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WO2009104990A1 - Dérivés de 2,4-diaminopyridine, composition pharmaceutique, produit médicinal à base desdits dérivés destinés au traitement ou à la prévention de maladies et troubles provoqués par l’hyperactivation de récepteurs nmda et/ou en tant que stimulateurs de fonctions congnitives et procédé d’utilisation correspondant - Google Patents

Dérivés de 2,4-diaminopyridine, composition pharmaceutique, produit médicinal à base desdits dérivés destinés au traitement ou à la prévention de maladies et troubles provoqués par l’hyperactivation de récepteurs nmda et/ou en tant que stimulateurs de fonctions congnitives et procédé d’utilisation correspondant Download PDF

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Publication number
WO2009104990A1
WO2009104990A1 PCT/RU2009/000083 RU2009000083W WO2009104990A1 WO 2009104990 A1 WO2009104990 A1 WO 2009104990A1 RU 2009000083 W RU2009000083 W RU 2009000083W WO 2009104990 A1 WO2009104990 A1 WO 2009104990A1
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Prior art keywords
compound
compounds
nmda
rule
substitute sheet
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English (en)
Russian (ru)
Inventor
Владимир Григорьевич ГРАНИК
Валерий Александрович ПАРШИН
Геннадий Яковлевич ШВАРЦ
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OBSCHESTVO S OGRANICHENNOI OTVETSTVENNOSTYU "VALEXPHARM"
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OBSCHESTVO S OGRANICHENNOI OTVETSTVENNOSTYU "VALEXPHARM"
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Publication of WO2009104990A1 publication Critical patent/WO2009104990A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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

