SK219192A3 - Quinolonecarboxylic acids derivatives, method of preparation thereof, intermediates for preparation thereof, their use and pharmaceutical agent containing them - Google Patents

Abstract

The invention relates to novel 8-vinyl- and 8-ethynyl- quinolonecarboxylic acids, a process for their preparation and antibacterial agents and feed additives containing them.

Description

Technical field

The present invention relates to novel 8-vinyl-quinolone carboxylic acids and 8-ethynyl quinolone carboxylic acids, to a process for their preparation, as well as to antibacterial compositions and feed additives containing said compounds.

BACKGROUND OF THE INVENTION

It is already known that 8-alkyl-quinolone carboxylic acids are antibacterially active. 8-Methyl-quinolonecarboxylic acids have already been described, for example in EP 237 955 and JP 2 019 377 and 3-trifluoromethyl-quinolonecarboxylic acids, for example in US 4 780 468, US 4 803 205 and US 4 933 335.

SUMMARY OF THE INVENTION

It has now been found that the novel compounds of formula (I)

R ^{1 is} straight or branched (C 1 -C 4) alkyl optionally substituted by hydroxy, halogen or C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl and C 2 -C 4 alkenyl, optionally substituted with halogen or (C1-C3) -alkyl, (C1-C3) -alkoxy,

V286 / 93H amino, monoalkylamino of 1 to 3 carbon atoms, dialkylamino of 2 to 6 carbon atoms or phenyl, optionally substituted one to three times by halogen atom,

R ² hydrogen, alkyl of 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl,

X ^{1 is a} hydrogen atom, a fluorine atom, a chlorine atom, an amino group or a methyl group,

X ^{2 is} -C = CH-R ³ , -OC-R ^5, or -CH ₂ -CH = CH ₂ , wherein

R ³ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or an alkoxymethyl group having 1 to 3 carbon atoms in the alkoxy moiety,

R ⁴ represents a hydrogen atom or a halogen atom;

R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, optionally substituted one to three times with a halogen atom, an alkenyl group having 2 to 3 carbon atoms, an optionally substituted one to three times a halogen atom, an alkoxy group having 1 to 3 carbon atoms, an alkoxymethyl group having 1 to 3 carbon atoms in the alkoxy moiety, a halogen atom or a trimethylsilyl group; and

Y groups

V286 / 93H

R ⁹ R ¹⁰

R ¹⁶ R ^{1 -} O / ^nch

R ¹ '

V286 / 93H where

R ⁶ represents a hydrogen atom, a C 1 -C 4 alkyl group which is straight or branched and optionally substituted by a hydroxy or methoxy group, a cyclopropyl group, a C 1 -C 4 oxoalkyl group or a C 1 -C 3 acyl group,

R ⁷ represents a hydrogen atom, a methyl group, a phenyl group, a thienyl group or a pyridyl group,

R ^{8 is a} hydrogen atom or a methyl group,

R ⁹ represents a hydrogen atom or a methyl group,

R ¹⁰ represents a hydrogen atom or a methyl group,

R ¹¹ represents hydrogen, methyl or

- ^ch * - <rio

R ¹² represents a hydrogen atom, a methyl group, an amino group, an alkylamino group or a dialkylamino group having 1 to 2 carbon atoms in the alkyl moieties, optionally substituted by hydroxy, aminomethyl, alkylaminomethyl or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl moiety -imidazolyl group,

R ¹³ represents a hydrogen atom, a hydroxy group, a methoxy group, a methylthio group, a halogen atom, a methyl group or a hydroxymethyl group,

R ¹⁴ represents a hydrogen atom or a methyl group,

R ¹⁵ represents a hydrogen atom, a methyl group or an ethyl group,

R ¹⁶ represents a hydrogen atom, a methyl group or an ethyl group,

V286 / 93H

R ¹⁷ represents a hydrogen atom, a methyl group or ethyl group R @ ¹⁸ is hydroxy, R @ 16 ^--N .

or - CH ₂ - R 16

R17

R ¹⁹ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, optionally substituted by hydroxy, an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety or an acyl group having 1 to 3 carbon atoms,

R ²⁰ represents a hydrogen atom, a hydroxy group, a group

a hydroxymethyl group or a group, R 19 - ^N C f 21 wherein

R ²¹ represents a hydrogen atom or a methyl group,

A represents a methylene group, an oxygen atom or a direct bond and n represents 1 or 2, and their pharmaceutically usable salts, hydrates and acid addition salts, as well as the corresponding carboxylic acids with alkali metals, alkaline earth metals, silver and guanidine, have a high antibacterial effect.

V286 / 93H

Accordingly, the compounds are useful as active substances in human and veterinary medicine, and veterinary medicine is also intended to treat fish for the treatment and prophylaxis of bacterial infections.

Preference is given to compounds of the formula I in which they are

R ^{1 is} C 1 -C 2 alkyl, optionally substituted by hydroxy, C 3 -C 5 cycloalkyl, vinyl, amino, C 1 -C 2 monoalkylamino, C 2 -C 4 dialkylamino or phenyl, optionally once or double substituted with a halogen atom,

R ² hydrogen, alkyl of 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl,

X ^{1 is a} hydrogen atom, a fluorine atom, a chlorine atom, an amino group or a methyl group,

X ² -C = CH-R ³ , -C = CR ⁵ or -CH ₂ -CH = CH ₂ ,

Pričom ⁴ where

R ³ is hydrogen, alkyl having 1 to 2 carbon atoms, methoxy or methoxymethyl,

R ⁴ represents a hydrogen atom and

R ⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, optionally substituted one to three times with a fluorine atom, an alkenyl group having 2 to 3 carbon atoms, a methoxy group or a trimethylsilyl group, and

Y group

V286 / 93H

Ί

ⁿ 5> -. ^R k 0 N- r ' X ⁿ - R ¹³ R ¹¹ R ⁸ Rló R ¹ ! 0 1 R ⁸ ~ VchC- r · ’' C »- CC-

V286 / 93H where

R ⁶ represents a hydrogen atom, a straight or branched alkyl group having 1 to 3 carbon atoms, optionally substituted by a hydroxyl group or an oxoalkyl group having 1 to 4 carbon atoms,

R ⁷ represents a hydrogen atom, a methyl group or a phenyl group,

R ⁸ represents a hydrogen atom or a methyl group,

R ⁹ represents a hydrogen atom or a methyl group,

R ¹¹ represents hydrogen, methyl or

-CH 2 -NH 2,

R ¹² represents a hydrogen atom, a methyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, a methylaminomethyl group or an ethylaminomethyl group,

R ¹³ represents a hydrogen atom, a hydroxy group, a methoxy group, a fluorine atom, a methyl group or a hydroxymethyl group,

R ¹⁵ represents a hydrogen atom or a methyl group,

R ¹⁶ represents a hydrogen atom or a methyl group,

R ¹⁷ represents a hydrogen atom or a methyl group,

R ¹⁸ represents a group

or a group

R16

R 17 - CH ₂ -

R ¹⁹ represents a hydrogen atom, a methyl group or ethyl

V286 / 93H group,

R is a group

while

R ²¹ represents a hydrogen atom or a methyl group,

A represents a methylene group, an oxygen atom or a direct bond and n represents the number 1 or 2.

Particularly preferred are the compounds of formula I in which R is

R ^{1 is} methyl, ethyl, cyclopropyl or phenyl, optionally substituted one or two times with fluorine,

R ² hydrogen, methyl or ethyl,

X ^{1 is a} hydrogen atom, a fluorine atom, a chlorine atom, an amino group or a methyl group,

X ^{2 is} -C =CH ₂ or -OC-R ⁵ wherein

R ^ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 3 carbon atoms or a methylsilyl group and

Y group

V286 / 93H

RLO R 1 _O £> ^ch H

R ¹⁷

R ⁸

V286 / 93H where

R ⁷ represents a hydrogen atom or a methyl group,

R ⁶ represents a hydrogen atom, a methyl group or an ethyl group optionally substituted by a hydroxy group,

R ⁸ represents a hydrogen atom or a methyl group,

R ⁹ represents a hydrogen atom or a methyl group,

R ¹¹ represents hydrogen or a group -CH 2 -NH 2,

R ¹² represents a hydrogen atom, a methyl group, an amino group, a methylamino group, an aminomethyl group or an ethylaminomethyl group,

R ¹³ represents a hydrogen atom, a hydroxy group or a methoxy group,

R ¹⁵ represents a hydrogen atom or a methyl group,

R ¹⁶ represents a hydrogen atom or a methyl group,

R ¹⁷ represents a hydrogen atom or a methyl group,

R ¹⁸ represents a group

R ¹⁹ represents a hydrogen atom or a methyl group,

R is a group

while

R ²¹ represents a hydrogen atom or a methyl group,

A represents a methylene group, an oxygen atom or a direct bond and n represents the number 1.

V286 / 93H

It has further been found that compounds of formula I can be obtained by reacting a compound of formula II

(H), wherein R ¹ , R ² , X ¹ and X ^{2 are} as defined above and

R represents a halogen atom, in particular fluorine or chlorine, with a compound of formula III

Y-H (H 1).

wherein Y is as defined above, optionally in the presence of acid binders.

For example, when 1cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolonecarboxylic acid and 1-methylpiperazine are used as starting compounds, the reaction may be represented by the following equation:

COOH +

8- (1-Chloro-vinyl) -quinolone-carboxylic acids can also be obtained by reacting 8-ethynyl-quinolone-carboxylic acids with hydrochloric acid at

V 2 S 6/93 H temperatures ranging from 10 to 100 ° C.

