TWI625331B - 可作為干擾素誘導物之化合物及其組合物及用途 - Google Patents
可作為干擾素誘導物之化合物及其組合物及用途 Download PDFInfo
- Publication number
- TWI625331B TWI625331B TW102130088A TW102130088A TWI625331B TW I625331 B TWI625331 B TW I625331B TW 102130088 A TW102130088 A TW 102130088A TW 102130088 A TW102130088 A TW 102130088A TW I625331 B TWI625331 B TW I625331B
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- Taiwan
- Prior art keywords
- pyrazolo
- butyl
- compound
- pyrimidin
- amine
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 272
- 239000000203 mixture Substances 0.000 title claims description 136
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- 108010050904 Interferons Proteins 0.000 title abstract description 10
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- 239000000411 inducer Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 126
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
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- -1 3- (6- (azetidin-1-yl) hexyl) -5-butyl-1 H -pyrazolo [4,3- d ] pyrimidin-7- Amine Chemical compound 0.000 claims description 58
- FWOBFZXKEUOXAS-UHFFFAOYSA-N 5-butyl-3-(6-pyrrolidin-1-ylhexyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCCN1CCCC1 FWOBFZXKEUOXAS-UHFFFAOYSA-N 0.000 claims description 16
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- HIAVOIORLCZTDY-BTJKTKAUSA-N (z)-but-2-enedioic acid;5-butyl-3-(6-pyrrolidin-1-ylhexyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound OC(=O)\C=C/C(O)=O.C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCCN1CCCC1 HIAVOIORLCZTDY-BTJKTKAUSA-N 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
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- JYODYWBHUFVENY-UHFFFAOYSA-N 1-[5-(7-amino-5-butyl-2h-pyrazolo[4,3-d]pyrimidin-3-yl)pentyl]piperidin-4-ol Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCN1CCC(O)CC1 JYODYWBHUFVENY-UHFFFAOYSA-N 0.000 claims description 3
- TZJRXMAXWCUEAT-UHFFFAOYSA-N 1-[6-(7-amino-5-butyl-2h-pyrazolo[4,3-d]pyrimidin-3-yl)hexyl]piperidin-4-ol Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCCN1CCC(O)CC1 TZJRXMAXWCUEAT-UHFFFAOYSA-N 0.000 claims description 3
- LPKOYEUWMBUNMX-UHFFFAOYSA-N 5-(2-methoxyethyl)-3-(6-piperidin-1-ylhexyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCOC)=NC(N)=C2NN=C1CCCCCCN1CCCCC1 LPKOYEUWMBUNMX-UHFFFAOYSA-N 0.000 claims description 3
- OVUVICOOCAYWBY-UHFFFAOYSA-N 5-(2-methoxyethyl)-3-(6-pyrrolidin-1-ylhexyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCOC)=NC(N)=C2NN=C1CCCCCCN1CCCC1 OVUVICOOCAYWBY-UHFFFAOYSA-N 0.000 claims description 3
- XCWNADLMFXTXPN-UHFFFAOYSA-N 5-butyl-3-(5-piperidin-1-ylpentyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCN1CCCCC1 XCWNADLMFXTXPN-UHFFFAOYSA-N 0.000 claims description 3
- LWOUPCAYSYQBEC-UHFFFAOYSA-N 5-butyl-3-(5-pyrrolidin-1-ylpentyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCN1CCCC1 LWOUPCAYSYQBEC-UHFFFAOYSA-N 0.000 claims description 3
- MVYRFQPEFMPHSQ-UHFFFAOYSA-N 5-butyl-3-[5-(4-fluoropiperidin-1-yl)pentyl]-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCN1CCC(F)CC1 MVYRFQPEFMPHSQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- IUWUVOYEZTXYMD-UHFFFAOYSA-N 5-butyl-3-(7-pyrrolidin-1-ylheptyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCCCN1CCCC1 IUWUVOYEZTXYMD-UHFFFAOYSA-N 0.000 claims description 2
- RMQGPTNSUGXEIB-UHFFFAOYSA-N 5-butyl-3-[6-(4-fluoropiperidin-1-yl)hexyl]-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCCN1CCC(F)CC1 RMQGPTNSUGXEIB-UHFFFAOYSA-N 0.000 claims description 2
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- KEPDVEKCVDFSJA-UHFFFAOYSA-N 5-butyl-3-(6-piperidin-1-ylhexyl)-2h-pyrazolo[4,3-d]pyrimidin-7-amine Chemical compound C12=NC(CCCC)=NC(N)=C2NN=C1CCCCCCN1CCCCC1 KEPDVEKCVDFSJA-UHFFFAOYSA-N 0.000 claims 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
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Abstract
本發明係關於式(I)化合物及其鹽,
其中R1係正-C1-6烷基或C1-2烷氧基C1-2烷基-,R2係鹵基、OH或C1-3烷基,m係具有4、5、6或7之值之整數,n係具有0、1、2或3之值之整數,且p係具有0、1或2之值之整數;其係人類干擾素誘導物。誘導人類干擾素之化合物可用於治療各種病症,例如治療過敏性疾病及其他發炎病況(例如過敏性鼻炎及氣喘)、傳染病及癌症,且亦可用作疫苗佐劑。
Description
本發明係關於化合物、其製備方法、含有其之組合物,且係關於其在各種病症、具體而言過敏性疾病及其他發炎病況(例如過敏性鼻炎及氣喘)、傳染病及癌症之治療中及作為疫苗佐劑之用途。
脊椎動物不斷地受到微生物侵襲之威脅且具有進化之免疫防禦機制以消除感染性病原體。在哺乳動物中,此免疫系統包含兩個分支:先天性免疫及後天性免疫。第一道主體防禦係先天性免疫系統,其由巨噬細胞及樹突細胞介導。後天性免疫涉及在感染晚期病原體之消除且亦能夠產生免疫記憶。後天性免疫因大量淋巴細胞具有已歷經基因重排之抗原特異性受體而具有高度特異性。
在哺乳動物中產生有效先天性免疫反應之關鍵係引起干擾素及其他作用於細胞以誘導多種效應之細胞介素之誘導之機制。在人體中,I型干擾素係由位於染色體9上且編碼至少13種干擾素α(IFNα)異型體及一種干擾素β(IFNβ)異型體之基因編碼之相關蛋白家族。干擾素最初係作為可保護細胞免於病毒感染之物質闡述(Isaacs & Lindemann,J.Virus Interference.Proc.R.Soc.Lon.Ser.B.Biol.Sci.1957:147,258-267)。重組IFNα係首個經批准之生物治療劑且已成為病毒感染及癌症之重要療法。除對細胞之直接抗病毒活性以外,亦已知干擾素係作用於免疫系統之細胞之高效免疫反應調節劑
(Gonzalez-Navajas J.M.等人,Nature Reviews Immunology,2012;2,125-35)。
Toll樣受體(TLR)係人體內經闡述之十種模式識別受體之家族(Gay,N.J.等人,Annu.Rev.Biochem.,2007:45,141-165)。TLR主要由先天性免疫細胞表現,其中其作用係監測感染徵兆之環境且在活化時動員旨在消除侵入病原體之防禦機制。由TLR觸發之早期先天性免疫反應限制感染擴展,同時促發炎細胞介素及趨化因子誘導抗原呈現細胞、B細胞及T細胞之募集及活化。TLR可調節適應性免疫反應之性質以經由樹突細胞活化及細胞介素釋放提供適當保護(Akira S.等人,Nat.Immunol.,2001:2,675-680)。自不同TLR促效劑看到之反應圖譜取決於受活化之細胞類型。
TLR7係位於細胞之內體室(endosomal compartment)中且專門檢測非自身核酸之TLR亞群(TLR3、TLR7、TLR8及TLR9)之成員。TLR7經由識別ssRNA在抗病毒防禦中發揮關鍵作用(Diebold S.S.等人,Science,2004:303,1529-1531;及Lund J.M.等人,PNAS,2004:101,5598-5603)。TLR7在人體中具有受限之表現圖譜且主要由B細胞及漿細胞樣樹突細胞(pDC)表現且在較小程度上由單核細胞表現。漿細胞樣DC係獨特的淋巴樣來源之樹突細胞群(外周血單核細胞(PBMC)為0.2-0.8%),其係分泌高含量反應病毒感染之干擾素-α(IFNα)及干擾素-β(IFNβ)之產生I型干擾素之原代細胞(Liu Y-J,Annu.Rev.Immunol.,2005:23,275-306)。
投與可溶刺激先天性免疫反應(包括經由Toll樣受體活化I型干擾素及其他細胞介素)之小分子化合物可成為治療或預防人類疾病之重要策略。已闡述可在動物及人中誘導干擾素α之TLR7之小分子促效劑(Takeda K.等人,Annu.Rev.Immunol.,2003:21,335-76)。長期以來人們已知可誘導干擾素α之TLR7促效劑包括咪唑并喹啉化合物(例如
咪喹莫特(imiquimod)及瑞喹莫德)、8-羥基鳥嘌呤類似物以及核苷類似物(例如洛索立賓(loxoribine)及7-噻-8-側氧基鳥苷)(Czarniecki.M.,J.Med,Chem.,2008:51,6621-6626;Hedayat M.等人,Medicinal Research Revievws,2012:32,294-325)。此類型免疫調節策略具有識別可用於治療過敏性疾病(Moisan J.等人,Am.J.Physiol.Lung Cell Mol.Physiol.,2006:290,L987-995)、病毒感染(Horcroft N.J.等人,J.Antimicrob.Chemther,2012:67,789-801)、癌症(Krieg A.,Curr.Oncol.Rep.,2004:6(2),88-95)、其他發炎病況(例如應激性腸病)(Rakoff-Nahoum S.,Cell.,2004,23,118(2):229-41)且作為疫苗佐劑(Persing等人,Trends Microbiol.2002:10(10增刊),S32-7之化合物之潛力。
更特定而言,過敏性疾病與偏向Th2之對過敏原之免疫反應相關。Th2反應與IgE含量升高相關,其經由作用於肥大細胞促進對過敏原之過敏性,從而產生(例如)在氣喘及過敏性鼻炎中所看到之症狀。在健康個體中,對過敏原之免疫反應與混合性Th2/Th1細胞反應及調控性T細胞反應更平衡。在活體內過敏性肺模型中已顯示TLR7配體減少Th2細胞介素並增強Th1細胞介素活體外釋放並改善Th2-類型發炎反應(Duechs M.J.,Pulmonary Pharmacology & Therapeutics,2011:24,203-214;Fili L.等人,J.All.Clin.Immunol.,2006:118,511-517;Tao等人,Chin.Med.J.,2006:119,640-648;Van L.P.Eur.J.Immunol.,2011:41,1992-1999)。因此,TLR7配體具有再平衡在過敏性個體中所看到之免疫反應之潛力並改善疾病。使用TLR7促效劑之最近臨床研究已顯示TLR7之重複鼻內刺激在患有過敏性鼻炎及過敏性氣喘二者之患者中產生對過敏原之反應性之持續降低(Greiff L.Respiratory Research,2012:13,53;Leaker B.R.等人,Am.J.Respir.Crit.Care Med.,2012:185,A4184)。
在人類干擾素IFNα之新穎小分子誘導物研究中,已研發出基於用化合物刺激原代人類供體細胞或全血之分析策略來表徵小分子(不論機制)且揭示於本文中。
在第一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正-C1-6烷基或C1-2烷氧基C1-2烷基-;R2係鹵基、羥基或C1-3烷基;m係具有4至7之值之整數;n係具有0至3之值之整數;p係具有0至2之值之整數。
本發明之某些化合物經證實係人類干擾素誘導物且與已知人類干擾素誘導物相比可具有合意之可擴展性特徵。另外,本發明之某些化合物亦可相對於TNFα對IFNα顯示選擇性。誘導人類干擾素之化合物可用於治療各種病症,例如治療過敏性疾病及其他發炎病況(例如過敏性鼻炎及氣喘),治療傳染病及癌症。因此,本發明進一步係關於包含式(I)化合物或其醫藥上可接受之鹽之醫藥組合物。本發明進一步係關於使用式(I)化合物或其醫藥上可接受之鹽、或包含式(I)化合物或其醫藥上可接受之鹽之醫藥組合物治療與其相關之病症之方法。
本發明化合物亦可用作疫苗佐劑。因此,本發明進一步係關於包含式(I)化合物或其醫藥上可接受之鹽及抗原或抗原組合物之疫苗組合物。
本發明之某些化合物係高效免疫調節劑且因此在其處置期間應小心地進行。
圖1 實例21之XRPD繞射圖
圖2 實例22之XRPD繞射圖
在第一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正-C1-6烷基或C1-2烷氧基C1-2烷基-;R2係鹵基、羥基或C1-3烷基;m係具有4至7之值之整數;n係具有0至3之值之整數;p係具有0至2之值之整數。
在又一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正-C3-6烷基或C1-2烷氧基C1-2烷基-;每一R2獨立地代表鹵基、OH或C1-3烷基;m係具有4、5、6或7之值之整數;
n係具有0、1、2或3之值之整數;p係具有0、1或2之值之整數。
在又一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正-C4-6烷基;R2係鹵基或OH;m係具有5、6或7之值之整數;n係具有1、2或3之值之整數;p係具有0或1之值之整數。
在又一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正丁基或2-甲氧基乙基;R2係鹵基或OH;m係具有5、6或7之值之整數;n係具有1、2或3之值之整數;p係具有0或1之值之整數。
在又一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正丁基或2-甲氧基乙基;R2係F或OH;m係具有5、6或7之值之整數;n係具有1、2或3之值之整數;p係具有0或1之值之整數。
在又一態樣中,本發明係關於式(I)化合物及其鹽,
其中:R1係正丁基或2-甲氧基乙基;m係具有5、6或7之值之整數;n係具有1、2或3之值之整數;p係0。
在又一態樣中,R1係正-C4-6烷基,例如正丁基。
在又一態樣中,R1係2-甲氧基乙基。
在又一態樣中,m係具有5或6之值之整數。
在又一態樣中,n係1或2。
在又一態樣中,p係0或1。
在又一態樣中,R2係鹵基或OH。
在又一態樣中,R2係F或OH。
式(I)化合物之實例提供於以下群中,且形成本發明之又一態樣:5-丁基-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-(2-甲氧基乙基)-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-(2-甲氧基乙基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(5-(六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(5-(吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(7-(六氫吡啶-1-基)庚基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(7-(吡咯啶-1-基)庚基)-1H-吡唑并[4,3-d]嘧啶-7-胺;3-(6-(氮雜環庚-1-基)己基)-5-丁基-1H-吡唑并[4,3-d]嘧啶-7-胺;3-(5-(氮雜環庚-1-基)戊基)-5-丁基-1H-吡唑并[4,3-d]嘧啶-7-胺;(S)-5-丁基-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;(S)-5-丁基-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;(R)-5-丁基-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;(R)-5-丁基-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;1-(6-(7-胺基-5-丁基-1H-吡唑并[4,3-d]嘧啶-3-基)己基)六氫吡啶-4-醇;1-(5-(7-胺基-5-丁基-1H-吡唑并[4,3-d]嘧啶-3-基)戊基)六氫吡啶-
4-醇;5-丁基-3-(6-(4-氟六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(5-(4-氟六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺、及其鹽。
在又一態樣中,本發明係關於5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺或其鹽。
本文所用術語「烷基」係指具有指定數目之成員原子之飽和烴鏈。除非另有說明,否則術語「烷基」包括直鏈及具支鏈烷基。舉例而言,C1-6烷基係指具有1至6個碳原子之飽和直鏈或具支鏈烴鏈,例如乙基及異丙基,且正-C1-6烷基係指具有1至6個碳原子之飽和直鏈烴鏈,例如正丙基及正丁基。
應瞭解,本文所提及之本發明化合物意指呈游離鹼形式或呈鹽(例如醫藥上可接受之鹽)形式之式(I)化合物。
在本發明之一態樣中,式(I)化合物係呈游離鹼形式。
式(I)化合物之鹽包括醫藥上可接受之鹽及可不為醫藥上可接受但可用於製備式(I)化合物及其醫藥上可接受之鹽的鹽。
在本發明之一態樣中,式(I)化合物係呈醫藥上可接受之鹽形式。
