NZ233142A

NZ233142A - 5-alkylquinolone carboxylic acid derivatives, pharmaceutical compositions and feed preparations

Info

Publication number: NZ233142A
Application number: NZ233142A
Authority: NZ
Inventors: Michael Schriewer; Klaus Grohe; Andreas Krebs; Uwe Petersen; Thomas Schenke; Ingo Haller; Karl Georg Metzger; Rainer Endermann; Hans-Joachim Zeiler
Original assignee: Bayer Ag
Priority date: 1989-04-03
Filing date: 1990-03-30
Publication date: 1992-09-25
Also published as: NO901274D0; JP3046035B2; IL93954A0; NO173547C; PH27364A; EP0391132A1; KR0156245B1; HU204811B; DE3910663A1; CN1035945C; JPH02289583A; CN1046162A; DD298400A5; AU5231790A; FI901615A0; ZA902510B; CA2013449A1; KR900016186A; HUT56563A; HUT58056A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £33142 Ik 23 3 1 4 2 -y Dgtc{s): 2>.. Apo.l..35?yC'^. 'Mjn C» : . \ .£a.Jtoa*rcbJ3<?Q •' >J...C&^(.Dl±aifo^> C^1..V.hhO.%j.<Dlt;T. j Coi.p.i^ii/.Qt^. j.4y..Cdn D^S-I ioic, j I 0O7.0^doi+.,J.O.v.feJ>5:i3../.Q^AbJ.k3.i7ia • . . - : ¥'5 SFP <e0? f :- . ✓. ..i,.n.-:\ ...i3ikrO. > " * 23s.v ^ __ $ UflF-l Vf iV* C'ass Corit: .. fei.S.SS& .?.<*,... ta&x-tlafl. co3J?sp7././.f. N.Z. No. NEW ZEALAND Patents Act, 1953 COMPLETE SPECIFICATION '-**4 5-ALKYLQUINOLONECARBOXYLIC ACIDS ?' :"i •M& We, BAYER AKTIENGESELLSCHAFT, a body of corporate organized under the laws o. the Federal Republic of Germany, at Leverkusen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be grante to us, and the method by which it is to be performed, to be particularl described in and by the following statement:- - 1 - (Followed by 1A) 2331 The invention relates to new quino!onecarboxylic acid derivatives which carry an alkyl, to processes for th preparation and to antibacterial agents and food additives containing them. It has been found that quinolonecarboxylic acid derivatives of the formula (I) F3 0 in which R1 represents straight-chain or branched Ci-Ct-alJcyl which is optionally substituted by hydroxyl, halogen, Cj^-Ca-alkoxy or C1-C3-alkylthio, C3-Cs-cyclo-alkyl which is optionally substituted by halogen, Ci-Ca-alkyl or C2-C4-alkenyl, Cj-Cj- alkoxy, amino# mono a Iky 1 amino having 1-3 C atoms, dialkylamino having 2-6 C atoms or phenyl which is optionally substituted by halogen, R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl}-methyl, R3 denotes Cj-Cj-alkyl, R* represents a radical, which is optionally substituted in the ring system by hydroxyl or methyl, of . i ~/lairing i i ~ ?• / * | / the formula / \ /\ ^ / 7^ S- ( CH2 ^N- , EG ^N- , EJs^N- , or E^G ^N- in which E represents R5-N, 0 or S, g represents -(ch2)j-, -ch2-o-ch2-, -ch2-s-ck2-, -ch2-s-t e6 or -ch2-n-ck2-, 5 j represents 1, 2 or 3, R5 represents hydrogen, or alkyl, alkenyl or alkinyl having up to 4 carbon atoms, which is optionally substituted, by hydroxvl, benzyl which is optionally substituted by nitro or amino, oxoalkyl having 2 to 10 4 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)- methvl, and R5 represents hydrogen or methyl, R4 in addition represe'nts a radical of the formula X1 i?8£i.p—f-( ch2 }*"w ii3ilp—f S"(ch2^ ' " kr(CH2^ , X2 ( CH-> )n ! x2 or ■ sloirP I ^CCH2)a in which, 15 p represents 0,1 or 2, w' m represents 1 or 2, where p + m together can be 1, : -9 APR 1992--. - 2 - 2 or 3, n represents 1 or 2, W represents , OR3, SR9, halogen or hydrocen, R8 .R7 X1 represents / OR9, SRs, halogen, CN, CONH2 COOH or C1-C4-afkyl, X2 and X3 can be identical or different and represent oxygen or N-CH3/ R7 represents hydrogen, Ci-Cj-alkyl, allyl or propargyl ana Rs represents hydrogen, C,-C3-al3cyl or C3-Cs-cyclcalkyl, or R7 + R8 together can also represent the groups -CH2CH2-0-CK2CH2- or - (CK2) k-, in which 3c can represent 3, 4 or 5, and R3 represents hydrogen, Ci-Cj-alkyl or C,-C3-acyl, and R*° represents hydrogen or C^-Cn-alJcyl, R" also denotes a radical of the structure s 15 T Z-S11 3:S K15 ■N ' i , -N^7" ' I -,12 \_L RM, or -X -N M /i X ^ V P1* V3 p_13 in which R11 represents H, Cj-C^-alkyl or C^-C^acyl, and R12 represents H, Ci-Cj-alkyl, OH or OCH3, or R11 and R" together can also, denote a C,-C2-alkylene bridge which is optionally monosubstituted or ~ _ 9 j^PR 1992-' - 3 - \ disubstituted by methyl, represents H, C-|-C~-a1kyl, a ry 1 , heteroaryl, benzyl, C^-C^-alkoxycarbonyl, C.-C^-acyl or (5-metnyl 2-oxo-l,3-di oxol-£) -methyl, R14 represents R15 represents R-6 represents R17 represents v represents H or Ci-Ci.-alkyl, H, CH3 or phenyl, H, CH3 or phenyl, H or CH3, and 0, CH2, CK2CH2 or CH2-0, where the linking of the CH2-0 group to the nitrogen can be both via 0 and via CH2, 2 represents 0 or S, and A represents hydrogen, halogen, methyl, cyano or nitro ' or, together with R1, can also form a bridge of the structure * X * -o-ch2ch-ch3 , -s-ch2-ch-ch3 or -ch2ch2-ch-ch2 having the R- or S-configoration, and their pharmaceutically utilizable hydrates and acid addition salts and also the alkali metal, alkaline earth metal, silver and guanidinium salts of the carboxylic acids on which they are based have a high antibacterial action, in particular in the gram-positive region. They are therefore suitable as active compounds for human and veterinary medicine, where veterinary medicine also includes the treatment of fish for the therapy or prevention of bacterial infections. Preferred compounds of the formula (I) are those 4* in which R* represents ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hvdroxyethyl, 2-fluoroethyl, amino, methylamino, phenyl, 4-fluoropnenyl or 2,4-aifluoro-5 phenyl, R2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl, R2 represents C1-C3-alkyl, R* represents a substituted radical, which is option-10 ally substituted in the ring system by methyl, of the formula 1 / N-CCH,); N-, EG N-, E G^N-,orE G/ S- , \ v; / \l f in which E represents R5-N or 0, R5 15 G represents -{CE2)j-, -CK2-0-CH2- or -CH2-N-CH2-, j represents 1, 2 or 3, R5 represents hydrogen, or alkyl, alkenyl or aikinyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, benzyl which is optionally 20 substituted by nitro or amino or oxoalkyl having 2 to 4 carbon atoms,and R6 represents hydrogen or methyl, in addition represents a radical of the formula X1 0 CCK2)_ 1— CCH->)_-W (CK?>n 0ia£iP I 2 n oioii53 I ^CCH2)a ' or iioii?' -X- in which \ _r* p represents 0, 1 or 2, m represents 1 or 2, where p + m together can be 1, 2 or 3, n represents 1 or 2, ^ R7 W represents , ORs or hydrogen, Rs X* represents , ORs, fluorine, chlorine, or C:-C2-alkyl, X2 and X3 can be identical or different and represent oxygen, sulphur or N-CH,, R7 represents hydrogen, C.-C2-alkyl or acetyl, Rs represents hydrogen or C-Cj-alkyl, or R7 + R8 together also denote the groups -CH2CH2-0-, -CK2CH2- or -(CH2)k-, in which k can represent 3, 4 or 5, R9 represents hydrogen, C:-C2-alkyl or acetyl, and R10 represents hydrogen or Cx-C2-alkyl, R* si so represents a radical of the structure r16 r16 | Rl3 R12 in which R" represents H, C-C^-alkyl or C:-C2-acyl, and R12 represents H, C1-C3-al3cyl, OH or OCH3, or R" and R12 together can also denote a C,-C2-alkylene bridge which is optionally monosubstituted or disubstituted by methyl, R"3 represents H, C^-Cj-alkyl, phenyl, benzyl, C^C,.-alkoxycarbonyl, Cz-C2-acyl or (5-methyl-2-oxo-l, 3-dioxol-4-yl)-methyl, R"4 represents H or C1-C2-alkyl, R" represents H or CH3, R16 represents H or CH,, R17 represents H or CE3, and Y represents 0, CE2, CH2CH2 or CH2-0, where the linking of the CE2-0-group to the nitrogen can be both via 0 and via CH2, 2 represents 0, and A represents H, fluorine, chlorine, methyl, or nitro or together with R1 can also form a bridge of the structure -o-ch2-ch-ch3 having the R- or S-configuration. Particularly preferred compounds of the formula ) are those in which represents ethyl, vinyl, t-butyl, cyclopropyl, 2-hydroxyethvl, 2-fluoroethvl, methylamino, 4-fluoro-phenyl or 2,4-difluorophenyl, represents hydrogen or alkyl having 1 to 2 carbon atoms, represents C:-C3-alkyl, represents a radical, which is optionally substituted in the ring system by methyl, of the formula ' ^ A \ / 7\ N- C CK2 )j^N- , G X- , E (3 N- , or EGN- . , which represents R3-N, represents -(CH2)_.