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1. WO2020109523 - NOVEL TUMOR ANTIGEN BINDING AGENTS AND USES THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1 . A compound according to General Formula (1 )(i) or (1 )(ii):


(1 )(ii)

wherein A is a diagnostic or therapeutic agent comprising a binding site for a tumor antigen, and the spacer comprises at least one C-N bond.

2. The compound according to claim 1 , wherein the tumor antigen is prostate-specific membrane antigen (PSMA).

3. The compound according to claim 1 or 2, wherein the diagnostic or therapeutic agent A comprises a radiolabel.

4. The compound according to claim 3, wherein the radiolabel is a non-metallic radionuclide or a radiometal.

5. The compound according to any one of claims 1 - 4, wherein the diagnostic or therapeutic agent A comprises a chelator.

6. The compound according to claim 5, wherein the diagnostic or therapeutic agent A comprises a radiometal coordinated via the chelator.

7. The compound according to any one of claims 1 - 6, wherein the compound is characterized by the following General Formula (l a):


wherein D is a chelator;

Tbm is a tumor-antigen binding moiety;

linker is a linker, preferably comprising a cyclic group or an aromatic group; spacer is a spacer comprising a C-N bond; and

a is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10.

8. A compound characterized by the following General Formula (1 a):


wherein D is a chelator;

Tbm is a tumor-antigen binding moiety;

linker is a linker, preferably comprising a cyclic group or an aromatic group; spacer is a spacer comprising a C-N bond; and

a is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

9. The compound according to claim 7 or 8, wherein the tumor-antigen binding moiety (Tbm) is a PSMA-binding moiety (Pbm).

10. The compound according to claim 9, wherein the PSMA-binding moiety is characterized by General Formula (3):

wherein

X and Y are each independently selected from O, N or NH or NH2, S or P, Z is selected from CH2 or substituted CH2, wherein one or both of the hydrogen atoms may be substituted,

R\ R2 and R3 are each independently selected from -COH, -C02H, -S02H, -SO3H,

-SO4H, -P02H, -PO3H, -P04H2, -QO)-(Ci-Cio)alkyl, -C(0)-0(Ci- Cio)alkyl, -C(0)-NHR4, or -C(0)-NR4R5 wherein R4 and R5 are each independently selected from H, bond, (Cl -Cl 0)alkylene, F, Cl, Br, I, C(O) or -CH(O), C(S) or -CH(S), -C(S)-NH-benzyl-, -C(0)-NH-benzyl, -QOMG-Golalkylene, -(CH2)P-NH, -(CH2)p-(C,-Cio)alkyene, -(CH2)P- NH-C(0)-(CH2)q, -(CHrCH2)t-NH-C(0)-(CH2)p, -(CH2)P-CO-COH,

-(CH2)P-C0-C02H, -(CH2)p-C(0)NH-C[(CH2)q-C0H]3, -C[(CH2)P- COHh, -(CH2)p-C(0)NH-C[(CH2)q-C02H]3, -C[(CH2)p-C02H]3 or

-(CFf2)P-(Cs-Ci4)heteroaryl, and

f, p, q, r and t are each independently an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7,

8, 9, or 10;

preferably

X O or S, and

Y NF1 or O or S.

1 1 . The compound according to claim 10, wherein f is an integer selected from 1 , 2, 3, 4, or 5; preferably f is 2 or 3.

12. The compound according to claim 10 or 1 1 , wherein Y is O or NH.

13. The compound according to any one of claims 10 - 12, wherein Z is CH or C=0.

14. The compound according to any one of claims 10 - 13, wherein the PSMA-binding moiety is characterized by General Formula (3)(ii):



/ / *’ ' 1 ^

1 J I I 1 I

n „/

wherein

X is selected from O, N or NH or NH2, S or P,

R', R2 and R3 are each independently selected from -COH, -C02H, -S02H, -SO3H,

-SO4H, -PO2H, -PO3H, -P04H2, -C(0)-(CrCio)alkyl, -C(0)-0(C,- Cio)alkyl, -C(0)-NHR4, or -C(0)-NR4R5' wherein R4 and R5 are each independently selected from H, bond, (Cl -CI O)alkylene, F, Cl, Br, I, C(O) or -CH(O), C(S) or -CH(S), -C(S)-NH-benzyl-, -C(0)-NH-benzyl, - C(O)-(Ci-C10)alkylene, -(CH2)P-NH, -(CH2)p-(Ci-Cio)alkyene, -(CH2)P- NH-C(0)-(CH2) , -(CHrCH2),-NH-C(0)-(CH2)p, -(CH2)P-CO-COH,

-(CH2)P-C0-C02H, -(CH2)p-C(0)NH-C[(CH2)q-C0H]3, -C[(CH2)P-

COH]3/ -(CH2)p-C(0)NH-C[(CH2)q-C02H]3, -C[(CH2)p-C02H]3 or

-(CH2)p-(C5-Ci4)heteroaryl, and

b, p, q, r and t are each independently an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7,

8, 9, or 10;

preferably

X O or S, and

Y NH or O or S.

