TW202416974A - Extracellular hsp90 (ehsp90)-targeted radiopharmaceuticals and use thereof - Google Patents
Extracellular hsp90 (ehsp90)-targeted radiopharmaceuticals and use thereof Download PDFInfo
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- TW202416974A TW202416974A TW112132347A TW112132347A TW202416974A TW 202416974 A TW202416974 A TW 202416974A TW 112132347 A TW112132347 A TW 112132347A TW 112132347 A TW112132347 A TW 112132347A TW 202416974 A TW202416974 A TW 202416974A
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- 101100285708 Dictyostelium discoideum hspD gene Proteins 0.000 title 1
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Abstract
Description
熱休克蛋白90 (HSP90)係一種分子伴護蛋白,其調節蛋白質折疊以確保正確之構象及易位並避免蛋白質聚集。許多致癌蛋白為HSP90客戶蛋白,諸如表皮生長因子受體(EGFR)突變體、週期蛋白依賴性激酶4 (CDK4)、缺氧誘導因子(HIF)-1α及基質金屬肽酶2 (MMP2)。Heat shock protein 90 (HSP90) is a molecular chaperone that regulates protein folding to ensure correct conformation and translocation and to prevent protein aggregation. Many oncogenic proteins are HSP90 client proteins, such as epidermal growth factor receptor (EGFR) mutants, CDK4, hypoxia-induced factor (HIF)-1α, and matrix metallopeptidase 2 (MMP2).
於許多細胞類型之表面處鑑別HSP90之一部分,即細胞外HSP90 (eHSP90),其可為適用於引起宿主免疫反應之腫瘤抗原。研究顯示eHSP90在維持致癌蛋白穩態中發揮關鍵作用且參與各種癌症(包括乳癌)之侵入及轉移過程,此使得eHSP90成為開發癌症療法之有吸引力標靶。A portion of HSP90, extracellular HSP90 (eHSP90), is identified on the surface of many cell types and may be a tumor antigen useful for eliciting a host immune response. Studies have shown that eHSP90 plays a key role in maintaining oncogenic protein homeostasis and is involved in the invasion and metastasis of various cancers, including breast cancer, making eHSP90 an attractive target for the development of cancer therapeutics.
已顯示HSP90抑制對細胞週期及DNA修復機制有顯著之直接影響,因此在治療範圍廣泛之實體及血液系統惡性腫瘤中提供極大前景。然而,早期臨床試驗已證實,某些HSP90抑制劑顯示有限之效用及各種副作用。HSP90 inhibition has been shown to have significant direct effects on cell cycle and DNA repair mechanisms, thus offering great promise in the treatment of a wide range of solid and hematologic malignancies. However, early clinical trials have demonstrated that some HSP90 inhibitors show limited efficacy and various side effects.
因此,需要藉由標靶某些蛋白質(例如,eHSP90)以良好之效用及可接受之安全性概況改善癌症之治療。Therefore, there is a need to improve the treatment of cancer by targeting certain proteins (eg, eHSP90) with good efficacy and an acceptable safety profile.
本發明包含以下見解:包含特異性結合至HSP90,特定言之eHSP90之標靶部分之某些放射性藥物可有效作為用於治療癌症之HSP90放射性配體療法(RLT)。放射性衰變可對組成細胞之生物分子造成直接物理損傷(諸如單股或雙股DNA斷裂)或間接損傷(諸如旁觀者或交叉火力效應(crossfire effect))。將放射性核素遞送至癌細胞之藥物(即放射性藥物)提供一種產生具有抗癌治療效應之DNA損傷的機制。本發明提供某些放射性藥物,具體言之,標靶HSP90過表現腫瘤及使用錒-225 ( 225Ac)、鎦-177 ( 177Lu)或其他合適之治療性放射性核素來標靶癌細胞以治療或改善癌症(諸如肺癌、肉瘤、胰臟癌、乳癌或結腸癌)之基於小分子之放射性藥物。 The present invention includes the following insights: Certain radiopharmaceuticals that include a targeting moiety that specifically binds to HSP90, in particular eHSP90, can be effective as HSP90 radioligand therapy (RLT) for the treatment of cancer. Radioactive decay can cause direct physical damage (such as single-strand or double-strand DNA breaks) or indirect damage (such as bystander or crossfire effects) to biological molecules that make up cells. Drugs that deliver radionuclides to cancer cells (i.e., radiopharmaceuticals) provide a mechanism for producing DNA damage that has anti-cancer therapeutic effects. The present invention provides certain radiopharmaceuticals, specifically, small molecule-based radiopharmaceuticals that target HSP90 overexpressing tumors and use tantalum-225 ( 225 Ac), tantalum-177 ( 177 Lu) or other suitable therapeutic radionuclides to target cancer cells to treat or ameliorate cancer (such as lung cancer, sarcoma, pancreatic cancer, breast cancer or colon cancer).
在一項態樣中,本發明提供式I化合物或其醫藥上可接受之鹽: (I), 其中 X係不存在、C=O或(C=O)NR 1,R 1係H、烷基、芳基、(C-CF 3)R 2或(SO 2)R 2,R 2係烷基或芳基; Y各獨立地係O或NR 3,R 3係H、烷基、芳基或醯基; n係0至5 (含)之整數; Z 1及Z 2各獨立地係不存在、胺基酸單元、(C=O)NR 4(CH 2CH 2)O或(C=O)NR 4(CH 2CH 2)NR 5,其中R 4及R 5中之各者獨立地係H或烷基或(C-CF 3)R 6或(SO 2)R 6,R 6係烷基或芳基;及 W係選自由以下組成之群之螯合劑:DOTA、DOTAGA、NOTA及NODAGA,各均如下文實施方式部分中定義, 其中當W係DOTA時,Z 1及Z 2中之至少一者係胺基酸單元,或Z 1及Z 2中之各者係不存在且n係等於或小於4;其中該化合物與HSP90結合;且其中該化合物視需要進一步包含由該螯合劑螯合之放射性核素。 In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof: (I), wherein X is absent, C=O or (C=O)NR 1 , R 1 is H, alkyl, aryl, (C-CF 3 )R 2 or (SO 2 )R 2 , R 2 is alkyl or aryl; Y is independently O or NR 3 , R 3 is H, alkyl, aryl or acyl; n is an integer from 0 to 5 (inclusive); Z 1 and Z 2 are independently absent, an amino acid unit, (C=O)NR 4 (CH 2 CH 2 )O or (C=O)NR 4 (CH 2 CH 2 )NR 5 , wherein each of R 4 and R 5 is independently H or alkyl or (C-CF 3 )R 6 or (SO 2 )R 6 , R Z1 and Z2 are alkyl or aryl groups; and W is a chelating agent selected from the group consisting of DOTA, DOTAGA, NOTA and NODAGA, each as defined in the embodiment section below, wherein when W is DOTA, at least one of Z1 and Z2 is an amino acid unit, or each of Z1 and Z2 is absent and n is equal to or less than 4; wherein the compound binds to HSP90; and wherein the compound further comprises a radionuclide chelated by the chelating agent as needed.
在一些實施例中,本發明之化合物特異性結合至細胞外HSP90 (eHSP90)。In some embodiments, the compounds of the present invention specifically bind to extracellular HSP90 (eHSP90).
在一些實施例中,本發明之化合物具有式II結構: (II), 其中X、Y、n、Z 1及Z 2中之各者係如上文定義。 In some embodiments, the compounds of the present invention have a structure of Formula II: (II), wherein each of X, Y, n, Z1 and Z2 is as defined above.
在一些實施例中,式I或式II化合物之特徵在於Z 1及Z 2中之至少一者係胺基酸單元。 In some embodiments, the compound of Formula I or Formula II is characterized in that at least one of Z 1 and Z 2 is an amino acid unit.
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元係由以下形成:甘胺酸(Gly)、天冬胺酸(Asp)、麩胺酸(Glu)、2,4-二胺基丁酸(Dab)、2,3-二胺基丙酸(Dap)、離胺酸(Lys)或精胺酸(Arg)。In some embodiments, the compound of Formula I or Formula II is characterized in that the amino acid unit is formed by glycine (Gly), aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys) or arginine (Arg).
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元係由以下形成:甘胺酸(Gly)、天冬胺酸(Asp)、麩胺酸(Glu)、2,4-二胺基丁酸(Dab)、2,3-二胺基丙酸(Dap)、離胺酸(Lys)、精胺酸(Arg),或其組合。In some embodiments, the compound of Formula I or Formula II is characterized in that the amino acid unit is formed by glycine (Gly), aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys), arginine (Arg), or a combination thereof.
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元包含由Asp形成之有機部分。In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit comprises an organic moiety formed from Asp.
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元係由Gly形成。In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by Gly.
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元係由Glu形成。In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by Glu.
在一些實施例中,式I或式II化合物之特徵在於X係不存在。In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent.
在一些實施例中,式I或式II化合物之特徵在於X係C=O。In some embodiments, the compound of formula I or formula II is characterized in that X is C═O.
在一些實施例中,式I或式II化合物之特徵在於X係(C=O)NR 1,其中R 1係H、烷基或芳基。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NR 1 , wherein R 1 is H, alkyl or aryl.
在一些實施例中,式I或式II化合物之特徵在於X係(C=O)NH。In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NH.
在一些實施例中,式I或式II化合物之特徵在於n係0。In some embodiments, the compound of formula I or formula II is characterized in that n is 0.
在一些實施例中,式I或式II化合物之特徵在於n係1、2或3。In some embodiments, the compound of Formula I or Formula II is characterized in that n is 1, 2 or 3.
在一些實施例中,式I或式II化合物之特徵在於n係4或5。In some embodiments, the compound of Formula I or Formula II is characterized in that n is 4 or 5.
在一些實施例中,式I或式II化合物之特徵在於n係4。In some embodiments, the compound of Formula I or Formula II is characterized in that n is 4.
在一些實施例中,式I或式II化合物之特徵在於n係5。In some embodiments, the compound of formula I or formula II is characterized in that n is 5.
在一些實施例中,式I或式II化合物之特徵在於Y各獨立地係O、NH或N(C 1-6烷基)。在一些實施例中,該式I或式II化合物之特徵在於Y各獨立地係O。在一些實施例中,該式I或式II化合物之特徵在於Y各獨立地係NH。 In some embodiments, the compound of formula I or formula II is characterized in that each Y is independently O, NH or N(C 1-6 alkyl). In some embodiments, the compound of formula I or formula II is characterized in that each Y is independently O. In some embodiments, the compound of formula I or formula II is characterized in that each Y is independently NH.
在一些實施例中,式I或式II化合物之特徵在於Z 1及Z 2中之各者係不存在。 In some embodiments, the compound of Formula I or Formula II is characterized in that each of Z 1 and Z 2 is absent.
在一些實施例中,式I或式II化合物之特徵在於Z 1係不存在。 In some embodiments, the compound of formula I or formula II is characterized in that Z 1 is absent.
在一些實施例中,式I或式II化合物之特徵在於Z 2係不存在。 In some embodiments, the compound of Formula I or Formula II is characterized in that Z 2 is absent.
在一些實施例中,式I或式II化合物之特徵在於Z 1係胺基酸單元。 In some embodiments, the compound of formula I or formula II is characterized in that Z 1 is an amino acid unit.
在一些實施例中,式I或式II化合物之特徵在於Z 2係胺基酸單元。 In some embodiments, the compound of formula I or formula II is characterized in that Z 2 is an amino acid unit.
在一些實施例中,式I或式II化合物之特徵在於Z 1係(C=O)NH(CH 2CH 2)NH。在一些實施例中,該式I或式II化合物之特徵在於Z 2係(C=O)NH(CH 2CH 2)NH。 In some embodiments, the compound of formula I or formula II is characterized in that Z 1 is (C=O)NH(CH 2 CH 2 )NH. In some embodiments, the compound of formula I or formula II is characterized in that Z 2 is (C=O)NH(CH 2 CH 2 )NH.
在一些實施例中,式I或式II化合物之特徵在於Z 1係(C=O)NH(CH 2CH 2)N(C 1-6烷基)。在一些實施例中,該式I或式II化合物之特徵在於Z 2係(C=O)NH(CH 2CH 2)N(C 1-6烷基)。 In some embodiments, the compound of formula I or formula II is characterized in that Z 1 is (C=O)NH(CH 2 CH 2 )N(C 1-6 alkyl). In some embodiments, the compound of formula I or formula II is characterized in that Z 2 is (C=O)NH(CH 2 CH 2 )N(C 1-6 alkyl).
在一些實施例中,式I或式II化合物之特徵在於Z 1係(C=O)N(C 1-6烷基)(CH 2CH 2)NH。在一些實施例中,該式I或式II化合物之特徵在於Z 2係(C=O)N(C 1-6烷基)(CH 2CH 2)NH。 In some embodiments, the compound of formula I or formula II is characterized in that Z 1 is (C=O)N(C 1-6 alkyl)(CH 2 CH 2 )NH. In some embodiments, the compound of formula I or formula II is characterized in that Z 2 is (C=O)N(C 1-6 alkyl)(CH 2 CH 2 )NH.
在一些實施例中,式I或式II化合物之特徵在於Z 1係(C=O)N(C 1-6烷基)(CH 2CH 2)N(C 1-6烷基)。在一些實施例中,該式I或式II化合物之特徵在於Z 2係(C=O)N(C 1-6烷基)(CH 2CH 2)N(C 1-6烷基)。 In some embodiments, the compound of formula I or formula II is characterized in that Z 1 is (C=O)N(C 1-6 alkyl)(CH 2 CH 2 )N(C 1-6 alkyl). In some embodiments, the compound of formula I or formula II is characterized in that Z 2 is (C=O)N(C 1-6 alkyl)(CH 2 CH 2 )N(C 1-6 alkyl).
在一些實施例中,式I或式II化合物之特徵在於X係不存在,n係0,Z 1係不存在,及Z 2係胺基酸單元。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, Z 1 is absent, and Z 2 is an amino acid unit.
在一些實施例中,式I或式II化合物之特徵在於X係C=O,n係4或5,Z 1係胺基酸單元,及Z 2係不存在。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z 1 is an amino acid unit, and Z 2 is absent.
在一些實施例中,式I或式II化合物之特徵在於X係C=O,n係4或5,Z 1係不存在,及Z 2係胺基酸單元。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z 1 is absent, and Z 2 is an amino acid unit.
在一些實施例中,胺基酸單元係選自由以下組成之群: 、 、 、 、 、 、 及 。 In some embodiments, the amino acid unit is selected from the group consisting of: , , , , , , and .
在一些實施例中,式I或式II化合物之特徵在於X係(C=O)NH,n係4或5,Z 1及Z 2中之各者係不存在。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NH, n is 4 or 5, and each of Z1 and Z2 is absent.
在一些實施例中,式I或式II化合物之特徵在於X係C=O,n係4或5,Z 1係不存在,及Z 2係(C=O)NH(CH 2CH 2)NH。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z 1 is absent, and Z 2 is (C=O)NH(CH 2 CH 2 )NH.
在一些實施例中,式I或式II化合物之特徵在於X係不存在,n係0,Z 1及Z 2中之各者係不存在。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, and each of Z1 and Z2 is absent.
在一些實施例中,式I或式II化合物係選自由以下組成之群: 、 、 、 、 、 、 、 、 、 、 、 及 。 In some embodiments, the compound of Formula I or Formula II is selected from the group consisting of: , , , , , , , , , , , and .
在一些實施例中,式I或式II化合物之特徵在於各化合物包含選自由以下組成之群之放射性核素: 43Sc、 44Sc、 47Sc、 55Co、 60Cu、 61Cu、 62Cu、 64Cu、 67Cu、 66Ga、 67Ga、 68Ga、 82Rb、 86Y、 87Y、 89Zr、 90Y、 97Ru、 99Tc、 99mTc、 105Rh、 109Pd、 111In、 117mSn、 133La、 134Ce、 149Pm、 149Tb、 153Sm、 152Tb、 155Tb、 161Tb、 166Ho、 177Lu、 186Re、 188Re、 198Au、 199Au、 201Tl、 203Pb、 211At、 212Pb、 212Bi、 213Bi、 223Ra、 225Ac、 227Th及 229Th。 In some embodiments, the compound of formula I or formula II is characterized in that each compound comprises a radionuclide selected from the group consisting of: 43 Sc, 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 90 Y, 97 Ru, 99 Tc, 99m Tc, 105 Rh, 109 Pd, 111 In, 117m Sn, 133 La, 134 Ce, 149 Pm, 149 Tb, 153 Sm, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 201 Tl, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th and 229 Th.
在某些實施例中,放射性核素係選自由以下組成之群: 68Ga、 89Zr、 90Y、 111In、 177Lu及 225Ac。 In certain embodiments, the radionuclide is selected from the group consisting of 68 Ga, 89 Zr, 90 Y, 111 In, 177 Lu, and 225 Ac.
在某些實施例中,放射性核素係 177Lu或 225Ac。 In certain embodiments, the radionuclide is 177 Lu or 225 Ac.
在某些實施例中,放射性核素係 177Lu。 In certain embodiments, the radionuclide is 177 Lu.
在某些實施例中,放射性核素係 225Ac。 In certain embodiments, the radionuclide is 225 Ac.
在另一態樣中,本發明亦涵蓋一種包含上文闡述之化合物中之一者及醫藥上可接受之賦形劑之醫藥組合物。In another aspect, the present invention also encompasses a pharmaceutical composition comprising one of the compounds described above and a pharmaceutically acceptable excipient.
仍於本發明之範圍內的係一種治療癌症之方法,該方法包括對有需要之個體投與上文闡述之化合物中之一者或上文描述之醫藥組合物。Still within the scope of the present invention is a method of treating cancer comprising administering to a subject in need thereof one of the compounds described above or the pharmaceutical composition described above.
在一些實施例中,治療癌症之方法包括以對放射治療計劃有效之量對有需要之個體投與第一劑量之上文描述之化合物或組合物中之一者,接著以治療有效量投與後續劑量之上文描述之化合物或組合物中之一者。In some embodiments, a method of treating cancer comprises administering to a subject in need thereof a first dose of one of the compounds or compositions described above in an amount effective for a radiation therapy program, followed by administering a subsequent dose of one of the compounds or compositions described above in a therapeutically effective amount.
在一些實施例中,癌症係小細胞肺癌、非小細胞肺癌、肉瘤、胰臟癌、乳癌或結腸癌。In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.
相關申請案Related applications
本申請案主張2022年8月26日申請之美國臨時申請案第63/401,227號之優先權,該案之全部內容係出於所有目的以引用之方式併入本文中。This application claims priority to U.S. Provisional Application No. 63/401,227 filed on August 26, 2022, the entire contents of which are incorporated herein by reference for all purposes.
本發明係關於包含特異性結合至HSP90,特定言之細胞外HSP90 (eHSP90)之標靶部分之放射性藥物化合物。The present invention relates to radiopharmaceutical compounds comprising a targeting moiety that specifically binds to HSP90, in particular extracellular HSP90 (eHSP90).
經放射性標記之標靶分子(亦稱為放射性藥物)係經設計以標靶在疾病狀態下經上調及/或病變細胞(例如,腫瘤細胞)特有的蛋白質或受體(例如,eHSP90),以遞送放射性有效載荷來損傷並殺死受關注之細胞。本發明中提供之標靶eHSP90之放射性藥物可用於治療各種癌症,包括(但不限於)小細胞肺癌、非小細胞肺癌、肉瘤、胰臟癌、乳癌及結腸癌。 定義 化學術語 Radiolabeled targeting molecules (also called radiopharmaceuticals) are designed to target proteins or receptors (e.g., eHSP90) that are upregulated and/or diseased cells (e.g., tumor cells) in disease states to deliver a radioactive payload to damage and kill the cells of interest. The radiopharmaceuticals provided in the present invention that target eHSP90 can be used to treat various cancers, including (but not limited to) small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, and colon cancer. Definitions Chemical Terms
除非另有規定,否則如本文使用,術語「烷基」包括1至20個碳(例如,1至10或1至6)之直鏈及分支鏈飽和基團兩者。烷基係由以下例示:甲基、乙基、正及異丙基、正、第二、異及第三丁基、新戊基,及類似物,且可視需要經一、二、三個或(在兩個碳或更多個之烷基之情況下)四個獨立地選自由以下組成之群之取代基取代:(1) C 1-6烷氧基;(2) C 1-6烷基亞磺醯基;(3)胺基,如本文定義(例如,未經取代之胺基(即-NH 2)或經取代之胺基(即-N(R N1) 2,其中R N1係如針對胺基定義);(4) C 6-10芳基-C 1-6烷氧基;(5)疊氮基;(6)鹵基;(7) (C 2-9雜環基)氧基;(8)羥基,視需要經O保護基取代;(9)硝基;(10)側氧基(例如,羧基醛或醯基);(11) C 1-7螺環基;(12)硫烷氧基;(13)硫醇;(14) -CO 2R A’,視需要經O保護基取代且其中R A’係選自由以下組成之群:(a) C 1-20烷基(例如,C 1-6烷基)、(b) C 2-20烯基(例如,C 2-6烯基)、(c) C 6-10芳基、(d)氫、(e) C 1-6烷-C 6-10芳基、(f)胺基-C 1-20烷基、(g) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;(15) -C(O)NR B’R C’,其中R B’及R C’中之各者係獨立地選自由以下組成之群:(a)氫、(b) C 1-6烷基、(c) C 6-10芳基,及(d) C 1-6烷-C 6-10芳基;(16) -SO 2R D’,其中R D’係選自由以下組成之群:(a) C 1-6烷基、(b) C 6-10芳基、(c) C 1-6烷-C 6-10芳基,及(d)羥基;(17) -SO 2NR E’R F’,其中R E’及R F’中之各者係獨立地選自由以下組成之群:(a)氫、(b) C 1-6烷基、(c) C 6-10芳基及(d) C 1-6烷-C 6-10芳基;(18) -C(O)R G’,其中R G’係選自由以下組成之群:(a) C 1-20烷基(例如,C 1-6烷基)、(b) C 2-20烯基(例如,C 2-6烯基)、(c) C 6-10芳基、(d)氫、(e) C 1-6烷-C 6-10芳基、(f)胺基-C 1-20烷基、(g) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;(19) -NR H’C(O)R I’,其中R H’係選自由以下組成之群:(a1)氫及(b1) C 1-6烷基,及R I’係選自由以下組成之群:(a2) C 1-20烷基(例如,C 1-6烷基)、(b2) C 2-20烯基(例如,C 2-6烯基)、(c2) C 6-10芳基、(d2)氫、(e2) C 1-6烷-C 6-10芳基、(f2)胺基-C 1-20烷基、(g2) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h2) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;(20) -NR J’C(O)OR K’,其中R J’係選自由以下組成之群:(a1)氫及(b1) C 1-6烷基,及R K’係選自由以下組成之群:(a2) C 1-20烷基(例如,C 1-6烷基)、(b2) C 2-20烯基(例如,C 2-6烯基)、(c2) C 6-10芳基、(d2)氫、(e2) C 1-6烷-C 6-10芳基、(f2)胺基-C 1-20烷基、(g2) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h2) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;及(21)脒。在一些實施例中,此等基團中之各者可如本文描述經進一步取代。例如,C 1-烷芳基之伸烷基可經側氧基進一步取代以提供各別芳醯基取代基。 Unless otherwise specified, as used herein, the term "alkyl" includes both straight and branched chain saturated groups of 1 to 20 carbons (eg, 1 to 10 or 1 to 6). Alkyl is exemplified by methyl, ethyl, n- and i-propyl, n-, sec-, i- and t-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or (in the case of an alkyl group of two carbons or more) four substituents independently selected from the group consisting of: (1) C 1-6 alkoxy; (2) C 1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., —NH 2 ) or substituted amino (i.e., —N( RN1 ) 2 , wherein R N1 is as defined for amino); (4) C 6-10 aryl-C 1-6 alkoxy; (5) azido; (6) halogen; (7) (C 6-10 aryl) (2-9 heterocyclic)oxy; (8) hydroxyl, optionally substituted with an O protecting group; (9) nitro; (10) pendoxy (e.g., carboxyaldehyde or acyl); (11) C 1-7 spirocyclic group; (12) thioalkoxy; (13) thiol; (14) -CO 2 RA ' , optionally substituted with an O protecting group and wherein RA' is selected from the group consisting of: (a) C 1-20 alkyl (e.g., C 1-6 alkyl), (b) C 2-20 alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 aryl, (d) hydrogen, (e) C 1-6 alkane-C 6-10 aryl, (f) amino-C 1-20 alkyl, (g) -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR' wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C 1-20 alkyl, and (h) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino-polyethylene glycol wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R N1 is independently hydrogen or optionally substituted C 1-6 alkyl; (15) -C(O)NR B' R C' , wherein each of RB ' and RC ' is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alkane- C6-10 aryl; (16) -SO2RD ' , wherein RD' is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) C1-6 alkane- C6-10 aryl , and (d) hydroxyl; (17) -SO2NRRE'RF ' , wherein each of RE ' and RF' is independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alkane- C6-10 aryl; (18) -C(O) RG' , wherein RG' is selected from the group consisting of: (a) C1-20 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C6-10 aryl, (d) hydrogen, (e) C1-6 alkane- C6-10 aryl, (f) amino- C1-20 alkyl, (g) polyethylene glycol of -(CH2)s2(OCH2CH2)s1(CH2)s3OR ' , wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C1-20 alkyl, and (h) -NRN1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each RN1 is independently hydrogen or an optionally substituted C 1-6 alkyl group; (19) -NR H'C (O) RI' , wherein RH ' is selected from the group consisting of (a1) hydrogen and (b1) C 1-6 alkyl, and RI ' is selected from the group consisting of (a2) C 1-20 alkyl (e.g., C 1-6 alkyl), (b2) C 2-20 alkenyl (e.g., C 2-6 alkenyl), (c2) C (d2) hydrogen, (e2) C 1-6 alkane- C 6-10 aryl , (f2) amino-C 1-20 alkyl, (g2) -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR' polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C 1-20 alkyl, and (h2) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino-polyethylene glycol, wherein s1 is 1 to 10 wherein each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 is independently hydrogen or an optionally substituted C 1-6 alkyl group; (20) -NR J' C(O)OR K' , wherein R J' is selected from the group consisting of (a1) hydrogen and (b1) C 1-6 alkyl, and R K' is selected from the group consisting of (a2) C 1-20 alkyl (e.g., C 1-6 alkyl), (b2) C 2-20 alkenyl (e.g., C 2-6 alkenyl), (c2) C 6-10 aryl, (d2) hydrogen, (e2) C 1-6 alkane-C 6-10 aryl, (f2) amino-C 1-20 alkyl, (g2) -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C 1-20 alkyl, and (h2) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R N1 is independently hydrogen or optionally substituted C 1-6 alkyl; and (21) amidine. In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene of the C 1 -alkaryl group may be further substituted with pendant oxy groups to provide the respective aryl substituents.
