Derivatives of anthranilic acid or its pharmacologically acceptable salts, intermediates for their preparation and pharmaceutical drugs based on them

 

(57) Abstract:

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms is a hydrogen atom, optionally halogenated lower alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6. Also described drug exhibiting inhibitory activity against cyclic guanozinmonofosfata on the basis of the compounds of formula (1). 5 C. p. F.-ly, 1 PL.

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The scope of the invention

The invention relates the VA.

Background of the invention prior art

Angina, which is one of ischaemic heart disease, known as a disease that often affects the elderly. Although nitrate and nitrite, calcium antagonists, blockers, etc. have been used as drugs for its treatment, these tools are not yet sufficiently effective in the treatment of angina or to prevent its development in myocardial infarction. In addition, recently discovered the lowering of the age of patients affected by stroke, and complications of patients, caused by a change in lifestyle and stress from the increasing complexity of social life, thus developing a new type of improved medicines urgently needed. As for the nitrates and nitrites from a number of currently used drugs, then I think their action is associated with cyclic guanosine monophosphate (hereinafter, abbreviated, cGMP), which is one of cyclic nucleotides, known as intracellular second pick. It is well known that cGMP has relaxants activity on smooth muscles of vessels and bronchi. Although the mechanism of action of this remedy is not always clear, but activity. However, these tools are low bioavailability and act in a relatively short time, it is also reported on the presence of resistance that becomes a clinical problem.

Description of the invention

Given these circumstances, the authors of the present invention have begun development of a new type of improved medicines.

Namely, the inventors have focused on the inhibitory activity against cGMP-phosphodiesterase (hereinafter, abbreviated as cGMP-PDE) and intensively studied compounds with such activity, for a number of years. The study found that a derivative of Anthranilic acid, described below, has the same action and effective for the treatment of various ischemic heart disease. The present invention is made on the basis of this finding.

The present invention relates to a derivative of Anthranilic acid of General formula (1) or its pharmacologically acceptable salts.

Derivatives of Anthranilic acid of General formula 1 or its pharmacologically acceptable salt

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where R1, R2, R3and R4- same or different and mean a hydrogen atom, a halogen atom, a long < / BR>
where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula

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where R13represents a hydrogen atom, a lower alkyl group;

q is an integer from 0 to 2;

R2may be 1,2,4-triazoline group;

R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring,

W represents a group-N= or-CH=,

R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group,

or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form piperidino or pyrolidine ring, A represents a hydrogen atom, optionally halogenated lower alkyl group or a group of the formula:

-X-(CH2)m- Z

where X represents-CO-, -CH2- or - S(O)2-;

Z represents hydrogen, halogen, phenyl group, which may piperidinol group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y represents an oxygen atom, and n is an integer from 0 to 6.

The invention also relates to intermediate products for their production, namely the derivative of Anthranilic acid of General formula II or their pharmacologically acceptable salts:

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where R1- R4the same or different and mean a hydrogen atom, halogen atom, cyano, lower alkoxygroup, pyrazolidine group, R2may be 1,2,4-triazoline group

R14is phenylalkyl, substituted lower alkoxygroup,

R15represents an amino group,

derivatives of Anthranilic acid of General formula III or their pharmacologically PfP hydrogen;

A denotes a hydrogen atom, a group of the formula

-X-(CH2)m- Z

where X represents CO;

Z represents a group of formula-NR11R12in which R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring, possibly substituted by a hydroxy group, a carboxy group or a lower alkoxycarbonyl group

m is an integer from 0 to 6,

derivatives of Anthranilic acid of General formula IV or their pharmacologically acceptable salts:

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where R1- R4represent a hydrogen atom, a halogen atom;

m is 0 to 6,

Z represents a phenyl group, a substituted lower alkoxycarbonyl group.

The invention relates also to pharmaceutical drug exhibiting inhibitory activity against cyclic guanosine monophosphate phosphodiesterase, which contains an effective amount of a derivative of Anthranilic acid or its pharmacologically acceptable salt of General formula I and the pharmacologically acceptable carrier.

Some compounds of the present invention form hydrates and needless to say that these hydrates are in the scope of this izobreteny the

The method of obtaining 1.

The connection represented by the General formula I, where Y is an oxygen atom, can be obtained in the following way:

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(where R1- R8, A and n are each as defined above).

Accordingly, this method is a method by which the derivative of Anthranilic acid represented by the General formula Ia can be obtained by condensation of a derivative of Anthranilic acid represented by the General formula IIIa with an amine represented by the General formula V, as usual.

Although this condensation can be performed in the usual method using a condensing means is preferred.

Condensing reagent used in this method may be any conventional condensing reagent, and its examples include N,N'-dicyclohexylcarbodiimide, N-ethyl-N'-(3 - dimethylaminopropyl)carbodiimide and 2 ethoxy-1-etoxycarbonyl-1,2 - dihydroquinoline.

Condensation can be accelerated in the presence of N-hydroxysuccinimide or N-hydroxybenzotriazole.

The solvent for the condensation may be any organic solvent inert to water and condensation. Examples of such a solvent include simple is'étang, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide and pyridine.

The reaction temperature can vary from about 0oC to the boiling point of the solvent.

The method of obtaining 2.

The connection represented by the General formula I where A is a group of formula-CO(CH2)m-Z (where Z and m are each as defined above), can also be obtained in the following way:

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(where R1-R8, m, n and Z are each as defined above).

Accordingly, this method is a method in which the target compound represented by General formula Ib can be obtained by the interaction of the compounds represented by the General formula VI, with a derivative of Anthranilic acid represented by the General formula VII.

The solvent used in this reaction may be any organic solvent inert to interaction, and its examples include ethers such as ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons, such as benzene, toluene and xylene; dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide and pyridine.

The reaction temperature can vary from about -20oC to the boiling point of the solvent.

Rea is whether lutidine; or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate or sodium hydroxide.

The method of obtaining 3.

The connection represented by the General formula I, where Z is a carboxyl group, can be obtained in the following way:

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(where R1- R8, m and n are each as defined above and Z' represents a protected carboxyl group).

Accordingly, this method is a method by which the target compound represented by the General formula Ic' can be obtained by hydrolysis of compounds represented by the General formula Ic.

The solvent used for the hydrolysis may be any organic solvent inert to hydrolysis, and its examples include alcohols such as methanol and ethanol; and ethers such as tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably varies from about 0oC to the boiling point of the solvent.

In addition, the presence of inorganic bases during hydrolysis gives the desired result, and examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide.

The way the UP> can be obtained also in the following way:

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(where R1- R8, R11, R12n and m , each, defined above; and L represents a leaving group such as halogen atom, p-toluensulfonate or methanesulfonamido).

Accordingly, this method is a method by which the target compound is represented by formula Id can be obtained by the interaction of the compounds represented by the General formula VII with an amine represented by the General formula VIII.

The solvent used in this reaction includes ethers such as ether, tetrahydrofuran and 1,4-dioxane; alcohols such as methanol and ethanol; dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, n, N-dimethylformamide and dimethylsulfoxide.

The reaction temperature preferably varies from about 0oC to the boiling point of the solvent.

The method of obtaining 5.

The connection represented by the General formula I, where R8denotes hydrogen and X is represented by the formula: -CH2- can be obtained in the following way:

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(where R1- R7, m, n and Z are each as defined above).

Accordingly, this method is the way to Kotor is submitted to the General formula IV, with a compound represented by the General formula V.

The above interaction can be carried out in a solvent inert to interaction, and examples of such solvents include ethers such as ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons, such as benzene, toluene and xylene; acetonitrile, N,N-dimethylformamide; dimethylsulfoxide; dichloromethane; chloroform and 1,2-dichloroethane.

The reaction temperature preferably varies from about 0oC to the boiling point of the solvent.

In addition, the use of catalytic amounts of base in the reaction gives the desired result, and examples of the base include 4-dimethylaminopyridine and 4-pyrrolidinedione.

The method of obtaining 6.

The connection represented by the General formula I, where R8and A, each represent a hydrogen atom, can also be obtained in the following way:

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(where R1- R7and n are each as defined above).

Accordingly, this method is a method in which the target compound represented by the General formula If can be obtained by reduction of compounds represented by the General formula If', in the usual way.

In the using palladium on coal or platinum oxide, or restore using a metal (such as iron, tin or zinc), the recovery with acid (such as hydrochloric or acetic acid) and restore using tin chloride (II).

The solvent used for the above reduction can be a solvent inert to the restoration, for example methanol or ethanol.

The reaction temperature varies preferably from about 0oC to the boiling point of the solvent.

The way to obtain 7.

The connection represented by the General formula IIIa, which is the initial product by Way of obtaining 1, can be obtained in the following way:

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(where R1- R4, R8and A, each defined above; and R14represents a group selected from the groups defined for R14with the exception of hydrogen atoms.

Accordingly, the connection represented by the General formula IIIa may be obtained by removing protection from compounds represented by the General formula III.

When R14denotes alkyl, preferably a solvent inert to the removal of protection (such as methanol, ethanol, tetrahydrofuran or 1,4-daily hydroxide barium, at a temperature of from about 0oC to the boiling point of the solvent.

When R14is benzyl, the compound represented by the General formula IIIa may be obtained by catalytic regeneration using palladium on coal or the like as a catalyst.

In addition, when R14is a 4-methoxybenzyl, benzhydryl or the like, the removal of protection can be performed using triperoxonane acid, in a solvent such as dichloromethane, chloroform or 1,2-dichloroethane, in the presence of anisole. In this case, it is preferable that the reaction temperature was changed from about 0oC to the boiling point of the solvent.

The method of obtaining 8.

The connection represented by the General formula III, where X is represented by the formula: -CO-; m= 0; and R8is a hydrogen atom, which is the initial product Method for producing a 7, can be obtained in the following way:

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(where Q and Q' each represent a chlorine atom, trichlormethiazide or imidazolidinyl group; and R1- R4and R11- R13each defined above), (1st stage).

Accordingly, this stage is the stage at which connection the connection represented by the General formula IX.

When carrying out the above reaction, it is possible to use an inert solvent, and examples of the solvent include ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2 - dichloroethane, benzene, toluene and xylene.

The reaction temperature varies preferably from about 0oC to the boiling point of the solvent.

If necessary, for smooth flow of the above reactions can be used a base, such as triethylamine or diisopropylethylamine.

Compound X obtained at this stage may be used without his selection to the next stage 2 (stage 2).

This stage is the stage in which the compound represented by the General formula I b, is produced by interaction of the compound X obtained in the above 1-th stage, with the compound represented by the General formula VIII.

The reaction temperature preferably varies from about 0oC to the boiling point of the solvent.

The method of obtaining 9.

Among the derivatives of Anthranilic acid (III') as the source of the product according to the Method of obtaining 8, can be obtained Anthranilic derivative of the free ka is higher).

Accordingly, this method is a method in which the compound represented by the General formula IIa', can be obtained by the interaction of the compounds represented by the General formula IIa with a compound represented by the General formula XII.

The reaction is preferably carried out in a solvent such as N,N-dimethylformamide, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran or 1,4-dioxane in the presence of a base such as sodium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate at a temperature of from about 0oC to the boiling point of the solvent.

The method of obtaining 10.

The connection represented by the General formula VII, which is the original product by the Method of 4, can be obtained in the following way:

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(where Hal represents a halogen atom; L represents a leaving group such as halogen atom, p-toluensulfonate or methansulfonate; and R1- R8, m, n and X are each as defined above).

Accordingly, this method is a method in which the compound represented by the General formula Id', can be obtained by the interaction of the compounds before Leshey in this reaction, can be any solvent inert to the reaction, and examples of such solvents include ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide and pyridine.

The reaction temperature preferably varies from -20oC to the boiling point of the solvent.

Moreover, the simultaneous presence of a base in the reaction gives the desired results, and examples of the base include organic bases such as triethylamine, diisopropylethylamine and lutidine; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and sodium hydroxide.

The method of obtaining 11.

The connection represented by the General formula IV, which is the initial product Method for producing a 5, can be obtained in the following way:

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(where R1- R4, m, X, Hal and Z are each as defined above).

Accordingly, this method is a method by which the target compound represented by the General formula IV can be obtained by the interaction of the compounds represented by the General formula XI, sodium hydroxide, potassium hydride or similar joint and the reactions it is possible to use a solvent, inert to the reaction, and examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide and tetrahydrofuran.

The reaction temperature preferably varies from about 0oC to the boiling point of the solvent.

The method of obtaining 12.

The connection represented by the General formula If', which is the starting product according to the Method of obtaining 6, can be obtained in the following way:

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(where R1- R7and n are each as defined above).

Accordingly, this method is a method in which the compound represented by the General formula If' can be obtained by the interaction of the carboxylic acid represented by the General formula IIa, or its reactive derivative, with a compound represented by the General formula V, by amidation.

The reactive derivative of compound IIa includes acid halides, such as acylchlorides and Allbreed; azides acids; their active esters of N-hydroxybenzotriazole and N-hydroxysuccinimide; and their mixed anhydrides of the acids with p-toluensulfonate and esters of phosphoric acid.

When the compounds IIa use the free carboxylic Ki is carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide or 2-ethoxy-1 - etoxycarbonyl-1,2-dihydroquinoline.

When carrying out the reaction it is possible to use an organic solvent inert to the reaction, and examples of the solvent include ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile and N,N-dimethylformamide.

The reaction temperature preferably varies from about 0oC to the boiling point of the solvent.

When using some reactive compounds, adding a base to the reaction system gives the desired results, and examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, sodium bicarbonate, sodium carbonate and potassium carbonate.

The method of obtaining 13.

The compound represented by formula IIa, which is the initial product by Way of 12, can be obtained in the following way:

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(where R1- R4and R14each defined above).

Accordingly, the connection represented by the General formula IIa can be obtained by removing protection from compounds represented by the General formula IIa'.

The above is or 1,4-dioxane) in the presence of a base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide at a temperature varying from about 0oC to the boiling point of the solvent.

The method of obtaining 14.

The connection represented by the General formula III', which is the starting product according to the Method of obtaining 8, can be obtained in the following way:

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(where R1- R4and R14each defined above).

Accordingly, the connection represented by the General formula III' can be obtained by condensation of the compounds represented by the General formula IIIa', with the compound represented by the General formula XII.

Although condensation can be performed in the usual way, using a condensing agent is preferable. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-(3 - dimethylaminopropyl)carbodiimide and 2 ethoxy-1-etoxycarbonyl-1,2 - dihydroquinoline, although you can use any well-known commonly used condensing agent.

The reaction can be accelerated by the addition of 4-dimethylaminopyridine or 4 - pyrrolidinedione.

The reaction is preferably carried out in inert to the reaction solvent, such as boiling point of the solvent.

The method of obtaining 15.

The connection represented by the General formula III, where X is represented by the formula: -CO-; m=0; R2is cyano; and R8denotes the hydrogen atom, which is the initial product Method for producing a 7, can be obtained in the following way:

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(where R1, R3, R4and R14each defined above; M represents a metal atom; and p is an integer from 1 to 3).

Accordingly, the compound represented by General formula XIV may be obtained by the interaction of the compounds represented by the General formula III, with cyanide transition metal represented by the General formula XX.

Cyanide transition metal is preferably copper cyanide(I).

The reaction is preferably carried out either without any solvent or in the presence of an organic solvent inert to the reaction, such as pyridine, quinoline, N,N-dimethylformamide, N-methyl-2-pyrrolidone or hexamethylphosphorotriamide (GMPTA) at a temperature of from about 0oC to the boiling point of the solvent.

The method of obtaining 16.

The connection represented by the General formula V, by Way of obtaining 1, where R7the two who are defined above).

Accordingly, the connection represented by the General formula V', can be obtained by removing protection from compounds represented by the General formula XIII. Although the removal of protection can be acid or alkaline hydrolysis, it is preferable to carry out the removal of protection with the use of hydrazine.

The solvent used in the above reaction may be any solvent inert to the reaction, and examples include methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

The reaction is preferably carried out at a temperature from about 0oC to the boiling point of the solvent.

The method of obtaining 17.

The connection represented by the General formula XIII, which is used as the source of the product by the Method of 16, can be obtained in the following way:

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(where R5,R6n and L are each as defined above).

Accordingly, the connection represented by the General formula XIII may be obtained by the interaction of the compounds represented by the General formula XIV, phthalimide represented by the General formula XV.

When L is a hydroxy-group, the compound represented by the General formula XIII can be obtained by condensation of soevndal in the usual way, it can be carried out using the derived phosphine, such as triphenylphosphine and tributylphosphine, and diethylazodicarboxylate or diapir isocarbophos acid, such as diethylazodicarboxylate.

The above reaction is preferably carried out in a solvent inert to the reaction such as tetrahydrofuran, 1,4-dioxane or acetonitrile, at temperatures from about 0oC to the boiling point of the solvent.

When L is a leaving group such as halogen atom, methanesulfonate or p-toluensulfonate, the compound represented by the General formula XIII may be obtained by the coupling of compounds of formula XIV with phthalimido or its salt with an alkaline metal. Salt of alkaline metal phthalimide includes its sodium and potassium salt.

The solvent used in the reaction may be inert to the reaction, and examples of such solvent include acetonitrile, N,N-dimethylformamide, methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

When using phthalimide, the reaction can be accelerated by the addition of inorganic bases such as sodium carbonate, sodium bicarbonate or potassium carbonate, or organic osnovatelno varies from about 0oC to the boiling point of the solvent.

The method of obtaining 18.

The connection represented by the General formula I, where Y is an oxygen atom, and R1and R7together with the formation of rings can be obtained in the following way:

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(where R2- R6, n and L each, defined above).

Accordingly, the connection represented by the General formula Ig can be obtained by the interaction of the compounds represented by the General formula Ig', with the compound represented by the General formula XVI.

Preferably, the reaction is carried out in the presence of a base such as sodium hydride, hydride or potassium tert-piperonyl potassium.

The reaction is preferably carried out in a solvent inert to the reaction such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone, at a temperature of from about 0oC to the boiling point of the solvent.

The method of obtaining 19.

The connection represented by the General formula Ig', which is the starting product according to the Method of obtaining 18, can be obtained in the following way:

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(where R2- R4, R14and L, each determined the General formula XVIII, produced by interaction of the compounds represented by the General formula XVII with ammonia.

When carrying out the reaction it is possible to use a solvent inert to the reaction, and examples of the solvent include methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably ranges from about 0oC to the boiling point of the solvent. (2nd stage)

Accordingly, the connection represented by the General formula Ig', obtained by reduction of compound represented by the General formula XVIII, in the usual way.

Recovery can be accomplished in the usual way, and examples of the method include catalytic reduction using palladium on coal or platinum oxide; and recovering a metal, such as iron, tin or zinc, and an acid, such as hydrochloric acid or acetic acid; and recovering the tin chloride (II).

The solvent used in the restoration, may be a solvent inert to the reaction, for example methanol or ethanol.

The reaction is carried out at a temperature of from 0oC to the boiling point of the solvent.

The method of obtaining 20.

The compound represented by the General method is:

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(where R2- R4, R14L and q are each as defined above). (1st stage)

Accordingly, the connection represented by the General formula XVIII, produced by interaction of the compounds represented by the General formula XVII with a metal cyanide.

When carrying out the above reaction can be used a solvent inert to the reaction, and examples of such solvents include water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide and dimethylsulfoxide.

The reaction temperature preferably ranges from about 0oC to the boiling point of the solvent. (2nd stage)

Accordingly, the connection represented by the General formula Ig', obtained by reduction of compound represented by the General formula XVIII, in the usual way.

This recovery can be carried out in the usual way, and the examples include catalytic reduction using palladium on coal or platinum oxide; and recovering a metal, such as iron, tin or zinc, and an acid, such as hydrochloric acid or acetic acid; and recovering the tin chloride(II).

The solvent used in the restoration, may be the preferably ranges from about 0oC to the boiling point of the solvent.

The method of obtaining 21.

The connection represented by the General formula Ig', where R2is a halogen atom, which is the starting product according to the Method of obtaining 18, can be obtained in the following way:

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(where R3, R4and X are each as defined above).

Accordingly, the connection represented by the General formula Ig', can be obtained by halogenoalkanes compounds represented by the General formula XIX, in the usual way.

This halogenoalkane can be performed in the usual way, and examples of the method include methods using chlorine, bromide, Tetra-n-butylamphetamine and benzyltrimethylammonium, respectively.

The solvent used in galogenirovannyie may be a solvent inert to galogenirovannyie, for example dichloromethane, chloroform or acetic acid.

The reaction temperature preferably ranges from about 0oC to the boiling point of the solvent.

The present invention also relates to the following compounds: compounds represented by the General formula II and their pharmaceutically acceptable salts:

about is possessing a hydrogen atom, optionally halogenated lower alkyl group or optionally substituted arylalkyl group; and R15is the nitro-group or amino group).

Compounds represented by the General formula III and their pharmaceutically acceptable salts:

General formula III

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(where R1, R2, R3, R4, R8, R14and A, each defined above);

and compounds represented by the General formula IV, and their pharmacologically acceptable salt:

the General formula IV

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(where R1, R2, R3, R4, m and Z are each as defined above; and X2represents a group-CH2-).

These compounds II, III and IV are used as intermediates for producing compounds I.

The following describes the Pharmacological experimental example to demonstrate the usefulness of the compounds of the present invention.

Pharmacological experimental example

Enzyme inhibiting activity using cGMP-PDE obtained from the aorta of a pig

1. Methodology experience

The enzymatic activity of cGMP-PDE obtained from the aorta of a pig, was determined by the method of Thompson and others, This definition is carried out in the presence of 1 mm EG and was added to the reaction system, to determine its inhibitory activity. The final concentration of DMSO in the reaction system is set to 4% and below.

cGMP-PDE was obtained in the following way:

The aorta of a pig cut into small pieces, was added a 10-fold volume of buffer A (20 mm Tris/HCl, 2 mm magnesium acetate, 1 mm dithiothreitol, 5 mm EDTA, 1400 TIU/l Aprotinin, 10 mg/l leupeptin, 1 mm benzamidine, 0.2 mm PMSF, pH 7.5). The resulting mixture was homogenized and centrifuged at 100,000 revolutions per hour. The obtained supernatant (supernatant) is placed in a column of DEAE-Toyopearl 650S (the product of the company Tosoh, Tokyo, Japan) followed by washing the column with buffer B (50 mm Tris/HCl, 0.1 mm EGTA, 2 mm magnesium acetate, 1 mm Dithiothreitol, 0.2 mm PMSF, pH 7.5). The received column is subjected to a gradient elution of 0.05-0.4 M sodium chloride to obtain a CaM-independent fractions cGMP-PDE.

2. The results of the experiment

Inhibiting the activity of cGMP-PDE compounds of the present invention, thus defined, are shown in table 1, where a lower value IC50(IR50) reflects the greater the effect.

