WO2007136302A2 - Substances actives, composition pharmaceutique et procédé de fabrication et d'utilisations correspondants - Google Patents

Substances actives, composition pharmaceutique et procédé de fabrication et d'utilisations correspondants Download PDF

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WO2007136302A2
WO2007136302A2 PCT/RU2007/000246 RU2007000246W WO2007136302A2 WO 2007136302 A2 WO2007136302 A2 WO 2007136302A2 RU 2007000246 W RU2007000246 W RU 2007000246W WO 2007136302 A2 WO2007136302 A2 WO 2007136302A2
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Prior art keywords
optionally substituted
general formula
alkyl
hydroxy
methyl
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PCT/RU2007/000246
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English (en)
Russian (ru)
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WO2007136302A8 (fr
WO2007136302A3 (fr
Inventor
Alexander Vasilievich Ivashchenko
Andrey Alexandrovich Ivashchenko
Irina Anatolievna Leneva
Nikolay Filippovich Savchuk
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Alla Chem, Llc
Zakrytoe Aktzionernoye Obschestvo 'masterklon'
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Priority claimed from RU2006117558/04A external-priority patent/RU2323221C9/ru
Priority claimed from RU2006117557/04A external-priority patent/RU2323210C9/ru
Priority claimed from RU2007105735/04A external-priority patent/RU2338531C1/ru
Priority claimed from RU2007106408/04A external-priority patent/RU2332421C1/ru
Application filed by Alla Chem, Llc, Zakrytoe Aktzionernoye Obschestvo 'masterklon' filed Critical Alla Chem, Llc
Publication of WO2007136302A2 publication Critical patent/WO2007136302A2/fr
Publication of WO2007136302A3 publication Critical patent/WO2007136302A3/fr
Publication of WO2007136302A8 publication Critical patent/WO2007136302A8/fr

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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
    • A61P31/12—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
    • 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
    • C07D401/14—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
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to new substituted indoles and their use as active substances in pharmaceutical compositions and their use in the manufacture of medicaments for the prevention and treatment of influenza and acute respiratory diseases.
  • Viral infections can cause many diseases, including those caused by influenza viruses, and other acute respiratory infections, which pose a serious threat to human health and life.
  • the search for new anti-influenza drugs, especially those with high activity and low toxicity, is of great importance.
  • a known pharmaceutical composition comprising, as active ingredient, 6-bromo-4- (dimethylaminomethyl) -5-hydroxy-methyl-2-phenylthiomethyl-III-indol-3-carboxylic acid A ethyl ester hydrochloride [Ipt. Arrl. WO 9008135, 1990]. Medicines manufactured in Russia on the basis of this pharmaceutical composition have received the trade name Arbidol.
  • Arbidol is used to treat and prevent type A and B flu and acute viral respiratory infections.
  • Other substituted esters of 2-aminomethyl-6-bromo-5-hydroxy-2-mercapto-III-indole-3-carboxylic acids of the general formula A are also known, which also show inhibitory activity against influenza viruses [PCT IPT Aprl. W02004060873, 2004; PCT IPT Arrl. WO 2005/087729 Al, 2005].
  • R 1 is an amino substituent selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl; W represents a substituted mercapto group; R 3 is optionally substituted alkyl; R 3 and R 4, independently of one another, are the same or different substituents of the amino group selected from hydrogen, alkyl, cycloalkyl, alkenyl or alkyne which may be substituted, or R 3 and R 4 together with the nitrogen atom to which they are attached form a gaunidine group, or optionally substituted azaheterocyclyl.
  • esters of 6-methyl-l, 2,3,7-tetrahydropyrpipolo [3,2-f] [l, 3] benzoxoxazine-5-carboxylic acids B also possess various types of biological activity [DE 2408603, 1974; DE 2462471, 1977].
  • 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 substitutions”.
  • Aliphatic 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 Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, apalkenil, apalkilokcialkil, aralkyloxycarbonyl alkyl, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkenyl annelated aryl heterocyclyl annelated heteroaryl heterocyclyl annelated a ilgeterotsiklenil, annelated heteroary
  • 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.
  • alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine.
  • 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, alkylthio heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl,
  • Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethylmethyloxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymethoxymeth
  • 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, isopropyloxycarbonyl, 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: methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl.
  • Aminogroup means R k a Ri ⁇ + i a N is a group substituted or unsubstituted by “a substituent of the amino group” Ri / and Rk + D, the meaning of which 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.
