Lactam compounds and their pharmaceutical using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

 

Background of invention

The present invention relates to lactam compounds and a therapeutic agent for diabetes, which contains the compound(I) as an active ingredient.

Drug treatment of diabetes type II is used when a significant improvement of the patient's condition cannot be achieved by dietary treatment or kinesitherapy, and here were developed pharmaceutical preparations containing insulin, which is an endogenous hormone to regulate hypoglycemic function, as well as oral hypoglycemic agents that affect the acceleration of insulin secretion or enhance peripheral insulin resistance. To date, the main drug treatment of type II diabetes includes the use of oral hypoglycemic agent for strict regulation of blood sugar levels. However, when it cannot be derived insulin-like action to regulate blood sugar, used mainly insulin therapy. On the other hand, insulin therapy is the only treatment for patients with diabetes type I, because they have lost the capacity for insulin secretion.

Although insulin therapy is, therefore, important treatment, the use of injection causes problems, which is how what technique of treatment is complicated and that the patient will have to teach this technique. Under these conditions, the improvement of the method of introduction of the urgent from the standpoint of ease of introduction of the drug. Recently tried to develop methods of insulin administration in the form of non-injection drugs instead of insulin injections. However, these methods have not been used in practice due to the low absorption efficiency or unstable absorption.

One of the important hypoglycemic functions of insulin is that it increases the ability of peripheral cells to transfer the sugar to turn sugar into blood cells and, as a result, reduces the level of sugar in the blood. If it was found as a new oral drug that can reduce the blood sugar level by increasing the ability of peripheral cells to migrate sugar, it could become the preferred therapy for patients. However, this drug has not yet been developed.

On the other hand, with regard lactam compounds, Khim-Farm. Zh., 25 (11), (1991) and Pharmaceutical Chemical Journal, 25 (11), 768 (1991) described compounds of General formula (I)below, where a represents a benzene ring, -X - and-Y-, each represent-NH-, -Z - represents-CH2-, -W - represents-NH -, and A(R2)(R3)(R4) is vanilin the th group, 4-bromperidol group, 4-hydroxyphenyl group, 4-metoksifenilny group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. They describe that these compounds do not have anxiolytic actions, antispasmodic actions or cardiotonic action. In the Journal of the Pharmaceutical Society of Japan, 715-20 (1986) Chem. Pharm. Bull., 3724-9 (1984) describes compounds of General formula (I)below, where a represents a benzene ring, -X - represents-NH-, -Z - represents-CR6R7-, -W - represents-NH - and R6and R7each represent a methyl group. They describe that these compounds have a weak analgesic effect.

In Synthesis, 937-8 (1987) described a compound of General formula (I)below, where a represents a benzene ring, -X - represents-NH-, -Z - represents-CO-, -W - represents-NR1and R1is p-taillow group. However, the activity of this compound in the publication are not described.

In the Journal of the Pharmaceutical Society of Japan, 1004-8 (1984) describes compounds of General formula (I)below, where a represents a benzene ring, -X - represents-NH-, Y is-S-, -Z - represents-CR6R7-, -W - represents-NH - and R6and R7each represents a methyl group. This publication describes that these compounds have a weak sterilizing effect is.

In Journal of Organic Chemistry, 4367-70 (1983) also described compounds of General formula (I)below, where a represents a benzene ring, -X - represents-NH-, -Y - is-S-, Z is-CH2- and-W - represents-O-. However, the activity of this compound in the publication are not described.

Description of the invention

The aim of the present invention is to propose a newly developed therapeutic agent for diabetes, with a strong therapeutic effect and weak side action.

Another purpose of this invention is the provision of an agent to enhance the ability of the transport of sugar.

Another objective of the present invention is to offer hypoglycemic agent.

Another objective of the present invention is to propose an agent for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathies, impaired glucose tolerance or obesity.

The next objective of the present invention is to offer new lactam compounds.

Another objective of the present invention is a pharmaceutical composition.

After intensive studies to detect compounds with action on the surface is increased by the ability of the transport of sugar and are useful for the treatment of diabetes, the authors of the present invention discovered compounds of General formula (I). The present invention was created on the basis of this discovery.

The present invention provides an agent for enhancing the ability of the transport of sugar, which contains a lactam compound(I) of the following General formula (I) or its pharmaceutically acceptable salt(s) as an active ingredient:

where a represents an aromatic ring, a heterocyclic ring or aliphatic ring; R2, R3and R4may be the same or different from each other and independently represent a hydrogen atom, halogen atom, hydroxyl group, alkyl group, mercaptopropyl, CNS group, allylthiourea, alkylsulfonyl group, acyl group, Allexinno group, amino group, alkylamino, carboxyl group, alkoxycarbonyl group, karbamoilnuyu group, a nitrogroup, cyano, triptorelin group, alkenylphenol group which may have a substituent(s), alkylamino group which may have a substituent(s), aryl group which may have a substituent(s), a heteroaryl group which may have a substituent(and), benzyloxyphenyl group which may have a substituent(s), aryloxyalkyl group which may have a substituent(s), getarea lexiline group, which may have a substituent(s), killingray, which may have a substituent(s), arylvinyl group which may have a substituent(s), or arelatively group which may have a substituent(s); b is an aromatic ring which may have a substituent(s), heterocyclic ring which may have a substituent(s), or aliphatic ring which may have a substituent(s), -X-, -Y - and-Z may be the same or different from each other and they independently represent -O-, -NH-, -NR5-, -S-, -SO-, -SO2-, -CH2-, -CR6R7- or-CO-, where R5represents a lower alkyl group which may have a substituent(s), acyl group which may have a substituent(s), alkoxycarbonyl group which may have a substituent(s), carbamoyl group which may have a substituent(s), or sulfonyloxy group which may have a substituent(s), R6and R7may be the same or different from each other and they independently represent a hydrogen atom, halogen atom, hydroxyl group, alkyl group which may have a substituent(s), mercaptopropyl, CNS group, allylthiourea, alkylsulfonyl group, acyl group, Allexinno group, amino group, alkylamino, carboxyl group, alkoxycarbonyl group, the carb is Olney group, the nitro-group, a cyano or triptorelin group; -W - represents-NR1-, -O -, or-CR8R9-where R1represents a hydrogen atom, a lower alkyl group which may have a substituent(s), or aryl group which may have a substituent(s), and R8and R9may be the same or different from each other and they independently represent a hydrogen atom, halogen atom, hydroxyl group, alkyl group, aryl group, mercaptopropyl, CNS group, allylthiourea, alkylsulfonyl group, acyl group, Allexinno group, amino group, alkylamino, carboxyl group, alkoxycarbonyl group, karbamoilnuyu group, a nitrogroup, cyano or triptorelin group and a, b and C each represent the position of the carbon atom, provided that:

(i) the substituent(s) selected from the group consisting of halogen atoms, hydroxyl groups, alkyl groups, aryl groups, mercaptopropyl, CNS groups, alkylthio, alkylsulfonyl groups, acyl groups, azidocillin groups, amino groups, alkylamino, carboxyl group, alkoxycarbonyl groups, carbamoyl groups, nitro, ceanography, triptoreline groups, aryl groups and heteroaryl groups.

The present invention also provides new lactam connect the of the above General formula (I), where:

(ii) when b is a benzene ring, -X - and-Y-, each represent-NH-, -Z - represents-CH2- and-W - represents-NH-, -A(R2)(R3)(R4cannot be phenyl group, 4-bromperidol group, 4-hydroxyproline group, 4-metoksifenilny group, 2-hydroxyproline group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyproline group,

(iii) when b is a benzene ring, -X - represents-NH-, -Z - represents-CR6R7- and-W - represents-NH-, as R6and R7cannot be a methyl group,

(iv) when b is a benzene ring, -X - represents-NH-, -Z - represents-CO - and-W - represents-NR1-, R1cannot be p-trilinos group,

(v) when b is a benzene ring, -X - represents-NH-, -Y - is-S-, -Z - represents-CR6R7- and-W-represents-NH-, as R6and R7cannot be a methyl group, and

(vi) when b is a benzene ring, -X - represents-NH-, -Y - is-S-, -Z - represents-CH2- and-W - cannot be-O-,

or their pharmaceutically acceptable salts.

The present invention also offers a hypoglycemic agent, and the agent for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic d is inpatie, diabetic macroangiopathies, impaired glucose tolerance or obesity, which contains the above lactam compound(I) or its pharmaceutically acceptable salt(s) as an active ingredient.

The best way of carrying out the invention

Detailed description the present invention will be presented below.

The term "action to improve the ability to transport sugar" refers to the action by enhancing the ability of sugar transport across the biological membrane. This action enables the transport of sugar from the outer side of the biological membrane in the inner side, and its transport from the inner side to the outer side of the biological membrane. Specifically, this step includes, for example, the effect of insulin on strengthening the transfer of glucose into muscle cells and fat cells.

Sugar, which should be transported, means pentoses and hexose, existing in a living organism, such as glucose, mannose, arabinose, galactose and fructose. The preferred sugar is glucose.

The term "lower alkyl group(s)" means a linear, branched or cyclic alkyl group(s)having from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. They include, for example, methyl group, ethyl group, n-sawn group, n-boutelou is the Rupp, n-pentelow group, n-hexoloy group, isopropyl group, isobutylene group, sec-boutelou group, tert-boutelou group, ISO-pentelow group, tert-pentelow group, neopentylene group, 2-pentelow group, 3-pentelow group, 3-hexoloy group, 2-hexoloy group, cyclopropyl group, cyclobutyl group, cyclopentyl group and tsiklogeksilnogo group. Among them, preferred are methyl group, ethyl group, etc.

The term "aryl group(s) refers to monocyclic or bicyclic aromatic substituent(s), consisting of 5-12 carbon atoms, such as phenyl group, angenlina group, naftalina group and fluorenyl group. Among them, preferred is a phenyl group.

Atom(s) of the halogen includes fluorine atom, chlorine atom, bromine atom and iodine atom.

The term "alkyl group(s)" means a linear, branched or cyclic alkyl group(s)having from 1 to 18 atoms, such as methyl group, ethyl group, n-sawn group, n-bucilina group, n-pencilina group, n-exilda group, n-heptylene group, n-aktiline group, n-nanlina group, n-decile group, n-angellina group, n-Godzilla group, isopropyl group, isobutylene group, sec-bucilina group, tert-bucilina group, isopentyl group, Tr is t-pencilina group, neopentylene group, 2-pencilina group, 3-pencilina group, 3-exilda group, 2-exilda group, tert-aktiline group, cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group and 1-adamantly group. Preferred alkyl groups are n-exilda group, n-heptylene group, n-aktiline group, n-nanlina group, n-decile group, n-angellina group, n-Godzilla group, ISO-sawn group, ISO-bucilina group, sec-bucilina group, tert-bucilina group, ISO-pencilina group, tert-pencilina group, neopentylene group, 2-pencilina group, 3-pencilina group, 3-exilda group, 2-exilda group, tert-aktiline group, cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, 1-adamantly group, etc. are preferred alkyl groups are ISO-sawn group, tert-bucilina group, tert-aktiline group, 1-adamantly group, etc.

The term "Alchemilla group(s) means a linear, branched or cyclic alkenylphenol group(s)having from 1 to 6 carbon atoms, such as vinyl group, 1-protanilla group, 2-protanilla group, ISO-protanilla group, 1-bucinellina group, 2-bucinellina group and 3-bucinellina group.

The term "Alchemilla the group(s)" means a linear, branched or cyclic alkylamino group(s)having from 1 to 6 carbon atoms, such as etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group and 3-Butyrina group.

The term "CNS group(s)" means the CNS group(s)having a linear, branched or cyclic alkyl group having from 1 to 18 carbon atoms, preferably from 1 to 8 carbon atoms, such as metaxylene group, amoxilina group, n-propoxyphene group, n-butoxylate group, n-pentylaniline group, n-hexyloxyphenyl group, n-heptyloxy group, n-octyloxyphenyl group, n-nonlocally group, n-decylaniline group, n-undecyloxy group, n-dodecyloxyphenyl group, isopropoxyphenyl group, isobutoxy group, sec-butoxylate group, tert-butoxylate group, cyclopropylacetylene group, cyclobutadiene group, cyclopentyloxy group, cyclohexyloxy group, cycloheptylamine group, 2-cyclohexylethyl group, 1-adamantylamine group, 2-adamantylidene group, 1-adamantanemethylamine group, 2-(1-substituted)ethoxyline group and triptoreline group. Among them, preferred CNS groups include metaxylene group, ethoxyline group, n-propoxyphenyl group from propoxyphenyl group, n-butoxyphenyl group, tert-butoxyl group, n-pentylaniline group and n-hexyloxyphenyl group.

The term "allylthiourea(s)" means allylthiourea(s)having a linear, branched or cyclic alkyl group having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, such as methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, second-butylthiourea, tert-butylthiourea, cyclopropylamino, cyclobutylamine, cyclopentylamine and cyclobutylamine.

The term "alkylsulfonyl group(s)" means alkylsulfonyl group(s)having a linear, branched or cyclic alkyl group having from 1 to 12 carbon atoms, such as methanesulfonyl group, acanaloniidae group, propanesulfonyl group, butanesulfonyl group, pentanesulfonic group, hexanesulfonic group, heptanesulfonic group, octanesulfonyl group, nonsulfonylurea group, decanesulfonate group, undecanesulfonate group and dodecanesulfonyl group.

The term "acyl group(s)" means a formyl group, acyl group(s)having a linear, branched or cyclic alkyl group having from 1 to 6 carbon atoms, acyl group(s)having a linear, R is svetlanna or cyclic alkenylphenol group, having from 1 to 6 carbon atoms, acyl group(s)having a linear, branched or cyclic alkylamino group having from 1 to 6 carbon atoms, or acyl group(s)having aryl group which may be substituted, such as formyl group, acetyl group, propylaniline group, Butyrina group, isobutylene group, valerina group, isovaleryl group, pivellina group, hexanoyl group, calolina group, methacryloyl group, crotonoideae group, isotretinoina group, benzoline group and napolina group.

The term "Allexinno group(s)" means formylamino group, Allexinno group(s)having a linear, branched or cyclic alkyl group having from 1 to 6 carbon atoms, or Allexinno group(s)having aryl group which may be substituted, such as formicoxenini group, acetylocholine group, propionyloxy group, butyryloxy group, isobutyryloxy group, valerianna group, isovalerylglycine group, pivaloyloxy group, hexaniacinate group, acryloyloxy group, methacryloyloxy group, crotononitrile group, isochronously group, benzoylacetone group and Avtoelektrika group.

The term "alkylamino(s)" means the kinogruppa(s), monosubstituted or disubstituted by alkyl group(s). Examples of alkyl groups are alkyl groups listed above for the "alkyl group". Alkylamino(s) include, for example, an amino group, methylaminopropyl, ethylamino, propylamino, isopropylamino, dimethylaminopropyl, diethylaminopropyl, dipropylamino, diisopropylamino and methylaminopropyl. The preferred alkylaminocarbonyl are alkylamino having from 1 to 6 carbon atoms.

The term "alkoxycarbonyl group(s)" means alkoxycarbonyl group(s)having a linear, branched or cyclic alkyl group having from 1 to 8 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group.

The term "carnemolla group(s)" means karbamoilnuyu group(s), which may be linear, branched or cyclic alkyl group having from 1 to 6 carbon atoms, a nitrogen atom, such as carnemolla group, N-methylcarbamoyl group, N-ethylcarbazole group, N,N-dimethylcarbamoyl group, N-pyrrolidinyl Vilna group, N-piperidinylcarbonyl group and N-morpholinylcarbonyl group.

The term "sulfonylurea group(s)" means sulfonyloxy group(s), which may be linear, branched or cyclic alkyl group having from 1 to 6 carbon atoms, sulfur atom, such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group and butylsulfonyl group.

The term "aromatic ring" means a monocyclic or bicyclic aromatic ring(a), consisting of carbon atoms, such as benzene ring, naphthalene ring, an indene ring and ring fluorine. Benzene ring, naphthalene ring, etc. are preferred.

The term "heterocyclic ring" means a heterocyclic ring(a), consisting of 1-3 rings, each of which includes from 5 to 7 members, such as carbon and nitrogen, oxygen, sulfur or the like. They are, for example, pyridine ring, dihydropyrrole ring, pyridazinyl ring, pyrimidine ring, pyrazinium ring, pyrrole ring, furan ring, thiophene ring, oxazolium ring, isoxazolyl ring, pyrazolones ring, imidazolium ring, thiazolium ring, isothiazolone ring, thiadiazole ring, pyrrolidinium ring, piperidinium ring, piperazinyl ring, indole the first ring, isoindoline ring, benzofuranyl ring, isobenzofuran ring, benzothiophene ring, benzimidazolium ring, benzoimidazole ring, benzoxazole ring, benzothiazole ring, purine ring, pyrazolopyrimidine ring, quinoline ring, isoquinoline ring, naphthyridine ring, hinazolinam ring benzodiazepine ring, carbazole ring and dibenzofurans ring. Heterocyclic rings, preferably, are pyridine ring, pyrimidine ring, pyridazine ring, furan ring and a thiophene ring. Preferred heterocyclic rings are pyridine ring, pyrimidine ring and a thiophene ring.

The term "aliphatic ring(s)" means a monocyclic or bicyclic aliphatic ring(a), consisting of atoms of carbon, such as cyclopropane ring, CYCLOBUTANE ring, cyclopentane ring, cyclohexane ring, Cycloheptane ring, cyclooctane ring, declinable ring and norbornane ring. Aliphatic ring, preferably, is a cyclohexane ring. The term "heteroaryl group(s)" means the heteroaromatic substituent(s), consisting of 1-3 rings, and each includes from 5 to 7 members from carbon atoms and nitrogen, oxygen and sulphur and the like, such as Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, pyrrolidine group, furazilina group, thienyl group, oxazoline group, isoxazolyl group, pyrazolidine group, imidazolidinyl group, thiazolidine group, isothiazolinone group, thiadiazolyl group, indayla group, isoindolyl group, benzoperylene group, isobenzofuranyl group, benzothiazoline group, benzoperylene group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, kinolinna group, izochinolina group, naphthylidine group and chinadaily group. Heteroaryl groups, preferable are 2-Peregrina group, 3-Peregrina group, 4-Peregrina group and 1-pyrazolidine group.

