HU211837A9 - 4-oxoquinoline-3-carboxylic acid derivatives and their use - Google Patents

Description

BACKGROUND OF THE INVENTION

The present invention relates to a series of novel 8- (fluorinated methoxy) -4-oxoquinoline carboxylic acid derivatives having valuable and potent antibacterial activity. The invention further relates to compositions containing such compounds, to the use of such compounds, and to the preparation of such compounds.

The compounds of the present invention are 1-cyclopropyl-4-oxo-6-fluoro-7- (optionally substituted heterocyclic) -8- (fluoro-methoxy) -quinoline-3-carboxylic acid derivatives and 1-cyclopropyl-4-oxo-5-amino- 6-fluoro-7 (optionally substituted heterocyclic) -8- (fluorinated methoxy) quinoline-3-carboxylic acid derivatives.

One unfortunate fact of modem medicine is that many infectious bacteria gradually become resistant to the antibiotics commonly used to treat the infections they cause, with the result that the importance of known antibacterial agents gradually decreases. Therefore, there is a continuing need to develop new antibacterial agents that are effective against infectious bacteria, even for a limited period. Most of the conventional antibacterial agents used today are originally derived from fermentation products, although some are entirely synthetic.

The use of certain 4-oxoquinoline-3-carboxylic acid derivatives as antibacterial agents has been previously proposed. For example, EP-A-78,362 discloses a limited group of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid derivatives wherein the piperazinyl group unsubstituted or substituted at the 4-position with methyl, ethyl or β-hydroxyethyl. These compounds resemble some of the compounds of the invention, except that they do not possess the 8-fluorinated methoxy group, which is found to be critical for the excellent activity of the compounds of the invention.

European Patent Publication Nos. 106,489, 153,163, 230,295, 235,762, and 241,206 disclose various quinoline derivatives including, among other things, certain 1-substituted

4-oxo-1,4-dihydro-6-halo-7- (optionally substituted heterocyclic) -8-substituted-quinoline-3-carboxylic acid derivatives, some of which carry an alkoxy group as 8-substituents, but no compounds are disclosed having an 8-substituent on the fluorinated methoxy group.

One of the compounds disclosed in EP-A-78362, Norfloxacin, systematically named 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid, published in The Merck Index (10th Edition), duplicated in 1983. in book number 6541. However, like the other compounds disclosed in EP 78362, this compound does not have the critical 8-fluorinated methoxy substituent of the invention.

Surprisingly, it has been discovered that the combination of a limited group of 8-fluorinated methoxy substituents with certain limited and highly specific 7-position heterocyclic substituents and optionally a 5-position amino group leads to the formation of compounds that unexpectedly have good antibacterial activity on Gram-positive and Gram-negative in many cases, this effect is greatly enhanced compared to the compounds known in the art. In particular, the compounds of the invention have surprisingly good activity against a number of Gram-positive bacteria for which the known compounds are ineffective or only active at high concentrations, such as Staphylococcus aureus and Entemcoccus faecalis.

It is believed that the closest known solutions in the art are those described in European Patent Application Nos. 78,362,230,295 and 241,206. Surprisingly, it has been found that the compounds of the present invention have exceptionally potent antibacterial activity against Gram-positive bacteria and Pseudomonas aeruginosa resistant to penicillin and cephalosporin, which are only difficult to control with β-lactam antibiotics and thus represent a major medical problem.

BRIEF SUMMARY OF THE INVENTION Thus, one object of the present invention is a series of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivatives having exceptional antibacterial activity.

It is a further object of the present invention to provide pharmaceutical compositions containing such a quinoline derivative as an antibacterial agent.

It is a further object of the present invention to provide methods of treating or preventing bacterial infections in animals (including man) by administering such a quinoline derivative.

The compounds of the invention are compounds of formula (I). In this formula

R ¹ is a methoxy group containing at least one fluorine substituent;

^R2 is selected from the group.

(i) groups of formula (II) - in this formula

R ⁴ is hydrogen; hydroxy;

amino; C 1-6 alkyl; C 1-6 alkyl substituted with at least one substituent selected from the group consisting of (a) as defined below; aralkyl; C 1-6 aliphatic acyl; or a C2-C6 aliphatic acyl group substituted with at least one substituent selected from the group consisting of (a) as defined below;

R ⁵ is hydrogen, (C 1 -C 6) alkyl or (C 1 -C 6) alkyl substituted with at least one substituent selected from the group consisting of (b);

A is ethylene, trimethylene or -COCH ₂ -; and

A9 m is 1 or 2;

(ii) groups of formula (III) - in this formula

R ⁶ is hydrogen; C 1-6 alkyl; C 1-6 alkyl substituted with at least one substituent selected from the group consisting of substituents (b) as defined below; hydroxy; C 1-6 alkoxy; or C 1 -C 6 alkoxy substituted with at least one fluoro substituent;

R ⁷ is R ⁸ R ⁹ N- (CH ₂ ) n - wherein R ⁸ and R ⁹ are each independently hydrogen or C 1-6 alkyl or aralkyl and q is 0 or 1; hydroxy; or C 1-6 alkoxy;

B is methylene, ethylene, triethylene or tetramethylene; and n is 1 or 2;

(iii) groups of formula (IV) - in this formula

R ¹⁰ is hydrogen or C 1-6 alkyl; or (iv) groups of formula V in this formula

Z is oxygen or sulfur;

R ³ is hydrogen or amino; the substituents (a) include hydroxy groups, C1-C6 alkoxy groups, C2-C6 aliphatic acyloxy groups, C1-C6 aliphatic acyl groups, carboxyl groups, C2-C6 alkoxycarbonyl groups, sulfo groups, amino groups, C2-C6 aliphatic acyl groups and the alkyl moiety or alkyl moieties include mono- and dialkylamino groups containing from 1 to 6 carbon atoms;

substituents (b) include hydroxy groups, C 1 -C 6 alkoxy groups and halogen atoms; and the aralkyl groups have from 1 to 4 carbon atoms in their alkyl moiety and from 6 to 10 carbon atoms in their aryl moiety, and the latter may be unsubstituted or substituted with at least one substituent selected from the group consisting of (c);

substituents (c) include hydroxy groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, C 2-6 aliphatic acyloxy groups, C 1-6 aliphatic acyl groups, carboxyl groups, C 2-6 alkoxycarbonyl groups, sulfo groups, nitro groups, cyano groups, amino groups, C2-C6 aliphatic acylamino groups and mono- and dialkylamino groups containing 1 to 6 carbon atoms in the alkyl moiety or alkyl moieties.

The present invention includes pharmaceutically acceptable salts, esters and amides of the compounds of formula (I).

The invention further relates to pharmaceutical compositions for treating bacterial infections comprising an effective amount of an antibacterial agent in combination with a pharmaceutically acceptable carrier or diluent, wherein the antibacterial agent is selected from the group consisting of compounds of Formula I and pharmaceutically acceptable salts, esters and amides thereof.

The invention further relates to a method of treating or preventing a bacterial infection comprising administering to an animal (which may be a mammal such as a human) an amount of an antibacterial agent sufficient to provide an antibacterial effect, wherein the antibacterial agent is a compound of formula (I). and an agent selected from the group consisting of compounds thereof, and pharmaceutically acceptable salts, esters and amides thereof.

The invention further relates to methods for preparing the compounds of the invention, which methods will be described in more detail below.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of the present invention, R ¹ is a methoxy group having at least one fluoro substituent, which may be monofluoromethoxy, difluoromethoxy or trifluoromethoxy, of which difluoromethoxy and trifluoromethoxy are preferred.

When R ² is a group of formula (II) and R ⁴ is an alkyl group, it may be a straight or branched alkyl group having 1 to 6, preferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, terepentyl, hexyl or 1,3-dimethylbutyl. Of these, methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups are preferred. Such alkyl groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of (a), as defined above, and in particular the following substituents:

hydroxyl brides;

straight or branched chain alkoxy groups having 1 to 6, preferably 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, tert-pentyloxy; and hexyloxy groups, of which methoxy, ethoxy, propoxy and isopropoxy groups are preferred;

Aliphatic acyloxy groups having from 2 to 6, preferably from 2 to 4 carbon atoms, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy groups. of which acetoxy, propionyloxy, butyryloxy and isobutyryloxy are preferred;

Aliphatic acyl groups having from 1 to 6, preferably from 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl, of which formyl, acetyl, propionyl -, butyryl and isobutyryl groups are preferred;

carboxyl groups;

alkoxycarbonyl groups having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms in total (i.e. the alkoxy moiety contains 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms), such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso

EN 211 837 A9 propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl groups, of which methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl groups are preferred;

sulfo;

amino groups;

Aliphatic acylamino groups having from 2 to 6, preferably from 2 to 4 carbon atoms, such as acetamido, propionamido, butyramido, isobutyramido, valeramido, isovaleramido and pivaloylamino, of which acetamido, propionamido, butiramido and isobutyramido are preferred. ; and mono- and dialkylamino groups having alkyl or alkyl moieties having from 1 to 6, preferably from 1 to 4, carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, pentylamino and hexylamino groups, of which methylamino, dimethylamino, ethylamino , propylamino, isopropylamino, butylamino and isobutylamino are preferred.

When R ⁴ is aralkyl, it has 1-4 alkyl groups in its alkyl moiety and its aryl moiety

It contains 6 to 10 carbon atoms. Examples of such groups include benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl and the like. 2-naphthylmethyl. These groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of (c) as defined above. Exemplary groups of substituents (c) include the same groups as those listed for substituents (a), C 1-6 alkyl, examples of which are mentioned with respect to R ⁴ in alkyl groups, and nitro and cyano groups, especially alkoxy. , amino, monoalkylamino and dialkylamino groups. Examples of such groups are benzyl, p-methoxybenzyl, p-aminobenzyl, p-methylamino-benzyl and p-dimethylamino-benzyl.

When R ⁴ is an aliphatic acyl group, it may contain from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutylryl, valeryl, isovaleryl, pivaloyl and hexanoyl, which may be mentioned. of which formyl, acetyl, propionyl, butyryl and isobutyryl are preferred. These groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of substituents (a) as defined and exemplified above.

When R ² is a group of formula (II) or (IV), each of R ⁵ and R ¹⁰ may be hydrogen or alkyl of 1 to 6, preferably 1 to 3 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl and 1,3-dimethylbutyl. Of these, methyl, ethyl, propyl and isopropyl groups are preferred. R ⁵ furthermore represent substituents selected from the group consisting defined above (b) is substituted by at least one substituent is an alkyl group, whereby these substituents may be as follows:

hydroxyl groups;

straight or branched chain alkoxy groups having from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, terepentyl; oxy and hexyloxy groups, of which methoxy, ethoxy, propoxy and isopropoxy are preferred; and halogen atoms such as fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

When R ² is a group of formula (ΠΙ), R ⁶ may be: hydrogen; C 1-6, preferably C 1-3 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl and 1,3-dimethyl. butyl, of which methyl, ethyl, propyl and isopropyl are preferred;

C 1 -C 6 substituted alkyl, which may be a substituent selected from the group consisting of substituents (b) as previously defined and exemplified, exemplified above; Alkoxy groups having from 1 to 6, preferably from 1 to 3 carbon atoms, such as methoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, tertiaryloxy and hexyloxy, of which methoxy -, ethoxy, propoxy and isopropoxy groups are preferred; or having at least one fluorine substituent,

Alkoxy groups having 1 to 6, preferably 1 to 3 carbon atoms, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy,

1-fluoro-ethoxy, 2-fluoro-ethoxy, 2,2-difluoro-ethoxy, 2,2,2-trifluoro-ethoxy, 3-fluoro-propoxy, 4-fluoro-butoxy, 5-fluoro- pentyloxy, 6-fluoro-hexyloxy, 3,3-difluoropropoxy,

3,3,3-trifluoropropoxy, 4,4-difluorobutoxy and 4,4,4-trifluorobutoxy, among which are fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1- fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy are preferred.

When R ² is a group of formula (III) and R ⁷ is a group of formula R ⁸ R ^{9 is} N- (CH ₂ ) _q -, then R ⁸ and R ^{9 are the} same or different hydrogen; C 1-6, preferably C 1-3 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl and 1,3-dimethyl. butyl, of which methyl, ethyl, propyl, and isopropyl are preferred; or aralkyl, the aralkyl group mentioned in the latter R ⁴ may be as defined and exemplified and optionally substituted with at least one substituent selected from the group consisting of (c), as defined above and exemplified, preferably C 1-6 alkoxy; the alkyl moiety or moieties having from 1 to 6 carbon mono- or dialkylamino groups, such aralkyl groups being, for example, benzyl, p-methoxybenzyl, p-aminobenzyl, p-methylamino-benzyl and p - (dimethylamino) benzyl.

HU 211 837 A9

Alternatively, R ^{7 is} hydroxy;

Alkoxy groups having 1 to 6, preferably 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, tert-pentyloxy and hexyloxy. of which methoxy, ethoxy, propoxy and isopropoxy are preferred.

In the formula (V), Z may be oxygen or sulfur; when it is oxygen, the group is morpholino; when it is sulfur, the group is a thiomorpholino group, i.e. perhydro-1,4-thiazin-4-yl.

Preferred compounds of formula (I) are those wherein R ² is (Π) (wherein R ⁴ , R ⁵ , A and m are as previously defined);

(Dia) (wherein R ⁶ is hydrogen or C 1-3 alkyl; B 'is methylene or ethylene; and n is as previously defined);

(IIIb) R (in which R ^6, R ^8, R ^9, Β ', n and q are as defined above);

(IIIe) (wherein R ¹¹ and R ¹² are independently selected from hydroxy or C 1-3 alkoxy);

A group of formula (IVa) (wherein R ¹⁰ is as previously defined); or a group of formula (V) (wherein Z is as previously defined).

Also preferred are compounds of formula I wherein R ^{1 is} preferably difluoromethoxy or trifluoromethoxy, and particularly preferably wherein R ¹ is difluoromethoxy or trifluoromethoxy and R ² is as defined above (Π). , (IIIa), (IIIb), (IIIc), (IVa) or (V) R, is H or ^R3, or ^R3 is amino.

The compounds of the invention contain a carboxyl group at the 3-position of the quinoline ring. This carboxyl group can form esters, amides and salts.

When the carboxyl group is esterified, the nature of the ester obtained is not critical to the invention. In principle, the compounds of the invention, as carboxylic acids, form esters with any alcohol suitable for esterification, and all such esters form part of the invention. However, if the esters are to be used for therapeutic purposes, it is of course necessary that the esters formed must be pharmaceutically acceptable, which, as is obvious in the literature, means that the esters cannot have reduced activity (or unacceptably reduced activity) and increased toxicity (or unacceptably increased toxicity) relative to the free acid. However, if the ester is used for other purposes, for example as intermediates in the preparation of other compounds, this criterion does not even apply.

Such esters may be mentioned by way of example

C 1-6, more preferably C 1-4 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl; aralkyl esters (including diaryl alkyl esters) such as benzyl, p-nitrobenzyl and benzhydryl esters; lower aliphatic acyloxyalkyl groups such as acetoxymethyl or pivaloyloxymethyl; alkoxycarbonylalkyl esters wherein both the alkoxy and alkyl moieties contain from 1 to 4 carbon atoms, in particular alkoxycarbonylmethyl and 1- (alkoxycarbonyl) ethyl esters such as ethoxycarbonylmethyl and tert-butoxy; carbonyl-methyl ester; alkoxycarbonyloxyalkyl esters wherein the alkoxy and alkyl moieties contain from 1 to 4 carbon atoms, in particular the 1- and 2- (alkoxycarbonyloxy) ethyl esters, such as 1- (ethoxycarbonyloxy) ethyl; , 1- (isopropylcarbonyloxy) ethyl, 2- (methoxycarbonyloxy) ethyl, 2- (ethoxycarbonyloxy) ethyl and 2- (tert-butoxycarbonyloxy) - ethyl esters; N, N-disubstituted aminocarbonylalkyl esters wherein the alkyl group has 1 to 6, preferably 1 to 4 carbon atoms and the amino substituents are preferably 1 to 4 carbon atoms, such as the Ν, Ν-dimethylaminocarbonylmethyl esters; and other specific esters such as phthalidyl, substituted phthalidyl, phenacyl, substituted phenacyl (e.g. p-nitrophenacyl), (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl- and (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esters.