Definitions

  • the invention relates to the field of chemistry, medicine and the pharmacological industry and relates to new derivatives of 2, 4-diaminopyridine of the general formula (I), their pharmaceutically acceptable salts and / or solvates, which are active against the central nervous system, the method for their preparation, compositions, drugs containing new derivatives of 2, 4-aminopyridine, and their use as blockers of NMDA receptors, as well as as stimulants of cognitive functions.
  • the glutamatergic system is the main exciting neurotransmitter system involved in the implementation of all the basic physiological functions of the brain, including maintaining its tone, wakefulness, psychological and physical activity, in the perception of sensory information.
  • SUBSTITUTE SHEET (RULE 26) various modality, especially sensitive and pain impulses. She also has one of the leading roles in the implementation of synaptic plasticity and the highest integrative functions of the brain, including the ability to learn, shape and function of memory, and regulate behavior (Lodge D. Expert Amipo Acids and Non-apd Disase. J. Wileu & Sops: Chestestr , 1988; Whael H., Thompson A. - Exitor Amipo Acids and Sapartis Trissmissiop. Asademis Press: Lopdop, 1991).
  • Glutamatergic mechanisms of transmission of nerve impulses are present in approximately 40% of nerve cells, and the remaining part falls to the share of all other mediators (norepinephrine, serotonin, acetylcholine, dopamine, etc.) (A. Boldyrev. Neuronal receptors in the cells of the immune system // Nature, 2005, Ns 7 (1079), pp. 3-8).
  • the receptors of the main excitatory neurotransmitter, glutamate, are divided into two main classes: ionotropic and metabotropic.
  • Ionotropic receptors are structurally associated with ion channels, their activation by glutamate or agonists that mimic the action of glutamate leads to the depolarization of cell membranes and the opening of ion channels and, as a result, to the generation of an exciting postsynaptic potential.
  • Metabotropic receptors are a family of receptors conjugated with G-proteins that act on the ion channel indirectly through a chain of biochemical reactions, in particular, through the activation of a system of secondary messengers.
  • Ionotropic receptors are divided into 3 subtypes, named after the corresponding selective agonists: AMPA (2-alpha receptor - amino-3-hydroxy-5-methyl-4-
  • SUBSTITUTE SHEET (RULE 26) isoxazole propionic acid), KA (kainic acid receptor) and NMDA (N-methyl-D-aspartate receptor) (Wattkeeps J, Kroggsard-Larsep P, Honor T accelerate receptors, supplements Terps PHARMACOL Sci., 1990, 11, p. 25-33).
  • Metabotropic glutamate receptors are divided into three groups (Moleculoperiologic schreibf glutamate receptors. Appl. Rev ⁇ proficienthusiol 54: 507-536) Nozzle PJ, Pin JP ⁇ réellermacolptosptosoptosptos Rev. Pharmacol. Toxico L, 1997, 37, p.205-237).
  • ionotropic receptors Activation of ionotropic receptors induces the electrical activity of a neuron, while metabotropic receptors regulate its size and duration (A. Boldyrev. Functional interactions between glutamate receptors of different classes // Bull. Expert. Biol. And Med., 2000, v. 130, JYo 9, p. 244-252).
  • NMDA receptor The activity of the NMDA receptor is regulated by many modulatory sites that can be targets for selective agonists and antagonists (McBaip CJ., Mauer M.L. N-metul-D-acrartis aspertortorstrucure apfuptiop // Prusio 1, Rev. 1. v. 74, N ° 3, p. 723-
  • glutamatergic neurotransmission normal activation of the NMDA receptor causes a short-term opening of the calcium channel.
  • glutamate NMDA receptors are overactivated, causing prolonged neural excitation and leading to excessive intake of calcium ions into the neurons.
  • excitotoxicity from the English word “exotoxicity” - toxicity that develops upon excitation (Rothmap, SM, Olpeu, JW // Trepds ip Nepur. 10, M> 7, p.299-302; Non-Disorders schreibf Amipo Acids Metabolism, New York: Masmillap, 1989, p.
  • Excitotoxicity is believed to be a universal molecular mechanism for the development of any neurodegenerative process, since it is observed in the most diverse etiology of neurological and psychiatric diseases associated with neuronal death or impaired function (Bespalov A.Yu., Zvartau E.E. Neuropsychopharmacology of NMDA receptor antagonists , St. Orlando: Nevsky dialect, 2000, 297 pp.; Brian S. ⁇ Brassldrum Glutamate réelles réelle N Foodur thoroughlytr réellepsmitter Appel ⁇ prionp: R Canalv Foodw THERf Rhusi Cincinnatilog apd Rath Desitritiop. 1.
  • Wipebapk AJ Mechanisms of peoroti with ipjuru apdll deat // Neurol. CHn., 2000, Aug, 18 (3), pp. 525-540; Rubi LL, Neuropal cell de: ap uradated viw // Prog. Vraip. Res., 1998, 117, p. 3-8; Shoi DW Glutamate peruhotisit apd diseses of the first system // Neurop, 1988, v. 1, p. 623-634).
  • Possible therapeutic indications for NMDA receptor antagonists include acute forms of neurodegenerative diseases caused, for example, by cerebral ischemia, stroke, hypoxia, hypoglycemia, brain injury or spinal cord injury; chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, multi dementia, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis; degenerative diseases of the retina, neurodegenerative diseases, associated with a bacterial or viral infection, neurological disorders and diseases, including causeless anxiety, psychosis, depression, schizophrenia, migraine, muscle cramps, urinary incontinence or paralysis; drug, drug or alcohol dependence, withdrawal syndrome; acute or chronic pain (EP1313703, AblKZ l / 445, published May 28, 2003; WO9511244, A61K31 / 50, published April 27, 1995; WO0234718, A61K31 / 404, published February 2, 2002; WO
  • SUBSTITUTE SHEET (RULE 26) 9505175, A61K31 / 44, publ. 02/23/1995; US4902695, C07D217 / 16, publ. 02.20. 1990; US5192751, A61KZ 1/4427, publ. 03/03/1993; WO9606081, A61K31 / 40, publ. 02/29. 1996; Parsops CG, Dapusz W., Quask G. Glutamate in CNS Distributors and Target Drug Drug: Drug // Drugs News Respect, 1998, vl, III, p. 523-580).
  • the search for compounds capable of preventing or blocking the hyperactivation of NMDA receptors is one of the highest priorities in the development of drugs for the treatment of diseases of the central nervous system (Illarioshkin C H. et al. Preventive neuroprotection in neurodegenerative diseases: use of antagonists glutamate receptors (literature review and own experience) // Neurological journal, 2006, vol. 1, N ⁇ 5, pp. 47-54; Lei SZ et al. Vloskade inevitablyf NMDA resertor-mediadot mobilizer Ca2 + oulr schizophreniav pts peurotokhisitu // Vraip. Res., 1992, v. 598, 34 ° 1-2, p. 196-202).
  • polyamines are described as antagonists of NMDA receptors in patent publications (WO9312777, A61K31 / 13, publ. 08.07.1993); arylalkylamines (WO9856752, C07C211 / 32, publ. 17.12. 1998); polycyclic alkaloids (WO9703979, A61KZ 1/135, publ. 02/06/1997); amide derivatives of carboxylic acids (US4968678, C07D401 / 06, publ. 11.06. 1990; EP0539057, A61KZ 1/675, publ. 16.07. 1997; WO0234718, A61KZ 1/404, publ. 02.05.
  • SUBSTITUTE SHEET (RULE 26) pyrido / 3,4-b / indoles (RU2106864, A61KZ 1/437, publ. 03.20.1998); pyridine derivatives (WO03040128, C07D 401/04, publ. 15.05. 2003); substituted hydroxypyridines (WO 9525721; WO 0075109; EP 824098; 2272027, 2178412); piperidine derivatives (WO9117156, A61KZ 1/425, publ. 14.11.1991; EP441506, A61K31 / 445, publ. 14.08. 1991; WO 9302052, A61KZ 1/445, publ.
  • NMDA receptor antagonists are known to have a drawback of most known NMDA receptor antagonists.
  • side effects including impaired coordination of movements, stimulation of the sympathetic nervous system, dizziness, headache, hallucinations, dysphoria, and mental impairment and memory, manifested in doses at which the known compounds exert their antagonistic effect on NMDA receptors.
  • SUBSTITUTE SHEET (RULE 26)
  • the closest structural analogues of the claimed compounds are derivatives of 4-aminopyridine, including 4-aminopyridine (fampridine), 3,4-diaminopyridine, 2,4-diaminopyridine, used in anesthesiology, as well as for the treatment of certain neuromuscular and neurodegenerative diseases (US4562196, 4461 A61K publ. 12/31/1985).
  • one of the objectives of the invention is the creation of new chemical compounds that would have strong antagonistic activity against NMDA receptors, but would not cause adverse side effects characteristic of known NMDA antagonists.
  • the objective of the invention is the development of new pharmaceutical compositions, drugs, methods for their use, which would be effective and safe for the treatment of neurodegenerative and psychiatric diseases and disorders caused by hyperactivation of the glutamatergic system.
  • the technical result of the invention is to obtain new pharmaceutically active compounds in a series of derivatives of 2,4-diaminopyridine, pharmaceutical compositions and medicines based on them, suitable for the treatment and prevention of neurological and psychiatric diseases and disorders and unexpectedly combining the properties of a high affinity antagonist
  • SUBSTITUTE SHEET (RULE 26) NMDA receptors with the properties of moderate acetylcholinesterase inhibitors and the properties of high-affinity agonists of nicotinic cholinergic receptors and sympathomimetics, which determines their complex normalizing effect on the imbalance of several neurotransmitter systems, including glutamatergic, cholinergic, and adrenergic effects, without the manifestation of previously observed undesirable NMDA , as well as activators of cognitive functions.
