AU2022359222A1 - A new class of antiviral drugs - Google Patents

A new class of antiviral drugs Download PDF

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AU2022359222A1
AU2022359222A1 AU2022359222A AU2022359222A AU2022359222A1 AU 2022359222 A1 AU2022359222 A1 AU 2022359222A1 AU 2022359222 A AU2022359222 A AU 2022359222A AU 2022359222 A AU2022359222 A AU 2022359222A AU 2022359222 A1 AU2022359222 A1 AU 2022359222A1
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derivative
independently selected
pharmaceutically acceptable
isomers
acceptable salts
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AU2022359222A
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Grigorii Mihajlovich BELOV
Ildar Rustemovich IUSUPOV
Denis Nikolaevich KAZYULKIN
Alexander Vital'evich KURKIN
Evgenii Renol'dovich LUKIANENKO
Ekaterina Vladimirovna MANASOVA
Mikhail Gennad'evich SHURYGIN
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Pharmasyntez JSC
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Pharmasyntez JSC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Abstract

The invention relates to new biologically active derivatives of substituted 2,3-dihydrofuran-3-ones, which can be used as antiviral agents with a broad spectrum of antiviral activity. The compound represented by Formula (I) is described: Formula (I). Also a method for treating viral disease, a method for preventing viral disease, pharmaceutical composition comprising compound according to claims 1-5 and pharmaceutically acceptable carrier and a method for obtaining of the compound of Formula (I) are described. The technical result of this invention is the development and production of new chemical compounds with high efficacy for the treatment of diseases caused by RNA viruses.

Description

A NEW CLASS OF ANTIVIRAL DRUGS
The invention relates to new biologically active derivatives of substituted 2,3- dihydrofuran-3-ones, which can be used as antiviral agents with a broad spectrum of antiviral activity.
Furanone derivatives have a broad spectrum of biological activity. The use of furanone derivatives as flavoring agents is well known from the prior art.
It is possible to use them as a treatment of central nervous system disorders (Ripka, Amy; Shapiro, Gideon; Chesworth, Richard 1,2-Disubstituted heterocyclic compounds as phosphodiesterase 10 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of CNS disorders and disorders affected by CNS function, W02009158393).
In addition, they can exhibit activity against enzymes from the mitogen- activated protein kinase pathway (Schiltz, Gary E.; Izquierdo-Ferrer, Javier; Vagadia, Purav; Clutter, Matthew R.; Mishra, Rama K.; Platanias, Leonidas C. SUBSTITUTED AROMATIC N-HETEROCYCLIC COMPOUNDS AS INHIBITORS OF MITOGEN-ACTIVATED PROTEIN KINASE INTERACTING KINASE 1 (MNK1) AND 2 (MNK2), US20180244654).
Furanones are known to be a structural component of natural compounds, particularly sorbifuranones, which inhibit tumor cell growth in culture (BRINGMANN GERHARD (DE) et al. Sorbifuranone, sorbivinetone, sorbivinetol and derivatives of these compounds, process for their preparation, medicines containing them and their use DE-102004005106-A1).
Furanones also possess antiparasitic activity (Li, Honglin; Zhao, Zhenjiang; Huang, Jin; Xu, Yufang; Xu, Minghao; Diao, Yanyan; Zhou, Hongchang; Jin, Huangtao; Gao, Rui; Zhu, Junsheng Preparation of heterocycles as DHODH inhibitors, WO2013075596).
It is also known that several furanone derivatives have antibacterial activity (WO 01/85664 A2). The closest structural analogue to the compounds of this invention is nivefuranone, a furanone derivative produced by Aspergillus niveus, which has activity against T-lymphotropic virus (proven on human lymphocyte cultures infected with type 2B T-lymphotropic virus with IC500.78 pg/mL in vitro) (Fujiwara T, Sato A, Kawamura Y, Matsumoto K, Itazaki H. Nivefuranone manufacture with Aspergillus niveus, Japanese Kokai Tokkyo Koho, Patent, 1994).
In the prior art, no furanone derivatives were identified as having a broad spectrum of antiviral activity, including antiviral activity against RNA viruses, in particular activity against coronaviruses such as MERS, SARS and SARS-CoV-2. The global CO VID-19 pandemic dictates the need of urgent development of a new generation of effective and safe antiviral drugs, since the existing antiviral drugs and vaccines have limited efficacy against SARS-CoV-2, especially its resistant strains.
The ability of the newly developed compounds to effectively inhibit the replication of RNA viruses of various types, including SARS-CoV-2, points to the potential applicability of 2,3-dihydrofuran-3-one structural class to treat infectious diseases in humans and animals.
Disclosure of the invention
The objective of the present invention is the design and creation of new compounds effective for the therapy of diseases caused by RNA viruses, in particular but not limited to the therapy of diseases caused by HCoV-OC43, HCoV-HKUl, HCoV-229E, HCoV-NL63, SARS, MERS and SARS-CoV-2 coronaviruses.
The technical result of the invention is the development and production of new chemical compounds with high efficacy for the treatment of diseases caused by RNA viruses.
The disclosed compounds are promising as therapies of infectious diseases, including but not limited to coronaviruses, in particular SARS-CoV-2 vims, as well as several other species.