-, represents 1 or 2, represents hydrogen, or alkyl, alkenyl or alkinyl having up to 3 carbon atoms, and optionally substituted by hydroxyl, benzyl which is optionally substituted by nitro or amino, or oxoalkyl having 2 to 4 carbon atoms, and represents hydrogen or methyl, in addition represents a radical of the formula or $ in which P represents 0, 1 or 2, m represents 1 or 2, where p + m together can be 1, 2 or 3, n represents 1, w represents N' ■*7 , OR3 or hydrogen, X1 .R, represents n; , OR9, chlorine or methyl, R' R R R4 10 and X3 can be identical or different ana represents oxygen or N-CH3, represents hydrogen or methyl, represents hydrogen or methyl and represents hydrogen or methyl, and represents hydrogen or methyl, additionally denotes a radical of 'the structure R152-R!1 - N 3 16 \ /""f >R14, or -N -N \ ' r R' in which R11 represents H, C^-^-alJcyl or acetyl, and represents H or Ci-Cj-alkyl, or R11 and R12 together can also denote a Ci-Cj-alJcylene bridge which is optionally substituted by methyl, represents H, C,-C2-alJcyl, hydroxyethyl, benzyl, a 12 313 7331 < C,-C4-alkoxycarbonyl or C1-C,-acyl/ R14 represents H or CH3, R" represents H or CH3, R"s represents K or CH3, 5 R:7 represents H or CH3, and Y represents 0, CH2, CH2CH2 or CH2-0, where the linking of the CH2-0-groups to the nitrogen can be both via 0 and via CH2, Z represents 0, and -V 10 A represents H, fluorine or chlorine, or together with R1 can also form a bridge of the structure ★ -0-CH2-CH-CK3 having the R- or S-configuration. It has furthermore been found that the compounds-15 of the formula (I) are obtained when a compound of the formula (II) ~3 0 !l CO?.2 C11) A in which , R1, R2, R3 and A have the abovementioned meaning and ^ 20 X* represents halogen, in particular fluorine or chlorine, is reacted with a compound of the formula (III) R*-H (III) v in which v--/ 25 R* has the abovementioned meaning, - 10 - 23314 if appropriate in the presence of acid scavengers and if appropriate protective groups contained in R* are removed. If, for example, l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and 1-methyl-octahydropyrrolo[ 3,4-b]pyridine are used as starting substances, the course of the reaction can be represented by the following equation: ch3 23 3142 If, for example, 8-chloro-l-cyclopropyl-6,7-dif luoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and 3-ethylaminomethyl-3-hydroxy-pyrrolidone are used as starting substances, then the course of the reaction can be represented by the following equation: €0 OH C2H5-NH-CH2 j NH hA-J Base -HF C->Hc -NH-CH-> j N Xj HO C00H 10 o If, for example, l-cyclopropyl-7-(2,7-diazabicy-clo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and ethanol/hydrogen chloride are used as starting substances, then the course of the reaction can be represented by the following equation: COOH hc1 * c2h5oh ch3 0 OOCjHg x HC1 - 12 - 23 3 1 4' 10 15 20 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: l-cyclopropyl-6,7 , 8-trifluoro-l, 4-dihydro-5-methyl-4-oxo- 3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-6 , 7-difluoro-1,4-dihydro-5-methyl- 4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6,7-difluoro-1,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid, l-ethyl-6,7,8-trifluoro-l, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid Ethyl l-cyclopropyl-6,7,8-trifluoro-l, 4-dihydro-5-methyl- 4-oxo-3-quinolinecarboxylate, Ethyl 8-chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methy1-4-oxo-3-quinolinecarboxylate, 6,7-difluoro-1-(4-fluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-cpiinolinecarboxylic acid, 6,7-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-raethy1-4-oxo-3-quinolinecarboxylic acid. 7 -Chloro-l-cyclopropyl-6,8-dif luoro-1,4-dihydro- 5-methyl-4-oxo-3-quinolinecarboxylic acid is not known. It can be prepared according to the following scheme. - 13 - 233142 h2 o COOH 'COOH dabco COOH DABCO = l,4-Diazabicyclo[2,2,2]octane The compounds of the formula III having the structures J \ /\ \ / y\ N - f C.W2 ) j N- , E G N- , E G N- , _i/ E G>/ N- are known (EP-PS 230,274). Some of the compounds of the formula III used as starting compounds and having the structures fCgjT CCH2)„-r (ch2),— R1 I I fa ill xO 3=3 kr<CH2'm 23 3142 are new. They can be prepared by various methods: 1. By reaction of the spiro-oxiranes protected on the nitrogen atom (1) [J. Med. Chem. 30, 222 (1987); 5 US-P 4,508,724; EP-PS 189,370] with amines (2), ring opening to give the hydroxylamines (3) occurs. Removal of the protective group yields starting compounds of the formula (Ilia): A 0H s*7 ■"2j 1—A I i + HN ' i I ~ ^N^CCH?)„ Vr?S \N^(CH2)n I 2 •" I i:s ois (1: (25 (3) R18 = COO-alkyl or CH2C6H5 OH ^R7 <CH2, _^_CH2-N^e H * * (Ilia) 10 2. The cyclization of the succinic acid ester (4) [Tetrahedron Letters 46, 4561 (1973)] with ben-zylamine yields the alkyl l-benzyl-3-hydroxy-5-oxo-pyrrolidin-3-carboxylate (5) which, by reaction with an amine (2), reacts to give the amide (6). Sub-15 sequent reduction with LiAlH* and hydrogenolytic cleavage of the benzyl group yields starting compounds of the formula (Illb): l* ft BF flff - 15 - 233142 oh Reaction of (l-benzyl-3-hydroxy-2,5-dioxo-pyr-rolidin-3-yl)-acetic acid (7) [Gazz. Chim. Ital. 24, 226 (1894)] to give the amide (8) and subsequent reduction with LiAlH* and removal of the benzyl group yields starting compounds of the formula (IIIc): h (iiic) 3-Hvdroxy-3-methyl-pyrrolidine can be prepared by LiAlH4 reduction of 4-hydroxy-4-methyl-pyrrolidin-2-one [Zh. Org. Xhim. L4, 7, p. 1420 (1978)] or by debenzvlation of 1-benzyl-3-hydroxy-3-methylpyr-rolidine (EP 132,845). Starting from cyclic oxo-amines (9) which are blocked on the nitrogen by a protective group, starting compounds of the formulae (Hid), (Hie), (Illf) can be synthesized [Acta Chem. Scana. B 34, 319 (1980)]. rtu OH (ch7> T J" "" (9) ch3no, (CH,)p—(c:-:2|p .. ± i- -1 F I — \ I • "" (:c i mid) fti0 = coc-Alfcyl, ru.-r, l"2 w6"3 (Ch^) p 1 ■ JTK (12) KCN or (C:-:3)3 s-cs / lCii2!p— \N"(CH2)- i». " NH, C CH21P—j/N°h V(CH25n» (Ille) NH; S"-<ra2>= h (Illf) 6. The hydroxy1 group of the hydroxylamines (Ilia) -(Ille) can be alkylated or halogenated. 7. Xetals, thioketals or aminals can be prepared from the cyclic oxaiaines (9) [Helv. Chim. Acta 50., 1289 (1967)]. By reaction of the spiro oxiranes protected on the nitrogen atom (1) with trimethylsilyl cyanide [J. Amer. Chem. Soc. 104. 5849 (1982)], the isonitriles (14) can be prepared which, by hydrolysing and removing the protective group, can be reacted to give the starting compounds of the formula (Illg): ( ch2 ) p—^2^. I I * (CH-)-: SiCN • i 1 ) nk2 NC ( CH2 ) D r^^OK (CH2 ) p i (CH3 ) 2 ! 11 " \N^(CH2)_ V^H2)n i R1S (14) (Illg) Examples of starting compounds of the formula (III) which may be mentioned are the following compounds, it being possible to employ chiral compounds both as racemates and as enantiomerically pure substances: 3 -Aminomethyl-3 -hydroxy-pyrrolidine, 3 -Ac e tyl am inome thy 1 - 3 -hydroxy-pyrrolidine, 4* * 233142 10 15 20 25 30 3-tert.-Butoxyc arbonylaminomethyl-3-hydroxy-pyrrolidine, 3 -Hydroxy- 3 -met hyl aminomethyl -pyrrol idine, 3-Ethylaminomethyl-3-hydroxy-pyrrol idine, 3-Hydroxy-3-propylaminomethyl-pyrro1idine, 3-Ethylaminomethyl-3-methoxy-pyrrolidine, 3 -Ethoxy- 3 -e thylaminome thyl -pyrrol idine, 3-Chloro-3-ethylaminome thyl-pyrrolidine, 3 -E thylaminomethyl-3-fluoro-pyrrolidine, 3-Ethylaminomethyl-3-me thyl-pyrrolidine, 3 -E thylaminomethyl-3 -mercapto-pyrrol idine, 3-Ethylaminomethyl-3-methylthio-pyrrolidine, 3 -Ace t oxy- 3 -et hylaminomethyl -pyrro 1 idine , 3 -Dime thy 1 aminomethyl-3-hydroxy-pyrrol idine, 3 -Hydroxy-3 -pyrrolidinomethyl-pyrrol idine, 3 -Hydroxy- 3 -morphol inome thy 1 -pyrro 1 i dine , 3 -Amino-3-ethylaminomethyl-pyrrolidine, 3 -Acetyl ami no- 3 -ethyl aminomethyl-pyrro 1 idine, 3 -Ethylaminomethyl-3-methylamino-pyrrolidine, 3 -Dimethylamino-3-ethylaminomethyl-pyrrolidine, 3 -Amino-3-hydroxymethyl-pyrrolidine, 3 -Acetylamino-3-hydroxymethyl-pyrrol idine, 3 -Amino- 3 -methoxymethyl -pyrrol idine, 3-tert. -Butoxycarbonylamino-3-methoxymethyl-pyrrolidine, 3-Amino-3-methylthiomethyl-pyrrolidine, 3-Amino-3-mercaptomethyl-pyrrolidine, 3 - Cy c 1 opr opy 1 aminomethyl - 3 -hydr oxy-pyr r o 1 idine, 3 - Is opropylaminomethyl-3-hydroxy-pyrrol idine, 1,4-Dioxa-7-azaspiro[4,4]nonane, l-0xa-4,7-diazaspiro[4,4]nonane, 4-Methyl-l-oxa-4,7-diazaspiro [4,4 ] nonane, 19 233142 l-Thia-4,7-diazaspiro[4,4]nonane, 1,4,7-Triazaspiro[4,4]nonane, 1,4-Dimethyl-1,4,7-tria zaspiro[4,4]nonane. Some of the compounds of the formula III used as a starting material and having the structures s:5i-p:1 h-5 r15 are also new. They can be prepared by the following methods. 