  • the present invention relates to new biologically active derivatives of 2,4-diaminopyridine of general formula (I)
  • R is hydrogen
  • R is hydrogen, Ci-C 7 alkyl or arylalkyl, or
  • R 1 and R 2 together mean piperidino, morpholino, N-methylpiperazino, pyrrolidino, hexahydroazepino,
  • X is hydrogen, a cyano group
  • Y is hydrogen, a cyano group (CN), a carboxyl group (COOH), an N-substituted or an N-, N-disubstituted urea group (CONHR 4 or CONR 4 R 5 , where R 4 and R 5 are C 1 -C 5 - alkyl)
  • R means unsubstituted and substituted benzyls, CrCg-alkyl, aminoalkyl, hydroxyalkyl, unsubstituted and variously substituted aryls, their pharmaceutically acceptable salts and / or solvates.
  • pharmaceutically acceptable salts of a compound of formula (I) means any salts of an inorganic or organic acid or base that possesses the necessary pharmacological activity of the parent compound. These salts can be prepared in situ during the synthesis, isolation or purification of the compounds of formula (I) or prepared specially.
  • salt formed by the acid examples include salts of mineral acids, in particular hydrohalic (hydrofluoric, hydrobromic, hydroiodic or hydrochloric acid), nitric, perchloric, carbonic, sulfuric or phosphoric acids; salts of alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid or paratoluenesulfonic acid; salts of organic carboxylic acids, such as acetic, fumaric, tartaric, oxalic, maleic, malic, succinic, benzoic, mandelic, ascorbic, lactic, gluconic, citric acid, etc.
  • the compounds of formula (I) according to the invention can be used in the form of various solvates, including in the form of a hydrate.
  • the most preferred compounds are 2-amino-4-phenylaminopyridine, 2-morpholino-3-cyano-4-phenylaminopyridine, 2-N-methylpiperazino-3-cyano-4-phenylaminopyridine, 2-N-methyl-2-piperin benzylamino-3-cyano-4-
  • SUBSTITUTE SHEET (RULE 26) phenylaminopyridine, 2-benzylamino-4-phenylaminopyridine 5 2-morpholin-4-p-chlorophenylaminopyridine.
  • the compounds of formula (I) and their physiologically acceptable salts or solvates possess an unexpected combination of complementary pharmacological properties that determine their complex effect on the central nervous system.
  • the new derivatives of 2,4-diaminopyridine are high-affinity antagonists of NMDA receptors, additionally combining the properties of moderate acetylcholinesterase inhibitors and high-affinity agonists of nicotinic cholinergic receptors, and, in addition, possessing the properties of sympathomimetics (i.e., have an affinity for the adrenergic system and low to dopamine receptors).
  • the compounds of the present invention possess the therapeutic potential of NMDA receptor antagonists, but at the same time do not exhibit the adverse and undesirable side effects inherent to known NMDA receptor antagonists.
  • the compounds of the present invention have less pronounced psychostimulating properties and exhibit them in doses 10 times higher than therapeutic doses, do not have a potentially adverse effect on blood pressure, respiration and heart rate, bioelectric activity of the heart, tone of bronchial muscles and periodic bowel activity.
  • the compounds of the present invention not only do not impair cognitive ability, but also possess the properties of nootropics and
  • SUBSTITUTE SHEET activators of cognitive functions that contribute to the development of memory, mental and behavioral abilities.
  • the compounds of the present invention improve the learning ability of animals in the development of simple and complex instrumental defensive reflexes (URAI and passive avoidance reaction), contribute to the consolidation and preservation of the memorable trace.
  • the new compounds stimulate cognitive function in animals with learning deficits, have an anti-amnestic effect in experimental memory impairment with the cholinolytic drug scopolamine and maximum electroshock (MES).
  • the pharmacological activity of the compounds of the present invention was determined using tests adopted to evaluate new pharmacological substances ("Guidelines for the experimental (preclinical) study of new pharmacological substances", Moscow, 2000). At the same time, studies of the receptor activity of new derivatives of 2, 4-diaminopyridine were carried out in accordance with the standard recommendations of SHPHAR ("G ⁇ det Scientific Resource Apd Chappels", S.P.N. Alekhapder, A.Matie apd J.A. Reporters, BJP, v. 147, Su ⁇ l. 3, 2006). The ability of compounds to competitively bind to NMDA glutamate receptors was determined based on the analysis of radioligand binding to
  • SUBSTITUTE SHEET (RULE 26) using tritium-labeled ligands of the glutamate receptors [G- ⁇ H] -MK-801 (disocylpin) (see Nowak G., Tgallas R., Lauer R., Skolpik R., and Paul I. Adaptive chemotherapy n-metul- D-Aspartate Reserter Compiler Achter Chrytophtheptum with imipramine and 1-aminocyclopropanecarboxylic acid // J. Pharmacol. Exp. Ther., 1993, 265, p.1380-1386).
  • the inventive compounds can be obtained by the method illustrated by reaction scheme 1 below:
  • R, 1 - rR.5, X and Y have the meanings indicated above.
  • a subject of the invention is also a pharmaceutical composition which contains, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, taken in an effective amount in a mixture with pharmaceutically acceptable excipients.
  • the term “effective amount)) means the amount of the active ingredient that, when administered to patients, provides a warning or amelioration of the disease and the symptoms of the disease to be prevented or treated.
  • any pharmaceutically acceptable components can be used that are compatible with the active ingredient and do not harm patients, traditionally used for the preparation of dosage forms, for example, fillers, binding agents, granulating agents, solubilizing agents , glidants, stabilizers, diluents, adjuvants, preservatives, components of buffer systems, solvents, d spergiruyuschie agents, preservatives, lubricants, flavorings, thickeners, colorants, emulsifiers, and prolonged delivery controllers, etc.
  • compositions are, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch and its modifications, sucrose,
  • SUBSTITUTE SHEET (RULE 26) magnesium aluminosilicate, synthetic aluminosilicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylated starch, calcium carboxymethyl cellulose, ion exchange resins, methyl cellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxyvinyl hydroxyhydrochloride, hydroxyhydroxyhydroxyhydrochloride hydroxyhydrochloride , carboxyvinyl polymer, titanium oxide, fatty acid ester of sorbitol, sodium lauryl sulfate, glycerin, glycerin fatty acid firm, lanolin, glycerolatin, polysorbate, macrogol, vegetable oil, wax, paraffins, propylene glycol, polyethylene glycol, water, ethanol, polyalcohols, polyoxyethylene hydrogenated castor oil, sodium chloride, sodium hydroxide, hydrochloric acid, dibasic sodium phosphate, monobasic citric acid, glutamic acid
  • compositions of the present invention can be in the form of an oral administration form, for example, in the form of tablets, granules, beads, powders, capsules, suspensions, syrups, emulsions, etc .; in injection form; suppository for rectal or vaginal administration; aerosols, spray, transdermal, intranasal, intraocular forms of administration, etc.
  • Solid forms of pharmaceutical compositions for oral administration and solutions for injection are preferred.
  • compositions may be prepared by any known method in the art using one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients for example, any known method in the art using one or more pharmaceutically acceptable excipients.
  • SUBSTITUTE SHEET (RULE 26) in the manufacture of tablets, the active ingredient is mixed with traditional tablet ingredients, such as fillers, binders, disintegrants, granulating agents, lubricants and glidants, followed by compression of the resulting mixture in a tablet machine.
  • traditional tablet ingredients such as fillers, binders, disintegrants, granulating agents, lubricants and glidants, followed by compression of the resulting mixture in a tablet machine.
  • fillers and disintegrants lactose, sodium citrate, calcium carbonate and dicalcium phosphate, and the like can be used; binding agents - starch or its derivatives, gelatin, glucose, lactose, natural or synthetic gums, such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, sodium lauryl sulfate and talc, etc.
  • Lubricants used in these dosage forms include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.
  • tablets may be coated with sugar, gelatin, film, or intestinal coatings by standard methods, for example, a tablet may include an inner core containing the active ingredient and an outer layer in the form of a shell covering the core.
  • the outer shell can serve to protect against disintegration in the stomach, which will allow the inner core to pass intact into the duodenum and slowly release.
  • a variety of substances can be used to form such protective layers or shells, including a number of polymeric acids and mixtures of polymeric acids with common substances, such as alkali, cetyl alcohol and cellulose acetate. Sweeteners and flavorings may be added to improve the taste of the oral form.
