TW202241445A - 組合 - Google Patents
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- TW202241445A TW202241445A TW110147061A TW110147061A TW202241445A TW 202241445 A TW202241445 A TW 202241445A TW 110147061 A TW110147061 A TW 110147061A TW 110147061 A TW110147061 A TW 110147061A TW 202241445 A TW202241445 A TW 202241445A
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- TW
- Taiwan
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- breast cancer
- use according
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 320
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims description 207
- 206010006187 Breast cancer Diseases 0.000 claims description 55
- 208000026310 Breast neoplasm Diseases 0.000 claims description 55
- 108010007005 Estrogen Receptor alpha Proteins 0.000 claims description 35
- 102100038595 Estrogen receptor Human genes 0.000 claims description 30
- -1 2-(4-fluoro-2,6-dimethylbenzyl)-6-hydroxyphenyl Chemical group 0.000 claims description 27
- 230000035772 mutation Effects 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 24
- BURHGPHDEVGCEZ-KJGLQBJMSA-N (e)-3-[4-[(e)-2-(2-chloro-4-fluorophenyl)-1-(1h-indazol-5-yl)but-1-enyl]phenyl]prop-2-enoic acid Chemical compound C=1C=C(F)C=C(Cl)C=1C(/CC)=C(C=1C=C2C=NNC2=CC=1)\C1=CC=C(\C=C\C(O)=O)C=C1 BURHGPHDEVGCEZ-KJGLQBJMSA-N 0.000 claims description 20
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- 229940122815 Aromatase inhibitor Drugs 0.000 claims description 13
- KISZAGQTIXIVAR-VWLOTQADSA-N 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid Chemical compound ClC1=C(C=CC(=C1)Cl)C1=C(C2=C(CCC1)C=C(C=C2)C(=O)O)C1=CC=C(C=C1)O[C@@H]1CN(CC1)CCCF KISZAGQTIXIVAR-VWLOTQADSA-N 0.000 claims description 12
- SIFNOOUKXBRGGB-AREMUKBSSA-N (6r)-6-[2-[ethyl-[[4-[2-(ethylamino)ethyl]phenyl]methyl]amino]-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-ol Chemical compound C1=CC(CCNCC)=CC=C1CN(CC)C1=CC(OC)=CC=C1[C@H]1CC2=CC=C(O)C=C2CC1 SIFNOOUKXBRGGB-AREMUKBSSA-N 0.000 claims description 11
- SJXNPGGVGZXKKI-NYYWCZLTSA-N (E)-3-[4-[[2-[2-(1,1-difluoroethyl)-4-fluorophenyl]-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl]prop-2-enoic acid Chemical compound FC(C)(F)C1=C(C=CC(=C1)F)C1=C(C2=C(S1)C=C(C=C2)O)OC1=CC=C(C=C1)/C=C/C(=O)O SJXNPGGVGZXKKI-NYYWCZLTSA-N 0.000 claims description 11
- DFBDRVGWBHBJNR-BBNFHIFMSA-N (e)-3-[3,5-difluoro-4-[(1r,3r)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H](N2CC(C)(C)F)C)=C(F)C=C(\C=C\C(O)=O)C=C1F DFBDRVGWBHBJNR-BBNFHIFMSA-N 0.000 claims description 11
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- KOAITBOFZOEDOC-BJMVGYQFSA-N (E)-3-[4-[[2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl]prop-2-enoic acid Chemical compound FC1=CC(=C(C(=O)C2=C(C3=C(S2)C=C(C=C3)O)OC2=CC=C(C=C2)/C=C/C(=O)O)C(=C1)C)C KOAITBOFZOEDOC-BJMVGYQFSA-N 0.000 claims description 8
- GQCXHIKRWBIQMD-AKJBCIBTSA-N 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol Chemical compound FC1=C(C(=CC(=C1)NC1CN(C1)CCCF)F)[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC(CO)(F)F GQCXHIKRWBIQMD-AKJBCIBTSA-N 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- JPFTZIJTXCHJNE-HMOQVRKWSA-N (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide Chemical compound CN(C(\C=C\CNCCOC1=NC=C(C=C1)\C(=C(\CC(F)(F)F)/C1=CC=CC=C1)\C=1C=C2C(=NNC2=CC=1)F)=O)C JPFTZIJTXCHJNE-HMOQVRKWSA-N 0.000 claims description 7
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 7
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 7
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- TZZDVPMABRWKIZ-XMOGEVODSA-N (3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound OC=1C=C2CC[C@@H]([C@@H](C2=CC=1)C1=CC=C(C=C1)N1CCC(CC1)CN1CCN(CC1)C=1C=C2CN(C(C2=CC=1)=O)[C@@H]1C(NC(CC1)=O)=O)C1=CC=CC=C1 TZZDVPMABRWKIZ-XMOGEVODSA-N 0.000 claims description 6
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- 238000009261 endocrine therapy Methods 0.000 claims description 5
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- PDGKHKMBHVFCMG-UHFFFAOYSA-N 2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[7,8-dihydropyrazino[5,6]pyrrolo[1,2-d]pyrimidine-9,1'-cyclohexane]-6-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 PDGKHKMBHVFCMG-UHFFFAOYSA-N 0.000 claims description 4
- QIOCQCYXBYUYLH-YACUFSJGSA-N 3-[1-[(3r)-3-[4-[[4-[4-[3-[2-(4-chlorophenyl)-5-methyl-4-methylsulfonyl-1-propan-2-ylpyrrol-3-yl]-5-fluorophenyl]piperazin-1-yl]phenyl]sulfamoyl]-2-(trifluoromethylsulfonyl)anilino]-4-phenylsulfanylbutyl]piperidine-4-carbonyl]oxypropylphosphonic acid Chemical compound CC(C)N1C(C)=C(S(C)(=O)=O)C(C=2C=C(C=C(F)C=2)N2CCN(CC2)C=2C=CC(NS(=O)(=O)C=3C=C(C(N[C@H](CCN4CCC(CC4)C(=O)OCCCP(O)(O)=O)CSC=4C=CC=CC=4)=CC=3)S(=O)(=O)C(F)(F)F)=CC=2)=C1C1=CC=C(Cl)C=C1 QIOCQCYXBYUYLH-YACUFSJGSA-N 0.000 claims description 4
