Derived pyridonecarboxylic acid or its salt

 

(57) Abstract:

The invention relates to a new derived pyridonecarboxylic acid of the formula I or salts thereof, which possess high antibacterial activity and can find application in medicine. 1 C. p. F.-ly, 2 PL.

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

Background of the invention

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 flow of infectious diseases found norfloxacin (tiled application 53-141286 patent Japan), enoxacin (tiled application 55-31042 patent Japan), ofloxacin (tiled application 57-46986 patent Japan), ciprofloxacin (tiled application 58-76667 patent Japan), tosufloxacin (tiled application 60-228479 patent Japan) and the like.

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

Disclosure of the invention

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

< / BR>
[In the formula, R1represents a hydrogen atom; R2represents a substituted or an unsubstituted amino group; R3represents a halogen atom; R4represents a halogen atom; R5is optional sameline a protected amino group;

X represents a nitrogen atom, Y represents-CR7(where R7represents a lower alkyl group, halogen atom or cyano), Z is CH= or-CR7(where R7represents lower alkyl or halogen), and W represents-CR8= (where R8represents a halogen atom or a lower alkyl group)] .

Thus, in accordance with the present invention offers derivatives pyridonecarboxylic acid represented by above General formula (1) or their salts and antibacterial agent containing the derivative pyridonecarboxylic acid or their pharmaceutically acceptable salts as active ingredients.

The best way of carrying out the invention

New derivatives of pyridonecarboxylic acid of the present invention represented by the General formula (1) above, and the term "lower" used for substituents derived pyridonecarboxylic acid represented by the General formula (1), means the Deputy contains 1-7, preferably 1-5, carbon atoms in the case of a linear Deputy and 3-7 carbon atoms in the case of a cyclic substituent.

In the General formula (1) R2represents a substituted or illegal is their as a methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, pencilina group, exilda group and heptylene group. Of the above substituents can be selected one or two substituent, which may be the same or different. It is expected that connection protected amino acid or Oligopeptide residues will have improved solubility in water.

Preferably R2represents an amino group, a lower alkylamino, di-lower alkylamino, lower alkanolamines, amino, protected amino acid residue or amino group, protected Oligopeptide balance. More preferred examples of R2include an amino group, methylaminopropyl, ethylamino and dimethylaminopropyl, of which the most preferred is an amino group.

Further, in General formula (1) R3represents a halogen atom; R4represents a halogen atom; R5represents an optionally substituted saturated cyclic amino group; R6represents a hydrogen atom, halogen atom or optionally protected amino group; X represents N and Y represents-CR77(where R7lower alkyl or halogen atom; and W represents-CR8= (where R8represents a halogen atom).

The halogen atoms represented by the symbols R3, R4, R5, R6, R7and R8include fluorine atom, chlorine atom, bromine atom and iodine atom. Of them, preferred are a fluorine atom and a chlorine atom and, in particular, R3-R7preferably represent fluorine atom, a R8preferably represents a chlorine atom.

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

It should also be noted that the compound of formula (1) has a quinoline skeleton, when W is- (CR8= (where R8represents a halogen atom or a lower alkyl group).

Further, optionally substituted, saturated cyclic amino group represented by the symbol R5may optionally contain in the ring one heteroatom such as nitrogen atom, and also the focus of a 4-membered ring. Examples of such cyclic amino groups include saturated monocyclic amino group having a 4-membered ring containing one nitrogen atom, such as aziridine-1-yl, azetidin-1-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 group, lower alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted amino lower alkyl groups.

Exemplary lower alkyl groups for the substituent a saturated cyclic amino group include those which contain 1 to 7 carbon atoms, such as methyl group, ethyl group, through the group, bucilina group, pencilina group, exilda group and heptylene group. Of the Vice saturated cyclic amino groups substituted amino and substituted amino lower alkyl group may have a Deputy, who may be identical with those described for R2and preferred examples of the substituted amino groups, and substituted and unsubstituted amino lower alkyl groups include methylaminopropyl, ethylamino, dimethylaminopropyl, aminomethyl group, 1-and lilou group, dimethylaminomethylene group, glycyl-amino group, leucyl-amino group, poured-amino group, alanyl-amino group and alanyl-alanyl-amino group.

