Compounds that are analogs of squalamine, used as antibacterial agents
Inventors
Brunel, Jean-Michel • MARC, Jean-Pascal
Assignees
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Publication Number
US-10729701-B2
Publication Date
2020-08-04
Expiration Date
Abstract
The invention relates to compounds of formula (I), to the pharmaceutical compositions comprising same, and to the use thereof in the treatment of bacterial, fungal, viral and parasitic infections or in the treatment of cancer in humans or animals. In formula (I), R1 and R2 are as defined in claim 1.
Core Innovation
The invention relates to squalamine analogs, including stereoisomers and pharmaceutically acceptable salts, based on an amphiphilic polyaminosterol scaffold. The compounds are defined by constrained substituent choices for R1, R2, X, Y, R3-R14, and integer parameters m, n, o, p, q, r, and s, with explicit exclusion of 3β-(norspermino)-7α-hydroxy-5α-cholestane and compounds having a further specified formula.
The compounds of formula (I) are presented for treating disease in a human or animal by administering a compound of formula (I). The disease is selected from bacterial infections, fungal infections, parasitic infections, dental infections, mastitis, metritis, pyodermatitis, and otitis, and the disclosure also includes use for cancer treatment.
The document further describes aminosteroidal derivatives prepared from cholesterol-derived intermediates, with reductive amination of a formula (II) compound with an amine R2NH2. Downstream processing includes isolation and purification and handling of stereoisomers, and the partial content provides named stereodefined products SA-1 to SA-12.
Claims Coverage
The independent claim coverage centers on administering a compound of formula (I) to treat a selected disease in a human or animal, with detailed substituent and integer-parameter definitions. Three inventive features are identified across the independent-claim content, including the treatment method, the defined compound of formula (I), and explicit exclusions of specified steroidal embodiments.
Treating a selected disease via administration of a compound of formula (I)
A method of treating a disease in a human or animal by administering a compound of formula (I) with R1-R14, X and Y, and integer parameters m, n, o, p, q, r, s defined according to the claim, where the disease is selected from bacterial infections, fungal infections, parasitic infections, dental infections, mastitis, metritis, pyodermatitis, and otitis.
Formula (I) defined by constrained substituent choices and integer parameters
The compound of formula (I) is defined with R1 chosen from H, SO3H, a C1-C8 alkyl group, a C6-C10 aryl group or a C(=O)R13 group; R2 having the form [(CR3R4)m-(X)p-(CR5R6)n-[(Y)-CR7R8]o]q-NR9R10; and with R3-R8 chosen independently from H, C1-C8 alkyl, C6-C10 aryl, and C(=O)OR14, together with R9 and R10 chosen from H, C1-C8 alkyl or a —(CH2)r—NH2 group or together forming a 5- to 7-membered heterocyclyl group optionally substituted by one to three R14 groups. X and Y are independently chosen from NR13, O, or a 5- to 6-membered nitrogenous heterocyclyl group, R11 and R12 are independently chosen from C1-C8 alkyl or C6-C10 aryl, and R13 is H, a C1-C6 alkyl group or a —(CH2)s—NH2 group, with R14 being a —O or —S group; m, n, o, p, q, r, and s are integers within specified ranges.
Excluding specified steroidal compounds and specific formula embodiments
The compound of formula I excludes 3β-(norspermino)-7α-hydroxy-5α-cholestane and compounds having the formula provided in the claim, including preferred exclusion constraints involving p=1 and q=0 together with m=3 and n=3 or 4 and X=NH, and conditional non-equality rules for m+n or m+n+o relative to 6 and 7.
Overall, the claim coverage is anchored on administering a defined squalamine-analog compound of formula (I) with strict substituent and parameter constraints, while excluding specified steroidal embodiments. The treatment scope is based on a defined disease list for human or animal use.
Stated Advantages
Improved antibacterial activity versus earlier analogs (e.g., IIc/IId).
Reduced cytotoxicity versus earlier analogs (e.g., IIc/IId).
Synergy with conventional antibiotics.
Intrinsic antibacterial activity measured by MICs for SA-1 to SA-6 and related formula (I) examples versus prior-art compounds.
Reduced cytotoxicity and/or comparative cytotoxicity shown by CHO-K1 IC50 comparisons.
Antibiotic potentiation demonstrated by restored MIC behavior with doxycycline and chloramphenicol at reduced antibiotic doses.
Documented Applications
Treatment of bacterial infections, fungal infections, parasitic infections, dental infections, mastitis, metritis, pyodermatitis, and otitis in humans or animals, using compounds of formula (I).
Animal bacterial indications including mastitis, metritis, dental infections, pyodermatitis, and otitis.
Combination therapy with conventional antibiotics.
Parasitic indications, including malaria and toxoplasmosis.
Viral applications, including FIV and FIP.
Cancer treatment.
Intrinsic antibacterial evaluation of named aminosteroidal examples SA-1 to SA-6 and related formula (I) examples versus prior-art formula (II) compounds, with MIC measurements.
Cytotoxicity evaluation in Chinese hamster ovary cells (CHO-K1) via IC50 comparisons.
Antibiotic potentiation evaluation showing synergy with doxycycline and chloramphenicol, with MIC restoration at reduced antibiotic doses.
Biofilm-destroying products.
Antiparasitic potentiation.
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