6.30(t,1 H,J=5.3Hz),5.32(brs,1 H),3.94(d,2 H,J=13.4Hz),2.99-2.94(m,2 H),2.67-2.58(m,3 H),1.91(t,2 H,J=7.4Hz),1.48-1.46(m,2 H),1.35-1.34(m,2 H),1.30-1.25(m,6 H)。
步驟1:(3S,5R)-1-二苯甲基-3,5-二甲基六氫吡嗪(化合物4-3)之合成
在室溫下,將(2R,6S)-2,6-二甲基六氫吡嗪(1.000g,8.757mmol)、(氯亞甲基)二苯(3.550g,17.515mmol)及碳酸鉀(6.052g,43.787mmol)溶於N,N-二甲基甲醯胺(10mL)中,且將溶液在同一溫度下攪拌17小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;甲醇/二氯甲烷=0%至10%)純化濃縮物並濃縮以提供白色固體形式之式4-3之期望化合物(0.798g,32.5%)。
步驟2:7-((2S,6R)-4-二苯甲基-2,6-二甲基六氫吡嗪-1-甲醯胺基)庚酸甲酯(式4-4)之合成
在0℃下,將三光氣(0.159g,0.535mmol)及二異丙胺(0.561mL,3.210mmol)溶於二氯甲烷(5mL)中,且向溶液中添加7-胺基庚酸甲酯鹽酸鹽(0.251g,1.284mmol),隨後在同一溫度下攪拌。向反應混合
物中添加在步驟1中製得之式4-3化合物(0.300g,1.070mmol),隨後在同一溫度下攪拌30分鐘。向反應混合物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至30%)純化濃縮物並濃縮以提供白色固體形式之式4-4之期望化合物(0.212g,42.6%)。
步驟3:(2S,6R)-4-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)-2,6-二甲基六氫吡嗪-1-羧基醯胺(化合物1188)之合成
在室溫下,將式4-4化合物(0.100g,0.215mmol,在步驟2中製得)、羥胺(50.00%水溶液,0.263mL,4.295mmol)及氫氧化鉀(0.121g,2.148mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液(30mL),隨後攪拌。過濾沈澱之固體,使用水洗滌並乾燥以提供白色固體形式之期望化合物1188(0.099g,98.8%)。
1H NMR(400MHz,DMSO-d6)δ 7.51(d,4 H,J=7.5Hz),7.30(t,4 H,J=7.6Hz),7.19(t,2 H,J=7.3Hz),6.23(t,1 H,J=5.3Hz),4.23(s,1 H),3.94(brs,2 H),3.03-2.98(m,2 H),2.60(d,2 H,J=10.9Hz),1.96-1.90(m,4 H),1.46-1.45(m,2 H),1.38-1.36(m,2 H),1.26-1.22(m,10 H)。
步驟1:(R)-4-二苯甲基-2-甲基六氫吡嗪-1-甲酸第三丁基酯(式4-5)之合成
在室溫下,將(R)-2-甲基六氫吡嗪-1-甲酸第三丁基酯(1.000g,4.993mmol)、(氯亞甲基)二苯(2.024g,9.986mmol)及碳酸鉀(3.450g,24.965mmol)溶於N,N-二甲基甲醯胺(10mL)中,且將溶液在80℃下攪拌17小時且然後冷卻至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至10%)純化濃縮物並濃縮以提供白色固體形式之式4-5之期望化合物(0.813g,44.4%)。
步驟2:(R)-1-二苯甲基-3-甲基六氫吡嗪(式4-6)之合成
在室溫下,將式4-5化合物(0.813g,2.218mmol,在步驟1中製得)溶於二氯甲烷(10mL)中且向溶液中添加鹽酸(4.00M二噁烷溶液,5.546mL,22.183mmol),隨後在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。獲得白色固體形式之式4-6之期望化合物(0.590g,99.8%),其並未進一步純化。
步驟3:(R)-7-(4-二苯甲基-2-甲基六氫吡嗪-1-甲醯胺基)庚酸甲酯(式4-7)之合成
在0℃下,將三光氣(0.167g,0.563mmol)及DIPEA(1.180mL,6.757mmol)溶於二氯甲烷(5mL)中,且向溶液中添加7-胺基庚酸甲酯鹽酸鹽(0.264g,1.351mmol),隨後在同一溫度下攪拌。向反應混合物中添加式4-6化合物(0.300g,1.126mmol),隨後在同一溫度下攪拌30分鐘。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至30%)純化濃縮物並濃縮。然後,藉由層析(Waters,C18;1%-甲酸水溶液/乙腈=75%至5%)再次純化濃縮物並藉由通過SPE柱(PL-HCO3樹脂)來進行濃縮以提供式4-7之期望化合物(0.106g,20.8%)。
步驟4:(R)-4-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)-2-甲基六氫吡嗪-1-甲醯胺(化合物1189)之合成
在室溫下,將式4-7化合物(0.100g,0.221mmol,在步驟3中製得)、羥胺(50.00%水溶液,0.271mL,4.429mmol)及氫氧化鉀(0.124g,2.214mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉水溶液(30mL),隨後攪拌。過濾沈澱之固體,使用水洗滌並乾燥以提供白色固體形式之期望化合物1189(0.099g,98.8%)。
1H NMR(400MHz,DMSO-d6)δ 9.42(brs,2 H),7.45(t,4 H,J=
6.3Hz),7.30(t,4 H,J=7.6Hz),7.19(t,2 H,J=6.8Hz),6.36-6.34(m,1 H),4.23(s,1 H),4.04(brs,1H),3.62(d,1 H,J=12.4Hz),3.01-2.93(m,3 H),2.67(d,1 H,J=9.6Hz),2.60(d,1 H,J=10.8Hz),1.95(dd,1 H,J=11.0,3.0Hz),1.88(t,2 H,J=7.3Hz),1.78(t,1 H,J=10.1Hz),1.44-1.43(m,2 H),1.36-1.35(m,2 H),1.20-1.18(m,7 H)。
步驟1:(S)-4-二苯甲基-2-甲基六氫吡嗪-1-甲酸第三丁基酯(式4-5)之合成
在室溫下,將(S)-2-甲基六氫吡嗪-1-甲酸第三丁基酯(1.000g,4.993mmol)、(氯亞甲基)二苯(2.024g,9.986mmol)及碳酸鉀(3.450g,24.965mmol)溶於N,N-二甲基甲醯胺(10mL)中,且將溶液在80℃下攪拌17小時,且然後冷卻至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至10%)純化濃縮物並濃縮以提供白色固體形式之式4-5之期望化合物(0.742g,40.5%)。
步驟2:(S)-1-二苯甲基-3-甲基六氫吡嗪(式4-6)之合成
在室溫下,將式4-5化合物(0.742g,2.025mmol,在步驟1中製得)溶於二氯甲烷(10mL)中,且向溶液中添加鹽酸(4.00M二噁烷溶液,5.061mL,20.246mmol),隨後在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。產物(0.530g,98.3%,白色固體)未經額外純化即使用。
步驟3:(S)-7-(4-二苯甲基-2-甲基六氫吡嗪-1-甲醯胺基)庚酸甲酯(式4-7)之合成
在0℃下,將三光氣(0.111g,0.375mmol)及DIPEA(0.582g,4.505mmol)溶於二氯甲烷(5mL)中,且向溶液中添加7-胺基庚酸甲酯鹽酸鹽(0.176g,0.901mmol),隨後在同一溫度下攪拌。向反應混合物中添加式4-6化合物(0.200g,0.751mmol,在步驟2中製得),隨後在同一溫度下攪拌30分鐘。向反應混合物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至30%)純化濃縮物並濃縮以提供淺黃色油狀物形式之4-7之期望化合物(0.213g,62.8%)。
步驟4:(S)-4-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)-2-甲基六氫吡嗪-1-甲醯胺(化合物1190)之合成
在室溫下,將式4-7化合物(0.100g,0.221mmol,在步驟3中製得)、羥胺(50.00%水溶液,0.271mL,4.429mmol)及氫氧化鉀(0.124g,2.214mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉水溶液(30mL),隨後攪拌。過濾沈澱之固體,使用水洗滌並乾燥以提供淺橙色固體形式之期望化合物1190(0.093g,92.8%)。
1H NMR(400MHz,DMSO-d6)δ 9.43(brs,2 H),7.45(t,4 H,J=6.3Hz),7.30(t,4 H,J=7.6Hz),6.35(t,1 H,J=5.5Hz),4.23(s,1 H),4.04(brs,1 H),3.62(d,1 H,J=12.6Hz),3.03-2.92(m,3 H),2.67(d,1 H,J=10.6Hz),2.60(d,1 H,J=11.2Hz),1.95(dd,1 H,J=11.1,3.1Hz),1.88(t,2 H,J=7.4Hz),1.80-1.75(m,1 H),1.45-1.43(m,2 H),1.36-1.34(m,2 H),1.20-1.18(m,7 H)。
步驟1:1-二苯甲基六氫吡啶-4-甲酸乙酯(式5-2)之合成
將六氫吡啶-4-甲酸乙酯(3.000g,19.083mmol)、(氯亞甲基)二苯(5.802g,28.624mmol)及碳酸鉀(13.187g,95.414mmol)溶於N,N-二甲基甲醯胺(50mL)中且,將溶液在室溫下攪拌17小時,且然後在80℃下攪拌3小時。然後,將溶液冷卻至室溫以終止反應。在減壓下濃縮
