New drug substances


 

(57) Abstract:

The invention relates to organic chemistry and can find application in medicine. Describes compounds or their salts having the following General formula (I):

where A=R-T1-, where R represents the radical of medicinal substance, such as defined in the claims, T1=(CO), O, S, N or NR1cwhere R1crepresents N or C1-C5alkyl;=-TB-X2-tBIwhere TBand tBIthe same or different and selected from (CO), O, S, N or NR1cwhere R1csuch as defined above, X2represents a bivalent bridging group, such as a suitable precursor, such as defined in the claims; represents a bivalent radical-Tc-Y-, where Twith=(CO), O, S, N or NR1cwhere R1csuch as defined above, Y has a value such as presented in the claims. Also describes a pharmaceutical composition based on compounds of the formula (I) for use in cases of oxidative stress and/or endothelial dysfunction. The technical result obtained new compounds and their salts possess useful biological is designed for systematic, and for occasional use, and compositions based on them for use in cases of oxidative stress and/or endothelial dysfunction.

Under oxidative stress refers to the appearance of free radicals or radical compounds that cause damage to both the cells and the surrounding tissues (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).

It is known that oxidative stress and/or endothelial dysfunction is associated with various pathologies, as described below. 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 phenomena have chronic, debilitating body, and very often awsomeeeee medicinal substances have a noticeable negative effect.

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, acne.

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 to the SS="ptx2">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, under the above conditions of oxidative stress and/or endothelial dysfunction many drugs exhibit low activity and/or high 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 those cases when specific States can be attributed, 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, page 73, Current Medical Diagnosis and Treatment 1998, pages 431 and 794).

The introduction of anti-inflammatory drugs to patients in the above-mentioned pathological composed, 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 the same is Glennie doses of medicinal substances, 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 significantly reduced, in particular, in the case of aspirin.

For the treatment of asthma and bronchitis use a bronchodilator, such as salbutamol and so on, and in the pathology of type cholinergic 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 drawbacks as listed ritalinic of respiratory diseases, show 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 resorbtive, such as diphosphonates (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, and so on, cause similar problems in these pathological conditions, particularly in relation to efficiency.

Antiangiogenesis medicinal substance, i.e., ACE inhibitors such as enalapril, captopril, and so on, or inhibitors of receptors, such as losartan, and so on, used for the treatment of cardiovascular areas.D.) in the above-mentioned pathological conditions.

Antidiabetic medicinal substance as improve insulin sensitivity and reduce glucose levels, such as, for example, sulfonylureas, tolbutamide, glipizide, gliclazide, gliburid, nicotinamide, and so on, 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, and so on, 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 other, 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, osobennosteyj substances, with 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 having the following General formula (I):

where A=R-T1-, where R represents the radical of drug substances, as defined below, having the formula A=R-T1-Z or A=R-T1-OZ, where Z represents N or C1-C5alkyl, selected from the following groups:

anti-inflammatory medicinal ingredients: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium salt, diflunisal, etodolac, flufenamic cuprofen, meclofenamic acid, marennikova acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, taftalenovaya acid, tolmetin, zomepirac;

pain medicinal ingredients: acetaminophen, atsetilsalitsilovaja acid, benoxaprofen and tramadol;

bronchodilators: albuterol, carbuterol, clenbuterol, Tefillin, etofillin, fenoterol, metaproterenol, pirbuterol, salmeterol and terbutaline;

expectorant medicinal ingredients: Ambroxol, Bromhexine and guaiacol;

antihistamine drug substances: cetirizine, levocabastine and terfenadine;

ACE inhibitors: captopril, enalapril, lisinopril and ramipril;

beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, and timolol;

antithrombotic and vasoactive drug substances: argatroban, clopidogrel, dalteparin, dipyridamole, enoxaparin, iloprost, ozagrel, triflusal and benforado hemisuccinate;

antidiabetic medicinal substances: nicotinamide;

antitumour substances: antrepo and pantoprazole;

antihyperlipidemic drug substances: lovastatin, pravastatin sodium salt, simvastatin, atorvastatin and fluvastatin;

antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, cefatrizine, cefoxitin, dicloxacillin, imipenem, meclocycline, metatsiklina, moxalactam, panipenem, bacampicillin, ampicillin, clomocycline and oxytetracycline;

antiviral medicinal ingredients: acyclovir, famciclovir, ganciclovir, penciclovir, vidarabine and zidovudine;

inhibitors of bone resorbtive: alendronat acid, heteronomy acid and pamidronate acid.

Medicinal substances against dementia: taken.

T1=(CO), O, S, N or NR1cwhere R1crepresents N or C1-C5alkyl,

=-TB-X2-TBI,

where TBand TBIthe same or different and selected from (CO), O, S, N or NR1cwhere R1cdefined above;

X2represents a bivalent bridging group, such as an appropriate precursor To having the formula

Z’-TB-X2Z’

where Z', Z’ are independently H or HE selected from setuserisjoin (VIII):

hydroxy acids: Gallic acid (DI), ferulic acid (DII), gentisic acid (DIII), caffeic acid (DV), hidrocortisona acid (DVI), p-coumarin acid (DVII), vanillic acid (DVIII), purple acid (DXI):

aromatic polyhydric alcohols: hydroquinone (EVIII), methoxyhydroquinone (EXI), hydroxyperoxide (EXII), coniferious alcohol (EXXXII), 4-hydroxyphenethyl alcohol (EXXXIII), p-coumarin alcohol (EXXXIV):

Is a bivalent radical-TcY,

where Twith=(CO), O, S, N or NR1c, R1cmatter, as defined above;

Y has the following values:

- linear or branched C1-C20accelerograph or cycloalkyl containing from 5 to 7 carbon atoms, and in cycloalkylation the ring one or more carbon atoms may be replaced by heteroatoms, and the ring may contain side chains of R’, with R’ as defined above, or

where nIX is an integer from 0 to 3;

nIIX is an integer from 1 to 3;

RTIX, R1-C4alkyl;

Y3represents a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen atom, and the specified ring consists of 5 or 6 atoms;

where n3 is an integer from 0 to 3 and n3’ is an integer from 1 to 3;

where n3 and n3’ have the above meaning;

where nf’ is an integer from 1 to 6;

where R1f=H, CH3and nf is an integer from 1 to 6.

In the formula (III) Y3preferably you should choose from the following radicals:

The most preferred values of Y3is Y12 (pyridyl), substituted in positions 2 and 6. Communication can also be located in asymmetrical positions, for example Y12 (pyridyl) can be substituted in positions 2 and 3; Yl (pyrazole) may be 3,5-disubstituted.

Compounds of the present invention having the formula (I), can be transformed into the corresponding salts. For example, one of the ways of formation of salts is as follows: if in the molecule one of the nitrogen atoms is sufficiently basic to form a salt, organic is the number of the corresponding organic or inorganic acid. For the formation of salts in the formulas of the compounds according to the invention preferably is a radical Y or Y' of formula (III).

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

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

Derivatives of the compounds of the present invention can be used according to therapeutic indications for which applied drug precursor chemicals that can achieve benefits that are given below by way of example, for some groups of these compounds.

- Anti-inflammatory medicinal substance NSAIDs:

compounds of the present 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-type: action spectrum of compounds having the formula (I) becomes wider than ishodniki beta-adrenergic signals, 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 drugs acting on cholinergic system: reduced side effects affecting the cardiovascular system (tachycardia, hypertension).

- Expectorant medicinal 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 of the present 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 is required to insulin and hypoglycemic), antibiotics, antiviral, antitumor, protivomoskitnye pharmaceutical substances, medicinal substances against dementia: superior efficacy and/or tolerability.

Examples of drugs precursors, which can be used may be mentioned the following.

From anti-inflammatory/pain medication drugs can be mentioned the following:

anti-inflammatory medicinal ingredients: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium salt, diflunisal, etodolac, flutamida acid, flunixin, flurbiprofen, ibuprofen, indomethacin, indoprofen, Ketoprofen, Ketorolac, lornoxicam, loxoprofen, meclofenamic acid, marennikova acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, taftalenovaya acid, tolmetin, zomepirac;

pain medicinal ingredients: acetaminophen, atsetilsalitsilovaja acid, benoxaprofen, tramadol.

