Derivatives pyridonecarboxylic acid or their salts and antibacterial

 

(57) Abstract:

The invention relates to new compounds of formula (1), where R1, R2, R3, R4, R5, R6X, Y, Z, W have the values. The compounds of formula (1) possess good antibacterial properties against gram-negative and gram-positive bacteria, and have very low toxicity, and therefore could be useful synthetic antibacterial agents. 2 C. and 8 C.p. f-crystals, 2 PL.

The invention relates to new derivatives pyridonecarboxylic acids or their salts having excellent antibacterial properties and oral absorption, and to antibacterial agents containing such compounds.

It is known that many compounds having a basic skeleton pyridonecarboxylic acid, useful as synthetic antibacterial agents due to their excellent antibacterial properties and a wide antibacterial spectrum. Of these compounds widely used in clinical practice for the treatment of infectious diseases found norfloxacin (application N 53-141286 patent Japan), enoxacin (application N 55-31042 patent I the NT Japan), tosufloxacin (application N 60-228479 patent Japan) and the like.

However, these compounds need further improvement in relation to antibacterial activity, absorption in the gastrointestinal tract, metabolic stability and side effects and, in particular, in respect of phototoxicity and cytotoxicity.

Thus, the present invention is the creation of new connections, which would be satisfactory in these respects.

Disclosure of the invention

In view of the above situation, the creators of the present invention conducted intensive studies in search of compounds that would be excellent synthetic antibacterial agents in clinical practice, and found that the new compounds represented by following General formula (1), possess good antibacterial properties against gram-negative and gram-positive bacteria, and have very low toxicity and therefore would be very useful synthetic antibacterial agents. Based on this finding and was created by the present invention.

< / BR>
[In the formula, R1issue alkoxygroup or a substituted or an unsubstituted amino group; R3represents a hydrogen atom or halogen atom; R4represents a hydrogen atom or halogen atom; R5represents a halogen atom or optionally substituted saturated cyclic amino group; R6represents a hydrogen atom, a halogen atom, a nitro-group or an optionally protected amino group;

X, Y and Z may be the same or different and respectively represent a nitrogen atom, -CH= or-CR7= (where R7represents a lower alkyl group, halogen atom or cyano) (provided that at least one of the symbols X, Y and Z represents a nitrogen atom and W represents a nitrogen atom or - CR8= (where R8represents a hydrogen atom, halogen atom or lower alkyl group)].

Thus, in accordance with the present invention offers derivatives pyridonecarboxylic acid represented by above General formula (I) or their salts and antibacterial agent containing the derivative pyridonecarboxylic acid or their pharmaceutically acceptable salts as active ingredients.

The best way of carrying out the invention

New derivatives of pyridonecarboxylic acid of the present invention presented is Borovoy acid, represented by the General formula (1), means the Deputy contains 1-7, preferably 1-5, carbon atoms in the case of a linear Deputy and 3-7 carbon atoms in the case of a cyclic substituent.

In the General formula (1) R1represents a hydrogen atom or carboxyl-protective group, and used herein, the term "carboxyl-protective group" means the ester residue of the carboxylate and carboxyl-protective group may be any carboxylate ester residue, relatively easily fissionable with the formation of the corresponding free carboxyl group. Approximate carboxyl-protective groups include groups which can be split by hydrolysis, catalytic reduction and other processing methods under mild conditions, such as lower alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, pencilina group, exilda group and heptylene group; lower alkeneamine groups such as vinyl group, allyl group, 1-protanilla group, bucinellina group, penttila group, examilia group and heptenyl naftalina group; and groups that can be easily split in the body, such as lower alkanoyloxy lower alkyl groups, such as acetoxymethyl group and pivaloyloxymethyl group; a lower alkoxycarbonyl lower alkyl groups, such as methoxycarbonyl-oxymethylene group and 1 - ethoxycarbonylmethylene group; lower alkoxymethyl groups, such as methoxymethyl group; Victorina group, such as phthalidyl; di-lower alkylamino lower alkyl group such as 1-dimethylaminomethylene group; and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group. It should be noted that most preferably R1represents a hydrogen atom.

In the General formula (1) R2represents a hydroxyl group, a lower alkoxygroup or a substituted or an unsubstituted amino group. Examples of substituents for the substituted amino group include lower alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, pencilina group, exilda group and heptylene group; lower alkeneamine groups such as vinyl group, allyl group, 1-protanilla group, butanilicaine group and 1-phenylethylene group; aryl groups such as phenyl group and naftalina group; lower alcoholnye groups such as formyl group, acetyl group, propylaniline group, bucilla group and isobutylene group; lower alkoxycarbonyl groups, such as methoxycarbonyl group and ethoxycarbonyl group; aroline groups, such as benzoline group and napolina group; amino acid residues or Oligopeptide residues, such as glycyl, leucyl, poured, alanyl, i.e. phenylalanyl, alanyl-alanyl, glycyl-poured and glycyl-glycyl - poured, and amino acid residues or oligo-peptide residues, in which the functional group is protected by acyl, lower aralkyl or other protective groups commonly used in the chemistry of peptides; and the cyclic amino group. Of the above substituents can be selected one or two substituent, which may be the same or different. It is expected that connection protected amino acid or Oligopeptide residues will have improved solubility in water.

Preferably R2represents an amino group, a lower alkylamino, di-lower alkylamino, lower alkanolamines, amino, protected amino acid which indicate the amino group, methylaminopropyl, ethylamino and dimethylaminopropyl, of which the most preferred is an amino group. It should be noted that for R2low alkoxygroup preferably include low alkoxygroup having 1-4 carbon atoms, such as methoxy group, ethoxypropan, propoxylate and butoxypropan, of which preferred is a methoxy group.

Further, in General formula (1) R3represents a hydrogen atom or halogen atom; R4represents a hydrogen atom or halogen atom; R5represents a halogen atom or optionally substituted saturated cyclic amino group; R6represents a hydrogen atom, a halogen atom, a nitro-group or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, -CH= or-CR7= (where R7represents a lower alkyl group, halogen atom or cyano), and W represents a nitrogen atom or-CR8= (where R8represents a hydrogen atom or halogen atom).

The halogen atoms represented by the symbols R3, R4, R5, R6, R7and R9include fluorine atom, chlorine atom, bromine atom and iodine atom.predstavlyaet fluorine atom, and R8preferably represents a chlorine atom or a bromine atom.

The lower alkyl groups represented by the symbols R7and R8include those which contain 1 to 7 carbon atoms, such as methyl group, ethyl group, through the group, bucilina group, pencilina group, exilda group and heptylene group, of which preferred is methyl group.

As for the radicals X, Y and Z, two or three of them may be the same or, alternatively, they may differ from each other. It is necessary, however, to at least one of X, Y and Z represented the nitrogen atom. Exemplary preferred combinations of X, Y and Z are nitrogen for X and-CH= or-CR7= (where R7represents a lower alkyl group, halogen atom or cyano) for Y and Z; nitrogen for Y, and-CH= or-CR7= (where R7represents a lower alkyl group or halogen atom) for X and Z; and nitrogen for X and Y, and-CH= or-CR7= (where R7represents a lower alkyl group or halogen atom) for z

It should also be noted that the compound of formula (1) has naphthylidine skeleton, when W is nitrogen, and quinoline skeleton, when W represents - CR8=, and most or lower alkyl group).

Further, optionally substituted, saturated cyclic amino group represented by the symbol R5may optionally contain in the ring one or more heteroatoms, such as nitrogen atom, oxygen atom and sulfur atom and the carbonyl carbon and may be either monocyclic or bi - or tricyclic. Saturated cyclic amino group preferably represents a 4-7-membered ring, when it is monocyclic, 7 to 11-membered ring, when she bicyclic, and 9-15-membered ring, when she tricyclic. Examples of such cyclic amino groups include saturated monocyclic amino group having 3-7-membered ring containing one nitrogen atom, such as aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl; a saturated monocyclic amino group having 3 to 7-membered ring containing two nitrogen atom, such as piperazine-1-yl and homopiperazin-1-yl; a saturated monocyclic amino group having 3-7-membered ring containing, in addition to the nitrogen atom, a heteroatom, selected from oxygen atom and sulfur atom, such as oxazolidin-3-yl, morpholine-4-yl, thiazolidin-1-yl and thiomorpholine-4-yl; a saturated bi - or tricyclic amino groups, such as tetrahydroquinolin-1-yl; and on the E., as 2,8-diaza-Spiro[4.4] nonan-2-yl, 5 - azaspiro [2.4]heptane-5-yl, 7-azabicyclo[2.2.1] heptane-7-yl, 2,8-diazabicyclo[4.3.0] nonan-8-yl, 5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl, 2,5-diazabicyclo-[2.2.1]heptane-2-yl and 3,8-diazabicyclo [3.2.1]Octan-3-yl.

The atom that is part of a ring such saturated cyclic amino group may be substituted with a suitable substituent and examples of such substituents include hydroxyl group, lower alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted amino lower alkyl group, lower alkoxygroup and halogen atoms.

Exemplary lower alkyl groups for the substituent a saturated cyclic amino group include those which contain 1 to 7 carbon atoms, such as methyl group, ethyl group, through the group, bucilina group, pencilina group, exilda group and heptylene group; an approximate lower alkoxygroup include those which contain 1 to 7 carbon atoms, such as methoxy group, ethoxypropan and n-propoxylate; and the approximate halogen group include a fluorine atom, a chlorine atom and a bromine atom. Of the Vice saturated cyclic amino groups substituted amino and substituted aminonitriles alkylsilane examples of the substituted amino groups, and substituted and unsubstituted eminently alkyl groups include methylaminopropyl, ethylamino, dimethylaminopropyl, aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-amino-1-ethyl group, methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group, leucyl-amino group, poured-aminogroup, alanyl-amino group and alanyl-alanyl-amino group.

From the above-described saturated cyclic amino groups are most preferred group for R5includes groups represented by the following formulas (a) and (b):

< / BR>
< / BR>
[where A represents an oxygen atom, a sulfur atom or NR9(where R9represents a hydrogen atom or a lower alkyl group), e represents a number from 3 to 5, f is a number from 1 to 3, g represents a number from 0 to 2, J1I , J2and J3which may be the same or different, represent a hydrogen atom, hydroxyl group, lower alkyl group, Eminescu alkyl group, amino group, lower alkylamino, lower alkoxygroup or halogen atom].

Examples of lower alkyl groups, minnisha alkyl groups, lower alkylamino, low alkoxygroup and the halogen atom in the above formulae (a) and (b) are the same as those described lidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl, and the approximate cyclic amino group represented by the formula (b) include piperazine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, homopiperazin-1-yl, N-diazolidinyl and N-oxazolidinyl. When R5represents a cyclic group, R5preferably represents a cyclic amino group represented by the formula (a), and most preferably, azetidin-1-yl or pyrrolidin-1-yl.

Most preferred are represented by formulas (a) and (b) are the following groups:

3-aminoamides-1-ilen group,

3-methylaminomethyl-1-ilen group,

3-dimethylimidazolidin-1-ilen group,

3-aminomethylpyridine-1-ilen group,

3-amino-2-methylaziridine-1-ilen group,

3-amino-3-methylaziridine-1-ilen group,

3-alanyl-aminotetralin-1-ilen group,

3-poured-aminotetralin-1-ilen group,

3-pyrrolidin-1-ilen group,

3-hydroxypyrrolidine-1-ilen group,

3,4-dihydroxypyrrolidine-1-ilen group,

3-ethoxypyrrolidine-1-ilen group,

3 methylpyrrolidine-1-ilen group,

3-hydroxy-4-methylpyrrolidine-1-ilen group,

3-aminopyrrolidine-1-ilen group,

3-methylaminopropyl-1-ilen group,

3-aminomethylpyrrolidine-1-ilen group,

3-amino-3-methylpyrrolidine-1-ilen group,

3-amino-4-methylpyrrolidine-1-ilen group,

3-amino-5-methylpyrrolidine-1-ilen group,

3-methylamino-4-methylpyrrolidine-1-ilen group,

3-dimethylamino-4-methylpyrrolidine-1-ilen group,

3 ethylamino-4-methylpyrrolidine-1-ilen group,

3 diethylamino-3-methylpyrrolidine-1-ilen group,

3 diethylamino-4-methylpyrrolidine-1-ilen group,

3-aminomethyl-4-methylpyrrolidine-1-ilen group,

3-methylaminomethyl-4-methylpyrrolidine-1-ilen group,

3-dimethylaminomethyl-4-methylpyrrolidine-1-ilen group,

3-ethylaminomethyl-4-methylpyrrolidine-1-ilen group,

3-(1-amino-ethyl)-4-methylpyrrolidine-1-ilen group,

3-(2-amino-ethyl)-4-methylpyrrolidine-1-ilen group,

3-amino-4-ethylpyrrolidin-1-ilen group,

3-methylamino-4-ethylpyrrolidin-1-ilen group,

3-dimethylamino-4-ethylpyrrolidin-1-ilen group,

3 ethylamino-4-ethylpyrrolidin-1-ilen group,

3 diethylamino-4-ethylpyrrolidin-1-ilen group,

3-aminomethyl-4-ethylpyrrolidin-1-ilen group,

3-methylaminomethyl-4-ethylpyrrolidin-1-ilen group,

3-dimethylaminomethyl-4-ethylpyrrolidin-1-ilen groups is metilamino-3-methylpyrrolidine-1-ilen group,

3-amino-3,4-dimethylpiperidin-1-ilen group,

3-amino-4,4-dimethylpiperidin-1-ilen group,

3-amino-4,5-dimethylpyrimidin-1-ilen group,

3-amino-2,4-dimethylpyridin-1-ilen group,

3-methylamino-3,4-dimethylpiperidin-1-ilen group,

2-methyl-3-aminopyrrolidine-1-ilen group,

2-methyl-3-dimethylaminopropan-1-ilen group,

3-amino-4-ethoxypyrrolidine-1-ilen group,

3-alanyl-aminopyrrolidine-1-ilen group,

3-poured-aminopyrrolidine-1-ilen group, piperazine-1-ilen group, 4-methylpiperazin-1-ilen group, 3-methylpiperazin-1-ilen group, 2-methylpiperazin-1-ilen group, 3,4-dimethylpiperidin-1-ilen group, 3,5-dimethylpiperazine-1-ilen group, 3,3-dimethylpiperazine-1-ilen group, 3,4,5-trimethylpyrazole-1-ilen group, piperidine-1-ilen group, 4-aminopiperidin-1-ilen group, 4-dimethylaminopyridine-1-ilen group, 4-hydroxypyrene-DIN-1-ilen group, morpholine-4-ilen group, 2-aminomethylpropanol-4-ilen group, 2 - methylaminomethyl-4-ilpa group, 2-dimethylaminomethyl-4 - ilen group, thiomorpholine-4-ilen group, homopiperazin-1-ilen group, 4-methylhomopiperazine-1-ilen group, N-thiazolidinedione group and N-oxazolidinyl group.

The preferred combination of R1, R2, R3, R4, R5, R6X, Y, Z and W are those in which R1represents a hydrogen atom, R2represents an amino group, a lower alkylamino or di-nor is that the nitrogen atom, Y and Z are-CH= or CR7= (where R7represents a lower alkyl group or halogen atom), W represents-CR8= (where R8represents a halogen atom or a lower alkyl group), R5represents a group of formula (a) (e = 3 or 4) and R6represents a hydrogen atom. The preferred combination of R1, R2, R3, R4, R5, R6X, Y, Z and W are those in which R1represents a hydrogen atom, R2represents the amino group, R3represents a fluorine atom, R4represents a fluorine atom, X represents a nitrogen atom, Y represents-CF= -, Z is-CH=, W is-CCl=, -CBr= or-CCH3=, R5represents a group of formula (a) (e = 3) and R6represents a hydrogen atom.

Salt described above derivatives pyridonecarboxylic acid of formula (1) can be acid-additive or basic additive salts. Used in this description, the term "salt" includes chelate salt with boron compound. Exemplary acid additive salts include (i) salt with a mineral acid, such as hydrochloric acid or sulfuric acid; (ii) salts with organic carboxylic acid, such as formic acid, citric acid, trichloroacetic, such as methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid, mesitylenesulfonic acid or naphthalenesulfonate acid; and estimated major additive salts include (i) salt with an alkaline metal such as sodium or potassium; (ii) salts with alkaline earth metal such as calcium or magnesium; (iii') ammonium salt; (iv') salts with nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholin, diethylamin, cyclohexylamine, procaine, dibenzylamine, N-benzyl-phenethylamine, 1-fenamin or N, N'-dibenziletilendiaminom. Exemplary boron compounds include boron halides such as boron fluoride, and the lower allocmemory, such as acetochlor.

Derivatives pyridonecarboxylic acids and their salts of the present invention may contain, in addition to resolutional form, also in the form of a hydrate or solvate. Thus, the connection of the present invention includes crystalline, hydrate and solvate forms. In addition, derivatives pyridonecarboxylic acids and their salts may be in the form of optically active substances such optically active substance is also in the sterile form (CIS - or TRANS-) stereoisomer and a stereoisomer is also in the scope of the compounds of the present invention.

Derivatives pyridonecarboxylic acids and their salts of the present invention represented by the above formula (1) can be obtained in any way, properly selected in accordance with such factors as the type of substituents, and the examples of such methods are described below.

(Method 1)

Of the compounds represented by the General formula (1), compounds (1A) in which R1represents a hydrogen atom or a lower alkyl group and R5represents a halogen atom, can be obtained, for example, method 1, shown in the reaction scheme presented in the end of the description.

More specifically, the compound (1A) of the present invention is produced by interaction of the compound (A) with orthoformates, such as meteorophobia or utilitiarian, derivatization acrylate (C), the interactions derived acrylate (C) aminoguanidinium (C) obtaining the compound (D) cyclization of the compound (D) to obtain the compound (E) and hydrolysis of the compound (E) to obtain the compound (1A).

The reaction between the compound (A) and orthoformiate usually carried out at 0-160oC, preferably 50-150oC, usually during the period of time from 10 violaron number or more, preferably 1 to 10-fold molar quantity.

Interaction with compound (C) can be carried out without solvent or in a solvent. Used in this reaction, the solvent can be any, but he would not impact adversely on the reaction, and exemplary solvents include aromatic hydrocarbons, such as benzene, toluene and xylene; ethers, such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; aliphatic hydrocarbons such as pentane, hexane, heptane and naphtha; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nephratonia polar solvents, such as dimethyl-formamide and dimethyl sulfoxide; alcohols such as methanol, ethanol and propanol. This reaction is usually carried out at 0-150oC, preferably at 0-100oC, usually for a period of from 10 minutes to 48 hours. The compound (C) used relative to the compound (A) in equimolar amount or more, preferably 1-2-fold molar quantity.

In accordance with another variant of the compound (A) may be subjected to interaction with acetal, such as dimethylacetal N,N - dimethylformamide or diethylacetal N-dimethylformamide is set to any, but he would not impact adversely on the reaction, and exemplary solvents are those described above. This reaction is usually carried out at 0 - 150oC, preferably at room temperature to 100oC usually during the time from 10 minutes to 48 hours, preferably for 1-10 hours.

