HK1243350A1

HK1243350A1 - Quinoline derivatives for use in the treatment or prevention of viral infection

Info

Publication number: HK1243350A1
Application number: HK18102964.8A
Authority: HK
Inventors: D．谢雷; A．加尔塞尔; N．坎波斯; J．塔泽; A．魏特琳; F．马于托; R．纳日曼; P．弗尔娜莱利
Original assignee: Abivax公司; 国家科研中心; 居里研究所; 蒙彼利埃大学
Priority date: 2015-02-23
Filing date: 2016-02-19
Publication date: 2018-07-13

Description

Quinoline derivatives for the treatment or prevention of viral infections

Technical Field

The object of the present invention is to reduce the viral load in patients infected with viruses, in particular HIV or virus-related conditions, which have a long lasting effect and are not resistant.

The invention also relates to novel dosing and regimens of said quinoline derivatives and use in the treatment or prevention of viral infections and in particular HIV or virus-related conditions, more in particular wherein said use maintains a low viral load after termination of treatment.

The invention also relates to the identification of quinoline derivatives that are effective in treating or preventing patients infected with viruses, particularly HIV or virus-related conditions, where ineffectiveness or a decrease in the effectiveness of previous anti-HIV treatments has been reported.

The invention also relates to the identification of quinoline derivatives which are effective in treating or preventing patients infected with viruses resistant to classical antiviral drugs, in particular HIV.

Background

Replication of the virus involves the formation of the virus during the infection process within the target host cell, including translation of viral RNA by endogenous machinery.

Identifying compounds for treating or preventing viral infections or virus-related conditions in patients brings about the development of new therapies.

One of the drawbacks of current treatments for viral infections and in particular HIV infections is that once the drug is discontinued, the virus begins to multiply again, which for the patient usually means a daily treatment for a lifetime.

Among virus-related conditions, AIDS has developed as a worldwide pandemic. Over 3 million people are infected with Human Immunodeficiency Virus (HIV). Current therapies have successfully controlled the disease, but long-term use of antiretroviral therapy (ART) is limited because of the cyclic nature of viral replication of those viruses but is also a problem with side effects.

Furthermore, those compounds do not necessarily inhibit the replication of viral strains harboring mutations for long periods of time, which are prone to lead to the development of resistant strains and which are also involved in the rebound of viral infections in otherwise treated patients.

Especially for HIV infection, current ART drugs need to be taken for a lifetime and only alleviate, rather than cure, the disease. One reason is that current Human Immunodeficiency Virus (HIV) therapy reduces viral load during treatment, but titers rebound after treatment interruption, which is one of the consequences of viral latency.

Alternative methods to ART have been proposed, including the combination of 3 TC-tenofovir-raltegravir and AZT (HAART).

Highly active antiretroviral therapy (HAART) has been developed, which has dramatically altered the prognosis of HIV infection based on a combination of HIV protease and reverse transcriptase inhibitors. As a result, HIV is considered a chronic disease in developed countries. However, long-term use of HAART is limited by problems of drug resistance and side effects.

For example, it has been observed that a new class of anti-HIV/AIDS drugs such as raltegravir(integrase inhibitors) and Enfuvirtide(entry inhibitor) resistance.

Explaining the causes of rebound viral infections in previously treated patients include:

(i) many viruses, including retroviruses such as HIV or DNA viruses of the Herpesviridae family (Herpesviridae), are characterized by viral latency, which is the ability of the virus to hibernate in the cell, thereby defining the lysogenic part of the viral life cycle. Latency is a phase of the viral replication cycle in which the proliferation of viral particles ceases but is not completely eradicated after initial infection. Viral latency is associated with the appearance of so-called "reservoirs" within the host, which are generally difficult to reach and which are one of the major reasons for the difficulty in providing a cure for HIV;

(ii) resistant strains emerge, particularly for viral infections that require long-term treatment. The possibility of the emergence of mutant strains is of particular importance for retroviruses, including HIV. Indeed, resistance to anti-HIV drugs can be explained at the biological level as follows. As a retrovirus, HIV uses reverse transcriptase to genetically synthesize DNA from its RNA and lacks a mechanism to correct errors in its genome replication. As a result, HIV genome replication has the highest known mutation rate in any 'living' organism. This constitutes an ideal case for natural selection to act on HIV populations, since genetic changes are the material of natural selection.

These mutations accumulate with generation in the population, causing significant genetic alterations in the HIV population, and an increased likelihood that virions will develop an evolutionary selective advantage over other virions. Natural selection then acts on HIV by selecting a more adaptive virion, since all other virions are eventually killed by drug therapy. Viral particles capable of escaping the deleterious effects of the drug then form a whole new drug resistant population.

As a result of the decreased effectiveness of previous treatments, virions replicate until patients have an increased, detectable viral population, e.g., the same size population as before treatment. This forms a cycle in which patients, particularly HIV positive patients, first experience success from treatment because:

its viral load is controlled or even reduced;

its CD4+ cell count level is maintained or even restored; and/or

The clinical signs typically associated with virus-related conditions such as AIDS stabilize or even disappear. The clinical signs of AIDS vary depending on the stage of infection.

Then over time, those patients may experience a decline in the effectiveness of the treatment as the virus develops resistance and reconstitutes its viral particle population.

In particular, this phenomenon is enhanced against HIV treatment for at least three reasons, including:

(i) HIV is a retrovirus, and the emergence of new mutant lines as described above is particularly important for this class of viruses;

(ii) HIV has the ability to enter the stealth phase and thereby form a "stealth" pool that cannot be effectively targeted by currently available therapies;

(iii) currently available treatments also tend to select HIV mutant strains over time, which have a major role in the emergence of drug resistance over the long term.

There is therefore a need for compounds that bring about a long lasting reduction in viral load after termination of treatment.

There is also a need for compounds that produce long-lasting therapeutic effects on viral load after treatment is terminated.

There is also a need to provide compounds that can be administered in a shorter period of time or at longer intervals than standard treatments, providing the ability to reduce health care costs and provide a wider range of treatment possibilities.

In particular, there is a continuing need for new drugs, especially those that act through new and unexplored mechanisms of action, to achieve infection control or cure in patients in whom a decline in the effectiveness of previous treatments has been reported and because of the formation of mutant forms resistant to the treatment.

There is thus also a need to find and optimize therapeutic approaches for treating or preventing patients, in particular HIV-positive patients, infected with viruses that exhibit resistance to classical therapies.

Some quinoline derivatives have recently been described in the following patent applications: WO2010/143169, WO2012080953, EP14306164 and EP14306166 for use in the treatment of AIDS or inflammatory diseases.

Summary of The Invention

The present invention relates to quinoline derivatives of formula (I) or any pharmaceutically acceptable salt and metabolite thereof as defined below, for use in the treatment or prevention of a viral infection, in particular an HIV infection or an HIV-related condition in a patient; the treatment was then terminated under the following conditions: low or undetectable viral load; and/or CD4+ cell count levels are maintained or restored.

The present invention also relates to quinoline derivatives of formula (I) or any pharmaceutically acceptable salt and metabolite thereof as defined below, for use in the treatment or prevention of a viral infection, in particular an HIV infection or an HIV-related condition in a patient, wherein a failure of a previous antiretroviral therapy or a decrease in the effectiveness of a previous antiretroviral therapy has been reported.

The present invention also relates to quinoline derivatives of formula (I) or any pharmaceutically acceptable salt and metabolite thereof as defined below, for use in the treatment or prevention of a viral infection, in particular an HIV infection or an HIV-associated condition, in a patient infected with a drug-resistant viral strain and in particular a drug-resistant HIV strain.

Brief Description of Drawings

FIG. 1 potency of quinoline derivatives to inhibit HIV-1 production in PBMC-and macrophage-infected cells. A) HIV-1 strain Ada-MR5 was used to repeatedly infect activated PBMCs from different donors (2 days stimulation with PHA and IL 2) in the absence or presence of increasing concentrations of compound 22, as defined below and more particularly in Table A. Supernatants were harvested 6 days post infection (pi) and viral capsid protein p24 antigen was quantified using standard ELISA protocols. Each dot represents 6 donors. B) HIV-1 strain YU2 was used to repeatedly infect monocyte-derived-macrophages from different donors in the absence or presence of increasing concentrations of compound 22. The supernatants were harvested at day 8 pi and viral capsid protein p24 antigen quantified using standard ELISA protocols. Each dot represents 8 donors.

FIG. 2. Compound 22 inhibits HIV p24 in different HIV-1 strains. A) Different HIV-1 lines (clade B, clade C and recombinant clade) were used to infect PBMC from 3 different donors in the absence or presence of 5 μ M compound 22. The supernatants were harvested at 6 days pi and the viral capsid protein p24 antigen quantified using standard ELISA protocols. B) RT activity (cpm) was measured in human PBMCs (K103N, K65R and M184V) infected with different resistance mutants of the NL4.3 line and treated with compound 22 or 3 TC.