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

< / BR>
[where s represents a number equal to 3, J1I , J2and J3that may be the same or different, represent a hydrogen atom, hydroxyl group, lower alkyl group, amino lower alkyl group, an amino group or a lower alkylamino] .

Examples of lower alkyl groups, amino lower alkyl groups and lower alkylamino in the above formula (a) are the same as those described for R2-R5.

Exemplary cyclic amino group represented by the formula (a) include azetidin-1-yl. When R5represents a cyclic group, R5preferably represents a cyclic amino group represented by the formula (a), and most preferably, azetidin-1-yl.

The most preferred examples of groups represented by formula (a) are the following groups:

3-hydroxyazetidine-1-ilen g is lidin-1-ilen group,

3-aminomethylpyridine-1-ilen group,

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

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

3-alanyl-aminotetralin-1-ilen group,

3-poured-aminotetralin-1-ilen group.

Optionally protected amino group represented by the symbol R6includes the amino group and the 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, naphthalocyanine or the like; aryloxy lower alkanoyloxy group, such as phenoxyacetyl, phenoxypropionyl or the like; aracelikarsaalyna group, such as benzyloxycarbonyl, ventilatsioonil Il="ptx2">

The preferred combination of R1, R2, R3, R4, R5, R6X, Y, Z and W are those in which R1represents a hydrogen atom, R2represents an amino group, a lower alkylamino or di-lower alkylamino, R3represents a halogen atom, R4represents a halogen atom, X represents a nitrogen atom, Y represents CR7= (where R7represents a lower alkyl group or halogen atom), Z is CH= or-CR7(where R7defined above), W is- (CR8= (where R8represents a halogen atom or a lower alkyl group), R5represents a group of formula (a) to (e= 3) and R6represents a hydrogen atom. The preferred combination of R1, R2, R3, R4, R5, R6X, Y, Z and W are those in which R1represents a hydrogen atom, R2represents the amino group, R3represents a fluorine atom, R4represents a fluorine atom, X represents a nitrogen atom, Y represents-CF= -, Z is-CH= , W is-CCL= , -GVS= or-CLO3= , R5represents a group of formula (a) to (e= 3) and R6represents a hydrogen atom.

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

Derivatives pyridonecarboxylic acids and their salts of the present invention can be chromene includes crystalline, hydrate and solvate forms. In addition, derivatives pyridonecarboxylic acids and their salts may be in the form of optically active substances, and such optically active substance is in a range of compounds of the present invention. And even that is derived pyridonecarboxylic acid and its salt can be in the form of (CIS - or TRANS-) stereoisomer, and a stereoisomer is also in the scope of the compounds of the present invention.

Derivatives pyridonecarboxylic acids and their salts of the present invention represented by the above formula (1) can be obtained in any way, properly selected in accordance with such factors as the type of substituents, and an example of such a method is described in scheme 1 (see the end of the description).

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

This reaction is carried out in a solvent which has no adverse effect on the reaction, such as aromatic hydrocarbons such as benzene, toluene or xylene; alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran, dioxane or monogram; halogenated carbohydrate is as dimethylformamide, dimethyl sulfoxide or N-organic; acetonitrile or pyridine, and in the optional presence of a catalyst, 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 1-5 times the molar quantity.

Compound (F) can be obtained by the method shown in the in the end of the description scheme 2 reactions.

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

The reaction between the compound (A) and orthoformiate usually carried out at 0-160oWith, preferably 50-150oWith, usually within periodinane (A) in equimolar amount or more, preferably 1 to 10-fold molar quantity.

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

In accordance with another variant of the compound (A) may be subjected to interaction with acetal, such as dimethylacetal N, N-dimethylformamide or diethylacetal N-dimethylformamide, whether any, but he would not impact adversely on the reaction, and exemplary solvents are those described above. This reaction usually takes place at 0-150oC, preferably at room temperature to 100oUsually 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 in the absence of 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; 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; toride metals, such as sodium fluoride and potassium fluoride; organic salts such as triethylamine and 1,8-diazabicyclo[5.4.0] undecene (DBU). This reaction is carried out at a temperature of 0-200oWith, preferably in the range from room temperature to 180oAnd 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 carboxylato group, R1Aand/or aminosidine group, R2awith obtaining the compounds (1a) (F).

