US-12616711-B2 - Therapeutic dendrimer

Abstract

Provided herein are dendrimers comprising a core unit, five generations of building units being a lysine residue or analogue thereof, a plurality of first terminal groups each comprising a residue of a nucleoside analogue, and a plurality of second terminal groups each comprising a hydrophilic polymeric group. Also provided herein are pharmaceutical compositions comprising the dendrimer, and methods and uses of the dendrimers in therapy of disorders such as cancer.

Inventors

• David James Owen
• Rashmi Pathak

Assignees

• STARPHARMA PTY LTD

Dates

Publication Date

20260505

Application Date

20200925

Priority Date

20190926

Claims (20)

1. 1 . A dendrimer comprising: i) a core unit (C) which is and ii) building units (BU), which are wherein the acyl group of each building unit provides a covalent attachment point for attachment to the core or to a previous generation building unit; and wherein each nitrogen atom provides a covalent attachment point for covalent attachment to a subsequent generation building unit, a first terminal group or a second terminal group; wherein the core unit is covalently attached to two building units via amide linkages, each amide linkage being formed between a nitrogen atom present in the core unit and the carbon atom of an acyl group present in a building unit; the dendrimer being a five generation building unit dendrimer; wherein building units of different generations are covalently attached to one another via amide linkages formed between a nitrogen atom present in one building unit and the carbon atom of an acyl group present in another building unit; the dendrimer further comprising: iii) a plurality of first terminal groups (T1) each comprising a residue of a nucleoside analogue, which nucleoside analogue has a hydroxyl group, covalently attached to a diacyl linker group of formula: and iv) a plurality of second terminal groups (T2) each comprising a hydrophilic polymeric group which is a polyethylene glycol (PEG) group; or a pharmaceutically acceptable salt thereof.
2. 2 . The dendrimer as claimed in claim 1 , wherein the nucleoside analogue is selected from the group consisting of gemcitabine, cytarabine, and azacitadine.
3. 3 . The dendrimer as claimed in claim 2 , wherein the nucleoside analogue is gemcitabine.
4. 4 . The dendrimer as claimed in claim 1 , wherein the nucleoside analogue is gemcitabine and is covalently attached to the diacyl linker group as shown below: or as shown below
5. 5 . The dendrimer as claimed in claim 4 , wherein the first terminal group is: or wherein the first terminal group is:
6. 6 . The dendrimer as claimed in claim 1 , wherein the second terminal groups comprise PEG groups having a mean molecular weight of at least 500 Daltons.
7. 7 . The dendrimer as claimed in claim 1 , wherein the second terminal groups each comprise a PEG group covalently attached to a PEG linking group (L1) via an ether linkage formed between a carbon atom present in the PEG group and an oxygen atom present in the PEG linking group, and each second terminal group is covalently attached to a building unit via an amide linkage formed between a nitrogen atom present in a building unit and the carbon atom of an acyl group present in the PEG linking group.
8. 8 . The dendrimer as claimed in claim 7 , wherein the dendrimer comprises surface units comprising an outer building unit attached to a first terminal group and a second terminal group, the surface units having the structure: and wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of from 500 to 2500 Daltons.
9. 9 . The dendrimer as claimed in claim 1 , wherein at least 40% of the nitrogen atoms present in the outer building units are each covalently attached to a first terminal group; and at least 40% of the nitrogen atoms present in the outer building units are each covalently attached to a second terminal group.
10. 10 . The dendrimer as claimed in claim 1 , wherein the dendrimer is a compound has the structure shown in FIG. 10 , in which T1′ represents a first terminal group which is and T2′ represents a second terminal group which is wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of from 500 to 2500 Daltons, or T2′ represents H, and wherein less than 5 of T2′ are H.
11. 11 . The dendrimer as claimed in claim 1 , wherein the second terminal groups comprise PEG groups having an average molecular weight in the range of from 1900 to 2300 Daltons.
12. 12 . A pharmaceutical composition comprising: i) the dendrimer as claimed in claim 1 , or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable excipient.
13. 13 . The dendrimer as claimed in claim 1 , wherein the diacyl linker is
14. 14 . The dendrimer as claimed in claim 1 , wherein the diacyl linker is
15. 15 . A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the dendrimer according to claim 1 .
16. 16 . The method as claimed in claim 15 , wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, non-small cell lung cancer, an upper gastrointestinal cancer, pancreatic cancer, and bladder cancer.
17. 17 . The method as claimed in claim 15 , wherein the amount of dendrimer administered is sufficient to deliver an amount of active agent in the range of from 5 mg to 200 mg of nucleoside analogue/m 2 .
18. 18 . The method as claimed in claim 17 , wherein the method comprises administering the dendrimer in combination with a second dendrimer, and wherein the second dendrimer comprises: i) a core unit (C); and ii) building units (BU), each building unit being a lysine residue or an analogue thereof; wherein the core unit is covalently attached to two building units via amide linkages, each amide linkage being formed between a nitrogen atom present in the core unit and the carbon atom of an acyl group present in a building unit; the second dendrimer being a five generation building unit dendrimer; wherein building units of different generations are covalently attached to one another via amide linkages formed between a nitrogen atom present in one building unit and the carbon atom of an acyl group present in another building unit; the second dendrimer further comprising: iii) a plurality of first terminal groups (T1) each comprising a residue of an oncology agent, which oncology agent has a hydroxyl group, covalently attached to a diacyl linker group of formula: wherein A is a C 2 -C 10 alkylene group which is interrupted by at least one O, S, NH, or N(Me), or in which A is a heterocycle selected from the group consisting of tetrahydrofuran, tetrahydrothiophene, pyrrolidine, and N-methylpyrrolidine; and iv) a plurality of second terminal groups (T2) each comprising a hydrophilic polymeric group; or a pharmaceutically acceptable salt thereof.
19. 19 . The method as claimed in claim 18 , wherein the oncology agent is a taxane.
20. 20 . The method as claimed in claim 18 , wherein the oncology agent is a topoisomerase I inhibitor.

