TWI440632B - 用於治療增生性疾病的化合物 - Google Patents
用於治療增生性疾病的化合物 Download PDFInfo
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- TWI440632B TWI440632B TW096130806A TW96130806A TWI440632B TW I440632 B TWI440632 B TW I440632B TW 096130806 A TW096130806 A TW 096130806A TW 96130806 A TW96130806 A TW 96130806A TW I440632 B TWI440632 B TW I440632B
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Description
本申請案主張美國臨時申請案第60/839,034號(於2006年8月21日提申)以及美國臨時申請案第60/841,408號(於2006年8月31日提申)之利益。以上申請案之完整教示係以引用方式纳入本文中。
本發明係關於用於治療具有增生性疾病之受藥者的化合物以及使用該化合物治療具有增生性疾病之受藥者的方法以及用於治療對Hsp70誘發及/或自然殺手誘發有反應之疾病的方法。本發明亦關於包含該化合物以及藥學上可接受的載劑之醫藥組成物。
熱休克蛋白(HSP)實際上係在所有的原核生物與真核生物細胞中找到,於該等細胞中其等支援初生多肽的摺疊,預防蛋白質聚集,並協助其他蛋白質跨越膜的運輸。於Hsp70家族中之蛋白質(一起稱為「Hsp70」)扮演一方面在環境性壓力後保護細胞免於致命性損害,而另一方面靶定細胞以供免疫介導性溶胞性攻擊之雙重角色。Hsp70在細胞質中之增加的表現已知會在壓力下保護許多種細胞,其係藉由預防細胞質蛋白質之錯誤摺疊、聚集、與變性以及抑制各種凋亡性途徑(Mosser等人,Mol Cell Biol.2000 October;20(19):7146-7159;Yenari,Adv Exp Med Biol,2002,513,281-299;Kiang與Tsokos,Pharmacol Ther.1998;80(2):182-201)。然而,膜結合性Hsp70提供用於藉由自然殺手細胞所介導之溶胞性攻擊的標靶結構。
細胞可由於溫度;傷害(創傷);遺傳性疾病;代謝性缺陷;凋亡;感染;毒素;輻射;氧化物;養分或代謝性產物之過剩/缺乏;以及類似者而遭受壓力。例如,技術領域中已知在以下各種醫學病症中之細胞損害可對Hsp70反應而經歷保護性效果。
導致包括阿茲海默症(Alzheimers’ disease)(Zhang等人,J.Neuroscience,2004,24(23),5315-5321;Klettner,Drug News Perspect,2004 17(5),299-306);杭丁頓舞蹈症(Huntington’s disease)(Klettner,ibid);巴金森氏病(Parkinson’s disease)(Auluck等人,Science,2002,295(5556),865-868);以及類似者之神經退化的蛋白質錯誤摺疊/聚集病症。其他神經退化性病症包括脊髓/延髓肌肉萎縮(Sobue,Nihon Shinkei Seishin Yakurigaku Zasshi,2001,21(1),21-25);與家族性肌萎縮性偏側硬化症(Howland等人,Proc Nat Acad Sci USA,2002,99(3),1604-1609;Sobue,ibid;Vleminck等人,J Neuropathol Exp Neurol,2002,61(11),968-974)。
局部缺血與相關的氧化性損害對包括以下者之各種各樣的組織產生影響:神經元與神經膠(Carmel等人,Exp Neurol,2004,185(1)81-96;Renshaw與Warburton,Front Biosci,2004,9,110-116;Yenari,Adv Exp Med Bio1,2002,513,281-299;Kelly與Yenari,Curr Res Med Opin,2002,18 Suppl 2,s55-60;Lee等人,Exp Neurol,2001,170(1),129-139;Klettner,ibid;Klettner與Herdegen,Br J Pharmacol,2003,138(5),1004-1012);心肌(Marber,M.S.等人,(1995)J.Clin.Invest.95:1446-1456;Plumier,J.C.等人(1995)J.Clin.Invest.95:1854-1860;Radford,N.B.等人(1996)Proc.Natl.Acad.Sci.USA 93(6):2339-2342;Voss等人,Am J Physiol Heart Circ Physiol 285:H687-H692,2003);肝臟組織(Doi等人,Hepatogastroenterology.2001 Mar-Apr;48(38):533-40;Gao等人,World J Gastroenterol 2004;10(7):1019-1027);骨骼肌(Lepore等人,Cell Stress & Chaperones,2001,6(2),93-96);腎臟組織(Chen等人,Kidney Int.1999;56:1270-1273;Beck等人,Am J Physiol Renal Physiol 279:F203-F215,2000.);肺的組織(Hiratsuka等人,J Heart Lung Transplant.1998 Dec;17(12):1238-46);胰臟的組織(Bellmann等人,J Clin Invest.1995 June;95(6):2840-2845)、以及類似者。
損害神經元之發作(seizure)病症包括(例如)癲癇性發作(Yenari,ibid;Blondeau等人,Neuroscience 2002,109(2),231-241);或化學誘導性發作(Tsuchiya等人,Neurosurgery,2003,53(5),1179-1187)。
熱壓力包括體溫過高病症,例如發燒、中暑、以及類似者(Barclay與Robertson,J Neurobiol,2003 56(4),360-271;Sato等人,Brain Res,1996,740(1-2),117-123);與體溫過低(Kandor與Goldberg,Proc Natl Acad Sci U S A.1997 May 13;94(10):4978-4981)。
老化包括例如動脈粥樣硬化(其對平滑肌細胞產生影響)之病症(Minowada,G.與Welch,W.J.,(1995)J.Clin.Invest.95:3-12;Johnson,A.J.等人,(1995)Arterio.Thromb.Vasc.Biol.15(1):27-36)。
其他病症包括(例如)自紫外光對組織(例如鼠類纖維母細胞)之輻射損害(Simon,M.M.等人,(1995)J.Clin.Res.95(3):926-933),與對視網膜細胞之光損害(Yu等人,Molecular Vision 2001;7:48-56)。
創傷包括(例如)機械性傷害,例如在青光眼中對視網膜神經節之壓力損害(Ishii等人,Invest Opthalmol Vis Sci,2003,44(5),1982-1992)。
中毒病症包括例如以下者之化學藥品或化學藥品之服用:甲基安非他命(Malberg & Seiden,Poster“MDMA Administration Induces Expression of HSP70 in the Rat Brain”Society for Neuroscience Annual Meeting,New Orleans,LA,October 25-30,1997);抗反轉錄病毒HIV療法(Keswani等人,Annals Neurology,2002,53(1),57-64);重金屬、胺基酸類似物、化學氧化劑、乙醇、麩胺酸、與其他毒素(Ashburner,M.與Bonner,J.J.,(1979)Cell:17:241-254;Lindquist,S.,(1986)Ann.Rev.Biochem.55:1151-1191;Craig,E.A.,(1985)Crit.Rev.Biochem.18(3):239-280;Morimoto等人,於:The Biology of Heat Shock Proteins and Molecular Chaperone,(1994)pp.417-455.Cold Spring Harbor Laboratory Press.Cold Spring Harbor,N.Y.);以及類似者。
因此,有對於增加Hsp70之表現以治療對Hsp70有反應之疾病的新方法之需求。
已顯示細胞外Hsp70與膜結合性Hsp70在先天免疫系統之活化中扮演關鍵角色。已顯示單核細胞會對可溶性Hsp70蛋白反應而分泌前發炎細胞介素,而已顯示膜結合性Hsp70會提供用於藉由自然殺手細胞之溶胞性攻擊的標靶結構。
自然殺手(NK)細胞,一種白血球,已知係一個身體免疫系統之重要構成要素。因為NK細胞之限定性功能係無先前致免疫之自發性細胞毒性,NK細胞可係在免疫系統中之防禦的第一線,且咸相信其在攻擊癌症細胞與感染性疾病中扮演某種角色。許多病症(例如免疫不全疾病、老化、毒素暴露、子宮內膜異位、以及類似者)可使受影響者有降低的NK細胞活性或功能異常的NK細胞。
例如,受影響者可能在(例如)以下病症中具有減少的或有缺陷的NK細胞活性:慢性疲勞症候群(慢性疲勞免疫功能異常症候群)或Epstein-Barr病毒、病毒感染後疲勞症候群、移植後症候群或宿主-移植物疾病(host-graft disease)、暴露至藥物,例如抗癌症劑或一氧化氮合酶抑制劑、自然老化、與各種免疫不全病症,例如嚴重複合性免疫不全(severe combined immunodeficiency)、變異性免疫不全症候群(variable immunodeficiency syndrome)、以及類似者(Caligiuri M、Murray C、Buchwald D、Levine H、Cheney P、Peterson D、Komaroff AL、Ritz J,Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome.Journal of Immunology 1987;139:3306-13;Morrison LJA、Behan WHM、Behan PO,Changes in natural killer cell phenotype in patients with post-viral fatigue syndrome.Clinical and Experimental Immunology 1991;83:441-6;Klingemann,HG,Relevance and Potential of Natural Killer Cells in Stem Cell Transplantation Biology of Blood and Marrow Transplantation 2000;6:90-99;Ruggeri L、Capanni M、Mancusi A、Aversa F、Martelli MF、Velardi A,Natural killer cells as a therapeutic tool in mismatched transplantation.Best Pract Res Clin Haematol.2004 Sep;17(3):427-38;Cifone MG、Ulisse S、Santoni A,Natural killer cells and nitric oxide.Int Immunopharmacol.2001 Aug;1(8):1513-24;Plackett TP、Boehmer ED、Faunce DE、Kovacs EJ,Aging and innate immune cells.J Leukoc Biol.2004 Aug;76(2):291-9.Epub 2004 Mar 23;Alpdogan O、van den Brink MR,IL-7 and IL-15:therapeutic cytokines for immunodeficiency.Trends Immunol.2005 Jan;26(1):56-64;Heusel JW、Ballas ZK,Natural killer cells:emerging concepts in immunity to infection and implications for assessment of immunodeficiency.Curr Opin Pediatr.2003 Dec;15(6):586-93;Hacein-Bey-Abina S、Fischer A、Cavazzana-Calvo M,Gene therapy of X-linked severe combined immunodeficiency.Int J Hematol.2002 Nov;76(4):295-8;Baumert E、Schlesier M、Wolff-Vorbeck G、Peter HH,Alterations in lymphocyte subsetsin variable immunodeficiency syndrome Immun Infekt.1992 Jul;20(3):73-5)。
已知NK細胞具有對抗許多種類的感染性病源體(例如細菌、病毒、真菌、原生動物寄生蟲、結合性感染(例如,結合性細菌性/病毒性感染)、以及類似者)之活性。咸相信NK細胞係於與細胞內(於該處病源體在受影響的細胞內複製)感染之作戰中特別地重要,例如病毒之實質上的部分與可形成細胞內感染之許多其他病源體。
例如,已有報導指出許多種類的真菌的感染會被NK細胞靶定,例如新型隱球菌(Cryptococcus neoformans)、皮癬菌,例如紅色髮癬菌(Trichophyton rubrum)、白色念珠菌(Candida albicans)、粗球黴菌(Coccidioides immitis)、巴西副球黴菌(Paracoccidioides brasiliensis)、或類似者(Hidore MR、Mislan TW、Murphy JW,Responses of murine natural killer cells to binding of the fungal target Cryptococcus neoformans Infect Immun.1991 Apr;59(4):1489-99;Akiba H、Motoki Y、Satoh M、Iwatsuki K、Kaneko F,Recalcitrant trichophytic granuloma associated with NK-cell deficiency in a SLE patient treated with corticosteroid.Eur J Dermatol.2001 Jan-Feb;11(1):58-62;Mathews HL、Witek-Janusek L,Antifungal activity of interleukin-2-activated natural killer(NK1.1+)lymphocytes against Candida albicans.J Med Microbiol.1998 Nov;47(11):1007-14;Ampel NM、Bejarano GC、Galgiani JN,Killing of Coccidioides immitis by human peripheral blood mononuclear cells.Infect Immun.1992 Oct;60(10):4200-4;Jimenez BE、Murphy JW,In vitro effects of natural killer cells against Paracoccidioides brasiliensis yeast phase.Infect Immun.1984 Nov;46(2):552-8.)。
NK細胞亦靶定細菌,特別是細胞內細菌(例如,結核分枝桿菌(Mycobacterium tuberculosis)、鳥分枝桿菌(Mycobacterium avium)、單核球增多性李氏菌(Listeria monocytogenes))、許多不同的病毒(例如人類免疫不全病毒、皰疹病毒、肝炎、以及類似者)、以及病毒性/細菌性共-感染(Esin S、Batoni G、Kallenius G、Gaines H、Campa M、Svenson SB、Andersson R、Wigzell H,Proliferation of distinct human T cell subsets in response to live,killed or soluble extracts of Mycobacterium tuberculosis and Myco.avium.Clin Exp Immunol.1996 Jun;104(3):419-25;Kaufmann SH,Immunity to intracellular bacteria.Annu Rev Immunol.1993;11:129-63;See DM、Khemka P、Sahl L、Bui T、Tilles JG,The role of natural killer cells in viral infections.Scand J Immunol.1997 Sep;46(3):217-24;Brenner BG、Dascal A、Margolese RG、Wainberg MA,Natural killer cell function in patients with acquired immunodeficiency syndrome and related diseases.J Leukoc Biol.1989 Jul;46(1):75-83;Kottilil S,Natural killer cells in HIV-1 infection:role of NK cell-mediated non-cytolytic mechanisms in pathogenesis of HIV-1 infection.Indian J Exp Biol.2003 Nov;41(11):1219-25;Herman RB、Koziel MJ,Natural killer cells and hepatitis C:is losing inhibition the key to clearance?Clin Gastroenterol Hepatol.2004 Dec;2(12):1061-3;Beadling C、Slifka MK,How do viral infections predispose patients to bacterial infections?Curr Opin Infect Dis.2004 Jun;17(3):185-91)。
此外,NK細胞與原生動物性感染(包括弓蟲症、錐蟲病、利什曼體病、瘧疾)(特別是細胞內感染)作戰(Korbel DS、Finney OC、Riley EM,Natural killer cells and innate immunity to protozoan pathogens.Int J Parasitol.2004 Dec;34(13-14):1517-28;Ahmed JS、Mehlhorn H,Review:the cellular basis of the immunity to and immunopathogenesis of tropical theileriosis.Parasitol Res.1999 Jul;85(7):539-49;Osman M、Lausten SB、El-Sefi T、Boghdadi I、Rashed MY、Jensen SL、Biliary parasites,Dig Surg.1998;15(4):287-96;Gazzinelli RT、Denkers EY、Sher A,Host resistance to Toxoplasma gondii:model for studying the selective induction of cell-mediated immunity by intracellular parasites.Infect Agents Dis.1993 Jun;2(3):139-49;Askonas BA、Bancroft GJ,Interaction of African trypanosomes with the immune system.Philos Trans R Soc Lond B Biol Sci.1984 Nov 13;307(1131):41-9;Allison AC、Eugui EM,The role of cell-mediated immune responses in resistance to malaria,with special reference to oxidant stress.Annu Rev Immunol.1983;1:361-92)。
已顯示NK細胞在攻擊表現膜結合性Hsp70之癌症細胞中扮演某種角色。咸相信膜結合性Hsp70結合至NK細胞之表面上的CD94受體,並使其等生產與分泌高量的酵素,粒酶(granzyme)B,其被認為會藉由與膜結合性Hsp70交互作用而進入腫瘤細胞並誘導凋亡(參見Radons與Multhoff,Exerc.Immunol.Rev.(2005),11:17-33)。因此,有對用於增加NK細胞活性以治療癌症與對NK誘發有反應之其他疾病之有效的治療之急迫需求。
某些本發明之化合物會在細胞中誘導Hsp70生產,並藉此增加Hsp70在細胞質中與在細胞的表面上之水平。此外,某些本發明之化合物對癌症細胞系(包括多重藥物抗性癌症細胞系)有細胞毒性,並提高汰癌勝(Taxol)與紫杉烷(taxane)類似物之抗增生性與凋亡性活性(例如,抗癌活性)。
在一個具體態樣中,本發明的化合物係由式(I):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中:R1
與R2
獨立地係視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、鹵基、硝基、氰基、胍基、-OR17
、-NR19
R20
、-C(O)R17
、-C(O)OR17
、-OC(O)R17
、-C(O)NR19
R20
、-NR18
C(O)R17
、-OP(O)(OR17
)2
、-SP(O)(OR17
)2
、-SR17
、-S(O)p
R17
、-OS(O)p
R17
、-S(O)p
OR17
、-NR18
S(O)p
R17
、或-S(O)p
NR19
R20
。
R3
與R4
獨立地係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基或視需要經取代的雜芳基;R5
與R6
獨立地係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基或視需要經取代的雜芳基;R13
係共價鍵、或經取代的或未經取代的C1-C6伸烷基基團;R17
與R18
(每次出現)(獨立地)係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、視需要經取代的芳烷基、或視需要經取代的雜芳烷基;R19
與R20
(每次出現)獨立地係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、視需要經取代的芳烷基、或視需要經取代的雜芳烷基;或R19
與R20
(與其等所接附的氮一起)形成視需要經取代的雜環基或視需要經取代的雜芳基;且p係1或2。
在一個式(I)化合物之具體態樣中,當R13
係-CH2
-、R3
與R4
皆係苯基且R5
與R6
皆係-H時,則R1
與R2
非皆係苯基。
在一個式(I)化合物之具體態樣中,當R13
係-CH2
-、R3
與R4
皆係苯基且R5
與R6
皆係-H時,則R1
與R2
非皆係甲基。
在另一個具體態樣中,本發明的化合物係由式(II)所代表:
其中:R7
與R8
各自獨立地係-H或視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基,或R7
係-H且R8
係視需要經取代的芳基或視需要經取代的雜芳基;且R1
、R2
、R3
、與R4
係如對式(I)所定義。
在另一個具體態樣中,本發明的化合物係由式(III)或(IV):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中:X1
、X2
、X3
、與X4
獨立地係選自由以下者所組成的群組:
Z1
、Z2
、Z3
、與Z4
各自獨立地係O或S;R9
、R10
、與R11
各自獨立地係-H、-NR19
R20
、鹵基、-OR17
、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基或視需要經取代的雜芳基;且R1
、R2
、R3
、R4
、R5
、R6
、與R13
係如對式(I)所定義。在一個式(III)化合物之具體態樣中,R1
與R2
非係-OH、-SH、或-NH2
。
在另一個具體態樣中,本發明的化合物係由式(V)所代表:
其中R1
、R2
、R3
、與R4
係如對式(I)所定義,X3
與X4
係如對式(III)所定義,且與R7
與R8
係如對式(II)所定義。
在另一個具體態樣中,本發明的化合物係由式(VI)所代表:
其中R1
、R2
、R3
、與R4
係如對式(I)所定義,X1
與X2
係如對式(IV)所定義,且R7
與R8
係如對式(II)所定義.
在另一個具體態樣中,本發明的化合物係由式(VII):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中:各個Z獨立地係O或S;X5
係-S(O)-、-S(O)2
-、-P(O)(OR12
)-、-S(O)2
R13
S(O)2
-、-S(O)2
OS(O)2
-、-S(O)2
SS(O)2
-、-S(O)2
N(R5
)S(O)2
-、-P(O)(OR12
)R13
P(O)(OR12
)-、P(O)(OR12
)OP(O)(OR12
)-、-P(O)(OR12
)SP(O)(OR12
)-、或-P(O)(OR12
)N(R5
)P(O)(OR12
)-;R12
獨立地係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、或鹵基;且R1
、R2
、R3
、R4
、R5
、R6
、與R13
係如對式(I)所定義。
在一個式(VII)化合物之具體態樣中,當Z3
或Z4
係O時,則R1
或R2
非係-OR17
。在一個式(VII)化合物之具體態樣中,當Z係O時,則R1
或R2
非係-OR17
或-NR19
R20
。
在另一個具體態樣中,本發明的化合物係由式(VIII)或(IX)所代表:
其中R1
、R2
、R3
、與R4
係如對式(I)所定義,R7
與R8
係如對式(II)所定義,且R12
係如對式(VII)所定義。
在另一個具體態樣中,本發明的化合物係由式(X):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中X6
係-O-、-S-、-N(R5
)-、或-C(R5
)2
-;X9
與X10
獨立地係-C(R5
)-;R1
、R2
、R3
、與R4
係如對式(I)所定義。Z係如對式(VII)所定義。
在另一個具體態樣中,本發明的化合物係由式(XI):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中X6
係-O-、-S-、-N(R5
)-、或-C(R5
)2
-,X7
與X8
獨立地係-O-、-S-、-N(R5
)-、或-C(R5
)2
-,且R2
、R3
、與R4
係如對式(I)所定義。X9
與X10
係如對式(X)所定義。
在另一個具體態樣中,本發明的化合物係由式(XII):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中X11
與X12
獨立地係-C(R5
)-或-N-,其條件為X11
或X12
至少一者係-N-。X7
與X8
係如對式(XI)所定義。R1
、R2
、R3
、與R4
係如對式(I)所定義。Z係如對式(VII)所定義.
在另一個具體態樣中,本發明的化合物係由式(XIII):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中:X13
係-C(O)-;-S(O)-、-S(O)2
-、-P(O)(OR12
)-、-S(O)2
R13
S(O)2
-、-S(O)2
OS(O)2
-、-S(O)2
SS(O)2
-、-S(O)2
N(R5
)S(O)2
-、-P(O)(OR12
)R13
P(O)(OR12
)-、P(O)(OR12
)OP(O)(OR12
)-、-P(O)(OR12
)SP(O)(OR12
)-、-C(O)R13
S(O)2
-、-C(O)C(=NNHR26
)C(O)-、-S(O)2
NR27
C(O)-或-P(O)(OR12
)N(R5
)P(O)(OR12
)-。R5
與R6
獨立地係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基或視需要經取代的雜芳基,或R5
與R6
(與其等所接附的氮以及X13
一起)形成以下環結構:
R26
係視需要經取代的烷基或視需要經取代的苯基基團。R27
係-H或視需要經取代的烷基基團。R1
、R2
、R3
、R4
、R12
與R13
係如對式(I)所定義。
在一個式(XIII)化合物之具體態樣中,當R3
、R4
、R5
、與R6
皆係-H時,則R1
或R2
皆非係-OR17
、-NR19
R20
、-NR18
C(O)R17
、或苯基。
在另一個具體態樣中,本發明的化合物係由式(XIV):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中:X14
係-C(O)-;-S(O)-、-S(O)2
-、-P(O)(OR12
)-;R22
與R23
各自獨立地係-N(R5
)-N(R5
)-C(R5
)2
-或-C(R5
)2
-N(R5
)-N(R5
)-;且R1
與R2
係如對式(I)所定義。
在一個式(XIV)化合物之具體態樣中,當兩個Z基團皆係O且X14
係-C(O)-時,則R1
或R2
皆非係-OR17
。
在另一個具體態樣中,本發明的化合物係由式(XV):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中R24
與R25
獨立地係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基或視需要經取代的雜芳基。R1
、R2
、R3
、R4
、R5
、R6
與Z係如對式(I)所定義。X14
係如對式(XIV)所定義。
在另一個具體態樣中,本發明的化合物係由式(XVI):
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥所代表,其中R1
、R2
、R3
、R4
、R5
、R6
、與Z係如對式(I)所定義。X14
係如對式(XIV)所定義。R24
與R25
係如對式(XV)所定義。
本發明之另一個具體態樣係醫藥組成物,其包括本發明之化合物、或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,以及藥學上可接受的載劑或稀釋劑。醫藥組成物可用於治療中(例如)以作為抗增生性劑(例如,抗癌劑)。此外,醫藥組成物可用於治療中以治療對Hsp70誘發有反應之疾病,或醫藥組成物可用於治療中以治療對自然殺手細胞誘發有反應之疾病,例如細菌性感染、真菌性感染、病毒性感染、或寄生蟲性感染。
本發明亦提供治療具有增生性疾病(例如癌症)之受藥者之方法。該方法包括投藥至該受藥者有效量的本發明之化合物、或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥。本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)可以單一-治療(即,作為投藥至受藥者之唯一的抗增生性藥物)之形式被投藥或係與一種或多種其他抗癌藥物共-投藥。在一個具體態樣中,本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)係與汰癌勝或紫衫烷衍生物一起投藥。
本發明亦提供本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)的用途,其係用於製造用於在個體中治療增生性疾病(例如癌症)之目的之醫藥品。
本發明亦提供治療具有Hsp70反應性疾病(例如阿茲海默症、杭丁頓舞蹈症、巴金森氏病、與肌萎縮性偏側硬化症)之受藥者之方法。該方法包括投藥至該受藥者有效量的本發明之化合物、或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥。
本發明亦提供本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)的用途,其係用於製造用於在個體中治療對Hsp70誘發有反應之疾病(例如阿茲海默症、杭丁頓舞蹈症、巴金森氏病、與肌萎縮性偏側硬化症)。
本發明亦提供用於治療具有自然殺手細胞反應性疾病(例如細菌性感染、真菌性感染、病毒性感染、或寄生蟲性感染)之受藥者之方法。該方法包括投藥至該受藥者有效量的本發明之化合物、或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥。
本發明亦提供本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)之用途,其係用於製造用於在個體中治療對自然殺手細胞誘發有反應之疾病(例如細菌性感染、真菌性感染、病毒性感染、或寄生蟲感染)之目的的醫藥品。
本發明亦提供製備本發明之化合物的方法。該方法包括以下步驟本發明之化合物或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥可用於治療增生性疾病(例如癌症,包括已成為多重藥物抗性之癌症),其係單獨使用或結合其他抗癌劑使用。因此,本發明之化合物可在其他藥物攝生法已經失敗或變成無效的之情況下用於治療癌症。此外,當本發明之化合物結合其他抗癌藥物(例如汰癌勝或紫衫烷類似物)使用時,係特別地有效的。
在一個具體態樣中,本發明提供如以下所提出的式(I)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R5
、R6
、與R13
係如以上所定義。
在一個式(I)化合物之具體態樣中,當R13
係-CH2
-,R3
與R4
皆係苯基且R5
與R6
皆係-H時,則R1
與R2
非皆係苯基。
在一個式(I)化合物之具體態樣中,當R13
係-CH2
-,R3
與R4
皆係苯基且R5
與R6
皆係-H時,則R1
與R2
非皆係甲基。
在一個具體態樣中,本發明提供如以下所提出的式(II)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R7
、與R8
係如以上所定義.
