WO2007133108A1 - Composition pharmaceutique, procédé de fabrication et d'application - Google Patents

Composition pharmaceutique, procédé de fabrication et d'application Download PDF

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WO2007133108A1
WO2007133108A1 PCT/RU2006/000528 RU2006000528W WO2007133108A1 WO 2007133108 A1 WO2007133108 A1 WO 2007133108A1 RU 2006000528 W RU2006000528 W RU 2006000528W WO 2007133108 A1 WO2007133108 A1 WO 2007133108A1
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pharmaceutical composition
racemates
pharmaceutically acceptable
effective amount
active substance
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PCT/RU2006/000528
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English (en)
Russian (ru)
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Alexander Vasilievich Ivashchenko
Sergey Yevgenievich Tkachenko
Ilya Matusovich Okun
Scott Andre Rivkees
Dmitry Vladimir Kravchenko
Alexander Viktorovich Khvat
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Chemdiv, Ink.
Ivashchenko Andrey Alexandrovich
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Publication of WO2007133108A1 publication Critical patent/WO2007133108A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention relates to a pharmaceutical composition for medicines for humans and warm-blooded animals used to treat diseases and conditions associated with excessive activity (secretion) of adrenocorticotropic hormone (ACTH), in particular, congenital or acquired adrenal cortical hyperplasia, Cushing's syndrome and disease.
  • ACTH adrenocorticotropic hormone
  • the invention also relates to new “molecular pharmacological tools)) for research (ip vitro and ip vivo) on the biochemical mechanisms of action of corticosteroid hormones and their specific receptors, in particular, the melanocortin receptor-2 (MC2R), the ACTH agonist of which.
  • M2R melanocortin receptor-2
  • the present invention relates to a pharmaceutical composition containing, as active substances, compounds comprising a fragment of l-oxo-3- (W-indol-3-yl) -l, 2,3,4-tetrahydroisoxinoline, and also to a method for producing of these compositions and the method of using these compositions for the treatment and prevention of the development of various diseases associated with increased activation of adrenocorticotropic hormone (ACTH), as well as the use of compounds including the fragment l-occo-3- ( ⁇ -indol-3-yl) -l , 2,3,4-tetrahydroisoxinoline, as a “molecular pharmacol cal instruments)) for studies (in vitro and in vivo) biochemical mechanisms of action of corticosteroids and their specific receptors, particularly melanocortin petseptopa-2 (MC2R), which is an agonist of CRF.
  • W-indol-3-yl compounds comprising a fragment of
  • the adrenal cortex produces steroid hormones that play an exceptional role in the physiology of humans and animals [a) Silvermap ML, Lee A.K. Apatom apd patologuf of the adpap glapds. Urol. CHn. North. Am. 1989; 16: 417-32. b) Rosol TJ, Yarripptop JT, Latendresse J., Capen CC. ⁇ drepal glapd: stasture, fuêtiop, ierip miquehapisms THERf tohicitu. Tohisol. Rathol. 2001; 29: 41-8].
  • These steroids include the mineralocorticoid aldosterone, glucocorticides cortisone and corticosterone, as well as a number of androgens.
  • the production of these steroids is regulated by ACTH, the secretion of which is controlled by the corticotropin-releasing hormone [Brodish A., Lumapgrover JR Thé hurothalamis-rituitar-adreposal system. Ipt. Rev. Phusiol. 1977; 16: 93-149].
  • ACTH produced by the pituitary gland, acts by binding specifically to its receptor, the so-called melanocortin receptor MC-2, which leads to increased steroidogenesis [Schioth HB, Cheljapi V., Muceniece R., Klusa V., Wikberg J.E. Major rharmacologic distinction of the ACTH Resource Fotom Theother Melaposort Resource. Lif Ssi. 1996; 59: 797-801]. Decreased ACTH secretion caused by congenital or acquired pituitary dysfunction leads to hypoadrenalism. Excessive secretion of ACTH leads to congenital or acquired hyperplasia of the adrenal cortex, Cushing's syndrome and disease, as well as ectopic production of ACTH.
