(3-arylsulphonyl quinolin-8-yl-dialkyl-amines - selective serotonin 5-ht6 receptor antagonists, methods for production and use thereof. RU patent 2500672.
 Polymorphous form of 3-phenylsulfonyl-8-piperasine-1-yl-quinoline / 2355681Invention concerns novel polymorphous form of 3-phenylsulfonyl -8-piperasine-1-yl-quinoline characterised by: infrared spectre with peaks at 724, 758, 777, 804, 818, 838, 856, 905, 918, 948, 1023, 1055, 1081, 1092, 1118, 1136, 1153, 1178, 1244, 1302, 1318, 1365, 1378, 1403, 1444, 1471, 1490, 1569, 1584, 1603 and 2819 cm-1, combination scattering spectre with peaks at 159, 184, 214, 241, 285, 304, 318, 429, 545, 558, 614, 706, 724, 803, 856, 1000, 1023, 1080, 1093, 1136, 1152, 1233, 1243, 1317, 1343, 1364, 1378, 1403, 1446, 1569, 1584, 1602, 3050 and 3073 cm-1, X-ray powder difractogram (XRPD) with calculated interplanar distances at angle values of 10.29, 11.94, 17.47, 19.55, 19.84 and 20.33° and melting point of 188°C. |
 Heterocyclic compounds, their using and pharmaceutical composition for treatment of states mediated by cxcr4 and ccr5 / 2277092Invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients. |
 Combined drug preparation / 2500415Invention refers to pharmaceutical industry, particularly to an oral preparation, possessing antihypoxic, nootropic and hypolipidemic action. The oral preparation possessing antihypoxic, nootropic and hypolipidemic action contains a combination of vinpocetine and gingko extract in the relation of 1:(3.5 -16). |
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Compositions containing unsaturated fatty acids and compounds releasing nitrogen oxide and using them for improving cognitive functions and related functions / 2500402 Group of inventions refers to medicine and veterinary science. Compositions containing one or more unsaturated fatty acids and one or more compounds releasing nitrogen oxide, and methods for using such compositions for enhancing the cognitive function, reducing or preventing the deterioration of social interaction, reducing or preventing the age-related behavioural changes, increasing the learning capability, maintaining the optimal cerebral function, relieving the learning and memory processes, reducing loss of memory, providing the retardation of cerebral aging, preventing or treating cerebral accidents, and preventing or treating dementia in an animal. |
 Method of treating disorders using selective nr2b subtype nmda receptor antagonist / 2499598Group of inventions refers to medicine and aims at treating, preventing or relieving a disease or a condition which is to be treated, prevented or relieved by NMDA receptor inhibition. The method involves administering a total daily dose of approximately 2 to approximately 50 mg of a compound of formula |
 Humanised antibody to beta amyloid / 2498999Versions of an antibody or its fragment, which are specific in relation to β-amyloid protein, are proposed. Each version is characterised by the fact that it includes H- and L-chains, or areas VH and VL, each of which contains three corresponding CDR. The following is described: polypeptide VL, polypeptide VH, as well as coding nucleic acid, expression vector containing it and a cell carrying the vector, which are used for obtaining an antibody or its functional fragment. The following is proposed; a test kit, versions of pharmaceutical composition, a mixture to be used as a medicine based on the antibody or its functional fragment. Versions of the method used for production of an antibody are described: using a cell, nucleic acid or a vector. A composite preparation method, as well as an in vitro amyloid disease diagnostics method, a method for determination of a degree of loading with in vitro amyloidogenic patches, a method for curing or relief of actions of amyloid disease, which use an antibody or its functional fragment, are described. Inventions can be used in therapy and diagnostics of Alzheimer disease and other enlisted amyloid diseases. |
 Novel vanilloid receptor ligands and use thereof in producing medicinal agents / 2498982Invention relates organic chemistry and specifically to novel pyridine amide derivatives of general formula I where n equals 1; R1 and R2 together denote a residue selected from a group consisting of -CH=N-NH- and -CH=CH-N=CH-, which is bonded in any desirable direction to the parent structure or R2 and R3 together denote a residue selected from a group consisting of -CH=N-NH-; -CR28=N-NH-; -S-C(=S)-NH-; -S-CR29=N-; -N=CR30-O-; -N=CH-NH-; -N=N-NH-; -O-CH2-O-; -CH2-CH2-CH2-NH, -O-CH2-CH2-O-; -N=CH-CH=N-; -CH=CH-CH=N-, which is bonded in any desirable direction to the parent structure, or R3 and R4 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, or R4 and R5 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, and the rest of the residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; where R28 denotes F; Cl; Br or I; R29 and R30, mutually independently, in each case denote -NH-C(=O)-R31; -NH2; -NH-S(=O)2-R32; -NH-C(=O)-O-R33; -S-R34; where R31, R32, R33 and R34, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R6 denotes H or denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R7 denotes hydrogen or -OH; R denotes -CF3; or denotes an unsubstituted tert-butyl residue; T denotes C-R35 and U denotes C-R36, V denotes N and W denotes C-R38; where R35 and R36 denote H; where R38 denotes -NR40R41; -OR42 or -SR43; where R40, R41, R42 and R43, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; or denote a saturated, unsubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-member cycloaliphatic residue, or where R40 and R41 in each case together with a nitrogen atom as a ring member which binds them together, form a saturated 6-member heterocycloaliphatic residue, optionally substituted with one R57 residue, where R57 denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; in each case in form of corresponding physiologically acceptable salts. The invention also relates to a method of producing a compound of formula I, a medicinal agent based on the compound of formula I and use of the compound of formula I. |
 Aqueous suspensions of riluzol / 2498802Aqueous suspensions contain riluzol or a pharmaceutical acceptable salt, at least one surfactant, and at least one suspending agent. Riluzol is found in the amount of approximately 0.1% to approximately 20% (weight/volume) and characterized by a particle size less than approximately 200 mcm. The surfactant is specified in anionic surfactants, nonionic surfactant or a mixture thereof. The suspending agent is specified in smectic clays, microcrystalline cellulose, natural gums or a mixture thereof. |
 6-substituted-thio (or -oxo-)-2-amino-quinoline derivatives used as β-secretase inhibitors / 2497821Present invention refers to organic chemistry, namely to new 2-aminoquinoline derivatives of formula , or to pharmaceutically acceptable salts thereof, wherein R1 represents 6-member heterocycloalkyl (tetrahydropyranyl); R2 is specified in a group consisting of hydrogen and halogen; L1 is specified in a group consisting of -CH2-NRA, -CH2CH2-NRA, -CH2-O- and -CH2-S-; wherein RA means hydrogen; R3 is specified in a group consisting of carboxy substituted C1-4alkyl, aryl(phenyl), -(C1-4alkyl)-aryl(phenyl), -(C1-4alkyl)-heteroaryl(imidazolyl, pyridinyl); wherein aryl analysed either individually, or as a part of a substituting group, carries one to three substitutes independently specified in a group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, -C1-4alkoxygroup- and -C1-4alkyl-CO2H; either RA and R3 together with a nitrogen atom whereto attached form a ring structure representing 6-member heterocycloalkyl (piperazinyl). Further, the invention refers specific compounds and , a pharmaceutical composition of the compounds of formula (I), (II-a) and (II-b), a method for preparing the pharmaceutical composition, a method for treating the above disorders, a method for inhibiting enzyme β-secretase activity and using the compounds of formulas (I), (II-a) and (II-b). |