From the results of Pharmacological experimental Example can be understood that the compound of the present invention has inhibitory activeday action to increase the concentration of cGMP in vivo through inhibition activity against cGMP-PDE. Accordingly, derivatives of Anthranilic acid of the present invention is effective in the prevention and treatment of diseases for which effective inhibiting cGMP-PDE activity. Examples of such diseases include ischemic heart diseases such as angina, myocardial infarction, chronic and acute heart failure; pulmonary hypertension, accompanied or not accompanied pulmonary heart, hypertension, due to various reasons; the insufficiency of peripheral circulation; the insufficiency of cerebral circulation: dysfunction of the brain; and allergic diseases such as bronchial asthma, atopic dermatitis and allergic rhinitis.

In addition, the compounds of the present invention are less toxic and safer, being thus useful in this sense.

The present invention relates to prophylactic and therapeutic agent for the treatment of diseases for which effective inhibition of phosphodiesterase, and means contain derivatives of Anthranilic acid or its pharmacologically acceptable salt, described above, as active components; and preventive and therapeutic agents for l is trailway acid or its pharmacologically acceptable salt, as described above, as the active ingredient.

The compound of the present invention is especially effective against ischemic heart disease, angina, hypertension, pulmonary hypertension, congestive heart failure and asthma.

In addition, the present invention relates to a medicinal product containing a pharmacologically effective amount of a derivative of Anthranilic acid or its pharmacologically acceptable salt described above and a pharmacologically acceptable carrier; and to a method for prevention and treatment of diseases, which includes the introduction of a pharmaceutically acceptable amount of a derivative of Anthranilic acid or its pharmacologically acceptable salt described above for inhibition of phosphodiesterase.

The compound of the present invention is administered as a drug orally or parenterally. It dose varies depending on the extent of disease; age, sex, weight and sensitivity to drugs; dosage regimen of the medication; the timing of dosing; the interval between meals; medication; drugs administered simultaneously; the active component, and so on, but is not limited to the preferably about 5-500 mg, which can be entered from one to three portions a day.

With the introduction in the form of injections daily dose usually ranges from about 1 μg/kg to 3000 μg/kg, preferably about 3-1000 mg/kg

Solid preparation for oral administration according to the present invention is obtained by adding a filler and, if necessary, a binder, baking powder, lubricant, colorant and/or additive to the active ingredient and forming the resulting mixture into tablets, coated tablets, granules, powders or capsules.

Examples of the filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide; examples of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, Arabian gum, tragakant, gelatin, shellac, hydroxypropylcellulose, calcium citrate, dextrin and pectin; examples of lubricating agents include magnesium stearate, talc, polyethylene glycol, silica and solidified vegetable oil; examples of the dye include dyes that are allowed as pharmaceutical additives; and examples of the additives include cocoa powder, menthol, aromatic powder, menthol oil, borneol and powdered coric is necessary.

When you get the injectable drug, according to the present invention can be added to the active ingredient pH regulator, buffer, suspendisse agent, solubilizers agent, stabilizer, isotonic agent and/or preservative, if necessary, and cook the mixture for intravenous, subcutaneous or intramuscular injection in the usual way. In addition, injection drug may be dried by freezing, if necessary.

Examples of the suspending agent include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, Arabic gum, powder tragakant, sodium carboxymethyl cellulose and polyoxyethylenesorbitan.

Examples solubilizing tools include polyoxyethylene, hardening castor oil, Polysorbate 80, nicotinamide, polyoxyethylenesorbitan, Macrogol (Macrogol) and ethyl ester of fatty acids of castor oil.

Next to a clearer understanding of the present invention will be described examples, although they are preceded by Preparative examples as examples of the synthesis, which are the source of connection that is required to obtain the compounds of the present invention.

Preparative example 1

1-[(2-CT the ENT-2-[(4 - methoxybenzyloxy)carbonyl] phenyl] carbarnoyl]piperidine-4-carboxylate, then added dropwise to 6.6 ml triperoxonane acid. The resulting mixture was stirred at room temperature for one hour and concentrate and add the ether. The resulting mixture is extracted with saturated aqueous sodium bicarbonate. the pH of the aqueous solution set 2 with concentrated hydrochloric acid to precipitate crystals. The crystals are filtered and washed with water to obtain 2,09 g specified in the title compound as a white powder (yield: 69%).

So pl. 159-160oC (decomp.)

(white needles from aqueous ethanol).

NMR (400 MHz , CDCl3):

1.27 (t, J-7.1 Hz, 3H), 1.78 (m, 2H), 2.02 (m, 2H), 2.58 (m, 1H), 3.10 (m, 2H), 4.11 (m, 2H), 4.18 (K, J=7.1 Hz, 2H), 7.47 (DD, J=2.7, 9.2 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H), 8.47 (d, J=9.2 Hz, 1H), 10.70 (s, 1H).

Preparative example 2

Ethyl-1-[[4-chloro-2-(4-metoksibenzoati)carbonitril] carbarnoyl] - piperidine-4-carboxylate

< / BR>
To 4-methoxybenzyl-2-amino-5-chlorobenzoate (20.74 g), dissolved in 180 ml of tetrahydrofuran, add 12.69 g of 1,1'-carbonyldiimidazole. The resulting mixture was refluxed for 43 hours and allowed to cool, then add 12.06 ml utilisedictated. The mixture was incubated at room temperature for one hour and concentrated, EXT is astorm of sodium bicarbonate and a saturated aqueous solution of common salt, successively, dried over anhydrous magnesium sulfate and the solvent is distilled off. Insoluble in benzene substance is filtered off and the filtrate is purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3:1)) and get 11.07 g specified in the title compound as a yellow oil with a yield of 33%.

NMR (400 MHz , CDCl3):

1.27 (t, J = 7.1 Hz, 3H), 1.76 (m, 2H), 2.01 (m, 2H), 2.54 (m, 1H), 3.07 (m, 2H), 3.83 (s, 3H), 4.12 (m, 2H), 4.32 (K, 7.1 Hz, 2H), 5.28 (s, 2H), 6.91-6.96 (m, 2H), 7.36-7.40 (m, 2H), 7.43 (DD, J 2.6, 9.2 Hz, 1H), 7.95 (d, J = 2.6 Hz), 8.66 (d, J = 9.2 Hz), 10.68 (s, 1H).

Preparative example 3

4-Methoxybenzyl-2-amino-5-chlorobenzoate

< / BR>
2-Amino-5-chlorobenzoyl acid (15.00 g), methoxybenzylamine (13.1 ml) and potassium carbonate (13.3 g) is added to N,N-dimethylformamide (175 ml). The resulting mixture was stirred at room temperature for 43 h, then added to the mixture of ice water. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified column chromatography on silica gel (solvent n-hexane/ethyl acetate (5:1)) and get 20.97 g specified in the title compounds as a pale yellow oil with a yield is 8.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.82 (d, J = 2.6 Hz, 1H).

Preparative example 4

Metil-2-amido-5-dimethylaminomethylene

< / BR>
Methyl-5-dimethylaminomethyl-2-nitrobenzoate (12.92 g) and chloride dihydrate tin(II) (60.39 g) are added to 110 ml of ethanol. The resulting mixture was stirred at 70oC for one hour, then add ice-cold water. The mixture is alkalinized with sodium carbonate and extracted with ethyl acetate. The organic phase is dried with anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified column chromatography on silica gel (solvent: dichloromethane/methanol (30: 1 to 10:1)) and get 10.93 g specified in the title compounds as a pale yellow liquid with a yield of 97%.

NMR (400 MHz , CDCl3):

2.20 (s, 6H), 3.29 (s, 2H), 3.85 (s, 3H), 5.68 (W, 2H), 6.63 (d, J = 8.4 Hz, 1H), 7.22 (DD, J = 2.2, 8.4 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H).

Preparative example 5

Methyl-5-dimethylaminomethyl-2-nitrobenzoate

< / BR>
To methyl 5-methyl-2-nitrobenzoate (8.06 g), dissolved in 140 ml of carbon tetrachloride, add 7.72 g of N-bromosuccinimide and 0.50 g of benzoyl peroxide. The resulting mixture was refluxed 5 h and filtered, the insoluble material. The filtrate is concentrated to obtain a yellow oil. This is ing the mixture is stirred at room temperature for 5 h and concentrated, then add water. The resulting mixture was extracted with ethyl acetate. The organic phase is dried with anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified column chromatography on silica gel (solvent: dichloromethane/methanol (30:1)) and obtain 3.17 g of the target compound as a yellow oil with a yield of 32%.

NMR (400 MHz , CDCl3):

2.26 (s, 6H), 3.51 (s, 2H), 3.93 (s, H) 7.59 (DD, J = 1.8, 8.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H).

Preparative example 6

6-Chloro-1-[4-(etoxycarbonyl)butyl] -1,2-dihydro-4H-1,3 - benzoxazin-2,4-dione

< / BR>
1.11 g of 60% sodium hydride (suspended in mineral oil) is suspended in 80 ml of N, N-dimethylacetamide and the parts add 5.00 g of 6-chloro-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione. The resulting mixture was stirred at room temperature for one hour and add 4.81 ml ethyl-5-bromovalerate. The resulting mixture was stirred at 50oC 24 h, poured into 200 ml of a mixture of 1H hydrochloric acid and ice and extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous salt solution, dried with anhydrous magnesium sulfate and the solvent is distilled off. To the resulting solid residue or add ether. The resulting mixture was filtered and receive 4.89 g of the target Saadet).

NMR (400 MHz , CDCl3):

1.25 (t, J = 7.1 Hz, 3H), 1.72 - 1.86 (m, 4H), 2.40 (t, J = 7.0 Hz, 2H), 4.07 (t, J = 7.3 Hz, 2H), 4.13 (K, J = 7.1 Hz, 2H), 7.17 (d, J = 9.0 Hz, 1H), 7.71 (DD, J = 2.6, 9.0 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H)

Preparative example 7

6-Chloro-1-[3-(etoxycarbonyl)propyl] -1,2-dihydro-4H-1,3 - benzoxazin-2,4-dione

< / BR>
Pale yellow powder is obtained with a yield of 60%.

So pl. 78-80oC

(pale yellow prisms from n-hexane/ethyl acetate)

NMR (400 MHz, CDCl3):

1.30 (t, J = 7.1 Hz, 3H), 1.99 - 2.09 (m, 2H), 2.51 (t, J = 6.2 Hz, 2H), 4.12 (t, J = 8.1 Hz, 2H), 4.19 (K, J = 7.1 Hz, 2H), 7.52 (d, J = 9.0 Hz, 1H), 7.75 (DD, J = 2.4, 9.0 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H)

Preparative example 8

6-Chloro-1-(4-methoxycarbonylbenzyl)-1,2-dihydro-4H-1,3 - benzoxazin-2,4-dione

< / BR>
Slightly yellow powder is obtained with a yield of 89%

So pl. 214-217oC

(white needles from EtOAc).

NMR (400 MHz , CDCl3):

3.91 (s, 3H), 6.97 (d, J = 9.0 Hz, 1H), 7.33 - 7.38 (m, 2H), 7.57 (DD, J = 2.6, 9.0 Hz, 1H), 8.02 - 8.06 (m, 2H), 8.14 (d, J = 2.6 Hz)

Preparative example 9

4-Methoxybenzyl-2-amino-5-bromobenzoate

< / BR>
2-Amino-5-bromobenzoyl acid (15.59 g), 4-methoxybenzyloxy alcohol (7.5 ml), 1,3-dicyclohexylcarbodiimide (14.89 g) and 4-dimethylaminopyridine (8.07 g) are added to 200 ml of acetonitrile. The resulting mixture was stirred at room temperature for 18 h and nextresult with ethyl acetate. Acelacelou phase is successively washed with water, 1H hydrochloric acid, water, 1H sodium hydroxide, water and saturated aqueous salt solution, dried over magnesium sulfate and the solvent is distilled off in vacuum. The residue is purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (8:1 to 5:1), yield 65%.

1H-NMR (400 MHz, CDCl3) :

3.82 (3H, s), 5.24 (2H, s), 5.76 (2H, s), 6.54 (1H, d, J = 8.8 Hz), 6.92 (2H, m), 7.30 (1H, DD, J = 8.8, 2.6 Hz), 7.37 (2H, m), 7.96 (1H, d, J = 2.6 Hz).

Preparative example 10

4-Methoxybenzyl-2-amino-5-cyanobenzoate

< / BR>
2-Amino-5-cyanobenzoic acid (32.18 g), 4-methoxybenzylamine (28.34 ml) and anhydrous potassium carbonate (28.89 g) are added to 400 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 15 hours, add ice water and extracted with ethyl acetate. An ethyl acetate phase is washed successively with water, 1H hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off in vacuum. The residue is purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (4: 1 to 3:1)). The obtained solid material was washed with cm the od 52%.

So pl. 120-122oC.

Mass.: 283 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.83 (3H, s), 5.26 (2H, s), 6.30 (2H, s), 6.65 (1H, d, J = 8.6 Hz), 6.91 - 6.98 (2H, m), 7.35 - 7.40 (2H, m), 7.43 (1H, DD, J = 8.6, 2.0 Hz), 8.19 (1H, d, J = 2.0 Hz).

Preparative example 11

Ethyl-1-[[4-bromo-2-[(4-methoxybenzyloxy)carbonyl] phenyl] - carbarnoyl]piperidine-4-carboxylate

< / BR>
4-Methoxybenzyl-2-amino-5-bromobenzoate (13.13 g) and 1,1'- carbonyldiimidazole (6.97 g) is added to 100 ml of tetrahydrofuran. The resulting mixture is heated to boiling under reflux for 41 hours, allowed to cool and then add 6.63 ml utilisedictated. The resulting mixture was stirred at room temperature for one hour and concentrated in vacuo. The residue is purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3: 1)) and obtain 4.40 g specified in the title compounds as a pale yellow solid, yield 20%.

So pl. 98-100oC.

Mass.: 520 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.76 (2H, m), 2.01 (2H, m), 2.55 (1H, m), 3.07 (2H, m), 3.83 (3H, s), 4.12 (2H, m), 4.17 (2H, K, J = 7.1 Hz), 5.28 (2H, s), 6.94 (2H, m), 7.38 (2H, m), 7.56 (1H, DD, J = 9.2, 2.6 Hz), 8.09 (1H, d, J = 2.6 Hz), 8.46 (1H, d, J = 9.2 Hz), 10.69 (1H, s).

Preparatively example 12

1-[[4-the connection get as in Preparative example 3 in the form of a white solid, exit 4%.

So pl. 112-114oC.

Mass.: 419 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.55 - 1.65 (3H, m), 1.98 (2H, m), 3.27 (2H, DDD, J = 13.7, 9.2, 3.3 Hz), 3.83 (3H, s), 3.91 - 4.00 (3H, m), 5.28 (2H, s), 6.91 - 6.96 (2H, m), 7.35 - 7.40 (2H, m), 7.43 (1H, DD, J = 9.2, 2.6 Hz), 7.95 (1H, d, J 2.6 Hz), 8.52 (1H, d, J = 9.2 Hz), 10.69 (1H, s).

Preparative example 13

1-[[4-Cyano-2-[(4-methoxybenzyloxy)carbonyl] phenyl] carbarnoyl] - 4-hydroxypiperidine

< / BR>
Specified in the header of the connection are given as in Preparative example 3, in the form of a white solid, yield 4%.

So pl. 167-169oC.

Mass.: 410 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.56 - 1.67 (3H, m), 1.99 (2H, m), 3.33 (2H, DDD, J 13.7, 9.0, 3.5 Hz), 3.84 (3H, s), 3.91 - 4.03 (3H, m), 5.31 (2H, s), 6.92 - 6.97 (2H, m), 7.35 - 7.40 (2H, m), 7.69 (1H, DD, J = 9.0, 2.2 Hz), 8.30 (1H, d, J = 2.2 Hz), 8.69 (1H, d, J = 9.0 Hz), 11.04 (1H, s).

Preparative example 14

Ethyl-1-[(4-bromo-2-carboxyphenyl)carbarnoyl]piperidine-4-Carbo - kilat

< / BR>
A mixture containing 3.82 g of ethyl-1-[[4-bromo-2-[(4 - methoxybenzyloxy)carbonyl] phenyl]carbarnoyl]piperidine-4-carboxylate, 4.02 ml of anisole and 5.7 ml triperoxonane acid, stirred at room temperature for 2.5 h and concentrated in vacuo. To the residue add an aqueous solution of sodium carbonate and ether for about the t and washed with ether. The resulting aqueous phase is acidified with concentrated hydrochloric acid, which gives a precipitate. The precipitate was separated by filtration and obtain 2.50 g of target compound in the form of a white powder, yield 85%.

So pl. 153 to 155oC (decomp.).

Mass.: 399 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.28 (3H, t, J = 7.1 Hz), 1.77 (2H, m), 2.02 (2H, m), 2.58 (1H, m), 3.09 (2H, m), 4.11 (2H, m), 4.18 (2H, K, J = 7.1 Hz), 7.61 (1H, DD, J = 9.2, 2.6 Hz), 8.16 (1H, d, J = 2.6 Hz), 8.42 (1H, d, J = 9.2 Hz), 10.67 (1H, s).

Preparative example 15

1-[(2-Carboxy-4-chlorophenyl)carbarnoyl]-4-hydroxypiperidine

< / BR>
Specified in the header of the connection are given as in Preparative example 6, in the form of a white solid, yield 77%.

So pl. 168-170oC (decomp.).

Mass.: 299 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.36 (2H, m), 1.78 (2H, m), 3.16 (2H, DDD, J = 13.5, 9.5, 3.1 Hz), 3.67 - 3.83 (3H, m), 7.57 (1H, DD, J = 9.2, 2.7 Hz), 7.89 (1H, d, J = 2.7 Hz), 8.43 (1H, d, J = 9.2 Hz), 10.85 (1H, s).

Preparative example 16

1-[(2-Carboxy-4-cyanophenyl)carbarnoyl]-4-hydroxypiperidine

< / BR>
Specified in the header of the connection are given as in Preparative example 6, in the form of a white solid, yield 77%.

So pl. 175-179oC (decomp.).

Mass: 290 (MH+).

8.30 (1H, d, J = 2.2 Hz), 8.55 (1H, d, J = 9.0 Hz), 11.23 (1H, s).

Preparative example 17

Methyl-2-amino-5-bromo-4-methoxybenzoate

< / BR>
Methyl-2-amino-4-methoxybenzoate (8.44 g) and calcium carbonate (5.13 g) was dissolved in a mixed solvent containing 250 ml of dichloromethane and 100 ml of methanol, and added in several portions 19.09 g benzyltrimethylammonium. The resulting mixture was stirred at room temperature for one hour and filtered, the insoluble material. The filtrate was concentrated in vacuo, to the residue is added ethyl acetate and the mixture filtered through silica gel. The filtrate was concentrated in vacuo and the residue purified column chromatography on silica gel (solvent n-hexane/ethyl acetate (4:1)). The obtained solid material was washed with n-hexane and get 10.37 g specified in the title compounds as a pale yellow solid, yield 86%.

So pl. 104-105oC.

Mass: 260 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.84 (3H, s), 3.87 (3H, s), 5.85 (2H, W, s), 6.12 (1H, s), 8.01 (1H, s).

Preparative example 18

7-Nitroisoquinoline-1-he

< / BR>
Methyl-2-methyl bromide-5-nitrobenzoate (6.59 g) suspended in 130 ml of methanol. Through the resulting suspension was passed large excess of ammonia at room ATCO was added water, insoluble material was filtered and washed with ether. Specified in the title compound was obtained as slightly yellow powder, yield 90%.

So pl. 218 to 221oC.

Mass: 179 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

4.48 (2H, s), 7.80 (1H, DD, J = 7.7, 7.3 Hz), 7.87 (1H, d, J = 7.3 Hz), 7.88 (1H, d, J = 7.7 Hz), 8.98 (1H, sh).

Preparative example 19

7-Iminoisoindolin-1-he

< / BR>
7 Nitroisoquinoline (6.52 g) suspended in 1000 ml of tetrahydrofuran, was added 1 g of 10% palladium on coal (aqueous). The resulting mixture was subjected to catalytic recovery under conditions of room temperature and 1 ATM. After 18 h the catalyst was filtered and the filtrate was concentrated in vacuum. The obtained solid was washed with ether and received 5.13 g of the target compound as slightly yellow powder, yield 95%.

So pl. 153 to 155oC.

Mass: 149 (MH+).

1H-NMR (400 MHz, CDCl3) : 4.36 (2H, s), 5.21 (2H, s), 6.57 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = 7.3 Hz), 6.72 (1H, s), 7.27 (1H, DD, J = 8.1, 7.3 Hz).

Preparative example 20

Methyl-2-cyanomethyl-6-nitrobenzoate

< / BR>
Methyl-2-methyl bromide-5-nitrobenzoate (at 11.64 g) suspended in 200 ml of methanol and the solution was added 2.19 g of sodium cyanide in 20 m the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3:1 to 2: 1)). The obtained solid material was washed with n-hexane and received 5.43 g specified in the title compound as a white solid, yield 58%.

So pl. 103-105oC.

Mass: 221 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.91 (2H, s), 3.98 (3H, s), 7.68 (lH, t, J = 8.1 Hz), 7.87 (1H, DD, J = 8.1, 1.1 Hz), 8.11 (1H, DD, J = 8.1, 1.1 Hz).

Preparative example 21

8-Amino-1,2,3,4-tetrahydro-1-athinaikon

< / BR>
Methyl-2-cyanomethyl-5-nitrobenzoate (54.43 g) is suspended in 200 ml of methanol and add 4.5 ml of concentrated hydrochloric acid and 0.18 g of platinum oxide. The resulting mixture was subjected to catalytic recovery at room temperature and a pressure of 3 kg/cm2. After 7 h the catalyst was filtered and the filtrate was concentrated in vacuo.

The residue was dissolved in 50 ml of methanol and added 7.50 g of anhydrous potassium carbonate. The resulting mixture was boiled under reflux 9.5 h and was filtered insoluble precipitate. The filtrate concentree water and saturated salt solution, was dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: dichloromethane/methanol (30:1)) was obtained 0.75 g specified in the title compound as a white powder, yield 19%.

So pl. 128-130oC.

Mass: 163 (MH+).

1H-NMR (400 MHz, CDCl3) :

2.90 (2H, t, J = 6.6 Hz), 3.47 (1H, dt, J = 6.6, 2.9 Hz), 5.98 (1H, s), 6.05 (2H, s), 6.43 (1H, DD, J = 7.3, 1.1 Hz), 6.52 (IH, DD, J = 8.3, 1.1 Hz), 7.12 (1H, DD, J = 8.1, 7.3 Hz).

Preparative example 22

7-Amino-4-promisingly

< / BR>
Specified in the header of the connection are given as in Preparative example 9, in the form of a white powder, yield 62%.

