NZ710585B2

NZ710585B2 - Dispiropyrrolidine derivatives

Info

Publication number: NZ710585B2
Application number: NZ710585A
Authority: NZ
Inventors: Masaki Miyazaki; Masaki Setoguchi; Yuuichi Sugimoto; Toru Taniguchi; Kouichi Uoto; Takanori Wakabayashi; Akitake Yamaguchi; Keisuke Yoshida; Shoko Yoshida
Original assignee: Daiichi Sankyo Company Limited
Priority date: 2011-03-10
Filing date: 2012-03-09
Publication date: 2017-05-25

Abstract

The disclosure relates to (2S,5R)-5-({[(3'R,4'S,5'R)-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'-yl]carbonyl}amino)tetrahydro-2H-pyran-2-carboxylic acid. It also relates to compositions and anticancer agents comprising this compound and their use in treating lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma. s comprising this compound and their use in treating lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma.

Description

COMPLETE SPECIFICATION Dispiropyrrolidine derivatives We, Daiichi Sankyo Company, Limited, of 31, Nihonbashi Honcho, Chuo-ku, Tokyo, 103-8426, Japan, hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page 1a) - 1a - [Document Name] Description [Title of Invention] DISPIROPYRROLIDINE DERIVATIVES [Technical Field] The present invention relates to a dispiropyrrolidine compound having anti-tumor activity by inhibition of murine double minute 2 (Mdm2) or a salt thereof. This application is a divisional from NZ614218.

The description of the present invention and the invention of NZ614218 is retained herein for clarity and completeness [Background Art] p53 is known as an important factor for inhibiting canceration of cells. p53 is a transcription factor that induces the expression of genes involved in the cell cycle and cellular apoptosis in response to various stresses. p53 is thought to inhibit canceration of cells by a transcription regulating function thereof. In fact, deletion or mutation of the p53 gene is observed in about half of human cancer cases.

Meanwhile, overexpression of murine double minute 2 (Mdm2), a type of E3 ubiquitin ligase, is known as a factor for canceration of cells that are cancerated in spite of the presence of normal p53. Mdm2 is a protein of which expression is induced by p53. Mdm2 negatively regulates p53 by mediating degradation of p53 by binding [followed by page 2] to the transcription activity domain of p53 to decrease the transcription activity of p53, exporting p53 out of the nucleus, and further acting as a ubiquitination ligase against p53. Therefore, it is thought that inactivation of functions of and degradation of p53 are promoted in cells in which Mdm2 is overexpressed, resulting in canceration (Non Patent Document 1).

Paying attention to such functions of Mdm2, many approaches have been attempted using substances that inhibit the suppression of p53 functions by Mdm2, as candidate anti-tumor agents. Examples of the Mdm2 inhibitors targeting the Mdm2-p53 binding site have been reported, which include spirooxindole derivatives (Patent Document 1-15, Non Patent Document 1-3), indole derivatives (Patent Document 16), pyrrolidine carboxamide derivatives (Patent Document 17), pyrrolidinone derivatives (Patent Document 18) and isoindolinone derivatives (Patent Document 19, Non Patent Document 4).

[Citation list] [Patent Documents] Patent Document 1: WO2006/091646 Patent Document 2: WO2006/136606 Patent Document 3: WO2007/104664 Patent Document 4: WO2007/104714 Patent Document 5: WO2008/034736 Patent Document 6: WO2008/036168 Patent Document 7: WO2008/055812 Patent Document 8: WO2008/141917 Patent Document 9: WO2008/141975 Patent Document 10: WO2009/077357 Patent Document 11: WO2009/080488 Patent Document 12: WO2010/084097 Patent Document 13: WO2010/091979 Patent Document 14: WO2010/094622 Patent Document 15: WO2010/121995 Patent Document 16: WO2008/119741 Patent Document 17: WO2010/031713 Patent Document 18: WO2010/028862 Patent Document 19: WO2006/024837 [Non Patent Documents] Non Patent Document 1: J. Am. Chem. Soc., 2005, 127, 10130-10131 Non Patent Document 2: J. Med. Chem., 2006, 49, 3432- 3435 Non Patent Document 3: J. Med. Chem., 2009, 52, 7970- 7973 Non Patent Document 4: J. Med. Chem., 2006, 49, 6209- 6221 [Summary of Invention] [Problem to be solved by the invention] The present invention provides a novel Mdm2 inhibiting compound. Furthermore, the present invention provides an anti-tumor agent containing the Mdm2 inhibiting compound.

