Derivatives of benzimidazole, pharmaceutical composition and therapeutic use of benzimidazole derivatives

 

(57) Abstract:

In the proposed invention the new compounds of formula (I) with gipoglikemicheskoy activity and inhibitory aldosteronism, 5-lipoxygenase, and the production of lipid peroxide activity: in which X is arbitrarily substituted benzimidazole group; Y represents an oxygen atom or sulfur; Z represents a 2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-hydroxyacetylamino group; R represents hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, amino or aralkyl; m is an integer from 1 to 5. The claimed pharmaceutical composition based on compounds of the formula I, taken in an effective amount, and containing a pharmaceutically acceptable carrier or diluent. 2 C. and 21 C.p. f-crystals, 8 PL.

This invention relates to a series of benzimidazole compounds having hypoglycemic, anti-diabetic, protivokataraktnoe and 5-lipoxygenase inhibitory activity, the ability to inhibit the formation of lipid peroxide and related activity described in more detail below, and provide the animaciya, including tolbutamide and glipizide, used for the treatment of diabetes and hyperglycemia. Recently discovered that compounds, which are similar to the compounds of this invention contain thiazolidinedione, oxazolidinedione or related group attached through a methylene or methylidene group to the benzene ring, have this type of activity proposed for the treatment of insulin-independent diabetes mellitus.

(1) Many derivatives of thiazolidine was found to have hypoglycemic activity, such as derivatives, are described in: Europen Patent Publication N 139421; European Patent Publication N 008203; Chemical Pharm. Bull. 30, 3580-3600 (1982) by Y. Kawamatsu et al.; Europen Patent Publication N 0441605.

(2) Compounds containing heterocyclic ring group, are disclosed, for example, in European Patent Publication N 208420; European Patent Publication N 528734; WO 92/07850A; WO 92/07839A; European Patent Publication N 177353; European Patent Publication N 306228; European Patent Publication N 356214.

(3) Oxazolidin-2, 4-dinavia compounds having hypoglycemic activity, are disclosed, for example, in WO 91/07107A; WO 92/02520A.

(4) in Addition, compounds containing N-hydroxyurea group or 3,5-dioxoimidazolidin-2-imlilfinishing group and having this type of activity are disclosed in WO 92/03425A.

In the following literature describes the relationship between the derivative of thiazolidine and various diseases.

The action of the compounds of thiazolidine on hyperglycemia reported in Diabetes 32(9), 804-810 (1983); Diabetes 37(11), 1549-1558 (1988); Prog. Clin. Biol. Res. 265, 177-192 (1988); Metabolism 37(3), 276-280 (1988); Arzneimittelforschung 40(1), 37-42 (1990); Arzneimittelforschung 40(2 Pt 1), 156-162 (1990); Arzneimittelforschung 40(3), 263-267 (1990).

The action of the compounds of thiazolidine on hyperlipidemia reported in Diabetes 40(12), 1669-1674 (1991); Am. J. Physiol. 267 (1 Pt 1), E95-E101 (1994); Diabetes 43(10), 1203-1210 (1994).

On the influence of the compounds of thiazolidine reduced glucose tolerance and insulinrezistentnost reported in Arzneimittelforschung 40 (2 Pt 1), 156-162 (1990); Metabolism 40(10), 1025-1030 (1991); Diabetes 43(2), 204-211 (1994); N. Engl. J. Med. 331(18), 1226-1227 (1994).

The action of the compounds of thiazolidine on hypertension reported in Metabolism 42(1), 75-80 (1993); Am. J. Physiol. 265 (4 Pt 2), R726-R732 (1993); Diabetes 43(2), 204-211 (1994).

The action of the compounds of thiazolidine on cachexia (General fatigue) are reported in Endocrinology 135(5), 2279-2282 (1994); and Endocrinology 136(4), 1474-1481 (1995).

The action of sedimentation disease coronary artery reported in Am. J. Physiol. 265 (4 Pt 2), R726-R732 (1993); Hypertension 24(2), 170-175 (1994).

The action of the compounds of thiazolidine on arteriosclerosis reported in Am. J. Physiol. 265 (4 Pt 2), R726-R732 (1993).

In addition, recently in N. Engl. J. Med. 331(18), 1226-1227 (1994) it was reported about the high risk of occurrence of diabetes in normal people who have insulin resistance, which is not accompanied by reduced glucose tolerance (in other words, insulinorezistentne non-IGT (NGT). This fact confirms that a tool that can improve insulin resistance, it may be useful to prevent this kind of diabetic cases in normal people.

We have found that the inclusion of such links to some specific bicyclic nitrogen-containing ring systems leads to compounds with greatly increased activity.

The invention

Thus, the purpose of this invention is to develop a series of new chemical compounds that contain a benzimidazole ring, and which may be regarded as derivatives of thiazolidine and oxazolidine or their derivatives with an open ring.

Another, more specific, object of this invention to provide such a connection is s, including one or more of: hyperlipemia, hyperglycemia, obesity, reduced glucose tolerance (IGT), insulin resistance and diabetic complications.

Other objectives and advantages of this invention will become apparent from consideration of the description.

Thus, the invention provides compounds of formula (I):

< / BR>
in which

X represents a benzimidazole group, which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined below;

Y represents an oxygen atom or a sulfur atom;

Z represents a group of the formula (i), (ii), (iii): (iv) or (v):

< / BR>
< / BR>
< / BR>
< / BR>
R represents a hydrogen atom;

alkyl group having from 1 to 4 carbon atoms;

alkoxy group having from 1 to 4 carbon atoms;

a halogen atom; hydroxy group;

nitro group;

group of the formula: -NRaRb,

in which Raand Rbthe same or different, and each represents a hydrogen atom, alkyl group having 1 to 8 carbon atoms, aracelio group in which an alkyl group having from 1 to 5 carbon atoms, a substituted carbocyclic aryl grupations acyl group of from 1 to 11 carbon atoms; aryl-aliphatic acyl groups in which the aliphatic acyl groups having from 1 to 6 carbon atoms, substituted by at least one carbocyclic aryl group having from 6 to 10 carbon atoms; or an aromatic acyl group having from 7 to 11 carbon atoms; or

aracelio group in which an alkyl group having from 1 to 5 carbon atoms, substituted carbocyclic aryl group having from 6 to 10 carbon atoms; and

m represents an integer from 1 to 5;

these substituents are selected from the group consisting of:

alkyl groups having from 1 to 4 carbon atoms;

alkoxy group having from 1 to 4 carbon atoms;

benzyloxy group;

the halogen atom;

hydroxy group;

acetoxy group;

phenylthio group;

alkylthio group having from 1 to 4 carbon atoms;

triptorelin group;

nitro group;

group of the formula: -NRaRbin which Raand Rbsuch as defined above;

carbocyclic aryl groups having from 6 to 10 carbon atoms, which is unsubstituted or substituted by at least one of the substituents defined below; or aranceles group in which an alkyl group, and is erode and which is unsubstituted or substituted, at least one Deputy, selected from the group consisting of the substituents defined below;

these substituents are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, hydroxy groups, nitro groups, phenyl groups, triptoreline groups and groups of formula-NRaRbin which Raand Rbsuch as defined above; and their salts.

This invention also provides a pharmaceutical composition for the treatment or prevention of insulin resistance, diabetes, hyperglycemia, arteriosclerosis, cataracts, hyperlipemia, obesity, reduced glucose tolerance, hypertension, polycystic ovary syndrome, diabetes during pregnancy, or insulinorezistentne not-IGT, cataracts and complications, and this composition includes an effective amount of the active compound in a mixture with a pharmaceutically acceptable carrier or diluent, in which the specified active compound selected from the group consisting of compounds of the formula (I) defined above, and their salts.

This invention also provides a method for the treatment or prophylactically to glucose, hypertension, polycystic ovary syndrome, diabetes during pregnancy, or insulinorezistentne not-IGT, cataracts and their complications in a mammal, which may be human, and this method includes the introduction of the specified mammal an effective amount of an active compound, where the specified active compound selected from the group consisting of compounds of the formula (I) defined above, and their salts.

This invention also provides a pharmaceutical composition for inhibiting elderadostone, 5-lipoxygenase or lipid peroxide and their complications, and this composition includes an effective amount of the active compound in a mixture with a pharmaceutically acceptable carrier or diluent, in which the specified active compound selected from the group consisting of compounds of the formula (I) defined above, and their salts.

This invention also provides a method of inhibiting elderadostone, 5-lipoxygenase or lipid peroxide and their complications in a mammal, which may be human, and this method includes the introduction of the specified mammal an effective amount of an active compound, where the specified active connection frame, provides methods for producing compounds of the present invention, and these methods are described in more detail below.

A detailed description of the invention

When X represents unsubstituted benzimidazole group, it may be, for example, 1-benzimidazole, 2-benzimidazole, 4-benzimidazole, 5-benzimidazole, 6-benzimidazole or 7-benzimidazole group. Alternative X may represent a substituted benzimidazole group, and in this case the Deputy is one or more of the substituents defined above and illustrated below. There is no limit on the number of substituents in the group in addition to the limitations imposed by the number capable of substitution provisions, i.e. 5. Therefore, the possible number of substituents is from 1 to 5. More preferably, in the case of those compounds that are intended for the treatment or prevention of hyperglycemia, the presence of from 1 to 3 such substituents, and one Deputy preferred. In the case of those compounds that are intended for the inhibition of lipid peroxide, the most preferred are those compounds, which have five deputies. When any of R, Deputy and/or assistant , is alkylene is laroda. Examples of such alkyl groups include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou and t-boutelou groups, of which we prefer the methyl group.

When any of R, Deputy and/or assistant , represents alkoxy group, this may be unbranched or branched chain alkoxy group having from 1 to 4 carbon atoms. Examples of such alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy groups, of which we prefer the methoxy group.

When any of R, Deputy and/or assistant , represents a halogen atom, this may be, for example, an atom of bromine, chlorine or fluorine, of which a fluorine atom is preferable.

When any of R, Deputy , Raand/or Rbis aracelio group, it may be the same as defined above, i.e. an alkyl group having from 1 to 5 carbon atoms, which is substituted by at least one carbocyclic aryl group having from 6 to 10 carbon atoms in the ring. In the case of R, Raand Rbaryl group is preferably unsubstituted. In the case of deputies , the group may be unsubstituted which as substituents in the alkyl part, preferred is the presence of only one such aryl groups. The total number of carbon atoms in the alkyl part and carbocyclic ring aryl part is preferably from 7 to 11. Alkyl part aranceles group can be non-branched chain alkyl group having from 1 to 5 carbon atoms. Examples of such unsubstituted Uralkalij groups include benzyl, 2-phenylethylene, 1-phenylethylene, 3-phenylpropanol, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 1-phenylbutyl, 5-phenylpentane, 1-naphthylmethyl and 2-naphthylmethyl group, of which the benzyl group is preferable.

When any of R, Deputy and/or assistant , represents a group of the formula: -NRaRbthis is amino group which is unsubstituted or may be substituted by any of the groups defined for Raand Rbexcept hydrogen atom. Examples of such groups include:

(1) Alkyl groups, which may be unbranched or branched chain groups having from 1 to 8 carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina, t-bucilina, pentilla, 1-methylbutyl, 1-ethylpropyl, 2-Mattila, 1-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, heptylene, 1-methylhexane, 1-ethylpentane, 1-propylethylene, 3,3-dimethylpentyl, anjilina, 1-methylheptane, 2-ethylhexyl and 1,1,3,3-TETRAMETHYLBUTYL group, of which preferred are those unbranched or branched chain alkyl group, which have from 1 to 6 carbon atoms, and most preferred are those unbranched or branched chain alkyl groups which have from 1 to 6 carbon atoms, and most preferred are those unbranched or branched chain alkyl groups which have from 1 to 4 carbon atoms, in particular methyl and ethyl groups.

(2) Kalkilya group, preferably having from only 7 to 11 carbon atoms in the alkyl group and the carbocyclic ring, which may be as defined and illustrated above in relation to substituents .

(3) Aryl groups having from 6 to 10 carbon atoms and preferably 6 or 10 carbon atoms in the carbocyclic colzi more of the substituents defined above and illustrated below. However, it is preferably unsubstituted. Examples of such aryl groups include phenyl, 1-naftalina and 2-naftalina group.

(4) Aliphatic acyl group which may be unbranched or branched chain groups having from 1 to 11 carbon atoms, for example formyl, acetyl, propylaniline, Butyrina, isobutylene, bialoleka, valerina, isovaleryl, hexanoyl, heptanoyl, actinaria, nonantola, dekheila and undecanoyl groups, of which the preferred formyl, acetyl, propylaniline, Butyrina, isobutylene, bialoleka, valerianna and hexanoyl group.

(5) Aryl-aliphatic acyl group, in which the aliphatic acyl group having from 2 to 6 carbon atoms, substituted by at least one carbocyclic aryl group having from 6 to 10 Atmos carbon. The aryl group may be as defined and illustrated in (3) above. Can be from 1 to 3 such aryl substituents, preferably one. Examples of such aryl-aliphatic acyl groups include phenylacetylene, 3-phenylpropionyl, 4-phenylbutyramide, 5-phenylbenzamidine group is preferable.

(6) an Aromatic acyl group having from 7 to 11 carbon atoms in which the aromatic part is a carbocyclic aryl group which may be as defined and illustrated in (3) above, for example benzoline, 1-napolina and 2-napolina group, of which benzoline group is preferable.

Group Raand Rbmay be the same or different. If they are the same and both hydrogen atoms, this group is simple unsubstituted amino group. Alternatively, one may be a hydrogen atom, and the other may be one of the other groups defined and illustrated above, or one may be one of the groups, in addition to hydrogen, as defined and illustrated above, and the other can be from other groups, in addition to hydrogen, as defined and illustrated above, or they may be the same and both can be one of the groups, in addition to hydrogen, as defined and illustrated above. In General we prefer that both be hydrogen atoms or to one would be a hydrogen atom, and the other would be one of the other groups defined and illustrated above.

