Aminosidine to obtain new derivatives pyridonecarboxylic acids or their salts

 

(57) Abstract:

Described new amino compounds of the formula (C), in which X is a nitrogen atom; Y represents a group-CH= or CR7=, where R7lower alkyl or halogen atom; Z is a group-CH=; R2A- optionally substituted amino group or protected amino group, and R3- the hydrogen atom and halogen; to obtain new derivatives pyridonecarboxylic acid or their salts exhibiting antibacterial properties and is used as antibacterial agents. 4 C.p. f-crystals, 2 tab.

The invention relates to new amino compounds to obtain new derivatives pyridonecarboxylic acids or their salts having excellent antibacterial properties and oral absorption and is used as antibacterial agents.

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 58-76667 patent 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 compounds that would be satisfactory mi in these respects.

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 (I) 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.

In accordance with the present invention proposed new amino compounds of General formula (C):

< / BR>
in which X predstavlyaemoi halogen;

Z - represents a group-CH=;

R2ais optionally substituted by an amino group or a protected amino group, and

R3represents a hydrogen atom or a halogen.

The preferred aminoguanidinium formula (C) is a compound in which

R3represents a fluorine atom or chlorine;

R7represents methyl, fluorine atom or chlorine;

substituted amino or a protected amino group in the definition of R2arepresents a group containing methylamino, isopropy a melamine, tert-butylamino, benzylamine, p-methoxybenzylamine or 1,1,3,3-tetramethylbutylamine.

R2arepresents preferably an unsubstituted amino group.

Compounds of the present invention is designed to obtain new derivatives pyridonecarboxylic acids and their salts having excellent antibacterial properties and oral absorption, the General formula (I):

< / BR>
in which R1represents a hydrogen atom or carboxyl-protective group;

R2represents hydroxy, lower alkoxy or substituted or an unsubstituted amino group;

R3represents a hydrogen atom or a halogen atom;

R4represents the atom of odor the symbolic value for the amino group;

R6represents a hydrogen atom, halogen atom, nitro or 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).

New derivatives of pyridonecarboxylic acid represented by the General formula (I) above, and the term "lower" used for substituents derived pyridonecarboxylic acid represented by the General formula (I), 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 (I) 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, relative to the Il-protective groups include groups, which can be split by hydrolysis, catalytic reduction and other processing methods in mild conditions, such as lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl and heptyl; lower alkeneamine groups such as vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl and heptenyl; kalkilya groups such as benzyl group; and aryl groups such as phenyl and naftalina group; and groups which can be easily derived in the body, such as lower alkanoyloxy lower alkyl groups, such as acetoxymethyl and pivaloyloxymethyl; lower alkoxycarbonyl lower alkyl groups, such as methoxycarbonylmethyl and 1-ethoxycarbonylmethyl; lower alkoxymethyl groups, such as methoxymethyl; Victorina group, such as phthalidyl; di-lower alkylamino lower alkyl group such as 1-dimethylaminoethyl and (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl. It should be noted that most preferably R1represents a hydrogen atom.

In the General formula (I) R2represents hydroxyl, lower alkoxy or substituted or an unsubstituted amino group. Examples of substituents for substituted and is t-butyl, pentyl, hexyl and heptyl; lower alkeneamine groups such as vinyl, allyl, 1-propenyl, butenyl, pentyl, hexenyl and heptenyl; kalkilya groups such as benzyl and 1-phenylethyl; aryl groups such as phenyl and naftalina group; lower alcoholnye groups, such as formyl, acetyl, propionyl, butill and isobutyryl; lower alkoxycarbonyl groups, such as methoxycarbonyl and etoxycarbonyl; aroline groups such as benzoyl and naphtol; amino acid residues or Oligopeptide residues, such as glycyl, lazil, poured, alanyl, i.e. phenylalanyl, alanyl-alanyl, glycyl-poured and glycyl-glycyl-poured; and amino acid residues or Oligopeptide 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 the compounds of the protected amino acid or Oligopeptide residues will have improved solubility in water.

Preferably R2represents amino, lower alkylamino, di-lower alkylamino, lower alkanolamine, aminotetraline examples R2include amino, methylamino, ethylamino and dimethylamino, 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, ethoxy, propoxy, butoxy, of which preferred is methoxy.

Further, in General formula (I) 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, halogen atom, nitro or 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 R8include fluorine atom, chlorine, bromine and iodine. Of them, preferred are a fluorine atom and chlorine and, in the t atom of chlorine or bromine.

The lower alkyl groups represented by the symbols R7and R8include those which contain 1 to 7 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl, 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 lower alkyl, halogen atom or cyano) for Y and Z; nitrogen for Y, and-CH= or CR7= (where R7represents lower alkyl or halogen atom) for X and Z; and nitrogen for X and Y, and-CH= or CR7= (where R7represents lower alkyl or halogen atom) for Z;

It should also be noted that the compound of formula (I) has naphthylidine skeleton, when W is nitrogen, and quinoline skeleton, when W is CR8=, and the most preferable is the case where W represents-CR8= (where R8represents a halogen atom or a lower alkyl group).

Further, optionally substituted, saturated cyclic is to heteroatoms, such as nitrogen atom, oxygen and sulfur, and carbon monoxide and can 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 3-7-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 saturated spiraling saturated or amino group with a transverse relationship with 5-12-membered ring, such as 2,8-diazaspiro[4.4] nonan-2-yl, 5-azaspiro[2.4] heptane-5-yl, 7-azabicyclo[2.2.1] heptane-7-yl, 2,8-DLO[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 substitute, and examples of such substituents include hydroxyl, lower alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted amino lower alkyl group, lower alkoxygroup and halogen atoms.