The compounds of formula II used as starting compounds are novel. They can be prepared by reacting the quinolinecarboxylic acid derivatives of the general formula IV

(IV), wherein R ¹ , R ² , X ¹ and X ^{3 are} as defined above, and

X ⁴ represents a halogen atom, in particular iodine, bromine or chlorine, with an organometallic vinyl or alkynyl compound of the general formula V

M - X ² (V), wherein X ^{2 is} as defined above and

M is SnR ' ₃ ' ZnX 'or B (OR') 2, wherein

R 'represents an alkyl group having 1 to 4 carbon atoms,

R "represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and

X 'represents a bromine or chlorine atom, in the presence of a transition metal catalyst and a protecting group, if any, present.

The organometallic vinyl and alkynyl compounds required for the coupling reaction can be synthesized by methods known in the literature or are known.

V286 / 93H

Thus, for example, vinyl trialkyltin compounds can be prepared from the corresponding vinyl iodides, vinyl bromides or vinyl chlorides by reaction with magnesium to obtain vinyl Grignard compounds and these are reacted with the trialkyltin chloride to the corresponding trialkyltin derivatives.

The organometallic alkynyl compounds can be prepared by known methods, for example, by metallizing 1-alkyne at a temperature in the range of -20 ° C to -78 ° C in an aprotic solvent such as tetrahydrofuran, with n-butyllithium, sec-butyllithium or tert. butyllithium and the obtained compound is reacted with a metal and halogen compound such as zinc chloride, magnesium bromide, copper iodide or trialkyltin chloride. It is preferred to carry out the reaction at -78 ° C. In addition to the preferred tetrahydrofuran solvent, other ethers such as diethyl ether, dipropyl ether or tert-butyl methyl ether or mixtures of such ethers with aprotic aliphatic or aromatic solvents such as n-hexane or toluene can also be used. For both vinyl and alkynyl derivatives, tin (II) chloride and trialkyltin derivatives are preferred. The term "alkyl" in trialkyltin compounds refers to an alkyl group having 1 to 6 carbon atoms, with methyl and n-butyl being preferred.

Trialkyltin compounds can also be obtained according to methods known in the literature by hydrosanylation of alkynes with trialkyltin hydrides in the presence of transition metal catalysts (J. Org. Chem. 55 (1990) 1857 1867).

The organometallic vinyl and alkynyl compounds are reacted with the 8-haloquinolone carboxylic acid derivatives of formula IV in the presence of a suitable catalyst in a manner known per se. Here, "halogen" represents iodine, bromine or chlorine, bromine and chlorine being preferred, bromine being particularly preferred.

Suitable catalysts are, for example, transition metal compounds such as cobalt, ruthenium, rhodium, iridium, nickel, palladium or platinum. Platinum, palladium and nickel compounds are preferred, and palladium is particularly preferred.

V286 / 93H

Such transition metals may be used in the form of their salts, such as cobalt (II) chloride, palladium (II) chloride or Pd (OAc) _2, or in the form of complexes with suitable ligands. The use of complexes is preferred. Phosphines such as triphenylphosphine, tri (o-tolyl) phosphine, trimethylphosphine, tributylphosphine and tri (2-furyl) phosphine may be used as ligands, with triphenylphosphine being preferred. Preferred complex catalysts include bis (triphenylphosphine) nickel (II) chloride, bis (triphenylphosphine) palladium (II) chloride, tris (triphenylphosphine) palladium (0) and tetrakis (triphenylphosphine) palladium (0).

The complex catalysts are used in a proportion of 0.1 to 20 mol%, based on the 8-haloquinolone carboxylic acid ester used, proportions in the range of 0.5 to 10 mol% being preferred, in particular in the range of 1 to 5 mol%.

The coupling reactions are carried out in suitable inert solvents such as benzene, toluene, xylene, dimethylformamide, dimethylacetamide, dimethoxyethane or mixtures of such solvents, with dimethylformamide and toluene being preferred. The solvents are dried and de-aerated in a known manner before use.

The coupling reactions are carried out at a temperature in the range of 20 to 200 ° C, preferably in the range of 50 to 180 ° C.

The duration of the reaction depends on the reactivity of the starting materials and is generally 2 to 40 hours, reaction times of 4 to 24 hours being preferred.

The reactions are carried out in a protective gas atmosphere. Suitable shielding gases are inert gases such as helium, argon or nitrogen, preferably nitrogen. The coupling reactions are generally carried out under normal pressure. However, it is of course also possible to carry out the reactions under reduced or elevated pressure.

The amines of formula III used as starting compounds are largely known. Chiral amines can be used both as racemates and as well

V286 / 93H as enantiomerically pure or diastereomerically pure compounds. Examples include:

piperazine,

1-methylpiperazine,

1-ethylpiperazine,

1- (2-hydroyxetyl) -piperazine,

3-methylpiperazine, cis-2,6-dimethylpiperazine, cis-2,3-dimethylpiperazine,

1,2-dimethyl,

1-cyclopropyl-piperazine,

2-Phenyl-piperazine

2- (4-pyridyl) piperazine,

2- (2-Thienyl) -piperazine

1,4-diazabicyclo (3.2.1) octane,

8-methyl-3,8-diazabicyclo (3.2.1) octane dihydrochloride,

3-Methyl-3,8-diazabicyclo (3.2.1) octane dihydrochloride

2.5-diazabicyclo (2.2.1) heptane dihydrochloride,

2-methyl-2,5-diazabicyclo (2.2.1) heptane-dihydrochloride,

2.5-diazabicyclo (2.2.2) octane dihydrochloride,

2-methyl-2,5-diazabicyclo (2.2.2) octane dihydrochloride,

1,4-diazabicyclo (3.1.1) heptane, morpholine,

2,6-dimethyl-morpholine, l

2-aminomethyl-morpholine,

2-tert-butoxycarbonylamino-methyl-morpholine,

2-methylaminomethyl-morpholine,

2-dimethylaminomethyl-morpholine, imidazole,

4-methyl-imidazole, pyrrole,

3-aminomethyl-2,5-dihydro-pyrrole,

V286 / 93H

3-aminomethyl-4-methyl-2,5-dihydro-pyrrole,

3- (1-aminoethyl) -2,5-dihydro-pyrrole,

3-amino-azetidine,

3-tert-butoxycarbonylamino-azetidine,

3-tert-butoxycarbonylamino-2-methyl-azetidine,

3-tert-butoxycarbonylamino-3-methyl-azetidine,

3-tert-butoxycarbonylaminomethyl-azetidine, pyrrolidine,

3-methylpyrrolidine,

3-amino-pyrrolidine,

3-t-butoxycarbonylamino-pyrrolidine,

3- (2 ₁ 2-Dimethyl-propylideneamino) -pyrrolidine

3-methylamino-pyrrolidine,

3-dimethylamino-pyrrolidine,

3-aminomethyl-pyrrolidine,

3-tert-butoxycarbonylaminomethyl-pyrrolidine,

4-chloro-3-tert-butoxycarbonylaminomethyl-pyrrolidine,

3-tert-butoxycarbonylamino-3-methylpyrrolidine,

3-tert-butoxycarbonylamino-4-methylpyrrolidine,

3-tert-butoxycarbonylamino-3-methoxy-pyrrolidine,

3-methylaminomethyl-pyrrolidine,

3-ethylaminomethyl-pyrrolidine,

4-tert-butoxycarbonylamino-2-methyl-pyrrolidine,

2-methyl-3-methylamino-pyrrolidine,

2-Methyl-4-methylamino-pyrrolidine

3- (2-hydroxyethylamino) -pyrrolidine,

3-hydroxy-pyrrolidine,

3-hydroxymethyl-pyrrolidine,

4-amino-3-hydroxy-pyrrolidine,

3-hydroxy-4-methylamino-pyrrolidine,

3-tert-butoxycarbonylamino-4-methoxy-pyrrolidine,

3-methylaminomethyl-3-hydroxy-pyrrolidine,

V286 / 93H

3-dimethylaminomethyl-3-hydroxy-pyrrolidine,

3-diethylaminomethyl-3-hydroxy-pyrrolidine,

3-tert.-butylaminomethyl-3-hydroxy-pyrrolidine,

3-methylamino-4-hydroxymethyl-pyrrolidine,

4-Methoxy-3-methylamino-pyrrolidine

3-methoxy-3-methylaminomethyl-pyrrolidine,

3-amino-4-methoxy-2-methyl-pyrrolidine,

3-tert-butoxycarbonylamino-3-methyl-pyrrolidine,

3-methyl-4-t-butoxycarbonylamino-pyrrolidine,

3- (1-imidazolyl) -pyrrolidine,

6-hydroxy-3-azabicyclo (3.3.0) octane,

G-S-amino-azabicyclo ^ .S.OJoktán,

amino-3-azabicyclo (3.3.0) octane,

1-aminomethyl-3-azabicyclo (3.3.0) octane,

1-ethylaminomethyl-3-azabicyclo (3.3.0) octane,

6-amino-3-azabicyclo (4.3.0) nonane,

3-amino-4-methylene-pyrrolidine,

7-amino-5-azaspiro (2.4) heptane

3.7- diazabicyclo (3.3.0) octane,

3-methyl-3,7-diazabicyclo (3.3.0) octane,

2.8- diazabicyclo (4.3.0) nonane,

2-Methyl-2,8-diazabicyclo (4.3.0) nonane

3-methyl-3,8-diazabicyclo (4.3.0) nonane,

2-oxa-5,8-diazabicyclo (4.3.0) nonane,

5-Methyl-2-oxa-5,8-diazabicyclo (4.3.0) nonane

2,7-diazabicyclo (3.3.0) octane,

2-Methyl-2,7-diazabicyclo (3.3.0) octane

3-Methyl-2,7-diazabicyclo (3.3.0) octane

4-Methyl-2,7-diazabicyclo (3.3.0) octane

5-methyl-2,7-diazabicyclo (3.3.0) octane-7-carboxylic acid (tert-butyl ester),

7-Methyl-2,7-diazabicyclo (3.3.0) octane

8-Methyl-2,7-diazabicyclo (3.3.0) octane

V286 / 93H

7.8-Methyl-2,7-diazabicyclo (3.3.0) octane

2,3-dimethyl-2,7-diazabicyclo (3.3.0) octane

2,8-Dimethyl-2,7-diazabicyclo (3.3.0) octane

1.4- diazabicyclo (6.2.0.0 ^2,6 ) decane,

1,4-diazabicyclo (6.3.0.0. ⁰² ' ⁶ ) undecane,

2.7-diazaspiro (4.4) nonane, 2-methyl-2,7-diazaspiro (4.4) nonane,

4-amino-1,3,3a, 4,7,7a-hexahydroisoindole,

4-methylamino-1,3,3a _{l l} 4,7,7a hexahydroisoindole

5-methyl-4-methylamino-1,3,3a, 4,7,7a-hexahydroisoindole,

6-methyl-4-methylamino-1,3,3a, 4,7,7a-hexahydroisoindole,

7-methyl-4-methylamino-1,3,3a, 4,7,7a-hexahydroisoindole, 7a-methyl-4-methylamino-3 1.3 _l, 4,7,7a-hexahydroisoindole,

