WO2020055368A2

WO2020055368A2 - Usage of terpenic coumarin derived molecules in treating viral diseases

Info

Publication number: WO2020055368A2
Application number: PCT/TR2019/050736
Authority: WO
Inventors: Fatma TOSUN; Mahmud MİSKİ
Original assignee: Istanbul Medipol Universitesi; T.C. İstanbul Üni̇versi̇tesi̇
Priority date: 2018-09-12
Filing date: 2019-09-09
Publication date: 2020-03-19
Also published as: WO2020055368A3

Abstract

The present invention is related to compounds suitable for use in treatment of viral diseases and pharmaceutical compositions comprising said compounds

Description

USAGE OF TERPENIC COUMARIN DERIVED MOUECUUES IN TREATING

VIRAU DISEASES

Technical Field

The present invention is related to compounds suitable for use in treatment of viral diseases and pharmaceutical compositions comprising said compounds.

Prior Art

Viruses are infectious agents that reproduce by infecting living cells, that are extremely durable against environmental conditions during dormant periods and that can remain without losing their viability during prolonged extreme conditions.

Only a limited number of active drug agents that are effective against viruses are available; a majority of people and animals infected by epidemics caused by viruses to which antiviral treatment can’t be applied, lose their lives. For example most of the patients infected by epidemics caused by the Ebola virus lose their lives. Due to this reason it is crucial to find molecules effective against viruses and to develop these molecules as active drug agents for the future of humanity.

The fact that existing antiviral molecules lose their antiviral effects due to mutations increases the importance of the discovery of new antiviral molecules.

Brief Description of the Invention

When the prior art was examined it was observed that in comparison to the agents present in the art, novel antiviral agents having higher selectivity, lower side effects, higher efficiency, having a structure that is different than the structures already known for fighting against viruses was required.

The inventors, who have carried out studies within this context, have discovered as a result of their studies, that terpenic coumarin derived compounds were efficient on viral diseases. Detailed Description of the Invention

The present invention is related to molecules shown with Formula I and/or Formula II or salts, hydrates, solvates, polymorphs, stereoisomers, optical isomers, geometric isomers, enantiomers, diastereomers, and/or a combination thereof;

Formula II; wherein Rl is selected from;

for use in the manufacture of a medicament for use in treatment of viral diseases.

In other words, the present invention is related to use of molecules shown with Formula I and/or Formula II;

Formula I

Formula II; wherein it is selected from;

or salts, hydrates, solvates, polymorphs, stereoisomers, optical isomers, geometric isomers, enantiomers, diastereomers, and/or a combination thereof for use in the treatment of viral diseases.

The molecules whose general structures have been shown with Formula I and Formula II are molecules that have different chemical structures from the active agents of antiviral drugs used nowadays; as viruses have not been subjected to these molecules they have not developed resistance against these compounds; as a result it is believed that these molecules that have a different structure from the known antiviral molecules will play a crucial role in the treatment of viral diseases that are caused by viruses that have developed resistance against the antiviral agent.

Moreover it has been noted that this agent has a more selective and stronger effect in comparison to known antiviral agents, on some virus types such as HSV-l (herpes virus).

The“*” sign used within the scope of the invention, shows the point where the Rl group binds to the structures, which shows that this group binds to the main structures shown in Formula I and Formula II with a single bond at the * point.

The wavy bond shaped that shows Formula I and Formula II within the scope of the invention, expresses that this bond may have been directed towards the outside of the page or towards the inside of the page.

It can be seen from the figures that there are several stereo centers on the molecules represented by Formula I and Formula II subject to the invention. The bonds included in the invention which have been defined above, express that the groups in said stereo center and illustrated with the wavy bond can be at the outside of the page or at the inside of the page. Within this context, all of the different optical isomers arising from this view, are included within the scope of the invention even if they have not been clearly illustrated in this description.

The wavy bonds in Formula I and Formula II subject to the invention and the groups bound to the molecules can be at the outside or inside with respect to the surface of the page, independent from each other. In other words, while one of the groups is towards the outside of the page surface, the other can be towards the inside of the page or all of the groups inside the molecule can be towards the outside or inside the of the page or 1, or 2 or 3 or 4 or 5 of the groups expressed with the wavy bond can be towards the inside of the page, whereas 1 or 2 or 3 or 4 or 5 of them can be towards the outside of the page. All of the different Formula I and Formula II optical isomers that are to be formed of these types of different combinations, are included within the scope of the invention.