In the General formulas (a-E) R1ais carboxylato group, and used herein, the term "carboxylamide group" means the ester residue of the carboxylate, and carboxylamide group can be any carboxylate ester residue, relatively easily fissionable with the formation of the corresponding free carboxyl group. Approximate carboxylate groups include groups which can be split by hydrolysis, catalytic reduction and other processing methods under mild conditions, such Kappa, n-bucilina group, isobutylene group, tert-bucilina group, pencilina group, exilda group and heptylene group; lower alkeneamine groups such as vinyl group, allyl group, 1-protanilla group, bucinellina group, penttila group, hexeline group and leptanillinae group; kalkilya groups such as benzyl group; and aryl groups such as phenyl group and naftalina group; and groups that can be easily split in the body, such as lower alkanoyloxy lower alkyl groups, such as acetoxymethyl group and pivaloyloxymethyl group; lower alkoxycarbonyl lower alkyl groups, such as methoxycarbonylamino-methyl group and 1-ethoxycarbonylmethylene group; lower alkoxymethyl groups, such as methoxymethyl group; Victorina group, such as phthalidyl; di-lower alkylamino lower alkyl group such as 1-dimethyl-aminoaniline group; and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group. It should be noted that most preferably R1represents a hydrogen atom.

The hydrolysis may be conducted under any conditions commonly used in the hydrolysis, for example, in the presence of a base, which, 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 140oWith, usually within 1-24 hours.

It should be noted that in the case of obtaining the compounds in which R6in the formula (1) represents an optionally protected amino group, first get the connection (S) via the above reaction using the compound (A), in which R6Arepresents a halogen atom or a nitro-group, as the source material, and then get a connection (E1aby amination of the above-mentioned halogen atom or by nitrogroup reduction and from the compound (E1a) get the compound (1A) by removing aminosidine group, if necessary, and remove carboxylamide group.

When in the source materials of the above-described method, there is an amino group, g is the response time, and at the end of 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 and P. G. M. Wuts, John Wiley & Sons Inc. , 1991).

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

2) Liebigs Ann. Chem. 29 (1987).

3) J. Med. Chem. 31, 991 (1988).

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

5) Posted application 62-246541 patent Japan.

6) Posted application 62-26272 patent Japan.

7) Posted application 63-145268 patent Japan.

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

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

10) Posted application 62-198664 patent Japan.

11) Posted application 63-264461 patent Japan.

12) Posted application 63-104974 patent Japan.

13) the Application 230948 for the European patent.

14) Posted application 2-282384 patent Japan.

15) Published Japanese pnoe the compound of the present invention is isolated and purified by usual method. The compound is obtained in the form of a salt, free carboxylic acid or free amine depending on the conditions of separation. However, due to the possibility of mutual transformation of forms of the compounds of the present invention can be obtained in the desired form.

The connection represented by the above General formula (1) or its salt can be prepared in the form of antibacterial compositions with a pharmaceutically acceptable carrier suitable for parenteral administration such as injection, rectal administration, instillation into the eye or oral administration in solid or liquid form.

The injectable form of antibacterial compositions of the present invention can be manufactured 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 a preservative, wetting agent, emulsifier and WM is the population of bacteria or by introducing a sterilizing agents in the form of a sterilizing substance or sterile solid composition, soluble in sterilized environment for injections, immediately prior to its application.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. When manufacturing such solid dosage forms of the compounds of the present invention is mixed with at least one inert diluent such as sucrose, lactose 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 resuspending substance, as well as sweetener, flavoring substance, flavouring substance.

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

The dose of a compound of the present invention varies depending on the nature of the input connection, the method of administration, the desired period of treatment and other factors. However, usually compounds of the present invention is administered in an amount of about 0.1 to 1000 mg/kg / day and, in particular, about 0.5-100 mg/kg per day. If necessary, this dose can be entered 2-4 portions.

New derivatives of pyridonecarboxylic acids and their salts of the present invention have a very strong antibacterial effect and low phototoxicity and cytotoxicity, and therefore could be widely used as medicines for humans and other animals, as well as medicines for fish, pesticides, preservatives for food, and the like. It is also expected that the compound of the present invention has antiviral properties and, in particular, anti-HIV (the virus immunodefi is her invention is described in more detail by examples and reference examples, which in no way limit the scope of the present invention.

