Medicinal substances and pharmaceutical compositions based on thereof for using in cases of oxidative stress

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

 

The present invention relates to a new medicinal substances intended for both systematic and unsystematic use, and compositions based on them for use in oxidative stress and/or endothelial dysfunctions medium intensity.

Under oxidative stress refers to the formation of free radicals or radical compounds, which cause the destruction of both the cells and their surrounding tissue (Pathophysiology: the biological basis for disease in adults and children McCance&Huether 1998, pp. 48-54).

Under endothelial dysfunction involve dysfunction related to vascular endothelium. It is known that damage to the vascular endothelium is one of the major reasons that can cause a series of pathological processes affecting various organs and systems of the body, as described in Pathophysiology: the biological basis for disease in adults and children McCance &Huether 1998, p. 1025).

As is known, oxidative stress and/or endothelial dysfunction is associated with various pathologies, which are described next. Oxidative stress can also be caused by the toxicity of a large number of various medicinal substances, which greatly affects the effectiveness of their actions.

These pathological manifestations are chronic, debilitating body, and very often I have are typical for elderly people. As already mentioned, in the above mentioned pathological conditions the effectiveness of drugs is significantly reduced.

We can cite the following examples of pathological conditions due to oxidative stress and/or endothelial dysfunctions or characteristic of the elderly:

For the cardiovascular system: myocardial and vascular ischemia in General, hypertension, stroke, atherosclerosis, etc.

For connective tissue rheumatoid arthritis and related inflammatory diseases, etc.

- Respiratory system: asthma and related inflammatory diseases, etc.

For the digestive system: ulcer and non-ulcer dyspepsia, intestinal inflammatory diseases, etc.

For the Central nervous system: Alzheimer's disease, etc.

For genitourinary: impotence, incontinence.

For the skin: eczema, neurodermitis, eels.

- Infectious diseases in General (see: Schwarz, Brady "Oxidative stress during viral infection: a review" Free Radical Biol. Med. 21/5, 641-649, 1996).

In addition, the aging process itself can be considered as a valid pathological condition (see Pathophysiology: the biological basis for disease in adults and children, pp. 71-77).

Known medicinal substances, with the introduction of their patients with pathologies associated with oxidative stress and/or endotelialnami dysfunction, show reduced activity and/or increased toxicity.

This occurs, for example, in the case of such drugs as anti-inflammatory, cardiovascular drugs, medicinal substances to the respiratory system, drugs for the Central nervous system, drugs for the skeletal system, antibiotics, drugs for urinary, endocrine system, etc.

Studies of drugs aimed at the search of new molecules with improved therapeutic index (the ratio of efficacy/toxicity), or low risk/beneficial effects, including for the above mentioned pathological conditions, in which therapeutic index of a significant number of medicinal substances is low. In fact, when the above conditions of oxidative stress and/or endothelial dysfunction many drugs exhibit reduced activity and/or increased toxicity.

In particular, anti-inflammatory drugs such as NSAIDs and medicinal substances against colic, such as 5-aminosalicylic acid and its derivatives, have the following disadvantages. NSAIDs are toxic properties, especially in cases when the body is weakened or is under the effects of the m pathological conditions, associated with oxidative stress. Specific States may include, for example, the following: advanced age, previously transferred ulcer, previously transferred stomach bleeding, chronic disease, debilitating body, particularly affecting the cardiovascular system, renal system, blood, etc. ("Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal anti-inflammatory drugs. A randomized, double blind, placebo-controlled trial." F.E. Silverstein et al. Ann. Intern. Med. 123/4, 241-9, 1995; Martindale 31 a ed. 1996, pag. 73, Current Medical Diagnosis and Treatment 1998, pages 431 and 794).

The introduction of anti-inflammatory drugs to patients in the above-mentioned pathological conditions, can only be done using lower doses of medicinal substances compared to those that are typically used for therapy in order to avoid noticeable toxic effects. Therefore, anti-inflammatory activity appears weakly.

Beta-blockers, used to treat angina, hypertension and cardiac arrhythmia have adverse effects on the respiratory system (cough, bronchostenosis), so they may have problems in patients with abnormalities of these organs (asthma, bronchitis). Thus beta-blockers even more worsen the condition when such diseases of the respiratory system, and as the TMA. Therefore, patients suffering from asthma should be prescribed a reduced dose of these drugs, so as not to expose more danger of their respiratory system. As a result, the effectiveness of beta-blockers significantly reduced.

Antithrombotic agents, such as dipyridamole, aspirin, etc. used for preventing symptoms of thrombosis, have the same disadvantages. In patients with pathologies associated with oxidative stress and/or endothelial dysfunction, therapeutic effect or tolerability of these drugs, particularly aspirin significantly reduced.

For the treatment of asthma and bronchitis use bronchodilators, such as salbutamol and so on, and such disorders as urinary incontinence use of medicinal substances acting on the cholinergic system. At their introduction may experience similar side effects on the cardiovascular system and cause problems in patients suffering from heart failure and hypertension. Heart failure and hypertension are pathologies associated, as mentioned above, oxidative stress and/or endothelial dysfunction. These medicinal substances also have the same disadvantages as listed previously.

Expectorants and localitiesrelocation substances, used for the treatment of inflammatory respiratory diseases, have the same disadvantages of the patients in the above-described conditions. Their introduction can cause heartburn and stomach irritation, especially in the elderly.

Inhibitors of bone resorption, such as diphosphonates (e.g., alendronate, and so on)are medicinal substances exhibiting increased gastrointestinal toxicity. Therefore, these medicinal substances can also have the same disadvantages as described above.

In the case of phosphodiesterase inhibitors, such as sildenafil, zaprinast used for the treatment of diseases of the cardiovascular and respiratory systems, there are similar problems with tolerability and/or efficacy in the above-mentioned pathological conditions of oxidative stress and/or endothelial dysfunction.

Anti-allergic drugs such as cetirizine, montelukast, etc. cause similar problems in these pathological conditions, particularly in relation to efficiency.

Antiangiogenesis medicinal substance, i.e. the ACE inhibitors such as enalapril, captopril, etc. or inhibitors, receptors, such as losartan, etc. is used for treatment of cardiovascular diseases. Their disadvantage is the full effects on the respiratory system (for example, the occurrence of cough and so on) in the above-mentioned pathological conditions.

Antidiabetic medicinal substances, as increasing insulin sensitivity and reduce glucose levels, such as, for example, sulfonylureas, tolbutamide, glipizide, gliclazide, gliburid, nicotinamide, etc. are ineffective for the prevention of diabetic complications. At their introduction may experience side effects such as lesions of the stomach. These effects are amplified when the above-mentioned pathological conditions.

In the case of antibiotics, such as ampicillin, clarithromycin, etc. and antiviral drugs such as acyclovir and other problems associated with their tolerability, in particular they cause irritation of the gastrointestinal tract.

Anticancer drugs such as doxorubicin, daunorubicin, cisplatin, and others, are highly toxic to various organs, including the stomach and intestines. This toxic effect is further enhanced when the above-mentioned pathological conditions of oxidative stress and/or endothelial dysfunction.

Medicinal substances against dementia, such as nicotine and cholinomimetic, are characterized by poor tolerability, especially in the case of the above pathologies.

Lek is stennie substances steroid structure, used for treatment of acute asthma etc) or chronic diseases (diseases of the intestine, liver, respiratory organs, diseases of the female reproductive system, hormonal disorders, skin diseases, etc), are noticeable toxic effects on various organs, especially in the aforementioned state of oxidative stress.

Class of steroid drugs including hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, hypertension, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone acetonide, fluopicolide acetonide, beclomethasone, acetoxyphenyl etc., has a significant pharmacotoxicology effects on various organs, and therefore, their clinical application, and the interruption cause a number of side effects, some of which can be very serious. See, for example, Goodman & Gilman's "The Pharmaceutical Basis of Therapeutics", 9th ed., pp. 1459-1465, 1996.

Among these toxic effects, it should be noted effects on bone tissue, which leads to changes in cellular metabolism and increase the likelihood of osteoporosis; the impact on the cardiovascular system, leading to hypertension; effects on the gastrointestinal system, leading to gastrointestinal disorders. See, for example, artindale "The Extrapharmacopoeia, 30th ed., pages 712-723,1993.

To the class of steroid drugs also belong bile acid used in the treatment of diseases of the liver and biliary colic. Ursodeoxycholic acid is also used in some disorders of the liver (cirrhosis of the liver biliary origin and so on). The tolerability of these drugs is greatly diminished in the presence of gastrointestinal complications (chronic liver damage, stomach ulcers, intestinal inflammation, and so on). In the case of bile acids oxidative stress also significantly affects the efficiency of drug substances: both the efficacy and tolerability chenodeoxycholic and ursodeoxycholic acid significantly reduced. Especially amplified unwanted effects on the liver. Among steroid compounds can also mention estrogens used to treat dyslipidemia, endocrine disorders, tumors of the female organs. Mentioned steroids also have the above side effects, especially PA liver.

Based on the above-described prior art, it is practically impossible to separate therapeutic activity of side effects (see Goodman et al, as above, page 1474).

Thus there is a need to develop affordable drugs, obladaushi the improved therapeutic effect, i.e. providing and reduced toxicity and/or increased efficiency, so you can enter the patients with pathologic conditions of oxidative stress and/or endothelial dysfunctions, without showing the drawbacks of medicinal substances known from the prior art.

It has been unexpectedly discovered that the above-mentioned problems arising from the introduction of drugs for patients suffering from oxidative stress and/or endothelial dysfunctions, or older people in General, can be solved by using a new class of drugs described below.

The object of the invention are compounds or their salts corresponding to the following General formula (I):

A-B-N(O)s(I)

where: s=2

A=R-T1-where

R represents a radical of medicinal substance, provided that the medicinal substance according to the formula R-T1-Z or R-T1-OZ, where T1=(CO) or, O, S, NH, and Z represents H or a linear or branched C1-C5alkyl, selected from paracetamol, salbutamol, Ambroxol, alendronova acid, cetirizine, ampicillin, acyclovir, doxorubicin, simvastatin, dyphylline, tacrine, clopidogrel, dimethylmercury, diclofenac, ferulic acid, enalapril, propranolol, venturedeal of hemisuccinate, tolrestat or sulindaka;

=-TB-X2-0-, where

TB=(CO), O, or NH;

X2is a bivalent radical equal to the radical R1B-X-R2Bwhere X represents a bond. O, S, NR1Cwhere R1Crepresents H or a linear or branched C1-C5alkyl, R1Band R2Bequal or different, are linear or branched C1-C6alkylene that the corresponding predecessor In does not match the test conditions 5 and meets the conditions of the test 4A; and the specified precursor has the formula-TB-X2Is HE, where TB=(JI), and the free valency of TBbusy

