TWI816880B - 治療***癌之組合療法 - Google Patents
治療***癌之組合療法 Download PDFInfo
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- TWI816880B TWI816880B TW108133128A TW108133128A TWI816880B TW I816880 B TWI816880 B TW I816880B TW 108133128 A TW108133128 A TW 108133128A TW 108133128 A TW108133128 A TW 108133128A TW I816880 B TWI816880 B TW I816880B
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- etv1
- erg
- compound
- prostate cancer
- enzalutamide
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- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229950003695 metribolone Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- BLIJXOOIHRSQRB-PXYINDEMSA-N n-[(2s)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide Chemical group C([C@H](C)NC(=O)C=1NN=C(C=1)C(C)O)N(N=1)C=CC=1C1=CC=C(C#N)C(Cl)=C1 BLIJXOOIHRSQRB-PXYINDEMSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
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- 230000037361 pathway Effects 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000006169 tetracyclic group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本發明提供用於治療***癌(包括轉移性去勢抵抗性***癌)之方法,其包含向有需要之個體投與BET溴結構域抑制劑與第二藥劑之組合。
Description
本發明係關於一種用於治療***癌之組合療法。
轉移性去勢抵抗性***癌(metastatic castration-resistant prostate cancer) (「mCRPC」)通常表徵為雄激素受體(「AR」)之信號傳遞持續驅動癌症增殖、腫瘤侵襲及轉移(Wyatt及Gleave,2015)。***癌之初步療法包括手術或化學去勢,繼之以雄激素去除療法。在許多個例中,觀察到癌症進一步進展及癌轉移,因此為術語轉移性去勢抵抗性***癌。mCRPC之一線標準護理療法包括AR拮抗劑恩雜魯胺(enzalutamide)、雄激素合成抑制劑,諸如細胞色素類固醇17-α-羥化酶/17,20解離酶(CYP17A1)抑制劑阿比特龍(abiraterone),及在一些情況下為化學療法。然而,近期研究顯示,經過一段時間個體對此等一線治療具有抗性,及需要額外藥物療法(Wyatt及Gleave,2015)。目前,不存在二線mCRPC之標準護理,因為二線環境中AR調節劑或化學療法之功效和緩。此外,已表明,阿比特龍及恩雜魯胺之抗性機制重疊(Azad等人,2015b;Bianchini等人,2014;Loriot等人,2013;Noonan等人,2013;Schrader等人,2014)。
對恩雜魯胺及阿比特龍之抗性機制包括:AR之替代性拼接,其致使缺失配位體結合結構域及組成性活性雄激素信號傳遞(Nakazawa等人,2014);交替路徑(諸如糖皮質激素受體(GR) (Arora等人,2013;Isikbay等人,2014)、活化B細胞之核因子κ輕鏈強化子(NF-κB) (Jin等人,2013;Nadiminty等人,2013))或MYC信號傳遞路徑(Lamb等人,2014;Nadiminty等人,2013;Zeng等人,2015)上調;以及神經內分泌分化(Aggarwal等人,2014;Beltran等人,2014;Dang等人,2015)。已顯示,在***癌(MYC表現:(Gao等人,2013);AR拼接變異體:(Chan等人,2015;Welti等人,2018);GR:(Asangani等人,2016;Shah等人,2017))或其他癌症(NF-κB:(Ceribelli等人,2014;Gallagher等人,2014;Zou等人,2014))中,此等若干抗性機制由BET蛋白質調節,表明BET抑制可能有益於患有對恩雜魯胺及阿比特龍具有抗性之mCRPC的個體。特定言之,近期表明雄激素受體拼接變異體7(AR-V7)與對恩雜魯胺及阿比特龍之抗性有關(Antonarakis等人,2014);表現此等變異體之細胞株具有BET依賴性及在培養物及異種移植物中對BETi敏感(Asangani等人,2014;Asangani等人,2016;Chan等人,2015;Gao等人,2013;Wyce等人,2013)。BET抑制劑(BETi)之建議作用機制中之一者為避免BET蛋白質與AR之N端相互作用及活化下游雄激素信號傳遞路徑(Asangani等人,2014)。
然而,目前尚不清楚當向患有***癌之患者投與時,何種BET抑制劑(若存在)將產生顯著臨床益處。亦不清楚在治療***癌中,何種BET抑制劑(若存在)將與其他藥物(諸如雄激素受體拮抗劑或雄激素合成抑制劑)協同組合;需要何種協同作用水準;及對於每種BET抑制劑,何種第二治療劑將為最佳組合搭配物,從而當向患有***癌之患者投與時產生臨床益處。除臨床益處以外,組合亦必須安全且在有效劑量下具有良好耐受性。目前,無法預測何種組合將展現出最佳總體概況。
本發明提供治療***癌之方法,其藉由向有需要之個體共投與BET溴結構域抑制劑、或BET溴結構域抑制劑之醫藥學上可接受之鹽或共晶體與第二治療劑。
在一些實施例中,BET溴結構域抑制劑與第二治療劑同時投與。在一些實施例中,BET溴結構域抑制劑與第二治療劑依序投與。在一些實施例中,BET溴結構域抑制劑以單一醫藥組合物與第二治療劑投與。在一些實施例中,BET溴結構域抑制劑及第二治療劑以單獨組合物形式投與。在一些實施例中,BET溴結構域抑制劑及第二治療劑與檢查點抑制劑組合投與。
在一些實施例中,第二治療劑為有益於治療***癌之藥劑。
在一些實施例中,第二治療劑為雄激素去除療法。在一些實施例中,第二治療劑為雄激素受體拮抗劑。在一些實施例中,第二治療劑為雄激素合成抑制劑。
在一些實施例中,***癌為轉移性去勢抵抗性***癌(mCRPC)。
在一些實施例中,BET溴結構域抑制劑為式Ia或式Ib化合物(化合物Ia)(化合物Ib)
或其立體異構體、互變異構體、醫藥學上可接受之鹽或共晶體或水合物,
其中:環 A
及環 B
可視情況經獨立地選自以下之基團取代:氫、氘、-NH2
、胺基、雜環(C4
-C6
)、碳環(C4
-C6
)、鹵素、-CN、-OH、-CF3
、烷基(C1
-C6
)、烷硫基(C1
-C6
)、烯基(C2
-C6
)及烷氧基(C1
-C6
);X
選自:-NH-、-CH2
-、-CH2
CH2
-、-CH2
CH2
CH2
-、-CH2
CH2
O-、-CH2
CH2
NH-、-CH2
CH2
S-、-C(O)-、-C(O)CH2
-、-C(O)CH2
CH2
-、-CH2
C(O)-、-CH2
CH2
C(O)-、-C(O)NH-、-C(O)O-、-C(O)S-、-C(O)NHCH2
-、-C(O)OCH2
-、-C(O)SCH2
-,其中一或多個氫可獨立地經氘、羥基、甲基、鹵素、-CF3
、酮置換,及其中S可氧化成亞碸或碸;R4
選自視情況經取代之3員至7員碳環及雜環;及D1
選自以下5員單環雜環:
其視情況經氫、氘、烷基(C1
-C4
)、烷氧基(C1
-C4
)、胺基、鹵素、醯胺、-CF3
、-CN、-N3
、酮(C1
-C4
