TW201712009A - 具抑制細菌葡萄醣醛酸酶活性之吡唑並[4,3-c]喹啉衍生物 - Google Patents
具抑制細菌葡萄醣醛酸酶活性之吡唑並[4,3-c]喹啉衍生物 Download PDFInfo
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- TW201712009A TW201712009A TW105116524A TW105116524A TW201712009A TW 201712009 A TW201712009 A TW 201712009A TW 105116524 A TW105116524 A TW 105116524A TW 105116524 A TW105116524 A TW 105116524A TW 201712009 A TW201712009 A TW 201712009A
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- Prior art keywords
- pyrazolo
- quinoline
- amino
- 1hydro
- quinolin
- Prior art date
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- ADEJACPCTOIQLO-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]quinoline Chemical class C1=NC2=CC=CC=C2C2=C1C=NN2 ADEJACPCTOIQLO-UHFFFAOYSA-N 0.000 title abstract description 15
- 230000005764 inhibitory process Effects 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 206010012735 Diarrhoea Diseases 0.000 claims abstract description 34
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
- 238000002512 chemotherapy Methods 0.000 claims abstract description 25
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 20
- 231100000357 carcinogen Toxicity 0.000 claims abstract description 13
- 239000003183 carcinogenic agent Substances 0.000 claims abstract description 13
- 230000000973 chemotherapeutic effect Effects 0.000 claims abstract description 6
- -1 methoxy , methylthio Chemical group 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 229910004013 NO 2 Inorganic materials 0.000 claims description 26
- 201000011510 cancer Diseases 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000003107 substituted aryl group Chemical group 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 15
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 15
- SVNCRRZKBNSMIV-UHFFFAOYSA-N 3-Aminoquinoline Chemical compound C1=CC=CC2=CC(N)=CN=C21 SVNCRRZKBNSMIV-UHFFFAOYSA-N 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 239000002246 antineoplastic agent Substances 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 12
- 239000004202 carbamide Substances 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 230000000711 cancerogenic effect Effects 0.000 claims description 10
- 230000023611 glucuronidation Effects 0.000 claims description 10
- 150000001350 alkyl halides Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 7
- 239000005711 Benzoic acid Substances 0.000 claims description 6
- 235000010233 benzoic acid Nutrition 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
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- 229960004768 irinotecan Drugs 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
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- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
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- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
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- YTKBUPUKMUAZRR-UHFFFAOYSA-N 1-[3-[(3-amino-1H-pyrazolo[4,3-c]quinolin-4-yl)amino]phenyl]ethanone Chemical compound NC1=NNC2=C1C(=NC=1C=CC=CC2=1)NC1=CC(=CC=C1)C(C)=O YTKBUPUKMUAZRR-UHFFFAOYSA-N 0.000 claims description 3
- PSLICVXIYMEBPJ-UHFFFAOYSA-N 1-[4-(4-chloroanilino)-1H-pyrazolo[4,3-c]quinolin-3-yl]-3-(4-methoxyphenyl)urea Chemical compound ClC1=CC=C(C=C1)NC1=NC=2C=CC=CC=2C2=C1C(=NN2)NC(=O)NC1=CC=C(C=C1)OC PSLICVXIYMEBPJ-UHFFFAOYSA-N 0.000 claims description 3
- PZHBTBKWMLOLLU-UHFFFAOYSA-N 1-[4-(4-chloroanilino)-1H-pyrazolo[4,3-c]quinolin-3-yl]-3-phenylurea Chemical compound ClC1=CC=C(C=C1)NC1=NC=2C=CC=CC=2C2=C1C(=NN2)NC(=O)NC1=CC=CC=C1 PZHBTBKWMLOLLU-UHFFFAOYSA-N 0.000 claims description 3
- OEHYRKSVBWTLLA-UHFFFAOYSA-N 4,8-dichloro-1H-pyrazolo[4,3-c]quinolin-3-amine Chemical compound ClC1=NC=2C=CC(=CC=2C2=C1C(=NN2)N)Cl OEHYRKSVBWTLLA-UHFFFAOYSA-N 0.000 claims description 3
- YWVKOIVUZIXZLA-UHFFFAOYSA-N 4-N-(2-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine Chemical compound NC1=NNC2=C1C(=NC=1C=CC=CC2=1)NC1=C(C=CC=C1)OC YWVKOIVUZIXZLA-UHFFFAOYSA-N 0.000 claims description 3
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- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本發明提供一種新穎的吡唑並[4,3-c]喹啉衍生物,對微生物β-葡萄醣醛酸酶展現專一地抑制活性,以提供有效的活性以預防癌症的化療導致的腹瀉(CID)。因此,本發明的化合物可作為(1)抑制化療佐劑以預防化療導致的腹瀉(CID)並增加癌症的化療效果;(2)預防致癌物質誘發的大腸癌之健康食品補充劑。
Description
本發明係關於抑制β-葡萄醣醛酸酶的新化合物,特別地,本發明提供吡唑並[4,3-c]喹啉(pyrazolo[4,3-c]quinoline)衍生物以抑制微生物β-葡萄醣醛酸酶。
單離喜樹鹼(Camptothecin),從喜樹(Camptotheca acuminata)分離的生物鹼(Wall,M.E.;Wani,M.C.;Cook,C.E.;Palmer,K.H.;McPhail,A.T.;Sim,G.A.J.Am.Chem.Soc.1966,88,3888-3890;Werbovetz,K.A.;Bhattacharjee,A.K.;Brendle,J.J.;Scovill,J.P.Bioorg.Med.Chem.2000,8,1741-1747)已發現具有顯著的抗癌活性(Wall,M.E.Camptothecin and taxol:discovery to clinic.Med.Res.Rev.18,299-314(1998))。然而,喜樹鹼的毒性頗劇烈且生物利用率低(J.F.Pizzolato,L.B.Saltz,Lancet 361,2235(2003)),導致臨床利用受限制。運用半合方式將喜樹鹼製成的癌康定(Topotecan)和抗癌妥(irinotecan,CPT-11),目前在臨床上以癌康定用於治療卵巢癌和非小細胞肺癌,抗癌妥用於大腸癌的治療(Mathijssen,R.H.,Loos,W.J.,Verweij,J.& Sparreboom,A.Pharmacology of topoisomerase I inhibitors irinotecan(CPT-11)and topotecan.Curr.Cancer Drug Targets 2,103-123(2002))。CPT-11是一個前驅藥(prodrug),具有胺甲酸酯(carbamate)連結的雙呱啶基(dipiperidino)基團,此基團於生物體內(in vivo)形成具活性的SN-38代謝物。SN-38在肝臟內經由二磷酸尿苷(uridine
diphosphate)葡萄糖醛酸轉移酶(glucuronosyltransferase)形成無活性的SN38-葡萄糖醛酸苷(SN38-glucuronide,SN-38G)後,從膽道排入腸胃道。一旦在腸道內,SN-38G作為微生物β-葡萄醣醛酸酶(microbiota β-glucuronidase,eβG)的底物(substrate),於水解成具生物活性的SN-38後,擔任著腹瀉的主要角色(Takasuna,K.et al.Optimal antidiarrhea treatment for antitumor agent irinotecan(CPT-11)-induced delayed diarrhea.Cancer Chemother.Pharmacol.58,494-503(2006);Yong,W.P.,et al.Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.Clin.Cancer Res.11,6699-6704(2005))。
已發現eβG抑制劑可降低SN-38G的生物活性和減輕CPT-11導致的腹瀉(Benson,A.B.,3rd et al.Recommended guidelines for the treatment of cancer treatment-induced diarrhea.J.Clin.Oncol.22,2918-2926(2004))。CPT-11在肝臟代謝成為SN-38G,隨即分泌到胃腸(GI)道,並經eβG水解成為生物活性的SN-38G,然後導致腸道損傷和腹瀉,以及CPT-11、SN-38及SN-38G的結構揭露於Takasuna,K.et al.Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride(CPT-11)-induced delayed diarrhea.Cancer Chemother.Pharmacol.58,494-503(2006)。
