TWI818930B - 8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其用於治療增生性疾病的用途 - Google Patents
8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其用於治療增生性疾病的用途 Download PDFInfo
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Abstract
本文描述了新穎的化合物8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其藥學上可接受的鹽,以及使用它們治療包括癌症在內的細胞增生性疾病的方法。
Description
本發明涉及化合物和藥學上可接受的鹽,藥物組合物,其製備方法,以及它們用於治療癌症和其他細胞增生性疾病的用途。
癌症等細胞增生性疾病是已開發國家最常見的死亡原因。對於存在治療方式的疾病,例如癌症,儘管持續進步,但現有的治療方式具有不良的副作用和有限的功效。腫瘤細胞經常對現有治療方式產生抗性。因此,需要用於細胞增生性疾病(包括癌症)的新穎的有效藥物。
細胞週期蛋白依賴性激酶(Cyclin dependant kinases,Cdk)及其伴侶週期蛋白(partner cyclins)是一類作為細胞增生調節劑的全酶(holoenzymes)。選擇性Cdk4抑制劑,例如palbociclib,其抗增生活性已被認識,且palbociclib已被批准用於治療某些形式的乳癌。然而,服用palbociclib的患者具有高發生率的副作用,包括嗜中性白血球減少和抗性。ARK5(AMPK related protein kinase-5,AMPK
相關蛋白激酶-5)是與細胞生長調節相關的另一種激酶,且該激酶的過度表現與多種形式的癌症,特別是多發性骨髓瘤的腫瘤侵襲和轉移相關。
本發明至少部分地肯定,在作為多特異性蛋白激酶抑制劑上,8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基(ON 1232580)被發現具有令人驚訝的改善的效力。此外,8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基在作為一種有效的細胞毒性劑,適用於廣泛的癌細胞類型,特別是針對B細胞非霍奇金淋巴瘤、前列腺癌、子宮頸癌和慢性骨髓性白血病(chronic myelogenous leukemia,CML)的方面,也是令人驚訝的。
及其藥學上可接受的鹽。
在本發明的第二態樣,提供了一種藥物組合物,其包含式I化合物及其藥學上可接受的鹽和一種或多種藥學上可接受的賦形劑。
在本發明的另一態樣,提供了一種透過給予有需要的患者治療有效量的式I化合物及其藥學上可接受的鹽來治療增生性疾病的方法。
在本發明的另一態樣,提供了一種透過給予有需要的患者治療有效量的式I化合物及其藥學上可接受的鹽來治療癌症的方法。
在本發明的另一態樣,提供了一種藥物組合物,其係用於透過給予有需要的患者治療有效量的式I化合物及其藥學上可接受的鹽來治療癌症和增生性疾病。
本發明還提供了治療個體的細胞增生性疾病的方法,包括給予個體有效量的式I化合物或其鹽中的至少一種。
在某些實施方式中,細胞增生性疾病係選自由新生兒血管瘤症(hemangiomatosis in newborn)、繼發進行性多發性硬化症(secondary progressive multiple sclerosis)、動脈粥樣硬化(atherosclerosis)、慢性進行性骨髓增生性疾病(chronic progressive myelodegenerative disease)、神經纖維瘤症(neurofibromatosis)、神經結細胞瘤(ganglioneuromatosis)、瘢痕瘤形成(keloid formation)、骨佩吉特氏病(Paget’s disease of the bone)、乳腺纖維囊性疾病(fibrocystic disease of the breast)、子宮肌瘤(uterine fibroids)、佩羅尼氏症(Peyronie’s disease)、掌腱膜攣縮症(Dupuytren’s disease)、再狹窄(restenosis)、良性增生性乳腺疾病(benign proliferative breast disease)、良性前列腺增生(benign prostatic hyperplasia)、X連鎖淋巴細胞增生性疾病(X linked lymphocellular proliferative disorder)、移植後淋巴細胞增生性疾病(post transplantation lymphocellular proliferative disorder)、黃斑退化(macular degeneration)、視網膜病變(retinopathies)、增生性玻璃體視網膜病變(proliferative vitreoretinopathy)和非癌性淋巴細胞增生性疾病(non-cancerous lymphocellular proliferative disorders)所組成之群組。
在特定實施方式中,細胞增生性疾病是癌症。在一些實施方式中,癌症係選自由卵巢癌(ovarian cancer);子宮頸癌(cervical cancer);乳癌(breast cancer);前列腺癌(prostate cancer);睾丸癌(testicular cancer)、肺癌(lung cancer)、腎癌(renal cancer);結直腸癌(colorectal cancer);皮膚癌(skin cancer);腦癌(brain cancer);白血病(leukemia),包括急性骨髓性白血病(acute myeloid leukemia)、慢性骨髓性白血病(chronic myeloid leukemia)、急性淋巴細胞白血病(acute lymphoid leukemia)和慢性淋巴細胞白血病(chronic lymphoid leukemia);淋巴瘤(lymphoma),包括B細胞淋巴瘤(B-cell lymphoma)、非何杰金氏淋巴瘤(non-Hodgkin’s lymphoma)和外膜細胞淋巴瘤(Mantle Cell lymphoma)所組成之群組。
本發明進一步提供一種誘導患有癌症的個體中的癌細胞凋亡(apoptosis)的方法,包括給予個體有效量的式I化合物或其鹽。
在一些實施方式中,癌細胞是腫瘤細胞。在特定實施方式中,腫瘤細胞選自卵巢(ovarian)、子宮頸(cervical)、子宮(uterine)、陰道(vaginal)、乳腺(breast)、前列腺(prostate)、睾丸(testicular)、肺(lung)、腎(renal)、結腸直腸(colorectal)、胃(stomach)、腎上腺(adrenal)、口腔(mouth)、食道(esophageal)、肝(hepatic)、膽囊(gall bladder)、骨(bone)、骨髓(bone marrow)、淋巴(lymphatic)、眼睛(eye)、皮膚(skin)和腦(brain)腫瘤細胞所組成之群組。
本發明進一步提供一種抑制需要這種治療的哺乳動物的激酶活性的方法,該方法包括給予治療有效量的式I化合物或其藥學上可接受的鹽。在某些實施方式中係抑制下列激酶中的一種或多種:ARK5、CDK4/6、ABL1、FGFR1、
FLT3、FLT4/VEGFR3、FYN、PDGFRb和RET。較佳地,其係抑制兩種或更多種,或三種或更多種該等激酶。
在本發明的另一態樣,提供了一種8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其藥學上可接受的鹽之用途,其係用於製備治療癌症和增生性疾病的藥物,其中所述藥物包含治療有效劑量。