Figure 3. efficacy of compound 22 in inhibiting viral replication in humanized mice. A) Reconstituted SCID mice were infected with JRCSF HIV-1 strain by intraperitoneal injection. The control group received labrafil and 5% DMSO (n-15) by gavage, while the treatment group received 20mg/kg b.i.d. compound 22/labrafil and 5% DMSO (n-14) for 15 days. Two independent experiments were performed with 5 and 10 reconstituted mice for each group. Viral load was assessed by measuring viral RNA using the Amplicor HIV-1 monitor from Roche. B) FACS analysis of peritoneal washes was performed on day 15 post-treatment to assess CD8/CD4 ratios. C) Transplanted NSG humanized mice were treated for 30 days by oral gavage of 20mg or 40mg/kg of compound 221 time per day and indicated lymphocyte populations (CD45 +; CD4+ and CD8+) were monitored by FACS analysis. D) NSG humanized mice were infected with YU2HIV-1 virus and treated for 30 days by oral gavage of 40mg/kg compound 221 time per day or by HAART (3 TC-tenofovir-raltegravir and AZT). For HAART food pellets the following was prepared: 2.5g each of 3TC, TDF and AZT, and 5g of RTV, and 5kg of ground protein-rich, vitamin-fortified food product (Nafag3432, Provimi Kliba AG, Switzerland) were mixed, which was subsequently formed into food pellets and sterilized by 25kGy of gamma-irradiation. Viral load was assessed by measuring viral RNA using the Amplicor HIV-1 monitor from Roche.

Detailed Description

The present invention has the object of meeting the aforementioned needs.

In the examples herein, it is shown that the quinoline derivatives of the present invention reduce HIV replication in HIV-infected mammals.

More particularly, the quinoline derivatives are shown herein to (i) reduce HIV-1 viral load in HIV-infected mammals, (ii) maintain or restore high CD4+ cell count levels in HIV-infected mammals.

The inventors also provide evidence that those quinoline derivatives have long-term therapeutic effects in patients and are suitable for the treatment or prevention of viral infections or virus-related conditions.

As used herein, "patient" can be extended to humans or mammals, such as cats or dogs. As used herein, "preventing" also encompasses "reducing the likelihood of presence" or "reducing the likelihood of relapse".

Without being bound by any particular theory, the inventors believe that such quinoline derivatives have the unexpected property of targeting latent viral reservoirs, particularly latent HIV reservoirs.

In addition, the above compounds have a broad spectrum of action, but are not liable to bring about the development of resistant strains and do not cause adverse effects. The key is that there is no or reduced or delayed viral load rebound for at least 2 months after cessation of treatment, whereas viral load dramatically increases after only 1 week of cessation of ART treatment. In other words, the inventors provide evidence that the quinoline derivatives of the invention are able to maintain a low viral load when administered to HIV-infected patients, even after termination of treatment. Thus, the compounds may also be administered less frequently and/or over a shorter period of time than standard treatments.

The above compounds are particularly suitable for treating or preventing viral infections or virus-related conditions in treatment-resistant individuals, particularly individuals infected with a resistant HIV-strain, including HAART-resistant and ART-resistant individuals.

In particular, the above-described methods are particularly suitable for treating or preventing viral infections or virus-related conditions, for example in lamivudine (3TC) -resistant, tenofovir-resistant, raltegravir-resistant and Azidothymidine (AZT) -resistant individuals.

As used herein, "antiretroviral" or "antiretroviral therapy" or more specifically "anti-HIV drug" or "anti-HIV therapy" means the administration of a classical drug or combination of drugs that combat viral infections, particularly HIV infections. It may be especially ART (antiretroviral therapy) or HAART (highly active antiretroviral therapy).

ART and HAART are known in the ART and generally involve the combination of two, three or more antiretroviral drugs. The antiretroviral drugs encompass:

(i) nucleoside/nucleotide reverse transcriptase inhibitors, also known as nucleoside analogs such as abacavir, emtricitabine and tenofovir;

(ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, etravirine and nevirapine;

(iii) protease Inhibitors (PIs), such as atazanavir, darunavir and ritonavir;

(iv) entry inhibitors such as enfuvirtide and maraviroc;

(v) integrase inhibitors such as dolutegravir and raltegravir.

Other examples of antiretroviral agents include, but are not limited to: zidovudine, lamivudine, emtricitabine, didanosine, stavudine, abacavir, zalcitabine, tenofovir, Racivir, amdoxovir, Apricitabine, efavirenz, nevirapine, etravirine, delavirdine, rilpivirine, tenofovir, Fosalvudine, amprenavir, tipranavir, indinavir, saquinavir, furinavir, ritonavir, darunavir, atavir, nelfinavir, lopinavir, retavir, Elvitegravir, Dolutegravir, enfuvirtide, maraviroc, virusol, and combinations thereof.

As used herein, "anti-HIV therapy" or "antiretroviral therapy" encompasses inter alia:

-the effect of anti-HIV drugs to reduce the viral load during a certain period of time, but not necessarily showing a long lasting reduction of the viral load after termination of the treatment;

the effect of anti-HIV drugs in HIV-infected patients to increase the level of CD4+ cell count, but do not necessarily show a long lasting increase or stabilization of the cell count after termination of the treatment.

The above compounds are particularly suitable for the treatment or prevention of viral infections or viral-related conditions, in particular HIV-infections or HIV-related conditions.

In addition, the above compounds are particularly suitable for treating potential viral infections, in particular HIV infections, in patients.

In addition, the above compounds are particularly suitable for eradicating viral infections or virus-related conditions, especially HIV-infections or HIV-related conditions, including eradication of HIV, and/or for curing HIV and HIV-related conditions in a patient.

In other words, these results allow the inventors to target a new class of viral infections and patients, including HIV-infected patients, who have had poor efficacy with previously available therapies, particularly patients infected with drug resistant strains and/or patients who no longer respond to the treatment.

The quinoline derivatives of the invention are useful in the treatment or prevention of all viral and viral-related conditions, and more particularly in the treatment or prevention of retroviruses, latent viruses and related conditions.

In particular, it has been found that one of the quinoline derivatives of formula (I) as defined below is capable of significantly reducing the viral load in HIV-infected mice in vivo after daily gavage, but more importantly, the compound is capable of maintaining a reduced viral load up to 50 days after termination of treatment compared to control or HAART-treated mice (see figure 4)

These unexpected results allow the inventors to devise dosing regimens suitable for achieving such long lasting reduced viral load and for treating patients infected with viruses, particularly HIV-infected patients, including patients who have reported a reduction in previous antiretroviral therapy, and corresponding methods of treatment.

According to a first embodiment, the present invention relates to quinoline derivatives of formula (I) as defined herein or any pharmaceutically acceptable salt and metabolite thereof for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition, in a patient, wherein: (ii) a low or undetectable viral load following termination of treatment; and/or CD4+ cell counts stabilize or increase.

According to said first embodiment, the present invention relates to quinoline derivatives of formula (I) as defined herein or any pharmaceutically acceptable salt and metabolite thereof for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition, in a patient, followed by termination of said treatment, wherein: (ii) a low or undetectable viral load following termination of treatment; and/or CD4+ cell counts stabilize or increase.

According to said first embodiment, the present invention relates to quinoline derivatives of formula (I) as defined herein or any pharmaceutically acceptable salt and metabolite thereof for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition, in a patient, followed by termination of said treatment, wherein: maintaining a low or undetectable viral load; and/or CD4+ cell count levels are maintained or restored.

Also according to said first embodiment, the present invention relates to quinoline derivatives of formula (I) or any pharmaceutically acceptable salt and metabolite thereof as defined herein for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition, in a patient, followed by termination of said treatment when the viral load in the plasma of said patient is undetectable.

According to a second embodiment, the present invention relates to quinoline derivatives of formula (I) or any pharmaceutically acceptable salt and metabolite thereof as defined below, for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition, in a patient, wherein a prior antiretroviral therapy inefficiency, or a prior antiviral or antiretroviral therapy effectiveness reduction, has been reported.

According to a third embodiment, the present invention relates to quinoline derivatives of formula (I) or any pharmaceutically acceptable salt and metabolite thereof as defined herein for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition in a patient, wherein the patient is infected with a drug resistant strain.

Virus

Examples of viruses contemplated by the present invention include, in a non-limiting manner, enveloped viruses and naked viruses, including DNA viruses, RNA viruses and retroviruses, including dsDNA viruses, ssDNA viruses, dsRNA viruses, (+) ssRNA viruses, (-) ssRNA viruses, ssRNA-RT viruses and dsDNA-RT viruses, including oncoviruses, lentiviruses and foamy viruses.

Oncoviruses are so named because they may be associated with cancer and malignant infections. Mention may be made, for example, of the leukemia viruses (such as the Avian Leukemia Virus (ALV), the murine leukemia virus (MULV), also known as moloney virus, the feline leukemia virus (FELV), the human leukemia viruses (HTLV) such as HTLV1 and HTLV2, the simian leukemia virus or STLV, the bovine leukemia virus or BLV, the primate type D oncoviruses, the type B oncoviruses as inducers of breast tumors, or the oncoviruses causing rapid cancer (such as the Rous sarcoma virus or RSV).

Foamy viruses exhibit a rather low specificity for a given cell type or a given species, and they are sometimes associated with immunosuppressive phenomena; this is for example simian foamy virus (or SFV).

Lentiviruses such as HIV are so named because they are responsible for a slowly progressing pathological condition, which is frequently involved in immunosuppressive phenomena, including AIDS.

Viruses and especially retroviruses such as HIV, HTLV-I and HTLV-II are known to rely on RNA splicing and splicing regulation for transmission and dissemination within cells and tissues of infected individuals. Other viruses of interest are human pathogenic viruses, including but not limited to viruses of the HSV family (including 1, 2, 6), CMV, VZV, HBV, HCV, hepatitis E virus, papilloma virus, RSV, rhinovirus (rhinovirus), influenza virus, adenovirus, EBV, Ebola, Nipah virus, and other arboviruses, dengue virus, chikungunya virus, West Nile virus, rift valley fever virus, Japanese encephalitis virus, SRAS other coronaviruses, parvovirus, enteroviruses.

Other viruses of interest are animal pathogenic viruses, including but not limited to influenza, FLV, pestiviruses, Hantavirus (Hantavirus), and Lyssavirus (Lyssavir).

