The donor of nitric oxide, which activates the soluble form of guanylate cyclase, inhibits platelet aggregation and has antispasmodic and vasodilator


Proposed: the tool is a donor of nitric oxide, which activates the soluble form of guanylate cyclase. This tool inhibits platelet aggregation, also has antispasmodic, vasodilator and is a 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-doxazosin (BAGHDAD) of formula (1). The invention can be used in the clinic as a means with antispasmodic and vasodilator effect and, unlike derivative furoxane, no significant impact on blood pressure, which suggests the possibility of its directional local use. 1 Il.

The invention relates to biochemistry, physiology and pharmacology, in particular to the use of known 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-dioxazine (BAGHDAD) of the formula Ias a donor of nitric oxide, which activates the soluble form of guanylate cyclase (RGC), inhibiting platelet aggregation and have antispasmodic and vasodilator.

This invention can be used in biochemistry, physiology and medicine.

Nitric oxide (NO) synthesized by endothelial cells and other tlaudio on systemic blood pressure. In addition, NO has an antispasmodic effect on the muscles of the gastrointestinal tract, biliary tract, ureter, uterus, bronchi and other organs, and also inhibits the processes of aggregation and adhesion of platelets and neutrophils (M. D. Mashkovsky "Drugs", so 1, "Torching", Kharkov, 1998, page 385 [1] ). The molecular mechanism of action of endogenous nitric oxide, synthesized from the amino acids L-arginine, includes its diffusion through the plasma membrane and binding to the heme group of the RHC. Guanilatziklazu /EC; guanosin-5'-triphosphate-pyrophosphatase (cyclessa)/ is the enzyme that catalyzes the biosynthesis of guanosine-3',5'-cyclophosphate (cGMP) as a secondary messenger in the role of a universal regulator of intracellular metabolism (F. Murad "Regulation of cytosolic guanylyl cyclase by nitric oxide: The NO-cGMP signal transduction system" Adv. Pharmacol. 1994, v. 26, p. 19-33). HZ exists in two forms - membrane and soluble. It is now established that the result of the interaction of NO with iron atom of heme, part of the enzyme, and education complex nitrosyl-heme occur conformational changes of the active centre of the enzyme, which lead to activation of the RHC and increased synthesis of cGMP (see drawing).

To this lie the other nitrates, used for the treatment of cardiovascular diseases as antiischemic and antianginal drugs ([1], pp. 385 - 392). However, a significant disadvantage is the weak antiplatelet activity, as well as the emergence of tolerance and other side effects with prolonged use. In addition, these organic nitrates in various dosage forms effectively reduce blood pressure, which significantly complicates their local application (for example, in cases of cerebral vasospasm, pulmonary hypertension, restenosis after angiography, and so on).

There are various heterocyclic compounds with the ability to generate NO, activate RHC and manifesting antiplatelet, antispasmodic and/or vasodilator properties.

Thus, the known derivatives of 1,2,4-oxadiazol-5-it General formula IIwhere R is phenyl, 4-chlorophenyl or styryl, which was seen as predecessors (depot form) NO-generating compounds (amidoxime). These derivative did not possess hypotensive activity, but inhibited the aggregation of platelets exposed to collagen in the models of ex vivo and in vivo (K. Rehse, F. Brehme "New NO-donors with antithrombotic and NO in vivo has not been established, their influence on the activity of the RHC, as well as antispasmodic and vasodilator properties were not studied.

There are various 3,4-disubstituted furoxone (1,2,5-oxadiazol-2-oxides) of General formula IIIwhere R1and R2is methyl, phenyl, phenylsulfonyl, nitrile, methoxy-, nitro - or amino group, which generates NO, which activates RHC showing antiplatelet properties and possessing marked vasorelaxant action on isolated rings of thoracic aorta of rabbit, shortened by the action of norepinephrine (R. Ferioli, G. C. Folco et al. "A new class of furoxan derivatives as NO-donors: mechanism of action and biological activity" Brit. J. Pharmacol. 1995, v. 144, 3, p. 816-820; PCT application 94/01422, C 07 D 271/08, a 61 K 31/41, 1993).