Similarly, when the carboxyl group forms an amide, the exact nature of the amide is not critical, provided that the amide is used for therapeutic purposes, since the amide formed must then be pharmaceutically acceptable. Accordingly, the carboxyl group can be replaced a carbamoyl or substituted carbamoyl group, preferably an alkyl-carbamoyl, dialkylaminocarbonyl in which the alkyl groups or the alkyl groups have 1-3 carbon atoms, such as defined in relation to R ⁴ substituent groups, the examples of such groups are methyl carbamoyl, ethylcarbamoyl, dimethylcarbamoyl or diethylcarbamoyl.

The carboxyl group may also form salts with suitable bases. The nature of such salts is not critical, provided that when used for therapeutic purposes the salts must be pharmaceutically acceptable. Examples of salts with bases include: salts with metals, especially alkali metals and alkaline earth metals such as lithium, sodium, potassium, calcium and magnesium, and salts with other metals such as manganese, iron and aluminum; ammonium salts; salts with organic amines such as cyclohexylamine, diisopropylamine or triethylamine; and salts with basic amino acids such as lysine or arginine.

The compounds of the present invention contain a basic nitrogen atom and may thus form acid addition salts. The nature of such salts is also irrelevant to the invention, provided that when used for therapeutic purposes, the salts must be pharmaceutically acceptable. A wide variety of acids can be used to form such salts, and mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, or sulfuric acid are representative examples of such acids; organic carboxylic acids such as acetic acid, oxal5

A9 acid, tartaric acid, citric acid, benzoic acid, glycolic acid, gluconic acid, gluconic acid, succinic acid, maleic acid or fumaric acid; and organic sulfonic acids, such as methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Such acid addition salts may be prepared by conventional methods.

The compounds of the invention may also be in the form of hydrates and thus form part of the invention.

Specific examples of compounds of the invention are given with reference to Formula I, the substituents of which are defined in Table I below. The following abbreviations are used in the table:

Ac acetyl AZP perhydroazepinylcarbonyl it azitidinil bz benzyl Diz perhydro-1,4-diazepinyl (= homopiperazinil) et ethyl etc Ethoxycarbonyl imide imidazole Me methyl Moorish morpholino Pip piperidyl Piz yl Pr isopropyl Pyrd yl SFO sulfo thz perhydro-1,4-thiazin-4-yl (= thiomorpholino)

TABLE 1

Serial number of compound: R ¹ R ³ R ² 1 OCHF ₂ H 1-Piz 2 ochf ₂ H 3-Me-l-Piz 3 ochf ₂ H 3,5-dimethyl-l-Piz 4 ochf ₂ H 2,5-dimethyl-l-Piz 5 ochf ₂ H 4-Me-1-Piz 6 ochf ₂ H 3,4-dimethyl-l-Piz 7 ochf ₂ H 3,4,5-trim-l-Piz 8 ochf ₂ H 4-Et-1-Piz 9 ochf ₂ H 4- (2-HOEt) - 1-Piz 10 ochf ₂ H 4- (2-HKC) -l-Piz 11 ochf ₂ H 4- (2- AcOEt) -1-Piz 12 ochf ₂ H 4- (2-NH ₂ Et) -1-Piz 13 ochf ₂ H 4- (2-NMe ₂ Et) -1-Piz 14 ochf ₂ H 4- (4-NH ₂ Bz) -1-Piz 15 ochf ₂ H 4 HCO-l-Piz 16 ochf ₂ H 4-Ac-1-Piz 17 ochf ₂ H 4- (ACME) -1-Piz

18 ochf ₂ H 4- (EtcMe) -1-Piz 19 ochf ₂ H 4- (SfoMe) -1-Piz 20 ochf ₂ H 1 Diz 21 ochf ₂ H 4-Me-1 -Design 22 ochf ₂ H 3-oxo-1-Piz 23 ochf ₂ H 4-Me-3-oxo-1-Piz 24 ochf ₂ H 3-HO-l-Pyrd 25 ochf ₂ H 4-HO-1-Pip 26 ochf ₂ H 3,4-diHO-l-Pyrd 27 ochf ₂ H 3-HO-4-MeO-l-Pyrd 28 ochf ₂ H 3-NH ₂ -l-Azt 29 ochf ₂ H 3-NHMe I-l 30 ochf ₂ H 3-NMe ₂ -l-Azt 31 ochf ₂ H 3- (NH ₂ Me) -1-Azt 32 ochf ₂ H 3 - [(NHEt) Me] -l-I 33 ochf ₂ H 3 - [(NMe2) Me] -l-I 34 OCHFj H 3-NH ₂ -l-Pyrd 35 ochf ₂ H 3-NHEt-l-Pyrd 36 ochf ₂ H 3-NMe ₂ -1-pyrid 37 ochf ₂ H 3- (NH ₂ Me) -1-pyrid 38 ochf ₂ H 3 - [(NHMe) Me] -l-Pyrd 39 ochf ₂ H 3 - [(NHEt) Me] -l-Pyrd 40 ochf ₂ H 3 - [(NMe ₂ ) Me] -1-pyrid 41 ochf ₂ H 3-NH ₂ -4-Me-1-Pyrd 42 ochf ₂ H 3-NH ₂ -4-HO-1-Pyrd 43 ochf ₂ H 3-NH ₂ -4-MeO-1-Pyrd 44 ochf ₂ H 3-NH ₂ -4-EtO-1-Pyrd 45 ochf ₂ H 4-NH ₂ -l-Pip 46 ochf ₂ H 4-NHMe-l-Pip 47 ochf ₂ H 4-NMe ₂ -l-Pip 48 ochf ₂ H 3-NH ₂ -l-Pip 49 ochf ₂ H 3-NHMe-l-Pip 50 ochf ₂ H 3-NH ₂ -1-Azp 51 OCHFj H 3-NH ₂ -3-Me-1-Pyrd 52 ochf ₂ H 1-imide 53 OCHFj H 4-Me-1-Imids 54 ochf ₂ H Moorish 55 ochf ₂ H thz 56 ochf ₂ H 3-Et-1-Piz 57 ochf ₂ H 3,3-diMe-1-Piz 58 ochf ₂ H 3-iPr-1-Piz 59 ochf ₂ H 3- (MeOMe) -1-Piz 60 ochf ₂ H 4- (HCOMe) -3-Me-l- Piz 61 ochf ₂ H 3,5-di (CH ₂ F) -1-Piz 62 ochf ₂ H 4-NH ₂ -1-Piz 63 ochf ₂ H 4-HO-1-Piz 64 ochf ₂ H 4- (2-Hoet) 3-Me-l-Piz

HU 211 837 A9

65 ochf ₂ H 4- (2-HKC) -3-Me-l- Piz 66 ochf ₂ H 3-CH ₂ Fl-Piz 67 ochf ₂ H 4-NH ₂ -3-Me-1-Piz 68 ochf ₂ H 4- (HCOMe) -1-Piz 69 ochf ₂ H 4-HO-3-Me-1-Piz 70 ochf ₂ H 4- (ACME) -3-Me-l-Piz 71 ochf ₂ H 3-Me-l-Diz 72 ochf ₂ H 3-NH ₂ -4- (MeOMe) -1- Pyrd 73 ochf ₂ H 3-NH ₂ -4- (CF ₃ CH ₂ O) -1-Pyrd 74 ochf ₂ nh ₂ 1-Piz 75 ochf ₂ nh ₂ 3-Me-l-Piz 76 ochf ₂ nh ₂ 3,5-dimethyl-l-Piz 77 ochf ₂ nh ₂ 2,5-dimethyl-1-Piz 78 OCHFj nh ₂ 4-Me-1-Piz 79 ochf ₂ nh ₂ 3,4-dimethyl-l-Piz 80 ochf ₂ nh ₂ 3,4,5-trim-l-Piz 81 ochf ₂ nh ₂ 4-Et-1-Piz 82 ochf ₂ nh ₂ 4- (2-Hoet) -1-Piz 83 ochf ₂ nh ₂ 4- (2-HKC) -1-Piz 84 ochf ₂ nh ₂ 4- (2-AcOEt) - 1-Piz 85 ochf ₂ nh ₂ 4- (2-NH ₂ Et) -1-Piz 86 ochf ₂ nh ₂ 4- (2-NMe ₂ Et) -1-Piz 87 ochf ₂ nh ₂ 4- (4-NH ₂ Bz) -1-Piz 88 ochf ₂ nh ₂ 4 HCO-l-Piz 89 ochf ₂ nh ₂ 4-Ac-1-Piz 90 ochf ₂ nh ₂ 4- (ACME) -I-Piz 91 ochf ₂ nh ₂ 4- (EtcMe) -1-Piz 92 ochf ₂ nh ₂ 4- (SfoMe) -1-Piz 93 ochf ₂ nh ₂ 1 Diz 94 ochf ₂ nh ₂ 4-Me-l-Diz 95 ochf ₂ nh ₂ 3-oxo-1-Piz 96 ochf ₂ nh ₂ 4-Me-3-oxo-1-Piz 97 ochf ₂ nh ₂ 3-HO-l-Pyrd 98 ochf ₂ nh ₂ L-4-HO-Pip 99 ochf ₂ nh ₂ 3,4-diHO-l-Pyrd 100 OCHFj nh ₂ 3-HO-4-MeO-l-Pyrd 101 ochf ₂ nh ₂ 3-NH ₂ -l-Azt 102 OCHFj nh ₂ 3-NHMe I-l 103 ochf ₂ nh ₂ 3-NMe ₂ -l-Azt 104 ochf ₂ nh ₂ 3- (NH ₂ Me) -1-Azt 105 ochf ₂ nh ₂ 3 - [(NHEt) Me] -l-I 106 ochf ₂ nh ₂ 3 - [(NMe ₂ ) Me] -1-Azt 107 ochf ₂ nh ₂ 3-NH ₂ -l-Pyrd 108 ochf ₂ nh ₂ 3-NHEt-l-Pyrd 109 ochf ₂ nh ₂ 3-NMe ₂ -1-pyrid 110 ochf ₂ nh ₂ 3- (NH ₂ Me) -1-pyrid

111 ochf ₂ nh ₂ 3 - [(NHMe) Me] -l-Pyrd 112 ochf ₂ nh ₂ 3 - [(NHEt) Me] -l-Pyrd 113 ochf ₂ nh ₂ 3 - [(NMe ₂ ) Me] -1-pyrid 114 ochf ₂ nh ₂ 3-NH ₂ -4-Me-1-Pyrd 115 ochf ₂ nh ₂ 3-NH ₂ -4-HO-1-Pyrd 116 ochf ₂ nh ₂ 3-NH ₂ -4-MeO-1-Pyrd 117 ochf ₂ nh ₂ 3-NH ₂ -4-EtO-1-Pyrd 118 ochf ₂ nh ₂ 4-NH ₂ -l-Pip 119 ochf ₂ nh ₂ 4-NHMe-l-Pip 120 ochf ₂ nh ₂ 4-NMe ^ l-Pip 121 ochf ₂ nh ₂ 3-NH ₂ -l-Pip 122 ochf ₂ nh ₂ 3-NHMe-l-Pip 123 ochf ₂ nh ₂ 3-NH ₂ -1-Azp 124 ochf ₂ nh ₂ 3-NH ₂ -3-Me-1-Pyrd 125 ochf ₂ nh ₂ 1-imide 126 ochf ₂ nh ₂ 4-Me-1-imide 127 ochf ₂ nh ₂ Moorish 128 ochf ₂ nh ₂ thz 129 ochf ₂ nh ₂ 3-Et-1-Piz 130 ochf ₂ nh ₂ 3,3-dimethyl-l-Piz 131 ochf ₂ nh ₂ Sd-3, 5-iPr-1-Piz 132 ochf ₂ nh ₂ 3- (MeOMe) - 1-Piz 133 ochf ₂ nh ₂ 4- (HCOMe) -3-Me-l- Piz 134 ochf ₂ nh ₂ 3,5-di (CH ₂ F) -1-Piz 135 OCHF ₂ nh ₂ 4-NH ₂ -l-Piz 136 ochf ₂ nh ₂ 4-HO-1-Piz 137 OCHFj nh ₂ 4- (2-Hoet) -3-Me-l- Piz 138 ochf ₂ nh ₂ 4- (2-HKC) -3-Me-l- Piz 139 OCHFj nh ₂ 3-CH ₂ Fl-Piz 140 ochf ₂ nh ₂ 4-NH ₂ -3-Me-1-Piz 141 ochf ₂ nh ₂ 4- (HCOMe) - 1-Piz 142 ochf ₂ nh ₂ 4-HO-3-Me-1-Piz 143 ochf ₂ nh ₂ 4- (ACME) -3-Me-1-Piz 144 ochf ₂ nh ₂ 3-Me-l-Diz 145 ochf ₂ nh ₂ 3-NH ₂ -4- (MeOMe) -1- Pyrd 146 ochf ₂ nh ₂ 3-NH ₂ -4- (CF ₃ CH ₂ O) -1-Pyrd 147 ocf ₃ H 1-Piz 148 ocf ₃ H 3-Me-1-Piz 149 ocf ₃ H 3,5-dimethyl-1-Piz 150 ocf ₃ H 2,5-dimethyl-1-Piz 151 ocf ₃ H 3,3-dimethyl-1-Piz 152 ocf ₃ H 4-Me-1-Piz 153 ocf ₃ H 3,4-dimethyl-l-Piz 154 ocf ₃ H 4-Et-1-Piz

HU 211 837 A9

155 ocf ₃ H 4- (2-Hoet) -l-Piz 156 ocf ₃ H 4- (2-HKC) -1-Piz 157 ocf ₃ H 4- (2-AcOEt) -1-Piz 158 ocf ₃ H 4- (2-NH ₂ Et) -1-Piz 159 ocf ₃ H 4- (4-NH ₂ Bz) -1-Piz 160 ocf ₃ H 4 HCO-1-Piz 161 ocf ₃ H 4-Ac-1-Piz 162 ocf ₃ H 4- (ACME) -l-Piz 163 ocf ₃ H 4- (HOOCMe) -1-Piz 164 ocf ₃ H 4- (EtcMe) -l-Piz 165 ocf ₃ H 1 Diz 166 ocf ₃ H 4-Me-l-Diz 167 ocf ₃ H 3-oxo-1-Piz 168 ocf ₃ H 4-Me-3-oxo-Piz 169 ocf ₃ H 3-HO-I-I 170 ocf ₃ H 3-HO-l-Pyrd 171 ocf ₃ H 3-HO-4-MeO-l-Pyrd 172 ocf ₃ H 3,4-diMeHO-l-Pyrd 173 ocf ₃ H 3-NH ₂ -l-Azt 174 ocf ₃ H 3-NHMe-1-I 175 ocf ₃ H 3-I-I-NHEt 176 ocf ₃ H 3- (NH ₂ Me) -1-Azt 177 ocf ₃ H 3 - [(NHMe) Me] -l-I 178 ocf ₃ H 3 - [(NMe ₂ ) Me] -1-Az 179 ocf ₃ H 3-NH ₂ -l-Pyrd 180 ocf ₃ H 3-NHMe-1-Pyrd 181 ocf ₃ H 3-NMe ₂ -1-pyrid 182 ocf ₃ H 3- (NH ₂ Me) -1-pyrid 183 OCF, H 3 - [(NHMe) Me] -l-Pyrd 184 ocf ₃ H 3 - [(NHEt) Me] -l-Pyrd 185 ocf ₃ H 3 - [(NMe ₂ ) Me] -1-pyrid 186 ocf ₃ H 3-NH ₂ -4-Me-1-Pyrd 187 ocf ₃ H 3-NH ₂ -4-HO-1-Pyrd 188 ocf ₃ H 3-NH ₂ -4-MeO-1-Pyrd 189 ocf ₃ H 3-NH ₂ -4-EtO-1-Pyrd 190 ocf ₃ H 4-NH ₂ -l-Pip 191 ocf ₃ H 4-NHMe-l-Pip 192 ocf ₃ H 3-NH ₂ -l-Pip 193 ocf ₃ H 3-NHMe-1-Pip 194 ocf ₃ H 3-NMe ₂ -l-Pip 195 ocf ₃ H 3-NH ₂ -1-Azp 196 ocf ₃ H 3-NH ₂ -3-Me-1-Pyrd 197 ocf ₃ H 1-imide 198 ocf ₃ H 4-Me-l-imide 199 ocf ₃ H Moorish 200 ocf ₃ H thz 201 och ₂ f H 3,3-dimethyl-1-Piz 202 och ₂ f H 4-Me-l-Diz