In particular, contemplated viruses and virus-related conditions include viruses, which require RNA splicing for viral replication and/or export of viral RNA from the nucleus to the cytoplasm.

Examples of viruses include latent viruses and/or retroviruses and/or viruses associated with chronic viral infections.

More particularly contemplated viruses are RNA viruses and retroviruses, including lentiviruses and preferably HIV. Accordingly, more particularly contemplated virus-related conditions are associated with RNA viruses or retroviruses, preferably HIV.

HIV may include HIV-I, HIV-2 and all subtypes thereof, including HIV-I lines belonging to HIV-I B subtype, HIV-I C subtype, and HIV-I recombinants. Examples include lines of HIV-I selected from Ad8, AdaM, isolate B, isolate C, CRF01, CRF02 and CRF 06.

Typical resistant lines are more particularly described in Pinar Iyodogan et al ("Current Perspectiveson HIV-1Antiretroviral Drug Resistance", Virus 2014,6, 4095-4139; doi 10.3390/4095).

Advantageously, the virus may comprise an HIV-strain that has developed resistance to current treatments.

According to a preferred embodiment, the virus-related condition is AIDS.

Examples of viruses include latent viruses and/or retroviruses.

According to a preferred and exemplary embodiment, the virus is HIV, which includes HIV-1 and HIV-2, and the virus-related condition is AIDS.

A compound of formula (I)

The quinoline derivatives are preferably selected from the compounds disclosed in the following patent applications: WO2010/143169, WO2012080953, EP14306164 and EP 14306166.

The compounds may be prepared according to the synthetic routes described in said patent applications.

The quinoline derivatives of formula (I) according to the invention are compounds of formula (I):

wherein:

z represents N or C, and z represents N or C,

meaning an aromatic ring, wherein V is C or N and where V is N, V is ortho, meta or para to z, i.e. forms a pyridazine, pyrimidine or pyrazine group, respectively,

r independently represents a hydrogen atom, a halogen atom or a group selected from: -CN group, hydroxy, -COOR₁Radical (C)₁-C₃) Fluoroalkyl group, (C)₁-C₃) Fluoroalkoxy group, (C)₃-C₆) Cycloalkyl, -NO₂Group, -NR₁R₂Radical (C)₁-C₄) Alkoxy, phenoxy, -NR_1-SO_2-NR₁R₂Group, -NR_1-SO_2-R₁Group, -NR₁-C(＝O)-R₁Group, -NR₁-C(＝O)-NR₁R₂Group, -SO_2-NR₁R₂Group, -SO₃H group, -O-SO₂-OR₃A radical, -O-P (═ O) - (OR)₃)(OR₄) A group, -O-CH₂-COOR₃Group and (C)₁-C₃) An alkyl group, optionally mono-substituted with a hydroxy group,

q is N or O, with the proviso that R' is absent if Q is O,

R₁and R₂Independently is a hydrogen atom or (C)₁-C₃) An alkyl group, a carboxyl group,

R₃and R₄Independently represent a hydrogen atom, Li⁺，Na⁺，K⁺，N⁺(R_a)₄Or a benzyl group, or a mixture of benzyl groups,

n is 1, 2 or 3,

n' is 1, 2 or 3,

r' independently represents a hydrogen atom or a group selected from: (C)₁-C₃) Alkyl, halogen atom, hydroxy, -COOR₁group-NO₂Group, -NR₁R₂A radical, morpholinyl or morpholino, N-methylpiperazinyl, (C)₁-C₃) Fluoroalkyl group, (C)₁-C₄) Alkoxy and-CN groups, and can further be a group selected from:

a is a covalent bond, an oxygen atom or NH,

b is a covalent bond or NH,

m is 1, 2, 3, 4 or 5,

p is 1, 2 or 3,

ra and Rb independently represent a hydrogen atom, (C)₁-C₅) Alkyl or (C)₃-C₆) A cycloalkyl group,

ra and Rb can further form, together with the nitrogen atom to which they are attached, a saturated 5-or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O and S, said heterocyclic ring being optionally substituted by one or more Ra, with the proviso that in the case where R ' is a group (IIa) or (IIIa), n ' can be 2 or 3 with the proviso that the further R ' group is different from said group (IIa) or (IIIa),

r' is a hydrogen atom, (C)₁-C₄) Alkyl or is a group (IIa) as defined above,

or any of its pharmaceutically acceptable salts.

The invention also relates to active metabolites using the compounds of formula (I) as defined above, more particularly human metabolites thereof, such as N-glucuronide metabolites. In particular, the use of N-glucuronide of compound 22, or one of its pharmaceutically acceptable salts, is also encompassed within the framework of the claimed subject matter. The N-glucuronide metabolite has the formula

It is shown herein that those metabolites exhibit antiviral activity and more particularly anti-HIV activity. They can be administered as active ingredients themselves. N-glucuronide as described more particularly above can be prepared according to the synthetic route described in patent application EP 15305274.

According to a preferred embodiment, Q is N.

According to yet another preferred embodiment, n is 1 or 2.

According to a further preferred embodiment, n' is 1 or 2.

According to a further preferred embodiment, R' is a hydrogen atom, (C)₁-C₄) Alkyl radicals or radicalsWherein m is 2 or 3 and X₁Is O, CH₂Or N-CH₃。

According to a further preferred embodiment, R independently represents a hydrogen atom, a methyl group, a methoxy group, a trifluoromethyl group, a halogen atom, and more particularly a fluorine or chlorine atom, a trifluoromethoxy group and an amino group.

According to a further preferred embodiment, R' independently represents a hydrogen atom, a halogen atom, and more particularly a fluorine or chlorine atom, an amino group, a methyl group or a groupWherein A is O or NH, m is 2 or 3 and X₁Is O, CH₂Or N-CH₃Provided that in case R 'is a group as defined above, n' is 1 or 2, and in case n 'is 2, the other R' groups are different from said group.

According to one aspect of said preferred embodiment, R' alternatively independently represents a hydrogen atom, a halogen atom, and more particularly a fluorine or chlorine atom, a methyl group or a groupWherein A is O or NH, m is 2 and X₁Is O, CH₂Or N-CH₃Provided that in case R 'is a group as defined above, n' is 1 or 2, and in case n 'is 2, the other R' groups are different from said group.

All the above and below specific embodiments can of course be combined together and form part of the invention.

Compounds of formula (I) include compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie), as defined below.

According to a particular embodiment, the quinoline derivative of formula (I) may be a compound of formula (Ia)

Wherein R, R ', n and n' are as defined above.

According to an aspect of said preferred embodiment, n is 1 or 2.

According to one aspect of said preferred embodiment, n' is 1 or 2.

According to one aspect of said preferred embodiment, R independently represents a hydrogen atom, a halogen atom or a group selected from: hydroxy (C)₁-C₃) Fluoroalkyl group, (C)₁-C₃) Fluoroalkoxy, -NR₁R₂Radical (C)₁-C₄) Alkoxy and (C)₁-C₃) An alkyl group.

According to one aspect of said preferred embodiment, R' independently represents a hydrogen atom, a halogen atom or a group selected from: (C)₁-C₃) Alkyl, hydroxy, -NR₁R₂A group, or a groupWherein A is O or NH, m is 2 or 3 and X₁Is O, CH₂Or N-CH₃Provided that in the case where R' is the above groupIn the case where n ' is 1 or 2 and where n ' is 2, the other R ' groups are different from the group.

According to one aspect of said preferred embodiment, R' is a hydrogen atom, (C)₁-C₄) Alkyl radicals or radicalsWherein m is 2 or 3 and X₁Is O, CH₂Or N-CH₃And preferably R' is a hydrogen atom or a methyl group.

According to a particular embodiment, the quinoline derivative of formula (I) may be a compound of formula (Ib)

Wherein R, R ', n and n' are as defined above.

According to an aspect of said preferred embodiment, n is 1 or 2.

According to one aspect of said preferred embodiment, n' is 1, 2 or 3.

According to one aspect of said preferred embodiment, R' independently represents a hydrogen atom, a halogen atom or a group selected from: (C)₁-C₃) Alkyl, hydroxy, -NR₁R₂A group, or a groupWherein A is O or NH, m is 2 or 3 and X₁Is O, CH₂Or N-CH₃Provided thatIn the case where R 'is the above group, n' is 1 or 2, and in the case where n 'is 2, the other R' groups are different from the group.

According to an aspect of that preferred embodiment, R' alternatively independently represents a hydrogen atom, a halogen atom or a group selected from: (C)₁-C₃) Alkyl, hydroxy or-NR₁R₂A group.

According to a particular embodiment, the quinoline derivative of formula (I) may be a compound of formula (Ic)

Wherein R, R ', n and n' are as defined above.

According to an aspect of the preferred embodiment, n is 1.

According to an aspect of said preferred embodiment, n' is 1.

According to an aspect of that preferred embodiment, R alternatively independently represents a hydrogen atom or a halogen atom.

According toIn one aspect of said preferred embodiment, R' independently represents a hydrogen atom, a halogen atom or a group selected from: (C)₁-C₃) Alkyl, hydroxy, -NR₁R₂A group, or a groupWherein A is O or NH, m is 2 or 3 and X₁Is O, CH₂Or N-CH₃With the proviso that in the case where R 'is a group as defined above, n' is 1 or 2 and in the case where n 'is 2, the other R' groups are different from the said group.

According to an aspect of that preferred embodiment, R' alternatively independently represents a hydrogen atom or a halogen atom.

According to a particular embodiment, the quinoline derivative of formula (I) may be a compound of formula (Id)

Wherein R, R ', n and n' are as defined above.