So PL, 253-258oC (decomp.).

Mass: 227 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

4.12 (2H, s), 6.20 (2H, s), 6.56 (1H, d, J = 8.6 Hz), 7.32 (1H, D, J = 8.6 Hz), 8.38 (1H, sh).

Preparatively example 23

5-Bromo-8-iminoisoindolin-1-he

< / BR>
Specified in the header of the connection are given as in Preparative example 9, in the form of a white powder, yield 66%.

So pl. 158-160oC (decomp.).

Mass: 241 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.01 (2H, t, J = 6.6 Hz), 3.48 (2H, dt, J = 6.6, 2.9 Hz), 6.13 (2H, s), 6.19 (1H, s), 6.45 (1H, d, J is - 2-amino-5-bromobenzoate (5.00 g) was dissolved in 10 ml of N-methyl-2-pyrrolidone was added 2.14 g of copper cyanide(I). The resulting mixture was stirred at 180oC 4 h and was added an aqueous solution of Ethylenediamine. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of salt, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3:1 to 2:1)) Obtained solid material was washed with n-hexane and received 2.84 g specified in the title compound as slightly yellow powder, yield 74%.

So pl. 127-130oC.

Mass: 177 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 6.30 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.45 (1H, DD, J = 8.6, 2.0 Hz), 8.20 (1H, d, J = 2.0 Hz).

Preparative example 25

2-Amino-5-cyanobenzoic acid

< / BR>
Methyl-2-amino-5-cyanobenzoate (2.84 g) was dissolved in 60 ml of ethanol and was added 24 ml of 1H of sodium hydroxide. The resulting mixture was stirred at room temperature for 6 h and concentrated in vacuum. To the residue was added water and ether and the aqueous phase was separated. The ether phase was extracted with water. Both aqueous phases were combined and acidified with concentrated hydrochloric acid and the precipitate discarded. The precipitate was separated by filtration and received specified in S="ptx2">

1H-NMR (400 MHz, DMSO-d6) :

6.85 (1H, d, J = 8.8 Hz), 7.49 (2H, s), 7.55 (1H, DD, J = 8.8, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz).

Preparative example 26

2-Amino-5-(1,2,4-triazole-1-yl)benzoic acid

< / BR>
Ethyl-2-amino-5-(1,2,4-triazole-1-yl)benzoate (2.00 g) suspended in 15 ml of ethanol and was added 9.2 ml 1H sodium hydroxide. The resulting mixture was stirred at 65oC for 1 h and concentrated in vacuum. To the residue was added water and the mixture was acidified with concentrated hydrochloric acid and the precipitate discarded. The precipitate was separated by filtration and received 2.55 g specified in the title compound as slightly yellow powder, yield 100%.

So pl. 229-231oC.

Mass: 235 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

8.24 - 8.27 (2H, m), 8.34 (1H, m), 8.36 (1H, s), 9.57 (1H, s).

Preparative example 27

2-Amino-5-(1-pyrazolyl)benzoic acid

< / BR>
Specified in the title compound was obtained as in Preparative example 18, in the form of a slightly yellow powder, yield 100%

So pl. 246-248oC.

Mass: 234 (MH+).

1H-NMR (400 MHz, DMSO-d6:

6.67 (1H, DD, J = 2.6, 1.8 Hz), 7.90 (1H, d, J = 1.8 Hz), 8.18 - 8.24 (2H, m), 8.27 (1H, m), 8.79 (1H, d, J = 2.6 Hz).

Preparative example 28

2-Amino-5-bromo-4-met the form of a slightly yellow powder, yield 97%.

So pl. 198oC (decomp.).

Mass: 245 (MH+).

1H-NMR (400 MHz, DMSO-d6): :

3.80 (3H, s), 6.42 (1H, s), 7.71 (1H, s)

Preparative example 29

5-Chloro-2-chloroacetamido-N-(3-chloro-4 - methoxybenzyl)benzamide

< / BR>
2-Amino-5-chloro-N-(3-chloro-4 - methoxybenzyl)benzamide (1.74 g) was dissolved in 18 ml of tetrahydrofuran, was added 0.82 ml of triethylamine. Under ice cooling was added dropwise chlorocatechol (0.47 ml). The resulting mixture was stirred at room temperature for 2 h and added water. The precipitation was separated by filtration, washed with water and ether and received 1.77 g specified in the connection header in the form of weakly-cream powder, yield 82%.

So pl. 174-176oC.

Mass: 401 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.91 (3H, s), 4.18 (2H, s), 4.54 (2H, d, J = 5.9 Hz), 6.55 (1H, m), 6.92 (1H, d, J = 8.4 Hz), 7.22 (1H, DD, J = 8.4, 2.2 Hz), 7.38 (1H, d, J = 2.2 Hz), 7.41 (IH, DD, J = 8.8, 2.4 Hz), 7.44 (IH, d, J = 2.4 Hz), 8.53 (1H, d, J = 8.8 Hz), 11.71 (1H, sh).

Preparative example 30

2-(4-Bromopropylamine)-5-chloro-N-(3,4-methylenedioxybenzyl)- benzamide

< / BR>
Specified in the title compound was obtained as in Preparative example 21, in the form of slightly orange powder, yield 95%.

So pl. 170-171oC..87 (total 2H, t, J = 6.8 Hz), 4.50 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.49 (1H, W m), 6.79 (1H, d, J = 7.9 Hz), 6.81 (1H, d, J = 7.9 Hz), 6.83 (1H, s), 7.41 (1H, d, J = 2.4 Hz), 7.41 (1H, DD, J = 9.5, 2.4 Hz), 8.57 (1H, d, J = 9.5 Hz), 11.12 (1H, sh).

Preparative example 31

2-(4-Bromoethylamine)-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the header of the connection are given as in Preparative example 21, in the form of weakly-buff powder, yield 90%.

So pl. 158-159oC.

Mass: 455 (MH+).

1H-NMR (400 MHz, CDCl3) :

2.28 (2H, TT, J = 7.1, 6.4 Hz), 2.61 (2H, t, J = 7.1 Hz), 3.52 (2H, t, J = 6.4 Hz), 4.51 (2H, d, J = 5.5 Hz), 5.98 (2H, s), 6.46 (1H, m), 6.78 - 6.86 (3H, m), 7.40 (1H, d, J = 2.4 Hz), 7.40 (1H, DD, J = 9.5, 2.4 Hz), 8.56 (1H, d, J = 9.5 Hz), 11.02 (1H, sh).

Preparative example 32

Ethyl TRANS-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate

< / BR>
Monotropy ether of TRANS-1,4-cyclohexanedicarboxylic acid (10.00 g) was dissolved in 200 ml of tert-butanol was added 7.67 ml of triethylamine and 11.85 ml diphenylphosphinite. The resulting mixture was boiled under reflux for 7 h, concentrated and added water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed 1H hydrochloric acid, water, 1H sodium hydroxide and saturated aqueous salt solution, dried over anhydrous soulful: n-hexane/ethyl acetate (8:1 to 4: 1) and received 5.36 g specified in the title compounds as white solids, yield 40%.

So pl. 89-91oC.

Mass: 270 (MH+).

1H-NMR (400 MHz, CDCl3) : 1.11 (2H, m), 1.25 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 1.52 (2H, m), 1.96 - 2.15 (4H, m), 2.20 (1H, dt, J = 12.3, 3.5 Hz), 3.41 (1H, s), 4.11 (2H, K, J = 7.1 Hz), 4.39 (1H, sh).

Preparative example 33

Ethyl TRANS-4-[- (5-bromobutyl)-N-(tert - butoxycarbonyl)amino] -cyclohexanecarboxylate

< / BR>
Ethyl TRANS-4-(tertbutoxycarbonyl)cyclohexanecarboxylate (5.36 g) and 1,5-dibromobutane (13.5 ml) was dissolved in 50 ml of n, N-dimethylformamide was added 0.87 g of 60% sodium hydride. The resulting mixture was stirred at 50oC 5 h and was poured into ice water. The mixture was extracted with ethyl acetate. The organic phase was washed 1H hydrochloric acid, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (from 10:1 to 5:1)) and got 4.32 g specified in the title compounds as colorless oil, yield 52%.

Mass: 420 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.25 (3H, t, J = 7.1 Hz), 1.35 - 1.60 (17H, m), 1.99 - 2.12 (2H, m), 2.19 (1H, m), 3.05 (2H, s), 3.41 (2H, t, J 6.8 Hz), 3.86 (1H, s), 4.12 (2H, Ethyl-Trent-4-[N-(5-bromobutyl)-N-(tert-butoxycarbonyl)- amino] cyclohexanecarboxylate (5.92 g) was dissolved in 20 ml of chloroform was added 18 ml 4H hydrochloric acid/ethyl acetate. The resulting mixture was stirred at room temperature for 14 h and then concentrated. The residue was dissolved in 30 ml of ethanol and added 5.85 g of anhydrous potassium carbonate. The resulting mixture was stirred at room temperature for 3 h, then 6 h at 80oC and was added Celite. Insoluble material was filtered and the filtrate was concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: dichloromethane/methanol/concentrated aqueous ammonia (1000:100:2)) and received 1.91 g specified in the title compounds as a pale yellow oil, yield 57%.

Mass: 240 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.25 (3H, t, J = 7.1 Hz), 1.28 (2H, m), 1.38 - 1.51 (4H, m), 1.54 - 1.62 (4H, m), 1.95 (2H, m), 2.04 (2H, m), 2.15 - 2.31 (2H, m), 2.48 - 2.53 (4H, m), 4.11 (2H, K, J = 7.1 Hz).

Preparatively example 35

TRANS-4-Piperidinylcarbonyl acid

< / BR>
Ethyl TRANS-4-piperidinecarboxylate (1.91 g) was dissolved in 20 ml of ethanol. The resulting solution was stirred at room temperature for 3 days, was established pH 7 1H hydrochloric acid, concentrated in vacuo and was purified column chromatography on ODS (solvent: water) and added water. The insoluble precipitate was filtered, the filtrate kontsentrirovannyi solid material was washed with ether and received 1.54 g specified in the title compound as slightly yellow powder, yield 91%.

Mass: 212 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.14 - 1.32 (4H, m), 1.36 (2H, m), 1.41 - 1.49 (4H, m), 1.73 (2H, m), 1.88 (2H, m), 1.96 (1H, m), 2.19 (1H, m), 2.36 - 2.48 (4H, m).

Preparative example 36

N-(3,4-Methylenedioxybenzyl)-2-nitro-5-(1-pyrazolyl)benzamide

< / BR>
2-Nitro-5-(1-pyrazolyl)benzoic acid (1.40 g), piperacillin (0.82 ml), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g), 1-hydroxybenzotriazol (0.89 g) and triethylamine (0.92 ml) was added to 20 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 14 h and was added to the water. The precipitate was separated by filtration and got 2.19 g specified in the title compound as slightly yellow powder, yield 100%.

So pl. 179-180oC.

Mass: 367 (MH+).

1H-NMR (400 MHz, CDCl3) :

4.56 (2H, d, J = 5.5 Hz), 5.95 (2H, s), 6.18 (1H, m), 6.56 (1H, DD, J = 2.6, 1.8 Hz), 6.78 (1H, d, J = 7.9 Hz), 6.85 (1H, DD, J = 7.9, 1.6 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.78 (1H, d, J = 1.8 Hz), 7.83 (1H, DD, J = 9.0, 2.4 Hz), 7.86 (1H, d, J = 2.4 Hz), 8.01 (1H, d, J = 2.6 Hz), 8.19 (1H, d, J = 9.0 Hz).

Preparative example 37

N-(3,4-Methylenedioxybenzyl)-2-nitro-5-(1,2,4-triazole-1-yl)- benzamide

< / BR>
Specified in the title compound was obtained as in Preparative example 28, in the form of a powder pale Oh what) :

4.58 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.12 (1H, s), 6.76 (1H, d, J = 7.9 Hz), 6.86 (1H, DD, J = 7.9, 1.7 Hz), 6.91 (1H, d, J = 1.7 Hz), 7.91 (1H, DD, J = 9.5, 2.6 Hz), 7.91 (1H, d, J = 2.6 Hz), 8.16 (1H, s), 8.27 (1H, d, J = 9.5 Hz), 8.69 (1H, s).

Preparative example 38

N-(4-Chloro-3-methoxybenzyl)phthalimide

< / BR>
Chloro-5-methylanisole (8.00 g), N-bromosuccinimide (9.55 g) and benzoyl peroxide (0.62 g) was added to 170 ml of carbon tetrachloride. The resulting mixture was boiled under reflux for 1 h and left to cool. Insoluble material was separated by filtration and the filtrate was concentrated in vacuum. The residue was dissolved in 100 ml of N,N-dimethylformamide and added 10.41 g phthalimide potassium. The resulting mixture was stirred at 50oC for 1 h and added to ice water. The precipitate was separated by filtration, washed with water and ether and received 8.66 g specified in the title compound as slightly yellow powder, yield 52%.

So pl. 156-159oC.

Mass: 301 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 4.80 (2H, s), 6.98 (1H, DD, J = 8.1, 1.8 Hz), 7.05 (1H, d, J = 1.8 Hz), 7.29 (1H, d, J = 8.1 Hz), 7.69 - 7.75 (2H, m), 7.82 -7.88 (2H, m).

Preparative example 39

N-[(2-Methoxy-5-pyridyl)methyl]phthalimide

< / BR>
2-Methoxy-5-pyridinemethanol (2.79 g), phthalimide (2.92 g) and triphenylphosphine (5.71 g) was added to 35 Plata in 5 ml of tetrahydrofuran. The resulting mixture was stirred under ice cooling for 1 h, then 15 h at room temperature and poured into water with ice. The mixture was extracted with ethyl acetate. The organic phase was washed 1H hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuo and added benzene. Insoluble material was filtered and the filtrate was concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3: 1)). The obtained solid was washed with n-hexane and received 4.07 g specified in the title compound as a white powder, yield 77%.

So pl. 122-124oC.

Mass: 269 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 4.78 (2H, s), 6.99 (1H, d, J = 8.6 Hz), 7.68 (1H, DD, J = 8.6, 2.6 Hz), 7.68 - 7.74 (2H, m), 7.81 - 7.87 (2H, m), 8.27 (1H, d, J = 2.6 Hz).

Preparatively example 40

N-(3-Formyl-4-methoxybenzyl)phthalimide

< / BR>
N-(4-Methoxybenzyl)phthalimide (14.00 g) was dissolved in 100 ml triperoxonane acid and parts added 8.09 g of hexamethylenetetramine. The resulting mixture was stirred at room temperature for 1 h, boiled with back hole is H and the insoluble material was filtered. The organic phase is washed with water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and the solvent is kept in vacuum. The obtained solid substance and the above-mentioned insoluble material were combined and washed with ethyl acetate and received 13.13 g specified in the title compound as slightly yellow powder, yield 85%.

So pl. 177-179oC.

Mass: 296 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 4.82 (2H, s), 6.95 (1H, d, J = 8.6 Hz), 7.64 (1H, DD, J = 8.6, 2.4 Hz), 7.69 - 7.74 (2H, m), 7.82 - 7.87 (3H, m), 10.41 (IH, s).

Preparative example 41

N-(3-Hydroxyimino-4-methoxybenzyl)phthalimide

< / BR>
N-(3-Formyl-4-methoxybenzyl)phthalimide (12.50 g) suspended in 200 ml of tetrahydrofuran was added 3.24 g of hydroxylamine hydrochloride, 7.64 g of sodium acetate and 30 ml of water. The mixture was stirred 30 min at 60oC and concentrated in vacuum. The precipitate was separated by filtration, washed with ether, and received 11.51 g specified in the title compound as slightly yellow powder, yield 88%.

So pl. 214-217oC.

Mass: 311 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.25 (1H, s), 3.82 (3H, s), 4.79 (2H, s), 6.85 (1H, d, J = 8.6 Hz), 7.44 (1H, DD, J = 8.6, 2.4 Hz), 7.66 - 7.72 (2H, m), 7.78 (1H, d, J = 2.4 Hz), 7.80 - 7.86 (2H, m)Mino-4-methoxybenzyl)phthalimide (11.00 g) suspended in 120 ml of xylene was added 3.68 ml of acetic anhydride. The mixture was boiled under reflux for 14 h and left to cool. The formed precipitate was separated by filtration, washed with xylene and received 9.11 g specified in the title compound as a white powder, yield 88%.

So pl. 205-209oC.

Mass: 293 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 4.78 (2H, s), 6.92 (1H, m), 7.62 - 7.66 (2H, m), 7.70 - 7.76 (2H, m), 7.83 - 7.88 (2H, m).

Preparative example 43

Hydrochloride 4-chloro-3-methoxybenzylamine

< / BR>
N-(4-Chloro-3-methoxybenzyl)phthalimide (8.40 g) and hydrazine monohydrate (1.49 ml) was added to 100 ml of ethanol. The mixture was boiled under reflux for 1.5 h, the insoluble material was separated by filtration, the filtrate was concentrated in vacuo and added 1H hydrochloric acid. Insoluble material was separated by filtration. The aqueous phase was washed with ether, podslushivaet concentrated aqueous ammonia and extracted with ether. The ether phase was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was dissolved in ethyl acetate and was added 4H hydrogen chloride/ethyl acetate. The formed precipitate was separated by filtration, washed with ethyl acetate and received 4.83 g specified in the title compound as a white powder, yield 83%.

Preparative example 44

The dihydrochloride of 5-amino-2-methoxypyridine

< / BR>
Specified in the title compound was obtained as in Preparative example 36, in the form of a white powder, yield 58%.

So pl. 165oC (decomp.).

Mass: 139 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

3.87 (3H, s), 3.98 (2H, K, J = 5.9 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.94 (1H, DD, J = 8.4, 2.4 Hz), 8.14 (1H, m), 8.29 (1H, d, J = 2.4 Hz), 8.58 (2H, sh).

Preparatively example 45

3-Cyano-4-methoxybenzylamine

< / BR>
N-(3-Cyano - 4-methoxybenzyl)phthalimide (8.60 g) and hydrazine monohydrate (1.71 ml) was dissolved in a mixed solvent containing 100 ml of ethanol and 100 ml of 1,4-dioxane. The resulting solution was boiled under reflux for 2 hours, the insoluble material was separated by filtration, the filtrate was concentrated in vacuo and added 1H sodium hydroxide. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous potassium carbonate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: dichloromethane/methanol/concentrated aqueous ammonia (100:10:1)) and got 4.24 g is specified in the header is connected to the Hz, CDCl3) :

1.40 (2H, s), 3.84 (2H, s), 3.92 (3H, s), 6.94 (1H, d, J = 8.4 Hz), 7.49 - 7.54 (2H, m).

Example 1

Hydrochloride of 2-amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
(1) 2-Nitro-5-chlorobenzoyl acid (5.0 g), thionyl chloride (3 ml) and 50 ml of benzene was boiled under reflux for 4 h and the mixture was concentrated to obtain acylchlorides. Acylchlorides was added to a solution of 3.2 ml of piperacillin and 5 ml of triethylamine in THF to the reaction. The reaction mixture was treated in the usual way, the product is recrystallized from ethyl acetate and obtained 5.8 g of 5-chloro-2-nitro-N-(3,4-methylenedioxybenzyl)benzamide.

NMR (CDCl3) :

4.56 (2H, d, J = 5.7 Hz), 5.97 (2H, s + 1H, sh.s), 6.80 (1H, d, J = 7.9 Hz), 6.85 (1H, DD, J = 7.9 Hz, 1.8 Hz), 6.90 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 2.2 Hz), 7.54 (1H, DD, J = 8.6 Hz, 2.2 Hz), 8.05 (1H, d, J = 8.6 Hz).

(2) 5-Chloro-2-nitro-N-(3,4-methylenedioxybenzyl)benzamide (620 mg), acetic acid (1 ml), water (1 ml) and ethanol (20 ml) was boiled under reflux was added 1.0 g of iron powder in portions while stirring. The mixture was boiled under reflux for 1 h and filtered hot to separate the brown insoluble material. The filtrate was concentrated and added ethanol. The mixture was heated for dissolution. Portions were added concentrically seed crystallization. The mixture was cooled and the crystals were isolated by filtration. The crystals were washed with ethanol and ether, dried and got 520 mg specified in the connection header.

So pl. 225-228oC (decomp.).

Mass: 305 (M - HCl H+).

NMR (400 MHz, DMSO-d6) :

4.32 (2H, d, J 5.6 Hz), 5.07 (3H, CL), 5.98 (2H, s), 6.78 (IH, DD, J = 8.0, 1.2 Hz), 6.84 (1H, d, J = 8.0 Hz), 6.85 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 1.2 Hz), 7.23 (1H, DD, J = 8.8, 2.4 Hz), 7.65 (1H, d, J = 2.4 Hz), 8.94 (1H, t, J = 5.6 Hz).

Example 2

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
2-Amino-5-chlorobenzoyl acid (10.0 g), 3,4-methylenedioxyaniline (7.62 ml), 1-(3-dimethylaminopropyl)-3 - ethyl-carbodiimide (11.74 g), N-hydroxybenzotriazole (8.27 g) and triethylamine (8.53 ml) was added to 200 ml of acetonitrile. The mixture was stirred at room temperature for 20 h, concentrated and added water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed sequentially 1H hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous solution of salt, dried over anhydrous magnesium sulfate and concentrated. The obtained solid was washed with ethanol and received 14.13 g specified in the connection header in the form of slightly orange powder, yield 80%.

Example 3

2-Amino-5-bromo-N-(3,4-methylenedioxybenzyl)benzamide.

< / BR>
Got pale cream needles, yield 92%.

So pl. 157-158oC

(pale orange-yellow needles from ethanol).

NMR (400 MHz, CDCl3) :

4.49 (d, J = 5.7 Hz, 2H), 5.57 (W, 2H), 5.97 (s, 2H), 6.20 (W, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.78 (DD, J = 0.7, 7.9 Hz, 1H), 6.81 (DD, J = 1.3, 7.9 Hz, 1H), 6.84 (DD, J = 0.7, 1.3 Hz, 1H), 7.27 (DD, J = 2.2, 8.8 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H).

Example 4

2-Amino-5-chloro-N-methyl-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as pale yellow powder, yield 91%

So pl. 122-124oC

(slightly yellow needles from aqueous ethanol

NMR (400 MHz, CDCl3) :

2.9 (s, 3H), 4.34 (s, 2H), 4.55 (W, 2H), 5.96 (s, 2H), 6.60 - 6.88 (m, 4H ), 6.66 (d, J = 8.6 Hz), 6.77 (d, J = 7.7 Hz), 7.06 - 7,13 (m, 2H).