)、-S(O)烷基(C1
-C4
)、-SO2
烷基(C1
-C4
)、-烷硫基(C1
-C4
)、-COOH及/或酯取代,其中之每一者可視情況經氫、F、Cl、Br、-OH、-NH2
、-NHMe、-OMe、-SMe、側氧基及/或硫基-側氧基取代。
在一些實施例中,BET溴結構域抑制劑為1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(本文中為化合物I),其具有以下式:(化合物I)
在一些實施例中,BET溴結構域抑制劑為化合物I或醫藥學上可接受之鹽或共晶體。在一些實施例中,BET溴結構域抑制劑為呈結晶形式I之化合物I的甲磺酸鹽/共晶體。
在一些實施例中,本發明之組合療法展現出出人意料的優越的安全性概況,因為其不會導致血小板減少所致之劑量限制性毒性。在一些實施例中,本發明之組合療法展現出協同治療效果。
定義
如本文所用,「治療(treatment/treating)」係指改善疾病或病症,或其至少一個可辨別之症狀。在另一實施例中,「治療(treatment/treating)」係指改善個體未必能辨別之至少一個可量測的物理參數。在另一實施例中,「治療(treatment/treating)」係指在物理上抑制疾病或病症之進展,例如穩定可辨別之症狀,或生理上抑制疾病或病症之進展,例如穩定物理參數,或兩者。在另一實施例中,「治療(treatment/treating)」係指延遲疾病或病症之發作。
「視情況存在之」或「視情況」意謂隨後描述之事件或情況可能發生或可能不發生,及描述包括事件或情況發生之例子及其不發生之例子。舉例而言,「視情況經取代之芳基」涵蓋下文所定義之「芳基」及「經取代之芳基」。熟習此項技術者應瞭解,對於含有一或多個取代基之任何基團,此類基團不意欲引入空間上不切實際、合成上不可行及/或本身不穩定之任何取代或取代模式。
如本文所用,術語「水合物」係指將化學計量或非化學計量之水的晶體形式併入晶體結構中。
如本文所用,術語「烯基」係指具有至少一個碳-碳雙鍵之不飽和的直鏈或分支鏈烴,諸如2至8個碳原子之直鏈或分支鏈基團,在本文中稱為(C2 -
C8
)烯基。例示性烯基包括(但不限於):乙烯基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基及4-(2-甲基-3-丁烯)-戊烯基。
如本文所用,術語「烷氧基」係指連接至氧之烷基(-O-烷基-)。「烷氧基」亦包括連接至氧之烯基(「烯基氧基」)或連接至氧之炔基(「炔基氧基」)。例示性烷氧基包括(但不限於):具有1至8個碳原子之烷基、烯基或炔基,在本文中稱為(C1 -
C8
)烷氧基。例示性烷氧基包括(但不限於)甲氧基及乙氧基。
如本文所用,術語「烷基」係指飽和的直鏈或分支鏈烴,諸如1至8個碳原子之直鏈或分支鏈基團,在本文中稱為(C1 -
C8
)烷基。例示性烷基包括(但不限於):甲基、乙基、丙基、異丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、異丁基、t-丁基、戊基、異戊基、新戊基、己基、庚基及辛基。
如本文所用,術語「醯胺」係指-NRa
C(O)(Rb
)或-C(O)NRb
Rc
,其中Ra
、Rb
及Rc
各獨立地選自:烷基、烯基、炔基、芳基、芳基烷基、環烷基、鹵烷基、雜芳基、雜環基及氫。醯胺可經由碳、氮、Ra
、Rb
或Rc
連接至另一基團。醯胺亦可為環狀的,例如Rb
與Rc
可結合形成3員至8員環,諸如5員或6員環。術語「醯胺」涵蓋諸如以下之基團:磺醯胺、脲、脲基、胺基甲酸酯、胺基甲酸及其環狀形式。術語「醯胺」亦涵蓋連接至羧基之醯胺基(例如-醯胺-COOH或鹽,諸如-醯胺-COONa)、連接至羧基之胺基(例如-胺基-COOH或鹽,諸如-胺基-COONa)。
如本文所用,術語「胺」或「胺基」係指形式-NRd
Re
或-N(Rd
)Re
-,其中Rd
及Re
獨立地選自:烷基、烯基、炔基、芳基、芳基烷基、胺基甲酸酯、環烷基、鹵烷基、雜芳基、雜環及氫。胺基可經由氮連接至母分子基團。胺基亦可為環狀的,例如Rd
與Re
中之任何兩者可結合在一起或與N結合形成3員至12員環(例如嗎啉基或哌啶基)。術語胺基亦包括任何胺基之對應的四級銨鹽。例示性胺基包括烷基胺基,其中Rd
或Re
中之至少一者為烷基。在一些實施例中,Rd
及Re
各自可視情況經羥基、鹵素、烷氧基、酯或胺基取代。
如本文所用,術語「芳基」係指單環、雙環或其他多碳環芳環系統。芳基可視情況稠合至選自芳基、環烷基及雜環基之一或多個環。本發明之芳基可經選自以下之基團取代:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、硝基、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺及硫酮。例示性芳基包括(但不限於):苯基、甲苯基、蒽基、茀基、茚基、薁基及萘基,以及苯并稠合之碳環部分,諸如5,6,7,8-四氫萘基。例示性芳基亦包括(但不限於):單環芳環系統,其中環包含6個碳原子,在本文中稱為「(C6
)芳基」。
如本文所用,術語「芳基烷基」係指具有至少一個芳基取代基之烷基(例如,-芳基-烷基-)。例示性芳基烷基包括(但不限於):具有單環芳環系統之芳基烷基,其中環包含6個碳原子,在本文中稱為「(C6
)芳基烷基」。
如本文所用,術語「胺基甲酸酯」係指形式-Rg
OC(O)N(Rh
)-、-Rg
OC(O)N(Rh
)Ri
-或-OC(O)NRh
Ri
,其中Rg
、Rh
及Ri
各自獨立地選自烷基、烯基、炔基、芳基、芳基烷基、環烷基、鹵烷基、雜芳基、雜環基及氫。例示性胺基甲酸酯包括(但不限於):胺基甲酸芳基酯或胺基甲酸雜芳基酯(例如其中Rg
、Rh
及Ri
中之至少一者獨立地選自芳基或雜芳基,諸如吡啶、噠嗪、嘧啶及吡嗪)。
如本文所用,術語「碳環」係指芳基或環烷基。
如本文所用,術語「羧基」係指-COOH或其相應羧酸鹽(例如,-COONa)。術語羧基亦包括「羧基羰基」,例如連接至羰基的羧基,例如-C(O)-COOH或鹽,諸如-C(O)-COONa。
如本文所用,術語「環烷氧基」係指連接至氧之環烷基。
如本文所用,術語「環烷基」係指由環烷衍生之3至12個碳或3至8個碳的飽和或不飽和之環狀、雙環或橋接雙環狀烴基,在本文中稱為「(C3
-C8
)環烷基」。例示性環烷基包括(但不限於):環己烷、環己烯、環戊烷及環戊烯。環烷基可經以下之基團取代:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、硝基、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺及硫酮。環烷基可稠合至其他環烷基飽和或不飽和芳基或雜環基。
如本文所用,術語「二甲酸」係指含有至少兩個羧酸基團之基團,諸如飽和及不飽和的烴二甲酸及其鹽。例示性二甲酸包括烷基二甲酸。二甲酸可經以下之基團取代:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、氫、羥基、酮、硝基、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺及硫酮。二甲酸包括(但不限於):丁二酸、戊二酸、己二酸、辛二酸、癸二酸、壬二酸、順丁烯二酸、鄰苯二甲酸、天冬胺酸、麩胺酸、丙二酸、反丁烯二酸、(+)/(-)-蘋果酸、(+)/(-)酒石酸、間苯二甲酸及對苯二甲酸。二甲酸進一步包括其羧酸衍生物,諸如酸酐、醯亞胺、醯肼(例如丁二酸酐及丁二醯亞胺)。
術語「酯」係指結構-C(O)O-、-C(O)O-Rj -
、-Rk
C(O)O-Rj -
或-Rk
C(O)O-,其中O不結合至氫,及Rj
及Rk
可獨立地選自:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、環烷基、醚、鹵烷基、雜芳基及雜環基。Rk
可為氫,但Rj
不能為氫。酯可為環狀的,例如碳原子與Rj
、氧原子與Rk
,或Rj
與Rk
可結合形成3員至12員環。例示性酯包括(但不限於)烷基酯,其中Rj
或Rk
中之至少一者為烷基,諸如-O-C(O)-烷基、-C(O)-O-烷基-及-烷基-C(O)-O-烷基-。例示性酯亦包括芳基或雜芳基酯,例如其中Rj
或Rk
中之至少一者為雜芳基,諸如吡啶、噠嗪、嘧啶及吡嗪,諸如菸鹼酸酯。例示性酯亦包括具有結構-Rk
C(O)O-之反向酯,其中氧結合至母分子。例示性反向酯包括丁二酸酯、D-精胺酸酯、L-精胺酸酯、L-離胺酸酯及D-離胺酸酯。酯亦包括羧酸酐及酸鹵化物。