在本發明的另一態樣,提供了一種8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其藥學上可接受的鹽,其係用於治療由異常細胞增生介導的病症。較佳地,這種病症是癌症;或者這種病症係選自由卵巢癌、子宮頸癌、子宮癌、陰道癌、乳癌、前列腺癌、睾丸癌、肺癌、腎癌、結腸直腸癌、胃癌、腎上腺癌、口腔癌、食道癌、肝癌、膽囊癌、骨癌、骨髓癌、白血病、淋巴瘤、眼睛癌、皮膚癌和腦癌所組成之群組的癌症;或者這種病症是選自白血病的癌症,包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病和慢性淋巴性白血病;或者這種病症是選自淋巴瘤的癌症,包括B細胞淋巴瘤、非何杰金氏淋巴瘤和外膜細胞淋巴瘤;或者這種病症是選自乳癌、多發性骨髓瘤、B細胞淋巴瘤、前列腺癌和子宮頸癌的癌症;或者這種病症是激素受體陽性、人表皮生長因子受體2陰性的晚期或轉移性乳癌。藥物治療包括使用治療有效量的式I化合物及其藥學上可接受的鹽來治療人類。
本說明書中提及的所有出版物和專利申請均以引用的方式整體併入本文,其程度如同每個單獨的出版物或專利申請具體和單獨地被指出透過引用併入。
本發明提供新穎的化合物8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基(8-Cyclopentyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile)(ON 1232580)及其藥學上可接受的鹽。發明人發現作為多特異性蛋白激酶抑制劑,8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基具有令人驚訝的改善的效力。此外,令人驚訝地,8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基係為一種有效的細胞毒性劑,適用於廣泛的癌細胞類型,特別是針對B細胞非何杰金氏淋巴瘤、前列腺癌、子宮頸癌和慢性骨髓性白血病。
本發明的化合物和組合物被認為能選擇性地抑制癌細胞的增生,並殺死各種腫瘤細胞類型。本發明化合物抑制各種蛋白激酶。如下面進一步詳細描述的,本發明化合物顯示出令人驚訝的抑制ARK5、CDK4/6以及ABL1、CDK9、FGFR1、FLT3、VEGFR3、FYN、PDGFRb和RET的效力。
本發明化合物被認為能抑制腫瘤細胞的增生並誘導細胞死亡。細胞死亡是由誘導細胞凋亡引起的。該化合物被認為對廣泛的腫瘤類型有效,包括但不限於以下:卵巢癌、乳癌、前列腺癌、肺癌、腎癌、結腸直腸癌、腦癌、淋巴瘤和白血病。令人驚訝的是,ON 1232580是GRANTA-519細胞的有效殺手,GRANTA-519細胞是B細胞非何杰金氏淋巴瘤細胞株,特別是外膜細胞淋巴瘤。相反,順鉑對GRANTA-519細胞毒性不大。如細胞毒性研究所示,ON 1232580
也是DU 145細胞(前列腺癌)、HeLa細胞(子宮頸癌)和K-562細胞(人類骨髓性白血病)的有效抑制劑。
該化合物還被認為能用於治療非癌細胞增生性疾病,包括但不限於以下:新生兒血管瘤症、繼發進行性多發性硬化症、動脈粥樣硬化、慢性進行性骨髓增生性疾病、神經纖維瘤症、神經結細胞瘤、瘢痕瘤形成、骨佩吉特氏病、乳腺纖維囊性疾病、子宮肌瘤、佩羅尼氏症、掌腱膜攣縮症、再狹窄、良性增生性乳腺疾病、良性前列腺增生、X連鎖淋巴細胞增生性疾病、移植後淋巴細胞增生性疾病、黃斑退化、視網膜病變、增生性玻璃體視網膜病變和非癌性淋巴細胞增生性疾病。
術語
除非另外定義,否則本文使用的所有技術和科學術語具有與本發明所屬領域的技術人員通常理解的含義相同的含義。
本說明書中使用的術語具有以下含義:如本文所用,術語「藥物組合物」是指例如在藥學上可接受的載體中含有特定量(例如:治療有效量)的治療化合物的混合物,用來給予哺乳動物(例如:人類)以治療疾病。
如本文所用,術語「藥學上可接受的」是指那些在合理的醫學判斷範圍內適合與哺乳動物,尤其是人類組織接觸而沒有過多毒性、刺激、過敏反應和其他有問題的併發症且相稱地具有合理的利益/風險比的化合物、材料、組合物和/或劑型。
如說明書和所附申請專利範圍中所使用的,除非上下文另有明確規定,單數形式「一」、「一個」和「該」包括複數指示物。
如本文所用,術語「治療」和「治療方式」可互換使用,意在表示疾病發展的延遲和/或將要或預期發展的症狀嚴重程度的降低。該等術語還包括改善現有症狀、預防其他症狀以及改善或預防症狀的潛在代謝原因。該等術語應理解為意指用於對抗疾病、病症或症狀的患者的管理和護理。
如本文所用,「個體」(如在治療的對象中)是指哺乳動物和非哺乳動物。哺乳動物包括例如:人類;非人靈長類動物,例如:猿猴;牛;馬;羊;和山羊。非哺乳動物包括例如:魚和鳥。
當用於描述患有癌症或其他細胞增生性疾病的個體的治療時,表述「有效量」是指式I的化合物的量,其抑制異常生長或增生,或者誘導癌症的細胞凋亡,較佳為腫瘤細胞,對增生細胞產生治療上有用和/或選擇性的細胞毒性作用。
術語「細胞增生性病症」是指其中發生多細胞生物體中一種或多種細胞亞群的不必要的細胞增生的病症。在一些此類病症中,細胞由生物體以非典型地加速的速率製造。
本發明之化合物
及其藥學上可接受的鹽。
在一個態樣中,較佳的是式I的化合物和選自無機酸(例如:HCl)和有機酸(例如:乳酸)的藥學上可接受的鹽。
在其他較佳的實施方式中,式I化合物或其任何實施方式是透過化學合成製備的純化合物,並透過分析方法確認純度。在其它較佳的實施方式中,式I化合物和含有所述化合物(包括藥物組合物)的組合物實質上不含有藥學上不可接受的污染物。藥學上不可接受的污染物是一種物質,如果其含量超過非實質量,將使該化合物或組合物不適合用來作為治療性給藥的藥物。實例包括有毒物質,如鹵化溶劑和重金屬,以及潛在傳染性的物質,如細菌、真菌、病毒、細菌和真菌孢子。
式I的化合物的鹽
本發明的化合物可以採取鹽的形式。術語「鹽」包括作為本發明化合物的式I化合物的加成鹽。術語「藥學上可接受的鹽」是指具有在藥學應用中提供效用的範圍內的具有毒性特徵的鹽。儘管如此,藥學上不可接受的鹽可具
有例如高結晶度的性質,其在本發明的實施中具有實用性,例如在本發明化合物的合成、純化或配製過程中的實用性。
合適的藥學上可接受的酸加成鹽可以由無機酸或有機酸製備。無機酸的實例包括鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、硫酸和磷酸。合適的有機酸可選自脂族酸、脂環族酸、芳族酸、芳脂族酸、雜環羧酸和磺酸,其實例包括甲酸(formic acid)、乙酸(acetic acid)、丙酸(propionic acid)、琥珀酸(succinic acid)、乙醇酸(glycolic acid)、葡萄糖酸(gluconic acid)、乳酸(lactic acid)、蘋果酸(malic acid)、酒石酸(tartaric acid)、檸檬酸(citric acid)、抗壞血酸(ascorbic acid)、葡萄糖醛酸(glucuronic acid)、馬來酸(maleic acid)、延胡索酸(fumaric acid)、丙酮酸(pyruvic acid)、天冬氨酸(aspartic acid)、谷氨酸(glutamic acid)、苯甲酸(benzoic acid)、鄰胺苯甲酸(anthranilic acid)、4-羥基苯甲酸(4-hydroxybenzoic acid)、苯乙酸(phenylacetic acid)、杏仁酸(mandelic acid)、撲酸(embonic(pamoic)acid)、甲磺酸(methanesulfonic acid)、乙磺酸(ethanesulfonic acid)、苯磺酸(benzenesulfonic acid)、泛酸(pantothenic acid)、三氟乙酸(trifluoroacetic acid)、三氟甲磺酸(trifluoromethanesulfonic acid)、2-羥基乙磺酸(2-hydroxyethanesulfonic acid)、對甲苯磺酸(p-toluenesulfonic acid)、對胺基苯磺酸sulfanilic(acid)、環己基胺基磺酸(cyclohexylaminosulfonic acid)、硬脂酸(stearic acid)、海藻酸(alginic acid)、β-羥基丁酸(β-hydroxybutyric)、水楊酸(salicylic acid)、半乳糖酸(galactaric acid)和半乳醣醛酸(galacturonic acid)。藥學上不可接受的酸加成鹽的實例包括,例如:過氯酸鹽(perchlorates)和四氟硼酸鹽(tetrafluoroborates)。
