WO2009016526A2 - Éthers d'acides 5-hydroxy-1h-indole-3-carboniques substitués, compositions pharmaceutique, procédé de fabrication et d'utilisation - Google Patents

Éthers d'acides 5-hydroxy-1h-indole-3-carboniques substitués, compositions pharmaceutique, procédé de fabrication et d'utilisation Download PDF

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WO2009016526A2
WO2009016526A2 PCT/IB2008/052302 IB2008052302W WO2009016526A2 WO 2009016526 A2 WO2009016526 A2 WO 2009016526A2 IB 2008052302 W IB2008052302 W IB 2008052302W WO 2009016526 A2 WO2009016526 A2 WO 2009016526A2
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optionally substituted
methyl
hydroxy
indole
carboxylic acid
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PCT/IB2008/052302
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Russian (ru)
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WO2009016526A3 (fr
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Andrey Alexandrovich Ivashchenko
Alexander Vasilievich Ivashchenko
Volodymyr Mikhailovich Kysil
Ilya Matusovich Okun
Nikolay Filippovich Savchuk
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Alla Chem, Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new esters of substituted lH-indol-3-carboxylic acids with antiviral activity, and their use as active ingredients in pharmaceutical compositions and the use of the latter for the preparation of drugs used for the prevention and treatment of viral diseases, especially caused by influenza A viruses and B and acute respiratory infections, infectious hepatitis (HCV, HBV), human immunodeficiency (HIV), SARS and bird flu.
  • HCV infectious hepatitis
  • HBV human immunodeficiency
  • SARS virus flu.
  • Viral infections can cause many diseases, which poses a serious threat to human health and life. Over the past 20 years, at least 30 completely new pathogens of infectious diseases have been discovered: AIDS, viral hepatitis, acute and chronic diarrhea, hemorrhagic fevers (Ebola, Venezuelan, Brazilian, Rift Valley) [a) Lednicky JA, Rayner J. O. Upsomoprespositorogu . ⁇ urr. Orip. PuIm. Honey. 2006, 12 (3), 235-239. b) Naudep FG Respirator viral threats. ⁇ urr. Orip. Ipfest. Dis. 2006, 19 (2), 169-178].
  • Arbidol An anti-influenza drug Arbidol is known which includes 6-bromo-4- [(dimethylamino) methyl] -5-hydroxy-l-methyl-2 - [(phenyl) thio] methyl-lH-indole-3 ethyl hydrochloride as an active ingredient - carboxylic acid [Arbidol, PCT Ipt. Arrl. WO 9008135, 1990].
  • Arbidol is used to treat and prevent diseases caused by influenza viruses.
  • Arbidol has the effect of inducing interferon and exhibits an immunomodulating effect [Arbidol. Drugs R. D. 1999, Ser; 2 (3), 171-172. Gluskova, T .; Glushk réellev, R. ⁇ bidol - Ipterferop, industrial, immulative, aptiapt. Rev. Esp. Quimioter. 2000, 13 (Suppl. 2), Abstr. M182].
  • the antiviral activity of Arbidol with respect to the avian influenza A / H5 viruses has recently been shown [Fedyakina I. T., Leneva I.
  • CC50 10-20 mm
  • SIso selectivity index
  • TCso 15–25 ⁇ g / ml
  • TCso 15–25 ⁇ g / ml
  • Antiviral pharmaceutical compositions comprising Arbidol analogues of the general formula Al [PCT Ipt Arrl. W02004060873, 2004; PCT IPT Arrl. WO 2005/087729 Al, 2005. Bioorg. Honey. Chem. 2006, 14 (4), 911-917].
  • R 1 represents alkyl or cycloalkyl
  • Ri 4 and R 2 4 independently represent an amino substituent selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl, or Ri and R 2 , together with the nitrogen atom to which they are bonded form through Ri and R 2 an optionally substituted azaheterocyclyl
  • W is a substituted mercapto group.
  • Analogues of Arbidol of the general formula Al also show inhibitory activity against influenza A and B viruses, as well as against hepatitis B viruses (HBV) and human immunodeficiency (HIV) [Viorg. Honey. Chem. 2006, 14 (4), 911-917. PCT IPT Arrl. WO 2005/087729 Al, 2005].
  • esters of substituted 5-hydroxy-6-bromo-III-indole-3-carboxylic acids of the general formula AIl are known, which are used to prepare compounds of the general formula Al having antiviral properties [PCT Ipt Arrl. W02004060873, 2004; PCT IPT Arrl. WO 2005/087729 Al, 2005. Bioorg. Honey. Chem. 2006, 14 (4), 911-917].
  • R 1 represents alkyl or cycloalkyl
  • R 2 is optionally substituted alkyl
  • W is a substituted mercapto group.
  • esters of substituted 6-bromo-5-hydroxy-2-methyl-III-indole-3-carboxylic acids A12 intermediates for the synthesis of substances exhibiting bactericidal [Joshi, Ragavepdra G .; Gadagipamat, Guru S .; Pujar, Vasauua G. J. IPdiap Chem. Soc. 1994, 71 (4), 175-178] and cardiovascular properties [Tavara, Tetsuua; Ikebe, Tsugio; Nakamata, Ishiro; Yaoka, Osamu. JP 63188665 A 19880804 Shaw. Arrlistiop: JP 87-21514 19870130].
  • R represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted phenyl.
