TW201002693A - Pyrazole compounds - Google Patents
Pyrazole compounds Download PDFInfo
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- TW201002693A TW201002693A TW098120493A TW98120493A TW201002693A TW 201002693 A TW201002693 A TW 201002693A TW 098120493 A TW098120493 A TW 098120493A TW 98120493 A TW98120493 A TW 98120493A TW 201002693 A TW201002693 A TW 201002693A
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- 239000008159 sesame oil Substances 0.000 description 1
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- 238000011125 single therapy Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
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- 229960001278 teniposide Drugs 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
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- 125000002889 tridecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
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- 210000003462 vein Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
201002693 六、發明說明: 【發明所屬之技術領域】 本發明係關於吼唑化合物,其製備方法,含有其之醫藥 組合物,製備該等醫藥組合物方 ’、 μ <万法,及其在療法中之用 途。 【先前技術】 蛋白激酶為一類調控多種細胞功能之蛋白質(酶)。此調 控係藉由蛋白質底物上特定胺基酸之碟酸化,從而引起底 物蛋白之構形改變來實現。構形改變調節底物之活性或其 與其他結合搭配物相互作用之能力。蛋白激酶之酶活性係 指激酶向底物上添加磷酸酯基團之速率。其可例如藉由測 定轉化成產物之底物的量作為時間之函數來量測。底物之 磷酸化發生在蛋白激酶之活性位點處。 酪胺酸激酶為催化三磷酸腺苷(ΑΤΡ)之末端磷酸酯基向 蛋白質底物上之酪胺酸殘基轉移之蛋白激酶的子集。此等 激酶在引起細胞增殖、分化及遷移的生長因子信號轉導之 傳播中起重要作用。 纖維母細胞生長因子(FGF)已經公認為許多生理學過程 (諸如發育及血管生成期間之形態發生)之重要介體。目前 存在25種以上已知的fGF家族成員。纖維母細胞生長因子 文體(FGFR)家族包含四個成員’其各自由細胞外配體結合 域、單一跨膜域及細胞内細胞質蛋白酪胺酸激酶域組成。 經FGF刺激後’ FGFR經歷二聚化及轉磷酸作用,此引起受 體活化。受體活化足以募集且活化參與調控諸如細胞生 140898.doc 201002693 長、細胞代謝及細胞存活之多種過程的特異性下游信號轉 導搭配物(評述於Eswarakumar, V.P.等人,Cytokine &
Growth Factor Reviews 2005,16,第 139-149 頁中)。因 此,FGF及FGFR具有起始及/或促進腫瘤形成的潛能。 如今存在大量的將FGF信號轉導與人類癌症直接相關聯 的證據。已在諸如(尤其)膀胱、腎細胞及***之多種範 圍之腫瘤類型中報導各種FGF之表現升高。FGF亦已經描 述為有效的血管生成因子。亦已報導FGFR在内皮細胞中 之表現。已將各種FGFR之活化突變與(尤其)膀胱癌及多發 性骨髓瘤相關聯,而亦已證明在尤其***癌及膀胱癌中 之受體表現(評述於Grose, R.等人,Cytokine & Growth Factor Reviews 2005,16,第 179-186 頁及 Kwabi-Addo, B. 等人,Endocrine-Related Cancer 2004, 1 1,第 709-724 頁 中)。出於此等原因’ FGF信號轉導系統為有吸引力之治療 標無,此尤其係因為靶向FGFR及/或FGF信號轉導之療法 ., 可影響腫瘤細胞(直接地)與腫瘤血管生成。 可作為FGFR用於靶向FGFR及/或FGF信號轉導之療法中 的吡唑醯胺經描述於2007年12月20曰申請之PCT申請案第 PCT/GB2007/004917號中。詳言之,某些所述π比吐酿胺經 製備為外消旋混合物形式。現已發現對於某些對映異構體 而言’在一或多種可能有利的生物學及或生理學特性方面 可走存在差異。 【發明内容】 根據本發明’提供一種式(Ia)或(Ib)之化合物: 140898.doc 201002693
OMe MeO
H
(la) OMe MeO
(lb)
或其醫藥學上可接受之鹽。 在本發明之另一態樣中,提供一種式(lb)化合物:
(Ib> 或其醫藥學上可接受之鹽。 本發明化合物之合適的醫藥學上可接受之鹽為例如具有 充分驗性的本發明化合物之酸加成鹽,例如與例如無機酸 或有機酸形成之酸加成鹽,該無機酸或有機酸為例如鹽 酸、氫溴酸、硫酸、磷酸、三氟乙酸、檸檬酸或順丁烯二 酸。另外,具有充分酸性之本發明化合物之合適的醫藥學 上可接受之鹽為··驗金屬鹽,例如納鹽或_鹽;驗土金屬 140898.doc 201002693 鹽’例如鈣或鎂鹽;銨鹽或與提供生理學上可接受之陽離 子之有機鹼形成的鹽’例如與甲胺、二甲胺、三甲胺、〇辰 °定、嗎琳或參-(2-經乙基)胺形成之鹽。 本發明係關於具有FGFR抑制活性之式(Ia)及(Ib)之化合 物的任何及所有互變異構形式。舉例而言’式(ia)化合物 為式(la)化合物之互變異構體。
+例而。’式(IB)化合物為式(η)化合物之互變異構
140898.doc 201002693 OMe
亦應瞭解某些式(la)及(lb)之化合物可以溶劑化形式以 及非溶劑化形式(諸如水合形式)存在。應瞭解本發明涵蓋 具有FGFR抑制活性之所有該等溶劑化形式。 在本發明之另一態樣中,本發明之特定化合物為實例化 合物或其任一者之醫藥學上可接受之鹽中的任一者。 本發明進一步提供一種製備如本文中所定義之式…或 (lb)之化合物或其醫藥學上可接受之鹽的方法,其包含使 式(Ila)或(lib)之化合物:
(Ila)
其中z表示離去基(例如鹵素(例如氯)、_cn、_&、七η -OR、-〇C⑼R、-OCR(NRf )2或 _〇c(=NR)NRaRb 基團 其中R為視情況經取代之烧基、芳基、雜芳基或貌芳基 且Ra、Rb各自獨立地為氫或視情況經取代之烷基、芳其 烧芳基); 140898.doc 201002693 與式(III)化合物反應:
其中Q為氫或保護基(例如t-Bu或BOC基團,或如 「Protective Groups in Organic Synthesis」,第二版, T.W· Greene 及 P.G.M. Wuts,Wiley-Interscience (1991)中所 述)’以提供式(la)或(Ib)之化合物,且視情況進行以下步 驟中之一或多者: •使所獲得之化合物轉化成本發明化合物; •形成該化合物之醫藥學上可接受之鹽。 合適的式(Ila)或(lib)之化合物包括羧酸或羧酸之反應性 何生物。羧酸或羧酸之反應性衍生物包括:醯基函,諸如 藉由使酸與例如亞硫醯氯之無機酸氯化物反應形成之醯 氣,此合酐,例如藉由使酸與諸如氣甲酸異丁酯之氣曱酸 ’例如藉由使羧酸與諸如五氟苯
140898.doc 酉曰反應形成之針;活性@旨, 酚之酚,與諸如三氟乙酸3 醇、異丙醇' 丁醇或7V-羥J 酿基疊氮化物,例如蕪 201002693 化物,或駄與諸如二環己基碳化二亞胺之碳化二亞胺或與 諸如六氟磷酸2-(7_氮雜苯并三唾小基)_u,3,3,甲錁⑺ 之錁化合物之反應產物。 可在例如齒化溶劑(諸如二氯甲烷、氯仿或四氯化碳)、 醇或酿(諸如甲醇、乙肖、異丙醇或乙酸乙醋)、鍵(諸如四 虱呋喃或1,4-二噁烷)、芳族溶劑(諸如甲苯)之合適惰性溶 劑或稀釋劑存在下便利地進行反應。亦可在諸如7V,沁二甲 基甲酉皿胺iV,7V-_甲基乙醯胺、,甲基σ比咯咬_2_嗣或二甲 亞颯之偶極非質子性溶劑存在下進行反應。便利地在範圍 為例如-20°C至10〇。(:、較佳地至環境溫度之間的溫度 下進仃反應,此取決於所進行之反應及離去基2之性質。 反應通常可在鹼存在下進行。合適的鹼包括:有機胺 鹼’諸如吡啶、2,6-二甲基吡啶、#,二異丙基乙基胺、 三曱基吼咬、4-二甲基胺基α比咬、三乙胺、嗎琳、沁甲基 嗎淋或二氮雜雙環[5.4.0]十—_7_烯;驗金屬或驗土金屬二 酸鹽或氫氧化物,諸如碟酸鋼、碳酸鉀、碳酸約、氫氧化 鈉或氫氧化鉀;鹼金屬醯胺,諸如雙(三曱基矽烷)胺基鈉 (NaHMDS);或驗金屬氫化物,諸如氫化納,此取決於所 進行之反應及離去基Z之性質。 亦可在例如二曱基鋁之路易斯酸(Lewis acid)存在下進行 反應,此取決於所進行之反應及離去基z之性質。 式(Ila)、(lib)或(III)之化合物可購得、在文獻中已知或 可使用已知技術製備。 可藉由文獻中已知之方法由2為_〇11之式(π)化合物製備 140898.doc -10- 201002693 Z為鹵素或-OR之式(π)化合物。舉例而言,可採用已知用 於由羧酸製備酸氯化物或酯的方法。 可藉由使2-曱基哌嗪與4-氟苯曱酸酯反應以提供苯甲酸 4(3-甲基旅嗪基)酯且隨後N_曱基化來製備2為_〇尺之式(π) . 化合物。 、 式(ΠΙ)化合物可藉由使式(IV)化合物:
與式(V)之肼反應製備:
I Q 〇 可便利地在諸如乙醇之溶劑中在60〇c至80。〇之溫度範圍 内進行反應。 式(IV)及(V)之化合物為市售化合物’或其在文獻尹已 知,或其係藉由在此項技術中已知之標準方法製備。 熟習此項技術者應瞭解,在本發明之方法中,起始試劑 或中間化合物中諸如羥基或胺基之某些官能基可能需要由 保護基保護。因此,式(Ia)或(Ib)之化合物的製備可包括 在多個階段添加及移除一或多個保護基。 官能基之保護及去保護經描述於rPr〇tective Gr〇ups in Organic Chemistry」,j.WF Mc〇mie 編,plenum press (1973)及「Protective Groups in 〇rganic 加加仏」,第2 140898.doc 201002693 版,T.W. Greene及 P.G.M. Wuts,Wiley_Interscience (1991) 中。 以上式(la)或(lb)之化合物可轉化成醫藥學上可接受之 鹽,例如酸加成鹽,諸如鹽酸鹽、氫溴酸鹽、磷酸鹽、乙 酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、酒石酸鹽、檸檬酸 鹽、草酸鹽、甲烷磺酸鹽或對甲苯磺酸鹽;或鹼金屬鹽, 諸如鈉鹽或钟鹽。 互變異構體及其混合物之使用亦構成本發明之態樣。 式(lb)化合物可以一或多種結晶形式存在。在本發明之 一特定態樣中,式(lb)化合物呈結晶形式,稱為形式A。 在本發明之另一態樣中,提供一種如本文中所定義之醫 藥組合物’其中式(Ib)化合物呈結晶形式。 在本發明之另一態樣中,提供一種如本文中所定義之醫 藥組合物’其包含大體上呈結晶形式A的式(Ib)化合物。 大體上呈結晶形式A意謂存在大於95%之形式a。詳言 之,存在大於96%之形式A。尤其存在大於97°/。之形式a。 詳言之,存在大於98%之形式A。尤其存在大於99%之形式 A。詳言之,存在大於99 5%之形式A。尤其存在大於 99.8%之形式A。 在一實施例中,提供式(Ib)化合物之結晶形式,其具有 包含在 2θ(λ=1.5418Α)5.288、17.935、18.011、20.513 及 20.753處之峰的xrd圖。 在另一實施例中,提供式(Ib)化合物之結晶形式,其具 有包含在 2θ(λ=1_5418Α)5·288、17.935、18.011、18 766、 140898.doc -12- 201002693
