New drugs


 

(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):

A-(IN)bo-C-N(O)2(I)

where bo=0 or 1; A=R-T1-, where R represents the radical of drug substances, 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 TC=(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, about the camping to new medicines for General use and compositions on their basis, used by oxidative stress and/or in cases of endothelial dysfunction.

Under oxidative stress understand the generation of free radicals or radical compounds that cause damage as cells and surrounding tissues (Phathophysiology: The biological basis for disease in adults and children McCance & Huether, 1998, pp. 48-54).

Under endothelial dysfunction understand that which relates to vascular endothelium. The damage to the vascular endothelium is known as one of those important events that can trigger a series of pathological processes affecting various organs and apparatuses of the body, as described below (Phathophysiology: The biological basis for disease in adults and children McCance & Huether, 1998, page 1025).

As is known, oxidative stress and/or endothelial dysfunction is associated with various pathologies, as described below. Oxidative stress may also be caused by toxicity of a wide range of medicines, which significantly affects their action.

The above pathological events are chronic, debilitating in nature and often normal for elderly people. As already mentioned, in the above-mentioned pathological conditions, the drugs have a remarkably degraded dysfunction or present in the elderly, are as follows:

For the cardiovascular system: myocardial and vascular ischemia, hypertension, stroke, arteriosclerosis, 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 skin system: eczema, neurodermitis, acne.

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

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

Known medications when administered to a patient suffering from pathologies associated with oxidative stress and/or endothelial dysfunctions, show low activity and/or high toxicity.

This is the case for drugs, such as protivovospalitel the military funds for the Central nervous system, medicines for bone, antibiotics, urogenital, endocrine drugs, etc.

Research in the field of medicines aimed at discovery of new molecules with improved therapeutic index (the ratio of efficacy/toxicity) or low ratio of risk/benefit, including the above-mentioned pathological conditions, and therapeutic index of a large number of drugs is reduced. In fact, in the above-mentioned conditions of oxidative stress and/or endothelial dysfunction many drugs exhibit reduced activity and/or higher toxicity.

For example, anti-inflammatory medicines, such as nonsteroidal anti-inflammatory drugs (SPVL - NSAIDs), medicines against colitis, such as 5-aminosalicylic acid and its derivatives, show the following disadvantages. NCPUL show toxicity, especially when the body is weakened or is under the influence of painful conditions associated with oxidative stress. The above conditions are as follows: age, pre-existing ulcer, pre-existing bleeding in renal units, hematocrits 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., Ahh. Intern. Med. 123/4, 241-9, 1995; Martindale 31a ed., 1996, p.73, Current Medical Diagnosis and Treatment 1998, pages 431 and 794).

The introduction of anti-inflammatory drugs to patients with the above-mentioned pathological conditions can be carried out only at doses that are lower than the doses used in therapy, in order to avoid phenomena of strong toxicity. Thus, the anti-inflammatory activity becomes low.

Beta-blockers used for the treatment of angina, hypertension and cardiac arrhythmia are the side effects against respiratory (shortness of breath, bronchostenosis) and, therefore, they can cause problems in patients with pathology of these organs (asthma, bronchitis). Therefore, beta-blockers may worsen respiratory diseases such as asthma. Therefore, for patients with asthma doses of the above drugs should be reduced in order not to expose a greater risk of respiratory activity. Thus, the efficacy of beta-blockers is very low.

Antitromboticescoy, have the same disadvantages. For patients with pathologies associated with oxidative stress and/or endothelial dysfunction, therapeutic effect or tolerance of these drugs, as in the case of aspirin, is very reduced.

Bronchodilators, such as salbutamol and so on, used to treat asthma and bronchitis and drugs active against cholinergic system, used in such pathologies as incontinence. Their introduction may cause similar side effects on the cardiovascular system, causing problems in patients with heart disease and hypertension. Heart disease and hypertension are pathologies associated, as described above, with oxidative stress and/or endothelial dysfunction. Also these medicines have the same drawbacks as mentioned above.

Expectorants and mucolytic drugs used in the treatment of inflammatory conditions of the respiratory organs, show deficiencies in patients with the above conditions. Their introduction can cause heartburn and stomach irritation, especially in the elderly.

Inhibitors of bone resorption, such as phosphonates (for example, Aleneva can also show the same defects, as specified above.

The phosphodiesterase inhibitor, such as, for example, sildenafil, zaprinast used in diseases of the cardiovascular and respiratory systems, are characterized by similar problems in relation to tolerance and/or effectiveness in the above-mentioned pathological conditions of oxidative stress and/or endothelial dysfunction.

Anti-allergic drugs such as cetirizine, montelukast and so on, have similar disadvantages in the above-mentioned pathological conditions, particularly with respect to their efficiency.

Antiangiogenic medicines, angiotenzinkonvertiruyuschego enzyme inhibitors (ACE inhibitors), such as enalapril, captopril, and so on, and inhibitors angiotensinogen receptors, such as losartan, are used in the treatment of cardiovascular diseases. Their disadvantage is the presence of side effects in relation to the respiratory apparatus (for example, cough and so on) in the above-mentioned pathological conditions.

Antidiabetic drugs and insulin and hypoglycemic type, such as, for example, sulfonylureas, tolbutamide, glipizide, gliclazide, gliburid, nicotinamide, and so on, are ineffective in the prevention of diabeti the population may become more intense in the above-mentioned pathological conditions.

Antibiotics, such as ampicillin, clarithromycin, and so on, and antiviral drugs, acyclovir and so on, have problems in relation to its portability, for example they cause gastrointestinal irritation.

Anticancer drugs such as doxorubicin, hydrochloride rubomycin, cisplatin, and so on, are highly toxic to various organs, including the stomach and intestines. The above-mentioned toxicity is also compounded in the above-mentioned pathologies of oxidative stress and/or endothelial dysfunction.

Medicines for dementia, such as nicotine and cholinomimetic, low portability, especially when the above-mentioned pathologies.

Felt the need to have drugs, showing the improved therapeutic effect, i.e. collateral and lower toxicity and/or higher efficiency, so that they could be administered to patients in painful conditions of oxidative stress and/or endothelial dysfunctions, without causing side effects to the medication prior art.

Currently, surprisingly and unexpectedly discovered that the above problems, demonstrate the dwelling in principle be solved by a new class of drugs, as is described below.

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

A-(B)bo-C-N(O)2(I)

where bo=0 or 1;

A=R-T1-, where R is a drug radical, as defined below, and has the formula R-T1-Z or R-T1-OZ, where Z represents N or C1-C5alkyl,

selected from the following groups:

anti-inflammatory drugs: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium, diflunisal, etodolac, floranova acid, flunixin, flurbiprofen, ibuprofen, indomethacin, indoprofen, Ketoprofen, Ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamovaya acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, telenova acid, tolmetin, zomepirac;

analgesic drugs: acetaminophen, atsetilsalitsilovaja acid, benoxaprofen, tramadol;

bronchodilator medications: albuterol, carbuterol, clenbuterol, fenoterol, metaproterenol, pirbuterol, salmeterol, toricheskie drugs: cetirizine, levocabastine, terfenadine;

ACE inhibitors: captopril, enalapril, lisinopril, ramipril;

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

antithrombotic and vasoactive drugs:

argatroban, venturedeal hemisuccinate, clopidogrel, dalteparin, dipyridamole, enoxaparin, iloprost, ozagrel, triflusal;

antidiabetic drugs: nicotinamide;

anticancer drugs: astromicin, daunorubicin, doxorubicin, epirubicin;

antiulcer drugs: cimetidine, omeprazole, pantoprazole;

antihyperlipidemic drugs: atorvastatin, fluvastatin, lovastatin, sodium salt of pravastatin, simvastatin;

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

antiviral drugs: acyclovir, famciclovir, ganciclovir, penciclovir, zidovudine;

inhibitors of bone resorption: alendronat 1=(CO), O, S, N or NR1Cwhere R1Cmeans N or C1-C5alkyl,