  • Esters of substituted 5-hydroxy-lH-indole-3-carboxylic acids of the general formula A21 are also known [WO 2004060873 (2004); SU 1258046 Al, 11/21/92; SU 1327491 Al,
  • R is an amino substituent selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted and optionally annelated heterocyclyl
  • R is an alkyl substituent selected from hydrogen, an optionally substituted mercapto group, an optionally substituted amino group, an optionally substituted hydroxyl
  • R 3 is optionally substituted lower alkyl
  • R 4 represents a substituent of a cyclic system selected from hydrogen or a bromine atom.
  • Esters of substituted 5-hydroxy-2-methyl-lH-indole-3-carboxylic acids of the general formula A22 are known which are obtained in connection with a study of the Nenicecu reaction [Behavior thoroughlyf 2-halo-apd 2-trifluoromethyl-l, 4-benzoquinones Nepitzesu ipodole supsis. Littell, Rudd; Allep, George R., Jr. J. Org. Chet. 1968, 33 (5), 2064-2069.] And as intermediates in the synthesis of CCR-5 chemokine receptor antagonists [Preraratiopof ruproloboxurol apd apalogs as CCR-5 chemoprograms chemoprotec. Narrimap, Geraldip C; KoIz, Christian Nulupd; LuIy, Jau R .; Roth, Vas David; Sopg, Yuptao; Trivedi, What Calidas. WO 2000042045 (2000)]
  • R 1 represents an amino group substituent selected from hydrogen, optionally substituted alkyl
  • R is an alkyl substituent selected from hydrogen, an optionally substituted amino group, an optionally substituted hydroxy group, R is an optionally substituted alkyl
  • Ri and R 2 independently from each other represent a substituent of the cyclic system selected from hydrogen, optionally substituted alkyl, halogen, CN, NO 2
  • “Aheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a cycle.
  • An azaheterocycle may have one or more ((cyclic substituents)) systems.
  • “Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH bond.
  • An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section.
  • aliphatic radicals include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksial- keel, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, nile geteroaralke-, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, nile geteroaralke-, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylheter cyclic, annelated arylhe
  • Alkenyl means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including a carbon-carbon double bond. Branched - means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n- butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylmethyl and pyridylmethyloxycarbonylmethyl.
  • Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylbutenyl.
  • Alkenyloxy means an alkenyl-O— group in which alkenyl is defined in this section. Preferred alkenyloxy groups are allyloxy and 3-butenyloxy. “Alkenyloxyalkyl” means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more “lower alkyl” substituents. Alkyl may have one or more identical or different substituents (“alkyl substituents))), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl.
  • Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentyl methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxymethyl, benzyl methoxycarbonylmethyl; and pyridylmethyloxycarbonylmethyl.
  • Alkyloxyalkyl means an alkyl-O-alkyl group in which the alkyl groups are independent of each other and are defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and isopropyloxyethyl.
  • Preferred alkyloxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, iso-propyloxycarbonyl, benzylcarbonyl and phenethylcarbonyl.
  • Alkylthio means an alkyl-S group in which an alkyl group is defined in this section.
  • Alkoxy means an alkyl-O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl.
  • Preferred alkoxycarbonylalkyl groups are: methoxy-carbonylmethyl, ethoxy-carbonylmethyl, methoxy-carbonyl-ethyl, ethoxy-carbonylethyl.
  • “Aminograppa” means Rk a Rk + i a N is a group substituted or unsubstituted ((by an amino group substituent)) Rk a and Rk + ⁇ whose meaning is defined in this section, for example, amino (H 2 N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino.
  • amino acid means a natural amino acid or a non-natural amino acid, the meaning of which is defined in this section.
  • Preferred amino acids are amino acids containing an ⁇ or ⁇ amino group.
  • natural amino acids are ⁇ -amino acids, they can be alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, series, threonine and cysteine.
  • Annelized cycle (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycycle with which it is “annealed” have at least two common atoms.
  • “Annelated apylheterocycloalkenyl” means annelated aryl and heterocycloalkenyl, the meaning of which is defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system.
  • the prefix “aza”, “okca” or “tia” before “heterocycloalkenyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated arylheterocycloalkenyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocycloalkenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
  • Representatives of annelated arylheterocycloalkenyls are indolinyl, ⁇ -2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroxinolinyl, and the like.
  • Annelated apylheterocycloalkyl means annelated aryl and heterocycloalkyl, the meaning of which is defined in this section. Annelated arylheterocycloalkyl can bind through any possible atom of the cyclic system.
  • the prefix "aza”, “okca” or “tia” before “heterocycloalkyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated arylheterocycloalkyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocycloalkyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
  • Representatives of annelated arylheterocycloalkyls are indolyl, 1,2,3,4-tetrahydroisoxinoline, 1,3-benzodiocol, and the like.
  • “Annelated apylcycloalkenyl” means annelated aryl and cycloalkenyl, the meanings of which are defined in this section. Annelated arylcycloalkenyl can bind through any possible atom of the cyclic system.
  • Annelated arylcycloalkenyl may have one or more ((cyclic substituents)), which may be the same or different.
  • Representatives of annelated arylcycloalkenyls are 1, 2-dihydro-naphthalene. inden, etc.
  • Annelated apylcycloalkyl means annelated aryl and cycloalkyl, the meanings of which are defined in this section. Annelated arylcycloalkyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkyl may have one or more ((cyclic substituents)), which may be the same or different. Representatives of annelated arylcycloalkyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-l-yl, and the like.
  • Annelated heteroapylcycloalkenyl means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system.
  • the prefix “aza”, “okca” or “tia” before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated heteroarylcycloalkenyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoxinolinyl, 4,5-dihydro-III-benimidazolyl, and the like.
  • “Annelated heteroapylcycloalkyl” means annelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system.