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Cerebroprotective agent / 2497540 Invention refers to medicine, more specifically to pharmacology, neurology and cell engineering. What is described is using Napelline as a cerebroprotective agent. The mode of action of the agent is activation of cerebral neural stem cells. |
 New oxime cholest-4-en-3-one derivatives, pharmaceutical compositions containing them, and method for preparing / 2496784Invention refers to oxime cholest-4-en-3-one derivatives of formula (I) and pharmaceutically acceptable salts and optical isomers thereof, and using them as cytoprotective drugs, as well as a based pharmaceutical composition. The radical values in general formula are presented in the patent claim. |
 Heterocyclic aspartyl protease inhibitors / 2496774Present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof. |
 Agent of hindu lotos seed (nelumbo nucifera) extract possessing anxiolytic and antidepressive action / 2497538Invention refers to pharmaceutical industry, namely preparing an agent of hindu lotus seed extract (Nelumbo nucifera) possessing anxiolytic and antidepressive action. The agent possessing anxiolytic and antidepressive action prepared by extraction of hindu lotus seed extract (Nelumbo nucifera) in 50% ethanol in a Soxhlet extraction apparatus in the specific proportions. |
![Imidazo[1,2-b]pyridazine compounds (versions), method for preparing imidazo[1,2-b]pyridazine compounds (versions), pharmaceutical composition and drug preparation for treating and/or preventing diseases related to gaba receptor inhibition](http://img.russianpatents.com/img_data/1001/10015395-s.gif) Imidazo[1,2-b]pyridazine compounds (versions), method for preparing imidazo[1,2-b]pyridazine compounds (versions), pharmaceutical composition and drug preparation for treating and/or preventing diseases related to gaba receptor inhibition / 2486188Present invention provides new imidazo[1,2-b]pyridazine compounds covered by general structural formula (I) wherein the radicals and symbols have the values presented in the patent claim, and pharmaceutically acceptable salts thereof. The compounds of structural formula (I) are effective both for treating or preventing the diseases related to GABA receptor inhibition, anxiety, epilepsy, sleep disorders, including insomnia, and for inducing a sedative-hypnotic, anaesthetic effect, sleep and muscle relaxation. |
![3-phenylpyrazolo[5,1-b]thiazole derivative](http://img.russianpatents.com/img_data/997/9975086-s.gif) 3-phenylpyrazolo[5,1-b]thiazole derivative / 2482120Invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim. |
 Amide derivative and pharmaceutical composition containing said derivative / 2481343Invention relates to a compound of formula (1), in which Ar is a group of formula (Ar-1) or (Ar-2), in which R1 is a halogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, alkyl or alkenyl, X is a nitrogen atom or CH, R5 and R6 are each hydrogen and h equals 1; 1 equals 1 or 2; m equals 1 or 2; n equals 0, 1 or 2; o equals an integer from 0 to 3, under the condition that n and o are equal to 0 at the same time. Values of group A are as given in claim 1 of the invention. Described also is a pharmaceutical composition having agonistic activity with respect to 7 serotonin (5-HT4-receptors), which contains a compound of formula (1) and an agent which stimulates enterokinesis or improves functioning of the alimentary canal, which contains a compound of formula (1) as an active ingredient. |
![Halogenised pyrazolo[1,5-a]pyrimidines (versions), methods for preparing them, based pharmaceutical composition, intermediate compounds and method for preparing them (versions)](http://img.russianpatents.com/img_data/993/9930983-s.gif) Halogenised pyrazolo[1,5-a]pyrimidines (versions), methods for preparing them, based pharmaceutical composition, intermediate compounds and method for preparing them (versions) / 2478101Invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them. |
 Solid forms containing (-)-o-desmethylvenlafaxine and use thereof / 2477269Invention relates to a novel crystalline form of desmethylvenlafaxine of formula in form of a hydrochloride salt of a stereomerically pure compound which is suitable for treating, preventing or managing a disease selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause. The crystalline form contains water in amount of about 4% to about 8% of the total weight of the sample, and molar ratio of the water to the hydrochloride salt is about 1:1, and the crystalline form has X-ray powder diffraction peaks at positions of about 12.7, 14.5, 19.1, 21.4, 23.0, 25.5 and 27.3°2θ, and is characterised by the following corresponding unit cell parameters measured at 150 K: a=6.78 A; b=9.29 A; c=27.65 A; α=90°; β=90°; γ=90°. The crystalline form is characterised by weight loss during thermal gravimetric analysis of about 4% to about 8%, primarily about 5.6% of the total weight of the sample when heated from about 25°C to about 110°C and endothermic effect during differential scanning calorimetry with onset temperature of the effect of about 50°C to about 125°C, primarily about 93°C. The crystalline form is non-hygroscopic at relative humidity from about 5% to about 85% and absolute form. |
![2-substituted-1,2,4,5-tetrahydro-3h-pyrrolo[1,2-a][1,4]diazepin-3-ones](http://img.russianpatents.com/img_data/988/9884281-s.gif) 2-substituted-1,2,4,5-tetrahydro-3h-pyrrolo[1,2-a][1,4]diazepin-3-ones / 2472795Invention relates to biologically active compounds, specifically to a group of 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of general formula where R denotes hydrogen, a straight or branched (C1-C4)-alkyl; a hydroxyalkyl having an alkyl chain with 2-3 C atoms; a phenylalkyl having an alkyl chain with 1-2 C atoms, wherein the phenyl ring can have one or two methoxy groups. The invention also relates to a method of producing said compounds. |
 1-substituted tetrahydroisoquinoline derivative, based on them pharmaceutical composition and methods of their application / 2468010Claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions. |
 Ligustilide derivatives for treating central nervous system disorders / 2462462Invention refers to a dietary and pharmaceutical composition containing ligustilide to be applied in a method of treating or preventing depression, generalised anxiety disorders, dysphoria, obsessive-compulsive behaviour, and affective disorders, as well as to a non-therapeutic application of the dietary composition containing ligustilide. |
FIELD: chemistry.
SUBSTANCE: invention relates to novel (3-arylsulphonyl quinolin-8-yl-dialkyl-amines of general formula 1 and pharmaceutically acceptable salts thereof, which are selective antagonists of serotonin 5-HT6 receptors. The compounds can be used as an active ingredient in pharmaceutical compositions and medicinal agents for treating diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors. In particular, the compounds can be used in case of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, in anxiety or cognitive disorders and for enhancing mental capabilities. In general formula 1 , Ar is phenyl, optionally substituted in position 3 with a halogen atom, or naphthyl, R1 and R2 are an unsubstituted methyl or ethyl.
EFFECT: improved method.
