Dispiropyrrolidine derivatives
A compound that inhibits interaction between murine double minute 2 (Mdm2) protein and p53 protein and exhibits anti-tumor activity is provided. The present invention provides a dispiropyrrolidine derivative represented by the following formula (1), which has various substituents, inhibits interaction between Mdm2 protein and p53 protein and exhibits anti-tumor activity, wherein R 1 , R 2 , R 3 , ring A, and ring B in formula (1) respectively have the same meanings as defined in the specification.
1. A compound represented by general formula (1) or a salt thereof:
wherein ring A represents a spiro-linked 4- to 6-membered saturated hydrocarbon ring optionally substituted with one or more substituents selected from Group 1, or a spiro-linked 6-membered saturated heterocyclic ring optionally substituted with one or more substituents selected from Group 1;
ring B represents a benzene ring optionally substituted with one or more substituents selected from Group 2, a pyridine ring optionally substituted with one or more substituents selected from Group 2, or a pyrimidine ring optionally substituted with one or more substituents selected from Group 2;
R 1 represents an aryl group optionally substituted with one or more substituents selected from Group 3, a heteroaryl group optionally substituted with one or more substituents selected from Group 3, a C 3 -C 6 cycloalkyl group optionally substituted with one or more substituents selected from Group 3, or a C 3 -C 6 cycloalkenyl group optionally substituted with one or more substituents selected from Group 3;
R 2 represents a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom; and
R 3 represents a group represented by the following general formula (2), (3), or (4):
wherein in formula (2), R 4 and R 5 each independently represent a hydroxy group, a C 1 -C 6 alkyl group, or a C 1 -C 6 alkoxy group, or R 4 and R 5 together with the carbon atoms to which the R 4 and R 5 groups are respectively bonded may together form a 4- to 6-membered saturated hydrocarbon ring;
in formula (3), the broken line in the ring structure indicates that the bond may be a double bond,
R 6 represents a C 1 -C 6 alkyl group optionally substituted with one or more substituents selected from Group 4, a carbamoyl group optionally substituted with one or more substituents selected from Group 5, a 5- or 6-membered nitrogen-containing heteroaryl group optionally substituted with an oxo group or one or more C 1 -C 6 alkyl groups optionally substituted with an oxo group or one hydroxy group, a hydroxy group, or —NR′R″,
wherein R′ and R″ each independently represent a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C 3 -C 4 cycloalkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R′ and R″ together with the nitrogen atom to which R′ and R″ are bonded may together form a 4- to 7-membered nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from a C 1 -C 6 alkyl group and a hydroxy group,
R 7 represents a C 1 -C 6 alkyl group optionally substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or
R 6 and R 7 may together form a spiro-linked 4- to 6-membered hydrocarbon ring or a spiro-linked 4- to 6-membered nitrogen-containing heterocyclic ring,
R 8 is absent or represents one or more substituents selected from a hydroxy group, a C 1 -C 6 alkyl group, and a C 1 -C 6 alkoxy group, and
Z represents CH 2 , NH, or an oxygen atom;
and in formula (4),
R 9 represents a C 1 -C 6 alkyl group optionally substituted with one or more substituents selected from Group 4, a carbamoyl group optionally substituted with one or more substituents selected from Group 5, a 5- or 6-membered nitrogen-containing heteroaryl group optionally substituted with an oxo group or one or more C 1 -C 6 alkyl groups optionally substituted with an oxo group or one hydroxy group, a hydroxy group, or —NR′R″,
wherein R′ and R″ each independently represent a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C 3 -C 4 cycloalkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R′ and R″ together with the nitrogen atom to which R′ and R″ are bonded may together form a 4- to 7-membered nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from a C 1 -C 6 alkyl group and a hydroxy group,
R 10 represents a C 1 -C 6 alkyl group optionally substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or
R 9 and R 10 may together form a spiro-linked 4- to 6-membered hydrocarbon ring or a spiro-linked 4- to 6-membered nitrogen-containing heterocyclic ring, and
R 11 represents one or more substituents selected from a hydroxy group, a C 1 -C 6 alkyl group, and a C 1 -C 6 alkoxy group,
wherein Group 1 represents a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms, a C 1 -C 6 alkoxy group, or a cyano group,
Group 2 represents a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms, a C 3 -C 4 cycloalkyl group optionally substituted with one to three halogen atoms, a vinyl group, an ethinyl group, a cyano group, or a C 1 -C 6 alkoxy group,
Group 3 represents a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, a C 3 -C 4 cycloalkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, a vinyl group, an ethinyl group, a cyano group, —OR′, —NR′R″, —COOR′, or —CONHR′,
wherein R′ and R″ each independently represent a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, a C 3 -C 4 cycloalkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R′ and R″ together with the nitrogen atom to which R′ and R″ are bonded may together form a 4- to 7-membered nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from a C 1 -C 6 alkyl group and a hydroxy group,
Group 4 represents a halogen atom, a hydroxy group, a carbamoyl group, a morpholino group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group, or —NR′R″,
wherein R′ and R″ each independently represent a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms, one to three hydroxy groups, or an oxo group, a C 3 -C 4 cycloalkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R′ and R″ together with the nitrogen atom to which R′ and R″ are bonded may together form a 4- to 7-membered nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from a C 1 -C 6 alkyl group and a hydroxy group, and
Group 5 represents a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms, one to three hydroxy groups, or a C 1 -C 6 alkoxy group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, or a tetrahydropyranyl group.