-OZ, where Z is as defined above, when TB=0, and the free valency of TBbusy N;

the medicinal substance A=R-T1-where the free valence is occupied, as defined above, and meets the conditions of at least one of the tests 1-3;

where test 1 (NEM) is a test that is carried out in vivo with four groups of rats (each consists of 10 rats), including the control group (two groups) and experimental group (two groups), with respectively one control and one test groups were subcutaneously injected with one dose of 25 mg/kg N-ethylmaleimide (NEM), the control group treated with the carrier, and the experimental group treated with carrier + drug substance formula is A=R-T 1-where the free valence is occupied, as described above, and injected dose of medicinal substance equivalent dose, maximum tolerated by the rats, which did not enter NEM, i.e. the highest dose, which you can enter the animal that it has not caused any obvious toxic effects, i.e. with visible symptoms; drug substance complies with the conditions of test 1, i.e. it can be used to obtain compounds of General formula (I), if the group of rats treated with NEM + carrier + drug, you experience gastrointestinal damage, or the group of rats treated NEM + carrier + drug, you experience gastrointestinal damage to a greater extent than the group treated only by the media, or than the group treated with carrier + drug, or than the group treated with carrier + NEM;

where test 2 (CIP) is an in vitro test, in which endothelial cells from umbilical vein grown in standard conditions, then divided into two groups (each experience plays five times), one of these groups is treated with a mixture of medicinal substance with a concentration of 10-4M in the culture medium, and another group treated with the carrier; then, for each of these two groups add the cumene hydroperoxide (CIP) with the oxygen is set to 5 mm in the culture medium; when this drug substance complies with the conditions of test 2, i.e. it can be used to obtain compounds of General formula (I), if not a statistically significant inhibition of apoptosis (cell damage)caused CIP, at p<0,01 compared with the group treated with the carrier and CIP;

where test 3 (L-NAME) is a test that is carried out in vivo for 4 weeks with four groups of rats (each consists of 10 rats receiving drinking water, including the control group (two groups) and experimental group (two groups), with respectively one control and one experimental group will receive during these 4 weeks of drinking water with the addition of methyl ester of N-ω-nitro-L-arginine (L-NAME) with a concentration of 400 mg/l, control groups within four weeks of the injected media, and experienced groups within four weeks of the injected carrier + drug, and the carrier or carrier + drug is administered once a day, and the medicinal substance is administered in a dose, maximum tolerated group of rats that were not pretreated with L-NAME, i.e. the highest dose, which you can enter the animal that it has not caused any obvious toxic effects, i.e. with visible symptoms; through the four weeks of access to water stop for 24 hours, and then W is animal death, measuring blood pressure for the first hour before killing after killing measure the level of plasma glutamate-pyruvate transaminase (ORT) and examine the condition of the tissues of the stomach; the medicinal substance meets the conditions of test 3, i.e. it can be used to obtain compounds of General formula (I), if the group of rats treated with L-NAME + carrier + drug, there are more severe liver damage (defined by higher levels of GPT), and/or damage to the stomach, and/or cardiovascular damage (identified by higher values of blood pressure compared with the group treated with media or with the group treated with carrier + drug, or with a group treated with carrier + L-NAME, respectively;

where is the test 4A, which corresponds to the precursor compounds, is an in vitro test, in which part of the suspension of erythrocytes, pre-seasoned at 4°C for 4 days, and these erythrocytes receive a standard way from male Wistar rats and suspended in saline solution, buffered at pH 7.4 with phosphate buffer, centrifuged at 1000 rpm./min for 5 minutes and 0.1 ml was centrifuged erythrocytes diluted with sodium phosphate buffer with pH 7.4 up to 50 ml; specify the ow of dilute suspensions of selected aliquots of 3.5 ml (5 samples) and incubated at 37° In the presence of cumene hydroperoxide at a concentration of 270 μm, and determine the turbidity of the suspension at 710 nm every 30 minutes to install, at what point in time (Tmax) is the maximum turbidity, which corresponds to the maximum number of cells subjected to lysis under the action of cumene hydroperoxide (hemolysis take equal 100%); then to a 3.5 ml aliquot of the diluted suspension was centrifuged erythrocytes add alcohol solutions of precursor compounds In the test carried out with 5 samples for each of the analyzed predecessors In) to 2 mm final concentration of the precursor, and then the resulting suspension is pre-incubated within 30 minutes, add the cumene hydroperoxide in an amount sufficient to achieve the same final concentration as described above, and when Tmax determine the inhibition of hemolysis percentage from the ratio of absorbance of the sample containing erythrocytes, predecessor In and cumene hydroperoxide, and the sample containing erythrocytes and cumene hydroperoxide, multiplied by 100; the predecessors To comply with the conditions of this test, if they inhibit the hemolysis induced by cumene hydroperoxide, more than 15%;

where test 5, which does not correspond to the precursor compounds, represents the analyte is worded definition performed by adding an aliquot of 10-4M methanolic solution of the precursor In the solution obtained by mixing 2 mm aqueous solution of desoxyribose with 100 mm phosphate buffer and 1 mm solution of salts of Fell(NH4)2(SO4)2; after the temperature of this solution at 37°C for 1 hour add aliquots of 2.8% aqueous solution of trichloroacetic acid and 0.5 M aqueous solution thiobarbiturate acid in this order, heat the solution at 100°C for 15 minutes and then measure the absorption of the test solutions at 532 nm; the inhibition of radical formation of FeIIcaused by precursor compounds, calculated as a percentage using the following formula:

(1-As/Ac)×100

where Asand awithrespectively represent the magnitudes of the absorption solution containing the test compound and a salt of iron, and the solution containing only salt of iron; a connection matches the test conditions 5, if the percentage of inhibition predecessor, defined as above, is greater than or equal to 50%;

provided that in the formula (I), when X2in the structure represents a linear or branched C1-C20alkylen,

medicinal substances of the formula A=R-T1-with the free valence occupied, as you specified is e, used in compounds of formula (I), does not apply to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID).

In the formula-TB-X2The predecessor of the connection that corresponds to the test conditions 4A and does not meet the conditions of the test 5, it is possible to use compounds in which X2represents the radical R1B-X-R2Bwhere R1Band R2Bidentical or different, represent a linear or branched C1-C6alkylene, and X as defined above.

Other examples of precursor compounds are: 1,4-butanediol: HE-(CH2)4-HE, 6-hydroxyhexanoic acid: IT is-(CH2)5-COOH, 4-hydroxipropionic acid: IT is-(CH2)3-COOH, N-methyldiethanolamine: HE-(CH2)2-N(CH3)-(CH2)2HE, diethylene glycol: IT is-(CH2)2-O-(CH2)2HE, thiodiethanol: HE-(CH2)2-S-(CH3)2-HE; preferably the precursor In N-methyldiethanolamine, diethylene glycol, thiodiethanol.

Compounds, which are precursors of drugs and are in accordance with the methods known from the prior art and described, for example, in "The Merck Index, 12 Ed.", (1996), included here as a reference.

Tests (1-5) in more detail are as follows:

Test 1 (NEM): the valuation of gastrointestinal damage due to oxidative stress, caused by free radicals formed after the introduction of N-ethylmaleimide (NEM) (N. G. Utiey, F. Bernheim, P. Hochstein "Effects of sulphydril reagents on peroxidation in microsomes," Archiv. Biochem. Biophys. 118, 29-32, 1967).

Animals (rats) are allocated to the following groups (10 animals per group):

(A) Control group:

1°: processing: only the media (aqueous suspension of 1% wt./about.

carboxymethylcellulose, dose: 5 ml/kg, if the medicinal substance is injected through the mouth, or a physiological solution, if it is administered parenterally, i.e. subcutaneously, intraperitoneally, intravenously or intramuscularly),

group 2°: treatment: carrier, as defined above, + NEM,

C) the Experimental group who inject drugs:

group I: treatment: carrier + drug,

group II: treatment: carrier + drug + NEM.

Methods of administration are known for this medicinal substance; this may be oral, subcutaneous, intraperitoneal, intravenous or intramuscular method.

Dose NEM is 25 mg/kg in saline solution (subcutaneous administration), and the medicinal substance is injected after 1 hour the suspension media, in the form of single dose corresponding to the maximum dose, or the highest dose tolerated by the animals of the groups of rats that were not subjected to the preliminary impact of the NEM, that is, the high the dose, you can enter the specified group that it did not cause the animals clear of toxic effects that can be clearly identified by noticeable symptoms. Animals killed after 24 hours, after which begin the damage assessment of gastrointestinal mucosa.

Drug substance complies with the conditions of test 1, i.e. it can be used to obtain compounds of General formula (I), if the group of rats treated with NEM + carrier-g drug are gastrointestinal damage, or observed in this group of gastrointestinal injuries are to a greater extent than those observed in the group treated only by the media, or the group treated with the carrier and the drug, or the group treated with the carrier and NEM, even if pharmacotherapeutic efficacy of medicinal substances investigated using special tests, significantly not reduced.

Test 2 (CIP): the level of protection of endothelial cells from oxidative stress induced by cumene hydroperoxide (CIP).

Endothelial cells from umbilical veins receive in accordance with standard procedure. Fresh umbilical vein fill 0.1 wt.% the collagenase solution and incubated at 37°C for 5 minutes.

After that ve is s pour medium M 199 (GIBCO, Grand Island, NY) with pH 7.4, to which subsequently add other substances, as described in the examples. Collect cells from perfusion solution by centrifugation and grown in culture flasks T-75, pretreated with fibronectin person. Then grow the cells in the same medium, which optionally add 10 ng/ml of growth factor hypothalamus cattle. When cells primary cell culture (i.e., obtained directly ex-vivo) form a continuous cell monolayer (approximately 8000000 cells per flask), the growth of the culture is stopped, the layers are washed and treated with trypsin. Transfer cell suspension to the wells of the 24-hole tablet for cell cultures, to half and then add the same culture medium containing the medicinal substance at a concentration of 10-4M, then grow the cells in an incubator at 37°and at a constant humidity. Only cells from these early cultures used for experiments with cumene hydroperoxide (CIP). Cells identified as endothelial cells by morphological analysis, as well as on their specific immunological response to factor VIII; these cultures do not contain any contaminants from myocytes or fibroblasts.

Before starting the test cell culture medium is removed and glue the internal layers gently washed with saline solution at a temperature of 37° C. the Wells of the culture of the tablet then incubated for 1 hour with CIP contained in the culture medium at a concentration of 5 mm. Assessment of cell damage (apoptosis) is carried out by determining the percentage change in DNA fragmentation compared to the control group (which were treated only CIP), evaluating the change in fluorescence at wavelengths 405-450 nm. For each sample the experience is repeated five times.

Drug substance complies with the conditions of the test, i.e. can be used to obtain the compounds of General formula (I), if a statistically significant inhibition of apoptosis (cell damage)caused CIP compared with the group that was treated with only the CIP that are not registered at p<0,01.

Test 3 (L-NAME): assessment of endothelial dysfunction induced by L-NAME (methyl ester of Nw-nitro-L-arginine), J. Clin. Investigation 90, 278-281, 1992.

Endothelial dysfunction assessed by determining the damage of the mucous membranes of the gastrointestinal tract, liver damage, and increased blood pressure induced by L-NAME.

Animals (rats) are divided into groups in accordance with the scheme set forth below. The group receiving L-NAME administered for 4 weeks the specified connection, dissolved in drinking water at a concentration of 400 mg/L. Distinguish the following groups (10 animals in each is):

A) Control group:

1°: only the media (water suspension of 1 wt.%/about. carboxymethylcellulose, dose: 5 ml/kg, if the medicinal substance is injected through the mouth, saline solution, if it is administered parenterally),

group 2°: carrier + L-NAME,

B) Experimental group - who injected drugs:

group 3°: carrier + drug,

group 4°: carrier + drug + L-NAME.

Methods of administration are known for this medicinal substance, and it can be oral or subcutaneous, intraperitoneal, intravenous or intramuscular method. The medicinal substance is administered in a dose corresponding to the maximum dose tolerated by the animals of the groups of rats that were not injected with L-NAME, i.e. the highest dose, which you can enter, so it did not cause the animals overt toxic effects, which can be recognized by noticeable symptoms. The medicinal substance is injected once a day for 4 weeks.

By the end of the fourth week of treatment to stop the animals ' access to water, and after 24 hours of their death.

One hour before the killing measure blood pressure, and increase take as a criterion of assessment of damage to the vascular endothelium. Damage of the gastric mucosa appreciate as illustrated is in test 1 (see Example F1). Liver damage is determined by evaluating the content of glutamate-pyruvate transaminase (increase GPT) after the killing.

