DD285601A5 - PROCESS FOR PREPARING 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of * and naphthyridone-carboxylic acid derivatives. According to the invention, compounds of the formula (I) are prepared in which R1, R2, R3, X1, X2 and A have the meaning given in the description and the claims. Formula (I) {new compounds; broad antibacterial spectrum; gray-positive, gray negative germs; Enterobacteriaceae; Application Medicines Human and Animal Medicine}

Description

2eu

Method zui. Preparation of 7- (1-pyrrolidinyl) -3-quinolone and naphthyridonecarboxylic acid derivatives

Field of application of the invention

The invention relates to a process for the preparation of novel 7- (1-pyrroldinyl) -3-quinolone and -naphthyridoncarboxylic acid derivatives and to antibacterial agents and feed additives containing them.

Characteristic of the known state of the art

A number of 3-quinolone and naphthyridonecarboxylic acids have already been disclosed, which are substituted in the 7-position by a pyrrolidinyl ring. DE patent application 3 318 145, EP patent applications ICS 489 and, 153 826.

Object of the invention

The aim of the invention is the provision of new compounds with strong antibacterial Wirkmig.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and methods for their production.

It has been found that the 7- (1-pyrrolidinyl) -3-quinolene and naphthyridonecarboxylic acid derivatives of the formula (I)

R LE a 26 108-Foreign countries

COOR '

(D,

2BS6 O]

⁵ in which

X ¹ for halogen, X ^{2 is} hydrogen, amino, alkylamino of 1 to 4

Carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxy, alkoxy having up to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms, arylthio, halogen,

R ^{1 is} alkyl of 1 to 4 carbon atoms, alkenyl

having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethylamino, optionally phenyl substituted by 1 or 2 fluorine atoms,

R ^{2 is} hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-l, 3-dioxol-4-yl) -methyl,

R ^{3 is} a residue of the structure

R ¹ ZR

-R ⁴

-N

R "

-N

R ¹

> -R ⁷ , -N

R "

-7

Le A 26 108

285 ^ O ί

stands «in which 5

R ^{4 is} H, C ₁ -C ₄ alkyl, aryl, C ₁ -C ₄ acyl R ^{5 is} H ₁ C ₁ -C ₄ -alkyl, OH, OCH ₃ , where R ⁴ and R ⁵

together also, if necessary, by

10 methyl mono- or di-substituted C ₁ -C ₃ -

Alkylene bridge can mean

R ° is H, optionally substituted by hydroxy C ₁ -C ₄ -AlKyI, and aryl, heteroaryl, benzyl, 15 C ^ C ^ -alkoxycarbonyl, C ₁ -C ₄ -acyl, (5-

Methyl-2-oxo-1,3-dioxol-4-yl) -methyl or C ₃ -C ₆ -cyclo-acyl,

R ^{7 is} H or C ₁ -C ₄ -alkyl, 20

R ^{1 is} H, CH ₃ or phenyl,

R "is H, CH ₃ or phenyl, R"'is H or CH ₃ ,

Y can be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, where the linking of the CH ₂ -, group to the nitrogen can take place both via O and via CH ₂ 30,

Z can stand for 0 or S,

A is N or CR ⁸ , wherein 35

Le A 26 108

2 8 5 i O \

R ⁸ for H "halogen, methyl, cyano, nitro, hydroxy or methoxy eteht or together with R ¹ a bridge of the structure

Can form -O-CH ₂ -CH-CH ₃ , -S-CH ₂ -CH-CH ₃ or -CH ₂ -CH ₂ -CH-! H ₃ ,

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

Preference is given to the compounds of the formula (I)

(I)

in which

X ¹ for fluorine or chlorine,

Le A 26 108

for WdTerstoff, amino, alkyl amino having 1 to carbon atoms, dimethylamines, hydroxy, methoxy, mercapto, methylthio, phenylthio, fluorine, chlorine,

for alkyl having 1 to 3 carbon atoms, alkenyl having 2 to 3 carbon atoms, cycloalkyl having 3 to 5 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethylamino, phenyl optionally substituted by 1 or 2 fluorine atoms,

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

for a remainder of the structure R ¹ ZR ⁴ R '

stands in which

for H, C ₁ -C ₃ -alkyl,

for H, C ₁ -C ₃ -alkyl OH, OCH ₃ , where R ⁴ and R ^{5 may} together also denote a C ₁ -C ₂ -alkylene bridge which is optionally monosubstituted or disubstituted by methyl,

Le A 26 108

R ^ for Η «optionally substituted by hydroxy-substituted C ₁ -C ₃ -AlRyI, and phenyl, benzyl, C ₁ -C

Alkoxycarbonyl, C ₁ -C ₂ -acyl, (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl or C ₃ -C ₅ -cycloalkyl

alkyl,

R ^{7 is} H or C ₁ -C ₂ R ^{1 is} H or CH ₃ ,

R "for H or CH ₃ , 15

R "'for H or CH ₃ ,

Y may be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, linking the CH ₂ O group to the nitrogen over both O and CH ₂

can be done

Z may be O or S, α is N or CR ⁸ , wherein

R ^{8 is} H, fluorine, chlorine, bromine, methyl, N'tro,

Hydroxy or methoxy eteht or together with R ¹ a bridge of structure 30th

-O-CH ₂ -CH-CH ₃ ,

can form, Le A 26 108

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

0OR '

in which

X ¹ for fluorine,

X ^ is hydrogen, amino, methylamino, fluoro, R ^{1 is} alkyl of 1 to 2 carbon atoms, vinyl,

Cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, methylamino, 4-fluorophenyl, 2,4-difluorophenyl,

R ^{2 is} hydrogen, alkyl having 1 to 2 carbon atoms,

r3 for a remainder of the structure

R ¹ ZR

-R ⁴

R "R ¹

> -r ⁷ , -ν

R "

R "

RIl I

Le A 26 108

in which 5

F ⁴ for H, C ₁ -C ₂ -Al) CyI ₁ acetyl,

R ⁵ is H, Cj-Cg-alkyl, wherein R ⁴ and R ⁵ may represent ₁ -C ₂ alkylene bridge and an optionally-substituted by methyl substitutable ¹⁰ C together,

R ^{6 is} H, CH ₃ , C ₂ H ₅ , HIGH ₂ CH ₂ , benzyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₂ -acyl,

R7 is H or CH _3, R 'is H or CH _3,

R "for H or CH ₃ , 20

R "'for H or CH ₃ ,

Y may be O, CH ₂ , CH ₂ CH ₂ or CH ₂ -O, linking the CH ₂ O group to the nitrogen over both O and CH ₂

can be done

Z can be O or S, A is N or CR ⁸ , where

R ⁸ for H, fluorine or chlorine,

or also common with R ¹ a bridge of structure 35

Le A 2 6 108

_ ₉ . 2 8 5 * 01

-O-CH ₂ -CH-CH ₃ ,

can form.

It has furthermore been found that the compounds of the formula (I) are obtained when compounds of the formula

¹⁵ , xu, _coor2

(II)

in which

R, R, X and X ² are as defined above and

X ^{3 is} halogen, in particular fluorine or chlorine,

with compounds of the formula (III)

R ³ -H (III),

in which

Le A 26

- 10 -

R ^{3 has} the abovementioned meaning, 5 optionally in the presence of acid scavengers, and optionally cleaved in R protecting groups (Method A).

Compounds of the formula (I) according to the invention

COOR '

in which

X, R, R ι R and A have the abovementioned meaning and

X ^{2 is} amino, alkylamino having 1 to 4 carbon atoms "dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms or arylthio,

can also be obtained by reacting a compound of the formula (IV)

Le A 26

- 11 -

285

(IV),

in which

X, Rj R, R ^ and A have the abovementioned meaning 15 with compounds of the formula (V)

X ² -H (V),

in which

X has the abovementioned meaning, if appropriate in the presence of acid scavengers (Method B),

Invention Compounds of Formula (Ia)

COOR ²

(Ie), 30

in which 35

Le A 26

X, X ² , R ¹ , R ² and A have the abovementioned meaning and R ^{3 is} a structure of the structure

R ¹ _ I ZR ⁴ R ¹ _Λ ι / i -N> u / I -N \ ι 10 I R " R ⁶ I R " stands. wherein

R ⁴ , R ⁵ , R ⁶ , R ", R", R " ¹ , Y and Z have the abovementioned meaning,

can also be obtained »by reacting a compound of the formula (VI)

COOR ²

(VI)

in which

X ¹ , X ² , R ¹ , R ² and A have the abovementioned meaning and

R ^3a for a remainder of structure 35

Le A 26

- 13 -

R ¹ ZR ⁴ R ¹

/ H ί / H

-N or -N

HL ⁵ H

stands,

wherein R ⁴ , R ⁵ , R '_# R ", R" ¹ , Y and Z are as defined above, 15

with compounds of the formula (VII)

_R 6_ _x a (VII), 20 in which

R "has the meaning given above and

X ^{a is} chlorine, bromine, iodine, hydroxy or acyloxy, 25

if appropriate in the presence of acid scavengers (Method C).

If, for example, l-cyclopropyl-6,7,8-trifluoro-1 ^ -dihydro-A-oxo-S-quinolinecarboxylic acid and i-methyl-octahydropyr: * ol0C3,4-b] pyridine are used as starting materials, the course of the reaction can be carried out by the following formula scheme are reproduced:

La A 26 108

8th

- 14 -

COOH

base

NH ►

RF

COOH

For example, using 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and cis-3-tert-butoxycarboxynyl-4- methoxy-pyrrnlidine as starting materials, the course of the reaction can be represented by the following formula:

Le A 26 108

801 92 y

HOOD

, > ΗΝ-00-0-Ο ^ε ( ^ε ΗΟ)

TDH

HOOD.

IDH

eseg

ΗΝ-ΟΟ-Ο-Ο ^ε ( ^ε ΗΟ)

Ο ^ε ΗΟ HOOD.

- ST S 8

- 16 -

5 * 01

For example, use is made of 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (2-methyl-2,7-diazabicycloC3.3.0] oct-3-yl) -4-oxo-3-quinolinecarboxylic acid and ammonia as starting materials, the reaction sequence can be represented by the following formula:

^NH 2 j}

For example, use is made of 1-cyclopropyl -? - (2,7-ciiazabicycloC3,3.0] oct-7-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and ethanol / hydrogen chloride as starting materials the course of the reaction can be represented by the following formula:

Le A 26 108

- 17 -

285 6

COOH HCl

^2H5 <

COOC ₂ H ₅

x HCl

The compounds of the formula (II) used are all known or can be prepared by known methods.

7-Chloro-1-CyClOPrOPyI-O-TlUOr-I, 4-dihydro-4-oxo-3-cinnin-1-carboxylic acid (German Patent Application 3,142,854).

1-Cyclopropyl-6,7-difluoro-1-dihydro-3-oxo-S-quinolinecarboxylic acid (European Patent Application 113 091),

6-Chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743), 35

Le A 26 108

- 18 -

e-chloro-1-cyclopropyl-o, 7-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743),

l-cyclopropyl-6,7,8-trifluoro-l, 4-dihydro-4-oxo-3-quino). incarbone acid (German Patent Application 10 3 318 145),

6,8-Di-chloro-1-eyeprophoty1-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743), 15

l-cyclopropyl-6,7-difluoro-l, 4-dihydro-8-methy1-4-oxo-3-chinolincarboneäure,

1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-chinolincarboneäure,

6,7-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-l-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1,4-dihydro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid, 30

6,7-difluoro-1- (2-fluoreLhyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

8-chloro-l- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-3b oxo-3-quinolinecarboxylic acid (European Patent Application 235,762),

Le A 26 108

8 5 * 01

- 19 -

7-chloro-6-fluoro-l, 4-dihydro-l-raethoxy-4-oxo-3-quinolinecarboxylic acid "

7-chloro-6-fluoro-1, 4-dihydro-1-methyl thyaryloM-oxo-S-quinoline arbonic acid,

6,7-difluoro-l, 4-dihydro-4-oxo-l-phenyl-3-chinolincarbonsaure,

Z-chloro-1-cyclopropyl-o-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 15

e ^ -dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

Ethyl l-cyclopropyl-6,7,8-trifluoro-l _} 4-dihydro-4-oxo-3-quinolinecarboxylate (German Patent Application 3,318,145),

9,10-Difluoro-2,3-dihydro-3-niethyl-7-oxo-7H-pyrido [l, 2,3-de] Cl, 4] benzoxacine-6-carboxylic acid (European Patent Application 47 005),

8,9-di-fluoro-6,7-dihydro-5-methyl-1-oxo-IH, 5H-benzoCi, j] -quinolyn-2-carboxylic acid,

7-chloro-6-fluoro-1-phenyl-1 ', 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (European Patent Application 153 580),

7-Chloro-6-fluoro-1- (4-fluorophenyl) -l, 4-dihydro-4-oxo-1,8-naphthydrin-3-carboxylic acid (European Patent Application 153 580),

Le A 2 6 108

2856

- 20 -

6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-5-quinolinecarboxylic acid (German Patent Application 3,409,922),

1-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,409,922) »10

6,7,8-trifluoro-1,4-dihydro-1-dimethylamino-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,409,922),

7-chloro-6-fluoro-l, 4-dihydro-8-nitro-4-oxo-I-phenyl-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1- (4-fluorophenyl) -l, 4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid, 20

6,7-difluoro-l- (4-fluorophenyl) -l, 4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid,

6-chloro-7-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 131 839),

5,6,7,8-Tetrafluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30

5,7-dichloro-6-fluoro-1- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid,

5,7-dichloro-l-cyclopropyl-6-fluoro ~ l, 4-dihydro-4-oxo-3-chinolincarboneäure,

Le A 26 108

2 8 5

- 21 -

6-chloro-7-fluoro-1- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-5-3-quinolinecarboxylic acid (European Patent Application 131 839),

6,7,8-trifluoro-1- (4-fluorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 10 154 780),

6,7,8-trifluoro-1- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 154,780), 15

6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid (European Patent Application 154,780),

7-chloro-l-ethyl-6-fluoro-l, 4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic acid,

6,7-Difluoro-1,4-dihydro-4-oxo-1-vinyl-3-quinolinecarboxylic acid, 25

1-Cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quineararboxylic acid,

5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-30 3-quinolinecarboxylic acid,

l-cyclopropyl-6,7,8-trifluoro-l, 4-dihydro-5-hydroxy-4-oxo-3-quinolinecarboxylic acid,

35 l-Cyclopropyl-6- »7-difluoro-l, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

Le A 2 6 108

- 22 -

2856

The compounds of the formula (III) used as starting compounds are partly new. They can be manufactured according to the following procedures «

1 »Starting from the N-carbonated 3,4-epoxypyrrolidine

(1) (German Offenlegungsschrift 1,929,237, US Pat. No. 4,254,135), which may optionally carry one or two methyl or phenyl radicals, »the starting compounds of the formula (IIIa) - (IIe) are obtained.

15 20 25

T 9 HN 3 base Ϊ - \ Schutζgruppen splitting H 1) C - τ *** (IIIb) ^ N ι R ⁴ XR ⁴ O ₁ R ⁹ I R ( R ⁴ O Protecting Group * R ⁵ Cleavage vr6

HQ,

H (Ilia)

30 35

Le A 26 108

- 23 -

8 5 6

R ^ = benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkyloyl, sulfonyl (examples of protecting groups),

X ³ - leaving group such as halogen, alkyl or arylsulfone

onyloxy

N.

(1)

HO (ι ν * ---- itfN o

Ι Π ^J d4 _y 3

base

""»< - ^ NH ₂ R ⁴ 0 ^^ ^ fNH

-COOC (CH ₃ )

H (IHc)

R ⁴ O "

(1)

OH

" ¹ XT" ¹

Le A 26 108

- 24 -

HR ⁶ R ⁴ Ob-

H ₂ / Pd

(IIIe)

H ₂ ZPd

R ⁴ CA.

- NH-R ⁶

I (HId) H

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

Cl

HO Cl ^V 'R ⁴ O "

R ⁴ O

OH

R ⁴ O

Le A 26

8 5 0

- 25 -

R ¹¹ ON ν /

R ^q 0 N ν /

H (IHf)

3. By addition of azides to optionally substituted with one or two methyl or phenyl radicals N-Benzylmaleinimide outer compounds of the formula (III g) can be prepared i

R-

reduction

Le A 26 108

- 26 -

(NIG)

R ¹⁰ = H, alkyl, benzyl.

4, From the 3,4-Epoxypyrrolidinen (1) is obtained via a cyclization with thionyl chloride, the outer compounds of formula (III h)!

HO "*», "rfNH-CO"

(1) ► \ N ^ ► \ N ^ SOCi ₂

R ⁷ R ⁷

R ⁹ H

(III h)

5. By reacting the 3,4-Epoxypyrrolidine (1) with ethanolamines obtained by intramolecular etherification the Auegangeverbindungen of formula (III i):

Le A 26

- 27 -

2 8 S 4 O 1

HO N

HO

(1)

O NR ⁶ N

- ♦ O N-R

-R ⁶

H (III i).

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

H ₂ N

R '

OCH

base

R ⁹ -N 30 R '

R ⁶ -NH-OH

R '

Le A 26

2856

- 28 -

R '·

R ¹ ·

R * H

(III j)

7, Starting from pyridine-2> 3-dicarboxylic acid N-benzylimide, starting compounds (III k) or (III 1) are prepared via the stated reaction steps,

Alkyl iodide

N-CH ₂ -C ₆ H ₅

OIH ₂ / Ru-C o-ler Pd-C

N-CH ₂ -C ₆ H ₅

I ^H

₂ / pto ₂

N-CH ₂ -C ₆ H ₅

N-CH ₂ -C ₆ H ₅

ILiAlH ₄ or NaBH ₄ / BF ₃ * 7C ₂ H ₅ ) ₂ O

N-CH ₂ -C ₆ H ₅

Le A 26

2δ S 6 O 1

LiAlH ₄

H ₂ / Pd-C

N-CH ₂ -C ₆ H ₅

alkyl

H ₂ / Pd-C

NH

(III 1)

NH

alkyl

(III k)

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

N-CH ₂ -C ₆ H ₅ + Cl-CH ₂ CH ₂ -NH-I O

Cl I Γ "<

^CH 2. ^N '~ ^CH 2 ^C 6 ^H 5

I / V

CH ₂ -N

Close

N "

H ₅ LiAlH ₄

-CH ₂ -C ₆ H ₅

L- 3 A 26

- 30 -

2B56 0 f

Ho / Pd-C

(III m)

9 »2-methyl-2-propenal-dimethylhydrazone reacts with N-benzylmaleimide to give a cycloadduct, which can be converted into the starting compound (III η) according to the reaction sequence indicated.