如本文所用,術語「鹵基」或「鹵素」係指F、Cl、Br或I。
術語「鹵烷基」係指經一或多個鹵素原子取代之烷基。「鹵烷基」亦涵蓋經一或多個鹵素原子取代之烯基或炔基。
如本文所用,術語「雜芳基」係指含有一或多個雜原子(例如1至3個雜原子,諸如氮、氧及硫)之單環、雙環或多環芳環系統。雜芳基可經包括以下之一或多個取代基取代:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、硝基、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺及硫酮。雜芳基亦可稠合至非芳環。雜芳基之說明性實例包括(但不限於):吡啶基、噠嗪基、嘧啶基、吡唑基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-***基及(1,2,4)-***基、吡嗪基、嘧啶基、四唑基、呋喃基、噻吩基、異噁唑基、噻唑基、呋喃基、苯基、異噁唑基及噁唑基。例示性雜芳基包括(但不限於)單環芳環,其中環包含2至5個碳原子及1至3個雜原子,在本文中稱為「(C2
-C5
)雜芳基」。
如本文所用,術語「雜環」、「雜環基」或「雜環」係指飽和或不飽和的3員、4員、5員、6員或7員環,其含有一個、兩個或三個獨立地選自氮、氧及硫之雜原子。雜環可為芳族(雜芳基)或非芳族。雜環可經包括以下之一或多個取代基取代:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、硝基、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺及硫酮。雜環亦包括雙環、三環及四環基團,其中以上雜環中之任一者稠合至獨立地選自芳基、環烷基及雜環之一個或兩個環。例示性雜環包括:吖啶基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、生物素基、㖕啉基、二氫呋喃基、二氫吲哚基、二氫哌喃基、二氫噻吩基、二噻唑基、呋喃基、高哌啶基、咪唑啶基、咪唑啉基、咪唑基、吲哚基、異喹啉基、異噻唑啶基、異噻唑基、異噁唑啶基、異噁唑基、嗎啉基、噁二唑基、噁唑啶基、噁唑基、哌嗪基、哌啶基、哌喃基、吡唑啶基、吡嗪基、吡唑基、吡唑啉基、噠嗪基、吡啶基、嘧啶基、嘧啶基、吡咯啶基、吡咯啶-2-酮基、吡咯啉基、吡咯基、喹啉基、喹惡啉基(quinoxaloyl)、四氫呋喃基、四氫異喹啉基、四氫哌喃基、四氫喹啉基、四唑基、噻二唑基、噻唑啶基、噻唑基、噻吩基、硫代嗎啉基、硫代哌喃基及***基。
如本文所用,術語「羥基(hydroxy)」及「羥基(hydroxyl)」係指-OH。
如本文所用,術語「羥基烷基」係指連接至烷基之羥基。
如本文所用,術語「羥基芳基」係指連接至芳基之羥基。
如本文所用,術語「酮」係指結構-C(O)-Rn
(諸如乙醯基、-C(O)CH3
)或-Rn -
C(O)-Ro
。酮可經由Rn
或Ro
連接至另一基團。Rn
或Ro
可為烷基、烯基、炔基、環烷基、雜環基或芳基,或Rn
或Ro
可結合形成3員至12員環。
如本文所用,術語「苯基」係指6員碳環芳環。苯基亦可稠合至環己烷或環戊烷環。苯基可經包括以下之一或多個取代基取代:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺及硫酮。
如本文所用,術語「烷硫基」係指連接至硫的烷基(-S-烷基-)。
「烷基」、「烯基」、「炔基」、「烷氧基」、「胺基」及「醯胺」基團可視情況經至少一個選自以下之基團取代或間雜有該(等)基團或由其分支:烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺基甲酸酯、羰基、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、磷酸酯、硫基、亞磺醯基、磺醯基、磺酸、磺醯胺、硫酮、脲基及N。取代基可經分支化形成經取代或未經取代之雜環或環烷基。
如本文所用,視情況經取代之取代基上的適合之取代係指不會破壞本發明化合物或適用於製備其之中間物的合成或醫藥效用的基團。適合之取代的實例包括(但不限於):C1 - 8
烷基、烯基或炔基;C1 - 6
芳基、C2 - 5
雜芳基;C37
環烷基;C1 - 8
烷氧基;C6
芳氧基;-CN;-OH;側氧基;鹵基、羧基;胺基,諸如-NH(C1 - 8
烷基)、-N(C1 - 8
烷基)2
、-NH((C6
)芳基)或-N((C6
)芳基)2
;甲醯基;酮,諸如-CO(C1 - 8
烷基))、-CO((C6
芳基)酯,諸如-CO2
(C1 - 8
烷基)及-CO2
(C6
芳基)。熟習此項技術者可基於本發明化合物之穩定性及藥理學及合成活性容易地選擇適合之取代。
如本文所用,術語「醫藥學上可接受之組合物」係指一種包含與一或多種醫藥學上可接受之載劑一起調配的至少一種本文所揭示之化合物的組合物。
如本文所用,術語「醫藥學上可接受之載劑」係指與醫藥投與相容之任何及所有溶劑、分散介質、包衣、等張劑及吸收延緩劑及其類似物。此類介質及藥劑用於醫藥活性物質之用途為此項技術中所熟知。組合物亦可含有提供補充、額外或增強治療功能之其他活性化合物。
如本文所用,術語「疾病進展」係指***特異性抗原(「PSA」)增加及/或進展性轉移性疾病。在一些實施例中,疾病進展如***癌工作組(PCWG)規範2中所定義(Scher等人,2008)。在一些實施例中,疾病進展出現在預先已接受雄激素去除療法之個體中。
本發明之例示性實施例
如上文所概述,本發明提供了治療***癌之方法,其藉由向有需要之個體伴隨投與BET溴結構域抑制劑、或BET溴結構域抑制劑之醫藥學上可接受之鹽或共晶體與第二治療劑。
在一個實施例中,本發明提供一種用於治療***癌之方法,其包含向有需要之個體伴隨投與式Ia或式Ib(式Ia)(式Ib)
或其立體異構體、互變異構體、醫藥學上可接受之鹽或共晶體或水合物的BET溴結構域抑制劑與第二治療劑,其中:環 A
及環 B
可視情況經獨立地選自以下之基團取代:氫、氘、-NH2
、胺基、雜環(C4
-C6
)、碳環(C4
-C6
)、鹵素、-CN、-OH、-CF3
、烷基(C1
-C6
)、烷硫基(C1
-C6
)、烯基(C1
-C6
)及烷氧基(C1
-C6
);X
選自:-NH-、-CH2
-、-CH2
CH2
-、-CH2
CH2
CH2
-、-CH2
CH2
O-、-CH2
CH2
NH-、-CH2
CH2
S-、-C(O)-、-C(O)CH2
-、-C(O)CH2
CH2
-、-CH2
C(O)-、-CH2
CH2
C(O)-、-C(O)NH-、-C(O)O-、-C(O)S-、-C(O)NHCH2
-、-C(O)OCH2
-、-C(O)SCH2
-,其中一或多個氫可獨立地經氘、羥基、甲基、鹵素、-CF3
、酮置換,及其中S可氧化成亞碸或碸;R4
選自視情況經取代之3員至7員碳環及雜環;及D1
選自以下5員單環雜環:
其視情況經氫、氘、烷基(C1
-C4
)、烷氧基(C1
-C4
)、胺基、鹵素、醯胺、-CF3
、-CN、-N3
、酮(C1
-C4
)、-S(O)烷基(C1
-C4
)、-SO2
烷基(C1
-C4
)、-烷硫基(C1
-C4
)、-COOH及/或酯取代,其中之每一者可視情況經氫、F、Cl、Br、-OH、-NH2
、-NHMe、-OMe、-SMe、側氧基及/或硫基-側氧基取代。
式Ia及Ib之化合物(包括化合物I)先前已描述於國際專利公開案WO 2015/002754中,專利公開案以全文引用之方式併入本文中,及尤其關於其對式Ia及式Ib之化合物(包括化合物I)的描述、其合成及其BET溴結構域抑制劑活性的證實。
在一些實施例中,式Ia或式Ib之BET溴結構域抑制劑選自:
1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-乙基-1H-咪唑并[4,5-b]吡啶-2-胺;
1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺;
N,1-二苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;
1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-(吡啶-3-基甲基)-1H-咪唑并[4,5-b]吡啶-2-胺;
