Product comprising at least one substance inhibiting activity of no-synthase in combination with at least one substance inhibiting activity of phospholipase a2

FIELD: medicine, biochemistry.

SUBSTANCE: invention relates to a method for treatment of pathology or disorder taken among inflammatory diseases. Method involves using the simultaneous, separating or distributed by time at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2. Also, invention relates to the composition comprising at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2 for using in the method for treatment of pathology or disorder taken among inflammatory diseases.

EFFECT: improved method for treatment.

21 cl, 4 ex

 

The invention relates to a product comprising at least one substance inhibiting NO synthase, in combination with at least one substance inhibiting phospholipase A2, in separate form or as a combination for simultaneous, separate or distributed in time use in the treatment of pathologies in which take an active part monoxide nitrogen and/or phospholipase A2. The invention relates also to pharmaceutical compositions comprising as an active beginning at least one substance inhibiting NO synthase, and at least one substance inhibiting phospholipase A2, and, if necessary, pharmaceutically acceptable carrier.

The product and the pharmaceutical composition according to the invention are of interest in the treatment of pathologies where participate actively monoxide nitrogen and phospholipase A2, and, in particular, such as:

- proliferative, inflammatory and edematous diseases, such as atherosclerosis, restenosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation of the gastro-intestinal tract (colitis, Crohn's disease, pancreatitis) or pulmonary system and the respiratory tract (asthma, sinusitis, respiratory distress syndrome), allergic rhinitis;

cardio-with Aditya and cerebrovascular disorders, including, for example, migraine, arterial hypertension, septic shock, heart attacks, heart or brain ischemic or hemorrhagic origin, ischemia and thrombosis;

- disorders of the Central or peripheral nervous system, such as, for example, neurodegenerative diseases, which include, in particular, the infarctions of the brain, senile dementia, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, spastic pseudosclerosis of Creutzfeldt-Jakob disease caused by prions disease, amyotrophic lateral sclerosis, pain, traumatic brain or trauma, opioid dependence, alcohol dependence and dependence relative to the substances that cause addiction to the excessive use of drugs;

dermatitis, solar radiation (ultraviolet radiation spectrum And the ultraviolet radiation spectrum);

- organ transplantation;

- autoimmune and viral diseases, such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis, myopathy;

cancer and eye diseases;

and, in a broader sense, all pathology characterized by products or hyperactivities of nitrogen monoxide and/or phospholipase A2.

There is experimental evidence indicating the involvement monoxide is the OST (J. Med. Chem.,, 4343-4362 (1995); ClIn. Exp. Immunol.,, 147-156 (1998)) and phospholipase A2 (Trends Pharmac. ScI.,, 16162-16170 (1999); BRain Res. Bull.,, 139-153 (1999)). This, in particular, the case of experimental inflammation in the paws of rats, which explains the invention of the Agents ' ActIons,, 292-300 (1989); Immunopharmacology,, 1-9 (1993); BR. J. Pharmacol.,, 1119-1126 (1998)) in the combination of these pathologies.

In this context, drugs that are able to inhibit the formation of nitrogen monoxide or to inhibit phospholipase A2, can lead to beneficial effects. Has not been implemented in any combination of these two active principles, namely, an inhibitor of NO-synthase and inhibitor of phospholipase A2. As shown in the experimental part, the combination of an inhibitor of NO-synthase and inhibitor of phospholipase A2, effectors, acting by different mechanisms, causes unexpected therapeutic effect of these effectors, namely their synagris. In fact, these current beginning enter in subactive doses (i.e. doses that do not cause themselves therapeutic effect), called when they are combined, a highly significant therapeutic effect.

The advantage of this combination of activities is aetsa decrease significantly doses of each of the active principles and, thus, the significant reduction in the extent of their adverse effects, with full achievement of therapeutic efficacy. The present invention is particularly well explained by pathological models of inflammation in the paws of rats due to carrageenin.

The object of the invention is, first, the product comprising at least one substance inhibiting NO synthase, in combination with at least one substance inhibiting phospholipase A2, in separate form or as a combination for simultaneous, separate or distributed in time use in the treatment of pathologies involving the nitric monoxide and/or phospholipids A2. Preferably, the above product contains a substance inhibiting NO synthase, in combination with the substance, inhibiting phospholipase A2.

Under the inhibitor of NO-synthase need to understand any specific or non-specific inhibitor of one of their isoforms, which is constitutive (neuronal or endothelial) or induced (J. Med. Chem.,, 4343-4362 (1995)). Inhibitors of NO-synthase, used according to the present invention, preferably are inhibitors of neuronal or inducible forms of NO-synthase.

Under the inhibitor of phospholipase A2 is necessary to understand any specific or nonspecific in hibitor secreted or cellular forms of phospholipase A2 (Medecine/Sciences, , 323-332 (1995); Trends Pharmac. Sci.,, 16162-16170 (1999); Brain Res. Bull.,, 139-153 (1999)).

In the product according to the invention, the inhibitor of NO-synthase and the inhibitor of phospholipase A2 can be on a separate form or in combined form, forming a salt. Salt preferably is formed from a derivative inhibiting NO synthase compounds containing at least one basic group, and derived inhibitor of phospholipase A2, which contains at least one acid group. Thus, salts can be formed according to well-known specialist ways of inhibitors of NO-synthase, such as, for example, amidine, guanidine, pyridine or piperidine, such as the following, and inhibitors of phospholipase A2, such as, for example, mepacrine, Aristolochia acid, atsilpirrolidinov or allindiaradio acid, such as the following. These substances can be natural or synthetic.

The object of the invention is a product comprising at least one substance inhibiting NO synthase, in combination with at least one derivative, inhibiting phospholipase A2, in separate form or as a combination for simultaneous, separate or distributed in time in therapeutic applications in the treatment of pathologies involving monoxide azo is a and/or phospholipase A2, such as, in particular, cardiovascular and cerebrovascular disorders, disorders of the Central or perifericheskoi nervous system, proliferative and inflammatory diseases, organ transplantation, autoimmune and viral diseases, cancer and in a broader sense all of a pathology characterized by either excessive production of nitrogen monoxide and/or phospholipase A2 or dysfunction associated with nitric monoxide and/or phospholipases A2.

Of inhibitors of NO-synthase, you can specify connection amino acid and nominaciones type. Inhibitors of NO-synthase amino acid type can be compounds such as described in applications WO-95/00505, WO-94/12163, WO-96/06076 and the application for the European patent EP 230037, incorporated into the present application by reference, or a derivative of L-arginine, ornithine and lysine, such as described in PCT applications WO-93/24126, WO-95/01972, WO-95/24382, WO-95/09619 and WO-95/22968 included in the present application by reference.

Inhibitors of NO synthases are not amino acid type can be the connection of families guanidino, estimacion, nitro - or cyanoacrylat, aminopyridines or aminopyrimidine, amidino, indazols or imidazoles.

Derivatives guanidino, inhibitors of NO-synthase can be compounds such as those described in PCT applications WO-95/28377, WO-91/04023, WO-94/21621, WO-96/18607 and WO-96/18608 included in the present application put the m links.

Estimacion, inhibitors of NO-synthase can be compounds such as those described in PCT applications WO-95/09619, WO-96/09286, WO-94/12165, WO-96/14842, WO-96/18607, WO-96/18608, WO-96/09286 and applications to the European patent EP 717040 and EP 718294 included in the present application by reference.

Nitro - or tionarily, inhibitors of NO-synthase, may constitute such compounds, as specified in the application PCT WO-94/12163 included in the present application by reference.

Aminopyridines or aminopyrimidine, inhibitors of NO-synthase can be compounds such as those described in PCT applications WO-94/14780, WO-96/18616 and WO-96/18617 included in the present application by reference.

Amidine, inhibitors of NO-synthase can be compounds such as those described in PCT applications WO-95/11014, WO-96/01817, WO-95/05363, WO-95/11231, WO-96/14844 and WO-96/19440 included in the present application by reference, or such compounds as N-phenyl-2-thiophenecarboxylate.

In addition, inhibitors of NO-synthase can also be simultaneously inhibitors of NO synthases (NOS) and the catchers reactive oxygen species (ROS = reactive oxygen species). The applicant was the first to describe such inhibitors in the patent application PCT WO-98/42696, WO-98/58934, WO-00/02860, WO-00/17190 and WO-00/17191 included in the present application by reference (the applicant also filed other, unpublished patent application, which describes the connection is to be placed, having such pharmacological activities, and connections, which are described there can also be used according to the present invention). These compounds also exhibit synergism in the case of pathological models of inflammation in the paws of rats due to carragenine while preserving the advantages already shown in PCT applications WO-98/42696 and WO-98/58934, WO-00/02860, WO-00/17190 and WO-00/17191.

Indazols, inhibitors of NO-synthase, may constitute compounds of General formula (IA)

in which R1means one or more substituents selected from among a hydrogen atom and nitro group, halogen atom, alkyl or alkoxyl;

or pharmaceutically acceptable salts of the compounds of General formula (IA).

The imidazoles, inhibitors of NO-synthase, may constitute compounds of General formula (IIA)

in which R1and R2denote independently a hydrogen atom or halogen atom, hydroxyl, amino, alkyl or alkoxy; or R1and R2linked together and form a phenyl fused with imidazole cycle, and the above-mentioned phenyl possibly substituted by one or more substituents selected among hydroxyl, trifloromethyl, halogen atom, carboxyl, alkyl, alkoxyl or alkenyl;

R3 means a hydrogen atom or alkyl, amino group, alkylamino or phenyl, with the above-mentioned phenyl possibly substituted by one or more substituents selected among hydroxyl, trifloromethyl, halogen atom, carboxyl, alkyl, alkoxyl or alkenyl; and

R4means a hydrogen atom or alkyl, amino group or alkylamino;

or pharmaceutically acceptable salts of the compounds of General formula (IIA).

Compounds, inhibitors of NO-synthase and ROS may constitute, in particular, compounds of General formula (IIIA)

in which R0means H or alkyl;

And means radical

in which R1and R2denote independently a hydrogen atom, a halogen atom, a group HE, a linear or branched alkyl with 1-6 carbon atoms, linear or branched alkoxy with 1-6 carbon atoms; and

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4where R4means alkyl with 1-6 carbon atoms;

or radical

in which R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4where R4means alkyl with 1-6 carbon atoms;

In the mean line or OSVETLENIE alkyl with 1-6 carbon atoms, phenyl, pyridinyl or the five-membered heterocycle with 1 to 4 heteroatoms chosen among O, S, N, and, in particular, thiophene, furan, pyrrole or thiazole, carbon atoms, which may substituted by one or more groups chosen among linear or branched alkyl with 1-6 carbon atoms, alkoxyl with 1-6 carbon atoms or halogen atom;

X is-CO-N (R3)-X’-, -NH-CO-X’-, -CH=, -CO -, or a bond, and X’ represents -(CH2)nwhere n means an integer from 0 to 6;

Y means Y’-, -CO-NH-Y’-, -Y’-NH-CO-, -CO-Y’-, -Y’-CO-, -N(R3)-Y’-, -Y’-N(R3)-, -Y’-CH2-N(R3)-CO-, -O-Y’-, -Y’-O-, -S-Y’-, -Y’-S-, -Y’-O-Y’-, -Y’-N(R3)-Y’- or a bond, and Y’ is -(CH2)nwhere n means an integer from 0 to 6;

Het means a heterocycle with 1 to 5 heteroatoms chosen among O, N, S, which can be substituted by one or more substituents X’-OR3X’-NR3X’-S-R3and, such as, for example, oxetan, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolan, piperazine, homopiperazine, 4-aminopiperidin-imidazole, imidazoline, dihydroimidazole-2-it, dihydroimidazole-2-tion, oxazol, isoxazol, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, as 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidin, 1,2,4-triazole--he tetrazol, tetrahydropyridine, azetidin; or pharmaceutically acceptable salts of these compounds.