Drug substance complies with the conditions of test 3, i.e. can be used to obtain the compounds of General formula (I), if in the groups of rats treated with L-NAME + drug + carrier, there are more significant liver damage (GPT), and/or more significant damage to the stomach, and/or more significant damage to the cardiovascular system (blood pressure) compared to the group treated only by the media, or the group treated with the carrier and the drug, or the group treated with the carrier and L-NAME, even if the pharmacotherapeutic efficacy of medicinal substances studied with the use of special tests are not significantly reduced.

In the conditions specified for the above in vivo tests 1 and 3, therapeutic index of the drug substance is reduced due to the fact that the usual dose at which this drug can be effective, not tolerated.

Test 4A is carried out in accordance with the method described in R. Maffei Facino, M. Carini, G. Aldini, M.T. Calloni, Drugs Exptl. Clin. Res. XXIII (5/8) 157-165, 1997. Test 4A is an in vitro test, in which the red blood cells, obtained in the standard way from the male is soba Wister rats (Charles River) was incubated for 4 days at 4° With the suspension in physiological solution, buffered at pH 7.4 with phosphate buffer. At the end of this period take an aliquot of the suspension and centrifuged at 1000 rpm./min for 5 minutes. 0.1 ml was centrifuged erythrocytes diluted to 50 ml sodium phosphate buffer with pH 7.4, getting 0,2% vol. suspension of erythrocytes. To 5 aliquot of 3.5 ml of diluted suspension add 0.1-0.3 ml of alcohol solution of cumene hydroperoxide to achieve a concentration of 270 μm and then incubated them at 37°C. This compound causes lysis of the cells, and increases the turbidity of the suspension. After lysis of the cells is monitored by using turbidimetry at 710 nm. Through measurement of absorbance (or transmittance) every 30 minutes, determine the time (Tmaxwhen the turbidity of the suspension maximum, which corresponds to the maximum number of cells in suspension subjected to lysis. Tmaxtake the time corresponding to 100% lysis of erythrocytes. To determine the inhibitory effects of predecessors In the hemolysis induced by cumene hydroperoxide, add 0.1-0.2 ml of each of the investigated compounds, the precursors In ethanol to 3.5 ml of the aliquot was centrifuged suspension of erythrocytes (5 samples for each connection) to achieve a final concentration of 2 mm, and the floor is obtained, the suspension is pre-incubated for 30 minutes.

Then add the cumene hydroperoxide in an amount sufficient to achieve the same final molar concentration, as defined previously, and inhibition of connection of hemolysis percentage when Tmax is determined from the relationship of absorption of the sample suspension containing erythrocytes, predecessor In and cumene hydroperoxide, and absorption of suspensions containing erythrocytes and cumene hydroperoxide, multiplied by 100; the precursor compounds To meet the conditions of the test 4A, if it inhibits hemolysis induced by cumene hydroperoxide, more than 15%.

Test 5 is a colorimetric test in which 0.1 ml aliquots of 10-4M methanolic solutions of test compounds are added to a test tube containing a solution obtained by mixing 0.2 ml of 2 mm aqueous solution of desoxyribose, 0.4 ml of 100 mm phosphate buffer pH 7.4, and 0.1 ml of 1 mm solution of FeII(NH4)2(SO4)2in 2 mm HCl. Then the tubes incubated at 37°C for 1 hour. Then to each tube add 0.5 ml of 2.8% aqueous solution of trichloroacetic acid and 0.5 ml of 0.1 M aqueous solution thiobarbiturate acid in that order. Transparent control solution is prepared by adding to a test tube containing only the above aqueous solution of the reagent, 0.1 ml of methanol. Tube closing the Ute and heated on an oil bath at 100° C for 15 minutes. Solutions painted in pink color, and the intensity of staining is proportional to the number of desoxyribose subjected to radical oxidative cleavage. The solution is cooled to room temperature and then measuring their absorption at 532 nm, comparing with its transparent control solution. Inhibition of radical formation caused by the predecessor In relatively radical formation salt of FeIIdetermined using the following formula:

(1-As/Ac)×100

where Asand awithare respectively the values of the absorbance of a solution containing the test compound and a salt of iron, and the solution containing only salt of iron; a connection matches the test conditions 5 V if inhibition is a precursor In the formation of radicals, expressed as a percentage, as stated above, greater than or equal to 50%.

Unexpectedly it was found that the products according to the invention of formula (I) in a state of oxidative stress have improved therapeutic index compared with drug-predecessors. The compounds of formula (I) according to the invention, where the precursor compound corresponds In the test conditions 4A, but does not meet the test conditions 5, can be used, as described above, as drugs for therapy of oxidative stress are medium strength. In this sense, in accordance with the present invention the object of treatment are conditions of oxidative stress medium strength.

The above tests will be illustrated using the following compounds (see Table):

Test 1: drug-predecessor: indometacin

- Maximum input dose for rats: 7.5 mg/kg orally. With the introduction of higher doses appears toxicity, characterized by disease, tremor, depression of consciousness until death (within 24 hours).

- The group of rats treated with NEM and indomethacin in the above dose was observed gastrointestinal damage.

Because indomethacin causes gastrointestinal damage in rats treated with NEM, he complies with the conditions of test 1.

Test 2: drug precursor chemicals: indomethacin, paracetamol and mesalamine

Indomethacin and paracetamol meet the conditions of test 2, as the inhibition of cellular damage (apoptosis)caused CIP, slightly different from a similar inhibition in the control groups.

Therefore, the above-mentioned medicinal substances can be used as drugs to obtain the compounds (I) of the present invention.

In contrast, mesalamine does not correspond at what the conditions of test 2, as inhibits apoptosis induced CIP. Therefore, in accordance with test 2 mesalamine could not be used as a precursor for producing compounds (I) of the present invention. However, it was found that mesalamine subjected to test 1, gastro-intestinal damage.

Therefore, mesalamine can also be used as a precursor for producing compounds (I) of the present invention.

Test 3 (L-NAME) drug precursor chemicals: acetaminophen, simvastatin, omeprazole

Paracetamol and simvastatin correspond to the test conditions 3, because their action causes damage to the stomach and liver to a greater extent than action as L-NAME + media, and systems drug + carrier.

Therefore, they can be used as precursors for producing compounds (I) of the present invention.

In contrast, it was found that omeprazole does not cause damage to the stomach or liver, and does not affect blood pressure. In accordance with the test 3 omeprazole could not be used as a precursor for producing compounds (I) of the present invention.

Test 4A test (for predecessor)

N-methyldiethanolamine by 54.4% (table V) inhibited the hemolysis induced by hydroperoxide ku is Ola. Therefore, it complies with the test conditions 4A and can be used as a predecessor, if he does not meet the conditions of the test 5.

Diethanolamin not inhibited hemolysis induced by cumene hydroperoxide and does not meet the conditions of the test 4A. Therefore, this compound cannot be used as a predecessor,

Test 5 (test for predecessor)

In Table III, related to this test, it is shown that N-methyldiethanolamine does not match the test conditions 5, as it did not inhibit the formation of radicals of FeII. Therefore, it can be used as a predecessor Century

The compounds of formula (I) according to the invention can be converted into the corresponding salt. For example, there is the following method of forming salts. If the molecule of the compounds of formula (I) is a nitrogen atom, basically enough for salt formation, the corresponding salts of these compounds are produced by their interaction in an organic solvent such as acetonitrile or tetrahydrofuran, with an equimolar amount of the corresponding organic or inorganic acid.

Examples of organic acids: oxalic, tartaric, maleic, succinic, citric acid.

Examples of inorganic acids: nitric, hydrochloric, sulphuric, phosphoric acid.

Derivatives is obreteniyu can be used according to therapeutic indications, which use of drug precursor chemicals that can achieve benefits that are given below by way of example, for some groups of these compounds are:

- Anti-inflammatory medicinal substance NSAIDs: connection according to the invention have a very good tolerability and effectiveness, even in cases when the body is weakened and is in a state of oxidative stress. These pharmaceutical agents can also be used in pathological conditions in which inflammation plays an important pathogenic role, such as cancer, asthma, myocardial infarction, but not limited to.

- Adrenergicheskie blockers αor βtype: range of action of the compounds of formula (I) becomes wider than the original drugs: the direct effect on the smooth musculature is added to the inhibition of the nervous beta adrenergicheskih signals that control the contraction of the blood vessels. Fewer side effects (difficulty in breathing, contraction of the bronchi), affecting the respiratory system.

- Antithrombotic drug substances: increases antiplatelet activity, and in the case of derivatives of aspirin also improved gastrointestinal tolerability.

- Bronchodilators and medicinal substance, the activities of the existing on cholinergic system: reduced side effects, acting on the cardiovascular system (tachycardia, hypertension).

- Expectorant in mucolytic drug substances: improved gastrointestinal tolerability.

- Diphosphonates: toxicity to the gastrointestinal tract is significantly reduced.

Inhibitors of phosphodiesterase (PDE) (bronchodilators): improving therapeutic effectiveness at the same doses; therefore, it becomes possible, using the compounds according to the invention, the introduction of low doses of a drug and reduce side effects.

- Antileukotriene drug substances: improved efficiency.

- ACE inhibitors: enhanced therapeutic efficacy and reduced side effects (shortness of breath, cough), affecting the respiratory apparat.

- Antidiabetic medicinal substance (increase insulin sensitivity and reduce glucose), antibiotics, antiviral, antitumor, protivogribkovye pharmaceutical substances, medicinal substances against dementia:

improved efficacy and/or tolerability.

Pharmaceutical substances that can be used as precursor compounds according to the invention are all those compounds that meet the criteria of at least one of their viewpo anutech tests 1, 2, 3.

The effectiveness of the compounds of the present invention as medicinal substances for use in oxidative stress average power was also demonstrated in pharmacological test, in which these compounds were able to inhibit the cytolytic effect of hydrogen peroxide on endothelial cells from umbilical veins of man. Endothelial cell is one of the first that suffers from pathological processes (Pathophysiology: the biological basis for disease in adults and children McCance&Huether, 1998, p. 1025), and hydrogen peroxide is a mild oxidizing agent and is considered to be the main mediator in the pathologies associated with oxidative stress (B. Halliwell and J. Gutteridge, "Free Radicals in Biology and Medicine", p. 416, 1993). The efficiency of neutralization own cytolytic impact is considered significant by the sign of the pharmacological activity of the compounds for use in oxidative stress (.Halliwell, J.Gutteridge "Free Radicals in Biology and Medicine", p. 416, 1993).

The compounds of formula (I) obtained using the reactions described below.

When the reactive functional group (for example, -COOH, -OH) medicinal substance forms a covalent bond, for example ester, amide, ether, before receiving the indicated compounds with this functional group may bateragarritasuna using methods, well known from the prior art.

The reactions used to obtain the compounds of formula (I)represent the interaction leading to the formation of, for example, ester, amide or thioester bonds are well known to specialists in this field.

If two compounds, reacts, there are other functional groups COOH and/or HX, where X is defined above, they must be protected before carrying out the reaction in accordance with methods well known in the prior art; for example, as described in the publication of Th. W. Greene: "Protective groups in organic synthesis", Harward University Press, 1980.

The compounds of formula (I), where s=2, are as follows.

IA) is a Medicinal substance has the General formula R-COOH, and the functional group of the precursor compound In which is connected with the carboxyl function of the medicinal substance has the formula XZ, where X is, as stated above, a Z is N, or a functional group or a halogen atom, at the same time as the reactive group of the precursor compound In the nitration reaction.

The General scheme of synthesis in the case when the precursor compounds present In IT is a group that includes the initial education of gelegenheid acid R-COHal (Hal=Cl, Br) and its subsequent interaction with the HX group of the precursor is connected to the I:

RCOOH→RCOHal+N-x-X2-COOH→R-T1-TB-X2-COOH (IA.1)

where X2, T1TBsuch as described above.