4-(1-苯甲基-2-(吡咯啶-1-基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基異噁唑;
4-(2-(氮雜環丁-1-基)-1-(環戊基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基異噁唑;
1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;
1-(環戊基甲基)-6-(3,5-二甲基異噁唑-4-基)-N-(四氫-2H-哌喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;
4-胺基-1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-苯并[d]咪唑并l-2(3H)-酮;
4-胺基-6-(3,5-二甲基異噁唑-4-基)-1-(4-甲氧基苯甲基)-1H-苯并[d]咪唑并l-2(3H)-酮;
4-胺基-6-(3,5-二甲基異噁唑-4-基)-1-(1-苯基乙基)-1H-苯并[d]咪唑并l-2(3H)-酮;
4-胺基-1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-3-甲基-1H-苯并[d]咪唑并l-2(3H)-酮;
或其醫藥學上可接受之鹽或共晶體。
在一些實施例中,本發明提供一種用於治療***癌之方法,其包含向有需要之個體伴隨投與一種選自以下之化合物與另一治療劑:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽/共晶體。
在一些實施例中,本發明提供一種用於治療***癌之方法,其包含向有需要之個體伴隨投與一種選自以下之化合物與另一治療劑及免疫檢查點抑制劑兩者:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽或共晶體。
在一個實施例中,第二藥劑為雄激素受體拮抗劑。
在一個實施例中,第二藥劑為雄激素合成抑制劑。
在一個實施例中,第二藥劑為恩雜魯胺。
在一個實施例中,第二藥劑為阿帕魯胺。
在一個實施例中,第二藥劑為達諾米德(darolutamide)。
在一個實施例中,第二藥劑為阿比特龍。
在一個實施例中,第二藥劑為雄激素受體拮抗劑及與免疫檢查點抑制劑組合投與。
在一個實施例中,第二藥劑為雄激素合成抑制劑及與免疫檢查點抑制劑組合投與。
在一些實施例中,免疫檢查點抑制劑為PD-1、PD-L1抑制劑或CTL-4抑制劑。
在一些實施例中,免疫檢查點抑制劑為伊派利單抗(Ipilimumab)、納武單抗(Nivolumab)、帕博利珠單抗(Pembrolizumab)PD-1、阿特珠單抗(Atezolizumab)、阿維魯單抗(Avelumab)、德瓦魯單抗(Durvalumab)或測米匹單抗(Cemiplimab)。
在一個實施例中,***癌為去勢抵抗性***癌或轉移性去勢抵抗性***癌。
在一個實施例中,個體預先已用***癌療法治療。
在一個實施例中,***癌療法為雄激素去除療法。
在一個實施例中,個體在雄激素去除療法時預先已展現出疾病進展。
在一個實施例中,患者仍對雄激素去除療法反應。
在一個實施例中,個體預先未用雄激素去除療法治療。
在一個實施例中,雄激素去除療法為恩雜魯胺、阿帕魯胺或阿比特龍。
在一個實施例中,醫藥學上可接受之鹽或共晶體為甲磺酸鹽或共晶體。
在一個實施例中,個體患有PSA升高及可量測疾病掃描為陰性之無症狀非轉移性疾病。
在一個實施例中,個體患有PSA升高及轉移性疾病掃描為陽性之轉移性疾病,及未用雄激素去除療法或化學療法治療(紫杉烷前)。
在一個實施例中,個體患有PSA升高及轉移性疾病掃描為陽性之轉移性疾病,及已用阿比特龍、恩雜魯胺或阿帕魯胺或化學療法治療(紫杉烷前)。
在一個實施例中,個體患有可量測疾病掃描為陰性之無症狀非轉移性疾病且PSA未升高。
在一個實施例中,個體患有轉移性疾病掃描為陽性之轉移性疾病但PSA未升高,及未用雄激素去除療法或化學療法治療(紫杉烷前)。
在一個實施例中,個體患有轉移性疾病掃描為陽性之轉移性疾病但PSA未升高,及已用阿比特龍、恩雜魯胺或阿帕魯胺或化學療法治療(紫杉烷前)。
在一個實施例中,個體患有轉移性疾病及已用阿比特龍、恩雜魯胺或阿帕魯胺治療,但未接受化學療法(紫杉烷前)。
在一個實施例中,向預先未接受化學療法(紫杉烷前)之個體用一種選自以下之化合物的雄激素去除療法之伴隨治療因沒有作為劑量限制性毒性之血小板減少而展現出出人意料的優良的安全性概況:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽或共晶體。
在一個實施例中,個體患有轉移性疾病及已用阿比特龍、恩雜魯胺或阿帕魯胺治療,但未接受化學療法(紫杉烷前),因此不建議用另一雄激素去除療法治療。
在一個實施例中,個體患有轉移性疾病及已用雄激素去除療法及化學療法治療。
在一些實施例中,個體為人類。
在一個實施例中,本文所述之BET溴結構域抑制劑與另一治療劑伴隨投與,及視情況進一步與免疫檢查點抑制劑組合。如本文所用,「伴隨」意謂將BET溴結構域抑制劑與其他治療劑以數秒(例如15秒、30秒、45秒、60秒或更低)、若干分鐘(例如1分鐘、2分鐘、5分鐘或更低、10分鐘或更低、15分鐘或更低)或1至8小時之時間間隔投與。當伴隨投與時,BET溴結構域抑制劑與其他治療劑可以兩種或更多種投與方式投與,且含於獨立組合物或劑型中,組合物或劑型可含於相同封裝或不同封裝中。
在某些實施例中,本發明之組合療法中投與的BET溴結構域抑制劑選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及將其以25至200毫克/天之劑量向個體投與。在一些實施例中,將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺的化合物以36至144毫克/天之劑量向個體投與。在一些實施例中,將用於本發明之組合療法的化合物以48至120毫克/天向個體投與,化合物選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺。在一些實施例中,將用於本發明之組合療法的化合物以48毫克、60毫克、72毫克、96毫克或120毫克/天向個體投與,化合物選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與80至160毫克恩雜魯胺組合投與。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與80毫克、120毫克或160毫克恩雜魯胺組合投與。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與500至1,000毫克阿比特龍組合投與。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與500毫克、750毫克或1,000毫克阿比特龍組合投與。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與120至240毫克阿帕魯胺組合投與。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與120毫克、180毫克或240毫克阿帕魯胺組合投與。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之化合物與100至300毫克達諾米德一天兩次組合投與。在本文所述之任一實施例中,可將36至144毫克化合物I與80至160毫克恩雜魯胺、500至1,000毫克阿比特龍、120至240毫克阿帕魯胺或100至300毫克達諾米德一天兩次組合投與。
