Piperidine derivatives as human papilloma virus inhibitors
Inventors
Blumenfeld, Marta • Compere, Delphine • Gauthier, Jean-Michel
Assignees
Publication Number
US-9452991-B2
Publication Date
2016-09-27
Expiration Date
2027-05-18
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Abstract
HPV inhibitors with formula (I) where G1 represents a hydrocarbonated bond or chain possibly substituted by one or two alkyl groups, G2 represents a group (see formula Ia+Ib) or R represents a hydrogen, an alkyl, halogenoalkyl, or a prodrug radical such as carbamate, acetyl or dialkylaminomethy, G represents a bond or a hydrocarbonated chain possibly substituted by one or two alkyls, W represents an oxygen or sulphur, R1 and R2 each represent a group chosen from among hydrogen, halogen, hydroxyl, thio, alkoxy, halogenoalkoxy, alkylthis, halogenoalkylthio, amino, monoalkylamino, dialkylamino, cycloalkyl, alkyl or halogenoalkyl, R3 represents an acid or a prodrug radical of the acid function or a bioisotere of the acid function, A represents an aryl, cycloalkyl, cycloalkenyl or a heterocycle with 6 chains, each possibly substituted, and pharmaceutically acceptable salts.
Core Innovation
The invention relates to novel antiviral compounds targeted against papilloma virus, particularly compounds of formula (I) and their pharmaceutical compositions. These compounds, including their preferred and more preferred derivatives, are designed to treat or prevent infections caused by human papilloma virus (HPV), with emphasis on low-risk types such as HPV6 and HPV11. The compounds are characterized by specific structural features, including a range of defined substituents and functional groups that provide the desired antiviral activity.
The problem addressed by the invention is the lack of specific antiviral treatments that target HPV replication. Existing therapies, such as procedures for physical destruction or application of cytotoxic and immunomodulatory agents, do not completely eliminate viral particles and are associated with recurrence and adverse effects. The invention aims to overcome this deficiency by proposing small molecules that inhibit replication of HPV by interfering with the formation of the E1/E2 protein complex, which is required and sufficient for HPV DNA replication.
The compounds disclosed in this invention are shown to inhibit interaction between HPV E1 and E2 proteins and thereby block viral genome replication in human cells. Pharmaceutical compositions containing these compounds can be formulated for various administration routes, including topical, oral, and parenteral methods, to treat or prevent diseases and lesions associated with HPV infection, such as anogenital warts, papillomas, and intra-epithelial neoplasias.
Claims Coverage
The patent includes two main independent inventive features relating to the treatment of HPV6 or HPV11 infection using specific piperidine-containing compounds and their application for treating HPV-related lesions.
Method for treating HPV 6 or HPV 11 infection with compounds of formula (I)
A method comprising administration to a patient in need thereof of an efficient quantity of a compound of formula (I): - The compound of formula (I) as defined in the specification, with G1 representing a bond or a saturated or unsaturated hydrocarbon chain comprising 1-4 carbon atoms, possibly substituted, and other structural and substituent requirements as detailed. - The method includes, but is not limited to, using any one of the compounds specifically enumerated in the claims (such as 5-bromo-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride and others listed in claim 3 and claim 10). - The method further encompasses a range of structural variations and preferred substituents for A, B, and other positions as elaborated in claim 2.
Treatment of lesions associated with HPV infection using the compounds
A method wherein the patient being treated has a lesion associated with infection by the papilloma virus, including but not limited to: - An ano-genital wart, laryngeal, conjunctive or buccal papilloma, or epithelial lesion. - The ano-genital wart can be an acuminated condyloma or plane condyloma. - The epithelial lesion can be recurrent respiratory papillomatoses, low grade or high grade intra-epithelial neoplasia, bowenoid papulosis, wart, epidermodysplasia verruciformis, carcinoma, or another lesion associated with the papilloma virus. - The wart includes, for example, verruca vulgaris, verruca plantaris, myrmecia wart, surface wart, or verruca plana. - The carcinoma includes, for example, ano-genital carcinoma.
The claims principally protect methods for treating HPV 6 or HPV 11 infections by administering specified piperidine-containing compounds, and further extend this coverage to treating a variety of HPV-associated lesions using these compounds.
Stated Advantages
The compounds inhibit replication of papilloma virus dependent on E1 and E2 interaction, effectively blocking viral genome replication in human cells.
The invention addresses the need for new strategies for controlling or eliminating infections by papilloma viruses, which current approaches fail to achieve due to recurrence and incomplete viral clearance.
Pharmaceutical compositions containing these compounds can be administered by numerous routes, accommodating a variety of clinical needs and patient populations.
Documented Applications
Treatment or prevention of infection by papilloma virus, especially HPV6 and HPV11, in humans.
Treatment or prevention of lesions and diseases associated with papilloma virus infections, including anogenital warts (acuminated condylomas and plane condylomas), laryngeal, conjunctive or buccal papillomas, respiratory recurrent papillomatoses, intra-epithelial neoplasias (low and high grade), bowenoid papuloses, warts (verruca vulgaris, verruca plantaris, myrmecia wart, surface warts, verruca plana), epidermodysplasia verruciformis, carcinomas (including anogenital carcinomas), and all lesions associated with the papilloma virus.
Preparation of pharmaceutical compositions for various routes of administration including topical, oral, and parenteral use.
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