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1. WO2020109428 - COMPOSÉS THÉRAPEUTIQUES, NANOPARTICULES ET LEURS UTILISATIONS

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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Claims

1. A compound comprising a maytansinoid covalently bonded to a linker group, wherein the linker group is covalently bonded to a ligand group having a cyclic polythiol moiety.

2. A compound according to claim 1 wherein the cyclic polythiol is a cyclic disulfide.

3. A compound according to any one of the preceding claims

wherein the cyclic polythiol is saturated.

4. A compound according to any one of the preceding claims

wherein the ligand group is of the following formula;


wherein;

Z is CR5 or N,

R3, R4, R5 and R6 are independently one of a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group,

q is an integer of 0, 1, 2, 3, 4, 5 or 6, and m and n are independently an integer of 0, 1, 2, 3,

4 or 5 and m + n equals 0, 1, 2, 3, 4 or 5.

5. A compound according to claim 4 wherein the ligand group is of the following formula;


and R3, R4, R5, R6, q, m and n are as defined above.

6. A compound according to any one of the preceding claims wherein the cyclic polythiol is selected from one of 1,2- dithiolane, 1 , 2-dithiane, 1 , 2-dithiopane and 1 , 2-dithiocane .

7. A compound according to any one of the preceding claims

wherein the cyclic polythiol is unsubstituted.

8. A compound according to any one of the preceding claims

wherein the linker group is an amino acid-derived linker group of the following formula:


wherein;

R1 and R2 are each independently a hydrogen atom or a naturally occurring amino acid side chain.

9. A compound according to claim 8 wherein R1 is a methyl group and R2 is a hydrogen atom.

10. A compound according to claim 8 or claim 9 wherein the linker group is of the following formula:


and R1 is a hydrogen atom or a naturally occurring amino acid side chain.

11. A compound according to any one of the preceding claims

wherein the linker group is covalently bonded to the 3-OH position of the maytansinoid via an ester bond.

12. A compound according to any one of the preceding claims

wherein the linker group is covalently bonded to the ligand group via an amide bond.

13. A compound according to claim 1 of the following formula;


each X is independently a hydrogen atom or methyl group,

Y is a hydrogen atom, fluorine atom, chlorine atom, bromine atom or iodine atom,

Z is CR5 or N,

R3, R4, R5 and R6 are independently one of a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group,

q is an integer of 0, 1, 2, 3, 4, 5 or 6, and m and n are independently an integer of 0, 1, 2, 3,

4 or 5 and m + n equals 0, 1, 2, 3, 4 or 5.

14. A compound according to claim 13 of the following formula;


wherein X, Y, R3, R4, R5, R6, q, m and n are as defined above .

15. A compound according to claim 1 of one of the following formulae :


wherein the alanine derived linker group stereochemistry is (S) , (R) or racemic and the cyclic disulphide

stereochemistry is (S) , (R) or racemic.

16. A compound according to claim 15 wherein the alanine derived linker group stereochemistry is (S) and the cyclic disulphide stereochemistry (S) , (R) or racemic.

17. A compound according to claim 16 wherein the alanine derived linker group stereochemistry is (S) and the cyclic disulphide stereochemistry (R) or racemic.

18. A compound according to claim 1 of one of the following

formulae :

19. A nanoparticle comprising:

a core comprising a metal and/or a semiconductor; and

a plurality of ligands covalently linked to the core,

wherein said ligands comprise:

(i) at least one compound of any one of claims 1 to 16 as a polydentate ligand;

(ii) optionally at least one targeting ligand; and

(iii) at least one dilution ligand.

20. A nanoparticle according to claim 19 wherein the at least one dilution ligand comprises one or more of an ethylene glycol (EG) moiety, a polyethyleneglycol (PEG) moiety, glutathione, a carbohydrate and HS- (CH2) v- (OCH2CH2) w-COOH, where v and w are independently between 1 and 30, optionally between 6 and 10, or between 20 and 60.

21. The nanoparticle according to claim 19 or claim 20, wherein the targeting ligand comprises a tumour-targeting ligand.

22. The nanoparticle according any one of claims 19 to 21, wherein the targeting ligand is covalently linked to the core via a first linker, said first linker having a chain length of 2 to 50 atoms.

23. The nanoparticle according to claim 22, wherein said first

linker comprises a group -(CH2)r~ and/or - (OCH2CH2) s- , wherein r and s are independently ³ 1.

