FR3108503A1 - Pharmaceutical composition active against a viral infection of the coronavirus type - Google Patents

Abstract

Pharmaceutical composition active against a viral infection of the coronavirus type The invention relates to a pharmaceutical composition comprising a pharmaceutical carrier and an amount of agent active against a viral infection of a human or animal body by a virus of the coronavirus type including SARS-CoV. , MERS-CoV and SARS-SoV-2 causing Covid-19 disease. The composition comprises a naphthylisoquinoline alkaloid or a mixture of naphthylisoquinoline alkaloids or their derivatives. The invention relates to a method of treating or preventing a viral infection comprising a step of administration by the oral route or by injection of such a pharmaceutical composition.

Description

Pharmaceutical composition active against a viral infection of the coronavirus type

Technical field of the invention

The present invention relates to a pharmaceutical composition active against a viral infection of the coronavirus type as well as a method for treating or preventing a viral infection of the human or animal body by a virus of the coronavirus type.

Prior art

Coronaviruses are a family of viruses, some of which can infect humans, most often causing mild cold-like symptoms.

However, this is not the case with all coronaviruses and some can lead to serious epidemics. Mention should be made, without being exhaustive, of SARS-CoV, MERS-CoV and SARS-CoV2 causing the Covid-19 pandemic.

There are no vaccines or antiviral drugs yet to prevent or treat coronavirus infections for humans or animals, including SARS-CoV2.

Early research, however, showed that a drug known to treat malaria called chloroquine was effective in preventing a SARS-CoV2-like viral infection.

Chloroquine is an antimalarial from the amino-4-quinoline family. It has been widely marketed in the form of hydroxychloroquine or salts. Chloroquine is with quinine, of which it is a synthetic substitute, the treatment which has been the most used, preventively as well as curatively, against malaria.

A recent clinical study published on February 19, 2020 in the journal Bioscience Trends by researchers Jianjun Gao, Zhenxue Tian and Xu Yang, based on a large sample of treated patients demonstrated that chloroquine phosphate was more effective than the treatment received by a control group to contain the progression of pneumonia, improve the condition of the lungs, make patients negative for the SARS-CoV2 virus again and shorten the duration of their illness. A treatment of 500 mg of chloroquine per day for ten days would thus be sufficient to treat Covid-19 disease.

However, the administration of chloroquine, either orally or by injection, has side effects, is not without toxicity and the dose of curative treatment for Covid-19 is relatively high compared to taking chloroquine against malaria. It was frequently cited as adverse effects of chloroquine in curative treatment, headaches, nausea, risk of abscess at the injection site and anaphylactic shock to sulphites with the injectable form. Cardiac risks have also been mentioned without this being formally proven.

In an anti-malarial treatment, it has therefore been proposed to replace chloroquine or to combine it with other drugs.

Document EP-B1-0 741 569 thus proposes the use of naphthylisoquinoline alkaloids and their derivatives as a pharmaceutical composition exhibiting anti-malarial activity and methods of using the compounds for the treatment or prevention of malaria.

However, in this document confined solely to the treatment or prevention of malaria, there is no teaching or suggestion that a pure naphthylisoquinoline alkaloid, nor a specific pharmaceutical composition of this type of alkaloid, would have any medicinal activity. against viruses, especially coronaviruses.

CN-A-110437149 teaches that an isoquinoline exhibits anti-tumor activity and can serve as a lung cancer cell growth inhibitor.

However, this document does not deal with an activity of an isoquinoline against viruses and in particular coronaviruses.

Consequently, the problem underlying the invention is to find a drug preventing or treating a disease of the human or animal body caused by a virus of the coronavirus type.

To this end, the present invention relates to a pharmaceutical composition comprising a pharmaceutical carrier and a quantity of active agent against a viral infection of a human or animal body by a virus of the coronavirus type including SARS-CoV, MERS-CoV and SARS-SoV-2 causing Covid-19 disease, characterized in that it comprises a naphthylisoquinoline alkaloid or a mixture of naphthylisoquinoline alkaloids or their derivatives.

The advantage of such a composition is its lower toxicity than that of chloroquine while having at least the same drug efficacy. Trials are underway to prove it.

Such naphthylisoquinoline alkaloids were certainly known for anti-malarial treatment as well as chloroquine but their anti-viral efficacy had never been tested.