19.628、19.667、2〇·5 13、20.753 及 23·892 處之峰的 XRD 圖。 在另一實施例中’提供式(Ib)化合物之結晶形式,其具 有包含在 2θ(λ=1.5418Α)5.288、17.761、17.935、ι8.〇n、 18.766、 19.094、19.628、19.667、20.513、20,753、 22.264及23.892處之峰的xrd圖。 在另一實施例中,提供式(Ib)化合物之結晶形式,其具 有包含在 2θ(λ=1·5418Α)5.288、10.483、1 1.388、11 912、 ν' 14.086、 15.671、16.322、17.761、17.935、18.011、 18.766、 19.094、19.628、19.667、20.513、20.753、 21.765、22_264、22.766、22.793 及 23.892 處之峰的 xrd 圖。 在另一實施例中’提供式(lb)化合物之結晶形式,其具 有包含在 2θ(λ=1.5418Α)3·642、4.357 ' 5.288、7.226、 9.062、9.482、10.483、1 1.388、11.85、11.912、1 3.078、 14.086、 14.559、15.671、16.156、16.179、16.322、 17.761、17.935、18.011、18.766、19.094、19.628、 19-667、20.513、20.753、21.765、22.264、22.766、 22.793、23.892、26.257及 36.269 處之峰的 XRD 圖。 熟習此項技術者應瞭解本文呈現之繞射圖資料不應理解 為絕對的(關於進一步資訊,參見Jenkins, R及Snyder, R.L., 「Introduction to X-Ray Powder Diffractometry」,
John Wiley & Sons, 1996)。因此,應瞭解結晶形式並不意 欲限於提供與本文所述之X射線粉末繞射圖一致的X射線 140898.doc •13· 201002693 粉末繞射圖之晶體。本發明亦包括任何提供與本文所述大 體上相同的x射線粉末繞射圖之晶體。熟習X射線粉末繞 射技術者能夠判斷X射線粉末繞射圖之大體上相似性且將 瞭解差異可為各種因素之結果,例如由量測條件(諸如所 用设備、樣品製劑或儀器)所產生之量測誤差;由量測條 件及樣品製劑所產生之強度變化;由晶體之尺寸或非一元 縱橫比之變化所產生的峰之相對強度變化;及可受樣品位 於繞射計中之精確高度及繞射計之零點校準影響的反射位 置,及樣品之表面平坦度。 式(la)或(lb)之化合物具有作為醫藥品之活性,尤其具 有作為FGFR活性之調節劑或抑制劑之活性,且其可用於 治療增生性及過度增生性疾病/病狀,該等疾病/病狀之實 例包括以下癌症: (1) 癌瘤’包括膀胱癌、腦癌、乳癌、結腸癌、腎癌、肝 癌、肺癌、卵巢癌、姨腺癌、***癌、胃癌、子宮頸 癌、結腸癌、甲狀腺癌及皮膚癌; (2) 淋巴系造血腫瘤’包括急性淋巴球性白血病、b細胞 淋巴瘤及柏克特氏淋巴瘤(Burketts lymphoma); (3) 骨髓系造血腫瘤,包括急性及慢性骨髓性白血病及前 髓球性白jk病; (4) 間葉細胞源腫瘤,包括纖維肉瘤及橫紋肌肉瘤;及 (5) 其他腫瘤’包括黑素瘤、精原細胞瘤、畸胎癌 '神經 母細胞瘤及神經膠質瘤。 在一貫施例中,本發明化合物適用於治療膀胱腫瘤、乳 140898.doc -14- 201002693 房腫瘤及***腫瘤以及多發性骨髓瘤。 因此,本發明提供如本文所定義之用於療法中的式(la) 或(lb)之化合物或其醫藥學上可接受之鹽。 根據本發明之另一態樣,提供如上文所定義之藉由療法 用於治療人體或動物體之方法中的式(1勾或(11))之化合物 或其醫藥學上可接受之鹽。
在另一樣中,本發明提供如本文所定義之式(Ia)或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 製造用於療法中之藥物。 在本說明書之上下文中,除非特定相反指示,否則術語 療法」亦包括「預防」。應相應地理解術語「治療」。 本發明亦提供一種治療癌症之方法,其包含向有需要之 患者投與治療有效量之如本文所定義之式(Ia)或(叫之化 合物或其醫藥學上可接受之鹽。 已發現本發明中所定義之化合物或其醫藥學上可接受之 鹽為有效抗癌齊丨,咸信該抗癌特性係由調節或抑制贿 活性而產生。因此預期本發明之化合物適用於治療僅由或 在某種程度上由阳叹介導之疾病或醫學病狀,亦即該等 化合物可用於在需要此治療之溫血動物内產生F 作用。 ,因此,本發明之化合物提供一種治療癌症之方法,其特 徵為抑制FGFR,亦即該等化合物可用於產生僅由或:某 種程度上由FGFR抑制所介導之抗癌作用。 八 預期本發明之此化合物具有多種抗癌特性,因為已在許 140898.doc •15· 201002693 多人類癌症(包括(但不限於)乳癌、膀胱癌、***癌及多 發性骨髓瘤)中觀測到FGFR之活化突變。因此,預期本發 明之化合物將具有對抗此等癌症之抗癌活性。另外,預期 本發明之化合物將具有對抗一系列白血病、淋巴惡性疾病 及實體腫瘤(諸如肝、腎、膀胱、***、***及胰腺之 組織中之癌瘤及肉瘤)的活性。在一實施例中,預期本發 明之化合物有利地減緩(例如)皮膚、結腸、甲狀腺、肺及 卵巢之原發性及復發性實體腫瘤的生長。更特定言之,預 期本發明之此等化合物或其醫藥學上可接受之鹽抑制與 FGFR相關之彼等腫瘤、尤其生長及散布顯著依賴於阳叩 之彼等腫瘤(包括例如膀胱、***、***之某些腫瘤及 多發性骨髓瘤)的生長。 因此,根據本發明之此態樣’提供如本文所定義之用作 藥物的式(la)或(lb)之化合物或其醫藥學上可接受之鹽。 根據本發明之另-態樣,提供如本文所定義之式(⑷或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 製造用以在溫血動物(諸如人類)中產生FGFR抑制作用之藥 物。 根據本發明之此態樣,提供如本文所定義之式(Η)或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 製造用以在溫血動物(諸如人類)中產生抗癌作用之藥物。' 根據本發明之另-特徵,提供如本文較義之式(Ia)或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 製造用以治療以下疾病之藥物:黑素瘤、乳頭狀甲狀腺 140898.doc •16- 201002693 瘤、膽管癌、結腸癌、卵巢癌、肺癌、白血病、林巴惡性 疾病、多發性骨髓瘤,肝、腎、膀胱、***、***及胰 腺中之癌瘤及肉瘤,及皮膚、結腸、甲狀腺、肺及印巢之 原發性及復發性實體腫瘤。 根據本發明之另一態樣,提供如本文所定義之式(Ia)或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 在溫血動物(諸如人類)中產生FGFR抑制作用。 根據本發明之此態樣,提供如本文所定義之式(ia)或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 在溫血動物(諸如人類)令產生抗癌作用。 根據本發明之另一特徵,提供如本文所定義之式(h)或 (lb)之化合物或其醫藥學上可接受之鹽的用途,其係用於 /α療黑素瘤、乳頭狀甲狀腺瘤、膽管癌、結腸癌、卵巢 癌、肺癌、白血病、淋巴惡性疾病、多發性骨髓瘤,肝、 腎膀胱、月9列$、***及胰腺中之癌瘤及肉瘤’及皮 膚、結腸、甲狀腺、肺及卵巢之原發性及復發性實體腫 瘤。 根據本务明之此態樣之另一特徵’提供一種用於在需要 治療之溫血動物(諸如人類)中I生FGFR抑制作用之方法,
Ms &㈣物投與有效量之如本文所定義之式⑼或 (lb)之化合物或其醫藥學上可接受之鹽。 根據本·明之此態樣之另一特徵,提供一種用於在需要 治療之溫血動物(諸如人類)中產生抗癌作用之方法,其包 S向》亥動物&與有效量之如本文所定義之式(⑷或(叫之 140898.doc -17- 201002693 化合物或其醫藥學上可接受之鹽。 根據本發明之此態樣 治療之溫血動物(諸如人提供-種治療需要此 乳頭狀甲狀腺瘤、膽管癌、二疾病的方法:黑素瘤、 ^ ρ s , …腸癌、卵巢癌、肺癌、白血 病、淋巴惡性疾病、多發 腺、n β ^生月咖瘤,肝、腎、膀胱、前列 腺、礼房及胰腺中之癌瘤及 艙 ^ ^ "田及皮膚、結腸、甲狀 腺、肺及印桌之原發性及復發性實體 該動物投與有效量之如本方法“向 物或其醫藥學上可接受之鹽。 ;“(叫之化合 在本發明之另—態樣令,提供一種包含如本文所定義之 Mia)或(lb)之化合物或其醫藥學上可接受之鹽與醫藥學 上可接受之稀釋劑或載劑的醫藥組合物,其係用於在溫血 動物(諸如人類)中產生FGFR抑制作用。 、在本發明之另一態樣中,提供一種包含如本文所定義之 式(la)或(lb)之化合物或其醫藥學上可接受之鹽與醫藥學 上可接受之稀釋劑或載劑的醫藥組合物,其係用於在溫血 動物(諸如人類)中產生抗癌作用。 在本發明之另一態樣中,提供一種包含如本文所定義之 式(la)或(lb)之化合物或其醫藥學上可接受之鹽與醫藥學 上可接受之稀釋劑或載劑的醫藥組合物,其係用於治療溫 血動物(諸如人類)之以下疾病:黑素瘤、乳頭狀甲狀腺 瘤、膽管癌、結腸癌、卵巢癌、肺癌、白血病、淋巴惡性 疾病、多發性骨髓瘤,肝、腎、膀胱、***、***及胰 腺中之癌瘤及肉瘤,及皮膚、結腸、曱狀腺、肺及卵巢之 140898.doc 201002693 原發性及復發性實體腫瘤。 式(la)或(lb)之化合物及其醫藥學上可接受之鹽可獨立 地使用,但通常將以醫藥組合物形式投與,其中式U勾或 (I b )之化合物或鹽(活性成份)與醫藥學上可接受之佐劑、
稀釋劑或載劑相締合。視投藥模式而定,醫藥組合物可包 含0.01重量%至99重量%(重量百分比)、〇 〇5重量%至⑶重 量%、0.10重量。/。至70重量%且或甚至0.10重量%至5〇重量 %的活性成份,所有重量百分比均係以全部組成計。 本發明亦提供一種醫藥組合物,其包含如本文所定義之 式(la)或(lb)之化合物或其醫藥學上可接受之鹽與醫藥學 上可接受之佐劑、稀釋劑或載劑。 本發明另外提供一種製備本發明之醫藥組合物之方法’ 其包含將如本文所定義之式(Ia)或(Ib)之化合物或其醫藥 〇接又之鹽與醫藥學上可接受之佐劑、稀釋劑或載劑 混合。 U °亥等商藥組合物可以例如乳膏劑、溶液、懸浮液、七氟 、元氣務訓及乾粉調配物形式局部地投與(例如至皮膚或至 肺及/或氣管);或例如以錠劑 '膠囊、糖漿劑、散劑或顆 粒形f藉由口服投與來全身性地投與;或以溶液或懸浮液 、藉由非經知投與來投與;或藉由皮下投與來投與;或 以检劑形式藉由直腸投與來投與;或經皮投與。 可猎由習知程序使用此項技術中所熟知之習知醫藥賦形 J g得本發明之組合物。因此,意欲口服使用之組合物 可3有(例如)一或多種著色劑、甜味劑、調味劑及/或防腐 140898.doc -19- 201002693 錠劑調配物之合適的醫藥學上可接受之賦形劑包括例如 情性稀釋劑,諸如乳糖、碳酸鈉、鱗酸舜或複成粒 d及崩解劑,S者如玉米澱粉或海藻酸;黏合劑,諸如澱 粉;潤滑劑’諸如硬脂酸鎂、硬脂酸或滑石;防腐劑,諸 如對經基苯甲酸乙g旨或對經基苯甲酸丙3旨;及抗氧化劑, 諸如抗壞血酸。錠劑調配物可未包覆包衣或包覆包衣,以 調節其崩解及隨後活性成份在胃腸道内之吸收或改良其穩 疋性及/或外觀’在任—情況下,使用此項技術中熟知之 習知包衣劑及程序來包覆包衣。 —入,…/ π农少工、,丹甲沽性成 與例如碳酸鈣、磷酸鈣或高嶺土之惰性固體稀釋劑混合 或壬权明膠膠囊形式,其中活性成份與水或諸如花生油 液體石蠟或橄欖油之油混合。 f性懸㈣通常含有細粉狀形式之活性成份與一或多: 懸/于劑’諸如缓f基纖維素納、甲基纖維素、經丙基甲: :、’.:、海藻酸鈉、聚乙烯_吼咯啶酮、黃蓍膠及阿拉> :二散劑或濕潤劑’諸如輪旨或氧化烯與脂肪酸之〗 ° (例如聚^烯硬脂酸g旨),或環氧 T之!合產物(例如十七伸乙基氧基她”, 烯二肪酸及己糖醇衍生之偏酯的縮合產物(諸如聚氧 烯山梨糖醇單油酿@^ ^ ^ —-曰),或環氧乙烷與長鏈脂族醇之縮, 歹如十七伸乙基氧基鯨蠟醇),或 酸及己糖醇衍生之低攸 衣虱乙烷與由脂) 之偏S曰的縮合產物(諸如聚氧乙烯山梨 140898.doc -20- 201002693 醇單油酸酯),或環氢7捻盘山 氧乙烷與由脂肪酸及己糖醇酐衍生之 偏酯的縮合產物(例如聚乙嫌盼 伞己炸脫水山梨糖醇單油酸酯)。水 性懸浮液亦可含有—或多箱咏府 次夕種防腐劑(諸如對羥基苯甲酸乙 酯或對羥基苯曱酸丙酯)、抗4 曰)柷虱化劑(諸如抗壞血酸)、著色 劑、調味劑及/或甜味劑(諸如 庶糖、糖精或阿斯巴甜糖 (aspartame)) ° 可藉由將活性成份懸浮於植物油(諸如花生油、橄禮 油、芝麻油或椰子油)或礦物油(諸如液體石壞)中來調配油 性懸浮液。油性料液亦可含有增㈣,諸如蜂犧、固體 石犧或絲蟻醇。可添加甜味劑(諸如以^ μ。口 居如以上闡明之彼等)及調 味劑以提供可口的口服製劑。可藉 ^ 精由H'、加邊如抗壞血酸之 抗氣化劑,為此等組合物進行防腐。
