IE19970856A1

IE19970856A1 - 7-(1-Pyrrolidinyl)-3-quinolone and naphthyridone carboxylic acid derivatives, method for their preparation and for substituted mono- and bicyclic pyrrolidine intermediates, and their antibacterial and feed additive compositions

Info

Publication number: IE19970856A1
Application number: IE1997/0856A
Authority: IE
Inventors: Petersen Uwe; Schenke Thomas; Krebs Andreas; Grohe Klaus; Schriewer Michael; Haller Ingo; Georg Metzger Karl; Endermann Rainer; Zeiler Hans-Joachim
Original assignee: Bayer Healthcare Ag
Filing date: 1989-07-14
Publication date: 2000-02-23

Abstract

ABSTRACT 7-(1-Pyrrolidinyl)-3-quinolone- and —naphthyridone- carboxylic acid derivatives, processes for their preparation and substituted (oxa)diazabicyclooctanes and -nonanes as intermediate products for their preparation, and antibacterial agents and feed additives containing them. This invention relates to 7—(l-pyrrolidinyl)-3- quinolone- and -naphthyridone—carboxylic acid derivatives of the formula I T2 ° x1\V/;-‘\"/I \/coon? (I) I I I 33/*§A;L\N in which X1, X2, R1, R2, R3 and A have the meanings given in the description, processes for their preparation and substituted (oxa)diazabicyclooctanes and ~nonanes as intermediate products for their preparation, and antibacterial agents and feed additives containing them. PATENTS ACT, 1992 7—(1—PYRROLIDINYL)-3-QUINOLONE— AND -N§§hTHYRIDONEcARBOxILIc ACID DERIVATIVES, PROCESSES FOR THEI§9PREPARATION AND SUBSTITUTED (OXA)DIAZABICYCLO0CTANES AND -NON%§§S As INTERMEDIATE PRODUCTS FOR THEIR PREPARATION, AND ANTIBAcTg§IAL AGENTS AND FEED ADDITIvEs cON3$ENING THEM I;-—-:_‘~:,,e~ -;~—-.».E. _. -. OP'.'.."I, ' ' " _ 'H’)N Sr_"“Y‘ ~_ yryl ‘_:.“-r,: '45-.’ 2‘ JNL .'~§O......:.\.'.§1......OF.....g..i'f3..{....;._‘3" . Im ct g ‘r '., ., I‘ (L: BAYER AKTIENGESELLSCHAF M114“ 3: /W7. ")1 /SZL’ 3D5$lﬂ23kQﬂ? ‘Q C/ A‘ /-(-.'S//—( IE 970856 The invention relates to new 7-(1-pyrro1idiny1)—3-quino- lone- and -naphthyridonecarboxylic acid derivatives, processes for their preparation and antibacterial agents and feed additives containing them. 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 and 153,826. It has been found that the 7-(1—pyrro1idinyl)-3—quino- lone- and naphthyridonecarboxylic acid derivatives of the formula (I) I2 3 xi _, x./coosz I if | R3 ~;y.~,, in which X‘ 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 10 R’ IE 970856 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, methylamino, ethylamino, dimethy1- 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-1,3-dioxol-4-y1)—methy1, represents a radical of the structure R‘ Z-R4 3- R x~+- H-—-z r+—,—~,;».~ . N\ ’ 5 ’ - N D ' N /Y R~\1‘ , l coon? (VI) R3‘/l§A N in which X’, X2, R3, R2 and A have the abovementioned meaning and 10 R“ represents a radical having the structure R‘ z-R4 54“ B‘ -N /w~ r ,4v \ 3 " ,- ‘-r-- ' or ’ T’. I Y P” N‘ *1 IV I 9” [ _ 11 - IE 970856 wherein R5’ R5’ R1’ Ru’ Ru!’ meaning, Y and 2 have the abovementioned is reacted with compounds of the formula (VII) R‘-x‘ (VII) in which R‘ has the abovementioned meaning and X‘ represents chlorine, bromine, iodine, hydroxyl or acyloxy, if appropriate in the presence of acid entrainers (method If, for A example, 1-cyclopropyl-6,7,8-trifluoro—1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methy1- octahydropyrrolo[3,4-b]pyridine are used as starting substances, the course of the reaction can be represented by the following equation: -12- IE 970856 F-‘\.V,_/, \ / ~.‘,r L .,:o,{ \/’ \ E 2 9 2- | !] | a [ I H H -—‘ — I r ‘»u/ 3 *», - If, for example, 7-ch1oro-6-f1uoro-1-(4-fluorophenyl)- 1,4-dihydro-4-oxo-1,B—naphthyrid1ne-3-carboxylicacidand cia-3—tert.—butoxycarbonylamino-4—methoxy-pyrrolidine are used as starting substances, the course of the reaction can be represented by the following equation: - 13 _ IE 970856 (CH3)3C-O-CO-NH cnao COOH ‘-“\ Base I + NH ———————~ c1 N ,———/ -HC1 CH3O (CH3)3C-O-CO-NH <9 0 9 coon 3: RC1 -14- IE 970856 If, for example, 1-cyclopropyl-5,6,8-trif1uoro-1,4- dihydro-7-(2-methyl—2,7-diazbicyclo[3.3.o]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, 1—cyc1opropy1-7-(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: -15- IE 970856 p\vé?\\/J\\/’COOH HC1 | if - C2}-l5OH —?' ,.x‘\ 2: 1 x HC1 The compounds of the formula (II) used as starting substances are known or can be prepared by known methods. Examples which may be mentioned are: 7-ch1oro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (German Patent Application 3,142,854), 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3~quino1ine- carboxylic acid (European Patent Application 113,091), 6-chloro-1-cyclopropyl-7,8-df1uoro—1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (German Patent Application 3,420,743), - 15 _ IE 970856 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro—4—oxo-3- quinolinecarboxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7,8-trifluoro-1,4—dihydro-4-oxo-3-quino- linecarboxylic acid (German Patent Application 3,318,145), 6,B-dichloro-1—cyclopropy1-7-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7—dif1uoro-1,4-dihydro-8-methy1-4-oxo-3- quinolinecarboxylic acid, 1-cyclopropyl-7—ch1oro-6-fluoro-1,4-dihydro-8-nitro-4- oxo-3-quinolinecarboxylic acid, 6,7—dif1uoro-1—ethyl—1,4-diyydro-4-oxo-3~quino1ine- carboxylic acid,’ 7—chlorc—6-fluoro-1-ethyl-1,4-dihydro-4—oxo-3—quino1ine- carboxylic acid, 7—ch1oro-6-fluoro—1,4-dihydro—1-(2-hydroxyethyl)-4-oxo- 3—quinolinecarboxy1ic acid, 6,7-difluoro-1-(2—f1uoroethyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, -17- IE 970856 8-chioro-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Patent Application 235,762), (European 7-chloro-6-fluoro-1,4-dihydro—1-methoxy-4-oxo-3-quino- linecarboxylic acid, 7-chloro-6-fluoro-1,4-dihydro-1-methy1amino-4-oxo-3- quinolinecarboxylic acid, 6,7-difluoro-1,4-dihydro-4-oxo—1-pheny1-3—quino1ine- carboxylic acid, 7-chloro-1-cyc1opropy1-6-f1uoro-1,4-dihydro-4-oxo—1,8- naphthyridine—3-carboxylic acid, 6,7-dich1oro-1-cyc1opropy1-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid, ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4—dihydro-4-oxo—3- quinolinecarboxylate Patent 3,319,145), (German Application 9,10-dif1uoro—2,3-dihydro-3-methyl~7—oxo-7H-pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid (European Patent Application 47,005), 8,9-diflnoro-6,7-dihydro-5-methy1-1—oxo-1H,SH-benzo[i,j}- quinolizine-2-carboxylic acid, -13- IE 970856 7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naph- thyridine-3-carboxylic acid (European Patent Application 153,580), 7-chloro-6-fluoro-1—(4-fluorophenyl)-1,4-dihydro-4—oxo— 1,B-naphthyridine-3-carboxylic acid (European Patent Application 153,580), 6,7,8-trifluoro-1,4-dihydro-1—methylamino-4-oxo—3-quino- linecarboxylic acid (German Patent 3,409,922), Application 1-amino-6,7,8—triflnoro-1,4-dihydro-4-oxo-3-quino1ine— carboxylic acid (German Patent Application 3,409,922), 6,7,8—trif1uoro-1,4-dihydro-1—dimethy1amino—4-oxo—3- quinolinecarboxylic acid (German Patent Application 3,409,922), 7-chloro-6-fluoro-1,4-dihydro-8-nitro-4—oxo—1-pheny1-3- quinolinecarboxylic acid, 7-chloro-6-fluoro~l-(4-fluorophenyl)-1,4-dihydro-8-nitro- 4-oxo-3-quinolinecarboxylic acid, 6,7-difluoro-1-(4-fluorophenyl)-l,4—dihydro~B-methyl-4- oxo-3-quinolinecarboxylic acid, 6—chloro-7-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid (European Patent Application - 19 - 131,839), 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-d1hydro- 4-oxo-3-quinolinecarboxylic acid, S,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid, 5,7—dich1oro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, 6-chloro-7-£luoro-1-(2,4-difluorophenyl)-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid (European Patent Applica- tion 131,839), 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (European Patent Application 154,780), 6,7,B-trifluoro-1-(2,4-difluorophenyl)-1,4—dihydro-4-oxo- 3-quinolinecarboxylic acid (European Patent Application 154,790), 6,7,8-trifluoro—1,4-dihydro-4-oxo-1-phenyl-3-quinoline- carboxylic acid (European Patent Application 154,780), 7-ch1oro-1—ethy1-6-fluoro-1,4-dihydro-4-oxo-1,B—naph— thyridine-3-carboxylic acid, 6,7-difluoro-1,4-dihydro-4-oxe-1-vinyl-3-qnino1ine- - 20 - IE 970856 carboxylic acid, 1-cyclopropl-5,6,7,3-tetrafluoro-1,4-dihydro-4-oxo-3- quinoinecarboxylic acid, 5-amino-1-cyclopropy1~6,7,8-trifluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-hydroxy-4- oxo-3-quinolinecarboxylic acid, and 1-cyclopropyl-6,7—dif1uoro-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) (German Offenlegungsschrift (German Published Specification) 1,929,237 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 (IIIa)-(IIIe) are prepared. -21- K E] . ,., .l"’ ‘x‘:L .____‘_/ R“ = x3 — C Ht; /R5 , . ‘\\R6 removal cf protective groups nrotcctiuu qrounr IE 970856 removal of HO,’ /R5 ‘ I \\R5 (IIIa) "- N \\R5 (IIIb) benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or sulphonyl (examples of protec- tive groups), a leaving group, arylsulphonyloxy - 22 _ such as halogen, or alkyl- or __ H0». 3 N R4x3 (1) T-0 N T--0 I Base IE 970856 ”Ir:; 3 N ———-. R40”mI:ﬁ;T(NH2 R4O“T:—:](NH-COOC(CH3)3 N —————~ N IE 970856 4 §I:_:]4NH-R5 R‘oL.__:]4N//Rs P40>T:f-I4“//R N_ N H2IPd T/ ' L‘ , w L\nf\\ H I L J .. ;~\ \\, \.IIP.) H2/F1! R‘0\I:f:](NH-R6 | (X1Id) 2. Starting compounds of the formula (IIIf) are obtained from 2-(1,2-dichloroethyl)-oxirane via the following reaction sequence: __'| . \\ ,, \ . IE 970856 / -RS R40 N P40 N .- \. \nt: [___ _]/ \R6 __\N’_,I '2 \“N'_, I, . ' -.,g m‘ H I . ‘J *1. ( I II I J 3. By addition of azidea onto N—henzylmaleimidea which are optionally substituted by one or two methyl or phenyl radicals, starting compounds of the formula 5 (III g) can be prepared: N¢N\N-R9 M W O a4om,.,,,o_ Jrlﬁ-R9 R“o#m, H-R10 I reduction 'fx‘H I - e——» - N i’ ‘an ‘ - 25 - YE L‘© R‘0ﬁ~Er:JtNH-R10 (IIIg) R” = H, alkyl or benzyl. 4. From the 3,4-epoxypyrrolidines (1), the starting compounds of the formula (III h) are obtained via 5 cyclization with thionyl chloride: H0”T:_:]4NH2 H0~«[___,4uH.c0-9" f 1 J ""'—'—’ T ‘ ‘\N/J SOC ‘- 3 - . :2 :77 (111 h) 5. By reaction of the 3,4-epoxypyrrolidines (1) with ethanolamines, the starting compounds of the formula (III 1) are-obtained by intramolecular etherifica- 10 tiona _ 25 _ IE 970856 I//A\v/OH //A\v/NH-R6 HO N HO r ——- H9 (1) [ } ____ r--\ »\ N-R6 0 N_Re \L‘u‘ {III i). The starting compounds of the formula (III j) are obtained from aminoacetaldehyde dimethyl acetal via intramolecular 1,3-dipolar cycloaddition. CH3 OCH3 I 3 HZN OCH3 ~—--* R9-NH,/“xaciocna H2c;“\v/X Base ’\ OCH3 6_ _ 9 ., .ocH3 Ho 9 ,/*\cHo R NH on R -N /CH2 --*-* R -N /CH2 \_.._< _ ¥:°‘ 5°60 o"‘Q. i Q ' ' ' 0 Q2‘ 2 2 0 = O I :: o : o : Q‘ \_/ \ / I 3: I I : IE 970856 ...u .....:z ... _I ll: : ulﬂl mu m u &£w Ilz : u Q. @T \_ 0% __ : .._ Bu 1 u Qox — z .ooe.z/\/\_ O : u Ox 2 :u : .. : ..TA V1 .2 Ave 1 90, u._ Illlivl ncomumacwucouv F odamp -54- IE 970856 ' |I|-1 - I H. : .._ zQU m:._. = .._ : raw 2 k Q z§€lf7iTL// «$5 mzu /04 I HID I.- go -2 : I h AW ¢s6\ OQ : nzo .... I “AV I um I / :6? .._ __ rmv _U ... - m .z wx _x mm ~ ncowumacmacouv p oaamp -55- IE 970856 ...u u t._ : mum! Cu : x._ : mum! .8 : u : \ m‘ ... < NM _X Nm .2 ncomumacwucouv p 322 IE 970856 .....m .m Acoznacmucouw .p|M..Hm...m: -67.. IE 970856 ...u 'II'II|| .... ,_ ﬁv , .Q ._ XWY ._ .Q mm .m acomunacmucouv w canon -58.. IE 970856 ...—U Acomumacmucouv — udmah. IE 970856 a tab e ccord to e 'nven Each tablet contains: Compound of Example 1 583.0 mg Microcrystalline cellulose 55.0 mg Maize starch 72.0 mg Insoluble poly~(1-vinyl-2-pyrrolidone) 30.0 mg Highly disperse silica 5.0 mg Magnesium stearate 5,9 mg 750.0 mg The lacquer shell contains: Poly-(O-hydroxypropyl—0-methyl)- cellulose 15 cp 6.0 mg Macrogol 4000, recommended INN polyethylene glycols (DAB) 2.0 mg Titanium(IV) oxide 2.0 mg 10.0 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- ticular against Enterobacteriaceae; above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cepha1o- sulphonamides and tetra- sporins, aminoglycosides, cyclines. - 70 _ IE 970856 These useful properties enable them to be used as chemo- therapeutic active compounds in medicine and as sub- stances for preserving inorganic and organic materials, in particular all types of organic materials, for example polymers, lubricants, paints, fibres, leather, paper and wood, and foodstuffs and water. The compounds according to the invention are active against a very broad spectrum of microorganisms. Gram- negative and Gram-positive bacteria and bacteria-like 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 according to the invention 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 patho- gens. For example, local and/or systemic diseases caused by the 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 Strept. pyogenes); Gram-negative cocci (Neisseria gonor- rhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haemo- _ 71 - IE 970856 philus influenzae, Citrobacter (Citrob. freundii and Citrob. divernis), Salmonella and Shigella; and further- more Klebsiella (xlebs. pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans), 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 anaerobic bacteria, such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; and fur- thermore Hycoplasma (M. pneumoniae, M. hominis and M. urealyticum) and Mycobacteria, for example Hycobacterium 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 patho- gens or mixed infections mentioned and can be prevented, alleviated or cured by the compounds according to the invention are: infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, nephritis, cystitis, endocarditis, systemic infections, bronchitis (acute and chronic), diseases of the upper respiratory tract, diffuse panbron- chiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, pyelo— septic infections, _ 72 - IE 970856 cystic fibrosis, skin infections, postoperative wound infections, phlegmons, wound infections, infected burns, burn. wounds, infections in the oral region, infections following dental operations, osteomye- litis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsil- litis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections. abscesses, 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, salmonellosis, mastitis—metritis-agalactia syndrome and mastitis; Ruminants (cattle, sheep and goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, myco- plasmosis 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 birds and others): mycoplasmosis, E. coli infections, chronic respiratory tract infections, salmonellosis, pasteurellosis and psittacosis. Bacterial diseases in the rearing and keeping of stock -73- IE 970856 and ornamental fishes can also be treated, the antibac- terial spectrum extending beyond the abovementioned pathogens to further pathogens, such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Erysi- pelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia. The present invention includes pharmaceutical formula- tions which contain, in addition to non-toxic, inert pharmaceutically suitable excipients, one or more com- pounds according to the invention or consist of one or more active compounds according to the invention, and processes for the preparation of these formulations. The present invention also includes pharmaceutical formulations in dosage units. This means that the for- mulations 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 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 adminis- tered in one application and which usually corresponds to a whole, one half, one third or a quarter of a daily dose. Non-toxic inert pharmaceutically suitable excipients are to be understood as solid, semi-solid or liquid diluents, -74- IE 970856 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- 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 extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example gly- cerol, (d) disintegrating agents, for example agar—agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary amonium compounds, (g) wetting agents, for example cetyl alcohol and gly- cerol monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesium stearate and solid polyethyl- ene glycols, or mixtures of the substances listed under (a) to (1). The tablets, coated tablets, capsules, pills and granules 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 - 75 _ IE 970856 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 water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C“-alcohol with C“-fatty acid) or mixtures of these substances. Ointments, pastes, creams and gels can contain, in addition to the active compound or compounds, the cus- tomary excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose deriva- tives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances. Dusting powders and sprays can contain, in addition to the active compound or compounds, the customary excipi- ents, for example lactose, talc, silicic acid, aluminium hydroxide, calcium. silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain the customary propellants, for example chloro- -76- IE 970856 fluorohydrocarbons. Solutions and emulsions can contain, in addition to the active compound or compounds, the customary excipients, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, di- methylformamide, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and 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 emul- sions can also be in a sterile form which is isotonic 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 ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, alumin- ium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. The formulation forms mentioned can also contain colour- ing agents, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyp- -77- IE 970856 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 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 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, parenterally (intra- 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 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 of animals, intake can also be in suitable formulations via the feed or drinking water. Gels, powders, dusting - 73 _ IE 970856 powders, tablets, delayed release tablets, premixes, concentrates, granules, pellets, boli, capsules, aero- sols, sprays and inhalants can furthermore be used on humans and animals. The compounds according to the 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 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- 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 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 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 - 79 - IE 970856 compounds can easily be determined by any expert on the basis of his expert knowledge. The new compounds can be administered in the customary concentrations and formulations together with the feed or 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 utiliza- tion can in this way be achieved. The minimum inhibitory concentrations (MIC) were deter- mined by the series dilution method on Iso—Sensitest agar (Oxoid). 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 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 agar plates were incubated at 37°C and the germ growth was read off after about 20 hours. The MIC value (pg/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 according to the invention are shown in comparison with ciprofloxacin in the following table. - go - 0 N m~.o 3.5 36 .35 m~.o m.o mmio comm 7: m m~.o m-.o mm.c oo.o m~_.o - m~_.o _o_n~ w_~muoa. n3 mﬂuuououwacm mm m~_.o eo.o mo.o m-.o m_a.ow mo.o mm_.o o:.o mm. mm_.o oo.o no.0 m~_.o m_o.ow eo.o mm_.o a:.o om». mm_.o eo.o no.0 w~_.o m~o.ow oo.o m~_.a oo.o Nmv xx msmgsm msu :uouo_>£amgw Nmo~_ Mwggmagm co mm c v m.o N u _ -mmu:wu_>ogm Nma mmCﬂmLDE m.o m.o oo.o m_o.ow m~o.ow no.o mo.o m_o.ow m__u:mmgoz n_o_ magma _ m.o oo.o mo.o m~o.ow m_o.ow m~_.o m.:.ow -.:> wsoguhm mum» w__«n o. m N N m.o a c _ INLmE msmaoum CCGESWZ ~00 mm_.o m~.o mHo.ow m_o.ow m~o.ow m#o.ow m~o.ow m_o.ow mdzu_Lw;umw cwmguw «mow udaloxw nummm am V . uuwmcum omm .Loum.:uocm ucmoamugaﬁ xvacoou umwu :owa=._u Lama u;. »n uu:_s.ouuu ,.\m:v nu:.a> um: 81 - IE 970856 mm.o m~.o mm.o m_o.ow m_o.ow m_o.oV cmumxO—uoLumU mm.o mmA.o mm_.o mm_.o eo.o u m.o 0 m.o m.o m~_.o m.o m~_.o who m~_.o 0 mm m.o 00.0 m.o 00.0 m~_.o oo.o B. o, mo.o mo.o no.0 mo.o mo.o 00.0 m_o.ow Agmmw umwu_mcumuom_ comu:._u gums wnu xa vozmsgwuwt a_\mEu meson: uaz mm.o m~.o mm.o m~.o ;:.: ugoumgzuocm m~.o mm~.o oo.o $0.0 oo.o mm~.o mo.o co.o omma _o_nm m__mumm. msuuououmgcm emm_ mwv zu uawgam mau auouo_>:am4w ~mo~_ _ouLm=4m :w_U:mt_>OLm N09 _mcwmLoE m__w:mmuoZ hqou wmumm nH=> wawaoum HNND mm_mn smL_E mawaoum ccmﬁzwz «_ou mmcumuwzuum cwmgum «mu» ucwonwu.:E xudcvov umwu IE 970856 The following examples illustrate the invention: Preparation of the intermediate products: am le A tert.—Butyl N-(cis-4-methoxy-pyrrolidin-3-yl)—carbamate a) trans-1—Benz 1- -h dro -4-metho rro1'dine 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 mol) of sodium methylate solution (30% strength) at 120°C in 200 ml of absolute methanol in an autoclave for 10 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. The filtrate is concentrated and the residue is dis- tilled. Yield: 40.9 g (91% of theory) Boiling point: 112-116°C/0.1 mbar Content: 92% pure b) cis-3—Amino-1-benzyl—4—metho§y-Qyrrolidine 5.6 g (25 mmol) of trans-1-benzyl-3-hydroxy-4-methoxy- pyrrolidine and 8.6 g (33 mol) of triphenylphosphine are initially introduced into 40 ml of absolute tetrahydro- -83- IE 970856 furan and a solution of 6 g (34 moi) of diethyl azodi- carboxylate in 40 ml of absolute tetrahydrofuran is added dropwise at NT. 3.9 g (27 mol) of phthalimide are then added in small portions at VT in the course of one hour. 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- dicarboxylate) are filtered off. The filtrate is con- centrated 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 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 carbonate 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 .{-«H.-C N-(cis-1—benzyl-4—methoxypyrrolidin-3- 3 g (l4.S mnol) of cis-3-amino-1-benzy1-4-methoxy-pyr- 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 -34- IE 970856 inorganic salts 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/0.05 mbar d) tert.-Butyl N-(cis-4-methoxypyrrolidin-3-yl)- carbamate _ 3.5 g (11.4 mol) of tert.-butyl N-(cis-1-benzy1—4- methoxypyrrolidin-3-yl)-carbamate are hydrogenated in 100 ml of methanol (n1 2 g of palladium-on-active charcoal (10% of Pd) at 100%: 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 Exam le B tert.-Butyl N-(trans-4-methoxy-pyrro1idin-3-yl)- carbamate a) ans- ~ o-1-ben - -metho - o d 27 g (0.41 mol) of sodium azide are dissolved in 50 ml of _ 35 _ IE 970856 water, and 17.5 g (0.1 mol) of 3—benzy1-6-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 con- centrated, 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) - 35 _ IE 970856 Boiling point: 91°C/0.07 mbar The product has a content of 75%, determined by gas chromatography (area method). b) ‘x-3;‘: .—i.'.u'.:',/2 N- r_*_2'<;.'!:4 1-—In‘;;'._'y'.-11--mu!iuruzc;/)1-{Irraliuiixt i— 8.2 g (30 mol) of trans-3-amino-l—benzyl-4-methoxy— pyrrolidine and 21 ml of tart.-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- 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)- carhaate_ 6.7 g (22 mmol) of tert.—buty1 N-(trans-1-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 -87- IE 970856 and the residue is distilled. Yield: 2.2 g (46% of theory) Boiling point: 94°C/0.05 mbar £rs2l2_§ trans-3-Amino-4-hydroxy—pyrro1idine a) 3- — o-1-benz 1- - - rolidine 8.9 g (50 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hex- 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 Melting point: B2—84°C b) gran;-3-Aing-5—hyg;Q§y—py;rolidine 5.2 g (27 mmol) of trans-3-amino-1-benzy1-4-hydroxy- pyrrolidine are hydrogenated in 40 ml of methanol on 1 g of palladium-on-active charcoal (10% of Pd) at 100%:under 100 bar. The catalyst is filtered off with auction, the filtrate is concentrated and the residue is distilled. Yield: 1 g (36.3% of theory) - 33 - IE 970856 Boiling point: 110°C/0.3 mbar ﬁgggple D trans-4—Hydroxy-3-(2-hydroxyethylamino)-pyrrolidine a) trans-1-Benzy1~4-hydroxy-3-(2-hydroxyethylamino)- pygrolidine 40 g (0.22 mol) of 3-benzyl-6-oxa-3—azabicyc1o[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 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-Hvgzggv-3-(2-hv o eth lamino - rolid'ne trans—1—Benzyl-4-hydroxy-3-(2-hydroxyethylamino)-pyr- rolidine is hydrogenated analogously to Example C b) to give the reaction product as an oil. - 39 - IE 970856 gxamgle E trans-4-Hydroxy—3-(2-hydroxyethy1-methyl-amino)- pyrrolidine a) trans-1-Benzyl-4—hydroxy-3-(2-hydroxyethyl-methyl- 9I_:1..rl.rr:a.<'a) -1_>.y.rr9.1..i::!.i.uv , 17.5 g (0.1 mol) of 3-benzy1-6-oxa-3—azabicyc1o[3.1.0]- hexane are reacted with 17 g (0.1 mol) of methy1amino- 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-Benzy1-4-hydroxy~3-(2-hydroxyethyl-methyl-amino)- pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oily compound. Examgle F 2—0xa—5,8—diazabicyc1o[4.3.0]nonane dihydrochloride a) 8-Benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane _ 90 - IE 970856 15.6 g (66 mol) of 1-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 concentrated sodium hydroxide solution, the sodium sulphate which has precipitated is filtered. off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and con- centrated and the residue is distilled. Yield: 4.1 g (28.5% of theory) Boiling point: 122-128°C (0.08 mbar) b) 2- xa- -diazabic clo 4. .0 nonane d'h drochloride A solution of 4 g (18.2 mmol) of 8-benzy1-2-oxa-5,8- diazabicyc1o[4.3.0]nonane in 100 ml of methanol and 3.5 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-on-active charcoal (10% of Pd) at 80%: 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 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 -91.. IE 970856 c) 2-Oxa-§,8-dia;abicygloL443-Olnonane 7.2 g (33 mol) of [4.3.0]nonane are hydrogenated in 400 ml of methanol with 8-benzyl-2—oxa-5,B-diazabicyclo— 2.5 g of palladium-on-active charcoal (10% of Pd) under 50 bar at 100°C. The catalyst is filtered off with suc- tion, the filtrate is concentrated and the residue is distilled. Yield: 3.1 g (73.4% of theory) Boiling point: 58°C/9.1 mbar. d) trans-2-Oxa-5,8-diazabicyclo/5.3.07nonane 3-benzyl-6-oxa-3-azabicyclo[3.l.0]hexane is reacted with 2-(benzylamino)-ethanol, analogously to Example D a), to give trans-l-benzyl-3-[N-benzyl~N-(2-hydroxy- ethyl)—amino]-4-hydroxypyrrolidine which is then reac- ted analogously to Example F a) to give 5,8-dibenzyl— 2—oxa-5,87diazabicyclo[4.3.0]nonane which is purified by chromatography (silica gel, cyclohexane/tert.-butyl methyl ether/ethyl acetate l:l:l). The hydrogenolytic debenzylation is carried out analo- gously to Example F c) to give trans—2-oxa-5,B-diaza- bicyclo[4.3.0]—nonane, boiling point: 60'C/0.1 mbar. IE 970856 Exam le 5-Methyl-2-oxa-5,B-diazabicyclo[4.3.0]nonane dihydrochloride a) -Benz 1- — th 1-2-oxa-S 8-diaz ‘c clo 4.3.0 nonane 18 g (71.9 mol) of 1-benzyl-4-hydroxy—3-(2-hydroxyethyl- methyl—amino)-pyrrolidine are reacted in 60 ml of con- centrated 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-S,8-diazabicyclo[4.3.0]nonane dihvdrochloride A solution of 9.4 g (40 mmol) of 8-benzyl-5-methy1-2-oxa- 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 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated. The residue is triturated with butanol/acetone 1:1 and the crystals are filtered off with suction and dried over P‘Om in a desiccator. The product is very hygroscopic. Yield: 8.2 g (95% of theory) Mass spectrum: m/e 142 (M’), 112 (1-1’-CI-I20), 100 (M’—CHz- N=CHz), 32 (C.H.No*), 68 (c.H5N*) Exam le H 2-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane a) Ethyl N-(2.2-dimethogyethyl1-carbamate 214 g (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde dimethyl acetal in - 93 - IE 970856 1 1 of toluene and 90 g of Nabﬂ 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 tol- uene. 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) Ethyl N-allvl-N-(2.2-dimethoxvethvll-carbamate 20 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—ally1-N-(2,2-dimethoxyethyl)- carbamate are heated with 150 ml of formic acid at 100°C organic phases are washed with sodium bicarbonate solu- for one hour. The mixture is poured onto ice extracted several times with methylene chloride, tion, dried over magnesium sulphate and concentrated and the residue is distilled. Yield: 46.7 g (87.2% of theory) IE 970856 Boiling point: 58°C/0.09 mbar d) Ethyl 2-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane—7- sarbozylgis 10 g (0.12 mol) of methylhydroxylamine hydrochloride are 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 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 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 chloro- form each time. The extract is dried over KZCO3 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- [3.3.0]octane-7-carhoxylate are heated under reflux in 300 ml of water with 41 g of Ba(0H)z.8I-I20 overnight. _ 95 _ IE 970856 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 and concentrated and the residue is distilled. Yield: 5.4 g (65% of theory) Boiling point: 80°C/10 mbar Exam le 1-Methyl-octahydropyrrolo[3,4-b]pyrrole diazabicyclo[3.3.0]octane) (2-methyl-2,7- a) 1-Benzyl—3—(2—ch1oroethyl~methyl—amino)—pyrrolidine— 245-dione 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 1Q_, 489 (l975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methy1- 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 2 l 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 silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. -95- IE 970856 1% value: 0.33 (silica gel, ethyl acetate/petroleum ether = 1:2) b) 5-Benzyl-4,6-dioxo-1-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 1-benzyl-3-(2—ch1oroethyl-methy1- amino)-pyrrolidine-2,5-dione are added dropwise as a solution in 50 ml of absolute dimethylformamide at room temperature. During this, an exothermic reaction takes place with foaming. The mixture is diluted with a further 50 ml of absolute dimethylformamide and subsequently stirred at room temperature for 1 hour and is then poured 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 acetate:petro- leum ether (1:2) and later (1:1). 