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WO2015020565A1 - [1,2,4]triazolo[4,3-a]pyridines substitués ayant des propriétés d'antagonistes de récepteurs a2a d'adénosyne, et utilisation de ces derniers - Google Patents

[1,2,4]triazolo[4,3-a]pyridines substitués ayant des propriétés d'antagonistes de récepteurs a2a d'adénosyne, et utilisation de ces derniers Download PDF

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WO2015020565A1
WO2015020565A1 PCT/RU2014/000514 RU2014000514W WO2015020565A1 WO 2015020565 A1 WO2015020565 A1 WO 2015020565A1 RU 2014000514 W RU2014000514 W RU 2014000514W WO 2015020565 A1 WO2015020565 A1 WO 2015020565A1
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Prior art keywords
triazolo
pyridine
carboxylic acid
pyridin
substituted
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Russian (ru)
Inventor
Андрей Александрович ИВАЩЕНКО
Николай Филиппович САВЧУК
Сергей Евгеньевич ТКАЧЕНКО
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OBSHCHESTVO S OGRANICHENNOY OTVETSTVENNOSTYU "NEWVAC" (OOO "NEWVAC")
Alla Chem LLC
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OBSHCHESTVO S OGRANICHENNOY OTVETSTVENNOSTYU "NEWVAC" (OOO "NEWVAC")
Alla Chem LLC
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    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to new compounds - substituted [1, 2,4] triazolo [4,3-a] pyridines exhibiting antagonistic activity against adenosine A2A receptors, and to their use as a drug substance, pharmaceutical compositions, drugs and Adyovants.
  • the invention also relates to methods for treating disorders of the central nervous system (CNS), neurodegenerative, inflammatory, infectious and oncological diseases.
  • CNS central nervous system
  • This protective response can manifest itself as increased blood supply (vasodilation or angiogenesis), ischemic preconditioning [Akaiwa K., Akashi H, Harada H, Sakashita H, Hiromatsu S, Kapo T, Aoyagi S. Moderate cerebral venous congestion induces rapid cerebral protection via adenosine A l receptor activation. Brain Res.
  • adenosine receptors There are four subtypes of adenosine receptors, designated as Al, A2A, A2B, and A3 (Table 1), each of which has a unique pharmacological profile, tissue distribution, and binding to effector molecules [Fredholm BB, IJzerman AP, Jacobson KA, Klotz N, Linden J. International Union of Pharmacology. Xxv. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001; 53: 527-552]. All adenosine receptors belong to the family of receptors associated with G-proteins (GPCRs), structurally resembling receptors for biogenic amines.
  • GPCRs G-proteins
  • a 1 receptors Activation of A 1 receptors leads to inhibition of adenylate cyclase via receptor-bound A l Gi / o proteins [Londos C, Cooper DM, Wolff J. Subclasses of external adenosine receptors. PNAS USA. 1980; 77: 255 1 -2554], and also increases the activity of phospholipase C PLC [Rogel A, Bromberg Y, Sperling O, Zoref-Shani E. Phospholipase C is involved in the adenosine activated signal transduction pathway conferring protection against iodoacetic acid-induced injury in primary rat neuronal cultures. Neurosci Lett. 2005; 373: 218-221].
  • the receptors A l activate potassium channels, including KATP channels, and block the Q-, P- and specialised ⁇ -types of calcium Ca2 + channels.
  • A2A receptors Activation of A2A receptors increases adenylate cyclase activity.
  • the main proteins conjugated to A2A receptors are Gs proteins.
  • Gs proteins In the striatum, where the content of A2A receptors is maximum, they are coupled with Golf proteins [Kull B, Svenningsson P, Fredholm BB.
  • Adenosine A2A receptors are colocalized with and activate Golf in rat striatum. Mol Pharmacol. 2000; 58: 771-777], which, like Gs proteins, are associated with adenylate cyclase.
  • A2A receptors are able to incorporate a PLC signaling cascade, induce inositol phosphate synthesis and increase intracellular calcium concentration, and also activate protein kinase C.
