Derivatives 1,4,2,5-deoxidizing

 

The invention relates to new chemical compounds, in particular derived 1,4,2,5-deoxidizing General formula I, where R denotes the formula II and R1denotes the N3or NO2. The described derivatives 1,4,2,5-deoxidizing are activators of soluble form of guanylate cyclase. The technical result - the creation of new activators of soluble form of guanylate cyclase. 1 C. p. F.-ly, 1 PL.

The invention relates to new chemical compounds derived 1,4,2,5-deoxidizing General formula I:where R =R1= N2or NO2.

Preferably these compounds are activators of soluble form of guanylate cyclase (RGC).

This invention can be used in biochemistry and physiology.

Guanilatziklazu /EC 4.6.1.2; 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 is novlene, that RHC plays a key role in the regulation of these physiological processes such as contraction and relaxation of smooth muscles of blood vessels and platelet aggregation.

It is shown that some low molecular weight compounds that are activators RHC, regardless of cGMP can also affect the activity of a number of other enzyme systems. One such biochemical objects is glyceraldehyde-3-phosphate dehydrogenase /nicotinamide dinucleotide(NAD)-dependent/ (GAPDH) (EC 1.2.1.12), catalyzing oxidative phosphorylation 3-phosphoglycerate aldehyde. In particular, nitric oxide and its donors, stimulating RHC, are able to reduce the activity of GAPDH (e.g., S. Dimmeler, F. Lottspeich, B. Brune "Nitric oxide causes ADP-ribosylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase" J. Biol. Chem. 1992, v. 267, 24, p. 16771-16774; B. Brune, E. G. Lapetina "Glyceraldehyde-3-phosphate dehydrogenase: a target for nitric oxide signaling" Adv. Pharmacol. 1995, v. 34, p. 351-360).

Creating compounds with high specificity of action against RHC, is of considerable interest from the point of view of selective regulation of cGMP-dependent physiological processes.

Known 4-nitroquinoline-1-oxide of formula II:providing an activating effect on RHC (Craven, P. A., De Rubertis, F. R, "Inhibition by connection has mutagenic properties. Selectivity its activating action on RHC was not studied (in particular, the influence on the activity of GAPDH is not known).

There are various 3,4-disubstituted furoxone (1,2,5-oxadiazol-2-oxides) of General formula III:where R1and R2is methyl, phenyl, phenylsulfonyl, nitrile, methoxy-, nitro - or amino group, generating nitric oxide and activating RHC (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).

The specificity of effects data derived furoxone on the activity of the RHC has not been studied.

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 4-aminopyrazine-3-carbohydratesonly acid Chemistry of heterocycle. Conn., 1992, 5, S. 687-691).

Biochemical, physiological and pharmacological properties of this compound have not been studied.

Closest to the compounds of the present invention in structure and properties is 4,7-dimethyl-1,2,5-oxadiazole[3,4-d] pyridazine-5,6-trioxide (DOPO) of formula IV:

containing in the molecule 1,2,5-oxadiazolyl cycle and Simich enzymes in particular, it activates the RHC and inhibits GAPDH (RF patent 2130490, C 12 N 9/88, 9/99, 1997).

Despite the high degree of activation RHC under the action of DAPTO, this connection was also an effective inhibitor of GAPDH.

The aim of the invention is the creation of new heterocyclic activators of soluble form of guanylate cyclase with improved biochemical properties, in particular, more pronounced and selective trigger action on RHC.

This goal is achieved by the new derivatives 1,4,2,5-deoxidizing above formula I, where R has the above significance, activating the RHC.

3,6-Bis(4-nitrofurazan-3-yl)-1,4,2,5-doxazosin was synthesized by the method based on the well-known oxidation reactions aminopyrazine to the corresponding nitro-derivatives (e.g., T. S. Novicova, T. M. Mel nikova et al. "An effective method for the oxidation of aminofurazans to nitrofurazans" Mendeleev Commun. , 1994, p. 138-140) and involves the processing of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing cryptanalyses acid at a temperature of 15-18oC.

3,6-Bis(4-azidopyridine-3-yl)-1,4,2,5-doxazosin was obtained by the method based on the known reaction of diazotization aminopyrazine with solutions of sodium nitrite in sulfuric acid and processing prom with. 1949-1954) and which consists in the interaction of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing with a solution of sodium nitrite in sulfuric acid at a temperature of 10-12oWith further dilution of the reaction mixture of phosphoric acid and adding an aqueous solution of sodium azide.

Source 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-doxazosin was obtained in a known manner, based on the reaction of the directed dimerization 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(C. G. Andrianov, V., Semenikhina, A. C. Eremeev "Halides 4-aminopyrazine-3-carbohydratesonly acid". Chemistry of heterocycle. Conn., 1992, 5, S. 687-691).

The invention is illustrated by the following examples.

Example 1. 3,6-Bis(4-nitrofurazan-3-yl)-1,4,2,5-doxazosin (1).

