DD298400A5 - 5-ALKYLCHINOLONCARBONSAEUREN - Google Patents

Abstract

The invention relates to novel quinolone and naphthyridinecarboxylic acid derivatives of the formula (I) in which R 1, R 2, R 3, R 4 and A have the meanings given in the description and which carry an alkyl or a substituted alkyl radical in the 5-position, processes for their preparation and antibacterial agents and feed additives containing them. Formula (I)

Description

R ⁴ -H

(III)

in which

R ^{4 has} the meaning given in claim 1,

if appropriate in the presence of acid scavengers and optionally cleaved off in R ⁴ protecting groups.

Compounds of formula (I) according to claim 1 for use in a method of therapeutic treatment of the human or animal body.

6. Medicaments containing compounds of the formula (I) according to claim 1.

7. Use of compounds of formula (I) according to claim 1 for and in the manufacture of medicaments.

8. T-Chloro-i-cyclopropyl-e.S-difluoro-1-dihydro-B-methyl-oxo-S-quinolinecarboxylic acid.

The invention relates to novel quinolonecarboxylic acid derivatives which carry an alkyl or a substituted acrylic radical in the 5-position, processes for their preparation and antibacterial agents and feed additives containing them. It has been found that quinolone derivatives of the formula (I)

COOR '

in which

R ^{1 is} optionally substituted by hydroxy, halogen, C ₁ -C ₃ -alkoxy or C, -C _s -alkylthio substituted geradkettiges or

branched C 1 -C ₄ -alkyl, C 1 -C 9 -cycloalkyl optionally substituted by halogen or C 1 -C 5 -alkyl,

C ₁ -C ₃ -alkenyl, furthermore C ₁ -C ₃ -alkoxy, amino, monoalkylamino having _{1 to 3} carbon atoms, dialkylamino having _{2 to} 6 carbon atoms

or represents optionally substituted by Halogon phenyl,

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

C 1 -C ₄ -alkyl,

for a in the ring system optionally substituted by hydroxy or methyl radical of the formula

EC N,

N-,

EGN-

in which

E for R ⁵ -N, O, S,

G is - (CH ₂ ) _r , -CHj-O-CHj -, -

R <

-CH ₂ -N-CH ₂ -, j is 1,2 or 3,

is hydrogen, optionally substituted by hydroxy alkyl, alkenyl or alkynyl with

1 to 4 carbon atoms, optionally substituted by nitro or amino-substituted benzyl, Oxoaikyi with

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

further for a radical of the formula

vl

stands in which,

I for O, 1 or 2,

m is 1 or 2, where I + m together may be 1,2 or 3,

η for 1 or 2,

for N, OR ⁹ , SR ⁹ , halogen or hydrogen, " ⁸

for N, OR ⁹ , SR ⁹ , Halogan, CN, CONH ₂ , COOH, or Ci-C ₄ - ^ ⁸

X ² and X ^{3 may be the} same or different and represent oxygen or N-CH ₃ , ⁷

is hydrogen, C, -C ₃ alkyl, AllyloderPropargylundfür hydrogen, C ₁ -C ₃ -alkyl or Cr-C _e cycloalkyl,

R ⁷ + R ⁸ together also form the group -CHjCHz-O-CHjCHr or-IC ^ K- in which k can be 3,4 or 5,

means and

is hydrogen, C 1 -C ₃ alkyl or C 1 -C ₃ acyl, hydrogen or C 1 -C 4 alkyl, also a residue of the structure

ZR ¹¹

> 15

) 15

-N

> 16

Vf ¹⁴ , -

-N ^

16

> 17

) 13

means, in which

R "WrH ₁ C ₁ -C ₃ -AlkV LC ₁ -C ₂ acyl R ' ^{2 is} H, C ₁ -C ₃ alkyl, OH, OCH ₃ , wherein R ¹¹ and R ¹² together are also optionally monosubstituted or disubstituted by methyl

substituted C ₁ -C ₂ -alkylene bridge, R ^{13 is} H, C ₁ -C ₃ -alkyl, aryl, heteroaryl, benzyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -acyl or

(5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl, for H or C, -C ₄ -alkyl, for H or CH ₃ or phenyl, for H or CH ₃ or phenyl, for H or CH ₃ ,

may be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, the linking of the CH ₂ O group to the nitrogen both via O

as well as via CH ₂ , which may be O or S,

A represents hydrogen, halogen, methyl, cyano or nitro or together with R ^{1 represents} a bridge of

structure

Can form -0-CH ₂ (JlH-CH ₃₁ -S-CHHpH-CH ₃ OdOr-CH ₂ CHHjIH-CH ₃ with R- or S-configuration

and their pharmaceutically usable hydrates and acid addition salts and the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids have a high antibacterial activity, in particular in the gram-positive region.

They are therefore suitable as active ingredients for human and veterinary medicine, whereby veterinary medicine also includes the treatment of fish for the treatment or prevention of bacterial infections. Preference is given to those compounds of the formula (I) in which R ^{1 is} ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methylamino, phenyl,

4-fluoroethyl or 2,4-difluorophenyl,

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

is C, -Ca-alkyl

for a in the ring system optionally substituted by methyl radical of the formula

N - (CH ₂ ) J ^ N-, EG N-, EG ^ N

EJ3 ^ N

in which E

r is R ⁶ -N, O,

R «N

für1,2oder3,

is hydrogen, optionally substituted by hydroxy alkyl, alkenyl or alkynyl with

1 to 3 carbon atoms, optionally substituted by nitro or amino-substituted benzyl or oxoalkyl with

2 to 4 carbon atoms and represents hydrogen or methyl, furthermore a radical of the formula

> m

(CHO)

stands in which

I for O, 1 or 2,

m is 1 or 2, where I + m together may be 1,2 or 3,

η for 1 or 2,

for N

, OR ⁹ or hydrogen,

X ¹ for N, OR ⁹ , fluorine, chlorine or

^ ⁸

C, -C} alkyl,

X ² and X ^{3 may be} identical or different and represent oxygen, sulfur or N-CH ₃ , R ^{7 is} hydrogen, C 1 -C -alkyl or acetyl,

R "is hydrogen or Ci-Ci-Alky I,

in which

R ⁷ + R ⁸ together also form the groups -CH ₂ CH ₂ -O-CH ₂ CH ₂ - or - (CH ₂ ) _k -, in which k can be 3,4 or 5,

means

is hydrogen, Ci-Cj-alkyl or acetyl, hydrogen or Ci-Cj-Alky I, also a residue of the structure

¹⁵ ZR ¹¹

R ¹⁵ ZR

-N

16

> 17

means, in which

for H, C, -C ₃ -alkyl, C ₁ -C ₂ -acyl,

for H, C ₁ -C ₃ -AlkYl, OH, OCH ₃ , wherein R "and R ¹² together also represents an optionally methyl by one or two times

may be substituted C, -C ₂ -alkylene bridge,

for H, C ₁ -C ₃ -alkyl, phenyl, benzyl, C ₁ -C ₄ -oxycarbonyl, C ₁ -C ₂ -acyl or (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl,

for H or C ₁ -C ₇ -alkyl, for H or CH ₃ ,

for H or CH ₃ ,

for H or CH ₃ ,

may be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, the linking of the CHr-O group to the nitrogen both via O

as well as via CH ₂ can take place, can stand for O,

represents H, fluorine, chlorine, methyl, cyano or nitro or together with R ¹ a bridge of the structure

-O-CHHfH-CH ₃

can form with R- or S-configuration.