Allalone RCOHal receive in accordance with the methods known from the prior art, for example using thionyl or oxalicacid, RIIIor Pvhalides, conducting the reaction in inert solvents, such as toluene, chloroform, DMF, etc. Then allalone enter into interaction with the NH group of the compounds of the predecessor In conducting the reaction in inert solvents, such as toluene, tetrahydrofuran, chloroform, etc. at a temperature in the range of 0°to 25°C.

Alternatively, the previous synthesis of the drug substance, the precursor having the formula R-COOH, can be treated with an agent activating the carboxyl group, selected from N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide, in an inert solvent, such as toluene, THF, chloroform, etc. at a temperature in the range from -5°to +50°C. the compound Obtained is injected into the interaction in situ from a precursor, after preliminary protection IT functions, for example, acetyl group, regenerating the original function at the final stage of synthesis using methods well known in the prior art. Synthesis is carried out according to the following scheme:

R-COOH+CDI+HX-X 2-OG→R-T1-TB-X2-OG→R-T1-TB-X2-OH (IA.1)

where X2, T1TBsuch as described above, a G is a protecting group IT function.

The compound having the formula (IA.1), then subjected to a halogenation reaction, for example, such agents as PBr3, PCl5, SOCl2, PPh3and I2in an inert solvent, such as toluene, tetrahydrofuran, chloroform, etc. at a temperature in the range from -5°to +50°halogen derivatives of S. then interacts with AgNO3in an organic solvent, such as acetonitrile, tetrahydrofuran, at a temperature in the range of 25°S-80°C. Synthesis is carried out according to the following scheme:

R-T1-TB-X2-OH→R-T1-TB-X2-Hal→R-T1-TB-X2-ONO2(IA.2)

Alternatively, if X2is linear With4the alkyl, the corresponding acid R-COOH interacts with triphenylphosphine in the presence of a halogenation agent such as CBr4or N-bromosuccinimide in tetrahydrofuran, and the obtained compound (IA.2), where X2is butylene, nitrous, as described above.

On the other hand, it is possible to turn acid R-COOH in its sodium salt by methods known from the prior art, and then enter it in the interaction with the halogen derivatives, have a formula Hal-X 2-R3where R3=HE, Hal, in an inert solvent, such as tetrahydrofuran, chloroform, etc. at a temperature in the range -5° - +25°C. If R3=Hal, derived nitrous, as described above. The reaction scheme is as follows:

R-COOH→R-COONa+Hal-X2-R3→R-T1-TB-X2-R3→R-T1-TB-X2-ONO2

IIA) is a Medicinal substance has the General formula R-XH, and the functional group of the precursor compound, which is associated with NC function medicinal substance is a carboxyl group, where X is, as described above, and the functional group HE or halogen atom simultaneously present in the composition of the precursor compounds as reactive groups for reaction nitration.

The General scheme of the synthesis involves the reaction of acid HOOC-X2-R4where R4is Hal or OG where G is a suitable protective group, with an activating agent, as specified in IA), with subsequent interaction with the NH-group of medicinal substances.

HOOC-X2-R4+CDI+HX-R→R-T1-TB-X2-R4(IIA.1)

where R4, T1TB, X2such as described above.

The compound obtained (IIA.1), later transformed into the corresponding nitro-derivatives, as specified in IA). If there is a Deputy OG, adelaidasity group by known methods.

Alternatively, the previous synthesis of the drug substance R-OH enter into interaction with allelochemical having the formula Hal-X2-COHal under the reaction conditions described in IA), and the resulting halogenated derivatives of next nitrous, as described above:

HalOC-X2-Hal+HX-R→R-T1-TB-X2-Hal→R-T1-TB-X2-ONO2

where X2, T1TBsuch as described above.

The compounds of formula I, where s=1, is obtained using the methods described below.

IB) is a Medicinal substance has the General formula R-COOH, and the functional group of the precursor compound In which is connected with the carboxyl function of the medicinal substance has the formula XZ, where X is, as described above, and 7 represents N, and the precursor compound contains a functional group or a halogen atom which is reactive groups for reaction nitration.

The compound having the formula R-T1-TB-X2-OH (IA.1), obtained as described in IA), in turn nitrosopropane by reaction with sodium nitrite in water in the presence of hydrochloric acid, in accordance with procedures known from the prior art.

R-T1-TB-X2-OH+NaNO2→R-T1-TB-X2-ONO

IIB) is a Medicinal substance has the General formula R-XH, and functional group preceded by the Tonika connection, associated with NC function medicinal substance is a carboxyl group, where X is the same as described above. Synthetic scheme similar to that described in IIA).

The compound having the formula R-T1-TB-X2-R4(IIA.1), obtained as described in IIA), in turn nitrosopropane by the method described in IIA).

Connection, which is the object of the present invention, were included in the relevant pharmaceutical compositions for parenteral, oral and topical application in accordance with well known prior art methods, together with the usual excipients; see for example "Remington's Pharmaceutical Sciences 15a Ed."

The molar amount of the active agent in these compositions is the same or lower compared with the amount used of the respective medicinal substance predecessor.

Daily input dose are the same or in some cases lower compared with daily doses of medicinal substances predecessors. The daily dose can be found in relevant publications on this topic, such as "Physician''s Desk Reference".

The following examples are given to illustrate the present invention and should not be construed as limiting its scope.

Example 1

Obtain 4'-acetylaminophenol ether 4-nitrosobutane the second acid

The drug is paracetamol, which has the formula:

The precursor compound is 4-hydroxybutanoic acid.

a) Obtaining 4'-acetylaminophenol ether 4-bromoethanol acid

To a solution of 4-bromoethanol acid (4.6 g, 27.6 mmol) in chloroform (45 ml) and N,N'-dimethylformamide (20 ml) is added paracetamol (4,17 g, 27.6 mmol), N,N'-dicyclohexylcarbodiimide (8,42 g and 40.8 mmol) and 4-dimethylaminopyridine (0.15 g, 1.25 mmol). The reaction mixture was stirred at room temperature for 72 hours, filtered and evaporated in vacuum. To the crude reaction material added ethyl acetate, then washed with saturated aqueous NaCl and then with water. The organic phase is dried with sodium sulfate and then evaporated in vacuum. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 4/6 (about./vol.). Get 5,33 g of the product as a white solid. So pl. 108-110°C.

b) Obtain 4'-acetylaminophenol ether 4-nitrosobutane acid

To a solution of 4'-acetylaminophenol ether 4-bromoethanol acid (5,33 g, 17.8 mmol) in acetonitrile (80 ml) is added silver nitrate (4,56 g, 26.9 mmol). The reaction mixture was kept without access of light at a temperature of 80°C for 7 hours, laidout to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 4/6. Obtain 4.1 g of product as a white solid. So pl. 80-83°C.

Elemental analysis:NN
Calculated:51,07%at 4.99%9,92%
Found:51,06%to 5.00%9,90%

Example 2

Getting 4-hydroxy-3-(4-microclimatological)-α-[(tert-butylamino)methyl]benzyl alcohol

Drug substance precursor is salbutamol, having the formula:

The precursor compound is 4-hydroxybutanoic acid.

The compound (E-2) synthesized in accordance with the procedure described in Example 1. Yield: 21%.

Elemental analysis:NN
Calculated:55,13%7,07%7,56%
Found:55,10%7,09%7.57 per cent

Example 3

Getting 4-[(2-and the Ino-3,5-dibromophenyl)methylamino]-TRANS-cyclohexylamino ether 4-nitrosobutane acid

Drug substance precursor is Ambroxol

The precursor compound is 4-hydroxybutanoic acid.

a) Obtaining 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl) methylamino]-TRANS-cyclohexanol

To a solution of Ambroxol (5 g, 13,22 mol) in dioxane (35 ml) and water (50 ml), add triethylamine (3,31 ml, with 23.7 mmol) and di-tert-BUTYLCARBAMATE (of 3.46 g, 15,86 mmol). Stirred the reaction mixture at room temperature for 24 hours, and then concentrated under reduced pressure. To the residue add portions of 1% aqueous HCl to achieve pH 7, then the solution is extracted with ethyl acetate. Dry the organic phase with sodium sulfate and evaporated in vacuum. Receive 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]-TRANS-cyclohexanol, which is used in the next stage without further purification.

b) Obtaining 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl) methylamino]-TRANS-cyclohexylamino ether 4-nitrosobutane acid

The compound is synthesized in accordance with the procedure described in Example 1. Yield: 57%.

C) Obtaining 4-[(2-amino-3,5-dibromophenyl)methylamino]-TRANS-cyclohexylamino ether 4-nitrosobutane acid

To a solution of 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl) mate the amino]-TRANS-cyclohexylamino ether 4-nitrosobutane acid (3.5 g, 5,74 mmol) in ethyl acetate (100 ml), cooled to 0°add 5N solution of HCl in ethyl acetate (5,95 ml). Stir the solution at 0°C for 5 hours, then filtered. The obtained solid is suspended in ethyl acetate and washed the organic layer with 5% sodium carbonate solution. The organic phase is washed with water, dried with sodium sulfate and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1 (vol./vol.). Receive 4-[(2-amino-3,5-dibromophenyl)methylamino]-TRANS-cyclohexyloxy ether 4-nitrosobutane acid. Yield: 31%.

Elemental analysis:NNBr
Calculated:40,10%4,55%of 8.25%31,38%
Found:40,07%4,54%compared to 8.26%31,39%

Example 4

Obtaining [4-[4-nitroxymethyl]amino-1-hydroxybutylidene]-bis-phosphoric acid

Drug substance precursor is alendronat acid having the formula:

The precursor compound is 4-hydroxybutanoic acid.

Connection Sintesi the Ute in accordance with the methodology described in Example 1. Yield: 11%

Elemental analysis:NN
Calculated:25,27%4,77%7,37%
Found:25,26%4,79%7,37%

Example 5

Getting [N-methyl-N-(2-nitroxyethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy]acetic acid

Drug substance precursor is cetirizine

The precursor compound is N-methyldiethanolamine with a formula BUT-(CH2)2-N(CH3)-(CH2)2HE.

a) obtaining a [N-methyl-N-(2-hydroxyethyl)]-2-aminoethylamide ether[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy] acetic acid

To a solution of cetirizine (5 g, is 12.85 mmol) in N,N-dimethylformamide (5 ml) and toluene (50 ml), cooled to 0°C, slowly add oxalicacid (1.1 ml, of 25.7 mmol). Stir the mixture at room temperature for 12 hours, then evaporated in vacuum. To the obtained crude product dissolved in tetrahydrofuran (40 ml), add N-methyldiethanolamine (of 4.05 g, 38,55 mmol) and stirred the mixture at room temperature in accordance with the ie 6 hours. Evaporated reaction mixture under reduced pressure. To the residue poured in ethyl acetate and washed with a solution of water. Dry the organic phase with sodium sulfate and evaporated. The crude product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 3/7 (about./vol.). Get [N-methyl-N-(2-hydroxyethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy] acetic acid.

b) obtaining a [N-methyl-N-(2-chloroethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy] acetic acid

To a solution of [N-methyl-N-(2-hydroxyethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy]acetic acid (3.8 g, of 7.75 mmol) in chloroform (70 ml), cooled to 0°add thionyl chloride (0,58 ml of 8.06 mmol) in chloroform (30 ml). Stir the solution at 0°C for 30 minutes and then at 40°C for 6 hours. After that, the reaction mixture is washed with saturated aqueous sodium bicarbonate solution and then with water. The organic phase is dried with sodium sulfate, evaporated under reduced pressure. The crude product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3 (about./vol.). Get [N-methyl-N-(2-chloroethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinil]ethoxy]acetic acid.

c) obtaining a [N-is ethyl-N-(2-nitroxyethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy] acetic acid

To a solution of [N-methyl-N-(2-chloroethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy] acetic acid (2.3 g, to 4.52 mol) in acetonitrile (100 ml) is added silver nitrate (1,53 g, 9,04 mmol). The reaction mixture was kept without access of light at a temperature of 80°C for 48 hours, cooled to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3 (about./vol.). Get [N-methyl-N-(2-nitroxyethyl)]-2-aminoethylamide ether [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil] ethoxy]acetic acid. Yield: 23%.

