New derivatives of spiridonovich carboxylic acids, method and intermediates for their production, pharmaceutical composition and method of treatment of infectious diseases

 

(57) Abstract:

Describes the new derivatives of Spiridonova carboxylic acids, their pharmaceutically acceptable salts and physiologically hydrolyzable esters which are represented by formula I, in which R1represents lower alkyl, C3- C6-cycloalkyl or substituted or unsubstituted phenyl group, R2represents a hydrogen atom or a lower alkyl or amino group, And a represents a nitrogen atom or a group-X in which X represents a hydrogen atom or halogen or alkoxygroup, and Z represents a group having formula II, where n = 1 or 2, R3and R4each represents a hydrogen atom or a group of lower alkyl, provided that when n = 2, then one of R3and R4represents a hydrogen atom, R5and R6each represents a hydrogen atom, or a hydroxy-group of lower alkyl, or amino group which is substituted or unsubstituted group of lower alkyl, provided that one of R5and R6represents a hydrogen atom, and that if n = 1 and one of R5and R6represents the amino group, one of R3and R4is not a hydrogen atom, and R7

< / BR>

The present invention relates to new derivatives Spiridonovich carboxylic acids, their pharmaceutically acceptable salts and physiologically hydrolyzable their esters and process for their preparation. The present invention relates also to pharmaceutical compositions containing one or more than one new derived Spiridonovich carboxylic acid as an active component and a method of treatment of bacterial infections, including the introduction of these compounds.

BACKGROUND OF THE INVENTION

Was developed a number of quinolone compounds and proved their success in trade due to the strong action and broad spectrum antibacterial properties. Among other such quinolone compounds included: norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc., In recent years there has been vigorous research to develop new patterns derived Spiridonovich carboxylic acids, which were more potent and would have greater antibacterial activity. The majority of such research is the firmness of the links, which reveal such derivatives may be mentioned U.S. patent 4,988,709, European patent 0 413 455 and Japanese Examined Patent Publication 89 - 56, 673.

DISCLOSURE OF THE INVENTION

The present invention provides a new derivative of Spiridonova carboxylic acid represented by the following formula:

< / BR>
in which R1represents lower alkyl, halogen, substituted lower alkyl, lower alkenyl, cycloalkyl or substituted or unsubstituted phenyl group; R2represents a hydrogen atom or a lower alkyl or amino group; A represents a nitrogen atom or the group C-X, where X represents a hydrogen atom or halogen, or alkoxygroup; Z represents a group having the formula:

< / BR>
where n = 1 or 2; R3and R4each represent a hydrogen atom or a group of lower alkyl, provided that when n = 2, then one of R3and R4represents a hydrogen atom; R5and R6each represents a hydrogen atom or lower alkyl, hydroxy or amino group, a substituted or unsubstituted group of lower alkyl, provided that when one of R5and R6represents a hydrogen atom and when n = 1 and one of R5and R6represent the Wallpaper hydrogen atom or a group of the lower alkyl; and their pharmaceutically acceptable salt or physiologically hydrolyzable esters.

The term "halogen" as used here includes chlorine, bromine and iodine. The term "lower alkyl" may include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and so on, the Term "lower alkenyl" may include, for example, vinyl, allyl, 1-propenyl and Isopropenyl. The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Deputy phenyl groups may include, for example, halogen atom and lower alkyl, lower alkoxy, halogenized alkyl, hydroxy and amino group. The term "alkoxy" includes, for example, methoxy, propoxy or butoxy group.

The compounds of formula (I) can be classified as two groups, depending on the integer value n.

The compounds of the first group are those compounds in which n = 1 and which can be represented by the following formula:

< / BR>
where R1, R2, R3, R4, R5, R6, R7and A have the meanings defined above.

Especially preferred compounds belonging to the first group and having the formula (Ia) are compounds carried away robonova acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

5-amino-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] -heptane-3 - yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1-(2,4-differenl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-6,8-debtor-5-methyl-1,4-dihydro-4-oxoindole-3 - carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-8 - chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1- (2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3 - carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-6 - fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-t - butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl - 3-azabicyclo[3.2.0] heptane-3-yl)-1- (2,4-debtor the CLO[3.2.0] heptane-3-yl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(+)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6,8-debtor-7-( [1,5,6] -hydroxy-1-methyl-3-azabicyclo [3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-( [1,5,6] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0]heptane-3-yl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 1-cyclopropyl-6,8-debtor-5-methyl-1,4-dihydro-4-oxoindole-3 - carboxylic acid;

(-)-5-amino-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] - heptane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3 - carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 1-t-butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3 - yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3 - carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3 - carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]jazabella[3.2.0] heptane-3-yl)-6,8-debtor-1-cyclopropyl-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 6-fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3 - carboxylic acid;

8-chloro-1-cyclopropyl-7-( [1,5,6] -6-amino-5-methyl-3-azabicyclo [3.2.0]heptane-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

7-( [1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

1-(2,4-differenl)-7-( [1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 1-(2,4-differenl)-1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthiridine - 3-carboxylic acid;

1-cyclopropyl-7-( [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0] heptane-3 - yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

5-amino-1-cyclopropyl-7-( [1,5,6]/ -6-hydroxy-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

1-cyclopropyl-7-( [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0] heptane-3 - yl)-6,8-debtor-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid;

1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)- 6,8-debtor-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid;

1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] hepta is yclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

1-cyclopropyl-7-( [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0] heptane-3 - yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1,4-dihydro - 6-fluoro-1-(4-forfinal)-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-8-chloro-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthiridine-3 - carboxylic acid;

(-)-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1-(t-butyl)- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl - 1,4-dihydro-6-fluoro-5-methyl-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3-the-1,8-naphthiridine-3 - carboxylic acid;

8-chloro-1-cyclopropyl-6-fluoro-7-( [1,5,6] -1-methyl-6-methylamino-3 - azabicyclo[3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6,8-debtor-7-( [1,5,6] -1-methyl-6-methylamino-3 - azabicyclo[3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-( [1,5,6] -1-methyl-6-methylamino-3-azabicyclo [3.2.0]heptane-3-yl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1-cyclopropyl - 6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid.

Compounds of the second group are those compounds where n = 2 and which have the following formula:

< / BR>
where R1, R2, R3, R4, R5, R6, R7and A have the meanings defined above.

Especially preferred compounds belonging to the second group and having the formula (lb) are the compounds listed below:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-4-oxo-1,8-n is 8-naphthiridine-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl - 6,8-debtor-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-4-yl)-8-chloro-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-4-yl)-5-amino-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0)octane-3-yl)-5-methyl-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-6-fluoro-1 - tert-butyl-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4. 2.0]Octan-3-yl)-8-chloro-6-fluoro - 5-methyl-1-cyclopropyl-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1-cyclopropyl-5 - methyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(+)-7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-( [1,6,8] -8-amino-3-amino-3-azabicyclo[4.2.0] octane-3-yl)-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl - 6-fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-( [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0]octane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid (hydrochloride);

7-( [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0]octane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, hydrochloride; and

7-( [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0]octane-3-yl)-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The compounds of formula I can be converted into their pharmaceutically acceptable, non-toxic salts according to conventional methods. In a non-toxic salt included salts of inorganic acids, such as hydrochloride, sulphates, phosphates and so on; organic acid salts such as acetates, privacy, oxalates, succinate, methanesulfonate, maleate, malonate, gluconate, etc.; salts of acidic amino acids such as aspartic acid, glutamic acid and so forth; metal salts, such as salts of sodium, potassium, calcium, magnesium, zinc, silver and etc.; salts of organic bases, for example salts of dimethylamine, triethylamine, dicyclohexylamine, benzylamine and so on; and salts of basic Minnie esters, which can physiologically hydrolyzed or easily converted into the compounds of formula I. Typical example includes esters of lower alkyl, such as methyl ether, ethyl ether and so on; acetoxymethyl ether, pivaloyloxymethyl ether, ethoxycarbonylethyl ether, kalinovy ether, aminoacylase esters such as 1-piperidinyloxy ether, dimethylaminoethyl ether and so on; 5-individuly ether or caliginosus ether, etc.

Compounds of the present invention can be obtained in the form of hydrates using well-known methods. Thus, it is necessary to understand that such hydrates fall within the boundaries of the present invention.

In addition, the compounds of the present invention can exist in the form of optical isomers due to the presence of an asymmetric carbon atom in position 7. The present invention covers such optically active compounds of formula I.

Another aspect of the present invention is the provision of a process of obtaining new compounds of the formula I, which contains the following stages:

the interaction of the compounds of formula

< / BR>
in which R1represents lower alkyl; lower alkyl substituted Galaga a hydrogen atom, or lower alkyl, or amino group; A represents a nitrogen atom or the group C-X, where X represents a hydrogen atom or halogen, or alkoxygroup; Y represents a halogen atom, R7represents a hydrogen atom or a group of the lower alkyl; with a compound of the formula

Z IS H, (III)

where Z represents a group having the formula:

< / BR>
where n = 1 or 2; R3and R4each represent a hydrogen atom or a group of lower alkyl, provided that when n = 2, then one of R3and R4represents a hydrogen atom; R5and R6each represents a hydrogen atom or lower alkoxy, hydroxy or amino group, a substituted or unsubstituted group of lower alkyl, provided that one of R5and R6represents a hydrogen atom; and

if necessary, gidrolizu compound of formula I, in which R7represents a group of the lower alkyl.

The interaction of the parent compounds of formulas (II) and (III) is preferably carried out in the presence of an inert organic solvent, for example alcohols, such as ethanol; ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane; aromatic hydrocarbons, such as beastlet at a temperature of from 0 to 200oC for a time from 10 minutes to 24 hours.

The compounds of formula (III) can be used in equivalent amounts or in excess of the compounds of formula (II) in the presence of an acid receptor. In this reaction, the compounds of formula (II) can play the role of this receptor. Thus, if a compound of the formula (III) is used in an excessive amount, the additional application of acid receptor is not necessary.

Acid receptors, which can be used in this invention are known. Among them are such acid receptors, as hydroxides, for example sodium hydroxide or potassium hydroxide; carbonates such as sodium carbonate or potassium; bicarbonates such as sodium bicarbonate or potassium hydroxide; or an organic base such as triethylamine, dimethylamine, N,N-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In this reaction, the starting compound (III) can be used such as they are, or protected amino group in position 1. This group should be easily removed upon completion of the reaction using known methods and not have negative impacts on the resulting connection. Such protected groups are well known in the chemistry of acetyl, TRIFLUOROACETYL or etoxycarbonyl, or benzyl group, etc.

The compounds of formula (II) can be obtained according to known in this field techniques. They are described in J. Med. Chem. 1988, 31, p.503; J. Org. Chem, 1981, 46, p. 846; European patent 0 132 845(1985); U.S. Patent 4,826,987 (1987); European patent 0 271 275(1987); Japanese patent (Hel) 01-268,662; Japanese patent (Sho) 64-16,746; J. Heterocyclic Chem, 1990, 27, p.1609; J. Heterocyclic Chem. 1991, 28, p.541.

The compounds of formula (III) used in the present invention are new and can learn some known methods. For example, 6-amino-1-methyl-3-azabicyclo [3.2.0]heptane can be obtained according to the reaction scheme A.

In the above reaction scheme for the N-p-toluensulfonyl-1-methyl-6-oxo-3-azabicyclo[3.2.0]heptane condense with methoxyamine or hydrochloride hydroxyamine in the presence of a base, while receiving the connection methoxyimino or hydroxyimino formula (V). The parent compound is known in this area, see Heterocycles (1989), 25, p. 29. The compound obtained is then restored using a suitable reductive agent to get aminosidine formula (VI). When removing the protection that aminosidine in the presence of acid gives [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane of the formula (VII) in racemic forms.

Scheme B illustrates the reactions, including the above-described optical separation.

Meanwhile, [1,5,6] -6-hydroxy-1-methyl-3-azabicyclo[3.2.0]heptane of the formula (XI) can be obtained according to a known method described in reaction scheme C, in which N-p-toluensulfonyl-1-methyl-6-oxo-3 - azabicyclo[3.2.0] heptane restore recovery agent, receiving an alcohol compound of the formula (X), which is subsequently subjected to conventional acid hydrolysis.

[1,6,8] -8-amino-3-azabicyclo[4.2.0]octane can be obtained also by a method similar to that shown in reaction scheme A. More precisely, N-p-toluensulfonyl-8-oxo-3-azabicyclo[4.2.0] octane condense with methoxyamine or hydrochloride hydroxyamine in the presence of a base, while receiving the corresponding connection methoxyimino or hydroxyimino. The original connection is known, see Heterocycles (1989), 25, p. 29. The compound obtained is then restored using a suitable restore the t [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane in racemic forms.

The resulting aminosidine in racemic form can also be divided into optical isomers, using the same procedure as in reaction scheme B.

The compounds of formula (I) obtained in the form of esters can also be converted into the corresponding free acid, gidrolizu essential fragment according to known methods. If necessary, the compounds of formula (I) in the form of free acid can be converted into the corresponding esters by standard methods.

The resulting compounds according to the present invention is isolated and purified by methods well-known in this field. Depending on the conditions of isolation and purification of the compounds of formula (I) can be obtained or in salt form or in the form of the free acid. These two forms of the compounds can be converted from one to another according to conventional methods.