=-TB-X2-TBI-,

where

TBand TBIequal to or different and can be selected from (CO), O, S, N or NR1Cwhere R1Cmatter, as defined above;

X2means a bivalent bridging group, as appropriate predecessor In having a formula

Z'-TB-X2-TBI-Z"

where Z', Z" are independent and denote H or HE, is selected from the following compounds:

- amino acids: aspartic acid (PI), histidine (PII), 5-hydroxy-tryptophane (PIII), 4-thiazolidinedione acid (PIV), 2-oxo-4-thiazolidinedione acid (PV)

- monosperma or thiols: 2-thiouracil (QI), 2-mercaptoethanol (QII),

- succinic acid (RI)

With means bivalent-TC-Y - moiety

where TC=(CO) when tx=O, TC=X, when txx=Oh, X is as defined above;

Y means

where nIX means an integer between 0 and 3, preferably 1;

nIIX means an integer between 1 and 3, preferably 1;

RTIX, RTIX', RTIIX, RTIIX'equal to or different from each other, means NTH' mean N;

Y3is a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen atom, preferably one or two nitrogen atom, and the above-mentioned ring contains from 5 to 6 atoms, or Y means Yoselected from the following:

- accelerograph R O, where R' is a linear or branched, when possible C1-C20preferably having from 1 to 6 carbon atoms, more preferably 2-4, or cycloalkyl having 5 to 7 carbon atoms, in cycloalkylation the ring one or more carbon atoms may be replaced by heteroatoms, the ring can have side chains of R'type, and R’ is as defined above, or

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

where n3 and n3' have the above meanings;

where nf’ is an integer from 1 to 6;

where R1f=N, CH3and nf denote an integer from 1 to 6,

provided that in compounds of formula (I):

when bo=0 and s=-TWITH-Yo-medication formula A=R-T1-Z or A=R-T1-OZ, as defined above, and belong to the group of ACE inhibitors;

when bo=R-T, ' represents a C1-C6alkyl.

It was unexpectedly found that the products of the invention of formula (I) have an improved therapeutic index in conditions of oxidative stress compared with medicines predecessors.

Y3in the formula (III) is preferably selected from the following:

The most preferred Y3is Y12 (pyridyl), substituted in positions 2 and 6. These links can also be placed in an asymmetric position, for example Y (pyridyl) can be substituted in positions 2 and 3; Y1 (pyrazole) may be 3,5-disubstituted.

Compounds according to the present invention of formula (I) can be converted into the corresponding salt. For example, one of the ways salt is the following: when the molecule contains a single nitrogen atom, being essential in order to participate in the formation of the salt, by reaction in an organic solvent, such as, for example, acetonitrile, tetrahydrofuran, this atom reacts with equimolecular the amount of the corresponding organic or inorganic acid. For the formation of a salt, preferably in the claims is Y or Y' of formula (III).

P is ASS="ptx2">Examples of inorganic acids are nitric, hydrochloric, sulphuric, phosphoric acid.

Derivatives according to the present invention can be used in therapeutic indications drugs predecessor, allowing you to receive the benefits shown below for some groups of these drugs:

Anti - inflammatory drugs NPLS: connection according to the present invention are portable and effective, even when the body is weakened and is in conditions of oxidative stress. The above medications can also be used in those pathological conditions where inflammation plays a significant pathogenic role, such as, for example, but not limited to, cancer, asthma, myocardial infarction.

- Adrenergic blockers or blokatorov type: range of action of the compounds of formula (I) leads to a more extensive results than the original drug; for direct action on the smooth musculature apply nervous inhibition of beta-adrenergic signals that control the contraction of blood vessels. Side effects (shortness of breath, bronchostenosis) that affect the respiratory system, are reduced.

- Antithrombotics is for the stomach improves.

- Bronchodilator drugs, active against cholinergic system: side effects that affect the cardiovascular system (tachycardia, hypertension) drop.

- Expectorants and mucolytic drugs: improved results of the gastro-intestinal tolerance.

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

Inhibitors of phosphodiesterase (PDE) (a bronchodilator): improved therapeutic efficacy, and at the same dosage; therefore, it is possible to use compounds of the invention for administration of lower doses of drugs and reduce side effects.

- Antileukotriene drugs: improved efficiency.

- ACE inhibitors: enhanced therapeutic efficacy and reduced side effects (cough, cough) in respect of the breathing apparatus.

Antidiabetic medication (insulin and hypoglycemic type), antibiotics, antiviral, antitumor, antispasmodic drugs, drugs for treatment of dementia: superior efficacy and tolerability.

Examples of precursors of drugs to the in can be given the following examples:

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

analgesic medications: acetaminophen, acetaminoohen.

As the drugs for respiratory and urogenital apparatus (bronchodilator drugs, expectorants drugs, anti-asthma drug) can be mentioned the following:

bronchodilator medications: albuterol, carbuterol, clenbuterol, fenoterol, metaproterenol, pirbuterol, salmeterol, terbutaline;

expectorant drugs: Ambroxol, Bromhexine, guaiacol;

anti-asthma medications: cetirizine, levocabastine, terfenadine.

As cardiovascular adiabaticheskie and hypoglycemic drugs) can be mentioned the following:

ACE inhibitors: captopril, enalapril, lisinopril, ramipril;

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

antithrombotic and vasodilator drugs: argatroban, venturedeal hemisuccinate, clopidogrel, dalteparin, dipyridamole, enoxaparin, iloprost, ozagrel, triflusal;

antidiabetic drugs: nicotinamide.

Among anticancer drugs can be mentioned the following: astromicin, daunorubicin, doxorubicin, epirubicin.

Among antiulcer drugs can be mentioned the following: cimetidine, omeprazole, pantoprazole.

Among antihyperlipidemic drugs (statins) can be mentioned the following: atorvastatin, fluvastatin, lovastatin, sodium salt of pravastatin, simvastatin.

Among antibiotics/antivirals can be mentioned the following:

antibiotics: amdinocillin, amoxicillin, aztreonam, biapenem, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, cefatrizine, cefoxitin, dicloxacillin, imipenem, moxalactam, panipenem, bacampicillin;

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 substances are the following:

among anti-inflammatory drugs: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium, diflunisal, etodolac, floranova acid, flunixin, flurbiprofen, ibuprofen, indomethacin, indoprofen, Ketoprofen, Ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamovaya acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, telenova acid, tolmetin, zomepirac;

among analgesic drugs: acetaminophen.

Among drugs for respiratory and urogenital apparatus (bronchodilator drugs, expectorants, drugs, anti-asthma drug):

bronchodilator medications: albuterol, carbuterol, clenbuterol, is:

Ambroxol, Bromhexine, guaiacol;

anti-asthma medications: 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 drugs: argatroban, clopidogrel, dalteparin, dipyridamole, enoxaparin, iloprost, ozagrel, refusal;

antidiabetic drugs: nicotinamide.

Among anticancer drugs: astromicin, daunorubicin, doxorubicin, epirubicin.

Among antiulcer drugs: cimetidine, omeprazole, pantoprazole.

Among antihyperlipidemic drugs: lovastatin, sodium salt of pravastatin, simvastatin.

Among antibiotics/antiviral drugs:

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

antiviral drugs: acyclovir Andronova acid, heteronomy acid, pamidronate acid.

Among the drugs against dementia: taken.

The above-mentioned substances, precursors And receive according to methods known in the prior art. See, e.g., “The Merck Index, 12 Ed.(1996), referred to here as a reference. Can be used corresponding isomers, including optical isomers, if they are available.

Comaximal receive according to the method described in European Patent 12866.

The compounds of formula (I) obtained by synthesis methods mentioned here below.

The choice of reactions for each method depends on the reactive groups present in the molecule drugs predecessor, in connection predecessor In or B1that may be, as mentioned above, bivalent or monovalent, and in connection predecessor With.