Examples of the lower alkyl groups for the substituent a saturated cyclic amino group include those which contain 1 to 7 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl; examples of the lower alkoxygroup include those which contain 1 to 7 carbon atoms, such as methoxy, ethoxy and n-propoxy; examples of groups of the halogen include fluorine atom, chlorine and bromine. Of the Vice saturated cyclic amino groups substituted amino and substituted amino lower alkyl group may have a Deputy, who may be the same as described for R2and preferred examples of the substituted amino groups, and substituted and unsubstituted amino lower alkyl groups include methylamino, ethylamino, dimethylamino, aminomethyl, 1-amino-ethyl, 2-amino-ethyl, 1-amino-1-ethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, glycyl-amino, the definition of amino groups, the 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 lower alkyl), e is equal to the number from 3 to 5, f is equal to the number from 1 to 3, g is equal to the number from 0 to 2, J1I , J2and J3that may be the same or different, represent a hydrogen atom, hydroxyl, lower alkyl, amino lower alkyl, amino, lower alkylamino, lower alkoxy or halogen atom.

Examples of lower alkyl, amino lower alkyl, lower alkylamino, lower alkoxy and halogen atom in the above formulae (a) and (b) are the same as those described for R2-R5.

Examples of cyclic amino groups represented by the formula (a) include azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl, and examples of cyclic amino groups provided by the formula (b) include piperazine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, homopiperazin-1-yl, N-diazolidinyl and N-oxazolidinyl. When R5is a cyclic group, R5preferably represents a cyclic amino group, of the formula (a), and most preferably, azetidin-1-yl or pyrrolidin-1-yl.

The most preferred primereality-1-Il,

3-aminomethylpyridine-1-Il,

3-amino-2-methylaziridine-1-Il,

3-amino-3-methylaziridine-1-Il,

3-alanyl-aminotetralin-1-Il,

3-poured-aminotetralin-1-Il,

3-pyrrolidin-1-Il,

3-hydroxypyrrolidine-1-Il,

3,4-dihydroxypyrrolidine-1-Il,

3-ethoxypyrrolidine-1-Il,

3 methylpyrrolidine-1-Il,

3-hydroxy-4-methylpyrrolidine-1-Il,

3-aminopyrrolidine-1-Il,

3-methylaminopropyl-1-Il,

3-dimethylaminopropan-1-Il,

3-ethylenepropylene-1-Il,

3-diethylaminopropyl-1-Il,

3-aminomethylpyrrolidine-1-Il,

3-amino-3-methylpyrrolidine-1-Il,

3-amino-4-methylpyrrolidine-1-Il,

3-amino-5-methylpyrrolidine-1-Il,

3-methylamino-4-methylpyrrolidine-1-Il,

3-dimethylamino-4-methylpyrrolidine-1-Il,

3 ethylamino-4-methylpyrrolidine-1-Il,

3 diethylamino-3-methylpyrrolidine-1-Il,

3 diethylamino-4-methylpyrrolidine-1-Il,

3-aminomethyl-4-methylpyrrolidine-1-Il,

3-methylaminomethyl-4-methylpyrrolidine-1-Il,

3-dimethylaminomethyl-4-methylpyrrolidine-1-Il,

3-ethylaminomethyl-4-methylpyrrolidine-1-Il,

3-(1-amino-ethyl)-4-methylpyrrolidine-1-Il,

3-(2-amino-ethyl)-4-methylpyrrolidine-1-Il,

3-amino-4-ethylpyrrolidin-1-Il,

3-methylamino-4-ethylpyrrolidin-1-mirrodin-1-Il,

3-aminomethyl-4-ethylpyrrolidin-1-Il,

3-methylaminomethyl-4-ethylpyrrolidin-1-Il,

3-dimethylaminomethyl-4-ethylpyrrolidin-1-Il,

3-amino-3-methylpyrrolidine-1-Il,

3-methylamino-3-methylpyrrolidine-1-Il,

3-dimethylamino-3-methylpyrrolidine-1-Il,

3-amino-3,4-dimethylpiperidin-1-Il,

3-amino-4,4-dimethylpiperidin-1-Il,

3-amino-4,5-dimethylpyrimidin-1-Il,

3-amino-2,4-dimethylpyridin-1-Il,

3-methylamino-3,4-dimethylpiperidin-1-Il,

2-methyl-3-aminopyrrolidine-1-Il,

2-methyl-3-dimethylaminopropan-1-Il,

3-amino-4-ethoxypyrrolidine-1-Il,

3-alanyl-aminopyrrolidine-1-Il,

3-poured-aminopyrrolidine-1-Il,

piperazine-1-Il,

4-methylpiperazin-1-Il,

3-methylpiperazin-1-Il,

2-methylpiperazin-1-Il,

3,4-dimethylpiperazine-1-Il,

3,5-dimethylpiperazine-1-Il,

3,3-dimethylpiperazine-1-Il,

3,4,5-trimethylpyrazine-1-Il,

piperidine-1-Il,

4-aminopiperidin-1-Il,

4-dimethylaminopyridine-1-Il,

4-hydroxypiperidine-1-Il,

morpholine-4-Il,

2-aminomethylation-4-Il,

2-methylaminomethyl-4-Il,

2-dimethylaminomethyl-4-Il,

thiomorpholine-4-Il,

homopiperazin-1-Il,

4-methylhomopiperazine-1-Il,

N-diazolidinyl and

the t of the amino group, and an amino group protected by a suitable protecting group. Examples of protected amino groups include amino group, protected lower alkanoyloxy group, such as formyl, acetyl, propionyl, pivaloyl, hexanoyl or the like; lower alkoxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxybenzoyl, hexyloxybenzoyl or the like; arolina group such as benzoyl, toluoyl, naphtol or the like; aryl lower alkanoyloxy group, such as phenylacetyl, phenylpropionyl or the like; aryloxyalkyl group, such as phenoxycarbonyl, naphthyloxy-carbonyl, or the like; aryloxy lower alkanoyloxy group, such as phenoxyacetyl, phenoxypropionyl or the like; aracelikarsaalyna group, such as benzyloxycarbonyl, ventilatsioonil or the like; or aranceles group, such as benzyl, phenethyl, benzhydryl, trityl or the like.

The preferred combination of R1, R2, R3, R4, R5, R6X, Y, Z and W are those in which R1represents a hydrogen atom, R2represents amino, lower alkylamino and dstanley the nitrogen atom, Y and Z are-CH= or CR7= (where R7represents lower alkyl or halogen atom), W represents-CR8= (where R8represents a halogen atom or a lower alkyl), R5represents a group of formula (a) (e = 3 or 4) and R6represents a hydrogen atom.