The compounds of formula (I), as well as their non-toxic salts and physiologically hydrolyzable esters which are useful as antibiotics for the treatment of infectious diseases in mammals, caused by bacteria. The compounds of formula (I) can also be used for treatment of diseases of fish and plants, or as conservatee human diseases, the dosage depends on various factors, such as age and weight of the individual patient in need of such treatment, the severity of the disease and the route of administration of the drug. However, the preferred dose, which may be a single dose or multidose, ranges from 5 mg to 5 g per 1 kg of body weight per day. Compounds of the present invention can be introduced orally, or parenterally.

The present invention also provides a pharmaceutical composition which contains as an active ingredient one or more compounds of the formula (I), or pharmaceutically acceptable salt or physiologically hydrolyzable esters in the mixture or compounds with pharmaceutically acceptable carriers, which do not interact with the active ingredient. The pharmaceutical composition according to the present invention can be in various forms, such as tablets, solutions for oral administration, or injections, capsules, granules, microgranules, powders, syrups, ointments, etc.

Pharmaceutically acceptable carrier, which can be used in the present invention, well-known in this field. As a carrier for oral administration can billcat, for example, water, physiological saline, glucose solution, the SAP of plants and the like.

THE BEST WAY TO IMPLEMENT THE PRESENT INVENTION

The present invention will be described in more detail using the following examples. These examples are for illustration only and should not be construed as limiting the present invention, which are precisely defined in the patent claims.

The drug 1:

[1,5,6] -6-methoxyimino-1-methyl-3-(p-toluensulfonyl)-3-azabicyclo [3.2.0] heptane

A mixture of 40.0 g [1,5] -1-methyl-6-oxo-3-(p-toluensulfonyl)-3 - azabicyclo[3.2.0-]heptane, 14.35 g of the hydrochloride methoxyamine and 400 ml of pyridine was stirred for 2 hours at room temperature. The resulting mixture is evaporated under high pressure. The residue was dissolved in 500 ml of ethyl acetate. The resulting solution was washed twice with 200 ml of 5% aqueous hydrochloric acid solution and once with 200 ml of saturated solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Resulting solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure to obtain 43.0 g of compound representing the product 1 in the form (3H, s), 1.3 (3H, s).

Drug 2:

[1,5,6] -6-amino-1-methyl-3-(p-toluensulfonyl)-3-azabicyclo [3.2.0] heptane

To a suspension of 27.0 g of NaBH4in 150 ml of tetrahydrofuran (THF) solution was added 55.0 ml triperoxonane acid (TFA) in 150 ml of THF for 2 hours at room temperature. Separately in 200 ml of THF was dissolved 43.0 g of compound representing the product 1. Resulting solution is then added for 2 hours at room temperature to a solution prepared above. The reaction mixture was stirred for 3 hours at room temperature, and then added 50 ml of water and 30 ml of 40% aqueous sodium hydroxide solution. The mixture was heated at reflux distilled for 5 hours. The resulting solution is evaporated at an elevated pressure to remove THF, and was extracted 3 times with 200 ml dichloromethane. The organic layer was washed with 200 ml saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The resulting solids were filtered at high pressure. The filtrate is evaporated under high pressure, to obtain 39.0 g of compound representing the product 2, in the form of a yellowish-brown oil (yield 98%)

1H-NMR is tan

A mixture of 5.0 g of compound representing the drug 2, and 30 ml of aqueous 48% Hydrobromic acid was heated for 5 hours at reflux distilled. The reaction solution is evaporated at an elevated pressure. The residue was dissolved in 5 ml of water and thereto was added 3 ml of 40% aqueous sodium hydroxide solution. The mixture was extracted with three times 100 ml of chloroform. The organic layer was dried with anhydrous sodium sulfate. Obtained in the solid particles were filtered at high pressure. The filtrate is evaporated at an elevated pressure to obtain 1.8 g of compound representing the product 3 as a pale-yellow oil (yield 80%)

1H-NMR(CDCl3) : 3.5-2.5 (10H, m), 1.3-1.1 (1H, m), 1.26 (3H, s).

Preparation 4:

[1,5,6] -6-hydroxy-1-methyl-3-(p-toluensulfonyl)-3-azabicyclo [3.2.0]heptane

To a solution of 2.00 g [1,5,6] -6-oxo-3- (p-toluensulfonyl)-3 - azabicyclo[3.2.0] heptane in 30 ml of ethanol was added 0.19 g of NaBH4. The resulting mixture was stirred for 1 hour at room temperature and evaporated under high pressure. The residue was dissolved in 20 ml of water, acidified with an aqueous solution of 5% hydrochloric acid, and then stirred for 1 hour at room temperature. The resulting solid particles with the tion, representing the product 4, in the form of a pale-yellow solid (yield 91%)

1H-NMR (CDCl3) : 7.6-7.1 (4H,m ), 4.3-3.9(1H, m), 3.7-1.8 (8H, m), 2.36 (3H, s), 1.13 (3H, s).

Preparation 5:

[1,5,6] -6-hydroxy-1-methyl-3-azabicyclo[3.2.0]heptane

A mixture of 1.50 g of compound representing the product 4, and 20 ml of 48% aqueous Hydrobromic acid was heated for 5 hours at reflux distilled and evaporated under high pressure. To the residue was added 5 ml of water and 3 ml of 40% aqueous sodium hydroxide solution. The resulting mixture was extracted with three times 50 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate. Resulting solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure to obtain 0.54 g of compound representing the product 5 as a pale-yellow oil (yield 80%)

1H-NMR (CDCl3) : 4.5-3.9 (1H, m), 3.6-1.7 (9H,m), 1.2 (3H,s).

Preparation 6:

(-)[1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane and (+)[1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane

(1) To a solution of 1.20 g [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane and 1.51 g of N-(p-toluensulfonyl)-L-phenylalanine in 30 ml of dimethylformamide was added 0.78 ml of diethylthiophosphate and 1.20 ml tree is racette, washed twice with 100 ml of 5% aqueous hydrochloric acid solution and once with 100 ml of saturated solution of acid sodium carbonate, and then dried over anhydrous magnesium sulfate. After filtering off solids under high pressure, the filtrate is evaporated at an elevated pressure. To the residue was added 20 ml of ethanol. The resulting solution was stirred for one hour at room temperature and was filtered at high pressure, to obtain 0.67 g of solid particles of white. The filtrate is evaporated at an elevated pressure and after chromatography using silica gel received 1.00 g of a colorless oil.

(2) a Solution of 0.67 g of colorless solid particles from the above section (I) in 20 ml of 48% aqueous Hydrobromic acid was heated at reflux distilled for 8 hours and evaporated at high pressure. The residue was dissolved in 5 ml of water. To this solution was added 2 ml of 40% aqueous sodium hydroxide solution. The resulting mixture was extracted three times with 30 ml of chloroform. The organic layers were combined together and dried over anhydrous sodium sulfate. The solids were filtered at high pressure. The filtrate is boiled away at high pressure of polv>D
0-15.2o(C=1.0, MeOH),

1H-NMR (CDCl3) : 3.5-2.5 (10H,m), 1.3-1.1 (1H,m), 1.26 (3H,s).

(3) a Solution of 1.00 g of oil from paragraph (1) above and 20 ml of 48% aqueous Hydrobromic acid was processed as described in the above item (2), to obtain(+)-[1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane in the form of a pale-yellow oil (yield 70%)

[]2D0+15.0o(C=1.0, MeOH)

1H-NMR (CDCl3) : 3.5-2.5 (10H,m), 1.3-1.1 (1H,m), 1.26 (3H,s).

Preparation 7:

[1,5,6] -6-methoxyimino-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0] heptane

A mixture of 35.5 g [1,5,6] -6-oxo-3-(p-toluensulfonyl)-3-azabicyclo [3.2.0] heptane, 15.0 g of the hydrochloride methoxyamine and 500 ml of pyridine was stirred for 3 hours at room temperature and evaporated under high pressure. The residue was dissolved in 500 ml ethyl acetate, washed twice with 200 ml of 5% aqueous hydrochloric acid solution and once with 200 ml of saturated solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The resulting solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure, receiving 39.0 g of compound representing the drug 7, in the form of yellowish-brown mA is Rath 8:

[1,5,6] -6-amino-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0]heptane

To a suspension of 20.0 g of NaBH4in THF was added 37.0 ml triperoxonane acid (TFA) in 200 ml of THF for 3 hours at room temperature. To this mixture for 2 hours at room temperature was added 25.0 g of compound representing the product 7 in 200 ml of THF. Then, after adding 50 ml of water and 50 ml of aqueous 40% sodium hydroxide solution the mixture was heated for 5 hours at reflux distilled. The resulting solution is evaporated at an elevated pressure to remove THF and was extracted three times with 200 ml dichloromethane. The organic layer was washed with 200 ml saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The resulting solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure, receiving 21.5 g of compound indicated in the title, in the form of a yellowish-brown oil (yield 95%)

1H-NMR (CDCl3) : 7.7-7.2 (4H,m), 3.5-2.0 (11H,m), 2.35 (3H,s).

Preparation 9:

[1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane

A mixture of 7.0 g of compound representing the drug is 8, and 50 ml of 48% aqueous Hydrobromic acid was heated for 5 hours pritnogo of sodium hydroxide solution. The mixture was extracted with three times 100 ml of chloroform. The organic layer was dried with anhydrous sodium sulfate. The solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure, receiving 2.1 g of compound indicated in the title, in the form of a pale yellow oil (yield 71.3%).

1H-NMR (CDCl3) : 3.5-2.4 (11H,m), 1.3-1.1 (1H,m).

Preparation 10:

[1,5,6] -6-hydroxy-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0]heptane

Was repeated by the same method as in the section "Preparation 4, except for using 1.90 g [1,5,6] -6-oxo-3-(p-toluensulfonyl)- azabicyclo[3.2.0] heptane instead of [1,5,6] -1-methyl-6-oxo-3-(p - toluensulfonyl)-3-azabicyclo[3.2.0] -heptane to obtain 1.76 g of compound indicated in the title (yield 92%)

1H-NMR (CDCl3) : 7.7-7.2 (4H,m), 4.3-3.8 (1H,m), 3.6-1.8 (9H,s), 2.4 (3H, s).

Preparation 11:

[1,5,6] -6-hydroxy-3-azabicyclo[3.2.0]heptane

To obtain 0.54 g of compound indicated in the title, was repeated the same procedure as for obtaining preparation 5 using 1.43 g of compound representing the drug 10. Output 90%.

1H-NMR (CDCl3) : 4.5-4.0 (1H, m), 3.6-1.6 (10H, m).

Preparation 12:

[1,5, a] -6-methoxyimino-5-methyl-3-(p-toluensulfonyl.2.0] heptane, 7.4 g of the hydrochloride methoxyamine and 300 ml of pyridine was stirred for 3 hours at room temperature. The reaction mixture was treated in the same way as when receiving the drug 7. Received 18.9 g of compound indicated in the title, in the form of a yellowish-brown oil (yield 85.6%)

1H-NMR (CDCl3) : 7.8-4.2 (4H,m), 3.85 (3H,s), 4.0 - 2.5 (7H,m), 2.45 (3H,s), 1.3 (3H,s).

Preparation 13:

[1,5,6] -6-amino-5-methyl-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0] heptane

To obtain 14.6 g of compound indicated in the title, repeated the same technique was used to obtain a preparation 8, using 18.9 g of compound obtained in the previous section (yield 85%).

1H-NMR (CDCl3) : 7.8-7.2 (4H,m), 3.5-2.1 (10H,m), 2.4 (3H,s), 1.35 (3H, s).

Preparation 14:

[1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0]heptane

To obtain 3.3 g of compound indicated in the title, was repeated the same procedure as for the preparation of 9, was used 11.0 g of compound indicated in the title of the previous section. Yield 67%.

1H-NMR (CDCl3) : 3.7-7.2 (10H,m), 1.5-1.5 (1H,m), 1.3 (3H,s).

Preparation 15:

(-)[1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane, and(+)-[1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane

(1) To a solution of 1.15 g [1,5,6] -6-amino-5-methyl-3A was added 0.78 ml diethylthiophosphate and 1.20 ml of triethylamine. The mixture was stirred for 5 hours at room temperature. The reaction mixture was diluted with 200 ml ethyl acetate and washed twice with 100 ml of 5% aqueous hydrochloric acid, twice with 100 ml of water and once with 100 ml saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Once at high pressure filtered solids, the filtrate is evaporated at an elevated pressure. To the residue was added 20 ml of ethanol. The resulting solution was stirred for 1 hour at room temperature and then filtered at high pressure; was thus obtained 0.67 g of solid particles of white. The filtrate is evaporated at an elevated pressure and subjected to chromatography over silica gel, received 1.00 g of a colorless oil.

(2) a Solution of 0.67 g of a white solid substance of the above paragraph (1) in 20 ml of 48% aqueous Hydrobromic acid was heated for 8 hours at reflux distilled, and then evaporated under high pressure. The residue was dissolved in 5 ml of water to which was added 2 ml of 40% aqueous sodium hydroxide solution. The resulting mixture was extracted three times with 30 ml of chloroform. The organic layers were combined and dried over water sulfate Natrii was obtained 0.13 g (-)[1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane in the form of a pale-yellow oil (yield 48%)

[]2D0-14.0o(C=170, MeOH),

1H-NMR (CDCl3) : 3.5-1.5 (12H,m).

