New derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

 

(57) Abstract:

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease. New derivatives of barbituric acid correspond to the General formula I, in which X, Y, Z is oxygen, R1represents the group W-V, where W is a valence bond or straight or branched C1-C4is an alkyl group, V is a monocycle selected from optionally substituted phenyl, pyridyl, piperidyl, thiophenyl, imidazolyl, or bicyclo selected from naphthyl, chinoline, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole or indolyl, each of which may be substituted, or W-V is an optionally substituted C1-C20is an alkyl group, R2, R3are both hydrogen, R4, R5denote independently of each A-D where a and D have different meanings indicated in the claims, or R4, R5together with the nitrogen atom to which they are linked, form a ring which may optionally interrupted by N atom and may be substituted as specified in the claims. The pharmaceutical composition of vklyuchaesh. 3 s and 5 C.p. f-crystals, 2 PL.

In normal tissue there is a balance between synthesis and degradation. Extracellular matrix is degraded under the influence of proteases that belong to at least three groups of matrix metalloprotease. This collagenase, gelatinase and stromelysin. OK there are specific inhibitors of these catabolic enzymes such as2macroglobulin and DFID (=tissue inhibitor of metalloprotease DFID), thus, excessive degradation of the extracellular matrix occurs. Related proteases group are Adamantine. Well-known member of the group agamaliev is TACE (TNF--converting enzyme).

Characterized by at least 11 different and yet vysokomolochnyh kinds of MMP, including interstitial fibroblast collagenase (MMP-1, HFC), neutrophil collagenase (MMP-8, HNC), two gelatinase, stromelysin (such as the HSL-1) and HPUMP (as a recent review see Birkedal-Hansen, N. Moore, W. G. I., Bodden, M. K., Windsor, L. J., Birkedal-Hansen, B., DeCarlo, A., Engler, J. A., Critical Rev. Oral Biol. Med. (1993), 4, 197-250. These proteases have a number of similar structural and functional characteristics, but differ in their specificity towards the substrate. Only HNC and HFC capable of splitting the length native circuit. This leads to the lowering of the melting temperature of collagen and makes them available for subsequent exposure to other matrix-splitting enzymes.

However, uncontrolled excessive degradation of this matrix represents a characteristic feature of many pathological conditions, for example, included in the clinical picture of rheumatoid arthritis, osteoarthritis, multiple sclerosis, takes place during the formation of tumor metastasis, corneal ulcer, inflammatory diseases and infestations, and diseases of bones and teeth.

It can be assumed that the introduction of inhibitors of matrix metalloprotease will favorably affect the pathogenesis of these diseases. Currently, a number of compounds known in the literature (see, for example, the review article by Nigel R. A., Beeley et al. Curr. Opin ther. Patents 4 (1), 7, (1994), or they are described in the patent literature, mainly peptides with the rest of the hydroxamic acid, a thiol or phosphine group as a group that binds zinc, (see , for example, among other WO-A-9260/9563 from Glycomed, EP-A-497192 from Hoffman-LaRoche, WO-A-9005719 from British Biotechnology, EP-A-489577 from Celltech, EP-A-320118 from Beecham, US-A-4595700 from Searle).

Some of these compounds have high activity as inhibitable new derivatives of barbituric acid is very effective as inhibitors of matrix metalloprotease and have good oral availability.

Therefore, the present invention relates to substances of General formula I

< / BR>
in which X, Y and Z are oxygen,

R1represents the group W-V, in which

W is a valence bond or straight or branched C1-C4is an alkyl group,

V is a monocycle selected from phenyl, optionally substituted by hydroxy, lower alkyl, lower alkoxy, phenyl, phenoxy; pyridyl, piperidinyl, thiophenyl, imidazolyl or bicyclo selected from naphthyl, chinoline, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, indolyl, each of which may be substituted, or

W-V is a C1-C20is an alkyl group optionally substituted by amino, hydroxy, lower allmineral, carboxypropyl, aminocarbonyl, lower alkylaminocarbonyl, aminocarbonyl-dissimilyatornaya, lower alkyl, lower alkoxyl, lower alkoxyalkyl,

R2and R3both are hydrogen,

R4and R5denote independently of each A-D, where And carboxamido, alkoxycarbonyl, amino or aminocarbonyl, optional one or two times substituted lower alkyl, nitrile, exography, thiocarboxanilide, their pharmacologically acceptable salts or their esters of carboxylic acids,

provided that

when-NR4R5is unsubstituted piperidine ring, then R1can not be phenyl, stands, ethyl, propylene, alkyl or crotonyl and when-NR4R5is diethylaminopropyl, then R1may not be the stands, ethyl or crotonyl.

Preferred are the following compounds of formula I:

The compound of the formula I, in which the monocycle G denotes phenyl, pyridyl, pyrimidinyl or pyridazinyl.

The compound of the formula I, in which W, R1denotes the methyl radical, ethyl or butyl; V denotes the radical phenyl, pyridyl, imidazolyl

or

W-V denotes the radicals n-octyl, n-decyl or biphenyl.

The compound of the formula I, in which nitrogen, R4and R5form a piperazine or piperidine, both of which are substituted at the 4 - position.

The compound of formula I, which represents 5-(4'-biphenyl)-5-[N-(4-nitrophenyl) piperazinil] barbituric acid.

The object of the invention is also a pharmaceutical composition having activity inhibitor of matrix metalloprotease, including at least one joint

The invention relate to compounds of formula I:

in which

X, Y and Z are oxygen,

R1represents the group W-V, in which

W is a valence bond or straight or branched C1-C4is an alkyl group,

V is a monocycle selected from phenyl, optionally substituted by hydroxy, lower alkyl, lower alkoxy, phenyl, phenoxy; pyridyl, piperidinyl, thiophenyl, imidazolyl or bicyclo selected from naphthyl, chinoline, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, indolyl, each of which may be substituted, or

W-V is a C1-C20is an alkyl group optionally substituted by amino, hydroxy, lower allmineral, carboxypropyl, aminocarbonyl, lower alkylaminocarbonyl, aminocarbonyl-dissimilyatornaya, lower alkyl, lower alkoxyl, lower alkoxyalkyl,

R2and R3both are hydrogen,

R4and R5denote independently of each A-D, where a represents a bond, C1-C8-alkyl, C1-C4-acyl, which may be interrupted by heteroatoms, selected from O, SO2and in which the alkyl group may be substituted AMI the ikl, selected from phenyl, pyridyl, piperidinyl, cyclohexyl, furil, imidazolyl, pyrrolidinyl, thiophenyl, or bicycl selected from naphthyl, indolyl, tetrahydroquinoline, fluorenyl, each of which may be substituted

or R4and R5together with the nitrogen atom to which they are linked, represent a ring which optionally may be interrupted by additional N atom,

the said ring optionally can be substituted one or more times by hydroxyl, alkoxyl, amino, alkylamino, dialkylamino, nitrile or E-G,

where E represents a valence bond, WITH1-C4alkyl, which is optionally substituted by hydroxy; C2-C4alkenyl;

G represents hydrogen, a 6-membered aromatic monocycle having 0, 1 or 2 nitrogen atom and the remaining atoms in the monocycle are carbon atoms, where the monocycle is unsubstituted or substituted by a Deputy selected from the group consisting of halogen, -NH2, -NO2, -SO2NH2, -SO2CH3, acetyl and cyano,

the radicals listed for R1, R4and R5can be optionally once or several times substituted by halogen, hydroxyl, alkyl, hydroxyalkyl, alkoxyl, alkylhalogenide, alkoxycarbonyl, amino or aminocarbonyl, optional one or two times substituted lower alkyl, nitrile, exography, thiocarboxamide, alkoxyaryl, alkylaminocarbonyl, Fofana, alkylphosphonium, dialkylphosphorous, alkylsulfonamides and their pharmacologically acceptable salts for obtaining a pharmaceutical composition having activity to inhibit matrix metalloprotease.

In particular, for obtaining a pharmaceutical composition having activity to inhibit Adamantine.

The compounds of formula I, pharmaceutically acceptable salts or prodrugs may be used to produce pharmaceuticals.

Among the listed values radicals optionally, you can specify the following:

Under monocycle listed in the case of R1, R4and R5, ponimayshi saturated or unsaturated ring of from 3-8, preferably 5-7 carbon atoms, which is optionally interrupted one or more times by heteroatoms, such as nitrogen, oxygen or sulphur, especially radicals cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiomorpholine, piperidine, piperazinil, tetrahydrofuranyl, tetrahydro satyasai, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl. In addition, as the Deputy may be implied lower alkyl, alkoxyl and halogen.

Under Bicycle listed for R1, R4and R5it is understood condensed Bicycle or Bicycle type monocycle1-L-monocycle2where L denotes a valence bond, WITH1-C4-accelgroup,2-C4-altergroup, oxygen or-S(O)-group.

Predpochtitelno Bicycle is a radical such as a naphthyl radical, tetrahydronaphthyl, decaline, chinoline, ethenolysis, tetrahydroquinoline, tetrahydroisoquinoline, indolyl, benzimidazolyl, indazoles, oxindoles, benzofuranyl, benzothiophene, benzothiazole, benzoxazole, purinol, biphenyl or (4 phenoxy phenyl and especially naphthyl, biphenyl, chinoline, ethenolysis, tetrahydropyranyl, indolyl or benzimidazolyl.

The radicals listed for R1, R4and R5not necessarily can be once or several times substituted by halogen, hydroxyl, tigraphy, alkyl, hydroxyalkyl, alkoxyl, alkylthiol, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, nitrogroup, carboxyla, carboxamido, alkometriem, exography, thiocarboxamide, alkoxyglycerols alternateservers, Fofana, alkylphosphonium, dialkylphosphorous, alkylsulfonamides, arylamino, aryl, hetaryl, alloxylon, arylthioureas, arylsulfonyl, arylsulfonyl or acyl.

In this case, the preferred halogen, hydroxy, oxo-, thio-, alkoxy-, alkylthio-, amino-, aminocarbonyl, carboxyl or accelgroup.

Lower alkyl is C1-C6-alkyl, preferably methyl, ethyl, propyl, isopropyl or tert.-butyl.

The lower acyl radicals in R2and R3most is-C(O)-C1-C6-alkyl or-C(O)H, preferably the acetyl group.

The alkyl radicals R1, R4and R5optional, may be interrupted once or more heteroatoms (O, S, NH).

The alkyl radicals in R4and R5means such or in combination with the radical alkoxyl, alkylthiol, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylenecarborane, alkylamino, alkoxycarbonyl, aryloxyalkyl, alkylaminocarbonyl, arylaminothiourea, radical straight, branched chain, saturated or unsaturated with 1-11, suppose the, 2,4-pentadienyl, isopropyl, secondary butyl, 3-methylbutyl, 2-hydroxyhexyl and especially methyl, propyl, isopropyl, pentyl, octyl, allyl, 3-methylbutyl, 2-hydroxyhexyl and propargyl.

Aryl, in combination with alloxylon, arylthioureas, arylsulfonyl, arylenecarborane, aryloxyalkyl, arylaminothiourea understood as the radical is phenyl or naphthyl, which may optionally be substituted with halogen, lower alkyl or alkoxyl.

WITH1-C20is an alkyl group, listed for R1is a saturated radical with a straight or branched chain such as, for example, methyl, ethyl, propyl, butyl, pentyl, octyl, decyl, undecyl, isobutyl, 3-methylbutyl or 7-metrotel. As Vice most of all it is necessary to mean the radicals hydroxyl and amine. The alkyl chain may have one or several times interrupted by oxygen, nitrogen or sulfur. The most preferred heteroatom to interrupt is oxygen (ether bond) or-C(O)NH-(amide bond). The most preferred radicals preryvayuscheesya the heteroatom are -(CH2-CH2O)n-(CH2)mH and n=2 or 3, m is 1 or 2.

W R1preferably is a radical metrostyle can be more than just substituted lower alkyl, by hydroxyl, alkoxyamino, sulfonamide or halogen. The most preferred radicals for R1are radical6-C12-alkyl or the radical -(CH2)n-C6H4-(CH2)mH, where m and n are equal to or less than 8, (CH2-group optionally interrupted by oxygen, sulfur or NH and one or two carbon atoms of the phenyl ring substituted by heteroatoms N. Alkyl, aryl, geurilla group optionally substituted by a small polar substituents.