In some cases, the compounds according to the present invention may include asymmetric carbon atoms. Therefore, the compounds according to the present invention have two possible enantiomeric forms, that is, the configuration of "R" and "S". Compounds according to the present invention include two enantiomeric form or any combinations of these forms, including racemic mixtures RS. For the sake of simplicity, when in structural formulas not specified no specific configuration, you should understand that both enantiomeric forms and mixtures thereof.

Under alkyl, when it more accurately is not specified, see linear or branched alkyl radical with 1-6 carbon atoms. Under alkenyl when it is not exactly specified, see linear or branched alkyl radical with 1-6 carbon atoms and having at least one double bond. Under halogenation understand alkyl radical, at least one of the carbon atoms (and possibly all) of which is replaced by a halogen atom.

Under alkoxyl, alkenyl or alkylaminocarbonyl see, respectively, alkyl, alkanniny or acylaminoalkyl, the alkyl part of which has the above value.

Under linear or branched alkyl with 1-6 atoms the carbon realize in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. Finally, under the halogen understand the atoms fluorine, chlorine, bromine or iodine.

Under a pharmaceutically acceptable salt see, in particular, additive salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate and stearate. In the scope of the present invention also includes, when used, salts derived from bases, such as sodium hydroxide or potassium hydroxide. Other examples of pharmaceutically acceptable salts can be referenced in the publication "Salt selectIon for basic drugs". Int. J. Pharm., 33, 201-217 (1986).

Of inhibitors of phospholipases A2, you can specify the connection type atsilpirrolidinov acids, allintalivay acids and derivatives pyrrolidine. Inhibitors of phospholipases A2 type atsilpirrolidinov acids, allintalivay acids and derivatives pyrrolidine may be such compounds as described in applications EP 97934481, WO-98/05637, EP 969225076 and WO-98/33797. Inhibitors of phospholipases A2 can also represent compounds such as those described in applications WO-99/43672, WO-99/43654, WO-99/43651, WO99/15493 and WO-98/37069. Inhibitors of phospholipases A2 may represent, in particular, derivatives of arylsulfonamides, such as described in the application WO-98/25893; derivatives of 1H-indole-3-glycinamide, such as described in the application WO-99/57100; derivatives of indoles, such as described in the application WO-00/07591; or derivatives of 2-phenylpyrimidine, such as described in the application WO-00/27824. All of the foregoing patent applications is incorporated into the present application by reference.

According to the invention inhibitors of phospholipases A2 preferably are:

compounds of General formula (IB) or (I’B)

in which R1 stands for a group-Y1-AR-Y2-Y3, where Y1 and Y2 denote independently (C1-C12)-alkyl, (C2-C12)-alkenyl, (C1-C12-alkoxy or (C2-C12)-alkenylacyl, and the radicals Y1 and Y2, if necessary, can be interrupted by one or more oxygen atoms; AR denotes aryl, possibly substituted with one, three times by substituents chosen independently among the groups R6, R7 and R8, and Y3 means the radical-COOR17, -CONR17R17, -CONHCOR19, -CONHS(O)2R19, -CONHNHS(O)2R19 or Tz;

R2 means-COOR17, -Y4-COOR17, -CONR17R17, -Y4-CONR17R17, -CONHCOR19, -Y4-CONHCOR19, -CONHS(O)2R19, Y4-CONHS(O)2R19, -CONHNHS(OH)2R19, -Y4-CONHNHS (OH)2R19, Tz or-Y4-Tz, and Y4 means (C1-C8)-alkyl, (C2-C8)-alkenyl and radical Y4 if required may be interrupted by one or more oxygen atoms;

R3 means a radical-CO-R9 in which R9 means a radical-Y5, aryl or-Y5-aryl, and Y5 means (C1-C19)-alkyl, (C2-C19)-alkenyl or (C2-C19)-quinil and radical Y5, if necessary, may be interrupted by one or more oxygen atoms, and aryl of values of the radical R9 may be substituted with one, three substituents chosen independently among the groups R10, R11 and R12;

each radical R4 denotes independently a hydrogen atom, halogen atom, -CF3, -Y6, aryl or-Y6 - aryl, and Y6 means (C1-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-quinil and radical Y6, if necessary, may be interrupted by one or more oxygen atoms, and aryl of values of the radical R4 may be substituted with one, three substituents chosen independently among the groups R13, R14 and R15; and two adjacent alkyl radical Y6 together with the carbon atoms to which they are linked, can form a 5-8-membered cycle, which if necessary may be substituted by one or two (C1-C4)-alkyl radicals;

n means the number 2;

m means the number 4;

Tz means 1H - or 2H-tetrazol-5-yl;

the radicals R6, R7, R8, R10, R11, R12, R13, R14, R15 and R16 is chosen independently from the group consisting of (C1-C20)-alkyl, (C2-C20-alkenyl or (C2 -C20) -quinil, possibly interrupted by one or more oxygen atoms; halogen atom, -CF3, -CN, -NO2or-PINES2HE and peralagan-(C2-C6-alkenyl, -OR17, -SR17, -COOR17, -COR18, -NHCOR17, -NR17R17, NHS(O)2R17, -SOR17, -S(O)2R17, -CONR17R17, -S (O)2NR17R17, -OOCR18, -OOCNR17R17, -OOCOR17, -(CH2)rOR23, -(CH2)rSR23, -(CH2)rNHR23 or (CH2)sR20;

R17 means independently in each case, when it is present, the radical -(CH2)tR20 or (C1-C20)-alkyl, (C2-C20)-alkenyl or (C2-C20)-quinil, possibly interrupted by one or more oxygen atoms;

R18 means independently in each case, when it is present, the radical R17, -CF3, -(CH2)uCOOH or - (CH2)uCOOR21;

R19 means independently in each case, when it is present, the radical R17 or-CF3;

R20 means independently in each case, when he has, aryl, substituted with one or two R22 groups;

R21 means independently in each case, when it is present, (C1-C6)-alkyl, benzyl or phenyl;

R22 means independently in each case, when it is present, hydrogen atom, halogen atom, (C1-C12)-alkyl, (C1-C12-alkoxy, (C1-C12)-allylthiourea, (C1-C12)-alkylsulfonyl, (C1-C12-alkylsulphonyl, -CF3, -CN Il is-NO 2;

R23 means independently in each case, when it is present, the hydrogen atom or the radical-COR21;

r is an integer from 1 to 20;

s and t denote independently integers from 0 to 12; and

u represents an integer from 0 to 4;

or compounds of General formula (IIB)

in which both groups X means oxygen atoms;

R1 is chosen from the group consisting of radicals

in which R10 is chosen independently include halogen atom and (C1-C10)-alkyl, (C1-C10)-alkoxyl, (C1-C10-allylthiourea and (C1-C10)-halogenoalkane,

t stands for an integer from 0 to 5;

R2 is chosen among a halogen atom and cyclopropyl, methyl, ethyl and propyl;

R4 and R5 are chosen independently from among hydrogen atom, nenterprise Deputy or (acidic) group-La-(acidic group), provided that-Lain the case of the radical R4 is chosen among-O-CH2-, -S-CH2-, -NH-CH2-, -CH2-CH2-, -O-CH(CH3)- and-O-CH(CH2-CH2-Ph)-, and Ph means phenyl, and-Lain the case of the radical R5 is chosen among the radicals

in which R84 and R85 is chosen independently from among hydrogen atom, halogen atom and (C1-C10)-alkyl, aryl, (C1-C10)-alkylaryl, aryl-(C1 -C10)-alkyl, carboxyl or carbalkoxy;

provided that at least one of R4 and R5 must mean the group-La-(acidic group) and that (acid group) in the radicals R4 and R5 is chosen among-CO2H, -SO3N and-P(O)(OH)2;

R6 and R7 independently choose among a hydrogen atom and nenterprise Deputy;

and nenterprise substituents chosen independently from the group consisting of (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, (C7-C18)-aralkyl, (C7-C18)-alkylaryl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, phenyl, toluyl, xylenyl, phenylmethyl, (C1-C6)-alkoxyl, (C2-C6-alkenylacyl, (C2-C6-alkyloxy, (C2-C12)-alkoxyalkyl,(C2-C12-alkoxyalkyl, (C2-C12-alkylcarboxylic, (C2-C12-alkoxyamino, (C2-C12)-alkoxycarbonyl, (C2-C12-alkylamino, (C1-C6-allylthiourea, (C2-C12)-alkylthiomethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonyl, (C1-C6)-halogenoalkanes, (C2-C6)-halogenallylacetic, (C2-C6)-halogenoalkane, (C1-C 6)-hydroxyalkyl, -C(O)O((C1-C6)-alkyl), -(CH2)n-O-((C1-C6)-alkyl), benzyloxy, fenoxaprop, phenylthiourea, -Cho, amino, amidinopropane, bromine atom, carbamoyl, carboxyl, carbalkoxy, -(CH2)n-CO2H, chlorine atom, ceanography, cyanoguanidine, fluorine atom, guanidinium, hydrazide group, hydratherapy, gidrazidov, hydroxyl, hydroxyamino, iodine atom, nitro, phosphonopropyl, -SO3N, thioacetal group, thiocarbonyl and (C1-C6)-alkylsulphonyl, and n means an integer from 1 to 8;

or compounds of General formula (IIIB)

in which R1 is selected from groups (a), (b) and (C):

(a) means (C7-C20)-alkyl, (C7-C20-halogenated, (C7-C20)-alkenyl or (C7-C20)-quinil, saturated or unsaturated 5 to 14-membered carbocycle, possibly substituted by a Deputy or deputies, chosen among reintervenciisa substituents, or (a) means 5-14-membered heterocycle with 1-3 heteroatoms, with the above-mentioned heterocycle is saturated or unsaturated and possibly replaced by a Deputy or deputies, chosen among reintervenciisa deputies;

(b) means one of the radicals (a), substituted by one or a few is Kimi substituents, choose among reintervenciisa deputies;

(c) means a group -(L1)-R11, in which(L1)means a group selected among the groups represented by the formula

in which Q1means the communication or one of the groups-CH2-, -O-, -S-, -NH - and-CO-, and each of the groups R10 denotes independently a hydrogen atom or a (C1-C8)-alkyl, (C1-C8-halogenated or (C1-C8-alkoxyl;

