NZ239485A - Diazabicyclo(3.3.0)octane and (4.3.0)nonane compounds and trans-3-(ethyl or methyl) amino-4-methylthio-pyrrolidine - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £39485 23 9 4 8 5 Patents Form 5 | Priority Date<s):..X^.....7X...O.^.f , Compel® Specification Filed: Ctass: . .C.Q. TI to. If &.T]. 1.C. T... <r£>. n .Q &./. .C. it- f. — - ^ -2l.U^U^ i^r.O.. . ,1 | >W<^ . b Sr»»* »VJ» «-^T.Cti i • «T»«/ * W*-* **• • •1 ■ -—to* Date: .'ubflcation Oaie: ^..^.1'— I P'O- Journal,-No: J.3.> .5it No: ~>3,wl.W; NO DRAWINGS Under the provisions o1 Regulation 23 (1) the ,, '•» r> \ -;• ;A:' ■ x ■ 1 v t • Divided out of NZ Patent Application No. 229914 Specification has been ante-dated to. 19 St NEW ZEALAND Patents Act 1953 Initials COMPLETE SPECIFICATION COMPOUNDS We, BAYER AKTIENGESELLSCHAFT, a body corporate organized under the laws of the Federal Republic of Germany, at Leverkusen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) 239485 The invention relates to new compounds.

A number of 3-quinolone- and naphthyridonecarboxylic acids which are substituted in the 7-position by a pyrro-lidinyl ring have already been disclosed. German Patent Application 3,318,145 and European Patent Applications 106,489, 126 355 and 153 826, It has been found that the 7-(1-pyrrolidinyl)-3-quinolone- and naphthyridonecarboxylic acid derivatives of the formula (I) in which X1 represents halogen, X2 represents hydrogen, amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms, arylthio or halogen, represents 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, methyl amino, ethylamino, dimethyl-amino or phenyl which is optionally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl, represents a radical of the structure wherein ra can represent H, Ci-C^-alkyl, aryl or Ci-C^-acyl, R5 can represent H, Ci-C^-alkyl, OH or OCH3, it also being possible for R* and R5 together to denote a C1-C3-allcylene bridge which is optionally mono- or disubstituted by methyl, R8 can represent H, optionally hydroxyl-substi- tuted C^-C^-alkyl, as well as aryl, heteroaryl, benzyl, 23 9* Cj-C^-alkoxycarbonyl, Ci-C^-acyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl, or C3-C6-cyclo-alkyl, R7 can represent H or C1-C4-alkyl, R' can represent H, CH3 or phenyl, R" can represent H, CH3 or phenyl, R'" can represent H or CH3, Y can represent 0, CH2, CH2CH2 or CH2-0, it being possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CH2, and Z can represent 0 or S, and represents N or C-Ra, wherein R8 represents H, halogen, methyl, cyano, nitro, hydroxyl or methoxy or, together with R1, can form a bridge having the structure -0-CH2-CH-CH3, -S-CH2-CH-CH3 or f t -ch2-ch2-ch-ch3 and phannaceutically usable hydrates and acid addition salts thereof and the alkali metal, alka 239485 (f* ,'aws line earth metal, silver and guanidinium salts of the underlying carboxylic acids, have a high antibacterial action, in particular in the Gram-positive region.

Preferred compounds are those of the formula (I) in which X1 represents fluorine or chlorine, X2 represents hydrogen, amino, alkylamino having 1 or 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercapto, methylthio, phenylthio, fluorine or chlorine, R1 represents alkyl having 1 to 3 carbon atoms, alkenyl having 2 or 3 carbon atoms, cycloalkyl having 3 to 5 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethylamino or phenyl which is optionally substituted by 1 or 2 fluorine atoms, R2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl, lo a as L 39 4 8 represents a radical having the structure p- R' Z-R* i / ■N -N R' -z /-f- ' "v -/ R" R" wherein R* can represent H, Ci-Cs-alkyI or C1-C2-acyl/ R3 can represent H, C1-C3-alkyl, OH or OCH3/ it also being possible for RA and R5 together to denote a Cj-C2-alkylene bridge which is optionally mono- or disubstituted by methyl, can represent H, optionally hydroxyl-substitu-ted Ci-Cj-alkyl, as well as phenyl, benzyl, C^-c -alkoxy-carbonyl, C1-C2-acyl , (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl, or C3-C5-cycloalkyl, can represent H or Ci-Cj-alkyl, can represent H or CH3, can represent H or CH3, R"' can represent H or CH3, Y can represent 0, CH2, CH2CH2 or CHz-0, it being » v m o. 2 3 8 p possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CHZ, and Z can represent 0 or S, and A represents N or C-R8, wherein R8 represents H, fluorine, chlorine, bromine, methyl, nitro, hydroxy1 or methoxy or together with R1 can form a bridge having the structure -Q-CHo-CH-CH3 .

* I Particularly preferred compounds are those of the formula 10 (I) in which X1 represents fluorine, X2 represents hydrogen, amino, methylamino or fluorine, IS R1 represents a-lkyl having 1 or 2 carbon atoms, vinyl, cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, methylamino, 4-fluorophenyl or 2,4-difluorophenyl, fca ft D'O (f* 2 3 8 4b? R2 represents hydrogen or alkyl having 1 or 2 carbon atoms, represents a radical having the structure -N R' Z-R Ah - R' R- Z)—R7 , -N^ -N H- V -N R" wherein R* can represent H, C^-Cj-alkyl or acetyl, can represent H or Ci-Cj-alkyl, it also being possible for R* and R5 together to form a Ci-Cj-alkylene bridge which is optionally substituted by methyl, R6 can represent H, CH3, C2H5, HOCH2CH2/ benzyl, Cx-C4-alkoxycarbonyl or Cj-Ci-acyl, R7 can represent H or CH3/ R' can represent H or CH3, can represent H or CH3, R"' can represent H or CH3/ Ijil a 20 i 5 9 4 P K Y can represent 0, CH2, CH2CH2 or CH2-0, it being possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CHZ, and R8 represents H, fluorine or chlorine, or together with R1 also can form a bridge having the structure Compounds of the formula (I), processes for their production and medicaments, animal feed or additives and premixes containing compounds of the formula (I) are described and claimed in New Zealand Patent Specification No. 229914.

It has furthermore been found that the compounds of the formula (I) are obtained by a process in which compounds of the formula (II) in which R1, R2, X1 and X2 have the abovementioned meaning and Z can represent 0 or S, and A represents N or C-Ra, wherein -o-ch2-ch-ch3 . x2 0 (II) represents halogsn, in particular fluorine or chlorine, are reacted with compounds of the formula (III) WW R3-H (III) in which R3 has the abovementioned meaning, if appropriate in the presence of acid entrainers, and if appropriate protective groups contained in R3 are removed (method A) .

Compounds of the formula (I) have been found in which X1, R1, R2, R3 and A have the abovementioned meaning and X2 represents amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, 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) 6+ i*s U 29 JAI,\199„ ~5JQ' j*L u €' ( ( f* f 231)485 F 0 X1\^V^A^coor2 <IV' •i R1 in which X1, R1, R2, R3 and A have the abovementioned meaning, with compounds of the formula (V) X2-H (V) in which X2 has the abovementioned meaning, if appropriate in the presence of acid entrainers (method B).

Compounds of the formula (la) have been found X2 0 X1>v_;^\w^\^CQ0p2 (Ia) ^ JL If II 'l R1 in which X1, X2, R1, R2 and A have the abovementioned meaning and R3 represents a radical having the structure ■K ' \ <*\\ '1 - 29 JAN 1992 iijVinjifi™.g.&iQ - 10 - " R' Z-R^ -N R R6 wherein R' or -N >-R' Y -Nx R*, R5, R6, R', R", R"', Y and Z have the abovementioned meaning, can also be obtained by a process in which a compound of the formula (VI) X2 0 COOR' (VI) in which X , X , R , R and A have the abovementioned meaning and R represents a radical having the structure - N R' Z-R4 A—( r i H R' or -N VI >-f Y R" liO Ik 2? lfi)9 2 3 8': wherein R*, R3, R', R", R"', Y and Z have the abovementioned meaning, is reacted with compounds of the formula (VII) R6-X* (VII) in which R6 has the abovementioned meaning and X* represents chlorine, bromine, iodine, hydroxyl or acyloxy, if appropriate in the presence of acid entrainers (method c).

If, for example, l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methyl-oc t ahydr opyrr olo[ 3,4-b] pyridine are used as starting 15 substances, the course of the reaction can be represented by the following equation: Lo A 239485 o ch3 If, for example, 7-chloro-6-fluoro-l-(4-fluorophenyl)-1,4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic acid and cis-3-tert.-butoxycarbonylamino-4-methoxy-pyrrolidine are used as starting substances, the course of the reaction can be represented by the following equation: 23 9 4 8 5 cooh CH30 NH (ch3)3c-o-co-nh Basa -HCl CH30fcY^-; (CH3)3C-O-CO-NHV cooh HCl CH.

COOH nh- F x HCl fca h ag liOB 2 3 9 4 6 5 If, for example, l-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7-(2-methyl-2,7-diazbicyclo[3.3.0]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid and ammonia are used as starting substances, the course of the reaction can be represented by the following equation: If, for example, l-cyclopropyl-7-(2,7-diazabicyclo-[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and ethanool/hydrogen chloride are used as starting substances, the course of the reaction can be represented by the following equation: F 0 VH2 0 'cooh The compounds of the formula (II) used as starting substances are known or can be prepared by known methods. 5 Examples which may be mentioned are: 7-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,142,854» corresponding to NZ 202 278), l-cyclopropyl-6,7 -dif luoro-1,4-dihydro-4-oxo-3-quinoline-10 carboxylic acid (European Patent Application 113,091), 6-chloro-l-cyclopropyl-7,8-df luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743, corresponding to NZ 212 272), Lft'-A SO 100 ( / 3 9 4 8 5 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743), l-cyclopropyl-6,7,8-trif luoro-1,4-dihycLro-4-oxo-3-quino-linecarboxylic acid (German Patent Application 3,318,145, corresponding to EP 0126 355), 6,8-dichloro-l-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743), l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3- quinolinecarboxylic acid, l-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid, 6,7-difluoro-l-ethyl-l,4-diyydro-4-oxo-3-quinoline-15 carboxylic acid, 7-chloro-6-fluoro-l-ethyl-1,4-dihvdro-4-oxo-3-quinoline-carboxylic acid, 7 -chloro-6-f luoro-1,4-dihydro-l- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid, 6,7-difluoro-1-f2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, T- * 2 3 9 4 8 5 8-chloro-l- (2 ,4-dif luorophenyl) -6,7-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 235,762), 7-chloro-6-fluoro-1,4-dihydro-l-methoxy-4-oxo-3-quino-5 linecarboxylic acid, 7-chloro-6-fluoro-1,4-dihydro-l-methylamino-4-oxo-3-quinolinecarboxylic acid, 6, 7-dif luoro-1,4-dihydro-4-oxo-l-phenyl-3 -qui'noline-carboxylic acid, 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid, 6 , 7-dichloro-l-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-15 quinolinecarboxylate (German Patent Application 3,318,145), 9,10-dif luoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][l,4]benzoxazine-6-carboxylic acid (European Patent Application 47,005), 8,9-dif luoro-6,7-dihydro-5-methyl-l-oxo-lH, 5H-benzo [ i, j ] - quinolizine-2-carboxylic acid, lip A 2G 100- I 3 9 / . 5 7-chloro-6-fluoro-1-phenyl-l,4-dihydro-4-oxo-l, 8-naph-thyridine-3-carboxylic acid (European Patent Application 153,580 ), 7-chloro-6-fluoro-1- (4-fluorophenyl)-1,4-dihydro-4-oxo-5 1,8-naphthyridine-3-carboxylic acid (European Patent Application 153,580), 6,7,8-trifluoro-1,4-dihydro-l-methylamino-4-oxo-3-quino-linecarboxylic acid (German Patent Application 3,409,922, corresponding to EP 015 587), l-amino-6,7,8-trifluoro-1,4-dihydro-4~oxo-3-quinoline-carboxylic acid (German Patent Application 3,409,922), 6,7, 8-trif luoro-1, 4-dihydro-l-dimethylamino-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,409,922), 7-chloro-6-f luoro-1,4-dihydro-8-nitro-4-oxo-l-phenyl-3- quinolinecarboxylic acid, 7 -chloro- 6 - f luoro-1- (4-f luorophenyl) -1,4 -dihydr o-8 -nitr o -4-oxo-3-quinolinecarboxylic acid, 6,7-dif luoro-1- (4-f luorophenyl) -1,4-dihydro-8-methyl-4-20 oxo-3-quinolinecarboxylic acid, 6-chloro-7-f luoro-1- (4-f luorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application Tib 1 If aflfl 2 3 9 131,839), ,6,7 ,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ,7-dichloro-6-fluoro-1- (2,4-dif luorophenyl) -1,4-dihydro-5 4-oxo-3-quinolinecarboxylic acid, ,7-dichloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chloro-7-fluoro-1- (2,4-dif luorophenyl )-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Applica- tion 131,839), 6 , 7 , 8-trif luoro-1- (4-f luorophenyl) -l/4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 154,780), 6,7,8-trif luoro-1- (2,4-dif luorophenyl) -1,4-dihydro-4-oxo-15 3-quinolinecarboxylic acid (European Patent Application 154,780), 6,7,8-trif luoro-1, 4-dihydro-4-oxo-l-phenyl-3-quinoline-carboxylic acid (European Patent Application 154,780), 7-chloro-l-ethyl-6-f luoro-1,4-dihydro-4-oxo-l, 8-naph-20 thyridine-3-carboxylic acid, 6,7-difluoro-1,4-dihydro-4-oxo-l-vinyl-3-quinoline- Lo ft 36 23ii< 18 5 t' carboxylic acid, l-cyclopropl-5 ,6,7, 8-tetraf luoro-1, 4-dihydro-4-oxo-3 -quinoinecarboxylic acid, -amino-l-cyclopropyl-6 ,7 , 8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-hydroxy-4-oxo-3-quinolinecarboxylic acid, and l-cyclopropyl-6 , 7-dif luoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.

The compounds of the formula (III) used as starting compounds are new in some cases . They can be prepared by the following processes. 1. Starting from the N-protected 3,4-epoxypyrrolidine (1) (U.S. Patent 3,657,274 and U.S. Patent 4,254,135), which can optionally also carry one or two methyl or phenyl radicals, the starting compounds of the formula (Ilia)-(Ille) are prepared. '21 239 4 65 HN \r6 HQ tr \r6 removal of H0'. protective groups yJt\ I H (Ilia) Basa /R5 removal of protective groups r4o tT I H (I lib) /R5 \r6 = benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or sulphonyl (examples of protective groups), = a leaving group, such as halogen, or alkyl- or arylsulphonyloxy : 3 9 4 -a' N- HO*.,, ^*2 a -5 R X ( 1 ) ri R4Q'".,.——^N3 Base N' R40 p^NH2 -N^ R4^ ^NH-COOC ( CH3 ) 3 -N' H (IIIc ) R40 R40/*,„ (1) 4 OH °K) H- R °V r^N q La ft ?g * L •' !> Q F rb . i r4 R40*« \r6 I K (I IIe ) H2/Pd p4nw (Illd) h 2. Starting compounds of the formula (Illf) are obtained from 2-(l,2-dichloroethyl)-oxirane via the following reaction seguence: la ft 36 iflfi 2 3 9 4 8 5 r4q i \r6 N R40 H- J N < "^R6 I H ( I 11 f ) 3. By addition of azides onto N-benzylmaleimides which are optionally substituted by one or two methyl or phenyl radicals, starting compounds of the formula (iii g) can be prepared: R9 N^Nv-N-R9 X R4Qft/«( H-R9 R40^f»,M -TNH-R10 reduction T~ * ^ ino m 239 D r4Q/^ WTIH-R -plO >ao 4.

I H C 111 g) = H, alkyl or benzyl.

From the 3,4-epoxypyrrolidines (1), the starting compounds of the formula (III h) are obtained via cyclization with thionyl chloride: ( l) HO'7'" HO"-. j_ j^NH-CO-F7 S0C1, R I (V^N U tr O^N y H (III h) - By reaction of the 3,4-epoxypyxrolidines (1) with ethanolamines, the starting compounds of the formula (III i) are obtained by intramolecular etherifica-10 tion: lift A 2G -4rfr9» 2 3 9 4 8 5 HO HO N ( 1 ) H ' ^ A 0 N-R® / S A 0 N-R6 N H (III i) The starting compounds of the formula (III j) are obtained from aminoacetaldehyde dimethyl acetal via intramolecular 1,3-dipolar cycloaddition.