1. Starting from the N-protected 3,4-epoxypyrrolidine _/corres. to US Patent (1) (German Offenlegungsschrift 1,929,237, us Patent 3657274 4,254,135), which can optionally carry a further one or two methyl or phenyl radicals, the starting compounds of the formula (Ilia)-(Ille) are prepared. a 12 _ i 2 ' R«aov*l of HN 13 Prot#ctiv* jroup« r.j >19 (1) >18 Yi w i H £ 111 h) >N" FnX5 Base r1*o /R12 11 1-5 of %— R prot«ctiv» group* T R18 (Hii) 23 3 1 42 R" = X = benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or sulphonyl (examples of protective groups), leaving group such as halogen, alkyl- or arylsul-phonyloxy HQ (1) Rl\ RUX5 I - Base R18 ?18 Rug sno RlS Q -^H-C00C(CH3)3 I H (Illj) w (1) R1* - 21 - m >12 P1 -01 XX""" ""XJ j?uOs__>N \R13 ^ H2/Pd 23 3 1 XX-- H <1111) H2 / Pd Rn(X -<NH-R12 XT I (II Ik) H 2. Starting compounds of the formula (Illm) are obtained from 2-(l,2-dichloroethyl)-oxirane via the following reaction sequence: EXx-nci CI HO CI u H11C- R:10 OH p11o o .-■*v 23 3 1 b1:0 n 12 \R13 r110 n H- ^R12 \Rl3 I h (Ilia) By addition of azides to N-benzylmaleimides optionally substituted with one or two methyl or phenyl radicals, starting compounds of the formula (III n) can be prepared: n^n^N-R18 0^N^( oMo R40"/ p-^H-RlS R<Q//„ ^H-Rl9 I I Reduction | T R110-''>'4 ^tiH - R19 H (Illn) 23 3 1 H, alkyl or benzyl. From the 3,4-epoxypyrrolidines (1) via a cyclization with thionyl chloride, the starting compounds of the formula (III o) are obtained: K3 'i. ^H2 HO ^//j H- CC- P- ^ (1) SOCl, R18 R18 R1 U I H (III o) By reacting the 3,4-epoxypyrrolidines (1) with ethanolamines by intramolecular etherification, the starting compounds of the formula (III p) are obtained: >14 oAN R 18 HO r!3 . , l^s^OH ^X^NH-R6 HO N (1 ) ■N^ >18 H 0 N-R13 > ( R»8 0 N-R13 I H (III p). 23 3 1 The starting compounds of the formula (III q) are obtained from amino acetaldehyde dimethyl acetal via an intramolecular 1,3-dipolar cycloaddition. r15 rls-nh, 0ch3 -och3 h2c; Base rls-n /ch2 OCH3 •och3 h + ,15 RiS-N f*2 ~ ^y^cno r13-kh-c:- 45 r13*h /°^N-R13 ,15. ol 8 /°^N-R13 ,15. I H (III q) Starting from N-benzyl-pyridine-2,3-dicarboximide, starting compounds (III r) or (III 1) are prepared via the reaction steps indicated. r> 7331 ^2 0 alkyl LiAlH4 H 2/Pd- 23 3 1 H7/?d-C v alkyl (III r) 8. N-benzyl-maleimide adds 2-chloroethylamine to give the 3-(2-chloroethylamino)-succinimides, which are reacted to give the starting compounds of the formula (III t): < j i n-ch2-c6h5 4 c1-ch,ch2-nh-r13 2 2 CI ch- NaH ch2-n 0 ( 13 n-ch2-c6h5 N ■N-CH2-C6H5 LiAlH4 >13 LJ n-ch2-c6hs 13 J"** 23 3 14 2 —' ■> r<* ~ (II: ♦) 9. 2-Methyl-2-propenal dimethylhydrazone reacts with N-benzylmaleimide to give a cycloadduct which can be converted into the starting compound (III u) by the reaction sequence indicated. ch3vj£h2 ch3-. ♦ |l^K-CH2-Ph • ||^ J^^N-CH2-ph NO K 0 / \ / \ ch3 ch3 ch3 ch3 -(ch3)2kh ch3n^v>x h2/ cata-CH3 Uiv/N-CH*-ph TJS" Us/N-c"2-p'' H T H T 0 0 LiAlH4 H2/Pd-C CH3Nr^'sSf^\ ~ W™2"'6 —' uv™ (in u) 5 According to this general reaction scheme, for example, the following starting compounds can be prepared. They can be prepared and employed as diastereoiner - 28 - 233142 mixtures, in diastereomerically pure and also in enantiomerically pure form. 4-Amino-3-hydroxypyrrolidine, 3 -Hydroxy- 4 -methylaminopyrrol idine, 5 4 - D ime t hy 1 amino- 3 -hydr oxypyrr o 1 idine, 4 - E thylamino- 3 -hydroxypyrrol idine, 3-Amino-4-methoxypyrrolidine, 4 -Methoxy- 3-methylaminopyrrolidine, 3-Dimethylamino-4-methoxypyrrolidine, 10 3 -Ethylamino-4-methoxypyrrolidine, 3 -Amino-4-ethoxypyrrolidine, 4 -Ethoxy-3-methylaminopyrrolidine, 3 -Dimethylamino-4 -e thoxypyrro 1 idine, 4-Ethoxy-3-ethylaminopyrrolidine, 15 3-Hydroxy-4-hydroxyaminopyrrolidine, 3 -Hydroxy-4 -methoxyaminopyrrolidine, 3-Hydroxyamino-4-methoxypyrrolidine, 4 -Methoxy- 3 -me thoxyaminopyrrol idine, 3-Benzylamino-4-methoxypyrrolidine, 20 4-Methoxy-3-( (5-methyl-2-oxo-l, 3-dioxol-4-yl)-methyl-amino) pyrrolidine, 3 -Amino-4 -methylmercaptopyrrolidine, 3-Acetoxy-4-dimethylaminopyrrolidine, 3-Acetamido-4-methoxypyrrolidine, 25 4-Methoxy-3-methoxycarbonylaminopyrrolidine, 3 -Formamido-4-methoxypyrrolidine, 3 -Amino - 4 -me tho xy- 2 -me thy lpyr ro 1 idine, 3-Amino-4-methoxy-5-methylpyrrolidine, 4 -Methoxy-2-methyl-3-methylaminopyrrolidxne, 30 4-Methoxy-5 -me thy 1 - 3 -methyl mn i nopyrrolidine, - 29 - 23 3 142 3-Amino-4-methoxy-2-phenylpyrrolidine, 4-Methoxy-3-meth.ylamino-5-phenylpyrrolidine, 3-Methyl-2,7-diazabicyclo[3.3.0]octane, 4-Methyl-2,7-diazabicyclo[3.3.0]octane, 5 5-Methyl-2,7-diazabicyclo[3.3.0]octane, 3,5-Dimethyl-2,7-diazabicyclo[3.3.0]octane, 1,5-Dimethyl-2,7-diazabicyclo[3.3.0]octane, 2-Oxa-4,7-diazabicyclo[3.3.0]octane, 3,3-Dimethyl-2-oxa-4,7-diazabicyclo[3.3.0]octane, 10 3-Oxa-2,7-diazabicyclo[3.3.0]octane, 1,2-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 2,5-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 2,8-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 5-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 15 2-Oxa-4,7-diazabicyclo[3,3,0]oct-3-ene, 3-Methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 3-Phenyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 6-Methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 8-Methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 20 3-Methyl-2,8-diazabicyclo[4.3.0]nonane, 4-Methyl-2,8-diazabicyclo[4.3.0]nonane, 5-Methyl-2,8-diazabicyclo[4.3.0]nonane, 6-Methyl-2,8-diazabicyclo[4.3.0]nonane, 3-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 25 4-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 1-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 3,5-Dimethyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 2-Thia-5,8-diazabicyclo[4.3.0]nonane, 5-Methyl-2-thia-5,8-diazabicyclo[4.3.0]nonane, 30 3,5-Dimethyl-2-thia-5,8-diazabicyclo £4.3.0]nonane, - 30 - - 23 3 1 A 2 3-Oxa-2,8-diazabicyclo[4.3.0]nonane, 2-Methyl-9-oxa-2,8-diazabicyclo[4.3.0]nonane, 4-Methyl-3-oxa-2,8-diazabicyclo[4.3.0]nonane, 2,5-Dimethyl-3-oxa-2,8-diazabicyclo[4.3.0]nonane, 5 3-Oxa-5,8-diazabicyclo[4.3.0]nonane, 5-Methyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane, 1,5-Dimethyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane, 4,4-Dimethyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane. The reaction of (II) with (III), in which the 10 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-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoramide, sulpholane, acetonitrile, water, an alcohol such as methanol, 15 ethanol, n-propanol or isopropanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used. Acid scavengers which can be used are all customary inorganic and organic acid-binding agents. These 20 preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Those which may be mentioned as being particularly suitable are: triethylamine, 1,4-diazabicyclo [2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-25 7-ene (DBU) or excess amine (III). The reaction temperatures can be varied within a relatively wide range. In general, the reaction is carried out between about 20 and 200°C, preferably between 80 and 180*C. 30 The reaction can be carried out at normal pres- - 31 - 23 3 142 sure, but also at elevated pressure. In general, the reaction is carried out at pressures between about 1 and 100 bar, preferably between 1 and 10 bar. When carrying out the process according to the 5 invention, 1 to 15 moles, preferably 1 to 6 moles, of the compound (III) are employed per mole of the carboxylic acid (II). Free hydroxyl groups can be protected during the reaction by a# suitable hydroxyl protective group, for 10 example by the tetrahydropyranyl radical, and after completion of the reaction are set free again (see J.F.W. McOmie, Protective Groups in Organic Chemistry (1973), page 104). Free amino functions can be protected during the 15 reaction by a suitable amino protective group, for example by the ethoxycarbonyl or the tert.