Purinoreceptor antagonists based on novel pyridoxin derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic biologically active heterocyclic substances having antagonist activity on purinoreceptors and which are products of modifying pyridoxin, particularly n-(1,5-dihydro-3-R-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where is selected from: a hydrogen atom, ethyl, heptyl or octyl.

EFFECT: compounds of the given formula have high antagonist activity on purinoreceptors and can be used in medicine and veterinary.

2 tbl, 5 ex

 

The invention relates to synthetic biologically active substances heterocyclic series, which has antagonistic activity against purinoreceptors and representing the products of modification of pyridoxine, namely n-(1,5-dihydro-3-R-8-methyl-9-hydroxy-[1,3]doxepin[5,6-c]pyridinyl-6-azo)vinylsulfonate and their salt forms of the General formula I:

,

where R is selected from the group of: a hydrogen atom, ethyl, heptyl or octyl.

Compounds of formula (I) have a high antagonistic activity against purinoreceptors (P2 receptors) and can find application in medicine and veterinary medicine.

P2 receptors are a target for pharmacological effects and the development of new medicines for the treatment of various diseases. Development of antagonists of P2-receptors is a promising direction of modern chemistry and pharmacology. The most important evidence of the enormous importance of purinergic neurotransmission is the introduction into clinical practice of medicines acting on P2 receptors and successfully used for the treatment of pathologies of the cardiovascular system [A. U. Ziganshin, P2-receptors: promising targets for future drugs / Ziganshin A. U., Ziganshina L. E. // GEOTAR-Media, Moscow - 2009].

The closest the x�economic structure and purpose analog of the claimed substances is PPADS (pyridoxal phosphate-6-Otopeni-2',4'-disulfonate acid) known antagonist of purinoreceptors [J. B. Schachter, Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoreceptor / J. B. Schachter, Q. Li, J. L. Boyer, et al. // Br. J. PharmacoL, 118, 167-173 (1996).]. PPADS was the basis for the creation of a number of antagonists purinoreceptors [N. Syed, Pharmacology of P2X receptors / N. Syed, Ch. Kennedy // WIREs Membr Transp Signal, - 2012, - V. 1, a - c. 16-30.], this modification affected mainly benzene ring, and in the third and fourth positions of the pyridine cycle is present as a phosphate, phosphonate, amino and aldehyde groups. Despite a significant amount of synthesized derivatives of PPADS, they all have a number of significant disadvantages, including the difficulty of getting associated with the necessity of introducing in the structure of pyridoxine phosphate fragment and aldehyde groups, which made the creation of new effective antagonists purinoreceptors remains relevant.

It should be noted that the compounds described above, according to the applicant, cannot be considered as analogues to the claimed technical solution due to the fact that they do not coincide with the claimed compounds according to the chemical structure. The applicant has not identified the sources containing information about technical solutions, identical to the present invention, which allows to make a conclusion about its compliance with the criterion of "novelty."

Task Savannah� technical solution consists in the creation of new biologically active compounds with high antagonistic activity against purinoreceptors.

The problem is solved by the synthesis of antagonists of purinoreceptors of the General formula (I):

,

where R is selected from the group of: a hydrogen atom, ethyl, heptyl or octyl.

The inventive substances of the General formula (I) can be used in neutral form or in the form of salts with cations of sodium, potassium, lithium, ammonium, magnesium, calcium or other pharmacologically acceptable cations.

In contrast, PPADS in the claimed compounds used acetaline protection of the hydroxymethyl groups, which greatly simplifies their receipt.

The closest in chemical structure and purpose to the claimed substances is PPADS, which was selected as reference compounds for comparison antagonistic activity.

The inventive substances showed high antagonistic activity against P2X-receptors at the smooth muscle cells of the bladder and VAS deferens and can find application in medicine and veterinary medicine.

The applicant has not identified the sources containing information about the impact of the distinctive features of invention technical result. This new property of an object is the creation of connections with high antagonistic activity against purinoreceptors causes, according to the applicant, compliance with the invention of the Cree�the eriya "inventive step".

Proposed in the claimed technical solution of a compound of formula (I) received under the following schemes:

Acetals pyridoxine II(a-g) were obtained as described in the literature methods [Pat. RF 2501801, IPC C07D 491/056. Derivatives of pyridoxine with nonlinear optical properties. [Text] / Shtyrlin Y. G., Petukhov A. S., Strelnik. A. D., Shtyrlin N. In., M. R. Garipov, Lodochnikova O. A., Litvinov I. A., Morozov O. A., A. V. Lovchev; WHAO HPE K(P)FU. - Publ. 20.12.2013].