The term "arrochela group(s)" means the group having the aryl group from the oxygen atom. Examples of aryl groups is the group listed above with a reference to "aryl group(s)". Examples of aryloxy are phenoxyl group, 1-naftalina group and 2-naftalina group.

The term "heteroallergy group(s)" means the group having a heteroaryl group from the oxygen atom. Examples of heteroaryl groups are the groups listed above with reference to the "heteroaryl group(s". Examples heteroarylboronic groups are 2-peridiocally group, 3-peridiocally group, 4-peridiocally group and 2-pyrimidinylidene group.

The term "killingray(s)" means the group having the aryl group at the nitrogen atom. Examples of aryl groups are listed above with reference to the "aryl group(s)". Examples of arylamino are phenylaminopropyl, 1-naphthylamine and 2-naphthylamine.

Arylvinyl groups are vinyl groups, substituted aryl group in position 1 or position 2. Examples of aryl groups are the groups listed above with reference to the "aryl group(s)". Examples arylvinyl groups are 1-fenilvinil group and 2-fenilvinil group.

Arelatively groups are etinilnoy group, substituted aryl group in position 2. Examples of aryl groups are the groups listed above with reference to the "aryl group". Example arelatively groups is phenylethylene group.

The expression "which may have a substituent(s)" means that the group has no substituent or that, if the group is substituted, the substituent(s) is at least one of the substituents listed in the above formula (I). The substituents may be the same or different from each other. P is the situation(I) and the number of substituent(s), in particular, it is not limited.

In the lactam compounds or their pharmaceutically acceptable salts in claim 1 preferred are compounds of General formula (I)where the symbols have the following meanings: R1represents preferably a hydrogen atom, methyl group, benzyl group or methoxycarbonylmethyl group, and R1is, in particular, preferably, a hydrogen atom or methyl group;

R2, R3and R4are each preferably a hydrogen atom, halogen atom, hydroxyl group, alkyl group, CNS group, acyl group, Allexinno group, amino group, alkoxycarbonyl group, karbamoilnuyu group, a nitrogroup, cyano, triptorelin group, aryl group which may have a substituent(s), a heteroaryl group which may have a substituent(s), benzyloxyphenyl group, aryloxyalkyl group which may have a substituent(s), or arelatively group which may have a substituent(s), R2, R3and R4are each more preferably a hydrogen atom, halogen atom, hydroxyl group, methyl group, ethyl group, through the group, isopropyl group, metaxylene group, ethoxyline group, n-propoxyphenyl group, isopropoxyphenyl group, n-butoxyl group or enterocele group, and R 2, R3and R4are each more preferably a hydrogen atom, halogen atom, methyl group, ethyl group or ethoxyline group;

-X - is preferably NH-, -NR5-where R5represents a lower alkyl group, -S - or-CH2- and-X-represents, more preferably, -NH - or-NMe-;

-Y - is preferably-NH-, -NR5-where R5represents an acyl group which may have a substituent (s), alkoxycarbonyl group which may have a substituent(s), carbamoyl group which may have a substituent(s), or sulfonyloxy group which may have a substituent(s), or-O-, -Y - is, more preferably, -NR5-where R5represents an acyl group which may have a substituent(s), alkoxycarbonyl group which may have a substituent(s), or carbamoyl group which may have a substituent(s), and-Y - is, more preferably, -NAc-, -N(PINES2CH3)-, -N(PINES2CF3)-, -N(COCF2CF3)-, -N(COCH2OEt)-, -N(COCH2HE)-, -N(COOMe)- or-N(COOEt)-;

-Z - is preferably-NH - or-CH2- and-Z - is, more preferably, -CH2-;

W is preferably-NH-, -NR1where R1represents a lower alkyl group or-CH2- and-W - representation is employed, more preferably, -NH - or-NMe-;

And is, preferably, an aromatic ring or a heterocyclic ring. And is, more preferably, a benzene ring, a pyridine ring, a pyrimidine ring or a thiophene ring. And is even more preferably, a benzene ring;

In is, preferably, an aromatic ring which may have a substituent(s), or aliphatic ring which may have a substituent(s). In is, more preferably, a benzene ring which may have a substituent(s), or a cyclohexane ring which may have a substituent(s). In is, even more preferably a cyclohexane ring which may have a substituent (s). When b is a cyclohexane ring which may have a substituent(s), absolute configuration of the carbon atoms in position a and position b is, preferably, R or S, more preferably R

In the present invention preferably, R5represented a lower alkyl group or acyl group which may have a substituent(s), to R6and R7could be the same or different from each other and they represent, independently, a hydrogen atom, atom galegeae, hydroxyl group, alkyl group, aryl group, mercaptopropyl, CNS group, al is itigroup, alkylsulfonyl group, acyl group, Allexinno group, amino group, alkylamino, carboxyl group, alkoxycarbonyl group, karbamoilnuyu group, a nitrogroup, cyano or triptorelin group, and to-W - was-NR1-.

In the present invention preferably-X - and-Y - in the General formula (I) can be the same or different from each other and each of them was represented by-NH - or-NR5where R5represents a lower alkyl group which may have a substituent(s), acyl group which may have a substituent(s), alkoxycarbonyl group which may have a substituent(s), carbamoyl group which may have a substituent(s), or sulfonyloxy group which may have a substituent(s), to-Z - was-CH2or CR6R7-where R6and R7may be the same or different from each other and they independently represented a hydrogen atom, halogen atom, hydroxyl group, alkyl group, mercaptopropyl, CNS group, allylthiourea, alkylsulfonyl group, acyl group, Allexinno group, amino group, alkylamino, carboxyl group, alkoxycarbonyl group, karbamoilnuyu group, a nitrogroup, cyano or triptorelin group, and to-W - was-NR1-where R1 represents a hydrogen atom, a lower alkyl group which may have a substituent(s), or aryl group which may have a substituent(s).

When the compounds of the present invention are sufficiently acidic, their pharmaceutically acceptable salts include ammonium salts, alkali metal salts (such as, preferably, sodium and potassium salts), salts of alkaline-earth metals (such as, preferably, calcium salts and magnesium salts), and salts of organic bases, such as salts dicyclohexylamine, benzathine salt, salts of N-methyl-D-glucan, salt hydramine and salts of amino acids such as arginine salt and lysine salt. When the compounds of the present invention are sufficiently basic, their pharmaceutically acceptable salts include the acid additive salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or with organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid and monoethylene acid. If necessary, salts may be water or hydrated.

The present invention includes all isomers such as optical isomers and geometrical isomers, hydrates, solvate and crystalline forms of the compounds. In this case, p is edocfile, to the absolute configuration of the carbon atoms in position a, b and C in the General formula (I) were R or S, independently of each other. It is preferable that the absolute configuration of the carbon atoms in position a and position b in the General formula (I) was R, and that the absolute configuration of the carbon atom at position c was R or S. Further, it is preferable that the absolute configuration of the carbon atoms in position a and position b in the General formula (I) was S and that the absolute configuration of the carbon atom in position was R or S.

Compounds of the present invention can be synthesized by the methods described below.

For example, the compound (I) of the present invention where W is-NH-, -Z - represents-CH2-, -X - and-Y-, each represent-NH -, and a and b each represent a benzene ring, can be synthesized by condensation Ternovoi acid (II) with 1,2-phenylenediamine (III) obtaining enamino compounds (IV) and the interaction of this compound (IV) with an appropriate aldehyde (V), as shown below:

where R and R'each represent a substituent in the benzene ring.

Compounds (VII), where the amino group in 4-position is substituted by an alkyl group, can be synthesized using N-substituted 1,2-phenylenediamine (III'), as shown below:

where R and R'each represent a substituent in the benzene ring, R" represents a Deputy at the amino group in 4-position.

Compounds (VIII), where the amino group at the 9-position is substituted by an alkyl group or acyl group, can be synthesized by alkylation or acylation of the compound (VI), as shown below.

where R and R'each represent a substituent in the benzene ring, and R" is alkyl or acyl group, which is a Deputy at the amino group at the 9-position, and X represents a leaving group such as halogen atom.

The compound (I) of the present invention where W is-NH-, -Z - represents-CH2-, -X - represents-NH-, -Y - is-NAc-, a represents a benzene ring and b is a cyclohexane ring, can be synthesized by condensation terminoloy acid (II) with 1,2-cyclohexanediamine (III'), the interaction of the compounds with the appropriate aldehyde (V) formation of cyclic compounds (X) and acetylation of this compound (X) in the usual way of obtaining the compound (XI). Compounds in which Y represents an acyl group other than-NAc can also be synthesized in the same manner as the method described above, or using a carboxylic acid condensing agent or the like.

is soedineniya (XI) can also be synthesized by diallylammonium cyclic compounds (X) to compound (XII), the excess amount of the acid anhydride or the like and selective removal of the acyl group at the 4-position in the presence of base such as potassium carbonate.

where R represents the substituent in the benzene ring.

Compounds of the above General formula, Y is-NR5where R5is alkoxycarbonyl group, can be synthesized by using appropriate alkylchlorosilanes, as shown by the formula (a)below.

Compounds of the above General formula, Y is-NR5where R5is karbamoilnuyu group, can be synthesized by using the appropriate isocyanate, as shown by formula (b)below.

Compounds of the above General formula, Y is-NR5where R5is sulfonyloxy group, can be synthesized by using appropriate sulphonylchloride, as shown by the formula (C)below.

where R represents the substituent in the benzene ring.

The compound (I) of the present invention where W is-NH-, -Z - represents-CH2-, -X - represents-S-, -Y - represents-NH -, and a and b each represent a benzene ring, can be synthesized by condensation terminoloy acid (II) with 2-aminothiophenol (XVI) with the formation of the sulfide compound (XVII) and the interaction of this with the organisations with the appropriate aldehyde (V).

where R and R'each represent a substituent in the benzene ring.

The compound (I) of the present invention where W is-NH-, -Z - represents-CH2-, -X - represents-NH-, -Y - is-O -, and a and b each represent a benzene ring, can be synthesized by condensation terminoloy acid (II) with 2-aminophenol (XIX) obtaining enamino compounds (XX) and the interaction of this compound with the appropriate aldehyde (V).

where R and R'each represent a substituent in the benzene ring.

The compound (I) of the present invention where W is-NH-, -Z - represents-NH-, -X - represents-CH2-, -Y - represents-NH -, and a and b each represent a benzene ring, can be synthesized by the interaction of 5-(2-AMINOPHENYL)methyl-1,2-dihydropyrazol-3-one (XXII), described in Journal of heterocyclic chemistry, 71-5 (1989), aldehyde (V), as shown below:

where R and R'each represent a substituent in the benzene ring.

Terminology acid used as starting material can be synthesized by the method shown below, or a known method [Journal of chemical society, perkin trans., 1, 2907 (1973)]:

Aldehydes can be synthesized well-known method or a method obtained is output from it.

Compounds of the present invention can be synthesized by the above reactions, as shown in the examples below.

Compounds of the present invention obtained by the above described methods, can be cleaned in different ways, usually used in the synthesis of organic compounds, such as extraction, distillation, crystallization and column chromatography.

Compounds of the present invention have an effect on increasing the ability of the transport of sugar and they are effective in the treatment of patients using this action. That is, these compounds are useful as agents for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathies, impaired glucose tolerance or obesity because they reduce the level of glucose in the Sahara increased carrying sugar abilities.

When the compounds of the present invention are used as agents for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathies, impaired glucose tolerance or obesity, they can be administered orally, intravenously or subcutaneously. The dose, which warier who are depending on symptoms, age and method of administration the patient is usually from 0.001 to 1000 mg/kg/day.

Compounds of the present invention can be manufactured in the form of a pharmaceutical preparation in the usual way. Dosage forms of the pharmaceutical preparations are, for example, injectables, tablets, granules, fine granules, powders, capsules, creams and suppositories. Media preparations are, for example, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, ethanol, carboxymethyl cellulose, calcium carboxymethyl cellulose, magnesium stearate, talc, cellulose acetate, white sugar, titanium oxide, benzoic acid, esters of para-hydroxybenzoic acid, dehydroacetic sodium, Arabian gum, tragakant, methyl cellulose, egg yolk, surfactants, regular syrup, citric acid, distilled water, ethanol, glycerin, propylene glycol, macrogol, secondary acidic sodium phosphate, monopotassium phosphate, sodium phosphate, dextrose, sodium chloride, phenol, thimerosal, and hydrosulfite sodium. The carrier is selected depending on the form of the drug and is mixed with the compound of the present invention.

The content of the active ingredient of the present invention in the preparation of the those present invention, in particular, it is not limited, since it varies considerably depending on the form of the drug. However, the content of the active ingredient is usually from 0.01 to 100 wt.%, preferably from 1 to 100 wt.%, calculated on the whole composition.

Examples

The following examples will further specifically illustrate the present invention but in no way limit the invention.

Example 1

Stage 1. Synthesis pyrrolidin-2,4-dione (II: terminowa acid)

The triethylamine (72 g, 0,713 mol) are added to a solution (800 ml) hydrochloride acylaminoacyl (54,68 g, 0,392 mol) in dichloromethane and the resulting mixture is cooled at 0°C. To the mixture for 30 minutes, added dropwise a solution (100 ml) of methyl 3-chloro-3-oxobutanoate (48,5 g, 0,355 mol) in dichloromethane. The resulting mixture was stirred at room temperature for additional 4 hours. After completion of the reaction, to the reaction mixture are added water (1000 ml) to separate the dichloromethane layer. After washing with an aqueous solution of sodium chloride followed by drying over anhydrous sodium sulfate the solvent is evaporated. To the residue is added methanol (600 ml) and activated charcoal (10 g) and the resulting mixture is stirred for some time and then filtered through celite. The solvent is evaporated, thus obtaining methyl-3-ethoxycarbonylmethylene-3-oxobutanoate (66,9 g, 93%)in the form of a yellow oil.

1H NMR (300 M Hz, DMSO-d6) δ=1,17(3H, t, J=7.2 Hz), 3,30(2H, s), of 3.60(3H, s), 3,83(2H, d, J=5.7 Hz), 4,07(2H, q, J=7,2 Hz)and 8.50(1H, Ust).

Methanol (40 ml) and toluene (400 ml) are added to the thus obtained methyl-3-ethoxycarbonylmethylene-3-oxobutanoate (66,9 g, 0.33 mol). To the obtained mixture under vigorous stirring, added dropwise 28% solution of sodium methoxide/methanol (70 g, 0,363 mol) and the mixture is heated at 65°C for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 2 M hydrochloric acid (185 ml of 0.37 mol). The thus obtained solid substance was separated by filtration and then dried, thus obtaining 3-ethoxycarbonylpyrimidine-2,4-dione (39.5 g, 0.25 mol) in the form of a beige powder.

1H NMR (300 M Hz, DMSO-d6) δ=3,62(3H, s), 3,82(2H, s)to 7.50(1H, USS).

1,4-Dioxane (2400 ml) and water (240 ml) is added to the thus obtained 3-ethoxycarbonylpyrimidine-2,4-dione (39.5 g, 0.25 mol) and the mixture heated to boiling under reflux for 30 minutes. After completion of the reaction the solvent is evaporated, thus obtaining pyrrolidin-2,4-dione (II:terminowa acid) (24,35 g, 100%) in the form of a light yellow solid.

1H NMR (300 M Hz, DMSO-d6) form of ketone δ=2,93(2H, s), of 3.77(2H, s), 8,23(1H, s), the form of the enol δ=3,74(2H, s), and 4.75(1H, s), 7,07(1H, s), the form of ketone:form enol=approximately 3:2.

Stage 2. Synthesis of 4-((2-and inopril)amino)-3-pyrrolin-2-it

The solution pyrrolidin-2,4-dione (6,93 g, 70 mmol), obtained in stage 1, and 1,2-phenylenediamine (7,88 g, 70 mmol) in methanol was stirred at 60°C for 1 hour. The reaction solution is cooled, and the thus formed crystals are separated by filtration to obtain 4-((2-AMINOPHENYL)amino)-3-pyrrolin-2-she (yield: 11.6 g, 87%).

1H NMR (300 M Hz, DMSO-d6) δ=3,94(2H, s), 4,56(1H, s), 4,91(2H, USS), 6,55(1H, dt, J=7,5, 1.5 Hz), 6,72(1H, DD, J=7,8, 1.5 Hz), to 6.80(1H, s)6,86(1H, dt, J=7,5, 1.5 Hz), 7,02(1H, DD, J=7,8, 1.5 Hz), 8,03(1H, s). MS(ESI) m/z 190(M+H)+.

Stage 3. The synthesis of the compound of example 1

A solution of 4-((2-AMINOPHENYL)amino)-3-pyrrolidin-2-it (50 mg, 0.26 mmol)obtained in step 2 and 4-benzyloxybenzaldehyde (61 mg, 0.29 mmol) in methanol (3 ml) is stirred in the presence of acetic acid as catalyst (0.01 ml) at 70°C for 2 hours. The solvent is evaporated and to the residue is added dichloromethane. Thus, the precipitated solid is separated by filtration to obtain the compound of example 1 (yield: 60 mg, 54%).

1H NMR (300 M Hz, DMSO-d6) δ=3,95(2H, s), to 4.98(2H, s), 4,99(1H, d, J=4, 2 Hz), of 5.81(1H, d, J=4, 2 Hz), of 6.49-6,69(3H, m), 6,74-6,84(3H, m), of 6.96-7,05(3H, m), 7.23 percent-7,41(5H, m), 9,14(1H, s). MS (ESI) m/z 384(M+H)+.

