Substituted condensed heterocyclic compound, the method of the pharmacological activity, the method of inhibiting 5-lipoxygenase, inhibiting the production of lipid peroxides or lower blood sugar levels

 

(57) Abstract:

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts. The invention also relates to a method of pharmacological effects, the method of inhibiting 5-lipoxygenase, inhibiting the production of lipid peroxides or decrease in blood sugar levels. The invention can be used in medicine as a therapeutic agent. 3 S. and 54 C.p. f-crystals, 10 PL.

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The invention relates to substituted condensed heterocyclic compound or its pharmaceutically acceptable salt with an excellent increase insulin resistance effect, anti-inflammatory, immune-modulating effect, the Alda is ucirvine lipid peroxide, trigger action in respect peroxisome proliferating activated receptor (which hereinafter will be abbreviated as "PPAR"), antiosteoporosis action, antagonism to leukotrienes, action, promoting the formation of fat cells, effect, inhibiting the proliferation of cancer cells and calcium antagonism; to pharmaceutical compositions containing as an effective ingredient the above-mentioned substituted condensed heterocyclic compound or its pharmacologically acceptable salt; to the application of the aforementioned substituted condensed heterocyclic compound or its pharmacologically acceptable salts, pharmaceutical compositions; to a method of prophylaxis or treatment of diabetes or similar diseases, which includes the introduction of an effective amount of the above-mentioned substituted condensed heterocyclic compound or its pharmacologically acceptable salt warm-blooded animal; or a pharmaceutical composition obtained by using, in combination, the above substituted condensed heterocyclic compound or its pharmacologically acceptable salt and at least real is, latinovich basic compounds, inhibitors of the synthesis of squalene, fibrotic basic compounds, promoters catabolism of LDL and inhibitors of the angiotensin converting enzyme.

[Background of invention]

It was reported that thiazolidinone connection oxazolidinone compounds and the like can be used as prophylactic agents and/or drugs for various diseases, such as diabetes and hyperlipidemia (high content of fat in the blood).

For example, the number of thiazolidinone compounds with hypoglycemic action described in Chem. Pharm. Bull., 30, 3580-3600 (1982), Prog. Clin. Biol. Res., 265, 177-192 (1988), Diabetes, 37(11), 1549-1558 (1988), Arzneim. - Forsch., 40(1), 37-42 (1990), ERA and the like.

Action thiazolidinone compounds against hyperlipidemia described in Diabetes, 40(12), 1669-1674 (1991), Am. J. Physiol., 267 (1 Pt 1), E95-E101 (1994), Diabetes, 43(10), 1203-1210 (1994) and things like that.

Action thiazolidinone compounds in respect of insufficiency glucose tolerance and insulin resistance are described in Arzneim-Forsch., 40 (2 Pt 1), 156-162 (1990), Metabolism, 40(10), 1025-1230 (1991), Diabetes, 43(2), 204-211 91994) and the like.

Recently in N. Engl. J. Med., 331(18), 1226-1227 (1994) it was reported that a normal person with carstone tool for improving insulin resistance can be used as a prophylactic agent in the early stages of diabetes in such a normal person.

Action thiazolidinone connections on hypertension described in Metabolism, 42(1), 75-80 (1993), Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1933), Diabetes, 43(2), 204-211 (1994) and things like that.

Action thiazolidinone connections on coronary artery disease described in Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1933), Hypertension, 24(2), 170-175 (1994) and things like that.

Action thiazolidinone connections on arteriosclerosis described in Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1933), and the like.

Action thiazolidinone connections on cachexia (severe wasting) described in Endocrinology, 135(5), 2279-2282 (1994), Endocrinology, 136(4), 1474-1481 (1995) and things like that.

From thiazolidinone compounds with hypoglycemic action, compounds containing heterocyclic group described in W092/07839A, W092/07850A and ERA.

In addition, derivative oxazolidin-2,4-dione, having a hypoglycemic action, described in W092/02520A and the like.

In W092/03425A described that compounds containing 3,5-dioxoimidazolidin-2-imlilfinishing or N-hydroxyurea group, possess hypoglycemic action.

In ERA 5-{4-[5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-3H-imidazo[4,5-b] pyridine-2-ylethoxy] benzyl} thiazolidine-2,4-dione is described only as one of the synthesis of some substituted condensed heterocyclic compounds and their pharmacological activity, the authors present invention installed, what a substituted condensed heterocyclic compound, having a new structure, excellent action, increase insulin resistance, inflammatory, immune-modulating action, illegitimatize-inhibitory action of 5-lipoxygenase-inhibiting action, action, inhibiting the production of lipid peroxide, trigger action in relation to PPAR, antiosteoporosis action, antagonism to leukotrienes, action, promoting the formation of fat cells, effect, inhibiting the proliferation of cancer cells, and calcium antagonism; has reduced side effects; and, in addition, has a high solubility in fats.

Another object of the present invention is a prophylactic and/or medicinal products that contain as an effective ingredient previously described substituted condensed heterocyclic compound or its pharmacologically acceptable salt, diseases, facilitate the above types of actions, such as diabetes, hyperlipidemia, adiposity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (Naples, gestational diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. coronary heart disease and the like), cell damage (e.g., brain damage caused by stroke, and the like), induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g., epiphyseal osteomyelitis, pain, fever, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergies, asthma, gastrointestinal ulcer, cachexia, autoimmune disease, pancreatitis and the like), cancer, osteoporosis and cataracts.

Another object of the present invention is a pharmaceutical composition (particularly suitable is a prophylactic and/or medication for diabetes or diabetic complications), obtained using, in combination, the above-described substituted condensed heterocyclic compound or its pharmacologically acceptable salt and at least one compound selected from inhibitors-glucosidase, inhibitors illegitimates, drugs biguanide, latinovich basic compounds, inhibitors of the synthesis of squalene, fiber is="ptx2">

In the present invention substituted condensed heterocyclic compound shown by the following formula (I):

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where R1represents a group of the following formula:

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or a group of the following formula:

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[in which R4represents a phenyl group which is substituted by 1-5 substituents selected from substituents , or pyridyloxy group which may be substituted by 1-4 substituents selected from substituents ,

R5represents a hydrogen atom or a Deputy selected from the substituents ,

R6represents a hydrogen atom, a C1-6alkyl group, a C6-10aryl group which may be substituted by 1-3 substituents selected from substituents , or C7-16aracelio group which may be substituted by 1-3 substituents selected from substituents ,

D represents an oxygen atom or sulfur and

E represents a CH group or a nitrogen atom],

R2represents a hydrogen atom or a Deputy selected from the substituents ,

R3represents a group having the following formula:

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or

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A represents C1-6alkylenes group and

In represents an oxygen atom or the toxi]benzyl}thiazolidine-2,4-dione is excluded].

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Halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6allylthiourea, amino group which may be substituted by substituents selected from the substituents of group C3-10cycloalkyl,6-10aryl, C7-16aralkyl, C6-10aryloxy, C7-16aralkylated and C6-10aaltio, each of which may be substituted by 1-3 substituents selected from substituents C1-7the aliphatic alloctype, 4-7-membered saturated nitrogen-containing heterocyclic group, 5 - or 6-membered aromatic nitrogen-containing heterocyclic group, the nitro-group and cyano.

<Deputy >

Halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, amino group which may be substituted by substituents selected from substituents C6-10aryl group and the nitro-group.

<Deputy >

C1-10alkyl group and C6-10aryl and C7-16kalkilya groups, each of which may have a Deputy, and acyl group which may have substituents (specified ACI is B>8-12aromatic aliphatic acyl, C4-11cycloalkylcarbonyl or 5 - or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group, each of which may have substituents).

In the above description of examples of the "halogen atom" in the definition of the substituents include fluorine atoms, chlorine, bromine and iodine, among which fluorine atoms and chlorine are preferred.

In the above description, "C1-6alkyl group" in the definition of R6and Vice , and represents a linear or branched C1-6alkyl group. Examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, 2-methylbutanol, neopentyl, 1-ethylpropyl, hexeline, 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-DIMET albuterol and 2-ethylbutyl group. When referring to R6preferred is C1-4alkyl group, in which more preferred C1-2alkyl group, and particularly preferred methyl gr reference to the substituents methyl, ethyl and tert-bucilina group are preferred.

In the above description of "halogen(C1-6alkyl) group" in the definition of substituents and is illustrated above C1-6alkyl group having associated with it one to three illustrated above halogen atoms. Examples include triptoreline, trichlorethylene, tribromaniline, deformational, dichlorethylene, dibromoethylene, formeterol, 2,2,2-trichlorethylene, 2,2,2-triptoreline, 2-bromatology, 2-chloraniline, 2-foretelling, 2-iodation, 3-chloropropylene, 4-terbutaline, 6-idexilu and 2,2-dibromoethylene groups, among which the preferred halogen(C1-2alkyl) group, and particularly preferred triptorelin group.

In the above description, "C1-6alkoxygroup" in the definition of substituents and represents the previously described C1-6the alkyl group attached to an oxygen atom. Examples include methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, isopentane, 2-methylbutoxy, neopentane, 1 ethylpropoxy, hexyloxy, 4-methylphenoxy, 3 methylpentane, 2-methylpentane, 3,3-Dimethylbutane, 2,2-di where C1-2alkoxygroup is preferred, and particularly preferred methoxy group.

In the above description, "C1-6allylthiourea" in the definition of substituents and is illustrated above C1-6the alkyl group attached to a sulfur atom. Examples include methylthio group, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, 2-methylbutyl, neopentyl, 1 ethylpropyl, hexylthio, 4-methylphenylthio, 3 methylphenylthio, 2-methylphenylthio, 1 methylpentyl, 3,3-dimethylbutyl, 2, 2 dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2 ethylbutyl, among which C1-2allylthiourea is preferred, and particularly preferred methylthiourea.

In the above description of the "amino group which may be substituted by the Deputy selected from substituents" in the definition of each of the Vice and means amino group which may be substituted by 1 or 2 substituents which are the same or different and selected from substituents including C1-10alkyl group, a C6-10aryl and C7-16kalkilya group, Kajsa from halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6alkylthio groups), acyl groups which may have substituents, each of which means C1-7aliphatic acyl group, or WITH7-11aromatic acyl, C8-12aromatic-aliphatic acyl, C4-11cycloalkylcarbonyl or 5 - or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group which may be substituted by 1-3 substituents selected from the group consisting of halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6alkylthio groups).

In the above description, "C1-10alkyl group" in the description of the substituents means a linear or branched alkyl group having from 1 to 10 carbon atoms, and examples include illustrated above C1-6alkyl group, heptylene, 1-methylhexane, 2-methylhexane, 3-methylhexane, 4-methylhexane, 5-methylhexane, 1-propylethylene, 4,4-dimethylpentyl, octillo, 1-methylheptane, 2-methylheptane, 3-methylheptane, 4-methylheptane, 5-methylheptane, 6-methylheptanoic, 1-propylpentyl, 2-ethylhexyl, 5,5 is exiling, 2-etilefrine, 6,6-dimethylheptyl, decile, 1-methylnonane, 3-methylnonane, 8-methylnonane, 3-atrakcyjny, 3,7-dimethyloctyl and 7.7-dimethyloctyl group, among which preferred C1-8alkyl group, and a methyl, bucilina, isobutylene, pentilla, hexeline, Reptilia and anjilina group are particularly preferred.

In the above description6-10aryl part WITH6-10aryl group which may have a substitute, in the definition of substituents means6-10aromatic hydrocarbon group, and examples include phenyl, indenolol and naftalina group, among which preferred phenyl groups.

In the above description of C7-16kalkilya part "C7-16aranceles group which may have a substitute, in the definition of substituents means described above WITH6-10aryl group associated with the previously described C1-6alkyl group, and examples include benzyl, naphthylmethyl, intermational, diphenylethylene, 1-fenetylline, 2-fenetylline, 1-naphthylethylene, 2-naphthylethylene, 1-phenylpropanol, 2-phenylpropyl, 3-phenylpropyl, 1-afterripening, 2-afterripening, 3-napolillo, 3-NativeWindow, 4-NativeWindow, 5-phenylpentane, 5-naphthylmethyl, 6-phenylhexanoic and 6-artilheiro group, among which preferred benzyl group.

In the above description, "C1-7aliphatic acyl group" in the definition of substituents means a hydrogen atom or a saturated or unsaturated hydrocarbon group with a C1-6the circuit associated with the carbonyl group, and examples include formyl, acetyl, propionyl, butyryloxy, isobutyryloxy, valerino, isovaleryl, pivaloyl, hexanoyl, acryloyloxy, methacryloyloxy and crotonoyl groups, among which the preferred acetyl, propylaniline and pivellina group, and particularly preferred acetyl group.

In the above description7-11aromatic acyl part "C7-11aromatic acyl group which may have substituents" in the definition of substituents means6-10the aryl group attached to a carbonyl group, and examples include benzoyloxy, 1-indocarbocyanine, 2-indocarbocyanine and 1 - and 2-naphthoylene group, among which preferred benzoline and napolina group.

In the above description With2-6aliphatic acyl group, and examples include phenylacetylene, 3-phenylpropionyl, 4-phenylbutyramide, 5-phenylmethanol and 6-phenylmethanol group, among which phenylacetylene group is preferred.

In the above description4-11cycloalkylcarbonyl part "C4-11cycloalkylcarbonyl group which may have substituents" in the definition of substituents means3-10cycloalkyl group (which means 3-10-membered saturated cyclic hydrocarbon group which may be condensed, and examples include cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptanol, norbornylene and adamantly group, among which preferred3-6cycloalkyl group) associated with the carbonyl group, and examples include cyclopropanol, cyclobutanol, Cyclopentanol, cyclohexanol, cyclohexylcarbonyl, norbinaltorphimine and adamantylidene group, among which preferred4-7cycloalkylcarbonyl group, and particularly preferred is an aromatic nitrogen-containing heterocyclic carbonyl part of a 5 - or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group, which may have substituents" in the definition of substituents means 5 - or 6-membered aromatic heterocycle that contains at least one nitrogen atom and at the same time, may contain additional heteroatoms selected from the group of heteroatoms consisting of nitrogen atom, oxygen atom and sulfur atom (examples of such heterocycles include pyrrolidino, imidazolidinyl, pyrazolidine, triazolyl, tetrazolyl, pyridyloxy, personilnya, pyrimidinyl, pyridazinyl, thiazolidine, oxazolidine, oxadiazolyl and thiadiazolyl group) associated with the carbonyl group, and examples include pyrrolidinedione, imidazoledicarbonitrile, pyrazolecarboxylate, triazolylmethyl, tetrachloroaniline, nicotinoyl, isonicotinoyl, pyrazinecarboxamide, pyrimidinecarbonitrile, pyridinecarboxylic, thiazolecarboxamide, oxazolidinyl, oxadiazolyl and cialisonlinenow group, among which preferred pyridylcarbonyl group, and particularly preferred nicotinoyl and isonicotinoyl group.

Examples of the "amino group which may be substituted by substituents selected from substituents" is amino, Deut-butylamino, tert-butylamino, pentylamine, hexylamine, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, diphenhydamine, digoxigenin, phenylamino, 2-, 3 - or 4-forfinally, 2-, 3 - or 4-chlorpheniramine, 2-, 3 - or 4-brompheniramine, 2,3-dipertanyakan, 2,4-dipertanyakan, 2,4-dichlorophenylamino, 1 - or 2-Ingenierie, 1 - or 2-naphthylamine, diphenylamine, benzylamine, 2-, 3 - or 4-forbindelsen, 2-, 3 - or 4-chlorobenzylamino, 2-, 3 - or 4-bromobenzylamine, 2,3-diferentiating, 2,4-diferentiating, 2,4-dichloraniline, 1 - or 2-naphthylenediamine, 1 intermetallide, 1 - or 2-phenethylamine, 1-, 2 -, or 3-phenylpropylamine, 4-phenylbutyramide, 1 phenylethylamine, 5-phenylenediamine, 6-phenylendiamine, dibenzylamino, formylamino, acetylamino, propionamido, bucillamine, isobutylamino, Valeriano, isovaleramide, paulolino, hexanamine, acrylamido, methacrylamido, crotonylene, benzoylamine, 1 indocarbocyanine, 1 - or 2-naphthylamine, 2-, 3 - or 4-perbenzoate, 2-, 3 - or 4-chlorobenzylamino, 2-, 3 - or 4-bromobenzylamine, 2,3-differentiating, 2,4-differentiating, 2,4-dichloraniline, 2,6-diisopropylethylamine, 4-triphtalocyaninine, 4-hydroxy-3,5-dimethylbenzylamine, 4-is pinellino, 4 phenylbutyramide, 5-phenylenediamine, 6-phenylhexanoic, 2-, 3 - or 4-perforazione, 2-, 3 - or 4-chlorophenylalanine, 2-, 3 - or 4-bromophenylacetate, 2,3-differentiationin, 2,4-differentiationin, 2,4-dichlorophenylamino, cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine, pyrrolidinedione, imidazolecarboxamide, pyrazolecarboxylate, thiazolecarboxamide, tetrachloroaniline, nicotianamine, isonicotinamide, pyrazinecarboxamide, pyrimidinecarbonitrile, pyridinecarboxamide, thiazolecarboxamide, oxazolidinedione, oxadiazolidine, thiadiazolidine, N, N-diatsetilamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamine, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N-benzene-N-butylamino, N-benzoyl-N-pentylamine, N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamine, N-4-trifloromethyl-N-2,4-differentiating, N-2,4-diferensial-N-nicotianamine, N-3-chlorobenzoyl-N-methylamino, N-3-chlorobenzoyl-N-hexylamino, N-3-Chlorobenzyl-N-acetylamino, N-2,4-ditto the-butylamino, N-3,5-di-tert-butyl-4-hydroxybenzoyl-N-hexylamino, N-hexyl-N-1 naphthylamine, N-hexyl-N-2-naphthylamine, N-hexyl-N-phenylacetylamino, N-isobutyl-N-cyclopentylamine, N-butyl-N-nicotianamine, N-hexyl-N-nicotianamine and N-isonicotinoyl-N-hexylamino group, among which preferred amino group, substituted by one or two substituents (the substituents may be the same or different, and each independently represents a group selected from the class consisting of C1-10alkyl groups and C6-10aryl and C7-16Uralkalij groups, each of which may have substituents) and alluminare, which can be substituted by the Deputy selected from substituents (alluminare means an amino group substituted previously described acyl group); more preferred amino, mono - or di-C1-10alkylamino and alluminare, each of which may be substituted C1-10alkyl group or a C7-16aranceles group which may have a Deputy; even more preferred amino, mono - or di-C1-10alkylamino or7-11aromatic acylamino,4-11cycloalkylcarbonyl and 5 - or 6-membered aromatic nitrogen-containing Goethe who are amino, dimethylamino, hexylamino, acetylamino, benzoylamine, 3 chlorobenzylamino, 2,4-differentiating, 4-hydroxy-3,5-di-tert-butylbenzylamine, naphthylamine, cyclopentylamine, cyclohexylamine, nicotianamine, isonicotinamide, N-acetyl-N-hexylamino, adamantylidene group.

WITH3-10cycloalkyl part "C3-10cycloalkyl group which may be substituted by 1-3 substituents selected from substituents ", has the same meaning as previously described. Preferred examples include3-10cycloalkyl groups, each of which may be substituted by one Deputy, selected from substituents including3-10cycloalkyl groups, each of which may be substituted by one Deputy, selected from the group comprising halogen atoms and C1-6alkyl and halogen (C1-6alkyl) group; more preferred group of Adamantine, which can be substituted by one fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, tert-butilkoi group, triptorelin group, methoxy group, amino group, methylaminopropane or dimethylaminopropoxy; and especially preferred group of adamantyl.

6and deputies and such, "6-10aryl group" in the definition of the substituents has the same meaning as previously described. As R6preferred phenyl groups which may be substituted by 1-3 substituents selected from the group consisting of halogen atoms and hydroxyl, C1-6alkyl and halogen (C1-6alkyl) groups, and particularly preferred phenyl groups, each of which may be substituted by one Deputy, selected from the group consisting of fluorine atoms and chlorine, hydroxyl, methyl, ethyl and triptoreline groups. With reference to the preferred substituents are6-10aryl group, each of which may be substituted by one Deputy, selected from substituents ; more preferred C6-10aryl group, each of which may be substituted with one amino group may be substituted by a halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup or Deputy selected from substituents ; even more preferred phenyl groups, which may Beth butilkoi group, triptorelin group, methoxy group, amino group, methylaminopropane or dimethylaminopropoxy; and particularly preferred phenyl or 4-hydroxyproline group. With reference to substituents , preferred is a phenyl group.

In the above description of C7-16kalkilya part "C7-16aranceles group which may be substituted by 1-3 substituents selected from substituents " in the definition of R6or Deputy has the same meaning as previously described. When referring to R6the preferred benzyl group which may be substituted by 1-3 substituents selected from the group consisting of halogen atoms and hydroxyl, C1-6alkyl and halogen(C1-6alkyl) groups, and particularly preferred benzyl group which may be substituted by the Deputy selected from the group comprising fluorine atoms and chlorine atoms, and hydroxyl, methyl, ethyl and triptorelin group. With reference to the Deputy preferred are C7-16kalkilya groups, each of which may be substituted by one Deputy, selected from substituents ; more preferred benzyl group which may be substituted amino group, knymi group, halogen (C1-6alkyl) group, a C1-6alkoxygroup and deputies ; even more preferred are benzyl group which may be substituted by one fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, tert-butilkoi group, triptorelin group, methoxy group, amino group, methylaminopropane or dimethylaminopropoxy; and especially preferred benzyl group.

In the above description6-10aryloxy part "C6-10aryloxy group which may be substituted by 1-3 substituents selected from substituents " means previously described WITH6-10the aryl group attached to an oxygen atom, and examples include phenoxy, 1 inderalici, 2-inderalici, 3 inderalici, 1 naphthyloxy and 2 naphthyloxy groups, including fenoxaprop are preferred.

In the above description of C7-16aralkylated part "C7-16aralkylated group which may be substituted by 1-3 substituents selected from substituents " in the definition of substituents means previously described C7-16aracelio group associated with the oxygen atom, and examples include benzyloxy, aftermarket, intermetalic, defineproperty, 1 naftemporiki, 2-naftemporiki, 3 naftemporiki, 1 phenylmethoxy, 2-phenylbutane, 3 phenylmethoxy, 4-phenylbutane, 1 natterbox, 2-natterbox, 3 natterbox, 4-natterbox, 5-phenylpentane, 5-naftemporiki, 6-phenylhexanoic and 6 afterexecute group, among which preferred are benzyloxy.

In the above description6-10aaltio part "C6-10aristocraty, which may be substituted by 1-3 substituents selected from substituents " means previously described WITH6-10aryl group associated with the sulfur atom, and examples include phenylthio, 1 indenity, 2-indenity, 3 indenity, 1 naphthylthio and 2-naphthylthiourea, among which preferred phenylthiourea.

In the above description, "C1-7the aliphatic alloctype" in the definition of the substituents is an illustrated above C1-7aliphatic acyl group linked to the oxygen atom. Examples include formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeriote, isovalerianic, pivaloyloxy, hexanoate, acryloyloxy, methacryloyloxy, crotonville group, among which preferred are acetochlor.

In the above description of the "5 - or 6-membered aromatic nitrogen-containing heterocyclic group" in the definition of the substituents has the same meaning as defined above, and preferable are imidazolidine, tetrataenia and pyridinoline groups, among which the group pyridine-2-yl and pyridin-3-yl is particularly preferred.

In the above description of the "phenyl group substituted by 1-5 substituents selected from substituents" in the definition of R4represents a phenyl group substituted by 1-5 substituents selected from the group which includes halogen atoms; hydroxyl groups; C1-6alkyl group, GoLoG is, which can be substituted by the Deputy, selected from substituents ; WITH3-10cycloalkyl,6-10aryl, C7-16kalkilya, C6-10aryloxy, C7-16aralkylated and C6-10aaltio groups, each of which may be substituted by 1-3 substituents selected from substituents ; C1-7aliphatic alloctype; 4-7-membered saturated nitrogen-containing heterocyclic group; a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group; nitro group and ceanography. Examples include 2-, 3 - or 4-forfinal, 2-, 3 - or 4-chlorophenyl, 2-, 3 - or 4-bromophenyl, 2-, 3 - or 4-itfeel, 2,4-differenl, 3,5-differenl, pentafluorophenyl, 3,5-dichlorophenyl, 2-, 3 - or 4-hydroxyphenyl, 3,5-dihydroxyphenyl, 2-, 3 - or 4-were, 2-, 3 - or 4-ethylphenyl, 2-, 3 - or 4-propylphenyl, 2-, 3 - or 4-isopropylphenyl, 2-, 3 - or 4-butylphenyl, 2-, 3 - or 4-second-butylphenyl, 2-, 3 - or 4-tert-butylphenyl, 2-, 3 - or 4-triptoreline, 2-, 3 - or 4-methoxyphenyl, 2-, 3 - or 4-ethoxyphenyl, 2-, 3 - or 4-propoxyphenyl, 2-, 3 - or 4-isopropoxyphenyl, 2-, 3 - or 4-butoxyphenyl, 2-, 3 - or 4-second-butoxyphenyl, 2-, 3 - or 4-tert-butoxyphenyl, 2-, 3 - or 4-methylthiophenyl, 2-, 3 - or 4-ethylthiophene, 2-, 3 - or 4-isopropylphenyl, 2-, 3 - or 4-AMINOPHENYL, 3,5-diaminophenol, 2-, 3 - or 4 - methylaminophenol, 2-, 3 - or 4-dimethylaminophenyl, 2-, 3 - or 4-(N-the l 2-, 3-or 4-feniletinil, 2-, 3 - or 4-benzylaminopurine, 2-, 3-or 4-formylamino, 2-, 3 - or 4-acetylaminophenol, 2-, 3-or 4-propionylcarnitine, 2-, 3 - or 4-benzoylmethyl, 2-, 3 - or 4-(2-, 3 - or 4-perbenzoate)phenyl, 2-, 3 - or 4-(2-, 3 - or 4-chlorobenzylamino)phenyl, 2-, 3 - or 4-(2,4-differentiating)phenyl, 2-, 3 - or 4-(4-hydroxy-3,5-dimethylbenzylamine)phenyl, 2-, 3 - or 4-(4-hydroxy-3,5-di-tert-butylbenzylamine)phenyl, 2-, 3 - or 4-(1 - or 2-naphthylamine)phenyl, 2-, 3 - or 4-phenylacetylamino, 2-, 3 - or 4-(2-, 3 - or 4-perforazione)phenyl, 2-, 3 - or 4-(2-, 3 - or 4-chlorophenylalanine)phenyl, 2-, 3 - or 4-(3-phenylpropionylamino)phenyl, 2-, 3 - or 4-cyclopentanemethanol, 2-, 3 - or 4-cyclohexanedimethanol, 2-, 3 - or 4-nicotinelibido.html, 2-, 3 - or 4-isonicotinamide, 2-, 3 - or 4-(N-acetyl-N-methylamino)phenyl, 2-, 3 - or 4-(N-acetyl-N-pentylamine)phenyl, 2-, 3 - or 4- (N-acetyl-N-hexylamino)phenyl, 2-, 3 - or 4-(N-benzoyl-N-hexylamino)phenyl, 2-, 3 - or 4-(N-3-chlorobenzoyl-N-methylamino)phenyl, 2-, 3 - or 4-(N-3-chlorobenzoyl-N-hexylamino)phenyl, 2-, 3 - or 4-(N-2,4-diferensial-N-hexylamino)phenyl, 2-, 3 - or 4-[N-(1 - or 2-naphtol)-N-hexylamino] phenyl, 2-, 3 - or 4-(N-hexyl-N-phenylacetylamino)phenyl, 2-, 3 - or 4-(N-isobutyl-N-cycloheptanol)amino)phenyl, 2-, 3 - or 4-(N-butyl-N-nicotianamine)phenyl, 2-, 3-or 4-(2'-, 3'- or 4'-hydroxy)biphenylyl, 2-, 3 - or 4-(4-hydroxy-3, 5dimethylphenyl)phenyl, 2-, 3 - or 4-(4-hydroxy-3,5-diisopropylphenyl)phenyl, 2-, 3 - or 4-(3,5-di-tert-butyl-4-hydroxyphenyl)phenyl, 2-, 3 - or 4-benzylphenol, 2-, 3 - or 4-(4-hydroxybenzyl)phenyl, 2-, 3 - or 4-(4-hydroxy-3,5-dimethylbenzyl)phenyl, 2-, 3 - or 4-(3,5-di-tert-butyl-4-hydroxybenzyl)phenyl, 2-, 3 - or 4-phenoxyphenyl, 2-, 3 - or 4-(4-hydroxyphenoxy)phenyl, 2-, 3 - or 4-(4-hydroxy-3,5-dimethylphenoxy)phenyl, 2-, 3 - or 4-(3,5-di-tert-butyl-4-hydroxyphenoxy)phenyl, 2-, 3 - or 4-benzyloxyphenyl, 2-, 3-or 4-(4-hydroxyethyloxy)phenyl, 2-, 3 - or 4-(4-hydroxy-3,5-dimethylsiloxy)phenyl, 2-, 3 - or 4-(3,5-di-tert-butyl-4-hydroxyethyloxy)phenyl, 2-, 3 - or 4-phenylthiophene, 2-, 3 - or 4-(4-hydroxyphenethyl)phenyl, 2-, 3 - or 4-(3,5-dimethyl-4-hydroxyphenethyl)phenyl, 2-, 3 - or 4-(3,5-di-tert-butyl-4-hydroxyphenethyl)phenyl, 2-, 3 - or 4-formyloxyethyl, 2-, 3 - or 4-acetoxyphenyl, 2-, 3 - or 4-propionyloxy, 2-, 3 - or 4-(1-azetidine)phenyl, 2-, 3 - or 4-(1-, 2 - or 3-pyrrolidinyl)phenyl, 2-, 3 - or 4-(1-, 2-, 3- or 4-piperidinyl)phenyl, 2-, 3 - or 4-(2-, 3 - or 4-morpholinyl)phenyl, 2-, 3 - or 4-(2-, 3 - or 4-thiomorpholine)phenyl, 2-, 3 - or 4-(1 - or 2-piperazinil)phenyl, 2-, 3 - or 4-(1-, 2 - or 4-imidazolyl)phenyl, 2-, 3 - or 4-(tetrazol-5-yl)phenyl, 2-, 3-or 4-(2-, 3 - or 4-pyridyl)phenyl, 2-, 3 - or 4-nitrophenyl, 2-, 3 - or 45-dimetilfenil, 3-fluoro-5-hydroxy-2,6-dimetilfenil, 4-fluoro-3-hydroxy-2,5-dimetilfenil, 2-chloro-4-hydroxy-3, 5dimethylphenyl, 3-chloro-5-hydroxy-2,6-dimetilfenil, 4-chloro-3-hydroxy-2,5-dimetilfenil, 2 - or 3-amino-4-chlorophenyl, 2,3-dichloro-4-AMINOPHENYL, 2 -, or 3-chloro-4-methylaminophenol, 2-hydroxy-3 - or 4-were, 2-hydroxy-3,4-dimetilfenil, 3-hydroxy-4 - or 5-were, 3-hydroxy-2,4-dimetilfenil, 4-hydroxy-2 - or 3-were, 2 - or 3-ethyl-4-hydroxyphenyl, 4-hydroxy-2 - or 3-propylphenyl, 4-hydroxy-2 - or 3-isopropylphenyl, 2 - or 3-tert-butyl-4-hydroxyphenyl, 4-hydroxy-2,3-dimetilfenil, 4-hydroxy-2,5-dimetilfenil, 4-hydroxy-3, 5dimethylphenyl, 3,5-diethyl-4-hydroxyphenyl, 3-tert-butyl-4-hydroxy-5-were, 4-hydroxy-3,5-DIPROPYLENE, 4-hydroxy-3,5-diisopropylphenyl, 2,5-di-tert-butyl-4-hydroxyphenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-hydroxy-2,3,5-trimetilfenil, 4-hydroxy-2,3,6-trimetilfenil, 4-hydroxy-2,3,5,6-tetramethylene, 4-hydroxy-3,5-acid, 2 - or 3-hydroxy-4-dimethylaminophenyl, 4-benzyl-(2 - or 3-hydroxy)phenyl, 3-, 5 - or 6-benzyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 3-amino-4-were, 4-amino-2,3-dimetilfenil, 4-amino-2,6-dimetilfenil, 4-amino-3, 5dimethylphenyl, 4-amino-3,5-diethylphenyl, 4-amino-3,5-DIPROPYLENE, 4-amino-3,5-diisopropylphenyl, 4-amino-3,5-di-tert-butylamino-3,5-di-tert-butylphenyl, 4 benzoylamino-3, 5dimethylphenyl, 4-acetoxy-3, 5dimethylphenyl, 4-acetoxy-2,3,5-trimetilfenil and 3,5-dimethyl-4-nitrophenyl group.