More preferred 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 are-CH=, W is-CCl=, -CBr= or-CCH3=, R5represents a group of formula (a) (e = 3 or 4) and R6represents a hydrogen atom.

Salt described above derivatives pyridonecarboxylic acid of the formula (I) can be acid-additive or basic additive salts. Used in this description, the term "salt" includes chelate salt with boron compound. Examples of the 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 acid, triptoreline acid, benzolsulfonat acid, p-toluensulfonate acid, mesitylenesulfonic acid or naphthalenesulfonate acid; and examples of the basic 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-methylmorpholine, diethylamine, cyclohexylamine, procaine, di-benzylamine, N-benzyl-phenethylamine, 1-fenamin or N,N'-dibenziletilendiaminom. Examples of boron compounds include boron halides such as boron fluoride, and the lower allocmemory, such as acetochlor.

Derivatives pyridonecarboxylic acids and their salts may contain, in addition to resolutional form, also in the form of a hydrate or solvate, and thus include 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 in a range of compounds of the formula (I), and may be in the form of (CIS - or TRANS-) stereoisomer and such statenew can 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-amine substitution. It should be noted that in the case of substituted amine, such as alkylamine or benzylamine, Deputy substituted amino group can be adequately removed in the traditional way, as shown in the diagram I reactions (see 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.

In scheme I, Hal represents a halogen atom such as F or Cl; HcNH and Hc'NH are respectively replaced by the amino group or the amino group, substituted by a protective group; HcNH2and Hc'NH2represent, respectively, their amine. R2ais hydroxyl or lower alkoxy. R3X, Y and Z such as defined above.

When there is no readily available candidate for the role of the source material, namely dehalogenation (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 easily accessible 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 a cyano, using this reaction, as the reaction of Sandmeyer or reaction Shiman; a process in which the halogen atom replaces 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; the process in which alkoxycarbonyl group or acyl group reduced to a lower alkyl group, isoeicosane; 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, having a high reactivity. In this case, if the fluorine atom is as a substituent in any of the other highly reactive places, this 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) according to the present invention can be obtained by recovering the nitro group to the amino group of the usual pic is of the formula (I), can be obtained in any way, properly selected in accordance with such factors as the type of the substituents, when using the original compounds of the present invention of the formula (C).

(Method 1)

Of the compounds represented by the General formula (I), 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 scheme III reactions (see below).

More specifically, the compound (1a) is produced by interaction of the compound (A) with orthoformates, such as meteorophobia or utilitiarian, derivatization acrylate (B), the interactions derived acrylate (B) aminoguanidinium (C) of the present invention to obtain compound (D) cyclization of the compound (D) to obtain the compounds (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 minutes to 48 hours, preferably for 1-10 hours. Orthoformiate use in relation to soedinitelnye with compound (C) according to the invention 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 dimethylformamide 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 connection according to the invention (C) is 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, and then with a compound of the invention (C) to obtain compound (D). The solvent used in the reaction with the acetal may be any leash is eakly 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, potassium hydroxide, sodium carbonate and potassium carbonate; alkoxides such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; metal fluorides such as ftory the Yu 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. The reaction is usually carried out at temperatures from room temperature up to 180oC, preferably from room temperature to 140oC, usually within 1-24 hours.

Should otmel the amino group, first get the connection (E) by 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 (I), compounds in which R5represents an optionally substituted saturated cyclic amino group, can be obtained, for example, method 2 is shown in scheme IV (see below).

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 hydrocarbons, such as benzene, toluene or xylene; alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran, dioxane or monogram; halogenated hydrocarbons, such is informed, dimethyl sulfoxide or N-organic; acetonitrile or pyridine, and 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 (I), compounds in which R1is carboxyl-protective group can be obtained, for example, method 3, is shown in scheme V (see the end of the description).

More specifically, the compound (I) is produced by interaction of the compound (H) with a halogen compound R1b-L2. Solvents that can be used in this reaction include aromatic hydrocarbons, such s 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 such 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 amino, imino, hydroxy, mercapto, 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 exempt from protection without degradation of its structure, and in accordance with the preferred option, you can use any group commonly used in the chemistry of peptides, amino sugars, and nucleic acids ("Protective Groups in Organic Synthesis", second edition, T. W. Green aBR>
4) 7. 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

14) Posted application N 2-282384 patent Japan

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

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

Obtained the compound of the present invention and the compound of formula (I) is isolated and purified by usual method. The compound of formula (I) are obtained in a salt form, the free carboxylic acid or free amine depending on the conditions of separation. Due to the possibility of mutual transformation of forms of the compounds of formula (I) can be obtained in the desired form.

The connection represented by the above General formula (I) or its salt can be prepared in the form of antibacterial compositions with a pharmaceutically acceptable carrier suitable for parenteral what Erdei or liquid form.

The injectable form is specified antibacterial composition may be made in the form of a solution, suspension or emulsion in a pharmaceutically acceptable sterilized water or non-aqueous 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 formula (I), 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 Gran is re one inert diluent, such as sucrose, lactose or starch. Dosage form may also contain other than inert diluents, substances such as lubricating 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 formula (I) varies depending on the nature of the input connection, the method of administration, the desired period of treatment and other factors. However, usually SOE mg/kg per day. If necessary, this dose can be

put 2-4 portions.

New derivatives of pyridonecarboxylic acids of the formula (I) and their salts 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 assumed that the specified connection 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.

Example 1 (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 is washed with 50 ml distillirovannoj 9.7 g specified in the title compounds as a pale yellow oil.

1H NMR (CDCl3) ;

1,45 (s, N), and 4.40 (SHS, 1H), 7,16 (DDD, J=7 Hz, 8 Hz, 9 Hz, 1H)

Example 2 (Reference Example 2)

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

To 20 ml of N-methylpyrrolidone was added 9.7 g of 2-(tert-butylamino)-3,5,6-cryptosporidia with 15.5 g of benzylamine 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.

Example 3 (Reference Example 3)

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

To 60 ml of methanol was added 10.7 g of the crude 2-benzylamino-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 is washed with 80 ml of 10% aqueous sodium carbonate solution, after washing again were extracted ongena 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 title compound as light brown oil.