The ability derivative furoxans as organic nitrates, effectively reduce systemic blood pressure (25-85 mm RT. Art. when administered intravenously to animals in doses of 0.05-0.1 mg/kg) (for example, European patents 0054872, C 07 D 271/08, a 61 K 31/41, 1984; 0054873, C 07 D 271/08, a 61 K 31/41, 1984) makes them difficult directional local application.

Known 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-doxazosin above formula I as the product of chemical synthesis (B. G. Andrianov, V., Semenikhina, A. C. Eremeev "Halides the definition and pharmacological properties of this compound have not been studied.

Closest to the connection of the present invention is 4,4'-diphenyl-3,3',4',3"-tripurasur-2,2',2"-trioxide of the formula III, where R1=R2=4-phenylphenoxide-3(2-oxido-4-phenyl-1,2,5-oxadiazol-3-yl), which is the donor of NO, which inhibits the aggregation of platelets exposed to collagen and causing vasodilation in isolated rings of thoracic aorta of rabbit, shortened by the action of norepinephrine (A. M. Gasco, A. Di Stilo et al. "Synthesis and structure of a trimer of the furoxan system with high vasodilator and platelet antiaggregatory activity" Liebigs Ann. Chem. 1993, p. 441-444 - prototype).

The effect of this compound on the activity of RHC and its hypotensive activity has not been studied. In addition, it had not sufficiently effective antispasmodic and vasodilator effect in the experiment.

The aim of the invention is the finding in a series of derivatives of 1,2,5-oxadiazole new donor of nitric oxide and the activator RHC with improved antispasmodic and vasodilator.

This goal is achieved by the use of known chemical compounds-3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing above formula I as a donor of NO, which activates RHC, inhibiting platelet aggregation and have antispasmodic and sosudorasshiryayuschee of nitrilosides and which consists in the interaction of the acid chloride (4-aminopyrazine-3-yl)hydroxamic acid with triethylamine in an inert organic solvent (acetonitrile) at a temperature of 0-5o[12] .

The description of the present invention contains 9 examples illustrating the experimental material.

Examples 1-4 show the chemical basis of molecular mechanism of action of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing, mainly consisting in the selective generation of NO.

Example 5 illustrates the biochemical effect BAGHDAD-mediated generation of nitric oxide, activation of partially purified RGC from the lungs of a bull.

Examples 6 and 7 illustrate the pharmacological properties of BAGHDAD - the ability to inhibit platelet aggregation, as well as antispasmodic and vasodilator activity in vitro.

Example 8 demonstrates the absence of BAGHDAD when administered intravenously at a dose of 0.5 mg/kg antihypertensive activity in vivo.

Example 9 describes a study of acute toxicity BAGHDAD.

Example 1. The formation of nitric oxide from 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing.

For the determination of nitric oxide used a known method based on the reaction of nitric oxide with oxygen in the aquatic environment with the formation of nitrite, the amount of which was measured by the intensity of staining of the sample with the reaction product of the result with a spectrophotometer. In casadonte as a result of chemical reactions, but not nitrite, the reaction is carried out in the presence of oxyhemoglobin, which quantitatively reacts with nitric oxide (but not nitrite), forming nitrate, which does not react to the result.

Sample final volume of 1 ml contained 50 mm potassium phosphate buffer (pH 7.4) or 20 mm potassium-citrate buffer (pH 5.0), 0.5 mm cysteine or glutathione, the target compound in a concentration of 0.1 mm and 0.2% dimethyl sulfoxide (DMSO), while incubation with oxyhemoglobin concentration was 0.1 mm. As a negative control was used an aqueous solution of DMSO at a concentration of 0.2%, and as a positive control, 0.1 mm sodium nitrite containing 0.2% DMSO. Samples were incubated for 60 min at 37oWith and added consistently 100 ál of 3 M sodium acetate, 400 µl 0,92% solution of sulfanilic acid in 30% acetic acid and 400 μl of 0.05% N-naphthylethylenediamine. Samples were incubated 10 min and measured the optical density at a wavelength of 554 nm on the spectrophotometer.

In the above conditions at pH 7.4 was not observed the formation of appreciable quantities of nitrite (<0.01 mol of water/mol of starting compound (ex. Conn. in the absence of thiols. In the presence of thiols BAGHDAD generated of 0.182 mol of nitrite per mole ex. Conn. in the presence of cysteine and 0,154 in the formation of nitrite.