These reactions are carried out according to methods well known in the prior art, which provide communication between the drug precursor, a drug precursor b or B1and the connection predecessor, as defined above.

When the reaction function of the medications the predecessor (for example, -COOH, -HE) enters the set ways, well known in the prior art.

Some synthesis scheme for producing compounds according to the invention are presented below:

A. Synthesis of compounds of formula (I).

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

1A. When a drug has the General formula R-COOH functional group of compounds of the predecessor, which connects itself with the carboxyl function of the drug has the formula XZ, and X is as defined above, and Z=H, the reaction is conducted depending on the nature of the second reactive group present in the compound-Century predecessor

1a.1. When the second reactive group present in the compound-the predecessor, is a carboxyl group, a General scheme of the synthesis involves the initial formation of the halide R-COHHal acid (Hal=CL, Br) and subsequent reaction with HX-group connections predecessor IN:

where X2, T1TBsuch as defined above.

When the two reactive compounds present other functional groups COOH and/or NC, they must be protected before the reaction according to methods known in the village is selgelid RCOHal get under way, known in the prior art, for example through tional or oxalicacid, RIIIor PvGulidov in inert solvents in the reaction conditions, such as, for example, toluene, chloroform, DMF, etc.

In particular, if the NH-group of compounds of the predecessor In the mean NH2or HE or SH, previous drug of formula R-COOH first converted into the corresponding allvalid RCOHal, as described above, and then injected into the reaction with NH-group of the preceding compound In the presence of organic bases such as triethylamine, pyridine, etc. using an inert solvent in the reaction conditions such as toluene, tetrahydrofuran, etc. at a temperature in the range of 0-25S.

An alternative to the previous synthesis of the drug precursor of the formula R-COOH can be treated with an agent activating the carboxyl group, selected from N,N'-carbonyldiimidazole (CBI), N-hydroxybenzotriazole and dicyclohexylcarbodiimide, in a solvent such as, for example, DMF, THF, chloroform, etc. at a temperature in the range from -5 to-50C, and received the connection is allowed to react in situ with the reaction function of the previous connection to obtain the compounds of formula IA.1).

where X, T1TB, X2are as defined above, and G is a protecting group NH-functions.

2. Synthesis nitrosopropane.

2A.1. When a 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 and then we can apply the methods known in the art, to obtain the final compounds, for example, according to one of the following synthesis schemes:

where T1TB, X2, TBITCare as defined above, R4selected from Cl, Br, Y are such as defined above, X1means Y is a radical that is free from oxygen atom, R3means CL, Br, iodine, HE. When R3=HE, the compound of formula (1A.1b) SUB>3in an organic solvent, such as acetonitrile, tetrahydrofuran. If R3means CL, Br, iodine, a compound of the formula (1A.1b) reacts directly with AgNO3as the above.

where R5=HE or other1C, R1C, R3and other symbols are as defined above.

Shown above reactions are well known in the prior art. See, for example, patent application in the name of this applicant's WO 94/12463, WO 95/09831 and WO 95/30641.

When X1is linear WITH4the alkyl, the corresponding acid R-T1-TB-X2-COOH is reacted with triphenylphosphine in the presence of a halogenation agent such as CSAs4or N-bromosuccinimide in tetrahydrofuran to obtain the compound (1A.1c), where R3=Br.

2A.2. When a connection is received at the end of the previous stage 1A, has the formula (IA.2), corresponding to nitrosopropane receive treatment halogencarbonic acid of the formula Hal-X1-COOH with this X1as defined above, first with an agent activating the carboxyl group, as described in 1A.1, and then with the compound of the formula (IA.2), receiving halogen derivatives, which is isolated and then dissolved in an organic solvent (CE T1TBX2, TBI, TCY are as defined above.

An alternative can be used halide Hal-X1-COCl, where Hal is preferably bromine, which reacts with the compound of the formula (IA.2).

1b. When the drug precursor is the reaction function HX, where X is as defined above, instead of the carboxyl group of the two functional groups present in the compound-the predecessor, can be the following.

1b.1. Carboxyl group which reacts with HX-function of precursor drugs, and NH-group, the latter reaction connection group predecessor In equal or different from the functional group of medicines predecessor. The formula of the compound predecessor In is H-h-h2-COOH, where X and X2such as defined above. N-X-function compounds predecessor To protect according to the known prior art method, and the carboxyl group reacts as described above, according to the following scheme:

At the end of the reaction function HX connection predecessor In recovering.

1b.2. When the connection predecessor In contains two carboxyl GRU is artelino described in 1a.1, and then carry out the reaction with the reaction HX-function molecule drugs predecessor. Other possible reaction functions of the NC-type present in the two compounds must be protected, as mentioned earlier. In conclusion, get the connection formula R-T1-TB-X2-COOH (IB.2).

2b. Synthesis nitrosopropane.

2b.1. To obtain the final nitrosopropane, starting with compounds of formula R-T1-TB-X2-X-N (1B.1) obtained at the end of the synthesis described in 1b.1, the compound (1V.1) reacts with the halogen acid of the formula Hal-X1-COOH, which is treated as previously described in paragraph 1a.1, or with the corresponding chloride halogen acids. The compound obtained is dissolved in an organic solvent, for example acetonitrile or tetrahydrofuran, and carry out the reaction with silver nitrate.

2b.2. To obtain the final nitrosopropane, proceeding from compounds of formula R-T1-TB-X2-COOH (1B.2) obtained at the end of the synthesis described in 1b.2, the acid is converted into the corresponding sodium salt, it reacts with the compound R4-X1-R3predefined in the reaction And schemes of paragraph 2A.1, the UB>1means linear WITH4alkyl, acid (1B.2) is reacted with triphenylphosphine in the presence of a halogenation agent such as CSAs4or N-bromosuccinimide in tetrahydrofuran, and the obtained compound is dissolved in an organic solvent, for example acetonitrile, tetrahydrofuran, reacts with silver nitrate.

2b.3. Alternative synthesis process according to 1b.1 and 2b.1 in the first stage to carry out the reaction HX-function compounds predecessor In NC-X2-COOH with acylchlorides halogen acids of the formula Hal-X1-CO-Cl, where Hal is preferably Br, and then the carboxyl functions of the thus obtained compound with medication the predecessor R-HX. The third and last stage of the Hal group replace-ONO2according to the process described in 2b.1. The reaction scheme is as follows:

where TCTB1TB, T1, X2X1Y are as defined above.

In the previous diagram, the nitration can alternatively be carried out with the acid of formula (2B.3).

The following examples serve to illustrate the invention and should not be construed as limiting it.

Example 1

Synthesis of 4-nitroxymethyl the CLASS="ptx2">

since flurbiprofen (formula IX) and predecessor In the form of (L)-4-thiazolidinones acid (formula PIV)

a) Synthesis of 3-[2-fluoro--methyl-(1,1’-biphenyl)-4-acetyl]thiazolidin-4-carboxylic acid

To a solution of 2-fluoro--methyl-(1,1’-biphenyl)-4-acetic acid (10 g, 41 mmol) in toluene (100 ml) and N,N-dimethylformamide (10 ml), cooled to 0C, add oxalicacid (3,52 ml, 82 mmole). After 2 hours at room temperature the solution is evaporated under reduced pressure. The resulting residue is dissolved in acetone (50 ml) and the solution added to a solution of 4-thiazolidinones acid (5,44 g, 41 mmole) and triethylamine (14.9 ml, 106 mmol) in acetone (50 ml), cooled to 0C. After 2 hours the solution is acidified with 4 N. Hcl, concentrated under vacuum, the residue is treated with ethyl acetate and the organic phase is washed first with 2 N. Hcl, then water. The organic phase is dehydrated sodium sulfate and evaporated under reduced pressure. By crystallization from ethyl acetate/n-hexane obtain 9.4 g of the expected product in the form of a white solid substance having a melting point of 142-S.