1H NMR (CDCl3) ;

of 1.43 (s, 9H), 4,11 (CL, 2H), 6,94 (t, J=10 Hz, 1H)

Receive 1 (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 etango powder.

Melting point: 203-205oC.

1H NMR (CDCl3) ;

of 1.39 (s, 9H), of 1.40 (t, J=7 Hz, 3H), and 4.40 (q, J=7 Hz, 2H), 4,70 (SHS, 1H), 7,21 (DD, J=8 Hz, 10 Hz, 1H), 8,31 (DD, J=8 Hz, 10H, 1H), and 8.50 (s, 1H)

Getting 2 (Example 2)

Synthesis of ethyl 8-bromo-1-[6-(tert-butylamino)-3,5-differencein-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 filtrowanie, washed successively with ethanol and diiso

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=* Hz, 10 Hz, 1H), at 8.36 (DD, J=9 Hz, 10H, 1H), 8,54 (s, 1H)

Getting 3 (Example 3)

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

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 obtained 0.15 g of the specified BP>H 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, 1H), 8,48 (s, 1H)

Getting 4 (Example 4)

Synthesis of ethyl 1-[6-(tert-butylamino)-3,5-differencein-2-yl] -7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylate

To 1 ml of a chloroform solution of ethyl 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 until the reaction control 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 connection header in the form of VC is C, 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, 1H), up 8.75 (s, 1H)

Getting 5 (Example 5)

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 10 ml of 4 N. hydrochloric acid and 10 ml of acetic acid was added 4,10 g of ethyl 1-[6-(tert-butylamino)-3,5-differencein-2-yl]-8-chloro-6,7-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, 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 (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 4 (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 primiarily 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)

Example 5 (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-benzylamino-3,5,6-cryptosporidia obtained as described above, together with 0.55 g of 10% palladium on coal and 2 ml of acetic acid and the mixture was first made at the 50oC during the day. Was separated by filtering the catalyst and drove away under reduced pressure, the solvent and the like. The precipitate was dispersible in n-hexane and collected by filtration receipt of 3.85 g specified in the title compound as a colourless solid.

1H NMR (CDCl3) ;

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

Example 6 (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 is, for example, the IDA 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)

Obtaining 6 (Example 6)

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

To 18 ml of a chloroform solution of ethyl 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 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 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 (kV,teaching 7 (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-1-[3,5-debtor-6-(p-methoxybenzylamine)pyridine-2-yl]-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated under reflux for 16 hours. The solution was allowed to cool and settle and the precipitate was collected by decantation and washed with 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, the precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 1.25 g specified in the title compound as light brown powder.

Getting 8 (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-carbonio-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 filtration and washed successively with ethanol and diisopropyl ether to obtain 41 mg specified in the title compound as 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=14 Hz, 1H), 8,73 (s, 1H)

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

9 (Example 9)

Synthesis of 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 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: 260-263oCJ=9 Hz, 1H), 8,68 (s, 1H)

10 (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

To 400 mg of N,N-dimethylformamide was added 90 mg of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 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, 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-DMCO) ;

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)

Receipt 11 (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 smessage was collected by filtration, washed with ethanol to obtain 64 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or higher.

1H NMR (d6-DMSO) ;

of 1.35 (s, 3H), 4,19 (m, 2H), 4,30 (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)

Receive 12 (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-hydroxyacetanilide and 150 mg of N-methylpyrrolidine and the mixture was heated under reflux for 1 hour. The precipitate was collected by filtration, 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)

13 (Example 13)

Synthesis of N-methylpyrrolidinone salt of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroc 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg 3-hydroxyacetanilide and 300 mg N-methylpyrrolidine, and the mixture was stirred at 80oC for 10 hours. After adding 2 ml of methanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with 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).

Getting 14 (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, 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 and 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)

EP 7 (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 and 10 ml of methylamine (10% aqueous solution) and the mixture was stirred at 50oC for 2 hours. To the solution was added 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 (SHS, 1H), 7,20 (DDD, J=7 Hz, 8 Hz, 9 Hz, 1H).

Example 8 (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 140oC 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.

Example 9 (Reference Example 9)
o
C during the night. Was separated by filtering 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 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)

Get 15 (Example 15)

Synthesis of ethyl 8-chloro-6,7-ditto-1-(3,5-debtor-6-methylaminomethyl-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 prom is nnom pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 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)

Receive 16 (Example 16)

Synthesis of 8-chloro-6,7-debtor-1-(3,5-debtor-6-methylaminomethyl-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 mixture was allowed to cool, after which the residue was collected by filtration, 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)

Polyhydramnion-3-carboxylic acid

To 400 mg of N,N-dimethylformamide were added 100 mg of 8-chloro-6,7-debtor-1-(3,5-debtor-6-methylaminomethyl-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoacetanilide 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, 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)

Example 10 (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.

oC during the day. Was separated by filtering the catalyst and drove away 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)

Example 12 (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 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)

Getting 18 (Example 18)

Synthesis of ethyl 8-chloro-1-[3,5-debtor-6-(p-methoxybenzylidene)-4-methylpyridin-2-yl]-6,7-di is benzoyl)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-6-(p-methoxybenzylidene)-4-methylpyridine. The solution was concentrated under reduced pressure and to the residue was added 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 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 obtain specified in the title compound as a brown crude oil.

Getting 19 (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-methylpyridin-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 distill 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 with stirring for 1 hour, then allowed it to cool. The precipitate was collected by filtration, washed successively with 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)

20 (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 28,0 mg 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, 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 (SHS is Idina

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 temperature, was added 150 ml of chloroform and the mixture was washed twice with 800 ml of distilled water. The chloroform 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.

Example 14 (Reference Example 14)

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

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 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)

Example 15 (Reference Example 15)

Synthesis of 2-amino-4-(tert-butyl)amino-3,5,6-cryptosporidia, obtained as described above, together with of 0.43 g of 10% palladium on coal and the mixture was first made at 60oC for 6 hours. Was separated by filtering 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.

Getting 21 (Reference Example 16)

Synthesis of ethyl 3-[(4-(tert-butylamino-3,5,6-triptorelin-2-yl)amino]-2-(3-chloro-2,4,5-tripersonality

To 1.4 g of ethyl 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, washed with diethyl ether to obtain 1,14 g specified in the connection header.