6,7-dimethyl-4-methylamino-1,3,3a, 4,7,7a-hexahydroisoindole,

4-dimethylamino-1,3,3a, 4,7,7a-hexahydroisoindole,

4-ethylamino-1,3,3a, 4,7,7a-hexahydroisoindole,

4-aminomethyl-1,3,3a, 4,7,7a-hexahydroisoindole,

4-methylaminomethyl-1,3,3a, 4,7,7a-hexahydroisoindole,

4-hydroxy-1,3,3a, 4,7,7a-hexahydroisoindole,

2.3.4.5.6.7- hexahydro-1H-pyrrolo (3.4) pyridine,

5-methyl-2,3,4,5,6,7-hexahydro-1 H -pyrrolo (3,4-c) pyridine, 5-ethyl-2,3,4,5,6,7-hexahydro-1 H -pyrrole ( 3,4-c) pyridine; 5- (tert-butoxycarbonyl) -2,3,4,5,6,7-hexahydro-1H-pyrrolo (3,4-c) pyridine.

The substituted 1,3,3a, 4,7,7a-hexahydroindoles are predominantly new. They can be obtained, for example, by the Diels-Adler reaction of the dienes of formula 1

R ²²

R ⁹ wherein R ^{9 is} as defined above and

V286 / 93H

R ²² is either identical to R ²⁰ or is a functional group which can be converted to R ²⁰ with dienophils of formula 2

in which it means

R ( ^{23) is a} hydrogen atom or a protecting group such as trimethylsilyl, benzyl, alkylphenylmethyl having 1 to 4 carbon atoms in the alkyl moiety, methoxybenzyl or benzhydryl, followed by reduction of the carbonyl groups and optional cleavage of the protecting group.

All inert organic solvents are suitable for the Diels-Adler reaction. These include, in particular, ethers such as diisopropyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran and anisole, hydrocarbons such as hexane, methylcyclohexane, toluene, xylene and mesitylene, and halogenated hydrocarbons such as chloroform, 1,2- dichloroethane and chlorobenzene. However, the Diels-Adler reaction can also be carried out without solvent.

The reaction temperatures can be varied within a wide range. In general, it is operated in the range of about -20 ° C to 200 ° C, preferably in the range of -20 ° C to 150 ° C. The Diels-Adler reaction is usually carried out at normal pressure. However, pressures of up to 1.5 GPa may be used to accelerate the reaction.

Reduction of carbonyl groups can be achieved by complex hydrides. As complex hydrides, for example

V286 / 93H lithium aluminum hydride, lithium borohydrides, lithium triethylborohydride, sodium bis (2-methoxyethoxy) aluminum hydride or sodium borohydride in the presence of Lewis acids, for example chlorotrimethylsilane, boron trifluoride etherate or aluminum chloride.

Suitable diluents are ethers, such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, and hydrocarbons, such as hexane, methylcyclohexane and toluene, or mixtures thereof.

The reaction temperatures can be -40 to 180 ° C, preferably 0 to 140 ° C. The reduction is generally carried out under normal pressure, but can also be carried out under reduced pressure or under positive pressure.

The use of pressures in the range of 100 to 1000 kPa is recommended in order to achieve higher reaction temperatures for easily boiling solvents.

The complex hydrides are used at least in an amount corresponding to the stoichiometry of the reduction. In general, however, an excess is used, preferably in the range of 30 to 300%.

The cleavage of any protecting groups present is carried out by known methods from protecting group chemistry (see, for example, TW Greene &quot; Protective Groups in Organic Synthesis ¹¹ , John Wiley &amp; Sons, New York 1981).

The starting materials of formulas 1 and 2 are known or can be prepared by known methods of organic chemistry (see, for example, J. Am. Chem. Soc. 100, 5179 (1978), J. Org. Chem. 43, 2164 (1978), DE). 39 27 115 and J. Org. Chem., 40, 24 (1975).

When, for example, 1- (tert-butyloxycarbonylamino) -1,3-butadiene and maleimide are used as starting materials and lithium aluminum hydride is used as the reducing agent, the reaction may be illustrated by the following reaction scheme:

V286 / 93H

C · C · Ο - C (CH ₃ ) ₃ ii

Ο

ΗΝ - C - Ο - C (CH ₃ ) ₃

II

Ο

nhch ₃

In a particular embodiment of the production process, all steps using a suitable solvent, for example tetrahydrofuran, can be carried out without isolation of the intermediates. When, for example, 1 (tert-butyloxycarbonylamino) -1,3-pentadiene and N-trimethylsilyl-maleimide are used as the starting material, the reaction may be illustrated by the following reaction scheme:

THF ch ₃ *

HN · C - OC (CH ₃ ) ₃ θ ii

ABOUT

2. LiA1H ₄

3. H ₂ O

HNCH ₃

By means of NMR spectroscopy, it can be shown in this case that all the substituents on the six-membered ring are cis to one another.

The reaction of a compound of the formula II with a compound of the formula III, in which the compounds of the formula III can also be used in the form of their salts, such as hydrochlorides, is preferably carried out

V286 / 93H in a diluent such as dimethylsulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water, alcohols such as methanol, ethyl alcohol, n-propyl alcohol, isopropanol, pyridine. Mixtures of these diluents may also be used.

All conventional inorganic and organic acid binding agents can be used as acid binders. These preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particularly suitable are, in particular, triethylamine, 1,4-diazabicyclo (2.2.2) octane (DABCO), 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU) or excess amine of formula III.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out at a temperature in the range of about 20 to 200 ° C, preferably 80 to 180 ° C.

The reaction can be carried out at normal pressure but also at elevated pressure. In general, the process is carried out at a pressure of from 1 to 100 bar, preferably from 1 to 10 bar.

In carrying out the process according to the invention, 1 to 15 mol, preferably 1 to 6 mol, of the compound of the formula III is used per mole of the compound of the formula II.

Free amino groups may be protected during the reaction by suitable amino acid protecting groups, for example tert-butoxycarbonyl, and upon completion of the reaction, the amino group is liberated again, for example by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, Methoden der Organischen Chemie) , Band E4, p. 144 (1983); JFW McOmie, Protective Groups in Organic Chemistry (1973), p. 43).

The esters of the present invention are obtained by reacting the corresponding alkali metal salt of a carboxylic acid, optionally on a nitrogen

A V286 / 93H atom protected with a protecting group such as a tert-butoxycarbonyl radical, with a suitable haloalkyl derivative in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide or tetramethylurea at a temperature in the range of about 0 to 100 ° C Deň: 32 ° C.

The acid addition salts of the compounds of the present invention are prepared by conventional methods, for example by dissolving betaine in a sufficient amount of aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethyl alcohol, acetone, acetonitrile and the like. Equivalent amounts of betaine and acid in water or an alcohol such as glycol monoethyl ether may also be heated and then evaporated to dryness or the precipitated salt aspirated. Pharmaceutically used salts are, for example, salts with hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

The alkali metal or alkaline earth metal salts of carboxylic acids are obtained, for example, by dissolving betaine in excess alkali metal or alkaline earth metal hydroxide, filtering the undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable are the sodium, potassium and calcium salts. Reaction of the alkali salt or alkaline earth salt with a suitable silver salt such as silver nitrate affords the corresponding silver salts.

In the case of chiral compounds, these can be prepared and used as diastereomeric mixtures as well as diastereomeric or enantiomerically pure compounds.

In addition to the active ingredients given in the examples, the active ingredients listed in the following table can also be prepared.

V286 / 93H

table

R ¹ R ² X ¹ X ² [> - H H HOC- [> ~ H H HOC- p- H H HOC- D> - H H HOC- H H HOC- D> - H H HOC- about- H H HOC-

CH,

HN N -) - '

CH ₃

) - 'c ₆ h ₅

V286 / 93H

Table (continued)

R ¹ R ² X ¹ X ²

O - HH HOC> - HH HC = CH ₂ n-ch ₂ nC ⁿ ch ₃ -nh> - H HHOC0-H HHOCH HHOCOh ₂ n-ch ₂

HOCH H HOCH H HOCHOC-

V286 / 93H

Table (continued)

R ¹ R ² X ¹ X ²

Y

C ^ H H HOC- [> - H H HOC- 0— H H HOC- > - c ₂ h ₅ H HOC- >> H F HOC- D> - H nh ₂ HOC- c ₂ h ₅ h H OCH F- O ~ h H OCH F F F H OCH F "Q ^ h H -oc-ch ₃ F

h ₂ nhQj

Hl / jN

V286 / 93H

Table (continued)

R ¹ R ² X ¹ X ²

Y

O— · HH

D> - HH - HH> “HH

HH

F-OCF-feCF Eye color _{3-O-OC 3} CsCCH C-

[> - HH

O- HH

O— HH

HH

CF3 OCCF3-OC-

CH ₃ O-CH ₂ -C = C- ch ₃ -nn -

V286 / 93H

Table (continued)

Y

R ¹ R ² X ¹ X ² > - H H _CH2 = CH ^F [> - H H ch ₂ = ch- ^c F H H CH ₂ = CH- about- H H CH ₃ O-CH = CH-CH H H ch ₃ o-ch = ch- H H ch ₃ o-ch ₂ -ch = ch- > - H H ch ₃ o-ch ₂ -ch = ch- > - H H ch ₂ = ch-ch ₂ -. l> - H H ch ₂ = ch-ch ₂ ^-h

[N N -) - '

CH ₃ h ₃

2 ^N

NH

: ₂ n-ch ₃ o

V286 / 93H

The compounds of the present invention are highly antibiotic and exhibit a particularly broad spectrum of antibacterial activity against Gram-positive and Gram-negative germs, in particular against enterobacteria, in particular those resistant to various antibiotics, such as penicillins, cephalosporins, aminoglycosides, sulfognamycides, .