  • the prefix "aza", “okca” or “tia" before "heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated heteroarylcycloalkyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • Representatives of annelated heteroarylcycloalkyls are 5,6,7,8-tetrahydro-quinolinyl, 5,6,7,8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-lH-benimidazolyl, and the like.
  • “Annelated heteroapylheterocycle” means annelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section.
  • Annelated heteroarylheterocyclenyl can bind through any possible atom of the ring system.
  • the prefix “aza”, “okca” or “tia” before ((heteroaryl)) means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated heteroarylheterocyclenyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • the nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
  • annelated heteroarylheterocyclenyls are l, 2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [l, 7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, etc. .
  • “Annelated heteroapylheterocyclyl” means annelated heteroaryl and heterocyclyl, the meanings of which are defined in this section. Annelated heteroaryl heterocyclyl can bind through any possible atom of the ring system.
  • heteroapyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated heteroaryl heterocyclyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • the nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
  • annelated heteroaryl heterocyclyls are 2,3-dihydro-III-pyrpolo [3,4-b] quinolin-2-yl, 2,3-dihydro-III-pyrpolo [3,4-b] indol-2-yl, l, 2,3,4-tetrahydro [l, 5] naphthyridinyl and the like.
  • “Aralkenyl” means an arylalkenyl group in which the meanings of aryl and alkenyl are defined in this section. For example, 2-phenethyl is an aralkenyl group.
  • Alkyl means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl. “Aralkylamino” means an arylalkyl-NH-group in which the meanings of aryl and alkyl are defined in this section.
  • Alkylcylfinyl means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.
  • Alkylcylphonyl means an aralkyl-SO2 group in which the meaning of aralkyl is defined in this section.
  • Alkylthio means an aralkyl-S- group in which the meaning of aralkyl is defined in this section.
  • Alkoxy means an aralkyl-O— group in which the meaning of aralkyl is defined in this section. For example, benzyloxy or 1- or 2-naphthylenmethoxy are aralkyloxy groups.
  • Alkoxyalkyl means an aralkyl-O-alkyl group in which the meanings of aralkyl and alkyl are defined in this section.
  • An example of an aralkyl-O-alkyl group is benzyloxyethyl.
  • An example of an aralkoxycarbonyl group is benzyloxycarbonyl.
  • An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.
  • Aromal means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
  • “Apyloxy” means an aryl-O- group in which the meaning of aryl is defined in this section. Representatives of the aryloxy groups are phenoxy and 2-naphthyloxy.
  • Representative aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.
  • Aminyl means an aryl-SO— group in which the meaning of aryl is defined in this section.
  • “Apylcylphone” means an aryl-SO-group in which the meaning of aryl is defined in this section.
  • “Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.
  • “Aromatic cycle” means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system including, according to the Hückel rule, (4n + 2) ⁇ -electrons (n is a non-negative integer).
  • aromatic cycles examples include benzene, naphthalene, anthracene, and the like.
  • Heteroapomatic rings in the conjugation system involve ⁇ -electrons and p-electrons of heteroatoms, their total number also equals (4n + X). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like.
  • An aromatic ring may have one or more ((cyclic substituents)) systems and may be annelated with a non-aromatic ring, heteroaromatic or heterocyclic system.
  • acylamino means an acyl-NH— group in which the meaning of acyl is defined in this section.
  • Halogen means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred.
  • Heteroneless loop means the loop that attaches
  • Heteroapalkenyl means a heteroaryl-alkenyl group in which heteroaryl and alkenyl are defined in this section.
  • heteroaryl alkenyl includes a lower alkenyl group.
  • Representatives of heteroaryl alkenyls are 4-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl, and the like.
  • Heteroapalkyl means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section.
  • Representative heteroarylalkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.
  • Heteroapalkyloxy means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section.
  • Representatives of heteroarylalkyloxy groups are 4-pyridylmethyloxy, 2-thienylmethyloxy and the like.
  • Heteroapyl means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with a heteroatom or hetero atoms, such as nitrogen, sulfur or oxygen.
  • aza means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • the nitrogen atom in the heteroaryl can be oxidized to N-oxide.
  • Heteroaryl may have one or more ((cyclic substituents)), which may be the same or different.
  • heteroaryl compounds are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1, 2,4-thiadiazolyl, imidinazinyl, pyridazinyl, pyridazinyl, -a] pyridinyl, imidazo [2, lb] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, pyrrolopyridinyl, thien
  • Heterocycle means a non-aromatic monocyclic or polycyclic system containing from 3 to 13 carbon atoms, preferably from 5 to 13 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom such as nitrogen, oxygen, sulfur and which contains at least at least one carbon-carbon double bond or carbon-nitrogen double bond.
  • aza, "okca” or “thia” before heterocyclenyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Heterocyclenyl may have one or more ((cyclic substituents)), which may be the same or different.
  • heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide.
  • Representatives of heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1, 2-dihydro-pyridine, 1,4-dihydropyridine, 2-pyrpolinyl, 3-pyrrolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl, etc.
  • Heterocyclyl means an aromatic or non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur.
  • aza, “okca” or “tia” before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Heterocyclyl may have one or more ((cyclic substituents)), which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide.
  • Heterocyclyloxy means a heterocyclyl-O— group in which heterocyclyl is defined in this section.
  • “Hydrate” means a solvate in which water is a molecule or molecules of a solvent.
  • Hydroalkyl means a HO-alkyl group in which alkyl is defined in this section.