Elemental analysis:NNCl
Calculated:58,37%6,59%10,47%6,63%
Found:58,38%to 6.58%10,45%6,60%

Example 6

Getting 5-(nitroxy)ethoxyethanol ester of 6-[D(-)-α-AMINOPHENYL-acetamido]penitsillanovoy acid

Drug substance precursor is ampicillin, having the formula:

The precursor compound is In diet lepicol.

a) Obtaining 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid

To a solution of ampicillin (3 g, 8,58 mmol) in a mixture of dioxane (18 ml) and water (25 ml) was added triethylamine (2.1 ml, and 15.3 mmol) and di-tert-BUTYLCARBAMATE (2.24 g, 10,29 mmol). Stirred the reaction mixture at room temperature for 24 hours, then concentrated under reduced pressure. To the residue add portions of 1% aqueous HCl to achieve in the aqueous phase of pH 7. Extracted the aqueous phase with ethyl acetate. Dry the organic phase with sodium sulfate and then evaporated in vacuum. Get 6-[D(-)-αtert-butyloxycarbonyl-phenylacetamido]penitsillanovoy acid, which is used in the subsequent synthesis without additional purification.

b) Obtain 5-(hydroxy)ethoxyethanol ester of 6-[D(-)-αtert-butyloxycarbonyl]penitsillanovoy acid

To a solution of 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid (3.8 g, 8,58 mmol) in a mixture of N,N-dimethylformamide (5 ml) and toluene (40 ml), cooled to 0°C, slowly add oxalicacid (0,74 ml, 17,16 mmol). Stir the solution at room temperature for 12 hours, after which it evaporated in vacuum. The crude product is dissolved in tetrahydrofuran (70 ml), and then to the solution was added ethylene glycol (at 2.45 ml, 25,7 the mol). The resulting solution was stirred at room temperature for 5 hours, and then evaporated under reduced pressure. To the residue poured in ethyl acetate and the organic phase is washed with water. Next, the organic phase is dried with sodium sulfate and evaporated to dryness. The crude product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 2/8 (about./vol.). Get a 5-(hydroxy)ETHYLACETYLENE ester of 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid.

C) Obtaining 5-(chloro)ethoxyethanol ester of 6-[D(-}-αtert-butyloxycarbonyl]penitsillanovoy acid

To a solution of 5-(hydroxy)ethoxyethanol ester of 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid (3 g, to 5.58 mmol) in chloroform (70 ml), cooled to 0°add thionyl chloride (0,42 ml, 5.8 mmol) in chloroform (30 ml). Stir the solution at 0°C for 30 minutes and then at 40°C for 4 hours. After that, the mixture was washed with saturated sodium bicarbonate solution and then with water. Dry the organic phase with sodium sulfate and evaporated under reduced pressure. The crude product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1 (vol./vol.). Get a 5-(chloro)ETHYLACETYLENE ester of 6-[D(-)-αtert-Butylochka is benjaminfranklin] penitsillanovoy acid.

d) Receiving 5-(nitroxy)ethoxyethanol ester of 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid

To a solution of 5-(chloro)ethoxyethanol ester of 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid (2.1 g, of 3.77 mmol) in acetonitrile (100 ml) is added silver nitrate (1.28 g, rate of 7.54 mmol). The reaction mixture was kept without access of light at a temperature of 80°within 24 hours, cooled to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1 (vol./vol.). Get a 5-(nitroxy)ETHYLACETYLENE ester of 6-[D(-)-αtert-butyloxycarbonyl-aminofenilatsetamido] penitsillanovoy acid.

e) Receiving 5-(nitroxy)ethoxyethanol ester of 6-[D(-)-α-aminofenilatsetamido] penitsillanovoy acid

To a solution of 5-(nitroxy)ethoxyethanol ester of 6-[D(-)-αtert-butyloxycarbonyl] penitsillanovoy acid (1.5 g, 2.57 mmol) in ethyl acetate (100 ml), cooled to 0°add 5N solution of HCl in ethyl acetate (2,67 ml). Stir the solution at 0°C for 7 hours, then filtered. The obtained solid is suspended in ethyl acetate and washed the organic layer with 5% wt./about. a solution of sodium carbonate. Washed organizations the practical phase of water, dried with sodium sulfate and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1 (vol./vol.). Get a 5-(nitroxy)ETHYLACETYLENE ester of 6-[D(-)-α-aminofenilatsetamido] penitsillanovoy acid. Yield: 13%.

Elemental analysis:NNS
Calculated:of 49.79%5,43%to 11.61%6,64%
Found:49,77%the 5.45%11,60%6,65%

Example 7

Obtaining 2-amino-1,9-dihydro-9-[[2-(4-nitroquinoline)ethoxy]methyl]-6N-purine-6-she

Drug substance precursor is acyclovir, which has the formula:

The precursor compounds And is a 4-hydroxybutanoic acid.

Connection (E-7) synthesized in accordance with the procedure described in Example 3. Yield: 14%.

Elemental analysis:NN
Calculated:42,36%4,74%24,70%
Found:42,38%24,68%

Example 8

Receiving (8S-CIS)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-[(4-nitroxy-butanoyloxy)acetyl]-1-methoxy-5,12-naphthacenedione

Drug substance precursor is doxorubicin, which has the formula (E-8A)

The precursor compound is 4-hydroxybutanoic acid.

The compound is synthesized in accordance with the procedure described in Example 1. Output: 7%.

Elemental analysis:NN
Calculated:56,53%5,20%4,25%
Found:56,55%5,22%to 4.23%

Example 9

Getting [1S-[1α,3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-(6-nitrosoguanidine)-6-oxo-2H-Piran-2-yl]ethyl]-1-neftianogo ether of 2,2-dimethylbutanol acid

Drug substance precursor is simvastatin, having the formula:

The predecessor to bridge communication is a 6-hydroxyhexanoic acid.

a) Receiving the s [1S-[1α ,3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-(6-bromohexadecane)-6-oxo-2H-Piran-2-yl]ethyl]-1-neftianogo ether of 2,2-dimethylbutanol acid

To a solution of simvastatin (4 g, of 9.56 mmol) in chloroform (50 ml) and N,N-dimethylformamide (20 ml) is added 6-bromhexinum acid (1.86 g, of 9.56 mmol), N,N'-dicyclohexylcarbodiimide (1.97 g, of 9.56 mmol) and 4-dimethylaminopyridine (52 mg, 0.43 mmol). Stirred the reaction mixture at room temperature for 24 hours, then diluted with chloroform and washed with water. The organic phase is dried with sodium sulfate and evaporated under reduced pressure. The crude product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1 (vol./vol.). Get [1S-[1α,3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-(6-bromohexadecane)-6-oxo-2H-Piran-2-yl]ethyl]-1-nattily ether of 2,2-dimethylbutanol acid.

b) Obtaining [1S-[1α,3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-(6-nitrosoguanidine)-6-oxo-2H-Piran-2-yl]ethyl]-1-neftianogo ether of 2,2-dimethylbutanol acid

To a solution of [1S-[1α,3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-(6-bromohexadecane)-6-oxo-2H-Piran-2-yl]ethyl]-1-neftianogo ether of 2,2-dimethylbutyl the new acid (1 g, to 1.67 mmol) in acetonitrile (60 ml) is added silver nitrate (0,57 g, 3.35 mmol). The reaction mixture was kept without access of light at a temperature of 80°C for 6 hours, cooled to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1 (vol./vol.). Get [1S-[1α,3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-(6-nitrosoguanidine)-6-oxo-2H-Piran-2-yl]ethyl]-1-nattily ether of 2,2-dimethylbutanol acid. Yield: 13%.

Elemental analysis:NN
Calculated:62,71%7,97%2,35%
Found:62,74%7,99%2,33%

Example 10

Getting teofillinom ester 6-(nitroxy)hexanoic acid

Drug substance precursor is Tefillin having the formula:

The precursor compound is 6-hydroxyhexanoic acid.

The compound having formula (E-10), synthesized according to the procedure described in Example 9. Yield: 23%.

Elemental analysis:NN
Calculated:44,76%5,39%to 16.31%
Found:44,77%5,41%16,33%

Example 11

9-[4-(nitroxy)butylamino]-1,2,3,4-tetrahydropyridine

Drug substance precursor is taken having the formula:

The precursor compound is 4-hydroxybutanoic acid.

a) 9-[4-bromoethylamine]-1,2,3,4-tetrahydropyridine

To a solution of tacrine (4 g, 20,17 mmol) in chloroform (50 ml) and N,N-dimethylformamide (15 ml) is added 4-bromothioanisole (3.5 ml, 30,25 mmol). Stirred the reaction mixture at room temperature for 6 hours, then diluted with chloroform and washed with water. The organic phase is dried with sodium sulfate and evaporated under reduced pressure. The crude product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 8/2 (about./vol.). Get 9-[4-bromoethylamine]-1,2,3,4-tetrahydropyridine.

b) Receiving 9-[4-(nitroxy)butylamino]-1,2,3,4-tetrahydropyridine

To a solution of 9-[4-bromoethylamine]-1,2,3,4-tetrahydropyridine (3.5 g, 10,56 mmol) in acetonitrile (150 ml) add the silver nitrate (2,08 g; 12,68 mmol). The reaction mixture was kept without access of light at a temperature of 80°C for 6 hours, cooled to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 8/2 (about./vol.). Get 9-[4-(nitroxy)butylamino]-1,2,3,4-tetrahydropyridine. Yield: 33%.

Elemental analysis:NN
Calculated:62,00%5,81%of 12.76%
Found:62,02%of 5.83%12,77%

Example 12

Getting 5-(nitroxy)ethylthioethyl ether (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H) acetic acid

Drug substance precursor is clopidogrel, having the formula:

The precursor compound is In thiodiethanol having the formula HO-(CH2)2-S-(CH2)2-OH.

Connection (E-12) is synthesized in accordance with the procedure described in Example 5, using thiodiethanol instead of diethylene glycol. Yield: 56%.

Ele is entry analysis: NNClS
Calculated:49,94%4,63%6,13%7,76%14,03%
Found:49,93%4,63%6,10%of 7.75%14,01%

Example 13

Getting 5-methoxy-2-[[4-(4-nitroquinoline)for 3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole

Drug substance precursor is demethylenation having the formula:

The precursor compound is 4-hydroxybutanoic acid.

Connection (E-13) is synthesized in accordance with the procedure described in Example 1. Yield: 22%.

Elemental analysis:NNS
Calculated:51,94%4,79%12,12%6,93%
Found:51,93%4,77%12,11%6,94%

Example 14

Getting [N-methyl-N-(2-hydroxyethyl)1-2-aminoethylamide ester 2-[(2,6-dichlorophenyl)amino]phenylacetic acid (E-14)

Drug-preds the factory worker is diclofenac, having the formula:

The precursor compound is N-methyldiethanolamine having the formula HO-(CH2)2-N(CH3)-(CH2)2-OH.

The compound is synthesized in accordance with the procedure described in Example 5. Yield: 52%.