  • Congenital hyperplasia of the adrenal cortex is a clinical symptom complex, the development of which is associated with impaired corticosteroid secretion due to a congenital defect in the enzymes responsible for the biosynthesis of these hormones [ ⁇ oll Canaltt-Solb Canalrg P.F. Soppital adrepal hurerlasia: from heptics apd bioshemistru to lipisal solution, picture 2. Slip. Radio. (Phil) 2001; 40: 125-32].
  • the reduced formation of cortisol leads to increased secretion of ACTH followed by the development of hyperplasia of the cortical layer of the adrenal cortex.
  • Cushing's syndrome combines the symptoms caused by a constantly elevated level of free cortisol in the blood, while Cushing's disease (Itsenko-Cushing's disease) is a special pituitary ACTH-dependent subtype of this syndrome [Giraldi FP, Putigpapo R., Savagpipi F. ⁇ ushi ⁇ g's super. Lapet 2001; 357: 2138]. According to statistics, every year there are 3 new cases of Cushing’s disease in the population of South Ossetia [Savagpi F., Resori F. Girdaldi apd foliw-ur anywayf ⁇ ushipg's dis spicys Canal. App Eposipro.
  • non-peptide antagonists of the MC2R receptor namely azaheterocyclic compounds, including a fragment of 4'-carbamoyl-G-carbonyl- [l, 4 '] complicatpidinyl, indole or 2- (4-oxo-5-sylphamoyl-4H-thieno [2,3-d] pirtmidin-3-yl) -acetamide.
  • this invention relates to a new pharmaceutical composition containing azaheterocyclic compounds comprising a fragment of 4'-carbamoyl-G-carbonyl- [l, 4 '] bipiperidinyl, indole or 2- (4-oxo-5-cyfamoyl-4H-thieno [ 2,3-d] pirtmidin-3-yl) -acetamide, in the form of active substances; as well as the method of its preparation and the method of its use for treating and preventing the development of various diseases associated with the action of excessively secreted ACTH (congenital or acquired hyperplasia of the adrenal cortex, Cushing's syndrome and disease, etc.).
  • “Aheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a cycle, the values of which are given in this section.
  • the azaheterocycle may have one or more cyclic substituents.
  • 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 representatives include the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, geteroaralkinil, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloal
  • Alkenyl means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including a carbon-carbon double bond.
  • Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, 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 a chain, in which branched alkyl groups 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
  • G 1 G 2 NC ( S) -, G 1 G 2 NSO 2 -, where G 1 and G 2 independently from each other represent an atom
  • 1 hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or G and G together with the N atom to which they are bonded form 4 to 7 membered heterocyclyl or heterocyclenyl with G and G.
  • 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 and methoxycarbonylmethyl piridilmetiloksikarbonilmetil .
  • 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.
  • 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 and ethoxycarbonylethyl.
  • Amino group means a G G N group substituted or unsubstituted
  • Substitute amino group G 1 and G 2 , 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.
  • Examples of natural amino acids are ⁇ -amino acids, for example, alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, series, threonine and cysteine.
  • Alated cycle (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycycle with which it
  • Annelated apylheterocycloalkenyl means annelated aryl and heterocycloalkenyl, the meaning of which is defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system.
  • the prefix "aza”, “okca” or “tia” before “heterocycloalkenyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated arylheterocycloalkenyl may have one or several substituents of the cyclic system, 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 substituents on the ring system, 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 “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 arylcycloalkenyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-l-yl, and the like.
  • “Anelated heteroapylcycloalkenyl” means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Annelated heteroarshchloalkenyl can bind through any possible atom of the cyclic system.
  • the prefix “aza”, “okca” or “tia” before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Annelated heteroarylcycloalkenyl may have one or more cyclic substituents, which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoxinolinyl, 4,5-dihydro-III-benzimidazole and the like.
  • “Annelated reteroylcycloalkyl” 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 can be oxidized to N-oxide.
  • Representatives of annelated heteroarylalkylalkyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-1 H-benzimidazolyl, 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 “cyclic system substitutes” that may be the same or different.
  • the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • the nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
  • 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.
  • “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 substituents of the cyclic system, which may be the same or different.