To a solution of cryptanalyses acid, prepared by careful addition of 3.4 ml (0.24 mol) triperoxonane anhydride to a 5.4 ml (0.2 mol) of 90% hydrogen peroxide with cooling with ice water, with vigorous stirring in small portions was added 1.26 g (0,005 mol) of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing within 3 to the reaction, which may occur after a certain induction period). Then the reaction mixture was kept at room temperature until the disappearance of the original amine (control by TLC) and then poured into cold water. Precipitated solid product is filtered off, washed with water until neutral wash water and dried in air. After two recrystallization from dichloroethane obtain 0.75 g of the target product (yield 20%). So pl. 101-102oC. IR spectrum (KBr),cm-1: 1675 SL., 1645 cf., 1587 S. , S. 1557, 1482 cf., 1358 cf., 1273 S., 1240 SL., 1088 S., 1030 S., 1011 Wed , 903 FF., 882 CL., 861 S., 827 S., 763 cf.

NMR13With spectrum (DMSO-d6),, M. D.: 160,53, 153,27, 140,55.

Found, %: C 23,22; N 36,17 (C6N8O8).

Calculated, %: C Results Were 23.08; N 35,89.

Example 2. 3,6-Bis(4-azidopyridine-3-yl)-1,4,2,5-deoxidized.

To a solution of 1.4 g (20 mmol) of sodium nitrite in 10 ml of concentrated sulfuric acid, obtained at a temperature not exceeding 15oC, with stirring and at a temperature of 10-12oWith added dropwise a solution of 2.5 g (10 mmol) of 3,6-bis(4-aminopyrazine-3-yl)-1,4,2,5-deoxidizing in 30 ml of sulfuric acid. The reaction mixture was incubated for 30 min at this temperature, then with stirring, add 40 ml of then portions with vigorous stirring and at a temperature not exceeding 15oWith added dropwise a solution of 5 g (77 mmol) of sodium azide in 13 ml of water and stirred for 30 minutes After the reaction mixture was poured on ice (200 g) emitted in the form of foam precipitate is filtered off, washed with water until neutral wash water and dried under reduced pressure in the presence of sodium hydroxide. Obtain 2.1 g of the target product (yield 66.2 per cent). The connection is unstable to light and decomposes during storage in the form of a solution in a polar organic solvents (dimethyl sulfoxide, dimethylformamide, acetone, methanol). So different. 110-112oC.

NMR13With spectrum (CDCl3),, M. D.: 153,49; 153,14; 137,42.

Found, %: C 23,96; N 55,54 (C6N12O4).

Calculated, %: C 23,70; N 55,26.

Example 3. Activation of the soluble form of guanylate cyclase derived 1,4,2,5-deoxidizing.

The RHC activity was measured in preparations of the pig's lungs, obtained in a known manner. The enzyme activity was determined 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 pigs) on ice was added to the incubation mixture (final volume of samples 100 ál) containing (con who, 5 mm creatine phosphate, 2 mm cGMP, 0.2 mm GTP, 10000-20000 pulse/min/pmol [-32P]GTP (Isotope, INP, 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. Samples were incubated at 37oC for 15 minutes the Reaction was stopped by boiling the samples for 2 min After cooling to room temperature the sample was added 0.5 ml of 30 mm Na2CO3and 0.6 ml of 36 mm Zn(CH3Soo)2were mixed , 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 [32P]cGMP was performed with 0.2 M ammonium formate in vials for scintillation counting, and the radioactivity was measured using liquid scintillation counter in a known manner.

Compounds of the present invention, depending on the concentration, increased the activity of RHC leg,8 times (100 μm). Known structural analogue, DAPTO, in the same conditions increased the activity of RHC 2.3 (25 μm) and 5.5 times (50 μm).

Example 4. Inhibition of glyceraldehyde-3-phosphate dehydrogenase derived 1,4,2,5-deoxidizing.

GAPDH isolated from rabbit muscle in a known manner (activity 100-105%) at a concentration of 1.7 mm, plaincourault in 20 mm buffer HEPES-NaOH (pH 7.5) in the presence of 68 μm of the compounds under study. As control was used DMSO in a concentration of 0.1%. In the sample also was added 2-mercaptoethanol to a concentration of 0.5 mm. After incubation at room temperature, an aliquot was transferred into a medium for measurement of enzyme activity, containing 0.1 M glycine buffer (pH 8.9), 0.5 mm NAD, 0.5 mm glyceraldehyde-3-phosphate and 20 mm sodium arsenate and registered the increase of optical density at 340 nm with a spectrophotometer in 15 seconds, recording the initial reaction rate. Compounds of General formula I had inhibitory effect on the activity of GAPDH. The results presented in the table.

As follows from the data table, the compounds of the present invention (in particular, 3,6-bis(4-nitrofurazan-3-yl)-1,4,2,5-doxazosin) at much higher concentrations had a less pronounced inhibitory action is om, new derivatives of 1,4,2,5-deoxidizing above formula I are representatives of a new class of activators RHC, providing a more efficient and selective effect on this enzyme.


Claims

1. Derivatives 1,4,2,5-deoxidizing General formula I

where R denotes

R1denotes the N3or NO2.

2. Derivatives 1,4,2,5-deoxidizing under item 1 as activators of soluble form of guanylate cyclase.

 

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5 cl, 3 tbl, 4 sch, 8 ex

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