16.4 g of educt are initially recovered here, and 17.2 g (44% of theory, based on the educt reacted) of an oily product are then isolated. Rf value = 0.26 (silica gel, ethyl acetate:petro1eum ether = 1:1). - 97 _ IE 970856 c) -Ben -1-me h 1-oc ah d o rro 4- role 1.52 g (40 mol) of lithium aluminium hydride are initially introduced into 30 ml of anhydrous tetrahydro- furan, and 4.9 g (20 mmol) of 5~benzyl-4,6-dioxo-1- methyl-octahydropyrrolo[3,4-bjpyrrole 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 added dropwise in succession to the batch and the pre- cipitate 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 point 80°C/0.07 mbar are obtained. d) 1-Methyl-Qggghyggopyrrolo[3,4-b]pyr;g1g 6.49 g (30 mmol) of 5-benzyl-1-methyl-octahydropyrrolo- [3,4-b]—pyrrole are dissolved in 100 ml of absolute ether, and 5.2 g of hydrogen chloride dried over phos- 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 (50 strength) at 80%: under 50 bar for 4 hours. The catalyst is subsequently filtered off, 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 -98- IE 970856 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/ 12 mbar are obtained. Purity: >99% Example J Octahydropyrrolo[3,4-b]pyrrole (2,?-diazabicyclo[3.3.0]- octane) a) l-Benzyl-§-[2-chloroethylamino)-pgrr0lidine—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 working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an R, value of 0.24 (on silica gel using ethyl acetate: petroleum ether = 1:1) are obtained. b) 5-Benzvl-446-dioxo—octahvdropvrrolo[3,4-blpvrrole 17.4 g (0.58 mol) of sodium hydride suspension are reacted with 119 g (0.45 mol) of 1-benzyl-3—(2-ch1oro- ethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute dimethylformamide in accordance with the working instruc- tions of Example Ib. After the mixture has been left to - 99 _ IE 970856 stand overnight, it is worked up under aqueous condi- tions. on purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetateamethanol (3:1) (R,value 0.55). 57.7 g of product (56% of theory) are isolated. c) -Benz 1-octah dro rolo 4- re e 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 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) cta o rolo 4-b role 21.0 g (0.104 mol) of 5-benzyl-octahydropyrrolo- [3,4-bjpyrrole are initially introduced into 180 ml of ice-cooled methanol, and 17.3 ml (0.208 mol) of concen- trated hydrochloric acid are added. The mixture is then hydrogenated with 2 g of Pd-on-C (5% strength) at 90%: under 100 bar for 4 hours. The catalyst is filtered off, 37.4 g (0.208 mol) of 30% strength sodiumm methylate solution are added to the filtrate, the mixture is filtered again and the filtrate is concentrated. The residue is distilled through a small Vigreux column. 5.6 g of a colourless oil (48% of theory) of boiling point 93-95°C/30 mbar, which fumes in air and slowly solidifies -100- IE 970856 in the receiver (melting point 40°C) are obtained. Eggmple 5 0ctahydropyrrolo[3,4—b]pyridine (2,B~diazabicyclo[4.3.0]— nonane) a) - enz -5 7-dio o-octah dro rrolo 3 4-b idine 47.6 g (0.2 mol) of pyridine—2,3-dicarboxylic acid N- benzylimide (British Patent 1,086,637; Chem. Abstr. gg, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90%: 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 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-Benzyl-octahydropyrrolo[3.4-b]py;idine 44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7- dioxo-octahydropyrro1o[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 — 101 - IE 970856 accordance with the working instructions of Example Ic. 24.4 g of a colourless oil having a boiling point of 93- 95°C/0.06 mbar are obtained on distillation. c) Qctahgdropg;rolo[3.4-b]Q1;idige 69 g (0.32 mol) of 6—benzyl—octahydropyrrolo[3,4-b]pyri— dine 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 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 mbsr are obtained. ﬁxgmgle L 1-Methyl-octahydropyrrolo[3,4-b]pyridine (2-methyl—2,8- diazabicyclo[4.3.0]nonane) I; ;:-_~:.zyl- 190.5 g (0.8 mol) of pyridine~2,3-dicarboxylic acid N- 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 OWZ). After cooling, the solid is filtered. off with suction and - 102 - IE 970856 washed with methylene chloride. 123 g of dark red crys- tals having a melting point of 162-165°C (decomposition) are obtained. b) 6-Benzy1~1-methyl-5,7-dioxo-octahydropyrrolo[3,4-b]- pyridine _ 38 g (0.1 mol) of 1-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 (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 sulphate, it is concentrated. 27 g of an oily residue remain. c) 6-Benzy;-1-methyl—Qg§ahyg;opy;ro1o[3,4-b]pyridine 19.2 g (0.08 mol) of crude 6-benzyl-1-methyl-5,7-dioxo- octahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g (0.16 mol) of lithium aluminium hydride in absolute tetrahydrofuran in accordance with the working instruc- tions of Example 1c. Yield: 9.5 g (52% of theory), Boiling point: 93-96°C/0.1 mbar. - 103 - IE 970856 d) - h 1-octah o rro o -b ‘dine 11.7 g (54 mol) 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 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 B3-85°/12 mbar). xam 1e trans-4-Methoxy-3-methylamino-pyrrolidine dihydrochloride a) trans-l-Benzy1-3-benzylmethylamino-4-hydroxy- pygrglidine ~ 19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3- 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 R5C03 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) - 104 - IE 970856 trans-1-Benzyl-3-benzylmethylamino-4-methoxy- Qgrrolidine 17.3 g (58 mmol) of crude trans-1-benzyl-3-benzyl— methylamino-4-hydroxy-pyrrolidine in 80 ml of abso- lute tetrahydrofuran are added dropwise to 2.8 g (93.3 mmol) of 30% 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 mol) 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 RQCO, and concentrated and the residue is distilled. Yield: 9.7 g (52% of theory) Boiling point: 140—1SWC/0.1 mbar trans-4-Methoxy-3-methylamino-pyrrolidine gihydrochloridgr 9.3 g (29 mmol) of trans-1-benzyl-3-benzylmethy1- 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%: 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) - 105 - Exam IE 970856 Melting point: 157-162°C 2,5-Dimethyl-3—oxa-2,7-diazabicyc1o[3.3.0]octane N-(2-Methy1prop—2—enyl)-N-(2,2-dimethoxyethy1)— ureghane _ 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 54 g (0.6 mol) of and the The sodium no further hydrogen is formed, methallyl chloride are added dropwise mixture is stirred overnight at 90%L chloride which has precipitated out is dissolved with a little water, the organic phase is separated off, dried over xgco, and concentrated and the residue is distilled. Yield: 71.3 g (61.7% of theory) Boiling point: 60°C/0.08 mbar N- 2—Meth 1 ro -2—en -N- -oxoeth -urethane 11.5 g (50 mol) of N-(2-methylprop-2-enyl)-N-(2,2- dimethoxyethy1)—urethane and ]”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 — 106 - IE 970856 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]— Qctane-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 hydro- chloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions of 200 ml of CHC13. The extracts are dried over Kgxr and concentrated and the residue is distilled. Yield: 13 g (55% of theory) Boiling point: 88-95°C/0.08 mbar 2 5-Dimeth 1- -oxa-2 7-diazabic clo . . octane 13 g (60.6 mmol) of ethyl 2,S-dimethyl-3-oxa-2,7- diazabicyclo[3.3.0]octane-7—carboxylate are heated under reflux with 33 g of Ba(0H)2.8Hg3 in 330 ml of - 107 - IE 970856 water overnight. The BaC03 is filtered off with suction, xzco, is added to the filtrate; the solid is filtered off with suction again and the filtrate is extracted ten times with 100 ml of CHCI3 each time. The extracts are dried over K200, and concentrated and the residue is distilled. Yield: 5.9 g (63.7% of theory) Boiling point: 64°C/5 mbar Ex_an;p.le_Q 2,8-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane - 1 1-D etho — - 1 - rethane 80 g (0.73 mol) of ethyl ohloroformate are added dropwise to 86.2 g (0.72 mol) of 2-aminopropion- 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 toluene solutions are dried over xgxr. The solution is concentrated and the residue is distilled. Yield: 132 g (95% of theory) Boiling point: 55°C/0.06 mbar - 108 - IE 970856 - 1- - 1- et r - - -ur ane 131 g (0.686 mol) of N-(1,1-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 KZCO, and concentrated and the residue is distilled. Yield: 78 g (31.7% of theory) Boiling point: 62-69°C/0.06 rnbar. Content: 64.5% pure (determined by gas chromato- graphy) - l-N- -o o -2- 1 - t ane 76.5 g (0.213 mol) of 64.5% pure N-a1ly1-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 cH,C1,, the extracts are washed neutral with Nal-ICO, solution, dried over ngso. 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 chromato- 91'5PhY) -109- IE 970856 Ethyl 2,8-dimethyl-3—oxa-2,7-diazabicyclo[3.3.0]- 0 ne-7-c ate A methanolic methylhydroxylamine solution is pre- pared from 16.4 g (0.2 mol) of N-methylhydroxylamine hydrochloride in 33 ml of absolute methanol and 36 g (0.2 mol) of 30% strength sodium methyiate solution, and the solution formed is diluted with 130 ml of toluene and added dropwise to 354 g (0.17 mol) of N-allyl-N-(1-oxoprop-2—yl)-urethane in 250 ml of toluene, which is heated under reflux using a water separator. The mixture is heated under reflux overnight, the product is extracted. with dilute hydrochloric acid and the hydrochloric acid solution is rendered alkaline with K,CO3 and extracted with CI-ICl,. The extract is dried over KZCO3 and concentrated and the residue is distilled. Yield: 18.5 g (50.8% of theory) Boiling point: 95-105°C/0.1 mbar 2 8—Dimeth - -o a-2 7- azabic clo . .0 octane 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(OH)2.8HgD in 235 ml of water’ overnight. The BaC03 is filtered off with suction, Kgxx is added to the filtrate and the solid is filtered off with suction again. The filtrate is extracted ten times with 50 ml of CHCl, each time, the extracts are dried over KZCO, and concentrated - 110 - IE 970856 and the residue is distilled. Yield: 1.7 g Boiling point: B7-92°C/10 mbar The product is a mixture of the possible stereo- isomers in a ratio of 3:1 (‘H-NMR). 4 g of starting material could to be recovered in the after-runnings. Hmpﬁi 2-Methyl-4-oxa—2,8-diazabicyclo[4.3.0]nonane 7 4 .V|I jj. Ethyl 4-hydroxymethyl-3-methylaminopyrrolidine-1- carboxvlate 10 g (50 mol) of ethyl 2-methyl-3-oxa-2,7-diazabi- cyclo[3.3.0]octane-7—carboxylate (Example H d)) are hydrogenated in 200 ml of ethanol on 3 g of Pd-on- active charcoal (10% of Pd) at 50%: 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-IANT/0.1 mbar Ethyl 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane- ,c,_,,c as _, 10.1 g (50 mmol) of ethyl 4-hydroxymethyl-3-methy1- amino—pyrrolidine-1-carboxylate and 8 g (0.1 mol) of - 111 - IE 970856 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 -Met --4-o - - c o 4. ane 9 g (42 mmol) of ethyl 2-methyl-4-oxa-2,8-diaza— bicyclo[4.3.0]nonane-8-carboxylate are heated under reflux with 28 g of Ba(OH),.8l-I20 in 280 ml of water overnight. The saco, is filtered off with auction, 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/3 mbar 4-ﬂ1dro;ygethyl-3-gethylaygigopyzrolidige 34 g (0.168 mol) of ethyl 4-hydroxymethyl—3-methy1- aminopyrrolidine-1-carboxylate are heated under reflux with 100 g of Ba(OH)2.8Hzo in 400 ml of water overnight. The BaCO, 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 filtered, the filtrate is concentrated and the residue is dis- tilled. solutions are -112- Exam IE 970856 Yield: 13 g (60.3% of theory) Boiling point: 85-88°C/0.08 mbar - t l—4-oxa- -d abic clo 4. . e 8.1 g (0.1 mol) of 37% strength formaldehyde solu- 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 tempera- ture. The mixture is stirred at room temperature overnight and concentrated and the residue is distilled. Yield: 8.7 g (61.2% of theory) Boiling point: 84°C/6 mbar 3-Oxa-2,7-diazabicyc1o[3.3.0]octane "40- Ethyl cyclo[3.3,p1octane-7-carbogylgte 2-(tetrahydropyran-2-yl)-3-oxa-2,7-diazabi— 18.1 g (0.106 mol) of ethyl N~allyl-N-(2-oxoethyl)- carbamate (Example H c)) are heated under reflux in 220 ml of toluene, and 14.2 g (0.12 mol) of 5- hydroxypentanal oxime (Acts Chim. Acad. Sci. Hung., lg, 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 - 113 - IE 970856 distilled. Yield: 15.5 g (54% of theory) Boiling point: 160°C/0.01 mbar Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7- carboxylate 15 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 mol) of 70% strength perchloric acid in 100 ml of ethanol for 30 minutes. 10.5 g (58 mmol) of 30 strength sodium methylate solution are added, the mixture is con- centrated, the residue is taken up in water and the solution is saturated with K300, and extracted with CHCl,. The extract is dried over xzco, and concentra- ted and the residue is distilled. Yield: 7.6 g (73.5% of theory) Boiling point: 125-130°C/0.1 mbar Eth 1 3-oxa-2 7-d'az c clo . . octan -7—carbo — leis 8.5 g (50 mmol) of ethyl N-(2-oxoethy1)-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. Yields 6.8 g (73% of theory) Boiling point: 120-122°C/0.05 mbar - 114 - IE 970856 d) - a- 7-diazabic c . ta e 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)2.8Hg3. Boiling point: 75°C/10 mbar. Exgggle R 3-Methyl-2,7-diazabicyclo[3.3.0]octane 3-Methyl-2,7-diazabicyclo[3.3.0]octane is obtained analogously to Example 1. Boiling point: 68-70°C/6 mbar. xam 1e 2,3—Dimethyl-2,7-diazabicyclo[3.3.0]octane 2,3-Dimethyl-2,7—diazabicyc1o[3.3.0]octane is obtained analogously to Example 1. Boiling point: 72-74°C/10 mbar. ggggple T 1,2-Dimethyl-3-oxa-2,7-diazabicyc1o[3.3.0]octane — 115 - l_!I IE 970856 N-Ally;-Q-(3,g-dimethggyproggl)-aceggmide 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 absolute toluene at 80%L The mixture is then stirred for one hour and 100 g (0.83 mol) of allyl bromide are subsequently added dropwise at BOYL The mixture is stirred overnight at 80°C and cooled and the salts are dissolved with water. The aqueous phase is separated off and extracted twice with 100 ml of toluene each time. The toluene solutions are dried over KZCO3 and concentrated and the residue is distilled. Yield: 112 g (75.6% of theory) Boiling point: 70°C/0.08 mbar. N-A1111-N-(2-oxogroggl)-acetamide 85.5 g (0.425 mol) of N-al1yl-N-(2,2-dimethoxy- propyl)-acetamide are heated under reflux with 212 ml of formic acid for one hour. The mixture is 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. - 116 - IE 970856 7-Acety1- 1 , 2-dimethyl-3-oxa-2 , 7-diazabicyclo [ 3 . 3 . 0 3- 9911599, 15.5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acet- amide 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 xzco, is added. The mixture is extracted with CHCl,, the extract is dried over KZCO3 and concentrated and the residue is distilled. Yield: 15.9 g (86.3% of theory) Boiling point: 75°C/0.1 mbar. - - -oxa-2 7-d . a 11.8 g (64 mmol) of '7-acetyl-1,2-dimethyl—3—oxa-2,7- diazabicyclo[3.3.0]octane are heated under reflux with 12 g of Naol-I in 36 ml of water overnight. The mixture is saturated with xzco, and extracted several times with CI-{C13, the extract is dried over x,co, and concentrated and the residue is distilled. Yield: 4.7 g (51.6% of theory) Boiling point: 40°C/0.2 mbar. -117- IE 970856 E2:2m2J..e_Q 2,4-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane Ethyl bamate N-(but-2-enyl)~N-(2,2-dimethoxyethy1)—car— 89 g (0.5 mol) of ethyl N—(2,2-dimethoxyethy1)- carhamate are added dropwise to 17.5 g (0.58 mol) of Nan (80% strength in paraffin oil) in 500 ml of absolute toluene at 80°C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dropwise at B0%L The mixture is stirred at 30%: overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over KZCO3 and concentra- ted and the residue is distilled. Yield: 90 g (77.8% of theory) Boiling point: 65°C/0.1 mbar. gthvl N-(but-2-envl1-N-I2-oxoethglj-cagggmggg 90 g (0.39 mol) of ethyl N-(but—2-eny1)-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 with sodium bicarbonate solution, dried over mag- - 118 - IE 970856 nesium sulphate and concentrated and the residue is distilled. Yield: 33.6 g (46.5% of theory) Boiling point: 65°C/0.1 mbar. Ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyc1o[3.3.0]- 9cLen¢~2r9a§§yxxinre 1 , 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 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 race, is added. The mixture is extracted with CI-ICl,, the extract is dried over Kzco, and concentrated and the residue is distilled. Yield: 15.0 g (70% of theory) Boiling point: '74-87°C/0.1 mbar. 13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,’h diazabicyc1o[ 3 . 3 . 0 Joctane-7-carboxylate are heated under reflux with 39 g of Ba(0H)z . 81120 in 200 ml of water overnight. xzco, is added, the saco, is fil- tered off with suction and the filtrate is extracted several times with CHCl,. The extract is dried over -119- IE 970856 BQCO3 and concentrated and the residue is distilled. Yield: 4.8 g (54.8? of theory) Boiling point: 74°C/8 mbar. Exggple V Ethyl 2,7—diazabicyc1o[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 0a) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane- 2-carboxylate, and this is then debenzylated hydrogeno- lytically analogously to Example Jd). A.oo1our1ees oil of boiling point 90°C/0.1 mbar is obtained. Example W 2-Pheny1—2,7-diazabicyclo[3.3.0]octane The preparation is carried out analogously to Example I); Boiling point: 103°C/0.08 mbar. - 120 - IE 970856 ma=.n.2J.§_X 4-Oxa-2,8-diazabicyclo[4.3.0]nonane Ethyl 3-amino—4-hydroxymethyl-pyrrolidine-1- carbogylate 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 3—Amino-4-hydrogyggghyl-pygrolidgge Ethyl 3-amino-4-hydroxymethyl-pyrrolidine-1-car- boxylate is hydrolyzed analogously to Example Pd). Boiling point: 78°C/0.06 mbar. 4- xa-2 —di zabic . . ne 3-Amino-4-hydroxymethyl-pyrrolidine is reacted with formaldehyde solution analogously to Example Pa). Boiling point: 50-60°C/0.07 mbar - 121 - IE 970856 1.’.sm2l9_Z trans-3-Ethylamino-4-methylthio-pyrrolidine 1-Benzoyl-trans-3-ethylamino—4-methylthio- 91n:ro_1 tgne 8.65 g (50 mmol) of 1-benzoyl-2,5-dihydropyrrole [Chem. Ber. gg, 2521 (1889)] are initially intro- duced into 30 ml of methylene chloride, and 4.94 g (60 mol) of methanesulphonyl chloride in 20 ml of methylene chloride are added dropwise at OWE. The mixture is subsequently stirred at 20-25%: 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 solu- tion are then added. The batch is boiled for 18 hours, while cooling under reflux, poured into water and extracted with methylene chloride. On concen- trating, 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). thic- 6.0 g (22 mmol) of 1-benzoyl-trans-3-ethylamino-4- methylthio-pyrrolidine are stirred vigorously with 22 ml of SN Naoﬁ at 100%: for 24 hours, until the - 122 - IE 970856 conversion is The mixture is then extracted with 3 x 80 ml of ether and the extract is dried over sodium sulphate and concentrated on a homogeneous. 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 Exam le Z trans-3—amino-4—methylthio-pvrrolidine 1—Benzoyl-2,5-dihydropyrrole is reacted with methylsu1fe- nyl chloride analogously to Example Y to give 1-benzyl—3— chloro-4-methylthiopyrrolidine which is reacted as a crude product with ammonia to give 3-amino-l-benzoyl—4-methyl- thio-pyrrolidine and the benzoyl radical is removed with sodium hydroxide solution. Yield over 3 stages: 47 % of theory Boiling point: 108-110°C/11 mbar. Example ZA 4—Methyl-2,B-diazabicyclojé.3.0jnonane a) 5-Methyl-l,4-dihydropyridine-2,3-dicarboxylic acid N-benzvlimido 33 g (0.29 mol) zone and 55 g of 2-methyl-2-propenal-dimethylhydra~ (0.29 mol) stirred in 225 ml of acetonitrile for 3 hours at 60°C. of N-benzylmaleinimide are - 123 - IE 970856 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 boiled for 1 hour under reflux. silica gel, the mixture is Then the mixture is filtered while hot and the silica boiled out with ethanol. The combined organic phases are concentrated in a rotary gel is several times evaporator. 17.5 g (24 % of theory) point of 184-186'C are obtained. of red crystals of a melting 5-MethylLhexahydropyridine-2,3-dioarboxylic acid N-benzylimide 17.5 g (70 mmol) of 5—methyl-1,4-dihydropyridine-2,3- dicarboxylic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70°C and under 100 bar Then the catalyst is filtered off and the filtrate is over palladium on active charcoal. concentrated by (13.0 g) is used evaporation. The solid oily residue as a crude product in the next stage. 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) absolute of lithium aluminium hydride in 100 ml of 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 hydrox- ide solution and 13.8 g of water are added dropwise The salts are filtered off, the one after the other. filtrate is concentrated by and residue is distilled. evaporation - 124 - IE 970856 Yield: 8.7 g (54 %, based on 5-methyl-1,4-dihydropyri- dine-2,3-dicarboxylic acid N-benzylimide); boiling point: 95-98'C/0.1 mbar. 4-Methyl-2,8-diazabicvQlo[4.3.0]nonane 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 cata- lyst is filtered off, evaporation and the residue is distilled. the filtrate is concentrated by Yield: 3.3 g (67 % of theory) boiling point: 88-B9’C/llmbar. The 1H-NMR spectrum shows the compound to be a mixture of two stereoisomers in a ratio of 7:2. Example AA 5,6,7,8-Tetrafluoro-1-(2,4—difluorophenyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Ethyl 2-(2,3,4,5,6—pentafluorobenzoyl)-3-(2,4- difluorophenglamino]-acrvlate 44.3 g of 2,4—difluoroani1ine are added dropwise to a solution of 115 g of ethyl 3-ethoxy-2-(2,3,4,5,6- pentafluorobenzoyl)-acrylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is 380 ml of and the washed stirred at room temperature for 1 hour, water are added, while cooling with ice, precipitate is filtered off with suction, with ethanol/Hg) (1:1) 135.4 g of the title compound of melting point 97-99°C are obtained. - 125 - and dried. IE 970856 b) Ethyl 5,6,7,8-tetrafluoro-1-(2,4—difluorophenyl)- 1.4-dihgdro-4—oxo-§—guinolinecarboxylate A mixture of 135.4 g of ethyl 2-(2,3,4,5,6— pentafluorobenzoyl)-3-(2,4-dif1uoropheny1amino)- acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide is heated at 140-150%: 10 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-Tetraf1uoro—l-(2,4-difluoropheny1)-1,4- dihgdro-4-oxo-§-gginolinecarboxvlic acid 40.1.g of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluoro- go phenyl)-1,4-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 suc- tion, washed with water and dried. 34.5 g of the title compound of melting point 250-252°C are obtained. 30 Example AB 5,7—Dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro—4-oxo-3- gyinolinecarboxyllc acid 35 a) h 2 4-d'ch1oro- -d uorobenzovl)-acetate — 126 - 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-difluoro- benzoyl chloride in 30 ml of toluene is slowly added dropwise at this temperature. The mixture is stirred at O%2for 1 hour and allowed to come to room temper- ature 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 Nazso. 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 CH2C1z solutions are washed once with saturated sodium chloride solution and -127- IE 970856 dried with Na3S0,, 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, n35: 1,5241. Ethyl 2- ( 2 , 4-dichloro-3 , 6-difluorobenzoyl ) -3-ethoxy- '~. <3 1'"/1 e: 1: «:4 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—d.i.fluorobenzoy1)-3- ethoxy-acrylate are obtained as an oil, nD Ethyl 2- ( 2 , 4-dichloro-3 , 6-difluorobenzoyl ) -3-cyclo- nronvlamino-acrvl ate 15.6 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)- 3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of cyclopropylamine 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-difluorobenzoyl ) -3-cyc lopropylamino-acrylate of melting point 106-107°C are obtained. -128~ 1,5302. IE 970856 Ethyl 5,7-dichloro—1-cyclopropyl-6-fluoro-1,4- dro- -oxo- - 1 ho ate 6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)- 3-cyclopropylamino-acrylate are heated in 100 ml of dimethylformamide 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-dich1oro-l-cyclopropyl-6—f1uoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 227-229°C are obtained. S,7-Dichloro-1-cyclopropy1-6-fluoro-1,4-dihydro-4- oxo-3-gginoigeggggogglic acid 5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-f1uoro- 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-1-cyclopropyb6-f1uoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277-278°C are obtained. - 129 - IE 970856 5,7—Dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Ethyl 2-(2.4-dichloro-3,6—difluorobenzoy1)-3-(2,4- §!i...f1.uoeropheny.1ame.ino) -acrxlaﬁ __e 35.3 g of ethyl 2-(2,4-dichloro-3,6-dif1uoro- benzoyl)-3-ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added 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/- I50 (1:1) and dried. 40.5 g of ethyl 2-(2,4—dichloro- 3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)- acrylate are obtained, melting point: 84-86°C. Ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)- 1 4- ' o-4-ox - - no ineca b te 43.6 g of ethyl 2-(2,4-dichloro-3,6-difluoro- benzoyl)-3-(2,4-difluorophenylamino)-acrylate are heated in 260 ml of dimethylformamide 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 with water and dried. 38.6 g of ethyl 5,7-dichloro- - 130 - IE 970856 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4—oxo— 3-quinolinecarboxylate are obtained. c) 5,7-Dichloro-6-fluoro-1-(2,4-difluoropheny1)-1,4- di - -ox - - o1‘ e o lic acid 41.6 g of ethyl 5,7-dich1oro-6-fluoro-1-(2,4—di- fluorophenyl)-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 con- centrated sulphuric acid for 3 hours. After cooling, 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- fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo—3- quinolinecarboxylic acid are obtained, me1ting point: 244-246°C. E.2¢A-El1P.l§._.l. A. 855 mg (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide in the presence of 330 mg (3.3 mmol) of 1,4-diazabicyclo[2.2.2]octane and 750 mg' of IE 970856 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.- butoxycarbony1amino—4-methoxy-1-pyrrolidinyl)—1—cyc1o- 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 a high vacuum. Yield: 0.73 g (70% of theory) of 7-(trans-3-amino-4— methoxy—l—pyrrolidinyl)-l-cyclopropyl—6,8—difluoro-4-oxo- 3-quinolinecarboxylic acid hydrochloride. Melting point: 279°C (with decomposition). -132’- IE 970856 1-Cyclopropyl-6,7-dif1uoro—l,4-dihydro-4-oxo-3—quino1ine- carboxylic acid is reacted analogously to Example 1 to 5 give: A. 7-(trans-3-tert.-Butoxycarbonylamino-4-methoxy—l- pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid, melting point: 247-249°C (with decomposition). 10 B. 7-(trans-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclo- propyl-6-fluoro-4-oxo-3—quinolinecarboxylic acid hydro- chloride, melting point: from 293°C (with decomposition). Exam le ‘-£;.r—."-5 " x HC1 47:‘ I ' /' 15 A reaction is carried out analogously to Example 1 with - 133 - IE 970856 cis—3—tert.-butoxycarbonylamino-4-methoxy-pyrrolidine‘to give: A. 7-(cis—3-tert.-Butoxycarbonylamino-4-methoxy-1- pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro—4- oxo-3—quinolinecarboxy1ic acid, melting point: 230-231°C (with decomposition). B. 7-(cis-3-Amino-4—methoxy-1-pyrrolidinyl)-1-cyc1o- propyl-6,8-difluoro—4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point 201-203°C (with decomposi- tion). Exam le 4 E-‘\4’\\//l\«’CO0H /it-\\_k;J H2513‘/Ax}; x CF'3COOl-I '1 I : c1-:3-3. ’*'*' e’ A. 1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-di- fluoro-1,4—dihydro-4—oxo-3—quinolinecarboxylic acid are heated under reflux in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide with 550 mg (5 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.2 g (5.6 mmol) of cia-3—tert.-butoxycarbonylamino-4-methoxy-pyrrolidine for 2 hours. The mixture is allowed to cool and the precipit- ate which has separated out is filtered off with suction, rinsed thoroughly with water and dried at 100°C in vacuo. - 134 - IE 970856 Yield: 2.0 g (80.7%) of 7-(cis-3-tert.-butoxycarbonyl- amino—4-methoxy-1-pyrrolidinyl)-8-ch1oro—1-cyclopropyl- 6-fluoro’-1,4-dihydro-4-oxo-3-quinolinecarboxylic 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 trifluoroacetic acid at room tempera— ture 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 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)-B-chloro-1-cyclopropyl-6—£luoro-1,4- dihydro—4-oxo-3-quinolinecarboxylic acid trif1uoro- acetate, melting point: 235-239°C (with decomposition). xam 1e h.Hm_-"$4 V J X551 cis—3-tert.-Butoxycarbonylamino-4-methoxy-pyrrolidine is reacted with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid analogously to Example 1 to give: - 135 — IE 970856 A. 7-(cis-3-tart.-Butoxycarbonylamino—4-methoxy-1- pyrrolidinyl)-1-cyclopropyl-6—f1uoro-1,4-dihydro-4-oxo- 3-quinoiinecarboxylic acid, melting point 232-233°C (with decomposition). B. 7-(cis-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyc1o- propyl-6-fluoro-1,4-dihydro-4-oxo-3—quinolinecarboxylic acid hydrochloride, melting point 252-256°C (with decom- position) (sintering beforehand). Es.4zmp.le_6. H>N\~/”\N xHCl - _ _ . " -2 _\_. cis-3-tert.-Butoxycarbonylamino-4-methoxypyrrolidine is reactedwith7-chloro-1-cyclopropyl-6-fluoro-1,4—dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid analogously to Example 1 to give: A. 7-(cis-tert.