- SGJLSPUSUBJWHO-UHFFFAOYSA-N 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperidin-4-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1C1CCNCC1 SGJLSPUSUBJWHO-UHFFFAOYSA-N 0.000 claims description 4
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- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 claims description 4
- YPJRHEKCFKOVRT-UHFFFAOYSA-N lerociclib Chemical compound C1CN(C(C)C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 YPJRHEKCFKOVRT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
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Abstract
本文中揭示用於治療疾病或病況(諸如癌症)的化合物之組合。
Description
本申請案關於化學、生物化學及醫學之領域。更具體而言,本文中揭示組合療法、及使用本文中所述之組合療法來治療疾病及/或病況之方法。
癌症是一種涉及異常細胞生長之疾病家族,此異常細胞生長有可能侵犯或擴散至身體其他部位。現今的癌症治療包括手術、荷爾蒙療法、輻射療法、化學療法、免疫療法、標靶療法、及其組合。存活率隨癌症類型及診斷出之癌症階段而有不同。在2019年,大約有180萬人將會診斷出癌症,並且估計在美國將會有606,880人死於癌症。因此,對於有效的癌症治療仍存在需求。
本文中所述之一些實施例係關於化合物之組合,其可包括有效量的化合物(A)、有效量的化合物(B)、及有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽。
本文中所述之一些實施例係關於化合物之組合用於治療疾病或病況之用途,其中該組合包括有效量的化合物(A)、有效量的化合物(B)、及有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽。本文中所述之其他實施例係關於化合物之組合在製造用於治療疾病或病況的藥劑之用途,其中該組合包括有效量的化合物(A)、有效量的化合物(B)、及有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽。本文中所述之又其他實施例係關於有效量的化合物(A)、有效量的化合物(B)、及有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽的組合,其用於治療疾病或病況。本文中所述之又其他實施例係關於一種用於治療疾病或病況的方法,其可包括組合投予有效量的化合物(A)、有效量的化合物(B)、及有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽。
在一些實施例中,該疾病或病況可係本文中所述之癌症,諸如乳癌。
定義
除非另外定義,否則本文中所使用之所有技術及科學用語具有與所屬技術領域中具有通常知識者所共同理解的相同含義。除非另有說明,本文所引用之所有專利、申請案、公開申請案、及其他出版物之全文均以引用之方式併入本文中。若在本文中之用語具有複數個定義,除非另有說明,否則以此節之定義為主。
用語「醫藥上可接受之鹽(pharmaceutically acceptable salt)」係指不會對其所投予至之生物體造成顯著刺激且不會使化合物之生物活性及性質無效化的化合物之鹽。在一些實施例中,鹽係化合物之酸加成鹽。醫藥鹽可藉由使化合物與無機酸反應而獲得,無機酸諸如氫鹵酸(例如,氫氯酸或氫溴酸)、硫酸、硝酸、及磷酸(諸如2,3-二羥丙基磷酸二氫鹽)。醫藥鹽亦可藉由使化合物與有機酸反應而獲得,有機酸諸如脂族或芳族羧酸或磺酸,例如甲酸、乙酸、琥珀酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、菸鹼酸、甲磺酸、乙磺酸、對甲苯磺酸、三氟乙酸、苯甲酸、水楊酸、2-側氧戊二酸、或萘磺酸。醫藥鹽亦可藉由使化合物與鹼反應以形成鹽而獲得,鹽諸如胺鹽、鹼金屬鹽(諸如鈉鹽、鉀鹽、或鋰鹽)、鹼土金屬鹽(諸如鈣或鎂鹽)、碳酸鹽、碳酸氫鹽、有機鹼(諸如二環己基胺、N-甲基-D-還原葡糖胺、參(羥甲基)甲基胺、C
1-C
7烷基胺、環己基胺、三乙醇胺、乙二胺)之鹽、及與胺基酸(諸如精胺酸及離胺酸)之鹽。針對化合物(A)、(B)、及(C),所屬技術領域中具有通常知識者理解,當鹽係藉由基於氮之基團(例如,NH
2)的質子化而形成時,基於氮之基團可與正電荷締合(例如,NH
2可變成NH
3 +),且該正電荷可由帶負電荷之相對離子(諸如Cl
-)平衡。
應理解,在本文所述之具有一或多個掌性中心之任何化合物中,若未明確指示絕對立體化學,則各中心可獨立地具有R-組態、或S-組態、或其混合物。因此,本文中所提供之化合物可係鏡像異構地純的、鏡像異構地富集的外消旋混合物、非鏡像異構地純的、非鏡像異構地富集的、或立體異構的混合物。此外,應當理解,在具有一或多個雙鍵產生幾何異構物(可定義為E或Z)之任何本文中所述化合物中,各雙鍵可獨立地係E或Z或其混合。同樣地,應理解,在任何所述化合物中,亦意欲將所有互變異構形式包括在內。
應理解,在本文中揭示之化合物具有未填滿價數時,則價數應以氫或其同位素填滿,例如氫-1(氕)及氫-2(氘)。
應理解,本文所述之化合物可經同位素標示。以諸如氘之同位素取代可得到由較高代謝穩定性帶來的某些治療優點,例如體內半衰期增長或劑量需求降低。在化合物結構中表示之各化學元素可包括該元素之任何同位素。例如,在化合物結構中,氫原子可明確揭示或理解成存在於化合物中。在化合物之可能存在氫原子的任何位置處,氫原子可為氫之任何同位素,包括但不限於氫-1(氕)及氫-2(氘)。因此,在本文中參照之化合物涵蓋所有潛在同位素形式,除非上下文清楚另行表明。
應理解,本文中所述之方法及組合包括結晶形式(亦稱為多形體,其包括相同元素組成的化合物之不同晶體堆積排列)、非晶相、鹽、溶劑合物、及水合物。在一些實施例中,本文所述之化合物以與醫藥上可接受之溶劑(諸如水、乙醇、或類似者)之溶劑合形式存在。在其他實施例中,本文描述之化合物以非溶劑合形式存在。溶劑合物含有化學計量或非化學計量之量的溶劑,且可與醫藥上可接受的溶劑(例如水、乙醇、或類似物)在結晶製程期間形成。當溶劑係水時即形成水合物,當溶劑係醇時即形成醇合物。此外,本文中所提供之化合物可以非溶劑合形式以及溶劑合形式存在。一般而言,針對本文中所提供之化合物及方法的目的,將溶劑合形式視為等同於非溶劑合形式。
當提供數值之範圍時,應理解範圍之上限及下限以及在上限及下限之間的各介入數值皆涵蓋於實施例之中。
本申請案及其變體特別是隨附之申請專利範圍中所使用之用語及短語,除非另有明確說明,否則應解讀為開放形式而非限制形式。作為前述之實例,用語「包括(including)」應解讀為意指「包括但不限於(including, without limitation/including but not limited to)」或類似者;如本文中所使用之用語「包含(comprising)」與「包括(including)」、「含有(containing)」、或「其特徵為(characterized by)」係同義詞,且係包含式或開放式且不排除額外、未列舉之元件或方法步驟;用語「具有(having)」應解讀為「具有至少(having at least)」;用語「包括(include)」應解讀為「包括但不限於」;用語「實例(example)」係用於提供討論項目之例示性例子而非其詳盡或限制性列表;且用語如「較佳地(preferably)」、「較佳的(preferred)」、「所欲(desired/desirable)」及類似意義文字的使用,不應理解為暗示某些特徵對於結構或功能而言係關鍵、必要、甚或重要的,反而只是意圖強調可在一具體實施例中利用或不利用之替代或額外特徵。此外,用語「包含(comprising)」應與片語「至少具有(having at least)」或「至少包括(including at least)」同義地解釋。當用於製程之上下文中時,用語「包含(comprising)」意指製程包括至少列舉之步驟,但可包括額外步驟。當用於化合物、組成物、或裝置之上下文中時,用語「包含」意指化合物、組成物、或裝置至少包括所列舉特徵或組分,但亦可包括額外特徵或組分。
關於在本文中使用實質上任何複數及/或單數用語,所屬技術領域中具有通常知識者可視適合上下文及/或應用之情況,從複數轉換成單數及/或從單數轉換成複數。各種單數/複數排列組合可在本文中明確闡述以求清晰。不定冠詞「一(a或an)」並不排除複數。在互不相同的附屬項中列舉某些措施的單純事實,並不表示這些措施之組合無法有益地使用。申請專利範圍中之任何元件符號不應解讀為範圍限制。
化合物
本文中所述之一些實施例係關於一種化合物之組合用於治療疾病或病況之用途,其中該組合可包括有效量的化合物(A)、有效量的化合物(B)、及有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽。如本文中所提供,化合物(A)或其醫藥上可接受之鹽可係Bcl-2抑制劑,化合物(B)或其醫藥上可接受之鹽可係SERD抑制劑,且化合物(C)或其醫藥上可接受之鹽可係CDK 4/6抑制劑。
化合物(A)連同其醫藥上可接受之鹽的實例包括下列:
維托拉斯(venetoclax) (ABT-199)、納維克拉斯(navitoclax) (ABT-263)、
(S55746/BCL201)、S65487、帕西克拉斯(palcitoclax) (APG-1252)、APG-2575、BGB-11417、FCN-338、AZD0466、
、
、
、
、
、
、
、
、
、及
、或前述中之任一者之醫藥上可接受之鹽。關於圖1所示之Bcl-2抑制劑的進一步資訊係提供於下列公開案中:WO 2020/089286、WO 2015/011400、U.S. 2014/0199234、WO 2018/027097、WO 2019/210828、WO 2018/192462、WO 2018/127130、WO 2018/154004、WO 2019/139899、WO 2019/139900、WO 2019/139902、及WO 2019/139907,出於描述圖1所示之化合物之各者的限定目的,其等之各者特此以引用方式併入本文中。