Of drugs for respiratory and genitourinary system (bronchodilators and drug ANTIALLERGICS antihistamine drug substances) can be mentioned the following:

bronchodilators and drugs acting on cholinergic system: albuterol, carbuterol, clenbuterol, Tefillin, etofillin, fenoterol, metaproterenol, pirbuterol, salmeterol, terbutaline;

expectorant medicinal ingredients: Ambroxol, Bromhexine, guaiacol;

antihistamine drug substances: cetirizine, levocabastine, terfenadine;

of cardiovascular drugs (ACE-inhibitors, beta-blockers, antiplatelet medications, vasodilators, antidiabetic and hypoglycemic medicinal substance) can be mentioned the following:

ACE inhibitors: captopril, enalapril, lisinopril, ramipril;

beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, timolol;

antithrombotic and vasoactive drug substances: argatroban, venturedeal hemisuccinate, clopidogrel, dalteparin,

dipyridamole, enoxaparin, iloprost, ozagrel, triflusal;

antidiabetic medicinal substances: nicotinamide;

of anticancer drugs: astromicin, daunorubicin, doxorubicin, epirubicin, epicyst is, antoprazole;

among antihyperlipidemic drugs (statins) can be mentioned the following: atorvastatin, fluvastatin, lovastatin, pravastatin sodium salt, simvastatin;

among antibiotics/antiviral drugs can be mentioned the following:

antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, cefatrizine, cefoxitin, dicloxacillin, imipenem, meclocycline, metatsiklina, moxalactam, panipenem, bacampicillin, ampicillin, clomocycline, oxytetracycline;

antiviral medicinal ingredients: acyclovir, famciclovir, ganciclovir, penciclovir, vidarabine, zidovudine;

among the inhibitors of bone resorption (diphosphonates) can be mentioned the following:

alendronat acid, heteronomy acid, pamidronate acid;

among the drugs against dementia can be mentioned the following: taken.

Preferred are the following compounds:

among the anti-inflammatory substances: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium salt, diflunisal, etodolac, flufenamic oxopropyl, meclofenamic acid, marennikova acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, Salalah, sulindac, suprofen, tenoxicam, tiaprofenic acid, telenova acid, tolmetin, zomepirac;

pain medicinal ingredients: acetaminophen, atsetilsalitsilovaja acid, benoxaprofen, tramadol;

among drugs for respiratory and urogenital systems (bronchodilators, expectorants drugs, antihistamine drug substances):

bronchodilators: albuterol, carbuterol, clenbuterol, Tefillin, etofillin, fenoterol, metaproterenol, pirbuterol, salmeterol, terbutaline;

expectorant medicinal ingredients: Ambroxol, Bromhexine, guaiacol;

antihistamine drug substances: cetirizine, levocabastine, terfenadine;

among cardiovascular drugs:

ACE inhibitors: captopril, enalapril, lisinopril, ramipril;

beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, timolol;

antithrombotic and vasoactive drug substances: argatroban, clopidogrel, d is s matter: nicotinamide;

among anticancer drugs: astromicin, daunorubicin, doxorubicin, epirubicin;

among antiulcer drugs; cimetidine, omeprazole, pantoprazole;

among antihyperlipidemic drugs: lovastatin, pravastatin sodium salt, simvastatin;

among antibiotics/antiviral drugs:

antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, cefatrizine, cefoxitin, dicloxacillin, imipenem, meclocycline, metatsiklina, moxalactam, panipenem, bacampicillin, ampicillin, clomocycline, oxytetracycline;

antiviral medicinal ingredients: acyclovir, famciclovir, ganciclovir, penciclovir, vidarabine, zidovudine;

among the inhibitors of bone resorption: alendronat acid, heteronomy acid, pamidronate acid;

among the drugs against dementia: taken.

The above-mentioned medicinal substance precursor obtained by methods known from the prior art. Examples can be found in The Merck Index, 12 Ed. (1996)", included here as a reference. If available can be used appropriate synthetic methods, described below.

The selection of the reaction for each method depends on the reactive groups present in the molecule drug substance, precursor, predecessor of the connection, which may be, as indicated above, bivalent or monovalent, and the predecessor connection With.

The reaction is conducted using methods widely known in the prior art, which allow you to form a connection between the drug-precursor, the precursor compounds and precursor compounds With.

When the reactive functional group (for example, -COOH, -OH) medicinal substances, precursor forms a covalent bond, for example ester, amide, ether, specified functional group can be regenerated using methods well known in the prior art.

Here are some of the synthesis scheme for producing compounds of the present invention.

A. Synthesis of compounds having formula (I).

1. The synthesis of the compounds obtained by the reaction between the drug-precursor and precursor compounds Century

1A. If the medicinal substance has a total fo is of medicinal substances has the formula XZ, and X is as defined above, a Z=N, then flowing the reaction depends on the nature of the second reactive group present in the precursor compound Century

1a.1. If the second reactive group present in the precursor compound In is a carboxyl group, a General scheme of the synthesis involves the initial formation of gelegenheid acid R-COHal (Hal=Cl, Br) and subsequent reaction with HX group of the precursor compound IN

where X2, T1,Tinsuch as described above.

If two compounds, reacts, there are other functional groups COOH and/or NC, 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.

Gelegenheid RCOHal receive in accordance with methods well known in the prior art, for example using thionyl or oxalicacid, PIII or PV halides, conducting the reaction in inert solvents, such as toluene, chloroform, DMF, etc.

In special cases, if the HX group of the precursor is cheroot in the appropriate gelegenheid RCOHal, as described above, and then carry out the reaction with HX group of the precursor compound In the presence of organic bases such as triethylamine, pyridine, etc. in an inert solvent, such as toluene, tetrahydrofuran, etc. at a temperature in the range from 0 to 25S.

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-hydroxybenzotriazole and dicyclohexylcarbodiimide, in such a solvent, such as DMF, THF, chloroform, etc. at a temperature in the range of -5 to 50 ° C, after which the compound obtained is injected into the interaction of in-situ reactive functional group of the precursor compound to obtain a compound having the formula (IA.1).

1a.2. If the predecessor connection contains two functional groups XZ, equal or different from each other, and X as above, and Z=H, the medicinal substance is precursor having the formula R-COOH, is first treated with an agent activating the carboxyl group, as described above in item 1a.1, and then carry out the reaction with predestin the tert-butyloxycarbonyl protection; remove protection at the end of the synthesis allows to regenerate the original functional group. The synthesis scheme is as follows:

where X, T1TBX2such as described above, a G is a protective group of a functional group NC.

2. Synthesis nitrosopropane.

2A.1. If the connection is received at the end of the previous stage 1A, has the formula (IA.1), the acid may be converted into the corresponding sodium salt, which is used to obtain the final compounds, following known methods, for example in accordance with one of the following synthesis schemes:

where T1TBX2TB1Twithsuch as above, R4selected from Cl, Br, Y as mentioned above, X1is the radical Y1not containing oxygen atom, R3is CL, Br, I, IT. If R3=HE, the compound of formula (IA.1b) is subjected to galogenirovannyie, for example, such agents as RVG3, PCl5, SOCl2, h3+I2and then it interacts with the gN3in an organic solvent, such as acetonitrile, tetrahydrofuran. If R3is CL, Br, I, a compound of the formula (1A.1b) directly interacts with the gN3as indicated Lena above.

The above reactions are well known in the prior art. Examples include patent applications of applicant: WO 94/12463, WO 95/09831 and WO 95/30641.

If X1is linear WITH4the alkyl, the corresponding acid R-T1-TB-X2-COOH interacts with triphenylphosphine in the presence of a halogenation agent such as CSAs4or N-bromosuccinimide in tetrahydrofuran, which leads to the compound (IA.1c), where R3=Br.

2A.2. If the connection is received at the end of the previous stage 1A, has the formula (IA.2), the corresponding nitrosopropane receive treatment halogencarbonic acid having the formula Hal-X1-COOH (X1as mentioned above, first, an agent activating the carboxyl group, as described above in paragraph 1A.1, and then compound having the formula (IA.2), which leads to halogen derivatives, which emit, are dissolved in an organic solvent (see paragraph 2A.1) and then treated with silver nitrate. The General reaction scheme is as follows:

where T1TBX2TB1Tc, Y such as described above.

An alternative method is the use of a halide Hal-Xl-COCl, where Hal is preferably Br, which is heat reactive functional group NH, where X is, as indicated above, instead of the carboxyl group, the two functional groups present in the precursor compounds, can be the following.

1b.1. Carboxyl group, which interacts with the functional group NH medicinal substance, precursor, and NC group, the latter reactive group of the precursor compound In the same or different from the functional groups of medicinal substances predecessor. The formula of the precursor compound In is a formula of the following type: H-h-h2-COOH, where X and X2such as described above. Functional group N-X-precursor compounds In protect in accordance with the methods known from the prior art, and the carboxyl group is reacted, as described above, according to the following scheme:

Upon completion of the reaction of the functional group NC predecessor connection To regenerate.

1b.2. If the predecessor connection contains two carboxyl groups, then it is treated with equimolar amount of an agent activating the carboxyl group, under the conditions previously described in paragraph 1a.1, and then carry out the reaction with the reactive group HX m is p, NC-type present in these two compounds should be protected, as indicated earlier. In the end you get a compound with the formula K-T1-Tin-X2-COOH (IB.2).

2b. Synthesis nitrosopropane.

2b.1. To obtain the final nitrosopropane of the starting compound having the formula R-T1-Tin-X2-X-H (IB.1) obtained at the end of the synthesis described in paragraph 1b.1, the connection (IE.1) is injected into the reaction halogenerators having the formula Hal-X1-COOH, which is treated as described previously in paragraph 1a.1, or with the corresponding acid chloride of halogenate. The compound obtained is dissolved in an organic solvent, for example acetonitrile or tetrahydrofuran, and then carry out the reaction with silver nitrate.