Description

RELATED APPLICATION This application is a 35 U.S.C. § 371 national stage filing of International Application No. PCT/AU2020/051028, filed on Sep. 25, 2020, which in turn claims the benefit of Australian Patent Application No. 2019903628, filed on Sep. 26, 2019 and Australian Patent Application No. 2019904094, filed on Oct. 30, 2019. The entire contents of each of the foregoing applications are incorporated herein by reference. FIELD The present disclosure relates to the delivery of nucleoside analogue-based oncology agents by means of drug-dendrimer conjugates. The drug-dendrimer conjugates comprise a dendrimer including a core and building units, with the outermost generation of building units including one or more nucleoside analogue oncology agents attached via a cleavable linker group. The present disclosure also relates to pharmaceutical compositions and methods of treatment comprising the drug-dendrimer conjugates, and to processes and synthetic intermediates for producing the drug-dendrimer conjugates comprising nucleoside analogue-based oncology agents. BACKGROUND Oncology agents are an important class of pharmaceuticals, and there have been significant advances in the chemotherapeutic treatment of cancer in recent decades. However, therapeutic application of oncology agents is often hampered by difficulties associated with their formulation and delivery, including poor pharmacokinetics properties such as rapid metabolism and/or excretion, and/or lack of targeting to the site of action. Further, a number of oncology agents are associated with severe side effects, providing a narrow therapeutic window, limiting the dosage regimen that can be used, and potentially reducing the efficacy of the treatment. Nucleoside analogues such as gemcitabine have been shown to be effective in the therapy of some cancers, including ovarian, breast pancreatic and lung cancers. Gemcitabine acts by being incorporated into the DNA and RNA of rapidly dividing cells, such as cancer cells, and interfering with their growth and repair. However, gemcitabine also has drawbacks as a pharmaceutical agent, in that it is rapidly metabolised in vivo by cytidine deaminase, and it also undergoes renal clearance (Ciccolini et al, Cancer Chemother Pharmacol, 2016, 78, p1-12), requiring high doses. Gemcitabine therapy is also associated with a number of side effects, including pulmonary toxicity and respiratory failure, haemolytic uremic syndrome, renal impairment, severe hepatic toxicity, capillary leak syndrome, and posterior reversible encephalopathy syndrome (see for example the prescribing information for Gemzar®). To combat some of these difficulties, oncology agents may be specially formulated to try and counter the limitations of the drug substance itself. For example, in the case of gemcitabine, approaches investigated include encapsulation of the pharmaceutically active agent in liposomes and micelles. Nonetheless, there remains a need for alternative and/or improved oncology therapies. SUMMARY It has been found that nucleoside analogue-dendrimer conjugates have surprising properties such that the amount of nucleoside analogue required (as part of the conjugate) to provide effective therapy is significantly reduced compared to free drug. The conjugates of the invention facilitate controlled release of the nucleoside analogue, and use of the conjugates is expected to have reduced side effects and/or enhanced efficacy. In a first aspect, there is provided a dendrimer comprising: i) a core unit (C); andii) building units (BU), each building unit being a lysine residue or an analogue thereof;wherein the core unit is covalently attached to two building units via amide linkages, each amide linkage being formed between a nitrogen atom present in the core unit and the carbon atom of an acyl group present in a building unit;the dendrimer being a five generation building unit dendrimer;wherein building units of different generations are covalently attached to one another via amide linkages formed between a nitrogen atom present in one building unit and the carbon atom of an acyl group present in another building unit;the dendrimer further comprising:iii) a plurality of first terminal groups (T1) each comprising a residue of a nucleoside analogue, which nucleoside analogue has a hydroxyl group, covalently attached to a diacyl linker group of formula: wherein A is a C2-C10 alkylene group which is interrupted by at least one O, S, NH, or N(Me), or in which A is a heterocycle selected from the group consisting of tetrahydrofuran, tetrahydrothiophene, pyrrolidine, and N-methylpyrrolidine; and iv) a plurality of second terminal groups (T2) each comprising a hydrophilic polymeric group; or a pharmaceutically acceptable salt thereof. In some embodiments, the nucleoside analogue is selected from the group consisting of gemcitabine, cytarabine, and azacitadine. In some embodiments, the nucleoside analogue is gemcitabine. In some embodiments, the