  • “Substituent” means a chemical radical that attaches to the scaffold (fragment), for example, “substituent alkyl”, “substituent of the amino group)),“ substituent carbamoyl, ”((substituent of the cyclic system)), the meanings of which are defined in this section.
  • alkyl substituent "means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section.
  • the alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy , alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylcycloalkyl, annelated heteroarylcycloalkyl otsiklenil, annelated heteroarylheterocyclyl, annelated arylcycl
  • Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl, methoxycarbonylmethyl and pyridylmethyloxycarbonylmethyl.
  • amino group substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, aryl sulfonyl, arylsulfonyl arylaminocarbonyl, heteroarylamino-carbonyl, heterocyclylaminocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcyclo lkenil, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system, including hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl , nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfonyl, heterocylsulfyl nile, arylsulfonic finil, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, heterocyclylthio,
  • Electrophilic substituent means a chemical radical that binds to scraffold as a result of a reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), esters of organic sulfonic acids or organic sulfonyl chlorides, organic haloformates, organic isocyanates and organic isothiocyanates.
  • Substituted amino group means an Rk a Rk + i a N group in which Rk a and Rk + i a are amino substituents, the meaning of which is defined in this section.
  • Substituted carboxyl means a C (O) OR group.
  • the substituted carboxyl has a substituent R, including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
  • Substituted group means an SR, S (O) R or S (O 2 ) R group in which the substituent R is alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
  • “Protection group” means a chemical radical that attaches to a scaffold or intermediate to temporarily protect the amino group in multifunctional compounds, including but not limited to: an amide substituent such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl, 3- phenylpropionyl and others), optionally substituted benzoyl and others; a carbamate substituent, such as optionally substituted Ci-C 7 alkyloxycarbonyl, for example, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; an optionally substituted Ci-C 7 alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylphyloinyl and the like; sulfonyl substituent, for example,
  • Protected primary or secondary amine "means a group of the formula Rk a Rk + i a N-, in which Rk a represents a protective group PG and Rk + i a represents hydrogen," a substituent of the amino group)), the meaning of which is defined in this section for example alkenyl, alkyl, aralkyl, aryl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, heteroalkyl heteroalkyl annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, heterocyclenyl or heterocyclyl.
  • “Inert substituent)) (or” not interfering)), “Nop -terferipg substituept”) means a low or non-reactive radical, including, but not limited to Ci - C 7 alkyl, C 2 - C 7 alkenyl, C 2 - C 7 alkynyl, Ci - C 7 alkoxy, C 7 - Ci 2 aralkyl substituted with inert aralkyl substituents, C 7 - Ci 2 heterocyclylalkyl, substituted with inert substituents heterocyclylalkyl, C 7 - Ci 2 alkaryl, C 3 - Ciu cycloalkyl, C 3 - Ciu cycloalkenyl , phenyl, substituted phenyl, toluyl, xylene, biphenyl, C 2 - Ci 2 alkoxyalkyl, C 2 - Ciu alkylsulfinyl, C 2 - Ciu alkylsulfony
  • Preferred "inert substituents)) are Ci - C 7 alkyl, C 2 - C 7 alkenyl, C 2 - C 7 alkynyl, Ci - C 7 alkoxy, C 7 - Ci 2 aralkyl , C 7 - Ci 2 alkaryl, C 3 - Cyu cycloalkyl, C 3 - Cyu cycloalkenyl, substituted with inert substituents Ci - C 7 alkyl, phenyl substituted with inert substituents phenyl, (CH 2 ) m -O- (Ci - C 7 alkyl), - (CH 2 ) m —N (Ci - C 7 alkyl) n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.
  • Carbamoyl may have one or more identical or different ((carbamoyl substituents "R k a and R k + i a including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
  • Carbamoylheterocycle means an azaheterocycle containing at least one carbamoyl group as ((a substituent of the cyclic system)).
  • the meanings of “asheterocycle”, ((substituent of the cyclic system)) and “carbamoyl group”) are defined in this section.
  • “Kapbocycle)> means a mono- or polycyclic system consisting only of carbon atoms.
  • Carbocycles can be either aromatic or alicyclic.
  • Alicyclic polycycles may have one or more common atoms.
  • one spirocarbocycles form (for example, spiro [2.2] pentane) in the case of a common atom, in the case of two
  • “Combinative library” means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold and the library is a collection of related homologs or analogues.
  • Methylene radical means —CH 2 — a group that contains one or two identical or different “alkyl substituents”, the meanings of which are defined in this section.
  • Non-aromatic cycle saturated cycle or partially saturated cycle
  • a non-aromatic ring may have one or more ((cyclic substituents)) systems and may be annelated with aromatic, heteroaromatic or heterocyclic systems.
  • Examples of non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidine.
  • Optional aromatic cycle means a cycle that can be either aromatic or non-aromatic, the meanings of which are defined in this section.
  • Optional substituted radical means a radical without substituents or containing one or more substituents.
  • 1,3-propylene radical means —CH 2 —CH 2 —CH 2 — a group that contains one or more identical or different ((alkyl substituents ”, the meanings of which are defined in this section.
  • Leader means a compound with outstanding (maximum) physiological activity associated with a specific biological target related to a specific (or several) pathology or disease.
  • Compound-hit (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.
  • “Family group” means R k a R k + i a NSO 2 is a group substituted or unsubstituted ((by amino substituents)) R] / and R k + A whose values are defined in this section.
  • Cylfonyl means R-SO 2 - a group in which R is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroaryl heterocyclylalkenyl, annelated heteroaryl heterocyclylalkylalkyl the meaning of which is defined in this section.