Further, the cyclization of the compound (D) compound (E) is carried out in a suitable solvent in the presence or absence of a base. Used in this reaction, the solvent can be any, but he would not impact adversely on the reaction, and exemplary solvents include aromatic hydrocarbons, such as benzene, toluene and xylene; ethers, such as diethyl ether, tetrahydrofuran, dioxane and monogram; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, propanol and butanol; and nephratonia polar solvents such as dimethylformamide and dimethylsulfoxide. Examples used basic compounds are alkali metals such as metallic sodium and metallic potassium; metal hydrides such as sodium hydride and calcium hydride; inorganic salts, such as sodium hydroxide, the hydroxide to the Aliya; the metal fluorides such as sodium fluoride and potassium fluoride; organic salts such as triethylamine and 1,8 - diazabicyclo[5.4.0]undecene (DBU). This reaction is carried out at a temperature of 0-200oC, preferably in the range from room temperature to 180oC and normally terminate within the time from 5 minutes to 24 hours. The primary connection is used relative to the compound (D) in equimolar amount or more, preferably 1-2-fold molar quantity.

The compound (E) is subjected to hydrolysis to remove carboxyl-protective group, R1aand/or amino-protective group, R2awith obtaining the compound (1A).

The hydrolysis may be conducted under any conditions commonly used in the hydrolysis, for example, in the presence of a base such as sodium hydroxide, potassium hydroxide and potassium carbonate, mineral acids such as hydrochloric acid, sulfuric acid and Hydrobromic acid, or organic acids such as p-toluensulfonate acid, in a solvent such as water, alcohol such as methanol, ethanol or propanol, or an ether, such as tetrahydrofuran or dioxane, a ketone such as acetone or methyl ethyl ketone, acetic acid or a mixture of such solvents is tours to 140oC, usually within 1-24 hours.

It should be noted that in the case of obtaining the compounds in which R6in the formula (1) represents an optionally protected amino group, first get the connection (S) via the above reaction using the compound (A), in which R6arepresents a halogen atom or a nitro-group, as the source material, and then get a connection (E1aby amination of the above-mentioned halogen atom or by nitrogroup reduction and compounds (E1a) get the compound (1A) by removing the amino-protective group, if necessary, and remove carboxyl-protective group.

(Method 2)

Of the compounds represented by the General formula (1), compounds in which R5represents an optionally substituted saturated cyclic amino group, can be obtained, for example, method 2, shown in the diagram at the end of the description.

More specifically, the compound (G) obtained by amination of the compound (F) using the compound represented by the formula, R5b-H.

This reaction is carried out in a solvent which has no adverse effect on the reaction, such as aromatic, as tetrahydrofuran, dioxane or monogram; halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; nephratonia polar solvents, such as dimethylformamide, dimethylsulfoxide or N - organic; acetonitrile or pyridine, and in the optional presence of a neutralizer such as sodium carbonate, calcium carbonate, sodium bicarbonate, triethylamine, 1,8-diazabicyclo[5.4.0] undecene (DBU) at a temperature of from room temperature up to 160oC. the reaction Time is from several minutes to 48 hours, preferably from 10 minutes to 24 hours. Connection5b-H is used relative to the compound (F) in equimolar amount or more, preferably 1 to 5-fold molar quantity. It should be noted that the compound (F) can be obtained as in the above-described method 1, and that, when R1is carboxyl-protective group, it can be replaced by a hydrogen atom by hydrolysis.

(Method 3)

Of the compounds represented by the General formula (1), compounds in which R1is carboxyl-protective group can be obtained, for example, method 3 shown in the diagram presented in the end of the description.

More specifically, Conn/SUP>. Solvents that can be used in this reaction include aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons, such as methylene chloride and chloroform; nephratonia polar solvents such as dimethylformamide and dimethylsulfoxide; and inert solvents, such as acetonitrile. The reaction temperature generally ranges from room temperature to 100oC. the Reaction is preferably carried out in the presence of a base, takaro as triethylamine, diisopropylethylamine, dicyclohexylamine, DBU, sodium carbonate, potassium carbonate and sodium hydroxide. It should be noted that the compound (H) can be obtained by the above-described methods 1 and method 2.

When in the source materials of the above-described method 1, 2 or 3 is the amino group, aminogroup, hydroxy group, mercaptopropyl, carboxyl group or the like, not participating in the reaction, such a group can be protected during the reaction and after the reaction, the protective group can be removed using the traditional method. As a protective group used in this case, can be any group, if only the resulting reaction compound of the present invention can be had is with any group, commonly used in the chemistry of peptides, amino sugars, and nucleic acids ("Protective Groups in Organic Synthesis", second edition, T. W. Green and P. G. M. Wuts, John Wiley & Sons Inc., 1991).

1) J. Heterocyclic Chem. 22, 1033 (1985)

2) Liebigs Ann. Chem. 29 (1987)

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4) J. Org. Chem. 35; 930 (1970)

5) Posted application N 62-246541 patent Japan

6) Posted application N 62-26272 patent Japan

7) Posted application N 63-145268 patent Japan

8) J. Med. Chem. 29, 2363 (1986)

9) J. Fluorin Chem. 28, 361 (1985)

10) Posted application N 63-198664 patent Japan

11) Posted application N 63-264461 patent Japan

12) Posted application N 63-104974 patent Japan

13) Application N 230948 for the European patent

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15) Published Japanese translation of PCT international publication of the application N 3-502452 patent

16) J. Het. Chem. 27, 1609 (1990)

The original compound (C) may be obtained by any method, and the following describes an exemplary method of obtaining.

The original compound (C) can be obtained by substitution of the halogen atom linked to a carbon atom that is part of a 6-membered ring, an amine, such as ammonia, alkylamine, benzylamine or the like, using known reactions of halogen-Aminogen, Deputy substituted amino group can satisfactorily remove the traditional way, as shown in reaction scheme A, is given at the end of the description. When R2arepresents a substituted or an unsubstituted amino group or an amino group substituted by a protective group can be carried out similar to the reaction of the halogen-amine substitution.

When there is no readily available candidate for the role of the source material, namely dehalogenating nitrogen-containing six-membered cyclic compounds having substituents corresponding to the substituents (R3and when X, Y and Z are CR7= or-CH=, R7or hydrogen) on nitrogen-containing six-membered ring of the target substance, the target substance can be obtained by using as source material more readily available dehalogenation six-membered nitrogen-containing cyclic compound. More specifically, an adequate reaction of substitution of substituents can be performed simultaneously with the reaction of the halogen - amine substitution of the substituted amino group. Examples of useful reactions of substitution of substituents is the process in which a halogen atom is substituted by the amino group and the amino group replaced by a halogen atom or Ciena replace a hydroxyl group, and then the hydroxyl group is replaced by a halogen atom, using a phosphorus halide or oxychlorine phosphorus; a process in which a bromine atom or a chlorine atom is replaced by fluorine atom, using this reagent, as potassium fluoride; a process in which the halogen atom is replaced by a hydrogen atom by hydrogenation, a process in which alkoxycarbonyl group or acyl group reduced to lower alkyl groups, using hydride compound; a process in which the carboxyl group is replaced by a hydrogen atom by decarboxylation; and combinations of the above processes. It should be noted that, when a compound that is introduced in this manner the amino group or hydroxyl group, is subjected to further reaction of substitution of substituents, it is sometimes necessary to protect the amino group or hydroxyl group. In this case, the protection can be carried out by telemedicine in the case of an amino group and by benzyloxypyridine in the case of hydroxyl groups. The protective group can be removed at the next appropriate stage. Participating in the reaction of halogen-amine substitution of the halogen atom represented on the diagram above the symbol Hal, not limited to any particular type. But preferred is a fluorine atom, possessing high is their highly reactive places such a place can be secured by replacing the fluorine atom by another halogen atom such as a bromine atom or a chlorine atom, using the reactions described above.

In accordance with another variation of the original compound (C) can be obtained by recovery of nitro group to amino conventional method, shown in scheme B, is provided at the end of the description.

Obtained the compound of the present invention is isolated and purified by usual method. The compound is obtained in the form of a salt, free carboxylic acid or free amine depending on the conditions of separation. However, due to the possibility of mutual transformation of forms of the compounds of the present invention can be obtained in the desired form. The connection represented by the above General formula (1) or its salt can be prepared in the form of antibacterial compositions with a pharmaceutically acceptable carrier suitable for parenteral administration such as injection, rectal administration, instillation into the eye or oral administration in solid or liquid form.

The injectable form of antibacterial compositions of the present invention may or nonaqueous environment. Examples of suitable nonaqueous carriers, diluents, and excipients include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters, suitable for injection, such as etiloleat. This composition may also contain additives such as preservative, wetting agent, emulsifier and suspendisse substance. The composition may be sterilized, for example, by filtration through a filter to remove bacteria or by introducing a sterilizing agents in the form of a sterilizing substance or sterile solid compositions, soluble in sterilized environment for injections, immediately prior to its application.

Dosage form for instillation in the eye, in addition to the compounds of the present invention, it is preferable to contain a solubilizer, preservative, isotherwise substance, thickening agent and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. When manufacturing such solid dosage forms of the compounds of the present invention is mixed with at least one inert diluent such as sucrose, lactose and the binding substance (for example, magnesium stearate, and so on). In the case of capsules, tablets or pills dosage form may also contain a buffering agent. Tablets and pills may have enterocele floor.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, the composition can also contain additives such as wetting agent, emulsifying agent, suspendisse substance and a sweetener, a flavoring substance, flavouring substance.

Dosage forms for enteral introduction preferably can, in addition to the compounds of the present invention, contain a filler, such as cocoa butter or wax for suppositories.

The dose of a compound of the present invention varies depending on the nature of the input connection, the method of administration, the desired period of treatment and other factors. However, usually compounds of the present invention is administered in an amount of about 0.1 to 1000 mg/kg / day and, in particular, about 0.5-100 mg/kg per day. If necessary, this dose the invention have a very strong antibacterial effect and low phototoxicity and cytotoxicity, and therefore could be widely used as medicines for humans and other animals, as well as medicines for fish, pesticides, preservatives for food, and the like. It is also expected that the compound of the present invention has antiviral properties and, in particular, anti-HIV (human immunodeficiency virus) activity and therefore will be effective in the prevention and treatment of AIDS.

Further, the present invention is described in more detail by examples and reference examples, which in no way limit the scope of the present invention.

Reference example 1

Synthesis of 2-(tert-butylamino)-3,5,6-cryptosporidia

To 40 ml of acetonitrile was added to 11.0 g of 2,3,5,6-tetrafluoropyridine and 18.5 g of tert-butylamine, and the mixture was stirred at 60oC for 3 days, then drove the solvent and the like. To the residue was added 100 ml of chloroform and the mixture was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.7 g specified in the title compounds as a pale yellow oil.

1H NMR (CDCl3)

of 1.45 (s, 9H), 4,40 (SHS, 1H), 7,16 (DDD, J=7 Hz, 8 Hz, 9 Hz, 1H)

Reference example 2

Synthesis of 2-benzylamino-6-(tert-butylamino)-3,5-d is Salamina; and the mixture was stirred at 160oC during the day and allowed to cool. After adding 50 ml of chloroform and the mixture was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to get about 16.5 g specified in the title compound as a dark green oil.

Reference example 3

Synthesis of 2-amino-6-(tert-butylamino)-3.5-diphereline

To 60 ml of methanol was added 10.7 g of crude 2-benzyl - amino-6-(tert-butylamino)-3.5-diphereline obtained as described above, together with 1.10 g of 10% palladium on coal and 3.8 g of concentrated hydrochloric acid, and the mixture was first made during the day. The catalyst was filtered

and drove away under reduced pressure, the solvent and the like. To the residue was added 150 ml of chloroform, and the mixture was washed with 80 ml of 10% aqueous sodium carbonate solution, and then washing was again extracted with 50 ml of chloroform. The chloroform layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 100 g; eluent: chloroform: n-hexane, 2:1, and then chloroform) to obtain 3.3 grams specified in the header aegc, 1H)

Example 1

Synthesis of ethyl 1-[6-tert-butylamino)-3,5-differencein-2-yl]-8 - chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 15 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro - 2,4,5-triterpenoid)acrylate obtained from 4,20 g of ethyl 3-chloro - 2,4,5-tripersonality in the usual way, was added 3,30 g 2 - amino-6-(tert-butylamino)-3.5-diphereline. The solution was concentrated under reduced pressure to obtain solid residue orange. To this residue was added 4.0 g of anhydrous potassium carbonate and 8 ml of N,N-dimethylformamide and the mixture was stirred at 90oC for 10 minutes, then allowed it to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water and the chloroform layer was washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and the result was 4,67 g specified in the title compounds as colorless powder.

Melting point: 203-205oC.

1H NMR (CDCl3) ;

of 1.39 (s, 9H), of 1.40 (t, J=7 Hz, 3H), 4,40 (kV, J-7 Hz, 2H), 4,70 (SHS, 1H), 7,21 iridin-2-yl]-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 5 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-bromo-2,4,5 - triterpenoid)acrylate obtained from 1,32 g of ethyl 3-bromo-2,4,5 - tripersonality in the usual way, was added 2-amino-6- (tert-butylamino)-3,5-giftability, while monitoring the reaction by TLC has confirmed the completion of the transformation in aminoacylating form. The solution was concentrated under reduced pressure to obtain a yellow solid residue. To this residue was added 1.2 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and the result was 1,41 g specified in the title compounds as colorless powder.

Melting point: 198-203oC

1H NMR (CDCl3) ;

to 1.38 (s, 9H), of 1.40 (t, J=7 Hz, 3H), and 4.40 (q, J= 7 Hz, 2H), 4,71 (SHS, 1H), 7,20 (DD, J = 8 Hz, 10 Hz, 1H), at 8.36 (DD, J=9 Hz, 10H), 8,54 (s, 1H)

Example 3


To 1 ml of a chloroform solution of ethyl 3-ethoxy-2-(2,3,4,5 - tetrafluorobenzoyl)acrylate obtained from 0.27 g of ethyl - 2,3,4,5 - tetrafluorobenzoate in the usual way, was added 2-amino-6- (tert-butylamino)-3,5-giftability, while monitoring the reaction by TLC has confirmed the completion of the transformation in aminoacylating form. The solution was concentrated under reduced pressure. To the residue was added 0.6 g of anhydrous potassium carbonate and 1 ml of N,N - dimethylformamide and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and the result was 0.15 g specified in the title compounds as colorless powder.

Melting point: 174-178oC

1H NMR (CDCl3) ;

of 1.40 (t, J= 7 Hz, 3H), of 1.42 (s, 9H), and 4.40 (q, J=7 Hz, 2H), 4,71 (SHS, 1H), 7,25 (DD, J=8 Hz, 10 Hz, 1H), 8,16 (DDD, J=2 Hz, 8 Hz, 10H), 8,48 (s, 1H)

Example 4

Synthesis of ethyl 1-[6-(tert-butylamino)-3,5-debtor the 3-ethoxy-2-(2,6-dichloro-5 - fornication)acrylate, obtained from 0.27 g of ethyl 2,6-dichloro-5 - porninterracial in the usual way, was added 2-amino-6- (tert-butylamino)-3,5-giftability, while monitoring the reaction by TLC has confirmed the completion of the transformation in aminoacylating form. The solution was concentrated under reduced pressure. To the residue was added 0.5 g anhydrous potassium carbonate and 1 ml of N,N - dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and as a result received 0,19 g specified in the title compound as yellow crystals.

Melting point: 158-160oC

1H NMR (CDCl3) ;

of 1.39 (t, J= 7 Hz, 3H), 1,45 (s, 9H), and 4.40 (q, J=7 Hz, 2H), 4,68 (SHS, 1H), 7,27 (t, J=9 Hz, 1H), 8,48 (d, J=7 Hz), is 8.75 (s, 1H)

Example 5

Synthesis of 1-[6-amino-3,5-divorciadas-2-yl] -8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To a mixed solution of 10 ml of 4 N. the 7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylate and the mixture was stirred at reflux for 5 hours. After adding 20 ml of distilled water the solution was allowed to cool. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain of 3.32 g specified in the title compounds as colorless powder.

Melting point: 280oC or higher

1H NMR (d-DMSO) ;

to 6.80 (s, 2H), 7,99 (t, J=9 Hz, 1H), scored 8.38 (t, J=9 Hz, 1H), 8,93 (s, 1H)

[Reference example 4]

Synthesis of 2-benzylamino-3,5,6-cryptosporidia

To 50 ml of acetonitrile was added 12.0 g 2,3,5,6-tetrafluoropyridine and 18.0 g of benzylamine and the mixture was stirred at reflux for 2 hours, then drove the solvent and the like. To the residue was added 150 ml of ethyl acetate, and the mixture was washed twice with 150 ml of distilled water and 150 ml of 10% aqueous citric acid solution. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 16.0 g specified in the title compounds as a pale yellow oil.

1H NMR (CDCl3) ;

4,58 (d, J=6 Hz, 2H), 4,81 (SHS, 1H), 7.23 percent (m, 1H), 7,35 (m, 5H)

[Reference example 5]

Synthesis of 2-amino-3,5, 6-cryptosporidia

To 40 ml of methanol was added 7,60 g of the crude 2-benzylmalonate, and the mixture was first made at the 50oC during the day. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the fact Podgornoe. The precipitate was dispersible in n-hexane and collected by filtration to obtain 3,85 g Kachanova the title compound as a colourless solid.

1H NMR (CDCl3) ;

4,53 (CL, 2H), 7,27 (m, 1H)

[Reference example 6]

Synthesis of 2-amino-3,5-debtor-6-(p-methoxybenzylamine)pyridine

To 10 ml of N-methylpyrrolidone added 3,90 g 2-amino-3,5,6 - cryptosporidia and 7.60 g of p-methoxybenzylamine.and the mixture was stirred in nitrogen atmosphere at 140oC during the day, and then allowed to cool. To the solution was added 50 ml of chloroform and washed solution three times 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, then the residue was subjected to chromatography (silica gel, 32 g; eluent: chloroform) to obtain 4,50 g specified in the title compounds as a pale yellow crude oil.

1H NMR (CDCl3) ;

of 3.80 (s, 3H), 4,18 (SHS, 1H), 4,49 (CL, 3H), 6.87 in (d, J=9 Hz, 2H), 6,99 (t, J=10 Hz, 1H), 7,28 (t, J=10 Hz, 2H)

Example 6

Synthesis of ethyl-8-chloro-1-[3,5-debtor-6- (p-methoxime the Il 3 ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate, obtained from 2,52 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 2.65 g of 2-amino-3,5-debtor - 6-(p-methoxybenzylamine)pyridine. The solution was concentrated under reduced pressure and to the residue was added 2.5 g of anhydrous potassium carbonate and 6 ml of N,N - dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layers were washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was dispersible in ethanol, collected by filtration and washed with ethanol to obtain 3,20 g specified in the title compound as a yellow powder.

Melting point: 197-200oC

1H NMR (CDCl3) ;

of 1.40 (t, J=7 Hz, 3H), of 3.80 (s, 3H), to 4.41 (q, J=7 Hz, 2H), 4,48 (m, 2H), 5,10 (SHS, 1H), 6,83 (d, J=7 Hz, 2H), 7,20 (d, J=7 Hz, 2H), 7,25 (DD, J=8 Hz, 9 Hz, 1H), 8,31 (DD, J=8 Hz, 10 Hz, 1H), of 8.47 (s, 1H)

Example 7

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid

To a mixed solution of 6 ml of 4 N. hydrochloric acid and 6 ml of acetic acid was added to 3.00 g of ethyl 8-chloro-evali under reflux for 16 hours. The solution was allowed to cool and settle and the precipitate was collected by decantation and washed by adding a small amount of distilled water, shaking, settling and decanting. To the precipitate was added to 10 ml of ethanol and the mixture was heated under reflux with stirring for 1 hour, allowed it to cool and settle and collect the precipitate by decantation. This draft was again added 10 ml of chloroform, and the mixture was stirred at reflux for 1 hour, allowed it to cool, and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1.25 g specified in the title compound as light brown powder.