在某些實施例中,本發明之組合療法中投與的BET溴結構域抑制劑選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之醫藥學上可接受之鹽或共晶體,及將BET溴結構域抑制劑以人類中之暴露量類似於25至200毫克/天對應游離鹼之量的劑量濃度向個體投與。在某些實施例中,可將選自以下之化合物以人類中之暴露量類似於36至144毫克/天對應游離鹼之量的劑量濃度在本發明之組合療法中投與:化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之醫藥學上可接受之鹽或共晶體。在某些實施例中,可將一種選自以下之化合物以人類中之暴露量類似於48至96毫克/天對應游離鹼之量的劑量濃度在本發明之組合療法中投與:化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之醫藥學上可接受之鹽或共晶體。在本文所述之任一實施例中,可將選自化合物I及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺之醫藥上可接受鹽及共晶體的化合物與80至160毫克恩雜魯胺、500至1,000毫克阿比特龍、120至240毫克阿帕魯胺組合投與。
在某些實施例中,個體經由活化突變及/或易位而具有ETS轉錄因子家族之活化,ETS轉錄因子家族包括:TMPRSS2-ERG、SLC45A3-ERG、NDRG1-ERG、DUX4-ERG、ELF4-ERG、ELK4-ERG、BZW2-ERG、CIDEC-ERG、DYRK1A-ERG、EWSR1-ERG、FUS-ERG、GMPR-ERG、HERPUD1-ERG、KCNJ6-ERG、ZNRF3-ERG、ETS2-ERG、ETV1-ERG、HNRNPH1-ERG、PAK1-ERG、PRKAB2-ERG、SMG6-ERG、SLC45A3-FLI1、TMPRSS2-ETV1、SLC45A3-ETV1、FOXP1-ETV1、EST14-ETV1、HERVk17-ETV1、ERVK-24-ETV1、C15ORF21-ETV1、HNRPA2B1-ETV1、ACSL3-ETV1、OR51E2-ETV1、ETV1 S100R、RBM25-ETV1、ACPP-ETV1、BMPR1B- ETV1、CANT1- ETV1、ERO1A-ETV1、CPED1-ETV1、HMGN2P46-ETV1、HNRNPA2B1-ETV1、SMG6-ETV1、FUBP1-ETV1、KLK2-ETV1、MIPOL1- ETV1、SLC30A4-ETV1、EWSR1-ETV1、TMPRSS2-ETV4、KLK2-ETV4、CANT1-ETV4、DDX5-ETV4、UBTF-ETV4、DHX8-ETV4、CCL16-ETV4、EDIL3-ETV4、EWSR1-ETV4、SLC45A3-ETV4、UBTF-ETV4、XPO7-ETV4、TMPRSS2-ETV5、SLC45A3-ETV5、ACTN4- ETV5、EPG5- ETV5、LOC284889-ETV5、RNF213-ETV5、SLC45A3-ELK4。
在某些實施例中,個體經由活化突變及/或易位而具有ETS轉錄因子家族之活化,包括在某些實施例中,個體經由活化突變及/或易位而具有TMPRSS2-ERG,ETS轉錄因子家族之活化。
在某些實施例中,個體在治療12週時PSA升高低於2.5倍。
在某些實施例中,個體在治療12週時PSA降低至少2倍。
在某些實施例中,個體在治療4週或8週時具有PSA尖峰。第4週時之尖峰經定義為相較於開始用化合物I治療時(第0週),處理4週時PSA升高,接著在處理第4週至第8週時PSA降低。第8週時之尖峰經定義為相較於處理4週時(第4週),處理8週時PSA升高,接著在處理第8週至第12週時PSA降低。
文獻
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實例
由賽默飛世爾科技獲得組織培養基及試劑。由Selleck Chemicals獲得恩雜魯胺、阿帕魯胺、乙酸阿比特龍(abiraterone acetate)及達諾米德。由Toronto Research Chemicals獲得美曲勃龍(metribolone) (R1881)。
實例 1 :合成化合物 I 步驟 A :合成 5- 溴 -N3
-( 苯基亞甲基 ) 吡啶 -2,3- 二胺 ( 化合物 B)
將起始物質A
溶解於甲醇及乙酸中。將溶液冷卻至0℃至5℃且逐滴添加苯甲醛。一旦反應完成,則逐滴添加處理水及NaHCO3
溶液,保持低溫(0℃至5℃)。濾出固體及用甲醇/水(1:1)洗滌,接著乾燥,得到由HPLC之產率為94%及純度為+99%的化合物B
。1
H-NMR (DMSO-d6
): δ 8.75 (1H), 8.04 (2H), 7.93 (1H), 7.65 (1H), 7.50-7.60 (3H)。
步驟 B :合成 N3
- 苯甲基 -5- 溴吡啶 -2,3- 二胺 ( 化合物 C)
將化合物B
溶解於乙醇中及逐份添加NaHB4
,保持溫度為15℃與25℃之間。將反應混合物攪拌8至15小時,直至由HPLC監測到反應完成。添加HCl溶液,將pH調節為6至7,接著添加處理水,保持溫度為15℃至25℃之間。將混合物攪拌1至5小時,過濾及用乙醇/水混合物洗滌。在約60℃下乾燥15至20小時後,得到化合物C
。1
H-NMR (DMSO-d6
): d 7.2-7.4 (6 H), 6.55 (1 H), 5.70-5.83 (3 H), 4.30 (2 H)。
步驟 C :合成 N3
- 苯甲基 -5-(3,5- 二甲基 -1,2- 噁唑 -4- 基 ) 吡啶 -2,3- 二胺 ( 化合物 D)
將化合物C
、化合物G
及磷酸三鉀三水合物混合,接著添加1,4-二噁烷及處理水。將所得混合物用氮氣充分吹掃。添加肆(三苯基膦)鈀(0)及將混合物加熱至≥90℃,直至化合物C與化合物D之比率不超過1%。冷卻後,將反應混合物過濾,用1,4-二噁烷洗滌固體且隨後濃縮。添加處理水及攪拌混合物,直至母液中之剩餘化合物D
的量不超過0.5%。藉由過濾分離化合物D
且將其用1,4-二噁烷/水及第三丁基甲基醚依序洗滌。將濕濾餅在二氯甲烷及矽膠中混合。攪拌後,將混合物過濾,隨後濃縮。將混合物冷卻及添加第三丁基甲基醚。藉由過濾分離產物及乾燥,直至二氯甲烷、第三丁基甲基醚及水分含量不超過0.5%。1
H-NMR (DMSO-d6
): δ 7.30-7.45 (4 H), 7.20-7.25 (2 H), 6.35 (1 H), 5.65-5.80 (3 H), 4.30-4.40 (2 H), 2.15 (3 H), 1.95 (3 H)。
步驟 D :合成 1- 苯甲基 -6-(3,5- 二甲基 -1,2- 噁唑 -4- 基 )-3H- 咪唑并 [4,5-b] 吡啶 -2- 酮 ( 化合物 E)
將羰基二咪唑固體添加至化合物D
與二甲基亞碸之攪拌混合物中。加熱混合物,直至化合物D與化合物E
之比率為NMT 0.5%。將混合物冷卻及添加處理水歷經若干小時。將所得混合物在環境溫度下攪拌至少2小時。藉由過濾分離產物及用處理水洗滌。在使用加熱及真空乾燥之前,二甲基亞碸經檢驗為NMT 0.5%。當水分含量為NMT 0.5%時,乾燥完成,得到化合物E
。1
H-NMR (DMSO-d6
): δ 11.85 (1 H), 7.90 (1 H), 7.20-7.45 (6 H), 5.05 (2 H), 3.57 (3 H), 2.35 (3 H), 2.15 (3 H)。
步驟 E :合成 4-[1- 苯甲基 -2- 氯 -1H- 咪唑并 [4,5-b] 吡啶 -6- 基 ]-3,5- 二甲基 -1,2- 噁唑 ( 化合物 F)
將化合物E
與***混合,及隨後用可逐滴添加之二異丙基乙基胺(DIPEA)處理。將所得混合物加熱若干小時,冷卻及對完成反應物進行取樣。若化合物E
與化合物F
之比率不超過0.5%,則反應完成。否則,將反應物再加熱一段時間及如前所述進行取樣。反應完成後,將混合物濃縮,隨後冷卻。添加乙酸乙酯及將混合物在真空下濃縮若干次。將乙酸乙酯(EtOAc)添加至濃縮物中,將混合物冷卻及隨後添加至碳酸氫鈉水溶液。分離有機相且將有機層用碳酸氫鈉水溶液洗滌,及隨後用水洗滌。濃縮有機相,添加乙酸乙酯,及將混合物濃縮以確保水分含量不超過0.2%。將混合物於乙酸乙酯中用碳脫色。將混合物濃縮及添加正庚烷。藉由過濾分離產物及在真空下乾燥。當殘餘水分、乙酸乙酯及正庚烷不超過0.5%時,乾燥完成。1
H-NMR (MeOH-d4
): δ 8.40 (1 H), 7.90 (1 H), 7.25-7.45 (5 H), 5.65 (2 H), 2.37 (3 H), 2.22 (3 H)。
步驟 F :合成 1- 苯甲基 -6-(3,5- 二甲基 -1,2- 噁唑 -4- 基 )-N- 甲基 -1H- 咪唑并 [4,5-b] 吡啶 -2- 胺 ( 化合物 I)