鹽可衍生自某些無機或有機酸。
本文所用術語「醫藥上可接受之鹽」係指保留標的化合物之期望生物活性並展示最小不期望毒理學效應之鹽。該等醫藥上可接受之鹽可在該化合物之最終分離並純化期間原位製備或藉由使經純化化合物以其游離酸或游離鹼形式分別與適宜鹼或酸反應來製備。此外,式(I)化合物之醫藥上可接受之鹽可在該游離酸或鹼形式之進一步處理期間(例如在製造成醫藥調配物期間原位)製備。
鹽之實例係醫藥上可接受之鹽。醫藥上可接受之鹽包括酸加成鹽。關於適宜鹽之綜述參見Berge等人,J.Pharm.Sci.,66:1-19(1977)。
式(I)化合物之醫藥上可接受之酸加成鹽之實例包括衍生自以下者:無機酸,例如鹽酸、氫溴酸、正磷酸、硝酸、磷酸或硫酸;或有機酸,例如,甲烷磺酸、乙烷磺酸、對-甲苯磺酸、乙酸、丙酸、乳酸、檸檬酸、富馬酸、蘋果酸、琥珀酸、水楊酸、馬來酸、甘油磷酸、酒石酸、苯甲酸、麩胺酸、天門冬胺酸、苯磺酸、萘磺酸(例如2-萘磺酸)、己酸或乙醯水楊酸。
式(I)化合物之鹽之所有可能化學計量及非化學計量形式均包括在本發明範圍內。例如,式(I)化合物之馬來酸氫鹽或半琥珀酸鹽。
可使用業內熟知技術來形成鹽,例如藉由自溶液沈澱隨後過濾或藉由蒸發掉溶劑。
通常,醫藥上可接受之酸加成鹽可藉由以下方式形成:視情況在適宜溶劑(例如有機溶劑)中使式(I)化合物與適宜酸(例如氫溴酸、鹽酸、硫酸、馬來酸、對-甲苯磺酸、甲烷磺酸、萘磺酸或琥珀酸)反應得到鹽,通常藉由例如結晶及過濾對其實施分離。
5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺之醫藥上可接受之鹽之實例係馬來酸鹽、馬來酸氫鹽及半琥珀酸鹽。
應瞭解,許多有機化合物可與溶劑形成複合物,該等化合物在該等溶劑中反應或自該等溶劑沈澱或結晶。該等複合物稱為「溶劑合物」。例如,與水之複合物稱為「水合物」。可使用具有高沸點之溶劑及/或具有高形成氫鍵傾向之溶劑(例如水、乙醇、異丙醇及N-甲基吡咯啶酮)來形成溶劑合物。識別溶劑合物之方法包括(但不限於)NMR及微量分析。式(I)化合物之溶劑合物係在本發明之範圍內。本文所用術語溶劑合物涵蓋游離鹼化合物以及其任一鹽二者之溶劑合
物。
某些本發明化合物可以互變異構形式存在。應瞭解,本發明涵蓋本發明化合物之所有互變異構物(以個別互變異構物形式或以其混合物形式)。
本發明化合物可呈結晶或非晶形形式。此外,本發明化合物之一些結晶形式可以多晶型物形式存在,其全部包括在本發明之範圍內。本發明化合物之熱力學最穩定多晶型形式尤其令人感興趣。
在又一態樣中,本發明係關於5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺馬來酸氫鹽之結晶固態形式,其特徵在於X-射線粉末繞射圖案在5.3、5.8、6.4、9.0、10.1、10.9、11.6、12.7、16.0及19.1之2θ值處具有繞射峰。
在又一態樣中,本發明係關於5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺半琥珀酸鹽之結晶固態形式,其特徵在於X-射線粉末繞射圖案在8.1、9.8、11.6、16.0、17.5、19.5、20.2、23.0及23.7之2θ值處具有繞射峰。
可使用多種習用分析技術來表徵並區分本發明化合物之多晶型形式,包括(但不限於)X-射線粉末繞射(XRPD)、紅外光譜(IR)、拉曼光譜(Raman spectroscopy)、差示掃描量熱法(DSC)、熱重分析(TGA)及固態核磁共振(ssNMR)。
本發明亦包括式(I)化合物或其醫藥上可接受之鹽之所有適宜同位素變化形式。式(I)化合物或其醫藥上可接受之鹽之同位素變化形式係定義為至少一個原子經原子序數相同但原子質量與自然界中通常所發現之原子質量不同之原子替代者。可納入本發明化合物中之同位素之實例包括氫、碳、氮、氧、氟及氯之同位素,例如分別2H、3H、13C、14C、15N、17O、18O、18F及36Cl。式(I)化合物或其鹽或溶劑合物之某些同位素變化形式(例如其中納入諸如3H或14C等放射性同位素之
彼等)可用於藥物及/或基質組織分佈研究。氚化(即,3H)及碳-14(即,14C)同位素因其易於製備及可檢測性而尤佳。此外,經諸如氘(即,2H)等同位素取代可提供歸因於較高代謝穩定性之某些治療優勢,例如活體內半衰期延長或劑量要求降低,且因此在一些情況下可能較佳。式(I)化合物或其醫藥上之鹽之同位素變化形式通常可藉由習用程序(例如藉由說明性方法)或藉由下文實例中所述之製劑使用適宜試劑之適當同位素變化形式來製備。
從上文應瞭解,式(I)化合物及其鹽及溶劑合物之溶劑合物、水合物、異構物、同位素變化形式及多晶型形式包括在本發明之範圍內。
式(I)化合物及其鹽可藉由下文所述方法製備,該等方法構成本發明之其他態樣。
因此,提供製備式(I)化合物之方法,該方法包含式(II)化合物之官能基互變或去保護:
其中R1、R2、m、n及p係如上文針對式(I)化合物所定義且Z係經適宜保護基團(例如3,4-二甲氧基苄基或2,4-二甲氧基苄基)取代之OH或胺基,且此後視需要製備如此形成之化合物之鹽。
例如當Z係OH時,將式(II)化合物溶解於氧氯化磷中並在適宜溫度(例如120℃)下加熱適宜時間段(例如45至120分鐘)。蒸發反應混合物並與適宜溶劑(例如甲苯)共沸。然後將氨水溶液(0.88)添加至該物質於適宜溶劑(例如異丙醇)中之溶液中。然後在微波加熱器中在適宜溫度(例如120℃至150℃)下將所得混合物加熱適宜時間段(例如1至2小時)。藉由去除溶劑來分離產物(I)並視需要純化。
例如當Z係(3,4-二甲氧基苯基)甲胺基團時,用適宜酸(例如三氟乙酸)處理式(II)化合物並在微波加熱器中在適宜溫度(例如120℃)下加熱適宜時間段(例如4小時)。藉由去除溶劑來分離產物(I),視需要水性處理並純化。
例如當Z係(2,4-二甲氧基苯基)甲胺基團時,用適宜酸(例如三氟乙酸)處理式(II)化合物並在適宜溫度(例如60℃)下加熱適宜時間段(例如2.5至4小時)。藉由去除溶劑來分離產物(I),視需要水性處理並純化。
式(II)化合物可藉由在觸媒存在下使式(III)化合物與氫氣反應來製備,
其中R1、R2、m、n及p係如上文針對式(I)化合物所定義且Z係如上文針對式(II)化合物所定義。
舉例而言,將式(III)化合物溶解於適宜溶劑(例如乙醇)中,並在適宜流動氫化裝置(例如Thales H-CubeTM)中在適宜溫度(例如20℃至60℃)下在氫氣存在下在適宜觸媒(例如10%鈀碳)上通過。另一選擇為,
將式(III)化合物溶解於適宜溶劑(例如乙醇)中並在適宜溫度(例如20℃)下在氫氣氣氛下在適宜觸媒(例如10%鈀碳)存在下攪拌適宜時間段(2至18小時)。藉由去除溶劑來分離產物(II),視需要水性處理並純化。
式(III)化合物可藉由使式(IV)化合物,
其中R1係如上文針對式(I)化合物所定義,Z係如上文針對式(II)化合物所定義且X係鹵素(例如碘或溴);與式(V)化合物反應來製備,
其中R2、m、n及p係針對式(I)化合物所定義。
舉例而言,在碘化銅(I)、適宜觸媒(例如雙(三苯基膦)二氯化鈀(II))及適宜鹼(例如三乙胺)存在下將式(IV)化合物溶解於適宜溶劑(例如N,N-二甲基甲醯胺)中。添加式(V)化合物於適宜溶劑(例如N,N-二甲基甲醯胺)中之溶液並在適宜溫度(例如20℃至55℃)下將混合物攪拌適宜時間段(例如0.5至17小時)。在水性處理並純化後對產物(III)實施分離。
式(V)化合物可藉由使式(VI)化合物,
其中m係針對式(I)化合物定義且Y係離去基團,例如鹵素(例如氯、溴或碘)或磺酸烷基酯(例如對-甲苯磺酸酯);與式(VII)化合物反應來製備,
其中R2、n及p係如針對式(I)化合物所定義。
舉例而言,將式(VI)化合物、式(VII)化合物及適宜鹼(例如碳酸氫鈉)溶解於適宜溶劑(例如N,N-二甲基甲醯胺)中,並在適宜溫度(例如80℃至100℃)下加熱適宜時間段(例如16至18小時)。在水性處理並純化後對產物(V)實施分離,藉由(例如)對適宜結晶鹽(例如草酸鹽)實施分離。
另一選擇為,式(III)化合物可藉由使式(VIII)化合物,
其中R1及m係如上文針對式(I)化合物所定義,Z係如上文針對式(II)化合物所定義且Y係如針對式(VI)化合物所定義之離去基團;與式(VII)化合物(其中R2、n及p係如針對式(I)化合物所定義)反應來製備。
舉例而言,將式(VIII)化合物、式(VII)化合物及適宜鹼(例如三乙胺)溶解於適宜溶劑(例如乙腈)中並在適宜溫度(例如60℃至80℃)下加熱適宜時間段(例如16至26小時)。在水性處理並純化後對產物(III)實施分離。
式(VIII)化合物可藉由使式(IV)化合物與式(VI)化合物反應來製備。舉例而言,在碘化銅(I)、適宜觸媒(例如雙(三苯基膦)二氯化鈀(II))及適宜鹼(例如三乙胺)存在下將式(IV)化合物溶解於適宜溶劑(例如N,N-二甲基甲醯胺)中。添加式(VI)化合物於適宜溶劑(例如N,N-二甲基甲醯胺)中之溶液並在適宜溫度(例如20℃至60℃)下將混合物攪拌適宜時間段(例如2至18小時)。在水性處理並純化後對產物(VIII)實施分離。
另一選擇為,式(II)化合物可藉由使式(IX)化合物,
其中R1及m係如上文針對式(I)化合物所定義,Z係如上文針對式(II)化合物所定義且X係離去基團,例如鹵素(例如氯、溴或碘);與式(VII)化合物(其中R2、n及p係如針對式(I)化合物所定義)反應來製備。
舉例而言,在適宜溫度(例如20℃)下在適宜溶劑(例如乙腈)中將式(IX)化合物、式(VII)化合物及適宜鹼(例如三乙胺)之混合物攪拌適宜時間段(例如17至19小時)。在水性處理並純化後對產物(IX)實施分離。
式(IX)化合物可使式(X)化合物與適宜鹵化試劑反應來製備,
其中R1及m係如上文針對式(I)化合物所定義,Z係如上文針對式(II)化合物所定義。
舉例而言,將三苯基膦於溶劑(例如二氯甲烷)中之溶液添加至式(X)化合物及四溴化碳於適宜溶劑(例如,二氯甲烷)中之混合物中。在適宜溫度(例如20℃)下將反應攪拌適宜時間段(18至20小時)。在水性處理並純化後對產物(X)實施分離。
式(X)化合物可藉由在觸媒存在下使式(XI)化合物與氫氣反應來製備,
其中R1及m係如上文針對式(I)化合物所定義,Z係如上文針對式
(II)化合物所定義。
舉例而言,將式(XI)化合物溶解於適宜溶劑(例如乙醇)中,並在氫氣氣氛下在適宜觸媒(例如10%鈀碳)存在下攪拌適宜時間段(例如22小時)。藉由去除溶劑來分離產物(XIV)並視需要純化。
式(XI)化合物可藉由使式(IV)化合物與適當炔-1-醇反應來製備。舉例而言,在碘化銅(I)、適宜觸媒(例如雙(三苯基膦)二氯化鈀(II))及適宜鹼(例如三乙胺)存在下將式(IV)化合物溶解於適宜溶劑(例如N,N-二甲基甲醯胺)中。添加炔-1-醇於適宜溶劑(例如N,N-二甲基甲醯胺)中之溶液並在適宜溫度(例如60℃)下將混合物攪拌適宜時間段(例如2至4小時)。在水性處理並純化後對產物(XI)實施分離。
式(IV)化合物(其中Z係經適宜保護基團取代之胺基)可自式(IV)化合物(其中Z係OH基團)製備。舉例而言,在適宜偶合劑(例如(苯并三唑-1-基氧基)叁(二甲基胺基)鏻六氟磷酸鹽)及鹼(例如,1,8-二氮雜雙環[5.4.0]十一-7-烯)存在下將式(IV)化合物(Z=OH)溶解於適宜溶劑(例如N,N-二甲基甲醯胺)中,用適宜胺(例如,(3,4-二甲氧基苯基)甲胺)處理。在適宜溫度(例如40℃)下將反應攪拌適宜時間段(例如3小時)。在水性處理並純化後對產物(IV)(其中Z係(3,4-二甲氧基苯基)甲胺)實施分離。
另一選擇為,在適宜偶合劑(例如((1H-苯并[d][1,2,3]三唑-1-基)氧基)三(吡咯啶-1-基)鏻六氟磷酸鹽(V))及鹼(例如,1,8-二氮雜雙環[5.4.0]十一-7-烯)存在下將式(IV)化合物(Z=OH)溶解於適宜溶劑(例如乙腈)中,用適宜胺(例如,(2,4-二甲氧基苯基)甲胺)處理。在適宜溫度(例如20℃)下將反應攪拌適宜時間段(例如6小時)。在藉由過濾並純化與副產物分離後分離出產物(IV)(其中Z係(3,4-二甲氧基苯基)甲胺)。
式(IV)化合物(其中Z係OH基團)可藉由使式(XII)化合物與鹵化試
劑(例如N-碘琥珀醯亞胺)反應來製備,
其中R1係如上文針對式(I)化合物所定義。
舉例而言,將式(XII)化合物溶解於適宜溶劑(例如N,N-二甲基甲醯胺)中,並在適宜溫度(例如60℃)下與N-碘琥珀醯亞胺反應適宜時間段(例如1至2小時)。在水性處理並純化後對產物(XII)實施分離。
式(XII)化合物可藉由使式(XIII)化合物與適宜鹼(例如氫氧化鈉)反應來製備,
其中R1係如上文針對式(I)化合物所定義。
用氫氧化鈉水溶液處理式(XIII)化合物於適宜溶劑中(例如乙醇)中之溶液,並在適宜溫度(例如80℃至100℃)下將反應混合物攪拌適宜時間段(例如1至4小時)。在水性處理並純化後對產物(XII)實施分離。
式(XIII)化合物可藉由使式(XIV)化合物,
與式(XII)化合物反應來製備,
其中R1係如上文針對式(I)化合物所定義。
舉例而言,在適宜溶劑(例如氯化氫於1,4-二噁烷中之溶液)中用氯化氫溶液處理式(XIV)化合物與式(XV)化合物之混合物並在適宜溫度(60℃至80℃)下加熱適宜時間段(例如16至24小時)。在蒸發掉溶劑後對產物(XIII)實施分離。
式(VI)、(VII)、(XIV)及(XV)之化合物係於文獻中獲知或自(例如)Sigma-Aldrich,UK購得或可以與已知程序(例如揭示於合成方法學之標準參考文件中之彼等)類似之方式製備,該等標準參考文件(例如)J.March,Advanced Organic Chemistry,第6版(2007),WileyBlackwell或Comprehensive Organic Synthesis(Trost B.M.及Fleming I.(編輯),Pergamon Press,1991),每一者因關於該等程序而以引用方式併入本文中。
可用於本文所述合成途徑之其他保護基團之實例及其去除方式可參見T.W.Greene「Protective Groups in Organic Synthesis」,第4版,J.Wiley and Sons,2006,其因關於該等程序而以引用方式併入本文中。
對於上文所述反應或方法中之任一者而言,可使用習用加熱及冷卻方法,分別例如溫度調控之油浴或溫度調控之熱塊、及冰/鹽浴或乾冰/丙酮浴。可使用習用分離方法,例如自水性或非水性溶劑萃取或萃取至其中。可使用乾燥有機溶劑、溶液或萃取物之習用方法,例如與無水硫酸鎂或無水硫酸鈉一起震盪、或通過疏水性玻璃料。視需要可使用習用純化方法,例如結晶及層析(例如二氧化矽層析或反相層析)。可使用習用溶劑(例如乙酸乙酯或甲醇、乙醇或丁醇及其水性混合物)來實施結晶。應瞭解,通常可藉由反應監測技術(例如薄層層析及LC-MS)來測定特定反應時間、溫度。
視需要,可使用習用程序(例如非鏡像異構衍生物之分步結晶或對掌性高效液相層析(對掌性HPLC))來製備本發明化合物之個別異構形式作為個別異構物。
可使用習用方法(例如X-射線結晶學)來測定化合物之絕對立體化學。
式(I)化合物及其醫藥上可接受之鹽於其中具有潛在地有益效果之疾病狀態之實例包括過敏性疾病及其他發炎病況(例如過敏性鼻炎及氣喘)、傳染病及癌症。式(I)化合物及其醫藥上可接受之鹽亦具有作為疫苗佐劑之潛在用途。
式(I)化合物及其醫藥上可接受之鹽作為免疫反應調節劑亦可用於治療及/或預防免疫介導之病症,包括(但不限於)發炎或過敏性疾病,例如氣喘、過敏性鼻炎及鼻結膜炎、食物過敏、過敏性肺病、嗜伊紅性肺炎、遲髮型過敏性病症、動脈粥樣硬化、胰臟炎、胃炎、結腸炎、骨關節炎、牛皮癬、類肉瘤病、肺纖維化、呼吸窘迫症候群、細枝氣管炎、慢性阻塞性肺病、竇炎、囊腫纖維化、日光性角化症、皮膚發育不良、慢性蕁麻疹、濕疹及所有類型皮炎。
式(I)化合物及其醫藥上可接受之鹽亦可用於治療及/或預防對呼吸感染之反應(包括(但不限於)呼吸道病毒加重及扁桃腺炎)。該等化合物亦可用於治療及/或預防自身免疫疾病,包括(但不限於)類風溼性關節炎、牛皮癬性關節炎、全身性紅斑狼瘡、斯耶格倫氏病(Sjöegrens disease)、關節黏連性脊椎炎、硬皮病、皮肌炎、糖尿病、移植物排斥(包括移植物抗宿主病)、發炎腸病(包括(但不限於)克隆氏病(Crohn’s disease)及潰瘍性結腸炎)。
式(I)化合物及其醫藥上可接受之鹽亦可用於治療傳染病,包括(但不限於)由肝炎病毒(例如B型肝炎病毒、C型肝炎病毒)、人類免疫缺陷病毒、乳突病毒、皰疹病毒、呼吸系統病毒(例如流感病毒、呼吸系融合細胞病毒、鼻病毒、間質肺炎病毒、副流行性感冒病毒、SARS)及西尼羅病毒(West Nile virus)引起之彼等。式(I)化合物及其醫藥上可接受之鹽亦可用於治療由(例如)細菌、真菌或原生動物引發之微生物感染。該等包括(但不限於)結核病、細菌性肺炎、麴黴病、組織漿菌症、念珠菌病、肺囊蟲病、麻瘋、披衣菌病、隱球菌病、隱胞
子蟲病、弓蟲病、利什曼原蟲病(leishmania)、瘧疾及錐蟲病。
式(I)化合物及其醫藥上可接受之鹽亦可用於治療各種癌症,具體而言治療已知對免疫療法有反應之癌症且包括(但不限於)腎細胞癌、肺癌、乳癌、結腸直腸癌、膀胱癌、黑色素瘤、白血病、淋巴瘤及卵巢癌。
熟習此項技術者應瞭解,本文所提及之治療或療法可端視病況擴展至預防以及治療既定病況。因此,作為本發明之又一態樣,提供式(I)化合物或其醫藥上可接受之鹽,其用於療法。
應瞭解,當式(I)化合物或其醫藥上可接受之鹽用於療法時,其係用作活性治療劑。
因此,亦提供式(I)化合物或其醫藥上可接受之鹽,其用於治療過敏性疾病及其他發炎病況、傳染病或癌症。
因此,亦提供式(I)化合物或其醫藥上可接受之鹽,其用於治療過敏性鼻炎。
因此,亦提供式(I)化合物或其醫藥上可接受之鹽,其用於治療氣喘。
進一步提供式(I)化合物或其醫藥上可接受之鹽在製造藥劑中之用途,該藥劑用於治療過敏性疾病及其他發炎病況、傳染病或癌症。
進一步提供式(I)化合物或其醫藥上可接受之鹽在製造藥劑中之用途,該藥劑用於治療過敏性鼻炎。
進一步提供式(I)化合物或其醫藥上可接受之鹽在製造藥劑中之用途,該藥劑用於治療氣喘。
進一步提供治療過敏性疾病及其他發炎病況、傳染病或癌症之方法,該方法包含向有需要的人類受試者投與治療有效量之式(I)化合物或其醫藥上可接受之鹽。
進一步提供治療過敏性鼻炎之方法,該方法包含向有需要的人
類受試者投與治療有效量之式(I)化合物或其醫藥上可接受之鹽。
進一步提供治療氣喘之方法,該方法包含向有需要的人類受試者投與治療有效量之式(I)化合物或其醫藥上可接受之鹽。
式(I)化合物及其醫藥上可接受之鹽亦具有作為疫苗佐劑之潛在用途。
因此,提供包含式(I)化合物或其醫藥上可接受之鹽及抗原或抗原組合物之疫苗組合物作為本發明之又一態樣,其用於療法。
因此,提供式(I)化合物或其醫藥上可接受之鹽及抗原或抗原組合物在製造藥劑中之用途作為又一態樣本發明,該藥劑用於療法。
進一步提供治療或預防疾病之方法,其包含向患有或易患疾病之人類受試者投與包含式(I)化合物或其醫藥上可接受之鹽及抗原或抗原組合物之疫苗組合物。
進一步提供疫苗組合物之用途,其用於製造用於療法之藥劑。
式(I)化合物及其醫藥上可接受之鹽在向患者投與前通常(但不一定)可調配成醫藥組合物。因此,在本發明之另一態樣中,提供包含式(I)化合物或其醫藥上可接受之鹽及一或多種醫藥上可接受之賦形劑之醫藥組合物。
式(I)化合物及其醫藥上可接受之鹽可經調配用於以習用方式投與。式(I)化合物及其醫藥上可接受之鹽可(例如)經調配用於經口、局部、吸入、鼻內、經頰、非經腸(例如靜脈內、皮下、真皮內或肌內)或經直腸投與。在一態樣中,式(I)化合物及其醫藥上可接受之鹽經調配用於經口投與。在又一態樣中,式(I)化合物及其醫藥上可接受之鹽經調配用於局部投與,例如鼻內或吸入投與。
用於經口投與之錠劑及膠囊可含有習用賦形劑,例如黏合劑,例如糖漿、亞拉伯樹膠、明膠、山梨醇、黃著膠、澱粉黏漿、纖維素
或聚乙烯基吡咯啶酮;填充劑,例如,乳糖、微晶纖維素、糖、玉米澱粉、磷酸鈣或山梨醇;潤滑劑,例如,硬脂酸鎂、硬脂酸、滑石粉、聚乙二醇或二氧化矽;崩解劑,例如,馬鈴薯澱粉、交聯羧甲纖維素鈉或澱粉羥乙酸鈉;或潤濕劑,例如月桂基硫酸鈉。錠劑可根據業內熟知方法來包衣。
口服液體製劑可呈(例如)水性或油性懸浮液、溶液、乳液、糖漿或酏劑形式,或可以在使用前與水或其他適宜媒劑重構之乾產物形式提供。該等液體製劑可含有習用添加劑,例如懸浮劑,例如,山梨糖醇糖漿、甲基纖維素、葡萄糖/糖漿、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁凝膠或氫化可食用脂肪;乳化劑,例如卵磷脂、山梨醇酐單油酸酯或阿拉伯膠;非水性媒劑(其可包括可食用油),例如杏仁油、分餾椰子油、油性酯、丙二醇或乙醇;或防腐劑,例如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯或山梨酸。該等製劑亦可視需要含有緩衝鹽、調味劑、著色劑及/或甜味劑(例如甘露醇)。
用於鼻內投與之組合物包括藉由滴劑或藉由加壓幫浦投與鼻之水性組合物。出於此目的,適宜組合物含有水作為稀釋劑或載劑。投與肺或鼻之組合物可含有一或多種賦形劑,例如一或多種懸浮劑、一或多種防腐劑、一或多種表面活性劑、一或多種張力調節劑、一或多種共溶劑,且可包括控制組合物之pH之組份,例如緩衝系統。此外,組合物可含有其他賦形劑,例如抗氧化劑(例如偏亞硫酸氫鈉)及遮味劑。組合物亦可藉由霧化投與鼻或呼吸道其他區域。
鼻內組合物可容許式(I)化合物或其醫藥上可接受之鹽遞送至鼻腔(目標組織)所有區,且此外,可容許式(I)化合物或其醫藥上可接受之鹽保持與目標組織接觸更長時間段。鼻內組合物之適宜給藥方案應為患者經鼻緩慢地吸入,隨後清洗鼻腔。在吸入期間,可向一個鼻孔投與該組合物,同時用手壓住另一鼻孔。然後可對另一鼻孔重複此程
序。通常,每日1次、2次或3次、理想地每日1次藉由以上程序投與每個鼻孔1次或2次噴霧。尤其令人感興趣者係適於每日1次投與之鼻內組合物。