  • Tempolate means the general structural formula of a group of compounds or compounds included in ((combinatorial library)).
  • (Therapeutic cocktail) is a simultaneously administered combination of two or more drugs that have a different mechanism of pharmacological action and are aimed at different biological targets involved in the pathogenesis of the disease.
  • Thiocarbamoyl may have one or more identical or different ((amino substituents)) Rk a and Rk + i a , the meaning of which is defined in this section, for example, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
  • Cycloalkyl means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more ((substituents on the cyclic system)), which may be the same or different. Representatives of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be annelated with an aromatic ring or heterocycle. Preferred ((substituents of the cyclic system)) are alkyl, aralkoxy, hydroxy or Rk a Rk + i a N, the meaning of which is defined in this section.
  • Representatives of cycloalkylcarbonyl groups are cyclopropylcarbonyl or cyclohexylcarbonyl.
  • Cycloalkoxy means a cycloalkyl-O— group in which the meaning of cycloalkyl is defined in this section.
  • “Pharmaceutical Composition” means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceptive agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents you, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like.
  • the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin.
  • suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • grinders and distributors are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • compositions for oral administration, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers.
  • suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, for example, therapeutic shakes, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of compounds or prepared specially. In particular, base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (A detailed description of the properties of such salts is given in Werg SM, et al, PHARMACECUTAL SALTS J.
  • Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized.
  • Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
  • Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
  • amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
  • amino acids the main amino acids can be used - lysine, ornithine and arginine.
  • “Fragment” means the structural formula of a part of a molecule characteristic of a group of compounds or a molecular framework characteristic of a group of compounds or compounds included in a “combination library)).
  • 1,2-Ethylene radical means —CH 2 —CH 2 - a group that contains one or more identical or different ((alkyl substituents ”, the meaning of which is defined in this section.
  • the aim of the present invention are new biologically active substances exhibiting antiviral activity.
  • R 1 is an amino group substituent selected from hydrogen, optionally substituted lower alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl selected from phenyl, naphthyl or 5-6 membered heteroaryl containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, and optionally condensed with a benzene ring, or optionally substituted saturated heterocyclyl, which is a possibly substituted 5-6 membered heterocyclyl with 1-2 heteroatoms in a heterocyclic ring lice selected from nitrogen and oxygen;
  • R represents an alkyl substituent selected from hydrogen; optionally substituted hydroxy; an optionally substituted mercapto group; an optionally substituted arylsulfinyl group; optionally substituted arylsulfonyl group; an optionally substituted amino group; optionally substituted saturated or unsaturated N-heterocyclyl;
  • R represents hydrogen or optionally substituted lower alkyl;
  • Ri and R 2 independently represent
  • esters of substituted Sh-indol-3-carboxylic acids are ethyl esters of substituted 5-hydroxy-l-methyl-Sh-indole-3-carboxylic acids of the general formula 1.1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • R 2 has the above meaning
  • Ar is an aryl or 5-6 membered heterocyclyl comprising at least one heteroatom selected from N, O or S, optionally fused to a benzene ring.
  • esters of substituted lH-indol-3-carboxylic acids are ethyl esters of substituted 5-hydroxy-2-hydroxymethyl-l-methyl-lH-indole-3-carboxylic acids of general formula 1.2 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • Ri 4 has the above meaning
  • R 5 represents a hydrogen atom, optionally substituted lower Ci-C 5 alkyl, optionally substituted aryl, or optionally substituted azaheterocyclyl, optionally fused to a benzene ring.
  • esters of substituted lH-indol-3-carboxylic acids are ethyl esters of substituted 5-hydroxy-2-apyloxymethyl-l-methyl-III-indole-3-carboxylic acids of the general formula 1.2.1 or their racemates, or their optical isomers or their pharmaceutically acceptable salts and / or hydrates.
  • Ri has the above meaning;
  • R is a cyclic system substituent selected from hydrogen, halogen, lower alkoxy, halogen-substituted alkyl, cyano.
  • esters of substituted S-indol-3-carboxylic acids are ethyl esters of substituted 5-hydroxy-2-mercaptomethyl-l-methyl-S-indole-3-carboxylic acids of the general formula 1.3 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • Ri has the above meaning;
  • R represents optionally substituted lower Ci-C 5 alkyl, optionally substituted aryl or optionally substituted azaheterocyclyl.
  • esters of substituted S-indol-3-carboxylic acids are ethyl esters of substituted 5-hydroxy-2-mercaptomethyl-l-methyl-S-indole-3-carboxylic acids of the general formula 1.3.1 or their racemates, or their optical isomers or their pharmaceutically acceptable salts and / or hydrates.
  • Ri 4 has the above meaning
  • R 8 is optionally substituted lower Ci-C 5 alkyl, optionally substituted aryl or optionally substituted azaheterocyclyl.
  • esters of substituted lH-indol-3-carboxylic acids are ethyl esters of substituted 2-aminomethyl-5-hydroxy-l-methyl-lH-indol-3-carboxylic acids of the general formula 1.4 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • Ri 4 has the above meaning
  • Ri 9 and R 2 9 independently represent an amino substituent selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl, or Ri and R 2 , together with the nitrogen atom to which they are bonded form through Ri and R 2 optionally substituted azaheterocyclyl.
  • esters of substituted lH-indole-3-carboxylic acids are ethyl esters of substituted 2-aminomethyl-5-hydroxy-l-methyl-III-indole-3-carboxylic acids of the general formula 1.4.1 or their racemates, or their optical isomers or their pharmaceutically acceptable salts and / or hydrates.