Connection examples 2-34 synthesized in the same manner as the method in stage 3 of example 1, except that the initial connection is replaced by the corresponding aldehyde. Aldehydes is yli aldehydes, bought on the market or synthesized in the usual way.

Example 2

The compound of example 2 (yield: 75%) was synthesized using 4-chlorobenzaldehyde as a starting compound in the same way as in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=of 3.97(2H, s), of 5.03(1H, d, J=4, 2 Hz), 5,90(1H, d, J=4.5 Hz), 6,51(1H, DD, J=8,1, 1.5 Hz), 6,59(1H, dt, J=7,5, 1.5 Hz), of 6.68(1H, dt, J=8,4, and 2.1 Hz), 6,83(1H, DD, J=7,5, 1.5 Hz), 7,06(1H, s), 7,13(2H, DD, J=6,6, 1.8 Hz), 7,22(2H, DD, J=6,6, 1.8 Hz), 9,23(1H, s). MS(ESI) m/z 312(M+N)+.

Example 3

The compound of example 3 (yield: 65%) was synthesized using 4-identilied as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,96(2H, s), to 4.98(1H, d, J=4.5 Hz), of 5.89(1H, d, J=4.5 Hz), 6,51(1H, d, J=7.8 Hz), 6,59(1H, t, J=7.8 Hz), to 6.67(1H, t, J=7.8 Hz), PC 6.82(1H, d, J=7.8 Hz), 6,91(2H, d, J=7.5 Hz), 7,05(1H with), 7,51(2H, d, J=7.5 Hz), which 9.22(1H, s). MS(ESI) m/z 404(M+H)+.

Example 4

The compound of example 4 (yield: 66%) was synthesized using 4-methylbenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=2,17(3H, s), of 3.95(2H, s), 5,90(1H, d, J=4.5 Hz), of 5.81(1H, d, J=4.5 Hz), 6,50(1H, DD, J=8,1, 1.5 Hz), 6,59(1H, dt, J=7,5, 1.5 Hz), of 6.68(1H, dt, J=8,4, and 2.1 Hz), for 6.81(1H, DD, J=7,5, 1.5 Hz), 6,92-7,00(5H, m), 9,16(1H, s). MS(ESI) m/z 292(M+H)+.

Example 5

The compound of example 5 (yield: 34%) are synthesized using 4-tert-butyl is soldered as a starting compound in the same way, as a way to stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=1,18(9H, s)to 3.92(2H, s), 4,96(1H, d, J=4.5 Hz), by 5.87(1H, d, J=4.5 Hz), 6,53 is 6.67(3H, m), to 6.80(1H, d, J=7.5 Hz), of 6.96-7,05(3H, m), to 7.15(2H, d, J=8,4 Hz)to 9.15(1H, s). MS(ESI) m/z 334(M+H)+.

Example 6

Stage 1. Synthesis of 4-(2-phenylethynyl)benzaldehyde

4-Bromobenzaldehyde (370 mg, 2 mmol), phenylacetylene (306 mg, 3 mmol) and tetranitropentaerithrite (45 mg) was dissolved in triethylamine (4 ml) and the resulting solution was stirred at 80°C in argon atmosphere for 24 hours. The solvent is evaporated and the product purified column chromatography on silica gel, thus obtaining 4-(2-phenylethynyl)benzaldehyde (yield: 258 mg, 63%).

1H NMR (300M Hz, CDCl3) δ=7,30-7,40(3H, m), 7,50-of 7.60(2H, m), to 7.68(2H, d, J=8.1 Hz), 7,87(2H, d, J=8.1 Hz), 10,02(1H, s).

Stage 2. Synthesis of compound of example 6

The compound of example 6 (yield: 34%) are synthesized using 4-(2-phenylethynyl)benzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,99(2H, s), is 5.06(1H, d, J=3,9 Hz)5,94(1H, d, J=4.5 Hz), 6,50-of 6.71(3H, m), at 6.84(1H, d, J=7.5 Hz), 7,80(1H, s), to 7.15(2H, d, J=8.1 Hz), 7,35(2H, d, J=8.1 Hz), 7,38-7,42(3H, m), of 7.48-rate of 7.54(2H, m), a 9.25(1H, s). MS(ESI) m/z 334(M+H)+.

Example 7

The compound of example 7 (yield: 24%) are synthesized using 4-phenylbenzimidazole as a starting compound in the same manner as the method in stage 3 when the EPA 1.

1H NMR (300 M Hz, DMSO-d6) δ =3,98(2H, s), 5,07(1H, d, J=4, 2 Hz), 5,95(1H, d, J=4, 2 Hz), 6,56-of 6.71(3H, m), at 6.84(1H, d, J=6.9 Hz), 7,05(1H, s), 7,20(2H, d, J=8.1 Hz), 7,26-7,49(5H, m), EUR 7.57(2H, d, J=8.1 Hz), which 9.22(1H, s). MS(ESI) m/z 354(M+H)+.

Example 8

Stage 1. Synthesis of 4-(4-nitrophenyl)benzaldehyde

1 M solution (1.2 ml, 1,22 mmol) hydride diisobutylaluminum in toluene is added slowly to a solution (10 ml) of 4-(4-nitrophenyl)benzonitrile (224 mg, 1 mmol) in toluene at room temperature and the mixture is stirred for 1 hour. After cooling to 0°to the resulting mixture is slowly added methanol (0.4 ml) and water (0.4 ml) and the mixture is stirred. The reaction mixture is dried over sodium sulfate. After purification column chromatography on silica gel (ethyl acetate/hexane) of 4-(4-nitrophenyl)benzaldehyde obtained in the form of a yellow solid (yield: 127 mg, 56%).

1H NMR (300M Hz, CDCl3) δ=7,80(4H, d, J=8.7 Hz), 8,03(2H, d, J=8,4 Hz), at 8.36(2H, d, J=9.0 Hz), 10,11(1H, s).

Stage 2. The synthesis of the compound of example 8

The compound of example 8 (yield: 67%) was synthesized using 4-(4-nitrophenyl)benzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=of 3.97(2H, s)5,08(1H, d, J=4, 2 Hz), 5,98(1H, d, J=4, 2 Hz), 6,55-6,70(3H, m), at 6.84(1H, d, J=7,2 Hz), 7,05(1H, s), 7,25(2H, d, J=8,4 Hz), to 7.59(2H, d, J=8,4 Hz), 7,87(2H, d, J=9.0 Hz), 8,23(2H, d, J=9.0 Hz), 9,24(1H, s). MS(ESI) m/z 397(M-H)-.

Example 9

Obedinenie example 9 (yield: 22%) are synthesized using 2-fluorenecarboxylic as a starting compound in the same way, as a way to stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=of 3.77(2H, s), of 4.00(2H, s), 5,12(1H, d, J=4.5 Hz), 5,90(1H, d, J=4.5 Hz), 6,50-6,69(3H, m), at 6.84(1H, d, J=7.5 Hz),? 7.04 baby mortality(1H, s), 7,14(1H, d, J=7.5 Hz), 7,21 and 7.36(3H, m), 7,51(1H, d, J=7.5 Hz), 7,66(1H, d, J=7.5 Hz), to 7.77(1H, d, J=7.5 Hz), of 9.21(1H, s). MS(ESI) m/z 366(M+H)+.

Example 10

The compound of example 10 (yield: 48%) are synthesized using 4-butoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=0,88(3H, t, J=7.4 Hz), 1,30-1,45(2H, m), 1.56 to its 1.68(2H, m), a-3.84(2H, t, J=6.3 Hz), of 3.95(2H, s), to 4.98(1H, d, J=4, 2 Hz), 5,79(1H, d, J=4, 2 Hz), 6,47-6,84(6H, m), 6,93-7,06(3H, m), 9,13(1H with). MS(ESI) m/z 350(M+H)+.

Example 11

Stage 1. Synthesis of 4-dodecyloxybenzoyl

4-Hydroxybenzaldehyde (673 mg, 5.5 mmol), 1-bromododecane (1.25 g, 5 mmol) and potassium carbonate (859 mg, from 6.22 mmol) are added to a dimethylformamide (3 ml) and the mixture was stirred at 65°C for 18 hours. After completion of the reaction, followed by extraction with ethyl acetate 4-dodecyloxybenzoyl (yield: 1.45 g, 99%) are in the form of white crystals.

Stage 2. The synthesis of the compound of example 11

The compound of example 11 (yield: 82%) was synthesized using 4-dodecyloxybenzoyl as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=0,85(3H, t, J=6.6 Hz), 1,10-1,40(18H, m), 1,55 by 1.68(2H, m), 3,82(2H, t, J=6.6 Hz), 3,95(2, C)to 4.98(1H, d, J=4.5 Hz), 5,78(1H, d, J=4.5 Hz), of 6.49-6,72(5H, m), to 6.80(1H, d, J=9.0 Hz), 6,97? 7.04 baby mortality(3H, m), 9,13(1H, s). MS(ESI)m/z 462(M+H)+.

Example 12

The compound of example 12 (yield: 79%) was synthesized using 4-cyclohexenecarboxaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 4-hydroxybenzaldehyde and bromocyclopentane in the same way as the method in stage 1 of example 11.

1H NMR (300 M Hz, DMSO-d6) δ=1,29-1,65(10H, m), 1,79-1,90(2H, m)to 3.92(2H, s), 4,28-and 4.40(1H, m), of 4.95(1H, d, J=3.6 Hz), 5,77(1H, d, J=4,8 Hz), 6.48 in-6,68(5H, m), 6,79(1H, d, J=7.8 Hz), 6,95-7,02(3H, m), 9,12(1H, s). MS(ESI) m/z 388(M-H)-.

Example 13

The compound of example 13 (yield: 55%) are synthesized using 4-(2-adamantylamine)benzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 4-hydroxybenzaldehyde and 2-bromoguanine in the same way as the method in stage 1 of example 11.

1H NMR (300 M Hz, DMSO-d6) δ=of 1.40-1.50(2H, similar to d), of 1.66-of 1.85(8H, m)of 1.97(4H, similar to C), 4,35(1H, s), equal to 4.97(1H, d, J=4, 2 Hz), 5,81(lH, d, J=4, 2 Hz), 6,50-6,85(6H, m), of 6.96-7,05(3H, m)to 9.15(1H, s). MS(ESI) m/z 428(M+H)+.

Example 14

The compound of example 14 (yield: 48%) are synthesized using 4-(1-adamantylamine)benzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthetic is irout of 4-hydroxybenzaldehyde and 1-adamantanemethylamine in the same way, as a way to stage 1 of example 11.

1H NMR (300 M Hz, DMSO-d6) δ=1,50-1,75(12H, m), 1,90-2,00(3H, OSS), to 3.41(2H, s), of 3.95(2H, s), to 4.98(1H, d, J=4.5 Hz), 5,78(1H, d, J=4.5 Hz), 6.48 in-6,76(5H, m), to 6.80(1H, d, J=8.1 Hz), of 6.96-was 7.08(3H, m), 9,14(1H, s). MS(ESI) m/z 442(M+H)+.

Example 15

The compound of example 15 (yield: 36%) are synthesized using 4-(2-(1-substituted)ethyl)oxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized by the reaction of Mitsunobu 4-hydroxybenzaldehyde and 2-(1-substituted)ethanol.

1H NMR (300 M Hz, DMSO-d6) δ=1,40-1,70(14H, m), 1,90(3H, USS), 3,90(2H, t, J=7.2 Hz), of 3.95(2H, s), to 4.98(1H, d, J=4.5 Hz), 5,79(1H, d, J=4.5 Hz), 6,50-6,85(6H, m), 6,98-6,97-7,03(3H, m), 9,14(1H, s). MS(ESI) m/z 456(M+H)+.

Example 16

The compound of example 16 (yield: 54%) are synthesized using 4-(2-cyclohexylethyl)oxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 4-hydroxybenzaldehyde and 2-cyclohexylethylamine in the same way as the method in stage 1 of example 11.

1H NMR (300 M Hz, DMSO-d6) δ=0,82 of 1.00(2H, m), 1,06-of 1.26(3H, m), 1.32 to-1,49(1H, m), 1,49-1,74(7H, m), a 3.87(2H, t, J=6.6 Hz), of 3.95(2H, s), to 4.98(1H, d, J=4, 2 Hz), 5,78(1H, d, J=4.5 Hz), of 6.49-6,72(5H, m), to 6.80(1H, DD, J=1.5 and 7.8 Hz), 6,97-7,03(3H, m), 9,13(1H, s). MS(ESI) m/z 402(M-H)-.

Example 17

Stage 1. Synthesis of 1-(4-formylphenyl)pyrazole

The copper acetate (91 mg, 0.5 mmol), pyridine (5 mg, 0.67 mmol) and the active molecular sieve 4A (250 mg) are added to a solution of 4-formylphenylboronic acid (100 mg, 0.67 mmol) and pyrazole (16 mg, 0.33 mmol) in 1,4-dioxane (4 ml) and the mixture is stirred at room temperature for 72 hours. The reaction mixture was filtered through celite and the resulting filtrate is concentrated and then purified by chromatography TLC on silica gel, thus obtaining 1-(4-formylphenyl)pyrazole (yield: 38 mg, 66%) in the form of white powder.

1H NMR (300M Hz, CDCl3) δ=6,53-8,04(7H, m), 10,02(1H, s).

Stage 2. The synthesis of the compound of example 17

The compound of example 17 (yield: 74%) are synthesized using 1-(4-formylphenyl)pyrazole as the starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,99(2H, s)5,08(1H, d, J=4, 2 Hz), to 5.93(1H, d, J=4.5 Hz), 6,47-of 8.37(11H, m), 7,07(1H, s), 9,23(1H, s). MS(ESI) m/z 344(M+H)+.

Example 18

The compound of example 18 (yield: 24%) are synthesized using 2-bromobenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=was 4.02(2H, s), 5,28(1H, d, J=4.5 Hz), of 5.39(1H, d, J=4.5 Hz), 6.42 per(1H, d, J=7.8 Hz), 6,56(1H, t, J=7.8 Hz), 6,68-6,77(2H, m), 6.87 in(1H, d, J=7.8 Hz), 7,01-to 7.09(2H, m), 7,12(1H, s), 7,53-a 7.62(1H, m), a 9.35(1H, s). MS(ESI) m/z 356, 358(M+H)+.

Example 19

The compound of example 19 (yield: 38%) are synthesized using 2-methoxybenzaldehyde is as a starting compound in the same way, as a way to stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=to 3.92(3H, s), of 3.97(1H, d, J=16.5 Hz), Android 4.04(1H, d, J=16.5 Hz), 5,16(1H, d, J=4.5 Hz), 5,33(1H, d, J=4.5 Hz), 6,38(1H, d, J=7.5 Hz), 6,48 of 6.68(4H, m), to 6.80(1H, d, J=7.5 Hz), to 6.95(1H, d, J=7.5 Hz), 7,00 for 7.12(2H, m), 9,19(1H, s). MS(ESI) m/z 308(M+H)+.

Example 20

The compound of example 20 (yield: 50%) are synthesized using 2,4-dichlorobenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=was 4.02(2H, s), of 5.39(1H, d, J=4.5 Hz), 5,43(1H, d, J=4.5 Hz), 6,47(1H, d, J=7.5 Hz), 6,59(1H, t, J=7.5 Hz), 6,69-6,77(2H, m), to 6.88(1H, d, J=7.5 Hz), 7,07-7,16(2H, m), 7,56(1H, USS), 9,36(1H, s). MS(ESI) m/z 346(M+H)+.

Example 21

Stage 1. Synthesis of 4-butoxy-2-methoxybenzaldehyde

Potassium carbonate (1.50 g, 10.9 mmol) and butylated (666 mg, 3.6 mmol) are added to a solution of 2,4-dihydroxybenzaldehyde (500 mg, 3.6 mmol) in dimethylformamide (5 ml) and the mixture is stirred at room temperature for 2 hours. Then to the reaction mixture add methyliodide (to 2.57 ml) and the mixture is stirred at room temperature for 12 hours. After extraction with ethyl acetate followed by chromatography on silica gel 4 butoxy-2-methoxybenzaldehyde (yield: 233 mg, 31%) are obtained in the form of a colorless oil.

1H NMR (300M Hz, CDCl3) δ=to 1.00(3H, t, J=7.5 Hz), 1,44-to 1.59(2H, m), 1,73 is 1.86(2H, m), 3,91(3H, s), Android 4.04(2H, t, J=6.6 Hz), 6,45(1H, USS), is 6.54(1H, d, J=8,4 Hz), 7,80(1H, d, J=8,4 Hz), 10,29(1H, s).

stage 2. The synthesis of the compound of example 21

The compound of example 21 (yield: 59%) are synthesized using 4-butoxy-2-methoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=0,89(3H, t, J=7.8 Hz), 1,31 of 1.46(2H, m), 1.56 to its 1.68(2H, m), a-3.84(2H, t, J=6.3 Hz), 3,90(3H, s)to 3.99(2H, OSS), to 5.08(1H, d, J=3,9 Hz), with 5.22(1H, d, J=3,9 Hz), x 6.15(1H, d, J=8,4 Hz), 6,35-to 6.58(4H, m), only 6.64(1H, t, J=8,4 Hz), 6,79(1H, d, J=8,4 Hz), 7,02(1H, s)to 9.15(1H, s). MS(ESI) m/z 380(M+H)+.

Example 22

Stage 1. Synthesis of 2,4-dimetocsibenzoy

Potassium carbonate (1.50 g, 10.9 mmol) and butylated (1.66 g, 9,05 mmol) are added to a solution of 2,4-dihydroxybenzaldehyde (500 mg, 3.6 mmol) in dimethylformamide (5 ml) and the mixture is stirred at room temperature for 12 hours. After extraction with ethyl acetate followed by chromatography on silica gel 2,4-dimetocsibenzoy (yield: 833 mg, 92%) is obtained in the form of a colorless oil.

