Amide derivatives of squalamine for the treatment of infections
Inventors
Brunel, Jean-Michel • BLANCHET, Marine • MARC, Jean-Pascal
Assignees
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Publication Number
US-10780101-B2
Publication Date
2020-09-22
Expiration Date
Abstract
A compound of formula (I) in which R′ represents a group —(CRaRb)n—X—(CRcRd)m—[Y—(CReRf)o]t—NR9R10 and X and Y independently represent a group —NR11-, a group —O— or a divalent 5-membered or 6-membered heterocyclic group comprising at least one nitrogen atom, and also the stereoisomers, mixtures of stereoisomers, and/or pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical or veterinary compositions containing the compound of formula (I) and also to the use thereof as medicament, more particularly in the treatment of bacterial, fungal, viral or parasitic infections. Also further disclosed are pharmaceutical or veterinary compositions including the compound of formula (I) in combination with an antibiotic other than such a compound of formula (I).
Core Innovation
The invention relates to compounds of formula (I) that include bile-acid-derived structures and squalamine-analog aminosteroid amide derivatives bearing defined substituent patterns. The disclosed structure family includes a steroidal core with hydroxyl groups on the steroid scaffold and an amide carbonyl attached to an N-containing substituent, and it is presented as a defined set of bile-acid based compounds with constrained linker and ring or heterocycle structures.
The compounds are described within a formula (I) framework that includes multiple choices for substituents on a bile-acid-derived scaffold, together with specified integer ranges for the linker elements. The family includes stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts, and the partial content indicates representative bile-acid scaffolds such as deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid.
The invention further links the formula (I) compounds to biological performance, including intrinsic antibacterial activity, antifungal activity, and antibiotic-potentiation/synergism. The document presents antibacterial and antifungal testing results using MIC and IC50 measurements, and describes use in treating bacterial and fungal infections as well as potentiating the antibiotic activity of ampicillin, erythromycin, and chloramphenicol.
Claims Coverage
The claim set provided includes four independent claims that cover: a broad structural genus of compounds of formula (I); a specific enumerated set of named bile-acid derivative compounds and salts; a further enumerated subset of named bile-acid derivative compounds and salts; and a method for potentiating antibiotic activity by administering a formula (I) compound with ampicillin, erythromycin, or chloramphenicol. Overall, the independent claims collectively define four main inventive areas: compound structure, compound selection, further compound selection, and antibiotic-potentiation use.
Bile-acid-derived compound of formula (I) with constrained substituents and indices
A compound of formula (I) in which R1 and R2 independently represent a hydrogen atom, an SO3H group or a hydroxyl group; multiple substituent positions are defined by hydrogen, alkyl, aryl, and nitrogen-containing heterocyclic options; indices n, m, o, s, and t are restricted to specified values; and stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof are included.
Enumerated bile-acid derivative amide compounds and salts
A compound chosen from a specified list of bile-acid derivative amides, including deoxycholamide, cholamide, chenodeoxycholamide, ursodeoxycholamide, and related spermino, norspermino, norspermidino, spermidino, piperazine, and polyamine-substituted variants, including a 50/50 mixture of two named compounds, or a pharmaceutically acceptable salt thereof.
Limited enumerated set of bile-acid derivative amide compounds and salts
A compound chosen from a smaller specified list including 3β-norspermino-N-isopropyldeoxycholamide, 3β-norspermidino-N-isopropyldeoxycholamide, 3β-norspermidino-N-isopropylcholamide, 3β-norspermidino-N,N-diethylchenodeoxycholamide, 3β-norspermidino-N-isopropylursodeoxycholamide, 3β-spermino-N-methyldeoxycholamide, and 3β-spermino-N,N-diethylchenodeoxycholamide.
Method for potentiating antibiotic activity using a formula (I) compound
A method for potentiating the antibiotic activity of antibiotic compounds selected from ampicillin, erythromycin, and chloramphenicol, comprising administration of an effective amount of a compound according to formula (I), including stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof.
Across the independent claims, the coverage is anchored on formula (I) bile-acid-derived compounds with specified substituent options and index ranges, is supplemented by multiple independent claims that enumerate specific named bile-acid derivative amides including a defined mixture, and includes a method claim that potentiates antibiotic activity of ampicillin, erythromycin, and chloramphenicol.
Stated Advantages
Intrinsic antibacterial activity, including improved antibacterial activity versus Gram+ and Gram−.
Antibiotic potentiation and synergism with doxycycline, ampicillin, erythromycin, and chloramphenicol.
Antifungal efficacy on Candida albicans and other strains as measured by MIC and IC50.
Lower cytotoxicity than squalamine.
Better chemical stability than earlier ester-containing disclosures.
Reduced resistance emergence due to a different mechanism.
Documented Applications
Treatment of bacterial and fungal infections in humans and animals by administering a compound of formula (I) in an effective amount.
Pharmaceutical or veterinary compositions comprising the compound of formula (I) with pharmaceutically acceptable excipients, optionally including an antibiotic.
Medical device coating and biofilm prevention.
Medicaments for preventing, inhibiting, or treating bacterial, fungal, viral, or parasitic infections in humans and animals.
A method for potentiating the antibiotic activity of ampicillin, erythromycin, and chloramphenicol by administering an effective amount of a compound according to formula (I).
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