According to an aspect of the preferred embodiment, n is 1.

According to an aspect of said preferred embodiment, n' is 1.

According to one aspect of said preferred embodiment, R represents, alternatively and independently, a hydrogen atom, (C)₁-C₃) Fluoroalkyl group, (C)₁-C₃) Fluoroalkoxy groups or halogen atoms.

According to one aspect of said preferred embodiment, R' independently represents a hydrogen atom, a halogen atom or a group selected from: (C)₁-C₃) Alkyl, hydroxy, -NR₁R₂A group, or a groupWherein A is O or NH, m is 2 or 3 and X₁Is O, CH₂Or N-CH₃With the proviso that in the case where R 'is a group as defined above, n' is 1 or 2 and in the case where n 'is 2, the other R' groups are different from the said group.

According to a particular embodiment, the quinoline derivative of formula (I) may be a compound of formula (Ie)

Wherein R, R ', n and n' are as defined above.

According to an aspect of the preferred embodiment, n is 1.

According to an aspect of said preferred embodiment, n' is 1.

According to an exemplary embodiment, the quinoline derivative may be selected from (see table a below for numbering):

- (1) 8-chloro-3-methyl-N-2- (4- (trifluoromethyl) pyridin-2-yl) quinoline-2, 5-diamine

- (2) 8-chloro-N-2- (4- (trifluoromethyl) pyridin-2-yl) quinoline-2, 5-diamine

- (3) 8-chloro-5- (2-morpholinoethoxy) -N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (4) 8-chloro-N4- (3- (piperidin-1-yl) propyl) -N-2- (4- (trifluoromethyl) pyridin-2-yl) quinoline-2, 4-diamine

- (5) 8-chloro-6- (2-morpholinoethoxy) -N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (6) 8-chloro-N-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (7) 8-chloro-N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (8)4, 8-dichloro-N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (9) 8-chloro-N- (3-morpholinopropyl) -N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (10) 8-chloro-5- (2- (piperidin-1-yl) ethoxy) -N- (4- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (11) (8-chloro-quinolin-2-yl) - (4-methyl) pyridin-2-yl) -amine

- (12) 8-chloro-N- (5-fluoropyridin-2-yl) quinolin-2-amine

- (13) N- (3-methoxypyridin-2-yl) quinolin-2-amine

- (14) N- (6- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (15) 6-chloro-N- (5-fluoropyridin-2-yl) quinolin-2-amine

- (16) N- (3-fluoropyridin-2-yl) quinolin-2-amine

- (17) 8-chloro-N- (6- (trifluoromethyl) pyridin-2-yl) quinolin-2-amine

- (18) 8-chloro-N- (3-chloro-4-methoxyphenyl) quinolin-2-amine

- (19) 8-chloro-N- (4- (methoxy) phenyl) quinolin-2-amine

- (20) 3-methyl-N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine

- (21) 8-chloro-N- (3- (piperidin-1-yl) propyl) -N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine

- (22) 8-chloro-N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine

- (23)4, 8-dichloro-N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine

- (24) 8-chloro-N-methyl-N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine

- (25) 8-chloro-N- (2-morpholinoethyl) -N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine

- (26) 8-chloro-N- (pyrazin-2-yl) quinolin-2-amine

- (27) 8-chloro-2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) quinoline

- (28)4- (2- ((8-chloro-2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) quinolin-6-yl) oxy) ethyl) morpholine

- (29) 8-chloro-2- (4- (trifluoromethoxy) phenoxy) quinoline

- (30)4- (2- ((8-chloro-2- (4- (trifluoromethoxy) phenoxy) quinolin-5-yl) oxy) ethyl) morpholine.

For the purposes of the present invention, quinoline derivatives of formula (I) include any of the compounds of formulae (Ia), (Ib), (Ic), (Id), and (Ie), and combinations thereof. Compounds of formula (I) include compounds (1) to (30), as defined in table a, and combinations thereof.

The compounds of the invention may exist as free bases or as addition salts with pharmaceutically acceptable acids.

Suitable physiologically acceptable acid addition salts of the compounds of formula (I) include the hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, methanesulfonate, formate, acetate and fumarate salts.

The compounds of formula (I) and or salts thereof may form solvates or hydrates and the present invention includes all such solvates and hydrates.

In short, the terms "hydrate" and "solvate" mean that the compound (I) according to the invention is capable of being in the hydrate or solvate form, i.e. combined or associated with one or more water or solvent molecules. This is merely a chemical feature of this compound that can be applied to all organic compounds of this type.

The compounds of formula (I) can contain one or more asymmetric carbon atoms. Thus, they can exist in enantiomeric or diastereomeric forms. These enantiomers, diastereomers and mixtures thereof (including racemic mixtures) are within the scope of the present invention.

In the context of the present invention, the term:

"halogen" is understood to mean chlorine, fluorine, bromine or iodine, especially chlorine, fluorine or bromine,

-"(C₁-C₅) Alkyl "as used herein refers to C independently₁-C₅Primary, secondary or tertiary saturated hydrocarbons. Examples are, but not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

-"(C₃-C₆) Cycloalkyl "as used herein refers to cyclic saturated hydrocarbons, respectively. Examples are, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

-"(C₁-C₄) Alkoxy "as used herein refers to O- (C) respectively₁-C4) alkyl moieties, wherein alkyl is as defined hereinbefore. Examples are, but not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy,

- "fluoroalkyl" and "fluoroalkoxy" mean, respectively, alkyl and alkoxy groups, as defined above, said groups being substituted by at least one fluorine atom. Examples are perfluoroalkyl groups such as trifluoromethyl or perfluoropropyl,

"saturated 5-or 6-membered heterocyclic ring" as used herein refers to a saturated ring comprising at least one heteroatom, respectively. Examples are, but not limited to, morpholine, piperazine, thiomorpholine, piperidine and pyrrolidine.

The chemical structures of certain compounds of formula (I) of the present invention are illustrated in Table A.

TABLE A

Treating drug-resistant patients and/or patients infected with resistant strains

According to one aspect of the invention, the present invention relates to quinoline derivatives of formula (I) as described above for use in the treatment or prevention of a viral infection or a virus-related condition in a patient, in particular a patient infected with HIV, wherein a decrease in the effectiveness of previous treatments has been reported.

As used herein, "prior or pretreatment" means that the patient is on anti-HIV therapy during any time period.

The consequences of ineffective or reduced effectiveness of previous treatments for HIV infection or HIV-related conditions in a patient generally consist of:

-an increase in HIV viral load; and/or

-a decrease in the level of CD4+ cell counts;

-an increase or the appearance of clinical signs generally associated with AIDS.

As used herein, "a decrease in effectiveness of a previous treatment has been reported" may refer to the emergence of resistant viral strains that are not resistant to anti-HIV drugs during the previous treatment.

In a non-limiting manner, a decrease in the effectiveness of a previous treatment in a patient may occur, for example, because of:

-the patient is infected with a viral strain, in particular an HIV strain, the replication and/or infectivity of which is considered stable or even reduced, but no longer responsive to therapy, including ART and HAART therapy; and/or

-the patient is infected with a drug resistant strain.

In particular, this definition covers pre-treated patients whose HIV viral load and/or CD4+ cell count level remain stable and/or decline, thereby establishing a reference value, and which show at least one of the following at the time of or after treatment:

-an increase in HIV viral load; and/or

-a decrease in the level of CD4+ cell counts;

wherein the HIV viral load and/or the CD4+ cell count level are preferably established in a plasma sample.

In this case, the report of the ineffectiveness or decline of the effectiveness of the previous treatment may be assessed by measuring the viral load, which increases above a detectable level, in particular in the case of treatment with an anti-HIV drug for consecutive weeks, such as at least 1 week or 2 weeks, in particular at least 3 weeks or 4 weeks; viral load is defined as follows.

Alternatively, the report of the ineffectiveness or decline in effectiveness of the previous treatment may be evaluated as follows: measuring CD4+ cell count in plasma, which again decreases to below 500/mm³Especially where the treatment with the anti-HIV agent is continued for a period of weeks, such as at least 1 or 2 weeks, especially at least 3 or 4 weeks; the CD4+ cell count is defined in more detail below.

Accordingly, the report of the ineffectiveness or decline in effectiveness of the previous treatment can be evaluated as follows: CD4+ cell counts were determined to decrease below physiological CD4+ cell counts.

For reference, the recovered CD4+ cell count may correspond to a physiological (or "normal") CD4+ cell count, which is generally equal to or greater than 500CD4+ cells/mm³Plasma, which varies generally from 500 to 1500CD4+ cells/mm³Plasma, although it may be lower for some individuals.

Alternatively, the recovered CD4+ cell count may correspond to an increase in CD4+ cell count compared to the CD4+ cell count in the patient prior to the treatment.

Correspondingly, low CD4+ cell counts included less than 500/mm³CD4+ cell count of plasma, including less than 450; 350 of (a); 300, respectively; 250 of (a); 200 of a carrier; 150 and 100/mm³Plasma.

According to one embodiment, the patient is infected with a drug resistant strain. The presence of resistant strains in patients may be the result of:

-selecting a drug resistant line from said patient after a previous treatment, as disclosed above; and/or

The patient is first infected with a drug resistant strain.

Because of the broad efficiency of the quinoline derivatives of the invention, it is now possible to provide new therapeutic strategies, even for patients who are first infected with otherwise untreatable strains.

As used herein, "HIV resistance" relates to the ability of HIV to mutate and replicate itself in the presence of antiretroviral drugs.

For reference, a "drug-resistant HIV strain" can be determined as follows: reverse Transcriptase (RT) activity in human PBMCs infected with the test lines is measured and then treated with a compound or combination of compounds suspected of resistance, as defined in example 1 and figure 2.