R11 stands for a group selected among the groups (a) and (b);

R2 means a hydrogen atom, halogen atom or (C1-C4)-alkyl, (C2-C4)-alkenyl, -O-(C1-C3)-alkyl, -S-(C1-C3)-alkyl, -(C1-C4-cycloalkyl, -CF3, -NR2, -CN or-SO3;

R3 means(L3)-Z, where

-(L3)means a group with a divalent linkage selected among communication and group-CH2-, -O-, -S-, -NH - and-CO-;

Z choose among acetamide, thioacetamide, glycylamino, thioglycollate, hydrazide or thiohydrazide groups represented by the General formula

in which R31 and R32 independently choose among a hydrogen atom and (C1-C8)-alkyl, (C1-C8)-halogenoalkane or (C3-C4)-cycloalkyl; and

X is independently in each case, when it is present, the oxygen atom or the market;

R4 and R5 are chosen independently from among hydrogen atom, nenterprise Deputy or the group - (La)-(arylsulfonamides group), in which

-(La- in the case of radical R4 means a group represented by the formula

in which Q2choose among-CH2-, -O-, -NH-, -C(O)- and-S-;

and each group R40 is chosen independently from among hydrogen atom, halogen atom and (C1-C8)-alkyl, aryl, (C1-C8)-alkylaryl, (C1-C8)-alkoxyl and aralkyl;

-(La- in the case of the radical R5 is chosen among the groups represented by the formula

in which R54, R55, R56 and R57 is chosen independently from the group consisting of hydrogen atom, halogen atom and (C1-C8)-alkyl, (C1-C8)-alkoxyl, (C1-C8)-halogenoalkane and aryl;

(arylsulfonamides) group is a group of the formula-CO-NH-SO2-R81, in which R81 is chosen from the group consisting of-CF3, (C1-C8)-alkyl, (C1-C8)-alkoxyl, (C1-C8-allylthiourea, (C1-C8-alkylamino, (C1-C8)-halogenoalkane, aryl-(C1-C14)-alkyl, (C1-C14)-alkylaryl, aryl, tiarella, (C3-C14)-cycloalkyl and 3-14-membered heterocycle, with the above-mentioned heterocycle which engages 1-3 heteroatoms and is saturated or unsaturated;

provided that at least one of R4 and R5 means a group - (La)-(arylsulfonamides group);

R6 and R7 denote independently a hydrogen atom, nenterprise Deputy, saturated or unsaturated 5 to 14-membered carbocycle, possibly substituted by a Deputy or deputies, chosen among reintervenciisa substituents, or a 5-14-membered heterocycle with 1-3 heteroatoms, with the above-mentioned heterocycle is saturated or unsaturated and possibly replaced by a Deputy or deputies, chosen among reintervenciisa deputies;

and nenterprise substituents chosen independently from the group consisting of the radicals (C1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C7-C12)-aralkyl, (C7-C12)-alkylaryl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, (C1-C8)-alkoxyl, (C2-C8-alkenylacyl, (C2-C8-alkyloxy, (C2-C12)alkoxyalkyl, (C2-C12-alkoxyalkyl, (C2-C12)-alkylsulphonyl, (C2-C12-alkylcarboxylic, (C2-C12-alkoxyamino, (C2-C12)-alkoxycarbonyl, (C1-C12-alkylamino, (C1-C 6-allylthiourea, (C2-C12)-alkylthiomethyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkylsulfonyl, (C2-C8)-halogenoalkanes, (C1-C8)-halogenallylacetic, (C2-C8)-halogenoalkane, (C1-C8)-hydroxyalkyl, -C(O)O((C1-C8)-alkyl), -(CH2)n-O-((C1-C8)-alkyl), benzyloxy, fenoxaprop, phenylthiourea, CONHSO2R, -CHO, amino, amidinopropane, bromine atom, carbamoyl, carboxyl, carbalkoxy, (CH2)n-CO2H, chlorine atom, ceanography, cyanoguanidine, fluorine atom, guanidinium, hydrazide group, hydratherapy, gidrazidov, hydroxyl, hydroxyamino, iodine atom, nitro, phosphonopropyl, -SO3N, thioacetal group, thiocarbonyl, and

n means an integer from 1 to 8;

R means (C1-C8)-alkyl;

or compounds of General formula (IVB)

in which R1 is chosen from the group consisting of a halogen atom and (C1-C6)-alkyl or (C1-C6)-alkoxyl;

R2 is chosen from the group consisting of one of the phenyl or benzyl radical, possibly substituted in the aromatic cycle, a halogen atom, or (C1-C6)-alkyl, (C1-C6-alkoxyl, amino group, al is laminography, dialkylamino, carboxyla, carbamoyl, (C1-C6)-acyl, sulfonyl, Tilney group or alkylthiol; and (C3-C7)-cycloalkyl and above (C3-C7-cycloalkyl may be condensed with a benzene cycle or heterocycle and may be substituted by a halogen atom or a (C1-C6)-alkyl;

R3 is chosen from the group consisting of a halogen atom and (C1-C6)-alkyl;

R4 is chosen from the group consisting of-H, -OH, -N3and the N3;

or pharmaceutically acceptable salts of the compounds of General formula (IB), (IIB), (IIIBor (IVB).

According to another preferred variant inhibitors of phospholipases A2 can be selected from the group consisting of mepacrine, aristolochias acids and their analogs, and pharmaceutically acceptable salts of these compounds.

The object of the invention preferably is a product, such as specified above, characterized in that

inhibitor or inhibitory NO-synthase selected from the group consisting of L-nitroarginine (LNA), methyl ester of L-nitroarginine (LNAME), L-N-monomethylaniline (LNMMA), aminoguanidine, agmatine, 2-amino-1-(methylamino)-benzimidazole, 5-nitroindazole, 6-nitroindazole, 7 nitroindazole, 1,2-(triptoreline)imidazole (TRIM), 2-amino-4-methyl-6-(2-amino-ethyl)pyridine, 2-aminopiperidin is, 2-aminoguanidine, 2-imino-5,6-dihydro-1,3-thiazine, 2-imino-5,6-dihydro-1,3-oxazine, N-phenyl-2-thiophenecarboxaldehyde, 2-aminomethylpyrimidine, S-utilizationfocused, S-methyl-L-thiocitrulline, S-ethyl-L-thiocitrulline, (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxaldehyde and 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolidinone, as well as pharmaceutically acceptable salts of these compounds; and

the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine and aristolochiae acids and their analogs, and pharmaceutically acceptable salts of these compounds.

Even more preferably the object of the invention is a product, such as specified above, characterized in that:

the inhibitor or inhibitors of NO-synthase selected from the group consisting of aminoguanidine, 7 nitroindazole and 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolidinone and farmatsevticheskii acceptable salts of the above compounds;

and the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine and aristolochiae acids and their analogs, and pharmaceutically acceptable salts of these compounds.

As already indicated, the product according to izopet the tion can be used in the treatment of pathologies in the case involving the nitric monoxide and/or phospholipase A2. These pathologies include, in particular, cardiovascular and cerebrovascular disorders, disorders of the Central or peripheral nervous system, proliferative and inflammatory diseases, diarrhea, vomiting, radiation, solar radiation, organ transplantation, autoimmune and viral diseases, cancer and in a broader sense all of a pathology characterized by either excessive production of nitrogen monoxide and/or phospholipase A2 or dysfunction associated with nitric monoxide and/or phospholipases A2.

According to a preferred variant of the product according to the invention can be used in the treatment of pathologies chosen among proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis and inflammation of the gastrointestinal system or pulmonary system and the respiratory tract.

According to another preferred variant of the product according to the invention can be used in the treatment of autoimmune and viral diseases, such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis, and myopathies.

The object of the invention is also farmace the political composition, including as applicable the beginning of at least one substance inhibiting NO synthase, and at least one substance inhibiting phospholipase A2, and, if necessary, pharmaceutically acceptable carrier.

Preferably, the above pharmaceutical composition comprises as an active beginning of a substance inhibiting NO synthase, and a substance inhibiting phospholipase A2.

In General, the pharmaceutical compositions according to the invention include the product, such as described above, and stored the same preferred directions.

In the pharmaceutical composition or product according to the invention, the inhibitor of NO-synthase and the inhibitor of phospholipase A2 can be in doses, which may be the same or different. The dosage is selected depending on the compounds, combined with appropriate diluents or excipients.

The inhibitor of NO-synthase and the inhibitor of phospholipase A2 can be introduced simultaneously or sequentially to the same by introducing or in different ways depending on whether they are in separate or combined form. The routes of administration are preferably oral, parenteral or local.

The pharmaceutical compositions according to the invention can be in the form of solids, such as powders, Gran the crystals, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone and wax.

Pharmaceutical compositions comprising the product according to the invention can also be in liquid form, such as solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, and mixtures thereof in various proportions with water.

Inhibitors of NO-synthase and inhibitors of phospholipases A2 are industrial products or can be obtained well-known specialist ways (or by analogy with these methods). In particular, compounds of General formula (IIIAdescribed in PCT applications WO-98/42696 and WO-98/58934, and compounds of General formula (IB) and (I’B), (IIB), (IIIBand (IVB) are described, respectively, in the patent application PCT WO-98/05637, WO-99/57100, WO-00/07591 and WO-00/27824.

Unless specified otherwise, all technical and scientific terms used in this description have the same meaning as such, usually understandable to an average expert in the field that is present and is gaining. Also, all publications, patent applications, all patents and other references mentioned herein incorporated by reference.

The following examples are presented to illustrate the above methods and in no way should be construed as limiting the scope of protection of the invention.

Experimental part

Pharmacological study of the products according to the invention

The active compounds according to the invention was evaluated in vivo using a model of edema due to carragenine on the paw of the rat.

Male rats Sprague Dawley (Charles River) weighing 170-180 g until the day of the experiment contained within 5-8 days under the conditions of the kennel experimental animals and over 18 hours before and during the experiment contained on an empty stomach in the cells. The group consisted of 8 animals. The products were administered intraperitoneally injected (ip, 2 ml/kg) 30 minutes before administration by injection 1 % (solution) carragenine pomodorini way in the back right paw of rats. Suitable swelling volume of the paw was determined using the water plethysmometer (Ugo Basile, APELEX) before injection carragenin (t0and 3 hours after injection. Volume paws allows you to define % inflammation (volume paws at time t after carrageenin - volume the same paws at time t0before injection products/volume paws at time t0)×100). Any product can greatly reduce the intensity of halogen with exceptiona is swelling (% inflammation), regarded as effective. This performance is statistically determined by student's t test.

In the following examples, the letter a indicates the inhibitor of NO-synthase, and a letter To indicate the inhibitor of phospholipase A2.

Example 1

Compound AB is a combination of active principles a and B.

Connection: 7-nitroindazole, the inhibitor of the neuronal form of NO-synthase. Connection: mepacrine, an inhibitor of phospholipase A2.

