NZ221681A

NZ221681A - 7-oxo-2,3-dihydro-7h-pyrido(3,2,1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid derivatives and pharmaceutical compositions thereof

Info

Publication number: NZ221681A
Application number: NZ221681A
Authority: NZ
Inventors: Masahiro Aoki; Miyako Kamata; Tatsuo Ohtsuka; Nobuo Shimma; Kazuteru Yokose
Original assignee: Hoffmann La Roche
Priority date: 1986-09-12
Filing date: 1987-09-04
Publication date: 1990-12-21
Also published as: NO873816D0; NO169125C; FI86428C; FI86428B; AU602534B2; FI873940A; HU199481B; HUT47294A; AT389119B; PT85686A; FI873940A0; JPH07138256A; JPS63132891A; ZA876636B; PT85686B; IE61624B1; IE872444L; CZ281195B6; KR880003954A; JPH0819120B2

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £21 681 22 1 6 8 1 NO DRAWINGS Priority Oate(s): .. Coinpiele Specification Filed: Clops^ ... £\b \V>&.). J S.5.S? Publication Date: *T. i. P£C\ !??P... P.O. Journal. No: . ...ASS3I: NEW ZEALAND PATENTS ACT. 1953 No. Date: COMPLETE SPECIFICATION TRICYCLIC COMPOUNDS -I-/We. F. HOFFMANN-LA ROCHE S CO., AKTIENGESELLSCHAFT 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss Company hereby declare the invention for which i / we pray that a patent may ~be granted to-me/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) -la- 22 1 6 8 f The present invention relates to novel tricyclic compounds, more particularly to pyridot3,2.1-ij]-l.3.4--benzoxadiazine derivatives, to a process for their manufacture. to pharmaceutical preparations containing them and to intermediates useful in said process. More particularly, the present invention relates to novel pyrido[3,2.1-ij]-l,3,4-benzoxadiazine derivatives represented by the general formula (I) wherein R1 is a hydrogen atom or a carboxy-protecting radical: R2 is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom; 3 4 R and R independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or with a substituted or unsubstituted amino radical; X is a halogen atom; and R5 and R6 are independently a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical, a lower alkoxy radical or a substituted or unsubstituted amino 5 6 radical; or R and R , taken together with the adjacent nitrogen atom, may form a 5 to 7 membered heterocyclic ring which may be substituted with one or 221681 - 2 - more substituents at the carbon atom(s), and the hetero- 7 cyclic ring may further contain -NR -0-. -S-, -SO-. 7 7 -S02- or -NR -CO-. [R is a hydrogen atom, a lower alkenyl radical, a lower alkyl or aralkyl radical which may be substituted, or a radical represented by the general formula -(CH2)QCOR 8 (II) (in which n is 0 to 4 and R is a hydrogen atom, a lower alkoxy radical, or an amino, lower alkyl or aryl radical which may be substituted)]. as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula I or their salts, which are useful as effective ingredients in antibacterial agents. C The respective radicals of the formula I which are defined above are explained in more detail as follows; reference to the term "lower" is intended to mean a carbon chain containing up to and including 7 carbon atoms, unless otherwise indicated. Explanation of R^: R is a hydrogen atom or a carboxy-protecting radical. Qj In the above, the carboxy-protecting radical means e.g. lower alkyl such as methyl, ethyl, n-propyl, t-butyl; other meanings are e.g. in vivo readily hydrolyzable carboxy--protecting radicals such as lower alkanoyloxyalkyl (e.g. acetoxymethyl, pivaloyloxymethyl. 1-acetoxyethyl and 1-pivaloyloxyethyl); lower alkoxycarbonyloxyalkyl (e.g. methoxycarbonyloxymethyl. 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl); lactonyl (e.g. phthalidyl and hiophthalidyl); lower alkoxymethyl (e.g. methoxymethyl); 14 SEP 1989*?