葡萄糖醛酸化反應係人類藥物排毒的主要途徑。然而,在腸道菌群中經由β-葡萄糖醛酸酶(βG)降解的葡萄糖醛酸苷,在癌症化療過程中引起嚴重的毒性反應,並發生促使大腸癌發展的癌變。目前使用的抗
癌藥物,如抗癌妥(CPT-11)(Kobayashi,K.Chemotherapy-induced diarrhea.Cancer & chemotherapy 30,765-771(2003))、5-氟尿嘧啶(5-FU)(Cascinu,S.et al.High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients.Supportive care in cancer,8,65-67(2000))、草酸鉑(oxaliplatin)(Dranitsaris,G.,et al.Severe chemotherapy-induced diarrhea in patients with colorectal cancer:a cost of illness analysis.Supportive care in cancer,13,318-324(2005))會引發嚴重的化療藥物導致腹瀉(chemotherapy-induced diarrhea,CID)副作用,因而可能導致的降低給藥劑量或甚至化療的中斷(Viele,C.S.Overview of chemotherapy-induced diarrhea.Semin.Oncol.Nurs.19,2-5(2003))。CID係一種常見的病症,尤其中晚期癌症病患更容易發生。因此,發現腸道內的特定βG抑制劑,即僅抑制如細菌的βG(E.coli βG;eβG),而非人類βG(hβG)的化合物頗具迫切需要性。
已發現一些βG抑制劑可降低SN-38G的生物活性,減輕CPT-11導致的腹瀉(Benson,A.B.,3rd et al.Recommended guidelines for the treatment of cancer treatment-induced diarrhea.J.Clin.Oncol.22,2918-2926(2004))。例如,發現葡萄糖-1,4-內酯(glucaro-1,4-lactone)可改善因投予CPT-11導致的CID症狀(Takasuna,K.et al.Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride(CPT-11)-induced delayed diarrhea.Cancer Chemother.Pharmacol.58,494-503(2006))。然而,投予葡萄糖-1,4-內酯(一種非選擇性的βG抑制劑),可能導致粘多醣症狀副作用,因對hβG擁有強烈的抑制效應(Fittkau,M.,et al.Saccharicacid 1,4-lactone protects against CPT-11-induced mucosa damage in rats.J.Cancer Res.Clin.130,388-394(2004);Constantopoulos,G.,et al.Experimental animal model for mucopolysaccharidosis:suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.Proc.Natl.Acad.Sci.USA.77,3700-3704(1980))。另外,文獻中揭示腸的eβG在葡萄糖醛酸苷共軛致癌劑的代謝活化過程中扮演重要的作用,從而導致結腸癌的形成(Kaderlik,K.R.et al.Metabolic activation pathway for the formation of DNA adducts of the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP)in rat extrahepatic tissues.Carcinogenesis 15,1703-1709(1994);Nalini,N.,et al.Effect of coconut cake on the bacterial enzyme activity in 1,2-dimethyl hydrazine induced colon cancer.Clin.Chim.Acta.342,203-210(2004);Nalini,N.,et al.Influence of spices on the bacterial(enzyme)activity in experimental colon cancer.J.Ethnopharmacol.62,15-24(1998))。Kim等揭露抑制腸的eβG可降低結腸癌的發生,且在結腸癌患者中eβG的活性較正常對照組高達為12.1倍(Kim,D.H.& Jin,Y.H.Intestinal bacterial beta-glucuronidase activity of patients with colon cancer.Arch.Pharm.Res.24,564-567(2001))。Humblot,C.等證明腸的eβG和結腸的遺傳毒性存在著正相關性(Humblot,C.et al.Beta-glucuronidase in human intestinal microbiota is necessary for the colonic genotoxicity of the food-borne carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline in rats.Carcinogenesis 28,2419-2425(2007))。最近,1-((6,8-二甲基-2-氧代-1,2-二氫基喹啉-3-基)甲基)-3-(4-乙氧苯基)-1-(2-羥乙基)硫脲(1-((6,8-Dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxy-ethyl)thiourea)(βG-Inh,為為一公開的eβG專一抑制劑)為最有效且專一的eβG抑制劑(Wallace,B.D.et al.Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.Science 330,831-835(2010))。下列結構式為葡萄糖-1,4-內酯及βG-Inh的結構。
美國專利第5447719號提供一β-葡萄醣醛酸酶抑制劑,至少包括選自黃芩苷(baicalin)、千層紙苷(oroxylin A-7-O-glucuronide)、木犀草素-3'-葡萄糖醛酸苷(luteolin-3'-glucuronide)的至少一化合物;黃芩根(scutellaria root)和荊芥穗(schizonepeta spike)萃取物;或含有作為生藥的黃芩根及/或荊芥穗的中國或日本傳統中藥處方。美國公開專利第20130345235號涉及抑制細菌葡萄醣醛酸酶的苯氧基噻吩磺胺(phenoxythiophene sulfonamides),和包括一個或多個此類化合物的組合物及運用一個或多個此類化合物作為與一喜樹鹼衍生抗癌藥物的併用藥物(co-drug)使用的方法。
然而,βG-Inh的療效和特異性並不理想,因此,更有效力的和選擇性的eβG抑制劑鑒定,成為關注焦點。
本發明提供一種具有下列結構式I的化合物,
本發明的化合物可作為(1)化療佐劑(chemotherapy-adjuvant)以預防化療導致之腹瀉(CID)並增加癌症的化療效果;(2)預防致癌物質誘發之大腸癌的健康食品補充劑。因此,本發明的化合物以及組合物用作為在
生物體內治療或預防化療導致之腹瀉和誘發結腸癌之致癌物質的療法。在又一實施例中,本發明提供用於減少/抑制經由在生物體中的葡萄糖醛酸化反應代謝的治療劑再活化的方法,包括對生物體投予有效量的化合物或如上述的組合物。
圖1A及1B為吡唑並[4,3-c]喹啉衍生物的選擇性抑制。(A)抑制eβG;(B)抑制hβG。
圖2為吡唑並[4,3-c]喹啉衍生物在低濃度(10μM)或高濃度(50μM)時對內源性eβG活性的抑制功效。
圖3A及3B為吡唑並[4,3-c]喹啉衍生物於人類胚胎腎細胞株(HEK293)(圖3A)及人類正常肝細胞株(CNL)(圖3B)的細胞存活試驗。
圖4為吡唑並[4,3-c]喹啉衍生物對大腸桿菌生長的影響。
圖5A及5B為體內的光學影像系統,其展現化合物17(TCH-3511)及化合物32(THC-3510)可顯著地抑制腸道的βG活性(圖5A)。17(TCH-3511)的抑制性較32(THC-3510)好。
圖6A及6B為17(TCH-3511)對腹瀉的功效及與CPT-11的抗癌活性。小鼠接種CT26細胞至第7天。水或17(TCH-3511)在整個實驗期間以3mg/kg/天的劑量每天以口服方式投藥(第0天以後)。小鼠從第2天開始每天給予腹膜內的CPT-11治療(50mg/kg/天)或生理鹽水。每隔一天記錄腹瀉程度及腫瘤大小。(A)17(TCH-3511)可減少CPT-11導致的腹瀉。(B)17(TCH-3511)對CPT-11治療的抗腫瘤功效沒有功效。
圖7為17(TCH-3511)對DMH在腸中誘發癌變的功效。水或17(TCH-3511)在整個實驗期間以3mg/kg/天的劑量每週以口服方式投藥3次
(~8週)。小鼠給予腹膜內DMH(30mg/kg/週)。17(TCH-3511)口服投藥可減少DMH誘發的癌變。
為了克服先前技術的缺點,本發明揭示一種新穎的吡唑並[4,3-c]喹啉(pyrazolo[4,3-c]quinoline)衍生物擁有專一地抑制微生物β-葡萄醣醛酸酶的活性,藉以提供有效的活性來預防癌症的化療導致之腹瀉(chemotherapy-induced diarrhea,CID)。因此,本發明的化合物可作為(1)化療佐劑以預防癌症化療導致之腹瀉(CID)並增加癌症的化療效果;(2)預防致癌物質誘發之大腸癌的健康食品補充劑。
定義
本文所用術語「一」或「一個」表示可能用於此處引用一個或多個(即至少一個)本文的語法物件。例如「類似物(analogue)」意味著一個類似物或多個類似物。
本文所用「包括(comprising)」表示各種元件可以共同從事於本發明的藥物組合物。因此,用「實質上由…組成(consisting essentially of)」和「由…組成(consisting of)」是包含用語的具體話用詞。
本文所用「取代」指一基團內的一個或多個氫原子可獨立地替換為相同或不同的取代基(substituent(s))。
本文所用術語「烷基」表示係具有1至20個碳原子的直鏈或支鏈之脂肪烴基(aliphatic hydrocarbon)。較佳烷基具有1到8個碳原子,更佳為具有1到6個碳原子較低烷基,最佳具有1到4個碳原子。直鏈烷基團之實例包含甲基、乙基、正丙基及正丁基。支鏈表示係以一個或多個如甲基、乙基、丙基或丁基的較低烷基鏈接到一個直鏈烷基鏈,支鏈烷基團之實例包含異丙基、第二丁基、第三丁基及異戊基。
本文所用術語「烯基自由基」表示包含從2到10個碳原子和包括一個或多個雙鍵的直鏈或分枝的不飽和烴基鏈。
本文所用術語「炔基自由基」表示包含從2到10個碳原子和包括一個或多個三鍵直鏈或分枝的不飽和烴基鏈。
本文所用術語「環烷基」表示具有3到大約10個碳原子之環烴基,並具有一個單環或多個的縮合環,包括融合和橋環系統,亦可選擇地以1到3碳的烷基取代。此類環烷基包括如環丙基、環丁基、環戊基、環辛基、1-甲基環丙基、2-甲基環戊基、2-甲基環辛基和類似的單環結構,以及如金剛烷基(adamantanyl)和類似的多環結構。
本文所用術語「芳烴基」表示芳香烴基環或兩個融合芳香烴基環,較佳的芳烴基為萘基、苯基。
本文所用術語「烷氧基」係指特定數目的碳原子(如C1-10烷氧基)或某數目範圍內之碳原子(即甲氧基(MeO-)、乙氧基、異丙氧基等)的直鏈或支鏈烷氧基化合物。
本文所用術語「烷硫基」係指特定數目的碳原子(如C1-10烷硫基)或某數目範圍內之碳原子(即甲硫基(MeS-)、乙硫基、異丙硫基等)的直鏈或支鏈烷硫基化合物。
本文所用術語「烷胺基」係指特定數目的碳原子(如C1-10烷胺基)或某數目範圍內之碳原子(即甲胺基、乙胺基、異丙胺基、叔丁基胺基等)的直鏈或支鏈烷胺基化合物。
本文所用術語「雜芳烴基」係指具有5至14個環狀原子的基團;在一個環狀的陣列內共用6、10或14 π電子;和含有碳原子和1、2或3個的氧原子、氮原子及/或硫原子之雜原子。雜芳烴基的例子包括吲唑基、呋喃基、噻吩基、吡咯基、咪唑基、噁唑基、噻唑基、吡唑基、異噁
唑基、異噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、四唑基、三嗪基、吖庚因基、氧雜草基、嗎啉基、硫氮雜卓基、二氮雜卓基、噻唑啉基、苯並咪唑、苯並噁唑基、咪唑並吡啶基、苯並噁嗪基、苯並噻嗪基、苯並噻酚基、噁唑並吡啶基、苯並呋喃基、喹啉基、喹唑啉基、喔啉基、苯並噻唑基、酞醯亞胺基、苯並二吖庚因基、吲哚基、茚滿基、含氮吲唑基(azaindazolyl)、去氮嘌呤基和異吲哚基。
本文所用術語「藥學上可接受的鹽類」係指本發明化合物的任何鹽類,保留著該化合物的生物學特性,且無毒性或其他不適宜供藥用。該鹽類可從各種眾所周知及涵蓋於藥學技術的有機離子或無機相對離子所衍生。
