[go: up one dir, main page]

WO2008026965A1 - Pyrrolo[4,3-b]indoles substitués, bibliothèques focalisées ou combinatoires, composition pharmaceutique, procédé de fabrication et d'utilisation - Google Patents

Pyrrolo[4,3-b]indoles substitués, bibliothèques focalisées ou combinatoires, composition pharmaceutique, procédé de fabrication et d'utilisation Download PDF

Info

Publication number
WO2008026965A1
WO2008026965A1 PCT/RU2007/000435 RU2007000435W WO2008026965A1 WO 2008026965 A1 WO2008026965 A1 WO 2008026965A1 RU 2007000435 W RU2007000435 W RU 2007000435W WO 2008026965 A1 WO2008026965 A1 WO 2008026965A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
compounds
indole
fluoro
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/RU2007/000435
Other languages
English (en)
Russian (ru)
Inventor
Andrey Alexandrovich Ivashchenko
Yevgeniy Borisovich Frolov
Sergey Yevgenievich Tkachenko
Alexander Viktororich Khvat
Sergey Viktorovich Malyarchuk
Oleg Dmitrievich Mitkin
Ilya Matusovich Okun
Alexandr Sergeevich Kyselev
Nikolay Filippovich Savchuk
Alexander Vasilievich Ivanshchenko
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alla Chem LLC
Original Assignee
Alla Chem LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alla Chem LLC filed Critical Alla Chem LLC
Publication of WO2008026965A1 publication Critical patent/WO2008026965A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the synthesis of new chemicals, the search for new physiologically active substances, leader compounds, “molecular tools)) and drug candidates obtained from screening of combinatorial and focused libraries of compounds, as well as to a pharmaceutical composition, methods for their preparation and use.
  • the present invention relates to new annelated azaheterocycles - hydrogenated pippolo [4,3-b] indoles, their optical and geometric isomers, mixtures of isomers, their pharmaceutically acceptable salts and / or hydrates, to methods for their preparation, pharmaceutical compositions containing these compounds in the form of active substances, as well as to a method for the treatment and prevention of the development of various diseases, including neurodegenerative diseases, for example, Alzheimer's disease (AD), associated with excessive entry of calcium ions into the nerve cells, which initiates a number of pathological metabolic processes that ultimately cause the death of neurons [D.W. Schoi, Neurope, 1988; 1: 623-634].
  • AD Alzheimer's disease
  • the pharmacological effect of the hydrogenated pirpolo [4,3-b] indoles is based on their ability to effectively lower the cytosolic concentration of calcium ions when the intracellular content of Ca + 2 ions becomes excessive as a result of various pathological processes.
  • Another pharmacological property of hydrogenated pyrpolo [4,3-b] indoles and azepino [4,3-b] indoles is their highly effective antihistamine effect, which allows the use of these substances in the form of these pharmaceutical compositions for the treatment of a wide range of allergic and autoimmune diseases, including hay fever, urticaria, bronchial asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke's edema, eczema, burn toxemia, as well as allergic reactions caused by drugs, food, cosmetics their agents, household dust, insect bites, etc.
  • the following complex interrelated processes occur: the transport of calcium ions by two families of Ca + 2 channels, namely: calcium channels of the cell membrane and calcium channels located in the endo (capco) membrane of the plasma reticulum (ER or CP), which form the pathways of calcium entry into cytoplasm; the removal of calcium from the cytoplasm due to the activity of calcium plasmalemma pumps and / or calcium exchangers; accumulation of calcium ions by intracellular calcium depots and mitochondria.
  • the latter serve as calcium buffer systems capable of accumulating and accumulating it, thus supporting calcium homeostasis in the cytoplasm.
  • calcium antagonists are a group of drugs that combines the ability to reversibly block the flow of calcium through voltage-dependent calcium channels.
  • these drugs are divided into two large subgroups - dihydropyridines (Nifedipine, Amlodipine, Felodipine, etc.), in the properties of which the effect of peripheral vasodilation predominates, and nedihydropyridines (Verapamil and Diltiazem), in the properties of which the negative chrono- and inotropic effect predominates as well as the ability to reduce atrioventricular conductivity [Si D.A.
  • Hydrogenated pyrrolo [4,3-b] ind 'oly moleno regarded as closest analogues of compounds of series hydrogenated pyrido [4,3-b] indoles.
  • Hydrogenated pyrido [4,3-b] indoles include antihistamines Dimebon and Diazolin [Mashkovsky M. D. Medicines. Ed. 13. Kharkov: Torsing, 1998.p. from. 280-281], as well as a neuroprotective agent, antioxidant and antiarrhythmic agent Stobadin, which is in the second stage of clinical trials, [Nokakova L., Stoels S.
  • Dimebon and Diazolin are blockers of Hl receptors and have a pronounced antihistamine and partial antiserotonin effect. Antiarrhythmic properties were found in Dimebon [Galepko-Iaroshevskii P. A., Schekapova O.A., Skibitskii VV, Cartashevis VV, Khapkova AI, Rolisova T. L. Apthiarthusperr of dimmebop. Vill Expr YOU Med.
  • Another pharmacological property of hydrogenated pippolo [4,3-b] indoles is their highly effective antihistamine effect, which allows the use of these substances in the form of these pharmaceutical compositions for the treatment of a wide range of allergic and autoimmune diseases, including hay fever, urticaria, asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke's edema, eczema, burn toxemia, and also allergic reactions caused by drugs, food, cosmetics, house dust, insect bites, etc.
  • a further aspect of the invention is the provision of pharmaceutical compositions comprising a therapeutically effective amount of a compound according to the invention and therapeutically acceptable inert auxiliary agents such as carriers, excipients, etc.
  • “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 “replaceable cyclic” systems.
  • "Aliphatic" radical means a radical obtained by removing a hydrogen atom from a non-aromatic C-H 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, reteroaralkiloksialkil, nile geteroaralke-, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylhetero iklil, annelated arylated
  • 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.
  • 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, benzyloxy carbonylmethyl, 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 R k a R k + i a N is a group substituted or unsubstituted
  • Noticeable amino groups R k a and R k + ⁇ , 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.
  • “Annelized 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 arylheterocycloalkenyl can bind through any possible atom of the ring system.