The most preferred radicals in the relation R1are radicals of the type n-octyle, n-decyl, biphenyl or Attila or decyl, having two or three heteroatoms of oxygen, such as 2-(2-(2-methoxyethoxy)ethoxy)ethyl, 2-(2-ethoxyethoxy) ethyl or biphenyl type, having one or two heteroatoms of nitrogen. Linking monocycle optionally substituted in the ortho-position and end monocycle biphenyl or radical type, biphenyl optionally substituted in the ortho - or para-position small polar Deputy, such as-NH2, -NO2, -SO2NH2, -SO2CH3, acetyl, hydroxyl, methoxy, ethoxy-, or nitrile group. More preferably, the substitution in the para-position terminal IU radicals, listed for R4and R5preferably means rings of pyridine, pyrazine, piperazine, imidazole, thiazole, thiophene or indole, is preferably pyridine, imidazole, and thiophene ring.

Acyl radical, listed for R4and R5means radical with 1-10, preferably 6-8 carbon atoms, such as radical hexanoyl or octanoyl. The alkyl group may be interrupted once or more heteroatoms or heteroatomic groups such as S, O, NH, SO2, amido, or carbonyl. These radicals may be replaced by amino groups, alkyl groups, aryl groups, arylalkyl groups, alkylaminocarbonyl, dialkylaminoalkyl, alkoxygroup and aromatic compounds. In this case, it may be the remains of amino acids, preferably, the residue is phenylalanine or tryptophan.

If R4and R5together form a ring with the nitrogen atom to which they are connected, it is a 5-7-membered ring, preferably a 6-membered ring. Preferred ring, piperidine, piperazine, tetrahydroquinoline and tetrahydroisoquinoline, bicyclo (9.4.0) pentadecyl and 1,2,3,4-tetrahydrobenzo (g) of isoquinoline.

If the connection imeye with the General formula I, also are the subject of the present invention.

Independently of one another preferred value for X, Y, Z is oxygen, R2and R3is hydrogen. A more preferred combination, if X, Y and Z each is oxygen and R2identical with R3and both are hydrogen.

Preferably, R4and R5both did not represent hydrogen.

The term "multiple" in respect of the heteroatoms in monocyclic or bicyclo means preferably one, two or three, more preferably one or two atoms, the most preferred heteroatom is nitrogen.

The term "multiple" in relation to substituents or substitution means preferably from one to five thereof, more preferably one, two or three, most preferably one or two.

The term "heteroatom" in relation to the alkyl or acyl group means preferably oxygen or NH, preferably oxygen.

Deputies of monociclo or bicyclo R1, R4and R5represent a halogen, a nitro-group, hydroxyl, alkoxyl, amino, alkylamino, dialkylamino, halogenmethyl, dehalogenation, trihalomethyl, phosphono, al is Kil) acetyl, formyl, nitrile, COOH, COO-alkyl, -OC(O)-alkyl, -NHC(O)O-alkyl, OC(O)O-aryl, NHC(S)NH2, -NHC(S)NH-alkyl, -NHC(O)-aryl.

The preferred annular structure formed by nitrogen, R4and R5is piperazine or piperidine, which are both preferably substituted at the 4th position. In the case of piperidine 4-th position is not necessarily displaced by the second Deputy, hydroxyl, amino, alkylamino, dialkylamino or alkoxyl. the 4th position of the piperidine can also form a double bond with a substituent in the 4-th position.

Preferred substituents in the 4-th position of the piperidine or piperazine are 6-membered aromatic monocyclic, which are more preferably substituted in the para-position small polar substituents such as hydroxyl, lower alkoxyl, amino, lower alkylamino, lower dialkylamino, the nitro-group, nitrile, SO2NH2, SO2NH lower alkyl, SO2lower alkyl. 6-membered aromatic monocycle preferably associated with the 4th position after a valence bond or a spatial group is lower alkyl.

If R4is hydrogen, lower alkyl, lower alkylaryl, then preferably R5is derived 53, R50and R51independently from each other are hydrogen, lower alkyl, lower alkoxyl. R52means hydrogen or lower alkyl, R53mean 6-membered aromatic monocycle, which is optionally once or several times substituted and linked to the nitrogen preferably via a valence bond or a spatial group is lower alkyl.

The most preferred combinations of values in the General formula I are

X is Y is Z is equal to the oxygen and

R2equal to R3equal to hydrogen and

R1equal to the radical of the type n-octyle, n-decyl, biphenyl or Attila, or decyl, having two or three heteroatoms of oxygen, like the radicals 2-(2- (2-methoxyethoxy)ethoxy)ethyl, 2-(2-ethoxyethoxy)ethyl or biphenyl type, having one or two heteroatoms of nitrogen; where the bridge monocycle optionally substituted in the ortho-position and end monocycle biphenyl or radical type, biphenyl optionally substituted in the ortho - or preferably in the para-position small polar Deputy type NH2, -NO2, -SO2NH2, -SO2CH3, acetyl, hydroxyl, metaxylene, ethoxyline or nitrile groups and

R4and R5form of nitrogen, which is and pirazidol, which is preferably substituted in the para-position small polar Deputy; in the case of piperidine 4 position may be optionally substituted by hydroxyl, lower alkoxyl, nitrile or amino which may be mono - or disubstituted by lower alkyl.

Compounds of General formula I can be synthesized by well known methods, preferred the fact that

a) compounds of General formula II

< / BR>
in which X, Y, Z, R1, R2and R3have the above values and T is a leaving group such as Hal or OSO2R6. Hal means chlorine, bromine or iodine and R6means an aryl radical or methyl, react with the compound of General formula III

< / BR>
in which R4and R5have the above values and do not necessarily turn into a pharmacologically acceptable salt or

b) compounds of General formula IV

< / BR>
in which R1, R4and R6have the above values, Y and Z independently of one another represent oxygen, sulfur or NH group and R7= the stands, ethyl or phenyl, to react with a compound of General formula V

< / BR>
in which R2, R3and X have the above meanings and do not necessarily turn into farm is sulfonyl, arylsulfonyl, alkylaminocarbonyl, allumination, alkoxycarbonyl, aryloxyalkyl, alkylaminocarbonyl or allumination

C) the compound of General formula VI

< / BR>
in which X, Y, Z, R1, R2and R3have the above meanings, is reacted with a compound of General formula VII or VIII

R6--- D --- Hal (VII) R8N===C===A (VIII),

in which R8represents optionally substituted alkyl radical or aryl, D=C(O) O-C(O), SO2or valence dash. Hal = chlorine, bromine or iodine, and a is oxygen or sulfur

and need not be converted into pharmacologically acceptable salts.

Compounds of General formula II are known in the literature. So, for example, 2,4,6-pyrimidine trions, brominated at the 5-position can be synthesized by reaction of the corresponding dialkylamino esters of bromomalonate acid with urea (e.g., Acta Chim. Acad. Sci. Hung. 107, 2, 139, 1981). The corresponding brominated or chlorinated compounds of General formula II can be obtained in the reaction of 2,4,6-pyrimidine trions, substituted R1in the 5th position with bromine (similar to J. pr. Chemie, 136, 329 (1933) or J. Chem. Soc. 1931, 1870) or chloride sulfuricum (J. Chem. Soc. 1938, 1622). In a similar way it is possible to synthesize 2-them. 8, 1, 299, (1933). The reaction of 2-thia-4,6-pyrimidine-diones substituted R1in 5th position, with bromine in glacial acetic acid (similar to Am. Chem. J. 34, 186) leads to the formation of compounds of General formula II, respectively brominated in the 5th position.

Amines of General formula III are commercially available and commonly known in the literature.

Compounds with the General formula IV react by known methods with urea (see , for example, J. Med. Chem. 10, 1078, 1967) Helvetica Chim. Acta 34, 459, 1959 or Pharmacie, 38, 1, 65, (1983), timeonline (see, e.g., Indian J. Chem. 24, 10, 1094, 1985 or J. Het. Chem. 18, 3, 635, (1981) or guanidine (see, for example. Collect. Czech. Chem. Comm. 45, 12, 3583, 1980) of General formula V.

The reaction is usually carried out in an alcohol such as methanol, ethanol or butanol in the presence of the corresponding sodium alcoholate at a temperature between 40oC and 100oC in the case of guanidino at temperatures up to 200oC (under pressure). In the case of thioureas process is often carried out in the presence of acetylchloride (as a solvent).

Compounds of General formula IV are known from the literature or can be obtained by methods known from the literature. They can be synthesized, for example, as a result of weak acid hydrolysis of the corresponding(1976) or Aust. J. Chem., 23, 6, 1229, (1970).

Urea, thiourea and guanidine General formula V are commercially available.

Compounds of General formula VI can be easily synthesized in the reaction of the corresponding substituted acetamidomalonate ester according to method b) and subsequent hydrolytic cleavage of acetyl groups (see Can. J. Chem. 42, 3, 605, 1964).

Chlorides of carboxylic acids of General formula VII are known or can be synthesized using well-known methods from the corresponding carboxylic acids. The reaction is usually carried out with chloride tiomila or tribromide phosphorus or patinopecten or with phosphorus pentachloride in an inert solvent such as dichloromethane, diethyl ether, dioxane or tetrahydrofuran at a temperature from 0oC to 50oC, preferably between 20oC and 40oC.

The esters of Harborview acid of General formula VII are known in the literature or may be obtained by commonly known methods from the corresponding alcohols by reaction with phosgene or diphosgene. The reaction is carried out in inert solvents such as diethyl ether, dichloromethane, dioxane, tetrahydrofuran or toluene at temperatures between -20oC and 20oC. In the case of phosgene, the reaction is performed in presence the of locality General formula VII are known and can be synthesized by methods similar to those described from the corresponding sulfonic acids in reaction with phosphorus pentachloride or chloride tiomila. The reaction is usually carried out in an inert solvent such as, for example, dimethylformamide or also without solvent at a temperature of 20oC to 180oC, preferably at 50 to 100oC.

The isocyanates of General formula VIII are known or can be synthesized by methods known in the literature. For example, the appropriate alkylhalogenide General formula R8-Hal can react with potassium cyanate similarly, Synthesis, 1978, 760. Additional methods are the reaction of amides of the acids with the General formula R8-CONH2with oxalylamino to thermal decomposition of the azide acid with the General formula R8-CON3or the reaction of the amine with the General formula R8-NH2with phosgene (similar to Ann. Chem. 562, 110).

Isothiocyanates of General formula VIII are known in the literature or can be synthesized analogously to known methods. The amine of General formula R8-NH2preferably introduced into the reaction with carbon disulfide in alkaline conditions similar to Chem. Weg. 74, 1375.

The reaction of halides of carboxylic acids, halides, sulfonic acids or esters of Harborview acid of General formula VII with amines of General formula VI is usually carried out in a solvent such as dichloromethane, dimethylformamide temperature between -10oC and 50oC, preferably at room temperature.

Compounds of General formula I can contain one or more chiral centers and therefore may be in racemic or optically active form. The racemates can be divided by the known methods for the enantiomers. Preferably diastereoisomeric salts which can be separated by crystallization, are formed from the racemic mixtures in the reaction with an optically active acid such as D - or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonate or with optically active amine such as D - or L-phenyl-ethylamine, ephedrine, quinidine or cinchonidine.

Salts of alkali metals, salts of alkaline-earth metals like Ca or Mg salts, ammonium salts, acetates or hydrochloride mainly used as pharmacologically acceptable salts, which receive the usual way, for example, by rubbing compounds with inorganic and organic bases or inorganic acids such as, for example, sodium hydroxide, potassium hydroxide, aqueous ammonia, C1-C4-bonds alkylamines such as triethylamine or hydrochloric acid. Salt is usually clear p is nterline or parenterally in liquid or solid form. In this regard, you can take into consideration all of the usual form for the purpose, such as tablets, capsules, coated tablets, syrups, solutions, suspensions, etc., Preferably water, including additives such as stabilizers, soljubilizatory and buffers that are normal for injection solutions, is used as the injection medium.