如本文使用,術語「伸烷基」、「亞烷基」及前綴「烷-」表示藉由移除兩個氫原子而衍生自直鏈或分支鏈飽和烴之飽和二價烴基,且係由以下例示:亞甲基、伸乙基、伸異丙基,及類似物。術語「C x-y烷基」、「C x-y伸烷基」、「C x-y亞烷基」及前綴「C x-y烷-」表示具有介於x與y個碳之間的烷基或伸烷基。例示性x值係1、2、3、4、5及6,且例示性y值係2、3、4、5、6、7、8、9、10、12、14、16、18或20 (例如,C 1-6、C 1-10、C 2-5、C 2-8、C 2-10或C 2-20烷基或伸烷基)。在一些實施例中,伸烷基可經1、2、3或4個如本文針對烷基定義之取代基進一步取代。 As used herein, the terms "alkylene", "alkylene" and the prefix "alk-" refer to saturated divalent hydrocarbon groups derived from straight or branched chain saturated hydrocarbons by removing two hydrogen atoms, and are exemplified by methylene, ethylene, isopropylene, and the like. The terms " Cxy alkyl", " Cxy alkylene", " Cxy alkylene" and the prefix " Cxy alk-" refer to alkyl or alkylene groups having between x and y carbons. Exemplary x values are 1, 2, 3, 4, 5, and 6, and exemplary y values are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C 1-6 , C 1-10 , C 2-5 , C 2-8 , C 2-10 , or C 2-20 alkyl or alkylene). In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group.
除非另有規定,否則如本文使用,術語「烯基」表示含有一或多個碳碳雙鍵之2至20個碳(例如,2至6或2至10個碳)之單價直鏈或分支鏈基團且係由以下例示:乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基,及類似物。烯基包括順式及反式異構體兩者。烯基可視需要經1、2、3或4個取代基取代,其等係獨立地選自如本文定義之胺基、芳基、環烷基或雜環基(例如,雜芳基),或本文描述之例示性烷基取代基中之任一者。Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent straight or branched chain radical of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl includes both cis and trans isomers. Alkenyl may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from amino, aryl, cycloalkyl, or heterocyclic (e.g., heteroaryl) as defined herein, or any of the exemplary alkyl substituents described herein.
如本文使用,術語「炔基」表示含有碳碳三鍵之2至20個碳原子(例如,2至4、2至6或2至10個碳)之單價直鏈或分支鏈且係由以下例示:乙炔基、1-丙炔基,及類似物。炔基可視需要經1、2、3或4個取代基取代,其等係獨立地選自如本文定義之芳基、環烷基或雜環基(例如,雜芳基),或本文描述之例示性烷基取代基中之任一者。As used herein, the term "alkynyl" refers to a monovalent straight or branched chain of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like. Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from aryl, cycloalkyl, or heterocycloalkyl (e.g., heteroaryl) as defined herein, or any of the exemplary alkyl substituents described herein.
如本文使用,術語「胺基」表示-N(R N1) 2,其中各R N1獨立地係H、OH、NO 2、N(R N2) 2、SO 2OR N2、SO 2R N2、SOR N2、N保護基、烷基、烯基、炔基、烷氧基、芳基、烷芳基、環烷基、烷環烷基、羧基烷基(例如,視需要經O保護基取代,諸如視需要經取代之芳基烷氧基羰基或任何本文描述者)、磺基烷基、醯基(例如,乙醯基、三氟乙醯基或其他本文描述者)、烷氧基羰基烷基(例如,視需要經O保護基取代,諸如視需要經取代之芳基烷氧基羰基或任何本文描述者)、雜環基(例如,雜芳基)或烷雜環基(例如,烷雜芳基),其中此等所列舉之R N1基團中之各者可視需要經取代,如本文針對各基團定義;或兩個R N1組合以形成雜環基或N保護基,且其中各R N2獨立地係H、烷基或芳基。胺基可為未經取代之胺基(即-NH 2)或經取代之胺基(即-N(R N1) 2)。在一較佳實施例中,胺基係-NH 2或-NHR N1,其中R N1獨立地係OH、NO 2、NH 2、NR N2 2、SO 2OR N2、SO 2R N2、SOR N2、烷基、羧基烷基、磺基烷基、醯基(例如,乙醯基、三氟乙醯基,或其他本文描述者)、烷氧基羰基烷基(例如,第三丁氧基羰基烷基)或芳基,且各R N2可為H、C 1-20烷基(例如,C 1-6烷基)或C 6-10芳基。 As used herein, the term "amino" refers to -N( RN1 ) 2 , wherein each RN1 is independently H, OH, NO2 , N( RN2 ) 2 , SO2ORN2 , SO2RN2 , SORN2 , N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkylcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl or any described herein), heterocyclic (e.g., heteroaryl) or alkheterocyclic (e.g., alkheteroaryl), wherein each of these listed R N1 groups may be optionally substituted as defined herein for each group; or two R N1s are combined to form a heterocyclic or N-protecting group, and wherein each R N2 is independently H, alkyl or aryl. The amino group can be an unsubstituted amino group (i.e., -NH2 ) or a substituted amino group (i.e. , -N( RN1 ) 2 ). In a preferred embodiment, the amino group is -NH2 or -NHRN1 , wherein RN1 is independently OH, NO2 , NH2 , NR N22 , SO2OR N2 , SO2RN2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., tert-butoxycarbonylalkyl) or aryl, and each RN2 can be H, C1-20 alkyl (e.g., C1-6 alkyl) or C6-10 aryl.
如本文描述之術語「胺基酸」係指具有側鏈、胺基及酸基(例如,-CO 2H之羧基或-SO 3H之磺基)之分子,其中該胺基酸由該側鏈、胺基或酸基(例如,該側鏈)連接至母體分子基團。在一些實施例中,該胺基酸係由羰基連接至該母體分子基團,其中該側鏈或胺基係連接至該羰基。例示性側鏈包括視需要經取代之烷基、芳基、雜環基、烷芳基、烷雜環基、胺基烷基、胺甲醯基烷基及羧基烷基。例示性胺基酸包括丙胺酸、精胺酸、天冬醯胺酸、天冬胺酸、半胱胺酸、麩胺酸、麩醯胺酸、甘胺酸、組胺酸、羥基戊胺酸、異白胺酸、白胺酸、離胺酸、甲硫胺酸、戊胺酸、鳥胺酸、苯丙胺酸、脯胺酸、吡咯離胺酸、硒半胱胺酸、絲胺酸、牛磺酸、蘇胺酸、色胺酸、酪胺酸及纈胺酸。胺基酸基團可視需要經一、二、三個或(在兩個碳或更多個之胺基酸之情況下)四個獨立地選自由以下組成之群之取代基取代:(1) C 1-6烷氧基;(2) C 1-6烷基亞磺醯基;(3)胺基,如本文定義(例如,未經取代之胺基(即-NH 2)或經取代之胺基(即-N(R N1) 2,其中R N1係如針對胺基定義);(4) C 6-10芳基-C 1-6烷氧基;(5)疊氮基;(6)鹵基;(7) (C 2-9雜環基)氧基;(8)羥基;(9)硝基;(10)側氧基(例如,羧基醛或醯基);(11) C 1-7螺環基;(12)硫烷氧基;(13)硫醇;(14) -CO 2R A’,其中R A’係選自由以下組成之群:(a) C 1-20烷基(例如,C 1-6烷基)、(b) C 2-20烯基(例如,C 2-6烯基)、(c) C 6-10芳基、(d)氫、(e) C 1-6烷-C 6-10芳基、(f)胺基-C 1-20烷基、(g) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;(15) -C(O)NR B’R C’,其中R B’及R C’中之各者係獨立地選自由以下組成之群:(a)氫、(b) C 1-6烷基、(c) C 6-10芳基及(d) C 1-6烷-C 6-10芳基;(16) -SO 2R D’,其中R D’係選自由以下組成之群:(a) C 1-6烷基、(b) C 6-10芳基、(c) C 1-6烷-C 6-10芳基,及(d)羥基;(17) -SO 2NR E’R F’,其中R E’及R F’中之各者係獨立地選自由以下組成之群:(a)氫、(b) C 1-6烷基、(c) C 6-10芳基及(d) C 1-6烷-C 6-10芳基;(18) -C(O)R G’,其中R G’係選自由以下組成之群:(a) C 1-20烷基(例如,C 1-6烷基)、(b) C 2-20烯基(例如,C 2-6烯基)、(c) C 6-10芳基、(d)氫、(e) C 1-6烷-C 6-10芳基、(f)胺基-C 1-20烷基、(g) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;(19) -NR H’C(O)R I’,其中R H’係選自由以下組成之群:(a1)氫及(b1) C 1-6烷基,及R I’係選自由以下組成之群:(a2) C 1-20烷基(例如,C 1-6烷基)、(b2) C 2-20烯基(例如,C 2-6烯基)、(c2) C 6-10芳基、(d2)氫、(e2) C 1-6烷-C 6-10芳基、(f2)胺基-C 1-20烷基、(g2) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h2) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;(20) -NR J’C(O)OR K’,其中R J’係選自由以下組成之群:(a1)氫及(b1) C 1-6烷基,及R K’係選自由以下組成之群:(a2) C 1-20烷基(例如,C 1-6烷基)、(b2) C 2-20烯基(例如,C 2-6烯基)、(c2) C 6-10芳基、(d2)氫、(e2) C 1-6烷-C 6-10芳基、(f2)胺基-C 1-20烷基、(g2) -(CH 2) s2(OCH 2CH 2) s1(CH 2) s3OR’之聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,及R’係H或C 1-20烷基,及(h2) -NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基;及(21)脒。在一些實施例中,此等基團中之各者可如本文描述經進一步取代。 As used herein, the term "amino acid" refers to a molecule having a side chain, an amine group, and an acid group (e.g., a carboxyl group of -CO 2 H or a sulfonyl group of -SO 3 H), wherein the amino acid is linked to a parent molecular group by the side chain, the amine group, or the acid group (e.g., the side chain). In some embodiments, the amino acid is linked to the parent molecular group by a carbonyl group, wherein the side chain or the amine group is linked to the carbonyl group. Exemplary side chains include optionally substituted alkyl, aryl, heterocyclic, alkaryl, alkaryl heterocyclic, aminoalkyl, carbamoylalkyl, and carboxyalkyl groups. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamine, glycine, histidine, hydroxyvaleric acid, isoleucine, leucine, lysine, methionine, valeric acid, ornithine, phenylalanine, proline, pyrrole lysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. The amino acid group may be optionally substituted with one, two, three or (in the case of two or more carbon amino acids) four substituents independently selected from the group consisting of: (1) C 1-6 alkoxy; (2) C 1-6 alkylsulfinyl; (3) amine, as defined herein (e.g., unsubstituted amine (i.e., -NH 2 ) or substituted amine (i.e., -N( RN1 ) 2 , wherein RN1 is as defined for an amine); (4) C 6-10 aryl-C 1-6 alkoxy; (5) azido; (6) halogen; (7) (C 2-9 heterocyclic )oxy; (8) hydroxy; (9) nitro; (10) pendoxy (e.g., carboxyaldehyde or acyl); (11) C 6-10 aryl-C 1-6 alkoxy; (12) C 6-10 aryl-C 1-6 alkoxy; (13) C 6-10 aryl-C 1-6 alkoxy; (14) C 6-10 aryl-C 1-6 alkoxy; (15) azido; (16) halogen; (17) (C 2-9 heterocyclic)oxy; (18) hydroxy; (19) nitro; (20) pendoxy (e.g., carboxyaldehyde or acyl); (21) C 6-10 aryl-C 1-6 alkoxy; (22) C 6-10 aryl-C 1-6 alkoxy; (23) C 6-10 aryl-C 1-6 alkoxy; (24) C 6-10 aryl-C 1-6 alkoxy; (25) C 6-10 aryl-C 1-6 alkoxy; (26) C 6-10 aryl-C 1-6 alk (12) thioalkoxy; (13) thiol; (14) -CO 2 RA' , wherein RA' is selected from the group consisting of (a) C 1-20 alkyl (e.g., C 1-6 alkyl), (b) C 2-20 alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 aryl, (d) hydrogen, (e) C 1-6 alkane- C 6-10 aryl, (f) amino-C 1-20 alkyl, (g) -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and each of s2 and s3 is independently 0 to 10. (h) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino - polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4 ), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each RN1 is independently hydrogen or an optionally substituted C 1-6 alkyl group; (15) -C(O)NR B' RC' , wherein each of RB ' and RC ' is independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 alkyl, (c) C (16) -SO 2 RD ' , wherein RD ' is selected from the group consisting of ( a) C 1-6 alkyl, (b) C 6-10 aryl, (c) C 1-6 alk- C 6-10 aryl , and (d) hydroxyl; (17) -SO 2 NR E ' RF ' , wherein each of RE ' and RF ' is independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-10 aryl, and (d) C 1-6 alk-C 6-10 aryl; (18) -C(O) RG ' , wherein RG ' is selected from the group consisting of (a) C 1-20 alkyl (e.g., C 1-6 alkyl), (b) C 1-6 (c) C 6-10 aryl, (d) hydrogen, (e) C 1-6 alkane-C 6-10 aryl, (f) amino-C 1-20 alkyl , ( g) polyethylene glycol of -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C 1-20 alkyl, and (h) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R N1 is independently hydrogen or an optionally substituted C 1-6 alkyl group; (19) -NR H'C (O) RI' , wherein RH' is selected from the group consisting of (a1) hydrogen and (b1) C 1-6 alkyl, and RI ' is selected from the group consisting of (a2) C 1-20 alkyl (e.g., C 1-6 alkyl), (b2) C 2-20 alkenyl (e.g., C 2-6 alkenyl), (c2) C 6-10 aryl, (d2) hydrogen, (e2) C 1-6 alkane-C (f2) amino-C 1-20 alkyl, (g2) -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C 1-20 alkyl, and (h2) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 wherein the alkylene group is an integer (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each RN1 is independently hydrogen or an optionally substituted C1-6 alkyl group; (20) -NR J'C (O)OR K' , wherein R J' is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and R K' is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) C6-10 aryl, (d2) hydrogen, (e2) C1-6 alkane- C6-10 aryl, (f2) amino- C1-20 alkyl, (g2) -( CH2 ) s2 ( OCH2CH2 ) s1 ( CH2 ) s3 (h2) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 amino -polyethylene glycol, wherein s1 is an integer from 1 to 10 ( e.g., 1 to 6 or 1 to 4 ), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4 , 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R N1 is independently hydrogen or optionally substituted C 1-6 alkyl; and (21 ) amidine. In some embodiments, each of these groups can be further substituted as described herein.
如本文使用,術語「芳基」表示具有一或兩個芳族環之單環、雙環或多環碳環形環系統,且係由以下例示:苯基、萘基、1,2-二氫萘基、1,2,3,4-四氫萘基、蒽基、菲基、茀基、二氫茚基、茚基,及類似物,且可視需要經1、2、3、4或5個獨立地選自由以下組成之群之取代基取代:(1) C 1-7醯基(例如,羧基醛);(2) C 1-20烷基(例如,C 1-6烷基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基亞磺醯基-C 1-6烷基、胺基-C 1-6烷基、疊氮基-C 1-6烷基、(羧基醛)-C 1-6烷基、鹵基-C 1-6烷基(例如,全氟烷基)、羥基-C 1-6烷基、硝基-C 1-6烷基或C 1-6硫烷氧基-C 1-6烷基);(3) C 1-20烷氧基(例如,C 1-6烷氧基,諸如全氟烷氧基);(4) C 1-6烷基亞磺醯基;(5) C 6-10芳基;(6)胺基;(7) C 1-6烷-C 6-10芳基;(8)疊氮基;(9) C 3-8環烷基;(10) C 1-6烷-C 3-8環烷基;(11)鹵基;(12) C 1-12雜環基(例如,C 1-12雜芳基);(13) (C 1-12雜環基)氧基;(14)羥基;(15)硝基;(16) C 1-20硫烷氧基(例如,C 1-6硫烷氧基);(17) -(CH 2) qCO 2R A’,其中q係零至四之整數,及R A’係選自由以下組成之群:(a) C 1-6烷基、(b) C 6-10芳基、(c)氫,及(d) C 1-6烷-C 6-10芳基;(18) -(CH 2) qCONR B’R C’,其中q係零至四之整數且其中R B’及R C’係獨立地選自由以下組成之群:(a)氫、(b) C 1-6烷基、(c) C 6-10芳基,及(d) C 1-6烷-C 6-10芳基;(19) -(CH 2) qSO 2R D’,其中q係零至四之整數且其中R D’係選自由以下組成之群:(a)烷基、(b) C 6-10芳基,及(c)烷-C 6-10芳基;(20) -(CH 2) qSO 2NR E’R F’,其中q係零至四之整數且其中R E’及R F’中之各者係獨立地選自由以下組成之群:(a)氫、(b) C 1-6烷基、(c) C 6-10芳基,及(d) C 1-6烷-C 6-10芳基;(21)硫醇;(22) C 6-10芳氧基;(23) C 3-8環烷氧基;(24) C 6-10芳基-C 1-6烷氧基;(25) C 1-6烷-C 1-12雜環基(例如,C 1-6烷-C 1-12雜芳基);(26) C 2-20烯基;及(27) C 2-20炔基。在一些實施例中,此等基團中之各者可如本文描述經進一步取代。例如,C 1-烷芳基或C 1-烷雜環基之伸烷基可經側氧基進一步取代以提供各別芳醯基及(雜環基)醯基取代基。 As used herein, the term "aryl" refers to a monocyclic, bicyclic or polycyclic carbocyclic ring system having one or two aromatic rings, and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, dihydroindenyl, indenyl, and the like, and may be substituted, if necessary, with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: (1) C 1-7 acyl (e.g., carboxyaldehyde); (2) C 1-20 alkyl (e.g., C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylsulfinyl-C 1-6 alkyl, amino-C 1-6 alkyl, azido-C 1-6 alkyl); (e.g., C 1-6 alkyl, (carboxyaldehyde)-C 1-6 alkyl, halogen-C 1-6 alkyl (e.g., perfluoroalkyl), hydroxyl-C 1-6 alkyl, nitro-C 1-6 alkyl or C 1-6 thioalkoxy-C 1-6 alkyl); (3) C 1-20 alkoxy (e.g., C 1-6 alkoxy, such as perfluoroalkoxy); (4) C 1-6 alkylsulfinyl; (5) C 6-10 aryl; (6) amino; (7) C 1-6 alkane-C 6-10 aryl; (8) azido; (9) C 3-8 cycloalkyl; (10) C 1-6 alkane-C 3-8 cycloalkyl; (11) halogen; (12) C 1-12 heterocyclic group (e.g., C 1-12 heteroaryl); (13) (14) hydroxyl; (15) nitro; (16) C 1-20 thioalkoxy (e.g., C 1-6 thioalkoxy); (17) -(CH 2 ) q CO 2 RA' , wherein q is an integer from zero to four, and RA ' is selected from the group consisting of (a) C 1-6 alkyl, (b) C 6-10 aryl, (c) hydrogen, and (d) C 1-6 alkane- C 6-10 aryl; (18) -(CH 2 ) q CONRB ' RC ' , wherein q is an integer from zero to four and wherein RB ' and RC ' are independently selected from the group consisting of (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-10 aryl, and (d) C 1-6 alkane-C (19) -(CH 2 ) q SO 2 RD ' , wherein q is an integer from zero to four and wherein RD ' is selected from the group consisting of: (a) alkyl, (b) C 6-10 aryl, and (c) alkane-C 6-10 aryl; (20) -(CH 2 ) q SO 2 NR E ' RF ' , wherein q is an integer from zero to four and wherein each of RE ' and RF ' is independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-10 aryl, and (d) C 1-6 alkane-C 6-10 aryl; (21) thiol; (22) C 6-10 aryloxy; (23) C 3-8 cycloalkoxy; (24) C 6-10 aryl-C (25) C 1-6 alkoxy; (26) C 2-20 alkenyl; and (27) C 2-20 alkynyl. In some embodiments , each of these groups may be further substituted as described herein. For example, the alkylene of the C 1 -alkaryl or C 1 - alkaryl heterocyclic group may be further substituted with pendant oxy groups to provide respective aryl and (heterocyclic) acyl substituents.
如本文使用,術語「醯基」表示通式-C(O)R之基團,其中R係烷基或芳基。「醯基」之實例包括(但不限於) -C(O)CH 3、-C(O)C 2H 5及-C(O)Ph。 As used herein, the term "acyl" refers to a group of the general formula -C(O)R, wherein R is an alkyl group or an aryl group. Examples of "acyl" include, but are not limited to, -C(O) CH3 , -C(O) C2H5 , and -C(O)Ph.
如本文使用,術語「羰基」表示C(O)基團,其亦可以C=O表示。As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented by C=O.
如本文使用,術語「羧基」意謂-CO 2H。 As used herein, the term "carboxy" means -CO 2 H.
除非另有規定,否則如本文使用,術語「環烷基」表示來自三至八個碳之單價飽和或不飽和非芳族環形烴基,且係由以下例示:環丙基、環丁基、環戊基、環己基、環庚基、雙環庚基,及類似物。當該環烷基包括一個碳碳雙鍵或一個碳碳三鍵時,該環烷基可分別稱為「環烯基」或「環炔基」。例示性環烯基及環炔基包括環戊烯基、環己烯基、環己炔基,及類似物。環烷基可視需要經以下取代:(1) C 1-7醯基(例如,羧基醛);(2) C 1-20烷基(例如,C 1-6烷基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基亞磺醯基-C 1-6烷基、胺基-C 1-6烷基、疊氮基-C 1-6烷基、(羧基醛)-C 1-6烷基、鹵基-C 1-6烷基(例如,全氟烷基)、羥基-C 1-6烷基、硝基-C 1-6烷基或C 1-6硫烷氧基-C 1-6烷基);(3) C 1-20烷氧基(例如,C 1-6烷氧基,諸如全氟烷氧基);(4) C 1-6烷基亞磺醯基;(5) C 6-10芳基;(6)胺基;(7) C 1-6烷-C 6-10芳基;(8)疊氮基;(9) C 3-8環烷基;(10) C 1-6烷-C 3-8環烷基;(11)鹵基;(12) C 1-12雜環基(例如,C 1-12雜芳基);(13) (C 1-12雜環基)氧基;(14)羥基;(15)硝基;(16) C 1-20硫烷氧基(例如,C 1-6硫烷氧基);(17) -(CH 2) qCO 2R A’,其中q係零至四之整數,及R A’係選自由以下組成之群:(a) C 1-6烷基、(b) C 6-10芳基、(c)氫,及(d) C 1-6烷-C 6-10芳基;(18) -(CH 2) qCONR B’R C’,其中q係零至四之整數且其中R B’及R C’係獨立地選自由以下組成之群:(a)氫、(b) C 6-10烷基、(c) C 6-10芳基,及(d) C 1-6烷-C 6-10芳基;(19) -(CH 2) qSO 2R D’,其中q係零至四之整數且其中R D’係選自由以下組成之群:(a) C 6-10烷基、(b) C 6-10芳基,及(c) C 1-6烷-C 6-10芳基;(20) -(CH 2) qSO 2NR E’R F’,其中q係零至四之整數且其中R E’及R F’中之各者係獨立地選自由以下組成之群:(a)氫、(b) C 6-10烷基、(c) C 6-10芳基,及(d) C 1-6烷-C 6-10芳基;(21)硫醇;(22) C 6-10芳氧基;(23) C 3-8環烷氧基;(24) C 6-10芳基-C 1-6烷氧基;(25) C 1-6烷-C 1-12雜環基(例如,C 1-6烷-C 1-12雜芳基);(26)側氧基;(27) C 2-20烯基;及(28) C 2-20炔基。在一些實施例中,此等基團中之各者可如本文描述經進一步取代。例如,C 1-烷芳基或C 1-烷雜環基之伸烷基可經側氧基進一步取代以提供各別芳醯基及(雜環基)醯基取代基。 Unless otherwise specified, as used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated and non-aromatic cyclic hydrocarbon radical from three to eight carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, and the like. When the cycloalkyl includes a carbon-carbon double bond or a carbon-carbon triple bond, the cycloalkyl may be referred to as a "cycloalkenyl" or "cycloalkynyl," respectively. Exemplary cycloalkenyl and cycloalkynyl groups include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like. The cycloalkyl group may be optionally substituted by: (1) C 1-7 acyl (e.g., carboxyaldehyde); (2) C 1-20 alkyl (e.g., C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylsulfinyl-C 1-6 alkyl, amino-C 1-6 alkyl, azido-C 1-6 alkyl, (carboxyaldehyde)-C 1-6 alkyl, halogen-C 1-6 alkyl (e.g., perfluoroalkyl), hydroxyl-C 1-6 alkyl, nitro-C 1-6 alkyl, or C 1-6 thioalkoxy-C 1-6 alkyl); (3) C 1-20 alkoxy (e.g., C 1-6 alkoxy, such as perfluoroalkoxy); (4) C 1-6 alkylsulfinyl; (5) C 6-10 aryl; (6) amino; (7) C 1-20 alkyl (8) azido; (9) C 3-8 cycloalkyl; (10) C 1-6 alkane- C 3-8 cycloalkyl; (11) halogen; (12) C 1-12 heterocyclic group (e.g., C 1-12 heteroaryl); (13) (C 1-12 heterocyclic group) oxy; (14) hydroxyl; (15) nitro; (16) C 1-20 thioalkoxy (e.g., C 1-6 thioalkoxy ) ; (17) -(CH 2 ) q CO 2 RA ' , wherein q is an integer from zero to four, and RA ' is selected from the group consisting of: (a) C 1-6 alkyl, (b) C 6-10 aryl, (c) hydrogen, and (d) C 1-6 alkane-C 3-8 cycloalkyl. (18) -(CH 2 ) q CONRB'RC ' , wherein q is an integer from zero to four and wherein RB' and RC ' are independently selected from the group consisting of: (a) hydrogen, (b) C 6-10 alkyl, (c) C 6-10 aryl, and (d) C 1-6 alkane-C 6-10 aryl; (19) -(CH 2 ) q SO 2 RD' , wherein q is an integer from zero to four and wherein RD' is selected from the group consisting of: (a) C 6-10 alkyl, (b) C 6-10 aryl, and (c) C 1-6 alkane-C 6-10 aryl; (20) -(CH 2 ) q SO 2 NR E'RF ' , wherein q is an integer from zero to four and wherein RE ' and R Each of F' is independently selected from the group consisting of (a) hydrogen, (b) C 6-10 alkyl, (c) C 6-10 aryl, and (d) C 1-6 alk-C 6-10 aryl; (21) thiol; (22) C 6-10 aryloxy; (23) C 3-8 cycloalkoxy; (24) C 6-10 aryl-C 1-6 alkoxy; (25) C 1-6 alk-C 1-12 heterocyclic group (e.g., C 1-6 alk-C 1-12 heteroaryl); (26) pendoxy; (27) C 2-20 alkenyl; and (28) C 2-20 alkynyl. In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene group of a C 1 -alkaryl or C 1 -alkheterocycloyl group may be further substituted with pendant oxy groups to provide the respective aryl and (heterocyclo)acyl substituents.