15. The compound according to any one of claims 10 - 14, wherein X is O.

1 6. The compound according to any one of claims 10 - 14, wherein R1, R2 and R3 are each independently selected from -COH, -CO2H, -S02H, -SO3H, -SO4H, -P02H, -PO3H, - PChhb.

1 7. The compound according to claim 16, wherein each of R1, R2 and R3 is -COOH.

18. The compound according to any one of claims 14 - 1 7, wherein b is an integer selected from 1 , 2, 3, 4 or 5, preferably b is 2, 3 or 4, more preferably b is 3.

1 9. The compound according to any one of claims 14 - 18, wherein R1, R2 and R3 are each COOH, X is O, and b is 3.

20. The compound according to any one of claims 9 - 19, wherein the PSMA-binding moiety is characterized by Formula (3)(a):


(3)(a)

21 . The compound according to any one of claims 9 - 13, wherein the PSMA-binding moiety is characterized by Formula (3)(b):


(3)(b)

22. The compound according to any one of claims 7 - 21 , wherein the linker is characterized by the Structural Formula (4):


wherein

X is each independently selected from O, N, S or P,

Q is selected from substituted or unsubstituted alkyl, alkylaryl and cycloalkyl, preferably from substituted or unsubstituted C5-Ci4 aryl, Cs-Cu alkylaryl or C5-C14 cycloalkyl, and

W is selected from— (CH )c-aryl or -(CH2)c-heteroaryl, wherein c is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 1 0.

23. The compound according to claim 22, wherein each X is O.

24. The compound according to claim 22 or 23, wherein Q is selected from substituted or unsubstituted C5-C7 cycloalkyl.

25. The compound according to claim 24, wherein Q is cyclohexyl.

26. The compound according to any one of claims 22 - 25, wherein W is selected from - (CH2)c-naphthyl, -(CH2)c-phenyl, -(CH2)c-biphenyl, -(CH2)c-indolyl, -(CH2)c- benzothiazolyl, wherein c is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 1 0. 27. The compound according to claim 26, wherein W is selected from -(CH2)-naphthyl, - (CH2)-phenyl, -(CH2)-biphenyl, -(CH2)-indolyl or -(CH2)-benzothiazolyl.

28. The compound according to claim 26 or 27, wherein W is -(CH2)-naphthyl.

29. The compound according to any one of claims 22 - 28, wherein the linker is characterized by the fol lowing Structural Formula (4a):


30. The compound according to any one of claims 1 - 29, wherein said compound is characterized by General Formula (1 )(b) or (1 )(c):


0 )(c) wherein D is a chelator;

spacer is a spacer comprising a C-N bond; and

a is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 0 or 1 ;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

31 . The compound according to any one of claims 1 - 30, wherein the spacer comprises a linear or branched, optionally substituted C1-C20 hydrocarbyl, more preferably C1-C12 hydrocarbyl, even more preferably C2-C6 hydrocarbyl, even more G-Gt hydrocarbyl, the hydrocarbyl comprising at least one, optionally up to 4 heteroatoms preferably selected from N.

32. The compound according to claim 30 or 31 , wherein the spacer comprises -[CHR6]U- NR7-, wherein R6 and R7 are each be independently selected from H and branched, unbranched or cyclic C1-C12 hydrocarbyl, and u is an integer selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein u is preferably 2, 3, or 4, more preferably 2 or 4.

33. The compound according to any one of claims 1 - 32, wherein the spacer is -[CH2]2- NH- or -[CH2]4-NH-

34. The compound according to any of claims 1 to 33, wherein the spacer comprises at least one amino acid residue or an amino acid residue side chain, wherein the amino acid is preferably selected from lysine, aspartate, asparagine, diaminobutyric acid, phenylalanine, tyrosine, threonine, serine, proline, leucine, isoleucine, valine, arginine, histidine, glutamate, glutamine, and alanine.

35. The compound according to claim 33 or 34, wherein the spacer comprises or consists of a lysine residue or a lysine residue side chain.

36. The compound according to claim 35, wherein the spacer further comprises a further amino acid residue or a side chain thereof.

37. .The compound according to claim 36, wherein the further amino acid residue or the side chain thereof is selected from aspartate, asparagine and diaminobutyric acid.