本文所用術語「溶質化物(solvate)」係指本發明的化合物或其鹽類,其包含以非共價分子間作用力所結合的化學計量或非化學計量之溶劑(solvent)。該溶劑為水,溶質為水合物。
本文所用術語「前藥(prodrug)」係指包含本發明化合物所衍生的化合物,具有裂解基團及藉由溶劑解離(solvolysis)或在生理條件下成為本發明在體內具有藥物活性的化合物。前藥包括但不限於膽鹼酯類衍生物及其類似物、N-烷基嗎啉類酯及其類似物等。
本文所用術語「障礙(disorder)」、「病症(condition)」、「疾病(disease)」可互換使用以係指生物體的狀況。此狀況可表徵為一種以上障礙。
本文所用術語「有效量(effective amount)」係指為減輕疾病或病症的化合物劑量。術語「足供療效用量(therapeutically effective amount)」意為當投予至生物體內以治療一疾病時,足以影響該疾病治療的
化合物劑量。「足供療效用量」係根據化合物、疾病種類和其嚴重程度、及需要治療的生物體的年齡、體重而改變。
本文所用術語「預防(prevent,preventing,prevention)」係指經由給予一種療法或結合療法,來預防生物體中障礙的一個或多個症狀的復發、發作或發展。
本文所用術語「治療(treat,treatment,treating)」係指經由給予生物體一種或多種療法以減少或改善一種障礙的進展、嚴重程度和持續時間,或障礙的一個或多個症狀。
本文所用術語「生物體(subject)」和「病患(patient)」係互換使用。術語「生物體(subject)」和「病患(patient)」係指動物,在某些實施例為包括非靈長類動物(如牛、豬、馬、貓、狗、大鼠和鼠)及靈長類動物(如馬來猴(cynomolgous monkey)之類的猴子、黑猩猩和人類)的哺乳類,以及較佳係人類。在某些實施例中,生物體係人類。
本發明的化合物
本發明之目的即在於提供一種具有下所示結構式I的化合物,
其中n代表0至4取代基;R1代表1至4取代取代基;R1各自獨立地選自下列取代基所組成的群
組:H、鹵素、OH、CN、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵化烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;R2選自下列取代基所組成的群組:H、鹵素、烷基、烷氧基、烷硫基、烷胺基、OH、CN、NH2、NO2、OR4、SR4、COR5、COOR6、烯基、炔基、鹵化烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;R3選自下列取代基所組成的群組:鹵素、CN、OH、NO2、NRaRb、烷基、烯基、炔基、烷氧基、鹵化烷基、環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;R4選自下列取代基所組成的群組:鹵素、CN、OH、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵化烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;R5與R6各自獨立地選自下列取代基所組成的群組:H、鹵素、CN、OH、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵化烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;Ra與Rb各自獨立地選自下列取代基所組成的群組:C(O)NRcRd、H、鹵素、OH、CN、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵化烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;以及Rc與Rd各自獨立地選自下列取代基所組成的群組:H、鹵素、CN、OH、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵化烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基;或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物。
在一些實施例中,任一環烷基、芳基以及雜芳基可為未取代,或以鹵素、CN、OH、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵烷基、未取代或取代的環烷基、未取代或取代的芳基、或未取代或取代的雜芳基加以取代。
在一些實施例中,雜芳基係C6-10元環,且具有1至3個選自氮原子、氧原子及硫原子的雜原子。
在一些實施例中,R1係H、鹵素或分別於C-5、C-6、C-7或C-8位加以取代的C1-10烷基。在另一實施例中,R1係H、鹵素或C1-4烷基。在另一實施例中,R1係H、Cl、F、Br、甲基。在另一實施例中,R1係H。
在一些實施例中,R2係H、鹵素、C1-10烷基、C1-10烷氧基、C1-10烷硫基、NH2、NO2、鹵烷基、COR5,或分別於C-2’、C-3’或C-4’位加以取代的COOR5。在另一實施例中,R2係H、鹵素、C1-4烷基、C1-4烷氧基、C1-4烷硫基、NH2、NO2、鹵化C1-4烷基、C(O)C1-4烷基、或COOH。在另一實施例中,R2係H、甲基、OH、NH2、甲氧基、甲硫基、CF3、Cl、F、NO2、COOH、C(O)CH3。
在一些實施例中,R3係NRaRb、OH或NO2,其中Ra與Rb各自獨立地分別為H或C(O)NRcRd,且Rc與Rd各自獨立地分別為H或未取代或取代的芳基。在一些實施例中,芳基係未取代或以C1-6烷氧基加以取代,較佳係-OCH3。較佳地,R3係NH2、OH、NO2、苯基,以-OCH3取代的苯基。
在一些實施例中,本發明的化合物具有下列結構式其中之一,
其中R1與R2如上文所述定義,和R係H或1-4鹵素、CN,OH、NH2、NO2、烷基、烯基、炔基、烷氧基、鹵烷基、未取代或取代的環烷基、未取代或取代的芳基,或未取代或取代之雜芳基。
在一些實施例中,本發明的化合物選自下列基團所組成的群組:4-羥基-8-甲基-2-氧代-1,2-二氫喹啉-3-甲腈(4-hydroxy-8-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile);2,6-溴基-4-羥基-2-氧代-1,2-二氫喹啉-3-甲腈(2,6-Bromo-4-hydroxy-2-oxo-1,2-dihydro-quinolone-3-carbonitrile);2,4-二氯基-8-甲基喹啉-3-甲腈(2,4-Dichloro-8-methylquinoline-3-carbonitrile);4,6-溴基-2,4-二氯基喹啉-3-甲腈(4,6-Bromo-2,4-dichloroquinoline-3-carbonitrile);4-氯基-6-甲基-1氫-吡唑並[4,3-c]喹啉-3-胺基(4-Chloro-6-methyl-1H-pyrazolo[4,3-c]quinolin-3-amine);4-氯基-7-氟基-1氫-吡唑並[4,3-c]喹啉-3-胺基(4-Chloro-7-fluoro-1H-pyrazolo[4,3-c]quinolin-3-amine);4,8-二氯基-1氫-吡唑並[4,3-c]喹啉-3-胺基(4,8-Dichloro-1H-pyrazolo[4,3-c]quinolin-3-amine);
8-溴基-4-氯基-1氫-吡唑並[4,3-c]喹啉-3-胺基(8-Bromo-4-chloro-1H-pyrazolo[4,3-c]quinolin-3-amine);3-氨基-4-(4-氯苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-chlorophenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-甲苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-methylphenylamino)-1H-pyrazolo[4,3-c]quinoline);N 4-(4-氯苯基)-6-甲基-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(4-Chlorophenyl)-6-methyl-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);6-甲基-N 4-(對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(6-Methyl-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);N 4-(4-氯苯基)-7-氟基-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(4-Chlorophenyl)-7-fluoro-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);7-氟基-N 4-(對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(7-Fluoro-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);8-氯基-N 4-(4-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Chloro-N 4-(4-chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);8-氯基-N 4-(4-對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Chloro-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);8-溴基-N 4 -(4-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Bromo-N 4-(4-chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);8-溴基-N 4-(4-對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Bromo-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);3-氨基-4-苯胺基-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-anilino-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-羥苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-hydroxyphenylamino)-1H-pyrazolo[4,3-c]quinoline);
3-氨基-4-(4-氨苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-aminophenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-氟苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-fluorophenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-三氟甲基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-trifluoromethylphenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-甲氧基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-methoxyphenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-甲基硫苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-methylthiophenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(4-硝基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-nitrophenylamino)-1H-pyrazolo[4,3-c]quinoline);4-(3-氨基-1氫-吡唑並[4,3-c]喹啉-4-基氨基)苯甲酸(4-(3-Amino-1H-pyrazolo[4,3-c]quinolin-4-ylamino)benzoic acid);3-氨基-4-(4-乙醯基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-acetylphenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(3-羥基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(3-hydroxyphenylamino)-1H-pyrazolo[4,3-c]quinoline);N 4-(間甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(m-Tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);N 4-(3-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(3-Chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);3-氨基-4-(3-甲氧基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(3-methoxyphenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-4-(3-乙醯基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(3-acetylphenylamino)-1H-pyrazolo[4,3-c]quinoline);
