Patent Application
20250057802
The present invention generally relates to broad-spectrum antiviral compounds that can be used as preventive and/or therapeutic antiviral medicine; pharmaceutical compositions or combinations comprising such compounds; and compounds or pharmaceutical compositions or combinations for use in the treatment (e.g., for preventive and/or therapeutic use) of viral infections.
Viral infections are one of the major causes of morbidity and mortality worldwide; and continue to threaten global public health causing a significant impact on society and economy. There is still a large group of infectious viruses for which no efficient vaccine or therapy has been approved.
A virus of great significance is the respiratory syncytial virus (RSV), also referred to as Human orthopneumovirus, which can lead to serious respiratory complications in premature infants, immunocompromised patients and elderly. RSV is an enveloped negative-sense single-stranded RNA virus of the family Pneumoviridae (genus Orthopneumovirus). RSV has a double layer lipid envelope, in which glycoproteins are embedded, including a Fusion (F) glycoprotein and an Adhesion (G) glycoprotein. There are two subgroups of RSV, A and B, which differ in the structure of the antigen of the Adhesion (G) glycoprotein. The Adhesion (G) glycoprotein is responsible for the specific adsorption of the virus particle onto the cell surface. During the entry of the virus into a host cell, the Fusion (F) glycoprotein induces fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. The Fusion (F) glycoprotein further interacts directly with heparan sulfate and may participate in virus attachment to the host cell.
RSV leads to infections of the respiratory tract, especially affecting the mucosa of the upper airways as well as the ciliated epithelium of the trachea and bronchia. Virus replication takes place in the ciliated epithelial cells of the mucous membranes of the respiratory tract. The epithelial cells are reversibly damaged by syncytia formation caused by the Fusion (F) glycoprotein and the body's own immune reaction.
Despite research efforts, there is neither a preventive vaccine nor an efficient treatment against RSV infection, and no effective, low-cost prophylactic or therapeutic approach has been developed. Many attempts for the development of effective vaccines or antibodies against RSV failed to confer protection either at preclinical or clinical stages. The only commercially available product is the monoclonal antibody Palivizumab (Synagis®, approved in 1998), the use of which is limited to high-risk patients in industrialized countries due to its high cost and the need of repetitive administrations. Palivizumab is used exclusively for seasonal immunoprophylaxis of RSV infection in populations with high risk for severe illness including premature infants and those suffering from chronic pulmonary disease. Palivizumab has limitations in clinical applications due to its high costs (Five doses of Palivizumab for a 5 kg infant cost approximately $5600) and the need for repeated administrations (IAN (1998): Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. PEDIATRICS 102 (3), pp. 531-537; Homaira et al. (2014): Effectiveness of Palivizumab in Preventing RSV Hospitalization in High Risk Children: A Real-World Perspective. International journal of pediatrics Volume 2014, Article ID 571609).
The treatment of RSV involves mainly symptom management and supportive care. Inhaled corticosteroids might be helpful in reducing RSV associated bronchiolitis symptoms. Ribavirin, a nucleoside analogue that blocks viral replication, is prescribed as a treatment in severe cases of RSV infection, but has little or no significant effect on reduction of RSV load. Besides, ribavirin is expensive, has teratogenic effects in animals and cannot be taken in pregnancy (Krilov, Leonard R. (2002): Safety issues related to the administration of ribavirin. In The Pediatric infectious disease journal 21 (5), pp. 479-481). Thus, unmet medical need for novel clinical and cost-effective antiviral agents against RSV remains a significant problem.
There is also unmet demand for clinically applicable and cost-effective antiviral agents against further viruses, such as Herpes simplex virus 1 (HSV-1), Human papillomavirus (HPV), the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Zika virus (ZIKV).
Besides the known viral strains with no available antiviral therapy, new strains emerge that might have epidemic potential and can rapidly spread worldwide leading to global pandemics. For other new emerging viruses, treatment is based mainly on supportive and symptomatic management whereas the prevention of infection depends solely on limiting the contact with infected individuals. Thus, broad-spectrum antivirals are of a great significance for fast combating of emerging viral infections.
Although some plant-derived antiviral compounds have been identified in the past, their therapeutic or prophylactic application has been compromised by poor activity and/or poor chemical stability.
To address these issues, there is demand for improved antiviral drugs having broad antiviral activity spectrum against different viral pathogens and allowing the prophylaxis and/or treatment of severe viral infections.
The present invention aims at providing compounds having potent antiviral activity. Preferably, the compounds should have broad-spectrum efficacy, including high inhibitory activity against Riboviria, more preferably Negarnaviricota (such as RSV), Pisuviricota (such as SARS-CoV-2), or Flavivirus (such as ZIKV); and/or further viruses, including Duplodnaviria (such as HSV-1) or Monodnaviria (such as HPV). Preferably, the compounds should exhibit low toxicity levels, to enable the treatment or prophylaxis against viral infections (such as RSV infection) in high-risk population, and/or may exhibit high stability.