Such additives are, for example, wine and citrate buffer, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salt), high-molecular polymers (such as liquid polyethylene oxide) for regulating the viscosity. Liquid substance carrier for injection solutions must be sterile and are preferably packaged in ampoules. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); suitable preparations for oral administration can optionally include a fragrance and podslastitel the individual health status. The dose that is prescribed daily, approximately 10-1000 mg/person, preferably 100-500 mg/person and can be taken once or divided into several destinations.

Prodrugs of compounds of the present invention are such that in vivo converted into pharmacologically active compounds. The most common prodrugs are esters of carboxylic acids.

According to the present invention in addition to the compounds mentioned in the examples and compounds that can be obtained by combining the values of the substituents mentioned in the claims, the following preferred derivatives of barbituric acid:

1. 5-(N-benzyl-N-octyl)-5-phenyl-barbituric acid

2. 5-(N-benzyl-N-phenethyl)-5-phenyl-barbituric acid

3. 5-(N-benzyl-N-[2-(4-pyridyl)ethyl]-5-phenyl-barbituric acid

4. 5-(N-benzyl-N-[2-(3-pyridyl)ethyl] -5-phenyl-barbituric acid

5. 5-(N-benzyl-N-[2-(2-pyridyl) ethyl] -5-phenyl-barbituric acid

6. 5-(N-benzyl-N-[2-(2-thiophenyl)ethyl]-5-phenyl-barbituric acid

7. 5-[N-(3-methylbutyl)-N-(3-phenylpropyl)] -5-phenyl-barbituric acid

8. 5-(N-benzyl-N-[3-(4-pyridyl)propyl])-5-phenyl-barbituric acid

9. 5-(N-benzyl-N-[2-(2-imidazo
11. 5-(N-butyl-N-phenylalanine)-5-phenyl-barbituric acid

12. 5-(N-butyl-N-tryptophanyl)-5-phenyl-barbituric acid

13. 5-(N-benzyl-N-cyclohexyl)-5-phenyl-barbituric acid

14. 5-[N-benzyl-N-(2-pyridyl)]-5-phenyl-barbituric acid

15. 5-[N-butyl-N-(4-piperidinyl)]-5-phenyl-barbituric acid

16. 5-[N-benzyl-N-(2-imidazolyl)]-5-phenyl-barbituric acid

17. 5-(N-octyl-N-phenyl)-5-phenyl-barbituric acid

18. 5-[N-(2-naphthyl)-N-propyl]-5-phenyl-barbituric acid

19. 5-[N-(4-tetrahydropyranyl)-N-propyl]-5-phenyl-barbituric acid

20. 5-[N-benzyl-N-(2-thiophenyl)]-5-phenyl-barbituric acid

21. 5-[N-(3-methylbutyl)-N-[3-(4-pyridyl)propyl)] -5-phenyl - barbituric acid

22. 5-[N-(7-metrotel)-N-[3-(2-pyridyl) propyl)]-5-phenyl-barbituric acid

23. 5-(N-(2-hydroxyhexyl)-N-[3-(3-pyridyl)propyl] ) -5-phenyl-barbituric acid

24. 5-(N-benzyl-N-hexanoyl)-5-phenyl-barbituric acid

25. 5-(N-benzyl-N-octanoyl)-5-phenyl-barbituric acid

26. 5-(N-benzyl-N-octanesulfonyl) -5-phenyl-barbituric acid

27. 5-[N-butyl-N-(2-naphthylmethyl)]-5-phenyl - barbituric acid

28. 5-(N-hexyloxybenzoyl-N-propyl)-5 - phenyl-barbituric acid

29. 5-[N-(4-methoxy-phenylsulfonyl) -N-hexyl]-5-Fe is-[N-benzyl-N-(2-phenethyl)]-5-(4-pyridyl)barbituric acid

32. 5-[N-benzyl-N-(2-phenethyl)]-5-(2-pyridyl) barbituric acid

33. 5-(N,N-dipentyl)-5-(4-piperidinyl)barbituric acid

34. 5-(N,N-dioctyl)-5-(2-thiophenyl)barbituric acid

35. 5-(N-benzyl-N-[2-(2-pyridyl)ethyl]-5-(3-imidazolyl)barbituric acid

36. 5-[1-(4-hydroxy)piperidinyl]-5-(4-pyridyl) barbituric acid

37. 5-[1-(4-hydroxy)piperidinyl]-5-(3-pyridyl)barbituric acid

38. 5-[1-(4-hydroxy) piperidinyl]-5-(2-pyridyl) barbituric acid

39. 5-[1-(4-hydroxy) piperidinyl]-5-(4-piperidinyl) barbituric acid

40. 5-[1-(4-hydroxy) piperidinyl]-5- (thiophenyl) barbituric acid

41. 5-[1-(4-hydroxy)piperidinyl]-5-(4-imidazolyl) barbituric acid

42. 5-benzyl-5-[1-(4-hydroxy) piperidinyl]barbituric acid

43. 5-[1-(4-hydroxy) piperidinyl]-5-(2-phenethyl)barbituric acid

44. 5-[1-(4-hydroxy)piperidinyl]-5-(1-naphthyl)barbituric acid

45. 5-[1-(4-hydroxy)piperidinyl] -5-(2-naphthyl)barbituric acid

46. 5-(2-chinoline)-5-[1- (4-hydroxy)piperidinyl]barbituric acid

47. 5-[1-(4-hydroxy)piperidinyl]-5-(1-ethenolysis)barbituric acid

48. 5-[1-(4-hydroxy)piperidinyl]-5-(2-tetrahydro-chinoline) barbituric acid

49. 5-(2-indolyl)-5-[1-(4-hydroxy) piperidin�5-(1-[4-(2-hydroxyethyl)piperazinil]) -5-octyl-barbituric acid

52. 5-decyl-5-(1-[4-(2-hydroxyethyl)piperazinil])barbituric acid

53. 5-(1-[4-(2-hydroxyethyl)piperazinil]) -5-undecyl-barbituric acid

54. 5-(1-[4-(2-hydroxyethyl)piperazinil])-5-(7-methyl-octyl) barbituric acid

55. 5-(1-[4-(2-hydroxyethyl)piperazinil])-5-(8-hydroxyacyl) barbituric acid

56. 5-(8-aminoacetyl)-5-(1-[4-(2- hydroxyethyl) piperazinil])barbituric acid

57. 5-(1-[4-(2- hydroxyethyl)piperazinil] )-5-(4-phenethyl)barbituric acid

58. 5-(1-[4-(2-hydroxyethyl)piperazinil])-5-(4-phenylbutyl) barbituric acid

59. 5-(1-[4-(2-hydroxyethyl) piperazinil])-5-(6-phenylhexa)barbituric acid

60. 5-(1-[4-(2-hydroxyethyl) piperazinil])-5-[6- (4-were)hexyl] barbituric acid

61. 5-(1-[4- (2-hydroxyethyl)piperazinil])-5-(2-pyridylmethyl)barbituric acid

62. 5-(1-[4-(2-hydroxyethyl)piperazinil])-5- (4-imidazolidinyl)barbituric acid

63. 5-(1-[4- (2-hydroxyethyl)piperazinil])-5-(1-imidazolidinyl)barbituric acid

64. 5-phenyl-5-[1-(4-propyl)piperazinil]barbituric acid

65. 5-phenyl-5-(1-tetrahydropyranyl)barbituric acid

66. 5-phenyl-5-(1-tetrahydroisoquinoline)barbituric acid

67. 5-phenyl-5-[2-(1,2,3,4-tetrahydrobenzo (g)ethenolysis]barbiturate [9.4.0] pentadecyl)]-5-phenyl-barbituric acid

70. 5-(1-[4-(1-oxo - propyl)]-piperidinyl)-5-phenyl-barbituric acid

71. 5-[1-(3- oxo-4-propyl)]piperidinyl]-5-phenyl-barbituric acid

72. 5-phenyl-5-[1-(4-propyl)piperazinil]barbituric acid

73. 5-[1-(3,5-dihydroxy-4-propyl)piperidinyl] -5-phenyl-barbituric acid

74. 5-(4-chlorophenyl)-5-[1-(4-hydroxy-piperidinyl] barbituric acid

75. 5-(4-Chlorobenzyl)-5-[1-(4-hydroxy) piperidinyl]barbituric acid

76. 5-[1-(4-hydroxy) piperidinyl] -5-(4-methoxybenzyl)-barbituric acid

77. 3-methyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid

78. 1-isopropyl-5-[1-(4-hydroxy)piperidinyl] -5-phenyl - barbituric acid

79. 3-acetyl-5-[1-(4-hydroxy)piperidinyl] -5-phenyl-barbituric acid

80. 5-[1-(4-methoxy)piperidinyl] -5-phenyl-2-thio-barbituric acid

81. 2-imino-5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid

82. 5-[1-(4-methoxy)piperidinyl] -5-phenyl-2,4, 6-triamino-barbituric acid

83. 4,6-diamino-5-[1-(4-methoxy)piperidinyl] -5-phenyl - barbituric acid

84. 5-[1-(4-methoxy)piperidinyl] -5-phenyl - 2,4,6-tritio-barbituric acid

85. 5-(6-aminohexyl)-5-[N- (2-hydroxyethyl)piperazinil] barbituric acid

86. 5-(6-formylamino)-5-[N-(2-hydroxyethyl) in order acid

88. 5-[7-(etoxycarbonyl)heptyl]-5-[N-(2-hydroxyethyl)- piperazinil]barbituric acid

89. 5-(8-hydroxyacyl)-5-[N- (2-hydroxyethyl)piperazinil]barbituric acid

90. 5-(7-carboxyethyl)-5-[N-(2-hydroxyethyl) piperazinil]barbituric acid

91. 5-(7-aminocarbonyl)heptyl]-5- [N-(2-hydroxyethyl) piperazinil]barbituric acid

92. 5-[3-((aminocarbonylmethyl)aminocarbonyl)propyl] -5-[N- (2-hydroxyethyl)piperazinil]barbituric acid

93. 5-[6-(methylamino)hexyl]-5- [N-(4-nitrophenyl)piperazinil]barbituric acid

94. 5-[4-(n-propyloxy)butyl]-5-[N-(4-nitrophenyl)piperazinil] barbituric acid

95. 5-[2-(2-(2-methoxyethoxy)ethoxy)ethyl] -5-[N-(4-nitrophenyl)piperazinil]barbituric acid

96. 5-[2-(2-(ethoxy)ethoxy)ethyl] -5-[N-(4-nitrophenyl) piperazinil]barbituric acid

97. 5-decyl-5-[N-(4-nitrophenyl)piperazinil]barbituric acid

98. 5-octyl-5-[N-(4-hydroxysulfonic)phenyl) piperazinil] barbituric acid

99. 5-octyl-5-[N-(4 - aminosulfonyl)phenyl)piperazinil]barbituric acid

100. 5-octyl-5-[N-(4-cyanophenyl)piperazinil]barbituric acid

101. 5-octyl-5-[N-(4-carboxyphenyl)piperazinil] barbituric acid

102. 5-octyl-5-[N-(4-butoxycarbonyl) phenyl)piperazinil] barbitistes)phenyl)piperazinil] barbituric acid

105. 5-octyl-5-[N-(4-(methylsulphonyl)phenyl)piperazinil] barbituric acid

106. 5-octyl-5-[N-(4-(aminocarbonyl)phenyl) piperazinil] -barbituric acid

107. 5-octyl-5-[N-(4 - methylcarbamoyl)phenyl)piperazinil]-barbituric acid

108. 5-octyl-5-[N-(4-(dimethylphenyl)phenyl)piperazinil] barbituric acid

109. 5-octyl-5-[N-(4-(amino)phenyl) piperazinil]barbituric acid

110. 5-octyl-5-[N-(4-(acetylamino)phenyl)piperazinil]- barbituric acid

111. 5-octyl-5-[N-(4-(triptorelin)phenyl) piperazinil]barbituric acid

112. 5-octyl-5-[N-(4- (methylsulfonylamino)phenyl)piperazinil]barbituric acid

113. 5-octyl-5-[N-(5-nitrapyrin-2-yl)piperazinil]barbituric acid

114. 5-octyl-5-[N-(N-occipied-4-yl)piperazinil] barbituric acid

115. 5-octyl-5-[N-(4-(5-thiazolyl) phenyl)piperazinil]barbituric acid

116. 5-octyl-5-[(N - benzoyl-N-benzyl)amino]barbituric acid

117. 5-[4-(phenyl) phenyl]-5-[(N-benzoyl-N-benzyl)amino]-barbituric acid

118. 5-(4-[4-nitrophenyl)piperazinil] -5-octyl-barbituric acid Mass spectrum (ionization by electron impact): m/e=445, estimated 445,23;

thin layer chromatography: Rf=0,61 (silica gel, dichloromethane/methanol 9: 1).