懸浮劑(若包括)以組合物之總重量計通常應以0.1%至5%(w/w)之量存在,例如1.5%至2.4%(w/w)。醫藥上可接受之懸浮劑之實例包括(但不限於)Avicel®(微晶纖維素及羧甲基纖維素鈉)、羧甲基纖維素鈉、矽酸鎂鋁、黃蓍膠、膨潤土、甲基纖維素、黃原膠、卡波普(carbopol)及聚乙二醇。
投與肺或鼻之組合物可含有一或多種賦形劑,可藉由納入一或多種防腐劑以免受微生物或真菌污染及生長。醫藥上可接受之抗微生物劑或防腐劑之實例包括(但不限於)四級銨化合物(例如氯化苄二甲烴銨(benzalkonium chloride)、氯化苯銨松寧(benzethonium chloride)、西曲溴銨(cetrimide)、氯化鯨蠟吡啶(cetylpyridinium chloride)、勞拉氯銨(lauralkonium chloride)及米吡氯銨(myristyl picolinium chloride))、汞製劑(例如硝酸苯汞(phenylmercuric nitrate)、乙酸苯汞(phenylmercuric acetate)及乙汞硫柳酸鈉)、醇試劑(例如氯丁醇、苯基乙醇及苄醇)、抗細菌酯(例如對-羥基苯甲酸之酯)、螯合劑(例如依地酸鈉(disodium edetate,EDTA))及其他抗微生物劑(例如氯己定(chlorhexidine)、氯甲酚(chlorocresol)、山梨酸及其鹽(例如山梨酸鉀)及多黏菌素)。醫藥上可接受之抗真菌劑或防腐劑之實例包括(但不限於)苯甲酸鈉、山梨酸、丙酸鈉、對羥苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯及對羥基苯甲酸丁酯。防腐劑(若包括)以組合物之總重量計可以0.001%至1%(w/w)之量存在,例如0.015%至0.5%(w/w)。
組合物(例如其中至少一種化合物係存於懸浮液中)可包括一或多種表面活性劑,其起作用以促進藥劑粒子在組合物之水相中之溶解。
舉例而言,所用表面活性劑之量係在混合期間不產生泡沫之量。醫藥上可接受之表面活性劑之實例包括脂肪族醇、酯及醚,例如聚氧乙烯(20)、去水山梨糖醇單油酸酯(聚山梨醇酯80)、聚乙二醇醚及泊洛沙姆(poloxamer)。表面活性劑以組合物之總重量計可以介於約0.01%至10%(w/w)之間之量存在,例如0.01%至0.75%(w/w),例如約0.5%(w/w)。
可包括一或多種張力調節劑以與體液(例如鼻腔流體)達成張力,從而降低刺激程度。醫藥上可接受之張力調節劑之實例包括(但不限於)氯化鈉、右旋糖、木糖醇、氯化鈣、葡萄糖、甘油及山梨醇。張力調節劑(若存在)以組合物之總重量計可以0.1%至10%(w/w)之量納入,例如4.5%至5.5%(w/w),例如約5.0%(w/w)。
可藉由添加適宜緩衝劑對本發明組合物實施緩衝,例如檸檬酸鈉、檸檬酸、胺丁三醇(trometamol)、磷酸鹽(例如磷酸氫二鈉(例如十二水合物、七水合物、二水合物及無水形式)或磷酸鈉及其混合物)。
緩衝劑(若存在)以組合物之總重量計可以0.1%至5%(w/w)之量納入,例如1%至3%(w/w)。
遮味劑之實例包括蔗糖素、蔗糖、糖精或其鹽、果糖、右旋糖、甘油、玉米糖漿、阿斯巴甜(aspartame)、乙醯舒泛鉀(acesulfame-K)、木糖醇、山梨醇、赤蘚醇、甘草酸銨、索馬甜(thaumatin)、紐甜(neotame)、甘露醇、薄荷腦、桉樹油、樟腦、天然調味劑、人造調味劑及其組合。
可包括一或多種共溶劑以幫助藥劑化合物及/或其他賦形劑溶解。醫藥上可接受之共溶劑之實例包括(但不限於)丙二醇、二丙二醇、乙二醇、甘油、乙醇、聚乙二醇(例如PEG300或PEG400)及甲醇。在一實施例中,共溶劑係丙二醇。
共溶劑(若存在)以組合物之總重量計可以0.05%至30%(w/w)之量
納入,例如1%至25%(w/w),例如1至10%(w/w)。
用於吸入投與之組合物包括藉由加壓幫浦或吸入器(例如,貯器式乾燥粉末吸入器、單位劑量乾燥粉末吸入器、預先計量式多劑量乾燥粉末吸入器、鼻吸入器或加壓氣溶膠吸入器、噴霧器或吹入器)投與呼吸道之水性、有機或水性/有機混合物、乾燥粉末或結晶組合物。出於此目的,適宜組合物含有水作為稀釋劑或載劑且可具有習用賦形劑,例如緩衝劑、張力改良劑及諸如此類。水性組合物亦可藉由霧化投與鼻及其他呼吸道區域。該等組合物可為利用適宜液化推進劑自加壓包裝(例如計量式劑量吸入器)遞送之水性溶液或懸浮液或氣溶膠。
用於局部投與鼻(例如,用於治療鼻炎)或肺之組合物包括加壓氣溶膠組合物及藉由加壓幫浦遞送至鼻腔之水性組合物。非加壓且適於局部投與鼻腔之組合物尤其令人感興趣。出於此目的,適宜組合物含有水作為稀釋劑或載劑。投與肺或鼻之水性組合物可具有習用賦形劑,例如緩衝劑、張力改良劑及諸如此類。水性組合物亦可藉由霧化投與鼻。
通常可使用流體分配器將流體組合物遞送至鼻腔。流體組合物可為水性的或非水性的,但通常係水性的。式(I)化合物或其醫藥上可接受之鹽可調配為懸浮液或溶液。此流體分配器可具有分配噴嘴或分配孔口,當使用者對流體分配器之幫浦機構施加力時,經計量劑量之流體組合物經由其分配。該等流體分配器通常具有多個經計量劑量之流體組合物之貯器,該等劑量在後續幫浦致動時可分配。另一選擇為,用於將流體組合物遞送至鼻腔之流體分配器經設計可為劑量受限,例如包含單一劑量之一次性使用分配器。分配噴嘴或孔口經組態可插入使用者之鼻孔中,以便將流體組合物噴霧分配至鼻腔中。上述類型之流體分配器闡述並說明於國際專利申請公開案第WO
2005/044354(Glaxo Group Limited)號中。該分配器具有外殼,其包繞流體卸載器件,該流體卸載器件具有安裝於含有流體組合物之容器上之壓縮幫浦。該外殼具有至少一個手指可操作側槓桿,其可相對於外殼向內移動,以藉助凸輪使容器在外殼中向上移動以使幫浦壓縮經計量劑量之組合物並經由該外殼之鼻噴嘴泵送至幫浦桿外部。在一實施例中,流體分配器具有WO 2005/044354圖30至圖40中所說明之一般類型。
含有式(I)化合物或其醫藥上可接受之鹽之水性組合物亦可藉由如國際專利申請公開案第WO2007/138084(Glaxo Group Limited)號中所揭示(例如,如參照其圖22至圖46所揭示)或如英國專利申請案第GB0723418.0(Glaxo Group Limited)號中所揭示(例如,如參照其圖7至圖32所揭示)之幫浦遞送。該幫浦可藉由如GB0723418.0圖1至圖6中所揭示之致動器來致動。
藉由吸入局部遞送至肺之乾燥粉末組合物可(例如)存於(例如)用於吸入器或吹入器之明膠膠囊及柱、或(例如)層壓鋁箔泡罩中。粉末摻合物組合物通常含有式(I)化合物或其醫藥上可接受之鹽及適宜粉末鹼(載劑/稀釋劑/賦形劑物質)(例如單-、二-、或多糖(例如乳糖或澱粉))之吸入式粉末混合物。除藥物及載劑以外,乾燥粉末組合物亦可包括又一賦形劑(例如三元試劑),例如糖酯,例如八乙酸纖維雙醣酯、硬脂酸鈣或硬脂酸鎂。
在一實施例中,可將適於吸入投與之組合物納入複數個密封劑量容器中,該等密封劑量容器係提供於安裝於適宜吸入器件內部之藥劑包上。該等容器可破裂、可剝離或可以其他方式操作(一次一個)且藉由在吸入器件之吹口上吸入來投與各劑量之乾燥粉末組合物,如業內已知。藥劑包可呈多種不同形式,例如盤形或長條。代表性吸入器件係由GlaxoSmithKline出售之DISKHALERTM及DISKUSTM器件。
乾燥粉末狀可吸入組合物亦可以大容積貯器形式提供於吸入器件中,該器件則具有用於對自貯器至吸入通道中之組合物之劑量進行計量之計量機構,在該吸入通道中該經計量劑量能夠藉由患者在器件吹口處吸入而吸入。此類型之例示性市售器件係TURBUHALERTM(AstraZeneca)、TWISTHALERTM(Schering)及CLICKHALERTM(Innovata.)。
乾燥粉末狀可吸入組合物之又一遞送方法係將經計量劑量之組合物提供於膠囊中(每個膠囊一劑量),然後通常視患者需要將其裝載至吸入器件中。該器件具有破裂、刺穿或以其他方式打開膠囊之構件以使得當患者在器件吹口處吸入時該劑量能夠夾帶至其肺中。可提及ROTAHALERTM(GlaxoSmithKline)及HANDIHALERTM(Boehringer Ingelheim.)作為該等器件之市售實例。
適於吸入之加壓氣溶膠組合物可為懸浮液或溶液,且可含有式(I)化合物或其醫藥上可接受之鹽及適宜推進劑,例如氟碳化物或含氫氯氟碳化物或其混合物,尤其氫氟烷烴,尤其1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟-正丙烷或其混合物。氣溶膠組合物可視情況含有業內熟知之其他組合物賦形劑,例如如(例如)WO 94/21229及WO 98/34596(Minnesota Mining and Manufacturing Company)中所述之表面活性劑(例如油酸、卵磷脂或寡聚乳酸或其衍生物)及共溶劑(例如乙醇)。加壓組合物通常將保存於利用閥(例如計量閥)封閉之罐(例如鋁罐)中,並安裝至具有吹口之致動器中。
軟膏、乳霜及凝膠可(例如)利用水性或油性鹼並添加適宜增稠劑及/或膠凝劑及/或溶劑調配。因此該等鹼可(例如)包括水及/或油(例如液體石蠟或植物油(例如花生油或蓖麻油))、或溶劑(例如聚乙二醇)。可根據鹼之性質使用之增稠劑及膠凝劑包括軟石蠟、硬脂酸鋁、鯨蠟硬脂醇、聚乙二醇、羊毛脂、蜂蠟、聚羧乙烯及纖維素衍生物、及/
或單硬脂酸甘油酯及/或無毒乳化劑。
洗劑可利用水性或油性鹼調配且一般將亦含有一或多種乳化劑、穩定劑、分散劑、懸浮劑或增稠劑。
外部施用粉末可借助任一適宜粉末狀鹼(例如,滑石粉、乳糖或澱粉)形成。滴劑可利用水性或非水性鹼調配,其亦包含一或多種分散劑、增溶劑、懸浮劑或防腐劑。
式(I)化合物及其醫藥上可接受之鹽可(例如)經調配以使組合物於貼劑或其他可將活性組份遞送至皮膚中之器件(例如加壓氣體器件)中經皮遞送。
對於經頰投與而言,組合物可呈以習用方式調配之錠劑或菱形錠劑形式。
式(I)化合物及其醫藥上可接受之鹽亦可調配為(例如)含有習用栓劑鹼(例如可可脂或其他甘油酯)之栓劑。
式(I)化合物及其醫藥上可接受之鹽亦可經調配由濃注或連續灌注非經腸投與且可以單位劑型提供,例如以安瓿、小瓶、小體積輸注器或經預先填充之注射器形式提供,或提供於含有所添加防腐劑之多劑型容器中。組合物可呈諸如存於水性或非水性媒劑中之溶液、懸浮液或乳液形式,且可含有調配劑(例如抗氧化劑,緩衝劑,抗微生物劑及/或張力調節劑)。另一選擇為,活性成份可呈粉末形式,以便在使用前用適宜媒劑(例如無菌無熱原水)構造。乾燥固體組成物(dry solid presentation)可藉由在無菌條件下將無菌粉末填充至個別無菌容器中或藉由在無菌條件下將無菌溶液填充至每一容器中並冷凍乾燥來製備。
式(I)化合物及其醫藥上可接受之鹽亦可作為佐劑與疫苗一起調配以調節其活性。該等組合物可含有抗體或抗體片段或抗原組份(包括(但不限於)蛋白質、DNA、活細菌或死細菌及/或病毒或病毒樣粒
子)與一或多種具有佐劑活性之組份(包括(但不限於)鋁鹽、油水乳液、熱休克蛋白、脂質A製劑及衍生物、糖脂、其他TLR促效劑(例如CpG DNA或類似試劑)、細胞介素(例如GM-CSF或IL-12或類似試劑)。
在本發明之又一態樣中,提供包含式(I)化合物或其醫藥上可接受之鹽之疫苗佐劑。
進一步提供包含式(I)化合物或其醫藥上可接受之鹽及抗原或抗原組合物之疫苗組合物。
式(I)化合物及其醫藥上可接受之鹽可單獨使用或與其他治療活性劑組合使用。在又一態樣中,本發明提供包含式(I)化合物或其醫藥上可接受之鹽與至少一種其他治療活性劑之組合。
式(I)化合物及其醫藥上可接受之鹽及其他治療活性劑可一起或單獨投與,且當單獨投與時,投與可同時進行或以任一順序依次進行。應選擇式(I)化合物或其醫藥上可接受之鹽及其他治療活性劑之量及相對投與時序以達成期望組合治療效果。式(I)化合物或其醫藥上可接受之鹽與其他治療劑之組合之投與可藉由以包括該兩種化合物之單一醫藥組合物或以分開的醫藥組合物(每一者包括該等化合物中之一者)同時投與。另一選擇為,該組合可以依序方式單獨投與,其中首先投與一種治療劑且隨後投與另一者或反之亦然。該等依序投與之時間可相距較近或較遠。
式(I)化合物及其醫藥上可接受之鹽可與一或多種可用於預防或治療病毒感染之藥劑組合使用。該等藥劑之實例包括(但不限於):聚合酶抑制劑,例如彼等揭示於WO 2004/037818-A1中者以及彼等揭示於WO 2004/037818及WO 2006/045613中者;JTK-003、JTK-019、NM-283、HCV-796、R-803、R1728、R1626以及彼等揭示於WO 2006/018725、WO 2004/074270、WO 2003/095441、
US2005/0176701、WO 2006/020082、WO 2005/080388、WO 2004/064925、WO 2004/065367、WO 2003/007945、WO 02/04425、WO 2005/014543、WO 2003/000254、EP 1065213、WO 01/47883、WO 2002/057287、WO 2002/057245中者及類似藥劑;複製抑制劑,例如阿昔洛韋(acyclovir)、泛昔洛韋(famciclovir)、更昔洛韋(ganciclovir)、西多福韋(cidofovir)、拉米夫定(lamivudine)及類似藥劑;蛋白酶抑制劑,例如HIV蛋白酶抑制劑沙奎那韋(saquinavir)、利托納韋(ritonavir)、茚地那韋(indinavir)、奈芬納韋(nelfinavir)、氨普那韋(amprenavir)、呋山那韋(fosamprenavir)、布瑞那韋(brecanavir)、阿紮那韋(atazanavir)、替拉那韋(tipranavir)、帕利那韋(palinavir)、拉西那韋(lasinavir)及HCV蛋白酶抑制劑BILN2061、VX-950、SCH503034;及類似藥劑;核苷及核苷酸逆轉錄酶抑制劑,例如齊多夫定(zidovudine)、去羥肌苷(didanosine)、拉米夫定、紮昔他賓(zalcitabine)、阿巴卡韋(abacavir)、司他夫定(stavudine)、阿德福韋(adefovir)、阿德福韋二匹伏酯(adefovir dipivoxil)、福齊夫定妥多酯(fozivudine todoxil)、恩曲他濱(emtricitabine)、阿洛夫定(alovudine)、氨多索韋(amdoxovir)、艾夫他濱(elvucitabine)及類似藥劑;非核苷逆轉錄酶抑制劑(包括具有抗氧化活性之藥劑,例如依穆諾特(immunocal)、奧替普拉(oltipraz)等),例如奈韋拉平(nevirapine)、地拉韋定(delavirdine)、依法韋侖(efavirenz)、洛韋胺(loviride)、依穆諾特、奧替普拉、卡普韋林(capravirine)、TMC-278、TMC-125、依曲韋林(etravirine)及類似藥劑:進入抑制劑,例如恩夫韋肽(enfuvirtide)(T-20)、T-1249、PRO-542、PRO-140、TNX-355、BMS-806、5-Helix及類似藥劑;整合酶抑制劑,例如L-870,180及類似藥劑;芽殖抑制劑,例如PA-344及PA-457及類似藥劑;趨化因子受體抑制劑,例如維克韋羅(vicriviroc)(Sch-C)、Sch-D、
TAK779、馬拉韋羅(maraviroc)(UK-427,857)、TAK449以及彼等揭示於WO 02/74769、WO 2004/054974、WO 2004/055012、WO 2004/055010、WO 2004/055016、WO 2004/055011及WO 2004/054581中者及類似藥劑;神經胺糖酸酶抑制劑,例如CS-8958、紮那米韋(zanamivir)、奧司他韋(oseltamivir)、帕拉米韋(peramivir)及類似藥劑;離子通道阻斷劑,例如金剛烷胺(amantadine)或金剛乙胺(rimantadine)及類似藥劑;及干擾RNA及反義寡核苷酸及例如ISIS-14803及類似藥劑;作用機制未確定之抗病毒劑,例如彼等揭示於WO 2005/105761、WO 2003/085375、WO 2006/122011中者、利巴韋林(ribavirin)及類似藥劑。式(I)化合物及其醫藥上可接受之鹽亦可與一或多種可用於預防或治療病毒感染之其他藥劑組合使用,該等其他藥劑例如免疫療法(例如干擾素或其他細胞介素/趨化因子、細胞介素/趨化因子受體調節劑、細胞介素促效劑或拮抗劑及類似藥劑);及治療性疫苗、抗纖維化劑、消炎藥(例如皮質類固醇或NSAID(非類固醇消炎藥))及類似藥劑。
式(I)化合物及其醫藥上可接受之鹽可與一或多種其他可用於預防或治療過敏性疾病、發炎疾病、自身免疫疾病之藥劑組合使用,該等藥劑例如抗原免疫療法、抗組胺、類固醇、NSAID、支氣管擴張藥(例如β2促效劑、腎上腺素促效劑、抗膽鹼劑、茶鹼)、胺甲喋呤、白三烯調節劑及類似藥劑;單株抗體療法,例如抗-IgE、抗-TNF、抗-IL-5、抗-IL-6、抗-IL-12、抗-IL-1及類似藥劑;受體療法,例如依那西普(entanercept)及類似藥劑;抗原非特異性免疫療法(例如干擾素或其他細胞介素/趨化因子、細胞介素/趨化因子受體調節劑、細胞介素促效劑或拮抗劑、TLR促效劑及類似藥劑)。
式(I)化合物及其醫藥上可接受之鹽可與一或多種其他可用於預防或治療癌症之藥劑組合使用,該等藥劑例如化學療法,例如烷基化
試劑、拓撲異構酶抑制劑、抗代謝藥、抗有絲分裂劑、激酶抑制劑及類似藥劑;單株抗體療法,例如曲妥珠單抗(trastuzumab)、吉姆單抗(gemtuzumab)及其他類似藥劑;及激素療法,例如他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)及類似藥劑。
本發明醫藥組合物亦可單獨使用或與至少一種其他用於其他治療領域(例如胃腸道疾病)之治療劑組合使用。本發明組合物亦可與基因替代療法組合使用。
在又一態樣中,本發明包括包含式(I)化合物或其醫藥上可接受之鹽與至少一種其他治療活性劑之組合。
可方便地提供用於以醫藥組合物形式使用之上文所提及之組合且因此包含如上文所定義之組合與其至少一種醫藥上可接受之稀釋劑或載劑之醫藥組合物代表本發明之又一態樣。
式(I)化合物或其醫藥上可接受之鹽之治療有效量將取決於多種因素。例如,接受者之種族、年齡及重量、需要治療之確切病況及其嚴重程度、組合物之性質及投與途徑均係考慮因素。治療有效量最終應由主治醫師確定。不論如何,用於治療患有虛弱之人類之本發明化合物之有效量通常應在每日0.0001mg/kg接受者體重至100mg/kg受試者體重之範圍內。更通常,有效量應在每日0.001mg/kg體重至10mg/kg體重之範圍內。因此,對於70kg成人而言,每日實際量之一實例通常應為7mg至700mg。對於鼻內及吸入投與途徑而言,70kg成人之典型劑量應在每日0.1微克至1mg之範圍內,例如1μg、10μg或100μg。此量可以每日單一劑量或以每日多個(例如2個、3個、4個、5個或更多個)分劑量提供以使得總日劑量相同。式(I)化合物之醫藥上可接受之鹽之有效量可以式(I)化合物或其醫藥上可接受之鹽本身之有效量之比例形式測定。類似劑量應適於治療本文所提及之其他病況。
式(I)化合物及其醫藥上可接受之鹽亦可以任一適當頻率(例如每
週1至7次)投與。當然,精確給藥方案將取決於諸如治療適應症、患者之年齡及狀況、及所選具體投與途徑等因素。在本發明之一態樣中,式(I)化合物或其醫藥上可接受之鹽可每週1次投與達4至8週時間段(例如4週、5週、6週、7週或8週)。可能需要重複治療循環。
醫藥組合物可以每單位劑量含有預定量之活性成份之單位劑型提供。作為限制性實例,此單元可含有0.5mg至1g式(I)化合物或其醫藥上可接受之鹽,此視所治療病況、投與途徑及患者年齡、體重及狀況而定。較佳單位劑量組合物係含有如上文所陳述之日劑量或分劑量、或其適當部分之活性成份之彼等。該等醫藥組合物可藉由任一配藥學領域內熟知方法來製備。
亦提供製備此醫藥組合物之方法,其包含將式(I)化合物或其醫藥上可接受之鹽與一或多種醫藥上可接受之賦形劑混合。
以下列表提供如本文所用之某些縮寫之定義。應瞭解,該列表並非具有排他性,但熟習此項技術者將易於明瞭下文未定義之彼等縮寫之含義。
NMR
在Bruker DPX 400或Bruker Avance DRX、Varian Unity 400光譜儀或JEOL Delta(全部在400MHz下工作)上在CDCl3或DMSO-d 6 中記錄1H NMR光譜。所用內標係四甲基矽烷或在7.25ppm(對於CDCl3而言)或2.50ppm(對於DMSO-d 6 而言)處之殘餘質子化溶劑。
LCMS
系統A
管柱:50mm×2.1mm ID,1.7μm Acquity UPLC BEH C18
流速:1mL/min。
溫度:40℃
UV檢測範圍:210nm至350nm
質譜:在質譜儀上使用交替掃描正向及負向模式電噴霧電離記錄。
溶劑:A:0.1%v/v存於水中之甲酸B:0.1%v/v甲酸/乙腈
系統B
管柱:50mm×2.1mm ID,1.7μm Acquity UPLC BEH C18
流速:1mL/min。
溫度:40℃
UV檢測範圍:210nm至350nm
質譜:在質譜儀上使用交替掃描正向及負向模式電噴霧電離記錄。
溶劑:A:用氨溶液調節至pH 10之存於水中之10mM碳酸氫銨B:乙腈
質譜定向之自動製備型HPLC係在下文所給出之條件下實施。UV檢測係來自210nm至350nm波長之平均信號,且於質譜儀上使用交替掃描正向及負向模式電噴霧電離來記錄質譜。
方法A
在環境溫度下於Sunfire C18管柱(通常150mm×30mm i.d.5μm填充直徑)上實施方法A。所用溶劑係:
A=甲酸存於水中之0.1%v/v溶液。
B=甲酸存於乙腈中之0.1%v/v溶液。
方法B
在環境溫度下在XBridge C18管柱(通常100mm×30mm i.d.5μm填充直徑)上實施方法B。所用溶劑係:
A=用氨溶液調節至pH 10之10mM碳酸氫銨水溶液。
B=乙腈。