As a solution, the present invention provides broad-spectrum antiviral compounds that can be used as preventive and/or therapeutic antiviral medicine; pharmaceutical compositions or combinations comprising such compounds; and compounds or pharmaceutical compositions or combinations for use in the treatment (e.g., for preventive and/or therapeutic use) of viral infections.
Specifically, the present invention provides compound, or a pharmaceutical composition comprising the compound, for use in a method for treating a viral infection caused by a virus belonging to a taxon selected from Duplodnaviria; Monodnaviria; Negarnaviricota; Pisuviricota; and Flavivirus; wherein the compound has a structure according to Formula (I), an enantiomer, a diastereoisomer, a hydrate, solvate, a crystal form, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein n is 0 or 1;
The present invention also provides a compound, or a pharmaceutical composition comprising the compound, for use in a method for treating a viral infection, wherein the compound has a structure according to the above Formula (I), an enantiomer, a diastereoisomer, a hydrate, a solvate, a crystal form, a tautomer, or a pharmaceutically acceptable salt thereof; and wherein in Formula (I):
wherein n is 0 or 1;
The present invention also provides a compound, or a pharmaceutical composition comprising the compound, wherein the compound has a structure according to the above Formula (I), an enantiomer, a diastereoisomer, hydrate, a solvate, a crystal form, a tautomer, or a pharmaceutically acceptable salt thereof, and wherein in Formula (I):
wherein n is 0 or 1;
The present invention also provides a pharmaceutical combination comprising: a compound having a structure according to the above Formula (I), an enantiomer, a diastereoisomer, hydrate, a solvate, a crystal form, a tautomer, or a pharmaceutically acceptable salt; and a peptide or a nanostructure;
the peptide having:
To design have identified improved antiviral compounds with unexpected antiviral potency. The designed compounds provide an attractive opportunity for potent and cost-effective antiviral therapies against viral infections, such as RSV infection and many other viral diseases.
Plant-based compounds with antiviral activity play an important role in the development of clinically useful antivirals and offer a source for the discovery of novel antiviral compounds. Plant-derived dicaffeoylquinic acid (DCQAs) compounds have been investigated for their antiviral activity. DCQAs showed strong inhibitory effects against RSV with low cytotoxicity in cell culture assays. Moreover, prophylactic treatment of mice with DCQAs lead to a reduction of viral loads in the lungs. However, the poor chemical stability of DCQA in the biological environment makes it rather unsuitable for clinical application. Additionally, there is a need for compounds with high antiviral activity against one or multiple viruses.
The present inventors have identified small-molecule compounds having high potential as effective broad-spectrum antiviral agents against a wide range of viruses, particularly RSV, SARS-CoV-2, HSV-1, HPV, and ZIKV. The compounds may have multiple advantages, including one or more of the following:
The compounds have potent antiviral activity against RSV as well as multiple other viruses including, but not limited to, SARS-CoV-2, HSV-1, ZIKV and HPV. The compounds may act directly on the viral particle, rather than on the target cells. These compounds may serve as cost-effective prophylactic and/or therapeutic broad-acting antiviral agents, and may be used either alone or in combinations with other viral inhibitors to treat viral single- or co-infections. Moreover, the antiviral compounds disclosed herein provide an opportunity for fast interventions against medically relevant emerging viruses.
The compounds may be used in combination with a peptide or nanostructure as further described below. The peptides show in vitro and in vivo antiviral efficacy. It has been demonstrated that the intranasal delivery of these peptides results in significant reduction of viral load in infected mice. A neutralizing epitope (Ø) may be chosen as a target and a computational method was used to design several peptide inhibitors of RSV fusion; the designed peptides bind specifically to the Ø site of the prefusion conformation of F protein and prevent its transition into the postfusion state. After binding, F protein cannot perform its fusion function anymore, and thus RSV infection of the host cell can be blocked.
Said peptides offer a variety of advantages. The mechanism of antiviral action of peptides involves preventing the fusion of RSV with target cell membrane by capturing RSV—F protein in its metastable prefusion conformation, thus making them suitable for RSV prophylaxis. Further, the targeting of RSV surface glycoprotein (F) by the peptides reduces undesirable side-effects. Moreover, short peptide sequences in the peptides offer a simpler and less expensive production opportunity than antibodies or proteins. Also, the peptides are safer and less toxic than synthetic molecules, and peptides are more stable than antibodies at different storage conditions. Further, the demonstrated in vivo efficacy after intranasal administration allows for non-invasive delivery of peptides directly to the site of action. This will minimize side-effects, decrease required doses and make the application outside hospital settings possible. In addition, the peptides can be used in a combination with small-molecule inhibitor compounds to achieve synergetic effects.