N-CH ₂ -Ph

N-CH ₂ -Ph

CH _;

- (CH ₃ ) ₂ NH ₃ CH

N-CHO-Ph

H ₂ / Kata-CH ₃ lyeator

N-CH ₇ Ph

LiAlH ₄

H ₂ / Pd-C .CH;

(III n)

NH

Le A 26

- 31 -

285 6 O y

10 · Auegangeverbindungen of the formulas (HIo), (IHp) 5 or (HIq) can be obtained starting from N-protected 2,5-dihydropyrroles (3-pyrrolines) by addition SuIfensäurechloriden in the following ways:

+ R ⁿ -S Cl

Clv

5-pll

1. + R ⁶ -NH ₂ (R ¹¹ = CH ₂ CH ₂ -Hal)

2, cleavage of R ⁹

+ NH R

R ⁶ -NS

N-H

(HIO)

-pH

'S-R

R ^e

(Hip)

Splitting of R **

(R ¹¹ = acyl, alkoxycarbonyl)

H (HIq)

; R11

optionally C ₁ -C 12 -alkyl substituted by halogen, phenyl optionally substituted by halogen, nitro, alkyl and alkoxy, and also acyl, alkoxycarbonyl.

Le A 26

- 32 -

According to this formula scheme, for example, the following ⁵ Auegangeverbindungen be produced. They can be produced and used as a dietetic acid, in diastereomerically pure and also enantionmer-pure form «

4-Amino-3-hydroxypyrrolidinol 3-hydroxy-4-methylaminopyrrolidine, 4-dimethylamino-3-hydroxypyrrolidine, 4-ethylamino-3-hydroxypyrrolidine, 3-amino-4-methoxypyrrolidine, 4-methoxy-3-methylaminopyrrolidine, 3-dimethylamino 4-methoxypyrrolidine, 3-ethylamino-4-methoxypyrrolidine, 3-amino-4-ethoxypyrrolidine, 4-etboxy-3-methylaminopyrrolidine, 3-dimethylamino-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-l, 3-dioxol-4-yl) methyl

amino) -pyrrolidine,

3-amino-4-methylmercaptopyrrolidine, 3-acetoxy-4-dimethylaminopyrrolidine, 3-acetamido-4-methoxypyrrolidine, 4-methoxy-3-tnethoxycarbonylaminopyrrolidine,

Le A 26 108

- 33 -

3-formamido-4-methoxypyrrolidine, 3-amino-4-methoxy-2-methylpyrrolidine, 3-amino-4-methoxy-5-methylpyrrolidine, 4-methoxy-2-methyl-3-methylaminopyrrole-idine, 4-methoxy-5 -methyl-3-methylaminopyrrolidine, 3-amino-4-methoxy-2-phenylpyrrolidine, 4-methoxy-3-methylamino-5-phenylpyrrolidine, 3-methyl-2,7-diazabicycloC.3.3.0] octane, 4-methyl 2,7-dia2a-bicycloC3,3,0] octane, 5-methyl-2,7-diazabicyclo [3.3.0 3octane, 3,5-dimethyl-2,7-diazabicyclo [3.3,03octane, 1,5-dimethyl-2 , 7-diazabicycloC3.3.0] octane, 2-oxa-4,7-diazabicyclo [3.3.0] octane, 3,3-dimethyl-2-oxa-4,7-diazabicyclo [3.3i0] octane, 3- Oxa-2,7-diazabicyclo [3.3, ODoctane, 1,2-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane, 2,5-dimethyl-3-oxa-2,7-diazabicyclo [ 3,3,0] octane, 2,8-dimethyl-3-oxo-2,7-diazabicyclo [3.3.0] octane, 5-methyl-3-oxa-2,7-diazabicycloC3.3.0 3octane, 2-oxa 4,7-diazabicyclo [3.3.0 3oct-3-ene, 3-methyl-2-oxa-4,7-diazabicycloC3,3.0] oct-3-ene, 3-phenyl-2-oxa-4,7- diazabicyclo [3.3.0] oct-3-ene, 6-methyl-2-oxa-4,7-diazabicyclo [3,3,03oct-3-ene, 8-methyl-2-oxa 4,7-diazabicyclo [3,3,0 3OCt-S-On, 3-methyl-2,8-diazabicycloC 4,3,03nonane, 4-methyl-2,8-diazabicyclo [4,3,0 3nonane, 5 Methyl 2,8-diazabicycloC 4,3,03nonane, 6-methyl-2,8-diazabicycloC 4,3,0 3nonane, 3-methyl-2-oxa-5,8-diazabicyclo [4,3,03nonane, 4-methyl 2-cxa-5,8-diazabicyclo [4,3,03nonane, 1-methyl-2-oxa-5,6-diazabicyclo [4,3,03nonane,

Le A 26 108

- 34 -

3,5-dimethyl-2-oxa-5,8-diazabicyclo [4,3,0] nonane, 2-thia-5,8-diazabicyclo [4,3,0] nonane, 5-methyl-2-thia-5, 8-diazabicyclo [4,3,0] nonane, 3,5-dimethyl-2-thia-5,8-diazabicyclo [4.3.0] nonane, 3-oxa-2,8-diazabicyclo [4,3,0] nonane, 2-methyl-9-oxa-2,8-diazabicyclo [4.3.0] nonane, 4-methyl-3-oxa-2,8-diazabicyclo [4.3.0] nonane, 2,5-dimethyl-3- oxa-2,8-diazabicyclo [4 »3.0] nonane, 3-oxa-5,8-diazabicyclo [4.3.0] nonane, 5-methyl-3-oxa-5,8-diazabicyclo [4,3,0] nonane, 1,5-dimethyl-3-oxa-S, 8-diazabieyelo [4,3,0] nonane, 4,4-dimethyl-3-oxa-5,8-diazabicyclo [4,3,0] nonane.

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

20 a diluent such as dimethyl sulfoxide, N, N-dimethylformamide ι N-methylpyrrolidone, hexamethyl-phosphoric acid trisamide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, Ieopropanol, glycol monomethyl ether or pyridine made. As well

Mixtures of these diluents may be used.

All acidic binders can be used with all common inorganic and organic acid binding agents

30 preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Specific examples which may be mentioned are: triethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1-8-diazabicyclo [5.4.0] undec-7-ene (DBU) or excess aminol (III )

Le A 26 108

5 * 01

- 35 -

The reaction temperatures can be varied within a substantial range. In general, one works between about 20 and 200 ⁰ C, preferably between 80 and 180 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, one works at pressures between about 1 and 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention, 1 to 15 hols, preferably 1 to 6 mols, of the compound (III) are employed per mole of the carboxylic acid (II),

Free hydroxy groups can be protected during the reaction by a suitable hydroxy protecting group, for example by the tetrahydropyranyl radical, and released again after the reaction has ended (see J.F.W. McOmie, Protective Groups in Organic Chemistry (1973), page 104).

Free amino-functional ions can be protected during the reaction by a suitable amino-protecting group, for example by the ethoxycarbonyl or tert-butoxycarbonyl radical, and released again after the reaction has ended by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, Chem. Methods of Organic Chemistry, Volume E4, page 144 (1983), JFW McOmie Protective Groups in Organic Chemistry (1973), page 43).

Le A Zh 108

* 85 "01

The reaction of (IV) with (V) according to Method B is preferably carried out in a diluent such as dimethyl sulfoxide, dioxane. N, N-Diraethylformamid, N-methylpyrrolidone, Kexamethyl-phosphoric acid trisamide «sulfolane, water» made an alcohol such as methanol, ethanol »n-propanol, isopropanol, glycol monomethyl ether or pyridine. Likewise, mixtures of these diluents can be used «

As an acid binder, it is possible to use all customary inorganic and organic acid binders. These include, preferably, the alkali metal hydroxides "alkali metal carbonates", organic amines and amidines. "Triethylamine" 1 "4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

20

The reaction temperatures can be varied within a substantial range "in general carried out between about 70 and about 200 ⁰ C, preferably between 100 and 180 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, one wipes at pressures about 1 bar and about 100 bar. preferably between 1 and 10 bar «

When carrying out the process according to the invention in accordance with Method B, 1 to 50 mol, preferably 1 to 30 mol, of the compound (V) are employed per mole of the compound (IV).

Le A 26 108

5 * 01

- 37 -

To prepare the esters of the invention, the underlying carboxylic acid is preferably 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 ° to 200 ⁰ C, preferably about to 120 ⁰ C reacted "The resulting reaction water can also be removed by azeotropic distillation with chloroform, carbon tetrachloride, benzene or toluene.

The preparation of esters also succeeds advantageously by heating the underlying acid with Dimethylformamiddialkylacetal in a solvent such as dimethyl formamide.

The (5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl) -ester used as prodrug are prepared by reacting an alkali metal salt of the underlying carboxylic acid with 4-bromomethyl- or 4-chloromethyl-5-ethyl-l, 3-dioxol-2-one in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or tetramethylurea at temperatures of about 0 ° to 10O ⁰ C, preferably 0 ° to 50 ⁰ C,

The preparation of the acid addition salts of the compounds according to the invention is carried out in a conventional manner, for example by dissolving the betaine in excess aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile

Le A 26 108

2 8SiO!

Heat quantities of betaine and acid in water or an alcohol such as glycol monomethyl, then evaporate to dryness or aspirate the precipitated salt. Examples of suitable pharmaceutically usable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methane sulfonic acid, 4-toluenesulfonic 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 betaines in lower alkali or alkaline earth metal solution, filtering undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable are sodium, potassium or calcium salts. By reacting an alkali or alkaline earth metal with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained «

In addition to the active compounds 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 diastereomer mixtures and as diastereomerically pure or enantiomerically pure compounds

 30

35

Le A 26 108

- 39 -

2 8 5 6

X U

(ζ. U

η X U O

Cz.

Z X

Z X

in X

N U

Le A 26

Table 1 (continued)

R ¹ R ² R ³ X ¹ X ² H A C H H co- F CH ti ^ "^ H NH ₂ ^C 2 ^H 5 H 9O- F H CF H CO F CF H JL JL H H CO F CF F H H -CH = CH ₂ H co- F CH N ^^ H

Table 1 (continued)

R ¹ R ² R ³ X ¹ X ² H A HO-CH ₂ CH ₂ - H CH ₃ -SA ^ ^N "H F F CH H F CF CH ₃ A ^ k ^^ H F / \ H CO F CF H H / \ -C ₂ H ₅ CC F H CF CH ₃ co-H F CF

Table 1 (continued)

00-

CO

OO

co-

00-

X ¹ X ² F NH ₂ F OH F H F H F H

CF

CF

CCI

CH

- 43 -

CJ

OS

(K

[Χ. U U

 CJ

X U

[Χ.

N X U

(M X U

Le A 26

Table 1 (continued)

CH ₃ O

CH ₃ -NH-

rrr

N K

iTT

CF

CCl CH CF

Table 1 (continued)

CH-

CH-

H CH-

CH ₃ O,

H ₂ N '

2 I

CF

CCI

CF

C-CH ₃

ul

1 (continued)

R ³ Il X ¹ F N Il Il CH ₃ I F O' N H H F 0 ^> F O' 's F H ₂ N, F C

Il

Il

ii

μ Table 1 (continued)

^C 2 ^H 5

H ₂ N vV ^

H ₂ N ν} ^ιν "'

H ₂ N

HoN V \ u> «'

H ₂ N

NH-

CF

CF

CF

CH

OO Crt

Table 1 (continued)

CHr

CH ₃ OW ^^ \ N-

H ₂ N

H ₂ N

CH ₃ Crv / \ N-

CH ₃ -NH

CF

CF

CF

CH

_ 49 -

2HS6 O ί

(VJ

ro 05

(M

ro X U

[Χ.

ro X υ υ

\ χ ^η / \

ro cj ro ro

X CJ

Le A 26

2850

- 50 -

(VJ

α,

(χ. U

[Χ. U

[χ

 U

Ct.

in X CM U

in X

(M U

Le A 26 100

tr ¹ α »

Table 1 (continued)

CH-

CH ₃ CO-

J I

CH-

CH ₃ CO-CTx / ^ N-

0 ¹ Ni

H, N ^

0 ^ C

CH-aCTvv / ^ N-

CHoOV ^^ N-

0 ^ C

CH CF CCl CH CF CCl

Table 1 (continued)

R ¹ R ² R ³ X ¹ X ² A H O ^ vCH ₂ F H N H cH ₃ o ^> s _r ^^. ^ F H H CH ₃ cr * Y ^ <t F H CF CH- CCI H F H / \ CH. T · CF H CH ₃ CTv ^ vI H ₂ N ^ F H CH Ϊ- 1- 3 3 "I-

Table 1 (continued)

CH ₃ O

H ₂ N

CH-

Choo.

* l ν

H ₂ N

CF

CF CF

C-CH

OJ

Table 1 (continued)

CH-

N-

CH ₃ O-CONH ^ '

CH

N-

OCH-NH ^ '

OCH

₃ OVX ^ N -NH -'- ''

CH-

HO-N

N-

CH ₃ O-NH ^

X ² A H CF H CF K CCI H CF H CF X ¹ F F F F F

Table 1 (continued)

CH ₃ O-CONH ^

CH

CH ₃ O-CONH ^

NT

rn r

N

CCl CH CH CF CCl

T able 1 (continued)

R ¹ r2 R ³ X ¹ X ² H A H "I F H H CF _Η N ^H 3 ^C Y ° V ^{/ SN} ~., I F H H CF / \ H N CC-H F C-CH ₃ H F H cc H F C-CH ₃ C-CH ₃

Table 1 (continued)

^C 2 ^H 5

N-

N-

CO

CO

co-

CH ₂ CH ₂ OH

NH ₂

CH

CCI

CF

CF

t- ¹ ro

Table 1 (continued)

N-

00-

X ^ A Cl CH Cl CF H N H CF H CH

cn

Table 1 (continued)

CO

N-

N-

CCI

CF

CF CH CF

VO

cc »cn

Table 1 (continued)

N-

00-

0O-

00-

00-

X ¹ X ² H F N F H F F F NH ₂ F

CH

CCI

CF

CF

Table 1 (continued)

CO

CO

CO

cc

Cl

Cl

CH

CF

CF

CH

- 62 -

8th

U [Χ. (Χ. χ ίχ.  < α υ υ υ ο (M X ac * rh

N *) O 0) jj UO (x.

Le Λ 26

Table 1 (continued)

CF

CH

CCl CF CF

01

U)

tr ¹ ro

Table 1 (continued)

^ι 3 H

CH--

XO

CH,

CO

Cl

CF

N.

σι

Table 1 (continued)

R '

CHoOW ^ N-

H ₂ N ^

CH-, 0W ^ \ N

H ₂ N VST

CH-

I i

H ₂ N ^V

CH

CCl CF CF

σι

- 66 -

CM X

Φ W λ)

X υ

u

X U

Le A 26

Table 1 (continued)

CH,

H ₂ N

Η, Ν

H ₃ C3 ^ - ^ N-Η, Ν

CH

CCl CF CF

σι

Table 1 (continued)

ο I οο

CH-

Η, Ν J

H ₂ N

CH CF

CF

: η

- 69 -

g Example of a tablet according to the invention Each tablet contains:

Compound of Example 1 583.0 mg

₁₀ microcrystalline cellulose 55.0 mg

Corn starch 72.0 mg Poly (1-vinyl-2-pyrrolidone) insoluble 30.0 mg Highly dispersed silica 5.0 mg Magnesium stearate 5.0 mg

₁₅ 750.0 mg

The paint cover contains: Poly (O-hydroxypropy1-0-methyl)

cellulose 15 cp 20 Macrogol 4000 rec. INN polyethylene glycols (DAB)

Titanium (IV) oxide

6 0 mg 2, 0 mg 2, 0 mq 10 0 mg

Le A 26

2BS6 O i

- 70 -

The erfinriungsgemäeen compounds show low toxicity a broad antibacterial spectrum against gram-positive and gram-negative bacteria, especially against Enterobakteriacoen; especially against those which are resistant to various antibiotics, e.g. Penicillins, cephalosporins, aminoglycosides, sulfonamides »tetracyclines,

These valuable properties allow their use as chemotherapeutic agents in medicine fiowie as materials for the preservation of inorganic and organic materials, in particular organic materials of all kinds, e.g. Polymers, lubricants, paints, fibers, leather, paper and wood, food and water »

The compounds according to the invention are effective against a very broad spectrum of microorganisms. With their help, it is possible to combat gram-negative and gram-positive bacteria and bacteria-like microorganisms and to prevent the diseases caused by these pathogens.

25 changed, improved and / or cured ·

The compounds according to the invention are particularly effective against bacteria and bacterium-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.

Le A 26 108

5 * 01

- 71 -

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 prevented: Gram-positive cocci »e.g. Staphylococci (Staphylococcus, Staph. Epidermidis) and Streptococci (Strept.

agalactiae »Strept · faecalis» Strept. pneumoniae, Strept pyogenes); gram-negative cocci (Neisseria gonorrhoeae) as well as Gram-negative rods such as Enterobacteriaceae »eg, Escherichia coli, Haemophilus influenzas, Citrobacter (Citrob, freundii, Citrob, divernis), Salmonella and Shigellaj also Klebsiella (Klebe, pneumoniae» Klebs «oxytoca), Enterobacter (Ent. Aorogenes, Ent. Agglomerans), Hafnia, Serratia (Serr. Marcescens), Proteus (Pr. Mirabilis, Pr. Rettgari, Pr. Vulgaris) "Providencia, Yersinia, as well as the genus Acinetobacter" In addition, the antibacterial spectrum includes the genus Peeudomonas (Ps. aeruginosa, Ps, sometimes tophi 1ia) and strictly anaerobic bacteria such as Bacteroides fragilis, members of the genus Peptococcus, Peptostraptococcus and the genus Clostridium; also mycoplasmas (M. pneumoniae "M. hominis, M. urealyticum) as well as mycobacteria" e.g. Mycobacterium tuberculosis.

The above charge of pathogens is merely exemplary and by no means restrictive. Ale diseases "caused by the mentioned pathogens or mixed infections and prevented by the inventive Vorbindungen" can be improved or cured "are, for example:

Le A 26 108

2850

- 72 -

Infectious diseases in humans 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 «

10 enteritis, liver 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 dental operations, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis , intra-abdominal abscesses, pancreatilis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid fever, meningitis and nervous system infections, salpingitis, endometritis, genital infections, pelvic peritonitis and ocular infections ·

Apart from humans, bacterial infections can also be treated in other species. "

genanntί

Pig: coli-diarrhea, enterotoxemia, sepsis, Dysentery, salmonellosis, maetitis metritis agalact.

Syndrome, ruminant mastitis (cattle, sheep, goats): diarrhea, sepsis,

Bronchopneumonia, salmonellosis, paeteurellosis, mycoplasma

mose, genital infections;

Horse: Bronchopneumonien, Fohlenlähme, puerperale and

postpuerperal infections, salmonellosis j dog and cat: bronchopneumonia, diarrhea, dermatitis,

Otitis, urinary tract infections, prostatitis;

Le A 2 6 108

2856O j

- 73 -

Poultry (chicken, turkey «quail» pigeon, ornamental bird and others)! Mycoplasmosis, E. coli infections, chronic airway diseases, salmonellosis, pasteurellosis, psittacosis.