203 och ₂ f H 1-Piz 204 och ₂ f H 1 Diz 205 och ₂ f H 3-NH ₂ -l-Pyrd 206 och ₂ f H 3-Me-l-Piz 207 och ₂ f H 4-Me-1-Piz 208 och ₂ f H 3-NH ₂ -4-Me-1-Pyrd 209 och ₂ f H 3,5-dimethyl-l-Piz 210 och ₂ f H 3,4-dimethyl-l-Piz 211 och ₂ f H 3-NHMe-1-Pyrd 212 och ₂ f H 3-NMe ₂ -1-pyrid 213 ocf ₃ nh ₂ 1-Piz 214 ocf ₃ nh ₂ 3-Me-1-Piz 215 ocf ₃ nh ₂ 3,5-dimethyl-l-Piz 216 ocf ₃ nh ₂ 2,5-dimethyl-l-Piz 217 ocf ₃ nh ₂ 3,3-dimethyl-1-Piz 218 ocf ₃ nh ₂ 4-Me-1-Piz 219 ocf ₃ nh ₂ 3,4-dimethyl-l-Piz 220 ocf ₃ nh ₂ 4-Et-1-Piz 221 ocf ₃ nh ₂ 4- (2-HOEt) - 1-Piz 222 ocf ₃ nh ₂ 4- (2-HKC) -1-Piz 223 ocf ₃ nh ₂ 4- (2-AcOEt) -1-Piz 224 ocf ₃ nh ₂ 4- (2-NH ₂ Et) -1-Piz 225 ocf ₃ nh ₂ 4- (4-NH ₂ Bz) -1-Piz 226 ocf ₃ nh ₂ 4-HCO-1-Piz 227 ocf ₃ nh ₂ 4-Ac-1-Piz 228 ocf ₃ nh ₂ 4- (ACME) -1-Piz 229 ocf ₃ nh ₂ 4- (HOOCMe) -1-Piz 230 ocf ₃ nh ₂ 4- (EtcMe) -1-Piz 231 ocf ₃ nh ₂ 1 Diz 232 ocf ₃ nh ₂ 4-Me-l-Diz 233 ocf ₃ nh ₂ 3-oxo-1-Piz 234 ocf ₃ nh ₂ 4-Me-3-oxo-1-Piz 235 ocf ₃ nh ₂ 3-HO-I-I 236 ocf ₃ nh ₂ 3-HO-l-Pyrd 237 ocf ₃ nh ₂ 3-HO-4-MeO-l-Pyrd 238 ocf ₃ nh ₂ 3,4-diMeO-1-pyrid 239 ocf ₃ nh ₂ 3-NH ₂ -l-Azt 240 ocf ₃ nh ₂ 3-NHMe-1-I 241 ocf ₃ nh ₂ 3-I-I-NHEt 242 ocf ₃ nh ₂ 3 - [(NH ₂ ) Me] -1-Azt 243 ocf ₃ nh ₂ 3 - [(NHMe) Me] -l-I 244 ocf ₃ nh ₂ 3 - [(NMe ₂ ) Me] -1-Azt 245 ocf ₃ nh ₂ 3-NH ₂ -l-Pyrd 246 ocf ₃ nh ₂ 4-NHMe-l-Pyrd 247 ocf ₃ nh ₂ 3-NMe ₂ -1-pyrid 248 ocf ₃ nh ₂ 3 - [(NH ₂ ) Me] -1-Pyrd 249 ocf ₃ nh ₂ 3 - [(NHMe) Me] -l-Pyrd 250 ocf ₃ nh ₂ 3 - [(NHEt) Me] -l-Pyrd

HU 211 837 A9

251 ocf ₃ nh ₂ S ^ KNMe MeI l-Pyrd 252 ocf ₃ nh ₂ 3-NH ₂ -4-Me-1-Pyrd 253 ocf ₃ nh ₂ 3-NH ₂ -4-HO-1-Pyrd 254 ocf ₃ nh ₂ 3-NH ₂ -4-MeO-1-Pyrd 255 ocf ₃ nh ₂ 3-NH ₂ 4-EtO-1-Pyrd 256 ocf ₃ nh ₂ 4-NH ₂ -l-Pip 257 ocf ₃ nh ₂ 4-NHMe-l-Pip 258 ocf ₃ nh ₂ 3-NH ₂ -l-Pip 259 ocf ₃ nh ₂ 3-NHMe-l-Pip 260 ocf ₃ nh ₂ 3-NMe ₂ -l-Pip 261 ocf ₃ nh ₂ 3-NH ₂ -1-Azp 262 ocf ₃ nh ₂ 3-NH ₂ -3-Me-1-Pyrd 263 ocf ₃ nh ₂ 1 -Imids 264 ocf ₃ nh ₂ 4-Me-l-lmid 265 ocf ₃ nh ₂ Moorish 266 ocf ₃ nh ₂ thz 267 och ₂ f nh ₂ 3,3-dimethyl-l-Piz 268 och ₂ f nh ₂ 4-Me-l-Diz 269 och ₂ f nh ₂ 1-Piz 270 ch ₂ f nh ₂ 1 Diz 271 och ₂ f nh ₂ 3-NH ₂ -l-Pyrd 272 OCH ₂ F nh ₂ 3-Me-1-Piz 273 och ₂ f nh ₂ 4-Me-1-Piz 274 och ₂ f nh ₂ 3-NH ₂ -4-Me-1-Pyrd 275 och ₂ f nh ₂ 3,5-dimethyl-l-Piz 276 och ₂ f nh ₂ 3,4-dimethyl-l-Piz 277 och ₂ f nh ₂ 3-NHMe-l-Pyrd 278 och ₂ f nh ₂ 3-NMe ₂ -1-pyrid 279 ochf ₂ H 3- (home) -1-Piz 280 och ₂ f nh ₂ 3- (home) -1-Piz 281 och ₂ f H 4- (SfoMe) -3-Me-1-Piz 282 och ₂ f nh ₂ 4- (SfoMe) -3-Me-1 -Piz 283 och ₂ f H 4- (AcEt) - 1-Piz 284 och ₂ f nh ₂ 4- (acetone) -1-Piz 285 och ₂ f H 4- (AcEt) -3-Me-1-Piz 286 och ₂ f nh ₂ 4- (acetate) 3-Me-1-Piz

Of the listed compounds, the following are preferred:

1, 2, 3, 5, 24, 34, 39, 41, 43, 45, 46, 48, 56,

59, 72, 74, 75, 76, 78, 79, 82, 93, 94, 97, 107,

114, 116, 129, 131, 133, 136, 137, 139, 141, 142,

144, 179, 186, 202, 203, 204, 205, 206, 207, 208,

209, 213, 214, 245, 252, 268, 269, 270, 271, 272,

273, 274, 275, 279, 280, 281, 282, 283, 284, 285.

and 286, and we particularly prefer the following numerals: 1, 2, 3, 5, 39, 43, 45,

46, 48, 56, 59, 72, 74, 75, 76, 78, 79, 82, 93,

94, 107, 116, 129, 131, 133, 136, 137, 139, 141,

141, 144, 179 and 284.

Most preferred are the following compounds:

1. 1-Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

2. 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

3. 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

34. 1-Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-amino-1-pyrrolidinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

74. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

75. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

76. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

78. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

93. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (1-homopiperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

107. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-amino-1-pyrrolidinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid;

139. 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

144. 5-Amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Pharmaceutically acceptable salts, esters and amides are also preferred, with salts and esters being particularly preferred, and hydrochlorides and methanesulfonates being most preferred with respect to the above-mentioned preferred and particularly preferred compounds.

In general, the compounds of the invention may be prepared by reacting a compound of formula (VI) (wherein R ¹ and R ³ are as defined above; X is halogen, preferably fluorine; and R ¹³ is hydrogen or carboxy protecting group) or an equivalent thereof. reacting a compound of formula VII (wherein R ² is as defined above) or a reactive derivative or equivalent thereof, and optionally subjecting the resulting product to one or more of the following reactions: deprotection, salt formation, esterification, and amidation.

R ^{13 for} any use in this type of compound may be a carboxy-protecting group known in organic chemistry and may be introduced and (if desired) removed from the compound by well-known methods not requiring detailed description herein. However, R ^{13 is} preferably hydrogen or C 1-6 alkyl, preferably C 1-4 alkyl

A9 such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or hexyl, most preferably hydrogen or methyl or ethyl.

Alternatively, R ¹³ may be boron difluoride (BF ₂ ). In this case, the boron difluoro group usually forms a bond coordinated to the 4-position oxygen atom of the quinoline ring.

A preferred method for preparing the compounds of the present invention is illustrated in detail in Scheme A below. In these formulas, R ¹ , R ² , R ³ , X and R ¹³ are as previously defined.

In the reactions outlined in the above Scheme, the compounds of formula (I) of the present invention may be prepared by reacting a compound of formula (VI) or a boron difluorelate of formula (IX) with an amine of formula (VII). increments. The reaction is carried out in the presence or absence of an acid acceptor and in the presence or absence of a solvent.

The molar ratio of the compound of formula (VI) or (IX) to the amine of formula (VII) is not critical, although it is generally preferred to use equimolar amounts of the two reagents or to use a molar excess of the amine.

When a solvent is used, its nature is not particularly cryogenic provided that it has no adverse effect on the reaction. Examples of suitable solvents include aprotic polar solvents, especially sulfoxides, such as dimethyl sulfoxide, or amides, such as dimethylformamide, hexamethylphosphoric triamide or dimethylacetamide; however, other solvents such as ketones, such as acetone or methyl ethyl ketone; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate; alcohols such as methanol, ethanol, propanes, isopropanol or butanol; and nitriles such as acetonitrile. Of these, aprotic polar solvents are preferred.

If an acid acceptor is used, its nature is also not critical provided that it has no adverse effect on the reaction and is capable of binding and thereby effectively removing the acid formed during the reaction. Suitable acid-binding agents include, by way of example, tertiary amines, e.g.

1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5-nonene, triethylamine, tributylamine, pyridine, picoline, lutidine or collidine; and organic bases, preferably alkali metal carbonates, such as sodium carbonate or potassium carbonate; or alkali metal alcoholates such as sodium methylate, sodium ethylate or potassium tert-butylate. The amount of acid-binding agent used is preferably in equimolar or molar excess to the compound (VI) or (IX), more preferably the molar ratio of the compound (VI) or (IX) to the acid-binding agent is 1: 1 to 1: 5. However, when one of the above-mentioned amines is used as an acid scavenger, it is preferably used in a large excess, in which case it can serve as both an acid scavenger and a solvent. The reaction may proceed smoothly even without the use of an acid acceptor, since excess of the amine of formula (VII) may serve as an acid acceptor.

The reaction can be carried out over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. However, in general, the reaction is conveniently carried out at a temperature between 0 'C and 200' C.

When R ^{13 in the} compound of formula (VIII) is a carboxy protecting group, it is removed to give the corresponding compound having R ^{13 as} hydrogen. This removal may be accomplished by a well-known method appropriate to the nature of the carboxy protecting group represented by R ¹³ .

When the reaction is complete, the desired compound of the invention can be isolated from the reaction mixture by conventional treatment and, if desired, further purified by conventional techniques such as recrystallization or various chromatographic techniques, in particular column chromatography.

Figures A2.-A6. In the reactions of Steps 1 to 2, the desired compound of formula (X) is first chelated and then converted to the compound of formula (I) BF ₂ X or the compound of formula (I) itself by treatment with aqueous alcohol or basic aqueous alcohol. by. The BF ₂ X addition product of the compound of formula (I) can be readily converted to the compound of formula (I) by treatment with a base.

Examples of suitable bases include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; alkali metal alcoholates such as sodium methylate, sodium ethylate or potassium tert-butylate; and tertiary amines such as 1,8-diazabicyclo [5.4.0] -7undecene, 1,5-diazabicyclo [4.3.0] -5-nonene, triethylamine or 4- (dimethylamino) pyridine.

The X addition product of the compound of formula (I) or BF _{2 of} formula (XI) may, if desired, be converted into the corresponding salt by conventional means.

Conversion of compound (VI) to boron difluoride chelate (IX) may be accomplished, for example, by reaction with hydrofluoroboric acid or boron trifluoride according to the method described in Japanese Patent Application Laid-Open No. 67290/84.

The compound of formula (I) thus obtained may be formed as a mixture of optical isomers with respect to the asymmetric carbon atom of the compound in R ² or as geometric (cis or trans) isomers with respect to the presence of two or more substituents on the heterocyclic group represented by R ² . In this case, individual isomers of the compound may be prepared, if desired, by using an optically resolved or pre-separated compound of formula (VII) as a mixture of the corresponding optical or geometric isomers of the desired compound of formula (I). by known methods for each isomer.

HU 211 837 A9

Compounds of formula (VI) used as starting materials in the aforementioned reactions may be prepared, for example, as shown in Scheme B. In this scheme

R ¹ , R ³ and X are as previously defined;

R ³ 'is hydrogen or nitro (NO ₂ ); ^R17 is a carboxy-protecting group, as already illsuztráltuk examples with ^R13;

X 'is a halogen atom such as fluorine, chlorine, bromine or iodine;

R ¹⁴ and R means C1-6 alkyl, such as alkyl groups exemplified above in relation to R ⁴ is one of ¹⁵ the same or different, or R ¹⁴ and R ¹⁵ together with the nitrogen to which they are attached, a 5- or 6-ring atoms and 0 thereof or a further heteroatom, namely a heterocyclic group containing nitrogen, oxygen or sulfur heteroatoms which is unsubstituted or substituted with one or two oxo substituents on the sulfur heteroatom;

Ac is acetyl;

Et is ethyl; and

Ts is p-tosyl (p-toluenesulfonyl).

AB. The reaction conditions and treatments after completion of the reaction for each step of the reaction scheme will be described in more detail in the Reference Examples. Of course, the details of the reaction conditions mentioned in the above reference examples are given by way of example only, and it is to be understood that these well-known reactions can be carried out in various ways.

B8. examples of suitable bases for use in step (a) include alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal alcoholates such as sodium methylate or potassium tert-butylate.

The compound of formula (XX) wherein R ³ 'is hydrogen may be the desired compound of formula (VI) or may be hydrolyzed in B9. step (b) to give the free acid of formula (XXI). However, when R ³ 'is a nitro group, it is necessary to reduce this nitro group to an amino group and then to produce compound (ΧΧΠ), which may then be the desired compound or be hydrolyzed to give compound (XXI).

When R ³ 'is a nitro compound used as a starting compound in this scheme, this compound can be prepared by nitration of a compound having the appropriate R ³ ' hydrogen atom, for example as shown in Scheme E.