L 適於藉由添加水來製備水性懸浮液的可分散性粉末及顆 粒通常含有活性成份與分散劑或濕潤劑、懸浮劑及一或多 種防腐劑。合適的分散劑或濕潤劑及懸浮劑係由上文已提 及之彼等者來例示。亦可存在諸如甜味劑、調味劑 劑之其他賦形劑。 本發明之醫藥組合物亦可呈水包油乳液形式。油相可為 植物油,諸如橄欖油或花生油;或礦 ‘ 碯·々, 八由s者如液體石 ^或任何該等油之混合物。合適的乳化劑可為例如天缺 存在之膠’諸如***膠或黃蓍膠;天然存在之碟脂,噹 如大豆、卵磷脂、由脂肪酸及己糖醇酐衍:曰,3 (例如脫水山梨糖醇單油酸酯)及該等偏酯與環氡乙俨 合產物(諸如聚氧乙稀脫水山梨糖醇單油酸 ^縮 ) 孔 >夜亦可 140898.doc 21 201002693 含有甜味劑、調味劑及防腐劑。 糖聚劑及酿劑可以諸如甘油、丙二醇、山梨糖醇 巴甜糖或庶糖之甜味劑來調配,且亦可含有緩和 劑、調味劑及/或著色劑。 竭 、醫藥組合物亦可呈無菌可注射水性或油性懸浮液之形 其可根據已知程序使用一或多種已於上文提及之適當 刀政劑或濕潤劑及懸浮劑來調配。無菌可注射製劑亦可為 ‘”、t卜生非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液 或懸浮液,例如1,3_丁二醇中之溶液。 、 栓劑調配物可藉由將活性成份與在常溫下為固體但在直 腸溫度下為液體且因此在直腸中炫融以釋放藥物的人適無 刺激性賦形劑混合來製備。合適的賦形劑包括例如;可脂 及聚乙二醇。 9 諸如乳膏劑、軟膏劑、凝膠及水性或油性溶液或懸浮液 之局部調配物通常可藉由使用在此項技術中熟知之習知程 序將活性成份與習知局部可接受之媒劑或稀釋劑一起調配 來獲得。 藉由吹入投與之組合物可呈含有平均直徑為例如3〇 ρ或 更小之粒子的細粉狀粉末形式,粉末本身包含單獨或經一 或多種生理學上可接受之載劑(諸如乳糖)稀釋的活性成 份。供吹入之粉末隨後便利地保留於含有例如丨至% mg之活性成份之膠囊中以供渦輪吸入器裝置使用,諸如用 於吹入已知藥劑色甘酸鈉。 用於藉由吸入投與之組合物可呈習知加壓氣霧劑形式, 140898.doc •22- 201002693 其經配置以分配呈含有細粉狀固體或液滴之氣霧劑形式之 活!生成份。可使用諸如揮發性氟化烴或烴之習知氣霧劑推 進劑且氣霧劑裝置便利地經配置以分配經計量量之活性成 份。 關於調配之其他資訊,讀者可參閱c〇mprehensive Medicinal try (Corwin Hansch ’ 編委會***(chairman of Editorial
Board)),pergam〇n Press 199〇之第 5卷中之第 25 2章。 根據熟知之醫學原則,本發明化合物用於治療目的之劑 畺大小自然應根據以下因素而變:病狀之性質及嚴重程 度、動物或患者之年齡及性別以及投藥途徑。 一般而言,將投與本發明化合物以便接收範圍為例如每 公斤體重0.1 mg至1000 mg活性成份之日劑量,其係視需 要以分次劑量給與。然而,日劑量必然將視所治療之宿 主、特定投藥途徑及所治療疾病之嚴重程度而變化。因 此’表佳劑3:可由正治療任何特定患者之專業人員進行確 定。一般而言’當使用非經腸途徑時將投與較低劑量。因 此,例如,對於靜脈内投藥而言,通常將使用在(例如)每 公斤體重0.1 mg至30 mg活性成份之範圍内的劑量。類似 地,對於藉由吸入投藥而言,通常將使用在(例如)每公斤 體重0_ 1 mg至25 mg活性成份之範圍内的劑量。然而,較 佳口服投與。舉例而言,意欲口服投與至人類之調配物通 常將含有例如〇 · 1 mg至2 g活性成份。 關於投藥途徑及給藥方案之其他資訊,讀者可參閱
Comprehensive Medicinal Chemistry (Corwin Hansch ;編 140898.doc -23- 201002693 委會***),Pergamon Press 1990之第5卷中之第25.3章。 在上文中定義之抗癌治療可應用為單獨療法或除本發明 之化合物以外可包括習知手術或放射線療法或化學療法。 該化學療法可包括以下種類之抗腫瘤劑中之一或多者: (1) 如用於醫學腫瘤學中之其他抗增殖性/抗贅生性藥 物及其組合,諸如院化劑(例如順鉑(cis platin) '奥賽力鉑 (oxaliplatin)、卡鉑(carboplatin)、環磷醯胺(cyci〇ph〇sphamide) 、氮芥(nitrogen mustard)、美法侖(melphalan)、苯丁酸氮 芥(chlorambucil)、白消安(busulphan)、替莫唑胺(temozolamide) 及亞硝基脲)’·抗代謝物(例如吉西他濱(genicitabine广及 抗葉酸物’諸如氟嘧啶(如5-氟尿嘧啶及喃氟啶(tegafur))、 §1替曲赉(raltitrexed)、曱胺嗓〇令(methotrexate)、阿糖胞苦 (cytosine arabinoside)及經基腺);抗腫瘤抗生素(例如蒽環 Μ 素(anthracycline),如阿黴素(adriamycin)、博來徽素 (bleomycin)、多柔比星(doxorubicin)、道諾黴素(daun ⑽ ydn) 、表柔比星(epirubicin)、黃膽素(idarubicin)、絲裂徽素 (mitomycin-C)、放線菌素 D(dactinomycin)及光神黴素 (mhhramycin));抗有絲***劑(例如長春花屬生物鹼(vinca alkaloid),如長春新鹼(vincristjne)、長春鹼(vinblastine)、 長春地辛(vindesine)及長春瑞賓(vinoreibine);及紫杉院類 (taxoid),如紫杉酚(taxol)& 克癌易(tax〇tere);及 p〇1〇激酶 抑制劑);及拓撲異構酶抑制劑(例如表鬼臼毒素 (epiP〇d〇Phyll〇toxin)(如依託泊苷(et〇p〇side)及替尼泊苷 (teniposide))、安 口丫咬(amsacri㈣、拓朴替康(t〇p〇tecan)及 140898.doc •24- 201002693 喜樹驗(camptothecin)); (η)細胞生長抑制劑’諸如抗***物(例如他莫昔芬 (tamoxifen)、氟維司群(fulvestrant)、托瑞米芬(t〇remifene) 、雷諾昔芬(raloxifene)、屈洛昔芬(dr〇i〇xifene)及艾多昔 芬(iodoxyfene))、抗雄激素物(例如比卡魯胺(bicaiut㈣也) 、氟他胺(flutamide)、尼魯米特(nilutamide)及乙酸環丙孕 酮(cyproterone acetate))、LHRH拮抗劑或 LHrh促效劑(例 如戈舍瑞林(goserelin)、亮丙瑞林(leuproreUn)及布舍瑞林 (buserelin))、孕激素(例如乙酸甲地孕酮(megestr〇1 acetate)) 、芳香酶抑制劑(例如阿那曲唑(anastr〇z〇le)、來曲哇 (letrozole)、維拉唑(vorazole)及依西美坦(exemestane))及 諸如非那雄安(finasteride)之5*-還原酶抑制劑; (ui)抗侵襲劑(例如c-Src激酶家族抑制劑,如4_(6_氣_ 2,3-亞曱基一氧基本胺基)_7-[2-(4-曱基派唤_1_基)乙氧基]_ 5-四氫η辰喃-4-基氧基喧〇坐琳(AZD0530 ;國際專利申請案 \¥〇 01/94341)及义(2-氯-6-曱基笨基)—2-{6-[4-(2-羥乙基) α底嗪-1 -基]-2-曱基哺咬-4-基胺基} 〇塞唾_5-曱酿胺(達沙替尼 (dasatinib),BMS-354825 ; J. Med. Chem·,2004, 47, 6658- 6661);及金屬蛋白酶抑制劑,如馬立馬司他(marimastat)、 尿激酶血漿素原活化劑受體功能抑制劑或肝素酶抗體); (iv)生長因子功能抑制劑:例如該等抑制劑包括主長 因子抗體及生長因子受體抗體(例如抗erbB2抗體曲妥珠單 抗(trastuzumab)[贺癌平(Herceptin)™]、抗 EGFR抗體盤尼 圖單抗(panitumumab)、抗erbB 1抗體西妥昔單抗(cetuximab) 140898.doc -25- 201002693 [愛必妥(Erbitux),C225]及由 Stern 等人,rr、·, • Critical reviews in 〇nc〇i〇gy/haemat〇i〇gy,2005,第54卷第 η,頁所揭 示之任何生長因子或生長因子受體抗體);該等抑制齊j = 包括絡胺酸激酶抑制劑,例如上皮生長因子家族之抑制劍 (例如EGFR家族酪胺酸激酶抑制劑,諸如n_(3_氯-肛氟苯 基)-7-甲氧基-6-(3-嗎啉基丙氧基)啥唑琳胺(吉非秩尼 (gefhinib),ZD1 839)、N-(3-乙块基苯基)-6,7-雙(I 甲 乙氧基)喹唑啉-4-胺(埃羅替尼㈣。tinib),⑽77句及心 烯酿基醯胺基-N-(3_氯_4_氟苯基)_7_(3_嗎琳基丙氧基)·喹 唾琳-4-胺(CI 1033)); erbB2路胺酸激酶抑制劑,諸如㈣ 替尼(I-。-),·肝細胞生長因子家族之抑制劑,·血小板 衍生生長因子家族之抑制#|,諸如伊馬替尼(_㈣;緣
