Compounds and therapeutics uses thereof
Inventors
WESTBY, Michael • GLOSSOP, Melanie • WATSON, Christine
Assignees
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Publication Number
US-12138292-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The invention relates to novel compounds with the ability to link an immune response to a pathogen, to the use of said compounds in a disease or disorder mediated and/or caused by an infective agent, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
Core Innovation
The process prepares a compound of formula (I) that includes a cationic anti-microbial peptide (L) linked to X1 by an amine, with S1 and S2 as selected spacer groups and F defined as Rhamnose and Cy defined as biphenyl. The architecture further includes defined connector groups for X1, Y1, and Y2, together with integer ranges and optional substitution of one or two CH2 groups by a C(O)NH or NHC(O) group.
The process is defined through multiple reaction sequences starting from different precursor formula combinations and proceeding to a suitable deprotection step. One route prepares the compound of formula (IA) by reacting a compound of formula (II) with a compound of formula (III), another prepares the compound of formula (IB) by reacting a compound of formula (IV) with a compound of formula (V), and a further route prepares a compound of formula (I) by reacting a compound of formula (VI) with a compound of formula (VII).
The suitable deprotection step is constrained by the peptide protecting group PG selected from Dde or tert-butoxycarbonyl (Boc). The process further allows interconversion of a compound of formula (I), or a protected derivative thereof, into an alternative compound of formula (I), or a protected derivative thereof.
Claims Coverage
The independent claims cover preparation of a compound of formula (I) with a defined cationic anti-microbial peptide architecture and three alternative preparation routes, together with deprotection using Dde or tert-butoxycarbonyl (Boc). The consolidated claim coverage includes 6 inventive features.
Defined compound architecture with cationic anti-microbial peptide linked via amine
A process for preparing a compound of formula (I) wherein L represents a cationic anti-microbial peptide linked to X1 by an amine, with F defined as Rhamnose and Cy defined as biphenyl, and where S1 and S2 are selected from specified spacer groups with optional C(O)NH or NHC(O) substitutions and defined integer ranges.
Route through compound IA via reacting formula II and III followed by deprotection
Preparing the compound of formula (IA) by reacting a compound of formula (II) with a compound of formula (III) followed by a suitable deprotection step.
Route through compound IB via reacting formula IV and V followed by deprotection
Preparing the compound of formula (IB) by reacting a compound of formula (IV) with a compound of formula (V) followed by a suitable deprotection step.
Direct route to compound I via reacting formula VI and VII followed by deprotection
Preparing a compound of formula (I) by reacting a compound of formula (VI) with a compound of formula (VII) followed by a suitable deprotection step.
Deprotection using Dde or tert-butoxycarbonyl (Boc) peptide protecting group
In the preparation routes, PG is a suitable peptide protecting group selected from Dde or tert-butoxycarbonyl (Boc).
Interconversion of compound I or protected derivatives
Interconversion of a compound of formula (I), or protected derivative thereof, into an alternative compound of formula (I), or protected derivative thereof.
The claims require preparation of formula (I) compounds defined by a cationic anti-microbial peptide (L) linked via an amine to X1, incorporating Rhamnose (F) and biphenyl (Cy) with defined spacer and connection selections. Preparation is supported by three reaction routes followed by deprotection using Dde or tert-butoxycarbonyl (Boc), and includes interconversion between compound (I) forms and protected derivatives.
Stated Advantages
Complement activation (e.g., C3b/iC3b), phagocytosis and killing via presentation of Rhamnose together with binding to bacterial lipid A.
Potential retention of activity against resistant Gram-negative strains by combining peptide binding to lipid A with anti-Rhamnose antibody engagement.
Documented Applications
Therapeutic use as immunity-linker therapeutic compounds against bacterial infections, with example infective agents/bacterial pathogens referenced in the document (e.g., MRSA, E. coli, Pseudomonas aeruginosa).
A flow cytometric anti-Rhamnose IgG antibody recruitment assay reports fold-change binding for Examples 1–6, including Example 6, relative to polymyxin B.
A flow cytometric human serum complement deposition assay uses pooled human serum to detect C3b/iC3b deposition, with fold-change values for Examples 1–6 including Example 6, relative to polymyxin B.
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