In the above description of "Peregrina group which may be substituted by 1-4 substituents selected from substituents" in the definition of R4represents pyridyloxy group which may be substituted by 1-4

substituents selected from the group comprising halogen atoms; hydroxyl groups; C1-6alkyl groups, halogen (C1-6alkyl) group; C1-6alkoxygroup; C1-6ancilliary; amino groups, each of which may be substituted by the Deputy selected from substituents ; WITH3-10cycloalkyl,6-10aryl, C7-16kalkilya,6-10aryloxy, C7-16aralkylated and C6-10aaltio groups, each of which may be substituted by 1-3 substituents selected from substituents ; C1-7aliphatic alloctype; 4-7-membered saturated nitrogen-containing heterocyclic group; a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group; nitro group and ceanography.

Examples include 2-, 3 - and 4-pyridyl, 3-, 4-, 5 - and 6-fluoro-2-pyridyl, 2-, 4-, 5 -, or 6-fluoro-3-pyridyl, 2 - or 3-fluoro-4-pyridi the 6-bromo-3-pyridyl, 2 - or 3-bromo - 4-pyridyl, 3-, 4-, 5 - or 6-iodine-2-pyridyl, 2-, 4-, 5 - or 6-iodine-3-pyridyl, 2 - or 3-iodine-4-pyridyl, 3-, 4-, 5 - and 6-hydroxy-2-pyridyl, 2-, 4-, 5 - or 6-hydroxy-3-pyridyl, 2 - or 3-hydroxy-4-pyridyl, 3-, 4-, 5 - and 6-methyl-2-pyridyl, 2-, 4-, 5 - or 6-methyl-3-pyridyl, 2 - or 3-methyl-4-pyridyl, 3,5-dimethyl-4-pyridyl, 3-, 4-, 5 - and 6-ethyl-2-pyridyl, 2-, 4-, 5 - or 6-ethyl-3-pyridyl, 2 - or 3-ethyl-4-pyridyl, 3,5-diethyl-4-pyridyl, 3-, 4-, 5 - and 6-propyl-2-pyridyl, 2-, 4-, 5 - or 6-propyl-3-pyridyl, 2 - or 3-propyl-4-pyridyl, 3,5-dipropyl-4-pyridyl, 3-, 4-, 5 - and 6-isopropyl-2-pyridyl, 2-, 4-, 5 - or 6-isopropyl-3-pyridyl, 2 - or 3-isopropyl-4-pyridyl, 3,5-aminobutiramida 4-pyridyl, 3-, 4-, 5 - and 6-tert-butyl-2-pyridyl, 2-, 4-, 5 - or 6-tert-butyl-3-pyridyl, 2 - or 3-tert-butyl-4-pyridyl, 3,5-di-tert-butyl-4-pyridyl, 3-, 4-, 5 - and 6-trifluoromethyl-2-pyridyl, 2-, 4-, 5 - or 6-trifluoromethyl-3-pyridyl, 2 - or 3-trifluoromethyl-4-pyridyl, 3-, 4-, 5 - and 6-methoxy-2-pyridyl, 2-, 4-, 5 - or 6-methoxy-3-pyridyl, 2 - or 3-methoxy-4-pyridyl, 3-, 4-, 5 - and 6-ethoxy-2-pyridyl, 2-, 4-, 5 - or 6-ethoxy-3-pyridyl, 2 - or 3-ethoxy-4-pyridyl, 3-, 4-, 5 - and 6-propoxy-2-pyridyl, 2-, 4-, 5 - or 6-propoxy-3-pyridyl, 2 - or 3-propoxy-4-pyridyl, 3-, 4-, 5 - and 6-isopropoxy-2-pyridyl, 2-, 4-, 5 - or 6-isopropoxy-3-pyridyl, 2 - or 3-isopropoxy-4-pyridyl, 3-, 4-, 5 - and 6-tert-butoxy-2-pyridyl, 2-, 4-, 5 - or 6-tert-butoxy-3-pyridyl, 2 - or 3-tert-butoxy-4-FDI 6-amino-3-pyridyl, 2 - or 3-amino-4-pyridyl, 3-, 4-, 5 - and 6-methylamino-2-pyridyl, 2-, 4-, 5 - or 6-methylamino-3-pyridyl, 2 - or 3-methylamino-4-pyridyl, 5-phenylamino-2-pyridyl, 5-benzylamino-2-pyridyl, 5-acetylamino-2-pyridyl, 5-benzoylamino-2-pyridyl, 5-phenylacetylamino-2-pyridyl, 6-phenyl-2-pyridyl, 6-(4-hydroxyphenyl)-2-pyridyl, 6-(4-hydroxy-3, 5dimethylphenyl)-2-pyridyl, 6-(3,5-di - tert-butyl-4-hydroxyphenyl)-2-pyridyl, 6-benzyl-2-pyridyl, 6-(4-hydroxybenzyl)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylbenzyl)-2-pyridyl, 6-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-pyridyl, 6-phenoxy-2-pyridyl, 6-(4-hydroxyphenoxy) -2-pyridyl, 6-(4-haproxy-3,5-dimethylphenoxy)-2-pyridyl, 6-(3,5-di-tert-butyl-4-hydroxyphenoxy)-2-pyridyl, 6-benzyloxy-2-pyridyl, 6-(4-hydroxyethyloxy)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylbenzylamine)-2-pyridyl, 6-(3,5-di-tert-butyl-4-hydroxybenzoate)-2-pyridyl, 6-phenylthio-2-pyridyl, 6-(4-hydroxyphenyl)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylphenyl)-2-pyridyl, 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-pyridyl, 3-, 4-, 5 - and 6-formyloxy-2-pyridyl, 2-, 4-, 5 - or 6-formyloxy-3-pyridyl, 2 - or 3-formyloxy-4-pyridyl, 3-, 4-, 5 - and 6-acetoxy-2-pyridyl, 2-, 4-, 5 - or 6-acetoxy-3-pyridyl, 2 - or 3-acetoxy-4-pyridyl, 6-(1-pyrrolidinyl)-2-pyridyl, 6-(1-piperidinyl)-2-pyridyl, 6-(4-morpholinyl)-2-pyridyl, 3-, 4-, 5 - and 6-nitro-2-pyridyl, 2-, 4-, 5 - yl 6-methoxy-5-methyl-3-pyridyl, 6-methyl-2-nitro-3-pyridyl, 6-chloro-3-nitro-2-pyridyl, 6-methoxy-3-nitro-2-pyridyl, 6-isopropoxy-3-nitro-2-pyridyl, 6-tert-butoxy-3-nitro-2-pyridyl and 6-(4-hydroxy-3,5-dimethylphenoxy)-5-nitro-2-pyridyl.

As such peredelnoj group which may be substituted by 1-4 substituents selected from substituents ", are preferred peredelnye group which may be substituted by the following substituents (the substituents are halogen atoms, hydroxyl groups, C1-6alkyl groups, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6allylthiourea, an amino group which may be substituted by substituents selected from substituents ,and nitro group); more preferred are peredelnye group which may be substituted by the following substituents (the substituents are fluorine atoms, chlorine atoms, hydroxyl group, methyl group, ethyl group, tert-butylene group, triptoreline group, metoxygroup, amino, methylaminopropyl, dimethylaminopropyl and nitro); and especially preferred are peredelnye group.

In the above description, "C1-6Allenova group" in the definition is METROTILE, ethylene, propylene, trimethylene, mutilation, ethylethylene, tetramethylene, 1-metallisation, 2-metallisation, 3-metallisation, 1,1-dimethylethylene, pentamethylene, 1-methyltyramine, 2-methyltyramine, 3-methyltyramine, 4-methyltyramine, propylethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 5-methylpentanediol, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 4,4-dimethyltrimethylene, mutilation and isobutylamine, among which C1-4alkylene group are preferred, more preferred C1-2alkylene group and the most preferred methylene group.

The compound (I) according to the present invention can be converted into a salt by conventional means. Examples of such salts include alkali metal salts such as sodium salts, potassium salts and lithium salts; salts of alkaline earth metals such as calcium salt and magnesium salt; metal salts such as aluminum salts, iron salts, zinc salts, salts of copper, Nickel salts and cobalt salts; inorganic salts such as ammonium salts and salts organicheskikh amines, takeov phenylglycine, salt, Ethylenediamine salt, N-methylglucamine, guanidine salts, salts of diethylamine, salt, triethylamine salt dicyclohexylamine, salts of N,N'-dibenziletilendiaminom, salt chloroprocaine, salts of procaine, salt, diethanolamine, salts of N-benzyl-N-phenethylamine, salt, piperazine salt of Tetramethylammonium and salt of Tris(hydroxymethyl)aminomethane; hydrohalogenation salts such as salts formotorola acid, hydrochloride, hydrobromide and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates and phosphates, salts of lower alkanesulfonyl, such as methanesulfonate, triftoratsetata and econsultancy; arylsulfonate salts such as benzosulfimide and p-toluensulfonate; organic acid salts such as acetates, malaty, fumarate, succinate, citrates, tartratami, oxalates and maleate; and salts of amino acids such as infinity, glutamate and aspartate, among which hydrohalogenation salts and organic acid salts are preferred.

When the compound (I) of the present invention is left in air or recrystallized, it can absorb water or contain absorbed water associated with its surface, and sometimes go into the hydrate. All such solvate full what Yu can absorb some solvents and to form their solvate. Such a solvate is also ohvatyvayutsya the present invention.

In addition, compounds which are converted under physiological conditions to the corresponding compound (I) or its pharmacologically acceptable salt, that is, the so-called proletarienne funds are also included in the scope of the present invention.

In addition, compound (I) of the present invention has various isomers.

More specifically, when R3is 2,4-dioxothiazolidine-5-ylmethylene group (IV-2) or 2,4-dioxoimidazolidin-5-ylmethylene group (IV-3), it thiazolidinone or oxazolidinone ring has an asymmetric carbon atom at the 5-position, so that there are stereoisomers in the R-form and S-form. Each of the stereoisomers and mixture of stereoisomers in any proportion, are also covered by the present invention. In the case of such a stereoisomer of the compound (I) can be synthesized from optically separated raw materials or synthesized compound (I) can be optically separated, if necessary, conventional optical separation, or methods of separation.

When in the compound (I) of the present invention R3is 2,4-Deakin-2-ylmethylene group (IV-4), it is assumed that it exists in the form of various tautomers, and each of them, or their mixture in any proportion are encompassed by the present invention. Such isomers are, for example, illustrated in the end of the description (see the Isomers (I).

Examples of medicines that can form a pharmaceutical composition, when used in combination with compound (I) of the present invention or its pharmacologically acceptable salt include inhibitors of a-glucosidase inhibitors illegitimates, drugs biguanide, satinowye basic compounds, inhibitors of the synthesis of squalene, fibrate basic compounds, promoters catabolism of LDL and inhibitors of the angiotensin converting enzyme.

In the above description, the inhibitor-glucosidase is a drug, possess inhibitory activity against digestive enzyme such as amylase, maltase, -dextrinase or sucrase (saharso--glucosidase), thereby slowing the enzymatic hydrolysis of starch or sucrose. Their examples include acarbose, N-(1,3-dihydroxy-2-propyl)arylamine (common name: voglibose) and miglitol.

In the above description inhibitive stage Paleologo path of metabolism, inhibiting thus diabetic complications. Examples include tolrestat, epalrestat, 2,7-dipersio(N-fluoro-9,4'-imidazolidine)-2', 5'-dione (common name: ameristat), 3-[(4-bromo-2-forfinal)methyl] -7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-chinataiwan acid (common name: zenarestat), 6-fluoro-2,3-dihydro-2',5' -dioxaspiro[4H-1-benzopyran-4,4'-imidazolidine] -2-carboxamid (SNK-860), zopolrestat, sorbinil and 1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209).

In the above description of the drug biguanide is a drug that has effect, stimulating anaerobic glycolysis, enhances the action of insulin in peripheral blood flow, inhibiting the absorption of glucose in the intestines, inhibiting hepatic gluconeogenesis and inhibiting oxylene fatty acids, and examples include phenformin, Metformin and buformin.

In the above description statinova the primary connection is a drug that inhibits hydroxymethylglutaryl COA (HMG-CoA) reductase, reducing as a result, the level of cholesterol in the blood, and its examples include pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin and fluvastatin.

In the above description vibrate the primary connection is a drug for the inhibition of synthesis and secretion of triglycerides in the liver and activation of lipoprotein lipase, downward as a result, the level of triglycerides in the blood. Examples include bezafibrat, beclobrate, unifibre, ciprofibrate, clinofibrate, clofibrate, clofibrate acid, etofibrate, fenofibrate, gemfibrozil, micofiber, peripheral, ronifibrate, simfibrate and defibrate.

In the above description, the promoter of LDL catabolism is a drug to increase LDL (low-density lipoprotein) receptors, lowering thus the level of cholesterol in the blood, and examples include compounds described in the patent application of Japan Kokai Hei 7-316144, or their salts, more specifically, N-[2-[4-bis(4-forfinal)methyl-1-piperazinil] ethyl]-7,7-diphenyl-2,4,6-heptatriene amide.

In the above description satinowye basic compounds, inhibitors of the synthesis of squalene, fibrate basic connectivity and promoters LDL ka is whether the level of triglycerides. Examples of such drugs include drugs based on the derivatives of nicotinic acid, such as nicomol and niceritrol; antioxidants, such as probucol; and drugs of ion-exchange resins such as cholestyramine.

In the above description, the inhibitor of the angiotensin converting enzyme is a drug for inhibiting angiotensin converting enzyme, lowering the blood pressure and at the same time, the partial lowering of the blood sugar level of a patient suffering from diabetes. Examples include captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalapril, fosinopril, multiperil, perindopril, inapril, spirapril, temocapril and trandolapril.

When referring to compound (I) according to the present invention, preferred examples include a

(1) compounds where R1represents a group of formula (II),

(2) compounds where R2and R5are the same or different and represent a hydrogen atom, halogen atom, hydroxyl group, C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6allylthiourea where R2and R5are the same or different, and each represents a hydrogen atom, fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, triptorelin group, a methoxy group, metalcorp or amino group,

(4) compounds, where R2and R5each represent a hydrogen atom,

(5) compounds, where R3represents any one of the groups of formulae (IV-1) to(IV-3),

(6) compounds, where R3represents a group of formula (IV-2) to(IV-3),

(7) compounds, where R3represents a group of formula (IV-2),

(8) compounds, where R4is pyridyloxy group which may be substituted by one of the following substituents (Deputy represents a halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6allylthiourea, an amino group which may be substituted by substituents selected from substituents ,or a nitro-group),

(9) compounds, where R4is pyridyloxy group which may be substituted by one of the following substituents (Deputy represents a fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, tert-methylaminopropyl or nitrogroup),

(10) compounds having as R4pyridyloxy group

(11) compounds, where R4represents a phenyl group substituted by at least one Deputy, selected from the following substituents (the substituents include3-10cycloalkyl,6-10aryl and C7-16aracelio groups, each of which may be substituted by 1-3 substituents selected from substituents , 4-7-membered saturated nitrogen-containing heterocyclic group or a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group),

(12) compounds, where R4represents a phenyl group substituted by one of the following substituents (the substituents are3-10cycloalkyl,6-10aryl and C7-16aracelio group which may be substituted by one Deputy, selected from the substituents , 4-7-membered saturated nitrogen-containing heterocyclic group or a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group),

(13) compounds, where R4represents a phenyl group substituted by one of the following substituents (the substituents are3-10cycloalkyl,6-10aryl and C7-16aracelio group >-6alkyl) group, a C1-6alkoxygroup or amino group which may be substituted by substituents selected from substituents , 4-7-membered saturated nitrogen-containing heterocyclic group or a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group),

(14) compounds, where R4represents a phenyl group substituted by one of the following substituents (the substituents are phenyl or benzyl group which may be substituted by a halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup or amino group which may be substituted by substituents selected from substituents adamantly group, pyrrolidinyl group, morpholinyl group, piperidinyl group, imidazolidinyl group, tetrazolyl group or pyridinyl group),

(15) compounds, where R4represents a phenyl group substituted by one of the following substituents (Deputy represents phenyl or benzyl group which may be substituted by a fluorine atom, a chlorine atom, a hydroxyl group, methyl group, ethyl group, tert-butilkoi group, cryptoloop, pyrrolidinyloxy group, morpholinyl group, piperidinyl group, imidazolidinyl group, tetrazolyl group or pyridinyl group),

(16) compounds, where R4is 4-biphenylyl, 4-benzylphenol, 4'-hydroxybiphenyl, (pyrrolidin-1-yl)phenyl, (morpholine-4-yl)phenyl, (piperidine-1-yl)phenyl, (pyridin-2-yl)phenyl, (pyridin-3-yl)phenyl or 4-(1-substituted)phenyl group,

(17) compounds, where R4represents a phenyl group substituted by one allmineral, in which the amino fragment can be replaced by the additional Deputy selected from the substituents of the phenyl group may be further substituted by 1-3 substituents selected from the following substituents (the substituents include halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6allylthiourea),

(18) compounds, where R4represents a phenyl group substituted by one allmineral, in which the amino fragment can be substituted by the Deputy selected from the substituents of the phenyl group may be further substituted by 1-3 substituents selected from the following substituents (mixing the phenyl group, substituted with one allmineral, in which the amino fragment may be optionally substituted C1-10alkyl group or a C7-12aranceles group which may have substituents, and the said phenyl group may be further substituted by 1-3 C1-6alkyl groups),

(20) compounds, where R4represents a phenyl group substituted by one of the following substituents (Deputy is7-11aromatic acylamino,4-11cycloalkylcarbonyl or 5 - or 6-membered aromatic nitrogen-containing heterocyclic carbonylation, which may have substituents),

(21) compounds, where R4represents a phenyl group, substituted benzoylamine, 3 chlorobenzylamino, 2,4-differentiating, 4-hydroxy-3,5-di-tert-butylbenzylamine, naphthylamine, cyclopentylamine, cyclohexylamine, nicotianamine, isonicotinamide, N-acetyl-N-hexylamino or adamantylidene group

(22) compounds, where R4represents a phenyl group substituted with one amino, amino substituted with 1 or 2 substituents (the substituents are the same or different and each represents a group selected from C1-10the alkyl and1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6allylthiourea),

(23) compounds, where R4represents a phenyl group which is substituted with one amino, mono - or di(C1-10) alkyl) amino or cyano and, at the same time, may be substituted by 1 or 2 C1-6alkyl groups

(24) compounds, where R4is 4-aminoaniline, 4-amino-3,5-dimethylaniline, 4-amino-3,5-di-tert-butylphenyl, 3-or 4-dimethylaminopyridine or 4-cyanophenyl group

(25) compounds, where R4represents a phenyl group which is substituted WITH one6-10aryloxy, C7-16aralkylated or6-10aaltio group which may be substituted by 1-3 substituents selected from the substituents of the phenyl group may be further substituted by 1-3 substituents selected from the following substituents (the substituents consist of atoms of halogen and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6alkylthio groups)

(26) compounds, where R4represents a phenyl group which is substituted C6-1st group may be optionally substituted by 1-2 C1-6alkyl groups

(27) compounds, where R4represents a phenyl group, substituted C6-10arroceros, which may be substituted by one Deputy, substituents selected from ,

(28) compounds, where R4is 4-phenoxyphenyl group

(29) compounds, where R4represents a phenyl group substituted by 1-5 substituents selected from the following substituents (the substituents include halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy, C1-6alkylthio and C1-7aliphatic alloctype),

(30) compounds, where R4represents a phenyl group substituted by one halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6alkylthiophene or C1-7aliphatic alloctype, and the said phenyl group may be optionally substituted by 1-4 substituents, selected from the following substituents (the substituents include halogen atoms and C1-6alkyl or halo (C1-6alkyl) group),

(31) compounds, where R4represents a phenyl group substituted by one C1-6

(32) compounds, where R4represents a phenyl group substituted with one halogen (C1-2alkyl), C1-2alkoxy or C1-2alkylthio group or 1-5 fluorine atoms or chlorine atoms,

(33) compounds, where R4is 4-triftormetilfullerenov, 4-methylthiophenyl, 4-metoksifenilny or pentafluorophenyl group

(34) compounds, where R4represents a phenyl group which is substituted with one hydroxyl or C1-7aliphatic alloctype, and the said phenyl group may be further substituted by 1-3 substituents selected from the following substituents (the substituents include halogen atoms and C1-6alkyl group),

(35) compounds, where R4represents a phenyl group which is substituted by one hydroxyl group, and the said phenyl group may be further substituted by 1-3 substituents selected from the following substituents (the substituents include halogen atoms and C1-6alkyl group),

(36) compounds, where R4represents a phenyl group which is substituted by one hydroxyl group, and the said phenyl group may be further substituted by 1-3 substituents selected from the following Zam is where R4is 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylaniline, 4-hydroxy-3,5-di-tert-butylaniline, 4-hydroxy-2,3,5-trimethylphenyl or 2-chloro-4-hydroxy-3,5-dimethylphenyl group

(38) compounds, where R6represents a hydrogen atom, a C1-6alkyl group or phenyl or benzyl group which may be substituted by 1-3 substituents selected from the following substituents (the substituents include halogen atoms and hydroxyl, C1-6alkyl and halogen (C1-6alkyl) group),

(39) compounds, where R6represents a hydrogen atom, a C1-4alkyl group or phenyl or benzyl group which may be substituted by one of the following substituents (the substituents are fluorine atom, chlorine atom, hydroxyl group, methyl group or ethyl group),

(40) compounds, where R6represents a hydrogen atom or a C1-4alkyl group,

(41) compounds, where R6represents C1-2alkyl group,

(42) compounds, where R6represents a methyl group,

(43) connection, where a represents C1-4alkylenes group

(44) connection, where a represents C1-2alkylenes group

(45) connect the 7) connection, where D represents an oxygen atom,

(48) connection, where D represents a sulfur atom,

(49) compounds, where E represents CH group, and

(50) connections, where E represents a nitrogen atom.

Any combination of from two to nine groups selected from(1), (2)-(4), (5)-(7), (8)-(37), (38)-(42), (43)-(45), (46), (47)-(48) and (49)-(50) is also preferred.

Some compounds of the present invention are presented in tables 1-10. It should be borne in mind that the present invention is not limited. Each of the compounds in tables 1-10 has the structural formula (1-1) to (1-10) and are shown in tables abbreviations are as follows:

AC: acetyl group

Ada(1): 1-adamantly group

VI: bucilina group

sBu: second-bucilina group

tBu: tert-bucilina group

Bz: benzyl group

Et: ethyl group

NC: exilda group

CNH: tsiklogeksilnogo group

Imid(l): 1-imidazolidinyl group

Me: methyl group

Could(4): 4-morpholinyl group

Np(1): 1-naftalina group

Np(2): 2-naftalina group

PH: phenyl group

Pip(l): 1-piperideine group

Pipra(l): 1-piperazinilnom group

RP: pencilina group

PSA: cyclopentenone group

RG: p the PA

Rog(4): 4-Peregrina group

Pyrd(l): 1-pyrrolidinyl group

TioMor(4): 4-thiomorpholine group

Tz: group tetrazol-5-yl

Compounds of the present invention, represented by formula (I) can easily be obtained in accordance with any one of the following ways.

Method a (scheme 1, is given at the end of the description).

In reaction scheme 1, R1, R2, A and b have the same meanings as described above; R1arepresents a group similar to those identified as group R1except that any amino and/or hydroxyl group included in R1represents amino and/or hydroxyl group which may be protected amino and/or hydroxylamino group; 2arepresents a group similar to those identified as group R2except that any amino and/or hydroxyl group included in R2represents amino and/or hydroxyl group which may be protected amino and/or hydroxylamino group;3arepresents the following group:

< / BR>
< / BR>
< / BR>
< / BR>
(where R8is triphenylmethyl group); and R3bis the following gruppy" for "amino group, which may be protected aminosidine group" in R1aand R2aprovided that this aminosidine group used in the field of synthetic organic chemistry. Examples include the "aliphatic acyl group", for example, illustrated previously, C1-7aliphatic acyl group, halogen (C2-7alkyl)carbonyl group, such as chlorocichla, dichloroacetylene, trichloroethylene and trifluoracetyl group, and C2-7acylcarnitine group, substituted C1-6alkoxygroup, such as methoxyacetyl group; an "aromatic acyl group", for example, illustrated previously WITH7-11aromatic acyl group, halogen(C7-11aromatic acyl) group, such as 2-bromobenzoyl and 4-chlorbenzoyl group7-11aromatic acyl groups, substituted C1-6alkyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl,7-11aromatic acyl groups, substituted C1-6alkoxygroup, such as 4-anisoyl,7-11aromatic acyl groups substituted by nitro groups, such as 4-nitrobenzoyl group and 2-nitrobenzoyl group7-11aromatic acyl groups, substituted C2-7acyl group, replaced WITH6-10aryl groups such as 4-phenylbenzyl group; "alkoxycarbonyl group", for example, illustrated previously, C2-7alkoxycarbonyl group and2-7alkoxycarbonyl group substituted with halogen or three(C1-6alkyl)silyl groups such as 2,2,2-trichlorocarbanilide and 2-trimethylsilylethynyl group; "altneratively groups, such as vinyloxycarbonyl group and allyloxycarbonyl group; "aracelikarsaalyna group having aryl ring which may be substituted by 1 or 2 C1-6alkoxy or nitro groups" such as benzyloxycarbonyl, 4-methoxybenzylideneamino, 3,4-dimethoxybenzonitrile, 2-nitrobenzisoxazole and 4-nitrobenzisoxazole group; "silyl groups", for example, three(C1-6alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropylideneuridine, tert-butyldimethylsilyl, methyldiisopropanolamine, methyldi-tert-butylsilane and triisopropylsilyl group and a silyl group substituted by three substituents selected from aryl and C1-6alkyl groups, such as diphenylmethylsilane, defenive, 1-6alkyl groups, substituted 1-3 aryl groups such as benzyl, fenetylline, 3-phenylpropionate, -naphthylethylene, -naphthylethylene, diphenylmethylene, triphenylethylene, -afterdirectly and 9-intellilink group, and C1-6alkyl groups, substituted 1-3 aryl groups having aryl ring, substituted C1-6alkyl, C1-6alkoxy or nitro groups, halogen atoms or cyano groups, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylethylamine, 2-nitroaniline, 4-nitroaniline, 4-chloraniline, 4-brombenzene, 4-cyanoaniline, 4-cyanobenzeneboronic, bis(2-nitrophenyl)methyl and piperella group; and a substituted methylene group, each of which forms a Schiff base such as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylaldehyde, diphenylmethylene and (5-chloro-2-hydroxyphenyl)phenylmethylene group, among which C1-7aliphatic acyl group7-11aromatic acyl groups and2-7alkoxycarbonyl group are preferred, and b the other group.