Example 5

2-Amino-5-dimethylaminomethyl-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Methyl-2-amino-5-dimethylaminomethyl)benzoate (10.93 g) was dissolved in 100 ml of ethanol and added 63.1 ml 1H sodium hydroxide. The mixture was stirred at room temperature for 14 h, then 4 h at 100oC and added 63.1 ml 1H Sol which it was dissolved in 270 ml of acetonitrile, containing 50% water, and added 7.19 ml of 3,4-methylenedioxyphenethylamine, at 11.93 g of 1,3-dicyclohexylcarbodiimide and 7.81 g of N-hydroxybenzotriazole. The mixture was stirred 14 h at 70oC was filtered and the insoluble material. To the filtrate was added a saturated aqueous solution of sodium bicarbonate and was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and the solvent drove away. The residue was purified column chromatography on silica gel (solvent; dichloromethane/methanol/concentrated aqueous ammonia 1000:100:3) and received 15.45 g specified in the title compounds as a pale yellow solid, yield 90%.

NMR (400 MHz, CDCl3) : 2.26 (s, 6H), 3.35 (s, 2H), 4.49 (d, J = 5.9 Hz, 2H), 5.58 (W, 2H), 5.95 (s, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.70 (W, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.82 (DD, J = 1.6, 7.9 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 7.10 (DD, J= 1.6, 8.4 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H).

Example 6

Ethyl-1-[[4-chloro-2-(3,4-methylenedioxybenzyl)carbarnoyl] phenyl]- carbarnoyl] piperidine-4-carboxylate

< / BR>
Ethyl-1-[(2-carboxy-4-chlorophenyl)carbarnoyl] piperidine-4 - carboxylate (850 mg), 3,4-methylenedioxyaniline (0.45 ml), 1,3-dicyclohexylcarbodiimide (0.54 g), N-gidroksibenzotriazola (0.36 g) and 4-dimethylaminopyridine (catalytic amount) was added to 10 ml Dimethylol was separated by filtration, separated organic phase was washed its 1H hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous solution of salt, dried over anhydrous magnesium sulfate and the solvent drove away. The residue was purified column chromatography on silica gel (solvent: dichloromethane/methanol (30:1)) and received 1.10 g specified in the title compound as a white solid, yield 99%.

So pl. 153 to 155oC

(white needles from aqueous ethanol).

NMR (400 MHz, CDCl3) :

1.27 (t, J = 7.1 Hz, 3H), 1.75 (m, 2H), 1.99 (m, 2H), 2.52 (m, 1H), 3.04 (m, 2H), 4.08 (m, 2H), 4.16 (K, J = 7.1 Hz, 2H), 4.47 (d, J = 5.7 Hz), 5.97 (s, 2H), 6.79 (DD, J = 0.5, 7.9 Hz, 1H), 6.82 (DD, J = 1.5, 7.9 Hz, 1H), 6.86 (DD, J = 0.5, 1.5 Hz, 1H), 7.01 (t, J = 5.7 Hz, 1H), 7.24 (DD, J = 2.6, 9.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 10.57 (s, 1H).

Example 7

Ethyl-1-[[4-chloro-2-(3-chloro-4-methoxybenzyl)carbarnoyl] phenyl] - carbarnoyl] piperidine-4-carboxylate

< / BR>
A white powder was obtained with the yield 96%

So pl. 131-132oC

(white needles from EtOH).

NMR (400 MHz, DCl3) ;

1.27 (t, J = 7.1 Hz, 3H), 1.75 (m, 2H), 1.99 (m, 2H), 2.52 (m, 1H), 3.05 (m, 1H), 3.91 (s, 3H), 4.08 (m, 2H), 4.16 (K, J = 7.1 Hz, 2H), 4.48 (d, J = 5.7 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 5.7 Hz, 1H), 7.22 (DD, J = 2.4, 9.0 Hz, 1H), 7.22 (DD, J = 2.2, 8.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 9.0 uridin-4-carboxylate

< / BR>
A white powder was obtained with the yield of 96%.

So pl. 120-122oC

(white needles from aqueous ethanol).

NMR (400 MHz, CDCl3) :

1.27 (t, J = 7.1 Hz, 3H), 1.75 (m, 2H), 2.00 (m, 2H), 2.52 (m, 1H), 3.05 (m, 2H), 3.22 (t, J = 8.8 Hz, 2H), 4.10 (m, 2H), 4.16 (K, J = 7.1 Hz, 2H), 4.49 (d, J = 5.5 Hz, 2H), 4.59 (t, J = 8.8 Hz, 2H), 6.69 (t, J = 5.5 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 7.09 (DD, J = 1.8, 8.1 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.28 (DD, J = 2.4, 9.2 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 10.68 (s, 1H).

Example 9

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(isonicotinoyl) benzamide

< / BR>
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (1.0 g) was dissolved in 10 ml of pyridine was added 0.64 g of the hydrochloride of isonicotinohydrazide. The mixture was stirred at room temperature for 1 h, was added ice water and was extracted with ethyl acetate. The organic phase was washed for 1H. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and a saturated aqueous saline solution, successively, dried over anhydrous magnesium sulfate and drove the solvent. The residue was purified column chromatography on silica gel (solvent; dichloromethane/methanol (50:1)), recrystallized from ethyl acetate and got 630 mg specified in the title compound as white needles, yield 47%.

So pl. 204-205oC 61.55, H 3.94, N, 10.25;

found (%): C at 61.58, H 3.99, N 10.16.

NMR (400 MHz, DMSO-d6) :

4.44 (d, J = 5.9 Hz, 2H), 5.99 (s, 2H), 6.85 (DD, J = 1.5, 8.1 Hz, 1H), 6.87 (DD, J = 0.5, 8.1 Hz, 1H), 6.96 (DD, J = 0.5, 1.5 Hz, 1H), 7.66 (DD, J = 2.4, 9.0 Hz, 1H), 7.78 - 7.82 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 8.82 - 8.87 (m, (2H), 9.49 (t, J = 5.9 Hz, 1H), 12.62 (s, 1H).

Example 10

5-Chloro-2-(nicotineamide)-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Got white needles, yield 81%.

So pl. 152-154oC

(ethyl acetate).

Mass: (FAB) 410 (MH+).

Elemental analysis:

calculated (%).: C 61.55, H 3.94, N, 10.25;

found (percent): C, 61.42, H 3.89, N, 10.23.

NMR (400 MHz, CDCl3) :

4.54 (d, J = 5.5 Hz, 2H), 5.96 (s, 2H) 6.79 (DD, J = 0.5, 7.9 Hz, 1H), 6.82 (W, 1H), 6.82 (DD, J = 1.6, 7.9 Hz), 6.85 (DD, J = 0.5, 1.6 Hz, 1H), 7.43 - 7.48 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 8.28 (DDD, J = 1.6, 2.4, 8.1 Hz, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.78 (DD, J = 1.6, 4.8 Hz, 1H), 9.26 (DD, J = 0.4, 2.4 Hz, 1H), 12.28 (s, 1H).

Example 11

5-Chloro-2-chloroacetamido-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
2-Amino-5-chloro-N-(3,4 - methylenedioxybenzyl)benzamide (5.00 g) was dissolved in 60 ml of tetrahydrofuran was added 2.52 ml of triethylamine. The mixture was stirred under ice cooling. To the resulting mixture was added dropwise chlorocatechol (1.44 ml) so that the temperature of the mixture did not exceed 10oC. Cheroy, saturated aqueous sodium hydrogen carbonate and a saturated aqueous saline solution, successively, dried over anhydrous magnesium sulfate and drove the solvent. The obtained solid substance was washed with a small amount of ethyl acetate and received 5.37 g specified in the title compound as slightly yellow powder, yield 86%.

So pl. 186-187oC

(white needles from ethanol).

NMR (400 MHZ, CDCl3) :

4.18 (s, 2H), 4.52 (d, J = 5.5 Hz, 2H), 5.98 (s, 2H), 6.49 (W, 1H), 6.79 (DD, J = 0.5, 7.9 Hz, 1H), 6.82 (DD, J = 1.6, 7.9 Hz, 1H), 6.85 (DD, J = 0.5, 1.6 Hz, 1H), 7.42 (DD, J = 2.6, 8.6 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 11.75 (W, 1H).

Example 12

2-Acetamido-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamidoxime (100 mg) was injected into the reaction with 40 ál acetylchloride in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was extracted with ethyl acetate and water, the product was recrystallized from a mixture of ethyl acetate/hexane and obtained 85 mg of the target compound with a yield of 84%.

So pl. 187-188oC

(decomp.).

Mass: 347 (MH+).

NMR (400 MHz, CDCl3) :

2.21 (3H, s), 4.51 (2H, d, J = 5.5 Hz), 5.98 (2H, s), 6.41 (1H, broad s), 6.81 (2H, s), 6.84 (1H, s), 7.38 - 7 is Beniamino - benzamide

< / BR>
Hydrochloride of 2-amino-5-chloro-N-(3,4-methylenedioxybenzyl)- benzamide (100 mg) was injected into the reaction with 50 μl of phenylcarbamate in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was extracted with ethyl acetate and water and subjected to recrystallization from a mixture of ethyl acetate/hexane and was obtained 110 mg of 5-chloro-N-(3,4-methylenedioxybenzyl)-2-phenoxycarbonylamino, yield 88%.

So pl. 149-150oC.

NMR (400 MHz, CDCl3) :

4.54 (2H, d, J = 5.6 Hz), 5.98 (2H, s), 6.41 (1H, s), 6.80 - 6.87 (3H, m), 7.17 - 7.26 (2H, m), 7.37 - 7.46 (5H, m), 8.38 (1H, d, J = 9.2 Hz), at 10.82 (1H, s).

Example 14

5-Chloro-2-[[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl] amino]- N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (1.5 g) was dissolved in 15 ml of pyridine and cooled with ice. Was added dropwise a solution of 2.28 g of TRANS-4-ethoxycarbonylmethoxy-carbonylchloride in 5 ml of dichloromethane, so that the reaction temperature did not exceed 10oC. the Mixture was stirred for 2 hours, added with ice water and was extracted with ethyl acetate. The organic phase was washed for 1H. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and a saturated aqueous saline solution, successively, dried over bezwaar: n-hexane/ethyl acetate (3:1)), was led from the ether and received 1.30 g specified in the title compounds as colorless prisms, yield 55%.

So pl. 156-158oC

(white needles from aqueous ethanol).

NMR (400 MHz, CDCl3) :

1.26 (t, J = 7.1 Hz, 3H), 1.43 - 1.62 (m, 4H), 2.06 2.14 (m, 4H), 2.22 - 2.36 (m, 2H), 4.13 (K, J = 7.1 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 5.97 (s, 2H), 6.70 (t, J = 5.7 Hz, 1H), 6.76 - 6.85 (m, 3H), 7.32 (DD, J = 2.4, 9.0 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 9.0, 1H), 11.02 (s, 1H).

Example 15

5-Bromo-2-[[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl] amino]- N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
A white powder was obtained with the yield 79%.

So pl. 147-149oC

(white needles of n-Hex/EtOAc).

NMR (400 MHz, CDCl3) :

1.26 (t, J = 7.1 Hz, 3H), 1.44 - 1.53 (m, 4H), 2.07 - 2.15 (m, 4H), 2.25 - 2.37 (m, 2H), 4.13 (K, J = 7.1 Hz, 2H), 4.51 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.51 (t like, J = 5 Hz, 1H), 6.78 - 6.83 (m, 2H), 6.84 (d, J = 0.9 Hz, 1H), 7.53 (DD, J = 2.4, 8.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H).

Example 16

5-Chloro-2-[[3-(etoxycarbonyl)acryloyl] amino] -N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
So pl. 181-184oC

(from ethyl acetate).

Mass: (FAB) 431 (MH+).

Elemental analysis:

calculated (%): C, 58.54, H 4.44, N 6.50;

found (percent): C, 58.44, H 4.41, N 6.49.

NMR (400 MHz, CDCl3) :

1.35 (t, J = 7.1 H), 8.69 (d, J = 9.7 Hz, 1H), 11.57 (s, 1H).

Example 17

5-Chloro-2-[[5-(etoxycarbonyl)valeryl] amino] - N-(3,4-methylene-dioxybenzene)benzamide

< / BR>
White needles was obtained with the yield of 54%.

So pl. 154-156oC

(white needles from aqueous EtOH).

NMR (400 MHz, CDCl3) :

1.25 (t, J = 7.1 Hz, 3H), 1.67 - 1.81 (m, 4H), 2.35 (t, J = 7.3 Hz, 2H), 2.43 (t, J - 7.0 Hz, 2H), 4.13 (J = 7.1 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.52 (t, J = 5.7 Hz), 6.75 - 6.87 (m, 3H), 7.37 - 7.42 (m, 2H), 8.57 (d, J = 9.3 Hz, 1H), 10.96 (c, 1H).

Example 18

5-Chloro-2-[[4-(methoxycarbonyl)benzoyl] amino] -N- (3,4-methylenedioxybenzyl)benzamide

< / BR>
Slightly yellow powder was obtained with the yield 73%.

So pl. 208-210oC

(white needles from aqueous ethanol).

NMR (400 MHz, DMSO-d6) :

3.90 (s, 3H), 4.42 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.83 (DD, J = 1.5, 7.9 Hz, 1H), 6.86 (DD, J = 0.5, 7.9 Hz), 6.95 (d, J = 0.5 Hz, 1H), 7.66 (DD, J = 2.6, 9.0 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.99 - 8.05 (m, 2H), 8.11 - 8.16 (m, 2H), 8.61 (d, J = 9.0 Hz, 1H), 9.47 (t, J = 5.7 Hz), 12.50 (s, 1H).

Example 19

5-Chloro-2-[(cyclohexylcarbonyl)amino] -N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
White needles was obtained with the yield 44%

So pl. 141-142oC

(from ether).

Mass: (FAB) 415 (MH+).

Elemental analysis:

calculated (%): C, 63.69, H 5.59, N, 6.75;

found (%): C at 63.47, H 5.60, N, 6.65.d, J = 5.5 Hz, 2H), 6.54 (PCs, 1H), 6.77 - 6.83 (m, 2H), 6.84 (m, 1H), 7.37 (DD, J = 2.2, 8.8 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 10.91 (s, 1H).

Example 20

5-Chloro-2-[(1-methylpiperidin-4-carbonyl)amino] -N-(3,4 - methylenedioxybenzyl)basamid

< / BR>
Slightly yellow needles were obtained with the yield of 13%.

So pl. 177-178oC

(EtOAc).

Mass: (FAB) 43 (MH+).

Elemental analysis:

calculated (%): C, 61.47, H 5.63, N, 9.77;

found (percent): C, 61.11, H 5.62, N 9.70.

NMR (400 MHz, CDCl3) :

1.80 - 1.92 (m, 2H), 1.94 - 2.06 (m, 4H), 2.70 (m, 1H), 2.29 (s, 3H), 2.88 - 2.98 (m, 2H), 4.51 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.52 (W, 1H), 6.77 - 6.86 (m, 3H), 7.39 (DD, J = 2.4, 9.7 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 9.7 Hz, 1H), 11.05 (s, 1H).

Example 21

5-Dimethylaminomethyl-2-[[4-(methoxycarbonyl)benzoyl] amino] - N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
A white powder was obtained with the yield of 50%.

So pl. 171-174oC

(white needles from water EtO).

NMR (400 MHz, CDCl3) :

2.24 (s, 6H), 3.40 (s, 2H), 3.96 (s, 3H), 4.54 (d, J = 5.7 Hz, 2H), 5.96 (s, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.83 (DD, J = 1.5, 7.9 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 6.88 (W, 1H), 7.42 (DD, J = 1.8, 8.4 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 8.08 - 8.13 (m, 2H), 8.15 - 8.21 (m, 2H), 8.76 (d, J = 8.4 Hz, 1H), 12.36 (s, 1H).

Example 22

5-Dimethylaminomethyl-2-[[TRANS-4-(etoxycarbonyl)- cyclohexanecarbonyl] amino]-N-(3,4-methylenedi the>NMR (400 MHz, CDCl3) :

1.25 (t, J = 7.1 Hz, 3H), 1.43 - 1.64 (m, 4H), 2.05 - 2.13 (m, 4H), 2.20 (s, 6H), 2.24 - 2.35 (m, 2H), 3.35 (s, 2H), 4.12 (K, J = 7.1 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 5.95 (s, 2H), 6.77 (DD, J = 0.5, 7.9 Hz, 1H), 6.80 (DD, J = 1.1, 7.9 Hz, 1H), 6.84 (DD, J = 0.5, 1.1 Hz), 6.86 (t, J = 5.7 Hz, 1H), 7.32 (DD, J = 1.8, 8.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 11.18 (s, 1H).

Example 23

5-Chloro-2-[[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl] - amino] -N-methyl-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
A white powder was obtained with the yield of 82%.

So pl. 153 to 155oC

(white needles from aqueous EtOH).

NMR (400 MHz, CDCl3) :

1.27 (t, J = 7.1 Hz, 3H), 1.41 - 1.62 (m, 4H), 1.96 - 2.35 (m, 6H), 2.88 - 3.08 (W, 3H), 4.14 (K, J = 7.1 Hz, 2H), 4.45, 4.62 (W, total 2H), 5.98 (W s, 2H,), 6.45 - 6.59, 6.71 - 6.93 ( W, total 3H), 7.24 (W m, 1H), 7.36 (DD, J = 2.4, 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.80 - 9.01 (W, 1H).

Example 24

5-Chloro-2-(4-hydroxypiperidine)acetamido-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
5-Chloro-2-chloroacetamido-N-(3,4-methylenedioxybenzyl)benzamide (570 mg) was dissolved in 5 ml of N,N-dimethylformamide, was added 450 mg of 4-hydroxypiperidine, 620 mg of potassium carbonate and a catalytic amount of Tetra-(n-butyl)AMMONOIDEA. The resulting mixture was stirred at room temperature for 1 h and then added water. The resulting mixture was extracted with ethyl acetate. The organic phase is good was purified column chromatography on silica gel (solvent: dichloromethane/methanol (30:1) and recrystallized from a mixture of ethyl acetate/n-hexane and was obtained a white powder, yield 84%.

So pl. 149-152oC

(ethyl acetate/n-hexane).

Mass: (FAB) 446 (MH+).

Elemental analysis:

calculated (%): C, 59.26, H 5.43, N 9.42;

found (percent): C, 59.28, H 5.51, N 9.37.

NMR (400 MHz, DMSO-d6) :

1.55 - 1.65 (m, 2H), 1.68 - 1.78 (m, 2H), 2.19 - 2.28 (m, 2H), 2.64 - 2.73 (m, 2H), 3.06 (s, 2H), 3.50 (m, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.58 (d, J = 3.7 Hz, 1H), 5.99 (s, 2H), 6.83 (DD, J = 1.3, 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 7.54 (DD, J = 2.6, 9.0 Hz, 1H), 7.73 (d, J = 2.6 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 9.23 (t, J = 5.9 Hz, 1H), 11.69 (s, 1H).

Example 25

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(piperidineacetate)- benzamide

< / BR>
A white powder was obtained with the yield 45%

So pl. 155-156oC

(ethyl acetate/n-hexane).

Mass: (FAB) 430 (MH+).

Elemental analysis (%):

calculated: C, 61.47, H 5.63, N, 9.77;

found: C, 61.38, H 5.61, N, 9.75.

NMR (400 MHz, DMSO-d6) :

1.32 - 1.42 (m, 2H), 1.52 - 1.51 (m, 4H), 2.35 - 2.45 (m, 4H), 3.03 (s, 2H), 4.38 (d, J = 5.9 Hz, 2H), 5.98 (s, 3H), 6.81 (DD, J = 1.3, 7.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 7.54 (DD, J = 2.6, 9.0 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 9.25 (t, J = 5.9 Hz, 1H), 11.70 (s, 1H).

Example 26

5-Chloro-2-[4-(etoxycarbonyl)piperidino] acetamido-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
White amorphous substance was obtained with a yield of 99%.

Example 27

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-[(4-methylpiperazine)- acetamido] benzamide

< / BR>
A white powder was obtained with the yield of 70%.

So pl. 162-164oC

(EtOAc/n-Hex).

Mass: (FAB) 445 (MH+).

Elemental analysis (%):

calculated: C, 59.39, H 5.66, N, 12.59;

found: C, 58.80, H 5.66, N, 12.45.

NMR (400 MHz, CDCl3) :

2.35 (s, 3H), 2.50 - 2.75 (m, 8H), 3.17 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 5.97 (s, 2H), 6.40 (W, 1H), 6.77 - 6.82 (m, 2H), 6.85 (m, 1H), 7.39 (DD, J = 2.0, 8.8 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 11.56 (W, 1H).

Example 28

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-[(3-oxopiperidine)- acetamido] benzamide

< / BR>
White flakes was obtained with the yield 52%

So pl. 202-203oC

(from aqueous ethanol).

Mass: (FAB) 445 (MH+).

Elemental analysis (%):

calculated: C 56.70, H 4.76, N, 12.59;

found: C, 56.65, H 4.78, N 12.56.

NMR (400 MHz, DMSO-d6) :

2.65 (t, J = 5.3 Hz, 2H), 3.10 (s, 2H), 3.21 (s, 2H), 3.23 - 3.30 (m, 2H), 4.36 (d, J = 5.7 Hz, 2H), 5.99 (s, 2H), 6.81 (DD, J = 1.6, 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 7.56 (DD, J = 2.6, 9.0 Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.83 (W s, 1H), 8.52 (grandiosity)benzamide

< / BR>
6-Chloro-1-[4-(etoxycarbonyl)butyl] -1,2-dihydro-4H-1,3 - benzoxazin-2,4-dione (3.50 g) was dissolved in 35 ml of dimethylformamide was added 0.13 g of 4-dimethylaminopyridine and 1.47 ml of 3,4-methylenedioxyphenethylamine. The mixture was stirred at room temperature for 1 h and added to ice water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed for 1H. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and a saturated aqueous saline solution, successively, dried over anhydrous magnesium sulfate and the solvent drove away. The obtained solid was washed with ethanol and received 3.35 g specified in the title compound as slightly yellow powder, yield 72%.

So pl. 89-91oC

(white needles from aqueous EtOH).

NMR (400 MHz, CDCl3) :

1.25 (t, J = 7.1 Hz, 3H), 1.65 - 1.80 (m, 4H), 2.35 (t, J = 7.0 Hz, 2H), 3.13 (m, 2H), 4.13 (K, J = 7.1 Hz, 2H), 4.46 (d, J = 5.7 Hz, 2H), 5.96 (s, 2H), 6.26 (W t, 1H), 6.60 (d, J = 9.0 Hz, 1H), 6.76 - 6.81 (m, 2H), 6.83 (m, 1H), 7.22 (DD, J = 2.4, 9.0 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.52 (W t, 1H).

Example 30

5-Chloro-2-[3-(etoxycarbonyl)propylamino] -N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
The pale yellow solid was obtained with the yield of 88%.