38. The compound according to any one of claims 1 - 37, wherein the spacer comprises or consists of Formula (2)(a) or Formula (2)(a)' or Formula (2)(a)":


(2)(a) (2)(a)' (2)(a)"

wherein k is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7 and 8, preferably 2, 3 or 4.

39. The compound according to any one of claims 1 - 38, wherein the spacer comprises or consists of Formula (2)(b):


wherein m is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5, preferably from 1 , 2 or 3.

40. The compound according to any one of claims 1 - 39, wherein the spacer comprises or consists of Formula (2)(c) or (2)(c)':


(2)(c)


(2)(c)'

wherein o is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 and k is as defined above.

41 . The compound according to any one of claims 1 - 38, wherein the spacer comprises or consists of Formula (2)(d) or (2)(d)':

(2)(d)


(2)(d)'

wherein A is an amino acid residue or— [A]n is absent and n is an integer selected from 0, 1 , 2, 3, 4, or 5, preferably from 0 or 1 , and k is as defined above.

42. The compound according to claim 41 , wherein the spacer comprises or consists of Formula (2)(d)(i) or (2)(d)(i)':


wherein k is as defined above.

43. The compound according to claim 41 , wherein the spacer comprises or consists of Formula (2)(d)(ii) or (2)(d)(ii)':


(2)(d)(ii)

wherein k is as defined above.

44. The compound according to claim 41 , wherein the spacer comprises or consists of Formula (2)(d)(iii) or (2)(d)(iii)':


ii)'

wherein k is as defined above.

45. The compound according to claim 41 , wherein the spacer comprises or consists of Formula (2)(d)(iv) or (2)(d)(iv)':


wherein k is as defined above.

46. The compound according to any one of claims 1 - 45, wherein said compound is characterized by General Formula (1 )(n) or (1 )(o):

(1 )(o)

wherein D is a chelator;

A is an amino acid residue, a side chain thereof or -[CHR6]U-NR7-, wherein R6 and R7 are each be independently selected from H and branched, unbranched or cyclic Ci-C12 hydrocarbyl, and u is an integer selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 1 0, wherein u is preferably 2, 3, or 4, more preferably 2 or 4 ;

V is absent or selected from a single bond, N or NH, or an optionally substituted C -C hydrocarbyl comprising up to 3 heteroatoms, wherein said heteroatom is preferably selected from N, wherein V more preferably contains 1 or 2 C-N bond(s);

a is an integer selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 1 0; and n is an integer selected from 0, 1 , 2, 3, 4, or 5, preferably from 0 or 1 ;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

47. The compound according to any one of claims 1 - 46, wherein said compound is characterized by Formula (7)(a) or (7)(a)':


or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

48. The compound according to any one of claims 1 - 46, wherein said compound is characterized by Formula (7)(b) or (7)(b)':


(7)( b)


(7)(b)'

wherein D is a chelator;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

49. The compound according to any one of claims 1 - 46, wherein said compound is characterized by Formula (7)(c) or (7)(c)':


(7)(c)'

wherein D is a chelator;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

50. The compound according to any one of claims 1 - 46, wherein said compound is characterized by Formula (7)(d) or (7)(d)':


(7)(d)'

wherein D is a chelator;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

51 . The compound according to any one of claims 1 - 46, wherein said compound is characterized by Formula (7)(e) or (7)(e)':

(7)(e)'

wherein D is a chelator;

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

52. The compound according to any one of claims 5 - 51 , wherein the chelator (D) is selected from 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOT A), N,N"-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 1 ,4,7-triazacyclononane-1 ,4,7-triacetic acid (NOT A), 2-(4,7- bis(carboxymethyl)-1 ,4,7-triazonan-1 -yl)pentanedioic acid (NODAGA), 2 -(4, 7, 10- tris(carboxymethyl)-1 ,4,7,10-tetraazacyclododecan-1 -yl)-pentanedioic acid

(DOTAGA), 1 ,4,7-triazacyclononane phosphinic acid (TRAP), 1 ,4,7- triazacydononane-1 -[methyl(2-carboxyethyl)-phosphinic acid]-4,7-bis[methyl(2- hydroxymethyOphosphinic acid] (NOPO), 3,6,9, 15-tetraazabicyclo[9,3,1 ]pentadeca- 1 (15),1 1 ,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[Acetyl(hydroxy)amino]pentyl}-N- [5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-

hydroxysuccinamicle (DFO), and Diethylenetriaminepentaacetic acid (DTPA), or derivatives thereof.

53. The compound according to any one of claims 5 - 52, wherein the chelator is selected from DOTA, DOTAGA, NODAGA, D03AP, D03APPrA or D03APABn.