To increase binding efficacy, the peptides can be conjugated to nucleic acid nanostructures of the invention, such as DNA nanostructures. Those nanostructures may function as scaffold material and in contrast to common antibodies, the number of binding sites (peptides) and distances between them may be variable. Since RSV—F is a trimeric surface protein, a three-armed DNA nanostructure is preferably be chosen and modified with three new RSV—F binding peptides, but also other arrangements are possible. Since the persistence length of DNA may be 50 nm, the arms can be stiff. However, the center junction may be flexible and varied by incorporating unpaired bases, for example 3 or 5 extra thymines. In addition, the attachment of such peptides to DNA may improve their solubility and stability against proteases. In embodiments, to enhance their antiviral activity, three peptides are conjugated to three-armed DNA structures to achieve multivalent binding.
The peptides can serve as cost-effective replacement for monoclonal antibodies such as palivizumab—the so far only available prophylaxis against viral infections, e.g., RSV infections. The prophylaxis with the combination comprising the peptides or the nanostructure offers an attractive strategy for the prevention of RSV infection in high-risk populations.
The pharmaceutical combinations comprising peptides and/or nanostructures are useful for inhibiting entry of viruses, such as RSV, into mammalian cells. Further, the combinations comprising peptides and nanostructures are useful for inhibiting virus (e.g., RSV) spreading.
The present invention provides the following aspects and embodiments.
wherein n is 0 or 1;
wherein n is 0 or 1, preferably 1;
wherein n is 0 or 1; Yc is selected, independently for each occurrence, from O and NR7; and Lc is, independently for each occurrence, optionally substituted C1-6 alkylene, wherein carbon atoms from two groups among La, Lb, and Lc can optionally form, together with Z1, part of an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring;
wherein n is 0 or 1;
wherein n is 0 or 1;
In the context of the pharmaceutical combination to which above aspects 22 to 35 and appended claim 15 relate, protection is or may be sought for any features disclosed on pages 1 to 66 and FIGS. 1 to 12 of WO 2020/212576 A1, the entire disclosure of which, including all definitions, features and examples, explicitly and clearly belongs to the description of the present invention, as a part of said pharmaceutical combination.
The expression “alkyl” as used herein, unless specifically limited, denotes a suitable alkyl group, e.g., C1-6 alkyl group, e.g. C1-4 alkyl group. Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl). The alkyl groups may be linear or branched, acyclic or cyclic C1-6 preferably C1-3 alkyl, more preferably methyl.
The term “alkyl” also comprises cycloalkyl groups. The expression “cycloalkyl”, denotes a suitable alicyclic alkyl group, e.g., C3-6 cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. A most suitable number of ring carbon atoms is three to six.
The expressions “carbocyclyl” and “carbocyclic”, unless specifically limited, denote any ring system in which all the ring atoms are carbon and which contains between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms. Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocyclyl groups include bridged ring systems (e.g. bicyclo[2.2.1]heptenyl). A specific example of a carbocyclyl group is a cycloalkyl group. A further example of a carbocyclyl group is a cycloalkenyl group.
The expression “aryl”, unless specifically limited, denotes a C6-12 aryl group, suitably a C6-10 aryl group, more suitably a C6-8 aryl group. Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings). An example of a typical aryl group with one aromatic ring is phenyl. An example of a typical aryl group with two aromatic rings is naphthyl.
The expressions “heterocyclyl” and “heterocyclic”, unless specifically limited, refer to a carbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O. A specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O. Exemplary heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine and piperazine. A further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O. An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).
The expression “heteroaryl”, unless specifically limited, denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O. Heteroaryl groups represent a particular subtype within the general class of “heterocyclyl” or “heterocyclic” groups. Exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran, benzothiophene, quinoline, isoquinoline, indazole, benzimidazole, benzothiazole, quinazoline and purine.
The expression “alk”, for example in the expression “alkylene” may be interpreted in accordance with the definition of “alkyl”. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), and hexoxy (e.g. n-hexoxy). Exemplary haloalkyl groups include fluoroalkyl e.g. CF3; exemplary haloalkoxy groups include fluoroalkyl e.g. OCF3.
The term “halogen” or “halo” comprises fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
The terms “hydrogen” or “H” as used herein encompass all isotopes of hydrogen, in particular protium (1H) and deuterium (2H, also denoted as D).
The term “optionally substituted” refers to optional substitution by one or several substituents independently selected from: halogen, OH, CN, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)OH, C(O)O(C1-6 alkyl), and O(C1-6 alkyl), wherein each C1-6 alkyl is independently selected and can be optionally substituted with one or more of halogen, OH, CN, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)OH, C(O)O(C1-6 alkyl), and O(C1-6 alkyl). Further possible substituents encompassed by the meaning of “optionally substituted” may encompass C1-6 alkyl, C1-6 heteroalkyl, C1-6 carbocyclyl, C1-5 heterocyclyl and C1-5 heteroaryl group, each of which may be substituted by one or several halogen atoms and/or hydroxyl groups; a halogen atom; a cyano group; a primary, secondary or tertiary amino group; a hydroxyl group; and a carboxyl group. Each of the preceding substituents may be further optionally substituted; preferably with one or more of the substituents selected from the preceding lists; and/or with further substituents comprising a total of no more than 10 non-H atoms.