中間體1:5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
在室溫下將氯化氫於1,4-二噁烷中之4M溶液(19.4mL,78mmol)添加至4-胺基-1H-吡唑-5-甲酸乙基酯鹽酸鹽(2g,10.44mmol)於戊腈(94mL)中之懸浮液中。在80℃下將所得混合物攪拌22小時。在真空中蒸發經冷卻反應混合物,得到褐色固體,將其溶解於乙醇(29mL)中,添加至氫氧化鈉(1.67g,41.7mmol)於水(7.1mL)中之溶液中並在100℃下攪拌1小時。將反應冷卻至室溫,用水(65mL)稀釋並使用2M檸檬酸水溶液將pH調節至10。用乙酸乙酯(220mL)萃取反應混合物。分離出有機相,通過疏水性玻璃料並在真空中蒸發,得到褐色固體。使用2M檸檬酸水溶液將剩餘水溶液調節至pH 7並用乙酸乙酯(220mL)萃取。分離出有機相,通過疏水性玻璃料並在真空中蒸發,得到褐色固體。合併兩個批次褐色固體,得到固體(3.3g)。在室溫下將N-碘琥珀醯亞胺(3.52g,15.66mmol)逐份添加至固體(3.3g)於無水N,N-二甲基甲醯胺(43mL)中之溶液中。在60℃下將混合物攪拌2小時。在真空中蒸發經冷卻反應並分配於乙酸乙酯與水/鹽水(1:1)之間。分離出有機層。通過疏水性玻璃料並在真空中蒸發,得到褐色固體(6.3g)。將固體溶解於乙酸乙酯中,裝載至2×50g ISOLUTE NH2柱上並使用乙酸乙酯(2×400mL)、5%存於二氯甲烷中之甲醇(2×200
mL)、10%存於二氯甲烷中之甲醇(2×100mL)、15%存於二氯甲烷中之甲醇(2×100mL)及最後20%存於二氯甲烷中之甲醇(2×700mL)作為洗脫液來實施純化。合併適當流份並在真空中蒸發,得到呈白色固體形式之標題化合物(2.12g)。
LCMS(系統A):tRET=0.79min;MH+ 319
中間體2:1-(己-5-炔-1-基)六氫吡啶
將6-氯己-1-炔(5mL,41.3mmol)、六氫吡啶(4.08mL,41.3mmol)及碳酸氫鈉(4.16g,49.5mmol)於DMF(50mL)中之溶液回流16小時。在真空中濃縮反應並將殘餘物分配於醚(150mL)與水(150mL)之間。分離出有機物及用二乙基醚(50mL)反萃取水溶液。用鹽水(150mL)洗滌合併有機物,乾燥(MgSO4),過濾並在真空中濃縮,得到粗製標題化合物樣品(3.74g)。將草酸(2.161g,24mmol)添加至粗製產物中。使所得固體自乙醇重結晶,藉由過濾來收集並在真空中乾燥,得到1-(己-5-炔-1-基)六氫吡啶草酸鹽(4.66g)。將固體分配於二乙基醚(150mL)與飽和碳酸氫鈉水溶液(150mL)之間。分離出有機物並乾燥(MgSO4),過濾並在真空中濃縮,得到呈黃色油狀物形式之標題化合物(1.93g)。
1H NMR(400MHz,氯仿-d)δppm 2.31-2.52(m,6 H)2.18-2.26(m,2 H)1.92-1.96(m,1 H)1.40-1.72(m,10 H)
中間體3:5-丁基-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
在室溫及氮氣氣氛下向5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(300mg,0.943mmol)於無水N,N-二甲基甲醯胺(7mL)中之經脫氣溶液中添加碘化銅(I)(36mg,0.189mmol)、四(三苯基膦)-鈀(0)(120mg,0.104mmol)及最後三乙胺(0.289mL,2.075mmol)。在室溫及氮氣氣氛下將混合物攪拌10分鐘且然後添加1-(5-己炔-1-基)六氫吡啶(343
mg,2.075mmol)於無水N,N-二甲基甲醯胺(1mL)中之溶液。在室溫下將反應混合物攪拌23小時。在真空中蒸發反應,得到褐色油狀物,用二氯甲烷(15mL)稀釋該油狀物,裝載至70g ISOLUTE NH2柱上並藉由層析使用0-25%存於二氯甲烷中之甲醇梯度經80分鐘純化(UV收集波長設定為233nm)。合併適當流份並在真空中蒸發,得到淺黃色油狀物(330mg)。使該油狀物(330mg)於乙醇(50mL)中之溶液通過H-cube(設定:45℃,全氫,流速1mL/min且10%鈀碳CatCart30作為觸媒)。在真空中蒸發溶液,得到無色油狀物。將該油狀物溶解於MeOH:DMSO(1:1)(4 x 1mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到白色固體(205mg)。使該固體(205mg)於乙醇(40mL)中之溶液通過H-cube(設定:45℃,全氫,流速1mL/min且10%鈀碳CatCart30作為觸媒)。在真空中蒸發溶液,得到白色固體標題化合物(201mg)。
LCMS(系統B):tRET=0.93min;MH+ 360
中間體4:3-碘-5-(2-甲氧基乙基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
在室溫下將氯化氫於1,4-二噁烷中之4M溶液(5.19mL,20.74mmol)添加至4-胺基-1H-吡唑-5-甲酸乙基酯鹽酸鹽(535mg,2.79mmol)於3-甲氧基丙腈(25.7mL,240mmol)中之懸浮液中。在80℃下將所得混合物攪拌2.5小時。在真空中蒸發經冷卻反應混合物,得到淺黃色固體,將其溶解於乙醇(7.7mL)中,添加至氫氧化鈉(447mg,11.17mmol)於水(1.9mL)中之溶液中並在室溫下攪拌20分鐘。在真空中蒸發反應,得到褐色固體。在室溫下將N-碘琥珀醯亞胺(942mg,4.19mmol)逐份添加至以上化合物於無水N,N-二甲基甲醯胺(DMF)(11.3mL)中之溶液中。在60℃下將混合物攪拌45分鐘。在真空中蒸發經冷卻反應。
將殘餘物溶解於最小體積之二氯甲烷中,裝載至2×50g
ISOLUTE NH2柱上並藉由層析使用0-50%MeOH/DCM梯度經60分鐘純化。合併適當流份並在真空中蒸發,得到奶油色固體(203mg)。合併來自管柱之含有期望產物之不純流份,在真空中濃縮,然後藉由層析使用與上文相同之方法再純化。合併來自該兩個管柱之產物,得到呈黃色固體形式之標題化合物(309mg)。
LCMS(系統A):tRET=0.54min;MH+ 321
中間體5:5-(2-甲氧基乙基)-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
在氮氣氣氛及室溫下向3-碘-5-(2-甲氧基乙基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(232mg,0.724mmol)於無水N,N-二甲基甲醯胺(5mL)中之經脫氣溶液中添加碘化銅(I)(27.6mg,0.145mmol)、四(三苯基膦)-鈀(0)(92mg,0.080mmol)及最後三乙胺(0.222mL,1.592mmol)。在室溫及氮氣氣氛下將混合物攪拌10分鐘且然後添加1-(5-己炔-1-基)六氫吡啶(263mg,1.592mmol)於無水N,N-二甲基甲醯胺(1mL)中之溶液。在室溫下將反應混合物攪拌20小時,然後加熱至55℃並使其攪拌5小時。在真空中蒸發反應,得到褐色油狀物。用二氯甲烷稀釋該油狀物,裝載至50g ISOLUTE NH2柱上並藉由層析使用0-50%存於二氯甲烷中之甲醇梯度經60分鐘純化(UV收集波長設定為230nm)。合併適當流份並在真空中蒸發,得到淺黃色油狀物(188mg)。使油狀物(188mg)於乙醇(30mL)中之溶液通過H-cube(設定:45℃,全氫,流速1mL/min且10%鈀碳CatCart30作為觸媒)。在真空中蒸發溶液,得到淺黃色油狀物並藉由MDAP(方法B)來純化粗製產物。合併適當流份並在真空中蒸發,得到呈透明油狀物形式之標題化合物(117mg)。
LCMS(系統B):tRET=0.76min;MH+ 362
中間體6:5-丁基-3-(6-氯己-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
向5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(4.97g,15.62mmol)於N,N-二甲基甲醯胺(100mL)中之溶液中添加雙(三苯基膦)二氯化鈀(II)(1.228g,1.750mmol)及碘化銅(I)(0.595g,3.12mmol)。攪拌溶液並用氮氣脫氣5分鐘,然後將反應混合物放置於氮氣氣氛下。經10分鐘逐滴添加6-氯-1-己炔(3.64g,31.2mmol)及三乙胺(4.36mL,31.2mmol)於N,N-二甲基甲醯胺(30mL)中之溶液。在環境溫度下將反應混合物再攪拌10分鐘,然後加熱至60℃,保持2.5小時。在60℃下在真空中濃縮反應混合物並將所得殘餘物分配於乙酸乙酯(250mL)與水:鹽水之1:1混合物(500mL)之間。分離出有機層並用乙酸乙酯(250mL)反萃取水層。藉助疏水性玻璃料來乾燥合併之有機相並在真空中濃縮,得到褐色固體(8.0g)。將殘餘物溶解於MeOH:DCM之1:1混合物中並吸附至Florisil上。裝載固體並藉由層析在二氧化矽(330g)上使用10倍管柱體積之0-100%之乙酸乙酯-環己烷梯度、隨後用9倍管柱體積之乙酸乙酯沖洗來純化。合併適當流份並在真空中蒸發,得到黃色固體(3.55g)。用二異丙基醚研磨固體,過濾並在50℃下在真空中乾燥,得到呈淺黃色固體形式之標題化合物(3.14g)。
LCMS(系統B):tRET=0.98min;MH+ 307,309
中間體7:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
向5-丁基-3-(6-氯己-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(2.59g,8.44mmol)於無水乙腈(115mL)中之懸浮液中添加吡咯啶(2.11mL,25.3mmol)及三乙胺(3.53mL,25.3mmol)。在80℃下將反應攪拌3.5小時。再向反應中添加2.11mL(25.3mmol)吡咯啶及3.53mL(25.3mmol)三乙胺。在80℃下將反應再攪拌18小時。將經冷卻反應分配於乙酸乙酯與水之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到黃色油狀物(1.9g)。用20%存於二氯甲烷中之甲醇再萃
取剩餘水溶液。使有機層通過疏水性玻璃料並在真空中蒸發,得到黃色油狀物(1.02g)。合併兩種黃色油狀物,得到黃色油狀物(2.92g)。在室溫及氫氣氣氛下將該油狀物與10wt%鈀碳(350mg)於乙醇(120mL)中之混合物攪拌90分鐘。在氮氣氣氛下再向反應中添加350mg10wt%鈀碳並在室溫及氫氣氣氛下將反應攪拌60分鐘。在氮氣氣氛下再向反應中添加350mg 10wt%鈀碳並在室溫及氫氣氣氛下將反應攪拌60分鐘。藉助10g矽藻土柱來過濾反應混合物並在真空中蒸發濾液,得到黃色油狀物(2.8g)。將該油狀物溶解於最小體積之二氯甲烷中,裝載至375g Biotage KP-NH柱上並使用12倍管柱體積之0-10%之存於二氯甲烷中之甲醇梯度、隨後3倍管柱體積之10%存於二氯甲烷中之甲醇來純化。合併適當流份並在真空中蒸發,得到呈淺黃色固體形式之標題化合物(1.845g)。
LCMS(系統B):tRET=0.85min;MH+ 346
合併來自層析之不純流份並在真空中蒸發,得到黃色油狀物(380mg)。將該油狀物溶解於MeOH:DMSO(1:1)(4×1ml)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到又一份標題化合物(淺黃色油狀物)(198mg)。
中間體8:5-丁基-N-(3,4-二甲氧基苄基)-3-碘-1H-吡唑并[4,3-d]嘧啶-7-胺
在室溫及氮氣氣氛下向5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(5g,15.72mmol)及(苯并三唑-1-基氧基)叁(二甲基胺基)鏻六氟磷酸鹽(10.43g,23.58mmol)於無水DMF(250mL)中之溶液中添加1,8-二氮雜雙環[5.4.0]十一-7-烯(4.23mL,28.3mmol)並將反應混合物攪拌2.5小時。添加(3,4-二甲氧基苯基)甲胺(20mL,94mmol)並將混合物升溫至40℃,保持3小時。在真空中蒸發反應混合物並將所得油狀物分配於乙酸乙酯與水之間。分離出有機層,用鹽水洗滌,經MgSO4乾燥,
過濾並在真空中蒸發,得到呈半結晶形式之黃色油狀物(23.7g)。將殘餘物吸附於Florosil上,裝載至經預處理之330g二氧化矽柱上並藉由層析使用1倍管柱體積之環己烷、隨後14倍管柱體積之0-100%之存於環己烷中之乙酸乙酯梯度、隨後4倍管柱體積之乙酸乙酯來純化。合併僅含有期望物質之適當流份(藉助LC-MS分析)並在真空中蒸發,得到呈淺黃色泡沫狀物形式之標題化合物(4.58g)。
LCMS(系統B):tRET=1.08-1.09min:MH+ 468
1H NMR(400MHz,DMSO-d 6)包括δ=7.90-7.65(m,1 H),7.05(s,1 H),6.93(s,2 H),4.70-4.61(m,2 H),3.73(s,6 H),2.75-2.67(m,2 H),1.78-1.67(m,2 H),1.40-1.28(m,2 H),0.90(t,3 H)
中間體9:5-丁基-3-(6-氯己-1-炔-1-基)-N-(3,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺
在氮氣氣氛下將5-丁基-N-(3,4-二甲氧基苄基)-3-碘-1H-吡唑并[4,3-d]嘧啶-7-胺(4.58g,9.7mmol)、碘化銅(I)(278mg,1.46mmol)及雙(三苯基膦)二氯化鈀(II)(515mg,0.734mmol)於無水N,N-二甲基甲醯胺(105mL)中之經氮氣脫氣之經攪拌混合物升溫至60℃,隨後經5分鐘逐滴添加6-氯-1-己炔(1.712g,14.69mmol)及三乙胺(2.047mL,14.69mmol)於經氮氣脫氣之無水N,N-二甲基甲醯胺(15mL)中之溶液。在60℃下將反應攪拌6小時。在真空中蒸發經冷卻反應混合物並將所得油狀物分配於1:1水/鹽水與乙酸乙酯之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到橙色油狀物。將該油狀物溶解於最小體積之二氯甲烷中,裝載至330g經預處理之二氧化矽柱上並藉由層析使用1倍管柱體積之環己烷、隨後14倍管柱體積之0-100%之存於環己烷中之乙酸乙酯梯度、隨後2倍管柱體積之乙酸乙酯來純化。合併適當流份並在真空中蒸發,得到呈黃色泡沫狀物形式之標題化合物(3.334g)
LCMS(系統B):tRET=1.26,1.28min;MH+ 456
1H NMR(400MHz,氯仿-d)δ=6.90(br.s.,2 H),6.81-6.70(m,1 H),4.77(br.s.,2 H),3.94-3.72(m,6 H),3.49(t,J=6.5Hz,2 H),2.88(t,J=7.8Hz,2 H),2.25(br.s.,2 H),1.90-1.71(m,4 H),1.62-1.52(m,2 H),1.48-1.31(m,2 H),0.93(t,J=7.3Hz,3 H)
中間體10:5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(吡咯啶-1-基)己-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7-胺
向5-丁基-3-(6-氯己-1-炔-1-基)-N-(3,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(3.334g,7.31mmol)於無水乙腈(4mL)中之溶液中添加三乙胺(3.06mL,21.94mmol)及吡咯啶(1.831mL,21.94mmol)。在70℃下將溶液攪拌18小時。再向反應混合物中添加1當量吡咯啶(0.61mL,7.31mmol)及三乙胺(1.019mL,7.31mmol)。在70℃下將溶液再攪拌3小時。在真空中蒸發經冷卻反應混合物並將殘餘物分配於乙酸乙酯與水之間/鹽水(1:1)。分離出有機相,通過疏水性玻璃料並在真空中蒸發,得到黏性褐色膠狀物(4.226g)。將膠狀物溶解於最小體積之二氯甲烷中,裝載至340g經預處理之二氧化矽柱上並藉由層析使用1倍管柱體積之二氯甲烷、隨後14倍管柱體積之0-30%之存於二氯甲烷中之甲醇(+1%三乙胺)梯度、隨後3倍管柱體積之30%存於二氯甲烷中之甲醇(+1%三乙胺)來純化。合併適當流份並在真空中蒸發,得到呈黏性褐色膠狀物形式之標題化合物(1.838g)。
LCMS(系統B):tRET=1.11-1.17min;MH+ 491
1H NMR(400MHz,甲醇-d 4)包括δ=7.07-7.04(m,1 H),7.00-6.95(m,1 H),6.92(s,1 H),4.76(s,2 H),3.83-3.78(m,6 H),2.82-2.56(m,10 H),1.90-1.67(m,10 H),1.44-1.32(m,2 H),0.94(t,J=7.3Hz,3 H)
中間體11:3-(6-氯己-1-炔-1-基)-5-(2-甲氧基乙基)-1H-吡唑并[4,3-d]
嘧啶-7(6H)-酮
在室溫及氮氣氣氛下向3-碘-5-(2-甲氧基乙基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(307mg,0.959mmol)於無水N,N-二甲基甲醯胺(6mL)中之經氮氣脫氣之溶液中添加碘化銅(I)(36.5mg,0.192mmol)、雙(三苯基膦)二氯化鈀(II)(75mg,0.107mmol)及最後三乙胺(0.267mL,1.918mmol)。在室溫及氮氣氣氛下將混合物攪拌10分鐘且然後添加6-氯己-1-炔(224mg,1.918mmol)於無水N,N-二甲基甲醯胺(1.5mL)中之溶液。在60℃下將該反應混合物攪拌2小時。添加另2當量6-氯己-1-炔(224mg,1.918mmol)並在60℃下使反應攪拌1小時。在真空中蒸發反應,得到深紅色油狀物。將該油狀物分配於水/鹽水(1:1)與乙酸乙酯之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到橙色油狀物(621mg)。將粗製物質溶解於最小之量DCM中,裝載至50g二氧化矽柱上並藉由層析使用0-100%之存於環己烷中之乙酸乙酯梯度經60分鐘純化。合併含有期望產物之適當流份並在真空中蒸發,得到呈淺黃色固體形式之標題化合物(163.5mg)。
LCMS(系統A):tRET=0.80min;MH+ 309,311
中間體12:5-(2-甲氧基乙基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
向3-(6-氯己-1-炔-1-基)-5-(2-甲氧基乙基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(84mg,0.230mmol)於無水N,N-二甲基甲醯胺(4mL)中之溶液中添加吡咯啶(0.132mL,1.579mmol)及三乙胺(0.293mL,2.105mmol)。在80℃下將反應攪拌2小時。向反應中再添加66μL(1.5當量)吡咯啶及147μL(2當量)三乙胺並在80℃下將反應攪拌2小時。向反應中再添加66μL(1.5當量)吡咯啶及147μL(2當量)三乙胺。在80℃下將反應攪拌1小時。在真空中蒸發反應,得到深黃色油狀物。使該油狀物於乙醇(35mL)中之溶液通過H-cube(設定:55℃,全氫,流速1
mL/min且10%鈀碳CatCart30作為觸媒)。將新10%鈀碳CatCart30柱插入H-cube中並使溶液再次通過H-cube(設定:55℃,全氫,流速1mL/min)。在真空中蒸發溶液,得到淺黃色油狀物並藉由MDAP(方法B)來純化粗製產物。合併適當流份並在真空中蒸發,得到呈透明油狀物形式之標題化合物(84mg)。
LCMS(系統A):tRET=0.46min;MH+ 348
中間體13:5-丁基-3-(5-氯戊-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
在室溫及氮氣氣氛下向5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(250mg,0.786mmol)於無水N,N-二甲基甲醯胺(6mL)中之經氮氣脫氣之溶液中添加碘化銅(I)(30mg,0.158mmol)、雙(三苯基膦)二氯化鈀(II)(62mg,0.088mmol)及最後三乙胺(0.219mL,1.572mmol)。在室溫及氮氣氣氛下將混合物攪拌10分鐘且然後添加5-氯-1-戊炔(161mg,1.572mmol)於無水N,N-二甲基甲醯胺(1.5mL)中之溶液。在60℃下將反應混合物攪拌80分鐘。在真空中蒸發反應,得到褐色油狀物。將該油狀物分配於水/鹽水(1:1)與乙酸乙酯之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到褐色固體。將固體吸附於Florisil上,裝載至50g二氧化矽柱上並藉由層析使用0-100%之存於環己烷中之乙酸乙酯梯度經60分鐘純化。合併適當流份並在真空中蒸發,得到呈淺黃色固體形式之標題化合物(172mg)。
LCMS(系統A):tRET=0.91min;MH+ 293,295
中間體14:5-丁基-3-(5-(六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
向5-丁基-3-(5-氯戊-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(168mg,0.574mmol)於無水N,N-二甲基甲醯胺(3.5mL)中之溶液中添加六氫吡啶(147mg,1.722mmol)及三乙胺(0.32mL,2.295mmol)於無