[Means for Solving the Problem] As a result of extensive studies, the present inventors have found that a compound having a structure represented by the following general formula (1) or a salt thereof had potent Mdm2 inhibiting activity and accomplished the present invention.

More specifically, the present invention provides: A compound represented by general formula (1) or a salt thereof: NH (1) wherein ring A represents a spiro-linked 4- to 6-membered saturated hydrocarbon ring which may have one or more substituents selected from Group 1, or a spiro-linked 6- membered saturated heterocyclic ring which may have one or more substituents selected from Group 1; ring B represents a benzene ring which may have one or more substituents selected from Group 2, a pyridine ring which may have one or more substituents selected from Group 2, or a pyrimidine ring which may have one or more substituents selected from Group 2; R represents an aryl group which may have one or more substituents selected from Group 3, a heteroaryl group which may have one or more substituents selected from Group 3, a C -C cycloalkyl group which may have one or more substituents selected from Group 3, or a C -C cycloalkenyl group which may have one or more substituents selected from Group 3; R represents a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom; and R represents a group represented by the following general formulae (2), (3), or (4): Z 10 wherein in formula (2), R and R each independently represent a hydroxy group, a C -C alkyl group, or a C -C alkoxy group, or R and R 1 6 1 6 together with the carbon atoms to which the R and R groups are respectively bonded may 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 represents a C -C alkyl group which may have one or more substituents selected from Group 4, a carbamoyl group which may have one or more substituents selected from Group 5, a 5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group, a hydroxy group, or -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or R and R 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 represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy 1 6 1 6 group, and Z represents CH , NH, or an oxygen atom; and in formula (4), R represents a C -C alkyl group which may have one or more substituents selected from Group 4, a carbamoyl group which may have one or more substituents selected from Group 5, a 5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group, a hydroxy group, or -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or 9 10 R and R 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 represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy 1 6 1 6 group: Group 1: a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a C - C alkoxy group, and a cyano group, Group 2: a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a C -C cycloalkyl group which may be substituted with one to three halogen atoms, a vinyl group, an ethynyl group, a cyano group, and a C -C alkoxy group, Group 3: a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a vinyl group, an ethynyl group, a cyano group, -OR', -NR'R'', -COOR', and -CONHR', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7-membered nitrogen- containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, Group 4: a halogen atom, a hydroxy group, a carbamoyl group, a morpholino group, a C -C alkoxy group, a C -C 1 6 1 6 alkylsulfonyl group, and -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, one to three hydroxy groups, or an oxo group, a C -C cycloalkyl group which may be 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 form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, and Group 5: a C -C alkyl group which may be substituted with one to three halogen atoms, one to three hydroxy groups, or a C -C alkoxy group, a C -C cycloalkyl group, 1 6 3 6 a C -C alkoxy group, and a tetrahydropyranyl group.

A compound according to [1] represented by general formula (5) or a salt thereof: NH (5) wherein in formula (5), 2 3 2 ring A, R , and R have the same meanings as ring A, R , and R , respectively, in [1]; 12 13 R and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; R represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; and R represents one or more substituents selected from Group 3 (which has the same meaning as Group 3 in [1]).

A compound according to [1] represented by general formula (6) or a salt thereof: R (6) wherein in formula (6), 2 3 2 ring A, R , and R have the same meanings as ring A, R , and R , respectively, in [1]; 12 13 16 R , R , and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; and R represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group.

A compound according to [1] represented by general formula (7) or a salt thereof: NH (7) wherein in formula (7), 2 3 2 ring A, R , and R have the same meanings as ring A, R , and R , respectively, in [1]; 12 13 16 R , R , and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; and R represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group.

A compound according to [1] represented by general formula (8) or a salt thereof: NH (8) wherein in formula (8), 2 3 2 ring A, R , and R have the same meanings as ring A, R , and R , respectively, in [1]; 12 13 16 R , R , and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; and R represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group.