  • a pharmaceutical composition in the form of capsules can be prepared by mixing the active ingredient with excipients, such as, for example, sorbitol or lactose, and filling the resulting mixture in capsules.
  • excipients such as, for example, sorbitol or lactose
  • a pharmaceutical composition in the form of oral medicines, elixirs, or syrups may contain water, polyols, sucrose, invert sugar, glucose, edible oils, for example, cottonseed oil, sesame oil, coconut oil or peanut oil, food flavorings, as pharmaceutically acceptable excipients, dyes, etc.
  • Potions, elixirs or syrups may additionally contain suspending agents and thickeners, such as synthetic and natural gums (tragacanth, Arabian gum), alginate, dextran, sodium carboxymethyl cellulose, gelatin, glycerin, methyl cellulose or polyvinyl pyrrolidone, or preservatives, for example.
  • a pharmaceutical composition in an injection form can be prepared by dissolving the active ingredient and possible adjuvants in part of the injection solvent, preferably in sterile water, adjusting the resulting solution to the desired volume, optionally adding a pH adjusting agent, solubilizer, stabilizer or antiseptic sterilizing the resulting solution and filling it with suitable ampoules or containers.
  • a solvent physiological saline, alcohols, poliols, glycol ethers, for example, polyoxyethylene sorbitan, monolaurate, monooleate or monostearate, glycerin, vegetable oils, etc. can be used.
  • SUBSTITUTE SHEET (RULE 26) are, for example, natural or hardened oils, for example, cocoa butter, waxes, fats, glycerol and saturated fatty acid esters, glycerogelatin, macrogol, semi-liquid or liquid polyols, triglycerides, and the like.
  • the suppository base may also include a surfactant or stabilizer.
  • composition according to the invention may also contain such components that provide a quick, sustained or delayed release of the active ingredient after administration by patients.
  • 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.
  • the active ingredient is included in the pharmaceutical composition of the present invention in unit dosage form.
  • in unit dosage form means any effective amount of an active ingredient which, in combination with pharmaceutically acceptable excipients, is contained in a dosage form of a pharmaceutical composition used for a single administration to a patient.
  • the pharmaceutical composition of the present invention in a single unit dose may contain the active ingredient in an amount of from 0.01 to 100 mg, preferably in an amount of from 0.1 to 10 mg of the active ingredient.
  • an effective amount of the active ingredient in some compositions may go beyond the above boundaries.
  • the invention also relates to a medicament containing
  • SUBSTITUTE SHEET (RULE 26) the compound of formula (I), its pharmaceutically acceptable salts, solvates, as such or in the form of a pharmaceutical composition, for the treatment and prevention of diseases or disorders of the central nervous system associated with increased activation of the glutamatergic system and / or impairment of intellectual and mnemonic functions.
  • Diseases or disorders to be treated or prevented with the drugs of the present invention include acute forms of neurodegenerative disorders or diseases associated with sudden damage to neurons or impairment of their functions, including, but not limited to, cerebrovascular insufficiency, cerebral ischemia, stroke, neuropathies caused by hypoxia or hypoglycemia, brain injury or damage to the spinal cord and the like; chronic neurodegenerative disorders or diseases associated with damage to motor neurons, including, but not limited to, amyotrophic lateral sclerosis, spinocerebellar degeneration, degenerative ataxia, cortico-basal degeneration, the Guam complex (amyotrophic lateral sclerosis-parkinsonism-dementia complex), subacute sclerosalitis ; chronic neurodegenerative demyelinating diseases associated with the destruction or violation of the formation of the myelin sheath of the nerve conductors, including, but not limited to, multiple (multiple) sclerosis, multiple encephalomyelitis, Schilder's sclerosis, inflammatory and
  • SUBSTITUTE SHEET (RULE 26) Bygnamy, central pontine myelinolysis, neurooptomyelitis, Devik's syndrome, Balo's disease, HIV myelopathy, secondary demyelinating diseases such as CNS lupus, polyarteritis nodosa, Sjogren's syndrome, sarcoidosis, localized cerebral vasculitis and the like; chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multi-infarction dementia, Huntington's disease; neurodegenerative diseases associated with bacterial or viral infections; neurological and psychiatric disorders and diseases associated with excitotoxic neuronal damage, including, but not limited to, feelings of causeless anxiety, psychosis, depression, schizophrenia, epilepsy, migraine, muscle cramps, urinary incontinence, paralysis, drug, drug or alcohol dependence, syndrome cancellation; conditions with acute or chronic pain syndrome; acute or chronic neurodegenerative disorders or diseases associated with impaired cognitive function, learning ability, memory impairment, remembering, impaired attention, which may
  • the therapeutic and prophylactic effect of the drugs of the present invention is based on several complementary mechanisms, which are based on the neuroprotective and cognitively activating effects of the new derivatives of 2,4-diaminopyridine.
  • SUBSTITUTE SHEET (RULE 26) Due to the presence of strong antagonistic activity against NMDA receptors, the proposed drugs are able to block the hyperactivation of NMDA receptors and inhibit the pathological influx of calcium into neurons associated with this process, thereby protecting neurons from pathological activation and excitotoxicity, which makes them suitable for treatment and prevention of various neurodegenerative and psychiatric diseases caused by hyperactivity of the glutamatergic system.
  • the cognitive activity of the drugs of the present invention is associated with the stimulation of cholinergic processes in the brain by the activation of nicotinic cholinergic receptors, as well as the inhibition of acetylcholinesterase.
  • Compounds that activate nicotinic receptors or block acetylcholinesterase activity are known to compensate for the deficiency of hypofunction of the cholinergic system and can have an anti-anamnestic and nootropic effect and can be used in the treatment of cognitive disorders (V.G. Granik, “Medicine”, 2006, M ., “Byzovskaya book”, pp. 173-177).
  • the compounds of the present invention also show the presence of sympathomimetic activity.
  • the presence of this activity determines the activation of cognitive functions (along with a psychostimulating effect), antidepressant effects and increased performance.
  • the compounds of the present invention possess the above activities, as a result of which they not only do not cause impaired mental ability, attention and memory, characteristic of known NMDA receptor antagonists, but, moreover, can
  • SUBSTITUTE SHEET (RULE 26) be suitable for the treatment and prevention of a number of diseases or disorders associated with impaired cognitive function and learning ability.
  • (Fropsis PT Alan M Ralmer, Mishail Spare apd Gordop K Wilsosk, J. Neurol. Neurosurg. Psihiatru; 66: 137-147, 1999, Dwoski LP apd P.A. Sprouts, JPET 298: 395-402a, 2001; , M., Le-pipg & Metoru, 11: 43-49; 2004).
  • the drugs according to the invention have a complex normalizing effect on the imbalance of several neurotransmitter systems, including glutamatergic, cholinergic, adrenergic systems, have an extremely low degree of affinity for dopamine receptors, and therefore can be more effective for the treatment or prevention of a number of diseases or disorders of the central nervous system without manifesting undesirable side effects, previously observed vshihsya the known NMDA antagonists.
  • the invention also relates to a method for the treatment or prophylaxis of diseases and disorders associated with increased activation of the glutamatergic system and / or impairment of intellectual-mnemonic functions, by introducing the patient
  • SUBSTITUTE SHEET (RULE 26) an effective dose of a compound of formula (I), a pharmaceutically acceptable salt, hydrate, pharmaceutical composition or a medicine thereof.
  • a compound of formula (I), pharmaceutically acceptable salts, solvates, a pharmaceutical composition or a medicament based thereon, are administered to the patient by conventional methods well known to those skilled in the art, for example, orally, rectally, intravaginally, transdermally, intranasally, intraocularly or parenterally injections.
  • a preferred method of administration of the invention is oral or parenteral administration.
  • the dose and course of administration prescribed to treat or prevent the above diseases or disorders can vary widely. In each case, the choice of the appropriate dosage depends on the age, body weight of the patient, route of administration, the particular type of disease to be treated or prevented, and the severity of the disease or condition of the patient.
  • the recommended daily dose for an adult patient is 0.01-300 mg / day, a dose of 0.01-30 mg / day is preferred for all of the above indications.
  • the full daily dose can be administered in a single dose, or the daily dose can be prescribed in divided doses two, three or four times a day.
  • Mass spectrum M + ' 210; IR spectrum, v cm ⁇ 1 : 2200 (CN), 3195, 3310, 3400 (NH, NH 2 ).