  • the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
  • the nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
  • annelated heteroaryl heterocyclyls are 2,3-dihydro-III-pyrpolo [3,4-b] quinolin-2-yl, 2,3-dihydro-III-pyrpolo [3,4-b] indol-2-yl, l, 2,3,4-tetrahydro [l, 5] naphthyridinyl and the like.
  • “Aralkenyl” means an 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 aryl-alkyl-NH—, 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 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 “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.
  • 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 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). Examples of aromatic cycles are 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.
  • An aromatic ring may have one or more ((substituents 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.
  • 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-formylthiophen-2-yl) 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.
  • 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.
  • heteroaralkenyl includes a lower alkyl group.
  • Representatives of heteroaralkenyls are 4-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl, etc.
  • Heteroapalkyl means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section. Representatives of heteroaralkyls 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 heteroaralkyloxy groups are A-pyridylmethyloxy, 2-thienylmethyloxy, and the like.
  • Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc.
  • 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 heteroaryl 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, - aypyridinyl, imidazo [2, lb] thiazolyl, benzofurazanil, indolyl, azainindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinylidene, imonazole, and etc.
  • Heterocycle means an aromatic or non-aromatic monocyclic or polycyclic system containing in the cycle at least one heteroatom, the meanings of which are defined in this section. Preferred heteroatoms are nitrogen, oxygen and sulfur. An azaheterocycle may have one or more “cyclic system substitutes”.
  • 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, by 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 atom oxygen or 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.
  • Representative 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 a 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 “cyclic system substitutes,” 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.
  • 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 attaches to the scaffold (fragment), for example, “substituent alkyl”, substituent amino group, substituent carboxylic)), “substituent carbamoyl”, “substituent of the cyclic group”, as defined herein.
  • 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, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aral
  • 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.
  • Substituent amino group is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, anneliro anny arylcycloalkenyl, annelated arylcycl
  • Carboxyl substituent means a substituent attached to the oxygen of the carboxyl group, the meaning of which is defined in this section.
  • the carboxy substituent is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or
  • GG N-, GG NC ( O) -alkyl annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkylaryl, annelated arylcycrylalkenyl,
  • Nucleophilic substituent means a chemical radical that attaches 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, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro, cyano carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,
  • Electrophilic substituent means a chemical radical that attaches to scaffold by reaction with an electrophilic reagent, for example, organic acids or their derivatives (anhydrides, imidazolides, halides), esters of organic sulfonic acids or organic sulfonyl chlorides, organic halocyanates, organic isocyanates and organic isothiocyanates and organic isothiocyanates and organic isothiocyanates and organic isothiocyanates .
  • “Protection group” means a chemical radical that attaches to a scaffold or intermediate to synthesize the amino group in multifunctional compounds including, but not limited to: an amide substituent such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl, 3- phenylpropionyl and others), optionally substituted benzoyl and others; a carbamate substituent such as optionally substituted C 1 -C 7 alkyloxycarbonyl, for example, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; an optionally substituted C 1 -C 7 alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethixibenzyl, 9-phenylphyloinyl and the like; sulfony
  • Protected primary or secondary amine “means a group of the formula GG N-, in which one of G 1 and G 2 is a PG protecting group, and the other of G 1 and G 2 is hydrogen, alkenyl, alkyl, aralkyl, aryl, annelated arylcycloalkenyl, annelated, arylcycloalkyl, annelated, arylheterocyclenyl, annelated arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, annelated, heteroarylcycloalkyl, heteroaryl arylcycloalkyl,
  • “Inert substituent” (or “not interfering", “Nope-substitute substitu”) means a low or non-reactive radical including, but not limited to 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 substituted with inert aralkyl substituents, C 7 - C 12 heterocyclylalkyl substituted with inert substituents heterocyclylalkyl, C 7 - C 12 alkaryl, C 3 - C 10 cycloalkyl, C 3 - C 10 cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C 2 - C 12 alkoxyalkyl, C 2 - C 10 alkylsulfinyl, C 2 - C 10 alkylsulfonyl, (
  • 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 - C 10 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” G 1 and G 2 including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meanings of which are defined in this section.
  • Carbamoyl-heterocyclic means an azaheterocycle containing, as a “substituent of the cyclic system”, at least one carbamoyl group, the value of “friendocyclic,” and the “cyclic system” of the group are defined.