  • A2B receptors are positively associated with adenylate cyclase and phospholipase C. Many functions of A2B receptors are determined by phospholipase C. which is activated by Gq proteins [Linden J, Thai T, Figler H, Jin X, Robeva AS. Characterization of human A2B adenosine receptors: radioligand binding, western blotting, and coupling to Gq in human embryonic kidney 293 cells and HMC- 1 mast cells. Mol Pharmacol. 1 999: 56: 705-71 3]. These receptors are also involved in the signaling cascade of arachidonic acid [Donoso MV, Lopez R, Miranda R, Briones R, Huidobro-Toro JP.
  • A2B adenosine receptor mediates human chorionic vasoconstriction and signals through the arachidonic acid cascade. Am J Physiol Heart Circ Physiol. 2005; 288: H2439-H2449]. Table 1. Properties of adenosine GPCR receptors
  • G-protein Gi Go Gs, Golf Gs, Gq Gi, Gq
  • A3 receptors are involved in classical signaling pathways, inhibiting adenylate cyclase, stimulating phospholipase C, and causing mobilization of calcium ions [Z ou QY, et al. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. PNAS USA. 1992; 89: 7432-7436].
  • A3 receptor agonists inhibit melanoma cell growth by participating in the WNT signaling cascade [Fishman P, et al. Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene. 2002; 21: 4060-4064].
  • A2A receptor antagonists A large number of scientific papers and patents are devoted to the use of A2A receptor antagonists as drug candidates for the treatment of central nervous system diseases, which include, but are not limited to:
  • Parkinson's disease [Pinna A. Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin I nvest Drugs. 2009; 1 8 (1 1): 1 619-163 1];
  • Adenosine by binding to type A2A adenosine receptors located on the cell membrane of lymphocytes, transmits an adenosine signal into cells, which reduces the ability of lymphocytes to attack tumor tissue [Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-Adenosinergic Tumor Immunosuppression Tum: Regulatory Cells and Cancerous Tissue Hypoxia. Clin Cancer Res. 2008; 14 (19): 5947-5952].
  • a new approach has been proposed to enhance the effectiveness of antitumor therapy (in particular, vaccines) using an adjuvant that is an antagonist of A2A receptors [Ohta A, Sitkovsky M. Methods and composition for improving immune responses. WO 2008/147482 04.12.2008].
  • A2A adenosine receptors are important regulators of inflammatory processes.
  • A2A agonists have been shown to have anti-inflammatory properties in vitro and in vivo.
  • Adenosine interacting with the surface receptors AI, A2A, A2B, and A3, has a different biological effect.
  • A2A is the most common and closely associated with the inflammatory response.
  • the studies revealed the ability of A2A to inhibit the phosphorylation of Zap-70 tyrosine kinase, the secretion of eosinophils and monocytes, weaken the perforin and cytotoxicity of lymphokine-activated killer cells.
  • A2A adenosine receptor suppresses the inflammatory signaling system in cytokines and accelerates the healing process.
  • the search for effective and selective A2A receptor antagonists seems to be an extremely important and promising task.
  • An object of the present invention is to provide novel selective A2A receptor antagonists.
  • A is not necessarily a substituted aminocarbonyl group -NC (O) -, wherein the amino group may be substituted and the substituents may be selected from hydrogen, SrSgal yl, optionally substituted Ci-Szalkoksi, Cs-C6 cycloalkyl, 5-6- membered heteroaryl in which the heteroatoms are selected from oxygen or nitrogen; an aryl selected from phenyl, optionally substituted with hydroxy, C hC ⁇ alkyl. With 1-C5 alkoxy, halogen, CrCgacylamino group, or naphthyl;
  • C) -C 6 alkylcarbonyl wherein the alkyl may be substituted by phenyl, substituted phenyl wherein the substituents are selected from the CDS b alkoxy;
  • heterocyclylcarbonyl in which heterocyclyl is selected from a 5-6 membered heterocyclyl, with 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzene ring and optionally substituted with Ci-C 1 -alkyl, halogen;
  • aryl selected from phenyl, substituted C1-C5 alkyl, Ci-Szalkoksi, ethylenedioxy, methylenedioxy, halogen, Ci -Szalkilkarbonilom;
  • B is a non-aromatic cyclic substituent selected from C - C 6 cycloalkyl
  • an aromatic cyclic substituent selected from phenyl which may be substituted with halogen, CpSalkalkoxy; a non-aromatic 5-6 membered heterocyclic substituent with a nitrogen atom as a heteroatom, and optionally ⁇ -substituted with C
  • Rla, Rib and Rlc independently represent hydrogen, C iC 3 alkoxy
  • Preferred aminocarbonyl groups are optionally substituted CrCalkyl, C
  • Amino group means a radical of the formula —NR 2 in which each R independently of one another is hydrogen, alkyl, alkenyl or cycloalkyl, for example, —NH 2 , methylamino, diethylamino, cyclohexylamino, tert-butyl pshino or ethylamino.