  • the aqueous mother liquor was extracted with chloroform (2 times 70 ml), the chloroform extracts were dried with CaCl 2 , filtered, evaporated, the residue was triturated with petroleum ether, and an additional 0.3 g was filtered off.
  • SUBSTITUTE SHEET (RULE 26) 100 ml of ethylene glycol is boiled for 4 hours, cooled, 100 ml are added. water, incubated for 1 hour at +2 0 C, 1.3 g of compound Ia were filtered off (80.5%).
  • reaction is carried out analogously to example 11, but take Ir 2-chlorop-3-cyano-4-p-chlorophenylaminopyridine, ml ml of morpholine and 20 ml of absolute alcohol, the mixture is heated for 10 hours at 200-210 0 C in an autoclave and get 2-Mopfolino-3 - cyano-4-p-chlorophenylaminopyridine
  • Example 17 Determination of the activity of compounds against the NMDA receptor.
  • SUBSTITUTE SHEET (RULE 26) tritium compound MK-801 (disocylpin), which is a known antagonist of NMDA receptors.
  • the affinity of the tested compounds for the NMDA receptor and their antagonistic activity was evaluated by the value of IC 5O , which reflects the ability of the compounds to displace the labeled ligand from the phencyclidine binding site to NMDA receptors.
  • NMDA receptors For the preparation of membrane preparations of NMDA receptors, the hippocampus and cerebellum isolated from rat brain frozen in liquid nitrogen are used. The tissue is thoroughly homogenized in a Potter homogenizer (Teflon-glass) in 10 volumes of 5 mM HEPES / 4.5 mM Tris buffer (pH 7.6) containing 0.32 M sucrose (JNkI buffer). The homogenate is diluted to 50 volumes with 5 mM HEPES / 4.5 mM Tris buffer (pH 7.6) (Ns2 buffer) and centrifuged for 10 min at 1000 g. The supernatant was collected and centrifuged again for 20 minutes at 25,000 g. The pellet was homogenized in 50 volumes of JN ° 2 buffer and centrifuged for 20 min at 8,000 g. The supernatant and its soft, unsteady layer are removed and centrifuged again for 20 minutes at 25,000 g.
  • a Potter homogenizer Teflon-glass
  • the resulting precipitate was suspended in 5 mM HEPES / 4.5 mM Tris buffer containing 1 mM Na4EDTA (pH 7.6) (JN ° 3 buffer), and the suspension was again centrifuged. This washing procedure is carried out four times, and with the last washing, EDTA is excluded from the buffer. The final precipitate was resuspended in 5 volumes of JN ° 2 buffer and stored in liquid nitrogen.
  • a tritium-labeled MK-801 with a specific activity of 210 Curie / mol is used in a receptor binding experiment.
  • the reaction mixture (final volume 0.5 ml) contains 200 ⁇ l of JN22 buffer, 50 ⁇ l of labeled ligand (50 nM pp) and 250 ⁇ l of membrane suspension.
  • SUBSTITUTE SHEET (RULE 26) Nonspecific binding is determined in the presence of 50 ⁇ l of unlabeled ligand.
  • the reaction mixture is incubated at room temperature for 2 hours in the presence of calculated concentrations of the test compounds of formula (I).
  • the samples are filtered through GF / B glass fiber filters (Whatmap), pre-soaked in 0.3% polyethyleneamine for 2 hours at 4 ° C. Each tube is washed once with cold N ° 2 buffer, then the filters are washed three times with the same buffer volume . The filters are dried in air until completely dry and transferred to scintillation vials. Filters fill 5 ml.
  • the values of the IC 5O index are determined for the tested compounds. As a result of these tests, it was found that the IC 5O value for the most active compound Ia of the present invention is 2.4 ⁇ M, which indicates a high degree of affinity for NMDA receptors and strong antagonistic activity against this glutamate receptor subtype.
  • Example 18 Determination of the activity of compounds against dopamine receptors.
  • striatums from 4 animals are thoroughly homogenized in 10 ml of ice
  • Radioligand analysis The resulting membrane fraction is incubated with [G-CH] -labeled ligand, which is added to the incubation mixture in a volume of 50 ⁇ l at a final concentration of 0.1 nM for 20 .min at a temperature of 37 ° C using a solid-state thermostat “Termmit” (NPO “ DHK diagnostics ”).
  • Non-specific binding is determined in the presence of 50 ⁇ l of unlabeled spiroperidol (20 ⁇ M) or - SCH23390, which on average does not exceed 12-14% of the total. Specific binding is calculated as the difference between total and non-specific binding.
  • IC 5O with respect to the [G-3H] -spiperidol (specific activity 95 Ci / mmol) or [G-3H] -SCH23390 (specific activity 60 BSi / mmol) is determined by adding 50 ⁇ l of the compounds under study to the incubation medium at final concentrations in the range of 10 "3 -10 " 10 M.
  • the volume of the incubation mixture is 500 ⁇ l.
  • SUBSTITUTE SHEET (RULE 26) binding is stopped by adding 2 ml of ice-cold 50 mM Tris-HCl buffer and rapid filtration through GF / B type glass filters (Whtmap), followed by washing with ice-cold buffer with a total volume of 14 ml.
  • the filters are pre-wetted before the experiment in ice-cold 50 mM Tris-Hcl buffer for 3 hours.
  • the filters are dried for 12 hours at room temperature, then placed in a scintillation fluid (Bray reagent) with a volume of 4 ml and used for scintillation counting.
  • the radioactivity of each sample is measured for 2 min on a WaIIaC 1411 scintillation counter.
  • the counting efficiency for tritium is 40-45%.
  • Determination of protein content in samples is carried out according to the Lowry method.
  • Optical density (X 700 nm) was measured on a SF-46 spectrophotometer (JIOMO): The results were processed with. using standard statistical programs with calculus of arithmetic mean and SEM.
  • IC 5O values are determined.
  • the test results indicate that the compounds of formula (I) in vitro do not show neurochemically significant tropism for the D-dopamine and D2-dopamine rat striatum receptors.
  • the value of IC 5O with respect to the D-dopamine receptor, for example, for compound Ia, is 220 ⁇ M, and the value of IC 5O with respect to the D2-dopamine receptor is 195 ⁇ M.
  • Example 19 Determination of the activity of compounds against cholinergic receptors.
  • SUBSTITUTE SHEET (RULE 26) radioactive selective ligand with rat brain membranes.
  • a ligand tritium-labeled ( ⁇ ) Nicotin with a specific activity of 140 Curie / mmol obtained by solid-phase labeling is used.
  • Isolation of plasma membranes of the brain is carried out according to the method of Romano C. apd A.Goldstep, (Sciepse, 1980, 210, p. 647-650).
  • outbred male rats weighing 200-250 g are decapitated, the whole brain is extracted and homogenized in 10 volumes of ice-cold buffer (Hepes, 50 mM; NaCl, 118 mM; CaCl 2 , 2.5 mM; KCl 5 4.8 mM; MgSO 4, 1.2 mM; pH 7.4) in a Teflon-glass homogenizer.
  • the homogenate is centrifuged for 30 minutes at 1750Og.
  • the resulting precipitate is suspended in 20 volumes of cold distilled water and left for an hour for osmotic destruction. The resulting suspension is again centrifuged for 30 minutes at 1750Og. The resulting precipitate was suspended in buffer and again precipitated under the same regime. The pellet was resuspended in buffer to a final concentration (40 mg of starting tissue per 1 ml of buffer).
  • Radioligand analysis The tubes are filled with a reaction mixture containing in a final volume of 50 ⁇ l of [3H] ( ⁇ ) Nicotin, 250 ⁇ l of buffer and 200 ⁇ l of a protein suspension of membranes prepared as described above. Nonspecific binding is determined by adding unlabeled ligand in a concentration range from 10 "10 to 10 4 M in triplicates.
  • Tubes with the reaction mixture are incubated with constant shaking at 37 ° C for 40 minutes.
  • the tubes are then quickly immersed in ice to stop the reaction. After 20 minutes, the contents of the tubes are ultrafiltered through GF / C filters, previously incubated for 24 hours in a 0.3% solution.
  • SUBSTITUTE SHEET (RULE 26) polyethyleneimine at 4 0 C. After washing with cold buffer, the filters are transferred to vials and dioxane-based scintillation fluid is added. The radioactivity of the samples is determined on a Wallac 1411 scintillation counter with a counting efficiency of about 40-44%.
  • the test results indicate that the compounds of formula (I) are characterized by a high degree of affinity for the binding sites of [3H] nicotin with rat brain membranes.
  • concentration dependence of the effect of nicotine on the binding of a labeled ligand is described by a classical curve with an IC 5O value of 0.13 ⁇ M.
  • Compound Ia shifts the concentration curve to the right to IC 5 Q values of 3.20 ⁇ M. This concentration range is considered as a high degree of receptor affinity.
  • Example 20 Determination of anticholinesterase activity of the compounds.
  • the anticholinesterase activity of the compounds of formula (I) was studied in vitro experiments using a standard set of reagents for the determination of cholinesterase (CE) of the company Lashema (Czech Republic).
  • CE cholinesterase
  • the principle of the method is that CE splits the butyryl-thiocholinium iodide substrate into butyric acid and thiocholinium iodide, which reacts with dithio-bisnitrobenzoic acid to form a yellow color.
  • the determination is carried out on the FEK model KF-2-UXL-4.2 ( Russian): To determine the ability to inhibit CE, the test compounds are added to a solution containing the CE enzyme and substrate and the color change is observed in comparison with the control.
  • SUBSTITUTE SHEET (RULE 26) activity is expressed in IK 5 o - the concentration of inhibitor at which the enzyme activity is blocked by 50% compared with the control.