Similarly, bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, with the antibacterial spectrum on the aforementioned pathogen addition to other pathogens such as Pasteurella, Brucella, Campylobacter, Lieteria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rikettsien, Yersinia, expanded »

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more compounds according to the invention or which consist of one or more active substances according to the invention, and 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, dragees, capsules, pills, suppositories and ampoules, the active substance content of which 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 1/2, 1/3 or 1/4 of a single dose. "A single dose preferably contains the amount of active ingredient which is administered in one application and which is usually one whole, one half or one third or one quarter of a daily dose.

Le A 26 108

- 74 -

Non-toxic »inert pharmaceutically suitable excipients are solid, semi-solid or liquid diluents» fillers and formulations of any kind «

Preferred pharmaceutical preparations are tablets, dragees, kapuein, pills, granules, suppositories, 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, for example, starches, lactose, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. Carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, ζ.Β · glycerol, (d) disintegrants, e.g. Agar-agar, calcium carbonate and sodium carbonate, (e) dissolution extender, e.g. Paraffin and (f) resorption accelerator, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent, e.g. Kaolin and bentonic acid and (i) lubricants e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures thereof under (a) to (i) listed substances.

The tablets, dragees, capsules, pills and granules may be provided with the usual coatings and shells containing, if appropriate, opacifying agents, and may also be composed such that they contain the active substance (s) only or preferably in a particular part

Le A 26 108

28S6 O I

- 75 -

optionally delaying the intestinal tract, using as embedding masses e.g. Polymer substances and waxes can be used.

The active substance (s) may optionally also be present in microencapsulated form with one or more of the abovementioned excipients.

Suppositories may contain in addition to the active substance (s) the customary water-soluble or water-insoluble excipients, for example polyethylene glycols; Fats, eg, cocoa fat and higher esters (eg, C ₁₄ -alcohol with C ₁₆ -fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels may contain, in addition to the active ingredient (s), the usual excipients, e.g. 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 may contain, in addition to the active substance (s), the usual excipients, e.g. Lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain the usual propellants, e.g. Chlorine-

30 fluorkohlenwasB-.retoffθ, included.

Solutions and emulsions may contain, in addition to the active substance (s), the usual excipients such as solvents, solvents,

Le A 26 108

- 76 -

solubilizers and emulsifiers »e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cotton anole oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formal, tetrahydrofurfuryl 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 ingredient (s) the usual carriers such as liquid diluents, z, B, 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 colorants, preservatives and odor and taste-improving additives, for example, peppermint oil and eucalyptus oil and sweeteners, for example, saccharin.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of from about 0.1 to 99.5, preferably from about 0.5 to 95, parts by weight of the total mixture.

Le A 26 108

2854

- π

The pharmaceutical preparations listed above may contain, in addition to the compounds according to the invention, other active pharmaceutical ingredients.

The preparation of the abovementioned pharmaceutical preparations is carried out in a customary manner by known methods, for example by mixing the active substance (s) with the carrier (s).

The preparations mentioned can be administered either orally rectally or parenterally (intravenously) to humans and animals.

15 muscular »subcutaneous)» intracisternal »intravaginal»

Intraperitoneal, local (powder »ointment» drops) and for the treatment of infections in cavities »Body cavities are used« Injection solutions are suitable preparations »Solutions and suspensions for oral therapy» Gels »Infusion» Emulsions »Ointments or drops in a collar. For local therapy, ophthalmic and dermatological formulations, silver and other salts »Ear drops» Eye ointments, powders or solutions can be used. In addition, it can also be absorbed via feed or drinking water in suitable formulations. Furthermore, gels, powders »Powder» Tablets »Retard tablets» Premixes »Conservates, granules» Pellets »BoIi, capsules, aerosols» Sprays »Inhalats bsi man and animals be applied« Furthermore, the compounds of the invention in other carrier materials such as plastics (Plastic chains for local therapy) »Collagen or bone cement are incorporated.

35

Le A 26 108

265 ^ 0

- 78 -

In general, it has proved to be advantageous both in human and in veterinary medicine "or the active compounds 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 A single dose contains the active substance (s) according to the invention preferably in amounts of about 1 to 80, in particular 3 to 30 mg / kg of body weight. However, it may be necessary to deviate from the stated dosages. and depending on the type and body weight of the object to be treated, the nature and severity of the disease, the method of preparation and the application of the drug and the period or interval within which the administration takes place »

Thus, in some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. "The determination of the optimal dosage and type of application of the active ingredients required can easily be determined by any person skilled in the art due to his expertise ,

The new compounds can be given in the usual concentrations and preparations together with the feed or "with food preparations or with the drinking water." This can prevent, ameliorate and / or cure an infection by gram-negative or gram-positive bacteria and thereby promote of growth and improvement in the use of feed

Le A 2 6 108

28S6 O \

- 79 -

The minimum inhibitory concentrations (MIC) were determined by Iso-Sensitest agar by 5 serial dilution methods

(Oxoid) determined. For each test substance a number of voi. The agar plates were inoculated with a multipoint inoculator (Denley). For inoculation, overnight cultures of the pathogens were used which were previously so diluted that each inoculum was approximately 10% colony forming Contains particles. The inoculated agar plates were incubated at 37 ° C "and germination was read after about 20 hours. The MIC value (Mg / ml) indicates the lowest active ingredient concentration at which no germ growth could be detected with the naked eye.

The table below shows the MIC values are some of _{t he} compounds of the invention compared to ciprofloxacin given.

Le A 26 108

MIC values (mg / l) determined by agar dilution assay (Denley Multipoint Inoculator; Iso-Sensitest agar)

example

12 3

test strain

Escherichia coli Neumann

Proteus mirabilis 8223

10.015 10.015 10.015 10.015 10.015 10.015 0.25 0.125

Proteus vul- 10 , 015 0 125 garis 1017 Morganella 10 , 015 0 , 03 morganii 932

Providencia 1 stuartei 12052

10.015 10.015 0.03

0.06

0.03 i.0.015 10.015 0.06

0.5 1

0,5 0,5

32 64

Staphylococcus aureus

FK 422 0.06

1756 0.06

133 0.06

Enterococcus faecalis 27101 0.125 9790 0.125

0,125 0.06 1 ° , 015 0,125 0.03 0.06 0 125 0,125 0.06 10 , 015 0,125 0.03 0.06 0 125 0,125 0.03 10 , 015 0,125 0.03 0.06 0 125 0,125 0 06 0.25 0,125 0.25 2 0.5 0.25 O, 06 0.25 0,125 0.25 2

ro co cn

φ * MIC values (mg / l) determined by agai dilution test

(Denley Multipoint Inoculator, Iso-Sensitest Agar, Oxide)

IO test strain Example 13 0 4 15 16 17 125 18 03 Ciprofloxac in I 00> O oo Escherichia coli Neumann 4 I Proteus mirabilis 8223 0.06 0 , 06 10.015 0.06 O, 5 O, 06 10.015 Proteus vulgaris 1017 1 0 0.5 4 8th 5 1 06 1 Morganella morganii 932 0.03 4 , 5 0.03 0.06 0 O, 10.015 Providencia 0,125 25 0.03 0.06 0 O, 10.015 2 1 32 8th 4 4

stuartei 12052

Staphylococcus aureus

FK 422 0.06 0.25

1756 0.06 0.25

133 0.06 0.25

Enterococcus

faecalie 27101 0.125 0.25 9790 0.25 0.5

0.03 0.03 0.03

0.03

0.5 0.5 0.5

1 2

0.125 0.125 0.125

0.25 0.5

0.25 0.25 0.25

0.05 0.25

-ul-

28S60i

A U S 1 Ü h Γ ϋ ΙΊ [j ü ü β j Ii μ j- (31

Uiε; explain folyan (jei) examples (Jiti invention: Heraeui j.lunu the Iv, LBcliüiipruciuktb ': ei υ is ρ i β 1 A

i - \ - (cis - '► - i · ieth ι) χ y - j) yrr ü 1 icii 1ι - 3 - y 1) - c; a r a ü id ä ur c u u u - - - - - - - -

a) 1: ra η s -1 - ü e η ζ y 1 - 3 - hy ei l ο χ y - 4 - ine th ο χ y ρ yrr ο 1 i ö i η

ίίαπ heats 34, ^c > [j (0,2 iüjI) jo

[3.1.u3 höxan (US: ^j atent 4 254 133) is 1.6 u (20 ί ,, ιηοΐ) M a l: i "i uir, ine thy latlcJsunij (3D" u) in 200 ri. I absolutini llthano. "" I. Autoclave 10 hours on 12 " ⁰ C. By cooling, neutralized, i., I., 1, 2, g (2h, ijhh,) cssiusic acid uride is dissolved in the solution of alcohol in i ^ otationsverdarnp fer. The JabataiG will revolt in Totrahyurofuran! dab i \ '3xriu [i) ac (; ta 1. ab ii llrier t., Ua ;; filtrate wir; üinyuuni; 1, and the Hückstaiid rJobti liiert ..

Yield: 40.9 u (91 -o Tjur Tiieurit) Siuiiiipuiikt: 112-115 ^Ü C / 0.1 bar fi = Ceholt: 52'Uj

Λ 26 1CÜ

28S6 O 1

- 83 -

b) c ie-3-amino-1-benzyl-4-r.t., thoxy-pyrrole in

You put 5.6 g (25 mmol) Trane l-Benzyl-S-hydroxy-'lmethoxy-pyrrolidine and 8.6 g (33 mmol) of triphenylphosphine in 40 ml of absolute tetrahydrofuran and before dropwise at ⁰ C a solution of 6 g (34 mmol) of diethyl azodicarboxylate in 40 ml of absolute tetrahydrofuran. Then, at ⁰ ° C., 3.9 g (27 mmol) of phthalimide are added in small portions within one hour. It is stirred overnight at room temperature and concentrated. The residue is dissolved in 50 ml of ethyl acetate and 80 ml of petroleum ether are added. The mixture is left to crystallize overnight and the crystals are filtered off (triphenylphosphine oxide and diethyl hydrazine dicarboxylate), the filtrate is concentrated and the residue is refluxed overnight with 60 ml of concentrated hydrochloric acid, decanted from undissolved residues and the solution is concentrated Water, the solution is made alkaline with solid potassium carbonate and extracted five times with 50 ml of chloroform, dried over potassium carbonate, concentrated and the residue is distilled.

Yield: 3.4 g (65.9X of theory) boiling point! 95 ° C / 0.2 mbar 30

Le A 26 108

2 8 5

- 84 -

c) N- (cis -1-Benzyl-4-methoxypyrrolidin-3-yl) -carbamic acid tert-butyl ester

To a solution of 0.65 g of NaOH in 8 ml of water is added 3 g (14.5 mmol) of cia-3-amino-1-benzyl-4-methoxy-pyrroli-

10 din and 11 ml of tert-butanol. Drip 3.5 g

(16 mmol) dicarbonic acid di-tert-butyl ester, stirred overnight at room temperature, sucks in inorganic brawn and extracted the filtrate with chloroform. It is dried over potassium carbonate, concentrated and distilled

15 residue.

Yield: 3.8 g (85.5X theory) Boiling point: 130-140 ° C / 0.05 mbar

d) N- (cis-4-methoxypyrrolidin-3-yl) -carbamic acid tert -butyl ester

Hydrogenating 3.5 g (11.4 mmol) of N- (cis-l-Benzyl-4-methoxypyrrolidin-3-yl) -carbamic acid tert, -butyleeter in 100 ml methanol at 100 ⁰ C and 100 bar on 2 g Palladium activated carbon \ 10X Pd), the catalyst is filtered off, the filtrate is concentrated and the residue is distilled off,

30 yield! 1.9 g (81.6X theory) Boiling point: 84 ° C / 0.1 mbar

Le A 26 108

2854

- 85 -

Example B 5

N- (trans-4-methoxy-pyrrolidin-3-yl) -carbamideäure tert-butyl ester

10 a) trane-3-amino-1-benzyl-4-methoxy-pyrrolidine

Dissolve 27 g (0.41 mol) of sodium azide in 50 ml of water and put 17.5 g (0.1 mol) of S-benzyl-n-oxa-S-azabicyclo -. '3,1 .Olhexan in 300 ml of dioxane added. Refluxed for 72 hours, concentrated, dissolved inorganic salts in water and extracted with chloroform. It is dried over potassium carbonate and concentrated. The residue is dissolved in 50 ml of absolute tetrahydrofuran and added dropwise to 4 g of sodium hydride (80X in paraffinol) in 200 ml of absolute tetrahydrofuran. The mixture is heated under reflux for one hour and then added dropwise 15 g (0.1 mol) of methyl iodide. It is then heated under reflux overnight, concentrated, taken up in water and extracted with chloroform. It is dried over potassium carbonate, concentrated and distilled. This gives 13.1 g of a 73% by gas chromatogram material. Of this is added dropwise 12.7 g in 40 ml of absolute tetrahydrofuran to a suspension of 4 g of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran and heated for 2 hours under reflux. Excess lithium aluminum hydride is decomposed by careful dropwise addition of 4 ml of water each time.

Le A 26 108

2850 OJ

- 86 -

15x potassium hydroxide solution and again 4 ml water. "The inorganic salts are filtered off with suction and washed several times with chloroform. The organic phases are dried over potassium carbonate and the residue is distilled.

10 Yield: 9 g (32.8% of theory) boiling point · 91 ° C / 0.07 mbar

The product has a gas chromatography (area method) determined content of 75%. 15

b) N- (trans-1-benzyl-4-methoxypyrrolidin-3-yl) -carbamic acid tert-butyl ester

To a solution of 1.3 g of NaOH in 15 ml of water are added 8.2 g (30 mmol) of trans-3-amino-1-benzyl-4-methoxy-pyrrolidine and 21 ml of tert-butanol. To this is added dropwise 7.1 g (31 mmol) of dicarbonic acid di-tert-butyl ester and then stirred overnight at room temperature. "It is suctioned off from inorganic salts, the filtrate is extracted with chloroform, dried over potassium carbonate, concentrated and the residue is distilled.

Yield: 7.7 g (84.4% of theory) 30 Boiling point: 148 ^c C / 0, l mbi.r Melting point: 88-90 ⁰ C

Le A 26 108

285 ό ΰ ί

- 87 -

c) N- (trans-4-methoxypyriolidin-3-yl) -carbamic acid tert-butyl ether

Hydrogenating 6.7 g (22 mmol) N- (Trane l-Benzyl-4-methoxypyrrolidin-3-yl) -carbamic acid tert-butyl ester in 150 ml of methanol at 100 bar and 10O ⁰ C to 2 g palladium Activated carbon (1OX Pd) "The catalyst is aspirated off, the filtrate is concentrated and the residue is distilled off.

Yield! 2.2 g (46X theory) 15 Boiling point: 94 ° C / 0.05 mbar

Example C trans-3-amino-4-hydroxy-pyrrolidine

a) trans-3-araino-1-benzyl-4-hydroxy-pyrrole id in

Heat 8.9 g (50 mmol) of S-benzyl-6-oxa-S-azabicyclo-3: 1 ODhexan in 75 ml of ammonia solution (25 ×) for 8 hours in an autoclave at 120 ° C. The solution is evaporated down and the residue is concentrated distilled

30 Yield: 6 g (62,4X of theory) Boiling point: 130-14Ü ⁰ C / 0.1 mbar Melting point: 82-84 ⁰ C

Le A 26 108

285

- 88 b) trans-3-amino-4-hydroxy-pyrrole idin

Hydrogenated 5.2 g (27 mmol) of trans-3-amino-1-benzyl-4-hydroxy-pyrrolidine in 40 ml of methanol at 100 ⁰ C and 100 bar of 1 g of palladium-carbon (10X Pd). The catalyst is suctioned off, the filtrate is concentrated and the residue is distilled off.

Yield: 1 g (36.3 * of theory) Boiling point: UO ° C / 0.3 mbar 15

Example D

Trane-4-hydroxy-3- (2-hydroxyethylamino) -pyrrolidine

a) trans-1-benzyl-4-hydroxy-3- (2-hydroxyethylamino) -pyrrolidine

40 g (0.22 mol) of S-benzyl-e-oxa-S-azabicyclo [3, l, 0] hexane are heated with 42 g (0.68 mol) of 2-aminoethanol in 450 ml of water overnight under reflux , The solution is extracted once with tert-butyl methyl ether and the aqueous phase is concentrated. The residue is distilled.

Yield: 34.1 g (65.6X of theory). Boiling point: 190 ° C./l, 1 mbar

Le A 26 108

2ϊ $ 6 O I

- 89 -

b) trans-4-hydroxy-3- (2-hydroxyethylamino) -pyrrolidine

The mixture is hydrogenated analogously to Example C b) trans-l-benzyl-4-hydroxy-3- (2-hydroxyethylamino) pyrrolidine and the reaction product is obtained as an oil »10

Example E

trans-4-hydroxy-3- (2-hydroxyethyl-methyl-amino) -

pyrrolidine η 15

a) trans-1-benzyl-4-hydroxy-3- (2-hydroxyethyl-methylamino) -pyrrolidine

17.5 g (0.1 mol) of 3-benzyl-6-oxa-3-azabicyclo [3 "1", 0] hexane are reacted with 17 g (0.1 mol) of methylaminoethanol analogously to Example O a) in 200 ml Water around «

25 Yield: 18.2 g (73X of theory) Boiling point: 180-190 ° C / 0.1 mbar

b) trans-4-hydroxy-3- (2-hydroxyethyl-methyl-amino) -pyrrolidine

Analogously to Example C b) hydrogenated trans-l-benzyl-4-hydroxy-3- (2-hydroxyethyl-methyl-amino) -pyrrolidine and receives the reaction product as an oily compound "35

Le A 26 108

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Example F '

2-oxa-5,8-d azabicyclo [4.3.Olnonan dihydrochloride!

a) 8-Bonyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane 10

15.6 g (66 mmol) of 1-benzyl-4-hydroxy-3- (2-hydroxyethylamino) -pyrrolidine are refluxed in a mixture of 60 ml of concentrated sulfuric acid and 20 ml of water for 6 hours. The mixture is made alkaline with concentrated sodium hydroxide solution , sucks precipitated sodium sulfate and extracted the filtrate with chloroform. It is dried over potassium carbonate, concentrated and the residue is distilled off,

20 Yield: 4.1 g (28.5% of theory) Boiling point: 122-128 ⁰ C (0.08 mbar)

b) 2-0xa-5,8-diazabicyclo [4,3, Olnonan dihydrochloride

A solution of 4 g (18.2 mmol) of 8-benzyl-2-oxa-5,8-diazabicycloC4,3.0] nonane in 100 ml of methanol and 3.5 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-activated carbon (10K Pd ) at 80 ° C and 100 bar. The CaLaIyeator is filtered off and washed with water. The filtrates are concentrated and crystallized by trituration with a little methanol. It is filtered off with suction, the crystals are washed with acetone and dried in air,

35 Yield: 1.85 g (51X of theory)

Melting point: 280 ° C with decomposition

Le A 2 6 108

2 8 5 rf O 1

- 91 -

c) 2-0xa-5,8-diazabicyclo [4.3.O] nonane

Hydrogenating 7.2 g (33 mmol) of 8-benzyl-2-oxa-5,8-diazabicyclo [4,3,0] nonane in 400 ml of methanol with 2.5 g of palladium-carbon (10 % Pd) at 50 bar and 100 ⁰ C. The catalyst is suctioned off, the filtrate is concentrated and the residue is distilled.