  • Azaheterocycle means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring.
  • the azaheterocycle may have substituents (see cyclic system substituents).
  • 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 substituents” which may be the same or different. Preferably phenyl or naphthyl.
  • Alkenyl means a linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including at least one carbon-carbon double bond.
  • Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkenyl chain.
  • Preferred and alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylbutenyl.
  • alkenyl group may have one or more substituents, see “Alkenyl Substituents”.
  • Alkenyl group substituents may be halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocycle il, heterocyclylalkyloxy, alkoxycarbonylcarbonyl.
  • Alkynyl means a linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including at least one carbon-carbon triple bond.
  • Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkynyl chain.
  • An alkynyl group may have one or more substituents, see “Alkenyl Substituents”.
  • Preferred alkynyl groups are ethynyl, propynyl, n-butyl, isobutynyl, 3-methylbut-2-ynyl, n-pentynyl, buta-1, 3-diine and hexa-1, 3,5-triine.
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1 to 6 carbon atoms in the chain.
  • a branched group means that the group C
  • Preferred straight or branched alkyl groups are those representing alkyl groups having from 1 to 10 carbon atoms. Most preferred lower alkyl groups have from 1 to 8 carbon atoms.
  • Preferred alkyl groups are C
  • Alkyl may have substituents, see "Substituted alkyl.”
  • Alkylcycloalyl means cycloalkyl substituted with alkyl. Preferably 4-, 2-, 3- or 4-methyl or ethylcyclohexyl.
  • Alkylcycloalkylalkyl means alkyl substituted with alkylcycloalkyl.
  • Alkyl means alkyl substituted with aryl.
  • Preferred aralkyl groups include benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl and phenethyl.
  • Alkyloxy or “Alkoxy” means a Ci-Sat Alkyl O- group in which alkyl is defined in this section. Preferred alkoxy groups are methoxy, ethoxy, i-propoxy, iso-propoxy, n-butoxy and tert-butoxy.
  • Aromatic cycle (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) ⁇ -electros (n is a non-negative integer).
  • aromatic cycles are benzene, naphthalene, anthracene, and the like.
  • heteroatom cycles ⁇ -electrons and p-electrons of heteroatoms participate in the conjugation system; 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 “ring system substituents” and may be anelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.
  • -C5alkyl-C ( 0) -, C
  • ⁇ -aminoacyl group ( ⁇ -aminoacyl) means R 2 k + 2 , where R ⁇ k , R k + i and R k + 2 can be hydrogen, C
  • the hydrazinocarbonyl group may have substituents, see “carbamoyl substituent” as defined in this section.
  • Heteroaryl (hetaryl) 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 replaced by a heteroatom or heteroatom and, such as nitrogen, sulfur or oxygen.
  • the prefix “aza”, “oxa” or “thia” 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 can be oxidized to the ⁇ -oxide.
  • Heteroaryl may have one or more “ring system substituents”, which may be the same or different.
  • Heteroaryl may have substituents (see cyclic system substituents).
  • Heterocycle means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 4 to 6 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom such as nitrogen, oxygen, sulfur, phosphorus.
  • a hetero atom such as nitrogen, oxygen, sulfur, phosphorus.
  • the prefix "aza”, “oxa” or “thia” before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • Heterocyclyl may have one or more substituents, which may be the same or different.
  • the nitrogen and sulfur atoms in the heterocyclyl can be oxidized to ⁇ -oxide, S- oxide or S-dioxide.