24. The nanoparticle according to any one of claims 20 to 24,

wherein said first linker is bound to the core via a terminal sulphur atom.

25. The nanoparticle according to any one of claims 19 to 24,

wherein said first linker is bound to the core via two terminal sulphur atoms .

26. The nanoparticle according to any one of claims 19 to 25,

wherein the at least one dilution ligand comprises HS- (CH2) 1- 10- (EG) 1-10-COOH or comprises a carbohydrate.

27. The nanoparticle according to any one of claims 19 to 26,

wherein the at least one dilution ligand comprises HS- (CH2) 1- 4- (OCH2CH2) 6-IO-COOH.

28. The nanoparticle according to any one of claims 19 to 27,

wherein the at least one dilution ligand comprises:


29. The nanoparticle according to any one of claims 19 to 28, wherein said plurality of ligands comprise:

at least one galactose ligand; and

at least one bidentate ligand of the following formulae; wherein the bidentate ligand is bound to the nanoparticle core by two thiol groups and the alanine derived linker group stereochemistry is (S) , (R) or racemic and the dithiol chain stereochemistry is (S) , (R) or racemic, and

at least one dilution ligand.

30. The nanoparticle according to claim 29 wherein the alanine

derived linker group stereochemistry is (S) and the dithiol chain stereochemistry is (S) , (R) or racemic.

31. The nanoparticle according to claim 29 wherein the alanine

derived linker group stereochemistry is (S) and the dithiol chain stereochemistry is (R) or racemic.

32. The nanoparticle according to any one of claims 19 to 31

wherein the at least one bidentate ligand is of one of the following formulae:

core by two thiol groups .

33. The nanoparticle according to any one of claims 19 to 32,

wherein the core comprises at metal selected from the group consisting of: Au, Ag, Cu, Pt, Pd, Fe, Co, Gd, Zn or any combination thereof.

34. The nanoparticle according to claim 33, wherein the core

comprises Au .

35. The nanoparticle according to any one of claims 19 to 34,

wherein the diameter of the core is in the range 1 nm to 10 nm .

36. The nanoparticle according to any one of claims 19 to 35,

wherein the diameter of the nanoparticle including its ligands is in the range 3 nm to 50 nm.

37. A nanoparticle according to claim 19 having the following structure :


wherein the alanine derived linker group stereochemistry is (S) , (R) or racemic and the dithiol chain stereochemistry is (S) , (R) or racemic.

38. A nanoparticle according to claim 37 wherein the alanine

derived linker group stereochemistry is (S) and the dithiol chain stereochemistry is (S) , (R) or racemic.

39. A nanoparticle according to claim 38 wherein the alanine

derived linker group stereochemistry is (S) and the dithiol chain stereochemistry is (R) or racemic.

40. A nanoparticle according to any one of claims 19 to 39 wherein the total number of ligands bound to the core is 20 or more including at least one maytansinoid .

41. A conjugate comprising a compound according to any one of claims 1 to 18 and a targeting agent.

42. A conjugate according to claim 41 wherein the targeting agent comprises an antibody, an antibody fragment, a peptide or an aptamer .

43. A conjugate according to claim 42 wherein the targeting agent comprises an antibody or an antibody fragment that selectively binds a tumour antigen.

44. A conjugate according to any one of claims 41 to 43, wherein the targeting agent comprises a therapeutic antibody.

45. A conjugate according to claim 44, wherein the therapeutic antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) effector function in vivo in a mammalian subject.

46. A conjugate according to any one of the preceding claims,

wherein said compound is conjugated to said targeting agent via a linker.

47. A conjugate according to claim 46, wherein the targeting agent comprises an antibody or an antibody fragment and wherein the linker comprises a cleavable portion.

48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 a nanoparticle according to any one of claims 20 to 40 or a conjugate according to any one of claims 41 to 47, and at least one pharmaceutically acceptable carrier or diluent.

49. A pharmaceutical composition according to claim 48, wherein the pharmaceutical composition is a sustained release

formulation and wherein at least a portion of the compound, the plurality of nanoparticles or the conjugate are encapsulated in a biocompatible polymer.

50. A pharmaceutical composition according to claim 49, wherein the sustained release formulation is in the form of a

microparticle, a microsphere, a bead or a film.