Said technical result is achieved through the development and creation of compounds with the following General Formula (I), Formula (I) where R1 represents substituents of the following type where A represents a condensed Ce-aryl or a derivative thereof, 5-6- membered heteroaryl or a derivative thereof containing 1 to 3 heteroatoms independently selected from N, S, and/or O, the asterisk denotes the attachment point of the substituent;
X represents N or a substituent of the CR4 type, where R4 is independently selected and represents -H, -D, -F, -Cl, -Br, -I, - CN,
-CH2F, -CHF2, -CF3, -NO2, alkyl or a derivative thereof, alkenyl or a derivative thereof, alkynyl or a derivative thereof, Cr,-aryl, 5-6-membered heteroaryl or a derivative thereof containing 1 to 4 heteroatoms, independently selected from
N, S and/or O, -Cs-Cg-cycloalkyl or a derivative thereof, or a 4-9-membered heterocycle containing 1 to 4 heteroatoms independently selected from N, S and/or
O, as well as substituents, such as CH2ORa or -CH2N(Ra)2, where
Ra is independently selected and represents -H, a substituted or unsubstituted Ci-Ce-alkyl, alkenyl or a derivative thereof, -Cs-Cg-cycloalkyl or a derivative thereof, -Ce-aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, or a 4-9-membered heterocycle or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O;
Y is independently selected and is -H or a substituent of the following type
Z is independently selected and represents -H, -Li+, -Na+, -K+, -[N(Rf)4]+;
Rf is independently selected and represents -H, or -alkyl;
R2 and R3 are independently selected and represent alkyl or a derivative thereof, alkenyl or a derivative thereof, -Ce-Cio-aryl or a derivative thereof, a 5-10- membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, C3-C9-cycloalkyl or a derivative thereof, or a substituted or unsubstituted 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, and also substituents of the following type, the asterisk denotes the attachment point of the substituent
Xi, X2 and X3 are independently selected from -(CH2)n-, -O-, -S-, -S(=O)-, - S(=O)2- or substituents of the following type: where n is independently selected for Xi, X2 and X3 and can take values from
1 to 4; the substituents R2 and R3 together with the carbon atom, to which they are attached, can form a 8-14-membered spirocycle. The compound of Formula (I) can be a pharmaceutically acceptable salt or optical isomers.
In some particular embodiments of the invention, substituent R1 is selected from a group of bicyclic condensed 8-9-membered heteroaryls of the following type
Rb is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F,
-CHF2, -CF3, -OCF3, -OCHF2, -CN, -NO2, alkyl or its derivative, alkenylyl or its derivative, Cs-Cg-cycloalkyl or its derivative, as well as substituents such as - ORC, -SRC, -N(RC)2, -CON(RC)2, -COORC, -SO2RC, -SO2N(RC)2;
Rc is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted -Cs-Cg-cycloalkyl, a substituted or unsubstituted Ce-aryl, a substituted or unsubstituted 5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle, containing 1 to 4 heteroatoms, independently selected from N, S and/or O.
A separate subclass of compounds of interest includes compounds of General Formula (lb),
Formula (lb)
Rd is independently selected and represents alkyl or a derivative thereof, C3- Cg-cycloalkyl or a derivative thereof;
Re is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F,
-CHF2, -CF3, -OCF3, -OCHF2, -OAlk, -CN, -NO2, alkyl or a derivative thereof, alkynyl or a derivative thereof, Ca-Ce-cycloalkyl or a derivative thereof, Cr,- aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, or a 4-9- membered heterocyclyl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, as well as substituents such as -ORa, - N(Ra)2, -SRa, -SO2Ra, -C(=O)N(Ra)2.
In some particular embodiments of the invention, the compounds of interest may be selected from the following group:
Definitions (terms)
The following definitions apply throughout this document unless otherwise explicitly stated. In addition, unless otherwise specified, all occurrences of functional groups are chosen independently, two occurrences may be the same or different.
The term “alkyl” by itself or as part of another substituent, refers to saturated hydrocarbon groups with a straight or branched chain, including hydrocarbon groups having a specified number of carbon atoms (i.e. Ci-6-alkyl means an alkyl containing one to six carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl.
The term “alkynyl” by itself or as part of another substituent refers to hydrocarbon groups, in which at least one carbon-carbon bond is a triple bond, while the remaining bonds may be single, double or supplementary triple bonds, including hydrocarbon groups containing 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc.
The term “alkenyl” by itself or as part of another substituent refers to hydrocarbon groups, in which at least one carbon-carbon bond is a double bond, while the remaining bonds may be single or supplementary double bonds, including hydrocarbon groups containing 2 to 6 carbon atoms. Examples of alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1 -propenyl, 2-methyl-2 -propenyl, etc.
The term “halogen” by itself or as part of another term refers to an atom of fluorine, chlorine, bromine, or iodine.
The term “cycloalkyl” as used herein refers to groups containing 3 to 12 carbon atoms arranged in a mono- or polycyclic structure, including spirocycles. By way of illustration, cycloalkyl radicals include but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octanyl, spiro[5.5]undecanyl, which, as in the case of other aliphatic, heteroaliphatic or heterocyclic substituents, may also be substituted. The term “heterocycle” or “heterocyclic” means in this document nonaromatic mono- or polycyclic systems (saturated or partially unsaturated) having from three to twelve atoms and containing N, O or S heteroatoms. A heterocycle can be attached to the main fragment of the molecule through a nitrogen atom (N- heterocycle) or through a carbon atom. Heterocycles can also be substituted.
The term “cycloalkenyl” refers herein to a partially unsaturated cycloalkyl containing 5 to 12 carbon atoms with one or two double carbon-carbon bonds.