Particular preference is given to those compounds of the formula (I) in which

for ethyl, vinyl, t-butyl, cyclopropyl, 2-hydroxyethyl, 1,2-fluoroethyl, methylamino, 4-fluorophenyl, 2,4-difluorophenyl,

for hydrogen, alkyl with 1 to ?. Carbon atoms, is C ₁ -C ₃ -alkyl,

for a in the ring system optionally substituted by methyl radical de ~ formula

EGN-,

EGN-,

EGN-

in which

for R ⁵ -N,

KJr- (CH ₂ ) -,

für1oder2,

is hydrogen, optionally substituted by hydroxy alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms, optionally substituted by nitro or amino-substituted benzyl or oxoalkyl with

2 to 4 carbon atoms and is hydrogen or methyl, furthermore a radical of the formula

(CH ₂ ) _n -W 2 η

(CHO) ¹ ^

(CHO)

stands in which

I for 0.1 or 2,

m is 1 or 2, where I + may be 1, 2 or 3 together,

η for 1,

W is N, OR ⁹ or hydrogen,

T? ^8th

stands for N, OR ⁹ , chlorine or methyl ^ ⁸

X ² and X ^{3 may be} identical or different and represent oxygen or N-CH ₃ , R ^{7 is} hydrogen or methyl,

R ^{8 is} hydrogen or methyl and

is hydrogen or methyl, as well as a residue of the structure

¹⁵ ZR ¹¹

R ¹⁵ ZR

¹⁵

-N

, -N 12V

-N

> 17

-N

13

means, in which

R "is H, C 1 -C 1 -alkyl, acetyl, R ^{12 is} H, C ₁ -C ₂ -alkyl, where R "and R ¹² together are also optionally substituted by methyl Ci-C ₂ -alkylene bridge may mean

is H, C, -C ₂ alkyl, hydroxyethyl, benzyl, C ^ alkoxycarbonyl, C ₁ -C ₂ -acyl,

for H or CH ₃ , for H or CH ₃ , for H or CH ₃ , for H or CH ₃ ,

may represent O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, the linking of the CHr-0 groups to the nitrogen both via

as well as via CH ₂ , Z can stand for O,

A is H, fluorine or chlorine, or together with R ¹ a bridge of the structure-O-CH ₂ -CH-CH ₃ with

R- or S-configuration can form. Furthermore, it has been found that the compounds of the formula (I) are obtained when compounds of the formula (II)

COOR ²

In which

R ¹ , R ² , R ³ and A have the abovementioned meaning and X ^{4 represents} halogen, in particular fluorine or chlorine, with compounds of the formula (III)

R ⁴ -H

in which

R ^{4 has} the meaning given above,

if appropriate in the presence of acid scavengers and if appropriate abspnUet contained in R ⁴ protective groups.

If, for example, i-cyclopropyl-ej.e-trifluoro-i ^ -dihydro-S-methyl-4-oxo-3-chloro-2-carbonone and 1-methyloctahydropyrrolo [3,4-b] pyridine are used as starting materials, the reaction variant can be described by the following equation reproduced ^r we to:

CH

COOH

CH-

base

^nh

RF

CH ₃ 0

COOH

If, for example, 8-chloro-1-cycloprophenyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-chlorolincarboxylic acid and 3-ethylaminomethyl-3-hydroxy-pyrrolidin are used as starting materials, cf. the Reaklionsablauf can be represented by the following equation:

Cl

COOH C ₂ H ₅ -NH-CH ₂ / NH

Base -HF

COOH

C ₂ H ₅ -NH-CH ₂

For example, if 1-cyclopropyl-7- (2,7-diazabicyclo [3.3.0] oct-7-yl) -6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and ethanol are used / Hydrogen chloride as starting materials, the course of the reaction can be represented by the following formula scheme:

CH ₃ O

3 Il

COOC ₂ H ₅

χ HCl

The ale starting materials used compounds of formula II are known or can be prepared by known methods

getting produced. Examples include:

i-Cyclopropyl-e ^ .e-trifluoro-M-dihydro-B-methyM-oxo-S-quinolinecarboxylic acid,

S-chloro-i-cyclopropyl-ej-difluoro-i ^ -dihydro-S-methyl ^ -oxo-S-quinolinecarboxylic acid,

i-Cyclopropyl-e ^ difluoro-i ^ -dihydro-Be-dimethyM-oxo-S-chlnollnnarbonsäure, 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo- 3-quinolinecarboxylic acid, i-cyclopropyl-ej.e-trifluoro-IAdihydro-e-methyl ^ -oxo-S-quinolinecarboxylic acid ethyl ester, e-chloro-i-cyclopropyl-ej-difluoro-i ^ -dihydro-S-methyl ^ -oxü -S-quinolinecarboxylic acid ethyl ester, 6,7-difluoro-1- (4-fluoro-phenyl) -1,4-dihydro-5-methyl-4-oxo-3-chinollncarbonsäure, 6,7-di (luor-1- ( 2,4-difluoro-phenyl) -1,4-dihydro-5-nnethyl-4-oxo-3-quinolinecarboxylic acid.

The 7-chloro-1-cyclopropyl-6 _< 8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is not known. She can after

following scheme are shown.

COOH 1. SOCl ₂ 2. EtOH

COOEt

EtOOC

CH 0

Close

CH,

" 'COOEt

COOEt

COOH

DABCO = 1,4-diazabicyclo [2,2,2] octane Dio compounds of formula III with the structures

DABCO

COOH

E _N J3 U

N-,

are known (El ^J -PS 230274).

The compounds of the formula III having the structures used as starting compounds

are partly new.

They can be produced by various methods:

1. By reaction of the nitrogen-protected spiro-oxiranes (1) (J.Mod.Chem.30,222 [1987], USP 4508724, EP-PS 189370) with amines (2), ring opening to the hydroxyamines (3) takes place. Cleavage of the protective group gives starting compounds of the formula (III a):

OH

COO-alkyl, CH ₂ C ₆ H ₅

(3)

_2m H

(purple)

2. Cyclization of the succinic acid ester (4) (Tetrahedron Letters 46, 4561 [1973]) with benzylamine affords the 1-benzyl-3-hydroxy-5-oxo-pyrrolidine-3-carboxylic acid alkyl ester (5) which, after reaction with an amine (2) reacts to amide (6). Subsequent reduction with LiAlH ₄ and hydrogenolytic cleavage of the benzyl group gives starting compounds of the Forrml (IIIb):

Alkyl-O-CO

(4)

COO-alkyl

(5)

OH M '

(6)

(IIIb)

3. Circulation of (1-benzyl-3-hydroxy-2,5-dioxo-pyrrolidin-3-yl) -acetic acid (7) (Gazz. Chim. Ital. 24,226 [1894]) to the amide (8) and subsequent reduction with LiAlH ₄ and elimination of the benzyl group gives starting compounds of the formula (HIc):

COOH

OH

(8th)

(HIC)

4. 3-Hydroxy-3-methylpyrrolidine can be prepared by LiAlH ₄ reduction of 4-hydroxy-4-methylpyrrolidin-2-one (Zh.Org.Khim., 14, 7, p by debenzylation of 1-benzyl-3-hydroxy-3-methyl-pyrrolidine <ζΡ 132845).

5. Starting from cyclic oxo-amines (9) which are blocked on the nitrogen by a protective group, starting compounds of the formulas (HId), (HIe), (HIf) can be built up (Acta Chem. Scand. B 34,319 (1980)) ,

OH

OH

(CH ₂ J ₁ - ^ CH ₃ NO ₂ (CH ₂ J ₁

^(CH 2Jl

(9)

R ¹⁸ = COO-alkyl, CH ₂ -C ₆ H ₅

(10)

HCN or (GH ₃ J ₃ SiCN

OH (CH ₂ J ₁ -J-CN

(11 Id)

Vl

^ N '(CH

NH,

NH ₂ (CH ₂ J ₁ -J-COOH

(CH ₂ J ₁

I 6

-UCN ^ K (CH,)

r ι

(CH ₂ J

(CH ₂ Jm

(12)

, 18

(13)

(IIIe)

NH2

(CH ₂ J ₁ -WiH ₂

(inn

6. The hydroxy group of the hydroxyamines (III aJ- (Hle) can be alkylated or halogenated.

7. From the cyclic oxoamines (9), ketals, thioketals or aminals can be prepared (HeIv. Chim. Acta 50, 1289 [19671]).

Reaction of the nitrogen-protected spirooxiranes (1) with trimethylsilyl cyanide (J.Amer.Chem.Soc.104.5849 [19821] can produce the isonitriles (14) which are obtained by saponifying and deprotecting the starting compounds of the formula (HIg) can be implemented:

(CH ₂ J

(CH ₃ J ₃ SiCN

(IJ

NH

NC

(CH ₂ J ₁ -

R ¹⁸ (14)

HIllg)

Examples of starting compounds of the formula (III) are the following compounds, where chiral compounds

can be used both as racemates and as enantiomerically pure substances:

3-aminomethyl-3-hydroxy-pyrrolidine,

S-Acetylamino-S-hydroxy-pyrrolidine, S-tert-butoxycarbonylaminomethyl ^ -hydroxy-pyrrolidine,

3-hydroxy-3-methylaminomethyl-pyrrolidine,

S-ethylaminomethyl-S-hydroxy-pyrrolidine,

3-hydroxy-3-propylaminomethyl-pyrrolidine, 3-ethylaminomethyl-3-methoxy-pyrrolidine,