反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,40g柱;乙酸乙酯/己烷=0%至15%)純化濃縮物並濃縮以提供無色油狀物形式之式5-2之期望化合物(1.410g,22.8%)。
步驟2:1-二苯甲基六氫吡啶-4-甲酸(式5-3)之合成
在室溫下,將式5-2化合物(1.410g,4.360mmol,在步驟1中製得)及LiOH(0.209g,8.719mmol)溶於甲醇(10mL)/水(5mL)中,且將溶液在60℃下攪拌17小時,且然後冷卻至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑,且然後使用1N鹽酸水溶液中和並在減壓下濃縮以去除溶劑。產物(1.300g,101.0%,白色固體)未經額外純化即使用。
步驟3:7-(1-二苯甲基六氫吡啶-4-甲醯胺基)庚酸甲酯(式5-4)之合成
在室溫下,將式5-3化合物(1.500g,5.078mmol,在步驟2中製得)、7-胺基庚酸甲酯鹽酸鹽(1.988g,10.156mmol)、EDC(1.947g,10.156mmol)、HBOt(1.372g,10.156mmol)及二異丙胺(4.435mL,25.391mmol)溶於二氯甲烷(30mL)中,且將溶液在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過
濾且然後在減壓下濃縮。藉由管柱層析(SiO2,40g柱;乙酸乙酯/己烷=0%至40%)純化濃縮物並濃縮以提供無色油狀物形式之式5-4之期望化合物(1.810g,81.6%)。
步驟4:1-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡啶-4-甲醯胺(化合物1209)之合成
在0℃下,將式5-4化合物(1.000g,2.290mmol,在步驟3中製得)、羥胺(50.00%水溶液,2.802mL,45.809mmol)及氫氧化鉀(1.285g,22.904mmol)溶於甲醇(15mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。
獲得淺橙色固體形式之期望化合物1209(1.000g,99.8%),其未經額外純化。
1H NMR(400MHz,DMSO-d6)δ 7.71(t,1 H,J=5.4Hz),7.40(d,4 H,J=7.3Hz),7.27(t,4 H,J=7.5Hz),7.16(t,2 H,J=7.3Hz),4.25(s,1 H),2.98(q,2 H,J=6.4Hz),2.79(d,2 H,J=11.0Hz),2.09~2.02(m,1 H),1.89(t,2 H,J=7.3Hz),1.77(t,2 H,J=9.8Hz),1.66~1.59(m,4 H),1.45~1.39(m,2 H),1.34~1.32(m,2 H),1.29~1.27(m,4 H);MS(ESI)m/z 438.2(M++H)。
步驟1:三氟甲烷磺酸1-((1H-咪唑-1-基)磺醯基)-3-甲基-1H-咪唑-3-鎓(式8-3)之合成
在室溫下,將1,1'-磺醯基雙(1H-咪唑)(5.000g,25.227mmol)及三氟甲烷磺酸甲酯(2.855mL,25.227mmol)溶於二氯甲烷(100mL)中,且將溶液在同一溫度下攪拌3小時。過濾沈澱之固體並乾燥以提供淺黃色油狀物形式之式8-3之期望化合物(5.160g,45.3%)。
步驟2:(1-((1H-咪唑-1-基)磺醯基)六氫吡啶-4-基)二苯基甲醇(式8-4)之合成
在室溫下,將二苯基(六氫吡啶-4-基)甲醇(1.000g,3.740mmol)及式8-3化合物(2.033g,5.610mmol,在步驟1中製得)溶於乙腈(20mL)中,且將溶液在同一溫度下攪拌17小時。在減壓下濃縮反應混合物,且藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至40%)純化濃縮物並濃縮以提供白色固體形式之式8-4之期望化合物(0.487g,32.8%)。
步驟3:(1-((3-甲基-1H-3l4-咪唑-1-基)磺醯基)六氫吡啶-4-基)二苯基甲醇三氟甲烷磺酸酯(式8-5)之合成
在0℃下,將式8-4化合物(0.487g,1.225mmol,在步驟2中製得)及三氟甲烷磺酸甲酯(0.146mL,1.286mmol)溶於二氯甲烷(10mL)中,且將溶液在室溫下攪拌2小時。過濾沈澱之固體,使用二氯甲烷
洗滌並乾燥以提供白色固體形式之式8-5之期望化合物(0.670g,97.4%)。
步驟4:7-((4-(羥基二苯基甲基)六氫吡啶)-1-磺醯胺基)庚酸甲酯(式8-6)之合成
在80℃下,將式8-5化合物(0.504g,0.897mmol,在步驟3中製得)及7-胺基庚酸甲酯鹽酸鹽(0.228g,1.167mmol)溶於乙腈(3mL)中,且將溶液在同一溫度下攪拌12小時,且然後冷卻至室溫以終止反應。向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=10%至60%)純化濃縮物並濃縮以提供白色固體形式之式8-6之期望化合物(0.147g,33.5%)。
步驟5:N-羥基-7-((4-(羥基二苯基甲基)六氫吡啶)-1-磺醯胺基)庚醯胺(化合物1210)之合成
在室溫下,將式8-6化合物(0.150g,0.307mmol,在步驟4中製得)、氫氧化鉀(0.172g,3.070mmol)及羥胺(50.00%溶液,0.188mL,3.070mmol)溶於甲醇(1mL)中,且將溶液在同一溫度下攪拌1小時。向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水
溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。獲得白色固體形式之期望化合物1210(0.067g,44.6%)且未經額外純化即使用。
1H NMR(400MHz,DMSO-d6)δ 10.34(s,1 H),8.68(s,1 H),7.52(d,4 H,J=7.4Hz),7.26(t,4 H,J=7.6Hz),7.12(m,3 H),3.46(m,2 H),2.82(m,2 H),2.63(m,3 H),1.93(t,2 H,J=7.3Hz),1.48-1.22(m,13 H);MS(ESI)m/z 490.6(M++H)。
步驟1:7-(4-二苯甲基-N-甲基六氫吡嗪-1-甲醯胺基)庚酸甲酯(式1-4)之合成
在0℃下,將7-(4-二苯甲基六氫吡嗪-1-甲醯胺基)庚酸甲酯(0.100g,0.229mmol)及氫化鈉(60.00%,0.046g,1.143mmol)溶於N,N-二甲基甲醯胺(3mL)中,且向溶液中添加碘甲烷(0.071mL,1.143mmol),隨後在同一溫度下攪拌10分鐘。向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=10%至40%)純化濃縮物並濃縮以提供無色油狀物形式之式1-4之期望化合物(0.097g,94.0%)。
步驟2:4-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)-N-甲基六氫吡嗪-1-甲醯胺(化合物1213)之合成
在室溫下,將式1-4化合物(0.097g,0.215mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.263mL,4.296mmol)及氫氧化鉀(0.121g,2.148mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。獲得白色固體形式之期望化合物1213(0.010g,10.3%),其未經額外純化。
1H NMR(400MHz,CD3OD)δ 7.44(d,4 H,J=7.4Hz),7.27(t,4 H,J=7.5Hz),7.17(t,2 H,J=7.3Hz),4.26(s,1 H),3.24-3.22(m,4 H),3.17(t,2 H,J=7.2Hz),2.81(s,3 H),2.41-2.38(m,4 H),2.07(t,2 H,J=7.4Hz),1.62-1.52(m,4 H),1.33-1.24(m,4 H);MS(ESI)m/z 453.4(M++H)。
步驟1:N,N-二苯基六氫吡啶-4-胺鹽酸鹽(式6-4)之合成
在室溫下,將4-(二苯基胺基)六氫吡啶-1-甲酸第三丁基酯(1.000g,2.837mmol)溶於二氯甲烷(10mL)中,且向溶液中添加鹽酸(4.00M 1,4-二噁烷溶液,3.546mL,14.185mmol),隨後在同一溫度下攪拌17小時。過濾沈澱之固體,使用二氯甲烷洗滌並乾燥以提供白色固體形式之式6-4之期望化合物(0.800g,97.6%)。
步驟2:N,N-二苯基六氫吡啶-4-胺(式6-5)之合成
在室溫下,將式6-4化合物(0.600g,2.077mmol,在步驟1中製得)溶於水(5mL)中,且向溶液中添加碳酸氫鈉飽和水溶液(50mL),隨後在同一溫度下攪拌1小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。產物(0.496g,94.6%,無色油狀物)未經額外純化即使用。
步驟3:7-(4-(二苯基胺基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式6-6)之合成
在0℃下,將式6-5化合物(0.100g,0.396mmol,在步驟2中製得)、7-胺基庚酸甲酯鹽酸鹽(0.078g,0.396mmol)、三光氣(0.059g,0.198mmol)及DIPEA(0.415mL,2.378mmol)溶於二氯甲烷(3mL)中,且將溶液在同一溫度下攪拌1小時。然後,在0℃下,向反應混合物中添加碳酸氫鈉飽和水溶液(50mL),隨後攪拌10分鐘。在完成反應之後,向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=10%至60%)純化濃縮物並濃縮以提供淺黃色油狀物形式之式6-6之期望化合物(0.096g,55.4%)。