在一個具體態樣中,本發明提供如以下所提出的式(III)與式(IV)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R5
、R6
、R13
、Z1
、Z2
、Z3
、Z4
、X1
、X2
、X3
、與X4
係如以上所定義。
在一個式(III)化合物之具體態樣中,R1
與R2
非係-OH、-SH、或-NH2
。
在一個具體態樣中,本發明提供如以下所提出的式(V)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R7
、R8
、X3
與X4
係如以上所定義。
在一個具體態樣中,本發明提供如以下所提出的式(VI)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R7
、R8
、X1
與X2
係如以上所定義。
在一個具體態樣中,本發明提供如以下所提出的式(VII)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中:R1
、R2
、R3
、R4
、R5
、R6
、與X5
係如以上所定義。
在一個式(VII)化合物之具體態樣中,當Z3
或Z4
係O時,則R1
或R2
非係-OR17
。在一個式(VII)化合物之具體態樣中,當Z係O時,則R1
或R2
非係-OR17
或-NR19
R20
。
在一個具體態樣中,本發明提供如以下所提出的式(VIII)或(IX)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R7
、R8
與R12
係如以上所定義。
在一個具體態樣中,本發明提供如以下所提出的式(X)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中X6
、R1
、R2
、R3
、R4
、與Z係如以上所定義。
在一個式(X)化合物之具體態樣中,當Z係O時,R1
或R2
非係-OR17
。
在一個具體態樣中,本發明提供如以下所提出的式(XI)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,X6
、X7
、X8
、R2
、R3
、與R4
係如以上所定義。
在一個具體態樣中,本發明提供如以下所提出的式(XII)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中X11
、X12
、X7
、X8
、R1
、R2
、R3
、R4
與Z係如上所定義。
在一個式(XII)化合物之具體態樣中,X11
或X12
至少一者係-N-。
在一個式(XII)化合物之具體態樣中,當兩個Z基團皆係O時,則R1
或R2
皆非係-OR17
。
在一個式(XII)化合物之具體態樣中,當兩個Z基團皆係O且X7
與X8
皆係-CH2
-時,則R1
或R2
皆非係-NR19
R20
、或苯基。
在一個具體態樣中,本發明提供如以下所提出的式(XIII)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中:X13
、R1
、R2
、R3
、與R4
係如以上所定義。在一個式(XIII)化合物之具體態樣中,當R3
、R4
、R5
、與R6
皆係-H時,則R1
或R2
皆非係-OR17
、-NR19
R20
、-NR18
C(O)R17
、或苯基。
在一個具體態樣中,本發明提供如以下所提出的式(XIV)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中X14
、R22
、R23
、R1
與R2
係如以上所定義。
在一個式(XIV)化合物之具體態樣中,當兩個Z基團皆係O且X14
係-C(O)-時,則R1
或R2
皆非係-OR17
。
在一個具體態樣中,本發明提供如以下所提出的式(XV)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,R24
、R25
、R1
、R2
、R3
、R4
、R5
、R6
、Z與X14
係如上所定義。
在一個具體態樣中,本發明提供如以下所提出的式(XVI)之化合物:
或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥,其中R1
、R2
、R3
、R4
、R5
、R6
、Z、X14
、R24
與R25
係如以上所定義。
在另一個由式(I)-(XVI)所代表之化合物的具體態樣中,R1
與R2
各自係視需要經取代的芳基或視需要經取代的雜芳基。在一方面,R1
與R2
各自係經取代的或未經取代的苯基基團。在一方面,R1
與R2
皆係苯基。在另一方面,R1
與R2
皆係4-氰基苯基。在另一方面,R1
與R2
皆係4-甲氧基苯基。在再一方面,R1
與R2
皆係2,5-二甲氧基苯基。在另一方面,R1
與R2
皆係3-氰基苯基。在再一方面,R1
與R2
皆係3-氟苯基。在另一方面,R1
與R2
皆係4-氯苯基。在再一方面,R1
與R2
皆係2-二甲氧基苯基。在另一方面,R1
與R2
皆係3-甲氧基苯基。在一方面,R1
與R2
皆係2,3-二甲氧基苯基。在另一方面,R1
與R2
皆係2,5-二氟苯基。在再一方面,R1
與R2
皆係2,5-二氯苯基。在另一方面,R1
與R2
皆係2,5-二甲基苯基。
在另一個由式(I)-(XVI)所代表之化合物的具體態樣中,R1
與R2
皆係視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基。在一方面,R1
與R2
皆係視需要地以至少一個烷基基團取代的C3-C8環烷基基團。在另一方面,R1
與R2
皆係環丙基或1-甲基環丙基。在一方面,R1
與R2
皆係環丙基。在再一方面,R1
與R2
皆係1-甲基環丙基。在另一方面,R1
與R2
皆係2-甲基環丙基。在一方面,R1
與R2
皆係2-苯基環丙基。在另一方面,R1
與R2
皆係1-苯基環丙基。在再一方面,R1
與R2
皆係環丁基。在另一方面,R1
與R2
皆係環戊基。在另一方面,R1
與R2
皆係環己基。在再一方面,R1
與R2
皆係甲基。在另一方面,R1
與R2
皆係甲基。在一方面,R1
與R2
皆係第三-丁基。在另一方面,R1
與R2
係乙基。在再一方面,R1
與R2
皆係正丙基。在另一方面,R1
與R2
係鹵烷基。
在另一個由式(I)-(XVI)所代表之化合物的具體態樣中,R1
與R2
皆係鹵基、硝基、氰基、胍基、-OR17
、-NR19
R20
、-C(O)R17
、-C(O)OR17
、-OC(O)R17
、-C(O)NR19
R20
、-NR18
C(O)R17
、-OP(O)(OR17
)2
、-SP(O)(OR17
)2
、-SR17
、-S(O)p
R17
、-OS(O)p
R17
、-S(O)p
OR17
、-NR18
S(O)p
R17
、或-S(O)p
NR19
R20
。在一方面,R1
與 R2
皆係-OR17
。在一方面,R1
與R2
皆係-NR19
R20
。
在另一個由式(I)-(XIII)、(XV)或(XVI)所代表之化合物的具體態樣中,R3
與R4
各自係視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基。在一方面,R3
與R4
各自係烷基基團。在另一方面,R3
與R4
各自係甲基或乙基。
在另一個由式(I)、(III)、(IV)、(VII)、(X)、(XIII)、(XV)、或(XVI)所代表之化合物的具體態樣中,R5
係-H且R6
係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基。在一方面,R6
係-H或甲基。
在另一個由式(I)、(III)、(IV)、(VII)、(X)、(XIII)、(XV)、或(XVI)所代表之化合物的具體態樣中,R1
與R2
各自係視需要經取代的芳基或視需要經取代的雜芳基;且R3
與R4
各自係視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基。
在另一個由式(I)、(III)、(IV)、(VII)、(X)、(XIII)、(XV)、或(XVI)所代表之化合物的具體態樣中,R5
係-H且R6
係-H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基;且R3
與R4
各自係烷基基團。
在另一個由式(I)、(III)、(IV)、(VII)、(X)、(XIII)、(XV)、或(XVI)所代表之化合物的具體態樣中,R1
與R2
各自係經取代的或未經取代的苯基基團與R3
與R4
各自係甲基或乙基。
在另一個由式(I)、(III)、(IV)、(VII)、(X)、(XIII)、(XV)、或(XVI)所代表之化合物的具體態樣中,R1
與R2
皆係視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基;R5
係-H;且R6
係-H或視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基。
在另一個由式(I)、(III)、(IV)、(VII)、(X)、(XIII)、(XV)、或(XVI)所代表之化合物的具體態樣中,R1
與R2
皆係視需要地以至少一個烷基基團取代的C3-C8環烷基基團;R3
與R4
皆係烷基基團;且R6
係-H或甲基。
在另一個由式(I)、(III)、(IV)、(VII)或(XIII)所代表之化合物的具體態樣中,R13
係共價鍵。
在另一個由式(I)、(III)、(IV)、(VII)或(XIII)所代表之化合物的具體態樣中,R13
係-CH2
CH2
CH2
-或-CH2
CH2
。
在另一個由式(I)、(III)、(IV)、(VII)或(XIII)所代表之化合物的具體態樣中,R13
係-C(R7
)(R8
)-。
在另一個由式(II)、(V)、(VI)、(VIII),或(IX)所代表之化合物的具體態樣中,R1
與R2
皆係苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係苯基;R3
與R4
皆係乙基;R7
與R8
皆係-H;R1
與R2
皆係4-氰基苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係4-甲氧基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係苯基;R3
與R4
皆係乙基;R7
係甲基;R8
係-H;R1
與R2
皆係4-氰基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,5-二甲氧基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,5-二甲氧基苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係3-氰基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係3-氟苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係4-氯苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係2-二甲氧基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係3-甲氧基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,3-二甲氧基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,3-二甲氧基苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係2,5-二氟苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,5-二氟苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係2,5-二氯苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,5-二甲基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,5-二甲氧基苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係苯基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2,5-二甲氧基苯基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係環丙基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係環丙基;R3
與R4
皆係乙基;R7
與R8
皆係-H;R1
與R2
皆係環丙基;R3
與R4
皆係甲基;R7
係甲基;R8
係-H;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R7
係甲基與R8
係-H;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R7
係乙基與R8
係-H;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R7
係正丙基與R8
係-H;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R7
與R8
皆係甲基;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係乙基;R7
與R8
皆係-H;R1
與R2
皆係1-甲基環丙基;R3
係甲基,且R4
係乙基;R7
與R8
皆係-H;R1
與R2
皆係2-甲基環丙基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係2-苯基環丙基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係1-苯基環丙基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係環丁基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係環戊基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係環己基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係環己基;R3
與R4
皆係苯基;R7
與R8
皆係-H;R1
與R2
皆係甲基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
皆係甲基;R3
與R4
皆係第三-丁基;R7
與R8
皆係-H;R1
與R2
皆係甲基;R3
與R4
皆係苯基;R7
與R8
皆係-H;R1
與R2
皆係第三-丁基;R3
與R4
皆係甲基;R7
與R8
皆係-H;R1
與R2
係乙基;R3
與R4
皆係甲基;R7
與R8
皆係-H;或R1
與R2
皆係正丙基;R3
與R4
皆係甲基;R7
與R8
皆係-H。
在另一個由式(III)或(IV)所代表之化合物的具體態樣中,Z1
與Z2
皆係O。
在另一個由式(III)或(IV)所代表之化合物的具體態樣中,Z1
與Z2
皆係S。
在另一個由式(III)或(IV)所代表之化合物的具體態樣中,Z3
與Z4
皆係O。
在另一個由式(III)或(IV)所代表之化合物的具體態樣中,Z3
與Z4
皆係S。
在另一個由式(III)或(IV)所代表之化合物的具體態樣中,R9
、R10
、與R11
各自獨立地係-H或視需要經取代的烷基。
在另一個由式(III)所代表之化合物的具體態樣中,X3
與X4
皆係
在另一個由式(IV)所代表之化合物的具體態樣中,X1
與X2
皆係
在另一個由式(V)所代表之化合物的具體態樣中,X3
與X4
皆係。更具體地,R9
係視需要經取代的烷基。甚至更具體地,R9
係甲基。
在另一個由式(VII)所代表之化合物的具體態樣中,X5
係-S(O)2
OS(O)2
-、-S(O)2
SS(O)2
-、-S(O)2
N(R5
)S(O)2
、P(O)(OR12
)OP(O)(OR12
)-、-P(O)(OR12
)SP(O)(OR12
)-、或-P(O)(OR12
)N(R5
)P(O)(OR12
)-。
在另一個由式(VII)、(X)、(XII)、(XIV)、(XV)、或(XVI)所代表之化合物的具體態樣中,兩個Z基團皆為S。
在另一個由式(VII)、(X)、(XII)、(XIV)、(XV)、或(XVI)所代表之化合物的具體態樣中,兩個Z基團皆為O。
在另一個由式(VII)所代表之化合物的具體態樣中,X5
係-S(O)-、-S(O)2
-、或-P(O)(OR12
)-。在一方面,X5
係-S(O)2
-。在一方面,X5
係-P(O)(OR12
)-。
在另一個由式(VII)所代表之化合物的具體態樣中,X5
係-S(O)2
R13
S(O)2
-或-P(O)(OR12
)R13
P(O)(OR12
)-。在一方面,X5
係-S(O)2
R13
S(O)2
-。在一方面,X5
係-P(O)(OR12
)R13
P(O)(OR12
)-。
在另一個由式(X)、(XI)或(XII)所代表之化合物的具體態樣中,X6
係-O-或-N(R5
)-。在一方面,X6
係-O-或-NH-。在一方面,X6
係-O-。在一方面,X6
係-NH-。
在另一個由式(X)、(XI)或(XII)所代表之化合物的具體態樣中,X6
係-S-。
在另一個由式(X)、(XI)或(XII)所代表之化合物的具體態樣中,X6
係-C(R5
)2
-。
在另一個由式(X)或(XI)所代表之化合物的具體態樣中,X9
與X10
皆係-CH-。
在另一個由式(X)或(XI)所代表之化合物的具體態樣中,X9
與X10
獨立地係-CH-、-C(CH3
)-或-C(CH2
CH3
)-。
在另一個由式(X)、(XI)或(XII)所代表之化合物的具體態樣中,R1
與R2
皆係苯基;R3
與R4
皆係甲基;R1
與R2
皆係苯基;R3
與R4
皆係乙基;R1
與R2
皆係4-氰基苯基;R3
與R4
皆係甲基;R1
與R2
皆係4-甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係4-氰基苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係3-氰基苯基;R3
與R4
皆係甲基;R1
與R2
皆係3-氟苯基;R3
與R4
皆係甲基;R1
與R2
皆係4-氯苯基;R3
與R4
皆係甲基;R1
與R2
皆係2-二甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係3-甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,3-二甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二氟苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二氯苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二甲基苯基;R3
與R4
皆係甲基;R1
與R2
皆係環丙基;R3
與R4
皆係甲基;R1
與R2
皆係環丙基;R3
與R4
皆係乙基;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係乙基;R1
與R2
皆係1-甲基環丙基;R3
係甲基,且R4
係乙基;R1
與R2
皆係2-甲基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係2-苯基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係1-苯基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係環丁基;R3
與R4
皆係甲基;R1
與R2
皆係環戊基;R3
與R4
皆係甲基;R1
與R2
皆係環己基;R3
與R4
皆係甲基;R1
與R2
皆係環己基;R3
與R4
皆係苯基;R1
與R2
皆係甲基;R3
與R4
皆係甲基;R1
與R2
皆係甲基;R3
與R4
皆係第三-丁基;R1
與R2
皆係甲基;R3
與R4
皆係苯基;R1
與R2
皆係第三-丁基;R3
與R4
皆係甲基;R1
與R2
係乙基;R3
與R4
皆係甲基;或R1
與R2
皆係正丙基;R3
與R4
皆係甲基。
在另一個由式(XI)或(XII)所代表之化合物的具體態樣中,X7
與X8
皆係-O-或-N(R5
)-。在一方面,X7
與X8
皆係-N(H)-。在一方面,X7
與X8
皆係-O-。
在另一個由式(XI)或(XII)所代表之化合物的具體態樣中,X7
與X8
皆係-S-。
在另一個由式(XI)或(XII)所代表之化合物的具體態樣中,X7
與X8
皆係-C(R5
)2
-。
在另一個由式(XI)或(XII)所代表之化合物的具體態樣中,X11
與X12
皆係N。
在另一個由式(XIII)所代表之化合物的具體態樣中,該化合物係由式(XIIIA)所代表:
在另一個由式(XIII)所代表之化合物的具體態樣中,該化合物係由式(XIIIB)所代表:
更具體地,R13
係經取代的或未經取代的C1-C6伸烷基基團。甚至更具體地,R13
係-CH2
-。
在另一個由式(XIII)所代表之化合物的具體態樣中,該化合物係由式(XIIIC)所代表:
更具體地,R26
係視需要地經取代的(例如,以低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
、與-OC(O)R30
)苯基基團或視需要地經取代的(例如,以低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
-與OC(O)R30
)的C1-C6烷基基團。
在另一個由式(XIII)所代表之化合物的具體態樣中,該化合物係由式(XIIID)所代表:
更具體地,R27
係-H。
在另一個由式(XIII)所代表之化合物的具體態樣中,該化合物係由式(XIIIE)所代表:
更具體地,R12
係視需要地經取代的(例如,以低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
、與-OC(O)R30
)烷基基團或視需要地經取代的(例如,以低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
與-OC(O)R30
)苯基基團。甚至更具體地,R12
係苯基基團。
在另一個由式(XIII)、(XIIIA)、(XIIIB)、(XIIIC)、(XIIID)或(XIIIE)所代表之化合物的具體態樣中,R1
與R2
各自係視需要地經取代的(例如,以低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
與-OC(O)R30
)芳基基團;且R3
與R4
各自係視需要地經取代的(例如,以低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
與-OC(O)R30
)烷基基團。更具體地,R1
與R2
各自係視需要經取代的苯基;且R3
與R4
各自係甲基或乙基。甚至更具體地,對式(XIII)、(XIIIA)、(XIIIB)、(XIIIC)、(XIIID)而言,R5
與R6
皆係-H。
在另一個由式(XIII)、(XIIIA)、(XIIIB)、(XIIIC)、(XIIID)或(XIIIE)所代表之化合物的具體態樣中,R1
與R2
皆係苯基;R3
與R4
皆係甲基;R1
與R2
皆係苯基;R3
與R4
皆係乙基;R1
與R2
皆係4-氰基苯基;R3
與R4
皆係甲基;R1
與R2
皆係4-甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係4-氰基苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係3-氰基苯基;R3
與R4
皆係甲基;R1
與R2
皆係3-氟苯基;R3
與R4
皆係甲基;R1
與R2
皆係4-氯苯基;R3
與R4
皆係甲基;R1
與R2
皆係2-二甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係3-甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,3-二甲氧基苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二氟苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二氯苯基;R3
與R4
皆係甲基;R1
與R2
皆係2,5-二甲基苯基;R3
與R4
皆係甲基;R1
與R2
皆係環丙基;R3
與R4
皆係甲基;R1
與R2
皆係環丙基;R3
與R4
皆係乙基;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係1-甲基環丙基;R3
與R4
皆係乙基;R1
與R2
皆係1-甲基環丙基;R3
係甲基,且R4
係乙基;R1
與R2
皆係2-甲基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係2-苯基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係1-苯基環丙基;R3
與R4
皆係甲基;R1
與R2
皆係環丁基;R3
與R4
皆係甲基;R1
與R2
皆係環戊基;R3
與R4
皆係甲基;R1
與R2
皆係環己基;R3
與R4
皆係甲基;R1
與R2
皆係環己基;R3
與R4
皆係苯基;R1
與R2
皆係甲基;R3
與R4
皆係甲基;R1
與R2
皆係甲基;R3
與R4
皆係第三-丁基;R1
與R2
皆係甲基;R3
與R4
皆係苯基;R1
與R2
皆係第三-丁基;R3
與R4
皆係甲基;R1
與R2
係乙基;R3
與R4
皆係甲基;或R1
與R2
皆係正丙基;R3
與R4
皆係甲基。更具體地,對式(XIII)、(XIIIA)、(XIIIB)、(XIIIC)或(XIIID)而言,R5
與R6
皆係-H。
在另一個由式(XIV)、(XV)、或(XVI)所代表之化合物的具體態樣中,X14
係-C(O)-。
在另一個由式(XIV)、(XV)、或(XVI)所代表之化合物的具體態樣中,X14
係-S(O)-。
在另一個由式(XIV)、(XV)、或(XVI)所代表之化合物的具體態樣中,X14
係-S(O)2
-。
在另一個由式(XIV)、(XV)、或(XVI)所代表之化合物的具體態樣中,X14
係-P(O)(OR12
)-。
在另一個由式(XV)或(XVI)所代表之化合物的具體態樣中,R24
與R25
各自係烷基基團。在一方面,R24
與R25
各自係甲基或乙基。
在另一個由式(XV)或(XVI)所代表之化合物的具體態樣中,R24
與R25
各自係-H。
本發明的例示性化合物(包括其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、水合物、多形體或前藥)係於以下表1描述。
在一個具體態樣中,本發明的化合物不包含列於表2之專利案與專利申請案所揭示之化合物。
用於本文,術語「烷基」意指一種飽和的直鏈或分支的非環狀碳氫化合物,其具有從1至10個碳原子。代表性飽和的直鏈烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基、與正癸基;而飽和的分支烷基包括異丙基、第二-丁基、異丁基、第三-丁基、異戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基、以及類似者。術語「(C1
-C6
)烷基」意指飽和的直鏈或分支的非環狀碳氫化合物,其具有從1至6個碳原子。代表性(C1
-C6
)烷基基團係該等以上所示且具有從1至6個碳原子者。包括於本發明之化合物中的烷基基團可視需要地以一個或多個取代基取代。
用於本文,術語「烯基」意指一種飽和的直鏈或分支的非環狀碳氫化合物,其具有從2至10個碳原子且具有至少一個碳-碳雙鍵。代表性直鏈與分支的(C2
-C10
)烯基包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、異丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、1-己烯基、2-己烯基、3-己烯基、1-庚烯基、2-庚烯基、3-庚烯基、1-辛烯基、2-辛烯基、3-辛烯基、1-壬烯基、2-壬烯基、3-壬烯基、1-癸烯基、2-癸烯基、3-癸烯基以及類似者。烯基基團可視需要地以一個或多個取代基取代。
用於本文,術語「炔基」意指一種飽和的直鏈或分支的非環狀碳氫化合物,其具有從2至10個碳原子且具有至少一個碳-碳三鍵。代表性直鏈與分支的炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、4-戊炔基、1-己炔基、2-己炔基、5-己炔基、1-庚炔基、2-庚炔基、6-庚炔基、1-辛炔基、2-辛炔基、7-辛炔基、1-壬炔基、2-壬炔基、8-壬炔基、1-癸炔基、2-癸炔基、9-癸炔基、以及類似者。炔基基團可視需要地以一個或多個取代基取代。
