In continuation of research and development of new high-efficacy drugs based on 5-HT6 receptor antagonists for the treatment of CNS disorders, we synthesized a series of new 3-(phenylsulfonyl)quinoline derivatives, performed their molecular docking, and studied the receptor activity spectrum. It was found that the antagonist activity of the 3-(phenylsulfonyl)quinolines with respect to 5-HT6 receptors depended on the nature of the 4- and 8-substituents of the heterocycle. It was expedient for high activity of this type to introduce a tertiary nitrogen atom (dimethylamine or piperazine fragment) in the 8-position and a secondary nitrogen (methylamine fragment) or hydrogen in the 4-position. The most promising compounds were N,N-dimethyl-3-(phenylsulfonyl) quinoline-8-amine (IV, K (i) (f) = 0.4 nM), 4-methylamino-8-dimethylamino-3-(phenylsulfonyl)quinoline (XXII, K (i) (f) = 0.3 nM), and N-methyl-8-(piperazin-1-yl)-3-(phenylsulfonyl)quinoline-4-amine (XXIII, K (i) (f) = 0.9 nM). Antagonist IV exhibited the maximum selectivity; XXIII, the maximum multimodality.

В продолжение поиска и разработки новых высокоэффективных лекарственных кандидатов — антагонистов 5-HT6 рецепторов для лечения заболеваний центральной нервной системы (ЦНС) нами синтезирован ряд новых производных 3-(фенилсульфонил)хинолина, осуществлен молекулярный докинг и изучен спектр их рецепторной активности. Установлено, что антагонистическая активность 3-(фенилсульфонил)хинолинов по отношению к 5-HT6 рецепторам зависит от природы заместителей в положениях 4 и 8 гетероцикла. Для проявления изучаемого вида высокой активности целесообразно наличие в положении 8 третичного атома азота (в данном случае — фрагмент диметиламина или пиперазина), а в положении 4 — вторичного азота (фрагмент метиламина) или водорода. Наиболее перспективными явились N,N-диметил-3-(фенилсульфонил)хинолин-8-амин (IV, Kif = 0,4 нМ), 4-метиламино-8-диметиламино-3-(фенилсульфонил)хинолин (XXII, Kif = 0,3 нМ), N-метил-8-(пиперазин-1-ил)-3-(фенилсульфонил)хинолин-4-амин (XXIII, Kif = 0,9 нМ), при этом наибольшую селективность проявил антагонист IV, а наибольшую мультимодальность — антагонист XXIII.

New 3-(arylsulfonyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidines with a substituent amino group in the 7 position were synthesized and their 5-HT6 antagonist activity was studied. The transition from 7-amino and 7-dimethylamino derivatives to 7-aminoalkyl derivatives was found to lead to a significant decrease in activity; a similar pattern was seen on substitution of the methyl group in position 5 by a phenyl or thiophen-2-yl substituent. The most active (at the picomolar level) compounds were 5-methyl-2-(methylthio)-3-(phenylsulfonyl) pyrazolo[1,5-a]pyrimidin-7-amine and N,N,5,6-tetramethyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo-[1,5-a]pyrimidin-7-amine (K i = 700 pM). The first member of the hydrogenated pyrazolo[1,5-a]pteridine class –5,6,9-trimethyl-2-(methylthio)-3-(phenylsulfonyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pteridine (K i = 14.4 nM) was synthesized. These relationships between structure and 5-HT6 antagonist activity support the adequacy of our pharmacophore model, such that it can be used for the further search for new highly effective 5-HT6 antagonists.

Both novel and previously reported (4-phenylsulfonyloxazol-5-yl)amine derivatives containing a substituted sulfonyl group were studied in order to discover highly active 5-HT6 receptor antagonists. A new pharmacophore model of 5-HT6 receptor antagonists was proposed based on the structure-5-HT6 antagonist activity relationship. It was established that the activity of the synthesized compounds depended strongly on the nature of the amine located vicinal to the sulfonyl. The most active ligands were methyl-(4-phenylsulfonyloxazol-5-yl)amines. Replacing the methyl by a bulkier alkyl radical and conversion to tertiary amines was accompanied by a dramatic reduction of their activity for 5-HT6 receptors.

Methods were developed for the synthesis of 3-butyl-2-(3-oxobutenyl)benzofurans and 3-(3-furylbenzofuran-2-yl)acrylic acids on the basis of 3-furyl-2-(3-oxobutyl)benzofurans.