2b.2. To obtain the final nitrosopropane of the starting compound having the formula R-T1-Tin-X2-COOH (IB.2) obtained at the end of the synthesis described in paragraph 1b.2, the acid is converted into the corresponding sodium salt, which interacts with the compound of the formula R4-X1-R3previously defined in the reaction scheme And paragraph 2A.1, receiving in accordance with the same aforementioned process end nitroxides what reperfusion in the presence of a halogenation agent, such as CSAs4or N-bromosuccinimide in tetrahydrofuran, and the resulting compound is dissolved in an organic solvent, for example acetonitrile or tetrahydrofuran, interacts with silver nitrate.

2b.3. Alternatively, the synthetic process described in paragraphs 1b.1 and 2b.1, in the first stage, the possible reaction HX-function of precursor compounds In the NC-X2-COOH with the acid chloride of halogenate having the formula Hal-X1-CO-Cl, where Hal is preferably Br, then the carboxyl function of the thus obtained compound interacts with the medicinal substance is a precursor R-X. In the third and last stage of the Hal group substituted by a group-ONO2in accordance with the process described in paragraph 2b.1.

The reaction scheme is as follows:

where TWITHTB1TB, T1X2X1, Y such as described above.

In the previous scheme, alternatively, may be spent nitration acid of the formula (2B.3).

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

EXAMPLE 1

CLASS="ptx2">

The predecessor is naproxen (formula VI), the precursor of b is N-acetylcysteine (formula VIII)

a) Synthesis of (S,S)-N-acetyl-S-(6-methoxy--methyl-2-naphthylacetyl)cysteine

To a solution of 6-methoxy--methyl-2-naphthylacetic acid (10 g, to 34.4 mmol) in chloroform (100 ml) and N,N-dimethylformamide (6 ml) is added 1,1’-carbonyldiimidazole (CDI) (? 7.04 baby mortality g, a 43.4 mmol). After 15 min to the resulting solution was added (S)-N-acetylcysteine (7,08 g, a 43.4 mmol) and incubated the reaction mixture at room temperature for 12 hours. Wash the reaction mixture with 5% Hcl, water and then saturated aqueous NaCl. The organic phase is dried with sodium sulfate and then evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira with ethyl acetate. Get 11,66 g of the desired product as a white solid with so pl. 122-S.

1H-NMR (CDCl3): 7,71-the 7.65 (3H, m), 7,34 (1H, DD), 7,16-to 7.09 (2H, m), 6,36 (1H, d), of 4.67 (1H, m) 4,00 (1H, K), 3,90 (3H, s), of 3.32 (2H, t), of 1.84 (3H, s) to 1.59 (3H, d).

b) Synthesis of 4-bromatologia ether (S,S)-N-acetyl-S-(6-methoxy--methyl-2-naphthylacetyl)cysteine

To a solution of (S,S)-N-acetyl-S-(6-methoxy--methyl-2-naphthylacetyl)cysteine (11.3 g, to 30.1 mmol) in tetrahydrofuran (200 ml) dalmatas temperature for 24 hours. The solvent is 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. Get 4 g of the target ester as white solids with so pl. 67-S.

c) Synthesis of 4-nitrocellulose ether (S,S)-N-acetyl-S-(6-methoxy--methyl-2-naphthylacetyl)cysteine

To a solution of the ester obtained in the previous step (1 g, a 1.96 mmol) in acetonitrile (20 ml) is added silver nitrate (0.66 g, to 3.92 mmol). Boil the reaction mixture for 7 hours without light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3. Get to 0.47 g of 4-nitrocellulose ether (S,S)-N-acetyl-S-(6-methoxy--methyl-2-naphthylacetyl)cysteine in the form of a white solid with so pl. 56-59S.

1H-NMR (CDCl3): 7,80-to 7.68 (3H, m), 7,37 (1H, d), 7,20-7,13 (2H, m), 6,12 (1H, d), and 4.40 (2H, DD), 4.26 deaths (1H, m), 4,15-a 3.87 (3H, m) to 3.92 (3H, s) to 3.33 (2H, d), of 1.86 (3H, d), 1,74-to 1.67 (4H, m) to 1.61 (3H, d).

Elemental analysis

Calculated: 56,08%; N 5,73%; N 5,71%; S 6,51%.

Found: 55,99%; N 5,68%; N Ceiling Of 5.60%; S 6,35%.

EXAMPLE 2

Synthesis of 4-nitrocellulose ether (S)-N-acetyl-is aetsa ibuprofen (formula VII), the precursor is N-acetylcysteine (formula VIII)

a) Synthesis of (S)-N-acetyl-S-{-methyl-[4-(2-methylpropyl " phenyl]acetyl}cysteine

To a solution of methyl-[4-(2-methylpropyl " phenyl]acetic acid (10 g, 48,48 mmol) in chloroform (100 ml) and N,N-dimethylformamide (6 ml) is added 1,1’-carbonyldiimidazole (7,86 g, 48,48 mmol). After 1 hour the resulting solution was added (S)-N-acetylcysteine (to $ 7.91 g, 48,47 mmol) and incubated the reaction mixture at room temperature for 24 hours. Wash the reaction mixture with 5% Hcl, water and then saturated aqueous NaCl. The organic phase is dried with sodium sulfate and then evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira with ethyl acetate. Obtain 13.3 g of the desired product in the form of butter.

1H-NMR (CDCl3): 10,17 (1H, s), 7,13 (2H, d), is 6.54 (1H, d), was 4.76 (1H, m), 3,93 (1H, K), 3,42-3,30 (2H, m), 2.49 USD (2H, d), 1,85 of-1.83 (4H, m) of 1.55 (3H, d), 0,93 (6N, e).

b) Synthesis of 4-bromatologia ether (S)-N-acetyl-S-{-methyl-[4-(2-methylpropyl " phenyl] acetyl}cysteine

To a solution of (S)-N-acetyl-S-{-methyl-[4-(2-methylpropyl " benzyl]acetyl}cysteine (12.8 g, of 36.4 mmol) in tetrahydrofuran (100 ml) is added triphenylphosphine (28,65 g, 109,23 mmol) and tetrabromomethane (36,23 g, 109,23 mmol). Mix the AI. The crude product was then purified using chromatography on silica gel, elwira with a mixture of cyclohexane/ethyl acetate 1/1. Get 5,79 g of the target ester in the form of butter.

c) Synthesis of 4-nitrocellulose ether (S)-N-acetyl-S-{-methyl-[4-(2-methylpropyl " phenyl]acetyl}cysteine

To a solution of the ester obtained in the previous stage (5.5 g, 11.3 mmol) in acetonitrile (100 ml) is added silver nitrate (2,69 g, 15.8 mmol). Boil the reaction mixture for 24 hours without light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira with a mixture of cyclohexane/ethyl acetate 7/3. Obtain 1.18 g of 4-nitrocellulose ether (S)-N-acetyl-S-{-methyl-[4-(2-methylpropyl " phenyl]acetyl}cysteine in the form of butter.

1H-NMR (CDCl3): 7,27-to 7.09 (4H, m), to 6.19 (1H, d), and 4.75 (1H, m), 4,47 (2H, t), 4,15-was 4.02 (2H, m), 3,86 (1H, K), and 3.31 (2H, d), 2,44 (2H, d), 1,89 (3H, d), 1,86 to 1.76 (5H, m) and 1.51 (3H, d), 0,89 (6N, e).

Elemental analysis

Calculated: 56,39%; N 6,88%; N 6,00%; S 6,84%.

Found: 56,22%; N 6,79%; N, 5.88 Per Cent; S 6,92%.

EXAMPLE 3

Synthesis of 4-nitrocellulose ether (S)-N-acetyl-S-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetyl]cysteine (NCX 2121), having the formula

a) Synthesis of (S)-N-acetyl-S-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetyl]cysteine

To a solution of 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetic acid (10 g, 28,00 mmol) in chloroform (100 ml) and N,N-dimethylformamide (2 ml) is added 1,1’-carbonyldiimidazole (4,53 g 28,00 mmol). After 1 hour the resulting solution was added (S)-N-acetylcysteine (4,56 g 28,00 mmol) and incubated the reaction mixture at room temperature for 24 hours. Wash the reaction mixture with 5% Hcl, water and then saturated aqueous NaCl. The organic phase is dried with sodium sulfate and then evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira with ethyl acetate. Get 7,79 g of the desired product as yellow solid with so pl. S.