用於本文,術語「環烷基」意指一種飽和的、單-或多環烷基,其具有從3至20個碳原子。代表性環烷基包括環丙基、1-甲基環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基、-環癸基、八氫-並環戊二烯基(octahydro-pentalenyl)、以及類似者。環烷基基團可視需要地以一個或多個取代基取代。在一些具體態樣中,環烷基包括從3至10個碳原子。在一些具體態樣中,環烷基包括從3至8個碳原子。在一些具體態樣中,環烷基包括從3至8個碳原子。
用於本文,術語「環烯基」意指單-或多-環狀非-芳香的烷基,其在環系統中具有至少一個碳-碳雙鍵以及從3至20個碳原子。代表性環烯基包括環戊烯基、環戊二烯基、環己烯基、環己二烯基、環庚烯基、環庚二烯基、環庚三烯基、環辛烯基、環辛二烯基、環辛三烯基、環辛四烯基、環壬烯基、環壬二烯基、環癸烯基、環癸二烯基、1,2,3,4,5,8-六氫萘基以及類似者。環烯基基團可視需要地以一個或多個取代基取代。在一些具體態樣中,環烯基包括從3至10個碳原子。在一些具體態樣中,環烯基包括從3至8個碳原子。在一些具體態樣中,環烯基包括從3至6個碳原子。
用於本文,術語「鹵烷基」意指一種烷基基團,其中一個或多個(包括所有的)氫基被鹵基基團置換,其中每個鹵基基團獨立地係選自-F、-Cl、-Br、與-I。術語「鹵基甲基」意指一種甲基,其中一至三個氫基已藉由鹵基基團置換。代表性鹵烷基基團包括三氟甲基、溴甲基、1,2-二氯乙基、4-碘丁基、2-氟戊基、以及類似者。
用於本文,「烷氧基」係一種烷基基團,其藉由一個氧連接子接附至另一個部分(moiety)。
用於本文,「鹵烷氧基」係一種鹵烷基基團,其藉由一個氧連接子接附至另一個部分。
用於本文,術語「芳香環」或「芳基」意指一種碳氫化合物單環或多環基,其中至少一個環係芳香的。適合的芳基基團之實例包括(但是不限於)苯基、甲苯基、蒽基、茀基、茚基、薁基、與萘基,以及苯并-稠合的碳環部分,例如5,6,7,8-四氫萘基。芳基基團可視需要地以一個或多個取代基取代。在一個具體態樣中,芳基基團係6-14員環。在一個具體態樣中,芳基基團係單環環,其中該環包括6個碳原子,本文稱為「(C6
)芳基」。
用於本文,術語「芳烷基」意指一種芳基基團,其藉由(C1
-C6
)伸烷基基團接附至另一個基團。代表性芳烷基基團包括苯甲基、2-苯基-乙基、萘-3-基-甲基以及類似者。芳烷基基團可視需要地以一個或多個取代基取代。
用於本文,術語「伸烷基」意指一種烷基基團,其具有兩個接附之點。術語「(C1
-C6
)伸烷基」意指一種伸烷基基團,其具有從一至六個碳原子。直鏈(C1
-C6
)伸烷基基團係較佳的。伸烷基基團之非-限制性實例包括伸甲基(-CH2
-)、伸乙基(-CH2
CH2
-)、正伸丙基(-CH2
CH2
CH2
-)、異伸丙基(-CH2
CH(CH3
)-)、以及類似者。伸烷基基團可視需要地以一個或多個取代基取代。
用於本文,術語「雜環基」意指單環(典型地具有3-至10-員)或多環(典型地具有7-至20-員)雜環環系統,其係飽和的環或不飽和的非-芳香環。3-至10-員雜環可含有至多至5個雜原子;且7-至20-員雜環可含有至多至7個雜原子。典型地,雜環具有至少一個碳原子環成員。每個雜原子獨立地係選自氮,其可係氧化的(例如,N(O))或四級化的;氧;與硫,包括亞碸與碸。雜環可藉由任何雜原子或碳原子接附。代表性雜環包括嗎福林基、硫代嗎福林基、吡咯啶酮基、吡咯啶基、哌啶基、哌基、尿囊素基(hydantoinyl)、戊內醯胺基(valerolactamyl)、氧口元基、氧雜丁環基(oxetanyl)、四氫呋喃基、四氫哌喃基、四氫吡啶基、四氫嘧啶基、四氫苯硫基、四氫硫代哌喃基、以及類似者。雜原子可以技術領域中具有通常知識者已知的保護性基團取代,例如,氮上的氫可使用第三丁氧羰基基團取代。此外,雜環基可視需要地以一個或多個取代基取代。在此定義中只考慮如此經取代的雜環基團之穩定的異構物。在一些具體態樣中,雜環基包括從3至10個環原子與1-3個雜原子(選自N、O、或S)。在一些具體態樣中,雜環基包括從3至8個環原子與1-3個雜原子(選自N、O、或S)。在一些具體態樣中,雜環基包括從3至6個環原子以及1-3個雜原子(選自N、O、或S)。
用於本文,術語「雜芳香的」、「雜芳基」或類似的術語意指單環或多環雜芳香環,其包括碳原子環成員與一個或多個雜原子環成員。每個雜原子獨立地係選自氮,其可為氧化的(例如,N(O))或四級化的;氧;與硫,包括亞碸與碸。代表性雜芳基基團包括吡啶基、1-酮基-吡啶基、呋喃基、苯并[1,3]二唑基、苯并[1,4]二基、噻吩基、吡咯基、唑基、咪唑基、噻唑基、異唑基、喹啉基、吡唑基、異噻唑基、嗒基、嘧啶基、吡基、三基、三唑基、噻二唑基、異喹啉基、吲唑基、苯并唑基、苯并呋喃基、吲哚基(indolizinyl)、咪唑并吡啶基、四唑基、苯并咪唑基、苯并噻唑基、苯并噻二唑基、苯并二唑基、吲哚基、四氫吲哚基、氮吲哚基、咪唑并吡啶基、喹唑啉基、嘌呤基、吡咯并[2,3]嘧啶基、吡唑并[3,4]嘧啶基、咪唑并[1,2-a]吡啶基、與苯并噻吩基。在一個具體態樣中,雜芳香環係選自5-8員單環雜芳基環。雜芳香的或雜芳基環接附至另一個基團的點可係雜芳香的或雜芳基環之碳原子或雜原子。雜芳基基團可視需要地以一個或多個取代基取代。
用於本文,術語「(C5
)雜芳基」意指一種5員的芳香環,其中環中至少一個原子係雜原子,例如(例如)氧、硫或氮。代表性(C5
)雜芳基包括呋喃基、噻吩基、吡咯基、唑基、咪唑基、噻唑基、異唑基、吡唑基、異噻唑基、吡基、三唑基、噻二唑基、以及類似者。
用於本文,術語「(C6
)雜芳基」意指一種6員的芳香環,其中環中至少一個原子係雜原子,例如(例如)氧、硫或氮。代表性(C6
)雜芳基包括吡啶基、嗒基、吡基、三基、四基以及類似者。
用於本文,術語「雜芳烷基」意指雜芳基基團,其係接藉由(C1
-C6
)伸烷基附至另一個基團。代表性雜芳烷基包括2-(吡啶-4-基)-丙基、2-(噻吩-3-基)-乙基、咪唑并1-4-基-甲基、以及類似者。雜芳烷基基團可視需要地以一個或多個取代基取代。
用於本文,術語「鹵素」或「鹵基」意指-F、-Cl、-Br、或-I。
對烷基、伸烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基、芳烷基、雜芳基、與雜芳烷基基團之適合的取代基係該等會形成穩定的本發明的化合物者。對烷基、伸烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基、芳烷基、雜芳基、與雜芳基烷基之取代基的實例包括視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、視需要經取代的芳烷基、視需要經取代的雜芳烷基、鹵烷基、-C(O)NR28
R29
、-C(S)NR28
R29
、-C(NR32
)NR28
R29
、-NR30
C(O)R31
、-NR30
C(S)R31
、-NR30
C(NR32
)R31
、鹵基、-OR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-C(S)R30
、-C(NR32
)R30
、-NR28
R29
、-C(O)OR30
、-C(S)OR30
、-C(NR32
)OR30
、-OC(O)R30
、-OC(S)R30
、-OC(NR32
)R30
、-NR30
C(O)NR28
R29
、-NR30
C(S)NR28
R29
、-NR30
C(NR32
)NR28
R29
、-OC(O)NR28
R29
、-OC(S)NR28
R29
、-OC(NR32
)NR28
R29
、-NR30
C(O)OR31
、-NR30
C(S)OR31
、-NR30
C(NR32
)OR31
、-S(O)h
R30
、-OS(O)p
R30
、、-NR30
S(O)p
R30
、-S(O)p
NR28
R29
、-OS(O)p
NR28
R29
、或-NR30
S(O)p
NR28
R29
。在一些具體態樣中,對烷基、伸烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基、芳烷基、雜芳基、與雜芳基烷基之取代基的實例包括烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、烯基、炔基、環烷基、環烯基、雜環基、芳基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、雜芳基、芳烷基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、雜芳烷基、鹵烷基、-C(O)NR28
R29
、-C(S)NR28
R29
、-C(NR32
)NR28
R29
、-NR30
C(O)R31
、-NR30
C(S)R31
、-NR30
C(NR32
)R31
、鹵基、-OR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-C(S)R30
、-C(NR32
)R30
、-NR28
R29
、-C(O)OR30
、-C(S)OR30
、-C(NR32
)OR30
、-OC(O)R30
、-OC(S)R30
、-OC(NR32
)R30
、-NR30
C(O)NR28
R29
、-NR30
C(S)NR28
R29
、-NR30
C(NR32
)NR28
R29
、-OC(O)NR28
R29
、-OC(S)NR28
R29
、-OC(NR32
)NR28
R29
、-NR30
C(O)OR31
、-NR30
C(S)OR31
、-NR30
C(NR32
)OR31
、-S(O)h
R30
、-OS(O)p
R30
、-NR30
S(O)p
R30
、-S(O)p
NR28
R29
、-OS(O)p
NR28
R29
、或-NR30
S(O)p
NR28
R29
。
可選擇地,例示性取代基包括低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、3-8員雜環基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、5-6員雜芳基、低碳數芳烷基(例如苯甲基,視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數雜芳烷基、低碳數鹵烷基、-C(O)NR33
R29
、-C(S)NR33
R29
、-C(NR32
)NR33
R29
、-NR30
C(O)R31
、-NR30
C(S)R31
、-NR30
C(NR32
)R31
、鹵基、-OR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-C(S)R30
、-C(NR32
)R30
、-NR33
R29
、-C(O)OR30
、-C(S)OR30
、-C(NR32
)OR30
、-OC(O)R30
、-OC(S)R30
、-OC(NR32
)R30
、-NR30
C(O)NR33
R29
、-NR30
C(S)NR33
R29
、-NR30
C(NR32
)NR33
R29
、-OC(O)NR33
R29
、-OC(S)NR33
R29
、-OC(NR32
)NR33
R29
、-NR30
C(O)OR31
、-NR30
C(S)OR31
、-NR30
C(NR32
)OR31
、-S(O)h
R30
、-OS(O)p
R30
、-NR30
S(O)p
R30
、-S(O)p
NR33
R29
、-OS(O)p
NR33
R29
、以及-NR30
S(O)p
NR33
R29
。可選擇地,例示性取代基包括低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、3-8員雜環基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、5-6員雜芳基、低碳數芳烷基(例如苯甲基,且視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數雜芳烷基、低碳數鹵烷基、-C(O)NR33
R29
、-C(S)NR28
R29
、-NR30
C(O)R31
、-NR30
C(S)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-C(S)R30
、-NR28
R29
、-C(O)OR30
、-C(S)OR30
、-OC(O)R30
、-OC(S)R30
、-OC(NR32
)R30
與-NR30
C(O)NR28
R29
。可選擇地,例示性取代基包括低碳數烷基、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基與-OH所組成的群組之取代基取代)、低碳數鹵烷基、-C(O)NR28
R29
、-NR30
C(O)R31
、鹵基、-OR30
、-SR30
、氰基、硝基、鹵烷氧基、-C(O)R30
、-NR28
R29
、-C(O)OR30
與-OC(O)R30
。
其中R28
與R29
,每次出現(獨立地)係H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、視需要經取代的芳烷基、或視需要經取代的雜芳烷基;或R28
與R29
與其等所接附的氮一起形成視需要經取代的雜環基或視需要地經取代的雜芳基;R30
與R31
每次出現(獨立地)係H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、視需要經取代的芳烷基、或視需要經取代的雜芳烷基;且R32
,每次出現(獨立地)係H、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的環烷基、視需要經取代的環烯基、視需要經取代的雜環基、視需要經取代的芳基、視需要經取代的雜芳基、視需要經取代的芳烷基、視需要經取代的雜芳烷基、-C(O)R30
、-C(O)NR28
R29
、-S(O)p
R30
、或-S(O)p
NR28
R29
;p係1或2;且h係0、1或2。
在一些具體態樣中,R28
與R29
,每次出現(獨立地)係H、烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、烯基、炔基、C3-C8環烷基、C3-C8環烯基、3-8員雜環基、C6-C14芳基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、5-14員雜芳基、芳烷基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或雜芳烷基;或R28
與R29
與其等所接附的氮一起形成3-8員雜環基或5-6員雜芳基;R30
與R31
每次出現(獨立地)係H、烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、烯基、炔基、C3-C8環烷基、C3-C8環烯基、3-8員雜環基、C6-C14芳基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、5-14員雜芳基、芳烷基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或雜芳烷基;且R32
,每次出現(獨立地)係H、烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、烯基、炔基、C3-C8環烷基、C3-C8環烯基、3-8員雜環基、C6-C14芳基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、5-14員雜芳基、芳烷基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或雜芳烷基、-C(O)R30
、-C(O)NR28
R29
、-S(O)p
R30
、或-S(O)p
NR28
R29
。
在一些具體態樣中,R28
與R29
,每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、3-6員雜環基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、5-6員雜芳基、低碳數芳烷基(例如苯甲基,且視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或低碳數雜芳烷基,或R28
與R29
與其等所接附的氮一起形成3-6員雜環基或5-6員雜芳基;R30
與R31
每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、3-6員雜環基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、5-6員雜芳基、低碳數芳烷基(例如苯甲基,且(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或低碳數雜芳烷基;且R32
,每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C8環烷基、C3-C8環烯基、3-6員雜環基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、5-6員雜芳基、低碳數芳烷基(例如苯甲基,且視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或低碳數雜芳烷基、-C(O)R30
、-C(O)NR28
R29
、-S(O)p
R30
、或-S(O)p
NR28
R29
。
在一些具體態樣中,R28
與R29
,每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C6環烷基、C3-C6環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或低碳數芳烷基(例如苯甲基,且視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代);或R28
與R29
與其等所接附的氮一起形成5-6員雜環基或5-6員雜芳基;R30
與R31
每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C6環烷基、C3-C6環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或低碳數芳烷基(例如苯甲基,且視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代);且R32
,每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、C3-C6環烷基、C3-C6環烯基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數芳烷基(例如苯甲基,且視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、-C(O)R30
、-C(O)NR28
R29
、-S(O)p
R30
、或-S(O)p
NR28
R29
。
在一些具體態樣中,R28
與R29
,每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)或苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代);或R28
與R29
與其等所接附的氮一起形成5-6員雜環基或5-6員雜芳基;R30
與R31
每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代);且R32
,每次出現(獨立地)係H、低碳數烷基(視需要地以一個或多個選自由苯基、苯甲基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、低碳數烯基、低碳數炔基、苯基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、或苯甲基(視需要地以一個或多個選自由低碳數烷基、鹵基、氰基、硝基、胺基、單(低碳數烷基)胺基、雙(低碳數烷基)胺基、低碳數烷氧基、低碳數鹵烷氧基、與-OH所組成的群組之取代基取代)、-C(O)R30
、-C(O)NR28
R29
、-S(O)p
R30
、或-S(O)p
NR28
R29
。
在一些具體態樣中,R28
與R29
,每次出現(獨立地)係H、低碳數烷基、低碳數鹵烷基、低碳數烯基、低碳數炔基、苯基或苯甲基;或R28
與R29
與其等所接附的氮一起形成5-6員雜環基或5-6員雜芳基;R30
與R31
每次出現(獨立地)係H、低碳數烷基、低碳數鹵烷基、低碳數烯基、低碳數炔基、苯基、或苯甲基;且R32
,每次出現(獨立地)係H、低碳數烷基、低碳數鹵烷基、低碳數烯基、低碳數炔基、苯基、或苯甲基、-C(O)R30
、-C(O)NR28
R29
、-S(O)p
R30
、或-S(O)p
NR28
R29
。
此外,烷基、環烷基、伸烷基、雜環基、與任何烯基、環烯基、炔基、芳烷基、與雜芳烷基基團之飽和的部分,亦可以=O、=S、=N-R32
取代。
當雜環基、雜芳基、或雜芳烷基基團含有氮原子時,其可係經取代的或未經取代的。當在雜芳基基團之芳香環中的氮原子具有取代基時,該氮可係四級氮。
用於本文,術語「受藥者」、「患者」、與「哺乳類動物」係可互換地使用。術語「受藥者」與「患者」意指一動物(例如,鳥類,例如雞、鵪鶉、或火雞、或哺乳類動物),較佳地為哺乳類動物,包括非-靈長類動物(例如,牛、豬、馬、綿羊、兔子、天竺鼠、大鼠、貓、狗、與小鼠)以及靈長類動物(例如,猴子、黑猩猩、與人類),且更佳地為人類。在一個具體態樣中,受藥者係非-人類動物,例如農場動物(例如,馬、牛、豬、或綿羊)、或寵物(例如,狗、貓、天竺鼠、或兔子)。在一個較佳的具體態樣中,受藥者為人類。
用於本文,術語「低碳數」意指一種有至多至四個碳原子之基團。例如,「低碳數烷基」意指一種具有從1至4個碳原子之烷基,「低碳數烷氧基」意指「-O-(C1
-C4
)烷基且「低碳數烯基」或「低碳數炔基」各自意指一種具有從2至4個碳原子之烯基或炔基。「低碳數芳烷基」意指一種芳基基團,其藉由一(C1
-C4
)伸烷基接附至另一個基團。「低碳數雜芳烷基」意指一種雜芳基基團,其藉由一(C1
-C4
)伸烷基接附至另一個基團。
除非另加指出,含有反應性官能基(例如(但不限於)羧基、羥基、硫基、與胺基部分)的本發明之化合物亦包括其經保護的衍生物。「經保護的衍生物」係該等其中一個或多個反應性位置或係以一個或多個保護性基團封阻之化合物。用於羥基基團之適合的保護性基團之實例包括苯甲基、甲氧基甲基、丙烯基、三甲基矽烷基、第三-丁基二甲基矽烷基、醋酸基、以及類似者。適合的胺保護性基團之實例包括苯甲氧羰基、第三-丁氧羰基、第三-丁基、苯甲基、與茀甲氧-羰基(Fmoc)。適合的硫基保護性基團之實例包括苯甲基、第三-丁基、乙醯基、甲氧基甲基、以及類似者。其他適合的保護性基團係該等技術領域中具有通常知識者所熟知者且包括該等於T.W.Greene,Protecting Groups in Organic Synthesis,John Wiley & Sons,Inc.1981找到者。
用於本文,術語「本發明的化合物」與類似的術語意指式(I)至(XVI)與表1之化合物、或其藥學上可接受的鹽、溶劑合物、晶籠化合物、水合物、多形體、或前藥,且亦包括其經保護衍生物。
本發明之化合物可含有一個或多個對掌性中心及/或雙鍵且(因此)以立體異構物的形式存在,例如雙鍵異構物(即
,幾何異構物)、鏡相異構物、或非鏡相立體異構物。根據本發明,本文所描繪的化學結構(包括本發明的化合物)包含所有對應的化合物之鏡相異構物、非鏡相立體異構物、與幾何異構物,即,立體化學純的形式(例如,幾何地純的、鏡相異構物地純的、或非鏡相立體異構地純的)與異構性混合物(例如,鏡相異構物性、非鏡相立體異構物性、與幾何異構性混合物)兩者。在一些實例中,一種鏡相異構物、非鏡相立體異構物、或幾何異構物相較於其他異構物會具有較高的活性或改善的毒性或動力學曲線。在該等實例中,本發明的化合物之如此鏡相異構物、非鏡相立體異構物、與幾何異構物係較佳的。
用於本文,術語「多形體」意指本發明化合物或其錯合物之固體結晶形式。相同化合物之不同多形體可展現不同的物理的、化學的、及/或光譜學的特性。不同的物理學的特性包括,但不限於穩定性(例如,對熱或光)、壓縮性與密度(在調配與產物製造中係重要的)、以及溶解率(其可對生物可利用性產生影響)。在穩定性中的差異可源自在化學反應性中的改變(例如,差異的氧化,使得一劑量形式當由一種多形體組成時較由另一種多形體組成時退色更快)或機械性特徵(例如,錠劑在儲存中由於動力學偏好的多形體轉變成熱力學上較穩定的多形體而粉碎)或兩者(例如,一種多形體之錠劑於高溼度易崩解)。多形體之不同的物理特性可對其等的加工產生影響。例如,一種多形體相較於另一多形體可更可能形成溶劑合物或可更困難濾除或洗去雜質,其係由於(例如)其顆粒之外型或尺寸分布。
用於本文,術語「水合物」意指本發明之化合物或其鹽,其進一步包括藉由非-共價分子間力結合之化學計量的或非-化學計量的量的水。
用於本文,術語「晶籠化合物」意指本發明的化合物或其鹽,其呈含有具有客體分子(guest molecule,例如,溶劑或水)陷於其內之空間(例如,通道)之晶格的形式。
用於本文且除非另有指示,術語「前藥」意指化合物之衍生物,其可在生物條件(試管內或活體內
)下水解、氧化、或否則反應以提供本發明的化合物。前藥可在生物條件下於如此反應變成活性的,或其等可於其等的非反應性形式具有活性。於本發明中所預期之前藥之實例包括(但不限於)式(I)至(XVI)與表1之化合物包含生物可水解部分(例如生物可水解的醯胺、生物可水解的酯、生物可水解的胺甲酸酯、生物可水解的碳酸酯、生物可水解的脲(ureide)、與生物可水解的磷酸酯類似物)的類似物或衍生物。前藥的其他實例包括式(I)至(XVI)、與表1之化合物包含-NO、-NO2
、-ONO、或-ONO2
部分的衍生物。前藥可典型地使用已經熟知的方法製備,例如該等由1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY(1995)172-178,949-982(Manfred E.Wolffed.,5th
ed)所敘述者。
用於本文且除非另有指示,術語「生物可水解的醯胺」、「生物可水解的酯」、「生物可水解的胺甲酸酯」、「生物可水解的碳酸酯」、「生物可水解的脲」、與「生物可水解的磷酸酯類似物」各自意指一種醯胺、酯、胺甲酸酯、碳酸酯、脲、或磷酸酯類似物,其:1)不會摧毀化合物之生物活性並賦予該化合物活體內
有益的特性,例如改善的水溶性、在血液中改善的循環半生期(例如,因為該前藥之減低的代謝)、改善的攝取、改善的作用期間、或改善的作用開始;或2)本身係生物不活性的但活體內被轉變成生物活性的化合物。生物可水解的醯胺之實例包括(但是不限於)低碳數烷基醯胺、α-胺基酸醯胺、烷氧基醯基醯胺、與烷基胺基烷基羰基醯胺。生物可水解的酯之實例包括(但是不限於)低碳數烷基酯、烷氧基醯氧基酯、烷基醯基胺基烷基酯、與膽鹼酯。生物可水解的胺甲酸酯之實例包括(但是不限於)低碳數烷基胺、經取代的乙二胺、胺基酸、羥基烷基胺、雜環與雜芳香胺、以及聚醚胺。
用於本文,「Hsp70」包括具有約70-千道耳吞之分子量之熱休克蛋白的家族之每個成員,包括例如構成性、同源性、細胞-專一性、葡萄糖-調節性、可誘導性、等等之形式。特殊Hsp70蛋白之實例包括hsp70、hsp70hom;hsc70;Grp78/BiP;mt-Hsp70/Grp75、以及類似者。典型地,所揭示之方法增加可誘導性Hsp70之表現。功能上地,70-kDa
HSP(HSP70)家族係一群在細胞質、粒腺體、與內質網中協助蛋白質之摺疊、運輸、與裝配的陪伴蛋白(chaperon)。在人類中膜結合性Hsp70,Hsp70家族包含至少11個基因,其編碼一群高度相關的蛋白質。參見(例如)Tavaria等人,Cell Stress Chaperones,1996;1(1):23-28;Todryk等人,Immunology.2003,110(1):1-9;以及Georgopoulos 與Welch,Annu Rev Cell Biol.1993;9:601-634;此等文獻之完整教示係以引用方式納入本文中。
用於本文,「Hsp70-反應性疾病」係一種醫學病症,其中受壓力的細胞可藉由增加的Hsp70表現而治療。如此疾病可由廣泛各種細胞壓力因子造成,其包括,但不限於阿茲海默症;杭丁頓舞蹈症;巴金森氏病;脊髓/延髓肌肉萎縮(例如,甘迺迪氏病(Kennedy’s disease))、脊髓性小腦萎縮症(spinocerebellar ataxic disease)、以及其他神經肌肉性萎縮;家族性肌萎縮性偏側硬化症;局部缺血;發作(seizure);體溫過低;體溫過高;燒傷;動脈粥樣硬化;輻射暴露;青光眼;毒素暴露;機械性傷害;發炎;自體疾病;感染(細菌的、病毒的、真菌的、或寄生蟲);以及類似者。
在一些具體態樣中,Hsp70-反應性疾病係神經退化性疾病。用於本文,神經退化性疾病包括神經元(例如小腦的、脊髓的、與周圍的神經元(例如,於神經肌肉性突觸)之降解,更典型地係大腦的與脊髓神經元的降解,或在較佳的具體態樣中,係大腦的神經元之降解。神經退化性疾病可包括阿茲海默症;杭丁頓舞蹈症;巴金森氏病;脊髓/延髓肌肉萎縮與其他神經肌肉性萎縮;以及家族性肌萎縮性偏側硬化症或與超氧化物歧化酶(SOD)突變相關的其他疾病。神經退化性疾病亦可包括由局部缺血、發作、熱壓力、輻射、毒素暴露、感染、傷害、以及類似者所造成的神經元之降解。
在一些具體態樣中,Hsp70-反應性疾病係蛋白質聚集/錯誤摺疊之疾病,例如阿茲海默症;杭丁頓舞蹈症;巴金森氏病;海綿狀腦病(spongiform encelphalopathies);以及類似者。