胺酸:蘇胺酸激酶之抑制劑(例如Ras/Raf信號轉導抑制劑, 諸如法呢基轉移酶抑制劑,例如索拉非尼(s_eni_AY 43-9006));細胞經由贿及/或akt激酶信號轉導之抑制 劑;肝細胞生長因子家斿 豕之抑制制;c-kit抑制劑;abl激酶 抑制劑;IGF受體(月奏i |e 島素‘生長因子)激酶抑制劑;極光 如_)激酶抑制劑(例如Azm 152、ρΗ739358、νχ_副、 MLN8054、R763、 5、ΜΡ529、VX-528及 ΑΧ39459); 及細胞週期素依賴性激醢 狡_抑制劑,諸如CDK2及/或CDK4 抑制劑; Ο) 抗血管生成劑,畔Λ 4, Α 风A 4如抑制血管内皮生長因子之作 用的彼等抗血管生成'添彳「/丨 θ [ Ή如抗血管内皮細胞生長因子抗 體貝伐單抗(bevacjZUmab)(田 ^ 癌心停(Avastin)™)及VEGF受體 140898.doc -26 - 201002693 酪胺酸激酶抑制劑,諸如(4-(4-溴-2-氟苯胺基)-6-曱氧基-7-(1-曱基哌啶-4-基甲氧基)喹唑啉(ZD6474; WO 01/3265 1 中之實例2)、4-(4-氟-2-曱基吲哚-5-基氧基)-6-曱氧基-7-(3-吡咯啶-1-基丙氧基)喹唑啉(AZD2171 ; WO 00/47212中 之實例 240)、凡塔藍尼(vataianib)(PTK787 ; WO 98/35985) 及 SU1 1248(舒尼替尼(sunitinib) ; WO 01/60814),諸如彼 等揭示於國際專利申請案WO 97/22596、WO 97/30035、 WO 97/32856及WO 98/13354中之化合物及由其他機制作 用之化合物(例如三敌胺基喧淋(linomide),整合素avb3功 能抑制劑及血管生長抑素)]; (vi) 血管損傷劑,諸如康布瑞汀A4(Combretastatin A4) 及揭示於國際專利申請案WO 99/02166、WO 00/40529、 WO 00/41669、WO 01/92224、WO 02/04434及 WO 02/08213 中之化合物; (vii) 反義療法,例如針對上文所列之標靶的彼等反向 療法,諸如ISIS 2503,抗ras反義藥物; (viii) 基因療法方法,包括例如置換諸如異常p53或異 常BRCA1或BRCA2之異常基因之方法;GDEPT(基因導向 酶前體藥物療法)方法,諸如使用胞嘧啶脫胺酶、胸苷激 酶或細菌硝基還原酶之彼等方法;及增加患者對於化學療 法或放射線療法之财受性之方法,諸如多藥抗性基因療 法;及 (ix) 免疫療法方法,包括例如增加患者腫瘤細胞之免 疫原性的離體及活體内方法,諸如以諸如介白素2、介白 140898.doc -27- 201002693 素4或顆粒球巨噬細胞群落刺激因子之細胞激素進行轉 染;降低T細胞無變應性之方法;使用諸如細胞激素轉染 之樹突狀細胞之經轉染免疫細胞的方法;使用細胞激素轉 染之腫瘤細胞系之方法;及使用抗遺傳型抗體之方法。 【實施方式】 實例 現將參考以下說明性實例來進一步描述本發明,除非另 外說明’否則在說明性實例中: (1)溫度以攝氏度fc )給出;在室溫或環境溫度,亦即在 範圍為1 8-25°c之溫度下進行操作; (η)經無水硫酸鎂乾燥有機溶液;在減壓下(6〇〇_4〇〇〇帕斯 卡(Pascal) ; 4·5_30 mmHg)以至多6〇t:之浴溫使用旋轉蒸 發器進行溶劑蒸發; (iii) 層析意謂矽膠急驟層析;薄層層析(TLC)係用矽膠板 進行; (iv) —般而言,反應過程後接著TLC且給出反應時間僅用 於說明; (V)最終產物具有令人滿意之質子核磁共振(NMR)譜及/或 質譜資料; (vi)產率僅為說明目的而給出且不必為可藉由不懈過程發 展而U得之彼等產率,若需要更多物質,則重複製備; (νΠ)當給出NMR資料時,其呈主要特徵質子之5值之形 式,以相對於作為内標之四曱基矽烷(TMS)的百萬分率 (Parts per miUi〇n,ppm)形式給出,除非另外指示否則 140898.doc -28- 201002693 其係在DMSO-d6中在300 MHz下測定; (viii)化學符號具有其通常含義;使用SI單位及符號; (IX)以體積:體積(v/v)計給出溶劑比率;且 Ο)質譜(MS)資料係用LC/MS系統產生,其中HPLC,組件 通常包含 Agilent 1100 或 Waters Alliance HT(2790 及 2795) 設備且在 Phenomenex Gemini C18 5 μηι,50x2 mm管柱(或 類似管柱)上用酸性溶離劑(例如’使用具有5%之於5〇:5〇 f 水.乙腈(v/v)混合物中之1 %曱酸的介於0-95%之間的水/ 乙腈梯度;或使用具有甲醇而非乙腈之等溶劑系統)或鹼 性溶離劑(例如,使用具有5%之於乙腈混合物中之〇.1% 880氨的介於〇_95%之間的水/乙腈梯度)溶離來操作;且1^8 組件通常包含Waters ZQ光譜分析儀。產生電喷霧(ESI)正 及負基峰強度之層析圖及220-3 00 nm之UV全吸收層析圖且 給出m/z之值;通常,僅報導指示母體質量之離子且除非 另作》兒明,否則所引用之值對於正離子模式為(M+H)+且對 i ^ 於負離子模式為(Μ-Η)·; (xi)用C1 8逆相二氧化矽,你 例如用Waters 「Xterra」製備
行製備型HPLC ; (xii)已使用以下縮寫: AHF 四氫呋喃; DMF 二曱基甲 140898.doc •29- 201002693
EtOAc 乙酸乙酯; DCM —氯曱烧;及 DMSO —甲亞礙 DIPEA 况落二異丙基乙基胺 (亦稱為N -乙基-N-丙-2 -基-丙-2-胺) PBS 磷酸鹽緩衝之生理食鹽水 HEPES W-[2-羥乙基]哌嗪-ΛΓ-[2-乙烷磺酸] DTT 二硫蘇糖醇 ATP 三磷酸腺苷 BSA 牛血清白蛋白 DMEM 杜貝卡氏改良伊格爾培養基(Dulbecco's modified Eagle's Medium) MOPS 3 -(N-嗎淋基)丙烧續酸 (X111)使用專屬命名軟體:〇peneye Lexicheni 1.4版,使用 IUPAC命名規則命名化合物; (xiv)除非另有說明,否則起始物質可購得。 實例1⑷(S)-N-(3-(3,5-二甲氧基苯乙基)-他吼唑冬基)-4_(3,4-二曱基哌嗪-1-基)苯甲醯胺的製備
C下將二曱基紹(曱笨中2 M,1.93 ,3.87 mmol) 140898.doc -30- 201002693 逐滴添加至3-(3,5-二甲氧基苯乙基)_1H_吡唑_5_胺(382 mg,L55 mmol)及(S)_4_(3,4_二曱基„辰嘻小基)苯甲酸甲錯 (384 mg’ 於甲苯(1〇ml)中之懸浮液中。在阶 下攪拌所得溶液18小時。將反應混合物傾入曱醇(5〇加”中 且以2 Μ鹽酸酸化。藉由離子交換層析法使用scx管柱純 化粗產物。使用7 Μ曱醇氨自管柱溶離所需產物且蒸發至 乾燥,得到不純產物。藉由製備型HPLC(Waten XU⑽
C18官柱,5 μ二氧化矽,30 mm直徑,1〇〇 mm長度)使用 1%氨水與乙腈之漸減極性混合物作為溶離劑純化粗產 物將S有所需化合物之溶離份蒸發至乾燥,得到呈白色 固體狀之(S)-N-(3-(3,5-二甲氧基苯乙基)_1H_吡唑_5_基)_4_ (’4 一甲基D底嗪-I-基)苯甲酸胺(387 mg,54%)。NMR (399.9 MHz, DMSO-d6) δ 1.07 (3Η, d), 2.09-2.14 (1Η, m), 2.18-2.25 (1H, m), 2.22 (3H, s), 2.44-2.53 (1H, m), 2.77-2·87 (2H, m), 2.88 (4H, s), 3.65-3.75 (2H, m), 3.73 (6H, s), 6.34 (1H, t), 6.43 (2H, d), 6.46 (1H, s), 6.96 (2H, d), 7.91 (2H,d), 10·31 (1H,s), 12 〇9 (1H,s)。ms: _ 464 (MH+) 〇 (S)_4_(3,4-二甲基哌嗪4•基)苯甲酸甲酯
C下將二乙醯氧基删氫化鈉(2·25 g,ίο』mm〇i)添 140898.doc -31 - 201002693 加至於甲醇(21 ml)中之(s)_4_(3_曱基哌嗪_丨_基)笨曱酸甲 酯(0.99 g,4.24 mm〇1)、曱醛(6·32 ml 37%水溶液,84 9 mmol)及乙酸(0.49 ml ’ 8.49 mmol)中。在環境溫度下在氣 氣下攪拌所得溶液1 8小時。以飽和NaHC〇3水溶液驗化反 應混合物且在減壓下濃縮。以EtOAc(200 ml)稀釋殘餘物 且依序以飽和NaHC03水溶液(200 ml)洗滌。以Et〇Ac(2x75 ml)進一步萃取水相且以水(200 ml)及飽和鹽水(2〇〇 mi)洗 滌經合併有機物。經MgS04乾燥有機層,過濾且蒸發,得 到粗產物。藉由急驟二氧化矽層析,以EtOAc/異己烷(極 性0:1 00增加至1 〇〇··〇)溶離來純化粗產物。將純溶離份蒸發 至乾燥’得到呈白色固體狀之(S)-4-(3,4-二曱基哌嗪-1-基) 苯曱酸曱酯(0.538 g,51%)。 *H NMR (399.9 MHz, CDC13) δ 1.14-1.15 (3Η, m), 2.18-2.26 (1Η, m), 2.34 (3Η, s), 2.35-2.41 (1H, m), 2.61-2.67 (1H, m), 2.87-2.91 (1H, m), 2.99-3.06 (1H, m), 3.58-3.62 (1H, m), 3.66-3.70 (1H, m), 3.86 (3H, s), 6.84-6.87 (2H, m),7.89-7.93 (2H,m)。MS: m/z 249 (MH+)。 (S)-4-(3-曱基哌嗪-1-基)苯曱酸甲酯
在25°C下將4-氟苯甲酸曱酯(1·〇〇 m卜7.73 mmol)添加至 於DMA(3 1 ml)中之(S)-( + )-2 -曱基痕嗔(1.55 g,15.5 mmol) 140898.doc •32- 201002693 中。在氮氣下在120°C下攪拌所得溶液3天。濃縮反應混合 物且以EtOAc(100 ml)稀釋’且依序以飽和NaHC03水溶液 (200 ml)洗滌。以EtOAc(2xl〇〇 ml)進一步萃取水相,且以 水(200 ml)及飽和鹽水(200 ml)洗滌經合併有機物。經 MgS〇4乾燥有機層’過濾且蒸發,得到呈棕色油狀之所需 (S)-4_(3-曱基哌嗪-1-基)苯甲酸甲酯(〇·995 g,55%),其在 靜置後結晶。無進一步純化直接使用此物質。iH NMr (399.9 MHz, CDC13) δ 1.14-1.15 (3Η, d), 2.44-2.50 (1Η, m), 2.80-2.86 (1H, m), 2.91-3.03 (2H, m), 3.10-3.15 (1H, m), 3.67-3.70 (2H, m), 3.86 (3H, s), 6.85-6.87 (2H, m), 7.89-7.93 (2H,m),未觀察到 NH。MS: m/z 235 (MH+)。 3-(3,5-二曱氧基苯乙基)-1Η-»比唑-5-胺
用作起始物質,其製備如下: 將乙腈(2.29 ml,43.61 mmol,1.2當量)添加至氫化鈉 (1.75 g於礦物油中之分散液’ 43.61 mmol,1.2當量)於無 水甲苯(7〇 ml)中之漿料中’且在室溫下授拌混合物30分 鐘。添加曱苯(60 ml)中之3-(3,5-二甲氧基苯基)丙酸乙酯 140898.doc •33- 201002693 (8·66 g,36.34 mmol ’ 1當量)且使反應回流18 h。冷卻 後’以水使反應混合物中止反應且在減壓下蒸發溶劑。將 殘餘物溶解於2 M HC1(50 ml)申。以乙酸乙酯萃取酸性溶 液。合併有機提取物且以水、鹽水洗滌且經硫酸鎂乾燥。 過濾後,在減壓下蒸發溶劑,得到呈黃色油狀之粗產物。 藉由二氧化矽管柱層析(以DCM溶離)純化該油狀物且合併 所需溶離份且蒸發,得到奶白色固體(3 76 g,產率44%)。 向乙醇(55 ml)中之奶白色固體(3 72 g,15 96 _ 當量)中添加水合肼(852 μ1,17.56 _〇1,U當量)。使反 應回流24 h,隨後使其冷卻。在減壓下蒸發後,將殘餘物 萃取至DCM中。以水、鹽水洗滌有機層,以硫酸鎮乾燥, 過濾'且在減壓下蒸發’得到呈淺黃色固體狀之3_(3,5-二甲 氧基苯乙基)-m-吼。坐-5_胺(3.76g,經2個步驟為似)。 4舰(瓶132職,麵0)52林2 82 (411,蚧371 (6H,s),4.07-4.72 (2H,m),5.20(1H,s),63i(iH t),638 (2H, d) 〇 MS: m/z 248 (MH+)。 實例1(b)⑴(R)-n-(3_(3,5_二甲氧基笨乙基)_ih_ 〇比唾_s 基)-4-(3,4_二甲基底嗓-1-基)苯甲酿胺的製備 OMe