  • Ri and R 2 have the above meanings;
  • R represents a bromine atom, a fluorine atom, CF3, CN, possibly substituted aryl, possibly substituted heterocyclyl.
  • esters of substituted lH-indole-3-carboxylic acids are 2 - [(dimethylamino) methyl] -6-fluoro-5-hydroxy-l-methyl-lH-indole-3-carboxylic acid ethyl ester 1.4.1 (1 ), 2 - [(dimethylamino) methyl] -6-trifluomethyl-5-hydroxy-l-methyl-lH-indol-3-carboxylic acid ethyl ester 1.4.1 (2), 2 - [(dimethylamino-5-methyl] ethyl ester] -hydroxy-l-methyl-6-cyano- ⁇ -indol-3-carboxylic acid 1.4.1 (3), ethyl 2 - [(dimethylamino) methyl] -5-hydroxy-l-methyl-6-phenyl-III -indole-3-carboxylic acid 1.4.1 (4), ethyl 2 - [(dimethylamino)
  • Esters of substituted H-indol-3-carboxylic acids of general formula 1 may form hydrates or pharmaceutically acceptable salts.
  • Inorganic acids and organic acids can be used to produce salts, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid , benzenesulfonic acid, para-toluenesulfonic acid. Hydrates are usually formed by recrystallization of compounds of general formula 1 or their salts from water or water containing solvents.
  • substituted Sh-indol-3-carboxylic acid esters of general formula 1 as biologically active ingredients of pharmaceutical compositions having antiviral activity, including against influenza A and B viruses, acute respiratory diseases, infectious hepatitis (HCV, HBV), SARS, bird flu and human immunodeficiency (HIV).
  • More preferred pharmaceutical compositions are those containing, as an active ingredient, at least one substituted 5-hydroxy-S-indole-3-carboxylic acid ester of general formula 1 or a racemate thereof, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and / or hydrate. More preferred pharmaceutical compositions are those containing, as an active ingredient, at least one substituted 5-hydroxy-S-indole-3-carboxylic acid ester of the general formula 1.1, 1.2, 1.3 or 1.4, or its racemate, or its optical isomer or a pharmaceutically acceptable salt and / or hydrate thereof.
  • compositions are those containing, as an active ingredient, at least one substituted 5-hydroxy-lH-indole-3-carboxylic acid ester of formula 1.4.1 (1) -1.4.1 (17) or its racemate, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate.
  • compositions may include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field.
  • the pharmaceutical composition along with the esters of substituted lH-indol-3-carboxylic acids of the general formula 1 of the present invention may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.
  • compositions of the present invention can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).
  • oral forms such as tablets, gelatine capsules, pills, solutions or suspensions
  • injection forms such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use
  • local forms such as ointments or solutions).
  • the carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical industry to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.
  • the aim of the present invention is also a method for producing pharmaceutical compositions.
  • This goal is achieved by mixing the active ingredient with an inert filler and / or solvent, the distinguishing feature of which is that at least one ester of a substituted lH-indol-3-carboxylic acid of the general formula 1 or its racemate is used as the active ingredient. or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate.
  • compositions containing, as an active ingredient, at least one ester of a substituted H-indol-3-carboxylic acid of general formula 1 or a racemate thereof, or an optical isomer thereof, or a pharmaceutically acceptable salt and / or thereof hydrate is used to obtain drugs in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, for the prevention and treatment of various viral diseases, including diseases caused by influenza A viruses and B, acute respiratory infections, infectious hepatitis viruses (HCV, HBV), SARS, bird flu and human immunodeficiency (HIV).
  • the subject of this invention is also therapeutic cocktails for the prevention and treatment of viral diseases, including diseases caused by influenza A and B viruses, acute respiratory infections, infectious hepatitis (HCV, HBV), SARS, bird flu and human immunodeficiency ( HIV), including, as one of the components, a drug obtained on the basis of a pharmaceutical composition containing, as an active ingredient, at least one ester of a substituted lH-indol-3-carbo new ki slots of the general formula 1, or its racemate, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate.
  • viral diseases including diseases caused by influenza A and B viruses, acute respiratory infections, infectious hepatitis (HCV, HBV), SARS, bird flu and human immunodeficiency ( HIV), including, as one of the components, a drug obtained on the basis of a pharmaceutical composition containing, as an active ingredient, at least one ester of a substituted lH-indol-3-carbo new ki slots of the general formula 1, or its race
  • Therapeutic cocktails for the prevention and treatment of influenza and acute respiratory diseases, along with the medicines of this invention may include other well-known anti-influenza drugs, for example: Adamantanamine hydrochloride (Serrebramed, Hocmapt, Lucovir, Mapadir, Zamelir, Zamelir, Zamelir phosphate (Oseltamivir rhosphate, Tamiflu), L-Glutamyl-L-tryptophan (Glufapide, Oglufapide, Tumogep, Timogep), Rimantadine hydrochloride (Flumadir, Irrevir, Irrevir, Irvir Therapeutic shakes for the prevention and treatment of hepatitis C (HCV), along with the drugs of this invention, may include: inosine-5-monophosphate dehydrogenase, for example, ribavirin (allowed) and ribamidine; hepatitis C protease NS3 inhibitors, for example, Telapre
  • Therapeutic shakes for the prevention and treatment of hepatitis B (HBV), along with the drugs of this invention, may include: reverse transcriptase inhibitors, for example, Lamivudine (Lamivudiipe) and Tenofovir (Tepofovir); DNA polymerase inhibitors, for example, Telbivudine (Telbivudiipe), Entecavir (Eptesavir) and Adefovir (Adefovir diropivil); immunostimulants, for example, Serion (Serosiop); as well as angiogenesis inhibitors, hepatoprotectors, various proteins (e.g. interferons), antibodies, vaccines, etc.