在另一個具體態樣中,Hsp70反應性疾病係造成或可能造成神經損害之處理或或病症。用於本發明之方法的化合物可用以於以下之於受藥者以減低或預防(抑制其開始)神經損害(即,提供神經保護)i)受造成或可能造成神經損害之病症所苦,或ii)接受造成或可能造成神經損害之治療。在一方面,造成或可能造成神經損害之治療係輻射治療。在另一方面,治療係化療。在一方面,化療包括投藥抗有絲分裂劑(例如長春新鹼、長春瑞寶、太平洋紫杉醇(paclitaxel)、或太平洋紫杉醇類似物)。在一方面,化療包括投藥太平洋紫杉醇。在另一方面,化療包括投藥鉑衍生物(例如順氯氨鉑(Cisplatin)、卡鉑(carboplatin)、或奧沙利鉑(oxaliplatin))。在某些具體態樣中,用於本發明之方法之化合物可與造成或可能造成神經損害之治療呈結合治療而同時投藥。在其他具體態樣中,用於本發明之方法之化合物可在造成或可能造成神經損害的治療之前或之後投藥。在某些具體態樣中,用於本發明之方法之化合物可在造成或可能造成神經損害的治療之前或之後30分鐘與12個小時間、1個小時與6個小時間投藥。
神經損害可由數種治療造成,包括(但不限於)輻射治療;化療,例如順氯氨鉑、卡鉑、奧沙利鉑、長春新鹼(vincristine)、長春花鹼(vinblastine)、長春瑞賓(vinorelbine)、長春地辛(vindesine)、異環磷醯胺(ifoafamide)、甲氨蝶呤(methotrexate)、克拉君寶(cladribine)、六甲蜜胺(altretamine)、氟達拉濱(fludarabine)、丙卡巴肼(procarbazine)、塞替哌(thiotepa)、替尼泊苷(tenipoaide)、三氧化砷、alemtuzumab、卡培他濱(capecitabine)、甲嗪咪唑胺(dacarbazine)、denileukin diftitox、干擾素阿伐、脂質體柔紅黴素(daunorubicin)、維A酸(tretinoin)、依托泊苷(etoposide)/VP-16、阿糖胞苷(cytarabine)、六甲密胺(hexamethylmelamine)、蘇拉明(suramin)、太平洋紫杉醇、多西紫杉醇(docetaxel)、吉西他濱(gemcitibine)、沙利度胺(thalidomide)、與硼替佐米(bortezomib);心臟或血管壓力藥物,例如胺碘酮(amiodarone)、肼屈嗪(hydralazine)、地高辛(digoxin)、與哌克昔林(perhxiline);對抗感染用之藥物,例如甲硝唑(metronidazole)、呋喃妥因(nitrofurantoin)、沙利度胺(thalidomide)、與INH;治療皮膚病症之藥物,例如氨苯碸(dapsone);抗驚厥藥物,例如苯妥因(phenytoin);抗酒精藥物,例如雙硫侖(disulfiram);HIV藥物,例如齊多夫定(zidovudine)、去羥肌苷(didanonsine)、司他伏定(stavudine)、扎西他賓(zalcitabine)、利托納維(ritonavir)、d4T、ddC、ddl、與安普那韋(amprenavir);膽固醇藥物,例如洛伐他汀(lovastatin)、普伐他汀(pravastatin)、吲達帕胺(indapamid)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、薛利伐史達丁(cerivastatin)、與吉非貝齊(gemfibrozil);抗風濕病藥物,例如氯喹(chloroquine)、秋水仙鹼(cholchicine)、有機金、與青黴胺(penicillamine);氧化亞氮;鋰;以及麥角類(ergots)。
在一些具體態樣中,Hsp70-反應性疾病係局部缺血。局部缺血可透過多重途徑(包括氧耗盡、葡萄糖耗盡、於再灌注之氧化性壓力、及/或麩胺酸毒性、以及類似者)損害組織。局部缺血可源自內源性病症(例如,中風、心臟病發作、以及類似者)、源自意外性機械性傷害、源自手術的傷害(例如,在移植器官之再灌注壓力)、以及類似者。可選擇地,可能因局部缺血而損害的組織包括神經元、心肌、肝臟組織、骨骼肌、腎臟組織、肺的組織、胰臟的組織、以及類似者。在一個較佳的具體態樣中,Hsp70-反應性疾病係大腦或脊髓局部缺血。在另一個較佳的具體態樣中,Hsp70-反應性疾病係心臟的局部缺血。
在各種具體態樣中,Hsp70-反應性疾病係發作,例如癲癇發作、傷害-誘導性發作、化學地-誘導性發作、以及類似者。
在一些具體態樣中,Hsp70-反應性疾病係由於熱壓力。熱壓力包括體溫過高(例如,源自發燒、中暑、燒傷、以及類似者)與體溫過低。在一個較佳的具體態樣中,疾病係體溫過高。在另一個較佳的具體態樣中,Hsp70-反應性疾病係燒傷。
在較佳的具體態樣中,Hsp70-反應性疾病係動脈粥樣硬化。
在各種具體態樣中,Hsp70-反應性疾病係係輻射損害,例如由於可見光、紫外光、微波、宇宙射線、阿伐輻射、貝他輻射、迦馬輻射、X-射線、以及類似者所造成。例如,損害可係對藉由輻射治療治療癌症之受藥者中的非-癌性組織之輻射損害。在一個較佳的具體態樣中,Hsp70-反應性疾病係源自可見光或紫外光之輻射損害。
在各種具體態樣中,Hsp70-反應性疾病係機械性傷害,例如源自手術、意外、某些疾病病症(例如,青光眼中之壓力損害)以及類似者之創傷。在一個較佳的具體態樣中,Hsp70-反應性疾病係大腦的或脊髓創傷。在另一個較佳的具體態樣中,Hsp70-反應性疾病係青光眼(導致對視網膜的神經節之壓力損害)。
在各種具體態樣中,Hsp70-反應性疾病係對毒素之暴露。在較佳的具體態樣中,Hsp70-反應性疾病係對選自以下者之神經毒素之暴露:甲基安非他命;抗反轉錄病毒的HIV療法(例如,核苷反轉錄酶抑制劑);重金屬(例如,汞、鉛、砷、鎘、其化合物、以及類似者)、胺基酸類似物、化學氧化劑、乙醇、麩胺酸、代謝性抑制劑、抗生素、以及類似者。
某些本發明之化合物亦增加自然殺手(NK)細胞活性。用於本文,「NK細胞-反應性疾病」係一種醫學病症,其可藉由在NK細胞活性之增加而改善。例如,具有NK細胞-反應性疾病之受藥者可能需要免疫系統擴大,因為感染或其可能性。在一些具體態樣中,如此受藥者可具有感染(或已暴露至病源體存在之感染性環境(例如於醫院)),其徵候可藉由本文所揭示的方法減輕。例如,需要治療之受藥者可具有感染(細菌的、病毒的、真菌的、或寄生蟲的、原生動物的),而對其而言所揭示的活化NK細胞之方法可為治療。
在一些具體態樣中,具有NK細胞-反應性疾病之之受藥者具有免疫不全。如此受藥者(例如,對感染具有不完全的、受損的或否則受累的(compromised)防禦、或遭遇感染性環境、或類似者的受藥者)需要或可受益於預防性治療。例如,受藥者可處於感染性環境,而該處存在病源體(例如在醫院中);可具有開放性傷口或燒傷;可具有先天或後天免疫不全(例如,嚴重複合性免疫不全或「泡泡男孩(bubble boy)」症候群、變異性免疫不全症候群、後天免疫不全症候群(AIDS)、或類似者);可由於身體病症、年齡、毒素暴露、藥物效果(免疫抑制劑,例如於移植接受者)或副作用(例如,由於抗癌劑)而具有被抑制的免疫系統;或類似者。
在一些具體態樣中,可在具有減少的或不全的NK細胞活性之受藥者中,於病症(例如慢性疲勞症候群(慢性疲勞免疫功能異常症候群)或Epstein-Barr病毒感染、病毒感染後疲勞症候群、移植後症候群(特別是同種異體移植)或宿主-移植物疾病、暴露至藥物,例如抗癌症劑或一氧化氮合酶抑制劑、自然老化、與各種免疫不全病症,例如嚴重複合性免疫不全、變異性免疫不全症候群、以及類似者)中增加NK細胞活性。
在一些具體態樣中,具有NK細胞-反應性疾病之受藥者需要針對菌血症之治療。菌血症係血流中細菌性感染之病症。敗血性休克包括伴隨全身性發炎之嚴重的局部化或菌血性感染,換而言之具有對液體治療有抗性之血流灌注過少與血壓過低的敗血病。敗血病(或全身性發炎性反應症候群)包括各種可造成急性發炎之嚴重病症,例如感染、胰臟炎、燒傷、創傷。敗血性休克典型地係與由葛蘭氏陰性生物體、葡萄球菌(staphylococcus)、或腦膜炎雙球菌(meningococcus)所造成的感染相關。敗血性休克之特徵為急性循環性衰竭,典型地具有血壓過低、與多重器官衰竭。
暫時性菌血症可由手術的或創傷傷口造成。葛蘭氏陰性菌血症可係間歇性的與機會性的;雖然其對健康的人可無影響,其在具有使其衰弱之疾病、化療之後、與在營養失調之設定的免疫受累患者中可為嚴重地重要。感染典型地可在肺、在泌尿生殖(GU)或胃腸(GI)道、或在軟組織,例如在具有褥瘡之患者的皮膚、在有口部潰瘍危險的患者之口部潰瘍、與具有心臟瓣膜疾病、心臟瓣膜義肢(prosthetic heart valve)、或其他移植義肢的患者。
典型地,葛蘭氏陰性菌血症可在慢性病與免疫受累的患者中顯露。在如此患者中,血流感染亦可由需氧性桿菌、厭氧性細菌、與真菌造成。擬桿菌屬(Bacteroides)可導致腹部的與骨盆的感染性併發症,特別係在雌性。暫時性或持續性菌血症典型地會造成腦膜或漿膜腔(serous cavities)之轉移性感染,例如心包或較大的關節。腸球菌(Enterococcus)、葡萄球菌、或真菌可導致心內膜炎,但對葛蘭氏陰性菌血症則較不常見。葡萄球菌性菌血症對IV藥物使用者可係典型的,且典型可為葛蘭氏陽性細菌性心內膜炎之成因。
全身性真菌性感染之發生率已明顯的增加,特別在人類中,其部分係因為在具有受累的免疫系統(例如老人、AIDS患者、進行化療之患者、燒傷患者、具有糖尿病性酮酸症(ketoacidosis)的患者、以及使用免疫抑制藥物之移植患者)的受藥者數目之增加。一項研究發現大約40%來自住院期間獲得的感染之死亡係由於黴菌病;參見Sternberg等人,Science,Vol.266,(1994),pp.1632-1634,其完整教示係以引用方式納入本文中。
在各種具體態樣中,具有NK細胞-反應性疾病之之受藥者可需要針對真菌性感染(例如致病性皮癬菌、致病性絲狀真菌、及/或致病性非-絲狀真菌(例如酵母菌)、或類似者)之治療。致病性皮癬菌可包括(例如)髮癬菌屬(Trichophyton)、癬(Tinea)、小芽孢菌屬(Microsporum)、表皮癬菌屬(Epidermophyton)、或類似者之屬的物種。致病性絲狀真菌可包括(例如)例如麴菌屬(Aspergillus)、組織漿菌屬(histoplasma)、隱球菌屬(Cryptococcus)、小芽孢菌屬、或類似者之屬的物種。致病性非-絲狀真菌(例如酵母菌)可包括(例如)念珠菌屬(Candida)、鱗斑霉屬(Malassezia)、毛芽胞菌屬(Trichosporon)、紅酵母屬(Rhodotorula)、球擬酵母屬(Torulopsis)、隱球菌屬(Blastomyces)、副球黴菌屬(Paracoccidioides)、球黴菌屬(Coccidioides)、或類似者之屬的物種。在各種具體態樣中,可針對來自麴菌屬或髮癬菌屬之屬的物種之真菌性感染治療受藥者。髮癬菌屬的物種可包括(例如)鬚髮癬菌(Trichophyton mentagrophytes)、紅色髮癬菌、捨恩萊髮癬菌(Trichophyton schoenleinii)、匐行疹髮癬菌(Trichophyton tonsurans)、疣狀髮癬菌(Trichophyton verrucosum)、與堇色髮癬菌(Trichophyton violaceum)。麴菌屬之物種可包括(例如)薰煙色麴菌(Aspergillus fumigatus)、黃麴菌(Aspergillus flavus)、黑麴菌(Aspergillus niger)、阿姆斯特丹麴菌(Aspergillus amstelodami)、亮白麴菌(Aspergillus candidus)、肉色麴菌(Aspergillus carneus)、小巢狀麴菌(Aspergillus nidulans)、米麴菌(A oryzae)、侷限麴菌(Aspergillus restrictus)、聚多麴菌(Aspergillus sydowi)、金色土麴菌(Aspergillus terreus)、焦麴菌(Aspergillus ustus)、雜色麴菌(Aspergillus versicolor)、淺藍灰麴菌(Aspergillus caesiellus)、棒狀麴菌(Aspergillus clavatus)、燕麥狀麴菌(Aspergillus avenaceus)、與彎頭麴菌(Aspergillus deflectus)。在一些具體態樣中,可針對來自以下者之真菌性感染治療受藥者:致病性皮癬菌,例如髮癬菌屬(例如,紅色髮癬菌)、癬、小芽孢菌屬、或表皮癬菌屬;或隱球菌屬(例如,新型隱球菌)、念珠菌屬(例如白色念珠菌)、副球黴菌屬(例如,巴西副球黴菌)、或球黴菌屬(例如,粗球黴菌)。在特別的具體態樣中,可針對來自紅色髮癬菌、新型隱球菌、白色念珠菌、巴西副球黴菌、或粗球黴菌的真菌性感染治療受藥者。
因此,在各種具體態樣中,受藥者可具有由選自以下屬之真菌造成之感染:髮癬菌屬、癬、小芽孢菌屬、表皮癬菌屬、麴菌、組織漿菌屬、隱球菌屬、小芽孢菌屬、念珠菌屬、鱗斑霉屬、毛芽胞菌屬、紅酵母屬、球擬酵母屬、隱球菌屬、副球黴菌屬、與球黴菌屬。在一些具體態樣中,受藥者可具有由選自以下者之屬的真菌造成感染:髮癬菌屬、癬、小芽孢菌屬、表皮癬菌屬、隱球菌屬、念珠菌屬、副球黴菌屬、與球黴菌屬。在某些具體態樣中,受藥者可具有由選自以下者的真菌所造成的感染:紅色髮癬菌、新型隱球菌、白色念珠菌、巴西副球黴菌、與粗球黴菌。
在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對由(例如)選自以下屬之細菌所造成的細菌性感染的治療:Allochromatium、不動菌屬(Acinetobacter)、桿菌屬、曲桿菌屬(Campylobacter)、披衣菌屬(Chlamydia)、嗜衣體屬(Chlamydophila)、梭菌屬(Clostridium)、檸檬酸桿菌屬(Citrobacter)、大腸桿菌屬(Escherichia)、腸內桿菌屬(Enterobacter)、腸球菌屬、弗朗西斯氏菌屬(Francisella)、嗜血桿菌屬(Haemophilus)、螺旋桿菌屬(Helicobacter)、克留氏菌屬(Klebsiella)、李氏菌屬(Listeria)、摩拉氏菌屬(Moraxella)、分枝桿菌屬(Mycobacterium)、微球菌屬(Micrococcus)、奈瑟菌屬(Neisseria)、變形桿菌屬(Proteus)、假單胞菌屬(Pseudomonas)、沙門氏桿菌屬(Salmonella)、鋸桿菌屬(Serratia)、志賀桿菌屬(Shigella)、寡養單胞茵屬(Stenotrophomonas)、葡萄球菌屬、鏈球菌屬(Streptococcus)、聚球藻屬(Synechococcus)、弧菌屬(Vibrio)、與耶氏桿菌屬(Yersina);或厭氧細菌的屬,例如消化鏈球菌屬(Peptostreptococci)、卟啉單胞菌屬(Porphyromonas)、放線菌屬(Actinomyces)、梭菌屬、擬桿菌屬、普雷沃氏菌屬(Prevotella)、厭氧螺菌屬(Anaerobiospirillum)、細梭菌屬(Fusobacterium)、與Bilophila。在一些具體態樣中,具有NK細胞-反應性疾病之之受藥者可需要針對來自以下者的細菌性感染之治療:Allochromatium vinosum、不動桿菌(Acinetobacter baumanii)、炭疽桿菌(Bacillus anthracis)、空腸曲桿菌(Campylobacter jejuni)、沙眼披衣菌(Chlamydia trachomatis)、肺炎披衣菌(Chlamydia pneumoniae)、梭菌屬物種、檸檬酸桿菌屬物種、大腸桿菌(Escherichia coli)、腸內桿菌屬物種、糞腸球菌(Enterococcus faecalis)、屎腸球菌(Enterococcus faecium)、土拉文氏桿菌(Francisella tularensis)、流感嗜血桿菌(Haemophilus influenzae)、幽門螺桿旋菌(Helicobacter pylori)、克留氏菌屬物種、單核球增多性李氏菌、卡他摩拉氏菌(Moraxella catarrhalis)、結核分枝桿菌、腦膜炎雙球菌(Neisseria meningitidis)、淋病雙球菌(Neisseria gonorrhoeae)、奇異變形桿菌(Proteus mirabilis)、普通變型桿菌(Proteus vulgaris)、繡色假單胞菌(Pseudomonas aeruginosa)、沙門氏桿菌屬物種、鋸桿菌屬物種、志賀桿菌屬物種、嗜麥芽寡養單胞茵(Stenotrophomonas maltophilia)、金黃色葡萄球菌(Staphyloccocus aureus)、表皮葡萄菌球(Staphyloccocus epidermidis)、肺炎鏈球菌(Streptococcus pneumoniae)、化膿鏈球菌(Streptococcus pyogenes)、無乳鏈球菌(Streptococcus agalactiae)、鼠疫耶氏桿菌(Yersina pestis)、與小腸大腸炎耶氏桿菌(Yersina enterocolitica)、或類似者;或不解糖消化鏈球菌(Peptostreptococci asaccharolyticus)、大消化鏈球菌(Peptostreptococci magnus)、微小消化鏈球菌(Peptostreptococci micros)、普氏消化鏈球菌(Peptostreptococci prevotii)、不解糖卟啉單胞菌(Porphyromonas asaccharolytica)、Porphyromonas canoris、牙齦卟啉單胞菌(Porphyromonas gingivalis)、Porphyromonas macaccae、伊斯若放線菌(Actinomyces israelii)、齲齒放線菌(Actinomyces odontolyticus)、無害梭菌(Clostridium innocuum)、梭狀梭菌(Clostridium clostridioforme)、難治梭菌(Clostridium difficile)、Bacteroides tectum、解脲擬桿菌(Bacteroides urealyticus)、纖細擬桿菌(Bacteroides gracilis,纖細曲桿菌(Campylobacter gracilis))、中間普雷沃氏菌(Prevotella intermedia)、解肝素普雷沃氏菌(Prevotella heparinolytica)、口-頰普雷沃氏菌(Prevotella oris-buccae)、二路普雷沃氏菌(Prevotella bivia)、產黑普雷沃氏菌(Prevotella melaninogenica)、Fusobacterium naviforme、壞疽熱細梭菌(Fusobacterium necrophorum)、可變細梭菌(Fusobacterium varium)、潰瘍細梭菌(Fusobacterium ulcerans)、Fusobacterium russii、Bilophila wadsworthia、杜氏嗜血桿菌(Haemophilus ducreyi);Calymmatobacterium granulomatis、或類似者。
咸相信本發明之化合物可係特別地有用於治療具有細胞內感染之受藥者。技術領域中一般咸相信NK細胞係特別地有效於對抗細胞內感染。細胞內感染係該等其中一部分的感染性病源體存在於受感染者之細胞內者。
例如,細胞內感染可係由選自以下者之一種或多種細菌造成:艾利希體屬(Ehrlichia)(例如,必要的,於淋巴細胞與嗜中性細胞中呈現小型細胞質包涵體之細胞內細菌,例如腺熱艾利希體(Ehrlichia sennetsu)、犬艾利希體(Ehrlichia canis)、查菲艾利希體(Ehrlichia chaffeensis)、嗜吞噬細胞艾利希體(Ehrlichia phagocytophilia)、或類似者);李氏菌屬(例如,單核球增多性李氏菌);退伍軍人菌屬(Legionella,例如,退伍軍人嗜肺病菌(Legionella pneumophila));立克次體屬(Rickettsiae,例如,普氏立克次體(Rickettsiae prowazekii)、斑疹傷寒立克次體(Rickettsiae typhi,摩氏立克次體(Rickettsiae mooseri))、立氏立克次體(Rickettsiae rickettsii)、恙蟲熱立克次體(Rickettsiae tsutsugamushi)、西伯利亞立克次體(Rickettsiae sibirica);澳大利亞立克次體(Rickettsiae australis);康氏立克次體(Rickettsiae conorii);螨立克次體(Rickettsiae akari);伯氏立克次體(Rickettsiae burnetii));披衣菌屬(例如,鸚鵡熱披衣菌(Chlamydia psittaci);肺炎披衣菌;砂眼披衣菌(Chlamydia trachomatis)、或類似者);分枝桿菌屬(結核分枝桿菌;海分枝桿菌(Mycobacterium marinum);鳥型結核分枝桿菌(Mycobacterium Avium Complex);牛分枝桿菌(Mycobacterium bovis);瘤癧分枝桿菌(Mycobacterium scrofulaceum);潰瘍分枝桿菌(Mycobacterium ulcerans);痲瘋分枝桿菌(Mycobacterium leprae)(痲瘋,Hansen氏桿菌));布氏桿菌屬(Brucella,例如,地中海熱布氏桿菌(Brucella melitensis);流產布氏桿菌(Brucella abortus);豬布氏桿菌(Brucella suis);牛布氏桿菌屬(Brucella canis));柯克斯氏體屬(Coxiella,例如,伯納特氏柯克斯氏體(Coxiella burnetii));或類似者。因此,在一些具體態樣中,受藥者可具有由選自屬艾利希體屬;李氏菌屬;退伍軍人菌屬;立克次體;披衣菌屬;分枝桿菌屬;布氏桿菌屬;以及柯克斯氏體屬的屬之細菌造成之細胞內細菌性感染。
在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要對來自一種或多種上呼吸道細菌之細菌性感染之治療。上呼吸道細菌之實例包括該等屬於例如退伍軍人菌屬、假單胞菌屬、以及類似者之屬者。在一些具體態樣中,細菌可係繡色假單胞菌。在特別的具體態樣,細菌可係退伍軍人嗜肺病菌(例如,包括血清型1、2、3、4、5、6、7、8、以及類似者)、杜莫夫退伍軍人菌(Legionella dumoffli)、長灘退伍軍人菌(Legionella longbeacheae)、米克戴德退伍軍人菌(Legionella micdadei)、Legionella oakridgensis、Legionella feelei、Legionella anisa、Legionella sainthelensi、博茲曼退伍軍人菌(Legionella bozemanii)、戈爾曼退伍軍人菌(Legionella gormanii)、華沃茲思退伍軍人菌(Legionella wadsworthii)、約旦退伍軍人菌(Legionella jordanis)、或戈爾曼退伍軍人菌。
在一些具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對來自在受感染者中會造成慢性支氣管炎之急性細菌性惡化(acute bacterial exacerbation of chronic bronchitis,ABECB)者之細菌性感染的治療。典型地,ABECB可由肺炎鏈球菌、流感嗜血桿菌、副流感嗜血桿菌(Haemophilus parainfluenzae)、或卡他摩拉氏菌造成。
在一些具體態樣中,具有NK細胞-反應性疾病支之受藥者可需要針對來自在受感染者中會造成急性社區獲得性肺炎(community acquired pneumonia,CAP)者之細菌性感染的治療。典型地,CAP可由肺炎鏈球菌、流感嗜血桿菌、卡他摩拉氏菌、肺炎漿黴菌(Mycoplasma pneumoniae)、肺炎披衣菌、或肺炎克留氏菌(Klebsiella pneumoniae)造成。在一個特別的具體態樣中,CAP可由抗藥抗性細菌(例如肺炎鏈球菌之多重抗藥性品系)造成。
在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對來自肺炎鏈球菌、流感嗜血桿菌、副流感嗜血桿菌、卡他摩拉氏菌、肺炎漿黴菌、肺炎披衣菌、肺炎克留氏菌、金黃色葡萄球菌、化膿鏈球菌、魯氏不動菌(Acinetobacter lwoffi)、產酸克留氏菌(Klebsiella oxytoca)、退伍軍人嗜肺病菌、或普通變型桿菌的細菌性感染之治療。
在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對來自上頷竇致病性細菌的細菌性感染細菌的治療。用於本文,上頷竇致病性細菌係分離自急性或慢性上頷竇炎的細菌品系,或(例如)以下者之上頷竇分離株:金黃色葡萄球菌、肺炎鏈球菌、嗜血桿菌屬物種、卡他摩拉氏菌、非-發酵性葛蘭氏陰性桿菌之厭氧性品系、腦膜炎雙球菌或β-融血性鏈球菌(β-Haemolytic Streptococcus)。在各種具體態樣中,上頷竇致病性細菌可包括分離自急性或慢性上頷竇炎之細菌品系;金黃色葡萄球菌、肺炎鏈球菌、嗜血桿菌屬物種、卡他摩拉氏菌、非-發酵性葛蘭氏陰性桿菌之厭氧性品系、腦膜炎雙球菌、β-融血性鏈球菌、流感嗜血桿菌、腸桿菌科(Enterobacteriaceae)、非-發酵性葛蘭氏陰性桿菌、肺炎鏈球菌、化膿鏈球菌、抗二甲氧苯青黴素性葡萄球菌物種、退伍軍人嗜肺病菌、漿黴菌屬物種、與披衣菌屬物種、流感嗜血桿菌、副流感嗜血桿菌、消化鏈球菌屬(Peptostreptococcus)、擬桿菌屬物種、與解脲擬桿菌之上頷竇分離株。
在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對會在受藥者中造成泌尿道感染(UTI)的細菌性感染之治療。UTI之實例包括尿道炎、膀胱炎、前列腺炎、腎盂腎炎(急性、慢性、與黃色肉芽腫性(xantho肉芽腫性))、以及造血性UTI(例如,來自具有劇毒性桿菌(例如沙門氏桿菌屬、金黃色葡萄球菌、以及類似者)之菌血症者)。典型地,UTI可由以下者造成:葛蘭氏陰性需氧性細菌,例如大腸桿菌屬(例如大腸桿菌)、克留氏菌屬、變形桿菌屬、腸內桿菌屬、假單胞菌屬、與鋸桿菌屬;葛蘭氏陰性厭氧性細菌;葛蘭氏陽性細菌,例如腸球菌屬(例如,糞腸球菌)與葡萄球菌物種(例如,腐生葡萄球菌(Staphylococcus saprophyticus)、金黃色葡萄球菌、以及類似者);結核分枝桿菌;以及性傳染性細菌性感染(例如,砂眼披衣菌、淋病雙球菌、以及類似者)。
在某些具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對來自會造成例如以下性傳染疾病之微生物的感染之治療:梅毒螺旋體;陰道鞭毛滴蟲(Trichomonas vaginalis);念珠菌屬(白色念珠菌);淋病雙球菌;砂眼披衣菌;生殖道黴漿菌(Mycoplasma genitalium)、溶尿尿黴菌(Ureaplasma urealyticum);杜克氏嗜血桿菌(Haemophilus ducreyi);肉芽腫鞘桿菌(Calymmatobacterium granulomatis)(之前稱為肉芽腫性杜諾凡氏菌(Donovania granulomatis));單純皰疹病毒(HSV-1或HSV-2);人類乳突病毒(HPV);人類免疫不全病毒(HIV);各種細菌性(志賀桿菌屬、曲桿菌屬、或沙門氏桿菌屬)、病毒性(A型肝炎)、或寄生蟲性(梨形鞭毛蟲屬(Giardia)或變形蟲屬(amoeba),例如迪帕司內變形蟲(Entamoeba dispar,之前稱為溶組織內變形蟲(Entamoeba histolytica));或類似者。
因此,在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對導致以下者的感染之治療:上呼吸道細菌性感染、慢性支氣管炎之急性細菌性惡化;急性社區獲得性肺炎、上頷竇致病性細菌;泌尿道感染;或性傳染感染。
咸相信本發明的方法可特別地有效於治療具有病毒性感染之受藥者。因此,在各種具體態樣中,具有NK細胞-反應性疾病之之受藥者可需要針對來自例如以下者的病毒的感染之治療:微小核糖核酸病毒(Picornavirus)(例如,小兒麻痺病毒、鼻病毒、與某些依科病毒(echovirus)與克沙奇病毒(coxsackievirus));小病毒科(Parvoviridae)(人類小病毒B19);肝炎,例如肝去氧核糖核酸病毒(Hepadnavirus)(B型肝炎);乳多空病毒(Papovavirus)(JC病毒);腺病毒(人類腺病毒);皰疹病毒(例如,細胞巨大病毒(Cytomegalo)、艾普斯坦-巴爾二氏病毒(Epstein Barr virus)(單核球增多症)、類單核球增多症症候群、玫瑰疹(Roseola Infantum)、水痘帶狀皰疹病毒(雞痘)、帶狀皰疹(帶狀皰疹(Shingles))、單純皰疹病毒(口部皰疹、生殖器皰疹))、痘病毒(天花);卡力西病毒(Calicivirus)(諾沃克病毒(Norwalkvirus))、節肢動物攜帶性病毒(Arbovirus)(例如披蓋病毒(Togavirus)(德國麻疹病毒、登革熱病毒)、黃病毒(Flavivirus)(黃熱病毒)、布尼亞病毒(Bunyavirus)(加州腦炎病毒)、呼腸孤病毒(Reovirus)(輪狀病毒(Rotavirus));冠狀病毒(Coronavirus)(冠狀病毒);反轉錄病毒(第1型人類免疫不全病毒、第2型人類免疫不全病毒);彈狀病毒(Rhabdovirus)(狂犬病病毒)、絲狀病毒(Filovirus)(馬爾堡病毒(Marburgvirus)、伊波拉病毒、其他出血性病毒的疾病);副黏液病毒(Paramyxovirus)(麻疹病毒、腮腺炎病毒);正黏液病毒(Orthomyxovirus)(流行性感冒病毒);砂狀病毒(Arenavirus)(拉薩熱);第I與II型人類T-細胞嗜淋巴球病毒(HTLV-I、HTLV II);人類乳突病毒(HPV);或類似者。因此,在各種具體態樣中,受藥者可具有由選自以下的病毒所造成之感染:微小核糖核酸病毒;小病毒科;肝炎病毒;乳多空病毒;腺病毒;皰疹病毒、痘病毒;卡力西病毒;節肢動物攜帶性病毒;冠狀病毒;反轉錄病毒;彈狀病毒;副黏液病毒;正黏液病毒;砂狀病毒;人類T-細胞嗜淋巴球病毒;人類乳突病毒;且人類免疫不全病毒.