Example 8

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-7-[(3S)]-3 - aminopyrrolidine-1-yl]-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 250 mg N,N-dimethylformamide was added 60 mg of 1-(6-amino-3, 5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1, 4 - dihydroquinoline-3-carboxylic acid and 60 mg of (3S)-3 - aminopyrrolidine and the mixture was heated under reflux with stirring at 90oC for 1 hour. After adding 1 ml ethanol mixture was allowed to cool, after which the precipitate was collected by filtre connection in the form of a light brown powder.

Melting point: 248-250oC (decomposition),

1H NMR (d6-DMSO) ;

of 1.73 (m, 1H), 2,03 (m, 1H), 4,67 (m, 2H), 6.75 in (CL, 2H), 7,95 (t, J=9 Hz, 1H), 7,98 (d, J=14Fu, 1H), 8,73 (s, 1H)

(Some signals obscured by the proton of the water and was indistinguishable).

Example 9

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3, 5-debtor - pyridine-2-yl]-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 350 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino - 3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid, 80 mg of 3-aminoacetanilide and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90oC for 1 hour. After adding 1 ml ethanol mixture was allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 86 mg specified in the title compounds as colorless powder.

Melting point: 260 - 263oC (decomposition)

1H NMR (d6-DMSO) ;

to 3.73 (m, 1H), 4.09 to (m, 2H), 4,67 (m, 2H), 6,74 (CL, 2H), 7,86 (d, J=14 Hz, 1H), 7,94 (t, J=9 Hz, 1H), 8,68 (s, 1H)

Example 10

Synthesis of 1-(6-amino-3,5-differencein-2-yl) -8-chloro-6-fluoro-7- (3-methylaminomethyl-1-yl) -4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

400 is-carboxylic acid, 80 mg 3 - methylaminoacetaldehyde and 160 mg N-methylpyrrolidone and the mixture was stirred at 90oC for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 92 mg specified in the title compounds as colorless powder.

Melting point: 259-265oC (decomposition)

1H NMR (d6-DMSO) ;

of 2.20 (s, 3H), of 3.48 (m, 1H), 4,14 (m, 2H), with 4.64 (m, 2H), 6.75 in (CL, 2H), 7,86 (d, J=14 Hz, 1H) 7,94 (t, J=9 Hz, 1H), 8,68 (s, 1H)

Example 11

Synthesis of 1- (6-amino-3,5-differencein-2-yl)-7-(3-amino-3 - methylaziridine-1-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 350 mg of N,N-dimethylformamide was added 80 mg of 1-(6-amino-3, 5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-3 - methyltetrahydrofolate and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90oC for 40 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed with ethanol to obtain 64 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or the C, 1H), 8,68 (s, 1H)

Example 12

Synthesis of 3-hydroxyazetidine salt of 1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 800 mg of acetonitrile were added 100 mg of 1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline - 3-carboxylic acid, 60 mg of 3-hydroxy-apatityvodokanala and 150 mg of N-methylpyrrolidine, and the mixture was heated under reflux for 1 hour. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 56 mg specified in the title compounds as colorless powder.

Melting point: 185-190oC (decomposition)

1H NMR (d6-DMSO) ;

of 3.45 (m, 2H), 3,65 (m, 2H), 4,14 (m, 2H), 4,39 (m, 1H), 4,46 (m, 1H), and 4.68 (m, 2H), 6,70 (CL, 2H), 7,80 (d, J=14 Hz, 1H), to $ 7.91 (t, J=9 Hz, 1H), charged 8.52 (s, 1H)

Example 13

Synthesis of N-methylpyrrolidinone salt of 1-(6-amino-3,5-differencein-2-yl)- 8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 2000 mg of N,N-dimethylformamide was added 300 mg of 1-(6 - amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 110 mg of 3-hydroxyacetanilide and 300 mg N-methylpyrrolidine, and the mixture peremabiri by filtration and washed sequentially ethanol and diisopropyl ether to obtain 222 mg specified in the title compounds as colorless powder.

Melting point: 234-238oC (decomposition)

1H NMR (d6-DMSO) ;

to 1.67 (m, 4H), 2,24 (s, 1H), of 2.38 (m, 4H), 4,18 (m, 2H), 4,47 (m, 1H), 4,71 (m, 2H), 5,73 (m, 1H), 6.75 in (CL, 2H), 7,86 (d, J=14 Hz, 1H), 7,94 (t, J=9 Hz, 1H), 8,67 (s, 1H)

Example 14

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro - 4-oxo-7-piperazine derivatives-1,4-dihydroquinoline-3-carboxylic acid

To 170 mg of N,N-dimethylformamide was added 50 mg of 1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 50 mg of piperazine, and the mixture was stirred at 90oC for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 33 mg specified in the title compounds as colorless powder.

Melting point: 273 - 277oC (decomposition)

1H NMR (d6-DMSO) ;

2,82 (m, 4H), and 3.16 (m, 4H), 6,76 (CL, 2H), 7,95 (t, J=9 Hz, 1H) 8,05 (d, J = 12 Hz, 1H), 8,79 (s, 1H),

Reference example 7

Synthesis of 3,5,6-Cryptor-2-(methylamino)pyridine

To 10 ml of acetonitrile was added to 4.5 g of 2,3,5,6-tetrafluoropyridine 50 ml of chloroform, and the mixture was washed four times with 250 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound as a light brown crude oil.

1H NMR (CDCl3) ;

to 2.99 (d, J=5 Hz, 3H), 4.53-in loops, 1H), 7,20 (DDD, J=7 Hz, 8 Hz, 9 Hz, 1H).

Reference example 8

Synthesis of 2-benzylamino-3,5-debtor-6-(methylamino)pyridine

To 20 ml of N-methylpyrrolidone was added the whole amount of the above 3,5,6-Cryptor-2-(methylamino) pyridine together with 10 g of benzylamine, and the mixture was stirred at the 14oC for 19 hours, then allowed to cool. To the solution was added 50 ml of chloroform and the mixture was washed six times with 200 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the connection header in the form of crude oil.

Reference example 9

Synthesis of 2-amino-3,5-debtor-6-(methylamino) pyridine

To a mixed solution of 10 ml of methanol and 1 ml of concentrated hydrochloric acid was added the whole amount of the above-described 2-benzylamino-3,5-debtor-6-(methylamino) pyridine together with 0.55 g of 10% palladium on the reduced pressure of the solvent and the like. To the residue was added 50 ml of chloroform, and the mixture was washed with 50 ml of 5% aqueous sodium carbonate solution. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid precipitate was collected by filtration to obtain 840 mg specified in the title compounds as a pale gray solid.

1H NMR (CDCl3) ;

2,95 (d, J=5 Hz, 3H), 4,19 (CL, 3H), 6,98 (t, J=10 Hz, 1H)

Example 15

Synthesis of ethyl 8-chloro-6,7-debtor-1-(3,5-debtor-6-methyl - aminopyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 5 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate obtained from 0,70 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 430 mg of 2-amino - 3, 5-debtor-6-(methylamino)pyridine. The solution was concentrated under reduced pressure. To the residue was added 0.3 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90oC for 10 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure is hapilovym ether with getting 784 mg specified in the title compounds as colorless powder.

Melting point: 207-209oC

1H NMR (CDCl3) ;

of 1.41 (t, J=7 Hz, 3H), 2,98 (d, J=5 Hz, 3H), to 4.41 (q, J=7 Hz, 2H), 4,85 (SHS, 1H), 7.23 percent (DD, J=8 Hz, 9 Hz, 1H), 8,32 (DD, J=8 Hz, 10 Hz, 1H) and 8.50 (s, 1H)

Example 16

Synthesis of 8-chloro-6,7-debtor-1-(3,5-debtor-6-methylamino - pyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 3 ml of a mixed solution (1:1, V/V) 4 ml 4 N. hydrochloric acid and 1 ml of acetic acid was added 510 mg of ethyl 8-chloro-6,7-debtor-1- (3,5-debtor-6-methylaminomethyl-2-yl] -4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated under reflux with stirring for 2.5 hours. After adding 2 ml of distilled water and the mixture was allowed to cool, after which the residue was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 454 mg specified in the title compound as a gray powder.

Melting point: 236-242oC

1H NMR (d6-DMSO) ;

to 2.67 (d, J=5 Hz, 3H),5,94 (SHS, 1H), 7,06 (t, J=8 Hz, 1H) 7,45 (DD, J=10 Hz, 12 Hz, 1H), to 8.41 (DD, J=9 Hz, 10 Hz, 1H), 8,72 (s, 1H)

Example 17

Synthesis of 7-(3-aminoamides-1-yl)-8-chloro-6-fluoro-1-(3,5-debtor-6 - methylaminomethyl-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 400 mg of N,N-dimethylformamide were added 100 mg of 8-chloro-6,7-is hydrochloride and 120 mg of N-methylpyrrolidine and the mixture was stirred at 100oC for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 102 mg specified in the title compounds as colorless powder.

Melting point: 222-227oC (decomposition)

1H NMR (d6-DMSO) ;

2,77 (d, J= 5 Hz, 3H), of 3.75 (m, 1H), 4,07 (m, 2H), 4,67 (m, 2H), 7,19 (SHS, 1H), 7,88 (d, J=14 Hz, 1H), 7,95 (t, J=7 Hz, 1H), to 8.70 (s, 1H)

Reference example 10

Synthesis of 2-benzylamino-3,5,6-Cryptor-4-methylpyridine

To 2 ml of N-methylpyrrolidone was added 1.65 g of 2,3,5,6 - titrator-4-methylpyridine and 2.30 g benzylamine, and the mixture was stirred at 80oC for 2 hours, then allowed to cool. After adding 25 ml of chloroform and the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound in crude form.

Reference example 11

Synthesis of 2-amino-3,5, 6-Cryptor-4-methylpyridine

To 4 ml of methanol was added the whole amount of the above crude 2-benzylamino-3,5,6-Cryptor-4-methylpyridine with 0.18 g of 10% palladium on coal and 2 motholeli under reduced pressure, the solvent and the like to obtain 1.35 g specified in the title compound as a colourless solid.

1H NMR (CDCl3) ;

of 2.26 (t, J=2 Hz, 3H), 4,40 (CL, 2H)

Reference example 12

Synthesis of 2-amino-3,5-debtor-6-(p-methoxybenzylidene)-4 - methylpyridine

To 3 ml of N-methylpyrrolidone was added 1.35 g of 2-amino-3,5,6 - Cryptor-4-methylpyridine together with 3.0 g of p-methoxybenzylamine and the mixture was stirred in nitrogen atmosphere at 140oC for 18 hours, then allowed to cool. After adding 30 ml of chloroform and the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 20 g; eluent: chloroform: hexane, 1:1, and then chloroform) to obtain 0,90 g specified in the title compounds as a pale yellow crude oil.

1H NMR (CDCl3) ;

of 2.15 (t, J=2 Hz, 3H), of 3.80 (s, 3H), 4,11 (CL, 2H), to 4.41 (SHS, 1H), 4,48 (m, 2H), 6.87 in (d, J=8 Hz, 2H), 7,27 (d, J=8 Hz, 2H)

Example 18

Synthesis of ethyl 8-chloro-1-[3,5-debtor-6-(p-methoxybenzylidene) - 4-methylpyridin-2-yl]-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylate

To 3 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate obtained from 0,78 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added to 0.90 g of 2-amino - 3,5-debtor-Lyali 1.3 g of anhydrous potassium carbonate and 3 ml of N, N-dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml distillirovannoi water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound as a brown crude oil.

Example 19

Synthesis of 1-(6-amino-3,5-debtor-4-methylpyridin-2-yl)-8-chloro - 6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To a mixed solution of 2.5 ml of 4 N. hydrochloric acid and 2.5 ml of acetic acid was added the whole amount of the above ethyl 8 - chloro-1-[3,5-debtor-6-(p-methoxybenzylidene)-4-methyl-pyridine-2-yl] -6,7-debtor-4 - oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 hours, then allowed it to cool and settle. To the precipitate was added to 10 ml of distilled water, and the solution was concentrated under reduced pressure. Repeated 3 times procedure add 10 ml of ethanol and concentrating the solution under reduced pressure and to the residue was added 6 ml of chloroform, and the mixture was heated under reflux at the PE sledovatelno ethanol and diisopropyl ether to obtain 128 mg specified in the title compounds as colorless powder. Melting point: 253-257oC

1H NMR (d6-DMSO) ;

2,24 (s, 3H), 6,67 (CL, 2H), scored 8.38 (t, J 9 Hz, 1H), 8,89 (s, 1H)

Example 20

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3,5-debtor-4 - methylpyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 280 mg of N,N-dimethylformamide was added 50 mg of 1-(6-amino - 3,5-debtor-4-methylpyridin-2-yl) -8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoacetanilide and 120 mg of N-methylpyrrolidine; and the mixture was stirred at 90oC for 1 hour. After adding 0.4 ml of ethanol, the mixture was allowed to cool. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 45 mg specified in the title compounds as colorless powder.

Melting point: 243-245oC (decomposition),

1H NMR (d6-DMSO) ;

of 2.23 (s, 3H), 3,71 (m, 1H), of 4.05 (m, 2H), 4,67 (m, 2H), 6,60 (CL, 2H), a 7.85 (d, J=14 Hz, 1H), 8,64 (s, 1H)

[Reference example 13]

Synthesis of 4-(tert-butylamino)-2,3,5,6-tetrafluoropyridine

To 100 ml of acetonitrile was added 24.5 g of pentafluoropyridine and the mixture was stirred in an ice bath simultaneously with the dropwise addition of 30 g of tert-butylamine. After the mixture has warmed to room the layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 23 g specified in the title compounds as a pale yellow oil.

Reference example 14

Synthesis of 2-benzylamino-4-(tert-butylamino)-3,5,6-Cryptor - pyridine

To 10 ml of N-methylpyrrolidone was added 6.8 g of 4-(tert - butylamino)-2,3,5, 6-tetrafluoropyridine together with 7.2 g of benzylamine, and the mixture was stirred at 115oC during the day, and then was allowed to cool, after adding 40 ml of chloroform and the mixture was washed three times with 400 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about 8.0 g specified in the connection header in the form of dark green crude oil.

1H NMR (CDCl3) ;

of 1.39 (s, 9H), 4,16 (SHS, 1H), 4,55 (CL, 2H), 4,48 (m, 2H), 7,35 (m, 5H)

Reference example 15

Synthesis of 2-amino-4-(tert-butylamino)-3,5,6-cryptosporidia

To 13 ml of acetic acid was added 4.0 g of the crude 2 - benzylamino-4-(tert-butyl)amino-3,5,6-cryptosporidia obtained as described above, together with of 0.43 g of 10% palladium on charcoal, and the mixture was first made at 60oC for 6 hours. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the like to obtain specified in the title compound as a brown crude oil.

Reference example 16
3-chloro-2,4,5-tripersonality was added 1.5 g of acetic anhydride and 1.5 g of triethylorthoformate, and the mixture was heated under reflux for 2 hours. Drove the solvent and to the residue was added toluene to azeotrope distillation. To half of the residue was added 3 ml of chloroform, and to the mixture was added dropwise under ice cooling, 5 ml chloroformed solution of 1 g of 2-amino-3,5,6-Cryptor-4-(tert-butylamino) of pyridine, after which the mixture was stirred at room temperature for 2 hours. Drove the solvent, and the solid precipitate was collected by filtration and washed with diethyl ether to obtain 1,14 g specified in the connection header.

Example 21

Synthesis of ethyl 1-(4-tert-butylamino-3,5,6-triptorelin-2-yl) -8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 6 ml of N,N-dimethylformamide solution of 1.14 g of ethyl 3- [(4-tert-butylamino-3,5,6-pyridine-2-yl)amino] -2-(3-chloro - 2,4,5-tryptophanyl)acrylate was added 700 mg of potassium carbonate, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into ice water and was added ethyl acetate for extraction. The organic layer was separated and dried over anhydrous magnesium sulfate, and then drove the solvent. The solid content was collected by filtration to obtain 1.25 g specified in the header is connected to the R>
of 1.40 (t, J= 7 Hz, 3H), of 1.48 (s, 9H), to 4.41 (q, J=7 Hz, 2H), 4,78 (1H, CL), 8,31 (t, J 9 Hz, 1H), 8,44 (1H, s)

Example 22

Synthesis of 1-(4-amino-3,5,6-triptorelin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid

To 300 mg of ethyl 1-(4-tert-butylamino-3,5,6-triptorelin-2 - yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 3 ml of 12 N. hydrochloric acid and 0.5 ml of acetic acid, and the mixture was heated under reflux for 1.5 hours. The reaction solution was allowed to cool and the precipitated precipitated solid substance was collected by filtration and washed successively with ethanol and diethyl ether to obtain 168 mg specified in the title compounds as colorless powder.

Melting point: 280-283oC

1H NMR (d6-DMSO) ;

rate of 7.54 (s, 1H), scored 8.38 (DD, J=9 Hz, 10 Hz, 1H), 8,98 (s, 1H)

Example 23

Synthesis of 7- (3-aminoamides-1-yl]-1-(4-amino-3,5,6-tri - herperidin-2-yl) -8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 1 ml dimethylsulfoxide solution of 70 mg of 3 - aminoacetanilide and 250 mg of triethylamine at 80oC was added with stirring to 150 mg of 1-(4-amino-3, 5,6 - triptorelin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dehydrocholic - 3-carboxylic acid, and the mixture was stirred at ATCO was added ethanol dispersion of solid content, then the solid content was collected by filtration, washed with ethanol and dried to obtain 85 mg specified in the title compounds as pale yellow powder.

Melting point: decomposition at 230oC or higher

1H NMR (d6-DMSO+TN) ;

of 4.05 (m, 1H), 4,45 (m, 2H),4,77 (m, 2H), 7,50 (2H, CL), to 7.93 (d, J=14 Hz, 1H), 8,32 (CL, 2H), 8,80 (s, 1H.)

[Reference example 17]

Synthesis of 3,5-diamino-2-chloropyridine

The mixture 2,19 iron powder, 5 ml of water and 10 ml ethanol was stirred at 80oC for 2 minutes. After the gradual addition of 1 ml of concentrated hydrochloric acid and the mixture was stirred at the same temperature until the solution became neutral. To the reaction solution was added a suspension of 1 g of 2 - chloro-3,5-dinitropyridine in 5 ml of ethanol, and the mixture was stirred at 80oC for 40 minutes. Given the reaction solution to cool, and remove the iron powder by filtration through celite, then the filtrate drove the solvent. To the residue was added ethanol dispersion of solid content, and then the solid content was collected by filtration to obtain 360 mg specified in the connection header.

[Referential example 18]

Synthesis of ethyl 3-[(5-amino-6-imously 1,5 acetic anhydride and 1.5 triethylorthoformate, and the mixture was heated under reflux for 2 hours. Drove the solvent, and to the residue was added toluene to azeotrope distillation. To half of the residue was added 3 ml of chloroform, and to the mixture at room temperature was added dropwise a solution of 360 mg of 3,5-diamino-2-chloropyridin in 3 ml of ethanol, after which the mixture was stirred at room temperature for 30 minutes. Drove the solvent, and the residue was purified by column chromatography to obtain 200 mg specified in the connection header.

Example 24

Synthesis of ethyl 1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To a solution of 180 mg of ethyl 3-[(5-amino-6-chloropyridin-3-yl)- amino]-2-(3-chloro-2,4,5-tryptophanyl)acrylate in 3 ml of N,N - dimethylformamide was added 57 mg of potassium carbonate, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was separated and dried over magnesium sulfate, and then drove the solvent. The solid content was collected by filtration to obtain 125 mg specified in the title compounds as pale yellow powder.