Reference example 1

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

Melting point: 203-205oC.

1 1H), of 8.50 (s, 1H).

Reference example 2

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 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 and washed successively with ethanol and diisopropyl ether to obtain of 3.32 g specified in the title compounds as colorless powder.

Melting point: 280oC or higher.

1H NMR (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 1

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-amino-setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 1 hour. the sequential ethanol and diisopropyl ether to obtain 86 mg specified in the title compounds as colorless powder.

Melting point: 260-263oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 2

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

Melting point: 259-265oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 3

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 of dobblemoneycreditcard and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 40 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed with ethanol to obtain 64 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or 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).

Example 4

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

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

Melting point: 185-190oC (with 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, fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To 2000 mg of N, N-dimethylformamide was added 300 mg of 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 110 mg of 3-hydroxy-apatityvodokanala and 300 mg N-methylpyrrolidone and the mixture was stirred at 80oC for 10 hours. After adding 2 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 222 mg specified in the title compounds as colorless powder.

Melting point: 234-238oC (with 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).

Reference example 3

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

To 5 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-triterpenoid)acrylate obtained from 0,70 g of ethyl 3-chloro-2,4,5-tripersonality in the usual way, was added 430 mg of 2-amino-3,5-debtor-6-(methylamino)pyridine. The solution was concentrated under reduced pressure. To the residue was added 0.3 g of anhydrous potassium carbonate and 2 ml of N, N-dimethylformamide and the mixture per Reforma and 300 ml of distilled water and the chloroform layer was washed two times with 300 ml of distilled water, was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration and 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 (Dl3) ;

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).

Reference example 4

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, about. /about. ) 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 and washed successively with ethanol and diisopropyl ether to obtain 454 mg specified in the title compound as a gray powder.

Melting point: 236-242oC.

Example 6

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

To 400 mg of N, N-dimethylformamide were added 100 mg of 8-chloro-6,7-debtor-1-(3,5-debtor-6-methylaminomethyl-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-setidentityproviderid and 120 mg of N-methylpyrrolidine and the mixture was stirred at 100oC for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, after which the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 102 mg specified in the title compounds as colorless powder.

Melting point: 222-227oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 5

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 distilled in the doctrine stated in the title compound in crude form.

Reference example 6

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

To 4 ml of methanol was added the whole amount of the above crude 2-benzylamino-3,5,6-Cryptor-4-methylpyridine with 0.18 g of 10% palladium on coal and 2 ml of acetic acid and the mixture was first made at the 50oWith 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).

Reference example 7

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

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

Reference example 8

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

To 3 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-triterpenoid)acrylate obtained from 0,78 g of ethyl 3-chloro-2,4,5-tripersonality in the usual way, was added to 0.90 g of 2-amino-3,5-debtor-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 divided

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.

Reference example 9

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 dobar-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated under reflux with stirring for 3 hours, then gave it to cool and settle. To the precipitate was added to 10 ml of distilled water and the solution was concentrated under reduced pressure. Repeated 3 times procedure add 10 ml of ethanol and concentrating the solution under reduced pressure and to the residue was added 6 ml of chloroform and the mixture was heated under reflux with stirring for 1 hour, then allowed it to cool. The precipitate was collected by filtration and 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).

Example 7

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

To 280 mg of N, N-dimethylformamide was added 50 mg of 1-(6-amino-3,5-debtor-4-methylpyridin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-amino-setidentityproviderid and 120 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 1 hour. After adding 0.4 ml of ethanol, the mixture was allowed to cool. The precipitate was collected by filtration and prom is in the form of colorless powder.

Melting point: 243-245oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 10

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 and washed successively with ethanol and diisopropyl ether to obtain 1.10 g specified in the title compounds as colorless powder.

Melting point: 272-278oC.

1H NMR (d6-DMSO) ;

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

Reference example 11

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

To a mixed solution of 0.5 ml of 4 N. hydrochloric acid and 0.5 ml of acetic acid was added 235 mg of ethyl 1-[6-(tert-butyl is Hladilnika under stirring for 7 hours. After adding 1 ml of distilled water mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 182 mg specified in the title compounds as colorless powder.