1H-NMR (DMSO-d6): 12,90 (1H, s), 8,21 (1H, d), 7,69-to 7.64 (4H, m), 7,06 (1H, d), of 6.96 (1H, d), of 6.73 (1H, DD), to 4.33 (1H, m), was 4.02 (2H, s), of 3.77 (3H, s), 3.33 and-2,96 (2H, m), 2,22 (3H, s) of 1.78 (3H, s).

b) Synthesis of 4-bromatologia ether (S)-N-acetyl-S-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetyl]cysteine

To a solution of (S)-N-acetyl-S-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetyl]cysteine (3,09 g, 6,14 mmol) in N,N-dimethylformamide (50 ml) add sodium ethylate (0,42 g, 6,14 IMO remediat the reaction mixture at room temperature for 20 hours, then diluted with ethyl ether and washed with water. After drying the organic phase with sodium sulfate the solvent is evaporated under reduced pressure. The crude product was then purified using chromatography on silica gel, elwira with a mixture of cyclohexane/ethyl acetate 1/1. Obtain 1.7 g of the target ester in the form of a yellow solid with so pl. 130-S.

c) Synthesis of 4-nitrocellulose ether (S)-N-acetyl-S-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetyl]cysteine

To a solution of the ester obtained in the previous stage (1.6 g, 2.5 mmol) in acetonitrile (30 ml) is added silver nitrate (0.6 g, 3,51 mmol). Boil the reaction mixture for 8 hours without light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira with a mixture of cyclohexane/ethyl acetate 4/6. Obtain 1.2 g of 4-nitrocellulose ether (S)-N-acetyl-S-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetyl]cysteine in the form of butter.

1H-NMR (CDCl3): 7,66 (2H, d), of 7.48 (2H, d), of 6.90 (2H, m), of 6.68 (1H, m), 6,14 (1H, d), of 4.77 (1H, m), 4,43 (2H, t) 4,08 (2H, m), a 3.87 (2H, s), 3,83 (3H, s) to 3.34 (2H, d), of 2.38 (3H, s), 1,90 (3H, s), 1,78 is 1.70 (4H, m).

Elemental analysis

RASSC the 4-nitrocellulose ether (S)-N-acetyl-[2-fluoro--methyl-(1,1’-biphenyl)-4-acetyl]cysteine (NCX 2131), having the formula

The predecessor is flurbiprofen (formula IX), the precursor of b is N-acetylcysteine (formula VIII)

Connection NCX 2131 synthesized in accordance with the procedure described in example 1. The connection is obtained as oil. Yield 26%.

1H-NMR (CDCl3): 7,41-7,38 (6N, m), 7,10 (2H, m), from 6.22 (1H, d), 4,78 (1H, m), 4,46 (2H, t), of 4.13 (2H, t) to 3.92 (1H, K) to 3.36 (2H, d), of 1.93 (3H, d), of 1.76 (4H, d), of 1.55 (3H, d).

Elemental analysis

Calculated: 56,91%; N 5.37 Percent; N 5,55%; S 6,33%; F 3,75%.

Found: 56,99%; N 5,41%; N 5,66%; S 6,41%; F 3,83%.

EXAMPLE 5

Getting 4-nitrocellulose ester of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid (NCX 2210), having the formula

The predecessor is ibuprofen (formula VII), the predecessor is ferulic acid (formula DII)

a) Synthesis of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid

To a solution of methyl-[4-(2-methylpropyl " phenyl]acetic acid (to 5.03 g, 24.4 mmol) in tetrahydrofuran (100 ml) and N,N-dimethylformamide (5 ml) is added 1,1’-carbonyldiimidazole (4,25 g of 24.8 mmol). After 1 hour the resulting solution was added Frolovo acid (4,90 g, 25 mm shall provide the reaction mixture with 5% Hcl, water, and then saturated aqueous NaCl. The organic phase is dried with sodium sulfate and then evaporated under reduced pressure.

The resulting residue is purified by means of chromatography on silica gel, elwira a mixture of ethyl acetate/n-hexane 7/3. Get a 5.1 g of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid in the form of a white solid with so pl. 131-S.

1H-NMR (CDCl3): 7,72 (1H, d), 7,32 (2H, DD), 7,26 (1H, m), 7,16-7,07 (4H, m), 6,98 (1H, d), 6,37 (1H, d), 3,99 (1H, K), of 3.73 (3H, s), 2,47 (2H, d), a 1.88 (1H, m), and 1.63 (3H, d), 0,92 (6N, e).

b) Synthesis of 4-bromatologia ester of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid

To a solution of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " benzyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid (5,33 g, 14 mmol) in N,N-dimethylformamide (130 ml) is added with stirring to the sodium ethylate (1.2 g, 16 mmol). After 1 hour, to the mixture add 1,4-dibromobutane (10 g, 46 mmol) and incubated the mixture at room temperature for 12 hours. Wash the reaction mixture with 5% Hcl, water and then saturated aqueous NaCl, dried the organic phase with sodium sulfate and then evaporated under reduced pressure. The resulting residue is purified of ppera TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid.

C) Synthesis of 4-nitrocellulose ester of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid

To a solution of 4-bromatologia ester of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " phenyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid (4 g, 7,72 mmol) in acetonitrile (70 ml) is added silver nitrate (2.58 g, 15 mmol). Boil the reaction mixture for 2 hours without light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 8/2. Obtain 2.4 g 4-nitrocellulose ester of TRANS-3-[4-[-methyl-[4-(2-methylpropyl " benzyl]atomic charges]-3-methoxyphenyl]-2-propanolol acid in the form of butter.

1H-NMR (CDCl3): a 7.62 (1H, d), 7,32 (2H, d), to 7.15 (2H, d), 7,16-7,05 (2H, m), of 6.96 (1H, d), 6.35mm (1H, d), 4,51 (2H, t), are 4.24 (2H, t) to 3.99 (1H, K), 3,74 (3H, s), 2,48 (2H, d), 1,89 of-1.83 (5H, m) of 1.62 (3H, d), 0,92 (6N, e).

Elemental analysis

Calculated: 64,91%; N 6,66%; N 2,82%.

Found: 64,83%; N 6,52%; N 2,69%.

EXAMPLE 6

Synthesis of 4-nitrocellulose ester of TRANS-3-[4-[2-fluoro--methyl-(1,1’-biphenyl)-4-acetoxy]-3-methoxyphenyl]-2-propanolol acid (NCX 2216), having the formula

The predecessor is flurbiprofen desirous in accordance with the methodology described in example 5. The total yield of 32%. The connection has the form of a solid amorphous material.

1H-NMR (CDCl3): 7,40-7,25 (N, m), 7,07-7,01 (2H, d), 6,98 (1H, m), 6,38 (1H, d), of 4.44 (2H, t), is 4.21 (2H, t), Android 4.04 (1H, K), of 3.73 (3H, s), 1,72 (4H, m), of 1.65 (3H, d).

Elemental analysis

Calculated: 64,79%; N 5,25%; N 2,62%; F 3,53%.

Found: 64,85%; N 5,31%; N 2,74%; F 3,48%.

EXAMPLE 7

Getting 4-acetamidophenyl ester of N-(4-nitrostyryl)--alanyl-(L)-histidine (NCX 2160), having the formula

where the precursor is acetaminophen (paracetamol), having the formula (X), and the precursor is L-carnosine (NCX 2053), having the formula (CI)

a) Synthesis of N-(4-bromobutyryl)--alanyl-(L)-histidine

To a solution of carnosine (5 g, to 22.1 mmol) in N,N-dimethylformamide (80 ml), add triethylamine (4,62 ml, up 33.1 mmol) and 4-bromobutyrate (acid chloride 4-bromoethanol acid, 83,85 ml, up 33.1 mmol). Stir the solution at room temperature for 24 hours, then dilute it with ethyl acetate and the organic phase is washed 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 with ethyl acetate, Yes Idina

To a solution of N-(4-bromobutyryl)--alanyl-(L)-histidine (3 g, 8 mmol) in chloroform (50 ml) and N,N-dimethylformamide (4 ml) is added under stirring paracetamol (1,21 g, 8 mmol), N,N-dicyclohexylcarbodiimide (1.65 g, 8 mmol) and dimethylaminopyridine (0.04 g, 0.36 mmol). Maintain the reaction mixture at room temperature for 6 hours. Next, the mixture is filtered, diluted with chloroform and washed 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 ethyl acetate/n-hexane 7/3. Receive a 4-acetamidophenyl ester of N-(4-bromobutyryl)--alanyl-(L)-histidine.

c) Synthesis of 4-acetamidophenyl ester of N-(4-nitrostyryl)--alanyl-(L)-histidine

To a solution of 4-acetamidophenyl ester of N-(4-bromobutyryl)--alanyl-(L)-histidine (4 g, 7.87 mmol) in acetonitrile (70 ml) is added under stirring silver nitrate (1,87 g, 11 mmol). Boil the reaction mixture for 5 hours without light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 3/7. Get the target product with CLASS="ptx2">EXAMPLE 8

Getting 4-nitrocellulose ester N-acetyl-S-[(S)--(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetyl]-(S)-cysteine (NCX 2136)

where the precursor is clopidogrel, having the formula (XI), and the precursor of b is N-acetyl cysteine having the formula (VIII)

The compound synthesized by the method described in example 1. Yield 23%.