(3) a Solution of 1.00 g of the oil obtained above in paragraph (1), and 20 ml of 48% aqueous Hydrobromic acid was treated in the same way as it was done in (2) to obtain 0.19 g(+)-[1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane in the form of a pale-yellow oil (yield 70%)

[]2D0+13.8o(C=1.0, MeOH).

1H-NMR (CDCl3) : 3.48-1.52 (12H,m).

Preparation 16:

[1,5,6] -1-methyl-6-(phthalimido-1-yl)-3-(p-toluensulfonyl)-3 - azabicyclo[3.2.0]heptane

To a solution of 7.00 g [1,5,6] -6-hydroxy-1-methyl-3- (p-toluensulfonyl)-3-azabicyclo[3.2.0] heptane, 7.35 g of phthalimide and 13.09 g of triphenylphosphine in 70 ml of THF was added 8.67 g of diethylazodicarboxylate. The resulting solution was stirred at room temperature for 1 hour. Resulting solids collected on the filter, and then dried. The result was 3.50 g of compound indicated in the title, in the form of a pale-yellow solid (yield 34%). Melting point 180-184oC

1H-NMR (CDCl3) : 7.9-7.6 (6H,m), 7.35 (2H, d, J=at 8.62 Hz), 4.7-4.3 (1H, m), 3.6 to 2.3 (7H,m), 2.45 (3H,s), 1.38 (3H,s).

Preparation 17:

[1,5,6] -6-amino-1-methyl-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0] heptane

RA and 40 ml of methanol was heated for 3 hours at reflux distilled, and then cooled to room temperature. Resulting solids were filtered. The filtrate is evaporated at an elevated pressure. To the residue was added 30 ml of ethyl acetate and stirred the mixture for 30 minutes at room temperature. The obtained solids were filtered. The filtrate is evaporated at an elevated pressure to obtain 0.45 g of compound indicated in the title, in the form of a pale-yellow oil (yield 95%). The melting temperature of 70-74oC.

1H-NMR (CDCl3) : 7.7-7.6 (4H,m), 3.4-2.0 (10H,m), 2.3 (3H,s), 1.3 (3H, s).

Preparation 18:

[1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane

A solution of 0.45 g [1,5,6] -6-amino-1-methyl-3-(p-toluensulfonyl)- 3-azabicyclo[3.2.0]heptane and 10 ml of 48% aqueous Hydrobromic acid was heated at reflux distilled for 3 hours. The resulting solution is evaporated at an elevated pressure. The residue was dissolved in 5 ml of water, to which was added 1 ml of 40% aqueous sodium hydroxide solution. The reaction mixture was extracted with three times 20 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under high pressure. Obtained 0.19 g of compound indicated in the title, in the form of a colorless oil (yield 95%)

1H-NMR (CDClwhat were radioactive)-3 - azabicyclo[3.2.0]heptane

To a solution of 4.53 g [1,5,6] -6-amino-1-methyl-3-(p - toluensulfonyl)-3-azabicyclo[3.2.0] heptane, 2.46 g of triethylamine and 20 ml of dichloromethane, cooled to 0oC, was added dropwise 1.93 g charitycardonate. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 50 ml dichloromethane and washed twice with 30 ml of 5% aqueous hydrochloric acid and once with 30 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated under high pressure. The residue was subjected to chromatography over silica gel, there was obtained 2.8 g of compound indicated in the title, in the form of a colorless oil (yield 49%)

1H-NMR (CDCl3) : 7.8-7.3 (4H,m), 5.4 (1H, d, J=9.45 Hz), 4.5-2.0 (8H, m), 4.11 (2H, q, J=7.22 Hz), 2.45 (3H,s), 1.25 (3H, t, J=7.2 Hz), 1.20 (3H, s).

Preparation 20:

[1,5,6] -1-methyl-6-methylamino-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0] heptane

To a solution of 2.80 g [1,5,6] -6-ethoxycarbonyl-1 - methyl-3-(p-toluensulfonyl)-3-azabicyclo[3.2.0] heptane and 30 ml of THF was added 0.45 g socialwise hydride. The mixture was heated at reflux distilled within 10 minutes To the reaction solution was added successively with 5 ml of water and 5 ml of 20% aqueous sodium hydroxide solution. The residue was dissolved in 50 ml of ethyl acetate, and ek is R sodium hydroxide. The aqueous layer was twice extracted with 30 ml dichloromethane. The resulting organic layers were combined, dried over anhydrous magnesium sulfate, and then evaporated under high pressure. Was obtained 0.85 g of compound indicated in the title, in the form of a pale-yellow oil (yield 36%)

1H-NMR (CDCl3) : 7.8-7.3 (4H,m), 3.8-1.5 (9H,m), 2.44 (3H,s), 2.30 (3H, s), 1.20 (3H,s).

Preparation 21:

[1,5,6] -1-methyl-6-methylamino-3-azabicyclo[3.2.0]heptane

A solution of 0.82 g [1,5,6] -1-methyl-6-methylamino-3-(p - toluensulfonyl)-3-azabicyclo[3.2.0]heptane and 10 ml of 48% aqueous solution of hydrochloric acid was heated for 1 hour at reflux distilled. The reaction mixture is evaporated under high pressure. The residue was dissolved in 5 ml of water, brought to pH 12 using 40% aqueous sodium hydroxide solution, and was extracted with twice 30 ml of chloroform. The organic layers were combined together, dried over anhydrous sodium sulfate, and then evaporated under high pressure. Received 0.37 g of compound indicated in the title, in the form of a pale-yellow oil (yield 96%)

1H-NMR (CDCl3) : 3.4-1.5 (10H,m), 2.28 (1H,s), 1.25 (3H,s).

Preparation 22:

[1,6]-8-methoxyimino-3-(p-toluensulfonyl)-3-azabicyclo[4.2.0] octane

A mixture of 2.1 g of [1,6] -8-oxo-3-(p-toluensulfonyl)-3 - asabis is mperature. The mixture is then evaporated at high pressure. The residue was dissolved in 20 ml of ethyl acetate. The remaining solution was washed twice with 10 ml 5% aqueous hydrochloric acid and once with 10 ml of saturated solution of sodium chloride, and then dried over magnesium sulfate. The resulting solids were filtered at high pressure. The filtrate is evaporated at elevated pressure, the result was obtained 2.3 g of compound indicated in the title, in the form of a light yellow oil (yield 100%)

1H-NMR (CDCl3) : 7.8-7.2 (4H,m),3.8-3.7 (4H,m), 2.4 (3H,s), 2.3-1.1 (6H,m).

Preparation 23:

[1,6,8] -8-amino-3-(p-toluensulfonyl)-3-azabicyclo[4.2.0]octane

To a suspension of 0.8 g of NaBH4in 20 ml of THF was added a solution of 1.7 ml of TFA in 5 ml of THF for 2 hours at room temperature. Separately, 2.3 g of compound obtained in the section "Preparation 22", dissolved in 5 ml of THF. Resulting solution was added to the solution obtained above for 2 hours at room temperature. The reaction mixture was stirred at room temperature for 3 hours, thereto was added 10 ml of water and 5 ml of 40% aqueous sodium hydroxide solution. The mixture was heated at reflux distilled for 5 hours. The resulting solution is evaporated at an elevated pressure to the aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Resulting solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure to obtain light yellow solid particles that have recrystallization from isopropyl ether. There was obtained 1.7 g of compound indicated in the title, in the form of a white powder (yield 76%). Melting point wing 112-116oC

1H-NMR (CDCl3) : 7.8-7.2 (4H,m), 3.7-2.5 (5H,m), 2.4 (3H,s), 2.4-1.3 (8H,m).

Preparation 24:

[1,6,8] -8-amino-3-azabicyclo[4.2.0]octane

A mixture of 3.5 g of compound indicated in the title of the Chapter "Preparation 23", and 30 ml of 48% aqueous Hydrobromic acid was heated for 15 hours at reflux distilled. The reaction mixture is evaporated under high pressure. The residue was dissolved in 5 ml of water to which was added 3 ml of 40% aqueous sodium hydroxide solution. The mixture was extracted 6 times with 100 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate. Resulting solids were filtered at high pressure. The filtrate is evaporated at an elevated pressure. There was obtained 1.4 g of compound indicated in the title, in the form of a light yellow oil (yield 94%)

1H-NMR (CDCl3) : 3.6-3.2 (1H, m), 3.2-2.6 (4H,m), 2.6 - the(4.2.0] octane

(1) To a suspension of 1.85 g [1,6,8] -8-amino-3-(p-toluensulfonyl)-3-azabicyclo [4.2.0] octane and 1.99 g of N-(p-toluensulfonyl)-L-phenylalanine in 30 ml of dimethylformamide was added 1 ml of triethylamine. After cooling in an ice bath to mix for 5 minutes was added 1.2 ml diethylthiophosphate. The solution was stirred at the same temperature for 30 minutes and then continued stirring for 3 hours at room temperature. After adding 200 ml of water the reaction mixture was twice extracted with ethyl acetate. The organic phase is washed once with water, dried over anhydrous magnesium sulfate, and then evaporated under high pressure to obtain solid particles in the form of a foamed material. These solid particles are added 20 ml of ethyl acetate and 10 ml n-hexane. Resulting mixture was heated for complete dissolution of the solids. The resulting solution was cooled, and then subjected to thin-layer chromatography. Was obtained 0.89 g of compound in the form of a highly polar white solid particles (Rf= 0.3, ethyl acetate:n-hexane = 2:1). The filtrate is evaporated at an elevated pressure. The concentrate is completely dissolved in 10 ml of ethyl acetate and 5 ml n-hexane, cooled and subjected to thin-layer chromatography. Obtained 0.96 g nizkouporyadochennoi acid and 5 ml of acetic acid was added 0.89 g of highly polar compounds from the above section (1). Resulting solution was heated at reflux distilled throughout the night, and then evaporated under high pressure. The residue was dissolved in 10 ml of water. The solution is brought to pH 13-14 with 40% sodium hydroxide solution. The resulting mixture was extracted 5 times with 20 ml of chloroform. The organic layers were combined together, dried over anhydrous sodium sulfate and evaporated under high pressure. There was obtained 0.17 g [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane in the form of a light yellow oil (yield 90%)

[]2D0-7.1o(C=1.4, MeOH).

1H-NMR (CDCl3) : 3.6-3.2 (1H,m), 3.2-2.6 (4H,m), 2.6-1.8 (5H,m), 1.8-1.2 (4H,m).

(3) in the same way as described above in paragraph (2), 0.96 g nizkoposhibnogo connection was subjected to thin-layer chromatography, to obtain 0.19 g(+)-[1,6,8] -8-amino-3-azabicyclo [4.2.0]octane in the form of a light yellow oil (yield 94%)

[]2D0+6.9o(C=1.0, MeOH),

1H-NMR (CDCl3) : 3.6-3.2 (1H, m), 3.2-2.6 (4H,m), 2.6 - 1.8 (5H,s), 1.8-1.2 (4H,m).

EXAMPLE 1:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] -heptane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid, hydrochloride

To a suspension of 150 mg of 1-cyclopropyl-6,7-debtor-1,4-dihydro-4 - oxoindole-3-carboxylic acid in 5 ml acetonitrile the mixture was heated at reflux distilled for 1 hour. The solvent is boiled away at high pressure. To the residue was added 5 ml of 5% aqueous solution of hydrochloric acid. The resulting mixture was stirred at room temperature for 3 hours. Solids collected on the filter, washed first with water and then with ethanol and dried. Received 140 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 61%). Melting point 285 - 290oC

1H-NMR (DMSO-d6+ TFA-d) : 8.55 (1H,s), 8.00 (1H, d, J=17 Hz), 7.24 (1H, d, J=7.4 Hz), 4.3-3,5 (4H,m), 3.5-3.3 (2H,m), 3.0 - 2.6 (2H,m), 2.3-2.0 (2H,m), 1.31 (3H,s), 1.4-1.0 (4H,m).

EXAMPLE 2:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid, hydrochloride

To a suspension of 140 mg of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro - 4-oxoindole-3-carboxylic acid in 3 ml of dimethylsulfoxide was added 100 mg of K2CO3and 180 mg [1,5,6] -6-amino-1-methyl-3 - azabicyclo[3.2.0]heptane. The reaction mixture was stirred for 4 hours at a temperature of from 60 to 80oC, and then cooled to room temperature. After adding 3 ml of 5% hydrochloric acid and the mixture was stirred for another 2 hours. The resulting solids were collected with filtration and washed THF, and then dried. Was obtained (decomposition) 290 - 293oC

1H-NMR (DMSO-d6+ TFA-d) : 8.69 (1H,s), 7.83 (1H, dd, J = 13.2 Hz, 1.96 Hz), 4.3-3.8 (1H, m), 3.8-2.8 (4H,m), 2.8-3.0 (3H,m), 1.35 (3H,s), 1.3-1.0 (4H,m).