A compound selected from the following group or a salt thereof: O N O N Cl Cl Cl H H H F OH F F N N N N Cl Cl Cl N O N O N O H H H H H H N N N O O N O Cl Cl Cl H H H F F OH N N N Cl Cl Cl N O N O N O H H H H H H O N N O N O N Cl Cl Cl OH H F F F N N N Cl Cl Cl N O N O N O H H H H H H N O N N O N N O N O O O Cl Cl Cl H H H OH NH OH F F F N N N Cl Cl Cl N O N O N O H H H H H H O N O N O N Cl Cl Cl H H H F F F N N N Cl Cl Cl N O N O N O H H H N O N N O N Cl Cl OH Cl Cl N O N O (3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro- 2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin yl)-4, 4-dimethyl-2"-oxo-1", 2"- dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"- indole]-5'-carboxamide hydrochloride. (3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro- 2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin yl)-4, 4-dimethyl-2"-oxo-1", 2"- dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"- indole]-5'-carboxamide sulfate. (3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro- 2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin yl)-4, 4-dimethyl-2"-oxo-1", 2"- dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"- indole]-5'-carboxamide methanesulfonate. (3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro- 2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin yl)-4, 4-dimethyl-2"-oxo-1", 2"- dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"- indole]-5'-carboxamide ethanesulfonate. (3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro- 2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin yl)-4, 4-dimethyl-2"-oxo-1", 2"- dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"- indole]-5'-carboxamide benzenesulfonate. (3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro- 2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin yl)-4, 4-dimethyl-2"-oxo-1", 2"- dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"- indole]-5'-carboxamide p-toluenesulfonate. (3'R, 4'S, 5'R)-6"-chloro-4'-(2-chlorofluoropyridin yl)-N-{(3R, 6S)[1-hydroxyethyl]tetrahydro-2H-pyranyl}-4, 4-dimethyl-2"-oxo-1", 2"-dihydrodispiro[cyclohexane-1, 2'- pyrrolidine-3', 3"-indole]-5'-carboxamide benzenesulfonate.

An inhibitor of Mdm2 comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13].

An inhibitor of Mdm2 ubiquitin ligase comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13].

An inhibitor of p53-Mdm2 binding comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13].

An inhibitor of suppression of p53 transcription activity comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13].

An inhibitor of p53 degradation comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13].

A medicament comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13] as an active ingredient.

An anticancer agent comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13] as an active ingredient.

An anticancer agent according to [20], wherein the cancer is lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma.

A pharmaceutical composition comprising a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13] and a pharmaceutically acceptable carrier.

A method for treating cancer, comprising administering a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13].

A method for treating cancer according to [23], wherein the cancer is lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma.

Use of a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13] for the manufacture of a medicament.

Use of a compound according to any one of [1] to [6] or a salt thereof or a compound according to any one of [7] to [13] for the manufacture of an anticancer agent.

[Advantages of the Invention] The present invention provides a novel spiroprolinamide derivative represented by the above formula (1), which has Mdm2 inhibiting activity. Such a novel compound is useful as an anti-tumor agent.

[Description of Embodiments] In the present invention, "Mdm2" means a protein encoded by the murine double minute 2 gene. "Mdm2" includes Mdm2 proteins encoded by a complete length of the Mdm2 gene, Mdm2 proteins encoded by mutated Mdm2 genes (including deletion mutants, substitution mutants, and addition mutants), and so forth. In the present invention, "Mdm2" also includes homologues derived from various animal species such as, for example, human Mdm2 homologue (HDM2).

In the present invention, "p53" means a protein encoded by the p53 gene. "p53" means the p53 protein encoded by a full length p53 gene or a p53 protein that has a mutation (including mutations by deletion, substitution, and addition), but functions normally.

In the present invention, "Mdm2 inhibitor" means a factor that restores p53 functions suppressed by Mdm2 by acting on either Mdm2 or p53, or on both p53 and Mdm2.

The p53 functions are not particularly limited so long as they are functions which p53 normally has. Examples thereof include inhibition of canceration of cells by inducing the expression of genes involved in the cell cycle or cellular apoptosis. Examples of Mdm2 inhibitors include factors that inhibit binding of Mdm2 to p53 (hereinafter, referred to as p53-Mdm2 binding inhibitors) or factors that inhibit ubiquitination of p53 by Mdm2 (hereinafter, referred to as Mdm2 ubiquitin ligase inhibitors).

In the present invention, "inhibitor of suppression of p53 transcription activity" means a factor that restores the functions of p53 as a transcription factor suppressed by Mdm2.