AB8., BIO. as an alternative to steps B11 and B11 wherein R ³ 'is nitro, the compound of formula XIX (shown in Scheme V' as compound of formula XIXa) can be reduced to an amino compound; the compound of formula (XVIII) (shown in Scheme B 'as compound of formula (XVIIIa)) containing a nitro group at R ³ ' can also be reduced to the corresponding amino compound followed by the treatment step shown in Scheme B '.

In Scheme B ', R ¹ , R ¹⁴ , R ¹⁵ , R ¹⁷ , X and X' are as previously defined.

Compounds of formula (ΧΠ) wherein R ³ 'is hydrogen and R ¹ is difluoromethoxy can be prepared as shown in Scheme C, while R ³ ' is hydrogen and R ¹ is trifluoromethoxy as shown in Scheme D. AC. in Schemes A and D, X and X 'are as previously defined; R ¹⁶ is C 1 -C 6 alkoxy or amino; X ^{to a} and X ^{b have the} same or different meanings as halogen, for example chromium, bromine or iodine, but not fluorine.

If an X is used instead of ^the compound of formula X compound CH2F ^CHF2 reaction, according to Scheme C, they can be prepared from the corresponding carrier monofluoromethyl methoxy group in the 3-position thereof.

The 2,4,5-trifluoro-3-hydroxybenzoic acid used as starting material in the reactions of Schemes C and D and the corresponding compounds containing other halogens in the 2- and 4-positions can be prepared from a known compound, e.g. -Trifluoro-4-hydroxyphthalic acid or a suitable compound containing the 3- and 5-position other halogen atoms by heat decarboxylation in an aqueous medium, 1 water or an aqueous solvent as shown in Scheme F.

The compounds of the invention have potent antibacterial activity. The assay by the agar plate dilution method shows excellent growth inhibitory activity against a wide range of pathogenic bacteria such as Gram-positive bacteria such as Staphylococcus aureus or Enterococcus species and Gram-negative bacteria such as Escheria coli, Dysentery bacillus, Shigella, , Myxomycetes, Sercatia, Enterobacter, Salmonella, or Pseudomonas aeruginosa, including strains resistant under normal conditions.

The compounds of the invention may be administered in the form of conventional pharmaceutical compositions, depending on the desired mode of administration. For example, for oral administration, they may be in the form of powders, granules, tablets, capsules, syrups or the like, which may be prepared by incorporating the active ingredient with carriers, excipients or diluents such as glucose, sucrose, lactose, sorbitol, starch, starch. , mannitol, calcium carbonate, calcium phosphate, sodium chloride or boric acid. For parenteral administration, they may be prepared as conventional injectable compositions, for example, for intravenous or intramuscular injection. The dose will depend on the nature of the disease, the route of administration and the symptoms, age and weight of the patient; however, in the case of an adult patient, oral administration will generally be in the range of from 100 mg to 1000 mg per day, which may be administered simultaneously or divided.

The invention is illustrated by the following examples which are various compounds of the invention

EN 211 837 describes the production of A9. The preparation of some of the starting compounds used in these Examples is described in the Reference Examples. The activity of some of the compounds of the present invention is shown in the following biological activity data.

REFERENCE EXAMPLE 1

3- (Difluoromethoxy) -2,4,5-trifluorobenzoic acid [(XXV), X = X '= F] (ester route) 1 (a) Ethyl 2,4,5-trifluoro-3-hydroxy benzoate [(XXIV),

X = X '= F, F, R ¹⁶ = C ₂ H _s O]

To a solution of 20.0 g (0.104 mol) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X = X '= F] prepared in Reference Example 13 in 500 ml of ethanol is added 5 ml of concentrated sulfuric acid and the resulting mixture was refluxed for 4 hours. The ethanol is then removed by distillation under reduced pressure and the residue is extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then with water, then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. 16.9 g of ethyl 2,4,5-trifluoro-3-hydroxybenzoate are obtained in the form of a colorless powder.

Mass Spec (Cl): m / e 221 (M ⁺ + 1), 175 (M ⁺ -OC ₂ H ₅ ). (The abbreviation "Cl" refers to chemical ionization.) L (b) Ethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoate [(XXVI), X = X '= F, R'^(> = C ₂ H ₅ O]

Under stirring and ice cooling, 8.83 g (0.04 mol) of ethyl 2,4,5-trifluoro-3-hydroxybenzoate [(XXIV), X = X '= F, R, prepared as described in step (a) above. ^{To a solution of 16} = C ₂ H ₅ O] in dimethylformamide (40 mL) was added a small amount of sodium hydride slurry (1.76 g, 0.044 mol) in mineral oil (60%), and after the addition was complete, the reaction mixture was ice-cooled. stir for an additional 30 minutes. The reaction mixture was then poured into a 200 ml stainless steel autoclave, followed by the addition of 100 ml of dimethylformamide containing 28.0 g (0.32 mol) of chlorodifluoromethane. The reaction mixture was then stirred under pressure at 95-100 ° C for 5 hours, then the dimethylformamide was removed by distillation under reduced pressure and water was added to the residue, followed by extraction with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using toluene as eluent. Ethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoate (4.85 g) was obtained as a colorless liquid.

Mass Spectrum (CI): m / e 271 (M ⁺ + 1), 225 (M ⁺ -OC ₂ H ₅ ).

1 (c) 3- (Difluoromethoxy) -2,4,5-trifluorobenzoic acid [(XXV), X = X '= F]

5.79 g (0.021 mole) of ethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoate, prepared as described in step (b) above [(XXVI), X = X '= F, ^R16 = To a solution of C ₂ H ₅ O] in ethanol (40 mL) was added 6% aqueous sodium hydroxide (20 mL) and the resulting mixture was allowed to stand at room temperature overnight. The reaction mixture was then acidified with concentrated aqueous hydrochloric acid (3.5 mL) and concentrated by evaporation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. 5.22 g of 3- (difluoromethoxy) -2,4,5-trifluorobenzoic acid are obtained in the form of a colorless powder, m.p. 68-70 ° C.

Mass spectrum (CI): m / e 243 (M ⁺ + 1), 225 (M ⁺ -OH), 223 (M ⁺ -F), 192 (M ⁺ -CF 2), 175 (M ⁺ -CF ² OH).

NMR (CDC1 _3, δ ppm): 6.67 (lH, triplet, J =

Hz); 7.83 (1H, multiplet); 10.74 (1H, broad).

2. REFERENCE EXAMPLE

3- (Difluoromethoxy) -2,4,5-trifluorobenzoic acid [(XXV), X = X '= F] (amide route)

2 (a) 2,4,5-Trifluoro-3-hydroxybenzoylamide [(XXIV), X = X '= F, R' ⁶ = NH ₂ ]

To a solution of 100.0 g (0.52 mol) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X = X '= F] prepared in Reference Example 13 in 400 ml of benzene was added 300 ml. of thionyl chloride and the resulting reaction mixture was refluxed for 3 hours. The solvent and excess thionyl chloride are then removed by distillation under reduced pressure to give 2,4,5-trifluoro-3-hydroxybenzoyl chloride. The entire amount of this chloride was added dropwise to 1500 ml of 28% aqueous ammonium hydroxide solution with stirring and ice-cooling, and the resulting reaction mixture was stirred for an additional 2 hours. The reaction mixture was allowed to stand at room temperature overnight and then acidified by the addition of dilute aqueous hydrochloric acid. The reaction mixture was then extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. 88.2 g

2,4,5-Trifluoro-3-hydroxybenzoylamide is obtained as a colorless powder, m.p. 153-155 ° C.

Mass spectrum (CI): m / e 192 (M ⁺ + 1), 175 (M ⁺ -NH ₂ ).

2 (b) 3- (Difluoromethoxy) -2,4,5-trifluorobenzoylamide [(XXVI), X = X '= F, R' ⁶ = NH ₂ ]

Dissolve 5.00 g (0.026 mol) of 2,4,5-trifluoro-3-hydroxybenzoylamide [(XXIV), X = X '= F in 130 ml of dimethylformamide. R ¹⁶ = NH _2], and treated with potassium carbonate (4.70 g, 0.034 mol) and 6.8 g (0.79 mole) of chlorodifluoromethane chloride to the solution. The reaction mixture was stirred in an autoclave at 100 ° C for 3 hours, then water (500 mL) was added and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography eluting with toluene

Using a 1: 1 mixture of A 9 ol and ethyl acetate to give 5.08 g of 3- (difluoromethoxy) -2,4,5-trifluorobenzoylamide, m.p. 102-104 ° C. in the form of solid crystals.

Mass Spec (Cl): m / e 242 (M ⁺ + 1), 225 (M ⁺ -NH ₂ ).

2 (c) 3- (Difluoromethoxy) -2,4,5-trifluorobenzoic acid [(XXV), X = X '= F]

Under stirring and ice cooling, 15.53 g (0.064 mol) of 3- (difluoromethoxy) -2,4,5-trifluorobenzoylamide [(XXVI), X = X, prepared as described in step (b) above. '= F, R ¹⁶ = NH _2] 30 ml of an aqueous solution of 20 ml of concentrated sulfuric acid dropwise to a suspension containing sodium nitrite (6.60 g, 0.096 mol). The resulting mixture was then refluxed for 30 minutes, cooled to room temperature, and water (50 mL) was added. The reaction mixture was then extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. 15.59 g of 3- (difluoromethoxy) 2.4.5-trifluorobenzoic acid are obtained in the form of a colorless powder.

This compound has the same melting point, mass spectrum and NMR spectrum as the esterified compound of Reference Example 1.

3. REFERENCE EXAMPLE

3- (Difluoromethoxy) -2,4,5-trifluorobenzoic acid

Í (XXV), X = X '= F] (direct method)

Under ice-cooling, a solution of 2.18 g (0.052 mol) of sodium hydroxide in 5 ml of water was treated with 20 ml of dimethylformamide followed by small portions of 4.97 g (0.026 mol).

2.4.5-Trifluoro-3-hydroxybenzoic acid is added. The resulting solution was stirred under ice-cooling for 30 minutes and then weighed into a 200 mL stainless steel autoclave. Thereafter, 100 ml of dimethylformamide containing 24.0 g (0.277 mol) of chlorodifluoromethane were added. The resulting mixture was stirred at 100 ° C to 110 ° C for 5 hours under pressure, then poured into water and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: ethanol = 9: 1). This gives 2.00 g of 3- (difluoromethoxy) -2,4,5-trifluorobenzoic acid as a colorless powder.

This compound has the same melting point, mass spectrum and NMR spectrum as the esterified compound of Reference Example 1.

4. REFERENCE EXAMPLE

2,4,5-Trifluoro-3- (trifluoromethoxy) benzoic acid 1 (XXIX), X = X '= F}

4 (a) Ethyl 3- (bromodifluoromethoxy) -2,4,5-trifluorobenzoate [(XXVII), X = X '= F, X ³ = Br, R ^{] b} = C ₂ H ₅ O While stirring and cooling with ice, 5.0 g (0.23 mol) of az

Ethyl 2,4,5-trifluoro-3-hydroxybenzoate [(XXIV), X = X '= F, R ¹⁶ = C ₂ H ₅ O] prepared in Example 1 (a) with 20 ml of dimethylformamide. To this solution was added in small portions 1.0 g (0.025 mol) of a 60% sodium hydride dispersion in mineral oil, and after the addition was complete, the reaction mixture was stirred under ice-cooling for an additional 30 minutes. Thereafter, 130 ml of dimethylformamide containing 28.0 g (0.13 mol) of dibromodifluoromethane were added. After stirring at room temperature for 23 hours, the reaction mixture was poured into 300 ml of water and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel column chromatography using toluene as eluent. 5.60 g of ethyl 3- (bromodifluoromethoxy) -2,4,5-trifluorobenzoate are obtained in the form of a colorless liquid.

Mass Spec (Cl): m / e 351 (M ⁺ +3), 349 (M ⁺ -1).

4 (b) Ethyl 2,4,5-trifluoro-3- (trifluoromethoxy) benzoate [(XXVIII), X = X '= F, R ^{} b} = C ₂ H ₅ O] Dissolve in 1.50 ml of toluene. g (0.0043 mole) of ethyl 3 (bromodifluoromethoxy) -2,4,5-trifluorobenzoate [(XXVII), prepared as described in step (a) above, (X = X '= F, X). ^a = Br, R ¹⁶ = C ₂ H ₅ O] and 2.50 g (0.013 mol) of silver tetrafluoroborate are added to the resulting solution. The reaction mixture was then refluxed in a dark room for 8 hours with stirring. The reaction mixture was filtered and the filtrate washed, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using toluene as eluent. 1.12 g of ethyl 2,4,5-trifluoro-3- (trifluoromethoxy) benzoate are obtained in the form of a colorless liquid.

Mass Spec (Cl): m / e 289 (M ⁺ + 1), 269 (M ⁺ -F).

4 (c) 2,4,5-Trifluoro-3- (trifluoromethoxy) -benzoic acid [(XXIX), X = X '= F]

5.05 g (0.0175 mole) of ethyl 2,4,5-trifluoro-3- (trifluoromethoxy) benzoate [(XXVIII), X = X '= F, R prepared in the same manner as in (b) above. To a solution of ⁶ = C ₂ H ₅ O] in ethanol (100 mL) was added 1N aqueous sodium hydroxide (19.3 mL, 0.0193 mol) and the resulting mixture was allowed to stand at room temperature for 2 hours. 19.3 ml of a 1N aqueous hydrochloric acid solution are then added and the reaction mixture is concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. 3.98 g

2,4,5-trifluoro-3- (trifluoromethoxy) -benzoic acid is obtained as a colorless powder.

Mass spectrum (CI): m / e 261 (M ⁺ + 1), 243 (M ⁺ -OH).

NMR (CDC1 _3, δ ppm): 7.88 (lH, multiplet).

HU 211 837 A9

5. REFERENCE EXAMPLE

3- (Difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoic acid [(XII), R) = -OCHF _V R ³ '= NO ₂ , X = X' = F] Stirring and water cooling 15.0 g (0.062 mol) of 3- (difluoromethoxy) -2,4,5-trifluorobenzoic acid [(XXV), X = X '= prepared as described in Reference Examples 1, 2 or 3. F] To a solution of 40 ml of concentrated aqueous sulfuric acid solution was added dropwise 20 ml of concentrated aqueous nitric acid (d = 1.42) and the resulting mixture was stirred at 60 ° C for 7 hours. The reaction mixture was allowed to cool to room temperature and then poured into ice water. After extraction with diethyl ether, the extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure to give 16.6 g of 3- (difluoromethoxy) -2.4 g. 5-Trifluoro-6-nitrobenzoic acid was obtained as a yellow powder, m.p. 77-80 ° C.

Mass Spec (Cl): m / e 287 (M ⁺ ), 243 (M ⁺ -CO ₂ ).

6. REFERENCE EXAMPLE

Ethyl] -cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-4-dihydro-4-oxo-quinoline-3-carboxylate [(XX)]. =

-OCHF ₂ , R ³ '= H, R' ⁷ = C ₂ H _s , X = F]

6 (a) Diethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoyl malonate [(XIV), R '= -OCHF ₂ , R ³ ' = H, R ' ⁷ = C ₂ H ₅ , X = X '= F]

(5.22 g, 0.0216 mol), 3- (difluoromethoxy) 2.4.5- trifluoro-benzoic acid prepared as described in Preparation 1, 2 or 3, using [(XII), R ¹ = -OCF 2 R ^{To a solution of 3} '= H, X = X' = F] in 300 ml of benzene was added 15 ml of thionyl chloride, and the resulting mixture was refluxed for 3 hours. Benzene and excess thionyl chloride are then removed by distillation under reduced pressure to give 3- (difluoromethoxy) -2,4,5-trifluorobenzoyl chloride [(XIII), R ¹ = -OCF 2, R ³ '. = Η, X = X '= F].