Output: 3.1 g (73.4 % of theory); cis-trans isomer mixture 1: 7 boiling point: 58 ° C / 0, l mbar.

d) trans-2-oxd-5,8-diazabicyclo [4.3.0] nonane

Analogously to Example D a), S-benzyl-O-oxa-S-azabicyclo- [3.1.0] hexane is reacted with 2- (benzylamino) -ethanol to give trans-1-benzyl-3- [N-benzyl-N- (2 -hydroxyethyl) -amino] -4-hydroxypyrrolidine and then reacted analogously to Example F a) to 5,8-dibenzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane and purified by chromatography (silica gel, cyclohexane / tert Butyl methyl ether / ethyl acetate 1: 1: 1).

The hydrogenolytic debenzylation is carried out analogously to Example F c) to give trans-2-oxa-5,8-diazabicyclo [4.3.0] nonane, boiling point: 60 * C / 0.1 mbar.

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Example G

5-Methyl-2-oxa-5,8-diazabicyclo C4.3.0 3nonane dihydrochloride

a) 8-Benzyl-5-methyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

As in Example F a), 18 g (71.9 mmol) of 1-15 benzyl-4-hydroxy-3- (2-hydroxyethyl-methylamino) -

pyrrolidine in 60 ml of concentrated sulfuric acid and 30 ml of water.

Yield: 10 g (60X theory) 20 Boiling point: 122 ° C / 0.08 mbar

b) 5-Methyl-2-oxa-5, B-diazabicyclo [4,3,0] nonane dihydrochloride

Hydrogenating a solution of 9.4 g (40 mmol) of 8-benzyl-5-methyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 150 ml of methanol and 7.4 ml of concentrated hydrochloric acid to 3 g Palladium activated carbon (1OX Pd) at 80 ° C and 100 bar. The

Catalyst is filtered off with suction and the filtrate is concentrated.

The residue is triturated with butanol / acetone 1: 1, the crystals are filtered off with suction and dried in a desiccator over P ₁₀ O _10. The product is very hygroscopic.

Le A 26 108

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Yield: 8.2 g (95% of theory)

Mass spectrum: ^m / _e 142 (M ⁺ ), 112 (M ⁺ -CH ₂ O), 100 (M ⁺ - CH ₂ -N = CH ₂ ), 82 (C ₄ H ₄ NO ⁺ ) -, 68 (C ₄ H ₆ N ⁺ )

₁₀ Example H

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

15 a) N- (2,2-dimethoxyethyl) carbamic acid ethyl ester

To 214 g (2 mol) Aminoacetaldehyddimethylacetal in 1 1 of toluene and 90 g of NaOH in 500 ml of water is added dropwise 214 g of 20 (2 mol) of ethyl chloroformate at 10 ⁰ C. It is stirred for two more hours at room temperature, the aqueous phase separates, saturates with common salt and extracted with toluene. The toluene solutions are dried over magnesium sulfate, concentrated and distilled.

Yield: 338 g (95.4 v. Of theory) Boiling point: 60 ° C / 0.03 mbar

Le A 26

8 5 6 0 1

- 94 -

b) N-Allyl-N- (2,2-diraethoxyethyl) -carbamic acid ethyl ester

Add 20 g of sodium hydride (8OX in paraffinol)

500 ml of toluene before and added dropwise at 80 ° C 89 g (0.5 mol) of N- (2,2-dimethoxyethyl) carbamidsäureethyleeter added. The mixture is stirred for one hour at 80 ° C and then added dropwise 73 g (0.6 mol) of allyl bromide within three hours. The mixture is stirred overnight at 80 ⁰ C, brings the salts in solution with water and separates the organic phase. The aqueous phase is extracted with toluene, the organic phases are dried over potassium carbonate, concentrated by evaporation and the residue is distilled.

Yield: 68 g (62.6X of theory) 20 Boiling point: 65 ° C / 0.09 mbar

c) N-Allyl-N (2-oxoethyl) -carbamic acid ethyl ester

It heated ε 8 g (0.313 mol) of N-allyl-N- (2,2-dimethoxyethyl) -carbamidsäureethyleeter with 150 ml of formic acid for one hour at 100 ⁰ C. It is poured onto ice, extracted several times with methylene chloride, washed with the organic phases Sodium hydrogencarbonate solution, dries

30 magnesium sulfate, concentrated and distilled.

Yield: 46.7 g (87.2 % of theory) Boiling point: 58 ° C / 0.09 mbar

Le A 26 108

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d) 2-Methyl-3-oxa-2,7-diazabicycloC3.3.0] octane-7-carboxylic acid ethyl ester

10 g (0.12 mol) of methylhydroxylamine hydrochloride are dissolved in 50 ml of methanol, cooled in an ice bath and 22 g (0.12 mol) of 30Xige Natriummethylatlöeung added in methanol. It is suctioned off from sodium chloride and the salt is washed with 80 ml of toluene. The solution of methylhydroxylamine is added dropwise within one hour to 20 \ i (0.117 mol) of N-allyl-N- (2- (oxoethyl) -carbamate, which is heated in 160 ml of toluene on a water separator under reflux. The mixture is heated under reflux overnight The product is extracted twice with 80 ml of hydrochloric acid each time, the hydrochloric acid solutions are saturated with potassium carbonate and extracted six times with 200 ml portions of chloroform, dried over K 2 CO 3, concentrated and the residue is distilled off.

Yield: 18.6 g (79.5X theory) Boiling point: 93 ° C / 0.09 mbar 25

e) 2-Methyl-3-oxa-2,7-diazabicyclo [3,3,0] octane

The mixture is heated 13 g (65 mmol) of 2-methyl-3-oxa-2,7-diazabicyelo [3,3.0] octan-7-carbonsäureethyIeeter in 300 ml water with 41 g of Ba (OH) ₂ ¹ SH ₂ O overnight under reflux. Potassium carbonate is added, precipitated barium carbonate is filtered off and the filtrate is extracted ten times with 100 ml of chloroform each time. It is dried over potassium carbonate, concentrated eii. and distilling the residue.

Yield: 5.4 g (65X of theory). Boiling point: 80 ° C / 10 mbar

Le A 26 108

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Example I 5

1-methyl-octahydiropyrroloC3 4-b! Pyrrole (2-methyl-2,7-diazabicyclo [3,3,0] octane)

a) 1-Benzyl-3- (2-chloroethyl-methyl-aniino) -pyrrolidine-2,5-dione

74.8 g (0.4 mol) of N-benzylmaleimide [Arch, Pharm. 308 , 489 (1975) 3 and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20 ° C, then boiled under reflux for 5 hours. Then, the mixture is poured onto 2 1 Eiswaeser, extracted with 3 times 400 ml of chloroform, the extract washed with water, dried over sodium sulfate and concentrated on a rotary evaporator, In the chromatography of the residue (101.1 g) on silica gel with ethyl acetate iPetrolether (1 2) 56.8 g (51% of theory) of an oil are obtained,

Rp value: 0.33 (silica gel, ethyl acetate / petroleum ether = 1: 2)

Le A 26 108

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b) 5-Benzyl-4,6-CUOXO-1-methyl-octahydropyrrolo E3,4-b] pyrrole

7.2 g (0.24 mol) of an 80% sodium hydride suepeneion in mineral oil are suspended in 150 ml of absolute dimethylformamide (dried over calcium hydride) and 62 g (0.22 mol) of 1-benzyl-3- (2-chloroethyl -methylamino) -pyrrolidine-2,5-dione as a solution in 50 ml of absolute dimethylformamide was added dropwise to room temperature. In this case, an exothermic reaction takes place with foaming. It is diluted with a further 50 ml of absolute dimethylformamide, stirred for 1 hour at room temperature, then enjoyed on ice-water and extracted with dichloromethane. The extract is washed with water, dried with sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel with Essigester'Tetrolethir (1: 2) and later (1: 1) chromatogaphy. In this case, first 16.4 g of starting material are recovered and then 17.2 g (44X of theory, based on reacted starting material)

isolated oily product, 25

R _f = 0.26 (silica gel, ethyl acetate / petroleum ether - 1: 1),

Le A 26 108

285 ^ f

- 98 c) 5-Benzyl-1-methyl-oct & hydropyrroloi3,4-b] pyrrole

1.52 g (40 mmol) of lithium aluminum hydride are dissolved in 30 ml

submitted anhydrous tetrahydrofuran and 4.9 g

(20 mmol) of 5-benzyl-4,6-dioxo · l-methyl-cctahydropyrrolo- [3,4-bJpyrrol was added dropwise as a solution in 15 ml of anhydrous tetrahydrofuran. The mixture is subsequently stirred for 3 hours at boiling temperature. Successively, 1.5 ml of water, 1.5 ml of 15% potassium hydroxide solution and 4.5 ml of water are added dropwise to the batch, then the precipitate is filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated on a rotary evaporator and the residue is distilled. There are obtained 3.1 g (72X of theory) of a colorless distillate of boiling point 80 ° C / 0.07 mbar.

20 d) 1-methyl-octahydropyrroloC3,4-b3pyrrole

6.49 g (30 mmol) of S-benzyl-1-methyl-octahydropyrrolo-C3,4-b] -pyrrole are dissolved in 100 ml of absolute ether and 5.2 g of phosphorus pentoxide-dried hydrogen chloride are introduced. The resulting hydrochloride suspension is concentrated in vacuo and the residue taken up in 100 ml of methanol. Then it is hydrogenated with 2 g of Pd-C (5 ×) for 4 hours at 80 ° C. and 50 bar. The catalyst is then filtered off, the filtrate is concentrated and the residue is combined with 30 ml of 40X sodium hydroxide solution and 50 ml of ether. The etheriache phase is separated and the aqueous phase extracted with 2 χ 50 ml of ether. The combined organic phases become

Le A 26 108

2856Oί

- 99 -

dried over sodium sulphate, »concentrated by evaporation and distilled«, 1.3 g (34% of theory) of a colorless oil of boiling point 65-66 ° C./12 mbar are obtained.

Fineness! > 99X 10 Example J

0ctahydropyrrolo [3,4-b] pyrrole (2,7-diazabicyclo [3,3,0] octane)

a) I-Benzyl-3- (2-chloroethylamino) -pyrrolidine-2,5-dione

According to the procedure of Example Ia 74.8 g (0.4 mol) of N-benzylmaleimide with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine are reacted Chromatographic workup, 81.6 g (77% of theory) of an oil with an Rp value of 0.24 (on silica gel with EssigesterPetrolother = lsi).

b) 5-Benzyl-4,6-dioxo-octahydropyrroloC3,4-b! pyrrole

According to the working instructions of Example Ib, 17.4 g (0.58 mol) of sodium hydrideugpension are mixed with 119 g (0.45 mol) of 1-benzyl-3- (2-chloroethylamino) pyrrolidine.

Le A 26 108

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Converted 2,5-dione in 550 ml of absolute dimethylformamide, after standing overnight, it is worked up with water,

In chromatographic purification, contaminants are first eluted with ethyl acetate and then the product is eluted with ethyl acetate.'methanol (3: 1) (R _p value 0.55). 57.7 g of product (56X of theory) are isolated, 10

c) δ-benzyl-octahydropyrroloCS-b-pyrrole

According to the paper of Example Ic, 57 »7 g (0.25 mol) of crude S-benzyl-ajo-dioxo-octahydropyrrolo [3,4-b] pyrrole are mixed with 21.4 g (0.56 mol) of lithium aluminum hydride by constant boiling in 700 ml abs. Reduces tetrahydrofuran, the distillative workup 21.0 g (41, IX of theory) of an oil of boiling point 95 ° C / 0, l mbar,

d) octahydropyrroloC3,4-b] pyrrole

21.0 g (0.104 mol) of 5-benzyl-octahydropyrrolo [3,4-b] pyrrole are introduced into 180 ml of ice-cooled methanol and admixed with 17.3 ml (0.208 mol) of concentrated hydrochloric acid. Then hydrogenated with 2 g of Pd-C (5 X) for 4 hours at 90 ° C and 100 bar, the catalyst is filtered off, the filtrate with 37.4 g (0.208 mol) of 30Xiger sodium methylate solution added, filtered again and the filtrate concentrated. The residue is distilled through a small Vigreux column »Ts are 5.6 g of a colorless oil (48X of theory) of boiling point 93-95 ⁰ C / 30 mbar obtained, which smokes in the air and in the template slowly erutarrt (melting point 40 ⁰ C).

Le A 26 108

iS6 0i

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Example K 5

Octahydropyrrolo [3,4-b] pyridine (2,8-ciazabicycloC4.3,0] nonane

a) 6-Benzyl-5 # 7-dioxo-octahydropyrrolo [3,4-b] pyridine

47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid N-benzylimide (Brit, Pat. 1 086 637; Chem, Abetr. 6_8, 95695w) are dissolved in 400 ml of glycol monomethyl ether over 15 g of ruthenium on activated carbon ( 5X) at 90 ° C and 100 bar hydrogenated until the calculated amount of hydrogen has been recorded. Then, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. It is 44 g of an oily

20 crude products received «

The corresponding hydrogenation with palladium / activated carbon (5 Xig) gives in quantitative yield a pure product of melting point 67-69 ⁰ C, 25th

b) 6-Benzyl-octahydropyrrolo [3,4-b] pyridine

According to the working instructions of Example Ic 44 g (ca «0.18 mol) of crude or pure 6-benzyl-5,7-dioxooctahydropyrrolo [3,4-b] pyridine with 15.2 g (0.40 mol) of lithium aluminum hydride in 390 ml of absolute tetrahydrofuran reduced within 10 hours "Distillation yields 24.4 g of a colorless oil with a boiling point of 93-95 ° C / 0.06 mbar."

Le A 26 108

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- 102 -

c) octahydropyrrolate 3,4-b] pyridine

69 g (0.32 mmol) of 6-benzyl-octahydropyrrolo [3,4-b3pyridine are hydrogenated in 450 ml of methanol at 90 ° C / 90 bar over 7 g of palladium on activated carbon (5 Xig) within 3 hours. Dor catalyst is then filtered off, the filtrate was concentrated and the residue was distilled. There are obtained 33.8 g (84% of theory) of a colorless solid having a melting point of 65-67 ⁰ C and a boiling point of 78 ° C / 9 mbar.

Example L

1-methyl-octahydropyrroloCS 1 -blpyridine (2-methyl-2,8-

diazabicycloC4,3,0] nonane)

a) 1-Methyl-pyridinium-2,3-dicarboxylic acid N-benzylimide iodide

190.5 g (0.8 mol) of pyridine-ZiS-dicarboxylic acid-N-benzylimide are dissolved with heating in 800 ml of nitromethane and added dropwise 136 g (0.96 mol) of methyl iodide. Then 8 hours under reflux cooling (cooling water C) ⁰ C) is boiled. After cooling, the solid is filtered off with suction and washed with dichloromethane. There are obtained 123 g of dark red crystals having a melting point 162-165 ⁰ C (decomposition).

Le A 26 108

IBS 6 OI

- 103 -

b) 6-Benzyl-1-methyl-5,7-dioxo-octahydopyrrolo [3,4-b3pyidin

38 g (0.1 mol) of 1-methylpyridinium-1,3-dicarboxylic acid N-benzylimide iodide are hydrogenated at 30 ° C. and 70 bar over 1 g of platinum oxide in 450 ml of glycol monomethyl ether until the hydrogen uptake is complete (51 hours). The catalyst is then filtered off, the filtrate is concentrated, the residue is taken up in 300 ml of chloroform and the solution is washed 2 × with 300 ml of sodium oxide solution each time and 300 ml of water. After drying, it is concentrated over sodium sulfate. There are 27 g of oily residue left behind.

c) 6-Benzyl-1-methyl-octahydropyrrolo [3,4-b] pyridine

According to the procedure of Example Ic, 19.2 g (0.08 mol) of crude 6-benzyl-1-methyl-5,7-dioxooctahydropyrrolo [3,4-b] pyridine with 6.1 g (0.16 mol) Lithium aluminum hydride reduced in absolute tetrahydrofuran »

Yield: 9.5 g (52K theory), boiling point: 93-96 ° C / 0, l mbar. 30

Le A 26 108

- 104 d) 1-Methyi-octahydropyrrolo [3 »4-b] pyridine

According to the working instructions of Examples Id, 11.7 g (54 mmol) of 6-benzyl-1-methyl-octahydropyrrolo- [3,4-b] pyridine ale dihydrochloride are hydrogenated in 100 ml of methanol over palladium on activated charcoal Obtained 2.6 g (34% of theory) of a colorless oil of boiling point 83-85 ° / 12 mbar.

¹⁵ Example M

trans-4-methoxy-3-methylamino-pyrrolidin-dihydrochloride

20 a) trans-1-benzyl-3-benzylmethylamino-4-hydroxypyrrolidine

19.4 g (0.1 mol) of 90 Xiges 3-benzyl-6-oxa-3-azabicyclo [3.1.0] hexane are heated with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml water under reflux overnight · It is extracted with CHCl _3, the extracts are dried with K ₂ CO _3, concentrated and distilled to 160 ⁰ C. (oil bath temperature). Crude yield: 18.3 g

Content: 100 X (determined by gas chromatography)

Le A 26 108

28 5 6

- 105 -

b) trans-1-benzyl-3-benzylmothyl-amino-4-methoxy-5-pyrrolidine

17.3 g (58 μmol) of crude trans-1-benzyl-3-benzylmethylamino-4-hydroxy-pyrrolidine in 80 ml are added dropwise.

10% tetrahydrofuran to 2.8 g (93.3 mmol)

80 Xigem sodium hydride in 40 ml of absolute tetrahydrofuran and heated at the same time under reflux. After the evolution of hydrogen is added dropwise to 8.7 g (61 mmol) of methyl iodide and then heated overnight at reflux, poured into ice water, extracted with toluene, the extracts are dried with K2CO3, concentrated and distilled. Yields 9.7 g (52 % of theory) Boiling point: 140-150 ° C / 0.1 mbar

c) trans-4-methoxy-3-methylaminopyrrolidine dihydrochloride

9.3 g (29 mmol) of trans-1-benzyl-3-benzyl are dissolved.

Methylamino-4-methoxy-pyrrolidine in 100 ml of methanol, adds 4.8 ml of concentrated hydrochloric acid and hydrogenated to 4 g of 10 Xiger Pd activated carbon at 90 ° C and 100 bar "sucks the catalyst, the filtrate is concentrated and crystallized Recrystallize the residue from isopropanol / methanol to "yield: 3.7 g (62.8 X of theory) melting point: 157-162 ⁰ C.