These valuable properties make it possible to use them as chemotherapeutic active substances in medicine, as well as substances for the preservation of inorganic and organic materials, in particular organic materials of all kinds, for example polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The compounds of the present invention are active against a very wide range of microorganisms. They can be used to kill gram-negative and gram-positive bacteria and bacterial microorganisms, as well as to suppress or improve and / or treat diseases caused by these agents.

The compounds of the present invention exhibit an enhanced effect on quiescent bacteria, i. j. bacteria that show no observable growth, these compounds act far below the concentrations of substances known to date. This applies not only to the amount used but also to the killing rate. Such results could be observed in Gram-positive and Gram-negative bacteria, in particular Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

Also, the bacteria according to the invention exhibit a surprising increase in activity against bacteria which are evaluated as being less active than comparable substances, in particular against resistant strains of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.

Due to the high activity of the compounds of the present invention against bacteria and bacterial microorganisms, they are particularly suitable for

V286 / 93H for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine caused by said pathogens.

Furthermore, the compounds of the present invention are useful for the control of protozoonoses and helminthoses.

The compounds of the present invention can be used in various pharmaceutical compositions. Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, lace, solutions, suspensions and emulsions, pastes, ointments, jellies, creams, lotions, powders and sprays.

Minimum inhibitory concentrations (MHK) were determined using an in-line dilution procedure on Iso-Sensitest agar (Oxoid). A series of agar plates are prepared for each test substance, each containing twice the dilution of the active substance. The agar plates are then seeded with a Multipoint Inoculator (Denley). Overnight cultured pathogenic cultures are used for inoculation and previously diluted so that each inoculation point contains about 10 ⁴ colony-forming particles. The inoculated agar plates are incubated at 37 ° C and germ growth is read after about 20 hours. The MHK value (pg / ml) indicates the lowest active compound concentration at which no growth is observed by the naked eye.

The following table shows the minimum inhibitory concentration (MKH) values of some of the compounds of the present invention compared to Ciprofloxacin.

V286 / 93H

Table: MHK values

Ciprofloxacin 0.02 CM 16 | 0.25 0.25 0.5 0.5 0.25 CN 0.03 [0,5 0.06 0.13 0.13 0.25 0.25 oo • H 0.03 - 0.13 0.13 vn CN ABOUT 0.25 0.03 m 0.02 OO o) en 0.02 CM O ABOUT - - 0.03 0.13 I 0,25 0.25 90 * 0 90 * 0 0.13 0.13 0.13 1 Ice 9 0.25 04 0.13 0.13 0.5 - 0.5 M. Ή M OO Cu 0.13 - - 90 * 0 90 * 0 0.25 0.25 0.25 Ό 0.02 0.25 - 90 * 0 90 * 0 0.13 0.13 0.13 v> 0.02 0.5 - 0.03 0.13 0.13 0.13 0.03 c5 0.02 0.13 0.13 CM * about 0.25 Test strain E. coli Ncumann Micrococcus lulcus 9341 Staphylococcus aurctis ICB 25701 1756 133 Entcrococcus laccalis 27101 9790 Acinclobactcr calcoaccticus 14068

DETAILED DESCRIPTION OF THE INVENTION

Production of intermediates

Example Z1

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester

3.72 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 4.4 g of tributylvinyl tin and 0.46 g of tetrakis (triphenylphosphine) palladium are heated in 40 ml of absolute toluene for 2 to 3 hours at reflux under nitrogen. Thereafter, the reaction mixture is filtered while hot, the product precipitated upon cooling to room temperature is filtered off with suction, washed with toluene and dried. It is obtained as follows

2.55 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester (79% of theory).

Melting point: 178-179 ° C.

Example Z2

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid

0.9 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0.2 ml of ethyl acetate. ml of concentrated sulfuric acid for 4 hours under reflux, then the reaction mixture is then treated with 10 ml of water at reflux. The solid is filtered off with suction at room temperature, washed with water and dried. 0.58 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid (71% of theory) is obtained.

M.p .: 182-184 ° C.

V286 / 93H

Example Z3

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (t ^'I' trimethylsilyl-ethynyl) -4-oxo-3-quinolinecarboxylic acid

22.2 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 30.2 g of tributylstannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis (triphenylphosphine) palladium (O) was heated to reflux for 3 hours in 300 mL of absolute toluene under nitrogen. After cooling the reaction mixture to about -18 ° C, the solid is filtered off with suction, washed with toluene and dried. 18.8 g of ethyl 1-cyclopropyl-

6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid (80% of theory).

Melting point: 171-172 ° C.

Example Z4

1-Cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

18.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8 (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester and 9.7 g of potassium fluoride are stirred in a mixture of 300 ml of dimethylformamide, 200 ml of chloroform and 15 ml of water for 3 hours at room temperature. The reaction mixture is then filtered, the filtrate is mixed with 120 ml of water and acidified with dilute aqueous hydrochloric acid. After shaking with chloroform, the organic phase is dried over sodium sulphate and concentrated. The residue is recrystallized from methanol to give 9 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (59% of theory).

Melting point: 186-187 ° C.

V286 / 93H

Example Z5

1-Cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

10.3 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are heated in a mixture of 100 ml of glacial acetic acid, 8 ml of water and 3 ml of concentrated sulfuric acid to reflux for 4 hours. After cooling to room temperature, the solid is filtered off with suction, washed with water and dried. 5.7 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (62% of theory) are obtained.

Mp .: 233 ° C.

Example Z6

1-Cyclopropyl-6,7-difluoro-8- (1-hexinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

1.9 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 3.5 g of 1-tributylstannyl-1-hexine and 0.29 g of tetrakis ( triphenylphosphine) palladium (0) was heated under reflux in 20 ml of absolute toluene for 8 hours under a nitrogen atmosphere. The reaction mixture is then concentrated, the residue is stirred with 30 ml of hexane and the solid thus obtained is recrystallized from cyclohexane. 0.7 g of 1-cyclopropyl-6,7-difluoro-8- (1-hexinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (36% of theory) is obtained.

^{@ 1} H-NMR (200 MHz, CDCl3): .delta. = 0.95 (t, 3H), 1.1-1.7 (m, 11H), 2.50 (t, 2H),

4.1-4.3 (m, 1H), 4.38 (q, 2H), 8.14 (dd, 1H), 8.56 (s, 1H) ppm.

Example Z7

1-Cyclopropyl-6,7-difluoro-8- (1-hexinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

V286 / 93H

0.7 g of 1-cyclopropyl-6,7-difluoro-8- (1-hexynyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was heated in a mixture of 6 ml of glacial acetic acid, 0.5 ml of water and 0.1 ml of concentrated sulfuric acid for 3 hours at reflux. After mixing the reaction time with 100 ml of water, the solid is suction filtered and dried. 0.5 g of 1-cyclopropyl-6,7-difluoro-8- (hexinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (85% of theory) is obtained.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.96 (t, 3H), 1.1-1.7 (m, 8H), 4.3-4.5 (m, 1H), δ 20 (dd, 1 H), 8.85 (s, 1 H) ppm.

Example Z8

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3,3-dimethylbutin-1-yl) 4-oxo-3-quinolinecarboxylic acid ethyl ester

Following the procedure of Example Z6, 0.87 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3,3-dimethylbutin-1-yl) ethyl ester was obtained from 1-tributylstannyl-3,3-dimethyl-1-butyne. ) -4-oxo-3-quinolinecarboxylic acid (46% of theory).

Melting point: 170-172 ° C.

Example Z9

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3,3-dimethylbutin-1-yl) -4-oxo-3-quinolinecarboxylic acid

The saponification of 0.75 g of the ester of Example Z8 according to the procedure described in Example Z7 gave 0.56 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3,3-dimethylbutin-1-yl) -4 -oxo-3-quinolinecarboxylic acid (81% of theory).

Melting point: 199-201 ° C.

Example Z10

1- (2,4-Difluorophenyl) -6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester

V286 / 93H

6.7 g of 8-bromo-1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (Example Z20), 10.8 g of tributylstannyltrimethylsilyl acetylene and 0.87 g of tetrakis (triphenylphosphine) palladium (0) was heated to reflux in 50 ml of absolute toluene for 24 hours under a nitrogen atmosphere. Upon cooling to -18 ° C, the product crystallizes from the reaction mixture. 4.8 g of 1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester (69% of theory) are obtained.

M.p .: 173-174 ° C.

Example Z11

1- (2,4-Difluorophenyl) -8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

A solution of 4.6 g of 1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester in 20 ml of chloroform is added dropwise at room temperature to solution of 2 g of potassium fluoride in a solvent mixture of 3 ml of water, 25 ml of chloroform and 50 ml of dimethylformamide. The reaction mixture is stirred for one hour at 20 [deg.] C., then treated with additional chloroform, shaken several times with water, then the organic phase is dried and concentrated. The residue obtained is crystallized from methanol. 3.4 g of 1- (2,4-difluorophenyl) -8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (87% of theory) are obtained.