3-(Arylsulfonyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidines containing substituents with an amine in the 6-position were synthesized. Their structure—activity (antagonist) relationship was studied with respect to serotonin 5-HT6 receptors. It was shown that 2-(methylthio)-3-(phenylsulfonyl)- and 2-(methylthio)-3-(3-chlorophenylsulfonyl)pyrazolo[1,5-a]pyrimidin-6-amines, the activity of which was comparable with 3-(arylsulfonyl)-2-(methylamino)pyrazolo[1,5-a]pyrimidin-6-amines and 3-(arylsulfonyl)-2-(methylamino)-and 3-(arylsulfonyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidin-7-amines that were reported earlier, were the most active picomolar ligands.

A series of new 3-(arylsulfonyl)-2-(methylthio)pyrazolo[1,5- a ]pyrimidines containing amino substituent in position 7 have been synthesized and their 5-HT6 receptor antagonist activity has been studied. It is established that the transition from 7-amino and 7-dimethylamino derivatives to 7-aminoalkyl derivatives is accompanied by a significant decrease in the activity, and a similar effect is observed upon replacement of methyl group in position 5 with phenyl or 5-thiophen-2-yl substituents. Maximum (picomolar) activity in the obtained series of compounds was displayed by 5-methyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo[1,5- a ]pyrimidine-7-amine and N,N,5,6-tetramethyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo[1,5- a ]pyrimidine-7-amine ( K i = 700 pM). The first representative of hydrogenated pyrazolo[1,5- a ]pteridines – 5,6,9-trimethyl-2-(methylthio)-3-(phenylsulfonyl)-6,7,8,9-tetrahydropyrazolo[1,5- a ]pteridin (with K i = 14,4 nM) was synthesized. The discovered structure – 5-HT 6 antagonist activity relationship and observed regularities confirm the validity of the adopted pharmacophore model, which allows it to be used in the search for effective drug candidates.

High-throughput screening of a specific set (focused library) of heterocyclic compounds containing alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries), has been performed and highly effective 5-HT6 receptors antagonists were discovered. The structure of most substances corresponds to the PhM2 pharmacophore model, which confirms its potential in the search for effective 5-HT6 receptor antagonists. It is established that the structure of a substituent introduced in the vicinity of the sulfonyl moiety in PhM2 ligands can affect their pharmacological activity, including the ability to block serotonin-induced 5-HT6 receptor-mediated cell responses. In particular, bulky electron-donor groups reduce the activity, whereas methylamine group significantly increases the 5-HT6 receptor antagonist ability of compounds. Based on these findings, a new conceptual pharmacophore model, PhM3, is proposed. It is shown that compounds from the combinatorial libraries with (i) sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylene carbon(s), (ii) heterocyclic compounds containing alkylsulfonyl moiety or endocyclic sulfonyl group, (iii) (5-arylsulfonyl-3H-[1,2,3]triazol-4-yl)-amines, and (iv) azoles substituted simultaneously with arylsulfonyl and alkylsulfonyl groups-all have low hit rate and, hence, are not promising for discovery of new 5-HT6 receptor antagonists.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

In continuation of studies on 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine derivatives as 5-HT6 receptor antagonists, new compounds with a pyridine moiety in the 5-and/or 7-position were obtained and their antagonistic activity was screened. It was established that the introduced pyridine changed the 5-HT6 activity. Some of the obtained 5-pyridin-3-yl-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidines 5-HT6 receptor antagonists with K i = 0.2 – 4.5 nM had therapeutic significance for the treatment of some CNS diseases.

Синтезированы 3-(арилсульфонил)-2-(метилтио)пиразоло[1,5-a]пиримидины, содержащие в положении 6 заместители, включающие аминогруппу, изучена связь их структуры с антагонистической активностью по отношению к серотониновым 5-НТ6 рецепторам. Показано, что наиболее активными пикомолярными лигандами являются 2-(метилтио)- 3-(фенилсульфонил)- и 2-(метилтио)-3-(3-хлорфенилсульфонил)пиразоло[1,5-a]пиримидин-6-амины, активность которых сопоставима с описанными ранее 3-(арилсульфонил)-2-(метиламино)пиразоло[1,5-a]пиримидин-6-аминами, 3-(арилсульфонил)-2-(метил- амино)- и 3-(арилсульфонил)-2-(метилтио)пиразоло[1,5-a]пиримидин-7-аминами.