步驟4:4-(二苯基胺基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡啶-1-甲醯胺(化合物1221)之合成
在室溫下,將式6-6化合物(0.096g,0.219mmol,在步驟3中製得)、羥胺(50.00%水溶液,0.268mL,4.388mmol)及氫氧化鉀(0.123g,2.194mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液(20mL)及二氯甲烷(5mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥以提供白色固體形式之期望化合物1221(0.076g,79.0%)。
1H NMR(400MHz,DMSO-d6)δ 7.27(t,4 H,J=7.8Hz),6.97(t,2 H,J=7.2Hz),6.79(d,4 H,J=7.8Hz),6.35(t,1 H,J=5.4Hz),4.10-4.04(m,1 H),3.97(d,2 H,J=13.1Hz),2.90(q,2 H,J=6.4Hz),2.78(t,2 H,J=12.5Hz),1.90(t,2 H,J=7.3Hz),1.84(d,2 H,J=12.5Hz),1.46-1.39(m,2 H),1.31-1.27(m,2 H),1.17-1.10(m,4 H),1.08-1.01(m,2 H)。
步驟1:二(吡啶-2-基)甲醇(式3-2)之合成
在0℃下,將二(吡啶-2-基)甲酮(2.000g,10.858mmol)溶於甲醇(20mL)中,且向溶液中添加NaBH4(0.452g,11.944mmol),隨後在同一溫度下攪拌1小時。然後,在0℃下,向反應混合物中添加碳酸氫鈉
飽和水溶液(10mL),隨後攪拌10分鐘。在完成反應之後,向反應混合物中添加水,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。獲得紅色油狀物形式之式3-2之期望化合物(2.000g,98.9%)且未經額外純化即使用。
步驟2:甲烷磺酸二(吡啶-2-基)甲酯(式3-3)之合成
在0℃下,將式3-2化合物(1.000g,5.370mmol,在步驟1中製得)、甲磺醯氯(0.623mL,8.055mmol)及三乙胺(2.246mL,16.111mmol)溶於二氯甲烷(10mL)中,且將溶液在同一溫度下攪拌1小時。向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至30%)純化濃縮物並濃縮以提供粉紅色固體形式之式3-3之期望化合物(0.670g,47.2%)。
步驟3:7-(4-(二(吡啶-2-基)甲基)六氫吡嗪-1-甲醯胺基)庚酸甲酯(式3-4)之合成
在室溫下,將式3-3化合物(0.258g,0.975mmol,在步驟2中製得)、式2-5化合物(0.200g,0.650mmol)及碳酸鉀(0.449g,3.249mmol)溶於N,N-二甲基甲醯胺(4mL)中,且將溶液在80℃下攪拌17小時且然後冷卻至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液
洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;甲醇/二氯甲烷=0%至10%)純化濃縮物並濃縮以提供橙色油狀物形式之式3-4之期望化合物(0.255g,89.3%)。
步驟4:4-(二(吡啶-2-基)甲基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡嗪-1-甲醯胺(化合物1222)之合成
在室溫下,將式3-4化合物(0.255g,0.580mmol,在步驟3中製得)、羥胺(50.00%水溶液,0.710mL,11.603mmol)及氫氧化鉀(0.326g,5.801mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且藉由管柱層析(Waters,C18;1%-甲酸水溶液/乙腈水溶液=70%至5%)純化濃縮物並藉由通過SPE柱(PL-HCO3樹脂)來進行濃縮,由此獲得白色固體形式之期望化合物1222(0.051g,20.0%)。
1H NMR(400MHz,DMSO-d6)δ 8.46(dt,2 H,J=4.8,0.8Hz),7.77(td,2 H,J=7.7,1.7Hz),7.62(d,2 H,J=7.8Hz),7.25-7.22(m,2 H),6.40(t,1 H,J=5.2Hz),4.64(s,1 H),3.28-3.27(m,4 H),2.96(q,2 H,J=6.6Hz),2.25(t,4 H,J=4.7Hz),1.92(t,2 H,J=7.3Hz),1.48-1.43(m,2 H),1.35-1.33(m,2 H),1.21-1.20(m,4 H)。
步驟1:4-((7-甲氧基-7-側氧基庚基)胺甲醯基)六氫吡嗪-1-甲酸第三丁基酯(式2-2)之合成
在0℃下,將三光氣(4.780g,16.107mmol)及二異丙胺(16.879mL,96.644mmol)溶於二氯甲烷(100mL)中,且向溶液中添加7-胺基庚酸甲酯鹽酸鹽(6.304g,32.215mmol),隨後在同一溫度下攪拌。向反應混合物中添加六氫吡嗪-1-甲酸第三丁基酯(6.000g,32.215mmol),隨後在同一溫度下攪拌1小時。然後,在0℃下,向反應混合物中添加碳酸氫鈉飽和水溶液(100mL),隨後攪拌10分鐘。在完成反應之後,向反應混合物中添加水,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,80g柱;甲醇/二氯甲烷=0%至5%)純化濃縮物並濃縮以提供淺黃色油狀物形式之式2-2之期望化合物(3.430g,28.7%)。
步驟2:7-(六氫吡嗪-1-甲醯胺基)庚酸甲酯鹽酸鹽(式2-5)之合成
在室溫下,將式2-2化合物(3.430g,9.233mmol,在步驟1中製得)溶於二氯甲烷(50mL)中,且向溶液中添加鹽酸(4.00M二噁烷溶液,11.542mL,46.167mmol),隨後在同一溫度下攪拌17小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加乙酸乙酯(50mL),隨後攪拌。過濾沈澱之固體,使用乙酸乙酯洗滌並乾燥以提供白色固體形式之式2-5之期望化合物(2.300g,80.9%)。
步驟3:4,4'-(氯亞甲基)雙(氟苯)(式2-4)之合成
將雙(4-氟苯基)甲醇(5.000g,22.706mmol)溶於二氯甲烷(50mL)中,且將溶液在室溫下攪拌4小時,且向其中添加亞硫醯氯(1.812mL,
24.976mmol)。然後,將溶液在40℃下攪拌2小時,且然後冷卻至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑。作為產物,獲得橙色油狀物形式之式2-4之期望化合物(5.350g,98.7%)且未經額外純化即使用。
步驟4:7-(4-(雙(4-氟苯基)甲基)六氫吡嗪-1-甲醯胺基)庚酸甲酯(式2-6)之合成
在室溫下,將式2-4化合物(0.233g,0.975mmol,在步驟3中製得)、7-(六氫吡嗪-1-甲醯胺基)庚酸甲酯鹽酸鹽(0.200g,0.650mmol)及碳酸鉀(0.449g,3.249mmol)溶於N,N-二甲基甲醯胺(4mL)中,且將溶液在80℃下攪拌17小時,且然後冷卻至室溫以終止反應。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;甲醇/二氯甲烷=0%至10%)純化濃縮物並濃縮以提供淺褐色油狀物形式之式2-6之期望化合物(0.101g,32.8%)。
步驟5:4-(雙(4-氟苯基)甲基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡嗪-1-甲醯胺(化合物1223)之合成
在室溫下,將式2-6化合物(0.101g,0.213mmol,在步驟4中製得)、羥胺(50.00%水溶液,0.261mL,4.266mmol)及氫氧化鉀(0.120g,2.133mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且藉由管柱層析(Waters,C18;1%-甲酸水溶液/乙腈=70%至5%)純化濃縮物並藉由通過SPE柱(PL-HCO3樹脂)來進行濃縮以提供白色固體形式之期望化合物1223(0.002g,2.0%)。
1H NMR(400MHz,CD3OD)δ 7.48-7.44(m,4 H),7.04(t,4 H,J=8.8Hz),6.44(t,1 H,J=5.3Hz),4.31(s,1 H),3.39(t,4 H,J=5.0Hz),3.16-3.12(m,2 H),2.36(t,4 H,J=5.0Hz),2.09(t,2 H,J=7.4Hz),1.64-1.61(m,2 H),1.51-1.48(m,2 H),1.35-1.33(m,4 H);MS(ESI)m/z 475.3(M++H)。
步驟1:4,4'-(氯亞甲基)雙(氯苯)(式2-4)之合成
在0℃下,將雙(4-氯苯基)甲醇(10.000g,39.507mmol)溶於二氯甲烷(100mL)中,且向溶液中添加亞硫醯氯(3.153mL,43.458mmol),隨後在室溫下攪拌5小時。在減壓下濃縮反應混合物以去除溶劑。獲得白色固體形式之式2-4之期望化合物(10.700g,99.7%),其未經額外純化。
步驟2:7-(4-(雙(4-氯苯基)甲基)六氫吡嗪-1-甲醯胺基)庚酸甲酯(式2-6)之合成
在室溫下,將式2-4化合物(0.265g,0.975mmol,在步驟1中製得)、式2-5化合物(0.200g,0.650mmol)及碳酸鉀(0.449g,3.249mmol)溶於N,N-二甲基甲醯胺(4mL)中,且將溶液在80℃下攪拌17小時,且然後冷卻至一溫度以終止反應。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加水,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;甲醇/二氯甲烷=0%至10%)純化濃縮物並濃縮以提供淺黃色油狀物形式之式2-6之期望化合物(0.271g,82.4%)。