1H NMR (300 M Hz, DMSO-d6) δ=0,94-of 1.05(6H, m), 1,43 is 1.60(4H, m), 1,73-1,89(4H, m), 3,47-4,08(4H, m), to 6.43(1H, USS), of 6.52(1H, d, J=8,l Hz), 7,80(1H, d, J=8,l Hz), 10,33(1H, s).

Stage 2. The synthesis of the compound of example 22

The compound of example 22 (yield: 12%) are synthesized using 2,4-dimetocsibenzoy as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=0,89(3H, t, J=7.5 Hz), of 1.02(3H, t, J=7.5 Hz), 1.30 and a 1.46(2H, m), 1,48-to 1.67(4H, m), 1,0-of 1.94(2H, m)a 3.83(2H, t, J=6.3 Hz), 3,92-4,18(4H, m), 4,89(1H, d, J=4.5 Hz), 5,23(1H, d, J=4.5 Hz), x 6.15(1H, DD, J=8,7, 2.4 Hz), 6,32(1H, d, J=7.5 Hz), of 6.45(1H, d, J=8.7 Hz), of 6.49(1H, d, J=2.4 Hz), 6,54(1H, t, J=7.5 Hz), of 6.65(1H, t, J=7.5 Hz), to 6.80(1H, d, J=7.5 Hz),? 7.04 baby mortality(1H, s), 9,17(1H, s). MS(ESI) m/z 422(M+H)+.

Example 23

The compound of example 23 (yield: 90%) was synthesized using 4-butoxy-2-ethoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 2,4-dihydroxybenzaldehyde, mutilated and ethylbromide in the same way as the method in stage 1 of example 21.

1H NMR (300 M Hz, DMSO-d6) δ=0,89(1H, t, J=7.5 Hz), 1,30-1,45(2H, m)to 1.48(3H, t, J=7.2 Hz), 1,55-to 1.67(2H, m), 3,83(2H, t, J=6.6 Hz), 3,99(2H, USS), 4,08-to 4.23(2H, m), to 4.98(1H, d, J=4.5 Hz), 5,23(1H, d, J=4.5 Hz), x 6.15(1H, DD, J=8A, 2.4 Hz), 6,36(1H, d, J=7.8 Hz), of 6.45(1H, d, J=8,4 Hz), 6,47(1H, d, J=2.4 Hz), 6,53(1H, t, J=7.8 Hz), of 6.65(1H, t, J=7.8 Hz), to 6.80(1H, d, J=7.8 Hz), 7,03(1H, s), 9,16(1H, s). MS(ESI) m/z 394(M+H)+.

Example 24

The compound of example 24 (yield: 79%) was synthesized using 4-butoxy-2-propoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 2,4-dihydroxybenzaldehyde, mutilated and propyl bromide in the same manner as the method in stage 1 of example 21.

1H NMR (300 M Hz, DMSO-d6) δ=0,89(3H, t, J=7.5 Hz), 1,10(3H, t, J=7.5 Hz), 1,30-1,45(2H, m), 1.56 to its 1.68(2H, m), 1,83-of 1.97(2H, m), 3,83(2H, t, J=6.6 Hz), 3,93 is 4.13(4H, m), the 4.90(1H, d, J=4.5 Hz), 5,24(1H, d, J=4, Hz), x 6.15(1H, DD, J=8,4, 2.4 Hz), 6,33(1H, d, J=7.8 Hz), 6,46(1H, d, J=8,4 Hz), 6.48 in(1H, d, J=2.4 Hz), is 6.54(1H, t, J=7.8 Hz), of 6.65(1H, t, J=7.8 Hz), to 6.80(1H, d, J=7.8 Hz),? 7.04 baby mortality(1H, s), 9,17(1H, s). MS(ESI) m/z 408(M+H)+.

Example 25

The compound of example 25 (yield: 80%) was synthesized using 4-ethoxy-2-propoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 2,4-dihydroxybenzaldehyde, ethylbromide and propyliodide in the same way as the method in stage 1 of example 21.

1H NMR (300 M Hz, DMSO-d6) δ=1,10(3H, t, J=7.5 Hz), 1,25(3H, t, J=7.2 Hz), 1,83-of 1.97(2H, m)to 3.89(2H, t, J=7.2 Hz), 3.95 to to 4.14(4H, m), 4,91(1H, d, J=4, 2 Hz), 5,24(1H, d, J=4, 2 Hz), x 6.15(1H, DD, J=8,4, 2.4 Hz), 6,33(1H, d, J=7.8 Hz), 6,46(1H, d, J=8,4 Hz), 6.48 in(1H, d, J=2.4 Hz), is 6.54(1H, t, J=7.8 Hz), of 6.65(1H, t, J=7.8 Hz), to 6.80(1H, d, J=7.8 Hz),? 7.04 baby mortality(1H, s), 9,17(1H,s). MS(ESI) m/z 380(M+H)+.

Example 26

The compound of example 26 (yield: 85%) are synthesized using 2-ethoxy-4-propoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 2,4-dihydroxybenzaldehyde, propyliodide and ethylbromide in the same way as the method in stage 1 of example 21.

1H NMR (300 M Hz, DMSO-d6) δ=0,92(3H, t, J=7.5 Hz), to 1.48(3H, t, J=7.2 Hz), 1.57 in-1,72(2H, m), of 3.78(2H, t, J=6.6 Hz), 4,00(2H, USS), 4,06-4,24(2H, m), to 4.98(1H, d, J=4.5 Hz), 5,23(1H, d, J=4.5 Hz), 6,14(1H, DD, J=8.4 and that 2.4 Hz), 6,36(1H, d, J=7.8 Hz), of 6.45(1H, d, J=8,4 Hz), 6,47(1H, d, J=2.4 Hz), is 6.54(1H, t, J=7.8 Hz), of 6.65(1H, t, =7,8 Hz), 6,79(1H, d, J=7.8 Hz), 7,03(1H, s), 9,16(1H, s). MS(ESI)m/z 380(M+H)+.

Example 27

The compound of example 27 (yield: 53%) are synthesized using 4-hexyloxy-2-methoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 2,4-dihydroxybenzaldehyde, hexylboronic and methyliodide in the same way as the method in stage 1 of example 21.

1H NMR (300 M Hz, DMSO-d6) δ=0,85(3H, t, J=7.2 Hz), 1,19 was 1.43(6H, m), 1.56 to was 1.69(2H, m), 3,83(2H, t, J=6.6 Hz), 3,90(3H, s)to 3.99(2H, OSS), to 5.08(1H, d, J=4, 2 Hz), with 5.22(1H, d, J=4, 2 Hz), x 6.15(1H, DD, J=8,4, 2.4 Hz), 6,38(1H, d, J=7.8 Hz), 6,44(1H, d, J=8,4 Hz), of 6.49(1H, d, J=2.4 Hz), 6,53(1H, t, J=7.8 Hz), only 6.64(1H, t, J=7.8 Hz), 6,79(1H, d, J=7.8 Hz), 7,02(1H, s)to 9.15(1H, s). MS(ESI) m/z 408(M+H)+.

Example 28

The compound of example 28 (yield: 23%) are synthesized using 4-benzyloxy-2-methoxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,90(3H, s), of 3.97(1H, d, J=15 Hz), was 4.02(1H, d, J=15 Hz), equal to 4.97(2H, s), 5,10(1H, d, J=4.5 Hz), 5,23(1H, d, J=4.5 Hz), of 6.26(1H, DD, J=2,4, and 8.4 Hz), 6,40(1H, d, J=7.5 Hz), 6,47(1H, d, J=8,4 Hz), 6,53(1H, t, J=7.5 Hz), 6,58-6,69(3H, m), 6,79(1H, d, J=7.5 Hz), 7,02(1H, s), 7,26-the 7.43(6H, m), 9,16(1H, s). MS(ESI) m/z 414(M+H)+.

Example 29

Stage 1. Synthesis of 4-hexyloxy-2-hydroxybenzaldehyde.

2,4-Dihydroxybenzaldehyde (3.00 g, and 21.7 mmol) and exelrod (a 7.62 ml, to 54.3 mmol) is stirred in the presence of lithium carbonate (4,00 g, 4.3 mmol) in dimethylformamide (5 ml) at 55° With throughout the night. After neutralization with hydrochloric acid followed by extraction with ethyl acetate the product was then purified column chromatography on silica gel, thus obtaining 4-hexyloxy-2-hydroxybenzaldehyde (yield: 1.77 g, 37%) in the form of a colorless oil.

1H NMR (300M Hz, CDCl3) δ=0,91(3H, m), 1,32 is 1.48(6H, m), 1.77 in-of 1.84(2H, m)to 4.01(2H, t, J=6.6 Hz), 6,41(1H, d, J=2.1 Hz), 6,53(1H, DD, J=8,7, and 2.1 Hz), 7,42(1H, d, J=8.7 Hz), to 9.70(1H, s).

Stage 2. The synthesis of the compound of example 29

The compound of example 29 (yield: 73%) are synthesized using 4-hexyloxy-2-hydroxybenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=0,85(3H, t, J=6.9 Hz), 1,17-of 1.41(6H, m), 1,53 by 1.68(2H, m), 3,76(2H, t, J=6.6 Hz), 3,99(2H, OSS), to 5.21(2H, s), 6,04(1H, DD, J=8,4, 2.4 Hz), 6,34(1H, d, J=2.4 Hz), 6.42 per(1H, d, J=8,4 Hz), 6,46(1H, d, J=7.8 Hz), to 6.57(1H, t, J=7.8 Hz), of 6.65(1H, t, J=7.8 Hz), for 6.81(1H, d, J=7.8 Hz), to 7.09(1H, s), 9,16(1H, s), 9,92(1H, s). MS(ESI) m/z 394(M+H)+.

Example 30

Stage 1. Synthesis of 4-tert-butyl-2-chlorobenzaldehyde

Stage 1-1. Synthesis of 2-chloro-4-tert-butylphenol

4-tert-butylphenol (2.76 g, 18.4 mmol) dissolved in dichloromethane (25 ml). To the resulting solution was added dropwise sulfurylchloride (1.6 ml, 9.9 mmol) and the mixture is stirred at room temperature for 3 days and then concentrated under reduced pressure. After purification column chromatography on silicocalcium 2-chloro-4-tert-butylphenol (yield: 2,71 g, 80%).

1H NMR (300M Hz, CDCl3) δ=1,28(9H, s), lower than the 5.37(1H, s)6,94(1H, d, J=8.6 Hz), 7,19(1H, DD, J=8,6 Hz, 2.5 Hz), 7,30(1H, d, J=2.5 Hz).

Stage 1-2. Synthesis of 2-chloro-4-tert-butyltrichlorosilane

Chloroethylene (1.84 g, 10 mmol), obtained in stage 1-1, and pyridine (1.2 ml) dissolved in dichloromethane (20 ml). To the resulting solution was slowly added dropwise triftormetilfullerenov anhydride (2.5 ml). After stirring at room temperature for 10 minutes to the reaction mixture was added hexane (20 ml). Insoluble matter is removed by filtration and the filtrate concentrated under reduced pressure. After purification column chromatography on silica gel get 2-chloro-4-tert-butyltrichlorosilane (output: 2,94 g, 93%).

1H NMR (300M Hz, CDCl3) δ=1,32(9H, s), 7,25(1H, d, J=8.6 Hz), 7,34(1H, DD, J=8.6 Hz, 2.1 Hz), to 7.50(1H, d, J=2.1 Hz).

Stage 1-3. Synthesis of 2-chloro-4-tert-butylbenzyl alcohol

Triflate compound (638 mg, 2 mmol), obtained in stage 1-2, palladium acetate (14 mg), 1,3-diphenylphosphinoethyl (25 mg), methanol (4 ml) and triethylamine (0.6 ml) dissolved in dimethylformamide (5 ml) and the resulting solution was stirred at 80°C in an atmosphere of carbon monoxide for 16 hours. After keeping the reaction mixture for cooling, followed by extraction with a mixture of ethyl acetate/hexane and purified column chromatography on silica gel which are square-methyl-2-chloro-4-tert-butylbenzoate. Thus obtained ester is dissolved in dichloromethane (2 ml). To the resulting solution at -78°C in an atmosphere of argon is added dropwise a 1 M solution (2.5 ml) diisobutylaluminium in toluene and the resulting solution stirred at this temperature for 5 minutes. To the reaction mixture of 0.5 M hydrochloric acid (20 ml) and the temperature was raised to room temperature. After extraction with ethyl acetate, followed by purification column chromatography on silica gel get 2-chloro-4-tert-butylbenzyl alcohol (yield: 204 mg, 51%).

1H NMR (300M Hz, CDCl3) δ=1,31(9H, s), 1,8-2,1(1H, ush.), of 4.75(2H, s), 7,29(1H, DD, J=7,8 Hz and 2.1 Hz), of 7.36-7,41(2H, m).

Stage 1-4. Synthesis of 2-chloro-4-tert-butylbenzaldehyde

Alcohol compound (195 mg, 0,981 mmol)obtained in stage 1-3, dissolved in chloroform (5 ml). To the resulting solution was added activated manganese dioxide (1.27 g) and the mixture vigorously stirred at 50°C for 2 hours. After keeping the mixture for cooling the manganese dioxide is filtered off and the filtrate is concentrated under reduced pressure. After purification column chromatography on silica gel get 2-chloro-4-tert-butylbenzaldehyde (output: 152 mg, 79%).

1H NMR (300M Hz, CDCl3) δ=of 1.34(9H, s), 7,40(1H, DDD, J=8,1 Hz, 1.8 Hz, 0.9 Hz), 7,44(1H, d, J=1,8 Hz), 7,86(1H, d, J=8.1 Hz), 10,43(1H, d, J=0.9 Hz).

Stage 2. The synthesis of the compounds is of example 30

The compound of example 30 (yield: 51%) are synthesized using 4-tert-butyl-2-chlorobenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=1,18(9H, s)to 4.01(2H, s), to 5.35(1H, d, J=4,8 Hz), 5,38(1H, d, J=4,8 Hz), 6.48 in-6,61(2H, m), 6,66-6,74(2H, m), 6,85-of 6.90(1H, m),? 7.04 baby mortality(1H, DD, J=8,3 Hz, 1.9 Hz), to 7.09(1H, s), 7,35(1H, J=1,9 Hz), to 9.32(1H, s). MS(ESI) m/z S(M-N)-.

Example 31

The compound of example 31 (yield: 56%) are synthesized using 4-(1,1,3,3-TETRAMETHYLBUTYL)-2-chlorobenzaldehyde as a starting compound in the same manner as the method in stage 3 of example 1. The original aldehyde synthesized from 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol in the same manner as the method in stage 1 of example 30.

1H NMR (300 M Hz, DMSO-d6) δ=0,55(9H, s)of 1.20(3H, s), 1,24(3H, s)to 1.60(2H, s), was 4.02(2H, s), 5,23(1H, d, J=4.5 Hz), of 5.39(1H, d, J=4, 2 Hz), 6,36(1H, d, J=7.5 Hz), 6,50(1H, t, J=7.5 Hz), is 6.61(1H, d, J=8,4 Hz), of 6.68(1H, t, J=7.5 Hz), at 6.84(1H, d, J=8,4 Hz), 7,00(1H, d, J=7.5 Hz), to 7.09(1H, s), 7,34(1H, s), 9.28 are(1H, s). MS(ESI) m/z 422(M-H)-.

Example 32

The compound of example 32 (yield: 64%) are synthesized using 2-pyridinecarboxamide as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,98(2H, s), 5,10(1H, d, J=4.5 Hz), of 5.84(1H, d, J=4.5 Hz), 6.48 in-6,59(2H, m), of 6.65(1H, t, J=7.5 Hz), 6,83(1H, d, J=7.5 Hz), 6,91(1H, d, J=7.5 Hz),? 7.04 baby mortality(1H, s), 7,06-7,13(1H, m), 7,53(1H, t, J=7.5 Hz), 8,39-8,44(1H, m), 9,23(1H, s). MS(ESI) m/z 279(M+) +.

Example 33

The compound of example 33 (yield: 52%) was synthesized using 5-bromothiophene-2-carboxaldehyde as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,93(2H, s), 5,16(1H, d, J=4.5 Hz), of 6.02(1H, d, J=4.5 Hz), 6,61-6,87(5H, m), 6,92(1H, d, J=3.6 Hz), to 7.09(1H, s), 9,26(1H, s). MS(ESI) m/z 362, 364(M+H)+.

Example 34

Stage 1. Synthesis of 2-phenyl-5-pyrimidinecarboxylic

The salt solution terraforming acid (4 mmol) 2-dimethylaminomethylene-1,3-bis(dimethylamino)propane obtained by the method described in "Syntesis" (1988, p. 641), hydrochloride of benzamidine (4 mmol) and ethoxide sodium (12 mmol) in ethanol (5 ml) was stirred at 80°C for 2 hours. After extraction with ethyl acetate, followed by purification column chromatography on silica gel get 2-phenyl-5-pyrimidinecarboxylic (output: 226 mg, 31%).

1H NMR (300M Hz, CDCl3) δ=7,50-of 7.60(3H, m), 8,54-8,58(2H, m), which 9.22(2H, s), 10,16(1H, s).

Stage 2. The synthesis of the compound of example 34

The compound of example 34 (yield: 37%) are synthesized using 2-phenyl-5-pyrimidinecarboxylic as a starting compound in the same manner as the method in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=was 4.02(2H, d, J=4.5 Hz), further 5.15(1H, d, J=4, 2 Hz), between 6.08(1H, d, J=4, 2 Hz), 6,60-6,70(2H, m), 6,72-of 6.78(1H, m), 6,93(1H, d, J=7.8 Hz), 7,16(1H, s), 7,44-7,51(3H, m), 8,25-of 8.33(2H, m), 8,58(2H,with), 9,38(1H, s) MS(ESI) m/z 354(M-H) -.