The term “aryl”, as used herein, means groups containing an aromatic cycle having five to ten carbon atoms. An example of aryl cyclic group is phenyl.
The term “heteroaryl,” “heteroaryl cycle”, as used herein, means a stable heterocyclic or polyheterocyclic aromatic fragment having 5-10 atoms in a cycle. A heteroaryl group may be substituted or unsubstituted and may consist of one or more rings. Possible substituents include but are not limited to any of the previously mentioned substituents. Examples of typical heteroaryl cycles are five- and sixmembered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, etc., as well as polycyclic heterocyclic groups such as benzo [b] thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, etc. The term “heteroaryl” can be used interchangeably with the terms “heteroaryl cycle” or “heteroaromatic.” An aryl or heteroaryl group (including the heteroaryl portion of heteroaralkyl or heteroaralkoxy fragments, etc.) may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include but are not limited to halogen (F, Cl, Br, or I), Ci-3-alkyl, -CN, -OH, -C1.3- alkyl and others.
The term “substituted” shall mean that one or more hydrogen atoms on any substitutable atom or group referred to as “substituted” is substituted with any of the abovementioned groups, provided that the said atom has normal valency, that the valency of the atom being replaced is not excessive, and that the substitution results in a stable compound. The term “substituted or unsubstituted” means that relevant compound or substructure is either unsubstituted or substituted, as defined in the application, with one or more substituents as mentioned or as defined here below.
In this document, alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups, as well as other substructures containing at least one hydrogen atom in their composition, can be substituted with one or more substituents:
-F, -Cl, -Br, -CN, -OH, -NO2, -NH2, -CF3, -CHF2, -CH2F, -Ci-C4-alkyl, -C2- C4-alkenyl, -C2-C4-alkynyl, -Cs-Cg-cycloalkyl, -4-9-membered heterocycle attached through C- or N-atoms, -phenyl, -5-6-membered heteroaryl attached through C- or N-atoms, -O-Rz, -N(RZ)2, -NRZ-C(=O)-RZ, -NRZ-S(=O)2-RZ, -S-Rz, -C(=O)-RZ, - C(=O)-ORZ, -C(=O)-N(RZ)2, -O-C(=O)-RZ, -O-C(=O)-(NRZ)2, -SO-N(RZ)2, -SO2-RZ, wherein each Rz is independently selected and represents -H, -Ci-Ce-alkyl, -C3-C9- cycloalkyl, -5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle containing 1 to 4 heteroatoms.
This invention contains only such combinations of substituents and derivatives that form stable or chemically possible compounds. A stable or chemically possible compound is a compound, the stability of which is sufficient for its synthesis and analytical detection. The preferred compounds of the present invention are sufficiently stable and do not decompose at temperatures up to 40 °C in the absence of chemically active conditions, for at least one week.
Some compounds of the present invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds unless otherwise specified.
The terms “isomer”, “optical isomer”, “stereoisomer” refer to any isomers — structural or optical isomers (i.e. stereoisomers). Unless otherwise indicated, the structures described herein also imply all their stereoisomers, i.e., the R- and S- isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of said compounds also belong to the subject matter of this invention. Therefore, the present invention covers each diastereomer or enantiomer that is largely free of other isomers (>90% and preferably >95% molar purity) as well as mixtures of such isomers.
Individual optical isomers can be obtained by racemate resolution according to a standard procedure, for example, obtaining diastereoisomeric salts by treatment with an optically active acid or base, subsequent separation of the mixture of diastereomers by crystallization followed by extraction of the optically active bases from these salts. Examples of suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric, and camphorsulfonic acid. Another technique for separating optical isomers involves using a chiral chromatographic column. Additionally, other method of racemate resolution involves the synthesis of covalent diastereomeric molecules by reacting compounds of this invention with an optically pure acid in activated form or an optically pure isocyanate. The resulting diastereomers can be separated by conventional methods such as chromatography, distillation, crystallization, or sublimation and then hydrolyzed to obtain enantiomerically pure compounds.
Optically active compounds of the present invention can be synthesized using optically active starting materials. Such isomers may be in the form of a free acid, free base, ester, or salt. The present invention includes all pharmaceutically acceptable isotopically labeled compounds according to the present invention, in which one or more atoms are substituted with atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature.
Examples of isotopes suitable for inclusion in compounds according to this invention include hydrogen isotopes, such as 2H and 3H, carbon isotopes, such as nC, 13C and 14C, chlorine isotopes, such as 36CI, fluorine isotopes, such as 18F, iodine isotopes, such as 123I and 125I, nitrogen isotopes, such as 13N and 15N, oxygen isotopes, such as 15O, 17O and 18O, phosphorus isotopes, such as 32P, and sulfur isotopes, such as 35S.
Some isotopically labeled compounds of Formula (I), such as those that include a radioactive isotope, are used in studies of drug and/or substrate distribution in tissues. In particular, radioactive isotopes such as tritium, i.e., 3H, and carbon-14, i.e., 14C, are used for this purpose because of the ease of their introduction and the availability of means of their detection.
Substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic effects due to metabolic stability, such as increased in vivo elimination half-life or reduced dosing rates, and, therefore, may be preferable in some cases.
Isotopically labeled compounds according to this invention can be prepared by conventional methods known to those skilled in the art or by methods similar to those described in the accompanying examples of synthesis methods, using appropriate isotopically labeled reagents instead of conventional (unlabeled) ones.