  • Table l presents the results of determining the anticholinesterase activity of the most active compounds of this invention in comparison with the most well-known drugs of this pharmacological group.
  • Example 21 Determination of the activity of compounds in relation to the adrenergic system.
  • norepinephrine HA
  • norepinephrine HA
  • norepinephrine-sensitive adenylate cyclase of the cell membrane of the adrenoreceptor system which leads to increased formation of a secondary cAMP mediator and further the implementation of adrenergic physiological effects.
  • the central sympathomimetic effect is due to the excitation of norepinephrine and dopaminergic brain structures and is expressed in behavioral hyperactivity, acceleration of the mnemonic and cognitive functions of the brain, activation of electroencephalographic (EEG) indicators - the electrical activity of the brain.
  • EEG electroencephalographic
  • Another way of activating the noradrenergic system is characteristic of indirect sympathomimetics such as amphetamine and other drugs of the ⁇ -phenylethylamine series, which cause the release of norepinephrine from the depot, which already further affects adrenoreceptors. This is typical for most drugs with the psychostimulating effect of the amphetamine series and structurally similar drugs - indirect sympathomimetics.
  • SUBSTITUTE SHEET (RULE 26) methyl p-tyrosine, an inhibitor of the synthesis of HA and dopamine (DA), as well as under conditions of emptying neuronal depot of mediators by reserpine, as described below.
  • Locomotor activity in animals placed in a new environment consists of an orientation-research reaction (OIR) during the first 4-6 minutes and locomotion, which is caused by cycles of behavioral activity.
  • OIR orientation-research reaction
  • the introduction of substances having psychostimulating activity increases the level of locomotion, i.e. transfers spontaneous locomotion to the level of locomotor hyperactivity, bypassing OIR.
  • mice Male mice weighing 20-22 g and male rats weighing 180-200 g.
  • the spontaneous locomotor activity of mice was recorded using an Opto-varimex actometer (Columbus, USA) according to the method of Swssssop, Thieme (1969).
  • Motor activity is recorded every 10 min for 2-4 hours, before and after administration of the test compound.
  • the test compounds are administered in doses of 1-10-12.5-25-50 and 100 mg / kg.
  • the locomotor activity of control animals is recorded, to which the corresponding volume of physiological saline is injected.
  • the EDgo value is calculated - the dose that causes a 2-fold increase in motor activity (200%) in relation to the control.
  • compound Ia when administered subcutaneously, is inferior in strength to the central stimulating effect of phenamine, and when administered orally, it is more than 3 times weaker than phenamine and close to sydnocarb. According to the severity of locomotor excitation in mice, the effect of compound Ia is similar to the effects of phenamine and sydnocarb.
  • ED 5 o is the dose causing the appearance of stereotypic reactions in 50% of rats.
  • EDgo is the dose causing a 2-fold increase in spontaneous motor activity in mice.
  • mice Male mice weighing 18-20 g, which are administered intraperitoneally with reserpine at a dose of 2 mg / kg.
  • Reserpine has a depressive effect on the central nervous system, causing a decrease in motor activity (hypolocomotion), ptosis and hypothermia.
  • the hypolocation is recorded using the Opto-Varimex actometer (Columbus, USA), ptosis is evaluated visually in points on a 4-point scale,
  • SUBSTITUTE SHEET (RULE 26) hypothermia is determined using a TPEM-1 electrothermometer by temperature in the rectum.
  • test compounds are administered orally and subcutaneously at doses of 1, 5 and 10 mg / kg.
  • Compound Ia administered at a dose of 10 mg / kg (subcutaneously) 2 hours after reserpine, restores the reduced locomotor activity of mice to the level of activity of animals in the control group, reduces ptosis by more than 70% and completely eliminates the hypothermic effect of reserpine, converting it to hyperthermic.
  • Compound Ia acts on the effects of reserpine about 2 times weaker than phenamine (in equal dose). Sydnocarb at a dose of 25 mg / kg in these experiments has a negligible effect on the effects of reserpine.
  • Compounds (I f-h) when administered orally to animals in a dose range of up to 100 mg / kg, change the severity of the depriving effects of reserpine (inactivity, ptosis, hypothermia) similar to compound Ia.
  • mice showed that in the central action of the compounds of the present invention there is a component associated with indirect sympathomimetic properties, expressed in antagonism to the effects of reserpine.
  • indirect sympathomimetic properties expressed in antagonism to the effects of reserpine.
  • SUBSTITUTE SHEET (RULE 26) the properties of the compounds of formula (I) are significantly inferior to phenamine, the psychostimulating effect of which is associated with the effect on the release of the mediator from the rapidly renewable (labile) NA depot in the presynaptic region of the neuron.
  • the central action mechanism of the studied compounds is also evaluated in experiments using ⁇ -methyl-p-tyrosine (alpha-MT), an inhibitor of the tyrosine hydroxylase enzyme, which is involved in the biosynthesis of dopamine from tyrosine in nerve endings as a pharmacological analyzer.
  • alpha-MT ⁇ -methyl-p-tyrosine
  • the experiments are carried out on male mice weighing 18-20 g, which are administered ⁇ -methyl-p---
  • SUBSTITUTE SHEET (RULE 26) tyrosine at a dose of 250 mg / kg, intraperitoneally.
  • Administration of ⁇ -methyl-p-tyrosine causes a decrease in locomotor activity of animals by more than 6 times, which reflects a decrease in the level of dopamine in the brain.
  • compound Ia Against the background of the preliminary administration of ⁇ -methyl-p-tyrosine, compound Ia has a weak effect on physical inactivity, which differs from phenamine and even more so from sydnocarb, which, the first partially and the second completely, eliminate the changes in the motor activity of animals caused by the introduction of a tyrosine inhibitor hydroxylases.
  • Compounds (I f-h) when administered orally in a dose range of up to 100 mg / kg, exhibit an effect similar to compound Ia.
  • the experiments performed show that the compounds of formula (I) have practically no effect on the effect of ⁇ -methyl-tyrosine in mice and differ in this respect from phenamine and sydnocarb.
  • the compounds of the invention are inferior to phenamine in influencing the spontaneous motor activity of animals, do not cause disorganization of targeted activity, but surpass phenamine in strength and duration.
  • SUBSTITUTE SHEET (RULE 26) activating effect on EEG in rats. In addition, they do not have a significant peripheral sympathomimetic effect.
  • Example 22 Evaluation of the neuroprotective activity of compounds in a model of multiple sclerosis.
  • the ability of the compounds of formula (I) to have a neuroprotective effect in the treatment or prevention of neurodegenerative diseases was determined ip vivo in an experimental model of human multiple sclerosis.
  • Such a model is experimental autoimmune (allergic) encephalomyelitis (EAE), a myelin antigen-induced and T-cell-mediated autoimmune disease in laboratory animals that is similar in clinical and histological features to multiple human sclerosis (Steimp, L. // Sprimps. , v. 14, p. 79-93).
  • EAE encephalomyelitis
  • the methodology for assessing the effect of the compounds of formula (I) on reducing the severity of EAE in experimental animals is presented below.
  • mice are immunized with 75 ⁇ g of myelin lipoprotein protein (hereinafter referred to as PLP) emulsified with Freund's adjuvant (CFA) and 0.6 mg / ml Musobacterium tubulosis H37RA (Difso, Detroit, MI, USA) to create an emulsion in a 1: 1 ratio.
  • PLP was synthesized by Heped sup Sprintsis (Sap Francisco CA).
  • Each mouse receives a subcutaneous injection of 200 ⁇ l of the emulsion divided into 4 parts into the axillary region and inguinal lymph nodes.
  • pertussis toxin Pertussis toxip, Calbiochem, Nottham, UK
  • pertussis toxin As a co-adjuvant, pertussis toxin (Pertussis toxip, Calbiochem, Nottham, UK) is used, which is administered intragastrically at a dose of 200 ng / mouse 0 and 2 days after immunization.
  • the animals of the experimental groups are administered an orally tested compound of the formula (I) 6 times a week: to the 1st experimental group - at a dose of 1.0 mg / kg; The 2nd experimental group - at a dose of -3.0 mg / kg; The 3rd experimental group - at a dose of -5.0 mg / kg. Treatment with the test compound is carried out for 30 days.
  • mice of the control and experimental groups were observed daily for 30 days after immunization, the clinical signs of EAE were weighed and recorded.
  • animals are sorted using the following scale: 0 - no symptoms (no disease); 1 - lowering the tone of the tail; 2 - weakening of the muscles of the hind limbs, impaired gait (moderate paraparesis); 3- hind limb paralysis (severe paraparesis); four -
  • SUBSTITUTE SHEET (RULE 26) complete paralytic immobility (state of dying); 5 - the death of an animal.
  • Example 23 Determination of the effect of compounds on the activation of cognitive functions.
