Granted Patent B2

US 11,576,986 · App. 16/869,771 · Granted Feb 14, 2023

Inventors: Rhys Salter (Doylestown, PA); Vadim Dudkin (Chalfont, PA); Fengbin Song (Doylestown, PA); Wei Zhang (Malvern, PA); Shalom Goldberg (Merion Station, PA); John Keith (San Diego, CA)

Assignee: JANSSEN BIOTECH, INC.

A61K51/025A61K51/0482A61K51/1027A61K51/1093

Abstract

Claims (151)

1. A chelator of formula (I):

wherein:

each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein each of ring A and ring B is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —OR 13 , —SR 13 , —(CH 2 ) p COOR 13 , —OC(O)R 13 , —N(R 13 ) 2 , —CON(R 13 ) 2 , —NO 2 , —CN —OC(O)N(R 13 ) 2 , and X;

each of Z 1 and Z 2 is independently —(C(R 12 ) 2 ) m — or —(CH 2 ) n —C(R 12 )(X)—(CH 2 ) n —;

each X is independently -L 1 -R 11 ;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1;

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R 13 is independently hydrogen or alkyl;

each of R 14 , R 15 , R 16 , and R 17 is independently hydrogen, alkyl, or X,

or alternatively R 14 and R 15 and/or R 16 and R 17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the chelator comprises at least one X, and when X is present on ring A or ring B, L 1 is a linker or at least one of R 12 and R 14 -R 17 is not hydrogen wherein L1 is selected from the group consisting of:

wherein n is an integer of 0 to 10, and m is an integer of 0 to 12.

2. The chelator of claim 1 , being a chelator of formula (II):

wherein:

A 1 is N or CR 1 or is absent;

A 2 is N or CR 2 ;

A 3 is N or CR 3 ;

A 4 is N or CR 4 ;

A 5 is N or CR 5 ;

A 6 is N or CR 6 or is absent;

A 7 is N or CR 7 ;

A 8 is N or CR 8 ;

A 9 is N or CR 9 ;

A 10 is N or CR 10 ;

provided that no more than three of A 1 , A 2 , A 3 , A 4 , and A 5 are N, and no more than three of A 6 , A 7 , A 8 , A 9 , and A 10 are N;

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —OR 13 , —SR 13 , —(CH 2 ) p COOR 13 , —OC(O)R 13 , —N(R 13 ) 2 , —CON(R 13 ) 2 , —NO 2 , —CN, —OC(O)N(R 13 ) 2 , and —X,

or, alternatively, any two directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are taken together with the atoms to which they are attached to form a five or six-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring;

each of Z 1 and Z 2 is independently —(C(R 12 ) 2 ) m — or —(CH 2 ) n —C(R 12 )(X)—(CH 2 ) n —;

each X is independently -L 1 -R 11 ;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1;

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R 13 is independently hydrogen or alkyl;

each of R 14 , R 15 , R 16 , and R 17 is independently hydrogen, alkyl, or X,

or alternatively R 14 and R 15 and/or R 16 and R 17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the chelator comprises at least one X, and when any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is X, then L 1 is a linker or at least one of R 12 and R 14 -R 17 is not hydrogen.

3. The chelator of claim 1 , being a chelator of formula (III):

wherein:

each A 11 is independently O, S, NMe, or NH;

each of Z 1 and Z 2 is independently —(C(R 12 ) 2 ) m — or —(CH 2 ) n —C(R 12 )(X)—(CH 2 ) n —;

each X is independently -L 1 -R 11 ;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1;

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R 13 is independently hydrogen or alkyl;

each of R 14 , R 15 , R 16 , and R 17 is independently hydrogen, alkyl, or X,

or alternatively R 14 and R 15 and/or R 16 and R 17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

each R 18 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —OR 13 , —SR 13 , —(CH 2 ) p COOR 13 , —OC(O)R 13 , —N(R 13 ) 2 , —CON(R 13 ) 2 , —NO 2 , —CN —OC(O)N(R 13 ) 2 , and —X,

provided that the chelator comprises at least one X, and when R 18 is X, then L 1 is a linker or at least one of R 12 and R 14 -R 17 is not hydrogen.

4. The chelator of claim 1 , wherein the chelator is selected from the group consisting of:

wherein:

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, —CH 3 , or —CH 2 CH 3 , provided at least one R 12 is —CH 3 or —CH 2 CH 3 .

5. The chelator of claim 1 , wherein R 11 is —NH 2 , —NCS, —NCO, —N 3 , alkynyl, cycloalkynyl, —C(O)R 13 , —COOR 13 , —CON(R 13 ) 2 , maleimido, acyl halide, tetrazine, or trans-cyclooctene.

6. The chelator of claim 5 , wherein R 11 is cyclooctynyl or a cyclooctynyl derivative selected from the group consisting of bicyclononynyl (BCN), difluorinated cyclooctynyl (DIFO), dibenzocyclooctynyl (DIBO), keto-DIBO, biarylazacyclooctynonyl (BARAC), dibenzoazacyclooctynyl (DIBAC, DBCO, ADIBO), dimethoxyazacyclooctynyl (DIMAC), difluorobenzocyclooctynyl (DIFBO), monobenzocyclooctynyl (MOBO), and tetramethoxy dibenzocyclooctynyl (TMDIBO).

7. The chelator of claim 6 , wherein R 11 is DBCO or BCN.

8. The chelator of claim 1 wherein R 11 comprises a targeting ligand, wherein the targeting ligand comprises an antibody or antigen binding fragment thereof, scaffold protein, small molecule, or aptamer.