  • heterocyclyls are piperidiyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc.
  • Heterocyclyl may have substituents.
  • Compounds are preferred: piperidinyl substituted with methyl; piperidinyl substituted with an optionally substituted hydroxy group; piperidinyl substituted with phenyl; piperazinyl substituted with CpSalkyl.
  • Hydro-group (Hydro-strong group) means —OH group.
  • Halogen means fluoro, chloro, bromo and iodo. Fluorine, chlorine are preferred.
  • Cycloalkyl means a saturated carbocyclic group having one or more rings having 3-10 carbon atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and decahydronaphthyl.
  • Cycloalkylalkyl means an alkyl group substituted with a cycloalkyl group.
  • Preferred cycloalkylalkyls include cyclopentylmethyl,
  • “Substituted alkyl” substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy.
  • Preferred alkyl substituents are: acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, halo, , hydroxy, iminoamino, nitro, oxo, phosphonamine, sulfinyl, sulfonamine, sulfonyl, thio, thioacylamine, thioureido or ureido.
  • “Substituted aryl” means phenyl or naphthyl substituted with one or more substituents of the aryl group, which may be the same or different, where the “substituent of the aryl group” includes alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy group, alkoxy group, aryloxy group, aralkoxy group , hydroxyalkyl, acyl, formyl, carboxy group, alkenoyl, aroyl, halogen, nitro group, trihaloimethyl, cyano group, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino group, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, aralkilkarbamoil, alkylsulfonyl, alkyl
  • halogen preferably chlorine, fluorine
  • aminocarbonyl group preferably sulfo group.
  • Aryl can be anelated with a non-aromatic ring system or heterocycle.
  • amino group substituents amino group substituents R 'and R “are hydrogen, optionally substituted with C] -C 5 a kil, optionally substituted with C3 - Czcycloalkyl (see the Deputy of the cyclic system), optionally substituted aryl (see the Deputy of the cyclic system), optionally substituted heteroaryl (see cyclic system substituent), optionally substituted heterocyclyl (see cyclic system substituent), alkoxycarbonyl substituted by linear or non-linear C
  • Substituents of the cyclic system may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Preferably phenyl substituted with hydroxy; C 1 -C 5 alkyl; halogen; aminocarbonyl group.
  • Aryl can be annelated with a non-aromatic ring system or heterocycle.
  • the cyclic system moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted With Csalkyl, hydroxy-group, With
  • “Substituent” means a chemical radical that is attached to a molecular skeleton (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.
  • Preferred aminocarbonyl groups are optionally substituted Ci-Csalkyl, C
  • “Arbamoyl substituent” means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section.
  • the carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R k a R k + i a N-, annelirovainy heteroarylcycloalkenyl, annelirovannyi heteroarylcycloalkyl, heteroarylheterocyclenyl annelirovainy, annelirovainy heteroaryl, heterocyclyl, annelirovainy arylcycloalkenyl, arylcycloalkyl annelirovainy, annelirovannyi arilgeterotsikleiil, annelirovannyi
  • Heterocycle substituents may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl.
  • Aryl can be anelated with a non-aromatic ring system or heterocycle.
  • Preferred cyclic system moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted CgSalkyl, optionally substituted cycloC Czalkyl, C 13 -C 5 alkene, hydroxy-group, C 1 -C 5 alkyloxy group (methoxy, ethoxy, propoxy), cyano, CpSalkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see “am inocarbonyl”), phenyl anelated with 5-7th- a saturated saturated ring containing 1 to 3 heteroatoms (nitrogen, oxygen and sulfur atoms are preferred).
  • Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.
  • Niro group means a group - O2.
