Drug conjugates
View Patent ↗A compound having the formula Y-A-Z, wherein: A is a phenyl group which is unsubstituted or substituted; Y and Z are substituents at adjacent positions on ring A; Y represents: Z represents: and wherein the remaining variables are as defined in the specification.
1. A compound having the formula Y-A-Z, wherein:
A is a phenyl group;
ring A is unsubstituted or substituted with 1 to 4 substituents selected from lower alkyl, aryl, heteroaryl, hydroxy-(lower alkyl), amino-(lower alkyl), N-(lower alkyl)amino-(lower alkyl), N,N-di(lower alkyl)amino-(lower alkyl), N-arylamino-(lower alkyl), N,N-diarylamino-(lower alkyl), N-(heteroaryl)amino-(lower alkyl), N,N-di(heteroaryl)amino-(lower alkyl), hydroxylamino, O-(lower alkoxy)amino, O-aryloxyamino, O-heteroaryloxyamino, fluoro, chloro, bromo, nitro, hydroxyl, lower alkoxy, aryloxy, hydroxycarbonyl, lower alkanoyl, lower alkanoyloxy, amino, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, formylamino, N-acylamino, N,N-diacylamino, hydrazido, N-(lower alkyl)hydrazido, N,N-di(lower alkyl)hydrazido, N-arylhydrazido, N,N-diarylhydrazido, N-(heteroaryl)hydrozido, N,N-di(heteroaryl)hydrazido, carbamoyl, N-(lower alkyl)carbamoyl, N,N-(lower alkyl)carbamoyl, N-arylcarbamoyl, N,N-diarylcarbamoyl, N-heteroarylcarbamoyl, N,N-di(heteroaryl)carbamoyl, hydroxysulfonyl, (lower alkoxy)sulfonyl, aryoxysulfonyl, heroaryloxysulfonyl, hydroxysulfonyl-(lower alkyl), (lower alkoxy)sulfonyl-(lower alkyl), aryoxysulfonyl-(lower alkyl), heroaryloxysulfonyl-(lower alkyl), (lower alkane)sulfonyl, arenesulfonyl, or heteroarenesulfonyl;
Y and Z are substituents at adjacent positions on ring A;
Y represents:
Z represents:
X represents O or S;
R 1 , R 2 , R 3 and R 4 independently represent H, lower alkyl or lower alkoxy, wherein the lower alkyl and lower alkoxy groups are unsubstituted or substituted with groups independently selected from aryl, heteroaryl or fluoro, wherein R 1 and R 2 or R 3 and R 4 are optionally connected to form a 3 to 8 member ring, wherein the 3 to 8 member ring is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl;
each of a and b independently represents 0 or 1;
a+b equals 1 or 2;
G is a metal ion, a quaternary ammonium ion, or comprised of a pharmaceutically active chemical compound or the precursor thereof, wherein said pharmaceutically active chemical compound or precursor thereof possesses at least one nucleophilic group prior to becoming G; or X-G represents a carbonyl-activating group selected from the group consisting of hydroxybenzotriazole-1-oxy, succinimide-N-oxy, p-nitrophenyloxy and pentafluorophenyloxy radical;
J is lower alkyl, aryl, heteroaryl, omega-hydroxycarbonyl-(lower alkyl), omega-(lower alkoxy)carbonyl-(lower alkyl), or comprised of a specific binding agent, wherein a specific binding agent is a protein, peptide, lectin, saccharide, or other moiety that selectively binds to a molecule on the surface of a cell; or omega-(X-G)-carbonyl-(lower alkyl) group, wherein X-G is a carbonyl-activating group defined above.
2. A compound according to claim 1 wherein X represents O.
3. A compound according to claim 1 wherein X represents S.
4. A compound according to claim 1 wherein R 1 and R 2 are independently H or methyl.
5. A compound according to claim 1 wherein R 3 and R 4 are independently H or methyl.
6. A compound according to claim 1 wherein a and b represent 1.
7. A compound according to claim 1 wherein a represents 1; b represents 0.
8. A compound according to claim 1 wherein b represents 1; a represents 0.
9. A compound according to claim 1 wherein G comprises a pharmaceutically active chemical compound.
10. A compound according to claim 9 wherein the pharmaceutically active chemical compound is a taxoid.
11. A compound according to claim 1 wherein J represents a specific binding agent.
12. A compound according to claim 11 wherein the specific binding agent comprises a hypervariable region of a monoclonal antibody.
