COMPOUNDS FOR TREATMENT OF HEPACI VIRUS INFECTION AND METHOD FOR DETERMINING THERAPY OF HEPACI VIRUS INFECTION, IN PARTICULAR, HCV INFECTION

Title:

COMPOUNDS FOR TREATMENT OF HEPACI VIRUS INFECTION AND METHOD FOR DETERMINING THERAPY OF HEPACI VIRUS INFECTION, IN PARTICULAR, HCV INFECTION

Document Type and Number:

WIPO Patent Application WO/2020/127211

Kind Code:

A3

Abstract:

In a first aspect, the present invention relates to new compounds based on diphenylpiperazine and diphenylpiperidine structures. In particular, the present invention provides new flunarizine derivatives having improved hepaci virus infection inhibitory activity. In a further aspect, the present invention relates to a pharmaceutical composition containing said compound as well as the use of said pharmaceutical composition and the compounds according to the present invention in preventing or treating hepaci virus infection, in particular, HCV virus infection, like HCV of genotype 2. Moreover, a method for determining effectiveness of prophylactic or therapeutic treatment of hepaci virus, like HCV infection as well as a method for determining the therapy regimen of an individual afflicted with hepaci virus infection including HCV infection is provided. Said method is based on determining the sequence or interfacial hydrophobicity of the hepaci virus E1 protein. This may include determining the presence of mutations at predetermined positions of the E1 sequence. Based on determining the interfacial hydrophobicity of the E1 protein, the sensitivity to a diphenylpiperazine or diphenylpiperidine based hepaci virus inhibitor as well as a phenothiazine and cycloheptenepiperidine based hepaci virus inhibitor can be determined. When the central hydrophobicity region is disrupted or the hydrophobicity is below zero applying the Wim ley-White hydropathy plot, or the mutations at positions 290, 299, 301 and 310 of SEQ ID No. 1 are present, it is submitted that the sensitivity against said compounds is reduced. Hence, it is possible to determine the therapy regimen of an individual afflicted with hepaci virus infection or being a risk of being afflicted with hepaci virus infection, in particular HCV infection like HCV genotype 2 infection.

Inventors:

PIETSCHMANN THOMAS (DE)
BANDA DOMINIC (BE)
KIRSCHNING ANDREAS (DE)
SOLODENKO WLADIMIR (DE)

Application Number:

PCT/EP2019/085576

Publication Date:

July 30, 2020

Filing Date:

December 17, 2019

Export Citation:

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Assignee:

UNIV HANNOVER GOTTFRIED WILHELM LEIBNIZ (DE)
TWINCORE ZENTRUM FUER EXPERIMENTELLE UND KLINISCHE INFEKTIONSFORSCHUNG GMBH (DE)

International Classes:

C07D229/02; A61P31/14; C07D249/06; C07D295/096; C07D295/135

Domestic Patent References:

WO1997026252A1

1997-07-24

Foreign References:

EP0187639A1	1986-07-16
EP0266549A1	1988-05-11
FR2159369A1	1973-06-22

Other References:

CHUN-HE BAO ET AL: "Synthesis of derivatives of flunarizine", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 22, no. 5, 1 January 1991 (1991-01-01), pages 211 - 212, XP055589096, DOI: 10.16522/j.cnki.cjph.1991.05.010
HIROSHI OHTAKA ET AL: "Design and Syntheses of Vinylogs of 1-Benzy1-4-diphenylmethylpiperazine Derivatives and Their Cerebral Vasodilating Activities", CHEM. PHARM. BULL, 1 January 1987 (1987-01-01), pages 4124 - 4129, XP055588038, Retrieved from the Internet [retrieved on 20190513]
SATORU KARIYA ET AL: "Oxidative Metabolism of Flunarizine and Cinnarizine by Microsomes from B-Lymphoblastoid Cell Lines Expressing Human Cytochrome P450 Enzymes.", BIOL. PHARM. BULL., vol. 19, 1 January 1996 (1996-01-01), pages 1511 - 1514, XP055588033, DOI: doi.org/10.1248/bpb.19.1511
PAULA M. PERIN ET AL: "Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1 : PERIN ET AL.", HEPATOLOGY, vol. 63, no. 1, 9 October 2015 (2015-10-09), pages 49 - 62, XP055588129, ISSN: 0270-9139, DOI: 10.1002/hep.28111