-Butoxycarbonylamino-4-methoxy-1- pyrrolidinyl)-1-cyc1opropy1—6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid, melting point 214- 216°C (with decomposition). B. 7-(cia-3-Amino-4—methoxy-1-pyrrolidinyl)-1-cyclopro- pyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- - 136 - IE 970856 carboxylic acid hydrochloride, melting point 205-210° (with decomposition). Mass spectrum: m/e 362 (1-1*), 330 (M*-32), 318 (M“-C02), 286, 250, 41 (c3H,), 35 (ncl). Exam le 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—1-pyrrolidinyl}-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid, Melting point: 274-278°C (with decomposition). - 137 - IE 970856 850 mg’ (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid.are heated under reflux in 9 ml of pyridine with 630 mg (3.1 mol) of 2- oxa—S,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 suction, washed with water, dried and recrystallized from glycol monomethyl ether. Yield: 840 mg (72% of theory) of 1-cyc1opropyl—6,8- difluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non- B-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 289-291°C (with decomposition); Mass spectrum: m/e 391 (M+), 347 (If-CO2), 331, 306, 294, 262, 234, 98, 41 (CJQ). - 138 - IE 970856 The reaction is carried out analogously to Example 8 with 5-methyl-2-oxa-5,8-dia2nbicyclo[4.3.0}nonane dihydro— chlorideeto give: 1-cyclopropyl-6,8-difluoro-1,4-dihydro- 7-(5-methyl-2-oxa—5,8-diazabicyc1o[4.3.0]non-8-yl)-4-oxa- 3-quinolinecarboxylic acid, melting point: from 270°C (with decomposition); Mass spectrum: m/e 405 (M"), 361 (If-C02), 331, 112, (100%). Exggple 10 N\cr-13 795 mg (3 mmol) of 1-cyclopropyl-6,7-dif1uoro-1,4-di- hydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide with 890 mg (4.1 mmol) of 5-methy1-2- oxa-5,3-diazabicyc1o[4.3.0]nonane dihydtochloride and - 139 - IE 970856 860 ng (7.8 mol) of 1,4-diazabicyc1o[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 from dimethylformamide. Yield: 0.8 g (69% of theory) of 1-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 already becomes dark from about 300°). Mass spectrum: rule (if), 343 (M*-coz), 313, 244, 112 (100%). Examgle 11 ./’.__.._.N‘,r‘ \\.‘/I\.h, 1:-—\ J I 1 I: 4‘ \ //\~\ \. " ‘ , ‘ ‘\ L _.. \cH3 The reaction is carried out analogously to Example 10 with B-chloro-1-cyclopropyl-6,7—difluoro-1,4-dihydro—4— oxo-3-quinolinecarboxylic acid to give 8-chloro—1-cyclo- propyl-6-f1uoro—1,4-dihydro-7-(5-methyl-2-oxa-5,8-diaza- bicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 258-262°C (with decomposition) (recrystal- lized from dimethylformamide). IE 970856 Eggmple 12 .:'\~/\\/jL\~//C OOH I ll 1 —— -N/-~> ,/\-.-;»J ‘l ‘IA V _ r . A\-CH3 The reaction is carried out analogously to Example 10 with 1—ethyl-6,7,8-trifluoro-1,4-dihydro—4—oxo-3-quino- linecarboxylic acid to give 1—ethy1-6,8-difluoro-1,4- dihydro-7-(5-methyl-2-oxa-5,8-diazabicyc1o[4.3.0]non-8- yl)-4-oxo-3-quinolinecarboxylic acid, melting point 279- 281°C (with decomposition). Example 13 O F / C00 \ I1 :1 r~“N/A\v/A\N/’ 1 I i ( '. . ./ \c1-13 0.84 g (3 mol) of 1-cyclopropyl-6,7,8—trif1uoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid are heated.under reflux in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide with 0.66 g (6 mmol) of 1,4—diazabi- cyc1o[2.2.2]octane and 0.49 g (3.5 mmol) of 2-methy1-2,B- diazabicyc1o[4.3.0]nonane for 2 hours. The suspension is concentrated, the residue is stirred with 20 ml of water, - 141 - IE 970856 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 mono- methyl ether. Yield: 0.? g (58% of theory) of 1-cyc1opropy1-6,8-di- fluoro-1,4-dihydro-7-(2-methyl-2,8-dia2abicyc1o[4.3.0]- non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 204-207°C. gxamgle 14 :7“ .,/,‘-‘\/’ ‘xx’ //*—N/" KN ._ $ I /r-1’ 1' Qk__N> J /”\\ \c1-:3 "coca Analogously to Example 13, 1-cyclopropyl—6-fluoro-1,4- dihydro-7-(2-methyl-2,8-diazabicyclo[4.3.0]non-8-y1)-4- oxo-3-quinolinecarboxylic acid, melting point 234—236°, is obtained with 1-cyclopropyl-6,7-dif1uoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid. - 142 - IE 970856 Example 1§ A. 1~Cyc1opropyl-6,7,B-trifluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid is reacted. with 2,8-diazabi- cyclo[4.3.0]nonane analogously to Example 13 to give 1- cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-y1)-6,8- difluoro-1,4-dihydro-4—oxo-3-quinolinecarboxylic acid, melting point 265-267° (with decomposition) (recrystal- lized from dimethylformamide). B. If the reaction of Example 15 A) is carried out in a mixture of acetonitrile/1-methyl-2-pyrrolidinone and the crude product is recrystallized from dimethy1- formamide, 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non- 8-yl)-6,8-difluoro-1,4-dihydro—4-oxo-3-quinoline- 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- 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 - 143 - IE 970856 precipitate is filtered off with suction, washed with ethanol and dried at 100°C in vacuo. Yield: 66.3 g (93% of theory) of 1-cyclopropy1-7-(2,8- diazabicyclo[4.3.0]non-8-y1)~6,8—dif1uoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 303-305°C (with decomposition). le 1 Analogously to Example 13, 1-cyclopropyl-7-(2,7-diazabi- cyclo[3.3.0]oct-7-y1)—6-fluoro-1,4-dihydro-4—oxo-3- quinolinecarboxylic acid, melting point: 260-282° (with decomposition), is obtained with 1-cyc1opropy1—6,7-di- fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2,7-diazabicyc1o[3.3.0]octane. Mass spectrum: m/e 357 (if), 313 (1oo%, 11*.-coz), 259, 257, 244, 82, 23. - 144 — IE 970856 Analogously to Example 13, 1-cyclopropyl-6-f1uoro—1,4- dihydro-7-(2-methyl-2,7-diazabicyc1o[3.3.0]oct-7-y1)—4— oxo-3-quinolinecarboxylic acid, melting point: 206—208°C (with decomposition), is obtained with 1-cyclopropy1-6,7- difluoro-1,4—dihydro-4-oxo-3—quinolinecarboxy1icacidand 2-methyl-2,7-diazabicyclo[3.3.0]octane. §.2F.QJ2l£_l_3 A F V‘//\\'/)\ "OCH! Jiﬁ [\\ I II Analogously to Example 13, 1-cyc1opropy1—6,8-difluoro- 1,4-dihydro-7-(2-methyl—2,7-diazabicyclo[3.3.0]oct-7-y1)- 4-oxo-3-quinolinecarboxylic acid, melting point 193- 200°C (with.decomposition), is obtained with 2-methyl-2,7- diazabicyc1o[3.3.0]octane. — 145 - IE 970856 Example 13 F~ ‘”«¢/‘x 1”” I H 1’. -"\—p.-' A mixture of 2.83 g (10 mol) of 1-cyclopropy1—6,7,8- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4—diazabicyc1o[2.2.2)octane and 1.4 g (11 mol) of 2—methy1-3-oxa-2,7-diazabicyc1o[3.3.- 0]octane in 20 ml of acetonitrile and 10 ml of l-methy1- 2-pyrrolidinone is heated under reflux for 1 hour. It is concentrated in vacuo, the residue is stirred with water (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 dimethylformamide. Yield: 1.9 g (49% of theory) of 1—cyclopropyl-6,8-di- fluoro-1,4-dihydro—7—(2-methyl-3-oxa-2,7-diazabicyclo- [3.3.0]oct—7—yl)-4-oxo-3-quinolinecarboxylic acid, melting point 221-223°C (with decomposition). - 146 - IE 970856 The reaction is carried out analogously to Example 19 with 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,5- dimethyl-3-oxa-2,7-diazabicyc1o[3.3.0]oct-7-yl)-4-oxo-3- quinolinecarboxylic acid of melting point 237-238°C (with decomposition). Example 2 ; ';\_ _,/ ~-.\ /" \\/f“"‘.,".'..:‘ . .“ The reaction is carried out analogously to Example 19 with 2,8-dimethyl-3-oxa-2,7—diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,8- dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]oct-7-y1)-4—oxo-3- quinolinecarboxylic acid of melting point 197-199°C. - 147 - IE 970856 Example 22 A. 3 g (10 mol) of 8—chloro-1-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 1-methyl-2-pyrrolidinone with 1.4 g (11 mmol) of 2,8-diazabicyc1o[4.3.0]nonane and 1.65 g (15 mol) of 1,4-diazabicyclo[2.2.2]octane for 1 hour. After cooling, the suspension is stirred with about 150 ml of 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 3-chloro-1-cyclopropyl- 7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,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 1N 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 100°C in vacuo. - 148 — IE 970856 Yield: 2.7 g (61% of theory) of 8-chloro-1-cyclopropyl- 7-(2,8—diazabicyc1o[4.3.0]non—8-yl)-6-fluoro-1,4-dihydro— 4-oxo-3—quinolinecarboxylic acid hydrochloride, melting point: from 225°C decomposition. Example 23 The reaction is carried out analogously to Example 22 with 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo—7H-pyrido- [l,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. -149- IE 970856 Egggple 24 6 g (20 mmol) of 1-cyclopropyl-S,6,7,8-tetrafluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid.are heated under reflux in 30 ml of 1-methyl-2-pyrrolidinone and 60 ml of acetonitrile with 2.2 g (20 mmol) of 1,4-diazabicyc1o- [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 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 1-cyclopropyl-7-(2,8- diazabicyc1o[4.3.0]non—8-yl]—5,6,8-trifluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Melting point: 266-269°C (with decomposition); after recrystallization from dimethylformamide: melting point: 272-273°C (with decomposition). - 150 - IE 970856 :7 ,.‘ 20 ml of saturated ethanolic ammonia solution are added to 4.1 g (10 mol) of the product from Example 24 in 40 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- tallized from glycol monomethyl ether. Yield: 0.? 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 ﬂf-HF), 290, 249, 96 (100%). - 151 — IE 970856 A. Analogously to Example 13, 1—cyclopropyl~7-(2,7- diazabicyc1o[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4- oxoo3-quinolinecarboxylic acid, melting point: 277-280” (with decomposition), is obtained with 2,7-diazabicyc1o— [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 undiasolved 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- linecarboxylic acid hydrochloride, melting point: 269- 271FC (with decomposition). - 152 - IE 970856 Exam e 27 ‘if ‘A K‘ CH3‘ NH\\‘ The reaction is carried out analogously to Example 8 with trans-4-methoxy-3-methylamino-pyrrolidine chloride. (trans-4-methoxy-3-methylamino—1-pyrrolidinyl)-4-oxo—3- dihydro- 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- quinolinecarboxylic acid, melting point: 268-270°C (with decomposition) is obtained. Example 28 ;—_' F) '.;~s§‘_,;"\\/ /’ \\- '/’/“‘:\/'1 N cH30L~ ? I . HZNWW xCF3C0OH A. 1.4 g (2.9 mmol) of the product from Example 3 A) and 1.98 ml (1.7 g, 12 mol) of dimethylformamide di- ethyl acetal are heated at 120%: in 15 ml of absolute dimethylformamide for 2 hours. The mixture is then concentrated in vacuo. The residue which remains is stirred with acetonitrile. The precipitate is filtered - 153 — IE 970856 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-1-pyrrolidinyl)-1-cyclo- propyl-6,8-difluoro-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 trifluoroacetic acid at 20°C for 10 minutes. The trifluoroacetic acid is then removed in vacuo. The residue solidifies on addition. of diethyl ether. The solid is isolated, washed with diethyl ether and dried. Yield: 0.25 g (80.6% of theory) of ethyl 7—(cis-3-amino- 4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro—4-oxo—3-quinolinecarboxylate trifluoroacetate Melting point: 124-126°C. Example 29 H3C\ Analogously to Example 13, 1-cyclopropyl-6,8-difluoro- 1,4—dihydro-7-(2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]non— 8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point IE 970856 258-260°C (with decomposition), is obtained with 2-methyl- 4-oxo-2,8-diazabicyc1o[4.3.0]nonane. Examgle 3Q Analogously to Example 19, 1-cyclopropyl-6,B-dif1uoro- 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-diazabicyc1o[3.3.0]octane. E am le 1 xHC1 A. 1.1 g (10 mmol) of 1,4-diazabicyc1o[2.2.2]octane and 1.4 g (11 mol) of 2,8—diazabicyclo[4.3.0]nonane are added to 2.53 g (10 mmol) of 1-ethyl-6,7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of acetonitrile and 15 ml of dimethylformamide and the mixture is heated under reflux for 1 hour. The mixture is - 155 - IE 970856 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,B-diazabicyc1o- [4.3.0]non-8-yl)-l-ethyl-6-fluoro-4-oxo-3-quinoline- carboxylic acid, melting point: 259-261°C (with decom- position). B. 2.9 g (B 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 l20°C/ 12 mbar. Yield: 1.8 g (57% of theory) of 7-(2,8-diazabicyclo- [4.3.0]non-8-yl)-1-ethyl-6-fluoro—4-oxo-3-quinoline- carboxylic acid hydrochloride, melting point, with decom- position: 299%: (dark coloration already starting from about 215°C). Example 32 Reaction analogously to Example 31 with 1-cyclopropy1- - 156 - IE 970856 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid gives: A. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-B-yl)- 6-fluoro-4-oxo-3-quinolinecarboxylic acid, melting point: 249-257°C (with decomposition) B. 1—Cyclopropyl-7—(2,B-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). Examgle 33 F\jf7\n/)\r/COQH "“N/*§,/*\g/J }w—~< l i If Fe: F //\\\ _ it 1.1 g (3 mmol) of 1-cyclopropyl-7-(2,8-dia2abicyclo- [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 dimethylformamide 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 dimethylformamide. Yield: 0.8 g (64% of theory) of 1-cyclopropy1-6,8—di- iluoro-7-(2-formyl-2,8-diazabicyclo[4.3.0]non-8-yl)-1,4- — 157 - IE 970856 dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 276-278°C. Example 34 C}'I3C0\ V’: I ‘|" 1.1 g (3 mmol) of 1—cyclopropyl-7-(2,8-diazabicyclo— [4.3.0]non-8-yl)-6,8—difluoro-1,4-dihydro—4-oxo-3~quino- linecarboxylic 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 1N sodium hydroxide solution and 260 mg of acetyl chloride are added, while cooling with ice. The mixture is subse- quently stirred at room temperature for 2 hours and diluted with 30 ml of water and the precipitate which has separated out is filtered off with suction. The crude product is recrystallized from glycol monomethyl ether. Yield: 0.6 g (46% of theory) of 7-(2-acetyl—2,8-diaza- bicyclo[4.3.0]non-8-yl)-1-cyclopropyl-6,B-difluoro—1,4- dihydro-4-oxo—3-quinolinecarboxylic acid, melting point: 261-263°C (with decomposition) — 158 - IE 970856 §_x_aLm_..;2 1.9. 3.2 A. Analogously to Example 13, B-chloro-1-cyclopropyl- 6-fluoro-1,4-dihydro-7~(2-methyl-2,7-dia2abicyclo[3.3.0]— oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 222-227°C (with decomposition), is obtained with 8-chloro-1-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 1N 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 B-chloro-1-cyclopropyl- 6-fluoro-1,4-dihydro-7-(2—methyl-2,7-diazabicyc1o[3.3.0]- oct-7-yl)-4-oxo—3—quinolinecarboxylicacidhydrochloride, melting point: 303-305°C (with decomposition). - 159 - IE 970856 Egample 3§ c}-:3 Analogously to Example 13, 1-cyclopropyl-6,8-dif1uoro- 1,4-dihydro-7-(3-methyl-2,7-diazabicyc1o[3.3.0]oct-7-y1)- 4—oxo-3-quinolinecarboxylic acid is obtained with 3- methyl-2,7-diazabicyclo[3.3.0]octane, and is converted into 1-cyclopropyl-6,B-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. Examgle 37 A. A mixture of 1.45 g (5 mol) of 1-cyclopropy1-6,7,3- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.85 g (7.5 mmol) of 1,4-diazabicyc1o[2.2.2]octane and 0.77 g (5.5 mol) of 2,3-dimethyl-2,7—diazabicyc1o- — 160 - IE 970856 [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 monomethyl ether. Yield: 1 g (47% of theory) of 1-cyclopropy1-7—(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: 203-209°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 is filtered off with suction, washed with ethanol and dried at 100°C/1 mbar. Yield: 0.64 g (84% of theory) of 1—cyclopropy1—7-(2,3- dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-6,8-difluoro— hydro- chloride, melting point: 233-236°C (with decomposition). 1,4-dihydro-4-oxo-3—quinolinecarboxy1ic acid -161 - IE 970856 Egamgle 33 1-13c\‘ .~ xi-[Cl Analogously to Example 37 A. and B., 8—ch1oro-1-cyclo- propyl-7-(2,3—dimethy1-2,7-diazabicyc1o[2.2.2]oct-7-y1)- 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 240-2419C (with decomposi- tion), is obtained with 8-chloro-1-cyclopropyl-6,7- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Exam le 9 P\/5‘\v/u\,/Coon 1 H H z*._\ ‘ 5}.’ \T/‘\—,’1~<'—. The reaction is carried out analogously to Example 19 with 1,2—dimethyl-3-oxa-2,7-diazabicyc1o{3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1,2- dimethyl—3-oxa-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3- quinolinecarboxylic acid of melting point 269-271°C (with decomposition). - 162 - IE 970856 Example 40 xHCl 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 mol) of 8-chloro-1—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 dimethylformamide 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-B-chloro—6-fluoro-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 1N 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 B-chloro-1-cyclopropyl- 6~fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non— 8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: from 29¢? decomposition. — 163 - IE 970856 Example 41 , ”*»~:ooH H3C\ Analogously to Example 13, 8-chloro-1-cyclopropyl-6- fluoro-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-1- cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo—3-quino1ine- carboxylic acid and 2-methyl-4-oxa-2,8-diazabicyclo- [4.3.0]nonane. FAB mass spectrum: m/e 422 ([M+H]U, 404 (422-Hgn. Example 42 P-.: . *~ H ‘cozczns A. The reaction is carried out analogously to Example 13 with ethyl 2 , 7-diazabicyclo [ 3 . 3 . 0 ]octane-2-carboxylate to give 1-cyclopropyl-7-(2-ethoxycarbonyl-2,7-diazabi- cyc1o[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid of melting point 191—192°C. - 164 - IE 970856 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 is filtered off with suction, washed with ethanol and dried at 120°C/12 mbar. Yield: 1.1 g (67% of theory) of 1-cyclopropyl—7-(2,7- diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4—dihydro-4- oxo-3-quinolinecarboxylic acid hydrochloride, melting 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 1-cyclopropyl-7-(2,8-diazabi- cyclo[4.3.0]non-8-yl)-6,B-difluoro-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 cool- ing the salt precipitates out, this being filtered off 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 1-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: 262—265°C (with decomposition). The following compounds are obtained analogously: — 165 - IE 970856 B. 1—Cyclopropyl-7—(2,8-diazabicyc1o[4.3.0]non-8—yl)- 6,8-difluoro-1,4—dihydro-4—oxo—3-quinolinecarboxylic acid tosylate, melting point: 248-250°C (with decomposition). C. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-B—yl)- 6,8-difluoro-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 1-cyclopropyl-7-(2,8—diazabicyclo- [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 1N sodium hydroxide solution are added at room temperature, whereupon the product largely dissolves. A slight turbidity is removed by filtration through a 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- hydro-4-oxo—3—quinolinecarboxylate; the salt decomposes slowly above 210°C without melting. - 166 - IE 970856 Egample 45 A mixture of 3.9 g (10 mmol) of 1-cyclopropyl-7-(2,8- diazabicyclo [ 4 . 3 . 0 ] non-8-yl ) -6 , 8-difluoro-1 , 4-dihydro-4w oxo-3-quinolinecarboxylic acid in 100 ml of dimethyl- formamide 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 gel (mobile phase: CI-Izclz/CH3OI-I/17% strength NH, = 30:B: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 1-cyclopropy1-6,8- difluoro-1,4—dihydro-7-[2-(2-hydroxyethyl)—2,8-diazabi- cyclo[4.3.0]non—8-yl]-4-oxo-3-quinolinecarboxylic acid, melting point: 200-206°C (with decomposition). Mass spectrum: m/e 433 (M7), 402 (M+ -cngnn, 140, 110 (100%), 96 -167- |,_i IE 970856 32H5NHaw " 2-“.v‘«yp Cl-I35 ,2 The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine to give 1-cyc 1op:r:opy1-7- ( trans-3-ethylamino—4-methylthio) -6 , 8- difluoro-1 , 4-clihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 215-216°C (with decomposition). Egamgle 47 The reaction is carried out analogously to Example 13 with 2-phenyl-2,7-diazabicyc1o[3.3.0]octane to give 1- cyclopropyl-6 , 8-difluoro-1 , 4-dihyd.ro-4-oxo—7- ( 2—pheny1- 2,7-diazabicyclo[3.3.0]0ct—7-yl)-3-quinolinecarboxylic acid, melting point: 259-260°C (with decomposition). -168- IE 970856 Examgle 43 F CH3 .1 Analogously to Example 13, 5,6,8-trifluoro-1—(2,4-di- fluorophenyl)-1,4-dihydro-7-(2-methyl-2,8-diazabicyc1o- [4.3.0]non-8-yl)—4-oxo-3-quinolinecarboxylic acid is obtainedwith5,6,7,8-tetrafluoro-1~(2,4-difluoropheny1)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Example 49 .Ana1ogously to Example 24, 7-(2.8-diazabicyc1o[4.3.0]non- 8—yl)-5,6,8-trifluoro-1~(2,4-difluorophenyl)-1,4-dihydro- 4-oxo—3-quinolinecarboxylic acid is obtained with 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)—1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid. - 169 — IE 970856 ggamgle 50 Analogoualy to Example 25, 5-amino-7-(2,B-diazabicyclo- [4.3.0]non-8~yl)-6,8-difluoro-1-(2,4-dif1uoropheny1)-l,4- 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. Examgle 51 Analogously to Example 15 A, 5-chloro-1-cyclopropyl-7- (2,8-diazabicyclo[4.3.0]non-B-yl)-6—fluoro-1,4-dihydro- 4-oxo-3—quinolinecarboxylic acid, melting point: 270°C (decomposition), is obtained with 5,7-dichloro-1-cyc1o- propyl-6-fluoro-1,4—dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours). - 170 - IE 970856 Analogously to Example 3, 5-ch1oro-1-cyc1opropyl-6- fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyc1o[4.3.0]non- 8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7—dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo—3- quinolinecarboxylic acid (reflux for 5 hours). Examgle 53 Analogous1y' to Example 15 A, 5~chloro~7—(2,8-diazabi- cyclo[4.3.0]non-8-yl)-6-fluoro-1-(2,4-difluorophenyl)— 1,4-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 hours). — 171 - IE 970856 Examgle 54 Analogously to Example 8, 5—chloro-6-f1uoro-1-(2,4- difluorophenyl)-1,4-dihydro-7-(2-oxa-S,8-diazabicyclo- [4.3.0]non-8-yl)-4-oxo—3-quinolinecarboxylic acid is 5,7-dichloro-6-fluoro-1-(2,4-dif1uoro- phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours). obtained with gxamgle 55 The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine and B- chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid to give B-chloro-1-cyclopropy1— 7-(trans-3-ethylamino-4-methylthio-1-pyrrolidinyl)-6- fluoro-1,4—dihydro-4-oxo—3-quinolinecarboxylic acid, melting point: 217—218°C (with decomposition). - 172 - IE 970856 Example 56 XHCI CH3S 7-(trans-3-Amino-4—methylthio-1-pyrrolidinyl)-1-cyclopro~ pyl-6,B-difluoro-1,4-dihydro—4-oxo-3-quinolinecarboxylic, melting point: 208-21l'C (with decomposition) and 7-(trans- 3-amino-4-methylthio-1-pyrrolidinyl)-l-cyclopropyl—6,8—di- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro? chloride, 255-257'C obtained with trans-3-amino-4-methylthio-pyrrolidine analogously to Examples 13 and 15. melting‘ point: (with decomposition), Example 57 XHCI 1—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 1-cyclo~ propyl-6,B-difluoro-1,4-dihydro-7-(4-methyl-2,B-diazabi- cyclo[4.3.0]non—8—yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, 204-2l2'C melting’ point: (with decomposi- - 173 - IE 970856 tion) are obtained with 4—methyl-2,8—diazabicyclo[4.3.Q7- nonane analogously to Examples 13 and 15. The product consists of a mixture of 2 stereoisomers. — 174 - IE 970856 Patent Qlaims: 1. 7-(1-Pyrrolidinyl)-3-quinolone- and -naphthyridone— carboxylic acid derivatives of the formula (I) X1 .. . 1 "COOR2 (I) in which represents halogen, represents hydrogen, amino, alkylamino having 1 dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio to 4 carbon atoms, 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 2-hydroxyethyl, 2- fluoroethyl, methoxy, amino, methylamino, ethyl- having 3 to 6 carbon atoms, amino, dimethylamino or phenyl which is option- ally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 4 carbon atomsor(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, - 175 - IE 970856 R’ represents a radical of the structure *3 .2-R‘ _. 3,5 . P6 wherein R‘ can represent C1-C.-alkyl, aryl or C,- C.-acyl, R’ can represent H, C,-C.-alkyl, OH or OCH3, R5 can represent H, optionally hydroxy1-aub- etituted C,-C.~elky1, as well as aryl, heteroary1, benzyl, C,-C.-alkoxycarbonyl, C1-C.-ecyl, (S-methyl-2-oxo-1 , 3-dioxol-4-yl ) -methyl , or C,-C,-cycloallcyl, R’ can represent H or C1-C.-alkyl, R’ can represent H, CH, or phenyl, R" can represent H, CH, or phenyl, R"' can represent H or CI-I3, Y can represent 0, CH2, CHzC!-I3 or CH,-0, it being possible for the CI-I2-O group to be linked to the nitrogen either via 0 or via CH1, and Z can represent 0 or S, and -176- IE 970856 A represents N or C-R‘, wherein R‘ represents H, halogen, methyl, cyano, nitro, hydroxyl or methoxy or, together with R‘, can form a bridge having the structure ‘CH2'CH2‘CH‘CH3 and pharmaceutically usable hydrates and acid addition salts thereof and the alkali. metal, 10 alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids. with the exception of compounds of the formula N} 4;, 0 wherein 15 R1 is C1-C4 alkyl, R2/R3 are each hydrogen or C1-C4 alkyl, R4 is cyclopropyl, phenyl, halophenyl or thienyl, which may be substituted by C1-C4 alkyl or halogen, and 20 R5 is halogen. 2. Compounds of the formula (I) according to Claim 1, in which X‘ represents fluorine or chlorine, X‘ represents hydrogen, amino, alkylamino having 1 - 177 - IE 970856 or 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercapto, methylthio, phenylthio, ‘fluorine or chlorine, 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, ethyl- amino, dimethylamino or phenyl which is option- ally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 3 carbon atomsor(5-methyl-2-oxo-1,3~dioxol-4—yl)-methyl, represents a radical having the structure R‘,Z-R‘ 4h, I . ?T‘~<““ ‘:-,é. wherein R‘ can represent C1-C,-alkyl or C,-C,-acyl, R’ can represent H, C¢4g-alkyl, OH or OCH3, it also being possible for, R‘ and R5 together to denote a Crxh-alkylene bridge which is optional1y'mono- or disubstituted by methyl, - 178- IE 970856 can represent H, optionally hydroxy1— substituted C1-C3-alkyl, as well as phenyl, benzyl, C,-C.-alkoxycarbonyl, C1-C2-acyl. (S- methyl-2-oxo-1,3-dioxol-4-yl)-methyl, or C3-C5-cycloalkyl, can represent H or Cfmg-alkyl, can represent H or CH“ can represent H or CH3, can represent H or CH3, can represent 0, CH2, CHZCH, or C!-I2-O, it being possible for the can-0 group to be linked to the nitrogen either via 0 or via CH2, and can represent 0 or S, and represents N or C-R‘, wherein represents H, fluorine, chlorine, bromine or hydroxyl or together with R’ can form a bridge having the structure - 179- IE 970856 Compounds of the formula (I) according to Claim 1, in which represents fluorine, represents hydrogen, amino, methylamino fluorine, represents alkyl having 1 or 2 carbon atoms, vinyl, cyclopropyl, 2-hydroxyethyl, 2-f1uoro- ethyl, methoxy, methylamino, 4-fluorophenyl or 2,4-difluorophenyl, represents hydrogen or alkyl having 1 or 2 carbon atoms, represents a radical having the structure e /Z-*‘ wherein R‘ can represent C,-C2-alkyl, R’ can represent H or C,-C,-alkyl, it also being possible for R‘ and R’ together to form a C,-C,-alkylene bridge which is - 180 - IE 970856 optionally substituted by methyl, can represent H, CH3, C211,, HOCHZCHZ, benzyl, C1-C.-alkoxycarbonyl or C,-C,-acyl, can represent H or CH“ can represent H or CH3, can represent H or CH3, can represent H or CH3, can represent 0, CH2, CHZCI-I, or CH2-0, it being possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CH2 , and can represent 0 or S, and represents N or C-R”, wherein represents H, fluorine or chlorine, or together with R’ also can form a bridge having the structure -0-CHz—|C1-I-CI-I3 . 4. Process for the preparation of the compounds of the formula (I) according to Claim 1, characterized in -181- IE 970856 that compounds of the formula (II) V;.pf;_ﬁ/~_\ m__FL (II) in which 1 2 1 A, R , R , X and X2 have the abovementioned meaning and X3 represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula (III) R’-H (III) in which R3 has the meaning given in Claim 1, if appropriate in the presence of acid entrainera, and if appropriate protective groups contained in R3 are removed. “Process for the preparation of the compounds of the formula (I) according to Claim 1 - 182 - IE 970856 ,~T®o&9 (1) in which X‘, R’, R’, R3 and A have the abovementioned meaning X’ 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, characterized in that a compound of the formula (IV) (IV) in which X‘, R’, R’, R’ and A have the abovementioned meaning, is reacted with compounds of the formula (V) - 183 - IE 970856 x‘-H (V) in which X2 has the abovementioned meaning, if appropriate in the presence of acid entrainers. 6. Process for the preparation of compounds of the formula (Ia) X 2 II’! ‘ ;« 2 / -_/ \‘ R3/*\A/“x? (Ia) in which X1, X2, R‘, R2 and A have the abovementioned meaning 10 and R3 represents a radical having the structure wherein R‘, R5, R5, R’, R", R"', Y and Z have the abovemen- tioned meaning, - 184 - IE 970856 characterized in that a compound of the formula (VI) X2 0 I 1| . L 'i 2 if‘ .x‘ ~ .-"coon 1’ H U \ ‘; _. (VI) in which X1, X‘, R‘, R2 and A have the abovementioned meaning R“ represents a radical having the structure 13- 2-124 ’“\ Q or ‘N -+—« /F‘ ‘—L———— H N’ P 1 Q :1:——‘.: \< wherein R‘, R’, R‘, R", R"', Y and Z have the abovementioned meaning, is reacted with compounds of the formula (VII) R°—x' (VII) in which - 185 - IE 970856 R“ has the abovementioned meaning and X‘ represents chlorine, bromine, iodine or acyloxy, if appropriate in the presence of acid entrainers. 7-(1-Pyrrolidinyl)-3-qu1nolone- and -naphthyridone— carboxylic acid derivatives of the formula (I) according to Claim 1 for use in a method for thera- peutic treatment of the human or animal body. Medicaments containing compounds of the formula (I) according to Claim 1. Use of compounds of the formula (I) according to Claim 1 for the preparation of medicaments. Use of compounds of the formula (I) according to Claim 1 as animal feed additives. Animal feeds or animal feed additives and premixes containing compounds of the formula (I) according to Claim 1. - 186 - IE 970856 Carboxylic acid derivatives in the S,S—configuration of the formula wherein A is C—Cl, C-F or C—OCH3 and pharmaceutically acceptable salts thereof. Medicaments containing a compound according to Claim Use of compounds according to Claim 12 for the preparation of animal feeds, animal feed additives and premixes. Use of compounds according to Claim 12 as antibacterial agents. Use of compounds according to Claim 12 for the ‘preparation of a medicament for the treatment of bacterial diseases. A compound according to Claim 1, which is any one of those specifically hereinbefore mentioned. A process for the preparation of a compound according to Claim 1, substantially as hereinbefore described and exemplified. - 187 - IE 970856 19. A compound according to Claim 1, whenever prepared by a process claimed in a preceding claim. 20 . A medicament according to Claim 8, substantially as hereinbefore described and exemplified. 21. An animal feed or animal feed additive or premix according to Claim 11, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS. - 188 —