S-EthoxyS-ethylaminomethyl-pyrrolidine, S-chloro-S-ethylaminomethyl-pyrrolidine,

3-ethylaminomethyl-3-fluoro-pyrrolidine, 3-ethylaminomethyl-3-methyl-pyrrolidine,

S-ethylaminomethyl S mercapio-pyrrolidine,

3-Ethylamlnomethyl-3-methylthio-pyrrolidine,

S-Acotoxy S ethylaminomethyl-pyrrolidine,

3-dimethylaminomethyl-3-hydroxy-pyrrol) din, 3-hydroxy-3-pyrrolidinomethyl-pyrrolidine,

S-hydroxy-S-morpholinomethyl-pyrrolidine,

3-Amino-3-ethylaminomethyl-pyrrolidine,

S-acetylamino-S-ethylaminomethyl-pyrrolldin, S-ethyleminomethyl-S-methylaminopyrrolidine, S-dimethylamino-S-ethylaminomethyl-pyrrolidine,

3-Amino-3-hydroxymethyl-pyrrolidine,

S-acetylamino-S-hydroxymethyl-pyrrolidine, S-amino-S-methoxymethyl-pyrrolidine, S-tert-Butoxycarbonyiamino-S-methoxymethyl-pyrrolidine,

3-amino-3-methylthiomethyl-pyrrolidine,

S-amino-S-mercaptomethyl-pyrrolidine, S-cyclopropylaminomethyl-S-hydroxy-pyrrolidine, S-lsopropylaminomethyl-S-hydroxy-pyrrolidine,

1,4-dioxa-7-azaspiro (4.4) nonane, 1-oxa-4,7-diazasplro [4.4] nonane, 4 -methyl-1-oxa-4,7-diazaspiro [4.4] nonane, 1-thia- 4,7-diazaspiro nonane (4.4) nonane, 1,4,7-triazaspiro [4.4) nonane, 1,4-dimethyl-1,4,7-triazaspiroI4.4].

The compounds of the formula III having the structures used as starting material

R ¹⁵ ZR ¹¹ R ¹⁵

-N

, -Ν 12V

-Z

,> - R ⁷ ₍ -N

R ¹³

R ¹⁶

-N

17

are also partly new. They can be prepared by the following methods.

1. Starting from the N-protected 3,4-Epoxypyrrolidin (1) (German Offenlogungsschrift 1929237, US Patent 4254135), which may optionally carry a c of the two methyl or phenyl, the starting compounds of

Formula (HIaHIiIe) produced.

A ^ Tjl2

♦ HN

HO / R ¹² protective group

** - * ¹ split off

HO.

R ¹¹ X ⁵ R ¹¹ Q

18

H (IIIh)

base

Deprotection

R ¹¹ O / R ¹²

18

(IIIi)

R ¹⁸ = benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, sulfonyl (examples of protecting groups), X = leaving group such as halogen, alkyl- or arylsulfonyloxy

HQ R ¹¹ O.

base

, 18

R ¹¹ O.

*. ^ NH-COOC (CH ₃ )

H (IHj)

R ¹¹ O

- NH-R ¹² R ¹¹ O *

\ 2 3

H ₂ / Pd

(1111)

H ₂ / Pd

R ¹¹ OV

(HIK)

2. Starting compounds of the formula (III m) are obtained from 2- (1,2-dichloroethyl) oxirane via the following reaction sequence:

HO Cl

Cl

R ¹¹ O OH

_R U ₀ -

R ¹¹ O

-N.

R ¹¹ O

/ R

¹²

H-

R ¹¹ ON

(Ulm)

3. Starting compounds of the formula (Hin) can be prepared by addition of azides to N-benzylmaleimides optionally substituted by one or two methyl or phenyl radicals:

-R ¹⁸

/ ^N \

R ⁴ O / "/ ', f ^ -NH-R ¹⁸

I reduction - o ^ N ^ o -

₁

R ^ll 0 ' ⁷ ' ·

'I> NH-R ¹⁹

(Hin)

R ¹⁹ = H ₁ alkyl, benzyl.

4. From the 3,4-Epoxypyrrolidinen (1) is obtained via a cyclization with thionyl chloride, the starting compounds of the formula (IMo):

ho

(1) ►

* CT ^H ' ^C0 " ^Rli

^ N ^ SOC1,

ie

»14

14

R ¹⁰ H

(III o)

5. By reacting the 3,4-Epoxypyrrolidine (1) with ethanolamines obtained by intramolecular etherification, the starting compounds of the formula (HIp):

HO

HO N

13

NO

_ol3

- ♦ 0 N-R

_ol3

> 16

H (IIIp)

6. The starting compounds of the formula (IIIq) are obtained from aminoacetaidehydedimethylacetai via an intramolecular 1,3-dipolar cycloaddition.

OCH.

15

, OCH '.

base

R ¹⁸ -N

, OCH ₃ -OCH ₃

> 15

^ - <

R ¹³ -NH-0H

) 18

(III q)

7. Starting from pyridine ^. S-dicarboxylic acid-N-benzylimide starting compounds (III r) or (III I) over the specified reaction steps are prepared.

Alkyl iodide

N-CH ₂ -C ₆ H ₅

0 IH ₂ / Ru-C or 1 Pd-C

N-CH ₂ -C ₆ H ₅

N-CH ₂ -C ₆ H ₅

LiAlH ₄ or

NaBH ₄ /

BF ₃ '(C ₂ H ₅ ) ₂ O

N-CH ₂ -C ₆ H ₅

O alkyl

[LiAlH ₄

N-CH ₂ -C ₆ H ₅

alkyl

H ₂ / Pd-C

cc "

Ills

H ₂ / Pd-C

NH

alkyl

(III r)

8. N-Benzyl-maleimide adds 2-chloroethylamines to the 3- (2-chloroethylamino) -succinimides which are converted to the starting compounds of the formula (With): O

I N-CH ₂ -C ₆ H ₅ + Cl-CH ₂ CH ₂ -NH-R ¹³ »

Cl

Close

N-CH ₂ -C ₆ H ₅

CH ₂ -N

13

H ₅ LiAlH ₄

H ₂ / Pd-C

13

(III t)

9. 2-methyl-2-propenal dimethylhydra2on reacts with N-Benzylmalelnsäurelmid to a cycloadduct, which can be converted to the specified reaction sequence in the Ausgangsve.bindung (UIu).

N-CH ₂ -Ph

CH ₃ CH ₃

- (CH ₃ J ₂ NH CH ₃ N ₂ SZN, H ₂ /.Kata CH ₃ "*

¹ 'N-CH ₂ -Ph ► [j ^ N-CH ₂ -Fh

lyst '

LiAlH ₄ CH ₃ S- / ^S s / ^S \. H ₂ / Pd-C CH

N-CHo-Ph »NH

(III υ)

According to this general formula scheme, for example, the following starting compounds can be prepared. They can be prepared and used as diastereomer mixtures in diastereomerically pure and also enantiomerically pure form.

4-amino-3-hydroxypyrrolidine, 3-hydroxy-4-methylamine pyrrolidine, 4-dimethylamino-3-hydroxypyrrolidine, 4-ethylamino-3-hydroxy-pyrrolidine, 3-amino-4-methoxypyrrolidine, 4-methoxy-3-methylaminopyrrolidine, 3 -dimethylamino-4-methoxypyrrolidine,

3-ethylamino-4-methoxypyrrolidine, 3-amino-4-ethoxypyrrolidine, 4-ethoxy-3-methylaminopyrrolidine, 3-dimethylcino-4-ethoxypyrrolidine, 4-ethoxy-3-ethylaminopyrrolidine, 3-hydroxy-4-hydroxyaminopyrrolidine, 3 Hydroxy-4-methoxyaminopyrrolidine, 3-hydroxyamino-4-methoxypyrrolidine, 4-methoxy-3-methoxyaminopyrrolidine, 3-benzylamino-4-methoxypyrrolidine, 4-methoxy-3 - ((5-methyl-2-oxo-1,3-) dioxol-4-yl) -methylamino) -pyrrolidine, S-amino-methylmercaptopyrrotidine, 3-acetoxy-4-dimethylaminopyrrolidine, 3-acetamido-4-methoxypyrrolidine, 4-methoxy-3-methoxycarbonylaminopyrrolidine, 3-formamido-4-methoxypyrrolidine , 3-Amino-4-methoxy-2-methylpyrrolidine, 3-amino-4-methoxy-5-methylpyrrolidine, 4-methoxy-2-methyl-3-methylaminopyrrolidine, 4-methoxy-5-methyl-3-methylaminopyrrolidine, 3 -Amino-4-methoxy-2-phenylpyrrolidine, 4-methoxy-3-methylamino-5-phenylpyrrolidine, 3-methyl-2,7-diazabicyclo (3.3.0) octane, 4-methyl-2,7-diazo .abicyclo [3.3.0] octane,