水N,N-二甲基甲醯胺(0.5mL)中之溶液。在80℃下將反應攪拌190分鐘。向反應中再添加73mg(0.857mmol)六氫吡啶及160μL(1.148mmol)三乙胺。在80℃下將反應再攪拌2.5小時且然後在室溫下攪拌15.5小時。向反應中再添加73mg(0.857mmol)六氫吡啶及160μL(1.148mmol)三乙胺。在80℃下將反應攪拌2.5小時。在真空中蒸發反應,得到深黃色油狀物。使該油狀物於乙醇(50mL)中之溶液通過H-cube(設定:30℃,全氫,流速1mL/min且10%鈀碳CatCart30作為觸媒)。將新10%鈀碳CatCart30柱插入H-cube中並使溶液再次通過H-cube(設定:30℃,全氫,流速1mL/min)。在真空中蒸發溶液,得到淺黃色油狀物。將該油狀物溶解於MeOH:DMSO(1:1)(3×1mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到呈淺黃色固體形式之標題化合物(91mg)。
LCMS(系統B):tRET=0.83min;MH+ 346
中間體15:5-丁基-3-(5-(吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮
在室溫及氮氣氣氛下向5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(79mg,0.248mmol)於無水N,N-二甲基甲醯胺(2.0mL)中之經脫氣溶液中添加碘化銅(I)(10mg,0.053mmol)、四(三苯基膦)-鈀(0)(32mg,0.028mmol)及最後三乙胺(0.076mL,0.546mmol)。在室溫及氮氣氣氛下將混合物攪拌10分鐘且然後添加1-(4-戊炔-1-基)吡咯啶(75mg,0.546mmol)(Chemical Communications 46(19),3351-3353;2010)於無水N,N-二甲基甲醯胺(0.5mL)中之溶液。在55℃下將反應混合物攪拌1小時。將1-(4-戊炔-1-基)吡咯啶(75mg,0.546mmol)於無水N,N-二甲基甲醯胺(0.5mL)中之溶液添加至反應中。在55℃下將反應混合物攪拌40分鐘。在真空中蒸發反應,得到深黃色油狀物。使該油狀物於乙醇(15mL)中之經過濾溶液通過H-cube(設定:45℃,全氫,流速1
mL/min且10%鈀碳CatCart30作為觸媒)。使溶液再通過H-cube 2次,每次皆使用新CatCart 30柱。在真空中蒸發溶液,得到無色油狀物。將該油狀物溶解於MeOH:DMSO(1:1)(1mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到呈白色固體形式之標題化合物(20mg)。
LCMS(系統B):tRET=0.79min;MH+ 332
中間體16:5-丁基-N-(2,4-二甲氧基苄基)-3-碘-1H-吡唑并[4,3-d]嘧啶-7-胺
用((1H-苯并[d][1,2,3]三唑-1-基)氧基)三(吡咯啶-1-基)鏻六氟磷酸鹽(V)(100g,192mmol)處理5-丁基-3-碘-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(50g,157mmol)、(2,4-二甲氧基苯基)甲胺(60g,359mmol)及2,3,4,6,7,8,9,10-八氫嘧啶并[1,2-a]氮呯(47.9g,314mmol)於乙腈(500mL)中之溶液並在室溫及氮氣下攪拌6小時。過濾所得懸浮液以去除沈澱物並蒸發濾液。在二氧化矽柱(1500g)上(以最少DCM施加)用0-80%環己烷-EtOAc(12倍管柱體積)洗脫來純化殘餘物。使含有產物之流份部分蒸發,得到重懸浮液,將其過濾並將固體風乾,得到呈白色粉末形式之標題化合物(37.5g,80mmol)。
LCMS(系統A):tRET=0.91min;MH+ 468
1H NMR(400MHz,氯仿-d)包括δ=6.43-6.33(m,2H),4.76(s,2H),3.79(s,3H),3.67(s,3H),2.90-2.80(m,2H),1.84(s,2H),1.48-1.35(m,2H),0.94(t,J=7.3Hz,3H)
蒸發母液及不純流份,得到黃色固體。用乙酸乙酯研磨合併之不純物質,得到奶油色固體(30g)。用二乙基醚(50mL)、隨後DCM/Et2O(1:1,30mL)進一步研磨,得到另一份呈白色固體形式之標題化合物(25.7g)。
中間體17:5-丁基-3-(6-氯己-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡
唑并[4,3-d]嘧啶-7-胺
在氮氣下將5-丁基-N-(2,4-二甲氧基苄基)-3-碘-1H-吡唑并[4,3-d]嘧啶-7-胺(50g,107mmol)、6-氯-1-己炔(18.71g,160mmol)、三乙胺(22.37mL,160mmol)、雙(三苯基膦)二氯化鈀(II)(5.63g,8.02mmol)及碘化銅(I)(3.04g,15.94mmol)於N,N-二甲基甲醯胺(1000mL)中之溶液加熱至70℃,保持4小時。蒸發經冷卻溶液並藉由層析在1.5kg二氧化矽柱上用12倍管柱體積之20-80%環己烷-EtOAc洗脫來純化殘餘物。蒸發適當流份,得到呈黃色泡沫狀物形式之標題化合物(25.5g)。
LCMS(系統A):tRET=1.05min;MH+ 456,458
1H NMR(400MHz,氯仿-d)包括δ=6.71-6.54(m,1H),6.41-6.31(m,2H),4.75(br.s.,2H),3.77(s,4H),3.67(br.s.,3H),3.50-3.43(m,2H),2.89-2.76(m,3H),2.26-2.15(m,2H),1.30-1.20(m,1H),0.92(t,J=7.3Hz,3H)
中間體18:5-丁基-N-(2,4-二甲氧基苄基)-3-(6-(吡咯啶-1-基)己-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7-胺
在70℃下將5-丁基-3-(6-氯己-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(30g,65.8mmol)、吡咯啶(16.32mL,197mmol)及Et3N(27.5mL,197mmol)於乙腈(400mL)中之溶液加熱16小時。添加另外的吡咯啶(7g)並在70℃下將溶液加熱8小時。蒸發經冷卻溶液並在二氧化矽柱(750g)上用EtOAc(2倍管柱體積)、隨後20-30%MeOH(+1%Et3N)/EtOAc(16倍管柱體積)洗脫來純化殘餘物,得到呈黃色膠狀物形式之標題化合物(23.3g)。
LCMS(系統B):tRET=1.15min;MH+ 491
1H NMR(400MHz,氯仿-d)包括δ=7.31-7.25(m,1H),6.42-6.23(m,2H),4.76(br.S.,2H),3.76(s,3H),3.65(s,3H),2.88-2.78
(m,6H),2.67-2.60(m,2H),2.18-2.11(m,2H),1.93-1.75(m,6H),1.63(br.S.,2H),1.43-1.28(m,4H),0.91(t,J=7.3Hz,3H)。
中間體19:5-丁基-N-(2,4-二甲氧基苄基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
在Pd-C(5g,4.70mmol)上對5-丁基-N-(2,4-二甲氧基苄基)-3-(6-(吡咯啶-1-基)己-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7-胺(20g,40.8mmol)於乙醇(500mL)中之溶液實施氫化4小時(H2完全消耗)。藉助Hyflo來過濾混合物並蒸發。在120g二氧化矽柱(Redisep Gold)上用甲苯-乙醇-NH3(85/15/1.5)以7個批次洗脫來純化存於DCM(30mL)中之殘餘物-每次取出產物及下游運行雜質並再循環柱(總體積為約3公升)。蒸發適當流份,得到呈黃色膠狀物形式之標題化合物(16.3g)。
LCMS(系統B):tRET=1.15min;MH+ 495
1H NMR(400MHz,氯仿-d)包括δ=6.49-6.41(m,2H),6.12-6.02(m,1H),4.82(br.s.,2H),3.85-3.78(m,6H),3.04-2.96(m,2H),2.88-2.80(m,2H),2.57(br.s.,4H),2.50-2.43(m,2H),0.97(t,J=7.3Hz,3H)
中間體20:7-(5-丁基-7-((2,4-二甲氧基苄基)胺基)-1H-吡唑并[4,3-d]嘧啶-3-基)庚-1-醇
將雙(三苯基膦)二氯化鈀(II)(68mg,0.097mmol)、三乙胺(0.537mL,3.85mmol)及碘化銅(37mg,0.194mmol)添加至5-丁基-N-(2,4-二甲氧基苄基)-3-碘-1H-吡唑并[4,3-d]嘧啶-7-胺(600mg,1.284mmol)於無水N,N-二甲基甲醯胺(15mL)中之經氮氣脫氣之溶液中。在氮氣氣氛下將混合物攪拌並加熱至60℃,隨後添加存於無水N,N-二甲基甲醯胺(2mL)中之庚-6-炔-1-醇(432mg,3.85mmol)。在60℃下將反應攪拌2.5小時。再向反應中添加存於無水N,N-二甲基甲醯胺(0.5mL)中之0.5當量庚-6-炔-1-醇(72mg,0.642mmol)。在60℃及氮氣氣氛下將混合物
再攪拌2.5小時。再向反應中添加存於無水N,N-二甲基甲醯胺(0.5mL)中之0.5當量庚-6-炔-1-醇(72mg,0.642mmol)。在60℃及氮氣氣氛下將混合物攪拌4小時且然後使其冷卻至環境溫度,過夜。在真空中蒸發反應混合物,得到褐色油狀物。將所得油狀物分配於乙酸乙酯(25mL)與水/鹽水(1:1,15mL)之間。分離出有機層並用乙酸乙酯(25mL)反萃取水相。使合併之有機萃取物通過疏水性玻璃料並在真空中蒸發,得到呈橙色油狀物形式之中間體炔(1.21g)。
在氫氣氣氛下將該油狀物及10%鈀碳(200mg)於乙醇(20mL)中之混合物攪拌22小時。藉助矽藻土柱(10g)過濾反應並在真空中蒸發,得到橙色油狀物。將該油狀物溶解於最小體積之二氯甲烷中,裝載至50g二氧化矽柱上並使用0-100%梯度之存於環己烷中之乙酸乙酯經60分鐘、隨後用乙酸乙酯(300mL)、然後10%存於二氯甲烷(70mL)中之甲醇洗脫來純化。合併適當流份並在真空中蒸發,得到橙色油狀物。將該油狀物溶解於最小體積之二氯甲烷中,裝載至50g二氧化矽柱上並使用0-10%梯度之存於二氯甲烷中之甲醇經40min純化。(檢測波長=230nm)。合併適當流份並在真空中蒸發,得到黃色油狀物(380mg)。在氫氣氣氛下將該油狀物及10%鈀碳(200mg)於乙醇(20mL)中之混合物攪拌20小時。藉助矽藻土柱(10g)過濾反應並在真空中蒸發,得到呈淺黃色油狀物形式之標題化合物(264mg)。
LCMS(系統B):tRET=1.17min;MH+ 456
中間體21:3-(7-溴庚基)-5-丁基-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺
將三苯基膦(182mg,0.695mmol)於二氯甲烷(2mL)中之溶液逐滴添加至7-(5-丁基-7-((2,4-二甲氧基苄基)胺基)-1H-吡唑并[4,3-d]嘧啶-3-基)庚-1-醇(264mg,0.579mmol)及四溴化碳(231mg,0.695mmol)於二氯甲烷(5mL)中之經攪拌溶液中。在室溫下將反應攪拌18小時。向
反應混合物中添加又一份四溴化碳(231mg,0.695mmol)及三苯基膦(182mg,0.695mmol)。在環境溫度下繼續攪拌2小時。在真空中蒸發溶劑,得到黃色油狀物。將該油狀物溶解於無水二氯甲烷(DCM)(7mL)中並在室溫下攪拌1.5小時。將四溴化碳(231mg,0.695mmol)及三苯基膦(182mg,0.695mmol)添加至反應混合物中。在環境溫度下繼續攪拌17.5小時。向反應混合物中添加額外四溴化碳(115mg,0.348mmol)及三苯基膦(91mg,0.348mmol)。在環境溫度下繼續攪拌2小時。在真空中蒸發反應,得到透明油狀物。將所得油狀物分配於乙酸乙酯(10mL)與水/鹽水(1:1,15mL)之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到淺黃色固體(1.40g)。將固體溶解於最小體積之二氯甲烷中,裝載至50g二氧化矽柱上並使用0-100%梯度之存於環己烷中之乙酸乙酯經60分鐘、隨後0-20%存於DCM中之甲醇經30分鐘純化。合併僅含有一種組份之流份並在真空中蒸發,得到呈淺黃色油狀物形式之標題化合物(55mg)。
LCMS(系統B):tRET=1.47min;MH+ 518,520
合併含有兩種組份之流份並在真空中蒸發,得到另一份呈1:1混合物形式之標題化合物及呈淺黃色油狀物形式之三苯基氧化膦(270mg)。
LCMS(系統B):tRET=1.47min;MH+ 518,520:0.98min;MH+ 279
中間體22:3-(6-(氮雜環庚-1-基)己基)-5-丁基-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺
在環境溫度下向5-丁基-3-(6-氯己-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(400mg,0.877mmol)及六亞甲基亞胺(0.297mL,2.63mmol)於乙腈(7mL)中之懸浮液中添加三乙胺(0.367mL,2.63mmol)。在60℃及氮氣下將該反應混合物攪拌16小時。將溫
度增加至80℃並在氮氣下使反應混合物再攪拌7小時。在60℃及氮氣下向反應混合物中添加六亞甲基亞胺(0.149mL,1.32mmol)及三乙胺(0.184mL,1.32mmol)之溶液並使攪拌72小時。在真空中蒸發反應混合物,得到褐色油狀物,將其分配於乙酸乙酯(50mL)與水(50mL)之間。萃取水層並用鹽水(50mL)洗滌有機層,使用疏水性玻璃料乾燥並在真空中濃縮,得到褐色油狀物。將油狀物溶解於最小量之二氯甲烷中,然後裝載至胺基丙基二氧化矽柱(50g)上並使用0-100%梯度之乙酸乙酯-環己烷、隨後0-25%梯度之甲醇-二氯甲烷純化60分鐘。合併適當流份並在真空中蒸發,得到褐色油狀物,然後將其與二氯甲烷與石油醚(40-60)共沸,得到褐色固體(0.185g)。
將固體溶解於乙醇(45mL)中並使用H-cube(設定:40℃,全H2,流速1mL/min)及5%Pd/C CatCart 30作為觸媒來實施氫化。在真空中濃縮所獲得溶劑,得到褐色油狀物,將其溶解於乙醇(20mL)中並使用H-cube(設定:40℃,全H2,1mL/min流速)及5%Pd/C CatCart 30作為觸媒來實施氫化。使用H-cube(設定:40℃,Full H2,1mL/min流速)及相同5%Pd/C CatCart 30作為觸媒對溶劑實施進一步氫化。在真空中蒸發所獲得溶液,得到褐色油狀物。然後將該褐色油狀物溶解於最小量之二氯甲烷中,然後將其裝載於胺基丙基二氧化矽(20g)上並藉由層析使用0-10%梯度之甲醇-二氯甲烷純化40分鐘。合併適當流份並在真空中蒸發,得到褐色油狀物,然後將其與二氯甲烷及石油醚(40-60)共沸,得到呈褐色油狀物形式之標題化合物(0.100g)。
LCMS(系統B):tRET=1.19min;MH+ 523
中間體23:5-丁基-3-(5-氯戊-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺
將雙(三苯基膦)二氯化鈀(II)(101mg,0.144mmol)、三乙胺(0.403mL,2.89mmol)及碘化銅(55.0mg,0.289mmol)添加至經氮氣脫
氣之5-丁基-N-(2,4-二甲氧基苄基)-3-碘-1H-吡唑并[4,3-d]嘧啶-7-胺(900mg,1.926mmol)於無水N,N-二甲基甲醯胺(23mL)中之溶液中。在氮氣氣氛下攪拌混合物並加熱至60℃,隨後添加存於無水N,N-二甲基甲醯胺(2mL)中之5-氯戊-1-炔(296mg,2.89mmol)。在60℃下將反應攪拌3小時。再向反應中添加存於無水N,N-二甲基甲醯胺(1mL)中之0.30當量5-氯戊-1-炔(59mg,0.575mmol)。在60℃下將混合物再攪拌2.5小時且然後使其冷卻至室溫,過夜。在真空中蒸發反應混合物,得到褐色油狀物。將所得油狀物分配於乙酸乙酯(25mL)與水/鹽水(1:1,10mL)之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到褐色油狀物(1.32g)。將該油狀物溶解於最小體積之二氯甲烷中,裝載至100g二氧化矽柱上並藉由層析使用0-100%梯度之存於環己烷中之乙酸乙酯經60分鐘純化。合併適當流份並在真空中蒸發,得到橙色油狀物。將該油狀物溶解於最小體積之二氯甲烷中,裝載至100g二氧化矽柱上並藉由層析使用0-100%梯度之存於環己烷中之乙酸乙酯經60分鐘再純化。合併適當流份並在真空中蒸發,得到呈橙色油狀物形式之標題化合物(720mg)。
LCMS(系統B):tRET=1.32min;MH+ 442,444
中間體24:(S)-5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
向5-丁基-3-(6-氯己-1-炔-1-基)-N-(3,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(225mg,0.493mmol)於乙腈(4mL)中之經攪拌溶液中添加三乙胺(0.413mL,2.96mmol)及(S)-3-氟吡咯啶鹽酸鹽(186mg,1.480mmol)。在60℃下將所得混合物加熱22小時。向反應混合物中添加另外的(S)-3-氟吡咯啶鹽酸鹽(186mg,1.480mmol)及另外的三乙胺(0.413mL,2.96mmol)並在75℃下繼續加熱20小時。在真空中濃縮反應混合物並將殘餘物分配於DCM(20mL)與水(20mL)之間。分離
出有機物並使用疏水性玻璃料乾燥,隨後在真空中濃縮,得到深紅色油狀物。將粗製物質溶解於MeOH(40mL)中並使用H-Cube(設定:40℃,全H2)來實施氫化。在真空中濃縮粗製混合物,重新溶解於最小量之DCM中並裝載於胺基丙基二氧化矽柱(70g)之頂部上。使用0-100%梯度之EtOAc/環己烷經60分鐘洗脫管柱,隨後用0-25%MeOH/DCM沖洗。合併適當流份並在真空中蒸發,得到橙色油狀物。將該油狀物溶解於甲醇(40mL)中並流經H-cube(設定:全H2,40℃,10%鈀碳CatCart30作為觸媒)。在真空中濃縮溶液,得到呈淺黃色油狀物形式之標題化合物(119mg)。
LCMS(系統B):tRET=1.19min;MH+ 513
中間體25:(S)-5-丁基-N-(2,4-二甲氧基苄基)-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
將三乙胺(0.860mL,6.20mmol)添加至(S)-3-氟吡咯啶鹽酸鹽(390mg,3.10mmol)及5-丁基-3-(5-氯戊-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(457mg,1.034mmol)於N,N-二甲基甲醯胺(7mL)中之混合物中。將混合物加熱至80℃並攪拌18小時。將另一份(S)-3-氟吡咯啶鹽酸鹽(195mg,1.55mmol)及三乙胺(0.430mL,3.10mol)添加至反應混合物中。在80℃下將反應再攪拌6小時。添加N,N-二甲基甲醯胺(3mL)並在80℃下將反應混合物再攪拌18小時且然後使其冷卻至室溫。在真空中蒸發混合物,得到褐色油狀物。將所得油狀物分配於二氯甲烷(50mL)與水/鹽水(20mL)之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到褐色油狀物。將油狀物溶解於最小體積之二氯甲烷中,裝載至50g經胺基丙基官能化之二氧化矽柱上並使用0-10%梯度之存於二氯甲烷中之甲醇經40分鐘純化。(檢測波長=230nm)。合併適當流份並在真空中蒸發,得到褐色油狀物(261mg)。在氫氣氣氛下將油狀物及10%鈀碳(50mg)於乙醇(20mL)中之混
合物攪拌3小時。反應中添加額外10%鈀碳(50mg)並在氫氣氣氛下將混合物攪拌18小時。將又一份10%鈀碳(50mg)添加至反應中並在氫氣氣氛下將混合物攪拌5小時。藉助矽藻土柱(10g)過濾反應並在真空中蒸發,得到褐色油狀物。將該油狀物溶解於最小體積之二氯甲烷中,裝載至50g經胺基丙基官能化之二氧化矽柱上並使用0-10%梯度之存於二氯甲烷中之甲醇經40min純化。(檢測波長=230nm)。合併適當流份並在真空中蒸發,得到呈褐色油狀物形式之標題化合物(175mg)。
LCMS(系統B):tRET=1.23min;MH+ 499
中間體26:(R)-5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與中間體24類似之方式自5-丁基-3-(6-氯己-1-炔-1-基)-N-(3,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺及(R)-3-氟吡咯啶鹽酸鹽製備。
LCMS(系統B):tRET=1.17min;MH+ 513
中間體27:(R)-5-丁基-N-(2,4-二甲氧基苄基)-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與中間體25類似之方式自5-丁基-3-(5-氯戊-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺及(R)-3-氟吡咯啶鹽酸鹽製備。