During incubation BAGHDAD in the above conditions in the presence of oxyhemoglobin and cysteine or glutathione was observed the formation of methemoglobin (see example 4).

According to known data of the NO-generating properties closest known analogue in the conditions described (in the presence of thiols), the study failed due to its very low solubility in the experiment.

Example 2. The formation of S-nitrosothiols (S-nitrosoglutathione) 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidation.

To determine the S-nitrosothiols used a method based on reaction with mercury chloride (II), during which there is a formation of nitrite. To account for the formation of nitrite during the reaction of the compounds of the present invention with glutathione the reaction was carried out as described in example 8, and then nitrite was determined by the method described in example 8, in the absence and in the presence of mercury chloride (II) in a concentration of 0.1%. The difference between the obtained values corresponds to the number of S-nitrosoglutathione.

In the above conditions does not result in formation of S-nitrosoglutathione of the compounds of formula I. the Ability to generate well-known analogue of S-nitrosothiols has not been studied.

Example 3. Alenia reduced forms of nitrogen oxide (NO-/HNO) used a known method, based on the fact that formed during the reaction nitroxyl reacts with thiols to form hydroxylamine (or competitive formation of N2O), which, after oxidation of ions of I3-gives nitrite, as defined by azocoupling reaction (see example 8). Since the studied compounds also generate and nitrite, which is similarly reacts result, at the final stage, as a positive control was used hydroxylamine hydrochloride and sodium nitrite in a concentration of 0.1 mm, and incubation was performed as described in example 1 at pH 7.4. After incubation, the samples were added to 100 ál of 3 M sodium acetate, 400 µl 0,92% solution of sulfanilic acid in 30% acetic acid, 100 μl of 1.25% I22% KI, 30 ál of 0.5 M 2-mercaptoethanol and 400 µl of 0.05% N-naphthylethylenediamine. Samples were incubated 15 min and measured the optical density at a wavelength of 554 nm on the spectrophotometer. In parallel with this experiment was carried out measuring the formation of nitrite, as described in example 1. The content of hydroxylamine was calculated by the formula: X=(A-YN)/H, where X corresponds to the concentration of hydroxylamine, μm; And optical density improvement is described in example 1, μm; N is the optical density of the positive control containing sodium nitrite, μm-1; and N is the optical density of the positive control containing hydroxylamine hydrochloride, μm-1.

In the above conditions was not observed the formation of hydroxylamine compounds of this invention in the presence of cysteine or glutathione. The ability to generate well-known analogue of reduced forms of nitrogen oxide have not been investigated.

Thus, BAGHDAD is a selective NO donor.

Example 4. The formation of methemoglobin from oxyhemoglobin under the action of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing.

The definition of generation of NO in the presence of oxyhemoglobin, accompanied by the formation of methemoglobin, studied in a known manner in a spectrophotometric cuvette final volume of 1 ml at 25oC. Samples contained 25 mm potassium phosphate buffer (pH 7.4), 3 μm oxyhemoglobin, 0.5 mm cysteine or glutathione and BAGHDAD at a concentration of 0.1 mm. Had determined the rate of increase of absorbance at 401 nm, and the linear initial plot was calculated the rate of formation of nitric oxide (molar ratio of absorption of methemoglobin was taken equal to 39.9 mmol-1

In the above-mentioned conditions BAGHDAD caused the formation of methemoglobin from oxyhemoglobin, and this effect was enhanced in the presence of cysteine and glutathione. The reaction rate constant (NO+GM-O2-->NO3-+mathm) in the presence of cysteine was set to 0,0348 min-1in the presence of glutathione - 0,0341 min-1

The RHC activity was measured in preparations from the lungs of a bull, obtained in a known manner.

