Using pyridoxin acetals derivatives as purinoreceptor antagonists

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

 

The invention relates to the use as antagonists of purinoreceptors synthetic biologically active compounds of the heterocyclic series, representing the products of modification of pyridoxine, namely n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]doxepin[5,6-C]pyridinyl-6-azo)vinylsulfonate and their salt forms of the General formula I:

where R1is a hydrogen atom or methyl, R2: methyl, ISO-propyl.

It has been previously shown that the compounds of formula (I) possess antibacterial activity [RF patent 2480471, IPC A61K 31/4375. Antibacterial compounds based on sulfanilamide acid and pyridoxine [Text] / Shtyrlin Y. G., Petukhov S. A., Strel'nik, A. D., Nikitina E. V., M. R. Garipov; WHAO HPE K(P)FU. - Publ. 27.04.2013], but data on their antagonistic activity against purinoreceptors was not known.

The authors found that the 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 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].

Despite a significant amount synthesized and investigated antagonists of P2-receptors of different chemical structures, each of them has certain drawbacks, in particular low selectivity, efficiency antagonism, significant influence on the activity of ecto-ATPase.

The closest in structure analog of the claimed substances is RRA (pyridoxal phosphate-6-Otopeni-2',4'-disulfonate acid) is a known antagonist of purinoreceptors [J. V. Schachter, Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor / 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, pp. 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.

p> 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."

The task of the claimed technical solution is the creation of 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 R1is a hydrogen atom or methyl, R2: methyl, ISO-propyl.

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.

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 on smoothly.�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 the object determines, according to the applicant, in accordance with the invention, the criterion of "inventive step".

Proposed in the invention compounds of formula (I) obtained according to the scheme below:

Pyridoxine I(a-b) were obtained as described in the literature method [RF patent 2480471, IPC A61K 31/4375. Antibacterial compounds based on sulfanilamide acid and pyridoxine [Text] / Shtyrlin Y. G., Petukhov S. A., Strel'nik, A. D., Nikitina E. V., M. R. Garipov; WHAO HPE K(P)FU. - Publ. 27.04.2013].

The results of the study of antagonistic activity against purinoreceptors shown in the examples of specific performance (table 1, 2).

An example of a specific implementation of the claimed technical solutions

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

Compounds I(a-b) were tested for biological activity in the form of water-soluble sodium salts. The study of antagonistic activity of the synthesized compounds against P2-receptors in a concentration of 10-2M studied in vitro in male rats line istar weighing 150-200 g (kennel "Pushchino", Moscow region). All the experiments were performed in accordance with the rules of compliance of works with the use of 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]. To explore RH-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 in substance Ia (PL. 1, 2), exceeding the effect of a known antagonist PPADS.

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

td align="center"> 1,8±0,25
Table 1
Antagonists purinoreceptors on the basis of new derivatives of pyridoxine (primary Assessment of antagonistic activity of the synthesized compounds (drugs bladder))
ConnectionFrequency, HzPrimary stimulationStimulation on the background of atropineExperienceControl
Ia42,54±0,321,92±0,131,82±0,161,89±0,35
83,56±0,222,52±0,152,20±0,252,29±0,31
IB41,61±0,171,32±0,151,11±0,151,1±0,28
82,4±0,231,44±0,141,28±0,18
IB40,47±0,060,31±0,050,29±0,030,25±0,04
80,7±0,110,54±0,030,33±0,020,23±0,04

Table 2
Antagonists purinoreceptors on the basis of new derivatives of pyridoxine (primary Assessment of antagonistic activity of the synthesized compounds (drugs of the VAS deferens))
ConnectionFrequency, HzPrimary stimulationStimulation on the background of phentolamineExperienceControl
1A42,97±0,121,94±0,131,17±0,111,19±0,13
83,3±0,15 2,23±0,221,34±0,261,46±0,16
1641,6±0,151,14±0,121,1±0,130,86±0,12
82,23±0,161,73±0,221,7±0,231,22±0,17
1B40,3±0,020,27±0,220,26±0,070,16±0,03
80,46±0,030,41±0,050,32±0,040,25±0,01

The use of n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]doxepin[5,6-C]pyridinyl-6-azo)phenylsulfonyl and their salt forms of the General formula I:

where R1is a hydrogen atom or methyl, R2- methyl, isopropyl, as antagonists purinoreceptors.



 

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8 cl, 2 tbl, 2 ex

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21 cl, 4 tbl, 26 ex

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6 cl, 4 tbl, 113 ex

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27 cl, 4 dwg, 8 tbl, 7 ex

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FIELD: chemistry.

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6 cl, 7 tbl, 10 ex

FIELD: medicine, pharmaceutics.

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6 cl, 30 dwg, 7 tbl

FIELD: medicine, pharmaceutics.

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14 cl, 8 dwg, 74 tbl, 10 ex

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2 cl, 2 dwg, 8 tbl, 4 ex

FIELD: chemistry.

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19 ex

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