  • “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.
  • spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two - systems condensing various (for example, decalin), in the case of three - bridging systems (for example, bicyclo [3.3.1] is not), in the case of a larger number, various polyhedral systems (for example, adamantane).
  • Alicyclics may be “saturated”, for example, as cyclohexane, or “partially saturated)), for example, as tetralin.
  • “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.
  • Metal radical means —CH 2 - a group that contains one or two identical or different alkyl substituents ”, the meaning of which in this section.
  • Non-aromatic cycle saturated cycle or partially saturated cycle
  • the non-aromatic ring may have one or more substituents of the cyclic system)) and can be annelated with aromatic, heteroaromatic or heterocyclic systems.
  • non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidine.
  • Natural amino acid means an amino acid of a non-nucleic nature.
  • unnatural amino acids are 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, 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 cycle or
  • Optionally substituted radical means a radical without substituents or containing one or more substituents.
  • annelated (condensed) cycle means a condensed or non-condensed cycle, the meaning of which is 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 refers to —CH 2 —CHi-CH 2 — a group that contains one or more identical or different “alkyl substituents”, the meaning of which is given 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.
  • Silicone group means G 1 G 2 NSO 2 - group, substituted or unsubstituted “substitute amino group)) G 1 and G 2 , the meanings of which are defined in this section.
  • Cylfonyl means G 3 -SO 2 - a group in which G 3 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl aryl, acyl, aryl, aryl 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)).
  • Thiocarbamoyl may have one or more identical or different “thiocarbamoyl substituents” G 1 and G 2 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 ring 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 substituents on the ring system are alkyl, aralkoxy, hydroxy or G 1 G 2 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, means deliveries 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 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.
  • the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin.
  • suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injection 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.
  • a pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration, an 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 salts” 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.
  • Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized.
  • Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
  • Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
  • amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
  • amino acids the main amino acids can be used - lysine, ornithine and arginine.
  • “Focussed library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances, specially organized in order 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 the molecular framework characteristic of a group of compounds or compounds included in a “combinational library)).
  • the “1,2-Ethylene radical” means -CH 2 -CH 2 - a group that contains one or more of the same or different “substituted alkyl”, the meaning of which is defined in this section.
  • An object of the present invention is to provide a new pharmaceutical composition in the form of tablets, capsules or injections in a pharmaceutically acceptable package.
  • a pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans which has an inhibitory effect on the MC2R receptor, in the form of tablets, capsules or injections in a pharmaceutically acceptable package containing a pharmaceutically effective amount of an azaheterocyclic compound as an active substance, including fragment of 4'-carbamoyl-G-carbonyl- [l, 4 '] bipiperidinyl of formula 1.1, indole of formula 1.2 or 2- (4-oxo-5-cyfamoyl-4H- thieno [2,3-d] pirtmidin-3-yl) -acetamide of the formula 1.3, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, having an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, a pharmaceutically effective amount of 4'-carbamoyl-G-carbonyl-
  • R represents a substituted alkyl, aryl, heteroaryl, heterocyclyl.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, having an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, a pharmaceutically effective amount of a substituted indole of the general formula 1.2.1 or its racemates, or optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 1 represents a substituent of an amino group
  • R 2 , R 3 and R 4 independently from each other represent a Deputy of the cyclic system; or R 3 and R 4 together with the carbon atoms to which they are bonded, short the azaheterocycle through R 3 and R, or R 1 together with the nitrogen atom to which it is bonded, R 3 and R 4 together with the carbon atoms to which they are connected, close through R, R and R azaheterocycle.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of N- [2- ( ⁇ -indol-3-yl) as an active substance ) -ethyl] -acylamide of the general formula 1.2.1.1 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 1 , R 2 and R 4 have the above meaning;