Connection example 1: 4 groups of animals were:

group 1: treated with excipient + carrageenin;

group 2: treated with A (25 mg/kg) + carrageenin;

group 3: treated with (30 mg/kg) + carrageenin;

group 4: treated with AB + carragenin.

no group% inflammation
158,9±4
272,5±16,1
 NS
364,5±3,7
 NS
428±6,2
 ***
(where: NS: angle of approach the result; ***: highly indicative result)

The results show that 7-nitroindazole (inhibitor of the neuronal form of NO-synthase) and mapcr the n inactive with regard to the protection of the animal from edema, caused by carrageenan. On the contrary, the combination of these two compounds in the highest degree significantly protects animals from edema caused by carrageenan.

Example 2

Compound AB is a combination of active principles a and b in separate form, and as connection: aminoguanidine, an inhibitor of the inducible form of NO-synthase; and as connection: mepacrine, an inhibitor of phospholipase A2.

Connection example 2: 4 groups of animals were:

group 1: treated with excipient + carrageenin;

group 2: treated with A (400 mg/kg) + carrageenin;

group 3: treated with (30 mg/kg) + carrageenin;

group 4: treated with AB + carragenin.

no group% inflammation
154,3±2,5
253,1±3,4
 NS
353,9±3,2
 NS
433±5
 **
(where: NS: angle of approach the result; **: highly indicative result)

The results show that aminoguanidine (an inhibitor of the inducible form of NO synthase) and mepacrine inactive in respect of the protection of the animal from edema, caused by carrageenan. On the contrary, the combination of these two compounds in the highest degree significantly protects animals from edema caused by carrageenan.

Example 3

Compound AB is a combination of active principles a and b in separate form, and as connection: aminoguanidine, an inhibitor of the inducible form of NO-synthase; and as connection: Aristolochia acid, an inhibitor of phospholipase A2.

Connection example 3: 4 groups of animals were:

group 1: treated with excipient + carrageenin;

group 2: treated with A (400 mg/kg) + carrageenin;

group 3: treated with (30 mg/kg) + carrageenin;

group 4: treated with AB + carragenin.

no group% inflammation
157,1±3,9
260,7±7,5
 NS
368±5,1
 NS
439,1±4,5
 **
(where: NS: angle of approach the result; **: highly indicative result)

The results show that aminoguanidine (an inhibitor of the inducible form of NO synthase) and arest the Hayseed acid inactive with regard to the protection of the animal from edema, caused by carrageenan. On the contrary, the combination of these two compounds in the highest degree significantly protects animals from edema caused by carrageenan.

Example 4

Compound AB is a combination of active principles a and b in separate form, and as compound A: 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolidinethione, a mixed inhibitor of the neuronal form of NO-synthase and lipid perechisleniya; and as connection: mepacrine, an inhibitor of phospholipase A2.

Connection example 4: 4 groups of animals were:

group 1: treated with excipient + carrageenin;

group 2: treated with A (30 mg/kg) + carrageenin;

group 3: treated with (30 mg/kg) + carrageenin;

group 4: treated with AB + carragenin.

no group% inflammation
151,5±2,2
252,8±4,0
 NS
351,9±2,7
 NS
437,4±4,6
 *
(where: NS: angle of approach the result; *: indicative result

In this case, while 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolidinethione (inhibitor of the neuronal form of NO-synthase and antioxidant) and mepacrine inactive with regard to the protection of the animal from edema caused by carrageenan, the combination of these two compounds significantly protects animals from edema caused by carrageenan.

Experimental results of examples 1, 2, 3 and 4, therefore, shows a synergistic effect between these two types of connections.

Conclusion

The results show that inhibtor NO-synthase and the inhibitor of phospholipase A2 inactive by themselves, have a synergistic anti-inflammatory effect when they are combined.

1. The method of treatment of diseases or disorders selected among inflammatory diseases, by simultaneous, separate or distributed in time applying at least one substance that inhibits NO synthase, and at least one substance that inhibits phospholipase A2.

2. The method according to claim 1, characterized in that the inhibiting NO synthase substance is inhibitory neuronal form of NO-synthase substance.

3. The method according to claim 1, characterized in that the inhibiting NO synthase inhibitory substance is inducible form of NO-si the pelvis substance.

4. The method according to any one of claims 1 to 3, characterized in that the inhibition of NO-synthase substance and inhibition of phospholipase A2 substance use in some form.

5. The method according to any one of claims 1 to 3, characterized in that the inhibition of NO-synthase substance and inhibition of phospholipase A2 substance use in salt form.

6. The method according to claim 5, characterized in that the salt is obtained from the derived inhibition of NO-synthase compounds containing at least one basic group, and a derivative inhibiting phospholipase A2 compounds containing at least one acid group.

7. The method according to any one of claims 1 to 6, characterized in that the inhibitor or inhibitors of NO-synthase selected from the group consisting of

the compounds of General formula (IA)

in which R1means one or more substituents selected from among a hydrogen atom and nitro group, halogen atom, alkyl or alkoxyl;

or pharmaceutically acceptable salt of this compound;

the compounds of General formula (IIA)

in which R1and R2denote independently a hydrogen atom or halogen atom, hydroxyl, amino, alkyl or alkoxy; or R1and R2linked together and form a phenyl fused with imidazole qi is scrap, moreover, the above-mentioned phenyl possibly substituted by one or more substituents selected among hydroxyl, trifloromethyl, halogen atom, carboxyl, alkyl, alkoxyl or alkenyl;

R3means a hydrogen atom or alkyl, amino group, alkylamino or phenyl, and phenyl possibly substituted by one or more substituents selected among hydroxyl, trifloromethyl, halogen atom, carboxyl, alkyl, lower alkoxyl or alkenyl; and

R4means a hydrogen atom or alkyl, amino group or alkylamino;

or pharmaceutically acceptable salt of this compound;

the compounds of General formula (IIIA)

in which R0means H or alkyl;

And means radical

in which R1and R2denote independently a hydrogen atom, a halogen atom, a group HE, a linear or branched alkyl with 1-6 carbon atoms, linear or branched alkoxy with 1-6 carbon atoms; and

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4where R4means alkyl with 1-6 carbon atoms;

or radical

in which R3oznacza the t hydrogen atom, linear or branched alkyl with 1-6 carbon atoms or the radical COR4where R4means alkyl with 1-6 carbon atoms;

In the mean linear or branched alkyl with 1-6 carbon atoms, phenyl, pyridinyl, or the five-membered heterocycle with 1 to 4 heteroatoms chosen among O, S, N, and in particular: thiophene, furan, pyrrole or thiazole, carbon atoms which can be substituted by one or more groups chosen among linear or branched alkyl with 1-6 carbon atoms, alkoxyl with 1-6 carbon atoms or halogen atom;

X is-CO-N (R3)-X’-, -NH-CO-X’-, -CH=, -CO -, or a bond, and X’ represents -(CH2)n-, where n means an integer from 0 to 6;

Y means Y’-, -CO-NH-Y’-, -Y-NH-CO-, -CO-Y’, -Y’-CO-, -N(R3)-Y’-, -Y’-N(R3)-, -Y’-CH2-N(R3)-CO-, -O-Y’-, -Y’-O-, -S-Y’-, -Y’-S-, -Y’-O-Y’-, -Y’-N(R3)-Y’- or a bond, and Y’ is -(CH2)n-, where n means an integer from 0 to 6;

Het means a heterocycle with 1 to 5 heteroatoms chosen among O, N, S, which can be substituted by one or more substituents X’-OR3X’-NR3X’-S-R3such as, for example: oxetan, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolan, piperazine, homopiperazine, 4-aminopiperidines, imidazolin, dihydroimidazole-2-it, digidroid Gasol-2-tion, oxazol, isoxazol, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, as 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidin, 1,2,4-triazole-3-one, tetrazol, tetrahydropyridine, azetidin;

or pharmaceutically acceptable salt of this compound;

the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine, aristolochias acids and their analogs, and pharmaceutically acceptable salts of these compounds.

8. The method according to any one of claims 1 to 6, characterized in that the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of compounds of General formula (IB) or (I’B)

in which R1 stands for a group-Yl-Ar-Y2-Y3, where Y1 and Y2 denote independently (C1-C12)-alkyl, (C1-C12)-alkenyl, (C1-C12-alkoxy or (C2-C12)-alkenylacyl, and the radicals Y1 and Y2, if necessary, can be interrupted by one or more oxygen atoms; AG means aryl, possibly substituted one - three substituents chosen independently among the groups R6, R7 and R8, and Y3 means the radical-COOR17, -CONR17R17, -CONHCOR19, -CONHS(O)2R19, -CONHNHS(O)2R19 or z;

R2 means-COOR17, -Y4-COOR17, -CONR17R17, -Y4-CONR17R17, CONHCOR19, -Y4-CONHCOR19, -CONHS(O)2R19, -Y4-CONHS(O) 2R19, -CONHNHS(O)2R19, -Y4-CONHNHS(O)2R19, Tz or CONHNHS(OH)2R19, -Y4-CONHNHS(OH)2R19, Tz or-Y4-Tz, and Y4 means (C1-C8)-alkyl, (C1-C8)-alkenyl, and the radical Y4, if necessary, may be interrupted by one or more oxygen atoms;

R3 means a radical-CO-R9 in which R9 means a radical-Y5, aryl or-Y5-aryl, and Y5 means (C1-C19)-alkyl, (C2-C19)-alkenyl or (C2-C19)-quinil, and the radical Y5, if necessary, may be interrupted by one or more oxygen atoms, and aryl of values of the radical R9 may be substituted for one - three substituents chosen independently among the groups R10, R11 and R12;

each radical R4 denotes independently a hydrogen atom, halogen atom, -CF3-Y6, aryl or-Y6-aryl, and Y6 means (C1-C8)-alkyl, (C2-C8)-alkenyl or (C1-C8)-quinil, and the radical Y6, if necessary, may be interrupted by one or more oxygen atoms, and aryl of values of the radical R4 can be substituted one-three substituents chosen independently among the groups R13, R14 and R15; and two adjacent alkyl radical Y6 together with the carbon atoms to which they are linked, can form a 5-8-membered cycle, which if necessary can be replaced by one and two (C 1-C4)-alkyl radicals;

n means the number 2; and

m means the number 4;

Tz means 1H - or 2H-tetrazol-5-yl;

the radicals R6, R7, R8, R10, R11, R12, R13, R14, R15 and R16 is chosen independently from the group consisting of (C1-C20)-alkyl, (C2-C20-alkenyl or (C2-C20)-quinil, possibly interrupted by one or more oxygen atoms; halogen atom, -CF3, -CN, -NO2or-COCH2OH and peralagan-(C1-C6-alkenyl, -OR17, -SR17, -COOR17, -COR18, -NHCOR17, -NR17R17, -NHS(O)2R17, -SOR17, -S(O)2R17, -CONR17R17, -S(O)2NR17R17, -OOCR18, -OOCNR17R17, -OOCOR17, -(CH2)rOR23, -(CH2)rSR23, -(CH2)rNHR23 or (CH2)sR20;