In the meantime, a suspension of diethyl ethoxymagnesium magnesium malonate in diethyl ether was prepared from 2.80 g (0.0238 mole) of magnesium ethylate and 3.81 g (0.0238 mole) of diethyl malonate in 60 ml of anhydrous diethyl ether by stirring. while refluxing is carried out for 1 hour. A suspension of 3- (difluoromethoxy) -2,4,5-trifluorobenzoyl chloride (50 ml) in anhydrous diethyl ether (50 ml) was added dropwise to the suspension with stirring at room temperature and the resulting mixture was stirred at room temperature for an additional 2 hours. . The reaction mixture was then treated with 35 ml of 1 N aqueous hydrochloric acid and then stirred vigorously. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. Thus, 7.07 g of diethyl 3- (difluoromethoxy) 2.4.5-trifluorobenzoyl malonate [(XIV), R ¹ = -OCHF 2, R ³ '= H, R ¹⁷ = C ₂ H ₅ , X are obtained as a brown liquid. = X '= F].

Mass spectrum (CI): m / e 385 (M ⁺ + 1), 339 (M ⁺⁾

-OC ₂ H ₅ ).

6 (b) Ethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoyl acetate [(XV), R '= -OCHF ₂ , R ³ ' = H, R ¹⁷ = C ₂ H ₅ , X = X '= F]

Diethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoyl malonate [(XIV), R ¹ = -OCHF 2, R ³ '= H, R ¹⁷ = C 2 H, prepared as described in step (a) above. ₅ , X = X '= F] is dissolved in dioxane (200 mL) and p-toluenesulfonic acid monohydrate (4.52 g, 0.0238 mol) is added. The resulting mixture was refluxed for 6 hours and concentrated by evaporation under reduced pressure. To the residue was added 100 ml of water and

Sodium bicarbonate (2.52 g, 0.03 mol) was added and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. 5.66 g of ethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoyl acetate are obtained in the form of a reddish-brown liquid.

Mass Spectrum (Cl): m / e 313 (M ⁺ + 1), 225 (M ⁺ -CH ₂ COOC ₂ H ₅ ).

6 (c) Ethyl 3- (cyclopmpylamino) -2- [3- (difluoromethoxy) -2,4,5-trifluorobenzoyl] acrylate [(XIX), R '= -OCHF ₂ , R ³ '- H, R' ⁷ = C ₂ H ₅ , X = X '= F]

Ethyl 3- (difluoromethoxy) -2,4,5-trifluorobenzoylacetate [(XV), R ¹ = -OCHF 2, R ³ '= H, R ¹⁷ = C 2 H, prepared as described in step (b) above. _{To a} total volume of ₅ , X = X '= F] is added acetic anhydride (20 ml) and ethyl ester of ortho-formic acid (6 ml), and the resulting mixture is refluxed for 2 hours, followed by evaporation under reduced pressure of excess acetic anhydride and ester is removed. The residue was dissolved in methylene chloride (200 mL) and cyclopropylamine (1.25 g, 0.022 mol) was added dropwise with stirring and cooling with ice. Stirring was continued for a further 1 hour under ice-cooling, and the reaction mixture was concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: toluene / ethyl acetate = 9: 1). 3.29 g of ethyl 3- (cyclopropylamino) -2- (3-difluoromethoxy) -2,4,5-trifluorobenzoyl] acrylate are obtained in the form of an amber liquid.

Mass spectrum (CI): m / e 380 (M ⁺ + 1), 225 [M ⁺ -c-Pr-NH-CH = C (COOEt)].

6 (d) Ethyl I-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XX),

R ^] = -OCHF 2, R ³ '= H, R' ⁷ = C ₂ H ₅ , X = F]

Ethyl prepared as described in step (c) above from 3- (cyclopropylamino) -2- [3- (difluoromethoxy) -2,4,5trifluor-benzoyl acrylate [(XIX), ^R1 = -OCHF2, R ^{A total amount of 3} '= H, R ¹⁷ = C ₂ H ₅ , X = X' = F] is dissolved in 150 ml of anhydrous diethyl ether and the resulting solution

0.39 g (0.0098 mol) of a 60% sodium hydride dispersion in mineral oil are added in small portions at room temperature with stirring. After the addition was complete, stirring was continued for 1 hour at room temperature, and then the reaction mixture was acidified with vigorous stirring by the addition of 1 N aqueous hydrochloric acid. The reaction mixture was filtered, washed with water and then with diethyl ether. This gives 1.44 g of colorless needles of ethyl 1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 224-226 ° C. form.

Mass Spec (Cl): m / e 360 (M ⁺ + 1).

7. REFERENCE EXAMPLE

-Cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [(XXI), R ^] = -OCHF, R ³ = H, X = E]

1.40 g (0.0039 mol) of ethyl 1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3, prepared as described in Reference Example 6, are obtained. To carboxylate [(XX), R ¹ = -OCHF 2, R ³ '= H, R ¹⁷ = C ₂ H ₅ , X = F] is added 9 ml of acetic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water, followed by the resulting mixture was refluxed for 1 hour. At this time, the reaction mixture was cooled to room temperature and poured into ice water. The precipitated crystals were collected by filtration, washed with water and then with diethyl ether. Thus 1.09 g of 1-cyclopropyl-8- (difluoromethoxy) 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [(XXI), R '= -OCHF ₂ , Η R ³ = X = F] is obtained, melting at 202-207 ° C as colorless needles.

Mass Spec (Cl): m / e 332 (M ⁺ + 1).

Calcd for _C14 H9F ₄ NO ₄ Calculated: C% = 50.77 H% = 2.74 N% = 4.23;

Found: C, 50.53; H, 2.79; N, 4.06.

8. REFERENCE EXAMPLE

-Cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoro-chelate [(IX), R '= -OCHF 2 R ³ = Η , X = F]

Ethyl 1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (9.50 g, 0.0265 mol), prepared as described in Reference Example 6. To a solution of [(VI), R ¹ = -OCHF 2, R ³ = H, R ¹³ = C ₂ H ₅ , X = F] is added 5.63 g of boron trifluoride diethyl etherate in 150 ml of methyl isobutyl ketone and The resulting reaction mixture was refluxed for 6 hours. The reaction mixture was then cooled in ice and the precipitated crystals were filtered off and washed first with diethyl ether and then with chloroform. 6.15 g of boron difluorelate of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, m.p. 225-233 ° C. in the form of a colorless powder.

Mass Spec (Cl): m / e 380 (M ⁺ + 1).

Analytical results according to the formula C ₁₄ H ₈ BF ₆ NO ₄ > / ₂ H ₂ O:

Calculated: C, 43.33; H, 2.34; N, 3.61.

Found: C, 43.06; H, 2.09; N, 3.78.

9. REFERENCE EXAMPLE

Ethyl 1-cyclopropyl-6,7-difluoro-8- (trifluoromethoxy) 1,4-dihydro-4-oxoquinoline-3-carboxylate [(VI), R ^] =

-OCF ₃ , R ³ = H, R ' ³ = C ₂ H ₅ , X = F]

In a similar manner to that described in Reference Example 6, but 6.02 g of 2,4,5-trifluoro-3- (trifluoromethoxy) benzoic acid [(XXIX), X = X '= F], prepared as described in Reference Example 4, and Using 2.41 g of ethyl 1-cyclopropyl-6,7-difluoro-8- (trifluoromethoxy) -1,4-dihydro-4-oxoquinoline-3-carboxylate, the title compound is obtained, m.p. 160-161 ° C. in the form of needle crystals.

Mass spectrum (CI): m / e 380 (M ⁺ + 1).

REFERENCE EXAMPLE 10

-Cyclopropyl-6,7-difluoro-8- (trifluoromethoxy) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid boron difluoride chelate [(IX), R ^} = -OCF ₃ , R ³ = Η , X = F]

In a similar manner to that described in Reference Example 8, but 2.10 g of ethyl 1-cyclopropyl-6,7-difluoro-8- (trifluoromethoxy) -1,4-dihydro-4-oxo-quinoline-3-carboxylate [(VI), R ¹ = -OCF 3, R ³ = H, R ¹³ = C ₂ H ₅ , X = F] 1.82 g of 1-cyclopropyl-6,7-difluoro-8- (trifluoromethoxy) -1,4-dihydro-4 oxoquinoline-3-carboxylic acid boron difluoride chelate can be prepared as a colorless powder, m.p.

Mass spectrum (CI): m / e 398 (M ⁺ + 1).

Analysis results for C | Based ₇ BF ₄ H ₇ NO ₄ '/ ₂ H ₂ OképIet:

Calculated: C, 41.42; H, 1.99; N, 3.45;

Found: C, 41.26; H, 1.69; N, 3.57.

IL REFERENCE EXAMPLE

5-Amino-1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [(XXII), R ^} = -OCHF * R ' ⁷ = H, X = F]

IJ (a) Diethyl [3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] malonate [(XrV), R '= -OCHF ₂ , R ³ ' = NO 2, R ^{] 1} = C 2 H _5, X = X '= FJ

15.97 g (0.056 mol) of 3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoic acid [(XII), R ¹ = OCHF 2, R ³ '= NO 2, X = X' = F] To a solution of 50 ml of benzene was added 40 ml of thionyl chloride and the resulting reaction mixture was refluxed for 2 hours. At this time, benzene and excess thionyl chloride were removed by distillation under reduced pressure to give 16.50 g of 3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl chloride [(XIII), R ¹ = OCHF 2 , R ³ '= NO 2, X = X' = F] is obtained.

In the meantime, a slurry of diethyl ethoxymagnesium magnesium malonate in diethyl ether was prepared from 6.82 g (0.058 mol) of magnesium ethylate and 9.35 g (0.058 mol) of diethyl malonate in 150 ml of anhydrous diethyl ether by stirring under reflux. reflux for an hour.

Thereafter, 3- (difluoromethoxy) 2,4,5-trifluoro-6-nitrobenzoyl chloride [(XIII), R ¹ = OCHF 2, R ³ '= NO 2, in 150 ml of anhydrous diethyl ether, was prepared. X = X '= F] and dissolve the resulting solution dropwise at room temperature

Add to a suspension of diethyl ethoxy magnesium malonate at A9 with stirring. The resulting reaction mixture was stirred at room temperature for an additional 2 hours and then treated with 100 ml of 1 N aqueous hydrochloric acid. After stirring vigorously, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. Thus, 31.2 g of diethyl [3- (difluoromethoxy) -2,4,5-trifluorobenzoyl] malonate [(XIV), R ¹ = -OCHF 2, R ³ '= NO 2, R ¹⁷ = C ₂ H ₅ , X = X '= F] is obtained as a red liquid.

Nuclear Magnetic Resonance Spectrum (CI): m / e 430 (M ⁺ + 1), 384 (M ⁺ -OEt), 270 [M ⁺ -CH (COOEt) ₂ ], II (b) Ethyl 3- (difluoromethoxy) -2 , 4,5-trifluoro-6-nitrobenzoyl acetate [(XV), R '= -OCHF ₂ , R ³ ' = NO

R ' ¹ = C ₂ H ₅ , X = X' = FJ

Diethyl [3- (difluoromethoxy) 2,4,5-trifluoro-6-nitrobenzoyl] malonate [(XIV), R ¹ = -OCHF 2, R] is dissolved in 300 ml of dioxane, prepared as described in step a) above. ³ '= NO 2, R ¹⁷ = C ₂ H ₅ , X = X' = F] and 10.6 g (0.056 mol) of p-toluenesulfonic acid monohydrate are added to the resulting solution. The reaction mixture was then refluxed for 4 hours and then evaporated under reduced pressure. To the residue was added water (150 mL) and sodium bicarbonate (4.7 g, 0.056 mol), followed by extraction with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. so

19.4 g of ethyl 3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl acetate are obtained as a red liquid.

Nuclear Magnetic Resonance Spectrum (Cl): m / e 358 (M ⁺ + 1), 312 (M ⁺ -OEt), 270 (M ⁺ -CH ₂ CO ₂ Et).

II (c) Ethyl 2- [3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] -3-ethoxyacrylate 1 (XVl), R 1 = -OCHF ₂ ,

R ³ '= NO 2, R' ¹ = C ₂ H ₅ , X = X '= F]

Ethyl prepared as described in step (b) above from 3- (difluoromethoxy) -2,4,5-trifluoro-6-nitro-benzoylacetate [(XV), ^R1 = -OCHF2, R ³ '= NO 2, R ¹⁷ To a total amount of C ₂ H ₅ , X = X 1 = F], 38 ml of acetic anhydride and 11 ml of ortho-formic acid ethyl ester are added and the resulting reaction mixture is refluxed for 3 hours. The excess acetic anhydride and ethyl ortho-acetic acid ester are then removed by evaporation under reduced pressure. 20.6 g of ethyl 2- [3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] -3-ethoxyacrylate are obtained in the form of a red liquid.

Tom spectrum (CI): m / e 414 (M ⁺ + 1), 367 (M ⁺ -NO ₂ ).

Il (d) Ethyl 3- (cyclopropylamino) -2- [3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] acrylate [(XIX), R ^} = -OCHF ₂ , R ³ '= NO 2, R' ¹ = C ₂ H ₅ , X = X '= FJ Ethyl 2- [3- (difluoromethoxy) -2,4,5-trifluoro-ethyl] prepared as described in step (c) above. 6-Nitrobenzoyl] -3-ethoxyacrylate [(XVI), R ¹ = -OCHF 2, R ³ '= NO 2, R ¹⁷ = C ₂ H ₅ , X = X' = F] is dissolved in 500 ml of methylene chloride and the resulting solution is added dropwise with stirring and ice-cooling

3.5 g (0.06 mol) of cyclopropylamine. The reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for an additional 1 hour, after which the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: toluene: ethyl acetate = 9: 1). 19.8 g of ethyl 3- (cyclopropylamino) -2- [3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] acrylate are obtained in the form of a yellow powder, m.p. 105-106 ° C. .

Mass spectrum (CI): m / e 425 (M ⁺ + 1), 379 (M ⁺⁾

-OEt).

Il (e) Ethyl I-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-5-nitro-1,4-dihydm-4-oxoquinoline-3-carboxylate [(XX), R '= -OCHF ^ R ³ '= NO- ^ R' ¹ = C ₂ H _it X = F] In 10 ml of tetrahydrofuran was dissolved 1.0 g (0.0024 mol) of ethyl 3- (prepared as described in step (d) above). cyclopropylamino) -2- [3- (difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] acrylate [(XIX), R ¹ = -OCHF 2, R ³ '= NO 2, R ¹⁷ = C ₂ H ₅ , X = X 1 = F], and a solution of 0.094 g (0.0024 mol) in 60% sodium hydride in mineral oil is added. The reaction mixture was then stirred at room temperature for 1 hour and then 1N aqueous hydrochloric acid was added. Intensive stirring is then carried out to acidify the entire reaction mixture. The precipitated crystals were collected by filtration and washed with water and diethyl ether. 0.6 g of ethyl 1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained, m.p. 262-268 ° C. in the form of a pale yellow powder.

Mass spectrum (CI): m / e 405 (M ⁺ + 1), 358 (M ⁺⁾

-NO ₂ ).

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide, δ ppm): 1.05 (4H, multiplet), 1.22 (3H, triplet), 3.91 (1H, multiplet), 4.18 (2H, quartet), δ , 24 (1H, triplet, J = 72 Hz), 8.56 (1H, singlet).