在一些實施例中,化合物(A)或其醫藥上可接受之鹽可係2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((2-(3-(二氟甲基)雙環[1.1.1]戊-1-基)-4,4-二甲基環己-1-烯-1-基)甲基)哌𠯤-1-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺、或其醫藥上可接受之鹽。在其他實施例中,化合物(A)係2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4,4-二甲基-2-(3-甲基雙環[1.1.1]戊-1-基)環己-1-烯-1-基)甲基)哌𠯤-1-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺、或其醫藥上可接受之鹽。在又其他實施例中,化合物(A)係2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((2-(3-(二氟甲基)雙環[1.1.1]戊-1-基)-4,4-二甲基環己-1-烯-1-基)甲基)哌𠯤-1-基)-N-((4-((4-氟四氫-2H-哌喃-4-基)甲氧基)-3-硝基苯基)磺醯基)苯甲醯胺、或其醫藥上可接受之鹽。在又其他實施例中,化合物(A)可係維托拉斯(ABT-199)、或其醫藥上可接受之鹽。在一些實施例中,化合物(A)可係納維克拉斯(ABT-263)、或其醫藥上可接受之鹽。在其他實施例中,化合物(A)可選自APG-1252、APG-2575、BGB-11417、FCN-338、及AZD0466、或前述中之任一者之醫藥上可接受之鹽。用於製備化合物(A)連同其醫藥上可接受之鹽的方法係所屬技術領域中具有通常知識者已知的。作為一實例,化合物(A)、連同其醫藥上可接受之鹽係提供於WO 2019/139907中。
如本文中所提供,化合物(B)或其醫藥上可接受之鹽可係雌激素受體拮抗劑,諸如選擇性雌激素受體降解劑(selective estrogen receptor degrader, SERD)抑制劑。例示性化合物(B)化合物包括:氟維司群(fulvestrant)、(E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1,3,4,9-四氫吡啶并[3,4-b]吲哚-1-基]苯基]丙-2-烯酸(AZD9496)、(R)-6-(2-(乙基(4-(2-(乙基胺基)乙基)苄基)胺基)-4-甲氧基苯基)-5,6,7,8-四氫萘-2-醇(艾拉司群(elacestrant),RAD1901)、(E)-3-(4-((E)-2-(2-氯-4-氟苯基)-1-(1H-吲唑-5-基)丁-1-烯-1-基)苯基)丙烯酸(布林司群(brilanestrant),ARN-810,GDC-0810)、(E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(LSZ102)、(E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)胺基)丁-2-烯醯胺(H3B-6545)、(E)-3-(4-((2-(4-氟-2,6-二甲基苄醯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(林多地司群(rintodestrant),G1T48)、D-0502、SHR9549、ARV-471、3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)吖呾-3-基)胺基)苯基)-3-甲基-1,3,4,9-四氫-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇(吉列德司群(giredestrant),GDC-9545)、(S)-8-(2,4-二氯苯基)-9-(4-((1-(3-氟丙基)吡咯啶-3-基)氧基)苯基)-6,7-二氫-5H-苯并[7]輪烯-3-羧酸(SAR439859)、N-[1-(3-氟丙基)吖呾-3-基]-6-[(6S,8R)-8-甲基-7-(2,2,2-三氟乙基)-6,7,8,9-四氫-3H-吡唑并[4,3-f]異喹啉-6-基]吡啶-3-胺(AZD9833)、OP-1250、LY3484356、及
、或前述中之任一者的醫藥上可接受之鹽。圖2所示之關於SERD抑制劑的資訊連同額外的SERD抑制劑係提供於WO 95/12383、WO 96/19997、WO 97/21440、WO 97/37653、WO 97/40823、WO 98/11902、WO 2004/058682、WO 2012/037410、WO 2014/130310、WO 2014/191726、WO 2016/097071、WO 2016/097072、WO 2016/196337、WO 2016/19634、WO 2016/202161、WO 2017/059139、WO 2017/080338、WO 2017/100712、WO 2017/100715、WO 2017/107754、WO 2017/136688、WO 2017/172957、WO 2017/182493、WO 2017/182495、WO 2017/216279、WO 2017/216280、WO 2018/001232、WO 2018/019793、WO 2018/077260、WO 2018/081168、WO 2018/091153、WO 2018/102725、WO 2018/130123、WO 2018/130124、WO 2018/138303、WO 2018/148576、WO 2019/066692、WO 2019/223715、WO 2017/059139、U.S. 2020/0017516、US 2018/0072711、WO 2020/014440、及WO 2017/172957,為了其等揭示係為SERD抑制劑之化合物的限制性目的,其等之各者特此以引用方式併入本文中。
在一些實施例中,化合物(B)可係氟維司群、或其醫藥上可接受之鹽。在其他實施例中,化合物(B)可係(R)-6-(2-(乙基(4-(2-(乙基胺基)乙基)苄基)胺基)-4-甲氧基苯基)-5,6,7,8-四氫萘-2-醇(艾拉司群,RAD1901)、或其醫藥上可接受之鹽。在又其他實施例中,化合物(B)可係3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)吖呾-3-基)胺基)苯基)-3-甲基-1,3,4,9-四氫-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇(吉列德司群,GDC-9545)、或其醫藥上可接受之鹽。在又其他實施例中,化合物(B)可係(S)-8-(2,4-二氯苯基)-9-(4-((1-(3-氟丙基)吡咯啶-3-基)氧基)苯基)-6,7-二氫-5H-苯并[7]輪烯-3-羧酸(SAR439859)、或其醫藥上可接受之鹽。在一些實施例中,化合物(B)可係N-[1-(3-氟丙基)吖呾-3-基]-6-[(6S,8R)-8-甲基-7-(2,2,2-三氟乙基)-6,7,8,9-四氫-3H-吡唑并[4,3-f]異喹啉-6-基]吡啶-3-胺(AZD9833)、或其醫藥上可接受之鹽。在其他實施例中,化合物(B)可選自(E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1,3,4,9-四氫吡啶并[3,4-b]吲哚-1-基]苯基]丙-2-烯酸(AZD9496)、(E)-3-(4-((E)-2-(2-氯-4-氟苯基)-1-(1H-吲唑-5-基)丁-1-烯-1-基)苯基)丙烯酸(布林司群,ARN-810,GDC-0810)、(E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(LSZ102)、(E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)胺基)丁-2-烯醯胺(H3B-6545)、及(E)-3-(4-((2-(4-氟-2,6-二甲基苄醯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(林多地司群,G1T48)、或前述中之任一者之醫藥上可接受之鹽。在又其他實施例中,化合物(B)可選自D-0502、SHR9549、ARV-471、OP-1250、及LY3484356、或前述中之任一者之醫藥上可接受之鹽。在又其他實施例中,化合物(B)可係
、或其醫藥上可接受之鹽。
化合物(C)(包括其醫藥上可接受之鹽)可係CDK 4/6抑制劑。化合物(C)之實例包括下列:帕博西尼(palbociclib)、阿貝西尼(abemaciclib)、瑞博西尼(ribociclib)、曲拉西尼(trilaciclib) (G1T28)、萊羅西尼(lerociclib) (G1T38)、SHR6390、FCN-437、AMG 925、BPI-1178、BPI-16350、吡羅西尼(Birociclib)、BEBT-209、TY-302、TQB-3616、HS-10342、PF-06842874、CS-3002、及MM-D37K、連同前述中之任一者之醫藥上可接受之鹽。在一些實施例中,化合物(C)可係帕博西尼、或其醫藥上可接受之鹽。在其他實施例中,化合物(C)可係阿貝西尼、或其醫藥上可接受之鹽。在又其他實施例中,化合物(C)可係瑞博西尼、或其醫藥上可接受之鹽。在又其他實施例中,化合物(C)可選自曲拉西尼(G1T28)及萊羅西尼(G1T38),或前述中之任一者之醫藥上可接受之鹽。在一些實施例中,化合物(C)可選自SHR6390、及FCN-437、或前述中之任一者之醫藥上可接受之鹽。在其他實施例中,化合物(C)可選自AMG 925、BPI-1178、BPI-16350、吡羅西尼、BEBT-209、TY-302、TQB-3616、HS-10342、PF-06842874、CS-3002、及MM-D37K、或前述中之任一者之醫藥上可接受之鹽。
化合物(A)、化合物(B)、及化合物(C)(包括前述中之任一者的醫藥上可接受之鹽)之組合的實施例係提供於表1中。在表1中,數字代表如圖1至圖3中所提供之化合物(包括其醫藥上可接受之鹽)。
表1
Cmpd:Cmpd |
1:1A:1B |
2:1A:1B |
3:1A:1B |
4:1A:1B |
5:1A:1B |
6:1A:1B |
7:1A:1B |
8:1A:1B |
9:1A:1B |
10:1A:1B |
11:1A:1B |
12:1A:1B |
13:1A:1B |
14:1A:1B |
15:1A:1B |
16:1A:1B |
17:1A:1B |
18:1A:1B |
19:1A:1B |
1:2A:1B |
2:2A:1B |
3:2A:1B |
4:2A:1B |
5:2A:1B |
6:2A:1B |
7:2A:1B |
8:2A:1B |
9:2A:1B |
10:2A:1B |
11:2A:1B |
12:2A:1B |
13:2A:1B |
14:2A:1B |
15:2A:1B |
16:2A:1B |
17:2A:1B |
18:2A:1B |
19:2A:1B |
1:3A:1B |
2:3A:1B |
3:3A:1B |
4:3A:1B |
5:3A:1B |
6:3A:1B |
7:3A:1B |
8:3A:1B |
9:3A:1B |
10:3A:1B |
11:3A:1B |
12:3A:1B |
13:3A:1B |