  • the prefix “aza”, “okca” or “tia” before “heterocycloalkenyl” means the presence of a nitrogen atom, atom, oxygen or sulfur atom in the cyclic system, respectively.
  • Annelated arylheterocycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocycloalkenyl moiety may 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 system substitutes,” 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 system substitutes,” 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 system 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 “ring system substituents)), which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety may 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 “ring system substituents)), 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-benzimidazole 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.
  • annellated heteroarylheterocyclenyls are l, 2-dihydropo [2,7] naphthyridinyl, 7,8-dihydro [l, 7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyrvinyl, and the like.
  • 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.
  • 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 heteroaryl heterocyclyl may have one or more
  • 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
  • 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.
  • Alkenyl means an aryl-alkenyl group in which the meanings of aryl and alkenyl are defined in this section.
  • 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.
  • aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl.
  • Alkylamino 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-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.
  • Aryl may contain one or more “cyclic system substitutes,” 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.
  • “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 a ⁇ yl-SO 2 —the group in which the meaning of aryl is defined in this section.
  • arylthio 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.
  • Examples of aroyl groups are benzoyl, 1st 2nd naphthoyl.
  • “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.
  • Representative aromatic radicals include aryl, annelated cycloalkenylaryl, annelated cycloalkylaryl, annelated heterocyclylaryl, annelated heterocyclylaryl, heteroaryl, annelated cycloalkylheteroaryl, annelated cycloalkenylheteroaryl heteroeryl 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 are benzene, naphthalene, anthracene and the like.
  • hetero matric cycles ⁇ electrons and p electrons of heteroatoms participate in the conjugation system; their total number also equals (4n + 2).
  • Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like.
  • An aromatic ring may have one or more “replaceable cyclic” 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.
  • Bifunctional reagent means a chemical compound having two reaction centers participating simultaneously or sequentially in the reactions.
  • Examples of bifunctional reagents are reagents containing a carboxyl group and an aldehyde or ketone group, for example, 2-formylbenzoic acid, 2- (2-oxo-ethylcarbamoyl) -benzoic acid, 2- (3-formyl-thiophen-2- and ) -benzoic acid or 2- (2-formylphenyl) -thiophene-3-carboxylic acid.
  • 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.
  • Hetero-linked loop means that a loop that attaches (annelates or condenses) to another loop or polycycle contains at least one heteroatom.
  • 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-pyridshi-vinyl, thienyl-ethenyl, imidazolylenethenyl, pyrazinyl-ethenyl, etc.
  • Heteroapalkyl means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section.
  • 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. Representatives of heteroaryl are pyrrolyl,.
  • 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.
  • 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 “substituents of the cyclic system)), which may be the same or different.
  • the nitrogen and sulfur atoms in heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide.
  • heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1,2-dihydropopyridine, 1,4-dihydropyridine, 2-pyrpolinyl, 3-pyrrolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl and the like.
  • 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.
  • 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 can be oxidized to N-oxide, S-oxide or S-dioxide.
  • Representatives of heterocyclyl 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 is attached 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, ariloksikarbnil, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, anneliro arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbony
  • 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 pyridyl - methyloxycarbonylmethyl.
  • 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, alkylaminocarbonyl, arylaminocarbonyl, geteroarilamino- carbonyl geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arilaminotiokar- Bonilla, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated heteroarylheterocyclyl, annel
  • Carbamoyl substituent means a substituent attached to a carbamoyl group, the meaning of which is defined in this section.
  • 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, heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfonyl, heterocylalkyl yl, arylsulfonic finil, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, heterocyclylthio, hetero
  • Electrophilic substituent means a chemical radical that attaches to scaffold by reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), organic sulfonic acid esters or organic sulfonyl chlorides, organic halides, organic isocyanides organic isothiocyanates.
  • Substituted amino group means an Rk a R k + 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 an R 5 substituent including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
  • Substituted mercapto 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 et al.) optionally substituted benzoyl et al .; a carbamate substituent, such as optionally substituted Ci-C 7 alkyloxycarbonyl, for example, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted Ci-C 7 alkyl substituent, for example, tert-butyl, benzyl, 2,4- dimethoxybenzyl, 9-phenylphyloinyl and others; sulfonyl
  • Protected primary or secondary amine means a group of the formula Rk a R k + i a N-, in which R k a is a PG protecting group and R k + 1 a is hydrogen, “a substituent of the amino group)), the meaning of which is defined in in this section, for example, alkenyl, alkyl, aralkyl, aryl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, annilated heteroalkyl, arylated heteroalkyl nelirovanny heteroarylheterocyclenyl, annelated geteraarilgeterotsiklil, heterocyclenyl or heterocyclyl.