13. A compound having the formula Y-A-Z, wherein A is a phenyl group;
ring A is unsubstituted or substituted with 1 to 4 substituents selected from lower alkyl, aryl, heteroaryl, hydroxy-(lower alkyl), amino-(lower alkyl), N-(lower alkyl)amino-(lower alkyl), N,N-di(lower alkyl)amino-(lower alkyl), N-arylamino-(lower alkyl), N,N-diarylamino-(lower alkyl), N-(heteroaryl)amino-(lower alkyl), N,N-di(heteroaryl)amino-(lower alkyl), hydroxylamino, O-(lower alkoxy)amino, O-aryloxyamino, O-heteroaryloxyamino, fluoro, chloro, bromo, nitro, hydroxyl, lower alkoxy, aryloxy, hydroxycarbonyl, lower alkanoyl, lower alkanoyloxy, amino, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, formylamino, N-acylamino, N,N-diacylamino, hydrazido, N-(lower alkyl)hydrazido, N,N-di(lower alkyl)hydrazido, N-arylhydrazido, N,N-diarylhydrazido, N-(heteroaryl)hydrozido, N,N-di(heteroaryl)hydrazido, carbamoyl, N-(lower alkyl)carbamoyl, N,N-(lower alkyl)carbamoyl, N-arylcarbamoyl, N,N-diarylcarbamoyl, N-heteroarylcarbamoyl, N,N-di(heteroaryl)carbamoyl, hydroxysulfonyl, (lower alkoxy)sulfonyl, aryoxysulfonyl, heroaryloxysulfonyl, hydroxysulfonyl-(lower alkyl), (lower alkoxy)sulfonyl-(lower alkyl), aryoxysulfonyl-(lower alkyl), heroaryloxysulfonyl-(lower alkyl), (lower alkane)sulfonyl, arenesulfonyl, or heteroarenesulfonyl;
Y and Z are substituents at adjacent positions on ring A;
Y represents:
Z represents:
a is 1; R 1 and R 2 are methyl; b is 1; R 3 and R 4 are hydrogen; X represents O; G is a taxoid; and J is an omega-(succinimide-N-oxycarbonyl)-1-(lower alkyl) wherein the lower alkyl is methylpropyl.
14. A compound having the formula Y-A-Z, wherein:
A is a phenyl group;
ring A is unsubstituted or substituted with 1 to 4 substituents selected from lower alkyl, aryl, heteroaryl, hydroxy-(lower alkyl), amino-(lower alkyl), N-(lower alkyl)amino-(lower alkyl), N,N-di(lower alkyl)amino-(lower alkyl), N-arylamino-(lower alkyl), N,N-diarylamino-(lower alkyl), N-(heteroaryl)amino-(lower alkyl), N,N-di(heteroaryl)amino-(lower alkyl), hydroxylamino, O-(lower alkoxy)amino, O-aryloxyamino, O-heteroaryloxyamino, fluoro, chloro, bromo, nitro, hydroxyl, lower alkoxy, aryloxy, hydroxycarbonyl, lower alkanoyl, lower alkanoyloxy, amino, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, formylamino, N-acylamino, N,N-diacylamino, hydrazido, N-(lower alkyl)hydrazido, N,N-di(lower alkyl)hydrazido, N-arylhydrazido, N,N-diarylhydrazido, N-(heteroaryl)hydrozido, N,N-di(heteroaryl)hydrazido, carbamoyl, N-(lower alkyl)carbamoyl, N,N-(lower alkyl)carbamoyl, N-arylcarbamoyl, N,N-diarylcarbamoyl, N-heteroarylcarbamoyl, N,N-di(heteroaryl)carbamoyl, hydroxysulfonyl, (lower alkoxy)sulfonyl, aryoxysulfonyl, heroaryloxysulfonyl, hydroxysulfonyl-(lower alkyl), (lower alkoxy)sulfonyl-(lower alkyl), aryoxysulfonyl-(lower alkyl), heroaryloxysulfonyl-(lower alkyl), (lower alkane)sulfonyl, arenesulfonyl, or heteroarenesulfonyl;
Y and Z are substituents at adjacent positions on ring A;
Y represents:
Z represents:
X represents O or S;
R 1 , R 2 , R 3 and R 4 independently represent H, lower alkyl or lower alkoxy, wherein the lower alkyl and lower alkoxy groups are unsubstituted or substituted with groups independently selected from aryl, heteroaryl or fluoro, wherein R 1 and R 2 or R 3 and R 4 are optionally connected to form a 3 to 8 member ring, wherein the 3 to 8 member ring is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl;
each of a and b independently represents 0 or 1; a+b equals 1 or 2;
G is hydrogen, a metal ion, a quaternary ammonium ion, lower alkyl, or comprised of a pharmaceutically active chemical compound or the precursor thereof, wherein said pharmaceutically active chemical compound or precursor thereof possesses at least one nucleophilic group prior to becoming G; or X-G represents a carbonyl-activating group selected from the group consisting of hydroxybenzotriazole-1-oxy, succinimide-N-oxy, p-nitrophenyloxy and pentafluorophenyloxy radical;