3-氨基-4-(2-羥基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(2-hydroxyphenylamino)-1H-pyrazo1o[4,3-c]quinoline);N 4-(鄰甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(o-Tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);N 4-(2-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(2-Chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine);3-氨基-4-(2-甲氧基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(2-methoxyphenylamino)-1H-pyrazolo[4,3-c]quinoline);3-氨基-1氫-吡唑並[4,3-c]喹啉-4(5氫)-酮(3-Amino-1H-pyrazolo[4,3-c]quinolin-4(5H)-one);1-(4-氧代-4,5-二羥基-1氫-吡唑並[4,3-c]喹啉-3-基)-3-苯基尿素(1-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-3-yl)-3-phenylurea);1-(4-甲氧基苯基)-3-(4-氧代-4,5-二羥基-1氫-吡唑並[4,3-c]喹啉-3-基)尿素(1-(4-Methoxyphenyl)-3-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-3-yl)urea);1-{4-[(4-氯苯基)氨基]-1氫-吡唑並[4,3-c]喹啉-3-基}-3-苯基尿素(1-{4-[(4-Chlorophenyl)amino]-1H-pyrazolo[4,3-c]quinolin-3-yl}-3-phenylurea);1-苯基-3-[4-(對甲苯基氨基)-1氫-吡唑並[4,3-c]喹啉-3-基]尿素(1-Phenyl-3-[4-(p-tolylamino)-1H-pyrazolo[4,3-c]quinolin-3-yl]urea);1-{4-[(4-氯苯基)氨基]-1氫-吡唑並[4,3-c]喹啉-3-基}-3-(4-甲氧基苯基)尿素(1-{4-[(4-Chlorophenyl)amino]-1H-pyrazolo[4,3-c]quinolin-3-yl}-3-(4-methoxyphenyl)urea);及1-(4-甲氧基苯基)-3-[4-(對甲苯基氨基)-1氫-吡唑並[4,3-c]喹啉-3-基]尿素(1-(4-Methoxyphenyl)-3-[4-(p-tolylamino)-1H-pyrazolo[4,3-c]quinolin-3-yl]urea);
或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物。
又於其他實施例,本發明的化合物選自下列結構式所組成之群組:
可瞭解擁有相同分子式,但其原子的鍵結性質或順序,或在原子的空間排列有所差異的化合物被稱為「同分異構物(isomers)」。原子在空間中排列有所差異的同分異構物稱為「立體異構物(stereoisomers)」。另一個無鏡像關係的立體異構物稱為「非鏡像異構物(diastereomers)」,而其中非疊加鏡像(non-superimposable mirror images)的稱為「對掌異構物
(enantiomers)」。擁有不對稱中心(asymmetric center)之化合物,例如當與4個不同基團鍵結時,可能有一對之對掌異構物。對掌異構物可依其不對稱中心的絕對組態(absolute configuration)的特徵,且根據坎-普利洛(Mata and Lobo,1993,Tetrahedron:Asymmetry 4:657-668)的規則標註為(R)或(S),或依分子旋轉偏振光(polarized light)平面的方式的特徵,而標註為右旋或左旋(即分別為(+)-或(-)-同分異構物)。掌性化合物(chiral compound)可存在個別的對掌異構物或兩者的混合物。含有同等比例混合物的對掌異構物為外消旋混合物(racemic mixture)。
在一實施例中,此處所述的化合物的藥學上鹽類包括但不限於:(1)與有機酸或無機酸所形成的酸加成鹽類,有機酸或無機酸如鹽酸、氫溴酸(hydrobromide)、硫酸、硝酸、磷酸、磺酸、乙酸、三氟乙酸、三氯乙酸、丙酸、正己酸、環戊基丙酸、甘醇酸(glycolic)、戊二酸、丙酮酸、乳酸、縮蘋果酸(malonic)、琥珀酸、山梨酸、抗壞血酸、蘋果酸、馬來酸、富馬酸、酒石酸、檸檬酸、安息香酸、3-(4-羥基苯甲醯)苯甲酸、苦味酸、肉桂酸、苦杏仁酸、鄰苯二甲酸、月桂酸、甲磺酸、乙磺酸、1,2-乙烷二磺酸、2-羥乙基磺酸、苯磺酸、4-氯基苯磺酸、2-萘磺酸、4-甲苯基磺酸、樟腦酸、樟腦磺酸、4-甲基雙環[2.2.2]辛-2-烯-羧酸、葡庚糖酸、3-苯基丙酸、三甲基乳酸、叔丁基乙酸、十二烷基硫酸酸、葡萄糖酸、麩氨酸、羥基萘甲酸、水楊酸、硬脂酸、環己基氨基磺酸、奎尼酸、已二烯二酸和類似酸;或是(2)當母體化合物的酸性質子(a)被金屬離子(如鹼金屬離子、鹼土離子或鋁離子)或鹼金屬或鹼土金屬的氫氧化物(如鈉氫氧化物、鉀氫氧化物、鈣氫氧化物、鎂氫氧化物、鋁氫氧化物、鋰氫氧化物、鋅氫氧化物及鋇氫氧化)、氨(ammonia)取代,或者(b)與有機鹼配位,有機鹼如脂肪族、脂環族,或芳香族的有機胺類(如氨、甲胺、二甲胺、二乙
胺、甲基吡(picoline)、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、賴氨酸、精氨酸、鳥氨酸、膽鹼,N,N'-二苄基乙二胺(N,N'-dibenzylethylene-diamine)、氯普魯卡因、普魯卡因、N-苄基苯乙胺、N-甲基葡糖胺呱嗪(N-methylglucamine piperazine)、三(羥甲基)-氨基甲烷、氫氧化四甲銨(tetramethylammonium hydroxide)及其類似物),所形成的鹽類。鹽類更包括,僅作為示例,鈉、鉀、鈣、鎂、銨、四甲基銨及其類似物,且該化合物包含的基本官能基係如鹽酸、氫溴酸、酒石酸、甲磺酸、苯磺酸(besylate)、醋酸、馬來酸、草酸等無毒之有機酸或無機酸所生成的鹽類。術語「生理上可接受的陽離子」係指酸性官能基上無毒性、生理上可接受的陽離子的相對離子(counter ion)。該等陽離子例如鈉、鉀、鈣、鎂、銨和四烷基銨(tetraalkylammonium)等陽離子及其類似物。
吡唑並[4,3-c]喹啉衍生物可依照如下列反應流程(流程圖1)製備。以三氯氧磷(POCl3)與4-羥基-2-氧代-1,2-二氫喹啉-3-甲腈(4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonitriles)(1)作用,生成2,4-二氯喹啉-3-甲腈(2,4-dichloroquinoline-3-carbonitriles)(2),然後與肼反應產生4-氯基-1氫-吡唑並[4,3-c]喹啉-3-胺(4-chloro-1H-pyrazolo[4,3-c]quinolin-3-amines)(3)。化合物3與取代的苯胺反應,產生3-氨基-4-取代苯胺基-1氫-吡唑並[4,3-c]喹啉(3-amino-4-substituted anilino-1H-pyrazolo[4,3-c]quinolines)(4-32)。
當作為藥品或食品補充劑時,本發明的化合物以藥品或食品的組合物方式給藥。該等組合物可以藥品或食品領域熟知的方式製備且包括至少一種活性化合物。一般來說,本發明的化合物以藥學上有效量的有效量投予。化合物實際投予的量通常由醫生依照包括治療病症、選擇的投藥途徑、實際投藥化合物、個別病患的年齡、體重與反應、病患症狀的嚴重程度及類似情況的相關情況決定。
本發明的藥品或食品組合物可依各種方式給藥,包括口服、肛門給藥、皮下注射、關節注射、靜脈注射和肌肉注射。根據需求的遞送途徑,本發明的化合物較佳以可注射或口服組合物配製,或以軟膏、以乳液或以經皮貼片投藥,。
對於口服,本發明的化合物可結合賦形劑並以可攝入片劑、口頰片、錠劑、膠囊、酏劑(elixirs)、懸浮液、糖漿、糯米紙(wafers)及類似的形式使用。口服藥品可採取散裝液體溶液或懸浮液,或散裝粉末的形式。然而,更常見的,組合物以單位劑型存在以促進精確的給藥。術語「單位劑型(unit dosage form)」係指物理上分散單位,適合作為人體和其他哺乳動物的單一劑量,每個含有計算的活性物質預定量的單位與適合的賦形劑、媒劑或載體結合產生預期的治療效果的。通常單位劑型包括預充填、預測量液體組合物的安瓿或注射器,或在固體組合物的情況下為丸劑、片劑、膠囊或類似劑型。在這樣的組合物中,苯發明的化合物通常是一個較少的成分主成分化合物通常佔微量部分(如1-6mg/kg/天),其餘則是各種媒劑或載體並加工以有利於形成所需劑型。
適合口服的液體劑型可包括含有緩衝液、懸浮和分散劑、色素、香精及類似物的適合的水性或非水性媒劑。固體劑型可包括例如以下的任何成分或相似性質的化合物:如微晶纖維素、黃蓍膠或明膠的黏合劑;如澱粉或乳糖的賦形劑;如褐藻酸、羧甲基澱粉鈉(Primogel®)或玉米澱粉的崩散劑;如硬脂酸鎂的潤滑劑;如膠狀二氧化矽的滑動劑;如蔗糖或糖精的甜味劑;或如薄荷、水楊酸甲酯或柳橙香料的矯味劑。
可注射性的組合物通常取決於本領域已知的無菌生理食鹽水、磷酸鹽緩衝生理食鹽水或其他可注射的載體。
對於肛門給藥,這裡敘述的化合物可以含有如可可脂(cocoa butter)的慣用栓劑基劑製備成栓劑形式。
本發明的組合物可包含額外的治療劑(additional therapeutic agent)。在一實施例中,該治療劑可以是經由葡萄醣醛酸化反應代謝的任何劑。在一些實施例中,治療劑為抗癌劑、免疫增強劑或免疫調節劑。例
如,抗癌劑包括但不限於三苯甲胺(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、碘多啥芬(iodoxyfene)、醋酸甲羥孕酮(megestrol acetate)、阿那曲唑(anastrozole)、來曲唑(letrazole)、硼唑(borazole)、依西美坦(exemestane)、氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、醋酸環丙孕酮(cyproterone acetate)、醋酸戈舍瑞林(goserelin acetate)、亮脯利特(luprolide)、非那雄胺(finasteride)、賀癌平(herceptin)、甲氨蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)、阿糖胞苷(cytosine arabinoside)、多柔比星(doxorubicin)、柔紅黴素(daunomycin)、表柔比星(epirubicin)、去甲氧柔紅黴素(idarubicin)、絲裂黴素-C(mitomycin-C)、放線菌素(dactinomycin)、光輝黴素(mithramycin)、順鉑(cisplatin)、卡鉑(carboplatin)、馬法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)、環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、亞硝基脲(nitrosoureas)、硫特福恩(thiotephan)、長春新鹼(vincristine)、紫杉醇(taxol)、剋癌易(taxotere)、滅必治(etoposide)、鬼臼噻吩苷(teniposide)、胺苯吖啶(amsacrine)、伊立替康(irinotecan)、甲苯胺(topotecan)、埃博黴素(epothilone)及類似物。
本發明的化合物可作為(1)化療佐劑(chemotherapy-adjuvant)以預防化療導致之腹瀉(CID)並增加癌症的化療效果;(2)預防致癌物質誘發之大腸癌的健康食品補充劑。
因此,本發明的化合物與組合物用作為在生物體內治療或預防化療導致之腹瀉以及致癌物質誘發之大腸癌的療法。