Description

This invention relates to 7—(l-pyrrolidinyl) quinolone- and -naphthyridone—carboxylic acid derivatives of the formula I in which X1, X2, R1, R2, R3 and A have the meanings given in the description, processes for their preparation and substituted (oxa)diazabicyclooctanes and ~nonanes as intermediate products for their preparation, and antibacterial agents and feed additives containing them.

The invention relates to new 7-(1-pyrro1idiny1)—3-quino- lone- and -naphthyridonecarboxylic acid derivatives, processes for their preparation and antibacterial agents and feed additives containing them.

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 and 153,826.

It has been found that the 7-(1—pyrro1idinyl)-3—quino- lone- and naphthyridonecarboxylic acid derivatives of the formula (I) in which X‘ 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 R’ IE 970856 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, methylamino, ethylamino, dimethy1- 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-1,3-dioxoly1)—methy1, represents a radical of the structure R‘ Z-R4 3- R x~+- H-—-z r+—,—~,;».~ . N\ ’ 5 ’ - N D ' N /Y R~\ \R6 R R" |6 wherein R‘ can represent H, C,—C,-alkyl, aryl or C,-C,-acyl, R’ can represent H, C1-C.-alkyl, OH or OCH3, it also being possible for R‘ and R’ together to denote a Crdy-alkylene bridge which is option- ally mono- or disubstituted by methyl, R‘ can represent H, optionally hydroxy1—substi- tuted C1-C4-a1ky1, as we11 as aryl, heteroary1, benzyl, IE 970856 C,-C.-alkoxycarbonyl, C,-C.-acyl, (5-methy1 oxo-1,3-dioxol-4~y1)-methyl, or Cy4;-cyc1o- alkyl, can represent H or C1-C.-alkyl, can represent H, CH3 or phenyl, can represent H, CH, or phenyl, can represent H or CH,, can represent 0, CH3, CHZCHZ or CH,-O, it being possible for the CH,-O group to be linked to the nitrogen either via 0 or via CH2, and can represent 0 or S, and represents N or C-R’, wherein represents H, halogen, methyl, cyano, nitro, hydroxyl or methoxy or, together with R‘, can form a bridge having the structure -o—cH,—cH-C11,, -S-CH,-‘CH-CH, or and pharmaceutically usable hydrates and acid addition salts thereof and the alkali metal, alka- IE 970856 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 represents fluorine or chlorine, represents hydrogen, amino, alkylamino having 1 or 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercapto, methylthio, phenylthio, chlorine, fluorine or represents alkyl having 1 to 3 carbon atoms, alkenyl having 2 or 3 carbon atoms, cycloalkyl having 3 to 2—hydroxyethy1, 2—fluoroethy1, methoxy, amino, methylamino, ethylamino, dimethyl- amino or phenyl which is optionally substituted by 1 or 2 fluorine atoms, carbon atoms, represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyloxo-1,3-dioxolyl)-methyl, IE 970856 represents a radical having the structure wherein R‘ can represent H, C1-C,-allcyl or C1-C2-acyl, R’ can represent H, C1-C,-alkyl, OH or OCI-£3, it also being possible for R‘ and R’ together to denote a C,-C,-alkylene bridge which is option- ally mono- or disubetituted by methyl, R‘ can represent H, optionally hydroxy1-substitu- ted C,-C,-alkyl, as weH as phenyl, benzy1, Cl-c4-a}k,_,,,y_ carbonyl, Cgia-acyl, (5-methyloxo-1,3- dioxolyl)-methyl, or Cy4y-cycloalkyl, R’ can represent H or C,-C,-alkyl, R’ can represent H or CH3, R" can represent H or CH3, R“ ' can represent H or CH3, '3' can represent 0, CH2, CHZCH2 or CH,-O, it being IE 970856 possible for the CHf43 group to be linked to the nitrogen either via 0 or via CH2, and 2 can represent 0 or S, and A represents N or C-R‘, wherein R‘ represents H, fluorine, chlorine, bromine, methyl, nitro, hydroxyl or methoxy or together with R? can form a bridge having the structure CH,-$11-I-CH, .

Particularly preferred compounds are those of the formula in which X‘ represents fluorine, X2 represents hydrogen, amino, methylamino or fluorine, R’ represents elkyl having 1 or 2 carbon atoms, vinyl, cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, methylamino, 4-fluorophenyl or 2,4—dif1uoropheny1, IE 970856 represents hydrogen or alkyl having 1 or 2 carbon atoms , represents a radical having the structure wherein R‘ can represent H, C,-C,-alkyl or acetyl, R’ can represent H or C54;-alkyl, it also being possible for R3 and R"together to form a C,-C,- alkylene bridge which is optionally substituted by methyl, R‘ can represent I-I, CH3, C211,, HOCH,CH2, benzyl, C,- C.-alkoxycarbonyl or C,-C2-acyl, R’ can represent H :n CH3, R’ can represent H ' CH3, R" can represent H or CH3, R" can represent H or CH3, -“ IE 970856 Y can represent 0, CH2, CI-I,CH2 or CH2-0, it being possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CH2, and can represent 0 or S, and “- A represents N or C-R‘, wherein R‘ represents H, fluorine or chlorine, or together with R1 also can form a bridge having the structure 3-O-CH,-$1-I-CH, .

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 R‘, R’, X‘ and X’ have the abovementioned meaning and X’ represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula (III) IE 970856 R3-H (II I) in which R3 has the abovementioned meaning, if appropriate in the presence of acid entrainers, and if appropriate protective groups contained in R’are removed (method A).

Compounds of the formula (I) according to the invention x2 I.‘ X1\I/\]|/‘ l/COORZ /"\N in which X‘, R’, R’, R’ 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) I ﬂ\ Xlxr,/\' /coma? 3,». Q, 3 5A, .W J (Iv) in which X‘, R’, R’, R3 and A have the abovementioned meaning, with compounds of the formula (V) x‘-H (V) in which X2 has the abovementioned meaning, if appropriate in the presence of acid entrainers (method B).

Compounds of the formula (Ia) according to the invention xi _,‘e V N (Ia) in which X’, X’, R’, R2 and A have the abovementioned meaning and R3 represents a radical having the structure IE 970856 F‘ 2-94 ‘ .~F*’ or -rz “W “\ ‘-%-~—+f ’ F5 R" I wherein R‘, R5, R‘, R’, R", R"', Y and Z have the abovementioned meaning, 3 can also be obtained by a process in which a compound of the formula (VI) x3 0 >1‘ , l coon? (VI) R3‘/l§A N in which X’, X2, R3, R2 and A have the abovementioned meaning and R“ represents a radical having the structure R‘ z-R4 54“ B‘ -N /w~ r ,4v \ 3 " ,- ‘-r-- ' or ’ T’. I Y P” N‘ *1 IV I 9” [ _ 11 - IE 970856 wherein R5’ R5’ R1’ Ru’ Ru!’ meaning, Y and 2 have the abovementioned is reacted with compounds of the formula (VII) R‘-x‘ (VII) in which R‘ has the abovementioned meaning and X‘ represents chlorine, bromine, iodine, hydroxyl or acyloxy, if appropriate in the presence of acid entrainers (method If, for A example, 1-cyclopropyl-6,7,8-trifluoro—1,4- dihydrooxoquinolinecarboxylic acid and 1-methy1- octahydropyrrolo[3,4-b]pyridine are used as starting substances, the course of the reaction can be represented by the following equation: IE 970856 F-‘\.V,_/, \ / ~.‘,r L .,:o,{ \/’ \ E 2 9 2- | !] | a [ I H H -—‘ — I r ‘»u/ 3 *», - If, for example, 7-ch1orof1uoro(4-fluorophenyl)- 1,4-dihydrooxo-1,B—naphthyrid1necarboxylicacidand cia-3—tert.—butoxycarbonylamino-4—methoxy-pyrrolidine are used as starting substances, the course of the reaction can be represented by the following equation: - 13 _ IE 970856 (CH3)3C-O-CO-NH cnao COOH ‘-“\ Base I + NH ———————~ c1 N ,———/ -HC1 CH3O (CH3)3C-O-CO-NH <9 0 9 coon 3: RC1 IE 970856 If, for example, 1-cyclopropyl-5,6,8-trif1uoro-1,4- dihydro(2-methyl—2,7-diazbicyclo[3.3.o]octyl) oxoquinolinecarboxylic acid and ammonia are used as starting substances, the course of the reaction can be represented by the following equation: If, for example, 1—cyc1opropy1(2,7-diazabicyclo— [3.3.0]octyl)fluoro-1,4-dihydrooxoquinoline- carboxylic acid and ethanool/hydrogen chloride are used as starting substances, the course of the reaction can be represented by the following equation: IE 970856 p\vé?\\/J\\/’COOH HC1 | if - C2}-l5OH —?' ,.x‘\ 2: 1 x HC1 The compounds of the formula (II) used as starting substances are known or can be prepared by known methods.