In the present invention, "inhibitor of p53 degradation" means a factor that inhibits degradation of p53 in proteasomes by inhibiting ubiquitination of p53 by Mdm2.

In the present invention, the terms "tumor" and "cancer" are used interchangeably. Furthermore, in the present invention, tumor, malignant tumor, cancer, malignant neoplasm, carcinoma, sarcoma, and the like may be collectively referred to as "tumor" or "cancer." In the present invention, "C -C alkyl group" means a straight or branched alkyl group having 1 to 6 carbon atoms. Examples of a "C -C alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a tert-butyl group.

"C -C alkoxy group" means an alkoxy group having a straight or branched alkyl group having 1 to 6 carbon atoms. Examples of a "C -C alkoxy group" include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.

Examples of "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

"Oxo group" means a group represented by "=O" unless otherwise specified.

"Carbamoyl group" also includes a cyclic carbamoyl group.

Hereafter, each substituent in formula (1) will be explained.

In the following general formula (1), NH (1) ring A represents a spiro-linked 4- to 6-membered saturated hydrocarbon ring which may have one or more substituents selected from Group 1 above or a spiro- linked 6-membered saturated heterocyclic ring which may have one or more substituents selected from Group 1 above.

Here, "spiro-linked" means that ring A and the pyrrolidine ring to which ring A is bonded form a spiro ring, as illustrated in, for example, the compounds of the Examples.

A substituent bonded to ring A may be positioned at any position. A plurality of substituents may be the same or different and two identical substituents are preferably bonded to the 2- to 6-positions.

The substituent(s) is preferably a C -C alkyl group which may be substituted with one to three halogen atoms, more preferably a C -C alkyl group which may be substituted with one fluorine atom, yet more preferably two methyl groups, ethyl groups, or fluoromethyl groups bonded to the 2-position for 4-membered ring A, bonded to the 3- and 4-positions for 5-membered ring A, or bonded to the 4-position for 6-membered ring A.

The 6-membered saturated heterocyclic ring represented by ring A is preferably dioxane or hexahydropyrimidine. The 5-position in these rings is preferably bonded to the pyrrolidine ring in the compound of formula (1).

Ring A is more preferably a 4- or 6-membered saturated hydrocarbon ring.

Ring B represents a benzene ring which may have one or more substituents selected from Group 2 above, a pyridine ring which may have one or more substituents selected from Group 2 above, or a pyrimidine ring which may have one or more substituents selected from Group 2 above.

A substituent bonded to ring B may be positioned at any position. A plurality of substituents may be the same or different. For the benzene ring, one or two substituents are preferably bonded to the 5- or 6- position. For the pyridine ring, one substituent is preferably bonded to the 6-position. For the pyrimidine ring, one substituent is more preferably bonded to the 2- position.

The substituent(s) is preferably a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a cyano group, or a C -C alkoxy group, more preferably a halogen atom or a cyano group, yet more preferably a halogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom.

R represents an aryl group which may have one or more substituents selected from Group 3 above, a heteroaryl group which may have one or more substituents selected from Group 3 above, a C -C cycloalkyl group which may have one or more substituents selected from Group 3 above, or a C -C cycloalkenyl group which may have one or more substituents selected from Group 3 above.

Here, examples of the aryl group include a phenyl group, a benzyl group, an indenyl group, a naphthyl group, a fluorenyl group, an anthryl group, and a phenanthryl group. A phenyl group is particularly preferred.

Here, examples of the heteroaryl group include a pyrrolyl group, a pyrazolyl group, a triazolyl group, an oxazolyl group, an oxadiazolyl group, a thiophenyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group, a benzimidazolyl group, a benzotriazolyl group, a benzofuranyl group, a benzothiophenyl group, a quinolyl group, a carbazolyl group, and a dibenzofuranyl group. A pyridyl group and a benzimidazolyl group are particularly preferred. The position of binding of the heteroaryl group to the pyrrolidine ring is not particularly limited and a pyridyl group, for example, is more preferably bonded at the 4-position.

Here, examples of the C -C cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. The C -C cycloalkyl group is preferably a cyclopentyl group or a cyclohexyl group, more preferably a cyclohexyl group.

Here, examples of the C -C cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group. The C -C cycloalkenyl group is preferably a cyclopentenyl group or a cyclohexenyl group, more preferably a cyclohexenyl group.