步驟3:4-(雙(4-氯苯基)甲基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡嗪-1-甲醯胺(化合物1224)之合成
在室溫下,將式2-6化合物(0.271g,0.535mmol,在步驟2中製得)、羥胺(50.00%水溶液,0.655mL,10.702mmol)及氫氧化鉀(0.300g,5.351mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且藉由管柱層析(Waters,C18;1%-甲酸水溶液/乙腈=70%至5%)純化濃縮物並藉由通過SPE柱(PL-HCO3樹脂)來進行濃縮以提供白色固體形式之期望化合物1224
(0.035g,12.9%)。
1H NMR(400MHz,DMSO-d6)δ 10.34(brs,1 H),8.69(brs,1 H),7.43(d,4 H,J=8.6Hz),7.37(d,4 H,J=8.4Hz),6.41(t,1 H,J=5.3Hz),4.40(s,1 H),3.28-3.27(m,4 H),2.96(q,2 H,J=6.4Hz),2.22-2.21(m,4 H),1.92(t,2 H,J=7.4Hz),1.48-1.44(m,2 H),1.37-1.35(m,2 H),1.24-1.21(m,4 H);MS(ESI)m/z 507.4(M++H)。
步驟1:8-(4-二苯甲基六氫吡嗪-1-羧基醯胺基)辛酸甲酯(式1-3)之合成
在0℃下,將三光氣(0.118g,0.396mmol)及二異丙胺(0.830mL,4.755mmol)溶於二氯甲烷(5mL)中,且向溶液中添加8-胺基辛酸甲酯鹽酸鹽(0.166g,0.793mmol),隨後攪拌1小時。向反應混合物中添加起始材料(0.200g,0.793mmol),隨後在同一溫度下攪拌1小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=10%至70%)純化濃縮物並濃縮以提供淺黃色固體形式之式1-3之期望化合物(0.158g,44.1%)。
步驟2:4-二苯甲基-N-(8-(羥基胺基)-8-側氧基乙基1)六氫吡嗪-1-甲醯胺(化合物1240)之合成
在室溫下,將式1-3化合物(0.158g,0.350mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.428mL,6.997mmol)及氫氧化鉀(0.196g,3.499mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌30分鐘。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液(20mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥以提供白色固體形式之期望化合物1240(0.074g,46.7%)。
1H NMR(400MHz,DMSO-d6)δ 9.49(brs,2 H),7.43(d,4 H,J=7.5Hz),7.30(t,4 H,J=7.6Hz),7.19(t,2 H,J=7.3Hz),6.42(t,1 H,J=5.2Hz),4.29(s,1 H),3.28-3.27(m,4 H),2.97(q,2 H,J=6.4Hz),2.23-2.22(m,4 H),1.90(t,2 H,J=7.3Hz),1.47-1.44(m,2 H),1.37-1.34(m,2 H),1.22(brs,4 H);MS(ESI)m/z 453.6(M++H)。
步驟1:7-(4-(1-苯基乙基)六氫吡嗪-1-甲醯胺基)庚酸甲酯(式9-2)之合成
將式2-5化合物(0.150g,0.553mmol)及苯乙酮(0.100g,0.829mmol)溶於二氯甲烷(3mL)中,且將溶液在室溫下攪拌10分鐘。然後,向溶液中添加NaBH(OAc)3(0.234g,1.106mmol),隨後在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;甲醇/二氯甲
烷=0%至5%)純化濃縮物並濃縮以提供無色油狀物形式之式9-2之期望化合物(0.038g,18.3%)。
步驟2:N-(7-(羥基胺基)-7-側氧基庚基)-4-(1-苯基乙基)六氫吡嗪-1-甲醯胺(化合物1241)之合成
在室溫下,將式9-2化合物(0.038g,0.101mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.124mL,2.024mmol)及氫氧化鉀(0.057g,1.012mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌30分鐘。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。獲得淺橙色固體形式之期望化合物1241(0.013g,34.1%),其未經額外純化。
1H NMR(400MHz,DMSO-d6)δ 7.32-7.30(m,4 H),7.26-7.23(m,1 H),3.71-3.34(m,5 H),3.11(t,2 H,J=7.1Hz),2.50-2.45(m,2 H),2.37-2.32(m,2 H),2.05(t,2 H,J=7.4Hz),1.61-1.56(m,2 H),1.49-1.44(m,2 H),1.37(d,3 H,J=7.6Hz),1.33-1.29(m,4 H);MS(ESI)m/z 477.2(M++H)。
步驟1:1-(1-苯基乙基)六氫吡啶-4-甲酸乙酯(式10-2)之合成
在室溫下,將苯乙酮(1.050g,8.739mmol)及六氫吡啶-4-甲酸乙酯(1.751mL,11.361mmol)溶於二氯甲烷(10mL)中,且向溶液中添加STAB(2.408g,11.361mmol),隨後在同一溫度下攪拌12小時。向反
應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供無色油狀物形式之式10-2之期望化合物(0.700g,30.6%)。
步驟2:1-(1-苯基乙基)六氫吡啶-4-甲酸(式10-3)之合成
在40℃下,將式10-2化合物(0.700g,2.678mmol,在步驟1中製得)及LiOH(0.096g,4.017mmol)溶於甲醇(3mL)/水(1mL)中,且將溶液在同一溫度下攪拌5小時,且然後冷卻至室溫。然後,在0℃下,向反應混合物中添加1M HCl,隨後攪拌10分鐘。在完成反應之後,向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。產物(0.500g,69.2%,白色泡狀固體)未經額外純化即使用。
步驟3:7-(1-(1-苯基乙基)六氫吡啶-4-甲醯胺基)庚酸甲酯(式10-4)之合成
在室溫下,將式10-3化合物(0.300g,1.286mmol,在步驟2中製得)、7-胺基庚酸甲酯鹽酸鹽(0.503g,2.572mmol)、EDC(0.493g,2.572mmol)、HOBt(0.347g,2.572mmol)及二異丙胺(1.123mL,6.429mmol)溶於二氯甲烷(4mL)/N,N-二甲基甲醯胺(1mL)中,且將溶液在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g
柱;甲醇/二氯甲烷=0%至10%)純化濃縮物並濃縮以提供褐色油狀物形式之式10-4之期望化合物(0.122g,25.3%)。
步驟4:N-(7-(羥基胺基)-7-側氧基庚基)-1-(1-苯基乙基)六氫吡啶-4-甲醯胺(化合物1243)之合成
在室溫下,將式10-4化合物(0.122g,0.326mmol,在步驟3中製得)、羥胺(50.00%水溶液,0.398mL,6.515mmol)及氫氧化鉀(0.183g,3.257mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌30分鐘。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。獲得橙色固體形式之期望化合物1243(0.074g,60.5%),其未經額外純化。
1H NMR(400MHz,DMSO-d6)δ 10.19(brs,1 H),8.71(brs,1 H),7.64(t,1 H,J=5.6Hz),7.32-7.27(m,4 H),7.23-7.20(m,1 H),3.40-3.37(m,1 H),3.00-2.95(m,3 H);MS(ESI)m/z 376.3(M++H)。
步驟1:7-(1-二苯甲基-N-甲基六氫吡啶-4-甲醯胺基)庚酸甲酯(式5-5)之合成
將7-(1-二苯甲基六氫吡啶-4-甲醯胺基)庚酸甲酯(0.200g,0.458mmol)及氫化鈉(60.00%,0.092g,2.290mmol)溶於N,N-二甲基甲醯胺(5mL)中,且將溶液在室溫下攪拌10分鐘。然後,向經攪拌溶液中添
加碘甲烷(0.143mL,2.290mmol),隨後在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=10%至70%)純化濃縮物並濃縮以提供淺黃色油狀物形式之式5-5之期望化合物(0.089g,43.1%)。
步驟2:1-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)-N-甲基六氫吡啶-4-甲醯胺(化合物1256)之合成
在室溫下,將式5-5化合物(0.089g,0.198mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.242mL,3.950mmol)及氫氧化鉀(0.111g,1.975mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。獲得白色固體形式之期望化合物1256(0.089g,99.8%),其未經額外純化。