2-oxa-4,7-diazabicyclo [3.3.0) octane,

1,2-dimethyl-3-oxa-2,7-diazabicyclo (3.3.0] octane,

2,6-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octa.i,

2,8-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane,

5-methyl-3-oxa-2,7-diazabicyclo [3.3.0] octane,

2-oxa-4,7-diazabicyclo [3.3.0] oct-3-ene,

4-methyl-2,8-diazabicyclo [4.3.0] nonane, 5-methyl-2,8-diazabicyclo [4.3.0] nonane, 6-methyl-2,8-diazabicyclo [4.3.0] nonane,

4-Methyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, 1-methyl-2-oxa-5,8-diazabicycloI4.3.0lnone, 3,5-dimethyl-2-oxa-5,8 diazabicyclo [4.3.0] nonane, 2-thia-5,8-diazabicyclo [4.3.0] nonane,

3-oxa-2,8-diazabicyclo (4.3.0lnonan,

2-methyl-9-oxa-2,8-diazabicyclo [4.3.0lnonan,

4-methyl-3-oxa-2,8-diazabicycloI4.3.0] nonane,

2,5-dimethyl-3-oxa-2,8-diazabicyclo nonane (4.3.p!,

3-oxa-5,8-diazabicyclo [4.3.0] nonane,

5-methyl-3-oxa-5,8-diazabicyc: o [4.3.0] nonane,

1,5-dimethyl-3-oxa-5,8-diazabicyclot4.3.0] nonane,

4,4-dimethyl-3-oxa-5,8-diazabicyclo [4.3.0] nonane.

The reaction of (II) with (III), in which the compounds (III) can also be used in the form of their hydrochlorides is

preferably in a diluent such as dimethyl sulfoxide, Ν, Ν-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric trisamide, suifolan, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol,

Glycol monomethyl ether or pyridine made. Likewise, mixtures of these diluents may be used

become.

From acid binders all common inorganic and organic acid binding agents can be used. These include

preferably the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Specifically, trieth, amine, 1,4-diazabicyclo [2,2,2] octane (DABCO), meta-diazabicyclic BAO-jundecene (DBU) or excess amine (III) are particularly suitable.

The reaction temperatures can be varied in a wider range. In general, you work between about 20

and 200 ^° C, preferably between 80 and 18O ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, one works at Printing between about 1 to 100 ml, preferably between 1 and 10 bar. When carrying out the process according to the invention, 1 to 15 mol, preferably 1, of 1 mol of the carboxylic acid (II) are used

to 6 moles of the compound (III).

Free hydroxy groups may be added during the reaction by a suitable hydroxy protecting group, for example by the Tetrahydropyranylrest, protected and released after completion of the reaction (see J. F. W. McOmie, Protective Groups in Organic Chemistry (1973), page 104). Free amino functions may occur during the reaction by a suitable amino-protecting group, for example by don Ethoxycarbonyl · or the tert-butoxycarbonyl, protected and after completion of the reaction by treatment with a

Reliable acids such as hydrochloric acid or trifluoroacetic acid are re-released (see Houben-Weyl, Methods of Organic Chemistry, Volume E4, page 144 [1983]; J.F.W. McOmie, Protective Groups in Organic Chemistry [1973], page 43).

To prepare the esters according to the invention, the underlying carboxylic acid is preferably present in excess Alcohol in the presence of strong acids such as sulfuric acid, anhydrous hydrogen chloride, methanesulfonic acid,

p-toluenesulfonic acid or acidic ion exchangers, at temperatures of about 20 ⁰ C to 200 ° C, preferably about 6O ⁰ C to 120 ° C reacted. The resulting water of reaction can also by azeotropic distillation with chloroform, carbon tetrachloride,

Benzene or toluene are removed. The preparation of esters also succeeds advantageously by heating the underlying acid with Dimethylformamiddialkylacetal in a solvent such as dimethylformamide. . The (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester used as a prodrug by reacting a Alkalisalzep the

basic carboxylic acid with 4-bromomethyl- or 4-chloromethyl-5-methyl-1,.. - dioxol-2-one in a solvent such as

Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or Iutramethylurea at temperatures

from about O ⁰ C to 100 ⁰ C, preferably O ⁰ C to 50 ⁰ C, obtained.

The preparation of the acid addition salts of the compounds according to the invention takes place in the usual way, for example by Dissolving the betaine in excess aqueous acid and precipitating the salt with a water-miscible organic Solvents such as methanol, ethanol, acetone, acetonitrile. You can also use equivalent amounts of betaine and acid in water or

Heat an alcohol such as glycol monomethyl ether and then evaporate to dryness or the precipitated salt. Examples of suitable pharmaceutically acceptable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid,

Glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-tolucylsulfonic acid, Galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in

submerged alkali or alkaline earth liquor, filtration of undissolved betaine and evaporation of the filtrate to dryness

receive. Pharmaceutically suitable are sodium, potassium or calcium salts. By reacting an alkali or alkaline earth metal salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.

In addition to the active ingredients mentioned in the examples, the compounds listed by way of example in Table 1 can likewise be prepared, these compounds being able to be present both as diastereomeric mixtures and as diastereomerically pure or enantiomerically pure compounds.

The compounds according to the invention exhibit, with low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative bacteria, in particular against enterobacteriaceae; especially against those that are resistant to various antibiotics, such. Penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

These valuable properties enable their use as chemotherapeutic agents in medicine as well as substances for the preservation of inorganic and organic materials, especially organic materials of all kinds,

z. As polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The compounds of the invention are effective against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled and the diseases caused by these pathogens prevented, ameliorated and / or cured.

The compounds of the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.

For example, local and / or systemic diseases caused and / or prevented by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:

Gram-positive cocci, z. Staphylococci (Staph aureus, Staph epidermidis) and streptococci (Strept agalactiae, Strept.

faecalis, Strept. pneumoniae, Strept. pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) as well as gram-resistant rods such as enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.friendii, Citrob. Divernis), Salmonella and Shigella; Klebsiella (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerate), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudomonas (Ps. Aeruginosa, Ps. Maltophilia) and strictly anaerobic bacteria such. B. Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, e.g. B.

Mycobacterium tuberculosis.

The above enumeration of pathogens is merely exemplary and by no means limiting. As diseases caused by said pathogens or mixed infections and prevented by the compounds of the invention,

be cured or cured, may be mentioned for example:

Human infectious diseases such as otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis (acute, chronic), septic infections, upper respiratory tract diseases, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, abscess abscesses , Urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth, infections after ten operations, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid fever, meningitis and nervous system infections, salpingitis, endometritis, genital infections, pelvic peritonitis and eye infections.

Apart from humans, bacterial infections can also be treated in other species. Examples include:

Pig: coli-diarrhea, enterotoxemia, sepsis, dysentery, sslmonellosis, mastitis metritis agalactia syndrome, mastitis; Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

Horse: bronchopneumonia, foal disease, puerperal and postpuerperal infections, salmonellosis; Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary infections, prostatitis; Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Likewise, bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, the antibacterial spectrum on the aforementioned pathogens on other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia, Yersinia, expanded.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and also processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, e.g. Tablets, Dragoes, capsules, pills, suppositories and ampoules are present, whose active substance content corresponds to a fraction or a multiple of a single dose. The dosage units may be e.g. 1,2,3 or 4 single doses or V2, Va or '/ 4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

By non-toxic, inert pharmaceutically acceptable excipients are meant solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind 7U.

Preferred pharmaceutical preparations selenium tablets, Dragoes, capsules, pills, granules, called supposito ^r ies, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, dragees, capsules, pills and granules may contain the active ingredient (s) in addition to the usual excipients, such as (a) fillers and extenders, e.g. Starches, lactose, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g.

Carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. Glycerol, (d) disintegrants, e.g.

Ag3r agar, calcium carbonate and sodium carbonate, (β) solution delayers, e.g. Paraffin and (f) sorption accelerators, z.

quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl-a.kohol, glycerol monostearate, (h) adsorbents, e.g.