14:3A:1B |
15:3A:1B |
16:3A:1B |
17:3A:1B |
18:3A:1B |
19:3A:1B |
1:4A:1B |
2:4A:1B |
3:4A:1B |
4:4A:1B |
5:4A:1B |
6:4A:1B |
7:4A:1B |
8:4A:1B |
9:4A:1B |
10:4A:1B |
11:4A:1B |
12:4A:1B |
13:4A:1B |
14:4A:1B |
15:4A:1B |
16:4A:1B |
17:4A:1B |
18:4A:1B |
19:4A:1B |
1:5A:1B |
2:5A:1B |
3:5A:1B |
4:5A:1B |
5:5A:1B |
6:5A:1B |
7:5A:1B |
8:5A:1B |
9:5A:1B |
10:5A:1B |
11:5A:1B |
12:5A:1B |
13:5A:1B |
14:5A:1B |
15:5A:1B |
16:5A:1B |
17:5A:1B |
18:5A:1B |
19:5A:1B |
1:6A:1B |
2:6A:1B |
3:6A:1B |
4:6A:1B |
5:6A:1B |
6:6A:1B |
7:6A:1B |
8:6A:1B |
9:6A:1B |
10:6A:1B |
11:6A:1B |
12:6A:1B |
13:6A:1B |
14:6A:1B |
15:6A:1B |
16:6A:1B |
17:6A:1B |
18:6A:1B |
19:6A:1B |
1:7A:1B |
2:7A:1B |
3:7A:1B |
4:7A:1B |
5:7A:1B |
6:7A:1B |
7:7A:1B |
8:7A:1B |
9:7A:1B |
10:7A:1B |
11:7A:1B |
12:7A:1B |
13:7A:1B |
14:7A:1B |
15:7A:1B |
16:7A:1B |
17:7A:1B |
18:7A:1B |
19:7A:1B |
1:8A:1B |
2:8A:1B |
3:8A:1B |
4:8A:1B |
5:8A:1B |
6:8A:1B |
7:8A:1B |
8:8A:1B |
9:8A:1B |
10:8A:1B |
11:8A:1B |
12:8A:1B |
13:8A:1B |
14:8A:1B |
15:8A:1B |
16:8A:1B |
17:8A:1B |
18:8A:1B |
19:8A:1B |
1:9A:1B |
2:9A:1B |
3:9A:1B |
4:9A:1B |
5:9A:1B |
6:9A:1B |
7:9A:1B |
8:9A:1B |
9:9A:1B |
10:9A:1B |
11:9A:1B |
12:9A:1B |
13:9A:1B |
14:9A:1B |
15:9A:1B |
16:9A:1B |
17:9A:1B |
18:9A:1B |
19:9A:1B |
1:10A:1B |
2:10A:1B |
3:10A:1B |
4:10A:1B |
5:10A:1B |
6:10A:1B |
7:10A:1B |
8:10A:1B |
9:10A:1B |
10:10A:1B |
11:10A:1B |
12:10A:1B |
13:10A:1B |
14:10A:1B |
15:10A:1B |
16:10A:1B |
17:10A:1B |
18:10A:1B |
19:10A:1B |
1:11A:1B |
2:11A:1B |
3:11A:1B |
4:11A:1B |
5:11A:1B |
6:11A:1B |
7:11A:1B |
8:11A:1B |
9:11A:1B |
10:11A:1B |
11:11A:1B |
12:11A:1B |
13:11A:1B |
14:11A:1B |
15:11A:1B |
16:11A:1B |
17:11A:1B |
18:11A:1B |
19:11A:1B |
1:12A:1B |
2:12A:1B |
3:12A:1B |
4:12A:1B |
5:12A:1B |
6:12A:1B |
7:12A:1B |
8:12A:1B |
9:12A:1B |
10:12A:1B |
11:12A:1B |
12:12A:1B |
13:12A:1B |
14:12A:1B |
15:12A:1B |
16:12A:1B |
17:12A:1B |
18:12A:1B |
19:12A:1B |
1:13A:1B |
2:13A:1B |
3:13A:1B |
4:13A:1B |
5:13A:1B |
6:13A:1B |
7:13A:1B |
8:13A:1B |
9:13A:1B |
10:13A:1B |
11:13A:1B |
12:13A:1B |
13:13A:1B |
14:13A:1B |
15:13A:1B |
16:13A:1B |
17:13A:1B |
18:13A:1B |
19:13A:1B |
1:14A:1B |
2:14A:1B |
3:14A:1B |
4:14A:1B |
5:14A:1B |
6:14A:1B |
7:14A:1B |
8:14A:1B |
9:14A:1B |
10:14A:1B |
11:14A:1B |
12:14A:1B |
13:14A:1B |
14:14A:1B |
15:14A:1B |
16:14A:1B |
17:14A:1B |
18:14A:1B |
19:14A:1B |
1:15A:1B |
2:15A:1B |
3:15A:1B |
4:15A:1B |
5:15A:1B |
6:15A:1B |
7:15A:1B |
8:15A:1B |
9:15A:1B |
10:15A:1B |
11:15A:1B |
12:15A:1B |
13:15A:1B |
14:15A:1B |
15:15A:1B |
16:15A:1B |
17:15A:1B |
18:15A:1B |
19:15A:1B |
1:16A:1B |
2:16A:1B |
3:16A:1B |
4:16A:1B |
5:16A:1B |
6:16A:1B |
7:16A:1B |
8:16A:1B |
9:16A:1B |
10:16A:1B |
11:16A:1B |
12:16A:1B |
13:16A:1B |
14:16A:1B |
15:16A:1B |
16:16A:1B |
17:16A:1B |
18:16A:1B |
19:16A:1B |
1:1A:2B |
2:1A:2B |
3:1A:2B |
4:1A:2B |
5:1A:2B |
6:1A:2B |
7:1A:2B |
8:1A:2B |
9:1A:2B |
10:1A:2B |
11:1A:2B |
12:1A:2B |
13:1A:2B |
14:1A:2B |
15:1A:2B |
16:1A:2B |
17:1A:2B |
18:1A:2B |
19:1A:2B |
1:2A:2B |
2:2A:2B |
3:2A:2B |
4:2A:2B |
5:2A:2B |
6:2A:2B |
7:2A:2B |
8:2A:2B |
9:2A:2B |
10:2A:2B |
11:2A:2B |
12:2A:2B |
13:2A:2B |
14:2A:2B |
15:2A:2B |
16:2A:2B |
17:2A:2B |
18:2A:2B |
19:2A:2B |
1:3A:2B |
2:3A:2B |
3:3A:2B |
4:3A:2B |
5:3A:2B |
6:3A:2B |
7:3A:2B |
8:3A:2B |
9:3A:2B |
10:3A:2B |
11:3A:2B |
12:3A:2B |
13:3A:2B |
14:3A:2B |
15:3A:2B |
16:3A:2B |
17:3A:2B |
18:3A:2B |
19:3A:2B |
1:4A:2B |
2:4A:2B |
3:4A:2B |
4:4A:2B |
5:4A:2B |
6:4A:2B |
7:4A:2B |
8:4A:2B |
9:4A:2B |
10:4A:2B |
11:4A:2B |
12:4A:2B |
13:4A:2B |
14:4A:2B |
15:4A:2B |
16:4A:2B |
17:4A:2B |
18:4A:2B |
19:4A:2B |
1:5A:2B |
2:5A:2B |
3:5A:2B |
4:5A:2B |
5:5A:2B |
6:5A:2B |
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本文中所述之組合中化合物的投予順序可有所變化。在一些實施例中,化合物(A)(包括其醫藥上可接受之鹽)可在化合物(B)(或其醫藥上可接受之鹽)、及化合物(C)(連同其醫藥上可接受之鹽)之前投予。在其他實施例中,化合物(A)(包括其醫藥上可接受之鹽)可在化合物(B)(或其醫藥上可接受之鹽)之前,且在投予化合物(C)(連同其醫藥上可接受之鹽)之後投予。在又其他實施例中,化合物(A)(包括其醫藥上可接受之鹽)可在化合物(C)(或其醫藥上可接受之鹽)之前,且在投予化合物(B)(或其醫藥上可接受之鹽)之後投予。在又其他實施例中,化合物(A)(包括其醫藥上可接受之鹽)可在化合物(B)(或其醫藥上可接受之鹽)、及化合物(C)(或其醫藥上可接受之鹽)之後投予。
在一些實施例中,化合物(B)(包括其醫藥上可接受之鹽)可在化合物(A)(或其醫藥上可接受之鹽)、及化合物(C)(連同其醫藥上可接受之鹽)之前投予。在其他實施例中,化合物(B)(包括其醫藥上可接受之鹽)可在化合物(A)(連同其醫藥上可接受之鹽)之前,且在化合物(C)(或其醫藥上可接受之鹽)之後投予。在又其他實施例中,化合物(B)(包括其醫藥上可接受之鹽)可在化合物(C)(或其醫藥上可接受之鹽)之前,且在化合物(A)(包括其醫藥上可接受之鹽)之後投予。在又其他實施例中,化合物(B)(或其醫藥上可接受之鹽)可在化合物(A)(連同其醫藥上可接受之鹽)、及化合物(C)(或其醫藥上可接受之鹽)之後投予。
在其他實施例中,化合物(C)(包括其醫藥上可接受之鹽)可在化合物(A)(或其醫藥上可接受之鹽)、及化合物(B)(連同其醫藥上可接受之鹽)之前投予。在其他實施例中,化合物(C)(包括其醫藥上可接受之鹽)可在化合物(A)(或其醫藥上可接受之鹽)之前,且在化合物(B)(或其醫藥上可接受之鹽)之後投予。在又其他實施例中,化合物(C)(包括其醫藥上可接受之鹽)可在化合物(B)(包括其醫藥上可接受之鹽)之前,且在化合物(A)(連同其醫藥上可接受之鹽)之後投予。在又其他實施例中,化合物(C)(或其醫藥上可接受之鹽)可在化合物(A)(連同其醫藥上可接受之鹽)、及化合物(B)(或其醫藥上可接受之鹽)之後投予。
在一些實施例中,化合物(A)(包括其醫藥上可接受之鹽)可與化合物(B)(或其醫藥上可接受之鹽)及/或化合物(C)(或其醫藥上可接受之鹽)同時投予。在其他實施例中,化合物(B)(包括其醫藥上可接受之鹽)可與化合物(A)(或其醫藥上可接受之鹽)及/或化合物(C)(或其醫藥上可接受之鹽)同時投予。