Melting point: 189 ° C.

Example Z12

1- (2,4-Difluorophenyl) -8-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

1.17 g of 1- (2,4-difluorophenyl) -8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was heated in a mixture of 9 ml of glacial acid

V286 / 93H acetic acid, 0.75 ml water and 0.2 ml concentrated sulfuric acid for one hour at reflux. The solid which crystallizes upon cooling to room temperature is filtered off with suction and dried. 0.93 g of 1- (2,4-difluorophenyl) -8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (90% of theory) is obtained.

Melting point: 220 ° C (dec.).

Example Z13

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8- (1-propynyl) -3-quinolinecarboxylic acid ethyl ester

7.5 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 9.1 g of 1-tributylstannyl-1-propine and 1.16 g of tetrakis ( The triphenylphosphine) palladium (0) was heated to reflux in 80 ml of absolute toluene for 8 hours under a nitrogen atmosphere. The solid which forms at -18 ° C is filtered off with suction and dried. 2.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8- (propyn-1-yl) -3-quinolinecarboxylic acid ethyl ester (31% of theory) is obtained.

¹ H-NMR (200 MHz, _CDCl3): delta = 1.1-1.35 (m, 4H), 1.40 (t, 3H), 2.16 (d, 3H), 4.1 -4 3 (m, 1H), 4.35 (q, 2H), 3.15 (dd, 1H), 8.56 (s, 1H) ppm.

Example Z14

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8- (propyn-1-yl) -3-quinolinecarboxylic acid

1.4 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8 (propyn-1-yl) -3-quinolinecarboxylic acid ethyl ester is boiled in a mixture of 20 ml of glacial acetic acid, 5 ml of water and 0.5 ml of concentrated sulfuric acid for one hour at reflux. After mixing with about 10 ml of water, the precipitated solid is isolated and dried. 1.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8- (propyn-1-yl) -3-quinolinecarboxylic acid are obtained as described above.

V286 / 93H (82% of theory).

¹ H-NMR (200 MHz, _CDCl3): delta = 1.4 (m, 4 H), 2.26 (d, 3H), 4.4-4.6 (m, 1H), 8.16 (dd 1 H, 8.81 (s, 1 H) ppm.

Mp .: 212-213 ° C.

Example Z15

1-Ethyl-6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester

5.4 g of 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g tetrakis (triphenylphosphine) palladium (0) was heated under reflux in 50 ml of absolute toluene under nitrogen for 24 hours. The reaction mixture is then concentrated, the residue is taken up in 100 ml of hexane and the solid obtained is filtered off with suction and dried. 4.53 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester (80% of theory) are obtained.

Melting point: 151-152 ° C.

Example Z16

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester

1.64 g of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 3 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis (triphenylphosphine) palladium ( O) was refluxed in 20 ml of absolute toluene for 42 hours under a nitrogen atmosphere. The reaction mixture was then cooled to about -18 ° C and filtered. After drying the filter residue, 0.74 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (trimethylsilylethynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester (38% of theory) is obtained.

V286 / 93H

Example Z17

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8- (methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester

1.86 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 2.8 g of 1-tributylstannyl-3-methyl-but-3-ene- 1-in and 0.29 g of tetrakis (triphenylphosphine) palladium (0) are heated to reflux in 20 ml of absolute toluene for 6 hours under a nitrogen atmosphere. The reaction mixture is then filtered hot, concentrated, and the residue is triturated with hexane. After suctioning and drying, 1.43 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3-methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained ( 80% of theory).

Melting point: 169-171 ° C.

Example Z18

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3-methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid

0.715 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3-methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester was heated in a mixture of 10 ml of ice of acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulfuric acid for 1.5 hours at reflux. The reaction mixture is then poured into 100 ml of water, the precipitated solid is filtered off with suction, washed with water and dried. 0.53 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8 (3-methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid (80 g) is obtained. % of theory).

Mp .: 204-206 ° C.

Example Z19

2- (3-Bromo-2,4,5-trifluorobenzoyl) -3- (2,4-difluorophenylamino) acrylic acid ethyl ester

V286 / 93H g (0,1 mol) of ethyl 2- (3-bromo-2,4,5-trifluorobenzoyl) -3-ethoxyacrylic acid are mixed with 14,5 g (0, 11 mol) 2,4-difluoroaniline. The reaction mixture is allowed to stand overnight at 10 ° C, the precipitate is filtered off with suction, washed with cold ethyl alcohol and dried in vacuo.

Yield: 38 g (81% of theory)

Melting point: 102 - 103 ° C (decomposition) (from isopropanol).

Example Z20

8-Bromo-1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester g (82 mmol) of 2- (3-bromo-2,4) -ethyl ester Of 5-trifluorobenzoyl) -3 (2,4-difluorophenylamino) -acrylic acid in 200 ml of dimethylformamide was heated at reflux for 2 hours with 7.6 g of sodium fluoride. The reaction mixture is then poured into ice water, the precipitate formed is filtered off with suction, washed well with water and dried in a hot-air oven at 80 ° C.

Yield: 34.7 g (95% of theory).

Melting point: 208 - 210 ° C (decomposition) (from glycol monoethyl ether).

Acidic saponification of this ester gives 8-bromo-1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 210-221 ° C (dec.) .

Example Z21

2- (3-Bromo-2,4,5-trifluoro-benzoyl) -3-ethylamino-acrylic acid ethyl ester g (0.05 mmol) of 2- (3-bromo-2,4,5-trifluoro) ethyl ester -benzoyl) -3-ethoxyacrylic acid is mixed with 5.5 g of a 50% aqueous solution of ethylamine in 40 ml of ethanol under ice-cooling. The reaction mixture is allowed to stand overnight at 10 ° C, then the suspension is mixed with 200 ml of water, and the precipitate formed is filtered off with suction,

The V286 / 93H was washed with water and dried under vacuum at 60 ° C.

Yield: 17.3 g (91% of theory).

Melting point: 101 - 102 ° C (decomposition) (from isopropanol).

Example Z22

8-Bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester g (42 mmol) of 2- (3-bromo-2,4,5-trifluoro) ethyl ester -benzoyl) -3-ethylaminoacrylic acid was reacted analogously to Example Z20.

Yield: 14.6 g (96% of theory).

Melting point: 172 - 173 ° C (decomposition) (from glycol monomethyl ether).

Acidic saponification yields 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid from this ester.

Melting point: 215 - 217 ° C (decomposition).

Example Z23

4-methylamino-1,3,3a, 4,7,7a-hexahydroisoindole

Method I:

14.4 g (60 mmol) of 70% 1- (tert-butoxycarbonylamino) -1,3-butadiene (J. Org. Chem. 43, 2164 (1973)) are added dropwise as a solution in 30 ml of absolute tetrahydrofuran to the present 10 1 g (60 mmol) of N-dimethylsilyl maleimide (J. Org. Chem. 40, 24 (1975)) in 30 ml of absolute tetrahydrofuran. After the exothermic reaction subsided, the reaction mixture was refluxed for an additional hour.

The cooled reaction mixture was then added dropwise under a nitrogen atmosphere

V286 / 93H to the present 7.6 g (0.2 mol) of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran, after which the reaction mixture was refluxed for 14 hours. To the cooled reaction mixture was then gradually added dropwise 7.6 g of water in 23 ml of tetrahydrofuran, 7.6 g of 10% sodium hydroxide and

22.8 g of water. The salts were filtered off and the filtrate was concentrated in vacuo. The residue (10.3 g) was distilled at 37 ° C / 0.8 mbar.

The distillate is then taken up in 80 ml of absolute pentane, filtered and the product crystallized by cooling to -70 ° C.

Yield: 3.3 g.

Melting point: 72-82 ° C.

Treatment with an equimolar amount of 2N hydrochloric acid affords 4-methylamino-1,3,3a, 4,7,7a-hexahydro-isoindole dihydrochloride.

Melting point: 265-268 ° C (from methanol).

Method II:

4- (t-butyloxycarbonylamino) -1,3-dioxo-1,3,3a, 4,7,7a-hexahydro-isoindole

48.0 g (0.5 mol) of maleimide are dissolved in 200 ml of absolute tetrahydrofuran and 120 g (0.5 mol) of about 70% of 1 (tert-butyloxycarbonylamino) -1,3-butadiene are added dropwise as a solution. in 500 mL of absolute tetrahydrofuran while maintaining the temperature in the range of 20-30 ° C. The reaction mixture was stirred at room temperature overnight, concentrated and the residue was crystallized from ethyl acetate. 57 g of product, m.p. 177 DEG-182 DEG C., are obtained. An additional 13 g of product is obtained from the mother liquor, m.p. 158-160 ° C.

a) 4-methylamino-1,3,3a, 4,7,7a-hexahydro-isoindole

27.1 g (0.71 mol) of lithium aluminum hydride are introduced into 300 ml of absolute tetrahydrofuran under a harsh atmosphere and a solution of 57 g is added dropwise.

V286 / 93H (0.21 mol) 4- (tert-butyloxycarbonylamino) -1,3-dioxo-1,3,3a, 4,7,7a-hexahydroisoindole in 570 ml absolute tetrahydrofuran. The reaction mixture was then refluxed overnight. After cooling, 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10% sodium hydroxide and 81.3 g of water are gradually added dropwise. The precipitated salts are filtered off with suction, washed with tetrahydrofuran and the filtrate is concentrated in vacuo. The residue was distilled under high vacuum.

Yield: 19.1 g.