  • “Inert substituent (or“ non-interfering)), “Nopperfer substitupt”) means a low or non-reactive radical, including but not limited to Cj - C 7 alkyl, C 2 - C 7 alkenyl, C 2 - .
  • inert substituents are C 1 - C 7 alkyl, C 2 - C 7 alkenyl, C 2 - C 7 alkynyl, C 1 - C 7 alkoxy, C 7 - C 12 aralkyl, C 7 - C 12 alkaryl, C 3 - C 10 cycloalkyl, C 3 - Cyu cycloalkenyl, substituted with inert substituents C 1 - C 7 alkyl, phenyl substituted with inert substituents phenyl, (CH 2 ) m -O- ( C 1 - C 7 alkyl), - (CH 2 ) m —N (C 1 - 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 Rk + ⁇ a including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
  • Carbamoylheterocycle means an azaheterocycle containing as
  • Kembocycle 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.
  • spiro-carbocycles are formed (for example, spiro [2.2] pentane), 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 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 ((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 piperidein.
  • Non-natural amino acid means an amino acid of a non-nucleic nature.
  • unnatural amino acids include the 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,
  • Optional aromatic cycle means a cycle that can be either an aromatic or a non-aromatic cycle, the meanings of which are defined in this section.
  • Optionally substituted radical means a radical without substituents or containing one or more substituents.
  • Optional 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.
  • 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 Rk a Rk + i a NSO 2 is a group substituted or unsubstituted “a substituent of the amino group)) R k a and Rk + D whose values are defined in this section.
  • Cylphonyl means R-SO 2 - a group in which R represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, 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 “combination library)).
  • Thiocarbamoyl may have one or more of the same or different ((amino substituents)) R k a and R k + A, 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 on the cyclic system)), which may be the same or different.
  • 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 ((cyclic substituents)) 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 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 delay 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 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 sion, e.g., therapeutic 'cocktail, 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. 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 Werge SM, et al, “Pharmaceut 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.
  • organic bases from which salts of the claimed acids can be obtained 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).
  • Such 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 basic amino acids can be used - lysine, ornithine and arginine.
  • “Focussed library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances specially organized to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization.
  • the design of focused libraries, as a rule, is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).
  • “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 meanings of which are defined in this section.
  • the aim of the present invention are unknown previously substituted hydrogenated pippolo [4,3-b] indoles having biological activity.
  • R 1 and R 2 independently of one another are amino substituents selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted with aryl, nitrogen-containing heteroaryl; C 1 -C 6 alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino, substituted acyl, possibly substituted arylsulfonyl, with the substituents in said R and R being independently selected from C 1 -C 6 alkyl, halogen atoms, nitro, carboxy, alkoxy aryl;
  • R ' n represents one or more identical or different substituents of the cyclic system selected from hydrogen, alkyl, aryl, cyano, halogen, 5-6-membered nitrogen-containing tetroaryl; excluding: l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (I), 2-methyl-A (2), 2-butyl-A (3), 2-cyclohexyl-A ( 4), 2-phenethidine-A (5), 2- (l-methyl-2-phenyl-ethyl) - A (6), 2-carbethoxy-A (7) and 2-benzyl-4-phenyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (8); 3- (2-butyl-A (9) and 3- (2-cyclohexyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indol-4-yl) -proponitrile A
  • R * H (1.20); CH 3 (2.21); C 4 H 9 (3,9,11,13); C 6 H 5 -CH 2 CH 2 (4.24); C 6 H 5 -CH 2 (5.17.25); cyclohexyl (6,10,12,14); CO 2 C 2 H 5 (7.28); iso-C 3 H 7 (15); mp.
  • -C 4 H 9 (16); 4-CH 3 OC 6 H 4 (18); C 3 H 7 (22,); (CHa) 3 CH 2 CH 2 CH 2 (23); CH 3 CH 2 CO (26); (CH 3 ) 3 CH 2 CH 2 CO (27); 4-F-C 6 H 4 -C (O) CH 2 CH 2 CH 2 (29); C 6 H 5 -C (OH) CH 2 CH 2 CH 2 (30); 4-FC 6 H 4 -C (OH) CH 2 CH 2 CH 2 (31); 4-FC 6 H 4 -C (O) CH 2 CH 2 CH 2 CH 2 (32); 4-FC 6 H 4 -C (OH) CH 2 CH 2 CH 2 CH 2 (33).
  • More preferred hydrogenated pyrpolo [4,3-b] indoles are g / wc-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indoles of general formula 1.2.
  • R 1 , R 2 and R ' n have the above meaning.
  • More preferred hydrogenated pyrpolo [4,3-b] indoles are l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles of the general formula 1.1.1, 1.1.2, 1.1.3 or cis-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indoles of the general formula 1.2.1, 1.2.2, 1.2.3.
  • More preferred hydrogenated pyrpolo [4,3-b] indoles are pyrpol [4,3-b] indoles of the general formula 1.1.4 - 1.1.15, 1.2.4 - 1.2.15.
  • R 1 , R 2 and R n 1 have the above meaning;
  • R 4 represents a possibly substituted alkyl, possibly substituted by aryl, carboxyalkyl, possibly substituted aryl;
  • R 5 represents CN, possibly substituted aryl or heterocyclyl; carboxyalkyl;
  • R represents carboxyalkyl, carbamoyl, CN, optionally substituted aryl or optionally substituted heterocyclyl;
  • R 7 represents an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heterocyclyl.
  • the aim of the present invention are methods for producing hydrogenated pirpolo [4,3-b] indoles of general formula 1, their racemates, their optical isomers, their geometric isomers, their pharmaceutically acceptable salts and / or hydrates.
  • a method for preparing compounds of general formula 1 consists in reacting phenylhydrazines of general formula 2 (or their salts) with an N-substituted pyppolidin-3-one of general formula 3 in an organic solvent.
  • R, R and R n 1 have the above meaning.
  • a process for the preparation of z / wc-l, 2,3,3a, 8,8a-hexahydro-pippolo [4,3-b] indoles of the general formula 1.2 consists in hydrogenation of a double bond ⁇ réelle' ⁇ Meeting in the corresponding l, 2,3, The 8-tetrahydro-pyrpolo [4,3-b] indole of general formula 1 with hydrogen in the presence of PtO 2 in an organic solvent medium.
  • R 5 R and R n have the above meaning.