// (f) Ethyl 5-amino-N-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 1 (XXU), R ' = -OCHF ^ R ' ¹ = H, X = F]

3.0 g (0.0074 mol) of ethyl 1-cyclopropyl-8- (difluoromethoxy) 6,7-difluoro-5-nitro-1,4-dihydro-4-cyclohexyl-8- (difluoromethoxy) prepared as described above. Oxoquinoline-3-carboxylate [(XX), R ¹ = -OCHF 2, R ³ '= NO 2, R ¹⁷ = C ₂ H ₅ , X = F] is dissolved in 800 ml of acetic acid with heating and then 0.75 5% Pd of palladium on carbon was added and the resulting mixture was stirred under a stream of hydrogen at 70-80 ° C for 3 hours. The reaction mixture is then filtered and the filtrate is evaporated under reduced pressure. The residue was washed with diethyl ether to give 1.78 g of ethyl 5-amino-16

A9 cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained as a colorless powder, m.p. 295-296 ° C.

Mass spectrum (CI): m / e 375 (M ⁺ + 1), 329 (M ⁺ -OEt).

II (f) Ethyl 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XXII), R '= -OCHF ^X1 = Η, X = F]

The compound of Step II (f) can also be prepared by the following method.

33.63 g (0.079 mol) of ethyl 3- (cyclopropylamino) -2- [3-difluoromethoxy) -2,4,5-trifluoro-6-nitrobenzoyl] acrylate are dissolved in 1300 ml of ethanol with heating. (XIXa), X = X '= F, R ¹ = OCHF 2, R ¹⁷ = C 2 H ₅ ] and hydrogen gas was bubbled through the solution at room temperature for 40 minutes with stirring in the presence of 8.4 g of 5% palladium on carbon. The reaction mixture is then filtered and the filtrate is concentrated by evaporation under reduced pressure. The resulting residue was then purified by column chromatography on silica gel using toluene / ethyl acetate 9: 1 (v / v) as the eluent. Thus, 25.1 g of ethyl 3- (cyclopropylamino) -2- [6-amino-3- (difluoromethoxy) -2,4,5-trifluorobenzoyl] acrylate [(XlXb), X = X '= F, R ¹ = OCHF 2, R ¹⁷ = C 2 H _5] was obtained from 103 to 104' C, pale yellow powder melting.

Mass Spec (Cl): m / e 395 (M ⁺ + 1).

The entire amount of ethyl 3- (cyclopropylamino) -2- [6-amino-3- (difluoromethoxy) -2,4,5-trifluorobenzoyl] acrylate prepared as described in the previous paragraph was dissolved in 340 mL of tetrahydrofuran, and 3.82 g (0.096 mol) of a 60 wt% sodium hydride dispersion in mineral oil are slowly added under ice-cooling. The reaction mixture was then stirred at the same temperature for 30 minutes and then at room temperature for an additional hour. The reaction mixture was then acidified by the addition of 96 ml of 1 N aqueous hydrochloric acid solution with vigorous stirring. The precipitate formed is filtered off, washed with water and then with ethanol. Thus, 18.76 g of ethyl 5-amino-1-cyclopropyl-8- (difluoromethoxy) 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XXII), R ¹ = -OCHF ₂ , R ¹⁷ = Η, X = F] m.p. 295-296 ° C as a colorless powder.

Mass Spec (Cl): m / e 375 (M ⁺ + 1).

11 (g) 5-Amino-1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid [(XXII), R 1 = -OCHF 3, R ^{] 1} = Η, X = F]

Ethyl 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4 (3.58 g, 0.0096 mol) prepared as described in steps (f) and (f) above. -dihydro-4-oxoquinoline-3-carboxylate [(XXII), R ¹ = -OCHF ₂ , R ¹⁷ = H, X = F], 21 ml of acetic acid, 2.8 ml of concentrated sulfuric acid and 15 ml of water under suspension with stirring reflux for 1 hour and allow to cool while standing. Water was added to the reaction mixture, and the insolubles were filtered off, washed with water and then with diethyl ether. This gives 3.0 g of 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, m.p. 284-286 ° C. in the form of pale yellowish green powder.

Mass spectrum (CI): m / e 374 (M ⁺ + 1), 329 (M ⁺ -OH), 302 (M ⁺ -CO ₂ ).

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide, δ ppm): 0.8-1.2 (4H, multiplet), 3.92 (1H, multiplet), 7.05 (1H, triplet, J = 73 Hz), δ , 92 (2H, broad singlet), 8.62 (1H, singlet), 14.25 (1H, singlet).

Analysis calculated for C ₁₄ H ₁₀ F ₄ N ₂ O ₄ : C, 48.57; H, 2.91; N, 8.09;

Found: C, 48.45; H, 2.53; N, 8.03.

12. REFERENCE EXAMPLE

5-Amino-1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate [(IX), R '= -OCHF R ³ = ΝΗ »X = FJ

1.17 g (0.0034 mol), all. This compound was prepared from 5-amino-l-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid [(XXII), ^R1 = -OCHF2, R ^{To a} mixture of ¹⁷ = Η, X = F or (VI), R ¹ = -OCHF 2, R ³ = NH ₂ , R ¹³ = Η, X = F] and 30 ml of methyl isobutyl ketone are added 0.96 g of boron trifluoride. diethyl etherate and the resulting reaction mixture was refluxed for 6 hours. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and washed with diethyl ether. 1.29 g of the title compound are thus obtained in the form of yellow crystals which do not melt below 300 ° C.

Mass spectrum (CI): m / e 395 (M ⁺ + 1).

Analysis results for C ₁₄ H ₉ BF ₆ N ₂ O ₄ :

Found: C, 42.68; H, 2.30; N, 7.11;

Found: C, 42.29; H, 2.20; N, 7.08.

13. REFERENCE EXAMPLE

2,4,5-Trifluoro-3-hydroxybenzoic acid [(XXIII), X =

X '= F)

2700 g of 3,5,6-trifluoro-4-hydroxyphthalic acid and 6 liters of water were added to the autoclave and the resulting mixture was stirred under nitrogen at 140 ° C for 3 hours. The reaction mixture was cooled to room temperature and concentrated by evaporation under reduced pressure. The precipitated crystals are filtered off, washed with chloroform and dried. 1623 g of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X = X '= F] are obtained in the form of a colorless powder, m.p. 144-146'C.

Mass spectrum (CI): m / e 192 (M ⁺ ).

NMR (CD ₃ OD, δ ppm): 4.94 (1H, broad singlet), 7.25 (1H, multiplet).

REFERENCE EXAMPLE 14 (2S) -Methylpiperazine

14 (a) Ethyl N- (cyanomethyl) -L-alanate per g (0.065 mol) of ethyl L-alanate hydrochloride in 10 ml

A9 water was added followed by 3.2 g (0.065 mol) of sodium cyanide. 5.3 g (0.065 mol) of an aqueous solution of 37% w / w formaldehyde are then added dropwise. During the addition, the temperature of the reaction mixture rises to about 40 ° C. The resulting mixture was then stirred at room temperature for 6 hours and then allowed to stand at the same temperature overnight. The reaction mixture was extracted with methylene chloride and the organic extract was washed with a saturated aqueous sodium bicarbonate solution and then with water. The reaction mixture was then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography over silica gel using toluene / ethyl acetate 9: 1 (v / v) as the eluent. 5.6 g of ethyl N- (cyanomethyl) -L-alanate are obtained in the form of a colorless oil.

Tom spectrum (CI): m / e 157 (M ⁺ + 1), 130 (M ⁺⁾

-CN).

NMR (CDC1 _3, δ ppm): 1.28 (3H, triplet, J = 6 Hz), 1.33 (3H, doublet, J = 6 Hz), 2.15 (IH, s), 3, 45 (1H, quartet, J = 6Hz), 3.60 (2H, singlet), 4.20 (2H, quartet, J = 6Hz).

14 (b) (3S) -Methyl-2-oxo-piperazine

A mixture of 5.0 g (0.321 mol) of ethyl N- (cyanomethyl) -L-alanate prepared as described in step (a) above, 56 g 4% w / w ammonia in ethanol and 1.38 g Raney nickel was autoclaved. and weighed at 50 kg / cm ² hydrogen at 90 ° C for 2 hours. The catalyst is filtered off and the solvent is removed from the filtrate by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol: chloroform = 1:20, v / v). This gave 2.8 g of (3S) -methyl-2-oxo-piperazine as colorless crystals. Tomato Spectrum (CI): m / e 115 (M ⁺ + 1).

NMR (CDC1 _3, δ ppm): 1.40 (3H, doublet, J = 6 Hz), 1.78 (IH, s), 2.9-3.6 (5H, m), 7.00 (1H, broad).

14 (c) (2S) -Methyl-piperazine

To a suspension of lithium aluminum hydride (1.53 g, 0.040 mol) in tetrahydrofuran (35 ml) was added dropwise (3S) -methyl-2-oxo-piperazine (2.29 g, 0.020 mol) as described in (b) above. ml of tetrahydrofuran and the resulting reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool and a small amount of water was added under ice-cooling to remove any excess reducing agent. The reaction mixture was filtered and the filtrate was stirred with 10 ml of concentrated aqueous hydrochloric acid and then concentrated to dryness under reduced pressure. The residue was triturated with a mixture of diethyl ether and ethanol to give 2.73 g of (2S) -methylpiperazine dihydrochloride as a colorless powder. This was dissolved in water (10 mL) and the pH of the aqueous solution was raised to at least 10 by addition of 10% w / v aqueous sodium hydroxide solution, followed by extraction with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. 1.30 g of (2S) -methylpiperazine are obtained in the form of colorless needles by vacuum distillation of the residue. HPLC analysis (using GITC (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate)) showed the product to be 98.5% optical purity S-isomer.

Mass spectrum (CI): m / e 101 (M ⁺ +1). Nuclear Magnetic Resonance Spectrum (CDCl ₃ , δ ppm): 1.00 (3H, doublet, J =

Hz), 1.85 (2H, singlet), 2.30 - 2.45 (1H, multiplet), 2.6 - 3.0 (6H, multiplet).

15th-18th REFERENCE EXAMPLE By proceeding in a similar manner to that described in Reference Example 14, but using the starting materials listed in Table 2, the following piperazine derivatives can be synthesized:

TABLE 2

Reference number of the reference example initial material Product (piperazine) mp CC) 15th L-Ot-aminobutyric acid (2S) -ethylpiperazine 2HCl 231-234 16th L-valine (2S) -izopro- propyl-piperazine 2HCl) 261-264 17th 2-amino-i- butyric 2,2-dimethylpiperazine 2HCl 229-240 18th D, L-O-methyl- serine D, L-2-methoxymethyl-piperazine 2HCl

REFERENCE EXAMPLE 19 (3S) -Amino-pyrrolidine dihydrochloride 19 (a) Ethyl N- (tert-butoxycarbonyl) -ct aspartate 14.88 g (0.066 mol) of ethyl L-aspartate hydrochloride in 200 ml of methylene triethylamine (7.33 g, 0.072 mol) was added and the resulting mixture was stirred for 20 minutes and then di-tert-butyl dicarbonate (14.4 g, 0.066 mol) was added in small portions. After the addition was complete, the reaction mixture was stirred for 2 hours and then concentrated by evaporation under reduced pressure. Toluene was added to the residue, and the precipitated triethylamine hydrochloride was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 4: 1). so

18.61 g of ethyl N- (tert-butoxycarbonyl) -L-aspartate are obtained as a colorless oil.

Mass spectrum (CI): m / e 234 [M ⁺ +1 -CH ₂ = C (CH ₃ ) ₂ ], 190 [M ⁺ +1 -CO ₂ -CH ₂ = C (CH ₃ ) ₂ ].

HU 211 837 A9

19 (b) (2S) (tert-Butoxycarbonyl) amino], 4-dihydroxybutane

To a solution of lithium borohydride (3.01 g, 0.138 mol) in tetrahydrofuran (100 ml) was added dropwise a solution of tetrahydrofuran (40 ml) in ethyl acetate (10.0 g, 0.035 mol) prepared as described in (a) above. -butoxycarbonyl) -L-aspartate. The drop rate is chosen so that the temperature of the reaction mixture is maintained at 40 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours, and any excess reducing agent was quenched by the addition of a small amount of water. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure to remove tetrahydrofuran. Sodium chloride was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. 6.15 g of (2S) (tert-butoxycarbonyl) amino-1,4-dihydroxybutone are obtained in the form of a colorless oil.

Mass Spectrum (CI): m / e 206 (M ⁺ l) 150 [M ⁺ 1 CH2 = C (CH3) 2R] 106 [M ⁺ 1 CO 2 CH ₂ (CH _{3) 2],}

19 (c) (tert-Butoxycarbonyl) amino-1,4-di (methylsulfonyloxy) butane

Under ice-cooling, (2S) (tert-butoxycarbonyl) amino-1,4-dihydroxybutone (13.0 g, 0.060 mol) prepared as described in (b) above and 14.54 g (0.144 mol) were obtained. To a solution of triethylamine in methylene chloride (250 mL) was added dropwise methanesulfonyl chloride (15.12 g, 0.132 mol). The reaction mixture was stirred under ice-cooling for 3 hours and then allowed to stand at room temperature overnight. The reaction mixture was then quenched with water and methylene chloride, and the organic layer was separated, dried over anhydrous sodium sulfate, and then the dried organic layer was concentrated by evaporation under reduced pressure. 20.22 g of (tert-butoxycarbonyl) amino-1,4-di-methylsulfonyloxy-butane are obtained in the form of colorless crystals.

Mass Spec (Cl): m / e 210 [M ⁺ -OSO ₂ -H ₃ CH ₂ = (C (CH ₃ ) ₂ ]).

J9 (d) (3S) -Amino-pyrrolidine dihydrochloride

To a suspension of 20.22 g (0.056 mol) of tert-butoxycarbonylamino-1,4-di (methylsulfonyloxy) butone prepared in step (c) above in 130 ml of methanol is added 6.0 g (0.059). mole) of triethylamine and then ammonia gas is passed through the reaction mixture to saturation. The reaction mixture was then stirred at room temperature for 2 days and then concentrated by evaporation under reduced pressure. The resulting residue was dissolved in methylene chloride (150 mL) and di-tert-butyl dicarbonate (12.22 g, 0.056 mol) was added. Triethylamine (23 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography over silica gel using toluene / ethyl acetate 9: 1 (v / v) as the eluent. This gives (3S) -tert-butoxycarbonylamino-1- (tert -butoxycarbonyl) pyrrolidine as an oil. This oil was mixed with 10 mL of concentrated aqueous hydrochloric acid and the resulting mixture was concentrated to dryness under reduced pressure. After rubbing with ethanol

2.87 g of the title compound of this step are obtained as a colorless powder.

Mass spectrum (CI): m / e 87 (M ⁺ +1), 70 (M ⁺ -NH ₂ ).

REFERENCE EXAMPLE 20

3-Amino-4- (2,2,2-trifluoroethoxy) pyrrolidine dihydrochloride

20 (a)] - (tert-Butoxycarbonyl) -3- (2,2,2-trifluoroethoxy) -4-methylsulfonyloxy-pyrrolidine

While cooling with water, 1.08 g (0.027 mol) of a 60% w / w sodium hydride dispersion in mineral oil are added to 15 ml of 2,2,2-trifluoroethanol and the resulting mixture is stirred for 20 minutes. Subsequently, 5.0 g (0.027 mol) of 1- tert -butoxycarbonyl-3,4-epoxypyrrolidine were added and the resulting reaction mixture was refluxed for 3 hours. The reaction mixture was then quenched with saturated brine and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was dissolved in 50 ml of pyridine and 3.23 g (0.028 mol) of methanesulfonyl chloride was added to the resulting solution under ice-cooling. The reaction mixture was stirred at room temperature for 5 hours and then allowed to stand overnight at the same temperature. After dilution with water (300 mL), the reaction mixture was extracted with toluene. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography over silica gel using toluene / ethyl acetate 9: 1 (v / v) as the eluent. 7.07 g of 1- (tert-butoxycarbonyl) -3- (2,2,2-trifluoroethoxy) -4-methylsulfonyloxypyrrolidine are obtained.