In the description above, there are no special restrictions regarding the "protective group for a hydroxyl group which may be protected hydroxylamine group" in R1aand R2aprovided that this hydroxylamine group used in the field of synthetic organic chemistry. Examples include the "aliphatic acyl group", for example, illustrated previously, C1-7aliphatic acyl group2-7acylcarnitine group, substituted carboxyglutamic, such as Coccinella, petrolina and dipolma group, halogen(C2-7alkyl)carbonyl group, such as chlorocichla, dichloroacetylene, trichloroethylene and trifluoracetyl group, and C2-7acylcarnitine group, substituted C1-6alkoxygroup, such as methoxyacetyl group; an "aromatic acyl group", for example, illustrated previously WITH7-11acyl group, halogen(C7-11aromatic acyl) group, such as 2-bromobenzoyl and 4-chlorbenzoyl group7-11aromatic acyl groups, substituted C1-6alkyl groups such as 2,4,6-trimethylbenzoyl and 4-toluylene group7-11aromatic acyl group, samedomain carboxyglutamic, such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl group7-11aromatic acyl groups substituted by nitro groups, such as 4-nitrobenzoyl and 2-nitrobenzoyl group7-11aromatic acyl groups, substituted C2-7alkoxycarbonyl groups, such as 2-(methoxycarbonyl)- benzoline group, and7-11aromatic acyl groups, substituted C6-10aryl groups such as 4-phenylbenzyl group; "tetrahydropyranyl or tetrahydropyranyl groups, such as groups tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytryptamine-4-yl; "tetrahydrofuranyl and tetrahydrofuranyl groups, such as group, tetrahydrofuran-2-yl and tetrahydrofuran-2-yl; "silyl groups", for example, three(C1-6alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropylideneuridine, tert-butyldimethylsilyl, methyldiisopropanolamine, methyldi-tert-butylsilane and triisopropylsilyl group and a silyl group substituted by three substituents selected from aryl and C1-6alkyl groups, such as the; alkoxymethyl group", for example, (C1-6alkoxy)methyl group, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethylene, propoxymethyl, isopropoxyaniline, butoxymethyl and tert-butoxymethyl group, (C1-6alkoxy)methyl group, zamienne C1-6alkoxygroup, such as 2-methoxyethoxymethyl group and halogen(C1-6alkoxy)methyl group, such as 2,2,2-trichloroethylene and bis(2-chloroethoxy)methyl group; "substituted ethyl groups, for example, (C1-6alkoxy)ethyl groups such as 1 - amoxicilina and 1-(isopropoxy)ethyl group, and a halogenated ethyl group such as 2,2,2-trichlorethylene group; "kalkilya group", for example, C1-6alkyl groups, substituted 1-3 aryl groups such as benzyl, -naphthylethylene, -naphthylethylene, diphenylmethylene, triphenylethylene, -afterdirectly and 9-intellilink group, and C1-6alkyl groups, substituted 1-3 aryl groups having aryl ring, substituted C1-6alkyl or C1-6alkoxygroup, by halogen atoms or cyano groups, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-metoksalena, 4-cyanoaniline, 4-cyanobenzylidene-letrina and piperella group; "alkoxycarbonyl groups, such as illustrated above WITH2-7alkoxycarbonyl group and2-7alkoxycarbonyl group, substituted by halogen atoms or three(C1-6alkyl)silyl groups such as 2,2,2-trichlorocarbanilide and 2-trimethylsilylethynyl group; "altneratively groups, such as vinyloxycarbonyl and allyloxycarbonyl group; "aracelikarsaalyna groups having aryl ring which may be substituted by 1 or 2 C1-6alkoxy or nitro groups, such as benzyloxycarbonyl, 4-methoxybenzylideneamino, 3,4-dimethoxybenzonitrile, 2-nitrobenzisoxazole and 4-nitrobenzisoxazole group;

among which C1-7aliphatic acyl group7-11aromatic acyl group2-7alkoxycarbonyl and (C1-6alkoxy)methyl group are preferred, and more preferred WITH7-11aromatic acyl and (C1-6alkoxy)methyl group, and most preferred benzoline and methoxymethyl group.

Method And represents spondoi formulas (IV-1) to(IV-4).

Stage A1 is a stage for obtaining the compounds of formula (VII) interaction of the compounds of formula (V) with the compound of the formula (VI) in an inert solvent in the presence of phosphine (preferably, tributylphosphine or triphenylphosphine) of azodicarboxylic acid (preferably, diethylazodicarboxylate or 1,1'-(azodicarbon)dipiperidino).

There are no particular restrictions on the nature of the inert solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; and mixtures of the above solvents, among which aliphatic hydrocarbons, aromatic hydrocarbons, galogenidov the s aromatic hydrocarbons and ethers, and particularly preferred toluene and tetrahydrofuran).

The reaction temperature depends on the nature of starting materials and solvent, and the like, but it usually ranges from -20 to 150oWith (preferably from 0 to 60oC).

The reaction time depends on the nature of starting materials and solvent, the reaction temperature and the like, but it usually ranges from 30 minutes to 5 hours, preferably from 5 hours up to 72 hours).

Upon completion of the reaction, the obtained compound (VII) according to the present invention is extracted from the reaction mixture in a known manner. For example, it can be obtained by removing insoluble substances from the reaction mixture by filtration; adding to the filtrate organic solvent which is not miscible with water such as ethyl acetate, separating the organic layer containing the target compound, and washing with water, or the like; drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distillation of the solvent. Thus obtained product may, if desired, be isolated and purified using

any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatogr is soedineniya (VII) with an acid in the presence or absence (preferably, in the presence of inert solvent and thereby remove triphenylmethyl group, R8and then remove, if necessary, amino - and/or hydroxylamino group in R1Aand R2A.

There are no particular restrictions regarding the nature of the acid used in the first of these stages of the reaction, provided that it is used in conventional reactions as acid catalyst. Examples include inorganic acids such as florodora acid, bromatologia acid, sulfuric acid, Perlina acid and phosphoric acid; acid Branstad, for example, organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, triperoxonane acid and triftormetilfullerenov acid; a Lewis acid such as zinc chloride, tin tetrachloride, trichloride boron TRIFLUORIDE boron and tribromide boron; acidic ion-exchange resin, among which inorganic and organic acids (especially florodora acid, acetic acid and triperoxonane acid) are preferred.

There are no particular restrictions regarding the nature inestablishing effect on this reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoramide; water; and mixtures of the above solvents, among which ethers, alcohols and water (especially dioxane, tetrahydrofuran, ethanol and water) are preferred.

The reaction temperature depends on the nature of the source materials, acids and solvents, and the like, but it usually ranges from -20oC to the boiling point (preferably from 0 to 100oC).

The reaction time depends on the nature of the letsa from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).

At this stage the target compound (1A) can also be obtained by catalytic reduction of compound (VII) in an inert solvent at atmospheric pressure or under pressure (preferably under pressure), and thereby remove triphenylmethyl group, R8and then remove, if necessary, the protective groups of the amino and/or hydroxyl group in the R1Aand R2A.

There are no particular restrictions regarding the nature of the catalyst for use in the above catalytic reduction, provided that it is used in conventional reactions catalytic reduction. Examples include palladium-on-charcoal, Raney Nickel, rhodium-aluminum oxide, triphenylphosphine-rhodium oxide, palladium-barium sulfate, palladium black, platinum oxide and platinum black, among which palladium-on-coal is preferred.

There are no particular restrictions on the nature of the inert solvent for use in the above catalytic reduction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petrolane chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n - propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoramide; water; organic acids such as acetic acid and triperoxonane acid; and mixtures of the above solvents, among which ethers, alcohols and organic acids (especially alcohol) are preferred.

The reaction temperature depends on the nature of the source material, catalyst and solvent used and the like, but it usually ranges from 0oWith up to 100oWith (preferably from 10oWith up to 50oC).

The reaction time depends on the nature of the source materials, catalyst and solvent used, the reaction temperature and the like, but it usually ranges from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).

Remove protective groups accordance with the method, known in the field of synthetic organic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis), John Wiley & Sons, or J. F. W. McOmis (Protective Groups in Organic Chemistry), Plenum Press.

When aminosidine group is a silyl group, it can be removed by treatment with a compound forming the fluoride anion, such as fluoride, tetrabutylammonium, pterodroma acid, pterodroma acid-pyridine or potassium fluoride.

There are no particular restrictions regarding the nature of the solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Preferred examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol.

Although the reaction temperature and reaction time and is not restricted by special limitations, communication is usually carried out at a temperature from 0 to 50oC for 10-18 hours.

When aminosidine group is an aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or a substituted methylene group, forming a Schiff base, it can be onogo restrictions on the nature of the acid, used in the above reaction, provided that it is commonly used as an acid and does not adversely affect the reaction. Examples include inorganic acids such as bromatologia acid, chlorodane acid, sulfuric acid, Perlina acid, phosphoric acid and nitric acid, among which florodora acid is preferred.

No particular limitation is imposed on the nature of the base for use in the above reaction, provided that it does not adversely affect another part of the connection. Preferred examples include carbonates of alkali metals such as lithium carbonate, sodium carbonate and potassium carbonate; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; and ammonia, such as aqueous ammonia and concentrated ammonia in methanol.

There are no particular restrictions regarding the nature of the solvent for use in the above reaction, provided that it can be used with conventional hydrolysis of the ol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; water; and mixtures of water and illustrated above organic solvents, among which ethers (especially dioxane) are preferred.

There are no particular restrictions on the reaction temperature and reaction time, and they depend on the nature of the source materials, the solvent and the acid or base. Communication is usually carried out at a temperature from 0 to 150oC for 1-10 hours to suppress side reactions.

When aminosidine group represents aralkyl or aracelikarsaalyna group, it is preferably removed by contact with a regenerating agent (preferably catalytic reduction in the presence of a catalyst at room temperature) in an inert solvent or by using an oxidizing agent.

There are no particular restrictions regarding the nature of the solvent for use in the removal by catalytic reduction, etc the ski hydrocarbons, such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; organic acids, such as acetic acid; water and mixed solvents of water and the above solvents, including alcohols, ethers, organic acids and water (especially alcohols and organic acids) are preferred.

There are no special restrictions on the nature of the catalyst, provided that it is used for catalytic reduction. Examples include palladium-on-charcoal, Raney Nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium oxide, palladium-barium sulfate.

Although no particular limitation is imposed on the pressure, the reaction of the Complex nature of the source material, catalyst and solvent, and the like, the reaction is usually carried out at a temperature from 0 to 100oC for from 5 minutes to 24 hours.

There are no special restrictions on the nature of the solvent used for removal by oxidation, provided that it does not adversely affect the present reaction. Preferably used organic solvents containing water.

Examples of such organic solvents include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; ketones, such as acetone; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide; and sulfolan, among them, halogenated hydrocarbons, ethers, and sulfoxidov (especially halogenated hydrocarbons and sulfoxidov) are preferred.

There are no special restrictions on the used oxidizing agent, if the service is phat sodium, suryamaninagar (CAMS) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDH). Although the reaction temperature and reaction time depend on the nature of the source material, catalyst and solvent, and the like, the reaction is usually carried out at a temperature from 0 to 150oC for from 10 minutes to 24 hours.

When aminosidine group is altneratively group, it can usually be removed by treatment with a base under conditions similar to those used in the case when aminosidine group represents the above-described aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or a substituted methylene group, forming a Schiff base.

Incidentally, when the protective group is allyloxycarbonyl group, it can usually be removed with less adverse reactions when used, in particular, palladium and triphenylphosphine or tetracarbonyl Nickel.

As hydroxylamino group is silyl group, it can usually be removed by treatment with a compound forming the fluoride anion, such as fluoride, tetrabutylammonium, pterodroma acid, pterodroma acid-pyridine or nafta, sulfuric acid, Perlina acid or phosphoric acid, or organic acid, such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, triperoxonane acid or triftormetilfullerenov acid.

By the way, if removing the silyl group is carried out using a fluoride ion, is that the reaction is accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.

There are no particular restrictions on the nature of the inert solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Preferred examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water and mixtures of the above solvents.

Although the reaction temperature and reaction time depend on the nature of the source material, catalyst and SUP>oC) for from 1 hour to 24 hours.

When hydroxylamine group represents aralkyl or aracelikarsaalyna group is usually preferable to remove the protective group by contact with a regenerating agent (preferably catalytic reduction at room temperature in the presence of a catalyst) or by using an oxidizing agent in an inert solvent.

There are no special restrictions on the nature of the solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; esters such as ethyl acetate and propyl; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; amides, such as formamide, Dimetra acid; water; and mixtures of the above solvents, including alcohols (particularly methanol) are preferred.

There are no special restrictions on the nature of the catalyst, provided that it is typically used for catalytic reduction. Examples include palladium-on-charcoal, palladium black, Raney Nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate, among which palladium-on-coal is preferred.

Although particular limitation is imposed on the pressure, the reaction is usually carried out under a pressure from 1 to 10 ATM.

Although the reaction temperature and reaction time depend on the nature of the starting materials, catalyst and solvent, and the like, the reaction is usually carried out at a temperature from 0 to 100oWith (preferably from 20 to 70oC) for from 5 minutes to 48 hours (preferably from 1 to 24 hours).

There are no special restrictions on the nature of the solvent used for removal by oxidation, provided that it does not adversely affect the present reaction. Preferred as solvents the solvent include ketones, such as acetone; halogenated hydrocarbons, such as methylene chloride, chloroform and carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides, such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; and sulfoxidov, such as dimethylsulfoxide.

There are no special restrictions on the used oxidizing agent, provided that it is usually used when ocalenia. Preferred examples include potassium persulfate, sodium persulfate, suryamaninagar (CAMS) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDH).

Although the reaction temperature and reaction time depend on the nature of the starting materials, catalyst and solvent, and the like, the reaction is usually carried out at a temperature from 0 to 150oC for from 10 minutes to 24 hours.

The protective group can also be removed by treatment with an alkaline metal such as lithium metal or sodium metal in liquid ammonia or alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellulosea, such as aluminum chloride-sodium iodide or trimethylsilylmethyl in solvent.

There are no special restrictions on the nature of the solvent, provided that it does not adversely affect the present reaction. Preferred examples include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; NITRILES, such as acetonitrile; and mixtures of the above solvents.

Although the reaction temperature and reaction time depend on the nature of the starting materials and solvent, and the like, the reaction is usually carried out at a temperature from 0 to 50oC for from 5 minutes to 72 hours.

Incidentally, when the reaction substrate has a sulfur atom, preferably using aluminum chloride-iodide of sodium.

When hydroxylamine group is an aliphatic acyl, aromatic acyl or alkoxycarbonyl group, it can be removed by treatment with a base in a solvent.

There are no special restrictions on the grounds for use in the above reaction, provided that it does not adversely affect the remainder s sodium and potassium carbonate; the bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; and ammonia, such as aqueous ammonia and concentrated ammonia in methanol, which include hydroxides of alkali metals, alkoxides of metals and ammonia (especially the hydroxides of alkali metals and alkoxides of metals) are preferred.

There are no particular restrictions regarding the nature of the solvent for use in the above reaction, provided that it can be used with conventional hydrolysis. Examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; water; a mixture of water and illustrated above organic solvents.

There are no special restrictions on temperaturea. The reaction is usually carried out at a temperature from -20 to 150oC for 1 to 10 hours to suppress side reactions.

When hydroxylamine group shall alkoxymethyl, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydrofuranyl, tetrahydropyranyl or substituted ethyl group, it is usually removed by treatment with an acid in a solvent.

There are no particular restrictions on the acid for use in the above reaction, provided that it is usually used as an acid Bronsted or Lewis acid. Preferred examples include acid Branstad, for example, hydrogen chloride, inorganic acids such as florodora acid, sulfuric acid and nitric acid, and organic acids such as acetic acid, triperoxonane acid, methanesulfonate acid and p-toluensulfonate acid and a Lewis acid such as Boron TRIFLUORIDE. Can also be used strongly acidic cation-exchange resin such as Dowex 50W.

There are no special restrictions on the nature of the solvent for use in the above reaction, provided that it does not adversely hcpa and petroleum ether; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, the cyclohexanol and methylcellosolve; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexane; water; and mixed solvents of illustrated above solvents, among which ethers (particularly tetrahydrofuran) and alcohols (particularly methanol) are preferred.

Although the reaction temperature and reaction time depend on the starting materials, acid and solvent, and the like, the reaction is usually carried out at a temperature from -10 to 200oWith (preferably from 0 to 150oC) for from 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).

the treatment for conditions similar to those used when the protective group of the hydroxyl represents the above-described aliphatic acyl, aromatic acyl or alkoxycarbonyl group.

Incidentally, when the protective group is allyloxycarbonyl group, it can be removed more easily with fewer adverse reactions, in particular, palladium and triphenylphosphine or hexaphosphate bis(methyldiphenylphosphine)(1, 5cyclooctadiene)iridium(I).

Through the above reaction, where the lead in the interaction of the compound (VII) and the acid or by catalytic reduction of compound (VII), it happens that aminosidine group and/or hydroxylamine group are removed at the same time.

Aminosidine group and/or hydroxylamine group can be removed sequentially in the desired order.

Upon completion of the reaction, the obtained compound (1A) of the present invention is extracted from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration; adding to the filtrate organic races of the spruce connection, and washing with water, or the like; drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Method B (scheme 2, shown at the end of the description)

In reaction scheme 2, R1, R1a, R2, R2a, A and b have the same meanings as described above, X represents the above-described halogen atom, and Y represents oxygen atom or sulfur.

The method is a method of producing compound (Ib), which is compound (I) in which R3represents the formula (IV-2) or (IV-3), or compound (1C), which is compound (I) in which R3represents the formula (IV-1).

Stage B1 is a stage for obtaining the compounds of formula (IX) by reacting compound (V) with a base in the presence or absence (preferably in the presence of an inert solvent and then the interaction of the compounds with the compound of the formula (VIII).

Examples onevenaarbare sodium and potassium carbonate; the bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]Nona - 5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), including hydrides, alkali metal (especially sodium hydride) are preferred.

There are no particular restrictions on the nature of the inert solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, directoryinformation; mixtures of the above solvents, of which amides (particularly dimethylformamide) are preferred.

The reaction temperature of the compound (V) with a base depends on the nature of the source materials, base and solvent, and the like, but it usually ranges from -50 to 200oWith (preferably from 0 to 120oC).

The time of reaction of compound (V) with a base depends on the nature of the source materials, base and solvent, the reaction temperature and the like, but it usually ranges from 15 minutes to 24 hours (preferably from 1 hour to 10 hours).

The reaction temperature of the compound (V) with compound (VIII) usually ranges from -20 to 200oWith (preferably from 0 to 150oC).

The time of reaction of compound (V) with compound (VIII) usually ranges from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).

Upon completion of the reaction, the obtained compound (IX) of the present reaction can be extracted from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances by filtration; adding to the filtrate organic solvent, which is s; washing with water or the like; drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then distillation of the solvent. Thus obtained product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Stage B2 is a stage for obtaining the compounds of formula (XI), and by the interaction of the compound (IX) with the compound of the formula (X) in an inert solvent in the presence or absence (preferably in the presence of a catalyst, such as sodium acetate, the acetate piperidine or benzoate piperidine.

There are no particular restrictions on the nature of the inert solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and tetrachloride uhler, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; NITRILES, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; mixtures of the above solvents, among which amides (particularly dimethylformamide) are preferred.

The reaction temperature depends on the nature of the source materials, base and solvent, and the like, but it usually ranges from 0 to 200oWith (preferably from 10oWith up to 150oC).

The reaction time depends on the nature of the starting materials, catalyst, solvent, reaction temperature and the like, but it usually ranges from 1 hour to 50 hours, preferably from 2 hours to 24 hours).

Upon completion of the reaction, the obtained compound (XI) in this reaction is removed from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, implement the organic solvent, which is not miscible with water such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then distillation of the solvent. Thus obtained product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Stage B3 is a stage for obtaining the compounds of formula (Ib) by catalytic reduction of compound (XI) in an inert solvent and then removing, if necessary, aminosidine group and/or hydroxylamino group in R1aand R2a. Catalytic reduction and removal, if desired, the amino - and/or hydroxylamino groups carried out by methods similar to that described for stage A2 of method A.

Alternatively, this stage can be carried out by reaction of the compound (XI) with a metal hydride, and then remove, if necessary, amino - and/or hydroxylamino group in R1aand R2a. The interaction between joint which is a stage for obtaining the compounds of formula (1C) by removing the amino - and/or hydroxylamino group in R1aand R2acompounds (XIa), which is compound (XI) having as Y a sulfur atom. This stage is performed by the method similar to that described in stage A2 of the way And to remove the amino - and/or hydroxylamino group.

Method C (scheme 3, shown at the end of the description)

In reaction scheme 3, R1, R1a, R2, R2a, A and b have the same values as described above.

The method is a method of obtaining a compound (Id), which is compound (I) in which R3represents the formula (IV-4) or the compound (1E), which is compound (I) in which R3represents the formula (IV-5).

Stage C1 is the stage of obtaining the compounds of formula (XII) by reacting compound (IX) with hydroxylamine (hydrochloride) in an inert solvent, and then contacting the reaction mixture with a regenerating agent.

There are no particular restrictions on the nature of the inert solvent for use in the interaction of the compound (IX) with hydroxylamine (hydrochloride), provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons, Talal; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; NITRILES, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoramide; water; mixtures of the above solvents, of which mixed solvents with alcohol (particularly methanol and ethanol are preferred.

The temperature of the interaction of the compound (IX) with hydroxylamine (hydrochloride), depends on the nature of the starting materials, catalyst, solvent and the like, but it usually ranges from -20 to 200oWith (preferably from 10 to 120oC).

Reacting compound (IX) with hydroxylamine (hydrochloride), depends on the nature of the source materials, catalogpagetitle from 2 hours to 24 hours).

Examples of reducing agents for use in the latter stages of the reaction include borhydride alkali metals such as sodium borohydride, lithium borohydride and cyanoborohydride sodium, and aluminum hydrides, such as diisobutylaluminium, sociallyengaged and laetrilelamygdalin, including borhydride alkali metal (especially sodium borohydride are preferred.

There are no particular restrictions on the ratio of the solvent for use in contact with a regenerating agent at the last stage of the reaction, provided that it does not adversely affect the present reaction. Preferably used solvents similar to those used when interacting compounds (IX) with hydroxylamine (hydrochloride).

Temperature interaction in contact with a regenerating agent at the last stage of the reaction depends on the nature of the source material, reducing agent, solvent and the like, but it usually ranges from -50 to 200oWith (preferably from 0 to 120oC).

Reacting in contact with the regenerating agent on poledouris reaction and the like, however, it usually ranges from 15 minutes to 24 hours (preferably from 1 hour to 12 hours).

Upon completion of the reaction obtained in this reaction, the compound (XII) is extracted from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Stage C2 is the stage of obtaining the compounds of formula (XIII) by reacting compound (XII) with trimethylsilylcyanation in an inert solvent.

There are no particular restrictions regarding the nature of the solvent for use in Viseu include aliphatic hydrocarbons, such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; mixtures of the above solvents, of which aromatic hydrocarbons, ethers, and amides (particularly diethyl ether, tetrahydrofuran and dimethylformamide are preferred.

The reaction temperature depends on the nature of the starting materials, solvent and the like, but it usually ranges from -50 to 200oWith (preferably from 0 to 120oC).

The reaction time depends on the nature of the starting materials, solvent, reaction temperature and the like, but it usually ranges from 15 minutes to 48 hours (preferably from 1 hour to 24 hours).

Upon completion of the reaction obtained in this reaction, the compound (XIII) is extracted from the reaction mixture in a known manner. For example, it may be polnay mixture by filtration and added to the filtrate organic solvent, which is not miscible with water such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Stage C3 is the stage of obtaining the compounds of formula (Id) by reacting compound (XIII) with carbonyliron agent in an inert solvent and then removing, if necessary, amino - and/or hydroxylamine groups in R1aand R2a.

There are no particular restrictions regarding the nature Carboniferous agent for use in the above reaction, provided that it is usually applied when carbonyliron. Examples include phosgene, diphosgene, triphosgene and 1,1'-carbonyldiimidazole.

There are no particular restrictions regarding the nature of the solvent for use in the above reaction of the compound (XIII) with carbonyliron agent, provided that he h is, such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; mixtures of the above solvents, of which aromatic hydrocarbons, halogenated hydrocarbons, ethers, and amides (particularly tetrahydrofuran, dioxane and dimethylformamide are preferred.

The reaction temperature of the compound (XIII) with carbonyliron agent depends on the nature of the starting materials, solvent and the like, but it usually ranges from -50 to 200oWith (preferably from 0 to 120oC).

The time of reaction of the compound (XIII) with carbonyliron agent depends on the nature of the starting materials, solvent, reaction temperature and so Podobedova amino - and/or hydroxylamino group in R1aand R2acarry out, if necessary, by methods similar to those described for stage A2 when removing the amino - and/or hydroxylamino group.

Upon completion of the reaction obtained by this reaction, the compound (1d) is removed from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then distillation of the solvent. Thus obtained product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Stage C4 represents the stage of obtaining the compounds of formula (1E) by removing the amino - and/or hydroxylamino group in R1and R2in the compound (XIII) in a trade is of amino - and/or hydroxylamine groups.

Stage C5 represents another stage of obtaining the compounds of formula (1d) by reaction of compound (XII) with N-(chlorocarbonyl)isocyanate in the presence or in the absence (preferably in the presence of an inert solvent and then removing the amino - and/or hydroxylamino group in R1aand R2a, if desired.

There are no particular restrictions regarding the nature of the solvent for use in the reaction of compound (XII) with N-(chlorocarbonyl)isocyanate, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide, HEXAMETHYL the hydrocarbons, ethers, and amides (particularly tetrahydrofuran, dioxane and dimethylformamide are preferred.

The reaction temperature depends on the nature of the starting materials, solvent and the like, but it usually ranges from -50 to 200oWith (preferably -20 to 50oC).

The reaction time depends on the nature of the starting materials, solvent, reaction temperature and the like, but it usually ranges from 15 minutes to 50 hours, preferably from 1 hour to 24 hours).

The removal of the amino - and/or hydroxylamino group in R1aand R2acarry out a method similar to that described in stage A2 of the way And to remove the amino - and/or hydroxylamino group.

Upon completion of the reaction obtained by this reaction, the compound (1d) is removed from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the target compound, washing voat sodium or the like and then distillation of the solvent. Thus obtained product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Method D (scheme 4, is provided at the end of the description).

In reaction scheme 4 R2, R2a, R4, R5, R6A , b, D, E and Y have the same meanings as described above;4arepresents a group of similar groups in the group definition R4except that the amino and/or hydroxyl group included in the definition of R4indicate the amino and/or hydroxyl group which may be protected amino and/or hydroxylamino group; R5arepresents a group that is similar to the definition of the group R5except that the amino and/or hydroxyl group included in the definition of R5indicate the amino and/or hydroxyl group which may be protected amino and/or hydroxylamino group; R7represents formyl, carboxy or2-7alkoxycarbonyl group, and BOC means tert-butoxycarbonyl group.

Method D is a method of obtaining compound (Ifa), which is joint and connection (Ifb), which is compound (I) in which R1represents a group of formula (III), and R3represents the formula (IV-2) or (IV-3).

Stage D1 represents the stage of obtaining the compounds of formula (Ifa), and carried out by reacting the compounds of formula (XIV) with the compound of the formula (XVa) and then removing the amino - and/or hydroxylamino group in R2a, R4aand R5aif necessary.

When R7in the compound (XIV) represents a formyl group, a compound (XIV) interacts with the compound (XVa) in an inert solvent and then tert-butoxycarbonyl group, which is aminosidine group is removed from the reaction mixture with acid to effect the ring closure followed by reaction with an oxidizing agent.

Alternatively, this stage can be carried out by reacting compound (XIV) with compound (XVa), isolation and purification of the intermediate product obtained by removal of the tert-butoxycarbonyl group, which is aminosidine group, acid from the reaction mixture to effect the ring closure, and then bringing the oxidizing agent in interaction with received premiumline by the reaction of compound (XIV) with compound (XVa), provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; acids such as acetic acid and propionic acid; sulfoxidov, such as dimethyl sulfoxide; sulfolane; mixtures of the above solvents, among which ethers (particularly tetrahydrofuran) are preferred.