  • Annelated cycle (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycyclic 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 aryl heterocycloalkenyl may bind through any possible atom of the cyclic 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 “substituent ring systems)), which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocyclenyl 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, etc.
  • 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 “substituent ring systems)), which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocyclyl 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 “ring system substituents)), which may be the same or different.
  • Representatives of annelated arylcycloalkenyls are 1,2-dihydro-naphthalene, indene, 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 reteroylcycloalkenyl 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 system substituents” that 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 system substitutes,” which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide.
  • Representatives of annelated heteroarylcycloalkyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-S-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 “heteroapyl” 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 “substituent ring systems)), which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety may 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.
  • Representatives of 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. .
  • “Annulled reteroapylheterocyclyl” 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.
  • 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 heteroarylheterocyclyl may have one or more “cyclic system substitutes,” which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety may 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 aryl-alkenyl 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 aryl-alkyl-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 aralkyl-SO 2 —the 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-naphthylenemethoxy are aralkoxy 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.
  • Aryl means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
  • Aryl may contain one or more “substituents of the cyclic system)), which may be the same or different.
  • Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl.
  • Aryl can be annelated with a non-aromatic ring system or heterocycle.
  • Aminyl means an aryl-SO— group in which the meaning of aryl is defined in this section.
  • Amylcylphone means apyl-SO 2 —the group in which the meaning of aryl is defined in this section.
  • Apilthio means an aryl-S- group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio. “Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.
  • “Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic CH bond.
  • the “aromatic” radical includes the aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents — aliphatic or aromatic radicals defined in this section.
  • aromatic radicals include aryl, annelated cycloalkenylaryl, annelated cycloalkylaryl, annelated heterocyclylaryl, annelated heterocyclylaryl, heteroaryl, annelated cycloalkyl heteroaryl, annelated cycloalkenyl heteroaryl, annelated heterocyclenyl heteroaryl and annelated heterocyclyl heteroaryl.
  • “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.
  • Hetero matric cycles” in the conjugation system involve ⁇ -electrons and p-electrons of heteroatoms, their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like.
  • the aromatic cycle may have one or more “replaceable cyclic” systems and can be annelated with a non-aromatic cycle, heteroaromatic or heterocyclic system.
  • acylamino means an acyl-NH— group in which the meaning of acyl is defined in this section.
  • 1,2-Vinyl radical means a —CH ⁇ CH— group which contains one or more identical or different “alkyl substituents”, the meanings of which are 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.
  • heteroarylalkenyl includes a lower alkenyl group.
  • Representatives of heteroarylalkenyls are 4-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl, etc.
  • 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 heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen.
  • 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.
  • the nitrogen atom in the heteroaryl may be oxidized to N-oxide.
  • Heteroaryl may have one or more “cyclic system substitutes,” 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, pyridinazinyl, pyridinazinyl, pyridazinyl, -a] pyridinyl, imidazo [2, lb] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, , furopyrrolyl, etc.
  • Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc.
  • Heterocycle means a non-aromatic monocyclic or polycyclic system comprising 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.
  • a hetero atom such as nitrogen, oxygen, sulfur
  • the prefix "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 system substitutes,” 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-tetraparidropyridine, 1,2-dihydropopyridine, 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.
  • a heteroatom such as nitrogen, oxygen, sulfur.
  • the prefix “aza”, “okca” or “thia” 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 (substituents of the cyclic system ", which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocyclyl may be oxidized to N-oxide, S-oxide or S-dioxide.
  • heterocycles are piperidine, pyrrolidine , piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.
  • 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 binds to a scaffold (fragment), for example, (substituent alkyl ”, ((substituent of amino group)), ((substituent of carbamoyl”, ((substituent of 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.
  • Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl , annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annel
  • a independently represent amino substituents, the meaning of which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R k a and R k + i a together with the atom N, with which they are connected, form through Ri ⁇ a and Rk + i a 4 - 7 membered heterocyclyl or heterocyclenyl.
  • 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.
  • the meaning of “Alkyl substituents” is defined in this section.
  • Amino group substituent "means a substituent attached to an amino group.
  • Amino group substituent represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkyl aminocarbonyl, arylaminocarbonyl, geteroarilamino- carbonyl geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arilaminotio- carbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annels ovanny arylcycloalkenyl, anne
  • the carbamoyl substituent is hydrogen, alkyl, cycloalkyl., Aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R
  • h a Ri ⁇ + i a N-, Ri ⁇ a Rk + ] a NC ( O) -alkyl annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, anpelated heteroaryl heterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl.