在一方面,本發明提供發明的化合物,或包含該發明的化合物的組合物,以作為醫藥品。
在一實施例中,本發明提供用於選擇性抑制微生物βG而非人類βG(hβG)的方法,包括對生物體投予有效量之本發明化合物。
在一實施例中,本發明提供用在生物體中減少/抑制經由葡萄醣醛酸化反應代謝的治療劑再活化的方法,包括對生物體投予有效量之本發明的化合物或本發明的組合物。
在另一實施例中,本發明提供用於治療或預防生物體中化療導致之腹瀉或致癌物質誘發之大腸癌,包括對生物體投予有效量之本發明的化合物。
在更多實施例中,本發明提供於生物體增進癌症的化療效果,包括對生物體投予有效量之本發明的化合物。
在發明更多方面,提供做為藥品或食品的本發明之化合物,以治療或預防上述症狀和疾病。亦提供本化合物在藥物製造或食品製備的用途,以治療或預防上述症狀和疾病。
本方法具體方案包括對遭受化療導致之腹瀉(CID)或致癌物質誘發之大腸癌的生物體投藥,,或投藥至生物體以增進癌症的化療效果。
本方法另一具體方案包括對接受一種或多種治療的生物體投藥,治療如血管新生抑制劑(angiogenic inhibitors)、化療、放射、手術,或本領域習知的治療以預防和/或治療癌症。方法的具體實施例包含投予有效量的本發明之化合物至生物體化療導致之腹瀉(CID)或致癌物質誘發之大腸癌。方法的另一具體實施例包含投予有效量的本發明之化合物至生物體
以增進癌症的化療效果。另一具體實施例,用量範圍從約1至約6mg/kg/天。
當使用以預防病症的發作,,通常在醫生建議及監督下,本發明的化合物會以上述的劑量被投予至具發展病症風險的病患。
本發明之化合物可作為活性劑單獨投予至生物體,或可與其他治療劑結合投予,較佳地,任何經由葡萄醣醛酸化反應代謝的藥劑包括抗癌藥、免疫增強劑或免疫調節劑。在一具體實施例中,可使用2種(或更多)藥劑的聯合給藥(co-administration)。
在一實施例中,本發明之化合物可與一抗癌藥聯合給藥用以治療及/或預防癌症,具體藥物包括但不限於經由葡萄醣醛酸化反應代謝之抗癌藥物。此外,本發明之化合物可與其他療法合併投藥,其他療法包括但不限於放射治療、化療、或手術。
作為相同治療方案的一部分的被包含在內的聯合給藥為任何投遞兩種或更多治療劑至病患的方法,這對本領域技術人員是顯而易見的。當兩種或更多藥劑可同時投藥至單一配方,即如單一藥物組合物,這是非必要的。藥劑可分開以不同配方及在不同時間投藥。
一般TLC:由EM實驗室(EM Laboratories,Inc.)預塗(0.2mm)矽土凝膠60 F254的板材;以紫外光(254nm)偵測。熔點(M.P.):電熱式IA9100數位熔點儀;未經校正。氫和碳核磁共振光譜(1H and 13C NMR spectra):Varian-Unity-400核磁共振儀(spectrometer)在400和100MHz測定,或Varian-Gemini-200核磁共振儀在200和50MHz測定,化學位移δ(ppm)以四
甲基矽烷(SiMe4)作為內部標準(=0ppm),偶合常數J(Hz)。以Heraeus CHN-O-Rapid元素分析儀進行元素分析,計算值結果在±0.4%內。
將溶於15mL二甲基甲醯胺(dimethylformamide,DMF)的3.46g(19.5mmol)8-甲基苯唑無水物(8-methyl-isatoic anhydride)、2.21g(19.5mmol)氰乙酸乙酯(ethyl cyanoacetate)和3mL(20mmol)三乙基胺(triethylamine,Et3N)混合物加熱到160℃維持18小時,以薄層層析(thin layer chromatography,TLC)監控反應之進行。於真空態濃縮反應混合物,再添加1N鹽酸。沉澱物藉由過濾收集,以水清洗後,乾燥以產生棕色固體。粗產物以甲醇(MeOH)再結晶獲得2.00g產率為51%的1b。MP.:276-277℃,1H-NMR(400MHz,DMSO-d 6 ):2.40(s,3H,8-Me)、7.15(dd,1H,J=7.2,7.6Hz,6-H)、7.49(d,1H,J=7.2Hz,7-H)、7.88(d,1H,J=7.6Hz,5-H)、10.88(br s,1H,NH)。
產率為95%。MP.:280-282℃。1H-NMR(200MHz,DMSO-d 6 ):7.23(d,1H,J=8.8Hz,8-H)、7.63(dd,1H,J=8.8,2.2Hz,7-H)、8.13(d,1H,J=2.2Hz,5-H)、11.73(br s,1H,NH)。
將溶於30mL三氯氧磷(POCl3)的1.99g(10mmol)1b的混合物加熱到140℃維持3小時,以薄層層析監控反應之進行。經冷卻後,將混合物傾入50mL冰水,以飽和的碳酸鈉(Na2CO3)中和到pH7。以50mL二
氯甲烷(CH2Cl2)萃取該含水混合物3次,再以硫酸鎂(MgSO4)乾燥,並濃縮以產生棕色固體。經由正己烷:二氯甲烷(n-hexane:CH2Cl2)=1:2的沖提液(eluent)的矽膠管柱純化粗產物,以獲得白色固體,以甲醇再結晶獲得1.50g的2b,產率為64%。MP.:156-158℃。1H-NMR(200MHz,DMSO-d 6 ):2.67(s,3H,8-Me)、7.80(dd,1H,J=6.4,8.4Hz,6-H)、7.97(d,1H,J=6.4Hz,7-H)、8.07(d,1H,J=8.4Hz,5-H)。
產率為65%。MP.:191-193℃。1H-NMR(200MHz,DMSO-d 6 ):8.05(d,1H,J=9.0Hz,8-H)、8.23(dd,1H,J=9.0,2.2Hz,7-H)、8.44(d,1H,J=2.2Hz,5-H)。
將溶於20mL水合聯胺(hydraize hydrate)和30mL乙醇之混合溶液的1.17g(5mmol)2b的混合物加熱到60℃維持10分鐘,以薄層層析監控反應之進行。於真空態濃縮反應混合物,接著將加入100mL水溶液。沉澱物藉由過濾收集,以水清洗後,乾燥以產生白色固體。粗產物以甲醇再結晶獲得0.98g的3b,產率為84%。MP.:216-217℃。1H-NMR(400MHz,DMSO-d 6 ):2.66(s,3H,8-Me)、5.63(br s,2H,NH2)、7.53-7.60(m,2H,Ar-H)、8.10(d,1H,J=7.6Hz,Ar-H)、13.24(br s,1H,NH)。
產率為72%。MP.:224℃(dec)。1H-NMR(200MHz,DMSO-d 6 ):5.84(br s,2H,NH2)、7.57(m,1H,Ar-H)、7.69(dd,1H,J=10.4,2.4Hz,Ar-H)、8.30(dd,1H,J=8.8,6.0Hz,Ar-H)、13.20(br s,1H,NH)。
產率為90%。MP.:282℃(dec)。1H-NMR(200MHz,DMSO-d 6 ):5.70(br s,2H,NH2)、7.73(d,1H,J=7.2Hz,Ar-H)、7.93(d,1H,J=9.0Hz,Ar-H)、8.34(s,1H,Ar-H)、13.28(br s,1H,NH)。
產率為90%。MP.:325℃(dec)。1H-NMR(200MHz,DMSO-d 6 ):5.70(br s,2H,NH2)、7.84(s,2H,Ar-H)、8.50(s,1H,Ar-H)、13.27(br s,1H,NH)。
將溶於20mL二甲基甲醯胺(DMF)的0.44g(2mmol)的4-氯基-1氫-吡唑並[4,3-c]喹啉-3-胺(4-chloro-1H-pyrazolo[4,3-c]quinolin-3-amine)3a和合適的芳香胺(4mmol)的混合物加熱攪拌迴流3小時,以薄層層析監控反應之進行。混合物於真空中冷卻並脫水以產生殘餘物,將殘餘物溶於50mL水。沉澱物藉由過濾收集,以水清洗後,乾燥以產生粗固體,再以乙醇再結晶。
產率為75%。MP.:246-248℃。1H-NMR(400MHz,DMSO-d 6 ):5.62(br s,2H,NH2)、7.26-7.30(m,1H,Ar-H)、7.35(d,2H,J=8.8Hz,Ar-H)、7.46-7.50(m,1H,Ar-H)、7.61(d,1H,J=8.0Hz,Ar-H)、7.99-8.05(m,3H,Ar-H)、8.31(br s,1H,NH)、12.92(br s,1H,NH)。C16H12ClN5.0.2H2O的元素分析計算值(anal.calcd.):C 61.33,H 3.99,N 22.35;實驗值(found):C 61.45,H 3.86,N 22.67。
產率為81%。MP.:292-294℃(lit.296-298℃)。1H-NMR(400MHz,DMSO-d 6 ):2.30(s,3H,Me),5.62(br s,2H,NH2)、7.16(d,2H,J=8.4Hz,Ar-H)、7.26-7.29(m,1H,Ar-H)、7.47-7.51(m,1H,Ar-H)、7.60(d,1H,J=8.4Hz,Ar-H)、7.84(d,2H,J=8.4Hz,Ar-H)、8.05(d,1H,J=8.0Hz)、8.15(s,1H,NH)、12.89(br s,1H,NH)。lit.為Mekheimer,R.A.Synth.Commun.31,1971-1982(2001)。
產率為81%。MP.:249-250℃。1H-NMR(400MHz,DMSO-d 6 ):2.61(s,3H,Me)、5.67(br s,2H,NH2)、7.20-7.24(m,1H,Ar-H)、7.39-7.43(m,3H,Ar-H)、7.94(d,1H,J=7.6Hz,Ar-H)、8.11(d,2H,J=8.8Hz,Ar-H)、8.37(br s,1H,NH)、12.90(br s,1H,NH)。
產率為81%。MP.:270-271℃。1H-NMR(400MHz,DMSO-d 6 ):2.29(s,3H,Me)、2.60(s,3H,Me)、5.65(br s,2H,NH2)、7.15-7.19(m,3H,Ar-H)、7.39(d,1H,J=6.8Hz,Ar-H)、7.90-7.97(m,3H,Ar-H)、8.18(s,1H,NH)、12.85(br s,1H,NH)。C18H17N5的元素分析計算值:C,71.67;H,5.65;N,23.09。實驗值:C,71.21;H,5.69;N,23.00。
產率為52%。MP.:254℃(dec.)。1H-NMR(400MHz,DMSO-d 6 ):5.70(br s,2H,NH2)、7.21(br m,1H,Ar-H)、7.35-7.42(m,3H,Ar-H)、8.00(d,2H,J=8.4Hz,Ar-H)、8.09-8.14(m,1H,Ar-H)、8.42(br s,1H,NH)、12.97(br s,1H,NH)。C16H11ClFN5的元素分析計算值:C,58.63;H,3.38;N,21.37。實驗值:C,58.72;H,3.45;N,21.45。
產率為81%。MP.:246-247℃。1H-NMR(400MHz,DMSO-d 6 ):2.30(s,3H,Me)、5.68(br s,2H,NH2)、7.14-7.17(m,3H,Ar-H)、7.29(dd,1H,J=11.2,2.4Hz,Ar-H)、7.80(d,2H,J=8.0Hz,Ar-H)、8.08(dd,1H,J=8.4,6.8Hz,Ar-H)、8.22(br s,1H,NH)、12.85(br s,1H,NH)。
C17H14FN5.1HCl的元素分析計算值:C,59.37;H,4.40;N,20.37。實驗值:C,59.31;H,4.27;N,20.36。
產率為33%。MP.:270-272℃。1H-NMR(400MHz,DMSO-d 6 ):5.72(br s,2H,NH2)、7.40(d,2H,J=8.8Hz,Ar-H)、7.51(d,1H,J=8.4Hz,Ar-H)、7.64(d,1H,J=8.4Hz,Ar-H)、8.00(d,2H,J=8.0Hz,Ar-H)、8.15(s,1H,Ar-H)、8.41(s,1H,NH)、12.98(br s,1H,NH)。C16H11Cl2N5.1.3HCl的元素分析計算值:C,49.04;H,3.17;N,17.88。實驗值:C,48.90;H,3.47;N,17.77。
產率為46%。MP.:261℃。1H-NMR(400MHz,DMSO-d6):2.30(s,3H,Me)、5.67(br s,2H,NH2)、7.16(d,2H,J=8.0Hz,Ar-H)、7.49(d,1H,J=7.6Hz,Ar-H)、7.60(d,1H,J=8.8Hz,Ar-H)、7.80(d,2H,J=8.0Hz,Ar-H)、8.13(s,1H,Ar-H)、8.23(s,1H,NH)、12.95(br s,1H,NH)。C17H14ClN5.1.3HCl的元素分析計算值:C,54.45;H,4.14;N,18.68。實驗值:C,54.24;H,4.36;N,18.38。
產率為50%。MP.:264℃(dec.)。1H-NMR(400MHz,DMSO-d 6 ):5.71(br s,2H,NH2)、7.39(d,2H,J=8.8Hz,Ar-H)、7.56-7.63(m,2H,Ar-H)、8.00(d,2H,J=8.8Hz,Ar-H)、8.30(s,1H,Ar-H)、8.40(s,1H,NH)、12.95(br s,1H,NH)。
產率為73%。MP.:276℃。1H-NMR(400MHz,DMSO):2.30(s,3H,Me)、5.68(br s,2H,NH2)、7.17(d,2H,J=8.4Hz,Ar-H)、7.52-7.61(m,2H,Ar-H)、7.79(d,2H,J=6.8Hz,Ar-H)、8.26(br s,2H,Ar-H and NH)、12.96(br s,1H,NH)。