In any of the embodiments, aspects or claims, or the compound preferably does not have the structure of one or more, more preferably any of the compounds listed below:
wherein p is 2, 4 or 12, preferably 2-12; q is 1, 2, 3 or 4, preferably 1-4, and Rd is H or OH;
All possible stereoisomers of the claimed compounds are included in the present invention.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base, or by salt formation with an optically active base, such as quinine, quinidine, quinotoxine, cinkotoxine, (S)-phenylethylamine, (1R,2S)-ephedrine, (R)-phenylglycinol, (S)-2-aminobutanol, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
Salts, hydrates and solvates of the compounds of Formula I are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts, hydrates and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts, hydrates and solvates.
Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalenes-acrylic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1,4-benzenediacrylic), isethionic acids, perchloric, propionic, glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic, saccharinic and trifluoroacetic acid.
Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention.
The peptides or nanostructures contained in the combinations, or the pharmaceutical compositions described herein, can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free carboxyl groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., those formed with free amine groups such as those derived from isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc., and those derived from sodium, potassium, ammonium, calcium, and ferric hydroxides, etc.
Furthermore, some of the individual crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. In view of the close relationship between the free compounds and the compounds in the form of their salts, hydrates or solvates, whenever a compound is referred to in this context, a corresponding salt, solvate or polymorph is also intended, provided such is possible or appropriate under the circumstances.
As used herein, the term “tautomer” refers to the migration of protons between adjacent single and double bonds. The tautomerization process is reversible. Compounds described herein can undergo any possible tautomerization that is within the physical characteristics of the compound.
The pharmaceutical composition according to the present invention comprises a compound as described above, and a pharmaceutically acceptable excipient.
As used herein, the term “pharmaceutical composition” is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the claimed compounds. As used herein, the term “excipient” refers to a carrier, a binder, a disintegrator and/or a further suitable additive for galenic formulations, for instance, for liquid oral preparations, such as suspensions, elixirs and solutions; and/or for solid oral preparations, such as, for example, powders, capsules, gelcaps and tablets. Carriers, which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, granulating agents, dyes, and coloring agents.
Suitable the pharmaceutical dosage forms include but are not limited to oral, ophthalmic, inhalation, parenteral, topical, suppository etc. Preferably, the dosage forms can be powders, capsules, gelcaps and tablets, pills, syrups, pastes, ophthalmic solutions, eye drops, eye lotions, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, aerosols, inhalers, nebulizers, vaporizers, creams, gels, ointments, balms, lotions, ear drops, skin patches, suppositories, etc.
The compounds, pharmaceutical compositions or pharmaceutical combinations described herein described herein may be administered in any manner including, but not limited to, orally, parenterally, sublingually, transdermally, transmucosally, topically, via inhalation, via buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intra-peritoneal, subcutaneous and intramuscular. In a preferred embodiment, the composition or combination is formulated, in accordance with routine procedures, as a pharmaceutical composition adapted for intranasal, or intravenous administration to human beings.
Typically, compositions or combinations for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition or combination may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition or combination is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition or combination is administered by injection, an ampoule of sterile water or saline for injection can be provided so that the ingredients may be mixed prior to administration.
Preferably, the pharmaceutical composition or combination described herein is formulated for intranasal administration. The compounds, pharmaceutical compositions or combinations can be formulated, for example, in liquid form as nose drops, spray, or suitable for inhalation, as powder, as cream, or as emulsion. For straightforward application, the compound, pharmaceutical composition or combination is preferably supplied in a vessel appropriate for distribution of the peptide or nanostructures in the form of nose drops or an aerosol. More preferably, compounds, pharmaceutical compositions or pharmaceutical combinations described herein are administered by inhalation or spraying.
Preferably, the compounds, pharmaceutical compositions or pharmaceutical combinations described herein are formulated for a method of administration to the lungs of a subject by inhalation of an aerosol by the subject. Typically, the aerosol is delivered to the endobronchial space of airways from the subject. For example, the compounds, pharmaceutical compositions or pharmaceutical combinations may be delivered by a dry powder inhaler or by a metered dose inhaler.
The present disclosure provides compounds and/or a pharmaceutical compositions as described above for use in a method for therapy or prophylaxis of viral infections. The present disclosure also provides a method for therapy or prophylaxis of viral infections the method comprising administering a therapeutically effective amount of said compound or composition to a subject in need thereof.
The term “subject” as used herein refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, therapy, prophylaxis, observation or experiment.