The number and position of the substituent(s) bonded to the aryl group, the heteroaryl group, the cycloalkyl group, and the cycloalkenyl group are not limited and a plurality of substituents may be the same or different.

Examples of the types of substituents include a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a vinyl group, an ethynyl group, a cyano group, -OR', -NR'R'', -COOR', and -CONHR', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7-membered nitrogen- containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group.

Here, examples of the "4- to 7-membered nitrogen- containing heterocyclic group" in the phrase "R' and R'' together with the nitrogen atom to which R' and R'' are bonded may form a 4- to 7-membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group, a hydroxy group, and an oxo group" include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a hexamethyleneiminyl group, a homopiperazinyl group, and a homomorpholinyl group.

Examples of preferred substituents include a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, - NR'R'', -CONHR', and a cyano group. A halogen atom, a hydroxy-C -C alkyl group, an amino group, -CONHR' wherein R' is a C -C alkyl group, or a cyano group is more preferred.

The position of a substituent on the ring is not particularly limited. For a phenyl group and cyclohexyl group, it is particularly preferred that one chlorine atom is bonded to the 3-position, or a chlorine atom and a fluorine atom are bonded to the 3- and 2-positions, respectively. For a cyclohexenyl group, the position of the double bond is not particularly limited. It is particularly preferred that one chlorine atom is bonded to the 3-position with respect to the position of binding to the pyrrolidine ring, or a chlorine atom and a fluorine atom are bonded to the 3- and 2-positions, respectively. For a pyridyl group, it is particularly preferred that one chlorine atom is bonded to the 2- position, or a chlorine atom and a fluorine atom are bonded to the 2- and 3-positions, respectively.

R represents a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom. A substituent bonded to the C -C alkyl group is preferably a fluorine atom or a hydroxy group. R is preferably a hydrogen atom, a methyl group, or an ethyl group, and it is particularly preferred that it is a hydrogen atom.

R represents a group represented by the following general formulae (2), (3), or (4): In formula (2), R and R each independently represent a hydroxy group, a C -C alkyl group, or a C -C 1 6 1 6 alkoxy group, or R and R together with the carbon atoms to which the R and R groups are respectively bonded may form a 4- to 6-membered saturated hydrocarbon ring.

Preferably, both of R and R are a hydroxy group, or 4 5 4 R and R together with the carbon atoms to which the R and R groups are respectively bonded form a 4- to 6- membered saturated hydrocarbon ring. More preferably, both of R and R are a hydroxy group.

In formula (3), the broken line in the ring structure indicates that the bond may be a double bond; R represents a C -C alkyl group which may have one or more substituents selected from Group 4 above, a carbamoyl group which may have one or more substituents selected from Group 5 above, a 5- or 6-membered nitrogen- containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group, a hydroxy group, or -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group; R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or R and R may together form a spiro-linked 4- to 6- membered hydrocarbon ring or a spiro-linked 4- to 6- membered nitrogen-containing heterocyclic ring (wherein "spiro-linked" means that a ring formed by R and R together and the Z-containing 6-membered ring form a spiro ring); R represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy 1 6 1 6 group; and Z represents CH , NH, or an oxygen atom.

When R is a "C -C alkyl group which may have one or more substituents", examples of the substituent(s) include a halogen atom, a hydroxy group, a carbamoyl group, a morpholino group, a C -C alkoxy group, a C -C 1 6 1 6 alkylsulfonyl group, and -NR'R''. Here, R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, one to three hydroxy groups, or an oxo group, a C -C cycloalkyl group which may be 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 form a 4- to 7-membered nitrogen- containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group. Here, examples of the "4- to 7-membered nitrogen-containing heterocyclic group" when "R' and R'' together with the nitrogen atom to which R' and R'' are bonded form a 4- to 7-membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group" include an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group.

The "C -C alkyl group which may have one or more substituents", represented by R , is preferably a hydroxymethyl group, a 1-hydroxyethyl group, a 2- hydroxypropyl group, a hydroxyethyl group, a 1-hydroxy methylethyl group, a 3,4-dihydroxybutyl group, a methoxymethyl group, a methylsulfonylmethyl group, an aminomethyl group, a di-C -C alkylaminomethyl group, a (hydroxyethyl)aminomethyl group, a C -C alkyloxy(hydroxyethyl)aminomethyl group, an aminooxoethyl group, or a di-C -C alkylaminooxoethyl group.