119. N-benzyl-3-(4-nil)amino] -barbituric acid

Thin layer chromatography: Rf=0.36 and (silica gel, heptane/ethyl ketone 1:1);

NMR (CDCl3): 8,4 (broad singlet 2H); of 7.0 to 7.4 (m, 15H); 4,5 (S., 2H).

121. N-benzyl-2-(3-bromo-phenyl)-N-(2,4,6 - trioxo-5-phenyl-hexahydro-pyrimidine-5-yl)ndimethylacetamide

EXAMPLE 1 5-(1-[4-(2-hydroxyethyl)piperazinil] )-5-phenyl - barbituric acid

5-bromo-5-phenyl-barbituric acid (Acta Chim. Acad.

Sci. Hung. 107, 139-45, 1981) (7 mmol) and N-(2-hydroxy - ethyl)piperazine (8 mmol) are suspended in 40 ml of absolute ethanol. After 3 hours boiling under reflux, it is concentrated under vacuum. The residue is purified by chromatography on silica gel (ethyl acetate/methanol 3:1). The colorless crystals obtained by recrystallization from isopropanol. Yield 56%; so pl.: 238-40oC (decomposition).

EXAMPLE 2

5-(1-[4-(4-were)methyl]piperazinil]-5-phenyl - barbituric acid

5-bromo-5-phenyl-barbituric acid (7 mmol) and N-(methyl-p - tolyl)piperazine (8 mmol) are suspended in 40 ml of absolute ethanol. After 2 hours boiling under reflux, it is concentrated under vacuum. The residue is ground to powder with diethyl ether, dried on a vacuum filter, washed again with 20 ml of diethyl ether and dried. The crude product is purified of chromatography the 5-(1-[4-(4-(4-were))butyl] piperazinil] -5-phenyl - barbituric acid

4-(p-tolyl)butylbromide

The get connection similar to that described in the literature. Synth. Commun., 22, 20, 2945-8, 1992. Exit 91% in the form of a colorless oil.

Phenyl-(4-p-tolyl) butyl) malonic acid diethyl ester

Diethyl ether of phenylmalonate acid (8,8 mmol) dissolved in 5 ml of absolute tetrahydrofuran, are added dropwise to 20 ml of absolute tetrahydrofuran and sodium hydride (9.7 mmol). Then after 15 minutes add 4-p-tributylamine (8,8 mmol) dissolved in 10 ml of absolute tetrahydrofuran. Within three days heated under reflux. The solvent is concentrated under vacuum. The residue was transferred to 50 ml ethyl acetate and extracted with water h ml of the Organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation. Its clear by chromatography on silica gel (heptane/ethyl acetate 9:1). Yield 55% in the form of a colorless oil.

5-1-[4-(4-(4-were)) butyl]piperazinil)-5-phenyl - barbituric acid

Urea (4.6 mmol) and diethyl ester of phenyl-(4-(p-tolyl) butyl) malonic acid (3.1 mmol) are added to a solution of ateleta sodium (6.2 mmol) in absolute ethanol. Within 12 hours, heated under reflux, then concentrated under vacuum is 30 ml The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation. The residue is purified by chromatography on silica gel (heptane/ethyl acetate 3:1).

The yield of colorless crystals 46%; so pl.: 163-165oC.

EXAMPLE 4

5-(1-[4-(2-hydroxyethyl)piperidinyl])-5-phenyl - barbituric acid

14.6 g (50 mmol) of diethyl ether phenylmalonate acid and then 10 g (166 mmol) of urea slowly added to 1.3 g of sodium in 40 ml of methanol under stirring. Heated for 2 hours at a low boil. In this process, a precipitate may form. It is cooled to 10-15oC, then slowly mixed with 12.9 g (100 mmol) of 4-(2-hydroxyethyl) piperidine, 13.8 g (100 mmol) of potassium carbonate are 2.87 ml (112,3 mmol) of bromine. The mixture is stirred for 2 hours at 10-15oC, then slowly heated to boiling and boiled for 1 hour under reflux. After cooling, it was poured into 240 ml of 1N nitric acid, the solution is once washed with toluene and neutralized with a saturated solution of sodium acetate. Precipitates fat mass, which is translated in hot ethanol. The hot solution is treated with active charcoal and mix with warm water until the turbidity. After cooling, the crystals otherthrow is R>
5-phenyl-5-(1-piperidinyl)barbituric acid with a yield of 92%; so pl.: 244-246oC get analogously to example 4, using piperidine instead of 4-(2-hydroxyethyl)piperidine.

EXAMPLE 6

5-[1-(4-hydroxy)piperidinyl]-3-phenyl-barbituric acid

5-[1-(4-hydroxy)piperidinyl] -5-phenyl-barbituric acid with a yield of 39%; so pl.: 241-242oC (from ethanol) are obtained analogously to example 4 using 4-hydroxy-piperidine instead of 4-(2 - hydroxyethyl)piperidine.

EXAMPLE 7

5-[1-(4,4-dimethyl)piperidinyl]-5-phenyl-barbituric acid

5-[1-(4,4-dimethyl)piperidinyl] -5-phenyl-barbituric acid with a yield of 69%; so pl.: 238-240oC (from ethanol/water) are obtained analogously to example 4, using 4,4-dimethylpiperidin instead of 4-(2-hydroxyethyl) piperidine.

EXAMPLE 8

5-[1-(4-methyl)piperidinyl]-5-phenyl-barbituric acid

5-[1-(4-methyl)piperidinyl] -5-phenyl-barbituric acid with a yield of 87%; so pl.: 208-209oC (from methanol/water) are obtained analogously to example 4, using 4-methyl-piperidine instead of 4-(2 - hydroxyethyl)piperidine.

EXAMPLE 9

5-[1-(4-methoxy)piperidinyl]-3-phenyl-barbituric acid

5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid with a yield of 67%; so pl.: 184-185oC (etano"ptx2">

EXAMPLE 10

5-ethyl-5-[1-(4-methyl)piperazinyl]barbituric acid

14.1 g (75 mmol) of diethyl ether ethylmalonic acid and then 15 g (264 mmol) of urea is added slowly to 1,95 g of sodium in 60 ml of methanol under stirring. After boiling for 2 hours, a precipitate may form. It is cooled to 10-15oC sequentially and slowly mixed with 15 g (15 mmol) 4-methylpiperidine, 21 g (150 mmol) of potassium carbonate and 4.3 ml (168 mmol) of bromine. The mixture is stirred for 2 hours at this temperature, slowly bring to a boil and heated for 1 hour under reflux. After cooling, it was poured into 360 ml of 1N nitric acid, the solution is once washed with toluene and mixed with an excess of a saturated solution of sodium acetate. Planted residue is recrystallized from ethanol with addition of active carbon. Yield: 4.4 g = 23%; so pl.: 194 - 195oC.

EXAMPLE 11

5-ethyl-5-[1-(4-methoxy) piperazinyl] barbituric acid

5-ethyl-5-[1-(4-methoxy) piperazinyl] barbituric acid with a yield of 15%; so pl. 201-202oC (from ethanol) are obtained analogously to example 10, using 4-methoxypiperidine instead of 4-methylpiperidine.

EXAMPLE 12

5-ethyl-5-[1-(4-hydroxy)piperidinyl]barbituric acid

5-this is ichno example 10, using 4-hydroxypiperidine instead of 4-methoxypiperidine.

EXAMPLE 13

5-ethyl-5-[1-(4-(2-hydroxyethyl)piperidinyl)]barbituric acid

5-ethyl-5-[1-(4-(2-hydroxyethyl)piperidinyl)] barbituric acid with a yield of 17%; so pl.: 238-240oC (from methanol) are obtained analogously to example 10, using 4-(2-hydroxyethyl)piperidine instead of 4-methylpiperidine.

EXAMPLE 14

5-(4-methoxyphenyl)-5-[N-(2-hydroxyethyl) piperazinil]barbituric acid

a) obtain ethyl 4-methoxyphenylacetate

A solution of 4-methoxyphenylacetic acid (2 g) and para-toluenesulfonic acid (230 mg) in 30 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure, and the residue is suspended in a saturated aqueous solution of acid sodium carbonate and extracted twice with ethyl acetate. The organic extracts are collected, washed with water and dried over sodium sulfate education after evaporation of the solvent under reduced pressure 2.14 g of product.

b) obtain ethyl 4-methoxyphenylalanine

A mixture of ethyl 4-methoxyphenylacetate (27.8 g) and sodium (3,68 g) in 90 ml dietilovogo ether is refluxed for 3 hours, then the solvent is evaporated T twice with diethyl ether. The organic extracts are combined and washed twice 1N sodium hydroxide and once with water, then the organic phase is dried over sodium sulfate and concentrated to dryness. Get a 34.2 g of product.

C) obtaining 5-(4-methoxyphenyl)barbituric acid

To a solution of 660 mg of sodium in 50 ml ethanol add 3,86 g of ethyl 4-methoxyphenylalanine and 1.28 g of urea. The reaction mixture is refluxed for 3 hours. Roll a white precipitate, which is collected by filtration and re-dissolved in 15 ml of water. The solution is acidified to pH 1-2 by addition of 6N hydrochloric acid. Roll a white precipitate, which is filtered off and washed on the filter with water. After drying under vacuum at 50oWith in a few hours, get a 2.2 8 g of product.

d) receiving 5-bromo-5-(4-methoxyphenyl)barbituric acid

To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 3 ml of water, cooled to 0-5oC in an ice bath, add 136 μl of 48% Hydrobromic acid and 56 μl of bromine dropwise. After 1 hour at a temperature below 10oC, the precipitation is collected by filtration and washed on the filter with water. The precipitate is dried for several hours under vacuum at 50oC, for poluchenogo acid (11.5 g) and N-(2-hydroxyethyl)piperazine (15,755 g) in 260 ml of methanol is refluxed for approximately 2 hours, then the precipitation is collected by filtration, re-dissolved in 100 ml of methanol and heated under reflux for 1 hour. The precipitate is again filtered off and dried at 80oC under vacuum to obtain 9 g of the product containing 8-9% methanol. The residue is dissolved in 40 ml of 1N hydrochloric acid, then the solution is alkalinized of 3.42 g of acid sodium carbonate and cooled at 0-5oC for 4 hours. The product distinguish by filtration and dried under vacuum at 80oC for several hours with the formation of 8,55 g of pure product; so pl. 247-248oC.

1H-NMR in d6-AMCO: at 2.36 ppm (m, 6H); to 2.55 ppm (m, 4H); 3,44 ppm (q, 2H); 3,74 ppm (s, 3H); 4,33 ppm (t, 1H); 6,95 ppm (d, 2H); 7,3 ppm (d, 2H); 11,54 ppm (br s, 2H).

EXAMPLE 15

5-[3-(4-methoxyphenyl)propyl]-5-[4-(2- hydroxyethyl)piperazinil]barbituric acid.

a) obtaining 3-(4-methoxyphenyl)propionitrile

To a suspension of 3-(4-methoxyphenyl)propionic acid (10 g) in 150 ml of toluene, add 8 ml of chloride tiomila and the mixture is heated to 64oC for 4 hours. The solvent is evaporated under reduced pressure and the residue again dissolved in toluene and concentrated to dryness. This step was repeated twice. Obtain 11 g of the product as a yellow oil.

b) receiving 5-[3-( drops is added 11 g of 3-(4-methoxyphenyl) propionitrile and the mixture is stirred at room temperature for 18 hours. The reaction mixture is poured on ice and acidified to pH 1 by addition of 6N hydrochloric acid. Precipitation, which is filtered and re-suspended in methanol. The suspension is stirred for 15 minutes, then separated by filtration residue with the formation of 12.2 g of the product; so pl.: 248-250oC.