  • R 5 represents an azaheterocycle.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, having an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of l l- ( ⁇ -indol-3-yl) - as an active substance 2,3,4,5,10, l l-hexahydro-dibenzo [b, e] [l, 4] diazepin-l-one of general formula 1.2.1.2 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R and R have the above meaning; R represents alkyl or cycloalkyl; R and R independently represent a hydrogen atom, alkyl or aryl.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of 7-acyl-6- (III-indole-3- as an active substance) il) -3-sulfonyl- 6,7,8,9-tetrahydro-l, 2,4-triazino [5, b-f] [l, 3] oxasepin of the general formula 1.2.1.3 or its racemates, or its optical isomer or a pharmaceutically acceptable salt and / or hydrate thereof:
  • R and R have the above meaning; R represents alkyl or alkenyl.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of l-occo-3- ( ⁇ -indole-3- as an active substance) il) -l, 2,3,4-tetrahydro-isoquinoline of the general formula 1.2.1.4 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 1 and R 2 have the above meaning;
  • R 10 represents a substituent of the cyclic system;
  • R 11 , R 12 and R 13 independently of each other represent an amino substituent.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of l-occo-3- ( ⁇ -indole-3- as an active substance) il) -l, 2,3,4-tetrahydro-isoquinoline of the general formula 1.2.1.4.1 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 1 , R 2 , R 10 , R 11 , R 12 and R 13 have the above meaning.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of l-occo-3- ( ⁇ -indole-3- as an active substance) il) -l, 2,3,4-tetrahydro-isoquinoline of the general formula 1.2.1.4.2 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 1 represents hydrogen or methyl:
  • R 10 , R 11 and R 13 have the above meaning.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, having an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of 1,2,3, 8-tetrahydro-l-oco as an active substance -ppro [3,4-b] indole of the general formula 1.2.1.5 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R and R have the above meaning;
  • R 1 represents an amino group substituent;
  • R represents aryl or heteroaryl.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, having an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of 2,3,4,5-tetrahydro-III-pyrido as an active substance [3,4-b] indole of the general formula 1.2.1.6 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 1 and R 2 have the above meaning; R 16 represents an amino group substituent.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, a pharmaceutically effective amount of an azaheterocycle of the general formula 1.2.1.7 or its racemates or its optical isomer or a pharmaceutically acceptable salt and / or hydrate thereof:
  • R 2 has the above meaning; R 17 represents an amino group substituent.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, which has an inhibitory effect on the MC2R receptor is a composition containing a pharmaceutically effective amount of 2- (6-methyl-4-oxo-5- as an active substance) sulfamoyl-4H-thieno [2,3-d] pyrimidin-3-yl) -acetamide of the general formula 1.3.1 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • R 18 , R 19 , R 20 and R 21 independently from each other are amino substituents.
  • a more preferred pharmaceutical composition for treating and preventing the development of various diseases of warm-blooded animals and humans, having an inhibitory effect on the MC2R receptor is a composition containing as an active substance pharmaceutically effective amount of 2 - [(6-methyl-4-oxo-5- (4-pyrimidin-2-yl-piperazin-1-cyclonyl) -4H-thieno [2,3-d] pyrimidin-3-yl] - acetamide of the general formula 1.3.1.1 or its racemates, or its optical isomer, or its pharmaceutically acceptable salt and / or hydrate:
  • the aim of the present invention is also a method for producing a pharmaceutical composition.
  • 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 a compound comprising a fragment of the formula 1.1, or 1.2, or 1.3, is used as the active substance. or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • the aim of the present invention is also a method of treating and preventing the development of various diseases of warm-blooded animals and people associated with increased activation of adrenocorticotropic hormone (ACTH).
  • ACTH adrenocorticotropic hormone
  • This goal is achieved by a method of treating and preventing the development of various diseases of warm-blooded animals and humans, by administering to a warm-blooded animal or human a pharmaceutical composition containing, as an active substance, a pharmacologically effective amount of a compound comprising a fragment of formula 1.1, or 1.2, or 1.3, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.
  • the aim of the present invention is also the creation of new
  • physiologically active azaheterocyclic compounds including a fragment of the formula 1.1, or 1.2, or 1.3, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates with properties to inhibit the MC2R receptor, for experimental (ip vitro or ip vivo) studies of processes associated with increased activation of adrenocorticotropic hormone (ACTH) as “pharmaceutical tools)).
  • ACTH adrenocorticotropic hormone
  • Asheterocyclic compounds comprising a moiety of the formula 1.1, or 1.2, or 1.3, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates are known compounds and are commercially available, for example, from the American company ChemDiv, Ips [Sap Diego, CA: www. Chemdiv.com].