如本文使用,術語「鹵素」表示選自溴、氯、碘或氟之鹵素。As used herein, the term "halogen" means a halogen selected from bromine, chlorine, iodine or fluorine.
如本文使用,術語「雜烷基」及「亞雜烷基」各係指如本文定義之烷基,其中組成碳原子中之一或兩者已各經氮、氧或硫置換。在一些實施例中,該雜烷基可經1、2、3或4個如本文針對烷基描述之取代基進一步取代。如本文定義,如本文使用,術語「雜烯基」及「雜炔基」分別係指烯基及炔基,其中該等組成碳原子中之一或兩者已各經氮、氧或硫置換。在一些實施例中,該雜烯基及雜炔基可經1、2、3或4個如本文針對烷基描述之取代基進一步描述。As used herein, the terms "heteroalkyl" and "heteroalkylene" each refer to an alkyl group as defined herein, wherein one or both of the constituent carbon atoms have been replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. As defined herein, as used herein, the terms "heteroalkenyl" and "heteroalkynyl" refer to alkenyl and alkynyl groups, respectively, wherein one or both of the constituent carbon atoms have been replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl and heteroalkynyl groups may be further described with 1, 2, 3, or 4 substituents as described herein for alkyl groups.
如本文使用,術語「雜芳基」表示如本文定義之雜環基之子集,其等為芳族的:即其等於單環或多環形環系統內含有4n+2個π電子。例示性未經取代之雜芳基具有1至12 (例如,1至11、1至10、1至9、2至12、2至11、2至10或2至9)個碳。在一些實施例中,該雜芳基係經1、2、3或4個如針對雜環基定義之取代基取代。As used herein, the term "heteroaryl" refers to a subset of heterocyclic groups as defined herein that are aromatic: that is, they contain 4n+2 π electrons within the monocyclic or polycyclic ring system. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents as defined for heterocyclic groups.
如本文使用,術語「側氧基」表示=O。As used herein, the term "oxo" refers to =0.
如本文使用,術語「聚乙二醇」表示包含一或多個單體單元之烷氧基鏈,各單體單元係由-OCH 2CH 2-組成。聚乙二醇(PEG)有時亦稱為聚環氧乙烷(PEO)或聚氧乙烯(POE),且出於本發明之目的可認為此等術語可互換。例如,聚乙二醇可具有結構-(CH 2) s2(OCH 2CH 2) s1(CH 2) s3O-,其中s1係1至10 (例如,1至6或1至4)之整數,且s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數。亦可認為聚乙二醇包括-NR N1(CH 2) s2(CH 2CH 2O) s1(CH 2) s3NR N1-之胺基-聚乙二醇,其中s1係1至10 (例如,1至6或1至4)之整數,s2及s3中之各者獨立地係0至10 (例如,0至4、0至6、1至4、1至6或1至10)之整數,且各R N1獨立地係氫或視需要經取代之C 1-6烷基。 As used herein, the term "polyethylene glycol" refers to an alkoxy chain comprising one or more monomer units, each of which consists of -OCH2CH2- . Polyethylene glycol (PEG) is sometimes also referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms are considered interchangeable for the purposes of the present invention. For example, polyethylene glycol can have the structure -( CH2 ) s2 ( OCH2CH2 ) s1 ( CH2 ) s3O- , where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10). Polyethylene glycol can also be considered to include amino-polyethylene glycol of -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 -, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each RN1 is independently hydrogen or optionally substituted C 1-6 alkyl.
如本文使用,術語「異構體」意謂任何化合物之任何互變異構體、立體異構體、對映體或非鏡像異構體。應認知該等化合物可具有一或多個對掌性中心及/或雙鍵,且因此以立體異構體,諸如雙鍵異構體(即幾何E/Z異構體)或非鏡像異構體、對映體(即(+)或(-))或順式/反式異構體)的形式存在。除非另有指示,否則本文繪示之化學結構包含所有相應立體異構體,即立體異構純形式(例如,幾何純、對映純或非鏡像異構純)及對映體及立體異構體混合物(例如,外消旋物)兩者。化合物之對映體及立體異構體混合物通常可藉由眾所周知的方法(諸如對掌性相氣相層析術、對掌性相高效液相層析術、使該化合物結晶成對掌性鹽複合物或使該化合物於對掌性溶劑中結晶)拆分為其等組分對映體或立體異構體。對映體及立體異構體亦可藉由眾所周知的不對稱合成方法獲自立體異構或對映純中間物、試劑、及觸媒。As used herein, the term "isomer" means any tautomer, stereoisomer, enantiomer or diastereoisomer of any compound. It is recognized that these compounds may have one or more chiral centers and/or double bonds and therefore exist in the form of stereoisomers, such as diastereoisomers (i.e., geometric E/Z isomers) or diastereoisomers, enantiomers (i.e., (+) or (-)) or cis/trans isomers). Unless otherwise indicated, chemical structures depicted herein include all corresponding stereoisomers, both stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or non-image-isomerically pure) and enantiomeric and stereoisomer mixtures (e.g., racemates). Enantiomers and stereoisomer mixtures of compounds can generally be resolved into their equal component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained by well-known asymmetric synthesis methods to obtain stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts.
如本文使用,術語「立體異構體」係指化合物可具有(例如,本文描述之任何式之化合物)的所有可能之不同異構體及構象形式,特定言之基礎分子結構之所有可能之立體化學及構象異構體形式、所有非鏡像異構體、對映體及/或構象異構體。一些化合物可以不同之互變異構體形式存在,後者中之所有均包括於本發明之範圍內。As used herein, the term "stereoisomers" refers to all possible different isomeric and conformational forms that a compound may have (e.g., a compound of any formula described herein), specifically all possible stereochemical and conformational isomeric forms of the basic molecular structure, all non-mirror isomers, enantiomers and/or conformational isomers. Some compounds may exist in different tautomeric forms, all of the latter are included within the scope of the present invention.
如本文使用,術語「非鏡像異構體」意謂彼此不為鏡像且彼此不可重疊之立體異構體。As used herein, the term "non-mirror isomers" refers to stereoisomers that are not mirror images of each other and are non-superimposable with each other.
如本文使用,術語「對映體」意謂化合物之各個別光學活性形式,其具有至少80% (即一種對映體為至少90%及另一對映體為至多10%),較佳至少90%及更佳至少98%之光學純度或對映體過量(如藉由此項技術中之標準方法測定)。 其他術語 As used herein, the term "enantiomer" means each individual optically active form of a compound having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% for one enantiomer and at most 10% for the other enantiomer), preferably at least 90% and more preferably at least 98% (as determined by standard methods in the art). Other Terms
如本文使用,除非另有指示或自內文推斷,否則術語「約」或「大約」係指自列舉之定量值(且包括列舉之定量值本身)之±10%變化。例如,除非另有說明或自內文推斷,否則約100 kBq/kg之劑量指示100±10% kBq/kg之劑量範圍,即90 kBq/kg至110 kBq/kg (含)。As used herein, unless otherwise indicated or inferred from the context, the term "about" or "approximately" refers to a ±10% variation from the recited quantitative value (and includes the recited quantitative value itself). For example, unless otherwise indicated or inferred from the context, a dose of about 100 kBq/kg indicates a dose range of 100±10% kBq/kg, i.e., 90 kBq/kg to 110 kBq/kg (inclusive).
如本文使用,術語「組合投與」、「組合之投與」或「共投與」意謂兩種或更多種藥劑係同時或於一定時間間隔內對個體投與,使得各藥劑對病患之影響可存在重疊。因此,組合投與之兩種或更多種藥劑無需一起投與。在一些實施例中,其等係彼此於90天內(例如,於80、70、60、50、40、30、20、10、5、4、3、2或1天內)、於28天內(例如,以14、7、6、5、4、3、2或1天)、於24小時內(例如,12、6、5、4、3、2或1小時,或於約60、30、15、10、5或1分鐘內)投與。在一些實施例中,該等藥劑之投與間隔地足夠緊密使得達成組合效應。As used herein, the term "combination administration", "combination administration" or "co-administration" means that two or more agents are administered to an individual at the same time or within a certain time interval, so that the effects of each agent on the patient can overlap. Therefore, the two or more agents administered in combination do not need to be administered together. In some embodiments, they are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2 or 1 day), within 28 days (e.g., in 14, 7, 6, 5, 4, 3, 2 or 1 day), within 24 hours (e.g., 12, 6, 5, 4, 3, 2 or 1 hour, or within about 60, 30, 15, 10, 5 or 1 minute) of each other. In some embodiments, the administration of the agents is spaced closely enough so that a combined effect is achieved.
如本文使用,對個體「投與」藥劑包括使該個體之細胞與該藥劑接觸。As used herein, "administering" an agent to a subject includes contacting cells of the subject with the agent.
術語「癌症」係指藉由惡性腫瘤細胞增殖引起之任何癌症,諸如腫瘤、贅生物、癌、肉瘤、白血病及淋巴瘤。「實體瘤癌症」係包含異常組織塊之癌症,例如,肉瘤、癌及淋巴瘤。本文中可互換使用之「血液系統癌症」或「液體癌症」係存在於體液中之癌症,例如,淋巴瘤及白血病。The term "cancer" refers to any cancer caused by the proliferation of malignant tumor cells, such as tumors, tumors, carcinomas, sarcomas, leukemias and lymphomas. "Solid tumor cancers" are cancers that include abnormal tissue masses, such as sarcomas, carcinomas and lymphomas. "Hematological cancers" or "fluid cancers" used interchangeably herein are cancers that are present in body fluids, such as lymphomas and leukemias.
如本文使用,術語「螯合物」係指可於兩個或更多個點處與中心金屬或放射性金屬原子結合之有機化合物或其部分。As used herein, the term "chelate" refers to an organic compound or a portion thereof that can bind to a central metal or radiometal atom at two or more points.
如本文使用,術語「結合物」係指含有螯合基團或其金屬錯合物、連接子基團,且視需要含有治療部分或標靶部分之分子。As used herein, the term "conjugate" refers to a molecule containing a chelating group or its metal complex, a linker group, and, optionally, a therapeutic moiety or a targeting moiety.
如本文使用之術語「治療部分」係指賦予治療益處之任何分子或分子之任何部分。在一些實施例中,該治療部分係蛋白質或多肽,例如,抗體、其抗原結合片段。在一些實施例中,該治療部分係小分子。As used herein, the term "therapeutic moiety" refers to any molecule or any portion of a molecule that confers a therapeutic benefit. In some embodiments, the therapeutic moiety is a protein or polypeptide, e.g., an antibody, an antigen-binding fragment thereof. In some embodiments, the therapeutic moiety is a small molecule.
如本文使用之術語「標靶部分」係指與給定標靶結合之任何分子或分子之任何部分。在一些實施例中,該標靶部分係蛋白質或多肽,諸如抗體或其抗原結合片段、奈米抗體、親和體或來自纖維連接蛋白III型域之一致序列。在一些實施例中,該標靶部分係肽或小分子。As used herein, the term "targeting moiety" refers to any molecule or any portion of a molecule that binds to a given target. In some embodiments, the targeting moiety is a protein or polypeptide, such as an antibody or antigen-binding fragment thereof, a nanobody, an affibody, or a consensus sequence from a fibronectin type III domain. In some embodiments, the targeting moiety is a peptide or a small molecule.
如本文使用,術語「化合物」意欲包括本文繪示之結構之所有立體異構體、幾何異構體及互變異構體。As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted herein.
本文描述之化合物可為不對稱(例如,具有一或多個立體中心)。除非另有指示,否則預期所有立體異構體(諸如對映體及非鏡像異構體)。含有不對稱取代之碳原子之本發明之化合物可以光學活性或外消旋形式分離。有關自光學活性起始材料製備光學活性形式之方法為此項技術中已知,諸如藉由拆分外消旋混合物或藉由立體選擇性合成。烯烴、C=N雙鍵及類似物之許多幾何異構體亦可存在於本文描述之化合物中,且本發明中審慎考慮所有此等穩定之異構體。本文描述本發明之化合物之順式及反式幾何異構體且可呈異構體之混合物或呈分離之異構體形式分離。The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereoisomers) are contemplated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are carefully considered in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described herein and may be isolated as a mixture of isomers or in separated isomeric forms.
本發明之化合物亦包括互變異構體形式。互變異構體形式由單鍵與相鄰雙鍵之交換及質子之伴隨遷移產生。互變異構體形式包括質子移變互變異構體,其等係具有相同經驗式及總電荷之異構質子化態。質子移變互變異構體之實例包括酮-烯醇對、醯胺-亞胺酸對、內醯胺-內醯亞胺對、醯胺-亞胺酸對、烯胺-亞胺對及其中質子可佔據雜環系統之兩個或更多個位置的環狀形式,諸如1H-及3H-咪唑、1H-、2H-及4H- 1,2,4-三唑、1H-及2H-異吲哚及1H-及2H-吡唑。互變異構體形式可處於平衡或藉由適當之取代在空間上鎖定為一種形式。The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactam pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of heterocyclic systems, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
於本說明書之多個地方,本發明之化合物之取代基係以群或範圍揭示。具體言之,本發明旨在包括此等群及範圍之成員之每一個個別子組合。例如,具體言之,術語「C 1-6烷基」旨在個別地揭示甲基、乙基、C 3烷基、C 4烷基、C 5烷基及C 6烷基。本文中形式「視需要經取代之X」(例如,視需要經取代之烷基)之片語旨在等同於「X,其中X係視需要經取代」(例如,「烷基,其中該烷基係視需要經取代」)。其非旨在意謂特徵「X」(例如,烷基)本身係任選的。 In various places in this specification, substituents of the compounds of the present invention are disclosed in groups or ranges. Specifically, the present invention is intended to include every individual subcombination of the members of these groups and ranges. For example, specifically, the term "C 1-6 alkyl" is intended to disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl individually. Phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) herein are intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) itself is optional.
如本文使用,術語「減少」、「經減少」、「增加」、「經增加」或「降低」、「經降低」 (例如,當提及治療結果或效應時)具有相對於參考水平之含義。在一些實施例中,該參考水平係藉由使用該方法以實驗動物模型或臨床試驗中之對照測定之水平。在一些實施例中,該參考水平係治療前或開始治療時之相同個體中之水平。在一些實施例中,該參考水平係未經該治療方法治療之群體中之平均水平。As used herein, the terms "reduce", "decrease", "increase", "increase" or "lower", "lower" (e.g., when referring to a treatment outcome or effect) have the meaning relative to a reference level. In some embodiments, the reference level is a level measured by using the method with a control in an experimental animal model or clinical trial. In some embodiments, the reference level is the level in the same individual before treatment or at the beginning of treatment. In some embodiments, the reference level is the average level in a population not treated with the treatment method.
如本文使用,術語藥劑(例如,前述化合物或結合物中之任一者)之「有效量」係足以實現有利或所需結果(諸如臨床結果)之量,且因此「有效量」取決於應用其之內文。As used herein, the term "effective amount" of an agent (e.g., any of the aforementioned compounds or conjugates) is an amount sufficient to achieve beneficial or desired results (such as clinical results), and thus "effective amount" depends on the context in which it is used.
如本文使用,術語「醫藥組合物」表示含有與醫藥上可接受之賦形劑調配之本文描述之化合物的組合物。在一些實施例中,該醫藥組合物係在政府監管機構之批准下作為用於治療哺乳動物之疾病之治療方案之部分製造或銷售。醫藥組合物可經調配(例如)用於以單位劑型(例如,錠劑、膠囊、囊劑、膠囊錠或糖漿)經口投與;用於局部投與(例如,呈藥膏、凝膠、洗劑或軟膏);用於靜脈內投與(例如,呈不含顆粒栓塞之無菌溶液及在適用於靜脈內使用之溶劑系統中);或於本文描述之任何其他調配物中。As used herein, the term "pharmaceutical composition" means a composition containing a compound described herein formulated with a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutical composition is manufactured or sold as part of a therapeutic regimen for treating a disease in a mammal with approval by a governmental regulatory agency. The pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, capsules, encapsulates, or syrups); for topical administration (e.g., as an ointment, gel, lotion, or cream); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
如本文使用,「醫藥上可接受之賦形劑」係指除本文描述之化合物外且具有於病患中無毒且非發炎之性質之任何成分(例如,可懸浮或溶解活性化合物之媒劑)。賦形劑可包括(例如):抗黏附劑、抗氧化劑、黏合劑、包衣劑、壓縮助劑、崩解劑、染料(著色劑)、軟化劑、乳化劑、填充劑(稀釋劑)、成膜劑或包衣劑、調味劑、香精、助流劑(流量增強劑)、潤滑劑、防腐劑、列印油墨、放射性防護劑、吸附劑、懸浮劑或分散劑、甜味劑或水合作用的水。例示性賦形劑包括(但不限於):抗壞血酸、組胺酸、磷酸鹽緩衝液、丁基化羥基甲苯(BHT)、碳酸鈣、磷酸鈣(二元酸)、硬脂酸鈣、交聯羧甲基纖維素、交聯聚乙烯吡咯啶酮、檸檬酸、交聯聚維酮、半胱胺酸、乙基纖維素、明膠、羥基丙基纖維素、羥基丙基甲基纖維素、乳糖、硬脂酸鎂、麥芽糖醇、甘露醇、甲硫胺酸、甲基纖維素、對羥基苯甲酸甲酯、微晶纖維素、聚乙二醇、聚乙烯吡咯啶酮、聚維酮、預糊化澱粉、對羥基苯甲酸丙酯、棕櫚酸視黃酯、蟲膠、二氧化矽、羧基甲基纖維素鈉、檸檬酸鈉、乙醇酸澱粉鈉、山梨醇、澱粉(玉米)、硬脂酸、硬脂酸、蔗糖、滑石、二氧化鈦、維生素A、維生素E、維生素C及木糖醇。As used herein, "pharmaceutically acceptable excipients" refers to any ingredient other than the compounds described herein that is non-toxic and non-inflammatory in a patient (e.g., a vehicle that can suspend or dissolve the active compound). Excipients may include, for example: anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming or coating agents, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Exemplary excipients include, but are not limited to, ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic acid), calcium stearate, cross-linked carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked povidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, magnesium stearate, maltitol, mannitol, methylcellulose, Thiamine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, wormwood, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol.
如本文使用,術語「醫藥上可接受之鹽」表示彼等本文描述之化合物之鹽,其等係於合理之醫學判斷之範圍內,適用於與人類及動物之組織接觸而無過度毒性、刺激或過敏反應。醫藥上可接受之鹽為此項技術中熟知。例如,醫藥上可接受之鹽係描述於Berge等人,J. Pharmaceutical Sciences 66:1-19, 1977中及描述於Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl及C.G. Wermuth編), Wiley-VCH, 2008中。該等鹽可在最終分離及本文描述之化合物之純化期間原位製備或藉由使游離鹼基與合適之有機酸反應單獨製備。As used herein, the term "pharmaceutically acceptable salt" means salts of the compounds described herein that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation or allergic reaction, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl and C.G. Wermuth, eds.), Wiley-VCH, 2008. Such salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
化合物可具有可電離基團以便於能夠製備成醫藥上可接受之鹽。此等鹽可為涉及無機或有機酸之酸加成鹽或該等鹽在化合物之酸性形式之情況下可由無機或有機鹼製備。通常,該等化合物係製備成或用作醫藥上可接受之鹽,該等鹽係經製備成醫藥上可接受之酸或鹼之加成產物。合適之醫藥上可接受之酸及鹼為此項技術中熟知,諸如用於形成酸加成鹽之鹽酸、硫酸、氫溴酸、乙酸、乳酸、檸檬酸或酒石酸,及用於形成鹼性鹽之氫氧化鉀、氫氧化鈉、氫氧化銨、咖啡因、各種胺。用於製備適當之鹽之方法為此項技術中公認的。The compounds may have ionizable groups so as to be able to prepare pharmaceutically acceptable salts. Such salts may be acid addition salts involving inorganic or organic acids or, in the case of acidic forms of the compounds, may be prepared from inorganic or organic bases. Typically, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid or tartaric acid for the formation of acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for the formation of basic salts. Methods for preparing suitable salts are well recognized in the art.
代表性酸加成鹽包括乙酸鹽、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、富馬酸鹽、葡庚酸鹽、甘油磷酸鹽、半硫酸鹽、葡庚糖酸鹽、己酸鹽、氫溴酸鹽、鹽酸鹽、氫碘酸鹽、2-羥基-乙磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽、十一烷酸鹽、戊酸鹽等。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽及鎂鹽,及無毒銨鹽、第四銨鹽,及胺陽離子,包括(但不限於)銨鹽、四甲基銨鹽、四乙基銨鹽、甲基胺、二甲基胺、三甲基胺、三乙基胺及乙基胺。Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrosulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyprolate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, glucoheptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, apple acid salt, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bis(hydroxynaphthoate), pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartaric acid, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkaline metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, and non-toxic ammonium salts, quaternary ammonium salts, and amine cations, including but not limited to ammonium salts, tetramethylammonium salts, tetraethylammonium salts, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
如本文使用,術語「放射性藥物」或「放射性結合物」係指包括放射性同位素或放射性核素,諸如本文描述之放射性同位素或放射性核素中之任一者之任何化合物或結合物。As used herein, the term "radiopharmaceutical" or "radioconjugate" refers to any compound or conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
如本文使用,術語「放射性核素」係指能夠經受放射性衰變之原子(例如, 3H、 14C、 15N、 18F、 35S、 47Sc、 55Co、 60Cu、 61Cu、 62Cu、 64Cu、 67Cu、 75Br、 76Br 、 77Br 、 89Zr、 86Y、 87Y、 90Y、 97Ru、 99Tc、 99mTc、 105Rh、 109Pd、 111In、 123I、 124I、 125I、 131I、 149Pm、 149Tb、 153Sm、 166Ho、 177Lu、 186Re、 188Re、 198Au、 199Au、 203Pb、 211At、 212Pb 、 212Bi、 213Bi、 223Ra、 225Ac、 227Th、 229Th、 66Ga、 67Ga、 68Ga、 82Rb、 117mSn或 201Tl)。術語放射性核素、放射性同位素或放射性同位素亦可用於描述放射性核素。放射性核素可用作偵測劑。本發明中使用之例示性放射性核素包括(但不限於) 43Sc、 44Sc、 47Sc、 55Co、 60Cu、 61Cu、 62Cu、 64Cu、 67Cu、 66Ga、 67Ga、 68Ga、 82Rb、 86Y、 87Y、 89Zr、 90Y、 97Ru、 99Tc、 99mTc、 105Rh、 109Pd、 111In、 117mSn、 133La、 134Ce、 149Pm、 149Tb、 153Sm、 152Tb、 155Tb、 161Tb、 166Ho、 177Lu、 186Re、 188Re、 198Au、 199Au、 201Tl、 203Pb、 211At、 212Pb、 212Bi、 213Bi、 223Ra、 225Ac、 227Th及 229Th。 As used herein, the term "radionuclide" refers to an atom that is capable of undergoing radioactive decay (e.g., 3 H, 14 C, 15 N, 18 F, 35 S, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 75 Br, 76 Br, 77 Br, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, 99 Tc, 99m Tc, 105 Rh, 109 Pd, 111 In, 123 I, 124 I, 125 I, 131 I, 149 Pm, 149 Tb, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 203 Radionuclides may also be used to describe radionuclides (e.g., 211 Pb, 212 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 229 Th, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 117m Sn, or 201 Tl). The terms radionuclide, radioisotope, or radioisotope may also be used to describe radionuclides. Radionuclides can be used as detectors. 177 Sm, 178 Tb, 179 Tb, 200 Rb, 212 Rb , 213 Sr, 214 Rb, 215 Rb-1, 216 Rb-2, 217 Rb-3, 218 Rb-4, 219 Rb-5, 220 Rb - 6 , 221 Rb - 7 , 222 Rb -8 , 223 Rb-9, 224 Rb-1, 225 Rb-1, 226 Rb-1, 227 Rb - 1 , 228 Rb - 2 , 229 Rb -3, 230 Rb -3, 231 Rb - 3 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th and 229 Th.
