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US-12617867-B2 - Ligand-drug conjugate of exatecan analogue, preparation method therefor and application thereof

US12617867B2US 12617867 B2US12617867 B2US 12617867B2US-12617867-B2

Abstract

The present invention relates to a ligand-drug conjugate of an exatecan analogue, a preparation method therefor and an application thereof. Specifically, the present invention provides a ligand-drug conjugate having a structure shown in formula (-D), a preparation method therefor, a pharmaceutical composition containing same, and use thereof in preparation of drugs for treating cancers by means of receptor regulation. The definition of each substituent in formula (-D) is the same as that in the description.

Inventors

  • Jianyan XU
  • Ying Zhang
  • Xiaofeng Cai
  • Bolei QU
  • Jindong Liang
  • Lianshan Zhang
  • Feng He
  • Weikang Tao

Assignees

  • JIANGSU HENGRUI MEDICINE CO., LTD.
  • SHANGHAI HENGRUI PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20190925
Priority Date
20180926

Claims (20)

  1. 1 . A ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, being a ligand-drug conjugate of formula (Pc-L-Y-Dr) or a pharmaceutically acceptable salt or solvate thereof: wherein: Y is —O—(CR a R b ) m —CR 1 R 2 —C(O)—; R a and R b are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, alkoxy, hydroxy, amino, cyano, nitro, hydroxyalkyl, cycloalkyl and heterocyclyl; or, R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; R 1 is selected from the group consisting of halogen, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from the group consisting of hydrogen atom, halogen, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl and heteroaryl; or, R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; or, R a and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; m is an integer from 0 to 4; n is 1 to 10, which can be an integer or a decimal; Pc is an antibody; and L is a linker unit.
  2. 2 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein n is 2 to 8, which can be an integer or a decimal.
  3. 3 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein the linker unit -L- is - L 1 - L 2 - L 3 - L 4 - , L 1 is selected from the group consisting of -(succinimide-3-yl-N)—W—C(O)—, —CH 2 —C(O)—NR 3 —W—C(O)-and-C(O)—W—C(O)—, wherein W is selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl-cycloalkyl and linear heteroalkyl comprising 1 to 8 atom(s), the heteroalkyl comprises 1 to 3 heteroatom(s) selected from the group consisting of N, O and S, wherein the C 1-8 alkyl, cycloalkyl and linear heteroalkyl are each independently optionally further substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; L 2 is selected from the group consisting of —NR 4 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)—, —NR 4 (CH 2 CH 2 O)p 1 CH 2 C(O)—, —S(CH 2 )p 1 C(O)— and a chemical bond, wherein p 1 is an integer from 1 to 20; L 3 is a peptide residue composed of 2 to 7 amino acids, wherein the amino acids are optionally further substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; L 4 is selected from the group consisting of —NR 5 (CR 6 R 7 ) t —, —C(O)NR 5 , —C(O)NR 5 (CH 2 ) t — and a chemical bond, wherein t is an integer from 1 to 6; R 3 , R 4 and R 5 are identical or different and are each independently selected from the group consisting of hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl; R 6 and R 7 are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl.
  4. 4 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 3 , wherein the linker unit - L 1 - L 2 - L 3 - L 4 - , L 1 is and s 1 is an integer from 2 to 8; L 2 is a chemical bond; L 3 is a tetrapeptide residue; L 4 is —NR 5 (CR 6 R 7 ) t —, R 5 is selected from the group consisting of hydrogen atom and alkyl, R 6 and R 7 are identical or different and are each independently selected from the group consisting of hydrogen atom and alkyl, and t is 1 or 2.
  5. 5 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 3 , wherein the L 1 terminal of the linker unit -L- is connected to the ligand, and the L 4 terminal of the linker unit -L- is connected to Y.
  6. 6 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , being a ligand-drug conjugate of formula (Pc-L a -Y-Dr) or a pharmaceutically acceptable salt or solvate thereof: wherein: W is selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl-cycloalkyl and linear heteroalkyl comprising 1 to 8 atom(s), the heteroalkyl comprises 1 to 3 heteroatom(s) selected from the group consisting of N, O and S, wherein the C 1-8 alkyl, cycloalkyl and linear heteroalkyl are each independently optionally further substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; L 2 is selected from the group consisting of —NR 4 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)—, —NR 4 (CH 2 CH 2 O)p 1 CH 2 C(O)—, —S(CH 2 )p 1 C(O)— and a chemical bond, wherein p 