Pharmaceutically acceptable solvates according to this invention include solvates where the crystallization solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.
The term “solvate” is applicable to an association or complex containing one or more molecules of a solvent and a compound according to this invention. Examples of solvents that form solvates include but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
The term “hydrate” is applicable to a complex where the solvent is water.
Compounds of the present invention may exist in free form or, if required, in the form of a pharmaceutically acceptable salt or other derivative. The term "pharmaceutically acceptable salt" as used herein is applicable to such salts, which, to the best of medical judgment, are suitable for use in contact with human or animal tissues without undue toxicity, irritation, allergic reaction, etc., and have a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. The salts may be obtained in situ in the process of extraction or purification of the compounds of this invention, or they may be obtained separately by reacting a free acid or base of a compound of this invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic salts are amino group salts formed by inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids, such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipinate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formiate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2- hydroxy ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 -naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Typical salts of alkali and alkaline earth metals contain sodium, lithium, potassium, calcium, magnesium, etc. In addition, pharmaceutically acceptable salts may contain, if required, nontoxic ammonium, quaternary ammonium or amine cations obtained using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
Compounds of General Formula (I) can be prepared by reacting a,P-acetylene y-hydroxy nitrile derivatives with carboxylic acid derivatives according to the method described in literature [Synthetic Communications, 45: 2718-2729, 2015],
Scheme of Synthesis 1
A wide range of a,P-acetylene y-hydroxy nitrile and carboxylic acid derivatives previously known in the art, which may be commercially available or obtained by methods known to specialists, were used as starting compounds for synthesising the structure corresponding to Formula (I).
Examples illustrating the synthesis scheme are given below, as well as information confirming the obtainment of the claimed structures.
2-(5-Chloro-lH-indole-2-yl)-5-(3,5-dimethylphenyl)-5-methyl-4-oxo-4,5- dihydrofuran-3 -nitrile (HT 2020081).
4-(3,5-dimethylphenyl)-4-hydroxypent-2-initrile (1 eq, 1-10'3 mol, 200 mg), 5-chloro-lH-indole-2-carboxylic acid (1.1 eq, 1.1-10'3 mol, 215 mg) and triethylamine (1.3 eq, 1.3-10 "3~ mol, 132 mg/180 pl) were mixed together in 6 ml acetonitrile in a vial. The vial was purged with argon and sealed. The mixture was heated to 100 °C and stirred at that temperature for 12 h. After cooling, the mixture was evaporated, and the residue was purified by preparative column chromatography on silica gel (eluent — n— hexane: ethyl acetate = 3:1 (vol.), Rf = 0.40 (n— hexane: ethyl acetate = 1:1 (vol.)).
Yellow powder, 210 mg (56%).
’H NMR (400 MHz, CDC13, 6, ppm, J, Hz): 1.92 (s, 3H), 2.32 (s, 6H), 7.01 (s, 1H), 7.08 (s, 2H), 7.40 (dd, 1H, Ji = 2.0 Hz, J2 = 8.9 Hz), 7.44-7.48 (m, 1H), 7.73- 7.77 (m, 1H), 7.83 (dd, 1H, Ji = 0.8 Hz, J2 = 2.2 Hz), 9.32 (broad singlet, 1H).
2-(5-Chloro-lH-indole-2-yl)-5-(3,5-dimethylphenyl)-5-methyl-4-oxo-4,5- dihydrofuran-3 -nitrile (HT 2020078).
Obtained by the method described in Example 1 from cyanoacetylene and acid:
Yellow powder, 362 mg (81%).
’H NMR (400 MHz, CDC13, 6, ppm, J, Hz): 1.90 (s, 3H), 2.35 (s, 6H), 7.02 (s, 1H), 7.08 (c, 2H), 7.55 (2H, s), 8.05 (broad singlet, 1H), 9.55 (broad singlet, 1H).
In the described method, any suitable solvent may be used, preferably aprotonic with a high dielectric constant, preferably selected from triethylamine, acetonitrile, dimethylformamide, etc.
Heating is an optional step, because if the heating step is excluded, the synthesis is feasible, sometimes with increasing reaction timeT
The use of inert gas medium is optional, since its use is determined by the selection of reagents and reaction conditions.
Using the general Scheme of Synthesis 1 to obtain compound (I), chemical structures containing the following substituents were provided as starting compounds: where R1 represents substituents of the following type where A represents a condensed Ce-aryl or a derivative thereof, 5-6- membered heteroaryl or a derivative thereof containing 1 to 3 heteroatoms independently selected from N, S, and/or O, the asterisk denotes the attachment point of the substituent;
X represents N or a substituent of the CR4 type, where R4 is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -NO2, alkyl or a derivative thereof, alkenyl or a derivative thereof, alkynyl or a derivative thereof, Cr,-aryl, -5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, -Cs-Cg-cycloalkyl or a derivative thereof, or -4-9-membered heterocycle, containing 1 to 4 heteroatoms independently selected from N, S and/or O, as well as substituents such as -CH2ORa or -CH2N(Ra)2, where
Ra is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, alkenyl or a derivative thereof, -Cs-Cg-cycloalkyl or a derivative thereof,
-Ce-aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a 4-9- membered heterocycle or a derivative thereof, containing 1 to 4 heteroatoms independently selected from N, S and/or O;
Y is independently selected and is -H or a substituent of the following type
Z is independently selected and represents -H, -Li+, -Na+, -K+, -[N(Rf)4]+; Rf is independently selected and represents -H, or -alkyl;
R2 and R3 are independently selected and represent alkyl or a derivative thereof, alkenyl or a derivative thereof, -Ce-Cio-aryl or a derivative thereof, a 5-10- membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, Cs-Cg-cycloalkyl or a derivative thereof, or a substituted or unsubstituted 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, and also substituents of the following type, the asterisk denotes the attachment point of the substituent
Xi, X2 and X3 are independently selected from -(CH2)n-,- -O-, S-, -S(=O)-, -
S(=O)2-, or substituents of the following type: where n is independently selected for Xi, X2 and X3 and can take values from 1 to 4; substituents R2 and R3 together with the carbon atom, to which they are attached, can form a 8-14-membered spirocycle, where the compound of Formula (I) is a pharmaceutically acceptable salt or optical isomers.