Getting 22 (Example 21)

Synthesis of ethyl 1-(4-tert-butylamino-3,5,6-triptorelin-2-yl)[(4-tert-butylamino-3,5,6-triptorelin-2-yl)amino] -2-(3-chloro-2,4,5-triterpenoid 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 title compounds as colorless powder.

Melting point: 145-146oC

1H NMR (CDCl3) ;

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)

23 (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, 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)

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 80oC for 1 hour. The reaction solution was allowed to cool and decentrali diethyl ether. To the residue was added ethanol dispersion of solid content, and 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 - when 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)

Example 16 (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 is by filtration through celite, then from 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.

Receive 25 (Reference Example 18)

Synthesis of ethyl 3-(5-amino-6-chloropyridin-3-yl)amino-2-(3-chloro-2,4,5-triterpenoid)acrylate

To 1.4 g of ethyl 3-chloro-2,4,5-tripersonality was added 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 column chromatography to obtain 200 mg specified in the connection header.

Getting 26 (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 - triterpenoid)acrylate in 3 ml of N,N-Demeu. 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

1H NMR (CDCl3) ;

of 1.39 (t, J= 7 Hz, 3H), and 4.40 (q, J=7 Hz, 2H), 4,46, (CL, 2H),? 7.04 baby mortality (s, 1H), 7,26 (s, 1H), 7,86 (s, 1H), 8,32 (t, J=9 Hz, 1H), of 8.37 (s, 1H)

Getting 27 (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)

Getting 28 (Example 26)

Synthesis of 7-(3-aminoate insulfating 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 dispersion of solid content, and then the solid content was collected by filtration, washed with 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)

Example 17 (Reference Example 19)

Synthesis of 2,4-dichloro-5-ftorpirimidinu

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%

1H NMR (CDCl3) ; 8,49 (s, 1H)

Example 18 (Reference 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 was concentrated under reduced pressure and separated by adding 40 ml of distilled water and 70 ml of chloroform. The chloroform 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)

Example 19 (Reference 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 t 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 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)

Example 20 (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 coal and the mixture was first made at 60oC for ten days. Was separated by filtering the catalyst and drove away under reduced pressure, the solvent and the like. Three times repeating a procedure of adding 10 ml of ethanol and concentrating under reduced pressure, then the residue was divided 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)

Getting 29 (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 is. 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 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 residue was divided by column chromatography (silica gel, 16 g; eluent: chloroform:methanol 200:1) and the 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, 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)

30 (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 4 N. hydrochloric acid and 1 ml of acetic cicloserina and the mixture was heated under reflux while moving in for 3 and a half hours, then let it cool. The precipitate was collected by filtration, 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) ;

8,04 (CL, 2H), with 8.33 (d, J=3 Hz, 1H) 8.34 per (t, J=9 Hz, 1H), of 9.02 (s, 1H)

Getting 31 (Example 29)

Synthesis of 7-(3-aminoamides-1-yl)-1-(4-amino-5-ftorpirimidinu-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-methylpyrrolidone 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, 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)

Example 21 (Reference Example 23)

Synthesis of 2-amino-3,5-Diphteria 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.

Getting 32 (Example 30)

Synthesis of ethyl 8-chloro-1-(3,5-debtor-6-methoxypyridine-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 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 the first 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)

Receive 33 (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 4 N. hydrochloric acid and 1 ml of acetic acid was added 385 mg of ethyl 8-chloro-1-(3,5-debtor-6-methoxypyridine-2-yl)-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated 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, 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)

Getting 34 (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-the refrigerator for 1 hour. The precipitate was collected by filtration, 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)

Receive 35 (Example 33)

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

To 10 ml of a chloroform solution of ethyl 3-ethoxy-2-(2,6-dichloro-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 ponie the m 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, 1H), 8,69 (s, 1H)

Getting 36 (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, V/V) and 3 N. hydrochloric acid and acetic acid was added 300 mg of ethyl 7-chloro-1-(3,5-debtor-methoxypyridine-2-yl)-6-fluoro-4-oxo-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, 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)

Getting 37 (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 is 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, washed successively with ethanol and diisopropyl ether to obtain 102 mg specified in the title compound as pale brown powder.

Melting point: 231-233oC

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).

Getting 38 (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-methylpyrrolidinone and 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, washed successively with ethanol is S="ptx2">

Melting point: 226-229oC

1H NMR (d6-DMSO) ;

0,94 (CL, J=8 Hz, 3H), of 2.16 (m, 1H) 3,95 8,02 (s, 3H), (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).

Getting 39 (Example 37)

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

To a mixed solution of 3.5 ml of 4 N. hydrochloric acid 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, 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), to 7.99 (d, J=9 Hz, 1H), scored 8.38 (t, J=9 Hz, 1H), 8,93 (s, 1H)

Getting 40 (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 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, 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), 8,04 (t, J=9 Hz, 1H), 8,23 (m, 1H), 8,98 (s, 1H)

Getting 41 (Example 39)

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3,5-differencein-2-yl)-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-3,5-differencein-2-yl)-8-bromo-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoacetanilide 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, 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)

Received the in-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-aminoacetanilide 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, washed successively with ethanol and diisopropyl ether to obtain 70 mg specified in the title compounds as colorless powder.

Melting point: 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)

Getting 43 (Example 41)

Synthesis of 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

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-methylaminoacetaldehyde and 300 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 and then the precipitate was collected by filtration, washed successively with ethanol and diisopropyl the temperature value 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 (1H)

Getting 44 (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-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-(ethylamino) 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, 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)

45 (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-lindenbergiana 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, 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-DMSO) ;

2,07 (s, 6H), 3,03 (m, 1H), 4,24 (m, 2H), 4,55 (m, 2H), 6,77 (CL, 2H), 7,86 (d, J=14 Hz, 1H), 7,95 (t, J=9 Hz, 1H), to 8.70 (s, 1H)

Getting 46 (Example 44)

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, washed successively with ethanol-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) is 4.21 (m, 2H), 4,49 (m, 2H), 6.73 x is-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 residue 200 ml of chloroform solution was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, after which the precipitate was collected by filtration to obtain 16.6 g specified in the application connection in the form of colorless flake crystals.