Melting point: 233-236oC

1
Example 25

Synthesis of 1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7-debtor - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 100 mg of ethyl 1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 3 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool and the precipitated precipitated solid substance was collected by filtration. The solid was washed with ethanol to obtain 86 mg specified in the title compounds as pale yellow powder.

Melting point: 277-281oC

1H NMR (d6-DMSO) ;

7,37 (s, 1H), 7,86 (s, 1H), to 8.41 (t, J=9 Hz, 1H), 8,69 (s, 1H)

Example 26

Synthesis of 7-(3-aminoamides-1-yl)-1-(5-amino-6-chloro - pyridine-3-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 1 ml dimethylsulfoxide solution of 53 mg of 3 - aminoacetanilide and 146 mg of triethylamine at 80oC was added with stirring to 80 mg of 1-(5-amino-6-chloropyridin-3-yl) -8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, and the mixture was stirred at 80oC for 1 hour. The reaction solution was allowed to cool and decantation with diethyl ether. To the residue was added ethanol on is whether ethanol and dried to obtain 45 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or higher

1H NMR (d6-DMSO) ;

of 3.78 (m, 1H), 4,14 (m, 2H), with 4.64 (m, 2H), 6,04 (width, 2H), 7,30 (s, 1H), of 7.75 (s, 1H), 7,89 (d, J=14 Hz, 1H), 8,49 (s, 1H)

[Reference example 19]

Fully mixed with 25.3 g of 5-fluorouracil from 72.9 g pentachloride phosphorus, and the mixture was gradually heated to 130oC and subjected to interaction within 4 hours. (The reaction mixture became liquid for about 1 hour and the reaction continued at high speed). After adding 300 ml of ice water and 200 ml of chloroform and the mixture was stirred for 20 minutes. The insoluble content was separated by filtration through celite and shared the filtrate. The chloroform layer was washed with 5% aqueous sodium carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to get 30,6 g specified in the title compound as a brown oil which crystallized at low temperature).

1H NMR (CDCl3) ; 8.49 (s, 1H)

[Referential example 20]

Synthesis of 4-(tert-butylamino)-2-chloro-5-ftorpirimidinu

To 20 ml of acetonitrile was added 6.4 g of 2,4-dichloro-5 - ftorpirimidinu and 7.0 g of tert-butylamine, after which the mixture was stirred at 50oC for 20 minutes. The solution of concentri oratory layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated precipitated pale yellow crystals were dispersible in diisopropyl ether and collected by filtration to obtain 4.1 g specified in the connection header.

1H NMR (CDCl3) ;

is 1.51 (s, 9H), 5,07 (SHS, 1H), 7,83 (d, J=3 Hz, 1H)

[Referential example 21]

Synthesis of 2-benzylamino-4-(tert-butylamino)-5-ftorpirimidinu

To 5 ml of N-methylpyrrolidone was added 1.8 g of 4-(tert-butylamino-2-chloro - 5-ftorpirimidinu and 4.0 g of benzylamine, and the mixture was stirred at 140oC for 17 hours, then separated by adding 300 ml of distilled water and 40 ml of chloroform. The chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated precipitated pale yellow crystals were dispersible in diisopropyl ether and collected by filtration to obtain 1.9 grams specified in the connection header.

1H NMR (CDCl3) ;

of 1.40 (s, 9H), of 4.54 (d, J=6 Hz, 2H), 4,71 (SHS, 1H), 5,06 (SHS, 1H), 7,33 (m, 5H), the 7.65 (d, J=3 Hz, 1H)

Reference example 22

Synthesis of 2-amino-4-(tert-butylamino)-5-ftorpirimidinu

To 8 ml of acetic acid was added 1.0 g of 2-benzylamino-4- (tert-butylamino)-5-ftorpirimidinu with 215 mg of 10% palladium on carbon and under reduced pressure, the solvent and the like. Three times repeating a procedure of adding ml of ethanol and concentrating under reduced pressure, then the residue was separated by column chromatography (silica gel, 25 g; eluent: chloroform and then chloroform:methanol 200: 1) and the appropriate fractions were collected and concentrated under reduced pressure to obtain 360 mg specified in the title compounds as a pale gray solid.

1H NMR (CDCl3) ;

of 1.47 (s, 9H), 4,92 (SHS, 1H), 5,57 (CL, 2H), 7,51 (d, J=3 Hz, 1H)

Example 27

Synthesis of ethyl-1-[4-(tert-butylamino)-5-ftorpirimidinu-2-yl] -8 - chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 3 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate obtained from 210 mg of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 340 mg of 2-amino - 4-(tert-butylamino)-5-ftorpirimidinu. The solution was concentrated under reduced pressure. To the residue was added 550 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90oC for 1 hour 10 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, the chloroform layer was washed two times with 300 ml of distilled water, sushilnoe chromatography (silica gel, 16 g; eluent: chloroform: methanol 200:1), and appropriate fractions were collected and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 98 mg specified in the title compounds as colorless powder.

Melting point: 201-205oC

1H NMR (CDCl3) ;

to 1.38 (t, J= 7 Hz, 3H), USD 1.43 (s, 9H), 4,39 (kV, J=7 Hz, 2H), and 5.30 (SHS, 1H), 8,02 (d, J=3 Hz, 1H), 8,24 (t, J=9 Hz, 1H), of 8.90 (s, 1H)

Example 28

Synthesis of 1- (4-amino-5-herperidin-2-yl]-8-chloro-6,7-debtor-4 - oxo-1,4-dihydroquinoline-3-carboxylic acid

To a mixed solution (1:1, V/V), 0.4 ml 4n. hydrochloric acid and 1 ml of acetic acid was added 90 mg of ethyl 1-[4-tert-butylamino)- 5-ftorpirimidinu-2-yl]-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylate, and the mixture was heated under reflux while moving in for 3 and a half hours, and then allowed it to cool. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 48 mg specified in the title compounds as colorless powder.

Melting point 242-246oC

1H NMR ((d6-DMSO) ;

Re - midin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 100 mg of N,N-dimethylformamide was added 25 mg of 1-[4-amino - 5-ftorpirimidinu-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoacetanilide and 50 mg N-methylpyrrolidine, and the mixture was stirred at 90oC for 1 hour. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 10 mg specified in the title compounds as colorless powder.

Melting point: 269 - 271oC (decomposition)

1H NMR (d6-DMSO) ;

to 3.73 (m, 1H), 4,07 (m, 2H), 4,67 (m, 2H), 7,81 (d, J=15 Hz, 1H),7,95 (SHS, 1H), 8,29 (d, J=3 Hz, 1H), 8,83 (s, 1H)

Reference example 23

Synthesis of 2-amino-3,5-debtor-6-methoxypyridine

To 1 ml of methanol was added 500 mg of 2-amino-3,5,6-cryptosporidia together with 800 mg of a 28% solution of sodium methoxide in methanol, and the mixture was stirred at 70oC for 3 and a half hours, then allowed to cool. After adding 25 ml of chloroform and the mixture was washed in 5 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the connection header.

Example 30

Chloroformed solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate, obtained from 0,78 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 2-amino-3,5 - debtor-6-methoxypyridine, while monitoring the reaction by TLC has confirmed the completion of the transformation in aminoacylating form. The solution was concentrated under reduced pressure and to the residue was added to 0.80 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration and washed with ethanol to obtain 615 mg specified in the title compound as pale brown powder.

Melting point: 140-143oC

1H NMR (CDCl3) ;

of 1.41 (t, J=7 Hz, 3H), 3,99 (s, 3H), to 4.41 (q, J=7 Hz, 2H), 7,44 (t, J=8 Hz, 1H), with 8.33 (DD, J=8 Hz, 10 Hz), to 8.45 (s, 1H)

Example 31

Synthesis of 8-chloro-1-(3,5-debtor-6-methoxypyridine-2-yl)-6,7 - debtor-4-oxo - -1, 4-dihydroquinoline-3-carboxylic acid

To a mixed solution of 1 ml of 4n. hydrochloric acid and 1 ml of acetic acid was added 385 is Ali under reflux with stirring for 30 minutes. After adding 2 ml of distilled water the solution was allowed to cool and settle. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 297 mg specified in the title compounds as colorless powder.

Melting point: 205-210oC

1H NMR (d6-DMSO) ;

to 3.92 (s, 3H), 8,39 (t, J=9 Hz, 1H), 8,40 (t, J=9 Hz, 1H), 9,03 (s, 1H)

Example 32

Synthesis of 7-(3-aminoamides-1-yl)-8-chloro-1-(3,5-debtor-6 - methoxypyridine-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 500 mg of acetonitrile was added 75 mg of 8-chloro-1-(3,5-debtor - 6-methoxypyridine-2-yl)-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid, 65 mg of 3-amino-setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was heated under reflux for 1 hour. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 28 mg specified in the title compounds as colorless powder.

Melting point: 171-175oC

1H NMR (d6-DMSO) ;

3,70 (m, 1H), 3,91 (s, 3H), of 4.05 (m, 2H), 4,66 (m, 2H), 7,88 (d, J=14 Hz, 1H), 8.34 per (t, J=9 Hz, 1H), 8,79 (s, 1H)

Example 33

Synthesis of ethyl 7-chloro-1-(3,5-debtor-6-methoxypyridine-2-yl)-6 - 5-fornication)acrylate, obtained from a 1.25 g of ethyl 2,6-dichloro - 5-porninterracial in the usual way, was added crude 2-amino-3,5-debtor-6-methoxypyridine, while monitoring the reaction by TLC has confirmed the completion of the transformation in aminoacylating form. The solution was concentrated under reduced pressure and to the residue was added 2.0 g of anhydrous potassium carbonate and 4 ml of N,N - dimethylformamide and the mixture was stirred at 90oC for 20 minutes, then allowed it to cool. The solution was separated by adding 50 ml of chloroform and 300 ml of distilled water and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1010 mg specified in the title compound as light brown powder.

Melting point: 208-212oC

1H NMR (CDCl3) ;

of 1.42 (t, J=7 Hz, 3H), Android 4.04 (s, 3H), and 4.40 (q, J=7 Hz, 2H), 7,50 (t, J=8 Hz, 1H), 8,48 (d, J=7 Hz), 8,69 (s, 1H)

Example 34

Synthesis of 7-chloro-1-(3,5-debtor-6-methoxypyridine-2-yl)-6 - fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylic acid

To 1.5 ml of a mixed solution (1:1, about/on the CSR-1,4-dihydro-1,8 - naftalin-3-carboxylate, and the mixture was heated under reflux with stirring for 1 hour. After adding 2 ml of distilled water and the mixture was heated under reflux for 10 minutes, then allowed it to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 248 mg specified in the title compound as light brown powder.

Melting point: 220-225oC

1H NMR (d6-DMSO) ;

of 3.97 (s, 3H), 8,42 (t, J=9 Hz, 1H), 8,76 (d, J=7 Hz, 1H), of 9.21 (s, 1H)

Example 35

Synthesis of 7-[(3S)-3-aminopyrrolidine-1-yl] -1-(3,5-debtor-6 - methoxypyridine-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3 - carboxylic acid

To 400 mg of N,N-dimethylformamide was added 82 mg of 7-chloro-1- (3,5-debtor-6-methoxypyridine-2-yl) -6-fluoro-4-oxo-1,1-dihydro-1,8 - naphthylidine-3-carboxylic acid, 70 mg of (3S)-3-aminopyrrolidine and 60 mg of triethylamine, and the mixture was heated under reflux at 80oC for 30 minutes. After adding 2.5 ml of ethanol and the mixture was heated under reflux for 5 minutes and then allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 102 mg specified in the UP>1H NMR (d6-DMSO) ;

of 1.65 (m, 1H), 1.93 and (m, 1H), 3,95 (s, 3H), 8,02 (d, J=13 Hz, 1H), 8,35 (t, J=9 Hz, 1H), to 8.94 (s, 1H)

(Some signals obscured by the proton of the water and was indistinguishable).

Example 36

Synthesis of 7-[(3S,4S)-3-amino-4-methylpyrrolidine-1-yl]-1-(3,5 debtor-6-methoxypyridine-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8 - naphthylidine-3-carboxylic acid

To 500 mg N,N-dimethylformamide was added 85 mg of 7-chloro-1- (3,5-debtor-6-methoxypyridine-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8 - naphthylidine-3-carboxylic acid, 70 mg of (3S,4S)-3-amino-4 - methylpyrrolidinyl 150 mg of triethylamine, and the mixture was heated under reflux at 80oC for 30 minutes. After adding 2.5 ml of ethanol and the mixture was heated under reflux for 5 minutes and then allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 105 mg specified in the title compounds as colorless powder.

Melting point: 226-229oC

1H NMR (d6-DMSO) ;

0,94 (CL, J=8 Hz, 3H), of 2.16 (m, 1H),3,95 (s, 3H), 8,02 (d, J=13 Hz, 1H), 8,35 (m, 1H), of 8.95 (s, 1H)

(Some signals obscured by the proton of the water and was indistinguishable).

Example 37

Synthesis of 1-(6-amino-3,5-differencein-2-yl]- is the notes and 3.5 ml of acetic acid was added to 1.38 g of ethyl 8-bromo-1-[6-(tert-butylamino) -3,5-differencein-2-yl] -6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 5 hours. After adding 5 ml of distilled water mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1.10 g specified in the title compounds as colorless powder.

Melting point: 272-278oC

1H NMR (d6-DMSO) ;

to 6.80 (s, 2H), 7,99 (t, J=9 Hz, 1H), scored 8.38 (t, J=9 Hz, 1H), 8,93 (s, 1H)

Example 38

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-6,7,8 - Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To a mixed solution of 0.5 ml of 4 N. hydrochloric acid and 0.5 ml of acetic acid was added 235 mg of ethyl 1-[6-(tert-butylamino) -3,5-differencein-2-yl] -6,7,8-Cryptor-4-oxo - 1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 7 hours. After adding 1 ml of distilled water mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 182 mg specified in the title compounds as colorless powder.

Melting point: 280oC or higher.

1H NMR (d6-DMSO) ;

for 6.81 (CL, 2H), 8-bromo-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 300 mg of N,N-dimethylformamide was added 105 mg 1-(6 - amino-C,5-differencein-2-yl)-8-bromo-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino - setidentityproviderid and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90oC for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 79 mg specified in the title compounds as colorless powder.

Melting point: 258-264oC (decomposition)

1H NMR (d6-DMSO) ;

to 3.73 (m, 1H), 4,06 (m, 2H), 4,69 (m, 2H), 6.75 in (CL, 2H), 7,89 (d, J=14 Hz, 1H), 7,94 (t, J=9 Hz, 1H), to 8.70 (s, 1H)

Example 40

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3,5-differencein - 2-yl)-6,8-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 270 mg of N,N-dimethylformamide was added 90 mg of 1-(6-amino-3,5-differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-amino-setidentityproviderid and 110 mg of N-methylpyrrolidine, and the mixture was stirred at 90oC for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether with the tion: 256-260oC (decomposition)

1H NMR (d6-DMSO) ;

3,76 (m, 1H), 3,94 (m, 2H), of 4.44 (m, 2H), 6,74 (CL, 2H), 7,78 (d, J=13 Hz, 1H), 7,99 (t, J=9 Hz, 1H), 8,73 (s, 1H)

Example 41

Synthesis of 1-(6-amino-C, 5-differencein-2-yl)-8-bromo-6-fluoro - 7-(3-methylaminomethyl-1-yl)-4-oxo-1,4-dihydroquinoline-Z - carboxylic acid

To 800 mg of N,N-dimethylformamide was added 260 mg of 1-(6-amino - 3,5-differencein-2-yl) -8-bromo-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 130 mg of 3-methyl - aminoethylethanolamine and 300 mg N-methylpyrrolidine, and the mixture was stirred at 90oC for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 247 mg specified in the title compounds as pale yellow powder.

Melting point: 238-245oC (decomposition)

1H NMR (d6-DMSO) ;

of 2.21 (s, 3H), 3.46 in (m, 1H), 4,12 (m, 2H), 4,63 (m, 2H), 6.75 in (CL, 2H), 7,88 (d, J=14 Hz, 1H), 7,94 (t, J=9 Hz, 1H), to 8.70 (s, 1H)

Example 42

Synthesis of 7-[3-(ethylamino)azetidin-1-yl]-1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino - 3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-hydroxy mixture was stirred at 90oC for 15 minutes. After adding 1 ml ethanol mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 107 mg specified in the title compounds as colorless powder.

Melting point: 241-245oC (decomposition).

1H NMR (d6-DMSO) ;

and 0.98 (t, J=7 Hz, 3H), 2.49 USD (kV, J=7 Hz, 2H), 3,55 (m, 1H), 4,14 (m, 2H), 4,66 (m, 2H) 6,76 (CL, 2H), 7,86 (d, J=14 Hz, 1H), 7,95 (t, J=9 Hz, 1H), 8,69 (s, 1H)

Example 43

Synthesis of 7-[3-(dimethylamino) azetidin-1-yl]-1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino - 3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)- setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 15 minutes. After adding 1 ml ethanol mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 87 mg specified in the title compounds as colorless powder.

Melting point: 283-287oC (decomposition).

1H NMR (d6 Synthesis of 7-[3-(aminomethyl)azetidin-1-yl] -1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 280 mg of N,N-dimethylformamide was added 80 mg of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(aminomethyl)-setidentityproviderid and 200 mg N-methylpyrrolidine, and the mixture was stirred at 90oC for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 42 mg specified in the title compounds as colorless powder.

Melting point: 249-254oC

1H NMR (d6-DMSO) ;

to 2.67 (m, 1H), 2,80 (m, 2H).4,21 (m, 2H), 4,49 (m, 2H), 6.73 x (CL, 2H), 7,80 (d, J=14 Hz, 1H), to 7.93 (t, J=10 Hz, 1H), 8,56 (s, 1H).

Reference example 24

Synthesis of 4-amino-3-chloro-2,5,6-cryptosporidia

In 100 ml of acetonitrile was dissolved 20,5 g of 3-chloro-2,4,5,6-tetrafluoropyridine, and to the solution was added 30 ml of 25% aqueous ammonia solution in three portions, and the mixture was stirred and cooled with water, and then continued stirring for another 30 minutes. The solution was concentrated under reduced pressure. After addition of the solid OST what LifeCam magnesium and concentrated under reduced pressure, then the precipitate was collected by filtration to obtain 16.6 g specified in the title compounds as colorless flake crystals.

Reference example 25

Synthesis of 4-bromo-3-chloro-2,5,6-cryptosporidia

In 45 ml of acetonitrile was dissolved 9.4 g of 4-amino-3-chloro-2,5,6 - cryptosporidia, and to the solution were added 7.5 g of tert-butylnitrite dropwise over 25 minutes with stirring at 45oC, and then heated under reflux for 40 minutes and concentrated under reduced pressure. The residue was separated by adding 150 ml of chloroform and 100 ml of 2 N. hydrochloric acid and the chloroform layer was washed with 20 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 10.2 g specified in the title compounds as a pale yellow oil.

Reference example 26

Synthesis of 4-bromo-2-(tert-butylamino)-5-chloro-3,6-diphereline

In 40 ml of acetonitrile was dissolved 10.2 g of 4-bromo-3-chloro-2,5,6 - cryptosporidia and 10.5 g of tert-butylamine and the mixture was heated under reflux for 1 hour and drove away under reduced pressure, the solvent, and the like. To the residue was added 80 ml of chloroform and the mixture was washed with 50 ml of distilled water. Chlor,8 g specified in the title compound as a reddish-orange oil.