Melting point: 280oC or higher.

1H NMR (d6-DMSO) ;

6.81 (CL, 2H), 8,04 (t, J= 9 Hz, 1H), 8,23 (m, 1H), 8,98 (s, 1H).

Example 8

Synthesis of 7-(3-aminoamides-1-yl)-1-(6-amino-3,5-debtor-pyridine-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-amino-setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 79 mg specified in the title compounds as colorless powder.

Melting point: 258-264oC (with 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).


To 270 mg of N, N-dimethylformamide was added 90 mg of 1-(6-amino-3,5-differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-amino-setidentityproviderid and 110 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 70 mg specified in the title compounds as colorless powder.

Melting point: 256-260oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 10

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-methyl-aminoethylethanolamine 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 and washed successively with ethanol and diiso">

Melting point: 238-245oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 11

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 and washed successively with ethanol and diisopropyl ether to obtain 107 mg specified in the title compounds as colorless powder.

Melting point: 241-245oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 12

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-diva acid, 100 mg of 3-(dimethylamino)setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 15 minutes. After adding 1 ml ethanol mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 87 mg specified in the title compounds as colorless powder.

Melting point: 283-287oC (with decomposition).

1H NMR (d6-DMSO) ;

2,07 (C, 6N), 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).

Example 13

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-methylpyrrolidone and the mixture was stirred at 90oC for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 42 mg specified in the title compounds as colorless powder.

Temperature is), 6.73 x (CL, 2H), 7,80 (d, J= 14 Hz, 1H), to 7.93 (t, J= 10 Hz, 1H), 8,56 (s, 1H).

Reference example 12

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, N-dimethylformamide and the mixture was stirred at 90oC for 25 minutes, then allowed it to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and gave him to settle. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and the result obtained 1.06 g specified in the title compounds as pale yellow powder.

Melting point: 210-213oC.

1H NMR (Dl3) ;

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 and washed successively with ethanol and diisopropyl ether to obtain 458 mg specified in the title compounds as pale yellow powder.

Melting point: 280oC or higher.

1H NMR (d6-DMSO) ;

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

Example 14

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

To 300 mg of N, N-dimethylformamide were added 100 mg of 1-(6-amino-3-chloro-5-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino-setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 30 minutes. After adding 0.3 m is isopropyl ether to obtain 95 mg specified in the title compounds as colorless powder.

Melting point: 268-270oC (with 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).

Example 15

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

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

Melting point: 277-280oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 14

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 alexbom, added 0,42 g 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, was added 2 ml of ethanol and gave him ostaetsya. The precipitate was collected by filtration, washed successively with ethanol and diisopropyl ether, and as a result received 0,48 g specified in the title compounds as pale yellow powder.

Melting point: 207-210oC.

1H NMR (Dl3) ;

of 1.37 (s, N), of 1.40 (t, J= 7 Hz, 3H), 4,50 (kV, J= 7 Hz, 2H), 4,82 (SHS, 1H), of 6.52 (DD, J= 3 Hz, 8 Hz, 1H), 7,25 (DD, J= 8 Hz, 10 Hz, 1H), 8,31 (DD, J= 8 Hz, 10 Hz, 1H), 8,61 (s, 1H).

Reference example 15

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 gewali 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).

Example 16

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-5-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino-setidentityproviderid and 80 mg N-methylpyrrolidone and the mixture was stirred at 90oC for 15 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 62 mg specified in the title compounds as colorless powder.

Melting point: 250-254oC (with 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 (fluoro-7-(3-methylaminomethyl-1-yl)-4-oxo-1,4-dihydropyridin-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 and washed successively with ethanol and diisopropyl ether to obtain 82 mg specified in the title compounds as colorless powder.

Melting point: 252-255oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 16

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, adding 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 the offer was stirred at 85oC for 15 minutes, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol and gave the mixture to settle in for the night. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 171 mg specified in the title compounds as colorless powder.

Melting point: 198-202oC.

1H NMR (Dl3) ;

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).

Reference example 17

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 solution gave the rising 145 mg specified in the title compound as pale brown powder.