  • the meaning of “carbamoyl substitutes” is defined in this section.
  • Nucleophilic substituent means a chemical radical that is attached to scaffold by reaction with a nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.
  • 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, heterocyclylalkylalkyl, alkyl sulfonyl, arylsulfonyl, heterocyclyl ynyl, arylsulfinyl, sul finil heterocyclyl, alkylthio, arylthio, heterocyclylthio, alkylsulfonyl, alky
  • Electrophilic substituent means a chemical radical that attaches to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), ethers of organic sulfonic acids or organic sulfonyl chlorides, organic halocyanates, organic halides organic isothiocyanates.
  • Substituted amino group means R k a Rk + i a N is a group in which Rj / and Rk + ⁇ 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 mercapto group” means SR, S (O) R or S (O 2 ) R — a 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 an amino group in multifunctional compounds, including, but not limited to: an amide substituent such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl, 3-phenylpropionyl et al.) optionally substituted benzoyl et al .; a carbamate substituent, such as optionally substituted C 1 -C 7 alkyloxycarbonyl, for example methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted C 1 -C 7 alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylphyloinyl and the like; s
  • 3-protected primary or secondary amine means a group of the formula R k 8 R k + i a N-, in which Ri / represents a protective group PG, and R k + ⁇ represents hydrogen , “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, cycloalkyl, cycloalkyl, cycloalkyl elated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, heterocyclenyl or heterocyclyl.
  • Nop-substitute substituep means a low or non-reactive radical, including, but not limited to C 1 - C 7 alkyl,
  • C 7 - C 12 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 / 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 as
  • “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. In the case of one common atom, spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two
  • Alicyclics may be “saturated”, for example, as cyclohexane, or “partially saturated)), for example, as tetralin.
  • “Combinational 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.
  • Metal radical means —CH 2 - a group that contains one or two identical or different“ alkyl substituents ”, the meaning of which is defined in this section.
  • Non-aromatic cycle)) saturated cycle or partially saturated cycle
  • a non-aromatic ring may have one or more “substituent cyclic)) 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
  • Natural amino acid means an amino acid of a non-nucleic nature.
  • unnatural amino acids include D-isomers of natural ⁇ -amino acids, aminobutyric acid, 2-aminobutyric acid, ⁇ -aminobutyric acid, N- ⁇ -alkylated amino acids, 2,2-dialkyl- ⁇ -amino acids, 1-amino-cycloalkyl carboxylic acids, ⁇ -alanine, 2-alkyl- ⁇ -alanines, 2-cycloalkyl- ⁇ -alanines, 2-apyl- ⁇ -alanines, 2-heteroapyl- ⁇ -alanines, 2-heterocyclyl- ⁇ -alanines and (1-amino-cycloalkyl ) -cyclic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.
  • Optional aromatic cycle means a cycle that can be either an aromatic or a non-alkyl
  • Optionally substituted radical means a radical without substituents or containing one or more substituents.
  • Optionally annelated (condensed) cycle means a condensed, non-condensed cycle, the meanings of which are defined in this section.
  • “Lower alkyl” means a linear or branched alkyl with 1-4 carbon atoms.
  • Parallel synthesis means a method for conducting chemical synthesis of a combinatorial library of individual compounds.
  • 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 3 R k + ] 8 NSO 2 is a group substituted or unsubstituted ((with an amino substituent)) Ri ⁇ a and R ⁇ ⁇ + i a , the meanings of which are defined in this section.
  • “Sulfonyl” means R-SO 2 - group in which R is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated reteroariltsiyutoalkenil, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, the meaning of which is defined in this section.
  • “Template” means the general structural formula of a group of compounds or compounds included in the “combinational library)).
  • “Therapeutic cocktail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biological targets involved in the pathogenesis of the disease.
  • Thiocarbamoyl may have one or more identical or different “amino substituents)) R k a and R k + D, the meaning of which is defined in this section, for example, including 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 of the cyclic system)), which may be the same or different. Representative 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 R k a R k + 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 means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents s, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and purpose of the method and dosage.
  • delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents s, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and purpose of the method 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 provided with 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. Prolonged action of the composition can be provided with 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.
  • the pharmaceutical composition for oral, 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, sublingual and buccal administration forms, aerosols, implants, local, 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.
  • salts can be prepared in situ during the synthesis, isolation or purification of compounds or prepared specially.
  • 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 (For a detailed description of the properties of such salts, see Werg SM, et al., “Pharmacut 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.