1H-NMR (CDCl3): 7,74 to 7.62 (4H, m), 7.35 (2H, t), 7.18 in-7,13 (2H, m), is 5.06 (1H, m), 4.63 (1H, d), 4,42 (1H, d), 4,14 (1H, q), of 3.13 (2H, m), 1,53 (2H, d).

b) Synthesis of the acid, obtained at the previous stage (a), (9,43 g, 26,24 mmole) in tetrahydrofuran (150 ml) is added triphenylphosphine (13,76 g, 52,49 mmole) and tetrabromide carbon (17,4 g, 52,49 mmole). The reaction mixture was allowed to mix for 24 hours at room temperature. The solvent is removed by evaporation under reduced pressure. The resulting crude product was then purified by chromatography on silica gel, diluting n-hexane/ethyl acetate 8/2. Obtain 2.25 g of ester in the form of butter.

C) Synthesis of 4-nitrocellulose ester 3-[2-fluoro--methyl-(1,1’-biphenyl)-4-acetyl]thiazolidin-4-carboxylic acid.

To a solution of ester obtained in the previous stage (2.6 g, 5,26 mmol) in acetonitrile (20 ml) is added silver nitrate (1.07 g, 6.3 mmole). The reaction mixture is heated under reflux for 4 hours in the absence of light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The obtained residue purified by chromatography on silica gel, elwira n-hexane/ethyl acetate, 7/3. Obtain 0.84 g of 4-nitrocellulose ester 3-[2-fluoro--methyl-(1,1’-biphenyl)-4-acetyl]thiazolidin-4-carboxylic acid in the form of butter.

1H-NMR (CDCl3): 7,56-to 7.09 (8H, m), 5,77 (1H, dd), of 4.67 (2H, d), 4,51 (3H, t), are 4.24 (2H, t), is 4.15 (1H, q), 3,30-ylacetic)thiazolidine-4-carboxylic acid (NO-naproxen) (NCX 2001)

on the basis of naproxen (formula VI) and predecessor In the form of (L)-4-thiazolidinones acid (formula PIV)

a) Synthesis of 3-(6-methoxy--methyl-2-naphthylacetyl)thiazolidin-4-carboxylic acid

To a solution of 6-methoxy--methyl-2-naphthylacetic acid (as 4.02 g, 17.5 mmol) in toluene (30 ml) and N,N-dimethylformamide (0.3 ml), cooled to 0C, add oxalicacid (2,92 ml, to 34.06 mmol). After 2 hours at room temperature the solution is evaporated under reduced pressure. The resulting residue is dissolved in acetone (50 ml) and this solution added to a solution of 4-thiazolidinones acid (2,33 g, 17.5 mmol) and triethylamine (6,34 ml, 45.5 mmol) in acetone (50 ml), cooled to 0C. After 2 hours the solution is acidified with 4 N. Hcl, concentrated under vacuum, the residue is treated with ethyl acetate and the organic phase is washed first with 2 N. Hcl, then water. The organic phase is dehydrated sodium sulfate and evaporated under reduced pressure. Get 4,43 g of the expected product in the form of a white solid substance having a melting point of 164-168S.

1H-NMR (CDCl3): 7,75-7,66 (3H, m), 7,34 (1H, d), 7,14-7,11 (2H, m), 5,14 (1H, m), 4.80 to br4.61 (2H, m), 4,07 (1H, q), 3,91 (3H, s), 3,30 is 3.23 (2H, m), 1.53 (3H, d).

b) Synthesis of 4-bromatologia ester 3-(6-methoxy--methyl-2-napht,6 mmol), in tetrahydrofuran (50 ml) is added triphenylphosphine (6,07 g of 23.1 mmol) and tetrabromide carbon (7,66 g, 23.2 mmol). The reaction mixture is left under stirring for 24 hours at room temperature. The solvent is removed by evaporation under reduced pressure. The resulting crude product was then purified by chromatography on silica gel, elwira n-hexane/ethyl acetate, 7/3. Obtain 2.25 g of ester in the form of oil.

c) Synthesis of 4-nitrocellulose ester 3-(6-methoxy--methyl-2-naphthylacetyl)thiazolidin-4-carboxylic acid

To a solution of ester obtained in the previous stage (2 g, 4.16 mmol) in acetonitrile (20 ml) is added silver nitrate (0.85 grams, 5 mmol). The reaction mixture is heated under reflux for 5 hours in the absence of light. The formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel, elwira n-hexane/ethyl acetate, 7/3. Get 0,99 g of 4-nitrocellulose ester 3-(6-methoxy--methyl-2-naphthaleneacetic)thiazolidin-4-carboxylic acid in the form of butter.

1H-NMR (D13): 7,66 (3H, m), 7,38 (1H, m), to 7.15 (2H, m), is 5.06 (1H, dd), of 4.66 (2H, d), 4,51 (2H, t), 4,25 (2H, t), 3,98 (1H, q) to 3.92 (3H, s), of 3.13 (2H, d), of 1.84 (4H, m), of 1.53 (3H, d).

Example 3

on the basis of naproxen (formula VI) and predecessor In the form of (L)-2-oxo-4-thiazolidinones acid (formula PV)

a) Synthesis of 3-(6-methoxy--methyl-2-naphthylacetyl)-(R)-2-oxothiazolidine-4-carboxylic acid

To a solution of 6-methoxy--methyl-2-naphthylacetic acid (7.0 g, 30.4 mmol) in toluene (100 ml) and N,N-dimethylformamide (10 ml), cooled to 0C, add oxalicacid (5,23 ml, 61 mmol). After 2 hours at room temperature the solution is evaporated under reduced pressure. To a solution of the obtained residue, dissolved in tetrahydrofuran (50 ml), add a mixture consisting of 2-oxothiazolidine-4-carboxylic acid (4,07 g, 27.6 mmol), 4-dimethylaminopyridine (0.84 g, 6.9 mmol), triethylamine (7,69 ml, 55.2 mmol) in tetrahydrofuran (50 ml), cooled to-10C. The mixture is left at room temperature for 24 hours. The reaction mixture is washed with 5% Hcl, then water. The organic phase is dehydrated with sodium sulfate and then evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel, elwira with methylene chloride/methanol 95/5. Get 6,79 g of the expected product in the form of an amorphous solid.

b) Synthesis of 4-bromatologia ester 3-(6-methoxy--methyl-2-naphthylacetyl)-(R)-2-okatovo acid (6,79 g, 18.9 mmol) in tetrahydrofuran (100 ml) is added triphenylphosphine (to 9.91 g, 37.8 mmol) and tetrabromide carbon (12,53 g, 37.8 mmol). The reaction mixture was left to mix for 16 hours at room temperature, then the solvent is removed by evaporation under reduced pressure. The resulting crude product was then purified by chromatography on silica gel, elwira n-hexane/ethyl acetate 7/3. Receive 1.83 g of ester in the form of oil.

c) Synthesis of 4-nitrobutyl ester 3-(6-methoxy--methyl-2-naphthylacetyl)-(R)-2-oxothiazolidine-4-carboxylic acid

To a solution of ester obtained in the previous stage (1.7 g, 3,44 mmole) in acetonitrile (20 ml) is added silver nitrate (0,82 g, to 4.81 mmol). The reaction mixture is heated for 6 hours under reflux in the absence of light. The formed salt is removed by filtration and the solution evaporated under pressure. The resulting residue is purified by chromatography on silica gel, elwira n-hexane/ethyl acetate 7/3. Gain of 0.77 g of 4-nitrocellulose ester 3-(6-methoxy--methyl-2-naphthylacetyl)-(R)-2-oxothiazolidine-4-carboxylic acid in the form of butter.