Melting point: 279-284oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 18

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

To 250 mg N, N-dimethylformamide was added 80 mg of 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-setidentityproviderid and 120 mg of N-methylpyrrolidine and the mixture was stirred at 85oC for 45 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 72 mg specified in the title compounds as colorless powder.

Melting point: 256-258oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 19

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-individualised and 70 mg N-methylpyrrolidone and the mixture was stirred at 85oC for 45 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 20 mg indicated in the title compounds as colorless powder.

Melting point: 251-253oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 18

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. Of the reaction solution is kept off the solvent and to the residue was added 3 ml of N, N-dimethylformamide and 210 mg of potassium carbonate, after which the mixture was stirred at room temperature for 90 minutes and at 80oC for 2 hours. The reaction solution was extracted by adding water and ethyl acetate and the organic layer was collected and dried over sulfatrim ether to obtain 280 mg of the indicated in the title compounds as pale yellow powder.

Melting point: 245oWith or above (with decomposition).

1H NMR (CDCl3) ;

of 1.39 (s, N), 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).

Reference example 19

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-fluoro-pyridin-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 and washed successively with ethanol and diethyl ether to obtain 120 mg specified in the title compounds as pale yellow powder.

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

1H NMR (d6-DMSO) ;

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

Example 20

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

A solution of 40 mg of 3-aminoacetanilide and 80 mg of triethylamine in 300 mg of N, N-dimethylformamide was stirred at 90oAnd dobavljanje 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).

Reference example 20

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 triethyl-orthoformate 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 0oTo a solution of 2.7 g of 2-amino-6-(tert-butylamino)-3.5-diphereline in 20 ml of ethanol and the mixture was stirred at room temperature for 20 minutes. Of the reaction solution is kept off the solvent and the residue was plunged column chromatography on silica gel with receipt of the eluent (ethyl acetate: hexane, 1: 8) of 4.6 g of ethyl 2-(2,4,5-Cryptor-3-methylbenzoyl)-3-[6-(trail 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, N), 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).

Reference example 21

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

Melting point: 274-277oC.

1H NMR (d6-DMSO) ;

of 1.84 (s, 3H), 6,91 (CL, 2H), 8,03 (iridin-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 100oWith and was added 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).

Example 22

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

Specified in the title compound (20 mg) was obtained as pale yellow powder in the same way as described in example (65) 21, 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-setdma) ;

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

Example 23

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

Specified in the title compound (60 mg) was obtained as pale yellow powder in the same way as described in example (65) 21, 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 (d6-DMSO) ;

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

Example 24

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

To 200 mg of N, N-dimethylformamide was added 65 mg of 1-(6-amino-3,5-differencein-2-yl)-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 45 mg of 3-methylamino-setidentityproviderid and 100 mg N-methylpyrrolidine together with 3 drops of ethanol and the mixture was stirred at 85oC for 30 minutes. After adding 0.2 ml of ethanol see the new ether to obtain 52 mg specified in the title compounds as colorless powder.

Melting point: 262-268oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 25

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-hydroxy-apatityvodokanala and 100 mg N-methylpyrrolidine together with 3 drops of ethanol and the mixture was stirred at 85oC for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 101 mg specified in the title compounds as pale yellow powder.

Melting point: 215-220oC.

1H NMR (d6-DMSO) ;

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

Example 26

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

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

Melting point: 235-238oC.

1H NMR (d6-DMSO) ;

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

Example 27

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-hydroxy-apatityvodokanala and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol and the mixture was stirred at 85oC for 10 minutes. After adding 0.8 ml of ethanol, the mixture was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 90 mg specified in the header of the(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).

Reference example 22

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 adding 2 ml of ethanol solution was allowed to settle. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0,53 g specified in the title compounds as pale yellow powder.

The 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).

Reference example 23

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 ml 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 and washed successively with ethanol and diisopropyl ether to obtain 345 mg specified in the title compounds as colorless powder.

Melting point: 245-251oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 28

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

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

Melting point: 245-250oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Example 29

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-methylamino-setidentityproviderid and 200 mg N-methylpyrrolidone and the mixture was stirred at 85oC for 10 minutes. After adding 0.5 ml of the ethanol solution was allowed to cool and then the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 66 mg specified in the title compounds as colorless powder.

Melting point: 210-218oC (with decomposition).