20 (b) 3-Amino-1 - (tert-butoxycarbonyl) -4- (2,2,2-trifluoroethoxy) pyrrolidine

3.95 g (0.011 mol) of 1- (tert-butoxycarbonyl) -3- (2,2,2-trifluoroethoxy) -4-methylsulfonyloxypyrrolidine obtained in the same manner as in the above step (a) are weighed into an autoclave and 100 ml are added. methanol and then 140 'Con for 10 hours. Subsequently, the solvent was removed by distillation under reduced pressure and the residue was mixed with a saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate, and the organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel

EN 211 837 A9 using a 1: 9 by volume mixture of ethanol and ethyl acetate as eluent. 1.61 g of 3-amino-1- (tert-butoxycarbonyl) -4- (2,2,2-trifluoroethoxy) pyrrolidine are obtained as a colorless oil.

Mass Spec (Cl): m / e 285 (M ⁺ +1), 229 [M ⁺ + 1CH ₂ = C (CH ₃ ) ₂ ],

20 (c) 3-Amino-4- (2,2,2-trifluoroethoxy) pyrimidine dihydrochloride

1.61 g (0.006 mol) of 3-amino-1- (tert-butoxycarbonyl) -4- (2,2,2-trifluoroethoxy) pyrrolidine, prepared as described in step (b) above, in 30 ml of ethanol A mixture of 2 ml of concentrated aqueous hydrochloric acid and 4 ml of water was allowed to stand overnight at room temperature and then evaporated to dryness under reduced pressure. 1.60 g of 3-amino-4- (2,2,2-trifluoroethoxy) pyrrolidine dihydrochloride are obtained in the form of colorless crystals.

Mass spectrum (CI): m / e 185 (M ⁺ +1).

REFERENCE EXAMPLE 21

3-Amino-4-methoxymethyl-pyrrolidine dihydrochloride (a) 1-Benzyl-3- (ethoxycarbonyl) -4- (hydroxyimino) pyrrolidine

At room temperature, a solution of 34.7 g (0.5 mol) of hydroxylamine hydrochloride in 135 ml of water was added a solution of 24.7 g (0.1 mol) of 1-benzyl-3- (ethoxycarbonyl) -4-pyrrolidone in 135 ml of ethanol. to the reaction mixture was added sodium carbonate (28.1 g, 0.265 mol). The reaction mixture was stirred at room temperature for 6.5 hours and then extracted with 300 ml of chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 2: 1). so

15.8 g of 1-benzyl-3-ethoxycarbonyl-4-hydroxyimino-pyrrolidine are obtained as a brown oil.

Mass Spec (Cl): m / e 263 (M ⁺ +1).

IR (capillary): cm ^-1 : 3300, 1740.

21 (b) 3-Amino-1-benzyl-4- (hydroxymethyl) -pyrrolidine) is added dropwise over 1 hour to a 3.4 molar solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene. A solution of 1-benzyl-3-ethoxycarbonyl-4-hydroxyimino-pyrrolidine (5.24 g, 0.02 mol) prepared in the above step (a) in 10 ml of toluene. The reaction mixture was then stirred at room temperature for 1.5 hours and then refluxed for 2 hours. The reaction mixture was allowed to cool at room temperature and ice and water were added. The precipitate formed is removed by filtration and the filtrate is concentrated by evaporation under reduced pressure. The residue was purified by column chromatography over silica gel using methanol as eluent. This gives 3.16 g of 3-amino-1-benzyl-4- (hydroxymethyl) pyrrolidine as a brown oil.

Mass spectrum (CI): m / e 207 (M ⁺ +1).

IR spectrum (capillary): cm ^-1 : 3150-3400.

21 (c) 1-Benzyl-3- (N-tert-butoxycarbonyl) amino-4-hydroxymethylpyrrolidine

At room temperature, a solution of 5.87 g (0.0285 mol) of 3-amino-1-benzyl-4- (hydroxymethyl) -pyrrolidine prepared as described in step (b) above with 100 ml of methylene chloride is added in small portions.

6.21 g (0.0285 mole) of di-tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 1 day. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate as the eluent. so

6.32 g of 1-benzyl-3- (N-tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine are obtained in the form of a pale bamboo oil.

IR (capillary): cm- ¹ : 3350, 16801720.

21 (d) 3- (N-tert-Butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine

Weigh it into a stainless steel autoclave

6.32 g (0.0207 mol) of 1-benzyl-3- (N-tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine prepared as described in step (c) above are prepared with 100 ml of ethanol. and 20 g of a palladium-on-carbon catalyst (2.0 g) and stirred at room temperature under 100 kg / cm ² hydrogen gas for 27 hours. The catalyst is then removed by filtration and the filtrate is concentrated by evaporation under reduced pressure. 3.99 g of 3- (N-tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine are obtained as a colorless crystalline oil.

Mass spectrum (CI): m / e 217 (M ⁺ +1).

IR (Br): cm ^-1 : 3350, 3270, 16801690.

21 (e) 1- (tert-Butoxycarbonyl) -3- (N-tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine At room temperature, 3.08 g (0.0143 mole) of the above compound was prepared. To a solution of 3- (N-tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine (50 ml) in methylene chloride (3.12 g) was added in small portions to a solution of 3- (N-tert-butoxycarbonyl) amino and the resulting reaction mixture is stirred at the same temperature for one day. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel using toluene / ethyl acetate (1: 1) as the eluent. 3.99 g of 1- (tert-butoxycarbonyl) -3- (tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine are obtained in the form of colorless crystals.

Mass spectrum (CI): m / e 317 (M ⁺ +1).

21 (f) 1- (tert-Butoxycarbonyl) -3- (N-tert-butoxycarbonyl) amino-4- (methoxymethyl) pyrrolidine

3.86 g (0.0122 mole) described in step (e) above

To a solution of 1- (tert-butoxycarbonyl) -3- (N-tert-butoxycarbonyl) amino-4- (hydroxymethyl) pyrrolidine (A9) prepared in A9 in 190 ml of diethyl ether was added dropwise 0 Boron trifluoride diethyl etherate (3 ml) and ether solution (0.126 mol) in diazomethane was added over 1.5 hours. The reaction mixture was then stirred at the same temperature for 0.5 hour and then allowed to stand at room temperature overnight. It is then mixed with a saturated aqueous solution of sodium chloride and the ether phase is separated off. The ethereal phase is dried and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 2: 1). 0.47 g of 1- (tert-butoxycarbonyl) -3- (N-tert-butoxycarbonyl) amino-4- (methoxymethyl) pyrrolidine is obtained as a colorless oil.

Mass Spec (Cl): m / e 331 (M ⁺ +1).

IR (capillary): cm ^-1 : 3330, 16701730.

21 (g) 3-Amino-4-methoxymethyl-pyrrolidine dihydrochloride

0.58 g (0.0021 mol) of 1- (tert-butoxycarbonyl) -3- (N-tert-butoxycarbonyl) amino-4-methoxymethyl, prepared as described in (f) above, To a solution of pyrrolidine in 30 ml of ethanol was added 7 ml of 6N aqueous hydrochloric acid, and the resulting mixture was refluxed for 2 hours and then concentrated to dryness under reduced pressure. 0.43 g of 3-amino-4-methoxymethylpyrrolidine dihydrochloride is obtained as a brown oil.

Mass Spec (Cl): m / e 131 (M ⁺ +1).

REFERENCE EXAMPLE 22

2-Fluoro-methylpiperazine dihydrochloride

22 (a) N-Benzyl-N- (3-fluoro-2-propylindol hidtOxi) -etanolamin

A solution of 22.20 g (0.3 moles) of epifluorohydrin and 67.95 g (0.45 moles) of N-benzylethanolamine in 200 ml of ethanol is refluxed for 5 hours and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by column chromatography over silica gel using ethyl acetate as the eluent. 64.93 g of N-benzyl-N- (3-fluoro-2-hydroxypropyl) ethanolamine are obtained in the form of a colorless oil.

Mass Spec (Cl): m / e 228 (M ⁺ +1).

22 (b) N- (3-Fluoro-2-methylsulfonyloxypropd) -N- (2-methyldisulfonyloxyethylbenzylamine)

To a solution of N-benzyl-N- (3-fluoro-2-hydroxypropyl) -ethanolamine (6.75 g, 0.03 mol) prepared in the above step (a) is added 7.27 g of ethyl acetate. g (0.072 mol) of triethylamine followed by stirring under ice-cooling with 8.24 g (0.072 mol) of methanesulfonyl chloride. The reaction mixture was stirred at the same temperature for 3 hours, and then aqueous sodium bicarbonate solution was added. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give N- (3-fluoro-2-methylsulfonyloxypropyl) -N- (2-methylsulfonyloxyethyl) benzylamine as a pale yellow oil (12.49 g). .

Mass spectrum (CI): m / e 384 (M ⁺ +1).

22 (c)], 4-Dibenzyl-2-fluoromethyl-piperazine Prepared as described in step (b) above.

To a solution of N- (3-fluoro-2-methylsulfonyloxypropyl) -N- (2-methylsulfonyloxyethyl) -benzylamine in 200 mL of ethanol was added 4.82 g (0.045 mol) of benzylamine and 9.09 triethylamine (0.09 mol) was added and the resulting mixture was refluxed for 2 hours and then concentrated by evaporation under reduced pressure. To the residue was added ethanol (100 ml) and 2N aqueous sodium hydroxide solution (40 ml), and the resulting reaction mixture was concentrated by evaporation under reduced pressure. Ethyl acetate was added to the residue and insoluble materials were removed by filtration. The filtrate was freed from the solvent by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel using toluene / ethyl acetate (9: 1) as the eluent. This gave 3.60 g of 1,4-dibenzyl-2-fluoromethylpiperazine as a yellow oil.

Mass spectrum (CI): m / e 299 (M ⁺ +1).

22 (d) 2-Fluoromethyl-piperazine dihydrochloride. 23.85 g (0.08 mol) of 1,4-dibenzyl-2-fluoromethyl-piperazine prepared in step (c) above are prepared in 500 ml of methanol. of aqueous solution of H 2 O and 33 ml of concentrated aqueous hydrochloric acid solution under vigorous stirring at room temperature under a hydrogen gas atmosphere at room temperature in the presence of 1.0 g of 20% palladium-on-carbon, followed by filtration and washing with water. The filtrate and washings were concentrated by evaporation under reduced pressure and the residue was dissolved in 200 ml of water. The resulting aqueous solution was washed extensively with ethyl acetate and separated. The aqueous phase is then concentrated by evaporation under reduced pressure and the residue is washed with ethanol. 13.76 g of 2-fluoromethylpiperazine dihydrochloride are obtained in the form of a colorless powder, m.p. 205-218 ° C.

Mass spectrum (CI): m / e 119 (M ⁺ +1).

Analysis results for C ₅ H ₁₃ CL ₂ FN ₂ :

Found: C, 31.43; H, 6.86; N, 14.66;

Found: C, 31.42; H, 6.81; N, 14.71.

REFERENCE EXAMPLE 23 (2S) -Methyl-homopiperazine dihydrochloride

23 (a) Etd N- (cyanoethyl) -α-alanate

A solution of ethyl L-alanate (15.3 g, 0.131 mol), acrylonitrile (5.0 g, 0.132 mol) and sodium methylate (1.0 g, 0.018 mol) in ethanol (150 mL) was heated at reflux for 7 hours, then let it cool down. thereafter

The reaction mixture was concentrated by evaporation under reduced pressure and the residue was purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 4: 1). 12.5 g of ethyl N- (cyanoethyl) -L-alanate were obtained as a colorless oil.

Mass Spec (Cl): m / e 119 (M ⁺ +1).

23 (b) (3S) -Methyl-2-oxo-homopiperazine

A mixture of ethyl N- (cyanoethyl) -L-alanate (9.8 g, 0.057 mol) prepared as described in (a) above, was autoclaved in 70 g of ethanol containing 4% by weight of ammonia and 1.79 g of Raney nickel. followed by stirring at 60 kg / cm ² hydrogen pressure at 90 ° C for 3 hours. The reaction mixture was allowed to cool, and the catalyst was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure. To the residue was added xylene (200 mL) and dibutyltin oxide (1.4 g), and the resulting mixture was refluxed for 10 hours. The ethanol-containing fraction formed during the reaction is eliminated from the reaction mixture. Subsequently, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: chloroform: methanol = 9: 1). 5.3 g of (3S) -methyl-2-oxo-homopiperazine are obtained in the form of pale brown crystals.

Mass Spec (Cl): m / e 129 (M ⁺ +1).

23 (c) (2S) -Methyl-homopiperazine dihydrochloride To a suspension of lithium aluminum hydride (2.91 g, 0.077 mol) in tetrahydrofuran (60 ml) was added dropwise, under ice-cooling, 4.92 g (0.038 mol) from (b) above. a mixture of (3S) -methyl-2-oxo-homopiperazine (60 ml) and tetrahydrofuran (60 ml). Subsequently, the reaction mixture was refluxed for 5 hours and then allowed to cool. A small amount of water is then added under ice-cooling to break down any excess reducing agent. The reaction mixture is then filtered and 20 ml of concentrated aqueous hydrochloric acid are added to the filtrate. The mixture was evaporated to dryness under reduced pressure and the residue was triturated with ethanol. 5.93 g of (2S) -methyl-homopiperazine dihydrochloride are obtained in the form of colorless crystals, m.p. 211-220 ° C.

Mass Spec (Cl): m / e 115 (M ⁺ +1).

REFERENCE EXAMPLE 24 2,6-Bis (fluoromethyl) piperazine dihydrin) chloride 24 (a) N, N-bis (3-fluoro-2-hydroxypropyl) -benzylamine

A solution of epifluorohydrin (27.28 g, 0.359 mol) and benzylamine (19.20 g, 0.1795 mol) in ethanol (200 ml) was heated at reflux for 4 hours and then concentrated by evaporation under reduced pressure. 46.6 g of N, N-bis (3-fluoro-2-hydroxypropyl) -benzylamine are obtained as a colorless oil.

Mass Spec (Cl): m / e 260 (M ⁺ +1).

24 (b)], 4-Dibenzyl-2,6-bis (fluoromethyl) piperazine

To a solution of 33.67 g (0.13 mol) of N, N-bis (3-fluoro-2-hydroxypropyl) benzylamine prepared in the above step (a) in 300 ml of tetrahydrofuran is added 28.89 g ( Triethylamine (0.286 mol) followed by dropwise addition of methanesulfonyl chloride (32.76 g, 0.286 mol) under ice-cooling. After stirring at room temperature for 6 hours, triethylamine (39.40 g, 0.39 mole), benzylamine (20.87 g, 0.195 mole) and ethanol (300 mL) were added. After refluxing for 3 hours, the reaction mixture was concentrated under reduced pressure. 300 ml of water containing 30 g of sodium hydroxide are added to the residue. The resulting aqueous mixture was extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene: ethyl acetate = 20: 1) to give 1,4-dibenzyl-2,6-bis (fluoromethyl) piperazine as colorless crystals (6.29 g). and 6.60 g of isomer B.

Isomer A _Rf value: 0.7.

Isomer B _Rf value: 0.5.

(TLC: Merck F ₂₅₄ silica gel; eluent: toluene / ethyl acetate 9: 1 v / v).

Mass spectrum (CI) for both A and B isomers: m / e 331 (M ⁺ +1).

24 (c) 2,6-Bis (fluoromethyl) piperazine dihydrochloride

A suspension of 5.03 g (0.015 mol) of the 1,4-dibenzyl-2,6-bis (fluoromethyl) piperazine B isomer prepared as described in step b) above in a mixture of 130 ml of methanol and 6 ml of concentrated aqueous hydrochloric acid Stir vigorously under a stream of hydrogen gas at room temperature in the presence of 0.6 g of 20% palladium on carbon for 1 hour, then remove the catalyst by filtration and concentrate the filtrate by evaporation under reduced pressure. Water (50 mL) was added to the residue and the insolubles formed were filtered off. The filtrate was concentrated by evaporation under reduced pressure and the residue was washed with ethanol to give 3.10 g of 2,6-bis (fluoromethyl) piperazine dihydrochloride B as a colorless powder, m.p. 207-225 ° C.