在一些具體態樣中,具有NK細胞-反應性疾病之之受藥者可需要針對來自病毒之感染或其感染的治療,例如人類免疫不全病毒-1、人類免疫不全病毒-2、細胞巨大病毒、艾普斯坦-巴爾二氏病毒、類單核球增多症症候群、玫瑰熱、水痘帶狀皰疹病毒、帶狀皰疹、單純皰疹病毒、或肝炎。
咸相信本發明的方法可特別地有效於治療具有寄生蟲感染之受藥者。因此,在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對來自以下者之感染的治療:瘧原蟲屬(Plasmodium)(例如,惡性瘧原蟲(Plasmodia falciparum)、間日瘧原蟲(Plasmodia vivax)、卵形瘧原蟲(Plasmodia ovale)、與三日瘧原蟲(Plasmodia malariae),典型地藉由瘧蚊傳播);利什曼原蟲屬(Leishmania)(藉由糠蚊傳播以及由例如以下者之必要的細胞內原生生物造成:杜氏利什曼原蟲(Leishmania donovani)、嬰兒利什曼原蟲(Leishmania infantum)、夏科氏利什曼原蟲(Leishmania chagasi)、墨西哥利什曼原蟲(Leishmania mexicana)、亞馬遜利什曼原蟲(Leishmania amazonensis)、委內瑞拉利什曼原蟲(Leishmania venezuelensis)、熱帶利什曼原蟲(Leishmania tropica);碩大利什曼原蟲(Leishmania major);依索匹亞利什曼原蟲(Leishmania aethiopica);以及亞屬Viannia,巴西利什曼原蟲(Leishmania Viannia braziliensis)、主亞那利什曼原蟲(Leishmania Viannia guyanensis)、巴拿馬利什曼原蟲(Leishmania Viannia panamensis)、以及秘魯利什曼原蟲(Leishmania Viannia peruviana));椎蟲屬(Trypanosoma)(例如,由布氏岡比亞錐蟲(Trypanosoma brucei gambiense)、與布氏羅得西亞錐蟲(Trypanosoma brucei rhodesiense)所造成的昏睡病);耐格里變形蟲屬(Naegleria)或棘變形蟲屬(Acanthamoeba)之屬的變形蟲屬;內變形蟲(Entamoeba)(溶組織內變形蟲與迪帕司內變形蟲)之屬的病源體;梨形鞭毛蟲(Giardia lamblia);隱胞子蟲屬(Cryptosporidium);等孢球蟲屬(Isospora);環孢子蟲屬(cyclospora);微孢子蟲(Microsporidia);蛔蟲(Ascaris lumbricoides);具有住血吸蟲屬(Schistosoma)(例如,埃及住血吸蟲(S.haematobium);曼森氏住血吸蟲(S.mansoni);日本住血吸蟲(S.japonicum);湄公住血吸蟲(S.mekongi);間插住血吸蟲(S.intercalatum))之血液吸蟲的感染;弓蟲病(例如,弓蟲(Toxoplasma gondii));梅毒螺旋體;陰道鞭毛滴蟲;或類似者。
在一些具體態樣中,具有NK細胞-反應性疾病之受藥者可具有由選自以下者之原生生物所造成的感染:弓蟲、布氏岡比亞錐蟲、布氏羅得西亞錐蟲、杜氏利什曼原蟲、嬰兒利什曼原蟲、夏科氏利什曼原蟲、墨西哥利什曼原蟲、亞馬遜利什曼原蟲、委內瑞拉利什曼原蟲、熱帶利什曼原蟲;碩大利什曼原蟲;依索匹亞利什曼原蟲;以及亞屬Viannia,巴西利什曼原蟲、圭亞那利什曼原蟲、巴拿馬利什曼原蟲、秘魯利什曼原蟲、惡性瘧原蟲、間日瘧原蟲、卵形瘧原蟲、與三日瘧原蟲。
在上一個世紀,發展出導致在死亡率之明顯減少的許多抗生素。不幸的,廣泛使用抗生素已導致抗生素抗性細菌之產生,例如二甲氧苯青黴素抗性金黃色葡萄球菌(MRSA)、萬古黴素抗性腸球菌(VRE)、與青黴素-抗性肺炎鏈球菌(PRSP)。一些細菌對某一範圍的抗生素有抗性,例如對isoniazid、雷發平(rifampin)、乙胺丁醇(ethambutol)、鏈黴素、乙硫異菸胺(ethionamide)、康黴素、與利福布丁(rifabutin)有抗性的結核分枝桿菌品系。除了抗性之外,全球旅行已將相對未知的細菌自隔離的區域散佈至新族群。此外,有這些細菌被用作生物武器之威脅。此等細菌可能無法輕易地使用現存的抗生素治療。
咸相信本發明之化合物可特別有效的於為受藥者治療藥物-抗性病源體(例如藥物抗性細菌)、或對其無藥物可用之病源體(例如許多病毒)。無意受限於理論,咸相信因為本發明之化合物可藉由增加NK細胞活性發生作用,且因此NK細胞可殺死感染性微生物或受感染的細胞(除了化合物對病源體或受感染的細胞之任何直接作用之外)。因此,咸相信本發明之化合物可具有至少一種與典型的抗感染性藥物(例如典型地可直接對細菌本身發生作用的抗生素)有區別的作用模式。
藥物抗性病源體可對至少一種以及典型地為多種劑有抗性,例如藥物抗性細菌可對一種例如以下者之抗生素、或典型地為至少兩種例如以下者之抗生素有抗性:青黴素、二甲氧苯青黴素、第二代頭孢菌素(例如,頭孢呋新(cefuroxime)、以及類似者)、巨環內酯、四環素、甲氧苄啶/甲唑(trimethoprim/methoxazole)、萬古黴素、或類似者。例如,在一些具體態樣中,可為受藥者治療選自以下品系之細菌:多重抗藥性肺炎鏈球菌(MDRSP,之前稱為青黴素抗性肺炎鏈球菌,PRSP)、萬古黴素抗性腸球菌、二甲氧苯青黴素抗性金黃色葡萄球菌、青黴素抗性肺炎雙球菌屬(Pneumococcus)、抗生素抗性沙門氏桿菌屬、抗性與多重抗性淋病雙球菌(例如,對四環素、青黴素、氟喹啉酮、頭孢菌素、頭孢曲松(ceftriaxone)(Rocephin)、頭孢克肟(Cefixime)(Suprax)、阿齊黴素(Azithromycin)、或類似者之一種、兩種、或多種有抗性)、以及抗性與多重-抗性結核病(例如,異菸肼(isoniazid)、雷發平、乙胺丁醇、吡甲醯胺、胺基醣苷、捲曲黴素(Capreomycin)、環丙沙星(Ciprofloxacin)、氧氟沙星(Ofloxacin)、吉米沙星(gemifloxacin)、環絲胺酸、乙硫異菸胺、對-胺基柳酸或類似者之一種、兩種、或多種有抗性)。
在一些具體態樣中,NK細胞活性可在具有免疫不全之受藥者中被增加。在各種具體態樣中,此可導源於減少的或有缺陷的NK細胞活性。在一些具體態樣中,免疫不全可係任何已知的免疫不全,即使是該等不直接對NK細胞產生衝擊者。無意受限於理論,咸相信促升NK細胞活性可在許多免疫不全病症中提高免疫功能以「補足(make-up)」至少部分免疫不全之方面,除了該等直接涉及NK細胞活性的方面之外。
在各種具體態樣中,免疫不全疾病可包括具有增加的對感染之敏感性之疾病,例如一個或多個選自以下者之疾病:循環性與全身性疾病(鐮形血球貧血症、糖尿病、腎病、靜脈曲張、先天性心臟缺陷);阻塞性疾病(輸尿管或尿道狹窄、支氣管性氣喘、支氣管擴張症、過敏性鼻炎、阻塞的耳咽管);皮的缺陷(濕疹、燒傷、頭顱骨折、中線竇束(midline sinus tracts)、纖毛異常);原發性免疫缺陷(X-關聯性低迦瑪球蛋白血症(agammaglobinemia)、DiGeorge異常(DiGeorge anomaly)、慢性肉芽腫性疾病、C3缺陷);次發性免疫缺陷(營養失調、早熟、淋巴瘤、脾切除術、尿毒症、免疫抑制治療、蛋白質-喪失性腸病變、慢性病毒性疾病);非平常微生物性因子(抗生素過度生長、具有抗性生物體之慢性感染、連續再感染(污染的水供給、感染性接觸、污染的吸入治療設備));外來物體、創傷(腦室分流(ventricular shunt)、中央靜脈導管、人工心臟辦膜、導尿管、吸出的外來物體)同種異體移植、移植-對抗-宿主疾病、子宮功能異常(例如,子宮內膜異位)、或類似者。
在各種具體態樣中,免疫不全疾病可包括(例如)嬰兒期之暫時性低迦瑪球蛋白血症、選擇性IgA缺陷、X-關聯性低迦瑪球蛋白血症(Bruton氏低迦瑪球蛋白血症;先天性低迦瑪球蛋白血症)、常見變異性免疫不全(common variable immunodeficiency)(後天低迦瑪球蛋白血症)、高-IgM(hyper-IgM)免疫不全、IgG次類型缺陷、慢性黏膜皮膚念珠菌病(Candidiasis)、結合性免疫不全、Wiskott-Aldrich症候群、共濟失調-毛細管擴張症、X-關聯性淋巴增生性症候群、高-IgE(hyper-IgE)症候群(Job-Buckley症候群)、慢性肉芽腫性疾病、白血球黏著缺陷(MAC-1/LFA-1/CR3缺陷)、或類似者。
在各種具體態樣中,免疫不全疾病可包括原發性免疫不全疾病,例如:B-細胞(抗體)缺陷(X-關聯性低迦瑪球蛋白血症;具有高-IgM之Ig缺陷(XL);IgA缺陷);IgG次類型缺陷、具有正常或提高的Ig之抗體缺陷、具有胸腺瘤之免疫不全、常見變異性免疫不全、嬰兒期之暫時性低迦瑪球蛋白血症);T-細胞(細胞性)缺陷(顯著性T-細胞缺陷:DiGeorge異常、慢性黏膜皮膚念珠菌病、具有Ig之結合性免疫不全(Nezelof症候群)、核苷磷醯酶缺陷(AR)、自然殺手細胞缺陷、特發性CD4淋巴球減少症、結合性T-與B-細胞結合:嚴重複合性免疫不全(AR或XL)、腺嘌呤核苷脫胺酶缺陷(AR)、網狀細胞發育不全(Reticular dysgenesis)、赤裸淋巴細胞症候群(bare lymphocyte syndrome)、共濟失調-毛細管擴張症(AR)、Wiskott-Aldrich症候群(XL)、短肢侏儒症、XL淋巴增生性症候群);吞噬細胞性疾病(細胞運動之缺陷:高免疫球蛋白血症E症候群、第1型白血球黏著缺陷(AR)、殺微生物活性之缺陷:慢性肉芽腫性疾病(XL或AR)、嗜中性細胞G6PD缺陷、髓過氧化物酶缺陷(AR)、謝迪亞克-東二氏症候群(Chediak-Higashi syndrome)(AR));補體疾病(補體構成要素之缺陷:C1q缺陷、控制蛋白之缺陷:C1抑制子缺陷(D1)、因子I(C3b失活子)缺陷(ACD)、因子H缺陷(ACD)、因子D缺陷(ACD)、備解素(Properdin)缺陷(XL));或類似者。
在各種具體態樣中,免疫不全疾病可包括次發性免疫不全疾病,例如一種或多種選自以下者之病症:早產與新生嬰兒(導因於免疫系統之不成熟的生理的免疫不全);遺傳性與代謝性疾病(染色體異常(例如,Down症候群)、尿毒症、糖尿病(即,來自糖尿病之併發症,例如與周圍循環以及神經功能異常相關的壞疽)、營養失調、維生素與礦物質缺乏、蛋白質-喪失性腸病變、腎病性症候群、肌緊張性榮養障礙、鐮形血球貧血症);免疫抑制劑(輻射、免疫抑制藥物、皮質類固醇、抗淋巴細胞或抗胸腺細胞球蛋白、抗T-細胞單株抗體);感染性疾病(先天性風診、病毒性紅斑(exanthema)(例如,麻疹、水痘)、HIV感染、細胞巨大病毒感染、感染性單核球增多症、急性細菌的疾病、嚴重分枝細菌的或真菌的疾病);滲透性與血液學疾病(組織球增多、類肉瘤病、Hodgkin氏病與淋巴瘤、白血病、骨髓瘤、顆粒性球缺乏症、與再生不全性貧血);手術與創傷(燒傷、脾切除術、麻醉、傷口);以及其他者(SLE、慢性活性肝炎、酒精性硬化、老化、抗驚厥藥物、移植-對抗-宿主疾病);或類似者。
在某些具體態樣中,具有NK細胞-反應性疾病之受藥者可需要針對燒傷或傷口之治療。典型地,如此傷口或燒傷係對受藥者之免疫防禦造成明顯的負擔之嚴重傷害。例如,在一些具體態樣中,係為受藥者治療覆蓋受藥者身體之表面積至少大約5%、10%、15%、20%、25%、30%、40%、50%、75%、或更多的二級或三級燒傷。此外,在一些具體態樣中,係為受藥者治療一個或多個傷口或傷口,例如至少大約1 cm2
、2 cm2
、5 cm2
、10 cm2
、20 cm2
、50 cm2
或更大,或受藥者身體之表面積的1%、2%、3%、4%、5%、10%、15%、或更多之開放傷口;或一個或多個穿透皮膚總長度至少1 cm、2 cm、3 cm、4 cm、5 cm、7 cm、10 cm、20 cm、25 cm、50 cm之切口;截肢;以及類似者。
在各種具體態樣中,具有NK細胞-反應性疾病之受藥者可具有由抗生素抗性細菌所造成之感染。在一些具體態樣中,受藥者可具有由選自以下者之細菌所造成之感染:多重抗藥性肺炎鏈球菌、萬古黴素抗性腸球菌、二甲氧苯青黴素抗性金黃色葡萄球菌、青黴素抗性肺炎雙球菌屬、抗生素抗性沙門氏桿菌屬、抗性/多重-抗性淋病雙球菌、與抗性/多重-抗性結核病。在一些具體態樣中,受藥者可具有對至少一種選自以下者之抗生素有抗性的細菌性感染:青黴素、二甲氧苯青黴素、第二代頭孢菌素、巨環內酯、四環素、甲氧苄啶/甲唑、萬古黴素、四環素、氟喹啉酮、頭孢曲松、頭孢克肟、阿齊黴素、異菸肼、雷發平、乙胺丁醇、吡甲醯胺、胺基醣苷、捲曲黴素、環丙沙星、氧氟沙星、吉米沙星、環絲胺酸、乙硫異菸胺、以及對-胺基柳酸。
因此,各種具體態樣,具有NK細胞反應性疾病之受藥者可具有免疫不全疾病。在一些具體態樣中,受藥者可具有原發性免疫不全疾病。在一些具體態樣中,受藥者可具有次發性免疫不全疾病。
在一些具體態樣中,免疫不全疾病可包括尿毒症、糖尿病(其感染性併發症、營養失調、維生素與礦物質缺乏、蛋白質喪失性腸病變、腎病性症候群、肌緊張性榮養障礙、鐮形血球貧血症;或類似者。
在一些具體態樣中,免疫不全疾病可全部或部分由免疫抑制劑(例如輻射、免疫抑制藥物、皮質類固醇、抗淋巴細胞或抗胸腺細胞球蛋白、抗T-細胞單株抗體;或類似者)造成。
在一些具體態樣中,免疫不全疾病可全部或部分由手術與創傷(例如燒傷、脾切除術、麻醉、傷口、所移植的醫學裝置;或類似者)造成。
在一些具體態樣中,免疫不全疾病可包括慢性疲勞症候群(慢性疲勞免疫功能異常症候群);Epstein-Barr病毒感染、病毒感染後疲勞症候群、移植後症候群(宿主-移植物疾病)、暴露至一氧化氮合酶抑制劑、老化、嚴重複合性免疫不全、變異性免疫不全症候群、以及類似者。
增加NK細胞活性亦會對治療具有包括但不限於神經退化性疾病之疾病的受藥者為有益的。用於本文,神經退化性疾病包括神經元(例如小腦的、脊髓、與周圍的神經元(例如,位於神經肌肉性接合點))的降解,更典型地為大腦的與脊髓神經元之降解。神經退化性疾病可包括阿茲海默症;杭丁頓舞蹈症;巴金森氏病;脊髓/延髓肌肉萎縮(例如,甘迺迪氏病)、脊髓性小腦萎縮症、與其他神經肌肉性萎縮;家族性肌萎縮性偏側硬化症;局部缺血;發作;體溫過低;體溫過高;燒傷;動脈粥樣硬化;輻射暴露;青光眼;毒素暴露;機械性傷害;發炎;癲癇性發作、傷害-誘導性發作、化學地-誘導性發作、或其他與超氧化物歧化酶(SOD)突變相關的疾病;以及類似者。神經退化性疾病亦可包括由局部缺血、發作、熱壓力、輻射、毒素暴露、感染、傷害、以及類似者所造成之神經元之降解。局部缺血可透過多重途徑(包括氧耗盡、葡萄糖耗盡、再灌注時的氧化性壓力、及/或麩胺酸毒性、以及類似者)損害組織。局部缺血可源自內源性病症(例如,中風、心臟病發作、以及類似者)、源自意外性機械性傷害、源自手術的傷害(例如,移植器官上的再灌注壓力)、以及類似者。可選擇地,可被局部缺血損害的組織包括神經元、心肌、肝臟組織、骨骼肌、腎臟組織、肺的組織、胰臟的組織、以及類似者。
其他其中增加NK細胞活性會係有益的疾病包括由於以下者之疾病:熱壓力(熱壓力包括體溫過高(例如,來自發燒、中暑、燒傷、以及類似者)與體溫過低);輻射損害,例如由於可見光、紫外光、微波、宇宙射線、阿伐輻射、貝他輻射、迦馬輻射、X-射線、以及類似者者(例如,損害可係對藉由輻射治療治療癌症之受藥者中的非-癌性組織之輻射損害);機械性傷害,例如來自手術、意外、某些疾病病症(例如,青光眼中之壓力損害)、以及類似者的創傷;與暴露至毒素,例如暴露至選自甲基安非他命之神經毒素;抗反轉錄病毒的HIV療法(例如,核苷反轉錄酶抑制劑;重金屬(例如,汞、鉛、砷、鎘、其化合物、以及類似者)、胺基酸類似物、化學氧化劑、乙醇、麩胺酸、代謝性抑制劑、抗生素、以及類似者。
本發明之另一個具體態樣係一種治療具有癌症之受藥者之方法。視需要地,本發明的方法可用於多重藥物抗性癌症,如以下所敘述。該方法包括投藥有效量的式(I)至(XVI)或表1之化合物、或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥的步驟。較佳地,一個或多個額外的抗癌藥物係與本發明之化合物共-投藥。抗癌藥物之實例係於以下敘述。較佳地,所共-投藥之抗癌藥物係會穩定化微管的劑,例如汰癌勝或紫衫烷衍生物。
如以上所指明,本發明的一個具體態樣係關於治療具有癌症的受藥者。「治療具有癌症之受藥者」包括(部分地或實質上地)達到一個或多個以下者:制止癌症之生長或散佈、降低癌症的程度(例如,降低腫瘤的大小或降低受影響位置之數目)、抑制癌症之生長率、與改善或改善臨床上與癌症相關的徵候或指標(例如組織或血清構成要素)。
在另一個具體態樣中,本發明之化合物可作為輔助治療投藥以預防癌症之復發。例如,第II期與第III期黑色素瘤典型地係以手術治療以移出黑色素瘤,接著化療的治療以預防癌症的復發。在一個具體態樣中,一個或多個額外的抗癌藥物係與本發明之化合物共-投藥作為輔助治療。抗癌藥物之實例係於以下敘述。在一個具體態樣中,所共-投藥的抗癌藥物係會穩定化微管之劑,例如汰癌勝或紫衫烷衍生物。在另一個具體態樣中,所共-投藥的抗癌藥物係免疫治療性抗癌劑。
可藉由本發明之方法治療或預防的癌症包括,但不限於人類肉瘤與癌,例如纖維肉瘤、黏液肉瘤、脂肪肉瘤、軟骨肉瘤、成骨性肉瘤、脊索瘤、血管肉瘤、內皮肉瘤、淋巴管肉瘤、淋巴管內皮肉瘤、滑膜瘤、間皮瘤、Ewing氏腫瘤、平滑肌肉瘤、橫紋肌肉瘤、直腸癌、直腸結腸癌、肛門癌、食道癌、胃癌(gastric cancer)、肝細胞癌、膀胱癌、子宮內膜癌、胰臟癌、乳癌、卵巢癌、前列腺癌、胃癌(stomach cancer)、心房黏液瘤、鱗狀細胞癌瘤、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、甲狀腺與副甲狀腺新生物(neoplasm)、乳頭狀癌、乳頭狀腺癌、囊腺癌、髓質癌、氣管原癌、腎臟細胞癌、肝細胞癌、膽管癌、絨毛膜癌、精原細胞瘤、胎性癌、Wilms氏瘤、子宮頸癌、睪丸的腫瘤、肺癌、小細胞肺癌、非小細胞肺癌、膀胱癌、上皮癌、神經膠瘤、腦垂體新生物、星形細胞瘤、神經管胚細胞瘤、顱咽管瘤、室管膜瘤、松果體瘤、血管母細胞瘤、聽神經瘤、神經鞘瘤、寡樹突膠質瘤、腦膜瘤、脊髓瘤、黑色素瘤、神經胚細胞瘤、嗜鉻細胞瘤、1-3型內分泌腺新生物形成、視網膜母細胞瘤;白血病,例如,急性淋巴細胞白血病與急性骨髓性白血病(骨髓胚細胞性、前骨髓細胞性、骨髓單核細胞性、單核細胞性、紅白血病);慢性白血病(慢性骨髓細胞性(顆粒細胞性)白血病與慢性淋巴細胞白血病);以及真性紅血球增多症、淋巴瘤(Hodgkin氏病與非Hodgkin氏病)、多發性骨髓瘤、Waldenstrobm氏巨球蛋白血症、以及重鏈病。
白血病之其他實例包括急性及/或慢性白血病,例如,淋巴細胞白血病(例如,如p388(鼠類)細胞系所例示者)、大顆粒淋巴細胞白血病、與淋巴胚細胞白血病;T-細胞白血病,例如,T-細胞白血病(例如,如CEM、Jurkat、與HSB-2(急性)、YAC-1(鼠類)細胞系所例示者)、T-淋巴細胞白血病、與T-淋巴胚細胞白血病;B細胞白血病(例如,如SB(急性)細胞系所例示者)、與B-淋巴細胞白血病;混合細胞白血病,例如,B與T細胞白血病以及B與T淋巴細胞白血病;骨髓性白血病,例如,顆粒細胞白血病、骨髓細胞白血病(例如,如HL-60(原骨髓細胞)細胞系所例示者)、與骨髓母細胞白血病(例如,如K562(慢性)細胞系所例示者);嗜中性白血球白血病;嗜曙紅白血球白血病;單核細胞白血病(例如,如THP-1(急性)細胞系所例示者);骨髓單核細胞白血病;Naegeli型形骨髓白血病;與非淋巴細胞白血病。其他白血病的實例係敘述於The Chemotherapy Sourcebook,Michael C.Perry Ed.,Williams & Williams(1992)第60章與Holland Frie Cancer Medicine第5版,Bast等人Eds.,B.C.Decker Inc.(2000)第36節。前述引證文獻之完整教示係以引用方式納入本文中。
可藉由本發明之方法治療或預防之額外的癌症包括,但不限於口腔與咽頭癌症,包括舌、口、咽頭、與其他口腔癌症;消化系統癌症,包括食管、小腸、直腸、肛門、肛門道、肛門直腸、肝臟與肝內膽管、膽囊與其他膽相關的、胰臟與其他消化器官;呼吸系統癌症,包括喉與支氣管;骨與關節癌症;軟組織(包括心臟)癌症;生殖系統癌症,包括子宮頸、子宮體、卵巢、陰戶、陰道與其他生殖器官相關的,雌性、睪丸、陰莖與其他其他生殖器官相關的,雄性;泌尿系統癌症,包括腎臟與腎盂、以及輸尿管與其他泌尿器官;眼與眼球癌症;白血病,包括急性骨髓性白血病與慢性骨髓性白血病。
在一個具體態樣中,所揭示的方法被認為係特別有效於治療具有非固體腫瘤(例如多發性骨髓瘤)之受藥者。在另一個具體態樣中,所揭示的方法被認為對T-白血病(例如,由Jurkat與CEM細胞系所例示者)、B-白血病(例如,由SB細胞系所例示者)、前骨髓細胞(promyelocyte,例如,由HL-60細胞系所例示者)、子宮肉瘤(例如,由MES-SA細胞系所例示者)、單核細胞性白血病(例如,由THP-1(急性)細胞系所例示者)、以及淋巴瘤(例如,由U937細胞系所例示者)係尤其有效。
在另一個具體態樣中,所揭示之方法被認為係特別有效於治療具有免疫敏感性癌症之受藥者。免疫敏感性癌症係對使用免疫治療之治療有反應的癌症。免疫治療係於以下更詳細敘述。對免疫治療有反應的癌症包括腎臟細胞癌、黑色素瘤(包括表面散佈性黑色素瘤、結節狀黑色素瘤、肢端痣樣黑色素瘤(acral lentiginous melanoma)、雀斑惡性黑色素瘤(lentigo maligna melanoma),其亦稱為Hutchinson氏斑點)、多發性骨髓瘤、骨髓瘤、淋巴瘤、非-小-細胞肺癌、鱗狀上皮細胞瘤、基底細胞癌、纖維肉瘤、與惡性腦腫瘤。
在另一個具體態樣中,所揭示之方法被認為係特別有效於治療具有黑色素瘤之受藥者。
在另一個具體態樣中,所揭示之方法被認為係特別有效於治療具有腎臟細胞癌之受藥者。
所揭示的方法係特別有效於治療其癌症已變成「多重抗藥性」之受藥者。當一種抗癌藥物不再有效於治療具有癌症的受藥者時,最初對該抗癌藥物會反應的該癌症變成對該抗癌藥物有抗性。例如,許多腫瘤起初會以使尺寸減小或甚至變成解緩之方式對使用抗癌藥物之治療反應,以發展出對該藥物之抗性。藥物抗性腫瘤之特徵為在已似乎轉為解緩後又再恢復其等之生長及/或再出現,即使投藥增加劑量之該抗癌症藥物亦如此。已發展出對二種或多種抗癌藥物之抗性的癌症稱為「多重抗藥性的」。例如,轉變成對三種或多種抗癌劑有抗性係對癌症而言係常見的,其往往係對五種或更多種抗癌症劑具有抗性,且有時對十種或更多種抗癌症劑具有抗性。
為數眾多的非-癌症疾病包括過剩的或過度增生性細胞生長,稱為過度增生。用於本文,術語「增生性疾病」、「過度增生性疾病」、與「細胞增生疾病」係可互換使用以意指包括細胞之病理學生長的疾病或醫學病症。如此疾病包括癌症。
非-癌性增生性疾病包括平滑肌細胞增生、全身性硬化症、肝臟之硬化、成年呼吸窘迫症候群、特發性心肌病、紅斑性狼瘡、視網膜病,例如糖尿病性視網膜病或其他視網膜病變、心臟過度增生、生殖系統相關性疾病,例如良性前列腺過度增生與卵巢囊腫、肺纖維化、子宮內膜異位、纖維瘤病、迷離瘤、淋巴管瘤病、類肉瘤病、硬纖維瘤、以及類似者。
平滑肌細胞增生包括增生性血管性疾病,例如,內膜平滑肌細胞增生、再狹窄、與血管閉塞,特別係跟隨生物性或物理性介導之血管損傷之後的狹窄,例如,與血管修復術相關的血管損傷或血管狹窄。此外,內膜平滑肌細胞增生可包括在血管系之外的平滑肌之增生,例如,在膽管封閉、在有氣喘的患者之肺的支氣管空氣道、在具有腎間質纖維化之患者的腎、以及類似者之增生。
非-癌性增生性疾病亦包括於皮膚之細胞過度增生,例如牛皮癬與其各種臨床的形式、Reiter氏症候群、毛囊性紅色糠疹、與角質化疾病之過度增生性變體(例如,光化性角化症、老年角化症)、硬皮病(scleroderma)、以及類似者。
其他抗增生性或抗癌治療可與本發明的化合物結合,以治療增生性疾病與癌症。可與本發明之發明性抗癌劑結合使用之其他治療或抗癌劑包括手術、放射線治療(包括,但不限於,迦瑪-輻射、中子束放射線治療、電子束放射線治療、質子治療、接近治療、與全身性放射活性同位素)、內分泌治療、生物反應修改子(包括,但不限於,干擾素、介白素、與腫瘤壞死因子(TNF))、高溫處理(hyperthermia)、與冷凍治療、減弱任何有害效果之劑(例如,止吐劑)、與其他許可的化療藥物。
本發明的結合治療之預防性或治療性劑可依序地或同時地投藥。
用於本文,術語「高溫處理」、「高溫處理治療」、「熱治療(thermal therapy)」、與「熱治療(thermotherapy)」係可互換地使用,以意指其中身體組織被暴露至高溫(至多至113℉)的治療。用於本文,該術語包括所有形式的高溫處理,包括局部的、部位的(regional)、與全身的。各種形式的能量可用於遞送熱至所欲的區域,例如微波、輻射頻率、雷射、與超音波。治療溫度係根據腫瘤的位置與所使用的途徑改變。
於局部的高溫處理,熱被施用至小區域(例如腫瘤)。用於局部高溫處理的方法依腫瘤位置而改變。外部的途徑係用於治療在皮膚中或緊接於皮膚之下的腫瘤。在此方法中,塗藥器係靠近腫瘤放置或置於腫瘤附近,並直接遞送能量至腫瘤。腔內或體腔內途徑使用探針以遞送能量至體腔中或靠近體腔的腫瘤。間質性途徑係用於治療深深位於體內之腫瘤(例如腦腫瘤),其係藉由在麻醉下將探針或針插入至腫瘤。
於部位的高溫處理,熱係施加至大區域的組織(例如體腔、器官、或肢體)。深部組織途徑係用以治療體內的癌症(例如頸部或膀胱癌),其藉由使用外部的塗藥器。部位的灌注途徑係用以治療肢體或器官中的癌症(例如黑色素瘤、肝臟、或肺癌)。於此途徑中,一些血液被移出並加熱,並接著泵回肢體或器官。抗癌藥物可在此過程中給藥。連續高溫處理腹膜灌注(CHPP Continuous hyperthermic peritoneal perfusion)係用以治療在腹腔中的癌症(例如腹膜的中皮瘤或胃癌)。於此途徑中,經加熱的抗癌藥物係通過腹腔抽吸。
全身高溫處理係用於治療轉移性癌症。於此途徑中,全身係藉由使用各種技術(例如熱室(heat chamber)或熱水毯)加熱至107-108℉。
高溫處理條件已知會誘發Hsp70的合成。
「有效量」係其中當化合物被投藥至受藥者時會達到有益的臨床結果之化合物的量。例如,當本發明之化合物被投藥至具有癌症之受藥者時,「有益的臨床結果」包括於受藥者(相較於缺乏該治療)在腫瘤質量的減少、在轉移的減少、在與癌症相關的徵候之嚴重性的減少、及/或在壽命之增加。當本發明之化合物被投藥至具有Hsp70-反應性疾病或NK細胞-反應性疾病之受藥者時,「有益的臨床結果」包括於受藥者(相較於缺乏該治療)在與疾病相關的徵候的嚴重性或數目之減少、感染之排除、或壽命之增加。投藥至受藥者的化合物之精確的量,會根據疾病或病症的類型與嚴重性,以及根據受藥者之特徵,例如一般健康、年齡、性別、體重、與對藥物之忍耐性。其亦可根據癌症之程度、嚴重性、與類型。熟悉該項技術者會能夠依據此等以及其他因子決定適當劑量。所揭示之化合物的有效量典型地落入介於大約1 mg/mm2
每日與大約10克/mm2
每日的範圍,且較佳地介於10 mg/mm2
每日與大約5克/mm2
。當與另一個抗癌劑共-投藥以治療癌症時,第二抗癌劑之「有效量」會根據所使用的藥物之類型而定。已核准的抗癌劑之適合的劑量係已知的,且可由熟悉該項技術者根據受藥者的病症、欲治療之癌症的類型、與所使用之本發明之化合物而調整。
本發明之另一個具體態樣係醫藥組成物,其包括本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)與藥學上可接受的載劑或稀釋劑。
適合的藥學上可接受的載劑可包含不會過度地抑制化合物之生物活性的惰性成分。藥學上可接受的載劑應係生物可相容的,即,非毒性的、非發炎性的、非致免疫性的,並且投藥至受藥者時沒有其他不欲的反應。可運用標準的醫藥調配技術,例如彼等於Remington's Pharmaceutical Sciences,Mack Publishing Company,Easton,PA所述者。用於非經腸投藥之適合的醫藥載劑包括(例如)無菌水、生理食鹽水、抑菌食鹽水(包含大約0.9% mg/ml苄基醇的食鹽水)、磷酸鹽緩衝食鹽水、Hank氏溶液、Ringer氏乳酸鹽、以及類似者。用於將組成物封入膠囊中(例如於硬明膠或環葡聚糖之塗層中)之方法在技術領域中係已知的(Baker等人,"Controlled Release of Biological Active Agents",John Wiley and Sons,1986)。
本發明之化合物可藉由任何適合的途徑投藥,其包括(例如)於膠囊、懸浮液、或錠劑口服、或藉由非經腸投藥。非經腸投藥可包括(例如)全身性投藥,例如藉由肌肉內、靜脈內的、皮下的、或腹膜內的注射。本發明之化合物亦可口服地(例如,飲食地)、局部地、藉由吸入(例如,支氣管內、鼻內、口部吸入或鼻內滴劑)、或直腸地投藥,其依據欲治療之癌症的類型。口部與非經腸投藥係較佳的投藥模式。
目前有許多新藥物可為腫瘤學者所用以用於治療具有癌症之患者。往往,當抗癌藥物係組合投藥時,腫瘤較當相同的藥物係個別並依序投藥時對治療更有反應。此方法的一個優點係抗癌劑往往為協同地作用,因為腫瘤細胞係同時以具有多種模式之多種劑作用。因此,藉由組合投藥此等藥物往往可能更快速達到於腫瘤尺寸之減少。另一個結合化療之優點係腫瘤更可能被完全根除且更不可能發展出對用於治療患者的抗癌藥物之抗性。