10 cl, 9 dwg, 2 tbl, 8 ex
This invention relates to a new (3--8-yl)-dialkyl-amines - selective antagonists of serotonin 5-HT 6 receptor, principles of drug and pharmaceutical compositions containing medicines as these compounds, as well as to method of treatment and prevention of various diseases of the Central nervous system (CNS), the pathogenesis of which is associated with 5-HT 6 receptors. In the basis of the pharmacological effect of the new drug is started their ability to interact with serotonin 5-HT 6 receptors play an important role for the treatment of Central nervous system diseases, in particular Alzheimer's disease (ad), Parkinson's disease, illness , schizophrenia, neurodegenerative diseases, cognitive and anxiety disorders and obesity.
The use of potent and selective antagonist of serotonin 5-HT 6 receptors for the treatment of CNS disorders, particularly schizophrenia, BA and other neurodegenerative disease and cognitive disorders is a perspective direction of new drugs [Holenz J. Pauwels P.J., Diaz J.L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT 6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. These receptors in mammals are exclusively in the Central nervous system, mainly in the areas of the brain responsible for learning and memory [Gerard C., Martres M-P, K. Lefevre, Miquel M-C., Verge D., Lanfumey L., Doucet E., Hamon M., El Mestikawy S. Immuno-localisation of serotonin 5-HT 6 receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. In addition, it is shown [Dawson L.A., Nguyen H.Q., P. Li The 5-HT 6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology.. 2001; 25:662-668]that 5-HT 6 receptors are modulators several neurotransmitter systems, including , , and . In view of the fundamental role of these systems in normal cognitive processes and their dysfunction in neurodegeneration is becoming obvious, and the exclusive role of 5-HT 6 receptors in the formation of normal or «pathological» memory. In a large number of modern works shown that blocking the 5-HT 6 receptors leads to a significant increase in memory consolidation in various animal models of training-remember-play [Foley A.G., Murphy K.J., Hirst W.D., Gallagher H.C., J. Hagan, Upton N., Walsh F.S., Regan C.M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100. Riemer C., Borroni E., Levet-Trafit Century, J.R. Martin, Poli S., Porter R.H., M. Bos Influence of the 5-HT 6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-l-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT 6 recepor antagonist. J. Med. Chem. 2003; 46:1273-1276. King M.V., Woolley M.L., Topham I.A., Sleight A.J., Marsden C.A., Fone K.C. 5-HT 6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation e an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47:195-204]. Also shown a significant improvement in cognitive function in old rats in a model of a water maze Morrison under the influence of an antagonist of 5-HT 6 receptors [Foley A.G., Murphy K.J., Hirst W.D., Gallagher H.C., J. Hagan, Upton N., Walsh F.S., Regan C.M. The 5-HT 6 receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100]. Recently achieved not only greater understanding of the role of 5-HT 6 receptors in the cognitive process, but over the formation of a clear ideas about possible pharmacophoric properties of their antagonists [Holenz J. Pauwels P.J., Diaz J.L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT 6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. This led to the creation of high-affinity selective ligands («molecular tools»), and clinical candidates. At the present time the range of 5-HT 6 receptors are at different stages of clinical trials as a candidate drugs for the treatment of BA and schizophrenia.
Therefore, the search for selective and effective antagonist of serotonin 5-HT 6 receptor seems to be an original and promising approach to the creation of new medicines for the treatment of a wide range of CNS diseases, including neurological and neurodegenerative disease and cognitive disorders.
In the literature there is a considerable number of publications on different ligands serotonin 5-HT 6 receptor (5-HT 6 P) [A.V.Ivachtchenko, Y.A.Ivanenkov,S.E.Tkachenko, Expert Opin Ther. Pat. 20, 1171-1196 (2010). A.V.Ivachtchenko, Y.A.Ivanenkov. 5 6 receptor antagonists: a patent update. Part 1. Sulfonyl derivatives. Expert Opin. Ther. Patents, 22, 917-964 (2012). A.V.Ivachtchenko, Y.A.Ivanenkov, A.V.Skorenko. 5-HT 6 receptor modulators: a patent update. Part 2. Diversity in heterocyclic scaffolds. Expert Opin. Ther. Patents, September 7, (2012); doi: 10.1517/13543776.2012.722205].
For example, the famous 3-phenylsulphonyl-, representing 8-piperazine-1-Il-3-phenylsulphonyl-isoquinoline (I, SB-742457) [Upton, N.; Chuang, ..; Hunter, A.J.; Virley, D.J. 5-HT 6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. New-other-apeutics, 2008, 5, 458-469], methyl-(8-piperazine-1-Il-3-phenylsulphonyl-chinoline-4-yl)amine (II) [EN 2443697] and N(4),N(8),N(8)-dimethyl-3-phenylsulphonyl-chinoline-4,8-diamine (III) [EN 2443697] and high antagonistic activity towards the 5-HT 6 receptors.
According to a source from US 7,799,774 A connection SB-742457 active cloned serotonin 5-HT 6 receptors order pK i >8.0, or about 10 nm, and according to the source WO 2005/026125 even less, about pK i >7.0, or about 100 nm. Our study of these ligands have shown that they are multimodal ligands and along with the 5-HT 6 receptors are active to a number of other receptors. So, SB-742457 (I), in conditions of the competitive at a concentration of 1 mmol l -1 (figure 1) along with the 5-HT 6 receptors (103%) shows a significant activity in relation to other serotonin (5-HT 1B (87%), 5-HT 2A (99%), 5-HT, 2B (99%), 5-HT 2C 86%)and nonselective adrenergic β receptors (74%) [A.V. Ivaschenko, .., ... Pharmacological activity of SB-742457. All-Russian scientific conference (with international participation): «the Success of synthesis and complexation». Theses of reports. Part 1. Section «Organic chemistry». P.118. M: RPFU, 2012. 312 S.].
Methyl-(8-piperazine-1-Il-3-phenylsulphonyl-chinoline-4-yl)amine (II AVN-562) on the panel, including 33 receptor (figure 2), in conditions of the competitive binding showed a wide spectrum of pharmacological activity. This multimodal ligand II has activity in relation to serotonin 5-HT 6
( I C 50 b = 0,116 n m about l ü Buna l - 1 )and 5-HT 2A
( I C 50 b = 0,318 n m about l ü Buna l - 1 )receptors and activity in relation to serotonin 5-HT 2B
( I C 50 b = 33 n m about l ü Buna l - 1 ), 5-HT 2C
( I C 50 b = 25 n m about l ü Buna l - 1 ), 5-HT, 7
( I C 50 b = 537 n m about l ü Buna l - 1 ), adrenergic α 2A
( I C 50 b = 177 n m about l ü Buna l - 1 ) , a 2B ( I C 50 b = 321 n m about l ü Buna l - 1 ) , a 2C ( I C 50 b = 951 n m about l ü Buna l - 1 ) , beta 1 ( I C 50 b = 668 n m about l ü Buna l - 1 ), dofaminovym D 1
( I C 50 b = 748 n m about l ü Buna l - 1 ) , D 2S ( I C 50 b = 298 n m about l ü Buna l - 1 ), histamine H 3
( I C 50 b = n m about l ü Buna l - 1 n M )and the Central I 2
( I C 50 b = 292 n m about l ü Buna l - 1 )receptors [A.V. Ivaschenko, .., ... Synthesis and pharmacological activity of methyl-(8-piperazine-1-Il-3-phenylsulphonyl-chinoline-4-yl)-amine. All-Russian conference «Organic synthesis chemistry and technology». Book of abstracts. C-62. Ekaterinburg, 2012].