Accordingly, the patient does not necessarily have to be pre-treated with an antiviral treatment other than said quinoline derivative, including an antiretroviral treatment or even an anti-HIV-treatment.

Accordingly, the present invention also relates to a quinoline derivative of formula (I) as defined hereinbefore or any metabolite thereof for use in the treatment or prevention of an HIV infection or an HIV-associated condition in a patient, wherein: after termination of treatment, a low or undetectable viral load is maintained; and/or CD4+ cell count is stabilized or increased; and wherein the patient has not previously been treated by antiretroviral therapy.

Accordingly, the present invention also relates to any one of the quinoline derivatives of formula (I) or metabolites thereof as defined hereinbefore for use in the treatment or prevention of an HIV infection or an HIV-associated condition in a patient, wherein the patient is infected with a drug-resistant viral strain and in particular a drug-resistant HIV strain and wherein the patient has not previously been treated with antiretroviral therapy.

Examples of drug-resistant HIV strains are selected from: NL4.3 line mutants, including K103N (anti-efavirenz), K65R (anti-tenofovir and 3TC) and M184V (anti-3 TC) mutants, HIV-1B lines and selected from Ad8 and AdaM; and a clinical isolate selected from CRF01, CRF02, and CRF 06.

In particular, the viral strain may be a strain resistant to a drug or therapy comprising administration of a drug selected from ART and/or HAART therapy, and/or

(iii) protease Inhibitors (PIs), such as atazanavir, darunavir, and ritonavir;

(iv) entry inhibitors such as enfuvirtide and maraviroc;

(v) integrase inhibitors such as Dolutegravir and raltegravir;

and combinations thereof.

Accordingly, drug resistant HIV strains encompass NRTIs, NNRTIs, PIs, entry inhibitors and integrase inhibitor-resistant HIV strains.

Resistant strains are known in the art and include, in a non-limiting manner, strains carrying resistance mutations, as disclosed by the International antiviral Association-USA (IAS-USA) and the Stanford HIV drug database.

Typical resistant HIV strains include strains carrying resistance mutations selected from the group consisting of:

-M41; k65; d67; k70; l74; y115; m184 (including M184V/I); l210; t215; k219; as the major NRTI resistance mutation;

-M41; a62; d67; t69; k70; v75; f77; f116; q151; l210; t215; k219; as a multi-NTRI resistance mutation;

-V90; a98; l100; k101; k103; v106; v108; e138; v179; y181; y188; g190; h221; p225; f227; m230; as a major NNRTI resistance mutation;

-L10; v11; g16; k20; l24; d30; v32; l33; e34; m36; k43; m46; i47; g48; i50; f53; i54; q58; d60; i62; l63; i64; h69; a71; g73; l74; l76; v77; v82; n83; i84; i85; n88; l89; l90; i93; as a major protease inhibitor resistance mutation;

-T66; l74; e92; t97; e138; g140, Y143; s147; q148; n155; as a major integrase inhibitor resistance mutation;

-G36; i37; v38; q39; q40; n42; n43; as a major entry inhibitor resistance mutation; and combinations thereof.

It should be noted that a particular subclass of mutant/resistant lines (including point mutations such as the substitution of one nucleotide for another) are known in the art and are contemplated by the present invention.

Examples of drugs that have been found to be resistant to HIV strains include: zidovudine, lamivudine, emtricitabine, didanosine, stavudine, abacavir, zalcitabine, tenofovir, Racivir, amdoxovir, Apricitabine, efavirenz, nevirapine, etravirine, delavirdine, rilpivirine, tenofovir, Fosalvudine, amprenavir, tipranavir, indinavir, saquinavir, furinavir, ritonavir, darunavir, atavir, nelfinavir, lopinavir, retavir, Elvitegravir, Dolutegravir, enfuvirtide, maraviroc, virusol, and combinations thereof.

In particular, the HIV strains treated may be resistant to lamivudine (3TC), tenofovir, raltegravir, zidovudine (AZT), Nevirapine (NVP), Efavirenz (EFV) and combinations thereof.

Both uses and methods are contemplated within the meaning of the present invention.

The present invention also relates to uses and methods for treating or preventing viral infections, in particular HIV infections or HIV-related conditions in a patient, wherein: after termination of treatment, a low or undetectable viral load is maintained; and/or CD4+ cell count is stabilized or increased.

The invention also relates to uses and methods for treating or preventing viral infections, in particular HIV infections or HIV-related conditions, in a patient, wherein a reduction in the effectiveness of prior antiretroviral therapy has been reported.

The invention also relates to uses and methods for treating or preventing a viral infection, in particular an HIV infection or an HIV-associated condition, in a patient, wherein said patient is infected with a drug-resistant HIV strain.

The present invention also relates to the use and methods as defined hereinbefore for the preparation of a composition for the treatment or prevention of a viral infection, in particular an HIV infection or an HIV-related condition, in said patient.

Low viral load and maintained or restored CD4+ cell count after treatment termination

Viral load is a measure of the severity of viral infection. Viral load can be used to monitor viral infection, guide treatment, determine treatment effectiveness, and predict how a disease caused by infection may progress. Measuring viral load is particularly important for the treatment, prevention and follow-up of viral infections and virus-related conditions.

Within the framework of the present invention, "keeping the viral load low after termination of treatment" covers keeping the viral load below detectable levels, or alternatively delaying the increase of the viral load for at least 2 weeks compared to ART and/or HAART treatment.

As used herein, "viral load" also refers to "viral titer" and can be determined directly or indirectly. For reference, viral load refers generally to:

-viral RNA or DNA copy number per mL plasma sample;

-number of virus particles/mL plasma sample; and/or

-activity of virus-associated proteins in plasma samples.

As used herein, "HIV viral load" also refers to "HIV viral titer" and can be determined directly or indirectly. For reference, viral load refers generally to:

-HIV RNA copy number/mL plasma sample;

-HIV particle count/mL plasma sample; and/or

-activity of HIV-associated proteins in a plasma sample, which may for example comprise determining Reverse Transcriptase (RT) activity in said plasma sample.

For reference, a method of determining HIV viral load in a sample comprises:

-determining HIV RNA copy number/mL sample;

-determining HIV particle number/mL sample; and/or

-determining the activity of the HIV-associated protein in the sample.

In other words, the viral load remains at an undetectable level preferably for at least 2 weeks after termination of treatment, including at least 3, 4 or 5 weeks after termination of treatment, as compared to ART or HAART treatment.

The HIV viral load test is mainly used to monitor HIV infection over time. It is generally a quantitative measure of HIV nucleic acid (RNA) reporting how many copies of the virus are present in the blood.

Preferably and as used herein, "HIV viral load" relates to HIV RNA copy number per mL plasma. It is typically expressed as copies of HIV RNA/mL plasma according to known methods, including nucleic acid-based assays such as reverse transcriptase polymerase chain reaction (RT-PCR), branched DNA (bDNA), or nucleic acid sequence-based amplification (NASBA) assays.

Typically, HIV viral load tests are scheduled when a human first diagnoses. The assay results serve as baseline measurements showing viral replication activity. HIV viral load tests are then performed over time and compared to the baseline measurement or reference value in order to assess the relative change in HIV viral load.

Accordingly, conventional methods for determining HIV viral load include:

(i) providing a whole blood sample from a patient;

(ii) removing cells from the sample by centrifugation to provide plasma;

(iii) determination of HIV RNA copy number per ml plasma is carried out, for example, by reverse transcriptase polymerase chain reaction (RT-PCR), branched DNA (bDNA) or Nucleic Acid Sequence Based Amplification (NASBA) analysis.

(iv) (iv) optionally comparing the results obtained in step (iii) with reference values and/or baseline measurements.

If the subject has a high HIV viral load (e.g., at least 1,000 copies/ml plasma), this may indicate treatment failure, i.e., the virus is replicating and the disease may progress more rapidly. If the HIV viral load is low (e.g. below 500 copies/mL plasma), this indicates that the antiviral treatment regimen is effective, i.e. the virus may not be actively replicating and the disease may progress more slowly or even be cured.

Low viral loads are typically less than 500 copies/mL plasma; it includes 20 to 500 copies/mL plasma, or 40 to 500 copies/mL plasma, depending on the type and sensitivity of the assay used. The results indicate that HIV is not actively replicating and that the risk of disease progression is low.

A low viral load may be a viral load of less than 500 copies/mL; including less than 450, 400, 350, 300, 250, 200, 150, 100, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1 copies/mL.

The viral load undetectable by conventional methods is typically less than 40 copies/mL plasma, which includes 20 copies/mL plasma, especially when measured with a method and/or kit selected from the group consisting of:AmpliPrep/HIV-1 test andAMPLICOR HIV-1 monitoring assay, sold by Roche molecular Diagnostic, or NucliSENSHIV-1, marketed by Biomerieux Diagnostics.

However, an undetectable viral load in a patient diagnosed with HIV infection does not mean that the patient is cured; it simply means that HIV RNA levels are currently below the threshold required for detection. Furthermore, an undetectable viral load does not necessarily preclude the presence of HIV in potential depots.

The change in viral load during HIV monitoring is generally more important than obtaining a single test result. The increased viral load indicates that the infection becomes worse or that the virus has developed resistance to the drug used for treatment and that the drug is no longer effective. Reduced viral load indicates improvement, therapeutic efficacy and reduction of HIV infection.

More particularly, according to this aspect the invention relates to dosages and regimens of quinoline derivatives of formula (I) for the treatment or prevention of viral infections or virus-related conditions, especially HIV infections, in patients, wherein the viral load is kept low after termination of the treatment.