  • Trifluoromethyl means a —CF3 group
  • substituted [1, 2,4] triazolo [4.3-a] pyridines represented by the general formulas 1-1, 1-2, 1-3, and their pharmaceutically acceptable with
  • R2a, R2b and R2c independently represent H, C1-C3 alkoxy;
  • R3a and R3b independently represent hydrogen, C 1 -C 5 alkyl, optionally substituted with C i-Szalkoxy, C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl, in which the heroatoms are selected from oxygen or nitrogen;
  • aryl selected from phenyl optionally substituted with hydroxy, C
  • R3a and R3b may together form cyclic substituents, wherein the group R3a-N-R3b represents a C 3 -C 7 heterocyclyl containing 1 -2 heteroatoms in the ring selected from nitrogen, oxygen or sulfur, optionally substituted with hydroxy, C
  • R4 is C 1 -C5 a kil, where alkyl may be substituted with phenyl, substituted with phenyl, in which the substituents are selected from CpSalkalkoxy;
  • heterocyclyl in which heterocyclyl is selected from a 5-membered heterocyclyl, with 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, possibly fused with a benzene ring and optionally substituted with C 1 -C 5 alkyl, halogen;
  • R5 is hydrogen
  • R6a and R6b independently represent hydrogen, C 1 -C3 alkyl substituted with phenyl, a 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur; C 2 -C 6 alkenyl, aryl selected from phenyl, substituted CDS b alkyl, C ⁇ Szalkoksi, ethylenedioxy, methylenedioxy, halogen, C ⁇ - C 3 alkylcarbonyl;
  • R6a and R6b may together form cyclic substituents, wherein the R6a-N-R6b group is a 5 membered heterocycle in which the heteroatoms are selected from a sulfur or oxygen atom, and optionally substituted with an alkyloxycarbonyl group;
  • the subject of this invention is the pharmaceutically acceptable salts of the compounds of general formula I.
  • a portion of the compounds of this invention contains ionic groups (secondary, tertiary amines) and can form salts which have been prepared by methods known in the art.
  • the subject of this invention is a method for producing derivatives of [1, 2,4] triazolo [4,3-a] pyridines of general formulas 1-2 and 1-3 (Scheme 2):
  • 2-hydrazino-3-nitropyridines L2 were obtained from 2-chloro-3-nitropyridines L.
  • Hydrazines b2 were cyclone-condensed with a suitable acyl derivative. obtaining [1, 2,4] triazolo [4,3-a] pyridines b3.
  • nitropyridines L3 were reduced with hydrogen over palladium on charcoal and a series of heterocyclic amines L4 was obtained.
  • the subject of this invention is an active component having the properties of an A2A receptor antagonist, which is a (substance) for the preparation of pharmaceutical compositions and finished dosage forms for the prevention and treatment of disorders of the CYS, neurodegenerative, inflammatory, infectious and oncological diseases and is a compound of the general formula I .
  • the subject of this invention is new compounds of general formula I, which are an agent (adjuvant) for enhancing the immune response or action of drugs in the combined treatment of disorders of the central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases.
  • the subject of this invention is a pharmaceutical composition having antagonistic activity against an adenosine ⁇ 2 ⁇ receptor, comprising, as an active component (substance) or agent (adjuvant), compounds of general formula I or their pharmaceutically acceptable salts in a therapeutically effective amount.
  • compositions in the form of tablets, capsules and injections, ointments, gels and other formulations placed in a pharmaceutically acceptable package.
  • Pharmaceutical compositions may include pharmaceutically acceptable excipients, namely, diluents, auxiliary agents, and / or carriers used in the pharmaceutical field.
  • the pharmaceutical composition, along with the compound of general formula I or a pharmaceutically acceptable salt thereof, of the present invention, may include other active substances, provided that they do not cause undesirable effects.
  • compositions of the present invention can be mixed for the manufacture of various forms, and they may 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 requires the addition of water for injection before use); local forms (such as ointments or solutions).
  • 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 requires the addition of water for injection before use); local forms (such as ointments or solutions).
  • the carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical industry to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.
  • the subject of this invention is a method for preparing a pharmaceutical composition by mixing with an inert excipient, auxiliary agent, carrier and / or solvent of at least one active component (substance) of the general formula I or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.
  • the subject of this invention is a method for selectively inhibiting the activity of an adenosine A2A receptor, which consists in the action of the active component (substance) of the general formula I on biological objects or samples whose functions are regulated by A2A adenosine receptors.