  • electrophilic reagents selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula 6 in the presence of a base as a
  • X represents a halogen atom;
  • Y represents a halogen atom, 3H-imidazol-1-ima hydroxide, R 7 -C (O) O.
  • a method for producing compounds of the general formulas 1.1.10 - 1.1.15, 1.2.10 - 1.2.15 consists in reacting the corresponding compounds 1.1.2, 1.1.3 or 1.2.2, 1.2.3 in an organic solvent with electrophilic reagents, selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula 6 in the presence of a base as a catalyst; aldehydes of the general formula 7 and NaBH (AcO) 3 , anhydrides or halides of the carboxylic acids of the general formula 8 in the presence of a base; from (thio) cyanides of the general formula 9 or sulfonyl chlorides of the general formula 10 in the presence of a base.
  • electrophilic reagents selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R n 1 , X and Y have the above meaning.
  • a method for producing new l, 2,3,8-tetrahydro-pyrpo [4,3-b] indoles of general formula 1 with various substituents carried out according to the well-known reaction of constructing a tricyclic nucleus using Fischer condensation, including the phenylhydrazine reaction of formula 2 ( or its salts with mineral acids) and N-substituted pyppolidin-3-one 3, is described in [Waelsh, WM; Narbert, C. A. J. Med. Chet., 1980 23, (b), 704-707].
  • Reduction of the Cz a- Cg a double bond in l, 2,3,8 ⁇ tetrahydro ⁇ pippolo [4,3-b] indole of general formula 1 is carried out using suitable reducing agents and selectively substituted z / wc-l, 2,3, 3a, 8,8a-recarcaridropipyrpolo [4,3-b] indoles 1.2 [V.A. Zagorevsky, S.G. Rosenberg, N.M. Sipilina, L.Y. Bykova, A.P. Rodionov - ZhVHO, 1982, v. 27, No. 1, pp. 102-104; and JG Verger, Supsisis, 1974, No. 7, pp. 508-510] relative to the Sza-C ⁇ a bond.
  • a compound containing a substituted ethyl group in which R 5 is CN or optionally substituted 2-, 3- or 4-pyridyl is obtained by alkylation of the corresponding hydrogenated pirpolo [4,3-b] indoles 1, 1.2 with electrophilic alkenes of formula 6 in the presence of catalyst base, as, for example, described in the works of [N.N. Kamzolova, N.F. Kucherova, V.A. Zagorevsky, Zhokh, 1964, 34, (7), 2383-2387; A.N. Coast, M.A. Yurovskaya, T.V. Melnikova, O.I. Potanin - Auth. testimonial. USSR, 367094, 1970].
  • a catalyst for example, quaternary ammonium or sodium alcoholate, sodium hydride, sodium ethylate and others, in a polar aprotic solvent such as DMF, DMSO or HMFTA;
  • acyl derivatives, (thio) carbamide derivatives and sulfamoyl derivatives are prepared by reacting the corresponding hydrogenated pyrpolo [4,3-b] indoles 1, 1.2 with acylating agents, respectively anhydrides or halides carboxylic acids of formula 8, alkyl, cycloalkyl or apyl-iso (thio) cyano compounds of formula 9 or sulfochlorides of formula 10, for example, by analogy, as described in [HK Kochetkov, N.F. Kucherova, I.G. Zhukov, Zhokh, 1961, 31, (3), 924-930].
  • Hydrogenated pppolo [4,3-b] indoles of the general formula 1 of the present invention may form hydrates or pharmaceutically acceptable salts.
  • Inorganic acids and organic acids 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 can be used to obtain salts.
  • the subject of this invention is also a combinatorial library of compounds with neuroprotective, cognitively stimulating and antihistamine effects for determining hit compounds and leaders, consisting of compounds of general formula 1.
  • the subject of this invention is also a focused library of compounds with neuroprotective, cognitively stimulating and antihistamine effects for the determination and / or optimization of leader compounds, containing at least one compound of the general formula 1.
  • hydrogenated pippolo [4,3-b] indoles of general formula 1, their racemates, their optical isomers, their geometric isomers, their pharmaceutically acceptable salts and / or hydrates can be used as an active ingredient in the manufacture of medicaments for the treatment of and prevention of various diseases.
  • the subject of this invention is also a pharmaceutical composition having a neuroprotective, cognitively stimulating and antihistamine effect, for treating diseases whose pathogenesis is associated with excessive intracellular content of Ca + 2 ions in animals and humans, and / or diseases associated with impaired histaminergic mediator system, in the form of tablets, capsules or injections in a pharmaceutically acceptable package containing, as an active substance, a pharmaceutically effective amount, according to ayney least one hydrogenated pyrrolo [4,3-b] indola general formula 1 or a racemate or an optical isomer or a geometric isomer or a pharmaceutically acceptable salt and / or hydrate.
  • the subject of this invention is also a method for producing a pharmaceutical composition, which consists in mixing the active substance with an inert excipient and / or solvent, the distinguishing feature of which is that a pharmacologically effective amount of at least one hydrogenated pippol is used as the active substance [4, 3-b] indole of general formula 1 or its racemate, or its optical isomer, or its geometric isomer, or its pharmaceutically acceptable salt and / or hydrate.
  • the subject of this invention is the use of a pharmaceutical composition for the preparation of drugs for the treatment and prevention of various diseases of warm-blooded animals and humans, the pathogenesis of which is associated with excessive intracellular content of Ca ions in animals and humans and / or diseases associated with impaired histaminergic mediator system.
  • a pharmaceutical composition for the preparation of drugs for the treatment and prevention of the development of neurological disorders (in particular, hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, etc.), as well as neurodegenerative diseases (including Alzheimer's disease, Huntington's chorea, latirism, amyotrophic lateral sclerosis, etc.).
  • neurological disorders in particular, hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, etc.
  • neurodegenerative diseases including Alzheimer's disease, Huntington's chorea, latirism, amyotrophic lateral sclerosis, etc.
  • a pharmaceutical composition for the preparation of medicaments for the treatment of allergic and autoimmune diseases including hay fever, hives, bronchial asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke edema, eczema, burn toxemia, and also allergic reactions, is more preferred according to this invention. due to medicines, food, cosmetics, house dust, insect bites, etc.
  • the subject of this invention is also a method for improving the processes of memorization and reproduction of memorized (cognitive stimulation) in humans and warm-blooded animals by introducing a pharmaceutical composition.
  • 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 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.