J is lower alkyl, heteroaryl, omega-hydroxycarbonyl-(lower alkyl), omega-(lower alkoxy)carbonyl-(lower alkyl), or comprised of a specific binding agent, wherein a specific binding agent is a protein, peptide, lectin, saccharide, or other moiety that selectively binds to a molecule on the surface of a cell; or omega-(X-G)-carbonyl-(lower alkyl) group, wherein X-G is a carbonyl-activating group defined above.
15. A compound according to claim 14 wherein X represents O.
16. A compound according to claim 14 wherein X represents S.
17. A compound according to claim 14 wherein a and b represent 1.
18. A compound according to claim 14 wherein a represents 1; b represents 0.
19. A compound according to claim 14 wherein b represents 1; a represents 0.
20. A compound according to claim 14 wherein G comprises a pharmaceutically active chemical compound.
21. A compound having the formula Y-A-Z, wherein:
A is a phenyl group;
ring A is unsubstituted or substituted with 1 to 4 substituents selected from lower alkyl, aryl, heteroaryl, hydroxy-(lower alkyl), amino-(lower alkyl), N-(lower alkyl)amino-(lower alkyl), N,N-di(lower alkyl)amino-(lower alkyl), N-arylamino-(lower alkyl), N,N-diarylamino-(lower alkyl), N-(heteroaryl)amino-(lower alkyl), N,N-di(heteroaryl)amino-(lower alkyl), hydroxylamino, O-(lower alkoxy)amino, O-aryloxyamino, O-heteroaryloxyamino, fluoro, chloro, bromo, nitro, hydroxyl, lower alkoxy, aryloxy, hydroxycarbonyl, lower alkanoyl, lower alkanoyloxy, amino, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, formylamino, N-acylamino, N,N-diacylamino, hydrazido, N-(lower alkyl)hydrazido, N,N-di(lower alkyl)hydrazido, N-arylhydrazido, N,N-diarylhydrazido, N-(heteroaryl)hydrozido, N,N-di(heteroaryl)hydrazido, carbamoyl, N-(lower alkyl)carbamoyl, N,N-(lower alkyl)carbamoyl, N-arylcarbamoyl, N,N-diarylcarbamoyl, N-heteroarylcarbamoyl, N,N-di(heteroaryl)carbamoyl, hydroxysulfonyl, (lower alkoxy)sulfonyl, aryoxysulfonyl, heroaryloxysulfonyl, hydroxysulfonyl-(lower alkyl), (lower alkoxy)sulfonyl-(lower alkyl), aryoxysulfonyl-(lower alkyl), heroaryloxysulfonyl-(lower alkyl), (lower alkane)sulfonyl, arenesulfonyl, or heteroarenesulfonyl;
Y and Z are substituents at adjacent positions on ring A;
Y represents:
Z represents:
X represents S;
R 1 , R 2 , R 3 and R 4 independently represent H, lower alkyl or lower alkoxy, wherein the lower alkyl and lower alkoxy groups are unsubstituted or substituted with groups independently selected from aryl, heteroaryl or fluoro, wherein R 1 and R 2 or R 3 and R 4 are optionally connected to form a 3 to 8 member ring, wherein the 3 to 8 member ring is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl;
each of a and b independently represents 0 or 1;
a+b equals 1 or 2;
G is a metal ion, a quaternary ammonium ion, lower alkyl, or comprised of a pharmaceutically active chemical compound or the precursor thereof, wherein said pharmaceutically active chemical compound or precursor thereof possesses at least one nucleophilic group prior to becoming G; or X-G represents a carbonyl-activating group selected from the group consisting of hydroxybenzotriazole-1-oxy, succinimide-N-oxy, p-nitrophenyloxy and pentafluorophenyloxy radical;
J is lower alkyl, aryl, heteroaryl, omega-hydroxycarbonyl-(lower alkyl), omega-(lower alkoxy)carbonyl-(lower alkyl), or comprised of a specific binding agent, wherein a specific binding agent is a protein, peptide, lectin, saccharide, or other moiety that selectively binds to a molecule on the surface of a cell; or omega-(X-G)-carbonyl-(lower alkyl) group, wherein X-G is a carbonyl-activating group defined above.