Kaolin and bentonite and (i) lubricants e.g. Talc, calcium and magnesium atearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, crags, capsules, pills and granules can be mixed with the usual, optionally opacifying

be provided coatings and shells and also be composed so that they deliver the or din agents only or preferably delayed in a certain part of the intestinal tract optionally delayed, as Einottottungsmassen z. B.

Polymer substances and waxes can be used. The active ingredient (s) may optionally also be incorporated with one or more of the excipients listed above

microencapsulated form.

Suppositories may contain the usual water-soluble or water-insoluble excipients in addition to the active substance (s)

included, for. As polyethylene glycols, fats, z. Cacao fat and higher esters (eg. B. C _l4 alcohol _ie with -Fettsöure C), or mixtures

of these substances.

Ointments, pastes, creams and gels, in addition to the active ingredient or the usual excipients may contain, for. B. animal and

vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid,

Talc and zinc oxide or mixtures of these substances. Powders and sprays can lead in addition to the active ingredient or the usual excipients entl, z. B. lactose, talc, Silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances, sprays may additionally

customary propellant, z. For example, chlorofluorocarbons.

Solutions and emulsions may contain, in addition to the active substance (s), the usual excipients such as solvents, Solubilizers and emulsifiers, eg. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, Corn oil, olive oil, Ricinusö! and sesame oil, glycerol, glycerol formal, te'rahydrofurfuryl alcohol, polyethylene glycols and Fatty acid esters of sorbitan or mixtures of these substances. For parenteral administration, the solutions and emulsions may also be present in sterile and blood isotonic form. Suspensions may contain, in addition to the active substance (s), the usual excipients such as liquid diluents, e.g. Water, Ethyl alcohol, propylene glycol, suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,

microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The formulation forms mentioned may also contain coloring agents, preservatives, and odorants

taste-improving additives, for. Peppermint oil and eucalyptus oil and sweeteners, e.g. For example, saccharin.

The therapeutically active compounds should preferably be described in the abovementioned pharmaceutical preparations in

a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95,% by weight of the total mixture.

The above-listed pharmaceutical preparations may, in addition to the compounds according to the invention also other

contain active pharmaceutical ingredients.

The preparation of the abovementioned pharmaceutical preparations is carried out in the customary manner by known methods,

z. B. by mixing the active substance or substances with the carrier or excipients.

The preparations mentioned can be administered either orally, rectally, parenterally (intravenously, intramuscularly, in humans and animals).

subcutaneous), intracisternal, intravaginal, intraperitoneal, local (powder, ointment, drops) and for the treatment of infections in

Cavities, body cavities are applied. Suitable preparations are injection solutions, solutions and Suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops in question. To the local Therapy may include ophthalmic and dermatological formulations, silver and other salts, ear drops, Eye ointments, powders or solutions are used. In animals, intake may also be via the food or drinking water in

suitable formulations take place.

Furthermore, gels, powders, powders, tablets, sustained-release tablets, premixes, concentrates, granules, pellets, tablets, capsules, Aerosols, sprays, inhalants are used in humans and animals. Furthermore, the compounds according to the invention can be described in

other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement

be incorporated.

In general, it has proved to be advantageous in both human and veterinary medicine

Agents according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight per 24 hours, optionally in the form of several single doses, to achieve the desired results. A

Single administration contains the active substance (s) according to the invention preferably in amounts of about 1 to about 80, in particular

3 to 30mg / kg body weight. However, it may be necessary to deviate from the stated dosages, in

Depending on the type and body weight of the object to be treated, the nature and severity of the disease, the Type of preparation and administration of the medicine and the period or interval within which the Administered. Thus, in some cases it may be sufficient to manage with less than the above-mentioned Monge agent while in

other cases, the above-mentioned amount of active ingredient must be exceeded. The definition of the respectively required optimum dosage and mode of administration of the active ingredients can easily be made by any person skilled in the art on the basis of his specialist knowledge

respectively.

The new compounds may in the usual concentrations and preparations together with the feed or with Feed preparations or be given with the drinking water. This can cause an infection by gram-negative or

Gram-positive bacteria prevents, ameliorates and / or heals and thereby promotes growth and growth

Improvement of the utilization of the feed can be achieved. Minimum inhibitory concentrations (MIC) were determined by serial dilution on Iso-Sensitest Agar (Oxoid)

certainly. For each test substance, a series of agar plates were prepared, each falling at double dilution

Concentrations of the drug contained. The agar plates were inoculated with a multipoint inoculator (Denley). To the Inoculation was used on overnight cultures of the pathogens, which were previously diluted so that each inoculation point was about 10 ⁴

containing colony forming particles. The inoculated agar plates were incubated at 37 ° C and seed growth was observed after ca.

20 hours read. The MIC value (Mg / ml) indicates the lowest drug concentration, with no visible to the naked eye

Germ growth was evident.

CO

OS

(C

ro X U

ro X U

co χ υ

ro

X U

Q ζ) Ö

in X

N ro ro X υ

ro X U

ro X υ

in in I Il X X CM CM U ^ J U I

Table 1 (continued)

HO-CH ₂ CH ₂ -

'2 "S

-CH-

CH.

N / A N

na | N-

NvI N-

NvT N-

NvV N-

CH,

NJ

HN / N-

CH, CH, ^C 2 «5

^C 2 ^H 5

CH, CH, CH-C ₂ H ₅

H H H

H F

M (D OO

Table 1 (continued)

F-CH ₂ -CH ₂

H ₂ -N / N-

N _n J N-CH ₃

Νλ / N-

CHr

CH-

thj

N \ J N-

CHr

CHRCHR

CHr

CHr

^C 2 ^H 5

CHr ^C 2 ^H 5

CHr

CN

Cl

Cl

CHr

N) (O OO

Table 1 (continued)

CH ₃ O-

CH ₃ -NH-

N-

, Nl N-

CH

CH ₃ NI N-

HN / N-Y /

HN / N- \ Z /

HN / N-

CH-CH,

CH, CH, CH,

^C 2 ^H 5

CH,

NO-

br

CN

CN

hi (O OO

Table 1 (continued)

^C 2 ^H 5 ^C 2 ^H 5

C ₂ H ₅

RYT

N ~ H

00-

N-

N-

N-

CH.

CH-

CH-

CH:

CH-

CH,

ro co oo

Table 1 (continued)

-CH = CH ₂

HO-CH ₂ CH ₂ -

CH-

CH-

N-

N-

N-

N-

N-

CO

N-

CH-

^C 2 ^H 5CH,

CH,

CH, CH, CH,

Cl

Cl

M (O OO

Table 1 (continued)

-CH-

CO

co

-2 ^M 5

^C 2 ^H 5

^C 2 ^H 5

CH-CH-

Cl

CN

NO-

Table 1 (continued)

H ₃ C

N-

N-

N-

CH,

CH-

co-

N ~ H

N "H

CH, C ₃ H ₇ CH,

CH.

CH, CH, CH-

CH-

Cl

cj

χ υ

co χ υ

ω χ ο

cn

X U

ζ χ

ζ χ

ζ χ

Z X

Z X

CNJ

ο π χ ο

X Z

π X U

Table 1 (continued)

CH ₃ O

// a

V-

H ₂ N

-N-

N ^- H

CH-

N-

co-

CO

H ₂ N

CH,

CH, CK, CH,

CH,

Table 1 (continued)

^C 2 ^H 5

^C 2 ^H 5

H ₂ N \ w ^v

H ₂ N

H ₂ N

H ₂ N

^C 2 ^H 5

^C 2 ^H 5 CH-

Cl

Cl

Table 1 (continued)

" ^C 2 ^H 5

CH-

CHoOW ^^ N-

H ₂ N

H ₂ N

H ₂ N

H ₂ N

N-

CH-, Ο- ^ ν ^^ Ν-

CH ₃ -NH

CH-CH-CH-CH-CH, CH- ^C 2 ^H 5

Cl

Table 1 (continued)

CH-

Choo \ ^^ N-

^C 2 ^H 5

CHr

nC ₃ H ₇

Cl

Table 1 (Continued)

R ¹ R ² H O CH ₃ H R ³ R ⁴ A H |> H H CH ₃ CHt-NHCHo / N- ρ ·. H H CH ₃ ·· Cl · ^C 2 ^H 5 CH ₃ ·· F  · H CH ₃ ·· F H CH ₃ H CN ·. H Chg - F ^C 2 ^H 5 ~ CH ₃ F CH ₃ CH ₃ -NHCH _2n ^ N- _HQ XI F H CH ₃ C ₂ H ₅ -NHCH _2n / N- F CH ₃  · F · C2 ^H 5 · H ^C 2 ^H 5- CH ₃ ··