Finally, when R, Deputy and/or assistant , predstatelnoy Deputy, i.e., Rarepresents a hydrogen atom and Rbrepresents an alkyl group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, t-butylamino, pentylamine, 1 methylbutylamine, 1 ethylpropylamine, 2-methylbutylamine, 3 methylbutylamine, 1,1-dimethylbutylamino, 1,2-methylpropylamine, 2,2-dimethylpropylene, hexylamino, 1 methylpentylamino, 1 ethylbutylamine, 2-methylpentylamino, 3 methylpentylamino, 4-methylpentylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, heptylamine, 1 methylhexanamine, 1 ethylmethylamino, 1 propylbetaine, 3,3-dimethylpentylamine, octylamine, 1 methylheptane, 2-ethylhexylamine and 1,1,3,3-tetramethylbutylamine group;

(2) amino groups having one Uralkaliy Deputy, i.e., Rarepresents a hydrogen atom and Rbis aracelio group, for example, benzylamino, 2-phenylethylamine, 1 phenylethylamine, 3 phenylpropylamine, 2-phenylpropylamine, 1 phenylpropylamine, 4-phenylbutyramide, 1 phenylethylamine, 5-phenylendiamine, 1 naphthylenediamine and 2 naphthylethylene group;

(3) s is t aryl group, for example, phenylamino, 1 naphthylamine and 2 naphthylamine group;

(4) amino groups having one aliphatic acyl Deputy, i.e., Rarepresents a hydrogen atom and Rbrepresents an aliphatic acyl group, for example, formylamino, acetylamino, propionamido, bucillamine, isobutylamino, paulolino, pentanediamine, hexanamine, leptanillinae, octanoylthio, nonboiling, decanoylamino, undecanoyl group;

(5) amino groups having one aryl-aliphatic acyl Deputy, i.e., Rarepresents a hydrogen atom and Rbrepresents an aryl-aliphatic acyl group, for example, phenylacetylamino, 3 phenylpropionylamino, 4-phenylbutyramide, 5-phenylenediamine, 6-phenylhexanoic, methylphenylethylamine and - dimethylphenylethylamine group;

(6) an amino group having one aromatic acyl Deputy, i.e., Rarepresents a hydrogen atom and Rbrepresents an aromatic acyl group, for example benzoylamine, 1 naphthylamine and 2 naphthylamine group;

(7) an amino group having two alkyl substituent, i.e., Raand Rbboth represent alkyl groups, which may be the same or different, for example one alkyl substituent and one Uralkaliy Deputy, i.e., Rarepresents an alkyl group, and Rbis aracelio group, for example N-ethyl-N-benzylamino, N-t-butyl-N-benzylamine and N-hexyl-N-benzylamino group;

(9) amino group having one alkyl substituent and one aryl Deputy, i.e., Rarepresents an alkyl group, and Rbrepresents aryl groups, for example N-methyl-N-phenylamino, N-ethyl-N-phenylamino and N-octyl-N-phenylamino group;

(10) amino groups having one alkyl substituent and one aliphatic acyl Deputy, i.e., Rarepresents an alkyl group, and Rbrepresents an aliphatic acyl group, for example, N-propyl-N-acetylamino, N-pentyl-N-propionamide and N-ethyl-N-hexanamine group;

(11) amino groups having one alkyl substituent and one aryl-aliphatic acyl Deputy, i.e., Rarepresents an alkyl group, and Rbrepresents an aryl-aliphatic acyl group, for example N-ethyl-N-phenylacetylamino, N-isopropyl-N-(2-phenylpropionyl)amino and N-methyl-N-(6-phenylhexanoic)amino group;

(12) amino groups having one alkyl substituent and one aromatic acyl Deputy, i.e., Rarepresents an alkyl group, and Rbpredstavlenie group;

(13) amino groups having two Uralkalij Deputy, i.e., Raand Rbboth represent kalkilya group, which may be the same or different, for example, dibenzylamine, N-benzyl-N-(3-phenylpropyl)amino and N-benzyl-N-(2-naphthylmethyl)amino group;

(14) amino groups having one Uralkaliy Deputy and one aryl Deputy, i.e., Rais aracelio group, and Rbrepresents an aryl group, for example N-benzyl-N-phenylamino and N-(3-phenylpropyl)-N-phenylamino group;

(15) amino groups having one Uralkaliy Deputy and one aliphatic acyl Deputy, i.e., Rais aracelio group, and Rbrepresents an aliphatic acyl group, for example N-benzyl-N-acetylamino, N-benzyl-N-pentanediamine group and N-benzyl-N-propionamido;

(16) amino groups having one Uralkaliy Deputy and one aryl-aliphatic acyl Deputy, i.e., Rais aracelio group, and Rbrepresents an aryl-aliphatic acyl group, for example N-benzyl-N-phenylacetylamino and N-benzyl-N-(4-phenylbutyl)amino group;

(17) amino groups having one Uralkaliy Deputy and one aromatic acyl Deputy, i.e., R is nil-N-benzoylamine and N-(2-phenylethyl)-N-benzoylamine group;

(18) amino groups having two aryl substituent, i.e., Raand Rbboth represent aryl groups which may be the same or different, for example, diphenylamino, N-(1-naphthyl)-N-phenylamino and N-(2-naphthyl)-N-phenylamino group;

(19) amino groups having one aryl Deputy and one aliphatic acyl Deputy, i.e., Rarepresents an aryl group, and Rbrepresents an aliphatic acyl group, such as N-phenyl-N-acetylamino, N-phenyl-N-propionamide and N-phenyl-N-hexanamine group;

(20) amino groups having one aryl Deputy and one aryl-aliphatic acyl Deputy, i.e., Rarepresents an aryl group, and Rbrepresents an aryl-aliphatic acyl group, such as N-phenyl-N-phenylacetylamino and N-phenyl-N-(4-phenylbutyl)amino group;

(21) amino groups having one aryl Deputy and one aromatic acyl Deputy, i.e., Rarepresents an aryl group, and Rbrepresents an aromatic acyl group, such as N-phenyl-N-benzoylamine and N-phenyl-N-(2-naphtol)amino group;

(22) amino groups having two aliphatic acyl substituent, i.e., Raand Rbboth represent aliphatic ANO and N-butyryl-N-hexanamine group;

(23) amino groups having one aliphatic acyl Deputy and one aryl-aliphatic acyl Deputy, i.e., Rarepresents an aliphatic acyl group, and Rbrepresents an aryl-aliphatic acyl group, such as N-acetyl-N-phenylacetylamino, N-acetyl-N-(4-phenylbutyl)amino and N-butyryl-N-phenylacetylamino group;

(24) amino groups having one aliphatic ecially Deputy and one aromatic acyl Deputy, i.e., Rarepresents an aliphatic acyl group, and Rbrepresents an aromatic acyl group, such as N-acetyl-N-benzoylamino and N-butyryl-N-(2-naphtol)amino group;

(25) amino groups having two aryl-aliphatic acyl substituent, i.e., Raand Rbboth represent aryl-aliphatic acyl group, which may be the same or different, for example N,N-diphenylacetylene, N-phenylacetyl-N-(2-phenylpropionyl)amino group;

(26) amino groups having one aryl-aliphatic acyl Deputy and one aromatic acyl Deputy, i.e., Rarepresents an aryl-aliphatic acyl group, and Rbrepresents an aromatic acyl group, such as N-phenylacetyl-N-benzoyl-Amin is La, i.e., Raand Rbboth represent aromatic acyl group, which may be the same or different, for example, dibenzylamine and N-benzoyl-N-(2-naphtol)amino group;

When the Deputy is alkylthio group, it may be unbranched or branched chain alkylthio group having from 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio and t-butylthio groups.

When the Deputy represents an aryl group, it may be carbocyclic aryl group having from 6 to 10 carbon atoms, which is unsubstituted or substituted by one or more substituents ./ Examples of unsubstituted aryl groups include phenyl, 1-naftalina and 2-naftalina group. When the aryl group is substituted, there is no restriction on the number of substituents, in addition to restrictions that may be imposed by a number of capable of substitution positions and possibly by steric constraints; thus, the maximum number of substituents on the phenyl group is 5, while the maximum number of substituents on naftilos group is 7. In General, however, it is preferable from 1 to 3 substituents, and newpw, having from 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, a halogen atom or a group of the formula: -NRaRbthey may be as defined and illustrated above, relative to the corresponding group or atom, represented by the Deputy . Alternatively, the Deputy may be a hydroxy group, nitro group, phenyl group or triptorelin group.

Examples of substituted aryl groups which may be represented by a Deputy , include:

(1) Aryl groups substituted by at least one unbranched or branched chain alkyl group having from 1 to 4 carbon atoms, for example 4-methylphenylene, 4-ethylvanillin, 4-propylaniline, 4-isopropylphenyl, 4-butylaniline, 4-isobutylphenyl, 4-second-butylaniline, 4-t-butylaniline, 4-methyl-1-naftalina, 5-ethyl-1-naftalina, 8-propyl-1-naftalina, 4-isopropyl-1-naftalina, 5-butyl-1-naftalina, 4-isobutyl-1-naftalina, 4-sec-butyl-1-naftalina, 4-t-butyl-1-naftalina, 4-methyl-2-naftalina, 5-ethyl-2-naftalina, 8-propyl-2-naftalina, 4-isopropyl-2-naftalina, 5-butyl-2-naftalina, 8-isobutyl-2-naftalina, 4-sec-butyl-2-naftalina and 5-t-butyl-2-naftalina group.

(2) the Arilje is the fact that from 1 to 4 carbon atoms, for example, 4-metoksifenilny, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyaniline, 4-solutocapillary, 4-second-butoxyaniline, 4-t-butoxyphenyl, 4-methoxy-1-naftalina, 5-ethoxy-1-naftalina, 8-propoxy-1-naftalina, 4-isopropoxy-1-naftalina, 5-butoxy-1-naftalina, 4-isobutoxy-1-naftalina, 4-Deut-butoxy-1-naftalina, 4-t-butoxy-1-naftalina, 4-methoxy-2-naftalina, 5-ethoxy-2-naftalina, 8-propoxy-2-naftalina, 4-isopropoxy-2-naftalina, 5-butoxy-2-naftalina, 8-isobutoxy-2-naftalina, 4-Deut-butoxy-2-naftalina and 5-t-butoxy-2-naftalina group.

(3) Aryl groups substituted by at least one halogen atom, such as 4-bromoaniline, 4-Chloroaniline, 4-feraferia, 4-iodoaniline, 3-Chloroaniline, 3-feraferia, 3-bromoaniline, 3-iodoaniline, 4-bromo-1-naftalina, 4-chloro-1-naftalina, 4-fluorescent-1-naftalina, 4-iodo-1-naftalina, 5-chloro-1-naftalina, 5-fluorescent-1-naftalina, 5-bromo-1-naftalina, 8-chloro-1-naftalina, 4-fluorescent-2-naftalina, 4-bromo-2-naftalina, 4-chloro-2-naftalina, 4-iodo-2-naftalina, 5-bromo-2-naftalina, 5-chloro-2-naftalina, 5-fluorescent-2-naftalina and 5-iodo-2-naftalina group.

(4) Aryl groups substituted by at least one guide is 5-hydroxy-1-naftalina, 8-hydroxy-1-naftalina, 4-hydroxy-2-naftalina, 5-hydroxy-2-naftalina and 8-hydroxy-2-naftalina group.

(5) Aryl groups substituted by at least one nitro group, such as 2-nitroaniline 3-nitro-phenyl, 4-nitroaniline, 4-nitro-1-naftalina, 5-nitro-1-naftalina, 8-nitro-1-naftalina, 4-nitro-2-naftalina, 5-nitro-2-naftalina and 8-nitro-2-naftalina group.

(6) Aryl groups substituted by at least one phenyl group, such as 3-phenylphenolate, 4-phenylphenolate, 4-phenyl-1-naftalina, 5-phenyl-1-naftalina, 8-phenyl-1-naftalina, 4-phenyl-2-naftalina, 5-phenyl-2-naftalina and 8-phenyl-2-naftalina group.

(7) Aryl groups substituted by at least one triptorelin group, such as 3-trifluoromethyl-phenyl, 4-triftormetilfullerenov, 4-trifluoromethyl-1-naftalina, 5-trifluoromethyl-1-naftalina, 8-trifluoromethyl-1-naftalina, 4-trifluoromethyl-2-naftalina, 5-tryptomer-2-naftalina and 8-trifluoromethyl-2-naftalina group.

(8) Aryl groups substituted by at least one unsubstituted amino group, such as 2-aminoaniline, 3-aminoaniline, 4-aminoaniline, 4-amino-1-naftalina and 8-amino-2-naftalina.

(9) Aryl groups substituted on what Rupay formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an alkyl group, such as 3-methylaminophenol, 4-atramentaria, 3-propylaminoethyl, 3-isopropylacetanilide, 4-butylaminoethyl and 3-isobutyleneisoprene group;

(ii) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom, and Rbis aracelio group, for example, 4-benzylaminopurine, 4-(2-phenylethylamine)phenyl, 4-(1-phenylethylamine)phenyl, 4-(4-phenylbutyramide)phenyl and 4-(1-naphthylethylene)phenyl group;

(iii) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an aryl group, for example 4-phenylenevinylene and 4-(1-naphthylamine)phenyl group;

(iv) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an aliphatic acyl group, for example 4-formylmorpholine, 4-acetylaminophenol, 4-butyrylthiocholine, 4-pivaloyloxymethyl, 4-exaniination, 4-octanoylthiophene and 4-underenumeration group;

(v) aryl groups, substituted limfaticheskoi acyl group, for example, 4-phenylacetonitrile, (4-(4-phenylbutyramide)phenyl, 4-(6-phenylhexanoic)phenyl, 4-(but-methylphenylethylamine)phenyl and 4-(,- dimethylphenylethylamine)phenyl group;

(vi) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an aromatic acyl group, for example 4-benzylaminopurine, 4-(1-naphthylamine)phenyl and 4-(2-naphthylamine)phenyl group;

(vii) aryl groups substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent alkyl groups which may be the same or different, for example 4-dimethylaminopyridine, 4-diethylaminophenyl and 4-(N-methyl-N-ethylamino)phenyl group;

(viii) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbis aracelio group, such as 4-(N-ethyl-N-benzylamino)phenyl, 4-(N-t-butyl-N-benzylamino)phenyl and 4-(N-hexyl-N-benzylamino)phenyl group;

(ix) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbrepresents an aryl group, such as 4-(N-methyl-N-phenylamino>Rbwhere Rarepresents an alkyl group, and Rbrepresents an aliphatic acyl group, such as 4-(N-propyl-N-acetylamino)phenyl and 4-(N-ethyl-N-hexanamine)phenyl group;

(xi) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-ethyl-N-phenylacetylamino)phenyl and 4-[N-methyl-N-(6-phenylhexanoic)amino]phenyl group;

(xii) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbrepresents an aromatic acyl group, for example, 4-(N-methyl-N-benzoylamino)phenyl and 4-(N-heptyl-N-benzoylamine)phenyl group;

(xiii) aryl groups substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent kalkilya group, which may be the same or different, for example 4-dibenzylidineacetone and 4-[N-benzyl-N-(2-naphthylmethyl)amino]phenyl group.

(xiv) aryl groups substituted by a group of the formula: -NRaRbwhere Rais aracelio group, and Rbrepresents an aryl group, such as 4-(N-benzyl-N-phenylamino: -NRaRbwhere Rais aracelio group, and Rbrepresents an aliphatic acyl group, such as 4-(N-benzyl-N-acetylamino)phenyl and 4-(N-benzyl-N-pentanediamine)phenyl group;

(xvi) aryl groups substituted by a group of the formula: -NRaRbwhere Rais aracelio group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-benzyl-N-phenylacetylamino)phenyl and 4-[N-benzyl-N-(4-phenylbutyl)amino]phenyl group;

(xvii) aryl groups substituted by a group of the formula: -NRaRbwhere Rais aracelio group, and Rbrepresents an aromatic acyl group, such as 4-(N-benzyl-N-benzoylamine)phenyl and 4-[N-(2-phenylethyl)-N-benzoylamine]phenyl group;

(xviii) aryl groups substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aryl groups which may be the same or different, for example 4-(diphenylamino)phenyl and 4-[N-(2-naphthyl)-N-phenylamino] phenyl group;

(xix) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an aryl group, and Rbrepresents an aliphatic acyl group, such as 4-(N-phenyl-is ppoi formula: -NRaRbwhere Rarepresents an aryl group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-phenyl-N-phenylacetylamino)phenyl and 4-[N-phenyl-N-(4-phenylbutyl)amino]phenyl group;

(xxi) aryl groups substituted by a group of the formula: -NRaRbwhere Rais aryl and Rbrepresents an aromatic acyl group, such as 4-(N-phenyl-N-benzoylamine)phenyl group;

(xxii) aryl groups substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aliphatic acyl groups which may be the same or different, for example 4-dietilaminoetanola and 4-(N-butyryl-N-hexanamine)phenyl group;

(xxiii) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an aliphatic acyl group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-acetyl-N-phenylacetylamino)phenyl and 4-(N-butyryl-N-phenylacetylamino)phenyl group;

(xxiv) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an aliphatic acyl group, and Rbrepresents an aromatic acyl group, such as 4-(N-acetyl-is a group of the formula: -NRaRbwhere Raand Rbboth represent aryl-aliphatic acyl group, which may be the same or different, such as 4-(N,N-diphenylacetylene)phenyl and 4-[N-phenylacetyl-N-(4-phenylbutyl)amino]phenyl group;

(xxvi) aryl groups substituted by a group of the formula: -NRaRbwhere Rarepresents an aryl-aliphatic group, and Rbrepresents an aromatic acyl group, such as 4-(N-phenylacetyl-N-benzoylamine)phenyl and 4-[N-phenylacetyl-N-(2-naphtol)amino]phenyl group; and

(xxvii) aryl groups substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aromatic acyl group, which may be the same or different, for example 4-dibenzoylethylene and 4-[N-benzoyl-N-(2-naphtol)amino]phenyl group.