Le A 26 108

2 8 5 <5 O f

- 106 -

Example N 5 2,5-Dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane

a) N- (2-methylprop-2-enyl) -N- (2,2-dimethoxyethyl) urethane

To 20 g of sodium hydride (80 Xig) in 500 ml of absolute toluene is added dropwise at 90 ° C 89 g (0.5 mol) of N- (2,2-dimethoxyethyl) urethane "If no more hydrogen is formed, is added dropwise 54 g (0 , 6 mol) of methallyl chloride and stirred overnight at 90 ⁰ C ₁ The precipitated sodium chloride is dissolved with a little water, the organic phase separated, over K2CO3 ge

20, dried, concentrated and distilled. Yield: 71.3 g (61.7 X of theory) Boiling point: 60 ° C / 0.08 mbar

b) N- (2-methylprop-2-enyl) -N- (2-oxoethyl) urethane

11.5 g (50 mmol) of N- (2-methylprop-2-enyl) -N- (2,2-dimethoxyethyl) urethane and 1.25 g (5 mmol) of pyridinium p-toluenesulfonate in 100 ml are heated Acetone and 10 ml of water for two days under reflux. It is concentrated and the residue is distilled off. Yield: 5.3 g (61.2 % of theory). Boiling point: 73 ° C./1.1 mbar

Le A 26 108

5 * 01

- 107 -

c) 2,5-dimethyl-3-0X8-2,7 ^ 1 azabicyclo [3,3,0] octane-7-carboxylic acid ethyl ester

To 10 g (0.12 mol) of N-methylhydroxylamine hydrochloride in 26 ml of methanol is added dropwise 21.7 g of 30 Xige sodium methylate solution. It sucks the sodium chloride and washed with ΰ ml of methanol and 80 ml of toluene. This solution is added dropwise to 19.2 g (0.11 mol) of N- (2-methylprop-2-enyl) -N- (2-oxoethyl) urethane, which is refluxed in 160 ml of toluene on a water separator heated under reflux overnight, the product was extracted with 160 ml of 10 Xiger hydrochloric acid, the hydrochloric acid solution alkaline with potassium carbonate and extracted with sechemal 200 ml CHCl _3. The extracts are dried over K ₂ CO ₃ , concentrated and

20 distilled,

Yield! 13 g (55 X theory) Boiling point: 88-95 ° C / 0.08 mbar

d) 2,5-Dimethyl-3-oxa-2,7-diazabicyclo [3,3,0] octane

13 g (60.6 mmol) of ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane-7-carboxylate are heated with 33 g of Ba (OH) ₂ * 8H ₂ O in 330 ml Waeser overnight under reflux. BaCO _{3 is} suctioned off, K ₂ CO _{3 is added} to the filtrate, and the mixture is again filtered off with suction and the filtrate is extracted ten times with 100 ml of CHCl ₃ each time. The extracts are dried over K ₂ CO ₃ , concentrated and distilled.

35 Yield: 5.9 g (63.7 X of theory) Boiling point: 64 ° C / 5 mbar

Le A 2 6 108

2 8 5 * O ί

- 108 -

Example Q 5

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

a) N- (I, l-dimethoxyprop-2-yl) urethane

10

To 86.2 g (0.72 mol) of 2-Aminopropionaldehyddimethylacetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water is added dropwise with ice cooling 80 g (0.73 mol) of ethyl chloroformate. The mixture is stirred for a further two hours at room temperature, the organic phase is separated off, the aqueous phase is extracted with toluene and the toluene solutions are dried over K 2 CO 3. The mixture is concentrated and distilled.

20 yield. ' 132 g (95% of theory) Boiling point: 55 ° C / 0.06 mbar

b) N-Allyl-N- (1,1-dimethoxyprop-2-yl) urethane

To 25 g Natriutuhydrid (80 Xig) in 700 ml of absolute toluene is added dropwise at 90 ° C 131 g (0.686 mol) of N- (1, l-dimethoxyprop-2-yl) urethane. After completion of the evolution of hydrogen is added dropwise at 90 ° C 61.2 g (0.8 mol) of allyl chloride and stirred overnight at 90 ⁰ C. precipitated sodium chloride is dissolved with water, the organic phase separated, dried over K ₂ CO ₃ , concentrated and distilled.

Le A 26 108

5 * 0 1

- 109 -

Output: 78 g (31.7 X of theory) Boiling point: 62-69 ° C / 0.06 mbar. Salary! 64.5 Xig (determined by gas chromatography)

c) N-Allyl-N- (1-oxoprop-2-yl) urethane

The mixture is heated, 76.5 g (0.213 mol) 64.5 Xiges N-allyl-N- (1, l-dimethoxyprop-2-yl) urethane in 180 ml of formic acid for one hour at 100 ⁰ C. It is poured onto ICE Bser extracted with CH ₂ Cl ₂ *, the extracts washed neutral with NaHC0 ₃ -LoBung, dried over MgSO ₄ , concentrated and distilled

 Yield: 36 g (80.9% of theory) Boiling point: 97-102 ° C./8 mbar Content: 88.8 × g (determined by gas chromatography)

d) 2,8-dimethyl-3-oxa-2, / ^; -diazbicyclo [3.3,0] octane-7-carbonseureelhylester

It is prepared from 16.4 g (0.2 mol) of N-Methylhydroxy1 amiη · hydrochloride in 33 ml of absolute methanol and 36 g (0.2 mol) of 30 Xiger sodium methylate a methanolic Methylhydroxylaminlosung forth, diluted with 130 ml of toluene and dripping to 354 g (0.17 mol) of N-ailyl-N- (1-oxoprop-2-yl) urethane in 250 ml.

Le A 26 108

28 5 6f

- 110 -

Toluene, which is heated under reflux at the water. It is refluxed overnight; the product is extracted with dilute hydrochloric acid, the hydrochloric acid solution with K2CO3 alkaline and extracted with CHCl 3, is dried over K ₂ CO _3, concentrated and distilled. Yield: 18.5 g (50.8 % of theory) boiling point! 95-i05 ° C / 0, l mbar

e) 2,8-dimethyl-3-oxa-2,7-diazabicycloC3,3,0] octane

9.2 g (42.9 mmol) of 2,8-dimethyl-3-oxa-2,7-diazabicyclo [3.3] ODoctane-Z-carboxylic acid ethyl ester are heated with 23.5 g of Ba (OH) ₂ ¹ SH ₂ O in 235 ml of water overnight under reflux. BaCO _{3 is} filtered off, the filtrate is treated with K ₂ CO ₃ and filtered off again with suction. The filtrate is extracted ten times with 50 ml CHCl ₃ each time, the extracts are dried over K ₂ CO ₃ , concentrated and distilled

 Yield: 1.7 g

25 boiling point: 87-92 ° C / 10 mbar

It is a mixture of the possible stereomers in the ratio 3: 1 ( ¹ H-NMR). In the wake 4 g of external material could be recovered.

Le A 26 108

2 a 5 ^ o

- Ill -

Example P 5 2-Methyl-4-oxa-2,8-diazabicyclo [4.3.0] nonane

a) 4-hydroxymethyl-3-methylaminopyrrole idin-1-carboxylic acid ethyl ester

Hydrogenated 10 g (50 mmol) of 2-methyl-3-oxa-2,7-diazabicyclo [3 »3.0] octane-7-carboxylic acid ethyl ester (Example H d)) in 200 ml of ethanol to 3 g of Pd activated carbon (10 X Pd) at 50 ⁰ C and 50 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled

 Yield: 8.1 g (80 X of theory)

20 boiling point! 135-140 ° C / 0.1 mbar

b) 2-Methyl-4-oxa-2 »8-diazabicycloC4.3.0] nonane-8-carboxylic acid he reads

Dissolve 10.1 g (50 mmol) of 4-hydroxymethyl-3-methylamino-pyrrolidine-l-carboneäureethylester and 8 g (0.1 mol) of 37 Xige formaldehyde solution in 100 ml of butanol and stirred overnight at room temperature. Then concentrated and distilled the residue.

Outlet: 9.5 g (88.7 X of theory) Boiling point: 110 ° C / 0.1 mbar

Le A 26 108

- 112 c) 2-methyl-4-axa-2,8-diazabicyclo [4.3.0] nonane

9 g (42 mmol) of 2-methyl-4-oxa-2,8-diazabicyclo [4.3%] ouenonane-e-carboxylic acid ethyl ester with 28 g of βa (OH) ₂ * 8H ₂ O in 280 ml of water are refluxed overnight. BaCO _{3 is} filtered off with suction and the residue is boiled with dioxane. The dioxane solution is concentrated and the residue is distilled. Yield * 1.3 g (21.8 % of theory)

Boiling point: 115 ° C / 8 mb-ar

 15

d) 4-hydroxymethyl-3-methylaminopyrrolidine

34 g (0.168 mol) of ethyl 4-hydroxymethyl-3-methylaminopyrrolidine-1-carboxylate are heated with 100 g of Ba (OH) ₂ .H ₂ O in 400 ml of water overnight under reflux. BaCO _{3 is} filtered off with suction, the filtrate is introduced and the residue is boiled ten times with 100 ml dioxane each time. The dioxane solutions are filtered. Narrows and distils.

Yield: 13 g (60.3% of theory) Boiling point: 85-88 ° C / 0.08 mbar

e) 2-MeMiyl-4-oxa-2,8-diazabicyclo [4,3,0] nonane

30

To 13 g (0.101 mol) of 4-hydroxymethyl-3-methylaminopyrrolidine in 100 ml of n-butanol is added dropwise at room temperature 8.1 g (0.1 mol) of 37 Xige formaldehyde 16-35

Le A 26 108

2 δ S 6 O 1

- 113 -

solution in 20 ml of n-butanol. The mixture is stirred overnight at room temperature, concentrated and distilled. Yield: 8.7 g (61.2 X of theory). Boiling point: 84 ° C./6 mbar

Example Q 10

3-0xa-2,7-diazabicyclo [3.3.0] octane

a) 2- (Tetrahydropyran-2-yl) -3-oxa-2,7-diazabicyclo- [3,3,0] octane-7-carboneaureyl ether

18.1 g (0.106 mol) of N-allyl-N- (2-oxoethyl) -carbamic acid ethyl ester (Example M c)) are refluxed in 220 ml of toluene and 14.2 g (0.12 mol) of 5-hydroxypentanal oxime are added dropwise (Acta Chim. Acad., Hung., 14, 333 (1958)) in 55 ml of hot toluene. The mixture is heated under reflux overnight, concentrated and distilled.

25 Yield: 15.5 g (54 X theory) Boiling point: 160 ° C / 0.01 mbar

b) 3-oxa-2,7-diazabicyclo [3.3.0] octane-7-carboxylic acid

ethyl ester

15 g (55.5 mmol) of 2- (tetrahydropyran-2-yl) -3-oxa-2,7-diazabicyclo [3.3.Q] octane-7-carboxylic acid ethyl ester are heated with 8.25 g (56 mmol) of 70 Xiger Perchloric acid in 100 ml of ethanol for 30 minutes under reflux. 10.5 g (58 mmol) of 30% sodium hydroxide are used.

Le A 2 6 108

- 114 -

methyl in solution "concentrates" in water 5, saturates with K ₂ CO ₃ and extracts with CHCl ₃ .

It is dried over K 2 CO 3 concentrated and distilled. Yield: 7.6 g (73.5 Y, of theory). Boiling point: 125-130 ° C / 0, t mbar

10 c) ethyl 3-0xa-2,7-diazabicyclo [3.3.0] octane-7-carboxylate

8.5 g (50 mmol) of ethyl N- (2-oxoethyl) -N-allyl · 15-carbamate are heated with 5.5 g (50 mmol) of o-trimethylsilylhydroxylamine in 10 ml of xylene overnight

under reflux. It is concentrated, distilled and distilled,

Yield: 6.8 g (73% of the tea)

Boiling point: 120-122 ° C / 0.05 mbar 20

d) 3-Oxa-2,7-diazabicyclo [3.3, O] octane

This substance is obtained analogously to Example Nd) 25 by esterification of 3-0xa-2,7-diazabicyclo [3.3.0] octane-7-carboxylic acid ethers with Ba (0H) ₂ * 8H ₂ O. Boiling point: 75 ° C / 10 mbar.

Example R 30

3-methyl-2,7-diazabicycloC3,3.0] octane

Analogously to Example I, 3-methyl-2,7-diazabicyclo [3.3.0] octane is obtained.

Boiling point: 68-70 ° C / 6 mbar.

Le A 26 108

- 115 -

Example S 5 2,3-dimethyl-2,7-diazabicyclo [3.3.0] octane

2,3-Dimethyl-2,7-diazabic-10-cycloC3.3.G.! Octane is obtained analogously to Example I.

Boiling point: 72-74 ° C / 10 mbar,

Example T 1,2-dimethyl-3-oxa-2,7-diazabicycloC3,3,0! Octane

a) N-Allyl-N- (2,2-dimethoxypropyl) -acetamide

To 29.6 g (0.987 mol) of sodium hydride (80 Xig in paraffinol) in 750 ml of absolute toluene is added dropwise at 80 ⁰ C 119 g (74 mol) of 2,2-dimethoxypropylacetamide, then stirred for one hour and dripped

25 then 1OG g (0.83 mol) of allyl bromide at 80 ° C was added. The mixture is stirred overnight at 80 ^° C., cooled and the salts are dissolved with water. The aqueous phase is separated off and extracted twice with 100 ml of toluene. The toluene solutions are dried over K ₂ CO ₃ ,

Angt and distilled.

Yield: 112 g (75.6 X of theory) Boiling point: 70 ° C / 0.08 mbar.

Le A 26

^! ^ F 6 O!

- 116 -

b) N-Allyl-N- (2-oxo-propyl) -acetamide

5

85.5 g (0.425 mol) of N-allyl-N- (2,2-dimethoxypropyl) -acetamide are refluxed with 212 ml of formic acid for one hour. The mixture is poured onto 500 g

¹⁰ ice, extracted several times with methylene chloride,

Wash the organic phases with sodium bicarbonate solution, dry over magnesium sulfate, concentrate and distill. Yield: 50 g (75.8 X of theory).

15 boiling point! 79 ° C / 0.25 mbar.

c) 7-Acetyl-1,2-dimethyl-3-oxa-2,7-diazabicycloid.3,0] octane

Dissolve 15.5 g (0.1 mol) of N-allyl-N- (2-oxopropyl) -acetamide in 100 ml of dioxane and add 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water , Refluxed overnight, cooled, sucks off salts and washed with dioxane. The filtrate is concentrated, the residue taken up in 100 ml of water and treated with K ₂ CO ₃ . It is extracted with CHCl ₃ , dried over K ₂ CO ₃ , concentrated and distilled.

30 liters.

Yield: 15.9 g (86.3 X of theory). Simmering point: 75 °: / 0, 1 mbar.

Le A 26 108

5 6 0 1

- 117 -

d) 1,2-dimethyl-3-oxa-2,7-diazabicyclo [3,3, O] octane

11.8 g (64 mmol) of 7-acetyl-1,2-dimethyl-3-oxa-2,7-diazabicycloC3.3.0] octane are refluxed overnight with 12 g of NaOH in 36 ml of water, and the mixture is saturated with K ₂ CO ₃ , extracted several times with CHCl ₃ , dried over K ₂ CO ₃ , concentrated and distilled. Yield: 4.7 g (51.6 % of theory) Boiling point: 40 ° C / 0.2 mbar.

Example ¹⁵ 2,4-Dimethyl-3-oxa-2,7-diazabicyclo [3,3,0] octane

a) N- (But-2-enyl) -N- (2,2-dimethoxyethyl) carbamic acid ethyl ester

To 17.5 g (0.58 mol) of NbM (80 Xig in paraffinol) in 500 ml of absolute toluene is added dropwise at 80 ° C 89 g (0.5 mol) of N- (2,2-dimethoxyethyl) -carbamidsäureethylester · Subsequently Is stirred for one hour and then added dropwise at 80 ° C 80 g (0.59 mol) of 1-bromo-2-butene, is stirred overnight at 80 ⁰ C, cooled, brings the salts with water in solution, separates the Aqueous phase and extracted with toluene, The toluene solutions are dried over K ₂ CO ₃ , concentrated and distilled, Ausbrüte. 90 g (77.8 X of theory) Boiling point: 65 ° C / 0, l mbar.

Le A 26 108

2 8 5 6 O i

- 118 -

b) N- (But-2-enyl) -N- (2-oxoethyl J-carbamic acid, ethyl ester

90 g (0.39 mol) of N- (but-2-enyl) -N- (2,2-dimethoxyethyl) -carbamic acid ethyl ester are refluxed with 200 ml of formic acid for one hour. It is poured onto 500 g Εΐε, extracted with methylene chloride, the organic phases washed with sodium bicarbonate, dried over magnesium sulfate, concentrated and distilled.

15 Yield: 33.6 g (46.5 % of theory) Boiling point: 65 ° C / 0, 1 mbar.

c) 2,4-dimethyl-3-oxa-2,7-diazabicyclo!, 3,0] octane-7-carboxylic acid ethyl ester

Dissolve 18.4 g (0.1 mol) of N- (but-2-enyl) -N- (2-oxoethyl) -carbamatesaureethylester in 100 ml of dioxane and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N- Methylhydroxylamine hydrochloride in 10 ml of water. Refluxed overnight, cooled, sucks off salts and washed with dioxane. The filtrate is concentrated, the Rücket nd taken up in 100 ml of water and treated with K2CO3. Extract with CHCl 3, dry over K 2 CO 3, concentrate and distill. Yield: 15.0 g (70 X of theory) Boiling point: 74-87 ⁰ CZO ,! mbar.

Le A 26 108

5 ^ 01

- 119 -

d) 2,4-dimethyl-3-oxa-2,7-diazabicyclo [3.3.

13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyclo [3,3,0] octane-7-carboxylate are heated with 39 g of Ba (OH) ₂ '. Reflux SH ₂ O in 200 ml of water overnight. K ₂ CO _{3 is added} , BaCO _{3 is} filtered off with suction and the filtrate is extracted several times with CHCl 3. It is dried over K ₂ CO ₃ , concentrated and distilled, yield: 4.8 g (54.8 % of theory)

15 boiling point! 74 ° C / 8 mbar,

Example V

2, ^ - Di azabicyclo [3.3.0] octane-2-carboxylic acid aryl ester

Analogously to Example Oa) 7-benzyl-2,7-diazabicyclo [3 »3" 0] octane (Example Jc) with ethyl chloroformate to 7-benzyl-2,7-diazabicyclo [3,3,0] octane-2-carboneaureethetereter reacted and this then debenzylated by hydrogenolysis analogously to Example Jd), It is obtained a colorless oil of boiling point 90 ° C / 0, l mbar.