視需要地,本發明之化合物(或其互變異構物、藥學上可接受的鹽、溶劑合物、晶籠化合物、或前藥)可與例如以下者之其他抗癌劑共-投藥以治療具有增生性疾病(例如癌症)之患者,或以預防增生性疾病(例如癌症)之復發:阿德力黴素(Adriamycin)、更生黴素(Dactinomycin)、博萊黴素(Bleomycin)、長春花鹼、順氯氨鉑、阿西维辛(acivicin);阿克拉黴素A(aclarubicin);鹽酸阿考達唑(acodazole hydrochloride);阿克羅寧(acronine);阿多來新(adozelesin);阿地介白素(aldesleukin);六甲蜜胺;安波黴素(ambomycin);醋酸阿美蒽醌(ametantrone acetate);氨魯米特(aminoglutethimide);安吖啶(amsacrine);阿那曲唑(anastrozole);氨茴黴素(anthramycin);天冬醯胺酶;曲林菌素(asperlin);阿扎胞苷(azacitidine);阿札替哌(azetepa);阿佐黴素(azotomycin);巴梯馬斯塔特(batimastat);苯佐替派(benzodepa);比卡魯米(bicalutamide);鹽酸比生群(bisantrene hydrochloride);二甲磺酸雙奈法德(bisnafide dimesylate);比折來新(bizelesin);硫酸博萊黴素;布喹那鈉(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放線菌素C(cactinomycin);卡魯睪酮(calusterone);卡醋胺(caracemide);卡貝替姆(carbetimer);卡鉑;卡莫司汀(carmustine);鹽酸洋紅黴素I(carubicin hydrochloride);卡折來新(carzelesin);西地芬戈(cedefingol);苯丁酸氮芥(chlorambucil);西羅黴素(cirolemycin);克拉君寶;甲磺酸庫理斯聶陀(crisnatol mesylate);環磷醯胺;阿糖胞苷;甲嗪咪唑胺;鹽酸柔紅黴素;地西他濱(decitabine);右奧馬鉑(dexormaplatin);地紮鳥嘌呤(dezaguanine);甲磺酸地紮鳥嘌呤;地吖醌(diaziquone);阿黴素(doxorubicin);鹽酸阿黴素;屈洛昔芬(droloxifene);檸檬酸屈洛昔芬;丙酸屈他維酮(dromostanolone propionate);達佐黴素(duazomycin);依達曲沙(edatrexate);鹽酸依氟鳥胺酸(eflornithine hydrochloride);依沙蘆星(elsamitrucin);恩洛鉑(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);鹽酸表柔比星(epirubicin hydrochloride);厄布洛唑(Erbulozole);鹽酸依索比星(esorubicin hydrochloride);雌莫司汀(estramustine);雌莫司汀磷酸鈉;依他硝唑(etanidazole);依托泊苷;磷酸依托泊苷;依托派(etoprine);鹽酸法倔唑(fadrozole hydrochloride);法扎拉濱(fazarabine);芬維A胺(fenretinide);氟尿苷(floxuridine);磷酸氟達拉濱;氟尿嘧啶;氟西他濱(flurocitabine);磷喹酮(fosquidone);福司曲星鈉(fostriecin sodium);吉西他濱;鹽酸吉西他濱;羥基脲;鹽酸伊達比星(idarubicin hydrochloride);異環磷醯胺;伊莫福新(ilmofosine);介白素II(包括重組介白素II、或rIL2)、干擾素阿伐-2a;干擾素阿伐-2b;干擾素阿伐-n1;干擾素阿伐-n3;干擾素貝他-I a;干擾素加馬-I b;異丙鉑(iproplatin);鹽酸伊立替康(irinotecan hydrochloride);醋酸蘭瑞肽(lanreotide acetate);來托唑(letrozole);醋酸亮丙里德(leuprolide acetate);鹽酸利阿唑(liarozole hydrochloride);洛美曲索鈉(lometrexol sodium);洛莫司汀(lomusitne);鹽酸洛索蒽醌(losoxantrone hydrochloride);馬索羅酚(masoprocol);美登素(maytansine);鹽酸氮芥(mechlorethamine hydrochloride);醋酸甲地孕酮(megestrol acetate);醋酸美侖孕酮(melengestrol acetate);美法侖(melphalan);美諾立爾(menogaril);巰基嘌呤;甲氨蝶呤;甲氨蝶呤鈉;美托派(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡新(mitocarcin);米托克羅明(mitocromin);米托潔林(mitogillin);米托馬星(mitomalcin);絲裂黴素(mitomycin);米托司培(mitosper);米托坦(mitotane);鹽酸米托蒽醌(mitoxantrone hydrochloride);麥考酚酸(mycophenolic acid);諾考達唑(nocodazole);諾拉黴素(nogalamycin);奧馬鉑(ormaplatin);奧昔舒崙(oxisuran);陪門冬酶(pegaspargase);培利黴素(peliomycin);奈莫司汀(pentamustine);硫酸諾拉黴素(peplomycin sulfate);過磷醯胺;哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);鹽酸吡羅蒽醌(piroxantrone hydrochloride);光輝黴素(plicamycin);普洛美坦(plomestane);卟吩姆鈉(porfimer sodium);泊非黴素(porfiromycin);潑尼氮芥(prednimustine);鹽酸丙卡巴肼;嘌羅黴素(puromycin);鹽酸嘌羅黴素;吡唑呋喃菌素(pyrazofurin);利波腺苷(riboprine);羅谷亞胺(rogletimide);沙芬戈(safingol);鹽酸沙芬戈(safingol hydrochloride);司莫司汀(semustine);辛曲秦(simtrazene);斯帕福斯酸鈉(sparfosate sodium);司帕黴素(sparsomycin);鹽酸鍺螺銨(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺鉑(spiroplatin);絳色黴素(streptonigrin);鏈佐星(streptozocin);磺氯苯脲(sulofenur);他利黴素(talisomycin);鐵可加侖鈉(tecogalan sodium);替加氟(tegafur);鹽酸替洛蒽醌(teloxantrone Hydrochloride);替莫泊芬(temoporfin);替尼泊苷;替羅昔隆(teroxirone);睪內酯;硫咪嘌呤(thiamiprine);硫鳥嘌呤;塞替哌(thiotepa);噻唑呋林(tiazofurin);替拉扎明(tirapazamine);檸檬酸托瑞米芬(toremifene citrate);乙酸曲托龍(trestolone acetate);磷酸曲西立濱(triciribine phosphate);三甲曲沙(trimetrexate);葡萄糖醛酸三甲曲沙;曲普瑞林(triptorelin);鹽酸妥布氯唑(tubulozole Hydrochloride);尿嘧啶氮芥(uracil mustard);烏瑞替哌(uredepa);伐普肽(vapreotide);維替泊芬(verteporfin);硫酸長春花鹼;硫酸長春新鹼;長春地辛;硫酸長春地辛;硫酸長春匹定(vinepidine sulfate);硫酸長春甘酯(vinglycinate sulfate);硫酸長春羅新(vinleurosine sulfate);酒石酸長春瑞賓;硫酸長春羅定(vinrosidine sulfate);硫酸長春利定(vinzolidine sulfate);伏氯唑(vorozole);傑尼鉑(zeniplatin);淨司他丁(zinostatin);鹽酸佐柔比星(zorubicin hydrochloride)。
其他可與本發明之化合物結合使用以治療具有增生性疾病(例如癌症)之患者、或以預防增生性疾病(例如癌症)之復發的藥物,包括(但不限於);20-表-1,25二羥基維生素D3;5-乙炔基尿嘧啶;阿比特龍(abiraterone);阿克拉黴素A(aclarubicin);醯基富烯(acylfulvene);阿迪塞普諾(adecypenol);阿多來新(adozelesin);阿地介白素(aldesleukin);ALL-TK拮抗劑;六甲蜜胺;氨莫司汀(ambamustine);阿米達克斯(amidox);氨磷汀(amifostine);胺基乙醯丙酸(aminolevulinic acid);氨柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿那曲唑(anastrozole);穿心蓮內酯(andrographolide);血管生成抑制劑;拮抗劑D;拮抗劑G;安塔雷力克司(antarelix);抗-背側化形態發生蛋白-1;抗雄激素,前列腺癌;抗雌激素;抗腫瘤同酮(antineoplaston);反義寡核苷酸;甘胺酸阿非迪黴素酯(aphidicolin glycinate);細胞凋亡基因調節劑;細胞凋亡調控劑;脫嘌呤核酸;阿拉伯糖-CDP-DL-PTBA;精胺酸脫胺酶;阿蘇勒克藍(asulacrine);阿他美坦(atamestane);阿莫司汀(atrimustine);阿克辛那司他丁1(a1axinastatin 1);阿克辛那司他丁2;阿克辛那司他丁3;阿扎司瓊(azasetron);偶氮毒素(azatoxin);偶氮酪胺酸(azatyrosine);巴卡丁III(baccatin III)衍生物;巴拉諾(balanol);巴梯馬斯塔特(batimastat);BCR/ABL拮抗劑;苯並克羅林(beznochlorins);苯甲醯基星形孢菌素(benzoylstaurosporine);貝他內醯胺衍生物;貝他-愛樂辛(beta-alethine);貝他克連辛B(beta-clamycin B);樺酸;bFGF抑制劑;比卡魯米(bicalutamide);比生群(bisantrene);雙吖丙啶基精胺(bisaziridinylspermine);雙奈法德(bisnafide);比司垂亭A(bistratene A);比折來新(bizelesin);布雷夫雷(breflate);溴匹立明(bropirimine);布度鈦(budotitane);s-丁基高半胱胺酸亞碸亞胺(buthionine sulfoximine);鈣泊三醇(calcipotriol);卡佛司丁C(calphostin C);喜樹鹼衍生物;金絲雀痘IL-2(canarypox IL-2);卡培他濱(capecitabine);羧醯胺-胺基-三唑(carboxamide-amino-triazole);羧基醯胺基三唑(carboxyamidotriazole);CaRest M3;CARN 700;軟骨衍生性抑制劑;卡折來新(carzelesin);酪蛋白激酶抑制劑(ICOS);栗籽豆鹼;殺菌肽B(cecropin B);西曲瑞克(cetrorelix);克羅林(chlorlns);氯喹啉磺醯胺(chloroquinoxaline sulfonamide);西卡前列素(cicaprost);順-紫質(cis-porphyrin);克拉君寶(cladribine);氯米芬(clomifene)類似物;克黴唑(clotrimazole);寇立司黴素A(collismycin A);寇立司黴素B;坎雷司他丁A4(combretastatin A4);坎雷司他丁類似物;寇內吉寧(conagenin);坎比西丁816(crambescidin 816);庫理斯聶陀(crisnatol);隱藻素8(cryptophycin 8);隱藻素A衍生物;庫拉素A(curacin A);環戊蒽醌;環鉑(cycloplatam);賽普黴素(cypemycin);阿糖胞苷奧克磷酸鹽(cytarabine ocfosfate);細胞溶解因子;細胞司他丁(cytostatin);達昔單抗(dacliximab);地西他濱(decitabine);脫氫被囊肽B(dehydrodidemnin B);地洛瑞林(deslorelin);地塞米松(dexamethasone);右異環磷醯胺(dexifosfamide);右雷佐生(dexrazoxane);右維拉帕米(dexverapamil);地吖醌(diaziquone);被囊肽B(didemnin B);戴度克斯(didox);二乙基降精素(diethylnorspermine);二氫-5-氮胞嘧啶核苷;9-二黴素(9-dioxamycin);二苯基螺莫司汀(diphenylspiromustine);二十二烷醇;多拉司瓊(dolasetron);去氧氟尿苷;屈洛昔芬(droloxifene);屈大麻酚(dronabinol);道卡黴素(duocarmycin)SA;依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依決洛單抗(edrecolomab);依氟鳥胺酸(eflornithine);欖香烯(elemene);依米呋(emitefur);表柔比星(epirubicin);依普斯特(epristeride);雌莫司汀類似物;雌激素激動劑;雌激素拮抗劑;依他硝唑(etanidazole);磷酸依托泊苷(etoposide phosphate);依西美坦(exemestane);法倔唑(fadrozole);法扎拉濱(fazarabine);芬維A(fenretinide)胺;非格司亭(filgrastim);非那雄胺(finasteride);福拉佛匹利多(flavopiridol);福雷扎拉司丁(flezelastine);福拉司特龍(fluasterone);氟達拉濱(fludarabine);鹽酸氟柔紅黴素;福酚美克(forfenimex);福麥斯坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);德卟啉釓(gadolinium texaphyrin);硝酸鎵;加洛他濱(galocitabine);加尼瑞克(ganirelix);明膠酶抑制劑;吉西他濱(gemcitabine);谷胱甘肽抑制劑;赫普沙分(hepsulfam);賀雷辜林(heregulin);六亞甲基雙乙醯胺;金絲桃素(hypericin);依班膦酸(ibandronic acid);伊達比星(idarubicin);吲哚昔酚(idoxifene);伊決孟酮(idramantone);伊莫福新(ilmofosine);伊洛馬司他(ilomastat);咪唑并吖啶酮;咪喹莫(imiquimod);免疫刺激性肽;類胰島素生長因子-1受體抑制劑;干擾素激動劑;干擾素;介白素;碘苄胍(iobenguane);碘阿黴素(iododoxorubicin);甘藷醇(ipomeanol),4-;伊羅普拉(iroplact);伊索拉定(irsogladine);異本加唑(isobengazole);異類黑力寇丁B(isohomohalicondrin B);伊他司瓊(itasetron);加司普拉基諾里(jasplakinolide);卡哈拉里F(kahalalide F);三乙酸片螺素-N(lamellarin-N triacetate);蘭瑞肽(lanreotide);連那黴素(leinamycin);來格司亭(lenograstim);硫酸香菇多醣(lentinan sulfate);來托司他丁(leptolstatin);來托唑(letrozole);白血病抑制因子;白血球阿伐干擾素;亮丙里德(leuprolide)+雌激素+孕酮;亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑(liarozole);線性聚胺類似物;親脂性雙糖肽;親脂性鉑化合物;利所克里醯胺7(lissoclinamide 7);洛鉑(lobaplatin);蚯蚓氨酸(lombricine);洛美曲索(lometrexol);氯尼達明(lonidamine);洛索蒽醌(losoxantrone);洛伐他汀(lovastatin);洛索立賓(loxoribine);勒托替康(lurtotecan);德卟啉鎦(lutetium texaphyrin);來索菲林(lysofylline);溶解肽;美坦新(maitansine);甘露司他丁A(mannostatin A);馬利馬司他(marimastat);馬索羅酚(masoprocol);馬司平(maspin);基質裂解素(matrilysin)抑制劑;基質金屬蛋白酶抑制劑;美諾立爾(menogaril);麥爾巴隆(merbarone);米特瑞林(meterelin);甲硫胺酸酶;甲氧氯普胺(metoclopramide);MIF抑制劑;米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);錯配雙股RNA;米托胍腙(mitoguazone);二溴衛茅醇(mitolactol);絲裂黴素類似物;米托奈法德(mitonafide);米托毒素(mitotoxin)成纖維細胞生長因子-皂草素;米托蒽醌(mitoxantrone);莫法羅汀(mofarotene);莫拉司亭(molgramostim);單株抗體,人類絨毛膜促性腺激素;單磷醯脂A+分支桿菌細胞壁sk;莫哌達醇(mopidamol);多重抗藥性基因抑制劑;基於多重腫瘤抑制劑1之治療法;氮芥抗癌劑;印度洋海綿B(mycaperoxide B);分支桿菌細胞壁粹取物;米力雅頗龍(myriaporone);N-乙醯基地那林(N-acetyldinaline);N-經取代的苯甲醯胺;那法瑞林(nafarelin);那葛力司地(nagrestip);那洛酮(naloxone)+潘他唑新(pentazocine);那帕平(napavin);那特平(naphterpin);那托司亭(nartograstim);奈達鉑(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);天然肽內切酶;尼魯米特(nilutamide);尼沙黴素(nisamycin);氧化氮調節劑;氧化氮抗氧化劑;奈土林(nitrullyn);O6-苄基鳥嘌呤;奧曲肽(octreotide);歐基甚農(okicenone);寡核苷酸;歐那李司酮(onapristone);昂丹司瓊(ondansetron);昂丹司瓊;歐拉辛(oracin);口服細胞因子誘發劑;奧馬鉑(ormaplatin);奧沙孕烯酮(osaterone);奧沙利鉑(oxaliplatin);奧艘諾黴素(oxaunomycin);帕勞胺(palauamine);棕櫚醯基利索新(palmitoylrhizoxin);帕米酸;人參三醇(panaxytriol);帕諾米芬(panomifene);副細菌素(parabactin);帕折普汀(pazelliptine);陪門冬酶(pegaspargase);培爾德辛(peldesine);木聚硫鈉(pentosan polysulfate sodium);噴司他丁(pentostatin);噴卓唑(pentrozole);十七氟溴辛烷(perflubron);過磷醯胺;紫蘇醇(perillyl alcohol);菲那吉諾黴素(phenazinomycin);苯基乙酸;磷酸酶抑制劑;皮西巴尼(picibanil);鹽酸毛果芸香(pilocarpine hydrochloride);吡柔比星(pirarubicin);吡曲克辛(piritrexim);普雷司亭A(placetin A);普雷司亭B;纖溶酶原活化子抑制劑;鉑錯合物;鉑化合物;鉑-三胺錯合物;卟吩姆鈉(porfimer sodium);泊非黴素(porfiromycin);潑尼松(prednisone);丙基雙-吖啶酮;前列腺素J2;蛋白酶體抑制劑;基於蛋白質A之免疫調節劑;蛋白質激酶C抑制劑;蛋白質激酶C抑制劑,微藻性;蛋白質酪胺酸磷酸酶抑制劑;嘌呤核苷磷酸化酶抑制劑;紅紫素(purpurin);吡唑并吖啶(pyrazoloacridine);吡哆化血紅蛋白聚氧乙烯共軛物;raf拮抗劑;雷替曲塞(raltitrexed);雷莫司瓊(ramosetron);ras法呢基蛋白質轉移酶抑制劑;ras抑制劑;ras-GAP抑制劑;去甲基化雷鐵力亭(retelliptine demethylated);羥乙磷酸錸Re 186;利索新(rhizoxin);核酶;RII視黃醯胺;羅谷亞胺(rogletimide);羅西圖基(rohitukine);羅莫肽(romurtide);羅喹美克(roquinimex);盧比基農B1(rubiginone Bl);盧巴克西爾(ruboxyl);沙芬戈(safingol);聖托平(saintopin);SarCNU;沙寇非陀A(sarcophytol A);沙莫司亭(sargramostim);Sdi 1模擬物;司莫司汀(semustine);衰老衍生性抑制劑1;意義寡核苷酸;訊號傳導抑制劑;訊號傳導調節劑;單鏈抗原結合性蛋白質;西佐喃(sizofiran);索布佐生(sobuzoxane);硼癸酸鈉;苯基乙酸鈉;索維龍(solverol);長生素介質(somatomedin)結合蛋白質;索納明(sonermin);斯帕福斯酸(sparfosic acid);司皮卡黴素D(spicamycin D);螺莫司汀(spiromustine);脾潘亭(splenopentin);海綿司他丁1(spongistatin 1);角鯊胺(squalamine);幹細胞抑制劑;幹細胞分裂抑制劑;司提皮醯胺(stipiamide);溶基質素抑制劑(stromelysin);硫諾辛(sulfinosine);超活性血管活性腸肽拮抗劑;蘇拉迪司塔(suradista);蘇拉明(suramin);苦馬豆素(swainsonine);合成型糖胺聚糖;他莫司汀(tallimustine);他莫昔芬(tamoxifen)甲碘化物;牛磺莫司汀(tauromustine);他札羅汀(tazarotene);鐵可加侖鈉(tecogalan sodium);替加氟(tegafur);鐵陸拉皮力(tellurapyrylium);端粒酶抑制劑;替莫泊芬(temoporfin);替莫唑胺(temozolomide);替尼泊苷(teniposide);四氯十烷氧化物;四氮胺(tetrazomine);沙力步拉司丁(thaliblastine);噻寇拉林(thiocoraline);血小板生成素;血小板生成素模擬物;胸腺法新(thymalfasin);胸腺生成素受體激動劑;胸腺曲南(thymotrinan);促甲狀腺素;乙基初卟啉錫(tin ethyl etiopurpurin);替拉扎明(tirapazamine);二氯環戊二烯鈦(titanocene bichloride);托森亭(topsentin);托瑞米芬toremifene;全能性幹細胞因子;轉譯抑制劑;維A酸(tretinoin);三乙醯基尿苷;曲西立濱(triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司瓊(tropisetron);妥羅雄脲(turosteride);酪胺酸激酶抑制劑;酪胺酸磷酸化抑制劑(tyrphostin);UBC抑制劑;烏苯美司(ubenimex);泌尿生殖竇衍生性生長抑制性因子;尿激酶受體拮抗劑;伐普肽(vapreotide);伐里歐林B(variolin B);載體系統,紅血球基因治療法;維拉雷瑣(velaresol);藜蘆胺(veramine);維丁(verdins);維替泊芬(verteporfin);長春瑞賓(vinorelbine);文沙亭(vinxaltine);維塔克辛(vitaxin);伏氯唑(vorozole);扎諾特隆(zanoterone);傑尼鉑(zeniplatin);亞芐維(zilascorb);以及淨司他丁司替美(Zinostatin stimalamer)。較佳的額外抗癌症藥物係5-氟尿嘧啶與甲醯四氫葉酸(leucovorin)
可與本發明之化合物結合使用以治療增生性疾病(例如癌症)、或以預防增生性疾病(例如癌症)之復發的治療性抗體之實例包括(但不限於):賀癌平(HERCEPTIN,曲妥珠單抗(Trastuzumab))(Genentech,CA),其係用於治療具有轉移性乳癌之患者的人化的抗HER2單株抗體;REOPRO(阿昔單抗(abciximab))(Centocor),其係用於預防血塊形成之抗在血小版上之糖蛋白質IIb/IIIa受體抗體;ZENAPAX(達昔單抗(daclizumab))(Roche Pharmaceuticals,瑞士),其係用於預防急性腎臟異體移植排斥之免疫抑制性、人化的抗CD25單株抗體;PANOREXTM
,其係鼠類抗17-IA細胞表面抗原IgG2a抗體(Glaxo Wellcome/Centocor);BEC2,其係鼠類抗體基因型(GD3抗原決定基)IgG抗體(ImClone System);IMC-C225,其係嵌合型抗EGFR IgG抗體(ImClone System);VITAXINTM
,其係人化的抗αVβ3整連蛋白抗體(Applied Molecular Evolution/MedImune);Campath 1H/LDP-03,其係人化的抗CD52 IgG1抗體(Leukosite);Smart M195,其係人化的抗CD33 IgG抗體(Protein Design Lab/Kanebo);RITUXANTM
,其係嵌合型抗CD20 IgG1抗體(IDEC Pharm/Genentech,Roche/Zettyaku);LYMPHOCIDETM
其係人化的抗CD22 IgG抗體(Immunomedics);LYMPHOCIDETM
Y-90(Immunomedics);Lymphoscan(經Tc-99m標定的;放射成像;Immunomedics);Nuvion(針對CD3;Protein Design Labs);CM3係人化的抗ICAM3抗體(ICOS Pharm);IDEC-114係靈長動物化的抗CD80抗體(IDEC Pharm/三菱);ZEVALINTM
係放射標定的鼠類抗CD20抗體(IDEC/Schering AG);IDEC-131係人化的抗CD40L抗體(IDEC/Eisai);IDEC-151係靈長動物化的抗CD4抗體(IDEC);IDEC-152係靈長動物化的抗CD23抗體(IDEC/Seikagaku);SMART抗CD3係人化的抗CD3 IgG(Protein Design Lab);5G1.1係人化的抗補體因子5(C5)抗體(Alexion Pharm);D2E7係人化的抗TNF-α抗體(CAT/BASF);CDP870係人化的抗TNF-α Fab片段(Celltech);IDEC-151係靈長動物化的抗CD4 IgG1抗體(IDEC Pharm/SmithKline Beecham);MDX-CD4係人類抗CD4 IgG抗體(Medarex/Eisai/Genmab);CD20-鏈酶抗生物素(+生物素-釔90;NeoRx);CDP571係人化的抗TNF-α IgG4抗體(Celltech);LDP-02係人化的抗α4β7抗體(LeukoSite/Genentech);OrthoClone OKT4A係人化的抗CD4 IgG抗體(Ortho Biotech);ANTOVATM
係人化的抗CD40L IgG抗體(Biogen);ANTEGRENTM
係人化的抗VLA-4 IgG抗體(Elan);而CAT-152係人類抗TGF-β2抗體(Cambridge Ab Tech)。
可與本發明的化合物結合使用以治療具有增生性疾病(例如癌症)之患者、或以預防增生性疾病(例如癌症)之復發的化學治療性劑包括但不限於烷基化劑、抗代謝物、天然產物、或激素。在本發明的方法與組成物中,有用於治療或預防T-細胞惡性腫瘤之烷基化劑的實例包括(但不限於)氮芥(nitrogen mustard,例如,甲基雙氧乙基胺(mechloroethamine)、環磷醯胺、苯丁酸氮芥、等等)、烷基磺酸酯(例如,白消安)、亞硝基脲(例如,卡莫司汀、洛莫司汀等等)、或三氮烯(達卡巴嗪(decarbazine)、等等)。有用於在本發明的方法與組成物中,治療或預防T-細胞惡性腫瘤之抗代謝物的實例包括但不限於葉酸類似物(例如,甲氨蝶呤)、或嘧啶類似物(例如,阿糖胞苷)、嘌呤類似物(例如,巰基嘌呤、硫鳥嘌呤、噴司他丁)。有用於在本發明的方法與組成物中,治療或預防T-細胞惡性腫瘤之天然產物的實例包括但不限於長春花生物鹼(例如,長春花鹼、長春新鹼)、鬼臼毒素(epipodophyllotoxin)(例如,依托泊苷)、抗生素(例如,柔紅黴素、阿黴素、博萊黴素)、酵素(例如,L-天冬醯胺酶)、或生物反應調節劑(例如,干擾素阿伐)。
有用於在本發明的方法與化合物中治療或預防增生性疾病(例如癌症)之烷基化劑的實例包括但不限於,氮芥(例如,甲基雙氧乙基胺、環磷醯胺、苯丁酸氮芥、美法侖、等等)、伸乙亞胺與甲基蜜胺(例如,六甲蜜胺、塞替哌)、烷基磺酸酯(例如,白消安)、亞硝基脲(例如,卡莫司汀、洛莫司汀、司莫司汀、鏈佐星、等等)、或三氮烯(達卡巴嗪、等等)。有用於在本發明的方法與組成物中,治療或預防癌症之抗代謝物的實例包括但不限於葉酸類似物(例如,甲氨蝶呤)、或嘧啶類似物(例如,氟尿嘧啶、氟去氧尿苷、阿糖胞苷)、嘌呤類似物(例如,巰基嘌呤、硫鳥嘌呤、噴司他丁)。有用於在本發明的方法與組成物中,治療或預防癌症之天然產物的實例包括但不限於長春花生物鹼(例如,長春花鹼、長春新鹼)、鬼臼毒素(例如,依托泊苷、替尼泊苷)、抗生素(例如,放射菌素D、柔紅黴素、阿黴素、博萊黴素、光輝黴素、絲裂黴素)、酵素(例如,L-天冬醯胺酶)、或生物反應調節劑(例如,干擾素阿伐)。有用於在本發明的方法與組成物中,治療或預防癌症之激素與拮抗劑的實例包括但不限於腎上腺皮質類固醇(例如,潑尼松)、孕酮(例如,己酸羥基孕酮、醋酸甲地孕酮、醋酸甲羥孕酮(medroxyprogesterone acetate))、雌激素(例如,二乙基己烯雌酚(diethlystilbestrol)、乙炔雌二醇(ethinyl estradiol))、抗雌激素(例如,他莫昔芬)、雄激素(例如,丙酸睪酮、氟甲睪酮(fluoxymesterone))、抗雄激素(例如,氟他醯胺(flutamide))、促性腺激素釋放激素類似物(例如,亮丙里德)。其他可有用於在本發明的方法與組成物中,用於治療或預防癌症的劑包括鉑配位錯合物(例如,順氯氨鉑、卡鉑)、蒽二酮(anthracenedione,例如,米托蒽醌)、經取代的脲(例如,羥基脲)、甲基肼衍生物(例如,丙卡巴肼)、腎上腺皮質抑制劑(例如,米托坦、氨魯米特)。
