Anti-proliferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines
Inventors
JACKSON, Paul joseph Mark • Thurston, David Edwin • Rahman, Khondaker Mirazur
Assignees
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Publication Number
US-11912700-B2
Publication Date
2024-02-27
Expiration Date
Abstract
The invention relates to substituted pyrridinobenzodiazepines (PDDs) of formula (XV) and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents.
Core Innovation
The invention relates to compounds of formula (XV) and pharmaceutically acceptable salts thereof, with extensive substituent-variable definitions for R1, R2, R3, R5, R6, R7, R9, R11, R12, R15, R17, R19, R20, R21, R4, R24, X1, X2, L, Y1, Y2, Y3, Y4, Y5, q, p, t, and related indices. The compounds are defined through explicit structural options, including O(CH2)nC(O)NHR7, O(CH2)nNHC(O)R7, O(CH2)sC(O)NR9H, O(CH2)sNHC(O)R9, and related substituent regimes, together with phenyl and heteroaryl substitution patterns for R4 and R24.
The structural core specifies X1 as CH2, CH2O, C(O), C(O)NH, C(O)O, NH, NHC(O), O, OC(O), or S, and X2 as absent or selected from CH2, C(O), C(O)NR15, or NR15C(O). The linker L is C1-12 alkylene, (OCH2)1-12, or (OCH2CH2)1-6, with optional interruption by NH, O, S, phenylene, and C5-9 heteroarylene. Additional structural constraints define Y3 as NR17, Y4 as CH, Y5 as CH or N, q as 1, p as 0, and Y1 and Y2 as CH or N.
The disclosure further provides preferred embodiments of compounds of formula (I) by selecting scaffold variants designated as formula (XIII) and (XIV)-(XX), and identifies a series of specific named compounds as further preferred selections. It includes compounds of formula (XV) and formula (XIX), with fixed or narrowed values in selected embodiments such as L as CH2CH2CH2, q as 1, p as 0, and R5 and R6 taken together with the N atom and C atom to form an N=C or N↔C unit.
Claims Coverage
The provided claims cover two independent compound classes, formula (XV) and formula (XIX), both including pharmaceutically acceptable salts. The claim set also includes dependent refinements and additional claim types, with the inventive features centered on defined substituent-variable frameworks, fixed linker selections, and narrowed substituent and index values.
Compound of formula (XV) with variable substituents and linker options
A compound of formula (XV) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined by O(CH2)nC(O)NHR7, O(CH2)nNHC(O)R7, O(CH2)sC(O)NR9H, O(CH2)sNHC(O)R9, or R7/R9; R3 is C1-6 alkyl; R5 and R6 are H/OH, H/OC1-6 alkyl, or together form N↔C; X1 is selected from specified functional groups; L is selected from specified alkylene and (OCH2)-containing linkers with optional interruption; X2 is absent or selected from specified groups; Y3 is NR17 with R17 being H or C1-6 alkyl; Y4 is CH; Y5 is CH or N; q is 1; p is 0; Y1 and Y2 are CH or N; and R19, R20, R21, R4, R11, R12, R24, j, and k are defined by explicit structural options and index ranges.
Compound of formula (XIX) with fixed linker and substituent values
A compound of formula (XIX) or a pharmaceutically acceptable salt thereof, wherein R5 and R6 taken together with the N atom and C atom form N=C or N↔C; L is CH2CH2CH2; Y5 is CH; q is 1; Y1 and Y2 are CH or N; R19 is H or (CH2)tNR20R21; R20 and R21 are H or C1-6 alkyl; p is 0; t is 0-6; R22 is (CH2)jNR11R12; R11 and R12 are H; and j is 0.
Pharmaceutical composition including excipient, carrier, or diluent
A pharmaceutical composition that includes a pharmaceutically acceptable excipient, carrier, or diluent and a compound of claim 1 or a pharmaceutically acceptable salt.
Method for inhibiting cancer cell proliferation
A method for inhibiting cancer cell proliferation in a patient by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
The claims define chemically specified compound classes by formula (XV) and formula (XIX), with the principal inventive content residing in the allowed substituent variability, linker definitions, and selected fixed parameters. The dependent coverage further extends to a pharmaceutical composition and a method for inhibiting cancer cell proliferation.
Stated Advantages
Used for treatment of proliferative diseases, including cancer and related proliferative conditions.
Inhibiting cancer cell proliferation in a patient.
Increased cytotoxicity.
DNA sequence selectivity.
Documented Applications
Payloads for treatment of proliferative diseases.
Antibody-drug conjugate (ADC) payloads with antibody targeting.
A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier, or diluent and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
A method for inhibiting cancer cell proliferation in a patient by administering a therapeutically effective amount of a compound of formula (XV) or a pharmaceutically acceptable salt thereof.
Use in therapy for a proliferative disease.
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