NMR (400 MHz, CDCl3) :

1.26 (t, J = 7.1 Hz, 3H), 1.97 (m, 2H), 2.42 (t, J = 7.3 Hz,Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.57 (m, 1H).

Example 31

5-Chloro-2-methylamino-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Grayish powder was obtained with the yield of 94%.

So pl. 152-154oC

(white needles from aqueous EtOH).

NMR (400 MHz, DMSO-d6) :

2.76 (d, J = 5.1 Hz, 3H), 4.31 (d, J = 5.9 Hz, 2H), 5.98 (s, 2H), 6.64 (d, J = 9.0 Hz, 1H), 6.73 (DD, J = 1.5, 7.9 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 7.31 (DD, J = 2.6, 9.0 Hz, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.74 (K, J = 5.1 Hz, 1H), 8.93 (t, J = 5.9 Hz, 1H).

Example 32

5-Chloro-2-(4-methoxycarbonylbenzyl)-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
Slightly yellow powder was obtained with the yield of 89%.

So pl. 156-158oC

(white needles from aqueous EtOH).

NMR (400 MHz, CDCl3) :

3.91 (s, 3H), 4.46 (d, J = 5.5 Hz, 2H), 4.50 (d, J = 5.5 Hz, 2H), 5.97 (s, 2H), 6.29 (W t, J = 5 Hz, 1H), 6.46 (d, J = 9.0 Hz, 1H), 6.79 (DD, J = 0.7, 7.9 Hz, 1H), 6.82 (DD, J = 1.5, 7.9 Hz), 6.85 (DD, J = 0.7, 1.5 Hz), 7.14 (DD, J = 2.6, 9.0 Hz), 7.31 (d, J = 2.6 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.97 - 8.02 (m, 2H), 8.16 (W t, J = 5 Hz, 1H).

Example 33

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(4-picolyl)aminobenzamide

< / BR>
A suspension of 60% sodium hydride in mineral oil (1.34 g) suspended in 50 ml of dimethylformamide and added in parts 3.0 g of 6-chloro-1,2-dihydro-4H-1,3-benzoxazine. The resulting mixture was stirred at room the 0oC, stirred 24 h and left to cool. To the mixture was added 3,4-methylenedioxyphenethylamine (2.1 ml) and 4-dimethylaminopyridine (0.19 g). The resulting mixture was stirred at room temperature for 1 h and added to ice water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and the solvent drove away. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (1:1 to 1:2) and recrystallized from ethanol and obtained 870 mg specified in the title compound as white needles, yield 14%.

So pl. 163-166oC.

Mass: (FAB) 396 (MH+).

Elemental analysis (%):

calculated: C, 63.72, H 4.58, N, 10.62;

found: C, 63.79, H 4.57, N, 10.62.

NMR (400 MHz, CDCl3) :

4.43 (d, J = 5.9 Hz, 2H), 4.51 (d, J = 5.7 Hz, 2H), 5.97 (s, 2H), 6.40 (m, 1H), 6.40 (d, J = 9.0 Hz, 1H), 6.79 (DD, J = 0.5, 7.9 Hz, 1H), 6.82 (DD, J = 1.5, 7.9 Hz, 1H), 6.85 (DD, J = 0.5, 1.5 Hz, 1H), 7.15 (DD, J = 2.4, 9.0 Hz, 1H), 7.24 - 7.27 (m, 2H), 7.33 (d, J = 2.4 Hz, 1H), 8.21 (t, J = 5.9 Hz, 1H), 8.52 - 8.55 (m, 2H).

Example 34

5-Chloro-2-[[TRANS-4-(etoxycarbonyl)cyclohexyl]methylamino]- N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
The pale yellow powder was obtained with a yield of 11%

So pl. 128-129oC

Example 35

2-[(4-Carboxybutyl)amino]-5-chloro-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (1.0 g) was dissolved in 10 ml of pyridine was added 0.41 g of glutaric anhydride. The mixture was stirred at room temperature for 20 h, concentrated, and added ethyl acetate. The resulting mixture was extracted with 1N. sodium hydroxide and was established in the aqueous phase pH 2. The precipitate was separated by filtration, recrystallized from aqueous ethanol and received 500 mg specified in the title compound as a white powder, yield 36%.

So pl. 154-155oC (aqueous ethanol).

Mass: (FAB) 419 (MH+).

Elemental analysis (%):

calculated: C, 57.35, H 4.57, N 6.69;

found: C, 57.17, H 4.56, N, 6.64.

NMR (400 MHz, DMSO-d6) :

1.80 (dt, J = 7.3, 7.5 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 2.38 (t, 7.5 Hz, 2H), 4.37 (d, J = 5.9 Hz, 2H), 5.99 (s, 2H), 6.82 (DD, J = 1.6, 7.9 Hz, 1H), 6.87 (DD, J = 0.4, 7.9 Hz, 1H), 6.93 (DD, J = 0.4, 1.6 Hz, 1H), 7.55 (DD, J = 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 9.30 (t, J = 5.9 Hz, 1H), 11.17 (s, 1H).

Example 36

So pl. 217 to 220oC (EtOH).

Mass: (FAB) 405 (MH+).

Elemental analysis (%):

calculated: C, 56.37, H 4.23, N, 6.92;

found: C, 56.24, H 4.25, N, 6.88.

NMR (400 MHz, DMSO-d6) :

2.48 - 2.60 (m, 4H), 4.38 (d, J = 5.9 Hz, 2H), 5.99 (c, 2H), 6.82 (DDD, J = 0.4, 1.7, 7.9 Hz, 1H), 6.87 (DD, J = 1.7, 7.9 Hz, 1H), 6.93 (DD, J = 0.4, 1.7 Hz, 1H), 7.55 (DD, J = 2.4, 9.0 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 9.31 (t, J = 5.9 Hz, 1H), 11.24 (s, 1H).

Example 37

2-[N-(4-Carboxybutyl)-N-methyl] amino-5-chloro-N'-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
White amorphous substance was obtained with the yield of 39%.

Mass: (FAB) 433 (MH+).

NMR (400 MHz, CDCl3) :

1.75 - 1.86 (m, 2H), 1.99 - 2.48 (m, 4H), 3.15, 3.22 (s, total 3H), 4.41 (DD, J = 5.7, 14.5 Hz, 1H), 4.46 (DD, J = 5.7, 14.5 Hz, 1H), 5.94 (s, 2H), 6.69, 7.04 (m, total 1H), 6.73 - 6.82 (m, 3H), 7.05, 7.12 (d, J = 8.4 Hz, total 1H), 7.40, 7.44 (DD, J = 2.4, 8.4 Hz, 1H), 7.47, 7.60 (d, J = 2.4 Hz, 1H).

Example 38

1-[[4-Chloro-2-[(3,4-methylenedioxybenzyl)carbarnoyl] phenyl] carbarnoyl]piperidine-4-carboxylic acid

< / BR>
Ethanol (100 ml), tetrahydrofuran (100 ml) and 1N. sodium hydroxide (65 ml) was added to 10.09 g of ethyl-1-[[4-chloro-2-[(3,4 - methylenedioxybenzyl)carbarnoyl] phenyl] carbarnoyl]piperidine-4 - carboxylate. The mixture was stirred at room temperature for 2 h and was added 100 ml of water. The resulting mixture of concentri sodium. Both aqueous phases were combined and set to pH 2 with concentrated hydrochloric acid. The precipitate was separated by filtration, recrystallized from aqueous ethanol and received 6.84 g specified in the title compound as white needles, yield 72%.

So pl. 263-264oC (EtOH).

Mass: (FAB) 460 (MH+).

Elemental analysis (%):

calculated: C, 57.46, H 4.82, N, 9.14;

found: C, 57.39, H 4.73, N, 9.09.

NMR (400 MHz, DMSO-d6) :

1.46 (m, 2H), 1.86 (m, 2H), 2.49 (m, 1H), 2.98 (m, 2H), 3.91 (m, 2H), 4.38 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.81 (DD, J = 1.5, 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 7.49 (DD, J = 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 9.35 (t, J = 5.7 Hz), 11.06 (s, 1H).

Example 39

2-(TRANS-4-Carboxyethylgermanium)-5-chloro-N- (3,4-methylenedioxybenzyl)benzamide

< / BR>
Ethanol (100 ml), tetrahydrofuran (100 ml) and 1N. sodium hydroxide (65 ml) was added to 10.0 g of 5-chloro-2-[TRANS-4-(etoxycarbonyl)- cyclohexanecarbonyl] amino-N-(3,4-methylenedioxybenzyl)benzamide. The resulting mixture was stirred at room temperature for 8 h and concentrated. The residue was dissolved in water and subjected to chromatography with reversed phase silica gel (solvent: mixture of water/methanol containing 30% water). Fractions were combined and concentrated to adelinaismali from aqueous ethanol and received 7.10 g specified in the title compound as white needles, a yield of 75%.

So pl. 228-230oC (from ethanol).

Mass: (FAB) 459 (MH+).

Elemental analysis (%):

calculated: C, 60.20, H 5.05, N, 6.10;

found: C, 59.95, H 5.11, N, 6.08.

NMR (400 MHz, DMSO-d6) :

1.31 - 1.48 (m, 4H), 1.87 - 2.03 (m, 4H), 2.13 - 2.29 (m, 2H), 4.38 (d, J = 5.7 Hz, 2H), 5.99 (s, 2H), 6.82 (DD, J = 1.6, 7.9 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 7.54 (DD, J = 2.6, 9.0 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 9.32 (t, J = 5.7 Hz, 1H), 11.19 (s, 1H).

Example 40

2-(5-Carboxyphenyl)amino-5-chloro-N-(3,4-methylenedioxybenzyl)- benzamide

< / BR>
White needles was obtained with the yield of 30%.

So pl. 197-199oC (from ethanol).

Mass: (FAB) 433 (MH+).

Elemental analysis (%):

calculated: C, 58.27, H 4.89, N 6.47;

found: C, 58.03, H 4.96, N 6.38.

NMR (400 MHz, DMSO-d6) :

1.49 - 1.63 (m, 4H), 2.23 (t, J = 7.3 Hz, 2H), 2.34 (t, J = 6.8 Hz, 2H), 4.37 (d, J = 5.7 Hz, 2H), 5.99 (s, 2H), 6.82 (DD, J = 1.6, 7.9 Hz, 1H), 6.87 (DD, J = 0.4, 7.9 Hz, 1H), 6.93 (DD, J = 0.4, 1.6 Hz, 1H), 7.55 (DD, J = 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 9.30 (t, J = 5.7 Hz, 1H), 11.15 (s, 1H).

Example 41

2-(4-Carboxybenzoyl)amino-5-chloro-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
White needles was obtained with the yield of 74%.

So pl. 260-262oC (from aqueous ethanol)

Mass: (FAB) 453 (MH+).

Element is:

4.42 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.83 (DD, J = 1.5, 7.9 Hz, 1H), 6.86 (DD, J = 0.5, 7.9 Hz, 1H), 6.95 (DD, J = 0.5, 1.5 Hz, 1H), 7.66 (DD, J = 2.4, 9.0 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.98 8.03 (m, 2H), 8.09 - 8.15 (m, 2H), at 8.62 (d, J = 9.0 Hz, 1H), 9.47 (t, J = 5.7 Hz, 1H), 12.50 (s, 1H).

Example 42

1-[[4-Chloro-2-[[(2,3-dihydrobenzofuran-5-yl)methyl] carbarnoyl] - phenyl] carbarnoyl]piperidine-4-carboxylic] acid

< / BR>
White needles was obtained with the yield 26%

So pl. 288-291oC

(aqueous EtOH).

Mass: (FAB) 458 (MH+).

Elemental analysis (%):

calculated: C, 60.33, H 5.28, N, 9.18;

found: C, 60.18, H 5.25, N, 9.16.

NMR (400 MHz, DMSO-d6) :

1.47 (m, 2H), 1.86 (m, 2H), 2.47 (m, 1H), 2.99 (m, 2H), 3.15 (t, J = 8.8 Hz, 2H), 3.91 (m, 2H), 4.38 (d, J = 5.9 Hz, 2H), 4.50 (t, J = 8.8 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 7.05 (DD, J = 1.8, 8.2 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 7.48 (DD, J = 2.6, 9.2 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 9.34 (t, J = 5.9 Hz, 1H), 11.12 (s, 1H).

Example 43

1-[[4-Chloro-2-(3-chloro-4-methoxybenzyl)carbarnoyl] phenyl] carbarnoyl]piperidine-4-carboxylic acid

< / BR>
White needles was obtained with the yield of 63%

So pl. 288-291oC

(aqueous EtOH).

Mass: (FAB) 480 (MH+).

Elemental analysis (%):

calculated: C, 55.01, H 4.83, N 8.75)

found: C, 54.80, H 4.81, N, 8.64.

NMR (400 MHz, DMSO-d6) :

1.47 (m, 2H), 1.86 (m, 2H), 2.46 (m, 1H), 2.99 (m, 2H), 3.83 (s, 31H), 8.31 (d, J = 9.0 Hz, 1H), 9.37 (t, J = 5.7 Hz), 11.02 (s, 1H).

Example 44

2-(3-Carboxybenzoyl)amino-5-chloro-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
White needles was obtained with the yield of 9%

So pl. 256-258oC (decomp.)

(ethanol).

Mass: (FAB) 403 (MH+).

Elemental analysis (%):

calculated: C, 56.66, H 3.75, N, 6.95;

found: C, 56.17, H 3.68, N 6.75.

NMR (400 MHz, DMSO-d6) :

4.38 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.64 (d, J = 15.4 Hz, 1H), 6.82 (DD, J = 1.5, 7.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 15.4 Hz, 1H), 7.60 (DD, J = 2.4, 8.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 9.29 (t, J = 5.7 Hz, 1H), 11.49 (s, 1H).

Example 45

5-Bromo-2-(TRANS-4-carboxylatomethyl)amino - N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
White needles was obtained with the yield of 74%.

So pl. 236-238oC

(white needles from aqueous EtOH).

NMR (406 MHz, DMSO-d6) :

1.31 - 1.47 (m, 4H), 1.85 - 2.03 (m, 4H), 2.14 - 2.30 (m, 2H), 4.38 (d, J = 5.9 Hz, 2H), 5.99 (s, 2H), 6.81 (DD, J = 1.5, 7.9 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 7.67 (DD, J = 2.4, 9.0 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 9.33 (t, J = 5.9 Hz, 1H), 11.20 (s, 1H), 12.09 (W, 1H).

Example 46

2-(TRANS-4-Carboxylatomethyl)amino-5-chloro-N - methyl-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
White prisms were obtained with the yield 78%(m, 4H), 1.66 - 2.01 (m, 4H), 2.10 - 2.42 (m, 2H), 2.67, 2.83 (s, total 3H), 4.22, 4.51 (s, total 2H), 6.00, 6.01 (s, total 2H), 6.62 - 6.67, 6.80 - 6.89 (m, total 2H), 6.77, 7.02 (s, total 1H), 7.35 - 7.57 (m, 3H), 9.57, 9.62 (s, total 1H), 12.08 (W, 1H).

Example 47

TRANS-4-[4-Chloro-2-(3,4-methylenedioxybenzyl)carbarnoyl] phenyl] aminomethyltransferase sodium

< / BR>
Ethanol (7 ml), tetrahydrofuran (7 ml) and 1N. sodium hydroxide (7 ml) was added to 800 mg of 5-chloro-2-[TRANS-4-(etoxycarbonyl)- cyclohexyl]methyl] amino-N-(3,4-methylenedioxybenzyl)benzamide and the mixture was stirred at room temperature for 17 h

The reaction mixture was concentrated and was purified column chromatography with reversed phase silica gel (solvent: 40% aqueous methanol). Fractions were combined and concentrated to dryness. The solid residue was washed with 2-propanol and got 780 mg specified in the title compound as slightly yellow powder, yield 98%.

So pl. 266-271oC (decomp.).

Mass: (FAB) 489 (M + Na)+, 467 (MH+).

NMR (400 MHz, DMSO-d6) :

0.85 - 1.00 (m, 2H), 1.13 - 1.28 (m, 2H), 1.44 (m, 1H), 1.69 - 1.80 (m, 2H), 1.80 - 1.92 (m, 2H), 2.85 2.97 (m, 2H), 4.32 (d, J = 5.5 Hz, 2H), 5.98 (s, 2H), 6.67 (d, J = 9.3 Hz, 1H), 6.78 (DD, J = 1.5, 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 7.26 (DD, J = 2.4, 9.3 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.97 (t, J = 5.5 Hz, 1H), 9.03 (t, J = 5.7 Hz, 1H).<>BR>
Slightly yellow powder was obtained with the yield 88%

So pl. > 300oC.

Mass: (FAB) 461 (MH+), 483 (M + Na)+).

NMR (400 MHz, DMSO-d6) :

4.33 (d, J = 5.7 Hz, 2H), 4.36 (d, J = 5.5 Hz, 2H), 5.99 (s, 2H), 6.63 (d, J = 9.0 Hz, 1H), 6.80 (DD, J = 1.5, 7.9 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.23 (DD, J = 2.6, 8.1 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 8.29 (t, J = 5.7 Hz, 1H), 9.03 (t, J = 5.5 Hz, 1H).

Example 49

4-[[4-Chloro-2-(3,4-methylenedioxybenzyl)carbarnoyl] phenyl] - aminobutyrate sodium

< / BR>
Slightly yellow powder was obtained with the yield of 35%.

Mass: (FAB) 435 (MH + Na+).

NMR (400 MHz, DMSO-d6) :

1.71 (m, 2H), 1.98 (m, 2H), 3.06 (m, 2H), 4.32 (d, J = 4.4 Hz, 2H), 5.98 (s, 2H), 6.72 (d, J = 9.0 Hz, 1H), 6.79 (DD, J = 1.1, 7.9 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 1.1 Hz, 1H), 7.25 (DD, J = 2.4, 9.0 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.86 (t, J = 4.4 Hz, 1H), 9.00 (d, J = 5.5 Hz).

Example 50

5-[[4-Chloro-2-(3,4-methylenedioxybenzyl)carbarnoyl] phenyl] - aminovaleric sodium

< / BR>
Slightly yellow powder was obtained with the yield of 41%.

Mass: (FAB) 449 (M + Na)+).

NMR (400 MHz, DMSO-d6) :

1.48 - 1.60 (m, 4H), 1.88 - 1.98 (m, 2H), 2.99 -3.08 (m, 2H), 4.32 (d, J = 5.3 Hz, 2H), 5.97 (s, 2H), 6.66 (d, J = 9.0 Hz, 1H), 6.79 (DD, J = 1.5, 7.9 Hz, 1H), 6.85 (d, J = 7.9 Hz), 6.89 (d, J = 1.5 Hz, 1H), 7.27 (DD, J = 2.4, 9.0 Hz), 7.67 (d, J = 2.4 Hz, 1H), 7.87 (t, J = 5.3 Hz, 1H), 9.04 is peridin-4-carboxylate sodium

< / BR>
A white powder was obtained with the yield 76%

So pl. 244-249oC (decomp.).

Mass: (FAB) 518 (M + Na)+), 496 (MH+).

NMR (400 MHz, DMSO-d6) :

1.68 - 1.85 (m, 4H), 2.05 - 2.16 (m, 2H), 2.67 - 2.77 (m, 2H), 3.01 (c, 2H), 3.42 (W, 1H), 4.38 (W, s, 2H), 5.98 (s, 2H), 6.85 (DD, J = 1.3, 8.1 Hz, 1H), 6.87 (DD, J = 0.7, 8.1 Hz, 1H), 6.93 (d, J = 0.7 Hz, 1H), 7.52 (DD, J = 2.6, 9.0 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H), 9.38 (W, 1H), 11.59 (W, 1H).

Example 52

4-[[[4-Dimethylaminomethyl-2-(3,4-methylenedioxybenzyl)carbarnoyl] phenyl] carbarnoyl]sodium benzoate

< / BR>
A white powder was obtained with the yield of 48%.

So pl. 280oC (decomp.).

NMR (400 MHz, DMSO-d6) :

2.16 (s, 6H), 3.38 (s, 2H), 4.33 (d, J = 4.9 Hz, 2H), 5.98 (s, 2H), 6.82 - 6.88 (m, 2H), 6.95 (s, 1H), 7.48 (DD, J = 0.5, 8.4 Hz, 1H), 7.92 (d, J = 0.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.1 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 9.45 (W, 1H), 12.42 (s, 1H).

Example 53

2-Amino-5-bromo-4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
2-Amino-5-bromo-4-methoxybenzoic acid (1.50 g), piperacillin (0.84 ml), the hydrochloride of 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide (1.29 g), 1-hydroxybenzotriazol (0.91 g) and triethylamine (0.93 ml) was added to 20 ml of N, N-dimethylformamide. The mixture was stirred at room temperature for 20 h and was added to the water. The precipitate was separated by filtration and recip is 378 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.85 (3H, s), 4.46 (2H, d, J = 5.7 Hz), 5.81 (2H, s), 5.95 (2H, s), 6.15 (1H, s), 6.15 (1H, m), 6.77 (1H, DD, J = 7.9, 0.5 Hz), 6.79 (IH, DD, J = 7.9, 2.2 Hz), 6.83 (1H, DD, J = 2.2, 0.5 Hz), 7.44 (1H, s).

Example 54

2-Amino-5-bromo-M-(3-chloro-4-methoxybenzyl)-4-methoxybenzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of slightly orange powder, yield 100%.

So pl. 146-148oC.

Mass: 400 (MH+).

NMR (400 MHz, CDCl3) :

3.85 (3H, s), 3.89 (3H, s), 4.47 (2H, d, J = 5.7 Hz), 5.81 (2H, s), 6.15 (1H, s), 6.23 (1H, t, J = 5.7 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.19 (1H, DD, J = 8.4, 2.2 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.45 (1H, s).

Example 55

2-Amino-5-chloro-N-(3-chloro-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of weakly-buff powder, yield 93%.

So pl. 176-178oC.

Mass: 324 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 4.50 (2H, d, J = 5.7 Hz), 5.54 (2H, s), 6.28 (1H, s), 6.63 (1H, d, J = 8.8 Hz), 6.90 (1H, d, J = 8.4 Hz), 7.15 (1H, DD, J = 8.4, 2.4 Hz), 7.21 (1H, DD, J = 8.4, 2.2 Hz), 7.27 (1H, d, J = 2.4 Hz), 7.36 (1H, d, J = 2.2 Hz).

Example 56

2-Amino-5-chloro-N-[(2-methoxy-5-pyridyl)methyl]benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a white p ) :

3.94 (3H, s), 4.52 (2H, d, J = 5.7 Hz), 5.54 (2H, s), 6.22 (1H, s), 6.63 (1H, d, J = 8.8 Hz), 6.75 (1H, d, J = 8.4 Hz), 7.15 (1H, DD, J = 8.8, 2.4 Hz), 7.25 (1H, DD, J = 2.4 Hz), 7.60 (1H, DD, J = 8.4, 2.6 Hz), 8.14 (1H, d, J = 2.6 Hz).