1H-NMR (CDCl3): 7,74-to 7.67 (3H, m), 7,47 (1H, m), 7,14-7,10 (2H, m), 5,28 (1H, dd), 4,12-3,91 (5H, m), 3,90 (3H, s), 3,63 (1H, dd), to 3.33 (1H, dd), of 1.55 (3H, d), 1.30 and of 1.23 (4H, m).

where drug-precursor compounds of the invention is diclofenac formula (XXIX) and the connection predecessor is (L)-histidine formula (R)

a) Synthesis of [2-[(2,6-dichlorophenyl)amino]benzoylacetonate]-(L)-histidine

To a solution of diclofenac (3 g, 10,13 mmol) in tetrahydrofuran (50 ml), cooled to 0C, add with stirring 1,1’-carbonyldiimidazole (1,69 g, 10,13 mmol). After 10 minutes the solution is treated with (L)-histidine (1,57 g, 10,13 mmol) and allowed to mix at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylene chloride and then washed sequentially with 1% Hcl and then with water. The organic phase is dehydrated sodium sulfate and evaporated under vacuum. The resulting residue is purified by chromatography on a column of silica gel, elwira with ethyl acetate. Get [2-[(2,6-dichlorophenyl)amino]benzoylacetonate]-(L)-histidine.

b) Synthesis of 4-bromatologia ether [2-[(2,6-dichlorophenyl)amino]benzoylacetonate]-(L)-histidine

To a solution of [2-[(2,6-dichlorophenyl)amino]benzoylacetonate]-(L)-histidine (5 g, 11,54 mmol) in tetrahydrofuran (100 ml) is added under stirring triphenylphosphine (remaining 9.08 g, 34,62 mmol) and tetrabromide carbon (11,48 g, wanam under reduced pressure. The resulting crude product was then purified by chromatography on silica gel, elwira n-hexane/ethyl acetate 1/1. Receive a 4-bromatology ether (S)-[2-[(2,6-dichlorophenyl)amino]benzoylacetonate]-(L)-histidine.

C) Synthesis of 4-nitrocellulose ether [2-[(2,6-dichlorophenyl)amino]benzoylacetonate]-(L)-histidine

To a solution of 4-bromatologia ether [2-[(2,6-dichlorophenyl)amino]-benzoylacetonate]-(L)-histidine (3 g, 5,28 mmol) in acetonitrile (30 ml) is added silver nitrate (1,79 g, 10.56 mmol). The reaction mixture is heated under reflux for 6 hours, hiding from the light, the formed salt is removed by filtration and the solution evaporated under reduced pressure. The obtained residue purified by chromatography on a column of silica gel, siurua n-hexane/ethyl acetate 1/1. Receive a 4-microclimatology ether [2-[(2,6-dichlorophenyl)amino]benzoylacetonate)-(L)-histidine. Yield 35%.

Example 5

Synthesis of 5-[[4-oxo-(4-nitrosobutane)butanoyl]amino]-1,2,3,4-tetrahydropyridine

where drug precursor compounds according to the invention is tacrine formula (XXXV) and the connection predecessor linking group is a succinic acid of the formula (RI)

a) Synthesis of 4-chlorobutyronitrile amber comply with stirring N,N’-dicyclohexylcarbodiimide (4,2 g, 20,35 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol). After 30 minutes add 4-chlorobutanol (2.1 g, 19,35 mmol). The reaction mixture is left at room temperature for 7 hours under stirring, then acidified with 5% model HC1 and extracted with ethyl acetate. The organic phase is washed with saline, dehydrated with sodium sulfate and evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elwira with methylene chloride/methanol 8/2. Get a 4-CHLOROTHALONIL succinic acid.

b) Synthesis of 5-[[4-oxo-(4-chlorobutyrate)butanoyl]amino]-1,2,3,4-tetrahydropyridine

To a solution of 4-chlorobutyronitrile succinic acid (2.9 g, 10.02 mmole) in N,N-dimethylformamide (30 ml), cooled to 0C, add with stirring N,N’-dicyclohexylcarbodiimide (2.2 g, 10,66 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol). After 5 minutes add taken (2 g, 10.08 mmole). The reaction mixture is left at room temperature for 24 hours, then acidified with 5% model HC1 and extracted with ethyl acetate. The organic phase is washed with saline, dehydrated with sodium sulfate and evaporated under reduced pressure. The crude product is purified by chromatography on silica gel, elwira with methylene chloride/methanol 8/2. Phtalate)butanoyl]amino]-1,2,3,4-tetrahydropyridine

To a solution of 5-[[4-oxo-(4-chlorobutyrate)butanoyl]amino]-1,2,3,4-tetrahydropyridine (3 g, 7,71 mmole) in acetonitrile (50 ml) is added under stirring silver nitrate (1,79 g, 10,56 mmole). The reaction mixture is heated under reflux for 36 hours in the absence of light, the formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel, elwira with ethyl acetate. Get 5-[[4-oxo-(4-nitrosobutane)butanoyl]amino]-1,2,3,4-tetrahydropyridine. The output is 27%.

Example 6

Synthesis of [4-amino-[4-oxo-(4-nitrosobutane)butanoyl]-1-hydroxybutyl]biphosphonates acid

where drug-precursor compounds of the invention is alendronat acid of the formula (XXXVI) and connection-the predecessor of the linking group is a succinic acid of the formula (RI)

This compound is synthesized using the synthesis procedure described in example 5. Exit 19%.

Example 7

Synthesis of [4-oxo-(4-nitrosobutane)butanoyl-4-(2-amino-3,5-dibromophenyl)methylamino]cyclohexanediol ether

where drug-precursor compounds of the invention is Ambroxol formula 2">a) Synthesis of 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]-TRANS-cyclohexanol

To a mixture of 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexanol (5 g, 13,22 mmol) in dioxane (35 ml) and water (50 ml)is added with stirring triethylamine (3,31 ml, 23.7 mmol) and di-tert-BUTYLCARBAMATE (of 3.46 g, 15,86 mmol). After 24 hours the solution is concentrated under vacuum, treated with 1% model HC1 to neutral pH and extracted with ethyl acetate. The organic phase is dehydrated sodium sulfate and evaporated under vacuum. Receive 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanol, which is used without further purification.

b) Synthesis of [4-oxo-(4-chlorobutyrate)butanoyl]-4-(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanediol ether

To a solution of 4-chlorbutanol of monoether succinic acid (4 g, MT 19: 18 mmol) in tetrahydrofuran (40 ml) is added under stirring 1,1’-carbonyldiimidazole (3.4 g, 20,96 mmol). After 10 minutes the solution is treated with 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanol (9,8 g, 20,5 mmole) at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylene chloride, washed with 1% model HC1 and then with water. The organization is silica gel, elwira n-hexane/ethyl acetate 1/1. Get [4-oxo-(4-chlorobutyrate)butanoyl]-4-(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanebis ether.

c) Synthesis of [4-oxo-(4-nitrosobutane)butanoyl-4-(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanediol ether

To a solution of [4-oxo-(4-chlorobutyrate)butanoyl-4-(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanediol ester (4 g, 5,98 mmol) in acetonitrile (70 ml) is added under stirring silver nitrate (1.5 g, 8,83 mmole). The reaction mixture is heated under reflux for 24 hours in the absence of light, the formed salt is removed by filtration and the solution evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel, elwira n-hexane/ethyl acetate 7/3. Get [4-oxo-(4-nitrosobutane)butanoyl-4-(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanebis ether.

d) Synthesis of [4-[4-oxo-(4-nitrosobutane)butanoyl](2-amino-3,5-dibromophenyl)methylamino]cyclohexanediol ether

To a solution of [4-oxo-(4-nitrosobutane)butanoyl-4-(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanediol ester (3.2 g, 4.6 mmol) in atilas at 0C, the precipitate is filtered off. The resulting crude product is treated with ethyl acetate and 5% sodium bicarbonate, then with water. The organic phase is dehydrated sodium sulfate and evaporated under reduced pressure. Get [4-[4-oxo-(4-nitrosobutane)butanoyl](2-amino-3,5-dibromophenyl)methylamino]cyclohexanebis ether. Exit 17%.