  • the metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, 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 the molecular framework characteristic of a group of compounds or compounds included in a “combinational library)).
  • 1,2-Ethyl radical means —CH 2 —CH 2 — a group that contains one or more of the same or different “alkyl substituents”, the meanings of which are defined in this section.
  • the aim of the present invention is the creation of new active substances for pharmaceutical compositions intended for the treatment and prevention of influenza and other acute respiratory diseases.
  • compositions having activity against influenza viruses and acute respiratory diseases substituted indoles of the general formula 1 or their racemates, or their optical isomers or their pharmaceutically acceptable salts and / or hydrates:
  • R 1 , R 1 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 R 1 and R 2 , together with the nitrogen atom to which they are attached form, via R 1 and R 2, an optionally substituted azaheterocyclyl or guanidyl;
  • R represents an alkyl substituent selected from hydrogen, an optionally substituted mercapto group, an optionally substituted amino group, an optionally substituted hydroxyl;
  • R 3 represents lower alkyl;
  • R 5 represents a hydrogen atom or R, together with the oxygen atom to which it is bonded, and R 2 , together with the nitrogen atom to which it is bonded, close the oxazine ring through R 5 and R 2 4 ;
  • R represents a cyclic system substituent selected from hydrogen, a halogen atom, a cyano group, an optionally
  • More preferred substituted indoles are 5-hydroxy-S-indole-3-carboxylic acid esters of the general formula 1.1 and 1,2,3,7-tetrahydro-pyryl esters [3,2 - /] [l, 3] benzoxazin- 5-carboxylic acids of the general formula 1.2 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • R 1 , R 2 , R 3 , R 1 4 , R 2 4 and R 6 have the above meanings;
  • R 7 represents a cyclic system substituent selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • More preferred substituted indoles are 4-aminomethyl-6-apyl (or heterocyclyl) -5-hydroxy-III-indol-3-carboxylic acid ethyl esters of the general formula 1.1.1 and 9-apyl (or heterocyclyl) -l, 2 ethyl esters , 3,7-tetrahydro-pippololo [3,2- /
  • R 1 , R 2 , R 1 4 , R 2 4 and R 7 have the above meanings
  • Ar is an aryl or 5-6 membered heterocyclyl comprising at least one heteroatom selected from N, O, or S.
  • More preferred substituted indoles are 4-aminomethyl-6-apyl (or pyridyl) -5-hydroxy-1-methylindinol-3-carboxylic acid ethyl esters of the general formula 1.1.2 and 9-apyl (or pyridyl) -7-methyl ethyl esters - 1,2,3,7-tetrahydro-pyrpolo [3,2- / J [l, 3] benzoxazin-5-carboxylic acids of the general formula 1.2.2 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • R 2 , R 1 4 , R 2 4 and R 7 have the above meanings;
  • Ar 1 represents aryl or pyridyl.
  • More preferred substituted indoles are 6-apyl (or pyridyl) -2,4-bis (aminomethyl) -5-hydroxy-1-methylindinol-3-carboxylic acid ethyl esters of the general formula 1.1.3 and 6-aminomethyl-9- ethyl esters apyl (or pyridyl) -7-methyl-l, 2,3,7-tetrahydro-pyrpolo [3,2- / J [l, 3] benzoxazazine-5-carboxylic acids of the general formula 1.2.3 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • R 1 4 , R 2 4 , R 7 and Ar 1 have the above meanings;
  • R 3 4 and R 4 4 independently represent an amino group substituent selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, or R 3 4 and R 4 4 , together with a nitrogen atom, with which they are linked, form optionally substituted azaheterocyclyl or guanidyl via R 3 4 and R 4 4 .
  • More preferred substituted indoles are 4-aminomethyl-6-apyl (or pyridyl) -5-hydroxy-2-dimethylaminomethyl-1-methylindinol-3-carboxylic acid ethyl esters of the general formula 1.1.4 and 9-apyl ethyl esters (or pyridyl) -6-dimethylaminomethyl-7-methyl-l, 2,3,7-tetrahydro-pyrpolo [3,2- / J [l, 3] benzoxazazine-5-carboxylic acids of the general formula 1.2.4 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • R 1 4 , R 2 4 , R 7 and Ar 1 have the above meanings.
  • More preferred substituted indoles are 6-apyl (or pyridyl) -2,4-bis (dimethylaminomethyl) -5-hydroxy-1-methylindin-3-carboxylic acid ethyl esters of the general formula 1.1.5 and 9-apyl (or pyridyl) ethyl esters ) - 3,7-dimethyl-6-dimethylaminomethyl-1, 2,3,7-tetrahydro-pyrpolo [3,2- / J [1, 3] benzoxazazine-5-carboxylic acids of the general formula 1.2.5 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • R 1 4 , R 2 4 , and Ar 1 have the above meanings.