This means that the quinoline derivatives of formula (I) and more particularly the compound 22 or the N-glucuronide metabolite as defined hereinbefore exhibit a surprisingly long lasting therapeutic effect.

The present invention also relates to a method for treating or preventing viral infections or virus-related conditions, including HIV infections, in a patient, comprising administering to a patient in need thereof an effective amount of a quinoline derivative of formula (I) as described above, wherein the method makes it possible to maintain a low viral load after termination of the treatment.

According to certain embodiments, the present invention also relates to methods for treating viral infections or virus-related conditions, including HIV infections, in a patient, said method consisting of:

(i) administering to a patient in need thereof an effective amount of a quinoline derivative of formula (I), thereby treating the patient;

(ii) terminating the treatment;

(iii) optionally measuring the viral load and/or CD4+ cell count in the patient after termination of treatment; wherein preferably after termination of treatment:

-a low or undetectable viral load is maintained; and/or

-CD4+ cell count stabilizes or increases;

(iv) optionally re-administering to said patient in need thereof an effective amount of a quinoline derivative of formula (I) provided that the viral load is not low or undetectable and/or the CD4+ cell count is reduced.

Preferably, the conditions for termination of treatment are: low or undetectable viral load; and/or CD4+ cell count levels are maintained or restored.

For reference and as disclosed above, low viral loads are typically below 500 copies/mL plasma and undetectable viral loads are typically below 40 copies/mL.

For reference and as disclosed above, the recovered CD4+ cell count may correspond to a physiological (or "normal") CD4+ cell count, which is generally equal to or greater than 500CD4+ cells/mm³Plasma, and it is generally between 500 and 1500CD4+ cells/mm³Plasma changes, although they may be lower for some individuals.

Dosage and regimen

The present invention also relates to a method of reducing the viral load of an HIV virus and/or increasing the CD4+ cell count, wherein the virus causes a chronic viral infection and is resistant to an antiviral drug, said method comprising the steps of: administering to a host an effective amount of a quinoline derivative of formula (I) as hereinbefore defined, especially at various frequencies, in a dose in the range 25 to 500mg, especially 25 to 200mg, or even 25 to 300mg, and for example 25 to 150 mg.

According to one embodiment, the frequency of treatment may be 1 time per day, 1 time every 3 days, 1 time per week, 1 time every 2 weeks or 1 time per month.

According to a particular embodiment, the treatment is continuous or discontinuous.

By "continuous treatment" is meant long-term treatment that can be administered at various dosing frequencies, such as 1 time every 3 days, or 1 time per week, or 1 time every 2 weeks or 1 time per month.

The treatment period, i.e. in the case of non-continuous treatment, may vary from 2 to 8 weeks, including 2, 3, 4, 5, 6, 7 and 8 weeks.

According to one embodiment, the quinoline derivative of formula (I) or any of its pharmaceutically acceptable salts and metabolites is administered in a dose of 25 to 500mg, especially 25 to 300mg, such as 25 to 200mg and especially 25 to 150 mg. Dosages in the range of 25 to 500mg include dosages of about 25, 50, 75, 100 and 150 mg.

The dosage may be adjusted depending on whether the treatment is continuous or discontinuous.

All combinations of dose, frequency and treatment period are contemplated within the scope of the invention.

According to a particular embodiment, the quinoline derivatives of formula (I) and more particularly compound 22 according to the invention can be administered in various doses and schedules, and in particular as continuous therapy or 1 time a day during a period of treatment, in a dose range of 25 to 150mg, or 1 time every 3 days in a dose range of 25 to 150 mg.

The treatment period may be 2 to 8 weeks, especially 2 to 5 weeks.

The quinoline derivative may be administered daily, 1 time every 3 days, 1 time per week, 1 time every 2 weeks or 1 time per month.

Several examples of dosages and regimens are provided below.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered 25mg during the treatment period or as a continuous treatment every 3 days.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered 25mg 1 time per day during the treatment period or as a continuous treatment.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered at 50mg during the treatment period or as a continuous treatment every 3 days.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered 50mg 1 time per day during the treatment period or as a continuous treatment.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered at 75mg every 3 days during the treatment period or as a continuous treatment.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered at 75mg 1 time per day during the treatment period or as a continuous treatment.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered at 100mg during the treatment period or as a continuous treatment every 3 days.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered at 100mg 1 time per day during the treatment period or as a continuous treatment.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered 150mg during the treatment period or as a continuous treatment every 3 days.

More particularly, the present invention relates to dosages and schedules wherein the quinoline derivative of formula (I) according to the present invention and more particularly compound 22 are administered 150mg 1 time per day during the treatment period or as a continuous treatment.

Thus, the results of the tests performed on the compounds disclosed herein show that quinoline derivatives of formula (I) as defined hereinbefore can be used to treat HIV infected patients, where a reduction in the effectiveness of previous anti-HIV treatment has been reported.

The results also show that quinoline derivatives of formula (I) as defined hereinbefore can be used for long lasting low or undetectable viral load and/or maintaining or increasing CD4+ cell count after termination of treatment.

The results also show that quinoline derivatives of formula (I) as defined hereinbefore may be suitable for long-term treatment, since no induced HIV strains are present in the treated patients.

Thus, the compounds according to the invention may be administered in a pharmaceutical composition, which may contain an effective amount of the compound and one or more pharmaceutical excipients.

The aforementioned excipients are selected according to the dosage form and the desired mode of administration.

In this context, they can be present in any pharmaceutical form suitable for enteral or parenteral administration, for example in the form of simple or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories, or drinks such as suspensions, syrups or injectable solutions or suspensions, in association with suitable excipients.

Any route of administration may be used. For example, the compounds of formula (I) can be administered orally, parenterally, intravenously, transdermally, intramuscularly, rectally, sublingually, mucosally, nasally or by other means. In addition, the compounds of formula (I) can be administered in the form of pharmaceutical compositions and/or unit dosage forms.

In particular, the pharmaceutical compositions of the present invention may be administered orally and/or parenterally.

According to one exemplary embodiment, the pharmaceutical composition of the present invention may be administered orally.

Suitable dosage forms include, but are not limited to, capsules, tablets (including fast dissolving and extended release tablets), powders, syrups, oral suspensions and solutions for parenteral administration, and more particularly capsules.

The pharmaceutical compositions may also contain other agents known to those skilled in the art for the treatment of HIV, in combination with the compounds according to the invention.

Advantageously, the compound of formula (I) or any pharmaceutically acceptable salt thereof and metabolites thereof may be administered in combination with one or more antiretroviral compounds, including ART and HAART treatments, such as those selected from: zidovudine, lamivudine, emtricitabine, didanosine, stavudine, abacavir, zalcitabine, tenofovir, Racivir, amdoxovir, Apricitabine, efavirenz, nevirapine, etravirine, delavirdine, rilpivirine, tenofovir, Fosalvudine, amprenavir, tipranavir, indinavir, saquinavir, furinavir, ritonavir, darunavir, atavir, nelfinavir, lopinavir, retavir, Elvitegravir, Dolutegravir, enfuvirtide, maraviroc, virusol, and combinations thereof.

Examples

Example 1: potency of compound 22 and its N-glucuronide metabolite to inhibit HIV-1 production in PBMC-and macrophage-infected cells

1. Materials & methods

A. Cell culture and infection

The buffy coat of HIV-negative individuals was obtained from the blood supply center in Zurich, Switzerland(http:// www.blutspendezurich.ch /) and Centre de transfusion sanguine Montpellier. Human Peripheral Blood Mononuclear Cells (PBMCs) were separated by Ficoll (Axis-Shield PoC AS) gradient centrifugation. Then, the cells were cultured to 1X10 in RPMIGLutamax medium (Life Technologies Ref 61870-010) at 37 ℃ with 5% CO2⁶cells/mL, supplemented with 10% Fetal Calf Serum (FCS) (Thermo Fischer RefSV30160.03), 1000U/mL IL2(Peprotech Ref 200-02), and 5 μ g/mL PHA (Roche Ref1249738) for activation. After 3 days, cells were pooled in RPMI Glutamax medium supplemented with 10% Fetal Calf Serum (FCS)1000U/mL IL-2 and resuspended at 1X10⁶Density of cells/mL for infection. HIV-1infection was performed with 10. mu.g of Ada-MR5HIV strain per mL of cells for 4 hours. Then centrifuged and the cells resuspended to 1x10 in medium supplemented with diluted DMSO solvated (final 0.05% DMSO concentration) drug (Sigma Ref D4818)⁶Density of cells/mL. Cells were treated for 6 days, with a portion of the medium being changed on day 3. Cell culture supernatant HIV p24 titration was performed by ELISA: the Ingen Innotest kit (Ingen Ref 80564) was used according to the manufacturer's instructions.

To generate monocyte-derived macrophages (MDMs), monocytes were isolated with CD14 microbeads (catalog No. 130-050-201; Miltenyi) and cultured for 6 days in X-VIVO10 medium (Lonza) supplemented with GM-CSF 1000U/ml and M-CSF 100 ng/ml. Monocytes were seeded in 96-well plates at a cell count of 50' 000 cells/well. After 6 days, the medium was replaced with X-VIVO10w/o cytokine. After 2 days, macrophages were treated with compound 22 and/or its N-glucuronide metabolite and the following day infected with Yu-2 virus for 6 hours, washed with PBS and cultured in medium containing compound for 12 days. Supernatants were collected 2 times per week for p 24.