Elemental analysis

Calculated: 50,55%; N Of 4.95%; N 7,40%; S 11,24%; Cl To 6.22%.

Found: 50,70%; N 4,99%; N 7,60%; S 11,20%; Cl 6,15%.

EXAMPLE 9

Getting 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexylamino ether [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid (NCX 2161)

where the precursor is Ambroxol, having the formula (XII), and the predecessor In the present ferulic acid, having the formula (DII)

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

To a solution of 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexanol (5 g, 13,22 mmol) in a mixture of dioxane (35 ml) and water (50 ml) is added with stirring triethylamine (3,31 ml, with 23.7 mmol) and di-tert-BUTYLCARBAMATE (of 3.46 g, 15,86 mmol). After 24 hours the solution was concentrated in vacuo, add 1% resurgences phase sodium sulfate and evaporated in vacuum. Receive 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]-TRANS-cyclohexanol, which is used without further purification.

b) Synthesis of 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexylamino ether [3-methoxy-4-hydroxyphenyl]-2-TRANS-propanolol acid

To a solution of ferulic acid (4 g, of 20.5 mmol) in tetrahydrofuran (40 ml) at 0C add 1,1’-carbonyldiimidazole (3,34 g of 20.5 mmol). After 10 minutes the solution was added 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexanol (9,8 g, 20,5 mmol) and maintain the reaction mass at room temperature for 4 hours. Concentrate the reaction mixture under vacuum, add dichloromethane, then washed with 1% Hcl solution and then with water. Dry the organic phase with sodium sulfate and then evaporated in vacuum. The resulting residue is purified by means of chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1. Receive 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexyloxy ether [3-methoxy-4-hydroxyphenyl]-2-TRANS-propanolol acid.

c) Synthesis of 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexylamino ether [3-methoxy-4-(4-bromobutyrate)FeNi is cloakroom ether [3-methoxy-4-hydroxyphenyl]-2-TRANS-propenoic acid (4 g, 6,11 mmol) in tetrahydrofuran (80 ml) is added with stirring triethylamine (0,85 ml, 6,11 mmol) and bromobutyrate (0.7 ml, 6,11 mmol). The reaction is carried out at room temperature for 8 hours, then evaporated organic solvent under reduced pressure. The crude product is treated with ethyl acetate and the organic phase is washed with water. Then the organic phase is dried with sodium sulfate and evaporated in vacuum. The residue is purified using chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3. Receive 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexyloxy ether [3-methoxy-4-(4-bromobutyrate)phenyl]-2-TRANS-propanolol acid.

d) Synthesis of 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexylamino ether [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid

To a solution of 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexylamino ether [3-methoxy-4-(4-bromobutyrate)phenyl]-2-TRANS-propanolol acid (4 g, to 4.98 mmol) in acetonitrile (70 ml) is added under stirring silver nitrate (0.87 g, to 4.98 mmol). Boil the reaction mixture for 7 hours without access of light, after which the resulting salt udalali on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3. Receive 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl)methylamino]cyclohexyloxy ether [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid.

e) Synthesis of 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexylamino ether [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid

To a solution of 4-[(2-tert-butyloxycarbonyl-3,5-dibromophenyl) methylamino]cyclohexylamino ether [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid (2 g, 2.54 mmol) in ethyl acetate (50 ml), cooled to 0C, was added with stirring 5 n solution of Hcl in ethyl acetate (3,17 ml). Stir the solution at 0C for 4 hours, after which the precipitation is filtered off. To the obtained crude product is poured in ethyl acetate to which was added 5% sodium bicarbonate solution. The mixture is shaken out, then replace the bicarbonate solution an equal volume of water, then shake again. Separate the organic phase, dried her sodium sulfate and evaporated under reduced pressure. Receive 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexyloxy ether [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid. Yield 36%.

Elemental analysis< Obtaining [4-amino-[[3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propenyl]-1-hydroxybutylidene]bisphosphonates acid (NCX 2211)

where the precursor is alendronat acid having the formula (XIII), and the predecessor is ferulic acid (formula DII)

a) Synthesis of [3-methoxy-4-(4-bromobutyrate)phenyl]-2-TRANS-propanolol acid

To a solution of ferulic acid (1.2 g, 6,11 mmol) in tetrahydrofuran (80 ml) with stirring, add triethylamine (0,85 ml, 6,11 mmol) and 4-bromobutyrate (0.7 ml, 6,11 mmol). Conduct the reaction at room temperature for 3 hours and then evaporated under reduced pressure. To the obtained crude product add ethyl acetate and wash the organic phase with water. Then the organic phase is dried with sodium sulfate and evaporated in vacuum. The resulting residue is purified by means of chromatography on silica gel, elwira a mixture of chloroform/methanol 8/2. Eventually emit [3-methoxy-4-(4-bromobutyrate)phenyl]-2-TRANS-propanolol acid.

b) Synthesis of [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid

To a solution of [3-methoxy-4-(4-bromobutyrate)phenyl]-2-TRANS-propanolol acid (1.5 g, 4.5 mmol) in acetonitrile (70 ml) is added under stirring silver nitrate (0.87 g, to 4.98 mmol). Boil the reaction mixture for 3 hours without access of light and peremeny the residue purified via chromatography on a column of silica gel, elwira a mixture of chloroform/methanol 8/2. Get [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid.

C) Synthesis of [4-amino-[[3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propenyl]-1-hydroxybutylidene]bisphosphonates acid

To a solution of [3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propanolol acid (2 g, 6.4 mmol) in N,N-dimethylformamide (30 ml), cooled to 0C, add with stirring N,N’-dicyclohexylcarbodiimide (1.3 g, 6.4 mmol) and 1-hydroxybenzotriazole (1.04 g, to 7.68 mmol). After 30 minutes add alendronate acid (1.6 g, 6.4 mmol). Stirred the reaction mixture at room temperature for 7 hours. Then acidified with 5% Hcl solution and extracted with the organic phase of ethyl acetate. The organic phase is washed with saturated aqueous NaCl solution, dried with sodium sulfate and then evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane/methanol 8/2. Get [4-amino-[[3-methoxy-4-(4-nitrosobutane)phenyl]-2-TRANS-propenyl]-1-hydroxybutylidene]bisphosphonic acid. Yield of 11%.

Elemental analysis

Calculated: 19,71%; N 4,36%; N 5,07%; P 11,17%.

Found: 19,56%;-1-piperazinil]ethoxy]acetyl]penitsillamin (NCX 2060), having the formula

where the precursor is cetirizine having the formula XIV, and it's predecessor is In penicillamine (formula CV)

a) Synthesis of 4-nitrocellulose ether S-[[2-[4-(4-chlorophenyl)phenylmethyl)-1-piperazinil]ethoxy]acetyl]-N-tert-butyloxycarbonyl

Connection receive in accordance with the method set forth in example 1, using N-tert-butyloxycarbonyl instead of N-acetylcysteine.

b) Synthesis of 4-nitrocellulose ether S-[[2-[4-(4-chlorophenyl)phenylmethyl)-1-piperazinil]ethoxy]acetyl]penitsillamin

The connection is obtained from the previous connection according to the method described in example 9 (stage e), removing the N-tert-butyloxycarbonyl protection and deblocare thus the amino group. Yield 26%.

Elemental analysis

Calculated: 55,78%; N Of 6.49%; N, 8.43 Per Cent; S 4,80%; Cl 5,31%.

Found: 55,61%; N Of 6.31%; N 8,29%; S 4,93%; Cl 5,43%.

EXAMPLE 12

Getting 4-nitrocellulose ester N-acetyl-S-[(S)-1-[N-[1-(etoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-Proline]cysteine (NCX 2134)

where the precursor is enalapril having the formula XV, and the precursor is N-acetylcysteine (formula VIII)

The connection Sintesi is 62%; S 4,91%.

Found: 55,30%; N 6,85%; N 8,71%; S 4,85%.

EXAMPLE 13

Getting 4-nitrocellulose ester 3-[4-[D-aminobenzylpenicillin]-3-methoxyphenyl]-2-TRANS-propanolol acid (NCX 2080), having the formula

where the precursor is represented by ampicillin (formula XVI), and the predecessor is ferulic acid (formula DII)

The compound synthesized by the method described in example 5. Yield of 11%.

Elemental analysis

Calculated: 56,04%; N 5,33%; N 8,75%; S Of 4.99%.

Found: 56,15%; N 5,48%; N 8,65%; S A 4.83%.