The reaction temperature of the compound (XIV) with compound (XVa) depends on the nature of the starting materials, solvent and the like, but it usually ranges from 0 to 200oWith (preferably from 10 to 120oC).

The time of reaction of the compound (XIV) with compound (XVa) depends on the nature of the source materials, base, solvent, reaction temperature and so"ptx2">

The removal of the tert-butoxycarbonyl group representing aminosidine group, acid carried out by the method similar to that described in stage A2 to remove alkoxycarbonyl group, which is aminosidine group.

There are no special restrictions on the nature of the oxidizing agent for use in the above reaction, provided that it is typically used in oxidation reactions. Examples include inorganic metal oxidizing agents such as manganese oxides, such as potassium permanganate and manganese dioxide; oxides of ruthenium such as ruthenium tetroxide; selenium compounds such as selenium dioxide; iron compounds such as iron chloride(III); osmium compounds such as osmium tetroxide, the osmate dihydrate potassium (K2OsO42H2O); silver compounds such as silver oxide; mercury compounds, such as acetate mercury; compounds of lead oxide such as lead oxide and leads to compounds, which lead; compounds, chromic acid, such as potassium chromate, complex chromic acid - sulfuric acid and a complex of chromic acid - pyridine; compound of cerium, such as cereomony nitrate (CAN); inorganic oxidizing Agena period acid, such as periodate sodium; ozone; hydrogen peroxide; connection of nitrous acid, such as nitrous acid; compounds, acid chloride, such as potassium chlorite and sodium chlorite; connection personnel acid, such as potassium persulfate and sodium persulfate; organic oxidizing agents, for example, the reagents used for DMSO oxidation (complexes between sulfoxide and dicyclohexylcarbodiimide, oxalicacid, acetic anhydride or phosphorous pentoxide or a complex between pyridine and sulphuric anhydride); a combination of a peroxide, such as tert-butylhydroperoxide and vanadium or molybdenum complex; stable cations, such as triphenylmethyl cations; the combination of succinimide, such as N-bromosuccinimide and alkali; oxirane, such as dimethyldioxirane; compounds, hypochlorous acid, such as tert-butyl hypochlorite; connection of azodicarboxylic acid, such as azodicarboxylate ester; percolate, such as m-chloroperbenzoic acid and Perfilieva acid; disulfides such as dimethyl disulfide, diphenyldisulfide and dipyridamole and triphenylphosphine; esters of nitrous acid, such as methylnitrite; tetragonopterinae hydrocarbons, such calculi halogen (especially molecules of iodine are preferred.

There are no special restrictions on the nature of the solvent for use in contact with oxidizing agent, provided that it does not adversely affect the present reaction. Preferably used solvents are used during the interaction of the compound (XIV) with compound (XVa).

The reaction temperature and reaction time in contact with the oxidizing agent are the same as those used in the interaction of the compound (XIV) with compound (XVa).

When R7in the compound (XIV) is a carboxyl group, the compound of formula (XIV) or its reactive derivative (gelegenheid acid, an active ester or a mixed anhydride of the acid) interact with the compound of the formula (XVa) or its acid salt additive (for example, salt of a mineral acid, such as hydrochloride, nitrate or sulfate), and then tert-butoxycarbonyl group, which is aminosidine group is removed with acid and subsequent closure of the ring.

Alternatively, at this stage it is possible to isolate and purify the amide compound which is an intermediate product, to delete in the resulting amide is person similar to that described for stage above, and then to carry out the ring closure.

Halogenosilanes the method is carried out by interaction of the compound (XIV) with a halogenation agent (for example, thionyl chloride, tierbroker, oxalicacid, oxalidales, phosphorus oxychloride, trichloride phosphorus or pentachloride phosphorus) to obtain gelegenheid acid and then by the interaction of the obtained gelegenheid acid with compound (XVa) or its acid salt additive in an inert solvent in the presence or in the absence (preferably in the presence) of the Foundation.

Examples of bases for use in the above reaction include carbonates of alkali metals such as lithium carbonate, sodium carbonate and potassium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; organic amines such as triethylamine, tributyl the Lin, 1,5-diazabicyclo[4.3.0]Nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), among which organic amines, especially triethylamine) are preferred.

There are no particular restrictions regarding the nature of the solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; hydrogenated hydrocarbons, such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide and sulfolane, among them, halogenated hydrocarbons, ethers, and amides are preferred (dichloromethane, chloroform, tetrahydrofuran and dimethylformamide are particularly preferred).

The reaction temperature depends on the nature of the original mother is neruhomogo agent with compound (XIV) and reaction gelegenheid acid with compound (XVa) or its acid salt additive. Preferably, the halogenation reaction of the agent with compound (XIV) is carried out at a temperature of from -10 to 100oC, whereas the reaction of gelegenheid acid with compound (XVa) or its acid salt additive is carried out at a temperature of from -20 to 100oC.

The reaction time depends on the nature of the starting materials, the reagents and the reaction temperature and the like, however, the reaction time ranges from 30 minutes to 80 hours, preferably from 1 hour to 48 hours) for each of the reactions of halogenation agent with compound (XIV) and gelegenheid acid with compound (XVa) or its acid salt additive.

An active way of ester is implemented by interaction of the compound (XIV) with an active etherification agent in an inert solvent to obtain its active complex of ether and then the interaction of ester with compound (XVa) or its acid salt additive in an inert solvent in the presence or in the absence (preferably in the presence) of the Foundation.

Examples of active tarifitsiruemih of agentov for use in the above reaction include N-hydroxycodone, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-gerokgak dicyclohexylcarbodiimide, carbonyldiimidazole and triphenylphosphine.

There are no special restrictions on the nature of the solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; ketones, such as acetone; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide and sulfolane, among which ethers, and amides (particularly dioxane, tetrahydrofuran and dimethylformamide are preferred.

The base for use in the above reactions similar to those used in the previously described halogenosilanes the way.

The reaction temperature depends on the nature of the starting material and reagents, and the like, but obecnie from -10 to 100oC), whereas the subsequent interaction between the active complex ester and compound (XVa) or its acid salt additive is carried out at a temperature of from -20 to 100oWith (preferably from 0 to 50oC).

The reaction time depends on the nature of the source material, reagents, reaction temperature and the like, but it usually ranges from 30 minutes to 80 hours, preferably from 1 hour to 48 hours) for each of the reactions for active complex ether and the active reaction of ester with compound (XVa) or its acid salt additive.

The method based on the mixed anhydride of the acid is carried out by reaction of compound (XIV) and the agent, forming a mixed acid anhydride, in an inert solvent in the presence or in the absence (preferably in the presence) of a base to obtain the corresponding mixed acid anhydride and then the interaction of the obtained mixed acid anhydride with the compound (XIVa) or its acid salt additive in an inert solvent.

Examples of bases for use in the above reaction include carbonates of alkali metals such as lithium carbonate, sodium carbonate and carbonate calidonia metals, such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N, N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]Nona-5-ene, 1/4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), among which organic amines, especially triethylamine) are preferred.

Examples of agents that form a mixed acid anhydride, for use in the above reaction include C1-4alkylaminocarbonyl, such as ethylchloride and isobutylparaben; (C1-5alkanoyl)halides, such as pivaloyloxy; and di(C1-4alkyl) or di(C6-14aryl)RIANovosti, such as diethylthiophosphate and diphenylcyanoarsine, among which di(C1-4alkyl) or di(C6-14aryl) cyanoformate (especially diethylthiophosphate) are preferred.

There are no special restrictions on the nature of the solvent for use is istia on this reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; ketones, such as acetone; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide and sulfolane, among which ethers, and amides (particularly tetrahydrofuran and dimethylformamide) are preferred.

The reaction temperature to obtain a mixed anhydride of the acid depends on the nature of the starting materials, reagents and the like, but it usually ranges from -50 to 100oWith (preferably from 0 to 60oC).

The reaction time of receipt of a mixed anhydride of the acid depends on the nature of the starting materials, reagents, reaction temperature and the like, but it usually ranges from 30 minutes to 72 hours (preferably from 1 hour to 24 hours).

A mixed anhydride of the acid of interaction between the s (preferably in the presence) of the Foundation, both the base and an inert solvent for use in this reaction are similar to those used in the reaction of obtaining the above-mentioned mixed acid anhydride.

The reaction temperature of the mixed acid anhydride with the compound (XVa) or its acid salt additive depends on the nature of the starting materials, reagents and the like, but it usually ranges from -30 to 100oWith (preferably from 0 to 80oC).

The time of reaction of the mixed acid anhydride with the compound (XVa) or its acid salt additive depends on the nature of the starting materials, reagents, reaction temperature and the like, but it usually ranges from 5 minutes to 24 hours (preferably from 30 minutes to 16 hours).

When this reaction using di(C1-4alkyl)cialisforyou acid or di(C6-14aryl)cialisforyou acid, compound (XIV) can interact with the compound (XVa) directly in the presence of a base.

The removal of the tert-butoxycarbonyl group representing aminosidine group, acid carried out by the method similar to that described in stage A2 of the way for removal of the protective group of the alkoxy who eat tert-butoxycarbonyl group, which is aminosidine group, using acid can be carried out by a method similar to that described in stage A2 method for removing the protective group from alkoxycarbonylmethyl amino group using acid.

When the compound (XIV) contains2-7alkoxycarbonyl group as R7the compound (XIV) interacts with the compound (XVa) in the presence or in the absence (preferably in the absence of inert solvent and in the presence or in the absence of base, tert-butoxycarbonyl group, which is aminosidine group is removed with acid and subsequent closure of the ring.

Alternatively, at this stage it is possible to isolate and purify the amide compound, which is an intermediate product, to remove tert-butoxycarbonyl group, which is aminosidine group of the obtained amide compound by the method similar to that described in the above reaction, and then to carry out the ring closure.

Examples of bases for use in the above reaction of the compound (XIV) with compound (XVa) include carbonates of alkali metals such as lithium carbonate, ka and potassium bicarbonate; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0] Nona-5-ene, 1,4-diazabicyclo[2.2.2] octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), among which organic amines, especially triethylamine) are preferred.

There are no particular restrictions regarding the nature of the solvent for use in the interaction of the compound (XIV) with compound (XVa), provided that it does not adversely affect the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, Nana, the cyclohexanol and methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; mixtures of the above solvents, of which ethers, and amides (particularly tetrahydrofuran, dioxane and dimethylformamide are preferred.

The reaction temperature depends on the nature of the source materials, bases, solvents and the like, but it usually ranges from 0 to 200oWith (preferably from 50 to 150oC).

The reaction time depends on the nature of the source materials, base, solvent, reaction temperature and the like, but it usually ranges from 1 hour to 50 hours, preferably from 5 hours to 24 hours).

Ring closure after removal of the tert-butoxycarbonyl group, which is aminosidine group, acid can be carried out in a manner analogous to that described for stage A2 in the way And for the removal of the protective group from alkoxycarbonylmethyl amino group using acid.

Remove, if necessary, amino - and/or hydroxylamine groups in R2a, R4aand R5acarried out in a manner analogous to that described for stage A2 of the way And for the connection (IFA) are recovered from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distillation of the solvent. The compound obtained may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Stage D2 is the stage of obtaining the compounds of formula (Ifb) and carry it out in a manner analogous to that described for stage D1 of method D, more specifically, the interaction of the compounds of formula (XIV) with the compound of the formula (XVb), and then removing, if necessary, amino - and/or hydroxylamine groups in R2a, R4aand R5a. This phase of the exercise the same way as described for stage D1.

If R4in compounds (Ia), (Ib), (Ic), (Id), (Ie), (Ifa) and (Ifb), is iridology group, substituted amino group, optionally to carry out the alkylation, atilirovanie, aralkylamines or acylation of the amino group. This reaction is known or can be carried out in a known manner or, alternatively, in a similar way [The Chemistry of Amino Group, chapter 6, 1968, John Wiley & Sons, The Chemistry of The Amino group, chapter 2, 1970, John Wiley & Sons, etc.].

The original substance (V), (VI), (VIII), (X), (XIV), (XVa) and (XVb) are known, or they can easily get by known methods, or, alternatively, in a similar way.

The original substance (V), (XIV), (XVa) and (XVb) can also be obtained, for example, in the following ways:

Method E (scheme 5, provided at the end of the description).

In reaction scheme 5, R4a, R5a, R6, R7, A, B, D, E and BOC have the same meanings as described above.

Method E is a method of obtaining the compounds (Va) and (Vb).

Stage E1 is a stage for obtaining the compound (Va) the interaction of the compounds of formula (XVI) with the compound (XVa) and then removing tert-butoxycarbonyl group, which is aminosidine group, acid and subsequent closure of the ring. This stage is carried out in a manner analogous to that described for a hundred who th is aminosidine group, remove the acid with the subsequent closure of the ring.

In particular, when the compound (XVa) E represents a nitrogen atom, ring closure is preferably carried out using the compound (XVI) in a large excess in the absence of solvent.

Stage E2 is a stage for obtaining the compound (Vb) by reacting the compounds of formula (XVI) with the compound (XVb), and then remove the tert-butoxycarbonyl group, which is aminosidine group, using acid. This stage is carried out in a manner analogous to that described for stage D1 of method D, where the compound (XIV), having as R7carbonyl group interacts with the compound (XVa), and then tert-butoxycarbonyl group, which is aminosidine group is removed with acid.

Ring closure also spend way similar to that described in stage D1 of the way D. However, when the compound (XVa) E represents a nitrogen atom, ring closure is preferably carried out using a large excess of compound (XVI) in the absence of solvent.

Upon completion of the reaction obtained in this reaction, compound (Va) or (Vb) remove bridges, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Method F (6, provided at the end of the description).

In reaction scheme 6 R2a, R7, R8A , b, X and Y have the same meanings as described above, and R7arepresents a group similar to the one defined for R7except that formyl or carboxyl group included in the definition of R7mean formyl or carboxyl group which may be protected by a protective group.

In the above description there are no special restrictions on "protective group" for "formyl group, which is in the field of synthetic organic chemistry. Examples include methyl group, substituted illustrated above C1-6alkoxygroup, such as dimethoxymethyl, diethoxylate, depropaniser and debutaniser, and groups 1,3-dioxane-2-yl, 1,3-dioxolane-2-yl, 1,3-dition-2-yl and 1,3-ditiolan-2-yl, among which group dimethoxymethyl, diethoxylate, 1,3-dioxolane-2-yl and 1,3-dition-2-yl are preferred.

In the above description there are no special restrictions regarding the "protective group for a carboxyl group which may be protected by a protective group", provided that it is carboxylamide group used in the field of synthetic organic chemistry. Examples include1-6alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl; and (C1-6alkyl groups, substituted WITH 1-36-10aryl groups which may be substituted C1-6alkyl group, a C1-6alkoxygroup, a nitro-group, a halogen atom or cyano, such as benzyl, fenetylline, 3-phenylpropionate, 1-naphthylethylene, diphenylmethylene, triphenylmethyl, 4-methylaniline, 4-methoxyaniline, 4-nitroaniline, 4-tormentilla and 4-cyanobenzyl groups, among which the method for obtaining the compound (XIV).

The F1 stage is the stage of obtaining the compound (XIV) by the interaction of the compounds of formula (XVII) with the compound of the formula (XVIII) in an inert solvent in the presence of a base and then removing the protective group, if formyl or carboxyl group, R7ais protected formyl or carboxyl group.

The base used in the interaction of the compounds of formula (XVII) with the compound of the formula (XVIII), similar to the base used in the above-described stage B1 of the way In, and preferably is a hydride of an alkali metal (especially sodium hydride).

The solvent used in the interaction of the compounds of formula (XVII) with the compound of the formula (XVIII), similar to that used in the above-described stage B1 of the way In, and preferably represents an amide or a mixed solvent of the amide and the other solvent (particularly dimethylformamide).

The reaction temperature in the interaction of the compounds of formula (XVII) with the compound of the formula (XVIII) depends on the nature of the source materials, bases, solvents and the like, but usually it ranges from -50 to 200oWith (preferably from 0 to 120oC).

The response time for collaboration is varicela, the reaction temperature and the like, but it usually ranges from 30 minutes to 24 hours (preferably from 1 hour to 10 hours).

Removal, if desired, the protective group, formyl group or a carboxyl group depends on its nature, but usually it is done using methods known in the field of synthetic organic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis), John Wiley & Sons, or J. F. W. McOmie: (Protective Groups in Organic Chemistry), Plenum Press.

The compound (XIV) wherein R7represents carboxyl group, or the compound (XVIII), where R7arepresents carboxyl group, can be easily obtained in a known manner from compounds where R7or R7arepresents formyl or protected formyl group.

Upon completion of the reaction obtained in this reaction, the compound (XIV) is extracted from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the target soedinitelny the sodium bicarbonate or the like and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Method G (scheme 7, provided at the end of the description).

In reaction scheme 7 R2a, R7, R7aA , b, X and Y have the same meanings as described above, and R9is carboxylato group (which has the same meanings as described above).

Method G is also a method of obtaining compound (XIV) and differs from the way F.

Stage G1 is the stage of obtaining the compounds of formula (XXI) the interaction of the compounds of formula (XIX) with a compound of formula (XX) in an inert solvent in the presence of a base. This stage is carried out in a manner analogous to stage F1 method F.

Stage G2 is the stage of obtaining the compounds of formula (XXII) the recovery of the compound (XXI). This interaction is carried out by catalytic reduction or zinc-acetic acid method, tin-alcoholic way or tin-hydrochloric acid method, commonly used in the restoration of the nitro-group.

Stage G3 is the stage of Itanium way similar to that described in the patent application of Japan Kokai Sho 55-22657 (USP4258193) or S. Oae et al., "Bull. Chem.Soc.Jpn., 53, 1065 (1980)".

Stage G4 is the stage of obtaining the compound (XIV) by the interaction of the compound (XXIII) with the compound of the formula (XXIV)with subsequent hydrolysis of the reaction mixture and, if desired, removing the formyl or carboxylamide group, as defined in the case of a group R7a.

The interaction of the compound (XXIII) with the compound (XXIV) and the subsequent hydrolysis is carried out in a manner analogous to the one described in the patent application of Japan Kokai Sho 55-22657 (USP4258193).

The removal of the formyl or carboxylamide group defined for group R7aperform in a manner analogous to that described for removal of the formyl or carboxylamide group in method F.

Upon completion of the reaction obtained in this reaction, the compound (XIV) is extracted from the reaction mixture in a known manner. For example, it may be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the Safed sodium, anhydrous sodium bicarbonate or the like and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

Method H (scheme 8, provided at the end of the description).

In reaction scheme 8 R4a, R5a, R6, D, E, X and BOC have the same meanings as described above.

Method H is a method of obtaining compound (XVa) and (XVb).

Stage HI is the stage of obtaining the compounds of formula (XXVIIa) the interaction of the compounds of formula (XXV) with a compound of formula (XXVIa) in the presence of a base. This stage is performed by the method similar to that described in stage F1 method F.

Stage N2 is the stage of obtaining compound (XVa) recovering the compound (XXVIIa). This stage is performed by the method similar to that described in stage G2 method G.

Stage N3 is the stage of obtaining compounds (XXVI1b) the interaction of the compounds of formula (XXV) with a compound of formula (XXVIb) in an inert solvent in the presence of a base. This stage is performed by the method similar to that described with the(XXVIIb). This stage is performed by the method similar to that described in stage G2.

Upon completion of the reaction obtained in this reaction, compound (XVa) and (XVb) are recovered from the reaction mixture in a known manner. For example, each of them can be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates and chromatography.

The way I (scheme 9, is provided at the end of the description)

In reaction scheme 9 R5a, R6, E, X and BOC have the same meanings as described above.

Method I is a method of obtaining compounds (XXVIa) and (XXVIb).

The study is VIIIa) tert-butoxycarbonyl group using the method similar to a conventional method known in the field of synthetic organic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis), John Wiley & Sons, or J. F. W. McOmie (Protective Groups in Organic Chemistry), Plenum Press.

Stage I2 is the stage of obtaining compounds (XXVIa) the interaction of the compounds of formula XXIXa) with the compound of the formula (XXX) in an inert solvent in the presence of a base.

The base used in the above reaction, similar to the base used in the above-described stage B1 of the way In, and hydrides of the alkali metal (especially sodium hydride) are preferred.

The solvent used in the above reaction, similar to that used in the above-described stage B1 of the way In, and ethers, and amides (particularly tetrahydrofuran, dioxane and dimethylformamide are preferred.

The reaction temperature depends on the nature of the source materials, bases, solvents and the like, but usually it ranges from -50 to 200oWith (preferably from 0 to 120oC).

The reaction time depends on the nature of the source materials, base, solvent, reaction temperature and the like, but it usually ranges from 30 minutes to 24 hours (suppose the means of protection of the amino group in the compound of formula (XXVIIIb) tert-butoxycarbonyl group. This stage is carried out in a manner analogous to that described for stage I1.

Stage I4 is the stage of obtaining compound (XXVIb) the interaction of the compounds of formula XXIXb) with the compound of the formula (XXX) in an inert solvent in the presence of a base. This stage is carried out in a manner analogous to that described for the above stage I2 method I.

Upon completion of the reaction obtained in this reaction, compound (XXVIa) or (XXVIb) are recovered from the reaction mixture in a known manner. For example, each of them can be obtained by neutralization, if necessary, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then distillation of the solvent. The resulting product may, if desired, be isolated and purified using any suitable combination of conventional methods, for example, recrystallization, the resultant deposition rates is 10 R5a, R6, D, E and BOC have the same meanings as described above, R10represents a hydrogen atom or triphenylmethyl group and the group of the following formula:

< / BR>
represents a phenyl group which may be substituted by 1-4 substituents selected from substituents , or pyridyloxy group which may be substituted by 1-3 substituents selected from substituents .

The way J is a method of obtaining compound (XVd) or (XVf), having as R4aphenyl or pyridyloxy group, substituted tetrazolyl group which may be protected, and differs from the way N.

Stage J1 is the stage of obtaining compounds (XVd) by reacting compound (XVc), which is a compound (XVa), having as R4lanzamiento phenyl or pyridyloxy group with azide compound in an inert solvent and then, if desired, protection tetrazolyl group of the obtained compound.

There are no special restrictions on the nature of the inert solvent for use in the above reaction, provided that it does not adversely affect the present reaction. Examples include aliphatic is angry toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; ketones, such as acetone; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxidov, such as dimethylsulfoxide, among which aromatic hydrocarbons (particularly toluene) are preferred.

Examples of the azide compounds for use in the above reaction include derivatives directorrelated, such as diphenylphosphoryl; trialkylsilyl, such as trimethylsilyl and triethylsilyl; azide salts of alkali metals such as sodium azide and potassium azide; azides triamcinolone, such as azide tri-n-butyanova, among which azides triamcinolone (especially azide tri-n-butyanova) are preferred.

In the above reaction of the azide compounds can be used either by themselves or in combination, for example, trialkylsilyl, such as trimethylsilyltriflate or triethylcitrate, or Kalra reaction depends on the nature of the source material, used azide and solvent, and the like, but usually it ranges from -10 to 200oWith (preferably from 50 to 150oC).

The reaction time depends on the nature of the source material used azide and solvent, the reaction temperature and the like, but it usually ranges from 15 minutes to 48 hours (preferably from 30 minutes to 30 hours).

Reaction to protect tetrazolyl group carry out, if necessary, by reacting the compound obtained in the above reaction with halogenated triphenylmethanol in an inert solvent in the presence of a base.

The base used in the above reaction, similar to that used in stage B1 of the way In, and organic amines, especially triethylamine) are preferred.

The solvent used in the above reactions, similar to those used when interacting compounds (XVc) with an azide compound, and a mixture of simple ester and amide (especially a mixture of tetrahydrofuran and dimethylformamide) is preferred.

The reaction temperature depends on the nature of the source material, base, solvent and the like, but usually it varies the first material, the base and solvent, the reaction temperature and the like, but it usually ranges from 15 minutes to 48 hours (preferably from 30 minutes to 30 hours).

Stage J2 is the stage of obtaining the compounds of formula (XVf) by reacting compound (XVe), which is a compound (XVb), having as R4alanzamiento phenyl or pyridyloxy group with azide compound and, if necessary, protection tetrazolyl group of the obtained compound. This stage is carried out in a manner analogous to that described for stage J1 method J.

Upon completion of the reaction obtained in this reaction, compound (XVd) or (XVf) are recovered from the reaction mixture in a known manner. For example, they can be obtained by neutralizing, if desired, the reaction mixture; removing insoluble substances from the reaction mixture by filtration and added to the filtrate organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and then othoni, methods commonly used for the isolation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent.

The original substance (XVI), (XVII), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVIIIa), (XXVIIIb) and (XXX) are known or can be easily obtained by a known method or an equivalent method [for example, the patent application of Japan kokai Hei 9-188669 (ERA) and the like].

The compound of formula (I) or its pharmacologically acceptable salt according to the present invention have excellent increase insulin resistance effect, impact, reduce blood sugar, anti-inflammatory, immune-modulating action, allegedretribution action, 5-lipoxygenation action, action, inhibiting the production of lipid peroxide activating PPAR action, antiosteoporosis action, antagonism to leukotrienes, action, promoting the formation of fat cells, effect, inhibiting the proliferation of cancer cells and calcium antagonism, and therefore can be used as a prophylactic and/or drugs for diabetes, hyperlipidemia, the EP, retinopathy, nephropathy, neurosis, cataracts and coronary diseases, and the like), arteriosclerosis, diabetes pregnant, polycystic ovary syndrome, cardiovascular diseases (e.g. coronary heart disease and the like), cell damage (e.g., when the brain damage caused by stroke, and the like), induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (such as epitimy osteomyelitis, pain, fever, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergies, asthma, gastrointestinal ulcers, exhaustion, autoimmune disease, pancreatitis and the like), cancer, osteoporosis and cataracts.

In addition, the compound of formula (I) or its pharmacologically acceptable salt according to the present invention can be used as a pharmaceutical composition (particularly as a preventive and/or drugs for diabetes or diabetic complications), obtained by using it in combination with at least one of the inhibitors-glucosidase, inhibitors illegitimates, drugs biguanide, latinovich major loadingitem-converting enzyme.

[Industrial applicability]

When the compound of formula (I) or its pharmacologically acceptable salt in accordance with the present invention is used as the above-mentioned pharmaceutical or prophylactic agent, it may be in itself or, if necessary, after mixing with a pharmacologically acceptable excipient, diluent or the like, orally in the form of tablets, capsules, granules, powders or syrups, or parenterally in the form of injections or suppositories.

The above pharmaceutical formulation can be obtained in a known manner with the use of additives. Examples of additives include excipients (for example, organic excipients, for example, sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, a-starch and dextrin; cellulose derivatives such as crystalline cellulose, gum Arabic, dextran and pullulan; and inorganic excipients such as silicate derivatives such as soft silicic anhydride, synthetic aluminum silicate, calcium silicate and metasilicate magnesium-aluminum; phosphate derivatives such as GI lubricating substance (for example, stearic acid, metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; benzoat sodium, DL leucine; sodium salts of fatty acids; laurilsulfate, such as sodium lauryl sulfate or lauryl sulfate, magnesium; silicic acids such as silicic anhydride or silicic hydrate, and illustrated above starch derivatives), binders (for example, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidine. Macrogol and similar compounds described above for the excipients), a disintegrator (e.g., derivatives of cellulose, such as hydroxypropylcellulose with a low degree of substitution, carboxymethylcellulose, carboxymethylcellulose calcium and internally crosslinked carboxymethylcellulose sodium, and chemically modified starch-cellulose, such as carboximetilkrahmal, carboximetilkrahmal sodium and cross-linked polyvinylpyrrolidone), a stabilizer (for example, peroxybenzoate, such as methylparaben and propylparaben; alcohol, such as chlorobutanol, pensional; dehydroacetic acid and sorbic acid), corrigent (for example, a commonly used sweetener, acidulant or flavoring) and thinner.

The dose of a compound according to the invention will vary depending on the condition and age of the patient, the route of administration and the like. It is administered orally in amounts of 0.001 mg/kg body weight (preferably 0.01 mg/kg of body weight) in a single dose as a lower limit and 500 mg/kg body weight (preferably 50 mg/kg of body weight) in a single dose as an upper limit, whereas it is administered intravenously in the amount of 0.005 mg/kg of body weight (preferably 0.05 mg/kg of body weight) in a single dose as the lower limit and 50 mg/kg (preferably 5 mg/kg of body weight) in a single dose as an upper limit. It is desirable to introduction once or several times a day depending on the condition of the patient.

[The best ways of carrying out the invention]

Hereinafter the present invention will be described more specifically by way of examples, reference examples, examples and pharmacological tests. However, it should be understood that the present invention is not restricted by these examples or by these examples.

Example 1

5-{4-[5-(4-Hydroxy-2,3,5-Tr is passive connection 1-651)

(1-1) 5-{ 4-[5-(4-Acetoxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b]pyridine-2-ylethoxy]benzyl}-3-triphenyltetrazolium-2,4-dione

To a mixture of 16.4 g of 5-(4-acetoxy-2,3,5-trimethylphenol)-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b] pyridine, with 32.5 g of 5-(4-hydroxybenzyl)-3-triphenylmethyl-thiazolidin-2,4-dione, 17,5 g azodicarbonamide and 400 ml of toluene was added dropwise at room temperature a solution of 17.2 ml of tributylphosphine in 50 ml of toluene, followed by irradiation with ultrasound for one hour and stirring at room temperature for 3 hours. The reaction mixture was left overnight at room temperature. The insoluble substance was filtered from the reaction mixture and the filtrate was concentrated by evaporation. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 2/1-->1/1) and was led from a solvent mixture of 2/1 n-hexane/ethyl acetate. The obtained crystals were collected were collected by filtration, receiving and 31.7 g of target compound.