Example Z24

4-amino-1,3,3a, 4,7,7a-hexahydro-isoindole

13.3 g (50 mmol) of 4-tert-butyloxycarbonylamino-1,3-dioxo-1,3,3a, 4,7,7ahexahydro-isoindole (from Example Z23, Method II) are stirred overnight at room temperature with 166 ml of trifluoroacetic acid. Then, trifluoroacetic acid is distilled off under reduced pressure, and the residue is freed from the acid esters at 50 ° C under high vacuum. The residue is then taken up in absolute tetrahydrofuran and concentrated in vacuo, then taken up in 100 ml of absolute tetrahydrofuran and added dropwise to a solution of 11.3 g (0.3 mol) of lithium aluminum hydride in 300 ml of absolute tetrahydrofuran under nitrogen. The reaction mixture was then refluxed for 16 hours. After cooling, 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10% sodium hydroxide and 34 ml of water are gradually added dropwise, and the precipitate formed is filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated and the residue is distilled.

Yield: 2.2 g, content: 92% (determined by chromatography).

Boiling point: 70 ° C / 0.2 mbar.

Example Z25

7-methyl-4-methylamino-1,3,3a, 4,7,7a-hexahydroisoindole

Analogously to Example Z23, Method I is left

V286 / 93H react 21,9 g (0,12 mol) 1-tert-butyloxycarbonylamino) -1,3-pentadiene with

20.3 g (0.12 mol) of N-trimethylsilyl-maleimide and then reduced with

15.2 g (0.4 mol) of lithium aluminum hydride. The crude product is crystallized from tetrahydrofuran.

Yield: 6.2 g. j

M.p .: 106-108 ° C.

Example Z26

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3-methoxy-propyn-1-yl) -4-oxo-3-quinolinecarboxylic acid

A. 1.86 g (5 mmol) of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are mixed with 2.5 g of absolute toluene in 20 ml of absolute toluene. 7 mmol) of 1-tributyl-stannyl-3-methoxy-propyne and 0.29 g (corresponding to 5% by mole) of tetrakis (triphenylphosphine) palladium (0) and the reaction mixture was refluxed for 4 hours under nitrogen. The reaction mixture is concentrated, the residue is triturated with hexane, the solid is filtered off with suction and purified by chromatography over a small amount of silica gel.

Yield: 0.74 g (41% of theory) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3-methoxy-propin-1-yl) -4-oxo-3-quinolinecarboxylic acid ethyl ester .

M.p .: 144-146 ° C.

!

B. 0.36 g (1 mmol) of the product of Step A was heated under reflux in a mixture of 3 ml of glacial acetic acid, 0.2 ml of water and 0.05 ml of concentrated sulfuric acid. This mixture is then poured into water, the precipitate formed is filtered off and crystallized from ethanol.

Yield: 153 mg (46% of theory) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- (3-methoxy-propin-1-yl) -4-oxo-3-quinolinecarboxylic acid.

V286 / 93H

Melting point: 170-172 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.24 m (2H), 1.4 m (2H), 3.45 s (OCH ₃ ), 4.35 m (1H), 4.41 s (O-CH ₂ -), 8.27 t (1H), 8.87 ppm s (1H).

Production of active substances

Example 1

F, ABOUT Jl U u c λ ch ₃ III AA CH

A) 2.32 g (8 mmol) of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide with 0 92 g (8 mmol) of 1,4-diazabicyclo (2.2.2) octane and 1.2 g (12 mmol) of N-methylpiperazine were refluxed for one hour. The resulting suspension is concentrated, the residue is triturated with acetonitrile and the undissolved crystallizate is filtered off with suction and concentrated.

Yield: 1.83 g (62% of theory) of 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid.

Melting point: 228-230 ° C (decomposition).

¹ H-NMR (d ⁶ -DMF): δ = 4.95 ppm s (-C = -H).

B) Analogously 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid is obtained with 2-methylpiperazine.

¹ H-NMR (d ⁶ -DMSO): δ = 5.03 ppm s (-C = CH),

Mass spectrum: m / e 369 (M ⁺ ), 325 (M ⁺ -CO ₂ ), 300, 293, 269, 243, 44 (CO ₂ ).

V286 / 93H

Analogously to Example 1, it is obtained with the products of Examples Z14, 7J and

Z9:

F. 0 COOH T n <N I I I l | N -NC ch ₃ C III c I R λ

Example 2 (R = CH ₃ )

1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo- (propyn-1-yl) -3-quinolinecarboxylic acid

Melting point: 246-249 ° C (dec.).

Example 3 (R = CH ₂ CH ₂ CH ₂ CH ₃ )

1-Cyclopropyl-6-fluoro-8- (hexin-1-yl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

M.p .: 206-208 ° C (dec.).

Example 4 (R = C (CH ₃ ) ₃ )

1-Cyclopropyl-8- (3,3-dimethylbutin-1-yl) -6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

Melting point: 234-237 ° C (decomposition).

V286 / 93H

Example 5

COOH

Analogously to Example 1, cis-2,8-diazabicyclo (4.3.0) nonane is reacted to 1-cyclopropyl-7- (cis-2,8-diazabicyclo (4.3.0) non-8-yl) -8-ethynyl acid. 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 225-227 ° C (decomposition).

¹ H-NMR ^(d6-DMF): delta = 4.9 s (-C-CH).

Example 6

3.6 g (12 mmol) of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 120 ml of acetonitrile and 60 ml of dimethylformamide with 1.56 g. (14 mmol) of 1,4-diazabicyclo (2.2.2) -octane and 2.75 g (18 mmol) of 3- (2,2-dimethylpropylideneamino) pyrrolidine for one hour at reflux. The solution is then concentrated, the residue is stirred with about 100 ml of water (pH 7), the precipitate is filtered off with suction, washed with water and then suspended in 50 ml of water for complete cleavage of the protecting group and treated for one hour in an ultrasonic bath. The precipitate is then filtered off with suction, washed with water and dried at 80 DEG C. in vacuo.

Yield: 3.8 g (82% of theory) of 7- (3-amino-1-pyrrolidinyl) -1H2O / 93H cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3 acid hydrate quinoline carboxylic

Melting point: 193-196 ° C.

Example 7

COOH

A: R = CO-OC _{(CH3) 3}

B: R = H x CF ₃ COOH

A) Analogously to the example, 3-tert-butoxycarbonylamino-3-methyl-pyridine is reacted to give 7- (3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-8-ethynyl-6- fluoro-1,4 dihydro-4-oxo-3-quinolinecarboxylic acid.

Mp .: 244-246 ° C (dec.).

¹ H-NMR (d ⁶ -DMSO): delta = 4.92 ppm s (-C-CH).

B) 500 mg of the product of Step A are dissolved in 5 ml of trifluoroacetic acid under ice-cooling, the solution is concentrated in vacuo, the residue is crystallized by stirring with about 1 ml of ethyl alcohol three times, the salt is filtered off with suction, washed with ethanol and dried.

Yield: 270 mg (52% of theory) of 7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid trifluoroacetate

Melting point: 242-244 ° C (decomposition).

Example 8

COOH

V286 / 93H

Analogously to Example 1, 2-oxa-5,8-diazabicyclo (4.3.0) nonane is reacted to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (2-oxa-5,8-) - diaza-bicyclo (4.3.0) non-8-yl) -4-oxo-3-quinolinecarboxylic acid.

Melting point: 290 ° C (decomposition, starting from about 170 ° C).

¹ H-NMR (d ⁶ -DMSO): δ = 5.0 ppm s (-O = CH).

Example 9

COOH

I

CH ₃

Analogously to Example 1, 2-oxa-5,8-diazabicyclo (4.3.0) nonane with the product of Example Z14 was reacted to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (2-oxa-5). , 8-diazabicyclo (4.3.0) non-8-yl) -4-oxo-8- (propyn-1-yl) -3chinolín-carboxylic acid.

Melting point; Mp 241-242 ° C (dec.).

Example 10

A: R = (CH ₃ ) ₃ CO-COB: R = H

A) 303 mg (1 mmol) of the product of Example Z14 are mixed with 240 mg of 3-tert-butoxycarbonylamino-3-methylpyrrolidine and 134 mg (1.2 mmol) of 1,4-diazabicyclo in a mixture of 6 ml of acetonitrile and ml of dimethylformamide. (2.2.2) octane and this mixture is added

The V286 / 93H was heated at reflux for 2 hours. It is then concentrated in vacuo, stirred with 30 ml of water and dried at 80 DEG C. in vacuo.

Yield: 420 mg (87% of theory) of 7- (3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8- (propyne- 1-yl) -3-quinolinecarboxylic acid.

M.p .: 195-196 ° C (dec.).

¹ H-NMR (d ⁶ -DMSO): δ = 1.42 s (CH ₃ on pyrrolidine), 2.12 ppm s (CH ₃ -C =C-).

B) 180 mg of the product from Step A was dissolved in 1.6 ml of trifluoroacetic acid at 0 ° C and the solution was concentrated after 1.25 hours. The residue is purified by chromatography (silica gel, dichloromethane / methanol / 17% aqueous ammonia = 30: 8: 1), whereby 10 mg of 7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro is isolated. -1,4-dihydro-4-oxo-8- (propyn-1-yl) -3-quinolinecarboxylic acid.

Mp .: 209-210 ° C (dec.).

Mass spectrum: m / e 383 (M &lt; ^{+ &gt;} ), 309, 298, 267, (100%), 133, 70.

Example 11

Analogously to Example 1, the product of Example Z12 is reacted with N-methylpiperazine to give 8-ethynyl-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) ) -4-oxa-3-quinolinecarboxylic acid.

Melting point: 193-195 ° C (decomposition).

V286 / 93H @ ¹ H-NMR (CDCl3): .delta. = 3.35 s (-C.dbd.CH).