  • the subject of this invention is a medicament having antagonistic activity with respect to the adenosine A2A receptor, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package intended for the prophylaxis and treatment of disorders of CYS. neurodegenerative, inflammatory, infectious and oncological diseases in humans and warm-blooded animals, including a new active component (substance) of general formula I or a pharmaceutical composition in a therapeutically effective amount.
  • Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically).
  • the clinical dosage of an agent of the general formula I in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the patient’s age, gender and disease.
  • the daily dose in adults is usually 10 ⁇ 500 mg, preferably 50 ⁇ 300 mg.
  • these drugs can be taken several times during certain periods of time (preferably from one to six times a day).
  • the subject of the present invention is a method for the prophylaxis and treatment of disorders of CYS, neurodegenerative, inflammatory, infectious and oncological diseases in animals and humans, which consists in administering in an effective amount to a patient a drug or pharmaceutical composition comprising a new active component (substance) general formula I, in a therapeutically effective amount.
  • LC-MS characteristics of the claimed compounds were determined using a Shimadzu HPLC unit equipped with a Waters XBridge Ci 8 3.5 mm column (4.6 mm ⁇ 150 mm), a PE SCIEX API 150 EX mass detector, or a Shimadzu detector spectrophotometric detector ( ⁇ , 220 and 254 nm). According to LC-MS data, all synthesized compounds had a basic substance content above 95%.
  • Analytical TLC was performed on silica gel on Si lufol UV254 aluminum plates (5 cm x 15 cm) (avalier, Czech Republic) or on glass plates with a 0.25 mm layer of silica gel 60 F254 (Merck, Germany). Visualization was carried out using UV light at a wavelength of 254 nm. Silica gel 5-40 ⁇ (Chemapol, Czech Republic) and 63 ⁇ (EM Science, USA) were used for chromatographic purification.
  • Example 2 General method for the synthesis of ethyl esters of 2 - [(2-aggl-substituted) hydrazinyl] -nicotinic acids.
  • Example 4 The general method for the synthesis of 3-substituted [1,2,4] trszolo [4,3-a pyridine-8-carboxylic acids a4 (see Scheme 1).
  • Example 5 General method for the synthesis of amides of 3-substituted [1, 2, 4] tr azolo [4,3-a] pyridine-8-carboxylic acids 1-1 The synthesis was carried out in accordance with Scheme 1. A mixture of acid a4 (1 .0 mmol). amine (1 .1 mmol), carbodiimide EDC (1 .0 mmol) and 1-hydroxybenzotriazole (1 .0 mmol) in 10 ml of DMF was stirred for 2-20 hours at room temperature, monitoring the progress of the reaction using LS-MS. At the end of the reaction, the mixture was diluted with 30 ml of water and extracted with methylene chloride (3x30 ml). The organic layer was dried over magnesium sulfate and evaporated. The product was purified by chromatography on silica gel (eluent CH2C12 / MeOH 19: 1). The yields of amides 1-1 25-85%.
  • Example 8 General method for the synthesis of 3-substituted 8-amino [1,2, 4 / triazolo / 4, 3-a / pyridine b4 (Scheme 2).
  • Tables 4-6 present data on the activity of some of the compounds of general formula I, confirming their high antagonistic activity with respect to the adenosine A2A receptor:
  • A means the inhibition of A2A receptors by the compound at a concentration of 10 ⁇ by more than 75%, B by more than 50% , C - more than 25%, D - more than 10%.
  • Part of the compounds of this invention contains ionic groups (secondary, tertiary amines) and can form salts that have been obtained by methods and known in the art.
  • an inert solvent such as alcohol, acetone, chloroform, ether, ethyl acetate
  • a solution of an equivalent amount (sometimes excess) of an organic or inorganic acid in an inert solvent was added and precipitation of the desired salt was achieved.
  • the inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid or hydroiodic acid.
  • the organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, lactic acid , gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, but not limited to them.
  • Table 7 presents examples of the obtained pharmaceutically acceptable salts and some of their properties. Table 7.
  • Example 11 The study of the antagonistic activity of compounds of General formula J and their pharmaceutically acceptable salts with respect to the adenosine A2A receptor.
  • the antagonistic activity of the new compounds of general formula I and their pharmaceutically acceptable salts with respect to the adenosine A2A receptor was carried out ex vitro in a functional test on cells.