  • More preferred substituted indoles are 2,4-bis (dimethylaminomethyl) -5-hydroxy-l-methyl-6- (3-pyridinyl) -indole-3-carboxylic acid ethyl ester of formula 1.1.5 (1) and ethyl ester 3, 7-dimethyl-6-dimethylaminomethyl-9- (3- pyridyl) -l, 2,3,7-tetrahydro-pyrpolo [3,2- / j [1, 3] benzoxazazine-5-carboxylic acid of formula 1.2.5 (1) or their pharmaceutically acceptable salts and / or hydrates.
  • More preferred substituted indoles are 2-dimethylaminomethyl-5-hydroxy-l-methyl-6- (3-pyridinyl) -4- (l-pyrolylmethyl) -indole-3-carboxylic acid ethyl ester of formula 1.1.5 (2), ethyl 2-dimethylaminomethyl-5-hydroxy-4- (l-imidazolyl) methyl-l-methyl-6- (3-pyridinyl) indole-3-carboxylic acid ester of the formula 1.1.5 (3), 2-dimethylamine ethyl ester 5-hydroxy-4-hyanidinylmethyl-l-methyl-6- (3-pyridinyl) -indole-3-carboxylic acid of the formula 1.1.5 (4), 4-dimethylaminomethyl-5-hydroxy-l-methyl-6 ethyl ester (3-pyridinyl) -2- (l-pyrpolylylmethyl) -indole-3-carboxylic acid of formula 1.1.5
  • the aim of the present invention are also pharmaceutical compositions having activity against influenza viruses and acute respiratory diseases.
  • the subject of this invention is also pharmaceutical compositions having activity against influenza viruses and acute respiratory diseases, containing as an active substance at least one substituted indole of general formula 1 or its racemate, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate.
  • compositions are those containing, as an active substance, at least one 5-hydroxy-S-indole-3-carboxylic acid ester of the general formula 1.1 or 1,2,3,7-tetrahydro-pyrphenol ester [3 , 2- / J [l, 3] benzoxazin-5-carboxylic acid of general formula 1.2, or their racemate, or their optical isomer, or their pharmaceutically acceptable salt and / or hydrate.
  • compositions are those containing, as an active substance, at least one 4-aminomethyl-6-apyl (or heterocyclyl) -5-hydroxy-S-indole-3-carboxylic acid ethyl ester of the general formula 1.1.1 or 9-apyl ethyl ester (or heterocyclyl) - 1, 2,3, 7-tetrahydro-pyrpolo [3, 2- / j [1, 3] benzoxazazine-5-carboxylic acid of the general formula 1.2.1 or their racemate, or their optical isomer, or their pharmaceutically acceptable salt and / or hydrate.
  • compositions are those containing, as an active substance, at least one ethyl 4-aminomethyl-6-apyl (n-pyridyl) -5-hydroxy-l-methylindinol-3-carboxylic acid of general formula 1.1.2 or ethyl 9-apyl (or pyridyl) -7-methyl-l, 2,3,7-tetrahydro-pyrpolo [3,2- /
  • More preferred pharmaceutical compositions are those containing, as active substance, at least one 6-apyl (or pyridyl) -2,4-bis (aminomethyl) -5-hydroxy-l-methylindinol-3-carboxylic acid ethyl ester general formula 1.1.3 and 6-aminomethyl-9-apyl (or pyridyl) -7-methyl-l, 2,3,7-tetrahydro-pyrpropyl [3,2- / J [l, 3] benzoxazin-5 ethyl ester -carboxylic acid of general formula 1.2.3 or their racemate, or their optical isomer, or their pharmaceutically acceptable salt and / or hydrate.
  • compositions containing, as an active substance, at least one 4-aminQmethyl-6-apyl (or pyridyl) -5-hydroxy-2-dimethylaminomethyl-l-methylindin-3-carboxylic acid ethyl ester of the general formula 1.1.4 and 9-apyl (or pyruvyl) -6-dimethyl ethyl ester 7-methyl-l, 2,3,7-tetrahydro-pyrpolo [3,2- / j [l, 3] benzoxoxazin-5-carboxylic acid of the general formula 1.2.4 or their racemate, or their optical isomer, or their pharmaceutically acceptable salt and / or hydrate.