Example 12

0 F " X-COOH / --- Ιψι J 'N ch ₃ -n y- ¹ C Á III Δ ch

Analogously to Example 1, 3-methyl-3,8-diazabicyclo (4.3.0) nonane is reacted and the crude product 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (3- The methyl-3,8-diazabicyclo (4.3.0) non-8-yl-4-oxo-3-quinolinecarboxylic acid is purified by chromatography (silica gel, dichloromethane / methanol / 20% aqueous ammonia = 2: 4: 1).

^{@ 1} H-NMR (CDCl3): .delta. = 4.15 s (-C.dbd.CH).

Example 13

COOH

Analogously to Example 1, 3-methyl-3,7-diazabicyclo (3.3.0) octane is reacted to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (7-methyl-

3,7-diazabicyclo (3.3.0) oct-3-yl) -4-oxo-3-quinolinecarboxylic acid.

Melting point: 221 - 216 ° C (decomposition).

¹ H-NMR ^(d6-DMF): delta = 4.95 s (-C-CH).

V286 / 93H

Example 14

0 F. JL.COOH CH ₃ -NH T iľ | T > - ( n C C III CH A

Analogously to Example 1, 4-methylamino-1,3,3a, 4,7,7a-hexahydro-isoindole is reacted to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (4-methylamino- 1,3,3a, 4,7,7a-hexahydro-isoindol-2-yl) -4-oxo-3-quinolinecarboxylic.

Melting point: 128 - 133 ° C (decomposition).

¹ H-NMR (d ⁶ -DMSO): delta = 4.93 ppm s (-C-CH).

V286 / 93H

Example 15

COOH

C

164 mg (0.5 mmol) of the product of Example Z18 was treated analogously to Example 1 with 1-methylpiperazine to 120 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-8- (3-methyl-but-3) acid. en-l-ynyl) -7- (4-methyl-piperazinyl) -4-oxo-3-quinolinecarboxylic.

Melting point: 195-197 ° C (decomposition) (crystallized from glycol monomethyl ether), 1 H-NMR (CDCl 3): δ = 5.36 m (= C = CH ₂ ), 2.4 s (N-CH ₃ ), 2.01 _(C-CH3).

V286 / 93H

Example 16

COOH

Analogously to Example 15, 2,8-diazabicyclo (4.3.0) nonane is reacted to 1-cyclopropyl-7- (2,8-diazabicyclo (4.3.0) non-8-yl) -6-fluoro-1,4-dihydro 8- (3-methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid.

Melting point: 201 - 202 ° C (decomposition).

Example 17

Analogously to Example 15, it was allowed to react

A. 1,4-Diazabicyclo (3.2.1) octane

B. 3-Hydroxypyrrolidine

C. 2-Methylpiperazine for the following compounds:

V286 / 93H

A. 1-Cyclopropyl-7- (1,4-diazabicyclo (3.2.1-oct-4-yl) -6-fluoro-1,4-dihydro-

8- (3-methyl-but-3-en-1-ynyl) -4-oxo-3-quinolinecarboxylic acid,

B. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -8- (3-methyl-but-3-en-1-ynyl) -4-oxo acid 3-quinolinecarboxylic acid,

Melting point: 190-198 ° C (decomposition).

C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8- (3-methyl-but-3-en-1-ynyl) -7- (3-methyl-1-piperazinyl) -4-oxo-3 acid quinoline carboxylic.

Example 18

ABOUT

COOH

CH ₂ x HCl

100 mg of the product of Example 1 are dissolved in 40 ml of hydrochloric acid and stirred for 2 hours at 30 ° C. The suspension obtained is concentrated, the residue is stirred with a small amount of isopropyl alcohol, the precipitate is filtered off with suction, washed with isopropyl alcohol and dried in vacuo at 90 ° C.

Yield: 0.1 g (83% of theory) of 8- (1-chloro-vinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3 hydrochloride quinoline carboxylic

Melting point: 251-252 ° C (decomposition).

¹ H-NMR (DMSO d ^G) d = 6.0 ppm dd (= C = CH _2).

V286 / 93H

Example 19

COOH xHCl

A) 100 mg (1 mmol) of the product of Example 2 is heated at 60 ° C for 5 hours in 58 ml of 4N hydrochloric acid, the reaction mixture is concentrated, the residue is triturated with diethyl ether and vacuum-dried at 70 ° C. dried.

Yield: 90 mg of cis-trans-8- (1-chloro-1-propenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo- hydrochloride 3-quinolinecarboxylic

Melting point: 236-237 ° C (decomposition).

Mass spectrum: m / e 419 (M ⁺ ), 71.58 (100%), 43.36 ¹ H-NMR (d ⁶ -DMSO): δ = 6.12 q and 6.35 q (= C = CH = CH ₃ , two signals for cistrans forms).

B) Analogously with the product of Example 3, cistrans-8- (1-chloro-1-hexenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4 hydrochloride oxo-3-quinolinecarboxylic acid.

Mass spectrum: m / e 461 (M ⁺ ), 425 (M-HCl), 71.58 (100%), 43.36.

V286 / 93H

Example 20

370 mg of the product of Example 10A are dissolved in 9 ml of semi-concentrated hydrochloric acid and this solution is concentrated under high vacuum.

Yield: 340 mg of cis-trans-7- (3-amino-3-methyl-1-pyrrolidinyl) -8- (1-chloro-1-propenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic.

¹ H-NMR (d ⁶ -DMSO): δ = 6.19 q and 6.36 q (= C = CH-CH 3, two signals for the cis-trans forms).

Example 21

mg of the product of Example 11 is heated at 60 ° C for one hour with 4.5 ml of 2.5N hydrochloric acid, then the reaction mixture is concentrated to give 8- (1-chloro-vinyl) -6-fluoro-hydrochloride as a residue. 1 (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

V286 / 93H

Example 22

COOH

291 mg (1 mmol) of the product of Example Z2 are mixed with 240 mg (2.2 mmol) of 1,4-diazabicyclo (2.2.2) octane and 360 mg (2.3 mmol) in a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide. - (2,2-Dimethyl-propylidenamino) -pyrrolidine and the reaction mixture was heated under reflux for 32 hours. The reaction mixture is concentrated, the dark oily residue is stirred with 10 ml of water and the precipitated solid (103 mg) is filtered off with suction and purified by chromatography (silica gel, dichloromethane / methanol / 17% aqueous ammonia = 30: 8: 1).

Yield: 58 mg (16% of theory) of 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid

Melting point: 179-182 ° C (decomposition).

CI-MS: m / e 358 ((M + H) ⁺ ), 340 ((M + H-H 5 O) +).

Example 23

145 mg (0.5 mmol) of the product of Example Z2 is heated in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide with 60 mg (0.54 mmol) of 1,4-diazabicyclo

V286 / 93H (2.2.2) octane and 140 mg (1.1 mmol) of cis-2,8-diazabicyclo (4.3.0) nonane for 4 hours at reflux. The solution is then concentrated, stirred with about 5 ml of water and the pH is adjusted to 7 with dilute hydrochloric acid. The precipitate formed is filtered off with suction, washed with water and dried at 90 DEG C. in vacuo.

Yield: 120 mg (61% of theory) 1-cyclopropyl-7 (cis-2,8-diazabicyclo (4.3.0) non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-8 vinyl-3-quinolinecarboxylic acid

Mp .: 205-207 ° C (dec.).

¹ H-NMR (CF 3 COOD): δ = 5.05 d (1H), 5.7 d (1H), 7.55 dd (1H) (signal groups for -CH = CH ₂ ).

Example 24

ABOUT

Analogously to Example 1, the product of Example Z26 was reacted to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -8 (3-methoxy-propyne-). 1-yl) -4-oxo-3-quinolinecarboxylic acid.

Mp 187-189 ° C.

^1H-NMR (CDCl3) d 8.95 s (1H), 8 d (1H), 4.37 s _(O-CH2), 4.35 m (1H), 3.58 m (4H) 3.43 s (O-CH3), 2.58 m (4H), 2.38 s (N-CH3), 1.33 m (2H), 1.02 ppm m (2H).

V286 / 93H

Example 25

COOH

Analogously to Example 1, the product 3,7-diazabicyclo (3.3.0) octane is reacted, the reaction product is chromatographed on silica gel with dichloromethane / methanol / 17% ammonia = 30: 8: 1 as the mobile phase to give acid 1. -cyclopropyl-7- (3,7-diazabicyclo (3.3.0) oct-3-yl) -8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in the form of a "solidified foam".

¹ H-NMR (d ⁶ -DMSO): delta = 4.9 s (-C-CH).

