Polymyxin derivatives and their use in combination therapy together with different antibiotics
Inventors
Brown, Pamela • Dawson, Michael • Simonovic, Mona • Boakes, Steven • Duperchy, Esther
Assignees
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Publication Number
US-10407467-B2
Publication Date
2019-09-10
Expiration Date
Abstract
Described are compounds of formula (I) for use in combination treatment with a second active agent, such as rifampicin, for example for treatment of a microbial infection. The compound of formula (I) is a polymyxin compound is:where the groups -A-, —R1, —R2, —R3, —R4, —R5, —R6, —R7, —R8, and —X— are described in detail within the description.
Core Innovation
The patent describes polymyxin compounds of formula (II) and pharmaceutically acceptable salts thereof, with defined structural constraints on X, R1, R2, R3, R4, R5, R6, R7, R8, and A-. X is selected from —C(O)—, —NHC(O)—, —OC(O)—, —CH2— or —SO2—, and the compounds include one of conditions (a) through (f). R1, R2 and R3 are constrained as phenylalanine, leucine, valine, threonine, iso-leucine, or nor-valine residues, while R6 and R7 are independently hydrogen or C1-4 alkyl and R8 is methyl or hydrogen.
The definition further constrains —R4, —R5, and the substitution patterns for —R5. In the stated conditions, —R4 is a C1-6 alkyl substituted with one hydroxyl group or one amino group, —A- is a covalent bond or an amino acid, and —R5 is defined as G-L2-L1- or D-L1- with additional constraints on G, L1, and L2. The substituent options on —R5 are defined using hydroxyl groups and groups —NR6R7, with provisos about when these substituents are optional depending on the nitrogen-containing nature of L1 and/or L2.
The compounds further include choices for L1 and L2 as covalent bond, alkylene, heteroalkylene, or heterocyclylene classes, together with provisos that couple the allowed choices to the selected identity of G. G is specified as C5-12 aryl, C3-10 cycloalkyl, or C2-12 alkyl in the relevant conditions, and pharmaceutically acceptable salts are included. The description also relates the polymyxin compounds to therapeutic use in microbial infections, especially Gram-negative bacterial infections, and to combination administration with a broad enumerated set of second active agents.
Claims Coverage
The consolidated claim coverage centers on clm-00001, which defines a polymyxin compound of formula (II) and pharmaceutically acceptable salts thereof. The independent claim contains multiple alternative structural conditions (a) through (f) that specify residue identity, linker architecture, and substitution patterns.
Polymyxin compound of formula (II) with constrained residues and linker options
A polymyxin compound of formula (II) and pharmaceutically acceptable salts thereof, where X is selected from —C(O)—, —NHC(O)—, —OC(O)—, —CH2— or —SO2—; R1, R2, and R3 are constrained to specific amino acid residue types; R6 and R7 are hydrogen or C1-4 alkyl; R8 is methyl or hydrogen; and one of conditions (a) through (f) defines —R4, —A-, and —R5.
Condition-dependent selection of —R5-linked moiety
One of conditions (a) through (f) defines —R5 as G-L2-L1- or D-L1- with G selected from the stated classes, L1 and L2 selected from covalent bond, alkylene, heteroalkylene, or heterocyclylene categories with provisos, and —R5 substituted with one, two or three hydroxyl groups, one, two or three groups —NR6R7, or combinations thereof, subject to provisos for optional substituents when the specified nitrogen-containing linker cases apply.
Condition (a) defines —R4 and aryl-linked —R5
Where condition (a) is met, —R4 is C1-6 alkyl substituted with one hydroxyl group or one amino group; —A- is a covalent bond or an amino acid; —R5 is G-L2-L1-; and G is C5-12 aryl optionally substituted with the listed substituent classes, with substitution counts and provisos on hydroxyl and —NR6R7 groups.
Condition (e) defines —R5 with alkyl, aryl, or cycloalkyl G
Where condition (e) is met, —R4 is C1-6 alkyl substituted with one hydroxyl group or one amino group; —A- is an amino acid; —R5 is G-L2-L1-; G is C2-12 alkyl, C5-12 aryl or C3-10 cycloalkyl; and L1 and L2 are constrained as stated, with provisos governing the substitution options on —R5.
Independent claim clm-00001 covers polymyxin compounds defined by formula (II) with specific residue constraints, defined limits for R6/R7/R8, and six alternative condition sets (a) through (f) that determine the form of —R5, including G-L2-L1- and D-L1- variants, along with allowable hydroxyl and —NR6R7 substitution patterns and pharmaceutically acceptable salts.
Stated Advantages
Reduced toxicity versus polymyxin/colistin, especially nephrotoxicity.
Enhanced potentiation of second antibiotics, particularly in combination therapy for Gram-negative infections.
Improved rifampicin-potentiated MIC compared with polymyxin B/colistin benchmarks.
Reduced renal toxicity markers versus polymyxin B/colistin benchmarks.
Enhanced in vivo efficacy in a mouse thigh infection model as indicated by log10 CFU reduction.
Documented Applications
Combination therapy for Gram-negative bacterial infection, including treatment with second antibiotics selected from an active-agent set.
Treatment and prophylaxis of microbial infections, especially Gram-negative bacterial infections.
Combination therapy by administering a polymyxin compound together with a second active agent selected from a broad enumerated list of antibiotics and antifungal agents.
Use in specified infection types including skin and soft tissue infections, gastrointestinal infection, urinary tract infection, pneumonia, sepsis, intra-abdominal infection, and obstetrical/gynaecological infections.
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