In some particular embodiments of the invention, substituent R1 is selected from a group of bicyclic condensed 8-9-membered heteroaryls of the following type
Rb is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F, -CHF2, -CF3, -OCF3, -OCHF2, -CN, -NO2, alkyl or its derivative, alkenylyl or its derivative, C3-C9-cycloalkyl or its derivative, as well as substituents such as - ORC, -SRC, -N(RC)2, -CON(RC)2, -COORC, -SO2RC, -SO2N(RC)2;
Rc is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted -C3-C9-cycloalkyl, a substituted or unsubstituted Ce-aryl, a substituted or unsubstituted 5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle, containing 1 to 4 heteroatoms, independently selected from N, S and/or O.
The structure of the obtained compounds was verified by elemental analysis. Elemental analysis for carbon, hydrogen, nitrogen, and sulfur was performed on an elemental analyzer Flash EA 1112 CHNS-O/MAS 200 (Thermo Scientific, USA). Elemental analysis for fluorine, sodium, chlorine, bromine, and phosphorus was performed on an energy dispersive X-ray fluorescence spectrometer EDX-8100 (Shimadzu, Japan).
All synthesized compounds with activity against a group of viruses are described in Table 1.
Example 3
Antiviral activity against MERS, SARS, and SARS-CoV-2 viruses was studied using Vero E6 cell culture. The cells were cultured on DMEM medium supplemented with 10% FBS, antibiotic mixture, and L-glutamine at 37°C in a humid atmosphere containing 5% CO2. SARS-CoV-2 virus strains (VIC01/2020 and SPE-RII-3524 V/2020), HCoV-229E, and HCoV-EMC/2012 were used to infect the culture.
To study antiviral activity of the substances, their solutions in DMSO were introduced into the supporting nutrient medium in 10-fold dilutions in the range of concentrations that do not cause cytotoxicity. Virus at a concentration of 1,000 TCID50in 100 pl of medium was added to plates with a 1-day monolayer of Vero cells. One hour after infecting, dilutions of the studied substances were introduced at 100 pl per well in 2 replications. A virus control (100 pl of medium containing virus at a concentration of 1,000 TCID50 + 100 pl of supporting medium) and a negative cell control (200 pl of medium was added to the wells) were also used. After 72-hour incubation at 37°C in an atmosphere containing 5% CO2, the cytopathic effect of the virus was recorded using the MTT assay. The IC50 of the studied substance was determined from the optical density curve.
The study of antiviral activity against HIV-1 virus was performed on human MT-4 cell culture. The following cell culture medium was used: RPMI-1640 containing 0.2% sodium bicarbonate, supplemented with 10% inactivated fetal serum, 2 mM of L-glutamine, and 20 pg/ml of gentamicin.
Before determining antiviral activity, cytotoxicity of the studied substances was examined using the MTT assay. Subsequently, dilutions of the studied substance in the nontoxicity zone were used to determine the antiviral activity against HIV-1.
Concentrations of live cells not destroyed by HIV-1 were determined in the presence of HIV and studied compounds on a 96-well plate using the MTT assay. 30,000 MT-4 cells in 100 pl of complete RPMI-1640 medium were added to each well of the plate. Then, dilutions of the studied substance were prepared in a separate vessel in 5 -fold dilution increments, using non-toxic concentrations of the substances. Then, three replicates of each dilution of the substance were added in the amount of 50 pl to the corresponding wells containing cell culture. The volume of liquid in each well was brought to 200 pl by adding 50 pl of complete RPMI- 1640 medium. MT-4 cells with the dilutions of the studied substance were incubated for 5 days in a CO2 incubator at 37°C and 5% CO2. After that, 20 pl of MTT reagent solution were added, followed by incubation for 1.5 hours, and then IC50 of the studied substance was determined from the optical density curve.
The obtained IC50 values are given in Table 1.
Example 4.
Using compounds corresponding to Formula (I), which include the substituents indicated hereabove, and can also be pharmaceutically acceptable salts or optical isomers, the structure and activity of which are described in Table 1, pharmaceutical compositions were obtained comprising the active ingredient and pharmaceutically acceptable additional compounds (excipients) well known to those skilled in the art.
Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Compositions may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, covering agents, glidants, processing aids, colouring agents, sweeteners, fragrances, flavorings, diluents, and other known additives to provide an elegant presentation of a drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (e.g., a medicine).
The compositions were made by combining one or more of the compounds described in Table 1 with suitable excipients.
Methods for preparing various compositions can be found in Remington's Pharmaceutical Sciences, A. Gennaro (ed.), 18th edition, 1990, Mack Publishing Co., Easton, Pennsylvania. The following examples are for illustrative purposes only and should not be construed as limiting this invention. The term “active ingredient” refers to one or more of the compounds described in Table 1.