Example 57

2-Amino-N-(3,4-methylenedioxybenzyl)-5-cryptomaterial

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a slightly yellow powder, yield 100%.

So pl. 150-153oC.

Mass: 354 (M+).

1H-NMR (400 MHz, CDCl3) :

4.50 (2H, d, J = 5.7 Hz), 5.59 (2H, s), 5.96 (2H, s), 6.19 (1H, s), 6.66 (1H, d, J = 8.8 Hz), 6.78 (1H, DD, J = 7.9, 0.5 Hz), 6.81 (1H, DD, J = 7.9, 1.5 Hz), 6.85 (1H, DD, J = 1.5, 0.5 Hz), 7.09 (1H, m), 7.14 (1H, d, J = 2.6 Hz).

Example 58

2-Amino-5-chloro-N-(3-cyano-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a white powder, yield 100%.

So pl. 174-177oC

Mass: 315 (M+).

1H-NMR (400 MHz, CDCl3) :

3.89 (3H, s), 4.36 (2H, d, J = 5.7 Hz), 6.59 (2H, s), 6.73 (1H, d, J = 8.8 Hz), 7.17 (1H, DD, J = 8.8, 2.6 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.58 -7.66 (3H, m), 8.89 (1H, t, J = 5.7 Hz).

Example 59

2-Amino-5-bromo-N-(3-chloro-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of slightly orange powder, yield 98%.

So pl. 168-170oC.

Wt is d, J = 8.8 Hz), 6.90 (1H, d, J = 8.4 Hz), 7.20 (1H, DD, J = 8.4, 2.2 Hz), 7.27 (1H, DD, J = 8.8, 2.2 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz).

Example 60

2-Amino-5-chloro-N-(4-chloro-3-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of weakly-buff powder, yield 99%.

So pl. 162-163oC.

Mass: 324 (M+).

H-NMR (400 MHz, CDCl3:

3.91 (3H, s), 4.55 (2H, d, J = 5.7 Hz), 5.54 (2H, s), 6.31 (1H, s), 6.46 (1H, d, J = 8.8 Hz), 6.87 (1H, DD, J = 8.1, 1.8 Hz), 6.92 (1H, d, J = 1.8 Hz), 7.16 (1H, DD, J = 8.8, 2.4 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.34 (1H, d, J = 8.1 Hz).

Example 61

2-Amino-5-cyano-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in example 1, in the form of a slightly yellow powder, yield 88%.

So pl. 163-166oC.

Mass: 295 (M+).

1H-NMR (400 MHz, CDCl3) :

4.49 (2H, d, J = 5.5 Hz), 5.96 (2H, s), 6.22 (1H, s), 6.40 (1H, m), 6.63 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.1 Hz), 6.81 (1H, DD, J = 8.1, 1.3 Hz), 6.84 (1H, d, J = 1.3 Hz), 7.40 (1H, DD, J = 8.1, 1.8 Hz), 7.65 (1H, d, J = 1.8 Hz).

Example 62

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzoic

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a pale yellow powder, yield 100%.

So pl. 184-186oC.

Mass: 316 (MH+).

Example 63

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a yellow powder, yield 79%.

So pl. 194-198oC.

Mass: 336 (M+).

1H-NMR (400 MHz, CDCl3) :

3.90 (3H, s), 4.53 (2H, d, J = 5.7 Hz), 6.50 - 6.64 (3H, m), 6.66 (1H, d, J = 9.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.23 (1H, DD, J = 8.4, 2.2 Hz), 7.38 (1H, d, J = 2.6 Hz), 8.08 (1H, DD, J = 9.2, 2.6 Hz), 8.34 (1H, d, J = 2.4 Hz).

Example 64

2-Amino-5-dimethylsulphamoyl-N-3-chloro-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a slightly yellow powder, yield 93%.

So pl. 195-199oC.

Mass: 398 (MH+).

1H-NMR (400 MHz, CDCl3) :

2.66 (6H, s), 3.89 (3H, s), 4.51 (2H, d, J = 5.9 Hz), 6.26 (2H, s), 6.72 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 8.4 Hz), 6.89 (1H, t, J = 5.9 Hz), 7.24 (1H, DD, J = 8.4, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.54 (1H, DD, J = 8.8, 2.0 Hz), 7.84 (1H, d, J = 2.0 Hz).

Example 65

2-Amino-5-methylsulfanyl-N-(3-chloro-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 53, in the form of a slightly yellow powder, yield 78%.

So pl. 154-155oC.

Example 66

2-Amino-N-(3,4-methylenedioxybenzyl)-5-(1-pyrazolyl)benzamide

< / BR>
N-(3,4-Methylenedioxybenzyl)-2-nitro-5-(1-pyrazolyl)benzamide (1.80 g) was dissolved in 120 ml of tetrahydrofuran was added 1.8 g of 10% palladium on coal (aqueous). The mixture was subjected to catalytic recovery at room temperature and 1 ATM. After 13 h, the catalyst was filtered and the reaction mixture was concentrated in vacuum. The residue was led out of the ether. The formed crystals were separated by filtration and received 1.50 g of target compound in the form of a powder, yield 91%.

So pl. 146-147oC.

Mass: 336 (M+).

1H-NMR (400 MHz, CDCl3) :

4.50 (2H, d, J = 5.7 Hz), 5.65 (2H, s), 5.95 (2H, s), 6.42 (1H, DD, J = 2.4, 1.8 Hz), 6.75 (1H, d, J = 8.8 Hz), 6.77 (1H, d, J = 8.2 Hz), 6.81 (1H, DD, J = 8.2, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.41 (1H, DD, J = 8.8, 2.4 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 2.4 Hz), 7.76 (1H, d, J = 2.4 Hz).

Example 67

2-Amino-N-(3,4-methylenedioxybenzyl)-5-(1,2,4-triazole-1 - yl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 66, in the form of a white powder, yield 94%.

So pl. .79 (2H, s), 5.96 (2H, s), 6.48 (1H, s), 6.78 (1H, d, J = 8.2 Hz), 6.78 (1H, d, J = 8.9 Hz), 6.81 (1H, DD, J = 8.2, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.41 (1H, DD, J = 8.9, 2.4 Hz), 7.62 (1H, d, J = 2.4 Hz), 8.03 (1H, s), 8.37 (1H, s).

Example 68

2-Amino-4-methoxy-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzoic

< / BR>
2-Amino-5-bromo-4-methoxy-N-(3-chloro-4-methoxybenzyl)benzamide (4.67 g) was dissolved in 10 ml of N-methyl-2-pyrrolidone was added 1.15 g of copper cyanide. The mixture was stirred at 180oC 4 h and was added an aqueous solution of Ethylenediamine. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3:2)). The obtained solid was washed with ether and received 1.58 g specified in the title compound as slightly yellow powder, yield 39%.

So pl. 184-185oC.

Mass: 346 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.83 (3H, s), 3.90 (3H, s), 4.48 (2H, d, J = 5.9 Hz), 6.08 (1H, s), 6.32 - 6.42 (3H, m), 6.91 (1H, d, J = 8.4 Hz), 7.21 (1H, DD, J = 8.4, 2.2 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.59 (1H, s).

Example 69

7-Amino-4-bromo-N-(3,4-methylenedioxybenzyl)isoindoline-1-he

< / BR>
7-Amino-4-promisingly (0.35 g) aseracare 45 min and was added 0.29 g of piperonylic. The resulting mixture was stirred at room temperature for 4 h and was added ice water and the mixture was extracted with ethyl acetate. The organic phase was washed for 1H. hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3:1)). The solid residue was washed with n-hexane and was obtained 0.25 g specified in the title compounds as a pale yellow powder, yield 46%.

So pl. 151-153oC.

Mass: 361 (MH+).

1H-NMR (400 MHz, CDCl3) :

4.08 (2H, s), 4.63 (2H, s), 5.26 (2H, s), 5.95 (2H, s), 6.50 (1H, d, J = 8.6 Hz), 6.76 - 6.79 (3H, m), 7.28 (1H, d, J = 8.6 Hz).

Example 70

8-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)-1,2,3,4 - tetrahydroisoquinoline-1-he

< / BR>
Specified in the title compound was obtained as in Example 69, in the form of a slightly yellow powder, yield 84%.

1H-NMR (400 MHz, CDCl3) :

2.94 (2H, t, J = 6.6 Hz), 3.40 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 5.94 (2H, s), 6.18 (2H, s), 6.46 (1H, d, J = 8.8 Hz), 6.75 (1H, DD, J = 7.9, 0.5 Hz), 6.78 (1H, DD, J = 7.9, 1.2 Hz), 6.82 (1H, DD, J = 1.2, 0.7 Hz), 7.30 (1H, d, J = 8.8 Hz).

Example 71

1-[[4-Chloro-2-[(3,4-methyland troxipide (0.5 g), piperacillin (0.42 ml), 1,3-dicyclohexylcarbodiimide (0.38 g), 1-hydroxybenzotriazole (0.25 g) and 4-dimethylaminopyridine (25 mg) was added to 8 ml of n, N-dimethylformamide. The mixture was stirred at room temperature for 61 h and was added water and ethyl acetate. Insoluble material was filtered, the organic phase was separated, washed with 1N. hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: dichloromethane/methanol (30:1)). The resulting substance was led from n-hexane/ethyl acetate, recrystallized from aqueous ethanol and received 0.39 g of target compound in the form of a white powder, yield 53%.

So pl. 151-155oC (decomp.).

Mass: 432 (MH+).

1H-NMR (400 MHz, CDCl3) :

0.56 (2H, m), 1.74 (1H, m), 1.95 (2H, m), 3.21 (2H, DDD, J = 13.6, 9.3, 3.3 Hz), 3.83 - 3.97 (3H, m), 4.47 (2H, d, J = 5.7 Hz), 5.96 (2H, s), 6.87 (1H, DD, J = 7.9, 0.5 Hz), 6.81 (1H, DD, J = 7.9, 1.6 Hz), 6.85 (1H, DD, J = 1.6, 0.5 Hz), 7.03 (1H, t, J = 5.7 Hz), 7.25 (1H, DD, J = 9.2, 2.4 Hz), 7.33 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 9.2 Hz), 10.57 (1H, s).

Example 72

Ethyl-1-[[4-bromo-2-[(3,4-methylenedioxybenzyl)carbarnoyl]phenyl]- carbarnoyl] uraniumin (0.56 ml), 1,3-dicyclohexylcarbodiimide (0.68 g), 1-hydroxybenzotriazol (0.45 g) and 4-dimethylaminopyridine (catalytic amount) was added to 10 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 20 h, then added water and ethyl acetate. Insoluble material was filtered, the organic phase was separated, washed with 1N. hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (2:1)). The obtained solid was washed with ether and was obtained 1.27 g specified in the title compound as a white powder, yield 77%.

So pl. 156-159oC.

Mass: 532 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.75 (2H, m), 1.99 (2H, m), 2.52 (1H, m), 3.05 (2H, m), 4.09 (2H, m), 4.16 (2H, q, J = 7.1 Hz), 4.47 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.79 (1H, DD, J = 8.1, 0.5 Hz), 6.82 (1H, DD, J = 8.1, 1.5 Hz), 6.85 (1H, DD, J = 1.5, 0.5 Hz), 6.89 (1H, t, J = 5.7 Hz), 7.39 (1H, DD, J = 9.0, 2.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.0 Hz), 10.57 (1H, s).

Example 73

1-[[4-Chloro-2-[(3-chloro-4-methoxybenzyl)carbarnoyl] phenyl]carbarnoyl]- 4-hydroxypiperidine (0.7 g), 1,3-dicyclohexylcarbodiimide (0.38 g), 1-hydroxybenzotriazole (0.25 g), 4-dimethylaminopyridine (25 mg) and triethylamine (0.47 ml) was added to 8 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 61 h and was added water and ethyl acetate. Insoluble material was filtered, the organic phase was separated and washed with 1N. hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, water and aqueous saturated salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent dichloromethane/methanol (30: 1)). The resulting substance was led from n-hexane/ethyl acetate and recrystallized from aqueous ethanol and obtained 0.51 g specified in the title compound as a white powder, yield 66%.

So pl. 173-174oC (decomp.).

Mass: 452 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.33 (2H, m), 1.76 (2H, m), 3.11 (2H, DDD, J = 13.0, 9.5, 3.1 Hz), 3.64 - 3.78 (3H, m), 3.84 (3H, s), 4.40 (2H, d, J = 5.7 Hz), 4.46 (1H, d, J = 4.2 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.28 (2H, DD, J = 8.6, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.50 (1H, DD, J = 9.2, 2.6 Hz), 7.82 (1H, d, J = 2.6 Hz), 8.32 (1H, d, J = 9.2 Hz), 9.37 (1H, t, J = 5.7 Hz), 11.02 (1H, s).

Example 74

1-[[2-[(3-Chloro-4-methoxybenzyl)carbarnoyl] -4-CRE 73, in the form of a white powder, yield 13%.

So pl. 194-196oC.

Mass: 443 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.35 (2H, m), 1.77 (2H, m), 3.16 (2H, m), 3.64 -3.80 (3H, m), 3.84 (3H, s), 4.42 (2H, d, J = 5.5 Hz), 4.77 (1H, d, J = 4.2 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.29 (1H, DD, J = 8.9, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.86 (1H, DD, J = 9.0, 1.6 Hz), 8.24 (1H, d, J = 1.6 Hz), 8.49 (1H, d, J = 9.0 Hz), 9.42 (1H, m), 11.47 (1H, s).

Example 75

Ethyl-1-[[4-bromo-2-[(3-chloro-4-methoxybenzyl)carbarnoyl] phenyl]- carbarnoyl] piperidine-4-carboxylate

< / BR>
Ethyl - 1-[(4-bromo-2-carboxyphenyl)carbarnoyl]piperidine-4 - carboxylate (1.0 g), 3-chloro-4-methoxybenzylamine (0.78 g), 1,3-dicyclohexylcarbodiimide (0.57 g), 1-hydroxybenzotriazol (0.37 g), 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.52 ml) was added to 8 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 66 h and was added water and ethyl acetate. Insoluble material was filtered, the organic phase was separated and washed with 1N. hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (2: 1)). T the od 72%.

So pl. 172-174oC.

Mass: 554 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.75 (2H, m), 1.99 (2H, m), 2.52 (1H, m), 3.05 (2H, m), 3.91 (3H, s), 4.08 (2H, m), 4.16 (2H, K, J = 7.1 Hz), 4.47 (2H, d, J = 5.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.22 (1H, m), 7.22 (1H, DD, J = 8.4, 2.2 Hz), 7.33 (1H, DD, J = 9.2, 2.4 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.45 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 9.2 Hz), 10.53 (1H, s).

Example 76

5-Chloro-N-(3-chloro-4-methoxybenzyl)-2-(piperidineacetate)benzamide

< / BR>
5-Chloro-2-chloroacetamido-N-(3-chloro-4-methoxybenzyl)benzamide (0.7 g), piperidine (0.51 ml), anhydrous potassium carbonate (0.72 g) and Tetra-n-butylammonium (catalytic amount) was added to 6 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 1.5 h, was added water and was extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-hexane/ethyl acetate (3:1)), recrystallized from aqueous ethanol and received 0.37 g specified in the title compound as white needles, yield 48%.

So pl. 126-129oC.

Mass: 450 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.42 - 1.50 (2H,), 7.32 (1H, DD, J = 9.0, 2.0 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.40 (1H, d, J = 2.4 Hz), 8.49 (1H, d, J = 9.0 Hz), 11.52 (1H, s).

Example 77

5-Chloro-N-(3-chloro-4-methoxybenzyl)-2-(pyrrolidinecarboxamido)- benzamide

< / BR>
Specified in the title compound was obtained as in Example 24, in the form of a slightly yellow prisms, yield 86%.

So pl. 98-100oC.

Mass: 436 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.81 - 1.92 (4H, m), 2.61 - 2.72 (4H, m), 3.28 (2H, s), 3.89 (3H, s), 4.49 (2H, d, J = 5.9 Hz), 6.88 (1H, d, J = 8.4 Hz), 6.89 (1H, t, J = 5.9 Hz), 7.19 (1H, DD, J = 8.4, 2.2 Hz), 7.27 (1H, DD, J = 9.0, 2.4 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.41 (1H, d, J = 2.4 Hz), 8.42 (1H, d, J = 9.0 Hz), 11.49 (1H, s).

Example 78

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(piperidinophenyl)- benzamide

< / BR>
Specified in the title compound was obtained as in Example 24, in the form of pale yellow needles, yield 60%.

So pl. 136-141oC.

Mass: 444 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.40 - 1.48 (2H, m), 1.56 - 1.64 (4H, m), 2.44 (4H, s), 2.56 (2H, t, J = 7.0 Hz), 2.70 (2H, t, J = 7.0 Hz), 4.48 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.26 (1H, m), 6.78 (1H, d, J = 7.8 Hz), 6.80 (1H, d, J = 7.8 Hz), 6.83 (1H, s), 7.35 (1H, DD, J = 9.0, 2.4 Hz), 7.40 (1H, d, J = 2.4 Hz), 8.31 (1H, d, J = 9.0 Hz), 11.03 (1H, s).

Example 79

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(4-piperidinylidene)- benzamide

< / BR>
Specified in ptx2">

Mass: 458 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.37 - 1.45 (2H, m), 1.51 - 1.59 (4H, m), 1.91 (2H, quintet, J = 7.5 Hz), 2.31 - 2.46 (8H, m), 4.50 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.43 (1H, m), 6.78 - 6.85 (3H, m), 7.39 (1H, d, J = 2.6 Hz), 7.39 (1H, DD, J = 9.7, 2.6 Hz), 8.56 (1H, d, J = 9.7 Hz), 10.96 (1H, s).

Example 80

5-Cyano-2-(isonicotinoyl)-N-(3-chloro-4-methoxybenzyl)- benzamide

< / BR>
2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzene (0.33 g) was dissolved in 5 ml of pyridine and cooled with ice. To the solution was added the hydrochloride isonicotinohydrazide (0.2 g) and the mixture was stirred at room temperature for 4 h and added water. The formed precipitate was separated by filtration, washed with water and ether, and recrystallized from ethyl acetate and obtained as pale-yellow needles, yield 64%.

So pl. 243-245oC (decomp.).

Mass: 421 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

3.83 (2H, s), 4.47 (2H, d, J = 5.7 Hz), 7.32 (1H, DD, J = 8.4, 2.2 Hz), 7.46 (1H, d, J = 2.2 Hz), 7.79 - 7.83 (2H, m), 8.06 (1H, DD, J = 8.8, 1.8 Hz), 8.40 (1H, d, J = 1.8 Hz), 8.77 (1H, d, J = 8,8 Hz), 8,84 - 8.88 (2H, m), of 9.56 (1H, t, J = 5.7 Hz), 12,90 (1H, s).

Example 81

5-Bromo-N-(3-chloro-4-methoxybenzyl)-2-(isonicotinoyl) benzamide

< / BR>
Specified in the title compound was obtained as in Example 80, in the form of white needles, yield 75%.

So pl. 190-192o
Example 82

5-Bromo-2-(isonicotinoyl)-4-methoxy-N-(3-chloro-4-methoxybenzyl) benzamide

< / BR>
Specified in the title compound was obtained as in Example 80, in the form of white needles, yield 40%.

So pl. 252-253oC (decomp.).

Mass: 506 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

3.83 (3H, s), 3.95 (3H, s), 4.45 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.30 (1H, DD, J = 8.6, 2.2 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.80 - 7.84 (2H, m), 8.24 (1H, s), 8.55 (1H, s), 8.84 - 8.88 (2H, m), 9.39 (1H, t, J = 5.7 Hz), 13.26 (1H, s).

Example 83

2-(Isonicotinoyl)-4-methoxy-N-(3-chloro-4 - methoxybenzyl)-5-cyanobenzoic

< / BR>
Specified in the title compound was obtained as in Example 80, in the form of white needles, yield 81%.

So pl. 262-267oC (decomp.).

Mass: 451 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

3.83 (3H, s), 4.00 (3H, s), 4.46 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.31 (1H, DD, J = 8.6, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.81 - 7.84 (2H, m), 8.40 (1H, s), 8.60 (1H, s), 8.85 - 8.90 (2H, m), 9.42 (1H, t, J = 5.7 Hz), 13.48 (1H, s).

Example 84

5-Bromo-2-(isonicotinoyl)-4-methoxy-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
Specified in the header CSS="ptx2">

Mass: 484 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

3.94 (3H, s), 4.42 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.83 (1H, DD, J = 8.0, 1.3 Hz), 6.86 (1H, DD, J = 8.0, 0.4 Hz), 6.94 (1H, DD, J = 1.3, 0.4 Hz), 7.80 - 7.84 (2H, m), 8.24 (1H, s), 8.55 (1H, s), 8.83 - 8.88 (2H, m), 9.36 (1H, t, J = 5.7 Hz), 13.32 (1H, s).

Example 85

5-Bromo-2-(isonicotinoyl)-N-(3,4-methylenedioxybenzyl)- benzamide

< / BR>
Specified in the title compound was obtained as in Example 80, in the form of pale yellow needles, yield 49%.

So pl. 207-211oC.

Mass: 454 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

4.42 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.83 (1H, DD, J = 7.9, 1.5 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.95 (1H, d, J = 1.5 Hz), 7.75 - 7.83 (3H, m), 8.10 (1H, d, J = 2.2 Hz), 8.53 (1H, d, J = 9.0 Hz), 8.81 - 8.87 (2H, m), 9.48 (1H, t, J = 5.7 Hz), 12.61 (1H, s).

So pl. 183-184oC.

Mass: 451 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.54 - 1.75 (4H, m), 2.08 - 2.16 (2H, m), 2.20 - 2.28 (2H, m), 2.39 (1H, m), 2.51 (1H, m), 3.91 (3H, s), 4.53 (2H, d, J = 5.7 Hz), 6.92 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.22 (1H, DD, J = 8.4, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.70 (1H, DD, J = 8.0, 2.0 Hz), 7.86 (1H, d, J = 2.0 Hz), 8.79 (1H, d, J = 8.8 Hz), 11.57 (1H, s).

Example 87

5-Bromo-2-[(TRANS-4-cyanocyclohexane)amino] -N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a Bel is P>1
H-NMR (400 MHz, CDCl3) :

1.54 - 1.73 (4H, m), 2.07 - 2.14 (2H, m), 2.19 - 2.27 (2H, m), 2.35 (1H, m), 2.50 (1H, m), 4.51 (2H, d, J = 5.5 Hz), 5.98 (2H, s), 6.47 (1H, m), 6.80 (2H, s), 6.84 (1H, s), 7.55 (1H, DD, J = 9.5, 2.2 Hz), 7.55 (1H, d, J = 2.2 Hz), 8.52 (1H, d, J = 9.5 Hz), 11.13 (1H, s).