  • compositions are those containing as active substance at least one ethyl ester of 6-apyl (or pyridyl) -2,4-bis (dimethylaminomethyl) -5-hydroxy-l-methylindinol-3-carboxylic acid general formula 1.1.5 and ethyl ester 9-apyl (or pyrvdyl) -3,7-dimethyl-6-dimethylaminomethyl-l, 2,3,7-tetrahydro-pyrpolo [3,2- / J [l, 3] benzoxazine -5-carboxylic acid of general formula 1.2.5 or a pharmaceutically acceptable salt and / or hydrate thereof.
  • compositions are those containing, as an active substance, at least one of the ethyl esters of 2,4-bis (dimethylaminomethyl) -5-hydroxy-1-methyl-b- (3-pyridinyl) -indole-3 -carboxylic acid of the formula 1.1.5 (1), 3,7-dimethyl-6-dimethylaminomethyl-9- (3-pyridyl) - 1, 2,3, 7 ⁇ tetrahydro-pyrpolo [3,2- / j [1, 3] benzoxazin-5-carboxylic acid of the formula 1.2.5 (1), 2-dimethylaminomethyl-5-hydroxy-1-methyl-6- (3-pyridinyl) -4- (1 - pyropolymethyl) -indole-3-carboxylic acid formulas 1.1.5 (2), 2-dimethylaminomethyl-5-hydroxy-4- (l-imidazolyl) methyl-l-methyl-6- (3-pyridinyl) indole-3-carboxylic
  • 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 substituted indoles of the general formula 1 of the present invention may include other active substances, 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 may include traditional pharmaceutical carriers; for example, peroral forms (such as tablets, • gelatin 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).
  • peroral forms such as tablets, • gelatin 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 field 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 substance with an inert filler and / or solvent, the distinguishing feature of which is that at least one substituted indole of the general formula 1 or its racemate, or its optical isomer, or its pharmaceutically, is used as the active substance. acceptable salt and / or hydrate.
  • compositions containing, as an active substance, at least one substituted indole of general formula 1 or its racemate, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate are used to produce drugs in the form tablets, capsules or injections in pharmaceutically acceptable packaging for the prevention and treatment of influenza and acute respiratory infections.
  • the subject of the present invention is also therapeutic cocktails for the prevention and treatment of influenza and acute respiratory diseases, comprising, as one component, a medicament derived from a pharmaceutical composition containing, as an active substance, at least one substituted indole of general formula 1, or the racemate, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate.
  • 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 (Serpermad, Hocmapt, Lucovir, Delivel, Zamelivel, Zamelam phosphate (Oseltamivir rhosphate, Tamiflu), L-Glutamyl-L-tryptophan (Glufapide, Oglufapide, Thumogep, Timogep), Rimantadine hydrochloride (Flumadir, Ziromirum), for example: Adamantanamine hydrochloride (Serpermad, Hocmapt, Lucovir, Delivel, Zamelivel, Zamelam phosphate (Oseltamivir rhosphate, Tamiflu), L-Glutamyl-L-tryptophan (Glufapide, Oglufapide, Thumogep, Timogep), Rimantadine
  • a method for the prevention and treatment of influenza and acute respiratory diseases consists in administering to a patient medicaments in the form of tablets, capsules or injections containing, as an active substance, at least one substituted indole of general formula 1 or a racemate thereof, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate, or therapeutic cocktails, including these drugs.
  • Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or locally.
  • the clinical dosage of the active substance of the substituted indole of general formula 1 in patients can be adjusted depending on: the therapeutic effectiveness and bioavailability of the active ingredients in the body, their metabolic rate and excretion from organism, as well as depending on the age, gender and stage of the patient’s disease, while the daily dose in adults is usually 10 ⁇ 500 mg, preferably 50 ⁇ 300 mg Therefore, when preparing the pharmaceutical composition of the medicine of the present invention in dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 10 ⁇ 500 mg of substituted indole of general formula 1, preferably 50 ⁇ 300 mg. 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).
  • the method for producing substituted 5-hydroxy-S-indole-3-carboxylic acid esters of general formula 1.1 consists in reacting substituted 5-hydroxy-S-indole-3-carboxylic acids of general formula 2 with formaldehyde and amines of general formula 3 according to Scheme 1.
  • R 1 , R 2 , R 3 , R 1 4 , R 2 4 and R 5 have the above meaning.