  • Pharmaceutical preparations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If any medicinal substance in the stomach is not stable, you can use it for the manufacture of tablets, coated with a film of a substance soluble in the stomach and intestines.
  • the clinical dosage of hydrogenated pippolo [4,3-b] indoles of general formula 1 or their racemates, or their optical isomers, or their geometric isomers, or their pharmaceutically acceptable salts and / or hydrates in patients can be adjusted depending on: therapeutic the effectiveness and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 10 ⁇ 500 mg, preferably 50 ⁇ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in dosage units, the aforementioned effective dosage must be considered, with each dosage unit containing 10 ⁇ 500 mg of the compound 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).
  • the subject of this invention are also compounds of the general formula 1 possessing neuroprotective, cognitively stimulating and antihistamine properties, as well as the ability to regulate the cytosolic concentration of calcium ions in nerve cells, intended for experimental study of physiological processes of ip vivo and ip vitro as "pharmacological agents".
  • the best embodiment of the invention possessing neuroprotective, cognitively stimulating and antihistamine properties, as well as the ability to regulate the cytosolic concentration of calcium ions in nerve cells, intended for experimental study of physiological processes of ip vivo and ip vitro as "pharmacological agents".
  • Example 1 Obtaining 2 ⁇ carbethoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ⁇ CO 2 C 2 H 5 ).
  • Activated carbon is added to the combined aqueous solution, brought to a boil, filtered hot through celite, the filtrate is cooled and treated with an excess of an aqueous solution of NH 3 . After cooling, the precipitate formed is filtered off, washed with a large amount of water, and 7-apyl- and 7-heteryl-2-carbetoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ⁇ CO 2 C 2 Hs), which, if necessary, is additionally subjected to flash chromatography, including: 7- (3-methylphenyl) -2-carbethoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (6), LC-MS: m / z 321 [M + H]; 7- (3-pyridyl) -2-carbetoxy-l, 2,3,4-tetrahydro-pyrpolo [4,
  • Example 3 General method for the preparation of l, 2,3,8-tetrahydro-propripo [4,3-b] indoles 1.1.3. Substances are prepared according to the procedure described for 7-fluorop 4- (4-fluorophenyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole [Welsh, WM, Narbert, CA, Weissmap, AJ Honey. Chet.
  • reaction mass was dissolved in 50 ml of dichloromethane, which was washed twice with a weak aqueous solution of potash, dried over Na 2 SO 4 , evaporated, and the residue was chromatographed on a silica gel column impregnated with triethylamine.
  • Example 5 General method for producing l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1.
  • reaction mass was dissolved in 50 ml of dichloromethane, which was washed twice with weak aqueous potash solution, dried over Na 2 SO 4 , evaporated, and the residue is chromatographed on a silica gel column impregnated with triethylamine.
  • the substance is purified chromatographically on silica gel impregnated with triethylamine. Elution is carried out with a 10% solution of triethylamine in dichloromethane.
  • the corresponding 2-methyl derivatives 1. are obtained with a yield of 61-75%, including: 2,7-dimethyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (9), LC-MS: m / z 187 [M + H], 1 H NMR (400 MHz, DMSO-d 6 ): 10.87 (br.s, IH), 7.26 (m, IH) 3 7.15 (s, IH), 6.89 (m, IH), 3.90 (m, 4H), 2.62 (s, 3H), 2.39 (s, 3H); 2-methyl-4- (3-methylbenzyl) -7-fluoro-l, 2,3,4 ⁇ tetrahydro-pyrpropyl [4,3-b] indole 1.1.4
  • the product is isolated from the residue by preparative chromatography on silica gel impregnated with triethylamine, eluting with a mixture of hexane-ethyl acetate-triethylamine (7: 2: 1).
  • Compounds 1.1.13 are obtained in a yield of 65-75%, including: 7-methyl-2-nicotinyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.13 (1), LC-MS: m / z 278 [M + H]; 2-carboxy-ipem.-butyl-7-methyl-l, 2,3,4-tetrahydro-p-ppprol [4,3-b] indole 1.1.13 (2), LC-MS: m / z 257 [M + H]; 4-benzyl-2-benzoyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.13 (3), LC-MS: m / z 353 [M + H] and others.
  • Example 6 General methods for producing z / wc ⁇ l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indoles of the general formula 1.2.
  • reaction mass was dissolved in 50 ml of dichloromethane, which was washed twice with a weak aqueous solution of potash, dried over Na 2 SO 4 , evaporated, and the residue was chromatographed on a silica gel column impregnated with triethylamine.
  • Example 7 General methods for producing salts. A solution of ⁇ 4-8 equivalents of acid in anhydrous dioxane or tetrahydrofuran is added to 1 equivalent of base 1 or 1.2 in dioxane. The precipitated white precipitate was separated, washed with dioxane or tetrahydrofuran and dried in vacuum.
  • Example 8 Testing the biological activity of compounds of the general formula 1.
  • a focused library was prepared including compounds of the general formula 1, some of which are presented in Table 2 below.
  • the compounds were tested as potential antagonists of the histamine Hl receptor, and also their ability to regulate the cytosolic concentration of calcium ions in cells by blocking calcium channels regulated by intracellular calcium depots was determined.
  • SK-N-SH cells ATCC, USA
  • DMEM medium Ivitrogep, USA
  • FBS fetal calf serum
  • penicillin-streptomycin antibiotics in a CO 2 incubator (5% CO 2 ) until a density was reached IxIO cells 5 cells / cm.
  • Cells were harvested by centrifugation, resuspended in HSFM, incubated in suspension for 15 minutes, harvested by centrifugation, washed twice in HSFM and resuspended in HSFM at a concentration of 4 x 10 6 cells / ml.
  • DMSO dimethyl sulfoxide
  • Transformation of the fluorescent signal into calcium concentration was carried out using the equation built into the Super IoProbe program (Smadzu), for which the maximum content of free calcium was determined by adding digitonin (Sigma, USA) to 0.1 mg / ml, and zero calcium content by adding ethylene diamine tetraacetate (EDTA) up to 10 mm.
  • digitonin Sigma, USA
  • EDTA ethylene diamine tetraacetate
  • [Ca] [Ca] max x exp (-K x T) + [Ca] min
  • T is the time after addition of the test compound
  • [Ca] max and [Ca] n U n correspond to the maximum (peak value after addition of histamine) and minimum (the equilibrium level to which the curve tends after adding the test compound) concentration of intracellular calcium