1H NMR(400MHz,DMSO-d6)δ 9.50(brs,2 H),7.40(d,4 H,J=7.2Hz),7.29(t,4 H,J=7.6Hz),7.18(t,2 H,J=7.3Hz),4.30(s,1 H),3.23(q,2 H,J=7.5Hz),2.94(s,2 H),2.81(d,2 H,J=11.4Hz),2.76(s,1 H),1.91-1.83(m,4 H),1.69-1.53(m,4 H),1.46-1.37(m,4 H),1.24-1.19(m,4 H);MS(ESI)m/z 452.6(M++H)。
步驟1:6-(4-二苯甲基六氫吡嗪-1-甲醯胺基)己酸甲酯(式1-3)之合成
在0℃下,將三光氣(0.294g,0.991mmol)及二異丙胺(2.076mL,11.888mmol)溶於二氯甲烷(10mL)中,且向溶液中添加6-胺基己酸甲酯鹽酸鹽(0.360g,1.981mmol),隨後在同一溫度下攪拌。向反應混合物中添加1-二苯甲基六氫吡嗪(0.500g,1.981mmol),隨後在同一溫度下攪拌1小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至40%)純化濃縮物並濃縮以提供黃色油狀物形式之式1-3之期望化合物(0.320g,38.1%)。
步驟2:4-二苯甲基-N-(6-(羥基胺基)-6-側氧基己基)六氫吡嗪-1-甲醯胺(化合物1257)之合成
在室溫下,將式1-3化合物(0.200g,0.472mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.578mL,9.444mmol)及氫氧化鉀(0.265g,4.722mmol)溶於甲醇(5mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。獲得淺黃色固體形式之期望化合物1257(0.049g,24.4%),其未經額外純化。
1H NMR(400MHz,DMSO-d6)δ 7.43(d,4 H,J=7.2Hz),7.30(t,4 H,J=7.6Hz),7.19(t,2 H,J=7.3Hz),6.42(t,1 H,J=5.4Hz),4.29(s,1 H),3.27(t,4 H,J=4.5Hz),2.96(q,2 H,J=6.4Hz),2.23(t,4 H,J=4.6Hz),1.90(t,2 H,J=7.4Hz),1.47-1.44(m,2 H),1.38-1.34(m,2 H),1.20-1.16(m,2 H);MS(ESI)m/z 425.5(M++H)。
步驟1:6-(1-二苯甲基六氫吡啶-4-甲醯胺基)己酸甲酯(式5-4)之合成
在室溫下,將式5-3化合物(0.300g,1.016mmol)、6-胺基己酸甲酯鹽酸鹽(0.369g,2.031mmol)、EDC(0.389g,2.031mmol)、HOBt(0.274g,2.031mmol)及二異丙胺(0.887mL,5.078mmol)溶於二氯甲烷(3mL)/N,N-二甲基甲醯胺(0.5mL)中,且將溶液在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至30%)純化濃縮物並濃縮以提供淺黃色油狀物形式之式5-4之期望化合物(0.161g,37.5%)。
步驟2:1-二苯甲基-N-(6-(羥基胺基)-6-側氧基己基)六氫吡啶-4-甲醯胺(化合物1316)之合成
在室溫下,將式5-4化合物(0.161g,0.381mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.466mL,7.620mmol)及氫氧化鉀(0.214g,3.810mmol)溶於甲醇(3mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。獲得白色固體形式之期望化合物1316(0.056g,34.7%),其未經額外純化。
1H NMR(400MHz,DMSO-d6)δ 10.33(brs,1 H),8.66(brs,1 H),7.70(t,1 H,J=5.6Hz),7.41(d,4 H,J=7.4Hz),7.17(t,2 H,J=7.4Hz),4.26(s,2 H),2.99-2.28(m,2 H),2.80(d,2 H,J=11.5Hz),2.09-2.02(m,1 H),1.91(t,2 H,J=7.5Hz),1.80-1.75(m,2 H),1.68-1.59(m,4 H)。
步驟1:8-(1-二苯甲基六氫吡啶-4-甲醯胺基)辛酸甲酯(式5-4)之合成
在室溫下,將式5-3化合物(0.300g,1.016mmol)、8-胺基辛酸甲酯鹽酸鹽(0.426g,2.031mmol)、EDC(0.389g,2.031mmol)、HOBt(0.274g,2.031mmol)及二異丙胺(0.887mL,5.078mmol)溶於二氯甲烷(3mL)/N,N-二甲基甲醯胺(0.5mL)中,且將溶液在同一溫度下攪拌17小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至30%)純化濃縮物並濃縮以提供無色油狀物形式之式5-4之期
望化合物(0.220g,49.6%)。
步驟2:1-二苯甲基-N-(8-(羥基胺基)-8-側氧基乙基)六氫吡啶-4-甲醯胺(化合物1317)之合成
在室溫下,將式5-4化合物(0.220g,0.488mmol,在步驟1中製得)、羥胺(50.00%水溶液,0.597mL,9.764mmol)及氫氧化鉀(0.274g,4.882mmol)溶於甲醇(5mL)中,且將溶液在同一溫度下攪拌1小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加碳酸氫鈉飽和水溶液(20mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥以提供白色固體形式之期望化合物1317(0.189g,85.7%)。
1H NMR(400MHz,DMSO-d6)δ 9.46(brs,2 H),7.73(t,1 H,J=5.3Hz),7.41(d,4 H,J=8.0Hz),7.28(t,4 H,J=7.5Hz),7.17(t,2 H,J=7.3Hz),4.26(s,1 H),2.99(q,2 H,J=6.4Hz),2.80(d,2 H,J=11.1Hz),2.10-2.04(m,1 H),1.87(t,2 H,J=7.3Hz),1.78(t,2 H,J=10.0Hz),1.67-1.56(m,4 H),1.46-1.42(m,2 H),1.36-1.33(m,2 H),1.21(brs,6 H)。
步驟1:2,2'-(氯亞甲基)雙(氟苯)(式2-4)之合成
在室溫下,將雙(2-氟苯基)甲醇(0.500g,2.270mmol)及三乙胺(0.348mL,2.498mmol)溶於二氯甲烷(5mL)中,且向溶液中添加甲磺醯氯(0.193mL,2.498mmol),隨後在同一溫度下攪拌18小時。向反應
混合物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至5%)純化濃縮物並濃縮以提供無色油狀物形式之式2-4之期望化合物(0.290g,53.5%)。
步驟2:7-(4-(雙(2-氟苯基)甲基)六氫吡嗪-1-甲醯胺基)庚酸甲酯(式2-6)之合成
在80℃下,將式2-4化合物(0.448g,1.877mmol,在步驟1中製得)、7-(六氫吡嗪-1-基)庚酸甲酯鹽酸鹽(0.746g,2.816mmol)及碳酸鉀(1.297g,9.386mmol)溶於N,N-二甲基甲醯胺(8mL)中,且將溶液在同一溫度下攪拌16小時,且然後冷卻至室溫以終止反應。向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至60%)純化濃縮物並濃縮以提供亮黃色固體形式之式2-6之期望化合物(0.170g,19.1%)。
步驟3:4-(雙(2-氟苯基)甲基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡嗪-1-甲醯胺(化合物1647)之合成
在0℃下,將式2-6化合物(0.200g,0.422mmol,在步驟2中製得)及羥胺(50.00%水溶液,0.258mL,4.223mmol)溶於甲醇(5mL)中,且
將溶液在室溫下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加甲醇(10mL)及碳酸氫鈉飽和水溶液(90mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥以提供白色固體形式之期望化合物1647(0.200g,99.8%)。
1H NMR(400MHz,DMSO-d 6 )δ 7.59-7.55(m,2 H),7.31-7.26(m,2 H),7.23-7.19(m,2 H),7.16-7.11(m,2 H),6.42(t,1 H,J=5.5Hz),4.96(s,1 H),3.29-3.28(m,4 H),2.99-2.94(m,2 H),2.28-2.26(m,4 H),1.93-1.89(m,2 H),1.47-1.43(m,2 H),1.37-1.33(m,2 H),1.19-1.20(m,4 H);MS(ESI)m/z 475.4(M++H)。
步驟1:3,3'-(氯亞甲基)雙(氟苯)(式2-4)之合成
將雙(3-氟苯基)甲醇(1.000g,4.541mmol)及三乙胺(0.696mL,4.995mmol)溶於二氯甲烷(10mL)中,且向溶液中添加甲磺醯氯(0.387mL,4.995mmol),隨後在同一溫度下攪拌18小時。向反應混合物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至5%)純化濃縮物並濃縮以提供無色油狀物形式之式2-4之期望化合物(0.670g,61.8%)。
步驟2:7-(4-(雙(3-氟苯基)甲基)六氫吡嗪-1-甲醯胺基)庚酸酯(式2-6)之合成