PHARMACOLOGICAL TRIALS

Example

Acute toxicity

Acute toxicity estimate introduction the group of 10 rats, weighing 20 g single dose of each of the test compounds through the cannula, oral in water suspension 2% (wt./about.) carboxymethylcellulose.

Animals observed for 14 days. No one animal from group showed no symptoms of toxicity even after a dose of 100 mg/kg

Example F1

Test 1 - experimental model in vivo N-ethylmaleimide (NEM): study of the gastric tolerance of certain drugs, was selected as precursor compounds of the present invention.

Animals (rats weighing approximately 200 g) are divided into the following groups (10 rats per group):

A) Control group:

10group: treatment: only media (aqueous suspension of 1% (wt./about.) carboxymethy path)

20group: treatment: carrier+NEM,

B) Group, in which you enter each medication:

Group I: treatment: carrier+drug,

Group II: treatment: carrier+drug+NEM.

Drugs analyzed in this experiment are the following (table I): indomethacin, Ambroxol, mesalamine, alendronate sodium, taken, omeprazole, misoprostol.

Indomethacin, Ambroxol and alendronate is administered through the mouth, mesalamine - rectal route and taken, omeprazole, misoprostol is the subcutaneous route.

The maximum tolerated dose defined by introducing each of the substances above routes in animals not treated with NEM, are presented in Table I. At higher doses than those presented in Table I, the animals appear enteropathy, diarrhea, depression, tremors, and a sedative effect.

In this experimental animal model is first treated with NEM via subcutaneous injection at a dose of 25 mg/kg in saline. The medication is injected through the hours in the suspension medium. Animals killed after 24 hours and damage assessment of gastrointestinal mucosa is carried out by counting the number of rats in each group with damage glucopnagew 100. The resulting percentages are presented in Table I. table I shows that in the groups of rats treated with the above drugs without NEM, not detectable damage to the stomach.

All rats of group II (treated NEM) demonstrate damage to the stomach after administration of the following drugs: indomethacin, Ambroxol, mesalamine, alendronate sodium, taken. Therefore, the above-mentioned drugs can be used in the synthesis of products of the invention.

Omeprazole and misoprostol may be used instead, based on the results presented in test 1, to obtain products of the invention.

Example F2

Test 2 (in vitro) inhibition of apoptosis (DNA fragmentation) induced in endothelial cells by CIP in the presence of certain drugs, was selected as precursor compounds of the present invention.

Were tested with the following medications precursor (table II): indomethacin, paracetamol, clopidogrel, salbutamol, Ambroxol, alendronate sodium, Tefillin, cetirizin, enalapril, nicotinamide, ampicillin, acyclovir, mesalamine, taken, simvastatin, omeprazole.

Endothelially cells human umbilical vein get is when S within 5 minutes.

Then Vienna pour medium M 199 (GIBCO, Grand Island, NY), pH of 7.4, with 0.1% (wt./about.) collagenase, which added 10 % fetal bovine serum (10 μg/ml), sodium heparin (50 μg/ml), thymidine (2.4 μg/ml), glutamine (230 µg/ml), penicillin (100 u/ml), streptomycin (100 μg/ml) and streptomycin (0.125 mg/ml). Cells collected from the perfusion solution by centrifugation at 800 rpm and grown in culture flasks T-75, pretreated with fibronectin person. Cells are then grown in the same environment, adding a bullish growth factor hypothalamus (100 ng/ml). When the cells of the primary culture cells (cells taken directly from ex vivo umbilical vein) form a monolayer fused cells (approximately 8,000,000 cells/flask), the growth stopped and the layers are washed and trypsinized. Cell suspension is transferred into a cell culture of the tablet, with 24 cells, and in half of the above cells added to the same culture medium containing the drug concentration of 10-4M, and raise thermostat at a temperature of S at constant humidity (90%), CO2=5%. When the drug is insoluble in this culture liquid, it is first dissolved in a small amount of dimethyl sulfoxide. The maximum number of dimethylsulfone the first subculture, can be used for tests with the hydroperoxide cumene (CIP). Cells identified as endothelial by morphological studies and specific immunological response against factor VIII; these cultures never showed contamination myocytes and fibroblasts.

Before beginning the test, remove the cell culture medium and cell layers washed thoroughly with standard saline solution, phosphate buffered (0.1 M, pH 7.0) at a temperature of C. The content of each cell is then incubated for one hour with a suspension of CIP in culture medium with a concentration of 5 mm. Assessment of cellular damage (apoptosis) is conducted by determining the percentage change DNA fragmentation in cultures containing medicine+CIP, relative to controls treated only CIP. The above % change DNA fragmentation determined by estimating the change in the fluorescence through a microscope VH Olympus microscope (Olympus Co., Roma) set the wavelength 405-450 nm, the samples of the test in relation to the optical density of the controls. The fluorescence of each sample was determined for 5 replicate. Statistical evaluation was performed with t-student test (p<0,01).On the contrary, Ambroxol, mesalamine and simvastatin inhibit apoptosis. Therefore, based on the results of test 2, these compounds cannot be used to obtain products of the invention.

Example F3

Test 3 - experimental model in vivo with NW-nitro-L-arginine methyl ester (L-NAME): gastric tolerance (case gastrointestinal damage), liver (dose GPT, alanine aminotransferase) and cardiovascular (blood pressure) tolerance of certain drugs, was selected as precursor compounds of the invention.

The experimental model is selected according to J. Clin. Investigation 90, 278-281, 1992.

Endothelial dysfunction assessed by determining the damage caused by L-NAME in the gastro-intestinal mucosa, liver damage (increase GPT) and damage to the vascular endothelium and cardiovascular damage in the form of blood hypertension.

Animals (rats, average weight 200 g) are divided into groups, as described here nirala 400 mg/l in drinking water. Create the following groups (10 animals per group).

A) Control group:

10group: treatment: only media (aqueous suspension of 1% (wt./about.) carboxymethylcellulose, a dose of 5 ml/kg when the drug is administered by mouth, saline - when parenterally),

20group: treatment: carrier+L-NAME,

B) Group treated with medication:

30group: treatment: carrier+drug,

40group: treatment: carrier+drug+L-NAME.

Drugs used in this test represent paracetamol, doxorubicin, simvastatin, omeprazole and misoprostol. Each medication is administered once a day for 4 weeks.

Maximum tolerated dose of drugs administered to the animals is determined by evaluation of the experiment in untreated animals with increasing single doses of occurrence in animals symptoms such as enteropathy, diarrhea, depression, tremor, sedation.

After 4 weeks, discontinue the supply of water and after 24 hours the animals death.

An hour before killing determine blood pressure and increase blood pressure is used as the measure of damages in vascular whom the liver is determined by evaluation after killing alanine aminotransferase (increase GPT).

The drug meets test 3 and, therefore, can be used to obtain the compounds of the invention, when in the group of rats treated with L-NAME+drug+carrier detected more severe liver damage (higher values GPT) and/or more severe damage to the stomach, and/or a stronger cardiovascular damage (high blood pressure) compared to the group treated only by the media or the group treated only carrier+drug, or the group treated with carrier+L-NAME.

The test results presented in Table IV. The percentage of damage of the stomach is determined as in Test 1. Values % GPT and % blood pressure correlated with the corresponding values found in animals of the 1st group control groups.The average blood pressure in this group is 105±8 mm RT.article.

The results obtained demonstrate that paracetamol, doxorubicin and simvastatin cause liver damage and gastroenteropathy values (GPT and damage to the stomach are % higher compared with the corresponding groups treated with medication, in the absence of L-NAME, and controls treated with L-NAME).

Therefore, these medications can be the substitutes on the basis of this test is to obtain products of the invention.