EXAMPLE 3:

5-amino-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3 - yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid, hydrochloride

To a suspension of 70 mg of 5-amino-1-cyclopropyl-6,7,8-Cryptor-1,4 - dihydro-4-oxoindole-3-carboxylic acid in 3 ml of acetonitrile was added 120 mg of DBU and 150 mg [1,5,6] -6-amino-1-methyl - 3-azabicyclo[3.2.0]heptane. The resulting mixture was heated at reflux distilled for 3 hours. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous solution of hydrochloric acid, and then stirred for one hour at room temperature. The resulting solids were collected with filtration, washed with water, and then dried. There was obtained 60 mg of the compound indicated in the title, as yellow solids (yield 63%). Melting point (decomposition) 195-200oC

1H-NMR (DMSO-d6+ TFA-d) : 8.3 (1H,s), 4.1-3.1 (5H,m), 3.0-2.5 (2H,m), 2.4-2.0 (2H, m), 1.0-2.6 (2H,m), 2.3 - 2.0 (2H,m), 1.25 (3H,s), 1.2-0.9 (4H, m).

EXAMPLE 4:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1-(2,4-differenl)-1,4-dihydro-4-oxoindole-3-carboxylic acid

To aspili 110 mg TLD and 150 mg [1,5,6] -6-amino-1 - methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was heated at reflux distilled for 2 hours and evaporated under high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for one hour. Solids collected on the filter, washed with water, and then dried. Received 100 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 89%). The melting temperature of 135-140oC

1H-NMR (DMSO-d6+ TFA-d) : 8.5 (1H,s), 8.0-7.0 (5H,m), 4.0-3.0 (5H,m), 2.9-2.5 (2H,m), 2.4-1.9 (2H,m), 1.2 (3H,s).

EXAMPLE 5:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-6,8-debtor-5-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 100 mg 1-cyclopropyl-5-methyl-6,7,8-Cryptor-1,4 - dihydro-4-oxoindole-3-carboxylic acid in 2 ml of acetonitrile were added 100 mg of DBU and 150 mg [1,5,6] -6-amino-1-methyl-3 - azabicyclo[3.2.0]heptane. The reaction mixture was heated at reflux distilled for one hour and evaporated under high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for one hour. Solids collected on the filter, washed with water, and then dried. There was obtained 70 is UP>C

1H-NMR (DMSO-d6+ TFA-d) : 8.5 (1H,s), 4.1-3.5 (5H,m), 2.6 (35H, d, J= 3.0 Hz), 2.3-2.0 (2H,m), 1.2 (3H,s), 1.2 - 0.8 (4H,m).

EXAMPLE 6:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-8 - chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 100 mg of 8-chloro-1-cyclopropyl-6,7-debtor-1,4 - dihydro-4-oxoindole-3-carboxylic acid in 2 ml of acetonitrile were added 100 mg of DBU and 70 mg [1,5,6] -6-amino-1-methyl-3 - azabicyclo[3.2.0]heptane. The reaction mixture was heated at reflux distilled for 5 hours and evaporated at high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous solution of hydrochloric acid and stirred for one hour at room temperature. The obtained solids were collected with filtration, washed with water, and then dried. Received 40 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 30%). Melting point 222-225oC

1H-NMR (DMSO-d6+ TFA-d) : 8.77 (1H,s), 7,86 (1H, d, J = 12.8 Hz), 4.5-4.0 (4H, m), 4.0-3.2 (4H,m), 2.9-2.5 (2H,m), 2.3 - 2.0 (2H,m), 1.25 (3H, s,), 1.1-0.7, 1.1-0,7 ( 4H,m).

EXAMPLE 7:

7- ( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-axle[3.2.0]heptane. The reaction mixture was heated at reflux distilled for 2 hours and evaporated under high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous solution of hydrochloric acid and stirred for one hour at room temperature. The obtained solids were collected with filtration, washed with water, and then dried. Received 100 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 77%). Melting point > 270oC

1H-NMR (DMSO-d6+ TFA-d) : 8.76 (1H,s), 8.00 (1H, d, J = 12.7 Hz), 4.7-4.3 (1H,m), 4.2-3.1 (6H,m), 2.7-2.1 (2H.m), 1.27 (3H,s), 1.1-0.8 (4H,m).

EXAMPLE 8:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1- (2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3 - carboxylic acid

To a suspension of 100 mg of 7-chloro-1-(2,4-differenl)-6-fluoro-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 2 ml of acetonitrile were added 100 mg of DBU and 150 mg [1,5,6] -6 - amino-1-methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was heated at reflux distilled for 2 hours and evaporated under high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for one hour. Solids collected on the filter, washed with water, ANM 88%). The melting temperature of 120-125oC

1H-NMR (DMSO-d6+ TFA-d) : 8.7 (1H,s), 8.0 (1H, d, J=12.7 Hz), 7.8-7.0 (3H,m), 4.0-3.2 (4H,m), 3.1-2.5 (2H,m), 2.2-1.8 (2H,m), 1.2 (3H,s).

EXAMPLE 9:

7 - (6-amino-1-methyl-3-azabicyclo[3. 2.0] heptane-3-yl)-6 - fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 60 mg of 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic acid in 2 ml of acetonitrile were added 100 mg of DBU and 100 mg [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane. The reaction mixture was stirred at room temperature for 2 hours and evaporated under high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for one hour. Solids collected on the filter, washed with water, and then dried. There was obtained 50 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 67%). Melting point (decomposition) 248 - 252oC

1H-NMR (DMSO-d6+ TFA-d) : at 8.62 (1H,s), 8.00 (1H, d, J = 16.0 Hz), 7.1 (4H,m), 4.1-3.2 (4H,m), 3.1-2.5 (2H,m), 2.3 - 1.8 (3H,m), 1.23 (3H,s).

EXAMPLE 10:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-t-butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 100 mg of 1-t-butyl-7-plomino-1-methyl-3 - azabicyclo[3.2.0] heptane. The reaction mixture was stirred at room temperature for 5 hours and evaporated at high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for one hour. Solids collected on the filter, washed with water, and then dried. There was obtained 60 mg of the compound indicated in the title, in the form of white solids (yield 48%). The melting temperature of 130-135oC

1H-NMR (DMSO-d6+ TFA-d) : 8.86 (1H,s), 8.05 (1H, d, J = 13.0 Hz), 4.5-2.0 (8H,m), 1.90 (9H,s), 1.38 (3H,s).

EXAMPLE 11:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1- (2,4-differenl)-6-fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthiridine - 3-carboxylic acid

To a suspension of 80 mg of 7-chloro-1-(2,4-differenl)-6-fluoro-5 - methyl-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 2 ml of acetonitrile was added 70 mg of DBU and 70 mg [1,5,6] -6 - amino-1-methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was stirred at room temperature for 4 hours and evaporated at high pressure. The residue was dissolved in 2 ml of water, neutralized with 10% aqueous solution of hydrochloric acid and stirred for one hour. Solids collected on the filter, washed with water, and then dried. Was polue 110-115oC

1H-NMR (DMSO-d6+ TFA-d) : 8.6 (1H,s), 7.5-6.9 (3H,m), 4.5 - 2.0 (10H, m), 2.8 (3H, d, J = 3.3 Hz), 1.3 (3H,s).

EXAMPLE 12:

(+)-7-( [1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 400 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 10 ml of acetonitrile was added 320 mg of DBU and 300 mg(-)-[1,5,6] -6- amino-1-methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was stirred at room temperature for 3 hours. Solids collected on the filter, washed with a small amount of acetonitrile, and then dried. Received 400 mg of the compound indicated in the title, in the form of white solids (yield 76%).

To a suspension of 400 mg of the thus obtained compound indicated in the title, in 8 ml of methanol is added dropwise at room temperature was added 1.2 ml of 1N aqueous hydrochloric acid solution, and the mixture was continuously stirred for one hour. The resulting solids collected on the filter at high pressure, washed with 5 ml of ethanol, and then dried. There was obtained 4.2 g of compound indicated in the title, in the form of the hydrochloride as white solids (yield 95%). The temperature of prawle is 8.00 (1H, d, J = 12.7 Hz), 4.7-4.3 (1H,m), 4.2-3.1 (6H,m), 2.7-2.1 (2H,m), 1.27 (3H,s), 1.1-0.8 (4H,m).

EXAMPLE 13:

(-)-7-([1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid, hydrochloride

To a suspension of 50 mg 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro-4 - oxoindole-3-carboxylic acid in 2 ml of acetonitrile was added 70 mg of DBU and 60 mg(-)-[1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was heated for 5 hours at reflux distilled and evaporated under high pressure. The residue was dissolved in 2 ml of water and brought to pH 1 using the appropriate amount of aqueous concentrated hydrochloric acid solution. The resulting solids were collected with filtration, washed with isopropyl alcohol and then dried. Received 30 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 34%). Melting point > 270oC

1H-NMR (DMSO-d6+ TFA-d) : 8.69 (1H,s), 7.83 (1H, dd, J = 12,6 Hz), 4.3-3.8 (2H,m), 3.8-2.8 (4H,m), 2.8-2.0 (3H,m), 1.35 (3H,s), 1.3-1.0 (4H,m).

EXAMPLE 14:

(+)-7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)- 1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid, hydrochloride

To a suspension of 100 mg 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro - 4-exohi is Aptana. The reaction mixture was heated for 3 hours at reflux distilled and evaporated under high pressure. The residue was dissolved in 2 ml of water and brought to pH 1 using the appropriate amount of aqueous concentrated hydrochloric acid solution. The resulting solids were collected with filtration, washed with isopropyl alcohol and then dried. There was obtained 60 mg of the compound indicated in the title, in the form of pale-yellow solids (yield 41%). Melting point >270oC

1H-NMR (DMSO-d6+ TFA-d) : 8.69 (1H,s), 7.83 (1H, dd, J = 13.2 Hz), 4.3-3.8 (2H,m), 2.8-2.0 (4H,m), 1.35 (3H,s), 1.3 - 1.0 (4H,m).

EXAMPLE 15:

1-cyclopropyl-6,8-debtor-7-( [1,5,6] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 150 mg of 1-cyclopropyl-6,7,8-Cryptor-1,4 - dihydro-4-oxoindole-3-carboxylic acid in 3 ml of acetonitrile was added 160 mg of DBU and 150 mg [1,5,6] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0]heptane. The reaction mixture was heated at reflux distilled for 4 hours and stirred at room temperature overnight. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then dried. Was obtained 170 mg of the compound, R>
1H-NMR (DMSO-d6+ TFA-d) : 8.65 (1H,s), 7.76 (1H, dd, J = 13.6 Hz, 1.9 Hz), 4.5-3.9 (2H, m), 3.7-3.1 (4H,m), 2.7 - 1.8 (3H,m), 1.3 (3H,s), 1.2-1.0 (4H,s).

EXAMPLE 16:

1-cyclopropyl-6-fluoro-7-( [1,5,6] -6-hydroxy-1-methyl-3-azabicyclo [3.2.0]heptane-3-yl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid in 3 ml of acetonitrile was added 150 mg of DBU and 130 mg [1,5,6] -6-hydroxy-1-methyl - 3-azabicyclo[3.2.0]heptane. The reaction mixture was heated at reflux distilled for one hour, evaporated under increased pressure and stirred at room temperature for one hour. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then dried. There was obtained 70 mg of the compound indicated in the title, in the form of solid particles pale yellow (yield 53%). Melting point (decomposition) 265oC

1H-NMR (DMSO-d6+ TFA-d) : 8.55 (1H,s), 7.93 (1H, d, J = 13.0 Hz), 4.7-3.1 (6H,m), 2.8-2.0 (3H,m), 1.32 (3H,s), 1.3 - 0.9 (4H,m).

EXAMPLE 17:

(-)-7-([1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-cyclopropyl-6,8-debtor-5-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 300 mg of 1-cyclopropyl-5-methyl-6,7,8-Cryptor-1,4 - dihydro-4-exogenity. The reaction mixture was stirred at 60oC for 8 hours and evaporated at high pressure. The residue was dissolved in 3 ml of water, neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for 2 hours. Solids collected on the filter, washed with water, and then dried. Received 340 mg of the compound indicated in the title, in the form of solid particles of white color (yield 84%). Melting point 275-280oC

[]2D0-221.2o(C=0.5, DMSO).

1H-NMR (DMSO-d6) : 8.54 (1H,s), 4.3-2.0 (9H,m), 2.71 (3H, d, J = 3.15 Hz), 1.33 (3H,s), 1.2-0.9 (4H,m).

EXAMPLE 18:

(-)-5-amino-7- [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6,8-debtor-5-methyl-1,4-dihydro-4 - oxoindole-3-carboxylic acid

To a suspension of 300 mg of 5-amino-1-cyclopropyl-6,7,8-Cryptor-1,4 - dihydro-4-oxoindole-3-carboxylic acid in 3 ml of dimethyl sulfoxide (DMSO) was added 190 mg(-)- [1,5,6] -6-amino-1-ethyl - 3-azabicyclo[3.2.0]heptane. The reaction mixture was stirred at 60oC for 5 hours and then cooled to room temperature. After adding 10 ml of water the resulting mixture was stirred for 2 hours. The resulting solids were collected with filtration, washed water (yield 83%). Melting point (decomposition) 196 - 200oC.

[]2D0-280.6o(C=0.5, DMSO).

1H-NMR (DMSO-d6) : 8.49 (1H,s), 7.19 (2H,s), 4.3-2.0 (9H,m), 1.34 (3H. s), 1.3-0.8 (4H,s).