將化合物F與甲胺於四氫呋喃(THF)中混合及在環境溫度下攪拌,直至由HPLC之化合物F與化合物I的比率為NMT 0.1%。反應完成後,將混合物在真空下濃縮,添加處理水,及藉由過濾分離產物。將濾餅用處理水洗滌。將濕濾餅溶解於鹽酸中及將所得溶液用二氯甲烷洗滌以移除雜質。將水溶液用氫氧化鈉溶液中和,且藉由過濾分離化合物I,用處理水洗滌及在真空下乾燥。為了移除任何剩餘鹽酸,必要時可將經乾燥的物質溶解於乙醇中,用氫氧化鈉於乙醇中之溶液處理,接著添加處理水,以使產物沈澱。藉由過濾分離化合物I,用處理水洗滌及乾燥。1
H-NMR (DMSO-d6
): δ 7.96 (d, 1H, J=2.0 Hz), 7.42 (d, 1H, J=2.0 Hz), 7.37 (q, 1H, J=4.2 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.24 (m, 2H), 5.30 (s, 2H), 3.00 (d, 3H, 4.5 Hz), 2.34 (s, 3H), 2.16 (s, 3H).13
C-NMR (DMSO-d6
): δ 164.8, 158.4, 157.7, 156.0, 141.1, 136.4, 128.6 (2C), 127.5, 127.4, 127.2 (2C), 115.8, 114.2 (2C), 44.5, 29.3, 11.2, 10.3。
實例 2 : 化合物 I 之結晶甲磺酸酯
將約5 g化合物I溶解於乙醇(115 mL)中及根據1:1之莫耳比添加甲磺酸於乙醇中之溶液(10 mL,158.7 mg/mL)。在50℃下將混合物振盪2小時,隨後濃縮至一半體積及攪拌隔夜。將所形成之固體(化合物I形式I之甲磺酸鹽/共晶體)分離、乾燥及表徵。
化合物I形式I之甲磺酸鹽/共晶體亦由其他溶劑及溶劑混合物(包括丙酮及乙腈)獲得。
化合物I形式I之甲磺酸鹽/共晶體表徵為包含以2θ表示之以下峰的XRPD,峰在8.4±0.2、10.6±0.2、11.7±0.2、14.5±0.2、15.3±0.2、16.9±0.2、18.2±0.2、19.0±0.2、19.9±0.2、20.5±0.2、22.6±0.2、23.8±0.2、24.5±0.2及27.6±0.2度處,其如使用Cu-Kα
輻射管在繞射儀上測定(圖4)。
化合物I形式I之甲磺酸鹽/共晶體表徵為具有在約207℃之溫度下之吸熱峰的DSC (圖5)。
化合物I形式I之甲磺酸鹽/共晶表徵為具有如圖6中所示之熱分析圖的TGA,證實化合物I形式I為無水形式。
實例 3 : 藉由將化合物 I 與恩雜魯胺組合來協同抑制 VCaP 細胞生存力
將VCaP細胞(CRL-2876)以每孔10,000個細胞之密度塗於96孔平底培養盤中含有10%炭去除FBS及青黴素/鏈黴素之D-MEM培養基中,及在37℃、5% CO2
下培育24小時。將培養基用含有10%炭去除FBS且具有恆定比率的化合物I或恩雜魯胺作為單一藥劑或以四種不同濃度(2×IC50,1×IC50,0.5×IC50,0.25×IC50)之兩種藥物的組合之D-MEM (具有0.1 nM R1881)置換及在37℃、5% CO2
下培育3至7天。若將細胞培育7天,則如上文所述在第3天或第4天對其進行再處理。若將細胞培育7天,則如上文所述在第3天或第4天對其進行再處理。每種濃度使用三個重複孔及將僅含有具有0.1% DMSO之培養基的孔用作對照。為了量測細胞生存力,將以1:100稀釋至分析緩衝液(CellTiter Fluor細胞生存力檢定(普洛麥格))中之100 μL GF-AFC受質添加至各孔中,及在37℃、5% CO2
下再培育30至90分鐘。在螢光計中讀取以380 nm至400 nm激發/505 nm發射之螢光,及在藉由減去空白孔的信號校正背景之後,對相對於經DMSO處理之細胞的細胞效價百分比進行計算。使用GraphPad Prism軟體計算單一藥劑之IC50值。協同定量藉由使用CalcuSyn軟體(Biosoft)基於Chou-Talalay演算法(Chou及Talalay,1984)來計算組合指數(CI)及針對有效劑量(ED) 50、75及90之CI值取平均值進行。如圖1中所示,相較於平均CI值為0.5之任一單一藥劑,將化合物I添加至恩雜魯胺提高了對細胞生存力的抑制。
實例 4 : 藉由將化合物 I 與阿帕魯胺 ( ARN - 509 ) 組合來協同抑制 VCaP 細胞生存力
將VCaP細胞(CRL-2876)以每孔10,000個細胞之密度塗於96孔平底培養盤中含有10%炭去除FBS及青黴素/鏈黴素之D-MEM培養基中,及在37℃、5% CO2
下培育24小時。將培養基用含有10%炭去除FBS且具有恆定比率的化合物I或阿帕魯胺作為單一藥劑或以四種不同濃度(2×IC50,1×IC50,0.5×IC50,0.25×IC50)之兩種藥物的組合之D-MEM (具有0.1 nM R1881)置換及在37℃、5% CO2
下培育3至7天。若將細胞培育7天,則如上文所述在第3天或第4天對其進行再處理。若將細胞培育7天,則如上文所述在第3天或第4天對其進行再處理。每種濃度使用三個重複孔及將僅含有具有0.1% DMSO之培養基的孔用作對照。為了量測細胞生存力,將以1:100稀釋至分析緩衝液(CellTiter Fluor細胞生存力檢定(普洛麥格))中之100 μL GF-AFC受質添加至各孔中,及在37℃、5% CO2
下再培育30至90分鐘。在螢光計中讀取以380 nm至400 nm激發/505 nm發射之螢光,及在藉由減去空白孔的信號校正背景之後,對相對於經DMSO處理之細胞的細胞效價百分比進行計算。使用GraphPad Prism軟體計算單一藥劑之IC50值。協同定量藉由使用CalcuSyn軟體(Biosoft)基於Chou-Talalay演算法(Chou及Talalay,1984)來計算組合指數(CI)及針對有效劑量(ED) 50、75及90之CI值取平均值進行。如圖2中所示,相較於平均CI值為0.4之任一單一藥劑,將化合物I添加至阿帕魯胺提高了對細胞生存力的抑制。
實例 5 : 藉由將化合物 I 與乙酸阿比特龍組合來協同抑制 LAPC - 4 細胞生存力
將LAPC-4細胞(CRL-13009)以每孔5,000個細胞之密度塗於96孔平底培養盤中含有10%炭去除FBS及青黴素/鏈黴素之IMDM培養基中,及在37℃、5% CO2
下培育24小時。將培養基用含有10%炭去除FBS且具有恆定比率的化合物I或乙酸阿比特龍作為單一藥劑或以四種不同濃度(2×IC50,1×IC50,0.5×IC50,0.25×IC50)之兩種藥物的組合之IMDM (具有1 nM R1881)置換及在37℃、5% CO2
下培育3至7天。每種濃度使用三個重複孔及將僅含有具有0.1% DMSO之培養基的孔用作對照。為了量測細胞生存力,將以1:100稀釋至分析緩衝液(CellTiter Fluor細胞生存力檢定(普洛麥格))中之100 μL GF-AFC受質添加至各孔中,及在37℃、5% CO2
下再培育30至90分鐘。在螢光計中讀取以380 nm至400 nm激發/505 nm發射之螢光,及在藉由減去空白孔的信號校正背景之後,對相對於經DMSO處理之細胞的細胞效價百分比進行計算。使用GraphPad Prism軟體計算單一藥劑之IC50值。協同定量藉由使用CalcuSyn軟體(Biosoft)基於Chou-Talalay演算法(Chou及Talalay,1984)來計算組合指數(CI)及針對有效劑量(ED) 50、75及90之CI值取平均值進行。如圖3中所示,相較於平均CI值為0.09之任一單一藥劑,將化合物I添加至乙酸阿比特龍提高了對細胞生存力的抑制。
實例 6 : 臨床發展
已將化合物I作為單一藥劑及與恩雜魯胺組合在患有CRPC之人類中進行測試。可以相同方式對化合物I之醫藥學上可接受之鹽或其共晶體、尤其化合物I形式I之甲磺酸鹽/共晶體以及其他治療劑(諸如阿比特龍、阿帕魯胺及達諾米德)進行測試。
階段1b劑量遞增研究(3+3設計)已對化合物I與恩雜魯胺之藥物動力學、安全性、耐受性及目標結合進行評估。測試了至144毫克劑量的劑量遞增,未達到最大耐受劑量。可探索額外劑量及給藥時程,以進一步定義最大治療功效。在血液分析中量測目標結合,及對mRNA含量變化之多種標記物進行偵測,標記物包括MYC、CCR1、IL1RN、GPR183、HEXIM1、PD-L1、IL-8、A2AR、TIM-3。