V286 / 93H

3,414

Claims (18)

Quinolone carboxylic acid derivatives of the general formula I in which is R ^{1 is} straight or branched (C 1 -C 4) alkyl optionally substituted by hydroxy, halogen or C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl and C 2 -C 4 alkenyl, optionally substituted with halo or C 1 -C 3 alkyl, C 1 -C 3 alkoxy, amino, C 1 -C 3 monoalkylamino, C 2 -C 6 dialkylamino or phenyl optionally substituted one to three times with halogen, R ² hydrogen, C ^ of 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, X ^{1 is a} hydrogen atom, a fluorine atom, a chlorine atom, an amino group or a methyl group, X ² -C = CH-R ³ , -OC-R ⁵ or -CH ₂ -CH = CH ₂ , Pričom ⁴ where V286 / 93H R ³ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or an alkoxymethyl group having 1 to 3 carbon atoms in the alkoxy moiety, R ⁴ represents a hydrogen atom or a halogen atom; R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, optionally substituted one to three times with a halogen atom, an alkenyl group having 2 to 3 carbon atoms, an optionally substituted one to three times a halogen atom, an alkoxy group having 1 to 3 carbon atoms, an alkoxymethyl group having 1 to 3 carbon atoms in the alkoxy moiety, a halogen atom or a trimethylsilyl group; and Y groups M R ⁷ R V286 / 93H where R ⁶ represents a hydrogen atom, a C 1 -C 4 alkyl group which is straight or branched and optionally substituted by a hydroxy or methoxy group, a cyclopropyl group, a C 1 -C 4 oxoalkyl group or a C 1 -C 3 acyl group, R ⁷ represents a hydrogen atom, a methyl group, a phenyl group, a thienyl group or a pyridyl group, R ^{8 is a} hydrogen atom or a methyl group, R ⁹ represents a hydrogen atom or a methyl group, R ¹⁰ represents a hydrogen atom or a methyl group, R ¹¹ represents hydrogen, methyl or R ¹² represents a hydrogen atom, a methyl group, an amino group, an alkylamino group or a dialkylamino group having 1 to 2 carbon atoms in the alkyl moieties optionally substituted by hydroxy, aminomethyl, alkylaminomethyl or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl moiety optionally substituted -imidazolyl group, R ¹³ represents a hydrogen atom, a hydroxy group, a methoxy group, a methylthio group, a halogen atom, a methyl group or a hydroxymethyl group, R ¹⁴ represents a hydrogen atom or a methyl group, R ¹⁵ represents a hydrogen atom, a methyl group or an ethyl group, V286 / 93H 1 fi R represents a hydrogen atom, a methyl group or ethyl group R ¹⁷ represents a hydrogen atom, a methyl group or ethyl group R 18 is OH, / R 16 - R 17 Ni ^ », or a group / R 16 - CH ₂ - N f ^ t R 17 R ¹⁹ is a hydrogen atom, an alkyl group having 1 to 3 C alkyl, optionally substituted by hydroxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or an acyl group having 1 to 3 carbon atoms, R ²⁰ represents hydrogen, hydroxy, / R 19 R 21 -K ^ hydroxymethyl, or - CH ₂ - R 19 R21 where R ²¹ represents a hydrogen atom or a metal group, A represents a methylene group, an oxygen atom or a direct bond and n represents 1 or 2, V286 / 93H and their pharmaceutically usable salts, hydrates and acid addition salts, as well as the corresponding alkali metal, alkaline earth metal, silver and guanidine salts of the corresponding carboxylic acids. 2. Quinolone carboxylic acid derivatives according to the formula I of general formula I, in which t> R ^{1 is} C 1 -C 2 alkyl, optionally substituted by hydroxy, C 3 -C 5 cycloalkyl, vinyl, amino, C 1 -C 2 monoalkylamino, C 2 -C 4 dialkylamino or phenyl, optionally once or double substituted with a halogen atom, R ² hydrogen, alkyl of 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, X ^{1 is a} hydrogen atom, a fluorine atom, a chlorine atom, an amino group or a methyl group, X ² -C = CH-R ³ , -C -CCR ⁵ or -ΟΗ ₂ -ΟΗ = ΟΗ _Ζ , Pričom ⁴ where R ³ represents hydrogen, alkyl having 1 to 2 carbon atoms, methoxy or methoxymethyl, R ⁴ represents a hydrogen atom and R ⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, optionally substituted one to three times with a fluorine atom, an alkenyl group having 2 to 3 carbon atoms, a methoxy group or a trimethylsilyl group, and Y group v2 86/93 H R ¹ ^ ZR ¹⁷ N-CH » V286 / 93H where R ⁶ represents a hydrogen atom, a straight or branched alkyl group having 1 to 3 carbon atoms, optionally substituted by a hydroxyl group or an oxoalkyl group having 1 to 4 carbon atoms, R ⁷ represents a hydrogen atom, a methyl group or a phenyl group, R ⁸ represents a hydrogen atom or a methyl group, R ⁹ represents a hydrogen atom or a methyl group, R ¹¹ represents hydrogen, methyl or -CH 2 -NH 2, R ¹² represents a hydrogen atom, a methyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, a methylaminomethyl group or an ethylaminomethyl group, R ¹³ represents a hydrogen atom, a hydroxy group, a methoxy group, a fluorine atom, a methyl group or a hydroxymethyl group, R ¹⁵ represents a hydrogen atom or a methyl group, R ¹⁶ represents a hydrogen atom or a methyl group, R ¹⁷ represents a hydrogen atom or a methyl group, R ¹⁸ is a group or a group - CH ₂ ^X N _X R 16 R 17 R ¹⁹ represents a hydrogen atom, a methyl group or an ethyl group, V286 / 93H R ²⁰ represents a group, R 19 -N 11 R 21 wherein R ²¹ represents a hydrogen atom or a methyl group, A represents a methylene group, an oxygen atom or a direct bond and n represents the number 1 or 2. 3. A compound according to claim 1, in which it is R ^{1 is} methyl, ethyl, cyclopropyl or phenyl, optionally substituted one or two times with fluorine, R ² hydrogen, methyl or ethyl, X ^{1 is a} hydrogen atom, a fluorine atom, a chlorine atom, an amino group or a methyl group, X ^{2 is} -C =CH 2 or -C =CR ⁵ wherein R ⁵ represents a hydrogen atom, a (C 1 -C 4) alkyl group, a (C 2 -C 3) alkenyl group or a ( ^R) -sylsilyl group; and Y group V286 / 93H ^ν 5>. v 0 N - R ^{11 R} >. R ¹³ R ⁸ r! 6 R ¹ ! q 1 \ -ch ₂ V- r · '' o> V286 / 93H where R ⁷ represents a hydrogen atom or a methyl group, R ⁶ represents a hydrogen atom, a methyl group or an ethyl group optionally substituted by a hydroxy group, R ⁸ represents a hydrogen atom or a methyl group, R ⁹ represents a hydrogen atom or a methyl group, R ¹¹ represents hydrogen or a group -CH 2 -NH 2, R ¹² represents a hydrogen atom, a methyl group, an amino group, a methylamino group, an aminomethyl group or an ethylaminomethyl group, R ¹³ represents a hydrogen atom, a hydroxy group or a methoxy group, R ¹⁵ represents a hydrogen atom or a methyl group, R ¹⁶ represents a hydrogen atom or a methyl group, R ¹⁷ represents a hydrogen atom or a methyl group, 1 δ R is a group R ¹⁹ represents a hydrogen atom or a methyl group, 20 ¹ R represents a group wherein R ²¹ represents a hydrogen atom or a methyl group, V286 / 93H A represents a methylene group, an oxygen atom or a direct bond and n represents the number 1. 4. A compound according to claim 1 which is 8-bromo-1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its pharmacologically active compounds. acceptable hydrates and acid addition salts as well as alkali metal, alkaline earth metal, silver and guanidine salts. 5. A compound according to claim 1, which is 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and pharmacologically acceptable hydrates and addition salts thereof. acids, as well as salts with alkali metals, alkaline earth metals, silver and guanidine. 6. A compound according to claim 1, which is 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-. quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as salts with alkali metals, alkaline earth metals, silver and guanidine. 7. A compound according to claim 1, which is 1-cyclopropyl-7- (cis-2,8-diazabicyclo (4.3.0) non-8-yl) -8-ethynyl-6-fluoro-1. 4-dihydro-4-oxo-3-quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as alkali metal, alkaline earth metal, silver and guanidine salts. 8. A compound according to claim 1, which is 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-. quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as salts with alkali metals, alkaline earth metals, silver and guanidine. V286 / 93H 9. A compound according to claim 1, which is 7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-trifluoroacetate. oxo-3-quinolinecarboxylic acid. 10. A compound according to claim 1, which is 1-cyclopropyl-6-fluoro-1,4-dihydro-8- (3-methyl-but-3-en-1-ynyl) -7- (4). methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as alkali metal, alkaline earth metal, silver and guanidine salts. - 11. A compound according to claim 1 which is 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (2-oxa-). 5,8-diazabicyclo (4.3.0) non-8-yl) -4-oxo-3-quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as salts with alkali metals, alkaline earth metals, silver and guanidine. 12. A compound of the quinolone of the eye to ^R 1 of the formula I which is 1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7- (7-methyl- 3,7-diazabicyclo (3.3.0) oct-3-yl) -4-oxo-3-quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as salts with alkali metals, alkaline earth metals, silver and guanidine. 13. A compound according to claim 1, wherein the compound is 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7- (4-methylamino-1,3,3a, 4,7,7a). (hexahydroisoindol-2-yl) -4-oxo-3-quinolinecarboxylic acid and its pharmacologically acceptable hydrates and acid addition salts as well as alkali metal, alkaline earth metal, silver and guanidine salts. 14. A compound according to claim 1, wherein the compound is 1-cyclopropyl-7- (cis-2,8-diazabicyclo (4.3.0) non-8yl) -6-fluoro-1,4-dihydro- 4-oxo-8-vinyl-3-quinolinecarboxylic acid, its pharmacologically acceptable hydrates and acid addition salts as well as alkali metal, alkaline earth metal, silver and guanidine salts. V286 / 93H 15. A process for the preparation of quinolone carboxylic acid derivatives of general formula 5c> of claim 1, wherein the compound is non-reactive of formula II X ¹ 0 F .COO-R ² X ³ 3 I (II), • < ² R ¹ wherein R ¹ , R ² , X ¹ and X ^{2 are} as defined above and R ³ represents a halogen atom, in particular fluorine or chlorine, with a compound of formula III Y-H (III), wherein Y is as defined above, optionally in the presence of acid binders. 16. Quinolonecarboxylic acid derivatives of the general formula II COO-R ² (Π) in which R ¹ , R ² , X ¹ and X ^{2 are} as defined above and X represents a halogen atom, in particular fluorine or chlorine, as intermediates for the preparation of the compounds of formula I. A pharmaceutical composition having an antibacterial action, characterized in that it contains at least one derivative as the active ingredient V286 / 93H quinolone carboxylic acid according to claims 1 to 3 and 6 to 16. · / ¥ The quinolone carboxylic acid derivatives according to claims 1 to 3 and 6 to 4 -4 for use as a medicament.