Example of obtaining a composition.
Sifted powder of a blend containing 10.0 g of active ingredient, 10.0 g of Crospovidone and 8.0 g of Macrogol 6000 is loaded into a ball mill and micronized for 30 minutes. The active ingredient mixed with Macrogol 6000 and Crospovidone is pelletized in a fluidized bed of 20% lactose and mannitol solution. The resulting pellet powder is dusted with sodium stearyl fumarate (2.0 g) in a cone mixer.
The resulting pharmaceutical formulation has the following composition (wt
%)
Other examples of pharmaceutical formulations may include acceptable excipients, both solid and liquid, forming the following compositions, for example:
Active ingredient — 95-99.99 wt%
Acceptable excipient — 0.1-5 wt%.
Or
Active ingredient — 0.1-4 wt%
Acceptable excipient — 96-99.99 wt% Solid finished dosage forms include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may contain from 0.1 to 100% of active ingredient.
Liquid finished dosage forms include solutions, suspensions and emulsions.
Aerosol preparations may include solutions or powders, which may be in combination with a pharmaceutically acceptable carrier.
Pharmaceutical product is preferably kept as a standard unit dose, i.e., in a form, in which it is present in standard unit doses of appropriate size containing appropriate amounts of the active ingredient.
Example 1. Tablets.
1.1. Tablets were produced by wet granulation and pressing.
The active ingredient was mixed with suitable excipients and carriers by means of wet granulation and pressing.
1.2. Tablets were produced by direct pressing of mixed ingredients.
Active ingredient was mixed with suitable excipients and carriers named hereabove by means of pressing.
Example 2. Capsules.
Capsules were produced by dispersing the active ingredient in suitable excipients and filling the mixture into capsules.
Example 4. Form for injections.
The active ingredient was mixed with liquid excipients, the mixture was filtered through a sterile microporous filter and sealed tightly in sterile glass ampoules.
Example. 5. Suspensions. Active ingredient was mixed with a suitable excipient to form suspensions.
The presented activity values of these compounds indicate that both the compounds and any blends thereof demonstrate positive effects in the treatment and prevention of viral diseases.
Methods for treating or/and preventing viral disease. A method for treating or/and preventing essentially consists of administration one or more compounds of Formula I and/or its pharmaceutically acceptable salt and/or one or more isomers (racemic mixture or single stereoisomer), pharmaceutical composition described above, and/or a combination thereof, which is not specifically limited and is determined depending on the drug's dosage form, patient's age, gender, other conditions, and severity of the disease.
Tablets, pills, liquids and solutions, suspensions, emulsions, granules and capsules were administered orally. Injections were administered intravenously in pure form or in a mixture with a common liquid substitute such as glucose, amino acids, etc.; if necessary intramuscular, intradermal, subcutaneous, or intraperitoneal administration of pure form of the drug was used. Suppositories are administered into the rectum.
The dosage of the aforementioned pharmaceutical product is chosen depending on intended use, patient's age, sex and other conditions and the severity of the disease, and the amount of the active ingredient is determined individually.
Table 1.

Claims (1)

  1. Claims
    1. A compound represented by Formula I, its pharmaceutically acceptable salt or isomer:
    Formula (I), where R1 represents substituents of the following type where A represents a condensed Ce-aryl or a derivative thereof, 5-6-membered heteroaryl or a derivative thereof containing 1 to 3 heteroatoms independently selected from N, S, and/or O, the asterisk denotes the attachment point of the substituent;
    X represents N or a substituent of the CR4 type, where R4 is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CN,
    -CH2F, -CHF2, -CF3, -NO2, alkyl or a derivative thereof, alkenyl or a derivative thereof, alkynyl or a derivative thereof, Ce-aryl, 5-6-membered heteroaryl or a derivative thereof containing 1 to 4 heteroatoms, independently selected from N, S and/or O, -Cs-Cgcycloalkyl or a derivative thereof, or a 4-9-membered heterocycle containing 1 to 4 heteroatoms independently selected from N, S and/or O, as well as substituents, such as CH2ORa or -CH2N(Ra)2, where
    Ra is independently selected and represents -H, substituted or unsubstituted -Ci-Ce-alkyl, alkenyl or a derivative thereof, -Cs-Cg-cycloalkyl or a derivative thereof, -Ce-aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a 4-9-membered heterocycle or a derivative thereof containing 1 to 4
    SUBSTITUTE SHEET (RULE 26) heteroatoms independently selected from N, S and/or O;
    Y is independently selected and is -H or a substituent of the following type
    Z is independently selected and is -H, -Li+, -Na+, -K+, -[N(Rf)4]+;
    Rf is independently selected and is -H, or -alkyl;
    R2 and R3 are independently selected and represent alkyl or a derivative thereof, alkenyl or a derivative thereof, -Ce-Cw-aryl or a derivative thereof, a 5-10-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, Cs-Cg-cycloalkyl or a derivative thereof, or a substituted or unsubstituted 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, and also substituents of the following type, the asterisk denotes the attachment point of the substituent
    Xi, X2 and X3 are independently selected from -(CH2)n-,- -O-, -S-, -S(=O)-, -S(=O)2-, or substituents of the following type: where n is independently selected for Xi, X2, and X3 and can take values
    SUBSTITUTE SHEET (RULE 26) from 1 to 4; where the compound of Formula I has substituents R2 and R3 together with the carbon atom, to which they are attached, can form an 8-14-membered spirocycle.
