RU2554883C1 - Using pyridoxin acetals derivatives as purinoreceptor antagonists - Google Patents

Abstract

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

Description

The invention relates to the use of heterocyclic synthetic biologically active substances as purinoreceptor antagonists, which are pyridoxine modification products, namely n- (1,5-dihydro-3-R ₁ -3-R ₂ -8-methyl-9-hydroxy- [1,3] dioxepino [5,6-c] pyridinyl-6-azo) phenyl sulfonic acids and their salt forms of the general formula I:

where R ₁ is a hydrogen atom or methyl, R ₂ : methyl, iso-propyl.

It was previously shown that the compounds of formula (I) have antibacterial activity [RF patent 2480471, IPC A61K 31/4375. Antibacterial compounds based on sulfanilic acid and pyridoxine [Text] / Shtyrlin Yu.G., Petukhov A.S., Strelnik A.D., Nikitina E.V., Garipov M.R .; VGAOU VPO K (P) FU. - Publ. 04/27/2013], but data on their antagonistic activity towards purinoreceptors was not known.

The authors found that the compounds of formula (I) have 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 drugs for the treatment of various diseases. The development of P2 receptor antagonists is a promising area of modern chemistry and pharmacology. The most important evidence of the enormous importance of purinergic neurotransmission is the introduction into clinical practice of drugs that act on P2 receptors and are successfully used to treat pathologies of the cardiovascular system [A.U. Ziganshin, P2 receptors: a promising target for future drugs / Ziganshin A.U., Ziganshina L.E. // Geotar-Media, Moscow - 2009].

Despite the significant number of synthesized and studied P2 receptor antagonists of different chemical structures, each of them has certain disadvantages, in particular, low selectivity, antagonism efficiency, and a significant effect on ecto-ATPase activity.

The closest in structure to the analogue of the claimed compounds is PPA08 (pyridoxalphosphate-6-azophenyl-2 ′, 4′-disulfonic acid), a known purinoreceptor antagonist [J. B. 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 served as the basis for the creation of a number of purinoreceptor antagonists [N. Syed, Pharmacology of P2X receptors / N. Syed, Ch. Kennedy // WIREs Membr Transp Signal, - 2012, - V. 1, - p. 16-30.], While the modifications affected mainly the benzene ring, and in the third and fourth positions of the pyridine ring there were phosphate, phosphonate, amino and aldehyde groups.

It should be noted that the above compounds, 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 in chemical structure. The applicant has not identified sources containing information about technical solutions identical to the present invention, which allows us to conclude that it meets the criterion of "novelty."

The objective of the claimed technical solution is to create biologically active compounds with high antagonistic activity against purinoreceptors.

The problem is solved by synthesis of purinoreceptor antagonists of the general formula (I):

where R ₁ is a hydrogen atom or methyl, R ₂ : methyl, iso-propyl.

The inventive substances of General formula (I) can be used in the form of neutral forms 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 chosen as a reference compound for comparing antagonistic activity.

The inventive substances showed high antagonistic activity against P2X receptors on smooth muscle cells of the bladder and vas deferens and can be used in medicine and veterinary medicine.

The applicant has not identified sources that would contain information about the influence of the distinguishing features of the invention on the achieved technical result. The specified new property of the object determines, according to the applicant, the compliance of the invention with the criterion of "inventive step".

The compounds of formula (I) according to the invention were prepared according to the scheme below:

Compounds of pyridoxine I (a-c) were obtained according to the methods described in the literature [RF patent 2480471, IPC A61K 31/4375. Antibacterial compounds based on sulfanilic acid and pyridoxine [Text] / Shtyrlin Yu.G., Petukhov A.S., Strelnik A.D., Nikitina E.V., Garipov M.R .; VGAOU VPO K (P) FU. - Publ. 04/27/2013].

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

An example of a specific implementation of the claimed technical solution

Investigation of the antagonistic activity of synthesized compounds with respect to P2 receptors.