To obtain drug RHC from the lungs of a bull tissue homogenized in 5 volumes of 50 mm Tris-HCl buffer (pH of 7.6) containing 10 mm MgCl2using homogenizer "glass-glass". The homogenate was centrifuged for 30 min at 30,000 g supernatant was collected and determined the enzyme activity by the number of [32P] cGMP formed from [-32P]GTP, in a known manner. Protein (about 0.2-0.5 μg protein partially purified preparation from the lungs of a bull) on ice was added to the incubation mixture (final volume of samples 100 ál) containing (final concentrations) 50 mm Tris-Hcl pH to 7.6, 1 mm 3-isobutyl-1-methylxanthines, 5 mm MgCl2, 0.4 mg/ml creatine phosphokinase, 5 mm creatine phosphate, 2 mm cGMP, 0.2 mm GTP, 10000-20000 pulse/min/pmol [-32P]GTP (IPPE, Obninsk), and 10 mm DTT. When defining a trigger actions in the incubation medium was made of the studied compound at a concentration of 10 μm in the form of a solution in aqueous DMSO, and in a control sample was added DMSO to a concentration of 0.02%. The control sample showed no effect of DMSO at the indicated concentrations on the basal activity of the RHC. Sample encubierta matney temperature of the sample was added 0.5 ml of 30 mm Na2CO3and 0.6 ml of 36 mm Zn(CH3Soo)2, incubated at 4oC for 10 min and centrifuged at 15000 g for 5 min the Supernatant was applied to a chromatographic column with alumina, balanced 1 M perchloric acid, which is then washed with water. The elution of [32R]cGMP was performed with 0.2 M ammonium formate in vials for scintillation counting, radioactivity was measured using liquid scintillation counter in a known manner.

The compound of the present invention, depending on the concentration of 11.0 (10 and 50 μm)-16,6 times (100 μm) increased the activity of RHC from the lungs of rats. Influence of known structural analogue to the RHC activity has not been studied.

Example 6. Inhibition of aggregation of human platelets caused 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidation.

The effect of the compounds of the present invention on the aggregation of human platelets was studied known turbidimetric method of born. This venous blood taken at 8 o'clock in the morning in healthy donors was centrifuged at 450 g at room temperature in plastic dishes for 10 min, using as an anticoagulant sodium citrate. The supernatant, i.e. platelet-rich plasma was collected and the or in platelet-rich plasma to 2.5108cells/ml with dilution platelet-poor plasma was added and the resulting suspension in a cuvette with a volume of 0.5 ml. Aggregation was induced by the addition of ATP to a concentration of 2-5 microns. The concentration of ADP was selected in each experiment so that the aggregation was reversible and maximum accounted for 2 min after addition of ADP, not exceeding 50%. The scattering suspension of platelets was measured using aggregometry developed in the laboratory of Bioorganic chemistry of biological faculty of Moscow state University. M. C. Lomonosov (Russia). The target compound was added to the sample to ADP.

The results show that BAGHDAD in the described conditions inhibited platelet aggregation. The value of the concentration at which was achieved premaxillae inhibition (IC50), for this connection amounted to 2.2 μm. Known analogue, according to the prototype, in similar conditions, had the value of the IC501.8 microns.

Example 7. Vasodilator and antispasmodic activity of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing.

Vasodilator and antispasmodic activity BAGHDAD studied on the model of isometric contraction of smooth muscle of the isolated segment of the aorta in rats under the action of InEU aorta of male rats of Wistar rats with average weight of 280 g (210-330 g) in a known manner. Rats were decapotable, cut the thoracic aorta and purified from adipose tissue. Then cut the rings with a width of 2.5 mm, which were hung on two parallel hooks stainless steel. One of the hooks fixed to the wall of the chamber, and the other was connected to an isometric transducer DY1 connected with eight-channel data logger (Beckman, USA). The camera contained 30 ml of Krebs solution (130 mm NaCl, of 4.7 mm KCl, 2.5 mm l2, 1,18 mm KN2RHO4at 14.9 mm Panso3, 1.2 mm MgSO4, 11 mm glucose) at 37oWith that was under constant aeration with 95% O2/5% CO2to maintain pH 7.4. In the Krebs solution was added indomethacin concentrations up to 1 μm. If necessary, the endothelium was removed mechanically. Rings before you experience balanced for one hour under a load of 2.5 g Before the beginning of the experiment ring presacral 10 nm norepinephrine, and after 20 min caused a reduction of the drug by the addition of phenylephrine in a concentration of 0.3 microns. After the stabilization muscles of the vessel was registered, it relaxes in response to cumulative doses of the compounds in the concentration range from 0.003 nm to 50000 nm. Then study the connection laundered 6-7 shifts incubation medium for 1 hour and kontrolliaparatuurile compounds in water the effect of solvent (DMSO) on the isometric contraction of the vessel was determined in separate experiments. It was found that DMSO at a concentration of 0.1-0.2% with almost no effect on vascular tone, allowing you to test vasorelaxant the active compound in concentrations up to 100 μm. All experiments were repeated at least 3 times. The concentration value of the compounds corresponding to 50% relaxation of the vessel (IC50), was calculated using the program SigmaPlot version 2.0 standard equation for a sigmoidal dependencywhere R corresponds to the relaxation of the vessel when the concentration of the connection, Rmax is the maximum relaxation under the influence of this same compound, and n is the virtual coefficient of cooperativity, warioware in the range from 1.1 to 1.8. The reliability of the selection of the parameters (n and IC50), which was controlled by the method of least squares, was at least 95-97%. Statistical analysis was performed by student's t test (t).