在80℃下,將式2-4化合物(0.670g,2.807mmol,在步驟1中製得)、7-(六氫吡嗪-1-基)庚酸甲酯鹽酸鹽(1.115g,4.211mmol)及碳酸鉀(1.940g,14.037mmol)溶於N,N-二甲基甲醯胺(10mL)中,且將溶液在同一溫度下攪拌16小時,且然後冷卻至室溫以終止反應。向反應混合物中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,24g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供白色固體形式之式2-6之期望化合物(0.294g,22.1%)。
步驟3:4-(雙(3-氟苯基)甲基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡嗪-1-甲醯胺(化合物1648)之合成
在0℃下,將式2-6化合物(0.100g,0.211mmol,在步驟2中製得)及羥胺(50.00%水溶液,0.129mL,2.112mmol)溶於甲醇(3mL)中,且將溶液在室溫下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加甲醇(10mL)及碳酸氫鈉飽和水溶液(90mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥以提供白色固體形式之期望化合物1648(0.097g,97.1%)。
1H NMR(400MHz,DMSO-d 6 )δ 10.34(s,1 H),8.72(s,1 H),7.38-7.33(m,2 H),7.28-7.25(m,4 H),7.06-7.01(m,2 H),6.40(t,1 H,
J=5.5Hz),4.41(s,1 H),3.29-3.27(m,4 H),2.99-2.94(m,2 H),2.24-2.22(m,4 H),1.93-1.90(m,2 H),1.47-1.44(m,2 H),1.37-1.33(m,2 H),1.21-1.20(m,4 H);MS(ESI)m/z 475.4(M++H)。
步驟1:7-(4-(羥基二苯基甲基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式7-4)之合成
在0℃下,將7-胺基庚酸甲酯鹽酸鹽(0.366g,1.870mmol)及三光氣(0.277g,0.935mmol)溶於二氯甲烷(10mL)中,且向溶液中添加N,N-二異丙基乙胺(0.977mL,5.610mmol),隨後攪拌1小時。向反應混合物中添加二苯基(六氫吡啶-4-基)甲醇(0.500g,1.870mmol),隨後在同一溫度下攪拌1小時。向反應混合物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供無色油狀物形式之式7-4之期望化合物(0.609g,71.9%)。
步驟2:7-(4-(氟二苯基甲基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式7-5)之合成
在0℃下,將式7-4化合物(0.300g,0.663mmol,在步驟1中製得)溶於二氯甲烷(5mL)中,且向溶液中添加二乙基胺基三氟化硫(DAST,
0.114mL,0.862mmol),隨後在室溫下攪拌16小時。向反應混合物中添加水,隨後使用二氯甲烷萃取。經由塑膠過濾器過濾萃取物以去除固體殘餘物及水層,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供白色固體形式之式7-5之期望化合物(0.143g,47.5%)。
步驟3:4-(氟二苯基甲基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡啶-1-甲醯胺(化合物1649)之合成
在0℃下,將式7-5化合物(0.140g,0.308mmol,在步驟2中製得)及羥胺(50.00%水溶液,0.188mL,3.080mmol)溶於甲醇(3mL)中,且將溶液在室溫下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加甲醇(10mL)及碳酸氫鈉飽和水溶液(90mL),隨後攪拌。過濾沈澱之固體,使用水洗滌,並乾燥以提供白色固體形式之期望化合物1649(0.122g,87.0%)。
1H NMR(400MHz,DMSO-d 6 )δ 7.49-7.47(m,4 H),7.37-7.33(m,4 H),7.26-7.22(m,2 H),6.36(t,1 H,J=5.5Hz),3.95-3.92(m,2 H),2.98-2.79(m,3 H),2.65-2.59(m,2 H),1.93-1.89(m,2 H),1.47-1.44(m,2 H),1.36-1.33(m,2 H),1.29-1.20(m,8 H);MS(ESI)m/z 456.6(M++H)。
步驟1:4-(苯基胺基)六氫吡啶-1-甲酸第三丁基酯(式6-2)之合成
在室溫下,將4-側氧基六氫吡啶-1-甲酸第三丁基酯(5.000g,25.094mmol)、苯胺(2.749mL,30.113mmol)及乙酸(2.155mL,37.641mmol)溶於二氯甲烷(50mL)中,且向溶液中添加三乙醯氧基硼氫化鈉(5.850g,27.604mmol),隨後在同一溫度下攪拌16小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。向濃縮物中添加乙酸乙酯(100mL),隨後攪拌。過濾沈澱之固體,使用己烷洗滌並乾燥以提供白色固體形式之式6-2之期望化合物(4.640g,66.9%)。
步驟2:4-((3-氟苯基)(苯基)胺基)六氫吡啶-1-甲酸第三丁基酯(式6-3)之合成
在110℃下,將式6-2化合物(0.500g,1.809mmol,在步驟1中製得)、1-氟-3-碘苯(0.422g,1.900mmol)、乙酸鈀(II,0.016g,0.072mmol)、2,2'-雙(二苯基膦基)-1,1'-聯萘基(0.051g,0.081mmol)及第三丁醇鉀(0.254g,2.261mmol)溶於甲苯(5mL)中,且將溶液在同一溫度下攪拌16小時,且然後冷卻至室溫以終止反應。經由矽藻土墊過濾反應混合物以去除固體,且向濾液中添加氯化鈉飽和水溶液,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至10%)純化濃縮物並濃縮以提供黃色固體形式之式6-3之期望化合物(0.292g,43.6%)。
步驟3:N-(3-氟苯基)-N-苯基六氫吡啶-4-胺鹽酸鹽(式6-4)之合成
在同一溫度下,將式6-3化合物(0.285g,0.769mmol,在步驟2中製得)溶於二氯甲烷(10mL)中,且向溶液中添加氯化氫(4.00M溶液於二噁烷中,0.962mL,3.846mmol),隨後在同一溫度下攪拌16小時。在減壓下濃縮反應混合物以去除溶劑。產物(0.212g,89.8%,黃色固體)未經額外純化即使用。
步驟4:7-(4-((3-氟苯基)(苯基)胺基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式6-6)之合成
在0℃下,將7-胺基庚酸甲酯鹽酸鹽(0.135g,0.691mmol)及三光氣(0.103g,0.345mmol)溶於二氯甲烷(10mL)中,且向溶液中添加N,N-二異丙基乙胺(0.361mL,2.073mmol),隨後在同一溫度下攪拌。向反應混合物中添加式6-4化合物(0.212g,0.691mmol,在步驟3中製得),隨後在室溫下攪拌3小時。然後,向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供無色油狀物形式之式6-6之期望化合物(0.219g,69.6%)。
步驟5:4-((3-氟苯基)(苯基)胺基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡啶-1-甲醯胺(化合物1719)之合成
在0℃下,將式6-6化合物(0.219g,0.481mmol,在步驟4中製得)、羥胺(50.00%水溶液,0.294mL,4.807mmol)及氫氧化鉀(0.270g,4.807mmol)溶於甲醇(5mL)中,且將溶液在室溫下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加甲醇(1mL)及碳酸氫鈉飽和水溶液(30mL),隨後攪拌。過濾沈澱之固體,使用己烷洗滌並乾燥以提供白色固體形式之期望化合物1719(0.196g,89.3%)。
1H NMR(400MHz,DMSO-d 6 )δ 7.44-7.42(m,2 H),7.32-7.28(m,1 H),7.16-7.10(m,1 H),7.05-7.03(m,2 H),6.51-6.46(m,1 H),6.37-6.32(m,3 H),4.10-4.08(m,1 H),3.97-3.94(m,2 H),2.92-2.87(m,2 H),2.83-2.77(m,2 H),1.92-1.88(m,2 H),1.85-1.52(m,2 H),1.45-1.41(m,2 H),1.30-1.27(m,2 H),1.16-1.08(m,4 H),1.06-1.00(m,2 H);MS(ESI)m/z 457.5(M++H)。
步驟1:4-(苯基(4-(三氟甲基)苯基)胺基)六氫吡啶-1-甲酸第三丁基酯(式6-3)之合成
在110℃下,將4-(苯基胺基)六氫吡啶-1-甲酸第三丁基酯(1.000g,3.618mmol)、1-碘-4-(三氟甲基)苯(1.033g,3.799mmol)、乙酸鈀(II,
0.032g,0.145mmol)、2,2'-雙(二苯基膦基)-1,1'-聯萘基(0.101g,0.163mmol)及第三丁醇鉀(0.507g,4.523mmol)溶於甲苯(5mL)中,且將溶液在同一溫度下攪拌16小時,且然後冷卻至室溫以終止反應。經由矽藻土墊過濾反應混合物以去除固體,且向濾液中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至10%)純化濃縮物並濃縮以提供褐色油狀物形式之式6-3之期望化合物(0.040g,2.9%)。