When the Deputy is aracelio group, it represents alkyl group having 1 to 5 carbon atoms, which is substituted by carbocyclic aryl group having from 6 to 10 carbon atoms in the carbocyclic ring. The aryl group may itself be substituted or unsubstituted and, if substituted, the substituents are selected from the substituents defined and Projet aranceles group may be unbranched or branched chain alkyl group, having from 1 to 5 carbon atoms. Examples of unsubstituted Uralkalij groups include benzyl, 2-phenylethylene, 1-phenylethylene, 3-phenylpropanol, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 1-phenylbutyl, 5-phenylpentane, 1-naphthylmethyl and 2-naphthylmethyl group. When the aryl part aranceles group is substituted, there is no restriction on the number of substituents, in addition to restrictions that may be imposed by a number of capable of substitution provisions, and possibly by steric constraints; thus, the maximum number of substituents on the phenyl group is 5, while the maximum number of substituents on naftilos group is 7. In General, however, it is preferable from 1 to 3 substituents, and one Deputy is usually preferred.

In addition, when the Deputy represents an alkyl group having from 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, a halogen atom or a group of the formula: -NRaRbthey may be as defined and illustrated above, relative to the corresponding group or atom, represented by the Deputy . Alternatively, the Deputy may be GI is x-aryl groups, which can be represented by a Deputy , include:

(1) Kalkilya group, substituted by at least one unbranched or branched chain alkyl group having from 1 to 4 carbon atoms, for example 4-methylaniline, 4-ethylaniline, 4-propylaniline, 4-isopropylbenzyl, 4-butylaniline, 4-isobutylbenzene, 4-fluoro-butylaniline, 4-t-butylaniline, 4-methyl-1-naphthylmethyl, 5-ethyl-1-naphthylmethyl, 8-propyl-1-naphthylmethyl, 4-isopropyl-1-naphthylethylene, 5-butyl-1-naphthylmethyl, 4-isobutyl-1-naphthylmethyl, 4-sec-butyl-1-naphthylmethyl, 4-t-butyl-1-naphthylmethyl, 4-methyl-2-naphthylmethyl, 5-ethyl-2-naphthylmethyl, 8-propyl-2-naphthylmethyl, 4-isopropyl-2-naphthylmethyl, 5-butyl-2-naphthylmethyl, 8-isobutyl-2-naphthylethylene, 4-sec-butyl-2-naphthylethylene and 5-t-butyl-2-naphthylmethyl group.

(2) Kalkilya group, substituted by at least one unbranched or branched chain alkoxy group having from 1 to 4 carbon atoms, for example 4-methoxyaniline, 4-ethoxyaniline, 4-propoxybenzene, 4-isopropoxyaniline, 4-butoxyaniline, 4-isobutoxyethene, 4-second-butoxyaniline, 4-t-butoxyaniline, 4-methoxy-1-nptlnptlonly, 4 isobutoxy-1-naphthylmethyl, 4-Deut-butoxy-1-naphthylmethyl, 4-t-butoxy-1-naphthylmethyl, 4-methoxy-2-naphthylmethyl, 5-ethoxy-2-naphthylmethyl, 8-propoxy-2-naphthylmethyl, 4-isopropoxy-2-naphthylmethyl, 5-butoxy-2-naphthylmethyl, 8-isobutoxy-2-naphthylmethyl, 4-Deut-butoxy-2-naphthylethylene and 5-t-butoxy-2-naphthylmethyl group.

(3) Kalkilya group, substituted by at least one halogen atom, such as 4-bromoaniline, 4-Chloroaniline, 4-forosesija, 4-iodoaniline, 3-Chloroaniline, 3-forosesija, 3-bromoaniline, 3-iodoaniline, 4-bromo-1-naphthylmethyl, 4-chloro-1-naphthylmethyl, 4-fluorescent-1-naphthylmethyl, 4-iodo-1-naphthylmethyl, 5-chloro-1-naphthylmethyl, 5-fluorescent-1-naphthylethylene, 5-bromo-1-naphthylmethyl, 8-chloro-1-naphthylmethyl, 4-fluorescent-2-naphthylmethyl, 4-bromo-2-naphthylmethyl, 4-chloro-2-naphthylmethyl, 4-iodo-2-naphthylmethyl, 5-bromo-2-naphthylmethyl, 5-chloro-2-naphthylmethyl, 5-fluorescent-2-naphthylethylene and 5-iodo-2-naphthylmethyl group.

(4) Kalkilya group, substituted by at least one hydroxy group, such as 2-hydroxybenzylidene, 3-hydroxybenzylidene, 4-hydroxybenzylidene, 4-hydroxy-1-naphthylmethyl, 5-hydroxy-1-naphthas and-2-naphthylmethyl group.

(5) Kalkilya group, substituted by at least one nitro group, such as 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 4-nitro-1-naphthylmethyl, 5-nitro-1-naphthylmethyl, 8-nitro-1-naphthylmethyl, 4-nitro-2-naphthylmethyl, 5-nitro-2-naphthylethylene and 8-nitro-2-naphthylmethyl group.

(6) Kalkilya group, substituted by at least one phenyl group, such as 3-phenylbenzyl, 4-phenylbenzyl, 4-phenyl-1-naphthylmethyl, 5-phenyl-1-naphthylmethyl, 8-phenyl-1-naphtylamine, 4-phenyl-2-naphthylmethyl, 5-phenyl-2-naphtylamine and 8-phenyl-2-naphthylmethyl group.

(7) Kalkilya group, substituted by at least one triptorelin group, such as 3-triphtalocyaninine, 4-triphtalocyaninine, 4-trifluoromethyl-1-naphthylmethyl, 5-trifluoromethyl-1-naphthylmethyl, 8-trifluoromethyl-1-naphthylmethyl, 4-trifluoromethyl-2-naphthylmethyl, 5-trifluoromethyl-2-naphthylethylene and 8-trifluoromethyl-2-naphthylmethyl group.

(8) Kalkilya group, substituted by at least one unsubstituted amino group, such as 2-aminoaniline, 3-aminoaniline, 4-aminoaniline, 4-amino-1-naphthylethylene and 8-amino-2-naphthylethylene.

(9) Aralkyl skylinee group, substituted group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an alkyl group, such as 3-methylaminomethyl, 4-ethylaminomethyl, 3-propylaminoethyl, 3-isopropylaminomethyl, 4-butylaminoethyl and 3-izabelinamirabelina group;

(ii) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbis aracelio group, for example 4-benzylaminopurine, 4-(2-phenylethylamine)benzyl, 4-(1-phenylethylamine)benzyl, 4-(4-phenylbutyramide)benzyl and 4-(1-naphthylethylene)benzyl groups;

(iii) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an aryl group, for example 4-phenylenevinylene and 4-(1-naphthylamine)benzyl groups;

(iv) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an aliphatic acyl group, for example 4-formylanhalonidine, 4-acetamidobenzoyl, 4-butylimidazole, 4-pivaloyloxymethyl, 4-exaniination, 4-octaneenhancing and 4-unle the Rarepresents a hydrogen atom and Rbrepresents an aryl-aliphatic acyl group, for example 4-phenylacetylglutamine, 4-(4-phenylbutyramide)benzyl, 4-(6-phenylhexanoic)benzyl, 4-(but-methylphenylethylamine)benzyl and 4-(,- dimethylphenylethylamine)benzyl groups;

(vi) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents a hydrogen atom and Rbrepresents an aromatic acyl group, for example 4-benzylaminopurine, 4-(1-naphthylamine)benzyl and 4-(2-naphthylamine)benzyl groups;

(vii) kalkilya group substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent alkyl groups which may be the same or different, for example 4-dimethylaminobenzene, 4-diethylaminobenzylidene and 4-(N-methyl-N-ethylamino)benzyl groups;

(viii) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbis aracelio group, such as 4-(N-ethyl-N-benzylamino)benzyl, 4-(N-t-butyl-N-benzylamino)benzyl and 4-(N-hexyl-N-benzylamino)benzyl groups;

(ix) kalkilya group substituted by a group of the formula: -NRaR
(x) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbrepresents an aliphatic acyl group, such as 4-(N-propyl-N-acetylamino)benzyl and 4-(N-ethyl-N-hexanamine)benzyl groups;

(xi) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-ethyl-N-phenylacetylamino)benzyl and 4-[N-methyl-N-(6-phenylhexanoic)amino]benzyl groups;

(xii) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an alkyl group, and Rbrepresents an aromatic acyl group, such as 4-(N-methyl-N-benzoylamine)benzyl and 4-(N-heptyl-N-benzoylamine)benzyl group:

(xiii) kalkilya group substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent kalkilya group, which may be the same or different, for example 4-dibenzylpiperazine and 4-[N-benzyl-N-(2-naphthylmethyl)amino]benzyl groups.

(xiv) kalkilya group substituted by a group of the formula: -NRaRbwhere Rais aralkyl the l)-N-phenylamino] benzyl groups;

(xv) kalkilya group substituted by a group of the formula: -NRaRbwhere Rais aracelio group, and Rbrepresents an aliphatic acyl group, such as 4-(N-benzyl-N-acetylamino)benzyl and 4-(N-benzyl-N-partnerline)benzyl groups;

(xvi) kalkilya group substituted by a group of the formula: -NRaRbwhere Rais aracelio group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-benzyl-N-phenylacetylamino)benzyl and 4-[N-benzyl-N-(4-phenylbutyl)amino]benzyl groups;

(xvii) kalkilya group substituted by a group of the formula: -NRaRbwhere Rais aracelio group, and Rbrepresents an aromatic acyl group, for example 4-(benzyl-N-benzoylamine)benzyl and 4-[N-(2-phenylethyl)-N-benzoylamine]benzyl groups;

(xviii) kalkilya group substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aryl groups which may be the same or different, for example 4-(diphenylamino)benzyl and 4-[N-(2-naphthyl)-N-phenylamino]benzyl groups;

(xix) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents aryl which is phenyl-N-hexanamine)benzyl groups;

(xx) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an aryl group, and Rbis arylaliphatic acyl group, such as 4-(N-phenyl-N-phenylacetylamino)benzyl and 4-[N-phenyl-N-(4-phenylbutyl)amino]benzyl groups;

(xxi) kalkilya group substituted by a group of the formula: -NRaRbwhere Rais aryl and Rbrepresents an aromatic acyl group, such as 4-(N-phenyl-N-benzoylamine)benzyl group;

(xxii) kalkilya group substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aliphatic acyl groups which may be the same or different, for example 4-diacetylpyridine and 4-(N-butyryl-N-hexanamine)benzyl groups;

(xxiii) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an aliphatic acyl group, and Rbrepresents an aryl-aliphatic acyl group, such as 4-(N-acetyl-N-phenylacetylamino)benzyl and 4-(N-butyryl-N-phenylacetylamino)benzyl groups;

(xxiv) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an aliphatic acyl g is[N-butyryl-N-(2-naphtol)amino]benzyl groups;

(xxv) kalkilya group substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aryl-aliphatic acyl group, which may be the same or different, such as 4-(N,N-diphenylacetylene)benzyl and 4-[N-phenylacetyl-N-(4-phenylbutyl)amino]benzyl groups;

(xxvi) kalkilya group substituted by a group of the formula: -NRaRbwhere Rarepresents an aryl-aliphatic acyl group, and Rbrepresents an aromatic acyl group, for example 4-N-phenylacetyl-N-benzoylamine)benzyl and 4-[N-phenylacetyl-N-(2-naphtol)amino]benzyl groups; and

(xxvii) kalkilya group substituted by a group of the formula: -NRaRbwhere Raand Rbboth represent aromatic acyl group, which may be the same or different, for example 4-dibenzoylbenzene and 4-[N-benzoyl-N-(2-naphtol)amino]benzyl groups.

When benzimidazole group represented by X is a substituent in the 1 - and/or 2-position, preferably the Deputy consisted of:

unbranched or branched chain alkyl group having from 1 to 4 carbon atoms,

aryl group having from 6 to 10 carbon atoms, which is ing chain aracelio group, having from 7 to 11 carbon atoms, which may be arbitrarily substituted with one or more substituents .

Examples of such benzimidazole groups having from 1 to 5 substituents include , for example, 1-methylbenzimidazole-2-yl, 1-ethylbenzamide-2-yl, 1-propylbenzamide-2-yl, 1-isopropylimidazole-2-yl, 1-butylbenzothiazole-2-yl, 6-methoxy-1H-benzimidazole-2-yl, 5-methoxy-1H-benzimidazole-2-yl, 6-methoxy-1-methylbenzimidazole-2-yl, 5-methoxy-1-methylbenzimidazole-2-yl, 1-ethyl-6-methoxybenzimidazole-2-yl, 1-ethyl-5-methoxybenzimidazole-2-Il,

6-methoxy-1-propylbenzamide-2-Il,

5-methoxy-1-propylbenzamide-2-Il,

1-isopropyl-6-methoxybenzimidazole-2-Il,

1-isopropyl-5-methoxybenzimidazole-2-Il,

1-isobutyl-6-methoxybenzimidazole-2-Il,

1-isobutyl-5-methoxybenzimidazole-2-Il,

6 ethoxy-1-methylbenzimidazole-2-Il,

5-ethoxy-1-methylbenzimidazole-2-Il,

1-methyl-6-propoxybenzene-2-Il,

1-methyl-5-propoxybenzene-2-Il,

6 isopropoxy-1-methylbenzimidazole-2-Il,

5-isopropoxy-1-methylbenzimidazole-2-Il,

6 butoxy-1-methylbenzimidazole-2-Il,

5-butoxy-1-methylbenzimidazole-2-Il,

6 isobutoxy-1-methylbenzimidazole-2-Il,

5-isobutoxy-1-methylbenzimidazole-2-Il,

6-verdata-2-Il,

5-t-butoxy-1-methylbenzimidazole-2-Il,

6 butoxy-1-propylbenzamide-2-Il,

5-butoxy-1-propylbenzamide-2-Il,

6-benzyloxy-1-methylbenzimidazole-2-Il,

5-benzyloxy-1-methylbenzimidazole-2-Il,

5-methoxy-1,6-dimethylbenzimidazole-2-Il,

5-metkei-1,5-dimethylbenzimidazole-2-Il,

6-bromo-5-methoxy-1-methylbenzimidazole-2-Il,

5-bromo-6-methoxy-1-methylbenzimidazole-2-Il,

6 ethoxy-6-fluorescent-1-methylbenzimidazole-2-Il,

6 ethoxy-5-fluorescent-1-methylbenzimidazole-2-Il,

5,7-Diptera-1-methylbenzimidazole-2-Il,

4,6-Diptera-1-methylbenzimidazole-2-Il,

6-fluorescent-1-methylbenzimidazole-2-Il,

5-fluorescent-1-methylbenzimidazole-2-Il,

5-chloro-1,6-dimethylbenzimidazole-2-Il,

6-chloro-1,5-dimethylbenzimidazole-2-Il,

5-chloro-1,6-diethylbenzamide-2-Il,

6-chloro-1,5-diethylbenzamide-2-Il,

5-ethyl-1-methylbenzimidazole-2-Il,

6-ethyl-1-methylbenzimidazole-2-Il,

5-bromo-1-methylbenzimidazole-2-Il,

6-bromo-1-methylbenzimidazole-2-Il,

7-bromo-1-methyl-5-trifluromethanesulfonate-2-Il,

4-bromo-1-methyl-6-trifluromethanesulfonate-2-Il,

7-chloro-1-methyl-5-trifluromethanesulfonate-2-Il,

4-chloro-1-methyl-6-trifluromethanesulfonate-2-Il,

1-methyl-7-trifluromethanesulfonate-6-trifluromethanesulfonate-2-Il,

5-bromo-1,6,7-trimethylpentanediol-2-Il,

6-bromo-1,4,5-trimethylpentanediol-2-Il,

5-fluorescent-6-chloro-1-methylbenzimidazole-2-Il,

6-fluorescent-5-chloro-1-methylbenzimidazole-2-Il,

5-bromo-1,7-dimethylbenzimidazole-2-Il,

6-bromo-1,4-dimethylbenzimidazole-2-Il,

6-t-butyl-1-methylbenzimidazole-2-Il,

5-t-butyl-1-methylbenzimidazole-2-Il,

6-hydroxy-1-methylbenzimidazole-2-Il,

5-hydroxy-1-methylbenzimidazole-2-Il,

1,7-dimethylbenzimidazole-2-Il,

1,4-dimethylbenzimidazole-2-Il,

6,7-sodium dichloro-1-methylbenzimidazole-2-Il,

4,5-sodium dichloro-1-methylbenzimidazole-2-Il,

5,6,7-triflora-1-methylbenzimidazole-2-Il,

4,5,6-triflora-1-methylbenzimidazole-2-Il,

5-bromo-6-benzyloxy-1-methylbenzimidazole-2-Il,

6-bromo-5-benzyloxy-1-methylbenzimidazole-2-Il,

7-chloro-1-methylbenzimidazole-2-Il,

4-chloro-1-methylbenzimidazole-2-Il,

6-hydroxy-1,5,7-trimethylpentanediol-2-Il,

5-hydroxy-1,4,6-trimethylpentanediol-2-Il,

1-methylbenzimidazole-6-Il,

1-ethylbenzamide-6-Il,

1-propylbenzamide-6-yl, 1-isopropylimidazole-6-Il,

1-butylbenzothiazole-6-yl, 1-benzylbenzimidazole-6-Il,

1-methylbenzimidazole-7-yl, 1-ethylbenzamide-7-Il,

1-benzylbenzimidazole-7-yl, 1-methylbenzimidazole-2-Il,

1-ethyl-5-hydroxy-4,6,7 there-trimethylpentanediol-2-Il,

1-benzylbenzimidazole-5-yl and

5-acetoxy-1,4,6,7-tetramethylbenzidine-2-ilen group.