N(4),N(8),N(8)-trimethyl-3--4,8-diamine (III) in conditions of the competitive binding on the panel, including 35 receptors (figure 3), showed, along with the activity in relation to the 5-HT 6 receptors
( K i b = 0,11 n m about l ü Buna l - 1 , K i f = 0,33 n m about l ü Buna l - 1 ), activity in relation to the 5-HT 2A P
( K i b = 24 n m about l ü Buna l - 1 ), 5-HT 2B P
( K i b = 18 n m about l ü Buna l - 1 )and 5-HT 2C P
( K i b = 270 n m about l ü Buna l - 1 )[.V.Ivachtchenko a,b , .G.Kadieva 3 , .D.Mitkin a , І.. b . 3D structure, docking and pharmacophore doesn models of 3-phenylsulfonylquinolin-4,8-diamines - antagonists of serotonine 5-HT 6 receptor (5-HT 6 R). The 6 th International Conference "Chemistry of nitrogen containing heterocycles" (CNCH-2012), 12-16 November, 2012, Kharkiv, Ukraine].
Mainly known derivatives of quinoline, having or deputies in the 8th position fragment disclosed in the sources of US 2007/0027161, WO 2003/080580, WO 2005/026125, WO 2005/113539 for stating in the properties affinity for serotonin 5-HT 6 receptors, but this property for them as disclosed in the experimental data.
From the source WO 2006/053785 known derivative quinoline with Deputy GSK215083 (IV), manifesting high activity (pK i =9,82) to serotonin 5-HT 6 receptors, which, however, demonstrates high activity also in relation to the 5-HT 2B and in relation to the 5-HT 2A (pK i =9,14). Furthermore connection GSK215083 was investigated at the panel of only 11 receptors and contains radioactive isotope labelled group.
Also known from a source WO 2007/039220 derivatives of quinoline, General formula V used as selective modulators of cannabinoid CB2 receptors,
where R 1 =, , or pyridyl; R 2 =halogen, -CN-CF 3 , -OCF 3 , -OCHF 2 , C 1-3 alkyl, C 1-3 alkoxy, -CO 1-3 alkyl, -NR 5 R 6 , R-5 and R 6 =N or With 1-3 alkyl; X=-(CR 7 R 8 )m-; R 7 and R 8 =N or C 1-3 alkyl; m=1-4; n=0-3; R3 and R4=N, halogen, -CN-CF 3 , -OCF 3 , -OCHF 2 , WITH 1-3 alkyl, C 1-3 alkoxy, SOS 1-3 alkyl, -NR 5 R 6 , -CONR 5 R 6 ;
A is aryl, , aryl-aryl -, aryl-.
With the aim of developing new highly effective medicinal preparations of the authors of this invention performed extensive research in a number of substituted quinoline derivatives, resulting found new high-performance and more selective antagonists of 5-HT 6 receptors.
Below are definitions of terms used in the description of the invention:
«Agonists» means ligands that binds with the receptor of this type, actively contribute to the transfer of these receptors to their inherent specific signal and thereby cause a biological cell response.
«» means aromatic or or system containing in the cycle, at least, one nitrogen atom. can have one or more «deputies cyclic system». «Alkyl» means hydrocarbon linear or branched group 1-12 carbon atoms in the chain. Preferred alkyl groups are methyl, ethyl, n-propyl, ISO-propyl, .
«» means C n H 2n+1 NH or (C n H 2n+1 )(C n H 2n+1 )N the group that alkyl defined in this section. Preferred groups are metilamino, , n-, and ISO-.
«Amino group» means
R k a R k + 1 a N-group, substituted or unsubstituted not necessarily the same «alternates amino group»
R k a and R k + 1 a, the value of which is defined in this section, for example, amino (H 2 N), metilamino, , , , piperazine derivatives, or . «Anxiolytic» or «Tranquilizer» means a drug intended for the treatment of anxiety disorders.
«Antagonists» means ligands that bind to the receptors of a certain type and does not induce an active immune response. Antagonists prevent the binding with the receptor agonists and thereby block the transmission of specific receptor signal.
«Antidepressant» means a drug designed to treat depression.
«Antipsychotic» means a drug intended for the treatment of psychotic disorders.
«Aryl» means aromatic or system, including from 6 to 14 carbon atoms, from 6 to 10 carbon atoms. Aryl may contain one or more «deputies cyclic system», which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be with non-aromatic cyclic system or a heterocycle. «» means aryl-SO 2-group in which the value of aryl defined in this section.
«Halogen» means fluorine, chlorine, bromine and iodine. Preferred include fluorine, chlorine and bromine.
«» means aromatic or or system containing in the cycle, at least one heteroatom. can have one or more «deputies cyclic system».
«Hydrate» means in which water is a molecule or molecules of the solvent.
«Depression» means great depression; a cameo, chronic and relapsing forms of major depression; disorder (); ; affective disorders; syndrome of seasonal affective disorder; bipolar disorder, including bipolar disorder type I and II; and other depressive disorders and conditions. The term depression also means depression that accompany Alzheimer's disease, vascular dementia; mood disorders, alcohol-induced and substances; disorder, depressive type; disorder. In addition, depression involves a depressive status of cancer patients; Parkinson's disease; depression following myocardial infarction; depression infertile women; pediatric depression; postpartum depression; and other depressive state, accompanying somatic, and other diseases.
«Deputy» means chemical radical who joins (fragment), for example, «Deputy », «the Deputy amino group», «Deputy aryl», «the Deputy whose values defined in this section.
«Deputy amino group» means the Deputy attached to an amino group. Deputy amino group is a hydrogen alkyl, cycloalkyl, aryl, , , acyl, , alkylsulfonyl, , , , , , , , , , , , , , , , , , , , , .
«Deputy aryl or » means the Deputy attached to or , including hydrogen alkyl, , , aryl, , , , , , , the amino group, , alkoxy, , acyl, , halogen, nitro group simultaneously, cyano group, , , , , , , , , -, alkylsulfonyl, , , , , , , , , , , , , , , , , , , , , , cycloalkyl, , , , ,
R k a R k + 1 a N - , R k a N = , R k a R k + 1 a N - and l to and l -, R k a R k + 1 a N C ( = O ) - or R k a R k + 1 a N S O 2 - , where R k a and R k + 1 aare independent of each other «deputies amino group, the value of which is defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted or optionally substituted , or Deputy
R k a R k + 1 a N - , where R k acan be acyl or , and the value of
R k + 1 adefined above, or «Deputy cyclic system» are
R k a R k + 1 a N C ( = O ) - or R k a R k + 1 a N S O 2 - , where R k a and R k + 1 atogether with nitrogen atom with which they are associated, formed through
R k a and R k + 1 a4-7 membered or .