Base R9-N OCH f*2 H* y^CHO r9-n fHz >6 _ NH-QH 239485 R" - R6 r" I I h (III j 7. Starting from pyridine-2,3-dicarboxylic acid N-benzylimide, starting compounds (III k) or (III 1) are prepared via the reaction steps shown. alkyl iodide n-ch2-c6h5 H2/Ru-C or Pd-C n-ch2-c6h5 |H2/Pt02 n-ch2-c6h5 0 Alkyl n-ch2-c6hs h LiAlH^ of NaBH4/ BP" 2 * (C 2Hj ) 20 rj^N-CH2-C6H5 h lip .r* <£3 9 4 8 i*mS LiAlH4 n-ch2-c6h5 I Alkyl H2/Pd-C CO™ Alkyl (III k) H2/Pd-C QC™ h (III 1) 8. N-Benzyl-maleimide adds onto 2-chloroethylamines to give 3-(2-chloroethylamino)-succinimides, which are converted into the starting compounds of the formula (III m): n-ch2-c6h5 ♦ ci-ch2ch2-nh-r® O CI I ch-, I 2 CH2-N NaH n-ch2-c6h5 O N-CH2-C6H5 LiAlH4 n-ch2-c6h5 N" R® la ft Id JMA L 5 9 4 n r, H2/Pd-C N" NH (III m) 9. 2-Methyl-2-propenal-dimethylhydrazone reacts with N-benzylmaleimide to give a cycloadduct, which cam be converted into the starting compound (Illn) by the reaction sequence shown. ch3^CH2 n ch3 ch3 N-CH2-Ph N-CH2-?h n 0 ch3 ch3 (ch3)2nh ch3 h2/ n-ch?-ph c catalyst N-CH2-?h LiAlH4 CH3 ,n-ch2-ph H2/Pd-C CH3 nh (III n) iASi 23 9 4 8 Starting compounds of the formulae (IIIo), (IIIp) or (Illq) can be obtained in the following way, starting from N-protected 2,5-dihydropyrroles (3-pyr-rolines) by addition of sulphenyl chlorides: Lffli A 26 V3A 239485 r11-s-cl Cl-N r^S-R 1 1 1. *R6-NH2 (R11 = CH2CH2-Hal) 2. Removal of" R R5\ NH r6-n s j N- H (IIIo) R6n b =6/ u /s-r 11 \ =6/ NV ^SH Removal, o-f R 11 H (r 11 rsx >6^ hTs = Acyl, Alkoxycarbonyl ) -*"s-r 11 (I lip ) <U' H (Illq) >ii = Ci-C^-alkyl which is optionally substituted by halogen or phenyl, which is optionally substituted by halogen, nitro, alkyl or alkoxy, as well as acyl or alkoxycarbonyl.

The following starting compounds, for example, can be prepared in accordance with these general equations. They le a — 32 — / * 2 5 SM o 3) V ^ can be prepared and employed as diastereomer mixtures or in the diastereomerically pure or enantiomerically pure form. 4-amino-3-hydroxypyrrolidine, 5 3-hydroxy-4-methylaminopyrrolidine, 4-dimethylamino-3-hydroxypyrrolidine, 4-ethylamino-3-hydroxypyrrolidine, 3-amino-4-methoxypyrrolidine, 4 -methoxy- 3 -methyl aminopyrro 1 idine, 10 3-dimethylamino-4-methoxypyrrolidine, 3 -ethyl amino -4 -methoxypyrr o 1 idine, 3-amino-4-ethoxypyrrolidine, 4-ethoxy-3-methylaminopyrrolidine, 3-dimethylamino-4-ethoxypyrrolidine, 4 -e thoxy- 3 -ethyl aminopyrro 1 idine, 3-hydroxy-4-hydroxyaminopyrrolidine, 3-hydroxy-4-methoxyaminopyrrolidine, 3-hydroxyamino-4-methoxypyrrolidine, 4 -methoxy- 3 -me thoxy aminopyrro 1 idine, 20 3-benzylamino-4-methoxypyrrolidine, 4-methoxy-3 - (5-methy"i-2-oxo-l ,3-dioxol - 4-y 1 )-me thy 1 -amino) -pyrrolidine, 3 -amino -4 -me thylmer capt opyrro 1 idine, 3-acetoxy-4-dimethylaminopyrrolidine, 25 3-acetamido-4-methoxypyrrolidine, 4-methoxy-3-methoxycarbonylaminopyrrolidine, 3-formamido-4-methoxypyrrolidine, 3-amino-4-methoxy-2-methylpyrrolidine, 3-amino-4 -methoxy- 5 -me thylpyrro lidine, Jm» ft 3f iQB ( 2 3 9 4 B H 4 -methoxy- 2 -methyl - 3 -methylaminopyrrol idine, 4 -methoxy- 5 -methyl - 3 -methyl aminopyrro 1 idine, 3-amino-4-methoxy-2-phenylpyrrolidine, 4 -me thoxy- 3 -methyl amino - 5-phenyl pyr r o 1 i di ne, 5 3-methyl-2,7-diazabicyclo[3.3.0]octane, 4-methyl-2,7-diazabicyclo[3.3.0]octane, -methyl-2,7-diazabicyclo[3.3.0]octane, 3,5-dimethyl-2,7-diazabicyclo[3.3.0]octane, 1,5-dimethyl-2,7-diazabicyclo [3.3.0] octane, 10 2-oxa-4,7-diazabicyclo [3.3.0 ] octane, 3,3-dimethyl-2-oxa-4,7-diazabicyclo [3.3.0] octane, 3-oxa-2,7-diazabicyclo[3.3.0]octane, 1,2-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane, 2,5-dimethyl-3-oxa-2,7 -diazabicyclo [3.3.0] octane, 15 2,8-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0] octane, -methyl-3-oxa-2,7-diazabicyclo [3.3.0 ]octane, 2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 3-methyl-2-oxa-4,7-diazabicyclo[3.3.0]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 . 0]oct-3-ene, 8-methyl-2-oxa-4,7-diazabicyclo[3.3 .0 ]oct-3-ene, 3-methyl-2,8-diazabicyclo[4.3.0]nonane, 4-methyl-2,8-diazabicyclo[4.3.0]nonane, -methyl-2,8-diazabicyclo[4.3.0]nonane, 25 6-methyl-2,8-diazabicyclo[4.3.0]nonane, 3-methyl-2-oxa-5,8-diazabicyclo [4.3.0 ]nonane, 4-methyl-2-oxa-5,8 -diazabicyclo [4.3.0] nonane, 1-methyl-2-oxa-5 ,"8-diazabicyclo [4.3.0 ] nonane, 3,5-dimethyl-2-oxa-5,8-diazabicyclo [4.3.0 ] nonane, 30 2-thia-5,8-diazabicyclo[4.3.0]nonane, la a 3c 1qb - 34 - 13 9 4 B R -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, 5 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-5,8-diazabicyclo[4.3.0]nonane and 10 4,4-dimethyl-3-oxa-5,8-diazabicyclo[4 .3 .0]nonane.

The reaction of (II) with (III) according to method A, in which the compounds (III) can also be employed in the form of their hydrochlorides, is preferably carried out in a diluent, such as dimethyl sulphoxide, N,N-dimethyl-15 formamide, N-methylpyrrolidone, hexamethyl-phosphoric acid triamide, sulpholane, acetonitrile, water, an alcohol, such as methanol, ethanol, n-propanol or iso-propanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used or the reaction can be carried out without any solvent.

Acid-binding agents which can be used are all the cus tomary inorganic and organic acid-binding agents. These include, preferably, the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particularly suitable acid-binding agents which may be mentioned 25 specifically are: triethylamine, l,4-diazabicyclo[2 .2.2]- octane (DABCO), 1',8-diazabicyclo[5,4,0]undec-7-ene (DBU) or excess amine (III). 11 9 4 H !> The reaction temperatures can be varied within a substantial range. The reaction is in general carried out between about 20 and 200°C, preferably between 80 and 180°C.

The reaction can be carried out under normal pressure, but also under elevated pressure. It is in general carried out under pressures between about 1 and 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention, 10 1 to 15 mol, preferably 1 to 6 mol, of the compound (III) are employed per mol of the carboxylic acid (II) .

Free hydroxy1 groups can be protected during the reaction by a suitable hydroxyl-protective group, for example by the tetrahydropyranyl radical, and can be liberated again 15 when the reaction has ended (see J.F.W. McOmie, Protective Groups in Organic Chemistry (1973), page 104).

Free amino functions can be protected during the reaction by a suitable amino-protective group, for example by the ethoxycarbonyl or tert.-butoxycarbonyl radical, and 20 liberated again when the reaction has ended by treatment with a suitable acid, such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, Kethoden der organischen Chemie (Methods of Organic Chemistry), Volume E4, page 144 (1983); and J.F.W. McOmie, Protective Groups 25 in Organic Chemistry (1973), page 43).

T'n T> IC 36 - > Q A 1 F Cc"- The reaction of (IV) with (V) according to method B is preferably carried out in a diluent, such as dimethyl sulphoxide, dioxane, N,N-dimethylformamide, N-methyl-pyrrolidone, hexamethyl-phosphoric acid triamide, sulpho-5 lane, water, an alcohol, such as methanol, ethanol, n- propanol or isopropanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used.

Acid-binding agents which can be used are all the customary inorganic and organic acid-binding agents. These 10 include, preferably, the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particularly suitable acid-binding agents which may be mentioned specifically are: triethylamine, l,4-diazabicyclo[2.2.2]-octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene 15 (DBU).

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

The reaction can be carried out under normal pressure, but also under increased pressure. It is in general carried out under pressures of between about 1 bar and about 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention by 25 method B, 1 to 50 mol, preferably 1 to 30 mol, of the compound (V) are employed per mol of the compound (IV).

Le x\ 2C - 37 - *39485 ""N To prepare the esters according to the invention, the carboxylic acid on which they are based is preferably reacted in excess alcohol in the presence of strong acids, such as sulphuric acid, anhydrous hydrochloric 5 acid, methanesulphonic acid, p-toluenesulphonic acid or acid ion exchangers, at temperatures from about 20° to 200°C, preferably about 60° to 120°C. The water of reaction formed can also be removed by azeotropic distillation with chloroform, carbon tetrachloride, benzene or 10 toluene.

The esters are also advantageously prepared by heating the acid on which they are based with dimethylformamide dialkyl acetal in a solvent, such as dimethylformamide.

The 5-methyl-2-oxo-l,3-dioxol-4-yl-methyl esters used as 15 a prodrug are obtained by reaction of an alkali metal salt of the carboxylic acid on which they are based with 4-bromomethyl- or 4-chloromethyl-5-methyl-1,3-dioxol-2-one in a solvent, such as dimethyl formamide, dimethyl-acetamide, N-methylpyrrolidone, dimethyl sulphoxide or 20 tetramethylurea at temperatures of about 0° to 100°C, preferably 0° to 50°C.

The acid addition salts of the compounds according to the invention are prepared in the customary manner, for example by dissolving the betaine in excess aqueous acid 25 and precipitating the salt with a water-miscible organic solvent, such as methanol, ethanol, acetone or aceto-nitrile. It is also possible to heat equivalent amounts iLa ft (f*. > "i 0 L R 5 of the betaine and acid in water or an alcohol, such as glycol monomethyl ether, and then to evaporate the mixture to dryness or filter off the precipitated salt with suction. Pharmaceutical^ usable salts are to be 5 understood as, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or 10 aspartic acid.

The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in excess alkali metal or alkaline earth metal hydroxide solution, filter-15 ing from the undissolved betaine and evaporating the filtrate to dryness. Sodium, potassium or calcium salts are pharmaceutically suitable. The corresponding silver salts are obtained by reaction of an alkali metal or alkaline earth metal salt with a suitable silver salt, 20 such as silver nitrate.

The compounds listed by way of example in Table 1 can also be prepared, in addition to the active compounds mentioned in the examples, it being possible for these compounds to be present both as diastereomer mixtures or 25 as the diastereomerically pure or enantiomerically pure compounds.

La A 3G 6 & Table 1 X2 O H li II ') 1 CH CP CF C-OCH3 ro Cf4 CO Oi 3 .Table 1 (continuation) H1 c2h5 c2h5 O -ch=ch2 f r' II M II 11 H r- II h N n- n- 11 nh II h H ch cf cf cf ch IV* OS CO or CJl Table 1 (continuation) r1 r2 ) 1 cm cf CF CF CF rci 04 CO CD CJl J fable 1 (continuation) R II h II H IV n- H N- N n- f nh CF oh cf h CCl h ch h N ro CM ) 1 CF CF CF CF CH ro CM CO 42- cc-on ") 1 x1 (S3 x j a f hh2 cf f ii n f h ccl f h cll f ii cf ro -S>- Un Table 1 (cont inuat ) r R' >1 II II II R' cm- Cll- n c1i -N N ii ch- c":j% II ,NV CJ ) 1 x1 x2 a f ii cf F ii ccl F ii cf F ii ccii3 F H CH C*i CO C;D 31 ab I c 1 (cont inuat ion) U1 H' H II II II II II n O^ O CH- H2N,v Xj i CF ch cf ch CCl CI <o QD •31 Table 1 (continuation) H C2"5 R< II II II C2»5 II ) II nh2 ii II II I! J N CF CF CF N IS3 CM OD Ol Table 1 (continuation) 3 3 *• V£> r1 c2»5 ch- h tl li h R' ch h2n ch ,OW/VN •7-I h2h ho tj' h2n* ho// cr h2it ch ch3-NH^ Tj > h h II II h CF n CF cf ch ro c*. to CO CJl ( & Table 1 (continuation) i y i ■> i 3 i 3 U1 o H h II H ii R' ch30 ch3-nh^ n- ch- 3°Y"V CH3-NH^ ch3O^ I- CH-jNH^ N cii30 ch3\ CIU^ CH3O" I ch3\ N^~ CH^ ') 3 H c-ch3 h CCl H n II cf nh- cf TV ■o Table 1 (continuation) r1 "c2»5 c2»5 R' h H li >1 II ch3° ch3\ ch- ch30 c2h5nh/ c2h5o «2N^ cu3s »2n" ch3s h2N- ) 1 x2 h h ii h 11 ch cf cf cf ch ro oj CO - " Table 1 (continuation) ;' > < * < > < > Ul M R1 R^ il II .A H II II H C Ji R CIUCO-OV^^N cl«3\ N/' cn3^ choco-ov i ch3\ n- Cll-,^ ch3co-ov i ch3\ ch- °YYc"3 CH3° O ^ -CH- -n ch3 ch3o o ^cn2 n CM3° O ^-CH, N ) 1 1 1 1 1 (S3 1 X 1 1 A li ch h cf h ccl h cii II cf ii ccl ro CM cc -£ Qr CT> Table 1 (continuation) 11 i 3 i 3 tn LJ r1 H II H II II R- °Y°Njr/CH3 CH30 O ^CH2 N CH-jCT-Y^^N h2nz CH-jCT I CH- h2N^ ^CH- Cll- C1I3Qv N h2N/ CH- h2n CIUO-v^^N J ~) 3 it h II II II N cf CC I CF ch ro c>; CO 4^* isi Table 1 (continuation) r' R' li II r- ch30 "\ N h2n ch3o ch3nh ch3o cii2-nh cii30 t> h2n ) J CF CF CF c-ch3 *V CO C3,T# CO Ol Table 1 (continuation) r1 r' II il h H II r* Cll30 ch3o-conh^ CHqO och-nh ch3o och-nh-^ ch3o ho- ch3o ch3o-nh 3 h cf ti cf h CCl h cf f II cf rv> CM CO Ol Table 1 (continuation) ch3o CH30-C0NH'- ch3o CH30-C0NH'' 1 H H II H A CCl CH ch CF CCl ro o* CO -£> or an CF CF C-CH C-CII- C-CH r Its ft.

CJl ~) ii li H nh- N cm ccl CF CF ro.

CH V OD cjl Table 1 (continuation) r' r' ii h li tl ii r- ii li n n n- n n f f ci ci (i ii ii ch cf n cf ch ro CM CD ) It ccl CF CF CH CF rs> c*3 cn ) 1 H N H NH- N CH cc 1 cf CF ro 0-4 ) 1 CI CI H li H CH CF N CF CH co .table 1 (continuation) R1 "(3"' -O' -O- R' ii 11 >1 H H ) 1 ccl CF CF CH cf 04 c£ -p QT o r i o & < i u u u [x. u u. u (S3 X (nj x i "Is. f! i K i o ^ n 2 2 n u z z— z fl. fl O *■> o m z en n z u r z (va T~ » oc 1"no lo cd 'o Osl mo n h3 1 c >nzii ^nzii rT n^^so^h r-^nzh n\^«^o5h2: >nzN n .u* 113 ^nzh no -m ii ii ii ii h ,u r-<o c I ( i (uoijenui juoj) P^TqeT Table 1 (continuation) r' r h ii ii h ii ) H ii ii Ml N CM cc i CF CF rv CO Taftle 1 (continuation) r a\ lD -c u h h 11 tl h* clhow^n ch-,ok/^n h2.P :2"5°>y^y h2n^ :2»5°k^n »2n^ :2h5(W^vn y___l CM cf N CF CH o*n n '■ x o £ ° K J b' L ■ Example of a tablet according "to the invention Each tablet contains: Compound of Example 1 583.0 mg Macrocrystalline cellulose 55.0 mg Maize starch 72.0 mg Insoluble poly-(l-vinyl-2-pyrrolidone) 30.0 mg Highly disperse silica 5.0 mg Magnesium stearate 5.0 mc 750.0 mg The lacquer shell contains: Poly-(O-hydroxypropyl-O-methyl)- cellulose 15 cp 6.0 mg Macrogol 4000, recommended INN polyethylene glycols (DAB) 2.0 mg Titanium(IV) oxide 2.0 ma .0 mg The compounds according to the invention, while having a low toxicity, exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative germs, in par-20 ticular against Enterobacteriaceae; above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cephalosporins , aminoglycosides, sulphonamides and tetracyclines . lie A 2 G 1 ( These useful properties enable them to be used as chemo-therapeutic active compounds in medicine and as substances for preserving inorganic and organic materials, ■"•"s xn particular all types of organic materials, for example 5 polymers, lubricants, paints, fibres, leather, paper and wood, and foodstuffs and water.