Aiming the search for new effective 5-HT 6 receptor antagonists, both new and known (4-phenylsulfonyloxazole-5-yl)amine derivatives containing differently substituted sulfonyl group have been studied. Based on the structure – 5-HT 6 antagonist activity relationship, a new pharmacophore model for 5-HT 6 antagonists is proposed. A strong influence of vicinal electron-donor substituent (methylthio or methylamino group) on the ligand – receptor interaction has been observed and explained by additional hydrogen bonding. 3D structure optimization of arylsulfonyloxazoles by molecular mechanics method, as well as conformation calculations show that topological features of the ligand molecules are particularly responsible for their 5-HT 6 antagonist activity. Replacement of the methyl radical by a more bulky alkyl radical, as well as the passage to tertiary amines, is accompanied by a dramatic decrease in this activity.

High-throughput screening of a specific set (focused library) of heterocyclic compounds containing an alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries) was performed in order to discover highly effective 5-HT 6 receptor antagonists. The screening identified several compounds that exhibited pronounced inhibiting properties for 5-HT 6 receptors that enabled them to be used to develop new highly effective drugs for treating central nervous system disturbances. The structures of most antagonists corresponded to the PhM2 pharmacophore model, which confirmed its potential in the search for effective 5-HT 6 receptor antagonists. It was established that the structure of the substituent introduced in the vicinity of the sulfonyl moiety in the PhM2 ligands could affect their pharmacological activity, including the ability to block serotonin-induced 5-HT 6 receptor-mediated cell responses. In particular, bulky electron-donating substituents decreased the activity whereas a methylamino group increased statistically significantly the 5-HT 6 antagonistic activity. Based on these findings, a new pharmacophore model for 5-HT 6 antagonists, PhM3, was proposed. It was shown that compounds from the combinatorial libraries with a sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylenes and heterocyclic compounds containing an alkylsulfonyl moiety or endocyclic sulfonyl, (5-aryl-sulfonyl-3 H -[1,2,3]triazol-4-yl)amines, and azoles substituted simultaneously by arylsulfonyl and alkylsulfonyl moieties all had low hit rates and were not promising for discovery of new 5-HT 6 receptor antagonists.

In continuation of studying derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a ]pyrimidines as 5-HT6 antagonists, new compounds with pyridine moiety in positions 5 and/or 7 were obtained and their antagonistic activity was evaluated. It is established that the introduced pyridine changes 5-HT6 activity. Some of the obtained 3-(phenylsulfonyl)pyrazolo[1,5-a] pyrimidines with Ki = 0.2 - 4.5 nM have therapeutic significance for the treatment of some CNS diseases.

FIELD: medicine, pharmaceutics. SUBSTANCE: present invention refers to new substituted phenoxyacetic acids of general formula 1 possessing the properties of a selective antagonist inhibiting A 2a adenosine receptor activity. The compounds may be used in preventing and treating central nervous system diseases, such as cognitive disorders, Parkinson's disease, or depression, tumour diseases, inflammatory processes. The invention also refers to an agent for intensification of immune response or action of drug preparations in the combination treatment of the diseases. In general formula , R1, R2 and R3, optionally simultaneously represent hydrogen. C 1 -C 5 alkyl, C 3 -C 5 alkenyl or C 3 -C 5 -alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy; R5 represents hydrogen, C 1 -C 3 alkyl, the group -C(O)R6;R6 represents hydroxyl, C 1 -C 5 alkyloxy, C 3 -C 5 alkenyloxy, C 3 -C 5 alkynyloxy optionally substituted by an amino group wherein the substitutes optionally identical are specified in hydrogen, C 1 -C 3 alkyl optionally substituted by a mono- or dialkylaminogroup, an alkyloxygroup, 5-6-member saturated heterocyclyl containing 1-2 heteroatoms specified in nitrogen and oxygen: pyridyl, phenyl optionally substituted by 1-3 methoxygroups; or optionally substituted 6-member, optionally annulated with 5-member unsaturated heterocyclyl, saturated heterocyclyl containing 2 nitrogen atoms wherein the substitutes are specified in C 1 -C 3 alkyl optionally substituted by 5- member heteroaryl containing 1-3 heteroatoms specified in nitrogen and oxygen; or 6- member optionally saturated heterocyclyl containing 1-2 nitrogen atom optionally substituted by C 1 -C 3 alkyl, oxo, optionally substituted by phenyl; a dashed line with an accompanying continuous line represents a single, double or triple bond. EFFECT: preparing new substituted phenoxyacetic acids of general formula 1 possessing the properties of the selective agonist inhibiting A 2a adenosine receptor activity. 15 cl, 3 tbl, 7 ex