R17 means independently in each case, when it is present, the radical -(CH2)tR20 or one (C1-C20)-alkyl, (C2-C20-alkenyl or (C2-C20) -quinil, possibly interrupted by one or more oxygen atoms;

R18 denotes, independently, in each case, when it is present, the radical R17, -CF3, -(CH2)uCOOH or - (CH2)uCOOR21;

R19 means independently in each case, when it is present, the radical R17 or CF3;

R20 means independently in each case, when he has, aryl, substituted with one or two R22 groups;

R21 means independently in ka is the case, when it is present, (C1-C6)-alkyl, benzyl or phenyl;

R22 means independently in each case, when it is present, hydrogen atom, halogen atom, (C1-C12)-alkyl, (C1-C12-alkoxy, (C1-C12)-allylthiourea, (C1-C12)-alkylsulfonyl, (C1-C12-alkylsulphonyl, -CF3, -CN or-NO2;

R23 means independently in each case, when it is present, the hydrogen atom or the radical-COR21;

r is an integer from 1 to 20;

s and t denote, independently, integers from 0 to 12; and

u represents an integer from 0 to 4;

compounds of General formula (IIB)

in which both groups X means oxygen atoms;

R1 is chosen from the group consisting of radicals

in which R10 is chosen, independently include halogen atom and (C1-C10)-alkyl, (C1-C10)-alkoxyl, (C1-C10)ancilliary and (C1-C10)-halogenoalkane and

t stands for an integer from 0 to 5;

R2 is chosen among a halogen atom and cyclopropyl, methyl, ethyl or propyl;

R4 and R5 are chosen independently from among hydrogen atom, not interfering substituent, or (acidic) group-La- (acidic group), provided that-La- if the radical R4 is chosen among-O-CH 2-, -S-CH2, -NH-CH2-, -CH2-CH2-, -O-CH(CH3)- and-O-CH(CH2-CH2-RH)-, and Ph means phenyl, and-Lain the case of the radical R5 is chosen among the radicals

in which R84 and R85 is chosen independently from among hydrogen atom, halogen atom and (C1-C10)-alkyl, aryl, (C1-C10)-alkylaryl, aryl-(C1-C10)-alkyl, carboxyl or carbalkoxy;

provided that at least one of R4 and R5 must mean the group-La- (acidic group) and that (acid group) in the radicals R4 and R5 is chosen among-CO2H, -SO3N and-P(O)(OH)2;

R6 and R7 is chosen, independently, from among a hydrogen atom and not interfering substituent;

not interfering substituents chosen independently from the group consisting of (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, (C7-C18)-aralkyl, (C7-C18)-alkylaryl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, phenyl, toluyl, xylenyl, phenylmethyl, (C1-C6)-alkoxyl, (C2-C6-alkenylacyl, (C2-C6-alkyloxy, (C2-C12)-alkoxyalkyl, (C2-C12-alkoxyalkyl, (C2-C12-alkylcarboxylic, C 2-C12-alkoxyamino, (C2-C12)-alkoxycarbonyl, (C2-C12-alkylamino, (C1-C6-allylthiourea, (C2-C12)-alkylthiomethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonyl, (C2-C6)-halogenoalkanes, (C2-C6)-halogenallylacetic, (C2-C6)-halogenoalkane, (C1-C6)-hydroxyalkyl, -C(O)O((C1-C6)-alkyl), -(CH2)n-O-((C1-C6)-alkyl), benzyloxy, fenoxaprop, phenylthiourea, -Cho, amino, amidinopropane, bromine atom, carbamoyl, carboxyl, carbalkoxy, -(CH2)n-CO2H, chlorine atom, ceanography, cyanoguanidine, fluorine atom, guanidinium, hydrazide group, hydratherapy, gidrazidov, hydroxyl, hydroxyamino, iodine atom, nitro, phosphonopropyl, -SO3H, thioacetal group, thiocarbonyl and (C1-C6)-alkylsulphonyl, and

n means an integer from 1 to 8;

compounds of General formula (IIIB)

in which R1 is selected from groups (a), (b) and (C):

(a) means (C7-C20)-alkyl, (C7-C20-halogenated, (C7-C20)-alkenyl or (C7-C20)-quinil, saturated or unsaturated 5-14-member of the config carbocycle, possibly substituted by a Deputy or deputies, chosen among non-interfering substituents, or (a) means 5-14-membered heterocycle with 1-3 heteroatoms, with the above-mentioned heterocycle is saturated or unsaturated and possibly replaced by a Deputy or deputies, chosen among non-interfering substituents;

(b) means one of the radicals (a), substituted by one or more substituents selected among non-interfering substituents;

(c) means a group -(L1)-R11, in which (L1) means a group selected among the groups represented by the formula

in which Q1means the communication or one of the groups-CH2-, -O-, -S-, -NH - and-CO-, and each of the groups R10 denotes independently a hydrogen atom or a (C1-C8)-alkyl, (C1-C8-halogenated or (C1-C8-alkoxyl; and

R11 stands for a group selected among the groups (a) and (b);

R2 means a hydrogen atom, halogen atom or (C1-C4)-alkyl, (C1-C4)-alkenyl, -O- (C1-C3)-alkyl, -S-(C1-C3)-alkyl, (C1-C4-cycloalkyl, -CF3, -NO2, -CN or-SO3;

R3 means (L3) -Z, where

- (L3) means a group with a divalent linkage selected among communication and group is-CH 2-, -O-, -S-, -NH - and-CO-;

and

Z choose among acetamide, thioacetamide, glycylamino, thioglycollate, hydrazide or thiohydrazide groups represented by the General formula

in which R31 and R32 independently choose among a hydrogen atom and (C1-C8)-alkyl, (C1-C8)-halogenoalkane or (C3-C4)-cycloalkyl; and

X is, independently, in each case, when it is present, oxygen atom or sulfur;

R4 and R5 are chosen independently from among hydrogen atom, not interfering substituent, or the group - (La) -(arylsulfonamides group), in which

- (La- in the case of radical R4 means a group represented by the formula

in which Q2choose among-CH3-, -O-, -NH-, -C (O)- and-S-;

and each group R40 is chosen independently from among hydrogen atom, halogen atom and (C1-C8)-alkyl, aryl, (C1-C8)-alkylaryl, (C1-C8)-alkoxyl and aralkyl;

- (La)- in the case of the radical R5 is chosen among the groups represented by the formula

in which R54, R55, R56 and R57 is chosen independently from the group consisting of hydrogen atom, halogen atom and (C1-C8)-alkyl, (C1-C 8)-alkoxyl, (C1-C8)-halogenoalkane and aryl;

(arylsulfonamides) group is a group of the formula-CO-NH-SO2-R81, in which R81 is chosen from the group consisting of-CF3, (C1-C8)-alkyl, (C1-C8)-alkoxyl, (C1-C8-allylthiourea, (C1-C8-alkylamino, (C1-C8)-halogenoalkane, aryl-(C1-C14)-alkyl, (C1-C14)-alkylaryl, aryl, tiarella, (C3-C14)-cycloalkyl and 3-14-membered heterocycle, with the above-mentioned heterocycle comprises 1-3 heteroatoms and is saturated or unsaturated;

provided that at least one of R4 and R5 means a group - (La) -(arylsulfonamides group);

R6 and R7 denote independently a hydrogen atom, not interfering Deputy, saturated or unsaturated 5 to 14-membered carbocycle, possibly substituted by a Deputy or deputies, chosen among non-interfering substituents, or a 5-14-membered heterocycle with 1-3 heteroatoms, with the above-mentioned heterocycle is saturated or unsaturated and possibly replaced by a Deputy or deputies, chosen among non-interfering substituents;

not interfering substituents chosen, independently, from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C7-C12)-aralkyl, (C7-C12)-alkaryl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, (C1-C8)-alkoxyl, (C2-C8-alkenylacyl, (C2-C8-alkyloxy, (C2-C12)-alkoxyalkyl, (C2-C12-alkoxyalkyl, (C2-C12)alkylsulphonyl, (C2-C12-alkylcarboxylic, (C2-C12)alkoxyamino, (C2-C12)-alkoxycarbonyl, (C1-C12-alkylamino, (C1-C6-allylthiourea, (C2-C12)-alkylthiomethyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkylsulfonyl, (C2-C8)-halogenoalkanes, (C1-C8)-halogenallylacetic, (C2-C8)-halogenoalkane, (C1-C8)-hydroxyalkyl, -C(O)O((C1-C8)-alkyl), -(CH2)n-O-((C1-C8)-alkyl), benzyloxy, fenoxaprop, phenylthiourea, -CONHSO2R, -Cho, amino, amidinopropane, bromine atom, carbamoyl, carboxyl, carbalkoxy, -(CH2)n-CO2H, chlorine atom, ceanography, cyanoguanidine, fluorine atom, guanidinium, hydrazide group, hydratherapy, gidrazidov, hydroxyl, hydroxyamino, iodine atoms, nitro uppy, phosphonopropyl, -SO3H, thioacetal group, thiocarbonyl, and

n means an integer from 1 to 8; and

R means (C1-C8)-alkyl;

compounds of General formula (IVB)

in which R1 is chosen from the group consisting of a halogen atom and (C1-C6)-alkyl or (C1-C6)-alkoxyl;

R2 is chosen from the group consisting of one of the phenyl or benzyl radical, possibly substituted in the aromatic cycle, a halogen atom, or (C1-C6)-alkyl, (C1-C6-alkoxyl, amino group, alkylamino, dialkylamino, carboxyla, carbamoyl, (C1-C8)-acyl, sulfonyl, Tilney group or alkylthiol; and (C3-C7)-cycloalkyl and above (C3-C7-cycloalkyl may be condensed with a benzene cycle or heterocycle and may be substituted by a halogen atom or a (C1-C6)-alkyl;

R3 is chosen from the group consisting of a halogen atom and (C1-C6)-alkyl; and

R4 is chosen from the group consisting of-H, -OH, -N3and-NHCOCH3;

and pharmaceutically acceptable salts of the compounds of General formula (IB), (IIB), (IIIBor (IVB).

9. The method according to claim 1, characterized in that the inhibitor or inhibi the ora NO-synthase selected from the group consisting of L-nitroarginine (LNA), methyl ester of L-nitroarginine (LNAME), L-N-monomethylaniline (LNMMA), aminoguanidine, agmatine, 2-amino-1-(methylamino)-benzimidazole, 5-nitroindazole, 6-nitroindazole, 7 nitroindazole, 1,2-(triptoreline) imidazole (TRIM), 2-amino-4-methyl-6-(2-amino-ethyl)pyridine, 2-imino-piperidine, 2-aminoguanidine, 2-imino-5,6-dihydro-1,3-thiazine, 2-imino-5,6-dihydro-1,3-oxazine, N-phenyl-2-thiophenecarboxaldehyde, 2-aminomethylpyrimidine, S-utilizationfocused, S-methyl-L-thiocitrulline, 3-ethyl-L-thiocitrulline, (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxaldehyde and 4[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolidinone, as well as pharmaceutically acceptable salts of these compounds; and the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine and aristolochiae acids and their analogs, and pharmaceutically acceptable salts of these compounds.