The compounds of the formula I are active against a very broad spectrum of microorganisms. Gram-negative and Gram-positive bacteria and bacteria-like 10 microorganisms can be combated and the diseases caused by these pathogens can be prevented, alleviated and/or cured with the aid of these compounds.

The compounds of the formula I are particularly active against bacteria and bacteria-like microorganisms .

They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens .

For example, local and/or systemic diseases caused by the 20 following pathogens or by mixtures of the following pathogens can be treated and/or prevented: Gram-positive cocci, for example Staphylococci (Staph, aureus.and Staph, epidermidis) and Streptococci (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae and 25 Strept. pyogenes); Gram-negative cocci (Neisseria gonor rhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haemo- ■lc a 20 i 0 0* . • -r p, ii W. , q\\ ^ \ ... . ' ^i.

JAN 1992 V ^30485 philus influenzae, Citrobacter (Citrob. freundii and Citrob. divernis), Salmonella and Shigella; and furthermore Klebsiella (Klebs. pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans) , 5 Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mira- bilis, Pr. rettgeri and Pr. vulgaris), Providencia and Yersinia, and the genus Acinetobacter. The antibacterial spectrum moreover includes the genus Pseudomonas (Ps. aeruginosa and Ps. maltophilia) as well as strictly 10 anaerobic bacteria, such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; and furthermore Mycoplasma (M. pneumoniae, M. hominis and M. urealyticum) and Mycobacteria, for example Mycobacterium 15 tuberculosis.

The above list of pathogens is to be interpreted merely as examples and in no way as limiting. Examples which may be mentioned of diseases which are caused by the pathogens or mixed infections mentioned and can be prevented, 20 alleviated or cured by the compounds of the formula I are: infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, 25 bronchitis (acute and chronic), septic infections, diseases of the upper respiratory tract, diffuse paxibron-chiolitis, pulmonary emphysema, dysentery, enteritis, ' liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, t ft r ' \n. : oK\ In n id inn - 72 - '2 9 JAN 1992 'o /' ■** \ -.ca . m- x 3 i**?. cystic fibrosis, skin infections, postoperative wound infections, abscesses, phlegmons, wound infections, infected burns, burn wounds, infections in the oral region, infections following dental operations, osteomye-5 litis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, 10 pelveoperitonitis and eye infections.

As well as in humans, bacterial infections can also be treated in other species. Examples which may be mentioned are: Pigs: colidiarrhoea, enterotoxaemia, sepsis, dysentery, 15 salmonellosis, mastitis-metritis-agalactia syndrome and mastitis; Ruminants (cattle, sheep and goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis and genital infections; Horses: bronchopneumonias, joint ill, puerperal and postpuerperal infections and salmonellosis; Dogs and cats: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections and prostatitis; Poultry (chickens, turkeys, quails, pigeons, ornamental 25 birds and others): mycoplasmosis, E. coli infections, chronic respiratory tract infections, salmonellosis, pasteurellosis and psittacosis.

Bacterial diseases in the rearing and keeping of stock Ll iii IC 1# - 73 y;i!)4ao and ornamental fishes can also be treated, the antibacterial spectrum extending beyond the abovementioned pathogens to further pathogens, such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Erysi-5 pelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.

Pharmaceutical formulations have been found which contain, in addition to non-toxic, inert pharmaceutically suitable excipients, one or more active compounds of the 0 formula I, as have processes for the preparation of these formulations.

Pharmaceutical formulations in dosage units have also been found. This means that the formulations are present in the form of individual parts, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, the active compound content of which corresponds to a fraction or a multiple of an individual dose. The dosage units can contain, for 20 example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is administered in one application and which usually corresponds to a whole, one half, one third or a quarter of a daily 25 dose.

Non-toxic inert pharmaceutically suitable excipients are to be understood as solid, semi-solid or liquid diluents, a .■ "i; p N f \ ,i -• © ^ \\ ■I "29 jan1992 ■gfta-ay-frfr '100"" - 74 - ... ./ r"*v i h 6 0 fillers and formulation auxiliaries of all types.

Preferred pharmaceutical formulations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emul-5 sions, pastes, ointments, gels, creams, lotions, dusting powders and sprays.

Tablets, coated tablets, capsules, pills and granules can contain the active compound or compounds in addition to the customary excipients, such as (a) fillers and 10 extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrating agents, for example agar-agar, 15 calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaolin 20 and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesium stearate and solid polyethylene glycols, or mixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules 25 can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of a composition such that they release the active La fti 36 4Aa 11 {i 4 b 5 compound or compounds only or preferentially in a certain part of the intestinal tract, if appropriate in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes.

If appropriate, the active compound or compounds can also be present in microencapsulated form with one or more of the abovementioned excipients.

Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or 10 water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C^-alcohol with C16-fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can contain, in 15 addition to the active compound or compounds, the cus tomary excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these 20 substances.

Dusting powders and sprays can contain, in addition to the active compound or compounds, the customary excipients, for example lactose, talc, silicic acid, aluminium hydroxide, calcium silicate and polyamide powder, or 25 mixtures of these substances. Sprays can additionally contain the customary propellants, for example chloro- La ft 16 76 - X o /- fluorohydrocarbons.

Solutions and emulsions can contain, in addition to the active compound or compounds, the customary excipients,. such as solvents, solubilizing agents and emulsifiers, 5 for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dime thy If ormamide , oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and 10 sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in a sterile form which is isotonic 15 with blood.

Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example water, ethyl alcohol and propylene glycol, and suspending agents, for example 20 ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

The formulation forms mentioned can also contain colour-25 ing agents, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyp- W'A 36 / \ 4 fear --'J ' Jt tus oil, and sweeteners, for example saccharin.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 5 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also contain other pharmaceutical active compounds in addition to the compounds according to the invention.

The abovementioned pharmaceutical formulations are 10 prepared in the customary manner by known methods, for example by mixing the active compound or compounds with the excipient or excipients.

The formulations mentioned can be used on humans and animals either orally, rectally, parenteraily (intra-15 venously, intramuscularly or subcutaneously) , intra- cisternally, intravaginally, intraperitoneally or locally (dusting powder, ointment, drops) and for the therapy of infections in hollow spaces and body cavities. Possible suitable formulations are injection solutions, solutions 20 and suspensions for oral therapy and gels, infusion formulations, emulsions, ointments or drops. Ophthal-mological and dermatological formulations, silver salts and other salts, eardrops, eye ointments, dusting powders or solutions can be used for local therapy. In the case 25 of animals, intake can also be in suitable formulations via the feed or drinking water. Gels, powders, dusting ia ft 36 10 ^ 2 3 9 ^ powders, tablets, delayed release tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays and inhalants can furthermore be used on humans and animals. The compounds according to the 5 invention can moreover be incorporated into other carrier materials, such as, for example, plastics (chains of plastic for local therapy), collagen or bone cement.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound 10 or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably contains the active com-15 pound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to deviate from the dosages mentioned, and in particular to do so as a function of the nature and body weight of the object to 20 be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament and the period or interval within which administration takes place.

Thus in some cases it can suffice to manage with less 25 than the abovementioned amount of active compound, whilst in other cases the abovementioned amount of active compound must be exceeded. The particular optimum dosage and mode of administration required for the active tn T\ 16 MUi \l 3! j 4 b f) compounds can easily be determined by any expert: on the basis of his expert knowledge.

The active compounds can be administered in the customary concentrations and formulations together with the feed or 5 with feed formulations or with the drinking water.

Infection by Gram-negative or Gram-positive bacteria can in this way be prevented, alleviated and/or cured and promotion of growth and an .improvement in feed utilization can in this way be achieved.

The minimum inhibitory concentrations (MIC) were deter mined by the series dilution method on Iso-Sensitest agar (Oxoia). For each test substance, a series of agar plates which contained concentrations of the active compound which decreased by a dilution factor of two each time was 15 prepared. The agar plates were inoculated with a multi point inoculator (Denley). Overnight cultures of the pathogens which had first been diluted so that each inoculation point contained about 10* colony-forming particles were used for the inoculation. The inoculated 20 agar plates were incubated at 37°C and the germ growth was read off after about 20 hours. The MIC value (/ig/ml) indicates the lowest active compound concentration at which no germ growth was to be detected with the naked eye.

The MIC values of some of the compounds of the formula I are shown in comparison with ciprofloxacin in the following table. v * ov>. •t.'a vi on i.0 & 36 108 ► - 80 - 29 J AN 1992*1 / 1 i CD MIC values (mg/l) determined by the agar dilution test (Oenley multipoint inoculator; Iso-sensitest agar) Example I 2 3 4 5 8 9 1Q J Test strain Escherichia 10.015 10.015 10.015 10.015 10.015 10.015 0.25 0.125 co1i Neumann Proteus raira- 1 4 1 0,5 2 2 8 16 b i 1 i s 8223 Proteus vuI - 10,015 0,125 10.015 10.015 0.03 0,06 0.5 1 gar i s 1017 Ho rgane11 a 10,015 0.03 0,03 10.015 10.015 0,06 0.5 0.5 morgani i 932 Providencia- 14 2 0,5 4 4 32 64 tiluarle i 1 2052 St aphy1ococ-cus aureus FK 422 0.06 0,125 0.06 10,015 0,125 0.03 0,06 0,125 1756 0.06 0,125 0,06 10.015 0.125 0.03 0,06 0,125 133 0.06 0.125 0,03 10.015 0.125 0.03 0,06 0,125 J En t. erococcus faocalis 27101 0,125 - 0,125 0.06 0,25 0,125 0,25 2 fNP 9790 0,125 0,5 0,2b 0,U6 0,25 0, 125 0,25 2 co ui t: J r MIC values (mg/l > determined by the agar dilution test (Oenley multipoint inoculator; Iso-sensitest agar) E x amp Ie 4> 13 14 15 16 17 18 Ciprofloxacin 11 < > i > Test strain Escherichia 0.06 0,06 10.015 0.06 0.125 0,03 10,015 co1i Neumann Proteus mira- bi1 is 8223 1 4 0.5 4 8 1 1 Proteus vul- 0.03 0.5 0,03 0,06 0.5 0,06 10,015 l gar i s 1017 00 KJ Morgane 1 1 a 0.125 0,25 0.03 0.06 0.5 0.06 10.015 1 morgan i i 932 Providencia- 2 4 1 32 8 4 4 sluartei 12052 SLaphy1ococ-cus aureus FK 422 0.06 0.25 0.03 0.125 0:5 0.125 0,25 1756 0.06 0.25 0.Q3 0.125 0.5 0,125 0.25 r 133 0.06 0,25 0.03 0.125 0.5 0,125 0.25 co «!>•' EnLerococciis CC5 (aecalis 27101 0,125 0.25 0,03 0.5 1 0.25 0,05 9790 0.25 0.5 - 0.5 2 0.5 0,25 c* / 2 3 9 4 6 5 The following examples illustrate the invention: Preparation of the intermediate products: Example A tert.-Butyl N-(cis-4-methoxy-pyrrolidin-3-yl)-carbamate 5 a) trans-l-Benzvl-3-hvdroxv-4-methoxvpyrrolidine 34,9 g (0.2 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]-hexane (U.S. Patent 4,254,135) are heated with 3.6 g (20 mmol) of sodium methylate solution (30% strength) at 10 120°C in 200 ml of absolute methanol in an autoclave for hours. After cooling, the mixture is neutralized with 1.2 g (20 mmol) of acetic acid and the solvent is removed on a rotary evaporator. The residue is taken up in tetrahydrofuran and the sodium acetate is filtered off. 15 The filtrate is concentrated and the residue is distilled.

Yield: 40.9 g (91% of theory) Boiling point: 112-116°C/0.1 mbar Content: 92% pure b) cis-3-Amino-l-benzvl-4-methoxv-ovrrolidine .6 g (25 mmol) of trans-l-benzyl-3-hydroxy-4-methoxy-pyrrolidine and 8.6 g (33 mmol) of triphenylphosphine are initially introduced into 40 ml of absolute tetrahydro- la ft Iflfli v r / p k 1 v furan and a solution of 6 g (34 mmol) of diethyl azodi-carboxylate in 40 ml of absolute tetrahydrofuran is added dropwise at 0°C. 3.9 g (27 mmol) of phthalimide are then I ^ added in small portions at 0°C in the course of one hour. 5 The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 80 ml of ethyl acetate and 80 ml of petroleum ether are added. The mixture is left to crystallize out overnight and the crystals (triphenylphosphine oxide and diethyl hydrazine-10 dicarboxylate) are filtered off. The filtrate is concentrated and the residue is heated under reflux with 60 ml of concentrated hydrochloric acid overnight. The undissolved residues are decanted and the solution is concentrated. The residue is taken up in a little water 15 and the solution is rendered alkaline with solid potas sium carbonate and extracted five times with 50 ml of chloroform. The extract is dried over potassium caorbonate and concentrated and the residue is distilled.

Yield: 3.4 g (65.9% of theory) Boiling point: 95°C/0.2 mbar c) tert.-Butyl N-(cis-l-benzyl-4-methoxypyrrolidin-3- yl ) -carbamate 3 g (14.5 mmol) of cis-3-amino-l-benzyl-4-methoxy-pyr-25 rolidine and 11 ml of tert.-butanol are added to a ^ solution of 0.65 g of NaOH in 8 ml of water. 3.5 g (16 mmol) of di-tert.-butyl dicarbonate are added dropwise. The mixture is stirred at room temperature overnight, the le a 2g 100 r r* '.J %J « inorganic 3alts are filtered off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.

Yield: 3.8 g (85.5% of theory) Boiling point: 130-140°C/Q.05 mbar d) tert.-Butyl N-(cis-4-methoxypyrrolidin-3-yl)-carbamate 3.5 g (11.4 mmol) of tert.-butyl N-(cis-l-benzyl-4-10 methoxypyrrolidin-3-yl)-carbamate are hydrogenated in 100 ml of methanol on 2 g of palladium-on-active charcoal (10% of Pd) at 100°C under 100 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

Yield: 1.9 g (81.6% of theory) Boiling point: 84°C/0.1 mbar Example B tert.-Butyl N-(trans-4-methoxy-pyrrolidin-3-yl)-carbamate - a) trans-3-Amino-1-benzvl-4-methoxv-ovrro1idine 27 g (0.41 mol) of sodium azide are dissolved in 50 ml of T~ » "»g I I 2 3 9 4 8 5 water, and 17.5 g (0.1 mol) of 3-benzyl-6-oxa-3-azabi-cyclo[ 3.1.0]hexane in 300 ml of dioxane are added. The mixture is heated under reflux for 72 hours and concentrated, the inorganic salts are dissolved in water and the mixture is extracted with chloroform. The extract is dried over potassium carbonate and concentrated. The residue is dissolved in 50 ml of absolute tetrahydrofuran and the solution is added dropwise to 4 g of sodium hydride (80% strength in paraffin oil) in 200 ml of absolute tetrahydrofuran. The mixture is heated under reflux for one hour and 15 g (0.1 mol) of methyl iodide are then added dropwise. The mixture is subsequently heated under reflux overnight and concentrated, the residue is taken up in water and the mixture is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled. 13.1 g of a material which is 73% pure according to the gas chromatogram are obtained. 12.7 g of this material in 40 ml of absolute tetrahydrofuran are added dropwise to a suspension of 4 g of lithium aluminium hydride in 150 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. Excess lithium aluminium hydride is decomposed by careful dropwise addition of 4 ml portions of water and 15% strength potassium hydroxide solution and again 4 ml of water. The inorganic salts are filtered off with suction and washed several times with chloroform. The organic phases are dried over potassium carbonate and concentrated and the residue is distilled.

Yield: 9 g (32.8% of theory) lip h dg 108 9 ! 2 3 y 4 b 5 Boiling point: 91°C/0.07 mbar The product has a content of 75%, determined by gas chromatography (area method). b) tert.-Butyl N-(trans-l-benzyl-4-methoxypyrrolidin-3-5 vl) carbamate 8.2 g (30 mmol) of trans-3-amino-l-benzyl-4-methoxy-pyrrolidine and 21 ml of tert.-butanol are added to a solution of 1.3 g of NaOH in 15 ml of water. 7.1 g (31 mmol) of di-tert.-butyl dicarbonate are added drop-10 wise and the mixture is then stirred at room temperature overnight. Inorganic salts are filtered off with suction, the filtrate is extracted with chloroform, the extract is dried over potassium carbonate and concentrated and the residue is distilled.

Yield: 7.7 g (84.4% of theory) Boiling point: 148°C/0.1 mbar Melting point: 88-90°C c) tert.-Butyl N-(trans-4-methoxypyrrolidin-3-yl)-carbaxnate 6.7 g (22 mmol) of tert.-butyl N-( trans-l-benzyl-4- methoxypyrrolidin-3-yl) carbamate are hydrogenated in 150 ml of methanol on 2 g of palladium-on-active charcoal (10% of Pd) under 100 bar at 100°C. The catalyst is filtered off with suction, the filtrate is concentrated ira ft "LQ9 f** 3 9 4 8 5 and the residue is distilled.