1 is an integer from 1 to 20; L 3 is a peptide residue composed of 2 to 7 amino acids, wherein the amino acids are optionally further substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; R 1 is selected from the group consisting of halogen, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from the group consisting of hydrogen atom, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or, R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are identical or different and are each independently selected from the group consisting of hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl; R 6 and R 7 are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl; m is an integer from 0 to 4; n is 1 to 10, which can be an integer or a decimal; Pc is an antibody.
  7. 7 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 6 , being a ligand-drug conjugate of formula (PC-L b -Y-Dr) or a pharmaceutically acceptable salt or solvate thereof: wherein: s 1 is an integer from 2 to 8; Pc, R 1 , R 2 , and R 5 ˜R 7 are as defined in claim 6 ; m is an integer from 0 to 4; and n is 1 to 10, which can be an integer or a decimal.
  8. 8 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , selected from the group consisting of: wherein: n is 1 to 10, which can be an integer or a decimal; Pc is an antibody.
  9. 9 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein Pc is an antibody or an antigen-binding fragment thereof, and the antibody is selected from the group consisting of chimeric antibody, humanized antibody and fully humanized antibody.
  10. 10 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 9 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody and antigen-binding fragments thereof.
  11. 11 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 9 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of Trastuzumab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96 and Glematumamab, or antigen-binding fragments thereof.
  12. 12 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , selected from the group consisting of: wherein n is 1 to 10, which can be an integer or a decimal.
  13. 13 . A pharmaceutical composition, comprising a therapeutically effective amount of the ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , and pharmaceutically acceptable carrier(s), diluent(s), or excipient(s).
  14. 14 . A method of treating or preventing a tumor, the method comprising administering to a subject in need thereof a ligand-drug conjugate according to claim 1 .
  15. 15 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein: n is 1 to 10, which can be an integer or a decimal; Pc is an antibody.
  16. 16 . A ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof: wherein n is 1 to 10, which can be an integer or a decimal.
  17. 17 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein: Y is —O—(CR a R b )m-CR 1 R 2 —C(O)—; R a and R b are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, and alkyl; R 1 is a C 3-6 cycloalkylalkyl or C 3-6 cycloalkyl; R 2 is selected from the group consisting of hydrogen atom, haloalkyl and C 3-6 cycloalkyl; or, R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; m is 0 or 1.
  18. 18 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein Y is selected from the group consisting of:
  19. 19 . The ligand-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1 , being a ligand-drug conjugate of formula (Pc-L-D1) or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1 is a C 3-6 cycloalkylalkyl or C 3-6 cycloalkyl; R 2 is selected from the group consisting of hydrogen atom, haloalkyl and C 3-6 cycloalkyl; or, R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; m is 0 or 1; n is 1 to 10, which can be an integer or a decimal; Pc is an antibody; and Lis a linker unit.
  20. 20 . A compound of formula (L a -Y-Dr): or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: W is selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl-cycloalkyl and linear heteroalkyl comprising 1 to 8 atom(s), the heteroalkyl comprises 1 to 3 heteroatom(s) selected from the group consisting of N, O and S, wherein the C 1-8 alkyl, cycloalkyl and linear heteroalkyl are each independently optionally further substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; L 2 is selected from the group consisting of —NR 4 (CH 2 CH 2 O) p 1 CH 2 CH 2 C(O)—, —NR 4 (CH 2 CH 2 O)p 1 CH 2 C(O)—, —S(CH 2 )p 1 C(O)— and a chemical bond, wherein p 1 is an integer from 1 to 20; L 3 is a peptide residue composed of 2 to 7 amino acids, wherein the amino acids are optionally further substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl; R 1 is selected from the group consisting of halogen, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from the group consisting of hydrogen atom, halogen, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl and heteroaryl; or, R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are identical or different and are each independently selected from the group consisting of hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl; R 6 and R 7 are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl; m is an integer from 0 to 4.