(C) obtain 5-[3-(4-methoxyphenyl)propyl]barbituric acid

To a suspension of 10 g of 5-[3-(4-methoxyphenyl)propionyl] barbituric acid in 100 ml of acetic acid are added in portions 4.5 g of laborgerate sodium, the mixture is then heated to 60oC. After 1 hour the reaction mixture is cooled to room temperature and poured on ice. After 30 minutes the receive filtering the precipitate, which is dried under vacuum at 50oC with the formation of a total of 8.74 g of the product; so pl.: 195-197oC.

d) receiving 5-bromo-5-[3-(4-methoxyphenyl)propyl] barbituric acid

A mixture of 5-[3-(4-methoxyphenyl) propyl] barbituric acid (2.5 g), N-bromosuccinimide (2 g) and peroxide of Dibenzoyl (catalytic amount) in 110 ml of carbon tetrachloride is refluxed for 1 hour, then the precipitate was separated by filtration. The precipitate is again dissolved in ethyl acetate and filtered through a layer of silica gel to remove the rest of the su is chlorantha carbon. Appears a pale yellow precipitate, which is collected by filtration and dried under vacuum at 60oC with the formation of 2.8 g of product; so pl.: 113-114oC.

e) obtaining the title compound

A mixture of 5-bromo-5-[3-(4 - methoxyphenyl)propyl]barbituric acid (710 mg) and N-(2-hydroxyethyl)piperazine (281 mg) in 25 ml of ethanol is refluxed for 4 hours. The solvent is evaporated under reduced pressure and the residue partitioned between 1N hydrochloric acid and ethyl acetate. The aqueous phase is alkalinized to pH 6-7 and extracted with ethyl acetate. The organic phase is concentrated to dryness and the residue crystallized from ethyl acetate with the formation of 30 mg of product.

1H-NMR in d6-DMSO: to 1.32 ppm (m, 2H); to 1.86 ppm (m, 2H), 2,33 ppm (m, 6H); at 2.45 ppm (m, 2H); 2,53 ppm (m, 4H); 3,43 ppm (q, 2H); at 3.7 ppm (s, 3H); of 4.35 ppm (t, 1H); to 6.8 ppm (d, 2H);? 7.04 baby mortality ppm (d, 2H); 11,53 ppm (br s, 2H).

EXAMPLE 16

5-phenyl-5-[4-(2-hydroxyethylidene)piperazinyl] barbituric acid

a) obtaining 4-(ethoxycarbonylmethylene)piperidine

To a suspension of sodium hydride (2.6 g) in 30 ml of tetrahydrofuran, cooled to 0oC and stored under nitrogen, is added dropwise 13 ml triethylphosphate dissolved in 10 ml of tetrahydrofuran. The temperature was then brought to room temperature and stirred is the adding to a solution of 4-piperidineacetate hydrochloride (10 g) in THF, 2.6 g of sodium hydride, filtered to remove the formed sodium chloride. At the end of the addition, the temperature is brought to room temperature and continue to stir for 20 hours. The solvent is evaporated under reduced pressure and the residue again dissolved in ethyl acetate and washed with 1N hydrochloric acid. The aqueous phase is extracted with ethyl acetate and chloroform, then alkalinized to pH 9-10 by the addition of 20% sodium hydroxide and extracted with chloroform. The aqueous phase is then vymalivayut and again extracted three times with chloroform. The combined extracts dried over sodium sulfate and evaporated with the formation of 7.1 g of product in the form of a yellow oil.

b) obtaining 4-(hydroxyethylidene)piperidine

To a solution of 15 ml of DIBAL (1.5 M solution in toluene) in 20 ml of toluene are added dropwise 0,976 g of 4-(ethoxycarbonylmethylene) of piperidine are dissolved in a few milliliters of toluene. The reaction mixture was stirred at room temperature for 2 hours, then cooled to 0-5oC and added dropwise methanol, while significantly the formation of gas. The mixture is concentrated to small volume and add diethyl ether: roll a white precipitate, which is filtered off. The organic phase is concentrated to dryness, NR the product.

C) obtaining the title compound

A mixture of 5-bromo-5-phenylbarbituric acid (2,45 g), 4 - hydroxyethylidene)piperidine (1,053 g) and triethylamine (1,15 ml) in 50 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue purified by chromatography on silica gel (40 g; eluent: ethyl acetate/petroleum ether 8:2) with the formation of 450 mg of product.

1H-NMR in d6-DMSO: 2,13 ppm (m, 4H); to 2.55 ppm (m, 4H); to 3.89 ppm (d, 2H); 4,46 ppm (br s, 1H); of 5.24 ppm (t, 1H); 7,42 ppm (m, 5H); 11,6 pp (br s, 2H).

50 mg of 5-phenyl-5- [4-(2 - hydroxyethyl)-1, 2,5,6-tetrahydropyridine] barbituric acid is obtained as a by-product.

1H-NMR in d6-DMSO: a 1.96 ppm (m, 2H); 2,09 ppm (t, 2H); 2,64 ppm (t, 2H); to 3.00 ppm (m, 2H); 3,47 ppm (q, 2H); 4,43 ppm (t, 1H); at 5.3 ppm (m, 1H); to 7.4 ppm (s, 5H); 11,63 ppm (br s, 2H).

EXAMPLE 17

5-phenyl-5-[N-(2-hydroxyethyl)piperazinil]-2 - thiobarbiturate acid

a) obtain diethyl 2-bromo-2-phenylmalonate

To a solution of diethyl 2-phenylmalonate (15 ml) in 200 ml of tetrahydrofuran, stored at 0oC and under nitrogen atmosphere, add 3,475 mg of sodium hydride and the mixture is kept for 30 minutes under stirring at 0oC, then the temperature is brought to room temperature. After cooling again to 0oC, the reaction mixture was added 14.3 g irout dry with the formation of a residue, which is again dissolved in chloroform and dried over sodium sulfate. The solvent is evaporated under reduced pressure to education 15,66 g of the product.

b) preparation of diethyl 2-phenyl-2-[4-(2-hydroxyethyl) piperazinil] malonate

A solution of diethyl 2-bromo-2-phenylmalonate (16,8 g) in 150 ml of dimethyl sulfoxide is heated to 90-100oC, then add N-(2 - hydroxyethyl)piperazine (27.9 g) and the reaction mixture is heated for an additional 4 hours. The mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts are washed with 1N hydrochloric acid. The aqueous phase is alkalinized 1N sodium hydroxide to pH 8-9 and extracted twice with ethyl acetate. The organic extracts are collected and washed with saturated aqueous sodium chloride and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue is crystallized from diethyl ether/petroleum ether 1:1 with the formation of 6.5 product; so pl.: 63-64oC.

C) obtaining the title compound

To a solution of sodium (27 mg) in 3 ml of ethanol is added 218 mg diethyl-2-phenyl-2-[4-(2-hydroxyethyl)piperazinil] malonate and 288 mg of thiourea, and the mixture is then refluxed for 13 hours the al is evaporated under reduced pressure. The residue is again dissolved in a mixture of ethyl acetate/methanol 9:1. Dropped the precipitate was separated by filtration and the filtrate is concentrated to dryness and purified by chromatography on silica gel(eluent: ethyl acetate to ethyl acetate/methanol 9:1), education after crystallization from ethyl acetate 30 mg of product; so pl.: > 250oC.

1H-NMR in d6-DMSO: 2,4 ppm (m, 6H); at 2.59 ppm (m, 4H); 3.46 in ppm (q, 2H); 4,4 ppm (t, 1H); to 7.4 ppm (m, 5H); 12,5 ppm (br s, 2H).

EXAMPLE 18

5-phenyl-5-[N-(2-hydroxyethyl)piperazinil]-2 - isobarically acid.

To a solution of sodium (70 mg) in 5 ml of ethanol is added 218 mg diethyl-2-phenyl-2-[4-(2-hydroxyethyl)piperazinil] malonate (example 4 - b) and 172 mg of guanidine hydrochloride and the mixture is refluxed for 8 hours. Then add another 57 mg of guanidine hydrochloride and the mixture is refluxed for another 6 hours. Bring to room temperature and add acetic acid until neutralization, precipitation, which is filtered off. The filtrate is concentrated to dryness and re-dissolved in ethanol, from which adding ethyl acetate precipitation. After 1 hour at -4oC get the white precipitate by filtration and recrystallized from methanol (2 ml) with the formation of polr in d6-DMSO: 2,33 ppm (m, 6H); to 2.54 ppm (m, 4H); 3,41 ppm (t, 2H); 4,33 ppm (br s, 1H); 7,00 ppm (br s, 1H); 7,33 ppm (m, 5H); 7.5 ppm (br s, 1H); to 11.4 ppm (br s, 1H).

EXAMPLE 19

5-benzyl-5-[N-(2-hydroxyethyl)piperazinil] barbituric acid

a) receiving 5-benzylideneamino acid

A suspension of 5 g of barbituric acid in 50 ml of water is heated before will completely dissolve, then add 4.3 ml of benzaldehyde. The mixture is refluxed for 1 hour, then filtered to separate the precipitate, washed several times with water and dried in vacuum at 100oC with the formation 8,17 g of the product; so pl.: > 258oC.

b) receiving 5-antibarbarus acid

To a suspension of 5-benzylideneamino acid (4 g) in 200 ml portions of methanol added 1.4 g sodium borohydride. 10 minutes after the end of add, add 100 ml of water and the mixture acidified with 1N hydrochloric acid to pH 2. The solvent is evaporated and the aqueous phase extracted with ethyl acetate. The combined extracts dried over sodium sulfate and concentrated to dryness. Crystallized 3.6 g of product; so pl.: 207-209oC.

C) obtaining 5-bromo-5-antibarbarus acid

To a suspension of 5-antibarbarus acid (1.7 g) in 15 ml of water, cooled to 0-5oC, add 1 ml of 4 with stirring at a temperature below 10oC, sediment is deposited, which is separated by filtration and washed with water. Obtain 2.17 g of product; so pl.: 164-166oC.

d) obtaining the title compound

A solution of 5-bromo-5-antibarbarus acid (2.15 g) and N-(2 - hydroxyethyl)piperazine in 50 ml of ethanol is refluxed for 4 hours, then cooled to room temperature and add 4 ml of triethylamine. The solvent is evaporated and a white precipitate is again dissolved in a mixture of ethyl acetate/methanol 3: 1. Crystallized orange solid residue, which is marked by filtration. After recrystallization from ethanol and 0.62 g of product, which is separated by filtration. After recrystallization from ethanol and 0.62 g of product; so pl.: 243-246oC.

1H-NMR in d6-DMSO: 2,43 ppm (t, 2H); 2,58 ppm (m, 4H); 3,03 ppm (m, 4H); 3,34 ppm (s, 2H); 3,49 ppm (q, 2H); 4,5 ppm (t, 1H); 7,13 ppm (m, 5H); and 8.8 ppm (br s, 2H).

EXAMPLE 20

5-[N-(2-hydroxyethyl)piperazinil] -5-(4-hydroxyphenyl) barbituric acid

a) obtaining 5-(4-hydroxyphenyl)barbituric acid

To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 5 ml of methylene chloride, and stored at -5/-10oC and under nitrogen atmosphere, is added dropwise trichromacy boron (473 μl) in 2 ml of methylene chloride. Paramasivan the ion mixture is again cooled to 0oC in an ice bath and alkalinized to pH 9-10 by adding dropwise a 5% sodium hydroxide. The aqueous phase is separated, filtered through a layer of celite, cooled in an ice bath and acidified to pH 1 with 37% hydrochloric acid. Precipitation, which is separated after 1 hour, filtered and dried in vacuum at 60oC with the formation of 215 mg of product.

b) receiving 5-[4-(tertBUTYLPEROXY)phenyl] barbituric acid

To a solution of 5-(4-hydroxyphenyl)barbituric acid (1.9 g) and tributyltinchloride (4.68 g) in 20 ml of anhydrous dimethylformamide added 4.4 g of imidazole and the mixture is heated to 55oC for 5 hours. The temperature was then brought to room temperature and the reaction mixture was poured into 1N hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts washed with water and dried over sodium sulfate. When the concentration of the solution of saliva, which has been stored overnight at 0oC, then filtered with education 2,185 g of the product.