10. The method according to claim 9, characterized in that the inhibitor or inhibitors of NO-synthase selected from the group consisting of aminoguanidine, 7 nitroindazole and 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino] phenyl}-N-methyl-2-thiazolidinone, as well as pharmaceutically acceptable salts of the above compounds; and the inhibitor or ing bitory phospholipase A2 is chosen from the group consisting of mepacrine and aristolochiae acids and their analogs, and pharmaceutically acceptable salts of these compounds.

11. The method according to any one of claims 1 to 10, characterized in that the pathology or disturbances choosing among inflammatory diseases, such as glomerulonephritis, psoriasis, rheumatoid arthritis and inflammation of the gastrointestinal system or pulmonary system and the respiratory tract.

12. Combination comprising at least one substance inhibiting NO synthase, and at least one substance inhibiting phospholipase A2, for use in the method according to claim 1.

13. The combination according to item 12, wherein the inhibiting NO synthase substance is inhibitory neuronal form of NO-synthase substance.

14. The combination according to item 12, wherein the inhibiting NO synthase inhibitory substance is inducible form of NO-synthase substance.

15. Combination according to any one of p-14, characterized in that the inhibition of NO-synthase substance and inhibition of phospholipase A2 substance use in some form.

16. Combination according to any one of p-14, characterized in that the inhibition of NO-synthase substance and inhibition of phospholipase A2 substance use in salt form.

17. The combination according to item 16, wherein the salt is obtained from the derived inhibition of NO-synthase compounds containing at least one OS the ESD group, and derived inhibition of phospholipase A2 compounds containing at least one acid group.

18. Combination according to any one of p-17, characterized in that the inhibitor or inhibitors of NO-synthase selected from the group consisting of

the compounds of General formula (IA)

in which R1means one or more substituents selected from among a hydrogen atom and nitro group, halogen atom, alkyl or alkoxyl;

or pharmaceutically acceptable salt of this compound;

the compounds of General formula (IIA)

in which R1and R2denote independently a hydrogen atom or halogen atom, hydroxyl, amino, alkyl or alkoxy; or R1and R2linked together and form a phenyl fused with imidazole cycle, and the above-mentioned phenyl possibly substituted by one or more substituents selected among hydroxyl, trifloromethyl, halogen atom, carboxyl, alkyl, alkoxyl or alkenyl;

R3means a hydrogen atom or alkyl, amino group, alkylamino or phenyl, and phenyl possibly substituted by one or more substituents selected among hydroxyl, trifloromethyl, halogen atom, carboxyl, alkyl, lower alkoxy is as or alkenyl; and

R4means a hydrogen atom or alkyl, amino group or alkylamino;

or pharmaceutically acceptable salt of this compound;

the compounds of General formula (IIIA)

in which R0means H or alkyl;

And means radical

in which R1and R2denote independently a hydrogen atom, a halogen atom, a group HE, a linear or branched alkyl with 1-6 carbon atoms, linear or branched alkoxy with 1-6 carbon atoms; and

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4where R4means alkyl with 1-6 carbon atoms;

or radical

in which R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4where R4means alkyl with 1-6 carbon atoms;

In the mean linear or branched alkyl with 1-6 carbon atoms, phenyl, pyridinyl, or the five-membered heterocycle with 1 to 4 heteroatoms chosen among O, S, N, and in particular: thiophene, furan, pyrrole or thiazole, carbon atoms which can be substituted by one or more groups chosen among linear mud is branched alkyl with 1-6 carbon atoms, alkoxyl with 1-6 carbon atoms or halogen atom;

X is-CO-N(R3)-X’-, -NH-CO-X’-, -CH=, -CO -, or a bond, and X’ represents -(CH2)n-, where n means an integer from 0 to 6;

Y means Y’-, -CO-NH-Y’-, -Y-NH-CO-, -CO-Y’-, -Y’-CO-, -N(R3)-Y’-, -Y’-N(R3)-, -Y’-CH2-N(R3)-CO-, -O-Y’-, -Y’-O-, -S-Y’-, -Y’-S-, -Y’-O-Y’, -Y’-N (R3)-Y’- or a bond, and Y’ is -(CH2)n-, where n means an integer from 0 to 6;

Het means a heterocycle with 1 to 5 heteroatoms chosen among O, N, S, which can be substituted by one or more substituents X’-OR3X’-NR3X’-S-R3such as, for example: oxetan, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolan, piperazine, homopiperazine, 4-aminopiperidines, imidazolin, dihydroimidazole-2-it, dihydroimidazole-2-tion, oxazol, isoxazol, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, as 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidin, 1,2,4-triazole-3-one, tetrazol, tetrahydropyridine, azetidin;

or pharmaceutically acceptable salt of this compound;

the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine, aristolochias acids and their analogs, and pharmaceutically acceptable what's salts of these compounds.

19. Combination according to any one of p-17, characterized in that the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of

compounds of General formula (IB) or (I’B)

in which R1 stands for a group-Y1-Ar-Y2-Y3, where Y1 and Y2 denote, independently, (C1-C12)-alkyl, (C1-C12)-alkenyl, (C1-C12-alkoxy or (C1-C12)-alkenylacyl, and the radicals Y1 and Y2, if necessary, can be interrupted by one or more oxygen atoms; AG means aryl, possibly substituted one - three substituents chosen independently among the groups R6, R7 and R8, and Y3 means the radical-COOR17, -CONR17R17, -CONHCOR19, -CONHS(O)2R19, -CONHNHS(O)2R19 or Tz;

R2 means-COOR17, -Y4-COOR17, -CONR17R17, -Y4-CONR17R17, CONHCOR19, -Y4-CONHCOR19, -CONHS(O)2R19, -Y4-CONHS(O)2R19, -CONHNHS(OH)2R19, -Y4-CONHNHS(OH)2R19, Tg or CONHNHS(OH)2R19, -Y4-CONHNHS(OH)2R19, Tz or-Y4-Tz, and Y4 means (C1-C8)-alkyl, (C2-C8)-alkenyl, and the radical Y4, if necessary, may be interrupted by one or more oxygen atoms;

R3 means a radical-CO-R9 in which R9 means a radical-Y5, aryl or-Y5-aryl, and Y5 means (C1-C19)-alkyl, (C2-C19)-alkenyl or (C2-C19)-quinil, and the radical Y5, think the bridges, may be interrupted by one or more oxygen atoms, and aryl of values of the radical R9 may be substituted for one - three substituents chosen independently among the groups R10, R11 and R12;

each radical R4 denotes, independently, a hydrogen atom, halogen atom, -CF3-Y6, aryl or-Y6-aryl, and Y6 means (C1-C8)-alkyl, (C2-C8)-alkenyl or (C1-C8)-quinil, and the radical Y6, if necessary, may be interrupted by one or more oxygen atoms, and aryl of values of the radical R4 can be substituted one-three substituents chosen independently among the groups R13, R14 and R15; and two adjacent alkyl radical Y6 together with the carbon atoms to which they are linked, can form a 5-8-membered cycle, which if necessary may be substituted by one or two (C1-C4)-alkyl radicals;

n means the number 2; and

m means the number 4;

Tz means 1H - or 2H-tetrazol-5-yl;

the radicals R6, R7, R8, R10, R11, R12, R13, R14, R15 and R16 is chosen independently from the group consisting of (C1-C20)-alkyl, (C2-C20-alkenyl or (C2-C20)-quinil, possibly interrupted by one or more oxygen atoms; halogen atom, -CF3, -CN, -NO2or-PINES2HE and peralagan-(C1-C6-alkenyl, -OR17-SR17, -COOR17, -COR18, -NHCOR17, -NR17R17, -NHS(O)2R17, -SOR17, -S(O)2R17, -CONR17R17, -S(O)2NR17R17, -OOCR18, -OOCNR17R17, -OOCOR17, -(CH2)rOR23, -(CH2)rSR23, - (CH2)rNHR23 or (CH2)sR20;

R17 means independently in each case, when it is present, the radical -(CH2)tR20 or one (C1-C20)-alkyl, (C2-C20-alkenyl or (C2-C20)-quinil, possibly interrupted by one or more oxygen atoms;

R18 means independently in each case, when it is present, the radical R17, -CF3, -(CH2)uCOOH or - (CH2)uCOOR21;

R19 means independently in each case, when it is present, the radical R17 or CF3;

R20 means independently in each case, when he has, aryl, substituted with one or two R22 groups;

R21 means independently in each case, when it is present, (C1-C6)-alkyl, benzyl or phenyl;

R22 means independently in each case, when it is present, hydrogen atom, halogen atom, (C1-C12)-alkyl, (C1-C12-alkoxy, (C1-C12)-allylthiourea, (C1-C12)-alkylsulfonyl, (C1-C12-alkylsulphonyl, -CF3, -CN or-NO2;

R23 means independently in each case, when it is present, the hydrogen atom or the radical-COR21;

r is an integer from 1 to 20;

< num="360"> s and t denote, independently, integers from 0 to 12; and

u represents an integer from 0 to 4;

compounds of General formula (IIB)

in which both groups X means oxygen atoms;

R1 is chosen from the group consisting of radicals

and in which R10 is chosen independently include halogen atom and (C1-C10)-alkyl, (C1-C10)-alkoxyl, (C1-C10)ancilliary and (C1-C10)-halogenoalkane and

t stands for an integer from 0 to 5;

R2 is chosen among a halogen atom and cyclopropyl, methyl, ethyl or propyl;

R4 and R5 are chosen independently from among hydrogen atom, not interfering substituent, or (acidic) group-La- (acidic group), provided that-Lain the case of the radical R4 is chosen among-O-CH2-, -S-CH2-, -NH-CH2-, -CH2-CH2-, -O-CH(CH3)- and-O-CH(CH2-CH2-RH)-, and Ph means phenyl, and-Lain the case of the radical R5 is chosen among the radicals

in which R84 and R85 is chosen independently from among hydrogen atom, halogen atom and (C1-C10)-alkyl, aryl, (C1-C10)-alkylaryl, aryl-(C1-C10)-alkyl, carboxyl or carbalkoxy;

when the service is provided that at least one of R4 and R5 must mean the group-La- (acidic group) and that (acid group) in the radicals R4 and R5 is chosen among-CO2H, -SO3N and-P(O)(OH)2;