Melting point: 190-191oC.

(1-2A) 5-{ 4-[5-(4-Hydroxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b]pyridine-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 27.0 g 5-{4-[5-(4-acetoxy-2,3,5-trimethylphenol)-3-m ml of acetic acid was stirred at 80oC for 5 hours and then poured into ice-cold water. To the mixture for neutralization was added sodium carbonate. To the mixture was added ethyl acetate and the insoluble substance was filtered. The residue was washed with ethanol, getting 10.2 g specified in the connection header. In addition, from the filtrate was separated organic layer and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, followed by washing with saturated saline and dried over anhydrous sodium sulfate.The solvent is then drove away under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 1/1-->1/2-->ethyl acetate) followed by crystallization from ethanol. The crystals were collected by filtration, thus obtaining 6,90 g specified in the connection header.

Melting point: 215-217oC.

(1-2b) Hydrochloride 5-{4-[5-(4-hydroxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b]pyridine-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 10.2 g 5-{4-[5-(4-hydroxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b] pyridine-2-ylethoxy] benzyl} thiazolidine-2,4-dione, 100 ml of ethyl acetate and 100 ml of a mixture of 4 N. florodora acid/ethyl acetate was stirred h the reaction mixture was filtered, the crystals, while receiving 10.7 g specified in the connection header.

Melting point: 148-150oC.

Example 2

5-{ 4-[6-(4-Hydroxy-2,3,5-trimethylphenol)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-650)

(2-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-methoxyethoxy-2,3,5-trimethylphenol )phenyl}-N-methylcarbamate

To a mixture of 18.7 g of tert-butyl N-[2-amino-5-(4-methoxyethoxy - 2,3,5-trimethylphenol)phenyl} -N-methylcarbamate, of 12.6 g of 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 4,55 g of triethylamine and 300 ml of anhydrous tetrahydrofuran was added 7,34 g diethylthiophosphate. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated by evaporation. To the concentrate was added water. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 1/1), to thereby obtain 23.1 g of the target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/atlasi]benzyl}thiazolidine-2,4-dione

0,49 g of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-methoxyethoxy-2,3,5-trimethylphenol)phenyl} -N-methylcarbamate was dissolved in 10 ml of 4 n solution florodora acid/dioxane. The resulting solution was left at room temperature for 2 days. To the reaction mixture were added water and aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent is then drove away under reduced pressure. The residue was purified by chromatography on a column of silica gel using ethyl acetate as an eluting solvent, to thereby obtain 0.27 g specified in the connection header.

Softening temperature: 137-147oC.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/2): the value of Rf=0.21 in.

(2-2b) Hydrochloride 5-{ 4- [6-(4-hydroxy-2,3,5-trimethylphenol)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl} thiazolidine-2,4-dione

18.0 g of the crude product 5-{4- [6-(4-hydroxy-2,3,5-trimethylphenol)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione was isolated and purified by chromatography on a column of silica gel using ethyl acetate as an eluting Uspenskiy was stirred over night at room temperature. From the reaction mixture was filtered, the crystals were washed with ethyl acetate, thus obtaining 14,7 g specified in the connection header.

Melting point: 160-165oC.

Example 3

5-{4-[6-(4-Hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-yl-methoxy]benzyl} thiazolidine-2,4-dione (Illustrative compound 1-70)

(3-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-hydroxyphenoxy)phenyl}-N-methylcarbamate

When using 0,79 g of tert-butyl N-[2-amino-5-(4-hydroxyphenoxy)phenyl} -N-methylcarbamate, 0.84 g of 4-(2,4 - dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 0,49 g diethylthiophosphate, of 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran spent interaction and cleaning method similar to that described in example (2-1), thus obtaining 1,49 g of target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/2): the value of Rf=0.35 in.

(3-2) 5-{ 4-[6-(4-Hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione

Using 1,49 g of tert-butyl N-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-hydroxyphenoxy) phenyl}-N-methylcarbamate and 10 ml of 4 n solution florodora keys the way they 0.26 g of the target compound.

Melting point: 126-131oC.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/3): Rf value=0,13.

Example 4

5-{ 4-[6-(4-Hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-520)

(4-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-methoxyethoxy-3,5-dimethylphenoxy )phenyl}-N-methylcarbamate

Using 0.96 g of tert-butyl N-[2-amino-5-(4-methoxyethoxy-3,5-dimethylphenoxy)phenyl} -N-methylcarbamate, 0.84 g of 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 0,49 g diethylthiophosphate, of 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, were interaction and cleaning method similar to that described in example (2-1), thus obtaining 1.44 g of the target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/1): Rf value=0,27.

(4-2A) 5-{ 4-[6-(4-Hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

Using 1.44 g of tert-butyl N-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-methoxy-methoxy-3,5-dimethylphenoxy)f the weave method, similar to that described in example (2-2A), thus obtaining 0,62 g specified in the connection header.

Melting point: 147-157oC.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/2): the value of Rf=0.21 in.

(4-2b) Hydrochloride 5-{ 4-[6-(4-hydroxy-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

Using 3.11 g 5-{4-[6-(4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and 50 ml of 4 n solution florodora acid/acetate, interaction and purification was carried out by a method similar to that described in example (2-2b), thus obtaining 3,18 g specified in the connection header.

Melting point: 206-209oC.

Example 5

5-{ 4-[6-(2-Chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-368)

(5a) 5-{ 4-[6-(2-Chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

The mixture 9,19 g of tert-butyl N-[5-(2-chloro-4-methoxyethoxy-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate, 2.5 g of 10% palladium on coal and 400 ml of methanol online is iltrovatore and the solvent from the filtrate drove away under reduced pressure. The residue was dissolved in 250 ml of anhydrous tetrahydrofuran. To the resulting solution was added to 15.8 g of 4-(2, 4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 9,18 g diethylthiophosphate and 5.69 g of triethylamine. The resulting mixture was stirred at room temperature for 64 hours. The reaction mixture was concentrated by evaporation. To the concentrate was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate=1/1) and then was dissolved in 200 ml of 2 n solution florodora acid/dioxane. The resulting solution was left at room temperature for 19 hours. The reaction mixture was concentrated by evaporation. The concentrate was neutralized with an aqueous solution of sodium bicarbonate, followed by extraction with a mixed solvent of ethyl acetate and tetrahydrofuran. The extraction solution was dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate=1/2) and preparative high-performance gidrostaticheskogo in the connection header.

Melting point: 240-243oC.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/2): the value of Rf=0.21 in.

(5b) Hydrochloride 5-{ 4-[6-(2-chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

Using 2,54 g 5-{4-[6-(2-chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and 50 ml of 4 n solution florodora acid/acetate, interaction and purification was carried out by a method similar to that described in example (2-2b), thus obtaining 2.67 g specified in the connection header.

Melting point: 174-176oC.

Example 6

5-{ 4-[6-(Pyridine-2-yloxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-821)

(6-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(pyridine-2-yloxy)phenyl}-N-methylcarbamate

A mixture of 0.34 g of tert-butyl N-[2-nitro-5-(pyridine-2-yloxy)phenyl]-N-methylcarbamate, 50 mg of 10% palladium on coal and 10 ml of methanol was intensively stirred at room temperature for 90 minutes in an atmosphere of hydrogen. Then the reaction mixture was filtered, the catalyst and rastvoriaetsia was added 0.34 g of 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 0.20 g diethylthiophosphate and 0.12 g of triethylamine and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated by evaporation. To the concentrate was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate=1/2), thus receiving and 0.37 g of the target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/2): Rf value=0,36.

(6-2) 5-{ 4-[6-(Pyridine-2-yloxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione

Using of 0.37 g of tert-butyl N-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(pyridine-2-yloxy)phenyl}-N-methylcarbamate and 20 ml of 4 n solution florodora acid/dioxane, cooperated and cleaning method similar to that described in example (2-2A), thus obtaining 0.20 g specified in the connection header.

Melting point: 200-210oC.

Thin layer chromatography on silica gel (manifesting solvent: ethyl acetate): Rf value=0,28.imidazol-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-595)

(7-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(3,5-di-tert-butyl-4-hydroxyphenethyl)phenyl} -N-methylcarbamate

The mixture 359 mg of tert-butyl N-[2-nitro-5-(3,5-di-tert-butyl-4-hydroxyphenethyl)phenyl]-N-methylcarbamate, 360 mg 10% palladium on coal and 50 ml of methanol was intensively stirred at room temperature for 9 hours in an atmosphere of hydrogen. Then the reaction mixture was filtered, the catalyst and the solvent drove away under reduced pressure. The residue was dissolved in 20 ml of anhydrous tetrahydrofuran. To the resulting solution was added 248 mg of 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 144 mg diethylthiophosphate and 89 mg of triethylamine. The resulting mixture was left at room temperature for 15 hours. The reaction mixture was concentrated by evaporation. To the concentrate was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate= 3/2), thus obtaining 275 mg of the target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/utilize idazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

259 mg of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(3,5-di-tert-butyl-4-hydroxy-phenylthio)phenyl}-N-methylcarbamate was dissolved in 10 ml of 4 n solution florodora acid/dioxane. The resulting solution was left at room temperature for 18 hours. The reaction mixture was evaporated to dryness under reduced pressure. After adding ether, the insoluble substance was collected by filtration and washed with ether. The obtained solid was purified by thin-layer chromatography with reversed phase (the solvent: acetonitrile/water=5/1), thus obtaining 115 mg specified in the connection header.

Melting point: 120-123oC.

(7-2b) Hydrochloride 5-{4-[6-(3,5-di-tert-butyl-4 - hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

Using to 2.29 g 5-{4-[6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and 4 N. the solution florodora acid/acetate, cooperated and cleaning method similar to that described in example (2-2b), thus obtaining a 1.25 g specified in the connection header.

Melting point: 144-146oC.

Example 8

5-{ 4-[6-(4-Am the administrative connection 1-739)

(8-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl}-N-methylcarbamate

Using 1.56 g of tert-butyl N-[2-amino-5-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl} -N-methylcarbamate, of 1.05 g of 4-(2,4-dioxothiazolidine-5-ilma-Tyl)peroxyoctanoic acid, and 0.61 g diethylthiophosphate, of 0.38 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, were interaction and cleaning method similar to that described in example (2-1), thus obtaining 1,89 g of target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 3/2): Rf value=0,19.

(8-2A) 5-{4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-

the benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

Using 1.88 g of tert-butyl N-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl} -N-methylcarbamate and 20 ml of 4 n solution florodora acid/dioxane, cooperated and cleaning method similar to that described in example (2-2A), thus obtaining 0.26 g specified in the connection header.

Melting point: 209-211oC.

Thin-layer is (b) Dihydrochloride 5-{4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

Using 0.25 g 5-{4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and 50 ml of 4 n solution florodora acid/acetate, cooperated and cleaning method similar to that described in example (2-2b), thus obtaining 0.25 g specified in the connection header.

Melting point: 165-175oC.

Example 9

Hydrochloride 5-{ 4-[6-(4-acetylamino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-808)

A mixture of 155 mg of the dihydrochloride 5-{4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione, 36 mg of acetic anhydride, 107 mg of pyridine, and 7.3 mg of 4-(N,N-dimethylamino) pyridine and 5 ml of anhydrous tetrahydrofuran was heated at the boil under reflux for 2 hours. The reaction mixture was concentrated by evaporation. To the concentrate was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. To the residue was added 10 ml of 4 n solution florodora acid/ethyl acetate, followed by stirring at room temperature for 21 hours. Nera the connection.

Softening point: 160-165oC.

Example 10

5-{ 4-(1-Methyl-6-[2-(morpholine-4-yl)phenoxy] -1H-benzimidazole-2-ylethoxy)benzyl}thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-284)

(10-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[2-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamate

Using 1.18 g of tert-butyl N-(2-amino-5-[2-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamate, to 0.92 g of 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 0,53 g diethylthiophosphate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, spent interaction and cleaned in a manner analogous to example (2-1), thus obtaining 1.47 g of the target compound.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/1): Rf value=0,30.

(10-2A) 5-{ 4-(1-Methyl-6-[2-(morpholine-4-yl)phenoxy]-1H-benzimidazole-2-ylethoxy)benzyl}thiazolidine-2,4-dione

Using 1.45 g of tert-butyl N-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-[2-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamate and 20 ml of 4 n solution florodora acid/dioxane, worked together and cleaned in a manner analogous to example (2-2A), thus obtaining 0,94 g decree is l: n-hexane/ethyl acetate=1/2): Rf value=0,33.

(10-2b) Dihydrochloride 5-{4-(1-methyl-6-[2-(morpholine-4-yl)phenoxy]-1H-benzimidazole-2-ylethoxy)benzyl}thiazolidine-2,4-dione

In a mixture of 30 ml of concentrated hydrochloric acid and 30 ml of 1,4-dioxane was dissolved 0.64 g of 5-{4-(1-methyl-6-[2-(morpholine-4-yl) phenoxy]-1H-benzimidazole-2-ylethoxy)benzyl} thiazolidine-2,4-dione. The resulting solution was stirred at room temperature for 90 minutes. The reaction mixture was evaporated to dryness followed by addition of ether. The insoluble product was filtered and washed with ether, thus obtaining 0.71 g specified in the connection header.

Softening temperature: 120-130oC.

Example 11

The dihydrochloride of 5-{ 4-(1-methyl-6-[3-(morpholine-4-yl)phenoxy]-1H-benzimidazole-2-ylethoxy)benzyl} thiazolidine-2,4-dione (Illustrative compound 1-292)

(11-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[3-(morpholine-4-yl)phenoxy]phenyl }-N-methylcarbamate

Using 1.18 g of tert-butyl N-{2-amino-5-[3-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamate, to 0.92 g of 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid, 0,53 g diethylthiophosphate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, spent interaction and cleaned in a manner analogous to example (2-1), Paul is the third solvent: n-hexane/ethyl acetate = 1/1): Rf value=0,26.

(11-2) the Dihydrochloride of 5-{4-(1-methyl-6-[3-(morpholine-4-yl)phenoxy]-1H-benzimidazole-2-ylethoxy)benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-[3-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamate and 20 ml of 4 n solution florodora acid/dioxane was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure followed by the addition of ether. The insoluble product was filtered and washed with ether, thus obtaining 1.27 g specified in the connection header.

Softening temperature: 150-160oC.

Example 12

The dihydrochloride of 5-{ 4-(1-methyl-6-[2-(piperidine-4-yl)phenoxy] -1H-benzimidazole-2-ylethoxy)benzyl} thiazolidine-2,4-dione (Illustrative compound 1-241)

(12-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[2-(piperidine-1-yl)phenoxy]phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1) using tert-butyl N-{2-amino-5-[2-(piperidine-1-yl)phenoxy] phenyl}-N-methylcarbamate (1.19 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,93 g), diethylthiophosphate (0.54 g), triethylamine (0.33 g) and anhydrous cromatografia on the plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,39.

(12-2) Dihydrochloride 5-{4-(1-methyl-6-[2-(piperidine-1-yl)phenoxy]-1H-benzimidazole-2-ylethoxy)benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[2-(piperidine-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.80 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 19 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the insoluble product was collected by filtration and subjected to high performance liquid chromatography with reversed phase, using as eluent a mixture of acetonitrile/water = 1/1 and then was treated with 4 N. solution of hydrogen chloride/ethyl acetate, getting mentioned in the title compound (0.47 in).

So pl.: 151-154oC.

Example 13

5-{4-[1-Methyl-6-(pyridine-2-ylthio)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-823)

(13-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(pyridine-2-ylthio)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(pyridine-2-ylthio)phenyl]-N-methylethylamine (0,38 g) and anhydrous tetrahydrofuran (20 ml), and the reaction mixture was purified by receiving the target product (0.68 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,51.

(13-2) 5-{ 4-[1-Methyl-6-(pyridine-2-ylthio)-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione

By the way, is similar to that described in example (2-2A), reaction was performed using tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(pyridine-2-ylthio)phenyl}-N-methylcarbamate (0,63 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified by receiving specified in the title compound (0.20 g).

Thin-layer chromatography plate with silica gel using ethyl acetate: Rf=0,26.

(13-2b) Dihydrochloride 5-{4-[1-methyl-6-(pyridine-2-ylthio)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

By the way, is similar to that described in example (2-2b) was subjected to reaction using 5-{ 4-[1-methyl-6-(pyridine-2-ylthio) -1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (0.20 g) and 4 n solution of hydrogen chloride/ethyl acetate (50 ml) and the reaction mixture was purified by receiving specified in the title compound (0.21 g).

So pl.: 139-147oC.

Example 14

5-{ 4-(1-Methyl-6-[2-(R> (14-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-[2-(pyrrolidin-1-yl)phenoxy] phenyl }-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-[2-(pyrrolidin-1-yl)phenoxy] phenyl} -N-methylcarbamate (0,77 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,90 g), diethylthiophosphate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified by receiving the target product (1.26 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0.40 in.

(14-2) 5-{4-(1-Methyl-6-[2-(pyrrolidin-1-yl)phenoxy]-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

The interaction was carried out by a method similar to that described in example (2-2A), using tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methylcarbamate (1,25 g) and 4 n solution of hydrogen chloride/dioxane (25 ml) and the reaction mixture was purified by receiving specified in the header connection (0,94 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,27.


(15-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(2-hydroxyphenoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(2-hydroxyphenoxy)phenyl}-N-methylcarbamate (0,99 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,93 g), diethylthiophosphate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (1.18 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/3: Rf=0,47.

(15-2) Hydrochloride 5-{ 4-[6-(2-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

By the way, is similar to that described in example (2-2A), reaction was performed using tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(2-hydroxyphenoxy)phenyl} -N-methylcarbamate (1/16 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified, and then a method similar to that described in example (2-2b), the product was subjected to interaction with 4 N. solution of hydrogen chloride/ethyl acetate (20 ml) and was purified by receiving specified in the header of the connection (0-1H-benzimidazole-2-ylethoxy)benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1182)

(16-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[4-(1-of substituted)phenoxy]phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-{2-amino-5-[4-(1-substituted)phenoxy] phenyl}-N-methylcarbamate (1, 34 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,93 g), diethylthiophosphate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (1,83 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,29.

(16-2) Hydrochloride 5-{ 4-(6-[4-(1-of substituted)phenoxy]-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-[4-(1-of substituted)phenoxy] phenyl} -N-methylcarbamate (1,82 g) and 4 N. hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 29 hours. The solvent of the reaction mixture was evaporated to dryness and to the residue was added ether, and the insoluble product was filtered and washed with ether, getting mentioned in the title compound (1.35 g).

So pl.: 160-165oC.


(17-1) tert-Butyl N-{ 5-(3-dimethylaminopropoxy)-2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]phenyl}-N-methyl-carbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(3-dimethylaminopropoxy)phenyl] -N-methylcarbamate (1,00 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1,57 g), diethylthiophosphate (0,91 g), triethylamine (0,57 g) and anhydrous tetrahydrofuran (40 ml) and the reaction mixture was purified by receiving the target product (1,69 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,26.

(17-2) 5-{ 4-[6-(3-Dimethylaminopropoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

The interaction was carried out by a method similar to that described in example (2-2A), using tert-butyl N-{ 5-(3-dimethylaminopropoxy)-2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] phenyl} -N-methylcarbamate (1.68 g) and 4 n solution of hydrogen chloride/dioxane (30 ml) and the reaction mixture was purified by receiving specified in the header of the connection (or 0.57 g). So pl.: 180-186oC.

Example 18

The dihydrochloride of 5-{ 4-[1-Methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-ylethoxy]benzyl}tiato is tetramino]-5-(pyridine-3-yloxy)phenyl}-N-methyl-carbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(pyridine-3-yloxy)phenyl]-N-methylcarbamate (0,63 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,62 g), diethylthiophosphate (0.36 g), triethylamine (0,22 g) and anhydrous tetrahydrofuran (15 ml) and the reaction mixture was purified by receiving the target product (0.88 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,38

(18-2) of the Dihydrochloride Of 5-{ 4-[1-Methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(pyridine-3-yloxy)phenyl}-N-methylcarbamate (0.87 g) and 4 n solution of hydrogen chloride/dioxane (15 ml) was stirred at ambient temperature for 4.5 hours and left for 9 days at ambient temperature. The insoluble product was collected by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,77 g).

So pl.: 146-156oC.

Example 19

The dihydrochloride 5-{ 4-(6-[4-(imidazol-1-yl)phenoxy]-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compounds which enyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-{2-amino-5-[4-(imidazol-1-yl)phenoxy] phenyl}-N-methylcarbamate (1,14 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,93 g), diethylthiophosphate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified by receiving the target product (1.75 g).

Thin-layer chromatography plate with silica gel using a mixture of ethyl acetate/methanol = 10/1, Rf=0,51

(19-2) Dihydrochloride 5-{4-(6-[4-(imidazol-1-yl)phenoxy]-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-[4-(imidazol-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.75 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 19 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the insoluble product was collected by filtration. The product was purified by high-performance liquid chromatography with reversed phase, using as eluent a mixture of acetonitrile/water = 7/13 and was treated with 4 N. solution of hydrogen chloride/acetate, receiving the criminal code of the 4-[1-methyl-6-(2-phenyleneoxy)-1H-Benzema-Gasol-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1327)

(20-1) of tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(2-phenyleneoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(2-phenyleneoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1.26 g), diethylthiophosphate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (2,33 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/2: Rf=0.25 in

(20-2) of the Hydrochloride of 5-{4-[1-methyl-6-(2-phenyleneoxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(2-phenyleneoxy)phenyl}-N-methylcarbamate (2,33 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 20 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the insoluble product was collected by filtration and washed with ethyl acetate, getting mentioned in the title compound (1,87 g).

So pl.: 142-152oC.

Example 21-dione (Illustrative compound 1-506)

(21-1) of tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-hydroxy-2,3-dimethylphenoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-hydroxy-2,3-dimethylphenoxy)phenyl] -N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1,38 g), diethylthiophosphate (0,80 g), triethylamine (0.50 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (2.35 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,54

(21-2) Hydrochloride 5-{4-[6-(4-hydroxy-2,3-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-hydroxy-2,3-dimethylphenoxy)phenyl}-N-methylcarbamate (2.35 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 44 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the insoluble product was collected by filtration and washed with ethyl acetate, getting mentioned in the title compound (Intimidator-2-ylethoxy]benzyl}thiazolidine-2,4-dione

(Illustrative compound 1-193)

(22-1) of tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-phenoxyphenoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (1.66 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1.26 g), diethylthiophosphate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (1,99 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,62

(22-2) of the Hydrochloride of 5-{4-[1-methyl-6-(4-phenoxyphenoxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-phenoxyphenoxy)phenyl}-N-methylcarbamate (1,99 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 22 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the insoluble product was collected by filtration and washed with ethyl acetate, getting mentioned in the title compound (1.57 in g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,19

(23-2b) Hydrochloride 5-{4-[6-(4-Hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

By the way, is similar to that described in example (2-2b) cooperated with the use of 5-{4-[6-(4-hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (0,72 g) and 4 n solution of hydrogen chloride/ethyl acetate (40 ml) and the reaction mixture was purified by receiving specified in the header is connected to benzimidazol-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-168)

(24-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(3-phenyleneoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(3-phenyleneoxy)phenyl]-N-methylcarbamate (1/60 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1.26 g), diethylthiophosphate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (to 2.57 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,32

(24-2) of the Hydrochloride of 5-{4-[1-methyl-6-(3-phenyleneoxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(3-phenyleneoxy)phenyl}-N-methylcarbamate (to 2.57 g) and 4 n solution of hydrogen chloride/dioxane (30 ml) was stirred at room temperature for 63 hours. The solvent of the reaction mixture was evaporated to dryness, the residue was added ethyl acetate, and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (2,01 g).

So pl.: 150-160oWITH

Example 25

Hydrohematite connection 1-501)

(25-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(3-tert-butyl-4-hydroxyphenoxy)phenyl }-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(3-tert-butyl-4-hydroxyphenoxy)phenyl] -N-methylcarbamate (1,11 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,89 g), diethylthiophosphate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (1.75 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,26

(25-2) Hydrochloride 5-{4-[6-(3-tert-butyl-4-hydroxyphenol-si)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(3-tert-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.75 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 14 hours. The solvent of the reaction mixture was evaporated to dryness, the residue was added ethyl acetate and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (1,11 g).


(26-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(2-tert-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5- (2-tert-butyl-4-hydroxyphenoxy)phenyl] -N-methylcarbamate (0.95 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,76 g), diethylthiophosphate (0,44 g), triethylamine (0.27 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (1.24 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,19

(26-2) Hydrochloride 5-{ 4-[6-(2-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(2-tert-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.24 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 14 hours. The solvent of the reaction mixture was evaporated to dryness, the residue was added ethyl acetate, and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound imidazol-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-169)

(27-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-phenyleneoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-phenyleneoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1.26 g), diethylthiophosphate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (2,39 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,32

(27-2) of the Hydrochloride of 5-{4-[1-methyl-6-(4-phenyleneoxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-phenyleneoxy)phenyl}-N-methylcarbamate (2,39 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 21 hours. The solvent of the reaction mixture was evaporated to dryness, the residue was added ethyl acetate, and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (1.90 g).

So pl.: 170-180oC.

Example 28

G is illustrative connection 1-513)

(28-1) of tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-hydroxy-2,5-dimethylphenoxy)phenyl }-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl] -N-methylcarbamate (0.54 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0.51 g), diethylthiophosphate (0.29 grams), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified by receiving the target product (0.71 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,68

(28-2) Hydrochloride 5-{4-[6-(4-hydroxy-2,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetamide] -5- (4-hydroxy-2,5-dimethylphenoxy) phenyl}-N-methylcarbamate (0.71 g) and 4 n solution of hydrogen chloride/dioxane (10 ml) was stirred at room temperature for 17 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate, and the insoluble product was isolated by filtration and subjected to high performance liquid chromatography with reversed f the th hydrogen/ethyl acetate, getting listed in the title compound (0,41 g).

So pl.: 170-171oC.

Example 29

Hydrochloride 5-{ 4-[6-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-593)

(29-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(3,5-di-tert-butyl-4-hydroxyphenoxy)phenyl} -N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(3,5-di-tert-butyl-4-hydroxyphenoxy)phenyl] -N-methyl-carbamate (0.55 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)Hairdryer-exucuse acid (0,42 g), diethylthiophosphate (0.24 g), triethylamine (0.15 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified, receiving target product (0,72 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,68

(29-2) Hydrochloride 5-{4-[6-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazole-DIN-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(3,5-di-tert-butyl-4-hydroxy-phenoxy)phenyl }-N-methylcarbamate (0,72 g) and 4 n solution of hydrogen chloride/Diwali dry. To the residue was added ethyl acetate and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,41 g).

So pl.: 173-178oC.

Example 30

Hydrochloride 5-{ 4-[6-(4'-hydroxybiphenyl-4-yloxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-171)

(30-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4'-hydroxybiphenyl-4-yloxy)phenyl }-N-methylcarbamate

A mixture of tert-butyl N-[2-amino-5-(4'-hydroxybiphenyl-1 yloxy)phenyl]-N-methylcarbamate (0,61 g), 4-(2, 4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0.51 g), diethylthiophosphate (0.29 grams), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) was stirred at ambient temperature for 2 days. The reaction mixture was concentrated, and the residue was distributed between ethyl acetate and water. An ethyl acetate layer was dried over anhydrous sodium sulfate. The ethyl acetate drove under reduced pressure and the residue was purified by chromatography on a column of silica gel using as eluent a mixture of n-hexane/ethyl acetate=1/1, obtaining the target product.

(30-2) Hydrochloride 5-{ 4-[6-(4'-hydroxybiphenyl-4-yloxy)-1-methyl-1H-benzimidazol-amino] -5-(4'-hydroxybiphenyl-4-yloxy)phenyl} -N-methylcarbamate (2,39 g) in 4 B.C. the solution of hydrogen chloride/dioxane (20 ml) was left at room temperature for 4 days. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate, and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,23 g).

So pl.: 160-163oC.

Example 31

Hydrochloride 5-{ 4-[6-(4-hydroxy-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-481) and hydrochloride 5-{4-[6-(4-hydroxy-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-486)

(31-1) of tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-hydroxy-2-methylphenoxy)phenyl}-N-methylcarbamate

The interaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-hydroxy-2-methylphenoxy)phenyl] -N-methylcarbamate and N-[2-amino-5-(4-hydroxy-3-methylphenoxy)phenyl] -N-methylcarbamate (1.88 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1,69 g), diethylthiophosphate (0,98 g), triethylamine (0,61 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified by receiving the target product (1,57 g).