  • cells of the ValiScreen cell line line (PerkinElmer, USA) expressing the recombinant human A2A type adenosine receptor were used.
  • a CGS-21680 agonist Tocris
  • adenylate cyclase is activated, which leads to an increase in the synthesis of intracellular cyclic adenosine monophosphate (cAMP or cAMP).
  • the amount of cAMP was determined using LANCE technology (LANCE Ultra cAMP kit, PerkinElmer).
  • test compounds By the ability of the test compounds to reduce the amount of cAMP synthesized in the presence of CGS-21680, their antagonistic activity was evaluated.
  • AT W-6002 antagonist (Axon Medchem, Netherlands) described in the literature was used as a standard (comparison compound).
  • Test compounds were dissolved in DMSO to a concentration of 6.32 mM and 3.16-fold serial dilutions in DMSO were prepared.
  • the prepared serial dilutions were diluted 50 times with SB 1 buffer solution (Hanks' medium + 5 mM HEPES (pH 7.4) +0.1% BSA).
  • the resulting solutions of the compounds in SB 1 buffer were mixed in a 1: 1 ratio with a solution of CGS-21680 (12.64 nM), previously prepared in SB3 buffer (SB 1 + 0. 1% Pluronic F 127).
  • test compounds with an agonist were added (5 ⁇ l in duplicates) to the plate wells containing 5 ⁇ l of cells (as described above) and the plates were incubated for 30 minutes at room temperature. Each plate also contained 16 holes for each control (MAX and MIN).
  • MAX - cells with 3. 1 6 nM CGS 21680 agonist concentration corresponding to ECod, that is, a concentration that causes 90% cell activity
  • the signal from these wells was used in the calculations as 100% activity (0% inhibition).
  • each plate contained wells (in 4 repetitions), where the cells were treated with an agonist (CGS-21680) at different concentrations.
  • the final concentration of DMSO in all wells was 1%.
  • the cAMP formed in the cells was quantified using the LAIMCE Ultra cAMP kit (PerkinElmer, USA), in accordance with the methodology recommended manufacturer.
  • the fluorescent signal was measured on a VictorSV instrument (PerkinElmer) equipped with a built-in LANCE High Count program.
  • ICso is the antagonist concentration at which adenylate cyclase activity is 50% of the maximum
  • L is the concentration of CGS-21680 at which measurements are carried out (3.16 pM)
  • Ko is the apparent affinity constant of CGS-2 1,680, quantitatively corresponding to ECso ( concentration of half-maximal cell stimulation) for CGS-21680 and determined from the stimulation curves of cAMP accumulation in cells at different agonist concentrations.
  • Tables 5-7 provide activity data for the compounds of general formula I.
  • Example 12 Radioligid analysis of the interaction of compounds of General formula I with adenosine A 1, A2A, A2B and A3 receptors.
  • a radioligand analysis of the interaction of compounds of general formula I with adenosine A1, A2A, A2B and A3 receptors was performed to determine the selectivity of the interaction of compounds of general formula I with adenosine A2A receptor.
  • membrane preparations were used, obtained from human kidney embryonic cells expressing the recombinant human A2A receptor. Receptor expression was 7 pmol / mg protein.
  • J H] CGS 21680 at a concentration of 0.05 ⁇ M.
  • test compounds were prepared in the same way as described in the functional test procedure, with the difference that, in addition to SB 1 medium, a buffer of the following composition was used: 50 mM Tris-HCl, pH 7.4, 10 tM MgCb, 1 t M EDTA, 2 U / mL Adenosine Deaminase.
  • Membrane preparations were incubated in the presence of a mixture of the test compounds and [H] CGS 2 1680 for 90 min at 25 ° C, and the mixtures were filtered on GF glass fiber filters (Millipor, USA). The radioactivity on the filters was determined using a MicroBeta liquid-oscillation counter (PerkinElmer, USA). Nonspecific binding was measured in the presence of 50 ⁇ M NECA, which amounted to no more than 15% of the total binding.