R6 and R7 independently choose among a hydrogen atom and not interfering substituent;

not interfering substituents chosen independently from the group consisting of (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, (C7-C18)-aralkyl, (C7-C18)-alkylaryl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, phenyl, toluyl, xylenyl, phenylmethyl, (C1-C6)-alkoxyl, (C2-C6-alkenylacyl, (C2-C6-alkyloxy, (C2-C12)-alkoxyalkyl, (C2-C12-alkoxyalkyl, (C2-C12-alkylcarboxylic, (C2-C12-alkoxyamino, (C2-C12)-alkoxycarbonyl, (C2-C12-alkylamino, (C1-C6)ancilliary, (C2-C12)-alkylthiomethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonyl, (C2-C6)-halogenoalkanes, (C2-C6)-halogenallylacetic, (C2-C6)-halogenoalkane, (C1-C6)-hydroxyalkyl, -C(O)O((C1-C6)-alkyl), -(CH2 )n-O-((C1-C6)-alkyl), benzyloxy, fenoxaprop, phenylthiourea, -Cho, amino, amidinopropane, bromine atom, carbamoyl, carboxyl, carbalkoxy, -(CH2)n-CO2H, chlorine atom, ceanography, cyanoguanidine, fluorine atom, guanidinium, hydrazide group, hydratherapy, gidrazidov, hydroxyl, hydroxyamino, iodine atom, nitro, phosphonopropyl, -SO3N, thioacetal group, thiocarbonyl and (C1-C6)-alkylsulphonyl, and

n means an integer from 1 to 8;

compounds of General formula (IIIB)

in which R1 is selected from groups (a), (b) and (C):

(a) means (C7-C30)-alkyl, (C7-C30-halogenated, (C7-C20)-alkenyl or (C7-C20)-quinil, saturated or unsaturated 5 to 14-membered carbocycle, possibly substituted by a Deputy or deputies, chosen among non-interfering substituents, or (a) means 5-14-membered heterocycle with 1-3 heteroatoms, with the above-mentioned heterocycle is saturated or unsaturated and possibly replaced by a Deputy or deputies, chosen among non-interfering substituents;

(b) means one of the radicals (a), substituted by one or more substituents, selected the mi among non-interfering substituents;

(c) means a group -(L1)-R11, in which (L1) means a group selected among the groups represented by the formula

in which Q1means the communication or one of the groups-CH2-, -O-, -S-, -NH - and-CO-, and each of the groups R10 denotes independently a hydrogen atom or a (C1-C8)-alkyl, (C1-C8-halogenated or (C1-C8-alkoxyl; and

R11 stands for a group selected among the groups (a) and (b);

R2 means a hydrogen atom, halogen atom or (C1-C4)-alkyl, (C1-C4)-alkenyl, -O- (C1-C3)-alkyl, -S-(C1-C3)-alkyl, (C1-C4-cycloalkyl, -CF3, -NO2, -CN or-SO3;

R3 means (L3) -Z, where

(L3) means a group with a divalent linkage selected among communication and group-CH2-, -O-, -S-, -NH - and-CO-; and

Z choose among acetamide, thioacetamide, glycylamino, thioglycollate, hydrazide or thiohydrazide groups represented by the General formula

in which R31 and R32 independently choose among a hydrogen atom and (C1-C8)-alkyl, (C1-C8)-halogenoalkane or (C3-C4)-cycloalkyl; and

X is independently in each case, when it is present, the oxygen atom is or sulfur;

R4 and R5 are chosen independently from among hydrogen atom, not interfering substituent, or the group - (La) -(arylsulfonamides group), in which

- (La- in the case of radical R4 means a group represented by the formula

in which Q2 is chosen among-CH3-, -O-, -NH-, -C(O)- and-S-;

and each group R40 is chosen independently from among hydrogen atom, halogen atom and (C1-C8)-alkyl, aryl, (C1-C8)-alkylaryl, (C1-C8)-alkoxyl and aralkyl;

- (La- in the case of the radical R5 is chosen among the groups represented by the formula

in which R54, R55, R56 and R57 is chosen independently from the group consisting of hydrogen atom, halogen atom and (C1-C8)-alkyl, (C1-C8)-alkoxyl, (C1-C8)-halogenoalkane and aryl;

(arylsulfonamides) group is a group of the formula-CO-NH-SO2-R81, in which R81 is chosen from the group consisting of-CF3(C1-C8)-alkyl, (C1-C8)-alkoxyl, (C1-C8-allylthiourea, (C1-C8-alkylamino, (C1-C8)-halogenoalkane, aryl-(C1-C14) -alkyl, (C1-C14)-alkylaryl, aryl, tiarella, (C3-C14)-cycloalkyl and 3-14 membered of heteros the KLA, moreover, the above-mentioned heterocycle comprises 1-3 heteroatoms and is saturated or unsaturated;

provided that at least one of R4 and R5 means a group - (La) -(arylsulfonamides group);

R6 and R7 denote independently a hydrogen atom, not interfering Deputy, saturated or unsaturated 5 to 14-membered carbocycle, possibly substituted by a Deputy or deputies, chosen among non-interfering substituents, or a 5-14-membered heterocycle with 1-3 heteroatoms, with the above-mentioned heterocycle is saturated or unsaturated and possibly replaced by a Deputy or deputies, chosen among non-interfering substituents;

not interfering substituents chosen independently from the group consisting of (C1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C7-C12)-aralkyl, (C7-C12)-alkaryl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, (C1-C8)-alkoxyl, (C2-C8-alkenylacyl, (C2-C8-alkyloxy, (C2-C8)-alkoxyalkyl, (C2-C12-alkoxyalkyl, (C2-C12)alkylsulphonyl, (C2-C12-alkylcarboxylic, (C2-C12)alkoxyamino the group, (C2-C12)-alkoxycarbonyl, (C2-C12)alkylamino, (C1-C6-allylthiourea, (C2-C12)-alkylthiomethyl, (C1-C8)-alkylsulfonyl, (C1-C8)-alkylsulfonyl, (C2-C8)-halogenoalkanes, (C1-C8)-halogenallylacetic, (C2-C8)-halogenoalkane, (C1-C8)-hydroxyalkyl, -C(O)O((C1-C8)-alkyl), -(CH2)n-O-((C1-C8)-alkyl), benzyloxy, fenoxaprop, phenylthiourea, -CONHSO2R, -Cho, amino, amidinopropane, bromine atom, carbamoyl, carboxyl, carbalkoxy, - (CH2)n-CO2H, chlorine atom, ceanography, cyanoguanidine, fluorine atom, guanidinium, hydrazide group, hydratherapy, gidrazidov, hydroxyl, hydroxyamino, iodine atom, nitro, phosphonopropyl, -SO3N, thioacetal group, thiocarbonyl, and

n means an integer from 1 to 8; and

R means (C1-C8)-alkyl;

compounds of General formula (IVB)

in which R1 is chosen from the group consisting of a halogen atom and (C1-C6)-alkyl or (C1-C6)-alkoxyl;

R2 is chosen from the group consisting of one of the phenyl or benzyl radical, possibly substituted what's in the aromatic cycle, a halogen atom, or (C 1-C6)-alkyl, (C1-C6-alkoxyl, amino group, alkylamino, dialkylamino, carboxyla, carbamoyl, (C1-C8)-acyl, sulfonyl, Tilney group or alkylthiol; and (C3-C7)-cycloalkyl and above (C3-C7-cycloalkyl may be condensed with a benzene cycle or heterocycle and may be substituted by a halogen atom or a (C1-C6)-alkyl;

R3 is chosen from the group consisting of a halogen atom and (C1-C6)-alkyl; and

R4 is chosen from the group consisting of-H, -OH, -N3and the N3;

and pharmaceutically acceptable salts of the compounds of General formula (IB), (IIB), (IIIBor (IVB).

20. The combination indicated in paragraph 12, characterized in that

the inhibitor or inhibitors of NO-synthase selected from the group consisting of L-nitroarginine (LNA), methyl ester of L-nitroarginine (LNAME), L-N-monomethylaniline (LNMMA), aminoguanidine, agmatine, 2-amino-1-(methylamino)-benzimidazole, 5-nitroindazole, 6-nitroindazole, 7 nitroindazole, 1,2-(triptoreline) imidazole (TRIM), 2-amino-4-methyl-6-(2-amino-ethyl)pyridine, 2-imino-piperidine, 2-aminoguanidine, 2-imino-5,6-dihydro-1,3-thiazine, 2-imino-5,6-dihydro-1,3-oxazine, N-phenyl-2-thiophenecarboxaldehyde, 2-aminomethylpyrimidine, S-utilizationfocused, S-methyl-L-tizit Ullin, S-ethyl-L-thiocitrulline, (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxaldehyde and 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2 diazomethylene, as well as pharmaceutically acceptable salts of these compounds; and

the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine and aristolochiae acids and their analogs, and pharmaceutically acceptable salts of these compounds.

21. The combination according to claim 20, characterized in that the inhibitor or inhibitors of NO-synthase selected from the group consisting of aminoguanidine, 7 nitroindazole and 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolidinone, as well as pharmaceutically acceptable salts of the above compounds; and the inhibitor or inhibitors of phospholipases A2 are selected from the group consisting of mepacrine and aristolochiae acids and their analogues, and also pharmaceutically acceptable salts of these compounds.



 

Same patents:

FIELD: medicine, cardiology.

SUBSTANCE: along with injecting antiarrhythmic remedy one should introduce varfarin at the dosage of 1-5 mg for 6-8 d followed by a maintenance course in 1-1.5 mo at the dosage of 2-3 mg for 6-7 d and in 2-3 mo at the dosage of 1-2 mg for 5-7 d.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, surgery.

SUBSTANCE: medicinal mixture consisting of 10 ml 0.25%-novocaine, 1 ml 1%-emoxypin and 64 c.u. lidase should be injected strictly subcutaneously per 1 ml for each point of injection into the center of plantar surface of nail phalanx of every toe, and for the first inter-toe space - subcutaneously in plantar and rear directions, then, after injections, it is necessary to carry out massage in area if injection with stretching and stroking movements in proximal direction for 10-15 sec, moreover curative seances should be performed every other day , the course being of 5-10 procedures, at repeating this course 3-6 mo later. The present innovation enables to activate transcapillary exchange due to pathogenetically proved impact onto surface and deep lymphatic network of inferior limbs.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves inducing angina pectoris attack on no medicament background. Provoking factor action time is measured to the moment the angina pectoris attack takes place. Nitroglycerine is administered in therapeutic dose to reach rapid relief of symptoms. The provoking factor action is repeated to reproduce attack of the same intensity. Provoking factor action time is measured once more. Prediction coefficient K value is calculated as ratio of the repeated provoking factor action time to the provoking factor action time to the moment the angina pectoris attack takes place. Prognosis is considered to be favorable, unfavorable or uncertain during the nearest year depending on K value.

EFFECT: high accuracy in evaluating coronary reserve.

2 tbl

FIELD: medicine, biochemistry.

SUBSTANCE: invention proposes applying CDP-choline (cytidinediphosphocholine) or its salt as a prophylactic agent for treatment of cerebral ischemia and a method for such prophylactic treatment. Invention found new and unknown early mechanism of action of CDP-choline or its salt: inhibition of activation of caspase cascade being the effectiveness of this effect is high in prophylactic intake of drug.

EFFECT: valuable medicinal properties of agent.

6 cl, 5 dwg, 4 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention relates to treatment of patients with post-infarct cardiosclerosis with circulation insufficiency of functional class 2. Method involves using diltiazem with individual setting doses. Method involves carrying out the simplified 2 h oral tolerance test to glucose. Diltiazem is prescribed in the initial dose 90 mg and in the maintenance dose 45 mg in positive result of test. In negative result of test diltiazem is prescribed in the initial dose 180 mg and in the maintenance dose 90 mg. Method provides enhancing effectiveness in treatment of patients with post-infarct cardiosclerosis with circulation insufficiency due to the more precise individual setting dose of the preparation and reducing frequency in arising adverse effects.