在饥下將三甲基銘(甲苯中— 140898.doc -34- 201002693 逐滴添加至3-(3,5 - —甲氧基苯乙基比。坐_5_胺(483 mg,1.95 mmol)及(R)-4-(3,4-二曱基哌嗪基)苯曱酸甲酯 (485 mg,1.95 mmol)於甲苯(10 ml)中之懸浮液中。將所得 溶液在60°C下攪拌18小時。將反應混合物傾入甲醇(5〇 m][) 中且以2 Μ鹽酸酸化。藉由離子交換層析法使用scx管柱 純化粗產物。使用7 Μ甲醇氨自管柱溶離所需產物且蒸發 至乾燥’得到不純產物。藉由製備型HPLC(Waters XTeuEi C18官柱’ 5 μ二氧化矽’ 30 mm直徑,loo mm長度),使 用1%氨水與乙腈之漸減極性混合物作為溶離劑純化粗產 物將S有所需化合物之溶離份蒸發至乾燥,得到呈白色 固體狀之(R)-N-(3-(3,5-二曱氧基苯乙基)_1H-吡唑-5-基)-4_ (3,4-二曱基哌嗪_1_基)笨曱醯胺(5611^,62〇/〇)。 H NMR (399.9 MHz, DMSO-d6) δ 1.07 (3Η, d), 2.09-2.14 (1Η, m), 2.18-2.25 (1H, m), 2.22 (3H, s), 2.44-2.53 (1H, m), 2.77-2.87 (2H, m), 2.88 (4H, s), 3.65-3.75 (2H, m), 3-73 (6H, s), 6.34 (1H, t), 6.43 (2H, d), 6.46 (1H, s), 6.96 (2H, d), 7.91 (2H, d), 10.31 (iH, s), 12.09 (1H, s) 〇 MS: m/z 464 (MH+) 〇 (R)-4-(3,4-二曱基哌嗪基)苯曱酸甲酯
在25C下將二乙醢氧基石朋氫化納(us g,7_63 mmol)添 140898.doc •35- 201002693 加至於曱醇(15 ml)中之(尺)_4_(3_甲基哌嗪_丨_基)苯曱酸甲 酉旨(0.715 g ’ 3·05 mmol)、甲醛(4 54 ml 37%水溶液,61 _〇1)及乙酸(0.35如,6.10麵〇1)中。在環境溫度下在氮 氣下攪拌所得溶液18小時❶以飽和NaHC〇3水溶液鹼化反 應混合物且在減壓下濃縮。以Et〇Ac(200 ml)稀釋反應混 合物且依序以飽和NaHC03水溶液(200 ml)洗滌。以
EtOAc(2x75 ml)進一步萃取水相且以水(2〇0 ml)及飽和鹽 水(200 ml)洗滌經合併有機物。經MgS〇4乾燥有機層,過 濾且蒸發’得到粗產物。藉由急驟二氧化矽層析,以 EtOAc/異己烷(極性30:70增加至100:0)溶離來純化粗產 物。將純溶離份蒸發至乾燥,得到呈奶白色固體狀之(R)_ 4-(3,4-二曱基哌嗪-1-基)苯曱酸曱酯(0.600 g,79%)。 !H NMR (399.9 MHz, CDC13) δ 1.14-1.15 (3Η, d), 2.19-2.24 (1Η, m), 2.34 (3H, s), 2.35-2.41 (1H, m), 2.61-2.67 (1H, m), 2.87-2.91 (1H, m), 2.99-3.06 (1H, m), 3.58-3.62 (1H, m), 3.66-3.71 (1H, m), 3.86 (3H, s), 6.84-6.87 (2H, m), 7.89-7.93 (2H, m)。MS: m/z 249 (MH+)。 (R)-4-(3-甲基哌嗪-1-基)苯甲酸甲酯
在25 °C下將4-氟苯甲酸甲酯(0.62 ml,4.79 mmol)添加至 DMA(19 ml)中之(R)-(-)-2-甲基0底嗓(0.96 g,9.58 mmol) -36- 140898.doc 201002693 中。在氮氣下在12(TC下攪拌所得溶液50小時。濃縮反應 混合物且以EtOAc(l〇〇 ml)稀釋,且依序以飽*NaHC〇^Jc 溶液(200 ml)洗滌。以EtOAc(2xl〇〇 ml)進一步萃取水相且 以水(200 ml)及飽和鹽水(200 ml)洗滌經合併有機物。經 Mg SO*乾燥有機層’過濾且蒸發’得到呈棕色固體狀之 (R)-4-(3-甲基哌嗪-1-基)苯甲酸曱酯(0 721 g,64〇/〇)。無進 一步純化直接使用此物質。
'H NMR (399.9 MHz, CDC13) δ 1.14-1.16 (3Η, m), 2.45-2.51 (1H, m), 2.80-2.87 (1H, m), 2.93-3.04 (2H, m), 3.11-3.15 (1H, m), 3.66-3.71 (2H, m), 3.86 (3H, s), 6.84-6.88 (2H,m),7.89-7.93 (2H, m),未觀察到 NH。MS: m/z 235 (MH+)。 實例 l(b)(ii) (R)-N-(3-(3,5-二曱氧基苯乙基)_1Η_η比峻 _5_ 基)-4-(3,4-二曱基哌嗪-1-基)苯甲醯胺的替代製備
使用迪恩-斯達克儀器(Dean-Stark apparatus)將5-(3,5-二 曱氧基苯乙基)-1Η-吡唑-3-胺(159 g ’ 0.643 mol,1當量)及 140898.doc -37· 201002693 (R)-4-(3,4-二甲基哌嗪-1-基)苯甲酸甲酯(191 g,ο.??] mol,1·2當量)於2-甲基四氫呋喃(3500 ml)中之溶液加熱至 回流。移除約300 ml溶劑且使溶液冷卻至7〇。(:。經30分鐘 添加第三戊醇鉀於甲苯中之溶液(25%,1.7 Μ,908 m卜 1·544 mol,2_4當量)。將所得懸浮液加熱至回流且經75 min在迪恩•斯達克條件下移除總計1.5 L溶劑。使懸浮液冷 卻至40°C,且LC展示完全轉化。 小心地添加水(20 ml)及2 Μ鹽酸(380 m卜0.76 mol)(自 40C放熱至50C)。形成深色溶液且以乙酸異丙酯(15〇〇 ml)稀釋此深色溶液。分離水層且以水(5〇〇 ml)及鹽水(5〇〇 ml)洗務有機層。經硫酸鎂乾燥有機層且在真空中在艽 下洛發’留下深色膠狀物。添加乙酸異丙酯(96〇 ml)且在 55 C下將混合物旋轉60 min。膠狀物緩慢溶解且沈澱出白 色固體。將漿料冷卻至0。〇且攪拌丨2〇 min。藉由過濾收集 產物,以冷乙酸異丙酯(2x4〇〇 ml)洗滌且在5〇它下乾燥 分鐘。獲得呈白色固體狀之產物(231 g ’ 78%:^ lH nmr (CDC13)與實例1(b)⑴之資料一致。LC :純度99.5〇/〇。 (R)_4~(3,4-二甲基哌嗪-1-基)苯甲酸甲酯 將(R)_4_(3-甲基哌嗪-1-基)苯甲酸曱酯(218 g,0.93 mol , 1當量)溶解於甲醇(22〇〇 ml,1〇體積)及乙酸(ιιι 7 g,1.86 mol,2當量)中。添加37%甲醛水溶液(88〇爪卜 11 ·74 mol,12.6當量)且沈澱出固體。攪拌混合物,同時 經1小時逐份添加三乙醯氧基硼氫化鈉(493 g爪以, 2.5當量)。溫度保持在3(rc以下。在氮氣下攪拌所得溶液 140898.doc -38- 201002693 隔夜。 在真空中在45°C下移除曱醇,且將殘餘物小心地傾入碳 酸氫鈉飽和溶液(5000 ml)中。在氮氣流下攪拌混合物15分 名里且沈殿出固體。以乙酸異丙酯(2〇〇〇⑹及丨5〇〇如)萃取 產物。以飽和碳酸氫鈉溶液(1000 ml)洗滌經合併有機層且 經硫酸鎂乾燥。在真空中濃縮乙酸異丙酯溶液且產物在低 體積時開始結晶。藉由過濾收集產物且獲得第二批收穫物 (196 g ’ 85°/。)。4 NMR (CDC13)與實例 i(b)(i)之資料一 致。LC :純度 99.5%。 (R)-4-(3·•甲基哌嗪-1-基)苯甲酸甲酯 在 37 C 下撥拌(R)-2-甲基。底嗪(203 g,2.03 mol,1.59當 量)於DMSO( 1200 ml ’ 6體積)中之懸浮液。添加碳酸鉀 (383 g ’ 2.77 mol ’ 2.16當量)且攪拌懸浮液,同時經20分 鐘添加4-氟苯甲酸甲酯(198 g,1.28 mol,1當量)於DMSO (200 ml ’ 1體積)中之溶液《在95°C下攪拌反應混合物24小 時。IPC展示剩餘小於1 %之4-氟苯甲酸甲酯。 將反應混合物冷卻至40°C,以乙酸乙酯(1600 ml)稀釋且 缓慢地傾入水(5000 ml)中。將混合物攪拌5分鐘且使各層 分離。以乙酸乙酯(1600 ml)萃取水層。以水(1200 ml)及鹽 水(1200 ml)洗滌經合併有機層。在真空中移除溶劑,得到 白色固體233 g(78%)。4 NMR (CDC13)與實例 l(b)(i)之資 料一致。LC ··純度98.4%。
XRD-形式A
使用Bruker D4 X射線燒射儀(X射線之波長:1.5418 A 140898.doc -39- 201002693
Cu源,電壓40 kV,燈絲發射40 mA)記錄粉末X射線繞射 圖。使用0.00570°步長及0.03秒之每步長時間計數在2-40° 2Θ範圍内掃描樣品。 在以下各處觀察到峰: 角 Γ2θ(λ=1.5418 A) 相對強度/% 36.269 6.9 26.257 16.3 23.892 44.9 22.793 24 22.766 22.5 22.264 35.2 21.765 28.3 20.753 49.1 20.513 65.2 19.667 41.7 19.628 40.5 19.094 30.9 18.766 47.5 18.011 82 17.935 60.7 17.761 38.7 16.322 27.2 16.179 15.9 16.156 15 15.671 29 14.559 14.2 140898.doc -40- 201002693 角/°2θ(λ=1·5418 A) 相對強度/% 14.086 24 13.078 18.4 11.912 20.3 11.85 19.8 11.388 22.5 10.483 20.4 9.482 15.6 9.062 17.6 7.226 13.2 5.288 100 4.357 10.7 3.642 15 形式A之XRD圖展示於圖1中。 酶檢定 FGFR1激酶檢定-Caliper Echo給藥 為測定FGFR1活性之抑制,使用Caliper技術進行激酶檢 定。 在Greiner 384孔低體積板中進行激酶活性檢定,其t總 反應體積為每孔12 μΐ。各反應孔中FGFR1活性激酶之最終 濃度為7.2 ηΜ。各檢定之底物為具有螢光標記之慣用肽 (長度為1 3個胺基酸,在第一個Κ上具有螢光標記之 KKSRGDYMTMQIG)。 使用Labcyte Echo 550聲學微滴喷射單元將化合物直接 分配至檢定板中。各孔接收120 nl含有化合物之DMSO, 140898.doc -41 - 201002693 使得添加終止溶液之前檢定中化合物之最終濃度範圍介於 3 0 μΜ與3 0 pM之間。除化合物之外,各板攜帶最大及最 小對照孔,最大孔含有120 nl DMSO且最小孔含有120 nl 10 mM星形孢菌素(LC Laboratories, ΜΑ 01801,USA,目 錄號S-93 00)。將酶(7_2 nM [最終])及底物(3.6 μΜ [最終]) 分別添加至化合物板中反應缓衝液[包含:50 mM MOPS (Sigma,目錄號Μ1254)(ρΗ 6·5),0.004% Triton(Sigma, 目錄號Χ-100),2·4 mM DTT,12 mM MgCl2,408 μΜ ATP]中,使得反應混合物中最終DMSO濃度為1%。 在室溫下培育檢定板1.5 h,隨後藉由添加缓衝液[包 含:100 mM HEPES(pH 7.5) > 0.033% Brij-35(Sigma 目錄 號B4184),0.22% Caliper塗布試劑#3(Caliper Life Sciences 目錄號 760050),88 mM EDTA ’ 5% DMSO]終止反應。接 著使用Caliper LabChip® LC3000(其使用微流體學來量測 螢光標記肽與此肽之FGFR1激酶磷酸化形式之間的遷移率 變化)讀取終止之檢定板。 在檢定中,在多種濃度下測試化合物。使用各濃度以及 未經處理對照孔及100%抑制對照孔之平均資料值獲得抑 制對濃度之圖。可根據此資料測定IC5〇值或固定濃度下之 抑制百分比值。 如本文中表示之1 μΜ下之抑制百分比為基於實驗產生之 曲線之擬合曲線的計算值。根據擬合曲線圖,以抑制百分 比形式計算化合物在1 μΜ濃度下之效應。IC5Q為在此檢定 之情形中抑制50%之FGFR1激酶活性的化合物之濃度。使 H0898.doc •42- 201002693 用標準曲線擬合軟體套件〇1^8丨111^計算此值。若化合物經 測試一次以上,則IC5G值可設置為幾何平均值。 實例 la - IC5〇 0.00074 μΜ 實例 lb _ IC5。0.0011 μΜ、0.00064 μΜ、0.00076 μΜ。 