-butoxycarbonyl radical, and after completion of the reaction are released again by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-20 Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], volume E4, page 144 (1983); J.F.W. McOmie, Protective Groups in Organic Chemistry (1973), page 43). To prepare the ester according to the invention, the carboxylic acid on which they are based is preferably 25 reacted in excess alcohol in the presence of strong acids, such as sulphuric acid, anhydrous hydrogen chloride, methanesulphonic acid, p-toluenesulphonic acid or acidic ion exchangers, at temperatures from about 20* to 200*C, preferably about 60* to 120*C. The resultant 30 water o£ reaction can also be removed by azeotropic - 32 - 23 3 14?. distillation using chloroform, tetrachloromethane, benzene or toluene. The preparation of esters is also advantageously-carried out by heating the acid on which they are based 5 with dimethyl formamide dialkyl acetal in a solvent such as dimethylformamide. The (5-methyl-2-oxo-l,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 10 are based with 4-bromomethyl or 4-chloromethyl-5-methyl-l,3-dioxol-2-one in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulph-oxide or tetramethylurea at temperatures from about 0° to 100°C, preferably 0° to 50°C. 15 The preparation of the acid addition salts of the compounds according to the invention is carried out in a customary manner, for example by dissolving the betaine in excess aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, 20 acetone or acetonitrile. Equivalent amounts of betaine and acid can also be heated in water or an alcohol such as glycol monomethyl ether and then evaporated to dryness or the precipitated salt filtered off with suction. Pharmaceutically utilizable salts are taken to mean, for 25 example, the salt of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. 30 The alkali metal or alkaline earth metal salts of ii pi or itr 33 - 233142 10 15 20 25 30 the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in a subequivalent amount of alkali metal or alkaline earth metal hydroxide solution, filtering off undissolved betaine and evaporating the filtrate to dryness. Pharma-ceutically suitable salts are those of sodium, potassium or calcium. The corresponding silver salts are obtained by reaction of an alkali metal salt or alkaline earth metal salt with a suitable silver salt such as silver nitrate. In addition to the active compounds mentioned in the examples, the compounds shown by way of example in Table 1 can also be prepared, it being possible for these compounds to be present both as diastereomer mixtures and also as diastereomerically pure or enantiomerically pure compounds. The compounds according to the invention show, combined with low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative bacteria, in particular against Enterobacteriaceae; above all also against those which are resistant to various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines. These useful properties facilitate their use as chemotherapeutic active compounds in medicine and also as substances for the preservation of inorganic and organic materials, in particular of organic materials of all types, for example polymers, lubricants, dyes, fibres, leather, paper and wood, and of foodstuffs and water. - 34 - 23 3 142 The compounds according to the invention are active against a very wide spectrum of microorganisms. Gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled with their aid, and 5 the diseases produced by these pathogens can also be prevented, improved and/or cured. The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly well 10 suited in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections which are produced by these pathogens. For example, local and/or systemic diseases which are caused by the following pathogens or by mixtures of 15 the following pathogens can be treated and/or prevented: gram-positive cocci, for example staphylococci (Staph, aureus, Staph, epidermidis) and streptococci (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes); gram-negative cocci (Neisseria gonorrhoeae) 20 and also gram-negative rods such as Enterobacteriaceae, for example Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divemis), Salmonella and Shigella; furthermore Klebsiella (Xlebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aero-25 genes, Ent. agglomerans), Hafnia, Serratia (Serr. mar-cescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia, and also the order Acinetobacter. Moreover, the antibacterial spectrum comprises the order Pseudomonas (Ps. aeruginosa, Ps. 30 maltophilia) and also strictly anaerobic bacteria such - 35 - 23 3 1 as, for example, Bacteroides fragilis, representatives of the order Peptococcus, Peptostreptococcus and also the order Clostridium; furthermore mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and also mycobacteria, for 5 example Mycobacterium tuberculosis. The above enumeration of pathogens is merely by way of example and in no way to be conceived as limiting. Examples of diseases which may be caused by the said pathogens or mixed infections and which may be prevented, 10 improved or cured by the compounds according to the invention, which may be mentioned are: infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, 15 bronchitis (acute, chronic), septic infections, diseases of the upper airways, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, hepatic abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, 20 skin infections, post-operative wound infections, abscesses, phlegmone, wound infections, infected burns, scalds, infections in the oral region, infections after dental operations, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, 25 intra-abdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhus, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections. 30 In addition to humans, bacterial infections can - 36 - ♦ • 2 3 3 14 2 also be treated in other species. Examples which may be mentioned are; pig: coli-diarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis, mastitis-metritis-agalactia syndrome, 5 mastitis; ruminants (cow, sheep, goat): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections; horse: bronchopneumonias, joint-ill, puerperal and post-10 puerperal infections, salmonellosis; dog and cat: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections, prostatitis; poultry (hen, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic 15 airway diseases, salmonellosis, pasteurellosis, psittacosis. Bacterial diseases in the rearing and keeping of productive and ornamental fish can likewise be treated, the antibacterial spectrum being widened beyond the 20 previously mentioned pathogens to further pathogens such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia. The present invention includes pharmaceutical 25 preparations which contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention in addition to non-toxic, inert pharmaceutically suitable excipients and processes for the production of these preparations. 