The term “therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
In the context of the present invention, the term “treatment” is intended to encompass any kind of therapeutic or prophylactic treatment of the human or animal body. The terms “therapy” and “therapeutic treatment” cover prophylactic methods of treating a disease, curative methods of treating a disease, and/or methods for alleviation of symptoms of a disease. The terms “prophylactic treatment”, “preventive treatment” and “preventing” have the same meaning and denote a treatment aiming at maintaining health by preventing ill effects that would otherwise arise.
Viral infection which can preferably be treated with the compounds disclosed herein are those caused by specific viruses or viruses belonging to taxa shown in Table u below. The classification in Table 1 is according to the ICTV Virus Taxonomy: 2020 Release. Human papillomaviruses (HPV), in particular Alpha papillomaviruses (alpha-PVs) and the classification of their viral variants are described in more detail in Burk R D, et al. Classification and nomenclature system for human Alphapapillomavirus variants: general features, nucleotide landmarks and assignment of HPV6 and HPV11 isolates to variant lineages. Acta Dermatovenerol Alp Pannonica Adriat. 2011 September; 20(3):113-23. PMID: 22131111; PMCID: PMC3690374.
Simplexvirus
Alphapapillomavirus,
Orthopneumovirus
Betacoronavirus
Flavivirus
Betapapillomavirus, or
Gammapapillomavirus
Sarbecovirus
Human
Alphapapillomavirus 9
Human
Severe acute
Zika virus
alphaherpesvirus
orthopneumovirus
respiratory
syndrome-related
coronavirus
A solution of the respective diol (1 eq) was dissolved in DCM (0.1 M). 3,4,5-Tris(benzyloxy)benzoic acid (2.1 eq), DCC (2.3 eq) and DMAP (2.2 eq) were added and the mixture was heated to reflux for 18 hours. After cooling the formed precipitate was filtered off. The filtrate was evaporated and the residue was purified by flash chromatography (silica, chloroform).
The ester obtained in step 1 was dissolved in MeOH, treated with a catalytic amount of Pd/C and hydrogenated at 1.5 bar overnight. The mixture was filtered and the volatiles were evaporated. The crude was purified by semi-preparative HPLC.
For the synthesis of the triesters, 2 eq of 3,4,5-Tris(benzyloxy)benzoic acid, 3.3 eq of DMAP and 3.4 eq of DCC were used in the first step, and chloroform was used as the solvent in the second step.
The compound was synthesized from 1,3-propandiol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 15% (115 mg, 0.3 mmol), 1H-NMR, DMSO, 400 MHz: δ 2.08 (quin, 2H, 3J=6.4 Hz), 4.29 (t, 4H, 3J=6.4 Hz), 6.96 (s, 4H), 8.94 (br s, 2H), 9.26 (br s, 4H), HPLC: 8.96 min (98%), APCI-MS: m/z 381.1 [M+H]+
The compound was synthesized from 1,3-pentanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 5% (42 mg, 0.1 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.45-1.53 (m, 2H), 1.70-1.77 (m, 4H), 4.17-4.21 (m, 4H), 6.96 (s, 4H), 8.92 (s, 2H), 9.25 (s, 4H), HPLC: 10.93 min (100%), ESI-MS: m/z 407.2 [M−H]−
The compound was synthesized from 1,3-octanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 11% (95 mg, 0.21 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.36-1.40 (br s, 8H), 1.63-1.70 (m, 4H), 4.14-4.18 (m, 4H), 6.95 (s, 4H), 8.92 (br s, 2H), 9.25 (br s, 4H), HPLC: 13.6 min (100%), ESI-MS: m/z 449.2 [M−H]−
The compound was synthesized from 2,2-dimethyl-1,3-propanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 20% (158 mg, 0.39 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.08 (s, 6H), 4.06 (s, 4H), 6.98 (s, 4H), 8.80-9.40 (m, 6H), HPLC: 11.09 min (100%), ESI-MS: m/z 409.2 [M+H]+