EXAMPLE 14

9-[[2-[N-acetyl-S-(4-nitroxymethyl)cysteinyl]ethoxy]methyl]guanine (NCX 2135)

where the precursor is acyclovir (formula XVII), and the precursor of b is N-acetylcysteine (formula VIII)

a) Synthesis of N-acetyl-S-(4-bromobutyryl)cysteine

Prepare a solution containing 4-bromoethanol acid (5.1 g, 30,6 mmol) and 1,1’-carbonyldiimidazole (5,61 g, 34.6 mmol) in chloroform (50 ml), and stirred at room temperature for 1 hour. Add to the reaction mixture a solution of N-acetylcysteine (5 g, of 30.6 mmol) in N,N-dimethylformamide (5 ml) containing sodium ethylate (50 mg). Mix a solution within 24 hatom sodium and evaporated under reduced pressure. The crude product was then purified using chromatography on a column of silica gel, elwira a mixture of ethyl acetate/chloroform 7/3. End up with N-acetyl-S-(4-bromobutyryl)cysteine.

b) Synthesis of N-acetyl-S-(4-nitroxymethyl)cysteine

To a solution of N-acetyl-S-(4-bromobutyryl)cysteine (3 g, 9.6 mmol) in acetonitrile (70 ml) is added silver nitrate (1.7 g, 10 mmol). Boil the reaction mixture for 2 hours without light. The formed salt is removed by filtration and evaporated the solution under reduced pressure. The resulting residue is purified by means of chromatography on a column of silica gel, elwira a mixture of ethyl acetate/chloroform 7/3. Get the result N-acetyl-S-(4-nitroxymethyl)cysteine.

c) Synthesis of 9-[[2-[N-acetyl-S-(4-nitroxymethyl)cysteinyl]ethoxy]methyl]guanine

Prepare a solution of N-acetyl-S-(4-nitroxymethyl)cysteine (2.8 g, 9.6 mmol) and 1,1’-carbonyldiimidazole (1.55 g, 9.6 mmol) in tetrahydrofuran (50 ml) and stirred at room temperature for 1 hour. Add to the reaction mixture acyclovir (2.16 g, 9.6 mmol). Conduct the reaction at room temperature for 6 hours, the solvent evaporated under reduced pressure, the obtained residue is dissolved in ethyl acetate and washed nassen the residue purified via chromatography on a column of silica gel, elwira with ethyl acetate. Get 9-[[2-[N-acetyl-S-(4-nitroxymethyl)cysteinyl]ethoxy]methyl]guanine. Exit 9%.

Elemental analysis

Calculated: 35,25%; N 3,95%; N 13,76%; S 47,05%.

Found: 35,38%; N 3,99%; N At 13.84%; S 47,20%.

EXAMPLE 15

Getting 4-nitrocellulose ester of TRANS-3-[4-(5-amino-2-hydroxybenzoyl)-3-methoxyphenyl]-2-propanolol acid (NCX 2212)

where the precursor is mesalamine (XVIII), and the predecessor is ferulic acid (formula DII)

a) Synthesis of 4-nitrocellulose ester of TRANS-3-[4-(5-tert-butyloxycarbonyl-2-hydroxybenzoyl)-3-methoxyphenyl]-2-propanolol acid

The compound is synthesized in accordance with methods described in example 5, pre protecting the primary amino group of mesalamine as described in example 9, step a).

b) Obtaining 4-nitrocellulose ester of TRANS-3-[4-(5-amino-2-hydroxybenzoyl)-3-methoxyphenyl]-2-propanolol acid

The target compound is obtained by hydrolytic splitting of the connection between the amino group and N-tert-butyloxycarbonyl protecting group, as described in example 9, step e). Yield 28%.

Elemental analysis

Calculated: 56,49%; N 4,96%; N, 6.30%, And.

Found: 56 the zoilus]tetracycline (NCX 2163)

where the precursor is metatsiklina (XIX), and the predecessor is gentisic acid (DIII)

a) Synthesis of 5-(4-bromobutyrate)-2-hydroxybenzoic acid

To a solution of 4-bromobutyronitrile (3 g, 16,17 mmol) in tetrahydrofuran (50 ml), cooled to 0 dropwise added triethylamine (4.5 ml, 32,34 mmol), and then entityname acid (2.4 g, 16,16 mmol). Conduct the reaction at 0 ° C and stirring for 4 hours, then the reaction mixture is evaporated under reduced pressure. To the obtained crude product add ethyl acetate, the organic phase is washed with 1% Hcl, then saturated aqueous NaCl. Dry the organic phase with sodium sulfate and evaporated. The resulting residue is purified by means of chromatography on a column of silica gel, elwira a mixture of dichloromethane/methanol 95/5. Get 5-(4-bromobutyrate)-2-hydroxybenzoic acid.

b) Synthesis of 5-(4-nitrosobutane)-2-hydroxybenzoic acid

To a solution of 5-(4-bromobutyrate)-2-hydroxybenzoic acid (3 g, 9.6 mmol) in acetonitrile (150 ml) is added silver nitrate (1.7 g, 10 mmol). Boil the reaction mixture for 7 hours without light. The formed salt is removed by filtration and evaporated solution is UYa mixture of dichloromethane/methanol 95/5. These operations produce pure 5-(4-nitrosobutane)-2-hydroxybenzoic acid.

C) Synthesis of 6-methylene-5-hydroxy-10-[2-hydroxy-5-(4-nitrosobutane)benzoyl]tetracycline

Prepare a solution of 5-(4-nitrosobutane)-2-hydroxybenzoic acid (5 g, 16.4 mmol) and 1,1’-carbonyldiimidazole (2.67 g, 16.4 mmol) in tetrahydrofuran (70 ml) and stirred at room temperature for 1 hour. Add adriamycin (7.2 g, 16.4 mmol). Conduct the reaction at room temperature and under stirring for 12 hours. Then the organic solution is evaporated under reduced pressure, the obtained residue is poured in ethyl acetate and washed with a mixture of saturated aqueous NaCl. The organic phase is dried with sodium sulfate and evaporated in vacuum. The resulting residue is purified by means of chromatography on a column of silica gel, elwira with ethyl acetate. Get a 6-methylene-5-hydroxy-10-[2-hydroxy-5-(4-nitrosobutane)benzoyl]tetracycline. Exit 19%.

Elemental analysis

Calculated: 55,84%; N 4,40%; N 5,95%.

Found: 55,95%; N 4,55%; N 5,98%.

EXAMPLE 17

Obtain 5-[[3-[3-methoxy-4-(4-nitroxy)butyryloxy]phenyl-2-TRANS-propenyl]amino]-1,2,3,4-tetrahydropyridine (NCX 2214)

II)

The compound is synthesized in accordance with methods described in example 10. Exit 7%.

Elemental analysis

Calculated: 64,13%; N 5,38%; N, 8.34 Per Cent.

Found: 64,28%; H 5.46 Percent; N Of 8.47%.

EXAMPLE 18

Getting 1,2,3,7,8,8-hexahydro-3,7-dimethyl-8-[tetrahydro-4-[2-hydroxy-5-(4-nitrosobutane)]benzoyloxy[6-oxo-2H-Piran-2-yl]ethyl]-1-neftianogo ether [1S-[1,3,7,8,(2S*,4S*)]]-2,2-dimethylbutanol acid (NCX 2164)

where the precursor is simvastatin (formula XXI), and the predecessor is gentisic acid (formula DIII)

The compound synthesized by the method described in example 16. Exit 13%.

Elemental analysis

Calculated: 63,15%; N 7,06%; N 2,01%.

Found: 63,68%; N 7,21%; N 2,19%.

EXAMPLE 19

Getting 5-methoxy-2-[[[4-[N-[4-nitroxymethyl--alanyl]-(L)-histidinate]-3,5-dimethyl-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole (NCX 2062)

where the precursor is a 4-gidroksiomeprazol (formula HHP) obtained from omeprazole as described in Acta Chem. Scand. 43, 6, 1989, pages 549-568, and a precursor To carnosine is (formula CI)

The compound synthesized in accordance with the procedure described in example 7. The output 25%.

Elimer 20

Getting 4-nitrocellulose ether N-nicotinoyl--alanyl-(L)-histidine (NCX 2073)

where the precursor is nicotinamide (formula XXIII), and a precursor To carnosine is (formula CI)

a) Synthesis of N-nicotinoyl--alanyl-(L)-histidine

To a solution of nicotinic acid (2.5 g, 20,5 mmol) in tetrahydrofuran (40 ml), cooled to 0C, add with stirring 1,1’-carbonyldiimidazole (3,34 g of 20.5 mmol). After 10 min this solution was added L-carnosine (4.6 g, 20,5 mmol) and stirred the mixture at room temperature for 4 hours. Concentrate the reaction mixture in vacuo, diluted with dichloromethane, washed with 1% Hcl and then with water. Dry the organic phase with sodium sulfate and evaporated in vacuum. The obtained residue chromatographic on a column of silica gel, elwira with ethyl acetate. Allocate N-nicotinoyl--alanyl-(L)-histidine.

b) Synthesis of 4-bromatologia ether N-nicotinoyl--alanyl-(L)-histidine

To a solution of N-nicotinoyl--alanyl-(L)-histidine (9,9 g, to 30.1 mmol) in tetrahydrofuran (200 ml) is added under stirring triphenylphosphine (23.7 g, 90,3 mmol) and tetrabromomethane (28,85 g of 90.3 mmol). Stirred the reaction mixture at room temperature for 24 hours. After e is ecografia on a column of silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1. Receive a 4-bromatology ether N-nicotinoyl--alanyl-(L)-histidine.

c) Synthesis of 4-nitrocellulose ether N-nicotinoyl--alanyl-(L)-histidine

To a solution of 4-bromatologia ether N-nicotinoyl--alanyl-(L)-histidine (0,91 g, a 1.96 mmol) in acetonitrile (20 ml) is added under stirring silver nitrate (0.66 g, to 3.92 mmol). Boil the reaction mixture for 4 hours with stirring and without light. The formed salt is removed by filtration and evaporated the solution under reduced pressure. The resulting residue is purified by means of chromatography on a column of silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1. Receive a 4-microclimatology ether N-nicotinoyl--alanyl-(L)-histidine. Yield 32%.