  • Example 1 Obtaining a combinatorial library of substituted 5-hydroxy-S-indol-3-carboxylic acid esters of the general formula 1.1. Heated at 70-80 0 C and with stirring 0.357 mmol of ether 2, 0.43 mmol of secondary amine 3 and 0.43 mmol of formaldehyde in the form of formalin in 3 ml of dioxane for 12-48 hours. Control of the progress of the reaction is carried out using chromato-mass spectrometry. After completion of the reaction, the reaction mass is diluted with water, the precipitate is filtered off and recrystallized from a suitable solvent or purified by chromatography.
  • esters of l, 2,3,7-tetrahydro-pyrpolo [3,2-f] [l, 3] benzoxazazine-5-carboxylic acids of the general formula 1.2 by reaction of 5-hydroxy-S-indole-3-carboxylic acid esters of the general formula 2 with aldehydes of general formula 4 and primary amines of general formula 5 according to scheme 2.
  • R 1 , R 2 , R 3 , R 1 4 , R 6 and R 7 have the above meaning.
  • R 1 , R 2 , R 3 , R 1 4 , R 6 and R 7 have the meaning indicated above.
  • Example 2 Obtaining a combinatorial library of esters of 1,2,3,7-tetrahydro-propylpol [3,2-f] [l, 3] benzoxazazine-5-carboxylic acids of the general formula 1.2.
  • Example 3 Determination of the antiviral activity of a pharmaceutical composition containing one of the compounds of the general formula 1 as an active substance, shown in table 1.
  • Antiviral activity against influenza viruses A / New Caledonia / 20/99 (HlNl) was determined by enzyme-linked immunosorbent assay (ELISA) in cell culture MDCK.
  • MDCK cells were seeded in 96-well Sostar plates with an average density of 35,000 cells per well and grown in Eagle's minimal medium in the presence of 5% fetal calf serum and 10 mM glutamine to a complete monolayer. Before infection with the virus, the cells were washed 2 times with serum-free medium. The studied pharmaceutical compositions were added to the cells at a 2-fold concentration of compounds 1 in 100 ⁇ l of the medium used.
  • 100 ⁇ l of the same medium was added to the virus control, and cell control 200 went.
  • the studied pharmaceutical compositions and virus dilutions were prepared on medium supplemented with 2.5 ⁇ g / ml TPCK trypsin. After incubation of the cells with the studied pharmaceutical compositions for 2 hours at 37 ° C, 100 ⁇ l of allantoic virus diluted in the medium used was added to the wells, excluding the cell control, with a multiplicity of infection of approximately 0.1 to 1 PFU per cell per depending on the experimental conditions. Next, the plates were incubated for 17 hours-20 hours.
  • the cells were examined under an inverted microscope to make sure that they had no cytotoxic and cytopathic changes. After confirming their absence, the medium was removed and the cells were fixed with 80% acetone in phosphate-buffered saline (PBS) for 20 minutes, dried well, and then washed 3 times with PBS with 0.05% Tween-20 (ELISA). These and all further washing procedures were performed with the indicated solution. Then, 100 ⁇ l of PBS solution with 1% fetal serum and 0.05% Tween-20 were added to the cells and incubated at 37 ° C for 30 minutes.
  • PBS phosphate-buffered saline
  • MKA monoclonal antibodies
  • CRP orthophenylenediamine
  • the plates were kept for 15-30 minutes in the dark until staining, the reaction was stopped by adding 50 ⁇ l of 4H H 2 SO 4 ,. Next, the optical density (OD) was measured on an automatic spectrophotometer at 492 nm using RPD. Wells not infected with the virus were used as a control. Typically, the OD value in the control did not exceed 0.1-0.2.
  • the primary screening of compounds was carried out on the basis of two experiments. Two multiplicities of infection were used (10-2 and 10-3, i.e. 0.1-1 PFU per cell). Three replicates (i.e., three wells of a plate) were used for one point of each experiment.
  • Example 4 Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of 4-dimethylaminomethyl-5 ⁇ hydroxy-l-methyl-2- (pippol-l-yl) methyl-6- (pyridin-3-yl) ethyl chloride are mixed ) -Sh-indol-3-carboxylic acid 1.1.5 (5c) or 3,7-dimethyl-9-pyridin-3-yl-6-pyrpol-l-ylmethyl-l ethyl ester hydrochloride, 2,3,7- tetrahydro-pippolol [3,2-f] [l, 3] benzoxazazine-5-carboxylic acid 1.2.3 (4) and pressed into a block.
  • compositions in the form of tablets are likewise prepared containing other substituted S-indol-3-carboxylic acids of the general formula 1 as an active ingredient.