  • the affinity of the tested compounds was determined by the formula:
  • 1C 50 is the concentration of the antagonist at which the binding of [ 3 H] CGS-21680 is reduced to 50% of the maximum
  • L is the concentration of [ 3 H] CGS-21 680, at which measurements are carried out (50 pM)
  • Table 8 The activity and selectivity of compounds 1-2-01 and the reference ligand W-6002 under conditions of radioligand analysis in relation to adenosine A l, A2A, A2B and A3 receptors.
  • Example 13 Obtaining a pharmaceutical composition.
  • the pharmaceutical composition according to the invention is prepared using methods generally accepted in the art and includes a pharmacologically effective amount of a drug substance representing a compound of the formula I or a pharmaceutically acceptable salt thereof, usually comprising from 5 to 30% by weight, in combination with one or more pharmaceutically acceptable auxiliary additives, such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents.
  • auxiliary additives such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents.
  • pharmaceutical compositions may be in various liquid or solid forms.
  • solid dosage forms include, for example, tablets, pills, gelatine capsules, etc.
  • liquid dosage forms for injection and parenteral administration examples include solutions, emulsions, suspensions, etc.
  • compositions are obtained using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier.
  • compositions containing other compounds of the general formula I as a drug substance are likewise prepared.
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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Abstract

L'invention concerne de nouveaux composés consistant en des [1,2,4]triazolo[4,3-A]pyridines substitués correspondant à la formule générale (I), ou leurs sels pharmaceutiquement acceptables, où : A représente un groupe aminocarbonyle -N-С(О)- éventuellement substitué, un groupe acylamino ou aminocarboynle ; B représente un substituant cyclique non aromatique choisi parmi С4-С6 cycloalkyle, un substituant aromatique cyclique choisi parmi phényle pouvant être substitué par un halogène, C1-С3 alcoxy, un substituant non aromatique à 5-6 membres hétérocyclique avec un atome d'azote en qualité d'hétéroatome, et un alkyle C1-С3 potentiellement substitué en N, un substituant aromatique à 5-6 membres hétérocyclique dans lequel les hétéroatomes sont choisis parme l'azote, l'oxygène et le soufre et qui peut être substitué par un alkyle C1-С6, ou un substituant aromatique à 5-6 membres hétérocyclique dans lequel l'hétéroatome est choisi parmi de l'azote condensé avec un anneau benzole ; ; R1a, R1b et R1c représentent indépendamment Н, alkyoxy С1-С3. Ces composés ont une activité antagoniste en ce qui concerne les récepteurs A2a d'adénosyne. L'invention concerne également leur utilisation en qualité de composant actif pour des compositions pharmaceutiques, des agents médicamenteux et des adjuvants. L'invention concerne également des procédés de traitement de troubles de l'activité du système nerveux central et de maladies neurodégénératives, inflammatoires infectieuses et oncologiques.
PCT/RU2014/000514 2013-08-05 2014-07-11 [1,2,4]triazolo[4,3-a]pyridines substitués ayant des propriétés d'antagonistes de récepteurs a2a d'adénosyne, et utilisation de ces derniers Ceased WO2015020565A1 (fr)

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KR20200055126A (ko) * 2017-09-28 2020-05-20 씨스톤 파마슈티컬즈 (쑤저우) 컴퍼니 리미티드 Ａ2ａ수용체 억제제로서의 축합 고리 유도체
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CN111542520B (zh) * 2017-09-28 2022-04-15 基石药业（苏州）有限公司 作为a2a受体抑制剂的并环类衍生物
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WO2020146795A1 (fr) 2019-01-11 2020-07-16 Omeros Corporation Procédés et compositions pour le traitement du cancer
WO2020192762A1 (fr) * 2019-03-28 2020-10-01 基石药业（苏州）有限公司 Forme de sel et forme cristalline d'un antagoniste du récepteur a2a et son procédé de préparation
CN113646313A (zh) * 2019-03-28 2021-11-12 基石药业（苏州）有限公司 一种a2a受体拮抗剂的盐型、晶型及其制备方法
CN113646313B (zh) * 2019-03-28 2023-05-30 基石药业（苏州）有限公司 一种a2a受体拮抗剂的盐型、晶型及其制备方法

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