Example W 2-Pheny1-2,7-diazabicyclo [3,3,0] octane

35 The preparation is carried out analogously to Example I); Boiling point: 103 ° C / 0.08 mbar.

Le A 26 108

2854

- 120 -

Example X 5

4-Gxa-2> 8-diazabicycloC4,3.0] nonane

a) 3-Araino-4-hydroxyr ethyl-pyrrolidine-l-carboxylic acid ethyl ester

Analogously to Example Pa), 3-oxa-2,7-diazabicycloCS, 3.0] octan-7-carboxylic acid aryl ester (Example Qc) is hydrogenated,

Boiling point: 163-168 ° C / 0.8 mbar

b) 3-amino-4-hydroxymethylpyrrolidine

Analogously to Example Pd) 3-Awino-4-hydroxymethylpyrrolidine-l-carboxylic acid ethyl ester is saponified «boiling point: 78 ° C / 0.06 mbar

25 c) 4-0xa-2 »8-diazabicyclo [4,3, cinonan

Analogously to Example Pe), 3-amino-4-hydroxymethylpyrrolidine is reacted with formaldehyde solution, boiling point: 50-60 ° C./0.07 mbar

Le A 26 108

5 * 01

- 121 -

Example Y 5

trans-3-ethylamino-4-methylthio-pyrrole idin

a) 1-Benzoyl-trans-3-ethylamino-4-methylthio-pyrrolidine

8.65 g (5 mmol) of t-benzoyl-ZjS-dihydropyrrole tChem. Ber. J22, 2521 (1819)] are introduced into 30 ml of dichloromethane and added dropwise at ^{0 0} C 4.94 g (60 mmol) of methanesulfonyl chloride in 20 ml of dichloromethane. The mixture is stirred for 16 hours at 20-25 ⁰ C, concentrated at 8 mbar and the residue dissolved in 50 ml of tetrahydrofuran «Then 18 g (0.2 mol) 50 xige aqueous ethylamine solution be added« The approach is 18 hours with recirculation cooling boiled, and poured into water and extracted with dichloromethane. Concentration gives 11.1 g of crude product, which is chromatographed on silica gel (RF 'value 0.34) with ethyl acetate / ethanol 5: 1. Yield: 7.4 g (56 X dar theory).

b) trans-3-ethylamino-4-methylthio-pyrrolidine

30

6.0 g (22 mmol) l-benzoyl-trans-3-ethylamino-4-methylthio-pyrrolidine "/ earth with 22 ml of 5 η NaOH for 24 h at 100 ⁰ C stirred vigorously, the mixture homogeneously bit 35

Le A 26 108

2 8 S ^ O ί

- 122 -

is. Then it is extracted with 3 × 80 ml of ether, the extract dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is distilled via a micro-puncture column. Yield: 1.56 g (44 X of theory) of colorless liquid, boiling point: 52 ° C / 0, l mbar

Example Z trans-3-amino-4-methylthio-pyrrolidine

In analogy to Example Y, 1-benzoyl-2,5-dihydropyrrole is allowed to react with methylsulfenyl chloride to give l-benzoyl-3-chloro-4-

methylthio-pyrrolidine reacts, this sets as Rohpro-20

with ammonia to S-amino-l-benzoyl - ^ - methylthio-pyrrolidine and removes the benzoyl with sodium hydroxide solution.

Yield over 3 stages: 47% of theory, boiling point: 108 -11O'C / ll mbar.

Example ZA

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

a) 5-methyl-1,4-dihydropyridine-2,3-dicarboxylic acid N-

benzylimide

33 g (0.29 mol) of 2-methyl-2-propenal dimethylhydrazone and 55 g (0.29 mol) of N-benzylmaleimide are stirred in 225 ml of acetonitrile at 60 * C for 3 hours. Then

Le A 26 108

2BS6 O 1

- 123 -

the solvent is removed on a rotary evaporator, the residue taken up in 600 ml of toluene and boiled under the addition of 150 g of silica gel for 1 hour under reflux. Then it is filtered hot and the silica gel is repeatedly boiled with ethanol. The combined organic phases are concentrated on a rotary evaporator. 17.5 g (24% of theory) of red crystals of melting point 184-186 ° C. are obtained.

b) 5-Methyl-hexahydropyridine-2,3-dicarboxylic acid N-benzyl imide

17.5 g (70 mmol) of 5-methyl-l, 4-dihydropyridine-2,3-dicarboxylic acid-N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70 * C and 100 bar over palladium on activated carbon. Then the catalyst is filtered off and the filtrate is concentrated. The oily solid residue (13.0 g) is used as the crude product in the next stage.

c) 8-Benzyl-4-methyl-2,8-diazabicyclo [4.3.0] nonane

13.0 g of crude 5-methyl-hexahydropyridine-2,3-dicarboxylic acid N-benzylimide are dissolved as a solution in 50 ml of absolute

Tetrahydrofuran submitted to 4.6 g (0.12 mol) of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. Then boiled under reflux for 17 hours. Successively 4.6 g of water in 14 ml of tetrahydrofuran, 4.6 g of 10% sodium hydroxide solution and 13.8 g of water are added dropwise. The salts are filtered off with suction, the filtrate is concentrated and the residue is distilled.

Le A 26 108

2850 0

- 124 -

Yield: 8.7 g (54% based on 5-methyl-l, 4-dihydro-pyridine-2,3-dicarboxylic acid N-benzylimide). Boiling point: 95-98 ° C./1.1 mbar.

d) 4-methyl-2,8-diazabicyclo [4.3.0] nonane

8.0 g (35 mmol) of 8-benzyl-4-methyl-2,8-diazabicyclo [4.3.0] nonane are dissolved in 60 ml of methanol and hydrogenated at 100 ° C. and 100 bar over palladium on activated carbon. Then the catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

20 Yield: 3.3 g (67% of theory), boiling point: 88-89'C / 11 mbar.

The ^ I NMR spectrum shows the compound as a mixture of two stereoisomers in a ratio of 1: 2 . 25

Le A 26 108

2 ß 5 6 O ί

- 125 -

Example AA

5,6,7,8-tetrafluoro-1- (2i4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

a) 2- (2,3,4,5,6-pentafluorobenzoyl) -3- (2,4-difluorophenyl 1-naphtho) -acrylic acid

To a solution of 115 g of 3-ethoxy-2- (2,3,4,5,6-

444 g of 2,4-difluoroaniline are added dropwise with ice cooling and stirring. Man stirred for 2 hours at room temperature, mixed with ice cooling with 380 ml of water, the precipitate is filtered off with suction, washed with ethanol / H ₂ O (UI) and dried. This gives 135.4 g of the title compound elzpunkt Sch from 97-99 ⁰ C.

Le A 26 108

.126- 285 ^ 0!

b) 5,6,7,8-Tetrafluoro-l- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

A mixture of 135.4 g of 2- (2,3,4,5,6-pentafluorobenzoyl) -3- (2,4-difluorophenylamino) -acrylic acid ethyl ester "20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide becomes 3 Hours heated to 140-150 ⁰ C. The suspension is poured hot onto 2 kg of ice, the precipitate is filtered off with suction, washed with water and dried. One receives 122 g of the

15 title compound of melting point 160-162 ⁰ C,

c) 5,6,7,8-Tetrafluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

To a mixture of 28.5 ml conc. Sulfuric acid, 250 ml of glacial acetic acid and 200 ml of water are added 40.1 g of 5,6,7,8-tetrafluoro-1- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and heated 2 hours under reflux. Pour the hot solution to 2 kg of oil, suck off the precipitate, wash with water and dry. There are 34.5 g of the title compound of melting point 250-252 ⁰ C.

30 received.

Le A 26 108

- 127 -

Example AB 5

^ Dichloro-l-cyclopropyl-e-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

a) (2,4-dichloro-3,6-difluorobenzoyl) -esaigeäureethylester

2.1 g of magnesium enices are suspended in 5 ml of anhydrous ethanol. The mixture is treated with 0.5 ml of carbon tetrachloride and, when the reaction has started, is added dropwise to a mixture of 14 g of ethyl malonate, 10 ml of abs. Ethanol and 41 ml of toluene too. The mixture is then heated for 1 5 5 hours at 70 ° C, cooled with acetone / dry ice to -5 ⁰ C to -10 ⁰ C and at this temperature, a solution of 21.5 g of 2,4-dichloro-3,6-difluorbenzoylchlorid slowly added dropwise in 30 ml of toluene. The mixture is stirred for 1 hour at ^{0 0} C, allowed to come to room temperature overnight and allowed to run under ice-cooling, a mixture of 35 ml of ice water and 5 ml of concentrated sulfuric acid. The phases are separated and back-extracted twice with toluene. The combined toluene solutions are washed once with saturated brine, dried with Na 2 SC 4, and the solvent removed in vacuo. This gives 34.7 g (2,4-dichloro-3,6-difluorobenzoyl) -malonaäurediethyleeter as a crude product,

Le A 26 108

An emulsion of 34.7 g of crude (2,4-dichloro-3,6-difluorobenzoyl) malonate diethyl ether in 40 ml of water is treated with 0.04 g of p-toluenesulfonic acid.

The mixture is heated with vigorous stirring for 3 hours to boiling, extracted the cooled emulsion several times with methylene chloride, the combined CH ₂ Cl ₂ solutions washed once with saturated brine, dried with Na ₂ SO ^ and the solvent is distilled off in vacuo «fractionation of the residue (33.9 g) in vacuo provides 13.9 g (2,4-dichloro-3,6-difluorobenzoyl) -eBsigsäureethylester of boiling point 110-115 ° C / 0.05 mbar. nj: ⁵ : 1.5241.

b) 2- (2,4-dichloro-3,6-difluorobenzoyl) -3-ethoxy-acrylic acid ethers

20

13.7 g (2,4-dichloro-3,6-difluorobenzoyl) -acetic acid ethyl ester are refluxed with 10.25 g of triethyl orthoformate and 11.8 g of acetic anhydride for 2 hours. Subsequently, until 140 ⁰ C.

Bath temperature is concentrated in vacuo and 15.7 g of 2-

(2,4-Di chior-3,6-difluorbenzoyl) -3-ethoxy-ethyl acrylate as an oil, nj " ⁵ : 1.5302.

c) 2- (2,4-dichloro-3,6-difluorobenzoyl) -3-cyclopropyl-amino-ethyl acrylate

15.6 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl) -3-ethoxyacrylate are dissolved in 50 ml of ethanol 35

Le A 26 108

- 129 -

2.75 g of cyclopropylamine are added dropwise with cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added while cooling with ice, the product is filtered off with suction, washed with ethanol / H ₂ O (1: 1) and dried. 14.1 g 2- (2,4-dichloro-3,6-difluorobenzoyl) -3-cyclopropylamino-acrylic acid ethyl ester of melting point 106-107 ⁰ C obtained.

d) 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinone-1-inearbonsäureethylester

6 g of 2- (2,4-dichloro-3,6-difluorobenzoyl) -3-cyclopropylamino-acrylic acid ethyl ester are heated in 2.5 ml of dimethylformamide with 2.75 g of potassium carbonate for 2.5 hours at 150 ⁰ C, the mixture is added to 600 ml Eiswaeser poured, the precipitate sucked off, washed with water and dried. It will be 5.2 g of 5,7-Dich! Lor-l-cyclopropyl-6-f luor-1,4-dihydro-4-oxo-3-chinolincarboneäureethyleeter of melting point 227-229 ⁰ C obtained.

e) 5,7-dichloro-1-cyclopiophenyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are dissolved in a mixture of 38 ml of acetic acid, 30 ml of water and 4.3 ml of concentrated sulfuric acid Heated under reflux for 2.5 hours. After cooling

Le A 26 108

2 ß 5 6 O i

- 130 -

is poured into 250 ml of ice water »the precipitate is filtered off, washed with water and dried. There are obtained 4.8 g of 5 ^ -dichloro-1-cyclopropyl-efluoro-1 # 4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277-278 ⁰ C »

10 example AC

, 7-dichloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-cihydro-4-oxo-3-quinolinecarboxylic acid

a) 2- (2,4-DiChIOr-S ₁ O-UIfluorobenzoyl) -3- (2,4-difluoropheny1amino) acrylic acid ethyl ester

35.3 g of ethyl 2- (2,4-dichloro-3,6-difluorobenzoyl) -3-ethoxyacrylate are dissolved in 120 ml of ethanol and 12.9 g of 2,4-difluoraniin 1 are added dropwise with ice-cooling. The mixture is stirred 1 , 5 hours at room temperature, added under cooling with 120 ml of water, filtered off with suction, washed with ethanol / H2O (IiI) and dried. There are obtained 40.5 g of 2- (2,4-dichloro-3,6-difluorobenzoyl) -3- (2,4-difluorophenylamino) -acrylic acid ethyl ester. Melting point: 84-86 ° C.

Le A 26 108

36 O i

- 131 -

b) 5,7-Dichloro-6-fluoro-1- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethylacetate

43.6 g of 2- (2,4-dichloro-3,6-difluorobenzoyl) -3- (2,4-dif luorphtmylaminol-acrylic acid ethyl ester in 260 ml of dimethylformamide with 15.2 g of potassium carbonate 2.5 hours at 150 ⁰ C. The mixture is poured onto 1 liter of ice water, the precipitate is filtered off with suction, washed with water and dried. 38.6 g of 5,7-dichloro-6-fluoro-1- (2,4-difluorophenyl) -l, 4 dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester.

c) 5,7-dichloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

41.6 g of ethyl 5,7-dichloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylate are mixed with 250 ml of acetic acid, 200 ml of water and 28.5 After cooling, it is poured onto 2 liters of ice-water, the precipitate is filtered off with suction, washed with water and dried. There are 35.5 g of 5,7-DiChIoT-O-Tluor-1- (2,4-difluorophoric)

30 nyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic obtained. Melting point: 244-246 ° C.

Le A 26 108

- 132 -

2 8 S 6 Q i

example 1

A. 855 mg (3 mmol) of l-cyclopropyl-6 _t 7, 8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide in the presence of 330 mg (3.3 mmol) of 1,4-diazabicyclo [2,2,2] octane and 750 mg of trans-3-tert-butoxycarbonylamino-4-methoxypyrrolidine are refluxed for 1 hour. The mixture is evaporated , Stirred with water and dried.

Yield: 1.3 g (90.5% of theory) of 7- (trana-3-tert-B'-toxycarbonylam: ino-4-methoxy-1-pyrrolidinyl) -1-cyclopropyl-1,6,8-difluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic "

Melting point: 222-224 ⁰ C (with decomposition) (from glycol monomethyl ether) "

B. 1.2 g (3.5 mmol) of the product from step A are added to 10 ml of 3N-hydrochloric acid, stirred to the solution and concentrated. The residue is rubbed with ethanol, filtered off with suction and dried at 60 ° in a high vacuum.

Le A 26 108

- 133 -

Yield: 0.73 g (7OX of theory) of 7- (trans-3-amino-4-methoxy-1-pyrrolidinyl) -l-cyclopropyl-6,8-difluoro-4-οκο-3-quinolinecarboxylic acid hydrochloride.

Melting point: 279 ⁰ C (with decomposition). Example 2

Choo

COOH

× HCl

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1, giving:

A, 7- (trans-3-tert, -butoxycarbonylamino-4-methoxy-1-pyrrolidinyl) -1-eye-lopropyl-6-fluoro-1 _} 4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 247- 249 ⁰ C (with decomposition)

7- (trans-3-amino-4-methoxy-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p .: from 293 ° C. (with decomposition)

Le A 26

- 134 -

Example 3

COOH

χ HCl

Analogously to Example 1 is reacted with cis-3-tert-butoxycarbonyl · amino-4-methoxy-pyrrolidine to!

A, 7- (cis-3-tert-butoxycarbonylamino-4-methoxy-1-pyrroleidinyl) -l-cyclopropyl ->, 8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 230-231 ⁰ C (with decomposition)

B, 7- (cie-3-amino-4-methoxy-l-pyrrolidinyl) -l-cyclopropyl-6 »8-difluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride Melting point 201-203 ⁰ C (with decomposition)

Example 4

0OH

₃ CF ₃ COOH

Le A 26 108

2856O ί

- 135 -

A, 1.5 g (5 mmol) of e-chloro-1-cyclopropyl-o, 7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarbone are in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide with 550 mg (5 mmol) of 1 "4-diazabicyclo [2.2.2] octane and 1.2 g (5.6 mmol) of cie-3-tert-butoxycarbonylamino-4-methoxy-pyrrolidine under reflux for 2 hours. It is allowed to cool, the precipitate is filtered off with suction, washed thoroughly with water and dried at 10O ⁰ C in vacuo.

Yield: 2.0 g (80.7X) of 7- (cie-3-tert-butoxycarbonylamino-4-methoxy-1-pyrrolidinyl) J-e-chloro-1-cyclopropyl-o-fluoro-1,4-dihydro-4 -oxo-3-chinolincarboneäure, melting point, '222-225 ⁰ C (with decomposition).

B. 1.9 g (3.8 mmol) of the product from Step A are stirred in 10 ml of trifluoroacetic acid at room temperature for 20 minutes, the solution is concentrated, the remaining oil is evaporated twice with dichloromethane and the residue is stirred with ether. The precipitate is filtered off, washed with ether and dried at 6O ⁰ C in vacuo.

Yield: 1.9 g (97% of theory) of 7- (cis-3-amino-4-methoxy-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid trifluoroacetate, mp 235-239 ⁰ C (with decomposition). 30

Le A 26 108

- 136 -

Example 5 5

× HCl

Analogously to Example 1, cis-3-tert-butoxycarbonylamino-4-methoxypyrrolidine is reacted with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give

A, 7- (cis-3-tertt-butoxycarbonylamino-4-methoxy-lpyrrolidinyl) -l-chinolincarboneäure cyclopropyJ-6-fluoro-l, 4-dihydro-4-oxo-3, melting point 232-233 ⁰ C (under Decomposition).

B, 7- (cis-3-amino-4-methoxy-l-pyrrolidinyl) -l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-chinolincarbonsaure- hydrochloride, melting point 252-256 ⁰ C. (with decomposition) (before sintering) ·

Le A 26 108

Example 6

- 137 -

× HCl

Analogously to Example 1, cie-3-tert-butoxycarbonylamino-4-methoxypyrrolidine is reacted with Z-chloro-1-cyclopropyl-o-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid !

A "7- (cis-tert-butoxycarbonylamino-4-methoxy-l-2Q pyrrole idinyl) -1-eye-l-propyl 1-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 carboxylic acid, mp 214-216 ⁰ C (with decomposition) ·

Β · 7- (cis-3-Amino-4-methoxy-1-pyrrolidinyl) -l- _cyclo-2- propyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 -

carboxylic acid hydrochloride, mp 205-210 ° (with decomposition).

Massenspaktrum! ^m / e 362 (M ⁺ ), 330 (M ⁺ -32), 318 (M ⁺ -CO ₂ ), 286, 260, 41 (C ₃ H ₅ ), 36 (HCl).

Le A 26 108

- 138 -

2S56 O 1

Example 7 5

1.33 g (5 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-ωκ-3-quinolinecarboxylic acid are dissolved in a mixture of 30 ml of acetonitrile and 5 ml of dimethylformamide with 1.1 g (10 mmol) of 1,4-diazabicyclo [2.2.2] octane and 0.55 g (5.4 mmol) of trans-3-amino-4-hydroxy-pyrrolidine and heated under reflux for 1 hour ι The suspension is concentrated 2Q, the The residue is mixed with water, the undissolved product is filtered off with suction and recrystallized from dimethylformamide.