在一個具體態樣中,本發明之化合物可與免疫治療劑結合使用,以治療增生性疾病(例如癌症)、或以預防增生性疾病(例如癌症)之復發。免疫治療(Immunotherapy,亦稱為生物反應修改子治療(biological response modifier therapy)、生物性治療(biologic therapy)、生物治療(biotherapy)、免疫治療(immune therapy)、或生物學治療(biological therapy))係使用免疫系統之部分以對抗疾病之治療。免疫治療可幫助免疫系統辨認癌症細胞、或提高針對癌症細胞的反應。免疫治療包括主動與被動免疫治療。主動免疫治療刺激身體本身的免疫系統,而被動免疫治療一般使用在身體外製造的免疫系統構成要素。
主動免疫治療之實例包括:癌症疫苗、腫瘤細胞疫苗(自體的或同種異體的)、樹突細胞疫苗、抗原疫苗、抗-體基因型疫苗、DNA疫苗、淋巴介質-活化性殺手(Lymphokine-Activated Killer,LAK)細胞治療、或腫瘤-滲透性淋巴細胞(Tumor-滲透性Lymphocyte,TIL)疫苗加上介白素-2(IL-2)。主動免疫治療目前正被用於治療或正在測試其用於治療各種類型之癌症的功效,包括黑色素瘤、腎臟(腎臟的)癌症、膀胱癌、前列腺癌、卵巢癌、乳症、直腸結腸癌、肺癌、白血病、前列腺癌、非-Hodgkin氏淋巴瘤、胰臟癌、淋巴瘤、多發性骨髓瘤、頭頸癌、肝癌、惡性腦腫瘤、與後期黑色素瘤。
被動免疫治療之實例包括:單株抗體與含有毒素之靶定性治療。單株抗體包括裸抗體與經結合抗體(亦稱為加標籤、經標定、或經裝載抗體)。裸單株抗體不具有藥物或放射活性物質接附其上,而經結合單株抗體係結合至化療藥物(化學裝載的(chemolabeled))、放射活性顆粒(放射裝載的(放射性標定的))、或毒素(免疫毒素)。一些裸單株抗體藥物已經被核准用於治療癌症,包括:利妥西單抗(Rituximab,Rituxan),一種用於治療B細胞非-Hodgkin淋巴瘤的針對CD20抗原之抗體;曲妥珠單抗(賀癌平),一種用於治療後期乳癌的針對HER2蛋白質之抗體;阿崙單抗(Alemtuzumab,Campath),一種用於治療B細胞慢性淋巴細胞性白血病(B-CLL)的針對CD52抗原之抗體;西妥昔單抗(Cetuximab,Erbitux),一種與irinotecan結合使用以治療後期直腸結腸癌與以治療頭頸癌的針對EGFR蛋白質之抗體;與貝伐單抗(Bevacizumab,癌思停(Avastin)),其係一種抗血管發生治療,其係對抗VEGF蛋白質而作用且係與化療結合使用以治療轉移性直腸結腸癌。一些經結合單株抗體已被核准用於治療癌症,包括:放射性標定的抗體替伊莫單抗(Ibritumomab tiuxetan,Zevalin),其直接遞送放射活性至癌性B淋巴細胞,並係用於治療B細胞非-Hodgkin淋巴瘤;放射性標定的抗體托西莫單抗(Tositumomab,Bexxar),其係用於治療某些類型的非-Hodgkin淋巴瘤;以及免疫毒素吉妥珠單抗奧唑米星(Gemtuzumab ozogamicin,Mylotarg),其含有加里剎黴素(calicheamicin)且係用於治療急性成骨髓性白血病(AML)。BL22係一種目前正在測試其用於治療毛狀細胞白血病的功效之經結合單株抗體,且有數個治療白血病、淋巴瘤、與腦腫瘤之免疫毒素臨床實驗正在進行。亦有已核准的用於偵測癌症之放射性標定的抗體,包括用於偵測直腸結腸與卵巢癌之OncoScint以及用於偵測前列腺癌之ProstaScint。含有毒素之靶定性療法係連結至生長因子之毒素且不含抗體。已核准之靶定性含有毒素之治療的實例為denileukin diftitox(Ontak)其係用於治療一類型的皮膚淋巴瘤(皮膚T細胞淋巴瘤)。
輔助性免疫治療之實例包括:細胞介素,例如顆粒性細胞-巨噬細胞群落-刺激性因子(GM-CSF)、顆粒性細胞-群落刺激性因子(G-CSF)、巨噬細胞發炎性蛋白(MIP)-1-阿伐、介白素(包括IL-l、IL-2、IL-4、IL-6、IL-7、IL-12、IL-15、IL-18、IL-21、與IL-27)、腫瘤壞死因子(包括TNF-阿伐)、與干擾素(包括IFN-阿伐、IFN-貝他、與IFN-迦瑪);白蛋白氫氧化物(alum);卡介苗(Bacille Calmette-Gurin,BCG);鑰孔帽貝血藍蛋白(Keyhole limpet hemocyanin,KLH);不完全的Freund氏佐劑(IFA);QS-21;DETOX;左旋咪唑(Levamisole);以及二硝基苯基(DNP)。臨床研究上已經顯示結合IL-2與其他細胞介素(例如IFN-阿伐)可導致協同反應。
數個類型的免疫治療正被用於治療黑色素瘤患者。IFN-阿伐與IL-2被核准用於治療具有轉移性黑色素瘤的人。目前正在測試BCG與黑色素瘤疫苗以及其他免疫治療結合的功效。在第一期臨床中,腫瘤-滲透性淋巴細胞已被顯示會使黑色素瘤腫瘤收縮。針對神經節苷脂抗原之人類單株抗體已被顯示會使皮膚的復發性黑色素瘤腫瘤消退。一些自體的與同種異體腫瘤細胞疫苗、抗原疫苗(包括多價抗原疫苗)、病毒疫苗、與樹突細胞疫苗亦已顯示會使腫瘤收縮。持續的有對此等與其他黑色素瘤免疫治療之臨床研究。具有高度IgM反應之黑色素瘤患者往往較該等不引起或引超低的IgM抗體者存活率佳(Morton等人,1992)。在三個在小鼠的腫瘤模式中(B16F10黑色素瘤、Lewis肺(LL/2)癌、與L1肉瘤),相較於對照組與使用單獨任一種細胞介素治療之小鼠,結合的IL-12/TNF-阿伐免疫治療已被顯示會明顯的延遲腫瘤生長。IFN-阿伐被核准用於治療惡性黑色素瘤、慢性成骨髓性白血病(CML)、毛狀細胞白血病、與Kaposi氏肉瘤。
數個類型的免疫治療正被用於治療具有腎臟癌之患者。IFN-阿伐與IL-2被核准用於治療具有轉移性腎臟(腎臟)癌之患者。目前正在測試使用IL-2、干擾素、與化療之結合治療治療腎臟癌之功效。在一些後期腎臟癌患者中,使用腫瘤細胞疫苗加上輔佐性BCG之治療已被顯示會使腫瘤收縮。目前亦正在測試DNA疫苗與腫瘤-滲透性淋巴細胞用於治療腎臟癌的功效。嵌合型雙專一性G250/抗CD3單株抗體已被顯示會藉由所選殖的人類CD8+T細胞或藉由IL-2刺激性周圍血液淋巴細胞介導腎臟細胞癌細胞系之細胞溶胞。
用於本文,「微管蛋白穩定劑」意指一種抗癌劑,其由於穩定化微管藉由將細胞制止於G2-M期而作用。為微管蛋白穩定劑之劑可與本發明之化合物結合使用以治療具有增生性疾病(例如癌症)之患者、或以預防增生性疾病(例如癌症)之復發。微管蛋白穩定劑之實例包括汰癌勝與汰癌勝類似物。其他微管蛋白穩定劑之實例包括但不限於以下市售藥物與正在研發中的藥物:盤皮海綿交酯(亦稱為NVP-XX-A-296);埃博黴素(例如埃博黴素A、埃博黴素B、埃博黴素C(亦稱為去氧埃博黴素A或dEpoA);埃博黴素D(亦稱為KOS-862、dEpoB、或去氧埃博黴素B);埃博黴素E;埃博黴素F;埃博黴素B正氧化物;埃博黴素AN-氧化物;16-氮雜-埃博黴素B;21-胺基埃博黴素B(亦稱為BMS-310705);21-羥基埃博黴素D(亦稱為去氧埃博黴素F與dEpoF)、26-氟埃博黴素);FR-182877(藤澤(Fujisawa),亦稱為WS-9885B)、BSF-223651(BASF,亦稱為ILX-651與LU-223651);AC-7739(味之素(Ajinomoto),亦稱為AVE-8063A與CS-39.HCl);AC-7700(味之素,亦稱為AVE-8062、AVE-8062A、CS-39-L-Ser.HCl、以及RPR-258062A);富山交酯B;勞力馬來;加勒比苷;加勒比素;箭根酮內酯;艾榴塞洛素;沙克敵丁;勞力馬來;迪提歐斯他丁-1;假白欖烷酯;以及其等的類似物與衍生物。
用於本文,「微管蛋白抑制劑」意指一種抗癌劑,其藉由抑制微管聚合或微管裝配而作用。為微管蛋白抑制劑之劑可與本發明之化合物結合使用於治療具有增生性疾病(例如癌症)之患者、或以預防增生性疾病(例如癌症)之復發。微管蛋白抑制劑之實例包括但不限於以下市售藥物與正在研發的藥物:厄布洛唑(亦稱為R-55104);多拉司他丁10(Dolastatin 10,亦稱為DLS-10與NSC-376128);2-羥乙磺酸米佛布林(Mivobulin isethionate,亦稱為CI-980);長春新鹼;NSC-639829;ABT-751(Abbot,亦稱為E-7010);阿爾托來丁(Altorhyrtin,例如阿爾托來丁A與阿爾托來丁C);海綿司他丁(例如海綿司他丁1、海綿司他丁2、海綿司他丁3、海綿司他丁4、海綿司他丁5、海綿司他丁6、海綿司他丁7、海綿司他丁8、以及海綿司他丁9);鹽酸西馬多丁(Cemadotin hydrochloride,亦稱為LU-103793與NSC-D-669356);奧利司他丁PE(Auristatin PE,亦稱為NSC-654663);索布利多丁(Soblidotin,亦稱為TZT-1027)、LS-4559-P(Pharmacia,亦稱為LS-4577);LS-4578(Pharmacia,亦稱為LS-477-P);LS-4477(Pharmacia)、LS-4559(Pharmacia);RPR-112378(Aventis);硫酸長春新鹼;DZ-3358(Daiichi);GS-164(武田(Takeda));GS-198(武田);KAR-2(匈牙利科學學院(Hungarian Academy of Sciences));SAH-49960(Lilly/Novartis);SDZ-268970(Lilly/Novartis);AM-97(Armad/協合發酵(Kyowa Hakko));AM-132(Armad);AM-138(Armad/協合發酵);IDN-5005(Indena);隱藻素52(亦稱為LY-355703);維提來霧醯胺(Vitilevuamide);土布來辛A(Tubulysin A);卡那丹索(Canadensol);矢四菊素(Centaureidin,亦稱為NSC-106969);T-138067(Tularik,亦稱為T-67、TL-138067、以及TI-138067);COBRA-1(Parker Hughes Institute,亦稱為DDE-261以及WHI-261);H10(堪薩斯州立大學(Kansas State University));H16(堪薩斯州立大學);殺癌素Al(Oncocidin Al,亦稱為BTO-956以及DIME);DDE-313(Parker Hughes Institute);SPA-2(Parker Hughes Institute);SPA-1(Parker Hughes Institute,亦稱為SPIKET-P);3-IAABU(Cytoskeleton/西奈山醫學學校(Mt.Sinai School of Medicine),亦稱為MF-569);那可辛(Narcosine,亦稱為NSC-5366);那司卡派(Nascapine)、D-24851(Asta Medica)、A-105972(Abbott);半阿司特林(Hemiasterlin);3-BAABU(Cytoskeleton/西奈山醫學學校,亦稱為MF-191);TMPN(亞利桑納州立大學(Arizona State University));乙醯丙酮酸瓦那多辛(Vanadocene acetylacetonate);T-138026(Tularik);蒙沙特羅(Monsatrol);依那諾辛(Inanocine,亦稱為NSC-698666);3-IAABE(Cytoskeleton/西奈山醫學學校);A-204197(Abbott);T-607(Tularik,亦稱為T-900607);RPR-115781(Aventis);艾榴塞洛素(例如去甲基艾榴塞洛素、去乙醯艾榴塞洛素、異艾榴塞洛素A、與Z-艾榴塞洛素);哈利康得林B(Halichondrin B);D-64131(Asta Medica);D-68144(Asta Medica);重氮醯胺A Diazonamide A);A-293620(Abbott);NPI-2350(Nereus);TUB-245(Aventis);A-259754(Abbott);戴歐索抑素(Diozostatin);(-)-苯基阿夕斯丁((-)-phenylahistin,亦稱為NSCL-96F037);D-68838(Asta Medica);D-68836(Asta Medica);肌基質蛋白B(Myoseverin B);D-43411(Zentaris,亦稱為D-81862);A-289099(Abbott);A-318315(Abbott);HTI-286(亦稱為SPA-110,三氟醋酸鹽)(Wyeth);D-82317(Zentaris);D-82318(Zentaris);SC-12983(NCI);利司伐抑素磷酸鈉(Resverastatin phosphate sodium);BPR-0Y-007(國家健康研究機構(National Health Research Institutes));SSR-250411(Sanofi);康普瑞汀A4(Combretastatin A4);以及其等的類似物與衍生物。
汰癌勝,亦稱為「太平洋紫杉醇」,係一種廣為人知的抗癌藥物,其藉由增加與穩定化微管形成而作用。汰癌勝之結構係於圖1顯示。許多汰癌勝之類似物係已知的,包括剋癌易(Taxotere),其結構係於圖2顯示。剋癌易亦稱為「docetaxol」。其他汰癌勝類似物之結構係於圖3-23顯示。此等化合物具有基本的紫衫烷骨架作為共通結構特徵,且亦已被顯示具有由於微管之穩定化而將細胞制止於G2-M期之能力。因此,從圖3-23可見,明顯地,廣泛各種取代基可修飾紫衫烷骨架而不會有害地對生物的活性產生影響。汰癌勝類似物的零、一、或兩個環己烷環可在所指示的位置具有雙鍵亦係明顯的。為了清楚起見,基本的紫衫烷骨架係於以下結構式(XXVI)顯示:
雙鍵已自在由結構式(XXVI)所表現之紫衫烷骨架中的環己烷環忽略。基本紫衫烷骨架可在一個或兩個環己烷環包括零或一個雙鍵,如於圖3-23以及以下結構式(XXVII)與(XXVIII)中所指出的。一些原子已自結構式(XXVI)中忽略以象徵其中在汰癌勝類似物間結構性改變通常發生的位置。例如,在紫衫烷骨架簡單地以氧原子取代象徵羥基、醯基、烷氧基、或另一帶有氧之取代基通常於該位置找到。可製造此等以及其他在紫衫烷骨架之取代而不伴隨能力之喪失,以提高與穩定化微管形成。因此,術語「汰癌勝類似物」於本文定義為意指一種化合物,其具有基本的紫衫烷骨架且其促進微管形成。汰癌勝類似物可調配成奈米顆粒膠體組成物以改善灌注時間以及以消除以Cremophor(其於一些患者造成過敏反應)遞送藥物之需要。被調配成奈米顆粒膠體調配物之汰癌勝類似物的一個實例係Abraxane,其係經蛋白質穩定化之太平洋紫杉醇(其係在食鹽水中再構成)的奈米顆粒膠體組成物。
典型地,用於本文之汰癌勝類似物係由結構式(XXVII)或(XXVIII)所代表:
R10
係低碳數烷基基團、經取代的低碳數烷基基團、苯基基團、經取代的苯基基團、-SR19
、-NHR19
、或-OR19
。
R11
係低碳數烷基基團、經取代的低碳數烷基基團、芳基基團、或經取代的芳基基團。
R12
係-H、-OH、低碳數烷基、經取代的低碳數烷基、低碳數烷氧基、經取代的低碳數烷氧基、-O-C(O)-(低碳數烷基)、-O-C(O)-(經取代的低碳數烷基)、-O-CH2
-O-(低碳數烷基)-S-CH2
-O-(低碳數烷基)。
R13
係-H、-CH3
、或(與R14
一起)-CH2
-。
R14
係-H、-OH、低碳數烷氧基、-O-C(O)-(低碳數烷基)、經取代的低碳數烷氧基、-O-C(O)-(經取代的低碳數烷基)、-O-CH2
-O-P(O)(OH)2
、-O-CH2
-O-(低碳數烷基)、-O-CH2
-S-(低碳數烷基)、或(與R20
一起)雙鍵。
R15
係-H、低碳數醯基、低碳數烷基、經取代的低碳數烷基、烷氧基甲基、烷硫甲基(alkthiomethyl)、-OC(O)-O(低碳數烷基)、-OC(O)-O(經取代的低碳數烷基)、-OC(O)-NH(低碳數烷基)、或-OC(O)-NH(經取代的低碳數烷基)。
R16
係苯基或經取代的苯基。
R17
係-H、低碳數醯基、經取代的低碳數醯基、低碳數烷基、經取代的、低碳數烷基、(低碳數烷氧基)甲基、或(低碳數烷基)硫代甲基。
R18
係-H、-CH3
、或與R17
以及R17
與R18
所接附之碳原子一起,係五或六員非-芳香的雜環狀環。
R19
係低碳數烷基基團、經取代的低碳數烷基基團、苯基基團、經取代的苯基基團。
R20
係-H或鹵素。
R21
係-H、低碳數烷基、經取代的低碳數烷基、低碳數醯基、或經取代的低碳數醯基。
較佳地,在結構式(XXVII)與(XXVIII)中之變數係如下定義:R10
係苯基、第三-丁氧基、-S-CH2
-CH-(CH3
)2
、-S-CH(CH3
)3
、-S-(CH2
)3
CH3
、-O-CH(CH3
)3
、-NH-CH(CH3
)3
、-CH=C(CH3
)2
、或對-氯苯基;R11
係苯基、(CH3
)2
CHCH2
-、-2-呋喃基、環丙基、或對-甲苯甲醯基;R12
係-H、-OH、CH3
CO-或-(CH2
)2
-N-馬福林基;R13
係甲基、或R13
與R14
一起係-CH2
-;R14
係-H、-CH2
SCH3
、或-CH2
-O-P(O)(OH)2
;R15
係CH3
CO-;R16
係苯基;R17
係-H、或R17
與R18
一起係-O-CO-O-;R18
係-H;R20
係-H或-F;且R21
係-H、-C(O)-CHBr-(CH2
)13
-CH3
、或-C(O)-(CH2
)14
-CH3
;-C(O)-CH2
-CH(OH)-COOH、-C(O)-CH2
-O-C(O)-CH2
CH(NH2
)-CONH2
、-C(O)-CH2
-O-CH2
CH2
OCH3
或-C(O)-O-C(O)-CH2
CH3
。
汰癌勝類似物亦可結合至藥學上可接受的聚合物(例如聚丙烯醯胺)或自其伸出。此種類型之聚合物的一個實例係於圖24中顯示。術語「汰癌勝類似物」,如其用於本文,包括如此聚合物。
在一些具體態樣中,汰癌勝類似物具有由結構式XXIX所代表的紫衫烷骨架,其中Z係O、S、或NR。具有結構式XXIX所顯示之紫衫烷骨架之汰癌勝類似物可如顯示(例如如圖3-23)具有各種取代基接附至紫衫烷骨架上,且可在零、一、或二個環己烷具有雙鍵。
各種汰癌勝類似物與汰癌勝調配物係於Hennenfent等人(2006)Annals of Oncology 17:735-749;Gradishar(2006)Expert Opin.Pharmacother.7(8):1041-53;Attard等人(2006)Pathol Biol 54(2):72-84;Straubinger等人(2005)Methods Enzymol.391:97-117;Ten Tije等人(2003)Clin Pharmacokinet.42(7):665-85;以及Nuijen等人(2001)Invest New Drugs.19(2):143-53敘述,其等之完整教示係以引用方式納入本文中。
在一些具體態樣中,本發明提供用於在需要治療或抑制血管發生之受藥者中治療或抑制血管發生的方法,其包括投藥至該受藥者有效量的由式(I)至(XVI)所代表、或表1的化合物。用於本文,術語「血管發生」意指一種在組織或器官中產生新血管之基礎過程。血管發生係包含於許多疾病或病症中或與許多疾病或病症相關,包括但不限於:癌症;眼的新血管疾病;老化-相關性黃斑性退化(ag-related macular degeneration);糖尿病性視網膜病、早熟之視網膜病;角膜移植排斥;新血管青光眼;晶狀體後纖維組織增生;流行性角膜結膜炎;維生素A缺乏;隱形眼鏡過渡配戴;遺傳性過敏性角膜炎(atopic keratitis);上邊角膜炎(limbic keratitis);眼翳性乾眼角膜炎(pterygium keratitis sicca);sjogrens;酒渣鼻性痤瘡(acne rosacea);疣;濕疹;phylectenulosis;梅毒;分枝桿菌感染;脂肪退化;化學燒傷;細菌性潰瘍;真菌性潰瘍;單純皰疹感染;帶狀皰疹感染;原生動物感染;Kaposi氏肉瘤;Mooren氏潰瘍;Terrien氏邊緣退化;邊緣角膜溶解(keratolysis);類風濕性關節炎;全身性狼瘡;多動脈炎;創傷;Wegener氏類肉瘤病;鞏膜炎;Stevens-Johnson疾病;天皰瘡(pemphigoid);放射狀角膜切開術;角膜移植排斥;糖尿病性視網膜病;肌肉退化;鐮形血球貧血症;類肉瘤;梅毒;彈性假黃瘤;Paget氏病;靜脈閉塞;動脈閉塞;頸動脈堵塞疾病;慢性葡萄膜炎/玻璃體炎(vitritis);分枝桿菌感染;Lyme氏病;全身性紅斑性狼瘡;早熟之視網膜病;Eales氏病;Behcet氏病;造成視網膜炎或脈絡膜炎之感染;推定性眼組織漿菌病;Best氏病;近視;視凹(optic pit);Stargardt氏病;葡萄膜平坦部炎(pars planitis);慢性視網膜分離;黏性過大症候群;弓蟲症;創傷與雷射後併發症;與麻疹相關的疾病(角(angle)的新血管化);由纖維血管或纖維組織異常增生造成之疾病,包括所有形式的增生性玻璃體視網膜病;類風濕性關節炎;骨關節炎;潰瘍性結腸炎;Crohn氏病;Bartonellosis;動脈粥樣硬化;Osler-Weber-Rendu疾病;遺傳性出血性毛細血管擴張;肺血管瘤病;前-驚厥(pre-eclampsia);子宮內膜異位;肝臟與腎臟之纖維化;發展異常(器官發生);皮膚脫色(discloloration)(例如,血管瘤、火焰痣(nevus flammeus)、或簡單痣(Nevus simplex));傷口治癒;肥厚性疤痕(即,蟹足腫(keloid);傷口粗糙化(wound granulation);血管黏著;貓抓病(catscratch disease,Rochele ninalia quintosa);潰瘍(幽門螺桿旋菌));角膜結膜炎;齒齦炎(gingivitis);牙周病;牙齦炎(epulis);肝炎;扁桃腺炎;肥胖;鼻炎;喉炎;氣管炎;支氣管炎;小支氣管炎;肺炎;間質性肺的纖維化;肺水腫;神經性皮炎;甲狀腺炎;甲狀腺腫大;子宮內膜異位;腎小球腎炎;胃炎;發炎性骨骼與軟骨破壞;血栓性栓塞疾病;以及Buerger氏病。抗血管發生可藉由任何熟習該項技術者已知的方法(例如於本文在實例9與10所敘述的方法)顯示。
可與本發明的化合物共-投藥之抗-血管生成劑包括達肝素(Dalteparin)、蘇拉明、ABT-510、坎雷司他丁A4磷酸鹽、來那度胺(Lenalidomide)、LY317615(Enzastaurin)、大豆異黃酮(Genistein;大豆蛋白質分離物)、沙利度胺、AMG-706、抗-VEGF抗體(貝伐單抗;癌思停TM
)、AZD2171、Bay 43-9006(Sorafenib甲苯磺酸酯)、PI-88、PTK787/ZK 222584(瓦他拉尼(Vatalanib))、SU11248(舒尼替尼(Sunitinib)蘋果酸酯)、VEGF-Trap、XL184、ZD6474、ATN-161、EMD 121974(Cilenigtide)、塞來考昔(Celecoxib)、血管抑素(Angiostatin)、血管內皮抑素(Endostatin)、Regranex、Apligraf、太平洋紫杉醇、四環素、克拉黴素(clarithromycin)、lasix、卡托普利(captopril)、阿司匹林、維生素D3類似物、類視黃醇、Imiquomod、干擾素阿伐2a、美諾四環素(Minocycline)、含銅肽敷藥(dressing)、LucentisTM、ATG002、哌加他尼鈉(Pegaptanib Sodium)、色胺醯基-tRNA合成酶、角鯊胺乳酸鹽、乙酸阿奈可他(anecortave acetate)、AdPEDF、AG-013958、JSM6427、TG100801、Veglin、抗壞血酸醚(以及其等的類似物)、與帕米膦酸(Pamidronate)。
用於本文,「預防」意指症狀或疾病當使用本發明的化合物治療時比不使用本發明的化合物治療時復發可能性低(例如,可能性低至少10%、20%、30%、40%或50%),例如部分預防或抑制復發。例如,所揭示的治療會降低欲治療的症狀或疾病之復發的可能性。
本發明的化合物可藉由根據以下之流程圖或藉由任何熟習該項技術者所知的方法製備。
在流程I中之式A化合物可根據美國專利案第6,800,660號、美國專利案第6,762,204號、或美國專利案第6,825,235號(其等之完整內容係以引用方式納入本文中),或藉由技術領域中之人士已知的方法製備。
對於流程II-VI,硫代醯肼(thiohydrazide)、硫代酸氯化物(thioacid chloride)、或另一個羰基模擬物可用於代替醯肼與酸氯化物。烷基化肼與醯肼可用於代替肼或醯肼。羰基模擬物可代替羰基或硫代羰基基團,來自一流程之肼模擬物可與來自另一流程的「親醯肼基(hydrazidophile)」反應。
於以上流程中所引用的文獻之每一者的完整教示皆係以引用方式納入本文中。
本發明係由以下實施例說明,其等非意欲以任何方式構成限制。
A.活體內抗腫瘤研究之一般程序新穎化合物之活體內抗癌增加效果係於帶有腫瘤的小鼠中使用腫瘤生長抑制分析評估。腫瘤細胞係藉由於小鼠脅腹皮下地注射腫瘤細胞懸浮液而移植。腫瘤使用本發明之化合物與另一個抗癌劑(例如,太平洋紫杉醇,其會從此處開始以實例之方式使用)之治療係腫瘤已經建立之後(體積係大約100 mm3
)開始。接著動物開始多重注射計畫表,其中化合物與太平洋紫杉醇係藉由IV投藥途徑給藥。腫瘤每週測量兩次。在此分析期間,動物被每日地監看毒性之徵兆,包括體重喪失。
B.程序經補充培養基係自以下者製備:50% DMEM/Dulbecco經修改的Eagle培養基(Dulbecco修改的ied Eagle培養基)(高葡萄糖)、50% RPMI 1640、10% FBS/胎牛血清(經雜種測試的;經無菌過濾的)、1% L-麩醯胺酸、1%青黴素-鏈黴素、1% MEM丙酮酸鈉、與1% MEM非-必須胺基酸。FBS係自Sigma化學公司(Sigma Chemical Co.)獲得而其他成分係自Invitrogen生命科技(Invitrogen Life Technologies,USA)獲得。經補充培養基被溫熱至37℃,並將50 mL的培養基加入至175 cm2
組織培養燒瓶。
用於分析的細胞係來自美國菌種保存中心之MDA-435人類乳癌細胞。移出1小瓶來自液態氮冷凍細胞儲藏品之MDA-435細胞。立即將細胞的冷凍小瓶置入37℃水浴並溫和地打轉直到融化。將冷凍-小瓶使用70%乙醇擦拭並立即地將細胞以移液管移入含有經補充培養基之175 cm2
組織培養燒瓶。將細胞培養過夜,並於次日將培養基移出以及以新鮮的經補充培養基置換。培養燒瓶直到燒瓶成為大約90%匯合。此一般需要從5-7天之任何時間。
將燒瓶以10 ml無菌的室溫磷酸鹽緩衝食鹽水(PBS)清洗。將細胞藉由將5 ml溫熱的胰蛋白腖-EDTA(Invitrogen)加入細胞的燒瓶中兒以胰蛋白腖處理。接著將細胞於37℃培養2-3分鐘直到細胞開始自燒瓶的表面分離。將相等體積的經補充培養基(5 ml)加入燒瓶。將所有的細胞收集至50 ml試管,並在20℃於1000 RPM離心共5分鐘。吸出上清液並將細胞小丸再懸浮於10 ml的經補充培養基,並計數細胞。將1-3百萬個細胞/燒瓶種入5-7個組織培養燒瓶(175 cm2
)。每個燒瓶應含有50 ml的經補充培養基。培養燒瓶直到大約90%匯合。重複細胞傳代直到得到足夠用於腫瘤移植之細胞。
按照以上用於以胰蛋白腖處理以及離心細胞的程序。吸出上清液並將細胞小丸再懸浮於10 ml的無菌PBS中並計數細胞。將細胞離心並接著以適當體積的無菌PBS再懸浮以用於腫瘤移植所需之正確數目的細胞之注射。在MDA-435的實例中,1億個細胞係以2.0 ml的無菌PBS懸浮至最終濃度5千萬個細胞s/ml,以以0.1 ml/小鼠注射5百萬個細胞。
小鼠(CD-1 nu/nu)係獲自查理斯河實驗室(Charles River Laboratories):命名:Crl:CD-1-nuBR,年齡:6-8週大。在小鼠被用於實驗程序之前允許其等適應1週。
MDA-435腫瘤細胞懸浮液一般係移植至雌性CD-1 nu/nu小鼠之脂體(corpus adiposum)。此脂肪體係位於在小鼠之腹面腹部臟器。腫瘤細胞係皮下地移植至位在髖骨(骨盆骨)與股骨(股骨)連接處腹右四分之一之脂肪體。將5百萬個於0.1 ml無菌PBS之MDA-435細胞使用27 G(1/2英吋)針注射。MDA-435腫瘤典型地於移植後發育2-3週。
化合物儲藏溶液係藉由將化合物以所欲的濃度溶解於細胞-培養-等級DMSO(二甲亞碸)而製備。此於DMSO之儲藏溶液係在超音波水浴中聲振直到所有的粉末皆溶解。
調配溶劑係如以下製備:20%的Cremophore RH40(獲得自BASF公司(BASF corp.)之聚氧基40氫化蓖麻油)水溶液係藉由首先將100% Cremophore RH40在50-60℃於水浴加熱直到液化且澄清而而製備。將10 ml的100% Cremophore RH40分裝至含有40 ml無菌水之圓錐形離心試管(Cremophore RH40的1:5稀釋)。再加熱20% Cremophore RH40溶液直到其再次成為澄清,並藉由翻轉試管數次而混合。此20% Cremophore RH40溶液係儲藏於室溫,且保存至多至3個月。