Reference example 27

Synthesis of 2-(tert-butylamino)-5-chloro-3,6-diphereline

To 30 ml of methanol was added 12.8 g of 4-bromo-2-(tert - butylamino)-5-chloro-3,6-diphereline and 2.5 g of triethylamine together from 0.57 g of 10% palladium on charcoal, and the mixture was first made at the 50oC for 5 days. Was separated by filtration of the catalyst, and drove away under reduced pressure, the solvent and the like. To the residue was added 80 ml of chloroform, and the mixture was washed with 70 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.3 g specified in the title compound as a brown oil.

Reference example 28

Synthesis of 2-benzylamino-6-(tert-butylamino)-3-chloro-5-herperidin

To 10 ml of N-methylpyrrolidone was added 6.8 g of 2-(tert - butylamino)-5-chloro-3,6-diphereline with 8.0 g of benzylamine, and the mixture was stirred at 150oC during the day and gave it to cool. After adding 80 ml of chloroform and the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 100 g; eluent: chloroform: n-hexane, 1:1 CLASS="ptx2">

Reference example 29

Synthesis of 2-amino-6-(tert-butylamino)-3-chloro-5-herperidin and 2-amino-6-(tert-butylamino)-5-herperidin

To a mixed solution of 18 ml of methanol and 1.4 g of concentrated hydrochloric acid was added 3.1 g of 2-benzylamino-6-(tert-butylamino)-3-chloro-5-herperidin together with 0.33 g of 10% palladium on charcoal, and the mixture was first made at the 30oC for 1 hour. Was separated by filtration of the catalyst, and drove away under reduced pressure, the solvent and the like. To the residue was added 50 ml of chloroform, and the mixture was washed with 10 ml of 6% aqueous sodium hydroxide solution. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform: n-hexane, 3:1 and then 1:1) to obtain 1.35 g of 2-amino-6-(tert-butylamino)-3-chloro-5-herperidin in the form of a light brown oil and 0.32 g of 2-amino-6-(tert-butylamino)-5 - herperidin in the form of a brown oil.

1H NMR (CDCl3) ;

the 1.44 (s, 9H), 4,32 (SHS, 1H), 4,37 (SHS, 1H), 7,02 (d, J=10 Hz, 1H) 2-amino-6-(tert-butylamino)-5-herperidin

1H NMR (CDCl3) ;

of 1.46 (s, 9H), 3,99 (SHS, 1H), 4,30 (SHS, 1H), 5,61 (DD, J=2 Hz, 8 Hz, 1H), 6,91 (DD, J=8 Hz, 11 Hz, 1H)

Example 45

Synthesis at ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate, obtained from 0.84 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 0.65 g of 2-amino - 6-(tert-butylamino)-3-chloro-5-herperidin. The solution was concentrated under reduced pressure to obtain a yellow solid residue. To this residue was added 0.7 g of anhydrous potassium carbonate and 3 ml of N - dimethylformamide, and the mixture was stirred at 90oC for 25 minutes, then allowed it to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and the obtained 1.06 g specified in the title compounds as pale yellow powder.

Melting point: 210-213oC.

1H NMR (CDCl3) ;

to 1.38 (s, 9H), of 1.41 (t, J=7 Hz, 3H), to 4.41 (KB, J=7 Hz, 2H), 4,84 (SHS, 1H)), 7,32 (d, J=10 Hz, 1H), 8,32 (DD, J=8 Hz, 10 Hz, 1H), 8,45 (s, 1H)

Example 46

Synthesis of 1-(6-amino-3-chloro-5-herperidin-2-yl)-8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 2.5 ml of a mixed solution (1:1) 4 N. hydrochloric acid and UKS is Kohinoor-3-carboxylate, and the mixture was heated under reflux with stirring for 4.5 hours. After adding 2 ml of distilled water the solution was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 458 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or higher

1H NMR (d6-DMSO) ;

7,10 (CL, 2H), to 7.99 (d, J=10 Hz, 1H), 8,40 (t, J=10 Hz, 1H), 8,89 (s, 1H)

Example 47

Synthesis of 7-(C-aminotetralin-1-yl)-1-(6-amino-3-chloro-5 - herperidin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino - 3-chloro-5-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino - setidentityproviderid and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90oC for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 95 mg specified in the title compounds as colorless powder.

Melting point: 268-270oC (decomposition).

1H NMR
Synthesis of 1-(6-amino-3-chloro-5-herperidin-2-yl)-8-chloro-6 - fluoro-7-(3-methylaminomethyl-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 300 mg of N,N-dimethylformamide was added 103 mg of 1-(6-amino - 3-chloro-5-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 85 mg of 3-methyl - aminoethylethanolamine and 150 mg of N-methylpyrrolidone and the mixture was stirred at 85oC for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 98 mg specified in the title compounds as colorless powder.

Melting point: 277-280oC (decomposition).

1H NMR (d6-DMSO) ;

of 2.20 (s, 3H), of 3.45 (m, 1H), 4,13 (m, 2H), with 4.64 (m, 2H),? 7.04 baby mortality (CL, 2H), 7,87 (d, J 14 Hz, 1H), 7,94 (d, J=10 Hz, 1H), to 8.62 (s, 1H)

Example 49

Synthesis of ethyl 1-[6-(tert-butylamino)-5-herperidin-2-yl-1-8 - chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 2 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate obtained from 0.56 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added at 0.42 g of 2-amino - 6-(tert-butylamino)-5-herperidin. The solution was concentrated under reduced pressure, the N,N - dimethylformamide, and the mixture was stirred at 90oC for 20 minutes, then allowed it to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and as a result got to 0.48 g specified in the title compounds as pale yellow powder.

Melting point: 207-210oC

1H NMR (CDCl3) ;

of 1.37 (s, 9H), of 1.40 (t, J=7 Hz, 3H), 4,40 (KB, J=7 Hz, 2H), 4,82 (SHS, 1H), of 6.52 (DD, J=3 Hz, 8 Hz, 1H, of 7.25 (DD, J-8 Hz, 10 Hz, 1H), 8,31 (DD, J=8 Hz, 10 Hz, 1H), 8,61 (s, 1H)

Example 50

Synthesis of 1-(6-amino-5-herperidin-2-yl)-8-chloro-6,7-debtor - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 2 ml of a mixed solution (1:1) 4 N. hydrochloric acid and acetic acid was added 450 mg of ethyl-[6-(tert-butylamino)- 5-herperidin-2-yl]-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylate and the mixture was heated under reflux with stirring for 3 hours. After adding 1 ml of distilled water mixture was allowed to cool and the precipitate was collected by filtration is VCE connection in the form of colorless powder.

Melting point: 232-235oC

1H NMR (d6-DMSO) ;

6,87 (CL, 2H), 6,91 (DD, J=3 Hz, 8 Hz, 1H), to 7.64 (DD, J=8 Hz, 11 Hz, 1H), at 8.36 (t, J=9 Hz, 1H), 8,77 (s, 1H)

Example 51

Synthesis of 7-(C-aminotetralin-1-yl)-1-(6-amino-5-herperidin-2-yl) -8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid

To 270 mg of N,N-dimethylformamide was added 55 mg of 1-(6-amino-6 - herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino-otitidiscaviarum and 80 mg N-methylpyrrolidone and the mixture was stirred at 90oC for 15 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 62 mg specified in the title compounds as colorless powder.

Melting point: 250-254oC (decomposition).

1H NMR (d6-DMSO) ;

3,71 (m, 1H), of 4.05 (m, 2H), 4,67 (m, 2H), 6,78 (DD, J=3 Hz, 8 Hz, 1H), 6,80 (CL, 2H), 7,60 (DD, J=8 Hz, 10 Hz, 1H), a 7.85 (d, J=14 Hz, 1H), at 8.60 (s, 1H)

Example 52

Synthesis of 1-(6-amino-5-herperidin-2-yl)-8-chloro-6-fluoro-7-(3-methylaminomethyl-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 300 mg of N,N-dimethylformamide was added 101 mg 1-(6-amino - 5-herperidin-2-yl)-8-chloro-6,7-tolidine, and the mixture was stirred at 85oC for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 82 mg specified in the title compounds as colorless powder.

Melting point: 252-255oC (decomposition).

1H NMR (d6-DMSO) ;

of 2.21 (s, 3H), 3.46 in (m, 1H), 4,13 (m, 2H), to 4.62 (m, 2H), 6,78 (m, 1H), for 6.81 (CL, 2H), 7,60 (DD, J=8 Hz, 10 Hz, 1H), to 7.84 (d, J=14 Hz, 1H), at 8.60 (s, 1H)

Reference example 30

Synthesis of N-(3-chloro-2,5,6-triptorelin-4-yl)-phthalimide

To a mixed solution of 40 ml of dichloromethane and 20 ml of N,N - methylformamide was added to 18.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine and 20.5 g of phthalimide potassium and stirred the mixture at 40oC during the day. After adding 40 ml of chloroform and the mixture was washed twice with 500 ml of distilled water and once with 500 ml of 0.5% aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersible in diisopropyl ether and collected by filtration to obtain 32,0 g specified in the title compounds as colorless powder.

Reference example 31
g N-(3-chloro-2,5,6 - triptorelin-4-yl)-phthalimide together with 42.2 g of tert-butylamine, and the mixture was heated under reflux with stirring for 30 minutes. The solution was concentrated under reduced pressure, after which was added 200 ml of chloroform and washed with 100 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about specified in the title compound as a colourless solid residue.

Reference example 32

Synthesis of N-(2-amino-5-chloro-3,6-differencein-4-yl)-phthalimide

To 80 ml triperoxonane acid was added the whole amount of N-[2- (tert-butylamino)-5-chloro-3,6-differencein-4-yl]phthalimide and the mixture was stirred at 70oC for 5 and a half hours. The solution was concentrated under reduced pressure. The precipitate was dispersible in chloroform and collected by filtration to obtain 19.5 g specified in the title compounds as colorless powder.

Reference example 33

Synthesis of N-(2,5-dichloro-3,6-differencein-4-yl)phthalimide

To 80 ml of acetonitrile was added to 21.3 g of N-(2-amino-5-chloro - 3,6-differencein-4-yl) phthalimide together with 14.0 g of copper chloride (2) and the mixture was stirred at room temperature with simultaneous dropwise addition of 15.8 tert-butylnitrite, dissolved reduced pressure. The residue was separated by adding 500 ml of chloroform and 250 ml of 2 N. hydrochloric acid, and the chloroform layer was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dissolved and collected by filtration to obtain 16.2 g specified in the title compounds as colorless powder.

Reference example 34

Synthesis of 4-amino-2,5-dichloro-3,6-diphereline

To a mixed solution of 100 ml of chloroform and 40 ml of methanol was added 16.2 g of N-(2,5-dichloro-3,6-giftability-4 - yl)phthalimide together with 20 ml of 25% aqueous ammonia solution, and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and after addition of 150 ml of chloroform to the residue and the mixture was washed with 20 ml of 15% aqueous ammonia solution and then 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to get 4,55 g specified in the title compounds as colorless powder.

Reference example 35

Synthesis of 4-amino-2,5-diphereline

To 40 ml of methanol was added 4.5 g of 4-amino-2,5-dichloro-3,6 - diphereline and 4.5 g of triethyl is the filtration of the catalyst and drove away under reduced pressure, the solvent and the like. To the residue was added 100 ml of chloroform and the mixture was washed with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added 1.5 g of triethylamine, 0.35 g of 10% palladium on coal and 30 ml of methanol, and the mixture was first made at the 50oC for 41 hours. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the like. To the residue was added 100 ml of chloroform, and the mixture was washed with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.67 g specified in the connection header in the form of precipitated precipitated colorless solid.

Reference example 36

Synthesis of 2-benzylamino-4-amino-5-herperidin

To 1 ml of N-methylpyrrolidone was added 410 mg of 4-amino-2,5 - diphereline together with 930 mg benzylamine and gave the mixture to interact in an atmosphere of nitrogen at 150oC for 3 days, then gave it to cool. After adding 30 ml of chloroform and the mixture was washed two times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Osem 400 mg specified in the title compound as a colourless solid.

1H NMR (CDCl3,) ;

4,06 (CL, 2H), and 4.40 (d, J=6 Hz, 2H), 4,60 (SHS, 1H), 5,69 (d, J=6 Hz, 1H), 7,33 (m, 5H), of 7.75 (d, J=3 Hz, 1H)

Reference example 37

Synthesis of 2,4-diamino-5-ftorpirimidinu

To 4 ml of methanol added to 400 mg of concentrated hydrochloric acid was added 350 mg of 2 - benzylamino-4-amino-5-herperidin together with 50 mg of 10% palladium on carbon and the mixture was first made in the 40oC for 2 days. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the like. Repeated 4 times a procedure for adding to the residue 10 ml of distilled water and concentration under reduced pressure, and 2 times the procedure of adding 10 ml of ethanol and concentrating under reduced pressure. As a residue was obtained 260 mg specified in the title compounds as a yellow-orange paste.

Reference example 38

Synthesis of ethyl 3-(4-amino-5-herperidin-2-yl)amino-2-(3-chloro - 2,4,5-triterpenoid)acrylate and ethyl 3-(2-amino-5-herperidin-4 - yl)amino-2-(Z-chloro-2,4,5-triterpenoid)acrylate

To 1.2 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro - 2,4,5-triterpenoid) acrylate obtained from 0.34 g of ethyl 3-chloro - 2,4,5-tripersonality in the usual way, was added 0.25 g of 2,4-di is the tion, and to the residue was added 0.52 g of anhydrous potassium carbonate and 0.8 ml N,N-dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 14 g: eluent: chloroform: methanol, 1:0 and then 100:1) and the fraction containing the main product were concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1.06 g indicated in the title mixture (1:1 by NMR) as a pale brown powder.

Example 53

Synthesis of ethyl 1-(4-amino-5-herperidin-2-yl)-8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 150 mg of a mixture of ethyl 3-(4-amino-5-herperidin-2-yl)amino-2- (3-chloro-2,4,5-triterpenoid)acrylate and ethyl 3-(2-amino-5 - herperidin-4-yl)amino-2-(3-chloro-2,4,5-triterpenoid)acrylate was added 230 mg of anhydrous potassium carbonate and 450 mg of N,N - dimethylformamide and the mixture was stirred at 100oC for 20 minutes, the, and the chloroform layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 3.2 g; eluent:chloroform:methanol, 100:1) and fractions containing the main product were concentrated under reduced pressure to obtain 35 mg specified in the title compound as a yellow solid residue.

Melting point: 140-148oC

1H NMR (CDCI3) ;

to 1.38 (t, J=7 Hz, 3H), 4,37 (kV, J=7 Hz, 2H), 4,78 (CL, 2H), 6,78 (d, J=6 Hz, 1H), 8,11 (d, J=3 Hz, 1H), 8,27 (DD, J=8 Hz, 10 Hz, 1H), 8,55 (s, 1H)

Example 54

Synthesis of 1-(4-amino-5-herperidin-2-yl)-8-chloro-6,7-debtor - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 400 mg of the mixed solution (1:1) 4 N. hydrochloric acid and acetic acid was added 35 mg of ethyl 1-(4-amino-5-herperidin-2 - yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 hours, then allowed it to cool. The precipitate was collected by filtration and washed sequentially with distilled water, ethanol and diisopropyl ether to obtain 31 mg specified in the title compounds as pale yellow powder.

T Is J=3 Hz, 1H), 8,39 (t, J=9 Hz, 1H), total of 8.74 (s, 1H)

Example 55

Synthesis of 7-(3-aminoamides-1-yl)-1-(4-amino-5-herperidin-2-yl) -8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 110 mg of N,N-dimethylformamide was added 23 mg of 1-[4 - amino-5-herperidin-2-yl]-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-Z-carboxylic acid, 20 mg of 3 - aminoacetanilide and 50 mg N-methylpyrrolidone and the mixture was stirred at 90oC for 20 minutes. After adding 500 mg of ethanol the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 23 mg specified in the title compounds as colorless powder.

Melting point: 280oC or higher.

1H NMR (d6-DMSO) ;

of 3.75 (m, 1H), 4,10 (m, 2H),4,66 (m, 2H).,b,77 (CL, 2H), 6,92 (d, J==7 Hz, 1H), 7,86 (d, J 14 Hz, 1H), 8,08 (d, J=3 Hz, 1H), to 8.57 (s, 1H)

Reference example 39

Synthesis of methyl 2,6-dichloro-5-fornicating

To 60 ml of dichloromethane was added to 21.0 g of 2,6-dichloro-5 - fornicating acid, 10 ml of oxalicacid and 10 drops of N,N - dimethylformamide and the mixture was stirred at room temperature during the day. Drove away under reduced pressure, the solvent and excess reagents and the residue was dissolved in 50 ml of chloroform the ut, then to the solution was added 15 g of anhydrous potassium carbonate and stirred the solution for another 30 minutes. Shared the solution by adding 150 ml of chloroform and 150 ml of distilled water and the chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to get to 26.6 g specified in the title compounds as colorless crude oily residue.

Reference example 40

Synthesis of methyl 6-tert-butylamino-2, 5-differntiate

To 30 ml of dimethylsulfoxide was added three quarters (19, 95 g) of methyl 2,6-dichloro-5-fornicating, synthesized as described above, 14.5 g of potassium fluoride (spray dried) and 1.6 g of Tetramethylammonium, and the mixture was stirred at 110oC for 2 and a half hours, and then allowed it to cool. After addition of 100 ml of chloroform and the mixture was washed twice with 1 liter of distilled water and once with 1 liter of 1% aqueous solution of sodium carbonate. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The result obtained crude methyl - 2,5,6-triptorelin in the form of a brown oily residues the residue was dissolved in 60 ml of acetonitrile and to rustom adding 100 ml of chloroform and 60 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersible in n-hexane and collected by filtration to obtain 6,85 g specified in the title compounds as colorless crystals.

1H NMR (CDCl3) ;

of 1.50 (s, 9H), 3,86 (s, 3H), 5,04 (SHS, 1H), 7,71 (DD, J=7 Hz, 11 Hz, 1H)

Reference example 41

Synthesis of methyl-6-tert-butylamino-5-fluoro-2-(1,1,3,3-Tetra - methylbutylamine)nicotinate

To 7 ml of N-methylpyrrolidone added 2,44 g of methyl 6-tert - butylamino-2,5-differntiate and 4.0 g of 1,1,3,3 - tetramethylbutylamine, and the mixture was stirred at 140oC for 16 hours and allowed it to cool. After adding 50 ml of chloroform and the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform: n-hexane, 1:1) to obtain the 2,90 g specified in the title compounds as a colorless oily residue.

1H NMR (CDCl3) ;

of 0.96 (s, 9H) and 1.51 (s, 9H), of 1.53 (s, 6H), 3,76 (s, 3H), 4,87 (SHS, 1H), 7,52 (d, J=12 Hz, 1H), scored 8.38 (SHS, 1H)

Reference example 42

Synthesis of 2-tert-butylamine is sociallyengaged. The dispersion was cooled water and stirred with a simultaneous dropwise addition 2,80 g methyl-6-tert - butylamino-5-fluoro-2-(1,1,3,3-tetramethylbutylamine) nicotinate, dissolved in 30 ml of tetrahydrofuran. The reactor was placed in an oil bath at 50oC and the mixture was stirred for two and a half hours. Then the reactor was cooled and water was added to the reaction mixture dropwise 8 ml of ethyl acetate, after which the mixture was stirred for 1 hour. Was added dropwise 8 ml of ethanol and the mixture was stirred 1 h, then was added dropwise 8 ml of distilled water, and the mixture was stirred overnight. The precipitate was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform: n-hexane, 1:1) to obtain 1,67 g specified in the title compounds as a colorless oily residue.