Z represents a group of the formula (i), (ii), (iii), (iv) and (v):

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
These formulas (i), (ii), (iii), (iv) and (v) are referred to below

2,4-dioxothiazolidine-5-ylidenemethyl group

2,4-dioxothiazolidine-5-ylmethylene group

2,4-dioxoimidazolidin-5-ylmethylene group

3,5-dioxoimidazolidin-2-ylmethylene group

N-hydroxyeicosatrienoic group, respectively.

Of the compounds of this invention, we prefer those compounds of formula (I) and their salts, in which:

(A1) X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents defined below:

the Deputy is

alkyl group having from 1 to 4 carbon atoms,

alkoxy group having from 1 to 4 carbon atoms,

benzyloxy group,

a halogen atom,

hydroxy group,

acetoxy group,

phenylthio group

alkylthio group having from 1 to 4 carbon atoms,

triptorelin group

nitro group,

amino group of the formula: -NRaRb,

in the SCP, having from 1 to 8 carbon atoms, aracelio group having from 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, aliphatic acyl group having from 1 to 11 carbon atoms; an aryl-aliphatic acyl group having from 8 to 12 carbon atoms, or an aromatic acyl group having from 7 to 11 carbon atoms,

the right group having from 6 to 10 carbon atoms, which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents ,

specified Deputy represents an alkyl group having from 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, triptorelin group or amino group of the formula: -NRaRbin which Raand Rbsuch as defined above;

or aracelio group having from 7 to 11 carbon atoms, which is unsubstituted or substituted by at least one of the deputies ;

and/or

(A2) R represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, or a halogen atom;

and especially compounds in which X is taiyi of the present invention are the compounds of formula (I) and their salts, where:

(B1) X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents defined below;

the Deputy is

alkyl group having from 1 to 4 carbon atoms,

alkoxy group having from 1 to 4 carbon atoms,

benzyloxy group,

a halogen atom,

hydroxy group,

acetoxy group,

phenylthio group

alkylthio group having from 1 to 4 carbon atoms,

triptorelin group

nitro group,

the amino group of the formula: -NRaRb,

in which Raand Rbthe same or different, and each represents a hydrogen atom, alkyl group having 1 to 8 carbon atoms, aracelio group having from 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, aliphatic acyl group having from 1 to 11 carbon atoms; an aryl-aliphatic acyl group having from 8 to 12 carbon atoms, or an aromatic acyl group having from 7 to 11 carbon atoms,

aryl group having from 6 to 10 carbon atoms, which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents ,

sametitled, a halogen atom, hydroxy group, nitro group, phenyl group, triptorelin group or amino group of the formula: -NRaRbin which Raand Rbsuch as defined above,

or aracelio group having from 7 to 11 carbon atoms, which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents ;/

and/or

(B2) Y represents an oxygen atom;

and/or

(B3) Z represents a 2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene or 2,4-dioxoimidazolidin-5-ylmethylene group;

and/or

(B4) R represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, or halogen atom;

and especially compounds in which X is as defined in (B1), and Y is as defined in (B2), Z is as defined in (B3), and R is as defined in (B4).

Even more preferred compounds of this invention are those compounds of formula (I) and their salts, in which:

(C1) X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents defined below;

replace the t 1 to 4 carbon atoms,

benzyloxy group,

a halogen atom,

hydroxy group,

acetoxy group,

phenylthio group

alkylthio group having from 1 to 4 carbon atoms,

triptorelin group

nitro group,

amino group of the formula: -NRaRb,

in which Raand Rbthe same or different, and each represents a hydrogen atom, alkyl group having 1 to 8 carbon atoms, aracelio group having from 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, aliphatic acyl group having from 1 to 11 carbon atoms, aryl-aliphatic acyl group having from 8 to 12 carbon atoms, or an aromatic acyl group having from 7 to 11 carbon atoms,

aryl group having from 6 to 10 carbon atoms, which is unsubstituted or substituted from 1 to 3 substituents selected from the group consisting of substituents ,

Deputy represents an alkyl group having from 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, triptorelin group or amino group of the formula: -NRaRbin which Raand Rbsuch as defined 3 substituents, selected from the group consisting of substituents ;

and/or

(C2) Y represents an oxygen atom;

and/or

(C3) Z represents a 2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene group;

and/or

(C4) R represents a hydrogen atom, methyl group, methoxy group, ethoxy group, a fluorine atom or a chlorine atom;

and/or

(C5) m is an integer from 1 to 3;

and especially compounds in which X is as defined in (C1), Y is as defined in (C2), Z is as defined in (C3), R is as defined in (C4), and m is as defined in (C5).

Even more preferred compounds of this invention are those compounds of formula (I) and their salts, in which:

(D1) X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents a, defined below;

Deputy a" represents the

alkyl group having from 1 to 4 carbon atoms,

alkoxy group having from 1 to 4 carbon atoms,

benzyloxy group,

a halogen atom,

phenylthio group

alkylthio group having from 1 to 4 carbon atoms,

triptorelin group

hydroxy group is ω oxygen;

and/or

(D3) Z represents a 2,4-dioxothiazolidine-5-ylmethylene group;

and/or

(D4) R represents a hydrogen atom, methyl group or methoxy group;

and/or

(D5) m is an integer from 1 to 3;

and especially compounds in which X is as defined in (D1), Y is as defined in (D2), Z is as defined in (D3), R is as defined in (D4), and m is as defined in (D5).

Even more preferred compounds of this invention are those compounds of formula (I) and their salts, in which:

(E1) X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents a', defined below;

Deputy a"' is

methyl group,

ethyl group, isopropyl group, methoxy group,

ethoxy group, propoxy group, isopropoxy group

benzyloxy group,

a fluorine atom, a chlorine atom,

phenylthio group, methylthio group, ethylthio group

hydroxy group,

acetoxy group,

benzyl group or phenyl group;

and/or

(E2) Y represents an oxygen atom;

and/or

(E3) Z represents a 2,4-dioxothiazolidine-5-ylmethylene g is
and especially compounds in which X is as defined in (E1), Y is as defined in (E2), Z is as defined in (E3), R is as defined in (E4), and m is as defined in (E5).

The most preferred compounds of this invention are those compounds of formula (I) and their salts, in which:

(F1) X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents a, defined below;

Deputy a"" is

methyl group, methoxy group,

hydroxy group, benzyl group or acetoxy group;

and/or

(F2) Y represents an oxygen atom;

(F3) Z represents a 2,4-dioxothiazolidine-5-ylmethylene group;

and/or

(F4) R represents a hydrogen atom;

and/or

(F5) m represents the integer 1;

and especially compounds in which X is as defined in (F1), Y is as defined in (F2), Z is as defined in (F3), R is as defined in (F4), and m is as defined in (F5).

The compounds of this invention each contain a basic group in its molecule and can therefore be converted into salts with acids of the s to be used for medical purposes, these connections must be pharmaceutically acceptable, i.e. not less active, less active or acceptable, not more toxic, or more toxic acceptable than a kindred connection. However, when the connection is to be used for non-medical purposes, for example as an intermediate in the production of other compounds, even this restriction does not apply, then there is no restriction on the nature of the salts that can be obtained. Examples of such salts include: salts with mineral acids, in particular, kaleidotrope acid (such as hydrofluoric acid, Hydrobromic acid, itestosterone acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonyl acids such as methanesulfonate acid, triftormetilfullerenov acid or econsultancy acid; salts with arylsulfonic acids, such as benzolsulfonat acid or p-toluensulfonate acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, Antara and citric acid; and salts with amino acids such as glutamic acid or aspartic acid. We prefer pharmaceutically acceptable salt.

In addition, the compound of this invention can be converted into a salt with a base in the usual way. Examples of such salts include: salts with an alkali metal such as sodium, potassium or lithium; salts with alkaline earth metal such as barium or calcium: salts with another metal, such as magnesium or aluminum. We prefer pharmaceutically acceptable salt.

The compounds of formula (I) of this invention can exist in the form of various isomers due to the presence of asymmetric carbon atoms. Thus, when Z represents a 2,4-dioxothiazolidine-5-ylmethylene group or 2,4-dioxoimidazolidin-5-ylmethylene group, the carbon atom at 5-position is asymmetric. Although these isomers are all represented here with a single molecular formula (I), the invention includes both the individual isolated isomers and mixtures, including their racemates, and these isomers may be present in such mixtures in any proportions. When using methods stereospecific synthesis or use of optically active compounds in kupolokun mixture of isomers, the individual isomers can be obtained by conventional separation techniques.

The compounds of formula (I) in which Z represents a 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene or 3.5-dioxoimidazolidin-2-ylmethylene group can exist in various tautomeric isomers as shown in the following diagrams a,, and, respectively, provided at the end of the description:

In the above formula (I) all tautomers based on it, and a mixture of equivalent layers or the equivalent weights of these tautomers represented by a single formula. Thus, all of these isomers and mixtures of these isomers are encompassed by this invention.

In addition, the invention includes also any solvate, such as hydrates, of the compounds of formula (I) and their salts, in the case when the compound capable of forming MES.

This invention also encompasses all compounds that can turn into a living body of a mammal, such as man, in the compound of formula (I) or its salt under the influence of metabolism, i.e., the so-called "Pro-drugs of compounds of formula (I) and their salts.

Examples of some soedineniyami formulae the substituents are as such as defined in the following one of Tables 1-5, respectively. I.e. table 1 relates to formula (I-1), table 2 relates to formula (I-2), and similarly with respect to other Tables up to 5, which refers to the formula (I-5). In the Tables use the following abbreviations:

Bu butyl

i-Bu isobutyl

s-Bu, sec-butyl

t-Bu t-butyl

Bz benzene

Et ethyl

Me methyl

Pr drunk

i-Pr is isopropyl

Of the compounds listed below, we particularly prefer the following, i.e., Compounds N 1-11, 1-16, 1-18, 1-22, 1-27, 1-49, 1-50, 1-54, 1-56, 1-98, 1-100, 1-109, 1-129, 1-146, 1-155, 1-156, 1-229, 1-237, 1-238, 1-247, 1-250, 2-11, 2-49, 2-146, 2-229, 2-237, 2-250, 3-11, 3-49, 3-146, 3-229, 3-237, 3-250, 4-11, 4-49, 4-146, 4-229, 4-237, 4-250, 5-11, 5-49, 5-146, 5-229, 5-237 and 5-250, from which the Compounds N 1-11, 1-16, 1-18, 1-22, 1-27, 1-49, 1-50, 1-54, 1-56, 1-98, 1-100, 1-109, 1-129, 1-146, 1-229, 1-237, 1-238, 1-247, 1-250, 2-11, 2-49, 2-146, 2-229, 2-237, 2-250, 3-11, 3-49, 3-146, 3-229, 3-237 and 3-250 more preferable. Even more preferred are Compounds N 1-11, 1-16, 1-27, 1-49, 1-50, 1-54, 1-98, 1-100, 1-109, 1-129, 1-146, 1-229, 1-237, 1-238 and 1-250.

The most preferred compounds are:

1-11. 5-[4-(1-Methylbenzimidazole-2-ylethoxy)benzyl]-thiazolidine-2,4-dione;

1-49. 5-[4-(6-Methoxy-1-methylbenzimidazole-2 - ylethoxy)benzyl] -thiazolidine-2,4-dione;

1-146. 5-[4-(5-Methoxy-1-methylbenzimidazole-2 - R> 1-237. 5- [4-(5-Hydroxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)-benzyl] thiazolidin-2,4-dione and

1-250. 5-[4-(5-Acetoxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)-benzyl] thiazolidin-2,4-dione,

and its pharmaceutical acceptable salts.

The compounds of this invention can be obtained in a number of ways, well known in this field, to obtain the compounds of this General type. For example, they can be obtained by the following Reaction Schemes A, B, D, and E, provided at the end of the description.

Reaction scheme A

The reaction scheme provides for obtaining compounds of formula (i) in which Z represents any of groups of the formula (i), (ii), (iii) and (iv), i.e., compounds (Ia).

In the above-mentioned formula:

X, Y, R and m are such as defined above;

R' represents an alkyl group having from 1 to 5 carbon atoms, which may be unbranched or branched chain group, for example, any of alkyl groups having from 1 to 5 carbon atoms, and which is included in the examples of groups which may be represented by the above Raand Rbin particular methyl, ethyl or bucilina group;

Z' represents a group of the formula (i'), (ii'), (iii') or (iv'):

< / BR>
< / BR>
< / BR>
< / BR>
(in Kotor is.

Stage A1

In stage A1 of this reaction scheme, the compound of formula (III) is obtained by recovery of the compounds of formula (II).

The reaction is usually carried out by restoring using the reducing agent.

There are no particular restrictions on the nature of the used reducing agents for this reaction, and any reducing agent commonly used in reactions of this type, equally can be used here. Examples of suitable reducing agents are metal hydrides, such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, socialwise hydride and Diisopropylamine hydride.

The reaction is normally and preferably carried out in the presence of a solvent. There are no specific restrictions on the nature of the solvent to be used, provided that it has no adverse effect on the course of the reaction or the reaction of the reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, ol, ethanol or isopropanol; and mixtures of any two or more of these solvents.

The reaction can be performed under a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature in the range from a temperature cooling with ice to heat, for example, the boiling point of the reaction medium, preferably at a temperature of cooling with ice or at a temperature close to the room. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents, in particular reducing agent and solvent used. However, provided that the reaction is carried out at defined above reaction conditions, is usually sufficient period of time the reaction is from 0.5 hours to several days.

The reaction is usually carried out in alcohol or mixture of alcohols and other organic solvents in the presence of lithium borohydride at a temperature of from room temperature up to the boiling temperature of the reaction mixture over a period of from 1 hour to 1 day; or in the hydrocarbon or ether in prisutstvie the Yeni from 1 to 10 hours.

Stage A2

In stage A2 obtain the connection formula (V) by reacting the compounds of formula (III), obtained as described in Stage A1, and the compounds of formula (IV) using the mitsunobu reaction (O. mitsunobu: Syntnesis, 1 (1981).

The reaction is usually conducted in a solvent in the presence of at least one azo compound and at least one phosphine.

There are no particular restrictions on the nature of the used azo compounds, and any azo compounds commonly used in this type of reaction, equally can be used here. Examples of such azo compounds are diethyl-azodicarboxylate and 1'1 - (azodicarbon) - dipiperidino. Similarly, there are no special restrictions on the nature of the used phosphines, and examples of them are triphenylphosphine and tributylphosphine.

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents, and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as 1,2-dichloroethane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; and mixtures of any two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature in the range from room temperature to heating, for example up to the boiling temperature of the reaction medium, more preferably in the temperature range from room temperature up to 60oC. the Time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents, in particular reducing agent and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several hours to several days, more preferably from 5 hours to 3 days.

Stage A3

In stage A3, obtain the connection formula (Ia) by removing the protection of the nitrogen atom in connection formatlities hydrogenation.