Molecules according to the invention can be richer in one or more diastereomers. For example molecules according to the invention can have at least 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de or 95% de. The expression“de” defines diastereomeric excess. For example in a mixture, if a rate of 30% from one diastereomer and 70% from another diasterometer is available,“de”, or in other words diasteromeric excess is expressed as 40%.

In order to ensure for the invention to be understood more clearly, the specific examples illustrated with Formula I and Formula II have been shown in the table below.

As it has been mentioned before the Rl group in the specific examples of Formula I and

Formula II given in the above mentioned table is selected from

or

or or

The molecules whose specific chemical structures have been provided above, have been given in order to better explain the invention and it should not be construed to limit this invention.

Molecules represented by Formula I and Formula II according to the invention can be prepared or purified by using methods known in the prior art.

According to another aspect, the present invention is related to the use of Formula I and/or Formula II or pharmaceutically acceptable salts, prodrugs, stereoisomers, optical isomers, enantiomers, diastereomers and/or combinations thereof for prophylaxis or treatment of viral diseases.

According to another aspect, the present invention is related to the use of Formula I and/or Formula II or pharmaceutically acceptable salts, prodrugs, stereoisomers, optical isomers, enantiomers, diastereomers and/or combinations thereof for the preparation of a medicament for use in prophylaxis or treatment of viral diseases.

The term “treatment” or “treating” as used herein defines the prevention, alleviation, reduction, curing and or blocking at least a symptom characterizing a pathological condition in a subject having a condition or being threatened by a condition.

The terms “viral disease” used within the scope of the invention, defines the diseases occurring, as a result of contact of the body of a living being, for example a human being, with pathogenic viruses and/or infectious virions.

A non limiting list relating to viruses that cause said viral diseases within the scope of the invention has been listed below: adenovirus, herpes simplex type 1, herpes simplex type 2, Varicella- zoster virus, Epstein-Barr virus, Human sitomegalo virus, human herpesvirus type 8, human papillomavirus, BK virus, JC virus, small pox virus, Hepatitis B virus, Parvovirus B19, human astrovirus, Norwalk virus, Hepatitis A virus, Polio virus, Rhino virus, severe acute respiratory tract syndrome virus, hepatitis C virus, yellow fever virus, dengue fever virus, west Nile virus, encephalitis virus caused by ticks, rubella virus, hepatitis E virus, human immunodeficiency virus, influenza virus, Lassa virus, Crimean-congo hemorrhagic fever, hantaan virus, measles virus, mumps virus, Ebola virus, Marburg virus, parainfluenza virus, respiratory syncytial virus, rabies virus, Hepatitis D virus, rotavirus, orbivirus, coltivirus, banna virus, coxsackie virus.

The molecules according to the invention can be used in treatment of viruses listed above.

In a preferred embodiment of the invention, the molecules according to the invention can be used in treating the following diseases and/or in the preparation of a medicament suitable for use in treating the following diseases of; gastroenteritis, kerato conjunctivitis, pharyngitis, croup, pharyngoconjunctival fever, pnemonia, cystitis, foot and mouth disease, pleurodynia, aceptic menengitis, pericarditis, myocarditis, infectious mononucleosis, Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, acute hepatitis, chronic hepatitis, hepatocirrhosis, hepatocellular carcinoma, herpes, gingivostomatitis, tonsilitis, mucosa/mouth/genital ulcers, aceptic menengitis, cytomegalic inclusion disease, kaposi's sarcoma, castleman diseases, primary effusion lymphoma, AIDS, Reye’s syndrome, post infection encephalomyelitis, mumps disease, hyperplastic epithelial lesions, anogenital warts, laryngeal papilloma, epidermal dysplasia, verruciform, cervical carcinoma, squamose cell carcinoma, bronchiolitis, influenza, poliomyelitis, rabies, severe bronchiolitis together with pneumonia, congenital rubella, German measles, smallpox, herpes zoster, congenital varicella syndrome.