Yield: 2.2 g (46% of theory) Boiling point: 94°C/0.05 mbar Example C trans-3-Amino-4-hydroxy-pyrrolidine a) trans-3-Amino-1-benzvl-4-hydroxv-pyrro1idine 8.9 g (50 mmol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0Jhex-10 ane are heated in 75 ml of ammonia solution (25% strength) at 120°C in an autoclave for 8 hours. The solution is concentrated and the residue is distilled.

Yield: 6 g (62.4% of theory) Boiling point: 130-140°C/0.1 mbar 15 Melting point: 82-84°C b) trans-3-Amino-4-hydroxv-pvrro1idine .2 g (27 mmol) of trans-3-amino-l-benzyl-4-hydroxy-pyrrolidine are hydrogenated in 40 ml of methanol on 1 g of palladium-on-active charcoal (10% of Pd) at 100°C under 20 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.

Yield: 1 g (36.3% of theory) fcta ft Iff iAA 2 3 9 4 8 5 Boiling point: 110°C/0.3 mbar Example D trans-4-Hydroxy-3-(2-hydroxyethylamino)-pyrrolidine a) trans-l-Benzyl-4-hydroxy-3-( 2-hydroxyethylamino) -pyrrolidine 40 g (0.22 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hex-ane are heated under reflux with 42 g (0.68 mol) of 2-aminoethanol in 450 ml of water overnight. The solution 10 is extracted once with tert.-butyl methyl ether and the aqueous phase is concentrated. The residue is distilled.

Yield: 34.1 g (65.6% of theory) Boiling point: 190°C/0.1 mbar b) trans-4-Hvdroxv-3-f2-hydroxyethylaTnino\-pyrrolidine trans-l-Benzyl-4-hydroxy-3-(2-hydroxyethylamino) -pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oil.

Le A JG 2 3 9 4 8 5 Example E trans-4-Hydroxy-3-(2-hydroxyethyl-methyl-amino) pyrrolidine a) trans-l-Benzyl-4-hydroxy-3-(2-hydroxyethyl-methyl-amino)-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 methylamino-ethanol in 200 ml of water analogously to Example D a).

Yield: 18.2 g (73% of theory) Boiling point: 180-190°C/0.1 mbar b) trans-4-Hydroxy-3-(2-hydroxyethyl-methyl-amino)-pyrrolidine trans-1-Benzyl-4-hydroxy-3- (2-hydroxyethyl-methyl-amino) -15 pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oily compound.

Example F 2-Oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride a) 8-Benzyl-2-oxa-5,8-diazabicyclo[4.3.0jnonane 2 3 9 4 35 .6 g (66 mmol) of l-benzyl-4-hydroxy-3-(2-hydroxyethyl-amino)-pyrrolidine are heated under reflux in a mixture of 60 ml of concentrated sulphuric acid and 20 ml of water for 6 hours. The mixture is rendered alkaline with 5 concentrated sodium hydroxide solution, the Bodium sulphate which has precipitated is filtered off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.

Yield: 4.1 g (28.5% of theory) Boiling point: 122-128°C (0.08 mbar) b) 2-Oxa-5,8-diazabicvclor4.3.Olnonane dihvdrochloride A solution of 4 g (18.2 mmol) of 8-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane in 100 ml of methanol and 3.5 15 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-on-active charcoal (10% of Pd) at 80°C under 100 bar. The catalyst is filtered off and washed with water. The filtrates are concentrated and the product is crystallized by trituration with a little 20 methanol. The crystals are filtered off with suction, washed with acetone and dried in air.

Yield: 1.85 g (51% of theory) Melting point: 280°C with decomposition La ft 36 W \ (>j k c) 2-Qxa-5,8-diazabicvclor4.3.0Inonane 7.2 g (33 mmol) of 8-benzyl-2-oxa-5,8-diazabicyclo-[4.3 . 0]nonane are hydrogenated in 400 ml of methanol with 2.5 g of palladium-on-active charcoal (10% of Pd) under 50 bar at 100°C. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is 10 distilled.

Yield: 3.1 g (73.4% of theory) Boiling point: 58°C/9.1 mbar. d) trans-2-Qxa-5,8-di azabi cyclo/4.3. 07 nonane 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane is reacted with 2-(benzylamino)-ethanol, analogously to Example Da), to give trans-l-benzyl-3-[N-benzyl-U-(2-hydroxy-ethyl)-amino]-4-hydroxypyrrolidine which is then reacted analogously to Example F a) to give 5,8-dibenzyl-2-oxa-5, S-^diazabicyclo [ 4 . 3 . 0 ] nonane which is 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-diaza-bicyclo[4.3.0]-nonane, boiling point: 60*C/0.1 mbar. 1. n 1 IS 119 92 - Example G 2 3 8^85 -Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride a) 8-Benzvl-5-inethvl-2-oxa-5 , 8-diazabicvclo [4.3. 01 nonane 18 g (71.9 mmol) of l-benzyl-4-hydroxy-3-(2-hydroxyethyl-10 methyl-amino) -pyrrolidine are reacted in 60 ml of concentrated sulphuric acid and 30 ml of water as in Example F a).

Yield: 10 g (60% of theory) Boiling point: 122°C/0.08 mbar b) 5-Methyl-2-oxa-5, 8-diazabicyclo [4.3. 0 jnonane dihydrochloride A solution of 9.4 g (40 mmol) of 8-benzyl-5-methyl-2-oxa-2o 5,8-diazabicyclo[4 . 3.0]nonane in 150 ml of methanol and 7.4 ml of concentrated hydrochloric acid is hydrogenated on 3 g of palladium-on-active charcoal (10% of Pd) at 80°C under 10 0 bar. The catalyst is filtered off with suction and the filtrate is concentrated. The residue is 25 triturated with butanol/acetone 1:1 and the crystals are filtered off with suction and dried over P4O10 in a desiccator. The product is very hygroscopic.

Yield: 8.2 g (95% of theory) Mass spectrum: m/e 142 (M1"), 112 (M*~CH20), 100 (*T-CH2-N=CH2), 82 (C*H*NO+), 68 (C„H6N*) Example H 2-Methyl-3-oxa-2,7-diazabicyclo [3.3.0] octane a) Ethvl N-( 2,2-dimethoxvethvl)-carbamate 214 g (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde dimethyl acetal in lil b 20 1-08 - 93 - rs t 23^8 1 1 of toluene and 90 g of NaOH in 500 ml of water at 10°C. The mixture is stirred at room temperature for a further 2 hours and the aqueous phase is separated off, saturated with sodium chloride and extracted with toluene. The toluene solutions are dried over magnesium sulphate and concentrated and the residue is distilled. Yield: 338 g (95.4% of theory) Boiling point: 60°C/0.03 mbar b) Ethvl N-allvl-N-(2,2-dimethoxvethvl)-carbamate g of sodium hydride (80% strength in paraffin oil) are initially introduced into 500 ml of toluene and 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 80°C. The mixture is stirred at 80°C for one hour and 73 g (0.6 mol) of allyl bromide are then added dropwise in the course of three hours. The mixture is stirred at 80°C overnight, the salts are dissolved with water and the organic phase is separated off. The aqueous phase is extracted with toluene, the organic phases are dried over potassium carbonate and concentrated and the residue is distilled.

Yield: 68 g (62.5% of theory) Boiling point: 65°C/0.09 mbar c) Ethvl N-allvl-N-(2-oxoethvl)-carbamate 68 g (0.313 mol) of ethyl N-allyl-N-(2,2-dimethoxyethyl)-carbamate are heated with 150 ml of formic acid at 100°C for one hour. The mixture is poured onto ice and extracted several times with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.

Yield: 46.7 g (87.2% of theory) Lo n infl - 94 - ♦ { i 3 S 4 8 5 Boiling point: 58°C/0.09 mbar d) Ethyl 2-methyl-3-oxa-2,7-diazabicyclo [ 3 . 3 . 0 ]octane-7- carboxvlate g (0.12 mol) of methylhydroxylamine hydrochloride are 5 dissolved in 50 ml of methanol, the solution is cooled in an ice-bath and 22 g (0.12 mol) of 30% strength sodium methylate solution in methanol are added dropwise. The sodium chloride is filtered off with suction and the salt is washed with 80 ml of toluene. The methylhydroxylamine 10 solution is added dropwise in the course of one hour to 20 g (0.117 mol) of ethyl N-( 2-(oxoethyl)-carbamate, which is heated under reflux in 160 ml of toluene, using a water separator. The mixture is heated under reflux overnight and the product is extracted twice with 80 ml 15 of 10% strength hydrochloric acid each time. The hydro chloric acid solutions are saturated with potassium carbonate and extracted six times with 200 ml of chloroform each time. The extract is dried over K2C03 and concentrated and the residue is distilled.

Yield: 18.6 g (79.5% of theory) Melting point: 93°C/0.09 mbar e) 2-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane 13 g (65 mmol) of ethyl 2-methyl-3-oxa-2,7-diazabicyclo-t3.3.0]octane-7-carboxylate are heated under reflux in 25 300 ml of water with 41 g of Ba(0H)2.8H20 overnight. s.a a 26 jma X / 0 K kj & "/ <u D Potassium carbonate is added, the barium carbonate which has precipitated out is filtered off with suction and the filtrate is extracted ten times with 100 ml of chloroform each time. The extract is dried over potassium carbonate 5 and concentrated and the residue is distilled.

Yield: 5.4 g (65% of theory) Boiling point: 80°C/10 mbar Example I l-Methyl-octahydropyrrolo[ 3,4-b] pyrrole (2-methyl-2, 7-10 diazabicyclo[3.3.0]octane) a) l-Benzyl-3-( 2-chloroethyl-methyl-amino)-pyrrolidine-2,5-dione 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308. 15 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methyl-amine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20°C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 20 2 1 of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on 3ilica gel using ethyl acetate:petroleum ether (1:2) 25 gives 56.8 g (51% of theory) of an oil. fco'niv 2 1: 8 Rf value: 0.33 (silica gel, ethyl acetate/petroleum ether = 1:2) b) 5-Benzyl-4,6-dioxo-l-methyl-octahydropyrrolo[3,4-b]-pyrrole 7.2 g (0.24 mol) of an 80% strength sodium hydride suspension in mineral oil are suspended in 150 ml of absolute dimethylformamide (dried over calcium hydride), and 62 g (0.22 mol) of l-benzyl-3-(2-chloroethyl-methyl-amino)-pyrrolidine-2,5-dione are added dropwise as a 10 solution in 50 ml of absolute dimethyl formamide at room temperature. During this, an exothermic reaction takes place with foaming. The mixture is diluted with a further 50 ml of absolute dimethyl formamide and subsequently stirred at room temperature for 1 hour and is then poured 15 into ice-water and extracted with methylene chloride. The extract is washed with water, dried with sodium sulphate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel using ethyl acetatepetroleum ether (1:2) and later (1:1). 16.4 g of educt are 20 initially recovered here, and 17.2 g (44% of theory, based on the educt reacted) of an oily product are then isolated.

Ri value = 0.26 (silica gel, ethyl acetate:petroleum ether = 1:1).

Tn A 16 JMA I i3 9 4 8 5 c) 5-Benzvl-l-methvl-octahvdropyrrolo r 3.4-blpvrrole 1.52 g (40 mmol) of lithium aluminium hydride are initially introduced into 30 ml of anhydrous tetrahydrofuran, and 4.9 g (20 mmol) of 5-benzyl-4,6-dioxo-l-5 methyl-octahydropyrrolo[3,4-b]pyrrole are added dropwise as a solution in 15 ml of anhydrous tetrahydrofuran. The mixture is then subsequently stirred at the boiling point for 3 hours. 1.5 ml of water, 1.5 ml of 15% strength potassium hydroxide solution and 4.5 ml of water are 10 added dropwise in succession to the batch and the precipitate is then filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated on a rotary evaporator and the residue is distilled. 3.1 g (72% of theory) of a colourless distillate of boiling 15 point 80°C/0.07 mbar are obtained. d) 1-Methvl-octahvdropvrrolor 3,4-b 1 pyrrole 6.49 g (30 mmol) of 5-benzyl-l-methyl-octahydropyrrolo-[3,4-b]-pyrrole are dissolved in 100 ml of absolute ether, and 5.2 g of hydrogen chloride dried over phos-20 phorus pentoxide are passed in. The hydrochloride suspen sion formed is concentrated in vacuo and the residue is taken up in 100 ml of methanol. It is then hydrogenated with 2 g of Pd-on-C (5% strength) at 80°C under 50 bar for 4 hours. The catalyst is subsequently filtered off, 25 the filtrate is concentrated and 30 ml of 40% strength sodium hydroxide solution and 50 ml of ether are added to the residue. The ethereal phase is separated off and the Lo A i9'6——— 98 I b k 8 5 aqueous phase is extracted with 2 x 50 ml of ether. The combined organic phases are dried over sodium sulphate and concentrated and the residue is distilled. 1.3 g (34% of theory) of a colourless oil of boiling point 65-66°C/ 5 12 mbar are obtained.

Purity: >99% Example J Octahydropyrrolo[3,4-b]pyrrole (2,7-diazabicyclof3.3.0]-octane) a) l-Benzvl-3-(2-chloroethvlamino)-pvrrolidine-2,5-dione 74.8 g (0.4 mol) of N-benzylmaleimide are reacted with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine in accordance with the 15 working instructions of Example la. After working up by chromatography, 81.6 g (77% of theory) of an oil with an Rf value of 0.24 (on silica gel using ethyl acetate: petroleum ether = 1:1) are obtained. b) 5-Benzvl-4,6-dioxo-octahvdropyrrolor 3,4-b1pyrrole 17.4 g (0.58 mmol) of sodium hydride suspension are reacted with 119 g (0.45 mol) of l-benzyl-3-(2-chloro-ethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute dimethylformamide in accordance with the working instructions of Example lb. After the mixture has been left to liL. a sg 1-frfr 6 b stand overnight, it is worked up under aqueous conditions. On purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetatesmethanol (3:1) (RF value 0.55). 57.7 g of product (56% of theory) are isolated. c) 5-Benzvl-octahvdropvrrolor3,4-blpyrrole 57.7 g (0.25 mol) of crude 5-benzyl-4,6-dioxo-octahydro-pyrrolo[3,4-b]pyrrole are reduced with 21.4 g (0.56 mol) of lithium aluminium hydride by boiling in 700 ml of 10 absolute tetrahydrofuran for 10 hours in accordance with the working instructions of Example Ic. Working up by distillation gives 21.0 g (41.1% of theory) of an oil of boiling point 95°C/0.1 mbar. d) Octahvdropvrrolor3,4-b]pyrrole 21.0 g (0.104 mol) of 5-benzyl-octahydropyrrolo- [3,4-b]pyrrole are initially introduced into 180 ml of ice-cooled methanol, and 17.3 ml (0.208 mol) of concentrated hydrochloric acid are added. The mixture is then hydrogenated with 2 g of Pd-on-C (5% strength) at 9Q°C 20 under 100 bar for 4 hours. The catalyst is filtered off, 37.4 g (0.208 mol) of 30% strength sodium methylate solution are added to the filtrate, the mixture is filtered again and the filtrate is concentrated. The residue is distilled through a small Vigraux column. 5.6 25 g of a colourless oil (48% of theory) of boiling point 93-95°C/30 mbar, which fumes in air and slowly solidifies Lu A EG 100 ? 3 9 4 8 5 in the receiver (melting point 40°C) are obtained. Example K f Octahydropyrrolo [3,4-b]pyridine (2,8-diazabicyclo [4.3.0]-nonane) a) S-Benzvl-5 ,7-dioxo-octahvdropvrrolof 3.4-b1 pyridine 47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid N-benzylimide (British Patent 1,086,637; Chem. Abstr. 68, 95695w) are hydrogenated in 400 ml of glycol monomethyl 10 ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90°C under 100 bar until the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is concentrated on a rotary evaporator. 44 g of an oily crude product are 15 obtained.

The corresponding hydrogenation with palladium-on-active charcoal (5% strength) gives a quantitative yield of a pure product of melting point 67-69°C. _b) 6-Benzvl-octahvdropvrrolor 3 ,4-b 7pyridine 44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7-dioxo-octahydropyxrolo[3,4-b]pyridine are reduced with 15.2 g (0.40 mol) of lithium aluminium hydride in 390 ml of absolute tetrahydrofuran in the course of 10 hours in 9 ~e\ Q A 8 accordance with the working instructions of Example Ic. 24.4 g of a colourless oil having a boiling point of 9 3-95°C/0.06 mbar are obtained on distillation. c) Octahvdropvrrolor3,4-b1pyridine 69 g (0.32 mol) of 6-benzyl-octahydropyrrolo[3/4-b]pyridine are hydrogenated in 450 ml of methanol over 7 g of palladium-on-active charcoal (5% strength) at 90°C/90 bar in the course of 3 hours. The catalyst is then filtered off, the filtrate is concentrated and the residue is 10 distilled. 33.8 g (84% of theory) of a colourless solid having a melting point of 65-67°C and a boiling point of 78°C/9 mbar are obtained.