Example 23 (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 to reverse the refrigerator 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 in polariser 24 (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. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 12.8 g specified in the title compound as a reddish-orange oil.

Example 25 (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 coal and the mixture was first made at the 50oC for 5 days. Was separated by filtering 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 mA is a

To 10 ml of N-methylpyrrolidine 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) to obtain approximately 7.0 g specified in the title compound as a light brown crude oil.

Example 27 (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 coal and the mixture was first made at the 30oC for 1 hour. Was separated by filtering 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 10 ml of 6% aqueous sodium hydroxide solution. The chloroform layer was dried over anhydrous sulfa is l, 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)

Getting 47 (Example 45)

Synthesis of ethyl 1-[6-(tert-butylamino)-3-chloro-5-herperidin-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 0.65 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 in the tank 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 (q, 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)

Getting 48 (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 acetic acid was added 600 mg of ethyl 1-[6-(tert-butylamino)-3-chloro-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 4.5 hours. After adding 2 ml of distilled water the solution was allowed to cool and the precipitate was collected by filtration, 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)

Getting 49 (Example 47)

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-animamina was 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-aminoacetanilide 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 the precipitate was collected by filtration, 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 (d6-DMSO) ;

3,71 (m, 1H), 4,08 (m, 2H), 4,67 (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)

Getting 50 (Example 48)

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-methylaminoacetaldehyde 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, washed successively with ethanol and diisopropyl ether to obtain 98 mg specified in the title compounds as colorless powder.

The temperature of the melt is, H),? 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)

Getting 51 (Example 49)

Synthesis of ethyl 1-[6-(tert-butylamino)-5-herperidin-2-yl]-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 to obtain a yellow solid residue. To this residue was added 0.6 g of 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 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 is for 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 1-[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 and washed successively with ethanol and diisopropyl ether to obtain 342 mg specified in the title compounds as 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)

Getting 53 (Example 51)

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-5-herperidin-2-yl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-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-aminoacetanilide and 80 mg N-methylpyrrolidone and the mixture was stirred at 90oC for 15 minutes. After adding 0.3 ml of ethanol by speciation 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)

Getting 54 (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-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylamino-setidentityproviderid and 150 mg of N-methylpyrrolidine 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, 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)

Receive 55 (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 established. 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, obtaining 32,0 g specified in the title compounds as colorless powder.

Getting 56 (Reference Example 31)

Synthesis of N-[2-(tert-butylamino)-5-chloro-3,6-differencein-4-yl]phthalimide

To 150 ml of acetonitrile was added 30.0 g of 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.

Getting 57 (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-[what Noah 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.

Getting 58 (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 in 30 ml of acetonitrile for 10 minutes. The mixture was stirred at 60oC for 1 hour and concentrated under 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.

Example 28 (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 (2,5-dichloro-3,6-debtonator within 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.

Example 29 (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 triethylamine together with 0.40 g of 10% palladium on carbon and the mixture was first made at the 50oC for 12 days. Was separated by filtering 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 filtering 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 included the ri reduced pressure to obtain 2.67 g specified in the connection header in the form of precipitated precipitated colorless solid.

Example 30 (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. The residue was subjected to column chromatography (silica gel, 15 g; eluent: chloroform:methanol, 1:0 and then 50:1) to give 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)

Example 31 (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 filtering the catalyst and drove away under reduced pressure, the solvent and the like. Outlinei 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.

Getting 59 (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-(3-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-diamino-5-ftorpirimidinu together with 0.28 g of N-methylpyrrolidine. The solution was concentrated under reduced pressure 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,Anna in the header of the mixture (1:1 by NMR) as a pale brown powder.

Receive 60 (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, 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,

was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 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 (CDCl3) ;

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)

Getting 61 (Example 54)

Synthesis of 1-(4-amino-5-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-digital 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 let it cool. The precipitate was collected by filtration, washed successively with distilled water, ethanol and diisopropyl ether to obtain 31 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or higher

1H NMR (d6-DMSO) ;

6,86 (CL, 2H), 7,00 (d, J=7 Hz, 1H) to 8.12 (d, J=3 Hz, 1H), 8,39 (t, J=9 Hz, 1H), total of 8.74 (s, 1H)

Getting 62 (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-3-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), 6,77 (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)

the and 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. To the solution was added dropwise 10 ml of methanol and stirred at room temperature for 60 minutes, after which the solution was added 15 g of anhydrous potassium carbonate and stirred the solution for another 30 minutes. Shared solution, 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.

Example 33 (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 distiller the first magnesium sulfate and concentrated under reduced pressure. The result obtained crude methyl 2,5,6-triptorelin in the form of a brown oily residue and this residue was dissolved in 60 ml of acetonitrile and to the solution was added 12.0 g of tributylamine. The solution was concentrated under reduced pressure and the residue was separated by 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)

Example 34 (Reference Example 41)

Synthesis of methyl 6-tert-butylamino-5-fluoro-2-(1,1,3,3-tetramethylbutylamine)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 powerglove connection in the form of 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)

Example 35 (Reference Example 42)

Synthesis of 2-tert-butylamino-3-fluoro-5-methyl-6-(1,1,3,3-tetramethylbutylamine)pyridine

In 20 ml of tetrahydrofuran was dispersively 850 mg sociallyengaged. The dispersion was cooled water and stirred with a simultaneous dropwise addition 2,80 g of 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), 1.9 to the pyridine

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 for 30 minutes. The solution was concentrated under reduced pressure to get crude 2,6-diamino-3-fluoro-5-methylpyridine as a pale brown solid residue.

Getting 63 (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 bezwodniki 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.