Advantageously, the composition further comprises an effective amount of chloroquine, hydroxychloroquine, quinine, mefloquine, phenantrene, artemisinin, artemether, pyrimethamine, azithromycin, these substances being present in the composition individually or in combination.

It was found that a synergistic effect existed due to the combination of several compositions mainly known for their anti-malarial action or of an antibiotic of the azithromycin type from the azalide group.

Advantageously, the composition further comprises an effective amount of an antiviral substance, in particular against influenza viruses, in particular influenza A(H1N1)v.

There is also a synergy resulting from the use of antiviral substances treating viruses related to coronaviruses contagious by the respiratory route, since pulmonary complications can result from a Covid-19 infection.

Advantageously, the composition comprises, taken individually or in combination, one or more naphthyl-isoquinolines, preferably a dimer naphthalene-tetrahydroisoquinoline, one or more dioncophyllins, one or more michelamines A or B or their derivatives.

Advantageously, the naphthyl-isoquinoline is extracted from one of the plant species of ancistrocladus, dionchophyllaceae or triphyophyllum peltatum.

Advantageously, the derivatives of naphthylisoquinoline alkaloid or of a mixture of naphthylisoquinoline alkaloids are one or more esters, ester sulfonates or ethers, an O-dimethyl, amides, sulfamides, amines or an aryl.

The invention also relates to a method for treating or preventing a viral infection of the human or animal body by a virus of the coronavirus type including SARS-CoV, MERS-CoV and SARS-SoV-2, characterized in that it comprises a step of administration orally or by injection into humans or animals of a pharmaceutical composition as described above.

Advantageously, the treatment is limited to one or two weeks.

Advantageously, the dose for oral administration is between 100 and 800 milligrams in one or more doses for a curative treatment and between 50 and 350 milligrams for a prophylactic preventive treatment.

The administration dose may vary depending on the size of the patient being treated and whether he is human or animal. This dose may vary if taken in combination with other medications. The dose may also take into account the pharmacokinetics of the composition since the naphthylisoquinoline alkaloids or their derivatives may exhibit different efficacies and treatment kinetics.

Detailed description of the invention

In the foreword, the chemical formula of chloroquine is recalled:

The present invention relates to a pharmaceutical composition comprising a pharmaceutical carrier and a quantity of active agent against a viral infection of a human or animal body by a virus of the coronavirus type including SARS-CoV, MERS-CoV and SARS-SoV -2 causing Covid-19 disease.

This pharmaceutical composition comprises a naphthylisoquinoline alkaloid or a mixture of naphthylisoquinoline alkaloids or their derivatives.

Alkaloids are molecules with nitrogenous bases, most often heterocyclic, very mainly of plant origin. They can be in the form of basic nitrogenous heterocyclic organic molecules. Chloroquine is also a heterocyclic organic molecule with a nitrogen atom as a heteroatom.

Generally, the basic structure of naphthylisoquinoline alkaloids comprises a biaryl system, for example an assembly of two aromatic compounds with aryl groups, the two aromatic compounds being connected by a single bond. The biaryl system can consist of a naphthalene and an isoquinoline or a dihydrogenated or tetrahydrogenated isoquinoline moiety with a methyl group.

Among the naphthylisoquinoline alkaloids, it is possible to cite, without this being exhaustive, dioncophyllins A, B and C, or their derivatives such as dioncophyllacines, epi-dioncophyllines, N-methyl-dioncophyllines and their derivatives -O- desmethyl-, benzyl-dioncophyllins, michellamines A and B, ancistrobrevins A, B and D and their derivatives, dioncopeltins, dioncolactones, ancistrocladins.

Reference will be made to the various articles by Gerhard Bringmann published in scientific journals and cited in the document EP-B1-0741 569 previously mentioned for the specific characteristics of naphthylisoquinoline alkaloids.

The derivatives of naphthylisoquinoline alkaloid or of a mixture of naphthylisoquinoline alkaloids can be ester(s), ester sulfonates or ethers, O-dimethyl, amides, sulfonamides, amines or aryl, which is not limiting.