In the case when conducting a reaction using the acid, there is no particular restriction on the nature of the used acid, and it can be used equally any acid commonly used for reactions of this type. Examples of suitable acids are triperoxonane acid, triftormetilfullerenov acid, acetic acid, hydrochloric acid and sulfuric acid in the presence or absence of solvent. In the case of using the solvent, there is no particular restriction on the nature of the subject use of the solvent, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents, and that he can, at least to some extent, to dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; esters such as ethyl acetate or methyl acetate; water; and mixtures of any two or more of these rastvorjaetsja essential for the invention. In General, we found that is suitable conducting the reaction at a temperature in the range from a temperature cooling with ice to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents, in particular reducing agent and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several tens minutes to several tens hours, more preferably from 0.5 to 10 hours.

This stage can be carried out by catalytic hydrogenation of compounds of formula (V). There is no particular restriction on the nature of the used catalysts, and here you can use equally any hydrogenation catalysts normally used for this type of reaction. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; ethers, such as dick dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; and mixtures of any two or more of these solvents.

The reaction can be performed under a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature in the range from room temperature to heating, for example at the boiling temperature of the reaction medium, preferably at room or when heated. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several hours to several days, more preferably from 1 hour to 1 day.

Reaction Scheme B

It is a way that you can use to obtain the compounds of formula (I) in which Y represents an oxygen atom and Z represents a group of the formula (i) or (ii), i.e., 2,4-dioxothiazolidine-5-ylidenemethyl or 2,4-dioxothiazolidine-5-ylmethylene group, so ei (VI) by treating the compounds of formula (III) base (first stage) and then by reacting the resulting product with the derived p-forobulgaria formula (VIa), such as 2-methoxy-4-florabundance or 3-methyl-4-florabundance (second stage).

There are no particular restrictions on the nature of the used grounds in the first stage, and it can be used equally any base commonly used for this type of reaction. An example of such a base is sodium hydride.

The reaction in the first stage, usually and preferably carried out in the presence of a solvent. There are no specific limitations to the nature of the subject use of the solvent, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; and mixtures of any two or more of these solvents.

The reaction can be performed under a wide range of temperatures and the precise temperature is not essential for the invention. In General, we have to ascertain is, the example up to the boiling temperature of the reaction medium, preferably at room or when heated. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions from a few tens of minutes to one day, more preferably from 1 to 10 hours.

Upon completion of the first reaction stage, the second stage can be done by adding the derived p-forobulgaria formulas (VIa) to the reaction mixture, and then allowing the mixture to interact. There is no need to isolate the reaction product of the first stage to the second stage.

The second reaction stage may be implemented with a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature in the range from room temperature to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely in the head But provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several tens minutes to several days.

Stage B2

In stage B2, obtain the connection formula (VII) by reacting the compounds of formula (VI) with thiazolidine-2,4-dione of the formula (VIIa).

The reaction can be carried out in the presence or absence of a catalyst, and there is no particular restriction on the nature of the used catalyst, there can be used equally any catalyst used in this type of reaction. Examples of such catalysts are sodium acetate, the acetate piperidine and benzoate piperidine.

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl of apyramid, dimethylacetamide or triamide hexamethylphosphoric acid; halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; NITRILES, such as acetonitrile or propionitrile; esters such as ethyl formate or ethyl acetate; and mixtures of any two or more of these solvents.

The reaction can be performed under a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction by heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction is from 1 to 50 hours.

The compound obtained of the formula (VII) represents the connection of the present invention and it may be the desired product; alternatively, it can be subjected to an optional stage B3.

Stage B3

In stage B3 get the connection formulas the restrictions on the nature of the used catalysts, and here you can use equally any of the hydrogenation catalysts used in this type of reaction. Examples of such catalysts are palladium-on-carbon and palladium black, preferably palladium-on-carbon.

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or ISO-propanol; organic acids such as formic acid, acetic acid or propionic acid; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; and mixtures of any two or more of these solvents.

The reaction is usually carried out at atmospheric pressure or at elevated pressure, preferably at an elevated pressure.

Ray of the invention. In General, we found that is suitable conducting the reaction at room temperature or while heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several hours to several days, more preferably from 1 hour to 1 day.

This stage can also be accomplished by treating compound of formula (VII) with a metal hydride according to the method disclosed in WO 93/1309A.

Reaction Scheme C

Under this scheme get the connection formula (I) in which Z is in the para-position and is a group of the formula (V), i.e., the compound of formula (X), or in which Z is in the para-position and is a group of formula (iv), i.e., the compound of formula (XI).

In the above formula, R, X and m are such as defined above.

Stage C1

In stage C1 receives the connection of the formula (IX) by reacting compounds of additional as hydrochloride) in the first stage and then in the second stage by restoring this product.

The reaction of the compound of formula (VI) with hydroxylamine (hydrochloride) is mainly carried out preferably in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or isopropanol; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; NITRILES, such as acetonitrile or propionitrile; esters, such as ethylformate or ethyl acetate; amines such as pyridine, triethylamine or N,N-aminobutiramida-N-ethylamine; and mixtures of any two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not sudeste in the range from room temperature to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several hours to several tens hours.

Subsequent recovery in the second stage this stage can be performed by hydrogenation in the presence of a reducing agent. There is no particular restriction on the nature of the used reducing agent, and here you can use equally any reducing agent used in this type of reaction. Examples of such reducing agents are metal hydrides, such as socialwise hydride, diisobutylaluminium hydride, lithium borohydride, borohydride sodium or cyanoborohydride.

The second step of the reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it is not about who to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, dioxane or tetrahydrofuran; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; alcohols such as methanol, ethanol or isopropanol; and mixtures of any two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature in the range of from cooling with ice to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from a few tens of minutes to one day, more preferably from 1 to 10 hours.

Stage C2

In stage C2, obtain the connection formula (Hnwu group).

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, dioxane or tetrahydrofuran; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; and mixtures of any two or more of these solvents.

The reaction can be performed under a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature under ice cooling to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, especially temperature reacts is the R above preferred reaction conditions, usually it is sufficient period of time the reaction from several tens minutes to several days.

The compound obtained of the formula (X) represents the connection of the present invention. However, if desired, the compound of formula (IX) may be subjected to optional Stage C3.

Stage C3

In stage C3 receive the compound of formula (XI) by reacting the compounds of formula (IX) with (N-(chlorocarbonyl)isocyanate, Cl.CO.NCO.

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-DIH is at; and mixtures of any two or more of these solvents.

The reaction can be performed under a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature under ice cooling to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from several tens minutes to several tens of hours.

Reaction Scheme D

This method, which can be used to obtain compounds of formula (I) in which Z represents a group of formula (ii) or (iii), i.e., 2,4-dioxothiazolidine-5-ylmethylene or 2,4-dioxoimidazolidin-5-ylmethylene group, i.e. compounds of formula (XV).

In the above-mentioned formula:

X, Y, R and m are such as defined above;

Y' represents an oxygen atom or sulfur;

Q represents the and hydroxy group; and

The halo represents a halogen atom.

Stage D1

In stage D1 receive compound of formula (XIV) by reacting the compounds of formula (XII) with the compound of the formula (XIII) in the presence of a base.

There is no particular restriction on the nature of the used grounds, and can be equally used any base commonly used in this type of reaction; examples of such bases include: inorganic bases, such as hydrides (such as sodium hydride or potassium hydride) and a carbonate (such as potassium carbonate or cesium carbonate; and organic bases such as triethylamine.

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or diox the two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature of from cooling with ice to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction is from 0.5 hours to several days.

The reaction is most preferably carried out under cooling or at room temperature amide or in a mixture, at least one amide, at least one other organic solvent in the presence of sodium hydride and during the period from 1 to 10 hours.

The compounds of formula (XIV), which is obtained by this method are important intermediates for producing compounds of formula (I) of the present invention, as well as for other valuable compounds. These compounds of the formula (XIV) s (XV) using one of the following two methods (a) and (b).

Stage D2(a)

The compound of formula (XV) can be obtained by reacting the compounds of formula (XIV) in which Q represents lower alkoxycarbonyl group, with a derivative of 1,2-diaminobenzene.

When Q is lower alkoxycarbonyl group, it preferably has from 2 to 7 carbon atoms (i.e. the alkoxy part has from 1 to 6 carbon atoms) and may be unbranched or branched chain group. Examples of such groups include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, second-butoxycarbonyl, t-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol, 2-methylbutadiene, 1-ethylpropoxy, 4-methylpentadiene, 3-methylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 1-methylbenzyloxycarbonyl, 3,3-dimethylbutyryl, 2,2-dimethylbutyryl, 1,1-dimethylethoxysilane, 1,2-dimethylbutadiene, 1,3-dimethylbutadiene, 2,3-dimethylbutadiene, 2-ethylbutanol, hexyloxybenzoyl and isohexadecane group. Among them, we prefer the following alkoxycarbonyl group having from 2 to 5 carbon atoms, preferably methoxycarbonyl, ataxia group, more preferably methoxycarbonyl and ethoxycarbonyl group, and most preferably ethoxycarbonyl group.

The reaction is normally and preferably carried out in the presence or absence of solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, preferably aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; alcohols such as methanol, ethanol or butanol; acids such as acetic acid or propionic acid; and mixtures of any two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction by heating, for example to Tempel depending on many factors, especially the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from 3 hours to several days.

The reaction is most preferably carried out in the absence of solvent by heating at a temperature of from 50oC to 150oC for a period of from 5 hours to 2 days.

Stage D2(b)

Alternatively, the compound of formula (XV) can be obtained by reacting the compounds of formula (XIV) in which Q represents a formyl group, at the first stage derived from 1,2-diaminobenzene and then at the second stage of processing of the product is an oxidizing agent.

The reaction of the first stage is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, which may be AK diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; alcohols such as methanol, ethanol or isopropanol; acids such as acetic acid or propionic acid; sulfoxidov, such as dimethyl sulfoxide; and mixtures of any two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at about room temperature or while heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction from 1 hour to several days.

The product is then treated in the second stage oxidizing agent. There are no specific restrictions on the nature of the used oxidizing agent is tion. Examples of such oxidizing agents include iodine, silver oxide and leads to compounds, which lead, among which preferred iodine.

Processing oxidizing agent in this second stage usually and preferably carried out in the presence of a solvent. There are no specific restrictions on the nature of the subject use of the solvent, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include the solvents cited above for use in the first stage, preferably ethers.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction by heating. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time is asianow formyl group, the formyl protecting group can be removed before the connection will be subjected to the reactions of the stage D2. Examples of such protected formyl group include for example dimethoxymethyl, dioxymethylene, 1,3-dioxane-2-ilen, 1,3-dioxolane-2-ilen, 1,3-dition-2-ilen and 1,3-ditiolan-2-ilen group. The formyl protecting group can be removed using conventional methods, well known in this field, for example by contacting the compound of formula (XIV) with the usual notification of protection (deprotecting agent under conditions normally used to remove the protection. These conditions are described in T. W. Green: Protective Groups in Organic Synthesis (John Wiley and Sons Ed.) or J. F. W. McOmie: Protective Groups in Organic Chemistry (Plenum Press Ed.).

Reaction Scheme E

It is a way that you can use to obtain the compounds of formula (I) in which Z represents a group of formula (ii) or (iii), i.e., 2,4-dioxothiazolidine-5-ylmethylene or 2,4-dioxoolean-5-ylmethylene group, i.e. compounds of formula (XV).

In the above formulas, Q, X, Y, R, R', halo, and m are as defined above.

Stage E1

In stage E1 receive the compound of formula (XVIII) by reacting the compounds of formula (XII) with the compound of the formula (XVI) in the presence of a base. This reaction, in announement and reaction conditions.

Stage E2

In Stage E2 obtain the compound (XVIII) by restoring the compounds of formula (XVII).

The reaction can be carried out by conventional catalytic hydrogenation or by using any reducing agent capable of restoring the nitro group with formation of amino groups, such as the zinc-acetic acid or tin-hydrochloric acid. It is a common type of reaction, and reaction conditions, solvents, etc. that may be used are well known in the art.

Stage E3

In Stage E3, obtain the connection formula (XIX), subjecting the compound of formula (XVIII) Meerwein reaction arilirovaniya.

The conditions used for the reaction, are well known and, in General, are similar to the conditions described in Japanese Patent Application Kokai N Sho 55-22657, or conditions reported by S. Oae et al.: Bull. Chem. Soc. Japan, 53, 1065 (1980).

Stage E4

In stage E4 obtain the connection formula (XIV) by reacting the compounds of formula (XIX) with urea or thiourea and then subjecting the product to hydrolysis.

The conditions used for this reaction are well known and, in General, are similar to the conditions described in Japanese Patent Application Kokai N Sho Stages D(a) and D(b). The reaction is completely analogous to the reaction represented by these Stages and it can be done, using the same reagents and reaction conditions.

In the above stages of the products of each stage can, if desired, to isolate from the reaction mixture using conventional method at the end of each reaction and, if necessary, the obtained compound can be further purified by a conventional method such as column chromatography, recrystallization, the resultant deposition rates or similar well known techniques. An example of one such technique comprises: adding a solvent to the reaction mixture, extraction of the desired connection; and, finally, the distillation of the solvent from the extract. To obtain the desired compound in the form of a pure sample obtained residue may be purified by using column chromatography on silica gel or other adsorbent.

Obtaining initial substances

Reaction Scheme F

This method, which can be used to obtain compounds of the formula (II) in which X represents 1-benzimidazolyl group, i.e. the compound of formula (IIa). The scheme is given at the end of the description.

In the above formulas, R', m and Halo are the same as the definition of the second ring in the compounds of formulae (XXII) and (IIa) may be unsubstituted or may be substituted in any one or more of 2-, 4-, 5-, 6 - and 7-positions of the Deputy selected from the group consisting of the substituents defined and illustrated above. Similarly, the benzene ring of the compounds of formula (XX) may be unsubstituted or may have from 1 to 4 substituents selected from the group consisting of the substituents defined and illustrated above. In addition, the hydrogen atom is specified in the connection formula (XXI) may be replaced by one of the deputies . In the case where there is one or more substituents in any of the compounds of formula (XX), (XXI), (XXII) and (IIa), it preferably represents an alkyl group having from 1 to 4 carbon atoms, aryl group having 6 to 10 carbon atoms in the carbocyclic ring or aracelio group having a total of 7 to 11 carbon atoms in the aryl and alkyl; aryl and aracelio group which can be unsubstituted or can be substituted by preferably 1 to 3 substituents, selected from the group consisting of the substituents defined and illustrated above.

When R" represents a lower alkyl group, it may be unbranched or branched chain alkyl group having from 1 to 6 carbon atoms; C is Il, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl group. One of them we preferred alkyl groups having from 1 to 4 carbon atoms; most preferred methyl or ethyl group.

The F1 stage

In stage F1 get the compound of formula (XXII) by reacting the compounds of formula (XX) with the compound of the formula (XXI). This reaction is basically the same as described in Stage D2 Reaction Scheme D, and it can be done, using the same reagents and reaction conditions.

Stage F2

In Stage F2 receive the connection formula (IIa) by condensation of compounds of formula (XXII) with a compound of formula (XXIII). It is a well known type of reaction, and it can be carried out using well known techniques, such as described in Liebigs Ann. Chem., 1078 (1983).

Reaction Scheme G

This method, which can be used to obtain compounds of the formula (II) in which X represents a benzimidazole group, which is substituted by a group of the formula: -(CH2)m-1-COOR', 4-, 5-, 6 - and 7-position, i.e., seeding defined above.

Benzimidazole ring in the compound of formula (IIb) may be unsubstituted or may be substituted at 1 to 5 of 1-, 2-, 4-, 5-, 6- and 7-positions of Deputy selected from the group consisting of the substituents defined and proillyustrirovany above. Similarly, the benzene ring of the compounds of formula (XXIV), (XXV) and (XXVI) may be unsubstituted or may have from 1 to 3 substituents selected from the group consisting of the substituents defined and illustrated above (provided that not more than one of the positions ortho to the amino group of compounds of formula (XXIV) can thus be replaced). In addition, the hydrogen atom is specified in the connection formula (XXI) may be replaced by one of the deputies . In addition, amino group or one of the amino groups of the compounds of formula (XXIV), (XXV) and (XXXI) may have a single Deputy, selected from the group consisting of the substituents defined and illustrated above. In the case when there is one or more substituents in any of the compounds of formula (XXI), (XXIV), (XXV), (XXVI) and (IIb), it preferably represents an alkyl group having from 1 to 4 carbon atoms, aryl group having 6 to 10 carbon atoms in the carbocyclic ring or aracelio groupbit unsubstituted or they may be substituted, preferably from 1 to 3 substituents selected from the group consisting of the substituents defined and illustrated above.