    2. A compound according to claim 1, where substituent R1 is selected from the group of bicyclic condensed 8-9-membered heteroaryls of the following type
    Rb is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CFhF,
    -CHF2, -CF3, -OCF3, -OCHF2, -CN, -NO2, alkyl or its derivative, alkenylyl or its derivative, Cs-Cg-cycloalkyl or its derivative, as well as substituents such as -ORC, -SRC, -N(RC)2, -CON(RC)2, -COORC, -SO2RC, -SO2N(RC)2;
    Rc is independently selected and represents -H, a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted -Cs-Cg-cycloalkyl, a substituted or unsubstituted Ce-aryl, a substituted or unsubstituted 5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle, containing 1 to 4 heteroatoms, independently selected from N, S and/or O.
    3. A compound of General Formula (lb), its pharmaceutically acceptable salt or optical isomer:
    SUBSTITUTE SHEET (RULE 26)
    Rd is independently selected and represents alkyl or a derivative thereof, Cs-Cg-cycloalkyl or a derivative thereof;
    Re is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F,
    -CHF2, -CF3, -OCF3, -OCHF2, -OAlk, -CN, -NO2, alkyl or a derivative thereof, alkynyl or a derivative thereof, Cs-Ce-cycloalkyl or a derivative thereof, Ce-aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, or a 4-9-membered heterocycle or a derivative thereof, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, as well as substituents such as -ORa, -N(Ra)2, -SRa, -SO2Ra, -C(=O)N(Ra)2.
    4. A compound, its pharmaceutical acceptable salt or optical isomer corresponding in structure to one of the following formulas
    SUBSTITUTE SHEET (RULE 26)
    5. A compound, its pharmaceutically acceptable salts or isomers corresponding in structure to the formula: senting a carboxylic acid derivative where R1 represents substituents of the following type where A represents a condensed Ce-aryl or a derivative thereof, 5-6-membered heteroaryl or a derivative thereof containing 1 to 3 heteroatoms independently selected from N, S, and/or O, the asterisk denotes the attachment
    42
    SUBSTITUTE SHEET (RULE 26) point of the substituent;
    X represents N or a substituent of the CR4 type, where R4 is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CN,
    -CH2F, -CHF2, -CF3, -NO2, alkyl or a derivative thereof, alkenyl or a derivative thereof, alkynyl or a derivative thereof, Ce-aryl, 5-6-membered heteroaryl or a derivative thereof containing 1 to 4 heteroatoms, independently selected from N, S and/or O, -Cs-Cgcycloalkyl or a derivative thereof, or a 4-9-membered heterocycle containing 1 to 4 heteroatoms independently selected from N, S and/or O, as well as substituents, such as CH2ORa or -CH2N(Ra)2, where
    Ra is independently selected and represents -H, substituted or unsubstituted -Ci-Ce-alkyl, alkenyl or a derivative thereof, -Cs-Cg-cycloalkyl or a derivative thereof, -Ce-aryl or a derivative thereof, a 5-6-membered heteroaryl or a derivative thereof, containing 1 to 4 heteroatoms independently selected from N, S and/or O, or a 4-9-membered heterocycle or a derivative thereof containing 1 to 4 heteroatoms independently selected from N, S and/or O;
    Y is independently selected and is -H or a substituent of the following type
    Z is independently selected and is -H, -Li+, -Na+, -K+, -[N(Rf)4]+;
    Rf is independently selected and is -H, or -alkyl; where substituent R1 is selected from a group of bicyclic condensed 8-9-membered heteroaryls such as
    SUBSTITUTE SHEET (RULE 26)
    Rb is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F,
    -CHF2, -CF3, -OCF3, -OCHF2, -CN, -NO2, alkyl or its derivative, alkenylyl or its derivative, C3-C9-cycloalkyl or its derivative, as well as substituents such as -ORC, -SRC, -N(RC)2, -CON(RC)2, -COORC, -SO2RC, -SO2N(RC)2;
    Rc is independently selected and represents -H, a substituted or unsubstituted Ci-Ce-alkyl, a substituted or unsubstituted C3-C9-cycloalkyl, a substituted or unsubstituted Ce-aryl, a substituted or unsubstituted 5-6-membered heteroaryl, containing 1 to 4 heteroatoms, independently selected from N, S and/or O, or a substituted or unsubstituted 4-9-membered heterocycle, containing 1 to 4 heteroatoms, independently selected from N, S and/or O to obtain compounds of General Formula I in accordance with any one of claims 1-5.