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the national stage of International Patent Application No. PCT/CN2019/107873, filed Sep. 25, 2019, which claims the benefit of and priority to Chinese Patent Application No. 201811123833.1, filed Sep. 26, 2018, each of which are incorporated herein by reference in their entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 25, 2019, is named “719074CPUS_126268-5013-US_Sequence_Listing.TXT” and is 18 kilobytes in size. FIELD OF THE INVENTION The present disclosure relates to a ligand-drug conjugate of exatecan analogue with a novel structure. Specifically, the present disclosure relates to a ligand-drug conjugate of exatecan analogue with a structural unit Y, a method for preparing the same, a pharmaceutical composition comprising the conjugate, and a use of the conjugate or the pharmaceutical composition. BACKGROUND OF THE INVENTION Chemotherapy remains one of the most important anti-cancer therapy along with surgery, radiotherapy and targeted therapy. Although there are many types of highly efficient cytotoxins, the difference between tumor cells and normal cells is very small, which limits the broad clinical application of these anti-cancer compounds due to the toxic side effect. Antibody drugs have become the frontline drugs for anti-tumor therapy because of the specificity of anti-tumor monoclonal antibody for tumor cell surface antigen. However, when the antibody is used alone as the anti-tumor drug, the efficacy is often unsatisfactory. Antibody drug conjugates (ADCs) enable the combination a monoclonal antibody or an antibody fragment with a biologically active cytotoxin through a chemically stable linker, taking full advantage of the specificity of antibody binding to the surface antigens of normal cells or tumor cells and the high efficiency of the cytotoxin, while avoiding low efficacy of the antibody and the toxic side effect of the cytotoxin. That means, comparing with conventional chemotherapy drugs, antibody drug conjugates can accurately bind to tumor cells and reduce the affect to normal cells (Mullard A, (2013) Nature Reviews Drug Discovery, 12:329-332; DiJoseph J F, Armellino D C, (2004) Blood, 103:1807-1814). In 2000, the first antibody drug conjugate Mylotarg (gemtuzumab ozogamicin, Wyeth Pharmaceuticals) was approved by the US Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (Drugs of the Future (2000) 25(7):686; U.S. Pat. Nos. 4,970,198; 5,079,233; 5,585,089; 5,606,040; 5,693,762; 5,739,116; 5,767,285; 5,773,001). In August 2011, Adcetris (brentuximab vedotin, Seattle Genetics Inc.) was approved through the US FDA Fast Track for the treatment of Hodgkin lymphoma and relapsed anaplastic large cell lymphoma (Nat. Biotechnol (2003) 21(7):778-784; WO2004010957; WO2005001038; U.S. Pat. Nos. 7,090,843A; 7,659,241; WO2008025020). Adcetris® is a novel target ADC drug, which enables the drug to act directly on the target CD30 of lymphoma cell, trigger endocytosis and consequently induce tumor cell apoptosis. Both Mylotarg and Adcetris are target therapies for hematologic tumors, the organizational structure of which is relatively simple compared with that of solid tumors. In February 2013, Kadcyla (ado-trastuzumab emtansine, T-DM1) was approved by FDA for the treatment of advanced or metastatic breast cancer patients who are HER2-positive with Trastuzumab (trade name: Herceptin)-resistant and paclitaxel-resistant (WO2005037992; U.S. Pat. No. 8,088,387). Kadcyla is the first ADC drug approved by FDA for the treatment of solid tumors. There are several types of cytotoxic small molecules used in antibody drug conjugate, one of which is camptothecin derivatives, which show anti-tumor effect by inhibiting topoisomerase I. Documents reporting the use of the camptothecin derivative, exatecan (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]imidazo[1,2-b]quinoline-10,13(9H,15H)-dione) in antibody drug conjugate (ADC) comprise WO2014057687, Clinical Cancer Research (2016) 22 (20): 5097-5108, and Cancer Sci (2016) 107: 1039-1046. However, further development of ADC drugs with better efficacy is still needed. SUMMARY OF THE INVENTION In order to improve the ligand, especially the coupling effect between antibody and drug, the present disclosure provides a ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate comprises a structure of formula (-D): wherein: Y is selected from the group consisting of —O—(CRaRb)m-CR1R2—C(O)—, —O—CR1R2—(CRaRb)m-, —O—CR′R2—, —NH—(CRaRb)m-CR1R2—C(O)— and —S—(CRaRb)m-CR1R2—C(O)—; Ra and Rb are identical or different and are each independently selected from the group consisting of hydrogen atom, deuteri