Elemental analysis:NNCl
Calculated:51,60%4,78%9,50%16,03%
Found:51,60%4,77%at 9.53%16,04%

Example 15

Getting 4-(nitroxy)butyl ether 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid

Drug substance precursor is ferulic acid, having the formula:

The precursor compound is 1,4-butanediol.

a) Obtaining 4-bromatologia ester 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid

To a solution of ferulic acid (10 g, 51,51 mmol) in tetrahydrofuran (400 ml) is added triphenylphosphine (27 g, 103 mmol) and tetrabromomethane (34,1 g, 103 mmol). Stirred the reaction mixture at room temperature for 4 hours, then filtered and evaporated under reduced pressure. accidenly the product was then purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3 (about./vol.). Receive a 4-bromatology ether 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid.

b) Obtaining 4-(nitroxy)butyl ether 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid

To a solution of 4-bromatologia ester 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid (2,72 g, 6,89 mmol) in acetonitrile (25 ml) is added silver nitrate (1.48 g, 8,71 mmol). The reaction mixture was kept without access of light at a temperature of 80°C for 7 hours, cooled to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3 (about./vol.). Receive a 4-(nitroxy)butyl ether 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid. Yield: 56%.

Elemental analysis:NN
Calculated:54,02%of 5.50%4,50%
Found:54,00%5,52%4,49%

PHARMACOLOGICAL TESTS

EXAMPLE

Acute toxicity

Acute toxicity was evaluated by introducing the group of 10 rats weighing 20 g single dose of each of the tested compounds in the oral hole, through the tube, the composition of the water is a suspension of 2% carboxymethyl cellulose (wt./vol.).

The animals were observed for 14 days. None of the animals in the test group did not appear toxic symptoms, even after the introduction of 100 mg/kg dose.

EXAMPLE F1

Test 1 - experimental model in vivo N-ethylmaleimide (NEM): a study of gastric tolerability of certain drugs, analyzed as precursors of the compounds of the present invention.

Animals (rats, weight approximately 200 g) were divided into following groups (10 animals in each group):

A) Control group:

1° group: treatment: only media (aqueous suspension of 1% (wt./about.) carboxymethylcellulose, dose: 5 ml/kg, if the medicinal substance was administered through the mouth, a physiological solution in the case of parenteral injection).

2° group: treatment: carrier + NEM,

(B) the Experimental group, which was administered medicinal substance:

group I: treatment: carrier + drug,

group II: treatment: carrier + drug + NEM.

These medicinal substances were investigated in this experiment (table I): indomethacin, Ambroxol, mesalamine, alendronate sodium, taken, omeprazole, misoprostol.

Indomethacin, Ambroxol and alendronate was administered through the mouth, mesalamine was introduced into the rectum (rectal), and taken, omeprazole and misoprostol subcutaneously.

The maximum tolerated dose, defined by introducing each of the substances specified ways animals that did not enter NEM, indicated in Table I. When exceeding the indicated doses in animals appeared enteropathy, diarrhea, depression, tremors and slow reactions.

In this experimental model animals were first injected dose NEM (25 mg/kg) in saline by subcutaneous injection. Drug was administered after 1 hour in the suspension medium. After 24 hours the animals were killed and assessed the damage to mucous membranes of the gastrointestinal tract, by counting the number of rats in each group, with visible damage to the stomach. The total number of these rats were then divided into the total number of rats in the group and multiplied by 100. Thus obtained percentages are presented in Table I. This table shows that in the groups of rats that were injected these medicinal substances without NEM, was not detected gastric damage.

In all rats of group II (which was introduced NEM) were detected damage to the stomach after administration of the following drugs: indomethacin, Ambroxol, mesalamine, alendronate sodium, taken.

Therefore, these medicinal substances can be used in the synthesis of the products of the present invention.

According to the results of test 1 of aprazol and misoprostol on the contrary, cannot be used to obtain products of the present invention.

EXAMPLE F2

Test 2 (in vitro): inhibition of apoptosis (DNA fragmentation)induced in endothelial cells by CIP connection, in the presence of certain drugs, analyzed as precursors of the compounds of the present invention.

Were tested following drug precursor chemicals (table II): indomethacin, paracetamol, clopidogrel, salbutamol, Ambroxol, alendronate sodium, Tefillin, cetirizine, enalapril, nicotinamide, ampicillin, acyclovir, mesalamine, taken, simvastatin, omeprazole.

Endothelial cells from umbilical veins receive in accordance with standard procedure. Fresh umbilical vein fill of 0.1% (by weight) solution of collagenase and incubated at 37°C for 5 minutes.

After this vein is subjected to perfusion in the medium M 199 (GIBCO, Grand Island, NY), pH of 7.4, containing 0.1% (wt./about.) collagenase with the addition of 10% fetal bovine serum (10 μg/ml), sodium salt of heparin (50 μg/ml), thymidine (2.4 μg/ml), glutamine (230 µg/ml), penicillin (100 IU/ml), streptomycin (100 μg/ml) and streptomycin (0.125 mg/ml). Collect cells from perfusion solution by centrifugation (800 rpm) and grown in culture flasks T-75, pretreated Phi is reection person. Then grow the cells in the same medium to which is added growth factor in the hypothalamus, bovine (100 ng/ml). When cells primary cell culture (that is obtained directly ex vivo from the umbilical vein) form a continuous cell monolayer (approximately 8000000 cells per flask), the growth of the culture is stopped, the layers are washed and treated with trypsin. Transfer the cell suspension into the wells of 24-monochro tablet for cell cultures, half of which add the same culture medium containing the medicinal substance at a concentration of 10-4M, then grow the cells in an incubator at 37°C, constant humidity (90%) and 5% concentrations of CO2. If the drug is insoluble in the culture medium, it is first dissolved in a small amount of dimethyl sulfoxide. The maximum amount of dimethyl sulfoxide, which may be added to the culture medium is 0.5%. Only cells derived from these early cultures used for experiments with cumene hydroperoxide (CIP). Cells identified as endothelial cells by morphological analysis, as well as on their specific immunological response to factor VIII; these cultures were not detected any contamination of myocytes or fibroblasts.

Before those whom the cell culture medium is removed and the cell layers gently washed with a standard saline solution, containing 0,1M phosphate buffer (pH 7.0), at a temperature of 37°C. the Contents of each well and then incubated for 1 hour with a suspension of CIP in the culture medium at a concentration of 5 mm. Assessment of cell damage (apoptosis) is carried out by determining the percentage change in DNA fragmentation in cultures containing the medicinal substance and CIP, relative to control groups, which were treated with only the CIP. The specified percentage change in DNA fragmentation determined by evaluating changes in the fluorescence at wavelengths 405-450 nm, using a microscope VH Olympus (Olympus Co., Rome), comparing the optical density of the test and control samples. For each sample spend 5 repeated measurements of fluorescence. Statistical evaluation of the results is done using t-test t-test (p<0,01).

The results in Table II show that indomethacin, paracetamol, clopidogrel, salbutamol, alendronate sodium, Tefillin, cetirizine, enalapril, nicotinamide, ampicillin, acyclovir, taken and omeprazole almost not inhibit apoptosis. Therefore, these medicinal substances can be used to obtain products of the present invention.

In contrast, Ambroxol, mesalamine and simvastatin inhibit apoptosis. Therefore, the results of test 2, these compounds could not be COI is used to obtain products of the present invention.

EXAMPLE F3

Test 3 - experimental in vivo model using methyl ester of Nw-nitro-L-arginine (L-NAME): analysis of gastric tolerability (the frequency of occurrence of damage of the gastrointestinal tract), portability for the liver (dose GPT, glutamate-pyruvate-transaminase) and cardiovascular system (blood pressure) of some medicinal substances used as precursors of the compounds of the present invention.

The experimental model is adapted model described in J.Clin. Investigation 90, 278-281,1992.

Endothelial dysfunction assessed by determining the damage of the mucous membranes of the gastrointestinal tract, liver damage (increase GPT), and damage of vascular endothelium and cardiovascular system (increased blood pressure)caused by L-NAME.

Animals (rats, average weight 200 g) are divided into groups in accordance with the following scheme. The group receiving L-NAME administered for 4 weeks the specified connection, dissolved in drinking water at a concentration of 400 mg/l Identified the following groups (10 animals each):

A) Control group:

1°: processing: only the media (aqueous suspension of 1% (wt./about.) carboxymethylcellulose, dose: 5 ml/kg when the drug substance is introduced through the mouth, the physiological age of the PRS, if you enter parenteral),

group 2°: treatment: carrier + L-NAME,

(B) the Experimental group, which was administered medicinal substance:

group 3°: treatment: carrier + drug,

group 4°: treatment: carrier + drug + L-NAME.

Were tested with the following medicinal substances: paracetamol, doxorubicin, simvastatin, omeprazole and misoprostol. Each of them was injected once a day for 4 weeks.

Maximum tolerated dose of medicinal substance, administered to the animals was determined in experiments with scaling of individual doses in animals, which no one entered, by assessing occurrence in animals symptoms of enteropathy, diarrhea, depression, tremor, and slowed down the reaction.

At the end of the fourth week the animals cease to provide water and after 24 hours of their death.

One hour before killing determine blood pressure, and increase take as an indicator of damage to the vascular endothelium.

Damage of the gastric mucosa appreciate as illustrated in test 1 (see Example F1). Liver damage is determined by evaluating the content of glutamate-pyruvate-transaminase (increase GPT) after the killing.

Drug substance complies with the conditions of Test 3, i.e. it can be used too to obtain the compounds of the present invention, if the groups of rats treated with L-NAME + drug + carrier detected more significant liver damage (higher values GPT) and/or more significant damage to the stomach and/or blood vessels (increased blood pressure) compared to the group treated only by the media, or the group treated with the carrier and the drug, or the group treated with the carrier and L-NAME.

The test results presented in Table IV. The frequency of occurrence (%) of gastric damage was determined as in Test 1. Values (in%) level of GPT and blood pressure are related to the corresponding values found in animals of the 1st group from the control group. The average blood pressure in this group was 105±8 mm RT. Art.

The results obtained indicate that the effect of paracetamol, doxorubicin and simvastatin cause liver damage and gastroenteropathy (level GPT and frequency of occurrence of damage to the stomach (in%) higher than the values in the respective groups, which were injected drug without L-NAME, and control groups, which were administered L-NAME).

Therefore, these medicinal substances can be used to obtain products of the present invention.

The results of this test omeprazole and misoprostol, on the contrary, not what may be used to obtain products of the present invention.

EXAMPLE F4

Test 4A: the activity of certain chemicals used as precursors In the products of the present invention, the inhibition of hemolysis of erythrocytes induced by cumene peroxide.

Test 4A is carried out in accordance with the method described in the publication R.Maffei Facino, M.Carini G.Aldini, M..Calloni, Drugs Exptl. Clin. Res. XXIII (5/8) 157-165, 1997.

Erythrocytes, isolated using standard procedures from male Wistar rats (Charles River), suspended in physiological solution containing phosphate buffer with pH 7.4, and the balance at 4°C for 4 days. Then an aliquot of the specified suspension is centrifuged at 1000 rpm./min for 5 minutes and 0.1 ml was centrifuged erythrocytes diluted to 50 ml sodium phosphate buffer having the same molar concentration. The result is a suspension containing 0.2% about. erythrocytes. To the specified portions of the diluted suspension of 3.5 ml add 0.1 ml 9,72 mm alcohol solution of cumene hydroperoxide, which causes lysis of the cells. The resulting suspension is incubated at 37°C. the Suspension becomes more turbid. The process of lysis of the cells observed by using turbidimetry at 710 nm by determining the absorbance (or transmittance) every 30 minutes. The point in time when the maximum number of cells were subjected to lysis, which corresponds to the maximum of the turbidity of the suspension, take for Tmax and believe that he is 100% lysis of the cells. 0.2 ml portions 38 mm ethanolic solutions of the test compounds, intended for use as precursors To add to the aliquot (3.5 ml) diluted suspension of red blood cells, prepared as described above, and preincubated the resulting suspension for 30 minutes. Then to this suspension add 0.1 ml 10,26 mm alcohol solution of cumene hydroperoxide and at time Tmax determine the inhibition of hemolysis for the sample as a percentage of the ratio between the absorption of the suspension sample containing erythrocytes, predecessor In and cumene hydroperoxide, respectively, and absorption of suspensions containing erythrocytes and cumene hydroperoxide, multiplied by 100. Predecessors To match the test conditions at if they inhibit the hemolysis induced by cumene hydroperoxide, 15% and more.