Characteristics of new compounds and the results of the study of antagonistic activity against purinoreceptors (PL. 1, 2) shown in the examples of specific performance.

Examples of a specific implementation of the claimed technical solutions

Example 1. Synthesis of n-(1,5-dihydro-3-heptyl-8-methyl-9-hydroxy-[1,3]doxepin[5,6-c]pyridinyl-6-azo)phenolsulfonic acid (Ia)

In a flask of 50 ml solution was prepared from diazocompounds 0.005 mol sulfanilate acid, 0.35 g (0.005 mol) of sodium nitrite in 50 ml (0.01 mol) of 0.2 n hydrochloric acid at a temperature of 0-5°C. a Separately prepared solution of 0.005 mol of acetal IIa and 0.6 g (0,015 mol) of sodium hydroxide in 15 ml of water. To a solution of the sodium salt of acetal dropwise with stirring and cooling to 0-5°C was added a solution of diazocompounds. The reaction mixture was stirred at room temperature for 30 minutes and neutralized� dilute hydrochloric acid to pH 7.5. The reaction mass was dried in vacuum to dryness, the product was recrystallized from ethyl alcohol. The yield of 40%. T. div. 225-226°C. NMR1H (400 MHz, DMSO-d6): δ 0.87 (t,3J=6.8 Hz, CH3, 3H); 1.23-1.37 (m, 5CH2, 10H); 1.58-1.63 (m, CH2, 2H); 2.19 (s, CH3, 3H); 4.54, 5.06 (AB-Quartet,2J=-15.0 Hz, CH2, 2H); 4.87 (t,3J=5.5 Hz, CH, 1H); 4.98, 5.56 (AB-Quartet,2J=-14.8 Hz, CH2, 2H); 7.63 (s, C6H4, 4H). ESI-HRMS m/z 462.1700 [(M-H)-] (calculated for C22H28N3O6S - 462.1699).

Example 2. Synthesis of n-(1,5-dihydro-3-octyl-8-methyl-9-hydroxy-[1,3]doxepin[5,6-c]pyridinyl-6-azo)phenolsulfonic acid (IB)

Synthesize and develop similarly to compound (Ia) using acetal (IIB) instead of acetal (IIA). The yield of 40%. T. div. 225-226°C. NMR1H (400 MHz, DMSO-d6): δ 0.86 (t,3J=6.7 Hz, CH3, 3H); 1.2-1.38 (m, 6CH2, 12H); 1.57-1.62 (m, CH2, 2H); 2.16 (s, CH3, 3H); 4.51, 5.05 (AB-Quartet,2J=-14.8 Hz, CH2, 2H); 4.88 (t,3J=5.6 Hz, CH, 1H); 5.00, 5.56 (AB-Quartet,2J=-14.6 Hz, CH2, 2H); 7.63 (s, C6H4, 4H). ESI-HRMS m/z 476.1855 [(M-H)-] (calculated for C23H30N3O6S - 476.1855).

Example 3. Synthesis of n-(1,5-dihydro-8-methyl-9-hydroxy-[1,3]doxepin[5,6-c]pyridinyl-6-azo)phenolsulfonic acid (IB)

Synthesize and develop similarly to compound (Ia) using acetal (IIB) instead of acetal (IIA). The yield of 65%. T. div. 239-240°C. NMR1H (400 MHz, DSO-d 6): δ 2.44 (s, CH3, 3H); 4.93 (s, CH2, 2H); 4.98 (s, CH2, 2H); 5.31 (s, CH2, 2H); 7.75, 7.82 (AB-Quartet,3J=8.4 Hz, C6H4, 4H). ESI-HRMS m/z 364.0603 [(M-H)-] (calculated for C15H14N3O6S - 364.0603).

Example 4. Synthesis of n-(1,5-dihydro-3-ethyl-8-methyl-9-hydroxy-[1,3]doxepin[5,6-c]pyridinyl-6-azo)phenolsulfonic acid (G)

Synthesize and develop similarly to compound (Ia) using acetal (IIG) instead of acetal (IIA). The yield of 45%. T. div. 225-226°C. NMR1H NMR1H (400 MHz, DMSO-d6): δ 0.91 (t,3J=7.2 Hz, CH3, 3H); 1.66 (m, CH2, 2H); 2.39 (s, CH3, 3H); 4.73, 5.09 (AB-Quartet,2J=to 15.6 Hz, CH2, 2H); 4.91 (t,3J=5.7 Hz, CH, 1H); 5.10, 5.51 (AB-Quartet,2J=-15.2 Hz, CH2, 2H); 7.72, 7.78 (AB-Quartet,3J=8.4 Hz, C6H4, 4H). ESI-HRMS m/z 392.0916 [(M-H)-] (calculated for C17H18N3O6S - 392.0916).