«Cognitive disorders or cognitive impairment (cognitive disorder)» means the violation (weakening) of the mental capabilities, including attention, memory, thinking, perception, learning, speech, thought, Executive and creative skills, orientation in time and space, in particular, cognitive disorders associated with Alzheimer's disease, Parkinson's disease and ; senile dementia; age-related memory disorders (age-associated memory impairment, AAMI); encephalopathy; psychogenic memory impairment; amnesia; disorders; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive impairment, MCI); syndrome of the attention with hyperactivity (attention deficit hyperactivity disorder (AD/HD), cognitive impairment, accompanying a psychotic illness, epilepsy, deliri, autism, psychosis, down syndrome, bipolar disorder and depression; AIDSassociated dementia; dementia when hypothyroidism; dementia induced by alcohol, addictive substances, and neurotoxins which; dementia accompanying neurodegenerative diseases, for example, degeneration and amyotrophic lateral sclerosis; cognitive disorders, developing of stroke, infectious diseases and cancer of the brain, and with traumatic brain injuries; cognitive impairment associated with autoimmune and endocrine diseases; and other cognitive disorders.
«Medicinal beginning» (drug substance, drug, drug-substance) means of physiologically active substance synthetic or another (biotechnology, plant, animal, microbial or other origin, possessing the pharmacological activity and being proactive pharmaceutical composition used for the manufacturing of medicinal product (drug).
«Medication (drug)a substance (or mixture of substances in the form of pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready-made forms, intended for recovery, repair or modifying physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others. «Ligands» (from the Latin ligo - bind) are chemical substances (small molecule, inorganic ion, peptide protein and other), capable of interacting with receptors that transform this interaction in a specific signal.
«Nootropics» or «», they neirometabolicescie stimulants - the substance is taken to improve mental abilities.
Mental disorders (mental illness) is a disease or conditions associated with the violation and/or disorder of the mind. Mental disorders include affective disorders (bipolar affective disorder, major depression, , small depression, maniakalny syndrome, the syndrome of Kotar, , schizoaffective disorder and other); intellectually-mnestic disorder, mania (, , kleptomania, persecution mania, , , and others); multiple personality disorder, , white runs, crazy, crazy syndrome, hallucinatory syndrome, hallucinations, Bazaar, , deliri, illusion, , clinical , , Manichean delirium, , drug addiction, nervous anorexia, oniric syndrome, , paranoia, , , psychosis, syndrome Kotar, schizoaffective disorder, disorder, schizophrenia, disorder, disorder, syndrome Schreber, Daniel Paul); phobias (, , , , , , , , , claustrophobic, , xenophobia, , , photophobia, , , , , , ); alcoholic psychosis, alcohol palimpsest, , , , dissociative Fugue, dissociative disorders, restlessness, Internet addiction, , hysteria, , the mania of persecution, melancholy, misanthropy, , panic attack, Asperger syndrome, Capgras syndrome, Munchausen syndrome, rett syndrome, syndrome , attention deficit and hyperactivity disorder, syndrome obsessions syndrome consequences of chronic anesthesia syndrome psychic automatism, syndrome of early children's autism, delirium, , anxiety syndrome , and other
«Psychotic illness» are all kinds of schizophrenia; disease; disorders; disorders, including bipolar and depressive types; delusional disorder, including brad relationship, prosecution, greatness, jealousy, , and hypochondriac, somatic, mixed and nonsense; short-term psychotic disorders; induced psychotic disorder; induced substances psychotic disorder; and other psychotic disorders.
«Receptors» (from the Latin recipere - receive, to learn) are biological macromolecules, located on the plasma membrane of the cell or intracellularly, capable to interact specifically with a limited set of physiologically active substances (ligands) and transform the signal about this interaction to a particular cell response.
«Anxiety disorders» (anxiety) means generalized (may become vague) anxiety; acute uncontrolled anxiety, panic disease; phobias, such as agoraphobia (strong fear of crowded places or social phobia (strong fear of humiliation in front of others) or any specific phobia (strong fear of specific objects, animals or situations, in the form of the fear of height, medical procedures, lifts, open space, etc); the obsessions (obsessive compulsive disorder); stress disorder, acute stress disorder. In addition to disturbing disorders include anxiety, alcohol-induced or substances; anxiety disorders adaptation; and mixed forms of anxiety disorders and depression.
«Schizophrenia» means all known types, forms and variants of the disease, including: simple, , , (), , , residual or schizophrenia and/or form of schizophrenia, defined in the classification of the American Psychiatric Association (American Psychiatric Association; in: Diagnostic and Statistical Manual of Mental Disorders, IV Edition, Washington D.C. 2000) or the International classification (International Statistical Classification of Diseases and Related Health Problems), or any other known forms.
«Pharmaceutical composition» refers to a composition, which includes the connection formula 1 and at least one of the components selected from the group consisting of pharmaceutically and pharmacologically compatible fillers, solvents, thinners, media, support, distribution and receiving facilities, means of delivery, such as, preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the ratio depends on the nature and method of dosage. Examples agents are ethoxylated alcohol, polyoxyethylene, sorbitol and ether, microcrystalline cellulose, aluminium, bentonite, agar-agar and tragakant, and mixtures of these substances. Protection from the action of microorganisms can be achieved by a variety of antibacterial and antifungal agents, such as parabens, , sorbic acid and similar compounds. Composition may also include isotonic agents, for example, sugar, sodium chloride and similar. Prolonged action of the composition can be achieved through agents that slow the absorption of the active principle, for example, monostearate aluminium and gelatin. Examples of suitable media, solvents, thinners and means of delivery are water, ethanol, and their blends, vegetable oils such as olive oil) and inject organic esters (such as etiloleat). Examples fillers are lactose, lactose, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributing funds are starch, acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal introduction of the active principle, single or in combination with other active beginning, can be introduced animals and people in a standard form of the introduction, in the form of a mixture with traditional pharmaceutical carriers. Suitable standard forms of administration include oral forms, such as tablets, capsules, pills, powders, granules, gums and oral solution or suspension, sublingwale and transbukkalnye forms of introduction, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of introduction, and rectal form of introduction. Pharmaceutical compositions, as a rule, receive with the help of standard procedures that provide for mixing of the active connection with liquid or finely shredded hard carrier.
dimethyl-(3-naphthalene-1--chinoline-8-yl)amine 1.6,
dimethyl-(3-naphthalene-2--chinoline-8-yl)amine 1.7,
diethyl-(3-naphthalene-1--chinoline-8-yl)amine 1.8, and
diethyl-(3-naphthalene-2--chinoline-8-yl)amine 1.9.
(3--chinoline-8-yl)amine General formula 1 receive recovery by reductive amination formaldehyde or 3--8- General formula 2 according to the following scheme:
It should be noted that new compounds of General formula 1, where R=Me, or Et, have a particularly high antagonistic activity towards 5-HT 6 receptors. In particular connection 1.1 (R=Me, Ar=Ph) in terms of functional analysis activity relative to the 5-HT 6 R has
p K i f = 9,7, while in the same conditions obtained connections 2.1 (also corresponding formula 1, where R=H, Ar=Ph) with
p K i f = 7,16and connections 4.1 (also corresponding formula 1, in which one of R=H, and the other R=Me and Ar=Ph) with
p K i f = 7,09inferior connection 1.1 activity 2 orders.