在一個態樣中,式I化合物的較佳的鹽包括鹽酸鹽和乳酸鹽。乳酸鹽包括使用(R)-、(S)-和(RS)-乳酸異構體製備的鹽。
這些鹽都可以透過常規方法由相應的式I化合物和適當的酸製備。較佳地,鹽是結晶形式,並且較佳地透過從合適的溶劑中的鹽的結晶來製備。本發明所屬技術領域中具有通常知識者將知道如何製備和選擇合適的鹽形式,例如,如Handbook of Pharmaceutical Salts:Pryperties,Selection,and Use By P.H.Stahl and C.G.Wermuth(Wiley-VCH 2002)中所述。
製備本發明化合物的方法
下面的實施例1提供了合成式I化合物及其鹽的方法。該化合物,包括本發明的鹽和中間體,可以從它們的反應混合物中分離並透過標準技術純化,例如過濾、液體-液體萃取、固相萃取、蒸餾、重結晶或色譜法,包括快速柱色譜法或HPLC。用於純化式I化合物或其鹽的較佳方法包括使化合物或鹽從溶劑中結晶,用以較佳地形成結晶形式的化合物或其鹽。結晶後,透過蒸發以外的方法(例如:過濾或傾析)除去結晶溶劑,然後較佳地使用純溶劑(或純溶劑的混合物)洗滌晶體。用於結晶的較佳溶劑包括水、醇,特別是含有最多四個碳原子的醇,例如:甲醇(methanol)、乙醇(ethanol)、異丙醇(isopropanol)和丁-1-醇(butan-1-ol)、丁-2-醇(butan-2-ol)和2-甲基-2-丙醇(2-methyl-2-propanol)、醚(ethers),例如:二乙醚(diethyl ether)、二異丙醚(diisopropyl ether)、甲基第三丁基醚(t-butyl methyl ether)、1,2-二甲氧基乙烷(1,2-dimethoxyethane)、四氫呋喃(tetrahydrofuran)和1,4-二噁烷(1,4-dioxane)、羧酸(carboxylic acids),例如:甲酸(formic acid)和乙酸(acetic acid)以及烴溶劑(hydrocarbon solvents),例如:戊烷(pentane)、己烷(hexane)、甲苯(toluene)及其混合物,特別是含水混合物,如含水乙醇。其他可能的溶劑包括乙酸乙酯(ethyl acetate)。較佳係使用純溶劑,較佳係至少為分析級,更佳係藥用級。在本發明方法的一個較佳實施方式中,產物是如
此分離的。在根據式I的本發明化合物或其鹽及其藥物組合物中,根據式I的化合物或其鹽較佳係在結晶形式中或由結晶形式製備,較佳係根據這種方式製備。
本發明所屬技術領域中具有通常知識者將理解,所述方法不是可以合成本發明化合物的唯一方法,並且可以使用極其廣泛的合成有機反應來有效地合成本發明化合物。本發明所屬技術領域中具有通常知識者知道如何選擇和實施合適的合成途徑。合適的合成方法可以參考文獻確定,包括參考資料例如:Comprehensive Organic Synthesis,Ed.B.M.Trost and I.Fleming(Pergamon Press,1991)、Comprehensive Organic Functional Group Transformations,Ed.A.R.Katritzky,O.Meth-Cohn,and C.W.Rees(Pergamon Press,1996)、Comprehensive Organic Functional Group Transformations II,Ed.A.R.Katritzky and R.J.K.Taylor(Editor)(Elsevier,2nd Edition,2004)、Comprehensive Heterocyclic Chemistry,Ed.A.R.Katritzky and C.W.Rees(Pergamon Press,1984)、Comprehensive Heterocyclic Chemistry II,Ed.A.R.Katritzky,C.W.Rees,and E.F.V.Scriven(Pergamon Press,1996)以及Advanced Organic Chemistry,4 th Ed.,J.March(John Wiley & Sons,1992)。
劑型和給予途徑
8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其藥學上可接受的鹽可以多種劑型給予。本發明化合物可以以藥物組合物的形式與藥學上可接受的載體組合給藥。此類製劑中可以包含0.1至99.99重量%的活性成分。「藥學上可接受的載體」是指任何載體、稀釋劑或賦形劑,其與製劑的其他成分相容並且對接受者無害。
較佳係將活性劑與基於所選擇的給藥途徑和標準藥學實施而選擇的藥學上可接受的載體一起給藥。根據藥物製劑領域的標準實施,可以將活性劑
配製成劑型。見Alphonso Gennaro,ed.,Remington’s Pharmaceutical Sciences,18th Edition(1990),Mack Publishing Co.,Easton,PA。合適的劑型可包括例如:片劑、膠囊、溶液、腸胃外溶液、錠劑、栓劑或懸浮液。
對於腸胃外給藥,包括注射給藥,可以將活性劑與合適的載體或稀釋劑混合,例如:水、油(特別是植物油)、乙醇、鹽水溶液,葡萄糖水溶液(葡萄糖)和相關的糖溶液、甘油或二醇,如:丙二醇(propylene glycol)或聚乙二醇(polyethylene glycol)。腸胃外給藥的溶液較佳係含有活性劑的水溶性鹽。還可以添加穩定劑、抗氧化劑和防腐劑。合適的抗氧化劑包括亞硫酸鹽、抗壞血酸、其鹽和酯、半胱氨酸及其衍生物、檸檬酸及其鹽和EDTA鈉。合適的防腐劑包括氯化烷基二甲基苄基銨(benzalkonium chloride)、對羥基苯甲酸甲酯(methyl-paraben)或對羥基苯甲酸丙酯(propyl-paraben)和氯丁醇(chlorbutanol)。用於腸胃外給藥的組合物可以採用水性或非水性溶液、分散液、懸浮液或乳液的形式。
對於口服給藥,活性劑可以與一種或多種固體非活性成分組合,用於製備片劑、膠囊、丸劑、粉劑、顆粒劑或其它合適的口服劑型。例如,活性劑可以與至少一種賦形劑組合,例如:填充劑、黏合劑、保濕劑、崩解劑、溶液緩凝劑、吸收促進劑、潤濕劑、吸收劑或潤滑劑。根據一個片劑實施方式,活性劑可以與羧甲基纖維素鈣(carboxymethylcellulose calcium)、硬脂酸鎂(magnesium stearate)、甘露醇(mannitol)和澱粉(starch)組合,然後透過常規壓片方法形成片劑。
當然,根據本發明的化合物的特定劑量以獲得治療細胞增生性疾病的治療益處,將由個體患者的特定情況決定,包括患者的大小、體重、年齡和性別、細胞增生性疾病的性質和階段、細胞增生性疾病的侵襲性和化合物的給藥途徑。
例如,可以使用約0.05至約50mg/kg/天的日劑量,更佳為約0.1至約10mg/kg/天。也考慮更高或更低的劑量,因為在某些情況下可能需要使用超出這些範圍的劑量。可以將每日劑量分開,例如將每日給藥等量地分成每天兩到四次。較佳係將組合物配製成單位劑型,每劑量含有每單位劑量約1至約500mg,更通常為約10至約100mg的活性劑。術語「單位劑型」是指適合作為人類受試者和其他哺乳動物的單位劑量的物理上離散的單位,每個單位含有預定量的活性物質,經計算可產生所需的治療效果,並與合適的藥物賦形劑結合。
用於配製藥物組合物的組分具有高純度並且基本上不含潛在有害的污染物(例如:至少國家食品級,通常至少為分析級,更通常至少為藥用級)。特別是用於人類服用,該組合物較佳在美國食品和藥物管理局(U.S.Food and Drug Administration)的適用法規中定義的良好作業規範(Good Manufacturing Practice,GMP)標準下製造或配製。舉例來說,合適的製劑可以是無菌的及/或基本上等滲的及/或完全符合美國食品和藥物管理局的所有良好作業規範法規。