The pharmaceutical composition may further comprise an effective amount of chloroquine, hydroxychloroquine, quinine, mefloquine, phenantrene, artemisinin, pyrimethamine and artemether, advantageously combined with lumefrantrine. These substances may be present in the pharmaceutical composition individually or in combination and are known for their anti-malarial action but their anti-viral activity was not known.

It may also be possible to add an antibiotic to the pharmaceutical composition, preferably a macrolide antibiotic from the azalide group. Azithromycin derived from erythromycin is preferred. Such an antibiotic can treat pulmonary complications resulting from a Covid-19 infection.

The pharmaceutical composition may also comprise an effective amount of an antiviral substance, in particular against influenza viruses, in particular influenza A(H1N1)v. These include oseltamivir and zanamivir, neuraminidase inhibitors. It is also possible to use amantadine and/or rimantadine which are M2 inhibitors.

The pharmaceutical composition may comprise, taken individually or in combination, one or more naphthyl-isoquinolines, preferably a dimer naphthalene-tetrahydroisoquinoline, one or more dioncophyllins, one or more michelamines A or B or their derivatives.

For illustrative purposes only, the chemical formula of a tetrahydroisoquinoline is given below.

The chemical formula of a dioncophyllin A is given below

The chemical formula of a michellamine B is given below

Advantageously, the naphthyl-isoquinoline is extracted from one of the plant species of ancistrocladus, dionchophyllaceae or triphyophyllum peltatum.

These plants grow mainly in tropical or equatorial environments, especially in West Africa. The extraction can be done from a plant dried with an organic solvent in order to obtain a starting extract from which a crude organic base fraction is obtained which is subjected to centrifugal partition chromatography.

The substance, for example naphthyl-isoquinoline, advantageously a naphthalene-tetrahydroisoquinoline, is then isolated in a liquid chromatography column in amino-linked phase which is a technique for the analytical separation and/or preparation of molecules present in a mixture.

The invention also relates to a method for treating or preventing a viral infection of the human or animal body by a virus of the coronavirus type including SARS-CoV, MERS-CoV and SARS-SoV-2.

The method comprises a step of administering orally or by injection into humans or animals of a pharmaceutical composition as previously described, that is to say comprising a naphthylisoquinoline alkaloid or a mixture of alkaloids naphthylisoquinoline or their derivatives.

This treatment can be limited to one or two weeks.

For oral intake, the dose of oral administration may be between 100 and 800 milligrams divided into one or more doses for a curative treatment and between 50 and 350 milligrams for a prophylactic preventive treatment.

The invention is in no way limited to the embodiments described and illustrated which have been given by way of examples only.

Claims (8)

Pharmaceutical composition comprising a pharmaceutical carrier and a quantity of agent active against a viral infection of a human or animal body by a virus of the coronavirus type including SARS-CoV, MERS-CoV and SARS-SoV-2 causing the disease of Covid-19, characterized in that it comprises a naphthylisoquinoline alkaloid or a mixture of naphthylisoquinoline alkaloids or their derivatives. Composition according to the preceding claim, which also comprises an effective amount of chloroquine, hydroxychloroquine, quinine, mefloquine, phenantrene, artemisinin, artemether, pyrimethamine, azithromycin, these substances being present in the composition individually or in combination. A composition according to any one of the two preceding claims, which additionally comprises an amount of an antiviral substance against influenza viruses. Composition according to the preceding claim, in which the said antiviral substance against influenza viruses is effective against influenza A(H1N1)v. Composition according to any one of the preceding claims, which comprises one or more naphthyl-isoquinolines, preferably a dimer naphthalene-tetrahydroisoquinoline, one or more dioncophyllins, one or more michellamines A or B or their derivatives, these substances being present in the combination singly or in combination. Composition according to the preceding claim, in which the naphthyl-isoquinoline is extracted from one of the plant species of ancistrocladus, dionchophyllaceae or triphyophyllum peltatum. Composition according to any one of the preceding claims, in which the derivatives of naphthylisoquinoline alkaloid or of a mixture of naphthylisoquinoline alkaloids are one or more esters, ester sulphonates or ethers, O-dimethyl, amides, sulfonamides, amines or aryl. Pharmaceutical composition according to any one of the preceding claims for use by oral administration or injection in the treatment or prevention of a viral infection of the human or animal body by a virus of the coronavirus type including SARS-CoV, MERS-CoV and SARS-SoV-2.