NJ (O OO

Table 1 (continued)

rl R ² H 0 R ³ R ⁴ ·· ·· A H -CH ₂ ^ Tt CH ₃ F ^C 2 ^H 5 0 CH ₃ C ₂ K ₅ -NHCH ₂ j IjT HO ^ ' CH ₃ > N-CH ₂ / -N- ^CH 3 XHO ^N ' F H ο- CH ₃ H CH ₃ CH ₃ ·· ^C 2 ^H 5 H · F ·· H H CH ₃ C ₂ H ₅ NH-CH ₂ ^ -N- CH ₃ O H F ** CH ₃ H _M CH ₃ F CH ₃ F Cl It CH ₃ H · CH ₃

Table 1 (continued)

rl R ² H R ³ R ⁴ ·· · A \> H CH ₃ C ₂ H ₅ -NH -CH ₂ , N-CH ₃ C-AJ ·· F ·· H CH ₃ ·· COHC-NH CHO / N CH ₃ SA-J ·· CI H CH ₃ C ₂ H ₅ -NH-CH _2n ZN-F ^> VJ ·· F ·· H ^C 2 ^H 5 , XH " F ·· H CH ₃ N H Cl ·· H CH ₃ CN  · H CH ₃ H ·· H CH ₃ F [> CH ₃ H H ·· H CH ₃ F ·· H ^C 2 ^H 5 F ·· H Π-CgHy F Il H CH ₃ Cl ·· CH ₃ F

IO (O OO

Table 1 (continued)

R ¹ R ² H H R ³ R ⁴ A H ·· H CH ₃ CH ₃ ·· NO ₂ CN F · H CH ₃ HO ^ ' F Il H CH ₃ H Il H CH ₃ Cl H CH ₃ (CH ₃ ) ₂ N-CH ₂ , - _s H ₂ O - ^ ^N " » CH ₃ ··

Table 1 (continued)

- ^C 2 ^H 5

-CH = CH-

HO-CH ₂ CH ₂ -

NnI n-

N> J N-

\ N

N / A N

NsI N-

NvT N-

CH-

CH-CH, CH, ^C 2 ^H 5

M (O OO

cn in (T) cn cn in cn CC X X X X X X N U U U N U U U

(M

ü ü y

χ υ

ΙΛ X

N U

Table 1 (continued)

F-CH ₂ -CH ₂

N-

CH-

H ^ -

CHr

- ^M 3

NJ

NxT N-

N-

CH-

CHrCoH

2 "5

NnT N-

CHr

C ₂ H ₅ CHrC ₂ H ₅ CHr

CHr

CN

Cl

Cl

CHr

CHr

N) (O OO

Table 1 (continued)

CH ₃ O-

CH ₃ -NH-

N-

CHON I N-

CH,

HN / N-

HN / N-

CH-CH,

CH, CH, CH,

^C 2 »5

NO-

br

CN

CN

co co co co co co co X X X X X X a, U U U U υ CJ

CM

co X U

z

2

Z X

m X

N U

in in X X N α U

ro in D ro π ro ω Ti X X X X χ χ χ α U M U υ U U U U

ro η X X U U

Il

X ι

O X

Table 1 (continued)

XT

N-

N-

CO

N-

00-

co-

CH, ^C 2 ^H 5 CoH.

^C 2 ^H 5 CH-CH-

Cl

CN

NO ₂

Table 1 (continued)

R ¹ R ² R ⁴ R ³ λ H ^H3C tX> Chg CH ₃ H H " ³¹ OO- C ₃ H ₇ H H H JCO CH ₃ F ^H 3 ^C ''> r ' ^^ H H Cb H ^CH 3 CH ₃ Cl H co- CH ₃ F-CH ₂ CH ₂ - H F

cn cn cn η η cn K X X X X X U υ U U U

U O b.

CVJ

Z X

Z X

Z X

Z X

X I Z O cn cn X X CJ U

Table 1 (continued)

CHr

N-

NT H

CHr

N "H

N-

H CHr

CH ₃ O

H ₂ N

N-

CHrCHrCHr

CHr

Cl

IO CD OO

Table 1 (continued)

T 1

CHr

CH,

CH-

N-

N-

CHoOV ^^ N-

LJ

CH-CH-.

CH-

CH-

Table 1 (continued)

^C 2 ^H 5

H ₂ N \\ w

H ₂ N

WV '

H ₂ N WN ^V '

H ₂ N

^C 2 ^H 5-2 "5 ^C 2 ^H 5CH-

Cl

Cl

IO (D OO

Table 1 (continued)

rl R ² R ⁴ R ³ A CH ₃ CH ₃ CJ ^ NH ₂ N Chg Cl H CHoOV - ^^ N- 1 t CH ₃ " ^C 2 ^H 5 H ₂ N F H CH ₃ / \ H ₂ N ^ F H CH ₃ ^ _N h ₂ ^nnS F H CHoCTv ^^^ N- ι ι CHg NH '' CH ₃ / \ H

CJI CJI I

N) (O OO

Table 1 (continued)

CHO]

CH ₃ -I

CH-

CH-

CH-

N-

CHoCrv ^^ M-

OI ι

CH-

^C 2 ^H 5

n-

Cl

Table 1 (continued)

R ¹ R ² H ρ H R ³ R ⁴ λ H |> H " ^cH 2 ~ czi H CH ₃ CH ₃ -NHCH ₂ / N- F H CH ₃ H CHO ·· Cl ·· ^C 2 ^H 5 CH ₃ ·· F ·· H CH ₃ ·· H F ·· H CH ₃ ·· H CN ·· CH ₃ ·· F ^C 2 ^H 5 "~ CH ₃ ·· F of CH ₃ CH ₃ -NHCH ₂ . / N- / \ I F H O- CH ₃ C ₂ H ₅ -NHCH _2n ^ N- F  · CH ₃ F '· ^C 2 ^H 5 H C ₂ H ₅ - CH ₃

Ii at le 1 (continued)

R ^! R ² H ^H 5 U R ³ C ₂ H ₅ R ⁴ ·· λ H Φ O O β CH ₃ F C ₂ ΐ ο ·· F ο- CH ₃ -NHCH ₇ / N ^ "XZi H [> CH ₃ CH ₃ F CH ₃ ^CH 3x ο- CH ₃ . · F - CH ₃ CH ₃ H ² N / I A. HO ^Ν ' H H CH ₃ ·· F H H Chg F Cl C ₂ H ₅ CH ₃

Table 1 (continued)

rl R ² H R ³ R ⁴ ·· A · H CH ₃  · H H CH ₃ C ₂ H ₅ -NH -CH ₂ ^ -N- CH ₃₀ Al F ·· H CH ₃ » ·· Cl  · H CH ₃ C ₂ H ₅ -NH-CH ₂ / N- F » H ^C 2 ^H 5 ·· F ·· H CH ₃ ·· Cl ·· H CH ₃ ·· CN ·· H H CH ₃ C ₂ H ₅ -NH -CH _2v y N-CH ₃ S ^ ' H CH ₃ CH ₃ F H H H CH ₃ » H ^C 2 ^H 5 O / N-Xj F » nC ₃ H ₇ H F ·· F

ro to co

Table 1 (continued)

rl R ² H R ³ R ⁴ λ ·· H CH ₃ ·· Cl ti H CH ₃ ^H2 "" ^C hoXIj " F " H CH ₃ NO ₂ H CH ₃ ·· CN · H CH ₃ H ₂ N-CH ₂ y V _n _ HO ^N ' F la H H CH ₃ H M O H CH ₃ CH ₃ (CH ₂ ) ₂ N-CH ₂ > s. Cl H ·· CH ₃ F

IO (O OO

Example A

8.0 g of i-cyclopropyl-e.e.sub.e.-tetrafluoro-i-dihydro-oxo-P-quinolinecarboxylic acid and 7.9 ml of thionyl chloride are boiled until no further gas escapes. Thereafter, it is concentrated in vacuo. The residue is added to 50 ml of ethanol and boiled for two hours.

It is cooled to room temperature and the precipitated solid is isolated. Yield: 8.6 g of ethyl 7-chloro-1-cyclopropyl-5,6,8-trifluoro-1/1-dihydro-1-oxo-S-quinolinecarboxylate

Melting point: 166-168 ⁰ C

EtOOC

00Et

In 50 ml of absolute dioxane is initially introduced 1.6 ml (0.015 mol) Cyanessigsäurenthylester and available at 2O ⁰ C 0.58 g sodium hydride (80% pure material) to. After 30 minutes, 3.45 g (0.01 mol) of substance from a) are added. Thereafter, it is refluxed for 6 hours.