When R is a "carbamoyl group which may have one or more substituents", examples of the substituent(s) include a C -C alkyl group which may be substituted with one to three halogen atoms, one to three hydroxy groups, or a C -C alkoxy group, a C -C cycloalkyl group, a C -C 1 6 3 6 1 6 alkoxy group, and a tetrahydropyranyl group.

The " carbamoyl group which may have one or more substituents", represented by R , is preferably an unsubstituted carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a diethylcarbamoyl group, a methylethylcarbamoyl group, an isopropylcarbamoyl group, a cyclopropylcarbamoyl group, a 2-hydroxyethylcarbamoyl group, a 2-methoxyethylcarbamoyl group, a 2-methoxyethyl-C -C alkylcarbamoyl group, or a 2-fluoroethylcarbamoyl group.

When R is a "5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group", examples of the "5- or 6-membered nitrogen-containing heteroaryl group" include an oxadiazolyl group, a triazolyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, and a triazinyl group. An oxadiazolyl group or a triazolyl group is preferred. An oxadiazolyl group, for example, is preferably bonded at the 2-position. The position of the substituent bonded to the "5- or 6-membered nitrogen- containing heteroaryl group" is not particularly limited.

For a 6-membered nitrogen-containing heteroaryl group, the substituent is positioned at any position. For a 5- membered nitrogen-containing heteroaryl group, the substituent is preferably substituted at the 5-position.

The "5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group", represented by R , is preferably an unsubstituted oxadiazolyl group, a triazolyl group, or a pyridyl group, and it is particularly preferred that it is an oxadiazolyl group.

Furthermore, R may be a hydroxy group or -NR'R''.

When R is "-NR'R''", R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7-membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group. Here, examples of the "4- to 7-membered nitrogen-containing heterocyclic group" when "R' and R'' together with the nitrogen atom to which R' and R'' are bonded form a 4- to 7-membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group" include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a 2-oxopiperazinyl group, a morpholinyl group, a homopiperidinyl group, a homopiperazinyl group, and a 1,4-oxazepanyl group.

"-NR'R''" represented by R preferably forms an azetidinyl group, a piperazinyl group, or a morpholinyl group.

R is preferably a hydroxymethyl group, a 1- hydroxyethyl group, a 2-hydroxypropyl group, a hydroxyethyl group, a 1-hydroxymethylethyl group, an oxazolyl group, an oxadiazolyl group, an oxathiazolyl group, or a carbamoyl group which may have an alkyl group having 1 to 6 carbon atoms as a substituent, more preferably a 1-hydroxyethyl group, an oxadiazolyl group, or an unsubstituted carbamoyl group.

R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a hydrogen atom.

R is more preferably a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxy group, or a hydrogen atom, yet more preferably a hydroxy group or a hydrogen atom.

Furthermore, R and R may together form a 4- to 6- membered spiro-linked hydrocarbon ring or a 4- to 6- membered spiro-linked nitrogen-containing heterocyclic ring. Examples of the ring formed include a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an azetidine ring, a pyrrolidine ring, and a tetrahydropyran ring. A cyclobutane ring or an azetidine ring is more preferred.

R is a substituent on the 6-membered ring in formula (3) and represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy group.

The position of R bonded to the 6-membered ring in formula (3) is not particularly limited so long as it is other than the position to which R and R are bonded.

The number of the substituents is not limited.

Furthermore, R is not necessarily required to be present.

R is preferably a hydroxy group, a methoxy group, or a methyl group. More preferably, R is absent, or one R group is present. Yet more preferably, R is absent, or a methoxy group is bonded in the same positional configuration as R on the carbon atom adjacent to the carbon atom to which R is bonded.

In formula (4), R represents a C -C alkyl group which may have one or more substituents selected from Group 4 above, a carbamoyl group which may have one or more substituents selected from Group 5 above, a 5- or 6-membered nitrogen- containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group, a hydroxy group, or -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be 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 form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group.

R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a 9 10 hydrogen atom, or R and R 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 represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy 1 6 1 6 group.

R has the same meaning as defined above for R in formula (3) and also has the same preferred examples. 7 R has the same meaning as defined above for R in formula (3) and also has the same preferred examples. 11 8 R has the same meaning as defined above for R in formula (3) and also has the same preferred examples. 9 10 The phrase "R and R may together form a spiro-linked 4- to 6-membered hydrocarbon ring or a spiro-linked 4- to 6- membered nitrogen-containing heterocyclic ring" means 9 10 that R and R together form a ring structure and this 9 10 ring and the cyclobutane ring to which R and R are bonded form a spiro ring.