Compounds I (a-c) were tested for biological activity in the form of water soluble sodium salts. The study of the antagonistic activity of the synthesized compounds with respect to P2 receptors at a concentration of 10 ^-2 M was studied in vitro on male Wistar rats weighing 150-200 g (Pushchino kennel, Moscow region). All experiments were performed in accordance with the rules of observance of work using experimental animals. The method of studying the mechanical activity of isolated organs was used [Ziganshin A.U., Ziganshina L.E. Pharmacology of ATP receptors. - M .: Geotar-Medicine, 1999. - 210 s]. To study the P2X-receptor-mediated contractions, the objects of study were bladder and vas deferens. To compare the activity of the studied compounds under the same conditions, the activity of the well-known P2 receptor antagonist - PPADS (Tocris, United Kingdom) was evaluated in all experiments. To exclude the effect of cholinergic and adrenergic receptors, experiments were carried out in the presence of the atropine M-anticholinergic blocker and phentolamine α-adrenergic blocker (Sigma, USA). The stimulation was carried out by an electric field with a frequency of 0.5-32 Hz. The magnitude of the antagonistic activity of substances was judged by the magnitude of the contractile response. The experimental results obtained during stimulation with a frequency of 4 and 8 Hz are presented.

The study of the antagonistic effect of the synthesized compounds showed the presence of significant activity against purinoreceptors in substance Ia (Tables 1, 2), exceeding the effect of the known PPADS antagonist.

The applicant has not identified sources containing information about technical solutions identical to the present invention, which allows us to conclude that it meets the criterion of "novelty."

Table 1 Purinoreceptor antagonists based on new pyridoxine derivatives (Assessment of the primary antagonistic activity of synthesized compounds (bladder preparations)) Compound frequency Hz Primary stimulation Atropine stimulation Experience The control Ia four 2.54 ± 0.32 1.92 ± 0.13 1.82 ± 0.16 1.89 ± 0.35 8 3.56 ± 0.22 2.52 ± 0.15 2.20 ± 0.25 2.29 ± 0.31 Ib four 1.61 ± 0.17 1.32 ± 0.15 1.11 ± 0.15 1.1 ± 0.28 8 2.4 ± 0.23 1.8 ± 0.25 1.44 ± 0.14 1.28 ± 0.18 Ic four 0.47 ± 0.06 0.31 ± 0.05 0.29 ± 0.03 0.25 ± 0.04 8 0.7 ± 0.11 0.54 ± 0.03 0.33 ± 0.02 0.23 ± 0.04

table 2 Purinoreceptor antagonists based on new pyridoxine derivatives (Assessment of the primary antagonistic activity of synthesized compounds (vas deferens) Compound frequency Hz Primary stimulation Phentolamine stimulation Experience The control 1a four 2.97 ± 0.12 1.94 ± 0.13 1.17 ± 0.11 1.19 ± 0.13 8 3.3 ± 0.15 2.23 ± 0.22 1.34 ± 0.26 1.46 ± 0.16 16 four 1.6 ± 0.15 1.14 ± 0.12 1.1 ± 0.13 0.86 ± 0.12 8 2.23 ± 0.16 1.73 ± 0.22 1.7 ± 0.23 1.22 ± 0.17 1c four 0.3 ± 0.02 0.27 ± 0.22 0.26 ± 0.07 0.16 ± 0.03 8 0.46 ± 0.03 0.41 ± 0.05 0.32 ± 0.04 0.25 ± 0.01

Claims (1)

The use of n- (1,5-dihydro-3-R ₁ -3-R ₂ -8-methyl-9-hydroxy- [1,3] dioxepino [5,6-c] pyridinyl-6-azo) phenyl sulfonic acids and their salt forms of the general formula I:

where R ₁ is a hydrogen atom or methyl, R ₂ is methyl, isopropyl, as antagonists of purinoreceptors.