步驟2:N-苯基-N-(4-(三氟甲基)苯基)六氫吡啶-4-胺鹽酸鹽(式6-4)之合成
在室溫下,將式6-3化合物(0.890g,2.494mmol,在步驟1中製得)溶於二氯甲烷(20mL)中,且向溶液中添加鹽酸(4.00M溶液,3.118mL,12.471mmol),隨後在同一溫度下攪拌16小時。在減壓下濃縮反應混合物以去除溶劑。產物(0.890g,100.0%,黃色固體)未經額外純化即使用。
步驟3:7-(4-(苯基(4-(三氟甲基)苯基)胺基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式6-6)之合成
在0℃下,將7-胺基庚酸甲酯鹽酸鹽(0.219g,1.121mmol)及三光
氣(0.166g,0.561mmol)溶於二氯甲烷(10mL)中,且向溶液中添加N,N-二異丙基乙胺(0.586mL,3.363mmol),隨後在同一溫度下攪拌。向反應混合物中添加式6-4化合物(0.400g,1.121mmol),隨後在室溫下攪拌3小時。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供無色油狀物形式之式6-6之期望化合物(0.277g,48.9%)。
步驟4:N-(7-(羥基胺基)-7-側氧基庚基)-4-(苯基(4-(三氟甲基)苯基)胺基)六氫吡啶-1-醯胺(化合物1726)之合成
在室溫下,將式6-6化合物(0.170g,0.336mmol,在步驟3中製得)及羥胺(50.00%水溶液,0.205mL,3.356mmol)溶於甲醇(5mL)中,且向溶液中添加氫氧化鉀(0.188g,3.356mmol),隨後在同一溫度下攪拌18小時。在減壓下濃縮反應混合物以去除溶劑,且過濾沈澱之固體,使用己烷洗滌並乾燥以提供白色固體形式之期望化合物1726(0.139g,81.8%)。
1H NMR(400MHz,DMSO-d 6 )δ 10.33(s,1 H),8.66(s,1 H),7.21-7.16(m,4 H),6.97-6.93(m,2 H),6.84-6.80(m,1 H),6.67-6.65(m,2 H),6.36-6.34(m,1 H),4.07-4.02(m,1 H),3.98-3.95(m,2 H),2.93-2.88(m,2 H),2.81-2.75(m,2 H),1.93-1.89(m,2 H),1.85-1.82(m,2 H),1.45-1.43(m,2 H),1.31-1.27(m,2 H),1.18-1.15
(m,4 H),1.05-1.01(m,2 H);MS(ESI)m/z 457.5(M++H)。
步驟1:4-((4-氟苯基)(苯基)胺基)六氫吡啶-1-甲酸第三丁基酯(式6-3)之合成
在110℃下,將4-(苯基胺基)六氫吡啶-1-甲酸第三丁基酯(0.820g,2.967mmol)、1-氟-4-碘苯(0.358mL,3.115mmol)、乙酸鈀(II,0.027g,0.119mmol)、2,2'-雙(二苯基膦基)-1,1'-聯萘基(0.083g,0.134mmol)及第三丁醇鉀(0.416g,3.709mmol)溶於甲苯(5mL)中,且將溶液在同一溫度下攪拌16小時,且然後冷卻至室溫以終止反應。經由矽藻土墊過濾反應混合物以去除固體,且向濾液中添加水,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,12g柱;乙酸乙酯/己烷=0%至10%)純化濃縮物並濃縮以提供亮黃色固體形式之式6-3之期望化合物(0.352g,32.0%)。
步驟2:N-(4-氟苯基)-N-苯基六氫吡啶-4-胺鹽酸鹽(式6-4)之合成
在室溫下,將式6-3化合物(0.340g,0.918mmol,在步驟1中製得)及鹽酸(4.00M溶液,1.147mL,4.589mmol)溶於二氯甲烷(5mL)中,且將溶液在同一溫度下攪拌18小時。在減壓下濃縮反應混合物以
去除溶劑。產物(0.281g,99.8%,黃色固體)未經額外純化即使用。
步驟3:7-(4-((4-氟苯基)(苯基)胺基)六氫吡啶-1-甲醯胺基)庚酸甲酯(式6-6)之合成
在0℃下,將7-胺基庚酸甲酯鹽酸鹽(0.179g,0.913mmol)及三光氣(0.135g,0.456mmol)溶於二氯甲烷(10mL)中,且向溶液中添加N,N-二異丙基乙胺(0.477mL,2.738mmol),隨後在同一溫度下攪拌。向反應混合物中添加式6-4化合物(0.280g,0.913mmol,在步驟2中製得),隨後在室溫下攪拌3小時。然後,向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;乙酸乙酯/己烷=0%至50%)純化濃縮物並濃縮以提供無色油狀物形式之式6-6之期望化合物(0.185g,44.5%)。
步驟4:4-((4-氟苯基)(苯基)胺基)-N-(7-(羥基胺基)-7-側氧基庚基)六氫吡啶-1-甲醯胺(化合物1734)之合成
在0℃下,將式6-6化合物(0.260g,0.569mmol,在步驟3中製得)及羥胺(50.00%水溶液,0.348mL,5.695mmol)溶於甲醇(5mL)中,且將溶液在室溫下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,
且過濾沈澱之固體,使用己烷洗滌並乾燥以提供白色固體形式之期望化合物1734(0.185g,71.2%)。
1H NMR(400MHz,DMSO-d 6 )δ 10.33(s,1 H),8.66(s,1 H),7.21-7.16(m,4 H),6.97-6.93(m,2 H),6.84-6.80(m,1 H),6.67-6.65(m,2 H),6.36-6.34(m,1 H),4.07-4.02(m,1 H),3.98-3.95(m,2 H),2.93-2.88(m,2 H),2.81-2.75(m,2 H),1.93-1.89(m,2 H),1.85-1.82(m,2 H),1.45-1.43(m,2 H),1.31-1.27(m,2 H),1.18-1.15(m,4 H),1.05-1.01(m,2 H);MS(ESI)m/z 457.5(M++H)。
步驟1:7-二苯甲基-2,7-二氮雜螺[3.5]壬烷-2-甲酸第三丁基酯(式4-5)之合成
在80℃下,將(氯亞甲基)二苯(0.439mL,2.467mmol)、2,7-二氮雜螺[3.5]壬烷-2-甲酸第三丁基酯(0.614g,2.714mmol)及碳酸鉀(1.705g,12.335mmol)溶於N,N-二甲基甲醯胺(10mL)中,且將溶液在同一溫度下攪拌16小時,且然後冷卻至室溫以終止反應。向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用乙酸乙酯萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾且然後在減壓下濃縮。然後,向濃縮物中添加乙酸乙酯(100mL),隨後攪拌,且過濾沈澱之固體,使用乙酸乙酯洗滌並乾燥以提供白色固體形式之式4-5之期望化合物(0.411g,42.4%)。
步驟2:7-二苯甲基-2,7-二氮雜螺[3.5]壬烷鹽酸鹽(式4-6)之合成
在室溫下,將式4-5化合物(0.411g,1.047mmol,在步驟1中製得)溶於二氯甲烷(8mL)中,且向溶液中添加鹽酸(4.00M溶液於二噁烷中,1.309mL,5.235mmol),隨後在同一溫度下攪拌16小時。在減壓下濃縮反應混合物以去除溶劑,且產物(0.344g,99.9%,白色固體)未經額外純化即使用。
步驟3:6-(7-二苯甲基-2,7-二氮雜螺[3.5]壬烷-2-甲醯胺基)己酸甲酯(式4-7)之合成
在0℃下,將6-胺基己酸甲酯鹽酸鹽(0.100g,0.549mmol)及三光氣(0.078g,0.261mmol)溶於二氯甲烷(5mL)中,且向溶液中添加N,N-二異丙基乙胺(0.273mL,1.569mmol),隨後在同一溫度下攪拌。向反應混合物中添加式4-6化合物(0.172g,0.523mmol,在步驟2中製得),隨後在室溫下攪拌3小時。然後,向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;甲醇/二氯甲烷=0%至3%)純化濃縮物並濃縮以提供亮紅色固體形式之式4-7之期望化合物(0.148g,61.0%)。
步驟4:7-二苯甲基-N-(6-(羥基胺基)-6-側氧基己基)-2,7-二氮雜螺[3.5]壬烷-2-甲醯胺(化合物1763)之合成
在室溫下,將式4-7化合物(0.148g,0.319mmol,在步驟3中製得)及羥胺(50.00%水溶液,0.195mL,3.192mmol)溶於甲醇(5mL)中,且將溶液在同一溫度下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加甲醇(1mL)及碳酸氫鈉飽和水溶液(30mL),隨後攪拌。過濾沈澱之固體,使用己烷洗滌並乾燥,且在25℃下自乙酸乙酯(10mL)將所得材料重結晶並過濾。使用己烷洗滌獲得固體並乾燥以提供白色固體形式之期望化合物1763(0.044g,29.7%)。
1H NMR(400MHz,DMSO-d 6 )δ 7.40-7.38(m,4 H),7.29-7.25(m,4 H),7.18-7.14(m,2 H),6.18-6.17(m,1 H),4.26(s,1 H),3.42-3.33(m,4 H),2.91-2.90(m,2 H),2.20-2.19(m,4 H),1.85-1.82(m,2 H),1.65-1.64(m,4 H),1.43-1.40(m,2 H),1.33-1.30(m,2 H),1.19-1.15(m,2 H);MS(ESI)m/z 465.3(M++H)。
步驟1:7-(7-二苯甲基-2,7-二氮雜螺[3.5]壬烷-2-甲醯胺基)庚酸甲酯(式4-7)之合成
在0℃下,將7-胺基庚酸甲酯鹽酸鹽(0.107g,0.549mmol)及三光氣(0.078g,0.261mmol)溶於二氯甲烷(5mL)中,且向溶液中添加N,N-