如本文使用及如此項技術中熟知,「治療」病症或病症之「治療」 (例如,本文描述之病症,諸如癌症)係一種用於獲得有利或所需結果(諸如臨床結果)之方法。有利或所需結果可包括(但不限於)一或多種症狀或病症之減輕或改善;減輕疾病、疾患或病症之程度;使疾病、疾患或病症之狀態穩定(即不惡化);預防疾病、疾患或病症之擴散;延遲或減緩該疾病、疾患或病症之進展;改善或緩和該疾病、疾患或病症;及緩解(無論部分或總體),無論可偵測或不可偵測。在癌症治療之內文中,「改善」可包括(例如)降低轉移之發生率、減小腫瘤體積、減少腫瘤血管化及/或降低腫瘤之生長速率。「緩和」疾病、疾患或病症意謂相較於在缺乏治療之情況下之程度或時間行程,該疾病、疾患或病症之程度及/或非所需之臨床表現係經減少及/或該進展之時間行程係經減緩或延長。 化合物 As used herein and as is well known in the art, "treatment" of a disorder or condition (e.g., a disorder described herein, such as cancer) is an approach for obtaining beneficial or desired results (e.g., clinical results). Beneficial or desired results may include, but are not limited to, a reduction or improvement in one or more symptoms or conditions; a reduction in the extent of the disease, disorder, or condition; stabilization (i.e., not worsening) of the disease, disorder, or condition; prevention of the spread of the disease, disorder, or condition; delay or slowing the progression of the disease, disorder, or condition; amelioration or alleviation of the disease, disorder, or condition; and relief (whether partial or total), whether detectable or undetectable. In the context of cancer treatment, "improvement" may include, for example, reducing the incidence of metastasis, reducing tumor size, reducing tumor vascularization, and/or reducing the growth rate of a tumor. "Reducing" a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are reduced and/or the time course of progression is slowed or prolonged compared to the extent or time course in the absence of treatment. Compounds
本發明係部分關於作為放射性藥物之化合物。在一些實施例中,本發明之化合物係選自由表1中鑑別之化合物組成之群。
表1.
式I化合物包含螯合部分或螯合劑。The compounds of formula I contain a chelating moiety or chelating agent.
如本文揭示,螯合劑可選自由以下組成之群:DOTA (1,4,7,10-四氮雜環十二烷-1,4,7,10-四乙酸)、DOTMA (1R,4R,7R,10R)-α,α’,α”,α’”-四甲基-1,4,7,10-四氮雜環十二烷-1,4,7,10-四乙酸、DOTAM (1,4,7,10-肆(胺甲醯基甲基)-1,4,7,10-四氮雜環十二烷)、DOTPA (1,4,7,10-四氮雜環十二烷-1,4,7,10-四丙酸)、DO3AM-乙酸(2-(4,7,10-參(2-胺基-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)乙酸)、DOTA-GA酸酐(2,2’,2”-(10-(2,6-二側氧基四氫-2H-哌喃-3-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸、DOTP (1,4,7,10-四氮雜環十二烷-1,4,7,10-四(亞甲基膦酸))、DOTMP (1,4,6,10-四氮雜環癸烷-1,4,7,10-四亞甲基膦酸、DOTA-4AMP (1,4,7,10-四氮雜環十二烷-1,4,7,10-肆(乙醯胺基-亞甲基膦酸)、CB-TE2A (1,4,8,11-四氮雜雙環[6.6.2]十六烷-4,11-二乙酸)、NOTA (1,4,7-三氮雜環壬烷-1,4,7-三乙酸)、NODA-GA (1,4,7-三氮雜環壬烷-4,7-二乙酸-1-[2-戊二酸])、NOTP (1,4,7-三氮雜環壬烷-1,4,7-三(亞甲基膦酸)、TETPA (1,4,8,11-四氮雜環十四烷-1,4,8,11-四丙酸)、TETA (1,4,8,11-四氮雜環十四烷-1,4,8,11-四乙酸)、HEHA (1,4,7,10,13,16-六氮雜環十六烷-1,4,7,10,13,16-六乙酸)、PEPA (1,4,7,10,13-五氮雜環十五烷-N,N’,N”,N’’’,N’’’’-五乙酸)、H 4octapa (N,N’-雙(6-羧基-2-吡啶基甲基)-乙二胺-N,N’-二乙酸)、H 2dedpa (1,2-[[6-(羧基)-吡啶-2-基]-甲基胺基]乙烷)、H 6phospa (N,N’-(亞甲基膦酸酯)-N,N’-[6-(甲氧基羰基)吡啶-2-基]-甲基-1,2-二胺基乙烷)、TTHA (三乙烯四胺-N,N,N’,N”,N’’’,N’’’-六乙酸)、DO2P (四氮雜環十二烷二甲烷膦酸)、HP-DO3A (羥基丙基四氮雜環十二烷三乙酸)、EDTA (乙二胺四乙酸)、去鐵胺、DTPA (二伸乙三胺五乙酸)、DTPA-BMA (二伸乙三胺五乙酸-雙甲基醯胺)及卟啉。 As disclosed herein, the chelating agent can be selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α,α',α",α'"-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetra(aminomethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid), DOTA-GA anhydride (2,2',2"-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid), DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylenephosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(acetamido-methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NODA-GA (1,4,7-triazacyclononane-4,7-diacetic acid-1-[2-pentanedioic acid]), NOTP (1,4,7-triazacyclononane-1,4,7-tri(methylenephosphonic acid), TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N''',N''''-pentaacetic acid), H 4 octapa (N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid), H 2 dedpa (1,2-[[6-(Carboxy)-pyridin-2-yl]-methylamino]ethane), H 6 phospa (N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine-N,N,N',N",N''',N'''-hexaacetic acid), DO2P (tetraazacyclododecanedimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide) and porphyrin.
在某些實施例中,螯合劑係選自DOTA、DOTA-GA、NOTA、NODA-GA、NODA-SA、DTPA、TETA、EDTA、TRITA、CDTA及DFO,其等係如下文定義: DOTA代表1,4,7,10-四氮雜環十二烷-1,4,7,10-四乙酸, 如本文使用之DOTA-GA或DOTAGA代表1,4,7,10-四氮雜環十二烷,1-(戊二酸)-4,7,10-三乙酸, NOTA代表1,4,7-三氮雜環壬烷三乙酸, 如本文使用之NODA-GA或NODAGA代表1,4,7-三氮雜環壬烷-N-戊二酸-N',N"-二乙酸, NODA-SA代表1,4,7-三氮雜環壬烷-1-琥珀酸-4,7-二乙酸, DTPA代表二伸乙三胺五乙酸, TETA代表1,4,8,11-四氮雜環十二烷-1,4,8,11-四乙酸, EDTA代表乙胺-N,N'-四乙酸, TRITA代表1,4,7,10 四氮雜環十三烷-l,4,7,10-四乙酸, CDTA代表反式-1,2-二胺基環己烷-N,N,N',N'-四乙酸, DFO代表螯合劑之去鐵胺(Desferal或Desferrioxamine)型基團,非限制性實例之化學名稱係N-[5-({3-[5-(乙醯基-羥基-胺基)-戊基胺甲醯基]-丙醯基}-羥基-胺基)-戊基]-N'-(5-胺基-戊基)-N'-羥基-琥珀醯胺, 且其具有如下化學結構: In certain embodiments, the chelating agent is selected from DOTA, DOTA-GA, NOTA, NODA-GA, NODA-SA, DTPA, TETA, EDTA, TRITA, CDTA and DFO, which are defined as follows: DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA-GA or DOTAGA as used herein represents 1,4,7,10-tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10-triacetic acid, NOTA represents 1,4,7-triazacyclononanetriacetic acid, NODA-GA or NODAGA as used herein represents 1,4,7-triazacyclononane-N-pentanedioic acid-N',N"-diacetic acid, NODA-SA represents 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid, DTPA stands for diethylenetriaminepentaacetic acid, TETA stands for 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid, EDTA stands for ethylamine-N,N'-tetraacetic acid, TRITA stands for 1,4,7,10-tetraazacyclotridecane-l,4,7,10-tetraacetic acid, CDTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, DFO represents a desferal or desferrioxamine type group of a chelating agent, a non-limiting example of which is named N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylaminomethyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide, and has the following chemical structure:
在某些實施例中,螯合劑係選自DOTA、DOTAGA、NOTA及NODAGA。In certain embodiments, the chelating agent is selected from DOTA, DOTAGA, NOTA and NODAGA.
在某些實施例中,螯合劑係DOTAGA且化合物具有式II結構: (II), 其中變量X、Y、n、Z 1及Z 2中之各者係如上文發明內容部分中定義。 In certain embodiments, the chelating agent is DOTAGA and the compound has the structure of Formula II: (II), wherein each of the variables X, Y, n, Z1 and Z2 is as defined above in the invention section.
在某些實施例中,螯合劑係由變量W表示。在一些實施例中,W係選自由以下組成之群: 、 、 及 。 放射性核素 In some embodiments, the chelating agent is represented by the variable W. In some embodiments, W is selected from the group consisting of: , , and . Radionuclides
本發明包括各包含放射性核素之放射性藥物。合適之放射性核素之實例包括(但不限於) 43Sc、 44Sc、 47Sc、 55Co、 60Cu、 61Cu、 62Cu、 64Cu、 67Cu、 66Ga、 67Ga、 68Ga、 82Rb、 86Y、 87Y、 89Zr、 90Y、 97Ru、 99Tc、 99mTc、 105Rh、 109Pd、 111In、 117mSn、 133La、 134Ce、 149Pm、 149Tb、 153Sm、 152Tb、 155Tb、 161Tb、 166Ho、 177Lu、 186Re、 188Re、 198Au、 199Au、 201Tl、 203Pb、 211At、 212Pb、 212Bi、 213Bi、 223Ra、 225Ac、 227Th及 229Th。 The present invention includes radiopharmaceuticals each comprising a radionuclide. Examples of suitable radionuclides include, but are not limited to, 43 Sc, 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 90 Y, 97 Ru, 99 Tc, 99m Tc, 105 Rh, 109 Pd, 111 In, 117m Sn, 133 La, 134 Ce, 149 Pm, 149 Tb, 153 Sm, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 201 Tl, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th and 229 Th.
在一些實施例中,放射性核素係選自由以下組成之群: 64Cu、 67Cu、 68Ga、 90Y、 111In、 149Tb、 153Sm、 177Lu、 211At、 212Bi、 212Pb、 213Bi、 223Ra、 225Ac及 227Th。 In some embodiments, the radionuclide is selected from the group consisting of 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra , 225 Ac, and 227 Th.
在一些實施例中,放射性核素係 68Ga、 89Zr、 90Y、 111In、 177Lu或 225Ac。在某些實施例中,該放射性核素係 177Lu或 225Ac。 In some embodiments, the radionuclide is 68 Ga, 89 Zr, 90 Y, 111 In, 177 Lu, or 225 Ac. In certain embodiments, the radionuclide is 177 Lu or 225 Ac.
在一些實施例中,本文使用之放射性核素係β發射放射性核素,諸如 177Lu。在一些實施例中,本文使用之放射性核素係發射α放射性核素,諸如 225Ac。 連接子 In some embodiments, the radionuclides used herein are beta emitting radionuclides, such as 177 Lu. In some embodiments, the radionuclides used herein are alpha emitting radionuclides, such as 225 Ac. Linkers
本發明之化合物包含如式I結構內顯示之獨特連接子,其包含 ,其中X係不存在或C=O;Y各獨立地係O或NR,R係H、烷基、芳基或醯基;n係0至5 (含)之整數;Z 1及Z 2各獨立地係不存在或胺基酸單元。 The compounds of the present invention comprise a unique linker as shown in the structure of Formula I, which comprises , wherein X is absent or C=O; Y is independently O or NR, R is H, alkyl, aryl or acyl; n is an integer from 0 to 5 (inclusive); Z1 and Z2 are independently absent or an amino acid unit.
本文描述之術語「胺基酸單元」係指一或多個各由胺基酸(例如,天然胺基酸或非天然胺基酸)形成之有機部分。通常,胺基酸單元係如下文顯示形成: 其中R 2表示烷基、環烷基、芳基或雜芳基,其等中之各者可視需要經本文描述之合適取代基(例如,-C(O)OH、-NH 2、-NH 3+、-NH(CNH 2 +)NH 2)取代;或者,R 2連同該胺基酸內之-NH 2基團一起形成雜環。 The term "amino acid unit" described herein refers to one or more organic moieties each formed from amino acids (e.g., natural amino acids or non-natural amino acids). Typically, an amino acid unit is formed as shown below: wherein R 2 represents an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, each of which may be substituted with a suitable substituent described herein (e.g., -C(O)OH, -NH 2 , -NH 3 +, -NH(CNH 2 + )NH 2 ) as required; or, R 2 together with the -NH 2 group in the amino acid forms a heterocyclic ring.
在一些實施例中,胺基酸單元係指由天冬胺酸(Asp)、麩胺酸(Glu)、2,4-二胺基丁酸(Dab)、2,3-二胺基丙酸(Dap)、離胺酸(Lys)或精胺酸(Arg)形成之有機部分,其等具有下文顯示之結構: 。 In some embodiments, the amino acid unit refers to an organic moiety formed by aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys) or arginine (Arg), which have the structures shown below: .
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元包含由天冬胺酸(Asp)形成之有機部分,例如,具有如顯示之結構(包括其立體異構體) 。 In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit comprises an organic moiety formed by aspartic acid (Asp), for example, having the structure shown (including stereoisomers thereof) .
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元係由甘胺酸(Gly)形成,例如,具有結構 。 In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by glycine (Gly), for example, having the structure .
在一些實施例中,式I或式II化合物之特徵在於胺基酸單元係由麩胺酸(Glu)形成,例如,具有下文顯示之結構(包括其立體異構體) 。 In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by glutamic acid (Glu), for example, having the structure shown below (including its stereoisomers): .
在一些實施例中,胺基酸單元係指包含多個由麩醯胺酸、麩胺酸及精胺酸形成之有機部分之片段,其等具有下文顯示之結構,包括所有其等立體異構體: 。 In some embodiments, the amino acid unit refers to a fragment comprising a plurality of organic moieties formed from glutamine, glutamine and arginine, which have the structures shown below, including all stereoisomers thereof: .
在一些實施例中,式I或式II化合物之特徵在於X係C=O。In some embodiments, the compound of formula I or formula II is characterized in that X is C═O.
在一些實施例中,式I或式II化合物之特徵在於n係1、2、3、4或5。在某些實施例中,n係4或5。In some embodiments, the compound of Formula I or Formula II is characterized in that n is 1, 2, 3, 4 or 5. In certain embodiments, n is 4 or 5.
在一些實施例中,式I或式II化合物之特徵在於Z 1及Z 2中之各者係不存在。 In some embodiments, the compound of Formula I or Formula II is characterized in that each of Z 1 and Z 2 is absent.
在一些實施例中,式I或式II化合物之特徵在於Z 1及Z 2中之各者係不存在,X係C=O,Y各獨立地係O或NH,及n係0、1、2、3、4或5。例示性連接子包括(但不限於)下列: 、 、 、 、 及 ,其等中之各者可視需要經本文描述之合適取代基取代。 In some embodiments, the compound of Formula I or Formula II is characterized in that each of Z 1 and Z 2 is absent, X is C=O, Y is each independently O or NH, and n is 0, 1, 2, 3, 4 or 5. Exemplary linkers include, but are not limited to, the following: , , , , and , each of which may be substituted with a suitable substituent described herein as necessary.
在一些實施例中,式I或式II化合物之特徵在於X係C=O,n係4或5,Z 1係胺基酸單元,及Z 2係不存在。代表性例示性化合物係下列中之一者: 及 。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z 1 is an amino acid unit, and Z 2 is absent. Representative exemplary compounds are one of the following: and .
在一些實施例中,式I或式II化合物之特徵在於X係C=O,n係4或5,Z 1係不存在,及Z 2係胺基酸單元。代表性例示性化合物係下列中之一者: 及 。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z 1 is absent, and Z 2 is an amino acid unit. Representative exemplary compounds are one of the following: and .
在一些實施例中,式I或式II化合物之特徵在於X係(C=O)NH,n係4或5,Z 1及Z 2中之各者係不存在。代表性例示性化合物係下列中之一者: 及 。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NH, n is 4 or 5, and each of Z1 and Z2 is absent. Representative exemplary compounds are one of the following: and .
在一些實施例中,式I或式II化合物之特徵在於X係C=O,n係4或5,Z 1係不存在,及Z 2係(C=O)NH(CH 2CH 2)NH。代表性例示性化合物係下列中之一者: 及 。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z 1 is absent, and Z 2 is (C=O)NH(CH 2 CH 2 )NH. Representative exemplary compounds are one of the following: and .
在一些實施例中,式I或式II化合物之特徵在於X係不存在,n係0,Z 1係不存在,及Z 2係胺基酸單元。因此,此等化合物之連接子將為: ,其中R 2表示烷基、環烷基、芳基或雜芳基,其等中之各者可視需要經本文描述之合適取代基取代;或者,R 2連同該胺基酸內之-NH 2基團一起形成雜環。 In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, Z 1 is absent, and Z 2 is an amino acid unit. Therefore, the linker of these compounds will be: , wherein R 2 represents an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, each of which may be substituted with a suitable substituent as described herein as necessary; or, R 2 together with the -NH 2 group in the amino acid forms a heterocyclic ring.
代表性例示性化合物係下列中之一者: 及 。 Representative exemplary compounds are one of the following: and .
在一些實施例中,式I或式II化合物之特徵在於X係不存在,n係0,Z 1及Z 2中之各者係不存在。代表性例示性化合物係下列中之一者: 及 。 個體 In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, and each of Z1 and Z2 is absent. Representative exemplary compounds are one of the following: and . Individual
在一些本文揭示之方法中,對個體投與療法(例如包含治療劑)。在一些實施例中,該個體係哺乳動物,例如人類。In some methods disclosed herein, a therapy (e.g., comprising a therapeutic agent) is administered to a subject. In some embodiments, the subject is a mammal, such as a human.
在一些實施例中,個體患有癌症或有發生癌症之風險。例如,該個體可能已診斷患有癌症。該癌症可為原發性癌症或轉移性癌症。個體可患有任何階段之癌症,例如I期、II期、II期或IV期,有或無淋巴結涉及,及有或無轉移。本發明提供之組合物可預防或減少該癌症之進一步生長及/或另外改善該癌症(例如預防或減少轉移)。在一些實施例中,該個體未患有癌症但已確定處於發生癌症之風險,例如由於存在一或多種風險因素,諸如環境曝露、一或多種基因突變或變異體之存在、家族史等。在一些實施例中,該個體尚未診斷患有癌症。In some embodiments, the individual has cancer or is at risk of developing cancer. For example, the individual may have been diagnosed with cancer. The cancer may be a primary cancer or a metastatic cancer. The individual may have cancer at any stage, such as stage I, stage II, stage III, or stage IV, with or without lymph node involvement, and with or without metastasis. The compositions provided by the present invention can prevent or reduce further growth of the cancer and/or otherwise improve the cancer (e.g., prevent or reduce metastasis). In some embodiments, the individual does not have cancer but has been determined to be at risk of developing cancer, for example, due to the presence of one or more risk factors, such as environmental exposure, the presence of one or more genetic mutations or variants, family history, etc. In some embodiments, the individual has not yet been diagnosed with cancer.
在一些實施例中,癌症係小細胞肺癌、非小細胞肺癌、肉瘤、胰臟癌、乳癌或結腸癌。 投與及劑量 有效劑量 In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer. Administration and Dosage Effective Dose
本發明提供使用式I化合物治療表現HSP90之臨床適應症之方法,及該化合物係以對於此治療之治療有效量投與個體(例如人類)。The present invention provides methods of using the compounds of formula I to treat clinical indications manifesting HSP90, and the compounds are administered to a subject (eg, a human) in a therapeutically effective amount for such treatment.
本發明亦涵蓋組合療法,其中各治療劑之量本身可為或可不為治療有效。在一些實施例中,如本文揭示之治療組合係以足夠治癒或至少部分遏制疾患及其併發症之症狀之方式(例如給藥量及時間)投與個體。在單藥療法(「單一療法」)之內文中,將足以達成此目的之量定義為「治療有效量」,足以實質上改善至少一種與疾病或醫學病症相關症狀之化合物之量。該「治療有效量」通常依治療劑而變化。針對已知治療劑,相關治療有效量可為熟習此項技術者已知或輕易決定。The present invention also encompasses combination therapies, in which the amount of each therapeutic agent may or may not be therapeutically effective by itself. In some embodiments, a therapeutic combination as disclosed herein is administered to a subject in a manner (e.g., dosage and duration) sufficient to cure or at least partially arrest the symptoms of a disease and its complications. In the context of monotherapy ("monotherapy"), an amount sufficient to achieve this purpose is defined as a "therapeutically effective amount," an amount of a compound sufficient to substantially improve at least one symptom associated with a disease or medical condition. The "therapeutically effective amount" generally varies depending on the therapeutic agent. For known therapeutic agents, the relevant therapeutically effective amount may be known or readily determined by those skilled in the art.
例如,在癌症之治療中,減少、預防、延遲、抑制或遏制疾病或病症之任何症狀之藥劑或化合物將為治療有效的。治療有效量之藥劑或化合物無需治癒疾病或病症,但將提供疾病或病症之治療,使得於個體中該疾病或病症之發病延遲、阻礙或預防,或該疾病或病症症狀改善,或該疾病或病症之期間改變,或例如較不嚴重,或加速復原。例如,若治療使得癌症消退或減緩癌症之生長,則該治療可為治療有效的。For example, in the treatment of cancer, an agent or compound that reduces, prevents, delays, inhibits or suppresses any symptom of the disease or disorder will be therapeutically effective. A therapeutically effective amount of an agent or compound need not cure the disease or disorder, but will provide treatment for the disease or disorder such that the onset of the disease or disorder in an individual is delayed, hindered or prevented, or symptoms of the disease or disorder are ameliorated, or the duration of the disease or disorder is altered, or is, for example, less severe, or recovery is accelerated. For example, a treatment may be therapeutically effective if it causes cancer regression or slows the growth of cancer.
針對此等用途有效之劑量方案(例如,各治療劑之量、療法之相對時間等)可取決於疾病或病症之嚴重程度及個體之體重及一般狀況。例如,施用至哺乳動物(例如,人類)之包含治療劑之特定組合物的治療有效量可由一般技術者在考慮該哺乳動物之年齡、體重及病症之個別差異後確定。由於本發明之某些結合物顯示標靶癌細胞及剩餘化之能力增強,因此此等化合物之劑量可低於未結合藥劑之治療效應所需之等同劑量(例如,小於或等於其約90%、75%、50%、40%、30%、20%、15%、12%、10%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.1%)。治療有效及/或最佳量亦可由熟習此項技術者憑經驗確定。因此,較低之有效劑量亦可由熟習此項技術者確定。Dosage regimens effective for these uses (e.g., the amount of each therapeutic agent, the relative duration of treatment, etc.) may depend on the severity of the disease or condition and the weight and general condition of the individual. For example, a therapeutically effective amount of a particular composition comprising a therapeutic agent administered to a mammal (e.g., a human) can be determined by one of ordinary skill in the art after considering the individual differences in age, weight, and condition of the mammal. Because certain conjugates of the present invention exhibit enhanced ability to target cancer cells and residual cancer, the dosage of these compounds may be lower than the equivalent dosage required for the therapeutic effect of the unconjugated agent (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%). Therapeutically effective and/or optimal amounts may also be determined empirically by those skilled in the art. Therefore, lower effective dosages may also be determined by those skilled in the art.
放射性藥物或組合物(例如,包含治療劑或放射性藥物之醫藥組合物)之單次或多次投與可以由主治醫師選擇之劑量及模式進行。劑量及投與時間表可基於個體之疾病或病症之嚴重程度確定及調整,其可在整個治療過程中根據由臨床醫生通常實踐之方法或彼等本文描述者監測。Single or multiple administrations of a radiopharmaceutical or composition (e.g., a pharmaceutical composition comprising a therapeutic agent or radiopharmaceutical) can be performed in a dose and mode selected by the attending physician. The dose and administration schedule can be determined and adjusted based on the severity of the individual's disease or condition, which can be monitored throughout the course of treatment according to methods commonly practiced by clinicians or those described herein.
如上文提供,本發明之放射性藥物化合物可與另一治療劑組合投與。在本文揭示之組合療法方法中,第一及第二療法可對個體循序或同時投與。例如,包含第一治療劑之第一組合物及包含第二治療劑之第二組合物可對該個體循序或同時投與。或者,包含第一治療劑及第二治療劑之組合之組合物可對該個體投與。As provided above, the radiopharmaceutical compounds of the present invention can be administered in combination with another therapeutic agent. In the combination therapy methods disclosed herein, the first and second therapeutic agents can be administered to the individual sequentially or simultaneously. For example, a first composition comprising a first therapeutic agent and a second composition comprising a second therapeutic agent can be administered to the individual sequentially or simultaneously. Alternatively, a composition comprising a combination of the first therapeutic agent and the second therapeutic agent can be administered to the individual.
在一些實施例中,放射性藥物係以單一劑量投與。在一些實施例中,該放射性藥物係以多於一次,即多個劑量投與。當該放射性藥物係以多於一次投與時,每次投與之劑量可係相同或不同的。In some embodiments, the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered more than once, i.e., in multiple doses. When the radiopharmaceutical is administered more than once, the doses administered each time may be the same or different.
在一些實施例中,出於放射治療計劃或診斷目的投與組合物(諸如包含放射性藥物之組合物)。當出於放射治療計劃或診斷目的投與時,組合物可以診斷有效劑量及/或有效確定治療有效劑量之量對個體投與。在一些實施例中,第一劑量之本文揭示之結合物或其組合物(例如,醫藥組合物)係以對放射治療計劃有效之量投與,接著投與包括如本文揭示之結合物及另一治療劑之組合療法。In some embodiments, a composition (e.g., a composition comprising a radiopharmaceutical) is administered for radiation therapy planning or diagnostic purposes. When administered for radiation therapy planning or diagnostic purposes, the composition can be administered to a subject in a diagnostically effective dose and/or in an amount effective to determine a therapeutically effective dose. In some embodiments, a first dose of a conjugate disclosed herein or a composition thereof (e.g., a pharmaceutical composition) is administered in an amount effective for a radiation therapy plan, followed by administration of a combination therapy comprising a conjugate as disclosed herein and another therapeutic agent.