Molecules according to the invention find use in the treatment of viral diseases and/or the protection against viral diseases as described herein. The molecules according to the invention in terms of such usage, are preferably going to be applied as pharmaceutical compositions.

An embodiment of the invention is related to pharmaceutical compositions comprising Formula I and/or Formula II or pharmaceutically acceptable salts, predrugs, stereoisomers, optical isomers, enantiomers, diastereomers and/or combinations thereof.

In another embodiment, the invention is related to the use of pharmaceutical compositions for use in treating viral diseases comprising Formula I and/or Formula II or pharmaceutically acceptable salts, prodrugs, stereoisomers, optical isomers, enantiomers, diastereomers and/or combinations thereof as active agent. Said pharmaceutical compositions comprise at least one or more excipients besides an active agent according to the invention.

According to another embodiment, the pharmaceutical composition comprising Formula I and/or Formula II or pharmaceutically acceptable salts, prodrugs, stereoisomers, optical isomers, enantiomers, diastereomers and/or combinations thereof as an active agent, can also comprise an at least one other active agent.

According to another preferred embodiment of the invention said other active agent is an antiviral agent.

The other active agent mentioned, can be selected from a sub group which comprises but is not limited to, fusion and entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors, maturation inhibitors, protease inhibitors, pharmacokinetic boosters, DNA synthesis inhibitors, nucleic acid inhibitors, interferons, NS3/4A protease inhibitors, NS5A inhibitors, NS5B RNA polymerase inhibitors, anti-influenza agents and other agents.

Fusion and entry inhibitors can be selected from a group comprising enfuvirtide, maraviroc, vicriviroc, cenicriviroc, ibalizumab and fostemsavir.

The reverse transcryptase inhibitors can be selected from a group comprising abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine, amdoxovir, apricitibine, censavudne, elvucitabine, racivir, stampidine, 4-etinil-2-floro-2’-deoxyadenosine, zalcitabine, efavirenz, nevirapine, delavirdine, etravirine, rilpivirine and doravirine.

The integrase inhibitors can be selected from a group comprising dolutegravir, elvitegravir, raltegravir, cabotegravir and bictegravir.

The maturation inhibitor can be bevirimat.

Protease inhibitors can be selected from a group comprising amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, darunavir and tipranavir. Pharmacokinetic boosters can be selected from a group comprising cobicistat and ritanovir. DNA synthesis inhibitors can be selected from a group comprising aciclovir, valaciclovir, ganciclovir, valganciclovir, penciclovir, famciclovir, idoxuridine, trifluridine, edoxudine, brivudine, sorivudine and cytarabine.

The nucleic acid inhibitor can be cidofovir.

Interferons; are selected from a group comprising interferon alpha 2b and peginterferon alpha 2a.

NS3/4A protease inhibitors are selected from a group comprising asunaprevir, boceprevir, ciluprevir, danoprevir, faldaprevir, glecaprevir, grazoprevir, narlaprevir, paritaprevir, simeprevir, sovaprevir, telaprevir, vaniprevir, vedroprevir, voxilaprevir.

NS5A inhibitors are selected from a group comprising daclatasvir, elbasvir, ledipasvir, odalasvir, ombitasvir, pibrentasvir, ravidasvir, ruzasvir, samatasvir, velpatasvir.

NS5B RNA polymerase inhibitors are selected from a group comprising beclabuvir, dasabuvir, deleobuvir, filibuvir, setrobuvir, sofosbuvir, radalbuvir and uprifosbuvir.

Anti-influenza agents are selected from a group comprising umifenovir, adapromine, amantadine, rimantadine, oseltamivir, zanamivir, peramivir and laninamivir.

Other agents are selected from a group comprising docosanol, fomivirsen, tromantadine, imiqumod, resiquimod, podophyllotoxin, rifampicin, methisazone, entecavir, lamivudine, telbivudine, clevudine, adefovir, tenofovir disoproxil, tenofovir alafenamide, ribavirin, taribavirin, elbasvir, moroxydine, favipiravir, remdesivir and mericitabine.