使用本文中所述的化合物之組合可能有數種益處。例如,相較於當將組合之化合物作為單一療法使用時,組合同時攻擊數個路徑之化合物在治療癌症(諸如本文中所述者)上可能是更有效的。
在一些實施例中,如本文中所述之組合(例如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者之醫藥上可接受之鹽)可減少可歸因於本文中所述之化合物(諸如化合物(B)、或其醫藥上可接受之鹽)的副作用之數目及/或嚴重程度。在其他實施例中,如本文中所述之組合(諸如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者之醫藥上可接受之鹽)可減少可歸因於化合物(B)(或其醫藥上可接受之鹽)的副作用之數目及/或嚴重性。
使用本文中所述的化合物之組合可導致累加(additive)、協同(synergistic)、或強烈協同效應。如本文中所述的化合物之組合可導致非拮抗性之效應。
在一些實施例中,如本文中所述的化合物(A)(包括其醫藥上可接受之鹽)、化合物(B)(連同其醫藥上可接受之鹽)、及化合物(C)(包括其醫藥上可接受之鹽)之組合可導致累加效應。在其他實施例中,如本文中所述之組合(諸如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者之醫藥上可接受之鹽)可導致協同效應。在又其他實施例中,如本文中所述之組合(例如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者之醫藥上可接受之鹽)可導致強烈協同效應。在又其他實施例中,如本文中所述之組合(例如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者之醫藥上可接受之鹽)係非拮抗性的。
如本文中所使用,用語「拮抗性(antagonistic)」意指化合物之組合的活性低於組合中化合物之活性(當各化合物之活性係個別判定時,即作為單一化合物)的總和。如本文中所使用,用語「協同效應(synergistic effect)」意指化合物之組合的活性高於組合中化合物之個別活性(當各化合物之活性係個別判定時)的總和。如本文中所使用,用語「累加效應(additive effect)」意指化合物之組合的活性約等於組合中化合物之個別活性的總和(當各化合物之活性係個別判定時,即作為單一化合物)。
使用如本文中所述的組合之一個可能益處可在於,相較於當各化合物係作為單一療法投予時,對於治療本文中所揭示之病況有效的化合物之所需量有所降低。例如,本文中所述的組合中所使用之化合物(B)(或其醫藥上可接受之鹽)的量可低於達到當化合物(B)(或其醫藥上可接受之鹽)作為單一療法投予時之相同疾病標記(例如,腫瘤大小)降低所需之化合物(B)(或其醫藥上可接受之鹽)的量。採用本文中所述的組合之另一個可能益處在於,使用二或更多種具有不同作用機制之化合物,相較於當將化合物作為單一療法投予時,可對於抗性出現創造出更高的障壁。採用本文中所述的組合之額外益處可包括在本文中所述的組合之化合物之間幾乎沒有或沒有交叉抗性;用於削除本文中所述的組合之化合物之不同途徑;及/或在本文中所述的組合之化合物之間幾乎沒有或沒有重疊毒性。
醫藥組成物
化合物(A)(包括其醫藥上可接受之鹽)可在醫藥組成物中提供。化合物(B)(包括其醫藥上可接受之鹽)可在醫藥組成物中提供。同樣地,化合物(C)(包括其醫藥上可接受之鹽)可在醫藥組成物中提供。本文描述化合物(A)、化合物(B)、及化合物(C)的實例。
用語「醫藥組成物(pharmaceutical composition)」係指本文中所揭示之一或多種化合物及/或鹽與其他化學組分(諸如稀釋劑、載劑、及/或賦形劑)之混合物。醫藥組成物促進化合物向生物體之投予。醫藥組成物亦可藉由使化合物與無機或有機酸(諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸、甲烷磺酸、乙烷磺酸、對甲苯磺酸、及水楊酸)反應來獲得。醫藥組成物通常將針對特定意圖投予途徑設計。
如本文中所使用,「載劑(carrier)」係指促進化合物併入細胞或組織中之化合物。例如(但不限於),二甲基亞碸(DMSO)係經常利用的載劑,其促進許多有機化合物被攝入對象的細胞或組織中。
如本文中所使用,「稀釋劑(diluent)」係指醫藥組成物中缺乏明顯藥理學活性但可能為醫藥上必需或所欲之成分。例如,稀釋劑可用於增加質量過小而無法用於製造及/或投予之有效藥物的體積。其亦可為用於溶解將藉由注射、攝取或吸入投予之藥物的液體。所屬技術領域中常見形式的稀釋劑為緩衝水溶液,諸如但不限於模擬人類血液之pH及等滲性之磷酸鹽緩衝鹽水。
如本文中所使用,「賦形劑(excipient)」係指基本上惰性的物質,其經添加至醫藥組成物中以向該組成物提供(但不限於)體積、稠度、穩定性、結合能力、潤滑、崩解能力等。例如,諸如抗氧化劑及金屬螯合劑之穩定劑係賦形劑。在一實施例中,醫藥組成物包含抗氧化劑及/或金屬螯合劑。「稀釋劑(diluent)」係一種類型的賦形劑。
在一些實施例中,化合物(B)(連同其醫藥上可接受之鹽)可在包括化合物(A)(包括其醫藥上可接受之鹽)及/或化合物(C)(包括其醫藥上可接受之鹽)的醫藥組成物中提供。在一些實施例中,化合物(C)(連同其醫藥上可接受之鹽)可在包括化合物(A)(包括其醫藥上可接受之鹽)及/或化合物(B)(包括其醫藥上可接受之鹽)的醫藥組成物中提供。在其他實施例中,化合物(B)(連同其醫藥上可接受之鹽)可在與包括化合物(A)(包括其醫藥上可接受之鹽)之醫藥組成物分開的醫藥組成物中投予。在又其他實施例中,化合物(B)(連同其醫藥上可接受之鹽)可在與包括化合物(C)(包括其醫藥上可接受之鹽)之醫藥組成物分開的醫藥組成物中投予。在又其他實施例中,化合物(C)(或其醫藥上可接受之鹽)可在與包括化合物(A)(連同其醫藥上可接受之鹽)之醫藥組成物分開的醫藥組成物中投予。在其他實施例中,化合物(A)(或其醫藥上可接受之鹽)可在與包括化合物(B)(或其醫藥上可接受之鹽)之醫藥組成物分開的醫藥組成物中投予。在其他實施例中,化合物(A)(或其醫藥上可接受之鹽)可在與包括化合物(B)(或其醫藥上可接受之鹽)之醫藥組合物分開的且與包括化合物(C)(或其醫藥上可接受之鹽)之醫藥組合物分開的醫藥組合物中投予。
在本文中描述之醫藥組成物本身可向人類患者投予,或可以其中彼等與其他活性成分(如在組合療法中)、或載劑、稀釋劑、賦形劑或其組合混合之醫藥組成物向人類患者投予。適當配方取決於選擇的投予途徑。用於本文所述之化合物的配方及投予之技術係所屬技術領域中具有通常知識者已知的。
在本文中揭示之醫藥組成物可以本身已知之方式製造,例如藉由習知之混合、溶解、造粒、糖衣錠製造、研調、乳化、囊封、包封、或製錠製程。此外,所含有的活性成分之量可有效達成其意圖目的。在本文中揭示之醫藥組合中使用的許多化合物可提供為含有醫藥上相容的相對離子之鹽。
所屬技術領域存在多種投予化合物、鹽、及/或組成物之技術,包括但不限於口服、直腸、肺、外用、氣溶膠、注射、輸注、及非經腸遞送,包括肌肉內、皮下、靜脉內、髓內注射、鞘內、直接心室內、腹膜內、鼻內、及眼內注射。在一些實施例中,化合物(A)(包括其醫藥上可接受之鹽)可經口服投予。在一些實施例中,化合物(B)(包括其醫藥上可接受之鹽)可經靜脈內、口服、肌肉內、皮下、及/或外用(topically)投予。在一些實施例中,化合物(C)(包括其醫藥上可接受之鹽)可經口服投予。在一些實施例中,化合物(A)(包括其醫藥上可接受之鹽)可藉由與化合物(B)(連同其醫藥上可接受之鹽)相同的投予途徑提供至對象。在其他實施例中,化合物(A)(包括其醫藥上可接受之鹽)可藉由與化合物(B)(連同其醫藥上可接受之鹽)不同的投予途徑提供至對象。在又其他實施例中,化合物(C)(包括其醫藥上可接受之鹽)可藉由與化合物(B)(連同其醫藥上可接受之鹽)相同的途徑來提供至對象。在又其他實施例中,化合物(C)(包括其醫藥上可接受之鹽)可藉由與化合物(B)(連同其醫藥上可接受之鹽)不同的途徑來提供至對象。
亦可以局部而非全身方式投予化合物、鹽、及/或組成物,例如經由將通常呈貯劑或持續釋放配方之化合物直接注射或植入至感染區域中。另外,可以標靶藥物遞送系統(例如塗佈組織特異性抗體之脂質體)投予化合物。脂質體將靶向器官且由器官選擇性吸收。例如,可能需要鼻內或肺遞送以靶向呼吸疾病或病況。
所欲時,組成物可呈現於可含有一或多個(含有活性成分之)單位劑型之包裝或分配裝置中。包裝可例如包含金屬或塑膠箔,例如泡殼包裝。包裝或分配器裝置可隨附投予說明。包裝或分配器亦可隨附與該容器相關聯之通知來規範藥品的製造、使用、或銷售,通知之形式係由政府機構規定,該通知反映該機構核准該藥物形式用於人類或獸醫投予。舉例來說,該通知可為美國食品與藥品管理局批准用於處方藥的標籤或產品仿單。亦可製備可包括在相容醫藥載劑中配製的本文描述之化合物及/或鹽的組成物、置於適當容器中並標示用來治療所指示之病況。
治療用途及方法
如本文中所提供,在一些實施例中,本文中所述的化合物之組合(諸如包括有效量的化合物(A)、有效量的一或多種化合物(B)、及有效量的一或多種化合物(C)、或前述中之任一者的醫藥上可接受之鹽的組合)可用於治療有需要之對象的疾病或病況。
如本文中所使用,「對象(subject)」係指作為治療、觀察、或實驗之目標的動物。「動物(animal)」包括冷血及溫血脊椎動物及無脊椎動物,例如魚、甲殼類動物、爬蟲類及特別是哺乳動物。「哺乳動物(mammal)」包括但不限於小鼠、大鼠、兔、天竺鼠、犬、貓、綿羊、山羊、牛、馬、靈長類動物,諸如猴、黑猩猩、及猿,且特別是人類。在一些實施例中,對象可以是人。在一些實施例中,對象可以是兒童及/或嬰兒,例如患有發燒的兒童或嬰兒。在其他實施例中,對象可為成人。
如本文中所使用,用語「治療(treat, treating, treatment, therapeutic)」及「療法(therapy)」不必然意指完全治癒或消除疾病或病況。可將疾病或病況之任何非所欲的徵象或症狀有任何程度的任何減輕視為治療及/或療法。另外,治療可包括可使對象對福祉或外觀的整體感覺惡化之行動。
用語「有效量(effective amount)」係用於指示引發指示生物或藥物反應之活性化合物或醫藥製劑的量。例如,化合物、鹽、或組成物之有效量可係預防、減輕、或改善疾病或病況之症狀、或延長所治療對象之存活所需的量。此反應可以在組織、系統、動物、或人類中發生,且包括減輕所治療疾病或病況之徵象或症狀。鑒於在本文中提供之揭露,有效量之判定完全在所屬技術領域中具有通常知識者之能力範圍以內。作為劑量所需的本文中所揭示之化合物的有效量將取決於投予途徑、所治療的動物(包括人類)類型、及所考慮的特定動物之身體特徵。可調整劑量以達到所預的效果,但是取決於諸如體重、飲食、併用藥物、及所屬醫學領域中具有通常知識者將認識到的其他因素之因素。
例如,有效量之化合物或輻射為導致以下結果之量:(a)由癌症引起之一或多種症狀減少、減輕、或消失,(b)腫瘤大小減小,(c)腫瘤消除,及/或(d)腫瘤之長期疾病穩定(生長停滯)。