Stage G1

In G1 Phase to obtain a compound of formula (XXXV) by nitration of compounds of formula (XXIV). This type of nitration is well known, and this reaction can be carried out according to known methods described, for example: J. G. Hogget, R. B. Moodie, J. R. Peton, K. Schofield, Nitration and Aromatic Reactivity, Cambridge University Press, Cambredge, 1971; K. Schofield, Aromatic Nitration, Cambridge University Press, Cambridge, 1980; P. B. D. de la Mare and J. H. Ridd, Aromatic Substitution, Nitration and Halogenation, Academic Press, New York, 1959; A. V. Topchiev, Nitration of Hydrocarbons and Other Organic Compounds, Pergamon Press, New York, 1959; L. F. Albright. in Kirk-Othmer, Encyclopedia of Chemical Technology, 2nd ed, vol. 13; The Intersience Encyclopedia, Inc., New York, pp. 784, 1967; H. A. Lubs, the Chemistry of Synthetic Dyes and Pigments, Reihold Publishing Corp., New York, 1955, pp. 12, 71, 350 etc.

Stage G2

In Stage G2 obtain the connection formula (XXVI) by restoring the compounds of formula (XXV).

There are no particular restrictions on the nature of the reducing agent used for this reaction, and it can be equally used any reducing agent commonly used in reactions of this type. Examples of suitable reducing agents include a combination of tin and chloritoid is in; and similar combinations.

This reaction can be carried out in the presence or absence of solvent. When using solvent, there is no particular limitation on its nature, provided that it has no adverse effect on the course of the reaction and includes reagents, and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; alcohols such as methanol, ethanol, propanol or t-butanol; esters such as ethyl acetate; water; and mixtures of any two or more of these solvents.

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at a temperature of from cooling with ice to heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, IU carried out at defined above preferred reaction conditions, usually it is sufficient period of time the reaction is from 0.5 hours to several days.

This stage can also be carried out by catalytic hydrogenation.

There is no particular restriction on the nature of the used catalyst, and here you can use equally any catalyst commonly used in reactions of this type. Examples of suitable catalysts include Raney Nickel, palladium-on-carbon, palladium-black, oxide of ruthenium and platinum.

The reaction is normally and preferably carried out in the presence of a solvent. Specific restrictions on the nature of the subject using the solvent does not exist, provided that it has no adverse effect on the course of the reaction or to be included in the reaction reagents and that he can, at least to some extent dissolve the reagents. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid; alcohols such as methanol, ethanol, propanol or ethylene glycol; halogenated uglevodih">

The reaction can be performed in a wide range of temperatures and the precise temperature is not essential for the invention. In General, we found that is suitable conducting the reaction at about room temperature or while heating, for example up to the boiling temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out at defined above preferred reaction conditions, is usually sufficient period of time the reaction is from 0.5 hours to a few days

Stage G3

In Stage G3 obtain the connection formula (IIb) by reacting the compounds of formula (XXVI) with a compound of formula (XXI). This reaction is basically a similar reaction to that described in Stage D2 Reaction Scheme D, and it can be done, using the same reagents and reaction conditions.

Reaction Scheme H

Derived 1,2-diaminobenzene, which is used in Stage D2 Reaction Schemes D and Stage F1 Reaction Scheme F, can be obtained by the method described in reaction scheme H, Romania the compounds of formula (XXVII). This reaction is, in General, similar reactions are described in the G1 Phase of the Reaction Scheme G, and it can be done, using the same reagents and reaction conditions.

Stage H2

In Stage H2 receives the connection of the formula (XX) by restoring the compounds of formula (XXVIII). This reaction is basically a similar reaction to that described in Stage G2 of the Reaction Scheme G, and it can be done, using the same reagents and reaction conditions.

Biological activity

The compound of formula (I) and their salts have the ability to lower insulin resistance, hyperlipidemia, hyperglycemia, diabetes in pregnancy, obesity, restore, reduced glucose tolerance, reduce diabetic complications, arteriosclerosis, cataracts, and the polycystic ovary syndrome and, in addition, the compounds of formula (I) and their salts have alderatutako inhibitory activity, 5-lipoxygenase inhibitory activity and ability to inhibit the formation of lipid peroxide. Therefore they can be used for the prevention and/or treatment of hyperlipidemia, hyperglycemia, obesity, reduced glucose tolerance, hypertension, osteoporosis, cachexia, fatty infiltration of the liver, Diab is related to the insulin resistance, including diabetes mellitus during pregnancy and polycystic ovary syndrome; to prevent and/or treat inflammatory diseases, acne, solar erythema, psoriasis, eczema, allergic diseases, asthma, G1-ulcers, cardiovascular diseases, atherosclerosis and cellular damage caused by ischemic diseases.

The compounds of this invention can be administered in various forms, depending on the disease to be treated, and the age, condition and body weight of the patient, as is well known in this field. For example, when connection is required to enter orally, they can be formulated in the form of tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), drugs for drip infusion (drop infusion) or suppositories. For use by ophthalmic route through the mucous membrane, they can be formulated in the form of eye drops or eye ointments. These formulations can be obtained in the usual way, and, if desired, the active ingredient can be mixed with any standard additives, such as filler, binder, DEZENT and dye.

Examples of fillers that may be used include organic fillers, including derivatives of sugars, such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, a-starch, dextrin and carboximetilkrahmal; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hypromellose, carboxymethylcellulose, calcium carboxymethylcellulose and sodium carboxymethylcellulose, connected internal bridge connection; Arabian gum; dextan; Pullulane; and inorganic excipients including silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate and magnesium aluminate of metasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.

Examples of lubricants that may be used include stearic acid; magnesium stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee resin and spermacoceae resin; boric acid; adipic acid; sulfates such as sodium sulfate; the atrium lauryl sulfate and magnesium lauryl sulfate; silicates such as silicic acid anhydride and silicic acid hydrate; and the above-mentioned derivatives of starch.

Examples of binders which can be used include: polyvinylpyrrolidone; macrogol (macrogol); and the same compounds mentioned above for fillers.

Examples of the disintegrator, which can be used include the same compounds mentioned above for fillers; and chemically modified starches and cellulose, such as sodium crosscarmellose, sodium carboximetilkrahmal and polyvinylpyrrolidone associated bridge connection.

Examples of stabilizers that can be used include: peroxybenzoate, such as methylparaben and propylparaben; alcohols such as chlorobutanol, Benzylalcohol and phenylethylamine; chloride benzalkonium (benzalkonium); phenols such as phenol and cresol; thimerosal (thimerosal); dehydroacetic acid; and sorbic acid.

Although the dose will vary depending on symptoms, age and body weight of the patient, nature and severity of the disease to be treated or prophylaxis, route of administration and the form of the medicinal product, in General, when a drug is subject onlinechicago 1 mg) up to a maximum of 2000 mg (preferably 500 mg or more, preferably 1 mg) connection, and it can be taken as a single (single) dose or in divided doses. In the case of appointment of medicines intravenously to adult patient-a person's recommended daily dose in the range from at least 0.01 mg (preferably 0.1 mg) up to a maximum of 500 mg (preferably 50 mg) connection, and it can be administered as a single dose or in divided doses.

The activity of the compounds of the present invention is illustrated by the following tests.

Test 1

Gipoglikemicheskaja activity

As test animals used hyperglycemic mice, males, QC lines, each weighing at least 40 g of the Compounds to be tested are mixed with 1:1 (by volume) mixture of glycol and water. Each animal orally injected the compound in the amount shown in the following Table 6, and then they had free access to food for 18 hours. At the end of this time the blood was collected from the tail vein without anesthesia. The level of glucose in the blood (UGC BGL) was determined using a glucose analyzer (GL-101, supplied by Mitsubishi Kasei Co. or Glucoroder-F supplied Shino-Test Co.)

The hypoglycemic effect was calculated using the following the>- the level of glucose in the blood, which was introduced only solvent, but not the active connection;

and

BGLt- the level of glucose in the blood, which injected the connection.

The results are presented in Table 6, in which each connection of the present invention are identified with numbers corresponding to the numbering of Examples that illustrate their preparation.

As follows from Table 6, the compounds of this invention demonstrate excellent activity.

Test 2

Inhibition elderadostone

Olderadults lens bulls-eye is isolated and partially purified by the method of S. Hyman and J. H. Kinoshita J. Biol. Chem., 240, 877 (1965) and K. Inagaki, S. Miwa and J. Okuda [Arch. Biochem. Biophys., 216, 337 (1982)] , and its activity determined photometrically by the method of Varma et al. , [Biochem. Pharmac., 25, 2505 (1976)]. Inhibition of enzyme activity was defined for compounds of this invention at a concentration of 5 μg/ml, and the measured values were used to calculate the IC50values. The results are presented in Table 7.

Test 3

Toxicity

The toxicity of the compounds of this invention were tested in male rats F344 line divided 50 mg/kg of body weight per day for 2 weeks. Test compounds were compounds of Examples 1 and 2. The animals were monitored for the next 2 weeks and during this period they found no anomalies that could be attributed to the test compounds. Taking into account the substantial dose, each animal entered, a zero mortality rate indicates that the compounds of this invention have very low toxicity.

Thus, the compounds of this invention have excellent activity, combined with very low toxicity, which makes them ideally suited for therapeutic applications.

Example 1

5-[4-(1-Methylbenzimidazole-2-ylethoxy)benzyl] -thiazolidine-2,4-dione (compound N 1-11)

A mixture of 1.0 g of N-methyl-1,2-phenylenediamine, 3.8 g of 5-[4-(ethoxycarbonylmethoxy-benzyl]thiazolidin-2,4-dione (obtained as described in Preparation 4), 20 ml of concentrated aqueous hydrochloric acid, 10 ml of 1,4-dioxane and 10 ml of water heated to boiling under reflux for 5 hours. At the end of this time landed from the reaction mixture, the insoluble matter is collected by filtration, and the residue, thus obtained, is dissolved in terline acidic sodium carbonate and then extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then the solvent is removed by evaporation under reduced pressure and the resulting residue purified by column chromatography on silica gel using ethyl acetate and then ethanol as eluent. The product is then recrystallized twice from a mixture of tetrahydrofuran and ethyl acetate, obtaining 1.3 g of the named compound, melting at 230 - 231oC.

Example 2

5-[4-(6-Methoxy-1-methylbenzimidazole-2-ylethoxy)-benzyl] thiazolidin-2,4-dione (Compound N 1-49)

A mixture of 21.8 g of 5-Methoxy-N-methyl-1,2-phenylenediamine (obtained as described in Preparation 9), and 63.4 g of 5-(4-methoxycarbonylbenzyl)thiazolidin-2,4-dione (obtained as described in Preparation 21) in 250 ml of 1,4-dioxane and 750 of concentrated aqueous hydrochloric acid is heated at the boil under reflux for 60 hours. At the end of this time the reaction mixture is cooled with ice, after which the solid is collected by filtration. 800 ml of 5% weight/about aqueous solution of acid sodium carbonate is added to this substance, and the resulting mixture was stirred at room temperature for 2 hours. Then a wrong the first solution discolor treatment with activated carbon, which is then separated by filtration. Then the filtrate is concentrated by evaporation under reduced pressure to a volume of about 50 ml. of the resulting concentrate is added to 750 ml of diethyl ether, and the solution thus obtained, allow to settle for two days. After this time the precipitate is collected by filtration, receiving of 20.1 g of the named compound, melting at 267 - 271oC with Rfvalue = 0,68 (according to thin layer chromatography on silica gel; using manifesting (developing) solvent: methylene chloride containing 5% V/V ethanol).

Example 3

5-[4-(5-Hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)- benzyl] thiazolidin-2,4-dione (Compound N1-237)

A mixture of 1.0 g of 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine (obtained as described in Preparation 19), 2.7 g of 5-(4-methoxycarbonylbenzyl)thiazolidin-2,4-dione (obtained as described in Preparation 21), 5 ml of 1,4-dioxane and 25 ml of concentrated aqueous hydrochloric acid is heated at the boil under reflux for 2 days. At the end of this time the reaction mixture was added to ice water, and the resulting mixture is neutralized by adding acid of Carbona and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure, then the residue purified by column chromatography on silica gel using ethyl acetate as eluent. The fractions containing the named compound are collected, and the solvent is removed by distillation under reduced pressure, obtaining a red oily residue. To the oil is added 150 ml of diethyl ether, and the mixture is stirred using ultrasound for 5 minutes. The residue is collected by filtration and dissolved in 300 ml of tetrahydrofuran. The resulting solution was concentrated to a volume of about 10 to 20 ml by evaporation under reduced pressure. To the concentrate is added 200 ml of ethyl acetate, and the mixture is stirred using ultrasound for 30 minutes. The residue is collected by filtration, getting 0.52 g of the named compound, melting at 240 - 244oC with Rfvalue = 0,44 (according to thin layer chromatography on silica gel; manifesting solvent: ethyl acetate.

Example 4

5-[4-(5-Hydroxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)- benzyl] thiazolidin-2,4-dione (Hydrochloride of the Compound N 1-237)

A suspension of 0.12 g of 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)benzyl] thiazolidin-2,4-dione (the floor is aces at room temperature, then, the suspension is kept on during the night. The insoluble matter is collected by filtration and washed with tetrahydrofuran, ethyl acetate and diethyl ether in this order to obtain 0.11 g of the named compound, melting at 228 - 231oC.

Example 5

5-[4-(5-Acetoxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)- benzyl] thiazolidin-2,4-dione (Compound N 1-250)

to 0.032 ml of acetic anhydride is added at room temperature to a solution of 0.12 g of 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)- benzyl]thiazolidin-2,4-dione (obtained as described in Example 3) in 2 ml of pyridine, and the mixture was stirred for 3 hours, after which the mixture was kept over night. At the end of this time the reaction mixture is freed from solvent by evaporation under reduced pressure and the resulting residue is mixed with water. The aqueous mixture was then extracted with ethyl acetate. The extract is washed with water and then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, after which the solid residue is ground into powder with diethyl ether and collected by filtration. The residue is then washed IER is 5-Methoxy-1-methylbenzimidazole-2-yl-methoxy)-benzyl] thiazolidin-2,4-dione (Compound N 1-146)

A mixture of 1.17 g of 4-methoxy-N-methyl-1,2-phenylenediamine (obtained as described in Preparation 25), 3.0 g of 5-(4-methoxycarbonylbenzyl)thiazolidin-2,4-dione (obtained as described in Preparation 21), 20 ml of 1,4-dioxane and 60 ml of concentrated aqueous hydrochloric acid is heated at the boil under reflux for 2 days. At the end of this time the reaction mixture is poured into ice water and the resulting mixture is neutralized by addition of acid sodium carbonate, after which it is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure, then the residue purified by column chromatography on silica gel using a solution of methylene chloride containing 3% by volume of ethanol as eluent, receiving 0.3 g of the named compound, melting at 209 - 210oC with Rfvalue = 0,56 (according to thin layer chromatography on silica gel; manifesting solvent: methylene chloride containing 5% by volume of ethanol).

Example 7

5-[4-(1-Benzylbenzimidazole-5-ylethoxy)benzyl] thiazolidin-2,4-dione hemihydrate (Polovina (received as described in Preparation 29), 3 ml of acetic acid and 1 ml of water is stirred for 3 hours at 50oC in the oil bath. At the end of this time the reaction mixture is neutralized with sodium carbonate and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then removed by evaporation under reduced pressure and the resulting residue is recrystallized from a mixture of ethanol and methanol, getting 116 mg of the named compound, melting at 185 - 187oC.