54. The compound according to claim 52 or 53, wherein the chelator is DOTA.

55. The compound according to any one of claims 1 - 54, wherein said compound is characterized by Structural Formula (8)(a) or (8)(a)':


(8)(a)

(8)(a)'

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

56. The compound according to any one of claims 1 - 54, wherein said compound is characterized by Structural Formula (8)(b) or (8)(b)':


(8)(b)

(8)(b)'

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

57. The compound according to any one of claims 1 - 54, wherein said compound is characterized by Structural Formula (8)(c) or (8)(c)':


(8)(c)

(8)(c)'

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

58. The compound according to any one of claims 1 - 54, wherein said compound is characterized by Structural Formula (8)(d) or (8)(d)':


(8)(d)

(8)(d)'

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

59. The compound according to any one of claims Ί 54, wherein said compound is characterized by Structural Formula (8)(e) or (8)(e)':


(8)(e)

(8)(e)'

or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof.

60. Use of a compound according to any one of claims 1 to 59 for the preparation of a radiolabeled complex.

61 . A compound according to any of claims 1 to 59 for use as a medicament or as a precursor of a medicament.

62. A radiolabeled complex comprising a radionuclide and a compound according to any one of the preceding claims.

63. The radiolabeled complex according to claim 62, wherein the radiolabel is selected from the group consisting of 94Tc, 99n c, 90ln, 111 ln, 67Ga, 68Ga, 86Y, 90Y, 177Lu, 151Tb, 186Re, 188Re, 64Cu, 67Cu, 55Co, 57Co, 43Sc, 44Sc, 47Sc, 225Ac, 213Bi, 212Bi, 212Pb, 227Th, , 53Sm, 166Ho, 152Gd, l 53Gd, 157Gd, or 166Dy.

64. The radiolabeled complex according to claim 62 or 63, wherein the radiolabel is 177Lu.

65. A pharmaceutical composition comprising the compound according to any one of claims 1 to 60, or a radiolabeled complex according to any one of claims 62 - 64, and, optionally, a pharmaceutically acceptable carrier, diluent and/or excipient.

66. A kit comprising a compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt, ester, solvate or radiolabeled complex thereof, a radiolabeled complex according to any one of claims 62 - 64 or a pharmaceutical composition according to claim 64.

67. The compound according to any one of claims 1 to 60, the radiolabeled complex according to any one of claims 62 - 64, the pharmaceutical composition according to claim 65 or the kit according to claim 66 for use in medicine and/or diagnostics.

68. The compound according to any one of claims 2 to 60, the radiolabeled complex according to any one of claims 62 - 64, the pharmaceutical composition according to claim 65 or the kit according to claim 66 for use in a method of detecting the presence of (isolated) cells and/or tissues expressing prostate-specific membrane antigen (PSMA).

69. The compound according to any one of claims 2 to 60, the radiolabeled complex according to any one of claims 62 - 64, the pharmaceutical composition according to claim 65 or the kit according to claim 66 for use in a method of diagnosing, treating and/or preventing cancer, preferably prostate cancer, pancreatic cancer, renal cancer or bladder cancer.

70. The compound, radiolabeled complex, pharmaceutical composition or kit for use according to any one of claims 67 - 69, wherein said method or use comprises

(a) administering said compound, radiolabeled complex or pharmaceutical composition to a patient, and

(b) obtaining a radiographic image from said patient.

71 . An in vitro method of detecting the presence of cells and/or tissues expressing prostate- specific membrane antigen (PSMA) comprising

(a) contacting said PSMA-expressing cells and/or tissues with a compound, radiolabeled complex, pharmaceutical composition or kit according to any one of the preceding claims;

(b) applying detection means, optionally radiographic imaging, to detect of said cells and/or tissues.

72. The compound, the radiolabeled complex, the pharmaceutical composition or the kit for use according to any one of claims 67 - 70, or the method according to claim 71 , wherein radiographic imaging comprises positron emission tomography (PET) or single photon emission computed tomography (SPECT).

73. The compound, the radiolabeled complex, the pharmaceutical composition or the kit for use according to any one of claims 67 - 70 or 72, or the method according to claim 71 or 72, wherein said one or more cells or tissues comprise (optionally cancerous) prostate cells or tissues, (optionally cancerous) spleen cells or tissues, or (optionally cancerous) kidney cells or tissues.

74. The compound, the radiolabeled complex, the pharmaceutical composition or the kit for use according to any one of claims 67 - 70 or 72 - 73, or the method according to any one of claims 71 - 73, wherein the presence of PSMA-expressing cells or tissues is indicative of a prostate tumor (cell), a metastasized prostate tumor (cell), a renal tumor (cell), a pancreatic tumor (cell), a bladder tumor (cell), and combinations thereof.