Example 88

2-[(TRANS-4-(Acetoxy)cyclohexanecarbonyl)amino] -N-(3 - chloro-4-methoxybenzyl)-5-cyanobenzoic

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of white needles, yield 60%.

So pl. 194-196oC.

Mass: 484 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.39 - 1.50 (2H, m), 1.62 - 1.74 (2H, m), 2.05 (3H, s), 2.05 - 2.15 (4H, m), 2.34 (1H, TT, J = 11.7, 3.3 Hz), 3.91 (3H, s), 4.54 (2H, d, J = 5.9 Hz), 4.73 (1H, TT, J = 11.0, 4.0 Hz), 6.82 (1H, t, J = 5.9 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.23 (1H, DD, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.70 (1H, DD, J = 8.8, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz), 8.81 (1H, d, J = 8.8 Hz), 11.47 (1H, s).

Example 89

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-[(TRANS-4 - piperidinylcarbonyl)amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of pale yellow needles, yield 17%.

So pl. 162-163oC.

Mass: 498 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.29 - 1.48 (4H, m), 1.50 - 1.63 (6H, m), 2.00 (2H, m), 2.10 (2H, m), 2.22 (1H, m), 2.32 (1H, m), 2.46 - 2.58 (4H, m), 4.51 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.51 (1H, t, J = 5.7 Hz), 6.77 - 6.85 (3H, -5-cyano-2-[(TRANS-4 - piperidinylcarbonyl)amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of white needles, yield of 2%.

So pl. 215-218oC (decomp.).

Mass: 509 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.31 - 1.48 (4H, m), 1.51 - 1.64 (4H, m), 2.01 (2H, m), 2.11 (2H, m), 2.22 - 2.38 (2H, m), 2.48 - 2.56 (4H, m), 3.91 (3H, s), 4.54 (2H, d, J = 5.7 Hz), 6.71 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.22 (1H, DD, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 8.8, 2.0 Hz), 7.79 (1H, d, J = 2.0 Hz), 8.81 (1H, d, J = 8.8 Hz), 11.34 (1H, s).

Example 91

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzene (1.2 g) was dissolved in 10 ml of pyridine and cooled with ice. To the solution was bury a solution of 1.0 g of TRANS-4-ethoxycarbonylmethylene in 2 ml of dichloromethane in a way that the temperature of the reaction mixture did not exceed 10oC. the resulting mixture was stirred 4 h, was added with ice water and was extracted with ethyl acetate. The organic phase was washed for 1H. hydrochloric acid, water, saturated aqueous solution of hydrochloride of sodium, water, and saturated aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (solvent: n-Gex is placed in the form of a white powder, yield 48%.

So pl. 153 to 155oC.

Mass: 498 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.64 (4H, m), 2.05 - 2.19 (4H, m), 2.28 - 2.38 (2H, m), 3.91 (3H, s), 4.14 (2H, K, J = 7.1 Hz), 4.54 (2H, d, J = 5.7 Hz), 6.82 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.23 (1H, DD, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.69 (1H, DD, J = 9.0, 1.8 Hz), 7.83 (1H, d, J = 1.8 Hz), 8.81 (1H, d, J = 9.0 Hz), 11.45 (1H, s).

Example 92

5-Nitro-N-(3-chloro-4-methoxybenzyl-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a pale yellow powder with a yield of 61%.

So pl. 166-169oC.

Mass: 518 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.47 - 1.66 (4H, m), 2.07 - 2.20 (4H, m), 2.29 - 2.40 (2H, m), 3.91 (3H, s), 4.14 (2H, K, J = 7.1 Hz), 4.57 (2H, d, J = 5.7 Hz), 6.79 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.24 (1H, DD, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 8.30 (1H, DD, J = 9.3, 2.6 Hz), 8.39 (1H, d, J = 2.6 Hz), 8.88 (1H, d, J = 9.3 Hz), at 11.64 (1H, s).

Example 93

5-Chloro-N-(3-chloro-4-methoxybenzyl)-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 83%.

So pl. 122-125oC.

Mass: 507 (MH+).

, .52 (2H, d, J = 5.7 Hz), 6.67 (1H, t, J = 5.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.21 (1H, DD, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.38 (1H, DD, J = 9.0, 2.4 Hz), 7.42 (1H, d, J = 2.4 Hz), 8.55 (1H, d, J = 9.0 Hz), 10.99 (1H, s).

Example 94.

5-Chloro-2-[(TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl)amino] - N-(2-methoxy-5-pyridylmethyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 94%.

So pl.: 141-144oC.

Mass: 474 (MH+)

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.45 - 1.63 (4H, m), 2.04 - 2.18 (4H, m), 2.24 - 2.36 (2H, m), 3.94 (3H, s), 4.14 (2H, K, J = 7.1 Hz), 4.54 (2H, d, J = 5.7 Hz), 6.55 (1H, t, J = 5.7 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 2.4 Hz), 7.40 (1H, DD, J = 9.7, 2.4 Hz), 7.59 (1H, DD, J = 8.6, 2.6 Hz), 8.16 (1H, d, J = 2.6 Hz), 8.58 (1H, d, J = 9.7 Hz), 10.98 (1H, s).

Example 95

5-Chloro-N-(3-cyano-4-methoxybenzyl)-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 87%.

So pl. 157-160oC.

Mass: 496 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.62 (4H, m), 2.03 - 2.17 (4H, m), 2.24 - 2.36 (2H, m), 3.94 (3H, s), 4.13 (2H, K, J = 7.1 Hz), 4.55 (2H, d, J = 5.9 Hz), 6.85 (1H, t, J = 5.9 Hz), 6.98 (1H, m), 7.39 (1H, DD, J = 9.0, 2.4 Hz), 7.44 (1H, d, J = 2.4 Hz), 7.53 - 7.58 (2H, m), 8.5 logiccontrol]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 83%.

So pl. 167-168oC.

Mass: 507 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.64 (4H, m), 2.04 - 2.18 (4H, m), 2.25 - 2.36 (2H, m), 3.92 (3H, s), 4.13 (2H, K, J = 7.1 Hz), 4.58 (2H, d, J = 5.7 Hz), 6.54 (1H, t, J = 5.7 Hz), 6.88 (1H, DD, J = 8.1, 1.6 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.42 (1H, DD, J = 9.5, 2.2 Hz), 8.60 (1H, d, J = 9.5 Hz), 10.99 (1H, s).

Example 97

5-Bromo-N-(3-chloro-4-methoxybenzyl)-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]-4-methoxybenzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 76%.

So pl. 160oC (decomp.).

Mass: 583 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.65 (4H, m), 2.08 - 2.16 (4H, m), 2.27 - 2.37 (2H, m), 3.91 (3H, s), 3.95 (3H, s), 4.13 (2H, K, J = 7.1 Hz), 4.51 (2H, d, J = 5.5 Hz), 6.41 (1H, t, J = 5.5 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.21 (1H, DD, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.61 (1H, s), 8.52 (1H, s), 11.62 (1H, s).

Example 98

5-Bromo-4-methoxy-N-(3-chloro-4-methoxybenzyl)-2- [[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with you is ) :

1.26 (ZN, t, J = 7.1 Hz), 1.43 - 1.62 (4H, m), 2.03 - 2.16 (4H, m), 2.24 - 2.35 (2H, m), 3.90 (3H, s), 4.13 (2H, K, J = 7.1 Hz), 4.52 (2H, d, J = 5.7 Hz), 6.79 (1H, t, J = 5.7 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.21 (1H, DD, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.50 (1H, DD, J = 9.0, 2.4 Hz), 7.57 (1H, d, J = 2.4 Hz), 8.47 (1H, d, J = 9.0 Hz), 11.01 (1H, s).

Example 99

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]-4-methoxybenzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 72%.

So pl. 193-195oC.

Mass: 526 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.65 (4H, m), 2.06 - 2.19 (4H, m), 2.28 - 2.39 (2H, m), 3.91 (3H, s), 3.98 (3H, s), 4.14 (2H, K, J = 7.1 Hz), 4.51 (2H, d, J = 5.7 Hz), 6.66 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.22 (1H, DD, J = 8.6, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.75 (1H, s), 8.58 (1H, s), 11.92 (1H, s).

Example 100

N-(3-Chloro-4-methoxybenzyl)-5-dimethylsulphamoyl-2- [[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 89%.

So pl. 197-198oC.

Mass: 580 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.47 - 1.65 (4H, m), 2.06 - 2.19 (4H, m), 2.29 - 2.39 (2H, m), 2.67 (6H, s), 3.90 (3H, s), 4.14 (2H, K, J = 7.1 Hz), 4.56 (2H2 Hz), 8.88 (1H, d, J = 9.0 Hz), 11.63 (1H, s).

Example 101

N-(3-Chloro-4-methoxybenzyl)-2-[[TRANS-4- (etoxycarbonyl)cyclohexanecarbonyl]amino]-5-methylsulfonylbenzoyl

< / BR>
Specified in the title compound was obtained as in Example 91, in the form of a white powder with a yield of 44%.

So pl. 190-191oC.

Mass: 566 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.46 - 1.65 (4H, m), 2.06 - 2.18 (4H, m), 2.29 - 2.39 (2H, m), 2.61 (3H, d, J = 5.3 Hz), 3.89 (3H, s), 4.14 (2H, K, J = 7.1 Hz), 4.53 (2H, d, J = 5.9 Hz), 4.65 (1H,, J = 5.3 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.20 (1H, t, J = 5.9 Hz), 7.23 (1H, DD, J = 8.6, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.84 (1H, DD, J = 9.0, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.83 (1H, d, J = 9.0 Hz), 11.58 (1H, s).

Example 102

2-[(TRANS-4-(Etoxycarbonyl)cyclohexanecarbonyl)amino] -N- (3,4-methylenedioxybenzyl)-5-(1-pyrazolyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a white powder with a yield of 85%.

So pl. 197-201oC.

Mass: 519 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.46 - 1.66 (4H, m), 2.08 - 2.18 (4H, m), 2.27 - 2.38 (2H, m), 4.14 (2H, K, J = 7.1 Hz), 4.52 (2H, d, J = 5.7 Hz), 5.96 (2H, s), 6.47 (1H, DD, J = 2.4, 1.6 Hz), 6.78 (1H, d, J = 7.9 Hz), 6.80 (1H, DD, J = 7.9, 1.6 Hz), 6.84 (1H, d, J = 1.6 Hz), 6.85 (1H, m), 7.59 (1H, DD, J = 9.2, 2.6 Hz), 7.68 (1H, d, J = 1.6 Hz), 7.89 (1H, d, J = 2.6 Hz), 7.95 (1H, d, J = is about] -N-(3,4 - methylenedioxybenzyl)-5-(1,2,4-triazole-1-yl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a white powder with a yield of 69%.

So pl. 204-206oC.

Mass: 520 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.27 (3H, t, J = 7.1 Hz), 1.45 - 1.65 (4H, m), 2.05 - 2.19 (4H, m), 2.28 - 2.38 (2H, m), 4.14 (2H, K, J = 7.1 Hz), 4.55 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.79 (1H, d, J = 7.9 Hz), 6.82 (1H, DD, J = 7.9, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 6.91 (1H, t, J = 5.7 Hz), 7.64 (1H, DD, J = 9.2, 2.6 Hz), 7.86 (1H, d, J = 2.6 Hz), 8.05 (1H, s), 8.49 (1H, s), 8.79 (1H, d, J = 9.2 Hz), 11.21 (1H, s).

Example 104

2-[[TRANS-4-(Etoxycarbonyl)cyclohexanecarbonyl] amino] -N-(3,4 - methylenedioxybenzyl)-5-cryptomaterial

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a white powder with a yield of 63%.

So pl. 179-180oC.

Mass: 537 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.64 (4H, m), 2.05 - 2.17 (4H, m), 2.25 - 2.37 (2H, m), 4.13 (2H, K, J = 7.1 Hz), 4.52 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.53 (1H, t, J = 5.7 Hz), 6.79 (1H, d, J = 7.9 Hz), 6.81 (1H, d, J = 7.9 Hz), 6.84 (1H, s), 7.28 (1H, d, J = 2.7 Hz), 7.32 (1H, DD, J = 9.2, 2.6 Hz), 8.66 (1H, d, J = 9.2 Hz), 11.03 (1H, s).

Example 105

5-Cyano-2-[[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl] - amino] -N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 86P>1
H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.64 (4H, m), 2.05 - 2.18 (4H, m), 2.28 - 2.38 (2H, m), 4.14 (2H, K, J = 7.1 Hz), 4.52 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.75 (1H, t, J = 5.7 Hz), 6.80 (1H, DD, J = 7.9, 0.7 Hz), 6.83 (1H, DD, J = 7.9, 1.3 Hz), 6.85 (1H, DD, J = 1.3, 0.7 Hz), 7.69 (1H, DD, J = 9.0, 2.0 Hz), 7.81 (1H, d, J = 2.0 Hz), 8.80 (1H, d, J = 9.0 Hz), 11.46 (1H, s).

Example 106

5-Bromo-2-[[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl] amino] - 4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a white powder with a yield of 67%.

So pl. 194-195oC.

Mass: 561 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.66 (4H, m), 2.08 - 2.16 (4H, m), 2.27 - 2.37 (2H, m), 3.95 (3H, s), 4.13 (2H, K, J = 7.1 Hz), 4.50 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.35 (1H, t, J = 5.5 Hz), 6.80 (2H, s), 6.84 (1H, s), 7.60 (1H, s), 8.52 (1H, s), 11.65 (1H, s).

Example 107

4-Bromo-7-[[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl] amino]- N-(3,4-methylenedioxybenzyl)isoindoline-1-he

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a white powder with a yield of 67%.

So pl. 135-137oC.

Mass: 543 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.68 (4H, m), 2.10 - 2.20 (4H, m), 2.29 - 2.41 (2H, m), 4.14 (2H, K, J = 7.1 Hz), 4.17 (2H, s), 4.66 (2H, s), 5.96 (2H, s) is Il)cyclohexanecarbonyl] - amino] -N-(3,4-methylenedioxybenzyl)-1,2,3,4-tetrahydroisoquinoline - 1-he

< / BR>
Specified in the title compound was obtained as in Example 86, in the form of a colourless oil with a yield of 86%.

Mass: 557 (MH+).

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.67 (4H, m), 2.06 - 2.17 (4H, m), 2.28 - 2.38 (2H, m), 3.01 (2H, t, J = 6.6 Hz), 3.46 (2H, t, J = 6.6 Hz), 4.13 (2H, K, J = 7.1 Hz), 4.67 (2H, s), 5.96 (2H, s), 6.77 (1H, DD, J = 7.2, 1.3 Hz), 6.79 (1H, d, J = 7.2 Hz), 6.81 (1H, d, J = 1.3 Hz), 7.60 (1H, d, J = 9.0 Hz), 8.57 (1H, d, J = 9.0 Hz), 12.38 (1H, s).

Example 109

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(TRANS-4 - hydroxycyclohexanone)amino]benzamide

< / BR>
2-(TRANS-4-Ecotoxicologically)-N-(3-chloro-4 - methoxybenzyl)-5-cyanobenzene (0.9 g) was dissolved in a mixed solvent containing 10 ml ethanol and 10 ml of tetrahydrofuran, was added 6 ml of 1N. of sodium hydroxide. The mixture was stirred at room temperature for 2 h, was added water and was extracted with a mixture of ethyl acetate/tetrahydrofuran/ethanol. The organic phase was washed with a saturated aqueous solution of salt, dried over anhydrous magnesium sulfate and the solvent is kept in vacuum. The solid was washed with ether, recrystallized from aqueous ethanol was obtained 0.33 g specified in the connection header in the form bedso-d6) :

1.14 - 1.26 (2H, m), 1.35 - 1.47 (2H, m), 1.83 - 1.93 (4H, m), 3.35 (1H, m), 3.84 (3H, s), 4.42 (2H, d, J = 5.5 Hz), 4.61 (1H, d, J = 4.4 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.30 (1H, DD, J = 8.4, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.94 (1H, DD, J = 8.8, 2.0 Hz), 8.25 (1H, d, J = 2.0 Hz), 8.58 (1H, d, J = 8.8 Hz), 9.24 (1H, t, J = 5.5 Hz), 11.54 (1H, s).

Example 110

2-[(TRANS-4-Carboxylatomethyl)amino] -N-(3 - chloro-4-methoxybenzyl)-5-cyanobenzoic

< / BR>
N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(TRANS-4 - ethoxycarbonylmethylene)benzamide (0.9 g) was dissolved in a mixed solvent containing 10 ml ethanol and 10 ml of tetrahydrofuran, was added 6 ml of 1N. of sodium hydroxide. The mixture was stirred at room temperature for 8 h and was added water and ethyl acetate. The aqueous phase was separated, and the ethyl acetate phase was extracted with water. Both aqueous phases were combined and acidified using 1N. the hydrochloric acid. The formed precipitate was separated by filtration, recrystallized from aqueous ethanol was obtained 0.42 g specified in the title compound as white needles, yield 72%.

So pl. 223-227oC.

Mass: 470 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.48 (4H, m), 1.89 - 2.02 (4H, m), 2.18 (1H, m), 2.31 (1H, m), 3.84 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.31 (1H, DD, J = 8.6, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.93 (1H, DD, J = 8.8, 2.0 Hz), 8.26 (1H, d, J = 2.0 g of the l)carbarnoyl]phenyl] carbarnoyl]piperidine-4-carboxylic acid

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of a white powder with a yield of 64%.

So pl. 259oC (decomp.).

Mass: 526 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.48 (2H, m), 1.87 (2H, m), 2.49 (1H, m), 2.98 (1H, m), 3.84 (3H, s), 3.91 (2H, m), 4.40 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.28 (1H, DD, J = 8.6, 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.94 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 9.2 Hz), 9.38 (1H, t, J = 5.7 Hz), 11.04 (1H, s), 12.30 (1H, s).

Example 112

2-[(TRANS-4-Carboxylatomethyl)amino] - 5-chloro-N-(3-chloro-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 77%.

So pl. 233-235oC.

Mass: 478 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.30 - 1.47 (4H, m), 1.85 - 2.02 (4H, m), 2.13 - 2.29 (2H, m), 3.84 (3H, s), 4.40 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.29 (1H, DD, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.55 (1H, DD, J = 9.0, 2.4 Hz), 7.82 (1H, d, J = 2.4 Hz), 8.39 (1H, d, J = 9.0 Hz), 9.35 (1H, t, J = 5.7 Hz), 11.15 (1H, s), 12.08 (1H, s).

Example 113

5-Bromo-2-[(TRANS-4-carboxylatomethyl)amino] - N-(3-chloro-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles, yield 58%.

So pl. 247-250oC.

Mass: 523 (MH+).

Example 114

2-[(TRANS-4-Carboxylatomethyl)amino] -N- (3-chloro-4-methoxybenzyl)-5-nitrobenzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of pale yellow needles with a yield of 65%.

So pl. 235-244oC (decomp.).

Mass: 490 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.50 (4H, m), 1.91 - 2.04 (4H, m), 2.13 (1H, m), 2.34 (1H, m), 3.84 (3H, s), 4.45 (2H, d, J = 5.3 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.31 (1H, DD, J = 8.4, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 8.38 (1H, DD, J = 9.3, 2.7 Hz), 8.68 (1H, d, J = 9.3 Hz), 8.69 (1H, d, J = 2.7 Hz), 9.68 (1H, t, J = 5.3 Hz), 11.76 (1H, s), 12.10 (1H, s).

Example 115

5-Bromo-2-[(TRANS-4-carboxylatomethyl)amino] - N-(3-chloro-4-methoxybenzyl)-4-methoxybenzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 67%.

So pl. 223-229oC.

Mass: 555 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.50 (4H, m), 1.90 - 2.02 (4H, m), 2.18 (1H, m), 2.26 (1H, m), 3.83 (3H, s), 3.87 (3H, s), 4.39 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.27 (1H, DD, J = 8.4, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 8.09 (1H, s), 8.42 (1H, s), 9.24 (1H, t, J = 5.7 Hz), 11.92 (1H, s), 12.01 (1H, s).

When the
< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles in 51% yield.

So pl. 255-257oC.

Mass: 500 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.33 - 1.51 (4H, m), 1.91 - 2.03 (4H, m), 2.19 (1H, m), 2.31 (1H, m), 3.84 (3H, s), 3.93 (3H, s), 4.41 (2H, d, J = 5.5 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.29 (1H, DD, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 8.27 (1H, s), 8.47 (1H, s), 9.28 (1H, t, J = 5.7 Hz), 12.01 (1H, s), 12.19 (1H, s).

Example 117

2-[(TRANS-4-Carboxylatomethyl)amino] - N-(3-chloro-4-methoxybenzyl)-5-dimethylaminobenzene

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 68%.

So pl. 245-246oC.

Mass: 552 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.46 (4H, m), 1.89 - 2.03 (4H, m), 2.19 (1H, m), 2.31 (1H, m), 2.63 (6H, s), 3.84 (3H, s), 4.45 (2H, d, J = 5.7 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.29 (1H, DD, J = 8.4, 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.86 (1H, DD, J = 8.8, 2.2 Hz), 8.10 (1H, d, J = 2.2 Hz), 8.64 (1H, d, J = 8.8 Hz), 9.58 (1H, t, J = 5.7 Hz), 11.50 (1H, s), 12.09 (1H, s).

Example 118

2-[(TRANS-4-Carboxylatomethyl)amino] - N-(3-chloro-4-methoxybenzyl)-5-methylsulfonylbenzoyl

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with 38%.

So pl. 247-249oC.

is), 2.41 (3H, d, J = 4.9 Hz), 3.84 (3H, s), 4.45 (2H, d, J = 5.9 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.30 (1H, DD, J = 8.4, 2.2 Hz), 7.40 (1H,, J = 4.9 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.86 (1H, DD, J = 8.8, 2.2 Hz), 8.10 (1H, d, J = 2.2 Hz), 8.55 (1H, d, J = 8.8 Hz), 9.53 (1H, t, J = 5.9 Hz), 11.30 (1H, s), 12.08 (1H, s).

Example 119

2-[(TRANS-4-Carboxylatomethyl)amino] -5-chloro - N-[(2-methoxy-5-pyridyl)methyl]benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 78%.

So pl. 219-221oC.

Mass: 446 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.30 - 1.46 (4H, m), 1.85 - 2.02 (4H, m), 2.13 - 2.29 (2H, m), 3.83 (3H, s), 4.41 (2H, d, J = 5.7 Hz), 6.80 (1H, d, J = 8.6 Hz), 7.54 (1H, DD, J = 9.0, 2.4 Hz), 7.70 (1H, DD, J = 8.6, 2.4 Hz), 7.81 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 2.4 Hz), 8.38 (1H, d, J = 9.0 Hz), 9.33 (1H, t, J = 5.7 Hz), 11.13 (1H, s), 12.08 (1H, s).