After cooling to 2O ⁰ C is diluted with water and acidified with hydrochloric acid. The solid is isolated, dried and

recrystallized from isopropanol. Yield: 2,3g7-chloro-5- (cyano-ethoxycarbonylmethyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester Melting point: 156-157 ⁰ C.

COOH

COOH

2.3 g of substance from b) are heated together with 6 ml of acetic acid, 5 ml of water and 0.5 ml of sulfuric acid at 140 ⁰ C for 4 hours. It is cooled to 20 ⁰ C and diluted with water. The solid is isolated, washed with water and dried. Yield: 1,6g5-carboxymethyl-7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid Yield: 236-238 ⁰ C (Z)

Analysis:

C H N Cl calculated: 50.3 3.0 3.9 9.9 found: 50.5 3.2 3.7 10.0 50.6 3.2 3.8 9.9

CHQ

I w II

COOH

1.0 g (2.8 mmol) of substance c) and 0.9 g (8,4mmol) of 1,4-diazabicyclo [2.2.2] octane are heated in dimethylsulfoxide 2OmI 3 hours at 14O ⁰ C. Thereafter, the solvent is removed in a high vacuum and the residue on silica gel (mobile phase:

Methylene chloride / methanol 99/1).

Yield: 0,2g7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid Melting point: 195-197 ⁰ C.

example 1

CH ₃ OF X Jl COOH

0.56 g (2 mmol) of 1-cyclopropyl-e1 -difluoro-1-dihydro-S-methyl-oxo-S-quinolinecarboxylic acid are mixed with 0.384 g (3 mmol) of 2,8-diazabicyclo [4.3.0] nonane and 0.672 g (6 mmol) of 1,4-diazabicyclo [2.2.2] octane in 3.5 ml of dimethyl sulfoxide for 2 hours at 140 ° C heated. After cooling, the DMSO is removed under high vacuum. The residue is taken up in acetonitrile. The solid is separated, washed with acetonitrile and dried at 50-80 ⁰ C.

Yield: 0.7 g of 1-cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid melting point : 174-176T under decomposition

Example 2

CH ₃ OF λ 1 .COOH

0.28 g (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinollecarboxylic acid are dissolved in 3.5 ml of dimethyl sulfoxide with 0.19 g (1.5 mmol) of 2 -Oxa-5,8-diazabicyclo [4.3.0] nonane and 0.34 g (3 mmol) of 1,4-diazabicyclo- [2.2.2] octane are heated to 14O ⁰ C for 2 hours. The dimethyl sulfoxide is distilled off in a high vacuum. The residue is stirred with acetonitrile and the solid is isolated.

Yield: 0.27 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo -3-quinolinecarboxylic

Melting point: 273-275 ⁰ C

Example 3

CH ₃ O '

J A COOH

0.14 g (0.5 mmol) of i-cyclopropyl-e-difluoro-i-dihydro-o-methyl-oxo-S-quinolinecarboxylic acid are dissolved in 3.5 ml of dimethylsulfoxide with 0.084 g (0.75 mmol) of 2,7-diazabicyclo [3.3.0] octane and 0.17 g (1.5 mmol) of 1,4-diazabicyclo (2.2.2) octane for 2 hours at 14O ⁰ C heated. Thereafter, dimethyl sulfoxide is distilled off under high vacuum. To the residue is added acetonitrile, forming a solid.

Yield: 0.15 g of 1-cyclopropyl-7- (2,7-diazabicyclo3.3.0] oct-7-yl) -6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. Melting point: 232-234 ° C with decomposition

Example 4

CH ₃ -N

0.28 g (1 mmol) of i-cyclopropyl-ej-difluoro-i-dihydro-o-methyl-oxo-S-quinolinecarboxylic acid are dissolved in 3.5 ml of dimethyl sulfoxide with 0.213 g (1.5 mmol) of 5-methyl-3-oxo -5,8-diazabicyclo [4.3.0] nonane and 0.34 g (3 mmol) of 1-diazabicycloU ^^ loctan heated to 140 ° C for 2 hours. Thereafter, the solvent is removed in a high vacuum. After stirring the residue with acetonitrile, 0.22 g of i-cyclopropyl-B-fluoro-i-dihydroquinolinecarboxylic acid is obtained

 Lard: 208-210 ° C with decomposition

Example 5

CH ₃ O

COOH

0.28 g (1 mmol) of i-cyclopropyl-ej-difluoro-i-dihydro-o-methyl-oxo-S-quinolinecarboxylic acid are dissolved in 3.5 ml of dimethylsulfoxide with 0.17 g (1.5 mmol) of i.sup.- diazabicycloO.sub.2 Hoctane and 0.34 g (3 mmol) of 1,4-oiazabicyclo [2.2.2] octane for 2 hours on 14O ⁰ Cerhitzt. After removal of the solvent in a high vacuum, the residue is stirred with acetonitrile and the solid is isolated. Yield: 0.24 g of 1-cyclopropyl-7- (1,4-diazabicyclo3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. Melting point: 274-276 ⁰ C with decomposition

Example B

COOH

6,7-Difluoro-1- {2,4-difluoro-phenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolone-carboxylic acid a)

O CH ₃ Κ

C-C

21 g of 3-ethoxy-2- (2,4,5-trifluoro-6-methyl-benzoyl) -r.crylsäureethylester are presented in 55 ml of ethanol. Under cooling, 9.4 g of 2,4-Difiuoranilin are added dropwise. Thereafter, the mixture is stirred at 25 ⁰ C for one hour. 55 ml of water are then added and the precipitated solid is isolated.

Yield: 25g3- (2,4-Difluoro-phenylamino) -2- (2,4,5-trifluoro-6-methyl-benzoyl) -acrylsäureethyloster Melting point: 109-110 ⁰ C.

CH ₃ O

^{1 3} Il

COOEt

12.5 g of substance from a) and 5.1 g of potassium carbonate are heated to 140 ° C. for 4 hours in 60 ml of dimethylformamide. After cooling to room temperature, it is diluted with water. de; precipitated solid is isolated and dried. Yield: 11.3 g 6,7-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid ethyl ester Melting point: 157-159 ⁰ C.

^CH 3?,

COOH

11.2 g of substance from b), 70 ml of acetic acid, 70 ml of water and 3.5 ml of sulfuric acid are heated to 14O ⁰ C for 4 hours. After cooling to room temperature, diluted with Wassnr. The solid is isolated and dried. 10.3 g of the title compound are obtained. Melting point: 277-278X

Example β

COOH

0.6 g of the substance from example B, 0.57 g of 1,4-diazabicyclo [2.2.2] octane and 0.25 g of 2,8-diazabicyclo [4.3.0] -nonane are stirred in 6 ml of DMSO at room temperature until no starting material can be detected in the thin-layer chromatogram is. After that will

concentrated in vacuo. The residue is mixed with water and the solid is isolated.

Yield: 0.6g7- (2,8-diazabicyclo [4.3.0n-non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-5-methyl-4-oxo 3

quinolinecarboxylic.

Melting point: 247-248 ° C.