B. P24 antigen levels were monitored.

Cells were treated with 0.01 μ M up to 30 μ M and the level of p24 antigen in the culture supernatant was monitored for a 12 day period. Cell culture supernatant HIV p24 titration was performed by ELISA: the Ingen Innotest kit (Ingen Ref 80564) was used according to the manufacturer's instructions.

2. Results

The first functional study was based on the use of freshly isolated human Peripheral Blood Mononuclear Cells (PBMCs) from healthy donors. These PBMCs were infected with the laboratory HIV strain Ada-MR 5.

FIG. 1A shows dose-dependent inhibition of HIV-1 replication in stimulated PBMCs from 7 different donors. Interestingly, treatment with compound 22 did not alter the different populations of lymphocytes present in PBMCs.

To summarize the effect of compound 22 on HIV-1 replication in other primary cells, the same protocol was repeated with infected macrophages acting as viral reservoirs. Cells were treated with 0.01 μ M up to 30 μ M and p24 antigen levels in the culture supernatants were monitored for 12 days (FIG. 1B).

The effect of N-glucuronide metabolites on p24 inhibition and HIV replication on macrophages infected with Yu-2 virus was also shown at concentrations of 1.5. mu.M, 10. mu.M and 30. mu.M. Interestingly, compound 22 and its N-glucuronide metabolite efficiently blocked viral replication in primary macrophages at 0.1 μ M and reached levels of inhibition of up to 90% in a dose-dependent manner. However, cell viability was not reduced in the case of compound 22 treatment (data not shown).

Those results provide evidence that the compounds of the invention have low toxicity, but are still suitable for inhibiting HIV-1 replication in PBMCs and macrophages.

Since previous experiments were all performed with primary human cells infected with macrophage-tropic (R5) lines (Ada-MR5 and YU2), we transferred to an in vitro system that could be more relevant to the clinical situation, since it involved infection of the primary cells with HIV-1 isolates of the patients. As shown in FIG. 2A, Compound 22 had a strong inhibitory effect against all HIV-1 subtypes tested, including subtype B, C and recombinant virus. In particular, compound 22 was very effective in inhibiting replication of virus lines harboring mutations that confer in vitro resistance to various therapeutic agents (fig. 2B), and no resistance-inducing mutations were detected for at least 24 weeks after treatment with compound 22, as further evidenced by the following:

to test for the appearance and/or selection of mutations associated with compound 22 treatment, we used a deep sequencing approach to sensitively detect low frequency viral variants throughout the HIV-1 genome. Viruses from infected primary macrophages from 4 different donors, treated and untreated, were sequenced and reads that did not fit the human genome arrangement were sequenced with gsnaps in the YU2 sequence, as detailed in Wu et al (Fast and SNP-tolerant detection of complete variations and sampling in short reads. bioinformatics 26,873-881 (2010)). Most low and high frequency mutations were also present in treated and untreated samples, demonstrating that compound 22 did not select for specific mutations.

To determine that viral amplification of treated samples did not mutate when amplified in PBMC, they were sequenced in the presence or absence of drug pressure after amplification.

Again, no new mutations were detected other than those present in the original sample prior to treatment. We concluded that compound 22 was unlikely to select for specific viral mutations. In addition, compound 22 was also very effective in inhibiting replication of virus lines harboring mutations that confer in vitro resistance to various therapeutic agents, and no resistance-inducing mutations were detected for at least 24 weeks after treatment with compound 22 (table 1).

Resistance to compound 22 was tested on human PBMC and compared to current therapies. At least 24 weeks after treatment with compound 22, no resistance-inducing mutations were detected. Various classes of antiviral drugs can affect the life cycle of HIV-1in different ways. Genetic heterogeneity is a characteristic of the virus that significantly contributes to its ability to generate mutations that overcome the efficacy of drug therapy. Selection of drug resistance mutants in vitro can be readily achieved as follows: the virus is maintained in a sub-optimal growth state and the amount of drug pressure used is slowly increased to regulate. This technique simulates the outcome of a drug treatment in a patient. In this manner, it is therefore possible to assess the selection characteristics of novel compounds and thus the likelihood of development of HIV-1 drug resistance in future clinical trials. Furthermore, drug combinations can be studied in the same way.

Table 1: mutation selection of various drugs on human PBMCs.

Those results provide evidence that compound 22 was not selective for HIV-specific mutations and was not genotoxic.

Example 2: efficacy of Compound 22 in inhibiting viral replication in humanized mice

1. Materials & methods

A. Generation of humanized mouse model

SCID mice were reconstituted with fresh human PBL for 2 weeks and The reconstitution rate was estimated by human IgG titration, according to Denton et al (manipulated mouse models of HIV infection. AIDS Rev 13,135-148(2011)) and Berges et al (The science of The new generation of manipulated mouse to study HIV-1infection: transmission, prediction, pathogenesis, and comparison. Regiolography 8,65 (2011)).

Reconstituted SCID mice were infected with JRCSF HIV-1 strain by intraperitoneal injection. The control group received labrafil and 5% DMSO (n-15) by gavage and the treatment group received 20mg/kg b.i.d of compound 22/labrafil and 5% DMSO (n-14) for 15 days.

Nod.scid.il2r-/- (NSG) mice were bred and kept in individually ventilated cages and fed autoclaved food and water. Mice with a human immune system (NSG-HIS) were generated as described in Nischang et al (human adaptive mice key features of HIV-1infection: a novel connecting low-acting anti-reflective drugs for treating HIV-1 PLoS ONE 7, e38853 (2012).

Briefly, neonatal (<5 days old) NSG mice received sublethal (1Gy) Cs source systemic irradiation and then received 2 × 105 transduced or untransduced CD34+ human HSCs via the intrahepatic (i.h.) route using a 50 μ l hamilton syringe. All manipulations of NSG-HIS mice were performed under laminar flow. Gavage was performed daily in mice using stainless steel gavage needles (straight 22 gauge, 1.4 inches long). Compound 22 was dissolved in DMSO (Sigma) and then diluted to 5% or less in an appropriate vehicle (Labrafil M1944 CS; COOPER INDUSTRE, Place Lucien Auvert 77020 MELUN CEDEX20) according to the dose required. Mice received no more than 150 μ l volume/day. Mice were monitored 3 times per week for symptoms or signs of adverse events according to a standard scale.

HIV virus stock and infection of mice

The JR-CSF virus stock was amplified in PBMCs, virus harvested 12 to 15 days post infection, filtered (0.45 μm), concentrated by centrifugation on a pad of sucrose and frozen at-80 ℃. The YU-2 virus stock was obtained as follows: polyethyleneimine (PEI) -mediated transfection of 293T cells (Polysciences) was performed with the pYU-2 (R5-tropic) plasmid supplied by NIH AIDSResearch and Reference Reagent Program. At 48 hours after transfection, the virus was harvested, filtered (0.45 μm), and frozen at-80 ℃. Virus titres were determined as described in McDougal et al (Immunoassay for the detection and quantification of infectious human retroviruses, Lymphadenopathy-associated viruses (LAV). J.Immunol.methods 76,171-183 (1985)).

Briefly, TCID50 (tissue culture infectious dose 50%) was determined as follows: human CD8+ T-cell-depleted Peripheral Blood Mononuclear Cells (PBMC) from 3 donors were infected and stimulated with the addition of IL-2, PHA and anti-CD 3 beads (Dynal 11131D, Life technologies). Then, virus stock was adjusted to 1x10⁶TCID50/ml, aliquoted and frozen at-80 ℃ before use. Mice were i.p. infected with JR-CSF, 1x10 intraperitoneally³TCID50 per mouse; and HIV YU-2, 1x106 TCID50 per mouse. HIV RNA plasma levels were measured by RT-PCR (Amplicor HIV-1 assay or Ampliprep/COBASS TaqMan HIV-1 assay, Roche) at various times after infection.

C. Flow cytometry

Labeling the cell suspension with anti-human monoclonal antibodies (mabs) that target the following cell-surface markers: CD45-FITC, CD3-PE, CD4-Pe Cy7, CD8-BV421 and CD19-APC (all from Biolegend). Washing and reagent dilution were done with FACS buffer (PBS, containing 2% fetal bovine serum and 0.05% sodium azide (NaN 3). all acquisitions were performed on a CyanADP (Beckman Coulter) flow cytometer.

2. Results

Humanized mice reconstituted with human lymphoid cells provide a rapid, reliable, reproducible experimental system for testing the in vivo efficacy of compound 22. In an initial setup, SCID mice were reconstituted with PBMCs and then infected with HIV-1 strain JR-CSF. Mice were treated with Compound 22 by oral gavage at a dose level of 20mg/kg 2 times daily for 15 days. Measurements of viral RNA showed that compound 22 oral treatment was able to significantly reduce viral load over a 15 day treatment period (fig. 3A). FACS analysis of blood samples showed that treatment with compound 22 prevented depletion of CD4+ cells in reconstituted mice after infection and thereby restored the CD8+/CD4+ ratio to that of non-infected mice (fig. 3B).

To test the long-term effect of compound 22 on the immune system and viral replication in infected hu mice, neonatal NOG mice were transplanted with CD34+ hematopoietic progenitor cells isolated from umbilical cord blood (see Nischang et al; human micecalate key defects of HIV-1infection: a novel connecting using a-activating-reconstructing drugs for ventilating HIV-1.PLoS ONE 7, e 38853; 2012). This hu mouse model has previously shown valuable utility for exploring the antiviral efficacy of new compounds targeting potential HIV reservoirs. NOG hu mice treated with 20mg/kg or 40mg/kg of compound 22 for 1 month did not change the engraftment value of CD45+ cells nor the CD8+/CD4+ ratio compared to untreated controls (FIG. 3C). In this study, NOG hu mice were infected with YU2HIV-1 virus and fed 40mg/kg daily of compound 22 or HAART (3 TC-tenofovir-raltegravir and AZT) for 30 days, with viral load measurements as above. Compound 22 reduced viral load over a 30 day treatment period, but more importantly remained low after at least 50 days of treatment termination (fig. 3D). In contrast, rebound was observed in the HAART group up to a level comparable to the initial infection (fig. 3D).