The compound represented by general formula (1) of the present invention is more preferably a compound represented by any of the following general formulae (5) to (8) (in formulae (5) to (8), ring A, R , and R have the same meanings as defined above and also have the same preferred examples): NH (5) R (6) NH (7) NH (8) 12 13 16 R , R , and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group and are preferably a halogen atom or a cyano group, more preferably a halogen atom, yet more preferably a chlorine atom or a fluorine atom.

R represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group and is not necessarily required to be present. 14 14 Preferably, R is absent or R , if present, is a fluorine atom. The position of the substituent bonded to the ring is not limited.

R represents one or more substituents selected from Group 3 above and is not necessarily required to be 15 present. More preferably, R is absent or R , if present, is a halogen atom, a hydroxy-C -C alkyl group, an amino group, -CONHR' wherein R' is a C -C alkyl group, or a cyano group.

The compound represented by general formula (1) of the present invention is more preferably a compound selected from the following group: H H H O N O N O N Cl Cl H H H F F F OH N N N N Cl Cl Cl N O N O N O H H H H H H N O N O N O N Cl Cl Cl H H H F OH N N N Cl Cl Cl N O N O N O H H H H H H O N N O N O N Cl Cl H H H F F F N N N Cl Cl Cl N O N O N O H H H H H H N N N N N N O O O O O O Cl Cl Cl H H H OH NH OH F F F N N N Cl Cl Cl N O N O N O H H H H H H N O N O N N O N Cl Cl Cl N H H H F F F N N N Cl Cl Cl N O N O N O H H H O N O N Cl Cl Cl Cl N O N O A compound represented by formula (1) of the present invention may have stereoisomers or optical isomers due to asymmetric carbon atoms, and all these stereoisomers, optical isomers, and mixtures thereof are included in the present invention.

In one embodiment of the present invention, a compound having an absolute configuration represented by the following formula is preferred: From the prior art, it is known that in a compound having a 6-oxo-2,7-diazaspiro[4.4]nonanecarboxamide structure, the central skeleton of general formula (9), which is unsubstituted or monosubstituted at the 2-position in the pyrrolidine ring, cleavage and recyclization at the C2-C3 carbon bond of the pyrrolidine ring occur in a polar solvent to facilitate isomerization of the spiro ring structure at the 3-position (Helv. Chim. Acta, 1996, 79, 151-168, etc.). The present inventors have found that introduction of the spiro ring structure A to the 2- position of the pyrrolidine ring can prevent the progression of this isomerization. The present inventors have also found that the compound group having an absolute configuration represented by general formula (9) is far superior in the ability to inhibit Mdm2-p53 binding to that reported in the prior art. Furthermore, the present inventors have obtained co-crystals with Mdm2 protein from compounds of Examples 18, 38, and 70 of the present application described later and consequently found that these compounds bind to Mdm2 protein in a manner different from that predicted in silico in Non Patent Document 1 and Non Patent Document 2.

The compound represented by general formula (1) of the present invention can form a pharmaceutically acceptable salt, if desired, when having a basic group such as an amino group. Examples of such salts can include: hydrohalides such as hydrochloride and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p- toluenesulfonate; organic acid salts such as formic acid, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithine salt, glutamate, and aspartate.

Hydrohalides and organic acid salts are preferred.

The compound represented by general formula (1) of the present invention may generally form a base addition salt when having an acidic group such as a carboxy group.

Examples of pharmaceutically acceptable salts can include: alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, diethanolamine salt, N- benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt.

The compound represented by general formula (1) of the present invention or the salt thereof may be present in a free or solvate form. The compound represented by general formula (1) of the present invention or the salt thereof may be present in a hydrate form, for example, by absorbing moisture in the air. The solvate is not particularly limited so long as it is pharmaceutically acceptable. Specifically, the solvate is preferably a hydrate, an ethanol solvate, a 2-propanol solvate, or the like. Moreover, the compound represented by general formula (1) of the present invention may be in an N-oxide form when containing a nitrogen atom. These solvate and N-oxide forms are also included in the present invention.