Melting point: 198-202oC

1H NMR (CDCl3) ;

of 1.40 (t, J= 7 Hz, 3H), 2,02 (s, 3H), 4,39 (kV, J=7 Hz, 2H), 4,71 (CL, 2H), 7,25 (d, J=10 Hz, 1H), 8.34 per (t, J=10 Hz, 1H), 8.34 per (s, 1H)

Getting 64 (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, 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)

Getting 65 (Example 58)
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-aminoacetanilide and 120 mg of N-methylpyrrolidine and the mixture was stirred at 85oC for 45 minutes. After addition of 0.5 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration, 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)

Getting 66 (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)setidentityproviderid and 70 mg N-methylpyrrolidone 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, washed the e 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)

Example 37 (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 of tert-butylamine and the mixture was stirred at room temperature overnight. Of the reaction solution is kept off 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)

Example 38 (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 chlorestrol of balance with obtaining 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)

Example 39 (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-herperidin was added 3 ml of acetic acid and 0.5 ml of ethanol, and then 10 microlivestock palladium mobiles and the mixture was stirred 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.

Getting 66 (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-3-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. From the reaction solution drove the RA is whether 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 with diethyl ether to obtain 280 mg of the indicated in the title compounds as pale yellow powder.

Melting point: 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)

Getting 67 (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-oxoindole-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, 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- tiden-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 - debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid, after which the mixture was stirred at 90oC for 10 minutes. To 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)

Getting 69 (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 economical and the residue was subjected to column chromatography on silica gel (eluent: ethyl acetate: hexane, 1: 8) to obtain 4.6 g of ethyl 2-(2,4,5-Cryptor-3-methylbenzoyl)-3-[6-(tert-butylamino)-3,5-differencein-2-yl]aminoacetate in the form of butter.

To a solution of 4.6 g obtained in the manner described ethyl 2-(2,4,5-Cryptor-3-methylbenzoyl)-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)

Getting 70 (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 with reverse holodilniki the scrap and then diethyl ether to obtain 1.7 g specified in the title compounds as pale yellow powder.

Melting point: 274-277oC

1H NMR (CDCl3) ;

of 1.84 (s, 3H), 6,91 (CL, 2H), 8,03 (t, J=9 Hz, 1H), 8,25 (t, J=9 Hz, 1H), 8,93 (s, 1H)

Getting 71 (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 (t, J=9 Hz, 1H), to 8.70 (s, 1H)

Getting 72 (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-oxoindole-3-carboxylic acid

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)

Getting 73 (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 Getting 71 (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-oxoindole-3-carboxylic acid and 110 mg of 3-amino-3-methyltetrahydrofolate.

Melting point: 235oC or higher

1H NMR (ds-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), to 8.70 (s, 1H)

Getting 74 (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-amidohlorida and 100 mg N-methylpyrrolidine together with 3 drops of ethanol and the mixture was stirred at 85oC for 30 minutes. After addition of 0.2 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 52 mg specified in the title compounds as colorless powder.

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)

Getting 75 (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-4-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, 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) ;


To 3.5 g of N,N-dimethylformamide was added to 2.00 g of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, and 1.00 g of 3-hydroxyacetanilide 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, 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)

Getting 77 (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 re is birali filtering washed successively with ethanol and diisopropyl ether to obtain 90 mg specified in the title compounds as pale yellow powder.

Melting point: 269-272oC

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)

Getting 78 (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. Sediment di with the receipt of 0.53 g specified in the title compounds as pale yellow powder.

Melting point: 192-195 (in Russian)oC

1H NMR (CDCl3) ;

of 1.37 (s, 9H), of 1.40 (t, J=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)

Getting 79 (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 ethyl 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, 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)

80 (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 is terpinolene and the mixture was stirred at 90oC for 10 minutes. After addition of 0.3 ml of the ethanol solution was allowed to cool and the precipitate was collected by filtration, 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)

Getting 81 (Example 75)

Synthesis of 1-(6-amino-5-herperidin-2-yl)-8-bromo-6-fluoro-7-(3-methylaminomethyl-1-yl)-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, 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, 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-D Example 40 (Reference Example 47)

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

To 25 ml of methanol was added 2.7 g of 2-amino-4-bromo-5-chloro-3,6-diphereline, and 1.15 g of triethylamine together with 0,145 g 10% palladium on coal and the mixture was first made at room temperature for 1.5 hours. Was separated by filtering 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: n-hexane (1:2) and collected by filtration receipt of 1.62 g specified in the connection header.

Example 41 (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: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 con the crude oil.

1H NMR (CDCl3) ;

of 3.80 (s, 3H), 4,35 (CL, 2H), 4,50 (m, 2H), 4,86 (SHS, 1H), 6.87 in (d, J=8 Hz, 2H), 7,15 (d, J=10 Hz, 1H), 7,27 (d, J=8 Hz, 2H)

Getting 82 (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-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 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, 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
(d, J=9 Hz, 2H), 7,53 (d, J=8 Hz, 1H), 8,29 (t, J=9 Hz, 1H), 8,48 (s, 1H)

Getting 83 (Example 77)

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

To 53,0 mg 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, 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), and 4.40 (q, 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)

Getting 84 (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-digile which was allowed to cool. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 375 mg specified in the title compounds as colorless 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)

Getting 85 (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 aminoethylethanolamine and 160 mg N-methylpyrrolidone 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, 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)

Example 42 (Reference Example 49)

Synthesis of 2,3,5-Cryptor-6-isopropylaniline at room temperature for 2 hours and concentrated under reduced pressure. After adding 40 ml of chloroform solution was washed with 50 ml of 3% aqueous potassium carbonate solution. The chloroform 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.

Example 43 (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: 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.

Example 44 (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 after which the solution was washed with 25 ml of 5% aqueous sodium carbonate solution. The chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform) to obtain 0.6 g specified in the title compound as a brown oil.

Getting 86 (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, washed successively with ethanol and diisopropyl ether to obtain 620 mg ukazannoj1H NMR (CDCl3) ;

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>
Getting 87 (Example 81)

Synthesis of 8-chloro-6,7-debtor-1-(3,5-debtor-6-isopropylpyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic 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-3-carboxylate and the mixture was heated under reflux for 19 hours with stirring. The precipitate was collected by filtration, 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)

Getting 88 (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-3-carb is> within 30 minutes. After addition of 0.5 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 51 mg specified in the title compounds as colorless powder.

Melting point: 220-223oC

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)

Getting 89 (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 distiller who was garofali in ethanol, collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 6,15 g specified in the title compounds as colorless powder.