Example 35

The solution pyrrolidin-2,4-dione (40 mg, 0,404 mmol) and 4,5-dimethyl-1,2-phenylenediamine (55 mg, 0,404 mmol) in dimethylformamide is stirred in the presence of molecular sieves for 9 hours. To the reaction mixture 4-bromobenzaldehyde (75 mg, 0,404 mmol) and acetic acid (0.01 ml) and the mixture was stirred at 70°With during the night. The reaction mixture is filtered. After adding water formed crystals thus separated by filtration and then washed with dichloromethane, thus obtaining the compound of example 35 (yield: 100 mg, 65%).

1H NMR (300 M Hz, DMSO-d6) δ=1,94(3H, s), a 2.01(3H, s), 3,93(2H, s), 4,96(1H, d, J=4, 2 Hz), 5,67(1H, d, J=4, 2 Hz), of 6.29(1H, s), 6,59(1H, s), of 6.99(1H, s),? 7.04 baby mortality(2H, d, J=7.8 Hz), 7,35(2H, d, J=7,8), the remaining 9.08(1H, ). MS(ESI) m/z 382, 384(M-H)-.

Example 36

Stage 1. Synthesis of 4-((1R,2R)-(2-aminocyclohexanol)amino)-3-pyrrolin-2-it

The solution pyrrolidin-2,4-dione (40 mg, 0,404 mmol) and (1R,2R)-1,2-diaminocyclohexane (46 mg, 0,404 mmol) in methanol (2 ml) was stirred at 60°C for 2 hours. The reaction solution concentrate. After purification column chromatography dioxide aluminium receive 4-((1R,2R)-(2-aminocyclohexanol)amino)-3-pyrrolin-2-on (yield: 66 mg, 84%).

1H NMR (300 M Hz, DMSO-d6) δ=1,09 is 1.91(8H, m)to 2.41(1H, m), 2.63 in(1H, m), 3,17(2H, s), 3,70(1H, d, J=16 Hz), of 3.78(1H, d, J=16 Hz), 4,39(1H, s), of 6.45(1H, s), is 6.61(1H, d, J=8.1 Hz). MS(ESI) m/z 196(M+H)+, 194(M-H)-.

Stage 2 SinTe the compound of example 36

4-((1R,2R)-(2-Aminocyclohexanol)amino)-3-pyrrolin-2-on (66 mg, of 0.337 mmol), obtained in stage 1, and 4-bromobenzaldehyde (63 mg, of 0.337 mmol) is stirred in ethanol at 70°With during the night. The reaction mixture was concentrated. The diastereomers are separated and purified column chromatography on silica gel. To the obtained solid substance, add diethyl ether. After filtration followed by washing the compound of example 36 (yield: 12 mg, 10%) are obtained in the form of compounds with low polarity.

1H NMR (300 M Hz, DMSO-d6) δ=1,17-of 1.40(4H, m), 1,68-of 1.74(2H, m), 1.93 and-to 1.98(2H, m), 2.63 in(1H, m)and 3.15(1H, m), 3,80(1H, d, J=16.6 Hz), of 3.94(1H, d, J=16.6 Hz), to 4.62(1H, s), 7,26(2H, d, J=6.6 Hz), 7,40(2H, d, J=6,6 Hz). MS(ESI) m/z 362, 364(M+H)+.

Example 37

The compound of example 37 (yield: 15 mg, 12%) are synthesized in the form of a substance with a high polarity for separation and purification of diastereomers column chromatography on silica gel in stage 2 of example 36.

1H NMR (300 M Hz, DMSO-d6) δ=1,06-of 1.27(4H, m), 1,47(1H, m), 1.56 to its 1.68(2H, m), 1,90(1H, m)to 2.29(1H, m), to 3.02(1H, m), 3,90(1H, d, J=16.5 Hz), was 4.02(1H, d, J=16.5 Hz), 4,96(1H, s), 7,20(2H, d, J=8,4 Hz), the 7.43(2H, d, J=8,4 Hz). MS(ESI) m/z 362, 364(M+H)+.

The compounds of examples 38 - 41 synthesized by separation and purification of diastereomers column chromatography on silica gel using the same method as the method of example 37, except that the initial connection is replaced by the corresponding aldehyde.

Prima is 42

Stage 1. Synthesis of 10-(4-bromophenyl)-1,2,3,4,9,10-tetrahydrobenzo[b]pyrrolo[3,4-e][1,4]diazepin-1-it

10-(4-Bromophenyl)-1,2,3,4,9,10-tetrahydrobenzo[b]pyrrolo[3,4-e][1,4]diazepin-1-he (yield: 95%) was synthesized in the same manner as the method in stage 3 of example 1, except that 4-bromobenzaldehyde used as the source of the connection.

1H NMR (300 M Hz, DMSO-d6) δ=of 3.97(2H, s), of 5.03(1H, d, J=4, 2 Hz), of 5.89(1H, d, J=4.5 Hz), 6,51(1H, DD, J=8,1, 1.5 Hz), 6,59(1H, dt, J=7,5, 1.5 Hz), of 6.68(1H, dt, J=8,4, and 2.1 Hz), 6,83(1H, DD, J=7,5, 1.5 Hz), 7,06(1H, s), 7,13(2H, d, J=6.6 Hz), was 7.36(2H, d, J=6.6 Hz), which 9.22(1H, s). MS(ESI) m/z 356, 358(M+H)+.

Stage 2. The synthesis of the compound of example 42

The compound (40 mg, 0.11 mmol)obtained in stage 1, and methyliodide (0,137 ml, 2.2 mmol) is stirred in the presence of triethylamine (0,023 ml of 0.17 mmol) in methanol for 4 hours. After completion of the reaction the product was then purified column chromatography on silica gel. To the obtained solid substance, add diethyl ether. After filtration followed by washing obtain the compound of example 42 (yield: 5 mg, 12%).

1H NMR (300 M Hz, DMSO-d6) δ=of 2.51(3H, s), of 3.97(1H, d, J=17 Hz), 3,99(1H, d, J=17 Hz), the 4.90(1H, s), 6,44(1H, d, J=8,4 Hz), of 6.71(1H, t, J=6.9 Hz), 6,82-6,94(4H, m), 7,10(1H, s), 7,16-7,34(2H, m), 9,27(1H, s). MS(ESI) m/z 368, 370(M-H)-.

Example 43

Acetic anhydride (0.05 ml, of 0.56 mmol) are added to a solution of the compound (50 mg, 0.14 mmol)obtained in stage 1 of example 42, in pyridine and the mixture is stirred for 5 hours. The reaction mixture was concentrated. To the obtained solid substance, add diethyl ether. After filtration followed by washing obtain compound 43 (yield: 43 mg, 77%).

1H NMR (300 M Hz, DMSO-d6) δ=1,70(3H, s), a 4.03(2H, s), 6,77-6,79(2H, m), 6,85(1H, s), to 6.95(1H, d, J=8,4 Hz),? 7.04 baby mortality(1H, m), 7,16(1H, m), of 7.36-7,39(4H, m), 9,50(1H, s). MS(ESI) m/z 396, 398(M-H)-.

Example 44

The compound of example 44 (yield: 41%) synthesized in the same manner as the method of example 1, except that 1,2-phenylenediamine is replaced by N-methyl-1,2-phenylenediamine in stage 2 of example 1 and 4-bromobenzaldehyde used as starting material in stage 3 of example 1.

1H NMR (300 M Hz, DMSO-d6) δ=3,34(3H, s), 4,11(1H, d, J=18 Hz), 4,30(1H, d, J=18 Hz), 5,04(1H, d, J=4 Hz), of 5.68(1H, d, J=4 Hz), to 6.43(1H, DD, J=7,8, 1.5 Hz), of 6.68(1H, d, J=7,2 Hz), for 6.81-7,10(3H, m), 7,28-7,39(3H, m), 9.28 are(1H, s). MS(ESI) m/z 368, 370(M-H)-.

The chemical structure of the compounds obtained in examples 1 to 44 are the following structures:

In examples 45 to 162 connection Sintesi the Ute way, which includes interaction enamino compounds (IX) with an appropriate aldehyde with obtaining cyclic compounds (X) and alkylation or acylation of the compound (X)as shown below:

where R represents the substituent in the benzene ring, R' represents a Deputy at the nitrogen atom in the 9-position, and Z represents a halogen atom or the like.

Example 45

Stage 1. The way to obtain the cyclic compound (XI) (R=2-OMe)

Acetic acid in the amount of 0.5 ml are added to a solution of 4-((1R,2R)-(2-aminocyclohexanol)amino)-3-pyrrolin-2-it (9.75 g, 50 mmol), obtained in stage 1 of example 36, 2-methoxybenzaldehyde (of 7.48 g, 55 mmol) in methanol (150 ml) and the mixture was stirred at 65°With during the night. The reaction mixture was concentrated and 90 ml of a mixed solvent of ether/dichloromethane (1/1) are added to the formed crystals. After continuous stirring, the solid is separated by filtration, thus obtaining a cyclic compound (XI) (R=2-OMe) in the form of white solids (8,80 g, 56%). This connection is the same as the compound obtained in example 39.

Stage 2. The method of obtaining the compound of example 45 (R=2-OMe, R'=the PINES3).

The method of obtaining A (way anhydride acid)

The triethylamine (of 5.05 g, 50 mmol) are added to a solution of cyclic compounds (XI) (R=2-OMe) (3.13 g, mol), obtained in stage 1 of example 45, in dichloromethane (200 ml). Then to the resulting mixture is added acetic anhydride (4,08 g, 40 mmol) and the mixture was stirred at 45°C for 4 hours. After cooling the mixture to ambient temperature formed crystals thus separated by filtration, thus obtaining the compound of example 45 as a white solid (1,96 g, 55%).

Compounds of examples 46 to 163 get in the same way as the ways in stages 1 and 2 of example 45.

In stage 2 compound synthesized by the above method of obtaining a or any of the following examples is received from V to F.

Way to get In (the way of carboxylic acid)

A solution of cyclic compounds (X) (0.33 mmol) and triethylamine (0.77 mmol) in dichloromethane (15 ml) cooled to 0°C. To the solution was added the appropriate acid chloride of acid (1.28 mmol) and the mixture is stirred at room temperature for 15 hours. After distillation of the solvent, the obtained product was then purified by chromatography TLC on silica gel, thus obtaining acylated compound (XXVIII).

The method of obtaining From (a method of the mixed anhydride of the acid)

The triethylamine (10 mmol) are added to a solution of the appropriate carboxylic acid (11 mmol) in anhydrous tetrahydrofuran (50 ml) and the mixture is cooled at -15°C. To the reaction mixture add atichart the IAT (10 mmol) with formation of a white solid. The mixture is stirred for 15 minutes. Then to the reaction mixture add a solution of the cyclic compounds (X) (2 mmol) in dichloromethane (60 ml) and the mixture is stirred at room temperature for 2 hours. After evaporation of the solvent followed by extraction with dichloromethane, the product was then purified column chromatography on silica gel, thus obtaining acylated compound (XXVIII).

The method of obtaining D (a way of condensing with WSC)

A solution of cyclic compounds (X) (0.25 mmol) in dichloromethane (10 ml) cooled at 0°C. To the solution was added the appropriate carboxylic acid (1 mmol) and WSC (hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1 mmol) and the mixture is stirred at room temperature for 15 hours. The solvent is evaporated and the product purified by thin-layer chromatography on silica gel, thus obtaining acylated compound (XXVIII).

The way to obtain E (a way of joining isocyanate)

The appropriate isocyanate (1.5 mmol) are added to a solution of cyclic compounds (X) (0.3 mmol) in dichloromethane (10 ml) and the mixture is stirred at room temperature for 24 hours. The solvent is evaporated and the product purified by thin-layer chromatography on silica gel, thus obtaining acylated compound (XXVIII).

The way to obtain F (a way of joining diketene)

Diketene (10) - Rev. mol) are added to a solution of cyclic compounds (X) (1 mmol) in ethanol (10 ml) and the mixture is heated at 70° C for 4 hours. The solvent is evaporated and the product purified by thin-layer chromatography on silica gel, thus obtaining acylated compound (XXVIII).

The chemical structural formulas of cyclic compounds (XI-25), obtained in stage 1, and these compounds are shown in tables 1-1 and 1-3.

Table 1-1
CoRD
X12-OMeMS:312(M-H)-, N1:1,07-2,82(10H, m), of 3.73(1H, d, J=16.5 Hz), 3,81(1H, d, J=16.5 Hz), of 3.84(3H, s), free 5.01(1H, s)of 6.29(1H, s), of 6.66(1H, s), 6,79-7,19(4H, m)
X22-OEtMS:327(M+H)+, N1:1,07-2,82(10H, m)to 1.38(3H, t, J=7.2 Hz), to 3.73(1H, d, J=16.5 Hz), 3,81(1H, d, J=16.5 Hz), 4,10(2H, m), 5,01(1H, s)of 6.29(1H, s), of 6.65(1H, s), 6,79-7,19(4H, m)
X32-OCHMe2MS:342(M+H)+, N1:1,07-2,82(17H, m), 3,71(1H, d, J=16.2 Hz), 3,81(1H, d, J=16.2 Hz), 4,99(1H, s), 6,27(1H, s), of 6.66(1H, s)6,70-7,20(4H, m)
X42-OCH2PhMS:390(M+H)+, N1:0,50 is 3.40(10H, m), 3,68(1H, d, J=16.2 Hz), 3,82(1H, d, J=16.2 Hz), of 5.05(1H, s)to 5.13(1H, d, J=15,0 Hz), 5,18(1H, d, J=15,0 Hz), 6,27(1H, s), of 6.65(1H, s), 6,78-6,84(2H, m),? 7.04 baby mortality-7,22(2H, m), 7,29-7,52(5H, m)
X52-OCF3MS:368(M+H)+, N1:0,50 is 3.40(10H, m), 3,70(1H, d, J=16.0 Hz), 3,83(1H, d, J=16.0 Hz), is 5.06(1H, s), to 6.39(1H, s), 6,72(1H, s), 7,00-7,07(1H, m), 7.18 in-7,37(3H,m)
X62-OMe-4-FMS:332(M+H)+, N1:0,85-3,48(10H, m), 3,70(1H, d, J=16,8 Hz), 3,83(1H, d, J=16,8 Hz), 3,85(3H, s), of 4.95(1H, s), 6,32(1H, s), 6,58 of 6.66(1H,sh), of 6.68(1H, s), 6,74-PC 6.82(1H, m), 6,84-6,92(1H, m)
X72-OMe-4-ClMS:348(M+H)+, N1:a 3.83(1H, d, J=16,8 Hz), 3,85(3H, s), of 4.95(1H, s), 6,32(1H, s), 6,58 of 6.66(1H, m), of 6.68(1H, s), 6,74-PC 6.82(1H, m), 6,84-6,92(1H, m)
X82-OMe-4-OCH2PhMS:420(M+H)+, N1:0,50 is 3.40(10H, m)to 3.67(1H, d, J=16.2 Hz), with 3.79(1H, d, J=16.2 Hz), 3,80(3H, s), 4,91(1H, s), 5,04(2H, s), 6,23(1H, s), 6,40-6,70(4H, m), 7,28-of 7.48(5H, m)

Table 1-2
CoRD
X92-OMe-5-FMS:332(M+H)+, N1:0,50 is 3.40(10H, m), 3,70(1H, d, J=16.2 Hz), 3,82(3H, s), 3,85(1H,d, J=16.2 Hz), 4,96(1H, s), 6,37(1H, s), 6.48 in-7,02(4H, m)
X102,3-(OMe)2MS:344(M+H)+, N1:0,50 is 3.40(10H, m), 3,68(1H, d, J=16.0 Hz), 3.72 points-3,83(7H, m), 5,04(1H, s), 6,27(1H, s), 6.42 per-6,50(1H, m), of 6.66(1H, s), 6,82-6,94(2H, m)
X112,4-(OMe)2MS:344(M+H)+, N1:0,50 is 3.40(10H, m), 3,60-3,88(2H, m), 3,71(3H, s), of 3.80(3H, s), is 4.93(1H, s), 6,20-6,40(2H, m), 6,51 return of 6.58(1H, m), 6,62-of 6.73(2H, m)
X122,5-(OMe)2MS:344(M+H)+, N1:0,50 is 3.40(10H, m), 3,62(3H, s), 3,68(1H, d, J=16.0 Hz), of 3.77(3H, s), 3,81(1H, d, J=16.0 Hz), 4,94(1H, s), 6,28(1H, s), 6,32(1H, d, J=3 Hz), of 6.66(1H, s), 6,72(1H, DD, J=3,0, to 8.7 Hz), to 6.88(1H, d, J=8.7 Hz)
X132-MeMS:298(M+H)+, N1:0,50 is 3.40(10H, m)to 2.41(3H, s), 3,68(1H, d, J=16.0 Hz), 3,82(1H, d, J=16.0 Hz), 4,91(1H, s), 6,24(1H, s), to 6.67(1H, s), 6,83-7,17(4H, m)
X142-EtMS:312(M+H)+, N1:0,50-3,40(12H, m)of 1.23(3H, t, J=7.5 Hz), 3,68(1H, d, J=16.5 Hz), 3,82(1H, d, J=16.5 Hz), 5,02(1H, s), 6,23(1H, s), to 6.67(1H, s), 6,85-7,17(4H, m)
H2-CHMe2MS:326(M+H)+, N1:0,50-3,60(15H, m), 3,68(1H, d, J=16.0 Hz), 3,82(1H, d, J=16.0 Hz), 5,10(1H, s), and 6.25(1H,s)6,70(1H, s), 6,80-7,30(4H, m)
X162-BrMS:362,364(M+H)+, N1 0,50-of 3.60(10H, m), and 3.72(1H, d, J=16.0 Hz), 3,83(1H, d, J=16.0 Hz), equal to 4.97(1H, s), 6.42 per(1H, s), of 6.73(1H, s), 6,95-7,03(1H, m), 7,10-7,29(2H, m), 7,56-7,63(1H, m)