Compounds of General formula 1 have a high selectivity of the interaction of 5-HT 6 receptors. For example, compounds 1.1 in conditions of the competitive linking [I. Okun, S.E. Tkachenko, A. Khvat, O. Mitkin, V. Kazey, A.V. Ivachtchenko. From Anti-allergic to Anti-Alzheimer's: Molecular Pharmacology of Dimebon™. Current Alzheimer Research, 2010, 7, 97-112] on the panel, including 35 receptor (figure 4)demonstrates along with high activity in relation to the 5-HT 6 receptors only some activity and even relative to the 5-HT 2 in .
The data presented in table 1 clearly show a higher selectivity of interaction of compounds 1.1 compared with selectivity known ligands SB-742457 (I), AVN-562 (II) and III, pharmacological profiles of activity which are presented on figures 1-3.
The subject of the present invention are also selective antagonists of serotonin 5-HT 6 receptor, representing compounds of General formula 1, their crystalline forms polycrystalline forms, pharmaceutically acceptable salts and/or hydrates.
The subject of this invention are also compounds of General formula 1, their crystalline forms polycrystalline forms, pharmaceutically acceptable salts and/or hydrates as a medicinal beginning to pharmaceutical compositions and medicines.
The subject of the invention is a medicinal beginning to pharmaceutical compositions and medicines, representing at least one selective antagonist 5-HT 6 receptor, which is a compounds of General formula 1, their crystalline forms polycrystalline forms, pharmaceutically acceptable salts and/or hydrates.
The subject of the invention is also a pharmaceutical composition for the treatment and prevention of conditions and disorders of the CNS humans and warm-blooded animals, the pathogenesis of which is associated with 5-HT 6 receptors containing pharmaceutically effective number of new medicinal beginning, which represents at least one connection with the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate.
Pharmaceutical composition may include pharmaceutically acceptable . Under pharmaceutically acceptable means used in the pharmaceutical industry thinners, auxiliary agents and/or media. Pharmaceutical composition along with the medicinal beginning of the present invention can also include other , provided that they do not cause unwanted effects, such as allergic reactions.
If necessary, the use of pharmaceutical compositions of the present invention in clinical practice may be mixed for the manufacture of various forms and they can be composed of traditional pharmaceutical media; for example, oral forms (such as tablets, capsules, pills, solutions or suspensions); forms for injection (such as, solvents, or suspension for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms (such as, ointments or solutions).
The media used by the pharmaceutical compositions of the present invention, are carriers, which are used in the pharmaceutical industry for obtaining of common forms, including: in oral forms are in use binding agents, lubricating agents, disintegrator, solvents, thinners, stabilizers, agents, colorless agents, taste; forms for injection are used antiseptic agents, soljubilizatory, stabilizers; in local forms are in use bases, solvents, lubricating agents, antiseptic agents.
The subject of the invention is also a way to get a new pharmaceutical compositions mixed with inert filler and/or solvent medicinal beginning, which represents at least one of the compounds of the General formula 1 or crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate.
The subject of the invention is a drug in the form of pills, capsules or injection are placed in a pharmaceutically acceptable packaging, for the prevention and treatment of diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT 6 receptors in warm-blooded animals and people, representing at least one of the compounds of the General formula 1 or crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate.
Is the preferred remedy in the form of pills, capsules or injection are placed in a pharmaceutically acceptable packaging, for the prevention and treatment of Alzheimer's disease, Parkinson's disease, illness , including pharmaceutically effective number of new medicinal beginning, which represents at least one of the compounds of the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate, or a pharmaceutical composition containing the new medicinal beginning.
The subject of the invention is also the drug in pill form, capsules or injection are placed in a pharmaceutically acceptable packaging, for the prevention and treatment of mental disorders and schizophrenia, including pharmaceutically effective number of medicinal beginning, which represents at least one of the compounds of the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate, or a pharmaceutical composition containing the new medicinal beginning.
Is the preferred drug anxiolytic or tranquilizer) for the prevention and treatment of anxiety disorders, including pharmaceutically effective number of medicinal beginning, which represents at least one of the compounds of the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate, or a pharmaceutical composition containing the new medicinal beginning.
Is the preferred medication () for the prevention and treatment of hyperkinetic disorders, in particular, to improve mental abilities, including pharmaceutically effective number of medicinal beginning, which represents at least one of the compounds of the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate, or a pharmaceutical composition containing the new medicinal beginning.
The subject of the invention is also therapeutic cocktail for the prevention and treatment different diseases pathogenesis of which is associated with 5-HT 6 receptors in animals and people, including medicinal product in the form of pills, capsules or injection are placed in a pharmaceutically acceptable packaging, including pharmaceutically effective number of medicinal beginning, which represents at least one of the compounds of the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate, or a pharmaceutical composition containing the new medicinal beginning.
The subject of the invention is also therapeutic cocktail for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases among animals and people, including for the prevention and treatment of Alzheimer's disease, Parkinson's disease, illness , mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive States, brain injury, , lateral amyotrophic lateral sclerosis, obesity and stroke, including pharmaceutically effective number of medicinal beginning, which represents at least one of the compounds of the General formula 1, its crystal form, polycrystalline form, pharmaceutically acceptable salt and/or hydrate, or a pharmaceutical composition containing the new medicinal beginning.
Therapeutic cocktails for prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases among animals and people, including for the prevention and treatment of Alzheimer's disease, Parkinson's disease, illness , mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive States, brain injury, , lateral amyotrophic lateral sclerosis and stroke, along with drugs at the present invention may include other medicines such as non-steroidal anti-inflammatory drugs (, Indomethacin, Ibuprofen, etc); inhibitors of acetylcholinesterase (, Amiridin, Physostigmine, , Phenserine etc); estrogens (e.g., Estradiol); antagonist of the NMDA receptor (for example, Memantine, Neramexane); nootropic drugs (for example, Piracetam, Phenibut etc); modulators AMPA receptors (for example, Ampalex); cannabinoid receptor antagonists DM-1 (for example, Rimonabant); monoamine oxidase inhibitors of MAO-A and/or MAO-A (for example, Rasagiline); drugs (e.g., Tramiprosate); substance reduce neurotoxicity of amyloid-beta (for example, Indole-3-propionic acid); inhibitors of gamma and/or beta-; muskarinovykh receptors agonists Ml (for example, Cevimeline); metals (for example, Clioquinol); antagonists GABA(A) receptors (for example, CGP-36742); monoclonal antibodies (for example, Bapineuzumab); antioxidants; neurotrophic agents (for example, Cerebrolysin); antidepressants (e.g., Imipramine, Sertraline etc) and other.
In accordance with the present invention method of prevention and treatment of various diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT 6 receptors in animals and humans, is the introduction of a pharmaceutically effective number of new medicinal beginning of a new pharmaceutical composition, a new drug or a new therapeutic cocktail.
Drugs can be administered orally or parenterally (for example, intravenous, subcutaneous and intraperitoneal or local). Clinical dosage medicinal beginning (substance), pharmaceutical composition or medicinal product, including pharmaceutically effective number of medicinal beginning, patients may be adjusted according to therapeutic effectiveness and bioavailability of the active ingredients in the body, their rate of metabolism and excretion from the body, and also depending on the age, sex, and stage of the disease, patient, with a daily dose in adults is usually 2-about 500 mg, preferably 50 Hz to 300 mg Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units must take into account the above mentioned effective dosage, each unit dose should contain 2 about 500 mg, preferably 2 of 300 mg In accordance with the instructions of the doctor or pharmacist these drugs can be taken several times during certain periods of time (preferably from one to six times).