產率為86%。MP.:256-258℃(lit.258-259℃)。1H-NMR(400MHz,DMSO-d 6 ):5.62(br s,2H,NH2)、6.99-7.03(m,1H,Ar-H)、7.27-7.37(m,3H,Ar-H)、7.48-7.52(m,1H,Ar-H)、7.63(d,1H,J=8.0Hz,Ar-H)、7.97(d,2H,J=8.0Hz,Ar-H)、8.06(d,1H,J=8.0Hz,Ar-H)、8.24(s,1H,NH)、12.92(s,1H,NH)。C16H13N5的元素分析計算值:C 69.80,H 4.76,N 25.44;實驗值:C 70.11,H 5.01,N 25.32。lit.為Mekheimer,R.A.Synth.Commun.31,1971-1982(2001)
產率為82%。MP.:347-349℃(Dec)。1H-NMR(400MHz,DMSO-d 6 ):6.96(d,2H,J=8.8Hz,Ar-H)、7.36(d,2H,J=8.4Hz,Ar-H)、7.39-7.43(m,1H,Ar-H)、7.51-7.56(m,1H,Ar-H)、7.79-7.81(m,1H,Ar-H)、8.14(m,1H,Ar-H)、9.96(br s,1H,NH)、10.59(br s,1H,OH)、12.21(br s,1H,NH)。C16H13N5O.2.0H2O的元素分析計算值:C 58.70,H 5.24,N 21.40;實驗值:C 58.47,H 5.24,N 21.70。
產率為61%。MP.:355-356℃。1H-NMR(400MHz,DMSO-d 6 ):5.57(br s,2H,NH2)、6.35(br s,2H,NH)、6.71(d,2H,J=8.8Hz,Ar-H)、7.17(d,2H,J=8.0Hz,Ar-H)、7.39-7.51(m,3H,Ar-H)、7.77-7.81(m,1H,Ar-H)、8.08(br s,1H,NH)、10.41(br s,1H,NH)、10.98(br s,1H,NH)、12.96(br s,1H,NH)。
產率為79%。MP.:266-268℃。1H-NMR(400MHz,DMSO-d 6 ):5.64(br s,2H,NH2)、7.16-7.21(m,2H,Ar-H)、7.27-7.30(m,1H,Ar-H)、7.47-7.51(m,1H,Ar-H)、7.60(d,1H,J=8.0Hz,Ar-H)、7.96-7.99(m,2H,Ar-H)、7.61(d,1H,J=7.6Hz,Ar-H)、8.25(br s,1H,NH)、12.91(br s,1H,NH)。C16H12FN5的元素分析計算值:C 65.52,H 4.12,N 23.88;實驗值:C 65.52,H 4.39,N 23.63。
產率為75%。MP.:251-252℃。1H-NMR(400MHz,DMSO-d 6 ):5.68(br s,2H,NH2)、7.34-7.38(m,1H,Ar-H)、7.53-7.57(m,1H,Ar-H)、7.68-7.72(m,3H,Ar-H)、8.40(d,1H,J=7.6Hz,Ar-H)、8.20(d,2H,J=8.8Hz,Ar-H)、8.61(br s,1H,NH)、13.00(br s,1H,NH)。C17H12F3N5的元素分析計算值:C 59.48,H 3.52,N 20.40;實驗值:C 59.55,H 3.57,N 20.26。
產率為81%。MP.:228-230℃(lit.235-237℃)。1H-NMR(400MHz,DMSO-d 6 ):3.67(s,3H,OMe)、5.62(br s,2H,NH2)、6.94(d,2H,J=9.2Hz,Ar-H)、7.23-7.26(m,1H,Ar-H)、7.44-7.48(m,1H,Ar-H)、7.56(d,1H,J=8.0Hz,Ar-H)、7.83(d,2H,J=7.6Hz,Ar-H)、8.03(d,1H,J=8.4Hz,Ar-H)、8.10(br s,1H,NH)、12.86(br s,1H,NH)。C17H15N5O.0.1H2O的元素分析計算值:C 66.47,H 5.00,N 22.80;實驗值:C 66.39,H 4.98,N 22.94。lit.為Mekheimer,R.A.Synth.Commun.31,1971-1982(2001)
產率為80%。MP.:269-271℃。1H-NMR(400MHz,DMSO-d 6 ):2.48(s,3H,SMe)、5.63(br s,2H,NH2)、7.29(d,1H,J=8.8Hz,Ar-H)、7.48-7.51(m,1H,Ar-H)、7.61(d,1H,J=8.0Hz,Ar-H)、7.95(d,1H,J
=8.4Hz,Ar-H)、8.05(d,1H,J=7.6Hz,Ar-H)、8.24(br s,1H,NH)、12.91(br s,1H,NH)。C17H15N5S.0.1HCl的元素分析計算值:C 62.82,H 4.68,N 21.54;實驗值:C 62.66,H 4.72,N 21.14。
產率為36%。MP.:303-305℃(Dec)。1H-NMR(400MHz,DMSO-d 6 ):5.73(br s,2H,NH2)、7.40-7.43(m,1H,Ar-H)、7.58-7.61(m,1H,Ar-H)、7.78(d,1H,J=7.6Hz,Ar-H)、8.14(d,1H,J=8.0Hz,Ar-H)、8.25(s,4H,Ar-H)、9.10(br s,1H,NH)、13.08(br s,1H,NH)。C16H12N6O2.0.3HCl的元素分析計算值:C 58.01,H 3.73,N 25.37;實驗值:C 57.72,H 4.03,N 24.98。
產率為76%。MP.:362-364℃。1H-NMR(400MHz,DMSO-d 6 ):5.65(br s,2H,NH2)、7.47-7.51(m,1H,Ar-H)、7.59-7.63(m,1H,Ar-H)、7.74-7.78(m,3H,Ar-H)、8.07(d,2H,J=8.4Hz,Ar-H)、8.19(d,1H,J=8.0Hz,Ar-H)、11.21(br s,1H,NH)、12.17(br s,1H,NH)、12.95(br s,1H,COOH)。C17H13N5O2.HCl的元素分析計算值:C 57.39,H 3.97,N 19.68;實驗值:C 57.45,H 3.84,N 19.76。
產率為83%。MP.:249-251℃。1H-NMR(400MHz,DMSO-d 6 ):2.55(s,3H,Me)、5.67(br s,2H,NH2)、7.35-7.38(m,1H,Ar-H)、7.54-7.58(m,1H,Ar-H)、7.72(d,1H,J=8.0Hz,Ar-H)、7.97(d,2H,J=8.8Hz,Ar-H)、8.10-8.15(m,3H,Ar-H)、8.65(br s,1H,NH)、13.01(br s,1H,NH)。C18H15N5O.0.1HCl的元素分析計算值:C 67.35,H 4.74,N 21.82;實驗值:C 67.22,H 4.82,N 21.57。
產率為84%。MP.:319-321℃。1H-NMR(400MHz,DMSO-d 6 ):6.82(d,1H,J=7.6Hz,Ar-H)、6.98(d,2H,J=6.8Hz,Ar-H)、7.30-7.34(m,1H,Ar-H)、7.42-7.46(m,1H,Ar-H)、7.54-7.58(m,1H,Ar-H)、7.78(d,1H,J=7.6Hz,Ar-H)、8.15(s,1H,Ar-H)、9.95(s,1H,NH)、10.81(br s,1H,OH)、11.78(br s,1H,NH)。C16H13N5O.1.25HCl的元素分析計算值:C 57.03,H 4.27,N 20.79;實驗值:C 56.95,H 4.62,N 21.02。
產率為50%。MP.:281-282℃。1H-NMR(400MHz,DMSO-d 6 ):2.39(s,3H,Me)、7.23(d,1H,J=7.6Hz,Ar-H)、7.38-7.47(m,4H,Ar-H)、7.57(dd,1H,J=8.0Hz,Ar-H)、7.78(d,1H,J=8.0Hz,Ar-H)、8.16(d,1H,J=6.4Hz,Ar-H)、10.88(br s,1H,NH),11.70(br s,1H,NH)。C17H15N5.1.1HCl的元素分析計算值:C,61.95;H,4.93;N,21.25。實驗值:C,61.95;H,4.67;N,21.18。
產率為57%。MP.:227-229℃。1H-NMR(400MHz,DMSO-d 6 ):5.66(br s,2H,NH2)、7.05(dd,1H,J=8.0,1.6Hz,Ar-H)、7.34-7.39(m,2H,Ar-H)、7.54(m,1H,Ar-H)、7.67(d,1H,J=7.6Hz,Ar-H)、7.89(d,1H,J=7.2Hz,Ar-H)、8.09(d,1H,J=7.6Hz,Ar-H)、8.27(s,1H,Ar-H)、8.39(br s,1H,NH)、12.97(br s,1H,NH)。C16H12ClN5的元素分析計算值:C,62.04;H,3.90;N,22.61。實驗值:C,61.91;H,3.88;N,22.40。
產率為76%。MP.:184-186℃。1H-NMR(400MHz,DMSO-d 6 ):3.81(s,3H,OMe)、3.81(s,3H,OMe)、5.63(br s,2H,NH2)、6.58-6.61(m,1H,Ar-H)、7.22-7.26(m,1H,Ar-H)、7.29-7.33(m,1H,Ar-H)、7.44(d,1H,J=8.0Hz,Ar-H)、7.50-7.54(m,1H,Ar-H)、7.65(d,1H,J=8.0Hz,Ar-H)、7.90(s,1H,Ar-H)、8.07(d,1H,J=7.6Hz,Ar-H)、8.24(s,1H,NH)、12.95(br s,1H,NH)。C17H15N5O的元素分析計算值:C 66.87,H 4.95,N 22.94;實驗值:C 66.64,H 4.98,N 22.68。
產率為84%。MP.:>380℃。1H-NMR(400MHz,DMSO-d 6 ):2.63(s,3H,Me)、7.45-7.49(m,1H,Ar-H)、7.57-7.60(m,1H,Ar-H)、7.68-7.72(m,1H,Ar-H)、7.76(d,1H,J=8.4Hz,Ar-H)、7.89(d,1H,J=8.8Hz,Ar-H)、7.97(d,1H,J=7.6Hz,Ar-H)、8.17-8.20(m,2H,Ar-H)、11.05(br s,1H,NH)、11.85(br s,1H,NH).C18H15N5O.0.5H2O的元素分析計算值:C 66.23,H 4.95,N 21.46;實驗值:C 66.31,H 4.66,N 21.26。
產率為64%。MP.:156-157℃。1H-NMR(400MHz,DMSO-d 6 ):5.51(br s,2H,NH2)、6.84-6.99(m,3H,Ar-H)、7.29-7.32(m,1H,Ar-H)、7.50-7.53(m,1H,Ar-H)、7.60(d,1H,J=7.2Hz,Ar-H)、8.06(d,2H,J=7.6Hz,Ar-H)、8.43(s,1H,NH)、11.22(br s,1H,OH)、13.06(s,1H,NH)。C16H13N5O.0.5H2O的元素分析計算值:C 63.98,H 4.71,N 23.32;實驗值:C 63.66,H 4.65,N 23.33。
產率為31%。MP.:228-230℃。1H-NMR(400MHz,DMSO-d 6 ):2.31(s,3H,Me)、5.48(br s,2H,NH2)、7.02-7.05(m,1H,Ar-H)、7.23-7.27(m,3H,Ar-H)、7.45(br s,1H,Ar-H)、7.55(d,1H,J=7.6Hz,Ar-H)、8.05(br s,2H,Ar-H)、8.31(br s,1H,NH)、12.96(br s,1H,NH)。
C17H15N5.0.2H2O的元素分析計算值:C,69.68;H,5.30;N,23.90。實驗值:C,69.95;H,5.17;N,23.70。
產率為52%。MP.:243-244℃。1H-NMR(400MHz,DMSO-d 6 ):5.46(br s,2H,NH2)、7.43-7.47(m,1H,Ar-H)、7.52-7.59(m,3H,Ar-H)、7.71-7.75(m,2H,Ar-H)、7.79(d,1H,J=8.0Hz,Ar-H)、8.17(d,1H,J=7.6Hz,Ar-H)、8.30(br s,1H,NH)、11.45(br s,1H,NH)。
產率為69%。MP.:210-211℃。1H-NMR(400MHz,DMSO-d 6 ):5.22(s,2H,NH2)、6.96-7.08(m,3H,Ar-H)、7.29-7.32(m,1H,Ar-H)、7.50-7.54(m,1H,Ar-H)、7.69(d,1H,J=8.0Hz,Ar-H)、8.06(d,1H,J=8.0Hz,Ar-H)、8.57(s,1H,NH)、8.99(d,1H,J=7.2Hz,Ar-H)、13.03(s,1H,NH)。C17H15N5O.0.45H2O的元素分析計算值:C 65.13,H 5.12,N 22.35;實驗值:C 65.31,H 5.03,N 21.99。
將溶於30mL二甲基甲醯胺(DMF)的0.22g(1.0mmol)的4-氯基-1氫-吡唑並[4,3-c]喹啉-3-胺(3a)與1mL 36%鹽酸的混合物加熱迴流2