階段2a劑量確認研究對未接受化學療法及在恩雜魯胺及/或阿比特龍時進展的個體中之化合物I (以48毫克及96毫克劑量)與恩雜魯胺之組合進行評估。使用藥物動力學、安全性、耐受性及目標結合、PSA反應以及良好耐受劑量下之放射線攝影進展時間來確定階段2a建議劑量。已對個體血液及腫瘤樣品進行分子分析,以確定對組合療法之反應性與非反應性個體及提供證明機制。
如圖7及下表中所示,階段2a研究評估資料顯示,相較於僅用恩雜魯胺之預期24至28週,用化合物I與恩雜魯胺處理之2線mCRPC患者繼續rPFS獲益,rPFS總體為44.6週。阿比特龍及恩雜魯胺進展顯示出與化合物I與恩雜魯胺之組合的類似益處。亦偵測到具有高腫瘤負荷及低腫瘤負荷之患者的rPFS延長,包括兩種部分反應,一種在預先阿比特龍進展之患者中,及一種在恩雜魯胺進展之患者中。兩種阿比特龍進展者之PSA90>117週,及7名具有恩雜魯胺之預先進展的患者接受化合物I與恩雜魯胺>52週。
如圖8及下表中所示,相較於未展示出此類PSA尖峰或反應之中值輻射無進展存活期為31.3週的患者,120週時具有PSA反應之患者的中值輻射進展存活期尚未達到,及第4週或第8週時具有PSA尖峰之患者的中值輻射進展存活期為45.9週。PSA反應經定義為相較於篩選值,PSA在12週時下降>50%。PSA尖峰定義於實例7中。
將使用隨機階段2b研究來確認較大群體中之階段2劑量,以及鑑別對組合療法充分反應的亞群。可探索化合物I與另一治療劑之多種組合。
階段3研究將為相較於安慰劑,患有CRPC之個體中之化合物I或其醫藥學上可接受之鹽或共晶體與另一治療劑(阿比特龍、恩雜魯胺、達諾米德或阿帕魯胺)的雙盲、隨機研究。一級端點可為總體存活期或放射線攝影進展時間。
實例 7 : 用化合物 I 與恩雜魯胺處理 4 週或 8 週時的 PSA 尖峰
將具有阿比特龍及/或恩雜魯胺之預先進展的mCRPC患者用化合物I與恩雜魯胺之組合給藥。在用化合物I給藥QD 4週或8週後,若干患者具有PSA尖峰。圖9展示了第4週時2名患者具有PSA尖峰及第8週時2名患者具有PSA尖峰的實例。第4週時之尖峰經定義為相較於處理開始時(第0週),處理4週時PSA升高,接著在處理第4週至第8週時PSA降低。第8週時之尖峰經定義為相較於處理4週時(第4週),處理8週時PSA升高,接著在處理第8週至第12週時PSA降低。如圖8中所示,相較於不具有PSA尖峰之患者,具有PSA尖峰之個體的輻射無進展存活期更長(45.9週對31.3週)。
實例 8 : mCRPC 患者中之 ETS 突變 / 融合的分佈及對化合物 I 與恩雜魯胺之組合的反應
將具有阿比特龍及/或恩雜魯胺之預先進展的mCRPC患者用化合物I與恩雜魯胺之組合給藥。具有特徵化突變或融合(包含ETS家族成員)或缺失此類融合或突變的患者及其對組合之反應描繪於圖10中。反應者經定義為在給藥化合物I >24週後不具有臨床或放射線攝影進展,及無反應者經定義為≤24週出現放射線攝影進展或臨床進展。在反應者與非反應者之間,具有ETS突變或融合之患者分佈類似,而在不具有ETS突變或融合之患者中無反應者存在。
實例 9 : mCRPC 患者中之 ETS 突變 / 融合的分佈、 PSA 反應或尖峰及對化合物 I 與恩雜魯胺之組合的反應
將具有阿比特龍及/或恩雜魯胺之預先進展的mCRPC患者用化合物I與恩雜魯胺之組合給藥。具有特徵化突變或融合(包含ETS家族成員)或缺失此類融合或突變及其對組合之反應以及在4週或8週時出現或缺失PSA反應或尖峰的患者描繪於圖11中。反應者經定義為在給藥化合物I >24週後不具有臨床或放射線攝影進展,及無反應者經定義為≤24週出現放射線攝影或臨床進展。PSA反應經定義為在開始給藥化合物I 12週後,PSA含量降低≥50%。4或8週時出現ETS突變或融合之患者在PSA反應或PSA尖峰之患者中富集。
實例 10 : mCRPC 患者對化合物 I 與恩雜魯胺之組合的反應誘導腫瘤中之免疫反應及干擾素 γ 信號傳遞
將具有恩雜魯胺之預先進展的患者用QD與化合物I給藥,同時繼續恩雜魯胺。在篩選(恩雜魯胺)及在給藥(恩雜魯胺與化合物I)8週後獲得腫瘤切片。在兩個切片上進行總轉錄本(RNA-Seq)分析及使用STAR軟體進行比對,且使用2018年12月與2019年8月之間的BaseSpace™序列Hub預設參數進行Cufflinks之差示基因表現分析。使用SALMON比對軟體及BioConductor進行額外獨立分析。使用基因集富集分析(GSEA)鑑別差示表現基因標籤,其使用來自分子標籤資料庫(Molecular Signature Database)之基因標籤(Subramanian A, Tamayo P等人(2005, PNAS 102, 15545-15550); Liberzon A等人(2011, Bionformatics 27, 1739-1740); Liberzon A等人(2015, Cell Systems 1, 417-425)。如圖12A中所示,處理時切片中之若干免疫相關標籤顯著上調。圖中表示相關基因集富集及各基因集富集中所涉及之基因可由MSigDB下載。在圖12B中,圖示了在此等基因集富集中發現的一些基因的上調程度。適應性免疫反應、抗原呈現及干擾素γ信號傳遞所涉及之基因集富集的上調表明化合物I與恩雜魯胺之組合已誘發免疫反應表型,及因此患者將對化合物I、恩雜魯胺與檢查點抑制劑之三種組合反應。
圖1展示了化合物I、恩雜魯胺及化合物I與恩雜魯胺之組合對VCaP細胞(AR陽性,AR擴增,TMPRSS2-ERG融合)之細胞增殖的影響(抑制)。
圖2展示了化合物I、阿帕魯胺(apalutamide) (ARN-509)及化合物I與阿帕魯胺之組合對VCaP細胞(AR陽性,AR擴增,TMPRSS2-ERG融合)之細胞增殖的影響(抑制)。
圖3展示了化合物I、阿比特龍(abiraterone)及化合物I與阿比特龍之組合對LAPC4細胞之增殖的影響(抑制)。
圖4展示了化合物I之甲磺酸鹽/共晶體的X射線粉末繞射圖(XRPD)。
圖5展示了化合物I之甲磺酸鹽/共晶體的差示掃描量熱計(DSC)曲線。
圖6展示了化合物I之甲磺酸鹽/共晶體的熱解重量分析(TGA)。
圖7展示了用化合物I及恩雜魯胺處理之患者(預先在用阿比特龍或恩雜魯胺處理時顯示出進展)及所有患者的卡本-麥爾存活曲線。患者數目、事件數目及中值無進展存活期(PFS)描繪於下表中。
圖8展示了在用化合物I及恩雜魯胺處理12週後具有PSA反應、PSA尖峰或均不具有(無PSA調節)之患者的卡本-麥爾曲線。患者數目、事件數目及中值無進展存活期(PFS)描繪於下表中。
圖9展示了在用化合物I與恩雜魯胺之組合處理QD之第4週或第8週時具有PSA尖峰的四名mCRPC患者之實例。
圖10展示了用化合物I與恩雜魯胺之組合處理QD之mCRPC患者中的ETS突變或融合之分佈,及患者反應(>24週不具有臨床或放射線攝影進展)抑或無反應(≤24週出現放射線攝影或臨床進展)。
圖11展示了用化合物I與恩雜魯胺之組合處理QD之mCRPC患者中的ETS突變或融合之分佈,及患者第4週或第8週時是否具有PSA尖峰。反應者經定義為在給藥化合物I >24週後不具有臨床或放射線攝影進展,及無反應者經定義為≤24週出現放射線攝影或臨床進展。
圖12A展示了mCRPC患者對化合物I與恩雜魯胺之組合的反應誘導腫瘤中之免疫反應。在前化合物I與後化合物I樣品中連續存在恩雜魯胺。圖12B展示了一些腫瘤中之免疫反應基因的上調。
Claims (18)
- 一種BET溴結構域抑制劑與第二治療劑之組合的用途,其係用於製備治療***癌的藥物,該藥物用於有需要之個體,其中該BET溴結構域抑制劑選自:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)、1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽/共晶體,且該第二治療劑為恩雜魯胺(enzalutamide)、阿帕魯胺(apalutamide)或阿比特龍(abiraterone)。
- 一種BET溴結構域抑制劑的用途,其係用於製備治療***癌的藥物,該藥物用於有需要之個體,該藥物與一第二治療劑組合,其中該BET溴結構域抑制劑選自:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)、1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽/共晶體,且該第二治療劑為恩雜魯胺、阿帕魯胺或阿比特龍。