30 The present invention also includes - 37 - 2 3 3 14 2 10 15 20 25 30 pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual portions, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, whose active compound content corresponds to a fraction or a multiple of an individual dose. The dosage units may 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 administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. Non-toxic, inert pharmaceutically suitable excipients are taken to mean solid, semi-solid or liquid diluents, fillers or formulation auxiliaries of any type. Preferred pharmaceutical preparations which may' be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets, capsules, pills and granules may contain the customary excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrants, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retardants, for example paraffin and (f) absorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol - 38 - 23 3 1 4 monostearate, (h) adsorption agents, for example kaolin and bentonite and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols or mixtures of the substances mentioned 5 under (a) to (i) in addition to the active compound(s). The tablets, coated tablets, capsules, pills and granules may be provided with the customary coatings and shells containing, if appropriate, opacifying agents and can be so composed that they release the active com-10 pound(s), if appropriate with a delay, only or preferably in a certain part of the intestinal tract, it being possible, for example, to use polymeric substances and waxes as embedding materials. If appropriate, the active compound(s) may also 15 be present in micro-encapsulated form with one or more of the abovementioned excipients. Suppositories may contain the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and 20 higher esters (for example C^-alcohol with C16-fatty acid) or mixtures of these substances in addition to the active compound(s). Ointments, pastes, creams and gels may contain the customary excipients, for example animal and vege-25 table fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances in addition to the active compound(s). Powders and sprays may contain the customary 30 excipients, for example lactose, talc, silica, aluminium - 39 - . 0^ 5 10 15 20 25 w' 30 23 3 1 4 hydroxide, calcium silicate and polyamide powder or mixtures of these substances in addition to the active compound(s). Sprays may additionally contain the customary propellants, for example chlorofluorohydrocarbons. Solutions and emulsions may contain the customary excipients, such as solvents, solubilizers and emul-sifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, 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 in addition to the active compound(s). For parenteral administration, the solutions and emulsions may also be present in sterile and blood-isotonic form. Suspensions may contain the customary excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances in addition to the active compound(s). The said formulation forms may also contain colorants, preservatives and also odour-improving and flavour-improving additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin. 23 3 142 The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight, of the total 5 mixture. The abovementioned pharmaceutical preparations may also contain further pharmaceutical active compounds in addition to the compounds according to the invention. The preparation of the abovementioned pharmaceu-10 tical preparations takes place in a customary manner by known methods, for example by mixing the active com-pound(s) with the excipient(s). The preparations mentioned may be used in humans and animals either orally, rectally, parenterally (intra-15 venously, intramuscularly, subcutaneously), intracister-nally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy of infections in hollow spaces and body cavities. Suitable preparations are injection solutions, solutions and suspensions for 20 oral therapy, gels, pour-on formulations, emulsions, ointments or drops. For local therapy, ophthalmological and dermatological formulations, silver salts and other salts, ear drops, eye ointments, powders or solutions may be used. In animals, the administration may also take 25 place in suitable formulations via the feed or drinking water. Furthermore, gels, powders, tablets, delayed-release tablets, premises, concentrates, granules, pellets, boli, capsules, aerosols, sprays and inhalants may be used in humans and animals. Furthermore, the 30 compounds according to the invention may be incorporated Iiu #i Cg TTBfc - 41 - 2 3 3 14 2 10 15 20 25 30 into other excipient materials such as, for example, plastics, (plastic chains for local therapy), collagen or bone cement. In general, it has proved advantageous both in human and veterinary medicine to administer the active compound(s) 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 attain the desired results. An individual dose preferably contains the active com-pound(s) 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 depart from the dosages mentioned, depending on the type and the body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the administration of the medicament and also the time period or interval within which the administration takes place. Thus in some cases it may be sufficient to manage with less than the abovementioned amount of active compound, whereas in other cases the abovementioned amount of active compound must be exceeded. The optimum dosage required in each case and the type of administration of the active compounds can easily be established by any person skilled in the art on the basis of his expert knowledge. The new compounds may be given in the customary concentrations and preparations together with the feed or feed preparations or with the drinking water. Infection by gram-negative or gram-positive bacteria can thus be 23 3 1 prevented, improved and/or cured and promotion of growth and an improvement in the utilization of the feed can thus be achieved. The minimum inhibitory concentrations (MIC) were determined by the serial dilution method on iso-sensitest agar (Oxoid). A series of agar plates which contained concentrations of the active compound decreasing in double dilutions in each case were prepared for each test substance. The agar plates were inoculated using a multipoint inoculator (Denley). For the inoculation, overnight cultures of the pathogens were used which were previously diluted in such a way that each inoculation point contained about 10" colony-forming particles. The inoculated agar plates were incubated at 37 #C and the bacterial growth was read off after about 20 hours. The MIC value (^g/ml) indicates the lowest active compound concentration with which no bacterial growth could be detected with the naked eye. 04 hO hO CNl id chd j chd h ch3 11 ciij v c" c ( / \ -n ~n an / \ -n j"n / \ -n >n \^-J ,U h h SHZ0 h * >a ,UOOD I aidVJi ) o TABLE 1 (continuation) R1 Ln ~c2h5 -c2«5 •o* F -ch=ch2 ho-ch2ch2- F' h h h h h h h IV V / nyj n- V / \ / N^N- \ / nT'V \ / n- \ / n- \ / i ) H' CH- II ch- cm- ch., CM' II CH- (:2»S h (I ro CM oi ro TABLE 1 (continuation) t i r1 r2 R3 a /\ h ft: z i j c2»5 f /\ /X -c2H5 -ch^ov^ ch3^ o CH3N0 A ch3nJ~^n- cu3 ch3 ' ii F /N h ch3 ii /N h hnT^h- C2»5 >1 A, H 0^H2-NSM" ch3 ii ro 0-4 o* ( ( ; table 1 (continuation) R1 R2 R4 /X H ,W>~C,I2-N^/ H N^T 'N- ch3 /N H H N- ch-, "X"' ch3 /N H 1 r2v z /N H ) ll- ch- ch- ch- C2H5 ch- C2»5 ch- cn CI CI ro CM CM 4> 1 c > TABLE 1 (continuation) R R' r' f-ch2-ch2~ ch30- H h h h H h5^H. \ / »TV V / r^\ hf n- /p=*A nxj n-\ / chth^ s n- J v: / ) R- CM' c5ht cm- cm- ch- 3 a f 5 ch3 ch3 no2 m jr* 1 >-• TABLE 1 (continuation) R R< r'1 chg-nh- h H H H CH- N2ZyN '£> hn hn / n v / r^\ hn j n ) iv R' CH- ch- ch- C2»5 !<• Ur cn cn ro CM CM r- ( ) f<"j ) TABLE 1 (continuation) r1 r2 r4 r3 a A, h rYT h ch3 ch3 A\ c2h5 ro- ii ch3 ii AN h 00- h cm3 ii AN h CO- h cii3 ii 04 £5 irv * po TABLE 1 (continuation) r1 r2 c2"5 h c2h5 h -o h f h -ch=ch2 h <; R" ch- CH. ch3 C2»5 cll- ll i'll f ro 04 CM TABLE 1 (continuation) R R< ho-ch2ch2- H h h ~C2H5 ■ch' YY° ^ o CHr t- ) ' ) N- N- n- N- n- R- cm- CM- Clb ch- CH- F C1 CI F ro Ol CM 4> ro ( ( > TABLE 1 (continuation) R> R2 r4 /N H 00- rf H H CO- n H /\ H 00- rf H /\ H 00- H rt . /N H CO M H c2»b ) c2»r, F C2M5 CI ch- cn cm- no- ro CM CM ro TABLE 1 (continuation) ( > r1 R< R f-ch2ch2- H h H H H h3C Hr H h3C H CH' II CH' () y lien- c3»7 cii- CH' ch-j cii-. K CI ro CM CM -£> ro ( TABLE .1 (continuation) r1 r2 r4 h ca h h ii z-N h par h ch3o- h C^r h chg-nh- h ro- ( ) lien. ch. cm- cm. CH' II F CI H II ro OJ CM ro TABLE 1 (continuation) ( > R' R< R ^N, XX h H h h cm h CH' h ch. sN- N h ch' CHoO, h2n n- i ) ' ) J ■ h3 a ch3 ii ch3 i.- cll3 ci c hj !•' ro CM CM ro TABLE 1 (continuation) ( ) R1 R' r' H H H H H O' I NT II N- CH' -N- N- II CO" H ch 3°Y^T H2N .V ) '•) i cm3 11 cn3 f ch3 ii ch3 k ch3 ch3 ro Ok CaI mnt^k ( C i TABLE 1 (continuation) r2 r4 A, h chgokj^^n-h2n \\nv h chaov^^n- h2n \vv ' "c2h5 h chgokj^-n- h2n \\v ' c2h5 chgcx/^n- h2n \wv ' /N h choov^^n- P h2n a F F CI CI F ro CM CM 4>* TABLE 1 (continuation) R R' R c2hs CHr H H H H CH H2N CH. '73 < HoN hov^N- Xj h2n H0.