The compound was synthesized from 2-(2-hydroxyethoxy)ethanol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 20% (158 mg, 0.39 mmol), 1H-NMR, DMSO, 400 MHz: δ 3.76-3.78 (m, 4H), 4.29-4.32 (m, 4H), 6.97 (s, 4H), 8.95 (br s, 2H), 9.27 (br s, 4H), HPLC: 8.37 min (100%), ESI-MS: m/z 411.1 [M+H]+
The compound was synthesized from cis-1,3-cyclohexanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 15% (120 mg, 0.29 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.34-1.47 (m, 3H), 1.49-1.58 (m, 1H), 1.82-1.86 (m, 1H), 1.98-2.01 (m, 2H), 2.37-2.40 (m, 1H), 4.85-4.91 (m, 2H), 6.95 (s, 4H), 8.93 (br s, 2H), 9.25 (br s, 4H), HPLC: 11.04 min (100%), ESI-MS: m/z 419.1 [M−H]−
The compound was synthesized from 2-benzyloxy-1,3-propanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 9% (70 mg, 0.18 mmol), 1H-NMR, DMSO, 400 MHz: δ 4.06-4.11 (m, 1H), 4.19-4.27 (m, 4H), 6.99 (s, 4H), 8.96 (br s, 2H), 9.27 (br s, 4H), HPLC: 7.44 min (100%), ESI-MS: m/z 395.0 [M−H]−
The compound was synthesized from 2-benzyloxy-1,3-propanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (4.2 mmol), DCC (4.6 mmol) and DMAP (4.4 mmol) as described above. Yield: 5% (36 mg, 0.09 mmol), 1H-NMR, DMSO, 400 MHz: δ 3.88-3.93 (m, 1H), 4.40-4.49 (m, 4H), 7.08 (s, 4H), 8.50 (br s, 3H), 9.28 (br s, 4H), HPLC: 6.03 min (97%), ESI-MS: m/z 396.2 [M+H]+
The compound was synthesized from glycerol (1 mmol), 3,4,5-tris(benzyloxy)benzoic acid (3.1 mmol), DCC (3.3 mmol) and DMAP (3.2 mmol) as described above. Yield: 6% (33 mg, 0.06 mmol), 1H-NMR, DMSO, 400 MHz: δ 4.45-4.58 (m, 4H), 5.53-5.58 (m, 1H), 6.95 (s, 6H), 8.60-9.60 (m, 9H), HPLC: 9.07 min (100%), ESI-MS: m/z 547.2 [M−H]−
The compound was synthesized from 2-Hydroxymethyl-1,3-propanediol (2 mmol), 3,4,5-tris(benzyloxy)benzoic acid (6.4 mmol), DCC (6.8 mmol) and DMAP (6.6 mmol) as described above. Yield: 10% (105 mg, 0.19 mmol), 1H-NMR, DMSO, 400 MHz: δ 2.67-2.73 (m, 1H), 4.37 (d, 6H, 3J=5.87 Hz), 6.99 (s, 6H), 8.99 (br s, 3H), 9.30 (br s, 6H), HPLC: 9.36 min (100%), ESI-MS: m/z 561.2 [M−H]−
The compound was synthesized from 1,1,1-Tris(hydroxymethyl)ethane (2 mmol), 3,4,5-tris(benzyl-oxy)benzoic acid (6.4 mmol), DCC (6.8 mmol) and DMAP (6.6 mmol) as described above. Yield: 1% (12 mg, 0.02 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.20 (s, 3H), 4.26 (s, 6H), 6.99 (s, 6H), 8.99 (br s, 3H), 9.30 (br s, 6H), HPLC: 9.95 min (100%), ESI-MS: m/z 575.2 [M−H]−
A solution of (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol (1 eq) in DCM (0.1 M) was treated with the respective benzoic acid derivative (1.1 eq), DCC (1.1 eq) and DMAP (1.1 eq) und heated to reflux overnight. The formed precipitate was removed by filtration and the filtrate was evaporated. The crude was purified by flash chromatography (silica, CHCl3).
The residue was dissolved in AcOH/H2O (3:1, v/v; 0.1 M) and heated to 90° C. for 4 hours. The volatiles were evaporated and the crude was purified by flash chromatography (silica, heptane/ethylacetate gradient).
The respective monoester was dissolved in DCM (0.1 M), treated with benzoic acid derivative (2.2 eq), DCC (2.2 eq) and DMAP (2.2 eq) and heated to reflux overnight. The formed precipitate was removed by filtration and the filtrate was evaporated. The crude was purified by flash chromatography (silica, CHCl3).
Deprotection of the phenol moieties was carried out by hydrogenation at 4 bar using Pd/C in CHCl3/MeOH (1:1, v/v). After completion, the solution was filtered through celite and evaporated. The crude was purified by semi-preparative HPLC.