Table 1-3
CoRD
X172-ClMS:318(M+H)+, N1:0,50 is 3.40(10H, m), 3,71(1H, d, J=16.2 Hz), 3,83(1H, d, J=16.2 Hz), 5,04(1H, s)6,41(1H, s), 6,72(1H, s), of 6.96-7,02(1H, m), 7,16-7,26(2H, m), 7,39-7,44(1H, m)
H2-FMS:302(M+H)+, N1:0,50 is 3.40(10H, m), 3,71(1H, d, J=16.2 Hz), 3,83(1H, d, J=16.2 Hz), 5,07(1H, s), to 6.39(1H, s), 6,72(1H, s), 6.90 to-7,30(4H, m)
X192-CF3MS:352(M+H)+
X20HMS:284(M+H) +, N1:0,50 is 3.40(10H, m), of 3.69(1H, d, J=16.0 Hz), a-3.84(1H, d, J=16.0 Hz), 4,79(1H, s), 6,32(1H, s), of 6.75(1H, s), 7,10-7,30(5H, m)
X212-NO2MS:329(M+H)+, N1:0,50 is 3.40(10H, m), 3,71(1H, d, J=16.2 Hz), with 3.79(1H, d, J=16.2 Hz), and 5.30(1H, s), to 6.43(1H, s), to 6.80(1H, s), 7,06-7,13(1H, m), 7,38-7,56(2H, m), 7,70 for 7.78(1H, m)
H3-ClMS:318(M+H)+, N1:0,50 is 3.40(10H, m), of 3.69(1H, d, J=16.2 Hz), 3,83(1H, d, J=16.2 Hz), 4,70(1H, s), 6,32(1H, s), of 6.73(1H, s), 7,16-7,30(4H, m)
H4-OMeMS:312(M-H)-, N1:0,50 is 3.40(10H, m), 3,60-and 3.72(4H, m), with 3.79(1H, d, J=16.2 Hz), of 4.66(1H, s), to 6.19(1H, s), of 6.65(1H, s), is 6.78(2H, d, J=8,4 Hz), 7,10(2H, d, J=8,4 Hz)
H4-BrMS:362,364(M+H)+, N1:1,06-of 1.27(4H, m), 1,47(1H, m), 1.56 to its 1.68(2H, m), 1,90(1H, m)to 2.29(1H, m), to 3.02(1H, m), 3,90(1H, d, J=16.5 Hz), was 4.02(1H, d, J=16.5 Hz), 4,96(1H, s), 7,20(2H, d, J=8,4 Hz), the 7.43(2H, d, J=8,4 Hz)
X 254-ClMS:m/z 315(M-H)-, N1:1,01-1,10(4H, m), 1.41 to of 1.52(3H, m), of 1.85(1H, m), 2,02(1H, m), 2,80(1H, m), 3,70(1H, d, J=16.5 Hz), 3,83(1H, d, J=16.5 Hz), 4,71(1H, s), 6,30(1H, s), 6,72(1H, s), 7.23 percent(2H, d, J=8.7 Hz), 7,30(2H, d, J=8.7 Hz)

The chemical structural formulas of the compounds obtained in stage 2 of examples 46 to 163, a method of acylation in stage 2, and data of the compounds are given in tables 2-1 - 2-10.

Table 2-1
NoRR'/td> SD
452-OMeCOCH3AMS:354(M-H)-, N1:0,90-of 1.97(8H, m), 2,12(3H, s), 2,82(1H, m), 3,74-a-3.84(5H, m)to 3.99(1H, m), 5,74(1H, s), of 6.66(1H, s)6,91(1H, d, J=6.9 Hz), 6,99-7,33(4H, m), [α]D=-129,6° (c=0,24, MeOH)
462-OMeCOCH2CH3AMS:370(M+H)+, N1:0,50 is 3.40(9H, m), and 0.98(3H, t, J=7.2 Hz), 2,24-of 2.38(1H, m), 2,60 was 2.76(1H, m), with 3.79(3H, s), 3,68-a 3.87(2H, m), 3,92-of 4.05(1H, m), 5,80(1H, s), 6,62(1H, s)6,70(1H, s), 6,84-7,34(4H, m)
472-OMeCOCH2CH2CH3AMS:382(M-H)-
482-OMeCOCF3AMS:408(M-H)-
492-OMeCOCH2CF3DMS:424(M+H)+, N1:0,50-3,40(N, m)of 3.84(3H, s), 3,55-are 3.90(4H, m), 3,93-4,06(1H, m), 5,62(1H, s), of 6.73(1H, s), is 6.78(1H, s), 6.90 to and 7.36(4H, m)
502-OMeCOCF2CF3AMS:460(M+H)+, N1:0,50 is 3.40(9H, m), with 3.79(3H, s), 3,76-of 3.95(3H, m), between 6.08(1H, s), 6,83(1H, s)6,86(1H, s), 6.90 to-7,40(4H, m)
512-OMeCOCH2OH*1MS:370(M-H)-, N1:0,73-3,07(9H, m), 3,88-4,22(8H, m), 5,73(1H, s), 6,93(1H, m), 7,10 for 7.12(3H, m), 7,32-to 7.35(2H, m)
522-OMeCOCH2OAcCESI-is With m/z 412(M-H)-, N1: 0,65-2,95(12H, m), 3,81-3,93(6H, m)and 4.65(1H, d, J=15 Hz), the 5.25(1H, d, J=15 Hz), 5,61(1H, s), to 6.80(2H, m), 6,98(1H, m), 7,06 for 7.12(2H, m), 7,35-7,41(1H, m)

Table 2-2
NoRR'SD
532-OMeCOCH2OMeCMS:386(M+H)+, N1:0,50 is 3.40(9H, m), and 3.31(3H, s), 3.72 points-3,88(2H, m), of 3.84(3H, s), 3,94-Android 4.04(1H, m), 4,08(1H, d, J=14.4 Hz), 4,34(1H, d, J=14.4 Hz), to 5.58(1H, s), 6,69(1H, s), of 6.73(1H, s), 6,88-7,34(4H, m)
542-OMeCOCH2OEtCMS:398(M-H)-
552-OMeCOCH2OPhCMS:446(M-H)-
562-OMeCOCH2PhCMS:430(M-H)-
572-OMeCOCH=CHPhCMS:442(M-H)-
582-OMeCOC=CPhCMS:440(M-H)-
592-OMeCOCH=CHCH3CMS:380(M-H)-, N1:0,77-is 3.08(12H, m), 3,85(3H, s), of 3.97(1H, d, J=17 Hz), of 3.97(1H, d, J=17 Hz), to 4.23(1H, m), from 6.22(1H, s), 6.87 in-7,13(4H, m)
602-OMeCOCH2CH2COOe CMS:428(M+H)+
612-OMeCOCH2CH2COOH*2MS:412(M-H)-
622-OMeCOCH2CH2CH2OH*3MS:400(M+H)+
632-OMeCOCH2NHZCMS:503(M-H)-
642-OMeCOCH2NH2*4MS:369(M-H)-
652-OMeCOCH2CH2NHZCMS:519(M+H)+
662-OMeCOCH2CH2NH2*5MS:384(M-H)-, N1:0,67-3,32(13H, m), 3.75 to 3,86(6H, m), to 6.19(1H,s), 6,53(1H, m), 6,66(1H, m), 6.87 in(1H, m), 6,93-6,99(2H, m), 7,26(1H, m)
672-OMeCOCH2CH2OMeCMS:400(M+H)+
682-OMeCOCH2CH2PhCMS:444(M-H)-, N1:0,88-2,97(13H, m), 3,71-3,86(5H, m), 4,07(1H, m), of 5.83(1H, d, J=5.4 Hz), 6,68-of 6.78(1H, m), 6,88-7,03(3H, m), 7,17-7,34(7H, m)

R'
Table 2-3
NoRSD
692-OMePINES2CH2-(2-OMe-Ph)MS:476(M+H)+
702-OMeCOCH2CH2-(3,4-F2-Ph)MS:482(M+H)+
712-OMePINES2CH2SMeMS:414(M-H)-
722-OMeCOCH2COCH3FMS:398(M+H)+
732-OMeCOCH2COOEtBMS:428(M+H)+
742-OMeCOCOOEtBMS:412(M-H)-
752-OMeCOPhCMS:416(M-H)-
762-OMeWITH-2-pyridylCMS:417(M-H)-, N1:0,95-2,99(9H, m), 3,68(3H, s), 3,83-of 3.85(2H, m), 4,08(1H, m)to 5.56(1H, s), 6,65-of 6.71(2H, m), 6,83-7,01(3H, m), 7,25(1H, m), 7,37-7,42(2H, m), of 7.90(1H, m), and 8.50(1H, m)
772-OMeCO-3-pyridylCMS:417(M-H)-
782-OMeCO-4-pyridylCMS:417(M-H)-
792-OMeCO-2-PersilC MS:418(M-H)-
802-OMeCOOMeBMS:370(M-H)-
812-OMeCOOEtBMS:384(M-H)-, N1:0,98-is 3.08(13H, m), 3,68-4,20(7H, m), to 6.43(1H, s), 6,67-7,39(4H, m)
822-OMeCOOCH2PhBMS:446(M-H)-
832-OMeCOOPhBMS:432(M-H)-
842-OMeCONHEtEMS:383(M-H)-, N1:0,76-3,20(14H, m), 3,89-of 3.96(5H, m), is 4.21(1H, m), 5,88(1H, s), of 6.26(1H, m), 6.89 in for 7.12(3H, m), 7,30(1H, m)
852-OMeCONHCH2CH2CH3EMS:399(M+H)+

Table 2-4
NoRR'SD
862-OMeSO2CH3BMS:432(M+CH3CN1+H)+, N1:0,73-2,90(9H, m), 3,26(3H, s), 3,67-a-3.84(6H, m), 5,02(1H, s), 6,30(1H, s), of 6.68(1H, s), for 6.81-6,83(2H, m), 7,00(1H, m), 7,18(1H, m)
872-OEtCOCH3AMS:370(M+H)+
882-OEt/td> PINES2CH3AMS:382(M-H)-, N1:0,57-3,42(17H, m in), 3.75(1H, d, J=17 Hz), 3,83(1H, d, J=17 Hz), 3,97-to 4.14(3H, m), of 5.81(1H, s), only 6.64(1H, s), 6,72(1H, s), to 6.88(1H, m), 6,98-7,01(2H, m), 7,27(1H, m)
892-OEtPINES2CH2CH3AMS:398(M+H)+, N1:0,61-2,82(19H, m), with 3.79(2H, d, J=26, 18 Hz), was 4.02-4,11(3H, m), of 5.81(1H, s), 6,63(1H, s)of 6.71(1H, s), to 6.88(1H, m), 6,98-7,01(2H, m), 7,27(1H, m)
902-OEtCOCF3AMS:424(M+H)+
912-OEtCOCH2SLACMS:428(M+H)+
922-OEtPINES2HE*6MS:386(M+H)+
932-OEtPINES2OMeCMS:400(M+H)+
942-OEtCOCH2OEtCMS:414(M+H)+
952-OEtThe soomaBMS:384(M-H)-, N1:0,62-3,42(12H, m), 3,61(3H, s), 3,71-4,06(5H, m), 6,16(1H, s), 6,56(1H, s), 6,69(1H, s), 6,85(1H, m), 6,93-6,97(2H, m), 7,24(1H, m)
962-OEtCOOEtBMS:400(M+H)+
972-OEtCONHEtEMS:399(M+H)+
982-OCHMe2PINES3AMS:384(M+H)+

Table 2-5
NoRR'SD
992-OCHMe2COCH2CH3AMS:398(M+H)+, N1:0,95-3,32(20H, m), of 3.77-of 3.85(2H, m)to 3.99(1H, m), 4,71(1H, m), 5,78(1H, s), 6,62(1H, s)of 6.71(1H, s), at 6.84(1H, m), 6,98-7,03(2H, m), 7,25(1H, m)
1002-Onme2COCH2OEtCMS:428(M+H)+, N1:0,62-3,51(20H, m), 3,74(1H, d, J=16 Hz), 3,83(1H, d, J=16 Hz), of 3.97(1H, m), 4,17(1H, d, J=18 Hz), 4,36(1H, d, J=18 Hz), to 4.73(1H, m), to 5.58(1H, s), of 6.66(1H, s), 6,74(1H, s), 6,85(1H, m,), 6,99? 7.04 baby mortality(2H, m), 7,26(1H, m)
1012-Onme2The soomaBMS:400(M+H)+
1022-OCH2PhCOCH2OEtCMS:476(M+H)+
1032-OH2PhPINES3AMS:432(M+H)+
1042-HECOCH2OEt*7MS:386(M+H)+, N1:0,58-3,49(11H, m)of 1.09(3H, t, J=6,9 Hz in), 3.75(2H, q, J=16.5 Hz), 3,90-a 4.03(1H, m) of 3.96(1H, d, J=13,8 Hz) to 4.38(1H, d, J=13,8 Hz), 5,63(1H, s), 6,63(1H, s)6,70(1H, s), 6.75 in-to 6.88(2H, m), 6.89 in-6,98(1H, m), 7,07-to 7.18(1H, m), 9,71(1H, USS)
1052-HEPINES3*8MS:342(M+H)+
1062-OCF3PINES3AMS: 410(M+H)+
1072-OMe-4-FPINES2CH3AMS:386(M-H)-, N1:0,50-3,40(11N, m)of 0.99(3H, t, J=7.2 Hz), 3,83(3H, s), 3,71-a 3.87(2H, m), 3,94-4,06(1H, m), of 5.75(1H, s), 6,62? 7.04 baby mortality(5H, m)
1082-OMe-4-FCOCH2OEtCMS:418(M+H)+

Table 2-6
NoRR'SD
1092-OMe-4-FPINES3AMS:374(M+H)+, N1:0,58-3,45(9H, m)to 2.13(3H, s), of 3.73-to 3.92(2H, m), 3,86(3H, s), 3,93-3,98(1H, m), 5,67(1H, s), 6,69(1H, OSS), to 6.75(1H, USS), 6,91? 7.04 baby mortality(3H, m)
1102-OMe-4-ClPINES3AMS:390(M+H)+
1112-OMe-4-OCH2PhPINES3AMS:462(M+H)+
1122-OMe-4-H PINES3*9MS:372(M+H)+
1132-OMe-5-FPINES3AMS:373(M+H)+
1142,3-(OMe)2PINES3AMS:386(M+H)+
1152,4-(OMe)2PINES3AMS:385(M+H)+
1162,5-(OMe)2PINES3AMS:386(M+H)+
1172-IUCOCF3AMS:394(M+H)+
1182-IUPINES2CH3AMS:354(M+H)+, N1:0,50-3,42(11H, m), 0,99(3H,t, J=6.9 Hz), to 2.35(3H, s), of 3.77(1H, d, J=16.2 Hz), 3,88(1H, d, J=16.2 Hz), 3,94-4,08(1H, m), the 5.65(1H, s), of 6.68(1H, s), is 6.78(1H, s), 7,01-was 7.08(1H, m), 7,12-7,30(3H, m)
1192-IUCOCH2OEtCMS:384(M+H)+, N1:0,43-3,55(11N, m)of 1.09(3H, t, J=6.9 Hz), to 2.35(3H, s), 3,81(2H, q, J=16.2 Hz), 3,99-4,07(2H, m)to 4.33(1H, d, J=14.4 Hz), the 5.51(1H, s)6,70(1H, s), is 6.78(1H, s), 6,98-7,07(1H, m), 7,09-7,30(3H, m)
1202-IUPINES2SLACMS:398(M+H)+
1212-IUCOCH2OH*10MS:56(M+H) +
1222-IUCOCH2OMeCMS:368(M-H)-
1232-IUPINES3AMS:340(M+H)+
1242-IUCOOEtBMS:370(M+H)+