1H NMR (CDCl3) ;

0,99 (s, 9H), of 1.47 (s, 9H), of 1.52 (s, 6H), 1.91 a (s, 3H), of 3.73 (SHS, 1H), 4,11 (SHS, 1H), for 6.81 (d, J=12 Hz, 1H)

Reference example 43

Synthesis of 2,6-diamino-3-fluoro-5-methylpyridine

To 800 mg triperoxonane acid was added 340 mg of 2-tert - butylamino-3-fluoro-5-methyl-6-(1,1,3,3-tetramethylbutylamine) of pyridine and the mixture was allowed to stand at room temperature is fluoro - 5-methylpyridine as a pale brown solid residue.

Example 56

Synthesis of ethyl 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro - 6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro - 2,4,5-triterpenoid)acrylate obtained from 280 mg of ethyl 3 - chloro-2,4,5-tripersonality in the usual way, added all of 2,6-diamino-3-fluoro-5-methylpyridin obtained as described above, together with 2 ml of methanol and 4 ml of chloroform. After sedimentation at room temperature for 40 minutes the solution was concentrated under reduced pressure. To the residue was added 600 mg of anhydrous potassium carbonate and 1 ml of N,N-dimethylformamide and the mixture was stirred at 85oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and gave the mixture to settle in for the night. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 171 mg specified in the title compounds as colorless powder.


Example 57

Synthesis of 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 800 mg of the mixed solution (1:1) 4 N. hydrochloric acid and acetic acid was added 160 mg of ethyl 1-(6-amino-5-fluoro-3 - methylpyridin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline - 3-carboxylate, and the mixture was heated under reflux with stirring for 30 minutes. After adding 0.5 ml of distilled water the solution was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 145 mg specified in the title compound as pale brown powder.

Melting point: 279-284oC (decomposition).

1H NMR (d6-DMSO) ;

of 1.94 (s, 3H), 6,62 (CL, 2H), EUR 7.57 (d, J=11 Hz, 1H), 8,40 (t, J=9 Hz, 1H), 8,72 (s, 1H)

Example 58

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-5-fluoro-3 - methylpyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-Z - carboxylic acid

To 250 mg N,N-dimethylformamide was added 80 mg of 1-(6-amino-5 - fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino - setidentityproviderid and 120 mg of N-methylpyrrolidine then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 72 mg specified in the title compounds as colorless powder.

Melting point: 256-258oC (decomposition).

1H NMR (d6-DMSO) ;

1,90 (s, 3H), of 3.69 (m, 1H), a 4.03 (m, 2H), 4,66 (m, 2H), 6,57 (CL, 2H), 7,52 (d, J=11 Hz, 1H), 7,87 (d, J 14 Hz, 1H), of 8.47 (s, 1H)

Example 59

Synthesis of 7-[3-(methylamino) azetidin-1-yl] -1-(6-amino - 5-fluoro-3-methylpyridin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid

To 90 mg of N,N-dimethylformamide was added 25 mg of 1-(6-amino-5 - fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 25 mg of 3- (methylamino)apatityvodokanala 70 mg N-methylpyrrolidine, and the mixture was stirred at 85oC for 45 minutes. After addition of 0.2 ml of ethanol, the mixture was allowed to cool, and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 20 mg indicated in the title compounds as colorless powder.

Melting point: 251-253oC (decomposition).

1H NMR (d6-DMSO) ;

1,90 (s, 3H), 2,20 (s, 1H), 3,44 (m, 1H), 4,12 (m, 2H), 4,63 (m, 2H), 6,57 (CL, 2H), 7,52 (d, J=11 Hz, 1H), 7,86 (d, J=14 Hz, 1H), of 8.47 (s, 1H)

Reference example 44

Synthesis of 6-tert-butylamino-2-chloro-3-cyano-5-herperidin

To a solution of 7.6 g of 2,6-dichloro-3-cyano-5-herperidin in 40 ml of acetonitrile was added 8.8 g Tr is whether the solvent. The residue was separated by adding methylene chloride and water. The organic layer was dried over anhydrous magnesium sulfate and drove the solvent to obtain 6 g specified in the title compounds as pale yellow powder.

Melting point: 84-85oC

1H NMR (CDCl3) ;

of 1.50 (s, 9H), 5,15 (SHS, 1H), 7,25 (d, J=11 Hz, 1H)

Reference example 45

Synthesis of 2-benzylamino-6-tert-butylamino-3-cyano-5-herperidin

To 40 ml of N-methylpyrrolidone solution of 6 g of 6-tert - butylamino-2-chloro-3-cyano-5-herperidin was added 6.3 g of benzylamine, and the mixture was stirred under nitrogen atmosphere at 160oC for 3 hours, then allowed it to cool. The reaction solution was separated by adding chloroform and water, the organic layer was dried over magnesium sulfate and drove the solvent. The precipitated crystals were filtered from the residue to obtain 2 g specified in the title compounds as pale yellow powder.

Melting point 138-140oC

1H NMR (CDCl3) ;

to 1.38 (s, 9H), 4,63 (d, J=6 Hz, 2H), 4,87 (SHS, 1H), 5.25-inch (SHS, 1H), 7,31 (s, 5H)

Reference example 46

Synthesis of 2-amino-6-tert-butylamino-3-cyano-5-herperidin

To 500 mg of 2-benzylamino-6-tert-butylamino-3-cyano-5 - ftoropirimidinami under nitrogen atmosphere at 60oC for 2 days. Using a membrane filter to remove the catalyst and the filtrate drove the solvent. To the residue was added chloroform, and the mixture was washed with an aqueous solution of sodium bicarbonate. The organic layer was collected and dried over magnesium sulfate. Drove the solvent to obtain 300 mg specified in the connection header.

Example 60

Synthesis of ethyl 1-(6-tert-butylamino-3-cyano-5-herperidin-2-yl) -8-chloro-6,7-debtor-1,4-dihydro-4-oxoindole-3-carboxylate

A solution of 300 mg of the crude 2-amino-6-tert-butylamino-C - cyano-5-herperidin in 2 ml of ethanol was added dropwise to a solution of 420 mg of ethyl 3-ethoxy-2-(3-chloro-2,4,5-triterpenoid) acrylate in 2 ml of ethanol at room temperature, and the mixture was stirred overnight. Of the reaction solution is kept off the solvent, and to the residue was added 3 ml of N,N-dimethylformamide 210 mg of potassium carbonate, after which the mixture was stirred at room temperature for 90 minutes and at 80oC for 2 hours. The reaction solution was extracted by adding water and ethyl acetate, and the organic layer was collected and dried over magnesium sulfate. Drove the solvent, and the residue was collected by filtration with ethanol and washed in diethyl ether is Lavinia: 245oC or above (with decomposition).

1H NMR (CDCl3) ;

of 1.39 (s, 9H), of 1.41 (t, J=7 Hz, 3H), to 4.41 (q, J=7 Hz, 2H), 5,39 (SHS, 1H), 7,43 (d, J=10 Hz, 1H), 8,32 (t, J=9 Hz, 1H), 8,53 (s, 1H)

Example 61

Synthesis of 1-(6-amino-3-cyano-5-herperidin-2-yl)-8-chloro - 6,7-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

To 280 mg of ethyl 1-(6-tert-butylamino-3-cyano-5-herperidin-2 - yl)-8-chloro-6,7-debtor-1,4-dihydro-4-oxo-chinolin-3-carboxylate was added 3 ml of 12 N. hydrochloric acid and the mixture was heated under reflux for 6 hours, then allowed it to cool. The solid precipitate was collected by filtration and washed successively with ethanol and diethyl ether to obtain 120 mg specified in the title compounds as pale yellow powder.

Melting point: 277oC or above (with decomposition).

1H NMR (d6-DMSO) ;

8,00 (CL, 2H), 8,21 (d, J=11 Hz, IH), 8,40 (t, J=9 Hz, 1H), 9,05 (s, 1H)

Example 62

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3-cyano-5 - herperidin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-4-oxoindole-3 - carboxylic acid

A solution of 40 mg of 3-aminoacetanilide and 80 mg of triethylamine in 300 mg of N,N-dimethylformamide was stirred at 90oC and added to it 50 mg 1-(6-amino-3-cyano-5-herperidin-2-yl)-8 - chloro-6,7-gift. the reaction solution was added 1 ml of ethanol and the solid precipitate was collected and dried to obtain 36 g specified in the title compounds as pale yellow powder.

Melting point: 290oC or higher

1H NMR (d6-DMSO) ;

4.09 to (m, 1H), 4,48 (m, 2H), 4,79 (m, 2H), of 7.90-of 8.06 (m, 3H), 8,16 (d, J= 11 Hz, 1H), 8,33 (CL, 2H), cent to 8.85 (s, 1H)

Example 63

Synthesis of ethyl 1-[6-(tert-butylamino)-3,5-differencein-2 - yl] -6,7-debtor-8-methyl-1,4-dihydro-4-oxoindole-3-carboxylate

To 3.4 g of ethyl 2,4,5-Cryptor-3-methylbenzylamine was added 3.2 g of acetic anhydride and 2.3 g of triethylorthoformate, and the mixture was heated under reflux for 4 hours, then drove the solvent. To the residue was added toluene, and subjected to a solution of azeotropic distillation. After adding to the residue 5 ml of ethanol was added dropwise at 0oC a solution of 2.7 g of 2-amino-6-(tert - butylamino)-3.5-diphereline in 20 ml of ethanol and the mixture was stirred at room temperature for 20 minutes. Of the reaction solution is kept off the solvent and the residue was subjected to column chromatography on silica gel with receipt of the eluent (ethyl acetate:hexane, 1:8) of 4.6 g of ethyl 2-(2,4,5-Cryptor-C - methylbenzoyl)-3-[6-tert-butylamino)-3,5-differencein-2 - yl]aminoate the-3-[6-(tert-butylamino)-3, 5-differencein-2-yl]aminoacetate in 10 ml of dimethylformamide was added 1.35 g of potassium carbonate, and the mixture was stirred at 100oC for 50 minutes. The reaction solution was extracted by adding water and acetic acid, and the organic layer was collected and dried over magnesium sulfate. Drove the solvent and the residue was collected by filtration with ethanol and washed with diethyl ether to obtain 2.6 g specified in the title compounds as pale yellow powder.

Melting point: 207-211oC

1H NMR (CDCl3) ;

of 1.34 to 1.48 (m, 12H), is 1.82 (d, J=3 Hz, 3H), and 4.40 (q, J=7 Hz, 2H), 4.75 in (SHS, 1H), 7.23 percent (t, J=9 Hz, 1H), they were 8.22 (t, J=10 Hz, 1H), and 8.50 (s, 1H)

Example 64

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-6,7-debtor-8 methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid

To 2.5 g of ethyl 1-[6-(tert-butylamino)-3,5-differencein-2-yl]- 6,7-debtor-8-methyl-1,4-dihydro-4-oxoindole-3-carboxylate was added 10 ml 12 N. hydrochloric acid, and the mixture was heated under reflux overnight. Given the reaction solution to precipitate and the solid precipitate was collected by filtration and washed with ethanol and then diethyl ether to obtain 1.7 g specified in the title compounds as pale yellow powder.

TT, J=9 Hz, 1H), 8,93 (s, 1H)

Example 65

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3,5-differencein - 2-yl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid

A solution of 70 mg of 3-aminoacetanilide 200 mg of 1,8 - diazabicyclo[5.4.0] undecene and 300 mg of pyridine was stirred at 100oC and added to it 110 mg of 1-(6-amino-3,5-differencein-2 - yl)-6,7-debtor-8-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid, and then stirred at 100oC for 6 minutes. Of the reaction solution is kept off the solvent and to the residue was added one drop of acetic acid and 3 ml of ethanol under heating, and then the solution was allowed to settle. The solid precipitate was collected and dried to obtain 13 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or higher

1H NMR (d6-DMSO) ;

to 1.60 (s, 3H), of 3.77 (m, 2H), 3,93 (m, 1H), 4,46 (m, 2H), 6,86 (CL, 2H), of 7.75 (d, J=13 Hz, 1H) 7.95 is (t, J=9 Hz, 1H), to 8.70 (s, 1H)

Example 66

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-6-fluoro-8-methyl - 7-(3-methylaminomethyl-1-yl)-1,4-dihydro-4-oxo-chinolin-3 - carboxylic acid

Specified in the title compound (20 mg) was obtained as pale yellow powder in the same way as described in example 65, except for the howl acid and 110 mg of 3-amino - azetidinone.

Melting point: 229oC or higher

1H NMR (d6-DMSO) ;

of 1.63 (s, 3H), of 2.21 (s, 3H), a 3.87 (m, 1H), was 4.02 (m, 1H), 4,43 (m, 2H), 6,86 (CL, 2H), of 7.75 (d, J=14 Hz, 1H), 7,97 (t, J=10 Hz, 1H), 8,71 (s, 1H)

Example 67

Synthesis of 7-(3-amino-3-methylaziridine-1-yl)-1-(6-amino-3,5 - differencein-2-yl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid

Specified in the title compound (60 mg) was obtained as pale yellow powder in the same way as described in example 65, except that used 180 mg of 1-(6-amino-3,5 - differencein-2-yl)-6,7-debtor-8-methyl-1,4-dihydro-4-oxo - quinoline-3-carboxylic acid and 110 mg of 3-amino-3-methyltetrahydrofolate.

Melting point: 235oC or higher

1H NMR (d6-DMSO) ;

of 1.37 (s, 3H), of 1.62 (s, 3H), a 3.87 (m, 1H), 4,08 (m, 3H), 6,85 (CL, 2H), 7,74 (d, J=14 Hz, 1H), of 7.96 (t, J=10 Hz, 1H), 8.70 (s, 1H)

Example 68

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-6,8-debtor-7- (3-methylaminomethyl-1-yl)-4-oxo-1, 4-dihydroquinoline-3 - carboxylic acid

To 200 mg of N,N-dimethylformamide was added 65 mg of 1-(6-amino-C, 5-differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline - 3-carboxylic acid, 45 mg of 3-methylamino-setidentityproviderid and 100 mg N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85o

Melting point: 262-268oC (decomposition).

1H NMR (d6-DMSO) ;

are 2.19 (s, 3H), 3,52 (m, 1H), 4,01 (m, 2H), of 4.44 (m, 2H), 6.75 in (CL, 2H), to 7.77 (d, J=13 Hz, 1H), 7,99 (t, J=9 Hz, 1H), total of 8.74 (s, 1H)

Example 69

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-8-bromo-6-fluoro - 7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 270 mg of N,N-dimethylformamide was added 110 mg of 1-(6-amino - 3,5-differencein-2-yl)-8-bromo-6,7-debtor-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyacetanilide and 100 mg N-methylpyrrolidine together with 3 drops of ethanol and the mixture was stirred at 85oC for 25 minutes. After addition of 0.5 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 101 mg specified in the title compounds as pale yellow powder.

Melting point: 215-220oC

1H NMR (d6-DMSO) ;

4,06 (m, 2H), 4,51 (m, 3H), 5,75 (SHS, 1H), 6,76 (CL, 2H), 7,79 (d, J=13 Hz, 1H), 7,99 (t, J=9 Hz, 1H), up 8.75 (s, 1H) 1

Example 70

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro - 7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 3.5 g of N,N-dimethylformamide was added to 2.00 g of 1-(6 - amino-3 is ochloride and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture was stirred at 85oC for 10 minutes. Drove away under reduced pressure, the solvent and the like. After adding to the residue 10 ml of ethanol and the mixture was heated under reflux for 10 minutes, then allowed it to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 2.10 g specified in the title compounds as pale yellow powder.

Melting point: 235-238oC

1H NMR (d6-DMSO) ;

4,18 (m, 2H), 4,48 (m, 1H), 4.72 in (m, 2H), 5,74 (d, J=6 Hz, 1H), 6,76 (CL, 2H), 7,86 (d, J=14 Hz, 1H), 7,95 (t, J=9 Hz, 1H), to 8.70 (s, 1H)

Example 71

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-6,8-debtor-7- (3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 280 mg of N,N-dimethylformamide was added 125 mg of 1-(6 - amino-3,5-differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyacetanilide and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85oC for 10 minutes. After addition of 0.8 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 90 mg of the decree is
1H NMR (d6-DMSO) ;

4,06 (m, 2H), 4,51 (m, 3H), 5,75 (SHS, 1H), 6,76 (CL, 2H), 7,79 (d, J=13 Hz, 1H), 7,99 (t, J=9 Hz, 1H), up 8.75 (s, 1H)

Example 72

Synthesis of ethyl 8-bromo-1-[6-(tert-butylamino)-5-herperidin-2 - yl] -6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-bromo-2,4,5 - triterpenoid)acrylate obtained from 0.65 g of ethyl 3-bromo-2,4,5 - tripersonality in the usual way, were added 0.3 g of 2-amino - 6-(tert-butylamino)-5-herperidin. The solution was concentrated under reduced pressure to obtain a yellow-orange residue. To this residue was added 0.4 g of anhydrous potassium carbonate and 2 ml of N-dimethylformamide, and the mixture was stirred at 90oC for 25 minutes, then allowed it to cool. The solution was separated by adding 25 ml of chloroform and 400 ml of distilled water, and the chloroform layer was washed with 400 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

After addition of 2 ml ethanol solution was allowed to settle. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0,53 g specified in the title compounds as a pale reltag=7 Hz, 3H), and 4.40 (q, J=7 Hz, 2H), a 4.83 (SHS, 1H), 6,50 (DD, J=3 Hz, 8 Hz, 1H), 7,24 (DD, J=8 Hz, 10 Hz, 1H), 8,35 (t, J=9 Hz, 1H), 8,65 (s, 1H)

Example 73

Synthesis of 1-(6-amino-5-herperidin-2-yl)-8-bromo-6,7-debtor - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 4 ml of a mixed solution (1:1) 4 N. hydrochloric acid and acetic acid was added 480 mg of 8-bromo-1-[6-(tert - butylamino)-5-herperidin-2-yl]-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylate and the mixture was heated under reflux with stirring for 2 hours. After adding 4 ml of distilled water the solution was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 345 mg specified in the title compounds as colorless powder.

Melting point: 245-251oC (decomposition).

1H NMR (d6-DMSO) ;

6,84-6,92 (m, 3H), of 7.64 (DD, J=8 Hz, 11 Hz, 1H), 8,40 (t, J=9 Hz, 1H), 8,79 (s, 1H)

Example 74

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-5-herperidin - 2-yl)-8-bromo-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 250 mg N,N-dimethylformamide was added 80 mg of 1-(6-amino-5 - herperidin-2-yl)-8-bromo-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid, 55 mg of 3-aminoacetanilide and 150 mg of N-metylene to cool, and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 68 mg specified in the title compounds as colorless powder.

Melting point: 245-250oC (decomposition).