The invention is illustrated by drawings.
Fig 1. The spectrum of pharmacological activity 1 mmol l -1 SB-742457 (I) in conditions of the competitive binding on the panel, including 33 receptor.
Figure 2. The spectrum of pharmacological activity methyl-(8-piperazine-1-Il-3-phenylsulphonyl-chinoline-4-yl)amine (II AVN-562) in conditions of the competitive binding on the panel, including 33 receptor.
Figure 3. The spectrum of pharmacological activity N(4),N(8),N(8)-trimethyl-3--4,8-diamine (III) in conditions of the competitive binding on the panel, including 35 receptor.
Figure 4. The spectrum of pharmacological activity dimethyl-(3--8-yl)amine (1.1) in terms of a competitive binding on the panel, including 35 receptor.
Figure 5. Improve memory in male mice of BALB/c, impaired , under the influence of connection 1.1 and drug comparison (memantine) in the test of «Passive avoidance of mice in the Shuttle chamber». Time through which animals do the first set in a dark chamber. Unlike scopolamine: * LS-Fisher test.
6. Improve memory in male mice of BALB/c, impaired , under the influence of connection 1.1 and drug comparison (memantine) in the test of «Passive avoidance of mice in the Shuttle chamber». The time during which the animals are kept in light camera. Unlike scopolamine: * LS-Fisher test.
Fig.7. Improve memory in male mice of BALB/c, impaired , under the influence of connection 1.1 and drug comparison (memantine) in the test of «Passive avoidance of mice in the Shuttle chamber». Number of visits in a dark chamber. Unlike scopolamine: * LS-Fisher test.
Fig.8. Influence of compounds 1.1 on braking wince in response to acoustic stimulus. Unlike apomorphine: * LS-test Fisher; & - Chi-square.
Fig.9. Duration of depressive-like behavior and swimming mice in the center and on the periphery of the basin in the test (average±standard error) after the introduction of mice for 4 days at a dose of 1 mg/kg connection. Contrast to groups placebo group: * - p<0.05.
The examples below illustrate, but are not limited to the invention.
Dimethyl-(3--8-yl)amine 1.1 LC-MS (M+1) 313. 1 H NMR spectrum (DMSO-D6 ), coth ppm: 9,15 (1H), 8,96 (1H), 8,07 (d, J=7.6 Hz, 2N), 7,67 (m, 4N), 7,56 (t, J=7.6 Hz, 1H), 7,22 (m, 1H), 3,09 (s, 6N). Dimethyl-[3-(3-)-chinoline-8-Il]-Amin 1.2 LC-MS (M+1) 347. Dimethyl-[3-(3-)-chinoline-8-Il]-Amin 1.3 LC-MS (M+1) 331. Diethyl-(3-phenylsulphonyl-chinoline-8-yl)amine 1.4 LC-MS (M+1) 341. Diethyl-[3-(3-)-chinoline-8-Il]-Amin 1.5 LC-MS (M+1) 375. Dimethyl-(3-naphthalene-1--chinoline-8-yl)amine 1.6 LC-MS (M+1) 363. Dimethyl-(3-naphthalene-2--chinoline-8-yl)amine 1.7 LC-MS (M+1) 363. Diethyl-(3-naphthalene-1--chinoline-8-yl)amine 1.8 LC-MS (M+1) 391. Diethyl-(3-naphthalene-2--chinoline-8-yl)amine 1.9 LC-MS (M+1) 391.
Example 2. Definition of antagonistic activity of compounds of General formula 1 in relation to the 5-HT 6 receptors. Compounds of General formula 1 were tested for their ability to inhibit activation of 5-HT 6 serotonin receptors. 5-HT 6 receptor was sub-cloned into a vector T-Rex (Invitrogen, Carlsbad, CA), which, in turn, was expressed in cells of NEK-293 (5-HT 6 R-HEK). The cells were grown in an incubator at 37 C in an atmosphere of 5%95% CO 2 :air (100% humidity) in the T-175 culture vials in the environment supplemented with 10% FBS 1% AAS, blasticidine S, and zeocin (all reagents were purchased in Invitrogen, Carlsbad, CA). Expression of 5-HT 6 receptors activated by adding a solution of tetracycline (1 mcg/ml) in accordance with the recommendations of the manufacturer of T-Rex vector. Tetracycline added a day before the start of the experiments. On the day of experiments, the cells were transferred to the suspension of the short-term treatment (5-10 min) 6 mm EDTA, washed HBSS saline environment and besieged by centrifugation at 1000 rpm for 6 minutes. , Which is formed to a Deposit cells added environment without serum and the number of cells was determined by using a camera Goryaeva. Cells resuspended to the concentration of 0.67 x 10 6 in Б2 buffer, consisting of HBSS with the addition of 5 mM HEPES, pH 7.4, 0.05% BSA, 1 mM IBMX (SigmaAldrich, St. Louis, MO) and Alexa Fluor 647-anti cAMP antibody (PerkinElmer, Waltham, MA). On 6 MKL of cell suspension (about 4000 cells per well) was transferred into the wells of the 384-hole dies (PerkinElmer White OptiPlate). Compound in different concentrations were previously mixed with (Sigma, MO) and these solutions (6 ml) were added using BIOMEK NX in the cells that contain the cell suspension in the environment Б2 (final concentration: serotonin - 10 nm, DMSO - 0.32%, IBMX - 500 microns). Each die, in addition, contain different concentrations of serotonin and camp for calibration curves. After 2 hours of incubation with mixes of serotonin/connection test, the cells were treated in accordance with the Protocol annexed to the test set cAMP LANCE (PerkinElmer, Waltham, MA). LANCE signal was measured using multimodal spot reader VICTOR 3 (PerkinElmer, Waltham, MA), using the built-in algorithm to LANCE detection. Dependence of cell responses to serotonin in the presence of different concentrations of the test compounds and the calculation of the concentrations inhibition (IC 50 ) conducted on the basis of 4-parametric equations using Prism 5 (Graph-Pad, CA). All experiments were performed in duplicate. Standard deviation (SD) were calculated using the built-in Prisms of statistical analysis. Values of the constants of inhibition
K i ffor blocking the 5-HT 6 receptors in the functional test was calculated using the modified equation Chiang [31]:
K i f = I C 50 / ( 1 + [ A g ] ) / E C 50 )where IC 50 is the concentration antagonist, causing 50% blockade induced by the serotonin cell response; [Ag] is the concentration of serotonin (10 nm), which was measured cellular response, and the EU 50 is the concentration of serotonin, causing 50% of the maximum cellular signal, calculated by reference to the serotonin curve. According to 4 independent experiments conducted in different days in 4-5 repetition (different die measured in each day), the average EU 50 5-HT 6 R NECK cells was equal to 1.91±0.13 nm.