Example L 1-Methyl-octahydropyrrolo[ 3,4-b] pyridine (2-methyl-2,8-15 diazabicyclo[4.3.0]nonane) a) 1-Methyl-pyridinium-2,3-dicarboxylic acid N-benzyl-imide iodide 190.5 g (0.8 mol) of pyridine-2,3-dicarboxylic acid N-20 benzylimide are dissolved in 800 ml of nitromethane, while heating, and 136 g (0.96 mol) of methyl iodide are added dropwise. The mixture is then boiled for 8 hours while cooling under reflux (cooling water 0°C). After cooling, the solid is filtered off with suction and C. 0. A r; n washed with methylene chloride. 123 g of dark red crystals having a melting point of 162-165°C (decomposition) are obtained. b) 6-Benzyl-l-methyl-5 ,7-dioxo-octahydropyrrolo[3,4-b]-5 pyridine 38 g (0.1 mol) of l-methyl-pyridinium-2,3-dicarboxylic acid N-benzylimide iodide are hydrogenated over 1 g of platinum oxide in 450 ml of glycol monomethyl ether at 30°C under 70 bar until the uptake of hydrogen has ended 10 (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 x with 300 ml of 10% strength sodium carbonate solution each time and with 300 ml of water. After drying over sodium 15 sulphate, it is concentrated. 27 g of an oily residue remain. c) 6-Benzvl-l-methvl-octahvdropvrrolor3 .4-blpyridine 19.2 g (0.08 mol) of crude 6-benzyl-l-methyl-5,7-dioxo-octahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g 20 (0.16 mol) of lithium aluminium hydride in absolute tetrahydrofuran in accordance with the working instructions of Example lc.

Yield: 9.5 g (52% of theory), Boiling point: 93-96°C/0.1 mbar. iia ft ac-aaa o f*. /, f> |? d) 1-Methvl-octahvdropvrrolo r 3 ,4-b 1 pyridine 11.7 g (54 mmol) of 6-benzyl-1-methyl-octahydropyrrolo-[3,4-b]pyridine as the dihydrochloride are hydrogenated in 100 ml of methanol over palladium-on-active charcoal 5 in accordance with the working instructions of Example Id. Working up by distillation gives 2.6 g (34% of theory) of a colourless oil of boiling point 83-85°/12 mbar).

Rvamplp M trans-4-Methoxy-3-methylamino-pyrrolidine dihydrochloride a) trans-l-Benzyl-3-benzylmethylamino-4-hydroxy-pyrrolidine 19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3-15 azabicyclo[ 3 .1.0] hexane are heated under reflux with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml of water overnight. The mixture is extracted with CHC13, the extracts are dried with K2C03 and concentrated and the residue is subjected to incipient distillation up to 160°C (oil bath temperature).

Crude yield: 18.3 g Content: 100% (determined by gas chromatography) in, a ao loo - 1Q4 - I ( b) trans-1-Benzyl-3-benzylmethylamino-4-methoxy-pyrrolidine 17.3 g (58 mmol) of crude trans-l-benzyl-3-benzyl-meth.ylamino-4-hydroxy-pyrrolidine in 80 ml of absolute tetrahydrofuran are added dropwise to 2.8 g (93.3 mmol) of 80% strength sodium hydride in 40 ml of absolute tetrahydrofuran and the mixture is heated under reflux at the same time. When the evolution of hydrogen has ended, 8.7 g (61 mmol) of methyl iodide are added dropwise and the mixture is then heated under reflux overnight. It is poured into ice-water and extracted with toluene, the extracts are dried with K2C03 and concentrated and the residue is distilled.

Yield: 9.7 g (52% of theory) Boiling point: 140-150°C/0 .1 mbar c) trans-4-Methoxy~3-methylamino-pyrrolidine dihydrochloride 9.3 g (29 mmol) of trans-l-benzyl-3-benzylmethyl-amino-4-methoxy-pyrrolidine are dissolved in 100 ml of methanol, 4.8 ml of concentrated hydrochloric acid are added and the mixture is hydrogenated on 4 g of 10% strength Pd-on-active charcoal at 90°C under 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is recrystallized from isopropanol/methanol. Yield: 3.7 g (62.8% of theory) Ln \ 16 1 f? R 239485 Melting point: 157-162°C Example N 2,5-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane a) N-(2-Methylprop-2-enyl)-N-(2,2-dimethoxyethyl)-urethane 89 g (0.5 mol) of N-(2 ,2-dimethoxyethyl)-urethane are added dropwise to 20 g of sodium hydride (80% strength) in 500 ml of absolute toluene at 90°C. When 10 no further hydrogen is formed, 54 g (0.6 mol) of methallyl chloride are added dropwise and the mixture is stirred overnight at 90°C. The sodium chloride which has precipitated out is dissolved with a little water, the organic phase is separated 15 off, dried over K2C03 and concentrated and the residue is distilled.

Yield: 71.3 g (61.7% of theory) Boiling point: 60°C/0.08 mbar b) N-(2-Methvlprop-2-envl)-N-f 2-oxoethvl)-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-toluenesulphate in 100 ml of acetone and 10 ml of water are heated under reflux for two days. The mixture is concentrated and the residue is T n A 16 2. 3 9 4 distilled.

Yield: 5.3 g (61.2% of theory) Boiling point: 73°C/0.1 mbar Ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]-octane-7-carboxvlate 21.7 g of 30% strength sodium methylate solution are added dropwise to 10 g (0.12 mol) of N-methyl-hydroxylamine hydrochloride in 26 ml of methanol. The sodium chloride is filtered off with suction and washed with 8 ml of methanol and 80 ml of toluene. This solution is added dropwise to 19.2 g (0.11 mol) of N- (2-methyl-prop-2-enyl) -N- (2-oxoethyl) -urethane, which is heated under reflux in 160 ml of toluene using a water separator. The mixture is heated under reflux overnight, the product is extracted with 160 ml of 10% strength hydrochloric acid and the hydrochloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions of 200 ml of CHC13. The extracts are dried over K2C03 and concentrated and the residue is distilled. Yield: 13 g (55% of theory) Boiling point: 88-95°C/0.08 mbar 2 , 5-Dimethyl-3-oxa-2 ,7-diazabicvclor 3.3.0 1 octane 13 g (60.6 mmol) of ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3 .3.0]octane-7-carboxylate are heated under reflux with 33 g of Ba(0H)2.8H2O in 330 ml of o 239485 water overnight. The BaC03 is filtered off with suction, K2C03 is added to the filtrate, the solid is filtered off with suction again and the filtrate is extracted ten times with 100 ml of CHC13 each time.

The extracts are dried over K2C03 and concentrated and the residue is distilled.

Yield: 5.9 g (63.7% of theory) Boiling point: 64°C/5 mbar Example 0 2,8-Dimethyl-3-oxa-2,7-diazabicyclo [3 . 3 .0 Joctane a) N-(1,l-Dimethoxyprop-2-vl)-urethane 80 g (0.73 mol) of ethyl chloroformate are added dropwise to 86.2 g (0.72 mol) of 2-aminopropion-.15 aldehyde dimethyl acetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred at room temperature for a further 2 hours, the organic phase is separated off, the aqueous phase is extracted with toluene and the 20 toluene solutions are dried over K2C03. The solution is concentrated and the residue is distilled.

Yield: 132 g (95% of theory) Boiling point: 55°C/0.06 mbar * ag 239485 b) N-Allyl-N- (1, l-dimethoxv"pror>-2-vl) -urethane 131 g (0 .686 mol) of N-(1,l-dimethoxyprop-2-yl)-urethane are added dropwise to 25 g of sodium hydride (80% strength) in 700 ml of absolute toluene at 90°C. When the evolution of hydrogen has ended, 61.2 g (0.8 mol) of allyl chloride are added drop-wise at 90°C and the mixture is stirred overnight at 90°C, The sodium chloride which has precipitated out is dissolved with water, the organic phase is separated off, dried over K2C03 and concentrated and the residue is distilled.

Yield: 78 g (31.7% of theory) Boiling point: 62-69°C/0.06 mbar.

Content: 64.5% pure (determined by gas chromatography) c) N-Allvl-N-(l-oxoprop-2-vl)-urethane 76.5 g (0.213 mol) of 64.5% pure N-allyl-N-( 1,1-dimethoxyprop-2-yl)-urethane are heated in 180 ml of formic acid at 100°C for one hour. The mixture is poured into ice-water and extracted with CH2C12, the extracts are washed neutral with NaHC03 solution, dried over MgSO,, and concentrated and the residue is distilled.

Yield: 36 g (80.9% of theory) Boiling point: 97-102°C/8 mbar Content: 88.8% pure (determined by gas chromatography) Ethyl 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3• 0]-cctane-7-carboxvlate A methanolic methylhydroxylamine solution is prepared from 16.4 g (0.2 mol) of N-methylhydroxylamine \vdrochloride in 33 ml of absolute methanol and 5 g (0.2 mol) of 30% strength sodium methyiate olution, and the solution formed is diluted with .30 ml of toluene and added dropwise to 354 g 0.17 mol) of N-allyl-N-(l-oxoprop-2-yl)-urethane in .50 ml of toluene, which is heated under reflux .sing a water separator. The mixture is heated under reflux overnight, the product is extracted with iilute hydrochloric acid and the hydrochloric acid solution is rendered alkaline with K2C03 and extracted with CHC13. The extract is dried over K2C03 ».nd concentrated and the residue is distilled, 'field: 18.5 g (50.8% of theory) Boiling point: 95-105°C/0.1 mbar 2 . 8-Djni<at-.hY'l -3-oxa-2 > 7-diazabicvclor 3.3.0 loctane 9.2 g (42.9 mmol) of ethyl 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 23.5 g of Ba(0H)2.8H20 in 235 ml of water overnight. The BaC03 is filtered off with suction, K2C03 is added to the filtrate and the solid is filtered off with suction again. The filtrate is extracted ten times with 50 ml of CHC13 each time, the extracts are dried over K2C03 and concentrated '> i. ^ [, £». sj 'i and the residue is distilled.

Yield: 1.7 g Boiling point: 87-92°C/10 mbar The product is a mixture of the possible stereoisomers in a ratio of 3:1 ^H-NMR) . 4 g of starting material could to be recovered in the after-runnings.

Example P 2-Methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane a) Ethyl 4-hydroxymet.hyl-3-methylaminopyrrolidine-l-carboxvlate g (50 mmol) of ethyl 2-methyl-3-oxa-2,7-diazabicyclo [3 .3 . 0 ]octane-7-carboxylate (Example H d)) are 15 hydrogenated in 200 ml of ethanol on 3 g of Pd-on- active charcoal (10% of Pd) at 50°C under 50 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

Yield: 8.1 g (80% of theory) Boiling point: 135-140°C/0 .1 mbar b) Ethyl 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane-8-carboxvlate .1 g (50 mmol) of ethyl 4-hydroxymethyl-3-methyl-amino-pyrrolidine-l-carboxylate and 8 g (0.1 mol) of - Ill - ! 3 9 4 8 37% strength formaldehyde solution are dissolved in 100 ml of butanol and the solution is stirred at room temperature overnight. It is then concentrated and the residue is distilled.

Yield: 9.5 g (88.7% of theory) Boiling point: 110°C/0.1 mbar 2-Methvl-4-oxa-2,8-diazabicvclor4.3.01nonane 9 g (42 mmol) of ethyl 2-methyl-4-oxa-2,8-diazabicyclo [4.3.0]nonane-8-carboxylate are heated under reflux with 28 g of Ba(0H)2.8H20 in 280 ml of water overnight. The BaC03 is filtered off with suction, the filtrate is concentrated and the residue is boiled up 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 mbar 4-Hvdroxvmethvl-3-iDg+,>'Yl ami nn-pyrrolidine 34 g (0.168 mol) of ethyl 4-hydroxymethyl-3-methyl-aminopyrrolidine-1-carboxylate are heated under reflux with 100 g of Ba(OH)2.8H20 in 400 ml of water overnight. The BaC03 is filtered off with suction, the filtrate is concentrated and the residue is boiled up ten times with 100 ml of dioxane each time. The dioxane solutions are filtered, the filtrate is concentrated and the residue is distilled.

' ! T, o A v j- b /"**s Yield: 13 g (60.3% of theory) Boiling point: 85-88°C/0.08 mbar e) 2-Methvl-4-oxa-2,8-diazabicvcloF4.3.01nonane 8.1 g (0.1 mol) of 37% strength formaldehyde solu-5 tion in 20 ml of n-butanol are added dropwise to 13 g (0.101 mol) of 4-hydroxymethyl-3-methylamino-pyrrolidine in 100 ml of n-butanol at room temperature . The mixture is stirred at room temperature overnight and concentrated and the residue is 10 distilled.

Yield: 8.7 g (61.2% of theory) Boiling point: 84°C/6 mbar Example 0 3-Oxa-2,7-diazabicyclo[3.3.0]octane a) Ethyl 2-(tetrahydropyran-2-yl)-3-oxa-2,7-diazabi-cvclor3.3.01octane—7-carboxvlate 18.1 g (0.106 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate (Example He)) are heated under reflux in 20 220 ml of toluene, and 14.2 g (0.12 mol) of 5- hydroxypentanal oxime (Acta Chim. Acad. Sci. Hung., 14. 333 (1958)), dissolved in 55 ml of hot toluene, are added dropwise. The mixture is heated under reflux overnight and concentrated and the residue is iif» ft 3C ?3 9 4 8 distilled.

Yield: 15.5 g (54% of theory) Boiling point: 160°C/0.01 mbar b) Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7-5 carboxvlate g (55.5 mmol) of ethyl 2-(tetrahydropyran-2-yl)-3-oxa-2/7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 8.25 g (56 mmol) of 70% strength perchloric acid in 100 ml of ethanol for 30 10 minutes. 10.5 g (58 mmol) of 30 strength sodium methylate solution are added, the mixture is concentrated, the residue is taken up in water and the solution is saturated with K2C03 and extracted with CHC13. The extract is dried over K2C03 and concentra-15 ted and the residue is distilled.

Yield: 7.6 g (73.5% of theory) Boiling point: 125-130°C/0 .1 mbar c) Ethvl 3-oxa-2 ,7-diazabicvclor 3 .3 .01 octane-7-carboxvlate 8.5 g (50 mmol) of ethyl N-(2-oxoethyl)-N-allyl- carbamate are heated under reflux with 5.5 g (50 mmol) of o-trimethylsilylhydroxylamine in 100 ml of xylene overnight. The mixture is concentrated and the residue is distilled.

Yield: 6.8 g (73% of theory) Boiling point: 120-122°C/0.05 mbar Tn n Tfi iflfl 2394 85 d) 3-Oxa-2,7-diazabicvclor 3.3.0loctane This substance is obtained analogously to Example N d) by hydrolysis of ethyl 3-oxa-2,7-diazabicyclo-[3.3.0]octane-7-carboxylate with Ba(OH)2.8HZ0. Boiling point: 75°C/10 mbar.

Example R 3-Methyl-2,7-diazabicyclo[3.3.0]octane 3-Methyl-2,7-diazabicyclo[3.3.0]octane is obtained 10 analogously to Example I.

Boiling point: 68-70°C/6 mbar.

Example S 2,3-Dimethyl-2,7-diazabicyclo[3.3.0]octane 2,3-Dimethyl-2,7-diazabicyclo[3.3.0]octane is obtained analogously to Example I.

Boiling point: 72-74°C/10 mbar. gtfarnpl** t 1,2-Dimethyl-3-oxa-2,7 -diazabicyclo [3.3.0] octane ? 3 9 4 8 5 a) N-Allvl-N- (2 . 2-dimethoxvoropyl) Hg 119 g (74 mol) of 2,2-dimethoxypropylacetamide are added dropwise to 29.6 g (0.987 mol) of sodium hydride (80% strength in paraffin oil) in 750 ml of 5 absolute toluene at 80°C. The mixture is then stirred for one hour and 100 g (0.83 mol) of allyl bromide are subsequently added dropwise at 80°C. The mixture is stirred overnight at 80°C and cooled and the salts are dissolved with water. The aqueous phase is 10 separated off and extracted twice with 100 ml of toluene each time. The toluene solutions are dried over K2C03 and concentrated and the residue is distilled.

Yield: 112 g (75.6% of theory) Boiling point: 70°C/0.08 mbar. b) N—Allvl-N— (2-.oxopropvl) -acetamide 85.5 g (0.425 mol) of N-allyl-N-(2,2-dimethoxy-propyl)-acetamide are heated under reflux with 212 ml of formic acid for one hour. The mixture is 20 poured onto 500 g of ice and extracted several times with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.

Yield: 50 g (75.8% of theory) Boiling point: 79°C/0.25 mbar. la ft 36 IBB - 116 - 23 0 4 8 5 7-Acetyl-1,2-dimethyl-3-oxa-2,7-diazabicyclo [ 3.3.0]-octane .5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acetamide are dissolved 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 are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2C03 is added. The mixture is extracted with CHC13/ the extract is dried over K2C03 and concentrated and the residue is distilled.

Yield: 15.9 g (86.3% of theory) Boiling point: 75°C/0.1 mbar. 1 r ?~nimethyl—3— oxa-2 ,7-diazabicvclor3. 3 .0 1 octane 11.8 g (64 mmol) of 7-acetyl-l,2-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane are heated under reflux with 12 g of NaOH in 36 ml of water overnight. The mixture is saturated with K2C03 and extracted several times with CHC13, the extract is dried over K2C03 and concentrated and the residue is distilled.