Example F4

Test 4 - inhibition of production of radicals from DDPH some substances used as precursors In and B1 (see formulas I and II of the present invention).

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

At the beginning prepare solutions of the test substances in methanol to a final concentration of 100 μm. 0.1 ml each of these solutions add to the aliquot 1 ml of methanolic solution of 0.1 M DPPH and then the final volume was adjusted to 1.5 ml After storage solutions at room temperature in the absence of light for 30 minutes, measure the absorbance at a wavelength of 517 nm. It is determined that the absorbance increases with respect to the absorbance of a solution containing the same concentration of DPPH.

The effectiveness of the tested compounds on the inhibition of production of radicals or radical-scavenging activity is expressed by the following formula:

(1-As/Ac)100,

where Asand awithmean respectively the absorbance values of the solution containing the test compound+DPPH, and the solution containing only DPPH.

Connection, kotorac defined above, 50% or above.

Table V presents the results obtained for the following substances: N-acetylcysteine, cysteine, ferulic acid, L-carnosine, gantsova acid, 4-thiazolidinedione acid and 2-oxo-4-thiazolidinedione acid.

Table V shows that

N-acetylcysteine, cysteine, ferulic acid, L-carnosine, gantsova acid answer test 4 because they inhibit the production of radicals by DPPH in more than 50%, therefore, they cannot be used as precursors In or B1compounds of the invention;

- 4-thiazolidinedione acid and 2-oxo-4-thiazolidinedione acid does not meet test 4, as they do not inhibit radical products of DPPH in a degree equal to or greater than 50% and, therefore, they can be used as precursors for the compounds b or B1according to the present invention, assuming that they correspond to the following test 5.

Example F5

Test 5 - inhibition of production of radicals of FeIIcompounds used as precursors IN, B1or=-Twith-Y-H.

0.1 ml aliquots of 10-4M methanolic solutions of 4-thiazolidinones acid and 2-ACS is mechaniem 0.2 ml 2 mm deoxyribose, 0.4 ml of phosphate buffer, pH 7.4, 100 mm and 0.1 ml of 1 mm FeII(NH4)2(S04)2in 2 mm Hcl. The test tubes are then incubated at a temperature of C within one hour. Then in each test tube add queue 0.5 ml of 2.8% solution of trichloroacetic acid in water and 0.5 ml of an aqueous solution of 0.1 M thiobarbituric acid. Control comparisons create, replacing these with 0.1 ml aliquots of the methanol solutions of the test compounds 0.1 ml of methanol. The test tube was closed and heated in an oil bath at 100C for 15 minutes. Pink staining gives the intensity, which is proportional to the number of desoxyribose subjected to radical oxidative degradation. The solution is cooled to room temperature and the absorbance at 532 nm was measured against the control.

The inhibition caused by the predecessor or B1or=-Tc-Y-H (where the free valence is saturated as defined above) in respect of the radical products of FeII, defined as the percentage by the following formula:

(1 - As/Ac)100,

where asand awithare respectively the absorbance values of the solution containing the test compound+salt W is about both the acid test match 5, because they inhibit radical products of FeIImore than 50%. Consequently, 4-thiazolidinedione acid and 2-oxo-4-thiazolidinedione acid can be used as precursors IN, B1or=-Tc-Y-H to obtain the compounds of the present invention.

Example F6

Test on gastric tolerability of the compounds according to the present invention in comparison with the corresponding drug precursors under conditions of endothelial dysfunction caused by L-NAME (NW-nitro-L-arginine-methyl ester).

Example F3 repeat and evaluate gastric tolerability and for the following drug precursors and for the corresponding derivatives according to the present invention:

The diclofenac and the corresponding derivative according to example 4.

- Ambroxol and the corresponding derivative according to example 7.

- Alendronate and corresponding derivative according to example 6.

- Taken and the corresponding derivative according to example 5.

The results are presented in Table VI and show that with the introduction of the same doses of the compounds of the invention and appropriate medications the predecessor results of cases gastr 8

Synthesis of 4-nitrocellulose ester 3-[2-(atomic charges)benzoyl]thiazolidin-4-carboxylic acid (formula XCI)

based on acetylsalicylic acid (HS), thiazolidin-4-carboxylic acid (formula PIV)

Connection (HS) synthesized according to the scheme shown in Example 3. Yield 26%.

Elemental analysis

Rasschitano, %: 49,51; N 4,89; N 6,79; S To 7.77.

Found, %: C 49,57; N 4,94; N 6,70; S 7,73.

Example 9

Synthesis of 2-(tert-butylamino)-1-[4-hydroxy-3-[4-oxo-(4-nitrosobutane)butyryloxy]were]ethanol of the formula (HS)

on the basis of salbutamol (XXV) and succinic acid (formula RI)

Connection (HS) are obtained according to the procedure of Example 7. Exit 14%.

Elemental analysis

Rasschitano, %: 55,26; N 7,06; N 6,14.

Found, %: C 55,20; N 7,10; N 6,17.

Example 10

Synthesis of 4-nitrocellulose ether 3-[[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy]acetyl]thiazolidin-4-carboxylic acid of the formula (XCV)

on the basis of cetirizine (XIV) and 2-oxo-4-thiazolidinones acid (formula PV)

Connection (HS) are obtained according to the procedure of Example 3. Yield 18%.

Elemental analysis

Rasschitano, %: silt ester N - [(S) - 1-[N - [1-(etoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-prolinol]histidine formula (XCVIII)

on the basis of enalapril formula (XV) and histidine formula (R)

Connection (XCVIII) are obtained according to the procedure of Example 7. Exit 14%.

Elemental analysis

Rasschitano, %: 57,75; N 6,88; N 13,04.

Found, %: C 57,85; N 6,95; N 13,01.

Example 12

Synthesis of 1-[(1-methylethyl)amino]-3-(1-naphthyloxy)-2-[4-oxo-(4-nitrosobutane)butanoyl]oxypropane formula (HSH)

on the basis of propranolol formula (XXIV) and succinic acid of the formula (RI)

Connection (HSH) are obtained according to the procedure of Example 7. A 30% yield.

Elemental analysis

Rasschitano,% 60,49; N 6,77; N 5,88.

Found, %: C 60,40; N. Of 6.75; N 5,91.

Example 13

Synthesis of 4-nitrocellulose ester 3-[-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetyl]thiazolidin-4-carboxylic acid of the formula (HSH)

on the basis of clopidogrel of formula (XI), thiazolidin-4-carboxylic acid of the formula (PIV)

Connection (HSH) are obtained according to the procedure of Example 1. Output 15%.

Elemental analysis

Rasschitano, %: 51,15; N Is 4.85; N 7,78; S 11.87 Per; 16,56.

Found, %: 55,48; N The Ceiling Of 5.60; N To 7.61; S 11,85; C 16,59.

Example 14

Synthesis of 4-nitrocellulose ether N-[1-[5-(2,5-dihydro-5-oxo-3-fu is agilemessenger formula (XXXI) and histidine formula (PII)

Connection (XCXIV) are obtained by following the procedure described in Example 4. Yield 35%.

Elemental analysis

Rasschitano, %: 56,86; N 5,26; N 9,15.

Found, %: C 56,92; N. Of 5.29; N 9,10.

Example 15

Synthesis of 4-nitrocellulose ester 3-nicotinereplacement acid of the formula (XCXVI)

based on the nicotinamide of formula (XXIII), thiazolidin-4-carboxylic acid of the formula (PIV)

The compound (XXIII) are synthesized according to the procedure described in Example 1, using nicotinic acid. Yield 35%.

Elemental analysis

Rasschitano, %: 47,32; N 4,82; N 11,82; S 9,01.

Found, %: C 47,30; N 4,79; N 1l,84; S 9,06.

Example 16

Synthesis of 5-methoxy-2-[[[4-oxo-4-(nitroxy)butyryloxy]-3,5-dimethyl-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole of the formula (XCXVIII)

on the basis of 4-gidroksiomeprazol formula (XXII) and succinic acid of the formula (RI)

Connection (XCXVIII) are obtained by following the procedure described in Example 7. Output 15%.