Elemental analysis

Calculated: 49,50%; H 5.54 Percent; N 19,32%.

Found: 49,35%; N 5,28%; N 19,17%.

EXAMPLE 21

Obtaining 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-propyl ester N-acetyl-S-(4-nitroxymethyl)cysteine (NCX 2132)

where the precursor is propranolol (formula XXIV), and the precursor of b is N-acetylcysteine (formula VIII)

The compound synthesized by the method described in example 14. Exit 7%.

Elemental analysis

where the precursor is salbutamol (albuterol) (formula XXV), and the precursor of b is N-acetylpenicillamine (formula CV)

The compound synthesized by the method described in example 14, using N-acetylpenicillamine instead of N-acetylcysteine. Yield 43%.

Elemental analysis

Calculated: 53,01%; N 6,86%; N 7,76%; S Of 5.89%.

Found: 53,19%; N, 6.80 Per Cent; N 7,66%; S 5,72%.

EXAMPLE 23

Obtain 7-[2-hydroxy-3-[3-methoxy-5-(4-nitrosobutane)benzoyl]-TRANS-2-propenyl]theophylline (NCX 2213)

where the precursor is Tefillin (formula XXVI), and the predecessor is ferulic acid (formula DII)

The compound is synthesized in accordance with the procedure described in example 9. Yield 22%.

Elemental analysis

Calculated: 51,31%; N 4,84%; N To 12.52%.

Found: 51,50%; N 4,91%; N 12,68%.

EXAMPLE 24

Getting 4-nitrocellulose ester N-acetyl-S-(2-acetylbenzoic)cysteine (NCX 2138), having the formula

where the precursor is acetylsalicylic acid (formula XXVII), and the precursor of b is N-acetylcysteine (formula VIII)

The compound is synthesized in accordance with the methodology described is,75%; N 5,02%; N 6,28%; S 7,12%.

EXAMPLE 25

Getting 4-[3-[3-methoxy-5-(4-nitrosobutane)phenyl]-2-propenyloxy]-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (NCX 2215)

where the precursor is piroxicam (formula XXVIII), and the predecessor is ferulic acid (formula DII)

The compound is synthesized in accordance with methods described in example 9. Yield 18%.

Elemental analysis

Calculated: 55,11%; N 4,47%; N 8,60%; S Of 4.90%.

Found: 55,18%; N To 4.52%; N 8,71%; S To 4.98%.

EXAMPLE 26

Getting 4-nitrocellulose ester S-[2-[(2,6-dichlorophenyl)amino]phenylacetylene]peniillin (NCX 2061), having the formula

where the precursor is diclofenac (formula XXIX), and the predecessor is penicillamine (formula CV)

The compound is synthesized in accordance with the procedure described in example 11. The output of 21%.

Elemental analysis

Calculated: 50,72%; N 5,00%; N Of 7.75%; S Of 5.89%; Cl 13,02%.

Found: 50,61%; N 4,89%; N 7,81%; S 6,01%; Cl 13,21%.

PHARMACOLOGICAL TESTS

Acute toxicity

Acute toxicity was evaluated by introducing the group of 10 rats weighing 20 g single dose of each of the tested soedinenii animals were observed for 14 days. None of the animals in the test group did not appear toxic symptoms, even after a dose of 100 mg/kg

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 the following groups (10 animals in each group).

A. Control group.

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

Group 2. Treatment: carrier + NEM.

B. Group, which was administered every medicinal substance.

Group I. Treatment: carrier + drug substance.

Group II. Treatment: carrier + drug + NEM.

The following compounds were investigated in this experiment (table I): indomethacin, Ambroxol, mesalamine, alendronate sodium, taken, omeprazole, misoprostol.

Endometrin, Ambroxol and alendronate was administered through the mouth, metal Enoshima 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 the mucous membranes of the gastrointestinal tract, by counting the number of rats in each group with visible pathological changes in 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 values in % 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 mo is 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: 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 0.1 wt.% the collagenase solution and incubated at C within 5 minutes.

After this vein fill medium M 199 (GIBCO, Grand Island, NY), pH of 7.4, containing 0.1% (wt./about.) collagenase with the addition of 10% petalioi the bovine serum (10 μg/ml), sodium salt of heparin (50 μg/ml), thymidine (2.4 μg/ml), glutamine (230 µg/ml), penicillin (100 m ie/ml), streptomycin (100 μg/ml) and streptomycin (0.125 mg/ml). Collect cells from perfusion solution using prices of man. 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 cell suspension to the wells of the 24-hole 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 the unit S, constant humidity (90%) and 5% concentrations of CO2. If the compound 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 that have occurred the first of these subcultures, 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 culture test cell culture medium is removed and the cell layers gently washed with a standard saline solution, containing 0.1 M phosphate buffer (pH 7.0), at a temperature T. The contents of each well and then incubated for 1 hour with suspensie CIP in 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).In contrast, Ambroxol, mesalamine and the Ana 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 occurrence of lesions 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. the following groups (10 animals each):

A. Control group.

Group 1. Treatment: only media (water suspen the ical solution if you enter parenteral).

Group 2. Treatment: carrier + L-NAME.

B. Group that was administered a medicinal substance.

Group 3. Treatment: carrier + drug substance.

Group 4. Treatment: carrier + drug + L-NAME.

Were tested with the following medicinal substances: paracetamol, doxorubicin, simvastatin, omeprazole and misoprostol. Each compound was administered once daily for 4 weeks.

Maximum tolerated dose of medicinal substance, administered to the animals was determined in experiments with scaling separate doses by assessing occurrence in animals symptoms of enteropathy, diarrhea, depression, shivering and inhibited reactions.

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 umerle the compounds of the present invention, if the groups of rats which were treated with L-NAME + drug + carrier detected more significant liver damage (higher level GPT) and/or more significant damage to the stomach and/or cardiovascular damage (high blood pressure) compared to the group that was treated with only the carrier, or group, which were treated by the media and medicinal substance, or group, which were treated by the media 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 is related to the corresponding values found in animals of the 1st of the control groups. The average blood pressure in this group was 105±8 mm RT.article.

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

EXAMPLE F4

Test 4 - inhibition of the formation of DPPH radicals from some substances intended for use as precursors In or B1(see formulas I and II of the present invention).

The method is based on colorimetric test in which the DPPH (2,2-diphenyl-1-picrylhydrazyl) is used as the compound forming radicals (M. S. Nenseter et al., Atheroscler. Thromb. 15, 1338-1344, 1995).

First prepare a methanol solution of the test compounds at final concentrations of 100 μm. 0.1 ml each of these solutions add to the aliquot of the methanol solution of 0.1 M DPPH volume of 1 ml, and then the volume was adjusted to 1.5 ml After keeping the solution at room temperature without light for 30 min, measure the absorbance at a wavelength of 517 nm. Determine the decrease in absorption with respect to the absorption solution containing the same concentration of DPPH.

The effectiveness of the tested compounds against inhibiting the formation of radicals or radical-scavenging activity, expressed by the following formula:

(1-As/Ac)X100, where Asand awithare the appropriate.

The connection meets the test conditions 4, if suppresses the formation of radicals with efficiency equal to or greater than 50%.

Table V presents the results obtained for the following compounds: N-acetylcysteine, cysteine, ferulic acid, L-carnosine, gentisic acid.

Table V demonstrates that N-acetylcysteine, cysteine, ferulic acid, L-carnosine, gentisic acid meet the test conditions 4 because they inhibit the formation of radicals of DPPH with efficiency exceeding 50%.

EXAMPLE F5

Anti-inflammatory activity and gastric tolerability of the compounds of the present invention in comparison with the corresponding drug-predecessors in conditions of endothelial dysfunction caused by the action of L-NAME (methyl ester of Nw-nitro-L-arginine)

Was used the experimental model described in Edwards et al, J. Patfaol. 134, 147-156, 1981.

Were formed groups containing 10 rats with an average weight of 200 g of the Animals in these groups, with the exception of one control group, within two weeks were administered L-NAME, dissolved in drinking water (400 mg/l).

