Antibody-drug conjugates comprising trabectedin and lurbinectedin derivatives

Abstract

The present invention relates novel trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates, and a process for the preparation of the antibody-drug conjugates. The invention further relates to pharmaceutical dosage forms comprising the novel trabectedin or lurbinectedin derivatives or the corresponding antibody-drug conjugates. Furthermore, the invention relates to new trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates, and corresponding pharmaceutical dosage forms for use as medicament or for use in the treatment of specific cancer types.

Description

Abstract This invention relates to novel trabectedine and rubitectin derivatives, corresponding antibody-drug conjugates, and methods for preparing these antibody-drug conjugates. The invention further relates to pharmaceutical dosage forms comprising novel trabectedine or rubitectin derivatives or corresponding antibody-drug conjugates. Furthermore, the invention relates to novel trabectedine and rubitectin derivatives, corresponding antibody-drug conjugates, and corresponding pharmaceutical dosage forms for use as medicines or for use in the treatment of specific types of cancer.

Claims

Claims1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl;R4is selected from -H , -CH2ORR4, -CH2NHRR4, and -CH2C(=O)ORR4, wherein RR4 is -H or -C1-4alkyl; and R5is -H or -C1-4alkyl; with the proviso that compounds of formula (I) having the following combination of R2,R3, R4and R5are excluded:- R2is -OCH3, R3is -OH, R4is -H and R5is -H.

2. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 1, wherein R1is -OH or -C=N.

3. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 or 2, whereinR2is -H, -ORR2, -OCH2CH2ORR2, -OCH2C(=O)ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(=O)OH or -NH2; and / or- R3is -H, -ORR3, -OCH2CH2NHRR3, -NHRR3, -NHC(=O)CH2ORR3or -NHC(=O)CH2NHRR3, wherein RR3is -H or -C1-4alkyl, preferably R3is -H, -OH, OCH2CH2NH2, -NH2, -NHC(=O)CH2OH or -NHC(=O)CH2NH2.

4. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 3, whereinR4is -H, -CH2ORR4 or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl, preferably R4is -H; and / or R5is -H or -C1-4alkyl, preferably R5is -H.

5. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 4, wherein- R1is -OH or -C=N;- R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(=O)OH or -NH2;- R3is -H, -OH, -OCH2CH2NH2, -NH2, -NHC(=O)CH2OH or -NHC(=O)CH2NH2;R4is -H; and- R5is -H.

6. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 1, wherein formula (I) is:

7. A compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -C1-4alkyl; with the proviso that compounds of formula (VII) having the following combination ofR2, R3and R4are excluded:R2is -H, R3is -H and R4is -H; andR2is -OCH3, R3is -H and R4is -H.

8. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 7, wherein R1is -OH or -C=N.

9. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 7 or 8, whereinR2is -H, -NHRR2or -NHC(=O)CH2ORR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -NH2or -NHC(=0)CH20H; and / orR3is -H or -NHRRS, wherein RR3 is -H or -C1-4alkyl, preferably R3is -H or -NH2.

10. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 7 to 9, whereinR4is -H or -CH3.

11. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 7 to 10, wherein R1is -OH or -C M:R2is -H, -NH2or -NHC(=O)CH2OH;R3is -H or -NH2; andR4is -H or -CH3.

12. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 7, wherein formula (VII) is:; or13. A compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate,wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- Rs is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -Ci-4 alkyl; andR4is -H or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl.

14. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 13, wherein R1is -OH or -C=N.

15. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 13 or 14, whereinR2is -ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -OCH3or -NH2; and / or- R3is -H.

16. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 13 to 15, whereinR4is -H.

17. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 13 to 16, wherein- R1is -OH or -C=N;- R2is -OCH3or -NH2;R3is -H; andR4is -H.

18. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 13, wherein formula (XIII) is:

19. An antibody-drug conjugate of formula (XIX):A L-D]Z(XIX) whereinAb denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof;L denotes a linker; andD denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to any of claims 1 to 18, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of claims 1 to 18; and whereinD covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

20. The antibody-drug conjugate according to claim 19, wherein z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.

21. The antibody-drug conjugate according to any of claims 19 or 20, wherein D covalently binds to L via nitrogen or oxygen present in any of R2, R3or R4, preferably in any of R2or R3.

22. The antibody-drug conjugate according to any of claims 19 to 21, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; an anti-HER2antibody, preferably Trastuzumab; an anti-HER3antibody, preferably Patritumab; an anti-FRoc antibody, preferably Mirvetuximab; or an anti-EGFR antibody, preferably Cetuximab.

23. The antibody-drug conjugate according to any of claims 19 to 22, wherein L has the following structure:and whereinT and U are independently spacer units, each having from 1 to 24 chain carbons, wherein t and u are independently 0 or 1, preferably t + u > 1; each A is independently an amino acid unit, wherein a is an integer from 0 to 12;H is a hydrophilic unit, wherein h is 0 or 1 ; andY is a conjugating group that covalently binds to Ab; wherein preferably the conjugating group Y covalently binds to a sulfur atom present in Ab.

24. The antibody-drug conjugate according to claim 23, wherein Y is such that L is one of the following:wherein, if present, Re is -H or -C1-4alkyl, preferably -H or -CH3.

25. The antibody-drug conjugate according to any of claims 23 or 24, wherein U is one of the following:; orwherein preferably n is an integer from 5 to 10, more preferably 6 to 8, and most preferably 7; and / orT is one of the following:wherein preferably n is an integer from 1 to 8, more preferably 1 to 6, and most preferably 2 or 5; orwherein preferably m is 1 and n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6; and / orH is derived from a PEGylated amino acid, preferably one of the following:wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7; orwherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7; orH is the following:wherein preferably n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6.

26. The antibody-drug conjugate according to any of claims 23 to 25, wherein each A has the following structure:and wherein R? is independently selected from the group consisting of -H, -CH3, -C(H)(CH3)2, benzyl, p-hydroxybenzyl and -(CH2)3NHC(C=O)NH2; preferably R7 is independently selected from the group consisting of -H, -C(H)(CH3)2, benzyl and -(CH2)3NHC(C=O)NH2; and / or a is an integer from 1 to 10, more preferably from 1 to 5, still more preferably 1 to 4, and most preferably 2 or 4.

27. The antibody-drug conjugate according to claim 23, wherein H and h, and A and a, andU and u are such that L is one of the following:; or28. The antibody-drug conjugate according to any of claims 19 to 22, wherein L is such that Formula (XIX) is one of the following:; or29. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 18 for use as a medicament.

30. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 31 for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.

31. The antibody-drug conjugate according to any of claims 19 to 28 for use as a medicament.

32. The antibody-drug conjugate according to claim 31 for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.

33. A process for the preparation of an antibody-drug conjugate of general formula (XIX):Ab L-D]z(XIX) the method comprising conjugating an antibody, an antigen-binding fragment or an immunologically active portion thereof (Ab) to a compound (D) via a linker (L), whereinD is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of claims 1 to 18;L is a linker according to any of claims 19, or 23 to 27;D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

34. The process according to claim 35, wherein z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.

35. The process according to any of claims 34 or 35, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; an anti-HER2antibody, preferably Trastuzumab; an anti-HER3antibody, preferably Patritumab; an anti-FRoc antibody, preferably Mirvetuximab; or an anti-EGFR antibody, preferably Cetuximab.

36. A pharmaceutical dosage form comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 18, or a therapeutically effective amount of the antibody-drug conjugate according to any of claims 19 to 28.

37. A method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 18, a therapeutically effective amount of the antibody-drug conjugate according to any of claims 19 to 28, or the pharmaceutical dosage form according to claim 36.

38. The method of claim 37, wherein the cancer is ovarian cancer, stomach cancer or breast cancer.