Elemental analysis

Rasschitano, %: 52,64; N Equal To 4.97; N 10,23; S 5,86.

Found, %: C 52,68; N 5,01; N 10,15; S 5,81.

Example 17

Synthesis 1,2,3,7,8,8-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-[4-oxo-(4-nitrosobutane)Boutillon"ptx2">

on the basis of simvastatin of formula (XXI) and succinic acid of the formula (RI)

Connection (XCXIX) synthesized by following the procedure of Example 7. Yield 12%.

Elemental analysis

Rasschitano, %: 62,35; N To 7.77; N 2,20.

Found, %: C 62,50; N 7,81; N 2,17.

Example 18

Synthesis of 4-nitrocellulose ester 3-[4-D--aminobenzylpenicillin]thiazolidinediones acid of the formula (HSHH)

on the basis of ampicillin formula (XVI) and 2-oxo-4-thiazolidinones acid of the formula (PV)

Connection (HSHH) are obtained by following the procedure of Example 3. Exit 19%.

Elemental analysis

Rasschitano, %: 48,39; N 4,91; N 11,76; S 10,77.

Found, %: 48,43; N 4,99; N 11,71; S A 10.74.

Example 19

Synthesis of 9-[[2-[4-oxo-(4-nitrosobutane)butyryloxy]ethoxy]methyl]guanine of formula (XCXXI)

on the basis of ganciclovir of formula (XVII) and succinic acid of the formula (RI)

Connection (XCXXI) synthesized by following the procedure of Example 7. Yield 23%.

Elemental analysis

Rasschitano, %: 46,26; N A 5.25; N 15,85.

Found, %: C 46,30; N 5,28; N 15,84.

Example 20

Synthesis of (8S-CIS)-10-[(3-amino,2,3,6 trideoxy--L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro, 6,8,11-trihydroxy-8x2">on the basis of doxorubicin formula (XXXII) and succinic acid of the formula (RI)

Connection (HSHH) synthesized according to the procedure of Example 7. Output 10%.

Elemental analysis

Rasschitano, %: 55,26; N And 5.30; N 3,68.

Found, %: 55,34; N 5,32; N 3,65.

Example F7

Repeating the Example F1 with four groups of rats (each group of 10 animals), and all of them receive NEM, and conducted oral administration as follows:

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

b) one group (group b - comparative) was administered at the same time, 5 mg/kg (0.02 mmol/kg) flurbiprofen + 2.7 mg/kg (0.02 mmol/kg) 4-thiazolidinones acid in the same above-mentioned medium,

(C) one group (group - comparative) was administered at the same time, 7.4 mg/kg (0.02 mmol/kg) 4-nitrocellulose ether flurbiprofen synthesized according to the method described in WO 94/12463, + 2.7 mg/kg (0.02 mmol/kg) 4-thiazolidinones acid in the same above-mentioned medium,

d) one group (group d) was administered to 9.8 mg/kg (0.02 mmol/kg) 4-nitrocellulose ester 3-[2-fluoro--methyl-(1,1’-biphenyl)-4-acetyl]thiazolidin-4-carboxylic acid, synthesized as in PR is taulani in Table VII and show that mixture, introduced respectively in group b and C (comparative), in contrast to the compounds of the invention, entered in group d, almost ineffective (group b) or much more effective (group C) in the reduction of lesions of the stomach.

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

A-(B)bo-C-N(O)2(I)

where bo=0 or 1;

A=R-T1-,

where R is a drug radical, as defined below, and has the formula R-T1-Z or R-T1-OZ, where Z represents N or C1-C5alkyl, selected from the following groups: anti-inflammatory drugs: acetylsalicylic acid, 5-aminosalicilova acid, carprofen, diclofenac sodium, diflunisal, etodolac, floranova acid, flunixin, flurbiprofen, ibuprofen, indomethacin, indoprofen, Ketoprofen, Ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamovaya acid, meloxicam, mesalamine, naproxen, niflumova acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, telenova acid, tolmetin, zomepirac; analgesic drugs: acetaminophen, acetylcho uterol, clenbuterol, fenoterol, metaproterenol, pirbuterol, salmeterol, terbutaline; expectorants drugs: Ambroxol, Bromhexine, guaiacol; anti-asthma medications: cetirizine, levocabastine, terfenadine; ACE inhibitors: captopril, enalapril, lisinopril, ramipril; Beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, timolol; antithrombotic and vasoactive drugs: argatroban, venturedeal hemisuccinate, clopidogrel, dalteparin, dipyridamole, enoxaparin, iloprost, ozagrel, triflusal; antidiabetic drugs: nicotinamide; anticancer drugs: astromicin, daunorubicin, doxorubicin, epirubicin; antiulcer drugs: cimetidine, omeprazole, pantoprazole; antihyperlipidemic drugs: atorvastatin, fluvastatin, lovastatin, sodium salt of pravastatin, simvastatin; antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenicillin, cefaclor, cephalo-Smoking, cefamandole, cefatrizine, cefoxitin, dicloxacillin, imipenem, moxalactam, panipenem, bacampicillin; antiviral drugs: acyclovir,PTA, heteronomy acid, pamidronate acid; drugs against dementia: taken;

T1=(CO), O, S, N or NR1Cwhere R1Cmeans N or C1-C5alkyl,

=-TB-X2-TBI-,

where TBand tBIequal to or different and can be selected from (CO), O, S, N or NR1Cwhere R1Cmatter, as defined above;

X2means a bivalent bridging group, as appropriate predecessor In having a formula

Z'-TB-X2-TBI-Z"

where Z', Z" are independent and denote H or HE, is selected from the following compounds:

amino acids: aspartic acid (PI), histidine (PII), 5-hydroxy-tryptophane (PIII), 4-thiazolidinedione acid (PIV), 2-oxo-4-thiazolidinedione acid (PV)

monosperma or thiols: 2-thiouracil (QI), 2-mercaptoethanol (QII),

succinic acid (RI)

With means bivalent-Tc-Y - radical, where

Tc=(CO), O, S, N or NR1C, R1Cis as defined above;

Y means:

where pH means an integer between 0 and 3

nIIX means an integer between 1 and 3

R C1-C4alkyl;

Y3is a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen atom and the above-mentioned ring contains from 5 to 6 atoms;

or Y means Yoselected from the following:

accelerograph R O, where R' is a linear or branched, when possible C1-C20, alkyl or cycloalkyl having 5 to 7 carbon atoms, in cycloalkylation the ring one or more carbon atoms may be replaced by heteroatoms, the ring can have side chains of R' type, and R' is as defined above; or

where n3 denotes an integer from 0 to 3, and n3' is an integer from 1 to 3;

where n3 and n3' have the above meanings;

where nf’ is an integer from 1 to 6;

where R1f=H, CH3and nf denote an integer from 1 to 6;

provided that in compounds of formula (I):

when bo=0 and s=-Tc-Yothe medication formula A=R-T1-Z or A=R-T1-OZ, as defined above, does not belong to the group of ACE inhibitors;

when bo=0 and s=-Tc-y-, medicine formula A=R-T1-Z or A=R-T1-OZ do not belong to the group of non-steroidal/SUB>-C6alkyl.

3. Connection on p. 1, where in formula (III) Y3selected from the following:

4. Connection on p. 3, where Y3means Y12 (pyridyl), substituted in positions 2 and 6.

5. Compounds or their salts, or their compositions on PP.1-4 for use as pharmaceuticals.

6. The use of compounds or their salts, or their compositions on PP.1-4 for the preparation of drugs for therapeutic use in cases of oxidative stress.

7. Pharmaceutical composition, for use in cases of oxidative stress and/or endothelial dysfunctions, containing as active principle compounds or their salts under item 1.

 

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