Pyrrolobenzodiazepine compounds
Inventors
Thurston, David Edwin • Rahman, Khondaker Mirazur • JACKSON, Paul joseph Mark
Assignees
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Publication Number
US-9999625-B2
Publication Date
2018-06-19
Expiration Date
Abstract
The invention relates to pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) of formula (I) and in particular to PBD dimers linked through the C1 position, and PBD monomers linked through the C1 position to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. (I) and salts or solvates thereof, wherein: the dotted lines indicates the optional presence of a double bond between C1 and C2 or C2 and C3; R2-R7 are independently selected substituent groups; and either: (i) R8 and R9 together form a double bond; (ii) R8 is H and R9 is OH; or (iii) R8 is H and R9 is ORA and RA is C1-6 alkyl; where R1 has the formula: -X-L-X′-D-X-L-X′- is a linker group and D has the formula (II) or (III): or where the compound is a dimer with each monomer being the same or different and being of formula (I) where the R1 of the first monomer and R′1 or R′6 of the second monomer, or R6 of the first monomer and R′1 of the second monomer, form together a bridge having the formula -X-L-X′- linking the monomers.
Core Innovation
The invention provides a compound of formula (I) and salts or solvates thereof, where the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3. The compound includes substituent definitions for R2 and R3, and for R4, R5, R6, and R7, with extensive selection options and constraints involving R8 and R9, including the cases where they form a double bond, or where one is H and the other is OH or ORA.
The framework includes dimer embodiments in which each monomer is of formula (I) and the monomers are linked by a bridge having the formula X-L-X′. The bridge can be formed using selected combinations of R1 and R1′, or R1 and R6 and/or R6 and R1′, and L is selected from an amino acid, a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from 2 to 12 carbon atoms, a paraformaldehyde chain, or a polyethylene glycol chain, with possible interruptions by hetero-atoms and/or heteroaryl and/or aryl groups.
The invention further defines an alternative structural option where R1 has the formula -X-L-X′-D, with D having the formula (II) or (III) and with parameters p, q, r, t, Y3, Y4, R10, Z, n, R11, and R12 constrained as specified. The provided content also states that DNA adduct formation is reported for a C1-linked PBD core compound, a C1-linked PBD monomer compound, and a C1-linked PBD dimer compound, and that cytotoxicity is evaluated using an MTT assay in MDA-MB-231 with reported IC50 values.
Claims Coverage
The provided independent claim content centers on one broad genus of formula (I) compounds, including optional C1–C3 double-bond presence and extensive substituent variability, plus explicit dimer-linked configurations via a bridge unit X-L-X′ and an alternative capped form using -X-L-X′-D. The inventive features comprise the formula (I) substitution rules, the bridge-linked dimer architecture, and the capped structural option with D of formula (II) or (III).
Compound of formula (I) with salts or solvates
A compound of formula (I) and salts or solvates thereof, wherein the optional presence of a double bond between C1 and C2 or between C2 and C3 is provided and where substituents R2, R3, R4, R5, R6 and R7 are independently selected from the listed groups, with defined constraints for R8/R9 and R/R′ selection conditions.
Dimer linking through bridge X-L-X′
A compound where each monomer is of formula (I), the monomers are the same or different, and R1 and R1′ together form a bridge having the formula X-L-X′ linking the monomers, with X and X′ selected from specified groups and L selected from an amino acid, a peptide chain of 2 to 6 amino acids, an alkylene chain, a paraformaldehyde chain, or a polyethylene glycol chain, including possible interruptions by hetero-atoms and/or heteroaryl and/or aryl groups.
Alternative dimer construction with R1 as -X-L-X′-D
A compound where R1 has the formula -X-L-X′-D, with X, L, and X′ selected from specified groups or X′ absent, and D defined by formula (II) or (III) with parameters p, q, r, t, Y3, Y4, R10, Z, n, R11 and R12 constrained as specified.
Across the provided independent claim, coverage centers on formula (I) compounds with optional double-bond presence and constrained substituent patterns, together with embodiments that are dimers connected through a defined bridge unit X-L-X′ and an alternative -X-L-X′-D construction with D governed by formula (II) or (III).
Stated Advantages
Anti-proliferative agents activity is stated for the disclosed PBD medicaments.
Therapeutic use is stated as treatment of proliferative diseases using the disclosed compounds.
Documented Applications
Treatment of proliferative diseases, including breast cancer, ovarian cancer, or leukemia.
DNA adduct formation is reported for a C1-linked PBD core compound, a C1-linked PBD monomer compound, and a C1-linked PBD dimer compound, followed by cytotoxicity evaluation using an MTT assay in MDA-MB-231 with reported IC50 values.
Ligand–DNA complexes evaluation using ion-pair RPLC with ESI-MS/MALDI-TOF and a DNA thermal denaturation assay using FRET with a fluorescence-tagged oligonucleotide, reporting melting temperature (Tm, ΔTm).
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