^| a h2n CH30"V^-*^N- ch3-NH-^ o 0 4 1 R- CH- CH. CH. CH- CH. CI F F H ro 04 CM 4>» ro 2 3 3 1 A 2 u El. n CJ cn; (J JP ~b u rj 5 n u EX C o ••H .P (0 3 C •H +> c o o K fr- CC < Eh N OS <] - 60 - CM ro K5 CM N3 Jj J 10 .'I II t c> OH ZHDHN-CHD h h 'hd h3- -S..Z HO shz3 h h h "<l ,U rU ( ) o o R1 R< H R- CH' in to C2H5* > H H H H H CoH 2n5 CH' CH- c2h5 CHo CH- CH- ) 1 R4 CH3-NHCH2v/ N- K HO' C2H5-NHCH2vy N- H HO'' F F II It ro CM CM —A. JO- ro ( O) u> r1 r2 r3 1> -c»2-<nr ;—0 ch3 ch3 •• c2h5 ch3 •1 -c"2-fr ch3 ch3 <1 h ch3 «» h ch3 •• h C2H5 II h ch3 M h ch3 ir c2h5-nhch2 ho CH' >n-ch ch- 2 ho c2h5nh -ch2 ch30 > ) 1 a Ii f f II f f CI II ro CM 04 45-FO 23 3 1 4 ii fa. u z u A 23 3 1 42 fc 'A CN3 o z z u i u <5^ t? ■ • ■ ■ R • • 0.. >c is NO O Z S U IS LJ i v • N Z I _N n 2m m I n ninn n n n n n n S SNUS X IS X II u u U I u U UU U 'JU c (VJ a h h h h h h h h h h II £5 ff <1 23 3 1 A 2 Is. r, y (M 6 i z c\j n n E J? S1 u u <VJ K H H a A . - 66 - 23 3142 Example A 7-Chloro-l-cyclopropyl-6,8-dif luoro-1 /4-dihydro-5-methyl 4-oxo-3-quinolinecarboxylic acid a) F 0 5 8.0 g of l-cyclopropyl-5/6,7,8-tetrafluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and 7.9 ml of thionyl chloride are boiled until gas no longer escapes. The mixture is then concentrated in vacuo. 50 ml of ethanol are added to the residue and the mixture is 10 boiled for two hours. It is then cooled to room temperature and the solid precipitated is isolated. Yield: 8.6 g of ethyl 7-chloro-l-cyclopropyl-5,6,8-trif luoro-1,4-dihydro-4-oxo-3-quinolinecarb-oxylate 15 Melting point: 166-168° b) EtOOC^ ^CN - 67 - 23314* " 9^ 1.6 ml (0.015 mol) of ethyl cyanoacetate are initially introduced into 50 ml of absolute dioxane and 0.58 g of sodium hydride (as the 80% strength material) are added at 20°C. After 30 minutes, 3.45 g (0.01 mol) of 5 substance from a) are added. The mixture is then boiled under reflux for 6 hours. After cooling to 20°, the mixture is diluted with water and rendered acidic with hydrochloric acid. The solid is isolated, dried and recrystallized from isopropanol. 10 Yield: 2.3 g of ethyl 7-chloro-5-(cyano-ethoxycarbonyl-methyl) -l-cyclopropyl-6,8-dif luoro-1,4-dihydro-4-oxo-3-quino1inecarboxy1ate Melting point: 156-57°. c) cooh cooh 15 2.3 g of substance from b) are heated at 140° for 4 hours together with 6 ml of acetic acid, 5 ml of water and 0.5 ml of sulphuric acid. The mixture is cooled to 20° and diluted with water. The solid is isolated, washed with water and dried. 20 Yield: 1.6 g of 5-carboxyxnethyl-7-chloro-l-cyclopropyl- 6, 8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acid - 68 - 23 3 1 4 Yield: 236-8° (d.) Analysis; calculated: C 50.3 H 3.0 N 3.9 CI 9.9 found: 50.5 3.2 3.7 10.0 5 50.6 3.2 3.8 9.9 d) 1.0 g (2.8 mmol) of substance from c) and 0.9 g (8.4 mmol) of 1,4-diazabicyclo[2.2 .2]octane are heated at 140° for 3 hours in 20 ml of dimethyl sulphoxide. The 10 solvent is then removed in a high vacuum and the residue is chromatographed on silica gel (eluent: methylene chloride/methanol 99/1). Yield: 0.2 g of 7-chloro-l-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid 15 Melting point: 195-7° Example 1 It il 1IT Tlf - 69 - 23 3 1 A? 0.56 g (2 mmol) of l-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated at 140°C for 2 hours with 0.384 g (3 mmol) of 2,8-diazabicyclo[4.3.0]nonane and 0.672 g (6 mmol) of 1,4-5 diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. After cooling, the DMSO is removed in a high vacuum. The residue is taken up using acetonitrile. The solid is separated off, washed with acetonitrile and dried at 60-80°. 10 Yield: 0.7 g of l-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]non-8-yl) -6-f luoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate Melting point: 174-6° with decomposition Example 2 COOH 15 0.28 g (1 mmol) of l-cyclopropyl-6,7-difluoro- 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate are heated at 140°C for 2 hours with 0.19 g (1.5 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.34 g (3 mmol) of l,4-diazabicyclo-[2.2.2. ]octane in 3.5 ml of dimethyl 20 sulphoxide. The dimethyl sulphoxide is distilled off in a high vacuum. The residue is stirred with acetonitrile and the solid is isolated. - 70 - 23 3 1 Yield: 0.27 g of l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl) -4-oxo-3-quinolinecarboxylic acid Melting point: 273-5° Example 3 CH, 0 F X A .COOH 0.14 g (0.5 mmol) of l-cyclopropyl-6,7-difluoro-1, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated at 140° for 2 hours with 0.084 g (0.75 mmol) of 2,7-diazabicyclo[3.3.0]octane and 0.17 g (1.5 mmol) of 10 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. Dimethyl sulphoxide is then distilled off in a high vacuum. Acetonitrile is added to the residue, whereupon a solid forms. Yield: 0.15 g of l-cyclopropyl-7-(2,7-diazabicyclo-15 [3.3.0] oct-7-yl) -6-f luoro-1,4-dihydro-5-methyl- 4-oxo-3-quinolinecarboxylic acid Melting point: 232-4° with decomposition Example 4 CH3 0 COOH - ** 23 3 1 42 0.28 g (1 mmol) of l-cyclopropyl-6,7-difluoro-1, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated to 140° for 2 hours with 0.213 g (1.5 mmol) of 5-methyl-3-oxo-5,8-diazabicyclo[4.3.0]nonane and 0.34 g (3 5 mmol) of l/4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. The solvent is then removed in a high vacuum. After stirring the residue with acetonitrile, 0.22 g of l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-7-(5-methyl-3-oxo-5,8-diazabicyclo[4.3.0]non-8-10 yl)-4-oxo-3-quinolinecarboxylic acid are obtained. Melting point: 208-10° with decomposition Example 5 0.28 g (1 mmol) of l-cyclopropyl-5,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are 15 heated at 140° for 2 hours with 0.17 g (1.5 mmol) of 1,4-diazabicyclo[3.2.1]octane and 0.34 g (3 mmol) of 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. After removing the solvent in a high vacuum, the residue is stirred with acetonitrile and the solid is 20 isolated. Yield: 0.24 g of l-cyclopropyl-7-(l,4-diazabicyclo-[3.2.1] oct-4-yl) -6-f luoro-1 / 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid Melting pointt 274-76* with decomposition Bill iiN'flf iTftf - 72 - 23 3 1 4 F 6,7-Difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolonecarboxylic acid a) o CH3 II yco OEt I C- C F F F 21 g of ethyl 3-ethoxy-2-(2,4,5-trifluoro-6-methyl-benzoyl)acrylate are initially introduced into 55 ml of ethanol. 9.4 g of 2,4-difluoroaniline are added dropwise with cooling. The mixture is then stirred at 25°C for one hour. 55 ml of water are then added and the solid which precipitates is isolated. Yield: 25 g of ethyl 3- (2,4-difluorophenylamino)-2-(2,4,5-trifluoro-6-methyl-benzoyl)-acrylate Melting point 109-10°C. 23 3 14 2 ■ F 12.5 g.of substance from a) and 5.1 g of potassium carbonate are heated at 140°C for 4 hours in 60 ml of dimethyl formamide. After cooling to room temperature, 5 the mixture is diluted with water. The solid which precipitates is isolated and dried. Yield: 11.3 g of ethyl 6,7-difluoro-1-(2,4-difluoro-phenyl ) -1 / 4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylate 10 Melting point: 157-9° 6^ I F 11.2 g of substance from b), 70 ml of acetic acid, 70 ml of water and 3.5 ml of sulphuric acid are heated at 140"C for 4 hours. After cooling to room 15 temperature, the mixture is diluted with water. The solid is isolated and dried. 10.3 g of the title compound are ft iC Tifr 74 9 3 314 2 obtained. Melting point: 277-8°C Example 6 F 0.6 g of substance from Example B, 0.57 g of 1,4-aiazabicyclo[2.2.2]-octane and 0.25 g of 2,8-diaza-5 bicyclo[4.3.0]-nonane are stirred at room temperature in 5 ml of dimethyl sulpfroxide until starting material is no longer detectable in the thin layer chromatogram. The mixture is then concentrated in vacuo. Water is added to the residue ana the solid is isolated. 10 Yield: 0.6 g of 7-(2#8-diazabicyclo[4.3.0]non-8-yl)-l-(2 , 4-dif luor ophenyl) -6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. Melting point: 247-8*C. ^ iU iJb - 75 - </div>