Yield: 4.7 g (51.6% of theory) Boiling point: 40°C/0.2 mbar. 239485 •Ryamplta TT 2,4-Dimethyl-3-oxa-2 , 7-diazabicyclo[3.3.0 ]octane a) Ethyl N-(but-2-enyl)-N-(2,2-dimethoxyethyl)-car-5 hamate 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl) -carbamate are added dropwise to 17.5 g (0.58.mol) of NaH (80% strength in paraffin oil) in 500 ml of absolute toluene at 80°C. The mixture is then stirred 10 for one hour and 80 g (0.59 mol) of l-bromo-2-butene are subsequently added dropwise at 80°C. The mixture is stirred at 80°C overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The 15 toluene solutions are dried over K2C03 and concentra ted and the residue is distilled.

Yield: 90 g (77.8% of theory) Boiling point: 65°C/0.1 mbar. b) Ethvl N— (but-2-enyl \ -N- (2-oxoethvl 1 -carbamate 90 g (0.39 mol) of ethyl N-(but-2-enyl)-N-(2,2- dimethoxyethyl)-carbamate are heated under reflux with 200 ml of formic acid for one hour. The mixture is poured onto 500 g of ice and extracted with methylene chloride, the organic phases are washed 25 with sodium bicarbonate solution, dried over mag 8 4 8 5 nesium sulphate and concentrated and the residue is distilled.

Yield: 33.6 g (46.5% of theory) Boiling point: 65°C/0.1 mbar. c) Ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyclo [ 3 . 3 .0]-octane-7-carboxvlate 18.4 g (0.1 mol) of ethyl N-(but-2-enyl) -N-( 2-oxo-ethyl)-carbamate are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 10 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken 15 up in 100 ml of water and K2C03 is added. The mixture is extracted with CHC13, the extract is dried over K2C03 and concentrated and the residue is distilled. Yield: 15.0 g (70% of theory) Boiling point: 74-87°C/0.1 mbar. d) 3 f A-nimethvl-3-oxa-2 ,7-diazabicvclor 3.3. 01 octane 13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 39 g of Ba(OH)2 • 8H20 in 200 ml of water overnight. K2C03 is added, the BaC03 is fil-25 tered off with suction and the filtrate is extracted several times with CHC13. The extract is dried over iia ft 3C 1QB r> 239485 K2C03 and concentrated and the residue is distilled. Yield: 4.8 g (54.8% of theory) Boiling point: 74°C/8 mbar. example* v Ethyl 2,7-diazabicyclo[3.3.0 ]octane-2-carboxylate 7-Benzyl-2,7-diazabicyclo[ 3. 3 .0 ]octane (Example- Jc) is reacted with ethyl chloroformate analogously to Example Oa) to give ethyl 7-benzyl-2, 7-diazabicyclo[3 .3 .0 ]octane-10 2-carboxylate, and this is then debenzylated hydrogeno- lytically analogously to Example Jd) . A colourless oil of boiling point 90°C/0.1 mbar is obtained.

Example W 2-Phenyl-2 ,7-diazabicyclo [ 3 .3.0 ]octane 15 The preparation is carried out analogously to Example I) ; Boiling point: 103°C/0.08 mbar. i ti i(T inn. 120 - 239485 Eyanvpl g X 4-Oxa-2,8-diazabicyclo[4.3.0]nonane a) Ethyl 3-amino-4-hydroxymethyl-pyrrolidine-l-carboxvlate Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7-car-boxylate (Example Qc) is hydrogenated analogously to Example Pa) .

Boiling point: l63-168°C/0.8 mbar b) 3 -Amino - 4 -hvdroxvme t hvl - pyrr o 1 idine Ethyl 3-amino-4-hydroxymethyl-pyrrolidine-1-car-boxylate is hydrolyzed analogously to Example Pd). Boiling point: 78°C/0.06 mbar. c) 4-0xa-2,8-diazabicvclo r 4.3.01nonane 3-Amino-4-hydroxymethyl-pyrrolidine is reacted with formaldehyde solution analogously to Example Pe). Boiling point: 50-60°C/0.07 mbar Example y trans-3-Ethylamino-4-methylthio-pyrrolidine a) l-Benzoyl-trans-3-ethylamino-4-methylthio-ovrrolidine 8.65 g (50 mmol) of l-benzoyl-2,5-dihydropyrrole [Chem. Ber. 22, 2521 (1889)] are initially introduced into 30 ml of methylene chloride, and 4.94 g (60 mmol) of methanesulphonyl chloride in 20 ml of methylene chloride are added dropwise at 0°C. The mixture is subsequently stirred at 20-25°C for 16 hours and concentrated under 8 mbar and the residue is dissolved in 50 ml of tetrahydrofuran. 18 g (0.2 mol) of 50% strength aqueous ethylamine solution are then added. The batch is boiled for 18 hours, while cooling under reflux, poured into water and extracted with methylene chloride. On concentrating, 11.1 g of crude product are obtained, and the crude product is chromatographed with ethyl acetate/ethanol 5:1 on silica gel (RF value 0.34). Yield: 7.4 g (56% of theory). b) trans-3-Ethvlamino-4-methvlthio-pyrrolidine 6.0 g (22 mmol) of l-benzoyl-trans-3-ethylamino-4-methylthio-pyrrolidine are stirred vigorously with 22 ml of 5N NaOH at 100°C for 24 hours, until the m n iti*aa 2 3 8 4 8; 5 conversion is homogeneous. The mixture is then extracted with 3 x 80 ml of ether and the extract is dried over sodium sulphate and concentrated on a rotary evaporator. The crude product is distilled through a micro-puncture column.

Yield: 1.56 g (44% of theory) of colourless liquid, Boiling point: 52°C/0.1 mbar Example Z trans-3-amino-4-methylthio-pyrrolidine l-3enzoyl-2,5-dihydrcpyrrole is reacted with methylsulfe-nyl chloride analogously to Example Y to give l-benzyl-3-chloro-4-methylthiopyrrolidine which is reacted as a crude product with ammonia to give 3-amino-l-benzoyl-4-me"chyl-thio-pyrrolidine and the benzoyl radical is removed with 20 sodium hydroxide solution.

Yield over 3 stages: 47 % of theory Boiling point: 108-110"C/11 mbar.

Example ZA 4-Methvl-2,8-diazabicvclo f4.3.0}nonane 30 a) 5-Methyl-l, 4-dihydropyridine-2,3-dicarboxylic acid N-benzylimide 33 g (0.29 mol) of 2-methyl-2-propenal-dimethylhydra-zone and 55 g (0.29 mol) of N-benzylmaleinimide are stirred in 225 ml of acetonitrile for 3 hours at 60'C.

I r T i ?g ]1g - 123 y V* 4 8 5 Then the solvent is removed in a rotary "evaporator, the residue is taken up in 600 ml of toluene and, after adding 150 g of silica gel, the mixture is boiled for 1 hour under reflux.

Then the mixture is filtered while hot and the silica gel is boiled out several times with ethanol. The combined organic phases are concentrated in a rotary evaporator. 17.5 g (24 % of theory) of red crystals of a melting point of 184-186"C are obtained. b) 5-Methyl-hexahydropyridine-2,3-dicarboxylic acid N-benzvlimide 17.5 g (70 mmol) of 5-methvl-l,4-dihydropyridine-2,3-dicarboxvlic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70 "C and under 100 bar over palladium on active charcoal. Then the catalysis filtered off ana the filtrate is concentrated by evaporation. The solid oily residue (13.0 g) is used as a crude product in the next stage. c) 8-3enzvl-4-methvl-2 , 8-diazabicvclo f 4.3.01nonane 13.0 g of crude 5-methyl-hexahydropyridine-2,3-dicarb-oxylic acid N-benzylimide are added in the form of a solution in 50 ml of absolute tetrahydrofuran to 4.6 g (0.12 mol) of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran, already present in the vessel. Then the mixture is boiled for 17 hours under reflux. 4.6 g of water in 14 ml of tetrahydrofuran, 4.6 g of 10 % strength sodium hydroxide solution and 13.8 g of water are added dropwise one after the other. The salts are filtered off, the filtrate is concentrated by evaporation and the residue is distilled. 2 3 9 4 8" Yield: 8.7 g (54 %, based on 5-methyl-l, t^dxhydropyri- dine-2,3-dicarboxylic acid N-benzylimide); boiling point: 95-98*C/0.1 mbar. d) 4-Methyl-2,8-diazabicvclo r 4.3.01nonane 8.0 g (35 mmol) of 8-benzyl-4-methyl-2,8-diaza-bicyclo[4 . 3.0]nonane are dissolved in 60 ml of methanol and hydrogenated over palladium on acitive charcoal at 100*C and under 100 bar. Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is distilled.

Yield: 3.3 g (67 % of theory) boiling point: 88-89 *C/llmbar.

The ^-NMR spectrum shows the compound to be a mixtu: of two stereoisomers in a ratio of 7:2.

Example AA ,6,7 , 8-Tetraf luoro-l-( 2 , 4-dif luorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid a) Ethyl 2-(2 , 3,4,5,6-pentafluorobenzoyl)-3-(2,4-difluoroohenvlamino^-acrvlate 44.3 g of 2,4-difluoroaniline are added dropwise to a solution of 115 g of ethyl 3-ethoxy-2-(2,3,4,5,6-pentaf luorobenzoyl)-acrylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 380 ml of water are added, while cooling with ice, and the precipitinc ■/:%.' Icff vith suction, washed with ejthcs.1 --1./H20 (1:1) and dried. 135.4 g of the title compound of melting point 97-99°C are obtained. 1 " * 1nQ - 125 - 2 4 / b) Ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihvdro-4-oxo-3-cruinolinecarboxvlate A mixture of 135.4 g of ethyl 2-(2,3,4,5,6-pentaf luorobenzoyl) -3- (2 , 4-difluorophenylamino) -acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dijnethylformamide is heated at 140-150°C for 3 hours. The suspension is poured hot onto 2 kg of ice and the precipitate is filtered off with suction, washed with water and dried. 122 g of the title compound of melting point 160-162°C are obtained. c) 5,6,7,8-Tetrafluoro-1- (2,4-difluorophenyl)-1,4-dihvdro-4-oxo-3-auinolinecarboxvlic acid 40.1 g of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl )-l, 4-dihydro-4-oxo-3-quinolinecarboxylate are added to a mixture of 28.5 ml of concentrated sulphuric acid, 250 ml of glacial acetic acid and 200 ml of water and the mixture is heated under reflux for 2 hours. The hot solution is poured onto ice and the precipitate is filtered off with suction, washed with water and dried. 34.5 g of the title compound of melting point 250-252°C are obtained.

Example AB ,7-Dichloro-l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-cralnolinecarboxvlic acid a) Ethvl <2,4-dichloro-3,6-difluorobenzoyl)-acetate Ua n ii i 88 126 23 9 4 2.1 g of magnesium filings are suspended in 5 ml of anhydrous ethanol. 0.5 ml of carbon tetrachloride is added and, when the reaction has started, a mixture of 14 g of ethyl malonate, 10 ml of absolute ethanol and 41 ml of toluene is added dropwise. The mixture is then heated at 70°C for a further 1.5 hours and cooled to -5°C to -10°C with acetone/dry ice, and a solution of 21.5 g of 2,4-dichloro-3,6-difluorobenzoyl chloride in 30 ml of toluene is slowly added dropwise at this temperature. The mixture is stirred at 0°C for 1 hour and allowed to come to room temperature overnight, and a mixture of 35 ml of ice-water and 5 ml of concentrated sulphuric acid is allowed to run in, while cooling with ice. The phases are separated and subsequent extraction is carried out twice with toluene. The combined toluene solutions are washed once with saturated sodium chloride solution and dried with Na2S04 and the solvent is stripped off in vacuo. 34.7 g of diethyl (2,4-dichloro-3,6-difluorobenzoyl)-malonate are obtained as a crude product. 0.04 g of p-toluenetoluenesulphonic acid is added to an emulsion of 34.7 g of crude diethyl (2,4-di-chloro-3,6-difluorobenzoyl)-malonate in 40 ml of water. The mixture is heated at the boiling point for 3 hours, while stirring thoroughly, the cooled emulsion is extracted several times with methylene chloride, the combined CH2C12 solutions are washed once with saturated sodium chloride solution and dried with Na2S04 and the solvent is distilled off in vacuo. Fractionation of the residue (33.9 g) in vacuo gives 13.9 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-acetate of boiling point 110-115°C/ 0 . 05 mbar, njj5 : 1 , 5241.

Ethyl 2- (2,4-dichloro-3,6-dif luorobenzoyl) -3-ethoxy-acrvlate 13.7 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-acetate are heated under reflux with 10.25 g of triethyl orthoformate and 11.8 g of acetic anhydride for 2 hours. The mixture is then concentrated in vacuo up to a bath temperature of 140°C and 15.7 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3- 2 5 ethoxy-acrylate are obtained as an oil, : 1,5 302 Ethyl 2- (2,4-dichloro-3, 6-dif luorobenzoyl) -3-cyclo-propvlamino-acrvlate .6 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of eyelopropylamine are added dropwise, while cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with ethanol/H20 (1:1) and dried. 14.1 g of ethyl 2-(2,4-dichloro-3,6-dif luorobenzoyl) -3-cyclopropylamino-acrylate of melting point 106-107°C are obtained. 2 3 9 4 8 5 d) Ethyl 5,7-dichloro-l-cyclopropyl-6-fluoro-l,4-dihvdro-4-oxo-3-cruinolinecarboxvlate 6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate are heated in 100 ml of 5 dimethyl formamide at 150°C with 2.75 g of potassium carbonate for 2.5 hours. The mixture is poured into 600 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 5.2 g of ethyl 5,7-dichloro-l-cyclopropyl-6-fluoro-10 l,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 227-229°C are obtained. e) 5 ,7-Dichloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3-auinoinecarboxvlic acid .2 g of ethyl 5,7-dichloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux in a mixture of 38 ml of acetic acid, 30 ml of water and 4.3 ml of concentrated sulphuric acid for 2.5 hours. After cooling, the mixture is poured into 250 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 4.8 g of 5,7-dichloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277-278°C are obtained. 23 9 4 S Example AC ,7 -Dichloro-6-f luoro-1- (2,4-dif luorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid a) Ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4-difluorophenvlamino)-acrvlate .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-difluoroaniline are added 10 dropwise, while cooling with ice. The mixture is stirred at room temperature for 1.5 hours, 120 ml of water are added, while cooling, and the precipitate is filtered off with suction, rinsed with ethanol/-H20 (1:1) and dried. 40.5 g of ethyl 2-(2,4-dichloro-15 3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)- acrylate are obtained, melting point: 84-86°C. b) Ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1.4-dihydro-4-oxo-3-auinolinecarboxvlate 43.6 g of ethyl 2-(2,4-dichloro-3,6-difluoro-20 benzoyl)-3-(2,4-difluorophenylamino)-acrylate are heated in 260 ml of dimethyl formamide at 150°C with 15.2 g of potassium carbonate for 2.5 hours. The mixture is poured into 1 litre of ice-water and the precipitate is filtered off with suction, washed 25 with water and dried. 38.6 g of ethyl 5,7-dichloro- tn n it ine 2. 3 9 4 8 5 6-fluoro-l- (2, 4-dif luorophenyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylate are obtained. c) 5,7-Dichloro-6-fluoro-1-{2,4-difluorophenyl)-1,4-dihvdro-4-oxo-3-quinolinecarboxvlic acid 41.6 g of ethyl 5,7-dichloro-6-fluoro-l-(2/4-di- f luorophenyl) -1, 4-dihydro-4-oxo-3-quinolinecar-boxylate are heated under reflux with 250 ml of acetic acid, 200 ml of water and 28.5 ml of concentrated sulphuric acid for 3 hours. After cooling/ 10 the mixture is poured into 2 litres of ice-water and the precipitate is filtered off with suction, washed with water and dried. 35.5 g of 5,7-dichloro-6-f luoro-1- ( 2 ,4-dif luorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting point: 244-2463C.

Example 1 0 A. 855 mg (3 mmol) of l-cyclopropyl-6/7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 20 ml of dimethyl formamide in the presence of 330 mg (3.3 mmol) of l,4-diazabicyclo[2.2.2]octane and 750 mg of *9 a ac loo 13 9 4 8 * trans-3-tert. -butoxycarbonyl-amino-4-methoxy-pyrrolidine for 1 hour. The mixture is evaporated, the residue is stirred with water and the mixture is dried.

Yield: 1.3 g (90.5% of theory) of 7-(trans-3-tert.-butoxycarbonylamino-4-methoxy-l-pyrrolidinyl)-1-cyclo-propyl-6 , 8-difluoro-1, 4-dihydro-4-oxo-3-quinoline-carboxylic acid.

Melting point: 222-224°C (with decomposition) (from glycol monomethyl ether).

B. 1.2 g (3.5 mmol) of the product from stage A are introduced into 10 ml of 3N hydrochloric acid, the mixture is stirred until a solution is obtained and the solution is concentrated. The residue is triturated with ethanol, filtered off with suction and dried at 60° under 15 a high vacuum.

Yield: 0.73 g (70% of theory) of 7-(trans-3-amino-4-methoxy- 1-pyrrolidinyl) -1 -eye lopr opyl - 6,8-difluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride.