Table V presents the results obtained for the following substances: N-methyldiethanolamine, diethylene glycol, thiodiethanol, 1,4-butanediol, butanol and diethanolamine.

From Table V it is seen that:

- N-methyldiethanolamine, diethylene glycol, thiodiethanol and 1,4-butanediol correspond to the test conditions 4, as they inhibit the hemolysis induced by cumene hydroperoxide, more than 15%.

- butanol and diethanolamin, APRODEV, are ineffective because inhibit the hemolysis induced by cumene hydroperoxide, less than 15%, and therefore, they cannot be used as precursors In the synthesis of compounds of the present invention.

EXAMPLE F5

Test 5: the Activity of the compounds used as precursors In the inhibition of radical formation from compounds of FeII.

0.1 ml aliquots of 10-4M methanol solutions, respectively, 1,4-butanediol, N-methyldiethanolamine, diethylene glycol and thiodiethanol added to tubes containing aqueous solution formed by mixing 0.2 ml of 2 mm solution desoxyribose, 0.4 ml of 100 mm phosphate buffer (pH 7.4) and 0.1 ml of 1 mm solution of FeII(NH4)2(SO4)2in 2 mm HCl solution. The tubes are then incubated at a temperature of 37°C for one hour. Then to each tube add 0.5 ml of 2.8% aqueous solution of trichloroacetic acid and 0.5 ml of an aqueous solution of 0.1 M thiobarbituric acid in that order. Control clear solution is prepared by replacing the above 0.1 ml aliquot of the methanol solution of the test compound in 0.1 ml of methanol. The tube was closed and heated in an oil bath at a temperature of 100°C for 15 minutes. Develops pink staining, the intensity of which is proportional to the kolichestvo desoxyribose, undergone radical oxidative cleavage. The solution is cooled to room temperature and measure their optical density at 532 nm is relatively transparent control solution.

The inhibition caused by the predecessor In relatively radical formation from FeIIdetermine the percentage by the following formula:

(1-As/Ac)×100

where Asand awithare, respectively, the values of the absorption of the solution containing the test substance + salt of iron, and the solution containing only salt of iron.

The results are presented in Table III, which shows that the tested compounds are ineffective in the inhibition of radical formation from iron ions. Therefore, these compounds can be used as precursors for producing compounds of the present invention.

EXAMPLE F6

Evaluated the activity of some compounds, which is the object of the present invention, and related drugs precursors in the inhibition of the degradation of DNA (apoptose) in endothelial cells exposed to hydrogen peroxide.

Hydrogen peroxide is a mild oxidizing agent, and is considered an important mediator in the pathologies associated with oxidative stress (.Halliwell, J. Gutteridge, "Free Radicals in Biology and Medcine", page 416, 1993). Therefore, the pharmacological activity of compounds, intended for use in conditions of oxidative stress, assessed by their ability to neutralize cell damaging effects of hydrogen peroxide (.Halliwell, J.Gutteridge "Free Radicals in Biology and Medicine", page 416, 1993).

This method is described by Herman et al. (Herman C., Zeiner M.A., Dimeller S, Arterioscler. Thromb. Vase. Biol. 17 (12), 3588-82, 1997).

Endothelial cells from umbilical veins were received in accordance with standard procedure. Fresh umbilical vein was filled with 0.1% (by weight) solution of collagenase and incubated at 37°C for 5 minutes.

After this vein were subjected to perfusion in the medium M 199 (GIBCO, Grand Island, NY), pH of 7.4, containing 20% human serum. Collected cells from perfusion solution by centrifugation at 800 rpm./min and grew them in culture flasks T-75, pretreated with fibronectin person. Then cells were grown in medium with a pH of 7.4, containing 20% human serum, and low molecular weight heparinate sodium (30 mg/ml), penicillin (100,000 IU/ml) and the growth factor in the hypothalamus, bovine (100 ng/ml). Primary fused cell monolayers (approximately 8,000,000 cells per flask) were washed and treated with trypsin. Transferred cell suspension into the wells of a 24-hole culture of the tablet, after which the cells were grown in an incubator at 37°permanent VL is gnosti (90%) and 5% concentrations of CO 2. Only cells that have occurred the first of these subcultures were used for experiments with hydrogen peroxide. The cells were identified as endothelial cells by morphological analysis, as well as on their specific coloring reaction. In these cultures were not detected any contamination of myocytes or fibroblasts.

For experiments with hydrogen peroxide cell culture medium was removed and cell layers were carefully washed with a saline solution containing 0.1 M phosphate buffer (pH 7.0), at a temperature of 37°C. the cells are Then incubated for 18 hours with hydrogen peroxide at concentrations of 200 µmol/L.

Assessment of cell damage (apoptosis) was performed by determining the percentage change in DNA fragmentation in the sample relative to the control group that was treated only with hydrogen peroxide. The analyzed products were tested at a concentration of 100 µmol/L. If it was found that these products are insoluble in the culture medium, was dissolved in a small amount of dimethyl sulfoxide (DMSO), taking into account that the maximum amount of DMSO that can be added to the culture medium, 0.5% vol./about. For each sample was performed three repeated measurements.

The results presented in Tab is itzá VI, show that in samples of cell cultures treated with the compounds of the present invention, inhibition of DNA fragmentation or, more generally, inhibition of cellular damage at least twice that observed in samples treated with the appropriate precursors.

EXAMPLE F7

Gastric damage caused by compounds of the present invention in comparison with the corresponding drug-predecessors.

Groups of male Wistar rats weighing 180-200 g (10 animals per group)sustained without food for 17 hours, was injected through the tube into the oral aperture 2% aqueous suspension of carboxymethylcellulose (medium)containing one of the following connections:

- Diclofenac dose of 20 mg/kg orally

- Nitrocefin derivative of diclofenac (PR. 14), the same dose orally

- Ambroxol, a dose of 100 mg/kg orally

- Nitrocefin derivative of Ambroxol (PR. 3), in the same dose orally

- Alendronate dose of 100 mg/kg orally

- Nitrocefin derived alendronova acid (PR. 4), in the same oral dose.

Taken and the corresponding nitroxides obtained in accordance with Example 11, was administered to rats subcutaneously in saline solution at a dose of 10 mg/kg

Animals were killed 6 hours after the injection of substances Mucous membrane of the gastro-intestinal tract was removed and examined. The degree of gastrointestinal damage was evaluated in the same way as described in experiment F1.

The results presented in Table VII, show that the compounds of the present invention either do not cause gastric damage or the extent of damage observed in some cases, substantially below that which cause drug precursor chemicals.

EXAMPLE 16

Synthesis of [2-(N-methyl-N'-(2-nitroxy)ethyl)amino]ethyl ester of (S)-1-[N-[1-(etoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-Proline of the formula

The predecessor is enalapril having the formula:

The precursor is N-methyl-diethanolamine:

Connection (E-16) is synthesized in accordance with the procedure described in Example 5. Yield: 19%. Elemental analysis:

Calculated, %:With 58,19%N 7,51%N 10,44%
Found, %:With 58,22%N 7,53%N 10,42%

EXAMPLE 17

Synthesis of 1-[(1-methylethyl)amino]-3-(1-naphthyloxy)-2-propyl ether (4 nitroxy)butane acid, having the formula:

The predecessor is propranolol, having the formula:

The predecessor is a 4-hydroxybutanoic acid.

Connection (E-17) is synthesized in accordance with the procedure described in Example 1. Yield: 25%. Elemental analysis:

Calculated, %:With 61,53%N of 6.71%N 7,17%
Found, %:With 61,58%N 6,74%N 7,15%

EXAMPLE 18

Synthesis of 1-[5-(2,5-dihydro-5-oxo-3-furanyl)-3-methyl-2-benzofuranyl]ethyl [(2-nitroxy)ethoxy]ethyl diapir butandiol acid

Drug substance precursor is benforado hemisuccinate having the formula:

The predecessor is diethylene glycol:

Connection (E-18) is synthesized in accordance with the procedure described in Example 6. Yield: 16%.

Elemental analysis:

Calculated, %:With 56,21%N 5,13%N 2,85%
Found, %:With 56.26 vertical%N 5,10%N 2,90%

EXAMPLE 19

Synthesis of [2-(N-methyl-N'-(2-nitroxyethyl)amino]ethyl ester of N-[[6-methoxy-5-(trifluoromethyl)-1-naphthyl]taxometer]-N-methylglycine having the formula:

Drug substance precursor is tolrestat having the formula:

The precursor is N-methyl-diethanolamine:

Connection (E-19) is synthesized in accordance with the procedure described in Example 5. Output: 12%.

Elemental analysis:

Calculated, %:With 50,10%N 4,80%N 8,35%S 6,30F 11,32
Found, %:With 50,15%N 4,82%N 8,30%S 6,25F 11,34

EXAMPLE 20

Synthesis of (8S-CIS)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-[[3-methoxy-4-(4-nitroquinoline]metroka]-1-methoxy-5,12-naphthacenedione formula

Drug substance precursor is doxorubicin, which has the formula:

The predecessor is a 4-hydroxybutanoic acid.

Connection (E-20) is synthesized in accordance with the procedure described in Example 1. Output: 12%.

Elemental analysis:

Calculated, %:With 55,19%N 5,08%N 28,01%
Found, %:With 55,21%N 5,09%N 28,08%

EXAMPLE 21

Synthesis of (4-nitroxy)butyl ester (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-inden-3-acetic acid, having the formula:

Drug substance precursor is sulindac, having the formula:

The predecessor is 1,4-butanediol.

a) Obtaining 4-bromatologia ether CIS-5-fluoro-2-methyl-1-[n-(methylsulfinyl)benzyliden]inden-3-acetic acid

To a solution of sulindaka (of 5.17 g, 14.5 mmol) in dimethylformamide (50 ml) was added EtONa (1.18 g, 16.4 mmol). Stirred the reaction mixture for 1 hour, then add a solution of 1,4-dibromobutane in dimethylformamide (20 ml). Stirred the reaction mixture at room temperature for 8 hours, then diluted with diethyl ether and washed with water. The organic phase is dried with sodium sulfate and then evaporated under reduced pressure. The crude product was then purified using column chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 3/7 (about./vol.). Receive a 4-bromatology ether CIS-5-fluoro-2-methyl-1-(n-(methylsulfinyl)benzyliden]inden-3-acetic acid.

b) Obtaining 4-(nitroxy)butyl ether CIS-5-fluoro-2-methyl-1-(n-(methylsulfinyl)benzyliden]inden-3-kusnoy acid

To a solution of 4-bromatologia ether CIS-5-fluoro-2-methyl-1-(n-(methylsulfinyl)benzyliden]inden-3-acetic acid (5,01 g, 10,18 mmol) in acetonitrile (60 ml) is added silver nitrate (3.5 g, to 20.6 mmol). The reaction mixture is stirred without access of light at a temperature of 80°C for 48 hours, cooled to room temperature, filtered to remove silver salts and evaporated under reduced pressure. The residue is purified using column chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 3/7 (about./vol.). After evaporation of the solvent receive (4 nitroxy)butyl ester (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-inden-3-acetic acid (so pl. 93-97°). Yield: 40%.