  • K - this is the rate constant for decreasing intracellular calcium concentration, which is calculated by minimizing the least squares of the deviations.
  • the compounds of general formula 1 are effective blockers of the histamine receptor (Phase 1 - substances block the entry of calcium ions into cells due to the antagonistic effect on Hl receptors), and also accelerate the excretion of intraplasmic calcium (Phase 2), which indicates their neuroprotective cognitive-stimulating and antihistamine action.
  • Example 9 Testing the effect of compounds of the general formula 1 on spatial memory in a test for recognizing new localization.
  • the object recognition test is based on the fact that rats and mice spontaneously examine a new object or a new localization of an object for more time than a known or known localization of an object. This test was first used in rats [A. Ermaseur and J. Delacour, and the first opera-test test for the periurbiological studio of the method of rats. 1 1: Behavioral dat. Behav. Vraip Res. 1988, 31, 47-59; J.S. Dodart, S. Matis and A. Upgerer, Sorolamipe-ipodsef defitsit and two-trial obbesestpogopitask ip miise.
  • the object recognition test is divided into two tests. This is a test for recognizing a new localization of an object, which is used to study spatial memory, and a test for recognizing a new object - for exploring non-spatial memory [D. Gaffap, Ampèsia forcomcomplex naturalistic scenes and forbjests forwillip forpix transaction in the Rhesus mopke. EUR. J. Neurosi. 1992, 4, 381-388; B. KoIb, K. Wuhrmärm, R. McDopal and R.
  • mice were kept in a vivarium of 5 pieces per cage under a light regime of 12 x 12 hours with a light part from 8 to 20 hours at free access to water and food.
  • the observation camera was made of white opaque organic glass 48x38x30 cm in size. Brown glass vials with a diameter of 2.7 cm and a height of 5.5 cm were used as objects for examination. For 2 - 3 minutes. Before placing the animal, the camera and the objects to be examined were wiped with 85% alcohol. Animals were always placed in the center of the chamber.
  • mice Familiarization with the behavioral camera.
  • the mice were brought to the research room and acclimatized for 20-30 minutes. After that, each animal was placed for 10 minutes. into an empty, pre-treated with alcohol, behavioral chamber for review. Then the animal was put into a cage and carried to the vivarium.
  • mice were brought to the research room, 20-30 minutes. acclimatized and then introduced an intragastric solution of the analyte. 1 hour after the substance was introduced, the animal was placed in a behavioral chamber, on the bottom of which two identical objects (glass bottles) were placed diagonally at a distance of 14.5 cm from the corners (glass bottles) for recognition. The duration of the training of each animal is 15 minutes After 15 minutes, he was put into a cage and returned to the vivarium.
  • testing was performed 48 hours after training. For this, after acclimatization, the animal was placed for 1 min. into the camera for re-familiarization. After a minute, it was removed and one object was placed at the bottom of the chamber in a location known to the animal, and the other in a new one. Using two electronic stopwatch, the time of examination of each object separately for 10 minutes was recorded, with an accuracy of 0.1 sec. The behavior of animals was observed through a mirror. As a positive reaction for examining the object, a targeted approach of the animal’s nose to the object at a distance of 2 cm or direct touching of the object with the nose was considered. The left object is in a known location, and the right one is in a new one.
  • the acute toxicity of the test compounds was determined on male C57BL / 6 mice.
  • the substance was administered to six mice intragastrically once at a dose of 100 mg / kg.
  • the observation period is 14 days.
  • Example 10 An example illustrating the preparation of tablets containing 100 mg of the active ingredient. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of 2,5-dimethyl-8- [2- (6-methyl-pyridin-3-yl) ethyl] -l, 2,3,8- are mixed tetrahydro-pyrpolo [4,3-b] indole 1.1.5 (2) and pressed into a block. Received bar 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 substituted pippolo [4,3-b] indoles as the active ingredient.
  • Example 11 Capsules containing 200 mg of Is-4-benzyl-2,7-dimethyl-l, 2,3, 3a, 4,8b-hexahydro-pippolo [4,3-b] indole 1.2.6 (2) , according to the invention, are obtained by thoroughly mixing compound 1.2.6 (2) with lactose powder in a ratio of 2: 1. The resulting powdery mixture is packaged in 300 mg in a suitable size gelatin capsule.
  • Example 12 Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with a suitable solubility, for example, z / ms-4-benzyl-2,7-dimethyl-l, 2,3, Za, 4 hydrochloride , 8b-rehydro-pyrpolo [4,3-b] indole 1.2.6 (2), with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed and sterilized in an autoclave.
  • a suitable solubility for example, z / ms-4-benzyl-2,7-dimethyl-l, 2,3, Za, 4 hydrochloride , 8b-rehydro-pyrpolo [4,3-b] indole 1.2.6 (2), with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Toxicology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la synthèse de nouvelles substances chimiques, la recherche de nouvelles substances physiologiquement actives, de composés principaux, d''outils moléculaires' et de médicaments candidats obtenus par le criblage de bibliothèques focalisées ou combinatoires, de même qu'une composition pharmaceutique ainsi que des procédés de leur fabrication. L'invention porte sur des pyrrolo[4,3-b]indoles possédant la formule générale 1, sur leurs racémates, leurs isomères géométriques, leurs sels et/ou hydrates pharmaceutiquement acceptables. Dans la formule (1), la ligne tiretée avec une ligne ininterrompue (------) désigne une liaison simple ou double; R1 et R2 sont indépendamment des substitutifs de groupe aminé sélectionné parmi hydrogène; un alkyle C1-C6 éventuellement substitué par un aryle; un azahétérocyclyle à 5 ou 6 éléments; un alkoxycarbonyle C1-C6; un phényle éventuellement substitué; des carbonylamino ou tiocarbonylamino éventuellement substitués; un acyle substitué; un arylsulphonyle éventuellement substitué; R in se présente comme un ou plusieurs substitutifs différents du système cyclique sélectionné parmi hydrogène, alkyle, aryle, cyano, halogène ou hétéroaryle azoté à 5 ou 6 éléments.
PCT/RU2007/000435 2006-08-24 2007-08-08 Pyrrolo[4,3-b]indoles substitués, bibliothèques focalisées ou combinatoires, composition pharmaceutique, procédé de fabrication et d'utilisation Ceased WO2008026965A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2006130507/04A RU2320662C1 (ru) 2006-08-24 2006-08-24 ЗАМЕЩЕННЫЕ ПИРРОЛО[4,3-b]ИНДОЛЫ, КОМБИНАТОРНАЯ И ФОКУСИРОВАННАЯ БИБЛИОТЕКИ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
RU2006130507 2006-08-24