  • reverse transcriptase inhibitors for example, Lamivudine (Lamivudiipe) and Tenofovir (Tepofovir
  • DNA polymerase inhibitors for example, Telbivudine (Telbivudiipe), Entecavir (Eptesavir
  • a method for the prevention and treatment of viral diseases of animals and humans including those caused by influenza A and B viruses, acute respiratory diseases, infectious hepatitis (HCV, HBV), human immunodeficiency (HIV), bird flu and SARS (SARS) ), consists in administering to a warm-blooded animal or human a medicine in the form of tablets, capsules or injections containing, as an active ingredient, at least one ester of a substituted 1 H-indole-3-carboxylic acid of the general formula 1 or e racemate, or optical isomer thereof, or a pharmaceutically acceptable salt and / or hydrate or therapeutic cocktails comprising these medicaments.
  • Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically).
  • the clinical dosage of the active substance of the general formula 1 in patients can be adjusted depending on: therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the age, sex and stage of the patient’s disease, with a daily dose of adults usually 10 ⁇ 500 mg, preferably 50 ⁇ 300 mg. Therefore, when preparing the pharmaceutical composition of the medicament of the present invention as dosage units, the above effective dosage, with each dosage unit containing 10 ⁇ 500 mg of the substituted lH-indol-3-carboxylic acid ester of general formula 1, preferably 50 ⁇ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).
  • Example 1 Obtaining a combinatorial library of esters of substituted 5-hydroxy-1 H-indole-3-carboxylic acids of the general formula 1. The synthesis is carried out according to known methods described in the articles and patents [PCT IPT Aprl. W02004060873, 2004; PCT IPT Arrl. WO 2005/087729 Al, 2005. Bioorg. Honey. Chem. 2006, 14 (4), 911-917. Joshi, Rahavepdra G .; Gadagipamat, Guru S .; Pujar, Vasauua G. J. IPdiap Chem. Soc. 1994, 71 (4), 175-178.
  • Example 3 The antiviral activity of a pharmaceutical composition containing one of the compounds of the general formula 1 as shown in Table 1 as an active ingredient was determined against viruses of specially cloned human hepatocytes (Huh7.5.1) with increased sensitivity to hepatitis C virus infection [RaIf Bartepsvichlagger * update Thomas Rietzhhapp. Rros Natl Acad S Kievi USA. 2005 JuIy 12; 102 (28): 9739-9740]. Cells were cultured in Dulbesso's modified Egg medium (DMEM) containing 9% calf serum and 1% essential amino acids.
  • DMEM Dulbesso's modified Egg medium
  • the membranes were kept with secondary anti-mouse immunoglobulin G conjugated with horseradish peroxidase (IgG, Pierce, 1: 10000 dilutiop).
  • the resulting protein bands were visualized using a LumiGl Center chemiluminescent reagent (CeIl Sigpalipg, Dapvers, MA) and exposure of the membranes with x-ray film.
  • the bands were digitized using the ImageJ software package [http: //rsb.info. ⁇ h.gov/ij/].
  • the number of living cells was determined using the ATLite kit (Reckip-Elmer, Bostop, MA) in accordance with the manufacturer's instructions.
  • Huh7, Huh7.5.1 and FL-Neocells cells were seeded in a black microplate with a transparent bottom (96 cells, 10 4 cells per cell). Substances in the indicated concentrations were added after 18 hours in triplicates. Cells were incubated with substances for 96 hours, washed twice with 0.2 ml / well of Phosphate-Salt Buffer, and lysed in 50 ⁇ l / well of Cell Buffer (part of the ATPLite kit).
  • L positive control, is the luminescence in cells with cells without substance
  • L otp negative control - luminescence in cells with a medium without cells
  • L ex luminescence in cells with a substance in a certain concentration
  • the CC50 values were calculated using the GrhPhad Prism program (GrhPhad Softwaer, Sap Diego, CA) according to the criterion of minimizing the squared deviation of the experimental points from the theoretical curve.
  • the data presented confirm the high efficacy of new antiviral agents.
  • results of tests of the claimed compounds show the presence of antiviral activity against various viruses, including against infectious hepatitis viruses (HCV, HBV), SARS (SARS), bird flu and human immunodeficiency (HTV), while the claimed compounds have relatively low cellular toxicity.
  • HCV infectious hepatitis viruses
  • SARS SARS
  • HTV human immunodeficiency
  • Example 4 Obtaining a drug in tablet form. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of 5-hydroxy-methyl-methyl-2 - [(dimethylamino) methyl] -6-cyano-III-indole-3-carboxylic acid ethyl ester hydrochloride are mixed 1.4. .1 (3) and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each. According to the invention, pharmaceutical compositions in the form of tablets are likewise prepared containing other esters of substituted IH-indol-3-carboxylic acids of the general formula 1 as an active ingredient.
  • Example 5 Obtaining a drug in the form of capsules. 5-Hydroxy-l-methyl-2 - [(dimethylamino) methyl] - 6-cyano-1 H-indol-3-carboxylic acid 1.4.1 (3) ethanol hydrochloride is mixed with lactose powder in a 2: 1 ratio The resulting powdery mixture is packaged in 300 mg in a suitable size gelatin capsule.