22. A compound having the formula Y-A-Z, wherein:
A is a phenyl group;
ring A is unsubstituted or substituted with 1 to 4 substituents selected from lower alkyl, aryl, heteroaryl, hydroxy-(lower alkyl), amino-(lower alkyl), N-(lower alkyl)amino-(lower alkyl), N,N-di(lower alkyl)amino-(lower alkyl), N-arylamino-(lower alkyl), N,N-diarylamino-(lower alkyl), N-(heteroaryl)amino-(lower alkyl), N,N-di(heteroaryl)amino-(lower alkyl), hydroxylamino, O-(lower alkoxy)amino, O-aryloxyamino, O-heteroaryloxyamino, fluoro, chloro, bromo, nitro, hydroxyl, lower alkoxy, aryloxy, hydroxycarbonyl, lower alkanoyl, lower alkanoyloxy, amino, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, formylamino, N-acylamino, N,N-diacylamino, hydrazido, N-(lower alkyl)hydrazido, N,N-di(lower alkyl)hydrazido, N-arylhydrazido, N,N-diarylhydrazido, N-(heteroaryl)hydrozido, N,N-di(heteroaryl)hydrazido, carbamoyl, N-(lower alkyl)carbamoyl, N,N-(lower alkyl)carbamoyl, N-arylcarbamoyl, N,N-diarylcarbamoyl, N-heteroarylcarbamoyl, N,N-di(heteroaryl)carbamoyl, hydroxysulfonyl, (lower alkoxy)sulfonyl, aryoxysulfonyl, heroaryloxysulfonyl, hydroxysulfonyl-(lower alkyl), (lower alkoxy)sulfonyl-(lower alkyl), aryoxysulfonyl-(lower alkyl), heroaryloxysulfonyl-(lower alkyl), (lower alkane)sulfonyl, arenesulfonyl, or heteroarenesulfonyl;
Y and Z are substituents at adjacent positions on ring A;
Y represents:
Z represents:
X represents O or S;
R 1 , R 2 , R 3 and R 4 independently represent H, lower alkyl or lower alkoxy, wherein the lower alkyl and lower alkoxy groups are unsubstituted or substituted with groups independently selected from aryl, heteroaryl or fluoro, wherein R 1 and R 2 or R 3 and R 4 are optionally connected to form a 3 to 8 member ring, wherein the 3 to 8 member ring is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl;
each of a and b independently represents 0 or 1;
a+b equals 1 or 2;
G is a metal ion, a quaternary ammonium ion, lower alkyl, or comprised of a pharmaceutically active chemical compound or the precursor thereof, wherein said pharmaceutically active chemical compound or precursor thereof possesses at least one nucleophilic group prior to becoming G; or X-G represents a carbonyl-activating group selected from the group consisting of hydroxybenzotriazole-1-oxy, succinimide-N-oxy, p-nitrophenyloxy and pentafluorophenyloxy radical;
J is comprised of a specific binding agent, wherein a specific binding agent is a protein, peptide, lectin, saccharide, or other moiety that selectively binds to a molecule on the surface of a cell.
23. A compound according to claim 22 wherein the specific binding agent comprises a hypervariable region of a monoclonal antibody.