小時,以薄層層析監控反應之進行。混合物於真空中脫水,以20mL水處理、過濾,且粗固體以乙醇再結晶,獲得0.15g的33黃色固體,產率為75%。MP.:316-318℃。1H-NMR(400MHz,DMSO-d 6 ):5.73(br s,2H,NH2)、7.60-7.72(m,2H,Ar-H)、7.89(d,1H,J=8.0Hz,Ar-H)、8.24(dd,1H,J=8.0,1.6Hz,Ar-H)、13.23(br s,1H,NH)。
將溶於8mL乙腈(acetonitrile)的0.20g(1.0mmol)的3-氨基-1氫-吡唑並[4,3-c]喹啉-4-酮(33)與0.36g(3.0mmol)的異氰酸苯酯(phenyl isocyanate)的混合物於室溫下攪拌混合2小時,以薄層層析監控反應之進行。沉澱物藉由過濾收集,以乙腈清洗後,乾燥以產生白色固體。粗產物以乙醇再結晶獲得0.23g的34,產率為72%。MP.:240-242℃。1H-NMR(400MHz,TFA-d):7.39-7.44(m,1H,Ar-H)、7.49-7.52(m,4H,Ar-H)、7.56-7.63(m,2H,Ar-H)、7.84-7.88(m,1H,Ar-H)、8.20(d,1H,J=8.0Hz,Ar-H)。
化合物35如上述34獲得的方法,從33與4-甲氧基異氰酸苯酯(4-methoxyphenyl isocyanate)獲得。產率為47%。MP.:224-225℃。1H-NMR(400MHz,TFA-d):3.90(s,3H,OCH3)、7.02(d,2H,J=8.8Hz,Ar-H)、7.37(d,2H,J=8.8Hz,Ar-H)、7.43-7.46(m,2H,Ar-H)、7.68-7.72(m,1H,Ar-H)、8.02(d,1H,J=8.0Hz,Ar-H)。
化合物36如上述34獲得的方法,從4與異氰酸苯酯獲得。產率為70%。MP.:282-283℃。1H-NMR(400MHz,TFA-d):7.98(d,2H,J=6.8,Ar-H)、8.06-8.29(m,10H,Ar-H)、8.92(d,1H,J=7.6Hz,Ar-H)。
化合物37如上述34獲得的方法,從5與異氰酸苯酯獲得。產率為73%。MP.:212-213℃。1H-NMR(400MHz,TFA-d):2.51(s,3H,CH3)、7.38-7.58(m,11H,Ar-H)、7.66-7.70(m,1H,Ar-H)、8.33(d,1H,J=7.6Hz,Ar-H)。
化合物38如上述34獲得的方法,從4與4-甲氧基異氰酸苯酯獲得。產率為80%。MP.:211-212℃。1H-NMR(400MHz,TFA-d):4.13(s,3H,OCH3)、7.26(d,2H,J=8.4Hz,Ar-H)、7.45(d,1H,J=8.4Hz,Ar-H)、7.54-7.77(m,8H,Ar-H)、8.39(d,1H,J=8.0Hz,Ar-H)。
化合物39如上述34獲得的方法,從5與4-甲氧基異氰酸苯酯獲得。產率為85%。MP.:163-164℃。1H-NMR(400MHz,TFA-d):TFA-d):2.89(s,3H,CH3)、4.43(s,3H,OCH3)、7.56(d,2H,J=9.2Hz,Ar-H)、7.73-7.78(m,3H,Ar-H)、7.86-7.95(m,5H,Ar-H)、8.03-8.06(m,1H,Ar-H)、8.68(d,1H,J=8.0Hz,Ar-H)。
為確認更有效力的及專一的eβG抑制劑,已經由高通量篩選(high throughput screening,HTS)來篩選大量化合物,並發現如結構式I的吡唑並[4,3-c]喹啉衍生物(TCH-系列),可專一抑制eβG活性,但對hβG則無功效。
測定吡唑並[4,3-c]喹啉衍生物對eβG或hβG活性的抑制性。純化的重組eβG或hβG蛋白分別以連續稀釋的抑制劑進行培養。βG活性以βG受質之呈色反應(4-硝基苯基-β-D-吡喃葡萄糖苷(p-nitrophenyl-β-D-glucopyranoside,pNPG))進行測定。該pNPG的水解產物(PNP)由OD420測定。結果以百分比顯示βG活性抑制性與無抑制劑處理的對照組的比較(如下表1)。該數據顯示包括如4(TCH-3561)、5(TCH-3562)、17(TCH-3511)、及32(TCH-3510)的抑制劑選擇性抑制eβG活性,而非hβG。該等化合物顯示比βG-Inh更好的eβG活性抑制效果(如圖5)。
表一 吡唑並[4,3-c]喹啉對eβG及hβG的抑制活性
a值為實驗至少獨立地重複操作3次的標準差(means±S.D.)。
bβG-Inh作為陽性對照。
測定吡唑並[4,3-c]喹啉衍生物對抑制內源性eβG活性的抑制性。此檢測與體外檢測相似。BL21大腸桿菌(BL21 E.coli)細胞於LB培養基(Lenox broth medium)生長至OD600為0.35。大腸桿菌稀釋4次後與各抑制劑進行培養。內源性eβG活性以上述檢測PNP方式進行測定。結果顯示包含4(TCH-3561)、5(TCH-3562)、17(TCH-3511)、及32(TCH-3510)的抑制劑,在低濃度(10μM)或高濃度(50μM)下對內源性eβG活性的抑制效果均較βG-Inh為佳(圖2)。
測定吡唑並[4,3-c]喹啉衍生物對人類細胞之細胞毒性。利用抑制劑處理HEK293人類胚胎腎細胞(human embryonic kidney cell)與CNL正常肝細胞(Chang normal liver)。利用生物發光法細胞增殖/毒性檢測試劑盒(PerkinElmer kit,ATPliteTM)來檢測培養細胞的三磷酸腺苷,以定量的評估抑制劑的增生效果。結果顯示在低濃度的抑制劑17(TCH-3511)或32(TCH-3510)所處理的細胞相較於以βG-Inh處理的細胞有相似的存活率(圖3)。
測定吡唑並[4,3-c]喹啉衍生物對影響大腸桿菌的生長。Top10大腸桿菌細胞於LB培養基生長至OD600為0.35,並以各種抑制劑處理。6小時後,以OD600監測大腸桿菌細胞培養基。與無抑制劑對照組比較細胞活力,並以%對照組顯示。5(TCH-3562)、17(TCH-3511)及32(TCH-3510)在高濃度(100μM)下對大腸桿菌株之生長無影響。
,17(TCH-3511)、32(TCH-3510)對小鼠腸道中βG活性的抑制性以體內造影(In vivo image)測定。5(TCH-3562)、17(TCH-3511)或32(TCH-3510)溶於ddH2O。健康6-10週大雌性Balb/cJ小鼠連續5天每天以口服方式給予5(TCH-3562)、17(TCH-3511)、32(TCH-3510)或ddH2O(60μg/200μl)。於第6天口服給予βG螢光前驅探針(pro-probe),螢光素2-β-D-葡糖苷酸(fluorescein di-β-D-glucuronide,FDGlcU)。經由體內光學影像系統偵測βG活性。結果顯示口服給藥17(TCH 3511)顯著減少腸道中的螢光信號,顯示17(TCH 3511)能有效地抑制腸道中βG活性(圖5)。
將17(TCH 3511)投予小鼠以測試藉由細菌抑制劑17(TCH 3511)與CPT-11結合的腸道內βG抑制性是否可消除荷瘤小鼠(tumor-bearing mice)中CPT-11誘發的腹瀉,並維持療效。將CT26鼠結腸腺癌細胞(CT26 murine colon adenocarcinoma cells)植入Balb/cJ小鼠皮下。形成實體腫瘤後,每天口服3mg/kg的17(TCH 3511)和腹腔內注射50mg/kg的CPT-11。腹
瀉的跡象是根據糞便形狀及肛門周邊染色。如圖6A所示,17(TCH 3511)能減少CPT-11誘發的腹瀉,不會影響CPT-11治療的抗癌效果。
將17(TCH 3511)投予至C57BL/6J-APC MIN/J小鼠,以確認是否預防DMH誘發的腸道損傷與癌變。將17(TCH 3511)以每週3次,每次口服3mg/kg,和DMH每週1次腹腔內注射30mg/kg一起投予。於8周治療後,將小鼠犧牲,並檢查腸道中的腫瘤。如圖7所示,只有DMH治療的群組中發現超過26個腫瘤,而有17(TCH 3511)的群組僅有6個腫瘤。因此,17(TCH 3511)能減少DMH誘發的腸道損傷與預防癌變。
Claims (24)
- 一種具有結構式I的化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R1為H、鹵素或於C-5、C-6、C-7或C-8位置取代的C1-10烷基。
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R1為H、鹵素、或C1-4烷基;在一實施例中,R1為H、Cl、F、Br或甲基。
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R1為H。
- 如申請專利範圍第1項所述之化合物或其立體異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R2為H、鹵素、或C1-10烷基、C1-10烷氧基、C1-10烷硫基、NH2、NO2、鹵烷基、COR5或於C-2’、C-3’或C-4’ 位置取代的COOR5。
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R2為H、鹵素、C1-4烷基、C1-4烷氧基、C1-4烷硫基、NH2、NO2、鹵化C1-4烷基、C(O)C1-4烷基或COOH。
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R2為H、甲基、OH、NH2、甲氧基、甲硫基、CF3、Cl、F、NO2、COOH、C(O)CH3。
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其中R3係NRaRb、OH或NO2,其中Ra與Rb各自獨立地為H或C(O)NRcRd,且Rc與Rd各自獨立地為H或未取代或取代的芳基。
- 如申請專利範圍第1項所述之化合物或其同分異構物、醫藥上可接受之鹽類、前藥或溶劑化物,其係選自下列基團所組成的群組:4-羥基-8-甲基-2-氧代-1,2-二氫喹啉-3-甲腈(4-hydroxy-8-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile)、2,6-溴基-4-羥基-2-氧代-1,2-二氫喹啉-3-甲腈(2,6-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinolone-3-carbonitrile)、2,4-二氯基-8-甲基喹啉-3-甲腈(2,4-Dichloro-8-methylquinoline-3-carbonitrile)、4,6-溴基-2,4-二氯基喹啉-3-甲腈(4,6-Bromo-2,4-dichloroquinoline-3-carbonitrile)、4-氯基-6-甲基-1氫-吡唑並[4,3-c]喹啉-3-胺基(4-Chloro-6-methyl-1H-pyrazolo[4,3-c]quinolin-3-amine)、4-氯基-7-氟基-1氫-吡唑並[4,3-c]喹啉-3-胺基(4-Chloro-7-fluoro-1H-pyrazolo[4,3-c]quinolin-3-amine)、4,8-二氯基-1氫-吡唑並[4,3-c]喹啉-3-胺基(4,8- Dichloro-1H-pyrazolo[4,3-c]quinolin-3-amine)、8-溴基-4-氯基-1氫-吡唑並[4,3-c]喹啉-3-胺基(8-Bromo-4-chloro-1H-pyrazolo[4,3-c]quinolin-3-amine)、3-氨基-4-(4-氯苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-chlorophenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-甲苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-methylphenyl-amino)-1H-pyrazolo[4,3-c]quinoline)、N 4-(4-氯苯基)-6-甲基-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(4-Chloro-phenyl)-6-methyl-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、6-甲基-N 4-(對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(6-Methyl-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、N 4-(4-氯苯基)-7-氟基-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(4-Chlorophenyl)-7-fluoro-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、7-氟基-N 4-(對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(7-Fluoro-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、8-氯基-N 4-(4-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Chloro-N 