Publications (1)

Publication Number Publication Date
WO2008026965A1 true WO2008026965A1 (fr) 2008-03-06

Family

ID=39136157

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2007/000435 Ceased WO2008026965A1 (fr) 2006-08-24 2007-08-08 Pyrrolo[4,3-b]indoles substitués, bibliothèques focalisées ou combinatoires, composition pharmaceutique, procédé de fabrication et d'utilisation

Country Status (2)

Country Link
RU (1) RU2320662C1 (fr)
WO (1) WO2008026965A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9802899B2 (en) 2012-10-02 2017-10-31 Bayer Cropscience Ag Heterocyclic compounds as pesticides

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2514084A1 (de) * 1974-04-01 1975-11-20 Pfizer Neue indolverbindungen
US3968231A (en) * 1974-04-01 1976-07-06 Bayer Aktiengesellschaft 4-Aryl-1,2,3,4-tetrahydropyrrolo(3,4-b)indoles for treating schizophrenic manifestations
US4006164A (en) * 1974-04-01 1977-02-01 Pfizer Inc. 4-Aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles
SU614108A1 (ru) * 1976-08-01 1978-07-05 Всесоюзный Научно-Исследовательский И Проектный Институт Полимерных Продуктов Способ получени производных 2,2а,7,7а,8-тетрагидропирроло(2,8-с)-индола