LCMS(系統B):tRET=1.23min;MH+ 499
中間體28:1-(6-(5-丁基-7-((2,4-二甲氧基苄基)胺基)-1H-吡唑并[4,3-d]嘧啶-3-基)己基)六氫吡啶-4-醇
以與中間體22類似之方式自5-丁基-3-(6-氯己-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺及4-羥基六氫吡啶製備
LCMS(系統B):tRET=1.09min;MH+ 525
中間體29:1-(5-(5-丁基-7-((2,4-二甲氧基苄基)胺基)-1H-吡唑并[4,3-d]嘧啶-3-基)戊基)六氫吡啶-4-醇
將三乙胺(0.327mL,2.355mmol)添加至4-羥基六氫吡啶(238mg,2.355mmol)及5-丁基-3-(5-氯戊-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(347mg,0.785mmol)於無水N,N-二甲基甲醯胺(5mL)中之溶液中。將溶液加熱至80℃並攪拌17小時。將另一份4-羥基六氫吡啶(79mg,0.785mmol)添加至反應混合物中並在80℃下繼續攪拌1小時。在真空中蒸發反應混合物,得到褐色油狀物。將所得油狀物分配於二氯甲烷(2×25mL)與水/鹽水(1:1,20mL)之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到褐色油狀物(643mg)。將該油狀物溶解於最小體積之二氯甲烷中,裝載至50g胺基丙基二氧化矽柱上並使用0-10%之存於二氯甲烷中之甲醇梯度經40分鐘純化(檢測波長=230nm)。合併適當流份並在真空中蒸發,得到褐色固體(253mg)。在氫氣氣氛下將固體及10%鈀碳(100mg)於乙醇(20mL)中之混合物攪拌6小時。將另一份10%鈀碳(100mg)添加至反應中並在氫氣下將混合物再攪拌16小時。將又一份10%鈀碳(50mg)添加至反應中並在氫氣下將混合物再攪拌3小時。藉助矽藻土柱(10g)過濾反應並在真空中蒸發,得到呈褐色油狀物形式之標題化合物(224mg)。
LCMS(系統B):tRET=1.07min;MH+ 511
中間體30:5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(4-氟六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與中間體24類似之方式自5-丁基-3-(6-氯己-1-炔-1-基)-N-(3,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺及4-氟六氫吡啶鹽酸鹽製備。
LCMS(系統B):tRET=1.23min;MH+ 527
中間體31:5-丁基-N-(2,4-二甲氧基苄基)-3-(5-(4-氟六氫吡啶-1-基)戊
基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與中間體25類似之方式自5-丁基-3-(5-氯戊-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺及4-氟六氫吡啶鹽酸鹽製備。
LCMS(系統B):tRET=1.26min;MH+ 513
實例1:5-丁基-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲酸鹽
在120℃下將5-丁基-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(87mg,0.242mmol)與氧氯化磷(1.5mL,16.09mmol)之混合物加熱45分鐘。將反應冷卻至室溫並逐滴添加至20%氫氧化鈉水溶液(24mL)中並劇烈攪拌(添加後混合物之pH為14)。使用2M檸檬酸水溶液將混合物調節至pH 12並於乙酸乙酯中萃取。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到紅色/褐色油狀物(95mg)。將該物質(95mg)懸浮於2-丙醇(2mL)及35%(0.88)氨溶液(2mL)中。在Biotago Initiator微波儀中在140℃下將反應攪拌90分鐘。在真空中蒸發反應,得到紅色油狀物。將該油狀物溶解於MeOH:DMSO(1:1)(2×1mL)中並藉由MDAP(方法A)來純化。合併適當流份並在真空中蒸發,得到呈無色油狀物形式之標題化合物(13.2mg)。
LCMS(系統A):tRET=0.44min;MH+ 359
實例2:5-(2-甲氧基乙基)-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
在120℃下將5-(2-甲氧基乙基)-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(116.5mg,0.322mmol)與氧氯化磷(1.9mL,20.38mmol)之混合物加熱45分鐘。將反應冷卻至室溫並在真空中蒸發,得到紅色/褐色油狀物。將甲苯(5mL)添加至該油狀物中並在真空中蒸發所得懸浮液,得到紅色/褐色油狀物。將該油狀物溶解於異丙醇(2mL)中並添加0.88氨(2mL,36.2mmol)。在Biotage Initiator微波儀中在100℃下將反應攪拌60分鐘,在真空中蒸發反應,得到紅色固體。將該油狀物溶解於MeOH:DMSO(1:1)(2×1mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到呈透明油狀物形式之標題化合物(15.6mg)。
LCMS(系統B):tRET=0.76min;MH+ 361
實例3:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
方法A
在120℃下將5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮(245mg,0.709mmol)與氧氯化磷(12.89mL,138mmol)之混合物攪拌45min。將反應冷卻至室溫並在真空中蒸發,得到紅色/
褐色油狀物。將甲苯(10mL)添加至該油狀物中並在真空中蒸發所得懸浮液,得到紅色/褐色油狀物。將該油狀物溶解於異丙醇(7mL)中並添加0.88氨(5.88mL,106mmol)。在Biotage Initiator微波儀中在120℃將反應攪拌60分鐘,然後在真空中蒸發反應,得到橙色固體。藉由反相層析使用MDAP(方法A)來純化粗製物質。在真空中蒸發含有產物之流份,得到呈無色油狀物形式之標題化合物(72.1mg)。
LCMS(系統B):tRET=0.84min;MH+ 345
方法B
在室溫及氫氣氣氛下將5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(吡咯啶-1-基)己-1-炔-1-基)-1H-吡唑并[4,3-d]嘧啶-7-胺(1.838g,3.75mmol)及10wt%鈀碳(200mg)於乙醇(53mL)中之混合物攪拌2小時。在氮氣氣氛下再向反應中添加300mg 10wt%鈀碳並在室溫及氫氣氣氛下將反應攪拌2小時。在氮氣氣氛下再向反應中添加250mg 10wt%鈀碳並在室溫及氫氣氣氛下將反應攪拌16小時。藉助10g矽藻土柱過濾反應混合物並在真空中蒸發濾液,得到黏性褐色油狀物(2.2g)。將該油狀物溶解於三氟乙酸(10mL)中並在Biotage Initiator微波儀(使用高初始吸收設定)中加熱至120℃,保持4小時,然後使其在室溫下保持17小時。在真空中蒸發黑色/墨綠色反應混合物並將剩餘殘餘物分配於25%存於氯仿中之2-丙醇(500mL)與0.1M氫氧化鈉水溶液(500mL)之間。使有機相通過疏水性玻璃料並在真空中蒸發,得到褐色膠狀物(1.74g)。將該膠狀物溶解於最小體積之二氯甲烷中,裝載至100g經二氯甲烷預處理之二氧化矽柱上並藉由層析使用1倍管柱體積之二氯甲烷、隨後18倍管柱體積之0-30%之存於二氯甲烷中之甲醇(+1%三乙胺)梯度、隨後6倍管柱體積之30%存於二氯甲烷中之甲醇(+1%三乙胺)(檢測波長=230nm)來純化。合併適當流份並在真空中蒸發,得到呈淺褐色固體形式之標題化合物(596mg)。
LCMS(系統A):tRET=0.80min;MH+ 345
方法C
在環境溫度下將5-丁基-N-(2,4-二甲氧基苄基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(5.33g,10.77mmol)溶解於三氟乙酸(45mL,584mmol)中。在60℃下將反應混合物攪拌3h。在真空中蒸發反應混合物並將殘餘物溶解於3:1氯仿:IPA(500mL)中並用稀(0.2M)氫氧化鈉水溶液(400mL)洗滌。用另外多份3:1氯仿:IPA(2×400mL)萃取水性混合物。藉助疏水性玻璃料過濾合併之有機相並在真空中蒸發濾液,得到黃色固體(4.7g)。將一部分粗製物質(1.26g)溶解於二氯甲烷/甲烷(1519:1)中並在真空下藉助玻璃纖維濾紙墊來過濾渾濁溶液。在真空中蒸發濾液並用醚研磨殘餘物。過濾懸浮液並用醚洗滌固體物質,得到呈灰白色固體形式之標題化合物(0.695g)。
LCMS(系統B):tRET=0.83min;MH+ 345
1H NMR(400MHz,甲醇-d4)δ=3.02-2.92(m,6H),2.87-2.80(m,2H),2.78-2.71(m,2H),1.95(s,4H),1.85-1.71(m,4H),1.68-1.58(m,2H),1.49-1.35(m,6H),0.96(t,J=7.3Hz,3H)
將剩餘物質溶解於二氯甲烷/甲烷(50mL,19:1)中並在真空下藉助玻璃纖維濾紙墊來過濾渾濁溶液。在真空中蒸發濾液並用醚研磨殘餘物。過濾懸浮液並用醚洗滌固體物質,得到又一份呈灰白色固體形式之標題化合物(2.174g)。
LCMS(系統B):tRET=0.85min;MH+ 345
實例4:5-(2-甲氧基乙基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例2類似之方式自5-(2-甲氧基乙基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮製備。
LCMS(系統B):tRET=0.65min;MH+ 347
實例5:5-丁基-3-(5-(六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例2類似之方式自5-丁基-3-(5-(六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮製備。
LCMS(系統B):tRET=0.84min;MH+ 345
實例6:5-丁基-3-(5-(吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例2類似之方式自5-丁基-3-(5-(吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7(6H)-酮製備。
LCMS(系統B):tRET=0.84min;MH+ 345
實例7:5-丁基-3-(7-(六氫吡啶-1-基)庚基)-1H-吡唑并[4,3-d]嘧啶-7-胺
將三乙胺(0.085mL,0.608mmol)添加至3-(7-溴庚基)-5-丁基-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(150mg,0.203mmol)及六氫吡啶(0.060mL,0.608mmol)於無水乙腈(7mL)中之溶液中。在環境溫度下將溶液攪拌1.5小時。將額外六氫吡啶(0.060mL,0.608mmol)及三乙胺(0.085mL,0.608mmol)添加至反應混合物中並在環境溫度下繼續攪拌17小時。在真空中蒸發反應混合物,得到透明油狀物。將該油狀物分配於乙酸乙酯(20mL)與水/鹽水(1:1,5mL)之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到透明油狀物。將該油狀物溶解於三氟乙酸(3mL,38.9mmol)中並在60℃下加熱3小時。在真空中蒸發反應混合物並將殘餘物溶解於3:1氯仿:IPA(20mL)中並用氫氧化鈉水溶液(0.1M,5mL)洗滌。使用疏水性玻璃料來分離有機相並用3:1氯仿:IPA(20mL)反萃取水溶液。在真空中蒸發合併之有機萃取物,得到黃色油狀物(215mg)。將該油狀物溶解於MeOH:DMSO(1:1)(3×1mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到褐色油狀物(88.2mg)。將該油狀物溶解於MeOH:DMSO(1:1)(1mL)中並藉由MDAP(方法A)來純化。合併適當流份並在真空中蒸發,得到呈白色固體形式之標題化合物(40.5mg)。
LCMS(系統B):tRET=0.94min;MH+ 373
實例8:5-丁基-3-(7-(吡咯啶-1-基)庚基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例7類似之方式自3-(7-溴庚基)-5-丁基-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺及吡咯啶製備。
LCMS(系統B):tRET=0.82min;MH+ 359
實例9:3-(6-(氮雜環庚-1-基)己基)-5-丁基-1H-吡唑并[4,3-d]嘧啶-7-胺
在環境溫度下將3-(6-(氮雜環庚-1-基)己基)-5-丁基-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(0.100g,0.191mmol)溶解於三氟乙酸(2mL,26.0mmol)中。在60℃下將反應混合物攪拌4小時。在真空中蒸發反應混合物並將殘餘物溶解於3:1氯仿:IPA(15mL)中並用氫氧化鈉水溶液(0.1M,5mL)洗滌。使用疏水性玻璃料來分離有機相並在真空中蒸發,得到褐色油狀物(0.157g)。將該油狀物溶解於MeOH:DMSO(1:1)(2mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到呈灰白色固體形式之標題化合物(38mg)。
LCMS(系統B):tRET=0.88min;MH+ 373
實例10:3-(5-(氮雜環庚-1-基)戊基)-5-丁基-1H-吡唑并[4,3-d]嘧啶-7-胺
將三乙胺(0.282mL,2.036mmol)添加至六亞甲基亞胺(0.229mL,2.036mmol)及5-丁基-3-(5-氯戊-1-炔-1-基)-N-(2,4-二甲氧基苄基)-1H-吡唑并[4,3-d]嘧啶-7-胺(300mg,0.679mmol)於無水N,N-二甲基甲醯胺(5mL)中之溶液中。將溶液加熱至80℃並攪拌3.5小時。再向反應混合物中添加存於無水N,N-二甲基甲醯胺(2mL)中之1.5當量六亞甲基亞胺(101mg,1.018mmol)及三乙胺(0.141mL,1.018mmol)並在80℃下繼續攪拌18小時。
將另一份存於無水N,N-二甲基甲醯胺(3mL)中之六亞甲基亞胺(101mg,1.018mmol)及三乙胺(0.141mL,1.018mmol)添加至反應混合物中並在80℃下繼續攪拌5.5小時。在真空中蒸發反應混合物,得到褐色油狀物。將所得油狀物分配於二氯甲烷(25mL)與水/鹽水(1:1,20mL)之間。分離出有機層,通過疏水性玻璃料並在真空中蒸發,得到褐色油狀物。將該油狀物溶解於最小體積之二氯甲烷中,裝載至50g胺基丙基二氧化矽柱上並使用0-10%之存於二氯甲烷中之甲醇梯度經40分鐘純化(檢測波長=230nm)。合併適當流份並在真空中蒸發,得到褐色油狀物(235mg)。將該油狀物溶解於最小體積之二氯甲烷中,裝載至50g胺基丙基二氧化矽柱上並使用0-10%之存於二氯甲烷中之甲醇梯度經40min再純化。(檢測波長=230nm)。合併適當流份並在真空中蒸發,得到呈褐色油狀物形式之中間體炔(195mg)。
在氫氣氣氛下將該油狀物及10%鈀碳(150mg)於乙醇(20mL)中之混合物攪拌19小時。向反應中添加額外10%鈀碳(100mg)並在氫氣氣氛下將混合物再攪拌23小時。向反應中添加額外10%鈀碳(100mg)並
在氫氣氣氛下將混合物再攪拌5小時。藉助矽藻土柱(10g)過濾反應並在真空中蒸發,得到褐色油狀物(180mg)。將該油狀物溶解於MeOH:DMSO(1:1)(3mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到黃色油狀物。
將該油狀物溶解於三氟乙酸(3mL,38.9mmol)中並在60℃下加熱3小時。在60℃下將反應再攪拌2小時且然後使其冷卻至室溫,過夜。在真空中蒸發反應混合物並將殘餘物溶解於3:1氯仿:IPA(15mL)中並用氫氧化鈉水溶液(0.1M,6mL)洗滌。使用疏水性玻璃料來分離有機相並用3:1氯仿:IPA(15mL)反萃取水溶液。在真空中蒸發合併之有機萃取物,得到褐色油狀物。將該油狀物溶解於MeOH:DMSO(1:1)(3mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到呈乳白色固體形式之標題化合物(32mg)。
LCMS(系統B):tRET=0.79min;MH+ 359
實例11:(S)-5-丁基-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺
在Biotage Initiator微波儀(使用高初始吸收設定)中在120℃下將(S)-5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(119mg,0.232mmol)於三氟乙酸(1mL,12.98mmol)中之溶液加熱2.5h。在真空中濃縮反應混合物並將殘餘物溶解於3:1氯仿:IPA(50mL)中並用氫氧化鈉水溶液(0.1M,50mL)洗滌。分離出有機相並用3:1氯仿:IPA(30mL)反萃取水溶液。乾燥(疏水性玻
璃料)合併之有機萃取物並在真空中濃縮。將該物質(223mg)溶解於MeOH:DMSO(1:1)(2mL)中並藉由MDAP(方法B)來純化。合併適當流份並在真空中蒸發,得到呈橙色固體形式之標題化合物(33mg)。
LCMS(系統B):tRET=0.91min;MH+ 363
實例12:(S)-5-丁基-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例9類似之方式自(S)-5-丁基-N-(2,4-二甲氧基苄基)-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺製備。
LCMS(系統B):tRET=0.85min;MH+ 349
實例13:(R)-5-丁基-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲酸鹽
以與實例11類似之方式自(R)-5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺製備。
LCMS(系統B):tRET=0.88min;MH+ 363
實例14:(R)-5-丁基-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例9類似之方式自(R)-5-丁基-N-(2,4-二甲氧基苄基)-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺製備。
LCMS(系統B):tRET=0.85min;MH+ 349
實例15:1-(6-(7-胺基-5-丁基-1H-吡唑并[4,3-d]嘧啶-3-基)己基)六氫吡啶-4-醇
以與實例9類似之方式自1-(6-(5-丁基-7-((2,4-二甲氧基苄基)胺基)-1H-吡唑并[4,3-d]嘧啶-3-基)己基)六氫吡啶-4-醇製備。
LCMS(系統B):tRET=0.76min;MH+ 375
實例16:1-(5-(7-胺基-5-丁基-1H-吡唑并[4,3-d]嘧啶-3-基)戊基)六氫吡啶-4-醇
以與實例9類似之方式自1-(5-(5-丁基-7-((2,4-二甲氧基苄基)胺基)-1H-吡唑并[4,3-d]嘧啶-3-基)戊基)六氫吡啶-4-醇製備。
LCMS(系統B):tRET=0.71min;MH+ 361
實例17:5-丁基-3-(6-(4-氟六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲酸鹽
以與實例11類似之方式自5-丁基-N-(3,4-二甲氧基苄基)-3-(6-(4-氟六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺製備。
LCMS(系統B):tRET=0.93min;MH+ 377
實例18:5-丁基-3-(5-(4-氟六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺
以與實例9類似之方式自5-丁基-N-(2,4-二甲氧基苄基)-3-(5-(4-氟六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺製備。
LCMS(系統B):tRET=0.90min;MH+ 363
實例19:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺馬來酸鹽
用IPA(1.4mL,10體積)處理裝填有5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(140mg,0.406mmol)之圓底烷瓶並在50℃及氮氣氣氛下攪拌直至產生均勻溶液。直接以固體形式添加馬來酸(47.2mg,0.406mmol)並攪拌所得反應混合物直至馬來酸已發生完