Thus, those results show that compound 22 is the first robust anti-HIV drug that is able to sustainably inhibit viral load after treatment is discontinued.

Example 3: compound 22 increases spliced HIV RNA levels

1. Materials & methods

A. Quantification of viral and non-viral RNA splicing

Quantification of viral RNA splicing was achieved using the protocol detailed in Bakkour et al (Small-molecular inhibition of HIVpre-mRNA splicing as a novel anti viral therapy to an overhead drug resistance. PLoS Patholog.3, 1530-1539 (2007).

Quantification of non-viral RNA splicing was achieved using the protocols detailed in Klinck et al (Multiple alternative splicing markers for alternative Cancer Res.68,657-663(2008)) and Venables et al (Cancer-associated regulation of alternative splicing Nat.Structure.mol.biol.16, 670-676 (2009)).

Other schemes are described in advance.

2. Results

To confirm that compound 22 did not significantly affect the splicing events of the endogenous gene (potentially leading to some adverse effects), the effect of compound 22 was tested by a global alternative splicing RT-PCR analysis of 382 alternative splicing events. These 382 Alternative Splicing Events (ASEs) represent a high-throughput snapshot of the overall change in alternative splicing. We performed high-throughput PCR analysis of this (essentially random) 382 ASE on multiple PBMC samples from untreated (cells) or treated with DMSO, compound 22 or control antiviral drug (darunavir). Data analysis allows for tighter quality control; the conditions for ASE are considered only if > 75% of the product is moving at the desired mobility (i.e. if the reaction is pure) and if the total desired PCR concentration is above 20nM (i.e. if the reaction is intense), which results in 264 residual ASE.

The splicing characteristics of 12 PBMC samples from the same donor showed that there was a slight difference in the splicing characteristics of the drug-treated PBMC samples, as they formed one of 3 separate columns with stem cells and their derived fibroblasts. Consistent with this, the percent splice values for untreated cells and cells treated with compound 22 correlated with R0.89 for the 264 ASE, whereas stem cells and derived fibroblasts correlated only with R0.59 (data not shown). In summary, these data show that compound 22 does not have an overall effect on precursor mRNA splicing.

To test whether compound 22 affects HIV RNA splicing in infected cells, array-based sequence capture was performed with custom-made library probes that target HIV sequences to remove cellular RNA. The probes were used to capture cDNAs prepared from infected treated and untreated PBMCs. After double capture, libraries were prepared and sequenced with 454 pyrophosphate sequencing (according to GS primary methods manual). An average read size of about 400bp allows for unambiguous assembly of viral genomes from untreated samples (after 3 and 6 days of infection), using reads that are not mapped to the human genome (hg 19). All sequencing data were analyzed using a gsnap, as detailed in Wu et al (Fast and SNP-tolerant detection of complex variants and applications in short reads. bioinformatics 26,873-881 (2010)).

After 3 days post infection, higher viral genome coverage was obtained for the untreated DMSO samples (32,289 reads) compared to compound 22 treated samples (4149 reads). Surprisingly, the corresponding splice sites were read at 17.4% of the treated samples at 3 days post infection, while 0.93% was read in the untreated samples. Although the number of reads obtained for the treated and untreated samples was similar at 6 days post infection (20585 and 27984 times, respectively), the fraction of the corresponding splice sites in the treated samples (13.3%) was equally greater (1.93%) compared to the untreated samples.

Based on these results it can be concluded that compound 22 favours spliced HIV RNA in infected PBMC, thus compromising subsequent full-length HIV-1 precursor mRNA synthesis and infectious particle assembly.

Claims

1. Quinoline derivatives of formula (I)

Wherein:

z represents N or C, and z represents N or C,

means an aromatic ring in which V is C or N and where V is N, V is located adjacent to zMeta-or para-position, i.e. form a pyridazine, pyrimidine or pyrazine radical respectively,

r independently represents a hydrogen atom, a halogen atom or a group selected from: -CN group, hydroxy, -COOR₁Radical (C)₁-C₃) Fluoroalkyl group, (C)₁-C₃) Fluoroalkoxy group, (C)₃-C₆) Cycloalkyl, -NO₂Group, -NR₁R₂Radical (C)₁-C₄) Alkoxy, phenoxy, -NR_1-SO_2-NR₁R₂Group, -NR₁-SO₂-R₁Group, -NR₁-C(＝O)-R₁Group, -NR₁-C(＝O)-NR₁R₂Group, -SO_2-NR₁R₂Group, -SO₃H group, -O-SO₂-OR₃A radical, -O-P (═ O) - (OR)₃)(OR₄) A group, -O-CH₂-COOR₃Group and (C)₁-C₃) An alkyl group, optionally mono-substituted with a hydroxy group,

q is N or O, with the proviso that R' is absent if Q is O,

n is 1, 2 or 3,

n' is 1, 2 or 3,

a is a covalent bond, an oxygen atom or NH,

b is a covalent bond or NH,

m is 1, 2, 3, 4 or 5,

p is 1, 2 or 3,

ra and Rb can further form, together with the nitrogen atom to which they are attached, a saturated 5-or 6-membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring being optionally substituted by one or more Ra, with the proviso that in the case where R ' is a group (IIa) or (IIIa), n ' can be 2 or 3 with the proviso that the other R ' groups are different from said group (IIa) or (IIIa),

r' is a hydrogen atom, (C)₁-C₄) Alkyl or is a group (IIa) as defined above,

or any pharmaceutically acceptable salt thereof, or any metabolite thereof,

for treating or preventing a viral infection or a virus-related condition, in particular an HIV infection or an HIV-related condition, in a patient, wherein ineffectiveness or a decrease in the effectiveness of previous antiviral therapy has been reported.

2. A quinoline derivative of the formula (I) or any pharmaceutically acceptable salt or metabolite thereof as defined in claim 1 for use in the treatment or prevention of a viral infection or a virus-related condition, in particular an HIV infection or an HIV-related condition in a patient, wherein said patient is infected with a drug-resistant viral strain and more particularly a drug-resistant HIV strain.

3. A quinoline derivative of the formula (I) or any pharmaceutically acceptable salt or metabolite thereof as defined in claim 1 for use in the treatment or prevention of a viral infection or a viral-related condition, in particular an HIV infection or an HIV-related condition in a patient; the treatment was then terminated under the following conditions: low or undetectable viral load; and/or CD4+ cell count levels are maintained or restored.

4. A quinoline derivative of the formula (I) as defined in claim 1 or any of its pharmaceutically acceptable salts and metabolites for use according to claim 3 wherein the condition of low viral load is below 500 copies/mL plasma, the condition of undetectable viral load is below 40 copies/mL plasma and the condition of recovery of the CD4+ cell count level is equal to or greater than 500CD4+ cells/mm³Plasma.

5. A quinoline derivative of formula (I) as defined in claim 1 or any pharmaceutically acceptable salts and metabolites thereof, for use according to claim 2, wherein the HIV strain is resistant to a drug selected from ART and/or HAART treatment.

6. A quinoline derivative of formula (I) as defined in claim 1 or any pharmaceutically acceptable salts and metabolites thereof, for use according to claim 2, wherein said HIV strain is resistant to a drug selected from the group consisting of: zidovudine, lamivudine, emtricitabine, didanosine, stavudine, abacavir, zalcitabine, tenofovir, Racivir, amdoxovir, Apricitabine, efavirenz, nevirapine, etravirine, delavirdine, rilpivirine, tenofovir, Fosalvudine, amprenavir, tipranavir, indinavir, saquinavir, furinavir, ritonavir, darunavir, atavir, nelfinavir, lopinavir, retavir, Elvitegravir, Dolutegravir, enfuvirtide, maraviroc, virusol, and combinations thereof.

7. A quinoline derivative of the formula (I) or any of its pharmaceutically acceptable salts and metabolites as defined in claim 1 for use according to claim 1 or 2, wherein said patient has not previously been treated with antiretroviral therapy.

8. A quinoline derivative of the formula (I) or any of its pharmaceutically acceptable salts and metabolites as defined in claim 1, wherein the quinoline derivative or a metabolite thereof is administered 1 time per day, 1 time per 3 days, 1 time per week, 1 time per 2 weeks or 1 time per month, especially at a dose of 25 to 500mg, especially 25 to 300mg, more especially 25 to 200mg, such as 25 to 150mg, during a treatment period or as continuous treatment, for use according to any of the preceding claims.

9. A quinoline derivative of the formula (I) as defined in claim 1 or any of the pharmaceutically acceptable salts and metabolites thereof for use according to the preceding claims wherein the treatment period is 2 to 8 weeks.

10. A quinoline derivative of formula (I) as defined in claim 1, or any pharmaceutically acceptable salts and metabolites thereof, for use according to any one of the preceding claims, wherein said quinoline derivative has the following formula (Ib)

Wherein R, R ', R ", n and n' are as defined in claim 1, or any pharmaceutically acceptable salt thereof, or any metabolite thereof.

11. A quinoline derivative of the formula (I) as defined in claim 1 or any of its pharmaceutically acceptable salts and metabolites, for use according to any of the preceding claims, wherein it is 8-chloro-N- (4- (trifluoromethoxy) phenyl) quinolin-2-amine or a metabolite thereof, especially an N-glucuronide metabolite thereof