在一些實施例中,疾病或病況可係乳癌。已知各種類型的乳癌。在一些實施例中,乳癌可係ER陽性乳癌。在一些實施例中,乳癌可係ER陽性、HER2陰性乳癌。在一些實施例中,乳癌可係局部乳癌(如本文中所使用,「局部」乳癌意指癌症並未擴散至身體其他區域)。在其他實施例中,乳癌可係轉移性乳癌。在又其他實施例中,乳癌可係三陰性乳癌。對象可患有先前尚未經過治療的乳癌。
在一些情況下,在乳癌治療後,對象可能復發(relapse)或乳癌再發(reoccurrence)。如本文中所使用,用語「復發(relapse)」及「再發(reoccurrence)」係如所屬技術領域中具有通常知識者所理解以其正常意義使用。因此,乳癌可係再發性(recurrent)乳癌。在一些實施例中,對象在先前針對乳癌之治療後已復發。例如,對象在接受一或多種使用SERM、SERD、及/或芳香酶抑制劑(諸如本文中所述者)之治療後已復發。
在ESR1內,已識別出數個胺基酸突變。已提出ESR1中的突變在抗性中發揮作用。有數種用於抑制雌激素受體之療法,包括選擇性ER調節劑(SERM)、選擇性ER降解劑(SERD)、及芳香酶抑制劑。可由前述癌症療法引起的一個問題係對癌症療法的抗性之發展。已在使用泰莫西芬(tamoxifen)及其他內分泌療法治療之將近三分之一的女性中注意到對癌症療法(諸如內分泌療法)的後天抗性。參見Alluri et al., “Estrogen receptor mutations and their role in breast cancer progression” Breast Cancer Research (2014) 16:494。研究者已懷疑在雌激素受體中的突變為對癌症療法(諸如內分泌療法)的後天抗性的原因之一。因此,需要可治療乳癌(其中癌症在ESR1內具有一或多個突變)的化合物。
本文中所揭示之一些實施例係關於本文中所述的化合物之組合(諸如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者的醫藥上可接受之鹽)在製造用於治療有需要之對象的乳癌之藥劑的用途,其中該乳癌在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內具有至少一個點突變。本文中之其他相關實施例係關於本文所述化合物之組合在用於治療有需要之對象的乳癌之用途,該化合物之組合包括有效量的化合物(A)(包括其醫藥上可接受之鹽)、有效量的化合物(B)(或其醫藥上可接受之鹽)、及有效量的化合物(C)(連同其醫藥上可接受之鹽),其中該乳癌在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內具有至少一個點突變。本文中所揭示之又其他實施例係關於一種使用本文中所述的化合物之組合(諸如化合物(A)、化合物(B)、及化合物(C)、連同前述中之任一者的醫藥上可接受之鹽)來治療有需要之對象的乳癌之方法,其中該乳癌在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內具有至少一個點突變。
在一些實施例中,突變可在ESR1之配體結合域(ligand binding domain, LBD)中。在一些實施例中,一或多個突變可在選自下列之胺基酸處:A593、S576、G557、R555、L549、A546、E542、L540、D538、Y537、L536、P535、V534、V533、N532、K531、C530、H524、E523、M522、R503、L497、K481、V478、R477、E471、S463、F461、S432、G420、V418、D411、L466、S463、L453、G442、M437、M421、M396、V392、M388、E380、G344、S338、L370、S329、K303、A283、S282、E279、G274、K252、R233、P222、G160、N156、P147、G145、F97、N69、A65、A58、及S47。在一些實施例中,一或多個突變可在選自下列之胺基酸處:D538、Y537、L536、P535、V534、S463、V392、及E380。在一些實施例中,一或多個突變可在選自下列之胺基酸處:D538及Y537。
在一些實施例中,一或多個突變可選自:K303R、D538G、Y537S、E380Q、Y537C、Y537N、A283V、A546D、A546T、A58T、A593D、A65V、C530L、D411H、E279V、E471D、E471V、E523Q、E542G、F461V、F97L、G145D、G160D、G274R、G344D、G420D、G442R、G557R、H524L、K252N、K481N、K531E、L370F、L453F、L466Q、L497R、L536H、L536P、L536Q、L536R、L540Q、L549P、M388L、M396V、M421V、M437I、M522I、N156T、N532K、N69K、P147Q、P222S、P535H、R233G、R477Q、R503W、R555H、S282C、S329Y、S338G、S432L、S463P、S47T、S576L、V392I、V418E、V478L、V533M、V534E、Y537D、及Y537H。
本文中所揭示之一些實施例係關於化合物之組合在製造用於治療有需要之對象中的乳癌之藥劑中的用途,該化合物之組合包括有效量的化合物(A)(包括其醫藥上可接受之鹽)及有效量的一或多種化合物(B)(或其醫藥上可接受之鹽),其中該乳癌不包括至少一個點突變(例如,在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內的點突變)。本文中之其他相關實施例係關於化合物之組合在用於治療有需要之對象的乳癌之用途,該化合物之組合包括有效量的化合物(A)、有效量的一或多種化合物(B)、及有效量的化合物(C)、連同前述中之任一者的醫藥上可接受之鹽,其中該乳癌不包括具有至少一個點突變,諸如在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內的點突變。本文中所揭示之又其他實施例係關於一種使用本文中所述的化合物之組合(諸如化合物(A)、化合物(B)、及化合物(C)、或前述中之任一者的醫藥上可接受之鹽的組合)治療有需要之對象的乳癌之方法,其中該乳癌不包括在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內具有至少一個點突變(例如,在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內的點突變)。
如本文中所提供,數個研究已顯示ER陽性乳癌中之抗性的潛在原因係由於因內分泌療法而引起之ESR1中的後天突變(acquired mutation)。在一些實施例中,對象先前已經過一或多種選擇性ER調節劑治療。例如,對象先前已經過一或多種選自下列之經選擇ER調節劑治療:泰莫西芬(tamoxifen)、雷洛昔芬(raloxifene)、奧培米芬(ospemifene)、巴多昔芬(bazedoxifene)、托瑞米芬(toremifene)、及拉索昔芬(lasofoxifene)、或任何前述者的醫藥上可接受之鹽。在一些實施例中,對象先前已經過一或多種選擇性ER降解劑(degrader)治療,諸如氟維司群、(E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1,3,4,9-四氫吡啶并[3,4-b]吲哚-1-基]苯基]丙-2-烯酸(AZD9496)、(R)-6-(2-(乙基(4-(2-(乙基胺基)乙基)苄基)胺基)-4-甲氧基苯基)-5,6,7,8-四氫萘-2-醇(艾拉司群,RAD1901)、(E)-3-(4-((E)-2-(2-氯-4-氟苯基)-1-(1H-吲唑-5-基)丁-1-烯-1-基)苯基)丙烯酸(布林司群,ARN-810,GDC-0810)、(E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(LSZ102)、(E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)胺基)丁-2-烯醯胺(H3B-6545)、(E)-3-(4-((2-(4-氟-2,6-二甲基苄醯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(林多地司群,G1T48)、D-0502、SHR9549、ARV-471、3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)吖呾-3-基)胺基)苯基)-3-甲基-1,3,4,9-四氫-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇(吉列德司群,GDC-9545)、(S)-8-(2,4-二氯苯基)-9-(4-((1-(3-氟丙基)吡咯啶-3-基)氧基)苯基)-6,7-二氫-5H-苯并[7]輪烯-3-羧酸(SAR439859)、N-[1-(3-氟丙基)吖呾-3-基]-6-[(6S,8R)-8-甲基-7-(2,2,2-三氟乙基)-6,7,8,9-四氫-3H-吡唑并[4,3-f]異喹啉-6-基]吡啶-3-胺(AZD9833)、OP-1250、及LY3484356、或前述中之任一者的醫藥上可接受之鹽。在一些實施例中,對象先前已經過一或多種芳香酶抑制劑治療。芳香酶抑制劑可係類固醇類芳香酶抑制劑或非類固醇類芳香酶抑制劑。例如,一或多種芳香酶抑制劑可選自依西美坦(exemestane)(類固醇類芳香酶抑制劑)、睪內酯(testolactone)(類固醇類芳香酶抑制劑);阿那曲唑(anastazole)(非類固醇類芳香酶抑制劑)、及來曲唑(letrazole)(非類固醇類芳香酶抑制劑),包括任何前述者的醫藥上可接受之鹽。
在一些實施例中,乳癌可能存在於對象中,其中該對象可為女性。隨著女性接近中年,女性可能進入更年期。在一些實施例中,對象可為停經前的女性。在其他實施例中,對象可為圍絕經期(perimenopausal)的女性。在又其他實施例中,對象可為更年期的女性。在又其他實施例中,對象可為停經後的女性。在其他實施例中,乳癌可能存在於對象中,其中該對象可為男性。對象的血清雌二醇水平可有所變化。在一些實施例中,對象之血清雌二醇水平(E2)可在>15 pg/mL至350 pg/mL之範圍內。在其他實施例中,對象之血清雌二醇水平(E2)可為≤ 15 pg/mL。在其他實施例中,對象之血清雌二醇水平(E2)可為≤ 10 pg/mL。
用於治療所需的化合物、鹽、及/或組成物的量將不僅隨著所選特定化合物或鹽而變化,且亦隨著投予途徑、所治療的疾病或病況之性質及/或症狀、及患者的年齡及病況而變化,而最終將由主治醫師或臨床醫師來決定。在投予醫藥上可接受之鹽的情況下,劑量可以游離鹼計算。所屬技術領域中具有通常知識者將理解,在某些情况下,可能需要以超過或甚至遠超過本文所述劑量範圍之量投予本文揭示之化合物,以有效及積極地治療特別是侵襲性疾病或病況。