全溶解。然後用5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺馬來酸鹽(0.5mg)於IPA(0.1mL)中之經超音波處理之漿液處理所得溶液並在50℃下將所得漿液陳化1小時,隨後經4小時使其冷卻至20℃。然後在20℃下將所得漿液攪拌過夜。在冰浴中將漿液冷卻至3℃並陳化30分鐘,隨後經由真空過濾來收集固體。用經冷凍之IPA(2×1mL)洗滌所得固體,隨後在40℃下在真空中實施烘箱乾燥,過夜,得到灰白色固體(122mg)。在40℃下在真空中將所得固體進一步乾燥,提供呈灰白色固體形式之標題化合物(95mg)。
LCMS(系統B):tRET=0.79min;MH+ 345
1H NMR(400MHz,DMSO-d6)包括δ=7.05(br.s,2H),6.02(s,2H),3.13-3.00(m,3H),2.83(br.s.,2H),2.64(br.s.,2H),2.03-1.83(m,4H),1.80-1.53(m,6H),1.43-1.25(m,6H),0.90(t,J=7.5Hz,3H)
實例20:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺半馬來酸鹽
用馬來酸(34.5mg,0.5當量)處理5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(205mg),隨後於IPA(2.0mL)中漿化。將所得反應混合物加熱至70℃,得到均勻溶液,其在70℃下陳化時開始沈澱出固體。發現所得漿液在70℃下30min後凝固,因此添加額外IPA(0.5mL)以使漿液可流動。使所得反應混合物冷卻至20℃並在20℃下陳化過夜,隨後過濾並用新鮮IPA(2×4mL)洗滌,得到白色固體,在40℃下在真空中(90毫巴)對其實施烘箱乾燥,過夜。在50
℃下在真空中將所得固體(199mg)進一步乾燥,提供標題化合物。
1H NMR(400MHz,DMSO-d6)包括δ=7.05(br.s,2H),6.01(s,1H),1.89-1.61(m,8H),1.56-1.43(m,2H),1.41-1.24(m,6H),0.89(t,J=7.4Hz,3H)
實例21:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺馬來酸氫鹽
用馬來酸(133mg,2.0當量)處理5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(197.3mg),隨後於IPA(2.0mL)中漿化。將所得反應混合物加熱至70℃,得到均勻溶液,其在70℃下陳化時開始沈澱出固體。發現所得漿液在70℃下凝固,因此添加額外IPA(2.0mL)以使漿液可流動。使所得反應混合物緩慢地冷卻至20℃並在20℃下陳化過夜,隨後過濾並用新鮮IPA(2×4mL)洗滌,得到白色固體,在40℃下在真空中(90毫巴)對其實施烘箱乾燥,過夜,提供標題化合物(294mg)。
1H NMR(400MHz,DMSO-d6)包括δ=6.07(s,4H),3.15-3.03(m,2H),2.80-2.64(m,2H),2.09-1.51(m,J=7.9Hz,10H),1.42-1.25(m,6H),0.91(t,J=7.4Hz,3H)
實例22:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺半琥珀酸鹽
用琥珀酸(33.7mg,0.5當量)處理5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(196.7mg),隨後於IPA(2.0mL)中漿化。將所得反應混合物加熱至70℃,得到均勻溶液,其在70℃下陳化時開始沈澱出固體。發現所得漿液在70℃下凝固,因此添加額外IPA(1.0mL)以使漿液可流動。使所得反應混合物緩慢地冷卻至20℃並在20℃下陳化過夜,隨後過濾並用新鮮IPA(2×4mL)洗滌,得到白色固體,在40℃下在真空中(90毫巴)對其實施烘箱乾燥,過夜。在50℃下在真空中將所得固體(193mg)進一步乾燥,提供標題化合物。
1H NMR(400MHz,DMSO-d6)包括δ=7.08(br.s.,2H),2.88-2.75(m,2H),2.32(s,2H),1.80-1.59(m,8H),1.53-1.22(m,8H),0.89(t,J=7.4Hz,3H)
實例23:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲烷磺酸鹽
在70℃下用無水甲烷磺酸(38μl,1.0當量)處理於乙腈(2mL)中漿化之5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(200.3mg)。在添加甲烷磺酸時所得反應混合物轉變成溶液並在70℃下陳化時開始沈澱出固體。發現所得漿液凝固且因此添加額外乙腈(2
mL)以使漿液可流動。使所得反應混合物冷卻至20℃並在20℃下陳化過夜,隨後過濾並用新鮮乙腈(2×4mL)洗滌,得到白色固體,在40℃下在真空中(90毫巴)對其實施烘箱乾燥,過夜,提供標題化合物(234mg)。
1H NMR(400MHz,DMSO-d6)包括δ=7.17-6.94(m,2H),2.89-2.76(m,2H),2.64(br.s.,2H),2.32(s,3H),1.68(s,6H),1.43-1.23(m,6H),0.90(t,J=7.4Hz,3H)
實例24:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺鹽酸鹽
在70℃下將5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺(197.2mg)於乙腈(2mL)中漿化,隨後用存於IPA(0.458mL)中之1.25M HCl處理,產生溶液。在70℃下陳化時反應物開始沈澱出固體且在70℃下在陳化期間此反應物保持可流動且因此將反應冷卻至20℃。在20℃下將所得漿液陳化過夜,隨後過濾並用新鮮乙腈(2×4mL)洗滌,得到白色固體,在40℃下在真空中(90毫巴)對其實施烘箱乾燥,過夜。在50℃下在真空中將所得固體(144mg)進一步乾燥,提供標題化合物。
1H NMR(400MHz,DMSO-d6)包括δ=7.18(br.s,2H),2.72-2.57(m,2H),2.04-1.54(m,10H),1.42-1.23(m,6H),0.90(t,J=7.4Hz,3H)
多晶型
根據以下方法對5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺實施X-射線粉末繞射(XRPD)。
XRPD
在PW3040/60型PANalytical X’Pert Pro粉末繞射計上使用X’Celerator檢測器來獲得數據。獲得條件係:輻射:Cu Kα,發生器電壓:40kV,發生器電流:45mA,開始角度:2.0° 2θ,結束角度:40.0° 2θ,步長:0.0167° 2θ,每一步驟時間:31.75秒。藉由將數毫克樣品安裝於矽晶圓(零背景)板上來製備樣品,從而得到粉末薄層。
實例21及22各批次之特徵XRPD角及d-間距記錄於表1中。每一峰指配之誤差幅度為約±0.1° 2θ。峰強度因佳定位而可隨樣品變化。
使用Highscore軟體來量測峰位置。
根據以下分析測試本發明化合物之活體外生物活性。
在平底微量滴定板中於DMSO中在100x所需濃度下以1.5μL體積製備化合物。管柱1至10含有1:4連續稀釋之測試化合物。在每一板上均包括連續稀釋之TLR7/8促效劑瑞喹莫德作為標準物且管柱11含有1.5μl 200μM瑞喹莫德(得到2μM最終濃度,用於定義對瑞喹莫德之近似最大反應)。對於每一供體,每一化合物均以一式兩份分析。
將來自三個人類供體之血液樣品收集至肝素鈉(10U/mL)中。將150μl全血分配至含有1.5μl存於DMSO中之測試化合物或標準物之分析板Col 1至11中。將板放置於培育箱中過夜(37℃,95%空氣,5%CO2)。在過夜培育後,自培育箱取出板並在定軌振盪器上混合約1分鐘。向每一孔中添加100μl 0.9%鹽水並再次在定軌振盪器上將板混合。然後對板實施離心(2500rpm,10min),此後使用Biomek FX取出血漿樣品並使用MSD(Mesoscale Discovery)電致化學發光分析平臺對IFN-α及TNF-α二者進行分析。IFN-α分析係以與上文所述類似之方式實施。TNF-α分析係根據套組說明書(目錄編號K111BHB)實施。
所釋放之細胞介素係以2μM瑞喹莫德對照(管柱11)之百分比表示。繪製此百分比對化合物濃度之曲線圖並藉由非線性最小平方曲線擬合來確定該反應之pEC50。對於IFN-α反應,通常選擇4參數對數模型。對獲得清除最大值反應之TNF反應(即在反應中觀察到輪廓分明之平穩段)則通常使用4參數模型。若曲線之上漸近線輪廓不分明,則曲線擬合通常受限於100%最大反應(即受限於對2μM瑞喹莫德之反應),或若此大於瑞喹莫德反應,則受限於所測試最高濃度之反應。一種或兩種細胞介素之一些曲線係鈴形且該擬合通常排除在該鈴形反
應之下坡(即高於產生最大反應之濃度之彼等)上之細胞介素數據,通常對剛好高於峰反應之濃度例外。由此濃縮之曲線擬合在劑量反應曲線之上坡。
實例1至24對IFNα具有5.9之平均pEC50。實例3、21及22對IFNα分別具有6.9、7.2及7.6之平均pEC50。
實例1至24對TNF-α具有5.4之平均pEC50。實例3、21及22對THF-α分別具有平均4.7、<4.3及4.7之pEC50。
Claims (18)
- 如請求項1之化合物或其鹽,其中R1係正丁基。
- 如請求項1之化合物或其鹽,其中R1係2-甲氧基乙基。
- 如請求項1至3中任一項之化合物或其鹽,其中m係具有5或6之值之整數。
- 如請求項1至3中任一項之化合物或其鹽,其中n係1。
- 如請求項1至3中任一項之化合物或其鹽,其中n係2。
- 如請求項1至3中任一項之化合物或其鹽,其中p係0或1。
- 如請求項1至3中任一項之化合物或其鹽,其中每一R2獨立地代表鹵基或OH。
- 如請求項8之化合物或其鹽,其中每一R2獨立地代表F或OH。
- 如請求項1之化合物或其鹽,其選自由下列組成之群:5-丁基-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-(2-甲氧基乙基)-3-(6-(六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-(2-甲氧基乙基)-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(5-(六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(5-(吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(7-(六氫吡啶-1-基)庚基)-1H-吡唑并[4,3-d]嘧啶-7-胺;5-丁基-3-(7-(吡咯啶-1-基)庚基)-1H-吡唑并[4,3-d]嘧啶-7-胺;3-(6-(氮雜環庚-1-基)己基)-5-丁基-1H-吡唑并[4,3-d]嘧啶-7-胺;3-(5-(氮雜環庚-1-基)戊基)-5-丁基-1H-吡唑并[4,3-d]嘧啶-7-胺;(S)-5-丁基-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;(S)-5-丁基-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;(R)-5-丁基-3-(6-(3-氟吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲酸鹽;(R)-5-丁基-3-(5-(3-氟吡咯啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺;1-(6-(7-胺基-5-丁基-1H-吡唑并[4,3-d]嘧啶-3-基)己基)六氫吡啶-4-醇;1-(5-(7-胺基-5-丁基-1H-吡唑并[4,3-d]嘧啶-3-基)戊基)六氫吡啶-4-醇;5-丁基-3-(6-(4-氟六氫吡啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺;及5-丁基-3-(5-(4-氟六氫吡啶-1-基)戊基)-1H-吡唑并[4,3-d]嘧啶-7-胺。
- 如請求項1至3及10中任一項之化合物或其鹽,其係呈醫藥上可接受之鹽形式。
- 如請求項12之化合物或其鹽,其選自由下列組成之群:5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺馬來酸鹽;5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺馬來酸氫鹽;及5-丁基-3-(6-(吡咯啶-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺半琥珀酸鹽。
- 如請求項14之化合物或其鹽,其係呈結晶固態形式,其中X-射線粉末繞射圖案在5.3、5.8、6.4、9.0、10.1、10.9、11.6、12.7、16.0及19.1之2θ值處具有繞射峰。
- 如請求項1至3及10中任一項之化合物或其鹽,其係呈游離鹼形式。
- 一種醫藥組合物,其包含如請求項1至16中任一項之化合物或其鹽及一或多種醫藥上可接受之賦形劑。
- 一種疫苗組合物,其包含如請求項1至16中任一項之化合物或其鹽及抗原或抗原組合物。
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Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA103195C2 (uk) | 2008-08-11 | 2013-09-25 | Глаксосмитклайн Ллк | Похідні пурину для застосування у лікуванні алергій, запальних та інфекційних захворювань |
BR112014001425A2 (pt) | 2011-07-22 | 2017-11-21 | Glaxosmithkline Llc | forma de dosagem farmacêutica, composição farmacêutica, e, composto (i) ou sal farmaceuticamente aceitável do mesmo |
SG11201500787YA (en) * | 2012-08-24 | 2015-03-30 | Glaxosmithkline Llc | Pyrazolopyrimidine compounds |
CA2890201A1 (en) | 2012-11-20 | 2014-05-30 | Glaxosmithkline Llc | Novel compounds |
RU2640200C2 (ru) | 2012-11-20 | 2017-12-27 | ГЛАКСОСМИТКЛАЙН ЭлЭлСи | Новые соединения |
RS56233B1 (sr) | 2012-11-20 | 2017-11-30 | Glaxosmithkline Llc | Nova jedinjenja |
WO2019209811A1 (en) | 2018-04-24 | 2019-10-31 | Bristol-Myers Squibb Company | Macrocyclic toll-like receptor 7 (tlr7) agonists |
US11554120B2 (en) | 2018-08-03 | 2023-01-17 | Bristol-Myers Squibb Company | 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor |
CN110772523B (zh) * | 2019-11-07 | 2020-06-26 | 黑龙江中医药大学 | 一种用于防治肾病的药物组合物 |
WO2021154661A1 (en) | 2020-01-27 | 2021-08-05 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
US20230131192A1 (en) | 2020-01-27 | 2023-04-27 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
KR20220132595A (ko) | 2020-01-27 | 2022-09-30 | 브리스톨-마이어스 스큅 컴퍼니 | 톨-유사 수용체 7 (TLR7) 효능제로서의 C3-치환된 1H-피라졸로[4,3-d]피리미딘 화합물 |
CN115210235A (zh) | 2020-01-27 | 2022-10-18 | 百时美施贵宝公司 | 作为Toll样受体7(TLR7)激动剂的1H-吡唑并[4,3-d]嘧啶化合物 |
CN115279765A (zh) | 2020-01-27 | 2022-11-01 | 百时美施贵宝公司 | 作为Toll样受体7(TLR7)激动剂的1H-吡唑并[4,3-d]嘧啶化合物 |
WO2021154666A1 (en) | 2020-01-27 | 2021-08-05 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
EP4097101A1 (en) | 2020-01-27 | 2022-12-07 | Bristol-Myers Squibb Company | 1h-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (tlr7) agonists |
US20230041738A1 (en) | 2020-01-27 | 2023-02-09 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
WO2021154662A1 (en) | 2020-01-27 | 2021-08-05 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005079195A2 (en) * | 2003-10-03 | 2005-09-01 | 3M Innovative Properties Company | Pyrazolopyridines and analogs thereof |
US20090234117A1 (en) * | 2005-05-27 | 2009-09-17 | Toshihiko Kashiwagi | Pyrazolopyrimidine Derivative |
WO2010018133A1 (en) * | 2008-08-11 | 2010-02-18 | Smithkline Beecham Corporation | Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases |
Family Cites Families (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW574214B (en) | 1994-06-08 | 2004-02-01 | Pfizer | Corticotropin releasing factor antagonists |
US6403599B1 (en) | 1995-11-08 | 2002-06-11 | Pfizer Inc | Corticotropin releasing factor antagonists |
US7067664B1 (en) | 1995-06-06 | 2006-06-27 | Pfizer Inc. | Corticotropin releasing factor antagonists |
WO1997049706A1 (en) | 1996-06-25 | 1997-12-31 | Novartis Ag | SUBSTITUTED 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES AND THE USE THEREOF |
US5985848A (en) | 1997-10-14 | 1999-11-16 | Albert Einstein College Of Medicine Of Yeshiva University | Inhibitors of nucleoside metabolism |
TW572758B (en) | 1997-12-22 | 2004-01-21 | Sumitomo Pharma | Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives |
US6187777B1 (en) | 1998-02-06 | 2001-02-13 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