Melting point: 279°C (with decomposition). la a as ■taa 2 3 S 4 8 5 v tramp 1 a 1 0 'COOH xHCl l-Cyclopropyl-6,7 -dif luoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid is reacted analogously to Example 1 to give: A. 7 -(trans-3-tert.-Butoxycarbonylamino-4-methoxy-l-pyrrolidinyl) -l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 247-24S°C (with decomposition).

B. 7-(trans-3-Amino-4-methoxy-1-pyrro1idiny1)-1-cyclo -propyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: from 293°C (with decomposition) .

Example 3 0 'COOH x HCl A reaction is carried out analogously to Example 1 with 239485 cis-3-tert. -butoxycarbonylamino-4-methoxy-pyrrolidine to give: A. 7- (cis-3-tert. -Butoxycarbonylamino-4-methoxy-1-pyrrolidinyl) -l-cyclopropyl-6,8-dif luoro-1,4-dihydro-4-5 oxo-3-quinolinecarboxylic acid, melting point: 230-231°C (with decomposition).

B. 7- (cis-3-Amino-4-methoxy-l-pyrrolidinyl) -1-cyclo-propyl-6,8-dif luoro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point 201-203°C (with decomposi-10 tion).

Example 4 x CF3COOH A. 1.5 g (5 mmol) of 8-chloro-l-cyclopropyl-6,7-di-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are 15 heated under reflux in a mixture of 10 ml of acetonitrile and 5 ml of dimethyl formainide with 550 mg (5 mmol) of l,4-diazabicyclo[2.2.2]octane and 1.2 g (5.6 mmol) of cis-3-tert. -butoxycarbonylamino-4-methoxy-pyrrolidine for 2 hours. The mixture is allowed to cool and the precipit-20 ate which has separated out is filtered off with suction, rinsed thoroughly with water and dried at 100°C in vacuo.

Lib A EG ) t 0 b. P 5 ir "■* Yield: 2.0 g (80.7%) of 7-(cis-3-tert. -butoxycarbonyl-amino-4-methoxy-l-pyrrolidinyl) -8-chloro-l-cyclopropyl-6 - f luor o-1,4-dihydro-4-oxo-3 -quinolinec ar boxy 1 ic ac id, melting point: 222-225°C (with decomposition).

B. 1.9 g (3.8 mmol) of the product from stage A are stirred in 10 ml of trif luoroacetic acid at room temperature for 20 minutes, the solution is concentrated, the oil which remains is evaporated twice with methylene chloride and the residue is stirred with ether. The 10 precipitate which has separated out is filtered off with suction, washed with ether and dried at 60°C in vacuo.

Yield: 1.9 g (97% of theory) of 7-(cis-3-amino-4-methoxy-1-pyrrolidinyl) -8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid trifluoro-15 acetate, melting point: 235-239°C (with decomposition).

Bvafflplp q COOH xHCl cis-3-tert.-Butoxycarbonylamino-4-methoxy-pyrrolidine is reacted with l-cyclopropyl-6,7-dif luoro-1,4-dihydro-4-20 oxo-3-quinolinecarboxylic acid analogously to Example 1 to give: .La. ft IS JAB - 13 5 - 2 'X ^ A v ^ * A. 7-(cis-3-tert. -Butoxycarbonylamino-4-methoxy~l-pyrrolidinyl) - l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 232-233°C (with decomposition).

B. 7-(c is-3-Amino-4-methoxy-l-pyrrolidinyl)- 1-cyclo- propyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecar bo xylic acid hydrochloride, melting point 252-256°C (with decomposition) (sintering beforehand). cis-3-tert. -Butoxycarbonylamino-4-methoxypyrrolidine is reacted with 7-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid analogously to Example 1 to give: A. 7-(cis-tert.-Butoxycarbonylamino-4-methoxy-l- pyrrolidinyl) -l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, melting point 214-216PC (with decomposition).

B. 7- (cis-3-Amino-4-methoxy-l-pyrrolidinyl) -1-cyclopro-20 pyl-6-fluoro-1,4-dihydro-4-oxo-l,8-naphthyridine-3- r~ * •|nq 9 T Q & u v' w' 4 carboxylic acid hydrochloride, melting point 205-210° (with decomposition).

Mass spectrum: m/e 362 (M*) , 330 (MT-32), 318 (M*-C02) , 286, 260, 41 (C3H5), 36 (HCl).

Example 7 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 are added to 1.33 g (5 mmol) of l-cyclopropyl-6,7-di-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 30 ml of acetonitrile and 5 ml of dimethyl-formamide and the mixture is heated under reflux for 1 hour. The suspension is concentrated, water is added to the residue and 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-l-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quino1inecarboxy1ic ac id, 0 COOH Melting point: 274-278°C (with decomposition). • & k-x-ampi «a fl fts 850 mg (3 mmol) of l-cyclopropyl-6, 7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under 5 reflux in 9 ml of pyridine with 630 mg (3.1 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride and 500 mg (4.5 mmol) of 1,4-diazabicyclo[2.2.2]octane for 1 hour. The mixture is concentrated, the residue is stirred with water and the precipitate is filtered off with 10 suction, washed with water, dried and recrystallized from glycol monomethyl ether.

Yield: 840 mg (72% of theory) of l-cyclopropyl-6,8-dif luoro-1,4-dihydro-7 - (2-oxa-5,8-diazabicyclo [4.3.0 ]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 289-291°C (with decomposition); Mass spectrum: m/e 391 (M*) , 347 (M*-C02), 331, 306, 294, 262, 234, 98, 41 (C3HSJ .

Tn ft ?fi mfl 2 3 9 4 8 5 Example 9 0 The reaction is carried out analogously to Example 8 with 5-methyl-2-oxa-5,8-diazabicyclo [4. 3.0]nonane dihydro-5 chloride to give: l-cyclopropyl-6,8-dif luoro-1,4-dihydro- 7 - (5-methyl-2-oxa-5,8-diazabicyclo [4 .3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: from 270°C (with decomposition); Mass spectrum: m/e 405 (M+) , 361 (M+-C02) , 331, 112, 10 (100%).

Example 10 0 795 mg (3 mmol) of l-cyclopropyl-6,7-dif luoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid are heated under 15 reflux 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 2, 3 9 4 8 5 860 mg (7.8 mmol) of 1,4-diazabicyclo[2.2.2]octane for 2 hours. The mixture is evaporated, the residue is stirred with water and the undissolved product is filtered off with suction, washed with water, dried and recrystallized 5 from dimethyl formamide .

Yield: 0.8 g (69% of theory) of l-cyclopropyl-6-fluoro-1,4 -dihydro-7 - (5-methyl-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 340°C (with decomposition) (on heating up, the substance 10 already becomes dark from about 300°) .

Mass spectrum: m/e (M+) , 343 (M+-C02) , 313, 244, 112 (100%).

Example 11 0 The reaction is carried out analogously to Example 10 with 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 8-chloro-l-cyclo-propyl-6-fluoro-1,4-dihydro-7-(5-methyl-2-oxa-5,8-diaza-bicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, 20 melting point 258-262°C (with decomposition) (recrystallized from dijnethylformamide).

La A 0 fi 2 3 9 4 P.vamplta 1? 0 The reaction is carried out analogously to Example 10 with l-ethyl-6,7,8-trif luoro-1,4-dihydro—4-oxo-3-quino-5 linecarboxylic acid to give l-ethyl-6,8-difluoro-1/4- dihydro-7- (5-methyl-2-oxa-5, 8-diazabicyclo [4.3.0 ]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 279-281°C (with decomposition).

Example 13 0.84 g (3 mmol) of l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 6 ml of acetonitrile and 3 ml of dimethyl formamide with 0.66 g (6 mmol) of 1,4-diazabi-15 cyclo[2 .2.2] octane and 0.49 g (3.5 mmol) of 2-methyl-2,8-diazabicyclo[4.3.0]nonane for 2 hours. The suspension is concentrated, the residue is stirred with 20 ml of water, t n n ts .Aaa 239485 the mixture is brought to pH 7 with 2N hydrochloric acid and the precipitate is filtered off with suction, washed with water, dried and recrystallized from glycol monomethyl ether.

Yield: 0.7 g (58% of theory) of l-cyclopropyl-6,8-di-f luoro-1,4-dihydro-7- (2-methyl-2,8-diazabicyclo [4.3.0]-non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 204-207°C.

Example 14 Analogously to Example 13, l-cyclopropyl-6-fluoro-1,4-dihydro-7 - (2-methyl-2,8-diazabicyclo[4.3 .0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 234-236°, is obtained with l-cyclopropyl-6,7-difluoro-1,4-dihydro-15 4-oxo-3-quinolinecarboxylic acid.

T 4 8 5 bvamplp o A. l-Cyclopropyl-6 / 7, 8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with 2,8-diazabi-5 cyclo[4.3.0]nonane analogously to Example 13 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, melting point 265-267° (with decomposition) (recrystallized from dimethylformamide).

B. If the reaction of Example 15 A) is carried out in a mixture of acetonitrile/l-methyl-2-pyrrolidinone and the crude product is recrystallized from dimethylformamide , l-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-l,4-dihydro-4-oxo-3-quinoline-15 carboxylic of melting point 269-271°C (with decomposition) is obtained. According to a comparison by chromatography and spectroscopy, the product is identical to the product prepared according to process A).

C. 65 g (167 mmol) of the betaine (stage A) are dis-20 solved in 330 ml of half-concentrated hydrochloric acid by heating, the solution is concentrated and the residue is stirred with 300 ml of ethanol. The undissolved &a ft 2i 9 precipitate is filtered off with suction, washed with ethanol and dried at 100°C in vacuo.

Yield: 66.3 g (9 3% of theory) of l-cyclopropyl-7-(2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 303-305°C (with decomposition).

COOH Analogously to Example 13, l-cyclopropyl-7-(2,7-diazabi-10 cyclo[3.3.0]oct-7-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 260-282° (with decomposition), is obtained with l-cyclopropyl-6,7-di-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2,7-diazabicyclo[3.3.0]octane.

Mass spectrum: m/e 357 (M+) , 313 (100%, M*-C02) , 269, 257, 244, 82, 28. '-w/ 2 3 9 4 8 5 Example 17 0 Analogously to Example 13, l-cyclopropyl-6-fluoro-l,4-dihydro-7-(2-methyl-2,7-diazabicyclo [3.3.0 ]oct-7-yl) -4-5 oxo-3-quinolinecarboxylic acid, melting point: 206-208°C (with decomposition), is obtained with l-cyclopropyl-6,7-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2-methyl-2,7-diazabicyclo [3.3.0] octane.

Example 18 0 Analogously to Example 13, l-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (2-methyl-2,7-diazabicyclo[ 3 .3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 198-200°C (with decomposition), is obtained with 2-methyl-2,7-15 diazabicyclo[3.3.0]octane. fce ft 36 10ft - 14b - f L O byampl <=> 1 q 0 A mixture of 2.83 g (10 mmol) of l-cyclopropyl-6,7,8-tri fluoro-1,4 -dihydr o - 4 -oxo - 3-quino 1 inec arboxy 1 ic ac id, 5 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.4 g (11 mmol) of 2-methyl-3-oxa-2,7-diazabicyclo[3.3.-0]octane in 20 ml of acetonitrile and 10 ml of 1-methyl-2-pyrrolidinone is heated under reflux for 1 hour. It is concentrated in vacuo, the residue i3 stirred with water 10 (pH 7) and the precipitate is filtered off with suction, washed with water and dried at 60° in vacuo. The crude product (3.7 g) is recrystallized from dimethyl formamide.

Yield: 1.9 g (49% of theory) of l-cyclopropyl-6,8-di-f luoro-1,4-dihydro-7- ( 2-methyl-3-oxa-2,7-diazabicyclo-15 [3.3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 221-223°C (with decomposition). fca ft I h G /■ H r kJ U ■ 0 The reaction is carried out analogously to Example 19 with 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to 5 give l-cyclopropyl-6,8-dif luoro-1,4-dihydro-7-( 2,5- dimethyl-3-oxa-2 , 7-diazabicyclo[3 . 3 . OJoct^-ylJ-^-oxo-S-quinolinecarboxylic acid of melting point 237-238°C (with decomposition).

Example 21 0 The reaction is carried out analogously to Example 19 with 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to give l-cyclopropyl-6 , 8-dif luoro-1,4-dihydro-7-( 2,8-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0 ]oct-7-yl) -4-oxo-3-15 quinolinecarboxylic acid of melting point 197-199°C.

La Ik 108. p-rattrpi <=> 0 A. 3 g (10 mmol) of 8-chloro-l-cyclopropyl-6,7-di-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 30 ml of acetonitrile and 15 ml of l-methyl-2-pyrrolidinone with 1.4 g (11 nnnol) of 2,8-diazabicyclo[4.3.0]nonane and 1.65 g (15 mmol) of 1,4-diazabicyclo [2 .2 .2]octane for 1 hour. After cooling, the suspension is stirred with about 150 ml of 10 water and the undissolved precipitate is filtered off with suction, washed with water and ethanol and dried at 80°C/12m bar. The crude product is recrystallized from 40 ml of glycol monomethyl ether.

Yield: 2.3 g (57% of theory) of 8-chloro-l-cyclopropyl-15 7- (2,8-diazabicyclo [4.3.0 ]non-8-yl) -6-f luoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid, melting point: 224-226°C (with decomposition).

B. The crude betaine is prepared analogously to Example 22 A. and is suspended in 50 ml of water and dissolved by addition of 17 ml of IN hydrochloric acid and heating.

After cooling in an ice-bath, the precipitate which has separated out is filtered off with suction, washed with ethanol and dried at 100aC in vacuo.

Tn n *7fi 2 3 9 4 8 5 Yield: 2.7 g (61% of theory) of 8-chloro-l-cyclopropyl-7 - (2,8-diazabicyc lo [ 4 .3 .0 ] non-8-yl) -6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: from 225°C decomposition. bvamplp 3 3 The reaction is carried out analogously to Example 22 with 9 ,10-dif luoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[ 1,2,3-de] [ 1,4]benzoxazine-6-carboxylic acid and the reaction product obtained is purified by chromatography on silica gel using methylene chloride/methanol/17% strength aqueous ammonia solution (30:8:1) as the mobile phase. 10-(2,8-Diazabicyclo[4.3.0]non-8-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo~7H-pyrido[ 1,2,3-de] [ l,4]benzoxa-zine-6-carboxylic acid of melting point 291-292°C (with decomposition) is obtained. 0 'COOH 3 n v x o 4 L U b -•* 3 Example 24 6 g (20 mmol) of l-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under 5 reflux in 30 ml of 1-methyl-2-pyrrolidinone and-60 ml of acetonitrile with 2.2 g (20 mmol) of l,4-dia2abicyclo-[2.2.2]octane and 2.7 g (21.4 mmol) of 2,8-diazabicyclo-[4.3.0]nonane for 1 hour. The mixture is concentrated to a substantial degree in vacuo, the residue is stirred 10 with 200 ml of water and the undissolved crystals are filtered off with suction, washed with water and dried. Yield: 6.3 g (77.4% of theory) of l-cyclopropyl-7-(2,8-diazabicyclo [4.3.0 ]non-8-yl ] -5,6,8-trif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 15 Melting point: 266-269°C (with decomposition); after recrystallization from dimethylformamide: melting point: 27 2-273°C (with decomposition).

Lo ft 36 -AOS n {L- o (\ a •ry ample *7 5 OOH ml of saturated ethanolic ammonia solution are added to 4.1 g (10 mmol) of the product from Example 24 in 40 5 ml of pyridine, and the mixture is heated at 120°C in an autoclave for 12 hours. The suspension is evaporated, the residue is stirred with water and the pH. is brought to 7 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction and recrys-10 tallized from glycol monomethyl ether.

Yield: 0.7 g (17% of theory) of 5-amino-l-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 275-277°C (with decomposition) .

Mass spectrum: m/e 404 (M*) , 384 (M^-HF), 290, 249, 96 (100%). •r> 23Q485 rvample 26 0 A. Analogously to Example 13, l-cyclopropyl-7-(2,7-diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid, melting point: 277-280° (with decomposition), is obtained with 2,7-diazabicyclo-[3.3.0]octane.

B. 370 mg of the betaine are dissolved in 13 ml of half-concentrated hydrochloric acid, the solution is concentrated and the residue is treated with 10 ml of ethanol. The undissolved product is filtered off with suction, washed with ethanol and dried.

Yield: 290 mg of l-cyclopropyl-7-(2,7-diazabicyclo-[3.3,0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino-15 linecarboxylic acid hydrochloride, melting point: 269- 271°C (with decomposition).

La i\ IS 118ft The reaction is carried out analogously to Example 8 with trans-4-methoxy-3-methylamino-pyrrolidine dihydro-5 chloride. l-Cyclopropyl-6, 8-dif luoro-l,4-dihydro-7-(trans-4-methoxy-3-methylamino-l-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid, melting point: 268-270°C (with decomposition) is obtained.

Example 28 COOC2H5 xCF 3COQH A. 1.4 g (2.9 mmol) of the product from Example 3 A) and 1.98 ml (1.7 g, 12 mmol) of dimethylformamide diethyl acetal are heated at 120°C in 15 ml of absolute dimethylformamide for 2 hours. The mixture is then 15 concentrated in vacuo. The residue which remains is stirred with acetonitrile. The precipitate is filtered IaC ■^| -36—44^4^ ( off with suction, washed with a little acetonitrile and dried.