  • Example 1 Inhibition of the MC2R receptor by azaheterocyclic compounds comprising a fragment of formula 1.1, or 1.2, or 1.3.
  • a mouse cell culture (Yl cells) is used, which is known [Heisler S, Talleriso-Meluk T, Yir C, Schimmer BP.
  • YI adposogtisl tumocells soptaip atril patriuretis repertéresertors whi resumeh regulyuset suslis pusleotide metabolism apd steroidogepesis.
  • Yl-CRE-Iu melanocorticotropic receptor type 2
  • Yl-CRE-Iu pHTS-CRE vector purchased from Biochem Tespologu (Sap Diego, CA) with a luciferase reporter gene and a transcription element sensitive to cyclic AMP.
  • adrenocorticotropic hormone (ACTH)
  • the level of cyclic AMP increases, which leads to stimulation of the expression of the luciferase gene and, as a result, enhances the luminescence of expressed luciferase, which can be recorded using a luminescent spot reader in a 96- or 384-well.
  • Screening was carried out as follows. Stably transfected with the luciferase gene, cells were plated in 96-well plates (5,000-7,000 cells / well) and incubated at 37 ° C in an atmosphere of 5% CO 2 for 24 hours.
  • Test compounds were added to the plate cells at a final concentration of 1 ⁇ M, the cells were incubated for an additional 15 minutes, after which ACTH was added to them at a concentration of 100 nM, and the incubation continued for an additional 4 hours.
  • the measurement of luciferase activity was carried out using a set of reagents manufactured by Biotium, Ips, (USA) and in accordance with their protocol.
  • the incubation medium was removed from the wells by aspiration, and the cells were washed with physiological saline with phosphate buffer. 20 ⁇ l of the reagent kit lysate buffer was added to the wells and the plates were shaken at room temperature for 15 minutes.
  • Tables 1-3 show some examples of the percent inhibition of the luminescent signal in the presence of the tested azaheterocyclic compounds, including a fragment of the formula 1.1 (table 1), 1.2 (table 2) and 1.3 (table 3), in relation to the signal developing in the presence of one ACTH.
  • the presented examples confirm the inhibition of the MC2R receptor by azaheterocyclic compounds, including a fragment of the formula 1.1, 1.2 and 1.3, which in many cases reaches more than 50%.
  • Example 2 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 azaheterocyclic compound 1.1 (9) or 1.2.1.4 (183), or 1.3.10 are mixed and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each. According to the invention, pharmaceutical compositions in the form of tablets are likewise prepared in the form of tablets containing other azaheterocyclic compounds as an active ingredient, including a fragment of formula 1.1, or 1.2, or 1.3.
  • Example 3 Capsules containing 200 mg of azaheterocyclic compound 1.1 (9), or 1.2.1.4 (183), or 1.3.10 according to the invention can be obtained by thoroughly mixing compound 1.1 (9), or 1.2.1.4 (183), or 1.3. 10 with lactose powder in a ratio of 2: 1. The resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.
  • Example 4 Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with suitable solvents, for example, azaheterocyclic hydrochloride 1.2.1.4 (183) 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.
  • suitable solvents for example, azaheterocyclic hydrochloride 1.2.1.4 (183)
  • chlorobutanol 2 ml of propylene glycol
  • injection water 100 ml
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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Abstract

L'invention concerne une composition pharmaceutique contenant en tant que substances actives des compositions contenant un fragment de 1-oxo-3-(1H-indol-3-il)-1,2,3,4-tetrahydroisoxynoline ainsi que des procédés de fabrication de ces compositions et des procédés d'utilisation de ces compositions dans le traitement et la prévention du développement de diverses maladies liées à une activation plus élevé de l'hormone adrénocorticoïde (ACTH), et l'utilisation de compositions contenant un fragment de 1-oxo-3-(1H-indol-3-il)-1,2,3,4-tetrahydroisoxynoline en tant 'qu'instruments pharmacologiques moléculaires' pour des recherches (in vitro et in vivo) des mécanismes biochimiques d'action d'hormones corticostéroïdes et de leurs récepteurs spécifiques, notamment, du récepteur-2 de mélanocortine (MC2R) dont l'agoniste se présente sous la forme d'ACTH.
