Dispiropyrrolidine derivatives
Inventors
Sugimoto, Yuuichi • Uoto, Kouichi • Wakabayashi, Takanori • Miyazaki, Masaki • Setoguchi, Masaki • Taniguchi, Toru • Yoshida, Keisuke • Yamaguchi, Akitake • Yoshida, Shoko
Assignees
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Publication Number
US-12545685-B2
Publication Date
2026-02-10
Expiration Date
Abstract
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 R1, R2, R3, ring A, and ring B in formula (1) respectively have the same meanings as defined in the specification.
Core Innovation
The invention relates to a compound represented by general formula (1) or a salt thereof, in which ring A is a spiro-linked 4- or 6-membered saturated hydrocarbon ring or a spiro-linked 6-membered saturated heterocyclic ring, and ring B is a benzene ring, pyridine ring, or pyrimidine ring. R1 is an aryl group, heteroaryl group, C3-C6 cycloalkyl group, or C3-C6 cycloalkenyl group, and R2 is a C1-C6 alkyl group optionally substituted with halogen atoms or hydroxy groups, or hydrogen.
R3 is represented by general formula (3) or (4), with the broken line in formula (3) indicating that a bond may be a double bond. R6 and R7, or R9 and R10, are defined by allowed groups including C1-C6 alkyl, carbamoyl, nitrogen-containing heteroaryl, hydroxy, oxo, and —NR′R″ patterns, and may together form a spiro-linked 4- to 6-membered hydrocarbon ring or a spiro-linked 4- to 6-membered nitrogen-containing heterocyclic ring. R8 is absent or represents hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, and Z is O.
The structural framework is further constrained by Group 1 through Group 5 substituent sets for ring A, ring B, and the variable substituents. The disclosure also describes salts of the compounds, and exemplified entries include characterized spiro/dispiro multi-ring compounds and defined salt or solvate forms with reported 1H-NMR, LC/MS, elemental analysis data.
Claims Coverage
The claims cover one broad class of compounds or salts defined by general formula (1) and a spiro-linked multi-ring scaffold. Dependent claims further narrow selected substituent positions through general formulas (5), (6), and (8). The claim set contains 5 inventive features.
Spiro-linked ring A and ring B scaffold
A compound represented by general formula (1) or a salt thereof, wherein ring A is a spiro-linked 4- or 6-membered saturated hydrocarbon ring or a spiro-linked 6-membered saturated heterocyclic ring optionally substituted with Group 1, and ring B is a benzene ring, pyridine ring, or pyrimidine ring optionally substituted with Group 2.
R1 and R2 substituent definitions
R1 is an aryl group, heteroaryl group, C3-C6 cycloalkyl group, or C3-C6 cycloalkenyl group optionally substituted with Group 3, and R2 is a C1-C6 alkyl group optionally substituted with one to three halogen atoms or one to three hydroxy groups, or hydrogen.
R3 defined by general formula (3) or (4) with spiro-linked ring options
R3 is represented by general formula (3) or (4), where formula (3) includes a broken line indicating a possible double bond, and where R6/R7 or R9/R10 may together form a spiro-linked 4- to 6-membered hydrocarbon ring or nitrogen-containing heterocyclic ring, with Z defined as O and R8 or R11 defined by hydroxy, alkyl, and alkoxy options.
Group-based optional substitution sets
Group 1, Group 2, Group 3, Group 4, and Group 5 define the allowed substituents for the scaffold and variable positions, including halogen, alkyl, alkoxy, cyano, vinyl, ethinyl, carbamoyl, morpholino, alkylsulfonyl, and tetrahydropyranyl options.
Dependent narrowing by general formulas (5), (6), and (8)
Dependent claims narrow selected substituent positions such as R12, R13, R14, R15, and R16 to defined sets including halogen, C1-C6 alkyl optionally halogen-substituted, cyano, and absence at specified positions.
The claims cover a spiro-linked multi-ring compound class defined by general formula (1), with ring A, ring B, R1, R2, and R3 constrained by Groups 1-5 and by general formulas (3) or (4). Dependent claims further narrow the scope by selecting specific substituent-position patterns in general formulas (5), (6), and (8).
Stated Advantages
Inhibits Mdm2-p53 interaction by Mdm2-p53 binding inhibition.
Suppresses p53 transcription activity.
Inhibits p53 degradation.
Exhibits anti-tumor or anticancer activity.
Provides pharmaceutical composition or medicament suitable for cancer treatment use.
The absolute-configuration compound group of formula (9) shows superior inhibition of Mdm2-p53 binding compared with prior studies.
Introducing the spiro ring at the 2-position of a pyrrolidine ring prevents polar-solvent isomerization of a related diazaspiro oxindole core.
Documented Applications
Cancer treatment use for cancer types including lung, breast, prostate, colon, AML, malignant lymphoma or melanoma, retinoblastoma, neuroblastoma, and sarcoma.
Pharmaceutical compositions and medicaments.
Suppression of p53 transcription activity.
Inhibition of p53 degradation.
Anti-tumor use.
Test Example 1 Mdm2/p53 binding assay (His-p53, GST-Mdm2; HTRF detection).
Test Example 2 cell growth inhibition assay (NCI-H460; MTT assay).
Test Example 3 anti-tumor activity test using a SJSA-1/SUSA-1-RE xenograft model.
Test Example 4 metabolic stability test using human liver microsomes.
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