(31-2) Hydrochloride 5-{4-[6-(4-hydroxy-2-methylphenoxy)- 1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione and

(31-2b) Hydrochloride 5-{ 4-[6-(4-hydroxy-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-hydroxy-2-methylphenoxy)phenyl}-N-methylcarbamate and tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)PHENOXYACETIC-amino]-5-(4-hydroxy-3-methylphenoxy)phenyl} -N-methylcarbamate (1,57 g) and 4 n solution of hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 66 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the insoluble product (1.24 g) was isolated by filtration and purified by high-performance liquid chromatography with reversible phase using a mixture of acetonitrile/water containing acetic acid (0.2 percent) and triethylamine (0.2 per cent),=2/3, and then was treated with 4 N. solution of hydrogen chloride/ethyl acetate, getting hydrochloride 5-{4-[6-(4-hydroxy-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-olmetec-C] benzyl} thiazolidin-2,4-dione (50 mg; so pl. 165-168oC) and hydrochloride 5-{4-[6-(4-hydroxy-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-is si]-1-methyl-1H-benzimidazole-2-ylethoxy} benzyl] thiazolidin - 2,4-dione (Illustrative compound 1-1269)

To a solution of hydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione (400 mg), cyclopentanecarbonyl acid (204 mg) and triethylamine (304 mg) in dimethylformamide (8 ml) was added the hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (287 mg). The mixture was stirred at ambient temperature for 1 hour and left for 2 nights. The reaction mixture was concentrated, and the residue was distributed between ethyl acetate and water. An ethyl acetate layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the ethyl acetate evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of n-hexane/ethyl acetate = 1/2 - 1/3 as eluent, receiving the remainder. The residue was recrystallized from a mixture of n-hexane/ethyl acetate = 1/3, obtaining the target compound (176 mg).

So pl.: 159,8-162,0oC.

Example 33

Hydrochloride 5-{ 4-[6-(4-benzyl-3-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (Illustrative compound 1-1230)

(33-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-benzyl-3-hydroxyphenoxy)phenyl}-N-methylcarbamate and tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-yl and by the way, similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-benzyl-3-hydroxyphenoxy)phenyl] -N-methylcarbamate (1.8 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (1,16 g), diethylthiophosphate (0,99 g), triethylamine (0,76 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified by receiving the target product (1.5 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,32

(33-2) Hydrochloride 5-{ 4-[6-(4-benzyl-3-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-benzyl-3-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.4 g) in 4 BC solution of hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 3 days. Adding ethyl acetate and n-hexane obrazovalsya insoluble product was isolated by filtration, getting mentioned in the title compound (1.5 g).

So pl.: 205-219oC.

Example 34

5-{ 4-[1-Methyl-6-(4-methylthiophene)-1H-benzimidazole-2-ylethoxy]benzyl} thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-136)

(34-1) tert-Butyl N-{2-[4-(2,4-dioxo who have been by way similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-methylthiophene)phenyl]-N-methylcarbamate (1,93 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (3,01 g), diethylthiophosphate (1,75 g), triethylamine (1.08 g) and anhydrous tetrahydrofuran (80 ml) and the reaction mixture was purified by receiving the target product (2,96 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 7/3: Rf=0,11

(34-2A) 5-{4-[1-Methyl-6-(4-methylthiophene)-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione

Similar to that described in example (2-2A) cooperated with the use of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-methylthiophene)phenyl} -N-methylcarbamate (2,95 g) and 4 n solution of hydrogen chloride/dioxane (60 ml) and the reaction mixture was purified by receiving specified in the title compound (2.15 g).

So pl.: 199-200oC.

(34-2b) of the Hydrochloride of 5-{ 4-[1-methyl-6-(4-methylthiophene)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

The reaction was carried out by a method similar to that described in example (2-2b), using 5-{ 4-[1-methyl-6-(4-methylthiophene) -1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (1,15 g) the compound (1.06 g).

So pl.: 137-147oC.

Example 35

5-{ 4-[1-Methyl-6-(4-methoxyphenoxy)-1H-benzimidazole-2-yl-methoxy]benzyl} thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-132)

(35-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-methoxyphenoxy)phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-methoxyphenoxy)phenyl]-N-methylcarbamate (2.0 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (2.0 g), diethylthiophosphate (1.3 g), triethylamine (0,81 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified by receiving the target product (3.3 grams).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,61

(35-2A) 5-{4-[1-Methyl-6-(4-methoxyphenoxy)-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione

A solution of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-methoxyphenoxy)phenyl}-N-methylcarbamate (3.28 g) in triperoxonane acid (50 ml) was stirred at 65oC for 8 hours and left for 1 night at ambient temperature. The reaction mixture was concentrated and to the residue was added water and naiively saturated water

a solution of sodium chloride and dried over anhydrous sodium sulfate, and then evaporated. Adding a mixture of ether/ethyl acetate =1/1 to the residue formed crystals, and was isolated by filtration, getting mentioned in the title compound (1,91 g).

So PL: 122-126oC.

(35-2b) of the Hydrochloride of 5-{ 4-[1-methyl-6-(4-methoxyphenoxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

The reaction was carried out by a method similar to that described in example (2-2b), using 5-{ 4-[1-methyl-6-(4-methoxyphenoxy)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (1.8 g) and a 4 n solution of hydrogen chloride/ethyl acetate (50 ml) and the reaction mixture was purified by receiving specified in the title compound (1.85 g).

So PL: 148-151oC.

Example 36

5-{ 4-[1-Methyl-6-(4-triptoreline)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-131)

(36-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ilma-Tyl)phenoxyacetamide]-5-(4-triptoreline)phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-triptoreline)phenyl]-N-methylcarbamate (0.68 g), 4-(2,4-dioxothiazolidine-5-ILEA (50 ml), and the reaction mixture was purified by receiving the target product (0.97 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,23

(36-2A) 5-{ 4-[1-Methyl-6-(4-triptoreline)-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A solution of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-triptoreline)phenyl} -N-methylcarbamate (0.95 g) in triperoxonane acid (20 ml) was stirred at 60oC for 3 hours and left over night at ambient temperature. The reaction mixture was concentrated and to the residue was added water and neutralized with an aqueous solution of sodium bicarbonate (5%). The mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated. The residue was purified by chromatography on a column of silica gel using as eluent n-hexane/ethyl acetate =1/2, taking specified in the header connection (0,60 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,29

(36-2b) of the Hydrochloride of 5-{4-[1-methyl-6-(4-triptoreline) -1H-benzimidazole-2-ilmetessaan 5-{ 4-[1-methyl-6-(4-triptoreline)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (of 0.58 g) and 4 N. solution of hydrogen chloride/ethyl acetate (20 ml) and the reaction mixture was purified by receiving specified in the title compound (0.55 g).

So PL: 145-147oC.

Example 37

Hydrochloride 5-{ 4-[6-(4-benzoylperoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-184)

(37-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(4-benzoylperoxy)phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(4-benzoylperoxy)phenyl]-N-methylcarbamate (0,61 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0.51 g), diethylthiophosphate (0.29 grams), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified by receiving the target product (0,91 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,26

(37-2) Hydrochloride 5-{4-[6-(4-benzoylperoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(4-benzoylperoxy)phenyl}-N-methylcarbamate (0,91 g) 4 N. solution of hydrogen chloride/dioxane (10 ml) was left at temperate, and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,69 g).

So PL: 170-180oC.

Example 38

Hydrochloride 5-{ 4-[6-(3-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-41)

(38-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-(3-hydroxyphenoxy)phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(3-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.95 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,89 g), diethylthiophosphate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified by receiving the target product (1.18 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,28

(38-2) Hydrochloride 5-{ 4-[6-(3-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(3-hydroxyphenoxy)phenyl} -N-methylcarbamate (1.18 g) in 4 BC solution of hydrogen chloride/dioxane (20 ml) stableloader ethyl acetate, and the mixture was irradiated with ultrasonic waves. The insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,86 g).

So PL: 192-195 (in Russian)oC.

Example 39

Hydrochloride 5-[4-{ 6-[4-(tetrazol-5-yl)phenoxy] -1-methyl-1H-benzimidazole-2-ylethoxy} benzyl] thiazolidin-2,4-dione (Illustrative compound 1-1154)

(39-1) tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]-5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-{2-amino-5-[4-(tetrazol-5-yl)phenoxy]phenyl]-N-methylcarbamate (0,69 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0,37 g), diethylthiophosphate (0.21 g), triethylamine (0,13 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified by receiving the target product (0,76 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,49

(39-2) Hydrochloride 5-[4-{ 6-[4-(tetrazol-5-yl)phenoxy]-1-methyl-1H-benzimidazole-2-ylethoxy}benzyl]thiazolidin-2,4-dione

A mixture of tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetamide] -5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylchrysene 24 hours. The solvent of the reaction mixture was evaporated. To the residue was added ethyl acetate and the insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,44 g).

So PL: 232-235oC.

Example 40

Hydrochloride 5-{ 4-[6-(4-cianfrocca)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1210)

The mixture 5-{ 4-[6-(4-cianfrocca)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} -3-triphenyltetrazolium-2,4-dione (0,69 g) and an aqueous solution of acetic acid (80%, 25 ml) was stirred at 70oC for 3 hours. The reaction mixture was concentrated and to the residue was added an aqueous solution of sodium bicarbonate (10%, 250 ml). The mixture was stirred at ambient temperature for several hours. The insoluble product was isolated by filtration and dried in the air, getting 5-{4-[6-(4-cianfrocca)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione. A mixture of the obtained product and a 4 n solution of hydrogen chloride/dioxane was stirred at ambient temperature for 2 hours. The insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (0,41 g).

So EIP)benzyl]thiazolidin-2,4-dione (Illustrative compound 1-1235)

(41) 5-[4-(6-Pantothenate-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione

A mixture of 2-hydroxymethyl-1-methyl-6-Pantothenate-1H-benzimidazole (1,17 g), 5-(4-hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione (1.86 g), azodicarbonamide (1.01 g), tri-n-butylphosphine (0,81 g) and toluene (50 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was subjected to chromatography on a column of silica gel. Collected fraction, elyuirovaniya a mixture of n-hexane/ethyl acetate = 3/2, and the solvent was evaporated, receiving 5-[4-(6-Pantothenate-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]-3-three-fenilmetiliden - 2,4-dione. A mixture of this product and aqueous acetic acid (80%, 100 ml) was stirred at 70oC for 1 hour. The reaction mixture was concentrated and then neutralized with an aqueous solution of sodium bicarbonate (10%). The insoluble product was isolated by filtration and washed with water, getting the crystals. The crystals were purified by chromatography on a column of silica gel, using as eluent a mixture of n-hexane/ethyl acetate = 1/1, getting mentioned in the title compound (1.29 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1: the and

The reaction was carried out by a method similar to that described in example (2-2b), using 5-[4-(6-Pantothenate-1 - methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione (1.29 g) and 4 n solution of hydrogen chloride/ethyl acetate (30 ml) and the reaction mixture was purified by receiving specified in the title compound (1.13 g).

So PL: 169-172oC.

Example 42

5-{ 4-[6-(2,5-Di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione and its hydrochloride (Illustrative compound 1-1234)

(42-1) of tert-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(2,5-di-tert-butyl-4-hydroxyphenoxy)phenyl} -N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using tert-butyl N-[2-amino-5-(2,5-di-tert-butyl-4-hydroxyphenoxy)phenyl] -N-methylcarbamate (0.71 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (0.68 g), diethylthiophosphate (0.39 g), triethylamine (0.24 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified by receiving the target product (1.13 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,41

(42-2A) 5-{ 4-[6-(2,5-Di-tert-butyl-4-hydroxyphenoxy)-1-semolina in example (2-2A), using tert-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide] -5-(2,5-di-tert-butyl-4-hydroxyphenoxy)phenyl} -N-methylcarbamate (1.12 g) and 4 n solution of hydrogen chloride/dioxane (25 ml) and the reaction mixture was purified by receiving specified in the title compound (0.73 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0,19

(42-2b) Hydrochloride 5-{ 4-[6-(2,5-di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

The reaction was carried out by a method similar to that described in example (2-2b), using 5-{ 4-[6-(2,5-di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2, 4-dione (0.73 g) and 4 n solution of hydrogen chloride/ethyl acetate (20 ml) and the reaction mixture was purified by receiving specified in the title compound (0.31 g).

So PL: 182-195oC.

Example 43

5-{ 4-[6-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy] benzylidene} thiazolidin-2,4-dione (Illustrative compound 5-135)

A mixture of 4-[6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy] benzaldehyde (502 mg), thiazolidin-2,4-dione (234 mg), piperidine (170 mg) and ethanol (60 matatko was added water, and the insoluble product was isolated by filtration, washed with water and diisopropyl ether, getting mentioned in the title compound (517 mg).

So PL: 247-249oC.

Example 44

5-{ 4-[6-(4-n-Hexylaniline)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1242)

A mixture of tert-butyl N-[2-amino-5-(4-tert-butoxycarbonyl-n-hexylaniline)phenyl] -N-methylcarbamate (4,10 g), 4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyalkanoic acid (2,81 g), diethylthiophosphate (1.63 g), triethylamine (1.01 g) and anhydrous tetrahydrofuran (100 ml) was stirred at ambient temperature for 28 hours. The reaction mixture was concentrated, and the residue was distributed between ethyl acetate and water. An ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The mixture of residue and 4 n solution of hydrogen chloride/dioxane (50 ml) was stirred at ambient temperature for 66 hours. To the reaction mixture were added water and the mixture of neutralizable sodium bicarbonate and was extracted with ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of n-hexane/acilac is S="ptx2">

Example 45

Hydrochloride 5- { 4- (6-[4-(N-acetyl-N-n-hexylamino)phenoxy]-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2, 4-dione (Illustrative compound 1-1318)

The mixture 5-{ 4-[6-(4-n-hexylaniline)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (502 mg), acetic anhydride (112 mg), pyridine (356 mg), 4-(dimethylamino)pyridine (37 mg) and anhydrous tetrahydrofuran was left at ambient temperature for 14 hours. The reaction mixture was concentrated and distributed between ethyl acetate and water, an ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of n-hexane/ethyl acetate = 1/3 and then was treated with 4 N. solution of hydrogen chloride/ethyl acetate (20 ml), getting mentioned in the title compound (410 mg).

Example 46

The dihydrochloride 5-{ 4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-142)

(46-1) tert-Butyl N-{5-(4-aminophenoxy)-2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in example (2-1), using the 5-ylmethyl)phenoxyalkanoic acid (366 mg), diethylthiophosphate (212 mg), triethylamine (132 mg) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified by receiving the target product (395 mg).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/3 Rf=0,51

(46-2) Dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione

A mixture solution of tert-butyl N-{5-(4-aminophenoxy-2-[4-(2, 4-dioxothiazolidine-5-ylmethyl)phenoxyacetamide]phenyl}-N-methylcarbamate (27,08 g) in 1,4-dioxane (50 ml) and 4 n solution of hydrogen chloride/dioxane (150 ml) was stirred at ambient temperature for 2 days. The insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (14,43 g).

So PL: 195oC (decomposition).

Example 47

5-{ 4-[6-(4-Acetylaminophenol)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-164)

The mixture dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (400 mg), acetylchloride (71 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at ambient temperature for 1 hour. R is sasenum aqueous solution of sodium chloride, was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a column of silica gel, using as eluent n-hexane/ethyl acetate=1/4 --> ethyl acetate --> ethyl acetate/methanol = 1/10, getting mentioned in the title compound (320 mg).

So PL: 92,2-95,0oC.

Example 48

5-{ 4-[6-(4-Benzylaminopurine)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1248)

The reaction was carried out by a method similar to that described in example 47, using dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (400 mg), benzoyl chloride (126 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified by receiving specified in the title compound (247 mg).

So PL: 200,2-204,4oC.

Example 49

5-[4-{ 6-[4-(3-Chlorobenzylamino)phenoxy] -1-methyl-1H-benzimidazole-2-ylethoxy}benzyl]thiazolidin-2,4-dione (Illustrative compound 1-1256)

The reaction was carried out by a method similar to that described in example 47, using dihydrochloride 5-{ 4-[6-(4-aminophenoxy) -1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (400 mg), 3-chlorobenzylchloride (123 mg), Tr is lowke compound (232 mg).

So PL: 237,8-238,8oC.

Example 50

5-{ 4-[6-(4-Isonicotinamide)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1311)

The reaction was carried out by a method similar to that described in example 47, using dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (400 mg), isonicotinohydrazide (142 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified by receiving specified in the title compound (306 mg).

So PL: 222oC (decomposition).

Example 51

5-{ 4-[6-(4-Nicotinamidase)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1305)

The reaction was carried out by a method similar to that described in example 47, using dihydrochloride 5-{ 4-[6-(4-aminophenoxy) -1-methyl-1H-benzimidazole-2-ylethoxy] benzyl }tiskiwin-2,4-dione (400 mg), nicotinanilide (195 mg), triethylamine (354 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified by receiving specified in the title compound (297 mg).

So PL: 213,0-214,7oC.

Example 52

5-[4-{ 6-[4-(2,4-Differentiating)phenoxy]-1-methyl-1H-benzimidazo the logical described in example 47, using dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione (400 mg), 2, 4-differentiald (141 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified by receiving specified in the title compound (251 mg).

So PL: which is 171,5-174,2oC.

Example 53

5-[4-{6-[4-(2-naphthylamine)phenoxy]-1-methyl-1H-benzimidazole-2-ylethoxy} benzyl]thiazolidin-2,4-dione (Illustrative compound 1-1277)

The reaction was carried out by a method similar to that described in example 47, using dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione (400 mg), 2-nafolklore (153 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified by receiving the specified C the title compound (337 mg).

So PL: 220,7-222,7oC.

Example 54

5-{ 4-[6-(4-Cyclohexylaminophenol)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1298)

To a solution of cyclohexanecarbonyl acid (90 mg) and triethylamine (232 mg) in anhydrous N, N-dimethylformamide (8 ml) at ambient temperature was added dropwise ethylchloride (87 mg). the mi dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}thiazolidine-2,4-dione (400 mg). The mixture was stirred at 50oC for 1.5 hours. The reaction mixture was concentrated and distributed between ethyl acetate and water. An ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. Adding to the residue ethyl acetate was formed insoluble product was isolated by filtration and washed with ethyl acetate, getting mentioned in the title compound (262 mg).

So PL: 181,7-183,7oC.

Example 55

5-{ 4-[6-(4-Cyclopentanepropionate)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl}thiazolidine-2,4-dione (Illustrative compound 1-1292)

To a solution of cyclopentanecarboxylic acid (90 mg) and triethylamine (232 mg) in anhydrous N, N-dimethylformamide (8 ml) at ambient temperature was added ethylchloride (87 mg). The mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added in small portions dihydrochloride 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl} thiazolidine-2,4-dione (400 mg). The mixture was stirred at ambient temperature for 5 hours and left overnight at the same temperature. After concentration to the reaction mixture was added water, and the insoluble product was isolated by filtrowanie>oC.

Reference example 1

4 Methoxyethoxy-2,3,5-trimethylphenol

50 g of sodium hydride (55% by weight) was washed with n-hexane was then added to 2000 ml of anhydrous tetrahydrofuran. To the mixture was added dropwise to 500 ml of a solution of 240 g of 2,3,6-trimethyl-4-pivaloyloxymethyl in anhydrous tetrahydrofuran for 90 minutes under ice cooling and then the mixture was stirred at room temperature for two hours. To the reaction mixture under ice cooling for 30 minutes was added dropwise 86 ml chloromethylmethylether simple ether, and the mixture was stirred at room temperature for one hour. From the reaction mixture under reduced pressure drove about 50% by volume of tetrahydrofuran. The residue was poured into ice-cold water followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium acetate. The solvent is kept at reduced pressure, thus obtaining 294 g of a yellow oil. The yellow oil was added to 1000 ml of methanol, followed by adding dropwise under ice cooling, 500 ml of a solution of 116 g of potassium hydroxide in methanol. The resulting mixture was stirred at room temperature for one hour. The solvent vodorodnoi acid followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 5/1-->3/1), resulting in 193 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 3/1): the value of Rf=0,47.

Reference example 2

6-(4-Methoxyethoxy-2,3,5-trimethylphenol)-2-methylamino-3-nitropyridine

To a suspension of 50 g of sodium hydride (55% by weight, washed with n-hexane) in 1000 ml of N,N-dimethylformamide was added dropwise under ice cooling to 300 ml 193 g of 4-methoxyethoxy-2,3,5-trimethylphenol in anhydrous N,N-dimethylformamide; the mixture is then stirred at room temperature for 2 hours. To the reaction mixture was added dropwise over one hour while cooling with ice (800 ml) solution of 197 g of 6-chloro-2-methylamino-3-nitropyridine in anhydrous N, N-dimethylformamide, followed by stirring at room temperature for 2 hours. The solvent is kept at reduced pressure. The residue was poured into ice water. To the mixture was added abrazos 141 g specified in the connection header. Separate the organic layer was separated from the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, then washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was washed with ethanol, resulting in 126 g specified in the connection header.

Melting point: 102-103oC.

Reference example 3

2-Hydroxymethyl-5-(4-hydroxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b]pyridine

A mixture of 288 g of 6-(4-methoxyethoxy-2,3,5-trimethylphenol)-2-methylamino-3-nitropyridine, 14 g of 10% palladium on coal and 1500 ml of methanol was stirred at room temperature for 2 hours in hydrogen atmosphere. To the reaction mixture was added 14 g of 10% palladium on coal, 500 ml of methanol and 500 ml of tetrahydrofuran, and the resulting mixture was stirred at 50oC for 8 hours in an atmosphere of hydrogen. From the reaction mixture was filtered palladium on coal and the filtrate was concentrated by evaporation. To the residue was added 500 g of glycolic acid and the mixture was stirred at 150oC for 6 hours. To the reaction mixture was added to 1000 ml of 4 N. aqueous solution of hydrochloric acid, and the mixture Ure. The reaction mixture was poured into ice water, followed by neutralization with an aqueous solution of sodium hydroxide and an aqueous solution of sodium carbonate. The obtained solid substance was separated by filtration and was purified by chromatography on a column of silica gel using tetrahydrofuran as an eluting solvent. Obtained from the eluate, the solid is washed with ethanol, resulting in a received 45,5 g specified in the connection header.

Melting point: 181-182oC.

Reference example 4

2-Acetoxymethyl-5-(4-acetoxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b]pyridine

To 400 ml of a solution of 38.0 g of 2-hydroxymethyl-5-(4-hydroxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b] pyridine in pyridine was added dropwise under ice cooling 69 ml of acetic anhydride. After stirring at room temperature for 3 hours the reaction mixture was left overnight at room temperature. The solvent is kept at reduced pressure. To the residue was added water, followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was separated and cleaned what about the received 39.5 g specified in the connection header.

Melting point: 128-129oC.

Reference example 5

5-(4-Acetoxy-2,3,5-trimethylphenol)-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine

To 500 ml 26,0 g 2-acetoxymethyl-5-(4-acetoxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b] pyridine in methanol was added dropwise at -18oWith 1.2 ml (28%) of sodium methoxide in methanol, followed by stirring at the same temperature for one hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was led from ethanol. The crystals were collected by filtration, resulting in a received 20,5 g specified in the connection header.

Melting point: 179-180oC.

Reference example 6

tert-Butyl N-[5-(4-methoxyethoxy-2,3,5-trimethylphenol) -2-nitrophenyl] -N-methylcarbamate

In 300 ml of N,N-dimethylformamide suspended 6.11 g of sodium hydride (55% by weight) followed by the addition of 27.5 g of 4-methoxyethoxy-2,3,5-trimethylphenol. The resulting mixture was stirred at room temperature for one hour. To the reaction mixture 120oC for 2 hours. The reaction mixture was concentrated by evaporation. To the concentrate was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 5/1), resulting in a received 57,0 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 4/1): Rf value=0,55.

Reference example 7

tert-Butyl N-[2-amino-5-(4-methoxyethoxy-2,3,5-trimethylphenol)phenyl] -N-methylcarbamate

The mixture to 57.0 g of tert-butyl N-[5-(4-methoxyethoxy-2,3,5-trimethylphenol)-2-nitrophenyl] -N-methylcarbamate, 3 g of 10% palladium on coal and 500 ml of methanol was intensively stirred at room temperature for 8 hours in an atmosphere of hydrogen. From the reaction mixture was filtered palladium on charcoal, and the filtrate was concentrated by evaporation. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 3/1), resulting in the received 52.5 g specified in the connection header.

Thin-layer chromatography for the
2-Chloro-3,5-xylene-1,4-diol

The mixture 12,08 g of 3,5-dimethyl-4-nitrosophenol, of 11.45 g of copper oxide (I), 100 ml of 1,4-dioxane, 10 ml of acetone and 100 ml of 6 N. hydrochloric acid was heated at the boil under reflux for 2 hours. The reaction mixture was poured into ice-cold water followed by extraction with ether. The extract was dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was dissolved in 150 ml of dichloromethane. To the resulting solution were added under ice cooling 3,61 g of sodium borohydride, followed by adding dropwise 50 ml of methanol at an internal temperature not exceeding 10oC. the Reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated by evaporation. The concentrate was poured into ice-cold water. The resulting mixture was acidified 3 N. hydrochloric acid. Precipitated precipitated product was collected by filtration, washed successively with water and n-hexane, which was given to 5.93 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 4/1): the value of Rf=0.35 in.

Reference example 9

3-Chloro-2,6-dimethyl-4-pivaloyloxy

To the mixture is Ohm 10 ml dichloromethane, containing 4,54 g pualeilani, followed by stirring at the same temperature for one hour and at room temperature for 90 minutes. The reaction mixture was concentrated by evaporation. To the concentrate was added water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 10/1), resulting in a received 8,02 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 4/1): the value of Rf=0.53 per share.

Reference example 10

2-Chloro-4-methoxyethoxy-3,5-dimethylphenol

To 20 ml of a suspension of anhydrous tetrahydrofuran containing 1.78 g of sodium hydride (55% by weight), was added dropwise 30 ml of a solution 8,02 g of 3-chloro-2,6-dimethyl-4-pivaloyloxymethyl in anhydrous tetrahydrofuran, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 3.28 g chloromethylmethylether simple ether, and the mixture was stirred at room temperature for 13 hours. Then the reaction mixture was concentrated UPA sodium sulfate, and the solvent is kept at reduced pressure. of 9.30 g of the residue was dissolved in 30 ml of methanol. To the resulting solution was added dropwise 30 ml of a solution of 3.51 g of potassium hydroxide in methanol, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated by evaporation. The concentrate was neutralized 3 N. hydrochloric acid and sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The residue was separated and purified by chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 10/1), resulting in a received 5,65 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 10/1): Rf value=0,29.

Reference example 11

2,6-Dimethyl-4-pivaloyloxy

With the use of 6.90 g of 2,6-xylene-1,4-diol, 6,63 g pualeilani, 11.85 g of pyridine and 60 ml of dichloromethane were interaction and cleaning method similar to that described in reference example 9, the resulting received 6,77 g specified in the connection header.

Melting point: 92-94o

Thin layer chromatography on silica gel (developing solution: n-hexane/ethyl acetate = 10/1): Rf value=0,39.

of 8.09 g of crude 4-methoxyethoxy-3,6-dimethylbutanoate was dissolved in 30 ml of methanol. To the resulting solution was added dropwise 30 ml of a solution 3,40 g of potassium hydroxide in methanol, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated by evaporation. To the residue was added water. The mixture was neutralized 3 N. hydrochloric acid and sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and ielem (eluting solvent: n-hexane/ethyl acetate = 4/1), as a result, we got to 5.58 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 10/1): Rf value=0,10.

Reference example 13

tert-Butyl N-[5-(4-benzyloxyphenyl)-2-nitrophenyl]-N-methylcarbamate

With the use of 1.60 g of 4-benzyloxyphenol, to 2.29 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 20 ml anhydrous N, N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, resulting in a received 3.33 g specified in the connection header.

Melting point: 108-110oC.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 5/1): Rf value=0,36.

Reference example 14

tert-Butyl N-[5-(4-methoxyethoxy-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate

With the use of 1.46 g of 4-methoxyethoxy-3,5-dimethylphenol, to 2.29 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 30 ml of anhydrous N,N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, so on the store solvent: n-hexane/ethyl acetate = 5/1): Rf value=0,29.

Reference example 15

tert-Butyl N-[5-(2-chloro-4-methoxyethoxy-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate

Using the 5.65 g of 2-chloro-4-methoxyethoxy-3,5-dimethylphenol, 8,88 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 1.35 g of sodium hydride (55% by weight) and 100 ml of anhydrous N,N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, resulting in a received 9,19 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 4/1): Rf value=0,47.

Reference example 16

tert-Butyl N-[5-(pyridine-2-yloxy)-2-nitrophenyl]-N-methylcarbamate

Using 0,76 g 2-hydroxypyridine, to 2.29 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 10 ml of anhydrous N, N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, which was obtained 0.36 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 4/1): Rf value=0,32.

Reference example 17

tert-Butyl N-[5-(3,5-di-tert-bursatil, 573 mg of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 175 mg of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, resulting in a received 371 mg specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 4/1): Rf value=0,59.

Reference example 18

tert-Butyl N-[5-(4-amino-3,5-dimethylphenoxy)-2-nitrophenyl] -N-methylcarbamate

Using 1.10 g of 4-amino-3,5-dimethylphenol, to 2.29 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 30 ml of anhydrous N,N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, resulting in a received 2,27 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 3/1): the value of Rf=0,24.

Reference example 19

tert-Butyl N-[5-[4-(tert-butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate

A mixture of 2.27 g of tert-butyl N-[5-(4-amino-3,5-dimethylphenoxy)-2-nitrophenyl] -N-methylcarbamate, 1.28 g of di-tert-Buti is the nickname for 6 hours. Then the reaction mixture was concentrated by evaporation. To the concentrate was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The rest of ocidate chromatography on a column of silica gel (eluting solvent: n-hexane/ethyl acetate = 10/1), resulting in a received 1,74 g specified in the connection header.