Yield: 0.8 g (54.4% of theory) of ethyl 7-(cis-3-tert.-butoxycarbonylamino-4-methoxy-l-pyrrolidinyl) -1-cyclo-propyl-6 , 8-dif luoro-1, 4-dihydro-4-oxo-3-quinoline-carboxylate, melting point: 151-152°C.

B. 0.3 g (0.6 mmol) of the product from Example 28 A) are stirred in 10 ml of trif luoroacetic 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% of theory) of ethyl 7-(cis-3-amino-4-methoxy-l-pyrrolidinyl) -l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate trifluoroacetate Melting point: 124-126°C.

Example 29 Analogously to Example 13, l-cyclopropyl-6,8-dif luoro-1,4-dihydro-7-(2-methyl-4-oxa-2,8-diazabicyclo [ 4.3.0 ]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 0 'C00H 238485 258-260°C (with decomposition) , is obtained with 2-methyl-4-oxo-2,8-diazabicyclo [4.3.0] nonane.

Example 30 0 Analogously to Example 19, l-cyclopropyl-6,8-difluoro- 1,4-dihydro-7-(3-oxa-2,7-diazabicyclo[3.3.0]octan-7-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 3-oxa-2,7-diazabicyclo[3.3.0]octane.

Example 31 0 A. 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.4 g (11 mmol) of 2,8-diazabicyclo [4.3.0] nonane are added to 2.53 g (10 mmol) of l-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of 15 acetonitrile and 15 mi of dimethylformamide and the mixture is heated under reflux for 1 hour. The mixture is lie ft' 155 - 2 3 9 4 8 5 concentrated, the residue is stirred with water and the precipitate is filtered off with suction, washed with water and dried.

Yield: 3.1 g (86% of theory) of 7-(2,8-diazabicyclo-5 [4.3.0]non-8-yl)-l-ethyl-6-fluoro-4-oxo-3-quinoline-carboxylic acid, melting point: 259-2 61°C (with decomposition) .

B. 2.9 g (8 mmol) of the betaine from stage A are dissolved in 20 ml of half-concentrated hydrochloric acid under the influence of heat, the solution is filtered hot and the hydrochloride is precipitated from the filtrate by addition of ethanol. This hydrochloride is filtered off with suction, washed with ethanol and dried at 120°C/ 12 mbar.

Yield: 1.8 g (57% of theory) of 7-(2 , 8-diazabicyclo-[4.3.0]non-8-yl)-l-ethyl-6-fluoro-4-oxo-3-quinoline-carboxylic acid hydrochloride, melting point, with decomposition: 299°C (dark coloration already starting from about 215°C).

Example 32 0 Reaction analogously to Example 31 with 1-cyclopropyl- iib ft 36 -1Q& 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid gives: A. l-Cyclopropyl-7- ( 2 , 8-diazabicyclo[ 4 . 3 . 0]non-8-yl) -6-fluoro-4-oxo-3-quinolinecarboxylic acid, melting point: 249-257°C (with, decomposition) B. l-Cyclopropyl-7- (2,8 -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point with decomposition: 320°C (dark coloration already starting from about 288°C) .

Example 33 0 1.1 g (3 mmol) of l-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0 ]non-8-yl) -6 , 8-difluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid are heated under reflux in 10 ml of dimethyl formamide and 1 ml of formic acid for 4 hours. The mixture is evaporated, the residue is stirred with 4 ml of water and the precipitate is filtered off with suction, dried (crude yield: 1 g, content: 99.5%) and recrystallized from dimethyl formamide.

Yield: 0.8 g (64% of theory) of l-cyclopropyl-6,8-di-fluoro-7-( 2-formyl-2,8-diazabicyclo[4.3.0]non-8-yl)-1,4- iic a aG *ae - 15 7 - # /-*• t-* O 7. f» /• ;•-< ^ if j "--j ^ •- dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 276-278°C.

Example 34 0 1.1 g (3 mmol) of l-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0 ]non-8-yl) - 6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of 8 ml of dioxane and a solution of 120 mg of sodium hydroxide in 1 ml of water, and at the same time 3 ml of IN sodium 10 hydroxide solution and 260 mg of acetyl chloride are added, while cooling with ice. The mixture is subsequently stirred at room temperature for 2 hour3 and diluted with 30 ml of water and the precipitate which has separated out is filtered off with suction. The crude 15 product is recrystallized from glycol monomethyl ether.

Yield: 0.6 g (46% of theory) of 7-(2-acetyl-2,8-diazabicyclo [4 . 3 .0 ]non-8-yl) -l-cyclopropyl-6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 261-263°C (with decomposition) fro A SC 10ft I 3 0h?c •ffvam-pl o 7 5 0 A. Analogously to Example 13, 8-chloro-l-cyclopropyl-6-f luoro-1,4-di hydro-7- (2-methyl-2,7-diazabicyclo [3.3.0]-5 oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 222-227°C (with decomposition), is obtained with 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2-methyl-2,7-diazabicyclo-[3.3.0]octane.

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

Yield: 2.2 g (87.7% of theory) of 8-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-7-( 2-methyl-2,7-diazabicyclo [3.3.0]-oct-7-yl)-4-oxo-3-guinolinecarboxylic acid hydrochloride, melting point: 303-305°C (with decomposition). * og iftQ - 159 - 2 3 9 A 8 5 By amp 1 «a 0 'COOH xhc 1 Analogously to Example 13, 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 is obtained with 3-methyl-2,7-diazabicyclo[3.3.0]octane, and is converted into l-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-quinolinecar-boxylic acid hydrochloride, melting point: 216-221°C (with decomposition), analogously to Example 15 C. with half-concentrated hydrochloric acid.

Example 37 A. A mixture of 1.45 g (5 mmol) of l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.85 g (7.5 mmol) of 1,4-diazabicyclo[2.2.2]octane and 0.77 g (5.5 mmol) of 2,3-dimethyl-2,7-diazabicyclo- o COOH 2 3 9 4 [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, washed with water and recrystallized from glycol 5 monomethyl ether.

Yield: 1 g (47% of theory) of l-cyclopropyl-7-(2,3-dimethyl-2, 7-diazabicyclo[2 .2 . 2]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 208-209°C (with decomposition).

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

Yield: 0.64 g (84% of theory) of l-cyclopropyl-7-(2,3-dimethyl-2,7 -diazabicyclo [2.2.2] oct-7-yl) -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro-20 chloride, melting point: 233-236°C (with decomposition). rs 2 3 9 4^ ry^mplia tp Analogously to Example 37 A. and B., 8-chloro-l-cyclo-propyl-7 - (2,3-dimethyl- 2,7 -diazabicyclo [2.2.2] oc t-7 -yl) -5 6-fluoro-l,4-dihydro-4-oxo-3~quinolinecarboxylic acid hydrochloride, melting point: 240-241°C (with decomposition), is obtained with 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Example 39 0 The reaction is carried out analogously to Example 19 with l,2-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to give l-cyclopropyl-6,8-difluoro-l,4-dihydro-7-( 1,2-dimethyl-3-oxa-2,7-diazabicyclo [3.3.0 ]oct-7-yl) -4-oxo-3-15 quinolinecarboxylic acid of melting point 269-271°C (with decomposition). t?-sr*tnp1 o an 0 0 / COOH xHCl H 1.45 g (13 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.23 g (9.6 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane are added to 2.6 g (8.7 mmol) of 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 25 ml of acetonitrile and 12.5 ml of dimethyl formamide and the mixture is heated under reflux for 1 hour. It is concentrated, the residue is stirred with water and the undissolved precipitate is filtered off with suction and washed with water. This crude 1-cyclopropyl-8-chloro-6-f luoro-1,4-dihydro-7-( 2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid is introduced into 85 ml of IN hydrochloric acid, and 6 ml of concentrated hydrochloric acid are added. The hydrochloride which has precipitated out is filtered off with suction, washed with ethanol and dried.

Yield: 3.0 g (77.7% of theory) of 8-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-7- (2-oxa-5,8-diazabicyclo [4.3.0 ]non-8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: from 29Q°C decomposition.

I 239485 rvampla at O 'COOH Analogously to Example 13, 8-chloro-l-cyclopropyl-6-f luoro-7 - (2-methyl-4-oxa-2,8-diazabicyclo [4.3.0] non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 202-203°C (with decomposition), is obtained with 8-chloro-l-cyclopropyl-6,7-dif luoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 2-methyl-4-oxa-2,8-diazabicyclo-[4.3.0]nonane.

FAB mass spectrum: m/e 422 ([M+H] + ), 404 (422-HzO) . Example 42 A. The reaction is carried out analogously to Example 13 with ethyl 2,7-diazabicyclo [3.3.0 ]octane-2-carboxylate to give l-cyclopropyl-7-(2-ethoxycarbonyl-2,7-diazabi-cyclo[3 . 3 .0]oct-7-yl) -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 191-192°C.

La ft 3C -iM - 164 - 0 cooh vco2c2hs i 2 3 9 4 8 5 B. 1.8 g (4 mmol) of the product from Example 42A are heated in 30 ml of concentrated hydrochloric acid under gentle reflux for 15 hours. The solution is concentrated, the residue is stirred with ethanol and the precipitate 5 is filtered off with suction, washed with ethanol and dried at 120°C/12 mbar.

Yield: 1.1 g (67% of theory) of l-cyclopropyl-7-(2,7-diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting 10 point: 273-275°C (with decomposition). The product is identical to the compound obtained according to'Example 26B.

Example 43 A. 7.8 g (20 mmol) of l-cyclopropyl-7-(2,8-diazabi-15 cyclo [4.3.0] non-8-yl) -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are introduced into 175 ml of ethanol, and 2.4 g (25 mmol) of methanesulphonic acid are added at about 70°C. The betaine dissolves, and on cooling the salt precipitates out, this being filtered off 20 with suction, washed with ethanol and dried at 120°C/12 mbar. It is readily soluble in water.

Yield: 8.6 g (88.6% of theory) of l-cyclopropyl-7-( 2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid mesylate, melting point: 25 262-265°C (with decomposition).

The following compounds are obtained analogously: lie A DC iOO 0 •- r >' h h C. v ■ B. l-Cyclopropyl-7-(2,8-diazabicyclo [4.3.0]non-8-yl) -6,8-dLif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid tosylate, melting point: 248-250°C (with decomposition).

C. l-Cyclopropyl-7 - (2,8-diazabicyclo[4.3.0]non-8-yl)-5 6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid lactate, melting point: 205°C-215°C, after sintering beforehand.

Example 44 3.9 g (10 mmol) of l-cyclopropyl-7-(2,8-diazabicyclo-10 [4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino- linecarboxylic acid are suspended in 50 ml of water, and 10 ml of IN sodium hydroxide solution are added at room temperature, whereupon the product largely dissolves. A slight turbidity is removed by filtration through a 15 membrane filter, the filtrate is concentrated under a high vacuum and the residue is stirred with ether, filtered off with suction and dried.

Yield: 3.4 g (82.7% of theory) of sodium 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-di-20 hydro-4-oxo-3-quinolinecarboxylate; the salt decomposes slowly above 210°C without melting.

Li A B0 - 15 5 - 2 3 9 4 8 5 f-yampi o a 5 0 A mixture of 3.9 g (10 mmol) of l-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-5 oxo-3-quinolinecarboxylic acid in 100 ml of dijnethylformamide is heated at 80-100°C with 4.2 g of triethyl-amine and 2.8 g of 2-bromoethanol for 20 hours. The solution is then concentrated in vacuo and the residue obtained is purified by chromatography on 200 g of silica 10 gel (mobile phase: CH2C12/CH30H/17% strength NH3 = 30:8:1).

The eluate is concentrated and the residue is stirred with ethanol, filtered off with suction and dried.

Yield: 1.8 g (41.6% of theory) of l-cyclopropyl-6,8-dif luoro-1,4-dihydro-7- [ 2- (2-hydroxyethyl) -2,8-diazabi-15 cyclo[4.3.0]non-8-yl]-4-oxo-3-quinolinecarboxylic acid, melting point: 200-206°C (with decomposition).

Mass spectrum: m/e 433 (M+), 402 (M+ -CH20H), 140, 110 (100%), 96 fca ft 2i AM- 394c.

Example 46 COOH The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine to give l-cyclopropyl-7- (trans-3~ethylamino-4-methylthio) -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 215-216°C (with decomposition) .

Example 47 0 The reaction is carried out analogously to Example 13 with 2-phenyl-2,7-diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-dif luoro-1,4-dihydro-4-oxo-7-( 2-phenyl-2,7-diazabicyclo [3.3. 0 ]oct-7-yl) -3-quinolinecarboxylic acid, melting point: 259-260°C (with decomposition) . rv 4 8 5 Example 48 F 0 CH- Analogously to Example 13, 5,6,8-trifluoro-1-(2,4-di-f luorophenyl) -1,4-dihydro-7- (2-methyl-2,8-diazabicyclo-[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5,6,7,8-tetraf luoro-1- (2,4-dif luorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Example 4 9 f 0 Analogously to Example 24, 7-(2,8-diazabicyclo [4.3.0]non-8-yl) -5,6,8-trif luoro-1-( 2,4-dif luorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained with 5,6,7,8-tetraf luoro-1-(2,4-dif luorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 2 3 9 4 8 5 byarnpl <a 5n Analogously to Example 25, 5-amino-7-(2,8-diazabicyclo-[4.3.0] non-8-yl) - 6,8-dif luoro-1- (2,4-dif luorophenyl) -1,4-5 dihydro-4-oxo-3-quinolinecarboxylic acid is obtained with 7-(2,8-diazabicyclo[4.3.0]non-8-yl)-5,6,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acid. example 51 Analogously to Example 15 A, 5-chloro-l-cyclopropyl-7-(2,8-diazabicyclo[4.3 .0]non-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 270°C (decomposition), is obtained with 5,7-dichloro-l-cyclo-15 propyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours).

T" * *>c inQ Z 3 9 4 P 5 ( bv amp | a fr? ci 0 cooh Analogously to Example 8, 5-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-7 - (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7-dichloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylie acid (reflux for 5 hours).

Example 53 Analogously to Example 15 A, 5-chloro-7-(2,8-diazabi-cyclo[4.3.0]non-8-yl)-6-fluoro-1-(2,4-difluorophenyl)-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 15 hours).

Sip#* ( 239 4 85 Example 54 ci 0 Analogously to Example 8, 5-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo-5 [4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7-dichloro-6-fluoro-l-(2,4-difluoro-phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours).

Example 55 0 The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine and 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 8-chloro-l-cyclopropyl-15 7-(trans-3-ethylamino-4-methylthio-l-pyrrolidinyl) -6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 217-218°C (with decomposition). la jl 36 afls 9TQ & *i.g> Example 5 6 H,n cooh x HCl ch3s 7- (trans-3-Ajnino-4-methylthio-l-pyrrolidinyl)-l-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic, melting point: 208-211*C (with decomposition) arid 7-(trans-3-amino-4-methylthio-l-pyrrolidinyl)-l-cyclopropyl-6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 255-257'C (with decomposition), are obtained with trans-3-amino-4-methylthio-pyrrolidine analogously to Examples 13 and 15.

Example 57 cooh x HCl l-Cyclopropyl-6,8-difluoro-l,4-dihydro-7-(4-methyl-2,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 213-215*C (with decomposition) (recrystallised from glycol monomethyl ether), and l-cyclopropyl-6, 8-difluoro-l,4-dihydro-7-(4-methyl-2,8-diazabicyclo [4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 204-212"C (with decomposi- Le A 0 6 lOt) ? x a >■ c» k, w c7 • - j/ tion) are obtained with 4-methyl-2r8-diazabicyclo^3.3.0/- nonane analogously to Examples 13 and 15.

The product consists of a mixture of 2 stereoisomers. la a og 10 0i /

Claims (2)

WHAT WE CLAIM IS:

1. A compound selected from the group consisting of 2-oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydrochloride , trans-2-oxa-5,8-diazabicyclo/$.3.0/nonane, 5-methyl-2-oxa-5,8-diazabicyclo/5.3,07nonane dihydrochloride, 2, 7 -diazabicyclo [3.3.0] octane, 2-methyl-2,7-diazabicyclo[3.3.0]octane, 3-oxa-2,7-diazabicyclo[3.3.Olocrane, 2-methyl-3-oxa-2 , 7-diazabicyclo [3.3.0 ]octane, 2,5-diinethyl-3-oxa-2 ,7-diazabicyclo [3 .3. Q ]octane, 2, 8-diaiethyl-3-oxa-2 ,7-diazabicyclo [3.3. 0 ]octane, 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane, 3-methyl-2,7-diazabicyclo[3.3.0]octane, 2,3-dimethyl-2,7-diazabicyclo[3 - 3.0]octane, erhyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylata, 2-phenyl-2,7-diazabicyclo[3.3.0]ocrane, 4-oxa-2,8-diazabicyclo[4.3.0]nonane, trans-3—ethylamino-4-methylthio-pyrrolidine and trans-3-methylamino-4-methylthio-pyrroIidine.

2. A compound according to claim 1 substantially as herein described or exemplified. BAYER AKTIENGESELLSCHAFT