Example 5. The study of antagonistic activity of the synthesized compounds against P2-receptors

The study of antagonistic activity of the synthesized compounds against P2-receptors in a concentration of 10-2M studied in vitro in male Wistar rats weighing 150-200 g (kennel "Pushchino", Moscow region). All the experiments were performed in accordance with the rules of work with experimental animals. Applied research method mechanical� activity of isolated organs [Ziganshin A. U., Ziganshina L. E. Pharmacology of ATP receptors. - M.: GEOTAR Medicine, 1999. - 210]. For the study of P2X receptor-mediated contractions of the objects of study were the drugs of the urinary bladder and VAS deferens. For comparison, the activity of the test compounds in the same conditions in all experiments, we evaluated the activity of known antagonists of P2-receptors - PPADS (Tocris, UK). To eliminate the influence of choline - and adrenoreceptors the experiments were carried out in the presence of M-holinoblokatory atropine and α-adrenoblocker phentolamine (Sigma, USA). Conducted electric field stimulation at a frequency of 0.5-32 Hz. About the size of the antagonistic activity of substances judged by the values of the contractile response. Experimental results obtained with stimulation frequency of 4 and 8 Hz.

Study of the antagonistic action of the synthesized compounds showed significant activity against purinoreceptors the inventive compounds (see Tab. 1, 2), not inferior to the known effect of antagonist PPADS.

The applicant has not identified the sources containing information about technical solutions, identical to the present invention, which allows to make a conclusion about its compliance with the criterion of "novelty."

Derivatives of pyridoxine, namely n-(1,5-�hydro-3-R-8-methyl-9-hydroxy-[1,3]doxepin[5,6-c]pyridinyl-6-azo)vinylsulfonate and their salt forms, which has antagonistic activity against purinoreceptors, of the General formula I:

where R is selected from the group of: a hydrogen atom, ethyl, heptyl or octyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to use of synthetic biologically active heterocyclic substances as purinoreceptor antagonists, said substances having antagonist activity on purinoreceptors and being a product of modifying pyridoxin, particularly n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where R1 is a hydrogen atom or methyl, R2 is methyl, isopropyl.

EFFECT: compounds of the given formula have high antagonist activity on purinoreceptors and can be used in medicine and veterinary.

2 tbl

FIELD: chemistry.

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2 tbl, 11 ex

FIELD: medicine, pharmaceutics.

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23 cl, 3 tbl, 15 ex

FIELD: chemistry.

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7 cl, 1 tbl, 11 dwg, 118 ex

FIELD: chemistry.

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4 cl, 2 tbl, 3 ex

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22 cl, 2 tbl, 211 ex

FIELD: chemistry.

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25 cl, 2 tbl, 24 ex

FIELD: chemistry.

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2 cl, 2 dwg, 6 ex

FIELD: chemistry.

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1 cl, 1 tbl, 7 ex

FIELD: medicine, pharmaceutics.

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8 cl, 1 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of synthetic biologically active heterocyclic substances as purinoreceptor antagonists, said substances having antagonist activity on purinoreceptors and being a product of modifying pyridoxin, particularly n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where R1 is a hydrogen atom or methyl, R2 is methyl, isopropyl.

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2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

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24 cl, 3 tbl, 19 ex

Hypotensive means // 2554815

FIELD: medicine.

SUBSTANCE: invention represents a hypotensive means, which contains felodipinum as an active component, as well as target additional components: mesoporous silicon dioxide, lactose, hypromeloza. Realisation of the invention ensures the high technological efficiency of the claimed medical means production with the provision of a prolonged release of an active substance with the application of available components. Felodipinum is included into spherical particles with a highly developed mesoporous structure of silicon oxide.

EFFECT: increase of stability in storage and protection from unfavorable environmental factors.

4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula I

which can be used for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis. In formula I A represents =S, -SR4 or =O, X represents F, Cl, Br or I, R1 represents phenyl, R2 and R3 are connected to form morpholine, and R4 represents C1-C6-alkyl.

EFFECT: invention refers to using the compound for producing the therapeutic agent for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis, and to the method for producing the above compounds.