Melting point: 154-156oC.

Reference example 20

tert-Butyl N-[2-amino-5-(4-hydroxyphenoxy)phenyl]-N-methylcarbamate

With the use of 3.32 g of tert-butyl N-[5-(4-benzyloxyphenyl)-2-nitrophenyl]-N-methylcarbamate, 0.39 g of 10% palladium on coal, 100 ml of methanol and 100 ml of 1,4-dioxane interaction and purification was carried out by a method similar to that described in reference example 7, the resulting received 2,40 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 1/2): Rf value=0,59.

Reference example 21

tert-Butyl N-[2-amino-5-(4-methoxyethoxy-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate

Using 3.12 g of tert-butyl N-[5-(4-methoxyethoxy-3,5-dimethylphenoxy)-2-nitrophenyl] -N-metalcorner described in reference example 7, as a result, we received a rating of 2.72 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 3/1): Rf value=0,14.

Reference example 22

tert-Butyl N-[2-amino-5-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate

The mixture 1,71 g of N-[5-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl] -N-methylcarbamate, 0.2 g of 10% palladium on coal and 100 ml of methanol was stirred

intensively at room temperature for 11 hours in an atmosphere of hydrogen. The catalyst was filtered from the reaction mixture and the filtrate was concentrated by evaporation, resulting in a received 1.56 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 3/1): Rf value=0,14.

Reference example 23

tert-Butyl N-{5-[2-(morpholine-4-yl)phenoxy]-2-nitrophenyl]-N-methylcarbamic

Using 0,72 g of 2-(4-morpholino)phenol and 1.15 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.17 g of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, the silica gel (the solvent: n-hexane/ethyl acetate = 4/1): the value of Rf=0.34 in.

Reference example 24

tert-Butyl N-{5-[3-(morpholine-4-yl)phenoxy]-2-nitrophenyl]-N-methylcarbamic

Using 2.16 g of 3-(4-morpholino)phenol, 3,37 g of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate and 15 ml of anhydrous N,N-dimethylformamide interaction and purification was carried out by a method similar to that described in reference example 6, which was obtained 5.0 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: benzene/ethyl acetate = 10/1): the value of Rf=0.34 in.

Reference example 25

tert-Butyl N-{2-amino-5-[2-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamic

Using 1.44 g of tert-butyl N-{5-[2-(morpholine-4-yl)phenoxy]-2-nitrophenyl}-N-methylcarbamate, 0.20 g of 10% palladium on coal and 50 ml of methanol interaction and purification was carried out by a method similar to that described in reference example 7, which was obtained 1.20 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: n-hexane/ethyl acetate = 2/1): the value of Rf=0.25 in.

Reference example 26

tert-Butyl N-{2-amino-5-[3-(morpholine-4-yl)phenoxy]phenyl}-N-methylcarbamic

Using 5.0 g of tert-butyl N-{5-[3-(morpholine-4-yl)Fe is 70 ml of toluene, interaction and purification was carried out by a method similar to that described in reference example 7, which was obtained 4.5 g specified in the connection header.

Thin layer chromatography on silica gel (manifesting solvent: benzene/ethyl acetate = 4/1): Rf value=0,23.

Reference example 27

tert-Butyl N-[2-amino-5-(2-piperidinyloxy)phenyl]-N-methylcarbamate

To a solution of 2-piperidinophenyl (3.4 g) in N,N-dimethylformamide (35 ml) in an ice bath under nitrogen atmosphere was added sodium hydride (55 wt.%, 1.04 g). The mixture was stirred at ambient temperature for 15 minutes. To the reaction mixture in small portions was added tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (the 5.25 g). The mixture was stirred at 60oC for 2 hours. At the end of this time the solvent was evaporated and to the residue was added water. The mixture was neutralized with concentrated hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using a mixture of C-hexane/isopropyl ether = 5/1 as eluent, obtaining tert-butyl N-[2-nitro-5-(2-piperidinophenyl using as eluent a mixture of C-hexane/isopropyl ether =5/1 amounted to 0.27. A mixture solution of this product in a mixture of toluene/methanol=7/3 (100 ml) and palladium on coal (10%, 0,63 g) are intensively mixed at room temperature in a hydrogen atmosphere in the course of 14.5 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was washed with chilled methanol and n-hexane, obtaining mentioned in the title compound (4.2-d).

So pl.: 108-110oC.

Reference example 28

tert-Butyl N-methyl-N-[2-nitro-5-(pyridine-2-ylthio)phenyl]carbamate

By the way, is similar to that described in reference example 6, reaction was performed using 2-mercaptopyridine (0,89 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (to 2.29 g), sodium hydride (55 wt.%, 0.11 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified by receiving specified in the title compound (1.13 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 5/1: Rf=0,20.

Reference example 29

tert-Butyl N-[2-amino-5-(2-pyrrolidinone)phenyl]-N-methylcarbamate

The interaction was carried out by a method similar to that described in reference example 27 using 2-pyrrolidineethanol (1.88 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamic the traveler tert-butyl N-[2-nitro-5-(2-pyrrolidinone)phenyl]-N-methylcarbamate, the Rf value for which thin-layer chromatography plate with silica gel using as eluent a mixture of C-hexane/ethyl acetate = 10/1 amounted to 0.25. By the way, is similar to that described in reference example 27, reaction was performed with the use of this product, palladium on coal (10%, 0.45 g) and a mixture of toluene/methanol =7/3 (50 ml) and the reaction mixture was purified by receiving specified in the title compound (3.0 g).

So pl.: 136-138oC.

Reference example 30

tert-Butyl N-[5-(2-benzyloxyphenyl)-2-nitrophenyl]-N-methylcarbamate

By the way, is similar to that described in reference example 6, reaction was performed using 2-benzyloxyphenol (2.00 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2,87 g), sodium hydride (55 wt.%, of 0.44 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified by receiving specified in the header connection (4,16 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/1: Rf=0,62.

Reference example 31

tert-Butyl N-{5-[4-(1-of substituted)phenoxy]-2-nitrophenyl}-N-methylcarbamate

By the way, is similar to that described in reference example 6, reaction was performed using 4-(1-substituted)phenol Informatica (40 ml) and the reaction mixture was purified, getting listed in the title compound (4.30 m).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/1: Rf=0,76.

Reference example 32

tert-Butyl N-[5-(3-dimethylaminopropoxy)-2-nitrophenyl]-N-methylcarbamate

By the way, is similar to that described in reference example 6, reaction was performed using 3-dimethylaminophenol (0,82 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (1,72 g), sodium hydride (55 wt.%, 0.26 g) and anhydrous N,N-dimethylformamide (50 ml) and the reaction mixture was purified by receiving specified in the title compound (2.17 g)

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 9/1, Rf=0.21 in.

Reference example 33

tert-Butyl N-[2-amino-5-(pyridine-3-yloxy)phenyl]-N-methylcarbamate

By the way, is similar to that described in reference example 27, spent interaction using 3-hydroxypyridine (3.1 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (9.3 g), sodium hydride (55 wt.%, 1.4 g) and anhydrous N,N-dimethylformamide (25 ml) and the reaction mixture was purified by receiving tert-butyl N-[2-nitro-5-(2-pyridin-3-yloxy)phenyl] -N-methylcarbamate (9.2 grams). By the way, is similar to that described in silo the si toluene/methanol =7/3 (100 ml) and the reaction mixture was purified, getting listed in the title compound (7.5 g).

So pl.: 101-102oC.

Reference example 34

tert-Butyl N-{5-[4-(imidazol-1-yl)phenoxy]-2-nitrophenyl}-N-methylcarbamic

By the way, is similar to that described in reference example 6, reaction was performed using 4-(imidazol-1-yl)phenol (4.1 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (a 7.85 g), sodium hydride (55 wt.%, 1,25 g) and anhydrous N,N-dimethylformamide (45 ml) and the reaction mixture was purified by receiving specified in the title compound (8.8 g).

So pl.: 182-184oC.

Reference example 35

tert-Butyl N-methyl-N-[2-nitro-5-(2-phenyleneoxy)phenyl]carbamate

By the way, is similar to that described in reference example 6, reaction was performed using 2-phenylphenol (3.5 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.6 g), sodium hydride (55 wt.%, 1,08 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified by receiving specified in the header connection (8,3 g).

Thin-layer chromatography plate with silica gel using a mixture of toluene/ethyl acetate = 10/1, Rf=0,56.

Reference example 36

tert-Butyl N-[5-(4-hydroxy-2,3-dimethylphenoxy)-2-nitrophenyl] -N-methylcarbamate

By the way, N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2,87 g), of sodium hydride (55 wt.%, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified by receiving specified in the title compound (1.92 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/1: Rf=0.35 in.

Reference example 37

tert-Butyl N-methyl-N-[2-nitro-5-(4-phenoxyphenoxy)phenyl] carbamate

By the way, is similar to that described in reference example 6, reaction was performed using 4-phenoxyphenol (4.0 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.8 g), sodium hydride (55 wt.%, 1.1 g) and anhydrous N, N-dimethylformamide (35 ml) and the reaction mixture was purified by receiving specified in the title compound (8.6 g).

Thin-layer chromatography plate with silica gel using a mixture of toluene/isopropyl ether = 20/1:

Rf=0,41.

Reference example 38

tert-Butyl N-[5-(4-hydroxyphenyl)-2-nitrophenyl]-N-methylcarbamate

By the way, is similar to that described in reference example 6, reaction was performed using 4-hydroxythiophenol (1.26 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2,87 g), sodium hydride (55 wt.%, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified by receiving yasenovaya mixture n-hexane/ethyl acetate = 3/1: Rf=0,27.

Reference example 39

tert-Butyl N-methyl-N-[2-nitro-5-(3-phenyleneoxy)phenyl] carbamate

By the way, is similar to that described in reference example 6, reaction was performed using 3-phenylphenol (4.0 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.5 g), sodium hydride (55 wt.%, 1.13 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified by receiving specified in the title compound (8.7 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 10/1, Rf=0,22.

Reference example 40

tert-Butyl N-[5-(3-tert-butyl-4-hydroxyphenoxy)-2-nitrophenyl] -N-methylcarbamate and tert-butyl N-[5-(2-tert-butyl-4-guide-roxypalace)-2-nitrophenyl]-N-methylcarbamate

By the way, is similar to that described in reference example 6, reaction was performed using tert-butylhydroquinone (1.66 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2,87 g), sodium hydride (55 wt.%, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified chromatographically on a column of silica gel using a mixture of n-hexane/ethyl acetate = 4/1, getting tert-butyl N-[5-(3-tert-butyl-4-hydroxyphenoxy)-2-nitrophenyl] -N-methylcarbamate (1.35 g), the Rf value of which amounted to 0.45 pet-butyl N-[5-(2-tert-butyl-4-hydroxyphenoxy)-2-nitrophenyl] -N-methylcarbamate (1,11 g), the Rf value of which amounted to 0.35 when thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/1.

Reference example 41

tert-Butyl N-methyl-N-[2-nitro-5-(4-phenyleneoxy)phenyl] carbamate

By the way, is similar to that described in reference example 6, reaction was performed using 4-phenylphenol (4.0 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.5 g), sodium hydride (55 wt.%, 1.13 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified by receiving specified in the title compound (5.5 g).

So pl.: 166-167oC.

Reference example 42

tert-Butyl N-[5-(3,5-di-tert-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate

By the way, is similar to that described in reference example 6, reaction was performed using 2,6-di-tert-butylhydroquinone (4.44 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (at 8.60 g), sodium hydride (55 wt.%, 2,18 g) and anhydrous N,N-dimethylformamide (50 ml) and the reaction mixture was purified by receiving specified in the header connection (0,60 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 10/1, Rf=0,22.

Reference example 43

tert-Butyl N-[5-(4-make-up artist 6, carried out the reaction using a 2.5-dimethylcathinone (1,38 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2,87 g), sodium hydride (55 wt.%, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified by receiving specified in the header connection (1,72 g).

Thin-layer chromatography plate with silica gel using a mixture of toluene/ethyl acetate = 5/1: Rf=0,58.

Reference example 44

tert-Butyl N-[2-amino-5-(4-hydroxy-2-methylphenoxy)phenyl] -N-methylcarbamate and tert-butyl N-[2-amino-5-(4-hydroxy-3-methylphenoxy)phenyl]-N-methylcarbamate

To a suspension of sodium hydride (55 wt.%, 0.87 g) in N,N-dimethylformamide (20 ml) was added methylhydrazine (1.24 g). The mixture was stirred at ambient temperature for 15 minutes. To this mixture was added in small portions tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2,87 g) and stirred at 120oC for 2 hours. The reaction mixture was concentrated and the residue was distributed between ethyl acetate and water. An ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using a mixture of n-hexane/ethyl acetate = 3/1 as eluent, obtaining a mixture (2.20 GSE)-2-nitrophenyl] -N-methylcarbamate. The mixture solution of the above product and palladium on coal (10%, 0.21 g) was intensively stirred at ambient temperature in an atmosphere of hydrogen for 2 hours. At the end of this time the catalyst was removed by filtration and the filtrate was concentrated, obtaining mentioned in the title compound (1.88 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0.16 and more.

Reference example 45

tert-Butyl N-[5-(4'-benzyloxyphenyl-4-yloxy)-2-nitrophenyl] -N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 6 using 4'-benzyloxyphenyl-4-ol (11,07 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (11.5g), sodium hydride (55 wt.%, 2.2 g) and a mixture of anhydrous N,N-dimethylformamide/anhydrous tetrahed-return/anhydrous toluene= 1/1/1 (360 ml) and the reaction mixture was purified by receiving specified in the header connection (14,75 g).

So pl.: 123-125oC.

Reference example 46

tert-Butyl N-[5-(4-cianfrocca)-2-nitrophenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 6 using 4-cyanophora (5,1 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-metil/3 (80 ml) and the reaction mixture was purified, getting listed in the title compound (8,45 g).

So pl.: 141-143oC.

Reference example 47

N-Methyl-N-[2-nitro-5-(Pantothenate)phenyl]amine

To a suspension of sodium hydride (55 wt.%, 1.66 g) in anhydrous N,N-dimethylformamide (50 ml) was added pentafluorophenol (6,38 g). The mixture was stirred at ambient temperature for several minutes. To this mixture was added in small portions) of tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10 g) and the mixture was stirred at 150oC for 15 hours. The reaction mixture was concentrated and the residue was distributed between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using a mixture of n-hexane/toluene =4/1 as eluent, obtaining mentioned in the title compound (2.2 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/toluene = 2/1: Rf=0,14.

Reference example 48

tert-Butyl N-[2-amino-5-(pyridine-2-ylthio)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-methyl-N-[2-nitro-5-(pyridine-is shown in the header connection (0,78 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/2: Rf=0,33.

Reference example 49

tert-Butyl N-[2-amino-5-(2-hydroxyphenoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(2-benzyloxyphenyl)-2-nitrophenyl]-N-methylcarbamate (4,14 g), palladium on coal (10%, 0,41 g) and methanol (60 ml) and the reaction mixture was purified by receiving specified in the header connection (2,89 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,26.

Reference example 50

tert-Butyl N-{5-[4-(1-of substituted)phenoxy]-2-AMINOPHENYL}-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-{5-[4-(1-of substituted)phenoxy]-2-nitrophenyl} -N-methylcarbamate (4,28 g), palladium on coal (10%, 0,42 g) and methanol (60 ml) and the reaction mixture was purified by receiving specified in the header connection (4,00 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,49.

Reference example 51

tert-Butyl N-[2-amino-5-(3-dimethylamino, using tert-butyl N-[5-(3-dimethylaminopropoxy)-2-nitrophenyl]-N-methylcarbamate (2.14 g), palladium on coal (10%, 2.14 g) and methanol (40 ml) and the reaction mixture was purified by receiving specified in the title compound (1.63 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,41.

Reference example 52

tert-Butyl N-{2-amino-5-[4-(imidazol-1-yl)phenoxy]phenyl}-N-methylcarbamic

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-{5-[4-(imidazol-1-yl)phenoxy]-2-nitrophenyl} -N-methylcarbamate (8.8 g), palladium on coal (10%, 0.8 g) and N,N-dimethylformamide (160 ml) and the reaction mixture was purified by receiving specified in the title compound (5.7 g).

So pl.: 115-116oC.

Reference example 53

tert-Butyl N-[2-amino-5-(2-phenyleneoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-methyl-N-[2-nitro-5-(2-phenyleneoxy)phenyl] carbamate (8,3 g), palladium on coal (10%, 0.66 g) and a mixture of toluene/methanol=7/3 (100 ml) and the reaction mixture was purified by receiving specified in the title compound (6.9 g).

Thin-layer chromatography for platlet-Butyl N-[2-amino-5-(4-hydroxy-2,3-dimethylphenoxy) phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(4-hydroxy-2,3-dimethylphenoxy)-2-nitrophenyl] -N-methylcarbamate (1,90 g), palladium on coal (10%, 0.20 g) and methanol (20 ml) and the reaction mixture was purified by receiving specified in the header connection (1,61 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,13.

Reference example 55

tert-Butyl N-[2-amino-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[2-nitro-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (8.6 g), palladium on coal (10%, 0.6 g) and a mixture of toluene/methanol = 16/3 (190 ml) and the reaction mixture was purified by receiving specified in the title compound (7.2 g).

So pl.: 105-106oC.

Reference example 56

tert-Butyl N-[2-amino-5-(4-hydroxyphenethyl)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(4-hydroxyphenyl)-2-nitrophenyl]-N-methylcarbamate (2,84 g), palladium on coal (10%, 1.52 g) and methanol (50 ml) and the reaction mixture was purified by receiving specified in C is silica gel using a mixture of n-hexane/ethyl acetate = 1/2: Rf=0,59.

Reference example 57

tert-Butyl N-[2-amino-5-(3-phenyleneoxy)phenyl]-N-methyl-carbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[2-nitro-5-(3-phenyleneoxy)phenyl]-N-methylcarbamate (8,70 g), palladium on coal (10%, 0,69 g) and a mixture of toluene/methanol= 7/3 (100 ml) and the reaction mixture was purified by receiving specified in the header of the connection (the 6.06 g).

So pl.: 114-115oC.

Reference example 58

tert-Butyl N-[2-amino-5-(3-tert-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(3-tert-butyl-4-hydroxyphenoxy)-2-nitrophenyl] -N-methylcarbamate (1.29 g), palladium on coal (10%, 0.16 g) and methanol (40 ml) and the reaction mixture was purified by receiving specified in the header connection (1,11 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,18.

Reference example 59

tert-Butyl N-[2-amino-5-(2-tert-butyl-4-hydroxyphenoxy)phenyl] -N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(2-tert-butyl-4-hydroxyphenoxy)-2-nia specified in the title compound (0.95 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,18.

Reference example 60

tert-Butyl N-[2-amino-5-(4-phenyleneoxy)phenyl]-N-methyl-carbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[2-nitro-5-( 4-phenyleneoxy)phenyl]-N-methylcarbamate (5.32 g), palladium on coal (10%, 0.68 g) and a mixture of toluene/ethyl acetate= 1/1 (140 ml) and the reaction mixture was purified by receiving specified in the header connection (4,82 g).

So pl.: 122-123oC.

Reference example 61

tert-Butyl N- [2-amino-5- (4-hydroxy-2,5-dimethylphenoxy) phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(4-hydroxy-2,5-dimethylphenoxy)-2-nitrophenyl] -N-methylcarbamate (1.73 g), palladium on coal (10%, 0.17 g) and methanol (50 ml) and the reaction mixture was purified by receiving specified in the title compound (1.44 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,17.

Reference example 62

tert-Butyl N-[2-amino-5-(4'-hydroxybiphenyl-4-yloxy)phenyl]-N-methylcarbamate

The reaction was carried out of spoke)-2-nitrophenyl] -N-methylcarbamate (14,75 g), palladium on coal (10%, 0,86 g) and a mixture of toluene/ethyl acetate = 1/1 (140 ml) and the reaction mixture was purified by receiving specified in the title compound (10.2 g).

So pl.: 89-91oC.

Reference example 63

tert-Butyl N-[2-amino-5-(4-hydroxy-3,5-di-tert-butylphenoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(4-hydroxy-3,5-di-tert-butylphenoxy)-2-nitrophenyl] -N-methylcarbamate (0,58 g), palladium on coal (10%, 0.12 g) and methanol (20 ml) and the reaction mixture was purified by receiving specified in the title compound (0.55 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 3/1: Rf=0,29.

Ssylochku example 64

[2-Amino-5-(4-cianfrocca)phenyl]methylamine

A solution of tert-butyl N-[5-(4-cianfrocca)-2-nitrophenyl]-N-methylcarbamate (3,29 g) and dihydrate tin dichloride (10,06) in a mixture of tert-butanol/ethyl acetate = 1/9 (100 ml) was stirred at 60oC for 1 hour. Then to the mixture was added sodium borohydride (0.17 g) and the mixture is then stirred at the same temperature for 2.5 hours. The reaction mixture was concentrated and to the residue was added water. This mixture was neutralized with bicarbonate starimage substances. An ethyl acetate layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of n-hexane/ethyl acetate=3/2, getting mentioned in the title compound (1,49 g).

So pl.: 80-82oC.

Reference example 65

tert-Butyl N-[5-(4-benzoyl-3-hydroxyphenoxy)-2-nitrophenyl] -N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 6, using 2,4-dihydroxybenzophenone (4.5 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.0 g), sodium hydride (55 wt.%, of 1.75 g) and anhydrous N,N-dimethylformamide (130 ml) and the reaction mixture was purified by receiving specified in the title compound (2.2 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 5/1: Rf=0.36 and.

Reference example 66

tert-Butyl N-[2-amino-5-(4-benzyl-3-hydroxyphenoxy)phenyl] -N-methylcarbamate

A mixture solution of N-[5-(4-benzoyl-3-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (2.1 g) in methanol/tetrahydrofuran =5,3 (80 ml) and palladium on coal (20%, 0.5 g) was stirred at ambient temperature in an atmosphere of hydrogen Vya specified in the title compound (1.8 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 2/1: Rf=0,26.

Reference example 67

tert-Butyl N-methyl-N-[5-(4-methylthiophene)-2-nitrophenyl]carbamate

The reaction was carried out by a method similar to that described in reference example 6 using 4-methylthiophenol (0,98 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.00 g), sodium hydride (55 wt.%, 0.31 g) and anhydrous N,N-dimethylformamide (60 ml) and the reaction mixture was purified by receiving specified in the title compound (2.56 in).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 9/1, Rf=0,17.

Reference example 68

tert-Butyl N-methyl-N-[5-(4-methoxyphenoxy)-2-nitrophenyl] carbamate

The reaction was carried out by a method similar to that described in reference example 6 using 4-methoxyphenol (5.0 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10/9 g), sodium hydride (55 wt.%, 2.2 g) and anhydrous N,N-dimethylformamide (120 ml) and the reaction mixture was purified by receiving specified in the title compound (12.2 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 8/1: Rf=0,32.

Silly way similar to that described in reference example 6 using 4-triptoreline (3.0 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (4.3 g), sodium hydride (55 wt.%, 1.1 g) and anhydrous N,N-dimethylformamide (70 ml) and the reaction mixture was purified by receiving specified in the title compound (1.26 g).

So pl.: 92-93oC.

Reference example 70

tert-Butyl N-methyl-N-[5-(4-benzoylperoxy)-2-nitrophenyl] carbamate

The reaction was carried out by a method similar to that described in reference example 6 using 4-benzylphenol (7 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (9,15 g), sodium hydride (55 wt.%, 1,74 g) and anhydrous N,N-dimethylformamide (70 ml) and the reaction mixture was purified by receiving specified in the title compound (12.2 g).

Thin-layer chromatography plate with silica gel using a mixture of toluene/diisopropyl ether = 20/1, Rf=0.40 in.

Reference example 71

tert-Butyl N-methyl-N-[5-(3-benzyloxyphenyl)-2-nitrophenyl]carbamate

The reaction was carried out by a method similar to that described in reference example 6 using 3-benzyloxyphenol (5 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6 g), sodium hydride (55 wt.%, 1.1 g) and anhydrous N,N-dimethylformamide (40 ml) and the raffia on the plate with silica gel using a mixture of n-hexane/ethyl acetate = 5/1: Rf=0,32

Reference example 72

tert-Butyl N-[2-amino-5-(4-methylthiophene)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-methyl-N-[5-(4-methylthiophene)-2-nitrophenyl] carbamate (2,53 g), palladium on coal (10%, 2.5 g) and methanol (55 ml) and the reaction mixture was purified by receiving specified in the header connection (1,94 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 4/1: Rf=0.15 in.

Reference example 73

tert-Butyl N-[2-amino-5-(4-methoxyphenoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(4-methoxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (7.2 g), palladium on coal (10%, 0.5 g) and methanol (100 ml) and the reaction mixture was purified by receiving specified in the header connection (6,23 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 5/1: Rf=0,18.

Reference example 74

tert-Butyl N-[2-amino-5-(4-triptoreline)phenyl]-N-methylcarbamate

To a solution of tert-butyl N-methyl-N-[5-(4-triptoreline)-2-nitrophenyl] carbamate in a mixture of water/dioc what holodilniki for 1 hour. At the end of this time the reaction mixture was distributed between ethyl acetate and water. An ethyl acetate layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of n-hexane/ethyl acetate =3/1 -2/1, getting listed in Seagrove compound (0.7 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 4/1: Rf=0,27.

Reference example 75

tert-Butyl N-[2-amino-5-(4-benzoylperoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(4-benzoylperoxy)-2-nitrophenyl]-N-methylcarbamate (12.2 g), palladium on coal (10%, 0,91 g) and a mixture of toluene/ethyl acetate = 1/1 (140 ml) and the reaction mixture was purified by receiving specified in the title compound (10.1 g).

So pl.: 114-115oC.

Reference example 76

tert-Butyl N-[2-amino-5-(3-hydroxyphenoxy)phenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-[5-(3-hydroxide the mixture was purified, getting listed in the title compound (6 g).

Thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate = 1/1, Rf=0.50 in.

Reference example 77

tert-Butyl N-methyl-N-[2-nitro-5-(4-tetrazol-5-elfenix) phenyl]carbamate

A mixture of tert-butyl N-[5-(4-cianfrocca)-2-nitrophenyl]-N - methylcarbamate (2,95 g), usedatabaseyou (7,97 g) and anhydrous toluene (30 ml) was heated at the boil under reflux for 23 hours. The reaction mixture was concentrated and then was distributed between ethyl acetate and water. An ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified liquid chromatography with reversed phase using a mixture of water/acetonitrile =1/1 as eluent, obtaining specified in the header connection (3,20 g).

So pl.: 81-84oC.

Reference example 78

tert-Butyl N-methyl-N-{ 2-nitro-5-[4-(2-triphenylmethanol-5-yl)phenoxy]phenyl}carbamate

A mixture of tert-butyl N-methyl-N-[2-nitro-5-(4-tetrazol-5-elfenix)phenyl]carbamate (3,22 g), triphenylmethylchloride (2,18 g), triethylamine (0,79 g), anhydrous tetrahydrofuran (30 ml) and anhydrous N,N-dimethylformamide was stirred at templom and water. An ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of n-hexane/ethyl acetate =5/1, getting mentioned in the title compound (3.15 g).

So pl.: 161-163oC.

Reference example 79

tert-Butyl N-methyl-N-{ 2-amino-5-[4-(2-triphenylmethanol-5-yl)phenoxy]phenyl}carbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-methyl-N-{2-nitro-5-[4-(2-triphenylmethanol-5-yl)phenoxy] phenyl}carbamate (0,98 g), palladium on coal (10%, of 0.13 g) and ethyl acetate (100 ml) and the reaction mixture was purified by receiving specified in the header connection (0,70 g).

So pl.: 192-193oC.

Reference example 80

2-Hydroxymethyl-1-methyl-6-Pantothenate-1H-benzimidazole

A mixture of N-methyl-N-[2-nitro-5-(Pantothenate)phenyl] amine (2.10 g), palladium on coal (10%, 0,23 g) in methanol (300 ml) was stirred in an atmosphere of hydrogen at ambient temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel using as the showing was 0.26 in thin-layer chromatography plate with silica gel using a mixture of n-hexane/ethyl acetate=4/1. A mixture of this product, glycolic acid (0,76 g), 4 N. hydrochloric acid (25 ml) and dioxane (25 ml) was heated at the boil under reflux for 16 hours. The reaction mixture was concentrated and to the residue was added water. The mixture was neutralized with sodium bicarbonate and was extracted with ethyl acetate. An ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of ethyl acetate/methanol =20/1. The product was led from n-hexane when exposed to ultrasound. The crystals were collected by filtration and washed with n-hexane, obtaining specified in the header connection (1,17 g).

So pl.: 121-128oC.

Reference example 81

4 Cianfrocca-2-hydroxymethyl-1-methyl-1H-benzimidazole

A mixture of N-[2-amino-5-(4-cianfrocca)phenyl]-N-methylamine (1.08 g), glycolic acid (0.68 g), 4 N. hydrochloric acid (20 ml) and 1,4-dioxane (20 ml) was heated at the boil under reflux for 9 hours. The reaction mixture was concentrated and to the residue was added water. The mixture was neutralized with sodium bicarbonate and was extracted with ethyl acetate. An ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated the/methanol=20/1, getting listed in the title compound (0,86 g).