C) obtaining 5-bromo-5-[(4-tertBUTYLPEROXY)phenyl] barbituric acid

To a suspension of 5-[4-(tertBUTYLPEROXY)phenyl] barbituric acid (330 mg) and peroxide of Dibenzoyl (catalytic coli temperature for 1 hour, then the solvent is evaporated and the residue purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate 8:2) with the formation of 260 mg of the product.

d) receiving 5-[N-(2-hydroxyethyl)piperazinil] -5-[(4 - tertBUTYLPEROXY)phenyl]barbituric acid

A solution of 5-bromo-5-[(4-tertBUTYLPEROXY)phenyl] - barbituric acid (260 mg) and N-(2-hydroxyethyl)piperazine (98 mg) in 5 ml of ethanol is refluxed for 1 hour, then brought to room temperature and add 0.3 ml of triethylamine. The solvent is evaporated and the residue purified by chromatography on silica gel (25 g; eluent: ethyl acetate/methanol 3:1) education after crystallization from ethyl acetate, 170 mg of product; so pl.: 220-221oC.

e) obtaining the title compound

A mixture of 5-[N-(2-hydroxyethyl)piperazinil] -5-[(4 - tertBUTYLPEROXY)phenyl] barbituric acid (148 mg), tetrabutylammonium fluoride (1.1 M in THF; 0.6 ml) and acetic acid (290 μl) in 10 ml of tetrahydrofuran is stirred for 2 hours 30 minutes at 0oC, then the solvent is evaporated and the residue purified by chromatography on silica gel (12 g, eluent: ethyl acetate/methanol 3: 1), education after crystallization from ethyl acetate and paracrystal is to 2.55 ppm (m, 4H); to 3.45 ppm (q, 2H); of 4.35 ppm (t, 1H); 6,76 ppm (d, 2H); 7,17 ppm (d, 2H); 9,72 ppm (s, 1H); 11,47 ppm (br s, 2H).

EXAMPLE 21

5-[N-(2-hydroxyethyl)piperazinil] -5-(3-hydroxyphenyl) barbituric acid

a) obtain ethyl 3-hydroxyphenylacetate

A suspension of 3-hydroxyphenylacetic acid (5.4 g) and para - toluenesulfonic acid (650 mg) in 80 ml of ethanol is refluxed for 4 hours, the solvent is then evaporated and the residue is dissolved in ethyl acetate and washed twice with a saturated aqueous solution of acid sodium carbonate. The organic phase is dried over sodium sulfate and the solvent is evaporated to education between 6.08 g of the product as a yellow oil.

b) obtain ethyl 3-(tertBUTYLPEROXY) phenylacetate

To a solution of ethyl 3-hydroxyphenylacetate (6 g) and tributyltinchloride (6 g) in 80 ml of anhydrous dimethylformamide add to 5.66 g of imidazole and the mixture is stirred at room temperature for 1 hour and 30 minutes. Then the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts dried over sodium sulfate and concentrated to dryness with the formation of 10 g of the product as a yellow oil.

C) obtaining diethyl-3-(tributyltinhydride portions add 0,86 tons of sodium and the mixture is refluxed for 2 hours. The solvent is evaporated and the residue poured into water (90 ml). the pH was adjusted to pH 6 with acetic acid and the mixture extracted with diethyl ether. The organic phase is dried over sodium sulfate and concentrated to dryness with the formation of 10 g of an orange oil, which was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate 95:5), with the formation of 2.45 g of the product.

d) receiving 5-[3-(tertBUTYLPEROXY)phenyl] barbituric acid

To a solution of diethyl 3-(tertBUTYLPEROXY) phenylmalonate (1.5 g) in 15 ml ethanol add 0,445 g ethylate sodium and 0,295 g of urea and the mixture is refluxed for 3 hours. The reaction mixture is cooled to room temperature and the resulting solid precipitate was filtered. The precipitate is again dissolved in water, pH adjusted to pH 1-2 6 N hydrochloric acid and the precipitated precipitate is removed by filtration. The filtrate is concentrated to remove ethanol, and then the solution is alkalinized and extracted with ethyl acetate. The organic phase is concentrated to dryness with the formation of 250 mg of residue, which combine with the previously filtered residue (350 mg). Thus obtained residue consists of a mixture of the product along with disilylgermane derived.

This OST is hillhold and 745 mg of imidazole. The mixture is heated to 55oC for 5 hours. Add 75 mg of imidazole and 79 mg of tributyltinchloride and continue heating for another hour. Then the reaction mixture was poured into 1 N hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts washed with water and dried over sodium sulfate. The solution is concentrated, and saliva. 710 mg of product are filtering.

e) receiving 5-[3-tertBUTYLPEROXY)phenyl]-5 - Promarmatura acid

A mixture of 5-[3-(tertBUTYLPEROXY)phenyl] barbituric acid (680 mg), N-bromosuccinimide (432 mg) and peroxide of Dibenzoyl (catalytic amount) in 10 ml of carbon tetrachloride was stirred at room temperature for 1 hour. The solvent is evaporated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/hexane 7:3) with the formation of 550 mg of product; so pl.: 170-172oC.

f) receiving 5-[N-(2-hydroxyethyl)piperazinil]-5-[3 - tertBUTYLPEROXY)phenyl]barbituric acid

A solution of 5-[3-(tertBUTYLPEROXY)phenyl] -5-bromo - barbituric acid (444 mg) and N-(2-hydroxyethyl)piperazine (420 mg) in 10 ml of methanol was stirred at room temperature for 5 methanol 3:1) with the formation of 70 mg of product.

g) obtaining the title compound

To a solution of 5-[N-(2-hydroxyethyl)piperazinil]-5-[3- (tertBUTYLPEROXY) phenyl]barbituric acid (170 mg) in 12 ml of tetrahydrofuran, stored at 0oC and under nitrogen atmosphere, add 333 μl of acetic acid and 0.69 ml of tetrabutylammonium fluoride. The mixture is stirred for 3 hours, then the solvent is evaporated and the residue purified by chromatography on silica gel (15 g; eluent: ethyl acetate/methanol 4:1), education after crystallization from methanol 35 mg of product; so pl.: 219-221oC.

1H-NMR in d6-DMSO: 2,37 ppm (m, 6H); at 2.59 ppm (m, 4H); to 3.45 ppm (q, 2H); of 4.35 ppm (t, 1H); 6,74 ppm (m, 2H); 6,92 ppm (t, 1H); 7.18 in ppm (t, 1H); 9,62 ppm (s, 1H); 11,54 ppm (br s, 2H).

EXAMPLE 22

5-[N-(2-hydroxyethyl)piperazinil]-5-(4-were) barbituric acid

a) obtaining 5-(4-were)barbituric acid

To a solution of sodium (184 mg) in 12 ml of ethanol added to 0.95 ml of diethyl 2-(4-were)malonate and 360 mg of urea, the mixture is then refluxed for 3 hours. Roll a white precipitate, which is filtered and re-dissolved in 4 ml of water. The solution is acidified to pH 1-2 by addition of 6N hydrochloric acid. Roll a white precipitate, which is collected by filtration, washed with 15 ml of water and dried under vacati

To a suspension of 5-(4-were) barbituric acid (218 mg) in 2 ml of water at 10oC under stirring, add 136 μl of 48% Hydrobromic acid, and then 56 μl of bromine dropwise and stirred for 3 hours. The resulting precipitates are filtered and washed with water, then dried under vacuum with the formation of 270 mg of product; so pl.: 210-213oC.

C) obtaining the title compound

A solution of 5-bromo-5-(4-were)barbituric acid (3.1 g) and N-(2-hydroxyethyl)piperazine (1,53 g) in 60 ml of ethanol is refluxed for 3 hours. The solvent is evaporated and the residue is dissolved in 1N hydrochloric acid and washed twice with ethyl acetate. The aqueous phase is alkalinized 1N sodium hydroxide and extracted with ethyl acetate. The organic extracts are concentrated to dryness and the residue purified by chromatography on silica gel (100 g, eluent: ethyl acetate/methanol 3:1) education after evaporation of the solvent of 1.97 g of the product in the form of the hydrobromide.

The free base is obtained by treatment of a suspension (200 ml) salt in ethyl acetate and 50 ml of a saturated aqueous solution of acid sodium carbonate and extraction of the aqueous phase with ethyl acetate. When concentrating to dryness combined organic e is m (t, 1H); 7,19 ppm (d, 2H); 7,28 ppm (d, 2H); for 11.55 ppm (br s, 2H).

EXAMPLE 23

5-octyl-5-[N-(2-hydroxyethyl)piperazinil] barbituric acid

a) obtain diethyl 2-octisalate

To a solution 2,63 g of sodium in 100 ml of ethanol is added dropwise a solution of 19.1 ml of diethylmalonate in 10 ml of ethanol. To the mixture successively added to 20.4 ml of 1-bromooctane dissolved in 10 ml of ethanol, then the mixture is refluxed for 6 hours. The reaction mixture is concentrated to small volume and the residue partitioned between saturated aqueous solution of monohydrogenphosphate sodium (200 ml) and ethyl acetate (200 ml). The organic phase is washed with 75 ml of water and 75 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness to education 3,18 g of the product as oil.

1H-NMR in CDCl3: to 0.80-0.95 ppm (m, 3H); 1,15-of 1.40 ppm (m, 18H); a 1.88 ppm (q, 2H); to 3.33 ppm (t, 1H); 4,19 ppm (q, 4H).

b) receiving 5-antibarbarus acid

To a solution of sodium (5.32 g) in 400 ml of anhydrous ethanol is added a solution of diethyl 2-octisalate (31.5 g) in 50 ml of ethanol and consistently 10,27 g of urea, the mixture is then refluxed for 2 hours 30 minutes. The mixture is rapidly cooled to room temperature and obrazovavshijsya 6N hydrochloric acid to pH of 1.5-2. Sediment is deposited. The mixture was added 200 ml of ethyl acetate and stirred for 2 hours, then add another 800 ml of warm ethyl acetate. The organic phase is separated and the aqueous phase is washed with 200 ml of ethyl acetate. The combined organic phases are washed with 250 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. Get 21,03 g of the product.

1H-NMR in d6-DMSO: 0,77-to 0.80 ppm (m, 3H); 1,23 ppm (s, 12H); of 1.80-1.95 ppm (m, 2H); to 3.52 ppm (t, 1H); of 11.15 ppm (s, 2H).

C) obtaining 5-bromo-5-antibarbarus acid

To a suspension of 5-antibarbarus acid (20 g) in 120 ml of water, cooled to 0-5oC add 12 ml of 48% Hydrobromic acid and successively dropwise 4,72 ml of bromine. After 2 hours stirring the resulting white precipitate was separated by filtration, washed with water and partitioned between 200 ml of diethyl ether and 100 ml of water. The aqueous phase is extracted with an additional 50 ml of diethyl ether. The combined organic phases are washed with 75 ml saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. Get to 25.8 g of the product in the form of a white precipitate.

1H-NMR in d6-AMCO: 0,78-of 0.90 ppm (m, 3H); 1,10-to 1.38 ppm (m, 12H); 2,20-2,34 ppm (m, 2H); 11,80 ppm (s, 2H).

d) receiving the, in nitrogen atmosphere and at a temperature of 5-10oC added dropwise N-(2-hydroxyethyl)piperazine (36.2 ml), the mixture is then stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was poured into water (1 l) with stirring and cooled in an ice bath. The resulting white precipitate obtained by filtration, washed with water and dried in vacuum at 40oC with formation after crystallization from ethanol (140 ml) 10,91 g of the product in the form of white sediment; so pl.: 183-184oC.

1H-NMR in d6-AMCO: of 0.75 to 0.88 ppm (m, 3H); 0,90-1,10 ppm (m, 2H); 1,12-of 1.30 ppm (m, 10H); 1,75-1,90 ppm (m, 2H); 2.23 to-to 2.40 ppm (m, 6H); 2,45-2,60 ppm (m, 4H); to 3.45 ppm (br t, 2H); 4.35 the ppm (br s, 1H); for 11.55 ppm (s, 2H).