51. A pharmaceutical composition according to any one of claims 48 to 50, wherein the composition is in injectable form.

52. A compound according to any one of claims 1 to 18, a

nanoparticle according to any one of claims 19 to 40, a conjugate according to any one of claims 41 to 47, or a composition according to any one of claims 48 to 51 for use in medicine .

53. A compound according to any one of claims 1 to 18, a

nanoparticle according to any one of claims 19 to 40, a conjugate according to any one of claims 41 to 47, or a composition according to any one of claims 48 to 51 for use in the treatment of a proliferative disorder.

54. A compound, nanoparticle, conjugate or composition for use according to claim 53 wherein the proliferative disorder is a cancer .

55. A compound, nanoparticle, conjugate or composition for use according to claim 54 wherein the cancer is a carcinoma.

56. A compound, nanoparticle, conjugate or composition for use according to claim 54 wherein the cancer is selected from renal cancer, ovarian cancer, skin cancer, lung cancer, pancreatic cancer, liver cancer, head and neck cancer and brain cancer.

57. A compound, nanoparticle, conjugate or composition for use according to claim 54 wherein the cancer is selected from hepatocellular carcinoma (HCC) , glioma, melanoma, epidermal carcinoma, non-small cell lung cancer (NSCLC) , pancreatic adenocarcinoma, renal adenocarcinoma and ovarian

adenocarcinoma .

58. A compound, nanoparticle, conjugate or composition for use according to claim 54 wherein the cancer is selected from: hepatoblastoma, cholangiocarcinoma, cholangiocellular

cystadenocarcinoma, angiosarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma and

rhabdomyosarcoma .

59. The compound, nanoparticle, conjugate or composition for use according to any one of claims 53 to 58, wherein said

compound, nanoparticle, conjugate or composition is

administered concurrently, sequentially or separately with a second anti-cancer agent.

60. The compound, nanoparticle, conjugate or composition for use according to claim 59, wherein said second anti-cancer agent comprises a kinase inhibitor selected from the group

consisting of: Sorafenib, Regorafenib and Lenvatinib.

61. A method of treating a proliferative disease in a mammalian subject, comprising administering a compound according to any one of claims 1 to 18, a nanoparticle according to any one of claims 19 to 40, a conjugate according to any one of claims 41 to 47 or a pharmaceutical composition according to any one of claims 48 to 51 to the subject in need of therapy.

62. A method according to claim 61 wherein the proliferative

disease is a cancer.

63. The method according to claim 62, wherein the cancer is a

carcinoma .

64. The method according to claim 62, wherein the cancer is selected from renal cancer, ovarian cancer, skin cancer, lung cancer, pancreatic cancer, liver cancer, head and neck cancer and brain cancer.

65. The method according to claim 62, wherein the cancer is

selected from hepatocellular carcinoma (HCC) , glioma, melanoma, epidermal carcinoma, non-small cell lung cancer (NSCLC) , pancreatic adenocarcinoma, renal adenocarcinoma and ovarian adenocarcinoma.

66. The method according to claim 62, wherein said cancer is

selected from: hepatoblastoma, cholangiocarcinoma,

cholangiocellular cystadenocarcinoma, angiosarcoma,

hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma and rhabdomyosarcoma.

67. The method according to any one of claims 61 to 66, wherein said compound, nanoparticle, conjugate or composition is administered concurrently, sequentially or separately with a second anti-cancer agent.

68. The method according to claim 67, wherein said second anti cancer agent comprises a kinase inhibitor selected from the group consisting of: Sorafenib, Regorafenib and Lenvatinib.

69. Use of a compound according to any one of claims 1 to 18, a nanoparticle according to any one of claims 19 to 40, a conjugate according to any one of claims 41 to 47 or a pharmaceutical composition according to any one of claims 48 to 51 in the preparation of a medicament for use in a method according to any one of claims 61 to 68.

70. An article of manufacture comprising:

a compound according to any one of claims 1 to 18, a nanoparticle according to any one of claims 19 to 40, a conjugate according to any one of claims 41 to 47 or a

pharmaceutical composition according to any one of claims 48 to 51;

a container for housing the compound, nanoparticle, conjugate or pharmaceutical composition; and

an insert or label .

71. The article of manufacture according to claim 70, wherein the insert and/or label provides instructions, dosage and/or administration information relating to the use of the

nanoparticle or pharmaceutical composition in the treatment of a cancer in a mammalian subject.