Preparation 1

Methyl 4-nitrophenoxyacetic

A mixture of 56 g of 4-NITROPHENOL, 90 g of methyl bromoacetate, 100 g of potassium carbonate and 500 ml of dimethylformamide is stirred at room temperature for 2 days. At the end of this time the solvent is removed by distillation under reduced pressure. The resulting residue is mixed with water and the aqueous mixture extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate, then the solvent is removed by distillation under reduced pressure. The resulting residue is ground to powder with hexane, receiving and 63.3 g of the named compound, So pl. 98 - 99oC.

Photoeye in Preparation 1) in 500 ml of methanol vibrate (shake) in the atmosphere of hydrogen and in the presence of 5.0 g of 10% W/W palladium-on-carbon for 6 hours. At the end of this time the reaction mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure, obtaining of 25.8 g of the above compounds having Rfvalue = 0,79 (according to thin layer chromatography on silica gel; manifesting solvent: ethyl acetate).

Preparation of 3

Methyl 4-(2-bromo-2-butoxycarbonylmethyl-1-yl)-phenoxyacetate

98 g of a 47% weight/weight of aqueous Hydrobromic acid with subsequent 33 ml of an aqueous solution containing 12.8 g of sodium nitrite, are added to a solution of 25.8 g of methyl-4-aminophenoxyethanol (obtained as described in Preparation 2) in 263 ml of 2:5 by volume mixture of methanol and acetone under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. Then add of 18.2 g of butyl acrylate, and the reaction mixture stirred for another 30 minutes while cooling with ice. To the mixture is added 3.2 g of copper bromide (I), and the mixture is stirred over night at room temperature. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure, and the residue is mixed with an aqueous solution of sodium chloride. Then extracted with ethyl acetate. The extract is washed with an aqueous solution of chloride is Oia, with Rfvalue = 0,46 (according to thin layer chromatography on silica gel; manifesting solvent: 5: 1 by volume mixture of hexane and ethyl acetate), in the form of a crude product.

Preparation of 4

5-[4-(Ethoxycarbonylmethoxy)benzyl]thiazolidin-2,4-dione

A mixture of 100 g of methyl 4-(2-bromo-2-butoxy-carbonylmethyl-1-yl)- phenoxyacetate (obtained as described in Preparation 3), 22 g of thiourea and 200 g of ethanol are heated at the boil under reflux for 2.5 hours, then added to the reaction mixture of 2 N aqueous hydrochloric acid. The mixture is then heated to boiling under reflux for 5 hours. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure. The obtained residue was diluted with water and the aqueous mixture extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and then remove the solvent by distillation under reduced pressure. The resulting residue is purified by column chromatography on silica gel using 2:5 by volume mixture ethylacetate and hexane as eluent, receiving and 19.4 g of the named compound, melting at 105 - 106oC.

Prigotovit room temperature to a solution of 25 g of 5-chloro-2-nitroaniline in 500 ml of 1,4-dioxane, and the resulting mixture is heated to boiling under reflux for 4 hours, after which the solvent is removed by distillation under reduced pressure. The obtained residue was diluted with water and the resulting aqueous mixture is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, then the solvent is removed by distillation under reduced pressure. The resulting residue is purified by column chromatography on silica gel, using a method with gradient elution with mixtures of ethyl acetate and hexane in the range of ratios from 1:4 to 1:2 by volume as the eluent, receiving 16.3 g of the named compound, melting at 124 - 128oC.

Preparation of 6

N-t-Butoxycarbonyl-5-methoxy-2-nitroaniline

25 g of di-t-butyl dicarbonate, 15 ml of pyridine and 0.6 g of dimethylaminopyridine added at room temperature to a solution of 16 g of 5-methoxy-2-nitroaniline (obtained as described in Preparation 5) in 500 ml digidratirovannogo of tetrahydrofuran, and the resulting mixture is stirred for 2 hours. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure, and the saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, then the solvent is removed by distillation under reduced pressure. The resulting residue is purified by column chromatography on silica gel, using 1: 10 (by volume) mixture of ethyl acetate and hexane as eluent, receiving 12.5 g of the named compound, melting at 112 - 114oC.

Preparation of 7

N-t-Butoxycarbonyl-N-methyl-5-methoxy-2-nitroaniline

A solution of 49.6 g of N-t-butoxycarbonyl-5-methoxy-2-nitroaniline (obtained as described in Preparation 6) in 300 ml digidratirovannogo of dimethylformamide are added during the cooling to a suspension of 12.0 g of sodium hydride (as a 55% W/W dispersion in mineral oil) in 300 ml digidratirovannogo of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes, then added at room temperature and 17.2 ml iodotope bromide. The reaction mixture is stirred for one hour, then give her the opportunity to stand over night at room temperature. The mixture is then concentrated to about 1/5 of the original volume by evaporation under reduced pressure. The concentrate is mixed with water with ice, and the resulting aqueous mixture is extracted with ethyl acetate. The extract is washed with water is the atrium. After distillation of the solvent get to 52.1 g of the named compound, melting at 122 - 124oC.

Preparation of 8

N-methyl-5-methoxy-2-nitroaniline

750 ml of 4 N solution of hydrogen chloride in 1,4-dioxane is added to 52 g of N-t-butoxycarbonyl-N-methyl-5-methoxy-2-nitroaniline (obtained as described in Preparation 7) at room temperature, and the mixture is stirred for two hours. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure and the resulting residue is mixed with water and ethyl acetate. The mixture was then neutralized by adding acid sodium carbonate, after which the mixture is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distillation of the solvent get to 35.3 g of the named compound, melting at 107 - 110oC.

Preparation 9

5-methoxy-N-methyl-1,2-phenylenediamine

346 g of tin chloride is added to a mixture of 35 g of N-methyl-5-methoxy-2-nitroaniline (obtained as described in Preparation 8), 900 ml of t-butanol and 100 ml of ethyl acetate at room temperature, and the mixture was stirred at 60oC tip is about 1 hour. The reaction mixture was then stirred at 60oC for 3 hours, after which it was incubated at room temperature for 2 days. Then it was poured into ice water and the aqueous mixture is neutralized by adding acid sodium carbonate. The mixture is extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed from the mixture by distillation under reduced pressure and the resulting residue purified by column chromatography on silica gel using 3:2 (by volume) mixture of ethyl acetate and hexane as eluent, obtaining of 21.9 g of the above compounds having Rfvalue = 0,18 (according to thin layer chromatography on silica gel; manifesting solvent: 1:1 (by volume) mixture of ethyl acetate and hexane).

Preparation 10

Trimethylbenzoquinone

A suspension of 25.6 g of iron chloride (III) in 50 ml of water is added at room temperature to a solution of 20 g of trimethylhydroquinone in 150 ml of acetone, and the resulting mixture is stirred for 1 hour, after which it was incubated for 2 days. At the end of this time the mixture is concentrated to approximately 1/2 of the original volume and the concentrate is mixed in with the thief of sodium chloride, after which it is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the resulting residue purified by column chromatography on silica gel using 1:6 (by volume) mixture of ethyl acetate and hexane as eluent, obtaining of 16.9 g of the above compounds having Rfvalue = 0,48 (according to thin layer chromatography on silica gel; manifesting solvent: 1:6 (by volume) mixture of ethyl acetate and hexane).

Preparation 11

2,3,6-trimethylbenzoquinone-4-oxime

Solution? 7.04 baby mortality g of hydroxylamine hydrochloride in 30 ml of water is added at room temperature to a solution of 16.9 g of trimethylbenzoquinone (obtained as described in Preparation 10) in 150 ml of methanol, and the resulting mixture is stirred for 2 hours, after which it was incubated for 2 days. At the end of this time the reaction mixture is diluted with 1000 ml of water. The residue is collected by filtration and recrystallized from a mixture of ethyl acetate and hexane, obtaining 11.2 g of the named compound, melting at 188 - 190oC.

Cooking 12

4-hydroxy-2,3,5-trimethylaniline

152 g of hydrosulfite sodium added with cooling to a mixture 36,15 g of 2,3,6-trimethylbenzoquinone-4-hydroxy who ü stirred at room temperature for 1 hour, then it kept on during the night. The reaction mixture was then poured into ice water, and the pH of the aqueous mixture is brought to a value from 4 to 5 by addition of 5 N aqueous hydrochloric acid, after which the mixture to neutralize the acid with sodium carbonate. The mixture thus obtained is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Then the solvent is removed by distillation under reduced pressure, after which the crystalline residue is ground to powder with diisopropyl ether and collected by filtration, and after washing, diisopropyl ether, get to 30.1 g of the named compound, melting at 131 - 134oC.

Preparation of 13

N-t-Butoxycarbonyl-4-hydroxy-2,3,5-trimethylaniline

22,0 ml of triethylamine added at room temperature to a solution of 20 g of 4-hydroxy-2,3,5-trimethylaniline (obtained as described in Preparation 12) in 500 ml of tetrahydrofuran followed by the addition of 34.6 di-t-butyl dicarbonate, and the resulting mixture is stirred for 6 hours, after which the mixture was kept over night. At the end of this time the reaction mixture is freed from solvent by distilla is by ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, after which the crystalline residue is ground to powder with hexane, getting to 31.9 g of the named compound, melting at 158 - 161oC.

Preparation 14

N-Methyl-4-hydroxy-2,3,5-trimethylaniline

A solution of 15 g of N-t-butoxycarbonyl-4-hydroxy-2,3,5-trimethylaniline (obtained as described in Preparation 13) in 200 ml digidratirovannogo of tetrahydrofuran is added to a suspension of 6.8 g of sociallyengaged 300 ml digidratirovannogo of tetrahydrofuran while cooling, and the mixture was stirred at room temperature for 3 hours, after which the mixture is heated to boiling under reflux for 2 hours. At the end of this time the mixture of 10 ml of water and 30 ml of tetrahydrofuran is added to the reaction mixture to destroy the excess sociallyengaged. Then the reaction mixture was stirred at room temperature for 1.5 hours, after which the insoluble matter is filtered off using a Celite (trade mark) filter material. These substances are washed with ethyl acetate, and an ethyl acetate-promyvkie, and the resulting residue purified by column chromatography on silica gel using 1:3 (by volume) mixture of ethyl acetate and hexane as eluent, obtaining of 5.1 g of the named compound, melting at 120 - 122oC.

Preparation 15

N-t-Butoxycarbonyl-N-methyl-4-hydroxy-2,3,5-trimethylaniline

5.0 ml of triethylamine and a solution of a 7.92 g of di-t-butyl dicarbonate in 30 ml of tetrahydrofuran added at room temperature to a solution of 5.0 g of N-methyl-4-hydroxy-2,3,5-trimethylaniline (obtained as described in Preparation 14) in 70 ml of tetrahydrofuran, and the mixture was stirred for 1 hour, after which the mixture was kept over night. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure and the resulting residue is mixed with water. The aqueous mixture is extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride in this order, after which it is dried over anhydrous magnesium sulfate. After removal of the solvent the remaining crystals are ground to powder with hexane and collected by filtration. Get to 7.35 g of the named compound, melting at 163 - 166oC.

Preparation 16

N-t-a Bout the reed added at room temperature to a solution of 7.2 g of N-t-butoxycarbonyl-N-methyl-4-hydroxy-2,3,5-trimethylaniline (received as described in Preparation 15) in 100 ml digidratirovannogo of tetrahydrofuran, and the resulting mixture is stirred for one hour, after which the mixture was kept over night. The reaction mixture is then diluted with water and the aqueous mixture extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride, after which it is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, then the residue is ground to powder with a cooled ice hexane to induce crystallization. The crystals are collected by filtration and washed with ice hexane, receiving 6.25 g of the named compound, melting at 103 - 104oC.

Preparation 17

N-Methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride

A mixture obtained by adding 10 ml of 4 N solution of hydrogen chloride in 1,4-dioxane to the 5.45 g of N-t-butoxycarbonyl-N-methyl-4-acetoxy-2,3,5-trimethylaniline (obtained as described in Preparation 16), at room temperature, stirred for 3 hours. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure, and the obtained residue is ground to powder with diisopropyl ether, getting 4,36 g of the named compound, melting at 172 - 176oC.

Preparation 18

N-Methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline

4.3 g of N-methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride (obtained as described in Preparation 17) are added to a cooled ice concentrated aqueous nitric acid, and the mixture was stirred under ice cooling for 10 minutes and then at room temperature for 10 minutes. At the end of this time the reaction mixture is poured into ice water, and the aqueous mixture is neutralized by addition of acid sodium carbonate, after which it is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Then the solvent is removed by distillation under reduced pressure, and then to the residue are added 50 ml of diisopropyl ether and 50 ml of hexane. The mixture is then stirred with ultrasound for 5 minutes. The insoluble residue is ground to a powder with a mixture of diisopropyl ether and hexane at a ratio of 1:1 (by volume). The resulting crystals are collected by means of filtration, then washed with a mixture of diisopropyl ether and hexane at a ratio of 1:1 (by obnoxi-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine

A solution of 2.65 g of N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitro-aniline (obtained as described in Preparation 18) in a mixture of 20 ml ethanol and 20 ml of ethyl acetate is subjected to shaking at room temperature for 3.5 hours and then at 40oC for 3 hours in an atmosphere of hydrogen and in the presence of 0.2 g of platinum oxide. At the end of this time the reaction mixture is filtered to separate the platinum oxide, and the filtrate is freed from solvent by distillation under reduced pressure. The resulting residue is purified by using column chromatography on silica gel using 1:1 (by volume) mixture of ethyl acetate and hexane as eluent, obtaining 1.3 g of the named compound, melting at 113 - 116oC.

Preparation 20

5-(4-Methoxycarbonylbenzyl)-3-triphenylmethyl-thiazolidin-2,4-dione

126 g of cesium carbonate added at room temperature to a solution of 120 g of 5-(4-hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione 2.5 liters of acetone and then adding 36 ml of methyl bromoacetate, and the resulting mixture is stirred for 1 hour. At the end of this time the reaction mixture is freed from solvent by distillation under reduced pressure and the resulting residue is mixed with in the or sodium chloride, after which it is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and then to the oil residue was added 1 liter of diethyl ether. Then the mixture is stirred by means of ultrasound for 10 minutes. Landed the solid is collected by filtration, getting 126,3 g of the named compound, melting at 158 - 162oC.

Preparation 21

5-(4-Methoxycarbonylbenzyl)thiazolidin-2,4-dione

1700 ml of acetic acid and then 400 ml of water is added at room temperature to a suspension of 344 g of 5-(4-methoxycarbonylbenzyl)-3-triphenyltetrazolium-2,4-dione (obtained as described in Preparation 20) in 400 ml of 1,4-dioxane, and the resulting mixture is stirred for 5 hours at 80oC. after this time the reaction mixture is freed from solvent by evaporation under reduced pressure and the resulting residue purified using column chromatography on silica gel using a 1:2 (by volume) mixture of ethyl acetate and hexane, 2:1 (by volume) mixture of ethyl acetate and hexane and then ethyl acetate as eluents, receiving of 161.7 g of the named compound, melting at 100 106oC.

Preparation 22

N-t-Butoxysilane added at room temperature to the suspension to 0.72 g of sodium hydride (as a 55% W/W dispersion in mineral oil) in 30 ml digidratirovannogo of dimethylformamide, and the resulting mixture was stirred at room temperature for 10 minutes, then a solution of 3.57 g of di-t-butyl carbonate in 20 ml of digidratirovannogo of dimethylformamide added at room temperature and then the mixture is stirred for 1 hour. At the end of this time the reaction mixture is poured into water with ice, and the mixture was extracted with ethyl acetate. The extract is washed with water and then saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. The extract is freed from solvent by distillation under reduced pressure, after which the resulting residue purified by column chromatography on silica gel using a 1:20 (by volume) mixture of ethyl acetate and hexane as eluent, obtaining of 1.94 g of the above compounds having Rfvalue = 0,39 (according to thin layer chromatography on silica gel; manifesting solvent: 1:20 (by volume) mixture of ethyl acetate and hexane).

Preparation 23

N-t-Butoxycarbonyl-N-methyl-4-methoxy-2-nitroaniline

Repeat the method similar to that described in Preparation 7, except that they use and 0.46 g of sodium hydride (as a 55% W/W dispersion in mineral oil), 15 ml dehydr is on (received as described in Preparation 22) in 15 ml digidratirovannogo of dimethylformamide, obtaining 2.0 g of the above compounds having Rfvalue = 0,34 (according to thin layer chromatography on silica gel; manifesting solvent 1:5 (by volume) mixture of ethyl acetate and hexane).