如所屬技術領域中具有通常知識者將顯而易知的,欲投予之有用體內劑量及特定投予模式將視年齡、體重、病痛嚴重性及所治療哺乳動物物種、所採用之特定化合物及所採用之這些化合物的特定用途而變化。有效劑量水準(即達到所欲效果所需之劑量水準)的判定可由所屬技術領域中具有通常知識者使用常規方法來達成,例如,人體臨床試驗、體內研究、及體外研究。例如,化合物(A)、(B)、及/或(C)、或前述中之任一者的醫藥上可接受之鹽的有用劑量可藉由比較其體外活性及在動物模型中之體內活性來判定。這種比較可藉由與已建立之藥物(諸如順鉑(cisplatin)及/或吉西他濱)比較來進行。
劑量及時間間隔可經個別地調節,以提供足以維持調節效應之活性部份之血漿水準或最小有效濃度(MEC)。各化合物之MEC將有所不同,但可自體內及/或體外數據估計。達成MEC所需之劑量將取決於個體特徵及投予途徑。然而,可使用HPLC檢定或生物檢定來判定血漿濃度。劑量時間間隔亦可使用MEC值來判定。組成物應使用維持血漿水準高於MEC達10至90%的時間、較佳地介於30至90%之間的時間且最佳的是介於50至90%之間的時間的方案投予。在局部投予或選擇性吸收之情況下,藥物之局部有效濃度可能與血漿濃度無關。
應注意,主治醫師會瞭解如何及何時因毒性或器官功能異常而終止、中斷或調整投予。相反地,主治醫師亦會知道若臨床反應不充足(排除毒性),則將治療調整至較高水平。管理所關注病症時投予劑量之量值將隨所治療疾病或病況之嚴重性及投予途徑而異。疾病或病況之嚴重程度可例如部分地依據標準預後評估方法來評估。另外,劑量及可能的給藥頻率亦將根據個別患者之年齡、體重及反應而異。與以上討論之計畫類似的計畫可用於獸醫學。
可使用已知方法評估本文揭示之化合物、鹽、及組成物之功效及毒性。例如,特定化合物或共用某些化學部份之化合物亞組之毒物學可藉由判定對細胞系(例如哺乳動物且較佳人類細胞系)之體外毒性來建立。此類研究之結果通常可預測在動物(例如哺乳動物)或更具體而言在人類中之毒性。替代地,可使用已知方法判定動物模型(諸如小鼠、大鼠、兔、狗、或猴)中特定化合物之毒性。特定化合物之療效可使用數種公認方法(例如體外方法、動物模型或人體臨床試驗)來建立。當選擇模型來判定療效時,熟習此項技術者可由目前最佳技術的引導以選擇適當模型、劑量、投予途徑及/或方案。
實例
額外實施例在下列實例中進一步詳細揭示,其並非以任何方式意圖限制申請專利範圍之範圍。
異種移植腫瘤模型
在37℃下在5% CO
2於空氣中之氣氛中使MCF-7細胞生長於用15%熱去活化胎牛血清增補之DMEM培養基中。使用95%活腫瘤細胞(1.5 × 10
7)於無血清之200 µL DMEM Matrigel混合物(1:1比率)中的單細胞懸浮液對BALB/c裸鼠在第2右乳腺脂肪墊上進行皮下植入。當腫瘤達到大約226 mm
3時,將動物隨機分配到每組8隻動物之治療組中,且每天一次對動物口服給藥達24天如下:與單劑治療組相同量的媒劑:200 mg/kg的化合物14;50 mg/kg的化合物1B;5 mg/kg的化合物15A。組合治療組如下:化合物15A (5 mg/kg)及化合物1B (50 mg/kg);化合物14 (200 mg/kg)及化合物1B (50 mg/kg);化合物15A (5 mg/kg)及化合物14 (200 mg/kg);及化合物14 (200 mg/kg)、化合物1B (50 mg/kg)、與化合物15A (5 mg/kg)之三重組合。此外,將安息香雌二醇酯注射劑皮下給予(40 mg/ 20 mL,每週兩次)至所有治療組。每週評估腫瘤體積兩次,以計算隨時間的腫瘤體積,並將小鼠每週稱重兩次作為毒性跡象的替代品。腫瘤生長抑制(tumor growth inhibition, TGI)係使用下列方程式來計算:TGI= (1-(Td - T0) / (Cd - C0)) × 100%。Td及Cd係經治療動物及對照組動物的平均腫瘤體積,而T0及C0係經治療動物及對照組動物在實驗開始時的平均腫瘤體積。腫瘤退縮係定義為個別腫瘤體積(TV)縮小(終點TV相對於初始TV)。腫瘤消退百分比係使用下式計算:(1 - (Td / T0)) × 100%。圖4及表2說明單劑治療導致0%至8%之腫瘤消退,且雙重組合導致18%至54%之腫瘤消退。相較於研究第24天的雙重組合治療,化合物14+化合物15Aa+化合物1B的三重組合治療導致顯著的腫瘤消退(76%)。化合物15a在整個說明書及圖式中替代地稱為「化合物15A」。如同化合物15a在整個說明書及圖式中稱為「化合物15A」,化合物1b在整個說明書及圖式中替代地稱為「化合物1B」。在圖4中,頂部線(用圓圈表示)代表媒劑之資料,自頂部線起的第二條線(用圓圈表示)代表化合物14 (200 mg/kg)之資料,自頂部線起的第三條線(用方形表示)代表化合物1B (50 mg/kg)之資料,自頂部線起的第四條線(用方形表示)代表化合物15A (5 mg/kg)之資料,自頂部線起的第五條線(用「x」表示)代表化合物14 (200 mg/kg)+化合物1B (50 mg/kg)之資料,自頂部線起的第六條線(用三角形表示)代表化合物15A (5 mg/kg)+化合物14 (200 mg/kg)之資料,自頂部線起的第七條線(用「x」表示)代表化合物15 (5 mg/kg)+化合物1B (50 mg/kg)之資料,且底部(用三角形表示)代表化合物14 (200 mg/kg)+化合物1B (50 mg/kg)+化合物15A (5 mg/kg)之資料。
表2
化合物 | TGI % (第 24 天) | 腫瘤消退 % (第 24 天) |
化合物 14 | 46 | - |
化合物 1B | 81 | - |
化合物 15a | 108 | 8 |
化合物 15a+ 化合物 1B | 152 | 54 |
化合物 2541+ 化合物 1B | 118 | 18 |
化合物 15a+ 化合物 14 | 143 | 44 |
化合物 14+ 化合物 15a+ 化合物 1B | 174 | 76 |
此外,雖然前述已藉由說明和示例之方式稍微詳細地描述以達清晰及理解之目的,所屬技術領域中具有通常知識者將理解可進行各式各樣的改良而不背離本揭露之精神。因此,應清楚理解在本文中揭示之形式僅用以說明,且並非意欲限制本揭露之範疇,而是亦涵蓋伴隨本揭露之真實範疇及精神而來的所有修改及替代方案。
〔圖1〕提供Bcl-2抑制劑之實例。
〔圖2〕提供SERD抑制劑之實例。
〔圖3〕提供CDK 4/6抑制劑之實例。
〔圖4〕顯示在MCF-7(ER+乳癌)小鼠模型中回應於單一療法、雙重及三重組合療法的腫瘤體積。
Claims (52)
- 一種化合物之組合用於治療疾病或病況之用途,其中該組合包括有效量的化合物(A)、有效量的化合物(B)、有效量的化合物(C)、或前述中之任一者的醫藥上可接受之鹽,其中: 化合物(A)係選自由以下組成之群組:維托拉斯(venetoclax) (ABT-199)、納維克拉斯(navitoclax) (ABT-263)、 (S55746/BCL201)、S65487、帕西克拉斯(palcitoclax) (APG-1252)、APG-2575、BGB-11417、FCN-338、AZD0466、 、 、 、 、 、 、 、 、 、及 、或前述中之任一者之醫藥上可接受之鹽; 化合物(B)係選自由下列所組成之群組:氟維司群(fulvestrant)、(E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1,3,4,9-四氫吡啶并[3,4-b]吲哚-1-基]苯基]丙-2-烯酸(AZD9496)、(R)-6-(2-(乙基(4-(2-(乙基胺基)乙基)苄基)胺基)-4-甲氧基苯基)-5,6,7,8-四氫萘-2-醇(艾拉司群(elacestrant),RAD1901)、(E)-3-(4-((E)-2-(2-氯-4-氟苯基)-1-(1H-吲唑-5-基)丁-1-烯-1-基)苯基)丙烯酸(布林司群(brilanestrant),ARN-810,GDC-0810)、(E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(LSZ102)、(E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)胺基)丁-2-烯醯胺(H3B-6545)、(E)-3-(4-((2-(4-氟-2,6-二甲基苄醯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(林多地司群(rintodestrant),G1T48)、D-0502、SHR9549、ARV-471、3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)吖呾-3-基)胺基)苯基)-3-甲基-1,3,4,9-四氫-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇(吉列德司群(giredestrant),GDC-9545)、(S)-8-(2,4-二氯苯基)-9-(4-((1-(3-氟丙基)吡咯啶-3-基)氧基)苯基)-6,7-二氫-5H-苯并[7]輪烯-3-羧酸(SAR439859)、N-[1-(3-氟丙基)吖呾-3-基]-6-[(6S,8R)-8-甲基-7-(2,2,2-三氟乙基)-6,7,8,9-四氫-3H-吡唑并[4,3-f]異喹啉-6-基]吡啶-3-胺(AZD9833)、OP-1250、LY3484356、及 、或前述中之任一者的醫藥上可接受之鹽;且 化合物(C)係選自由以下組成之群組:帕博西尼(palbociclib)、阿貝西尼(abemaciclib)、瑞博西尼(ribociclib)、曲拉西尼(trilaciclib) (G1T28)、萊羅西尼(lerociclib) (G1T38)、SHR 6390、FCN-437、AMG 925、BPI-1178、BPI-16350、吡羅西尼(Birociclib)、BEBT-209、TY-302、TQB-3616、HS-10342、PF-06842874、CS-3002、及MM-D37K、或前述中之任一者之醫藥上可接受之鹽。
- 如請求項2之用途,其中化合物(A)係2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((2-(3-(二氟甲基)雙環[1.1.1]戊-1-基)-4,4-二甲基環己-1-烯-1-基)甲基)哌𠯤-1-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺、或其醫藥上可接受之鹽。
- 如請求項2之用途,其中化合物(A)係2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4,4-二甲基-2-(3-甲基雙環[1.1.1]戊-1-基)環己-1-烯-1-基)甲基)哌𠯤-1-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺、或其醫藥上可接受之鹽。
- 如請求項2之用途,其中化合物(A)係2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((2-(3-(二氟甲基)雙環[1.1.1]戊-1-基)-4,4-二甲基環己-1-烯-1-基)甲基)哌𠯤-1-基)-N-((4-((4-氟四氫-2H-哌喃-4-基)甲氧基)-3-硝基苯基)磺醯基)苯甲醯胺、或其醫藥上可接受之鹽。