EFFECT: improved method for setting, enhanced effectiveness of treatment.

2 tbl, 2 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention, in particular, relates to prolonged therapeutical form of domestic slow calcium channel blocker, namely ankardin-retard-AZIn (active principle 7,7-ethylenedioxybenzopyran-2,2-dione) in the form of 0.1% solution administered in dose 1 ml in the form of complex with poly(ethylene oxide) 400. Pre-clinical investigations indicated that Ankardin-retard-AZIn was a sufficiently active calcium ion antagonist and, after clinical investigations, it could be applied in medical practice for prevention and treatment of cardiovascular diseases.

EFFECT: extended choice of drugs.

6 tbl, 4 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with preventing and treating oxygen deficiency due to applying birch bark extract to increase body resistance to oxygen deficiency. Moreover, the above-mentioned extract could be applied at treating diseases accompanying oxygen deficiency. Birch bark extract provides more efficient prophylaxis and therapy of oxygen deficiency.

EFFECT: higher efficiency of application.

4 cl, 2 ex, 2 tbl

FIELD: pharmaceutics, medicine.

SUBSTANCE: the present innovation deals with cardiotherapy for treating and preventing coronary deficiency. The preparation is designed as a plate (film) consisted of three layers, each of them is manufactured out of co-polymer of vinyl pyrrolidone, acrylamide and nitroglycerin-containing ethylacrylate; moreover, internal layer additionally contains solid fat - cacao oil, and weight ratio for the sum of external layers to internal corresponds to 1 : 1. The suggested preparation could additionally contain brilliant green dyestuff. The preparation should be manufactured out of pre-obtained mixture of nitroglycerin and copolymer in solution of alcohol and water followed by layer-by-layer forming three-layer film due to spreading the mixture onto solid bottom plate and drying at 30-50 C. The innovation provides higher adhesion to gingival mucosal surface, decreased side action, improved bioavailability and stability of therapeutic effect.

EFFECT: higher efficiency of therapy.

3 cl, 3 ex

FIELD: medical engineering.

SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.

EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.

3 cl

FIELD: medicine, oncology, chemical-pharmaceutical industry and technology, pharmacy.

SUBSTANCE: tablet with antitumor effect contains acceptable carrier on which the following mixture of aqueous-alcoholic tinctures is applied: bloody geranium, penny-cress, common cocklebur and European wild ginger. Tablets by mass 1 g including slipping substance contains the following amounts of indicated tinctures as measure for dry matters, g: bloody geranium, 0.015-0.020; penny-cress, 0.011-0.015; common cocklebur, 0.011-0.017, and European wild ginger, 0.024-0.036. Method for preparing tablet involves applying on carrier the mixture of aqueous-alcoholic tinctures of above indicated plants, the following drying the prepared mass, its granulating and tableting. Method for prophylaxis and treatment of oncological patients involves prescription 0.5-2 tablets with oncological designation, tree times per a day and the treatment course is determined individually based on objective data of treatment. Tablet made by claimed methods shows complex properties: it delays tumor growth and metastazing and can be recommended for treatment and prophylaxis of oncological pathology both independently and in combination with chemo-radiation therapy. Invention can be used in technology for making medicinal formulations of preparations with oncological designation and for treatment of patients with oncological pathology of different organs and body systems.

EFFECT: improved for making tablet, valuable medicinal properties of tablet.

7 cl, 4 ex

FIELD: medicine, oncology, chemical-pharmaceutical technology, pharmacology, pharmacy.

SUBSTANCE: tablet eliciting the antitumor effect comprises active dose of aconite alkaloids in the amount 0.0125-0.0375 mg. Invention relates to a method for making tablet with antitumor effect. Method involves treatment suitable carrier taken in the amount corresponding to the content of alkaloids in tablet 0.0125-0.0375 mg with aconite tincture wherein amount of the total content of alkaloids is determined preliminary. Then carrier treated by such manner is dried at temperature 30-35°C, not above, granulated, granules are powdered and tableted. Also, invention relates to a method for treatment of oncological patients that involves prescription to patient 0.5-2 tablets with oncological designation being this treatment is determined individually. Invention can be used in manufacturing medicinal formulations of preparations used for treatment of patients with oncological pathology.

EFFECT: improved method for treatment and making, valuable medicinal properties of tablet.

8 cl, 2 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds - pluraflavines of the formula (I): wherein R1 represents sugar group of the formula: ; R2 represents -COOH or -CH2-O-(R7)m wherein R7 represents sugar group of the formula: ; R3 is taken among the groups: and , and to all its stereochemical forms and mixtures of indicated forms in any ratio, and to their physiologically acceptable salts; R5 means hydrogen atom; R4 and R6 represent in common group -X2 with a double bond wherein X2 means oxygen atom (O); R8 and R10 represent in common group -X2 with a double bond wherein X2 means oxygen atom (O), and m = n = 1, and to all its stereochemical forms and mixtures of indicated forms in any ratio and to its physiologically acceptable salts. Invention relates to a method for preparing these compounds from culture of microorganism actinomycetes HAG 003959, DSM 12931 by fermentation, to the strain Actinomycetales HAG 003959, DSM 12931 used for preparing compounds of the formula (I) and to pharmaceutical composition inhibiting transcriptase activity and eliciting cytotoxic effect based on above said compounds. Compounds of the formula (I) are used as medicinal agents, for example, as antitumor agents.

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

19 cl, 3 tbl, 12 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with inhibiting the growth of host's cerebral tumors. It deals with introducing therapeutically efficient quantity of integrin αv antagonists being cyclo(Arg-Gly-Asp-D-Phe-[N-Me]-Val). The innovation enables to considerably inhibit cerebral oncogenesis in vivo, moreover, despite antiangiogenesis, due to induction of direct lethality of tumor cells.

EFFECT: higher efficiency of inhibition.

9 dwg, 2 tbl

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for assay of efficacy on post-operative intrathecal chemotherapy of patients with intracerebral malignant tumors. Method involves determination of total protein level in cerebrospinal fluid before and after carrying out chemotherapy in autoliquor. Increase of the level of total protein by 5.6-6.3 times indicates on effectiveness of the post-operative chemotherapy. Method provides the objective evaluating dynamic of cytolysis of tumor cells that is the reliable method for estimation of efficacy of indicated treatment.

EFFECT: enhanced and improved method for treatment.

1 ex

FIELD: experimental medicine, oncology, biology.

SUBSTANCE: invention relates to a method for inhibition of tumor growth using radiation therapy as ionizing radiation with additional administration of mixture of octa-4,5-carboxyphthalocyanine sodium cobalt salt or oxocobalamine with sodium ascorbate in the ratio = (1:10)-(1:30). Method of combined using irradiation and indicated mixture of substances provides enhancing the effectiveness of anti-tumor treatment resulting to 70-100% recovery of experimental animals and reducing radiation loading and toxicity.

EFFECT: improved method for inhibition.

2 tbl, 3 dwg, 3 ex

FIELD: medicine, oncology.

SUBSTANCE: method involves surgery treatment and chemotherapy. In preoperative period 150 ml of blood is taken off in patients, blood is centrifuged for separating for plasma and formed elements. Standard dose of cytostatic agent is separated and placed into the first flask with 20-40 ml of autoplasma and remained plasma part and formed elements are placed into the second flask. Flasks are incubated separately for 40 min at 37°C followed by carrying out a procedure when blood incubated with the chemopreparation from the second flask is administrated by intravenous route by drops. After removing tumor its bed in infiltrated with autoplasma incubated with the chemopreparation from the first flask or autoplasma with the chemopreparation are added in blood vessels in zone of regional blood supply of tumor. Method provides reducing frequency of topical relapses and alienated metastasis after surgery treatment of solid tumors and shows low toxicity. Invention can be used in the complex cancer treatment, in particular, regionally distributed cancer in large intestine and mammary glands.

EFFECT: enhanced effectiveness of treatment.

3 ex

FIELD: medicine.

SUBSTANCE: the method deals with 2 courses of polychemotherapy at the first stage due to regional intra-arterial introduction of cisplatin at the dosage of 100 mg/m2 during the first day of every course and 6-h-long intra-arterial infusion of 5-fluorouracil at total dose of 750 mg/m2 in the morning since the 2nd to the 6th d of every course. Chemotherapy should be performed at the background of total magnetotherapy at frequency of magnetic field being 98-112 Hz, intensity of 25-30 oersted, duration of every seance being 30 min, the number of seances corresponds to the duration of chemotherapeutic courses. At the second stage in 2-3 wk after finishing chemotherapy it is necessary to conduct the course of distance radiation therapy (DRT) at multifractioning the dosage by SFD being 1.2 Gy twice daily 5 times weekly up to TFD being equivalent to TDF (time-dosage-fraction) of 62-70 Gy onto primary focus and 40-46 Gy onto areas of regional lymph outflow. As modifiers one should apply cisplatin during the first 2 wk of radiation therapy, hyperbaric oxygenation during the first 10 d of radiation therapy and total magnetotherapy since the 11th d of DRT course till its ending. At the third stage in case of residual metastases in lymph nodes of patient's neck in 2-3 wk after the end of radiation therapy one should conduct operative interference in lymph outflow pathways. The method enables to decrease toxicity of chemo-and radiation therapy due to decreased radiation reactions, stimulation of immune system and improved microcirculation.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5,7-diones of the general formula (1)

wherein: -R1 means residue of mono- or disaccharide in pyranose form taken among the group: D-Rib, L-Ara, D-Xyl, D-Gal, D-Glc, D-Lac; -R2 means hydrogen atom, methyl group or residue of mono- or disaccharide; -R3 means hydrogen atom, hydroxyl group, amino-group or formamido-group; each -X1 and -X2 means independently of one another hydrogen atom or bromine atom under condition that they can't mean hydrogen atom simultaneously and under condition also that if R1 means disaccharide residue then R2 differs from hydrogen atom. Prepared derivatives show, in particular, cytotoxic and antitumor activity against melanoma B16 and Ehrlich tumor.

EFFECT: valuable medicinal properties of derivatives.

3 cl, 3 tbl, 2 dwg, 8 ex

FIELD: veterinary virology, biotechnology.

SUBSTANCE: method involves using virus-containing material of rabbit myxoma virus of the strain "B-82" prepared on transplantable strain of cells of line RK-13 on nutrient medium without addition of serum under stationary conditions for 48-72 h, at temperature 33°C and pH value 7.2-7.4. Material is mixed with protective medium in the volume ratio 85:15 and lyophilized. Method provides simplifying process in preparing vaccine and to standardize a method for preparing vaccine against rabbit myxomatosis based on the strain "B-82" grown on transplantable cell line, and also reducing cost and simplifying the technological process.

EFFECT: improved method for preparing.

2 ex

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