Examples which may be mentioned are: 7-ch1orocyclopropylfluoro-1,4-dihydrooxo quinolinecarboxylic acid (German Patent Application 3,142,854), 1-cyclopropyl-6,7-difluoro-1,4-dihydrooxo-3~quino1ine- carboxylic acid (European Patent Application 113,091), 6-chlorocyclopropyl-7,8-df1uoro—1,4-dihydrooxo quinolinecarboxylic acid (German Patent Application 3,420,743), - 15 _ IE 970856 8-chlorocyclopropyl-6,7-difluoro-1,4-dihydro—4—oxo quinolinecarboxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7,8-trifluoro-1,4—dihydrooxoquino- linecarboxylic acid (German Patent Application 3,318,145), 6,B-dichloro-1—cyclopropy1fluoro-1,4-dihydrooxo quinolinecarboxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7—dif1uoro-1,4-dihydromethy1oxo quinolinecarboxylic acid, 1-cyclopropyl-7—ch1orofluoro-1,4-dihydronitro oxoquinolinecarboxylic acid, 6,7—dif1uoro-1—ethyl—1,4-diyydrooxo-3~quino1ine- carboxylic acid,’ 7—chlorc—6-fluoroethyl-1,4-dihydro-4—oxo-3—quino1ine- carboxylic acid, 7—ch1orofluoro—1,4-dihydro—1-(2-hydroxyethyl)oxo- 3—quinolinecarboxy1ic acid, 6,7-difluoro(2—f1uoroethyl)-1,4-dihydrooxo quinolinecarboxylic acid, IE 970856 8-chioro(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro- 4-oxoquinolinecarboxylic acid Patent Application 235,762), (European 7-chlorofluoro-1,4-dihydro—1-methoxyoxoquino- linecarboxylic acid, 7-chlorofluoro-1,4-dihydromethy1aminooxo quinolinecarboxylic acid, 6,7-difluoro-1,4-dihydrooxo—1-pheny1-3—quino1ine- carboxylic acid, 7-chlorocyc1opropy1f1uoro-1,4-dihydrooxo—1,8- naphthyridine—3-carboxylic acid, 6,7-dich1orocyc1opropy1-1,4-dihydrooxo-1,8- naphthyridinecarboxylic acid, ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4—dihydrooxo—3- quinolinecarboxylate Patent 3,319,145), (German Application 9,10-dif1uoro—2,3-dihydromethyl~7—oxo-7H-pyrido[1,2,3- de][1,4]benzoxazinecarboxylic acid (European Patent Application 47,005), 8,9-diflnoro-6,7-dihydromethy1-1—oxo-1H,SH-benzo[i,j}- quinolizinecarboxylic acid, IE 970856 7-chlorofluorophenyl-1,4-dihydrooxo-1,8-naph- thyridinecarboxylic acid (European Patent Application 153,580), 7-chlorofluoro-1—(4-fluorophenyl)-1,4-dihydro-4—oxo— 1,B-naphthyridinecarboxylic acid (European Patent Application 153,580), 6,7,8-trifluoro-1,4-dihydro-1—methylaminooxo—3-quino- linecarboxylic acid (German Patent 3,409,922), Application 1-amino-6,7,8—triflnoro-1,4-dihydrooxoquino1ine— carboxylic acid (German Patent Application 3,409,922), 6,7,8—trif1uoro-1,4-dihydro-1—dimethy1amino—4-oxo—3- quinolinecarboxylic acid (German Patent Application 3,409,922), 7-chlorofluoro-1,4-dihydronitro-4—oxo—1-pheny1 quinolinecarboxylic acid, 7-chlorofluoro~l-(4-fluorophenyl)-1,4-dihydronitro- 4-oxoquinolinecarboxylic acid, 6,7-difluoro(4-fluorophenyl)-l,4—dihydro~B-methyl oxoquinolinecarboxylic acid, 6—chlorofluoro(4-fluorophenyl)-1,4-dihydrooxo- 3-quinolinecarboxylic acid (European Patent Application 131,839), ,6,7,8-tetrafluoro(2,4-difluorophenyl)-1,4-d1hydro- 4-oxoquinolinecarboxylic acid, S,7-dichlorofluoro(2,4-difluorophenyl)-1,4-dihydro- 4-oxoquinolinecarboxylic acid, ,7—dich1orocyclopropylfluoro-1,4-dihydrooxo quinolinecarboxylic acid, 6-chloro£luoro(2,4-difluorophenyl)-1,4-dihydro oxoquinolinecarboxylic acid (European Patent Applica- tion 131,839), 6,7,8-trifluoro(4-fluorophenyl)-1,4-dihydrooxo quinolinecarboxylic acid (European Patent Application 154,780), 6,7,B-trifluoro(2,4-difluorophenyl)-1,4—dihydrooxo- 3-quinolinecarboxylic acid (European Patent Application 154,790), 6,7,8-trifluoro—1,4-dihydrooxophenylquinoline- carboxylic acid (European Patent Application 154,780), 7-ch1oro-1—ethy1fluoro-1,4-dihydrooxo-1,B—naph— thyridinecarboxylic acid, 6,7-difluoro-1,4-dihydrooxevinylqnino1ine- IE 970856 carboxylic acid, 1-cyclopropl-5,6,7,3-tetrafluoro-1,4-dihydrooxo quinoinecarboxylic acid, -aminocyclopropy1~6,7,8-trifluoro-1,4-dihydrooxo- 3-quinolinecarboxylic acid, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydrohydroxy oxoquinolinecarboxylic acid, and 1-cyclopropyl-6,7—dif1uoro-1,4-dihydromethoxyoxo- 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) (German Offenlegungsschrift (German Published Specification) 1,929,237 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 (IIIa)-(IIIe) are prepared.

K E] . ,., .l"’ ‘x‘:L .____‘_/ R“ = x3 — C Ht; /R5 , . ‘\\R6 removal cf protective groups nrotcctiuu qrounr IE 970856 removal of HO,’ /R5 ‘ I \\R5 (IIIa) "- N \\R5 (IIIb) benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or sulphonyl (examples of protec- tive groups), a leaving group, arylsulphonyloxy - 22 _ such as halogen, or alkyl- or __ H0». 3 N R4x3 (1) T-0 N T--0 I Base IE 970856 ”Ir:; 3 N ———-.

R40”mI:ﬁ;T(NH2 R4O“T:—:](NH-COOC(CH3)3 N —————~ N IE 970856 4 §I:_:]4NH-R5 R‘oL.__:]4N//Rs P40>T:f-I4“//R N_ N H2IPd T/ ' L‘ , w L\nf\\ H I L J ..

;~\ \\, \.IIP.) H2/F1! R‘0\I:f:](NH-R6 | (X1Id) 2. Starting compounds of the formula (IIIf) are obtained from 2-(1,2-dichloroethyl)-oxirane via the following reaction sequence: __'| . \\ ,, \ .

IE 970856 / -RS R40 N P40 N .- \. \nt: [___ _]/ \R6 __\N’_,I '2 \“N'_, I, . ' -.,g m‘ H I . ‘J *1. ( I II I J 3. By addition of azidea onto N—henzylmaleimidea which are optionally substituted by one or two methyl or phenyl radicals, starting compounds of the formula (III g) can be prepared: N¢N\N-R9 M W O a4om,.,,,o_ Jrlﬁ-R9 R“o#m, H-R10 I reduction 'fx‘H I - e——» - N i’ ‘an ‘ YE L‘© R‘0ﬁ~Er:JtNH-R10 (IIIg) R” = H, alkyl or benzyl. 4. From the 3,4-epoxypyrrolidines (1), the starting compounds of the formula (III h) are obtained via cyclization with thionyl chloride: H0”T:_:]4NH2 H0~«[___,4uH.c0-9" f 1 J ""'—'—’ T ‘ ‘\N/J SOC ‘ . :2 :77 (111 h) . By reaction of the 3,4-epoxypyrrolidines (1) with ethanolamines, the starting compounds of the formula (III 1) are-obtained by intramolecular etherifica- tiona _ 25 _ IE 970856 I//A\v/OH //A\v/NH-R6 HO N HO r ——- H9 (1) [ } ____ r--\ »\ N-R6 0 N_Re \L‘u‘ {III i).

The starting compounds of the formula (III j) are obtained from aminoacetaldehyde dimethyl acetal via intramolecular 1,3-dipolar cycloaddition.

CH3 OCH3 I 3 HZN OCH3 ~—--* R9-NH,/“xaciocna H2c;“\v/X Base ’\ OCH3 6_ _ 9 ., .ocH3 Ho 9 ,/*\cHo R NH on R -N /CH2 --*-* R -N /CH2 \_.._< _ ¥: -27..

IE 970856 (III j) Starting from pyridine-2,3-dicarboxylic acid N- benzylimide, starting compounds (III k) or (III 1) are prepared via the reaction steps shown.

Blkyl Rmido J O H2/Ru-C or J Pd-C C) Q ’'’‘‘‘~ /u\ \ E F’ l,/'/ \* , -" .*’, o”’C”2‘C6“s I N-CH -C H 2 " 5 I « 1 H b 0 :2 O Alkyl LiA1H4 or l”2’P1°2 lNaBH4/ BF3'(C2H5)2O -23..

H 2 I Pd ’ C \'v‘ A\ \_ .' /'/‘\\ I. L ‘N-CH2-C6H5 ( » P“ Alkyl ' (111 1) H2/Pd-C I inn \_:r -' \ r ‘ Alkyl (III K) B. 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): .__( 6 E N-CH2-CGH5 + C1-CHZCHZ-NH-R c1 0 I ---( NaH (EH2 N-CH2-C6}-£5 CH2-? 0 I ° I R6 R6 (111111) 2-Methylpropenal-dimethylhydrazone reacts with N- benzylmaleimide to give a cycloadduct, which can be converted into the starting compound (IIIn) by the reaction sequence shown.

CH3 ,cH3 CH3‘ . H—:H3~?r < I I N—:H3«?H H4 \VN /‘\ / I I H N v H 0 / \ /’ \ CH3 CH3 CH3 CH3 0 :- . H U ' ( ) ‘~E ' \‘~\ I CH3.‘\ /“\~» /’/ “~-.

~— ' I I N-CH -Ph -?-' L /1 N-CH -Fh N, \ ',/ 2 catatyst W3 2 H H H LSAIH‘ CH3 H2/Pd-C CH3 ——————« H-CH3-Ph L\ NH (III 11) IE 970856 Starting compounds of the formulae (IIIo), (IIIp) or (IIIq) can be obtained in the following way, start- ing from N-protected 2,5—dihydropyrro1es (3-pyr- rolines) by addition of aulphenyl chlorides: IE 970856 1. ~R°-NH2 (R119: CHZCHZ-Hal) R5\ 2- Removal of’ R ‘ NH f"\ R°\ R6-N s 5-311 .1, _ <1 ‘I V T N” -' ,w’ H , ' R9 (1:12) /»’ 1 /’/',‘l’ r/.' R5\ L 11 R5\ 1_ F 5-? ‘ R6/NW5” Removal of R R6/ ‘\-j/ V “\N»‘ (R11 = Acyl, A1koxy- *xu« H carbonyl) H (IIIp) R” = Cy4h—a1kyl which is optionally substituted by halogen or pheny1, which is optiona11y substituted by ha1ogen, nitro, a1ky1 or alkoxy, as we11 as acyl or aTkoxycarb0ny1.

The following starting compounds, for example, can be prepared in accordance with these general equations. They IE 970856 can be prepared and employed as diastereomer mixtures or in the diastereomerically pure or enantiomerically pure form. 4—am1no-3—hydroxypyrro1idine, 3-hydroxymethylaminopyrrolidine, 4-dimethylaminohydroxypyrrolidine, 4-ethy1aminohydroxypyrrolidine, 3-aminomethoxypyrrolidine, 4-methoxymethylaminopyrrolidine, 3-dimethylaminomethoxypyrrolidine, 3-ethylaminomethoxypyrrolidine, 3-amino~4-ethoxypyrrolidine, 4-ethoxymethylaminopyrrolidine, 3-dimethylaminoe4-ethoxypyrrolidine, 4-ethoxyethylaminopyrrolidine, 3—hydroxyhydroxyaminopyrrolidine, 3-hydroxymethoxyaminopyrrolidine, 3-hydroxyaminomethoxypyrrolidine, 4-methoxymethoxyaminopyrrolidine, 3-benzylamiho-4—methoxypyrrolidine, 4-methoxy(5-methyloxo-1,3-d1oxo1yl)-methy1- amino)-pyrrolidine, 3-aminomethylmercaptopyrrolidine, 3-acetoxydimethylaminopyrrolidine, 3-acetamidomethoxypyrrolidine, 4-methoxy-3—methoxyqarbonylaminopyrrolidine, 3-formamidomethoxypyrrolidine, 3-aminomethoxymethylpyrrolidine, 3-aminomethoxymethylpyrrolidine, _ 33 _ IE 970856 4-methoxymethylmethylaminopyrrolidine, 4-methoxy-S-methylmethylaminopyrrolidine, 3-aminomethoxyphenylpyrrolidine, 4-methoxymethylaminophenylpyrrolidine, 3-methyl-2,7-diazab1cyc1o[3.3.0]octane, 4-methyl-2,7-diazabicyc1o[3.3.0]octane, -methyl-2,7-diazab1cyc1o[3.3.0}octane, 3,5-dimethyl-2,7-diazabicyclo[3.3.0]octane, 1,5-dimethyl-2,7-diazabicyc1o[3.3.0]octane, 2—oxa-4,7-diazabicyc1o[3.3.0]octane, 3,3—dimethy1oxa~4,7-diazabicyclo[3.3.0]octane, 3-oxa-2,7-diazab1cyc1o[3.3.0]octane, 1,2-dimethyloxa-2,7-diazabicyc1o[3.3.0]octane, 2,5-dimethyl-3—oxa-2,7-diazabicyc1o[3.3.0]octane, 2,8—dimethy1ox:-2,7-diazabicyc1o[3.3.0]octane, -methyl—3-oxa-2,7-d1azabicyc1o[3.3.0]octane; 2-oxa-4,7-diaznb1cyclo[3.3.0]octene, 3—methy1oxa-4,7-d1azabicyclo[3.3.0]octene, 3—phenyloxa-4,7-diazabicyc1o[3.3.0]octene, 6-methyloxa—4,7-diazabicyc1o[3.3.0]oct—3-ene, 8-methyl—2—oxa-4,7-diazabicyc1o[3.3.0]oct—3-ene, 3-methyl-2,8—diazabicyc1o[4.3.0]nonane, 4-methyl-2,8-diazabicyc1o[4.3.0]nonane, -methyl-2,8-diazab1cyc1o[4.3.0]nonane, 6-methy1—2,B—d1azab1cyc1o[4.3.0]nonane, 3—methy1oxa-5,8-d1azab1cyc1o[4.3.0]nonane, 4-methyloxa-5,8-diazabicyc1o[4.3.0]nonane, 1—methy1b2-oxa~5,8-d1azab1cyc1o[4.3.0]nonane, 3,S-dimethyl-2—oxa-5,8-diazabicyclo[4.3.0]nonane, 2-thin-5,8-d1azabicyc1o[4.3.0]nonane, -34..

IE 970856 -methylthia-5,8-diazabicyclo[4.3.0]nonane, 3,5—dimethy1thia—5,8—diazabicyc1o[4.3.0]nonane, 3-oxa—2,8-diazabicyc1o[4.3.0]nonane, 2-methyloxa-2,8-diazabicyclo[4.3.0jnonane, 4-methy1—3-oxa-2,8-diazabicyclo[4.3.0]nonane, 2,5-dimethyloxa-2,8-diazabicyclo[4.3.0]nonane, 3—oxa—5,8-diazabicyclo[4.3.0]nonane, —methy1oxa-5,8-diazabicyc1o[4.3.0]nonane, 1,5-dimethyl-3—oxa-5,8-diazabicyc1o[4.3.0]nonane and 4,4-dimethyl-3—oxa-5,8-diazabicyc1o[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- formamide, N-methylpyrrolidone, acid triamide, sulpholane, alcohol, such as methanol, ethanol, n-propanol or iso- propanol, glycol monomethyl ether or pyridine. Mixtures hexamethyl-phosphoric acetonitrile, water, an 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. Particu- larly suitable acid-binding agents which may be mentioned specifica11y'are: triethylamine, 1,4-diazabicyclo[2.2.2]- octane (DABCO), 1,8-diazabicyclo[5,4,0]undecene (DBU) or excess amine (III).

IE 970856 The reaction temperatures can be varied within a substan~ tial range. The reaction is in general carried out between about 20 and 200%, 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, 1 to 15 mol, preferably 1 to 6 mol, of the compound (III) are employed per mol of the carboxylic acid (II).

Free hydroxyl groups can be protected during the reaction by a suitable hydroxyl-protective group, for example by the tetrahydropyranyl radical, and can be liberated again when the reaction has ended (see J.F.W. Hcomie, Protec- tive 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 liberated again when the reaction has ended by treatment with a suitable acid, such as hydrochloric acid or trifluoroacetic acid (see Houben-weyl, Hethoden der organischen Chemie (Methods of Organic Chemistry), volume 34, page 144 (1983); and J.F.W. Mcomie, Protective Groups in Organic Chemistry (1973), page 43).

IE 970856 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- 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 cus- tomary inorganic and organic acid-binding agents. These include, preferably, the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particu- larly suitable acid-binding agents which may be mentioned specifically'are:‘triethylamine, 1,4—diazabicyclo[2.2.2]- octane (DABCO) or 1,8-diazabicyclo[5.4.0]undecene (Dam.

The reaction temperatures can be varied within a substan- tial 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 method B, 1 to 50 mol, preferably 1 to 30 mol, of the compound (V) are employed per mol of the compound (IV).

IE 970856 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 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 reac- tion formed can also be removed by azeotropic distilla- tion with chloroform, carbon tetrachloride, benzene or 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-1,3-dioxol-4—yl-methyl esters used as 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-chloromethylmethyl-1,3-dioxol one in a solvent, such as dimethylformamide, dimethy1- acetamide, N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea at temperatures of about 0° to 100%; 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 and precipitating the salt with a water—miscib1e organic solvent, such as methanol, ethanol, acetone or aceto- nitrile. It is also possible to heat equivalent amounts IE 970856 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. Pharmaceutically usable salts are to be understood as, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methane- sulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in excess alkali metal or alkaline earth metal hydroxide solution, filter- 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, 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 as the diastereomerically pure or enantiomerically pure compounds. _ 39 - IE 970856 m:uo-o ndmx IE 970856 :0 x 1.. -28 : ~:un:u, : .._ $5 : w. z .._u 1 ... 64+ -28 : .._\®| 50 x no ~22 .._ - : mzmu .6 : ... ..A\/®u : mxmu < ~x _x mm ~m _z acomumacmucouv F mass» IE 970856 mu m u -zmx1A%xT1= $9 2 mu : u «w. -2 «V : no u u Aw -2 Av : Q nxu mu m u -zmx@%&ﬁ%&%\ : ¢¢ zu : u -2 < Nx .x mm 444< : -~:o~:u-o: mm _m ¢_o.£~.::.Zco8..l3|._4_.1».

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IE 970856 a tab e ccord to e 'nven Each tablet contains: Compound of Example 1 583.0 mg Microcrystalline cellulose 55.0 mg Maize starch 72.0 mg Insoluble poly~(1-vinylpyrrolidone) 30.0 mg Highly disperse silica 5.0 mg Magnesium stearate 5,9 mg 750.0 mg The lacquer shell contains: Poly-(O-hydroxypropyl—0-methyl)- cellulose 15 cp 6.0 mg Macrogol 4000, recommended INN polyethylene glycols (DAB) 2.0 mg Titanium(IV) oxide 2.0 mg .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- ticular against Enterobacteriaceae; above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cepha1o- sulphonamides and tetra- sporins, aminoglycosides, cyclines. - 70 _ IE 970856 These useful properties enable them to be used as chemo- therapeutic active compounds in medicine and as sub- stances for preserving inorganic and organic materials, in particular all types of organic materials, for example polymers, lubricants, paints, fibres, leather, paper and wood, and foodstuffs and water.

The compounds according to the invention are active against a very broad spectrum of microorganisms. Gram- negative and Gram-positive bacteria and bacteria-like 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 according to the invention 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 patho- gens.

For example, local and/or systemic diseases caused by the 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 Strept. pyogenes); Gram-negative cocci (Neisseria gonor- rhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haemo- _ 71 - IE 970856 philus influenzae, Citrobacter (Citrob. freundii and Citrob. divernis), Salmonella and Shigella; and further- more Klebsiella (xlebs. pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans), 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 anaerobic bacteria, such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; and fur- thermore Hycoplasma (M. pneumoniae, M. hominis and M. urealyticum) and Mycobacteria, for example Hycobacterium 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 patho- gens or mixed infections mentioned and can be prevented, alleviated or cured by the compounds according to the invention are: infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, nephritis, cystitis, endocarditis, systemic infections, bronchitis (acute and chronic), diseases of the upper respiratory tract, diffuse panbron- chiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, pyelo— septic infections, _ 72 - IE 970856 cystic fibrosis, skin infections, postoperative wound infections, phlegmons, wound infections, infected burns, burn. wounds, infections in the oral region, infections following dental operations, osteomye- litis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsil- litis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections. abscesses, 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, salmonellosis, mastitis—metritis-agalactia syndrome and mastitis; Ruminants (cattle, sheep and goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, myco- plasmosis 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 birds and others): mycoplasmosis, E. coli infections, chronic respiratory tract infections, salmonellosis, pasteurellosis and psittacosis.

Bacterial diseases in the rearing and keeping of stock IE 970856 and ornamental fishes can also be treated, the antibac- terial spectrum extending beyond the abovementioned pathogens to further pathogens, such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Erysi- pelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.

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

The present invention also includes pharmaceutical formulations in dosage units. This means that the for- mulations 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 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 adminis- tered in one application and which usually corresponds to a whole, one half, one third or a quarter of a daily dose.

Non-toxic inert pharmaceutically suitable excipients are to be understood as solid, semi-solid or liquid diluents, IE 970856 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- 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 extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example gly- cerol, (d) disintegrating agents, for example agar—agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary amonium compounds, (g) wetting agents, for example cetyl alcohol and gly- cerol monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesium stearate and solid polyethyl- ene glycols, or mixtures of the substances listed under (a) to (1).

The tablets, coated tablets, capsules, pills and granules 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 - 75 _ IE 970856 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 water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C“-alcohol with C“-fatty acid) or mixtures of these substances.

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

Dusting powders and sprays can contain, in addition to the active compound or compounds, the customary excipi- ents, for example lactose, talc, silicic acid, aluminium hydroxide, calcium. silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain the customary propellants, for example chloro- IE 970856 fluorohydrocarbons.

Solutions and emulsions can contain, in addition to the active compound or compounds, the customary excipients, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, di- methylformamide, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and 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 emul- sions can also be in a sterile form which is isotonic 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 ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, alumin- ium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

The formulation forms mentioned can also contain colour- ing agents, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyp- IE 970856 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 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 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, parenterally (intra- 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 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 of animals, intake can also be in suitable formulations via the feed or drinking water. Gels, powders, dusting - 73 _ IE 970856 powders, tablets, delayed release tablets, premixes, concentrates, granules, pellets, boli, capsules, aero- sols, sprays and inhalants can furthermore be used on humans and animals. The compounds according to the 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 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- 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 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 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 IE 970856 compounds can easily be determined by any expert on the basis of his expert knowledge.

The new compounds can be administered in the customary concentrations and formulations together with the feed or 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 utiliza- tion can in this way be achieved.

The minimum inhibitory concentrations (MIC) were deter- mined by the series dilution method on Iso—Sensitest agar (Oxoid). 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 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 agar plates were incubated at 37°C and the germ growth was read off after about 20 hours. The MIC value (pg/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 according to the invention are shown in comparison with ciprofloxacin in the following table. - go - 0 N m~.o 3.5 36 .35 m~.o m.o mmio comm 7: m m~.o m-.o mm.c oo.o m~_.o - m~_.o _o_n~ w_~muoa. n3 mﬂuuououwacm mm m~_.o eo.o mo.o m-.o m_a.ow mo.o mm_.o o:.o mm. mm_.o oo.o no.0 m~_.o m_o.ow eo.o mm_.o a:.o om». mm_.o eo.o no.0 w~_.o m~o.ow oo.o m~_.a oo.o Nmv xx msmgsm msu :uouo_>£amgw Nmo~_ Mwggmagm co mm c v m.o N u _ -mmu:wu_>ogm Nma mmCﬂmLDE m.o m.o oo.o m_o.ow m~o.ow no.o mo.o m_o.ow m__u:mmgoz n_o_ magma _ m.o oo.o mo.o m~o.ow m_o.ow m~_.o m.:.ow -.:> wsoguhm mum» w__«n o. m N N m.o a c _ INLmE msmaoum CCGESWZ ~00 mm_.o m~.o mHo.ow m_o.ow m~o.ow m#o.ow m~o.ow m_o.ow mdzu_Lw;umw cwmguw «mow udaloxw nummm am V . uuwmcum omm .Loum.:uocm ucmoamugaﬁ xvacoou umwu :owa=._u Lama u;. »n uu:_s.ouuu ,.\m:v nu:.a> um: 81 - IE 970856 mm.o m~.o mm.o m_o.ow m_o.ow m_o.oV cmumxO—uoLumU mm.o mmA.o mm_.o mm_.o eo.o u m.o 0 m.o m.o m~_.o m.o m~_.o who m~_.o 0 mm m.o 00.0 m.o 00.0 m~_.o oo.o B. o, mo.o mo.o no.0 mo.o mo.o 00.0 m_o.ow Agmmw umwu_mcumuom_ comu:._u gums wnu xa vozmsgwuwt a_\mEu meson: uaz mm.o m~.o mm.o m~.o ;:.: ugoumgzuocm m~.o mm~.o oo.o $0.0 oo.o mm~.o mo.o co.o omma _o_nm m__mumm. msuuououmgcm emm_ mwv zu uawgam mau auouo_>:am4w ~mo~_ _ouLm=4m :w_U:mt_>OLm N09 _mcwmLoE m__w:mmuoZ hqou wmumm nH=> wawaoum HNND mm_mn smL_E mawaoum ccmﬁzwz «_ou mmcumuwzuum cwmgum «mu» ucwonwu.:E xudcvov umwu IE 970856 The following examples illustrate the invention: Preparation of the intermediate products: am le A tert.—Butyl N-(cismethoxy-pyrrolidinyl)—carbamate a) trans-1—Benz 1- -h dro metho rro1'dine 34.9 g (0.2 mol) of 3-benzyloxaazabicyclo[3.1.0}- hexane (U.S. Patent 4,254,135) are heated with 3.6 g (20 mol) of sodium methylate solution (30% strength) at 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.

The filtrate is concentrated and the residue is dis- tilled.

Yield: 40.9 g (91% of theory) Boiling point: 112-116°C/0.1 mbar Content: 92% pure b) cis-3—Aminobenzyl—4—metho§y-Qyrrolidine .6 g (25 mmol) of transbenzylhydroxymethoxy- pyrrolidine and 8.6 g (33 mol) of triphenylphosphine are initially introduced into 40 ml of absolute tetrahydro- IE 970856 furan and a solution of 6 g (34 moi) of diethyl azodi- carboxylate in 40 ml of absolute tetrahydrofuran is added dropwise at NT. 3.9 g (27 mol) of phthalimide are then added in small portions at VT in the course of one hour.

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- dicarboxylate) are filtered off. The filtrate is con- centrated 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 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 carbonate 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 .{-«H.-C N-(cis-1—benzyl-4—methoxypyrrolidin 3 g (l4.S mnol) of cisaminobenzy1methoxy-pyr- 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 IE 970856 inorganic salts 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/0.05 mbar d) tert.-Butyl N-(cismethoxypyrrolidinyl)- carbamate _ 3.5 g (11.4 mol) of tert.-butyl N-(cisbenzy1—4- methoxypyrrolidinyl)-carbamate are hydrogenated in 100 ml of methanol (n1 2 g of palladium-on-active charcoal (10% of Pd) at 100%: 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 Exam le B tert.-Butyl N-(transmethoxy-pyrro1idinyl)- carbamate a) ans- ~ oben - -metho - o d 27 g (0.41 mol) of sodium azide are dissolved in 50 ml of _ 35 _ IE 970856 water, and 17.5 g (0.1 mol) of 3—benzy1oxaazabi- cyclo[3.1.0]hexane in 300 ml of dioxane are added. The mixture is heated under reflux for 72 hours and con- centrated, 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) - 35 _ IE 970856 Boiling point: 91°C/0.07 mbar The product has a content of 75%, determined by gas chromatography (area method). b) ‘x-3;‘: .—i.'.u'.:',/2 N- r_*_2'<;.'!:4 1-—In‘;;'._'y'.-mu!iuruzc;/)1-{Irraliuiixt i— 8.2 g (30 mol) of transamino-l—benzylmethoxy— pyrrolidine and 21 ml of tart.-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- 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-(transmethoxypyrrolidinyl)- carhaate_ 6.7 g (22 mmol) of tert.—buty1 N-(transbenzyl-4— methoxypyrrolidinyl)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 IE 970856 and the residue is distilled.