The compound was synthesized from (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol (6 mmol), benzoic acid (6.6 mmol), DCC (6.6 mmol) and DMAP (6.6 mmol) for step 1 and 3,4,5-Tris(benzyloxy)benzoic Acid (3.6 mmol), DCC (3.6 mmol) and DMAP (3.6 mmol) for step 2 as described above. Yield: 7% (230 mg, 0.44 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.22 (s, 3H), 4.32-4.36 (m, 6H), 6.99 (s, 4H), 7.49-7.53 (m, 2H), 7.65-7.68 (m, 1H), 7.98-8.00 (m, 2H), 8.84-9.46 (m, 6H), HPLC: 13.28 min (100%)
The compound was synthesized from (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol (6 mmol), 3,4,5-Tris(benzyloxy)benzoic Acid (6.6 mmol), DCC (6.6 mmol) and DMAP (6.6 mmol) for step 1 and benzoic Acid (5.2 mmol), DCC (5.2 mmol) and DMAP (5.2 mmol) for step 2 as described above. Yield: 16% (445 mg, 0.93 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.24 (s, 3H), 4.37-4.41 (m, 6H), 6.99 (s, 2H), 7.48-7.52 (m, 4H), 7.64-7.68 (m, 2H), 7.97-7.99 (m, 4H), 8.88-9.42 (m, 3H), HPLC: 17.68 min (100%)
The respective amine (1 eq) was dissolved in DCM and cooled to 0° C. The triethylamine (2.1 eq) and 3,4,5-trimethoxybenzoyl chloride (2.1 equiv) were added portionwise. The mixture was stirred at 0° C. for one hour, then allowed to warm up to room temperature and stirring was continued overnight. The reaction was quenched by addition of water. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (silica, CHCl3/MeOH gradient).
The compound was dissolved in DCM and cooled to 0° C. BBr3 (9 eq, 1 M solution in DCM) was added dropwise. After stirring at room temperature overnight, the reaction was quenched by addition of water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated. The crude was purified by semi-preparative HPLC.
For the synthesis of the triamides, 3.3 eq of the respective benzoylchloride and 3.3 eq of TEA were used in the first step.
The compound was synthesized from 1,3-diaminopropan (1.5 mmol) and 3,4,5-trimethoxybenzoyl chloride (3.2 mmol) as described above. Yield: 3% (12 mg, 0.03 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.66-1.70 (quin, 2H, 3J=6.8 Hz), 3.20-3.24 (m, 4H), 6.83 (s, 4H), 8.07-8.10 (m, 2H), 8.50-9.60 (m, 6H), HPLC: 5.76 min (100%), ESI-MS: m/z 377.2.1 [M−H]−
The compound was synthesized from cadaverin (1.5 mmol) and 3,4,5-trimethoxybenzoyl chloride (3.2 mmol) as described above. Yield: 3% (17 mg, 0.04 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.28-1.33 (m, 2H), 1.46-1.54 (m, 4H), 3.14-3.19 (m, 4H), 6.81 (s, 4H), 8.02-8.05 (m, 2H), 8.59 (s, 2H), 8.98 (s, 4H), HPLC: 6.69 min (100%), ESI-MS: m/z 407.1 [M+H]+
The compound was synthesized from 1,10-diaminodecane (1.5 mmol) and 3,4,5-trimethoxybenzoyl chloride (3.2 mmol) as described above. Yield: 13% (95 mg, 0.2 mmol), 1H-NMR, DMSO, 400 MHz: δ 1.22-1.33 (m, 12H), 1.45-1.48 (m, 4H), 3.13-3.18 (m, 4H), 6.81 (s, 4H), 8.00 (m, 2H), 8.61 (br s, 2H), 8.98 (br s, 4H), HPLC: 11.14 min (100%), ESI-MS: m/z 475.1 [M−H]−
The compound was synthesized from diethylenetriamine (1.5 mmol) and 3,4,5-trimethoxybenzoyl chloride (5 mmol) as described above. Yield: 5% (39 mg, 0.07 mmol), 1H-NMR, DMSO, 400 MHz: δ 4.28-4.61 (m, 8H), 7.51-7.78 (m, 2H), 8.32 (s, 2H), 8.71 (s, 4H), 9.48-9.78 (m, 3H), 9.78-10.18 (m, 6H), HPLC: 5.55 min (100%), ESI-MS: m/z 558.0 [M−H]−
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and 3,4,5-trimethoxybenzoyl chloride (3.3 mmol) as described above. Yield: 18% (104 mg, 0.18 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.78 (s, 3H), 3.07-3.09 (m, 6H), 6.91 (s, 6H), 8.32-8.36 (m, 3H), 8.72 (br s, 1H), 9.13 (br s, 4H), HPLC: 7.68 min (>99%)
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and 4-methoxybenzoyl chloride (3.3 mmol) as described above. Yield: 16% (75 mg, 0.16 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.84 (s, 3H), 3.16 (d, 6H, 3J=6.4 Hz), 6.86 (d, 6H, 3J=8.7 Hz), 7.79 (d, 6H, 3J=8.7 Hz), 8.49 (t, 3H, 3J=6.4 Hz), 10.05 (br s, 3H), HPLC: 11.41 min (>99%); ESI-MS: m/z 478.5 [M+H]+
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and 3-methoxybenzoyl chloride (3.3 mmol) as described above. Yield: 13% (61 mg, 0.13 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.85 (s, 3H), 3.20 (d, 6H, 3J=6.6 Hz), 6.94-6.98 (m, 3H), 7.29-7.34 (m, 9H), 8.58 (t, 3H, 3J=6.6 Hz), 9.73 (br s, 3H), HPLC: 12.91 min (>99%); ESI-MS: m/z 478.2 [M+H]+