2. A compound according to claim 1 represented by general formula (5) or a salt thereof:
wherein ring A, R 2 , and R 3 have the same meanings as ring A, R 2 , and R 3 , respectively, in claim 1 ;
R 12 and R 13 represent a group selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group;
R 14 represents one or more substituents selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group; and
R 15 represents one or more substituents selected from Group 3, wherein Group 3 has the same meaning as Group 3 in claim 1 .
3. A compound according to claim 1 represented by general formula (6) or a salt thereof:
wherein ring A, R 2 , and R 3 have the same meanings as ring A, R 2 , and R 3 , respectively, in claim 1 ;
R 12 , R 13 , and R 16 represent a group selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group; and
R 14 represents one or more substituents selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group.
4. A compound according to claim 1 represented by general formula (7) or a salt thereof:
wherein ring A, R 2 , and R 3 have the same meanings as ring A, R 2 , and R 3 , respectively, in claim 1 ;
R 12 , R 13 , and R 16 represent a group selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group; and
R 14 represents one or more substituents selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group.
5. A compound according to claim 1 represented by general formula (8) or a salt thereof:
wherein ring A, R 2 , and R 3 have the same meanings as ring A, R 2 , and R 3 , respectively, in claim 1 ;
R 12 , R 13 , and R 16 represent a group selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group; and
R 14 represents one or more substituents selected from a halogen atom, a C 1 -C 6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, and a cyano group.
6. A compound selected from the following group or a salt thereof:
7. (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide hydrochloride.
8. (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide sulfate.
9. (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide methanesulfonate.
10. (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide ethanesulfonate.
11. (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide benzenesulfonate.
12. (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide p-toluenesulfonate.
13. (3′R,4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-N-{(3R,6S)-6-[1-hydroxyethyl]tetrahydro-2H-pyran-3-yl}-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide benzenesulfonate.
14. A method of inhibiting Mdm2 comprising administering a compound according to claim 1 or a salt thereof to a subject in need thereof.
15. A method of inhibiting Mdm2 ubiquitin ligase comprising administering a compound according to claim 1 or a salt thereof to a subject in need thereof.
16. A method of inhibiting p53-Mdm2 binding comprising administering a compound according to claim 1 or a salt thereof to a subject in need thereof.
17. A method of inhibiting suppression of p53 transcription activity comprising administering a compound according to claim 1 or a salt thereof to a subject in need thereof.
18. A method of inhibiting p53 degradation comprising administering a compound according to claim 1 or a salt thereof to a subject in need thereof.
19. A pharmaceutical composition comprising a compound according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.
20. A method of inhibiting Mdm2 comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a salt thereof to a subject in need thereof.
21. The method of claim 20 wherein the salt is selected from hydrochloride salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt.
22. A method of inhibiting Mdm2 ubiquitin ligase comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a salt thereof to a subject in need thereof.
23. The method of claim 22 wherein the salt is selected from hydrochloride salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt.
24. A method of inhibiting p53-Mdm2 binding comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a salt thereof to a subject in need thereof.
25. The method of claim 24 wherein the salt is selected from hydrochloride salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt.
26. A method of inhibiting suppression of p53 transcription activity comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a salt thereof to a subject in need thereof.
27. The method of claim 26 wherein the salt is selected from hydrochloride salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt.
28. A method of inhibiting p53 degradation comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a salt thereof to a subject in need thereof.
29. The method of claim 28 wherein the salt is selected from hydrochloride salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt.
30. A pharmaceutical composition comprising (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
31. The pharmaceutical composition of claim 30 wherein the salt is selected from hydrochloride salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt.