Dihydrobenzodiazepines, methods for their preparing and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

 

This invention relates to dihydroisocodeine that can be used in the treatment of dyslipidaemia, atherosclerosis, and diabetes and its complications.

In most countries, cardiovascular diseases remain one of the major diseases and the leading cause of death. About a third of men suffer from cardiovascular disease before the age of 60 years, the risk for women less (ratio of 1 to 10). Over the years (after 65 women are almost as susceptible to cardiovascular disease as men) percent of this disease is even greater. Vascular diseases such as coronary heart disease, strokes, restenosis and peripheral vascular disease, remain the first cause of death and disability worldwide.

At that time, nutrition and lifestyle can accelerate the development of cardiovascular disease, genetic predisposition, leading to dyslipidemia, is a significant factor in cardiovascular disease and death. The development of atherosclerosis is associated mainly with dyslipidaemia, which means abnormal lipoprotein levels in plasma. This dysfunction is especially evident when coronary disease, diabetes and obesity.

The concept is intended to explain the development of atherosclerosis, mainly focused on metabol is the ZMA cholesterol and metabolism of triglycerides.

Men hypertriglyceridaemia is relatively normal complaint, 10% of men 35 to 39 years show plasma concentrations above 250 mg/DL (LaRosa J.C., L.E.Chambless, M.H.Criqui, I.D.Frantz, C.J.Glueck, G.Heiss and J.A.Morisson, 1986. Circulation: Suppl. 1.12-29). In some patients the violation is of genetic origin, while for the other dominated by secondary causes, such as excessive alcohol consumption, obesity, diabetes, or excessive thyroid function.

Genetic causes hypertriglyceridemia that have been clearly defined, are homozygosis by dysfunctional alleles LPL or Aro S [Fojo S.S., J.L. de Gennes, U.Beisiegel, G.Baggio, S.F.Stahlenhoef, J.D.Brunzell and ..Brewer, Jr 1991. Adv. Exp. Med. Biol. 285: 329-333; Brunzell, J.D. 1995. in the Metabolic Basis of Inherited Disease, 6eed. .Scriver, A.Sly and D.Valle, published by McGraw-Hill, Inc., New York. 1913-1932]. However, these conditions are only in one case out of a million and are considered rare. There are tests based on studies in humans and mice, which have a deficiency of LPL [Brunzell, J.D. 1995. in the Metabolic Basis of Inherited Disease, 6eed. .Scriver, A.Sly and D.Valle, published by McGraw-Hill, Inc., New York. 1913-1932; T. Coleman, and others, 1995. J. Biol. Chem. 270: 12518-12525; Aalto-Setala K-, Weinstock P.H., Bisgaier C.L., Lin Wu, J.D. Smith, and J.L. Breslow, 1996. Journal of Lipid Research, 37, 1802-1811], indicating that heterozygosity for dysfunctional allele LPL may affect hypertriglyceridaemia, but re is to occur in the population. Plasmatic concentration of apolipoprotein CIII (APO CIII)regulated gene expression of APO CIII, perhaps in conjunction with a secondary reason may be new and more frequent cause hypertriglyceridemia people [Weinstock P.H., C.L.Bisgaier, .Aalto-Setala, H.Radner, R.Ramakrishnan, S.Levak-Frank, A.D.Essenburg, R. Zechner, and J.L. Breslow, 1995. J. Clin. Invest.: 2555-2568].

The APO CIII is a component of very low density lipoproteins (VLDLs), chylomicrons and high-density lipoproteins (HDLs).

Many studies show that the APO CIII plays an important role in the metabolism of rich glipizide lipoprotein (TGRLs). Clinical studies show a strong correlation between plasma APO CIII and concentration of triglycerides [Schonfeld. G., ..George, J.Miller, P.Reilly, and J.Witztum, 1979.: 1001-1010; Shoulders S., and others, 1991. Atherosclerosis 87: 239-247; Le N-A., J.C.Gibson and H.N.Ginsberg, 1988. J.Lipid Res. 29: 669-677]. Moreover, epidemiological studies suggest a link between certain alleles of the APO CIII and concentration of triglycerides [Rees, A., J.Stocks, C.R.Sharpe, M.A.Vella, ..Shoulders, J.Katz, N.I.Jowett, F.E.Baralle, and D.J.Galton, 1985 J.Clin. Invest.: 1090-1095; Aalto-Sefcala, etc. 1987. Atherosclerosis: 145-152; Tas, S. 1989. Clin. Chem.: 256-259; Ordovas J.M., and others, 1991. Atherosclerosis: 75-86; Ahn, Y.I., etc. 1991. Hum. Hered: 281-289; Zeng Q., MDammerman, Y.Takada, A.Matsunage, J.I.Breslow and J.Sasaki, 1994. Hum. Genet: 371-375].

The APO CIII has the ability to inhibit the activity of lipoprotein lipase (LPL) [C.S.Wang, W.J.McConnafchy, H.U.Kloer and P.Alaupovic, J.Clin. Invest.,, 384 (1984)] and to reduce the destruction of the “leftovers” of lipoproteins rich in triglycerides (TGRLs), through receptors apoprotein E [F.Shelburne, J.Hanks, W.Meyers and S.Quarfordt, J.Clin. Invest.,, 652 (1980); E.Windier and R.J.Havel, J.Lipid Res.,, 556, (1985)]. In patients with deficiency of APO CIII, catabolism TGRLs accelerated [H.N.Ginsberg, N.A. Le, I.A.Goldberg, J.C.Gibson, A.Rubinstein, P.Wang-Iverson, R.Norum and W.V.Brown, J.Clin. Invest.,, 1287 (1986)]. On the contrary, netexpress human APO CIII transgenic mice is associated with acute hypertriglyceridemia [Y.Ito, N.Azrolan, A.O''connell, A.Walsh and J.L.Breslow, Science, 249, 790 (1990)].

Through these mechanisms the APO CIII leads to decreased catabolism TGRLs, which leads to an increase in the concentration of triglycerides. Reduced plasma concentrations of APO CIII thus has some value, when the reduction triglyceridemia is desirable as a therapeutic target in populations with increased risk.

Compounds according to the invention are dihydroisocodeine, which are able to reduce the secretion of APO CIII.

Compounds according to the invention have the formula I:

in Kotor the th dashed lines indicate the possible presence of a double bond;

R1represents an optionally halogenated (C1-C18) alkyl, optionally halogenated (C1-C18) alkoxy, halogen, nitro, hydroxyl or (C6-C10) aryl (optionally substituted by optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy, halogen, nitro or hydroxyl);

n represents 0, 1, 2, 3 or 4;

R2and R3represent, independently from each other hydrogen; optionally halogenated (C1-C18) alkyl, (C1-C18) alkoxy; a (C6-C10) aryl; (C6-C10) aryl (C1-C6) alkyl; heteroaryl; heteroaryl (C1-C6) alkyl, (C6-C10) aryloxy; and (C6-C10) aryl (C1-C6) alkoxy; heteroaromatic; or heteroaryl (C1-C6) alkoxy; in which heteroaryl is a 5-7-membered aromatic heterocycle containing one, two or three endocycles heteroatoms, which are selected from 0, N and S and where the aryl and heteroaryl portions of these radicals optionally substituted with halogen, optionally halogenated (C1-C6) alkoxy, optionally halogenated (C1-C6) alkyl, nitro and hydroxyl;

R4represents hydrogen, (C1-C18 ) alkyl or (C6-C10) aryl, mentioned aryl group optionally substituted with halogen, optionally halogenated (C1-C6) alkoxy, optionally halogenated (C1-C6) alkyl, nitro or hydroxyl;

X represents S, O or-NT, where T represents a hydrogen atom, (C1-C6) alkyl, (C6-C10) aryl, (C6-C10) aryl (C1-C6) alkyl or (C6-C10) arylcarbamoyl;

R5is a (C1-C18) alkyl; hydroxy(C1-C18) alkyl, (C6-C10) aryl (C1-C6) alkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C5-C8) cycloalkenyl-(C1-C6) alkyl; isoxazolyl(C1-C6)alkyl, optionally substituted (C1-C6) alkyl; a group-CH2-CRa=CRbRcin which Ra, Rband Rcchosen independently from (C1-C18) alkyl, (C2-C18) alkenyl, hydrogen, and (C6-C10) aryl; a group-CH2-CO-Z, in which Z represents a (C1-C18) alkyl, (C1-C6) alkoxycarbonyl, (C6-C10) aryl (C1-C6) alkyl, (C6-C10) aryl, optionally fused with a 5-7 membered aromatic or unsaturated heterocycle, containing one, two or three andazi the symbolic heteroatoms, which are selected from O, N and S; or a 5-7 membered heteroaryl containing one, two or three heteroatoms, which are selected from O, N and S; aryl and heteroaryl portions of these radicals optionally substituted with halogen, hydroxyl, optionally halogenated (C1-C6)alkyl, optionally halogenated (C1-C6) alkoxy, nitro, di(C1-C6) alkoxy-phosphoryl (C1-C6) alkyl or (C6-C10) aryl (optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy, nitro or hydroxyl);

or alternatively, R4and R5together form a group-CR6=CR7-in which CR6associated with X and in which:

R6represents a hydrogen atom; (C1-C18) alkyl, (C3-C8) cycloalkyl; (C6-C10) aryl; carboxy (C1-C6) alkyl, (C1-C6)alkoxycarbonyl (C1-C6) alkyl; heteroaryl; (C1-C6) aryl (C1-C6) alkyl; and heteroaryl (C1-C6) alkyl; where heteroaryl is a 5-7-membered aromatic heterocycle containing one, two or three endocycles heteroatoms, which are selected from O, N and S and where the aryl and heteroaryl portions of these radicals neoba is consequently replaced by (C 1-C6) alkyl, (C1-C6)alkoxy, hydroxyl, nitro, halogen or di(C1-C6) alkoxyphenyl (C1-C6) alkyl;

R7represents a hydrogen atom; hydroxyl; di (C1-C6) alkylamino (C1-C6) alkyl, (C1-C18) alkyl; carboxyl; (C1-C6) alkoxycarbonyl; (C6-C10) aryl; heteroaryl; (C6-C10)aryl (C1-C6) alkyl; or heteroaryl (C1-C6) alkyl; in which heteroaryl is a 5-7-membered aromatic heterocycle containing one, two or three endocycles heteroatoms, which are selected from O, N and S, and where the aryl and heteroaryl portions of these radicals optionally substituted with halogen, hydroxyl, optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy, carboxyla, (C1-C6) alkoxycarbonyl, nitro, di(C1-C6) alkoxyphenyl (C1-C6) alkyl, (C6-C10) aryl (this radical optionally substituted by hydroxyl, nitro, optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy or halogen) or (C6-C10) aryl, fused with a 5-7 membered aromatic or unsaturated heterocycle comprising one, d is a or three endocycles heteroatoms, selected from O, N and S;

or alternatively, R6and R7together form a3-C6alkylenes chain, optionally interrupted by a nitrogen atom, which is optionally substituted C1-C6) alkyl or (C6-C10) aryl or (C6-C10) aryl (C1-C6) alkyl, (aryl part of these radicals optionally substituted with halogen, nitro, hydroxyl, optionally halogenated (C1-C6) alkyl or optionally halogenated (C1-C6) alkoxy).

It should be clear that the compounds of formula I, in which X=S; n=0; R2represents methyl and R3represents a hydrogen atom; R4and R5together form a group-CR6=CR7-in which CR6associated with X, R6and R7together form a chain -(CH2)3- or - (CH2)4or alternatively, R6represents a hydrogen atom or through group and R7represents a phenyl group, optionally substituted-co3or a hydroxyl group, excluded from the context of the invention.

Pharmaceutically acceptable salts of compounds of formula I with acids or bases are also part of the invention.

J.Heterocycl. Chem. 1969, 6 (4), 491 describes derivatives of benzodiazepine, whose structure of podobn is on the structure of tetramisole (hydrochloride DL-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole), which is a potent anthelminthic agent. Among these compounds are those whose structure corresponds to formula I, above, were excluded from the context of the invention.

The invention is directed not only to the compounds of formula I, but also their salts.

If the compound of formula I contains an acid function, such as carboxyl function, it can form a salt with a mineral or organic compound.

As an example, salts with organic or mineral bases may be mentioned salts formed with metals, especially alkali metals, alkaline earth metals and transition metals (such as sodium, potassium, calcium, magnesium and aluminium) or with bases, for example ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with asaminami (such as meglumine) or aminoalcohols (such as 3-aminobutanol and 2-aminoethanol).

If the compound of formula I contains a primary function, for example, a nitrogen atom, it may form a salt with an organic or mineral acid.

Salts with organic or mineral acids are, for example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, fumarate, 2-naphthalenesulfonate and para-tol is onsultant.

The invention also includes salts, allowing for easy selection or crystallization of the compounds of formula I, such as picric acid, xalilov acid or optically active acid, for example tartaric acid,

Dibenzylideneacetone acid, mendelova acid or camphorsulfonic acid.

Formula I includes all types of geometric isomers and stereoisomers of the compounds of formula I.

According to the invention, the term “alkyl” means a linear or branched radical having as a basis the hydrocarbon, preferably containing from 1 to 18 carbon atoms, from 1 to 12 carbon atoms, for example from 1 to 10 atoms and especially from 1 to 6. Examples are preferably methyl, ethyl, sawn, ISO-propyl, bucilina, tert-bucilina, isobutylene, pentilla, hexeline, heptylene, anjilina, Danilina, decile, angellina, Godzilla, redecilla, tetradecyl, pentadactyla, hexadecimally, heptadecyl and octadecyl group.

The term “alkoxy” means an alkyl group as defined above linked to an oxygen atom. Examples are methoxy, ethoxy, isopropoxy, butoxy, hexyloxy radicals.

The expression “optionally halogenated” refers to optionally substituted by one or more halogen atoms.

the hen alkyl group optionally galogenirovannami, it preferably represents performance and especially pentafluoroethyl or trifloromethyl.

When alkoxygroup galogenirovannami, it preferably represents-O-CHF2or is perfluorinated. Examples of perfluorinated radicals are F3and-O-CF2-CF3.

The expression “Allenova group” denotes a linear or branched alkylene groups that are devalentino radicals which are linear or branched divalent alkyl chain.

The term “cycloalkyl” means saturated, based on the hydrocarbon group which may be mono - or polycyclic, and preferably contain from 3 to 18 carbon atoms, from 3 to 12 carbon atoms, for example from 3 to 8.

Polycyclic cycloalkyl group consist of monociclo, merged in pairs (for example, ortho-fused or peralite), which means that a pair of rings contain at least two common carbon atom.

Monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl and cyclododecyl are more preferred.

Among the polycyclic cycloalkyl mention should be made of substituted, norbornyl or a group of the formula:

According to the invention “cycloalkenyl” means cycloalkyl group, as defined above, containing one or more double bonds, preferably one double bond.

The term “halogen” means fluorine atom, chlorine, bromine or iodine.

The term “alkenyl” denotes a linear or branched, based on the hydrocarbon chain containing one or more double bonds. Examples alkenyl groups which are particularly preferred are alkeneamine group, bearing only one double bond, such as-CH2-CH2-CH=C (CH3)2, vinyl or allyl.

The term “aryl” represents a mono - or polycyclic aromatic-based hydrocarbon group, preferably containing from 6 to 18 carbon atoms, for example from 6 to 14 carbon atoms, especially from 6 to 10 carbon atoms.

Each polycyclic aryl group includes two or more monocyclic aromatic nuclei, fused in pairs, which means there are pairs of rings containing at least two common carbon atom.

Preferred examples of the polycyclic aromatic groups are bicyclic, tricyclic or tetracyclic group.

Among these may be mentioned phenyl, naftalina, untilnow, phenanthroline, pyranyloxy, christelow and naphthalenyloxy group.

The term “heteroaryl” means a mono - or polycyclic radical, containing one or more heteroatoms selected from O, N, S and P. Preferably heteroaryl contains from 1 to 3 heteroatoms selected from O, N and S.

If the radical is a polycyclic aromatic radical, it consists of two or more monocyclic aromatic nuclei are fused in pairs, each monocyclic nucleus may contain one or more endocycles heteroatoms.

Preferably polycyclic heteroaryl moiety is bicyclic or tricyclic.

Mainly monocyclic heteroaryl group, and a monocyclic nucleus, forming a polycyclic heteroaryl are 5-7-membered. Examples of monocyclic heteroaryl are furilla, thienyl, pyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolinone, imidazolidine, pyrazolidine, oxadiazolidine, triazoline, thiadiazolidine, perederina, pyridinoline, piratininga and trainline group.

Examples of polycyclic heteroaryl are indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthiridine, pteridine, pyrazoloacridine, triazolopyrimidine is, pyrazolopyrimidine, carbazole, acridine, fenesin, phenothiazines, phenoxazine or a group of the formula

in which X represents O or S.

An example of heteroaryl is (C6-C18)aryl, fused aromatic heterocycle, such as 5-7-membered aromatic heterocycle containing 1, 2 or 3 endocycles heteroatoms selected from O, N and S.

The expression “saturated or unsaturated heterocycle” denotes a mono - or polycyclic group containing one or more heteroatoms selected from O, N, S and R. the Heterocycle preferably contains from one to three heteroatoms selected from O, N and S. If the heterocycle is polycyclic, it contains two or more saturated or unsaturated monocyclic nuclei, which are preferably 5-7-membered, fused in pairs.

If a heterocycle of monosilicon, he is a 5-7-membered.

Among the polycyclic heterocycles preferred bicyclic or tricyclic heterocycles.

Examples of saturated heterocycles include tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrooxazolo, dioxolane, tetrahydrothieno, tetrahydroimidazo, tetrahydropyranol, tetrahydrooxazolo, tetrahydrocortisol, tetrahydrooxazolo, tetrahydrocarbazol, tetrahydrocortisol, piperidine, dioxane, m is Holin, dition, thiomorpholine, piperazine and Titian.

Among the saturated heterocycles can also mention saturated derivatives of polycyclic heteroaryl listed above as preferred radicals.

Examples of unsaturated heterocycles are unsaturated derivatives of saturated heterocycles mentioned above, as well as unsaturated derivatives of heteroaryl mentioned above.

The expression “unsaturated heterocycle” refers to the non-aromatic heterocycle containing one or more unsaturated bonds of the ethylene type.

Preferably unsaturated heterocycle contains only one double bond. Preferred examples of the unsaturated heterocycles are dihydrofuran, dehydration, dihydropyrrole, pyrrolidyl, oxazolines, thiazolines, imidazolines, pyrazolines, isoxazolyl, isothiazolines, oxadiazolyl, pyranyl and unsaturated monoprosopi piperidine, dioxane, piperazine, Tatiana, research, titiana and thiomorpholine and tetrahydropyridines, tetrahydropyrimidines and tetrahydrocanabinol.

If Z or R7contains or represents a (C6-C10) aryl, optionally fused with an unsaturated heterocycle, optionally substituted by oxo, unsaturated heterocycle preferably contains at least one unsaturated bond together the aryl group

Examples of aryl groups fused with unsaturated heterocycle, are, in particular:

If Z or R7contains a group of the formula:

R preferably represents 0 or 1 and St preferably represents phenyl.

Preferably the ends 1 and 2 of this radical attached to two adjacent carbon atoms mentioned aryl, heterocycling, cycloalkyl or heteroaryl plot. Preferably, St represents phenyl. Examples which may be mentioned are the radical Z of formula:

Example 133 below the radical R7formula:

Example 11 below.

According to the invention, the expression “optionally substituted” in General means “optionally substituted by one or more of the mentioned radicals”.

As an example, if R1is a (C6-C10) aryl, aryl group optionally substituted by one or more radicals chosen from:

- optionally halogenated (C1-C6)alkyl;

- (C1-C6) alkoxy;

- halogen;

- nitro; and

- hydroxyl.

However, the number of substituents is limited possible number of substitutions.

T is thus, if R6and R7together form alkylenes chain, which is interrupted by a nitrogen atom, this atom can be substituted by only one radical chosen from alkyl, aryl and arylalkyl.

The first group of compounds according to the invention comprises a bicyclic derivatives, in which R4and R5do not together form a group-CR6=CR7-.

The second group of compounds according to the invention consists of tricyclic derivatives, in which R4and R5together form a group- (CR6=CR7-realizing that R6and R7do not form together alkylenes chain, optionally interrupted by a nitrogen atom.

The third group of compounds according to the invention consists of a tetracyclic derivatives, in which R4and R5together form a group- (CR6=CR7-, in which R6and R7together form alkylenes chain, optionally interrupted by a nitrogen atom.

If R6and R7together form alkylenes chain, optionally interrupted by a nitrogen atom, the ring formed CR6=CR7can be merged with (C6-C18) aryl group, optionally substituted one or more Su groups.

Preferably CR6=CR7forms a group:

According to the invention the first group of preferred joint is (group 1) consists of compounds of the formula I, in which X represents-NT, where T is as above, R4and R5together form a-CR6=CR7-.

Among these compounds, preferred are those in which R6represents a hydrogen atom; and R7represents a hydroxyl; or (C6-C10) aryl, optionally substituted with halogen, nitro, hydroxyl, optionally halogenated (C1-C6)alkyl or (C1-C6) alkoxy.

More specifically, R7chosen from hydroxyl and phenyl.

The preferred values of T are the hydrogen atom and (C1-C6) alkyl, for example methyl.

A second preferred group of compounds (group 2) consists of compounds of the formula I, in which X represents S;

R4represents a hydrogen atom;

R5represents-CH2-CRand=CRbRwithin which Rarepresents a hydrogen atom, (C1-C6) alkyl or (C6-C10) aryl, Rbis a (C1-C6) alkyl or a hydrogen atom and Rcrepresents a hydrogen atom or (C2-C10) alkenyl; group-CH2-CO-Z, in which Z represents a (C1-C10) alkyl, (C6-C10)aryl (C1-C6) alkyl, 5 - or 6-membered heteroaryl or (C6-C10) aryl, optionally if the output with a 5-7 membered aromatic or unsaturated heterocycle; aryl and heteroaryl plots of these radicals optionally substituted with halogen, hydroxyl, (C1-C6) alkyl, (C1-C6) alkoxy, nitro or (C6-C10) aryl (optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy or nitro); and (C1-C6) alkyl; hydroxy (C1-C6) alkyl, (C6-C10) aryl (C1-C6) alkyl, (C5-C8) cycloalkenyl (C1-C6) alkyl; or isoxazolyl(C1-C6)alkyl, optionally substituted by one or more (C1-C6) alkyl;

or alternatively, R4and R7together form a group-CR6=CR7-where

R6represents a hydrogen atom, (C1-C6) alkyl, (C6-C10) aryl (optionally substituted with halogen, hydroxyl, nitro, (C1-C6) alkyl or (C1-C6) alkoxy), carboxy (C1-C6) alkyl, or (C1-C6) alkoxycarbonyl (C1-C6) alkyl; and

R7represents a hydrogen atom; hydroxyl; di(C1-C6) alkylamino (C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy carbonyl; (C6-C10) aryl; heteroaryl; (C6-C10) aryl(C 1-C6) alkyl; aryl and heteroaryl plots of these radicals optionally substituted C1-C6) alkoxycarbonyl, halogen, hydroxyl, (C1-C6)alkyl, (C6-C10)aryl, (this radical is optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, (C1-C6) alkoxy or nitro) or (C6-C10) aryl fused with a 5-7 membered aromatic or unsaturated heterocycle comprising one, two or three endocycles heteroatoms selected from O, N and S; or alternatively, R6and R7together form alkylenes chain, which is interrupted by a nitrogen atom, optionally substituted (C6-C10) aryl (C1-C6) alkyl, in which aryl plot optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, (C1-C6) alkoxy, hydroxyl or nitro.

Among these compounds, particularly preferred compounds in which one or more of the substituents R4, R5, R6and R7defined as follows:

- R5represents-CH2-CRa=CRbRcin which Rais a (C1-C6) alkyl, phenyl or hydrogen atom, Rbis a (C1-C6)alkyl or a hydrogen atom and Rcpresent is employed, a hydrogen atom or monounsaturated (C 2-C10) alkenyl; group - CH2COZ in which Z represents a (C1-C10) alkyl, benzyl, (C1-C6) alkoxycarbonyl, phenyl (optionally substituted by phenyl or hydroxyl), naphthyl, phenyl, fused with dihydrofuran, dihydrothieno or dihydropyrrolo, furyl, thienyl or pyrrolyl; (C1-C6)alkyl; hydroxy(C1-C6) alkyl; benzyl; and (C3-C8) cycloalkenyl (C1-C6) alkyl; or isoxazolyl (C1-C6) alkyl, optionally substituted (C1-C6) alkyl;

- R4and R5together form a-CR6=CR7-in which either R6or R7or both of them are defined below a (i), (ii) or (iii):

(i) R6represents a hydrogen atom; (C1-C6) alkyl; phenyl, optionally substituted with halogen, (C1-C6) alkyl, (C1-C6) alkoxy, hydroxyl or nitro; carboxy(C1-C6) alkyl; or (C1-C6) alkoxycarbonyl (C1-Ce) alkyl;

(ii) R7represents a hydrogen atom; hydroxyl; di(C1-C6) alkylamino (C1-C6) alkyl, (C1-C10) alkyl, (C1-C6)alkoxycarbonyl; naphthyl; phenyl, optionally substituted with halogen, (C1-C6) alkoxycarbonyl, hydroxyl, phenyl (itself optionally substituted ha is ogena, by hydroxyl, optionally halogenated (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxycarbonyl or nitro), or phenyl, fused with dihydrofuran, dihydrothieno or dihydropyrrolo; pyridyl; furyl; thienyl; pyrrolyl; or benzyl;

(iii) R6and R7together form alkylenes chain, which is interrupted by a nitrogen atom, optionally substituted phenyl (C1-C6) alkyl, in which alkyl plot optionally substituted with halogen.

Among the preferred compounds of groups 1 and 2, it is preferable that at least one of n, R1, R2and R3matter, as follows:

- R3represents a hydrogen atom;

- R2represents a hydrogen atom or a (C6-C10) aryl group, optionally substituted with halogen, (C1-C6) alkoxy, optionally halogenated (C1-C6) alkyl, nitro or hydroxyl;

- R1represents a halogen atom;

n represents 0, 1 or 2 and better, so that n was represented by a 0 or 1. More preferably n is 0.

Connection Examples 1-67 below are preferred.

Among these compounds the most preferred are:

3-(biphenyl-4-yl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine (Example 4);

<> 3-(2-furyl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine (Example 43);

3-[4-(etoxycarbonyl)phenyl]-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine (Example 36);

1-(2-furyl)-2-(4,5-dihydro-3H-1,3-benzodiazepine-2-ylsulphonyl)alanon (Example 14);

1-(biphenyl-4-yl)-2-(4,5-dihydro-3H-1,3-benzodiazepine-2-ylsulphonyl)alanon (Example 5);

3-(biphenyl-3-yl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine (Example 38);

1-(3,4-dihydroxyphenyl)-2-(4,5-dihydro-3H-1,3-benzodiazepine-2-ylsulphonyl)alanon (Example 29);

3-(3,4-dihydroxyphenyl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine (Example 59); and

3-(biphenyl-4-yl)-7-chloro-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine (Example 66).

The compounds of formula I can just get by applying one of the methods described below.

A) In the case of compounds of the formula I, in which X represents S, R4and R5do not form a jointly-CR6=CR7and the dotted line is nothing to do.

These compounds can simply be obtained by reaction of the thione of formula II:

in which:

n, R1, R2, R3and R4defined above in formula I, with haloperidolum formula III:

in which Hal1represents a halogen atom, (C1-C6) alkylsulfonyl, in which the alkyl plot optional galogenidov, or (C6-C10) arylsulfonyl, to the torus aryl plot optionally substituted C 1-C6) alkyl; and R5has the values specified for formula I.

Mostly Hal1represents halogen, tosyl or mesyl. The reaction is preferably carried out in polar solvent, which inneren relative to the reactants.

Suitable solvent is a linear or cyclic ether, such as dialkyl ethers (diethyl ether or diisopropyl ether, or cyclic ethers (such as tetrahydrofuran or dioxane), or alternatively, the polyether type, such as dimethoxyethane or diethylethylenediamine ether.

The temperature at which the reaction is carried out, usually between 0 and 50°better from 15 to 35°With, for example at room temperature.

One special case of the application of this method is illustrated below for the compounds of formula I in which X represents S, R4as indicated above, and R5represents-CH2-CO-Z, in which Z has the meanings indicated for formula I.

According to this method tion of formula II is subjected to reaction under the same conditions as described above with α-haloketones formula IVa:

In which Z has the meanings indicated above and Hal2represents a halogen atom. In the context of this particular implementation, it is preferable to use a soft conditions re the functions, such as, in particular, the temperature within the 0-60°and preferably from 15 to 35°C.

If the compounds of formula I obtained by implementing the method As described above, so that R4represents a hydrogen atom, obtaining the corresponding compounds in which R4is a (C1-C18) alkyl, already carried out by alkylation using a suitable alkylating agent.

Thus, the compound in which R4=H can be subjected to reaction with haloperidolum General formula R4-X, in which R4is a (C1-C18) alkyl and X represents halogen, in the presence of a base.

Examples of bases which are particularly preferred are triethylamine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine, N,N-diethylamine, mineral Foundation of the type of alkali metal hydroxides (NaOH or KOH), alkali metal carbonates (Panso3or2CO3and alkali metal hydrides, such as NaH.

C) if the compounds of formula I in which X represents S, R4and R5together form a group-CR6=CR7and the dotted line denotes nothing.

These compounds can be obtained according to the invention by reaction α-galactono formula IVb:

In which R6and R7who have values, above and Hal3represents a halogen atom, with tion of the formula IIA:

in which R1, n, R2and R3have the meanings specified for formula I, With a2-C6aliphatic carboxylic acid as solvent at a temperature between 90 and 130°C.

The exact conditions for implementation may be determined by the specialist in the art depending on the chemical activity of the present compounds.

Examples of carboxylic acids that may be mentioned include acetic acid, propionic acid, butyric acid, Pavlovo acid and valeric acid.

Perhaps in the context of the present invention to implement the method in the presence of a solvent mixture comprising one or more aliphatic carboxylic acids and optionally one or more compatible polar solvents, which are inert with respect to the present compounds.

Such additional solvents are, for example, C2-C6monohydroxylated aliphatic alcohols, such as ethanol, isopropanol and tert-butanol.

Preferred temperatures lie within 100-125°C.

It may be convenient to carry out the method at a temperature of phlegmy solvent, and particularly if the solvent Prim is applied acetic acid.

(C) In the case of compounds of the formula I, in which the dotted line denotes nothing, X represents NH, R4and R5together form- (CR6=CR7and R7is not a hydroxyl group.

According to the invention, these compounds can just get in two stages, carrying out the following method.

In the first stage, the sulfide of formula V:

in which R1, n, R2and R3have the meanings indicated above for formula I, alk is a (C1-C6) alkyl, are subjected to reaction with a protected derivative of acetone formula VI:

in which a carbonyl group, R6protected by a protective group which is labile in an acid medium, R6and R7have the values specified above.

Examples of protective groups for carbonyl functions, which are labile in an acid medium, are given in “Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, published by John Wiley and Sons, 1991, and in Protecting Groups, Kocienski, P.J., 1994, Georg Thieme Verlag.

Especially mainly carbonyl group can be protected in the form of cyclic or acyclic Catala.

Thus, a protected derivative of a ketone of formula VI, reacts with sulfide V, preferably has the formula Via, to the following:

in which R6and R7have the meanings indicated above for formula I, and Raand Rbrepresent, independently from each other, (C1-C6) alkyl or together form a linear or branched (C2-C6) alkylenes chain, preferably (C2-C3) alkylenes chain.

The preferred ketals are, in particular, 1,3-dioxolane and metalmetal.

Nevertheless, it is possible to consider the protection of the carbonyl group other protective groups, such as dithio and genetically, or the formation of enol ether, thiazolidine or imidazolidine.

The solvent used for this reaction is a polar solvent capable of dissolving the present reagents. The solution, which thus can be selected, is a nitrile, such as acetonitrile or isobutyronitrile.

If you are reaction based on Catala Via connection obtained after the first stage, is a compound of the formula:

in which n, R1, R2, R3, R6, R7, Raand Rbhave the meanings indicated above for formula I and Via. The compound obtained in the reaction of II with a protected derivative of a ketone of formula VI, and, for example, compounds VII, above, is then treated acidic environment that had occurred the cyclization.

For this you can use the acid Bronsted or a Lewis acid, mineral acid or organic acid without any preferences.

Examples of suitable acids are, in particular, acetic acid, formic acid, xalilov acid, methanesulfonate acid, p-toluensulfonate acid, triperoxonane acid, trifluromethanesulfonate acid, a Lewis acid such as trichloride boron, boron TRIFLUORIDE, tribromide boron or hydrochloric acid.

The reaction is usually carried out at temperatures 15-50°With, in particular between 20 and 30°C.

The solvent used for the reaction depends on the acid used. If acid is a hydrochloric acid, the reaction is mainly carried out in (C1-C6) alkanol, this cat ethanol.

The above process leads to the formation of compounds of formula I in which T represents a hydrogen atom.

As for the synthesis of the corresponding compounds of formula I in which T represents a (C1-C6) alkyl, (C6-C10) aryl or (C6-C10) aryl (C1-C6) alkyl, the compound obtained I for which T represents a hydrogen, is subjected to reaction with glorianna formula Hal-T, in which T represents a (C1-C6) alkyl, (C6-C10) aryl or (C6-C10) aryl (C1 -C6) alkyl and Hal represents a halogen atom, in the presence of a suitable base.

Examples of bases are, in particular, organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-(1-pyrrolidinyl)pyridine, picoline, 4-(N,N-dimethylamino)-pyridine, N,N-dimethylaniline and N,N-diethylaniline.

Conditions for this reaction are known to the person skilled in the technical field.

D) In the case of compounds of the formula I, in which the dotted line is nothing to indicate that X is a-NT, where T is different from a hydrogen atom, R4and R5together form a group- (CR6=CR7and R7represents hydroxyl.

These compounds can be obtained by reaction of a sulfide of the formula V:

in which n, R1, R2, R3, R4and alk have the meanings indicated above, with a derivative of formula VIII:

in which T and R6indicated above for formula I and Y represents a leaving group, at a temperature of from 50 to 150°C, preferably at a temperature of from 60 to 100°C.

Leaving groups that may be mentioned include halogen atom, (C1-C6) alkoxygroup, imidazolidinyl group, and (C6-C10) aryl (C1-C6

This reaction is usually carried out in a polar solvent and, in particular, nitrile, such as acetonitrile or isobutyronitrile. Preferably the solvent used acetonitrile.

E) In the case of compounds of the formula I, in which the dotted line denotes nothing, X represents-NT, R4is not a hydrogen atom and R4and R5not form - (CR6=CR7-.

These compounds can be obtained by reaction of sulfide Va:

in which n, R1, R2, R3, R4and alk have the meanings indicated above for formula I and V, with an amine of the formula IX:

in which T and R5have the meanings indicated above for formula I. This reaction is preferably carried out at a temperature from 15 to 50°With, for example between 20 and 30°With, in the nitrile solvent type, such as acetonitrile or isobutyronitrile, preferred is acetonitrile.

F) In the case of compounds of the formula I, in which the dotted line denotes nothing, X=S, R4and R5together form- (CR6=CH7and R7represents hydroxyl.

These compounds are obtained by reaction of the thione of the formula IIA:

in which n, R1, R2and R3have the meanings indicated above for formula I, with haloperidol the m formula X:

in which Hal4is a halogen and R6and Y have the meanings indicated above for formula VIII.

This reaction is preferably carried out in C6-C10aromatic hydrocarbon type toluene or benzene. The temperature at which carry out the reaction, usually about 80-130°With, for example 100-120°C. the Preferred condition is, for example, delegacia in toluene.

G) In the case of compounds of the formula I, in which the dotted line denotes nothing X=S and R4and R5together form a-CH=CH-.

According to the invention these compounds are obtained by reaction of the thione of the following formula XI:

in which n, R1, R2, R3, Raand Rbhave the meanings indicated above for formula I and VII, with a strong acid, such as sulfuric acid or hydrochloric acid, Ala, alternatively, with one of the acids listed above for option C.

In this method the desired reaction temperature depends on the strength of acid used.

Typically the temperature from 10 to 40°rather, for example 20-30°C.

This reaction can be carried out in the aquatic environment. In this case, the reaction medium should be homogeneous.

H) In the case of compounds of the formula I, in which the dotted line denotes nothing X performance is to place them On and R 4and R5together form a-CR6=CR7-.

These connections receive thermal cyclization of the compounds of formula XII:

in which n, R1, R2, R3, R6and R7have the meanings indicated above for formula I, alk is a (C1-C6)alkyl, followed by dehydrophenylalanine the resulting compounds of formula XIII:

according to the standard methods of organic chemistry to obtain the expected compound of formula I. Thermal cyclization can be performed, for example, C2-C6monohydroxylated aliphatic alcohol, such as ethanol, isopropanol or tert-butanol as solvent at temperatures from 80 to 160°C.

I) In the case of compounds of the formula I, in which the dotted line indicates the presence of double bonds.

These compounds are dehydrogenative corresponding compounds of the formula I, in which the dotted line denotes nothing.

This reaction dehydrogenation carried out by the method known per se, for example, action:

- sulfur (cf. Organic Synthesis, vol. 2 published by John Wiley & Sons, 1988, page 423; Organic Synthesis, vol. 3 published by John Wiley & Sons, 1988, page 729);

- 5% palladium on coal in delegateuser decline (cf. Organic Synthesis, vol. 4 published by John Wiley & Sons, 1988. Page 536);

- 2,3-sodium dichloro-5,6-dicyano-1,4-benzoquinone or DDQ (cf. Organic Synthesis, vol. 5 published by John Wiley & Sons, 1988, page 428; Synthesis, 1983, 310).

The thiones of formula II and IIA are compounds that receive organic synthesis of commercial products.

The thiones of the formula IIA are thiones of the formula II in which R4represents a hydrogen atom.

These compounds, in particular, can be obtained via the following methods and, optionally adapting any of the methods described in:

- Spindler Juergen; Kempter Gerhard; Z. Chem.; 27; 1. 1987; 36-37 or

- Setescak Linda L.; Dekow Frederick W.; Kitzen Jan M.; Martin Lawrence L-; J. Med. Chem.; 27; 3; 1984; 401-404.

These two publications more detail the synthesis of 1,3,4,5-tetrahydro-(1H,3H)-1,3-benzodiazepine-2-thione, 1,3,4,5-tetrahydro-(1H,3H)-4-phenyl-1,3-benzodiazepine-2-thione and 1,3,4,5-tetrahydro-(1H,3H)-3-methyl-4-phenyl-1,3-benzodiazepine-2-thione.

As an example, if R2represents optionally substituted aryl or heteroaryl and R3represents H, Scheme 1, below, offers one of the ways of synthesis thione of the formula II, in which the dotted line denotes nothing.

Ketone XIV handle under normal conditions the reagent Gringard formula CH3gl6in which Hal6represents a halogen atom. The method is carried out, for example, in an ether, preferably in Alif the political ether, such as diethyl ether or diisopropyl ether or tetrahydrofuran, at a temperature of 20-50°C, preferably at 30-40°C.

After dehydrogenation of the intermediate alcohol (in acidic medium) compound XV restore in salt form. The nature of the counterion in the compound XV (the counterion is not represented in figure 1) depends on the acid used for dehydrogenation. At the next stage, compound XV is treated with sodium nitrite in the presence of a strong acid, such as hydrochloric acid, and the intermediate compound is then treated with base, preferably a hydroxide of the type of alkali metal hydroxide or ammonium hydroxide.

The resulting diazoketone formula XVI is then subjected to hydrogenation in the presence of Nickel in the polar solvent type, such as (C1-C6) alkanol or amide, type of dimethylformamide, at a temperature of 30-100°C, preferably at temperatures from 50 to 70°C.

Tion in the end get a reaction hydrogenerating compound XVII with carbon disulfide under appropriate conditions, such as, for example, by heating under reflux in C1-C6aliphatic alcohol, for example in delegateuser ethanol.

Another way to get thiones of the formula II in which R2and R3both represent a hydrogen atom and the dotted line is not about who means nothing illustrated in Scheme 2, below.

Amine of formula XXIa receive the usual way by the action of thionyl chloride and then ammonia and at the end of the catalytic hydrogenating in the presence of Raney Nickel.

Further, the carbonyl function of the compound XXIa restore the action of a suitable reducing agent. Examples of suitable reducing agents are the hydrides (such as hydride layalina, borohydride sodium, cyanoborohydride sodium, NR3/F3-E2Oh and Et3SiH), zinc in the environment of hydrochloric acid or Raney Nickel in ethanol medium.

Recovery can also be carried out by catalytic hydrogenation, e.g. in the presence of palladium on coal or platinum oxide.

The method preferably is carried out in the presence of LiAlH4. Reconnection XXIa network connection XXIb.

Amin XXIb then subjected to reaction with carbon disulfide, preferably in a polar solvent C1-C6balkanologie type (such as, for example, ethanol) at a temperature of 80-150°at the end of the reaction.

Sulfides of formula Va directly obtained from the corresponding thiones of the formula II.

One possible synthetic schemes consists of the reaction of the corresponding thione of the formula II:

in which n, R , R2, R3and R4have the meanings stated above, with a halide Hal5-alk in which Hal5represents a halogen atom and alk represents a (C1-C6) alkyl, proton polar solvent such as an aliphatic alcohol, for example (C1-C6) alkanol. It is desirable that the alkyl chain of the alcohol used as solvent to closely match the chain alk in haloperidolum.

The reaction of the thione II with this haloperidolum preferably carried out at a temperature of between 15 and 50°C, preferably 20-30°With, for example, at room temperature.

This method is particularly advantageous for producing compounds of formula Va, in which alk is a methyl.

Preferably Hal5is an atom of iodine.

The compounds of formula XI in which R3represents a hydrogen atom, can be obtained using the method shown in Scheme 3, below.

Amide of formula XXIV receive the usual way, on the basis of the acid of formula XXII, by the action of thionyl chloride and the appropriate amine of the formula NH2-CH2-CH(ORa) (Or SIGb), in which Raand Rbhave the meanings indicated above for formula XI.

Next, amide XXIV subjected to hydrogenation reactions in the presence of palladium on coal for transfer nitrofen the tion in aminophenol. This translation is carried out under standard conditions of organic chemistry.

The carbonyl function of the resulting amine is then restored by the action of a suitable hydride, such as hydride layalina, sodium borohydride, cyanoborohydride or sodium hydride diisobutylaluminum.

Then, the obtained amine XXVI is treated with carbon disulfide under the same conditions as described above in the case of compound XVII (Scheme 1) or in the case of compound XXIb (Scheme 2).

The compounds of formula XII in which R3represents hydrogen, can be synthesized by the method shown in Scheme 4 below:

Amine of formula XXVII is produced simply by the reaction of an amine of the formula NH2-CHR7-CHR6-OH, in which R6and R7have the meanings indicated above for formula I, with an acid chloride of formula XXIII. This reaction is carried out under standard conditions, preferably in the presence of a base and preferably an organic base. The following three stages, which lead to the compounds of formula XXX, carried out under conditions comparable with the case of conversion of compound XXIV in connection XI (Scheme 3). Further, the connection XXX subjected to reaction with Hal7-alk, in which Hal7represents a halogen atom and alk represents a (C1-C6) alkyl. This reaction can Provo is arranged under the conditions above for the conversion of thione II in the sulfide of formula Va. This reaction is preferably carried out in Ci-C6alkanol whose alkyl chain corresponds exactly alkyl chain alk alk-Hal7and with halide alk-Hal7in which Hal7is an atom of iodine.

Hypolipidemia activity of the compounds according to the invention is manifested in their ability to reduce the secretion of APO CIII. Biological test below was provided to demonstrate this activity. It reveals the ability of the compounds according to the invention to reduce the secretion of APO CIII line of human hepatocytes ner G2 in culture.

Cell line ner G2 comes from human liver carcinoma (Ref. ESAS No. 85011430).

Cells were cultured at 37°C, 5% CO2in 96-pornih microtiter plates at a ratio of 40000 cells (200μl) by time in the buffer DMEM, 10% fetal calf serum, 1% Glutamax + antibiotic within 24 hours. The substrate is then removed and replaced by the same substrate containing the test substance at a concentration of 10 μm Cells incubated 24 hours at 37°C, 5% CO2and the substrate is then removed.

The amount of apolipoprotein CIII, secreted in the substrate, measured by analysis type ELISA. Each sample substrate was diluted 5 times in 100 mm phosphate buffer, 1% BSA. 100 μl of each dilution is placed in the ora 96-pornih microtiter plates in advance sensitizing anti(human APO CIII) polyclonal antibody for 18 hours and Passepartout at level 1 μg time in 100 mm PBS and Passepartout 200 μl of 100 mm PBS 1% BSA for 1 hour at 20°C.

Each dilution of the substrate is incubated for 2 hours at 37°With pores and then washed with 4 tubs of 100 mm PBS with 0.3% Tween 20. 100 μl of a solution dissolved in 100 mm PBS, 1% BSA anti(APO CIII) polyclonal antibodies together with peroxidase add on each time and incubated at 37°2 hours. After further washing, identical to the previous washing, each time add 100 μl 50 mm phosphate buffer, 15 mm citrate, pH 5.5, containing 1.5 mg/ml of orthophenylphenol and 0.5 μl/ml of hydrogen peroxide (H2About2). The plate is incubated for 20 minutes in the dark and the reaction is then stopped by the addition of 100 μl 1N Hcl.

Determine the optical density directly using a spectrophotometer at 492 nm. The number of APO CIII is calculated against a calibration curve obtained by using the analyzed human serum APO CIII and dissolved under the same conditions as the APO CIII contained in the substrate.

In the absence of chemical treatment response of cells is 100% (inhibition of 0%). When the applied conditions the influence of DMSO on the cells can be neglected. Toxicity of chemical substances the TV in relation to the cells is measured using neutral red staining.

Active substances lead to decrease in the secretion of APO CIII in the environment of the cells being treated. The concentration of APO CIII measured for each treatment and compared with the control test (without processing).

The percentage inhibition is calculated according to:

The percentage inhibition is calculated only for substances that do not exhibit toxicity towards cells ner G2.

As an example, the percentage of inhibition measured for the compounds of formula I, in which X=S; n=0; R2=R3=R6=H; R7=4-biphenyl and R4and R5together form a-CR6=CR7(Example 4 below), is 80-100 micromolar %. The concentration of the compound in Example 4, which gives 50% inhibition of the secretion of Apo CIII, this test is 17,4 μM Toxicity towards cells is not observed in the case of compound from Example 4 for the studied concentrations.

The invention is illustrated below by the methods and examples. It is in no way limited to these specific examples.

GETTING 1

Getting thione of the formula IIA, in which n=0 and R2=R3=N

The title compound is obtained by carrying out the method described in Spindler Juergen; Kempter Gerhard; Z. Chem.; 27; 1; 1987; 36-37. Its melting point is 195°C.

GETTING 2

Getting thione of the formula IIA, in which n=0; 2=C6H5and R3=N

The title compound receive according to FR 2 528 838.

GETTING 3

Getting thione of the formula XI, in which n=0; R2=R3=H; Ra=Rb=-CH3

(a) N-(2,2-Dimethoxymethyl)-2-(2-nitrophenyl)ndimethylacetamide

21,0 g (0.2 mol) of aminoacetaldehyde dissolved in 200 ml of chloroform, are placed in a reactor together from 22.2 g (0.22 mol) of triethylamine. Reagents bring to and maintain at a temperature of 10°C. To this solution was added a solution of 0.2 mol of 2-nitrophenylacetylene in 200 ml of chloroform. The reagents allowed to return to room temperature, stirring is continued for 12 hours.

Then add aqueous sodium hydroxide solution, after which the organic phase is allowed to separate by settling, and it is separated and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure to obtain a solid beige color, which recrystallized from a mixture of hexane and ethyl acetate. Get 35 g of solid substance with a melting point of between 89 and 90°C.

(b) N-(2,2-Dimethoxymethyl)-2-(2-AMINOPHENYL)ndimethylacetamide

40 g of the compound from step (a)described above, dissolved in 750 ml of ethanol, gidrogenit in an autoclave in the presence of 5 g of 5% palladium on coal at a pressure of 120 bar of hydrogen.

After filtering off the catalyst and evaporating the solvent is entitled to 35 g butter, which is used in crude form in the further synthesis.

(c) N-(2,2-Dimethoxymethyl)-2-(2-AMINOPHENYL)-ethylamine

of 28.1 g (of 0.74 mol) of hydride layalina, suspended in 280 ml of anhydrous tetrahydrofuran are placed in a 1 l reactor with a supported in an inert atmosphere.

The reactants are cooled to a temperature below 10°and 35.3 g of compound obtained in stage (b), dissolved in 350 ml of anhydrous tetrahydrofuran, is added to this solution supported at this temperature. The mixture is maintained at the point deligny solvent for 8 hours, stirring.

Reagents again cooled to a temperature below 10°and slowly add 100 ml of water to decompose the excess present in the solution of the hydride. The resulting aluminum hydroxide dried and washed with chloroform.

The separated organic phase is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. Thus emit 23 g of oil, which is used crude in the next stage.

(d) 3-(2,2-Dimethoxymethyl)-4,5-dihydro-(1H,3H)-1,3-benzodiazepine-2-tion

22,6 g (0,298 mol) of sulphide of carbon dissolved in 180 ml of ethanol is placed in a 500 ml reactor.

0,149 mol of compound obtained in the preceding stage, dissolved in 150 ml of ethanol, is added to this solution at room temperature. The temperature of vozraste is from 18 to 22° C. the Reagents are left under stirring for 12 hours at room temperature and the reagents then maintain at a temperature of deligny solvent for 6 hours. The mixture then allow to return to room temperature, after which the solvent is evaporated under reduced pressure. Get a thick green oil, which recrystallized from 100 ml of ethanol. Thus allocate 21 g of solid substance with a melting point 79-81°C.

GETTING 4

Getting thione of formula XXX in which n=0; R2=R6=H; R7=-C6H5

The title compound receive according to FR 2518544.

GETTING 5

Obtaining the compounds of formula XIII, in which n=0; R2=R3=R6=H; R7=-C6H5

11.6 g (0,039 mol) of 3-(2-hydroxy-1-phenylethyl)-(1H,3H)-1,3-benzodiazepine-2-thione, suspended in 120 ml of ethanol was placed in a 250 ml reactor.

To this solution was added to 11.0 g (0,078 mol) of methyliodide, the reagents are then supported on the point deligny solvent for 1 hour. There is a significant formation of mercaptan.

Allow the mixture to return to room temperature and the solvent then evaporated under reduced pressure. The residue is taken in diethyl ether and dilute aqueous ammonium hydroxide solution. A white precipitate is formed, which is marked by drying. Obtain 7.6 g of product from point of plvl is of 137-139° And recrystallized from a mixture of hexane and ethyl acetate. The product, isolated, therefore, has a melting point of 142-144°C.

The hydrochloride of the title compound recrystallized from acetone and has a melting point 132-135°C.

GETTING 6

Getting sulfide of the formula V in which n=0; R2=R3=N and alk=-CH3

the 33.2 g (0,1862 mol) thione obtained in the Obtaining 1, and 300 ml of methanol are placed in a 1 liter reactor. The mixture is stirred until complete dissolution. Next, 23,2 ml (0,3724 mol, 2 EQ.) CH3I, dissolved in 50 ml of methanol, are added dropwise to this mixture.

Reagents stand on the back of the refrigerator. After 1 hour, the solvent is evaporated under reduced pressure and the residue taken in 500 ml of diethyl ether. A precipitate, which is dissolved and washed 3 times with 50 ml diethyl ether, and then dried under reduced pressure. Thus emit 59.3 g of product cream color (output=99,4%) with a melting point of 171-173°C.

1H NMR (300 MHz, DMSO) δ (ppm):

11,42 (1H, s); 10,10 (1H, s); 7,45-7,24 (4H, m); 3,80-of 3.77 (2H, m); 3.27 to 3,24 (2H, m); 2,85 (3H, s),

EXAMPLE 1

Obtaining the compounds of formula I, in which X=-N3; n=0; R2=R3=R6=H; R4+R5=-CR6=CR7-; R7=HE

8.5 g (0, 264 mol) sulfide of the formula V obtained by Receiving 6, 125 ml of acetonitrile, dried over molecular sieves is m (4 ), and 6.8 g of ethylacrylate placed in a 250 ml reactor, supported under nitrogen atmosphere. The mixture is stirred at room temperature for 15 hours, then add 2 g of ethylacrylate, and the reagents are heated under reflux for 6 hours. Further, the reagents add 2 grams of ethylacrylate and the mixture is heated under reflux for 14 hours. After this reaction time is no longer observed the formation of CH3S.

The reagents are then concentrated by evaporation under reduced pressure, and then the obtained solid beige color selected in 200 ml of water plus 30 ml of 7% aqueous sodium bicarbonate solution. The solution is extracted with dichloromethane and dried on anhydrous sodium sulfate, and the solvent then evaporated. The residue is then purified by chromatography on silica gel using a mixture of 4/1 dichloromethane/ethyl acetate.

Thus emit 3.4 g of a solid yellow substance with a melting point 132-134°C. After recrystallization from a mixture of 30 ml of hexane and 40 ml of ethyl acetate, emit 2.7 g of pale yellow solid (yield=47,5%) with a melting point 132-134°C.

1H NMR (300 MHz, DMSO) δ (ppm):

7,30-7,27 (1H, m); 7,22-7,16 (2H, m); 7,05-6,99 (1H, m); 4,18 (2H, s); 3,88 (2H, s); 3,14 (3H, s); 3,12-of 3.07 (2H, s).

EXAMPLE 2

Obtaining the compounds of formula I, in which X=-NH; n=0; R2=R3=R6=H; R4+Rsub> 5=-CR6=CR7-; R7=-C6H5

a) Obtaining the compounds of formula VII, in which R6=R2=R3=N; n=0; R7=-C6H5; Raand Rbtogether form a-CH2-CH2-

4.4 g ((0,01381 mol) sulfide obtained in the Obtaining 6, 80 ml of acetonitrile and 5.2 g (0,029 mol; 2.1 EQ.) following Amin

placed in a 100 ml reactor, supported in a nitrogen atmosphere.

Reagents incubated at 50°With 12 hours and then allowed to return to room temperature (20°). Then add 100 ml of diethyl ether. The formed precipitate is filtered off at 20°and washed With 3 times 15 ml of diethyl ether and then dried under reduced pressure. Thus obtained 5.5 g of solid cream-colored product with a melting point of 220°C. the Residue is taken in 7% aqueous sodium bicarbonate solution (100 ml) and left to mix for 30 min, and then filtered, washed with water and dried under reduced pressure.

Thereby obtaining 4.5 g cream solid color with a melting point 217-219°C. After recrystallization from 100 ml of ethanol emit 4.3 g of a white solid substance with a melting point 217-219°C. This compound is hydroiodide salt of the title compound, as can be seen from the elementary analysis of the obtained product (yield=69%).

1H NMR (300 MHz, DMSO) δ (ppm):

9,39 (s, 1H); AT 8.36 (1H, s); 7,32-7,00 (7H, m); 6.87 in (2H, t, J=7 Hz); 3.9 to 3,88 (2H, m); 3,62-of 3.60 (2H, m); of 3.48 (2H, s); 3,26 (2H, t, J=4.5 Hz); 2,80 (2H, t, J=4.6 Hz).

b) Obtaining the compounds of formula I, in which X=NH; n=0; R2=R3=R6=H; R4+R5=-CR6=CR7-; R7=-C6H5

3 g of compound obtained in stage a) (0,009277 mol), 200 ml of ethanol and 200 ml of 5N Hcl are placed in a 500 ml reactor, supported in a nitrogen atmosphere. The mixture is heated under reflux for 5 hours and the solvent then evaporated under reduced pressure. To the residue is added 200 ml of water and the mixture is washed with twice 150 ml of diethyl ether. The solution is alkalinized 30% aqueous sodium hydroxide solution, keeping the temperature below 20°C. the Resulting cream-colored precipitate is filtered off and then washed with water and dried under reduced pressure at 80°C. Thus produce 1.8 g (yield=73,8%) cream solid color with a boiling point 194-206°C.

1H NMR (300 MHz, DMSO) δ (ppm):

9,18 (1H, s); 7,28-7,11 (8H, m); 6,67-of 6.65 (1H, m); 6,55 (1H, s); of 3.94 (2H, t, J=4,7 Hz); 2.91 in (2H, t, J=4.6 Hz).

EXAMPLE 3

Obtaining the compounds of formula I, in which X=N3; n=0; R2=R3=R6=H; R4+R5=-CR6=CR7; R7=-C6H5

1.4 g (0,00531 mol) of the compound obtained in Example 2, and 46 ml of dimethylformamide, vysusena what about the over molecular sieve (4 ), placed in a 100 ml reactor. The mixture is stirred until complete dissolution. Then add 0,22 g of 60% dispersion of sodium hydride in oil (0,005575; of 1.05 equiv.) at 20°and the mixture is allowed to react with stirring for 30 minutes Then disposable add 0.4 ml (0,006371; 1.2 EQ.) methyliodide. The reagents are stirred for 48 hours and then poured onto 600 ml of water and the solution extracted with dichloromethane. The combined extracts washed with water and dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure. Obtain 1.1 g of a yellow oil. Sol - maleato salt of this compound is produced by action of one equivalent of maleic acid in methanol at room temperature. The solvent is evaporated and the residue recrystallized from methanol. Allocate 0,78 g (yield=37.5%) of a white solid substance with a boiling point of 173-175°C.

1NMR (300 MHz, DMSO) δ (ppm):

7,51-7.23 percent (10 H, m); 6,10 (2H, s); 4,11-4,08 (2H, m); of 3.54 (3H, s); 3,19 (2H, t, J=5,1 Hz).

EXAMPLE 4

Obtaining the compounds of formula I, in which X=S; n=0; R2=R3=R6=H; R7=p-(phenyl) phenyl; R4and R5together form- (CR6=CR7-

16.5 g thione obtained and Obtaining 1, 390 ml of glacial acetic acid and 25.5 g (of 92.5 mmol) bromomethyl para-phenylmethylene introduced into a 500 ml reactor equipped with a condenser. The gradient mixture is heated to reverse the m refrigerator with stirring and kept at the reflux 3 hours.

The reactants are then cooled to 15°C. the Precipitate (hydrobromide) is filtered off, washed with diethyl ether and dried. The residue is taken in 200 ml of ice water and the resulting solution slowly alkalinized by addition of 30% aqueous sodium hydroxide solution under continuous stirring. Add the amount of sodium hydroxide required to reach a stable alkaline pH. The solution is then extracted twice with methylene chloride. Next, the extracts washed with water and dried over anhydrous sodium sulfate and the solvent is then evaporated under reduced pressure. Thus emit yellow solid (yield=85%), which recrystallizing of toluene, and thus obtained the title compound in pure form, having a melting point of 199, 9-200° (Example 4).

Cleaners containing hydrochloride salt of this compound is produced by adding 33% solution of hydrogenchloride in ethanol. The melting point of this salt 299,5-300°With (Example 44).

1H NMR (300 MHz, DMSO-d6):

to 3.02 (2H, m); of 3.97 (2H, m); at 6.4 (1H, s); 6,8 (1H, m); 7 (2H, m); and 7.1 (1H, m); between 7.4 to 7.6 (5H, m), and 7.7 to 7.9 (4H, m),

1H NMR (300 MHz, DMSO-d6) hydrochloride:

3 (2H, m); 4 (2H, m); 6,8-7,7 (14N); 13 (1H, exchange s).

EXAMPLE 5

Obtaining the compounds of formula I, in which X=S; n=0; R4=R2=R3=H; R5=CH2-CO- (p-phenylphenyl)

2.7 g (15 mmol) thione obtained in the Obtaining 1, and 150 ml of tetrahydrofuran is amemait in a 250 ml flask with three necks, equipped with a condenser with a leading pipe CaCl2.

The reagents gently heated until complete dissolution thione, followed by slow addition of 6.6 g (25 mmol; 1.6 EQ.) bromomethyl para-phenylphenolate in 50 ml of tetrahydrofuran. There is loss of product in the sediment. Reagents continue to mix for 30 minutes Then the precipitate is filtered off and washed with diethyl ether. The precipitate is then suspended in 200 ml of ice water, and the suspension is slowly alkalinized by addition of 33% aqueous hydroxide with constant stirring. Sodium hydroxide add as many as needed to achieve a stable alkaline pH. The white precipitate is then filtered off and recrystallized from ethanol. Highlight the title compound having a melting point 239,5-240° (yield=68%).

1H NMR (300 MHz, DMSO-d6) δ (ppm): 3 (2H, m); 3,2 (1H, m); 3,4 (1H, m), 3,5 (1H, d, J=11.8 Hz); 3,7 (1H, d, J=11.8 Hz); 6,9-7,9 (13H, m).

EXAMPLE 6

Obtaining the compounds of formula I, in which X=S; n=0; R4and R5together form- (CR6=CR7-; R2=-C6H5; R3=H; R6=H; R7=HE

10 g (0,039 mol) thione obtained in the Obtaining 2, was placed in a 250 ml reactor containing 125 ml of acetic acid. 7.9 g (0,047 mol) of ethylbromoacetate added dropwise to this solution and the reagents allowed to heat under reflux in those who tell 9 hours. A white precipitate is formed. After cooling to room temperature the resulting bromide is filtered off. The product is dried and suspended in water. To this suspension is added a 30% solution of the hydroxide ammonia to establish a basic pH. The product is filtered, then dried, after which recrystallized in a mixture of hexane and ethyl acetate. While allot of 8.2 g of the title compound that has a melting point of 156-158°C.

EXAMPLE 7

Obtaining the compounds of formula I, in which X=S; n=0; R4and R5together form- (CR6=CR7-; R2=R3=R6=H; R7=HE

3.0 g (0,0168 mol) 2-tion-4,5-dihydro-1,3-benzodiazepine and 3.75 ml (0,0336 mol) of ethyl bromoacetate in 50 ml of toluene was placed in a 250 ml flask with three necks.

The reaction mixture is heated with stirring under reflux for 1 hour. Mixture is allowed to return to room temperature, then add water and aqueous ammonium hydroxide solution and extracted with ethyl acetate. After drying the organic extracts over anhydrous sodium sulfate reagent is evaporated. Thus obtain 1.4 g of a solid substance ochre, which recrystallized from ethanol. After recrystallization the melting point of this solid substance is 111-112°C.

1H NMR (300 MHz, l3) δ (ppm): 3,23-of 3.25 (2H, m); 4,18 (4 is, s); 7,26 of 7.3 (2H, m); 7,43 is 7.5 (2H, m).

EXAMPLE 8

Obtaining the compounds of formula I, in which X=S; n=0; R4and R5together form- (CR6=CR7-; R2=R3=R6=R7=N

14.0 g of the compound obtained in the Obtaining 3, 140 ml of 50% aqueous solution of sulfuric acid was placed in a 250 ml reactor. The mixture is kept for 2 hours at the point phlegmy solvent. The reagents allowed to return to room temperature and then poured on a mixture of water and ice. After extraction with chloroform and drying of the extracts over anhydrous sodium sulfate the solvent is evaporated. Thus obtain 9 g of a thick oil. This oil is dissolved in 100 ml of acetone. Then add 5.7 g of maleic acid. The product obtained by concentration of the solution is the maleate of the title compound.

This product recrystallized from acetone. The resulting product has a melting point of between 121 and 123°C.

Connection Examples 9-192 get the methods described for examples 1-8 above.

Tables 1-6 provide a distinctive data for each of these compounds.

so pl. denotes the melting point.

An NMR spectrum was recorded at 300 MHz solvent S.

Abbreviations s, d, t and m have the following meanings:

s: single

d: double

t: triple

m: plural).

Table 1

ExampleR5MP (°)1H NMR δ ppm)
9CH2-CO-tBu200-200,5S=CDCl3

1,2 (9H, s); 3,2 (2H, m);7 (1H, d, J=7,5 Hz); and 7.1(1H, t, J=7,5 Hz); and 7.3 (1H, t, J=75 Hz); 7.5 (a 1H exchange, s);7,8(1H, d, J=7.5 Hz).
10CH2-CO-CO-Oet174-175S=DMSO-d6

1,2 (3H, t, J=7,1 Hz); 3,2(2H, m); 3,7 (2H, m); 3,7, (1H, d, J=12.3 Hz); 4,0 (1H, d, J=12.3 Hz); 4,2 (2H, m, J=71 Hz); and 7.3 (4H, m); for 8.7 (1H exchange, s); 12,3(1H exchange, s),
11, HBr119-119,5S=DMSO-d6

of 1.5-1.7 (9H, m); and 3.1 (2H, m); 3,6 (2H, m); 4 (2H); 5 (1H); 5,3 (1H); and 7.1 to 7.4 (4H, m); 10,5 (1H exchange, s); 11,5 (1H exchange, s).
12194-195S=DMSO-d6

3 (2H, m); 3,3 (1H, m); 3,6 (1H, m); and 3.8 (1H, d, J=12,2 Hz); 4 (1H, d, J=12,2 Hz).

13200-200,5S=DMSO-d6

of 2.9 (2H, m); 3,1 (1H, m); 3,3 (1H, m); 3,4 (1H, d, J=11.8 Hz); 3,6 (1H, d, J=11.8 Hz,); 6,8 (1H, m); 6,9 (2H, m); and 7.1 (1H, m); 7,4 (1H exchange, s); 7,5 (1H, m); 7,9 (1H, m); and 8.6 (1H, m); 8,8 (1H, m).
14158-158,5S=DMSO-d6

3 (2H, m); 3,3 (2H, m); 3,5 (1H, d, J=11.8 Hz); 3,9 1H, d, J=11.8 Hz); 6,6-6,8 (2H, 2m); 7 (1H, t, J==1.5 Hz);and 7.1 (2H, d); of 7.25 (4H, t); 7,5 (1H, s); 7,9 (1H, s).
15217,2-217,4S=DMSO-d6

of 2.9 (2H, m); 3,1 (1H, m); 3,3 (1H, m); 3,4 (1H, d, J=12.1 Hz); 3,5 (1H, d, J=12.1 Hz); 7.5 (a 1H exchange, s); 6,8-7,2 (4H, m); and 7.5 (2H, d, J=6 Hz); 8,6 (2H, d, J=6 Hz).
16-CH2-C(=CH2)-C6H5209,8-210S=DMSO-d6

of 3.1 (2H, m); 3,6 (2H, m);4,5 (2H, s), and 5.5 (1H, s); 5,6 (1H, s); a 7.2 to 7.5(9H, m); 10,5 (1H exchange, s); 11,4 (1H exchange, s);
17CH2-C6H5187,5-188S=DMSO-d6

of 4.8 (2H, s); 3( 2H, m); 3,6 (2H, m); 7,1-7,5 (m).
18-CH2-CH=C(CH3)2159,7-160S=DMSO-d6

1,5 (6N); 3 (2H); 3,5 (2H); 3,9 (2H); 5,1 (1H); 74 (4H); 10,8 (1H, exchange); 11,5 (1H).

19187-187,5S=DMSO-d6

the 2.7 and 3.4 (8H, m); 4,4 (2H, m); of 6.6 to 7.3 (7H, m)
20199-199,2S=DMSO-d6

3,8 (1H, d, J=12.3 Hz); 4,0 (1H, d, J=12.3 Hz); 3-3,7 (4H, m); 6.5 to about 7.8 (7H, m); for 8.7 (1H exchange, s); 13 (1H exchange, s).
21-CH2-CO-C6H5210°S=DMSO-d6

2,7-2,8 (2H, m), 2,8-2,9 (1H, m); 3,1-3,2 (1H, m); 3,3 (1H, d, J=12 Hz); 3,4 (1H, d, J=12 Hz); 6,7-7,0 (5 is, m); 7,2-7,4 (4H, m).
22-CH2-CO-CH3184-186S=DMSO-d6

1,4 (3H, s); 2,9 (2H, m); 3,2 (1H, d, J=11 Hz); 3,3 (1H, d, J=11 Hz); 3,3-3,5 (2H, m); and 6.5 (1H, s); 6,8-7, 1 (4H, m).
23-CH2-CH2-CH3152-154S=DMSO-d6

of 0.9 (3H, t, J=7 Hz); 1,5-1,6 (2H, m); 3,0-3,1 (2H, m); 3,3 (2H, t, J=7 Hz); 3,5-3,6 (2H, m); to 7.0, and 7.1 (1H, m); 7,2-73 (2H, rn); 7,3-74 (1H, m).
24-CH2-CO-(CH2)7-CH3134-1368=l3to 0.8 (3H, t, J=7 Hz); 1,2-1,4(N, m); 1,7-1,8 (2H, m); 2.8 to 3.0 (3H, m), 3,3-3,4 (2H, m); up 3.6-3.7 (1H, m); 4,0 (1H, s, proton exchanged with D2O); 6.8 or 6.9 (2H, m); to 7.0, and 7.1 (2H, m).
25-(CH2)7-CH3150-152S=DMSO-d6

0.7 to 0.9 (3H, m); 1,1-1,3 (10H, m); 1,4-1,6 (2H, m); 2,5-2,6 (2H, m); 3,1-3,2 (2H, m); from 4.2 to 4.3 (2H, m); 6,8 (1H, s), to 7.0, and 7.1 (1H, m); and 7.1 to 7.4(3H, m).

26-CH2-CO-CH2-C6H5185-187S=DMSO-d6

2,8-2,9 (5H, m): 3,2 (1H, d, J=12 Hz); 3,3-3,4 (1H, m); 3,5-3,6 (1H, m)to 6.5 (1H, s, exchange with CF3D); 6,7-6,9 (4H, m)and 7.1 to 7.2 (5H, m).
27-CH2- (CH3)=CH2170-172S=DMSO-d6

1,6 (3H, s); 2,8-2,9 (2H, m); 3,4-3,5 (2H, m); 3,9 (2H, s); 4,7(1H, s); 4,8 (1H, s); 6,9-7,1 (3H, m); 7.3 to 7.4 (1H, m).
28121123 S=DMSO-d6

2,5 (3H, s); 2,6 (3H, s); 3,2-3,3 (2H, m); 3,6 (2H, s, exchange with CF3OOD); 3,8-3,9 (2H, m); and 4.8 (2H, s); 7,4-7,6 (3H, m); of 7.7 to 7.8 (1H, m).
29180-185S=DMSO-d6

2,85-3,66 (6H, m); 6,77-7,26 (8H, m), 9,06 (2H, s) exchange CF3D).
3074-76S=CDCl3

the 1.6-and 1.4 (4H, m); a 2.0 to 1.9 (4H, m); a 3.0 a 2.9 (2H, m); 3,7-3,5 (4H, m); 5,0 (1H, s, exchange D2O); 5,6 (1H, s); 7,1-6,8 (4H, m).

The following three compounds in Table 2 further illustrate the formation of compounds of the formula I, in which X=S, R4=H, R3=N.

Table 2

Approx.n/R1R2R5t, PL (°)1H NMR δ (ppm)
310/-202-204S=DMSO-d6

of 3.4 to 3.2 (4H, m); 4,4-up was 4.3 (1H, m); 7,9-6,7 (17H, m)
320/-C6H5CH2-CHg-HE181-185 
331/7-CLN 190-192S=DMSO-d6

of 2.75 (m, 2H); of 2.9-3.0 (m, 1H); 3,1-3,2 (m, 1H); 3,3 (d, J=12 Hz, 1H); 3,4 (d, J=12 Hz, 1H); from 6.9 to 6.8 (m, 2H); 7,1-a 7.0 (m, 1H); 7,6 to 7.2 (m, 9H).

Table 3

Approx.R6R7t, PL (°)-1H NMR: δ (ppm)
34-CH3C6H5112-113S=DMSO-d6

2,1 (3H, s); 3,1 (2H, m); 3,9 (2H, m); 7-7,3 (4H, m); of 7.6 to 7.7 (5H, m).
35-N-CO-Oet140-150S=DMSO-d6

1-5 (3H, t, J=7,1 Hz); 3,5 (2H, m); 4,5 (2H, d, 7,1 Hz)and 4.9 (2H, m); of 7.3 and 7.6 (4H, m); for 8.2 (1H, s).
36-N231-233S=DMSO-d6

of 1.3 (3H, t, J=7,1 Hz); 4,3 (2H, d, J=7,1 Hz); 3,3 (2H, m); for 4.2 (2H, m); of 7.2 to 7.4 (5H, m), and 7.7 (2H, d, J=8,2 Hz); 8,1 (2H, d, J=8,2 Hz).
37-N-tBu112,3S=DMSO-d6

of 1.26 (9H, s); 3,1 (2H, m); a 4.1 (2H, m); 1,95 (1H, s); 6,7-7 (4H, m).

38-N138-139=DMSO-d6

3 (2H, m); 4 (2H, m); and 6.5 (1H, s); 6,8 (1H, t, J=7,3 Hz); 6,9 (2H, m); and 7.1 (1H, t, J=7,3 Hz); 7,4-7,6 (5H, m), and 7.7 (4H, m).
39 -N188,5-189,5S=DMSO d6

of 6.6 (1H, s); the 6.9 and 7.3 (4H, m), and 7.7 (3H, m); 8,1 (4H, m); and 3.1 (2H, m); a 4.1 (2H, m).
40N198,5-199S=l3

2 (1H, m); 2,6 (1H, m), 3,4 (2H, m), 6 (1H, s); 6,7 (2H, m); and 7.1 (2H, m); of 7.3 and 7.6 (9H, m).
41-N209,3S=DMSO-d6

of 2.9 (2H, m); 3,5 (2H, m); at 6.4 (1H, s); 6,7 (1H, m); 6,8 (1H, m); 7 (1H, m); and 7.1 (1H, m); 76 (4H, m); 77 (1H, m); 8 (2H, m).
42-C6H5N199,5-200S=DMSO-d6

3 (2H, m); 4 (2H, m); of 6.8 to 7.3 (10H, m).

43-N157-158S=DMSO-d6

of 3.1 (2H, m); for 4.2 (2H, m); and 6.5 (1H); 6,8 (1H, s); the 6.9 and 7.3 (5H, m), and 7.7 (4H, s); 13,5 (1H exchange, s).
44 Hcl-N299,5-300--
45-CH2-COOH-C6H5216--
46-N-C6H5223-231S=DMSO-d6

3,4-3,5 (2H, m); 4,3-4,4 (2H, m); 7,3-7,5 (4H, m); of 7.6 to 7.7 (6N, m); 14 (1 with non-CF3COOD).
47-N2-naphthyl188,5-189,5--
48-CH3-C6H5112-113 
49-N154°S=Dl3

3.04 from-is 3.08 (2H, m); 3.9 to 3,93 (2H, m), 5,94 (1H, s); 6,9-to 6.95 (2H, m), 7.18 in-7,29 (4H, m); 7,41-7,44 (2H, m).
50-N-CH3194-196S=DMSO-d6

of 0.7 (3H, s); 3,3-3,4 (2H, m); 4,3-4,4 (2H, m); 7,0 (1H, s); 7,1-7,2 (1H, m); 7.3 to 7.4 (2H, m); 7,50-of 7.55 (1H, m).
51-N-CH2-C6H5130-132S=l3

the 2.8 and 2.9 (2H, m); 3,7 (2H, s); 3,7-3,5 (2H, m); 5,6 (1H, s); 6,7-6,8 (2H, m); 7,0-of 7.3 (7H, m).

52-N154°C3=Dl3

3,26 be 3.29 (2H, m); 4,12-to 4.15 (2H, m); x 6.15 (1H, s); 7,11-to 7.18 (2H, m); of 7.36 and 7.5 (4H, m); 7,78-7,8 (2H, m)
53-N189°S=CDCl3

3.04 from-of 3.07 (2H, m); of 3.85 (3H, s); 3.96 points-4 (2H, m); of 5.92 (1H, s); 6,86 and 7.6 (12H, m).
54-N226-228S=DMSO-d6

of 3.0 (2H, m); 3,9 (2H, m); at 6.4 (1H, s); 6,8-7,0 (4H, m); a 7.5 and 7.6 (4H, m); 7,-7,8 (4H, m).
55-N201°S=COCl3

2,88-only 2.91 (2H, m); 3,79-3,82 (2H, m) 5,79 (1H, s); 6,68-6,77 (2H, m); of 6.96-7,02 (2H, m); 7,07-7,26 (2H, m); 7,46-7,56 (6H, m).
56-N213S=l3

of 2.58 (3H, s); 3,24 (2H, t; J=4.6 Hz); 4, 16 (2H, t; J=4.6 Hz); 6,11 (1H, s); 7,02 for 7.12 (2H, m), 7,31-7,81 (10H, m).
57-N174-175S=l3of 3.23 (2H, q; J=2,33 Hz); to 4.14 (2H, q; J=2,33 Hz); 6,14 (1H, s); 7,07-to 7.09 (2H, m), 7,34-7,79 (10H, m).

58-N173S=l3

is 3.08 (2H, t; J=4.6 Hz); of 3.32 (2H, t; J=8,75 Hz); was 4.02 (2H, t; J=4.6 Hz); of 4.67 (2H, t; J=8,78 Hz); 5,96 (1H, s); 6,88-7,01 (3H, m); 7,2-7,4 (6H, m); to 7.77-7,86 (2H, m).
59-N183-185S=DMSO-d6

3,11-of 3.12 (2H, m); 3,98-4,01 (2H, m); 6,28 (1H, s); for 6.81-of 7.23 (7H, m); 9,4 (2H, s, exchange-CF3SOOO),
60-N176S=CDCl3

of 1.52 (9H, s); is 3.21 (2H, q, J=2.3 Hz); to 4.14 (2H, q, J=2.3 Hz); 6,09 (1H, s); 7-7 07 (2H, m); 7-32-7,8 (10H, m).
61-N 120-123S=CDCl3

a 3.15 (2H, 1; J=4,65 Hz); 4,07 (2H, t; J=4,65 Hz); between 6.08 (1H, s); of 6.96-8,54 (12H, m).

Table 4, below, illustrates the formation of compounds corresponding to the formula:

Table 4

Approx.n/R1R6R7so square (°)1H NMR: δ (ppm)
62O/-CH2-CO-OEt-C6H5192-193-
63O/--N-CH2-CH2-Net2104-106-
64O/-223-225-

65O/-299-301--------
661/7-CL-N190-1928=l3

of 3.0 and 2.9 (2H, m); 3,9-3,8 (2H, m); at 5.9 (1H, s); 6,8 (1H, m); 7,1-6,9 (2H, m); of 7.6 to 7.3 (9H, m).

EXAMPLE 66

Using the methods shown what's in the previous examples, get the compound of the formula:

having a melting point of 184-185°C.

The invention also relates to pharmaceutical compositions containing an effective amount of at least one of the compounds of formula I, described above, in combination with at least one pharmaceutically acceptable carrier.

According to another aspect of the invention relates to the use of compounds of formula I, as described above, for obtaining a medicinal product for preventing or treating dyslipidaemia, atherosclerosis, and diabetes or its complications.

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TABLE 5

ExampleRR7R6Description
67N4-phenoxyphenylNTPL=204-205

NMR 300 MHz (DMSO): 3,2 (2H, m); a 4.1 (2H, m); and 6.3(1H, s); 6.8 or 6.9 (2H, m); 6,9-7,0 (2 H, m); 7,1-7,2 (4H, m); 7,2-7,3 (1H, m); to 7.4 and 7.5 (4H, m)

MS:371,3 (ES+)
68, HclN4-(p-chlorobenzoyl)phenylNTPL=253-255°

NMR 300 MHz (DMSO): 3,2 (2H, m); for 4.2 (2H, m); 7,1-7,5 (5H, m); to 7.68 (2H, d, J=8.7 Hz); 7,73 (2H, d, J=8.7 Hz); 7,81 (2H, d, J=8.7 Hz); 7,89 (2H, d, J=8.7 Hz); 12,9(1H, s)

MS: 417,3 (ES+)
69, HclNNNMR 300 MHz (DMSO): 3,2-3,3(2H, m); 4,1-4,2 (2H, m); to 4.3 (4H, s); the 6.9 to 7.0 (3H, m); 7,1-7,2 (2H, m); 7,2-7,3 (1H, m); 7.3 to 7.4 (2H, m); 13,0 (1H, s)

MS: 337,3 (ES+)

70, HclN4-cyanophenyl14MS: 304 (ES+)
71, HclN3,4-methylendioxyphenylNMS: 322,8 (ES+)
72, HclNNOMS: 368,8 (ES+)
73, HclNNMS: 358,8 (ES+)
74, HclN3,4,5-trimethoxyphenylNMS: 369 (ES+)
75, HclNNMS: 367 (ES+)
76, HclNNMS: 447 and 449 (ES+)
77, HclNNMS: 516 (ES+)
78, HclN3-cyanophenylNMS: 304 (ES+)

Nbestien-3-ylHMS: 335 (ES+)
80, HclnNMS: 440,8 (ES+) (+N2O); 438,8 (ES-) (+N2Oh)
81, HclNNMS: 550, 551, 552 and 553 (ES+)
82, HclnNMS: 536, 537, 538 and 539 (ES+); 534, 535, 536 and 537 (ES-)

83, HclNNMS: 414 (ES+)
84, HclN4-carboxymethylNMS: 337 (ES+)
85, HclNNMS: 379 (ES+)
86, HclNNMS: 343,2 (ES+)
67, HclN4-methylthiophenylNMS: 325,2 (ES+)
88, HclNNMS: 333,2 (ES+)
89, HclN3-(phenylsulfonyl)phenyl NMS: 419,2 (ES+)
90, HclN2-formatexceptionNMS: 363,1 (ES+)

91, HclNNMS: 416,2( Es+)
92, HclNNMS: 321,2 (ES+)
93, HclN4-(hydroxyethoxy)phenylNMS: 339,1 (ES+)
94, HclNNMS: to 379.2 (ES+)
95, HclN3-nitro-4-phenylthiopheneNMS: 432,1 (ES+)
96, HclNSP3the carbon atom is linked to CSMS: 291,1 (ES+)

97, HclN4-(deformedarse)phenylNF=278,5-279

NMR 300 MHz (CDCl3): 3,1-3,3 (2H, m); 4,1-4,3 (2H, m); 6,7 (1H, t, J=72,6 Hz); and 7.1 and 7.6 (8H, m); 8,1 (1H, d, J=8.7 Hz); 14,7 (1H, s)

MS: 345,1 (ES+)
98, HclN3-methylbenzofuran-2-ylN MS: 349,1 (ES+)
99, HclNNMS: 346,1 (ES+)
100NNMS: 591,4 (ES+)
101, HclN4-phenylsulfonyl)phenylNMS: 419,1 (ES+)

102NNMS: 389,2 (ES+)
103, HclNNMS: 303,1 (ES+)
104NNMS: 383,4 (ES-)
1051)NMS: 432,5 (ES+)

106N4-(diethylamino)phenylNMS: 350,4 (ES+)
107NphenylMS: 389 (ES+)
108N4-morpholinomethylNMS: 364,4 (ES+)
109 NNMS: 429,3 (ES+)
110NNMS: 350,3 (ES+), 348,3 (ES-)
111NNMS: 498,1 and 500,1 (ES+)

112NHMS: 369,4 (Es+)
113NHMS: 337,4 (ES+), 335,4 (ES-)
114N4-pyrrolidinoneHMS: 348,2 (ES+)
115NHMS: 432,1 (ES+) (+H2O)
116NHMS: 290,2 (ES+), 288,3 (ES-)

N
117NNMS: spreads for about 319.2 (ES+), 317,3(ES-)
118, HclNNMS: 351,1 (ES+)
119NMS: 353,3 (ES+)

TABLE 6

ExampleAndZDescription
120NMP=198°

NMR 300 MHz (DMSO): 2,3-2,9 (2H, m); 3,0-3,1 (1H, m): 3,2 and 3.3 (1H, m); 3,4-3,6 (2H, m); 6.8 or 6.9 (1H, m); 6,9-7,2 (9H, m); between 7.4 to 7.5 (2H, m); 7.5 to about 7.6 (2H, m) MS: 387,3 (ES-)
121NTPL=232-233

NMR 300 MHz (DMSO): 2,5 (2H, m); 2,8 (1H, m); 3,1 (1H, m); 3,2-3,4 (2H, m); 6.8 or 6.9 (1H, m); the 6.9 to 7.0 (2H, m); 7,0-7,2 (1H, m); 7.3 to 7.4 (1H, s); of 7.6 to 7.7 (2H, m); of 7.7 to 7.8 (6H, m); MS: 435,4 (ES+)
122N4-trifloromethylMS: 365,2 (ES+)
123N4-sapogeninMS: 322,2 (ES+)
‘124-CeHs-SC,MS: 373,3 (ES+)
125Snz

i
-CeHsNMR 300 MHz (DMSO): 1,1 (3H, d, J=7.2 Hz); 2.8 to 3.0 (2H, m); 3,0-3,3 (2H, m); 3,9 (1H, q, J=7.2 Hz); 6,8-7,2 (5H, m); of 7.3 and 7.6 (5H, m)

MS: 311,3 (ES+)
126NMS: 440,8 (ES+)

127NMS: 394,8 (ES-)
128NMS: 340,7 (ES+)
129NMS: 416,9 (ES-)
130NMS: 386,8 (ES+)
131NMS: 376,8 (ES+)
132NMS: 387 (ES+)
133NMS: 385 (ES+)
134NMS: 433 (ES+)

135N4-carboxymethylMS: 355 (ES+)
136NMS: 465 and 467 (ES+)
137NMS: 367 (ES+)
138N4-triftormetilfosfinovMS: 445 (ES+)
139 -C6HsMS: 407 (ES+)
140Nbestien-3-ylMS: 353 (ES+}
141NMS: 568, 569, 570 and 571 (ES+)
142NMS: 554, 555, 556 and 557 (ES+); 552, 553, 554 and 555 (ES-)
143N4-cyanomethyleneMS: 336 (ES+), 334 (ES-)
144NMS: 432 (ES+)

4-methylthiophenyl
145NMS: 385 (ES+); 429 (+HCOOH) and 383 (ES-)
146NMS: 369 (ES+), 367 (ES-)
147NMS: 455 e (ES+)
148N4-morpholinomethylMS:382 (ES+)
149NMS: 413,5 and 454,5 (+CH3SP) (ES+)
150NMS: 447 (ES+)
151NMS: 343,2 (ES+)
152N2-chlorotritylMS: sauce 337,1 (ES+), 335, 1 (ES-)
153NMS: 351,2 (ES+), 349,2 (ES-)

154NMS: 437,2 (ES+)
155N2 trifluromethane-phenylMS: 381,2 (ES+)
156NMS: 434,2 (ES+), 432,2 (ES-)
157NMS: 399,3 (ES+), 397,4 (ES-)
158NMS: 387,4 (ES+), 385,4 (ES-)
159NMS: 609,6 (ES+), 607,6 (ES-)
160NMS: 371,3, 372,3 and 373,3 (ES+); 369,4 (ES-)
161NMS: 385,3, 386,4 and 387,4 (ES+); 383,4 (ES-)

162N MS: 413,4 (ES+), 411 4 (ES-)
163NMS: 450,3 (ES+), 448,4 (ES-)
164NMS: 407,4 (ES), to 405.5 (ES-)
165NMS: 355,4 (ES+), 353,4 (ES-)
166NMS: 349,4, 350,4 and 351,4 (ES+), 347,4 (ES-)
167NMS: 421,4 (ES+), 419,4 (ES-)
168CH34-bromophenylMS: 389,3 and 391,3 (ES+); 387,3 and 389,3 (ES-)
169NpentafluoroethylMS: 339,3 (ES+), 337,3 (ES-)
170N4-pyrrolidinoneMS: 366,4 (ES+), 364,4; (ES-)
171N4-(deformedarse)phenylMS: 363,3 (ES+), 361,3 (ES-)
172-C6H514-courseMS: 407,3 (ES+), 405,3 (ES-)
1734-courseMS: 421,3 (ES+); 419,4 (ES-)
174-CH33-chloro-4-were MS: 359,3 (ES+), 357,3 (ES-)

175N3-methylbenzofuran-2-ylMS: 365,3 (ES-)
176NMS: 364,3 (ES+), 362,3 (ES-)
177NMS: 433,2 (ES-)
178NMS: 369,3 (ES+), 367,4 (ES-)
179NMS: 498,4 (ES+)
180N4-cyclohexylphenolMS: 379,4 (ES+), 377,4 (ES-)
181IHNMR 300 MHz (DMSO):

the 2.8 and 2.9 (2H, m); 3,0-3,4 (2H, m); 3,4-3,6 (2H, m); 5,4 (2H, S); 6.8 or 6.9 (1H, m);the 6.9 to 7.0 (2H, m); 7,1-7,2 (1H, m); between 7.4 to 7.5 (3H, m); 7,6-7,8 (3H, m); for 8.0 and 8.1 (1H, m)

MS: 517,3 (ES+), 514,3 (ES-)
182N4-trifloromethylMS: 397,3 (ES+), 395,3 (ES-)
183NMS: 387,4 (ES+), 385,4 (ES-)

184-NNMR 300 MHz (DMSO):

2,4 (3H, s); 2,8-2,9 (2H, m); ,1-3,4 (2H, m); 3,4-3,7 (2H, m); 6,8 -7,2 (4H, m); between 7.4 to 7.5 (1H, m); 7,7-7,8 (2H, m); of 7.9 to 8.0 (1H, m)

MS: 401,3 (ES+); 399,3 (ES-)
185-CH34-forefeelMS: 329,3 (ES+); 327,3 (ES-)
186NMS: 437,5 (ES+), 435,5 (ES-)
187NMS: 450,5 (ES+), 448,5 (ES-)
188NMS: 478,4 (ES+), 476,4 (ES-)
189NMS: 397,1 (ES+), 395,0 (ES-)
190NMS: 368,2 (ES+), 366,2 (ES-)
191N4-methylcarbamoylmethylMS: 354,2 (ES+), 352,2 (ES-)

EXAMPLE 192

MS: 309,3, 310,3 and 311,3 (ES+), 307,3 (ES-)

1. Derived benzodiazepine of formula I

in which

dashed lines indicate the possible presence of a double bond;

R1represents an optionally halogenated (C1-C18)alkyl, optionally halogenated (C1-C18)alkoxy, halogen, nitro, hydroxyl or (C6-C10 )aryl (optionally substituted by optionally halogenated (C1-C6)alkyl, optionally halogenated (C1-C6)alkoxy, halogen, nitro or hydroxyl);

n represents 0, 1, 2, 3 or 4;

R2and R3represent, independently from each other hydrogen; optionally halogenated (C1-C18)alkyl, (C1-C18) alkoxy; and (C6-C10)aryl; and (C6-C10)aryl (C1-C6) alkyl; heteroaryl; heteroaryl (C1-C6) alkyl, (C6-C10) aryloxy; and (C6-C10) aryl (C1-C6) alkoxy; heteroaromatic; or heteroaryl (C1-C6) alkoxy; in which aryl and heteroaryl portions of these radicals optionally substituted with halogen, optionally halogenated (C1-C6)alkoxy, optionally halogenated (C1-C6) alkyl, nitro and hydroxyl;

R4represents hydrogen, (C1-C18) alkyl or (C6-C10) aryl, mentioned aryl group optionally substituted with halogen, optionally halogenated (C1-C6) alkoxy, optionally halogenated (C1-C6) alkyl, nitro or hydroxyl;

X represents S or NT, where T represents a hydrogen atom, (C1-C6) alkyl, (C6-C10)aryl, (C6-C10) aryl (C1-C6) alkyl or (C6-C10) arylcarbamoyl;

R5is a (C1-C18) alkyl; hydroxy (C1-C18) alkyl, (C6-C18) aryl (C1-C12) alkyl, (C3-C12) cycloalkyl (C1-C12) alkyl, (C5-C12) cycloalkenyl-(C1-C12)alkyl; heteroaryl(C1-C12)alkyl, optionally substituted by one or more substituents Su as listed below; and (C3-C12) cycloalkyl, optionally substituted by oxo, and optionally fused with (C6-C18) aryl, also optionally substituted by one or more substituents Su as follows; group-CH2-CRa=CRbRc(in which Ra, Rband Rcchosen independently from (C1-C18) alkyl, (C2-C18) alkenyl, hydrogen and (C6-C18) aryl); group-CHA-CO-Z {in which Z represents an optionally halogenated (C1-C18)alkyl; optionally halogenated (C1-C18) alkoxy; and (C3-C12) cycloalkyl; and (C3-C12) cycloalkyl, optionally substituted by oxo, and optionally fused with (C6-C18) aryl; and (C6-C18) aryl (C1-C18) alkyl, (C6-C18) aryl (C1-C12)-alkoxycarbonyl the Ino (C 1-C12) alkyl, in which alkyl optionally substituted C1-C12) alkoxycarbonyl (C1-C12) alkyl, (C1-C12) alkoxycarbonyl; (C1-C12) alkoxycarbonyl (C1-C12) alkyl, (C6-C10) aryl; and (C6-C18)aryl, fused with unsaturated heterocycle, optionally substituted by oxo; or heteroaryl; aryl, heterocycle, cycloalkyl and heteroaryl portions of these radicals optionally substituted with halogen; hydroxyl; optionally halogenated (C1-C12) alkyl; optionally halogenated (C1-C12) alkoxy; nitro; cyano; (C1-C12) alkylenedioxy; (C1-C12) alkylen; carboxy (C1-C12) alkyl, (C2-C12) alkenylamine; optionally halogenated (C1-C12) alkylsulfonate; cyano (C1-C12)-alkyl; -Cy-alk-NH-SO2-Ar, in which alk represents a (C1-C12) alkyl, su is a (C3-C12) cycloalkyl, optionally substituted by one or more substituents Su as listed below, and AG is a (C6-C18)aryl, optionally substituted by one or more substituents Su as follows; -alk-Cy, in which alk and su have the meanings specified below; (C1-C12) alkoxycarbonyl (C1-C12) alkoxy; a (C1-C12)alkoxycarbonyl (C 1-C12) alkyl; rich heterocycle, optionally substituted by one or more substituents Su as specified below; (C1-C12) alkylcarboxylic; (C1-C12) alkylcarboxylic; optionally halogenated (C1-C12) alkylthio; (C1-C12) alkylcarboxylic (C1-C12) alkoxy; a group of the formula

in which p=0, 1, 2, 3 or 4 and in which St represents a (C6-C18) aryl, optionally substituted by one or more substituents Su as specified below; (C1-C12) alkoxycarbonyl; and (C6-C18) aaltio, optionally substituted by one or more substituents Su as listed below; and (C3-C12)cycloalkyl, optionally substituted by one or more substituents Su as follows; -Cy-CO-O-alk in which alk and su have the meanings indicated above; -alk-Cy-alk'-NH-CO-alk, in which alk and su have the meanings indicated above, alk' and alk" represent, independently from each other, (C1-C12) alkyl; -NR°-CO-alk'-Het, in which alk' is the value above R° represents H or (C1-C12) alkyl and Het is heteroaryl, optionally substituted by one or more substituents Su as follows; di(C1-C12)alkoxyphenyl(C1-C12) alkyl; or (C6-C18the ar is l, optionally substituted by one or more substituents Su as listed below; and (C6-C18) aryloxy, optionally substituted by one or more substituents Su as listed below; and (C6-C18)aryl, fused with unsaturated heterocycle, optionally substituted on the heterocyclic segment oxo, all optionally substituted by one or more substituents Su as listed below; and (C6-C18) aryl (C1-C12) alkoxy, optionally substituted by one or more substituents Su as listed below; and (C6-C18) arylsulfonyl, optionally substituted by one or more substituents Su as listed below; and (C6-C18) aryl (C1-C12) alkyl, in which aryl optionally substituted by one or more substituents Su as listed below; and (C6-C18)arylcarbamoyl, optionally substituted by one or more substituents Su as indicated below; and

Represents a hydrogen atom, (C6-C18)aryl group, optionally substituted by one or more substituents Su or (C1-C12) alkyl};

or alternatively, R4and R5together form a group- (CR6=CR7-in which CR6associated with X and in which

R6represents a hydrogen atom; (C1-C18) alkyl, (C3-C12) cycloalkyl; and (C6 -C18) aryl; carboxy (C1-C12) alkyl, (C1-C12) alkoxycarbonyl (C1-C12) alkyl; heteroaryl; and (C6-C18) aryl (C1-C12) alkyl; and heteroaryl (C1-C12) alkyl; in which aryl and heteroaryl portions of these radicals optionally substituted (C1-C12)alkyl, (C1-C12) alkoxy, hydroxyl, nitro, halogen or di(C1-C12) alkoxyphenyl (C1-C12) alkyl;

R7represents a hydrogen atom; hydroxyl; di(C1-C12)alkylamino (C1-C12) alkyl; optionally halogenated (C1-C18) alkyl; carboxyl; carboxy (C1-C12) alkyl, optionally substituted amino; (C1-C12) alkoxycarbonyl; and (C6-C18) aryl; heteroaryl; and (C6-C18) aryl (C1-C12) alkyl; or heteroaryl (C1-C12) alkyl, (C6-C18)aryl, fused with unsaturated heterocycle, optionally substituted on the heterocyclic segment oxo; (C3-C12) cycloalkyl; in which aryl, heterocyclics, cycloalkenyl and heteroaryl plots of these radicals optionally substituted with halogen; hydroxyl; hydroxy (C1-C12) alkoxy; optionally halogenated (C1-C12) alkyl; optionally halogenated (C1 -C12) alkoxy; carboxyla; (C1-C12)alkoxycarbonyl; nitro; cyano; cyano (C1-C18) alkyl, (C1-C18) alkylcarboxylic; (C2-C12) alkylene; (C1-C12) alkylenedioxy; (C1-C12) alkylthio; and (C6-C18) aaltio, optionally substituted by one or more substituents Su as above; di(C1-C12) alkylamino; a group of the formula

in which p=0, 1, 2, 3 or 4 and in which St represents a (C6-C18) aryl; -alk-Cy-NH-SOz-Ar, in which alk represents a (C1-C12) alkyl, su is a (C3-C12) cycloalkyl, optionally substituted by one or more substituents Su as listed below, and AG is a (C6-C18)aryl, optionally substituted by one or more substituents Su as follows; -Cy-alk-NH-SO2-Ar, where su, alk and ar have the meanings stated above; -alk-Cy, in which alk and su have the meanings indicated above; -alk-Cy-alk'-NH-CO-alk, in which alk and su have the meanings given above and alk' and alk" represents, independently, (C1-C12) alkyl; di(C1-C12) alkoxyphenyl (C1-C12) alkyl, (C6-C18)aryl, optionally substituted by one or more substituents Su as listed below; and (C6-C18) aryloxy, optional the part substituted by one or more substituents Su as follows; (C6-C18)arylcarbamoyl, optionally substituted by one or more substituents Su as listed below; and (C6-C18) arylsulfonyl, optionally substituted by one or more substituents Su as listed below; and (C6-C18) aryl (C1-C12) alkoxy in which aryl plot, optionally substituted by one or more substituents Su as follows; rich heterocycle, optionally substituted by one or more substituents Su as listed below; and (C6-C18) aryl (C1-C12) alkyl, optionally substituted by one or more substituents Su as described below;

Su chosen from hydroxyl, halogen, cyano, nitro, optionally halogenated (C1-C12)alkyl and optionally halogenated (C1-C12)alkoxy;

or alternatively, R6and R7together they form with3-C12alkylenes chain, optionally interrupted by a nitrogen atom, which is optionally substituted C1-C12) alkyl or (C1-C18) aryl or (C6-C18) aryl (C1-C12) alkyl, the ring formed CR6=CR7not necessarily merged with (C6-C18) aryl (aryl plots of these radicals optionally substituted with halogen, nitro, hydroxyl, optionally halogenated (C1-C2 )alkyl or optionally halogenated (C1-C12) alkoxy);

and their pharmaceutically acceptable salts with acids or bases, it is understood that the compounds corresponding to one of the definitions (a)-(e)listed below are excluded from the context of the invention:

(a) X=S; n=0; R2represents methyl and R3represents a hydrogen atom; R4and R5together form a group-CR6=CR7-in which CR6associated with X, R6and R7together form a chain -(CH2)3- or -(CH2)4or alternatively, R6represents a hydrogen atom or through group and R7represents a phenyl group, optionally substituted-co3or a hydroxyl group;

(b) n=0 or 2; X=S; R2=R3=R4=H; R5=CH3;

(c) n=0; R2=H; R3=C6H5; R4=H or CH3; X=S; R5=CH3;

(d) n=0 or 1; R2=optionally substituted phenyl; R3=R4=H; X=NT; T=N or CH3; R5represents optionally substituted benzyl, CH3or phenethyl;

(e) n=0; R2=R3=R4=H; X=NH; R5represents benzyl, phenethyl, hydroxyethyl or 3,4-dimethoxyphenethyl.

2. The compound according to claim 1, characterized in that the is a-NT, in which T is the value specified in claim 1, and R4and R5together form- (CR6=CR7.

3. The compound according to claim 1 or 2, wherein R3represents a hydrogen atom.

4. The compound according to any one of claims 1 to 3, wherein R2represents a hydrogen atom or (C6-C10)aryl group, optionally substituted with halogen, (C1-C6) alkoxy, optionally halogenated (C1-C6) alkyl, nitro and hydroxyl.

5. The compound according to any one of claims 1 to 4, characterized in that n represents 0 or 1 and R1represents a halogen atom.

6. The compound according to any one of claims 1 and 3-5, wherein X represents S;

R4represents a hydrogen atom;

R5is a (C1-C6) alkyl; hydroxy (C1-C6) alkyl, (C6-C10) aryl (C1-C6) alkyl, (C5-C8) cycloalkenyl (C1-C6) alkyl; or isoxazolyl (C1-C6) alkyl, optionally substituted by one or more (C1-C6) alkilani; -CH2-CRa=CRbRcin which Rarepresents a hydrogen atom, (C1-C6) alkyl or (C6-C10) aryl, Rbis a (C1-C6) alkyl or a hydrogen atom and Rcis the battle hydrogen atom or (C 2-C10) alkenyl; group-CH2-CO-Z, in which Z represents a (C1-C10) alkyl, (C6-C10) aryl (C1-C6) alkyl, 5 - or 6-membered heteroaryl or (C6-C10) aryl, optionally fused with a 5-7 membered aromatic or unsaturated heterocycle; aryl and heteroaryl plots of these radicals optionally substituted with halogen, hydroxyl, (C1-C6) alkyl, (C1-C6) alkoxy, nitro or (C6-C10) aryl (optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy or nitro);

or alternatively, R4and R5together form a group- (CR6=CR7-where

R6represents a hydrogen atom, (C1-C6) alkyl, (C6-C10)aryl (optionally substituted with halogen, hydroxyl, nitro, (C1-C6) alkyl or (C1-C6) alkoxy), carboxy (C1-C6) alkyl, or (C1-C6) alkoxycarbonyl (C1-C6) alkyl; and

R7represents a hydrogen atom; hydroxyl; di(C1-C6) alkylamino (C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxycarbonyl; and (C6-C10) aryl; heteroa the sludge; (C6-C10) aryl(C1-C6) alkyl; aryl and heteroaryl plots of these radicals optionally substituted C1-C6) alkoxycarbonyl, halogen, hydroxyl, (C1-C6) alkyl, (C6-C10)aryl, (these are optional substituted with halogen, optionally halogenated (C1-C6) alkyl, (C1-C6) alkoxy or nitro) or (C6-C10) aryl, fused with a 5-7 membered aromatic or unsaturated heterocycle comprising one, two or three endocycles heteroatoms selected from O, N and S; or alternatively, R6and R7together form alkylenes chain, which is interrupted by a nitrogen atom, optionally substituted (C6-C10) aryl (C1-C6) alkyl, in which aryl plot optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, (C1-C6) alkoxy, hydroxyl or nitro.

7. The compound according to any one of claims 1 to 5, characterized in that X represents-NT; and R4and R5together form a group-CR6=CR7-, in which R6represents a hydrogen atom and R7represents a hydroxyl or (C6-C10) aryl optionally substituted with halogen, nitro, hydroxyl, optionally halogenated (C1-C6) Alki the om, or (C 1-C6) alkoxy.

8. The compound according to claim 1, selected from

3-(biphenyl-4-yl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine;

3-(2-furyl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine;

3-[4-(etoxycarbonyl)phenyl]-5,6-dihydrothiazolo-[2,3-b]-1,3-benzodiazepine;

1-(2-furyl)-2-(4,5-dihydro-3H-1,3-benzodiazepine-2-ylsulphonyl)Etalon;

1-(biphenyl-4-yl)-2-(4,5-dihydro-3H-1,3-benzodiazepine-2-ylsulphonyl)Etalon;

3-(biphenyl-3-yl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine;

1-(3,4-dihydroxyphenyl)-2-(4,5-dihydro-3H-1,3-benzodiazepine-2-ylsulphonyl)Etalon;

3-(3,4-dihydroxyphenyl)-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine; or

3-(biphenyl-4-yl)-7-chloro-5,6-dihydrothiazolo[2,3-b]-1,3-benzodiazepine.

9. A method of obtaining compounds of formula I according to claim 1, in which X represents S; and R4and R5do not form a jointly-CR6=CR7comprising the reaction of the thione of formula II

in which

R1, n, R2, R3and R4have the meanings indicated in claim 1, with haloperidolum formula III

in which R5has the meaning specified in claim 1, and l1represents a halogen atom, optionally halogenated (C1-C6) alkylsulfonyl or (C6-C10)arylsulfonyl optional is about substituted by aryl (C 1-C6) alkyl.

10. The method according to claim 9, characterized in that the tion of formula II is subjected to reaction with haloketones formula IVa

in which Z has the meaning indicated in claim 1, and Hal2represents a halogen atom, to obtain the corresponding compounds of the formula I, in which R5represents-CH2-CO-Z.

11. The method according to claim 9 or 10, also comprising the alkylation of compounds of formula I obtained according to the method of claim 9 or 10, in which R4represents a hydrogen atom, using a suitable alkylating agent to obtain the corresponding compounds of the formula I, in which R4is a (C1-C18) alkyl.

12. Method of producing compounds of the formula I according to claim 1, in which X represents S and R4and R5together form a group-CR6=CR7-comprising reaction of the thione of the formula IIA

in which n, R1, R2and R3have the meanings indicated in claim 1, haloketones formula IVb

in which R6and R7have the meanings indicated in claim 1, and Hal3represents a halogen atom, a C2-C6aliphatic carboxylic acid, at temperatures between 90 and 130°C.

13. Method according to item 12, characterized in that the Alif is practical carboxylic acid is acetic acid.

14. Method according to any of PP and 13, characterized in that the temperature of the support between 100 and 125°C.

15. Method of producing compounds of the formula I according to claim 1, in which X represents-NH, R4and R5together form a group- (CR6=CR7and R7is not hydroxyl, comprising the reaction of a sulfide of the formula V

in which n, R1, R2and R3have the values listed claim 1, R4and R5together form a group- (CR6=CR7and alk represents a (C1-C6) alkyl, protected derivative of the ketone fomula VI

in which a carbonyl group protected by a protective group, labile with respect to the acidic environment, R6and R7as stated in claim 1, followed by treatment of the resulting compound with an acid.

16. Method of producing compounds of the formula I according to claim 1, in which X represents-NT, where T is not a hydrogen atom, R4and R5together form a group- (CR6=CR7and R7represents hydroxyl, comprising the reaction of a sulfide of the formula V

in which n, R1, R2and R3have the meanings indicated in claim 1 and alk represents a (C1-C6) alkyl, with the derived fo the mules VIII

in which T and R6have the meanings indicated in claim 1, and Y is a leaving group, at a temperature between 50 and 150°and preferably at a temperature between 60 and 100°C.

17. The method of clause 15, also comprising the reaction of the compound obtained by the process according to item 15, halogenated reagent of formula Hal-T, in which T represents a (C1-C6) alkyl, (C6-C10) aryl or (C6-C10) aryl (C1-C6) alkyl and Hal represents a halogen atom, in the presence of a base, so that synthesized the corresponding compound of formula I in which T represents a (C1-C6) alkyl, (C6-C10) aryl or (C6-C10) aryl (C1-C6) alkyl.

18. Pharmaceutical composition having hypolipidaemic activity, containing an effective amount of at least one of the compounds of formula (I) according to any one of claims 1 to 8, in combination with at least one pharmaceutically acceptable carrier.

19. The compound of formula I according to any one of claims 1 to 8 to obtain a medicinal product with hypolipidaemic activity.

20. Derived benzodiazepine of formula I

in which

the dotted lines indicate possible presets is of a double bond;

R1represents an optionally halogenated (C1-C18) alkyl, optionally halogenated (C1-C18) alkoxy, halogen, nitro, hydroxyl or (C6-C10)aryl (optionally substituted by optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy, halogen, nitro or hydroxyl);

n represents 0, 1, 2, 3 or 4;

R2and R3represent, independently from each other hydrogen; optionally halogenated (C1-C18)alkyl, (C1-C18) alkoxy; and (C6-C10) aryl; and (C6-C10) aryl (C1-C6) alkyl; heteroaryl; heteroaryl (C1-C6) alkyl, (C6-C10) aryloxy; and (C6-C10) aryl (C1-C6) alkoxy; heteroaromatic; or heteroaryl (C1-C6) alkoxy; in which heteroaryl is a 5-7-membered aromatic heterocycle containing one, two or three endocycles heteroatoms, which are selected from O, N and S, and in which aryl and heteroaryl plots of these radicals optionally substituted with halogen, optionally halogenated (C1-C6)alkoxy, optionally halogenated (C1-C6)alkyl, nitro and hydroxyl;

R4is the battle hydrogen, (C1-C18) alkyl or (C6-C10)aryl, mentioned aryl group optionally substituted with halogen, optionally halogenated (C1-C6) alkoxy, optionally halogenated (C1-C6) alkyl, nitro or hydroxyl;

X represents S or NT, where T represents a hydrogen atom, (C1-C6) alkyl, (C6-C10) aryl, (C6-C10) aryl (C1-C6) alkyl or (C6-C10) arylcarbamoyl;

R5is a (C1-C18) alkyl; hydroxy (C1-C18) alkyl, (C6-C10) aryl (C1-C6) alkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C5-C8) cycloalkenyl(C1-C6) alkyl; isoxazolyl (C1-C8) alkyl, optionally substituted (C1-C6) alkyl; a group-CH2-CRa=CRbRcin which Ra, Rband Rcchosen independently from (C1-C18) alkyl, (C2-C18) alkenyl, hydrogen and (C6-C10) aryl; a group-CH2-CO-Z, in which Z represents a (C1-C18) alkyl, (C1-C6) alkoxycarbonyl, (C6-C10) aryl (C1-C6) alkyl, (C6-C10) aryl, optionally fused with a 5-7 membered aromatic or unsaturated heterocycle, VK is uchusen one, two or three endocycles heteroatoms selected from O, N and S; or a 5-7 membered heteroaryl containing one, two or three endocycles heteroatoms selected from O, N and S; aryl and heteroaryl plots of these radicals optionally substituted with halogen, hydroxyl, optionally halogenated (C1-C6)alkyl, optionally halogenated (C1-C6) alkoxy, nitro, di(C1-C6) alkoxyphenyl (C1-C6) alkyl or (C6-C10)aryl (optionally substituted with halogen, optionally halogenated (C1-C6) alkyl, optionally halogenated (C1-C6) alkoxy, nitro or hydroxyl);

or alternatively, R4and R5together form a group- (CR6=CR7-in which CR6associated with X and in which

R6represents a hydrogen atom; (C1-C18) alkyl, (C3-C8) cycloalkyl; and (C6-C10) aryl; carboxy (C1-C6) alkyl, (C1-C6) alkoxycarbonyl (C1-C6) alkyl; heteroaryl; (C1-C6) aryl (C1-C6) alkyl; and heteroaryl (C1-C6) alkyl; in which heteroaryl is a 5-7-membered aromatic heterocycle containing one, two or three endocycles heteroatoms, chosen by the C O N and S, and where the aryl and heteroaryl portions of these radicals optionally substituted C1-C6) alkyl, (C1-C6) alkoxy, hydroxyl, nitro, halogen or di(C1-C6) alkoxyphenyl (C1-C6) alkyl;

R7represents a hydrogen atom; hydroxyl; di(C1-C6) alkylamino(C1-C6) alkyl, (C1-C18) alkyl; carboxyl; (C1-C6) alkoxycarbonyl; and (C6-C10) aryl; heteroaryl; and (C6-C10)aryl (C1-C6) alkyl; or heteroaryl (C1-C6) alkyl; in which heteroaryl is a 5-7-membered aromatic heterocycle containing one, two or three endocycles heteroatoms, which are selected from O, N and S, and where the aryl and heteroaryl portions of these radicals optionally substituted with halogen, hydroxyl, optionally halogenated (C1-C6)alkyl, optionally halogenated (C1-C6) alkoxy, carboxyla, (C1-C6) alkoxycarbonyl, nitro, di(C1-C6) alkoxyphenyl (C1-C6) alkyl, or (C6-C10) aryl (these radicals optionally substituted by hydroxyl, nitro, optionally halogenated (C1-C6)alkyl, optionally halogenated (C1-C6) alkoxy or halogen) or (C 6-C10) aryl, fused with a 5-7 membered aromatic or unsaturated heterocycle, containing one, two or three endocycles heteroatoms selected from O, N and S;

or alternatively, R6and R7together form a3-C6alkylenes chain, optionally interrupted by a nitrogen atom, optionally substituted (C1-C6) alkyl, or (C6-C10) aryl or (C6-C10) aryl (C1-C6) alkyl, (aryl plots of these radicals optionally substituted with halogen, nitro, hydroxyl, optionally halogenated (C1-C6) alkyl or optionally halogenated (C1-C6) alkoxy);

and their pharmaceutically acceptable salts with acids or bases, it is understood that the compounds corresponding to one of the definitions (a)-(e)listed below are excluded from the context of the invention:

(a) X=S; n=0; R2represents methyl and R3represents a hydrogen atom; R4and R5together form a group- (CR6=CR7-in which CR6associated with X, R6and R7together form a chain -(CH2)3or (CH2)4or alternatively, R6represents a hydrogen atom or through group and R7represents phenyl GRU is PU, optionally substituted-co3or a hydroxyl group;

(b) n=0 or 2; X=S; R2=R3=R4=H; R5=CH3;

(c) n=0; R2=H; R3=C6H5; R4=H or CH3; X=S; R5=CH3;

(d) n=0 or 1; R2=optionally substituted phenyl; R3=R4=H; X=NT; T=N or CH3; R5represents optionally substituted benzyl, CH3or phenethyl;

(e) n=0; R2=R3=R4=H; X=NH; R5represents benzyl, phenethyl, hydroxyethyl or 3,4-dimethoxyphenethyl.



 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

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where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

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-converting enzyme)" target="_blank">

The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

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wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

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