Table 2-7
NoRR'SD
1252-MeThe soomaBMS:370(M+H)+, N1:from 0.50 to 3.50(10H, m), of 2.25(3H, OSS), to 3.64(3H, s), and 3.72(1H, d, J=15,0 Hz), 3,80(1H, d, J=15,0 Hz), 6,01(1H, USS), 6,60(1H, OSS), was 6.73(1H, USS), 6,98-7,22(4H, m)
1262-EtCOCH2CH2CH3AMS:382(M+H)+
1272-EtCOCH2CH3AMS:368(M+H)+
1282-Et 2COOMeCMS:417(M-H)-, N1:0,53-3,40(16H, m), of 3.60(3H, s), 3.72 points-of 3.97(3H, m)to 5.56(1H, s), 6,77(1H, s), PC 6.82(1H, s), 7,05-to 7.18(1H, m), 7,28-7,42(2H, m)
1292-EtCOCH2OEtCMS:398(M+H)+, N1:0,50-3,60(19H, m), of 3.73(1H, d, J=15,0 Hz), 3,85(1H, d, J=15,0 Hz), 3,90-Android 4.04(2H, m), 4.26 deaths(1H, d, J=14.1 Hz), the ceiling of 5.60(1H, USS), 6,70(1H, USS), 6,78(1H, USS), 7,00-7,30(4H, m)
1302-EtCOCH2OMeCMS:384(M+H)+
1312-EtPINES3AMS:354(M+H)+, N1:0,50-3,40(14H, m), 2,10(3H, s), of 3.77(1H, d, J=15,0 Hz), 3,85(1H, d, J=15,0 Hz), 3,91-a 4.03(1H, m), 5,64(1H, USS), 6,69(1H, USS), 6,77(1H, USS), 7,00-7,30(4H, m)
1322-EtThe soomaBMS:370(M+H)+
1332-CHMe2PINES3AMS:366(M-H)-
1342-BrCOCH2CF3CMS:72(M-H) -MS:0,62-3,51(11N, m), 3,82-3,99(3H, m), vs. 5.47(1H, m)6,86(1H, s), make 6.90(1H, s), 7,20(1H, m), 7,31-7,41(2H, m), of 7.70(1H, m)

td align="left"> MS:360(M+H)+, N1:0,48-3,64(9H, m)of 2.16(3H, s), 3,81(1H, d, J=16.2 Hz), with 3.89(1H, d, J=-16,2 Hz), 3,94-4,08(1H, m), 5,64(1H, s), 6,85(1H, s)6,86(1H, s), 7,16-of 7.23(1H, m), 7,30-7,42(2H, m), 7,46-7,56(1H, m)
Table 2-8
NoRR'SD
1352-BrCOCH2CH3AMS:418(M+H)+, N1:0,52-3,42(11H, m), and 0.98(3H, t, J=7.2 Hz), with 3.79(1H, d, J=15,9 Hz), a 3.87(1H, d, J=15,9 Hz), 3,94-4,08(1H, m), 5,62(1H, s), to 6.80(1H, s), at 6.84(1H, s), 7,16-of 7.23(1H, m), 7.24 to to 7.35(1H, m), 7,26-7,45(1H, m), 7,66-7,74(1H, m)
1362-BrPINES2The soomaCMS:462(M+H)+, N1:0,60-3,43(9H, m), 3,51(1H, d, J=15 Hz)and 3.59(3H, s), 3,79-3,98(4H, m), 5,43(1H, s), 6.89 in(1H, s), make 6.90(1H, s), 7,21(1H, m), 7,31 was 7.45(2H, m), of 7.70(1H, m)
1372-BrCOCH2OEtCMS:448(M+H)+, N1:0,50-3,50(11N, m)of 1.07(3H, t, J=6.6 Hz), 3,76(1H, d, J=16.0 Hz), 3,86(1H, d, J=16.0 Hz), 3,91-a 4.03(1H, m), 4,13(1H, d, J=15,0 Hz), 4,42(1H, d, J=15,0 Hz), 5,42(1H, USS), PC 6.82(1H, OSS), at 6.84(1H, USS), 7,15-7,41(3H, m), of 7.64-of 7.70(1H, m)
1382-BrCOCH2OMeCMS:434(M-H)-
1392-BrPINES3AMS:402(M-H)-
1402-ClPINES3A
1412-ClPINES2CH3AMS:374(M+H)+

Table 2-9
NoRR'SD
1422-ClPINES2CH2CH3AMS:388(M+H)+, N1:0,50-3,50(16H, m), of 3.77(1H, d, J=15,9 Hz), 3,85(1H, d, J=15,9 Hz), 5,71(1H, USS), 6,78(1H, USS), for 6.81(1H, USS), 7,14-7,22(1H, m), 7,28-7,40(2H, m), 7,45-7,53(1H, m)
1432-ClPINES2CF3CMS:426(M-H)-, N1:0,62-3,55(11H, m), 3,81-4,07(3H, m), of 5.03(1H, s), 6.89 in-6,95(2H, m), 7,27(1H, m), 7,43-7,44(2H, m), 7,58(1H, m)
1442-ClCOCH2OMeCMS: 388(M-H)-
1452-ClCOCH2OEtCMS:404(M+H)+, N1:0,50-3,50(11H, m)of 1.07(3H, t, J=6.6 Hz), 3,76(1H, d, J=16.0 Hz), 3,86(1H, d, J=16.0 Hz), 3,91-a 4.03(1H, m), 4,16(1H, d, J=14.4 Hz), 4,32(1H, d, J=14.4 Hz), of 5.55(1H, OSS), to 6.80(1H, USS), 6,83(1H, USS), 7,14-7,52(4H, m)
1462-ClCOCH2OOMe CMS:416(M-H)-, N1:0,61-3,52(10H, m), 3,59-3,99(4H, m), 5,52(1H, m), 6.87 in(1H, s), to 6.88(1H, s), 7,52(1H, t)
1472-ClThe soomaBMS:376(M+H)+
1482-FPINES3AMS:344(M+H)+
1492-FCOCH2CH3AMS:358(M+H)+, N1:0,63-3,39(14H, m), 3,81-to 3.89(2H, m), a 4.03(1H, t), 5,86(1H, s), 6,77(1H, s), PC 6.82(1H, s), 7,09-of 7.25(3H, m), 7,38(1H, t)

Table 2-10
NoRR'SD
1502-FCOCH2OEtCMS:388(M+H)+, N1:0,67-3,49(14N, t)3,76(1H, d, J=16 Hz), 3,85(1H, d, J=16 Hz)to 4.01(1H, m), 4,18(2H, t)5,80(1H, s), 6,79(1H, s), 6,83(1H, s), 7,11-7,26(3H, m), of 7.36(1H, t)
1512-FCOOMeBMS: 360(M+H)+, N1:0,62-3,92(10H, m)to 3.64(3H, s), 3,76(1H, d, J=16,8 Hz), 3,83(1H, d, J=16,8 Hz), 6,16 - 7,01(1H, m), 6,69(1H, s), 6,79(1H, s), 7,07-7,26(3H, m), 7,31-7,44(1H, m)
1522-CF3COCH3AMS:394(M+H)+
153HCOCH3 MS:326(M+H)+
154HCOCH2CH3AMS:340(M+H)+, N1:0,63-3,32(14H, m), of 3.73-a 3.87(2H, m)4,00(1H, m), of 5.68(1H, s), 6,69(1H, s), 6,79(1H, s), 7,26-7,37(3H, m)
155HCOCH2OEtCMS:370(M+H)+, N1:0,60-to 3.58(14H, m), 3,74 - 4,00(4H, m), 4,27(1H, d, J=14 Hz), 5,74(1H, s), 6,72(1H, s), to 6.80(1H, s), 7,25-7,38(5H, m)
156HCOOMeBMS:342(M+H)+, N1:0,58-3,88(10H, m), 3,42(3H, s), 3,74(1H, d, J=16.5 Hz), 3,82(1H, d, J=16.5 Hz), 5,93-the 6.06(1H, m), only 6.64(1H, s), 6,77(1H, s), 7,14-7,37(5H, m)
1572-NO2COCH3AMS:371(M+H)+
1582-NH2COCH3*11MS:341(M+H)+
1593-ClCOCH3AMS:360(M+H)+
1604-OMeCOCH3AMS:356(M+H)+
1614-BrCOCH3AMS:404(M-H)-
1624-ClCOCH3AMS:358(M-H)-
1634-ClCOCH2OEtCMS:404(M+H)+

The symbols in the above table have the following meanings:

Co: the number of connections

No: the number of the example,

R: the substituent in the benzene ring,

R': Deputy at the nitrogen atom,

D: data connections,

S: the Way to obtain in stage 2,

ST: chemical structural formula

MS: ESI-MS, m/z,

N1: 1H NMR (DMSO-d6, TMS internal standard, δ ppm) and

*: notes.

The number before the substituents denote the position of the substituents in the benzene ring. For example, 2,5-(OMe)2means metaxylene groups are in the 2 - and 5-positions, and COCH2CH2-(3,4-F2-Ph) means 3-(3,4-differenl)propanolol group. Z represents benzyloxycarbonyl group.

Notes (*1 to *11) in the tables indicate the following:

*1: Compound synthesized by hydrolysis of the compound of example 52 sodium hydroxide in the usual way.

*2: Compound synthesized by hydrolysis of the compound of example 60 with sodium hydroxide in the usual way.

*3: the Compound is synthesized by reduction of compound of example 60 sociallyengaged in the usual way.

*4: Connection synthesize the removal of the protective group of the compound of example 63 by hydrogenation over palladium on coal in the usual way.

*5: Connection synthesize the removal of the protective group of compound 65 by hydrogenation over palladium on coal in the usual way.

*6 Compound synthesized by hydrolysis of the compound of example 91 with sodium hydroxide in the usual way.

*7: Connection synthesize the removal of the protective group of compound 102 by hydrogenation over palladium on coal in the usual way.

*8: Connection synthesize the removal of the protective group of compound 103 by hydrogenation over palladium on coal in the usual way.

*9: Connection synthesize the removal of the protective group of compound 111 by hydrogenation over palladium on coal in the usual way.

*10: Compound synthesized by hydrolysis of the compound of example 120 sodium hydroxide in the usual way.

*11: Connection synthesize the removal of the protective group of the compound of example 157 by hydrogenation over palladium on coal in the usual way.

Compounds of examples from 164 to 168 synthesized in the same manner as the method in example 45.

Example 169

Acetic anhydride (130 mg, 1.3 mmol) are added to a solution of the compound of example 39 (20 mg, 0.06 mmol) in pyridine (1 ml) and the mixture was stirred at 90°C for 4 hours. The solvent is evaporated and the product purified by thin-layer chromatography on silica gel, thus obtaining the compound of example 169 (23 mg, 89%) in the form of a white solid.

Examples 170 and 171

Connection examples 170 and 171 are synthesized by methylation of the compound of example 45 methyliodide in the usual way.

Example 172

Methyliodide (0,08 ml, 1.3 mmol) are added to a solution of the compound of example 39 (40 mg, 0.13 mmol) in dichloromethane (1 ml) and the mixture AC who're asked at room temperature for 48 hours. The solvent is evaporated and the product purified by thin-layer chromatography on aluminum oxide, thus obtaining the compound of example 172 in the form of a white solid (9 mg, 21%).

Example 173

The compound of example 173 synthesized in the same manner as the method in example 172, except that methyliodide used for alkylation, replace ethylbromoacetate.

Example 174

The compound of example 174 synthesize the same reaction as the reaction in stage 1 of example 36 and example 45, except that Ternovoy acid substituted 1,3-cyclopentanedione.

Example 175

The compound of example 175 synthesize the same reaction as the reaction in example 1, except that 1,2-phenylenediamine is replaced by 2-aminothiophenol and that 4-bromobenzaldehyde used as aldehyde.

Example 176

The compound of example 176 synthesize the same reaction as the reaction in example 1, except that 1,2-phenylenediamine substituted 2-aminophenol and 4-bromobenzaldehyde used as aldehyde.

Example 177

Acetic acid (10 mg) and 4-bromobenzaldehyde (54 mg, 0.29 mmol) are added to a solution of 5-(2-AMINOPHENYL)methyl-1,2-dihydropyrazol-3-one (50 mg, 0.25 mmol) in methanol (3 ml) and the mixture was stirred at 70°C for 20 hours. After completion of the reaction the solvent is evaporated and to the obtained solid substance add Aut diethyl ether. After filtration the product was washed, thus obtaining the compound of example 177 (1 mg, 2%).

In tables 3-1 - 3-3 shows the chemical structural formulas of the compounds obtained in examples from 164 to 177, and the data for compounds.

Table 3-1
NoSTD
164MS:332(M+H)+, N1:0,50-3,40(20H, m), a 1.88(3H, s), 3,50-3,71(2H, m), 3,78-of 3.94(1H, m), as 4.02-4,20(1H, m), 6,40(1H, s), to 6.57(1H, s)
165MS:327(M+H)+, N1:0,50 is 3.40(9H, m)of 2.16(3H, s), of 3.77(1H, d, J=15,0 Hz), 3,83(1H, d, J=15,0 Hz), 3,93-4,08(1H, m), the 5.65(1H, s), is 6.78(1H, s), at 6.84(1H, s), 7,32-7,44(1H, m), 7,60-of 7.69(1H, m), 8,40-8,54(2H, m)
166MS:410(M+H)+, N1:0,50 is 3.40(9H, m), of 2.08(3H, in), 3.75(2H, s), 3,90-Android 4.04(1H, m), of 5.68(1H, s), 6,72(1H, d, J=3,9 Hz), for 6.81(1H, s), PC 6.82(1H, s), 7,07(1H, d, J=3,9 Hz)
167MS:354(M-H)-, N1:0,90-2,90(N, m), 2,12(3H, s), 3,74-a-3.84(5H, m), 3-99(1H, m), of 5.75(1H, s), only 6.64(1H, s), 6,92(1H, 2s), 6,99-7,33(4H, m), [α]D=+127,9° (c=0,215, MeOH)
168MS:350(M+H)+, N1:1,60(3H, s), 3,82(3H, s)to 3.99(1H, d, J=16.2 Hz), was 4.02(1H, d, J=-16,2 Hz), 6,50-7,10(9H, m), 7,22(1H, s), 9,40(1H, s)

Table 3-2
NoSTD
169MS:398(M+H)+, N1:0,57-of 3.46(9H, m)to 2.18(3H, s), is 2.30(3H, s), 3,86(3H, s), a 4.03-to 4.14(1H, m), 4,20(1H, d, J=15.6 Hz), 4,28(1H, d, J=15.6 Hz), 5,80(1H, s), 6,88-6,98(1H, m), 7.03 is-7,14(2H, m), 7,29-7,38(1H, m), 7,53(1H, s)
170MS:384(M+H)+, N1:0,50 is 3.40(9H, m), 2,12(3H, s)of 2.75(3H, s), 2,80(3H, s), 3,82(3H, s), 3,88-to 4.14(3H, m), of 5.68(1H, s) 6,84-6,92(1H, m), 6,98-7,05(2H, m), 7.24 to to 7.32(1H, m)
171MS:370(M+H)+, N1:0,50 is 3.40(9H, m), 2,12(3H, s), a 2.71(3H, s), 3.72 points-Android 4.04(6H, m)5,72(1H, s), of 6.68(1H, s), 6,84-7,06(3H, m), 7.24 to to 7.32(1H, m)
172MS:326(M+H)+, N1:0,98-3,14(12H, m), 3,84-4,00(5H, m), 5,09(1H, s), for 6.81(1H, m), 6,94-7,02(2H, m), 7,20(1H, m)
173MS:400(M+H)+, N1:0,83-3,50(14H, m), 3,69-a-3.84(5H, m), 4.04 the-4,17(3H, m)5,00(1H, s), 6,30(1H, s), 6,62(1H, m), to 6.80(1H, m), 6,91-6,94(2H, m), 7,18(1H, m)

Table 3-3
NoSTD
174MS:355(M+H)+MS:0,90-2,90(13H, m) 2,11(3H, s), 3,83(3H, s)to 4.01(1H, m), USD 5.76(1H, s), 6,80-7,30(4H, m), 7,45(1H, s)
175/td> MS:374(M+N)+, N1:was 4.02(2H, s), and 5.30(1H, s), from 6.22(1H, s), 6,77-to 7.18(8H, m), 7,60(1H, s)
176MS:357,359(M+H)+, N1:4,08(2H, s), equal to 6.05(1H, s), 6,51 was 7.45(8H, m), 7,30(1H, s), 9,58(1H, s)
177MS:357(M+H)+, N1:3,75(1H, d, J=16.2 Hz), 3,88(1H, d, J=16.2 Hz), 5,10-to 5.21(2H, m), 6,62-6,69(1H, m), 6,76-6,85(1H, m), 6,92-7,00(1H, m), 7,05-7,14(3H, m), 7,35-7,42(2H, m)

Symbols in the tables have the following meanings:

No: the number of the example,

ST: chemical structural formula

D: data connections,

MS: ESI-MS, m/z,

N1: 1H NMR (DMSO-d6, TMS internal standard, δ ppm).

Compounds of chemical structural formulas shown in tables 4 and 5, you can easily get a way essentially similar to the methods described in the above examples, or in any manner apparent to a person skilled in this field.

Symbols in the tables have the following meanings:

REF: the reference number of the example,

R: the substituent in the benzene ring,

R': Deputy at the nitrogen atom and the

ST: chemical structural formula.

Table 4

2td align="center"> COCH2OEt
REFRR'
12-SMePINES3
2-SO2MePINES3
32-COMePINES3
42-SoomaPINES3
52-COOHPINES3
63-OMePINES3
73-OEtPINES3
83-IUPINES3
93-EtPINES3
103 Snme2PINES3
113-BrPINES3
123-HEPINES3
134-IUPINES3
144-EtPINES3
154 Snme2PINES3
164-HEPINES3
174-SoomaPINES3
182,4-Me2PINES3
192,5-Me2PINES3
202,6-Me2COCH2OEt
212-SMe
222-SO2MeCOCH2OEt
232-COMeCOCH2OEt
242-SoomaCOCH2OEt
252-COOHCOCH2OEt
263-OMeCOCH2OEt
273-OEtCOCH2OEt
283-MeCOCH2OEt
293-EtCOCH2OEt
303 Snme2COCH2OEt
313-BrCOCH2OEt
323-HECOCH2OEt
334-IUCOCH2OEt
344-EtCOCH2OEt
354-CHMe2COCH2OEt
364-HECOCH2OEt
374-SoomaCOCH2OEt
382,4-Me2COCH2OEt
392,5-Me2COCH2OEt
402,6-Me2COCH2OEt
2-SMeCOOMe
422-SO2MeCOOMe
432-COMeCOOMe
442-SoomaCOOMe
452-COOHCOOMe
463-OMeCOOMe
473-OEtCOOMe
483-IUCOOMe
493-EtCOOMe
503 Snme2COOMe
513-BrCOOMe
523-HECOOMe
534-IUCOOMe
544-EtCOOMe
554 Snme2COOMe
564-HECOOMe
574-COOMeCOOMe
582,4-Me2COOMe
592,5-Me2COOMe
602,6-Me2COOMe

Table 5-1
REFSTREFST/td>
6162
6364
6566
6768

Table 5-2
REFSTREFST
6970
7172
7374
7576

The test example 1

Evaluation of sugar-Laden activity

1. Obtaining cells adipose tissue of rats

After decapitate is and venesection 6 male Wistar rats (body weight: 150-200 g) was made an incision into the abdominal cavity of each rat to highlight just 6 grams of fat tissue of the epididymis of the ovary. Tissue was cut into pieces of 2 mm x 2 mm in 6 ml of KRH buffer (Krebs-Ringer Hepes, composition: 130 mm sodium chloride, a 4.7 mm KCl, 1.2 mm potassium dihydrophosphate, 1.2 mm magnesium sulfate, 1 mm calcium chloride and 25 mm Hepes, pH to 7.6)containing 5% BSA (bovine serum albumin). To the resulting system was added 24 mg of collagenase (type I) and process for the cleavage was carried out for approximately 40 minutes to obtain approximately 6 ml of the selected cells of adipose tissue. Collagenase was removed by buffer exchange. To the residue was added a 2% solution of BSA/KRH for re-suspension to get 45 ml of suspension cells of adipose tissue.