Claims (4)

claims: in which R ¹ C ₁ -C ₄ -alkyl which is unsubstituted or substituted by hydroxyl, halogen, C ₁ -C ₃ -alkoxy or C ₁ , C ₁ -C -cycloalkyl optionally substituted by halogen or C ₁ -C ₃ -alkyl, C ₁ - C ₄ alkyl, further C ₁ -C ₃ alkoxy, amino, monoalkylamine having 1-3 C atoms, dialkylamino and 2-6 C atoms or optionally substituted by halogen, phenyl, hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl is C ₁ -C ₄ -alkyl, for a in the ring system optionally substituted by hydroxy or methyl Remainder of the formula N- (CH ₂ ) J N-, N-, in which for R ⁵ -N, O, S,
for- (CH ₂ ) _r , -CH ₂ -O-CH ₂ -, for 1,2 or 3, is hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms, optionally substituted by nitro or amino-substituted benzyl, oxoalkyl having 2 to 4 carbon atoms or (5-methyl -) - 2-oxo-1,3-dioxol-4-yl) -methyl, is hydrogen or methyl, further a radical of the formula ^ - (CHg) _n , stands in which I for 0.1 or 2, m is furl odor 2, where I + m together may be 1,2 or 3, η for 1 or 2, for N, OR ⁹ , SR ⁹ , halogen or hydrogen, ^ R ⁸ for N, OR ⁹ , SR ⁹ , halogen, CN, CONH ₂ , COOH ^ ⁸ or C ₁ -C ₄ -alkyl, X ² and X ^{3 may be the} same or different and represent oxygen, sulfur, NH or N-CH ₃ , is hydrogen, C ₁ -C ₃ -alkyl, allyl or propargyl and is hydrogen, C ₁ -C ₃ -alkyl or C ₁ -C -cycloalkyl, where R ⁷ + R ⁸ together also the group-CH ₂ CH ₂ -O-CH ₂ CH ₂ -or- (CH ₂ ) _k -, in which k is 3,4 or 5, and is hydrogen, C ₁ -C ₃ -alkyl, OrOrC ₁ -C ₃ -acyl, hydrogen or C ₁ -C ₃ -alkyl, also a radical of the structure R ^{] C:} -pH Z-R 15 -N > 14 -N 16 16 -N 16 -hi I 13 means, in which R ¹¹ WrH ₁ C ₁ -C ₃ alkyl, ₁ C ₁ -C ₂ acyl R ^{12 is} H, C ₁ -C ₃ -alkyl, OH, OCH ₃ , where R ¹¹ and R ¹² together are also an optionally R ^{1 is} H, C ₁ -C ₃ -alkyl, aryl, heteroaryl, benzyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkyl or methyl-substituted or unsubstituted by C ₁ -C ₄ -alkylene for H is OdOrC ₁ -C ₄ -alkyl, for H, CH ₃ or phenyl, for H, CH ₃ or phenyl, for H "the CH ₃ , may be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, the linking of the CH ₂ -O-GrUpPe to nitrogen over both O and CH ₂ , O or S may be represents hydrogen, halogen, methyl, cyano or nitro or together with R ¹ a bridge dor structure -O-CH ₂ Ch-CH ₂ -S-CH ₂ -CH-CH ₃ OdOr-CH ₂ CH ₂ -CH-CH ₃ can form with R- or S-configuration and their pharmaceutically usable hydrates and acid addition salts and the alkali, alkaline earth, silver and Gusnidiniumsalze the underlying carboxylic acids. 2. Compounds of formula (I) according to claim 1, in which R ^{1 is} ethyl, isopropyl, cyclopropyl, vinyl, tert-butyl, 2-hydroxyethyl, 2-fluoroethyl, Amino, methylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl, R ^{2 is} hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl, R ^{3 is} C ₁ -C ₃ -alkyl R ^{4 is} optionally substituted by hydroxy or methyl in the ring system Remainder of the formula N - (CH ₂ ) J ^ N-, EU N-, E ^ Q ^ N-, E ^ in which E for R ⁶ -N, O, S, G Mr- (CH ₂ I _n -CH ₂ -O-CH ₂ ^ -CH ₂ -N-CH ₂ -, j for 1,2 or 3, R ^{5 is} hydrogen, optionally substituted by hydroxy alkyl, alkenyl or Alkynyl with 1 to 3 carbon atoms, optionally substituted by nitro or amino-substituted benzyl or oxoalkyl having 2 to 4 carbon atoms and R ^{6 is} hydrogen or methyl, R ⁴ furthermore represents a radical of the formula x ¹ jq (CHO) ₁ - « Nc · ι · 1 -X _R 1O stands in which, I for O, 1 or 2, m is 1 or 2, where I - * - m can be 1, 2 or 3 together, η for 1 or 2, R ⁷ W is N, OR ⁹ or hydrogen, R ⁷ X ¹ for N, OR ⁹ , fluorine, chlorine or C ₁ -C ₂ alkyl "^ ⁸ stands, X ² and X ^{3 may be} identical or different and represent oxygen, sulfur or N-CH ₃ , R ^{7 is} hydrogen, C ₁ -C ₂ -alkyl or acetyl, R ^{8 is} hydrogen OdOrC ₁ -C ₂ -alkyl, in which R ⁷ + R ⁸ also together form the group-CH ₂ CH ₂ -O-CH ₂ CH ₂ -or- (CH ₂ ) k-, in which k stands for 3,4, or 5, stands, stands, R ^{9 is} hydrogen, C ₁ -C ₂ alkyl or acetyl and R ^{10 is} hydrogen OdBrC ₁ -C ₂ -alkyl, also a rest of the structure ¹⁵ ZR ¹¹ ZR ¹ 15 12 -N 16 -ζ -N , 14 R Λ 15 -N ^ R 17 16 -N 13 means, in which for H, C ₁ -C 6 -alkyl, C ₁ -C ₂ -acyl is H, C ₁ -C ₃ -AIkYI, OH, OCH ₃ , wherein R ¹¹ and R ¹² together also represent an optionally monosubstituted by methyl or zeifach substituted Ci-C ₂ alkylene can mean for H, C ₁ -C ₃ -alkyl, hydroxyalkyl, phenyl, benzyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₂ -acyl or (5-methyl-2-oxo-1,3-dio-ol-4-yl) -methyl, for H or C ₁ -C ₂ -alkyl, for H or CH ₃ , for H or CH ₃ , for H or CH ₃ , may be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, the linking of the CH ₂ -O-GrUpPe to nitrogen both via O and via CH ₂ can take place, for O, represents H, fluorine, chlorine, methyl, cyano or nitro or together with R ¹ a Bridge of the structure -0-CH ₂ - ^ H-CH ₃ can form with R- or S-configuration. 3. Compounds of formula (I) according to claim 1, in which for ethyl, vinyl, t-butyl, cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methylamino, 4-fluorophenyl, 2,4-difluorophenyl, is hydrogen, alkyl having 1 to 2 carbon atoms, is C ₁ -C ₃ -alkyl for a in the ring system optionally substituted by methyl radical of the formula N- (CH ₂ ) J N-, EG N-, N-, EGN- in which for R ⁵ -N, for- (CH ₂ ) -, for1 or 2, is hydrogen, optionally substituted by hydroxy alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms, optionally substituted by nitro or amino-substituted benzyl or oxoalkyl having 2 to 4 carbon atoms and represents hydrogen or methyl, furthermore a radical of the formula (CHO) ₁ U (CHo) _n -W \ N ^ (CHO) " (CHO) ₁ - _R 10. (CHO) R ¹ -N "(CH ₂ J _n , where I for 0.1 or?., stands for 1 or 2, where I + m together can be 1,2 or 3, For!. for N, OR ⁹ , or hydrogen, for N, OR ⁹ , chloro or alkyl is ⁸ X ² and X ^{3 may be the} same or different and are oxygen or N-CH ₃ , R ^{7 is} hydrogen or methyl and R ^{8 is} hydrogen or methyl, in which R ⁷ + R ⁸ together also represent the groups -CH ₂ CHz-O-CH ₂ CH ₂ - or - (CH ₂ ) _k -, in which k can be 3,4 or 5, and for hydrogen, C ₁ C ₃ alkyl or C ₁ -C ₃ acyl, represents hydrogen or C ₁ -C ₃ alkyl, also a residue of the structure 15 -pH Z-R 15 15 -N 12 , 14 16 -N ^ R 17 13 16 13 means, in which R ^{11 is} H, C ₁ -C ₂ alkyl, acetyl, R ^{12 is} H, C ₁ -C ₂ alkyl, wherein R ¹¹ and R ¹² together are also optionally substituted by Methyl-substituted C ₁ -C ₂ -alkylene bridge, for H, C ₁ -C ₂ -alkyl, hydroxyethyl, benzyl, C ₁ -C ₂ -alkoxycarbonyl, C ₁ -C ₂ -acyl, for H or CH ₃ , for H or CH ₃ , for H or CH ₃ , for H or CH ₃ , O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, where the linking of the CH ₂ -O-groups to the nitrogen can take place both via O and via CH ₂ , can stand for O, R ¹³ R ¹⁴ R ¹⁵ R ¹⁶ R ¹⁷ Y A represents H, fluorine or chlorine, or together with R ¹ a bridge of the structure Can form -O-CH ₂ -CH-CH ₃ with R- or S-configuration. 4. Process for the preparation of compounds of the formula (I) according to Claim 1, characterized in that compounds of the formula (II) COOF ² in which R ¹ , R ² , R ³ and A have the meaning given in claim 1 and X ^{4 is} halogen, in particular fluorine or chlorine, with compounds of the formula (III)