包含一或多種藥劑(例如,放射性藥物)之醫藥組合物可經調配以根據本文揭示之方法及系統用於各種藥物遞送系統中。一或多種生理上可接受之賦形劑或載劑亦可包括於該組合物中用於進行適當之調配。合適之調配物之實例係於Remington’s Pharmaceutical Sciences, Mack出版公司,Philadelphia, PA,第17版1985中找到。為簡要回顧用於藥物遞送之方法,例如,參見Langer (Science 249:1527-1533, 1990)。 調配物 Pharmaceutical compositions comprising one or more agents (e.g., radiopharmaceuticals) can be formulated for use in various drug delivery systems according to the methods and systems disclosed herein. One or more physiologically acceptable excipients or carriers may also be included in the composition for proper formulation. Examples of suitable formulations are found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th edition 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990). Formulations
醫藥組合物可經調配用於非經腸、鼻內、局部、經口或局部投與,諸如藉由透皮方式,用於預防性及/或治療性治療。醫藥組合物可非經腸投與(例如,藉由靜脈內、肌內或皮下注射),或藉由經口給藥,或藉由於受血管或癌症病症影響之區域處局部施用或關節內注射。另外投與途徑之實例包括血管內、動脈內、腫瘤內、腹膜內、腦室內、硬膜外及經鼻、經眼、鞏膜內、眶內、經直腸、局部或氣霧劑吸入投與。亦經明確審慎考慮的係緩釋投與,藉由諸如儲庫型注射物或易侵蝕植入物或組分之方式。合適之組合物包括包含溶解或懸浮於可接受之載劑,較佳水性載劑,例如,水、經緩衝之水、生理鹽水或PBS等中,例如,用於非經腸投與之藥劑(例如,如本文揭示之化合物)的組合物。組合物可含有接近生理條件之醫藥上可接受之輔助物質,諸如pH調節劑及緩衝劑、張力調節劑、潤濕劑或洗滌劑等。在一些實施例中,組合物係經調配用於經口遞送;例如,組合物可含有惰性成分,諸如黏合劑或填充劑用於調配單位劑型,諸如錠劑或膠囊。在一些實施例中,組合物係經調配用於局部投與;例如,組合物可含有惰性成分,諸如溶劑或乳化劑用於調配乳膏、軟膏、凝膠、糊劑或滴眼液。The pharmaceutical composition can be formulated for parenteral, intranasal, topical, oral or local administration, such as by transdermal means, for preventive and/or therapeutic treatment. The pharmaceutical composition can be administered parenterally (e.g., by intravenous, intramuscular or subcutaneous injection), or by oral administration, or by topical application or intraarticular injection at an area affected by a vascular or cancer condition. Additional examples of routes of administration include intravascular, intraarterial, intratumoral, intraperitoneal, intraventricular, epidural, and nasal, ocular, intrascleral, intraorbital, rectal, topical or aerosol inhalation administration. Also expressly contemplated is sustained release administration, by means such as depot injections or erodible implants or compositions. Suitable compositions include compositions comprising a pharmaceutical agent (e.g., a compound as disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, such as water, buffered water, saline or PBS, etc., for parenteral administration. The composition may contain pharmaceutically acceptable auxiliary substances that approximate physiological conditions, such as pH adjusters and buffers, tonicity adjusters, wetting agents or detergents, etc. In some embodiments, the composition is formulated for oral delivery; for example, the composition may contain inert ingredients, such as binders or fillers for formulation of unit dosage forms, such as tablets or capsules. In some embodiments, the composition is formulated for topical administration; for example, the composition may contain inert ingredients such as solvents or emulsifiers for formulation of creams, ointments, gels, pastes, or eye drops.
組合物可(例如)藉由習知滅菌技術進行滅菌,或經無菌過濾。水溶液可經包裝以原樣使用,或經凍乾,凍乾製劑在投與前係與無菌水性載劑組合。該等製劑之pH通常將介於3與11之間,更佳介於5與9之間或介於6與8之間,及最佳介於6與7之間,諸如6至6.5。在一些實施例中,呈固體形式之組合物係以多個單劑量單元包裝,各含有固定量之上文提及之一或多種藥劑,諸如於錠劑或膠囊之密封包裝中。在一些實施例中,呈固體形式之組合物係以彈性量包裝於容器中,諸如包裝於為可局部施用乳膏或軟膏設計之可擠壓管中。 包含式I化合物之放射性藥物之合成 The composition can be sterilized, for example, by conventional sterilization techniques, or aseptically filtered. The aqueous solution can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier before administration. The pH of such preparations will generally be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7, such as 6 to 6.5. In some embodiments, the composition in solid form is packaged in multiple single dosage units, each containing a fixed amount of one or more of the above-mentioned agents, such as in a sealed package of tablets or capsules. In some embodiments, the composition in solid form is packaged in a flexible container, such as a squeezable tube designed for topical application as a cream or ointment. Synthesis of Radiopharmaceuticals Comprising Compounds of Formula I
式I化合物包含標靶HSP90之結合物,其可用放射性核素,諸如銦-111 ( 111In)、鎦-177 ( 177Lu)或錒-225 ( 225Ac)放射性標記以形成與放射性核素螯合之放射性藥物。式I化合物或其等與放射性核素螯合之放射性藥物之合成可參考WO 2020/205948。下文係可遵循以合成相應化合物之合成方案或草案。一般技術者基於本文提供之本發明及該領域中之知識將已可製備本文繪示之化合物及其等結構相似之類似物(例如,具有不同螯合劑,諸如DOTA、NOTA及NODA-GA之化合物)。 The compound of formula I comprises a binder that targets HSP90, which can be radiolabeled with a radionuclide, such as indium-111 ( 111In ), indium-177 ( 177Lu ) or indium-225 ( 225Ac ) to form a radiopharmaceutical chelated with a radionuclide. The synthesis of the compound of formula I or its radiopharmaceutical chelated with a radionuclide can be referred to WO 2020/205948. The following is a synthetic scheme or draft that can be followed to synthesize the corresponding compound. A person of ordinary skill will be able to prepare the compounds depicted herein and their structurally similar analogs (for example, compounds with different chelators, such as DOTA, NOTA and NODA-GA) based on the present invention provided herein and the knowledge in the field.
合成方案1. Synthesis Scheme 1.
合成方案2. Synthesis Scheme 2.
合成方案3. Synthesis Scheme 3.
合成方案4. Synthesis Scheme 4.
合成方案5. Synthesis Scheme 5.
合成方案6. Synthesis Scheme 6.
合成方案7. 材料及分析檢定 下文提供用於表徵式I化合物之分析檢定。 Synthesis Scheme 7. Materials and Analytical Assays The analytical assays used to characterize compounds of Formula I are provided below.
錒-225 ( 225Ac)係由美國能源部核子物理科學辦公室之同位素項目(the U.S. Department of Energy Isotope Program in the Office of Science for Nuclear Physics)供應。鎦-177 ( 177Lu)係接收自ITG Isotope Technologies Garching GmbH。銦-111 ( 111In)係由BWXT供應。 Ac) was supplied by the US Department of Energy Isotope Program in the Office of Science for Nuclear Physics. Lu ) was received from ITG Isotope Technologies Garching GmbH. Indium-111 (111In ) was supplied by BWXT.
RadioTLC係使用Bioscan AR-2000成像掃描儀進行,於iTLC-SG玻璃微纖維層析紙(Agilent Technologies, SGI0001)盤或iTLC-SA玻璃微纖維層析紙(Agilent Technologies, A120B12)盤上進行。RadioTLC was performed using a Bioscan AR-2000 imaging scanner on iTLC-SG glass microfiber chromatography paper (Agilent Technologies, SGI0001) or iTLC-SA glass microfiber chromatography paper (Agilent Technologies, A120B12).
放射性HPLC係使用Waters系統進行,該Waters系統包含Waters 1525二元HPLC泵、Waters 2489紫外/可見光偵測器(於254及214 nm處監測)及Bioscan流量計數放射性偵測器(FC-3300)及反相(C18)管柱。或者,分析係使用Waters Acquity UPLC系統進行,該Waters Acquity UPLC系統包含Waters Acquity二元溶劑管理器、Waters Acquity樣品管理器、Waters Acquity管柱管理器(管柱溫度30℃)、Water Acquity光電二極體陣列偵測器(於254 nm及214 nm處偵測)、Bioscan流量計數放射性偵測器(FC-3300)及反相(C18)管柱。Radio-HPLC was performed using a Waters system comprising a Waters 1525 binary HPLC pump, a Waters 2489 UV/Vis detector (monitoring at 254 and 214 nm), a Bioscan flow-counter radioactivity detector (FC-3300), and a reversed phase (C18) column. Alternatively, the analysis was performed using a Waters Acquity UPLC system comprising a Waters Acquity binary solvent manager, a Waters Acquity sample manager, a Waters Acquity column manager (column temperature 30°C), a Water Acquity photodiode array detector (detecting at 254 and 214 nm), a Bioscan flow-counter radioactivity detector (FC-3300), and a reversed phase (C18) column.
分析HPLC-MS係使用Waters Acquity HPLC-MS系統進行,該Waters Acquity HPLC-MS系統包含Waters Acquity二元溶劑管理器、Waters Acquity樣品管理器、Waters Acquity管柱管理器(管柱溫度30℃)、Waters Acquity光電二極體陣列偵測器(於254 nm及214 nm處監測)、具有電噴霧電離之Waters Acquity TQD及Waters Acquity BEH C18,2.1 x 50 mm (1.7 µm)管柱。製備型HPLC係使用Waters HPLC系統進行,該Waters HPLC系統包含Waters 1525二元HPLC泵、Waters 2489紫外/可見光偵測器(於254 nm及214 nm處監測)及Waters XBridge製備型C18 19 x 100 mm (5 µm)管柱。Analytical HPLC-MS was performed using a Waters Acquity HPLC-MS system comprising a Waters Acquity binary solvent manager, a Waters Acquity sample manager, a Waters Acquity column manager (column temperature 30°C), a Waters Acquity photodiode array detector (monitoring at 254 nm and 214 nm), a Waters Acquity TQD with electrospray ionization, and a Waters Acquity BEH C18, 2.1 x 50 mm (1.7 µm) column. Preparative HPLC was performed using a Waters HPLC system consisting of a Waters 1525 binary HPLC pump, a Waters 2489 UV/Vis detector (monitoring at 254 nm and 214 nm), and a Waters XBridge Preparative C18 19 x 100 mm (5 µm) column.
HPLC溶析方法1:Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm)管柱;流動相A:H 2O (0.1% v/v TFA);流動相B:乙腈(0.1% v/v TFA);流動速率= 0.3 mL/min;波長= 214、254 nm;初始= 90% A,8 min = 0% A,10 min = 0% A,11 min = 90% A,12 min = 90% A。 HPLC elution method 1: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H 2 O (0.1% v/v TFA); mobile phase B: acetonitrile (0.1% v/v TFA); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 8 min = 0% A, 10 min = 0% A, 11 min = 90% A, 12 min = 90% A.
HPLC溶析方法2:Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm)管柱;流動相A:H 2O (0.1% v/v TFA);流動相B:乙腈(0.1% v/v TFA);流動速率= 0.3 mL/min;波長= 214、254 nm;初始= 90% A,3 min = 0% A,3.5 min = 0% A,4 min = 90% A,5 min = 90% A。 HPLC elution method 2: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H 2 O (0.1% v/v TFA); mobile phase B: acetonitrile (0.1% v/v TFA); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 3 min = 0% A, 3.5 min = 0% A, 4 min = 90% A, 5 min = 90% A.
HPLC溶析方法3:Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm)管柱;流動相A:H 2O (0.1% v/v甲酸);流動相B:乙腈(0.1% v/v甲酸);流動速率= 0.3 mL/min;波長= 214、254 nm;初始= 90% A,3 min = 0% A,3.5 min = 0% A,4 min = 90% A,5 min = 90% A。 HPLC elution method 3: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H 2 O (0.1% v/v formic acid); mobile phase B: acetonitrile (0.1% v/v formic acid); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 3 min = 0% A, 3.5 min = 0% A, 4 min = 90% A, 5 min = 90% A.
HPLC溶析方法4:Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm)管柱;流動相A:H 2O (0.1% v/v甲酸);流動相B:乙腈(0.1% v/v甲酸);流動速率= 0.3 mL/min;波長= 214、254 nm;初始= 90% A,8 min = 0% A,10 min = 0% A,11 min = 90% A,12 min = 90% A。 HPLC elution method 4: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H 2 O (0.1% v/v formic acid); mobile phase B: acetonitrile (0.1% v/v formic acid); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 8 min = 0% A, 10 min = 0% A, 11 min = 90% A, 12 min = 90% A.
HPLC溶析方法5 (放射性HPLC):Phenomenex Gemini 5 µm C18 110 Å,LC管柱150 x 4.6 mm;流動相A:H 2O (0.1% v/v TFA);流動相B:乙腈(0.1% v/v TFA);流動速率= 1.0 mL/min;波長= 214、254 nm;初始= 100% A,2 min = 100% A,10 min = 0% A,12 min = 0% A,14 min = 100% A,15 min = 100% A。 HPLC Elution Method 5 (RadioHPLC): Phenomenex Gemini 5 µm C18 110 Å, LC column 150 x 4.6 mm; Mobile Phase A: H 2 O (0.1% v/v TFA); Mobile Phase B: Acetonitrile (0.1% v/v TFA); Flow Rate = 1.0 mL/min; Wavelength = 214, 254 nm; Initial = 100% A, 2 min = 100% A, 10 min = 0% A, 12 min = 0% A, 14 min = 100% A, 15 min = 100% A.
HRMS係使用Agilent G1969 ESI TOF系統進行。
實例
實例1:(R)-2,2',2''-(10-(20-羧基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,17-二側氧基-4,7,10,13-四氧雜-16-氮雜二十烷-20-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物A)之合成
步驟1:(R)-17-側氧基-20-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-4,7,10,13-四氧雜-16-氮雜二十一烷二酸1-苯甲酯21-(第三丁基)酯(中間物1 - A)之合成
向20 mL閃爍瓶添加(R)-DOTAGA(tBu)
4(500 mg,0.71 mmol,1當量)及攪拌棒,接著添加無水二氯甲烷(3.6 mL)以形成0.2 M溶液。接著添加CDI (126 mg,0.74 mmol,1.1當量)並在室溫下攪拌該溶液及藉由HPLC-MS監測。3 h後,僅觀察到~35%轉化,因此用CDI (70 mg,0.43 mmol,0.6當量)對該反應重新給藥並在室溫下攪拌18.5 h。此時,檢查該反應之等分試樣且發現具有相同之近似轉化。
將反應溶液轉移至含有於無水二氯甲烷(1 mL)中之胺基-PEG4-苯甲基酯(279 mg,0.78 mmol,1.1當量)之第二小瓶內並在室溫下攪拌。藉由HPLC-MS監測反應及在3 h後發現產物之~29%轉化及藉由HPLC-MS,殘餘物為DOTAGA(tBu)
4。
藉由在真空下濃縮對反應進行後處理及然後藉由添加下列試劑重新經受反應條件:無水THF (4.6 mL)及HBTU (803 mg,2.12 mmol,3當量),此時將該反應攪拌5分鐘,然後添加DIPEA (0.62 mL)並在室溫(22.5℃)下攪拌整個週末。
88 h後,反應已完成並藉由在真空下濃縮進行後處理。藉由反相C18管柱層析術純化粗產物以提供呈淺黃色黏稠固體之中間物1 - A (436 mg,47%,純度:>96%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.90 min;MS (正ESI):實測值m/z 1038.6 [M+H]
+;C
53H
92N
5O
15(計算值1038.6)。
1H NMR (700 MHz, DMSO-d
6) δ 7.96 (br s, 1H), 7.38-7.31 (m, 5H), 5.11 (s, 2H), 4.62-2.65 (與H
2O重疊之多重峰,43H), 2.60 (t, J = 7.0 Hz, 2H), 2.49-2.43 (m, 1H), 2.43-2.35 (m, 1H), 1.47 (br s, 9H), 1.46 (br s, 9H), 1.42 (br s, 9H), 1.40 (br s, 9H);
13C NMR (176 MHz, DMSO-d
6) δ 171.6, 170.6, 158.3 (TFA, q, J = 35.2 Hz), 136.5, 128.4, 128.0, 127.8, 115.8 (TFA, q, J = 299.2 Hz), 83.8 (br), 81.6 (br), 69.8 (2C), 69.7 (2C), 69.6, 69.1, 66.0, 65.4, 54.5 (br), 53.4 (br), 38.5, 34.7, 31.8 (br), 27.8, 27.7, 27.6 (2C)。
步驟2:(R)-2,2-二甲基-4,8-二側氧基-5-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-3,12,15,18,21-五氧雜-9-氮雜二十四烷-24-酸(中間物1 - B)之合成
於20 mL小瓶中向中間物1 - A (396 mg,0.30 mmol,1當量)於無水MeOH (4 mL)中之溶液添加攪拌棒及Pd/C,10% Pd基質(32 mg,0.03 mmol,0.1當量)。使該反應混合物脫氣並經由氣球(3X)經受H
2氣氛。然後在室溫(22攝氏度)下攪拌該反應並藉由HPLC-MS監測。
18 h後,使反應濾過Acrodisc One (0.2 µm PTFE)注射器過濾器進入20 mL閃爍瓶內。然後用MeOH (4 mL)沖洗反應小瓶,並亦使此過濾至該閃爍瓶內。然後在減壓下濃縮粗反應物以提供387 mg透明膜。
粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物1 - B (237 mg,66%,純度:99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.06 min;MS (正ESI):實測值m/z 948.7 [M+H]
+;C
46H
86N
5O
15(計算值948.6)。
1H NMR (700 MHz, DMSO-d
6) δ 7.98 (s, 1H), 4.62-2.60 (與H
2O重疊之多重峰,43H), 2.48-2.45 (m, 1H), 2.44 (t, J = 7.0 Hz, 2H), 2.41-2.35 (m, 1H), 1.45 (br s, 18H), 1.41 (br s, 18H);
13C NMR (176 MHz, DMSO-d
6) δ 172.6, 171.7, 158.2 (TFA, q, J = 33.4 Hz), 116.4 (TFA, q, J = 303.8 Hz), 69.8, 69.7 (2C), 69.6 (2C), 69.1, 66.2, 54.6 (br), 53.7 (br), 38.6, 31.8 (br), 27.8, 27.7 (2C), 27.6。
步驟3:2,2',2''-(10-(24-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,2-二甲基-4,8,24-三側氧基-3,12,15,18,21-五氧雜-9-氮雜二十四烷-5-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物1 - D)之合成
向20 mL小瓶添加中間物1 - B (14 mg,15 µmol,1當量),接著添加1份無水DMF (1 mL)及攪拌棒。然後於容器中裝入HBTU (5.6 mg,15 µmol,1當量)及最後DIPEA (12.4 µL,71 µmol,5當量)並在室溫(22℃)下攪拌5 min。然後添加中間物1 - C (8 mg,1當量)於無水DMF (1 mL)中之溶液,並使用另外1 mL無水DMF沖洗含有該中間物之小瓶並添加至反應容器。在室溫(22℃)下攪拌所得溶液並藉由HPLC-MS監測。1 h後,藉由在真空下濃縮對該反應進行後處理。
粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物1 - D (12.4 mg,96%,純度:96%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.72 min;MS (正ESI):實測值m/z 1393.9 [M+H]
+;C
72H
117N
10O
17(計算值1393.8)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 4.35-0.92 (與H
2O及DMSO重疊之多重峰及於0.99 ppm處之三重峰,97H), 0.99 (t, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 6H)。
步驟4:(R)-2,2',2''-(10-(21-羧基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,18-二側氧基-5,8,11,14-四氧雜-2,17-二氮雜二十一烷-21-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物A)之合成
向20 mL小瓶添加中間物1 - D (10.4 mg,6.4 µmol,1當量)及攪拌棒,接著添加2 mL TFA/TIPS/H
2O (95:2.5:2.5 v/v/v)。將所得澄清溶液放置於37℃油浴中並藉由HPLC-MS監測反應。3 h後,該反應完成並在空氣流下濃縮。
粗產物係藉由反相C18管柱層析術純化以提供呈白色固體之化合物A (6.5 mg,75%,純度:>99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.00 min;HRMS (正ESI):實測值m/z 1169.6074 [M+H]
+;C
56H
85N
10O
17(計算值1169.6089)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.23 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 4.30 (br d, 2H), 4.05-2.35 (與H
2O及DMSO重疊之多重峰,47H), 1.90-1.80 (br m, 3H), 1.77-1.71 (m, 2H), 1.61-1.55 (m, 3H), 1.11-1.08 (m, 2H), 1.00 (t, J = 7.0 Hz, 3H), 0.98-0.95 (m, 2H), 0.76 (d, J = 7.0 Hz, 6H);
13C NMR (175 MHz, DMSO-d
6) δ 171.7, 168.5, 157.9 (TFA, app q, J = 31.5 Hz), 157.3, 156.2 (2C), 154.4, 147.8, 141.4, 133.2, 129.6, 127.3, 125.8, 125.5, 117.3 (TFA, app q, J =297.5 Hz), 102.6, 102.5, 69.8 (2C), 69.7 (2C), 69.6, 69.1, 66.9, 53.7, 45.1, 41.7, 41.1, 40.0, 38.6, 37.3, 33.6, 32.9, 32.2, 31.3, 25.3, 22.4, 14.5。
實例2:2,2',2''-(10-(24-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,24-二側氧基-6,9,12,15,18,21-六氧雜-3-氮雜二十四烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物B)之合成
步驟1:2-側氧基-1-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-6,9,12,15,18,21-六氧雜-3-氮雜二十四烷-24-酸(中間物2 - A)之合成
向DOTA參(第三丁基酯) (50 mg,0.09 mmol,1當量)於MeCN (2.0 mL)中之溶液添加N,N’-二琥珀醯亞胺基碳酸酯(DSC) (32 mg,0.11 mmol,1.3當量)及吡啶(0.20 mL,2.5 mmol,28當量)。在室溫(22.5℃)下攪拌該反應混合物並藉由HPLC-MS監測。70 min後,殘餘~80%起始材料,因此對反應給藥HBTU (34 mg,0.09 mmol,1當量)並在室溫下攪拌10 min。然後將該反應混合物轉移至含有於無水DMF (1 mL,有限溶解度)中之胺基-PEG6-酸(64 mg,0.17 mmol,2當量)之第二小瓶並在室溫下攪拌。
藉由HPLC-MS監測反應並在64小時後藉由在真空下濃縮進行後處理以提供澄清油。粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物2 - A (35 mg,36%,純度>99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.70 min;MS (正ESI):實測值m/z 908.9 [M+H]
+;C
43H
82N
5O
15(計算值908.6)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 4.20-2.46 (與H
2O重疊之多重峰,於3.57 ppm處之三重峰J = 7.0 Hz,2H及DMSO;總50H), 2.42 (t, J = 7.0 Hz, 2H), 1.44 (br s, 9H), 1.36 (br s, 18H)。
步驟2:2,2',2''-(10-(24-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,24-二側氧基-6,9,12,15,18,21-六氧雜-3-氮雜二十四烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物2 - C)之合成
向中間物2 - A (30 mg,26 µmol,1當量)於MeCN (2 mL)中之溶液添加HBTU (12 mg,32 µmol,1.2當量)及DIPEA (18 µL,0.11 mmol,4當量)。在室溫(22.5℃)下將此攪拌10 min,然後添加中間物2 - B (22 mg,32 µmol,1.2當量)並攪拌該溶液及藉由HPLC-MS監測。1 h後,藉由在真空下濃縮至乾燥對該反應進行後處理。
粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物2 - C (35 mg,77%,純度>99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:5.52 min;MS (正ESI):實測值m/z 1533.7 [M+H]
+;C
83H
125N
10O
17(計算值1533.9)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.27-7.26 (m, 8H), 7.19 (d, J = 6.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.67 (s, 1H), 5.01 (s, 2H), 4.88 (s, 2H), 4.27 (d, J = 14.0 Hz, 1H), 3.78 (d, J = 14.0 Hz, 1H), 3.55 (t, J = 7.0 Hz, 2H), 3.49-2.36 (與H