Yield: 2.2 g (46% of theory) Boiling point: 94°C/0.05 mbar £rs2l2_§ transAminohydroxy—pyrro1idine a) 3- — obenz 1- - - rolidine 8.9 g (50 mol) of 3-benzyloxaazabicyclo[3.1.0]hex- 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 Melting point: B2—84°C b) gran;Aing-5—hyg;Q§y—py;rolidine .2 g (27 mmol) of transaminobenzy1hydroxy- pyrrolidine are hydrogenated in 40 ml of methanol on 1 g of palladium-on-active charcoal (10% of Pd) at 100%:under 100 bar. The catalyst is filtered off with auction, the filtrate is concentrated and the residue is distilled.

Yield: 1 g (36.3% of theory) IE 970856 Boiling point: 110°C/0.3 mbar ﬁgggple D trans-4—Hydroxy(2-hydroxyethylamino)-pyrrolidine a) transBenzy1~4-hydroxy(2-hydroxyethylamino)- pygrolidine 40 g (0.22 mol) of 3-benzyloxa-3—azabicyc1o[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 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) transHvgzggv(2-hv o eth lamino - rolid'ne trans—1—Benzylhydroxy(2-hydroxyethylamino)-pyr- rolidine is hydrogenated analogously to Example C b) to give the reaction product as an oil.

IE 970856 gxamgle E transHydroxy—3-(2-hydroxyethy1-methyl-amino)- pyrrolidine a) transBenzyl-4—hydroxy(2-hydroxyethyl-methyl- 9I_:1..rl.rr:a.<'a) -1_>.y.rr9.1..i::!.i.uv , 17.5 g (0.1 mol) of 3-benzy1oxa-3—azabicyc1o[3.1.0]- hexane are reacted with 17 g (0.1 mol) of methy1amino- 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) transHydroxy(2-hydroxyethyl-methyl-amino)- pyrrolidine transBenzy1hydroxy~3-(2-hydroxyethyl-methyl-amino)- pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oily compound.

Examgle F 2—0xa—5,8—diazabicyc1o[4.3.0]nonane dihydrochloride a) 8-Benzyloxa-5,8-diazabicyclo[4.3.0]nonane _ 90 - IE 970856 .6 g (66 mol) of 1-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 concentrated sodium hydroxide solution, the sodium sulphate which has precipitated is filtered. off with suction and the filtrate is extracted with chloroform.

The extract is dried over potassium carbonate and con- centrated and the residue is distilled.

Yield: 4.1 g (28.5% of theory) Boiling point: 122-128°C (0.08 mbar) b) 2- xa- -diazabic clo 4. .0 nonane d'h drochloride A solution of 4 g (18.2 mmol) of 8-benzy1oxa-5,8- diazabicyc1o[4.3.0]nonane in 100 ml of methanol and 3.5 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-on-active charcoal (10% of Pd) at 80%: 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 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 -91..

IE 970856 c) 2-Oxa-§,8-dia;abicygloL443-Olnonane 7.2 g (33 mol) of [4.3.0]nonane are hydrogenated in 400 ml of methanol with 8-benzyl-2—oxa-5,B-diazabicyclo— 2.5 g of palladium-on-active charcoal (10% of Pd) under 50 bar at 100°C. The catalyst is filtered off with suc- tion, the filtrate is concentrated and the residue is distilled.

Yield: 3.1 g (73.4% of theory) Boiling point: 58°C/9.1 mbar. d) transOxa-5,8-diazabicyclo/5.3.07nonane 3-benzyloxaazabicyclo[3.l.0]hexane is reacted with 2-(benzylamino)-ethanol, analogously to Example D a), to give trans-l-benzyl[N-benzyl~N-(2-hydroxy- ethyl)—amino]hydroxypyrrolidine which is then reac- ted analogously to Example F a) to give 5,8-dibenzyl— 2—oxa-5,87diazabicyclo[4.3.0]nonane which is purified by chromatography (silica gel, cyclohexane/tert.-butyl methyl ether/ethyl acetate l:l:l).

The hydrogenolytic debenzylation is carried out analo- gously to Example F c) to give trans—2-oxa-5,B-diaza- bicyclo[4.3.0]—nonane, boiling point: 60'C/0.1 mbar.

IE 970856 Exam le -Methyloxa-5,B-diazabicyclo[4.3.0]nonane dihydrochloride a) -Benz 1- — th 1oxa-S 8-diaz ‘c clo 4.3.0 nonane 18 g (71.9 mol) of 1-benzylhydroxy—3-(2-hydroxyethyl- methyl—amino)-pyrrolidine are reacted in 60 ml of con- centrated 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-Methyloxa-S,8-diazabicyclo[4.3.0]nonane dihvdrochloride A solution of 9.4 g (40 mmol) of 8-benzylmethy1oxa- ,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 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated. The residue is triturated with butanol/acetone 1:1 and the crystals are filtered off with suction and dried over P‘Om in a desiccator. The product is very hygroscopic.

Yield: 8.2 g (95% of theory) Mass spectrum: m/e 142 (M’), 112 (1-1’-CI-I20), 100 (M’—CHz- N=CHz), 32 (C.H.No*), 68 (c.H5N*) Exam le H 2-Methyloxa-2,7-diazabicyclo[3.3.0]octane a) Ethyl N-(2.2-dimethogyethyl1-carbamate 214 g (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde dimethyl acetal in IE 970856 1 1 of toluene and 90 g of Nabﬂ in 500 ml of water at °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 tol- uene. 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) Ethyl N-allvl-N-(2.2-dimethoxvethvll-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—ally1-N-(2,2-dimethoxyethyl)- carbamate are heated with 150 ml of formic acid at 100°C organic phases are washed with sodium bicarbonate solu- for one hour. The mixture is poured onto ice extracted several times with methylene chloride, tion, dried over magnesium sulphate and concentrated and the residue is distilled.

Yield: 46.7 g (87.2% of theory) IE 970856 Boiling point: 58°C/0.09 mbar d) Ethyl 2-methyloxa-2,7-diazabicyclo[3.3.0]octane—7- sarbozylgis g (0.12 mol) of methylhydroxylamine hydrochloride are 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 solution is added dropwise in the course of one hour to 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 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 chloro- form each time. The extract is dried over KZCO3 and concentrated and the residue is distilled.

Yield: 18.6 g (79.5% of theory) Melting point: 93°C/0.09 mbar e) 2-Methyloxa-2,7-diazabicyclo[3.3.0]octane 13 g (65 mmol) of ethyl 2-methyl-3—oxa-2,7-diazabicyclo- [3.3.0]octanecarhoxylate are heated under reflux in 300 ml of water with 41 g of Ba(0H)z.8I-I20 overnight. _ 95 _ IE 970856 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 and concentrated and the residue is distilled.

Yield: 5.4 g (65% of theory) Boiling point: 80°C/10 mbar Exam le 1-Methyl-octahydropyrrolo[3,4-b]pyrrole diazabicyclo[3.3.0]octane) (2-methyl-2,7- a) 1-Benzyl—3—(2—ch1oroethyl~methyl—amino)—pyrrolidine— 245-dione 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 1Q_, 489 (l975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methy1- 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 2 l 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 silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil.

IE 970856 1% value: 0.33 (silica gel, ethyl acetate/petroleum ether = 1:2) b) 5-Benzyl-4,6-dioxomethyl-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 1-benzyl(2—ch1oroethyl-methy1- amino)-pyrrolidine-2,5-dione are added dropwise as a solution in 50 ml of absolute dimethylformamide at room temperature. During this, an exothermic reaction takes place with foaming. The mixture is diluted with a further 50 ml of absolute dimethylformamide and subsequently stirred at room temperature for 1 hour and is then poured 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 acetate:petro- leum ether (1:2) and later (1:1). 16.4 g of educt are initially recovered here, and 17.2 g (44% of theory, based on the educt reacted) of an oily product are then isolated.

Rf value = 0.26 (silica gel, ethyl acetate:petro1eum ether = 1:1). - 97 _ IE 970856 c) -Ben me h 1-oc ah d o rro 4- role 1.52 g (40 mol) of lithium aluminium hydride are initially introduced into 30 ml of anhydrous tetrahydro- furan, and 4.9 g (20 mmol) of 5~benzyl-4,6-dioxo methyl-octahydropyrrolo[3,4-bjpyrrole 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 added dropwise in succession to the batch and the pre- cipitate 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 point 80°C/0.07 mbar are obtained. d) 1-Methyl-Qggghyggopyrrolo[3,4-b]pyr;g1g 6.49 g (30 mmol) of 5-benzylmethyl-octahydropyrrolo- [3,4-b]—pyrrole are dissolved in 100 ml of absolute ether, and 5.2 g of hydrogen chloride dried over phos- 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 (50 strength) at 80%: under 50 bar for 4 hours. The catalyst is subsequently filtered off, 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 IE 970856 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/ 12 mbar are obtained.

Purity: >99% Example J Octahydropyrrolo[3,4-b]pyrrole (2,?-diazabicyclo[3.3.0]- octane) a) l-Benzyl-§-[2-chloroethylamino)-pgrr0lidine—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 working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an R, value of 0.24 (on silica gel using ethyl acetate: petroleum ether = 1:1) are obtained. b) 5-Benzvldioxo—octahvdropvrrolo[3,4-blpvrrole 17.4 g (0.58 mol) of sodium hydride suspension are reacted with 119 g (0.45 mol) of 1-benzyl-3—(2-ch1oro- ethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute dimethylformamide in accordance with the working instruc- tions of Example Ib. After the mixture has been left to - 99 _ IE 970856 stand overnight, it is worked up under aqueous condi- tions. on purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetateamethanol (3:1) (R,value 0.55). 57.7 g of product (56% of theory) are isolated. c) -Benz 1-octah dro rolo 4- re e 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 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) cta o rolo 4-b role 21.0 g (0.104 mol) of 5-benzyl-octahydropyrrolo- [3,4-bjpyrrole are initially introduced into 180 ml of ice-cooled methanol, and 17.3 ml (0.208 mol) of concen- trated hydrochloric acid are added. The mixture is then hydrogenated with 2 g of Pd-on-C (5% strength) at 90%: under 100 bar for 4 hours. The catalyst is filtered off, 37.4 g (0.208 mol) of 30% strength sodiumm methylate solution are added to the filtrate, the mixture is filtered again and the filtrate is concentrated. The residue is distilled through a small Vigreux column. 5.6 g of a colourless oil (48% of theory) of boiling point 93-95°C/30 mbar, which fumes in air and slowly solidifies IE 970856 in the receiver (melting point 40°C) are obtained.

Eggmple 5 0ctahydropyrrolo[3,4—b]pyridine (2,B~diazabicyclo[4.3.0]— nonane) a) - enz -5 7-dio o-octah dro rrolo 3 4-b idine 47.6 g (0.2 mol) of pyridine—2,3-dicarboxylic acid N- benzylimide (British Patent 1,086,637; Chem. Abstr. gg, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90%: 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 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-Benzyl-octahydropyrrolo[3.4-b]py;idine 44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7- dioxo-octahydropyrro1o[3,4-b]pyridine are reduced with .2 g (0.40 mol) of lithium aluminium hydride in 390 ml of absolute tetrahydrofuran in the course of 10 hours in — 101 - IE 970856 accordance with the working instructions of Example Ic. 24.4 g of a colourless oil having a boiling point of 93- 95°C/0.06 mbar are obtained on distillation. c) Qctahgdropg;rolo[3.4-b]Q1;idige 69 g (0.32 mol) of 6—benzyl—octahydropyrrolo[3,4-b]pyri— dine 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 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 mbsr are obtained. ﬁxgmgle L 1-Methyl-octahydropyrrolo[3,4-b]pyridine (2-methyl—2,8- diazabicyclo[4.3.0]nonane) I; ;:-_~:.zyl- 190.5 g (0.8 mol) of pyridine~2,3-dicarboxylic acid N- 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 OWZ). After cooling, the solid is filtered. off with suction and IE 970856 washed with methylene chloride. 123 g of dark red crys- tals having a melting point of 162-165°C (decomposition) are obtained. b) 6-Benzy1~1-methyl-5,7-dioxo-octahydropyrrolo[3,4-b]- pyridine _ 38 g (0.1 mol) of 1-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 °C under 70 bar until the uptake of hydrogen has ended (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 sulphate, it is concentrated. 27 g of an oily residue remain. c) 6-Benzy;methyl—Qg§ahyg;opy;ro1o[3,4-b]pyridine 19.2 g (0.08 mol) of crude 6-benzylmethyl-5,7-dioxo- octahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g (0.16 mol) of lithium aluminium hydride in absolute tetrahydrofuran in accordance with the working instruc- tions of Example 1c.

Yield: 9.5 g (52% of theory), Boiling point: 93-96°C/0.1 mbar.

IE 970856 d) - h 1-octah o rro o -b ‘dine 11.7 g (54 mol) of 6-benzylmethyl-octahydropyrrolo- [3,4-b]pyridine as the dihydrochloride are hydrogenated in 100 ml of methanol over palladium-on-active charcoal 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 B3-85°/12 mbar). xam 1e transMethoxymethylamino-pyrrolidine dihydrochloride a) trans-l-Benzy1benzylmethylaminohydroxy- pygrglidine ~ 19.4 g (0.1 mol) of 90% strength 3-benzyloxa 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 R5C03 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) IE 970856 transBenzylbenzylmethylaminomethoxy- Qgrrolidine 17.3 g (58 mmol) of crude transbenzylbenzyl— methylaminohydroxy-pyrrolidine in 80 ml of abso- lute tetrahydrofuran are added dropwise to 2.8 g (93.3 mmol) of 30% 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 mol) 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 RQCO, and concentrated and the residue is distilled.

Yield: 9.7 g (52% of theory) Boiling point: 140—1SWC/0.1 mbar transMethoxymethylamino-pyrrolidine gihydrochloridgr 9.3 g (29 mmol) of transbenzylbenzylmethy1- 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%: 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) Exam IE 970856 Melting point: 157-162°C 2,5-Dimethyl-3—oxa-2,7-diazabicyc1o[3.3.0]octane N-(2-Methy1prop—2—enyl)-N-(2,2-dimethoxyethy1)— ureghane _ 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 54 g (0.6 mol) of and the The sodium no further hydrogen is formed, methallyl chloride are added dropwise mixture is stirred overnight at 90%L chloride which has precipitated out is dissolved with a little water, the organic phase is separated off, dried over xgco, and concentrated and the residue is distilled.

Yield: 71.3 g (61.7% of theory) Boiling point: 60°C/0.08 mbar N- 2—Meth 1 ro -2—en -N- -oxoeth -urethane 11.5 g (50 mol) of N-(2-methylpropenyl)-N-(2,2- dimethoxyethy1)—urethane and ]”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 — 106 - IE 970856 distilled.

Yield: 5.3 g (61.2% of theory) Boiling point: 73°C/0.1 mbar Ethyl 2,5-dimethyloxa-2,7-diazabicyclo[3.3.0]— Qctanecarboxvlate 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—propenyl)—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 hydro- chloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions of 200 ml of CHC13. The extracts are dried over Kgxr and concentrated and the residue is distilled.

Yield: 13 g (55% of theory) Boiling point: 88-95°C/0.08 mbar 2 5-Dimeth 1- -oxa-2 7-diazabic clo . . octane 13 g (60.6 mmol) of ethyl 2,S-dimethyloxa-2,7- diazabicyclo[3.3.0]octane-7—carboxylate are heated under reflux with 33 g of Ba(0H)2.8Hg3 in 330 ml of IE 970856 water overnight. The BaC03 is filtered off with suction, xzco, is added to the filtrate; the solid is filtered off with suction again and the filtrate is extracted ten times with 100 ml of CHCI3 each time.

The extracts are dried over K200, and concentrated and the residue is distilled.

Yield: 5.9 g (63.7% of theory) Boiling point: 64°C/5 mbar Ex_an;p.le_Q 2,8-Dimethyloxa-2,7-diazabicyclo[3.3.0]octane - 1 1-D etho — rethane 80 g (0.73 mol) of ethyl ohloroformate are added dropwise to 86.2 g (0.72 mol) of 2-aminopropion- 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 toluene solutions are dried over xgxr. The solution is concentrated and the residue is distilled.

Yield: 132 g (95% of theory) Boiling point: 55°C/0.06 mbar IE 970856 - 1- - 1- et r - - -ur ane 131 g (0.686 mol) of N-(1,1-dimethoxypropyl)- 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 KZCO, and concentrated and the residue is distilled.

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

Content: 64.5% pure (determined by gas chromato- graphy) - l-N- -o o 1 - t ane 76.5 g (0.213 mol) of 64.5% pure N-a1ly1-N-(1,1- dimethoxypropyl)-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 cH,C1,, the extracts are washed neutral with Nal-ICO, solution, dried over ngso. 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 chromato- 91'5PhY) IE 970856 Ethyl 2,8-dimethyl-3—oxa-2,7-diazabicyclo[3.3.0]- 0 nec ate A methanolic methylhydroxylamine solution is pre- pared from 16.4 g (0.2 mol) of N-methylhydroxylamine hydrochloride in 33 ml of absolute methanol and 36 g (0.2 mol) of 30% strength sodium methyiate solution, and the solution formed is diluted with 130 ml of toluene and added dropwise to 354 g (0.17 mol) of N-allyl-N-(1-oxoprop-2—yl)-urethane in 250 ml of toluene, which is heated under reflux using a water separator. The mixture is heated under reflux overnight, the product is extracted. with dilute hydrochloric acid and the hydrochloric acid solution is rendered alkaline with K,CO3 and extracted with CI-ICl,. The extract is dried over KZCO3 and concentrated and the residue is distilled.

Yield: 18.5 g (50.8% of theory) Boiling point: 95-105°C/0.1 mbar 2 8—Dimeth - -o a-2 7- azabic clo . .0 octane 9.2 g (42.9 mmol) of ethyl 2,8-dimethyloxa—2,7- diazabicyclo[3.3.0]octanecarboxylate are heated under reflux with 23.5 g of Ba(OH)2.8HgD in 235 ml of water’ overnight. The BaC03 is filtered off with suction, Kgxx is added to the filtrate and the solid is filtered off with suction again. The filtrate is extracted ten times with 50 ml of CHCl, each time, the extracts are dried over KZCO, and concentrated IE 970856 and the residue is distilled.

Yield: 1.7 g Boiling point: B7-92°C/10 mbar The product is a mixture of the possible stereo- isomers in a ratio of 3:1 (‘H-NMR). 4 g of starting material could to be recovered in the after-runnings.

Hmpﬁi 2-Methyloxa—2,8-diazabicyclo[4.3.0]nonane 7 4 .V|I jj.

Ethyl 4-hydroxymethylmethylaminopyrrolidine carboxvlate g (50 mol) of ethyl 2-methyloxa-2,7-diazabi- cyclo[3.3.0]octane-7—carboxylate (Example H d)) are hydrogenated in 200 ml of ethanol on 3 g of Pd-on- active charcoal (10% of Pd) at 50%: 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-IANT/0.1 mbar Ethyl 2-methyloxa-2,8-diazabicyclo[4.3.0]nonane- ,c,_,,c as _, .1 g (50 mmol) of ethyl 4-hydroxymethylmethy1- amino—pyrrolidinecarboxylate and 8 g (0.1 mol) of IE 970856 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 -Met -o - - c o 4. ane 9 g (42 mmol) of ethyl 2-methyloxa-2,8-diaza— bicyclo[4.3.0]nonanecarboxylate are heated under reflux with 28 g of Ba(OH),.8l-I20 in 280 ml of water overnight. The saco, is filtered off with auction, 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/3 mbar 4-ﬂ1dro;ygethylgethylaygigopyzrolidige 34 g (0.168 mol) of ethyl 4-hydroxymethyl—3-methy1- aminopyrrolidinecarboxylate are heated under reflux with 100 g of Ba(OH)2.8Hzo in 400 ml of water overnight. The BaCO, 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 filtered, the filtrate is concentrated and the residue is dis- tilled. solutions are Exam IE 970856 Yield: 13 g (60.3% of theory) Boiling point: 85-88°C/0.08 mbar - t l—4-oxa- -d abic clo 4. . e 8.1 g (0.1 mol) of 37% strength formaldehyde solu- tion in 20 ml of n-butanol are added dropwise to 13 g (0.101 mol) of 4-hydroxymethylmethylamino- pyrrolidine in 100 ml of n-butanol at room tempera- ture. The mixture is stirred at room temperature overnight and concentrated and the residue is distilled.

Yield: 8.7 g (61.2% of theory) Boiling point: 84°C/6 mbar 3-Oxa-2,7-diazabicyc1o[3.3.0]octane "40- Ethyl cyclo[3.3,p1octanecarbogylgte 2-(tetrahydropyranyl)oxa-2,7-diazabi— 18.1 g (0.106 mol) of ethyl N~allyl-N-(2-oxoethyl)- carbamate (Example H c)) are heated under reflux in 220 ml of toluene, and 14.2 g (0.12 mol) of 5- hydroxypentanal oxime (Acts Chim. Acad. Sci. Hung., lg, 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 IE 970856 distilled.

Yield: 15.5 g (54% of theory) Boiling point: 160°C/0.01 mbar Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane carboxylate g (55.5 mmol) of ethyl 2-(tetrahydropyranyl)- 3-oxa~2,7-diazabicyclo[3.3.0]octanecarboxylate are heated under reflux with 8.25 g (56 mol) of 70% strength perchloric acid in 100 ml of ethanol for 30 minutes. 10.5 g (58 mmol) of 30 strength sodium methylate solution are added, the mixture is con- centrated, the residue is taken up in water and the solution is saturated with K300, and extracted with CHCl,. The extract is dried over xzco, and concentra- ted and the residue is distilled.

Yield: 7.6 g (73.5% of theory) Boiling point: 125-130°C/0.1 mbar Eth 1 3-oxa-2 7-d'az c clo . . octan -7—carbo — leis 8.5 g (50 mmol) of ethyl N-(2-oxoethy1)-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.

Yields 6.8 g (73% of theory) Boiling point: 120-122°C/0.05 mbar IE 970856 d) - a- 7-diazabic c . ta e This substance is obtained analogously to Example N d) by hydrolysis of ethyl 3-oxa-2,7-diazabicyclo— [3.3.0]octanecarboxylate with Ba(OH)2.8Hg3.

Boiling point: 75°C/10 mbar.

Exgggle R 3-Methyl-2,7-diazabicyclo[3.3.0]octane 3-Methyl-2,7-diazabicyclo[3.3.0]octane is obtained analogously to Example 1.

Boiling point: 68-70°C/6 mbar. xam 1e 2,3—Dimethyl-2,7-diazabicyclo[3.3.0]octane 2,3-Dimethyl-2,7—diazabicyc1o[3.3.0]octane is obtained analogously to Example 1.

Boiling point: 72-74°C/10 mbar. ggggple T 1,2-Dimethyloxa-2,7-diazabicyc1o[3.3.0]octane — 115 - l_!I IE 970856 N-Ally;-Q-(3,g-dimethggyproggl)-aceggmide 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 absolute toluene at 80%L The mixture is then stirred for one hour and 100 g (0.83 mol) of allyl bromide are subsequently added dropwise at BOYL The mixture is stirred overnight at 80°C and cooled and the salts are dissolved with water. The aqueous phase is separated off and extracted twice with 100 ml of toluene each time. The toluene solutions are dried over KZCO3 and concentrated and the residue is distilled.

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

N-A1111-N-(2-oxogroggl)-acetamide 85.5 g (0.425 mol) of N-al1yl-N-(2,2-dimethoxy- propyl)-acetamide are heated under reflux with 212 ml of formic acid for one hour. The mixture is 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.

IE 970856 7-Acety1- 1 , 2-dimethyloxa-2 , 7-diazabicyclo [ 3 . 3 . 0 3- 9911599, .5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acet- amide 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 xzco, is added. The mixture is extracted with CHCl,, the extract is dried over KZCO3 and concentrated and the residue is distilled.

Yield: 15.9 g (86.3% of theory) Boiling point: 75°C/0.1 mbar. - - -oxa-2 7-d . a 11.8 g (64 mmol) of '7-acetyl-1,2-dimethyl—3—oxa-2,7- diazabicyclo[3.3.0]octane are heated under reflux with 12 g of Naol-I in 36 ml of water overnight. The mixture is saturated with xzco, and extracted several times with CI-{C13, the extract is dried over x,co, and concentrated and the residue is distilled.

Yield: 4.7 g (51.6% of theory) Boiling point: 40°C/0.2 mbar.

IE 970856 E2:2m2J..e_Q 2,4-Dimethyloxa-2,7-diazabicyclo[3.3.0]octane Ethyl bamate N-(butenyl)~N-(2,2-dimethoxyethy1)—car— 89 g (0.5 mol) of ethyl N—(2,2-dimethoxyethy1)- carhamate are added dropwise to 17.5 g (0.58 mol) of Nan (80% strength in paraffin oil) in 500 ml of absolute toluene at 80°C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromobutene are subsequently added dropwise at B0%L The mixture is stirred at 30%: overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over KZCO3 and concentra- ted and the residue is distilled.

Yield: 90 g (77.8% of theory) Boiling point: 65°C/0.1 mbar. gthvl N-(butenvl1-N-I2-oxoethglj-cagggmggg 90 g (0.39 mol) of ethyl N-(but—2-eny1)-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 with sodium bicarbonate solution, dried over mag- IE 970856 nesium sulphate and concentrated and the residue is distilled.

Yield: 33.6 g (46.5% of theory) Boiling point: 65°C/0.1 mbar.

Ethyl 2,4-dimethyloxa-2,7-diazabicyc1o[3.3.0]- 9cLen¢~2r9a§§yxxinre 1 , 18.4 g (0.1 mol) of ethyl N-(butenyl)-N-(2-oxo- ethyl)-carbamate 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 race, is added. The mixture is extracted with CI-ICl,, the extract is dried over Kzco, and concentrated and the residue is distilled.

Yield: 15.0 g (70% of theory) Boiling point: '74-87°C/0.1 mbar. 13.2 g (61.6 mmol) of ethyl 2,4-dimethyloxa-2,’h diazabicyc1o[ 3 . 3 . 0 Joctanecarboxylate are heated under reflux with 39 g of Ba(0H)z . 81120 in 200 ml of water overnight. xzco, is added, the saco, is fil- tered off with suction and the filtrate is extracted several times with CHCl,. The extract is dried over IE 970856 BQCO3 and concentrated and the residue is distilled.