- 一種第二治療劑的用途,其係用於製備治療***癌的藥物,該藥物用於有需要之個體,該藥物與一BET溴結構域抑制劑組合,其中該BET溴結構域抑制劑選自:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)、1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽/共晶體,且該第二治療劑為恩雜魯胺、阿帕魯胺或阿比特龍。
- 如請求項1至3中任一項之用途,其中該BET溴結構域抑制劑為化合物I。
- 如請求項1至3中任一項之用途,其中該BET溴結構域抑制劑為化合物I形式I之甲磺酸鹽/共晶體。
- 如請求項1至3中任一項之用途,其中該第二治療劑為恩雜魯胺(enzalutamide)。
- 如請求項1至3中任一項之用途,其中該第二治療劑為阿帕魯胺(apalutamide)。
- 如請求項1至3中任一項之用途,其中該第二治療劑為阿比特龍(abiraterone)。
- 如請求項1至3中任一項之用途,其中該***癌為去勢抵抗性***癌(castration-resistant prostate cancer)或轉移性去勢抵抗性***癌(metastatic castration-resistant prostate cancer)。
- 如請求項1至3中任一項之用途,其中該個體預先已用***癌療法治療。
- 如請求項10之用途,其中該***癌療法為雄激素去除療法。
- 如請求項1至3中任一項之用途,其中該個體在用雄激素去除療法時已預先顯示出疾病進展。
- 如請求項1至3中任一項之用途,其中該個體未預先用雄激素去除療法治療。
- 如請求項11之用途,其中該雄激素去除療法為恩雜魯胺、阿帕魯胺或阿比特龍。
- 如請求項12之用途,其中該雄激素去除療法為恩雜魯胺、阿帕魯胺或阿比特龍。
- 如請求項1至3中任一項之用途,其中將選自以下之化合物與雄激素去除療法一起給藥而不導致作為劑量限制性毒性之血小板減少:1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺(化合物I)及1-苯甲基-6-(3,5-二甲基異噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺,及其醫藥學上可接受之鹽或共晶體。
- 如請求項1至3中任一項之用途,其中該個體經由活化突變及/或易位而具有ETS轉錄因子家族之活化,該等ETS轉錄因子家族包括: TMPRSS2-ERG、SLC45A3-ERG、NDRG1-ERG、DUX4-ERG、ELF4-ERG、ELK4-ERG、BZW2-ERG、CIDEC-ERG、DYRK1A-ERG、EWSR1-ERG、FUS-ERG、GMPR-ERG、HERPUD1-ERG、KCNJ6-ERG、ZNRF3-ERG、ETS2-ERG、ETV1-ERG、HNRNPH1-ERG、PAK1-ERG、PRKAB2-ERG、SMG6-ERG、SLC45A3-FLI1、TMPRSS2-ETV1、SLC45A3-ETV1、FOXP1-ETV1、EST14-ETV1、HERVk17-ETV1、ERVK-24-ETV1、C15ORF21-ETV1、HNRPA2B1-ETV1、ACSL3-ETV1、OR51E2-ETV1、ETV1 S100R、RBM25-ETV1、ACPP-ETV1、BMPR1B-ETV1、CANT1-ETV1、ERO1A-ETV1、CPED1-ETV1、HMGN2P46-ETV1、HNRNPA2B1-ETV1、SMG6-ETV1、FUBP1-ETV1、KLK2-ETV1、MIPOL1-ETV1、SLC30A4-ETV1、EWSR1-ETV1、TMPRSS2-ETV4、KLK2-ETV4、CANT1-ETV4、DDX5-ETV4、UBTF-ETV4、DHX8-ETV4、CCL16-ETV4、EDIL3-ETV4、EWSR1-ETV4、SLC45A3-ETV4、UBTF-ETV4、XPO7-ETV4、TMPRSS2-ETV5、SLC45A3-ETV5、ACTN4-ETV5、EPG5-ETV5、LOC284889-ETV5、RNF213-ETV5、SLC45A3-ELK4。
- 如請求項1至3中任一項之用途,其中該個體在治療4週或8週時具有PSA尖峰。
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CN114644687B (zh) * | 2022-04-07 | 2023-06-27 | 华中科技大学同济医学院附属协和医院 | 一种可拮抗rbm25蛋白rna结合活性的多肽rbip-21及其应用 |
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CN105407888A (zh) * | 2013-06-21 | 2016-03-16 | 齐尼思表观遗传学公司 | 新双环溴结构域抑制剂 |
TW201823238A (zh) * | 2016-11-22 | 2018-07-01 | 美商基利科學股份有限公司 | Bet抑制劑的固體形式 |
TW201825096A (zh) * | 2016-12-06 | 2018-07-16 | 美商基利科學股份有限公司 | 藉由伴隨投予布羅莫結構域(bromodomain)抑制劑與第二藥劑之***癌治療 |
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GB0919434D0 (en) * | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
CA2812744A1 (en) * | 2010-09-27 | 2012-04-05 | Exelixis, Inc. | Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases |
JP6548641B2 (ja) * | 2013-10-28 | 2019-07-24 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 転移性前立腺癌の治療 |
NO2719005T3 (zh) * | 2014-07-28 | 2018-01-20 | ||
WO2016171470A1 (en) * | 2015-04-21 | 2016-10-27 | Kainos Medicine, Inc. | Bromodomain-inhibiting compounds and methods to prevent or treat a cancer |
WO2017216772A2 (en) * | 2016-06-16 | 2017-12-21 | The University Of Chicago | Methods and compositions for treating breast and prostate cancer |
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CN105407888A (zh) * | 2013-06-21 | 2016-03-16 | 齐尼思表观遗传学公司 | 新双环溴结构域抑制剂 |
TW201823238A (zh) * | 2016-11-22 | 2018-07-01 | 美商基利科學股份有限公司 | Bet抑制劑的固體形式 |
TW201825096A (zh) * | 2016-12-06 | 2018-07-16 | 美商基利科學股份有限公司 | 藉由伴隨投予布羅莫結構域(bromodomain)抑制劑與第二藥劑之***癌治療 |
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US20220117942A1 (en) | 2022-04-21 |
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IL281281A (en) | 2021-04-29 |
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SG11202102492PA (en) | 2021-04-29 |
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