2O及DMSO重疊之多重峰,57H), 1.70-1.63 (m, 1H), 1.52-1.17 (與寬2單重峰重疊之多重峰,於1.42 ppm及1.33 ppm處,29H), 1.05-0.98 (於1.00 ppm處與三重峰重疊之m,J = 7.0 Hz,總4H), 0.95 (d, J = 7.0 Hz, 6H), 0.92-0.85 (m, 1H)。
步驟3:2,2',2''-(10-(24-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,24-二側氧基-6,9,12,15,18,21-六氧雜-3-氮雜二十四烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物2 - D)之合成
於微波小瓶中向中間物2 - C (28.3 mg,16.1 µmol,1當量)於MeOH (2.5 mL)中之溶液添加攪拌棒及Pd/C,10% Pd基質(7 mg,6 µmol,0.4當量)。使該反應混合物脫氣並經由氣球(3X)經受H
2氣氛。然後在室溫(23℃)下攪拌該反應並藉由HPLC-MS監測。
16 h後,使反應濾過Acrodisc PSF注射器過濾器進入20 mL閃爍瓶內。用MeOH (2 x1.5 mL)沖洗反應小瓶,及亦使此過濾至該閃爍瓶內。然後在真空下濃縮粗反應以提供23 mg黃色膜。
將粗產物溶解於MeOH (2 mL)中並用SiliaMetS
®硫醇(SH)金屬清除劑樹脂(200 mg,40至63 µm,負載=1.46 mmol/g)沖洗以於37℃油浴中移除視Pd配位並藉由HPLC-MS監測。1 h後,使反應濾過Acrodisc PSF注射器過濾器進入20 mL閃爍瓶中。用MeOH (2 x 1.5 mL)沖洗該反應小瓶,及亦使此過濾至該閃爍瓶內。然後在真空下濃縮粗反應以提供呈透明膜之中間物2 - D (20.8 mg,81%,純度>97%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.45 min;MS (正ESI):實測值m/z 1354.3 [M+H]
+;C
69H
113N
10O
17(計算值1353.8)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 4.30 (br d, J = 14.0 Hz, 1H), 4.20-2.36 (與H
2O重疊之多重峰,於3.57 ppm處之三重峰J = 7.0 Hz,於3.14 ppm處之q,J = 7.0 Hz及DMSO, 60H), 1.76-1.70 (m, 1H), 1.62-1.55 (m, 2H), 1.49 (br s, 9H), 1.34 (br s, 18H), 1.12-1.06 (m, 1H), 1.01-0.92 (於0.99 ppm處與三重峰重疊之m,J = 7.0 Hz,總4H), 0.77 (d, J = 7.0 Hz, 6H)。
步驟4:2,2',2''-(10-(24-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,24-二側氧基-6,9,12,15,18,21-六氧雜-3-氮雜二十四烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物B)之合成
向20 mL小瓶添加中間物2 - D (18.0 mg,11.4 µmol,1當量),及攪拌棒,接著添加2 mL TFA/TIPS/H
2O (95:2.5:2.5 v/v/v)。將所得澄清溶液放置於37℃油浴中並藉由HPLC-MS監測反應。2.5 h後,該反應完成及隨後在真空下濃縮。
粗產物係藉由反相C18管柱層析術純化以提供呈白色固體之化合物B (4.6 mg,29%,純度:99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.15 min;HRMS (正ESI):實測值m/z 1185.6386 [M+H]
+;C
57H
89N
10O
17(計算值1185.6402)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 4.30 (br d, J = 14.0 Hz, 2H), 4.10-2.38 (與H
2O及DMSO重疊之多重峰,57H), 1.76-1.68 (m, 2H), 1.63-1.52 (m, 3H), 1.13-1.07 (m, 1H), 0.99-0.93 (於0.99 ppm處與三重峰重疊之m,J = 7.0 Hz,總4H), 0.77 (d, J = 7.0 Hz, 6H)。
實例3:2,2',2''-(10-(42-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,42-二側氧基-6,9,12,15,18,21,24,27,30,33,36,39-十二氧雜-3-氮雜四十烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物C)之合成
步驟1:2-側氧基-1-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-6,9,12,15,18,21,24,27,30,33,36,39-十二氧雜-3-氮雜四十二烷-42-酸(中間物3 - A)之合成
向DOTA參(第三丁基酯) (50 mg,0.09 mmol,1當量)於MeCN (2.0 mL)中之溶液添加N,N’-二琥珀醯亞胺基碳酸酯(DSC) (32 mg,0.11 mmol,1.3當量)及吡啶(0.20 mL,2.5 mmol,28當量)。在室溫(22.5℃)下攪拌該反應混合物並藉由HPLC-MS監測。70 min後,殘餘~80%起始材料,因此對反應給藥HBTU (34 mg,0.09 mmol,1當量)並在室溫下攪拌10 min。然後將該反應混合物轉移至含有於於無水DMF (1 mL,有限溶解度)中之胺基-PEG12-酸(81 mg,0.13 mmol,1.5當量)之第二小瓶並在室溫下攪拌。
藉由HPLC-MS監測反應並在64小時後藉由在真空下濃縮進行後處理以提供澄清油。粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物3 - A (49 mg,32%,純度80%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.70 min;MS (正ESI):實測值m/z 1173.2 [M+H]
+;C
55H
106N
5O
21(計算值1172.7)。
步驟2:2,2',2''-(10-(42-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,42-二側氧基-6,9,12,15,18,21,24,27,30,33,36,39-十二氧雜-3-氮雜四十烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物3 - B)之合成
向中間物3 - A (49 mg,35 µmol,1當量)於MeCN (2 mL)中之溶液添加HBTU (14 mg,46 µmol,1.3當量)、DIPEA (24 µL,0.14 mmol,5當量)及攪拌棒。在室溫(22.5℃)下將該反應攪拌10 min,然後添加中間物2 - B (26 mg,38 µmol,1.3當量)並攪拌該溶液及藉由HPLC-MS監測。1 h後,藉由在真空下濃縮至乾燥對該反應進行後處理。
粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物3 - B (40 mg,70%,純度>99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:5.40 min;MS (正ESI):實測值m/z 1797.9 [M+H]
+;C
95H
149N
10O
23(計算值1798.1)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.36-7.26 (m, 8H), 7.19 (d, J = 7.0 Hz, 2H), 7.05 (d, J = 7.0 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J = 7.0 Hz, 2H) 6.67 (s, 1H), 5.01 (s, 2H), 4.88 (s, 2H), 4.27 (br d, J = 14.0 Hz, 1H), 3.78 (br d, J = 14.4 Hz, 1H), 3.55 (t, J = 7.0 Hz, 2H), 3.52-2.37 (與H
2O及DMSO重疊之多重峰,81H), 1.69-1.63 (m, 1H), 1.52-1.38 (於1.42 ppm處與br s重疊之m,12H), 1.34 (br s, 18H), 1.05-0.98 (於1.00 ppm處與三重峰重疊之m,J = 7.0 Hz,總4H), 0.96 (d, J = 7.0 Hz, 6H)。
步驟3:2,2',2''-(10-(42-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,42-二側氧基-6,9,12,15,18,21,24,27,30,33,36,39-十二氧雜-3-氮雜四十烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物3 - C)之合成
於微波小瓶中向中間物3 - B (33 mg,0.02 mmol,1當量)於MeOH (2.5 mL)中之溶液添加攪拌棒及Pd/C,10% Pd基質(7 mg,6 µmol,0.4當量)。使該反應混合物脫氣並經由氣球(3X)經受H
2氣氛。然後在室溫(23℃)下攪拌該反應並藉由HPLC-MS監測。16 h後,使該反應濾過Acrodisc PSF注射器過濾器進入20 mL閃爍瓶內。用MeOH (2 x1.5 mL)沖洗該反應小瓶,及亦將此過濾至該閃爍瓶內。然後在減壓下濃縮粗反應以提供30 mg淺黃色膜。
然後將粗混合物溶解於MeOH (3 mL)中並用SiliaMetS
®硫醇(SH)金屬清除劑樹脂(200 mg,40至63 µm,負載=1.46 mmol/g)攪拌一半以於50℃油浴中移除視Pd配位,及藉由HPLC-MS監測。2 h後,使該反應濾過Acrodisc PSF注射器過濾器進入20 mL閃爍瓶內。用MeOH (2 x 2 mL)沖洗該反應小瓶,及亦將此過濾至該閃爍瓶內。然後在真空下濃縮粗反應。此方案用第2半粗材料重複並組合以提供呈透明膜之中間物3 - C (19.8 mg,66%,純度>99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.40 min;MS (正ESI):實測值m/z 1618.2 [M+H]
+;C
81H
137N
10O
23(計算值1618.0)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (br d, J = 7.0 Hz, 2H), 7.19 (br d, J = 7.0 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 4.41-2.37 (與H
2O重疊之多重峰,d於3.83 ppm處J = 14.7 Hz,t於3.57 ppm處,J = 7.0Hz,q於3.14 ppm處,J = 7.0 Hz及DMSO, 85H), 1.75-1.68 (m, 1H), 1.62-1.52 (m, 2H), 1.51-1.04 (與br單重峰重疊之多重峰,於1.42處,1.34及1.18 ppm, 28H), 1.00-0.92 (於0.99 ppm處與多重峰重疊之三重峰,4H), 0.76 (br d, J = 7.0 Hz, 6H)。
步驟4:2,2',2''-(10-(42-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,42-二側氧基-6,9,12,15,18,21,24,27,30,33,36,39-十二氧雜-3-氮雜四十烷基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物C)之合成
向20 mL小瓶添加中間物3 - C (18.0 mg,9.8 µmol,1當量)及攪拌棒,接著添加2 mL TFA/TIPS/H
2O (95:2.5:2.5 v/v/v)。將所得澄清溶液放置於37℃油浴中並藉由HPLC-MS監測反應。2.5 h後,該反應似乎完成並藉由轉移至50 mL費爾肯(Falcon)管進行後處理。用TFA (2x0.5 mL)清洗該反應小瓶,及亦將此添加至該費爾肯管。於冰浴中冷卻該費爾肯管及然後添加Et
2O (於該冰浴中預先冷卻)至45 mL標記。5 min後,於該冰浴中離心(5 min,4℃,3700 rpm)燒瓶以提供灰白色集結粒。將Et
2O層傾析至圓底燒瓶內,並將該集結粒溶解於ACN/H
2O (2 mL,1:1 v/v)中並轉移至去皮20 mL閃爍瓶。用另外ACN/H
2O (2x2 mL,1:1 v/v)沖洗該費爾肯管,將其添加至該閃爍瓶並在真空下濃縮以提供呈透明膜之9 mg粗產物。
粗產物係藉由反相C18管柱層析術純化以提供呈白色固體之化合物C (6.6 mg,40%,純度:97%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.27 min;HRMS (正ESI):實測值m/z 1487.7508 [M+K]
+;C
69H
112KN
10O
23(計算值1487.7533)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 4.30 (br d, J = 14.0 Hz, 1H), 4.10-2.37 (與H
2O及DMSO重疊之多重峰,84H), 1.76-1.71 (m, 1H), 1.61-1.54 (m, 2H), 1.13-1.06 (m, 1H), 1.01-0.92 (於0.99 ppm處與三重峰重疊之m,J = 7.0 Hz,總4H), 0.77 (d, J = 7.0 Hz, 6H)。
實例4:(R)-2,2',2''-(10-(21-羧基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,18-二側氧基-5,8,11,14-四氧雜-2,17-二氮雜二十一烷-21-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物D)之合成
步驟1:2,2',2''-(10-(1-胺基-22,22-二甲基-16,20-二側氧基-3,6,9,12,21-五氧雜-15-氮雜二十三烷-19-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物4 - A)之合成
於20 mL閃爍瓶中裝入(R)-DOTAGA(
tBu)
4(1.00 g,1.41 mmol,1當量)、胺基-PEG4-胺(511 mg,2.12 mmol,1.5當量)、HBTU (607 mg,1.56 mmol,1.1當量)、無水乙腈及最後DIPEA (1.24 mL,7.06 mmol,5當量)。在室溫(22℃)下攪拌該反應並藉由HPLC-MS監測。
2 h後,藉由在真空下濃縮對反應進行後處理以提供淺黃色油。粗產物係藉由反相C18管柱層析術純化以提供呈透明黏稠膜之中間物4 - A (448 mg,26%,純度:>93%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.63 min;MS (正ESI):實測值m/z 919.5 [M+H]
+;C
45H
87N
6O
13(計算值919.6)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 4.40-2.30 (包括與H
2O及DMSO重疊之多重峰,45H), 1.92-1.80 (br m, 1H), 1.69-1.57 (br m, 1H), 1.44 (br s, 18H), 1.33 (br s, 9H), 1.31 (br s, 9H)。
步驟2:2,2',2''-(10-(1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-24,24-二甲基-1,18,22-三側氧基-5,8,11,14,23-五氧雜-2,17-二氮雜二十五烷-21-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物4 - B)之合成
向中間物4 - A (50 mg,41 µmol,1當量)於無水THF (1 mL)及攪拌棒中之溶液添加DIPEA (28.7 µL,164 µmol,4當量)並冷卻至0℃,接著在0℃下一次添加全量4-硝基苯基氯甲酸酯(8.6 mg,41 µmol,1當量)。添加後,自冰浴移除該反應以在室溫(21.5℃)下攪拌,用氬氣球吹掃並藉由HPLC-MS監測。
45 min後,觀察到完全轉化為硝基苯基中間物並繼續將中間物1 - C (24 mg,46 µmol,1.1當量)直接添加至反應,接著添加DIPEA (7.2 µL,46 µmol,1.1當量)及自後用氬氣球吹掃該反應。在室溫下攪拌該反應並藉由HPLC-MS監測。1 h後,添加無水DMF (1 mL),其導致均質溶液並在室溫下繼續攪拌該反應及藉由HPLC-MS監測。1 h後,使該反應溫度升溫至50℃並藉由HPLC-MS監測。
43 h後,對反應重新給藥DIPEA (28.7 µL,164 µmol,4當量),用氬氣球吹掃並在50℃浴下再攪拌21 h,此導致完全轉化。然後藉由在真空下濃縮對該反應進行後處理以提供黃色膜。
粗產物係藉由反相C18管柱層析術純化以提供呈透明膜之中間物4 - B (26 mg,38%,純度:>98%),TFA鹽。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.42 min;MS (正ESI):實測值m/z 1408.8 [M+H]
+;C
72H
118N
11O
17(計算值1408.9)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 6.56 (s, 1H), 6.35 (s, 1H), 4.38-2.29 (包括與H
2O及DMSO重疊之多重峰,55H), 1.67-1.59 (m, 2H), 1.52 (br d, J = 12.9 Hz, 2H), 1.50-1.21 (4個重疊之寬單重峰,36H), 1.04-0.94 (於0.99 ppm處與t重疊之m,及J = 7.2 Hz,總5H), 0.75 (d, J = 7.0 Hz, 6H)。
步驟3:(R)-2,2',2''-(10-(21-羧基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,18-二側氧基-5,8,11,14-四氧雜-2,17-二氮雜二十一烷-21-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物D)之合成
向20 mL小瓶添加中間物4 - B (16.2 mg,9.7 µmol,1當量)、攪拌棒,接著添加2 mL TFA/TIPS/H
2O (95:2.5:2.5 v/v/v)。將所得澄清溶液放置於37℃油浴中並藉由HPLC-MS監測反應。3.5 h後,該反應已完成並在空氣流下濃縮。
粗產物係藉由反相C18管柱層析術純化以提供呈白色固體之化合物D (10 mg,72%,純度:>99%),TFA鹽。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:2.97 min;HRMS (正ESI):實測值m/z 1184.6175 [M+H]
+;C
56H
86N
11O
17(計算值1184.6198)。
1H NMR (700 MHz, DMSO-d
6+ ~10% D
2O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 4.10-2.30 (包括與H
2O及DMSO重疊之多重峰,52H), 1.95-1.77 (m, 3H), 1.68-1.59 (m, 2H), 1.52 (app br d, J = 14.0 Hz, 2H), 1.03-0.97 (於0.99 ppm處與三重峰重疊之m,及J = 7.1 Hz,總5H), 0.76 (d, J = 7.1 Hz, 6H)。
實例5:(R)-2,2',2''-(10-(22-羧基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,14,19-三側氧基-4,7,10-三氧雜-13,15,18-三氮雜二十二烷-22-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物E)之合成
步驟1:2,2',2''-(10-(5-((2-胺基乙基)胺基)-1-(第三丁氧基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物5-A)之合成:向具有攪拌棒之20 mL閃爍瓶添加(R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊酸-(R)-DOTAGA(
tBu)
4(1.50 g,2.09 mmol,1當量)、單Fmoc乙二胺鹽酸鹽(817 mg,2.51 mmol,1.2當量)、HBTU (900 mg,2.09 mmol,1.1當量)及然後裝入無水乙腈(11 mL)及然後裝入DIPEA (1.84 mL,1370 mg,10.46 mmol,5當量)並在室溫下攪拌。藉由HPLC-MS監測反應並在18 h後停止,及在真空下蒸發溶劑以產生粗產物,其係經受Fmoc去保護。向溶解於無水DMF (8 mL)中之粗產物添加哌啶(2 mL)並在室溫下攪拌所得澄清橙色溶液。反應在30 min後停止並蒸發溶劑。獲得之粗產物係藉由RP層析術純化以產生呈白色固體呈TFA鹽之中間物5-A (550 mg,24%,純度:90%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.55 min;MS (正ESI):實測值m/z 743.5 [M+H]
+;C
37H
71N
6O
9(計算值743.5)。針對C
37H
71N
6O
9,HRMS (ESI-TOF) m/z: [M + H]
+計算值743.5277;實測值743.5291。
1H NMR (700 MHz, DMSO-d6 + 10% D
2O) 4.40 - 4.17 (m, 2H), 3.82 - 3.43 (m, 8H), 3.40 - 2.88 (m, 9H), 2.87 - 2.79 (m, 2H), 2.62 (br s, 2H), 2.60 (br s, 3H), 2.47 - 2.38 (m, 2H), 1.98 - 1.79 (m, 1H), 1.65 (s, 1H), 1.54 - 1.26 (m, 36H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:(R)-14,19-二側氧基-22-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-4,7,10-三氧雜-13,15,18-三氮雜二十三烷二酸23-(第三丁基)酯1-甲酯(中間物5-B)之合成
向2,2',2''-(10-(5-((2-胺基乙基)胺基)-1-(第三丁氧基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸三第三丁酯(中間物5-A) (50 mg,0.07 mmol,1當量)於無水THF (3 mL)及攪拌棒中之溶液添加DIPEA (35.5 µL,0.20 mmol,3當量)並冷卻至0℃,接著在0℃下一次添加全量4-硝基苯基氯甲酸酯(14.1 mg,0.07 mmol,1當量)。添加後,使該反應升至室溫及藉由HPLC-MS監測。30 min後,藉由HPLC-MS觀察到完全轉化為硝基苯基中間物。在氬下將溶解於無水DMF (1 mL)中之3-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)丙酸甲酯(30.4 mg,0.13 mmol,2當量)添加至該反應,接著添加DIPEA (23.6 µL,0.13 mmol,2當量)。在室溫下繼續攪拌,16小時後,使該反應停止並在真空下濃縮,接著進行RP層析術以提供呈白色固體呈TFA鹽之中間物5-B (25 mg,36%,純度:98%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.24 min;MS (正ESI):實測值m/z 1004.6 [M+H]
+;C
48H
90N
7O
15(計算值1004.6)。
1H NMR (700 MHz, DMSO-d6) δ 7.94 (s, 1H), 6.07 (s, 1H), 5.98 (s, 1H), 4.32-3.68 (br s, 15H), 3.62 (t, J = 6.2 Hz, 2H), 3.59 (s, 3H), 3.52 - 3.47 (m, 2H), 3.49 (s, 6H), 3.36 (t, J = 5.8 Hz, 2H), 3.13 (t, J = 5.8 Hz, 2H), 3.09 - 2.92 (m, 6H), 2.54 (t, J = 6.2 Hz, 2H), 2.07 (s, 4H), 1.61 - 1.27 (m, 42H)。
步驟3:(R)-2,2-二甲基-4,8,13-三側氧基-5-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-3,17,20,23-四氧雜-9,12,14-三氮雜二十六-26-烷酸(中間物5-C)之合成
向含有中間物5-B (32 mg,0.03 mmol,1當量)之燒瓶添加THF (2 mL)及水(1 mL)並放置於冰浴中且攪拌10 min。一次添加全量呈固體之無水氫氧化鋰(2.96 mg,0.12 mmol),及該反應係於冰-水浴中繼續。藉由HPLC-MS監測該反應,及1 h後升至室溫並繼續攪拌整夜。用Amberlite IR120 [H],~200 mg藉由在室溫下攪拌10 min,然後過濾以移除樹脂將該反應溶液酸化(pH ~4)。該樹脂係用ACN,MeOH進一步清洗及然後在真空下蒸發溶劑。將粗產物溶解於1:1 ACN/水/0.1TFA混合物中並經受凍乾,以產生粗中間物5-C (29 mg,87%,純度90%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.15 min;MS (正ESI):實測值m/z 991.3 [M+H]
+;C
47H
88N
7O
15(計算值990.6)。
步驟4:2,2',2''-(10-(26-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2,2-二甲基-4,8,13,26-四側氧基-3,17,20,23-四氧雜-9,12,14-三氮雜二十六-5-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物5-D)之合成
向具有攪拌棒之20 mL閃爍瓶添加中間物5-C (19.9 mg,0.02 mmol,1當量)及DMF (2 mL)。將該反應混合物冷卻至0℃並添加DIPEA (13.8 µL,10.2 mg,0.08 mmol,4當量),接著添加HBTU (7.7 mg,0.04 mmol,1當量)及在0℃下攪拌10 min。使該溶液升至室溫並攪拌30 min及然後添加呈固體之中間物1-C (10 mg,0.02 mmol,1當量)。在室溫下攪拌並藉由HPLC-MS監測反應。2 h後使該反應停止,並在真空下蒸發溶劑以產生粗產物,其係藉由製備型HPLC純化以提供呈白色固體呈TFA鹽之中間物5-D (21.4 mg,64%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:2.39 min;MS (正ESI):實測值m/z 1435.4 [M+H]
+;C
73H
119N
12O
17(計算值1435.9)。針對C
73H
119N
12O
17,HRMS (ESI-TOF) m/z: [M + H]
+計算值1435.8811;實測值1435.8833。
1H NMR (700 MHz, DMSO-d6) δ 9.82 (br s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.97 (br s, 1H), 7.29 - 7.24 (m, 4H), 7.10 (br s, 2H), 6.57 (s, 1H), 6.36 (s, 1H), 6.06 (br s, 1H), 5.97 (br s, 1H), 4.36 (d, J = 13.1 Hz, 1H), 3.98 - 3.74 (m, 12H), 3.61 (t, J = 6.7 Hz, 2H), 3.53 - 3.47 (m, 9H), 3.37 (t, J = 5.7 Hz, 2H), 3.19 - 3.12 (m, 5H), 3.07 (s, 3H), 3.01 (s, 3H), 2.94 - 2.87 (m, 2H), 2.60 - 2.51 (m, 4H), 2.49 - 2.42 (m, 2H), 2.07 (s, 4H), 1.81 - 1.73 (m, 1H), 1.66 - 1.57 (m, 2H), 1.52 - 1.31 (m, 42H), 1.17 - 1.10 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.01 - 0.98 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H)。
步驟5:(R)-2,2',2''-(10-(22-羧基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,14,19-三側氧基-4,7,10-三氧雜-13,15,18-三氮雜二十二烷-22-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物E)
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物5-D (37 mg,0.03 mmol)及4.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。3 h後使該反應停止並將反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型HPLC純化以提供呈白色固體TFA鹽之化合物E (20 mg,54%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.02 min;MS (正ESI):實測值m/z 1211.5 [M+H]
+;C
57H
87N
12O
17(計算值1211.6)。針對C
57H
87N
12O
17,HRMS (ESI-TOF) m/z: [M + H]
+計算值1211.6307;實測值1211.6330。
1H NMR (700 MHz, DMSO-d6) δ 12.98 (s, 3H), 10.65 (s, 1H), 9.83 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.87 (s, 1H), 7.26 (s, 4H), 6.57 (s, 1H), 6.37 - 6.34 (m, 1H), 6.18 (s, 1H), 6.05 (s, 1H), 4.36 (d, J = 12.8 Hz, 1H), 4.05 - 3.73 (m, 11H), 3.61 (t, J = 6.8 Hz, 2H), 3.53 - 3.47 (m, 10H), 3.37 (t, J = 5.8 Hz, 2H), 3.22 - 3.10 (m, 5H), 3.07 - 2.99 (m, 4H), 2.96 - 2.87 (m, 3H), 2.60 - 2.51 (m, 4H), 2.46 (td, J = 12.9, 2.9 Hz, 1H), 2.35 (s, 3H), 1.88 (s, 2H), 1.80 - 1.73 (m, 1H), 1.63 (d, J = 12.7 Hz, 1H), 1.59 (d, J = 13.0 Hz, 1H), 1.18 - 1.10 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.96 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
實例6:2,2',2''-(10-((15S,20R)-20-羧基-15-(羧基甲基)-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,14,17-三側氧基-4,7,10-三氧雜-13,16-二氮雜二十烷-20-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物F)之合成
步驟1:((R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊醯基)-L-天冬胺酸4-(第三丁酯)1-甲酯(中間物6-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加(R)-DOTAGA(
tBu)
4(869 mg,0.04 mmol,1當量)、THF (25 mL)及DMF (5 mL)。將該反應混合物冷卻至0℃及DIPEA (650 µL,18.7 mg,0.14 mmol,3當量),接著添加HBTU (719 mg,0.04 mmol,1.5當量)並在0℃下攪拌5 min。使該溶液升至室溫並攪拌15 min及然後添加呈固體之L-天冬胺酸4-(第三丁酯)1-甲酯鹽酸鹽(300 mg,0.04 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。3 h 30 min後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物6-A (722 mg,64%,純度:98%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.60 min;MS (正ESI):實測值m/z 886.7 [M+H]
+;C
44H
80N
5O
13(計算值886.6)。
1H NMR (700 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.11 (s, 2H), 4.58 (q, J = 7.1 Hz, 1H), 4.06 (br s, 8H), 3.63 (s, 3H), 3.35 - 2.93 (m, 8H), 2.65 (dd, J = 16.1, 6.8 Hz, 2H), 2.56 - 2.49 (m, 2H), 1.87 (s, 2H), 1.52 - 1.40 (m, 36H), 1.39 (s, 9H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:(S)-4-(第三丁氧基)-2-((R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊醯胺基)-4-側氧基丁酸(中間物6-B)之合成:
將含有中間物6-A (400.00 mg,0.45 mmol,1當量)之燒瓶溶解於THF (6 mL)及水(3 mL)中並放置於冰浴中及攪拌15 min。一次添加全量呈固體之無水氫氧化鋰(LiOH) (64.87 mg,2.71 mmol,6當量),及該反應係於冰-水浴中繼續。藉由HPLC-MS監測該反應,30 min後,觀察到主要產物。1 h後,用Amberlite IR120 [H],~600 mg藉由在室溫下攪拌15 min,然後過濾以移除該樹脂將該反應溶液酸化。該樹脂係用乙腈,MeOH進一步清洗並在真空下蒸發該溶劑。凍乾粗產物以產生呈白色固體之中間物6-B (394 mg,95%,純度:95%)且無需進一步純化即可用於下一步驟。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.55 min;MS (正ESI):實測值m/z 872.5 [M+H]
+;C
43H
78N
5O
13(計算值872.6)。
1H NMR (700 MHz, DMSO-d6) δ 12.77 (br s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 4.57 (td, J = 7.9, 5.9 Hz, 1H), 3.75 (s, 3H), 3.53 (s, 2H), 3.42 - 3.30 (m, 5H), 3.12 - 3.06 (m, 5H), 2.91 - 2.81 (m, 5H), 2.80 - 2.73 (m, 2H), 2.66 (dd, J = 15.9, 5.9 Hz, 1H), 2.54 - 2.48 (m, 2H), 2.23 - 2.13 (m, 2H), 1.93 - 1.85 (m, 1H), 1.82 - 1.75 (m, 1H), 1.48 - 1.41 (m, 36H), 1.39 (s, 9H)。
步驟3:(5R,10S)-10-(2-(第三丁氧基)-2-側氧基乙基)-2,2-二甲基-4,8,11-三側氧基-5-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-3,15,18,21-四氧雜-9,12-二氮雜二十四烷-24-酸(中間物6-C)之合成