The compound represented by general formula (1) of the present invention may have various isomers such as geometrical isomers (e.g., cis and trans forms), tautomers, and optical isomers (e.g., d and l forms), depending on the types or combinations of substituents.

The compound of the present invention also encompasses all these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio, unless otherwise specified.

The compound represented by general formula (1) of the present invention may contain an isotope in a non- natural proportion as one or more constituent atoms.

Examples of an isotope include deuterium ( H), tritium 3 125 14 ( H), iodine-125 ( I), and carbon-14 ( C). These compounds are useful as a therapeutic or preventive agent, a research reagent (e.g., an assay reagent), and a diagnostic agent (e.g., an in vivo diagnostic imaging agent). All isotopic variants of the compound represented by general formula (1) are included in the scope of the present invention, regardless of the presence or absence of radioactivity.

Moreover, the present invention also encompasses a compound that is converted to the compound (1) as an active ingredient in the pharmaceutical composition of the present invention due to a reaction induced by an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that is converted to the compound (1) through enzymatic oxidation, reduction, hydrolysis, or the like or a "pharmaceutically acceptable prodrug compound" that is converted to the compound (1) through hydrolysis or the like induced by gastric acid or the like.

Examples of a prodrug can include: compounds in which an amino group in the compound (1) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyloxo-1,3-dioxolen yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert- butylated); compounds in which a hydroxy group in the compound (1) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxy group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); and compounds in which a carboxy group in the compound (1) is esterified or amidated (e.g., compounds in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated).

A prodrug of the compound of the present invention can be produced from the compound (1) according to a method known in the art. Moreover, a prodrug of the compound of the present invention also includes those converted to the compound (1) under physiological conditions as described in "Development of Pharmaceutical Products", vol. 7, Molecule Design, p. 163-198, Hirokawa- Shoten Ltd. (1990).

Next, a representative method for producing a compound represented by general formula (1) will be explained. A compound of the present invention can be produced by various production methods and the following production methods are illustrative and should not be construed in any limitative way. Reactions shown below can be performed by protecting substituents with appropriate protective groups, if necessary, and the types of protective groups are not particularly limited.

[Production Method 1] + + + ( 1 ) ( 2 ) ( 3 ) ( 4 ) ( 5 ) O O N H R N ( 7 ) ( 10 ) ( 6 ) ( 8 ) O OH ( 7 ) ( 9 ) 1 2 3 wherein ring A, ring B, R , R , and R have the same meanings as defined above.

Synthesis of compound (3) A compound (3) can be obtained by subjecting an oxindole compound (1) and an aldehyde compound (2) to a dehydration reaction through treatment with an organic base such as pyrrolidine, piperidine, or diisobutylethylamine as a catalyst. Here, the solvent used in the reaction is not particularly limited and examples thereof include lower alcohols such as methanol and ethanol, and mixed solvents in which any of these solvents are mixed with water in an arbitrary ratio. The reaction temperature is not particularly limited and examples thereof include room temperature to 120

Claims

What we claim is:

1. A compound which is (2S,5R)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro fluoropyridinyl)-4,4-dimethyl-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''- indole]-5'-yl]carbonyl}amino)tetrahydro-2H-pyran carboxylic acid.

2. An inhibitor of Mdm2 comprising a compound according to claim 1.

3. An inhibitor of Mdm2 ubiquitin ligase comprising a compound according to claim 1.

4. An inhibitor of p53-Mdm2 binding comprising a compound according to claim 1.

5. An inhibitor of suppression of p53 transcription activity comprising a compound according to claim 1.

6. An inhibitor of p53 degradation comprising a compound according to claim 1.

7. A medicament comprising a compound according to claim 1.

8. An anticancer agent comprising a compound according to claim 1.

9. An anticancer agent according to claim 8, wherein the cancer is lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. Use of a compound according to claim 1 for the manufacture of a medicament.

12. Use of a compound according to claim 1 for the manufacture of an anticancer agent.

13. A compound according to claim 1, substantially as herein described with reference to any one of the Examples thereof.

14. A compound according to claim 1, substantially as herein described.

15. An inhibitor according to any one of claims 2 to 6, substantially as herein described.

16. A medicament according to claim 7, substantially as herein described.

17. An anticancer agent according to claim 8 or 9, substantially as herein described.

18. A pharmaceutical composition according to claim 10, substantially as herein described.

19. Use according to claim 11 or 12, substantially as herein described.