EXAMPLE 24

5-naphthyl-5-[N-(2-hydroxyethyl)piperazinil] barbituric acid

a) obtain ethyl 2-naphthylacetate

To a solution of 2-naphthylacetic acid (5 g) in 50 ml ethanol, add 0.5 g of para-toluenesulfonic acid, then the reaction mixture is refluxed for 4 hours. The solvent is evaporated and the residue is dissolved in diethyl ether, washed twice with a saturated aqueous solution of acid sodium carbonate and once with brine, then the combined organic extracts dried over sodium sulfate and concentrated to dryness. Get 5,64 g preata (2 g) 23.3 ml diethylmalonate under stirring at room temperature portion add 0,232 g of sodium. The reaction mixture is refluxed for 2 hours 30 minutes, then concentrated to remove unreacted diethylmalonate and add 20 ml of cold water. The resulting mixture was acidified with acetic acid to weak acidity, then three times extracted with diethyl ether. The combined organic extracts dried over sodium sulfate and the solvent is evaporated to education after recrystallization from diethyl ether (19 ml), 1,015 g of the product in the form of a white precipitate.

C) obtaining 5-nativemethods acid

In a solution of sodium (0.32 g) in 30 ml of anhydrous ethanol is added diethyl 2-nafcillin (2 g) and consistently urea (0,63 g). The mixture is refluxed for 2 hours, then the resulting precipitate was separated by filtration, then dissolved in 7 ml of water and acidified to pH 1 6 N hydrochloric acid. After 30 minutes stirring falls white precipitate, which is filtered off and washed with water. The precipitate is dried overnight under vacuum at 40oC with the formation of 0.96 g of product.

d) receiving 5-bromo-5-nativemethods acid

A suspension of 5-nativemethods acid (0.2 g) in 1.5 ml of 95% ethanol, cooled to 0oC and PR is 4 hours stirring at room temperature the precipitate is filtered off and washed with water, then dried under vacuum at 40oC during the night. Obtain 0.25 g of the product.

e) obtaining the title compound

To a suspension of 5-bromo-5-nativemethods acid (0.24 g) in 3.5 ml of ethanol is added a solution of N-(2-hydroxyethyl)-piperazine (0,112 g) in 1.5 ml of ethanol. The reaction mixture is refluxed for 5 hours, then cooled to room temperature and the residue is filtered off. To the filtrate was added 100 μl of triethylamine, the solvent is then evaporated with education 0,364 g of sediment, which is recrystallized from a mixture of methanol (4.5 ml) and ethyl acetate (10 ml). The obtained residue (70 mg) is washed by stirring with a mixture of ethyl acetate/water for 2 hours and dried in vacuum at 40oC for 8 hours with the formation of 60 mg of product.

1H-NMR in d6-DMSO: of 2.3-2.5 ppm (m, 6H); to 2.6 ppm (m, 4H); to 3.45 ppm (m, 2H); of 4.35 ppm (t, 1H); of 7.4 to 8.1 ppm (m, 7H); 11,65 ppm (s, 2H).

EXAMPLE 25

5-(4'-biphenyl)-5-[N-(2-hydroxyethyl) piperazinil]barbituric acid

a) obtaining ethyl (4'-biphenyl)acetate

To a suspension of (4'-biphenyl) acetic acid (6.4 g) in 60 ml of ethanol is added 1.1 g of para-toluenesulfonic acid, then the reaction mixture is refluxed for 4 hours and 30 minutes. Dissolve the n aqueous solution of acid sodium carbonate and once with brine. Then the organic phase is dried over sodium sulfate and the solvent is evaporated with the formation of 7.1 g of product as a yellow oil.

b) obtaining diethyl - (4'-biphenyl)malonate

To a solution of ethyl (4'-biphenyl) acetate (7,1 g) in 60 ml of diethylmalonate in nitrogen atmosphere the portion of added sodium (0,734 g), then heated at 120oC for 3 hours. The solvent is evaporated and the residue is dissolved in 65 ml of cold water and acidified with acetic acid to pH 5-6. The aqueous phase is extracted three times with diethyl ether and the combined organic extracts dried over sodium sulfate and concentrated to dryness. The residue is purified by chromatography on silica gel (eluent: petroleum ether/diethyl ether 9,4:0,6) education 7.05 product; so pl.: 51-53oC.

C) obtaining 5-(4'-biphenyl)barbituric acid

To a solution of sodium (0,322 g) in 40 ml of anhydrous ethanol is added diethyl (4'-biphenyl)malonate (2.2 g) and consistently urea (0,63 g). The reaction mixture is refluxed for 3 hours and 30 minutes, then cooled to room temperature and the precipitate are filtered. The precipitate is again dissolved in 40 ml of warm water and the resulting aqueous phase is acidified to pH 1 6N hydrochloric acid. the>. Obtain 1.1 g of product; so pl.: > 240oC.

d) receiving 5-bromo-5-(4'-biphenyl)barbituric acid

To a suspension of 5-(4'-biphenyl)barbituric acid (0.28 g) in 1.4 ml of water, cooled to 0oC and with stirring, added dropwise to 0.14 ml of 48% Hydrobromic acid and consistently 55,5 μl of bromine. The temperature is brought to room temperature and stirring is continued for 1 hour. Suspended sediment allocate by filtration, washed with water and dried under vacuum at 60oC for 2 hours with the formation of 0,336 g of the product; so pl.: 203-205oC.

e) obtaining the title compound

To a suspension of 5-bromo-5-(4'-biphenyl)barbituric acid (0.323 g), 4.4 ml of ethanol is added 0.14 g of N-(2-hydroxyethyl) piperazine and the reaction mixture is refluxed for 2 hours. Suspended sediment is filtered and the resulting clear solution is treated with 125 μl of triethylamine, and then the solvent is evaporated. The residue is again dissolved in 2 ml of ethanol, from which the crystallized residue which is stirred for 30 minutes, then filtered. The remainder will recrystallized from ethanol with the formation of 100 mg of pure product; so pl.: 225-226oC.

1H-NMR in d6-DMSO: of 2.3-2.5 ppm (m, is arsenil] barbituric acid

To a solution of 5-bromo-5-(4'-biphenyl)barbituric acid (0,359 g, example 25, paragraph (d) in 9 ml of methanol add 0,622 g of N-(4 - nitrophenyl)piperazine and the mixture is refluxed for approximately 2 hours. The solvent is evaporated and the residue partitioned between water and ethyl acetate. The organic phase is separated, washed with brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure with the formation of 0.74 g of residue which purify by chromatography on silica gel (eluent: methylene chloride/acetone 9:1) with the formation of 400 mg of the product; so pl.: 181oC.

1H-NMR in d6-DMSO: to 2.8 ppm (m, 4H); and 3.5 ppm (m, 4H); 7,00 ppm (d, 2H); 7.3 to a 7.85 ppm (m, 9H); with 8.05 ppm (d, 2H); to 11.7 ppm (s, 2H).

EXAMPLE 27

5-(4'-phenoxyphenyl)-5-[N-(2-hydroxyethyl)piperazinil] barbituric acid

a) obtaining N-[4'-phenoxybenzyl)thiocarbonyl]research

A mixture of (4'-phenoxyphenyl)ketone (19,1 g), research (20 ml) and sulfur (4,32 g) is refluxed for 24 hours, then extracted with diethyl ether. The organic phase is concentrated to dryness with education after crystallization from a mixture of petroleum ether/ethyl acetate 8:2 (600 ml), 12.2 g of the product; so pl.: 75-77oC.

C) getting (4'-phenoxyphenyl)acetic acid

With what these lamps for 8 hours 30 minutes then the temperature of the reaction mixture is brought to room temperature and acidified with 1N hydrochloric acid. Precipitated white precipitate is stirred for 30 minutes and filtered. The precipitate is washed with water and dried under vacuum to education 1,095 g of the product; so pl.: 70-72oC.

C) obtaining ethyl (4'-phenoxyphenyl)acetate

To a suspension of (4'-phenoxyphenyl) acetic acid (0,456 g) in 4 ml ethanol add a para-toluensulfonate (0,076 g) and the resulting mixture is refluxed for 2 hours. The solvent is evaporated, the residue is dissolved in diethyl ether and the organic phase is washed with saturated aqueous acidic sodium carbonate and then brine. The organic phase is dried over sodium sulfate and concentrated to dryness to education 0,458 g of the product in the form of a brown oil.

d) receiving 5-(4'-phenoxyphenyl)barbituric acid

To a solution of ateleta sodium (0.27 g) in 3 ml of anhydrous ethanol add 0,657 g of ethyl (4'-phenoxyphenyl)acetate, dissolved in 5 ml of ethanol, then urea (0.18 g). The reaction mixture is refluxed for 2 hours 30 minutes, then cooled to room temperature and the suspended solid is filtered off. About what filtrowanie education 0,165 g of the product; so pl. > 240oC.

e) receiving 5-bromo-5-(4'-phenoxyphenyl)barbituric acid

To a suspension of 5-(4'-phenoxyphenyl)barbituric acid (48 mg) in 0,23 ml of water, cooled to 0oC and under stirring, add 23 ál of 48% Hydrobromic acid and consistently 9 μl of bromine. After 2 hours at room temperature add 9 μl of bromine and stirring is continued for 2 hours. Suspended sediment allocate by filtration and washed with water with formation after drying under vacuum at 60oC, 57 mg of product; so pl.: 125-126oC.

f) obtaining the title compound

To a solution of 5-bromo-5-(4'-phenoxyphenyl)barbituric acid (50 mg) in 0.2 ml of methanol is added dropwise a solution of N-(2 - hydroxyethyl)piperazine (52 mg) in 0.6 ml of methanol and the mixture is stirred for 2 hours. A white precipitate is collected by filtration and dried under vacuum at 60oC during the night. Get of 42.6 mg of product; so pl. > 240oC.

1H-NMR in d6-DMSO: 2,2 at 2.45 ppm (m, 6H); to 2.55 ppm (m, 4H); to 3.45 ppm (m, 2H); 4,4 ppm (t, 1H); from 6.9 to 7.7 ppm (m, 9H); to 11.6 ppm (s, 2H).

EXAMPLE 28

5-decyl-5-[N-(2-hydroxyethyl)piperazinil] barbituric acid

a) obtaining diethylmalonate

To a solution of sodium (0,46 g) in 10 ml of anhydrous ethane, the Reaction mixture is refluxed for 4 hours, then the precipitate is filtered off and the filtrate concentrated to dryness. The residue is again dissolved in a saturated aqueous solution of acidic sodium sulfate and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and the solvent is evaporated. The resulting residue is used as such in subsequent reactions.

b) receiving 5-decemberpetrovac acid

To a solution of diethylmalonate in paragraph (a) in 40 ml ethanol add 2,72 g ethylate sodium and then 1.8 g of urea. The reaction mixture is refluxed for 2 hours, then the precipitate is filtered and re-dissolved in 40 ml of water. The resulting aqueous solution is acidified with 6N hydrochloric acid. Precipitated solid precipitate was separated by filtration and dried under vacuum at 40oC during the night with the formation of 2,152 g of the product; so pl.: 190oC.

C) obtaining 5-bromo-5-decemberpetrovac acid

To a suspension of 5-decemberpetrovac acid (0,537 g) in 2.9 ml of water under stirring at room temperature is added dropwise to 0.29 ml of 48% Hydrobromic acid. The mixture is cooled to 0oC and added dropwise 0,113 ml of bromine. The reaction mixture was stirred at room temperature for 1 hour 30 minutes FYROM, the organic phase is separated, washed with brine and in the end it is dried over sodium sulfate. Upon evaporation of the solvent under reduced pressure gain of 0.62 g of product.

d) obtaining the title compound

To a solution of 5-bromo-5-decemberpetrovac acid (0,619 g) in 1.3 ml of dimethyl sulfoxide with stirring at 0oC, are added dropwise with 0.93 g of N-(2-hydroxyethyl)piperazine in 0.7 ml of dimethyl sulfoxide, and then the reaction mixture was stirred at room temperature for 1 hour. The mixture is then cooled to 0oC and add 30 ml of water. The separated white precipitate is stirred for 1 hour, then collected by filtration and dried under vacuum at 50oC. Get 0,309 g of the product; so pl.: 181-182oC.

1H-NMR in d6-DMSO: to 0.85 ppm (t, 3H); 0,9-1,1 ppm (m, 2H); of 1.15 to 1.4 ppm (m, 14H); as 1.8-1.9 ppm (m, 2H); 2,2-of 2.45 ppm (m, 6H); to 2.55 ppm (m, 4H); to 3.45 ppm (m, 2H); of 4.35 ppm (t, 1H); for 11.55 ppm (s, 2H).

EXAMPLE 29 5-hexadecyl-5-[N-(2-hydroxyethyl) piperazine]barbituric acid

The title compound get a similar manner as the compound in example 28.

EXAMPLE 30

5-amoxil-5-[N-(2-hydroxyethyl)piperazine]barbituric acid

The title compound is prepared similarly to the compound in example 28.

.

1H-NMR in d6-AMCO: of 0.91 ppm (t, 3H); 1,4 ppm (m, 2H); rate of 1.67 ppm (m, 2H); at 2.36 ppm (m, 6H); to 2.55 ppm (m, 4H); 3,44 ppm (q, 2H); 3.95 to ppm (t, 2H); 4,37 (t, 1H); 6,95 ppm (d, 2H); 7,28 ppm (d, 2H); 11,5 ppm (br s, 2H).

The compound is prepared as described in example 14. The only difference is that the starting material is ethyl 4-butoxyaniline, which can be prepared starting from 4-hydroxyphenylarsonic acid by esterification with ethanol (see example 14) and subsequent alkylation with ethyl 4-hydroxyphenylacetate and butylbromide by known methods.

EXAMPLE 32

As a result of methods of preparation, are described in the specification and the previous examples, synthesize compounds that are characterized by mass spectroscopy (see tab. 1).

EXAMPLE 33

In order to determine the inhibition of MMP, for example, HNC, catalytic domain (allocation and cleanup, see, for example, Schnierer, S., Kleine, T., Gote, I. , Hillemann, A., Knauper, V., Tshesche, H.,Biochem. Biophys. Res. Commun. (1993) 191, 319-326) were incubated with inhibitors having different concentrations. Then by the method similar to Grams F. et al., FEBS, 335, 1993, 76-80, determine the initial reaction rate of the conversion of a standard substrate.

The results were evaluated when constructing a curve corresponding correctly plot the x-axis by Dixon, M., Biochem. J. (1953) 55, 170-202.

Synthetic substrate for collagenase is heptapeptide, which is conjugate to C-end with DNP (dinitrophenol). Mentioned the remainder DNP inhibits steric shielding of the related fluorescence of tryptophan in heptapeptide. After removal of Tripeptide, including DNP group, the fluorescence of tryptophan increases. Therefore proteolytic cleavage of the substrate is determined by the fluorescence readings.

a) the first method

The methodology was carried out at 25oC in freshly prepared 50 mm Tris buffer (pH 8.0), treated with dithizone to remove traces of heavy metals. Added 4 mm CaCl2and the buffer was saturated with argon. Royal solutions Adamantine II was obtained by centrifugation of the protein from the suspension resulting from the deposition of ammonium sulfate, and subsequent dilution in the buffer for analysis. Royal solutions of collagenase was diluted with buffer for analysis. The concentration of the enzyme was determined spectrophotometrically (280= 2,8104M-1cm-1,288= 2,2 104M-1cm-1and the mother solutions were stored in the cold. This solution was diluted 1: 100 to obtain the final concentration for the analysis of 16 nm. Used Plone Kialso used a concentration of 12.8 μm. The fluorescence of the substrate was determined at wavelengths of excitation and emission, equal =320 and 420 nm, respectively, on a spectrophotometer (Perkin Elmer Model 650-40), equipped with a thermostated cell camera. The hydrolysis of the substrate was carried out for 10 minutes immediately after adding the enzyme. All reactions were placed in three Parallels. The value of Kiinhibitors were determined from the intersection points of the straight lines obtained on the basis of the graphs of V0/Viagainst [the concentration of inhibitor], while the values of the IC50expected schedule Vi/V0[the concentration of the inhibitor] nonlinear regression with simple gross weighing.

b) the Second method

Buffer for analysis:

50 mm Tris/HCl pH to 7.6 (Tris=Tris (hydroxymethyl)-aminomethan)100 mm NaCl/10 mm CaCl2/5% Meon (requires the highest quality).

Enzyme: 8 nm catalytic domain (Met80-Gly242) human nerofiles collagenase.

Substrate: 10 Microm DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg - NH2.

The total amount of samples for analysis: 1 ml

Prepared in a solution of enzyme and inhibitor in buffer (25oC) for analysis. The reaction started immediately upon introduction into the solution of Sultan excitation and emission 280 and 350 nm, respectively. IC50were expressed as the concentration of inhibitor required to reduce the reaction rate by half compared to the reaction without inhibitor.

Table 2 shows the obtained values of the IC50.

Data on toxicity for compounds of example 26:

LD50= > 1000 mg/kg

All other compounds of the present invention are similar to the given level of toxicity.

1. Derivatives of barbituric acid of General formula I

< / BR>
in which X, Y and Z are oxygen;

R1represents the group W-V, where W is a valence bond or straight or branched C1-C4is an alkyl group, V is a monocycle selected from phenyl, optionally substituted by hydroxy, lower alkyl, lower alkoxy, phenyl, phenoxy; pyridyl, piperidinyl, thiophenyl, imidazolyl or bicyclo selected from naphthyl, chinoline, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, indolyl, each of which may be substituted, or W-V is a C1-C20is an alkyl group optionally substituted by amino, hydroxy, lower allmineral, carboxypropyl, aminocarbonyl, lower alkylaminocarbonyl, amino is 2 and R3both are hydrogen;

R4and R5denote independently of each A-D, where a represents a bond, C1-C8-alkyl, C1-C4-acyl, which may be interrupted by heteroatoms, selected from O, SO2and in which the alkyl group may be substituted amino group; sulfonyl, aminocarbonyl, alkoxycarbonyl, oxycarbonyl, D represents hydrogen, monocycle selected from phenyl, pyridyl, piperidinyl, cyclohexyl, furil, imidazolyl, pyrrolidinyl, thiophenyl, or bicycl selected from naphthyl, indolyl, tetrahydroquinoline, fluorenyl, each of which may be substituted, or R4and R5together with the nitrogen atom to which they are linked, represent a ring which optionally may be interrupted by additional N atom, the ring optionally can be substituted one or more times by hydroxyl, alkoxyl, amino, alkylamino, dialkylamino, nitrile or E-G, where E represents a valence bond, C1-C4-alkyl, which is optionally substituted by hydroxy; C2-C4alkenyl; G is hydrogen, 6-membered aromatic monocycle having 0, 1 or 2 nitrogen atom and the remaining atoms in the monocycle are atoms operina, -NH2, -NO2, -SO2NH2, -SO2CH3, acetyl and cyano;

the radicals listed for R1, R4and R5can be optionally once or several times substituted by halogen, hydroxyl, alkyl, hydroxyalkyl, alkoxyl, alkylthiol, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, nitrogroup, carboxyla, carboxamido, alkoxycarbonyl, amino or aminocarbonyl, optional one or two times substituted lower alkyl, nitrile, exography, thiocarboxamide, alkoxyaryl, alkylaminocarbonyl, Fofana, alkylphosphonium, dialkylphosphorous, alkylsulfonamides,

their pharmacologically acceptable salts or their esters of carboxylic acids, provided that when-NR4R5is unsubstituted piperidine ring, then R1can not be phenyl, stands, ethyl, propylene, alkyl or crotonyl and when-NR4R5is diethylaminopropyl, then R1may not be the stands, ethyl or crotonyl.

2. The compound of formula I under item 1, in which the monocycle G denotes phenyl, pyridyl, pyrimidinyl or pyridazinyl.

3. The compound of formula I according to one of paragraphs.1-2, will cocoabased radicals n-octyl, n-decyl or biphenyl.

4. The compound of formula I according to one of paragraphs.1-3, in which nitrogen, R4and R5form a piperazine or piperidine, both of which are substituted at the 4-position.

5. The compound of formula I according to one of paragraphs.1-4, which represents 5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinil]barbituric acid.

6. Pharmaceutical composition having activity inhibitor of matrix metalloprotease comprising at least one compound of formula I according to one of paragraphs.1-5, and optionally, conventional substance-carriers and excipients.

7. The compounds of formula I

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in which X, Y and Z are oxygen;

R1represents the group W-V, where W is a valence bond or straight or branched C1-C4is an alkyl group, V is a monocycle selected from phenyl, optionally substituted by hydroxy, lower alkyl, lower alkoxy, phenyl, phenoxy; pyridyl, piperidinyl, thiophenyl, imidazolyl or bicyclo selected from naphthyl, chinoline, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, indolyl, each of which may be substituted, or W-V is a C1-C20is an alkyl group, optional C is enacarbil, aminocarbonyl-lowest alkylaminocarbonyl, lower alkyl, lower alkoxyl, lower alkoxyalkyl;

R2and R3both are hydrogen;

R4and R5denote independently of each A-D, where a represents a bond, WITH1-C8-alkyl, C1-C4-acyl, which may be interrupted by heteroatoms, selected from O, SO2and in which the alkyl group may be substituted amino group; sulfonyl, aminocarbonyl, alkoxycarbonyl, hydroxy-carbonyl, D represents hydrogen, monocycle selected from phenyl, pyridyl, piperidinyl, cyclohexyl, furil, imidazolyl, pyrrolidinyl, thiophenyl, or bicycl selected from naphthyl, indolyl, tetrahydroquinoline, fluorenyl, each of which may be substituted, or R4and R5together with the nitrogen atom to which they are linked, represent a ring which optionally may be interrupted by additional N atom, the ring optionally can be substituted one or more times by hydroxyl, alkoxyl, amino, alkylamino, dialkylamino, nitrile or E-G, where E represents a valence bond, WITH1-C4-alkyl, which is optionally substituted by hydroxy; C2-C4alkenyl; G represents vodor the carbon atoms, where monocycle is unsubstituted or substituted by a Deputy selected from the group consisting of halogen, -NH2, -NO2, -SO2NH2, -SO2CH3, acetyl and cyano;

the radicals listed for R1, R4and R5can be optionally once or several times substituted by halogen, hydroxyl, alkyl, hydroxyalkyl, alkoxyl, alkylthiol, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, nitrogroup, carboxyla, carboxamido, alkoxycarbonyl, amino or aminocarbonyl, optional one or two times substituted lower alkyl, nitrile, exography, thiocarboxamide, alkoxyaryl, alkylaminocarbonyl, Fofana, alkylphosphonium, dialkylphosphorous, alkylsulfonamides,

and their pharmacologically acceptable salts for obtaining a pharmaceutical composition having activity to inhibit matrix metalloprotease.

8. The compounds of formula I according to p. 7 for obtaining a pharmaceutical composition having activity to inhibit Adamantine.

 

Same patents:

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to benzothiophene compounds of formula I, where R1-H, - OH, -O(C1-C4alkyl), - EA6H5-, OCO(C1-C6alkyl), or-OSO2(C2-C6alkyl);

R2IS-H, -OH, -O(C1-C4alkyl), EA6H5, CCA(C1-C6alkyl) , -OSO2(C2-C6alkyl), or halogen; R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino; n = 2 or 3; Z Is-O - or-S-, or their pharmaceutically acceptable salts

The invention relates to a derived aydinonat or salts thereof, useful for use as a medicine, particularly as an inhibitor of activated factor X coagulation

The invention relates to certain CIS - and TRANS-benzopyrane having substituted benzamide in position C-4, and to their use for the treatment and/or prevention (prophylaxis) of certain CNS disorders

The invention relates to substituted chromalusion (thio)ureas of the formula (I):

< / BR>
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;

R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;

Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

A denotes the residue of a saturated or unsaturated lactam of the formula:

< / BR>
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

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and their physiologically acceptable salts

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis

-alaninemia and their derivatives, method for the treatment glycolipoprotein diseases, the prevention of ischemic myocardial damage, the pharmaceutical composition" target="_blank">

The invention relates to derivatives of indole-2-carboxamide that can be used as inhibitors of glycogen phosphorylase, and to methods of treatment of glycogenolysis-dependent diseases or conditions using these compounds and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1
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