EXAMPLE 19:

(-)-7- [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-t-butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 300 mg of 1-tert-butyl-7-chloro-6-fluoro-1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 150 mg(-)- [1,5,6] -6-amino-1-methyl - 3-azabicyclo[3.2.0]heptane. After stirred for 2 hours at 70oC, the reaction mixture was cooled to room temperature and evaporated under high pressure. The residue was dissolved in 3 ml of water, neutralized with 5% aqueous hydrochloric acid solution and was stirred for 2 hours at room temperature. Solids collected on the filter, washed with water, and then dried. Was obtained 260 mg of the compound indicated in the title, in the form of solid particles pale yellow (yield 67%). Melting point 134-138oC

[]2D0-20.4o(C=0.5, DMSO).

1H-NMR (DMSO-d6) : 8.87 (1H,s), 8.0 (1H, d, J= 12.9 Hz), 4.5-2.0 (8H, m), 1.90 (9H,s), 1.39 (3H,s).

EXAMPLE 20:

(-)-7- [1,5,6] -6-amino-1-methyl-3-Isabel mg of 8-chloro-1-cyclopropyl-6,7-debtor - 1,4-dihydro-4-oxoindole-3-carboxylic acid in 4 ml of acetonitrile was added 190 mg of DBU and 150 mg(-)- [1,5,6] -6- amino-1-methyl-3-azabicyclo[3.2.0]heptane. After stirring for 3 hours at 50oC the reaction mixture was stirred for another at room temperature throughout the night. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then dried. Received 290 mg of the compound indicated in the title, in the form of solid particles, white (71% yield). Melting point 222-228oC

[]2D0-111.2o(C=0.5, DMSO),

1H-NMR (DMSO-d6) : 8.77 (1H,s), 7.88 (1H, d, J=12.2 Hz), 4.5-4.0 (1H, m), 4.0-3.2 (4H,m), 2.9-2.5 (2H,m), 2.3 - 2.0 (2H,m), 1.0-0.7 (4H,m).

EXAMPLE 21:

(-)-7- [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1- (2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 200 mg of 7-chloro-1-(2,4-differenl)-6-fluoro-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 2 ml of acetonitrile was added 140 mg of DBU and 140 mg(-)- [1,5,6] -6-amino-1-methyl - 3-azabicyclo[3.2.0]heptane. The reaction mixture was stirred for 12 hours at room temperature and evaporated under high pressure. The residue was dissolved in 3 ml of water, neutralized with 5% aqueous hydrochloric acid solution and was stirred for 2 hours at room temperature. The resulting solids were collected during the entire solids (yield 84%). Melting point 123-127oC

[]2D0-17.0o(C=0.5, DMSO).

1H-NMR (DMSO-d6+ TFA-d) : 8.7 (1H,s), 8.0 (1H, d, J=12.7 Hz), 7.8-7.0 (3H,m), 4.0-3.2 (4H,m), 3.1-2.5 (2H,m), 2.2-1.8 (2H,m), 1.2 (3H,s).

EXAMPLE 22:

(-)-7-[1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6 - fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

To a suspension of 200 mg of 7-chloro-6-fluoro-1-(4-forfinal)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 2 ml of acetonitrile was added 140 mg of DBU and 140 mg(-)- [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was stirred for 12 hours at room temperature and evaporated under high pressure. The residue was dissolved in 3 ml of water, neutralized with 5% aqueous hydrochloric acid solution and was stirred for 2 hours at room temperature. Solids collected on the filter, washed with water, and then dried. There was obtained 140 mg of the compound indicated in the title, in the form of white solids (yield 56%). Melting point 250-253oC

[]2D0-37.6o(C=0.5, DMSO).

1H-NMR (DMSO-d6+ TFA-d) : 8.6 (1H,s), 8.0 (1H, d, J=16.0 Hz), 7.8-7.1 (4H,m), 4.1-3.2 (4H,m), 3.1-2.5 (2H,m), 2.3-1.8 (2H,m), 1.2 (3H,s).

EXAMPLE 23:

7- [1,5,6] -6-amino-5-methyl-3-sabich 1-cyclopropyl-1,4-dihydro-6,7,8-Cryptor - 4-oxo-3-quinoline-carboxylic acid in 10 ml of acetonitrile were added 100 mg of DBU and 150 mg [1,5,6] -6-amino-5-methyl-3 - azabicyclo[3.2.0]heptane. After reflux distilled for 10 hours at 80oC the reaction mixture was cooled to room temperature and left overnight. The resulting solids collected on the filter at high pressure, washed with isopropyl ether, and then dried. Received 90 mg of the compound indicated in the title (yield 55%). Melting point (decomposition) 235 - 240oC

1H-NMR (DMSO-d6+ TFA-d) : 8.68 (1H,s), 8.08 (2H, brs.), 7.81 (1H, dd, J= 2 Hz), 4.2-3.5 (6H,m), 3.0-2.5 (1H,m), 2.2 - 1.8 (2H,m), 1.4 (3H,s), 1.2-0.9 (4H,m).

EXAMPLE 24:

7- [1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-6-fluoro - 1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 200 mg of 7-chloro-1,4-dihydro-1-(4-forfinal)- 6-fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 110 mg of DBU and 100 mg [1,5,6] -6-amino-5 - methyl-3-azabicyclo[3.2.0]heptane. The mixture was stirred for one hour at room temperature. The solvent is evaporated at an elevated pressure. The residue was dissolved in 2 ml of distilled water. The resulting solution was neutralized with 10% aqueous hydrochloric acid solution and stirred at room temperature for 2 hours. The resulting solids were collected with filtration, washed with a small amount disteli (yield 79%). Melting point (decomposition) 253 - 255oC

1H-NMR (DMSO-d6+ TFA-d) : 8.63 (1H,s), 8.05 (1H, d, J = 12,9 Hz), 7.6-7.3 (4H, m), 4.4-4.1 (1H,m), 3.70-3.35 (2H,m), 2.5 and 2.1 (2H,m). 1.7-1.3 (4H.m), 1.22 (3H,s).

EXAMPLE 25:

8-chloro-1-cyclopropyl-7- [1,5,6] -6-amino-5-methyl-3-azabicyclo [3.2.0] heptane-3-yl)-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 200 mg of 8-chloro-1-cyclopropyl-6,7-debtor-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid in 5 ml of acetonitrile was added 130 mg of DBU and 100 mg [1,5,6] -6-amino-5-methyl-3-azabicyclo [3.2.0]heptane. The mixture was subjected to reflux distilled for 4 hours at 80oC. the Solvent is boiled away at high pressure. The residue was dissolved in 3 ml of distilled water. The resulting solution was neutralized with 5% aqueous hydrochloric acid solution and stirred at room temperature for 2 hours. The resulting solids collected on the filter at high pressure, washed with distilled water and then with isopropyl ether, and then dried. Received 140 mg of the compound indicated in the title (yield 54%). Melting point 175 - 178oC

1H-NMR (DMSO-d6+ TFA-d) : 8.85 (1H,s), 7.91 (1H, d, J = 12.8 Hz), 4.5-4.3 (1H, m), 3.9-3.7 (1H,m), 3.6-3.0 (4H,m), 2.5 - 2.3 (2H,s), 2.0-1.8 (1H,m), 1.34 (3H,s), 1.1-0.9 (4H,m).

EXAMPLE 26:

7-([1, the slot

To a suspension of 180 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6 - fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 130 mg of DBU and 100 mg [1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0] heptane. The reaction mixture was stirred at 50oC for 1.5 hours and cooled to room temperature. The resulting solids were collected with filtration, washed with isopropyl alcohol and then dried. Received 200 mg of the compound indicated in the title (yield 84 %). Melting point (decomposition) 265 - 270oC

1H-NMR (DMSO-d6+ TFA-d) : 8.55 (1H,s), 7.94 (1H, d, J = 12.9 Hz), 4.5-4.3 (1H, m), 4.1-3.8 (1H,m), 3.7-3.3 (4H,m), 2.7 - 2.4 (2H,m), 1.9-1.6 (1H,m), 1.37 (3H,s), 1.3-1.1 (4H,m).

EXAMPLE 27:

1-(2,4-differenl)-7-([1,5,6] -6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

To a suspension of 200 mg of 7-chloro-1-(2,4-differenl)-1,4-dihydro - 6-fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 110 mg of DBU and 100 mg [1,5,6] -6-amino-5 - methyl-3-azabicyclo[3.2.0] heptane. The mixture was stirred at a temperature of from 30 to 40oC for one hour. The solvent is boiled away at high pressure. The residue was dissolved in 2 ml of distilled water. The resulting solution was brought to pH 6-7 using 5% aqueous solution is filtrowanie, washed first with a small amount of distilled water and then with isopropyl alcohol, and dried. There was obtained 220 mg of the compound indicated in the title (yield 88%). Melting point 110 - 115oC

1H-NMR (DMSO-d6+ TFA-d) : 8.80 (1H,s), 8.08 (1H, d, J = 12.7 Hz), 7.9-7.2 (3H,m), 4.2-4.0 (1H,m), 3.6-3.1 (4H,m), 2.7-2.3 (2H,m), 1.8-1.5 (1H, m), 1.27 (3H,s).

EXAMPLE 28:

(-)-7-(-6-amino-5-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 100 mg of 7-chloro-1-(2,4-differenl)-1,4-dihydro - 6-fluoro-5-phenyl-4-oxo-1,8-naphthiridine-3-carboxylic acid in 4 ml of acetonitrile was added 80 mg of DBU and 70 mg(-)- [1,5,6] -6-amino-1-methyl-3 - azabicyclo[3.2.0] heptane. The reaction mixture was stirred for 3 hours at 50oC. the Solvent is evaporated at an elevated pressure. The residue was dissolved in 1 ml of distilled water. The resulting solution was neutralized with 5% aqueous hydrochloric acid solution. The resulting solids were collected with filtration, washed with isopropyl ether, and then dried. Received 100 mg of the compound indicated in the title (yield 80.6%). The melting point of 113 - 115oC

1H-NMR (CDCl3) : 8.6 (1H,s), 7.6-6.8 (3H,m), 4.5 - 2.0 (10H,m), 2.8 (3H, d, J=3.2 Hz)), 1.3 (3H,s).

EXAMPLE 29:

1-C is a

To a suspension of 250 mg of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro-4 - oxo-3-quinoline-carboxylic acid in 5 ml of dimethyl sulfoxide was added 250 mg [1,5,6]-6-hydroxy-3-azabicyclo[3.2.0] heptane. The reaction mixture was subjected to reflux distilled for 8 hours at a temperature of from 60 to 80oC, and then cooled to room temperature. This mixture is poured 5 ml of distilled water. The resulting solids were collected with filtration, washed with isopropyl alcohol and then dried. Was obtained 280 mg of the compound indicated in the title (yield 84.3%). Melting point 235 - 240oC

1H-NMR (DMSO-d6+ TFA-d) : 8.26 (1H,s), 7.71 (1H, dd, J = 2.0 Hz, J=12 Hz), 4.8-4.4 (3H, m), 3.9-3.3 (4H, m), 3.3 - 2.85 (1H,s), 2.8-2.2 (2H,m), 1.9-1.5 (1H,m), 1.4-1.05 (4H, d, J=6.2 Hz).

EXAMPLE 30:

5-amino-1-cyclopropyl-7-([1,5,6]-6-hydroxy-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

To a suspension of 300 mg of 5-amino-1-cyclopropyl-6,7,8-Cryptor - 1,4-dihydro-4-oxo-3-quinoline-carboxylic acid in 5 ml of dimethyl sulfoxide was added 250 mg [1,5,6] -6-hydroxy-3 - azabicyclo[3.2.0] heptane. The reaction mixture was subjected to reflux distilled for 5 hours at 90oC, and then cooled to room temperature. This mixture is poured 5 ml of distilled water. The resulting TV is soedineniya, specified in the title (yield 38%). Melting point (decomposition) 220oC

1H-NMR (DMSO-d6+ TFA-d) : 8.48 (1H,s), 4.4-3.8 (3H,m), 3.8 - 2.8 (5H, m), 1.9-1.5 (1H,s), 1.3-0.9 (4H,m).

EXAMPLE 31:

1-cyclopropyl-7-( [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0]heptane - 3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

To a suspension of 110 mg of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro - 4-oxo-3-quinoline-carboxylic acid in 3 ml of acetonitrile were added 100 mg of DBU and 100 mg [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0] heptane. The reaction mixture was heated at reflux distilled for one hour, and then left at room temperature for 5 hours. The resulting solids were collected with filtration, washed with isopropyl ether, and then dried. Received 100 mg of the compound indicated in the title (yield 69%). Melting point (decomposition) 190-200oC

1H-NMR (DMSO-d6+ TFA-d) : 8.61 (1H,s), 4.3-3.84 (3H,m), 3.80-3.25 (4H,m), 3.20-2.85 (1H,m), 2.77 (3H, dd, J=3.12 Hz, J=1.41 Hz), 2.65-2.1 (2H, m), 1.80-1.35 (1H,m), 1.32-1.0 (4H,m).