1H NMR (d6-DMSO) ;

and 3.72 (m, 1H), was 4.02 (m, 2H), 4,67 (m, 2H), 6.73 x (DD, J=2 Hz, 8 Hz, 1H, 6,82 (CL, 2H), to 7.59 (DD, J=8 Hz, 10 Hz, 1H), 7,87 (d, J=14 Hz, 1H), 8,69 (s, 1H)

Example 75

Synthesis of 1-(6-amino-5-herperidin-2-yl)-8-bromo-6-fluoro-7-(C - methylimidazolidine-1-yl)-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid

To 250 mg N,N-dimethylformamide was added 80 mg of 1-(6-amino-5 - herperidin-2-yl)-8-bromo-6,7-debtor-4-oxo-1,4-dihydroquinoline - 3-carboxylic acid, 80 mg of 3-methylaminoacetaldehyde and 200 mg N-methylpyrrolidone and the mixture was stirred at 85oC for 10 minutes. After addition of 0.5 ml of the ethanol solution was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 66 mg specified in the title compounds as colorless powder. Melting point: 210 - 218oC (decomposition).

1H NMR (d6-DMSO) ;

2,22 (s, 3H), of 3.48 (m, 1H), 4,12 (m, 2H), br4.61 (m, 2H), 6,74 (d, J=10 Hz, 2H), for 6.81 (CL, 2H), to 7.59 (t, J=10 Hz, 1H), 7, 87 (d, J=balali 2.7 g of 2-amino-4-bromo-5-chloro - 3,6-diphereline, and 1.15 g of triethylamine together with 0, 145 g of 10% palladium on charcoal, and the mixture was first made at room temperature for 1.5 hours. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the like. To the residue was added 50 ml of chloroform and the mixture is washed with 30 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained colorless flake crystals were dispersively in a mixed solvent of diisopropyl ether and n-hexane (1:2) and collected by filtration to obtain 1,62 g specified in the connection header.

Reference example 48

Synthesis of 2-amino-5-chloro-3-fluoro-6-(p-methoxybenzylamine) pyridine

To 2 ml of N-methylpyrrolidone was added 510 mg of 2-amino-5 - chloro-3,6-diphereline and 910 mg of p-methoxybenzylamine, and the mixture was stirred at 150oC during the day, then gave it to cool. After adding 60 ml of a mixed solution of benzene and n-hexane (1:1, V/V) solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 960 mg specified in the title compound as a brown crude oil.


Example 76

Synthesis of ethyl 8-chloro-1-[5-chloro-3-fluoro-6-(p-methoxybenzylamine) -pyridine-2-yl]-6,7-debtor-4-oxo-1,4-dihydroquinoline-Z-carboxylate

To 2 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate obtained from 0.56 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 0.66 g of 2-amino - 5-chloro-3-fluoro-6-(p-methoxybenzylamine) pyridine. The solution was concentrated under reduced pressure. To the residue was added 0.5 g anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide and the mixture was stirred at 90oC for 20 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced, pressure. After addition of 4 ml of ethanol solution was allowed to settle. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0.56 g specified in the title compounds as pale yellow powder.

Melting point: 168-171oC

1H NMR (CDCl3,) ;

of 1.40 (t, J=7 Hz, 3H), of 3.80 (s, 3H), and 4.40 (d, J=7 Hz, 2H), 4,42 (kV, J= Hz, 2H), 5,46 (SHS, 1H), 6,83 (d, J=9 G is one-2-yl)-8-chloro - 6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 530 mg of ethyl 8-chloro-1-[5-chloro-3-fluoro-6-(p - methoxybenzylamine)pyridine-2-yl]-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylate was added 2 ml of triptoreline and the solution was allowed to stand for 30 minutes at room temperature. The solution was concentrated under reduced pressure and to the residue was added 4 ml of ethanol, after which the solution was concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 462 mg specified in the title compounds as pale yellow powder.

Melting point: 186-189oC

1H NMR (CDCl3) ;

of 1.40 (t, J=7 Hz, 3H), 4,40 (KB, J=7 Hz, 2H), 5,02 (CL, 2H), EUR 7.57 (d, J=8 Hz, 2H), 8,30 (t, J=9 Hz, 1H), 8,48 (s, 1H)

Example 78

Synthesis of 1-(6-amino-5-chloro-3-herperidin-2-yl)-8-chloro-6,7 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 2 ml of a mixed solution (1:1) 4 N. hydrochloric acid and acetic acid was added 430 mg of ethyl 1-(6-amino-5-chloro-3 - herperidin-2-yl]-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 6 hours, then allowed to cool. The precipitate was collected by filtration and washed poseshchennogo powder.

Melting point: 280oC or higher

1H NMR (d6-DMSO) ;

6,86 (CL, 2H), 8,15 (d, J=9 Hz, 1H), scored 8.38 (t, J=9 Hz, 1H), of 8.95 (s, 1H)

Example 79

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-5-chloro - 3-herperidin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 280 mg of N,N-dimethylformamide was added 90 mg of 1-(6-amino-5 - chloro-3-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 70 mg of 3 - aminoacetanilide and 160 mg N-methylpyrrolidine, and the mixture was stirred at 85oC for 20 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 50 mg specified in the title compounds as colorless powder.

Melting point: 240-245oC (decomposition).

1H NMR (d6-DMSO) ;

3,71 (m, 1H), 4,06 (m, 2H), 4,66 (m, 2H), 6,79 (CL, 2H), a 7.85 (d, J=14 Hz, 1H), 8,08 (d, J=9 Hz, 1H), to 8.70 (s, 1H)

Reference example 49

Synthesis of 2,3,5-Cryptor-6-isopropylpyridine

To 20 ml of acetonitrile was added to 6.0 g of 2,3,5,6 - tetrafluoropyridine and 6.0 g of Isopropylamine, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced oratory layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.9 grams specified in the title compounds as colorless oils.

Reference example 50

Synthesis of 3,5-debtor-2-isopropylamino-6-(p-methoxybenzylamine) pyridine

To 4.1 g of N-methylpyrrolidone was added the whole amount of 2,3,5 - Cryptor-6-isopropylpyridine obtained as described above, together with 3.1 g of p-methoxybenzylamine, and the mixture was stirred at 150oC for 15 hours, then allowed it to cool. After addition of 50 ml of a mixed solution of benzene and n-hexane (1:1, V/V) solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.9 g specified in the title compound as a brown crude oil.

Reference example 51

Synthesis of 2-amino-3,5-debtor-6-isopropylpyridine

To 1.9 g of 3, 5-debtor-2-isopropylamino-6-(p-methoxybenzylamine) of pyridine was added 4 ml of triptoreline and the mixture was allowed to stand at room temperature for 15 minutes. The solution was concentrated under reduced pressure and to the residue was added 25 ml of chloroform, and the solution was washed with 25 ml of 5% aqueous sodium carbonate solution. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue under connection in the form of a brown oil.

Example 80

Synthesis of ethyl-8-chloro-6,7-debtor-1-(3,5-debtor-6 - isopropylpyridine-2-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 2.5 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro - 2,4,5-triterpenoid)acrylate obtained from 0,70 g of ethyl 3-chloro - 2,4,5-tripersonality in the usual way, was added 600 mg of 2 - amino-3,5-debtor-6-isopropylpyridine. The solution was concentrated under reduced pressure. To the residue was added 600 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide; and the mixture was stirred at 90oC for 20 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 400 ml of distilled water and the chloroform layer was washed twice with 400 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to settle. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 620 mg specified in the title compounds as pale yellow powder.

Melting point: 206-209oC

1H NMR (CDCI3) ;

of 1.20 (d, J=7 Hz, 3H), 1,24 (d, J=7 Hz, 3H), of 1.40 (t, J=7 Hz, 3H), 4,11 (m, 1H), and 4.40 (q, J=7 Hz, 2H), 4,60 (SHS, 1H), 7,22 (DD, J=8 Hz, 9 Hz, 1H), 8,32 (DD, J=8 Hz, 10 Hz, 1H), 8,49(s, 1H)< / BR>
new acid

To 3 ml of a mixed solution (1:1, V/V) 4 N. hydrochloric acid and acetic acid was added 300 mg of ethyl 8-chloro-6,7 - debtor-1-(3,5-debtor-6-isopropylpyridine-2-yl]-4-oxo - 1,4-dihydroquinoline-Z-carboxylate, and the mixture was heated under reflux for 19 hours with stirring. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 265 mg specified in the title compound as a yellow powder.

Melting point: 226-230oC

1H NMR (d6-DMSO);

of 1.10 (d, J=7 Hz, 3H), of 1.16 (d, J=7 Hz, 3H), of 3.94 (m, 1H), 7,02 (sm, J=8 Hz, 2H), 7,97 (t, J=9 Hz, 1H), 8,39 (t, J=9 Hz, 1H), of 8.92 (s, 1H)

Example 82

Synthesis of 7-(3-aminoamides-1-yl)-8-chloro-6-fluoro-1-(3, 5-debtor-6-isopropylpyridine-2-yl)-4-oxo-1,4-dihydroquinoline - 3-carboxylic acid

To 160 mg of N,N-dimethylformamide was added 55 mg of 8-chloro-6,7 - debtor-1-(3,5-debtor-6-isopropylpyridine-2-yl)-4-oxo-1,4 - dihydroquinoline-Z-carboxylic acid, 35 mg of 3 - aminoacetanilide and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 80oC for 30 minutes. After addition of 0.5 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether obtained is/BR>1H NMR (d6-DMSO) ;

of 1.13 (d, J=7 Hz, 3H), of 1.16 (d, J=7 Hz, 3H), 3,70 (m, 1H), 3.96 points (m, 2H), 4,06 (m, 1H) and 4.65 (m, 2H), 6,92 (sm, J=7 Hz, 2H), 7,87 (d, J 14 Hz, 1H), 7,92 (t, J=9 Hz, 1H), 8,66 (s, 1H)

Example 83

Synthesis of ethyl 1-[3,5-debtor-6-(p-methoxybenzylamine) pyridine-2-yl] -5,6,7,8-titrator-4-oxo-1,4-dihydroquinoline-3 - carboxylate

To 20 ml of a chloroform solution of ethyl 3-ethoxy-2 - pentafluorobenzonitrile obtained from 5.6 g of ethyl 2,3,4,5,6 - pentafluorobenzoate in the usual way, was added 2-amino-3,5 - debtor-6-(p-methoxybenzylamine) pyridine, while TLC analysis has not disappeared ethylacrylate spot. The solution was concentrated under reduced pressure. To the residue was added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide, and the mixture was stirred at 90oC for 15 minutes, then allowed it to cool. The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water and the chloroform layer was washed twice with 1 liter of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate

was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 6,15 g specified in the title compounds as colorless p(C, 3H), and 4.40 (d, J=7 Hz, 2H), 4,42 (kV, J=7 Hz, 2H), 5,46 (SHS, 1H), 6,83 (d, J=9 Hz, 2H), 7,18 (d, J=9 Hz, 2H), 7,53 (d, J=8 Hz, 1H), 8,29 (t, J=9 Hz, 1H), 8,48 (s, 1H)

Example 84

Synthesis of ethyl 1-(6-amino-3,5-differencein-2-yl)-5,6,7,8 - titrator-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 1080 mg of ethyl 1-[3,5-debtor-6-(p-methoxybenzylamine) pyridine-2-yl]-5,6,7,8-titrator-4-oxo-1,4 - dihydroquinoline-3-carboxylate was added 4 ml triperoxonane acid, and the mixture was allowed to stand for 30 minutes at room temperature. The solution was concentrated under reduced pressure and to the residue was added 4 ml of ethanol, after which the solution was concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed with ethanol to obtain 960 mg specified in the title compound as a gray powder.

Melting point: 223-230oC

1H NMR (CDCI3) ;

of 1.39 (t, J=7 Hz, 3H), of 4.38 (d, J=7 Hz, 2H), a 4.83 (CL, 2H), 6,83 (d, J=9 Hz, 2H), 7,35 (t, J=9 Hz, 1H), 8,32 (s, 1H)

Example 85

Synthesis of 1-(6-amino-3,5-differencein-2-yl)-5,6,7,8 - titrator-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 2 ml of a mixed solution (1:1) 4 N. hydrochloric acid and acetic acid was added 320 mg of ethyl 1-6-(amino-3,5 - differencein-2-yl)-5,6,7,8-titrator-4-oxo-1,4-dihydroquinoline-3-CT is to state. The precipitate was collected by filtration and washed with ethanol to obtain 280 mg of the indicated in the title compounds as colorless powder.

Melting point: 236-242oC

1H NMR (d6-DMSO) ;

6,82 (CL, 2H), 8,03 (t, J=9 Hz, 1H), of 8.92 (s, 1H)

Example 86

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3,5 - differencein-2-yl)-5,6,8-Cryptor-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino - 3,5-differencein-2-yl)-5,6,7,8-titrator-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino - setidentityproviderid 150 mg N-methylpyrrolidine, and the mixture was stirred at 90oC for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 50 mg specified in the title compounds as pale yellow powder.

Melting point: 264-271oC (decomposition).

1H NMR (d6-DMSO) ;

of 3.77 (m, 1H), 3.96 points (m, 2H), 4,46 (m, 2H), 6.75 in (CL, 2H), 7,97 (t, J=9 Hz, 1H), 8,66 (s, 1H)

Example 87

Synthesis of ethyl 5-benzylamino-1-[3,5-debtor-6- (p-methoxybenzylamine)pyridine-2-yl]-6,7,8-Cryptor-4-oxo-1,4 - dihydroquinoline-3-carboxylate

hydrochinon-3-carboxylate together with 0,68 g benzylamine, and the mixture was stirred at 110oC for 20 minutes, then allowed it to cool. After addition of 15 ml of toluene and 15 ml of n-hexane and the mixture was washed two times with 300 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added 4 ml of ethanol, gave the solution to precipitate, and the precipitate was collected by filtration and washed with ethanol to obtain 1.20 g specified in the title compound as a yellow powder.

Melting point: 146-148oC

1H NMR (CDCl3) ;

of 1.37 (t, J= 7 Hz, 3H), 3,79 (s, 3H), 4,37 (kV, J=7 Hz, 2H), 4,47 (SHS, 1H), and 4.68 (m, 2H), 5,01 (SHS, 1H), at 6.84 (d, J=9 Hz, 2H), 7,16-7,40 (m, 10H), by 8.22 (s, 1H)

Example 88

Synthesis of ethyl 1-(6-amino-3,5-differencein-2-yl] -5 - benzylamino-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 600 mg of ethyl 5-benzylamino-1-[3,5-debtor-6- (p-methoxybenzylamine)pyridine-2-yl] -6,7,8-Cryptor-4-oxo-1,4 - dihydroquinoline-3-carboxylate was added 2 ml triperoxonane acid and the mixture was allowed to stand at room temperature for 20 minutes. The solution was concentrated under reduced pressure and to the residue was added 3 ml of ethanol, after which he again concentrated under reduced pressure. The precipitate was dispersible in AA in the form of a yellow powder.

Melting point: 176-180oC

1H NMR (CDCl3) ;

of 1.36 (t, J=7 Hz, 3H), 4,36 (kV, J=7 Hz, 2H), 4,47 (SHS, 1H), and 4.68 (d, J 4 Hz, 2H), 4,74 (SHS, 1H), at 6.84 (d, J=9 Hz, 2H), 7.24 to 7,40 (m, 6H), 8,21 (s, 1H)

Example 89

Synthesis of ethyl 5-amino-1-(6-amino-3,5-differencein-2-yl)- 6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 5 ml of acetic acid was added 260 mg of ethyl 1-(6-amino-3,5-differencein-2-yl)-5-benzylamino-6,7,8-Cryptor-4-oxo-1,4 - dihydroquinoline-3-carboxylate together with 50 mg of 10% palladium on coal and the mixture was first made at room temperature for 4 hours. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the like. Twice repeating a procedure of adding to the residue 10 ml of ethanol and concentrating under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl, ether to obtain 160 mg specified in the title compounds as pale yellow powder.

Melting point: 225-230oC

1H NMR (CDCl3) ;

to 1.38 (t, J=7 Hz, 3H), of 4.38 (KB, J=7 Hz, 2H), 4,73 (CL, 2H), and 4.68 (d, J=4 Hz, 2H), 6,8 (CL, 2H), at 6.84 (d, J=9 Hz, 2H), 7,32 (t, J=9 Hz, 1H), of 8.25 (s, 1H)

Example 90

Synthesis of 5-amino-1-(6-amino-3,5-differering acid and acetic acid was added 145 mg of ethyl 5-amino-1-(6-amino-3,5 - differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3 - carboxylate and the mixture was heated under reflux for 17 hours with stirring and then allowed to cool. The precipitate was collected by filtration and washed with ethanol to obtain 129 mg specified in the title compound as a yellow powder.

1H NMR (d6-DMSO) ;

6,78 (CL, 2H), 7,75 (SHS, 1H), 7,99 (t, J=9 Hz, 1H), 8,77 (s, 1H)

Example 91

Synthesis of 5-amino-7-(3-aminoamides-1-yl)-1-(6-amino-3,5 - differencein-2-yl)-6,8-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 210 mg of N, N-dimethylformamide was added 50 mg of 5-amino-1- (6-amino-3,5-differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoacetanilide and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90oC for 1 hour and concentrated under reduced pressure. Twice repeating a procedure of adding to the residue, 2 ml of diisopropyl ether, mixing and decanting. To the residue was added 2 ml of ethanol and 40 ml of N-methylpyrrolidine, the mixture was allowed to stand overnight and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 26 mg specified in the title compounds as pale yellow powder.

Melting point: 205-210oC (decomposition).

1H NMR (d6-DMSO) ;

and 3.72 (m, 1H), 3,88 (m, 2H), 4,37 (m, 2H), of 6.71 (CL, 2H), 7.23 percent (shifter-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To 10 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro - 2,4,5-Cryptor-6-nitrobenzoyl)acrylate obtained from 3.25 g of ethyl 3-chloro-2,4,5-Cryptor-6-nitrobenzylamine in the usual way, was added 2.14 g of 2-amino-3,5-debtor-6-tert - butylaniline. The solution was concentrated under reduced pressure and to the residue was added 2.7 g of anhydrous potassium carbonate and 10 ml of N, N-dimethylformamide, and the mixture was stirred at 90oC for 5 minutes, then allowed it to cool. The solution was separated by adding 100 ml of chloroform and 500 ml of 2% aqueous citric acid solution and the chloroform layer was washed twice with 500 ml of 2% aqueous citric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 3.13 g specified in the title compounds as pale yellow powder.

Melting point: 215-217oC

1H NMR (CDCl3) ;

of 1.37 (t, J= 7 Hz, 3H), of 1.39 (s, 9H), 4,39 (KB, J=7 Hz, 2H), 4,77 (SHS, 1H), 7,24 (t, J=8 Hz,1H), 8,35 (t, J=9 Hz, 1H), charged 8.52 (s, 1H)

Example 93

Synthesis of 5-amino-1-(6-amino-3,5-differencein-2-yl)- 8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carbocloro-6,7-debtor-5-nitro-4 - oxo-1,4-dihydroquinoline-3-carboxylate together with 1.0 g of iron powder and the mixture was stirred at 80-90oC for 5 hours and 40 minutes. The insoluble content was separated by filtration through celite and the contents separated telicom celite and washed with formic acid and chloroform. The filtrate and the washing water was concentrated under reduced pressure. To the residue was added 6 ml of a mixed solution of 4 G. hydrochloric acid and acetic acid (1:1), and the mixture was heated under reflux for 2 hours with stirring, then allowed it to cool. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 625 mg specified in the title compound as a yellow powder.

Melting point: 280oC or higher

1H NMR (d6-DMSO) ;

6,77 (CL, 2H), 7,94 (t, J=9 Hz, 1H), 8,20 (CL, 2H), to 8.70 (s, 1H)

Example 94

Synthesis of 5-amino-7-(3-aminoamides-1-yl)-1-(6-amino-3,5 - differencein-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid

To 550 mg of pyridine was added 185 mg of 5-amino-1-(6-amino-3, 5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 110 mg of 3-aminoacetanilide and 200 mg N-methylpyrrolidine, and the mixture was stirred at 100oC for 30 minutes and concentrated under reduced pressure. consequently ethanol and diisopropyl ether to obtain 48 mg specified in the title compound as a yellow powder.