Elemental analysis:

Calculated, %: C, in comparison with 60.87% N 5,11% F 4,01 N 2,96% S 6,77

Found, %: C 60,85% N 5,13% F 3,93 N 2,94% S 6,75

EXAMPLE F8

Example F1 was repeated with three groups of rats (10 animals in each group), which is orally introduced the NEM in accordance with the following scheme:

(a) control group: a carrier formed with an aqueous suspension of 1% (wt./about.) carboxymethylcellulose,

b) one group (comparison group b), the animals from which at the same time has introduced 10 mg/kg (0,034 mmol/kg) of diclofenac and 4 mg/kg (0,034 mmol/kg) N-methyldiethanolamine in the above media

(C) one group (the comparison group), the animals which were administered 15 mg/kg (0,034 mmol who/kg) ether derivative of diclofenac according to the invention (see Ave. 14) in the above media

The results presented in Table VIII show that the mixture administered to the animals of group b (the control group), was much less effective in reducing the frequency of occurrence of damage to the stomach than the compound of the present invention, administered to the animals of group C.

EXAMPLE F9

Anti-inflammatory and obezbolivaushee activity of 4-(N-acetylamino)phenyl ester 4-(nitroxy)butane acid (NO-paracetamol) and its predecessor paracetamol.

Introduction

The main therapeutic effect of NSAIDs (non-steroidal anti-inflammatory drugs) is associated with their ability to inhibit the production of prostaglandins ("Goodman & Gilman's, The Pharmacological Basis of Therapeutics" 9thEd. 1996, McGraw Hill page 620), and these agents are classified in accordance with this principle. Sulindac and paracetamol have mechanisms of action, different from most currently used NSAIDs with regard to their very little ability to inhibition of production of prostaglandins. Both of these substances react with free radicals of oxygen.

Anti-inflammatory and analgetic activity was measured in accordance with the methods of measurement of the swelling of the paws of rats under the influence of carrageenan and counting of convulsing mice under the action of acetic acid. Were used male CCA and rats (Wistar, 100-150 g) and mice (LACA, 22-35 d). NO-paracetamol, paracetamol or media was introduced as part of the suspension of carboxymethylcellulose (0.5 percent wt./about.) in the amount of 1 mg/kg

Swelling of the legs under the action of carrageenan

The experiments were conducted as described in the publication Al-Swayeh et al, Brit. J. Pharmacol. 129, 343-350, 2000. The volume of the hind paws was determined by plethysmography combined to interplanetary injection of carrageenan (100 µl, 2% wt./about.) and 3 hours later after her. Compounds were administered intraperitoneally in a volume of 15 ml before injection of carrageenan. At the end of the experiment animals were killed by displacement of the cervical vertebrae and bleeding. The results, shown in Table IX, expressed in terms of percentage inhibition of edema of the legs, i.e., by subtracting from the volume of the paws of animals from the control (media only) volume of the paws of animals, which were injected substance, and then dividing the obtained difference by the amount of feet in control animals.

Counting seizures under the action of acetic acid

The experiments were conducted in accordance with how it is described in the publication of Moore et al., Brit. J. Pharmacol. 102, 198-202, 1990. Compounds were administered orally 15 minutes before the intraperitoneal injection of acetic acid (2% wt./about. in saline solution with a pH of 2.7, 10 ml/kg). Immediately after that, mice transferred into cells for individual observations and during the next 30 minutes is counted the number of abdominal contractions. At the end of the observation period, the animals were killed by displacement of the cervical vertebrae and bleeding. The results are expressed as the number of abdominal contractions (cramps) during the 30-minute observation period, as a percentage of the number of beats in the control groups.

The results presented in the Table demonstrate that the NO-paracetamol is much more active in both tests than paracetamol.

EXAMPLE F10

Security for liver introducing NO-paracetamol and paracetamol

Rats were injected NO-paracetamol (1.4 g/kg intraperitoneally)or paracetamol (1,16 g/kg intraperitoneally)or vehicle (0.9% wt./about. NaCl containing 20% vol./about. tween-20). After 6 hours the animals were killed by displacement of the cervical vertebrae, collected the blood from the artery and analyzed the plasma aspartate-aminotransferase (AST) and alanine-aminotransferase activity concentration in the liver of glutathione and bilirubin.

Reduced levels of glutathione caused by paracetamol, is a sign of oxidative stress (B. Halliwell, J. Gutterbridge "Free radicals in biology and medicine" 1993, Clarendon Press, pages 334-335).

The results are expressed as percentage values are calculated relative to the corresponding values in the control (media) group (100%).

The results demonstrate that the introduction of paracetamol causes liver damage results and the intent of values as AST and ALT transaminase, and bilirubin relative to the corresponding values in the control groups.

The introduction of NO-paracetamol causes a much smaller increase in AST and ALT, while the concentration of bilirubin is reduced compared with the control group.

Thus, in contrast to paracetamol NO-paracetamol has a more gentle effect on the liver, even in conditions of oxidative stress (i.e., the hepatic content of glutathione in equally reduced under the action of paracetamol and NO-paracetamol).

Table I
Test 1: Gastric tolerability of drug substances which are illustrated in the present invention drug classes, in animals that were injected or not injected NEM (state of oxidative stress). This value (in%) calculated as ratio between the number of animals with lesions of the stomach and the total number of animals in the group.
ConnectionDose (mg/kg) / route of administrationGastroenteropathy (% of cases)
Without NEMWith NEM
Media00
Indometacin7,5/R. is. 0100
Ambroxol25/p.o.080
Mesalamine750/i.c.060
Alendronate15/p.o.090
Taken1/s.c.0100
Omeprazole30/s.c.00
Misoprostol0,5/s.c.00
p.o. - oral; i.c. - vnutriserdechno; s.c. - subcutaneous

Table II
Test 2: Inhibition of apoptosis (DNA fragmentation), caused by the action of the CIP, in endothelial cells in the presence of compounds which are illustrated in the present invention classes of drugs
ConnectionApoptosis (%) compared with the control group, the animals of which was introduced only CIP
Indometacin95
Paracetamol120
Clopidogrel110
Salbutamol90
Ambroxol70
Alendronate160
Tefillin95
Cetirizine115
Enalapril80
Nicotinamide98
Doxorubicin94
Acyclovir95
Mesalamine74
Taken90
Simvastatin72
Omeprazole90

Table III
Test 5: Screening the effectiveness of the listed compounds in relation to the inhibition of radical formation of FeII
ConnectionInhibition (%) of radical formation of FeII
Control0
N-methyldiethanolamine0
Diethylene glycol0
1,4-butanediol0
Thiodiethanol0

Table IV
Test 3: Gastric (level of gastrointestinal lesions), liver (dose GPT, glutamate-pyruvate-transamine is s) and cardiovascular (blood pressure) portability of some compounds, representing illustrated in the present invention drug classes in terms of endothelial damage caused by the action of L-NAME. Results related to blood pressure and GPT, expressed (in%) relative to the values of these parameters found in animals that were injected only media without L-NAME.
ConnectionDose, mg/kg route of administrationBlood pressure, %GPT,%Gastroenteropathy, %
without L-NAMEwith L-NAMEwithout L-NAMEwith L-NAMEwithout L-NAMEwith L-NAME
Media100152100155030
Paracetamol300/I.P. Pavlova.1081551805002090
Doxorubicin1/I.P. Pavlova.12014519536030100
Simvastatin50/p.o.85148122220060
Omeprazole30/s.c. 100150100160010
Misoprostol0,5/s.c.10014210016005

Table V
Test 4A: Screening of the effectiveness of the listed compounds in the inhibition of hemolysis of erythrocytes induced by cumene hydroperoxide
ConnectionInhibition of hemolysis (%)
N-methyldiethanolamine54,4
Diethylene glycolthe 33.4
Thiodiethanol26
1,4-Butanediol17,4
Butanol10,5
Diethanolamin2,5

Table VI
Experiment F6: Inhibition of apoptosis (DNA fragmentation)induced in endothelial cells by hydrogen peroxide precursors presented in this invention drug classes, as well as their respective derivatives according to the invention.
ConnectionApoptosis, % (against the structure to control groups, processed only CIP)
Media0
Diclofenac (compare.)15
Nitrocefin diclofenac PR72
Ambroxol (compare.)25
Nitrocefin Ambroxol PR50
Alendronate (compare.)18
Nitrocefin alendronate PR54
Taken (compare.)8
Nitrocefin of tacrine Proverbs 1173

Table VII
Experiment F7: screening of gastric tolerability derivatives of the present invention in comparison with the corresponding drug-predecessors
ProcessingDose, mg/kgThe frequency of gastropathy (%)
Media-0
Diclofenac (compare.)20 oral70
Nitrocefin diclofenac PR20 oral0
Ambroxol (compare.)100 oral60
Nitrocefin Ambroxol PR 100 oral10
Alendronate (compare.)100 oral100
Nitrocefin alendronate PR100 oral10
Taken (compare.)10 oral60
Nitrocefin of tacrine Proverbs 1110 subcutaneously20

Table VIII
Test on gastric tolerance after oral administration NEM (PR. F8)
GroupDose, mg/kg oralThe frequency of gastropathy (%)
the control group--
the comparison group b mixture of diclofenac (A) + N-methyldiethanolamine (In)10 (a)+4 (In)50
the group with a derivative of diclofenac according to the invention (PR)1420

1. Compounds or their salts having the following General formula (I):

A-B-N(O)s(I)

where s=2;

A=R-T1-, where R represents the radical of medicinal substance, provided that

the medicinal substance according to the formula R-T1-Z or R-T1-OZ, where Z represents N or C1-C5 alkyl, selected from paracetamol, salbutamol, Ambroxol, alendronova acid, cetirizine, ampicillin, acyclovir, doxorubicin, simvastatin, dyphylline, tacrine, clopidogrel, dimethylmercury, diclofenac, ferulic acid, enalapril, propranolol, venturedeal of hemisuccinate, tolrestat or sulindaka;

T1=(CO), O, or NH;

=-TB-X2-O-, where TB=(CO) or;

X2is a bivalent radical equal to R1B-X-R2Bin which R1Band R2Bequal or different, are linear or branched C1-C6alkylene and X represents a failure of communication, O, S or NR1Cwhere NR1Crepresents H or a linear or branched C1-C6alkyl;

the corresponding predecessor In is represented by the formula-TB-X2Is HE, where TB=(JI), and the free valency of TBbusy OZ, where Z is as defined above, or TB=0, and the free valency of TBbusy N;

provided that in the formula (I), when X2a predecessor is a linear or razvetvlenii2-C20alkylene, drug substance according to the formula R-T1-Z or R-T1-OZ, used in the formula (I), belongs to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID).

2. Connection is whether their salts according to claim 1, where predecessors connections are:

1,4-butanediol: HE-(CH2)4HE

6-hydroxyhexanoic acid: IT is-(CH2)5-COOH,

4-hydroxybutiric acid: IT is-(CH2)3-COOH,

N-methyldiethanolamine:HE-(CH2)2-N(CH3)-(CH2)2HE

diethylene glycol: IT is-(CH2)2-O-(CH2)2HE

codetranslator: OH-(CH2)2-S-(CH2)2-OH.

3. Compounds or their salts according to claims 1 and 2 for use as pharmaceuticals for use in cases of oxidative stress.

4. Pharmaceutical compositions for use in cases of oxidative stress, containing as active principle compounds or their salts according to claims 1 and 2.

5. The compound 4'-acetylamino phenyl ester 4-nitrosobutane acid.

6. 4'-acetylamino phenyl ester 4-nitrosobutane acid according to claim 5 as a means for receiving analgesic drugs.

7. 4'-acetylamino phenyl ester 4-nitrosobutane acid as a means to obtain anti-inflammatory drugs.



 

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5 cl, 7 ex

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6 cl, 1 tbl, 16 ex

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26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

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EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

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