4-(4-chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、8-氯基-N 4-(4-對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Chloro-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、8-溴基-N 4 -(4-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Bromo-N 4-(4-chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、8-溴基-N 4-(4-對甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(8-Bromo-N 4-(p-tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、3-氨基-4-苯胺基-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-anilino-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-羥苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4- hydroxyphenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-氨苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-aminophenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-氟苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-fluorophenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-三氟甲基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-trifluoromethylphenylamino)-1H-pyrazolo-[4,3-c]quinoline)、3-氨基-4-(4-甲氧基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-methoxyphenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-甲基硫苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-methylthiophenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(4-硝基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-nitrophenylamino)-1H-pyrazolo[4,3-c]quinoline)、4-(3-氨基-1氫-吡唑並[4,3-c]喹啉-4-基氨基)苯甲酸(4-(3-Amino-1H-pyrazolo[4,3-c]quinolin-4-ylamino)benzoic acid)、3-氨基4-(4-乙醯基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(4-acetylphenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基4-(3-羥基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(3-hydroxyphenylamino)-1H-pyrazolo[4,3-c]quinoline)、N 4-(間甲苯基)-1氫-吡唑並[4,3-c]喹啉3,4-二胺基(N 4-(m-Tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、N 4-(3-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(3-Chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、3-氨基-4-(3-甲氧基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(3-methoxyphenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(3-乙醯基苯基氨基)-1氫-吡唑並[4,3-c]喹啉 (3-Amino-4-(3-acetylphenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-4-(2-羥基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(2-hydroxy-phenylamino)-1H-pyrazolo[4,3-c]quinoline)、N 4-(鄰甲苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(o-Tolyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、N 4-(2-氯苯基)-1氫-吡唑並[4,3-c]喹啉-3,4-二胺基(N 4-(2-Chlorophenyl)-1H-pyrazolo[4,3-c]quinoline-3,4-diamine)、3-氨基-4-(2-甲氧基苯基氨基)-1氫-吡唑並[4,3-c]喹啉(3-Amino-4-(2-methoxyphenylamino)-1H-pyrazolo[4,3-c]quinoline)、3-氨基-1氫-吡唑並[4,3-c]喹啉-4(5氫)-酮(3-Amino-1H-pyrazolo[4,3-c]quinolin-4(5H)-one)、1-(4-氧代-4,5-二羥基-1氫-吡唑並[4,3-c]喹啉-3-基)-3-苯基尿素(1-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-3-yl)-3-phenylurea)、1-(4-甲氧基苯基)-3-(4-氧代-4,5-二羥基-1氫-吡唑並[4,3-c]喹啉-3-基)尿素(1-(4-Methoxyphenyl)-3-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-3-yl)urea)、1-{4-[(4-氯苯基)氨基]-1氫-吡唑並[4,3-c]喹啉-3-基}-3-苯基尿素(1-{4-[(4-Chlorophenyl)amino]-1H-pyrazolo[4,3-c]quinolin-3-yl}-3-phenylurea)、1-苯基-3-[4-(對甲苯基氨基)-1氫-吡唑並[4,3-c]喹啉-3-基]尿素(1-Phenyl-3-[4-(p-tolylamino)-1H-pyrazolo[4,3-c]quinolin-3-yl]urea)、1-{4-[(4-氯苯基)氨基]-1氫-吡唑並[4,3-c]喹啉-3-基}-3-(4-甲氧基苯基)尿素(1-{4-[(4-Chlorophenyl)amino]-1H-pyrazolo[4,3-c]quinolin-3-yl}-3-(4-methoxyphenyl)urea)及1-(4-甲氧基苯基)-3-[4-(對甲苯基氨基)-1氫-吡唑並[4,3-c]喹啉-3-基]尿素(1-(4-Methoxyphenyl)-3-[4-(p-tolylamino)-1H-pyrazolo[4,3-c]quinolin-3-yl]urea)。
- 如申請專利範圍第1項所述化合物,其係選自下列所組成之群組:
- 一種製備具有如下結構式I化合物的方法,包括:
- 一種組合物,包含如申請專利範圍第1項所述之化合物,及一醫藥上可接受之載體。
- 如申請專利範圍第12項所述之組合物,其係一藥物或一食品補充劑。
- 如申請專利範圍第12項所述之組合物,其係包含一額外的治療劑(additional therapeutic agent),該治療劑經由葡萄醣醛酸化反應代謝。
- 如申請專利範圍第14項所述之組合物,其中該額外的治療劑為一抗腫瘤劑、一免疫增強劑或一免疫調節劑。
- 如申請專利範圍第15項所述之組合物,其中該抗腫瘤劑係三苯甲胺(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、碘多啥芬(iodoxyfene)、醋酸甲羥孕酮(megestrol acetate)、阿那曲唑(anastrozole)、來曲唑(letrazole)、硼唑(borazole)、依西美坦(exemestane)、氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、醋酸環丙孕酮(cyproterone acetate)、醋酸戈舍瑞林(goserelin acetate)、亮脯利特(luprolide)、非那雄胺(finasteride)、賀癌平 (herceptin)、甲氨蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)、阿糖胞苷(cytosine arabinoside)、多柔比星(doxorubicin)、柔紅黴素(daunomycin)、表柔比星(epirubicin)、去甲氧柔紅黴素(idarubicin)、絲裂黴素-C(mitomycin-C)、放線菌素(dactinomycin)、光輝黴素(mithramycin)、順鉑(cisplatin)、卡鉑(carboplatin)、馬法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)、環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、亞硝基脲(nitrosoureas)、硫特福恩(thiotephan)、長春新鹼(vincristine)、紫杉醇(taxol)、剋癌易(taxotere)、滅必治(etoposide)、鬼臼噻吩苷(teniposide)、胺苯吖啶(amsacrine)、伊立替康(irinotecan)、甲苯胺(topotecan)或埃博黴素(epothilone)。
- 一種選擇性抑制微生物βG而非人類βG(hβG)的方法,包含:將一有效量之如申請專利範圍第1至7項任一項所述之化合物,或申請專利範圍第12至16項任一項所述之組合物,投予於一生物體。
- 如申請專利範圍第17項所述之方法,其中該生物體係罹患一癌症。
- 一種用於在生物體中減少/抑制經由葡萄糖醛酸化反應代謝的治療劑再活化的方法,包括:將一有效量之如申請專利範圍第1至10項任一項所述之化合物,或申請專利範圍第12至16項任一項所述之組合物,投予於一生物體。
- 一種用於在生物體中治療和/或預防化療導致的腹瀉或致癌物質誘發的大腸癌的方法,包括:將一有效量之如申請專利範圍第1至10項任一項所述之化合物,或申請專利範圍第12至16項任一項所述之組合物,投 予於一生物體。
- 一種用於在生物體中增進癌症的化療功效的方法,包括:將一有效量之如申請專利範圍第1至10項任一項所述之化合物,或申請專利範圍第12至16項任一項所述之組合物,投予於一生物體。
- 如申請專利範圍第17至21項任一項所述之方法,其中該生物體係接受一種或更多如血管新生抑制劑(angiogenic inhibitors)、化療、放射線、手術的治療。
- 如申請專利範圍第17至22項任一項所述之方法,其中如申請專利範圍第1項所述之化合物與包含經由葡萄糖醛酸化反應代謝的一抗癌劑、一免疫增強劑或一免疫調節劑的一額外治療劑合併投藥。
- 如申請專利範圍第23項所述之方法,其中如申請專利範圍第1項所述之化合物及該額外治療劑為同時或分開投藥。
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CN102885800B (zh) * | 2012-09-06 | 2014-08-06 | 中国药科大学 | 一种姜黄素的用途 |
US10654848B1 (en) * | 2018-11-09 | 2020-05-19 | Chang Gung University Of Science And Technology | Neutrophil inflammation inhibitor and uses thereof |
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EP3662751B1 (en) | 2021-10-13 |
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EP3302060A1 (en) | 2018-04-11 |
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WO2016191576A1 (en) | 2016-12-01 |
JP6607962B2 (ja) | 2019-11-20 |
TWI614251B (zh) | 2018-02-11 |
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