Claims

1.1 g (3.5 mmol) of the compound according to Example A d). 0.59 g (5.3 mmol) 2,8-cia2abicycio[4.5.0]nonane and 1.58 g (10.5 mmol) l?4-diazabicyclo[2.2.2]octane are dissolved in 20 ml dimethylsulfoxiae and are heated to 140=C for three hours. Subsequently, me reaction mixture is cooled down to room temperature and the solvent is removed in vacuo. The residue is dissolved in water and the pK is adjusted to 7. The precipitate is isolated by nitration, washed with water ana dried.

1.0 g' l-cycIopropyi-7-f2,8-aiaza-bicycio[4.3.0]non-S-yi)-6.8-difiuoro-l,4-dihydro-5-methyi-4-oxo-S-quinoione carboxylic acid is obtained. Melting point: 185 - 7CC. - 76 - A! AT WE CLAIM IS: Quinolonecarboxylic crmula (I) acid derivatives of the n which represents straight-chain or branched C,-C»-alkyl which is optionally substituted by hydroxyl, halogen, C.-Cj-aIkoxy or C^C^-aiJcvlthio, C2-Cs-cyclo-alJcvl which is optionally substituted by halogen t C,-C3-alley! or C2-C4-alkenyl, Ct-C3-alkoxy, amino, monoalkylamino having 1-3 C atoms, dialkylamino having 2-o C atoms or phenyl which is optionally substituted by halogen, ~2 represents hydrogen, alkyl having 1 to 4 carhon atoms or (5-methyI-2-cxo-l, 3—aioxol-4-yl) -methyl, ~3 denotes C-Ct-alkyl, i represents a radical, which is optionally substituted in the ring system by hydroxyl or methyl, of the formula N- (CH2 ) , EJ3 N- , EVGC^N" « or £vg//" n which represents R5-N, 0 or S, represents -(ch23j-, -ch2-o-ch2-, / '/ 3 31 4 2 ch,-n-c:-:2-, -ch2-s-ch2-, or -ch2-s-, j represents 1, 2 or 3, R5 represents hydrogen, or aikyi. alkenvl or alkinvl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, benzyl which is optionally substituted by nitro or amino, oxoalkyl having 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3—dioxol-4-vl) -methyl, and Rs represents hydrogen or methyl, Ri alternatively may represent a radical of the formula x^ sioil P—i~*Ch'2; n ~ w Ifclip' r r i , « r ! ( CH- )a C CK2 J m ' or (ch3J0—L 510T;P I ^CC;-"2Ja in which, p represents 0, 1 or 2, m represents 1 or 2, where p + m together can be 1, 2 or 3, n represents 1 or 2, ^7 W represents ^ t OR3, SRa, balocen or hydrogen, - 78 - V PA? /0~ >33142 ~7 X1 represents X > OR3, SR3, halogen, CN, CONE,, COOE, ^ or C:-C<.-alkyI; X* and X3 can be identical or different and represent: oxygen, sulphur, NK or N-CH,, R' represents hydrogen, C:-C3-2lkyl, allyl or prcpargyl and Ra represents hydrogen, C1-C3-al3cyi or C3-Ce-cyclcaIkyl, or R7 + Ra together can also represent the groups -CH2CH2-0-CH,CH2- or -(CH2)j.-, in which k can represent 3, 4 or 5, and R3 represents hydrogen, C,-C2-alkyi or C:-C3-acyI, and Ri0 represents hydrogen or C1-C,-al:<yl, R* alternatively may represent a radical of the structure — 2 5 Z-r*11 hIS s:5 # •' /~r -N Vs » "N 12 \_l i >-Rw, or./ 1 -N V- T / -X H16 ^12 R16 5^ * w in which R11 represents H, C,-C2-alkyI or C:-C2-acyl, and R12 represents E, C.-Cj-alkyl, OH or OCE3, or R"1 and R12 together can also denote a C-Cj-alkylene bridge which is optionally nonosubstituted or disubatituted by methyl, R13 represents H, C;-C3-alkyl, aryl, heteroaryl, benzyl, C.-C^-alkoxycarbonyl, C-C*-acyl or (5-methyl-2-oxo-l, 3-dioxol-4-yl) -methyl, v PA^ y ^ ■ii - 79 - *, % R14 represents R15 represents R16 * 7 represents sC represents v represents H or Ci-Ci-alkyl, H , CH3 or phenyl, H , CH3 or phenyl, K or CH3, and 0, CH2, CH2CH2 or CK2-0, where the linking of the CE2-0 group to the nitrogen can be both via 0 and via CH2, Z represents 0 or S, and A represents hydrogen, halogen, methyl, or nitro or, together with R1, can also form a bridge of the structure X X -0-CH2CH-CHt , -S-CH-,-CH-CH- or -ch2ck2-ch-ch; having the R- or S-configuration, ana their pharmaceutically utilizable hydrates and acid addition salts and also the alkali metal, alkaline earth metal, silver and guanidinium salts of the carboxylic acids on which they are based.