Yield: 1.2 g (73% of theory) of 7- (trans-3-amino-4-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- chinolincarboneaure,

Melting point: 274-278 ⁰ C (with decomposition) ·

Le A 26

2856 O

- 139 -

Example 8 5

850 mg of O mmol) of 1-cyclopropyl-6,7,8-trifluorol * -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 9 ml of pyridine with 630 mg (3.1 mmol) of 2-0 × 5,8-diazabicyclo [4,3, O] nonane dihydrochloride and 500 mg (4.5 mmol) of 1,4-diazabicyclo [2.2.2] octane were refluxed for 1 hour. The mixture is concentrated, the residue with

Water stirred, the precipitate sucked off, with water

washed, dried and recrystallized from glycol monomethyl ether,

Yield: 840 mg (72X of theory) of 1-cyclopropyl-6,8-di-

fluoro-1,4-dihydro-7- (2-oxa-5,8-diazabicycloC4 "3.0] non-8 × yl) -4-oxo-3-quinolinecarboxylic acid, Melting point: 289-291 ⁰ C (with decomposition ); Mase spectrum ^m / e 391 (K ⁺ ), 347 (M ⁺ -CO ₂ ), 331, 306,

294, 262, 234, 98, 41 (C ₃ H ₅ ), 30

Le A 26 108

- 140 -

2856 0 y

Example 9

COOH

Analogously to Example 8 is reacted with 5-methyl-2-oxa-5,8-diazabicyclo [4.3,0] nonane dihydrochloride to give: l-cyclopropyl-6,8-difluoro-1 ^ -dihydro -? - (5 _{-methyl-2-oxa-5>} 8-diazabicyclot4,3,0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid "melting point: from 270 ⁰ C (with decomposition); Mass spectrum: ^m / e 405 (M ⁺ ), 361 (M ⁺ -CO ₂ ) * 331 »112, (100 *).

example

COOH

Le A 26

56 OJ

- 141 -

795 mg (3 mmol) of 1-cycloprapyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide with 890 mg (4.1 mmol) of 5-methyl-2-oxa-5,8-diazabicyclo [4 "3" 0] nonane dihydrochloride and 860 mg (7.8 mmol) of 1,4-diazabicyclo [2.2.2] octane for 2 hours under reflux heated. The

Mixture is evaporated, stirred with water, the

undissolved product is filtered off with suction, washed with water, dried and recrystallized from dimethylformamide. Yield: 0.8 g (69% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-methyl-2-one oxa-5,8-diazabicyclo [4,3,0] -non-8-yl) -4-oxo-3-quinolinecarboxylic acid, melting point 340 ° C. (with decomposition) (the substance already becomes dark when heated above about 300 ° )

Measurement spectrum: ^m / e (M ⁺ ), 343 (M ⁺ -CO ₂ ), 313, 244, 112, (100X).

Example 11

Analogously to Example 10 is reacted with 8-chloro-1-cyclopropyl-6,7-difluoro-l ^ -dihydro ^ -oxo-S-quinolinecarboxylic

Le A 26 108

- 142 -

2850

and obtains e-chloro-1-cyclopropyl-e-fluoro-1> 4-dihydro-7- (5-methyl-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) - 4-oxo-S-quinolinecarboxylic acid, mp 258-262 ⁰ C (with decomposition) (recrystallized from dimethylformamide),

example

COOH

F CoH

2 ⁿ 5

Analogously to Example 10, the reaction is carried out with 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and l-ethyl-6,8-difluoro-1,4-dihydro-4-hydroxybenzoyl 7- (5-methyl-2-oxa-5,8-diazabicyclo [4,3.0} non-8-yl) -4-oxo-3-chinolincarbünsäure, mp 279-281 ⁰ C (with decomposition).

Example

COOH

Le A 26

_ ₁₄₃ - 2856

0.84 g (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4,5-dihydro-4-oxo-3-quinolinecarboxylic acid are in a

Mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide with 0.66 g (6 mmol) of 1,4-diazabicyclo [2.2.2] octane and 0.49 g (3.5 mmol) of 2-methyl-2,8-diazabicyclo [ 4.3, OJnonan heated under reflux for 2 hours. The suspension is concentrated, stirred with 20 ml of water, adjusted to pH 7 with 2N hydrochloric acid, the precipitate is filtered off, washed with water, dried and recrystallized from glycol monomethyl ether,

Yield; 0.7 g (58% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (2-methyl-2,8-diazabicyclo [4,3,0] -non-8- yl) -4-oxo-3-quinolinecarboxylic acid, mp 204.times.207.degree.

20 Example 14

'COOH' Il Il 25

Analogously to Example 13 is obtained with l-cyclopropyl-6,7-

Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (2-methyl-2,8-diazabicyclo [4.3.0] non-8- yl) -4-oxo-3-chinolincarbonsaure,

Melting point 234-236 °. 35

Le A 26 108

- 144 -

2856

Example 15

COOH

Man, It is analogous to Example 13 l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 2,8-diazabicyclo [4,3,0] nonane to give 1 -Cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 265-267 ° (under Decomposition) (recrystallized from dimethylformamide).

B. If the reaction of Example 15 A) is carried out in a mixture of acetonitrile / 1-methyl-2-pyrrolidinone and the crude product is recrystallised from dimethylformamide, l-cyclopropyl-7- <2,8-diazabicyclo [4.3 , 0] Non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of lard 269-271 ⁰ C (with decomposition) The product is identical by chromatographic and spectroscopic comparison with the product prepared according to method A) «

C. 65 g (167 mmol) of Betaine (step A) are dissolved in 330 ml of half-concentrated hydrochloric acid by heating, the solution is concentrated and the residue treated with 300 ml of ethanol is stirred "The undissolved precipitate is washed sucked" with ethanol and 10O ⁰ C dried in vacuum ·

Le A 26 103

2 δ 5 6 O ί

- 145 -

Yield: 66.3 g (93 X of theory) of 1-cyclopropyl-7- (2,8-diazabicycloC4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4- oxo-3-chinolincarbonsaure hydrochior-id, melting point: 303-305 ⁰ C (with decomposition).

Example 16

, Il

0OH

Analogously to Example 13 is obtained with 1-cyclopropyl-6,7-difluoro-1 »4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2,7-diazabicyclo ^, 3.0] octane l-cyclopropyl-7- (2,7 -diasabicycloC3,3,0] oct-7-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 260-282 ° (with decomposition).

Mass Spectrum: ^m / e 357 (M ⁺ ), 313 (100X, M ⁺ -CO ₂ ). 269, 257, 244, 82, 28.

Example 17

'COOH

ι ti ti

__ Analogously to Example 13 is obtained with 1-cyclopropyl-6,7-di

fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2-

La A 26 108

- 146 -

O ί

Methyl 2,7-diazabicyclo [3.3.0] octane 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (2-methyl-2,7-diazabicyclo [3,3,0] oct-7 -yl) -4-oxo-3-chinolincarboneäure, melting point 206-208 ⁰ C (with decomposition).

example

COOH

Analogously to Example 13 is obtained with 2-methyl-2,7-diazabicyr. lo [3,3,0] octane 1-cyclop ropy 1-6,8-di-fluoro-1,4-dihydra-7- (2-methyl-2,7-diazabicyclo [3.3.0] oct-7-yl ) -4-2Q oxo-3-quinolinecarboxylic acid, mp 198-200 ⁰ C (with decomposition).

Example

COOH

A mixture of 2.83 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4-diazabicyclo [2.2.23octane and 1.4 g (1 mmol) 2-methyl-3-oxa-2,7-diazabicycloC3,3,0] octane

Le A 26

- 147 -

856 0

It is refluxed for 1 hour in 20 ml of acetonitrile and 10 ml of 1-methyl-2-pyrrolidinone. The mixture is concentrated in vacuo. The residue is stirred with water (pH 7) and the precipitate is filtered off with suction. The residue is washed with water and dried at 60.degree in vacuo · The crude product (3.7 g) is recrystallized from dimethylformamide,

Yield: 1.9 g (49X of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (2-methyl-3-oxa-2,7-diazabicyclo [3,3 * 0] oct-7-yl) -4-oxo-3 ·· quinol inc ar bonsäur β, mp 221-223 ⁰ C (with decomposition).

Example 20

COOH

Analogously to Example 19, with 2,5-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane to give l-cyclopropyl-6,8-difluoro-1,4 · dihydro-7- (2,5-) Dimethyl-3-oxa-2,7-diazabicyclo [3.3,03-oct-7-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 237-238 ⁰ C reacted (with decomposition).

Example 21

COOH

Le A 26 108

2856 f

- 148 -

Analogously to Example 19, with 2,8-dimethyl-3-oxa-2,7-diazabicyclot.3.3, O] octane to give l-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (2,8- dimethyl-3-oxa-2,7-diazabicyclo [3,3, O] -oct-7-yl] -4-oxo-3-quinolinecarboxylic acid of melting point 197-199 ⁰ C reacted.

¹⁰ Example 22

A, 3 g (10 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1 »4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of 30 ml of acetonitrile and 15 ml of 1-methyl-2 -pyrrolidinone with 1.4 g (11 mmol) of 2,8-diazabicyclo [4.3,03nonane and l, 65g (15 mmol) of 1,4-diazabicyclo [2,2,2] octane for 1 hour under reflux. The suspension is stirred after cooling with e'.wa 150 ml of water before, the undissolved precipitate is filtered off, washed with water and ethanol and dried at 80 ° C / 12 mbar. The crude product is recrystallized from 40 ml of glycol monomethyl ether.

Yield: 2.3 g (57X of theory) of e-chloro-1-cyclopropyl-7- (2,8-diazabicycloC4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid, m.p .: 224-226 ° C (with decomposition),

Le A 26 108

2 8 5 4 0!

- 149 -

B. Prepare analogous to Example 22 A. the crude BeLain, this suspended in 50 ml of water and bring it by the addition of 17 ml of 1 N hydrochloric acid and heating in solution. After cooling in an ice bath, the precipitate is filtered off, washed with ethanol and dried at 100 ⁰ C in vacuo.

Yield: 2.7 g (61 % of theory) of e-chloro-1-cyclopropyl-7- (2,8-diazabicyclo [4,3,0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p .: from 225 ° C decomposition.

Example 23

COOH

Analogously to Example 22, the reaction with 9,! O-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [l, 2,3-de] [1,4] benzoxacin-6-carboxylic acid and the resulting reaction product was purified by chromatography on kiosel gel with dichloromethane / methanol / 17 Xiger aqueous ammonia solution (30: 8: 1) as the eluent. 10- (2,8-DiazabicycloC4,3,0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3- de] [1 »4] benzoxacin-6-carboxylic acid of melting point 291-292 ⁰ C (with decomposition).

Example 24

COOH

Le A 26 108

28S6 OJ

- 150 -

6 g (20 mmol) of i-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro - ^ - oxo-S-quinolinecarboxylic acid are dissolved in 30 ml of 1-methyl-2-pyrrolidinone and 60 ml of acetonitrile with 2 , 2 g (20 mmol) of 1,4-diazabicyclo [2.2.2] octane and 2.7 g (21.4 mmol) of 2,8-diazabicyclo [4,3,0] nonane are heated under reflux for 1 hour, the mixture is in Vacuum largely concentrated, the residue stirred with 200 ml of water, the undissolved crystals filtered off, washed with water and dried.

Yield: 6.3 g (77.4 % of theory) of 1-cyclopropyl-7- (2,8-diazabicycloC4,3,0] non-8-yl] -5,6,8-trifluoro-l, 4- di-

15 hydro-4-oxo-3-quinolinecarboxylic acid

Melting point: 266-269 ⁰ C (with decomposition); after recrystallization from dimethylformamide: melting point * <* 72-273 ° C (under 7.setzung),

20 Example 25

NH ₂ Ο

COOH

4.1 g (10 mmol) of the product from Example 24 are mixed in 40 ml of pyridine with 20 ml of saturated ethanolic ammonia solution and the mixture is heated in an autoclave at 120 ^° C. for 12 hours. The suspension is evaporated, the residue is stirred with water and adjusted to pH 7 with 2N-SalzsBure. The precipitate is filtered off with suction and converted from glycol monomethyl ether.

35 crystallized.

Le A 26 108

2 8 S 6 O j

- 151 -

Yield: 0.7 g (17 X theory) of S-amino-1-cyclopropyl-7- (2, P-diazabicycloC4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro- 4-ojCo-3-quinolinecarboxylic acid, melting point: 275-277 ⁰ C (under Zereetzunq).

Mass spectrum ^m / e 404 (M ⁺ ), 384 (M ⁺ -HF), 290, 249,

96 (100X).

Example 26

COOH

λ. Analogously to Example 13 is obtained with 2,7-diazabicyclo [3,3,0] octane l-cyclopropyl-7- (2,7-diazabicyclo-C3,3iO] oct-7-yl) -6,8-difluoro-l , 4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 277-280 ° (with decomposition),

B. 370 mg of the betaine are dissolved in 13 ml of half-concentrated hydrochloric acid, the solution was concentrated and the residue treated with 10 ml of ethanol. The undissolved product is filtered off with suction, washed with ethanol and dried. Yield: 290 mg of 1-cyclopropyl-7- (2,7-diazabicyclo-C3.3.0] oct-7-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 269-271 ⁰ C (with decomposition).

Le A 26 108

- 152 -

5 * 01

example

COOH

CH ₃ -NH /

The reaction is carried out analogously to Example 8 using trans-4-methoxy-3-methylaminopyrrolidine dihydrochloride. 1-Cyclopropyl-6,8-difluoro-1-dihydro-ω- (trans-4-methoxy-3-methylamino) is obtained. 1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid, m.p .: 268-270 ⁰ C (with decomposition) «

example

COOC ₂ H ₅

H ₂ N

XCF ₃ COOH

A. 1.4 g (2.9 mmol) of product from Example 3 A) and 1.98 ml (1 * 7 g, 12 mmol) of dimethylformamide-diethyl acetal are heated in 2o ml of absolute dimethylformamide for 2 hours at 120 ⁰ C. Then you narrow in a vacuum. The remaining residue is stirred with acetonitrile. The precipitate is filtered off, washed with a little acetonitrile and dried.

Le λ 26

2866

- 153 -

Auebeute; T, 8 g (54.4 X of theory) of 7- (cie-3-tert-butoxycarbonylamino-4-methoxy-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1-dihydro-A- oxo-S-quinolinecarboxylic acid ethyl ester, m.p. 151-152 ⁰ C.

B. 0.3 g (0.6 mmol) of Example 28 A) are stirred in 10 ml of trifluoroacetic acid at 20 ° C for 10 minutes. The trifluoroacetic acid is then removed in vacuo. The residue solidifies on addition of diethyl ether. The solid is isolated, washed with diethyl ether and dried.

Yield: 0.25 g (80.6 X of theory) of 7- (cis-3-amino-4-methoxy-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxo-3-chinolincarbonsäureethy1ester trifluoroacetate melting point: 124-126 ⁰ C.

Example 29

COOH

Analogously to Example 13, with 2-methyl-4-oxo-2,8-diazabicyclo [4.3.0] nonane 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (2-methyl-4-) oxa-2,8-diazabicycloC4.3,03non-8-yl) -4-oxo-3-chinolincarbonsiure, mp 258-260 ⁰ C (with decomposition).

Le A 26 108

example

- 154 -

COOH

Analogously to Example 19, 3-0xa-2,7-diazabicyclo [3,3,0] octane gives 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-oxa-2,7-diazabicyclo [ 3,3,0] octan-7-yl) -4-oxo-3-cholinecarboxylic acid.

example

COOH

× HCl

^C 2 ^H 5

A. 2.53 g (10 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 30 ml of acetonitrile and 15 ml of dimethylformamide with 1.1 g (10 mmol). 1,4-diazabicyclo [2.2.2] octane and 1.4 g (11 mmol) of 2,8-diazabicyclo [4.3.0] nonane are added and the mixture is refluxed for 1 hour. The mixture is concentrated, combined with water

Le A 26

2 ö 5 ό 0 I

- 155 -

stirred and the precipitate removed, washed with water and dried. "

Yield: 3.1 g (86% of theory) of 7- (2,8-diazabicyclo [4.3,03non-8-yl) -l-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid, m.p .: 259- 261 ⁰ C (under decomposition)

 10

B. 2.9 g (8 mmol) of the betaine from stage A are dissolved in 20 ml of half-concentrated hydrochloric acid in the heat, the solution filtered hot and precipitated from the filtrate by addition of ethanol, the hydrochloride, this

15 is filtered off, washed with ethanol and dried at 120 ° C / 12 mbar,

Yield: 1.8 g (57 Y, theory) of 7- (2,8-diazabicyclo-C4,3,0] non-8-yl) -1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid Hydrochloride, melting point with decomposition: 299 ° C

20 (starting at about 215 ⁰ C incipient dark coloring)

Example 32

'COOH

Analogously to Example 31 is obtained with 1-cyclopropyl-6,7-di

fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ·

Le A 26 108

HS6 O i

- 156 -

A. 1-Cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) 6-fluoro-4-oxo-3-quinolincarboxylic acid,

Melting point: 249-257 ^J C (with decomposition)

B, l-cyclopropyl -? - (2,8-diazabicycloC4.3.0] non-o-yl) 6-fluoro-4-oxo-3-quinolcarboxylic acid hydrochloride, melting point with decomposition: 320 ° C (already from approx 288 ⁰ C dark hibernation).

Example 33

, U

'COOH

1.1 g (3 mmol) of 1-cyclopropyl -? - (2,8-diazabicyclo [4,3,0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo 3-quinolinecarboxylic acid are refluxed in 10 ml of dimethylformamide and 1 ml of formic acid for 4 hours. The mixture is concentrated by evaporation »the residue is stirred with 4 ml of water, the precipitate is filtered off with suction, dried (crude yield: 1 g, content: 99.5 ×) and recrystallised from dimethylformamide.

Example: 0.8 g (64 X of theory) of 1-cyclopropyl-6,8-difluoro-7- (2-formyl-2,8-diazabicycloC4,3,0] non-8-yl) -l, 4-dihydro- 4-oxo-3-quinolinecarboxylic acid, melting point: 276-278 ⁰ C.

Le A 26 108

35

- 157 -

3 5 6

Example 3 4 5

1.1 g (3 nunol) of 1-cyclopropyl - - (2,8-diazabieyelo [4,3,0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3- chinolincar-

<c Bonsäure are dissolved in a mixture of 8 ml of dioxane and a solution of 120 mg of sodium hydroxide in 1 ml of haters and treated simultaneously with 3 ml of in-Natrcnlauge and 260 mg of acetyl chloride with ice cooling. The mixture is stirred for 2 hours at room temperature, diluted with

2q 30 ml of water and sucks off the precipitate. The crude product is recrystallized from glycol monomethyl ether.

Yield: 0.6 g (46 X theory) of 7- (2-acetyl-2,8-diazabic eye lo [4, 3.0] non-8-yl) -l-cyclopropyl-6,8-difluoro-

2g 1 »4-dihydro-4-oxo-3-chinolincarboneäure, Melting point: 261-263 ⁰ C (with decomposition)

Example 35 30

: ooh

Ls A 26 10 8

- 158 -

A similar to Example 13 is obtained with 8-chloro-l-cyclopropyl-6,7-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2-methyl-2,7-diazabicyclo [3,3, O] octane 8-chloro-1-eyepropyl-6-fluoro-1,4-dihydro-7- (2-methyl-2,7-diazabicycloC 3,3,0] oct-7-yl) -4-oxo-3 quinolinecarboxylic acid, melting point: 222-227 ⁰ C (with decomposition) «

B, 2.3 g (5.8 mmol) of the betaine from stage A are dissolved in 15 ml of 1N hydrochloric acid under heat, the solution is evaporated and the residue is treated with ethanol. The precipitate is filtered off with suction, washed with ethanol and dried.