EXAMPLE 32:

1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)- 6,8-debtor-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid

To a suspension of 200 mg of 1-cyclopropyl-1,4-dihydro-5-methyl - 6,7,8-Cryptor-4-oxo-3-quinoline-carboxylic acid in 5 ml acetonitrile under 100oC for 6 hours. After cooling to room temperature the resulting solution was evaporated under high pressure. To the residue was added 10 ml of distilled water. The resulting solution was neutralized with 10% aqueous solution of hydrochloric acid. The resulting solids were collected with filtration, washed first with a small amount of distilled water and then with isopropyl ether, and then dried. Received 120 mg of the compound indicated in the title (yield 46%). Melting point 260oC

1H-NMR (DMSO-d6+ TFA-d) : 8.26 (1H,s), 8.5-7.7 (2H, brs), 4.3-3.5 (6H, m), 3.5-2.8 (3H, m), 2.74 (3H, d, J=3.2 Hz), 2.2 - 1.7 (1H,m), 3.9-3.3 (4H,m), 3.3-2.85 (1H,s), 1.3-1.1 (4H,m).

EXAMPLE 33:

1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3 - yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

To a suspension of 200 mg of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8 - Cryptor-3-quinoline-carboxylic acid in 6 ml of acetonitrile was added 160 mg of DBU and 240 mg [1,5,6] -6-amino-3-azabicyclo [3.2.0]heptane. The reaction mixture was heated at reflux distilled at 80oC for 10 hours, then cooled to room temperature and evaporated under high pressure. The residue was dissolved in 5 ml of distilled water. The resulting solution was neutralized with 10% aqueous plant washed first with a small amount of distilled water and then with isopropyl alcohol, and dried. There was obtained 160 mg of the compound indicated in the title (yield 60%). Melting point 240oC

1H-NMR (DMSO-d6+ TFA-d) : 8.71 (1H,s), 3.4-7.8 (2H, brs), 7.86 (1H, dd, J=2 Hz, 12 Hz), 4.4-3.4 (6H,m), 3.4-2.6 (3H,m), 2.1-1.6 (1H,m), 1.4-1.1 (4H,m).

EXAMPLE 34:

5-amino-1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

To a suspension of 180 mg of 5-amino-1-cyclopropyl-1,4-dihydro-4-oxo - 6,7,8-Cryptor-3-quinoline-carboxylic acid in 2.2 ml of dimethyl sulfoxide was added 270 mg [1,5,6] -amino-3-azabicyclo[3.2.0] heptane. The reaction mixture was heated at reflux distilled at 80oC for 5 hours, then cooled to room temperature. The residue was dissolved in 5 ml of distilled water. The resulting solution was brought to pH 1-2 using 10% aqueous solution of hydrochloric acid. The resulting solids were collected with filtration and washed with isopropyl alcohol. The thus treated solid particles added to 20 ml of methyl alcohol and dissolved therein by heating. The resulting solution was placed in a refrigerator for 24 hours. The resulting pale yellow solid particles abramovichevna pressure. Was obtained 130 mg of the compound indicated in the title (yield 50%). Melting point (decomposition) 243 - 245oC

1H-NMR (DMSO-d6+ TFA-d) : 8.48 (1H,s), 8.1 (2H, brs), 4.3-3.3 (7H,m), 3.2-2.7 (3H,m), 1.2-0.9 (4H,m).

EXAMPLE 35:

1-cyclopropyl-7-( [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0]heptane - 3-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 200 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6 - fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 150 mg of DBU and 260 mg [1,5,6] -6-hydroxy-3-azabicyclo[3.2.0] heptane. The reaction mixture was subjected to reflux distilled at 80oC for 30 minutes, then evaporated at high pressure. After pouring 5 ml of distilled water, the mixture was neutralized with 5% aqueous solution

of hydrochloric acid. The resulting solids collected on the filter at high pressure, and then dried. There was obtained 160 mg of the compound indicated in the title (yield 63%). Melting point 243oC

1H-NMR (DMSO-d6+ TFA-d) : 8.51 (1H,s), 7.96 (1H, d, J = 13.0 Hz), 4.7-4.05 (3H, m), 4.0-3.4 (5H,m), 3.2-3.0 (1H,m), 2.7-2.5 (2H,m), 1.2-1.0 (4H,m).

EXAMPLE 36:

1-cyclopropyl-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acidoC for one hour, the reaction mixture was cooled to room temperature and left overnight. The resulting solids were collected with filtration, washed with isopropyl ether, and then dried. There was obtained 70 mg of the compound indicated in the title (yield 55%). Melting point (decomposition) 242oC

1H-NMR (DMSO-d6+ TFA-d) : 8.60 (1H,s), 8.2 (2H, brs), 8.00 (1H, d, J= 13.0 Hz), 4.6-2.9 (8H,m), 2.6-2.4 (1H,m), 1.2-0.95 (4H,m).

EXAMPLE 37:

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthiridine - 3-carboxylic acid

To a suspension of 260 mg of 7-chloro-1-(2,4-differenl)-1,4-dihydro - 6-fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 4 ml of acetonitrile was added 280 mg of DBU and 110 mg [1,5,6] -6-amino-1-methyl - 3-azabicyclo[3.2.0]heptane. After reflux distilled at 80oC for 12 hours, the reaction mixture was cooled to room temperature and left overnight. The resulting solids were collected with filtration, washed with isopropyl ether, and then dried. Received 156 mg of the compound indicated in the title (exit 49.5%). Melting point 200oC

1H-NMR (DMSO-d6+ TFA-d) : 8.83 (1H,s), 8.14 (1H, d, J = 12,0 Hz), 8.2-7.3 (3H,m), 4.5-2.7 (8H,m), 2.4-1.6 (1H,m).


To a suspension of 200 mg of 7-chloro-1,4-dihydro-6-fluoro-1-(4-forfinal)-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 110 mg of DBU and 80 mg [1,5,6] -6-amino - 3-azabicyclo[3.2.0]heptane. The reaction mixture was stirred at room temperature for 5 hours. The solvent is acetonitrile is boiled away at high pressure. The resulting solution was brought to pH 6-7 with 10% aqueous hydrochloric acid solution. The resulting solids were collected with filtration, washed first with a small amount of distilled water and then with isopropyl ether, and then dried. Received 200 mg of the compound indicated in the title (yield 82%). Melting point (decomposition) 275 - 277oC

1H-NMR (DMSO-d6+ TFA-d) : 8.65 (1H,s), 8.14 (1H, d, J = 12.8 Hz), 7.8-7.3 (4H,m), 4.3-1.5 (9H,m).

EXAMPLE 39:

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-8-chloro-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

To a suspension of 200 mg of 8-chloro-1-cyclopropyl-6,7-debtor-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid in 3 ml of acetonitrile was added 140 mg of DBU and 100 mg [1,5,6] -6-amino-3 - azabicyclo[3.2.0]heptane. The reaction mixture was subjected to reflux distilled at 80oC for 6 hours and then cooled to room temperature. Races who have teralithe 5% aqueous solution of hydrochloric acid. The resulting solids were filtered and added 3 ml of ethyl alcohol. After dissolution of the solid particles when heated resulting solution was placed in a refrigerator for 12 hours. The resulting solids collected on the filter at high pressure and washed with isopropyl alcohol. After drying there was obtained 80 mg of the compound indicated in the title (yield 31%). Melting point (decomposition) 205 - 207oC

1H-NMR (DMSO-d6+ TFA-d) : 9.20 (1H,s), 8.2 (1H, d, J = = 12.8 Hz), 4.8-4.2 (1H, m), 4.2-3.6 (4H,m), 3.5-2.8 (3H,m), 2.4 - 2.0 (2H,m), 1.3-1.1 (4H,m).

EXAMPLE 40:

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthiridine-3 - carboxylic acid

To a suspension of 130 mg of 7-chloro-1-(2,4-differenl)-1,4-dihydro - 6-fluoro-5-methyl-4-oxo-1,8-naphthiridine-3-carboxylic acid in 4 ml of acetonitrile was added 90 mg of DBU and 80 mg [1,5,6] -6-amino-3 - azabicyclo[3.2.0] heptane. The reaction mixture was stirred at 50oC for 3 hours and then evaporated under high pressure. After pouring 2 ml of distilled water and the resulting solution was neutralized with 5% aqueous hydrochloric acid solution. The resulting solids collected on the filter at an elevated dais. Received 120 mg of the compound indicated in the title (yield 77%). Melting point (decomposition) 130 - 135oC

1H-NMR (DMSO-d6+ TFA-d) : 8.76 (1H,s), 8.10 (1H, d, J = 12.8 Hz), 7.85-7.17 (3H,m), 4.2-4.0 (1H,m), 3.8-3.3 (4H,m), 3.2-2.9 (2H,m), 2.75 (3H, d, J = 3.36 Hz), 2.35-2.0 (1H,m), 1.75 - 1.5 (1H,m).

EXAMPLE 41:

(-)-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1-(2,4 - differenl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 180 mg of 7-chloro-1-(2,4-differenl)-1,4-dihydro-6 - fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile were added 100 mg of DBU and 80 mg(-)- [1,5,6] -6-amino - 3-azabicyclo[3.2.0]heptane. The resulting mixture was stirred at 50oC for 2 hours. Was repeated by the same method as in example 37. The result was obtained 80 mg of the compound indicated in the title (yield 37%). Melting point 200oC

1H-NMR (DMSO-d6+ TFA-d) : 8.83 (1H,s), 8.13 (1H,s), 8.3 - 7.25 (3H,m), 4.6-4.1 (1H, m), 3.8-3.3 (4H,m), 3.2-2.9 (2H,m), 2.4 - 2.0 (1H,m), 1.6-1.4 (1H,m).

EXAMPLE 42:

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1-(tert-butyl)- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 200 mg of 1-(tert-butyl)-7-chloro-1,4-dihydro-6 - fluoro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 3 ml of acetonitrile was added 130 mg of DBU and [1,5,6] -6-amino-3-azabicyclo[3 in example 39. The result is a 100 mg of the compound indicated in the title (yield 40%). Melting point 230-233oC

1H-NMR (DMSO-d6+ TFA-d) : 8.86 (1H,s), 8.02 (1H, d, J = 12.8 Hz), 4.3-4.15 (1H,m), 3.83-3.63 (4H,m), 3.12-3.0 (2H.m), 2.54 - 2.25 (2H,m), 1.89 (9H,m).

EXAMPLE 43:

(-)-7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-1,8-naphthiridine-3 - carboxylic acid

To a suspension of 140 mg of 7-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro - 5-methyl-1,8-naphthiridine-3-carboxylic acid in 4 ml of acetonitrile were added 100 mg of DBU and 80 mg [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane. The resulting mixture was stirred at room temperature for 24 hours. Was repeated by the same method as in example 39. The result was obtained 80 mg of the compound indicated in the title (yield 45%). The melting point of 140-145oC

1H-NMR (DMSO-d6+ TFA-d) : 8.72 (1H,s), 4.5-4.2 (1H, m), 4.10-3.90 (1H, m), 3.7-3.3 (4H,m), 2.75 (3H, d, J = 3.2 Hz), 2.7 - 2.4 (2H,m), 1.9-1.6 (2H, m), 1.3-1.1 (4H,m).

EXAMPLE 44:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1 - cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid

100 mg of 1-cyclopropyl-6,7-debtor-8-methoxy-1,4-dihydro-4 - oxoindole-3-carboxylic acid and 120 mg [1,5,6]-6-amino-1-methyl - 3-azabicyclo[3.2.0]heptane was added to 2 ml of DMSO. Polyml water. The resulting solution was brought to pH 7 using 5% aqueous solution of hydrochloric acid, and then twice held the extraction with 30 ml of chloroform. The chloroform layer was removed and boiled away at high pressure. To the residue was added a small amount of water and ethanol. The resulting solution was stirred for one hour at room temperature. The resulting solids were collected during the filtration, and then dried. Received 20 mg of the compound indicated in the title, in the form of white solids (yield 15%). The melting temperature of 195-200oC

1H-NMR (DMSO-d6+ TFA-d) : 8.73 (1H,s), 7.77 (1H, d, J = 14.2 Hz), 4.3-1.9 (9H,m), 3.65 (3H,s), 1.35 (3H,s).

EXAMPLE 45:

7-( [1,5,6] -6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 95 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid in 3 ml of acetonitrile were added 100 mg of DBU and 93 mg [1,5,6] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane. The reaction mixture was stirred at room temperature for 3 hours and evaporated under high pressure. The residue was dissolved in water and neutralized with 10% aqueous solution of hydrochloric acid. The resulting solids collected on the filter is STIC (yield 78%). Melting point (decomposition) 237-240oC

1H-NMR (DMSO-d6+ TFA-d) : 8.52 (1H,s), 7.94 (1H, d, J = 12.8 Hz), 4.3-3.4 (6H,m), 2.9-2.7 (1H,m), 2.5-2.0 (2H,m), 1.37 (3H,s), 1.3-1.0 (4H,m).

EXAMPLE 46:

8-chloro-1-cyclopropyl-6-fluoro-7-( [1,5,6] -1-methyl-6-methylamino - 3-azabicyclo[3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3 - carboxylic acid

To a suspension of 100 mg of 8-chloro-1-cyclopropyl-6,7-debtor-1,4 - dihydro-4-oxoindole-3-carboxylic acid in 2 ml of acetonitrile was added 60 mg of DBU and 60 mg [1,5,6] -1-methyl-6-methylamino-3 - azabicyclo[3.2.0] heptane in 1 ml of acetonitrile. The reaction mixture was heated at reflux distilled for 18 hours and evaporated at high pressure. The residue was dissolved in 3 ml of water, brought to pH 7 with 5% aqueous hydrochloric acid solution and left overnight in the refrigerator. The resulting solids were collected with filtration, washed with a small amount of water and simple ether, and then dried. Received 30 mg of the compound indicated in the title, in the form of light yellow solids (yield 21%). The melting point of 250 - 255oC

1H-NMR (DMSO-d6+ TFA-d) : 8.87 (1H,s), 7.94 (1H, d. J = 12.8 Hz), 4.6-4.2 (1H,m), 4.0-2.0 (8H,m), 2.46 (3H,s), 1.36 (3H,m), 1.3-0.8 (4H,m).