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and Piperonyloyl chloride (3.3 mmol) as described above. Yield: 3% (17 mg, 0.03 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.85 (s, 3H), 3.19 (d, 6H, 3J=6.5 Hz), 6.13 (s, 6H), 7.05 (d, 3H, 3J=8.2 Hz), 7.42 (d, 3H, 4J=1.7 Hz), 7.50 (dd, 3H, 3J=8.2 Hz, 4J=1.7 Hz), 8.51 (t, 3H, 3J=6.5 Hz), HPLC: 17.89 min (>99%); ESI-MS: m/z 562.4 [M+H]+
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and 2,4-dimethoxybenzoic acid (3 mmol). Amide coupling was performed using TBTU (3.3 mmol) and DIPEA (4.5 mmol) in DMF (5 ml) at room temperature overnight. The reaction was quenched with water and diluted HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (silica, CHCl3/MeOH gradient). Ether deprotection was carried out as described above. Yield: 6% (31 mg, 0.06 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.85 (s, 3H), 3.21 (d, 6H, 3J=6.5 Hz), 6.30 (d, 3H, 4J=2.4 Hz), 6.36 (dd, 3H, 3J=8.7 Hz, 4J=2.4 Hz), 7.73 (d, 3H, 3J=8.7 Hz), 8.73 (t, 3H, 3J=6.5 Hz), 10.09 (br s, 3H), 12.37 (br s, 3H), HPLC: 14.29 min (>99%); ESI-MS: m/z 526.4 [M+H]+
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and 3,4-dimethoxybenzoic acid (3 mmol). Amide coupling was performed using TBTU (3.3 mmol) and DIPEA (4.5 mmol) in DMF (5 ml) at room temperature overnight. The reaction was quenched with water and diluted HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (silica, CHCl3/MeOH gradient). Ether deprotection was carried out as described above. Yield: 16% (86 mg, 0.16 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.80 (s, 3H), 3.11 (d, 6H, 3J=6.5 Hz), 6.82 (d, 3H, 3J=8.2 Hz), 7.26 (dd, 3H, 3J=8.2 Hz, 4J=2.1 Hz), 7.36 (d, 3H, 4J=2.1 Hz), 8.42 (t, 3H, 3J=6.5 Hz), 9.21 (br s, 3H), 9.52 (br s, 3H), HPLC: 9.52 min (96.9%); ESI-MS: m/z 526.5 [M+H]+
The compound was synthesized from 2-(aminomethyl)-2-methyl-propane-1,3-diamine (1 mmol) and 2,3-dimethoxybenzoic acid (3 mmol). Amide coupling was performed using TBTU (3.3 mmol) and DIPEA (4.5 mmol) in DMF (5 ml) at room temperature overnight. The reaction was quenched with water and diluted HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (silica, CHCl3/MeOH gradient). Ether deprotection was carried out as described above. Yield: 23% (120 mg, 0.23 mmol), 1H-NMR, DMSO, 400 MHz: δ 0.90 (s, 3H), 3.29 (d, 6H, 3J=6.4 Hz), 6.67 (t, 3H, 3J=8.0 Hz), 6.96 (dd, 3H, 3J=8.0 Hz, 4J=1.4 Hz), 7.31 (dd, 3H, 3J=8.0 Hz, 4J=1.4 Hz), 8.87 (t, 3H, 3J=6.4 Hz), 9.30 (br s, 3H), 12.05 (br s, 3H), HPLC: 14.93 min (>99%); ESI-MS: m/z 526.5 [M+H]+
Compounds listed in Table 2 were synthesized as described above, screened for antiviral activity against RSV using an established in vitro RSV inhibitory assay, and displayed concentration-dependent inhibition of virus infection in the nanomolar concentration range. Compounds were also tested against SARS-CoV-2 in viral inhibition assay. Treatment of cells with compounds at nanomolar concentrations led to concentration-dependent inhibition of SARS-CoV-2 infection.
Dose-response curves for identified inhibitors against RSV and SARS-CoV-2, and for in vitro cytotoxicity analysis are exemplified in
To identify the site of action of designed inhibitors, compounds were either incubated with virus and then applied to cells or incubated on the cells and washed out prior to infection.
The results presented in
The antiviral activity of the identified molecules was not limited to RSV or SARS-CoV-2. Other viruses including HSV-1, HPV and ZIKV can be inhibited by the compounds at similarly low concentrations, as shown in
RSV was incubated with increasing concentrations either of small molecule compound 23 (
The results reveal that the compounds, compositions and combinations have the potential to be effective and inhibit different viruses in vitro. The inhibitors can serve as a cost-effective therapeutic or prophylactic approach for population groups for which the benefits of vaccination are limited, such as immunocompromised patients and elderly.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21184516.9 | Jul 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/069087 | 7/8/2022 | WO |