  • Example 5 Obtaining a drug in capsule form. 4-Dimethylaminomethyl-5-hydroxy-l-methyl-2- (pyrpol-l-yl) methyl-6- (pyridin-3-yl) -Sh-indol-3-carboxylic acid ethyl ester hydrochloride 1.1.5 ( 5c) or 3,7-dimethyl-9-pyridin-3-yl-6-pyrpol-l-ylmethyl-l ethyl ester hydrochloride, 2,3,7-tetrahydropyrpropyl [3,2-f] [l, 3] benzoxazine -5-carboxylic acid 1.2.3 (4) with lactose powder in a ratio of 2: 1. The resulting powdery mixture is Packed 300 mg in gelatin capsules of the appropriate size.
  • Example 6 Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection.
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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Abstract

L'invention concerne de nouveaux indoles substitués et leur utilisation en tant que substances actives de compositions pharmaceutiques ainsi que l'utilisation de ces dernières pour obtenir des préparations médicamenteuses utilisées dans la prévention et le traitement de la grippe et de maladies respiratoires aiguës. Elle propose en tant que substances actives de compositions pharmaceutiques possédant un action contre le virus de la grippe ou de maladies respiratoires aiguës des indoles substitués ayant la formule générale (1) ou leurs racémates, ou leurs isomères optiques, ou leurs sels et/ou hydrates pharmaceutiquement acceptables (Formule 1) dans laquelle R1, R14 et R24 sont indépendamment un substitutif 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, ou R1, R14 et R24, conjointement avec l'atome d'azote auquel ils sont liés, forment via R14 et R24 un azahétérocyclyle ou un guanidyle éventuellement substitué; R2 se présente comme un substitutif alkylé, sélectionné parmi l'hydrogène, d'un groupe mercapto éventuellement substitué, un groupe aminé éventuellement substitué, un hydroxyle éventuellement substitué; R3 se présente comme un alkyle inférieur; R5 se présente comme un atome d'hydrogène ou R5, conjointement avec l'atome d'oxygène auquel il lié, et R24, conjointement avec l'atome d'azote auquel il est lié, referment le noyau oxazine; R6 se présente comme un substitutif du système cyclique sélectionné parmi l'hydrogène, un atome halogène, un groupe cyano, un aryle éventuellement substitué ou un hétérocyclyle éventuellement substitué.
PCT/RU2007/000246 2006-05-23 2007-05-17 Substances actives, composition pharmaceutique et procédé de fabrication et d'utilisations correspondants WO2007136302A2 (fr)

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RU2006117558 2006-05-23
RU2006117558/04A RU2323221C9 (ru) 2006-05-23 2006-05-23 ЗАМЕЩЕННЫЕ ЭФИРЫ 1,2,3,7-ТЕТРАГИДРОПИРРОЛО[3,2-f][1,3]БЕНЗОКСАЗИН-5-КАРБОНОВЫХ КИСЛОТ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБ ИХ ПОЛУЧЕНИЯ (ВАРИАНТЫ) И ПРИМЕНЕНИЯ
RU2006117557/04A RU2323210C9 (ru) 2006-05-23 2006-05-23 Замещенные эфиры 1н-индол-3-карбоновой кислоты, фармацевтическая композиция, способ их получения и применения
RU2006117557 2006-05-23
RU2007105735/04A RU2338531C1 (ru) 2007-02-16 2007-02-16 Активные субстанции, фармацевтическая композиция, способ получения и применения
RU2007105735 2007-02-16
RU2007106408/04A RU2332421C1 (ru) 2007-02-21 2007-02-21 Активные субстанции, фармацевтическая композиция, способ получения и применения
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EP2204173A1 (fr) * 2007-09-14 2010-07-07 Zakrytoe Aktsionernoe Obschestvo "Masterklon" Composition pharmaceutique possédant un effet antidiabétique
CN104193669A (zh) * 2014-08-01 2014-12-10 大连理工大学 一类阿比朵尔类似物或其盐、其制备方法及应用

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WO2004060873A1 (fr) * 2003-01-04 2004-07-22 Shenyand Pharmaceutical University Nouveaux derives de 5-hydroxyindole-3-carboxylate

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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
CN101801373B (zh) * 2007-09-14 2013-03-27 马斯捷尔克劳内部股份公司 具有抗糖尿病作用的药物组合物
CN104193669A (zh) * 2014-08-01 2014-12-10 大连理工大学 一类阿比朵尔类似物或其盐、其制备方法及应用

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