所述化合物可以透過任何途徑給予,包括但不限於:口服、直腸、舌下、口腔、眼、肺和腸胃外給藥,或作為口腔或鼻腔噴霧劑(例如:吸入霧化蒸氣、液滴或固體顆粒)。腸胃外給藥包括,例如:靜脈內、肌肉內、動脈內、腹膜內、鼻內、陰道內、膀胱內(例如:至膀胱)、皮內、透皮、局部或皮下給藥。藥物組合物可以是用於腸胃外使用的無菌可注射溶液的形式,包括在給藥前稀釋的濃縮溶液。在本發明範圍內還考慮以受控製劑在患者體內滴注藥物,藥物的全身或局部釋放在稍後時間發生。舉例來說,藥物可以位於貯存庫中以控制到循環中的釋放,或控制到腫瘤生長的局部位點的釋放。
可用於實施本發明的一種或多種化合物可以透過相同或不同的途徑,同時或在治療期間的不同時間給藥。該等化合物可以在其他藥物(包括其他抗增生化合物)之前、同時或之後給藥。
治療可以根據需要在一個單一的、不間斷的區段中或在離散的區段中進行一段時間。治療醫師將根據患者的反應了解如何增加、減少或中斷治療。根據一個實施方案,治療進行約4周至約16週。可根據需要重複治療時間表。
活性劑可以配製用於腸胃外給藥(例如:透過注射,例如:在稀釋濃縮製劑後透過連續輸注),並且可以以在含有或不含防腐劑的安瓿、小瓶、預填充注射器、小體積輸注或多劑量容器中的單位劑量的形式存在。腸胃外製劑可包括合適的抗氧化劑、滲透壓調節劑、穩定劑和其他藥學上可接受的賦形劑。合適的抗氧化劑包括:亞硫酸氫鈉(sodium bisulfite)、亞硫酸鈉(sodium sulfite)、抗壞血酸鈉(sodium ascorbate)、L-半胱胺酸(L-cysteine)及其衍生物、硫代硫酸鈉(sodium thiosulfate)、甲醛次硫酸鈉(sodium formaldehyde sulfoxylate)、檸檬酸(citric acid)、d,l-α-生育酚(d,l-α-tocopherol)、丁基化羥基苯甲醚(butylated hydroxy anisole)、丁基化羥基甲苯(butylated hydroxy toluene)、單硫代甘油(monothioglycerol)、抗壞血酸(ascorbic acid)、其鹽和酯,以及沒食子酸丙酯(propyl gallate)。
本發明包括藥物包或藥物套組,包含口服劑型、小瓶或安瓿,口服劑型、小瓶或安瓿包含8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2.3-d]嘧啶-6-氰基及其藥學上可接受的鹽,以及選擇性地作為載體的合適液體(如:水)的容器。選擇性地,藥物包或藥物套組可以包括或具有與其相關的須
知,其形式由管理藥品或生物製品的製造、使用或銷售的政府機構規定,該須知反映了製造、使用或銷售的機構對於人類給藥的核准。
治療方法
根據本發明的另一個實施方式,提供了治療患有細胞增生性疾病,特別是癌症的個體的方法,包括給予所述個體有效量的至少一種式I化合物或藥學上可接受的鹽,其可單獨使用,或與藥學上可接受的載體組合使用。
根據本發明的另一個實施方式,提供了在患有癌症的個體中誘導癌細胞,較佳為腫瘤細胞凋亡的方法,包括給予所述個體有效量的至少一種式I的化合物,或其藥學上可接受的鹽,其可單獨使用,或與藥學上可接受的載體組合使用。
本發明還涉及式I化合物或其藥學上可接受的鹽在藥物中的用途。
本發明還涉及式I化合物及其藥學上可接受的鹽,其用於治療增生性疾病或用於誘導腫瘤細胞的凋亡。
本發明還涉及包含式I化合物或其藥學上可接受的鹽的藥物,其用於治療增生性疾病或用於誘導腫瘤細胞的凋亡。
本發明還涉及式I化合物或其藥學上可接受的鹽在製備用於治療細胞增生性疾病(特別是癌症)的藥物中的用途,或其在製備用於誘導患有癌症的個體中腫瘤細胞凋亡的藥物中的用途。
本發明化合物可以給予患有細胞增生性疾病如癌症、惡性和良性腫瘤、血管增生性疾病、自身免疫性疾病和纖維變性疾病的個體(哺乳動物,包括動物和人)。在本發明的一個具體實施方式中,所治療的個體、對象或患者是人類。
該化合物被認為對多種腫瘤類型有效,包括但不限於下列:卵巢癌;子宮頸癌;乳癌;前列腺癌;睾丸癌;肺癌;腎癌;結直腸癌;皮膚癌;腦癌;白血病,包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴細胞白血病和慢性淋巴細胞白血病、淋巴瘤,包括B細胞淋巴瘤、非何杰金氏淋巴瘤和外膜細胞淋巴瘤。
更具體地,可以透過本發明的化合物,組合物和方法治療的癌症包括但不限於下列:乳癌(Breast cancers),包括例如:導管癌(ductal carcinoma)、管狀癌(tubular carcinoma)、髓樣癌(medullary carcinoma)、黏液癌(mucinous carcinoma)、乳突癌(papillary carcinoma)和篩狀癌(cribriform carcinoma);賁門癌(cardiac cancers),包括例如:肉瘤(sarcoma),如:血管肉瘤(angiosarcoma),纖維肉瘤(fibrosarcoma)、橫紋肌肉瘤(rhabdomyosarcoma)和脂肪肉瘤(liposarcoma);黏液瘤(myxoma);橫紋肌瘤(rhabdomyoma);纖維瘤(fibroma);脂肪瘤(lipoma)和畸胎瘤(teratoma);肺癌(lung cancers),包括例如:支氣管肺癌(bronchogenic carcinoma),如:鱗狀細胞(squamous cell)、未分化的小細胞(undifferentiated small cell)、未分化的大細胞(undifferentiated large cell)和腺癌(adenocarcinoma);肺泡(alveolar)和細支氣管癌(bronchiolar carcinoma);支氣管腺瘤(bronchial adenoma);肉瘤(sarcoma);淋巴瘤(lymphoma);軟骨錯構瘤(chondromatous hamartoma);和間皮瘤(mesothelioma);胃腸癌(gastrointestinal cancer),包括例如:食道癌(cancers of the esophagus),如:鱗狀細胞癌(squamous cell carcinoma)、腺癌(adenocarcinoma)、
平滑肌肉瘤(leiomyosarcoma)和淋巴瘤(lymphoma);胃癌(cancers of the stomach),如:惡性腫瘤(carcinoma)、淋巴瘤(lymphoma)和平滑肌肉瘤(leiomyosarcoma);胰臟癌(cancers of the pancreas),如:導管腺癌(ductal adenocarcinoma)、胰島素瘤(insulinoma)、升糖素瘤(glucagonoma)、胃泌素瘤(gastrinoma)、類癌瘤(carcinoid tumors)和VIP瘤(vipoma);小腸癌(cancers of the small bowel),如:腺癌(adenocarcinoma)、淋巴瘤(lymphoma)、類癌瘤(carcinoid tumors)、卡波西氏肉瘤(Kaposi’s sarcoma)、平滑肌瘤(leiomyoma)、血管瘤(hemangioma)、脂肪瘤(lipoma)、神經纖維瘤(neurofibroma)和纖維瘤(fibroma);大腸癌(cancers of the large bowel),如:腺癌(adenocarcinoma)、管狀腺瘤(tubular adenoma)、絨毛狀腺瘤(villous adenoma)、錯構瘤(hamartoma)和平滑肌瘤(leiomyoma);泌尿生殖道癌(genitourinary tract cancers),包括例如:腎癌(cancers of the kidney),如:腺癌(adenocarcinoma)、威爾姆氏瘤(Wilm’s tumor)(腎母細胞瘤(nephroblastoma))、淋巴瘤(lymphoma)和白血病(leukemia);膀胱癌(cancers of the bladder)和尿道癌(cancers of the urethra),如:鱗狀細胞癌(squamous cell carcinoma)、移行細胞癌(transitional cell carcinoma)和腺癌(adenocarcinoma);前列腺癌(cancers of the prostate),如:腺癌(adenocarcinoma)和肉瘤(sarcoma);睾丸癌(cancer of the testis),如:精原細胞瘤(seminoma)、畸胎瘤(teratoma)、胚胎癌(embryonal carcinoma)、畸胎癌(teratocarcinoma)、絨毛膜癌(choriocarcinoma)、肉瘤(sarcoma)、間質細胞癌(interstitial cell carcinoma)、纖維瘤(fibroma)、纖維腺瘤(fibroadenoma)、腺瘤樣腫瘤(adenomatoid tumors)和脂肪瘤(lipoma);肝癌(liver cancers),包括例如:肝細胞瘤(hepatoma),如:肝細胞癌(hepatocellular carcinoma);膽管癌(cholangiocarcinoma);肝母細胞瘤