Preparation 24

N-Methyl-4-methoxy-2-nitroaniline

Repeat the method similar to that described in Preparation 8, except that the use of 2.0 g of N-t-butoxycarbonyl-N-methyl-4-methoxy-2-nitroaniline (obtained as described in Preparation 23) and 30 ml of 4 N solution of hydrogen chloride in 1,4-dioxane, getting 1,17 g of the above compounds having Rfvalue = 0,62 (according to thin layer chromatography on silica gel; manifesting solvent: 1:5 (by volume) mixture of ethyl acetate and hexane).

Preparation 25

4-Methoxy-N-methyl-1,2-phenylenediamine

A solution of 1.16 g of N-methyl-4-methoxy-2-nitroaniline (obtained as described in Preparation 24) in 50 ml of ethanol is shaken in an atmosphere of hydrogen and in the presence of 0.3 g of 10% W/W palladium-on-carbon for 3 hours. At the end of this time palladium-on-carbon is filtered off and the filtrate is freed from solvent by evaporation under reduced pressure, the floor is the Kagel; manifesting the solvent is 1:3 (by volume) mixture of ethyl acetate and hexane).

Preparation 26

Methyl 5-benzimidazolecarboxylate

A mixture of 10 g of 5-benzimidazolecarbamic acid, 150 ml of methanol and 100 ml of 4 N solution of hydrogen chloride in 1,4-dioxane is stirred with ultrasound for 4 hours. At the end of this time the solvent is removed by distillation under reduced pressure, then the residue is added 30 ml of methanol and 3.5 g of lithium borohydride, and the mixture is stirred for 1 hour. Then the solvent is removed by evaporation under reduced pressure, and the residue is mixed with an aqueous solution of sodium chloride, after which make extraction with ethyl acetate. The solvent is removed by distillation under reduced pressure, getting 5,44 g of the named compound, melting at 136 - 138oC.

Preparation 27

Methyl 1-benzyl-5-benzimidazolecarboxylate

A mixture of 2.8 g of methyl 5-benzimidazolecarboxylate (obtained as described in Preparation 26), to 3.52 g of benzyl bromide, 3 g of potassium carbonate and 50 ml of acetone is stirred for 3 days at room temperature. At the end of this time the solvent is removed by evaporation under reduced pressure, and the residue is mixed with water concrete is Oia, then the solvent is removed by distillation under reduced pressure. The residue is then recrystallized from a mixture of ethyl acetate and hexane, obtaining 0,94 g of the named compound, melting at 156 - 162oC.

Preparation 28

1-Benzyl-5-benzimidazolethiol

0.87 g of methyl 1-benzyl-5-benzimidazolecarboxylate (obtained as described in Preparation 27) in 18 ml digidratirovannogo of tetrahydrofuran is added to a suspension of 0.23 g of sociallyengaged in 10 ml digidratirovannogo of tetrahydrofuran under ice cooling, and the mixture was stirred for 2 hours at room temperature. Then to the reaction mixture add an additional 0.11 g of sociallyengaged and 10 ml digidratirovannogo of tetrahydrofuran, and the mixture is stirred for 1 hour at room temperature and then for 4.5 hours at 50oC in an oil bath, after which the mixture is heated to boiling under reflux for 2 hours. The reaction mixture is cooled to room temperature, giving her the opportunity to settle, after which it add excess decahydrate sodium sulfate, and the mixture is stirred for 2 hours at room temperature. At the end of this time the reaction well of the solvent by distillation under reduced pressure. Then the residue is recrystallized from a mixture of ethanol and diisopropyl ether, receiving 383 mg of the named compound, melting at 148 - 150oC.

Preparation 29

5-[4-(1-Benzylbenzimidazole-5-ylethoxy)benzyl] -3 - triphenyltetrazolium-2,4-dione

The mixture 822 mg of 5-(4-hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione, 454 g isochronically, 6 ml digidratirovannogo toluene and 0.44 ml of tributylphosphine stirred for 30 minutes at room temperature. At the end of this time 349 mg of 1-benzyl-5-benzimidazolethiol added to the reaction mixture, and the mixture is then stirred for 3 hours, after which it allow to stand for 10 days at room temperature. Then the solvent is removed by distillation under reduced pressure, and the resulting residue purified by column chromatography on silica gel using the method of gradient elution with mixtures of ethyl acetate and hexane in ratios ranging from 3:1 to 1:0 (by volume) as eluent, getting 0.32 g of the named compound, razmyagchayuschiesya at 90 - 91oC.

Formula 1 (the Technology of preparation of medicines)

The drug in powder form

4 g of 5-[4-(6-methoxy-is droxyprogesterone (brand name: TC-5E: product of Shin-Etsu Chemical Industry Co. Co., Ltd.) mixed and sprayed using a vibrating mill for 30 minutes to obtain the desired powdered drug.

Recipe 2

The drug is in the form of capsules

20 g of 5-[4-(6-methoxy-1-methylbenzimidazole-2-ylethoxy)benzyl]-thiazolidine-2,4-dione (Compound N 1-49) and 20 g of polyvinylpyrrolidone dissolved in a mixture of 100 g of acetone and 100 g of ethanol, and then the solution is sprayed on 200 g of sodium croscarmelose using a granulator, fluidized bed, in order to obtain granules. 0.1 g of hydroxypropylmethylcellulose (brand name: TC-5E, Shin-Etsu Chemical Industry Co., Ltd.) and 1.9 g of lactose were then added to 10 g of these granules and mix. Then gelatin capsules filled 0.24 g of this mixture, receiving the drug in the form of capsules. The drug is in the form of capsules contains 0.1 g of active connections on the capsules.

Recipe 3

Drug pill

1 g of 5-[4-(6-methoxy-1-methylbenzimidazole-2-ylethoxy)- benzyl]-thiazolidine-2,4-dione (Compound N 1-49) and 1 g of polyvinylpyrrolidone dissolved in a mixture of 5 g of acetone and 5 g of ethanol, and then, using a rotary evaporator removed by evaporation under reduced pressure of the organic solvent. The obtained solid substance is sprayed, receiving fine granules, 0.25 g cristalla brand: TC-5E; the product of Shin-Etsu Chemical Industry Co., Ltd.), 0.18 g of lactose and 0.2 g of magnesium stearate is added to 1 g of these fine granules and mix. Then get tablets using the machine for tableting.

Experiment A: Inhibition of the production of lipid peroxide

5 μl of Compound in example 3, dissolved in DMCO, mixed with 400 µl of buffer and 100 μl of a preparation of liver microsomes of rats and pre-incubated at 37oC for 5 minutes. The initiate reaction by adding 10 ál of the reaction mixture (0.5 mm FeSO47H2A : 50 mm cysteine = 1:1), incubated at 37oC for 30 minutes, and finish by adding 1.0 ml of 10% TCA. After centrifugation of the reaction mixture at 3000 rpm for 10 minutes to collect 1 ml of supernatant. The supernatant is mixed with an equal volume of 0.67% solution thiobarbiturate acid and boiled at 100oC for 15 minutes. After cooling, measure the optical density at 535 nm and this value is used to determine the IC50.

Experiment B: Inhibition of 5-lipoxygenase

5 μl of Compound in example 3, dissolved in DMCO, mixed with 750 µl of 1/15 M phosphate buffer (pH 7,4), 40 μl of 30 mm CaCl2, 50 μl of 20 mm glutathione, and 100 μl of a solution of polymorph is eakly initiated by adding 5 μl of a solution of arachidonic acid (10 mg/ml ethanol), incubated at 25oC for 5 minutes, and finish by adding 50 µl of 2 N. HCl. To the mixture is added 2 ml of ethyl acetate containing internal standard material (parahydroxybenzoic acid, isoamyl ester : 2 ál/ml), and extracted by stirring with a mixer for 1 minute and centrifugation at 3000 rpm for 5 minutes. An ethyl acetate layer is collected, evaporated under reduced pressure and dissolved in 200 ml of acetonitrile. Received 5-NET analyzed by HPLC and the measured value is used to determine the IC50.

The results of experiments A and B are presented in table 8.

1. The compounds of formula (I)

< / BR>
in which X represents a benzimidazole group, which is unsubstituted or substituted by at least one of the substituents defined below;

Y represents an oxygen atom or a sulfur atom;

Z represents a group of the formula (i), (ii), (iii), (iv) or (v):

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R represents a hydrogen atom; alkyl group having from 1 to 4 carbon atoms; alkoxygroup having from 1 to 4 carbon atoms, and halogen atom;

m is an integer from 1 to 5;

these substituents selected from alkyl groups having oroxylum, acetochlor, triptorelin group, and aranceles group in which an alkyl group having from 1 to 5 carbon atoms, substituted unsubstituted carbocyclic aryl group which has from 6 to 10 carbon atoms,

and their salts.

2. Connection on p. 1, in which X represents a benzimidazole group, which is unsubstituted or substituted from 1 to 5 zamestitelyami1defined below: Deputy1represents an alkyl group having from 1 to 4 carbon atoms, alkoxygroup having from 1 to 4 carbon atoms, benzyloxy, a halogen atom, a hydroxy-group, acetoxyl, triptorelin group, aracelio group having from 7 to 11 carbon atoms which are not substituted.

3. Connection on p. 1, in which Y represents an oxygen atom.

4. Connection on p. 1, in which Z represents a 2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene or 2,4-dioxoimidazolidin-5-ylmethylene group.

5. Connection on p. 1, in which X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents 1defined below: Deputy1represents an alkyl group having from 1 to 4 carbon atoms, and the PU, triptorelin group or aracelio group having from 7 to 11 carbon atoms which are not substituted;

Y represents an oxygen atom;

Z represents a 2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene or 2,4-dioxoimidazolidin-5-ylmethylene group;

R represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, alkoxygroup having from 1 to 4 carbon atoms, or a halogen atom.

6. Connection on p. 1, in which Z represents a 2,4-dioxothiazolidine-5-ylidenemethyl or 2,4-dioxothiazolidine-5-ylmethylene group.

7. Connection on p. 1, in which R represents a hydrogen atom, methyl group, methoxy group, ethoxypropan, a fluorine atom or a chlorine atom.

8. Connection on p. 1, in which m is an integer from 1 to 3.

9. Connection on p. 1, in which X represents a benzimidazole group, which is unsubstituted or substituted by 1 to 5 substituents 1defined below: Deputy1represents an alkyl group having from 1 to 4 carbon atoms, alkoxygroup having from 1 to 4 carbon atoms, benzyloxy, a halogen atom, a hydroxy-group, acetoxyl, triptorelin group or aracelio group, the ima is dioxothiazolidine-5-ylidenemethyl or 2,4-dioxothiazolidine-5-ylmethylene group;

R represents a hydrogen atom, methyl group, methoxy group, ethoxypropan, a fluorine atom or a chlorine atom;

m is an integer from 1 to 3.

10. Connection on p. 1, in which X represents a benzimidazole group, which is not substituted or is substituted by from 1 to 5 substituents defined below: Deputy represents an alkyl group having from 1 to 4 carbon atoms, alkoxygroup having from 1 to 4 carbon atoms, benzyloxy, halogen atom, triptorelin group, a hydroxy-group, acetoxy or benzyl group.

11. Connection on p. 1, in which Z represents a 2,4-dioxothiazolidine-5-ylmethylene group.

12. Connection on p. 1, in which R represents a hydrogen atom, methyl group or methoxy group.

13. Connection on p. 1, in which X represents a benzimidazole group, which is not substituted or is substituted by from 1 to 5 substituents defined below: Deputy represents an alkyl group having from 1 to 4 carbon atoms, alkoxygroup having from 1 to 4 carbon atoms, benzyloxy, halogen atom, triptorelin group, a hydroxy-group, acetoxy or benzyl group;

Y represents an oxygen atom,

Z represents a 2,4-deok is/BR> m is an integer from 1 to 3.

14. Connection on p. 1, in which X represents a benzimidazole group, which is not substituted or is substituted by from 1 to 5 substituents defined below: Deputy represents methyl group, ethyl group, ISO-propyl group, a methoxy group, ethoxypropan, propoxylate, isopropoxy, benzyloxy, a fluorine atom, a chlorine atom, a hydroxy-group, acetoxy or benzyl group.

15. Connection on p. 1, in which R represents a hydrogen atom.

16. Connection on p. 1, in which m is an integer from 1 to 2.

17. Connection on p. 1, in which X represents a benzimidazole group, which is not substituted or is substituted by from 1 to 5 substituents defined below: Deputy represents methyl group, ethyl group, ISO-propyl group, a methoxy group, ethoxypropan, propoxylate, isopropoxy, benzyloxy, a fluorine atom, a chlorine atom, a hydroxy-group, acetoxy or benzyl group;

Y represents an oxygen atom;

Z represents a 2,4-dioxothiazolidine-5-ylmethylene group;

R represents a hydrogen atom;

m is an integer from 1 or 2.

18. Connection on p. 1, in which X represents benzimidazole AET methyl group, a methoxy group, a hydroxy-group, a benzene group, or acetoxy.

19. Connection on p. 1, in which m is the integer 1.

20. Connection on p. 1, in which X represents a benzimidazole group, which is not substituted or is substituted by from 1 to 5 substituents defined below: Deputy represents a methyl group, a methoxy group, a hydroxy-group, benzyl group, or acetoxy;

Y represents an oxygen atom;

Z represents a 2,4-dioxothiazolidine-5-ylmethylene group;

R represents a hydrogen atom;

m is an integer 1.

21. The compound of formula (I) under item 1, selected from the group including:

5-[4-(1-Methylbenzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione;

5-[4-(6-Methoxy-1-methylbenzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione;

5-[4-(5-Methoxy-1-methylbenzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione;

5-[4-(1-Benzylbenzimidazole-5-ylethoxy)benzyl]thiazolidin-2,4-dione;

5-[4-(5-Hydroxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)benzyl] thiazolidin-2,4-dione;

5-[4-(5-Acetoxy-1,4,6,7-tetramethylbenzidine-2-ylethoxy)benzyl] thiazolidin-2,4-dione,

and their pharmaceutically acceptable salts.

22. Pharmaceutical composition having gipoksica activity containing an effective amount of the active compound in a mixture with a pharmaceutically acceptable carrier or diluent, wherein the active compound contains at least one compound according to any one of paragraphs. 1 - 21.

23. Compounds according to any one of paragraphs. 1 - 21 to obtain drugs having hypoglycemic activity and inhibitory alsoreported, 5-lipoxygenase and the production of lipid peroxide activity.

Priority points:

01.06.95 under item 1, except for the value of the Deputy-kalkilya group;

on PP.2 - 23; p. 21 - connections 1 - 4.

04.03.96 - p. 1, is Vice-kalkilya group on p. 21 - connections 5 and 6.

 

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-CC1-Calkyl or -CH-Swhere n is an integer in the range 0-3, including both extreme values;

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O-C1-C4alkyl where R9represents hydrogen, C1-C4alkyl or the group --C1-C4-alkyl

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in which R1, R2, R3and X have the above values, Q represents N-R8(where R8has the specified values), and R6and R7together form a group S, with the aim of obtaining the compounds of formula

in which R1, R2, R3, R6, R7, X and Q have the above meanings;

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O-C1-C4alkyl, where R9,R11and R12have the listed meanings: (e) atilirovanie the compounds of formula II in which R8represents a hydrogen in order to obtain the compounds of formula II in which R8represents -(CH2)n-Y, where n is an integer in the range 0-3, including both extreme values of the interval, and Y represents -R10where R10has the specified values;

(f) oxidation of compounds of formula II, Kotor is Lew obtain the compounds of formula II, in which X represents a group -m is 1;

(K) the recovery of the compounds of formula II in which R3represents a group -(CH2)n-Y where n has values in the range 0-3, including extreme values of the interval, Y is a OR9where R9represents a group --C1-C4alkyl order to obtain the compounds of formula II in which R8represents a group -(CH2)n-Y where n is 0-3, including both extreme values, and Y is a OR9where R9represents hydrogen;

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