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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Abstract

La présente invention concerne de nouveaux éthers d'acides 1H-indole-3-carboniques substitués possédant une activité antivirale et leur utilisation en tant que principes actifs de compositions pharmaceutiques et leur utilisation pour fabriquer des médicaments employés dans la prévention et le traitement de maladies virales provoquées notamment par les virus de la grippe A et B et les maladies respiratoires aigues, les hépatites infectieuses (HCV, HBV), l'immunodéficience humaine (VIH), la pneumonie atypique (SARS) et la grippe aviaire. On propose d'utilise en tant que substance bioactive possédant une activité antivirale de nouveaux éthers d'acides 5-hydroxy-1H-indole-3-carboniques substitués correspondant à la formule (1) ou leur racémates ou leurs isomères optiques ou leurs sels/hydrates pharmaceutiquement acceptables (formule 1), dans laquelle R(1) est un substituant d'un groupe aminé sélectionné parmi l'hydrogène, un alkyle éventuellement substitué, un cycloalkyle éventuellement substitué, un aryle éventuellement substitué, ou un hétérocyclyle éventuellement substitué; R(2) représente un substituant alkyle sélectionné parmi l'hydrogène, un groupe hydroxy éventuellement substitué, un groupe mercapto éventuellement substitué, un groupe arylsulphinyle éventuellement substitué, un groupe aminé éventuellement substitué, et un N-hétérocyclyle saturé ou instaturé éventuellement substitué; R(3) est l'hydrogène ou un alkyle inférieur éventuellement substitué; R(1)(4) et R(2)(4) sont indépendammentun substituant sélectionné parmi un atome d'hydrogène, un halogène, un groupe cyano, un trifluorométhyle, un aryle éventuellement substitué ou un hétérocyclyle éventuellement substitué.
PCT/IB2008/052302 2007-06-19 2008-06-11 Éthers d'acides 5-hydroxy-1h-indole-3-carboniques substitués, compositions pharmaceutique, procédé de fabrication et d'utilisation WO2009016526A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2204173A1 (fr) * 2007-09-14 2010-07-07 Zakrytoe Aktsionernoe Obschestvo "Masterklon" Composition pharmaceutique possédant un effet antidiabétique
RU2564919C1 (ru) * 2014-06-03 2015-10-10 Общество С Ограниченной Ответственностью "Гамаветфарм" Противовирусное средство
CN108017569A (zh) * 2017-05-19 2018-05-11 南开大学 一种取代吲哚酸衍生物及其制备方法与用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
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GR1010098B (el) * 2020-07-02 2021-10-08 Uni-Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε, Ινδολ-3-ικοι καρβοξυλεστερες με δραση αναστολης της αυτοταξινης

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1731506A1 (fr) * 2004-03-12 2006-12-13 Shenyang Pharmaceutical University Derives de 5-hydroxyindol-3-carboxylate et leur utilisation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU1327491C (ru) * 1984-12-29 1992-11-23 Всесоюзный научно-исследовательский химико-фармацевтический институт им.Серго Орджоникидзе 1-Метил-2-хлорметил-3-карбэтокси-5-ацетокси-6-броминдон в качестве промежуточного продукта в синтезе гидрохлорида 1-метил-2-диметиламинометил-3-карбэтокси-5-окси-6-броминдола, обладающего противовирусным действием
RU1258046C (ru) * 1984-12-29 1992-11-23 Всесоюзный Научно-Исследовательский Химико-Фармацевтический Институт Им.С.Орджоникидзе Гидрохлориды производных 1-алкил(арил)-2-диметиламинометил-3-карбэтокси-5-ацетокси(окси)индола, обладающие противовирусной активностью

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1731506A1 (fr) * 2004-03-12 2006-12-13 Shenyang Pharmaceutical University Derives de 5-hydroxyindol-3-carboxylate et leur utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MEZENTSEVA M.V. ET AL.: 'Sintez i protivovirusnaya aktivnost 2-fenoksimetilnykh proizvodnykh 5-oksiindola.' KHIMIKO- FARMATSEVTICHESKII ZHURNAL. vol. 25, no. 5, 1991, pages 35 - 37 *
ZOTOVA S.A. ET AL.: 'Sintez i protivovirusnaya aktivnost sulfidov indola i benzofurana.' KHIMIKO-FARMATSEVTICHESKII ZHURNAL vol. 26, no. 1, 1992, pages 52 - 55 *
ZOTOVA S.A. ET AL.: 'Sintez i protivovirusnaya aktivnost sulfidov indola i benzofurana.' KHIMIKO-FARMATSEVTICHESKII ZHURNAL. vol. 29, no. 1, 1995, pages 51 - 53 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2204173A1 (fr) * 2007-09-14 2010-07-07 Zakrytoe Aktsionernoe Obschestvo "Masterklon" Composition pharmaceutique possédant un effet antidiabétique
JP2010539160A (ja) * 2007-09-14 2010-12-16 ザクリトー・アクチオネルノー・オブシェストヴォ “マスタークローン” 抗糖尿病作用を備える医薬組成物
EP2204173A4 (fr) * 2007-09-14 2010-12-29 Zakrytoe Aktsionernoe Obschestvo Masterklon Composition pharmaceutique possédant un effet antidiabétique
US8247407B2 (en) 2007-09-14 2012-08-21 Zakrytoe Artsionernoe Obschestvo “Masterclone” Pharmaceutical composition with anti-diabetic action
RU2564919C1 (ru) * 2014-06-03 2015-10-10 Общество С Ограниченной Ответственностью "Гамаветфарм" Противовирусное средство
CN108017569A (zh) * 2017-05-19 2018-05-11 南开大学 一种取代吲哚酸衍生物及其制备方法与用途

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