(hepatoblastoma);血管肉瘤(angiosarcoma);肝細胞腺瘤(hepatocellular adenoma);和血管瘤(hemangioma);骨癌(bone cancers),包括例如:成骨肉瘤(osteogenic sarcoma)(骨肉瘤(osteosarcoma))、纖維肉瘤(fibrosarcoma)、惡性纖維組織細胞瘤(malignant fibrous histiocytoma)、軟骨肉瘤(chondrosarcoma)、尤文氏肉瘤(Ewing’s sarcoma)、惡性淋巴瘤(malignant lymphoma)(網狀細胞肉瘤(reticulum cell sarcoma))、多發性骨髓瘤(multiple myeloma)、惡性巨細胞瘤脊索瘤(malignant giant cell tumor chordoma)、骨軟骨瘤(osteochrondroma)(骨軟骨外生骨疣(osteocartilaginous exostoses))、良性軟骨瘤(benign chondroma)、軟骨母細胞瘤(chondroblastoma)、軟骨瘤纖維瘤(chondromyxofibroma)、骨樣骨瘤(osteoid osteoma)和巨細胞瘤(giant cell tumors);神經系統癌(nervous system cancers),包括例如:頭骨癌(cancers of the skull),如:骨瘤(osteoma)、血管瘤(hemangioma)、肉芽腫(granuloma)、黃瘤(xanthoma)和變形性骨炎(osteitis deformans);腦膜癌(cancers of the meninges),如:腦膜瘤(meningioma)、腦膜肉瘤(meningiosarcoma)和膠質瘤病(gliomatosis);腦癌(cancers of the brain),如:星形細胞瘤(astrocytoma)、成神經管細胞瘤(medulloblastoma)、神經膠質瘤(glioma)、室管膜瘤(ependymoma)、生殖細胞瘤(germinoma)(松果體瘤(pinealoma))、多形性膠質母細胞瘤(glioblastoma multiform)、寡樹突神經膠細胞瘤(oligodendroglioma)、神經鞘瘤(schwannoma)、視網膜母細胞瘤(retinoblastoma)和先天性腫瘤(congenital tumors);和脊髓癌(cancers of the spinal cord),如:神經纖維瘤(neurofibroma)、腦膜瘤(meningioma)、神經膠質瘤(glioma)和肉瘤(sarcoma);
婦科癌症(gynecological cancers),包括例如:子宮癌(cancers of the uterus),如子宮內膜癌(endometrial carcinoma);子宮頸的癌症(cancers of the cervix),如子宮頸癌(cervical carcinoma)、腫瘤前期子宮頸發育不良(pre-tumor cervical dysplasia);卵巢的癌症(cancers of the ovaries),如卵巢癌(ovarian carcinoma),包括漿液性囊腺癌(serous cystadenocarcinoma)、黏液性囊腺癌(mucinous cystadenocarcinoma)、非分類癌(unclassified carcinoma)、錐形細胞瘤(cone-thecal cell tumors)、Sertoli-Leydig細胞瘤(Sertoli-Leydig cell tumors)、無性胚胎瘤(dysgerminoma)和惡性畸胎瘤(malignant teratoma);外陰癌(cancers of the vulva),如:鱗狀細胞癌(squamous cell carcinoma)、上皮內癌(intraepithelial carcinoma)、腺癌(adenocarcinoma)、纖維肉瘤(fibrosarcoma)和黑色素瘤(melanoma);陰道癌(cancers of the vagina)、如:透明細胞癌(clear cell carcinoma)、鱗狀細胞癌(squamous cell carcinoma)、葡萄狀肉瘤(botryoid sarcoma)和胚胎性橫紋肌肉瘤(embryonal rhabdomyosarcoma);和輸卵管癌(cancers of the fallopian tubes),如:惡性腫瘤(carcinoma);血液系統癌症(hematologic cancers),包括例如:血液的癌症(cancers of the blood),如:急性骨髓性白血病(acute myeloid leukemia)、慢性骨髓性白血病(chronic myeloid leukemia)、急性淋巴細胞白血病(acute lymphoblastic leukemia)、慢性淋巴細胞白血病(chronic lymphocytic leukemia)、骨髓增生性疾病(myeloproliferative diseases)、多發性骨髓瘤(multiple myeloma)和骨髓增生異常綜合癥(myelodysplastic syndrome)、何杰金氏淋巴瘤(Hodgkin’s lymphoma)、非何杰金氏淋巴瘤(non-Hodgkin’s lymphoma)(惡性淋巴瘤(malignant lymphoma))和華氏巨球蛋白血症(Waldenström’s macroglobulinemia)、;
皮膚癌(skin cancers),包括例如:惡性黑素瘤(malignant melanoma)、基底細胞癌(basal cell carcinoma)、鱗狀細胞癌(squamous cell carcinoma)、卡波西氏肉瘤(Kaposi’s sarcoma)、發育不良痣(moles dysplastic nevi)、脂肪瘤(lipoma)、血管瘤(angioma)、皮膚纖維瘤(dermatofibroma)、瘢痕瘤(keloids)、牛皮癬(psoriasis);和腎上腺癌(adrenal gland cancers),包括例如:神經母細胞瘤(neuroblastoma)。
癌症可為轉移性或非轉移性的實體瘤。癌症也可能像白血病一樣以瀰漫性組織發生。因此,如本文提供的術語「腫瘤細胞」包括患有上述任何一種疾病的細胞。
該化合物還被認為可用於治療非癌細胞增生性疾病,即以良性適應症為特徵的細胞增生性疾病。此類病症也可稱為「細胞增生性」或「過度增生性」,因為細胞由身體以非典型升高的速率製造。認為可透過本發明化合物治療的非癌細胞增生性疾病包括,例如:新生兒血管瘤症、繼發進行性多發性硬化症、動脈粥樣硬化、慢性進行性骨髓增生性疾病、神經纖維瘤症、神經結細胞瘤、瘢痕瘤形成、骨佩吉特氏病、乳腺纖維囊性疾病、子宮肌瘤、佩羅尼氏症、掌腱膜攣縮症、再狹窄、良性增生性乳腺疾病、良性前列腺增生、X連鎖淋巴細胞增生性疾病(鄧肯病(Duncan disease))、移植後淋巴細胞增生性疾病(post-transplantation lymphocellular proliferative disorder,PTLD)、黃斑退化、和視網膜病變,如:糖尿病視網膜病變(diabetic retinopathies)和增生性玻璃體視網膜病變(proliferative vitreoretinopathy,PVR)