向具有攪拌棒之20 mL閃爍瓶添加中間物6-B (70 mg,0.08 mmol,1當量)及DMF (3 mL)。將該反應混合物冷卻至0℃並添加DIPEA (42 µL,31.1 mg,0.24 mmol,3當量),接著添加HBTU (31.1 mg,0.08 mmol,1.0當量)及在0℃攪拌10 min。使該溶液升至室溫並攪拌15 min,及然後添加呈固體之3-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)丙酸4-(第三丁基)酯(19.7 mg,0.08 mmol,1當量)。在室溫攪拌該反應並藉由HPLC-MS監測。1 h 45 min後使該反應停止並在真空下蒸發溶劑產生粗產物,其係藉由RP層析術純化,提供白色固體呈TFA鹽之中間物6-C (70 mg,66%,純度:99%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.40 min;MS (正ESI):實測值m/z 1075.5 [M+H]
+;C
52H
95N
6O
17(計算值1075.7)。針對C
52H
95N
6O
17,HRMS (ESI-TOF) m/z: [M + H]
+計算值1075.6748;實測值1075.6750。
1H NMR (700 MHz, DMSO-d6) 8.12 (d, J = 8.4 Hz, 1H), 7.91 (br s, 1H), 7.08 (br s, 1H), 4.59 - 4.49 (m, 1H), 3.75 (s, 1H), 3.61 - 3.57 (m, 2H), 3.52 - 3.45 (m, 10H), 3.39 (dt, J = 6.1, 3.1 Hz, 3H), 3.27 - 3.20 (m, 2H), 3.20 - 3.12 (m, 3H), 3.12 - 3.02 (m, 3H), 2.91 - 2.72 (m, 2H), 2.61 (dd, J = 15.6, 5.4 Hz, 1H), 2.44 (t, J = 6.4 Hz, 2H), 2.41 - 2.29 (m, 1H), 1.93 - 1.70 (m, 2H), 1.50 - 1.39 (m, 36H), 1.38 - 1.36 (m, 9H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟4:(5R,10S)-10-(2-(第三丁氧基)-2-側氧基乙基)-2,2-二甲基-4,8,11-三側氧基-5-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)-3,15,18,21-四氧雜-9,12-二氮雜二十四烷-24-酸(中間物6-D)之合成
向具有攪拌棒之20 mL閃爍瓶添加中間物6-C (40 mg,0.04 mmol,1當量)及2.5 mL DMF。將該反應混合物冷卻至0℃並添加DIPEA (30.8 µL,22.8 mg,0.14 mmol,4當量),接著添加HBTU (13.7 mg,0.04 mmol,1當量)並在0℃攪拌5 min。使該溶液升至室溫及攪拌20 min及然後添加呈固體之中間物1-C (17.9 mg,0.04 mmol,1當量)。在室溫攪拌該反應並藉由HPLC-MS監測。75 min後使該反應停止並在真空下蒸發溶劑產生粗產物,其係藉由RP層析術純化,提供白色固體呈TFA鹽之中間物6-D (36 mg,57%,純度:98%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.62 min;MS (正ESI):實測值m/z 1520.9 [M+H]
+;C
78H
126N
11O
19(計算值1520.9)。針對C
78H
126N
11O
19,HRMS (ESI-TOF) m/z: [M + H]
+計算值1520.9226;實測值1520.9172。
1H NMR (700 MHz, DMSO-d6) δ 9.82 (br s, 2H), 8.95 (t, J = 5.9 Hz, 1H), 8.15 (br s, 1H), 7.93 (br s, 1H), 7.29 - 7.23 (m, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.61 - 4.47 (m, 1H), 4.41 - 4.27 (m, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.79 - 3.65 (m, 10H), 3.63 - 3.59 (m, 8H), 3.54 - 3.47 (m, 11H), 3.39 (t, J = 6.1 Hz, 3H), 3.28 - 3.19 (m, 2H), 3.16 (qd, J = 7.1, 4.2 Hz, 3H), 3.08 (s, 1H), 2.97 - 2.80 (m, 4H), 2.61 - 2.51 (m, 6H), 2.49 - 2.43 (m, 3H), 1.81 - 1.73 (m, 2H), 1.68 - 1.56 (m, 2H), 1.50 - 1.39 (m, 36H), 1.37 (s, 9H), 1.21 - 1.08 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.00 (dd, J = 12.2, 4.2 Hz, 1H), 0.80 (d, J = 6.9 Hz, 6H)。
步驟5:2,2',2''-(10-((15S,20R)-20-羧基-15-(羧基甲基)-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,14,17-三側氧基-4,7,10-三氧雜-13,16-二氮雜二十烷-20-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物F)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物6-D (46 mg,0.03 mmol,1當量)及2.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。4 h後使該反應停止並將反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物F (10.3 mg,26%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:3.07 min;MS (正ESI):實測值m/z 1240.3 [M+H]
+;C
58H
86N
11O
19(計算值1240.6)。針對C
58H
86N
11O
19,HRMS (ESI-TOF) m/z: [M + H]
+計算值1240.6096;實測值1240.6109。
1H NMR (700 MHz, DMSO-d6) δ 10.65 (br s, 1H), 9.80 (br s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.89 (q, J = 6.0 Hz, 1H), 7.29 - 7.23 (m, 4H), 6.57 (s, 1H), 6.35 (s, 1H), 4.51 (dtd, J = 15.8, 7.9, 5.7 Hz, 2H), 4.36 (d, J = 13.0 Hz, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.61 (td, J = 6.7, 1.6 Hz, 2H), 3.52 - 3.47 (m, 20H), 3.42 - 3.35 (m, 2H), 3.28 - 3.19 (m, 1H), 3.19 - 3.11 (m, 6H), 3.09 (s, 1H), 2.96 - 2.86 (m, 5H), 2.65 - 2.57 (m, 2H), 2.55 (tt, J = 7.2, 3.6 Hz, 4H), 2.50 - 2.43 (m, 4H), 2.40 - 2.38 (m, 1H), 1.91 (s, 1H), 1.80 - 1.72 (m, 2H), 1.64 (d, J = 13.0 Hz, 1H), 1.59 (d, J = 12.7 Hz, 1H), 1.14 (qd, J = 12.6, 4.0 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.96 (m, 2H), 0.81 (d, J = 6.9 Hz, 6H)。*未觀察到4個可交換質子。
實例7:(R)-2,2',2''-(10-(1-羧基-4-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物G)之合成
步驟1:(R)-(5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊醯基)甘胺酸(中間物7-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加(R)-DOTAGA(
tBu)
4(462.2 mg,0.66 mmol,1當量)及DMF (3 mL)。將該反應混合物冷卻至0℃並添加DIPEA (345 µL,256 mg,1.98 mmol,3當量),接著添加HBTU (255 mg,0.66 mmol,1當量)並在0℃下攪拌10 min。使該溶液升至室溫及攪拌30 min及然後添加呈固體之甘胺酸(50 mg,0.66 mmol,1當量)。甘胺酸於反應混合物中之溶解度差,因此將TFA (0.3 mL)及吡啶(0.6 mL)添加至該反應混合物並在室溫,pH ~5下繼續攪拌。藉由HPLC-MS監測該反應。3 h 30 min後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物7-A (409 mg,59%,純度:95%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.12 min;MS (正ESI):實測值m/z 758.4 [M+H]
+;C
37H
68N
5O
11(計算值758.5)。針對C
37H
68N
5O
11,HRMS (ESI-TOF) m/z: [M + H]
+計算值758.4910;實測值758.4928。
1H NMR (700 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.10 (s, 1H), 4.51-3. 96 (m, 1H), 3.90 - 3.57 (m, 4H), 3.28 (s, 1H), 3.07 (s, 2H), 2.87 (s, 1H), 2.45 (s, 1H), 2.07 - 1.63 (m, 1H), 1.57 - 1.31 (m, 36H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:2,2’,2’’-(10-(1-(第三丁氧基)-5-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)®-三乙酸第三丁酯(中間物7-B)之合成
向具有攪拌棒之20 mL閃爍瓶添加中間物7-A (66.2 mg,0.08 mmol,1.4當量)及DMF (3 mL)。將該反應混合物冷卻至0℃並添加DIPEA (51.7 µL,38.4 mg,0.3 mmol,5當量),接著添加HBTU (23 mg,0.06 mmol,1當量)及在0℃下攪拌10 min。使該溶液升至室溫及攪拌15 min及然後添加呈固體之中間物1-C (30 mg,0.06 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。2 h後使反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之中間物7-B (67 mg,77%,純度:98%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:5.21 min;MS (正ESI):實測值m/z 1203.4 [M+H]
+;C
63H
99N
10O
13(計算值1203.7)。針對C
63H
99N
10O
13,HRMS (ESI-TOF) m/z: [M + H]
+計算值1203.7388;實測值1203.7361。
1H NMR (700 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.98 (s, 1H), 7.30 - 7.25 (m, 4H), 7.14 (s, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 4.39 - 4.28 (m, 1H), 3.89 (s, 2H), 3.82 - 3.70 (m, 2H), 3.18 - 3.13 (m, 2H), 3.07 (s, 2H), 2.96 - 2.87 (m, 1H), 2.59 - 2.52 (m, 3H), 2.47 - 2.45 (m, 1H), 1.80 (t, J = 8.1 Hz, 1H), 1.64 (t, J = 15.6 Hz, 2H), 1.49 - 1.37 (m, 36H), 1.21 - 1.07 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟3:(R)-2,2',2''-(10-(1-羧基-4-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物G)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物7-B (35 mg,0.03 mmol)及4 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。3 h後使該反應停止並將反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物G (20 mg,57%,純度:99%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:1.70 min;MS (正ESI):實測值m/z 979.3 [M+H]
+;C
44H
62N
10O
11(計算值979.4)。針對C
44H
62N
10O
11,HRMS (ESI-TOF) m/z: [M + H]
+計算值979.4884;實測值979.4885。
1H NMR (700 MHz, DMSO-d6) δ 10.62 (br s, 1H), 9.84 (br s, 1H), 8.95 (t, J = 6.0 Hz, 1H), 7.96 (br s, 1H), 7.28 - 7.25 (m, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.34 - 4.30 (m, 1H), 4.07 (s, 1H), 3.91 (d, J = 5.6 Hz, 2H), 3.79 (d, J = 13.5 Hz, 2H), 3.50 (m, 13H), 3.16 (app. p, J = 7.0 Hz, 2H), 3.08 (s, 4H), 2.97 - 2.86 (m, 3H), 2.60 - 2.51 (m, 3H), 1.92 (br s, 2H), 1.83 - 1.75 (m, 1H), 1.64 (dd, J = 22.7, 12.9 Hz, 2H), 1.19 - 1.13 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H), 1.02 - 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H)。*未觀察到4個可交換質子。
實例8:2,2',2''-(10-((R)-1-羧基-4-(((S)-1-羧基-4-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-4-側氧基丁基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物H)之合成
步驟1:(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-5-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-5-側氧基戊酸第三丁酯(中間物8-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加(S)-4-((((9H-茀-9-基)甲氧基)羰基)胺基)-5-(第三丁氧基)-5-側氧基戊酸(43 mg,0.10 mmol,1當量)及DMF (3 mL)。將該反應混合物冷卻至0℃並添加DIPEA (70 µL,51.7 mg,0. 40 mmol,4當量),接著添加HBTU (38.7 mg,0.10 mmol,1當量)及在0℃下攪拌15 min。使該溶液升至室溫並攪拌20 min及然後添加呈固體之中間物1-C (50 mg,0.10 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。2 h後使該反應停止並在真空下蒸發溶劑以產生粗產物。該粗產物係藉由RP層析術純化以提供呈無色膜/固體之中間物8-A (66 mg,75%,純度:98%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:3.15 min;MS (正ESI):實測值m/z 870.9 [M+H]
+;C
50H
59N
6O
8(計算值871.4)。針對C
50H
59N
6O
8,HRMS (ESI-TOF) m/z: [M + H]
+計算值871.4389;實測值871.4396。
1H NMR (700 MHz, DMSO-d6) δ 9.80 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.89 (t, J = 6.6 Hz, 2H), 7.73 (t, J = 7.0 Hz, 2H), 7.69 (dd, J = 8.0, 2.9 Hz, 1H), 7.42 (td, J = 7.5, 3.1 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.30 - 7.19 (m, 4H), 6.58 (d, J = 4.1 Hz, 1H), 6.37 (d, J = 1.2 Hz, 1H), 4.39 - 4.21 (m, 4H), 4.00 - 3.92 (m, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.20 - 3.14 (m, 2H), 2.95 - 2.88 (m, 2H), 2.57 - 2.54 (m, 1H), 2.49 - 2.44 (m, 1H), 2.43 - 2.31 (m, 2H), 1.97 - 1.90 (m, 1H), 1.83 - 1.74 (m, 2H), 1.67 - 1.55 (m, 2H), 1.40 (s, 9H), 1.12 - 1.07 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.99 (td, J = 12.4, 4.3 Hz, 1H), 0.82- 0.78 (m, 6H)。*未觀察到2個可交換質子。
步驟2:(S)-2-胺基-5-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-5-側氧基戊酸第三丁酯(中間物8-B)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物8-A (60 mg,0.07 mmol,1當量),接著添加6 mL於DMF中之15%哌啶溶液。藉由HPLC-MS監測該反應。1 h後使反應停止並在真空下蒸發溶劑以產生粗產物。藉由用乙腈沈澱獲得產物以提供呈無色膜/固體之中間物8-B (37 mg,67%,純度:96%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.07 min;MS (正ESI):實測值m/z 649.0 [M+H]
+;C
35H
49N
6O
6(計算值649.4)。
步驟3:2,2',2''-(10-((R)-1-(第三丁氧基)-5-(((S)-1-(第三丁氧基)-5-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,5-二側氧基戊烷-2-基)胺基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物8-C)之合成:向具有攪拌棒之20 mL閃爍瓶添加(R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊酸(16.5 mg,0.02 mmol,1當量)及DMF (1.5 mL)。將反應混合物冷卻至0℃並添加DIPEA (16.2 µL,12 mg,0.09 mmol,4當量),接著添加HBTU (9.2 mg,0.02 mmol,1當量)及在0℃下攪拌15 min。使該溶液升至室溫並攪拌20 min及然後添加呈於DMF (0.5 mL)中之溶液之中間物8-B (18.5 mg,0.02 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。3 h 30 min後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物8-C (24 mg,64%,純度:97%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:5.31 min;MS (正ESI):實測值m/z 1331.8 [M+H]
+;C
70H
111N
10O
15(計算值1331.8)。針對C
70H
111N
10O
15,HRMS (ESI-TOF) m/z: [M + H]
+計算值1331.8225;實測值1331.8283。
1H NMR (700 MHz, DMSO-d6) δ 9.84 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 8.24 (br s, 1H), 7.31 - 7.25 (m, 4H), 7.10 (br s, 1H), 6.57 (s, 1H), 6.37 (d, J = 1.8 Hz, 1H), 4.37 (d, J = 12.9 Hz, 1H), 4.11 - 4.07 (m, 2H), 3.83 - 3.68 (m, 3H), 3.19 - 3.14 (m, 2H), 3.08 (s, 2H), 2.98 - 2.81 (m, 3H), 2.57 (d, J = 7.0 Hz, 2H), 2.50 - 2.45 (m, 1H), 2.43 (s, 1H), 2.37 - 2.31 (m, 2H), 1.91 - 1.86 (m, 2H), 1.82 - 1.76 (m, 3H), 1.68 - 1.60 (m, 2H), 1.49 - 1.42 (m, 36H), 1.40 (s, 9H), 1.11 (s, 1H), 1.04 (t, J = 7.2 Hz, 3H), 1.02 - 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟3:2,2',2''-(10-((R)-1-羧基-4-(((S)-1-羧基-4-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-4-側氧基丁基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物H)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物8-C (17 mg,9.3 µmol,1當量)及2.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。2 h30 min後使該反應停止並將該反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物H (10.5 mg,87%,純度:99%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:1.71 min;MS (正ESI):實測值m/z 1051.6 [M+H]
+;C
50H
71N
10O
15(計算值1051.5)。針對C
50H
71N
10O
15,HRMS (ESI-TOF) m/z: [M + H]
+計算值1051.5095;實測值1051.5125。
1H NMR (700 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 1.6 Hz, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.38 - 4.34 (m, 1H), 4.20 - 4.16 (m, 1H), 3.80 (d, J = 13.5 Hz, 1H), 3.18 - 3.13 (m, 2H), 2.97 - 2.86 (m, 3H), 2.62 - 2.52 (m, 2H), 2.49 - 2.41 (m, 5H), 2.40 - 2.32 (m, 2H), 1.96 - 1.89 (m, 3H), 1.84 - 1.76 (m, 1H), 1.66 (d, J = 12.5 Hz, 1H), 1.59 (d, J = 12.8 Hz, 1H), 1.18 - 1.09 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.98 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
實例9:2,2',2''-(10-((R)-1-羧基-4-(((S)-4-羧基-1-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-1-側氧基丁-2-基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物I)之合成
步驟1:((R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊醯基)-L-麩胺酸5-(第三丁酯)1-甲酯(中間物9-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加(R)-DOTAGA(
tBu)
4(350 mg,0.5 mmol,1當量)及7 mL DMF。將該反應混合物冷卻至0℃並添加DIPEA (348 µL,258 mg,2 mmol,4當量),接著添加HBTU (208mg,0.55 mmol,1.1當量)及在0℃下攪拌10 min。使該溶液升至室溫並攪拌15 min及然後添加呈固體之L-麩胺酸5-(第三丁酯)1-甲酯HCl (127 mg,0.5 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。2 h後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物9-A (412 mg,71%,純度:97%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.67 min;MS (正ESI):實測值m/z 900.4 [M+H]
+;C
45H
82N
5O
13(計算值900.6)。針對C
45H
82N
5O
13,HRMS (ESI-TOF) m/z: [M + H]
+計算值900.5904;實測值900.5936。
1H NMR (700 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.05 (s, 1H), 4.35 (s, 1H), 4.24 - 4.19 (m, 1H), 3.62 (s, 3H), 3.28 (s, 3H), 3.07 (s, 2H), 2.58 - 2.51 (m, 1H), 2.45 (s, 1H), 2.25 (t, J = 7.6 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.82 - 1.74 (m, 1H), 1.52 - 1.40 (m, 36H), 1.39 (s, 9H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:(S)-5-(第三丁氧基)-2-((R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊醯胺基)-5-側氧基戊酸(中間物9-B)之合成
將含有((R)-5-(第三丁氧基)-5-側氧基-4-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)戊醯基)-L-麩胺酸5-(第三丁酯)1-甲酯(中間物9-A) (164 mg,0.18 mmol,1當量)之燒瓶溶解於THF (5 mL)及水(2.5 mL)中並放置於冰浴中及攪拌10 min。一次添加全量呈固體之無水氫氧化鋰(LiOH) (21.8 mg,0.91 mmol,5當量)並於冰-水浴中攪拌該反應。藉由HPLC-MS監測該反應,1 h後藉由在室溫下用Amberlite IR120 [H]酸化至pH ~5,然後經由0.2 µM過濾盤過濾以移除樹脂進行後處理。該樹脂係用CAN,MeOH進一步清洗並在真空下蒸發溶劑。將粗產物溶解於乙腈/水中並凍乾以產生呈白色固體之中間物9-B (159 mg,94%,純度:95%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.57 min;MS (正ESI):實測值m/z 886.3 [M+H]
+;C
44H
80N
5O
13(計算值886.6)。
步驟3:(2-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺甲酸(9H-茀-9-基)甲酯(中間物9-C)之合成
向具有攪拌棒20 mL閃爍瓶添加(((9H-茀-9-基)甲氧基)羰基)甘胺酸(24.4 mg,0.08 mmol,1當量)及DMF (1.5 mL)。將該反應混合物冷卻至0℃並添加DIPEA (28 µL,0.16 mmol,2當量),接著添加HBTU (31.4 mg,0.08 mmol,1當量)及在0℃下攪拌5 min。使該溶液升至室溫及攪拌20 min及然後添加中間物2-B (55 mg,0.08 mmol,1當量)於含有DIPEA (53 µL,0.24 mmol,3當量)之DMF (1.5 mL)中之溶液。在室溫下攪拌該反應並藉由HPLC-MS監測。1 h 30 min後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由正相層析術純化以提供呈白色固體之中間物9-C (58 mg,76%,純度:98%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:3.48 min;MS (正ESI):實測值m/z 923.1 [M+H]
+;C
57H
59N
6O
6(計算值923.5)。針對C
57H
59N
6O
6,HRMS (ESI-TOF) m/z: [M + H]
+計算值923.4491;實測值923.4525。
1H NMR (700 MHz, DMSO-d6) δ 8.97 (t, J = 5.9 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.5 Hz, 2H), 7.44 - 7.30 (m, 13H), 7.25 (d, J = 7.4 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 7.05 (s, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 5.08 (s, 2H), 4.94 (s, 2H), 4.33 - 4.21 (m, 4H), 3.83 (qd, J = 16.7, 5.9 Hz, 2H), 3.78 - 3.72 (m, 1H), 3.66 - 3.59 (m, 1H), 3.18 (q, J = 6.9 Hz, 2H), 3.13 - 3.08 (m, 1H), 2.92 - 2.86 (m, 1H), 2.69 (s, 1H), 2.49 - 2.47 (m, 1H), 1.77 - 1.69 (m, 1H), 1.52 (dd, J = 22.9, 13.0 Hz, 2H), 1.27 - 1.25 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 6H)。
步驟4:5-(2,4-雙(苯甲氧基)-5-異丙基苯基)-N-乙基-4-(4-((1-甘胺醯基哌啶-4-基)甲基)苯基)-4H-1,2,4-三唑-3-甲醯胺(中間物9-D)之合成
將哌啶(0.45 mL)添加至(2-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺甲酸(9H-茀-9-基)甲酯(中間物9-C) (50 mg,0.05 mmol,1當量)於DMF (2.55 mL)中之溶液並在室溫下攪拌該混合物。藉由HPLC-MS監測反應及在1 h後在室溫下使該反應停止。在真空下蒸發溶劑及粗產物係藉由RP層析術純化以產生呈白色固體之中間物9-D (24.6 mg,64%,純度98%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.48 min;MS (正ESI):實測值m/z 701.1 [M+H]
+;C
42H
49N
6O
4(計算值701.4)。
步驟5:2,2',2''-(10-((R)-5-(((S)-1-((2-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-5-(第三丁氧基)-1,5-二側氧基戊烷-2-基)胺基)-1-(第三丁氧基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物9-E)之合成
向具有攪拌棒之20 mL閃爍瓶添加中間物9-B (22.8 mg,0.02 mmol,1當量)及DMF (2 mL)。將該反應混合物冷卻至0℃並添加DIPEA (19 µL,14.2 mg,0.11 mmol,4.5當量),接著添加HBTU(9.4 mg,0.02 mmol,1當量)及在0℃下攪拌15 min。使該溶液升至室溫及攪拌20 min及然後添加溶解於DMF (1 mL)中之中間物9-D (18 mg,0.02 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。1 h 45 min後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物9-E (30 mg,65%,純度:95%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:3.12 min;MS (正ESI):實測值m/z 1569.5 [M+H]
+;C
86H
126N
11O
16(計算值1568.9)。針對C
86H
126N
11O
16,HRMS (ESI-TOF) m/z: [M + H]
+計算值1568.9379;實測值1568.9403。
1H NMR (700 MHz, DMSO-d6) δ 8.98 (td, J = 6.0, 2.2 Hz, 1H), 7.92 (s, 1H), 7.41 - 7.36 (m, 4H), 7.36 (t, J = 7.4 Hz, 2H), 7.35 - 7.29 (m, 2H), 7.27 - 7.23 (m, 2H), 7.10 - 7.06 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.77 (s, 1H), 5.08 (s, 2H), 4.95 (d, J = 3.3 Hz, 2H), 4.31 - 4.29 (m, 2H), 4.00 - 3.81 (m, 2H), 3.74 (d, J = 13.6 Hz, 2H), 3.22 - 3.14 (m, 2H), 3.13 - 3.06 (m, 2H), 2.96 - 2.85 (m, 1H), 2.49 - 2.48 (m, 4H), 2.28 - 2.20 (m, 2H), 1.92 - 1.84 (m, 1H), 1.77 - 1.69 (m, 3H), 1.47 - 1.40 (m, 36H), 1.38 (s, 9H), 1.05 (t, J = 7.2 Hz, 3H), 1.01 (dd, J = 6.9, 2.0 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟6:2,2',2''-(10-((R)-1-(第三丁氧基)-5-(((S)-5-(第三丁氧基)-1-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-1,5-二側氧基戊烷-2-基)胺基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物9-F)之合成
在室溫下向含有中間物9-E (26 mg,16.6 µmol,1當量)及甲醇(5 mL)之燒瓶添加10% Pd/C (3.4 mg,3.32 µmol,0.2當量)。在真空下使該反應混合物脫氣並經由氣球經受氫氣。將該反應攪拌整夜並藉由HPLC-MS監測。15小時後使該反應停止,濾過0.2 µM過濾盤並在真空下蒸發溶劑以產生呈無色膜之粗中間物9-F (22 mg,86%,純度:90%),其無需進一步純化即可用於下一步驟。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.73 min;MS (正ESI):實測值m/z 1389.4 [M+H]