Table 2Antagonistic activity K i compounds of General formula 1 in relation to serotonin 5-HT 6 receptors
No.Formula antagonist
K i , nM 1.1dimethyl-(3-phenylsulphonyl-chinoline-8-yl)amine
0,31 1.2dimethyl-[3-(3-)-chinoline-8-Il]-Amin
0,95 1.3dimethyl-[3-(3-)-chinoline-8-Il]-Amin
0,29 1.4diethyl-(3-phenylsulphonyl-chinoline-8-yl)amine
0,57 1.5diethyl-[3-(3-)-chinoline-8-Il]-Amin
1,05 1.6dimethyl-(3-naphthalene-1--chinoline-8-yl)amine
0,73 1.7dimethyl-(3-naphthalene-2--chinoline-8-yl)amine
0,61 1.8diethyl-(3-naphthalene-1--chinoline-8-yl)amine
1,92 1.9diethyl-(3-naphthalene-2--chinoline-8-yl)amine
1,61As seen in the table 2 data, tested compounds show high antagonistic activity towards serotonin 5-HT 6 receptors.
Example 3. Obtaining of medicinal product in the form of tablets. Mix 1600 mg starch, 1600 mg of powdered lactose, 400 mg talc and 1000 mg connection 1.1 and pressed in the bar. The resulting block is crushed in granules and sift through a sieve, collecting granules in the size 14-16 mesh. The received granules tabletirujut in a suitable form pills weight of 560 mg each.
Example 6. Nootropic action (improving memory impaired ) compounds of General formula 1 testing «Passive avoidance of mice in the Shuttle chamber». Used the Shuttle Luggage (Ugo Basile, Italy), which consisted of two compartments. All walls are one of the compartments were opaque, and the second compartment was the transparent cover. Compartments connected hole, which could be closed vertical door. The floor was made, and transverse metal rods, which could be pulsed DC. Experiments conducted on adult male mice of BALB/c weight 20-24,
On the first day of the experience of 30 minutes prior to training mice intraperitoneally injected with a saline solution, scopolamine (0.3 mg/kg), or scopolamine in conjunction with the connection 1.1. Each group will be used not less than 8 animals. The animals were placed in a compartment light and registered a latent period of the first entry in a dark chamber. The door between the compartments closed, and the animal within 3 seconds received punishment current of 0.6 mA. After that the animal is returned in a living cell. Through 22-24 hours animal again placed in the compartment light Shuttle camera and recorded the latent period of the first entry in the dark compartment, the total time of stay in the bright compartment, and the number of visits in the dark compartment. The duration of observations was 5 minutes.
The experiment was carried out during daylight hours in an isolated laboratory room using a white noise intensity is about 70 dB above the threshold of audibility person.
Scopolamine causes a violation of training (memory), which is expressed in the form of increase of the latent period of the 1st call in the dark compartment, increasing the time spent in the bright compartment and reducing the number of visits in the dark compartment.
The ability of a joint 1.1 improve training breached , is seen as evidence of them nootropic action. The results (figure 5-7) demonstrate the capacity of the connection 1.1 to more effectively nootropic action.
Example 7. activity of the compounds of the General formula 1 testing « braking wince in mice». In our experiments we used mice SHK mass 24-30 . conducted in light time of the daily cycle of animals. Apomorfina hydrochloride and haloperidol were obtained from Sigma chemicals, USA. Apomorfina hydrochloride dissolved in 0.1% solution of ascorbic acid, prepared on sterilised water, and was administered subcutaneously 15 minutes before the test. Haloperidol was dissolved in sterile water using the emulsifier tween 80 and were injected 60 minutes before the test. Connection 1.1 was dissolved in sterile water and injected subcutaneously 60 minutes before the test. The amount of fluid given was 10 ml/kg of the Control animals were treated 0,1%» solution of ascorbic acid, cooked-to-sterilized water with 80.
Apparatus consisted of a camera, made of transparent Plexiglas (manufacturer - company Columbus Instrument, USA), located on the platform, which was inside of the Cabinet of soundproofing. 2 cm from the platform was high frequency sound column, through which the transmitted acoustic stimuli. When animal there were fluctuations platform that analog Converter and were registered by the computer. Background noise level was 65 dB. The animals received on 4 presentation of a single tester («pulse») stimulus duration of 50 MS and volume 105 dB or pending («pre-pulse») stimulus duration of 20 MS, volume 85 dB, followed by 30 MS pulse followed stimulus duration of 50 MS volume of 105 dB. The interval between repeated presentations pulse or pre-pulse in conjunction with the pulse of incentives was 10 C. the Weakening of the jerks in response to a pulse stimulus in the presence of pre-pulse incentive calculated as a percentage relative to the amplitude of the jerks in response to an isolated pulse stimulus. Introduction of apomorphine, which is used in experiments on animals for modeling -related conditions, caused a decrease braking wince, which reflects a decline in the ability of the Central nervous system filter sensory stimuli. The experimental results show (Fig.8), haloperidol (1 mg/kg) and investigated the connection 1.1 (1 mg/kg) warned violation braking wince at introduction of apomorphine.
1. (3--8-yl)-dialkyl-amines General formula 1 or pharmaceutically acceptable salts
where Ar represents phenyl, optionally substituted in position 3 halogen atom, or naphthyl, R 1 and R 2 are loose methyl or ethyl.
2. Connection according to claim 1, representing dimethyl-(3-phenylsulphonyl-chinoline-8-yl)amine 1.1, dimethyl-[3-(3-)-chinoline-8-Il]-Amin 1.2, dimethyl-[3-(3-)-chinoline-8-Il]-Amin 1.3, diethyl-(3-phenylsulphonyl-chinoline-8-yl)amine 1.4, diethyl-[3-(3-)-chinoline-8-Il]-Amin 1.5, dimethyl-(3-naphthalene-1--chinoline-8-yl)amine 1.6, dimethyl-(3-naphthalene-2--chinoline-8-yl)amine 1.7, diethyl-(3-naphthalene-1--chinoline-8-yl)amine 1.8, diethyl-(3-naphthalene-2--chinoline-8-yl)amine 1.9.
3. Selective antagonist of serotonin 5-HT 6 receptor, which is a compound of the formula 1, or pharmaceutically acceptable salts on any of claim 1 or 2.
4. Medicinal beginning to pharmaceutical compositions and medicines, representing at least one selective antagonist of serotonin 5-HT 6 receptors on p.3.
5. Pharmaceutical composition, possessing properties antagonist of serotonin 5-HT 6 receptor, for the treatment and prevention of conditions and disorders of the Central nervous system, the pathogenesis of which is associated with 5-HT 6 receptors containing pharmaceutically effective number of medicinal beginning of claim 4, inert filler and/or solvent.
6. The drug is in the form of tablets, capsules or injection are placed in a pharmaceutically acceptable packaging, for the prevention and treatment of diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT 6 receptors, including pharmaceutically effective number of medicinal beginning of claim 4 or pharmaceutical composition according to claim 5.
7. Medicine 6 for the prevention and treatment of cognitive disorders and neurodegenerative diseases.
8. Medicine 6, has anxiolytic activity for the prevention and treatment of anxiety disorders.
9. Medicine 6, possessing nootropic activity, to improve mental abilities.
10. The method of treatment or prevention of diseases of the Central nervous system of humans or animals, the pathogenesis of which is associated with 5-HT 6 receptors, which consists in the enactment of the effective number of medicinal beginning of claim 4, or pharmaceutical composition according to claim 5, or medicinal product on any of p.6-9.