認為可透過本發明化合物治療的其他非癌細胞增生性疾病包括與進展為癌症的風險升高相關的癌前淋巴組織增生細胞的存在。許多非癌性淋巴細胞增生性疾病與潛伏性病毒感染如艾伯斯坦-巴爾病毒(Epstein-Barr virus,EBV)和C型肝炎有關。這些疾病通常以良性病變開始並隨著時間的推移發展形成淋巴瘤。
獲得性抗性癌症和組合療法
根據本發明的一個實施方式,式I化合物及其藥學上可接受的鹽可以施用於抗藥性癌症患者,其具有對一種或多種特異性抗癌劑具有抗性的腫瘤細胞。
根據本發明的另一個實施方式,式I化合物及其藥學上可接受的鹽可以在施用另一種抗癌劑之前、同時或之後施用於癌症患者。
可以產生抗性和/或可以與式I化合物及其藥學上可接受的鹽組合使用的抗癌劑的實例包括:細胞毒性劑(cytotoxic agents)、化學治療劑(chemotherapeutic agents)(包括:烷化劑(alkylating agents)、抗代謝物(antimetabolites)、蒽環類(anthracyclines)、生物鹼(alkaloids)、拓撲異構酶抑制劑(topoisomerase inhibitors)、單株抗體(monoclonal antibodies)等)、CDK4/6抑制劑(CDK4/6 inhibitors),包括palbociclib、包含ESAs的紅細胞生成調節劑(erythropoiesis modulating agents),ESAs包括:EPO(內源性、重組和/或合成EPO)、epoetin alfa、Procrit、Epogen、epoetin beta、darbepoetin alfa和/或甲氧基聚乙二醇-epoetin beta;DNA甲基轉移酶抑制劑(DNA methyltransferase inhibitors)(包括:阿扎胞苷(azacitidine)、地西他濱(decitabine)、5-氟-2'-脫氧胞苷(5-fluoro-2'-deoxycitidine)、5,6-二氫-5-氮雜胞苷(5,6-dihydro-5-azacytidine)、
zebularine、fazarabine、hydralizine、普魯卡因(procaine)、普魯卡因醯胺(procainamide)、表沒食子兒茶素沒食子酸酯(epigallocatechin gallate)、psammaplin A或(S)-2-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-3-(1H-吲哚-3-基)-丙酸((S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(lH-indol-3-yl)-propionic acid)或其藥學上可接受的鹽)、免疫調節劑,如:來那度胺(lenalidomide)等。
患者的癌症未能對特定治療做出反應可能是由於兩種常見原因:宿主因素和癌細胞中特定的遺傳或表觀遺傳改變二者之一。宿主因素包括:吸收不良或藥物快速代謝或排泄,導致血清水準低;對藥物作用的耐受性差,特別是在老年患者中,導致需要將劑量降低到最佳水準以下;無法將藥物輸送到腫瘤部位,可能發生在例如:大體積腫瘤或高分子量和低組織滲透的生物製劑如單株抗體和免疫毒素。此外,宿主-腫瘤環境的各種改變可以影響腫瘤對癌症治療的反應,這些影響包括正常細胞對藥物的局部代謝、可能影響腫瘤內藥物的運輸時間的腫瘤血液供應的異常和/或不正常的特徵等。
如申請專利範圍所述的本發明的藥物組合物和治療方案透過提高對抗癌劑或療法的耐受性或抗性來有效克服癌症治療中的一種或多種上述障礙。因此,本發明的方法提供了用於有效癌症治療的額外工具,以對抗和消除癌症患者的抗藥性。
多重抗藥性是許多癌症對化療藥物產生抗性的主要機制,是許多形式化療失敗的主要因素。它影響患有各種血液癌和實體瘤的患者。腫瘤通常由混合的惡性細胞群組成,其中一些對藥物敏感,而另一些則具有抗藥性。化療可以破壞藥物敏感細胞,但留下更高比例的抗藥細胞。隨著腫瘤再次開始生長,化療可能失敗,因為現下剩餘的腫瘤細胞具有抗藥性。
對治療的抗性與腫瘤細胞膜中至少兩個分子「泵」的存在相關,所述腫瘤細胞膜主動從內部排出化療藥物。這允許腫瘤細胞避免細胞核或細胞質內的藥物毒性作用或分子過程。通常發現在癌症中賦予化學抗性的兩種泵是P-糖蛋白(P-glycoprotein)和所謂的多抗藥性相關蛋白(multidrug resistance-associated protein,MRP)。由於它們的功能和重要性,它們是幾種抗癌努力的目標。
根據一個實施方式,本發明的組合物和方法克服了對DNA甲基轉移酶抑制劑、ESAs或其組合的抗性。
本發明的方法和組合物可用於治療癌症和與癌症相關的貧血,特別是對已經對外源性促紅細胞生成素(exogenous erythropoietin,EPO)獲得抗性的患者。對外源性EPO的抗性與死亡風險增加有關。癌症患者的貧血程度透過許多不同的作用和途徑機制上升,它可以是癌細胞在體內的直接作用,作為癌細胞的生物活性產物的結果,或作為癌症治療的結果。貧血與血癌發展之間也存在關聯。貧血的主要原因是促紅細胞生成素(EPO)的產生不足、缺鐵和具有內源性EPO抗性的慢性疾病。接受EPO的患者中高達10%的患者對治療反應遲鈍,且需要大劑量的藥物。促炎細胞因子(Proinflammatory cytokines)透過對紅血球原始細胞(erythroid progenitor cells)發揮抑制作用並透過破壞鐵代謝來拮抗EPO的作用。參見美國專利8,664,272 B2。
本發明還提供了藥物包或藥物套組,其包含一個或多個裝有一種或多種本發明藥物組合物成分的容器。選擇性、與容器相關地,可具有一須知,其形式由管理藥品或生物製品的製造、使用或銷售的政府機構規定,該須知反映了製造、使用或銷售的機構對於人類給藥的核准。
透過以下實施例進一步說明本發明,這些實施例不應以任何方式解釋為對其範圍施加限制。相反地,應該清楚地理解,可以採用各種其他實施例、修改和均等物,在閱讀本文的描述之後,在不脫離本發明的精神和/或所附申請專利範圍的情況下,本發明所屬技術領域中具有通常知識者可以想到這些實施例、修改和均等物。
實施例
實施例1:8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基(ON 1232580)的合成
4-[4-(6-氰基-8-環戊基-7-側氧基-7,8-二氫-吡啶[2,3-d]嘧啶-2-基胺基)-苯基]-哌嗪-1-羧酸第三丁基酯
(4-[4-(6-Cyano-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester)(ON 1232570)的合成:
將4-(4-氨基苯基)-哌嗪-1-羧酸第三丁基酯(4-(4-Aminophenyl)-Piperazine-1-carboxylic acid tert-butylester)(1.2g,3.96mmol)溶解在甲苯(25mL)中並攪拌10分鐘。將8-環戊基-2-甲亞磺醯基-7-側氧基-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基
(8-Cyclopentyl-2-methanesuffinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile)(1.0g,3.31mmol)加入上述溶液中,用10mL甲苯洗滌燒瓶並加熱至70-80℃並保持4小時。在透過質譜監測反應完成後,將反應混合物冷卻至室溫並放置過夜。過濾所形成的固體,用甲苯(20mL)洗滌,並在真空下乾燥。產量:1.56g(91%)。
1H NMR(300Hz,CDCl3):δ 1.51(s,9H,3 X CH3),1.64(br s,4H,2 X CH2),1.88(br s,2H,CH2),2.30(br s,2H,CH2),3.01(t,4H,J=10.2,7.5Hz,2 X CH2),3.63(t,4H,J=5.4,4.8Hz,2 X CH2),5.86(t,1H,J=8.4,8.1Hz,CH),6.98(d,2H,J=9.0Hz,Ar-H),7.47(d,2H,J=9.0Hz,Ar-H),7.98(s,1H,Ar-H)以及8.58(s,1H,Ar-H).