Yield: 4.8 g (54.8? of theory) Boiling point: 74°C/8 mbar.

Exggple V Ethyl 2,7—diazabicyc1o[3.3.0]octanecarboxylate 7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is reacted with ethyl chloroformate analogously to Example 0a) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane- 2-carboxylate, and this is then debenzylated hydrogeno- lytically analogously to Example Jd). A.oo1our1ees oil of boiling point 90°C/0.1 mbar is obtained.

Example W 2-Pheny1—2,7-diazabicyclo[3.3.0]octane The preparation is carried out analogously to Example I); Boiling point: 103°C/0.08 mbar.

IE 970856 ma=.n.2J.§_X 4-Oxa-2,8-diazabicyclo[4.3.0]nonane Ethyl 3-amino—4-hydroxymethyl-pyrrolidine carbogylate Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octanecar- boxylate (Example Qc) is hydrogenated analogously to Example Pa).

Boiling point: l63—168°C/0.8 mbar 3—Aminohydrogyggghyl-pygrolidgge Ethyl 3-aminohydroxymethyl-pyrrolidinecar- boxylate is hydrolyzed analogously to Example Pd).

Boiling point: 78°C/0.06 mbar. 4- xa-2 —di zabic . . ne 3-Aminohydroxymethyl-pyrrolidine is reacted with formaldehyde solution analogously to Example Pa).

Boiling point: 50-60°C/0.07 mbar IE 970856 1.’.sm2l9_Z transEthylaminomethylthio-pyrrolidine 1-Benzoyl-transethylamino—4-methylthio- 91n:ro_1 tgne 8.65 g (50 mmol) of 1-benzoyl-2,5-dihydropyrrole [Chem. Ber. gg, 2521 (1889)] are initially intro- duced into 30 ml of methylene chloride, and 4.94 g (60 mol) of methanesulphonyl chloride in 20 ml of methylene chloride are added dropwise at OWE. The mixture is subsequently stirred at 20-25%: 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 solu- tion are then added. The batch is boiled for 18 hours, while cooling under reflux, poured into water and extracted with methylene chloride. On concen- trating, 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). thic- 6.0 g (22 mmol) of 1-benzoyl-transethylamino methylthio-pyrrolidine are stirred vigorously with 22 ml of SN Naoﬁ at 100%: for 24 hours, until the IE 970856 conversion is The mixture is then extracted with 3 x 80 ml of ether and the extract is dried over sodium sulphate and concentrated on a homogeneous. 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 Exam le Z trans-3—amino-4—methylthio-pvrrolidine 1—Benzoyl-2,5-dihydropyrrole is reacted with methylsu1fe- nyl chloride analogously to Example Y to give 1-benzyl—3— chloromethylthiopyrrolidine which is reacted as a crude product with ammonia to give 3-amino-l-benzoyl—4-methyl- thio-pyrrolidine and the benzoyl radical is removed with sodium hydroxide solution.

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

Example ZA 4—Methyl-2,B-diazabicyclojé.3.0jnonane a) 5-Methyl-l,4-dihydropyridine-2,3-dicarboxylic acid N-benzvlimido 33 g (0.29 mol) zone and 55 g of 2-methylpropenal-dimethylhydra~ (0.29 mol) stirred in 225 ml of acetonitrile for 3 hours at 60°C. of N-benzylmaleinimide are IE 970856 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 boiled for 1 hour under reflux. silica gel, the mixture is Then the mixture is filtered while hot and the silica boiled out with ethanol. The combined organic phases are concentrated in a rotary gel is several times evaporator. 17.5 g (24 % of theory) point of 184-186'C are obtained. of red crystals of a melting -MethylLhexahydropyridine-2,3-dioarboxylic acid N-benzylimide 17.5 g (70 mmol) of 5—methyl-1,4-dihydropyridine-2,3- dicarboxylic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70°C and under 100 bar Then the catalyst is filtered off and the filtrate is over palladium on active charcoal. concentrated by (13.0 g) is used evaporation. The solid oily residue as a crude product in the next stage. 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) absolute of lithium aluminium hydride in 100 ml of 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 hydrox- ide solution and 13.8 g of water are added dropwise The salts are filtered off, the one after the other. filtrate is concentrated by and residue is distilled. evaporation IE 970856 Yield: 8.7 g (54 %, based on 5-methyl-1,4-dihydropyri- dine-2,3-dicarboxylic acid N-benzylimide); boiling point: 95-98'C/0.1 mbar. 4-Methyl-2,8-diazabicvQlo[4.3.0]nonane 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 cata- lyst is filtered off, evaporation and the residue is distilled. the filtrate is concentrated by Yield: 3.3 g (67 % of theory) boiling point: 88-B9’C/llmbar.

The 1H-NMR spectrum shows the compound to be a mixture of two stereoisomers in a ratio of 7:2.

Example AA ,6,7,8-Tetrafluoro(2,4—difluorophenyl)-1,4-dihydro- 4-oxoquinolinecarboxylic acid Ethyl 2-(2,3,4,5,6—pentafluorobenzoyl)(2,4- difluorophenglamino]-acrvlate 44.3 g of 2,4—difluoroani1ine are added dropwise to a solution of 115 g of ethyl 3-ethoxy(2,3,4,5,6- pentafluorobenzoyl)-acrylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is 380 ml of and the washed stirred at room temperature for 1 hour, water are added, while cooling with ice, precipitate is filtered off with suction, with ethanol/Hg) (1:1) 135.4 g of the title compound of melting point 97-99°C are obtained. and dried.

IE 970856 b) Ethyl 5,6,7,8-tetrafluoro(2,4—difluorophenyl)- 1.4-dihgdro-4—oxo-§—guinolinecarboxylate A mixture of 135.4 g of ethyl 2-(2,3,4,5,6— pentafluorobenzoyl)(2,4-dif1uoropheny1amino)- acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide is heated at 140-150%: 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-Tetraf1uoro—l-(2,4-difluoropheny1)-1,4- dihgdrooxo-§-gginolinecarboxvlic acid 40.1.g of ethyl 5,6,7,8-tetrafluoro(2,4-difluoro- go phenyl)-1,4-dihydrooxo—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 suc- tion, washed with water and dried. 34.5 g of the title compound of melting point 250-252°C are obtained.

Example AB ,7—Dichlorocyclopropylfluoro-1,4-dihydro—4-oxo gyinolinecarboxyllc acid a) h 2 4-d'ch1oro- -d uorobenzovl)-acetate — 126 - 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-difluoro- benzoyl chloride in 30 ml of toluene is slowly added dropwise at this temperature. The mixture is stirred at O%2for 1 hour and allowed to come to room temper- ature 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 Nazso. 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 CH2C1z solutions are washed once with saturated sodium chloride solution and IE 970856 dried with Na3S0,, 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, n35: 1,5241.

Ethyl 2- ( 2 , 4-dichloro-3 , 6-difluorobenzoyl ) ethoxy- '~. <3 1'"/1 e: 1: «:4 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—d.i.fluorobenzoy1) ethoxy-acrylate are obtained as an oil, nD Ethyl 2- ( 2 , 4-dichloro-3 , 6-difluorobenzoyl ) cyclo- nronvlamino-acrvl ate .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 cyclopropylamine 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-difluorobenzoyl ) cyc lopropylamino-acrylate of melting point 106-107°C are obtained. -128~ 1,5302.

IE 970856 Ethyl 5,7-dichloro—1-cyclopropylfluoro-1,4- dro- -oxo- - 1 ho ate 6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)- 3-cyclopropylamino-acrylate are heated in 100 ml of dimethylformamide 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. .2 g of ethyl 5,7-dich1oro-l-cyclopropyl-6—f1uoro- 1,4-dihydrooxoquinolinecarboxylate of melting point 227-229°C are obtained.

S,7-Dichlorocyclopropy1fluoro-1,4-dihydro oxogginoigeggggogglic acid .2 g of ethyl 5,7-dichlorocyclopropylf1uoro- 1,4-dihydrooxoquinolinecarboxylate are heated under reflux in a mixture of 38 ml of acetic acid, 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-dichlorocyclopropyb6-f1uoro- 1,4-dihydrooxoquinolinecarboxylic acid of melting point 277-278°C are obtained.

IE 970856 ,7—Dichlorofluoro(2,4-difluorophenyl)-1,4-dihydro- 4-oxoquinolinecarboxylic acid Ethyl 2-(2.4-dichloro-3,6—difluorobenzoy1)(2,4- §!i...f1.uoeropheny.1ame.ino) -acrxlaﬁ __e .3 g of ethyl 2-(2,4-dichloro-3,6-dif1uoro- benzoyl)ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added 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/- I50 (1:1) and dried. 40.5 g of ethyl 2-(2,4—dichloro- 3,6-difluorobenzoyl)(2,4-difluorophenylamino)- acrylate are obtained, melting point: 84-86°C.

Ethyl 5,7-dichlorofluoro(2,4-difluorophenyl)- 1 4- ' oox - - no ineca b te 43.6 g of ethyl 2-(2,4-dichloro-3,6-difluoro- benzoyl)(2,4-difluorophenylamino)-acrylate are heated in 260 ml of dimethylformamide at 150°C with .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 with water and dried. 38.6 g of ethyl 5,7-dichloro- IE 970856 6-fluoro(2,4-difluorophenyl)-1,4-dihydro-4—oxo— 3-quinolinecarboxylate are obtained. c) 5,7-Dichlorofluoro(2,4-difluoropheny1)-1,4- di - -ox - - o1‘ e o lic acid 41.6 g of ethyl 5,7-dich1orofluoro(2,4—di- fluorophenyl)-1,4-dihydro-4—oxoquinolinecar- boxylate are heated under reflux with 250 ml of acetic acid, 200 ml of water and 28.5 ml of con- centrated sulphuric acid for 3 hours. After cooling, 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 fluoro(2,4-difluorophenyl)-1,4-dihydrooxo—3- quinolinecarboxylic acid are obtained, me1ting point: 244-246°C.

E.2¢A-El1P.l§._.l.

A. 855 mg (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro- 1,4-dihydrooxoquinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide in the presence of 330 mg (3.3 mmol) of 1,4-diazabicyclo[2.2.2]octane and 750 mg' of IE 970856 transtert.-butoxycarbonyl-aminomethoxy-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-(transtert.- butoxycarbony1amino—4-methoxypyrrolidinyl)—1—cyc1o- propyl-6,8-difluoro-1,4-dihydrooxoquinoline- 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 a high vacuum.

Yield: 0.73 g (70% of theory) of 7-(transamino-4— methoxy—l—pyrrolidinyl)-l-cyclopropyl—6,8—difluorooxo- 3-quinolinecarboxylic acid hydrochloride.

Melting point: 279°C (with decomposition). -132’- IE 970856 1-Cyclopropyl-6,7-dif1uoro—l,4-dihydrooxo-3—quino1ine- carboxylic acid is reacted analogously to Example 1 to give: A. 7-(transtert.-Butoxycarbonylaminomethoxy—l- pyrrolidinyl)cyclopropylfluoro-1,4-dihydrooxo- 3-quinolinecarboxylic acid, melting point: 247-249°C (with decomposition).

B. 7-(transAminomethoxypyrrolidinyl)cyclo- propylfluorooxo-3—quinolinecarboxylic acid hydro- chloride, melting point: from 293°C (with decomposition).

Exam le ‘-£;.r—."-5 " x HC1 47:‘ I ' /' A reaction is carried out analogously to Example 1 with IE 970856 cis—3—tert.-butoxycarbonylaminomethoxy-pyrrolidine‘to give: A. 7-(cis—3-tert.-Butoxycarbonylaminomethoxy pyrrolidinyl)cyclopropyl-6,8-difluoro-1,4-dihydro—4- oxo-3—quinolinecarboxy1ic acid, melting point: 230-231°C (with decomposition).

B. 7-(cisAmino-4—methoxypyrrolidinyl)cyc1o- propyl-6,8-difluoro—4-oxoquinolinecarboxylic acid hydrochloride, melting point 201-203°C (with decomposi- tion).

Exam le 4 E-‘\4’\\//l\«’CO0H /it-\\_k;J H2513‘/Ax}; x CF'3COOl-I '1 I : c1-:3-3. ’*'*' e’ A. 1.5 g (5 mmol) of 8-chlorocyclopropyl-6,7-di- fluoro-1,4—dihydro-4—oxo-3—quinolinecarboxylic acid are heated under reflux in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide with 550 mg (5 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.2 g (5.6 mmol) of cia-3—tert.-butoxycarbonylaminomethoxy-pyrrolidine for 2 hours. The mixture is allowed to cool and the precipit- ate which has separated out is filtered off with suction, rinsed thoroughly with water and dried at 100°C in vacuo.

IE 970856 Yield: 2.0 g (80.7%) of 7-(cistert.-butoxycarbonyl- amino—4-methoxypyrrolidinyl)ch1oro—1-cyclopropyl- 6-fluoro’-1,4-dihydrooxoquinolinecarboxylic 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 trifluoroacetic acid at room tempera— ture 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 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-(cisaminomethoxy- 1-pyrrolidinyl)-B-chlorocyclopropyl-6—£luoro-1,4- dihydro—4-oxoquinolinecarboxylic acid trif1uoro- acetate, melting point: 235-239°C (with decomposition). xam 1e h.Hm_-"$4 V J X551 cis—3-tert.-Butoxycarbonylaminomethoxy-pyrrolidine is reacted with 1-cyclopropyl-6,7-difluoro-1,4-dihydro oxoquinolinecarboxylic acid analogously to Example 1 to give: - 135 — IE 970856 A. 7-(cistart.-Butoxycarbonylamino—4-methoxy pyrrolidinyl)cyclopropyl-6—f1uoro-1,4-dihydrooxo- 3-quinoiinecarboxylic acid, melting point 232-233°C (with decomposition).

B. 7-(cisAminomethoxypyrrolidinyl)cyc1o- propylfluoro-1,4-dihydrooxo-3—quinolinecarboxylic acid hydrochloride, melting point 252-256°C (with decom- position) (sintering beforehand).

Es.4zmp.le_6.

H>N\~/”\N xHCl - _ _ . " -2 _\_. cistert.-Butoxycarbonylaminomethoxypyrrolidine is reactedwith7-chlorocyclopropylfluoro-1,4—dihydro- 4-oxo-1,8-naphthyridinecarboxylic acid analogously to Example 1 to give: A. 7-(cis-tert.-Butoxycarbonylaminomethoxy pyrrolidinyl)cyc1opropy1—6-fluoro-1,4-dihydrooxo- 1,8-naphthyridinecarboxylic acid, melting point 214- 216°C (with decomposition).

B. 7-(ciaAmino-4—methoxypyrrolidinyl)cyclopro- pylfluoro-1,4-dihydrooxo-1,8-naphthyridine IE 970856 carboxylic acid hydrochloride, melting point 205-210° (with decomposition).

Mass spectrum: m/e 362 (1-1*), 330 (M*-32), 318 (M“-C02), 286, 250, 41 (c3H,), 35 (ncl).

Exam le 7 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 0.55 g (5.4 mmol) of transaminohydroxy-pyrrolidine are added to 1.33 g (5 mmol) of l-cyclopropyl-6,7—di- fluoro-1,4-dihydrooxoquinolinecarboxylic 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-(transamino hydroxy—1-pyrrolidinyl}cyclopropylfluoro-1,4- dihydrooxoquinolinecarboxylic acid, Melting point: 274-278°C (with decomposition).

IE 970856 850 mg’ (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4- dihydrooxoquinolinecarboxylic acid.are heated under reflux in 9 ml of pyridine with 630 mg (3.1 mol) of 2- oxa—S,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 suction, washed with water, dried and recrystallized from glycol monomethyl ether.

Yield: 840 mg (72% of theory) of 1-cyc1opropyl—6,8- difluoro-1,4-dihydro(2-oxa-5,8-diazabicyclo[4.3.0]non- B-yl)oxoquinolinecarboxylic acid, Melting point: 289-291°C (with decomposition); Mass spectrum: m/e 391 (M+), 347 (If-CO2), 331, 306, 294, 262, 234, 98, 41 (CJQ).

IE 970856 The reaction is carried out analogously to Example 8 with -methyloxa-5,8-dia2nbicyclo[4.3.0}nonane dihydro— chlorideeto give: 1-cyclopropyl-6,8-difluoro-1,4-dihydro- 7-(5-methyloxa—5,8-diazabicyc1o[4.3.0]nonyl)oxa- 3-quinolinecarboxylic acid, melting point: from 270°C (with decomposition); Mass spectrum: m/e 405 (M"), 361 (If-C02), 331, 112, (100%).

Exggple 10 N\cr-13 795 mg (3 mmol) of 1-cyclopropyl-6,7-dif1uoro-1,4-di- hydrooxoquinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide with 890 mg (4.1 mmol) of 5-methy1 oxa-5,3-diazabicyc1o[4.3.0]nonane dihydtochloride and IE 970856 860 ng (7.8 mol) of 1,4-diazabicyc1o[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 from dimethylformamide.

Yield: 0.8 g (69% of theory) of 1-cyclopropylfluoro- 1,4-dihydro-7—(5-methyloxa-5,8-diazabicyclo[4.3.0]non- 8-yl)oxoquinolinecarboxylic acid, melting point 340°C (with decomposition) (on heating up, the substance already becomes dark from about 300°).

Mass spectrum: rule (if), 343 (M*-coz), 313, 244, 112 (100%).

Examgle 11 ./’.__.._.N‘,r‘ \\.‘/I\.h, 1:-—\ J I 1 I: 4‘ \ //\~\ \. " ‘ , ‘ ‘\ L _.. \cH3 The reaction is carried out analogously to Example 10 with B-chlorocyclopropyl-6,7—difluoro-1,4-dihydro—4— oxoquinolinecarboxylic acid to give 8-chloro—1-cyclo- propylf1uoro—1,4-dihydro(5-methyloxa-5,8-diaza- bicyclo[4.3.0]nonyl)oxoquinolinecarboxylic acid, melting point 258-262°C (with decomposition) (recrystal- lized from dimethylformamide).

IE 970856 Eggmple 12 .:'\~/\\/jL\~//C OOH I ll 1 —— -N/-~> ,/\-.-;»J ‘l ‘IA V _ r .

A\-CH3 The reaction is carried out analogously to Example 10 with 1—ethyl-6,7,8-trifluoro-1,4-dihydro—4—oxoquino- linecarboxylic acid to give 1—ethy1-6,8-difluoro-1,4- dihydro(5-methyloxa-5,8-diazabicyc1o[4.3.0]non yl)oxoquinolinecarboxylic acid, melting point 279- 281°C (with decomposition).

Example 13 O F / C00 \ I1 :1 r~“N/A\v/A\N/’ 1 I i ( '. . ./ \c1-13 0.84 g (3 mol) of 1-cyclopropyl-6,7,8—trif1uoro-1,4- dihydrooxoquinolinecarboxylic acid are heated.under reflux in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide with 0.66 g (6 mmol) of 1,4—diazabi- cyc1o[2.2.2]octane and 0.49 g (3.5 mmol) of 2-methy1-2,B- diazabicyc1o[4.3.0]nonane for 2 hours. The suspension is concentrated, the residue is stirred with 20 ml of water, IE 970856 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 mono- methyl ether.

Yield: 0.? g (58% of theory) of 1-cyc1opropy1-6,8-di- fluoro-1,4-dihydro(2-methyl-2,8-dia2abicyc1o[4.3.0]- nonyl)oxoquinolinecarboxylic acid, melting point 204-207°C. gxamgle 14 :7“ .,/,‘-‘\/’ ‘xx’ //*—N/" KN ._ $ I /r-1’ 1' Qk__N> J /”\\ \c1-:3 "coca Analogously to Example 13, 1-cyclopropyl—6-fluoro-1,4- dihydro(2-methyl-2,8-diazabicyclo[4.3.0]nony1) oxoquinolinecarboxylic acid, melting point 234—236°, is obtained with 1-cyclopropyl-6,7-dif1uoro-1,4-dihydro- 4-oxoquinolinecarboxylic acid.

IE 970856 Example 1§ A. 1~Cyc1opropyl-6,7,B-trifluoro-1,4-dihydrooxo quinolinecarboxylic acid is reacted. with 2,8-diazabi- cyclo[4.3.0]nonane analogously to Example 13 to give 1- cyclopropyl(2,8-diazabicyclo[4.3.0]nony1)-6,8- difluoro-1,4-dihydro-4—oxoquinolinecarboxylic acid, melting point 265-267° (with decomposition) (recrystal- lized from dimethylformamide).

B. If the reaction of Example 15 A) is carried out in a mixture of acetonitrile/1-methylpyrrolidinone and the crude product is recrystallized from dimethy1- formamide, 1-cyclopropyl(2,8-diazabicyclo[4.3.0]non- 8-yl)-6,8-difluoro-1,4-dihydro—4-oxoquinoline- 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- 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 IE 970856 precipitate is filtered off with suction, washed with ethanol and dried at 100°C in vacuo.

Yield: 66.3 g (93% of theory) of 1-cyclopropy1(2,8- diazabicyclo[4.3.0]nony1)~6,8—dif1uoro-1,4-dihydro oxoquinolinecarboxylic acid hydrochloride, melting point: 303-305°C (with decomposition). le 1 Analogously to Example 13, 1-cyclopropyl(2,7-diazabi- cyclo[3.3.0]octy1)—6-fluoro-1,4-dihydro-4—oxo quinolinecarboxylic acid, melting point: 260-282° (with decomposition), is obtained with 1-cyc1opropy1—6,7-di- fluoro-l,4-dihydrooxoquinolinecarboxylic acid and 2,7-diazabicyc1o[3.3.0]octane.

Mass spectrum: m/e 357 (if), 313 (1oo%, 11*.-coz), 259, 257, 244, 82, 23. - 144 — IE 970856 Analogously to Example 13, 1-cyclopropylf1uoro—1,4- dihydro(2-methyl-2,7-diazabicyc1o[3.3.0]octy1)—4— oxoquinolinecarboxylic acid, melting point: 206—208°C (with decomposition), is obtained with 1-cyclopropy1-6,7- difluoro-1,4—dihydrooxo-3—quinolinecarboxy1icacidand 2-methyl-2,7-diazabicyclo[3.3.0]octane. §.2F.QJ2l£_l_3 A F V‘//\\'/)\ "OCH! Jiﬁ [\\ I II Analogously to Example 13, 1-cyc1opropy1—6,8-difluoro- 1,4-dihydro(2-methyl—2,7-diazabicyclo[3.3.0]octy1)- 4-oxoquinolinecarboxylic acid, melting point 193- 200°C (with.decomposition), is obtained with 2-methyl-2,7- diazabicyc1o[3.3.0]octane. — 145 - IE 970856 Example 13 F~ ‘”«¢/‘x 1”” I H 1’. -"\—p.-' A mixture of 2.83 g (10 mol) of 1-cyclopropy1—6,7,8- trifluoro-1,4-dihydrooxoquinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4—diazabicyc1o[2.2.2)octane and 1.4 g (11 mol) of 2—methy1oxa-2,7-diazabicyc1o[3.3.- 0]octane in 20 ml of acetonitrile and 10 ml of l-methy1- 2-pyrrolidinone is heated under reflux for 1 hour. It is concentrated in vacuo, the residue is stirred with water (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 dimethylformamide.

Yield: 1.9 g (49% of theory) of 1—cyclopropyl-6,8-di- fluoro-1,4-dihydro—7—(2-methyloxa-2,7-diazabicyclo- [3.3.0]oct—7—yl)oxoquinolinecarboxylic acid, melting point 221-223°C (with decomposition).

IE 970856 The reaction is carried out analogously to Example 19 with 2,5-dimethyloxa-2,7-diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro(2,5- dimethyloxa-2,7-diazabicyc1o[3.3.0]octyl)oxo quinolinecarboxylic acid of melting point 237-238°C (with decomposition).

Example 2 ; ';\_ _,/ ~-.\ /" \\/f“"‘.,".'..:‘ . .“ The reaction is carried out analogously to Example 19 with 2,8-dimethyloxa-2,7—diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro(2,8- dimethyloxa-2,7-diazabicyclo[3.3.0]octy1)-4—oxo quinolinecarboxylic acid of melting point 197-199°C.

IE 970856 Example 22 A. 3 g (10 mol) of 8—chlorocyclopropyl~6,7-di- fluoro-1,4-dihydrooxoquinolinecarboxylic acid are heated under reflux in a mixture of 30 ml of acetonitrile and 15 ml of 1-methylpyrrolidinone with 1.4 g (11 mmol) of 2,8-diazabicyc1o[4.3.0]nonane and 1.65 g (15 mol) of 1,4-diazabicyclo[2.2.2]octane for 1 hour. After cooling, the suspension is stirred with about 150 ml of 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 3-chlorocyclopropyl- 7-(2,8-diazabicyclo[4.3.0]nonyl)fluoro-l,4-dihydro- 4—oxoquinolinecarboxylic 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 1N 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 100°C in vacuo. - 148 — IE 970856 Yield: 2.7 g (61% of theory) of 8-chlorocyclopropyl- 7-(2,8—diazabicyc1o[4.3.0]non—8-yl)fluoro-1,4-dihydro— 4-oxo-3—quinolinecarboxylic acid hydrochloride, melting point: from 225°C decomposition.

Example 23 The reaction is carried out analogously to Example 22 with 9,10-difluoro-2,3-dihydromethyloxo—7H-pyrido- [l,2,3-de][1,4]benzoxazinecarboxylic 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-methyloxo-7H-pyrido[1,2,3—de][l,4]benzoxa- zine-6—carboxylic acid of melting point 291-292°C (with decomposition) is obtained.

IE 970856 Egggple 24 6 g (20 mmol) of 1-cyclopropyl-S,6,7,8-tetrafluoro-1,4- dihydrooxoquinolinecarboxylic acid.are heated under reflux in 30 ml of 1-methylpyrrolidinone and 60 ml of acetonitrile with 2.2 g (20 mmol) of 1,4-diazabicyc1o- [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 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 1-cyclopropyl(2,8- diazabicyc1o[4.3.0]non—8-yl]—5,6,8-trifluoro-1,4-dihydro- 4-oxoquinolinecarboxylic acid Melting point: 266-269°C (with decomposition); after recrystallization from dimethylformamide: melting point: 272-273°C (with decomposition).

IE 970856 :7 ,.‘ ml of saturated ethanolic ammonia solution are added to 4.1 g (10 mol) of the product from Example 24 in 40 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- tallized from glycol monomethyl ether.