2. Evaluation of the activity of transport of sugar

Active transport of sugar compounds of the present invention was evaluated with reference to the method described in the literature [Annual Review of Biochemistry, Vol. 55, p. 1059 (1986)]. In the test, 200 μl of the suspension of cells of adipose tissue was poured into each test tube for testing of polystyrene, to the suspension was added 100 μl of a solution of the test substance (obtained by dilution of a solution of 10 mg/ml of the substance in dimethyl sulfoxide KRH) and the resulting mixture was shaken and then cultivated at 37°C for 30 minutes.

Active transport of sugar was estimated by measuring the amount included 2-[14S(U)]-deoxy-D-glucose per unit of time. That is, 2-[14S(U)]-deoxy-D-glucose was added to the cell suspension W the world of fabrics after pre-cultivation (final concentration of 0.5 µci/sample). After 5 minutes, to the mixture was added cytochalasin (final concentration: 10 μm) to complete the transport of sugar. After the formation of the layer dinnerplate formed mixture was centrifuged to separate the cells of adipose tissue from the buffer. Number 2-[14S(U)]-deoxy-D-glucose contained in the layer of fatty tissue cells, was determined with a scintillation counter to determine the number of included sugar. In this evaluation system, when used insulin (100 nm), which has the effect to increase the transport of sugar, the action was about 7 times higher than the activity obtained in the control group without insulin.

The results of the evaluation activity transport of sugars derived using 100 μg/ml of each compound of the present invention, is shown in table 6. Active transport of sugar in table 6 were evaluated on the basis of enhancing the action of insulin (100 nm). "+" means that the action has been from 20 to 40%, "++" means that the action was from 40 to 70%, and "+++" indicates that the action was, at least 70%, based on enhancing the action of insulin.

Symbols in the table have the following meanings:

no. : No. of example;

A: the active transport of sugar.

Table 6
No.And
1 ++
2+
3+
5+
6++
7++
8+++
9++
10+
11++
12+
13++
14+++
15++
16++
17+
20+
21++
22+++
23+++
24+++
25++
26++
27++
28++
29+
30+
31+++
34+
37++
38+++
39+++
40+++
41+++
43++
44+

The results of the assessment of the activity of transport of sugar, obtained using each of the compounds of the present invention, are shown in table 7. Active transport of sugar in table 7 was determined in units of concentration (EC: μg/ml) of the test compounds, which have a synergistic effect, corresponding to 50%, based on the reinforcing actions of insulin, which has a synergistic effect 100%.

Table 7
Number exampleActive transport of sugar
451,3
460,77
474,6
484,5
490,47
509,5
512
525,9
532
542,2
554,6
565
591,1
604,8
624,8
658
668
673,4
680,9
694
704,2
712,6
725,5
7610
7720
7818
798,6
806
814,2
826
8311
843,6
857
8715
881,9
891,3
905
9113
92the 3.8
933,6
944
951,5
967
9712
9814
992
1002
1014,8
1024
1033,6
1041
1053,7
10620
1070,82
1087,8
1098
1106
112 20
11310
11412
11510
1176
1182
1194
1208
1212,5
1226
1235
1247
1252
1265
1272,2
1282
129of 5.4
1306
1314
1324
13320
1340,5
1351,5
1361,5
1378,6
1386
1396
14020
1413
1424
1430,5
1445
14510,7
1462
1472,4
14820
1492
1502
1512
15320
1541,5
1552,7
1562
15720
15812
1604,4
16117
1636
16619

In the above tests to establish estimates of the compounds of the present invention had the effect of increasing the activity of transport of sugar.

The test example 2

Evaluation of hypoglycemic effect in mice db/db

The test compound orally was administered to mice C57BL/KsJ-db/dbJcl after fasting for 20 hours. A blood sample was collected from the tail vein of each mouse immediately before the introduction and after 30, 60, 120 and 180 minutes after administration to determine the level of sugar in the blood. The test compound was administered in the form of a suspension in 0.5% solution of methylcellulose or solution of polyethylene glycol 400.

When 100 mg/kg of each of the compounds obtained in examples 80, 88, 119, 129, 131, 137, 140, 154, 155 and 156, gave once, they found the effect in reducing blood glucose levels at least 30% compared with the level of blood sugar in to ntalnyh groups.

From these results it is evident that the compounds of the present invention have the effect to increase the activity of the transport of sugar and what they are useful for the treatment of patients suffering from diabetes. That is because they are able to reduce the blood sugar level through actions to increase the activity of the transport of sugar, they are suitable as agents for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathies, impaired glucose tolerance or obesity.

1. Lactam compound of the following General formula (I) or its pharmaceutically acceptable salt:

where a represents phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl;

R2, R3and R4may be the same or different from each other and independently represent hydrogen, halogen, hydroxyl group, With1-C6alkyl, C1-C6alkoxy, an amino group, a nitrogroup, triptorelin group, phenyl which may have a substituent(s), benzyloxy, which may have a substituent(s), phenylphenyl; and one of R2, R3and R4can be triptoreline, and other means hydrogen;

B is phenyl, which may have mandated the tel(s), monocyclic aliphatic C3-C8ring, dihydropyrrole ring;

-X-, -Y - may be the same or different from each other and they independently represent-O-, -NH-, -NR5-, -S-; Z denotes-CH2-,-NH-;

W - represents-NR1-, CR8R9-where R1is hydrogen; and R8and R9identical and denote hydrogen; where R5represents a lower alkyl group which may have a substituent(s), C1-C8linear or branched alkoxycarbonyl group, acyl group selected from formyl group, acyl groups having From1-C6alkyl, C1-C6alkenylphenol or1-C6alkylamino group which may have a substituent(s); karbamoilnuyu group having From1-C6alkyl group at the nitrogen atom, which may have substituents; sulfonyloxy group having From1-C6the alkyl group from the sulfur atom, which may have a substituent(s);

and a, b and C each represent the position of the carbon atom, provided that:

(i) the substituent(s) selected from the group consisting of halogen, hydroxy, C1-C6of alkyl, mercapto, C1-C6alkoxy, nitro, carboxy, trifloromethyl, phenyl, amino, C1-C8linear or branched alkoxycarbonyl group 1-C8linear or branched acyl group; C1-C8linear or branched alloctype;

(ii) when b is a benzene ring, -X - and-Y-, each represent-NH-,-Z - represents-CH2- and-W - represents-NH-, and R2, R3, R4cannot be phenyl group, 4-bromperidol group, 4-hydroxyproline group, 4-metoksifenilny group, 2-hydroxyproline group, 3,4-dimethoxyphenyl group, 3-methoxy-4-hydroxyproline group.

2. Lactam compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (I), a represents phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3and R4may be the same or different from each other and independently represent hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, amino, nitro-group, trifluoromethyl, phenyl, which may have a substituent(s), benzyloxy, which may have a Deputy, phenylphenyl; represents phenyl which may have a substituent(s), monocyclic aliphatic C3-C8ring, dihydropyrrole ring; -X-, -Y - may be the same or different from each other and they independently represent-O-, -NH-, -NR5-, -S-, where R5represents a lower alkyl group which may have a substituent(and, acyl group selected from formyl group, acyl groups having C1-C6alkyl, C1-C6alkenylphenol or1-C6alkylamino group which may have a substituent(s); -Z - means-CH2-, -NH-; -W - represents-NR1-where R1represents hydrogen,

a, b, C each represents a position of carbon atom, provided that:

(i) the substituent(s) selected from the group consisting of halogen, hydroxy, C1-C6of alkyl, mercapto, C1-C6alkoxy, nitro, carboxy, trifloromethyl, phenyl, amino, C1-C8linear or branched alkoxycarbonyl group1-C8linear or branched acyl group; C1-C8linear or branched alloctype;

(ii) when b is a benzene ring, -X - and-Y-, each represent-NH-, -Z - represents-CH2and-W - represents-NH-, and R2, R3, R4cannot be phenyl group, 4-bromperidol group, 4-hydroxyproline group, 4-metoksifenilny group, 2-hydroxyproline group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyproline group.

3. Lactam compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (I) -X - and-Y - may be the same or different from each other and they each n is dependent represent-NH - or-NR 5where R5represents a lower alkyl group which may have a substituent(s), acyl group selected from formyl group, acyl groups having C1-C6alkyl, C1-C6alkenylphenol or1-C6alkylamino group which may have a substituent(s); -Z - is-CH2- or-NH-, and-W - represents-NR1-where R1means hydrogen.

4. Lactam compound or its pharmaceutically acceptable salt according to claim 3, where in the General formula (I) is phenyl, which may have a substituent(s).

5. Lactam compound or its pharmaceutically acceptable salt according to claim 3, where in the General formula (I) represents a monocyclic aliphatic C3-C8ring.

6. Lactam compound or its pharmaceutically acceptable salt according to claim 3, where in the General formula (I) represents cyclohexane ring.

7. Lactam compound or its pharmaceutically acceptable salt according to claim 6, where in the General formula (I), a represents benzene ring.

8. Lactam compound or its pharmaceutically acceptable salt according to claim 7, where the absolute configuration of the carbon atoms in position a, b and C in the General formula (I) is R or S independently from each other.

9. Lactam compound or its pharmaceutically acceptable salt of claim 8, where the absolute configuration of the carbon atoms in the floor of the terms and and in the position b in the General formula (I) is R and the absolute configuration of the carbon atom in position is R or S.

10. Lactam compound or its pharmaceutically acceptable salt of claim 8, where the absolute configuration of the carbon atoms in position a and position b in the General formula (I) is S and the absolute configuration of the carbon atom in position is R or S.

11. Lactam compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (I) is a benzene ring, R2, R3, R4each represents a hydrogen atom, A represents a cyclohexane ring, -X - represents-NH-, Y is-NR5where R5represents acetyl group which may have a substituent(s), -Z - represents-CH2-, -W-represents-NH, provided that (i) the substituent(s) selected from the group consisting of hydroxyl group, With1-6alkyl groups, and C1-6alkoxygroup.

12. Lactam compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (I) is a benzene ring, R2, R3, R4each independently represents a hydrogen atom, a C1-6alkyl group, and C1-6alkoxygroup, represents cyclohexane ring, -X - represents-NH-, -Y - is-N(COCH2OH)-, -Z - represents-CH2-, -W - represents NH, and the absolute configuration of the carbon atoms in a and b is R.

13. Agent to enhance the ability of the transport of sugar, which contains a lactam compound of General formula (I) or its pharmaceutically acceptable salt as an active ingredient:

where a represents phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl;

R2, R3and R4may be the same or different from each other and independently represent hydrogen, halogen, hydroxyl group, C1-C6alkyl, C1-C6alkoxy, an amino group, a nitrogroup, triptorelin group, phenyl which may have a substituent(s), benzyloxyphenyl group which may have a substituent(s), fineliner, one of R2, R3and R4can be triptoreline, and other means hydrogen; represents phenyl which may have a substituent(s), monocyclic aliphatic C3-C8ring, dihydropyrrole ring; -X-, -Y - may be the same or different from each other and they independently represent-O-, -NH-, -NR5-, -S-; Z denotes-CH2-, -NH-; W is-NR1-, CR8R9where R1is hydrogen; and R8and R9identical and denote hydrogen; where R5represents a lower alkyl group which may have a batch is Italy(and), C1-C8linear or branched alkoxycarbonyl group, acyl group selected from formyl group, acyl groups having C1-C6alkyl, C1-C6alkenylphenol or1-C6alkylamino group which may have a substituent(s); karbamoilnuyu group having C1-C6alkyl group at the nitrogen atom, which may have substituents; sulfonyloxy group having From1-C6the alkyl group from the sulfur atom, which may have a substituent(s);

and a, b and C each represent the position of the carbon atom, provided that:

(i) Deputy selected from the group consisting of halogen, hydroxy, C1-C6of alkyl, mercapto, C1-C6alkoxy, nitro, carboxy, trifloromethyl, phenyl, amino, C1-C8linear or branched alkoxycarbonyl group1-C8linear or branched acyl group; C1-C8linear or branched alloctype;

(ii) when b is a benzene ring, -X - and-Y-, each represent-NH-, -Z - represents-CH2- and-W - represents-NH-, and R2, R3, R4cannot be phenyl group, 4-bromperidol group, 4-hydroxyproline group, 4-metoksifenilny group, 2-hydroxyproline group, 3,4-dimethoxyphenyl group or 3-labels and-4-hydroxyproline group.

14. Agent to enhance the ability of the transport of sugar indicated in paragraph 13, where in the General formula (I) R1represents hydrogen, a represents phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3and R4may be the same or different from each other and independently represent hydrogen, halogen, hydroxyl group, C1-C6alkyl, C1-C6alkoxy, an amino group, a nitrogroup, triptorelin group, phenyl which may have a substituent(s), benzyloxy, which may have a substituent(s), phenylphenyl; represents phenyl which may have a substituent(s), monocyclic aliphatic C3-C8ring, dihydropyrrole ring; -X-, -Y - and may be the same or different from each other and they independently represent-O-, -NH-, -NR5-, -S-; where R5represents a lower alkyl group which may have a substituent(s), acyl group selected from formyl group, acyl groups having From1-C6alkyl, C1-C6alkenylphenol or1-C6alkylamino group which may have a substituent(s); Z denotes-CH2-, -NH-.

15. Agent to enhance the ability of the transport of sugar, which contains a lactam compound or its pharmaceutically acceptable salt according to any one of claims 1 to 12 as an active ingredient.

16. Hypo is Litichevsky agent, which contains a lactam compound or its pharmaceutically acceptable salt according to any one of claims 1 to 12 as an active ingredient.

17. Agent for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathies, impaired glucose tolerance or obesity, which contains a lactam compound or its pharmaceutically acceptable salt according to any one of claims 1 to 12 as an active ingredient.

18. Pharmaceutical composition for use as a hypoglycemic agent containing lactam compound or its pharmaceutically acceptable salt according to any one of claims 1 to 12 as an active ingredient.

19. The pharmaceutical composition according p, for use as a hypoglycemic agent for preventing and/or treating diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathies, impaired glucose tolerance or obesity.



 

Same patents:

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical compound, namely, 7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the curative effect in lung toxic edema. The melting point of this compound is 267-269°.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical substance, namely, 4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the prophylactic effect in lung toxic edema. The melting point of this substance is 264-265°C.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole hydrobromide of the formula (1) that is able to protect body against hypoxia and liver against poisoning with carbon tetrachloride. The melting point of this compound is 266-267°C (with decomposition). The compound is synthesized from 1-acetyl-5-bromo-3-indolinone and elemental bromine in dioxane medium followed by addition of thiourea in isopropyl alcohol.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

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

15 cl, 5 tbl, 6 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetyl-8b-hydroxy-3a,8b-dihydrothiazole[5,4-d]indole as a substance protecting body against hypoxia effect. Invention provides enhanced effectiveness of the protection effect.

EFFECT: enhanced effectiveness of effect of agent.

1 tbl, 1 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetylthiazolo[5,4-d]indole for protection of body against effect of hemic and hypercapnic hypoxia. Invention proves high effectiveness of the protection effect.

EFFECT: enhanced effectiveness of agent.

2 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

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

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoxazepine and describes derivative of benzoxazepine of the general formula (I): wherein X represents -CO or -SO2; R1, R2, R3 and R4 are chosen independently from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkyloxy-(C1-C4)-alkyl, -CF3, halogen atom, nitro-group, cyano-group, -NR8R9, -NR8COR10 and -CONR8R9; R5, R6 and R7 represent independently hydrogen atom (H) or (C1-C4)-alkyl; R8 and R9 represent independently hydrogen atom (H) or (C1-C4)-alkyl; or R8 and R9 in common with nitrogen atom to which they are bound form 5- or 6-membered saturated heterocyclic ring comprising optionally the additional heteroatom chosen from oxygen atom (O), sulfur atom (S) or the group -NR11; R10 represents (C1-C4)-alkyl; R11 represents (C1-C4)-alkyl; A represents residue of 4-7-membered saturated heterocyclic ring comprising optionally oxygen atom wherein ring is substituted optionally with 1-3 substitutes chosen from (C1-C4)-alkyl, (C1-C4)-alkoxy-, hydroxy-group, halogen atom and oxo-group, or to its pharmaceutically acceptable salt under condition that compounds of the formula (I) are excluded wherein X represents -CO, and each among R1-R7 represents hydrogen atom (H), and A represents -(CH2)3 or -(CH2)4; compounds of the formula (I) wherein X represents -CO; R1 represents hydrogen atom (H); R2 represents methyl (CH3); each among R3-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; R1 and R2 represent hydrogen atom (H); R3 represents methyl; each among R4-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; each among R1-R3 represents hydrogen atom (H); R4 represents methyl; each among R5-R7 represents hydrogen atom (H), and A represents -(CH2)3, and compounds of the formula (I) wherein X represents -CO; each among R1-R4 represents hydrogen atom (H); R5 represents methyl; R6 and R7 represent hydrogen atom (H), and A represents -(CH2)3. Also, invention describes pharmaceutical compositions comprising indicated derivatives and using these benzoxazepine derivatives in treatment of neurological diseases and psychotic disorders sensitive to enhancing responses mediated by AMPA receptors in the central nervous system. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

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

11 cl, 2 tbl, 27 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

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