1H NMR (d6-DMSO) ;

a 3.83 (m, 1H), 4,14 (m, 2H), br4.61 (m, 2H), of 6.71 (CL, 2H), 7,52 (CL, 2H), 7,89 (t, J=9 Hz, 1H), 8,51 (s, 1H)

Example 95

Synthesis of ethyl 6,7-debtor-1-(3,5-debtor-6-p - methoxybenzylideneamino-2-yl)-8-methyl-5-nitro-1,4-dihydro - 4-oxoindole-3-carboxylate

To 5.0 g ethyl 3,4,6-Cryptor-5-methyl-2-nitrobenzylamine was added to 11.5 g of acetic anhydride and 4.7 g of triethylorthoformate and the mixture was heated under reflux for 1.5 hours. The reaction solution was allowed to cool, drove the reagent and the like, and to the residue was added toluene to azeotrope distillation. The precipitate was added to 10 ml of ethanol and to the mixture was added dropwise in an ice bath, a solution of 5.0 g of 2-amino-3,5-debtor-6-p - methoxybenzylamine)of pyridine in 15 ml of ethanol and stirred at room temperature for 10 minutes. Of the reaction solution is kept off the solvent, and the residue was subjected to column chromatography on silica gel with receipt of 7.1 g of oil from the fractions, buervenich a mixture of ethyl acetate:hexane (1:10). To 7.0 g of this oil was added 10 ml of N,N-dimethylformamide and 2.0 g of potassium carbonate, and the mixture was stirred at 70oC for 30 minutes. To the reaction solution were added ethyl acetate and water, and the organic layer was separated and dried over sulfate mage who was harvested by filtration to obtain 1.5 g specified in the title compounds as pale yellow powder.

Melting point: 225-227oC

1H NMR (CDCl3) ;

of 1.37 (t, J=7 Hz, 3H), 1,68 (d, J=3 Hz, 3H), 3,81 (s, 3H), 4,39 (KB, J=7 Hz, 2H),4,45 (s, 2H), from 5.29 (SHS, 1H), 6,83 (d, J=8 Hz, 2H), 7,17 (d, J=8 Hz, 2H), 7,31 (t, J=9 Hz, 1H), 8,45 (s, 1H)

Example 96

Synthesis of ethyl-5-amino-6,7-debtor-1-(3,5-debtor-6-p - methoxybenzylideneamino-2-yl)-8-methyl-1,4-dihydro-4 - oxoindole-3-carboxylate

To 10 ml of a solution of 1.7 g of ethyl 6,7-debtor-1-(4,6-debtor-3-p - methoxybenzylidene-2-yl)-8-methyl-5-nitro-1,4-dihydro-4 - oxoindole-3-carboxylate acetic acid was added 1.4 g of iron powder and the mixture was heated and stirred at 90oC for 4 hours and 40 minutes. Of the reaction solution was removed by filtering the catalyst and the filtrate drove the solvent. The residue was subjected to column chromatography on silica gel. Faction elyuirovaniya a mixture of chloroform:methanol (10:1) was concentrated and to the residue was added ethanol. Powdery precipitate was collected by filtration to obtain 1.3 g specified in the title compound as pale brown powder.

Melting point: 150-153oC

1H NMR (d6-DMSO) ;

to 1.24 (t, J=7 Hz, 3H), of 1.30 (s, 3H), 3,71 (s, 3H), 4,20 (kV, J=7 Hz, 2H), 4,33 (DD, J= 5 Hz, 12 Hz, 2H), 6,76 (d, J=Q Hz, 2H) 7,14 (d, J=8 Hz, 2H), 7,85 (SHS, 1H), to 7.93 (t, J=10 Hz,the quinoline-3-carboxylic acid

To 0,99 g of ethyl 5-amino-6,7-debtor-1-(3,5-debtor-6-p - methoxybenzylideneamino-2-yl)-8-methyl-1,4-dihydro-4 - oxoindole-3-carboxylate was added 10 ml 12 N. hydrochloric acid and the mixture was heated under reflux for 10 hours. The reaction solution was allowed to cool, and the solid content was collected by filtration. The solid content was washed with ethanol and then diethyl ether to obtain 880 mg specified in the title compound as a yellow powder.

Melting point: 250oC or above (with decomposition).

1H NMR (d6-DMSO) ;

to 1.60 (s, 3H), 6,80 (CL, 2H),7,96 (t, J=9 Hz, 1H) 8,69 (s, 1H)

Reference example 52

Synthesis of 2-amino-4-bromo-5-chloro-3,6-diphereline

To 20 ml of acetonitrile was added 4.9 g of 4-bromo-3-chloro-2,5,6 - cryptosporidia and 4 ml of 25% aqueous ammonia solution, and the mixture was stirred at 55oC for 2 hours. Drove away under reduced pressure, the solvent and the like. To the residue was added 50 ml of chloroform and washed with a solution of 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dispersively in the mixed solution diisopropylamido ether and n-hexane and collected by the filter is x2">

Reference example 53

Synthesis of 2-amino-4-bromo-5-chloro-3-fluoro-6-(1,1,3,3 - tetramethylbutylamine)pyridine

To 6 ml of N-methylpyrrolidone was added 2.4 g of 2-amino-4-bromo-5 - chloro-3,6-diphereline and 3.5 g of 1,1,3,3-tetramethylbutylamine and the mixture was stirred at 140oC for 82 hours, then allowed it to cool. After addition of 50 ml of a mixed solution of benzene and n-hexane (1:1, V/V) solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 30 g; eluent: chloroform: n-hexane, 1:1) to give 1.6 g specified in the title compounds as a colorless oily residue.

Reference example 54

Synthesis of 2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamine) pyridine

To 10 ml of methanol was added 1.6 g of 2-amino-4-bromo-5-chloro-3 - fluoro-6-(1,1,3,3-tetramethylbutylamine)pyridine together from 0.47 g of triethylamine and 0.09 g of 10% palladium on charcoal, and the mixture was first made at room temperature for 39 hours. Was separated by filtration of the catalyst and drove away under reduced pressure, the solvent and the like. To the residue was added 50 ml of chloroform and who has demonstrated under reduced pressure. The residue was subjected to chromatography (silica gel, 25 g; eluent:chloroform) to obtain 0.75 g of 2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamine)pyridine as a pale brown oil and 0.2 g of 2-amino-4-bromo-3-fluoro-6- (1,1,3,3-tetramethylbutylamine)pyridine as a brown oil.

Example 98

Synthesis of ethyl 1-[3-fluoro-6-(1,1,3,3-tetramethylbutylamine) pyridine-2-yl]-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylate

To 3 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5 - triterpenoid)acrylate obtained from 0.84 g of ethyl 3-chloro-2,4,5 - tripersonality in the usual way, was added 0.75 g, 2 - amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamine)pyridine. The solution was concentrated under reduced pressure and to the residue was added 0.65 g of anhydrous potassium and 1.5 ml of N,N - dimethylformamide and the mixture was stirred at 90oC for 1 h, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0.45 g specified in the reasons of the NMR (CDCl3) ;

of 0.96 (s, 9H), of 1.41 (m, 9H), 1.77 in (DD, J=15 Hz, 22 Hz, 2H), 4,42 (kV, J=7 Hz, 2H), 4.53-in loops, 1H), 6,44 (DD, J 3 Hz, 9 Hz, 1H), 7,30 (t, J=9 Hz, 1H), 8,30 (t, J=9 Hz, 1H), 8,56 (s, 1H)

Example 99

Synthesis of 1-(6-amino-3-herperidin-2-yl)-8-chloro-6,7-debtor - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 1.2 ml of a mixed solution (1:1) 4 N. hydrochloric acid and acetate was added 235 mg of ethyl 1-[3-fluoro-6-(1,1,3,3 - tetramethylbutylamine)pyridine-2-yl] -8-chloro-6,7-debtor-4-oxo - 1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 6 hours with stirring and then allowed to cool. The precipitate was collected by filtration and washed with ethanol to obtain 145 mg specified in the title compound as a gray powder.

Melting point 228-230oC

1H NMR (d6-DMSO) ;

6,70 (DD, J=3 Hz, 9 Hz, 1H), 7,66 (t, J=9 Hz, 1H), scored 8.38 (t, J=9 Hz, 1H), 8,87 (s, 1H)

Example 100

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3-herperidin - 2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 190 mg of N,N-dimethylformamide was added 57 mg of 1-(6-amino-3 - herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid, 37 mg of 3-aminoacetanilide and 100 mg N-methylpyrrolidine, and the mixture was stirred at 90oC for 30 minutes. Pollino ethanol and diisopropyl ether to obtain 40 mg indicated in the title compounds as colorless powder.

Melting point: 250-255oC (decomposition).

1H NMR (d6-DMSO) ;

3,71 (m, 1H), Android 4.04 (m, 2H), 4,67 (m, 2H), 6,44 (CL, 2H), 6,62 (DD, J=3 Hz, 9 Hz, 1H),.7,61 (d, J=9 Hz, 1H), 7,85 (t, J=14 Hz, 1H), 8,63 (s, 1H)

Example 101

Synthesis of 5-amino-1-(6-amino-3,5-differencein-2-yl)- 8-chloro-6-fluoro-7-(3-methylaminomethyl-1-yl)-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid

To 300 mg of pyridine was added 120 mg of 5-amino-1-(6-amino - 3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 80 mg of 3 - methylaminoacetaldehyde and 250 mg N-methylpyrrolidine, and the mixture was stirred at 100oC for 10 minutes. After addition of 5 ml of diethyl ether and the mixture was stirred in for 1 hour gave it to cool and then decantation. Was added to a mixture of 2 ml of ethanol and stirred it. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 72 mg specified in the title compound as a yellow powder.

Melting point: 204-213oC

1H NMR (d6-DMSO) ;

2,02 (s, 3H), of 4.05 (m, 2H), 4,57 (m, 2H), 6,70 (CL, 2H), of 7.48 (SHS, 1H), 7,89 (t, J=10 Hz, 1H), 8,49 (s, 1H)

Example 102

Synthesis of 5-amino-1-(6-amino-3,5-differencein-2-yl)- 8-chloro-6-fluoro-7-(3-gidroksibenziliden-1-yl)-4-OK the DIN-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid, 80 mg 3-hydroxyeicosatetraenoic and 250 mg N-methylpyrrolidone and the mixture was stirred at 100oC for 3 minutes. After addition of 5 ml of diethyl ether mixture was allowed to stand for 1 hour and then decantation. Was added to a mixture of 2 ml of ethanol and stirred it. The precipitate was collected by filtration and washed successively with ethanol and diethyl ether to obtain 64 mg specified in the title compound as a yellow powder.

Melting point: 267-290oC (decomposition).

1H NMR (d6-DMSO) ;

4.09 to (m, 2H),4,45 (m, 1H), 4,63 (m, 2H), 5,69 (d, J=6 Hz, 1H), of 6.71 (CL, 2H), of 7.48 (SHS, 1H), 7,89 (t, J=-10 Hz, 1H), 8,51 (s, 1H)

(1) Antibacterial action

Compounds of the above examples 9, 10, 12, and 39 were assessed by their minimum dose (concentration), inhibiting the growth of bacteria (MIC, μg/ml), the standard method of the Japanese chemotherapeutic society (Japan Chemotherapy Society) (Chemotherapy 29(1), 76, 1981) using standard strains (S. aureus 209P, S. epidermidis IF012293, P. (aeruginosa IFO 3445). The results are shown in table 1. It should be noted that ciprofloxacin, levofloxacin, sparfloxacin and tosufloxacin, which is the traditional antibacterial agents was also assessed by their minimum ingibiruet the s in table 1, show that the compounds of the present invention have excellent antibacterial activities superior to those possessed by conventional bacterial funds.

(2) Test for phototoxicity

Compounds of the above examples 9, 10, 12, and 39 were tested for toxicity following method.

The ICR female mice (5-6 weeks of age) were injected intravenously test compound (40 mg/kg2/10 ml) and was irradiated with UV (320-400 nm, 1,8 mW/cm2/sec) for 4 hours. Checked the anomaly on the ears at 0 hours (immediately after exposure) and after 24 hours and 48 hours. Ear abnormality was assessed by the following indicators: no anomalies (0 points), very faint erythema (score 1) pronounced erythema (2 points), erythema moderate to strong and the formation of edema (3 points). The results are shown in table 2. In order to compare experienced tosufloxacin, which is the traditional well-known antibacterial agent. The results are also shown in table 2. Table 2

The results presented in table 2 show that the compounds of the present invention have very low toxicity.

1. Derived pyridonecarboxylic acid, provided the ilen group;

R2is lower alkoxygroup or amino group, possibly substituted lower alkyl group, benzyl group, bentilee group, di-(lower alkyl)amino group;

R3represents a hydrogen atom or a halogen atom;

R4represents a hydrogen atom or a halogen atom;

R5represents a halogen atom or a group represented by the following formula (a) or (b):

< / BR>
< / BR>
where a represents a group NR9where R9represents a hydrogen atom or a lower alkyl group;

f = 3 - 5;

f = 1 - 2;

g = 1 - 2;

I1, I2and I3that may be the same or different, represent a hydrogen atom, hydroxyl group, lower alkyl group, amino-lower alkyl group, amino group, lower alkylamino;

R6represents a hydrogen atom, a halogen atom, a nitro-group or unsubstituted or is substituted by an amino group which may be substituted by benzyl;

X, Y, Z may be the same or different and respectively represent a nitrogen atom, -CH= or CR7=;

R7represents a lower alkyl group, halogen atom or cyano, provided that at least one of the symbols X, Y,odorata, halogen atom or a lower alkyl group.

2. Derived pyridonecarboxylic acid or its salt under item 1, where W represents-CR8= , where R8represents a hydrogen atom, halogen atom or lower alkyl group.

3. Derived pyridonecarboxylic acid or its salt under item 1 or 3, where R5is a group represented by the following formula (a) or (b):

< / BR>
< / BR>
where a is NR9where R9represents a hydrogen atom or a lower alkyl group;

f = 3 - 5;

f = 1 - 2;

g = 0 - 2;

I1I2and I3that may be the same or different, represent a hydrogen atom, hydroxyl group, lower alkyl group, Eminescu alkyl group, amino group, lower alkylamino, lower alkoxygroup or halogen atom.

4. Derived pyridonecarboxylic acid or its salt under item 4, where R5is a group represented by the formula (a).

5. Derived pyridonecarboxylic acid or its salt under item 5, where e in the formula (a) represents the number 3 or 4.

6. Derived pyridonecarboxylic acid or its salt under item 6, where R1represents a hydrogen atom, R2represents the amino group, the lower AET halogen atom, R6represents a hydrogen atom, X represents a nitrogen atom, Y and Z are-CH= or-CR7where R7represents a lower alkyl group or halogen atom, W represents-CR8=, where R8represents a halogen atom or a lower alkyl group.

7. Derived pyridonecarboxylic acid or its salt under item 7, where R2represents the amino group, R3represents a fluorine atom, R4represents a fluorine atom, Y represents-CF= -, Z is-CH=, W is-CR8=, where R8represents a chlorine atom, a bromine atom or methyl group, and e in the formula (a) represents the number 3.

8. Derived pyridonecarboxylic acid or its salt under item 1, where the compound represented by formula (1) is 1-(6-amino-3,5-differencein-2-yl)-8-bromo-6-fluoro-7-(3-methylaminomethyl-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

9. Derived pyridonecarboxylic acid or its salt under item 1, where the compound represented by formula (1) is 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

10. Antibacterial agent containing the derivative pyridonecarboxylic acid or its salt

 

Same patents:

- aminohydroxylation and carboxylic acid" target="_blank">

The invention relates to new compounds of General formula I, where Q, A, R1n, m are listed in the value formula

The invention relates to new pharmacologically active 2,3-substituted derivatives of octahydro-1H-pyrido[1,2-a] pyrazine, their acid additive salts and some of their predecessors

The invention relates to a new derived chinainternational acids with antibacterial activity, in particular the hydrochloride monohydrate 1-cyclopropyl-7-([S, S]-2,8-diazabicyclo[4.3.0]non-8-yl)- 6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid formula

< / BR>
in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D.

The invention relates to new nitrogen-containing heterocyclic compounds which possess valuable biological properties, in particular derived cycloalkane-indole-azaindole, mixtures of their isomers, or individual isomers and their pharmaceutically acceptable salts, derivatives of carboxylic acid as starting compounds and pharmaceutical compositions inhibiting the release associated with apolipoprotein B - 100 lipoproteins

The invention relates to new derivatives of imidazopyridines formula I

< / BR>
where R denotes a group of the formula Ia

< / BR>
R1means F, R2-SO2NHCOR5, R3- A, R4group of the formula CnH2nR9; R5- A, - CtH2t(C3-C8cycloalkyl), - CtH2t-Ar; R9-COOA, Ar-CO-NR6R7, -CO-Ar; R6and R7respectively N And ArCnH2nor R6and R7together mean alkylenes chain with C-5, R8means1-C6-alkyl, AND - C1-C6-alkyl, AG - unsubstituted phenyl group, t is 0, 1, 2 or 3, n=1, 2, 3, 4 or 5 or their salts, and method of production thereof, pharmaceutical composition and method for producing the composition

The invention relates to new nitrogen-containing heterocyclic compounds with valuable biological properties, in particular to new derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2, having biological activity

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

The invention relates to 2-[1',2',4'-triazole-3'-roximation] anilides formula I

< / BR>
in which the index and the substituents have the following meanings:

n means 0, 1, 2, 3 or 4, where the substituents R1may be different if n is greater than 1;

X represents a direct bond, O, or NRa;

Rameans hydrogen, alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl;

R1means nitro, cyano, halogen, optionally substituted alkyl, alkenyl, quinil, alkoxy, alkenylacyl, alkyloxy or

if n is 2, additionally represents associated with two adjacent ring atoms optionally substituted by a bridge containing three or four members from the group containing 3 or 4 carbon atoms, 1-3 carbon atoms and 1 or 2 nitrogen atom, oxygen and/or sulphur, and this bridge together with the ring to which it is linked, may form a partially unsaturated or aromatic radical;

R2means hydrogen, nitro, cyano, halogen, C1-C4alkyl, C1-C4halogenated, C1-C4alkoxy, C1-C4alkylthio or C1-C4alkoxycarbonyl; R3means optionally substituted is which, together with the carbon atoms may contain one to three heteroatoms as members of a cycle of the following: oxygen, sulfur and nitrogen, or an optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms or one or two nitrogen atom and one oxygen atom or sulfur or one oxygen atom or sulfur;

R4means hydrogen, optionally substituted alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkylaryl or alkoxycarbonyl;

R5means alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl or if X is NRaadditionally represents a hydrogen

The invention relates to new 4-aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridine F.-ly (I), where Y is CH or N; R1-H, halogen, CF3; R2-H, halogen, (C3- C4)alkyl or (C1- C4)alkoxy; R3and R4- H or (C1- C3)alkyl; X represents: (a) (C3- C6)alkyl, (C3- C6)alkoxy or (C1- C4)alkoxycarbonyl(C3- C6)alkoxy, (b), (C3- C7)cycloalkyl or c) Deputy chosen from the group comprising phenyl, phenoxybenzyl, their salts, solvate or Quaternary ammonium salts

The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and method of production thereof
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