9. The chelator of claim 1 selected from the group consisting of:

10. The chelator of claim 1 , wherein the chelator comprises a radiometal ion bound to the chelator via coordinate bonding thereby forming a radiometal complex.

11. A radiometal complex comprising a chelator bound to an alpha-emitting radiometal ion via coordinate bonding, wherein the radiometal complex has the structure of formula (I-m):

wherein:

M is a radiometal ion;

each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein each of ring A and ring B is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —OR 13 , —SR 13 , —(CH 2 ) p COOR 13 , —OC(O)R 13 , —N(R 13 ) 2 , —CON(R 13 ) 2 , —NO 2 , —CN —OC(O)N(R 13 ) 2 , and X;

each of Z 1 and Z 2 is independently —(C(R 12 ) 2 ) m — or —(CH 2 ) n —C(R 12 )(X)—(CH 2 ) n —;

each X is independently -L 1 -R 11 ;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1;

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R 13 is independently hydrogen or alkyl;

each of R 14 , R 15 , R 16 , and R 17 is independently hydrogen, alkyl, or X,

or alternatively R 14 and R 15 and/or R 16 and R 17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the radiometal complex comprises at least one X, and when X is present on ring A or ring B, L 1 is a linker or at least one of R 12 and R 14 -R 17 is not hydrogen wherein L1 is selected from the group consisting of:

wherein n is an integer of 0 to 10, and m is an integer of 0 to 12.

12. The radiometal complex of claim 11 , being a radiometal complex of formula (II-m):

wherein:

M is a radiometal ion;

A 1 is N or CR 1 or is absent;

A 2 is N or CR 2 ;

A 3 is N or CR 3 ;

A 4 is N or CR 4 ;

A 5 is N or CR 5 ;

A 6 is N or CR 6 or is absent;

A 7 is N or CR 7 ;

A 8 is N or CR 8 ;

A 9 is N or CR 9 ;

A 10 is N or CR 10 ;

provided that no more than three of A 1 , A 2 , A 3 , A 4 , and A 5 are N, and no more than three of A 6 , A 7 , A 8 , A 9 , and A 10 are N;

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —OR 13 , —SR 13 , —(CH 2 ) p COOR 13 , —OC(O)R 13 , —N(R 13 ) 2 , —CON(R 13 ) 2 , —NO 2 , —CN —OC(O)N(R 13 ) 2 , and —X,

or, alternatively, any two directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are taken together with the atoms to which they are attached to form a five or six-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring;

each of Z 1 and Z 2 is independently —(C(R 12 ) 2 ) m — or —(CH 2 ) n —C(R 12 )(X)—(CH 2 ) n —;

each X is independently -L 1 -R 11 ;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1;

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R 13 is independently hydrogen or alkyl;

each of R 14 , R 15 , R 16 , and R 17 is independently hydrogen, alkyl, or X,

or alternatively R 14 and R 15 and/or R 16 and R 17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the radiometal complex comprises at least one X, and when any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is X, then L 1 is a linker or at least one of R 12 and R 14 -R 17 is not hydrogen.

13. The radiometal complex of claim 11 , being a radiometal complex of formula (III-m):

wherein:

M is a radiometal ion;

each A 11 is independently O, S, NMe, or NH;

each of Z 1 and Z 2 is independently —(C(R 12 ) 2 ) m — or —(CH 2 ) n —C(R 12 )(X)—(CH 2 ) n —;

each X is independently -L 1 -R 11 ;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1;

L 1 is absent or a linker;

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand;

each R 12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R 13 is independently hydrogen or alkyl;

each of R 14 , R 15 , R 16 , and R 17 is independently hydrogen, alkyl, or X,

or alternatively R 14 and R 15 and/or R 16 and R 17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X; and

each R 18 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —OR 13 , —SR 13 , —(CH 2 ) p COOR 13 , —OC(O)R 13 , —N(R 13 ) 2 , —CON(R 13 ) 2 , —NO 2 , —CN —OC(O)N(R 13 ) 2 , and —X,

provided that the radiometal complex comprises at least one X, and when R 18 is X, then L 1 is a linker or at least one of R 12 and R 14 -R 17 is not hydrogen.

14. The radiometal complex of claim 11 , wherein the radiometal complex is selected from the group consisting of:

wherein:

M is actinium-225 ( 225 Ac), L 1 is absent or a linker; and

R 11 is a nucleophilic moiety or an electrophilic moiety, or R 11 comprises a targeting ligand; and

each R 12 is independently hydrogen, —CH 3 or —CH 2 CH 3 , provided at least one R 12 is —CH 3 or —CH 2 CH 3 .

15. A radioimmunoconjugate comprising the radiometal complex of claim 11 conjugated to an antibody or antigen binding fragment thereof.

16. The radioimmunoconjugate of claim 15 , wherein the antibody or antigen binding fragment thereof is linked to R 11 of the radiocomplex via a triazole moiety.

17. A radioimmunoconjugate having a structure selected from the group consisting of:

wherein:

M is a radiometal ion;

L 1 is a linker;

mAb is an antibody or antigen binding fragment thereof;

each R 12 is independently hydrogen, —CH 3 , or —CH 2 CH 3 , provided at least one R 12 is —CH 3 or —CH 2 CH 3 .

18. The radioimmunoconjugate of claim 17 , wherein the radioimmunoconjugate is selected from the group consisting of:

wherein mAb is an antibody or antigen binding fragment thereof.

19. A pharmaceutical composition comprising the radioimmunoconjugate of claim 15 , and a pharmaceutically acceptable carrier.

20. A method of selectively targeting neoplastic cells for radiotherapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 19 .

21. A method of treating a neoplastic disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 19 .

22. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 19 .

Assignments (1)

Continuity (2)

Cited By (9)

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