Mass:m/z 516.10
8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基三氟乙酸鹽
(8-Cyclopentyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate)(ON 1232580)的合成:
將4-[4-(6-氰基-8-環戊基-7-側氧基-7,8-二氫-吡啶[2,3-d]嘧啶-2-基胺基)-苯基]-哌嗪-1-羧酸第三丁基酯(0.75g,14.5mmol)溶解在二氯甲烷(90mL)中並冷卻至0℃。在30分鐘內,於攪拌下將溶於30mL二氯甲烷的19.41g(170.23mmol)三氟乙酸中緩慢加入到冷卻的溶液中,並在0℃下保持4小時。在透過質譜監測反應完成後,在室溫下真空蒸發溶劑,並將殘餘物用乙醚(100mL)稀釋,並在0℃下攪拌15分鐘。過濾所形成的固體,用乙醚(50mL)洗滌,真空乾燥,並以原樣使用於下一步驟。粗產量:0.85克(定量)。
1H NMR(300Hz,D2O):δ 1.38(br s,4H,2 X CH2),1.68(br s,4H,2 X CH2),3.12(br s,4H,2 X CH2),3.28(br s,4H,2 X CH2),5.03(br s,1H,CH),6.37(br s,2H,Ar-H),6.66(d,2H,J=7.5Hz,Ar-H),7.71(s,1H,Ar-H)以及8.12(s,1H,Ar-H).
Mass:m/z 416.10(質譜顯示為游離鹼)
式I化合物之游離鹼,8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基
(8-Cyclopentyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile)(ON 1232580游離鹼)的合成:
將8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基三氟乙酸(0.045g)溶解於水(15mL)並攪拌10分鐘。過濾溶解的溶液並冷卻至0℃。加入7%氫氧化鈉溶液(6-7滴)直至溶液的pH調節至7.0-7.5,並將溶液保持在0℃1小時。過濾所形成的固體,用水(5mL)洗滌,真空乾燥並放置過夜。產量:0.020g(57.1%)。
1H NMR(300Hz,DMSO-d6):δ 1.57(br s,2H,CH2),1.79(br s,4H,2 X CH2),2.20(br s,2H,CH2),2.84(br s,4H,2 X CH2),3.02(br s,4H,2 X CH2),5.73(br s,1H,CH),6.94(d,2H,J=8.1Hz,Ar-H),7.49(d,2H,J=8.7Hz,Ar-H),8.53(s,1H,Ar-H),8.78(s,1H,Ar-H)以及10.38(br s,1H,NH).
Mass:m/z 416.10
實施例2:8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基
(8-Cyclopentyl-7-oxo-2-(4-piperazin-1-yl-phenylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile)(ON 1232580)的激酶抑制:
根據國家癌症研究所,palbociclib是一種口服吡啶并嘧啶衍生的細胞週期蛋白依賴性激酶(cyclin-dependent kinase,CDK)抑制劑,具有潛在的抗腫瘤活性。特別地,palbociclib選擇性地抑制細胞週期蛋白依賴性激酶(特別是Cdk4/ 細胞週期蛋白D1激酶(Cdk4/cyclin D1 kinase)),這可能抑制視網膜母細胞瘤(retinoblastoma,Rb)蛋白磷酸化,因而阻止Rb陽性腫瘤細胞進入細胞週期的S期(停滯在G1期)。這導致DNA複製的抑制和腫瘤細胞增生的減少。
表1中的化合物抑制所列蛋白激酶的激酶活性的能力係被測試。以6劑量IC50模式測試化合物,從100μM開始10倍連續稀釋。作為控制組,星形孢菌素(Staurosporine),一種已知的蛋白激酶抑制劑,以10劑量IC50模式進行測試,從20μM開始進行4倍連續稀釋。反應在10μM ATP中進行。基於可用的最佳曲線擬合,估計小於1nM或高於100μM的IC50值。
空欄位表示無法抑制或化合物活性不能與IC50曲線擬合
縮寫:ABL1=Abelson酪胺酸蛋白激酶1(Abelson tyrosine protein kinase 1);ARK5=AMPK相關蛋白激酶5(AMPK related protein kinase 5);CDK=細胞週期蛋白依賴性激酶(Cyclin dependent kinases);FGFRI=成纖維細胞生長因子受體1(fibroblast growth factor receptor 1);FLT3=類fms酪胺酸激酶3(fms like tyrosine kinase 3);FLT4=類fms酪胺酸激酶4(fms like tyrosine kinase 4);VEGFR3=血管內皮生長因子受體3(vascular endothelial growth factor receptor 3);FYN=fyn酪胺酸蛋白激酶(fyn tyrosine protein kinase);PDGFRb=血小板衍生生長因子受體β(platelet derived growth factor receptor beta);PGK2=蛋白激酶G 2(protein kinase G 2);RET=受體酪胺酸激酶(receptor tyrosine kinase)
如表1所示,相較於palbociclib,ON 1232580具有顯著不同的蛋白激酶抑制特性,並且令人驚訝地作為更為有效的多特異性蛋白激酶抑制劑,例如針對ARK5、CDK9/細胞週期蛋白K和CDK6/細胞週期蛋白D3。
實施例3:癌細胞株中的細胞毒性分析,比較8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基(ON 123580)與作為對照細胞毒劑的順鉑的活性
在四種癌細胞株中測試化合物:DU145(人類前列腺癌)、GRANTA-519(人類B細胞淋巴瘤)、HeLa(人類子宮頸癌)和K-562(人類慢性骨髓性白血病)。令人驚訝的是,ON 123580是對抗包括人類B細胞淋巴瘤細胞在內的所有四種細胞株的有效細胞毒性劑。
試劑和材料:
胎牛血清(Fetal Bovine Serum,FBS),(Cat # FND500,ExCell Bio。在-20℃儲存)
96孔平底透明底黑色聚苯乙烯TC處理微孔盤(Cat # 3340,Corning)。
CellTiter-Glo®發光細胞活性分析(Cat # G7572,Promega,在-20℃儲存)。在96孔盤中每一分析100μL,基質足以進行1,000次分析。
包含:
‧1×100mL CellTiter-Glo®緩衝液
‧1×小瓶 CellTiter-Glo®基質(冷凍乾燥)
CellTiter-Glo®發光細胞存活率分析法是一種均相方法,用於根據現存ATP的定量來確定培養基中存活細胞的數量,該信號表明代謝活性細胞的存在。均相分析方法包括將單一試劑(CellTiter-Glo®試劑)直接添加到在補充血清的培養基中培養的細胞中。均相的「添加-混合-測量」形式導致細胞裂解並產生與