2. Compounds of the formula (I) according to Claim 1, in which R1 represents ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methyl amino, phenyl, 4-fluorophenyl or 2,4-dif luoro-phenyl , 233142 ! -K R~ represents hydrogen, alkyl having 1 -to 3 carbon atoms or (5-methyi-2-oxo-l,3-dioxol-4-yI)-methyl, R2 represents C1-C2-aikyi, R4 represents a substituted radical, which is optionally substituted in the ring system by methyl, of the formula / ^ a ^ j 7^ j .xs n- <ch2 , e^g s~, °r £^g ^n~ in which S represents R5-N, 0 or S, R6 I G represents -(CH;,)^-, -CH2~0-CH2- or -CH,-N-CH2-, j represents 1, 2 or 3, R5 represents hydrogen, oraJkyl, alkenvl or alkinyl having up to 3 carbon atoms, which is optionally' substituted by hydroxyl, benzyl which is optionally substituted by nitro or amino or oxoalkyl having 2 to 4 carbon atoms, and Rs represents hydrogen or methyl, R alternatively may represent a radical of the formula X1 ...... . ... ^ E cch2)0 l_<ch2) -w (CH-,) ^ia£_Lp ^ n -i nz» P ( CH2 ) a ' C CH2) 2Jra n X2 <CH-,)n ! X- or | ^ ^(CH23a in which. p represents 0, 1 or 2, v- V .\o - - 31 - 233142 m represents 1 cr 2, where p -r m together can be 1, 2 or 3, n represents 1 or 2, W represents r orS or hydrocen, represents_ . OR3, fluorine, chlorine/or sk Ci-Cj-alkvI, X" and X3 can be identical or different and represent oxygen, sulphur or N-CH,, R' ■ represents hydrogen, C,-C2-al]cyI or acetyl, and Ra represents hydrogen or C-—C2-alkyI, or R' -i- Ra together also denote the groups -CH2CZ,-0-, -CH2CH2- or -(CE,)k-, in which k can represent 3, 4 or 5, R3 represents hydrogen, C1-C2-alI<yl or acetyl, and R10 represents hydrogen or C-Cj-alkyl, R" alternatively may represent a radical of the structure in which R" represents • E, C-C3-alkyl or C^-Co-acy!, and <- Vp *" ^ / nr -rr - 82 - 33142 £ represents H, C;-C3-alkyI, OH or OCH3, or R" and R12 together can also denote a C.-C2-aIkylene bridge which is optionally monosubstiruted or ?eaas disubstitutec by aiethvl, 3-" represents H, C-C.-alkyl, hycroxvalkyl, phenyl, benzyl, C«-C4-alkoxycarbonyl, C1-C--acvl or (5-methyI-2-oxo-l,3-dioxoi-4-yI)-methyl, r1a represents H or C^-Cz -alkyl, r-5 represents . H or CH3, r16 represents H or CH,, r17 represents H or CH,, and v represents 0, CH2, CH-CH; or CH--0, where the linking of the CH2-0-group to the nitrogen can be both via 0 and via CH,, Z represents 0, and A represents H, fluorine, chlorine, methyl, or _ * _ _ ... — the stncttre x -c-ch--ch-ch- ** I having the R- or S-configuraticn.

3. Compounds of the formula (I) according to Claim 1, in which R1 represents ethyl, vinyl, t-butyl, cycloprcpyi, 2-hydrojcyethyl r 2-fluoroethyl, methylamino, 4-fluorophenyl or 2,4-diflucrophenyl, R2 represents hydrogen or alkyl having 1 to 2 carbon atoms, R3 represents Cj-Cj-alkyl, R* represents a radical, which is optionally substi- - 83 - ^ *A'*, ^ -^ ; •% - •a ?33K2 tuted in the ring system by methyl, cf the fcmula ^ N\"'Ch'2}J\/V-^ \C- N-, S^V, or zT^X- , in which E represents Rs-N, G represents -(CH,),-, j represents 1 cr 2, R£ represents hydrogen, or alkyl, alkenyl or alkinyl having up to 3 carbon atoms, and optionally substituted by hydroxyl, benzyl which is optionally substituted by nitro cr amino, or oxoalkyl having 2 to 4 carbon atoms/ and Rs represents hydrogen or methyl, R* alternatively may represent a radical of the formula liSid? —r(cy'2 3 a"w - *o2 ■? — ^ r i 5 l i ^r«CH2)a , Vtca,)- / i5g2^ rc —T X2 -X- 0r ^CCH2)a in which P represents 0, 1 or 2, m represents 1 or 2, where p 4- m together can be 1, 2 or 3, u ' v "N >r S\J £ \kfv V - . .O ' v' lEM^i - 84 - ■:> 7 7, 1 AO J J I -r L n represents I, ,R/ W represents N N=a , 0Ra cr hydrogen, represents. ,F' '"Ka N , CR3, chlorine cr alkyl, X" R7 R8 -13 rt. and X" can be identical cr different and represent oxygen cr N-CH2, represents hydrogen cr methyl, and represents hydrogen or methyl, or R7 ~ Ra together can also denote the groups -CH,CH2- , G-CH-CH-- or -(CH-.ji-, in which k can represent 3, 4 cr 5, and represents hydrogen, Ci-Cj-alkyi cr C:~C;-acyI, and represents hydrogen cr C-C3-alkyl, R* also denotes a radical of the structure in which R11 R12 p.- ■ /r -N ' "N /)—or -N /i R16 -16 -N =16 -N represents E, Ci-C=-al3cyl or acetyl, and represents n or C^-C^-alky!, or R" and R~ together can also denote a C1-C.-alkyiene bridge which is optionally substituted by methyl, . represents E, C1-C2-alkyl, hydrcxyethyl, benzyl, C;-C,-alkoxycarbcnyi or C, ~C--acyl, - 35 - ' c \ % s m>*#' R1a represents H or CH,, represents H or CH,, R1S represents H cr CH3, R"7 represents H or CH,, and Y represents 0, CH2/ CH2CH, or CH2-0, where the linking of the CH,-0-groups to the nitrogen can be both via 0 and via CH2, z represents 0, ana A represents H, fluorine or chlorine, or together with R1 can also form a bridge of the structure * -0-CH2-CH-CH, having the R- or S-configuration.

4. - Process for the preparation of compounds cf the formula (I) according to Claim 1, characterized in that a compound of the formula (II) (II) in which R1, R2, R3 and A have the meaning indicated in Claim 1 and represents halogen, is reacted with a compound of the formula (III) R*-H (III) in which R* has the meaning indicated in Claim 1 and optionally contains protective groups, J s 3 3 ] if acprocriate in the presence of an acid scavenger and if • • • » 9 appropriate protective croups contained in R* are removed.

5. A process as claimed in claim wherein X" represents fluorine or chlorine.

6. Compounds cf the formula (I) according to Claim 1 for use in a method for the therapeutic treatment of the human or animal bocv.

7. Medicaments, containing compounds of the formula (I) according to Claim 1.

8. 7-Chloro-l—cyclopropyl-5,8-cif luoro-1, 4-dihvdro— 5-methyl-4-oxo-3-cuinolinecarboxylic acic.

9. A compound according to claim 1 substantial!;;- as herein described or exemplified.

10. A process according to claim - substantially as herein described or exemplified.

11. A medicament according to claim 6 substantially as herein described. BAYER AKTIEpESELLSCHAFT By Their /it/torneys LTD f% * ^ - 87 -