EXAMPLE 47:

1-cyclopropyl-6,8-debtor-7-( [1,5,6] -1-methyl-6-methylamino-3 - azabicyclo[3.2.0]g the DRO - 4-oxoindole-3-carboxylic acid in 2 ml of acetonitrile was added 60 mg of DBU and 60 mg [1,5,6] -1-methyl-6-methylamino-3-azabicyclo[3.2.0] heptane in 1 ml of acetonitrile. The reaction mixture was heated at reflux distilled within 18 hours. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then dried. There was obtained 65 mg of the compound indicated in the title, in the form of white solids (yield 46%). Melting point (decomposition) 260 - 265oC

1H-NMR (DMSO-d6+ TFA-d) : 8.64 (1H,s), 7.78 (1H, dd, J = 13.6 Hz, 1.84 Hz), 4.2-2.0 (9H,m), 2.50 (3H.s), 1.32 (3H,s), 1.3-0.9 (4H,m).

EXAMPLE 48:

1-cyclopropyl-6-fluoro-7-( [1,5,6] -1-methyl-6-methylamino-3-azabicyclo [3.2.0]heptane-3-yl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid in 2 ml of acetonitrile was added 60 mg of DBU and 60 mg [1,5,6] -1-methyl-6-methylamino-3-azabicyclo [3.2.0]heptane in 1 ml of acetonitrile. The reaction mixture was stirred at room temperature for 2 hours. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then dried. Received 102 mg of the compound indicated in the title, in the form of white solids (yield 74%). Melting point (decomposition) 245 - 250oC

1H-NMR (DMSO-d6+ TFA-d) : 8.58 (1H,s), 8.01 (1H, d, J = 12.8 Hz), 4.l - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

To a suspension of 140 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid in 5 ml of acetonitrile was added 140 mg of DBU and 70 mg [1,5,6] -6-amino-3 - azabicyclo[3.2.0]heptane. The reaction mixture was stirred at room temperature for 2 hours. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then recrystallize from ethanol. Received 120 mg of the compound indicated in the title, in the form of a white powder (yield 68%). Melting point 225 - 230oC

1H-NMR (DMCO-d6+ TFA-d) : 8.54 (1H,s), 8.17 (2H, brs), 7.95 (1H, d, J= 12.8 Hz), 4.5-1.8 (10H,m), 1.2-1.0 (4H,m).

EXAMPLE 50:

7-( [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane-3-yl)-1-cyclopropyl - 6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 100 mg 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro - 4-oxoindole-3-carboxylic acid in 4 ml of acetonitrile was added 60 mg of DBU and 60 mg [1,5,6] -6-amino-3-azabicyclo[3.2.0]heptane. After heating at reflux distilled for 2 hours, the reaction mixture was cooled to room temperature and was stirred for one hour. The resulting solids were collected with filtration, washed with a small amount of acetonitrile, and then dried. Received the tion) 250oC

1H-NMR (DMSO-d6+ TFA-d) : 8.63 (1H,s), 8.16 (2H, brs), 7.75 (1H, dd, J=12.8 Hz, 1.44 Hz), 4.3-1.8 (10H,m), 1.2 - 1.0 (4H,m).

EXAMPLE 51:

7-( [1,5,6] -6-amino-3-azabicyclo[4.2.0]octane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3 - carboxylic acid

A mixture of 100 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid, 70 mg [1,6,8] -8-amino-3-azabicyclo [4.2.0] octane and 30 mg of DBU in 5 ml of acetonitrile was stirred for 3 hours at 40oC. the Solvent was boiled away at high pressure, and then added 4 ml of ethanol. To the resulting solution to dissolve the residue was added 4 - 5 drops of concentrated hydrochloric acid. Besieged thus the solids were filtered at high pressure, washed with ethanol, and then dried. Received 100 mg of the compound indicated in the title (yield 69%). Melting point (decomposition) 282 - 284oC

1H-NMR (DMSO-d6) : 8.594 (1H, s), 8,70-2.95 (1H, d, J = 13.7 Hz), 4.90-3.10 (6H,m), 3.10-1.40 (4H,m).

EXAMPLE 52:

7-( [1,5,6] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-(2,4 - differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

Was repeated by the same method as in example 51. Using 100 mg of 7-chloro-1-(2,4-differenl)-6-fluoro-1,4 - dihydro-4-oxo-1,8-naftnog in the title (yield 74%). Melting point 267 - 268oC

1H-NMR (DMSO-d6) : 8.83 (1H,s), 8.29 (1H, d. J=13 Hz), 7.91-2.70 (3H, m), 4.50-1.40 (13H,m), 4.50-1.40 (13H,m).

EXAMPLE 53:

7-( [1,5,6] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-4-forfinal)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, hydrochloride

Was repeated by the same method as in example 51. Using 100 mg of 7-chloro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic acid, 30 mg of DBU and 70 mg [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane received 108 mg of the compound indicated in the title (yield 88%). Melting point 258 - 260oC

1H-NMR (DMSO-d6) : 11.17 (1H,s), at 10.89 (2H, brs), 8.10 (1H, d, J=13 Hz), 7.88-7.25 (4H,m), 4.54-1.23 (11H,m).

EXAMPLE 54:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl - 6,8-debtor-4-oxoindole-3-carboxylic acid

A mixture of 100 mg of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro - 4-oxoindole-3-carboxylic acid and 60 mg [1,6,8] -8-amino-3 - azabicyclo[4.2.0]octane in 3 ml of acetonitrile was heated at reflux distilled with stirring for 4 hours, and then cooled to room temperature. Besieged thus the solids were filtered and washed with acetonitrile. Received contaminated solid particles suspended in 3 ml of water. For the deposition of solid particles that suspe the particles collected on the filter, washed first with cold water and then with acetonitrile, and dried. Received 100 mg of the compound indicated in the title (yield 72%). Melting point 183 - 185oC

1H-NMR (DMSO-d6+ TFA-d) : 8.68 (1H,s), 8.00 (2H, brs), 7.81 (1H, dd, J=12 Hz, J=2 Hz), 4.08-1.40 (11H,m), 1.10 (4H,m).

EXAMPLE 55:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-8-chloro-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid

Was repeated by the same method as in example 54. Using 100 mg of 8-chloro-1-cyclopropyl-6,7-debtor-1,4-dihydro-4 - oxoindole-3-carboxylic acid and 60 mg [1,6,8] -8-amino-3-azabicyclo [4.2.0]octane was obtained 86 mg of the compound indicated in the title (yield 67%). The melting point of 135 - 137oC

1H-NMR (DMSO-d6) : 8.8 (1H,s), 7.9 (1H, d, J=12.8 Hz), 4.3-1.5 (14H,m), 1.5-0.9 (4H,m).

EXAMPLE 56:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-5-amino-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

A suspension of 100 mg of 5-amino-1-cyclopropyl-6,7,8-Cryptor-1,4 - dihydro-4-oxoindole-3-carboxylic acid and 60 mg [1,6,8] -8-amino - 3-azabicyclo[4.2.0] octane in 5 ml of acetonitrile was heated at reflux distilled with stirring for 5 hours, the volatile matter is evaporated at an elevated pressure. To the residue was added 5 ml of water. For p the Solution is brought to pH 2 to 3 with an aqueous solution of diluted hydrochloric acid. Saducees while solid particles collected on the filter, washed with water, and then suspended in 5 ml of acetonitrile. Then the solids were stirred for 30 min, collected on the filter and dried. Received 75 mg of the compound indicated in the title (yield 55%). Melting point 223 - 226oC

1H-NMR (DMSO-d6) : 8.77 (1H,s), 4.2-1.3 (12H,m), 1.3 - 0.8 (4H,m).

EXAMPLE 57:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid

There was repeated the same procedure as in example 56. Using 100 mg of 1-cyclopropyl-6,7-debtor-1,4-dihydro-4 - oxoindole-3-carboxylic acid and 50 mg [1,6,8] -8-amino-3 - azabicyclo[4.2.0]octane was obtained 104 mg of the compound indicated in the title (yield 74%). Melting point 193 - 195oC

1H-NMR (DMSO-d6) : 8.6 (1H,s), 7.8 (1H, d, J=14 Hz), 7.5 (1H,d, J=8.0 Hz), 1.5-0.9 (4H,m).

EXAMPLE 58:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-5-methyl-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

A suspension of 100 mg of 5-methyl-1-cyclopropyl-6,7,8-Cryptor-1,4 - dihydro-4-oxoindole-3-carboxylic acid and 60 mg [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane in 3 ml of acetonitrile was heated at reflux distilled with stirring t is suspended in 3 ml of water. For the complete dissolution of solids pH this

the suspension is brought to 11-12 with a small amount of dilute sodium hydroxide solution. Upon completion of the neutralization traces of insoluble impurities. These impurities filtered out. The filtrate is brought to pH 2 to 3 with a small amount of dilute sodium hydroxide solution and then cooled in an ice bath. Saducees while solid particles collected on the filter, washed with cold water, and then dried. There was obtained 84 mg of the compound indicated in the title (yield 62%). Melting point 232 - 236oC

1H-NMR (DMSO-d6) : 8.6 (1H,s), 4.3-3.1 (6H,m), 2.7 (3H, d, J=4 Hz), 2.6-1.4 (6H,m), 1.3-0.9 (4H,m).

EXAMPLE 59:

7-([1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-6-fluoro-1-tert-butyl - 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

A suspension of 100 mg of 7-chloro-6-fluoro-1-tert-butyl-1,4-dihydro-4 - oxo-1,8-naphthiridine-3-carboxylic acid and 60 mg [1,6,8] -6-amino-3-azabicyclo[4.2.0] octane in 5 ml of acetonitrile was stirred at reflux distilled for 30 minutes the Solution was cooled to room temperature. A small number osadivshih solid particles filtered out. The filtrate is evaporated at an elevated pressure. To the residue was added dropwise an aqueous solution of time is then dried. Received 93 mg of the compound indicated in the title (yield 71%). Melting point 218 - 223oC

1H-NMR (DMSO-d6+ TFA-d) : 8.90 (1H,s), 8.09 (1H, d, J = 12.6 Hz), 4.80-2.35 (11H,m), 1.90 (9H,s).

EXAMPLE 60:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-8-chloro-6 - fluoro-5-methyl-1-cyclopropyl-1,4-dihydro-4-oxoindole-3-carboxylic acid

A suspension of 100 mg of 8-chloro-6,7-debtor-5-methyl-1-cyclopropyl-1,4 - dihydro-4-oxoindole-3-carboxylic acid and 6 mg [1,6,8] -8-amino-3 - azabicyclo[4.2.0] octane in 3 ml of acetonitrile was heated at reflux distilled with stirring for 4 hours, washed with a small amount of cold water, and then dried. There was obtained 55 mg of the compound indicated in the title, in the form of light yellow solids (yield 48%). The melting point of 162 - 166oC

1H-NMR (DMSO-d6) : 8.78 (1H,s), 4.60-2.90 (5H,m), 2.70 (3H, d, J=3.2 Hz), 2.30-1.40 (6H,m), 0.85 (4H,m).

EXAMPLE 61:

7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)- 1-cyclopropyl-5-methyl-6-fluoro-1,4-dihydro-4-oxoindole-3 - carboxylic acid

A suspension of 100 mg of 1-cyclopropyl-5-amino-6,7-debtor-1,4 - dihydro-4-oxoindole-3-carboxylic acid and 40 mg [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane in 8 ml of acetonitrile was heated at reflux distilled with stirring for 5 hours. After cooling down to to the small amount of dilute aqueous sodium hydroxide solution. A small amount nerastvorim solid particles filtered out. The filtrate is brought to pH 7 with dilute hydrochloric acid. Saducees the damp yellow solids were filtered. Saducees then light yellow solid particles collected on the filter, washed with water, and then dried. Was obtained 64 mg of the compound indicated in the title (yield 46%). The melting point of 172 - 175oC

1H-NMR (DMSO-d6) : 8.54 (1H,s), 7.38 (1H, d, J=8 Hz), 4.40-3.09 (5H, m), 2.75 (3H, d, J=4 Hz), 2.40-1.45 (6H,m), 0.40 - 0.90 (4H,m).

EXAMPLE 62:

(+)-7-( [1,6,8]-8-amino-3-azabicyclo[4.2.0]octane-3-yl-)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

Was repeated by the same method as in example 51. Using 100 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic acid and 50 mg(-)- [1,6,8] -3- azabicyclo[4.2.0]octane, obtained previously in the section "Preparation 19", received 110 mg of the compound indicated in the title (yield 76%). Melting point 285 - 287oC

[]2D0+50.6o(C=0.33, DMSO)

1H-NMR (DMSO-d6) : 8.59 (1H,s), 8.02 (1H, d, J=13.7 Hz), 4.90-7.10 (6H,m), 3.10-1.40 (6H,m), 1.40-0.80 (4H,m).