現存ATP量成比例的發光信號。ATP的量與培養基中存在的細胞數直接成正比。該分析產生由螢光素酶反應產生的發光信號。
試劑製備
a.解凍CellTiter-Glo緩衝液,並在使用前平衡至室溫。為方便起見,可在使用前將CellTiter-Glo緩衝液解凍並在室溫下儲存長達48小時。
b.在使用前將冷凍乾燥的CellTiter-Glo基質平衡至室溫。
c.將適當體積(100mL)的CellTiter-Glo緩衝液轉移到含有CellTiter-Glo基質的琥珀色瓶中,以重建冷凍乾燥的酶/基質混合物。以形成CellTiter-Glo試劑。
注意:CellTiter-Glo緩衝液瓶的整個液體體積可以添加到CellTiter-Glo基質瓶中。
d.透過溫和地渦旋、旋轉或透過倒置內容物來混合以獲得均相的溶液。CellTiter-Glo基質應在不到一分鐘的時間內輕鬆進入溶液狀態。
半數最大抑制濃度IC50的測定:
1.在對數生長期期間收穫細胞並使用Count-star計數細胞數。
2.用各自的培養基將細胞濃度調節至4.44×104個細胞/mL。
3.向兩個96孔盤(盤A和盤B)中加入90μL細胞懸浮液,最終細胞密度為4×103細胞/孔。(根據資料庫或密度最佳化分析調整細胞濃度。)
隔天:針對T0讀數的盤:
1)向盤A的每個孔中加入10μL培養基用於T0讀數。
2)在室溫下平衡盤及其內容物約30分鐘。
3)每孔中加入50μL CellTiter-Glo(CTG)試劑。
4)在軌道振盪器上混合內容物5分鐘以誘導細胞裂解。
5)使盤在室溫下培育20分鐘以穩定發光信號。
注意:溫度梯度、細胞接種不均勻或多孔盤中的邊緣效應可能導致標準盤內的發光信號不均勻。
6)使用EnVision多標籤讀取器記錄發光(T0)。
針對測試讀數的盤:
1)製備10×測試物溶液(最高工作濃度:100μM測試物在培養基中進行3.16倍連續稀釋以達到9個劑量水準。在DMSO中起始藥物濃度為40mM,最終稀釋藥物濃度為4μM)。
2)製備10x參照控制溶液順鉑(最高工作濃度:100μM,在培養基中進行3.16倍連續稀釋。(起始順鉑(來自Hospira Australia)濃度為3.33mM),最終稀釋藥物濃度在細胞培養基中為100nM)。
3)在盤B的每個孔(每種藥物濃度一式三份)中分配10μL(10x)測試物和參照控制的藥物溶液(DMSO在培養基中的最終濃度:0.25%[v/v])。
4)將測試盤B在37℃、5% CO2的潮濕培養箱中培育72小時,然後透過CTG分析法測量。
5)在室溫下平衡盤及其內容物約30分鐘。
6)每個孔中加入50μL的CellTiter-Glo試劑。
7)在軌道振盪器上混合內容物5分鐘以誘導細胞裂解。
8)使盤在室溫下培育20分鐘以穩定發光信號。
注意:溫度梯度、細胞接種不均勻或多孔盤中的邊緣效應可能導致標準盤內的發光信號不均勻。
9)記錄發光值。
為了計算絕對IC50(EC50),使用具有S形劑量反應的非線性回歸模型擬合劑量-反應曲線。計算存活率的公式如下所示,並且根據GraphPad Prism 5.0產生的劑量-反應曲線計算絕對IC50(EC50)。
存活率(%)=(Lum測試物-Lum控制基質)/(Lum未處理-Lum控制基質)×100%.
IC50(導致50%細胞死亡的藥物濃度)總結在表2中。
令人驚訝的是,ON 1232580是GRANTA-519細胞的有效殺手,其係B細胞非何杰金氏淋巴瘤(外膜細胞)細胞株。相對而言,順鉑對GRANTA-519細胞的毒性不大。如表2所示,ON 1232580也是DU145細胞(前列腺癌)、HeLa細胞(子宮頸癌)和K-562細胞(人類骨髓性白血病)的有效抑制劑。
本文引用的所有參考文獻,包括專利、專利申請和出版物,均透過引用而整體併入本文,無論前文是否有特別引入。
在上述各個部分中提及的本發明的各種特徵和實施方式可適當地適用於其他部分、加以必要的變更。因此,一個部分中特定的特徵可以適當地與其他部分中特定的特徵組合使用。
一些特定實施方式的前述描述提供了足夠的資訊,使其他人可以透過應用當前知識,容易地修改這些特定的實施例或將這些特定的實施例適應於
各種應用,而不脫離一般概念,因此,這些改編和修改應當並且旨在被理解為係在所公開的實施方式的均等物的含義和範圍內。應理解,本文採用的詞彙或術語是出於描述的目的而非限制的目的。在所附圖式和說明書中,已經公開了示例性實施方式,並且儘管可能已經採用了特定術語,但是除非另有說明,否則它們僅用於一般性和描述性意義而不是用於限制的目的,因此申請專利範圍並不以此為限。此外,本發明所屬技術領域中具有通常知識者將理解,本文所討論的方法的某些步驟可以以替代順序排序,或者可以組合步驟。因此,所附申請專利範圍旨在不限於本文公開的特定實施方式。本發明所屬技術領域中具有通常知識者將認識到或能夠使用不超過常規的實驗來確定本文所述的本發明實施方式的許多均等物。這些均等物包含在以下申請專利範圍中。
Claims (7)
- 一種如請求項1所述的化合物或其藥學上可接受的鹽在製備治療由異常細胞增生介導的病症之藥物的用途,該由異常細胞增生介導的病症選自由B細胞非何杰金氏淋巴瘤、前列腺癌、子宮頸癌和人類骨髓性白血病所組成之群組,該用途包括:將有效量的如請求項1所述的化合物或其藥學上可接受的鹽給予有需要的對象。
- 如請求項3所述的用途,其中所述對象是人類。
- 一種如請求項1所述的化合物或其藥學上可接受的鹽在製備抑制哺乳動物激酶活性之藥物的用途,該哺乳動物激酶選自由ABL1、ARK5/NUAK1、CDK4/cyclin D1、CDK4/cyclin D3、CDK6/cyclin D1、CDK6/cyclin D3、CDK9/cyclin K、FGFR1、FLT3、FLT4/VEGFR3、FYN、PDGFRb和RET所組成之群組,該用途包括給予需要這種治療的患者治療有效量的如請求項1所述的化合物或其藥學上可接受的鹽。
- 如請求項5所述的用途,其中所述患者是患有人類骨髓性白血病、B細胞非何杰金氏淋巴瘤、前列腺癌或子宮頸癌的人類。
- 一種如請求項1所述的化合物或其藥學上可接受的鹽在製備在患有癌症的個體中誘導癌細胞凋亡之藥物的用途,該癌症選自由B細胞非何杰金氏淋巴瘤、前列腺癌、子宮頸癌和人類骨髓性白血病所組成之群組,該用途包括向個體施用有效量的如請求項1所述的化合物或其鹽。
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期刊 M Reddy et al., Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3‑d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4(CDK4) and AMPK-Related Kinase 5 (ARK5), J. Med. Chem. 57, 2014, 578−599. |
期刊 M Reddy et al., Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3‑d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4(CDK4) and AMPK-Related Kinase 5 (ARK5), J. Med. Chem. 57, 2014, 578-599. * |
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