FGFR4激酶檢定-Caliper 為測定FGFR4活性之抑制,使用Caliper技術進行激酶檢 定。使用 FGFR4酶(8 μΜ,目錄號 PR4380B,Invitrogen)。 在Greiner 3 84孔低體積板中進行激酶活性檢定,其中總反 應體積為每孔12 μί。各反應孔中FGFR4活性激酶之最終 濃度為25 ηΜ。各檢定之底物為具有螢光標記之慣用肽(長 度為 13個胺基酸,5FAM-EEPLYWSFPAKKK-CONH2),其 序列對FGFR4激酶具有特異性。 在5%(v/v)DMSO中連續稀釋化合物,隨後添加至檢定板 中。將酶(25 ηΜ(最終))及底物(1.5 μΜ(最終))分別添加至 化合物板中反應緩衝液(包含:100 mM HEPES(pH 7.5), 0.004% Triton > 1 mM DTT(最終)、10 mM MnCl2(最終)、 30 μΜ ATP(最終))中,使得反應混合物中最終DMSO濃度 為 0.8%。 在室溫下培育檢定板2 h,隨後藉由添加緩衝液(包含: 100 mM HEPES(pH 7.5) > 0.033% Brij-35 > 0.22% Caliper 塗布試劑#3,40 mM EDTA,5% DMSO)終止反應。接著 使用Caliper LabChip™ LC3000(其使用微流體學來量測螢 光標記肽與此肽之FGFR4激酶磷酸化形式之間的遷移率變 化)讀取終止之檢定板。 140898.doc -43 - 201002693 在檢定中,在多種濃度下測試化合物。使用各濃度以及 未經處理對照孔及100%抑制對照孔之平均資料值獲得抑 制對濃度之圖。可根據此資料測定IC50值或固定濃度下之 抑制百分比值。 實例 lb - IC5。0·022 μΜ、0.016 μΜ、0.016 μΜ。 細胞檢定 細胞FGFR1 (ECHO)-經由使用ECHO技術對暫時表現之 FGFR1 IIIc磷酸化之基於細胞的抑制(使用磷酸特異性一 級抗體及螢光二級抗體進行量測)。 此檢定經設計以藉由使用Array Scan技術伯測的固定細 胞之抗體染色來偵測暫時表現之FGFR1磷酸化的抑制劑。 通常,使Cos-Ι細胞在 DMEM(Gibco BRL,41966)加上 3%胎牛血清(FCS)、1% L-麩胺醯胺(Gibco BRL,25030)中 傳代至80%長滿。為進行檢定,在9〇%_95%長滿時收集 Cos-Ι細胞用於細胞轉染。對於各96孔板,將24 μΐ
Lipofectamine 2000添加至8〇9 μι 〇ptiMEM中且在室溫下培 育5分鐘。對於各96孔板’以〇ptiME]vl將20 jig 3' FLAG標 記之FGFRl/pcDNA3.1(室内純系 15 , MSD 4793)稀釋至 833 μΐ之總體積。合併相等體積之DNA與Lipofectamine 2000 (DNA ·脂質=1:1.2比率)且在室溫下培育2〇分鐘。 使用庫爾特計數器(c〇uher c〇unter)計數所收集cos_i細 胞且以1%?08/0\^以1進一步稀釋至每毫升2.5\105個細 胞。對於各96孔’需要8.33瓜丨細胞。將複合轉染溶液添加 至細胞溶液中且在96孔板(c〇star,39〇4)中在DMEM加上 140898.doc -44 - 201002693 1%胎牛血清、1% L-麩胺醯胺中以每孔2·5 Χίο5個細胞之密 度接種細胞且在37°C (+5% C02)下在濕潤恆溫箱中培育隔 夜(24小時)。 次日,將來自乾重樣品之化合物溶解於1 00% DMSO中 以提供10 mM濃度。將40 μΐ化合物分配至384 Labcyte板 (Labcyte目錄號P-05525)上各象限的孔中(包括陽性對照 (100% DMSO)、陰性對照(10 μΜ)及參考化合物(250 nM))。 接著,將384 Labcyte板轉移至Hydra以按照1:100將化合物 稀釋至象限之剩餘孔中。使用Quadra自檢定板抽吸出70 μΐ 培養基,隨後將板轉移於ECHO 550上。亦將384 Labcyte 化合物板轉移於ECHO 550上。化合物至ECHO 550上之檢 定板的轉移在以下濃度範圍:1)10 μΜ ; 2)3 μΜ ; 3)1 μΜ ; 4)0.3 μΜ ; 5)0.1 μΜ ; 6)0.01 μΜ。 輕輕敲打板以混合化合物與細胞培養基且使其在37°C 5% C02下培育1小時。
使用真空抽吸自孔中移除培養基;藉由添加50 μΐ 100% 甲醇至各孔來固定細胞且在室溫下培育20分鐘。接著移除 固定溶液且以200 μΐ磷酸鹽緩衝生理食鹽水(PBS/A)將扎洗 滌一次,隨後在室溫下藉由添加每孔50 μΐ 0.1% triton/PBS/A 使細胞滲透20分鐘。接著移除滲透溶液且以每孔200 μΐ PBS/A再次洗滌細胞,隨後向各孔中添加40 μΐ 1/1000—級 抗體溶液(Cell Signalling Technologies #CS3476 ;稀釋於具 有 10% FCS+0.1% Tween20 之 PBS/A 中之小鼠抗磷酸 FGFR1)。 在室溫下培育1小時後,移除抗體溶液且以200 μΐ/孔PBS/A 140898.doc • 45- 201002693 洗滌孔一次。接著,添加40 μ1 1/500二級抗體(A1 1005 ; 山羊抗小鼠594)溶液及1/10000 Hoechst(—起稀釋於具有 10% FCS + 0.1% Tween20之PBS/A中)且在黑暗中在室溫下 培育板1小時。最終’以每孔2〇〇 μΐ PBS/A洗滌板一次’在 孔中保留最終洗滌液’隨後將板密封。用Arrayscan (〇611〇111沁3)讀取板。使用自板内未給藥(最大)及參考化合 物(最小)孔獲得之通道2(594 nm)值來設定0%及100%化合 物抑制之邊界。針對此等值正規化化合物資料以測定提供 磷酸化FGFR1之50%抑制的測試化合物之稀釋範圍。實例 lb _ IC5〇<0.01 μΜ、0.0011 μΜ、0.0022 μΜ、0.0048 μΜ ° 細胞FGFR2(ECHO)檢定 經由使用ECHO技術對組成性表現之FGFR2磷酸化之基 於細胞的抑制(使用磷酸特異性一級抗體及螢光二級抗體 進行量測)。 可使用此檢定藉由使用ArrayScan技術偵測的固定細胞 之抗體染色來偵測組成性表現之FGFR2磷酸化的抑制劑。 通常,使SUM52-PE 細胞在 RPMI 1640(Gibco BRL,31870) 加上10%胎牛血清(FCS)、1% L-麩胺醯胺(Gibco BRL, 2503 0)中傳代至70%長滿。使用庫爾特計數器計數所收集 SUM52-PE細胞且以1% FCS/RPMI 1640進一步稀釋至每毫 升1 ·5 X 105個細胞。對於各96孔板,需要1 0 mL細胞。將 1 00 pL細胞懸浮液添加至96孔板(Costar,3904)之各孔 中,且在37°C( + 5% C02)下在濕潤恆溫箱中培育隔夜(24小 時)。次曰,將來自乾重樣品之化合物溶解於100% DMS0 140898.doc -46· 201002693 中以提供100 μΜ濃度。將40 pL化合物溶液分配至3 84 Labcyte板(Labcyte目錄號P-05525)上各象限的孔中(包括陽 性對照(100°/。DMSO)、陰性對照(1〇 μΜ)及參考化合物 (250 ηΜ)-1-第二丁基-3-[2-{[3-(一乙基胺基)丙基]胺基}-6_ (3,5_二曱氧基苯基)-。比咬并[2,3_外密π定_7_基]脲_ pD173〇74 -市售FGFR抑制劑)。接著將384 Labcyte板轉移至Hydra以 按照1:100將化合物稀釋至象限之剩餘孔中。使用Quadra 自檢定板抽吸出70 pL培養基,隨後將板轉移於ECHO 5 50 、 上。亦將384 Labcyte化合物板轉移於ECHO 550上。化合 物至ECHO 550上之檢定板的轉移在以下濃度範圍:(”}〇〇 nM ; (2)33.3 nM ; (3)11.1 nM ; (4)3.70 nM ; (5)1.23 nM ; (6)0.4 1 nM。輕輕敲打板以混合化合物與細胞培養基且使 其在37°C 5% C〇2下培育1小時。使用真空抽吸自孔中移除 培養基;藉由添加50 pL 1 00%曱醇至各孔來固定細胞且在 室溫下培育20分鐘。接著移除固定溶液且以200 gL磷酸鹽 緩衝生理食鹽水(PBS/A)將孔洗滌一次,隨後在室溫下藉 {. 由添加每孔50 0.1% triton/PBS/A使細胞滲透20分鐘。 接著移除滲透溶液且以每孔200 μί PBS/A再次洗滌細胞, • 隨後向各孔中添加40 μΕ 1/1000 —級抗體溶液(Cell
Signalling Technologies #CS3476 ;稀釋於具有 10% FCS+0.1% Tween20之PBS/A中之小鼠抗磷酸FGFR)。在室溫下培育1 小時後,移除抗體溶液且以每孔200 μί PBS/A洗滌孔一 次。接著,添加40 gL 1/5 00二級抗體(All 005 ;山羊抗小 鼠594)溶液及1/10000 Hoechst(—起稀釋於具有10% 140898.doc •47- 201002693 FCS + 0.1% Tween20之PBS/A中)且在黑暗中在室溫下培育 板1小時。最終,以每孔200 pL PBS/A洗滌板一次,在孔 中保留最終洗滌液,隨後將板密封。用Arrayscan(Cellomics) 讀取板。使用自板内未給藥(最大)及參考化合物(最小)孔 獲得之通道2(594 nm)值來設定0%及100%化合物抑制之邊 界。 細胞FGFR3(ECHO)檢定 經由使用ECHO技術對暫時表現之FGFR3 IIIc磷酸化之 基於細胞的抑制(使用磷酸特異性一級抗體及螢光二級抗 體進行量測)。 可使用此檢定,藉由使用ArrayScan技術债測的固定細 胞之抗體染色來偵測暫時表現之FGFR3磷酸化的抑制劑。 通常,使Cos-Ι細胞在 DMEM(Gibco BRL,41966)加上3% 胎牛血清(卩€8)、1%1^-麩胺醯胺(〇丨1^〇8111^,25 03 0)中傳 代至長滿80%。為進行檢定,在長滿90%-95°/〇時收集Cos-1 細胞,用於細胞轉染。對於各96孔板,將24 pL脂染胺 (Lipofectamine)2000添加至 809 pL OptiMEM且在室溫下培 育5分鐘。對於各96孔板,以OptiMEM將20 pg標記3' FLAG之 FGFR3/pcDNA3.2 全長 FGFR3 稀釋至 833 pL之總體 積。合併相等體積之DNA及脂染胺(Lipofectamine)2000 (DNA ··脂質=1·· 1.2比率)且在室溫下培育20分鐘。使用庫 爾特計數器計數所收集Cos-Ι細胞且以1〇/〇 FCS/DMEM進一 步稀釋至每毫升2」xl05個細胞。每96孔需要8.33 mL細 胞。將複合轉染溶液添加至細胞溶液中且在96孔板 140898.doc -48· 201002693 (Costar ’ 3 904)中’在DMEM加上1%胎牛血清、1% l_缝胺 醯胺中,以每孔2· 1 X 104個細胞之密度接種細胞,且在 3 7°C (+5% C〇2)之濕潤恆溫箱中培育隔夜(24小時)。次 曰’將來自乾重樣品之化合物〉谷解於100% DMS0中,以 提供10 mM濃度。將40 pL化合物溶液分配至384 Labcyte 板(Labcyte目錄號P-05525)上各象限的孔中(包括陽性對照 (100% DMSO)、陰性對照(10 μΜ)及參考化合物(25〇 nM): 1-第二丁基-3-[2-{[3-(二乙基胺基)丙基]胺基}_6_(3,5_二甲 氧基本基)-°比π定并[2,3-<i]a密σ定-7-基]脲,pj)i73074,市售 FGFR抑制劑)。接著,將384 Labcyte板轉移至Hydra,按 照1.1 00將化合物稀釋至象限之剩餘孔中。使用Quadra自 檢疋板抽吸出70 pL培養基’隨後將板轉移於ECHO 550 上。亦將384 Labcyte化合物板轉移於ECHO 550上。要移 至ECHO 550上之檢定板的化合物在以下濃度範圍:(ι)1〇 μΜ ; (2)3 μΜ ; (3)1 μΜ ; (4)0.3 μΜ ; (5)0.1 μΜ ;及 (6)0_0 1 μΜ。