    7. A compound representing a derivative of a,P-acetylene y-hydroxy nitrile where R2 and R3 are independently selected and represent alkyl or a derivative thereof, alkenyl or a derivative thereof, -Ce-Cio aryl or a derivative thereof, a 5-10-membered heteroaryl or a derivative thereof, containing 1 to 4
    SUBSTITUTE SHEET (RULE 26) heteroatoms, independently selected from N, S and/or O, a Cs-Cg-cycloalkyl or a derivative thereof, or a substituted or unsubstituted 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, and also substituents of the following type, the asterisk denotes the attachment point of the substituent
    Xi, X2 and X3 are independently selected from -(CH2)n-,- -O-, -S-, -S(=O)-, -S(=O)2-, or substituents of the following type: where n is independently selected for Xb X2, and X3 and can take values from 1 to 4; where the compound of Formula I has substituents R2 and R3 together with the carbon atom, to which they are attached, can form an 8-14-membered spirocycle, as well as R2 and R3 are independently selected and represent: Rd is independently selected and represents an alkyl or a derivative thereof, C3-C9-cycloalkyl or a derivative thereof; Re is independently selected and represents -H, -D, -F, -Cl, -Br, -I, -CH2F, -CHF2, -CF3, -OCF3, -OCHF2, -OAlk, -CN, -NO2, alkyl or its derivative, alkynyl or its derivative, C3-C6-cycloalkyl or its derivative, Ce-aryl or its derivative, a 5-6-membered heteroaryl or its derivative, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, or a 4-9-membered heterocycle or a derivative thereof, containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, as well as substituents such as -ORa, -N(Ra)2, -SRa, -SO2Ra, -C(=O)N(Ra)2 to obtain compounds of General Formula I in accordance with any one of
    45
    SUBSTITUTE SHEET (RULE 26) claims 1-5.
    8. A compound according to any one of claims 1-5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for use as a medicine with antiviral activity.
    9. A compound according to claim 3 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for use as a medicine with antiviral activity.
    10. A compound according to claim 4 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for use as a medicine with antiviral activity.
    11. A compound according to claim 5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for use as a medicine with antiviral activity.
    12. A compound according to any one of claims 1-5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for preparing a medicine with antiviral activity.
    13. A compound according to claim 3 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for preparing a medicine with antiviral activity.
    14. A compound according to claim 4 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for preparing a medicine with antiviral activity.
    15. A compound according to claim 5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers for preparing a medicine with antiviral activity.
    16. A pharmaceutical composition comprising one or more compounds according to claims 1-5 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof and one or more excipients.
    17. A pharmaceutical composition comprising one or more compounds
    46
    SUBSTITUTE SHEET (RULE 26) according to claim 3 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof, and one or more excipients.
    18. A pharmaceutical composition comprising one or more compounds according to claim 4 and/or one or more pharmaceutically acceptable salts thereof and/or one or more optical isomers thereof, and one or more excipients.
    19. A pharmaceutical composition comprising the compound according to claim 5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers, and one or more excipients.
    20. A pharmaceutical composition according to claim 16 for use as a medicine with antiviral activity.
    21. A pharmaceutical composition according to claim 17 for use as a medicine with antiviral activity.
    22. A pharmaceutical composition according to claim 18 for use as a medicine with antiviral activity.
    23. A pharmaceutical composition according to claim 19 for use as a medicine with antiviral activity.
    24. A pharmaceutical composition according to claim 16 for preparing a medicine with antiviral activity.
    25. A pharmaceutical composition according to claim 17 for preparing a medicine with antiviral activity.
    26. A pharmaceutical composition according to claim 18 for preparing a medicine with antiviral activity.
    27. A pharmaceutical composition according to claim 19 for preparing a medicine with antiviral activity.
    28. A method for treating viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claims 1-5 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof.
    29. A method for treating viral disease comprising administration to a
    SUBSTITUTE SHEET (RULE 26) subject a therapeutically effective and safe amount of one or more compounds according to claim 3 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof.
    30. A method for treating viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claim 4 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof.
    31. A method for treating viral disease comprising administration to a subject a therapeutically effective and safe amount of the compound according to claim 5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers.
    32. A method for treating viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claims 1-15 and/or one or more pharmaceutical compositions according to claims 16-27.
    33. A method for preventing viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claims 1-5 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof.
    34. A method for preventing viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claim 3 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof.
    35. A method for preventing viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claim 4 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof.
    36. A method for preventing viral disease comprising administration to a subject a therapeutically effective and safe amount of the compound according to
    48
    SUBSTITUTE SHEET (RULE 26) claim 5 and/or one or more of its pharmaceutically acceptable salts and/or one or more of its isomers.
    37. A method for preventing viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more compounds according to claims 1-15 and/or one or more pharmaceutical compositions according to claims 16-27.
    38. A method for treating viral disease option comprising administration to a subject a therapeutically effective and safe amount of one or more pharmaceutical compositions according to claims 16-19.
    39. A method for preventing viral disease comprising administration to a subject a therapeutically effective and safe amount of one or more pharmaceutical compositions according to claims 16-19.
    40. A method of obtaining any compound according to claims 1-5, comprising in the reaction of an a,P-acetylene y-hydroxy nitrile derivative with a carboxylic acid derivative in the presence of a base in a solvent.
    41. The use of one or more compounds according to any one of claims 1-15 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof for preparing a medicine with antiviral activity.
    42. The use of one or more pharmaceutical compositions according to any one of claims 16-27 for preparing a medicine with antiviral activity.
    43. The use of one or more medicines according to claims 8-27 for treating or preventing viral disorders.
    44. A medicine obtained from one or more compounds according to claims 1-15 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof and/or compositions according to claims 16- 27 for treating or preventing viral disorders.
    45. A medicine having antiviral activity in the form of tablets, capsules, powders, dispersible granules, cachets, suppositories, injections, solutions, suspensions or emulsions placed in a pharmaceutically acceptable packaging,
    49
    SUBSTITUTE SHEET (RULE 26) where said medicine comprises therapeutically effective and safe amounts of one or more compounds according to any one of claims 1-15 and/or one or more pharmaceutically acceptable salts thereof and/or one or more isomers thereof and/or a pharmaceutical composition according to claims 16-27.
    50
    SUBSTITUTE SHEET (RULE 26)
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