  • the cognitive-stimulating activity of the compounds of the present invention is evaluated in a number of behavioral experiments on animals by their ability to improve memory and learning in mice, as well as exert anti-amnestic effects in animals with experimentally induced amnesia.
  • SUBSTITUTE SHEET (RULE 26) (conditioned reflex of passive avoidance). Violation of training and information storage is modeled using the amnestic action of the central anticholinergic scopolamine.
  • the experiments are carried out on male mice weighing 20-22 g, forming groups of 10-12 animals for each study dose.
  • Passive avoidance reaction is produced according to the ster dowp method, in an illuminated chamber with an electrode floor and a rescue platform in the middle.
  • the behavior of an animal when it is placed in a chamber is expressed in the form of tentative research activity (examination of the chamber).
  • the animal descends from the platform to the electrode floor, it receives an electric shock on its paws (50 V for 3-5 seconds), after which it is returned back to the living cage.
  • the training is carried out in three sessions, the criterion for the training of animals is to stay on the platform for 1 minute.
  • the functional state of memory is evaluated by the ability of mice to reproduce the developed passive avoidance reaction skill when an animal is placed in a chamber on a rescue platform 2 hours after the development of a conditioned reflex reaction and amnestic effect.
  • scopolamine is administered to mice at a dose of 1 mg / kg, intraperitoneally, for 15-20 minutes. before the introduction of the test compounds.
  • Scopolamine is a central M-anticholinergic drug that causes memory impairment (amnesia) and reduces learning ability.
  • the test compounds are administered orally, at a dose of 10 mg / kg, 40 minutes before training.
  • the basis for the use of these doses is the initial active dose of compound Ia, taken as a comparison drug, and component 3 mg / kg, orally.
  • SUBSTITUTE SHEET mice and rats using standard tests, such as passive avoidance reaction, URAI (active avoidance conditioned reflex test), electroshock-induced amnesia (MES), scopolamine amnesia, and electrophysiological experiments.
  • URAI active avoidance conditioned reflex test
  • MES electroshock-induced amnesia
  • scopolamine amnesia and electrophysiological experiments.
  • reference drugs use piracetam, meclofenoxate
  • the compounds of the present invention have a positive effect on cognitive functions in animals with learning disabilities, as well as on amnesia models caused by the administration of the cholinolytic drug scopolamine (1.0 mg / kg, s / c) and the effect of maximum electroshock.
  • compound Ia when producing URAI and passive avoidance reaction, surpasses the nootropic drugs piracetam and meclofenoxate.
  • nootropic drugs act primarily in conditions of impaired function.
  • an improvement in the associative functions of the brain is observed, as evidenced by the results of experiments to solve the extrapolation problem in animals under stressful conditions, in which it also exceeded piracetam and acefen.
  • compound Ia has an activating effect on the EEG of old rats, increasing the power of its spectrum and restoring impaired functional asymmetry between the cerebral hemispheres, which is characteristic of
  • Example 24 Determination of the antidepressant activity of the compounds.
  • the antidepressant activity of the compounds is evaluated by their effect on the psychoemotional and behavioral characteristics of animals in standard tests simulating the development of an emotional-stress state.
  • the stress state in animals is caused when they are placed in a chamber with water equipped with a rotating ribbed wheel.
  • mice were carried out on male mice weighing 20-22 g.
  • the test compound was administered subcutaneously to experimental animals at doses of 5 and 10 mg / kg.
  • the control group of animals injected with saline in the same doses. For each dose, 8-10 animals are taken.
  • Example 25 The effect of connections on health.
  • mice An assessment of the effect of the compounds of formula (I) on physical performance is examined in a “swimming” test.
  • the experiments are carried out on mice.
  • the test compound is administered to experimental animals subcutaneously in doses of 5-15 mg / kg.
  • the control group of animals injected with saline in the same doses.
  • 8-10 animals are taken.
  • a load of 7.5% of body weight was recorded on each animal and placed in a chamber with water at a water temperature of 24-26 0 C Record the time during which the mouse is able to hold
  • Example 26 Obtaining a pharmaceutical composition in the form of a tablet containing 0.1 mg of the active ingredient.
  • the active ingredient take the compound of formula (I) obtained in examples 1, mixed with the calculated amount of microcrystalline cellulose, silicon dioxide, stearic
  • the compound of formula (I) - 0.1 mg Microcrystalline cellulose - 30 mg Silicon dioxide - 20 mg Stearic acid - 1, 9 mg Tablet weight - 52 mg.
  • Example 27 Obtaining a pharmaceutical composition in the form of tablets containing 1 mg of the active ingredient.
  • a compound of formula (I) is taken, mixed with the calculated amount of corn starch, microcrystalline cellulose, lactose, povidone, croscarmellose sodium, magnesium stearate are thoroughly mixed and pressed to obtain tablets weighing 90 mg each.
  • Example 28 Obtaining a pharmaceutical composition in tablet form containing 2.5 mg of the active ingredient.
  • a compound of formula (I) is taken, mixed with the calculated amount of milk sugar, polyvinylpyrrolidone of low molecular weight potato starch,
  • Example 29 Obtaining a pharmaceutical composition in the form of a tablet containing 5 mg of the active ingredient.
  • a compound of formula (I) is taken, mixed with the calculated amount of corn starch, lactose, hydroxypropylcellulose and crystalline cellulose. Hydroxypropyl cellulose dissolved in water is added and thoroughly mixed again. The resulting mixture was dried, granulated and magnesium stearate and light anhydrous silicic acid were added and pressed to obtain tablets weighing 70 mg. The tablets are then coated in the usual manner with a film coating using hydroxypropyl cellulose.
  • the mass of the tablet core is 70 mg.
  • a compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of milk sugar, polyvinylpyrrolidone of low molecular weight potato starch, calcium stearate is thoroughly mixed and pressed to obtain tablets weighing 320 mg each. Get tablets of the following composition, mg (per tablet):
  • Example 31 Preparation of tablets containing 100 mg of active ingredient.
  • a compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of starch, crushed lactose, talc, mixed thoroughly and pressed into a block.
  • the resulting bar is crushed into granules and sieved through sieves.
  • the granules obtained are tabletted into a suitable tablet form weighing 460 mg each.
  • the weight of the tablet is 460 mg.
  • the active ingredient (compound of formula 1), starch and cellulose are passed through a sieve and mixed thoroughly.
  • the resulting powder is mixed with a solution of polyvinylpyrrolidone and granulated.
  • the granules are dried at 50 ° C and combined with sodium carboxymethyl, magnesium stearate and talc. Thoroughly mixed and pressed in a machine for making tablets to obtain tablets weighing 150 mg each.
  • the weight of the tablet is 150 mg.
  • Example 33 Obtaining a pharmaceutical composition in the form of suppositories.
  • a compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of lanolin and melted cocoa butter and mixed thoroughly.
  • the manufacture of suppositories is carried out on machines with the necessary technological conditions by molding.
  • Example 34 Obtaining a pharmaceutical composition in the form of a capsule containing 5 mg of the active ingredient.
  • a compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of crystalline lactose and corn starch, mixed thoroughly. Next, talc and magnesium stearate are added and mixed again. The resulting mixture is filled in hard gelatin capsules of the appropriate size.
  • the mass of the contents of the capsule is 200 mg.
  • Example 35 Obtaining a pharmaceutical composition in the form of a capsule containing 50 mg of the active ingredient.
  • a compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of crystalline lactose and microcrystalline cellulose to a homogeneous state, sieved, and then talc and magnesium stearate are mixed. Hard or soft gelatin capsules of the appropriate size are filled with the finished mixture.
  • the mass of the contents of the capsule is 150 mg.
  • the active ingredient take the compound of formula (I), mix with the calculated amount of excipients.
  • the resulting solution is filtered and poured into ampoules of the appropriate size, which are sealed and sterilized in an autoclave.
  • the compound of formula (I) 0.5 mg Sorbitol - 5.1 mg Acetic acid - 0.08 mg Water for injection - up to 1 ml.
  • the compound of formula (1) 100 mg Mannitol - 100 mg 5 n sodium hydroxide - 200 ⁇ l Purified water - up to 5 ml.
  • the compound of formula (1) 50 mg Citric acid - 210 mg D-mannitol - 100 mg distilled water - up to 10 ml.
  • a compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of ethanol, a dispersant of chlorodifluoromethane cooled to -3O 0 C is added and aerosol cans are filled.