8 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-phenylpropionic acid derivatives of formula

wherein R1A represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl, R1B is hydrogen or methyl, R2A represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, R2B is hydrogen or methyl or R1A and R2A are combined together, and in a combination to carbon atoms to which they are attached, form a cyclopropyl ring of formula

wherein R1B and R2B have the values as specified above, or R2A and R2B are combined together, and in a combination to a carbon atom, to which they are attached, form a cyclic group of formula or

wherein n means a number 1 or 2, R3 is hydrogen, fluorine or methyl, R4 represents hydrogen, fluorine, chlorine or a cyanogroup, R5A represents methyl, R5B is trifluoromethyl or R5A and R5B are combined together, and in a combination to a carbon atom, to which they are attached, form a difluorosubstituted cycloalkyl ring of formula or

R6 represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl; alkyl with 1-4 carbon atoms and alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, cyclopropyl and cyclobutyl up to three fluorine atoms as substitutes, and R7 represents hydrogen, fluorine, chlorine, methyl or a methoxy group. The invention also refers to a therapeutic agent containing the above compounds and to a method for producing the compounds of formula (I).

EFFECT: compounds of formula (I) activate the form of soluble haem-free guanylate cyclase and are applicable in the method of treating and/or preventing cardiac failure, angina, hypertension, pulmonary hypertension, ischemia, vascular diseases, disturbed microcirculation, thromboembolic diseases and arterial sclerosis.

6 cl, 4 tbl, 113 ex

FIELD: food industry.

SUBSTANCE: invention relates to a polyphenol grape extract, a compound for oral administration, a food product, beverage, a taste additive, a nutraceutical product, a revitalising composition and therapeutic remedy including the said grape extract. According to the invention, the grape extract contains nearly 5-15 wt % of monomers, nearly 5-20 wt % of dimers, nearly 3-10 wt % of trimers, nearly 2-10 wt % of tetramers and nearly 2-10 wt % of pentamers.

EFFECT: grape extract reduces blood pressure with patients suffering from prehypertonic condition or metabolic syndrome.

27 cl, 4 dwg, 8 tbl, 7 ex

Vasopressor agent // 2552529

FIELD: chemistry.

SUBSTANCE: invention refers to N, S-substituted isothiourea derivatives of the general formula (1) in the form of salts with pharmacologically acceptable acids as a NOS-inhibitory and vasopressor agent wherein: n=1, 3, i.e. an acyl substitute represents cyclobutanoyl or cyclohexanoyl; R represents an alkyl group: C2H5, i-C3H7; HX represents a pharmacologically acceptable inorganic or organic acid: HCl, HBr, HI, hydrogen methyl sulphate, oxalic, succinic acids, etc.

EFFECT: extending the range of products of the vasopressor action.

6 cl, 7 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to implanted medical devices. A device for drug delivery includes an implanted intra-lumen framework, which has a luminal surface and abluminal surface; a multitude of through hollows in the intra-lumen framework, where each of the multiple through holes contains a composition, selected from the following groups. Compositions of a mTOR inhibitor and base structure, which has the configuration, which will make it possible for the mTOR inhibitor in the composition of the mTOR inhibitor to elute, mainly in the abluminal direction for seven (7) to one hundred and twenty (120) days, with the composition of the mTOR inhibitor containing a polymer in a combination with the mTOR inhibitor and the base structure containing a multitude of polymer layers with the absence of mTOR inhibitors; compositions of a phosphodiesterase III inhibitor and an upper covering structure, which has the configuration, making it possible for the phosphodiesterase III inhibitor in the composition of the phosphodiesterase III inhibitor to elute, mainly in the luminal direction for five (5) to sixty-one (61) day, with the composition of the phosphodiesterase III inhibitor containing the polymer in a combination with the phosphodiesterase III inhibitor, and the upper covering structure containing a multitude of polymer layers in the absence of the phosphodiesterase III inhibitor.

EFFECT: invention makes it possible to provide independent on each other rates of sirolimus and cistazol release, simultaneously providing the targeted delivery of each of the medications.

6 cl, 30 dwg, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to application of composition for preparation of medications aimed at secondary prevention of cardiac infarction. Application of composition based on substances, applied in Chinese medicine, for preparation of medications aimed at secondary prevention of cardiac infarction, with composition, based on substances, applied in Chinese medicine, is prepared from composition, which contains Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae, taken in specified ratio.

EFFECT: composition makes it possible to prepare medication, which is effective for secondary prevention of cardiac infarction, prevents stenocardia, improves coronary blood flow.

14 cl, 8 dwg, 74 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of synthetic biologically active heterocyclic substances as purinoreceptor antagonists, said substances having antagonist activity on purinoreceptors and being a product of modifying pyridoxin, particularly n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where R1 is a hydrogen atom or methyl, R2 is methyl, isopropyl.

EFFECT: compounds of the given formula have high antagonist activity on purinoreceptors and can be used in medicine and veterinary.

2 tbl

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