Medicinal substance was administered via the oral aperture, at a dose of 10 mg/kg, the x groups, except as described below the control groups were injected drug, L-NAME and the media.

Were formed following the control group.

Control group 1. Treatment: carrier.

Control group 2. Treatment: carrier + L-NAME.

In the experiment we used the following drug substances: diclofenac and its corresponding thioether with remainder 4-nitroquinazoline (PR.26), piroxicam and the corresponding ester of n-(4-nitroxy)butyrylacetate acid (PR.25), acetylsalicylic acid and the corresponding thioether with residue N-acetyl-4-nitrostilbene (PR.24).

Two weeks after the beginning of the experiment the animals successively introduced three air injection (subcutaneously) in the back region in accordance with the following procedure:

the first injection of 20 ml,

later, 3 days after the first injection of 10 ml,

later, 6 days after the first injection of the same dose, 10 ml.

Then the animal has ceased to give food until the next morning. One hour prior to subcutaneous injection carragenin (2 ml of 1% aqueous solution carragenine) in inflammatory bleed and have exudate animals were injected through the mouth hole of the carrier or one of the test compounds is yli euthanized. Inflammatory bleed and have exudate was collected and measured to assess the infiltration of leukocytes.

Table VI anti-inflammatory activity was expressed as inhibition (%) infiltration of leukocytes compared with the magnitude of the infiltration of leukocytes in animals that were injected carrier and pre L-NAME inhibition (%) of lesions of the gastrointestinal tract was evaluated as previously described for test 1 (PR.1), and blood pressure (%) was evaluated one hour before the killing and was compared with the blood pressure in the first control group (treatment: carrier). In this group of animals the average blood pressure was 108±10 mm RT.article.

Table VI demonstrates that the compounds of the present invention possess the same activity as the corresponding precursors in the test anti-inflammatory activity, but, unlike the latter, they reduce the damage to the cardio-vascular endothelium (less than significant increase in blood pressure (%) compared with that for the corresponding predecessor), and in addition, only slightly damage the stomach, or no hurt.

EXAMPLE F6

In the second experiment for the study of apoptosis were compared and is built in accordance with the present invention. The results presented in table 3, indicate that the compound of the present invention inhibits, unlike its predecessor, the apoptosis induced by cumene hydroperoxide (CIP).

EXAMPLE F7

Gastrointestinal tolerability of some medicinal substances used as precursors, and related compounds of the present invention.

Test was repeated on the damage of the gastrointestinal tract (example F5), except that excluded the pretreatment of animals with L-NAME. Tested drugs, injected dose and the test results are presented in table VII. The table shows that the level of gastropathy significantly lower in the groups that were administered compounds of the present invention, compared with the group that was administered the appropriate precursors.

EXAMPLE 27

Synthesis of 4-nitrocellulose ether (S)-N-acetyl-S-[[1-[5-(2,5-dihydro-5-oxo-3-furanyl)-3-methyl-2-benzofuranyl]ethyloxy]-4-oxobutanoic]cysteine having the formula

where the precursor is benforado hemisuccinate (formula XXXI), and the precursor of b is N-acetylcysteine (formula VIII)

The compound is synthesized in accordance ሺ%; S of 5.17%.

Found: 54,25%; N 5,22%; N 4,47%; S 5,15%.

EXAMPLE 28

Synthesis of (8S-CIS)-10-[(3-amino-2,3,6-trideoxy--L-lyxo-octopyranoside)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-[[[3-methoxy-4-(4-nitroxymethyl)phenyl]-2-TRANS-propenyloxy]metroka]-1-methoxy-5,12-naphthacenedione having the formula

where the precursor is doxorubicin (formula HHH), and the predecessor is ferulic acid (formula DII)

The compound is synthesized in accordance with the procedure described in example 9. Yield of 11%.

Elemental analysis

Calculated: 57,88%; N To 4.98%; N 3,29%.

Found: 57,91%; N 5,02%; N, 3.27 Per Cent.

EXAMPLE F8

Example F1 was repeated with four groups of rats (each group of 10 animals), each of which received NEM, and the following substances, administered orally:

(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 have introduced 5 mg/kg (0.014 mmol/kg) indomethacin, and 2.3 mg/kg (0.014 mmol/kg) of N-acetylcysteine in the above media;

(C) one group (the comparison group), the animals from which at the same time was introduced to 6.6 blokowanie in WO 95/09831, and of 2.3 mg/kg (0.014 mmol/kg) of N-acetylcysteine in the above media;

d) one group (group d), animals which were introduced to 8.7 mg/kg (0.014 mmol/kg) tiefer indometacin with the remaining N-acetyl-(4-nitroxy)butylsilane (see PR.3), in the above-mentioned media.

The results presented in table VIII show that the mixture introduced respectively to the animals of groups b and C (the comparison group), in contrast to the compounds of the present invention, administered to the animals of group d were almost ineffective (group b) or less effective (group C) in reducing damage to the stomach.

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

where A = R-T1-,

where R represents the radical of drug substances, as defined below, having the formula A=R-T1-Z or A=R-T1-OZ, where Z represents N or C1-C5alkyl, selected from the following groups: anti-inflammatory medicinal ingredients: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium salt, diflunisal, etodolac, flutamida acid, meclofenamic acid, marennikova acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, taftalenovaya acid, tolmetin, zomepirac; pain medicinal ingredients: acetaminophen, atsetilsalitsilovaja acid, benoxaprofen and tramadol; bronchodilators: albuterol, carbuterol, clenbuterol, Tefillin, etofillin, fenoterol, metaproterenol, pirbuterol, salmeterol and terbutaline; expectorant medicinal ingredients: Ambroxol, Bromhexine and guaiacol; antihistamine drug substances: cetirizine, levocabastine and terfenadine; ACE inhibitors: captopril, enalapril, lisinopril and ramipril; beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, and timolol; antithrombotic and vasoactive drug substances: argatroban, clopidogrel, dalteparin, dipyridamole, enoxaparin, iloprost, ozagrel, triflusal and benforado hemisuccinate; antidiabetic medicinal substances: nicotinamide; antitumour substances: astromicin, daunorubicin, doxorubicin and epirubicin; antiulcer drug substances: cimetidine, mediatemplate, atorvastatin and fluvastatin; antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, cefatrizine, cefoxitin, dicloxacillin, imipenem, meclocycline, metatsiklina, moxalactam, panipenem, bacampicillin, ampicillin, clomocycline and oxytetracycline; antiviral medicinal ingredients: acyclovir, famciclovir, ganciclovir, penciclovir, vidarabine and zidovudine; inhibitors of bone resorbtive: alendronat acid, heteronomy acid and pamidronate acid; medicinal substances against dementia: taken;

T1=(CO), O, S, N or NR1cwhere R1crepresents N or C1-C5alkyl;

IN - -Tin-X2-Tbiwhere Tinand tbithe same or different, selected from (CO), O, S, N or NR1cwhere R1cdefined above;

X2represents a bivalent bridging group, such as an appropriate precursor To having the formula

Z’-Tin-X2Z’

where Z’, Z’ are independently H or HE, is selected from the following compounds: amino acids: L-carnosine (CI), penicillamine (CV), N-acetylpenicillamine (CVI), cysteine (CVII), N-acetylcysteine (VIII):

aromatic polyhydric alcohols; hydroquinone (EVIII), methoxyhydroquinone (EXI), hydroxyperoxide (EXII), coniferious alcohol (EXXXII), 4-hydroxyphenethyl alcohol (EXXXIII), p-coumarin alcohol (EXXXIV);

Is a bivalent radical-Tc-Y-, where Twith- (CO), O, S, N or NR1c, R1cdefined above; Y has the following values: linear or branched C1-C20accelerograph or cycloalkyl containing from 5 to 7 carbon atoms, and in cycloalkylation the ring one or more carbon atoms may be replaced by heteroatoms, and the ring may contain side chains of R’, with R’ as defined above; or

where nIX is an integer from 0 to 3;

nIIX is an integer from 1 to 3;

rtix, rtix', rtiix, Rtiix'the same or different from each other, represent H or a linear or branched C1-C4is lzo, containing at least one nitrogen atom, and the specified ring consists of 5 or 6 atoms.

where n3 is an integer from 0 to 3;

n3’ is an integer from 1 to 3;

where n3 and n3’ have the above meaning;

where nf’ is an integer from 1 to 6;

where R1f- H, CH3and nf is an integer from 1 to 6.

2. Connection on p. 1, where Y3in the formula (III) selected from the following compounds:

3. Connection on p. 1, where Y represents a linear or branched C1-C6accelerograph.

4. Compounds or their salts, or their compositions on PP.1-3 for use as drugs.

5. Compounds or their salts on PP.1-3 to obtain drugs for therapeutic use in the state of oxidative stress.

6. Pharmaceutical composition for use in cases of oxidative stress and/or endothelial dysfunctions, containing as active principle compounds or their salts on PP.1-3.

 

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