So pl.: 183-185oC.

Reference example 82

5-{ 4-[6-(4-Cianfrocca)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl}-3-triphenyltetrazolium-2,4-dione

A mixture of 4-cianfrocca-2-hydroxymethyl-1-methyl-1H - benzimidazole (279 mg), 5-(4-hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione (558 mg), azodicarbonamide (378 mg), tri-n-butylphosphine (303 mg) and toluene (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was purified by chromatography on a column of silica gel using as eluent n-hexane/ethyl acetate=1/1, receiving specified in the header connection (706 mg).

So pl.: 135-138oC.

Reference example 83

4-Benzyloxy-2,5-di-tert-butylphenoxyacetyl

To a solution of 2,5-di-tert-butyl-4-hydroxyphenylacetate (5.3g) in acetone (40 ml) was added benzylbromide (of 5.17 g) and potassium carbonate (4.15 g). The mixture was stirred at ambient temperature for 48 hours. The reaction mixture was distributed between ethyl acetate and water. An ethyl acetate layer was dried over anhydrous surfcom sodium and concentrated. The residue was purified by chromatography on a column of silica gel using as eluent the second chromatography of the plate with silica gel using a mixture of C-hexane/diisopropyl ether = 10/1, Rf=0.35 in.

Reference example 84

4-Benzyloxy-2,5-di-tert-butylphenol

To a solution of potassium hydroxide (1.51 g) in methanol (12 ml) was added 4-benzyloxy-2,5-di-tert-butylphenoxyacetyl (4.9 g). The mixture was left overnight at ambient temperature. The reaction mixture was neutralized with diluted hydrochloric acid and then was extracted with ethyl acetate. An ethyl acetate solution was dried over anhydrous sodium sulfate and was evaporated to dryness, obtaining mentioned in the title compound (4.3 g).

Thin-layer chromatography plate with silica gel using a mixture of C-hexane/diisopropyl ether = 10/1, Rf=0,44.

Reference example 85

tert-Butyl N-[5-(4-benzyloxy-2,5-di-tert-butylphenoxy)-2-nitrophenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 6 using 4-benzyloxy-2,5-di-tert-butylphenol (4.3 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (3.51 g), sodium hydride (55 wt.%, 0,72 g) and anhydrous N,N-dimethylformamide (15 ml) and the reaction mixture was purified by receiving specified in the header connection (7,1 g).

Thin-layer chromatography plate with silica gel using. a mixture of C-hexane/diisopropyl ether = 10/1, Rf=0,20.

Slackiavelli way similar to that described in reference example 7, using tert-butyl N-[5-(4-benzyloxy-2,5-di-tert-butylphenoxy)-2-nitrophenyl]-N-methyl-

carbamate (7,1 g), palladium on coal (10%, 0.7 g) and a mixture of toluene/methanol/ethyl acetate = 16/16/25 (57 ml) and the reaction mixture was purified by receiving specified in the header of the connection (of 3.56 g).

So pl.: 208-210oC.

Reference example 87

6-(3,5-Di-tert-butyl-4-hydroxy)phenylthio-2-hydroxymethyl-1-methyl-1H-benzimidazole

To a solution of [2-amino-5-(3,5-di-tert-butyl-4-hydroxyphenethyl)phenyl] methylamine (11,68 g), which was obtained by hydrogenation and treatment with acid tert-butyl N-[5-(3,5-di-tert-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate, 4 N. hydrochloric acid (300 ml) was added glycolic acid (7,43 g). The mixture was heated at boiling under reflux for 6 hours. The reaction mixture was poured into a mixture of ice and water and was neutralized with sodium bicarbonate and was extracted with ethyl acetate. An ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of ethyl acetate/methanol =20/1, getting mentioned in the title compound (8,66 g).

So pl.: 195-198othe si]benzaldehyde

A mixture of 6-(3,5-di-tert-butyl-4-hydroxy)phenylthio-2-hydroxymethyl-1-methyl-1H-benzimidazole (5,33 g), 4-hydroxybenzaldehyde (2,22 g), 1,1'-(azodicarbon) dipiperidino (4.59 g), tri-n-butylphosphine (3,68 g) and anhydrous toluene was stirred at ambient temperature for 64 hours. The reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of n-hexane/ethyl acetate = 1/1, giving specified in the header connection (3,74 g).

So pl.: 219-221oC.

Reference example 89

tert-Butyl N-[5-(4-tert-butoxycarbonylamino)-2-nitrophenyl]-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 6, using tert-butyl (4-hydroxyphenyl)carbamate (15.6 g), tert-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (21 g), sodium hydride (55 weight. %, up 3.22 g) and anhydrous N,N-dimethylformamide (130 ml) and the reaction mixture was purified by receiving specified in the title compound (27.7 g).

Thin-layer chromatography plate with silica gel using a mixture of toluene/diisopropyl ether = 10/1, Rf=0,33.

Reference example 90

tert-Butyl N-[2-amino-5-(4-tert-butoxycarbonylamino)phenyl] -N-mettre-butyl N-[5-(4-tert-butoxycarbonylamino)-2-nitrophenyl] -N-methylcarbamate (27.7 g), palladium on coal (10%, 1.07 g) and a mixture of tetrahydrofuran/ethyl acetate = 9/8 (170 ml) and the reaction mixture was purified by receiving specified in the header connection (26,2 g).

Thin-layer chromatography plate with silica gel using a mixture of C-hexane/tetrahydrofuran = 2/1: Rf=0,37.

Reference example 91

tert-Butyl N-{5-[4-(tert-butoxycarbonyl-n-hexylamino) phenoxy)-2-nitrophenyl]-N-methylcarbamate

To a suspension of sodium hydride (55 wt.%, 1.26 g) in anhydrous N,N-dimethylformamide (100 ml) was added N-[5-(4-tert-butoxycarbonylamino)-2-nitrophenyl] -N-methylcarbamate (12.1 g). The mixture was stirred at ambient temperature for several minutes. To the mixture was added bromily hexyl (6.5 g) under ice cooling and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1.0 hour. The reaction mixture was concentrated and the residue was distributed between ethyl acetate and water. An ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a column of silica gel using as eluent a mixture of toluene/diisopropyl ether = 100/7, getting mentioned in the title compound (13.8 g).

Thin-x2">

Reference example 92

tert-Butyl N-{2-amino-5-[4-(tert-butoxycarbonyl-n - hexylamino)phenoxy] phenyl}-N-methylcarbamate

The reaction was carried out by a method similar to that described in reference example 7, using tert-butyl N-{5-[4-(tert-butoxycarbonyl-n-hexylamino)phenoxy] -2-nitrophenyl}-N-methylcarbamate (13.8 g), palladium on coal (10%, 1.0 g) and a mixture of toluene/ethyl acetate = 1/1 (140 ml) and the reaction mixture was purified by receiving specified in the title compound (13.1 g).

Thin-layer chromatography plate with silica gel using a mixture of toluene/ethyl acetate = 3/1:Rf=0,44

Pharmacological test example 1

Effect against lipid peroxides

The inhibitory activity of the compounds of the invention against the production of lipid peroxide was performed using liver microsomes of rats.

To 400 μl of a mixture of 1:2 buffer [0.1 M aqueous solution of Tris(hydroxymethyl)aminomethane, brought to pH 7.4 with hydrochloric acid} and 0.15 M aqueous solution of potassium chloride was added 5 μl of a solution with a predetermined concentration of the test compound in dimethyl sulfoxide and 100 µl of the hepatic microsome assay from Wister rats (age 10 weeks), followed by stirring at 37oWith over 5 mine the hydrate of iron sulfate (II) and 50 mm aqueous solution of cysteine and the resulting mixture was stirred at 37oC for 30 minutes. To the reaction mixture to complete the reaction was added 1 ml of 10% aqueous solution of trichloroacetic acid. The reaction mixture was centrifuged at 3000 rpm during 5oC for 10 minutes and supernatant was separated. To 1.0 ml of supernatant was added 1.0 ml of a 50% aqueous solution of acetic acid containing 0,67% thiobarbituric acid and the mixture was heated at 100oC for 15 minutes. Then the reaction mixture was left at room temperature for 15 minutes and measured the absorption at a wavelength of 535 nm. From acquisitions of control, measured without the test compound, and absorption in the presence of the tested compounds with a predefined concentration was determined by the degree of inhibition (%) was determined concentration of 50% inhibition of the test compounds against lipid peroxide. The results are as follows:

Connection example - IC50(ág/ml)

1-2A - 0,97

2-2A - 0,54

4-2A - 0,83

5b - 1,3

7-2A - 0,65

8-2b - 3,2

From the above results it was found that the compounds of the present invention have an excellent effect against lipid peroxides.

Pharmacological test example 2

Inhibitory effect in respect to ostatniego buffer (pH 7.4), which was obtained by dissolving the powder packing phosphate buffer (Yatron) in 10 ml of water, 40 μl of 30 mm aqueous solution of calcium chloride, 50 μl of 20 mm water GSH (glutathion, reduced form) solution, 50 μl of 40 mm aqueous solution of ATP (adenosine-5-triphosphate) and 100 µl of polymorphing leucocytes of fermenta Guinea pigs, followed by stirring at 25oC for 5 minutes. To initiate the reaction to this mixture was added 5 μl of arachidonic acid (10 mg/ml ethanol) and the mixture was stirred at 25oC for 5 minutes. To terminate the reaction, to the reaction mixture were added 50 μl of 2 N. hydrochloric acid. Then to the reaction mixture were added 2.0 ml of ethyl acetate containing substance internal standard (internal standard substance: 2 µg/ml isoamylamine). The resulting mixture was extracted within 1 minute using a mixer, followed by the separation in a centrifuge at 3000 rpm for 5 minutes. An ethyl acetate layer was separated, evaporated to dryness under reduced pressure and then dissolved in 200 μl of acetonitrile. Using high-performance liquid chromatography was determined by the number of 5-NET. From definition 5-NET to control without the test compounds and test compounds najomilenite. The results are as follows:

Example . THE IC50(ág/ml)

1-2A - 0,59

2-2A - 0,10

4-2A - 0,20

5b - 0,53

From the above results it was found that the compounds according to the present invention have an excellent 5-lipoxygenation action.

Pharmacological test example 3

Hypoglycemic effect

A blood sample was collected from the tail vein of each of the mice QC (age 4-5 months) with diabetes, and measured the blood sugar levels. Then mice were classified into groups (4 mice per group) so that in mice was approximately equal to the level of sugar in the blood. For three days the mice were given powdered food (F-1, produced Funabashi Farm) is adjusted so that it contains 0.01% of the tested compounds. The group of mice that were administered the test compound, referred to as "the group with the administration of a medicinal product", while that in which mice received powder food that does not contain the test compound, called "control". Three days later took blood samples from the tail vein of each mouse was measured concentration of glucose in plasma, obtained by separation in the centrifuge, using a glucose analyzer ("Glucoroder" A&T Esahara in blood (%) = (average blood sugar level for control - the average blood sugar level for a group with administration of a medicinal product) 100/ blood sugar control

Example No. - The extent of lowering blood sugar (%)

1-2b - 48,1

2-2b and 49.2

3-2 - 60,1

4-2A - 67,5

6-2 - 62,6

7-2A - 71,7

13-2b - 68,1

19-2 - 66,8

34-2b - 71,2

40 - 66,4

51 - 63,6

From the above results it was found that the compounds of the present invention have excellent hypoglycemic action. T TC

1. Substituted condensed heterocyclic compound represented by the following formula (I)

< / BR>
where R1represents a group of formula (II)

< / BR>
in which R4represents a phenyl group which is substituted by 1-5 substituents selected from the substituents defined below,or pyridyloxy group which may be substituted by 1-4 substituents selected from the substituents defined below ;

R6represents a hydrogen atom or a C1-6alkyl group;

D represents an oxygen atom or sulfur;

E represents a CH group or a nitrogen atom;

R3represents a group selected from the following formulas (IV-1 and IV-2) or their tautomers in the case of oxygen;

provided that 5-{ 4-[5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-3H-imidazo[4,5-b] pyridine-2-ylethoxy] benzyl} thiazolidine-2,4-dione is excluded, and that, when R4represents a substituted phenyl group, and D represents a sulfur atom, then E is a nitrogen atom,

or its pharmacologically acceptable salt, prodrug or MES,

where the substituents is halogen atom, hydroxyl group, C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6allylthiourea, amino group which may be substituted by substituents selected from the substituents defined below , group C3-10cycloalkyl, C6-10aryl, C7-16aralkyl and C6-10aryloxy, each of which may be substituted by 1-3 substituents selected from the substituents defined below , C1-7the aliphatic alloctype, 4 - to 7-membered saturated nitrogen-containing heterocyclic group, 5 - or 6-membered aromatic nitrogen-containing heterocyclic group, and cyano;

the substituents is halogen atom, hydroxyl group, and C1-6alkoxygroup;

Deputy - C1-10alkyl group, a C6-10aryl group, each of which may have 1 and C1-6alkoxygroup, and acyl group (indicated acyl group represents a C1-7aliphatic acyl group, or WITH7-11aromatic acyl, C4-11cycloalkylcarbonyl or 5 - or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group, each of which may have 1-3 substituent selected from halogen atoms and hydroxyl, and C1-6alkyl groups).

2. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 1, where R1represents a group of formula (II).

3. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 1 or 2, where R3represents a group of formula (IV-2) or its tautomer.

4. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-3, where R4represents pyridyloxy group which may be substituted by one halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxy of deputies , as defined in paragraph 1.

5. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-3, where R4represents pyridyloxy group which may be substituted by one fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, tert-butilkoi group, triptorelin group, a methoxy group, methylthiourea, amino group, methylaminopropane or dimethylaminopropoxy.

6. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-3, where R4represents pyridyloxy group.

7. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-3, where R4represents a phenyl group substituted by at least one Deputy, selected from C3-10cycloalkenes,6-10aryl and C7-16aranceles groups, each of which may be substituted by 1-3 substituents selected from the substituents defined in paragraph 1, 4-7-membered saturated azatadine the>

8. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 7, where R4represents a phenyl group substituted by one Deputy, selected from C3-10cycloalkenes,6-10aryl and C7-16aranceles groups which may be substituted by 1 Deputy selected from the substituents defined in paragraph 1, 4 - to 7-membered saturated nitrogen-containing heterocyclic groups and 5 - or 6-membered aromatic nitrogen-containing heterocyclic groups.

9. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 7, where R4represents a phenyl group substituted by one Deputy, selected from C3-10cycloalkenes,6-10aryl and C7-16aranceles groups which may be substituted by one halogen atom, a hydroxyl group or a C1-6alkoxygroup, 4 - to 7-membered saturated nitrogen-containing heterocyclic groups and 5 - or 6-membered aromatic nitrogen-containing heterocyclic groups.

10. Substituted condensed heterocyclic compound or its farmacologicas the ing one Deputy, selected from phenyl or benzyl group which may be substituted by one halogen atom, a hydroxyl group or a C1-6alkoxygroup, adamantyl groups, pyrrolidinyl groups, morpholinyl groups, piperidinyl groups, imidazolinium groups, tetrazolyl groups and pyridinoline groups.

11. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 10, where R4represents a phenyl group substituted by one Deputy, selected from phenyl or benzyl group which may be substituted by one fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, adamantyl groups, pyrrolidinyl groups, morpholinyl groups, piperidinyl groups, imidazolinium groups, tetrazolyl groups and pyridinoline groups.

12. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 7, where R4is a 4-biphenylyl, 4-benzylphenol, 4'-hydroxy-biphenylyl, (pyrrolidin-1-yl)phenyl, (morpholine-4-yl)phenyl, (piperidine-1-yl)phenyl, (pyridin-2-yl)phenyl, (pyridin-3-yl)Obedinenie or its pharmacologically acceptable salt, the prodrug or the MES according to any one of paragraphs. 1-3, where R4represents a phenyl group which is substituted by one allmineral in which the amino group may be optionally substituted by a Deputy selected from the substituents as defined in paragraph 1, and the said phenyl group may be further substituted by 1-3 substituents selected from halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6alkylthio.

14. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 13, where R4represents a phenyl group which is substituted by one allmineral in which the amino group may be optionally substituted by a Deputy selected from the substituents as defined in paragraph 1, and the said phenyl group may be further substituted by 1-3 substituents selected from halogen atoms and C1-6alkyl groups.

15. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 13, where R4represents phenyl Gruene C1-6alkyl group, the phenyl group may be further substituted by 1-3 C1-6alkyl groups.

16. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 13, where R4represents a phenyl group which is substituted WITH one7-11aromatic acylamino, C4-11cycloalkylcarbonyl or 5 - or 6-membered aromatic nitrogen-containing heterocyclic carbylamines, which may have 1-3 substituent selected from halogen atoms, hydroxyl and C1-6alkyl groups.

17. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 13, where R4represents a phenyl group, substituted benzoylamine, 3 chlorobenzylamino, 2,4-differentiating, 4-hydroxy-C, 5-di-tert-butylbenzylamine, naphthylamine, cyclopentylamine, cyclohexylamine, nicotianamine, isonicotinamide, N-acetyl-N-hexylamino or adamantylidene group.

18. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, p amino group, amino group, substituted by 1 or 2 substituents (the substituents are the same or different, and each represents a C1-10alkyl group or a C6-10aryl group which may have 1-3 substituent selected from halogen atoms, hydroxyl and C1-6alkyl groups), or cyano, and the said phenyl group may be further substituted by 1-3 substituents selected from halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6alkylthio.

19. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 18, where R4represents a phenyl group substituted with one amino, mono - or di-C1-10alkylamino or cyano, and the said phenyl group may be optionally substituted by 1 or 2 C1-6alkyl groups.

20. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 18, where R4is a 4-aminoaniline, 4-amino-3,5-dimethylaniline, 4-amino-3,5-di-tert-butylphenyl, 3-dimethylamino eroticlinks compound or its pharmacologically acceptable salt, the prodrug or the MES according to any one of paragraphs. 1-3, where R4represents a phenyl group which is substituted by one C6-10arroceros, which may be substituted by 1-3 substituents selected from substituents as defined in paragraph 1, and the said phenyl group may be further substituted by 1-3 substituents selected from halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy and C1-6alkylthio.

22. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 21, where R4represents a phenyl group substituted WITH6-10arroceros, which may be substituted by 1-3 substituents selected from substituents as defined in paragraph 1, and the said phenyl group may be optionally substituted by 1 or 2 C1-6alkyl groups.

23. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 21, where R4represents a phenyl group substituted WITH one6-10arroceros, which may be substituted by one Deputy, wybielanie or its pharmacologically acceptable salt, the prodrug or MES on p. 21, where R4is a 4-phenoxyphenyl group.

25. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-3, where R4represents a phenyl group substituted by 1-5 substituents selected from halogen atoms and hydroxyl, C1-6alkyl, halogen (C1-6alkyl), C1-6alkoxy, C1-6alkylthio and C1-7aliphatic acyloxy.

26. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 25, where R4represents a phenyl group substituted by one halogen atom, a hydroxyl group, a C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup, C1-6alkylthiophene or C1-7aliphatic alloctype, and the said phenyl group may be optionally substituted by 1-4 substituents selected from halogen atoms and C1-6alkyl and halogen(C1-6alkyl) groups.

27. Substituted condensed heterocyclic compound or its farmakologicheskoi one C1-6alkyl group, halogen (C1-6alkyl) group, a C1-6alkoxygroup or C1-6alkylthiophene.

28. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 25, where R4represents a phenyl group substituted with one halogen(C1-2alkyl) group, a C1-2alkoxygroup or C1-2alkylthiophene or 1-5 fluorine atoms or chlorine atoms.

29. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 25, where R4is a 4-triftormetilfullerenov, 4-methylthiophenyl, 4-metoksifenilny or pentafluorophenyl group.

30. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 25, where R4represents a phenyl group substituted with one hydroxyl or C1-7aliphatic alloctype, and the said phenyl group may be further substituted by 1-3 substituents selected from halogen atoms and C1-6alkyl groups.

31. Substituted condense p. 25, where R4represents a phenyl group substituted with one hydroxyl group, and the said phenyl group may be further substituted by 1-3 substituents selected from halogen atoms and C1-6alkyl groups.

32. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 25, where R4represents a phenyl group substituted with one hydroxyl group, and the said phenyl group may be further substituted by 1-3 substituents selected from fluorine atoms and chlorine and methyl and tert-butilkoi groups.

33. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES on p. 25, where R4is a 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylaniline, 4-hydroxy-3,5-di-tert-butylaniline, 4-hydroxy-2,3,5-trimethylphenyl or 2-chloro-4-hydroxy-3,5-dimethylphenyl group.

34. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6, where R6represents a hydrogen atom or a C1-6and the automatic acceptable salt, the prodrug or the MES according to any one of paragraphs. 1-6, where R6represents a C1-2alkyl group.

36. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6, where R6represents a methyl group.

37. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33, where R6represents a hydrogen atom or a C1-4alkyl group.

38. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33, where R6represents a C1-2alkyl group.

39. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33, where R6represents a methyl group.

40. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6 and 34-36, where a represents a C1-4alkalineforming salt, the prodrug or the MES according to any one of paragraphs. 1-6 and 34-36, where a represents a C1-2alkylenes group.

42. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6 and 34-36, where a represents a methylene group.

43. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33 and 37-39, where a represents a C1-4alkylenes group.

44. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33 and 37-39, where a represents a C1-2alkylenes group.

45. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33 and 37-39, where a represents a methylene group.

46. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6, 34-36 and 40-42, where In represents an oxygen atom.

47. Sameso or MES according to any one of paragraphs. 7-33, 37-39 and 43-45, where In represents an oxygen atom.

48. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6, 34-36, 40-42 and 46, where D represents an oxygen atom.

49. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33, 37 to 39 and 43 to 45 and 47, where D represents an oxygen atom.

50. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6, 34-36, 40-42 and 46, where D represents a sulfur atom.

51. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 7-33, 37 to 39 and 43 to 45 and 47, where D represents a sulfur atom.

52. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-6, 34-36, 40-42, 46, 48 and 50, where E is a CH group.

53. Substituted condensed heterocyclic compound or its pharmacologists who tx2">

54. Substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES under item 1, selected from the following group of compounds and their pharmacologically acceptable salts, prodrugs and solvate:

5-{ 4-[6-(4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[1-methyl-6-(4-triptoreline)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[1-methyl-6-(4-methoxyphenoxy)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[1-methyl-6-(4-methylthiophene)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(3-dimethylaminopropoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-acetylaminophenol)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[1-methyl-6-(4-phenyleneoxy)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4'-hydroxybiphenyl-4-yloxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-benzoylperoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-(6-[2-(pyrrolidin-1] -1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-(6-[2-(morpholine-4-yl)phenoxy] -1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-(1-methyl-6-[3-(morpholine-4-yl)phenoxy] -1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(2-chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-hydroxy-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-hydroxy-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-hydroxy-2,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-hydroxy-2,3,5-trimethylphenol)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[5-(4-hydroxy-2,3,5-trimethylphenol)-3-methyl-3H-imidazo[4,5-b] pyridine-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-olmeto benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(pyridine-2-yloxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[1-methyl-6-(pyridine-2-ylthio)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[1-methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-(6-[4-(imidazol-1-yl)phenoxy] -1-methyl-1H-benzimidazole-2-ylethoxy)benzyl} thiazolidine-2,4-dione,

5-{ 4-(6-[4-(1-of substituted)phenoxy] -1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-cianfrocca)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(2,5-di-tert-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-[4-(6-Pantothenate-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-benzylaminopurine)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-[4-{ 6-[4-(2,4-differentiating)phenoxy] -1-methyl-1H-benzimidazole-2-ylethoxy} benzyl] thiazolidin-2,4-dione,

5-{ 4-[6-(4-cyclopentadienylmanganese)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione,

5-{ 4-[6-(4-nicotinamidase)-1-methyl-1H-benzimidazole-2-ylethoxy] benzyl} thiazolidine-2,4-dione, and

5-{ 4-[6-(3,5-di-tert-butyl-4-hydroxydiphenylamine heterocyclic compound or its pharmacologically acceptable salt, the prodrug or the MES according to any one of paragraphs. 1-54 as the active ingredient of the medicinal product for use in pharmacological effect in a warm-blooded animal, where the specified drug possesses hypoglycemic activity, inhibiting 5-lipoxygenase activity or inhibitory activity against the production of lipid peroxides.

56. How pharmacological effect on a warm-blooded animal by means having hypoglycemic activity, inhibiting 5-lipoxygenase activity or inhibitory activity against the production of lipid peroxides, which includes the introduction of the specified warm-blooded animal an effective amount of the active ingredient, which is substituted condensed heterocyclic compound or its pharmacologically acceptable salt, prodrug or MES according to any one of paragraphs. 1-54.

57. Method of inhibiting 5-lipoxygenase, ingibirovaniya production of lipid peroxides or reduce blood sugar levels in warm-blooded animal, which includes the introduction of the specified warm-blooded animal an effective amount of the active ingredient, where the specified active Ingram is acceptable salt, the prodrug or the MES according to any one of paragraphs. 1-54.

 

Same patents:

The invention relates to new derivatives of imidazo[1,2-a] pyridine f-ly I or its pharmaceutically acceptable salts, where R1is CH3or CH2HE, R2and R3is lower alkyl, R4Is h or halogen, R5Is h, halogen or lower alkyl, X is NH or O

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to new derivatives of 6-arrepiado[2,3-d]pyrimidine and-naphthiridine, their pharmaceutically acceptable salts, pharmaceutical composition having inhibitory effect of cell proliferation caused by protein tyrosinekinase, and to a method of inhibiting cell proliferation

The invention relates to new visakapatnam tritium monitoringand formula I

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where

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or

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which can be used in biology and in medicine for the study of physiologically active compounds

The invention relates to new derivatives of indole-2,3-dione-3-oxime of the formula I

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where R1means hydrogen, C1-C6alkyl; R3means Het or a group of the formula

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where Het means tetrahydrofuryl, which can be substituted one or more times with substituents selected from the group consisting of halogen, C1-C6of alkyl, C1-C6alkoxy and oxo; at least one of R31, R32and R33independently represents hydrogen, C1-C6alkyl or hydroxy WITH1-C6alkyl and at least one of R31, R32and R33independently represents (CH2)nR34where R34represents hydroxyl, carboxyl,1-C6alkoxycarbonyl,3-C7-cycloalkyl-C1-C6-alkoxycarbonyl, isoxazolidine ring which may be substituted one or more times with substituents selected from the group consisting of halogen, C1-C6of alkyl, C1-C6alkoxy, oxo, or СОNR35R36where R35and R36is hydrogen, C1-C6alkyl, гUB>6alkoxycarbonyl,3-C7cycloalkyl-C1-C6-alkoxycarbonyl, or R35and R36together with the N atom to which they are attached, form a saturated 6-membered heterocyclic ring may contain one additional atom On; n represents 0, 1, 2 or 3; R5means phenyl which may be substituted by phenyl or SO2NR51R52where R51and R52each independently mean C1-C6alkyl, or R51and R52together with the N atom to which they are attached, form a saturated 6-membered monocyclic heterocyclic ring; a is a ring condensed with the benzene ring at the positions marked "a" and "b", and formed the following bivalent radicals: a-CH2-NR6-CH2-CH2-b, where R6means1-C6alkyl, or pharmaceutically acceptable salt

The invention relates to a new process for the preparation of 2,3-pyridinecarboxamide formula (I), where R is hydrogen, C1-C6alkyl or C1-C6alkoxymethyl, R1means hydrogen, C1-C6alkyl, C(O)R2, phenyl, benzyl, R2means C1-C6alkyl, benzyl or phenyl, which is that the compound of formula (II), where R has the above meaning, R6means C1-C6alkyl, R7means OR8or NR9R10, R8means hydrogen, C1-C6alkyl, C(O)R11, phenyl, benzyl, R11means C1-C6alkyl, OR12, NR12, R13, benzyl or phenyl, R12and R13denote hydrogen, C1-C6alkyl, benzyl or phenyl, R9and R10denote hydrogen, C1-C6alkyl, benzyl or phenyl, is subjected to the interaction with the imide of maleic acid of the formula (III), where R1have the above values

The invention relates to compounds of General formula (I) in which X represents hydrogen or halogen or alkyl, CNS, triptorelin or phenylmethoxy, R1represents hydrogen or alkyl, cyclopropyl or phenylmethylene group, R2represents either an alkyl group, possibly substituted, or phenylalkyl group, possibly substituted, or cyclohexylmethyl group, or thienylmethyl group, or pyridinylmethyl group, or phenyl group, possibly substituted, or pyridinyl group, or 5-methyl-1,2-oxazolidinyl group, or 5-methyl-1,3,4-thiadiazolyl group, or naphthalenyloxy group, R3and R4each represents hydrogen or alkyl, 2-methoxyaniline, hydroxyalkyl, carboxialkilnuyu, alkoxycarbonylmethyl or phenylalkyl group, or together with the nitrogen atom which carries them, form or pyrrolidinyloxy group, possibly substituted, or piperidinyl group, or morpholinyl group, or 4-methylpiperidino group, or azetidinol group, or thiazolidinedione group, and the bond between carbon atoms at positions 3 and 4 is a simple or double

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to a new, more thermodynamically stable crystalline form of the hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-chroman

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative
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