用於化合物投藥之給藥溶液的製備:將化合物儲藏溶液使用20% Cremophore RH40以1:10稀釋:1)2.0 ml的10 mg/ml本發明之化合物之給藥溶液係藉由將100 mg/ml的化合物儲藏溶液以1.8 ml的20% Cremophore RH40水溶液稀釋而製備;且2)包括2.0 ml的1 mg/ml太平洋紫杉醇(獲得自Sigma化學公司)與5 mg/ml的化合物(1)之給藥溶液係係藉由混合0.1 ml的本發明化合物之DMSO儲藏溶液(50 mg/ml)與0.1 ml的太平洋紫杉醇DMSO儲藏溶液(10 mg/ml)並以1.8 ml的20% Cremophore RH40水溶液`稀釋而獲得。用於給藥溶液之最終調配物係10% DMSO、18% Cremophore RH40、與72%水。
將給藥溶液(給藥體積:0.01 ml/克=10 ml/kg)靜脈內地的注射至帶有MDA-435人類乳房腫瘤之小鼠。以下表顯示典型的給藥方法。
結果本發明之化合物預期到會明顯地提高太平洋紫杉醇之抗腫瘤活性而不會增加毒性。
熱休克蛋白(Hsp)係在各種壓力條件下被誘發且結合至其他蛋白質以預防其等變性。Hsp可保護細胞免於凋亡性死亡。誘導Hsp70生產之劑可對許多種類的攻擊具有保護性活性,且可神經學疾病中具有特別的功效。本發明之Hsp70誘發性化合物之神經保護活性可於各種動物神經學的疾病模式中評估。特別地,中風、肌萎縮性偏側硬化症、杭丁頓舞蹈症、巴金森氏病、與阿茲海默症的動物模式係用於測試功效之適當設定。以下提供一些動物模式之實例。
所揭示之使用本發明之Hsp70誘發性化合物治療的好處可於中風的齧齒動物模式中評估。例如可利用敘述於Longa等人(Longa,E.Z.,Weinstein,P.R.,Carlson,S.,與Cummins,R.(1989)Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke
20:84-91)之中風模式。
將大鼠克他明(ketamine)以麻醉,並接著藉由顱外血管閉塞誘導梗塞。將4-0尼龍腔內縫線置入頸部內部頸動脈並顱內地前進以封阻流至中大腦動脈的血液。並行血流係藉由中斷外部頸動脈的所有分支與內部頸動脈的所有顱外分支而減低。本發明之化合物可在梗塞之誘發之前或之後立即給藥。給藥可為(例如)10至100 mg/kg體重投藥每週一次、每週三次、或每日地,其藉由任何慣用的投藥模式,例如,口部地或靜脈內地。可分析神經學缺失、死亡率、總體病變(梗塞大小)、與組織化學染色以評估化合物的功效。由於此係非常急性的模式,且死亡往往在梗塞之後三天內觀察到,此模式可能僅僅由單一之藥物投藥構成。
本發明之化合物於治療ALS之功效可使用SOD1基因轉殖小鼠模式模擬(Gurney,M.E.,Pu,H.,Chiu,A.Y.,Dal Canto,M.C.,Polchow,C.Y.,Alexander,D.D.,Caliendo,J.,Hentati,A.,Kwon,Y.W.,與Deng,H.X.(l994)Motor neuron degeneration in mice that express a human CuZn superoxide dismutase mutation.Science 264:1772-1775)。人類CuZn超氧化物歧化酶(SOD)之突變係在具有家族性ALS患者中發現。於胺基酸93含有甘胺酸-至-丙胺酸之取代的人類SOD基因之表現在基因轉殖小鼠中導致運動神經元疾病。由於運動神經元自脊髓喪失,小鼠成為癱瘓的且在5至6個月內大時死亡。
為了測試本發明之Hsp70誘發性化合物之功效,具有SOD1突變(SOD1G93A
)之基因轉殖小鼠係以本發明的化合物治療,並監看對疾病之效果。徵候在此等動物於2.5至3個月大時係臨床上明顯的。化合物可於此時開始給藥。給藥可為(例如)10至100 mg/kg體重投藥每週一次或每週三次,藉由口部或靜脈內的途徑。終點(Endpoint)包括運動功能之功能性損害以及組織學的改變。後者終點包括在脊髓運動神經元中評估運動神經元之退化與富神經絲包涵體的出現的腦與脊髓之組織病理學。若進行長期投藥,可評估小鼠存活的衝擊。
存在有一種HD之基因轉殖小鼠模式,其允許測試本發明之Hsp70誘發性化合物對於此疾病設定之功效(Mangiarini,L.,Sathasivam,K.,Seller,M.,Cozens,B.,Harper,A.,Hetherington,C.,Lawton,M.,Trottier,Y.,Lehrach,H.,Davies,S.W.,與Bates,G.P.(1996)Exon 1 of the HD gene with anexpanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice.Cell 87:493-506;Carter,R.J.,Lione,L.A.,Humby,T.,Mangiarini,L.,Mahal,A.,Bates,G.P.,Dunnett,S.B.,與Morton,A.J.(1999)Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation.J.Neuroscience 19:3248-3257)。HD係由CAG/聚麩醯胺酸重複擴展造成。此等基因轉殖小鼠(R6/2基因轉殖)具有含有(CAG)115-(CAG)150重複擴展之人類HD基因之5'端。小鼠展現類似於HD之漸進性神經學病變,包括異常與不自主的運動、顫抖、與癲癇性發作。
此等基因轉殖小鼠大約8週大時顯示明顯行為上的改變。早至5至6週大時,其等在運動技巧顯露更微小的缺陷。本發明之Hsp70誘發性化合物可藉由靜脈內或口部投藥以10-100 mg每kg體重於各種時間開始投藥(例如,於5至6週大)。化合物可以多重不同的給藥計畫表(例如,每週一次相對於每週三次)給藥。可進行對一個或多個齧齒動物運動測試(例如游泳水槽(swimming tank)、平衡稈行走(beam walking)、滾輪機械(rotarod apparatus)、與足跡測試(參見Carter等人,1999))之進行,以評估化合物在HD小鼠預防神經學功能喪失之活性。
有兩種廣泛地利用的PD模式,其中疾病係藉由化療誘導。此等係6-OHDA(Zigmond,M.J.與Stricker,E.M.(1984)Parkinson's disease:studies with an animal model.Life Sci.35:5-18;Sauer,H.與Oertel,W.H.(1994)Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-Hydroxydopamine:a combined retrograde tracing and immunocytochemical study in the rat.Neuroscience 59:401-415)以及MPTP(Langston,J.W.,Forno,L.S.,Rebert,C.S.,與Irwin,I.(1984)Selective nigral toxicity after systemic administration of l-methyl-4-phenyl-1,2,5,6-tetrahydropyrine(MPTP)in the squirrel monkey.Brain Res.292:390-4)模式。以下敘述本發明之Hsp70誘發性化合物使用6-OHDA的測試之實例。
年輕的成年雄性大鼠係以氟-金(FG)藉由立體定位(stereotactic)注射至腦的紋狀體而注射,以促進神經在黑質(PD之位置)之顯像。在麻醉下,0.2 μ l的FG 4%溶液係藉由立體定位注射投藥(於前囟前面1 mm,側面3 mm,以及從硬膜到兩個紋狀體腹面4.5 mm)。FG注射一週之後,大鼠接受6-OHDA之立體定位注射(20 μ g,溶解於4 μ l食鹽水;Sigma)至紋狀體於腦的一側,其於FG注射之相同座標。本發明之Hsp70誘發性化合物可藉由靜脈內或口部投藥以10-100 mg每kg體重之劑量而投藥。化合物可於6-OHDA注射之時或6-OHDA處理一些時間之後(例如,2-4週)給藥。大鼠係於6-OHDA注射8與16週之後犧牲。此模式之終點係1)行為上的改變,其由在一生內於數個時間監看,其藉由使用傳統的神經學的讀出(read-out)之翻身(旋轉)行為的評估,以及2)腦於犧牲之後移出,使用低溫恆溫器製作薄切片,並進行免疫組織化學,如於Zigmond與Stricker(1984)所敘述。本發明之Hsp70誘發性化合物的功效係由旋轉行為之減少以及在黑質多巴胺能神經元之喪失的減少而證實。
有數個AD之基因轉殖小鼠模式。此等模式其中一個廣泛地用於測試藥物在AD之功效者係由Holcomb等人敘述(Holcomb,L.,Gordon,M.N.,McGowan,E.,Yu,X.,Benkovic,S.,Jantzen,P.,Wright,K.,Saad,I.,Mueller,R.,Morgan,D.,Sanders,S.,Zehr,C.,O'Campo,K.,Hardy,J.,Prada,C.M.,Eckman,C.,Younkin,S.,Hsiao,K.,與Duff,K.(1998)Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.Nature Medicine 4:97-100)。此模式含有兩種不同的與AD相關的基因。一個係在類澱粉蛋白前驅蛋白質(APP)之突變。突變的APP(K670N,M671L)基因轉殖系,Tg2576,已在年齡早期提升類澱粉蛋白貝他-蛋白質水平,且(之後)發展出於腦部之細胞外AD-型A貝他沈積。另一個基因係圖變的衰老蛋白-1(presenilin-1,PS1)基因。來自Tg2576與PS1突變PS1M146L基因轉殖系之雜交的雙重基因轉殖後代相較於其等的單一基因轉殖Tg2576小鼠遠較早在大腦皮質與海馬體發展出大數目的纖維狀A貝他沈積。
本發明之Hsp70誘發性化合物可於各種時間給藥小鼠。小鼠開始藥物給藥的年齡可多變的。例如,治療開始時間可係3個月大,其為腦沈積首次可偵測的時間。劑量可為(例如)10至100 mg/kg體重每週投藥一次或每週三次,藉由口部或靜脈內途徑。藥物治療之效果可藉由在腦部測量AD-型沈積以及藉由評估小鼠於迷宮中的功能而測試而評估。
血漿Hsp70可藉由夾層ELISA套組(Stressgen生物試劑(Stressgen Bioreagents)Victoria,British Columbia,CANADA)根據組織內經修改方法測量。簡而言之,血漿樣本之Hsp70與Hsp70標準品之系列濃度被捕捉至96-槽孔盤(其上有抗Hsp70抗體塗附)。接著被捕捉的Hsp70係以生物素基化的抗Hsp70抗體偵測接著以結合銪的鏈黴抗生物素蛋白(streptavidin)培養。每次培養後,未結合物質係藉由清洗而移出。最終,抗體-Hsp70錯合物係藉由銪的時間分辨性螢光術(time resolved fluorometry)而測量。Hsp70之濃度係自標準曲線計算。
可利用以下程序分析NK細胞在受藥者中的活性。該程序係改寫自Kantakamalakul W,Jaroenpool J,Pattanapanyasat K.A novel enhanced green螢光protein(EGFP)-K562 flow cytometric method for measuring natural killer(NK)cell cytotoxic activity.J Immunol Methods.2003 Jan 15;272:189-197,其完整教示係以引用方式納入本文中。
材料與方法:人類紅血球白血球細胞系(erythroleukaemic cell line),K562,係獲得自美國菌種保存中心(CCL-243,美國菌種保存中心,Manassas,VA),並於37℃使用5% CO2
培養於以10%熱失活化胎牛血清(Gibco)、2mM L-麩醯胺酸、100 μg/ml鏈黴素、與100 IU/ml青黴素補充之RPMI-1640培養基(Cat#11875-093 Gibco Invitrogen公司(Gibco Invitrogen Corp),Carlsbad,CA)中。K562細胞係以編碼綠色螢光蛋白(eGFP)之反轉錄病毒載體轉導。穩定的細胞系係以抗生素(G418)選擇。選擇之後大約99.6%的G418抗性細胞係eGFP陽性。
受藥者之周邊血液單核細胞(PBMC)係藉由臨床研究地點製備並容納在含有接受肝素鈉之BD Vacutainer細胞製備試管(BD Vacutainer Cell Preparation Tube,產品編號:362753,Becton Dickinson,Franklin Lakes,NJ)中。
將以1X106
個細胞/mL之濃度開始的800 μl效應細胞(患者的PBMC)之兩倍系列稀釋置入四各個別的聚苯乙烯12X75-mm試管中。對數期生長性目標細胞(K562/eGFP)係以生長培養基(RPMI-1640)調整至1X105
個細胞/mL之濃度且接著將100 μL之目標加入試管內以提供80:1、40:1、20:1、10:1之效應/目標(E/T)比率。單獨效應細胞與單獨靶定細胞係用作為對照組。將所有的試管以5% CO2
培養於37℃大約3.5個小時。十微升碘化丙錠(PI)以1 mg/mL之濃度加入至包括效應與目標對照組試管之每個試管並接著於室溫15分鐘培養。
細胞毒性活性係以FACSCalibur流動式細胞儀(Becton Dickinson)分析。獲得正向(forward)與側向散射(side scatter)(FSC/SSC)訊號之線性擴增,以及eGFP與PI發射在綠色與紅色螢光之對數擴增。每個樣本試管收集一萬個不具有獲取之限制(gating for acquisition)的事件以用於分析。eGFP對PI之二變量點座標圖的數據分析係使用CELLQuest(Becton Dickinson Biosciences)軟體進行以數活與死目標細胞。碎片與死細胞係藉由設定正向光散播(forward light scatter)之閾值而排除。
為檢查是否本發明之化合物對內皮細胞功能產生影響,在本發明之化合物存在下進行試管內人類臍帶靜脈內皮細胞(HUVEC)遷移分析。HUVEC細胞(傳代數目4)係培養於12-槽孔盤上,且時間間隔影像(time-lapse image)係以在補充6-7% CO2
之倒立顯微鏡上之活細胞影像系統進行。溫度係維持在37℃。每30分鐘使用2X目鏡鏡獲取影像至多至106個小時或每60秒使用20X目鏡獲取影像共30分鐘。將匯合的HUVEC培養類似地刮擦以製造空白區域,接著培養於HUVEC培養基共15個小時而無處理。遷移區域,其對每個槽孔以時間間隔序列照像,係用作為用於標準化/校正遷移率之基礎。接著,細胞在不同的處理下之遷移,係於相同的時間照相以對每個槽孔產生時間間隔影像序列。時間間隔移動係藉由測量被遷移性細胞遮蓋的區域而進一步分析。在實驗期間,HUVEC細胞係藉由VEGF以及鹼性FGF之存在而活化。本發明之化合物(例如100 nM與1 μM)被預期到會完全地封阻HUVEC細胞遷移至空白區域,暗示本發明之化合物對試管內藉由VEGF與鹼性FGF誘導而活化的HUVEC細胞之遷移持有有效的抑制效果。
亦可能在以上處理期間追蹤HUVEC行為。預期到HUVEC細胞在以本發明之化合物處理24個小時之後會開始皺縮。
藉由使用抗VE-鈣依黏聯蛋白抗體進行免疫螢光研究以檢查HUVEC細胞間的VE-鈣依黏聯蛋白接合點。HUVEC細胞係以DMSO或本發明之化合物(例如10、100、與1000nM)處理24個小時,並固定以免疫染色。對所有的處理DMSO濃度皆係1:100。為了促升免疫螢光訊號,將細胞以2種多株抗人類VE-鈣依黏聯蛋白Ab之混合物染色,接著以螢光次級抗體之混合物染色。相較於以DMSO處理之培養,預期到在使用本發明之化合物時,VE-鈣依黏聯蛋白染色在細胞-細胞接合點部位會極端的強,但非在非-接觸部位。本發明之化合物被預期到會提高活化的人類內皮細胞之細胞-細胞接合點之裝配,其可能係透過VE-鈣依黏聯蛋白分子於接合點之堆積之誘發。此效果可造成有限的細胞能動性以及減低內皮細胞之可穿透性,因此對本發明之化合物之細胞遷移抑制與可能的抗血管發生效果有貢獻。
A.N'1,N'3-雙(甲磺亞胺(苯基)甲基)-N'1,N'3-二甲基丙二醯肼(dimethylmalonohydrazide)(化合物67)之合成
將燒杯以二氯甲烷(10 mL)、N-(甲基磺醯基)亞胺苄基氯化物(188 m.;1.1 mmol)、N'1,N'3-二甲基丙二醯肼(88 m.;0.55 mmol)、與二異丙基乙基胺(0.5 mL)填充,並將溶液攪拌過夜。接著將溶液以1N NH4
Cl洗滌,並將產物使用管柱色層分析法純化以得到呈白色泡沫之N'1,N'3-雙(甲磺亞胺(苯基)甲基)-N'1,N'3-二甲基丙二醯肼(138 mg.)。C21
H26
N6
O6
S2
之ESMS計算值:522.1;實際值:523.2(M+1)。
N-(甲基磺醯基)亞胺苄基氯化物之合成將燒杯以N-甲磺醯胺基苯甲醯胺(1.0 g.;5 mmol)磷五氯化物(1 g)與氯苯(20 mL)填充,並將溶液於回流加熱另一小時。將產物藉由管柱色層分析法純化以得到N-(甲基磺醯基)亞胺苄基氯化物(256 mg)。
N'1,N'3-二甲基丙二醯肼之合成將燒杯以來自以下步驟之粗N'1,N'3-二羧基苯甲氧基-N'1,N'3-二甲基丙二-醯肼、甲醇、10%在碳上之鉑填充,置於氫大氣壓下,並攪拌過夜。將懸浮物通過矽鈣石過濾並蒸發至亁以得到N'1,N'3-二甲基丙二醯肼(2.4 g;15 mmol)。
N'1,N'3-二羧基苯甲氧基-N'1,N'3-二甲基丙二醯肼之合成將燒杯以苯甲基1-甲基肼碳酸酯(9.0 g.;50 mmol)、丙二酸(2.5 g;25 mmol)、二氯甲烷(50 mL)、與1-乙基-3-(3’-二甲基胺基丙基)碳二亞胺(10 g;5.25 mmol)填充並將溶液攪拌一小時。將有機溶液以飽和的氯化銨洗滌,並將產物藉由管柱色層分析法純化以得到N'1,N'3-二羧基苯甲氧基-N'1,N'3-二甲基丙二醯肼(15 mmol)。
B.N'-甲基-2-(2-甲基-2-(苯基碳噻吩基(phenylcarbonothioyl))肼基)-2-側氧基-N'-(苯基碳噻吩基)乙磺醯肼(化合物68)之合成
逐滴將2-(氯磺醯基)乙醯基氯化物(5 mmol)加入N-甲基苯并硫醯肼(10 mmol)於DCM(20 mL)與吡啶(1 mL)的0℃溶液。在混合物被倒入水中(20 mL)前,將其保持在室溫共2小時。將有機層分開,乾燥並蒸發,並將得到的殘餘物藉由管柱色層分析法純化以得到呈淡黃色固體的化合物68(0.8 g)。1
H-NMR(CDCl3
)10.5(m,1H),7.4(m,10H),4.4(m,1H),3.4-3.8(m,8H)ppm;C18
H20
N4
O3
S3
ESMS計算值:436.1;實際值:437.2(M+H+
)。
C.二甲基N,N'-伸甲基雙(N'-甲基-N'-(苯基碳噻吩基)-磷醯肼化物(phosphonohydrazidate))(化合物30)之合成
逐滴將伸甲基二膦酸二氯化物(9 mmol)加入N-甲基苯并硫醯肼(18 mmol)於DCM(20 mL)與TEA(1 mL)之0℃溶液。在將絕對甲醇(2 mL)加入混合物並於室溫攪拌1天前,將混合物保持在室溫共2小時。濃縮混合物並於EtOAc(10 mL)與水(10 mL)中分成多份;將有機層分開,乾燥並蒸發,並將得到的殘餘物藉由管柱色層分析法純化以得到呈淡黃色油的化合物30(0.20 g)。1
H-NMR(CDCl3
)8.5(m,2H),7.2-7.4(m,10H),3.6-4.0(m,6H),3.3-3.6(m,8H)ppm;ESMS計算值C19
H26
N4
O4
P2
S2
:500.1;實際值:501.2(M+H+
)。
D.化合物69之合成
逐滴將二氯磷酸苯(5mmol)加入N-甲基苯并硫醯肼(10 mmol)於DCM(20 mL)的0℃溶液。在將混合物倒入水(20 mL)中之前,將其保持在室溫共2小時。將有機層分開,乾燥並蒸發,並將得到的殘餘物藉由管柱色層分析法純化以得到呈淡黃色固體之化合物69(0.8 g)。
1
H-NMR(CDCl3
)8.6(m,4H),7.2-7.5(m,16H),3.3-3.6(m,6H)ppm;ESMS計算值C28
H26
N4
O4
P2
S2
:608.1;實際值:609.2(M+H+
)。
E.化合物70與71之合成
化合物70與71係如於流程A中所述而製備:
流程A將EDC(480mg,2.5 mmol)加入Comp.A(335 mg,2.0 mmol)與二羧酸(1.0mmol)於DMF或DCM(10 mL)之溶液。將反應混合物攪拌共12小時。反應之完成程度係以TLC判斷。將反應混合物以DCM(25mL)稀釋並以水與鹵水洗滌。將有機層以MgSO4
乾燥並過濾。在移出溶劑後,將產物藉由色層分析法管柱純化。
N'1,N'3-二甲基-N'1,N'3-二(苯基碳噻吩基)-2-(2-苯基亞肼基)-丙二醯肼(化合物70)
C25
H24
N6
O2
S2
之ESMS計算值:504.14;實際值:505.2(M+H)+
。
N'1,N'3-二甲基-2-(2-甲基亞肼基)-N'1,N'3-二(苯基碳噻吩)-丙二醯肼(化合物71)
C20
H22
N6
O2
S2
之ESMS計算值:442.12;實際值:443.3(M+H)+
。
F. 2-甲基-N-(2-甲基-2-(苯基碳噻吩基)肼基磺醯基)-2-(苯基碳噻吩基)肼甲醯胺(化合物72)之合成
化合物72係如於流程B中所述製備
將Et3
N(300mg,3.0 mmol)加入comp.A(335 mg,2.0 mmol)與異氰酸酯化合物(1.0 mmol)於THF或EtOH(15mL)之溶液。將反應混合物攪拌共12小時。反應的完成度係以TLC判斷。將反應混合物在真空下濃縮,並將殘餘物以DCM(25mL)稀釋並以水與鹵水洗滌。將有機層以MgSO4
乾燥並過濾。在移出溶劑後,將產物藉由色層分析法管柱純化。
C17
H19
N5
O3
S3
之ESMS計算值:437.07;實際值:438.1(M+H)+
。
本發明之化合物誘導Hsp70 RNA誘發之能力係藉由定量性PCR分析檢查。Ramos B細胞係以500nM之每種化合物處理6個小時,並自細胞分離RNA。定量性PCR係如以下敘述進行:定量性PCR之細節係如下:將來自每個樣本之500ng的RNA用於cDNA合成,其使用iScript cDNA合成套組(iScript cDNA Synthesis Kit,Biorad,Cat# 170-8891)。使用1 ul的cDNA混合物加上iQ SYBR Green超混合物(iQ SYBR Green Supermix,Biorad,Cat# 170-8882)以於iCycler機械(Biorad)使用標準方法進行定量性PCR。以二重複進行對每個樣本/時間點之QPCR。使用以下用於可誘導性人類Hsp70以及gapdh之引子:Hsp70-F3 5`-AAG-GAC-ATC-AGC-CAG-AAC-AAG-CG-3’ Hsp70-R3 5`-AAG-AAG-TCC-TGC-AGC-AGC-TTC-TGC-3’ Gapdh-F2 5`-AAG-GTC-GGA-GTC-AAC-GGA-TTT-GGT-3` Gapdh-R2 5`-CAT-GGT-TCA-CAC-CCA-TGA-CGA-ACA-3’自iCycler程式獲得Ct值並將其用於方程式(2-△△C T
)以測定目標相對於gapdh表現之量。此比較在每個樣本中Hsp70對gapdh之對應水平的相對表現。平均二重複槽孔。Hsp70之正丙二醯基-雙(N’-甲基-N’硫代苯甲醯基醯肼)(化合物B
)誘發的量係設定為100%,而藉由本發明之化合物之Hsp70誘發的百分比係相對於100%測定。
藉由定量性PCR分析測定之本發明之化合物誘導Hsp70 RNA誘發之能力係列於以下表中。
所有本文所引用且並未明白指出係以引用方式納入本文中之刊物的相關教示,其全文係以引用方式納入本文中。
雖然本發明已特別地以參照其較佳的具體態樣之方式顯示與敘述,熟習該項技術者會瞭解可在其中做出各種在形式上與在細節上之改變,而不會偏離本發明為所附申請專利範圍所涵蓋之範圍。
圖1係汰癌勝(太平洋紫杉醇)之結構。
圖2係剋癌易(多西紫杉醇)之結構。
圖3-23各自描繪特別的汰癌勝類似物之結構。
圖24係包括自聚合物骨架伸出之汰癌勝類似物基團之聚合物之結構。該聚合物係三個如所示之單體單元之三聚物。
Claims (13)
- 一種由式(VII)所代表的化合物,
- 根據申請專利範圍第1項的化合物,其中兩個Z基團皆為S。
- 根據申請專利範圍第1項的化合物,其中兩個Z基團皆為O。
- 根據申請專利範圍第1項的化合物,其中:R1 與R2 皆係苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係苯基;R3 與R4 皆係乙基;R7 與R8 皆係-H;R1 與R2 皆係4-甲氧基苯基;R3 與R4 皆係甲基;R7 與 R8 皆係-H;R1 與R2 皆係4-氰基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2,5-二甲氧基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係3-氰基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係3-氟苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2-二甲氧基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係3-甲氧基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2,3-二甲氧基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2,5-二氟苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2,5-二氯苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2,5-二甲基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;R1 與R2 皆係2,5-二甲氧基苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H;或R1 與R2 皆係苯基;R3 與R4 皆係甲基;R7 與R8 皆係-H。
- 根據申請專利範圍第1項的化合物,其由以下結構式代表:
- 一種由式(XIII)所代表的化合物,
- 根據申請專利範圍第6項的化合物,其由以下結構式代表:
- 一種醫藥組合物,其包括藥學上可接受的載劑或稀釋劑與根據申請專利範圍第1或6項的化合物。
- 根據申請專利範圍第8項的醫藥組合物,其進一步包括一種或多種額外的治療劑。
- 一種根據申請專利範圍第1或6項的化合物之用途,其係用於製備用於治療具有癌症之受藥者的醫藥品。
- 根據申請專利範圍地第10項的用途,其中該癌症係多重抗藥性癌症。
- 根據申請專利範圍地第10項的用途,其中該醫藥品係偕同額外的抗癌劑投藥,其中該額外的抗癌症劑係微管穩定劑。
- 根據申請專利範圍地第10項的用途,其中該醫藥品係偕同汰癌勝或汰癌勝類似物投藥。
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TW200815383A (en) | 2008-04-01 |
JP2013216662A (ja) | 2013-10-24 |
KR20090045354A (ko) | 2009-05-07 |
WO2008024303A2 (en) | 2008-02-28 |
AU2007288338B2 (en) | 2012-05-03 |
WO2008024303A3 (en) | 2008-11-27 |
NZ575350A (en) | 2012-02-24 |
IL196937A0 (en) | 2009-11-18 |
RU2475478C2 (ru) | 2013-02-20 |
CA2660524A1 (en) | 2008-02-28 |
SG174087A1 (en) | 2011-09-29 |
US9156783B2 (en) | 2015-10-13 |
US20100081635A1 (en) | 2010-04-01 |
NO20090623L (no) | 2009-03-20 |
RU2009109949A (ru) | 2010-09-27 |
MX2009001877A (es) | 2009-03-02 |
EP2057117A2 (en) | 2009-05-13 |
JP2010501562A (ja) | 2010-01-21 |
BRPI0716435A2 (pt) | 2014-03-04 |
AU2007288338A1 (en) | 2008-02-28 |
TW201422598A (zh) | 2014-06-16 |
US8609720B2 (en) | 2013-12-17 |
JP5775545B2 (ja) | 2015-09-09 |
US20150025042A1 (en) | 2015-01-22 |
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