PCT/RU2006/000528 2006-05-12 2006-10-12 Composition pharmaceutique, procédé de fabrication et d'application WO2007133108A1 (fr)

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WO2008146774A1 (fr) * 2007-05-28 2008-12-04 Astellas Pharma Inc. Dérivé de tétrahydroisoquinolin-1-one ou sel de celui-ci
WO2009149054A1 (fr) 2008-06-03 2009-12-10 Siga Technologies, Inc. Inhibiteurs à petites molécules pour le traitement et la prévention de l'infection par le virus de la dengue
US8101580B2 (en) 2005-04-21 2012-01-24 Astellas Pharma Inc. Therapeutic agent for irritable bowel syndrome
US9505749B2 (en) 2012-08-29 2016-11-29 Amgen Inc. Quinazolinone compounds and derivatives thereof
JP2021528375A (ja) * 2018-06-05 2021-10-21 クリネティックス ファーマシューティカルズ，インク． メラノコルチンサブタイプ−２受容体（ｍｃ２ｒ）アンタゴニストおよびその使用
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
EP4142714A4 (fr) * 2020-04-29 2024-05-15 Univ Emory Dérivés de n-acétylsérotonine en tant qu'activateurs de trkb et leurs utilisations

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US8101580B2 (en) 2005-04-21 2012-01-24 Astellas Pharma Inc. Therapeutic agent for irritable bowel syndrome
US9150541B2 (en) 2007-05-28 2015-10-06 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
JP5336359B2 (ja) * 2007-05-28 2013-11-06 セルダー ファーマ インコーポレイテッド テトラヒドロイソキノリン−１−オン誘導体またはその塩
US9526719B2 (en) 2007-05-28 2016-12-27 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
US10532048B2 (en) 2007-05-28 2020-01-14 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
WO2008146774A1 (fr) * 2007-05-28 2008-12-04 Astellas Pharma Inc. Dérivé de tétrahydroisoquinolin-1-one ou sel de celui-ci
US10016410B2 (en) 2007-05-28 2018-07-10 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
US8486970B2 (en) 2007-05-28 2013-07-16 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
CN102056483A (zh) * 2008-06-03 2011-05-11 西佳技术公司 用于治疗或预防登革病毒感染的小分子抑制剂
WO2009149054A1 (fr) 2008-06-03 2009-12-10 Siga Technologies, Inc. Inhibiteurs à petites molécules pour le traitement et la prévention de l'infection par le virus de la dengue
EP2293671A1 (fr) * 2008-06-03 2011-03-16 Siga Technologies, Inc. Inhibiteurs à petites molécules pour le traitement et la prévention de l'infection par le virus de la dengue
US9029376B2 (en) 2008-06-03 2015-05-12 Siga Technologies, Inc. Small molecule inhibitors for the treatment or prevention of dengue virus infection
JP2011522054A (ja) * 2008-06-03 2011-07-28 シガ・テクノロジーズ・インコーポレーテッド デングウイルス感染の処置または予防のための小分子インヒビター
EP2293671A4 (fr) * 2008-06-03 2012-03-21 Siga Technologies Inc Inhibiteurs à petites molécules pour le traitement et la prévention de l'infection par le virus de la dengue
US9505749B2 (en) 2012-08-29 2016-11-29 Amgen Inc. Quinazolinone compounds and derivatives thereof
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
JP7359783B2 (ja) 2018-06-05 2023-10-11 クリネティックス ファーマシューティカルズ，インク． メラノコルチンサブタイプ－２受容体（ｍｃ２ｒ）アンタゴニストおよびその使用
JP2021528375A (ja) * 2018-06-05 2021-10-21 クリネティックス ファーマシューティカルズ，インク． メラノコルチンサブタイプ−２受容体（ｍｃ２ｒ）アンタゴニストおよびその使用
EP4142714A4 (fr) * 2020-04-29 2024-05-15 Univ Emory Dérivés de n-acétylsérotonine en tant qu'activateurs de trkb et leurs utilisations

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