輕輕敲打板,以混合化合物與細胞培養基, 且使其在37〇C與5% C02下培育1小時。 使用真空抽吸自孔中移除培養基;藉由添加5〇 pL 100% 甲醇至各孔來固定細胞且在室溫下培育2〇分鐘。接著移除 固疋/谷液且以200 pL鱗酸鹽緩衝生理食鹽水(pbs/a)將孔 洗滌一次’隨後在室溫下藉由添加每孔5〇 pL 〇1% triton/PBS/A使細胞滲透20分鐘。接著移除滲透溶液且以 每孔200 PBS/A再次洗滌細胞,隨後向各孔中添加4〇 PL l/iooo -級抗體溶液(CeU SignaUing Techn〇1〇gies 140898.doc -49- 201002693 #CS3476 ;稀釋於具有 10% FCS + 0.1% Tween20之 PBS/A 中 之小鼠抗磷酸FGFR1)。在室溫下培育1小時後,移除抗體 溶液且以每孔200 pL PBS/A洗滌孔一次。接著,添加40 μί 1/500二級抗體(A1 1005 ;山羊抗小鼠594)溶液及 1/10000 Hoechst(—起稀釋於具有 10% FCS + 0.1% Tween20 之PBS/A中)且在黑暗中在室溫下培育板1小時。最終,以 每孔200 pL PBS/A洗滌板一次,在孔中保留最終洗滌液, 隨後將板密封。用Arrayscan(Cellomics)讀取板。使用自板 内未給藥(最大)及參考化合物(最小)孔獲得之通道2(594 nm)值來設定0%及1 00°/。化合物抑制之邊界。針對此等值正 規化化合物資料以測定提供磷酸化FGFR3之50%抑制的測 試化合物之稀釋範圍。 細胞FGFR4(ECHO)檢定 經由使用ECHO技術對暫時表現之FGFR4磷酸化之基於 細胞的抑制(使用磷酸特異性一級抗體及螢光二級抗體進 行量測)。 此檢定經設計以藉由使用Array Scan技術债測的固定細 胞之抗體染色來偵測暫時表現之FGFR4磷酸化的抑制劑。 通常,使Cos-l細胞在DMEM(GibcoBRL,41966)加上30/0 胎牛血清(?08)、1%1-麩胺醯胺(0比〇〇6111^,25 03 0)中傳 代至80%長滿。為進行檢定,在90%-95%長滿時收集Cos-1 細胞用於細胞轉染。對於各96孔板,將24 μι Lipofectamine 2000添加至809 pL OptiMEM中且在室溫下培育5分鐘。對 於各96孔板,以OptiMEM將20 pg 3’ FLAG標記之 140898.doc -50- 201002693 FGFR4/pcDNA3.1(MSD 6273)稀釋至 833 μί 之總體積。合 併相等體積之DNA及Lipofectamine 2000(DNA :脂質= 1:1.2比率)且在室溫下培育20分鐘。 使用庫爾特計數器計數所收集Cos-Ι細胞且以1% FCS/DMEM進一步稀釋至每毫升12χ1〇5個細胞。對於各96 孔’需要8.33 mL細胞。將複合轉染溶液添加至細胞溶液 中且在96孔板(Biocoat # 6640)中在DMEM加上1 %胎牛血 清、1% L-麩胺醯胺中以每孔1〇x 1〇4個細胞之密度接種細 胞且在37 C (+5% C〇2)下在濕潤恆溫箱中培育隔夜(24小 時)。 次曰’將來自乾重樣品之化合物溶解於1 〇〇% DMS0中 以提供10 mM濃度。將40 μί化合物分配至384 Labcyte板 (Labcyte目錄號P-05525)上各象限的孔中(包括陽性對照 (100% DMSO)、陰性對照(10 μΜ)及參考化合物(25〇 ηΜ))。接著,將384 Labcyte板轉移以按照1:1〇〇將 化合物稀釋至象限之剩餘孔中。使用Quacjra自檢定板柚吸 出70 μΐ^培養基’隨後將板轉移於ECHO 550上。亦將384 Labcyte化合物板轉移於ECHO 550上。化合物至ECHO 550 上之檢定板的轉移在以下濃度範圍:(1)1() μΜ ; (2)3 μΜ ; (3)1 μΜ ; (4)0.5 μΜ ; (5)0.1 μΜ ; (6)〇.〇3 μΜ ; (7)0.01 μΜ ; (8)0.001 μΜ。 輕輕敲打板以混合化合物與細胞培養基且使其在37°c 5% C〇2下培育1小時。 使用真空抽吸自孔中移除培養基;藉由添加5〇 1〇〇% 140898.doc -51 - 201002693 甲醇至各孔來固定細胞且在室溫下培育20分鐘。接著移除 固定溶液且以200 pL磷酸鹽缓衝生理食鹽水(PBS/A)將孔 洗滌一次,隨後在室溫下藉由添加每孔50 μί 0.1% triton/PBS/A使細胞渗透20分鐘。接著移除渗透溶液且以 每孔100 μί PBS/A將細胞洗滌4次,隨後向各孔中添加40 μί 1/1000 —級抗體溶液(Cell Signalling Technologies #CS3476 ;稀釋於具有 10% FCS + 0.1% Tween20之 PBS/A 中 之小鼠抗磷酸FGFR1)。在室溫下培育1小時後,移除抗體 溶液且以每孔100 gL PBS/A洗滌孔4次。接著,添加40 pL 1/500二級抗體(A 1 1005 ;山羊抗小鼠594)溶液及1/10000 Hoechst(—起稀釋於具有 10°/。FCS+0.1% Tween20 之 PBS/A 中)且在黑暗中在室溫下培育板1小時。最終,以每孔100 pL PBS/A洗滌板4次,且接著添加每孔200 pL PBS/A,隨 後將板密封。用Arrayscan(Cellomics)讀取板。使用自板内 未給藥(最大)及參考化合物(最小)孔獲得之通道2(594 nm) 值來設定0%及1 00%化合物抑制之邊界。針對此等值正規 化化合物資料以測定提供磷酸化FGFR4之50%抑制的測試 化合物之稀釋範圍。實例lb-IC5〇 0.029 μΜ、0.03 3 μΜ、 0.045 μΜ、0.028 μΜ ° 細胞色素Ρ450抑制檢定 使用根據Crespi(Crespi及 Stresser, J P/zarmaco/ roxz’co/ Mei/zo心2000, 44 : 325-331)改良之自動螢光終點活體外檢 定來分析測試化合物對5種人類細胞色素P450(CYP)同功異 型物(1A2、2C9、2C19、3A4及 2D6)之抑制潛力(IC5〇值)。 I40898.doc -52- 201002693 在此檢定中,將自表現各人類CYP同功異型物的酵母細胞 株製備之微粒體亞細胞部分用作酶源。在NADpH存在 下自夕種香豆素底物向螢光代謝物之生物轉化測定5種 主要人類CYP之活性。此等CYP之抑制使得所形成螢光代 謝物之量降低。比較在不同濃度之測試化合物存在下所觀 察到之螢光與測試化合物不存在下所觀察到之螢光以使得 可計算ICS()值。進行初始實驗以最佳化檢定之動力學參數 且此等麥數已列於表丨中。在磷酸鹽緩衝液(pH 7 4)中製備 各CYP與其各別底物之儲備溶液(參見表υ且將178 y添加 至300 μ1 96孔黑色實心平底微量滴定板(Corning Costar)2 孔中。在DMSO/乙腈中連續稀釋測試化合物且添加(2 μΐ) 至反應物中以提供(Μ μΜ、〇·3 μΜ、丨μΜ、3 μΜ&ι〇 之最終濃度。在37°C下預培育5 min後,藉由添加NADpH (2〇 μ卜濃度展示於表1中)起始反應。各培育之最終溶劑 含置£2%(自測試化合物1%且自底物最大值1%)。各實驗中 包括適當溶劑對照及底物空白以分析對照活性且鑑別歸因 於測試化合物之任何固有螢光。另外,包括各CYp之已知 抑制劑作為陽性對照(關於抑制劑濃度及預期1(:5〇值範圍, 參見表3)。藉由以1〇〇 μ1溶劑(乙腈:〇 5 M THs緩衝液 0.2〇 v/v)中止在限疋時間點(參見表1)終止反應。用螢光 计(Spectrafluor Plus)在適當激發及發射波長(列於表2中)下 吻取板,且將關於對照校正之活性百分比對測試化合物濃 度作圖。接著根據此等圖之斜率測定各CYP2IC5〇值(引起 代谢活性之50%抑制所需的測試化合物之濃度)。 140898.doc •53· 201002693 CYP CYP溶液 (pmol/ 200 μΐ) 底物 底物 (μΜ) 磷酸鹽 緩衝液 ⑽ NADP Η (μΜ) 培育 時間 (min) 1A2 1 3-氰基-7-乙氧基香 豆素(CEC) 3 0.1 250 20 2C9 3 7-甲氧基-4-三氟甲 基-香豆素(MFC) 50 0.025 250 40 2C19 5 7-甲氧基-4-三氟甲 基-香豆素(MFC) 50 0.05 250 60 2D6 3 7-甲氧基-4-(胺基曱 基)-香豆素(MAMC) 20 0.1 60 35 3A4 5 7-苄氧基-4-(三氟甲 基)-香豆素(BFC) 15 0.1 250 35 表1 :檢定試劑之濃度及檢定條件。 140898.doc -54- 201002693 CYP 底物 代謝物 激發 發射 λ(ητη) λ(ηηι) 1A2 3-乳基-7-乙氧基-香旦 3 -氣基-7-經基-香丑素 405 460 素(CEC) (CHC) 2C9 7-曱氧基-4-三氟曱基- 7-羥基-4-三氟甲基-香 405 535 香豆素(MFC) 豆素(HFC) 2C19 7-曱氧基-4-三氟曱基- 7-羥基-4-三氟甲基-香 405 535 香豆素(MFC) 豆素(HFC) 2D6 7-曱氧基-4-(胺基曱 7-羥基-4-(胺基甲基)- 390 460 基)-香豆素(MAMC) 香豆素(HAMC) 3A4 7-苄氧基-4-(三氟曱 7-羥基-4-三氟曱基-香 405 535 基)-香豆素(BFC) 豆素(HFC) 表2 : Spectrafluor Plus螢光計所用以彳貞測螢光代謝物之激 發及發射波長。CEC及HFC係獲自Ultrafine Chemicals ; CHC 係獲自 Molecular Probes ; MFC、MAMC、HAMC 及 BFC係獲自 Gentest Corporation。 140898.doc 55- 201002693 CYP 底物 標準抑制劑濃度之範圍 IC50範圍 _ _ (MM)_ (μΜ) 1A2 3 11伏沙明(Fluvoxamine) 0.01-0.07 卜 0.3、0.1、0.03、0.01 2C9 50 石黃胺苯°比唾(Sulphaphenazole) 0.1-1.0 10、3、1、0·3、0.1 2C19 50 奥美拉唾(Omeprazole) 1.5-4.6 10'3 ' 1 Ό.3 ' 0.1 2D6 20 奎尼定(Quinidine) 0.003-0.03 0.1 ' 0.03 ' 0.01 ' 0.003、0.001 3A4 15 酮康0坐(Ketoconazole) 0.005-0.015 0.25 ' 0.075 ' 0.025 ' 0.0075 ' 0.0025 表3 : 5種人類CYP同功異型物之各者的已知抑制劑及最佳 化實驗條件。氟伏沙明係獲自Tocris Cookson Ltd ;續胺苯 0比0坐及奎尼定係獲自Sigma ;奥美拉α坐係獲自AstraZeneca ; 酮康嗤係獲自 Ultrafine Chemicals。 結果