二異丙基乙胺(0.273mL,1.569mmol),隨後在同一溫度下攪拌。向反應混合物中添加實例26之式4-6化合物(0.172g,0.523mmol,在步驟2中製得),隨後在室溫下攪拌3小時。然後,向反應混合物中添加碳酸氫鈉飽和水溶液,隨後使用二氯甲烷萃取。使用氯化鈉飽和水溶液洗滌有機層,使用無水硫酸鎂乾燥,過濾,且然後在減壓下濃縮。藉由管柱層析(SiO2,4g柱;甲醇/二氯甲烷=0%至3%)純化濃縮物並濃縮以提供亮紅色固體形式之式4-7之期望化合物(0.136g,54.4%)。
步驟2:7-二苯甲基-N-(7-(羥基胺基)-7-側氧基庚基)-2,7-二氮雜螺[3.5]壬烷-2-甲醯胺(化合物1764)之合成
在室溫下,將式4-7化合物(0.136g,0.285mmol,在步驟1中製得)及羥胺(50.00%,0.188g,2.847mmol)溶於甲醇(5mL)中,且將溶液在同一溫度下攪拌3小時。在減壓下濃縮反應混合物以去除溶劑,且向濃縮物中添加甲醇(1mL)及碳酸氫鈉飽和水溶液(30mL),隨後攪拌。過濾沈澱之固體,使用己烷洗滌並乾燥,且在25℃下自乙酸乙酯(10mL)將所得材料重結晶並過濾。使用己烷洗滌獲得固體並乾燥以提供白色固體形式之期望化合物1764(0.021g,15.4%)。
1H NMR(400MHz,DMSO-d 6 )δ 7.40-7.38(m,4 H),7.29-7.25(m,4 H),7.18-7.14(m,2 H),6.16(t,1 H,J=5.5Hz),4.26(s,1 H),3.42-3.41(m,4 H),2.92-2.88(m,2 H),2.19-2.18(m,4 H),1.88-1.84(m,2 H),1.65-1.64(m,4 H),1.43-1.42(m,2 H),1.32-1.31(m,2 H),1.19-1.18(m,4 H);MS(ESI)m/z 479.6(M++H)。
因選擇性HDAC6抑制劑對於引起副效應之HDAC1之抑制選擇性較為重要,故分析HDAC1/6酶選擇性及細胞選擇性(HDAC1:組織蛋白乙醯化;HDAC6:微管蛋白乙醯化)。
1.實驗方法
使用HDAC1螢光藥物篩選分析套組(Enzolifesciences:BML-AK511)及HDAC6人類重組體(Calbiochem:382180),量測測試化合物之HDAC酶抑制能力。對於HDAC1分析使用100nM、1000nM及10000nM濃度進行處理,且對於HDAC6分析使用0.1nM、1nM、10nM、100nM及1000nM濃度進行處理。在37℃下反應60分鐘,且然後使用顯影劑處理並在37℃下反應30分鐘,然後使用FlexStatin3(Molecular Device)量測螢光強度(Ex 390nm;Em 460nm)。
2.實驗結果
實驗結果展示於下表4中。
如上表4中所展示,對照化合物ACY-1215展示48倍選擇性(對於HDAC6為0.01μM且對於HDAC1為0.48μM),化合物1102展示960倍選擇性(對於HDAC6為0.004μM且對於HDAC1為3.84μM),化合物1124展示170倍選擇性(對於HDAC6為0.024μM且對於HDAC1為4.09μM),且化合物1209展示193倍選擇性(對於HDAC6為0.006μM且對於HDAC1為1.16μM),從而表明本發明之新穎衍生物對於HDAC1/6酶展示優良選擇性。
1.實驗方法
將100ul完全弗氏佐劑(complete Freund's adjuvant)(Chondrex)經真皮內注射至每一Lewis大鼠之尾部中以誘導動物模型。自誘導前一
天,基於體重將大鼠分組,且以不同劑量每天一次向大鼠經口投與測試化物,隨後進行評估。
自首次投與測試化合物之日起每週兩次量測臨床評分及體重。將臨床評分記錄為0-4點,且在觀察每一大鼠之腳之後評估總臨床評分(0:正常;且16:最嚴重水腫)。
2.實驗結果
實驗結果展示於圖1中。基於關節水腫之程度來評估測試化合物在關節炎模型中之醫學效應,且較高臨床評分指示較嚴重之水腫程度。
如圖1中所展示,未使用化合物治療之組(媒劑)展示9-11之評分(嚴重水腫),而投與1mg/kg化合物1102之組展示6-8之評分,投與10mg/kg化合物1102之組展示4-6之評分,且投與50mg/kg化合物1102之組展示1-3之評分,從而指示本發明化合物1102緩和關節炎症狀。
本發明之藉由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽可選擇性抑制HDAC,且由此可有效地用於預防或治療組織蛋白去乙醯酶介導之疾病。
Claims (9)
- 一種由下式I代表之化合物、其光學異構體或其醫藥上可接受之鹽,
- 如請求項1之由式I代表之化合物、其光學異構體或其醫藥上可接 受之鹽,其中X係或{其中Z及W各自獨立地係C或N,且Z及W中之至少一者係N,a、b、c及d各自獨立地係1、2或3,且R3、R4、R5及R6各自獨立地係-H或-C1-C4烷基};Y係C或N;A及B各自獨立地係-C1-C4烷基、-C6-C10芳基或-C3-C12雜芳基{其中該-C1-C4烷基之一或多個氫原子可經-OH或鹵素取代,且該-C6-C10芳基或-C3-C12雜芳基可各自獨立地未經取代或在其一或多個氫原子處經-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或鹵素取代};Q係C=O或SO2;R1係-H或-C1-C4烷基;R2係-H、-OH、鹵素或不存在{限制條件係在Y係C時,R2係-H、-OH或鹵素,且在Y係N時,R2不存在};且n為1、2、3或4。
- 如請求項2之由式I代表之化合物、其光學異構體或其醫藥上可接 受之鹽,其中X係{其中Z及W各自獨立地係C或N,Z及W中之至少一者係N,且R3及R4各自獨立地係-H或-C1-C4烷基};Y係C或N;A及B各自獨立地係-C1-C4烷基、-C6-C10芳基或-C3-C12雜芳基{其中該-C1-C4烷基之一或多個氫原子可經-OH或鹵素取代,且該C6-C10芳基及C3-C12雜芳基可各自獨立地未經取代或在其一或多個氫原子處經-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或鹵素取代};Q係C=O;R1係-H或-C1-C4烷基;R2係-H、-OH、鹵素或不存在{限制條件係在Y係C時,R2係-H、-OH或鹵素,且在Y係N時,R2不存在};且n為3。
- 如請求項1之由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽,其中該由式I代表之化合物係選自由下表中所闡述之化合物組成之群:
- 如請求項4之由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽,其中該由式I代表之化合物係選自由下表中所闡述之化合物組成之群:
- 一種醫藥組合物,其用於預防或治療組織蛋白去乙醯酶介導之疾病且包含如請求項1至5中任一項之由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽作為活性成份。
- 如請求項6之醫藥組合物,其中該組織蛋白去乙醯酶介導之疾病係細胞增殖性疾病、發炎性疾病、體染色體顯性疾病、遺傳性代謝疾病、自體免疫疾病、急性/慢性神經性疾病、肥大、心臟衰竭、眼部疾病或神經退化疾病。
- 一種治療組織蛋白去乙醯酶介導之疾病之方法,其包含投與治療有效量之如請求項1至5中任一項之由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽。
- 一種如請求項1至5中任一項之由式I代表之化合物、其光學異構體或其醫藥上可接受之鹽之用途,其用以製備用於治療組織蛋白去乙醯酶介導之疾病之藥劑。
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CN112004539A (zh) * | 2018-04-10 | 2020-11-27 | 株式会社钟根堂 | 用于预防或治疗干眼的组合物 |
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EP3297992B1 (en) | 2020-02-05 |
PT3297992T (pt) | 2020-03-17 |
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DK3297992T3 (da) | 2020-04-20 |
MX2017014953A (es) | 2018-08-15 |
US11420950B2 (en) | 2022-08-23 |
CN108026057A (zh) | 2018-05-11 |
JP2018517693A (ja) | 2018-07-05 |
HK1251556A1 (zh) | 2019-02-01 |
WO2016190630A1 (en) | 2016-12-01 |
EP3297992A4 (en) | 2018-12-26 |
AU2016267872B2 (en) | 2019-01-17 |
RU2683022C1 (ru) | 2019-03-26 |
JP6507267B2 (ja) | 2019-04-24 |
MY195058A (en) | 2023-01-05 |
PH12017501823A1 (en) | 2018-04-23 |
NZ736015A (en) | 2019-04-26 |
CA2985769A1 (en) | 2016-12-01 |
AU2016267872A1 (en) | 2017-10-26 |
KR20160137441A (ko) | 2016-11-30 |
EP3297992A1 (en) | 2018-03-28 |
BR112017024952A2 (pt) | 2018-07-31 |
HRP20200554T1 (hr) | 2020-07-24 |
CN108026057B (zh) | 2021-08-06 |
PH12017501823B1 (en) | 2018-04-23 |
KR101796601B1 (ko) | 2017-11-10 |
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