- 如請求項1之用途,其中化合物(A)係維托拉斯(ABT-199)、或其醫藥上可接受之鹽。
- 如請求項1之用途,其中化合物(A)係納維克拉斯(ABT-263)、或其醫藥上可接受之鹽。
- 如請求項1之用途,其中該化合物(A)係選自由下列所組成之群組:APG-1252、APG-2575、BGB-11417、FCN-338、及AZD0466、或前述中之任一者的醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係氟維司群、或其醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係(R)-6-(2-(乙基(4-(2-(乙基胺基)乙基)苄基)胺基)-4-甲氧基苯基)-5,6,7,8-四氫萘-2-醇(艾拉司群,RAD1901)、或其醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)吖呾-3-基)胺基)苯基)-3-甲基-1,3,4,9-四氫-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇(吉列德司群,GDC-9545)、或其醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係(S)-8-(2,4-二氯苯基)-9-(4-((1-(3-氟丙基)吡咯啶-3-基)氧基)苯基)-6,7-二氫-5H-苯并[7]輪烯-3-羧酸(SAR439859)、或其醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係N-[1-(3-氟丙基)吖呾-3-基]-6-[(6S,8R)-8-甲基-7-(2,2,2-三氟乙基)-6,7,8,9-四氫-3H-吡唑并[4,3-f]異喹啉-6-基]吡啶-3-胺(AZD9833)、或其醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係選自由下列所組成之群組:(E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1,3,4,9-四氫吡啶并[3,4-b]吲哚-1-基]苯基]丙-2-烯酸(AZD9496)、(E)-3-(4-((E)-2-(2-氯-4-氟苯基)-1-(1H-吲唑-5-基)丁-1-烯-1-基)苯基)丙烯酸(布林司群,ARN-810,GDC-0810)、(E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(LSZ102)、(E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)胺基)丁-2-烯醯胺(H3B-6545)、及(E)-3-(4-((2-(4-氟-2,6-二甲基苄醯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(林多地司群,G1T48)、或前述中之任一者之醫藥上可接受之鹽。
- 如請求項1至9中任一項之用途,其中化合物(B)係選自由下列所組成之群組:D-0502、SHR9549、ARV-471、OP-1250、及LY3484356、或前述中之任一者之醫藥上可接受之鹽。
- 如請求項1至17中任一項之用途,其中化合物(C)係帕博西尼、或其醫藥上可接受之鹽。
- 如請求項1至17中任一項之用途,其中化合物(C)係阿貝西尼、或其醫藥上可接受之鹽。
- 如請求項1至17中任一項之用途,其中化合物(C)係瑞博西尼、或其醫藥上可接受之鹽。
- 如請求項1至17中任一項之用途,其中化合物(C)係選自由下列所組成之群組:曲拉西尼(G1T28)、及萊羅西尼(G1T38)、或前述中之任一者的醫藥上可接受之鹽。
- 如請求項1至17中任一項之用途,其中化合物(C)係選自由下列所組成之群組:SHR6390、及FCN-437、或前述中之任一者之醫藥上可接受之鹽。
- 如請求項1至18中任一項之用途,其中化合物(C)係選自由以下組成之群:AMG 925、BPI-1178、BPI-16350、吡羅西尼、BEBT-209、TY-302、TQB-3616、HS-10342、PF-06842874、CS-3002、及MM-D37K、或前述中之任一者之醫藥上可接受之鹽。
- 如請求項1至23中任一項之用途,其中該疾病或病況係乳癌。
- 如請求項24之用途,其中該疾病或病況係選自由下列所組成之群組:三陰性乳癌及ER+乳癌。
- 如請求項24至25中任一項之用途,其中該乳癌不包括任何點突變ER突變。
- 如請求項24至25中任一項之用途,其中該乳癌在編碼雌激素受體α (ERα)之雌激素受體1 (ESR1)內具有至少一個點突變,其中該突變係選自由下列所組成之群組:K303R、D538G、Y537S、E380Q、Y537C、Y537N、A283V、A546D、A546T、A58T、A593D、A65V、C530L、D411H、E279V、E471D、E471V、E523Q、E542G、F461V、F97L、G145D、G160D、G274R、G344D、G420D、G442R、G557R、H524L、K252N、K481N、K531E、L370F、L453F、L466Q、L497R、L536H、L536P、L536Q、L536R、L540Q、L549P、M388L、M396V、M421V、M437I、M522I、N156T、N532K、N69K、P147Q、P222S、P535H、R233G、R477Q、R503W、R555H、S282C、S329Y、S338G、S432L、S463P、S47T、S576L、V392I、V418E、V478L、V533M、V534E、Y537D、及Y537H。
- 如請求項24至25中任一項之用途,其中該乳癌係ER陽性乳癌。
- 如請求項24至25中任一項之用途,其中該乳癌係ER陽性/HER2陰性乳癌。
- 如請求項24至25中任一項之用途,其中該乳癌係局部乳癌。
- 如請求項24至25中任一項之用途,其中該乳癌係轉移性乳癌。
- 如請求項24至25中任一項之用途,其中該乳癌係再發性乳癌。
- 如請求項24至32中任一項之用途,其中該乳癌先前已經過內分泌療法治療。
- 如請求項33之用途,其中該治療係使用選擇性ER調節劑(selective ER modulator, SERM)。
- 如請求項34之用途,其中該選擇性ER調節劑係選自由下列所組成之群組:泰莫西芬(tamoxifen)、雷洛昔芬(raloxifene)、奧培米芬(ospemifene)、巴多昔芬(bazedoxifene)、托瑞米芬(toremifene)、及拉索昔芬(lasofoxifene)、或前述中之任一者的醫藥上可接受之鹽。
- 如請求項33之用途,其中該治療係使用選擇性ER降解劑(selective ER degrader, SERD)。
- 如請求項36之用途,其中該選擇性ER降解劑係選自由下列所組成之群組:氟維司群、(E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1,3,4,9-四氫吡啶并[3,4-b]吲哚-1-基]苯基]丙-2-烯酸(AZD9496)、(R)-6-(2-(乙基(4-(2-(乙基胺基)乙基)苄基)胺基)-4-甲氧基苯基)-5,6,7,8-四氫萘-2-醇(艾拉司群,RAD1901)、(E)-3-(4-((E)-2-(2-氯-4-氟苯基)-1-(1H-吲唑-5-基)丁-1-烯-1-基)苯基)丙烯酸(布林司群,ARN-810,GDC-0810)、(E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(LSZ102)、(E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)胺基)丁-2-烯醯胺(H3B-6545)、(E)-3-(4-((2-(4-氟-2,6-二甲基苄醯基)-6-羥基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸(林多地司群,G1T48)、D-0502、SHR9549、ARV-471、3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)吖呾-3-基)胺基)苯基)-3-甲基-1,3,4,9-四氫-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇(吉列德司群,GDC-9545)、(S)-8-(2,4-二氯苯基)-9-(4-((1-(3-氟丙基)吡咯啶-3-基)氧基)苯基)-6,7-二氫-5H-苯并[7]輪烯-3-羧酸(SAR439859)、N-[1-(3-氟丙基)吖呾-3-基]-6-[(6S,8R)-8-甲基-7-(2,2,2-三氟乙基)-6,7,8,9-四氫-3H-吡唑并[4,3-f]異喹啉-6-基]吡啶-3-胺(AZD9833)、OP-1250、及LY3484356、或前述中之任一者的醫藥上可接受之鹽。
- 如請求項33之用途,其中該治療係使用芳香酶抑制劑。
- 如請求項38之用途,其中該芳香酶抑制劑係類固醇類芳香酶抑制劑。
- 如請求項39之用途,其中該類固醇類芳香酶抑制劑係選自由下列所組成之群組:依西美坦(exemestane)及睪內酯(testolactone)、或前述中之任一者的醫藥上可接受之鹽。
- 如請求項38之用途,其中該芳香酶抑制劑係非類固醇類芳香酶抑制劑。
- 如請求項41之用途,其中該非類固醇類芳香酶抑制劑係選自由下列所組成之群組:阿那曲唑(anastazole)及來曲唑(letrazole)、或前述中之任一者的醫藥上可接受之鹽。
- 如請求項24至32中任一項之用途,其中該乳癌先前未經過治療。
- 如請求項24至43中任一項之用途,其中該乳癌係存在於女性中。
- 如請求項44之用途,其中該對象為停經前的女性。
- 如請求項44之用途,其中該對象為圍絕經期(perimenopausal)的女性。
- 如請求項44之用途,其中該對象為更年期的女性。
- 如請求項44之用途,其中該乳癌係存在於停經後的女性中。
- 如請求項24至43中任一項之用途,其中該乳癌係存在於男性中。
- 如請求項24至49中任一項之用途,其中該乳癌係存在於具有在> 15 pg/mL至350 pg/mL之範圍內的血清雌二醇水平之對象中。
- 如請求項24至49中任一項之用途,其中該乳癌係存在於具有≤ 15 pg/mL的血清雌二醇水平之對象中。
- 如請求項25至49中任一項之用途,其中該乳癌係存在於具有≤ 10 pg/mL的血清雌二醇水平之對象中。
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CA3087262A1 (en) * | 2018-01-10 | 2019-07-18 | Recurium Ip Holdings, Llc | Benzamide compounds |
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