1H NMR (d6-DMSO) ;

2,22 (s, 3H), of 3.48 (m, 1H), 4,12 (m, 2H), br4.61 (m, 2H), 6,74 (d, J= 10 Hz, 2H), for 6.81 (CL, 2H), to 7.59 (t, J= 10 Hz, 1H), 7,87 (d, J= 14 Hz, 1H), 8,68 (s, 1H).

Reference example 24

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-carboxyla the Il 3-chloro-2,4,5-tripersonality in the usual way, 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 adding 4 ml of ethanol solution was allowed to settle. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0.56 g specified in the title compounds as pale yellow powder.

Melting point: 168-171oC.

1H NMR (Dl3) ;

of 1.40 (t, J= 7 Hz, 3H), of 3.80 (s, 3H), and 4.40 (d, J= 7 Hz, 2H), 4,42 (kV, J= Hz, 2H), 5,46 (SHS, 1H), 6,83 (d, J= 9 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).

Reference example 25

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

Melting point: 185-189oC.

1H NMR (Dl3) ;

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).

Reference example 26

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

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

To 280 mg of N, N-dimethylformamide was added 90 mg of 1-(6-amino-5-chloro-3-herperidin-2-yl)-8-chloro-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino-setidentityproviderid 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 and washed successively with ethanol and diisopropyl ether to obtain 50 mg specified in the title compounds as colorless powder.

Melting point: 240-245oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 27

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 90oIn taceai water and the chloroform layer was washed twice with 400 ml of distilled water, was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to settle. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 620 mg specified in the title compounds as pale yellow powder.

Melting point: 206-209oC.

1H NMR (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).

Reference example 28

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

To 3 ml of a mixed solution (1: 1, about. /about. ) 4 N. hydrochloric acid and acetic acid was added 300 mg of ethyl 8-chloro-6,7-debtor-(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 and washed successively with ethanol and diisopropyl ether to obtain 265 mg specified in the title compound as a yellow powder.

Melting point: 226-230oC.

1H NMR (d6-DMSO) ;

of 1.10 (d, J= 7 Hz, 3H) the ez 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-carboxylic acid, 35 mg of 3-aminoacetanilide and 120 mg of N-methylpyrrolidine and the mixture was stirred at 80oC for 30 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 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).

Reference example 29

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 did not disappear ethylacrylate spot. The solution was concentrated under reduced pressure. To the residue was added 4.3 g of betwedn what about gave it to cool. The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water and the chloroform layer was washed twice with 1 liter of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 6,15 g specified in the title compounds as colorless 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).

Reference example 30

Synthesis of ethyl 1-(6-amino-3,5-differencein-2-yl)-5,6,7,8-titrator-4-oxo-l, 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-dihydro-quinoline-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, the FDS is orosco.

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).

Reference example 31

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

To 2 ml of a mixed solution (1: 1) 4 N. hydrochloric acid and acetic acid was added 320 mg of ethyl 1-(6-amino-3,5-differencein-2-yl] -5,6,7,8-titrator-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated under reflux for 3 hours with stirring, then allowed to cool. The precipitate was collected by filtration and washed with ethanol to obtain 280 mg of the indicated in the title compounds as colorless powder.

Melting point: 236-242oC.

1H NMR (d6-DMSO) ;

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

Example 32

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

To 300 mg of N, N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-differencein-2-yl)-5,6,7,8-titrator-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-amino-setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture peremeshivaniem and washed successively with ethanol and diisopropyl ether to obtain 50 mg specified in the title compounds as pale yellow powder.

Melting point: 264-271oC (with decomposition).

1H NMR (d6-DMSO) ;

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

Reference example 32

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 adding 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 and washed with ethanol to obtain 1.20 g specified in the title compound as a yellow powder.

Melting point: 146-148oC.

1H NMR (CDCl3) ;

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

Reference example 33

The synthesis of the g ethyl 5-benzylamino-1-[3,5-debtor-6-(p-methoxybenzylamine)pyridine-2-yl] -6,7,8-Cryptor-4-oxo-1,4-dihydro-quinoline-3-carboxylate was added 2 ml triperoxonane acid and the mixture was allowed to stand at room temperature for 20 minutes. The solution was concentrated under reduced pressure and to the residue was added 3 ml of ethanol, after which he again concentrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed with ethanol to obtain 530 mg specified in the title compound as a yellow powder.