Yield: 2.2 g (87.7 X of theory) 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (2-methyl-2,7-diazabieye 1o [3.3.0 ] oct-7-yl) -4-oxo-3-chino1inearboneäure hydrochloride, melting point: 303-305 ⁰ C (with decomposition)

Example 36

COOH

× HCl

Analogously to Example 13, with 3-methyl-2,7-diazabicyclo [3,3, O] octane l-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-methyl-2,7- diazabicyclo [3,3,0] oct-7-yl) -4-oxo-3-quinolinecarboxylic acid and, analogously to Example 15, C. with half-concentrated hydrochloric acid in 1-cyclopropyl-6,8-diol;

Le A 26 108

- 159 -

fluoro-1,4-dihydro-7- (3-methyl ^^ - diazabicycloCS, 3.0] oct-7-yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point 216-221 ⁰ C (with decomposition) Überfuhrt.

Example 37

COOH

A. A mixture of 1.45 g (5 mmol) of 1-cyclopropyl

6 »7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.85 g (7.5 mmol) of 1, 4-diazabirycyclo [2,2,2] octane and 0 , 77 g (5.5 mmol) of 2,3-dimethyl-2,7-diazabicyclo [3,3,0] octane in 15 ml of acetonitrile and 7.5 ml of dimethylformamide is heated under reflux for 1 hour. After cooling, the precipitate is filtered off with suction, mi '. Water and recrystallized from glycol monomethyl ether, yield: 1 g (47 X of theory) of 1-cyclopropyl-7- (2,3-dimethyl-2,7-diazabicycloC2,2.2] oct-7-yl) -6,8-difluoro -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point '208-209 ⁰ C (with decomposition).

B. 0.7 g (1.7 mmol) of the betaine from stage A are dissolved hot in 6 ml of half-concentrated hydrochloric acid, the solution filtered and largely concentrated in vacuo. It is mixed with about 15 ml of ethanol, cooled in an ice bath, the salt is filtered off with suction, washed with ethanol and dried at 100 ° C / 1 mbar.

Le A 26 108

2 8 5 6 O I

- 160 -

Yield: 0.64 g (84 Y, theory) of 1-cyclopropyl-7- (2,3-dimethyl-2,7-diazabicycloC2,2,2 3ocL-7-yl) -6,8-d-fluoro-1 , 4-dihydro-4-oxo-3-chinolinearboneäure hydrochlorides melting point: 233-236 ⁰ C (with decomposition).

example

COOH

× HCl

Analogously to Example 37 A. and B. obtained with 8-chloro-1-cyclopropyl-6,7-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid 8-chloro-l-cyclopropyl-7- (2 , 3-dimothyl-2,7-diazabicycloC2.2.2] oct-7-yl) -6-fluoro-1 '4-dihydro-4-oxo-3-chinolincarboneäure hydrochloride, melting point: 240-241 ⁰ C (with decomposition ) ·

example

COOH

Analogously to Example 19, 1,2-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane is converted into 1-cyclopropyl-6,8-difluoro-1> 4-

Le A 26

2 8 5 <O i

- 161 -

dihydro-7- (l, 2-dimethyl-3-oxa-2,7-di-azabicyclo [, 3.0] -oct-7-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 269-271 ⁰ C (with decomposition ) implemented.

Example 40 ¹⁰ O

, Il

COOH

× HCl

2.6 g (8.7 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of

Echung from 25 ml acetonitrile and 12.5 ml dimethylformamide with 1.45 g (13 mmol) 1,4-diazabicyclo [2.2.2] octane and 1.23 g (9.6 mmol) 2-oxa-5,8- added diazabicyclo [4,3,0] nonane and heated under reflux for 1 hour · The mixture is concentrated, the residue stirred with water

and the undissolved precipitate was filtered off with suction and washed with water. This crude 1-cyclopropyl-e-chloro-o-fluoro-1,4-dihydro-7- (2-oxa-5,8-diazabicyclo [4,3,0] non-8-yl) -4-oxo-3 Quinoline carboxylic acid is introduced into 85 ml of 1N hydrochloric acid and mixed with 6 ml of concentrated hydrochloric acid.

The precipitated hydrochloride is filtered off, with Ethanol and dried.

Yield: 3.0 g (77.7 X theory) of 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (2-oxa-5,8-diazabicyclo-C4.3.0 ] non-8-yl) -4-oxo-3-quinolinecarboxylic acid hydro-chloride, melting point: from 290 ° C decomposition »

Le A 26 108

- 162 -

285

example

COOH

Analogously to Example 13 is obtained with 8-chloro-1-cyclopropyl-6 »7-di-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2-methyl-4-oxa-2,8-diazabicyclo [4 , 3.0] nonane 8-chloro-1-cyclopropyl-o-fluoro-Z- (2-methyl-4-oxa-2,8-diazabicyclo [4,3,0] non-8-yl) -4-oxo-3 -quinolinearbone acid, melting point! 202-203 ⁰ C (with decomposition) FAB mass spectrum ί ^m / e 422 UM + H] ⁺ ), 404 (422-H ₂ O).

example

COOH

A. Analogously to Example 13, with 2,7-diazabicyrjlo-C3.3.0] octane-2-carboxylic acid ethyl ester, 1-cyclopropyl-7- (2-ethoxycarbonyl-2,7-diazabicyclo [3,3,0] oct-7-yl) is obtained. -6,8

Le A 26

- 163 -

difluoro-1 »4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 191-192 ⁰ C reacted.

B, 1.8 g (4 mmol) of the product from Example 42A are heated in 30 ml of concentrated hydrochloric acid with gentle reflux for 15 hours. The solution is concentrated. The residue is stirred with ethanol, the precipitate is filtered off with suction, washed with ethanol and concentrated at 140.degree ° C / 12 mbar dried.

Yield: 1.1 g (67 X of theory) of 1-cyclopropyl -? - (2,7-diazabicyclo [3.3.0] oct-7-yl) -6,8-difluoro-1,4-dihydro-4- oxo-S-quinolinecarboxylic acid hydrochloride, melting point: 273-275 ⁰ C (with decomposition), the product is identical with the compound obtained according to example 26B.

Example 43 20

A, 7.8 g (20 mmol) of 1-cyclopropyl-7- (2,8-diazabicyclo- [4,3,0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo 3-Chino-1incarbonsaure be entered in 175 ml of ethanol and treated at about 7O ⁰ C with 2.4 g (25 mmol) of methanesulfonic acid. The betaine dissolves and on cooling the salt precipitates, which is filtered off, washed with ethanol and dried at 120 ° C / 12 mbar. It is easily soluble in water

Yield: 8.6 g (88.6 X of theory) of 1-cyclopropyl-7- (2,8-diazabieyelo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihy- dro-4-oxo-2-quinolinecarboxylic acid mesylate, m.p. 262-265 ί ⁰ C (with decomposition)

Analogously, one obtains: 35

Le A 26 108

2 β 5 ^ O ί

- 164 -

B. 1-Cyclopropyl-7- (2, 8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

Tosylate, melting point: 248-250 ⁰ C (with decomposition).

C. 1-Cyclopropyl-7- (2,8-diazabicyclo [4,3'0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid lac did, melting point: 205 ° C-215 ° C after previous sintering

Example 44

15 3.9 g (ίο mtnol) 1-cyclopropyl - - - (2,8-diazabicyclo-)

C4.3.0] non-8-yl) -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 50 ml of water and admixed at room temperature with 10 ml of 1N sodium hydroxide solution, the product is largely dissolved off. A slight turbidity is separated off by filtration through a membrane filter, the filtrate is concentrated under high vacuum and the residue is stirred with ethanol, filtered off with suction and dried

Yield: 3.4 g (82.7 X of theory) of 1-cyclopropyl-7- (2,8-diazabicycloC.sub.4 "3,0" non-8-yl) -6,8-difluoro-1,4-dehydro-O- 4-oxo-3-quinolincarboxylic acid sodium salt; the salt decomposes slowly above 210 ^° C. without melting,

Example 45 30

HO-CH ₂ CH _2x N

COOH

Le A 26 108

- 165 -

A mixture of 3.9 g (10 mmol) of 1-cyclopropyl -? - (2, βαχazabicycloC4,3,0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo 3-quinolinecarboxylic acid in 100 ml of dimethylformamide with 4.2 g of triethylamine and 2.8 g of 2-bromoethanol is heated to 80-100 ⁰ C for 20 hours. Thereafter, the solution is concentrated in vacuo and the residue obtained is purified by chromatography on 200 g of silica gel (eluent CH ₂ Cl ₂ / CH ₃ OH / 17 X -NH ₃ = 30: 8: 1). The eluate is concentrated, stirred with ethanol, filtered off with suction and dried. Yield! 1.8 g (41.6 X of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [2- (2-hydroxyethyl) -2,8-diazabicyclo ^ · 3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid, melting point: 200-206 ⁰ C (with decomposition).

Mass spectrum: ^m / e 433 (M ⁺ ), 402 (M ⁺ -CH ₂ OH), 140, UO

(100X), 96

Example 46

COOH

Cho

Analogously to Example 13, with trans-3-ethylamino-4-methylthio-pyrrolidine to give l-cyclopropyl-7- (trans-3-ethylamino-4-methylthio) -6,8-difluoro-1,4-dihydro-4 reacted oxo-3-quinolinecarboxylic acid, melting point: 215-216 ⁰ C (with decomposition).

Le A 26 108

example

2856 Ö ί

- 166 -

 "-Ν-

Analogously to Example 13, 2-phenyl-2,7-diazabicyclo-C3,3,0] octane is added to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (2-phenyl) 2,7-diarabicyclo [3,3,0] oct-7-yl) -3-chinolincarbonsaure reacted, melting point: 259-260 ⁰ C (with decomposition) "

example

COOH

Analogously to Example 13 is obtained with 5,6,7,8-tetrafluoro-1- (2,4-difluorophenyl) -1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid 5,6,8-trifluoro-1- ( 2,4-difluorophenyl) -1,4-dihydro-7- <2-methyl-2,8-diazabicyclo [4,3,0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid.

Le A 26

Example 49

- 167

28S6 O I

10

F O

OOH

20

Analogously to Example 24 is obtained with 5,6,7,8-tetrafluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinearbonsäure 7- (2,8-diazabicyclo [4.3. 0] non-8-yl) -5,6,8-trifluoro-1- (2,4-difluorophenyl) -1 '4-dihydro-4-oxo-3-quino-1incarbonsaure,

Example 50

25 30

NH ₂ Q

COOH

35

Analogously to Example 25, 7- (2,8-diazabicyclo- [4,3,0] non-8-yl) -5,6,8-trifluoro-1- (2,4-difluorophenyl) -1,4 is obtained dihydro-4-oxo-3-quinolinecarboxylic acid 5-amino-7- <2.8-

Le A 26 108

5 * 0!

- 168 -

diazabicyclo [4,3,0] non-8-yl) -6,8-difluoro-1- (2,4-difluoro-phenyl) -l-dihydroM-oxo-S-quinolineearbonic acid.

Example 51

Cl O

COOH

Analogously to Example 15 A is obtained with 5, / - dichloro-1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid (5 hours reflux) S-chloro-l-cyclopropyl-Z- ( 2,8-diazabicyclo [4,3,01non-8-yl) -6-fluoro-l "4-dihydro-4-oxo-3-chinolincarbonsaure. Melting point: 270 ° C (decomposition).

Example 52

Cl

COOH

Le A 26 108

2 BUO

- 169 -

Analogously to Example 8 is obtained with 5, / - dichloro-1-cyclopropyl-of luor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (5 hours reflux) S-chloro-1-cyclopropyl-e-fluoro-1 , 4-dihydro-7- (2-oxa-5,8-diazabicyclo [4,3,0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid.

example

Cl

COOH

Analogously to Example 15 A are obtained with 5,7-dichloro-6-fluoro-1- (2, 4-difluorophenyl) -l '4-dihydro-4-oxo-3-quinolinecarboxylic acid (5 hours under reflux) of 5-chloro-7 - (2,8-diazabicyclo [4,3.0] non-8-yl) -6-fluoro-1- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid,

example

Cl 0

COOH

Le A 26

2BS6 O ί

- 170-

Analogously to Example 8, 5 -7-dichloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (5 hours reflux) is obtained in the same way. Chloro-6-fluoro-1- (2,4-difluorophenyl) -l, 4-dihydro- 7- (2-oxa-5,8-diazabicyclo C4, 3.0 3non-8-yl) -4-oxo-3- quinolinecarboxylic "

10 Example 55

₁₅ C ₂ H ₅ NH

Analogously to Example 13, with trans-3-ethylamino-4-methylthio-pyrrolidine and e-chloro-1-cyclopropyl-o, 7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to 8-chloro-l-cyclopropyl -7- (Trane-3-ethylamino-4-methylthio-l-pyrrolidinyl) -6-fluoro-1, 4-dihydro-4-oxo-3-chinoIinearbonsäure reacted, melting point: 217-218 ⁰ C (with decomposition). 25

Le A 26 108

- 171 -

2β 5 rf OJ

Example 56

10 15 20

Η, Ν im

COOH

χ HCI

CH ₃ S

Analogously to Examples 13 and 15, trans-3-amino-4-methylthiopyrrolidine gives 7- (trans-3-amino-4-methylthio-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid, m.p .: 208-211 * C (with decomposition) and 7- (trans-3-amino-4-methylthio-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, mp: 255-257 * C (with decomposition).

Example 57

25 30 35

COOH

χ HCl

Analogously to Example 13 and 15, 4-methyl-2, e-diazab-1-cyclo-1,3-nano-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (4-) is obtained. methyl-2,8-diazabicyclo [4,3,0] non-8-yl) -4-OXO-3-quinolinecarboxylic acid, m.p .: 213-215 * C (with decomposition) (recrystallized from glycol monomethyl ether) and 1-cyclopropyl-6, 8-difluoro-1,4-dihydro-7- (4-methyl-2, βA 26, 108

2856 O \

- 172 -

, diazabicyclo [4.3.0] non-8-yl) ^ - oxo-S-quinolinecarboxylic acid-5 hydrochloride, m.p .: 204-212 * C (with decomposition).

The product consists of a mixture of 2 stereoisomers,

Le A 26 108

Claims (1)

claims Process for the preparation of 7- (1-pyrrolidinyl) -3-quinolone and -naphthyridone-carboxylic acid derivatives and their pharmaceutically usable hydrates and acid addition salts, and the alkali, alkaline earth, silver and guanidiniuine salts of the underlying carboxylic acids and optionally their pharmaceutical Administration form, characterized in that
(A) Compounds of the formula (I) COOR ' (D, in which X is halogen, X is hydrogen, amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms each
Alkyl group, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms,
Arylthio, halogen, R is alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethylamino, phenyl optionally substituted by 1 or 2 fluorine atoms, R is hydrogen, alkyl having 1 to 4 carbon atoms or (5-i'iethyl-2-oxo-l, 3-dioxol-4-yl) -methyl and R for a rest of the structure X 7-R R "M R " is v / orin, for H, , Aryl, C ₁ -U ₄ - R ^{5 is} H, C ₁ -C ₄ -alkyl, QH, OCrI ₃ , where R ⁴ and R together may also denote a C ₁ -C ₄ -alkylene bridge, which is optionally monosubstituted or disubstituted by methyl, R ° is H, optionally substituted by hydroxy C ₁ -C ₄ -AlkVl, and aryl, heteroaryl, benzyl, C, -C ₄ alkoxycarbonyl, C ₁ -C ₄ acyl, (5-methyl-2-oxo-l , 3-dioxol-4-yl) -methyl or CjC.-cycloalkyl, R ^{7 is} H or R ^{1 is} H, CH ₇ or phenyl, 8 5 - 475 " R "is H, CH ₃ or phenyl, R " ¹ for H or CH ₃ , Y is Q, CH _2, CH ^ CH ₂ or CH ₂ -O can stand, wherein the combination of the CH ₂ -0 group to the nitrogen can take place both via 0 or via CH _2, Z can stand for 0 or S,
A is N or CR ⁸ in which R is H, halogen, methyl, cyano, nitro, hydroxy or methoxy or together with R a bridge of the structure -Q-CH ₂ -CH-CH ₃ , -S-CH ₂ -CH-Ch ₃ or CH ₂ -Ch ₂ -CH-CH ₃ can be formed by reacting compounds of the formula (II) in which COOR ' (II) 12 1 2
R, R, X and X are as defined above and X is halogen, in particular fluorine or chlorine, with compounds of the formula (III) R ³ -H (III) in which 2854 \\ iii (j in claim 1 lint, ueduutuuy has, Lsuuuutiiny eUiiiiKiii'alis in Geyenwari. translated by Se'urelsnyern, and, if necessary, included in R ^J , SchtitZyrupoen ibdspal tt - 'i :; dl! he iJ) Lljunj ft η animal Forrnül (O ybiTiäü Aiis [) ruoil]., COOR ' (D, 1 1 V ⁿ X, i \ ", R ', R ^J and A uie üol ^j ii iinijeyebenä iJecieutunn have and X "for amino, Alkylan.ino with 1 to 4 cooling stage la toniün, Uialkylaiiiiriü with 1 to 3 Kuhlens tuf fatuiiieii per alkyl -jujjpe, HyiJroxy, alkoxy with 1 to 4 Kohlenstuffaturnen or Auylthiü stands, t, by adding a connection. the Furrnol (IV) 2856 f - 477 ' (IV), in which 112 X, R, R, R and A are as defined above, with compounds of the formula (V) X ² -H in which 2
X has the abovementioned meaning, if appropriate in the presence of bäursfängern converts; or C) compounds of the formula (Ia) (Ia) in which 2 ß 5 6 O 1 12 12
X, X, R, R and A are as defined above and R is a radical of the structure , 4 R 'Z-R R " R ¹ ^ R ¹ R "R ¹ stands in what R ⁴ , R ⁵ , R ⁶ , R ¹ , R ", R" ¹ , Y and Z have the abovementioned meaning, prepared by reacting a compound of the formula (VI) COOR ' in which 19 1? X, X ₁ R, R and A are as defined above and 3a
R for a rest of the structure 2856 O ί Z-R ' 173 ' or R ^! R " stands, wherein R ⁴ , R ⁵ , R ', R ", R ¹ ", Y and Z are as defined above, with compounds of the formula (VII) R ⁶ -X ^a (VII) in which R has the meaning given above and X is chlorine, bromine, iodine, hydroxy or acyloxy, if appropriate in the presence of acid scavengers and, if appropriate, and the compounds prepared by this process are processed with a pharmaceutical carrier to pharmaceutical administration forms, for example to medicines or animal feeds.