Under these conditions BAGHDAD caused the reduction of isometric contraction of the vessel with intact endothelium in the presence of phenylephrine (IC50=22 nm).

According to the prototype, well-known compound in vitro, close to the above, possessed immediately is eparate (glyceryltrinitrate), used as the standard of comparison in the above conditions, this parameter had a value of 5.3 nm.

Example 8. Hypotensive activity of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing.

Hypotensive activity of the compounds of the present invention of General formula I were determined in vivo in awake rats of Wistar rats with average weight of 280 g in a known manner. For measurement of mean arterial pressure and heart rate and for the introduction of the drug in the bloodstream for days before the experiment, animals were implanted polyethylene catheters (grades D-10, D-50) into the femoral artery and femoral vein. The free ends of the catheter taken out and fixed on the head. The operation was conducted under geksenalovy anesthesia (150 mg/kg). The next day the rat took in the experience. During the experiment were recorded blood pressure sensor company Stadham (USA) with the following registration data using a computer program Bioshell, Faculty of Fundamental Medicine, Moscow state University. University, Russia). Compounds were injected bolus intravenous dose of 2.5 mg/kg in a volume of 0.2 ml in 5% DMSO. During the whole experiment the animals were awake and could move freely in the cage. During C indicators carried out continuously during the entire experience. The original values of mean arterial pressure and heart rate was 98,3 mm RT. Art. and 315,6 beats/min, respectively.

Bolus BAGHDAD at a dose of 0.5 mg/kg had no effect on blood pressure within 5 minutes there was observed a short-term minor increase in heart rate followed by a decrease to the initial level. Thus, BAGHDAD does not show the hypotensive effect when administered intravenously to rats at doses up to 0.5 mg/kg the Effect of known similar to blood pressure in vivo has not been studied.

Example 9. Acute toxicity of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing.

Acute toxicity of the compounds of the present invention was determined in a known manner by LD50using outbred mice of both sexes with average weight of 21 g at room temperature; standard diet and water was given ad libitum during the whole experiment; the mobility of the animals is not restricted. Solutions of the compounds in DMSO were injected using a sterile syringe intraperitoneally. After injection the animals were observed for 48 hours; after this time the mice were observed updat the scientists, the results suggest what is LD50for 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing is ~ 150-300 mg/kg Acute toxicity-known analogue has not been studied.

According to known data, the same indicator for basic pharmaceuticals - glyceryltrinitrate in similar conditions corresponds 7-9 mg/kg (RF patent 2086534 (07 With 203/04) 1994, PL.2).

The above examples 1 to 5 show that the 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-doxazosin is an efficient donor of nitric oxide and the activator RHC. From example 7, the conclusion must be that this compound has a pronounced antispasmodic and vasodilator, surpassing the appropriate pharmacological effect in vitro known structural analogue. However, in contrast to the known derivatives of furoxane, BAGHDAD had no significant effects on blood pressure when administered intravenously at a dose of 0.5 mg/kg, which can be directed local use.

Thus, 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-doxazosin above formula I is representative of a new class of NO donors, activators RHC, platelet aggregation inhibitors, antispasmodic and vasodilators.

as a donor of nitric oxide, which activates the soluble form of guanylate cyclase, inhibits platelet aggregation and has antispasmodic and vasodilator.


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