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Abstract

L’invention concerne de nouveaux dérivés de 2,4-diaminopyridine, leurs sels et/ou solvates pharmaceutiquement acceptables, leurs compositions, des produits médicamenteux contant de nouveaux dérivés de 2,4-diaminopyridine et leur utilisation en tant que bloqueurs de récepteurs NMDA ainsi qu’en tant que stimulateurs de fonctions cognitives. Les nouveaux dérivés allient les qualités d’un antagoniste à affinité élevée des récepteurs NMDA aux propriétés d’inhibiteurs modérés d’acétylcholinestérase et d’agonistes à affinité élevée de sympathomimétiques et cholinorécepteurs nicotiniques, ce qui assure leur action combinée normalisante sur le déséquilibre de plusieurs systèmes neurotransmetteurs, y compris les systèmes glutamatergique, cholinergique et adrénergique, sans effets secondaires qui se sont manifestés préalablement chez les antagonistes connus de MDMA. Sans provoquer de baisse de capacités intellectuelles ni de troubles de l’attention et de la mémoire, ce qui caractérise les antagonistes connus de MDMA, ces dérivés peuvent s’utiliser dans le traitement et la prévention d’une série de troubles et de maladies liés à la perturbation des fonctions cognitives et de la capacité d’apprentissage. L’invention concerne aussi un procédé de traitement et de prévention des maladies et des troubles liés à une activation élevée du système glutamatergique et/ou à l’affection des fonctions intellectuelles et mnésiques.
PCT/RU2009/000083 2008-02-21 2009-02-20 Dérivés de 2,4-diaminopyridine, composition pharmaceutique, produit médicinal à base desdits dérivés destinés au traitement ou à la prévention de maladies et troubles provoqués par l’hyperactivation de récepteurs nmda et/ou en tant que stimulateurs de fonctions congnitives et procédé d’utilisation correspondant Ceased WO2009104990A1 (fr)

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EA200801639 2008-02-21
EA200801639A EA014100B1 (ru) 2008-02-21 2008-02-21 Производные 2,4-диаминопиридина, фармацевтическая композиция, лекарственное средство на их основе для лечения или предупреждения заболеваний и нарушений, вызванных гиперактивацией nmda-рецепторов и/или в качестве стимуляторов когнитивных функций и способ лечения

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WO2009104990A1 true WO2009104990A1 (fr) 2009-08-27

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WO2011101774A1 (fr) 2010-02-16 2011-08-25 Pfizer Inc. (r)-4-((4-((4-(tétrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)méthyl) pipéridin-1-yl)méthyl)tétrahydro-2h-pyran-4-ole, agoniste partiel des récepteurs 5-ht4
WO2013048949A3 (fr) * 2011-09-26 2013-07-18 Bristol-Myers Squibb Company Antagonistes du nr2b sélectifs
CN120459095A (zh) * 2025-06-18 2025-08-12 北京生命科学研究所 氨基吡啶类物质抑制α-突触核蛋白聚集和路易小体形成的用途

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RU2438672C1 (ru) 2010-04-30 2012-01-10 Общество с ограниченной ответственностью "Клевер Фарм" Агент, проявляющий свойства активатора когнитивных функций (варианты)

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RU2303037C2 (ru) * 2001-11-09 2007-07-20 Ф.Хоффманн-Ля Рош Аг Производные пиридина и лекарственное средство на их основе, обладающее селективной блокирующей активностью в отношении подвида nmda-рецепторов

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KR100804111B1 (ko) * 2000-08-11 2008-02-18 에자이 알앤드디 매니지먼트 가부시키가이샤 2-아미노피리딘 화합물 및 그의 의약 용도
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RU2303037C2 (ru) * 2001-11-09 2007-07-20 Ф.Хоффманн-Ля Рош Аг Производные пиридина и лекарственное средство на их основе, обладающее селективной блокирующей активностью в отношении подвида nmda-рецепторов
WO2004024711A1 (fr) * 2002-09-10 2004-03-25 Pharmacia Italia S.P.A. Derives de pyridine substitues utilises comme agent antitumoral

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101774A1 (fr) 2010-02-16 2011-08-25 Pfizer Inc. (r)-4-((4-((4-(tétrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)méthyl) pipéridin-1-yl)méthyl)tétrahydro-2h-pyran-4-ole, agoniste partiel des récepteurs 5-ht4
WO2013048949A3 (fr) * 2011-09-26 2013-07-18 Bristol-Myers Squibb Company Antagonistes du nr2b sélectifs
US8841301B2 (en) 2011-09-26 2014-09-23 Bristol-Myers Squibb Company Selective NR2B antagonists
CN120459095A (zh) * 2025-06-18 2025-08-12 北京生命科学研究所 氨基吡啶类物质抑制α-突触核蛋白聚集和路易小体形成的用途

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EA200801639A1 (ru) 2009-08-28

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