Melting point: 176-180oC.

1H NMR (Dl3) ;

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, 6N), 8,21 (s, 1H).

Reference example 34

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 and washed successively with ethanol and diisopropyl ether melting point: 225-230oC.

1H NMR (Dl3) ;

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).

Reference example 35

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-dihydro-quinoline-3-carboxylate and the mixture was heated under reflux for 17 hours with stirring and then allowed to cool. The precipitate was collected by filtration and washed with ethanol to obtain 129 mg specified in the title compound as a yellow powder.

1H NMR (d6-DMSO) ;

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

Example 33

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-amino-setidentityproviderid and 150 mg of N-methylpyrrolidine and the mixture was stirred at 90oC for 1 hour and to the th ether, mixing and decanting. To the residue was added 2 ml of ethanol and 40 ml of N-methylpyrrolidine, the mixture was allowed to stand overnight and the precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 26 mg specified in the title compounds as pale yellow powder.

Melting point: 205-210oC (with 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).

Reference example 36

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-butyl-aminopyridine. 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 prom who has demonstrated under reduced pressure. The precipitate was dispersible in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 3.13 g specified in the title compounds as pale yellow powder.

Melting point: 215-217oC.

1H NMR (CDCl3) ;

of 1.37 (t, J= 7 Hz, 3H), 1.39 in (C, N), 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).

Reference example 37

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 the title compound as a yellow powder.

Melting point: 280oC or higher.

1H NMR (d6-DMSO) ;

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

Example 34

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-aminoamides-dihydrochloride and 200 mg N-methylpyrrolidone and the mixture was stirred at 100oC for 30 minutes and concentrated under reduced pressure. After adding 2 ml of ethanol and the mixture was stirred and the precipitate was collected by filtration and 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).

Reference example 38

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

To 3 ml of a chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-triterpenoid)acrylate obtained from 0.84 g of ethyl 3-chloro-2,4,5-tripersonal under reduced pressure and to the residue was added 0.65 g of anhydrous potassium carbonate and 1.5 ml of N, N-dimethylformamide and the mixture was stirred at 90oC for 1 hour, then allowed it to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water and the chloroform layer was washed two times with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0.45 g specified in the title compounds as pale yellow powder.

Melting point: 178-180oC.

1H NMR (CDCl3) ;

of 0.96 (s, N), of 1.41 (m, N), or 1.77 (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).

Reference example 39

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

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

1H NMR (d6-DMSO) ;

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

Example 35

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-aminoamides-dihydrochloride and 100 mg N-methylpyrrolidone and the mixture was stirred at 90oC for 30 minutes. After adding 0.2 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 40 mg indicated in the title compounds as colorless powder.

Melting point: 250-255oC (with 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).

Example 36

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

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

Melting point: 204-213oC.

1H NMR (d6-DMSO) ;

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

Example 37

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 adding 5 ml of diethyl ether mixture was allowed to stand for 1 hour and then decantation. Was added to a mixture of 2 ml of ethanol and stirred it. The precipitate was collected by filtration and washed successively with ethanol and diethyl ether to obtain 64 mg of yzlozhenye).

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(9) 1, (10) 2, (12) 4 and (39)8 was evaluated by the minimum dose (concentration), inhibiting the growth of bacteria (MIC, μg/ml), the standard method of the Japanese chemotherapeutic society (Japan Chemotherapy Society) (Chemotherapy 29 (1), 76, 1981) using standard strains (S. aureus 209P, S. epidermidis IFO12293, 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 (MIC, μg/ml) for comparison purposes. The results are also shown in table 1.

The results, shown in table 1, show that the compounds of the present invention have excellent antibacterial activities superior to those possessed by conventional bacterial funds.

(2) Test for phototoxicity

Compounds of the above examples(9) 1, (10) 2, (12) 4 and (39) 8 was tested for toxicity following method.

Sa is a 1.8 mW/cm2/C) 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 the present invention have very low toxicity.

1. Derived pyridonecarboxylic acid represented by the following formula or its salt:

< / BR>
2. Derived pyridonecarboxylic acid or its salt under item 1 as an antibacterial agent.

 

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