Ic50 1A2 Ic50 2C9 Ic50 2C19 Ic50 2D6 Ic50 3A4 實例la >10 3.76 >10 >10 2.94 實例lb >10 9.12 8.01 >10 >10 結論:本發明之對映異構體化合物在展示良好FGFR抑制 的同時亦展示其細胞色素P 4 5 0抑制之差異。低的細胞色素 P45 0抑制為改善潛在藥物:藥物相互作用所需。 140898.doc -56- 201002693 物理特性測試及方法 蛋白質結合 藉由平衡透析測定蛋白質結合。在37°C之溫度下將20 μΜ濃度之化合物針對10%血漿透析18 h。使用通用HPLC-UV方法聯同質譜峰鑑別分析所得樣品。所報導K1值為第 一表觀締合常數[蛋白質配位體]/([蛋白質][配位體]),所有 濃度均以莫耳/公升計進行量測(J. Med. Chem·,2006, 49(23), 6672-6682) ° < 可在高產量篩檢中藉由平衡透析與液相層析及質譜分析 量測蛋白質結合(Wan, Η.及Rehngren, Μ·, J. Chromatogr, A 2006, 1 102,125-134)。 實例la : 0.91%游離(大鼠) 實例lb : 0.62%游離(大鼠) 實例la : 3.72%游離(人類) 實例lb : 2.79%游離(人類) 結論:蛋白質結合降低指示存在更多游離藥物(未結合)。 {j 此可為有利的,因為可能存在更多可用以作用於標靶位點 處之藥物。 清除率: 對於0.927 mg/kg(2 μηιοΐ/kg)之大鼠劑量,將化合物以1 μιηοΐ/ml 調配於 20% DMA:80% 索倫森緩衝液(sorensens buffer)(pH 5)中。將各調配物給與(2 mL/kg)四隻自由取用 食物之雄性大鼠(250-300 g)。經由尾靜脈在給藥後5分鐘 及20分鐘以及1小時及4小時時自2隻大鼠取血樣,且在給 140898.doc -57- 201002693 藥後1 〇分鐘及40分鐘以及2小時及6小時時自其他2隻大鼠 取血樣。在12小時時自第一對大鼠取最終樣品且在24小時 時自第二對大鼠取最終樣品。分析前以水1:1稀釋血樣。 對於0.927 mg/kg(2 μιηοΐ/kg)之犬劑量,將化合物以以2 μηιοΐ/ml調配於索倫森緩衝液(pH 5)中之10% DMSO:90%羥 基-丙基-β-環糊精(25 w/v%)中。將各調配物給與(1 mL/kg) 已禁食隔夜之雄性及雌性犬(8-15 kg)。經由頸靜脈在給藥 後5分鐘、1 0分鐘、20分鐘及40分鐘以及1小時、2小時、4 小時、6小時、12小時及24小時時取血樣。分析前以水1:1 稀釋血樣。 藉由空白基質(1:1血液:水)加料,製備涵蓋濃度範圍 (0.001 μιηοΙ/L至10 μιηοΙ/L)之一組10個校準標準。使用固 相萃取板萃取樣品及標準、在氮氣下吹掃且隨後在曱醇: 水(20:80)中重構。使用LC-MSMS分析樣品且使用所獲得 結果測定各化合物之0時刻至無限時刻之曲線下面積 [AUCO-inf(gg,hr/ml)]、清除率[Cl(ml/min/kg)]及穩態體積 分布[Vss(L/kg)]。 雄性大鼠之資料 實例 劑量 Cl Vss AUC O-inf mg/kg (ml/min/kg) (L/Ks) (pg-hr/ml) la 0.927 60.9 2.58 0.254 lb 0.927 32.7 1.74 0.473 140898.doc -58- 201002693 雄性犬之資料 實例 劑量 Cl Vss AUC 0-inf mg/kg (ml/min/kg) (L/Kg) pg.hr/ml la 0.927 26.4 3.71 0.585 lb 0.927 12.5 6.55 1.24 雌性犬之資料 實例 劑量 Cl Vss AUC 0-inf mg/kg (ml/min/kg) (L/Kg) pg-hr/ml la 0.927 36.2 7.08 0.427 lb 0.927 11.5 1.71 1.35 結論:清除率降低指示藥物保留較長時間。此可為有利 的,因為有可能由較小藥物劑量達成且維持功效所需之藥 物暴露水準。 【圖式簡單說明】 圖1為形式A之XRD圖。 140898.doc -59-
Claims (1)
- 201002693 七、申請專利範圍: 1. 一種式(la)或(lb)之化合物:(lb) 或其醫藥學上可接受之鹽。 2.如請求項1之化合物,其中該化合物為式(lb)化合物:3. 4. 如請求項2之式(lb)化合物,或其醫藥學上可接受之鹽, 其係用作藥物。 一種如請求項2之式(lb)化合物或醫藥學上可接受之鹽的 用途,其係用於製造用於療法中的藥物。 一種如請求項2之如本文所定義的式(lb)化合物或其醫藥 140898.doc 201002693 學上可接受之鹽的用途, 之藥物:黑素瘤、乳頭狀;造:於治療以下疾病 印巢癌、肺癌、白血病、:腺瘤、膽管癌、結腸癌、 瘤,肝、腎、膀胱、***巴疾病、多發性骨髓 瘤,及皮膚、結腸、甲狀腹房及姨腺中之癌瘤及肉 性實體腫瘤。 #及卵巢之原發性及復發 6. -種用於在需要治療的諸如 抑制作用之方法,其包…咖血動物中產生· 項^ 、 亥動物投與有效量之如請求 7. 之式⑽化合物或其醫藥學上可接受之趟。 -種用於在需要治療的諸: 8. 作用之方法,其包括向動物中產生抗癌 .'"動物投與有效量之如請求項2 之式(lb)化合物或其醫藥學上可接受之鹽。 -種醫藥組合物,其包含如請求項2之如本文令所定義 的式(lb)化合物或其醫筚 褚老予上可接受之鹽與醫藥學上可 接又之佐劑、稀釋劑或載劑。 9. 方法為Γ:二療的諸如人類之溫血動物治療以下疾病的 巢声.肺、Γ頭狀甲狀腺瘤、膽管癌、結腸癌、印 肝、腎、膀胱、***、乳;、多發性骨趙瘤, m 4房及胰腺中之癌瘤及肉瘤, -腫:甲狀腺、肺及卵巢之原發性及復發性實 :瘤、、包括向該動物投與有效量之如請求項2之如 踏文中所疋我的式(Ib)化合物4其醫藥學i可接受之 鹽0 爪如凊求項8之醫藥組合物,其中該式⑽化合物呈結晶形 140898.doc 201002693 式。 11.如請求項8之醫藥組合物,其中該式(lb)化合物呈結晶 式5稱為形式A。 ( L 140898.doc
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EA (1) | EA201100030A1 (zh) |
EC (1) | ECSP10010693A (zh) |
IL (1) | IL210082A0 (zh) |
MX (1) | MX2010014234A (zh) |
PE (1) | PE20110062A1 (zh) |
SV (1) | SV2010003767A (zh) |
TW (1) | TW201002693A (zh) |
UY (1) | UY31918A (zh) |
WO (1) | WO2009153592A1 (zh) |
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2009
- 2009-06-17 BR BRPI0914233A patent/BRPI0914233A2/pt not_active Application Discontinuation
- 2009-06-17 WO PCT/GB2009/050684 patent/WO2009153592A1/en active Application Filing
- 2009-06-17 EP EP09766153A patent/EP2328872A1/en not_active Withdrawn
- 2009-06-17 MX MX2010014234A patent/MX2010014234A/es not_active Application Discontinuation
- 2009-06-17 KR KR1020117000437A patent/KR20110020904A/ko not_active Application Discontinuation
- 2009-06-17 JP JP2011514127A patent/JP2011524888A/ja active Pending
- 2009-06-17 EA EA201100030A patent/EA201100030A1/ru unknown
- 2009-06-17 CA CA2728063A patent/CA2728063A1/en not_active Abandoned
- 2009-06-17 PE PE2010001161A patent/PE20110062A1/es not_active Application Discontinuation
- 2009-06-17 CN CN2009801328063A patent/CN102123989A/zh active Pending
- 2009-06-17 AU AU2009261683A patent/AU2009261683A1/en not_active Abandoned
- 2009-06-18 UY UY0001031918A patent/UY31918A/es not_active Application Discontinuation
- 2009-06-18 TW TW098120493A patent/TW201002693A/zh unknown
- 2009-06-19 AR ARP090102262A patent/AR072261A1/es unknown
- 2009-06-19 US US12/487,838 patent/US20090318468A1/en not_active Abandoned
-
2010
- 2010-12-16 IL IL210082A patent/IL210082A0/en unknown
- 2010-12-17 SV SV2010003767A patent/SV2010003767A/es not_active Application Discontinuation
- 2010-12-17 CL CL2010001470A patent/CL2010001470A1/es unknown
- 2010-12-17 EC EC2010010693A patent/ECSP10010693A/es unknown
- 2010-12-17 CR CR11857A patent/CR11857A/es not_active Application Discontinuation
- 2010-12-17 DO DO2010000387A patent/DOP2010000387A/es unknown
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2011
- 2011-01-18 ZA ZA2011/00471A patent/ZA201100471B/en unknown
- 2011-01-19 CO CO11005446A patent/CO6351726A2/es not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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IL210082A0 (en) | 2011-02-28 |
PE20110062A1 (es) | 2011-03-09 |
WO2009153592A1 (en) | 2009-12-23 |
BRPI0914233A2 (pt) | 2015-11-03 |
EP2328872A1 (en) | 2011-06-08 |
AR072261A1 (es) | 2010-08-18 |
KR20110020904A (ko) | 2011-03-03 |
ZA201100471B (en) | 2012-06-27 |
EA201100030A1 (ru) | 2011-08-30 |
AU2009261683A1 (en) | 2009-12-23 |
SV2010003767A (es) | 2011-05-20 |
UY31918A (es) | 2010-01-29 |
CR11857A (es) | 2011-02-25 |
JP2011524888A (ja) | 2011-09-08 |
CO6351726A2 (es) | 2011-12-20 |
US20090318468A1 (en) | 2009-12-24 |
CA2728063A1 (en) | 2009-12-23 |
DOP2010000387A (es) | 2012-09-30 |
MX2010014234A (es) | 2011-03-25 |
ECSP10010693A (es) | 2011-01-31 |
CL2010001470A1 (es) | 2011-05-06 |
CN102123989A (zh) | 2011-07-13 |
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