EXAMPLE 63:

(-)-7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl-)-1 - cyclopropyl-6-fluoro-1,4-DIH,8-naphthiridine-3-carboxylic acid and 50 mg(+)-[1,5,6] -8-amino-3 - azabicyclo[4.2.0] octane received earlier in the section "Preparation 25", in 5 ml of acetonitrile was stirred for 3 hours at a temperature of from 40 to 50oC. the resulting solution was cooled to room temperature and to it was added 3 - 4 drops of acetic acid. The formed precipitation was filtered and washed with cold acetonitrile. The resulting solids recrystallized twice from a mixture of chloroform and ethanol (3:2). There was obtained 70 mg of the compound indicated in the title (yield 53%). The melting point of 204 - 206oC

[]2D0-38.8o(C=0.4, DMSO)

1H-NMR (DMSO-d6) : 8.51 (1H,s), 7.98 (1H, d, J=14.6 Hz), 6.80-5.80 (2H, brs), 4.60-1.30 (12H,m), 1.30-0.90 (4H,m).

EXAMPLE 64:

(-)-7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1-cyclopropyl - 6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

To a suspension of 0.8 g of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro - 4-oxoindole-3-carboxylic acid and 0.51 g(-)- [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane in 10 ml of acetonitrile, in order to lighten the solution was added dropwise DBU. The resulting solution was cooled to -20oC. Precipitation was collected with filtration and washed with cold acetonitrile. The obtained solids were recrystallize from a mixture of chloroform and ethanol (3:1). There was obtained 0.78 g connection isC.

[]2D0- 8.2o(C=1.0, CHCl3)

1H-NMR (DMSO-d6+ TFA) : 8.68 (1H,s), 8.00 (2H, brs), 7.81 (1H, dd, J= 12 Hz, J=2 Hz), 4.08-1.40 (11H,m), 1.10 (4H,m).

EXAMPLE 65:

(+)-7-( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

There was repeated the same procedure as in example 64. Using 0.3 g of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro-4-oxoindole-3-carboxylic acid and 0.21 g(+)- [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane from the section "Preparation 25", was obtained 0.32 g of compound indicated in the title, in the form of a white powder (yield 78%). Melting point 186 - 190oC

[]2D0+ 9.8o(C=0.4, CHCl3)

1H-NMR (DMSO-d6+ TFA) : 8.68 (1H,s), 8.00 (2H, brs), 7.81 (1H, dd, J= 12 Hz, J=2 Hz), 4.08-1.40 (11H,m), 1.00 (4H,m).

EXAMPLE 66:

7- ( [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane-3-yl)- 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3 - carboxylic acid

To 100 ml of pyridine was added 100 mg of 1-cyclopropyl-6,7-debtor - 8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid and 50 mg [1,6,8] -8-amino-3-azabicyclo[4.2.0] octane. The resulting mixture was heated at reflux distilled with stirring for 2 hours, and then cooled to room temperature. To a solution of dobavilabi, washed with cold ethanol, and then dried. There was obtained 60 mg of the compound indicated in the title, in the form of white solids (yield 44%). Melting point 186 - 190oC

1H-NMR (DMSO-d6+ TFA) : 8.15 (1H,s), 7.70 (1H, d, J = 12 Hz), 4.50-3.76 (6H,m), 3.70 (3H,s), 3.57-1.28 (3H,m), 1.09 (4H,m).

EXAMPLE 67:

7-( [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0] octane-3-yl-)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, hydrochloride

150 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo - 1,8-naphthiridine-3-carboxylic acid and 190 mg [1,6,8] -8-amino-6-methyl - 3-azabicyclo[4.2.0] octane was added to 3 ml of acetonitrile. The resulting mixture was stirred at 50oC for 30 minutes After cooling to room temperature, to the resulting solution was added 3 drops of acetic acid and stirred for another 10 minutes Saducees solids were filtered and washed with acetonitrile. The resulting hard particles suspended in 3 ml of ethanol. To the suspension was added 4 - 5 drops of concentrated hydrochloric acid with stirring to completely dissolve any solids. The resulting solution was left overnight. Saducees solid particles collected on the filter, washed first with cold ethanol, and then isopropyl EPI - 266oC

1H-NMR (DMSO-d6) : 15.37 (1H, brs), 8.57 (1H,s), 8.47 (1H, brs), 7.97 (1H, d, J=13.5 Hz), 4.60-2.60 (6H,m), 2.65-1.57 (5H,m), 1.48-0.93 (7H,m).

EXAMPLE 68:

7-( [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0]octane-3-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, hydrochloride

Was repeated by the same method as in example 67. By using 150 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid and 190 mg [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0] octane was obtained 175 mg of the compound indicated in the title (yield 77%). Melting point 252 - 256oC

1H-NMR (DMSO-d6) : 15.19 (1H, brs), 8.57 (1H,s), 7.99 (1H,s), 7.99 (1H, d, J=13.4 Hz), 4.55-3.25 (6H,m), 2.27 - 1.56 (5H,m), 1.56-0.98 (7H,m).

EXAMPLE 69:

7-( [1,6,8] -8-amino-6-methyl-3-azabicyclo[4.2.0]octane-3-yl-)-1 - cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole--3-carboxylic acid

Was repeated by the same method as in example 14. Using 100 mg of 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro-4 - oxoindole-3-carboxylic acid and 120 mg [1,6,8] -8-amino-6-methyl-3 - azabicyclo[4.2.0]octane was obtained 95 mg of the compound indicated in the title (yield 72%). Melting point 265 - 268oC

1H-NMR (DMSO-d6+ TFA) : 8.67 (1H,s), 8.02 (2H, brs), 7.81 (1H, d, J= 11.7 Hz), 4.25-2.90 (6H,m), 2.36-1.50 (5H,m), 1.50-0.97 (7H,m).

In vitro antibacterial activity

To prove the antibacterial activity of derivatives of Spiridonova carboxylic acid according to the present invention in accordance with the method described in Chemotherapy, 29(1), R. 76 (1981), was determined by minimum inhibitory concentration (g/ml) of some compounds synthesized in the above examples. For this test were selected compounds of examples 12, 18, 20, 21, 31, 39, 41, 55, 56, 62 and 64. Ofloxacin (OFLX) and ciprofloxacin (CPFX) was used as control compounds. The results are shown below in table 3.

Note:

A: Staphylococcus aureus smith

B: Streptococcus pyogenes C4003

C: Methicilline Resistant Staphylococcus aureus C2208

D: Escherichia coli A10536

E: Klebsiella pneumoniae A10031

F: Pseudomonas Aeruginosa A278531

1. Derivatives Spiridonova carboxylic acid of the following formula I

< / BR>
in which R1represents lower alkyl, C3- C6-cycloalkyl, phenyl group, substituted by one or two halogen atoms;

R2represents a hydrogen atom, lower alkyl or amino group;

A represents a nitrogen atom or the group C - X, in which X represents a hydrogen atom, or halogen, or alkoxygroup;

Z represents the hydrogen or the group of lower alkyl, provided that if n = 2, then one of R3or R4at least, represents a hydrogen atom, one of R5or R6represents a hydrogen atom, and the other is a hydroxy-group of the lower alkyl or amino group, which is substituted or unsubstituted group of lower alkyl, provided that when n = 1 or one of R5and R6represents the amino group, one of R3or R4is not a hydrogen atom;

R7represents a hydrogen atom,

or their pharmaceutically acceptable salts.

2. Derived Spiridonova carboxylic acid of the formula I on p. 1, representing one of the following connections:

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

5-amino-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1-(2,4-differenl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane is abicyclo[3.2.0] heptane-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6-fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-t-butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4-differenl)-6-fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(+)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(+)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6,8-debtor-7-([1,5,6]-6-hydroxy-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-([1,5,6]-6-hydroxy-1-methyl-3-azabicyclo[3.] heptane-3-yl)-1-cyclopropyl-6,8-debtor-5-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(-)-5-amino-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(-)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-t-butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(-)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6-fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,6]-6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1-cyclopropyl-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,5,6]-6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6-fluoro-1-(4-forfinal)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

8-chloro-1-cyclopropyl-7-([1,5,6]-6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

7-([1,5,6]-6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

1-(2,4-differenl)-7-([1,5,6]-6-amino-5-methyl-3-azabicyclo[3.2.0] heptane-3-the EN-3-yl)-1-(2,4-differenl)-1,4-dihydro-6-fluoro-5-methyl-4-oxo-1,8-naphthiridine-3-carboxylic acid;

1-cyclopropyl-7-([1,5,6]-6-hydroxy-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

5-amino-1-cyclopropyl-7-([1,5,6]-6-hydroxy-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid;

1-cyclopropyl-7-([1,5,6]-6-hydroxy-3-azabicyclo[3.2.0] heptane-3-yl)-6,8-debtor-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,5,6]-6-amino-1-methyl-3-azabicyclo[3.2.0] heptane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

8-chloro-1-cyclopropyl-6-fluoro-7-([1,5,6]-1-methyl-6-methylamino-3-azabicyclo[3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6,8-debtor-7-([1,5,6]-1-methyl-6-methylamino-3-azabicyclo[3.2.0]heptane-3-yl)-1,4-dihydro-4-oxoindole-3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-([1,5,6]-1-methyl-6-methylamino-3-azabicyclo[3.2.0] heptane-3-yl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,5,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-(2,4-differenl)-1,4-dihydro-4-about the oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6,8-debtor-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-4-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-(-8-amino-3-azabicyclo[4.2.0] octane-4-yl)-5-amino-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-5-methyl-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-6-fluoro-1-tert-butyl-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-8-chloro-6-fluoro-5-methyl-1-cyclopropyl-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-5-methyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid;

(+)-7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid;

(-)-7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] the lo[4.2.0] Octan-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid;

7-([1,6,8]-8-amino-6-methyl-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, hydrochloride;

7-([1,6,8]-8-amino-6-methyl-3-azabicyclo[4.2.0] octane-3-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid.

3. Azabicyclo [3.2.0] heptane or 3-azabicyclo [4.2.0] octane General formula

< / BR>
in which n is 1 or 2;

R3and R4each represents a hydrogen atom or a group of lower alkyl, provided that when n = 2, then one of R3or R4at least, represents a hydrogen atom;

one of R5or R6represents a hydrogen atom, and the other is a hydroxy-group of the lower alkyl or amino group, which is substituted or unsubstituted group of lower alkyl, provided that when n = 1 and one of R5and R6represents the amino group, one of R3or R4is not a hydrogen atom.

4. The method of obtaining derivatives of Portonovo carboxylic acid of the formula I

< / BR>
in which R1represents lower alkyl, C3- C6-cycloalkyl is aroda, or lower alkyl, or amino group;

A represents a nitrogen atom or the group C - X, in which X represents a hydrogen atom or halogen, or alkoxygroup;

Z represents a group having the formula IV

< / BR>
where n is 1 or 2;

R3and R4each represents a hydrogen atom or a group of lower alkyl, provided that when n = 2, then one of R3or R4at least represents a hydrogen atom;

one of R5or R6represents a hydrogen atom, and the other is a hydroxy-group of lower alkyl, or amino group which is substituted or unsubstituted group of lower alkyl, provided that when n = 1 or one of R5and R6represents the amino group, one of R3or R4is not a hydrogen atom;

R7represents a hydrogen atom,

or their pharmaceutically acceptable salts, characterized in that the compound of formula II

< / BR>
in which Y represents a halogen atom;

R7represents a hydrogen atom;

R1, R2and A have the meanings given in paragraph 1,

subjected to interaction with the compound of the formula III

Z - H,

in which Z has the same meaning, which is efticiency acceptable salt.

5. Pharmaceutical composition having antibacterial activity which contains as an active ingredient one or more derivatives of Spiridonova carboxylic acid of the formula I under item 1 or 2, or their pharmaceutically acceptable salts.

6. The method of treatment of infectious diseases caused by bacteria, which includes the introduction in the organism an effective amount of one or more compounds of Spiridonova carboxylic acid of the formula I under item 1 or 2, or their pharmaceutically acceptable salts.

7. Derivatives Spiridonova carboxylic acid of General formula I or their pharmaceutically acceptable salts under item 1, which have antibacterial activity.

 

Same patents:

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

The invention relates to new derivatives of imidazopyridines formula I

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

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

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

The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

The invention relates to compounds of the following formula I which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only their

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

The invention relates to 2-[(dihydro)pyrazolyl-3'-oxymethylene] anilides formula I

< / BR>
in whichmeans simple or double bond, and the index and the substituents have the following meanings:

n means 0, 1 or 2;

m means 0, 1 or 2 and the substituents R2may be different if m is greater than 1;

X represents a direct bond, O or NRa;

Rameans hydrogen;

R1means halogen or C1-C4alkyl, or, if n is 2, represents optionally associated with two adjacent ring atoms of the hydrocarbon bridge containing 3 or 4 carbon atoms;

R2means nitro, halogen, C1-C4alkyl, C1-C4halogenated or1-C4alkoxycarbonyl;

R3means optionally substituted alkyl, optionally substituted saturated cycle or optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms;

R4means hydrogen, optionally substituted alkyl;

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid
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