Mass spectrum (CI): m / e 151 (M ⁺ +1).

Calcd for C _{6 H] 4} C 1 ₂ F ₂ N ₂ O: Calculated: C% = 32.30 H% = 6.32 N% = 12.56;

Found: C, 32.38; H, 6.26; N, 12.60.

Following the procedure described above but using the 1,4-dibenzyl-2,6-bis (fluoromethyl) piperazine A isomer, the 2,6-bis (fluoromethyl) piperazine dihydrochloride A is obtained as a colorless powder.

Mass spectrum (CI): m / e 151 (M ⁺ +1).

Analysis results for C ₆ H ₁₄ Cl ₂ F ₄ N ₂ '/ ₂ H ₂ O:

Calculated: C, 31.04; H, 6.51; N, 12.07;

Found: C, 30.66; H, 6.22; N, 11.78.

HU 211 837 A9

EXAMPLE 7 1-Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl)], 4-dihydro-4-oxo-quinoline-3-carboxylic acid

2.58 g (0.0068 mol) of 1-cyclopropyl-8- (difluoromethoxy) -6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-cyclopropyl, prepared as described in Reference Example 8. To a solution of the carboxylic acid boron difluoride chelate in 20 mL of dimethyl sulfoxide was added 1.63 g (0.016 mol) of 2-methylpiperazine and the resulting mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water (100 mL) and the precipitated crystals were collected by filtration and washed with water. The crystals were then dissolved in 500 ml of 80% aqueous methanol containing 15 ml of triethylamine and the resulting solution was refluxed for 3 hours. The solvent was removed by evaporation under reduced pressure and the residue was washed with water to give 2.30 g of a pale yellow powder. A total amount of this powder was dissolved in water (50 mL) and insoluble materials were removed by filtration and the pH of the filtrate was adjusted to 7.5 by addition of 1 N aqueous sodium hydroxide solution. The precipitated crystals are filtered off, washed with water and then with ethanol. 1.74 g of the title compound are obtained in the form of pale yellow needle crystals, m.p. 223-225 ° C.

Mass spectrum (CI): m / e 412 (M ⁺ +1).

Calcd for C _l9 H ₂₀ F ₃ N ₃ O ₄ H ₂ O wherein:

Found: C, 53.14; H, 5.17; N, 9.79;

Found: C, 53.44; H, 4.93; N, 9.77.

EXAMPLE 2 1-Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

1.00 g (0.0024 mol) of 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4-one prepared as described in Example 1 were obtained. To a suspension of oxoquinoline-3-carboxylic acid in 50 ml of methanol was added 240 ml (0.0024 mol) of 1 N aqueous hydrochloric acid to give a clear solution. This was then concentrated by evaporation under reduced pressure and the residue was washed with ethanol. 0.97 g of the title compound (hydrochloride) is obtained in the form of a colorless powder, m.p. 277-287 ° C (dec.).

Analysis for C ₁₉ H ₂ | basis C1F ₃ O ₃ N ₄ O:

Found: C, 50.95; H, 4.73; N, 9.38;

Found: C, 50.84; H, 4.44; N, 9.29.

EXAMPLE 3] -Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl)], 4-dihydro-4-oxo-quinoline-3-carboxylic acid methanesulfonic acid salt

0.40 g of 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4-oxo, prepared as described in Example 1, is obtained. To a suspension of quinoline-3-carboxylic acid in methanol (50 ml) was added methanesulfonic acid (0.093 g, 0.00097 mole) and the resulting clear solution was concentrated by evaporation under reduced pressure. The resulting residue was washed with ethanol to give 0.47 g of the title compound (methanesulfonic acid salt) as a colorless powder, m.p. 289292C (dec.).

Analysis results for C ₂₀ H ₂₄ F ₃ N ₃ O ₇ S '/ ₂ H ₂ O:

Found: C, 46.51; H, 4.88; N, 8.14;

Found: C, 46.44; H, 4.65; N, 7.97.

In a similar manner to that described in Examples 1, 2 or 3, the following compounds can be prepared.

TABLE 3

The serial number of the example Number of compound Advertising, salt, etc. op. (° C) 4th 34th hydrate 220-221 5th 34th hydrochloride, sesquihydrate 218-224 6th 34th methanesulfonate 282-284 (Dec) 7th 5th hydrochloride, sesquihydrate 247-251 8th 43 cis hydrate 187-188 9th 39th hydrochloride 249-253 10th Cis 3 hydrate 240-241 11th Cis 3 hydrochloride, hydrate (gradual decomposition from 295 'C) > 300 12th Cis 3 methanesulfonate > 300 13th 32nd hydrochloride dihydroisoindol Ra 213-217 14th 45th sesquihydrate 167-170 15th First hydrate 265-268 (Dec) 16th 179th hydrate 251-253 (Dec) 17th 148th hydrate 232-237 18th 152nd - 226-229 19th 188. cis sesquihydrate 241-245 20th 149 cis - 237-241 21st 147th hydrate 249-251 22nd 72nd hydrochloride, sesquihydrate 230-235 23rd 59th hydrochloride, hemihydrate 252-255 24th 73rd hydrochloride 228-235 (Dec) 25th 46th hydrate 269-271 (Dec) 26th 48th hydrate 160-163

HU 211 837 A9

The serial number of the example Number of compound Advertising, salt, etc. op. CC) 27th Second hydrochloride at the 3-position of the piperazinyl ring in the R (or S -) configuration 283-289 (Dec) 28th Second hydrochloride at the 3-position of the piperazinyl ring in the R (or S -) configuration 283-286 (Dec) 29th 56th hydrochloride, sesquihydrate 270-275 (Dec)

EXAMPLE 30

5-amino-l-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-piperazinyl) -l, 4-dihydro-4-oxo-quinoline-3-carboxylic acid

0.90 g (0.0026 mol), all. To a solution of 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 5-amino-1-cyclopropyl-8,7-dichloromethane in 8 ml of pyridine was added mole) of 2-methylpiperazine and the resulting mixture was stirred at 105-110 ° C for 2 hours. The solvent is then removed by distillation under reduced pressure. Water was added to the residue and the resulting mixture was neutralized (to a pH of about 7) by the addition of acetic acid. After extraction with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was washed with ethanol to give 0.72 g of 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4 Oxoquinoline-3-carboxylic acid is obtained as a yellow powder, m.p. 283-286 ° C.

Analysis: Calculated for C ₁₉ H ₂₁ F ₃ N ₄ O ₄ : C, 53.52; H, 4.96; N, 13.14;

Found: C, 53.35; H, 4.93; N, 13.00.

31-60. EXAMPLES

In a similar manner to that described in Example 30, the following compounds were prepared.

TABLE 4

The serial number of the example Number of compound Hydrate, salt, etc. mp CC) 31st 107th hemi hydrate 242-245 32nd 74th hemi hydrate 282-283 33rd 78th hemihydrate > 300 34th 76 cis dihydrate 297-300 35th 116 cis - 244-245 36th 76 cis hydrochloride > 300 37th 75th hydrochloride, hemihydrate 296-298 (Dec)

The serial number of the example Number of compound Hydrate, salt, etc. mp CC) 38th 75th the hemihydrate at the 3-position carbon atom of the piperazinyl ring is in the R configuration 278-281 39th 75th sesquihydrate the 3-carbon of the piperazinyl ring has the S configuration 278-281 40th 129th - 275-280 41st 93rd hydrate 264-266 (Dec) 42nd 94th - 274-275 (Dec) 43rd 139th - 270-273 (Dec) 44th 129th dihydrate the piperazinyl ring Its 3-position carbon atom has the S configuration 270-275 (Dec) 45th 109th hydrochloride, hemihydrate 257-259 46th 82nd - 273-274 (Dec) 47th 130th - 285-291 (Dec) 48th 134th hydrochloride 255-259 (Dec) 49th 144th the hemihydrate is the S-configuration of the 3-carbon of the piperazinyl ring 252-256 50th 131st the 3-position carbon atom of the piperazyl ring has the S configuration 264-267 51st 90th - 254-257 (Dec) 52nd 143rd - 217-221 (Dec) 53rd 107th the piperazinyl ring Its 3-position carbon atom has the S configuration 234-238 54th 79th - 291-294 (Dec) 55th 141st - 239-242 (Dec) 56th 133rd - 242-246 (Dec) 57th 137th - 271-273 (Dec) 58th 136th - 253-257 (Dec) 59th 142nd - 263-265 (Dec) 60th 284th - 252-253 (Dec)

HU 211 837 A9

EXAMPLE 61

Magnesium [5-amino] -cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate]

1.00 g (0.00234 mol) of 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1, prepared as in Example 30, To 4-dihydro-4-oxo-quinoline-3-carboxylic acid was added 23.0 mL (0.0023 mol) of 0.1 N aqueous sodium hydroxide solution and the resulting insoluble matter was removed by filtration. To the filtrate was added 0.11 g (0.00115 mol) of anhydrous magnesium chloride, and the resulting mixture was stirred at room temperature for 90 minutes. The precipitate formed is then filtered off and washed with water. 0.91 g of magnesium [5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3- Carboxylate] m.p. 291-293 ° C (dec.) as a yellow powder.

Analysis results for C3 ₈ H ₄₀ F ₆ N ₈ O ₈ Mg-2H ₂ O:

Calc'd: C, 50.09; H, 4.86; N, 12.29;

Found: C, 50.13; H, 4.75; N, 12.19.

BIOLOGICAL ACTIVITY

The antibacterial activity of some of the compounds of the invention is studied in a broad range of bacteria, both Gram-positive and Gram-negative, and the results obtained are as follows.

Are given in Tables 5 and 6 as minimum inhibitory concentrations (pg / ml).

For comparison purposes, we also provide data for a known compound, Norfloxacin, referred to in the table as "Compound A" for simplicity. Each compound of the invention is identified by a serial number for the preparation example.

TABLE 5

micro-organisms organism Example number of compound First 5th 30th 31st 39th THE Staphylococcus au- resus 209P 0.05 <0.01 <0.01 <0.01 <0.01 0.2 56 0.05 <0.01 <0.01 <0.01 <0.01 0.4 535 1.2 <0.01 0.02 0.02 <0.01 6.2 Enterococcus faecalis 681 0.2 0.05 0.05 0.05 0.05 3.1 Escherichia coli NIHJ <0.01 <0.01 0.02 <0.01 <0.01 0.2 609 0.4 0.4 0.2 0.2 0.05 3.1 Salmonella enteritidis <0.01 <0.01 <0.01 <0.01 <0.01 0.1 Klebsiella pneumoniae 806 0:05 <0.01 0.05 0.02 0.02 0.4 846 0.02 <0.01 0.02 <0.01 <0.01 0.4

micro-organisms organism Example number of compound First 5th 30th 31st 39th THE Enterobacter cloacae 963 0.1 0.02 0.1 0.05 0.05 0.4 Servatia marces- cens 1184 0.4 0.1 0.4 0.2 0.2 0.2 Proteus vulgar 1420 <0.01 <0.01 <0.01 <0.01 <0.01 0.02 Morganella morganii 1510 0.1 0.02 0.2 0.1 0.2 0.05 Pseudomonas aeruginosa 1001 0.4 0.4 0.4 0.4 0.2 0.8

PATENT CLAIMS

Claims (14)

PATENT CLAIMS A compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, wherein R ¹ is methoxy substituted with at least one fluorine substituent; R ² is selected from the group consisting of: (i) groups of formula (Π) - in this formula R ⁴ is hydrogen: hydroxy; amino; C 1-6 alkyl; C 1-6 alkyl substituted with at least one substituent selected from the group consisting of (a), as defined below; aralkyl; C 1-6 aliphatic acyl; or a C2-C6 aliphatic acyl group substituted with at least one substituent selected from the group consisting of (a) as defined below; R ⁵ is hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with at least one substituent selected from the group consisting of (b) as defined below; A is ethylene, trimethylene or -COCH ₂ -; and m is 1 or 2; R ³ is hydrogen or amino; the substituents (a) include hydroxy groups, C1-C6 alkoxy groups, C2-C6 aliphatic acyloxy groups, C1-C6 aliphatic acyl groups, carboxyl groups, C2-C6 alkoxycarbonyl groups, sulfo groups, amino groups, C2-C6 aliphatic acyl groups and the alkyl moiety or alkyl moieties include mono- and dialkylamino groups containing from 1 to 6 carbon atoms; substituents (b) include hydroxy groups, C 1 -C 6 alkoxy groups and halogen atoms; and A9 aralkyl groups have from 1 to 4 carbon atoms in their alkyl moiety and from 6 to 10 carbon atoms in their aryl moiety, and the latter may be unsubstituted or substituted with at least one substituent selected from the group consisting of substituents (c) as defined below; substituents (c) include hydroxy groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, C 2-6 aliphatic acyloxy groups, C 1-6 aliphatic acyl groups, carboxyl groups, C 2-6 alkoxycarbonyl groups, sulfo groups, nitro groups, cyano groups, amino groups, C2-C6 aliphatic acylamino groups and mono- and dialkylamino groups containing 1 to 6 carbon atoms in the alkyl moiety or alkyl moieties. 2. A compound according to claim 1, characterized in that R ¹ represents a difluoromethoxy group or trifluoromethoxy. The compound according to claim 1, which is 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof. an acceptable salt, ester or amide thereof. The compound according to claim 1, which is 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and a pharmaceutically acceptable salt, ester or amide thereof. The compound according to claim 1, which is 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethylpiperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, and a pharmaceutically acceptable salt, ester or amide thereof. 6. A compound according to claim 1, which is 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, and a pharmaceutically acceptable salt, ester or amide thereof. 7. The compound of claim 1 which is 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline. A 3-carboxylic acid and a pharmaceutically acceptable salt, ester or amide thereof. 8. A compound according to claim 1 which is 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxo. quinoline-3-carboxylic acid; and a pharmaceutically acceptable salt, ester or amide thereof. 9. The compound according to claim 1, which is 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7- (4-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3- a carboxylic acid; and a pharmaceutically acceptable salt, ester or amide thereof. 10. The compound of claim 1 which is 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7- (3-fluoromethyl-piperazinyl) -1,4-dihydro-4-oxo-quinoline. 3-carboxylic acid, and a pharmaceutically acceptable salt, ester or amide thereof. 11. A pharmaceutical composition for the treatment of bacterial infections comprising an effective amount of an antibacterial agent in combination with a pharmaceutically acceptable carrier or diluent, wherein the antibacterial agent is a compound of formula (I) as defined in claim 1, and pharmaceutically acceptable salts, esters and amides thereof. a compound selected from. 12. The composition of claim 11, wherein the antibacterial agent is a compound selected from the group consisting of: and pharmaceutically acceptable salts, esters, and amides thereof: l-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (l-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 3-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 1-Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. 13. A method of treating bacterial infections comprising administering to an animal an amount of an antibacterial agent sufficient to provide an antibacterial effect, wherein the antibacterial agent is a compound of formula (I) as defined in claim 1, and pharmaceutically acceptable salts, esters and amides thereof. 14. The method of claim 13, wherein the antibacterial agent is a compound selected from the group consisting of: and pharmaceutically acceptable salts, esters, and amides thereof: 1-Cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; l-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-1-piperazinyl) -l, 4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-amino-l-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (l-piperazinyl) -l, 4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-amino-l-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3,5-dimethyl-l-piperazinyl) -l, 4-dihydro-4-oxoquinoline-3-carboxylic acid; HU 211 837 A9 5-amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid; 5-Amino-1-cyclopropyl-8- (difluoromethoxy) -6-fluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.