Melting point: 203-208oC

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=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)

Getting 90 (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, washed with ethanol to obtain 960 mg specified in the title compound as a gray powder.

Melting point: 223-230oC

1H NMR (CDCl3) ;

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)

Proveu 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-carboxylate and the mixture was heated under reflux for 3 hours with stirring, then allowed to cool. The precipitate was collected by filtration, 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)

Getting 92 (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-aminoacetanilide 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 the precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 50 mg specified in the title compounds as pale yellow powder.

Melting point: 26 (t, J=9 Hz, 1H), 8,66 (s, 1H)

Getting 93 (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

To 8 ml of toluene was added 1,58 g of ethyl 1-[3,5-debtor-6-(p-methoxybenzylamine)pyridine-2-yl] -5,6,7,8-titrator-4-oxo-1,4-dihydroquinoline-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 settle and the precipitate was collected by filtration, 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)

Getting 94 (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)and 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 ethanol, collected by filtration, washed with ethanol to obtain 530 mg specified in the title compound as 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)

Getting 95 (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 filtering 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, washed successively with ethanol and diisopropyl ether to obtain 160 P>oC

1H NMR (CDCl3) ;

to 1.38 (t, J=7 Hz, 3H), of 4.38 (q, 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)

Getting 96 (Example 90)

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

To 1.5 ml of a mixed solution (1:1) 4 N. hydrochloric 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, 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)

Getting 97 (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 at the air traffic management 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, 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 (CL, 2H), 7,94 (t, J=9 Hz, 1H), and 8.50 (s, 1H)

Getting 98 (Example 92)

Synthesis of ethyl 1-(6-tert-butylamino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-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 races the dock was dispersible in ethanol, collected by filtration, 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 (kV, 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)

Getting 99 (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-carboxylic acid

To 10 ml of formic acid was added 960 mg of ethyl 1-(6-tert-butylamino-3,5-differencein-2-yl)-8-chloro-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, and the celite was 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, washed successively with ethanol is ptx2">

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)

Obtaining 100 (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-methylpyrrolidone and the mixture was stirred at 100oC for 30 minutes and concentrated under reduced pressure. After addition of 2 ml ethanol and the mixture was stirred and the precipitate was collected by filtration, washed successively with 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)

Getting 101 (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 is such that 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 magnesium sulfate. Drove the solvent and to the residue was added ethanol dispersion solid content was collected 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 (kV, J=7 Hz, 2H), of 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)< / BR>
Getting 102 (Example 96)

Synthesis of ethyl 5-amino-6,7-debtor-1-(3,5-debtor-6-p-metoxi-(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=8 Hz, 2H) 7,14 (d, J=8 Hz, 2H), 7,85 (SHS, 1H), to 7.93 (t, J=10 Hz, 1H), 8,27 (s, 1H)

Getting 103 (Example 97)

Synthesis of 5-amino-1-(6-amino-3,5-differencein-2-yl)-6,7-debtor-8-methyl-1,4-dihydro-4-oxoindole-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 connection header SUP>H NMR (d6-DMSO) ;

to 1.60 (s, 3H), 6,80 (CL, 2H), of 7.96 (t, J=9 Hz, 1H) 8,69 (s, 1H)

Example 45 (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 a mixed solution of diisopropyl ether/n-hexane and collected by filtration to obtain 3.8 g specified in the title compounds as pale yellow needle crystals.

Example 46 (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:n-hexane (1:1, V/V) solution was washed twice with 400 ml of distilled water. the first 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.

Example 47 (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 coal and the mixture was first made at room temperature for 39 hours. Was separated by filtering 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 50 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, 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.

Getting 104 (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-2m, was added 0.75 g of 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 washed successively with ethanol and diisopropyl ether to obtain 0.45 g specified in the title compounds as pale yellow powder.

Melting point: 178-180oC

1H 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)

Getting 105 (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 nortropane, 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)

Getting 106 (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-methylpyrrolidone and the mixture was stirred at 90oC for 30 minutes. After addition of 0.2 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration, washed successively with 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), to 7.61 (d, J=9 Hz, 1H), 7,85 (t, J=14 Hz, 1H), 8,63 (s, 1H)

Getting 107 (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-dihydropyrido-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg 3-methylaminoacetaldehyde and 250 mg N-methylpyrrolidone 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 2 ml of ethanol and the mixture was stirred. The precipitate was collected by filtration, 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)

Getting 108 (Example 102)

Synthesis of 5-amino-1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-gidroksibenziliden-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-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 2 ml of ethanol and the mixture was stirred. The precipitate was collected and filtered the deposits in the form of a yellow powder.

Melting point: 267-290oC (decomposition).

1H NMR (d6-DMSO) ;

4.09 to (m, 2H), of 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 get 9, 10, 12, and 41 (39) evaluated at their minimum dose (concentration), inhibiting the growth of bacteria (MIG, ug/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 evaluated by minimum inhibitory dose (MIG, ug/ml) for comparison purposes. The results are also shown in table 1.

The results, shown in table 1, show that the compounds of formula (I) possess excellent antibacterial activities superior to those possessed by conventional bacterial funds.

(2) Test for phototoxicity

Compounds of the above Examples get 9, 10, 12, and 41(39) were tested on phototoxic is connected (40 mg/kg/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.

The results presented in table 2 show that the compounds of formula (I) show a very low toxicity.

1. Aminosidine General formula (C)

< / BR>
in which X represents a nitrogen atom;

Y - represents-CH = or CR7=, where R7is lower alkyl or a halogen atom;

Z - represents-CH=;

R2ais optionally substituted by an amino group or a protected amino group;

R3represents a hydrogen atom or a halogen.

2. Aminosidine under item 1, in which R3represents a fluorine atom or chlorine.

3. Aminosidine under item 1 or 2, wherein Y - represents-CH= or CR7=, where R7javljaetsja amino group or protected amino group in the definition of R2ais methylamino, isopropylamino, tert-butylamino, benzylamine, p-methoxybenzylamine or 1,1,3,3-tetramethylbutylamine.

5. Aminosidine according to any one of paragraphs.1 to 3, in which R2Ais unsubstituted amino group.

 

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< / BR>
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