Pyrridinobenzodiazepine and benzopyrridodiazecine compounds
Inventors
Thurston, David Edwin • Rahman, Khondaker Mirazur • JACKSON, Paul joseph Mark
Assignees
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Publication Number
US-10399970-B2
Publication Date
2019-09-03
Expiration Date
Abstract
The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7- 6-membered rings and to benzopyrridodiazecines (BPDs) comprising three fused 6-8- 6-membered rings and, in particular, to PDD or BPD dimers linked together or PDD and BPD monomers linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, such as anti-proliferative agents. PDDs and BPDs may be represented by formula (I): and salts or solvates thereof, wherein R2, R4-R6 and R8 are independently selected substituent groups; and either: (i) R9 and R10 together form a double bond; (ii) R9 is H and R10 is OH; or (iii) R9 is H and R10 is ORA and RA is C1-6 alkyl; wherein each of m, n, u and w may be 0 or 1; where (a) the compound is a dimer with each monomer being the same or different and being of formula (I) where one of R1, R2, R3 and R7 of the first monomer and one of R′1, R′2, R3 and R′7 of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers and m+n+u+w=1; or (b) a dimer and one of R1, R2 and R3 of the first monomer and one of R′1, R′2 and R3 of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers and m=n=u=w=o; or (c) one of R1, R2, R3 and R7 has the formula: —X-L-X′-D or —(CH2)f-O—R14 and m+n+u+w=o or 1; or (d) R7 has the formula: —X-L-X′— D or —(CH2)g—O—15 and m+n+u+w=1; and X-L-X′— is a linker group and D has the formula (II) or (III).
Core Innovation
The patent describes pyrridinobenzodiazepine (PDD) and benzopyrridodiazecine (BPD) compounds, including salts or solvates, based on a tricyclic scaffold with optional double bond placement between one or more of C1 and C2, C2 and C3, and C3 and C4. The substituent pattern is defined by formula (I) with extensive variability of R4, R5, R6, and R8, and with R9 and R10 constrained to selected double-bond or hydroxy/alkoxy cases.
A central structural theme is the provision of these compounds in dimeric forms or as linked monomers, where the dimer architecture is specified by a bridge group —X-L-X′— that links monomers. The bridge group is defined to include L as an amino acid, a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from 1 to 12 carbon atoms, a paraformaldehyde chain (OCH2)1-12—, or a polyethylene glycol chain —(OCH2CH2)1-6—, with the chains optionally interrupted by hetero-atoms and/or heteroaryl and/or aryl groups.
The patent further specifies linked forms of formula (I) through bridge alternatives where one of R1, R2 and R3 has a formula —X-L-X′-D or (CH2)f—O—R14, and additional alternatives where R7 has analogous formula features. D has a formula (II) or (III), with defined parameters p, q, r, t, Y3 and Y4, and includes sub-forms D1 to D4 that specify additional heteroaryl ring substituent variability for the linked architecture.
Claims Coverage
The independent claim set comprises one independent claim, which defines a compound of formula (I) including salts or solvates and imposes extensive substituent-variable selections. The inventive coverage is organized around optional dotted double-bond placement, substituent selection constraints including special relationships between R9 and R10, and a requirement that the compound conform to one of dimer or linked forms (a) to (d) using a bridge of the form —X-L-X′— and/or alternative linker motifs, with D defined by formula (II) or (III).
Compound of formula (I) with optional double-bond placement
A compound of formula (I), including salts or solvates thereof, in which the dotted lines indicate the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4, and with detailed selectable substituent sets for R4, R5, R6, and R8 and constraints on R9 and R10.
Dimer or linked architecture through a bridge group —X-L-X′—
The compound of formula (I) is according to (a), (b), (c) or (d), wherein in the dimer forms one of R1, R2, R3 of the first monomer and one of R1′, R2′, R3′ of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers, with bridge participation constrained by m+n+u+w or by m=n=u=w=0 in the specified embodiments.
Bridge and linker definitions for X, X′, L and D
X is selected from O, S, NR3, —CR3—, CR3R22, CR3R22O, C(=O), C(=O)NR3, NR3C(=O), O—C(=O) and C(=O)—O; L is selected from an amino acid, a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from 1 to 12 carbon atoms, a paraformaldehyde chain (OCH2)1-12—, or a polyethylene glycol chain —(OCH2CH2)1-6—; and D has the formula (II) or (III) with defined variables including p, q, r, t, Y3, Y4, R13, Z, k, R11 and R12.
Linked forms using —X-L-X′-D or (CH2)f—O—R14
The compound includes additional linked forms where one of R1, R2 and R3 has the formula —X-L-X′-D or (CH2)f—O—R14, and where R7 has analogous formula features, with f or g equal to 0 or 1 and with the stated m, n, u and w constraints in the respective embodiments.
The independent claim covers compounds of formula (I) defined by optional double-bond placement and detailed substituent rules, together with required structural constraints that place the compound into specific dimer or linked frameworks (a) to (d). These frameworks are governed by a bridge group —X-L-X′— with defined selections for X, X′ and L, and by a D component defined by formulas (II) or (III), including D sub-forms.
Stated Advantages
Anti-proliferative medicaments.
Documented Applications
Treating proliferative disease using formula (I) compounds, including use as drug payloads and in antibody-drug conjugates.
Anti-proliferative medicaments.
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