CZ27399A3 (cs) | 1999-01-26 | 2000-08-16 | Ústav Experimentální Botaniky Av Čr | Substituované dusíkaté heterocyklické deriváty, způsob jejich přípravy, tyto deriváty pro použití jako léčiva, farmaceutická kompozice a kombinovaný farmaceutický přípravek tyto deriváty obsahující a použití těchto derivátů pro výrobu léčiv |
DE60118521T2 (de) | 2000-01-07 | 2006-10-12 | Universitaire Instelling Antwerpen | Purin derivate, ihre herstellung und verwendung |
TWI306859B (en) | 2000-04-28 | 2009-03-01 | Acadia Pharm Inc | Muscarinic agonists |
GB0114286D0 (en) | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
TW200301251A (en) | 2001-12-20 | 2003-07-01 | Wyeth Corp | Azaindolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands |
ATE478872T1 (de) | 2002-03-28 | 2010-09-15 | Ustav Ex Botan Av Cr V V I I O | Pyrazoloä4,3-düpyrimidine, verfahren zu ihrer herstellung und therapeutische anwendung |
MXPA04010983A (es) | 2002-05-06 | 2005-02-14 | Genelabs Tech Inc | Derivados de nucleosidos para tratar infecciones por el virus de la hepatitis c. |
US6713241B2 (en) | 2002-08-09 | 2004-03-30 | Eastman Kodak Company | Thermally developable emulsions and imaging materials containing binder mixture |
CN100379750C (zh) | 2002-08-21 | 2008-04-09 | 阿尔伯爱因斯坦医科叶希瓦大学 | 核苷磷酸化酶和核苷酶抑制剂 |
BR0314761A (pt) | 2002-09-27 | 2005-07-26 | Sumitomo Pharma | Composto de adenina e seu uso |
CN1816530A (zh) | 2003-07-01 | 2006-08-09 | 麦克公司 | 用于治疗高眼压症的眼用组合物 |
US20070161582A1 (en) | 2003-08-08 | 2007-07-12 | Dusan Mijikovic | Pharmaceutical compositions and methods for metabolic modulation |
OA13310A (en) | 2003-09-05 | 2007-04-13 | Anadys Pharmaceuticals Inc | TLR7 ligands for the treatment of hepatitis C. |
WO2005092892A1 (ja) | 2004-03-26 | 2005-10-06 | Dainippon Sumitomo Pharma Co., Ltd. | 8−オキソアデニン化合物 |
WO2005092893A1 (ja) * | 2004-03-26 | 2005-10-06 | Dainippon Sumitomo Pharma Co., Ltd. | 9置換−8−オキソアデニン化合物 |
EA012873B1 (ru) | 2004-04-02 | 2009-12-30 | Оси Фармасьютикалз, Инк. | 6,6-бициклические кольцевые замещенные гетеробициклические ингибиторы протеинкиназ |
US20060074102A1 (en) | 2004-05-14 | 2006-04-06 | Kevin Cusack | Kinase inhibitors as therapeutic agents |
JP2007530579A (ja) * | 2004-06-10 | 2007-11-01 | スリーエム イノベイティブ プロパティズ カンパニー | アミド置換イミダゾピリジン、イミダゾキノリン、およびイミダゾナフチリジン |
US20060029642A1 (en) | 2004-08-03 | 2006-02-09 | Dusan Miljkovic | Methods and compositions for improved chromium complexes |
GB0420719D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
BRPI0611435A2 (pt) | 2005-05-04 | 2010-09-08 | Pfizer Ltd | derivados de 2-amido-6-amino-8-oxopurina, composições farmacêuticas, uso e processo de preparo dos mesmos |
NZ540160A (en) | 2005-05-20 | 2008-03-28 | Einstein Coll Med | Inhibitors of nucleoside phosphorylases |
AU2006272876A1 (en) * | 2005-07-22 | 2007-02-01 | Sunesis Pharmaceuticals, Inc. | Pyrazolo pyrimidines useful as aurora kinase inhibitors |
WO2007024707A2 (en) | 2005-08-22 | 2007-03-01 | The Regents Of The University Of California | Tlr agonists |
US8003624B2 (en) | 2005-08-25 | 2011-08-23 | Schering Corporation | Functionally selective ALPHA2C adrenoreceptor agonists |
WO2007024944A1 (en) | 2005-08-25 | 2007-03-01 | Schering Corporation | Imidazole derivatives as functionally selective alpha2c adrenoreceptor agonists |
CN101253173A (zh) | 2005-09-02 | 2008-08-27 | 辉瑞有限公司 | 羟基取代的1h-咪唑并吡啶和方法 |
TW200801003A (en) | 2005-09-16 | 2008-01-01 | Astrazeneca Ab | Novel compounds |
JPWO2007034917A1 (ja) | 2005-09-22 | 2009-03-26 | 大日本住友製薬株式会社 | 新規なアデニン化合物 |
US20080269240A1 (en) | 2005-09-22 | 2008-10-30 | Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan | Novel Adenine Compound |
US20090192153A1 (en) | 2005-09-22 | 2009-07-30 | Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan | Novel adenine compound |
TW200745114A (en) | 2005-09-22 | 2007-12-16 | Astrazeneca Ab | Novel compounds |
EP1939202A4 (en) | 2005-09-22 | 2010-06-16 | Dainippon Sumitomo Pharma Co | NEW COMPOUND OF ADENINE |
JPWO2007034916A1 (ja) | 2005-09-22 | 2009-03-26 | 大日本住友製薬株式会社 | 新規アデニン化合物 |
CN1947717B (zh) | 2005-10-14 | 2012-09-26 | 卓敏 | 选择性抑制腺苷酸环化酶1的化合物在制备用于治疗神经性疼痛和炎性疼痛的药物中的应用 |
BRPI0707945A2 (pt) | 2006-02-17 | 2011-05-17 | Pfizer Ltd | derivados de 3-deazapurina como modulares de tlr7 |
BRPI0709145A2 (pt) | 2006-03-24 | 2011-06-28 | Siemens Ag | método para a operação de uma unidade compressora, e uma unidade compressora associada |
CA2914168C (en) | 2006-03-28 | 2018-05-08 | Atir Holding S.A. | Pyrido[1,2-a]pyrimidin-4-one derivatives and their use in the treatment of sexual disorders |
GB0610666D0 (en) | 2006-05-30 | 2006-07-05 | Glaxo Group Ltd | Fluid dispenser |
US8846697B2 (en) | 2006-05-31 | 2014-09-30 | The Regents Of The University Of California | Purine analogs |
US8138172B2 (en) | 2006-07-05 | 2012-03-20 | Astrazeneca Ab | 8-oxoadenine derivatives acting as modulators of TLR7 |
WO2008005555A1 (en) | 2006-07-07 | 2008-01-10 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
TW200831105A (en) | 2006-12-14 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
TW200843779A (en) | 2007-02-19 | 2008-11-16 | Smithkline Beecham Corp | Compounds |
JP5480637B2 (ja) | 2007-03-19 | 2014-04-23 | アストラゼネカ・アクチエボラーグ | Toll様受容体(tlr7)モジュレーターとしての9−置換−8−オキソ−アデニン化合物 |
EP2139894B1 (en) | 2007-03-19 | 2011-10-26 | AstraZeneca AB | 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators |
TW200902018A (en) | 2007-03-20 | 2009-01-16 | Dainippon Sumitomo Pharma Co | Novel adenine compound |
WO2008114819A1 (ja) | 2007-03-20 | 2008-09-25 | Dainippon Sumitomo Pharma Co., Ltd. | 新規アデニン化合物 |
US7928111B2 (en) | 2007-06-08 | 2011-04-19 | Senomyx, Inc. | Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors |
KR101561710B1 (ko) | 2007-06-29 | 2015-10-19 | 길리애드 사이언시즈, 인코포레이티드 | 퓨린 유도체 및 그것의 톨 유사 수용체 7의 조절 인자로서 용도 |
GB0715087D0 (en) | 2007-08-03 | 2007-09-12 | Summit Corp Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
AU2008287421A1 (en) | 2007-08-10 | 2009-02-19 | Glaxosmithkline Llc | Nitrogen containing bicyclic chemical entities for treating viral infections |
UY31531A1 (es) | 2007-12-17 | 2009-08-03 | Sales derivadas de 8-oxoadenina composiciones farmacéuticas que las contienen y su uso en terapia como moduladores de receptor tipo toll (tlr) | |
WO2009151910A2 (en) | 2008-05-25 | 2009-12-17 | Wyeth | Combination product of receptor tyrosine kinase inhibitor and fatty acid synthase inhibitor for treating cancer |
US8946239B2 (en) | 2008-07-10 | 2015-02-03 | Duquesne University Of The Holy Spirit | Substituted pyrrolo, -furano, and cyclopentylpyrimidines having antimitotic and/or antitumor activity and methods of use thereof |
WO2010018132A1 (en) | 2008-08-11 | 2010-02-18 | Smithkline Beecham Corporation | Compounds |
US8802684B2 (en) | 2008-08-11 | 2014-08-12 | Glaxosmithkline Llc | Adenine derivatives |
EP2320905B1 (en) | 2008-08-11 | 2017-06-28 | Glaxosmithkline LLC | Novel adenine derivatives |
EA201100114A1 (ru) | 2008-08-11 | 2011-10-31 | ГЛАКСОСМИТКЛАЙН ЭлЭлСи | Производные пурина для применения в лечении аллергических, воспалительных и инфекционных заболеваний |
ES2433371T3 (es) | 2008-08-11 | 2013-12-10 | Glaxosmithkline Llc | Derivados de purina para uso en el tratamiento de enfermedades alérgicas, inflamatorias e infecciosas |
CN102548999A (zh) | 2009-01-20 | 2012-07-04 | 山东轩竹医药科技有限公司 | 含有取代的含氮稠杂环的头孢菌素衍生物 |
AU2010279299B2 (en) | 2009-08-07 | 2015-10-01 | Glaxosmithkline Biologicals Sa | Lipidated oxoadenine derivatives |
KR101773541B1 (ko) | 2010-02-10 | 2017-08-31 | 글락소스미스클라인 엘엘씨 | 6-아미노-2-{[(1s)-1-메틸부틸]옥시}-9-[5-(1-피페리디닐)-7,9-디하이드로-8h-퓨린-8-온 말레이트 |
EP2534148A1 (en) | 2010-02-10 | 2012-12-19 | GlaxoSmithKline LLC | Purine derivatives and their pharmaceutical uses |
WO2012009258A2 (en) | 2010-07-13 | 2012-01-19 | Edward Roberts | Peptidomimetic galanin receptor modulators |
WO2012092552A1 (en) | 2010-12-30 | 2012-07-05 | Selecta Biosciences, Inc. | Synthetic nanocarriers with reactive groups that release biologically active agents |
EP2670733B1 (en) | 2011-02-01 | 2019-04-10 | The Board of Trustees of the University of Illionis | N-hydroxybenzamide derivatives as hdac inhibitors and therapeutic methods using the same |
US9139590B2 (en) | 2011-02-04 | 2015-09-22 | Duquesne University Of The Holy Spirit | Bicyclic and tricyclic pyrimidine tyrosine kinase inhibitors with antitubulin activity and methods of treating a patient |
BR112014001425A2 (pt) | 2011-07-22 | 2017-11-21 | Glaxosmithkline Llc | forma de dosagem farmacêutica, composição farmacêutica, e, composto (i) ou sal farmaceuticamente aceitável do mesmo |
SG11201500787YA (en) | 2012-08-24 | 2015-03-30 | Glaxosmithkline Llc | Pyrazolopyrimidine compounds |
RU2640200C2 (ru) | 2012-11-20 | 2017-12-27 | ГЛАКСОСМИТКЛАЙН ЭлЭлСи | Новые соединения |
RS56233B1 (sr) | 2012-11-20 | 2017-11-30 | Glaxosmithkline Llc | Nova jedinjenja |
CA2890201A1 (en) | 2012-11-20 | 2014-05-30 | Glaxosmithkline Llc | Novel compounds |
RU2676684C2 (ru) | 2014-02-20 | 2019-01-10 | ГлаксоСмитКлайн Интеллекчуал Проперти (No.2) Лимитед | ПРОИЗВОДНЫЕ ПИРРОЛО[3,2-d]ПИРИМИДИНА В КАЧЕСТВЕ ИНДУКТОРОВ ЧЕЛОВЕЧЕСКОГО ИНТЕРФЕРОНА |
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2013
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005079195A2 (en) * | 2003-10-03 | 2005-09-01 | 3M Innovative Properties Company | Pyrazolopyridines and analogs thereof |
US20090234117A1 (en) * | 2005-05-27 | 2009-09-17 | Toshihiko Kashiwagi | Pyrazolopyrimidine Derivative |
WO2010018133A1 (en) * | 2008-08-11 | 2010-02-18 | Smithkline Beecham Corporation | Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases |
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