+;C
72H
114N
11O
18(計算值1388.8)。
步驟7:2,2',2''-(10-((R)-1-羧基-4-(((S)-4-羧基-1-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-1-側氧基丁-2-基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物I)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物9-F (22 mg,15.68 µmol)及2.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。4 h後使該反應停止並將該反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物I (5 mg,23%,純度:97%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:2.84 min;MS (正ESI):實測值m/z 1108.5 [M+H]
+;C
52H
74N
11O
16(計算值1108.5)。針對C
52H
74N
11O
16,HRMS (ESI-TOF) m/z: [M + H]
+計算值1108.5310;實測值1108.5332。
1H NMR (700 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.79 (s, 1H), 8.95 (td, J = 5.9, 2.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.28 - 7.26 (m, 3H), 6.57 (d, J = 1.9 Hz, 1H), 6.35 (s, 1H), 4.34 - 4.28 (m, 2H), 4.04 - 3.84 (m, 1H), 3.77 (d, J = 13.5 Hz, 1H), 3.19 - 3.13 (m, 2H), 3.09 (s, 2H), 2.97 - 2.86 (m, 3H), 2.58 - 2.52 (m, 3H), 2.44 (s, 2H), 2.32 - 2.26 (m, 2H), 1.94 - 1.87 (m, 3H), 1.81 - 1.71 (m, 1H), 1.65 - 1.60 (m, 2H), 1.18 - 1.14 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
實例10:2,2',2''-(10-(2-(((S)-1-(((S)-1-(((S)-5-胺基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,5-二側氧基戊烷-2-基)胺基)-4-羧基-1-側氧基丁-2-基)胺基)-5-胍基-1-側氧基戊烷-2-基)胺基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物J)之合成
步驟1:N
2-((S)-5-(第三丁氧基)-5-側氧基-2-((S)-5-(3-((2,2,4,6,7-五甲基-2,3-二氫苯并呋喃-5-基)磺醯基)胍基)-2-(2-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)乙醯胺基)戊醯胺基)戊醯基)-N
5-三苯甲基-L-麩醯胺酸(中間物10-A)之合成
藉由固相肽合成(SPPS)於2-氯三苯甲基氯樹脂(Chem-Impex,0.72 mmol/g,139 mg,0.1 mmol)上合成受保護之肽。將Fmoc-Gln(Trt)-OH (305 mg,0.5 mmol)溶解於具有碘化鉀(16 mg,0.1 mmol)及DIPEA (174 µL,1.0 mmol)之DMF (4 mL)中。所得溶液係與該樹脂組合並在室溫下攪拌整夜。Fmoc去保護係以於DMF中之20%哌啶進行5及15分鐘。後續偶合係使用於DMF中之0.3 mmol受保護之胺基酸(Fmoc-Glu(OtBu)-OH、Fmoc-Arg(Pbf)-OH及DOTA(OtBu)
3) 0.3 mmol HBTU及0.6 mmol DIPEA進行1小時。偶合係藉由卡瑟(Kaiser)檢測進行監測。在最終偶合後,用DCM徹底清洗該樹脂。自樹脂裂解係以於DCM (5 mL)中之20% HFIP進行30分鐘。將該樹脂瀝乾並用DCM (2 mL)清洗,及在空氣流下濃縮經組合之洗滌液。將所得之受保護之粗肽溶解於DMSO中並藉由製備型RP HPLC純化。凍乾後獲得呈無色固體之經純化之受保護之肽中間物10-A (38.5 mg,25%,純度:98%)。藉由HPLC-MS使用溶析方法4分析等分試樣;滯留時間:4.98 min;針對C
80H
118N
11O
17S [M+H]
+,MS (ESI+) m/z計算值1536.8;實測值1536.9。
1H NMR (700 MHz, DMSO-d
6) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.31 (s, 1H), 7.28 - 7.24 (m, 7H), 7.21 - 7.18 (m, 3H), 7.17 - 7.15 (m, 7H), 6.68 (s, 1H), 6.37 (s, 1H), 4.35 - 4.29 (m, 1H), 4.26 (s, 1H), 4.22 - 4.12 (m, 2H), 4.12 - 4.01 (m, 1H), 3.92 (s, 1H), 3.60 - 3.43 (m, 5H), 3.36 (s, 3H), 3.32 - 3.19 (m, 3H), 3.19 - 3.09 (m, 2H), 3.08 - 2.97 (m, 4H), 2.95 (s, 3H), 2.89 (s, 2H), 2.81 (d, J = 26.0 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.39 - 2.34 (m, 2H), 2.24 (t, J = 8.5 Hz, 2H), 2.07 (s, 1H), 2.00 (s, 3H), 1.93 - 1.85 (m, 2H), 1.79 - 1.73 (m, 2H), 1.73 - 1.66 (m, 1H), 1.47 (s, 9H), 1.40 (s, 9H), 1.38 (m, 27H)。
步驟2:2,2',2''-(10-((6S,9S,12S)-6-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-羰基)-9-(3-(第三丁氧基)-3-側氧基丙基)-3,8,11,14-四側氧基-12-(3-(3-((2,2,4,6,7-五甲基-2,3-二氫苯并呋喃-5-基)磺醯基)胍基)丙基)-1,1,1-三苯基-2,7,10,13-四氮雜十五烷-15-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物10-B)之合成
將中間物10-A (21 mg,0.02 mmol)、中間物2-B (15 mg,0.022 mmol)、HBTU (7.6 mg,0.02 mmol)及DIPEA (18 µL,0.1 mmol)溶解於DMF (2 mL)中並在室溫下攪拌1小時。在減壓下蒸發溶劑並將殘餘物重新溶解於DMSO (<1 mL)中。粗產物係藉由製備型RP HPLC純化以在凍乾後產生呈無色固體之中間物10-B (23 mg,54%,純度:98%)。藉由HPLC-MS使用溶析方法4分析等分試樣;滯留時間:6.15 min;針對C
120H
162N
16O
19S [M+2H]
2+,MS (ESI+) m/z計算值1082.1;實測值1082.3。
步驟3:2,2',2''-(10-(2-(((S)-1-(((S)-1-(((S)-5-胺基-1-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,5-二側氧基戊烷-2-基)胺基)-4-羧基-1-側氧基丁-2-基)胺基)-5-胍基-1-側氧基戊烷-2-基)胺基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物J)之合成
將10% w/w碳載鈀(30% w/w, 3.5 mg)添加至具有攪拌棒之5 mL微波小瓶並用隔膜及螺旋蓋密封。用氮吹掃該小瓶,接著添加溶解於甲醇(2 mL)中之中間物10-B (23 mg,10.8 µmol)。然後用氫及附接至該小瓶之氫氣球吹掃該小瓶。在室溫下攪拌2小時後,用氮吹掃該小瓶且該小瓶未密封。使該反應混合物濾過0.2 µm注射器過濾器並在減壓下蒸發溶劑。將所得產物溶解於2 mL 95:2.5:2.5 TFA/ /TIPS/H
2O (v/v/v)中並在37℃下於加熱塊中攪拌90分鐘。然後在空氣流下蒸發該溶劑並將所得粗產物重新溶解於DMSO中,濾過0.2 µm注射器過濾器並藉由製備型RP HPLC純化。凍乾後獲得呈無色固體呈TFA鹽之化合物J (5.9 mg,34%,純度:99%)。藉由HPLC-MS使用溶析方法4分析等分試樣;滯留時間:4.53 min;針對C
58H
88N
16O
16[M+2H]
2+,HRMS (ESI+) m/z計算值632.3277;實測值632.3268。
1H NMR (700 MHz, DMSO-d
6) δ 9.86 (s, 1H), 8.96 (t, J = 5.4 Hz, 1H), 8.71 (s, 1H), 8.27 - 8.03 (m, 2H), 7.81 (s, 1H), 7.29 - 7.25 (m, 4H), 7.25 (m, 1H), 6.82 (m, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 4.79 - 4.67 (m, 2H), 4.43 - 4.32 (m, 4H), 4.32 - 4.28 (m, 1H), 4.27 - 4.22 (m, 1H), 4.12 - 3.88 (m, 9H), 3.71 - 3.52 (m, 4H), 3.47 - 3.24 (m, 7H), 3.19 - 3.15 (m, 2H), 3.13 - 3.02 (m, 8H), 3.02 - 2.93 (m, 1H), 2.90 (h, J = 6.7 Hz, 1H), 2.32 - 2.20 (m, 2H), 2.20 - 2.00 (m, 2H), 1.97 - 1.82 (m, 2H), 1.81 - 1.68 (m, 3H), 1.68 - 1.59 (m, 3H), 1.59 - 1.45 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.7 Hz, 6H)。*未觀察到9個可交換質子。
實例11:(S)-2,2',2''-(10-(1-羧基-4-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-甲醯胺基)乙基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物K)之合成
步驟1:2,2',2''-(10-(5-((2-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-甲醯胺基)乙基)胺基)-1-(第三丁氧基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(S)-三乙酸第三丁酯(中間物11-A)之合成
向2,2',2''-(10-(5-((2-胺基乙基)胺基)-1-(第三丁氧基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸三第三丁酯(中間物5-A) (50 mg,0.06 mmol,1當量)於無水THF (4 mL)及攪拌棒中之溶液添加DIPEA (32 µL,0.18 mmol,3當量)並冷卻至0℃,接著在0℃下一次添加全量4-硝基苯基氯甲酸酯(12.7 mg,0.06 mmol,1當量)。最初在0℃下將該反應攪拌20 min,然後使其升至室溫並藉由HPLC-MS監測。在室溫下30 min後,藉由HPLC-MS觀察到完全轉化為硝基苯基中間物。將中間物2-B (59 mg,0.08 mmol,1.4當量)作為固體添加至該反應並在室溫下繼續攪拌。1 h後,添加另外中間物2-B (26 mg,0.04 mmol,0.6當量),接著添加DIPEA (32 µL,0.18 mmol,3當量)。使該反應混合物升至50℃並繼續攪拌整夜。在50℃下16 h後,藉由添加甲醇使該反應停止並在室溫下攪拌10 min。在真空下濃縮該反應混合物,接著進行RP層析術以提供呈白色固體呈TFA鹽之中間物11-A (34 mg,40%,純度:95%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.92 min;MS (正ESI):實測值m/z 1412.5 [M+H]
+;C
78H
114N
11O
13(計算值1412.9)。針對C
78H
114N
11O
13,HRMS (ESI-TOF) m/z: [M + H]
+計算值1412.8592;實測值1412.8552。
1H NMR (700 MHz, DMSO-d6) δ 8.99 (t, J = 5.9 Hz, 1H), 7.96 (br s, 1H), 7.42 - 7.34 (m, 6H), 7.36 - 7.30 (m, 2H), 7.28 - 7.24 (m, 2H), 7.11 - 7.06 (m, 4H), 7.03 (s, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 6.51 (t, J = 5.5 Hz, 1H), 5.09 (s, 2H), 4.96 (s, 2H), 4.43 - 3.94 (m, 1H), 3.89 (d, J = 12.8 Hz, 2H), 3.20 - 3.15 (m, 2H), 3.14 - 2.98 (m, 7H), 2.56 (t, J = 12.5 Hz, 2H), 2.48 (d, J = 7.1 Hz, 2H), 1.51 - 1.39 (m, 40H), 1.05 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:2,2',2''-(10-(1-(第三丁氧基)-5-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-甲醯胺基)乙基)胺基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(S)-三乙酸第三丁酯(中間物11-B)之合成
在室溫下向含有中間物11-A (30 mg,19.11 µmol)及甲醇(4.5 mL)之燒瓶添加10% Pd/C (8 mg,7.64 µmol,0.4當量)。在真空下使該反應混合物脫氣並經由氣球經受氫氣。將該反應攪拌整夜並藉由HPLC-MS監測。15小時後使該反應停止,濾過0.2 µM過濾盤並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物11-B (18.4 mg,66%,純度:98%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.78 min;MS (正ESI):實測值m/z 1232.5 [M+H]
+;C
64H
102N
11O
13(計算值1232.8)。針對C
64H
102N
11O
13,HRMS (ESI-TOF) m/z: [M + H]
+計算值1232.7680;實測值1232.7680。
1H NMR (700 MHz, DMSO-d6) δ 9.82 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.31 - 7.25 (m, 4H), 7.11 (s, 2H), 6.57 (s, 1H), 6.54 (br s, 1H), 6.37 (s, 1H), 3.92 (d, J = 13.4 Hz, 2H), 3.20 - 3.13 (m, 2H), 3.10 - 3.01 (m, 8H), 2.94 - 2.87 (m, 1H), 2.61 - 2.54 (m, 4H), 2.47 - 2.39 (m, 2H), 1.72 - 1.65 (m, 1H), 1.57 (d, J = 12.6 Hz, 2H), 1.51 - 1.37 (m, 38H), 1.09 - 1.05 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.0 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟3:(S)-2,2',2''-(10-(1-羧基-4-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-甲醯胺基)乙基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物K)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物11-B (18 mg,10.73 µmol,1當量)及2.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。4 h後使該反應停止並將反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物K (13 mg,97%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:2.89 min;MS (正ESI):實測值m/z 1009.0 [M+H]
+;C
48H
70N
11O
13(計算值1008.5)。針對C
48H
70N
11O
13,HRMS (ESI-TOF) m/z: [M + H]
+計算值1008.5149;實測值1008.5157。
1H NMR (700 MHz, DMSO-d6) δ 13.14 (br s, 2H), 10.71 (br s, 1H), 9.84 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.93 (br s, 1H), 7.29 - 7.24 (m, 4H), 6.58 (s, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 3.92 (d, J = 12.9 Hz, 2H), 3.29 - 3.20 (m, 1H), 3.19 - 3.13 (m, 2H), 3.07 (d, J = 5.6 Hz, 6H), 2.93 - 2.87 (m, 1H), 2.61 - 2.53 (m, 4H), 2.42 - 2.33 (m, 3H), 2.00 - 1.83 (m, 2H), 1.71 - 1.64 (m, 1H), 1.56 (app. dd, J = 13.3, 3.6 Hz, 2H), 1.09 - 1.05 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
實例12:2,2',2''-(10-((R)-1-羧基-4-(((S)-4-羧基-1-((2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)胺基)-1-側氧基丁-2-基)胺基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物L)之合成
步驟1:2,2',2''-(10-(2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸第三丁酯(中間物12-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加2-(4,7,10-參(2-(第三丁氧基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1-基)乙酸、DOTA-參(
tBu)酯(20.2 mg,0.04 mmol,1當量)及DMF (2 mL)。將該反應混合物冷卻至0℃並添加DIPEA (25 µL,18.2 mg,0.14 mmol,4當量),接著添加HBTU (13.6 mg,0.04 mmol,1當量)及在0℃下攪拌10 min。使該溶液升至室溫並攪拌15 min及然後添加呈固體之中間物1-C (18 mg,0.04 mmol,1當量)。在室溫下攪拌並藉由HPLC-MS監測反應。4 h後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物12-A (38 mg,73%,純度:85%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.44 min;MS (正ESI):實測值m/z 1018.0 [M+H]
+;C
54H
84N
9O
10(計算值1018.6)。針對C
54H
84N
9O
10,HRMS (ESI-TOF) m/z: [M + H]
+計算值1018.6336;實測值1018.6345。
1H NMR (700 MHz, DMSO-d6) δ 9.88 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.34 (br s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.55 (s, 1H), 6.37 (s, 1H), 4.32 (d, J = 12.8 Hz, 1H), 4.13 (br s, 5H), 3.67 - 3.62 (m, 2H), 3.16 (p, J = 6.9 Hz, 2H), 3.08 - 3.00 (m, 1H), 2.98 - 2.86 (m, 3H), 2.65 - 2.53 (m, 3H), 1.86 - 1.78 (m, 1H), 1.70 (d, J = 12.6 Hz, 1H), 1.62 (d, J = 12.6 Hz, 1H), 1.52 - 1.35 (m, 32H), 1.23 (t, J = 10.4 Hz, 1H), 1.06 (d, J = 10.4 Hz, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.78 (dd, J = 7.0, 3.2 Hz, 6H)。未報告由H
2O及DMSO遮蔽之質子。
步驟2:2,2',2''-(10-(2-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-2-側氧基乙基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物L)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物12-A (25 mg,21µmol)及2.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。2 h 30min後使該反應停止並將該反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物L (11 mg,48%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:2.78 min;MS (正ESI):實測值m/z 850.0 [M+H]
+;C
42H
60N
9O
10(計算值850.4)。針對C
42H
60N
9O
10,HRMS (ESI-TOF) m/z: [M + H]
+計算值850.4458;實測值850.4456。
1H NMR (700 MHz, DMSO-d6) δ 12.95 (br s, 2H), 9.85 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.77 (br s, 1H), 7.31 - 7.25 (m, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.39 - 4.01 (m, 6H), 3.59 (d, J = 13.3 Hz, 1H), 3.39 (br s, 8H), 3.19 - 3.13 (m, 2H), 3.09 (d, J = 17.5 Hz, 2H), 2.99 - 2.87 (m, 2H), 2.68 - 2.55 (m, 3H), 1.85 - 1.79 (m, 1H), 1.68 - 1.63 (m, 2H), 1.28 - 1.21 (m, 1H), 1.16 - 1.09 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.9 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
實例13:(R)-2,2',2''-(10-(1-羧基-4-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物M)之合成
步驟1:2,2',2''-(10-(1-(第三丁氧基)-5-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物13-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加(R)-DOTAGA(
tBu)
4(15 mg,0.02 mmol,1當量),接著添加THF (0.9 mL)及DMF (0.1 mL)。將該反應混合物冷卻至0℃並添加DIPEA (11.3 µL,8.4 mg,0.06 mmol,3當量)及HBTU (11 mg,0.03 mmol,1.3當量)及在0℃下攪拌10 min。使該溶液升至室溫並攪拌15 min及然後呈於THF (0.4 mL)及DMF (0.3 mL)中之溶液連同5 µL DIPEA一起添加中間物1-C (12 mg,0.02 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。2 h後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物13-A (8.6 mg,33%,純度:96%)。藉由HPLC-MS溶析使用溶析方法2分析等分試樣;滯留時間:2.64 min;MS (正ESI):實測值m/z 1146.5 [M+H]
+;C
61H
96N
9O
12(計算值1146.7)。針對C
61H
96N
9O
12,HRMS (ESI-TOF) m/z: [M + H]
+計算值1146.7173;實測值1146.7145。
1H NMR (700 MHz, DMSO-d6) δ 10.67 (br s, 2H), 9.80 (br s, 1H), 8.96 (t, J = 6.5 Hz, 1H), 7.31 - 7.23 (m, 5H), 6.56 (d, J = 4.0 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 4.36 (s, 3H), 3.90 - 3.78 (m, 4H), 3.72 (br s, 2H), 3.18 - 3.13 (m, 3H), 3.06 (br s, 5H), 2.94 - 2.86 (m, 4H), 2.77 (br s, 3H), 2.58 - 2.54 (m, 2H), 1.96 - 1.87 (m, 2H), 1.84 - 1.73 (m, 3H), 1.68 - 1.59 (m, 3H), 1.51 - 1.37 (m, 38H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (app. dd, J = 6.9, 2.7 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:(R)-2,2',2''-(10-(1-羧基-4-(4-(4-(3-(2,4-二羥基-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物M)之合成
在0℃下向具有攪拌棒之20 mL閃爍瓶添加中間物13-A (7 mg,0.01 µmol)及0.6 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。5 min後,使該反應升至室溫並藉由HPLC-MS監測。18 h後使該反應停止並將反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物M (4.3 mg,79%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:2.83 min;MS (正ESI):實測值m/z 922.2 [M+H]
+;C
45H
64N
9O
12(計算值922.5)。針對C
45H
62N
9O
12,HRMS (ESI-TOF) m/z: [M - H]
-計算值920.4523;實測值920.4518。
1H NMR (700 MHz, DMSO-d6) δ 9.80 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.27 (d, J = 4.1 Hz, 4H), 6.57 (s, 1H), 6.35 (s, 1H), 4.36 (t, J = 14.6 Hz, 2H), 3.89 - 3.77 (m, 5H), 3.19 - 3.13 (m, 5H), 3.07 (s, 1H), 2.98 - 2.87 (m, 6H), 2.63 - 2.52 (m, 5H), 1.92 (s, 1H), 1.81 - 1.75 (m, 2H), 1.66 (d, J = 12.6 Hz, 1H), 1.61 (d, J = 12.6 Hz, 1H), 1.15 - 1.12 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.97 (m, 2H), 0.81 (d, J = 6.8 Hz, 6H)。*未報告由H
2O及DMSO遮蔽之質子。
實例14:(R)-2,2',2''-(10-(4-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1-羧基-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物N)之合成
步驟1:2,2',2''-(10-(5-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1-(第三丁氧基)-1,5-二側氧基戊烷-2-基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)(R)-三乙酸第三丁酯(中間物14-A)之合成
向具有攪拌棒之20 mL閃爍瓶添加(R)-DOTAGA(
tBu)
4(24.5 mg,0.03 mmol,1當量)及2 mL DMF。將該反應混合物冷卻至0℃並添加DIPEA (30.3 µL,22.5 mg,0.17 mmol,5當量),接著添加HBTU (13.5 mg,0.03 mmol,1當量)及在0℃下攪拌15 min。使該溶液升至室溫並攪拌15 min及然後添加呈固體之中間物2-B (23 mg,0.03 mmol,1當量)。在室溫下攪拌該反應並藉由HPLC-MS監測。16 h後使該反應停止並在真空下蒸發溶劑以產生粗產物,其係藉由RP層析術純化以提供呈白色固體呈TFA鹽之中間物14-A (47 mg,83%,純度:95%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:6.31 min;MS (正ESI):實測值m/z 1327.0 [M+H]
+;C
75H
108N
9O
12(計算值1326.8)。針對C
75H
108N
9O
12,HRMS (ESI-TOF) m/z: [M + H]
+計算值1326.8112;實測值1326.8142。
1H NMR (700 MHz, DMSO-d6) δ 8.98 (td, J = 6.1, 2.6 Hz, 1H), 7.41 - 7.38 (m, 4H), 7.38 - 7.30 (m, 5H), 7.28 - 7.24 (m, 2H), 7.08 (dd, J = 15.5, 8.0 Hz, 2H), 7.04 - 6.98 (m, 3H), 6.78 (s, 1H), 5.08 (s, 2H), 4.97 (s, 2H), 4.34 - 4.30 (m, 1H), 3.91 - 3.65 (m, 3H), 3.28 (br s, 1H), 3.20 - 3.15 (m, 2H), 3.14 - 3.00 (m, 2H), 2.94 - 2.85 (m, 1H), 2.79 - 2.63 (m, 2H), 2.49 - 2.41 (m, 2H), 1.77 - 1.70 (m, 1H), 1.60 - 1.51 (m, 2H), 1.47 (br s, 11H), 1.43 - 1.34 (m, 25H), 1.05 (t, J = 7.2 Hz, 3H), 1.02 - 0.99 (m, 6H), 0.97 - 0.90 (m, 1H)。*未報告由H
2O及DMSO遮蔽之質子。
步驟2:(R)-2,2',2''-(10-(4-(4-(4-(3-(2,4-雙(苯甲氧基)-5-異丙基苯基)-5-(乙基胺甲醯基)-4H-1,2,4-三唑-4-基)苯甲基)哌啶-1-基)-1-羧基-4-側氧基丁基)-1,4,7,10-四氮雜環十二烷-1,4,7-三基)三乙酸(化合物N)之合成
在室溫下向具有攪拌棒之20 mL閃爍瓶添加中間物14-A (25 mg,18.65 µmol,1當量)及2.5 mL去保護混合物TFA:TIPS:H
2O - 95:2.5:2.5 (v/v/v)。藉由放置在37℃下之預熱油浴上使該反應升至37℃並藉由HPLC-MS監測。2 h 30 min後使該反應停止並將該反應混合物放置在空氣流下以移除TFA。粗產物係藉由製備型RP HPLC純化以提供呈白色固體呈TFA鹽之化合物N (15 mg,60%,純度:99%)。藉由HPLC-MS溶析使用溶析方法1分析等分試樣;滯留時間:4.37 min;MS (正ESI):實測值m/z 1102.2 [M+H]
+;C
59H
76N
9O
12(計算值1102.6)。針對C
59H
76N
9O
12,HRMS (ESI-TOF) m/z: [M + H]
+計算值1102.5608;實測值1102.5624。
1H NMR (700 MHz, DMSO-d6) δ 13.16 (br s, 2H), 8.98 (t, J = 5.9 Hz, 1H), 7.40 - 7.38 (m, 4H), 7.37 - 7.30 (m, 4H), 7.25 (dd, J = 7.0, 1.7 Hz, 2H), 7.09 (dd, J = 8.5, 2.5 Hz, 2H), 7.03 (d, J = 1.6 Hz, 1H), 6.99 (dd, J = 8.4, 2.3 Hz, 2H), 6.77 (s, 1H), 5.08 (s, 2H), 4.95 (app. d, J = 2.9 Hz, 2H), 4.41 - 4.26 (m, 1H), 3.90 - 3.85 (m, 15H), 3.79 (t, J = 15.0 Hz, 1H), 3.56 - 3.24 (m, 5H), 3.21 - 3.14 (m, 2H), 3.14 - 3.06 (m, 1H), 2.96 - 2.86 (m, 2H), 2.62 - 2.54 (m, 1H), 2.50 - 2.41 (m, 2H), 1.99 - 1.84 (m, 1H), 1.77 - 1.69 (m, 1H), 1.58 (d, J = 12.3 Hz, 1H), 1.52 - 1.49 (m, 1H), 1.11 - 1.07 (m, 1H), 1.05 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 6.9 Hz, 6H), 0.98 - 0.90 (m, 1H)。*未報告由H
2O及DMSO遮蔽之質子。
實例15:用於放射性標記本發明揭示之化合物之方法
在放射性標記之前,藉由將適當量之化合物溶解於乙酸鈉緩衝液中製備各化合物之儲備溶液。可添加乙醇高達10體積%來改善該等化合物之溶解度。於1.5 mL埃彭多夫(Eppendorf)管中裝入所需化合物,接著裝入乙酸鈉緩衝液以視需要增加總體積(0.05至0.5 mL)。接著,添加[177Lu]LuCl
3或[111In]InCl
3或[225Ac]AcNO
3(或[225Ac]AcCl
3)於鹽酸溶液中之溶液並加熱該混合物。在將該反應加熱所需量之時間後,該反應混合物之iTLC分析(固相:矽膠(SG)或矽酸(SA)盤;流動相:具有5% MeOH之0.02 M檸檬酸鹽緩衝液)指示可接受之放射化學轉化(RCC),通常>95%。向該反應混合物添加L-抗血壞酸鈉及二伸乙基三胺-五乙酸鈣三鈉鹽水合物(DTPA)之乙酸鈉緩衝溶液。合成結束(EOS)時之iTLC及反相HPLC (溶析方法5)指示以通常>95%放射化學純度(RCP)形成所需之經放射性標記之產物。
表1:用[177Lu]LuCl
3放射性標記化合物。
熟習此項技術者將認知或可使用不多於例行性實驗確定本文描述之特定實施例之許多等同物。此等等同物旨在包含於隨附申請專利範圍中。Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the scope of the appended claims.
圖1.表現HSP90之異種移植腫瘤對使用225Ac-化合物D之治療產生反應的腫瘤生長。Figure 1. Tumor growth of xenograft tumors expressing HSP90 in response to treatment with 225Ac-Compound D.
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