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE266033T1 (de) * 1992-03-12 2004-05-15 Smithkline Beecham Plc N- (1-nbutyl-4-piperidyl)methyl -3,4-dihydro-2h- 1,3 oxazino 3,2-a indol-10-carboxamid oder ein pharmazeutisch annehmbares salz davon
JPH1087666A (ja) * 1996-09-18 1998-04-07 Kyorin Pharmaceut Co Ltd デュオカルマイシンｓａ及びその誘導体の製造中間体と製造方法
JPH10265473A (ja) * 1997-01-24 1998-10-06 Kyorin Pharmaceut Co Ltd ピロロインドール誘導体及びその製造中間体
CA2278682C (fr) * 1997-01-24 2005-10-04 Kyorin Pharmaceutical Co., Ltd. Derives de pyrroloindole et substances intermediaires pour les produire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2514084A1 (de) * 1974-04-01 1975-11-20 Pfizer Neue indolverbindungen
US3968231A (en) * 1974-04-01 1976-07-06 Bayer Aktiengesellschaft 4-Aryl-1,2,3,4-tetrahydropyrrolo(3,4-b)indoles for treating schizophrenic manifestations
US4006164A (en) * 1974-04-01 1977-02-01 Pfizer Inc. 4-Aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles
SU614108A1 (ru) * 1976-08-01 1978-07-05 Всесоюзный Научно-Исследовательский И Проектный Институт Полимерных Продуктов Способ получени производных 2,2а,7,7а,8-тетрагидропирроло(2,8-с)-индола

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9802899B2 (en) 2012-10-02 2017-10-31 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US10435374B2 (en) 2012-10-02 2019-10-08 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US10689348B2 (en) 2012-10-02 2020-06-23 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US10961201B2 (en) 2012-10-02 2021-03-30 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US11332448B2 (en) 2012-10-02 2022-05-17 Bayer Cropscience Ag Heterocyclic compounds as pesticides
US11548854B2 (en) 2012-10-02 2023-01-10 Bayer Cropscience Ag Heterocyclic compounds as pesticides

Also Published As

Publication number Publication date
RU2320662C1 (ru) 2008-03-27

Similar Documents

Publication Publication Date Title
WO2008123800A2 (fr) 2,3,4,5-tétrahydro-1h-pyrido[4,3-b]indoles substitués
WO2008115098A2 (fr) 2,3,4,5-tétrahydro-1h-pyrido[4,3-b]indoles substitués ainsi que procédés de leur fabrication et leur utilisation
RU2329044C1 (ru) Лиганды 5-ht6 рецепторов, фармацевтическая композиция, способ ее получения и лекарственное средство
EA016234B1 (ru) ЗАМЕЩЕННЫЕ 2,3,4,5-ТЕТРАГИДРО-1Н-ПИРИДО[4,3-b]ИНДОЛЫ, СПОСОБ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
WO2008024029A1 (fr) Azépino[4,3-b]indoles substitués, composition pharmaceutique, procédé de fabrication et d'utilisation
WO2007117180A1 (fr) Bibliothèques combinatoire et focalisée d'azahétérocycles, composition pharmaceutique et procédés de leur fabrication
TWI574691B (zh) Anti - tumor agents for intermittent administration of FGFR inhibitors
WO2009010925A2 (fr) Amides azahétérocycliques annelés comprenant un fragment de pyrimidine, procédé de leur fabrication et utilisation
ES2558604T3 (es) Derivados de 6-difluorometil-5,6-dihidro-2H-[1,4] oxazin-3-amina
TW201109327A (en) Heterocyclic compound
WO2007105989A2 (fr) 1-oxo-3-(1h-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines, procédés de production associés, bibliothèque combinatoire et bibliothèque ciblée
WO2009011617A2 (fr) Azahétérocycles annelés comprenant un fragment de pyrimidine, procédé de leur fabrication et inhibiteurs de pi3k kinases
ES2842289T3 (es) Compuestos para tratar el síndrome del dolor y otros trastornos
RU2303597C1 (ru) Фармацевтическая композиция, способы ее получения и применения
WO2007136300A2 (fr) Indoles substitués et procédé de production et d'utilisation de ceux-ci
CN105531272B (zh) 作为5‑ht6拮抗剂的吡咯并喹啉衍生物、其制备方法和用途
TW200533656A (en) Therapeutic agents
TW200808779A (en) Novel compound
CZ111497A3 (cs) Diazepinoindoly jako inhibitory fosfodiesterásy IV
KR101651933B1 (ko) 세로토닌 5-ｈｔ6 수용체의 2-아미노-3-설포닐-테트라하이드로-피라졸로[1,5-ａ]피리도-피리미딘 길항제, 이의 제조방법 및 이의 용도
WO2009093934A2 (fr) 3-sulphonyl-tiène[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines fonctionnant comme des antagonistes des récepteurs 5-ht6 de sérotonine, procédés de fabrication et d'utilisation
RU2369600C1 (ru) ЗАМЕЩЕННЫЕ 4-СУЛЬФОНИЛ-ПИРАЗОЛЫ И 3-СУЛЬФОНИЛ-ПИРАЗОЛО[1,5-a]ПИРИМИДИНЫ - АНТАГОНИСТЫ СЕРОТОНИНОВЫХ5-HT6 РЕЦЕПТОРОВ, АКТИВНЫЙ КОМПОНЕНТ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ЛЕКАРСТВЕННОЕ СРЕДСТВО И СПОСОБЫ ИХ ПОЛУЧЕНИЯ
CA2694994C (fr) Derives de n-heteroaryl-carboxamides tricycliques, leur preparation et leur application en therapeutique
TW202530210A (zh) Ｋｒａｓ抑制劑之晶型
WO2008026965A1 (fr) Pyrrolo[4,3-b]indoles substitués, bibliothèques focalisées ou combinatoires, composition pharmaceutique, procédé de fabrication et d'utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07834963

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07834963

Country of ref document: EP

Kind code of ref document: A1