The composition comprising the molecules according to the invention can be in any suitable form depending on the method preferred in terms of application of this composition to a patient. The composition comprising the molecules according to the invention, can be in solid form, for example a tablet or capsule or coated tablet form or can be formulized to be applied orally such as liquid dispersions or aqueous or lipid suspensions or the composition can be formulized for parenteral application such subcutaneous, intravenous, intramuscular, intrasternal, intraperitoneal, intradermal, transdermal or other similar infusion techniques. The composition comprising the molecules according to the invention can be formulized as a solution to be applied through the respiratory tract, such as a spray tube, or as a solution to be applied with an inhalation device or nebulizer. The molecules according to the invention are applied to the patient preferably as transdermal, subcutaneous, intranasal, intravenous, intramuscular, intratumoral or by inhalation. The most suitable way of application in any case shall be determined according to the molecules subject to the invention, the disposition of the disease and severity of the disease and the physical condition of the patient.

Within the context of this description document, the term comprising also defines the term including.

In technically suitable areas, the embodiments of the invention can be combined.

The embodiments have been described to include the certain features/components.

The description also includes other embodiments that comprise the features/components mentioned herein or embodiments that are made of said features/components.

Technical references such as the patents and applications have been incorporated herein by reference.

The embodiments that have been specifically or clearly described herein, may form a basis for re-arrangement with a disclaimer alone or together with one or more embodiments.

Several embodiments can be developed regarding the subject to the invention within the scope of these basic concepts and the invention is principally as defined in the claims and therefore it cannot be limited to the examples provided herein.

It is apparent that a person skilled in the art can convey the novelty subject to the invention using similar embodiments and/or can apply this embodiment to other fields using the art, having similar aims. Therefore it is obvious that these embodiments shall be void of novelty and especially the surpassing of the prior art criteria.

Claims

1. Molecules shown with Formula I and/or Formula II or salts, hydrates, solvates, polymorphs, stereoisomers, optical isomers, geometric isomers, enantiomers, diastereomers, and/or a combination thereof;

Formula II

wherein Rl is selected from;

CF₃ for used in the manufacture of a medicament for use in trematment of viral diseases.

2. Use according to claim 1, wherein Formula I molecule is Formula 1.25. .

Formula 1.25

3. Use according to claim 1, wherein Formula II molecule is Formula 11.23. .

Formula 11.23

4. A use according to claim 1, wherein the viral disease is selected from the group comprising; gastroenteritis, kerato conjunctivitis, pharyngitis, croup, pharyngoconjunctival fever, pnemonia, cystitis, foot and mouth disease, pleurodynia, aceptic menengitis, pericarditis, myocarditis, infectious mononucleosis, Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, acute hepatitis, chronic hepatitis, hepatocirrhosis, hepatocellular carcinoma, herpes, gingivostomatitis, tonsilitis, mucosa/mouth/genital ulcers, aceptic menengitis, cytomegalic inclusion disease, kaposi's sarcoma, castleman diseases, primary effusion lymphoma, AIDS, Reye’s syndrome, post infection encephalomyelitis, mumps disease, hyperplastic epithelial lesions, anogenital warts, laryngeal papilloma, epidermal dysplasia, verruciform, cervical carcinoma, squamose cell carcinoma, bronchiolitis, influenza, poliomyelitis, rabies, severe bronchiolitis together with pneumonia, congenital rubella, German measles, smallpox, herpes zoster, congenital varicella syndrome.

5. Pharmaceutical compositions comprising Formula I and/or Formula II or pharmaceutically acceptable salts, prodrugs, stereoisomers, optical isomers, enantiomers, diastereomers and/or combinations thereof for use in treatment of viral diseases;

Formula I

Formula II ;

wherein Rl is selected from;

OF₃

6. Pharmaceutical composition according to claim 5, comprising at least one or more excipients in addition to the active agent according to the invention.

7. Pharmaceutical composition according to claim 5 or 6, comprising at least one other active agent.

8. Pharmaceutical composition according to claim 7, wherein the other active agent is selected from a group comprising fusion and entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors, maturation inhibitors, protease inhibitors, pharmacokinetic boosters, DNA synthesis inhibitors, nucleic acid inhibitors, interferons, NS3/4A protease inhibitors, NS5A inhibitors, NS5B RNA polymerase inhibitors, anti-influenza agents and other agents.