Example 120

2-[(TRANS-4-Carboxylatomethyl)amino] -5 - chloro-N-(3-cyano-4-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 77%.

So pl. 190-193oC.

Mass: 470 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.30 - 1.46 (4H, m), 1.84 - 2.02 (4H, m), 2.12 - 2.28 (2H, m), 3.90 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 7.23 (1H, d, J = 8.8 Hz), 7.55 (1H, DD, J = 9.0, 2.6 Hz), 7.65 (1H, DD, J = 8.8, 2.4 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.78 (1H, d, J = 2.6 Hz), 8.36 (1H, d, J is Ino] - 5-chloro-N-(4-chloro-3-methoxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with 38%.

So pl. 224-225oC.

Mass: 479 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.29 - 1.46 (4H, m), 1.85 - 2.01 (4H, m), 2.13 - 2.28 (2H, m), 3.86 (3H, s), 4.47 (2H, d, J = 5.9 Hz), 6.93 (1H, DD, J = 8.1, 1.5 Hz), 7.15 (1H, d, J = 1.5 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.56 (1H, DD, J = 9.0, 2.4 Hz), 7.85 (1H, d, J = 2.4 Hz), 8.39 (1H, d, J = 9.0 Hz), 9.39 (1H, t, J = 5.9 Hz), 11.16 (1H, s), 12.08 (1H, s).

Example 122

1-[[4-Bromo-2-[(3,4-methylenedioxybenzyl)carbarnoyl] phenyl] carbarnoyl]piperidine-4-carboxylic acid

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of a white powder with a yield of 62%.

So pl. 276-280oC (decomp.).

Mass: 504 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.47 (2H, m), 1.86 (2H, m), 2.49 (1H, m), 2.98 (1H, m), 3.91 (2H, m), 4.37 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.81(1H, DD, J = 7.9, 1.6 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.92 (1H, d, J = 7.9 Hz), 7.61 (1H, DD, J = 9.2, 2.4 Hz), 7.94 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 9.2 Hz), 9.35 (1H, t, J = 5.7 Hz), 11.07 (1H, s), 12.30 (1H, s).

Example 123

4-Bromo-7-[(TRANS-4-carboxylatomethyl)amino] - N-(3,4-methylenedioxybenzyl)isoindoline-1-he

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of Belinda-d6) :

1.34 - 1.54 (4H, m), 1.95 - 2.06 (4H, m), 2.21 (1H, m), 2.37 (1H, m), 4.29 (2H, s), 4.63 (2H, s), 6.00 (2H, s), 6.83 (1H, DD, J = 7.9, 1.6 Hz), 6.89 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.71 (1H, d, J = 8.8 Hz), 8.28 (1H, d, J = 8.8 Hz), 10.38 (1H, s), 12.01 (1H, s).

Example 124

5-Bromo-8-[(TRANS-4-carboxylatomethyl)amino] - N-(3,4-methylenedioxybenzyl)-1,2,3,4-tetrahydro-1-athinaikon

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 45%.

So pl. 241-244oC.

Mass: 529 (MH+).

1H-NMR (400 MHz, DMSO-d6:

1.33 - 1.52 (4H, m), 1.92 - 2.04 (4H, m), 2.20 (1H, m), 2.28 (1H, m), 2.97 (2H, t, J = 6.8 Hz), 3.50 (2H, t, J = 6.8 Hz), 4.64 (2H, s), 6.00 (2H, s), 6.83 (1H, DD, J = 8.1, 1.5 Hz), 6.88 (1H, d, J = 8.1 Hz), 6.92 (1H, d, J = 1.5 Hz), 7.73 (1H, d, J = 9.0 Hz), 8.45 (1H, d, J = 9.0 Hz), 12.10 (1H, s), 12.39 (1H, s).

Example 125

2-[(TRANS-4-Carboxylatomethyl)amino] - N-(3,4-methylenedioxybenzyl)-5-cryptomaterial

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 72%.

So pl. 245-250oC.

Mass: 509 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.31 - 1.48 (4H, m), 1.86 - 2.03 (4H, m), 2.14 - 2.32 (2H, m), 4.39 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.82 (1H, DD, J = 8.1, 1.6 Hz), 6.87 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.52 (1H, DD, J = 9.2, 2.8 Hz), 7.76 (1H, d, J = 2.8 carbonyl)amino] -N- (3,4-methylenedioxybenzyl)-5-(1-pyrazolyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 65%.

So pl. 219-221oC.

Mass: 491 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.49 (4H, m), 1.89 - 2.03 (4H, m), 2.15 -2.31 (2H, m), 4.42 (2H, d, J = 5.9 Hz), 5.99 (2H, s), 6.56 (1H, DD, J = 2.4, 1.8 Hz), 6.84 (1H, DD, J = 7.8, 1.5 Hz), 6.87 (1H, d, J = 7.8 Hz), 6.95 (1H, d, J = 1.5 Hz), 7.76 (1H, d, J = 1.8 Hz), 7.94 (1H, DD, J = 9.0, 2.6 Hz), 8.16 (1H, d, J = 2.6 Hz), 8.48 (1H, d, J = 9.0 Hz), 8.48 (1H, d, J = 2.4 Hz), 9.38 (1H, t, J = 5.9 Hz), 11.18 (1H, s), 12.08 (1H, s).

Example 127

2-[(TRANS-4-Carboxylatomethyl)amino] -N-(3,4 - methylenedioxybenzyl)-5-(1,2,4-triazole-1-yl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 73%.

So pl. 278-281oC (decomp.).

Mass: 492 (MH+).

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.50 (4H, m), 1.90 - 2.03 (4H, m), 2.15 - 2.33 (2H, m), 4.43 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.84 (1H, DD, J = 8.1, 1.1 Hz), 6.87 (1H, d, J = 8.1 Hz), 6.95 (1H, d, J = 1.1 Hz), 7.96 (1H, DD, J = 9.0, 2.4 Hz), 8.21 (1H, d, J = 2.4 Hz), 8.25 (1H, s), 8.54 (1H, d, J = 9.0 Hz), 9.24 (1H, s), 9.37 (1H, t, J = 5.7 Hz), 11.23 (1H, s), 12.09 (1H, s).

Example 128

2-[(TRANS-4-Carboxylatomethyl)amino] -5-cyano - N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained, as in the Use of the

1H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.48 (4H, m), 1.89 - 2.03 (4H, m), 2.19 (1H, m), 2.31 (1H, m), 4.40 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.83 (1H, DD, J = 7.9, 1.5 Hz), 6.87 (1H, d, J = 7.9 Hz), 6.95 (1H, d, J = 1.5 Hz), 7.93 (1H, DD, J = 8.8, 2.0 Hz), 8.26 (1H, d, J = 2.0 Hz), 8.60 (1H, d, J = 8.8 Hz), 9.40 (1H, t, J = 5.7 Hz), 11.61 (1H, s), 12.09 (1H, s).

Example 129

5-Bromo-2-[(TRANS-4-carboxylatomethyl)amino] -4 - methoxy-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 110, in the form of white needles with a yield of 26%.

So pl. 245-249oC.

Mass: 533 (MH+).

+H-NMR (400 MHz, DMSO-d6) :

1.32 - 1.50 (4H, m), 1.90 - 2.18 (1H, m), 2.26 (1H, m), 3.87 (3H, s), 4.37 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.80 (1H, DD, J = 7.9, 1.6 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 1.6 Hz), 8.10 (1H, s), 8.42 (1H, s), 9.21 (1H, t, J = 5.7 Hz), 11.96 (1H, s), 12.01 (1H, s).

Example 130

5-Chloro-2-(2,5-dimethoxybenzamide)-N-(3,4 - methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 56%.

Mass: 469 (MH+).

1H-NMR (400 MHz, CDCl3) :

3.84 (3H, s), 4.04 (3H, s), 4.52 (2H, d, J = 5.7 Hz), 5.94 (2H, s), 6.34 (1H, t, J = 5.7 Hz), 6.73 - 6.84 (3H, m), 6.95 (1H, d, J = 9.0 Hz), 7.06 (1H, DD, J = 3.1, 9.0 Hz), 7.38 - 7.44 (2H, m), 7.77 (1H, d, J = 3.1 Hz), 11.71 (1H, s).

Example 131

4-Amino-5-b which was olocale, as in Example 34, in the form of light brown crystals with a yield of 78%.

1H-NMR (400, DMSO-d6) :

4.38 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.19 (2H, s), 6.80 (1H, DD, J = 1.6, 7.9 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.80 (2H, d, J = 5.9 Hz), 8.05 (1H, s), 8.22 (1H, s), 8.84 (2H, d, J = 5.9 Hz), 9.10 (1H, t, J = 5.7 Hz), 13.35 (1H, s).

Example 132

4-Amino-5-bromo-2-[(4-tert-butylbenzenesulfonyl)amino] - N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystalline powder with a yield of 79%.

So pl. 234-235oC.

1H-NMR (400 MHz, DMSO-d6) :

1.25 (9H, s), 4.28 (2H, d, J = 5.8 Hz), 6.00 (2H, s), 6.78 (1H, DD, J = 1.6, 8.1 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.88 (1H, d, J = 8.1 Hz), 7.00 (1H, s), 7.49 - 7.54 (2H, m), 7.66 - 7.71 (2H, m), 7.86 (1H, s), 8.97 (1H, t, J = 5.8 Hz), 12.68 (1H, s).

Example 133

4-Amino-5-bromo-2-(methanesulfonyl)amino-N-(3,4 - methylenedioxy benzyl)benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 41%.

So pl. 178-180oC.

1H-NMR (400 MHz, DMSO-d6) :

3.08 (3H, s), 3.83 (3H, s), 4.33 (2H, d, J = 5.7 Hz), 6.17 (2H, s), 6.94 (1H, s), 7.11 (1H, d, J = 8.6 Hz), 7.25 (1H, DD, J = 2.0, 8.6 Hz), 7.36 (1H, d, J = 2.0 Hz), 8.00 (1H, s), 9.07 (1H, t, J = 5.7 Hz), 11.80 (1H, s).

Example 134

5-Bromo-2-bansilal the e 34, in the form of white crystals with a yield of 69%.

So pl. 172-173oC.

1H-NMR (400 MHz, DMSO-d6) :

4.31 (2H, d, J = 5.9 Hz), 6.77 (1H, DD, J = 1.6 Hz, 7.9 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.89 (1H, d, J = 7.9 Hz), 7.45 - 7.55 (3H, m), 7.60 - 7.74 (4H, m), 9.33 (1H, m), 11.56 (1H, s).

Example 135

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[[(S)-5 - oxo-2-tetrahydrofuranyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 24%.

1H-NMR (400 MHz, DMSO-d6) :

2.23 - 2.35 (1H, m), 2.52 - 2.63 (3H, m), 3.84 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 5.12 - 5.17 (1H, m), 7.12 (1H, d, J = 8.6 Hz), 7.32 (1H, DD, J = 8.0, 2.4 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.00 (1H, DD, J = 1.6, 8.9 Hz), 8.30 (1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 8.9 Hz), 9.41 (1H, t, J = 5.7 Hz), 12.02 (1H, s).

Example 136

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[((R)-5 - oxo-2-tetrahydrofuranyl)amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 42%.

So pl. 231-232oC.

1H-NMR (400 MHz, DMSO-d6) :

2.23 - 2.35 (1H, m), 2.52 - 2.63 (3H, m), 3.84 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 5.12 - 5.17 (1H, m), 7.12 (1H, d, J = 8.6 Hz), 7.32 (1H, DD, J = 8.0, 2.4 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.00 (1H, DD, J = 1.6, 8.9 Hz), 8.30 (1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 8.9 Hz), 8.30 (1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 8.9 Hz), 9.41 (1H, t, J = 5.7 Hz), rendiesel)benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 59%.

1H-NMR (400 MHz, CDCl3) :

1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.64 (4H, m), 2.06 - 2.14 (4H, m), 2.25 - 2.36 (2H, m), 4.13 (2H, K, J = 7.1 Hz), 4.42 - 4.49 (4H, m), 5.97 (2H, s), 6.30 (1H, t, J = 5.5 Hz), 5.97 (2H, s), 6.83 (1H, s); 7.49 (1H, s), 8.20 (1H, s), 11.57 (1H, s).

Example 138

4-Amino-5-bromo-N-(3-chloro-4-methoxybenzyl)-2- [[TRANS-4-(etoxycarbonyl)cyclohexanecarbonyl]amino]benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 67%.

1H-NMR (400 MHz, DMSO-d6) :

1.26 (3H, t, J = 7.1 Hz), 1.42 - 1.64 (4H, m), 2.24 - 2.37 (2H, m), 3.91 (3H, s), 4.13 (2H, K, J = 7.1 Hz), 4.46 (2H, s), 4.49 (2H, d, J = 5.6 Hz), 6.30 (1H, t, J = 5.6 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.20 (1H, DD, J = 2.2, 8.4 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.49 (1H, s), 8.21 (1H, s), 11.54 (1H, s).

Example 139

4-Amino-5-bromo-2-[(TRANS-4-carboxylatomethyl)- amino] -N-(3,4-methylenedioxybenzyl]benzamide

< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 75%.

1H-NMR (400 MHz, DMSO-d6) :

1.30 - 1.47 (4H, m), 1.90 - 1.99 (4H, m), 2.13 - 2.24 (2H, m), 4.33 (2H, d, J = 5.6 Hz), 5.98 (2H, s), 6.00 (2H, s), 6.77 (1H, DD, J = 1.6, 8.1. Hz), 6.88 (1H, d, J = 1.6 Hz), 7.90 (1H, s), 8.04 (1H, s), 8.95 (1H, t, J 4.0 Hz), at 11.93 (1H, s).

BR>
< / BR>
Specified in the title compound was obtained as in Example 34, in the form of white crystals with a yield of 64%.

So pl. 274-276oC.

1H-NMR (400 MHz, DMSO-d6) :

1.30 - 1.47 (4H, m), 1.90 - 1.98 (4H, m), 2.12 -2.23 (2H, m), 3.83 (3H, s), 4.35 (2H, d, J = 5.6 Hz), 6.01 (2H, s), 7.11 (1H, d, J = 8.6 Hz), 7.25 (1H, DD, J = 8.6, 2.2 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.90 (1H, s), 8.03 (1H, s), 8.98 (1H, t, J = 5.4 Hz), 11.89 (1H, s).

Example 141

2-[[(R)-4-Carbarnoyl-2-hydroxybutyryl] amino] -N- (3-chloro-4-methoxybenzyl)-5-cyanobenzoic

< / BR>
N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[[(R)-5-oxo-2 - tetrahydrofuranyl] amino] benzamide (500 mg) was dissolved in 2.5 ml of 1,4-dioxane was added 2.5 ml of concentrated aqueous ammonia. The mixture was boiled under reflux and then concentrated. The residue was purified column chromatography on silica gel (solvent: ethyl acetate) and received 150 mg specified in the title compound as white crystals, yield 29%.

So pl. 168-170oC.

1H-NMR (400 MHz, DMSO-d6) :

1.68 - 1.80 (1H, m), 1.95 - 2.05 (1H, m), 2.12 - 2.30 (2H, m), 3.84 (3H, s), 4.05 - 4.13 (1H, m), 4.40 - 4.47 (2H, m), 6.35 (1H, s), 6.79 (1H, s), 7.09 - 7.15 (1H, m), 7.29 - 7.42 (2H, m), 7.43 (1H, d, J = 2.0 Hz), 7.96 (1H, DD, J = 2.0, 8.8 Hz), 8.27 (1H, d, J = 2.0 Hz), 8.77 (1H, d, J = 8.8 Hz), 9.40 (1H, t, J = 5.7 Hz), 12.16 (1H, sh).

Example 142

2,4-Diamino-N-hexylcaine (8.78 g) and 1-hydroxybenzotriazol (5.75 g) was added in 500 ml of acetonitrile. The mixture was heated 3 h at 60oC, cooled and filtered, the resulting crystals. The filtrate was concentrated and extracted with ethyl acetate. The ethyl acetate was removed and obtained crude crystals. To the crystals was added ethanol (50 ml), dimethylformamide (50 ml) and platinum oxide (50 mg). The resulting mixture was subjected to catalytic hydrogenation at high pressure for 2 h at room temperature. The catalyst was separated by filtration and the solvent drove away. To the residue was added dichloromethane to conduct crystallization. The crystals were separated by filtration, dried and received 4.63 g specified in the connection header in the form of grey crystals, yield 42%.

So pl. 180-182oC.

1H-NMR (400 MHz, DMSO-d6) :

4.25 (2H, d, J = 6.0 Hz), 5.28 (2H, s), 5.76 - 5.80 (2H, m), 5.96 (2H, s), 6.39 (2H, s), 6.81 - 6.86 (2H, m), 7.28 (1H, d, J = 9.2 Hz), 8.21 (1H, t, J = 6.0 Hz).

Example 143

5-Bromo-2,4-diamino-N-(3,4-methylenedioxybenzyl)benzamide

< / BR>
2,4-Diamino-N-(3,4-methylenedioxybenzyl)benzamide (6.47 g) suspended in 50 ml of ethanol and slowly added 3 ml of 47% aqueous Hydrobromic acid. After completion of the deposition of crystals in the solvent is completely drove in a vacuum. To the residue was added dimethyl sulfoxide (30 ml), cm is full-time chromatography on silica gel (solvent: toluene/ethyl acetate (1:1)) and received 1.80 g specified in the title compound as white crystals, yield 22%.

So pl. 148-150oC.

1H-NMR (400 MHz, DMSO-d6) :

4.25 (2H, d, J = 5.9 Hz), 5.45 (2H, s), 5.97 (2H, s), 6.02 (1H, s), 6.49 (2H, s), 6.74 (1H, DD, J = 1.6, 8.1 Hz), 6.82 - 6.86 (2H, m), 7.62 (1H, s), 8.44 (1H, t, J = 5.9 Hz).

The study claimed compounds on acute toxicity

Connection example 43 is injected rats in Vienna. The compound obtained in example 110 administered to rats orally. In the case of compound from example 43 there were no deaths in rats at introducing the compound at a dose of about 20 mg/kg or less. In the case of compound from example 110 there were no deaths in rats at introducing the compound at a dose of about 600 mg/kg or less.

1. Derivatives of Anthranilic acid of General formula I or their pharmacologically acceptable salts

< / BR>
where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula

< / BR>
where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group, R is an integer from 0 to 6,

a group of the formula

< / BR>
where R13represents a hydrogen atom, a lower alkyl group,
6
are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring;

W represents a group - N = or-CH=;

R7and R8is the same or different and represent a hydrogen atom, a lower alkyl group,

or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form piperidino or pyrolidine ring;

A represents a hydrogen atom, optionally halogenated lower alkyl group or a group of the formula-X- (CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-;

Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, CT is ora can be replaced by actigraphy, by cyano, lower alkylcarboxylic group, carboxypropyl or lower alkoxycarbonyl group, piperidino group;

m is an integer from 0 to 6;

Y represents an oxygen atom;

n is an integer from 6 to 6.

2. Derivatives of Anthranilic acid of General formula II or their pharmacologically acceptable salts

< / BR>
where R1- R4- same or different and mean a hydrogen atom, halogen atom, cyano, lower alkoxygroup, pyrazolidine group;

R2may be 1,2,4-triazoline group;

R14is phenylalkyl, substituted lower alkoxygroup;

R15represents the amino group.

3. Derivatives of Anthranilic acid of General formula III or their pharmacologically acceptable salts

< / BR>
where R1- R4have the meanings specified in paragraph (2 formulas;

R8means a hydrogen atom;

A represents a hydrogen atom, a group of the formula-X- (CH2)m-Z, where X is;

Z represents a group of formula-NR11R12in which R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring, possibly substituted by hydroxy is proizvodnye Anthranilic acid of General formula IV or their pharmacologically acceptable salts

< / BR>
where R1- R4represent a hydrogen atom, a halogen atom;

m is an integer from 0 to 6;

Z represents a phenyl group, a substituted lower alkoxycarbonyl group.

5. Drug exhibiting inhibitory activity against cyclic guanozinmonofosfata, characterized in that it contains an effective amount of a derivative of Anthranilic acid or its pharmacologically acceptable salt according to p. 1 and a pharmacologically acceptable carrier.

6 Priority signs:

27.12.93 - R1, R2, R3or R4are the same or different and represent a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, a nitrogroup, a cyano, a group of the formula -(CH2)p-NR9R10, triazolyl group, pyrazolidine group, a group of the formula-S-(O)q-R13(where R13represents a hydrogen atom or a lower alkyl group and q is an integer from 0 to 2);

R7and R8is the same or different and represent a hydrogen atom or a lower alkyl group,

W represents a group of formula-CH=;

A represents an atom Bogoroditse-CO - or-CH2-;

09.11.94 - R1, R2, R3or R4are the same or different and represent a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, a nitrogroup, a cyano, a group of the formula -(CH2)p-NR9R10, triazolyl group, pyrazolidine group, a group of the formula-S-(O)q-R13(where R13represents a hydrogen atom or a lower alkyl group and q is an integer from 0 to 2);

R7and R8is the same or different and represent a hydrogen atom or a lower alkyl group, or R1and R7together with the carbon atoms and the nitrogen to which they are respectively attached, form a ring;

W represents a group of formula - N = or-CH=;

A represents a hydrogen atom, optionally halogenated lower alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-

 

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The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to organic chemistry, namely, the method of production of new derivatives etilaminopodandov General formula I

R4---N< / BR>
where a and b independently of one another are H, fluorine, chlorine, bromine, C1-C4alkyl, C1-C4alkoxy group or a halogen (C1-C4) alkyl, provided that a and b cannot simultaneously represent H; D and E independently represent H or fluorine, R1represents H, C1-C4alkyl, R2is1-C4the alkyl, C1-C4alkoxy group or phenyl, or R1and R2together with the nitrogen atom to which they are attached, form morpholino, piperidine, pyrolidine or azetidinone ring, optionally substituted C1-C4-alkyl, R3represents H, R4is trichloromethyl,2-C8the alkyl (optionally substituted with halogen, C1-C8-alkoxy group, or R12S(0)nwhere R12is1-C4-alkyl, and n is 0,1>-quinil,1-C8-alkoxy group, mono - or di(C1-C4-alkylaminocarbonyl or group R8ON= C(CN), where R13represents a C1-C4-alkyl, or R3and R4together with the group C(O)N to which they are attached, form azetidin-2-about the ring, which possess fungicidal properties and can be used to fight fungal infections of plants

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The invention relates to new chemical substances possessing valuable properties, in particular derivatives pyridyl General formula (I)

< / BR>
where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts
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