Yield: 0.? g (17% of theory) of 5-amino-l-cyclopropyl (2,8-diazabicyclo[4.3.0]nonyl)-6,8-difluoro-1,4- dihydrooxoquinolinecarboxylic acid, melting point: 275-277°C (with decomposition).

Mass spectrum: m/e 404 (M’), 384 ﬂf-HF), 290, 249, 96 (100%). - 151 — IE 970856 A. Analogously to Example 13, 1—cyclopropyl~7-(2,7- diazabicyc1o[3.3.0]octyl)-6,8-difluoro-1,4-dihydro oxoo3-quinolinecarboxylic acid, melting point: 277-280” (with decomposition), is obtained with 2,7-diazabicyc1o— [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 undiasolved product is filtered off with suction, washed with ethanol and dried.

Yield: 290 mg of l-cyclopropyl(2,7-diazabicyclo- [3.3.0]octyl)-6,8-difluoro-1,4-dihydrooxoquino- linecarboxylic acid hydrochloride, melting point: 269- 271FC (with decomposition).

IE 970856 Exam e 27 The reaction is carried out analogously to Example 8 with transmethoxymethylamino-pyrrolidine chloride. (transmethoxymethylamino—1-pyrrolidinyl)oxo—3- dihydro- 1-Cyclopropyl-6,8-difluoro-1,4-dihydro quinolinecarboxylic acid, melting point: 268-270°C (with decomposition) is obtained.

Example 28 xCF3C0OH A. 1.4 g (2.9 mmol) of the product from Example 3 A) and 1.98 ml (1.7 g, 12 mol) of dimethylformamide di- ethyl acetal are heated at 120%: in 15 ml of absolute dimethylformamide for 2 hours. The mixture is then concentrated in vacuo. The residue which remains is stirred with acetonitrile. The precipitate is filtered - 153 — IE 970856 off with suction, washed with a little acetonitrile and dried.

Yield: 0.8 g (54.4% of theory) of ethyl 7-(cistert.- butoxycarbonylaminomethoxypyrrolidinyl)cyclo- propyl-6,8-difluoro-1,4-dihydrooxoquinoline- 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 trifluoroacetic acid at 20°C for 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—(cisamino- 4-methoxypyrrolidinyl)cyclopropyl-6,8-difluoro-1,4- dihydro—4-oxo—3-quinolinecarboxylate trifluoroacetate Melting point: 124-126°C.

Example 29 H3C\ Analogously to Example 13, 1-cyclopropyl-6,8-difluoro- 1,4—dihydro(2-methyloxa-2,8-diazabicyclo[4.3.0]non— 8-yl)oxoquinolinecarboxylic acid, melting point IE 970856 258-260°C (with decomposition), is obtained with 2-methyl- 4-oxo-2,8-diazabicyc1o[4.3.0]nonane.

Examgle 3Q Analogously to Example 19, 1-cyclopropyl-6,B-dif1uoro- 1,4-dihydro(3-oxa-2,7-diazabicyclo[3.3.0]octanyl)- 4-oxoquinolinecarboxylic acid is obtained with 3-oxa- 2,7-diazabicyc1o[3.3.0]octane.

E am le 1 xHC1 A. 1.1 g (10 mmol) of 1,4-diazabicyc1o[2.2.2]octane and 1.4 g (11 mol) of 2,8—diazabicyclo[4.3.0]nonane are added to 2.53 g (10 mmol) of 1-ethyl-6,7-difluoro-1,4- dihydrooxoquinolinecarboxylic acid in 30 ml of acetonitrile and 15 ml of dimethylformamide and the mixture is heated under reflux for 1 hour. The mixture is IE 970856 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,B-diazabicyc1o- [4.3.0]nonyl)-l-ethylfluorooxoquinoline- carboxylic acid, melting point: 259-261°C (with decom- position).

B. 2.9 g (B 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 l20°C/ 12 mbar.

Yield: 1.8 g (57% of theory) of 7-(2,8-diazabicyclo- [4.3.0]nonyl)ethylfluoro—4-oxoquinoline- carboxylic acid hydrochloride, melting point, with decom- position: 299%: (dark coloration already starting from about 215°C).

Example 32 Reaction analogously to Example 31 with 1-cyclopropy1- IE 970856 6,7-difluoro-1,4-dihydrooxoquinolinecarboxylic acid gives: A. 1-Cyclopropyl(2,8-diazabicyclo[4.3.0]non-B-yl)- 6-fluorooxoquinolinecarboxylic acid, melting point: 249-257°C (with decomposition) B. 1—Cyclopropyl-7—(2,B-diazabicyclo[4.3.0]nonyl)- 6-fluoro-4—oxoquinolinecarboxylic acid hydrochloride, melting point with decomposition: 320°C (dark coloration already starting from about 288°C).

Examgle 33 1.1 g (3 mmol) of 1-cyclopropyl(2,8-dia2abicyclo- [4.3.0]non—8-yl)-6,8-difluoro-1,4-dihydro—4-oxoquino- linecarboxylic acid are heated under reflux in 10 ml of dimethylformamide 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 dimethylformamide.

Yield: 0.8 g (64% of theory) of 1-cyclopropy1-6,8—di- iluoro(2-formyl-2,8-diazabicyclo[4.3.0]nonyl)-1,4- dihydrooxoquinolinecarboxylic acid, melting point: 276-278°C.

Example 34 1.1 g (3 mmol) of 1—cyclopropyl(2,8-diazabicyclo— [4.3.0]nonyl)-6,8—difluoro-1,4-dihydro—4-oxo-3~quino- linecarboxylic 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 1N sodium hydroxide solution and 260 mg of acetyl chloride are added, while cooling with ice. The mixture is subse- quently stirred at room temperature for 2 hours and diluted with 30 ml of water and the precipitate which has separated out is filtered off with suction. The crude product is recrystallized from glycol monomethyl ether.

Yield: 0.6 g (46% of theory) of 7-(2-acetyl—2,8-diaza- bicyclo[4.3.0]nonyl)cyclopropyl-6,B-difluoro—1,4- dihydrooxo—3-quinolinecarboxylic acid, melting point: 261-263°C (with decomposition) — 158 - IE 970856 §_x_aLm_..;2 1.9. 3.2 A. Analogously to Example 13, B-chlorocyclopropyl- 6-fluoro-1,4-dihydro-7~(2-methyl-2,7-dia2abicyclo[3.3.0]— octyl)oxoquinolinecarboxylic acid, melting point: 222-227°C (with decomposition), is obtained with 8-chlorocyclopropyl-6,7-difluoro-1,4-dihydrooxo 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 1N 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 B-chlorocyclopropyl- 6-fluoro-1,4-dihydro(2—methyl-2,7-diazabicyc1o[3.3.0]- octyl)oxo—3—quinolinecarboxylicacidhydrochloride, melting point: 303-305°C (with decomposition).

IE 970856 Egample 3§ c}-:3 Analogously to Example 13, 1-cyclopropyl-6,8-dif1uoro- 1,4-dihydro(3-methyl-2,7-diazabicyc1o[3.3.0]octy1)- 4—oxoquinolinecarboxylic acid is obtained with 3- methyl-2,7-diazabicyclo[3.3.0]octane, and is converted into 1-cyclopropyl-6,B-difluoro-1,4-dihydro(3-methyl- 2,7-diazabicyclo[3.3.0]octyl)oxoquinolinecar- boxylic acid hydrochloride, melting point: 216-221°C (with decomposition), analogously to Example 15 C. with half- concentrated hydrochloric acid.

Examgle 37 A. A mixture of 1.45 g (5 mol) of 1-cyclopropy1-6,7,3- trifluoro-1,4-dihydrooxoquinolinecarboxylic acid, 0.85 g (7.5 mmol) of 1,4-diazabicyc1o[2.2.2]octane and 0.77 g (5.5 mol) of 2,3-dimethyl-2,7—diazabicyc1o- — 160 - IE 970856 [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 monomethyl ether.

Yield: 1 g (47% of theory) of 1-cyclopropy1-7—(2,3- dimethyl-2,7-diazabicyclo[2.2.2]octyl)-6,8—difluoro- 1,4—dihydro—4-oxoquinolinecarboxylic acid, melting point: 203-209°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 is filtered off with suction, washed with ethanol and dried at 100°C/1 mbar.

Yield: 0.64 g (84% of theory) of 1—cyclopropy1—7-(2,3- dimethyl-2,7-diazabicyclo[2.2.2]octyl)-6,8-difluoro— hydro- chloride, melting point: 233-236°C (with decomposition). 1,4-dihydrooxo-3—quinolinecarboxy1ic acid IE 970856 Egamgle 33 1-13c\‘ .~ xi-[Cl Analogously to Example 37 A. and B., 8—ch1orocyclo- propyl(2,3—dimethy1-2,7-diazabicyc1o[2.2.2]octy1)- 6-fluoro-1,4-dihydrooxoquinolinecarboxylic acid hydrochloride, melting point: 240-2419C (with decomposi- tion), is obtained with 8-chlorocyclopropyl-6,7- difluoro-1,4-dihydrooxoquinolinecarboxylic acid.

Exam le 9 P\/5‘\v/u\,/Coon 1 H H z*._\ ‘ 5}.’ \T/‘\—,’1~<'—.

The reaction is carried out analogously to Example 19 with 1,2—dimethyloxa-2,7-diazabicyc1o{3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro(1,2- dimethyl—3-oxa-2,7-diazabicyclo[3.3.0]octyl)oxo quinolinecarboxylic acid of melting point 269-271°C (with decomposition).

Example 40 xHCl 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 mol) of 8-chloro-1—cyclopropyl- 6,7-difluoro-1,4-dihydrooxoquinolinecarboxylic acid in a mixture of 25 ml of acetonitrile and 12.5 ml of dimethylformamide 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-B-chloro—6-fluoro-1,4-dihydro-7—(2-oxa-5,8- diazabicyclo[4.3.0]nonyl)oxo-3~quinolinecarboxylic acid is introduced into 85 ml of 1N 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 B-chlorocyclopropyl- 6~fluoro-1,4-dihydro(2-oxa-5,8-diazabicyclo[4.3.0]non— 8-yl)oxoquinolinecarboxylic acid hydrochloride, melting point: from 29¢? decomposition. — 163 - IE 970856 Example 41 , ”*»~:ooH H3C\ Analogously to Example 13, 8-chlorocyclopropyl fluoro(2-methyl—4-oxa-2,8-diazabicyclo[4.3.0]non yl)oxoquinolinecarboxylic acid, melting point: 202- 203°C (with decomposition), is obtained with 8-chloro cyclopropyl-6,7-difluoro-1,4-dihydrooxo—3-quino1ine- carboxylic acid and 2-methyloxa-2,8-diazabicyclo- [4.3.0]nonane.

FAB mass spectrum: m/e 422 ([M+H]U, 404 (422-Hgn.

Example 42 P-.: . *~ H ‘cozczns A. The reaction is carried out analogously to Example 13 with ethyl 2 , 7-diazabicyclo [ 3 . 3 . 0 ]octanecarboxylate to give 1-cyclopropyl(2-ethoxycarbonyl-2,7-diazabi- cyc1o[3.3.0]octyl)-6,8-difluoro-1,4-dihydrooxo quinolinecarboxylic acid of melting point 191—192°C.

IE 970856 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 is filtered off with suction, washed with ethanol and dried at 120°C/12 mbar.

Yield: 1.1 g (67% of theory) of 1-cyclopropyl—7-(2,7- diazabicyclo[3.3.0]octyl)-6,8-difluoro-1,4—dihydro oxoquinolinecarboxylic acid hydrochloride, melting 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 1-cyclopropyl(2,8-diazabi- cyclo[4.3.0]nonyl)-6,B-difluoro-1,4—dihydro-4—oxo 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 cool- ing the salt precipitates out, this being filtered off 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 1-cyclopropyl(2,8- diazabicyclo[4.3.0]nonyl)-6,8—difluoro—1,4-dihydro oxoquinolinecarboxylic acid mesylate, melting point: 262—265°C (with decomposition).

The following compounds are obtained analogously: — 165 - IE 970856 B. 1—Cyclopropyl-7—(2,8-diazabicyc1o[4.3.0]non-8—yl)- 6,8-difluoro-1,4—dihydro-4—oxo—3-quinolinecarboxylic acid tosylate, melting point: 248-250°C (with decomposition).

C. 1-Cyclopropyl(2,8-diazabicyclo[4.3.0]non-B—yl)- 6,8-difluoro-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 1-cyclopropyl(2,8—diazabicyclo- [4.3.0]nonyl)-6,8-difluoro—1,4—dihydrooxoquino- linecarboxylic acid are suspended in 50 ml of water, and ml of 1N sodium hydroxide solution are added at room temperature, whereupon the product largely dissolves. A slight turbidity is removed by filtration through a 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- hydrooxo—3—quinolinecarboxylate; the salt decomposes slowly above 210°C without melting.

IE 970856 Egample 45 A mixture of 3.9 g (10 mmol) of 1-cyclopropyl(2,8- diazabicyclo [ 4 . 3 . 0 ] nonyl ) -6 , 8-difluoro-1 , 4-dihydro-4w oxoquinolinecarboxylic acid in 100 ml of dimethyl- formamide 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 gel (mobile phase: CI-Izclz/CH3OI-I/17% strength NH, = 30:B: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 1-cyclopropy1-6,8- difluoro-1,4—dihydro[2-(2-hydroxyethyl)—2,8-diazabi- cyclo[4.3.0]non—8-yl]oxoquinolinecarboxylic acid, melting point: 200-206°C (with decomposition).

Mass spectrum: m/e 433 (M7), 402 (M+ -cngnn, 140, 110 (100%), 96 |,_i IE 970856 32H5NHaw " 2-“.v‘«yp Cl-I35 ,2 The reaction is carried out analogously to Example 13 with transethylaminomethylthio-pyrrolidine to give 1-cyc 1op:r:opy1 ( transethylamino—4-methylthio) -6 , 8- difluoro-1 , 4-clihydrooxoquinolinecarboxylic acid, melting point: 215-216°C (with decomposition).

Egamgle 47 The reaction is carried out analogously to Example 13 with 2-phenyl-2,7-diazabicyc1o[3.3.0]octane to give 1- cyclopropyl-6 , 8-difluoro-1 , 4-dihyd.rooxo—7- ( 2—pheny1- 2,7-diazabicyclo[3.3.0]0ct—7-yl)quinolinecarboxylic acid, melting point: 259-260°C (with decomposition).

IE 970856 Examgle 43 F CH3 .1 Analogously to Example 13, 5,6,8-trifluoro-1—(2,4-di- fluorophenyl)-1,4-dihydro(2-methyl-2,8-diazabicyc1o- [4.3.0]nonyl)—4-oxoquinolinecarboxylic acid is obtainedwith5,6,7,8-tetrafluoro-1~(2,4-difluoropheny1)- 1,4-dihydrooxoquinolinecarboxylic acid.

Example 49 .Ana1ogously to Example 24, 7-(2.8-diazabicyc1o[4.3.0]non- 8—yl)-5,6,8-trifluoro-1~(2,4-difluorophenyl)-1,4-dihydro- 4-oxo—3-quinolinecarboxylic acid is obtained with ,6,7,8-tetrafluoro(2,4-difluorophenyl)—1,4-dihydro- 4-oxoquinolinecarboxylic acid. - 169 — IE 970856 ggamgle 50 Analogoualy to Example 25, 5-amino(2,B-diazabicyclo- [4.3.0]non-8~yl)-6,8-difluoro(2,4-dif1uoropheny1)-l,4- dihydro-4—oxo—3-quinolinecarboxylic acid is obtained‘with 7-(2.8-diazabicyclo[4.3.0]nonyl)-5,6,8-trifluoro (2,4—difluorophenyl)-1,4-dihydrooxoquinolinecar- boxylic acid.

Examgle 51 Analogously to Example 15 A, 5-chlorocyclopropyl (2,8-diazabicyclo[4.3.0]non-B-yl)-6—fluoro-1,4-dihydro- 4-oxo-3—quinolinecarboxylic acid, melting point: 270°C (decomposition), is obtained with 5,7-dichlorocyc1o- propylfluoro-1,4—dihydrooxoquinolinecarboxylic acid (reflux for 5 hours).

IE 970856 Analogously to Example 3, 5-ch1orocyc1opropyl fluoro-1,4-dihydro(2-oxa-5,8-diazabicyc1o[4.3.0]non- 8-yl)oxoquinolinecarboxylic acid is obtained with ,7—dichlorocyclopropylfluoro-1,4-dihydrooxo—3- quinolinecarboxylic acid (reflux for 5 hours).

Examgle 53 Analogous1y' to Example 15 A, 5~chloro~7—(2,8-diazabi- cyclo[4.3.0]nonyl)fluoro(2,4-difluorophenyl)— 1,4-dihydrooxoquinolinecarboxylic acid is obtained with 5,7-dichlorofluoro(2,4-difluorophenyl)-1,4- dihydrooxoquinolinecarboxylic acid (reflux for 5 hours). — 171 - IE 970856 Examgle 54 Analogously to Example 8, 5—chlorof1uoro(2,4- difluorophenyl)-1,4-dihydro(2-oxa-S,8-diazabicyclo- [4.3.0]nonyl)oxo—3-quinolinecarboxylic acid is ,7-dichlorofluoro(2,4-dif1uoro- phenyl)-1,4-dihydrooxoquinolinecarboxylic acid (reflux for 5 hours). obtained with gxamgle 55 The reaction is carried out analogously to Example 13 with transethylaminomethylthio-pyrrolidine and B- chlorocyclopropyl-6,7-difluoro-1,4-dihydrooxo quinolinecarboxylic acid to give B-chlorocyclopropy1— 7-(transethylaminomethylthiopyrrolidinyl) fluoro-1,4—dihydrooxo—3-quinolinecarboxylic acid, melting point: 217—218°C (with decomposition).

IE 970856 Example 56 XHCI CH3S 7-(transAmino-4—methylthiopyrrolidinyl)cyclopro~ pyl-6,B-difluoro-1,4-dihydro—4-oxoquinolinecarboxylic, melting point: 208-21l'C (with decomposition) and 7-(trans- 3-aminomethylthiopyrrolidinyl)-l-cyclopropyl—6,8—di- fluoro-1,4-dihydrooxoquinolinecarboxylic acid hydro? chloride, 255-257'C obtained with transaminomethylthio-pyrrolidine analogously to Examples 13 and 15. melting‘ point: (with decomposition), Example 57 XHCI 1—Cyclopropyl-6,8-difluoro-l,4—dihydro-7—(4-methyl-2,8- diazabicyclo[4.3.0]nonyl)oxoquinolinecarboxylic acid, melting point: 213-215'C (with decomposition) (recrystallised from glycol monomethyl ether), and 1-cyclo~ propyl-6,B-difluoro-1,4-dihydro(4-methyl-2,B-diazabi- cyclo[4.3.0]non—8—yl)oxoquinolinecarboxylic acid hydrochloride, 204-2l2'C melting’ point: (with decomposi- IE 970856 tion) are obtained with 4—methyl-2,8—diazabicyclo[4.3.Q7- nonane analogously to Examples 13 and 15.

The product consists of a mixture of 2 stereoisomers. — 174 - IE 970856

Claims

Patent CLAIMS 1. 7-(1-Pyrrolidinyl)quinolone- and -naphthyridone— carboxylic acid derivatives of the formula (I) X1 .. . 1 "COOR2 (I) in which represents halogen, represents hydrogen, amino, alkylamino having 1 dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio to 4 carbon atoms, 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 2-hydroxyethyl, 2- fluoroethyl, methoxy, amino, methylamino, ethyl- having 3 to 6 carbon atoms, amino, dimethylamino or phenyl which is option- ally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 4 carbon atomsor(5-methyloxo-1,3-dioxolyl)-methyl, IE 970856 R’ represents a radical of the structure *3 .2-R‘ _. 3,5 . P6 wherein R‘ can represent C1-C.-alkyl, aryl or C,- C.-acyl, R’ can represent H, C,-C.-alkyl, OH or OCH3, R5 can represent H, optionally hydroxy1-aub- etituted C,-C.~elky1, as well as aryl, heteroary1, benzyl, C,-C.-alkoxycarbonyl, C1-C.-ecyl, (S-methyloxo-1 , 3-dioxolyl ) -methyl , or C,-C,-cycloallcyl, R’ can represent H or C1-C.-alkyl, R’ can represent H, CH, or phenyl, R" can represent H, CH, or phenyl, R"' can represent H or CI-I3, Y can represent 0, CH2, CHzC!-I3 or CH,-0, it being possible for the CI-I2-O group to be linked to the nitrogen either via 0 or via CH1, and Z can represent 0 or S, and IE 970856 A represents N or C-R‘, wherein R‘ represents H, halogen, methyl, cyano, nitro, hydroxyl or methoxy or, together with R‘, can form a bridge having the structure ‘CH2'CH2‘CH‘CH3 and pharmaceutically usable hydrates and acid addition salts thereof and the alkali. metal, 10 alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids. with the exception of compounds of the formula N} 4;, 0 wherein 15 R1 is C1-C4 alkyl, R2/R3 are each hydrogen or C1-C4 alkyl, R4 is cyclopropyl, phenyl, halophenyl or thienyl, which may be substituted by C1-C4 alkyl or halogen, and 20 R5 is halogen.
2. Compounds of the formula (I) according to Claim 1, in which X‘ represents fluorine or chlorine, X‘ represents hydrogen, amino, alkylamino having 1 IE 970856 or 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercapto, methylthio, phenylthio, ‘fluorine or chlorine, 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, ethyl- amino, dimethylamino or phenyl which is option- ally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 3 carbon atomsor(5-methyloxo-1,3~dioxol-4—yl)-methyl, represents a radical having the structure wherein R‘ can represent C1-C,-alkyl or C,-C,-acyl, R’ can represent H, C¢4g-alkyl, OH or OCH3, it also being possible for, R‘ and R5 together to denote a Crxh-alkylene bridge which is optional1y'mono- or disubstituted by methyl, - 178- IE 970856 can represent H, optionally hydroxy1— substituted C1-C3-alkyl, as well as phenyl, benzyl, C,-C.-alkoxycarbonyl, C1-C2-acyl. (S- methyloxo-1,3-dioxolyl)-methyl, or C3-C5-cycloalkyl, can represent H or Cfmg-alkyl, can represent H or CH“ can represent H or CH3, can represent H or CH3, can represent 0, CH2, CHZCH, or C!-I2-O, it being possible for the can-0 group to be linked to the nitrogen either via 0 or via CH2, and can represent 0 or S, and represents N or C-R‘, wherein represents H, fluorine, chlorine, bromine or hydroxyl or together with R’ can form a bridge having the structure Compounds of the formula (I) according to Claim 1, in which represents fluorine, represents hydrogen, amino, methylamino fluorine, represents alkyl having 1 or 2 carbon atoms, vinyl, cyclopropyl, 2-hydroxyethyl, 2-f1uoro- ethyl, methoxy, methylamino, 4-fluorophenyl or 2,4-difluorophenyl, represents hydrogen or alkyl having 1 or 2 carbon atoms, represents a radical having the structure e /Z-*‘ wherein R‘ can represent C,-C2-alkyl, R’ can represent H or C,-C,-alkyl, it also being possible for R‘ and R’ together to form a C,-C,-alkylene bridge which is IE 970856 optionally substituted by methyl, can represent H, CH3, C211,, HOCHZCHZ, benzyl, C1-C.-alkoxycarbonyl or C,-C,-acyl, can represent H or CH“ can represent H or CH3, can represent H or CH3, can represent H or CH3, can represent 0, CH2, CHZCI-I, or CH2-0, it being possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CH2 , and can represent 0 or S, and represents N or C-R”, wherein represents H, fluorine or chlorine, or together with R’ also can form a bridge having the structure CHz—|C1-I-CI-I3 . 4. Process for the preparation of the compounds of the formula (I) according to Claim 1, characterized in IE 970856 that compounds of the formula (II) V;.pf;_ﬁ/~_\ m__FL (II) in which 1 2 1 A, R , R , X and X2 have the abovementioned meaning and X3 represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula (III) R’-H (III) in which R3 has the meaning given in Claim 1, if appropriate in the presence of acid entrainera, and if appropriate protective groups contained in R3 are removed. “Process for the preparation of the compounds of the formula (I) according to Claim 1 IE 970856 ,~T®o&9 (1) in which X‘, R’, R’, R3 and A have the abovementioned meaning X’ 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, characterized in that a compound of the formula (IV) (IV) in which X‘, R’, R’, R’ and A have the abovementioned meaning, is reacted with compounds of the formula (V) IE 970856 x‘-H (V) in which X2 has the abovementioned meaning, if appropriate in the presence of acid entrainers. 6. Process for the preparation of compounds of the formula (Ia) in which X1, X2, R‘, R2 and A have the abovementioned meaning 10 and R3 represents a radical having the structure wherein R‘, R5, R5, R’, R", R"', Y and Z have the abovemen- tioned meaning, IE 970856 characterized in that a compound of the formula (VI) X2 0 in which X1, X‘, R‘, R2 and A have the abovementioned meaning R“ represents a radical having the structure wherein R‘, R’, R‘, R", R"', Y and Z have the abovementioned meaning, is reacted with compounds of the formula (VII) R°—x' (VII) in which IE 970856 R“ has the abovementioned meaning and X‘ represents chlorine, bromine, iodine or acyloxy, if appropriate in the presence of acid entrainers. 7-(1-Pyrrolidinyl)qu1nolone- and -naphthyridone— carboxylic acid derivatives of the formula (I) according to Claim 1 for use in a method for thera- peutic treatment of the human or animal body. Medicaments containing compounds of the formula (I) according to Claim 1. Use of compounds of the formula (I) according to Claim 1 for the preparation of medicaments. Use of compounds of the formula (I) according to Claim 1 as animal feed additives. Animal feeds or animal feed additives and premixes containing compounds of the formula (I) according to Claim 1. IE 970856 Carboxylic acid derivatives in the S,S—configuration of the formula wherein A is C—Cl, C-F or C—OCH3 and pharmaceutically acceptable salts thereof. Medicaments containing a compound according to Claim Use of compounds according to Claim 12 for the preparation of animal feeds, animal feed additives and premixes. Use of compounds according to Claim 12 as antibacterial agents. Use of compounds according to Claim 12 for the ‘preparation of a medicament for the treatment of bacterial diseases. A compound according to Claim 1, which is any one of those specifically hereinbefore mentioned. A process for the preparation of a compound according to Claim 1, substantially as hereinbefore described and exemplified. IE 970856 19. A compound according to Claim 1, whenever prepared by a process claimed in a preceding claim. 20 . A medicament according to Claim 8, substantially as hereinbefore described and exemplified. 21. An animal feed or animal feed additive or premix according to Claim 11, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS. - 188 —