^enzyloxyi[net:hyl: C5-metliy1-2-oxo-1' 3-dioxol-4-yl)methyl; or , < v O t i «' 22 1 6 8 t - 3 - lower alkanoylaminoraethyl (e.g. acetamidomethyl). Other ester groups e.g. benzyl, cyanomethyl, phenacyl. phenyl and the like can also be used. 2 Explanation of R : 2 R is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom. In the above, the lower alkyl radical preferably contains 1 to 4 carbon atoms, especially methyl, ethyl, n-propyl. iso-propyl, n-butyl and the like, and the halogen atom is fluorine, chlorine or bromine, preferably fluorine. Explanation of R3 and R4: 3 4 . R and R independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or a substituted or unsubstituted amino radical. In the above, the lower alkyl radicals preferably contain 1 to 4 carbon atoms, especially methyl, ethyl, n-propyl. iso-propyl, n-butyl. and the like. The substituted amino radicals can be di-lower alkylamino such as dimethylamino. diethylamino; lower alkylamino such as methylamino. ethylamino and the like; lower cycloalkylamino such as cyclopropylamino. Explanation of R5 and R6: 5 6. R and R independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical, a lower alkoxy radical or a substituted or unsubstituted amino radical; or R5 and R6, taken together with the adjacent nitrogen atom, may form a 5 to 7 membered heterocyclic ring which may be substituted with one or more substituents at the carbon atom(s). and the heterocyclic 7 ring may further contain -NR -. -0-. -S-. -SO-. -S02~ or 22 1 6 8 1 4 - 10 7 7 . -NR -CO- [wherein R is a hydrogen atom, a lower alkenyl radical, a lower alkyl or aralkyl radical which may be substituted, or a radical represented by the general formula -CcH2)nc°R8 (II) 8 (in which n is 0 to 4 and R is a hydrogen atom, a lower alkoxy radical, or an amino, lower alkyl or aryl radical which may be substituted)]. The above defined radicals will be further illustrated in more detail as follows: The lower alkyl radical preferably contains l to 4 15 carbon atoms, such as methyl, ethyl, n-propyl. iso-propyl. n-butyl. and the like. The lower alkoxy radical preferably contains 1 to 4 carbon atoms such as methoxy, ethoxy, n-pro-poxy, iso-propoxy. n-butoxy. and the like. The substituted ■ amino radical can be di-lower alkylamino such as dimethyl- 20 amino, diethylamino, ethylmethylamino: lower alkylamino such ( ' as methylamino, ethylamino, n-propylamino. iso-propylamino; i lower cycloalkylamino such as cyclopropylamino and the like. 1 c The 5 to 7 membered heterocyclic ring formed by R and 25 R6 can be piperazinyl, morpholinyl, thiomorpholinyl, piperidyl, homopiperazinyl. pyrrolidinyl, pyrrolinyl, pyrrolyl. imidazolyl, triazolyl and the like. Examples of the substituents at the carbon atom(s) of the heterocyclic ring are hydroxy, lower alkoxy such as methoxy. ethoxy. 30 n-propoxy; amino: lower alkylamino such as methylamino. ethylamino. n-propylamino, iso-propylamino: lower cycloalkylamino such as cyclopropylamino; di-lower alkylamino such as dimethylamino, diethylamino. ethylmethylamino; lower alkanoylamino such as acetylamino; benzylamino optionally 35 substituted by nitro, amino, halogen, hydroxy and/or lower alkoxy. e.g. (4-aminobenzyl)amino; a group of the general formula 4 22 1 6 8 1 ^ C - 5 - N-CH=N- where R50 and R51 are lower alkyl or together with the 5 nitrogen atom represent a 5 to 8 membered saturated N-heterocycle such as (dimethylamino)methyleneamino, (hexa-hydro-iH-azepin-l-yl)methylenearaino: benzyloxycarbonylamino; halogen, such as fluoro. chloro. bromo; lower alkyl such as methyl, ethyl, n-propyl. iso-propyl; amino-lower alkyl, j 10 lower alkylamino-lower alkyl. lower cycloalkylamino-lower i I alkyl, di-lower alkylamino-lower alkyl. lower alkanoylamino- -lower alkyl, examples of these substituents being: amino-methyl, (methylamino)methyl, (ethylamino)methyl. (n-propyl-amino)methyl. (iso-propylamino)methyl. (cyclopropylaminoj-15 methyl, (dimethylamino)methyl, (diethylamino)methyl. (ethylmethylamino )methyl. acetylaminomethyl. 2-aminoethyl. 2-! -(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(diethylamino)- ethyl. 2-(dimethylamino)ethyl. 2-(ethylmethylamino)ethyl; ■ hydroxy-(lower alkyl) such as hydroxymethyl. 2-hydroxy- I ! 20 ethyl: phenyl, optionally substituted by amino, halogen, j hydroxy and/or lower alkoxy such as 4-aminophenyl, j 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl. 4-methoxy- phenyl: a heterocyclic ring such as pyrrolyl, 4-methyl-l--piperazinyl and the like. 25 7 The lover alkenyl radical represented by R is e.g. allyl, 3-methyl-2-butenyl. 2-butenyl. l-methyl-2-propenyl. 3-butenyl and the like. 7 30 The substituted alkyl radical represented by R is e.g. hydroxy-(lower alkyl) such as 2-hydroxyethyl. 3-hydroxybutyl; lower alkoxy-lower alkyl such as 2-methoxy-ethyl. 2-ethoxyethyl: amino-lower alkyl such as 2-aminoethyl. 3-aminobutyl; lower alkylamino-lower alkyl such as 35 2-(methylamino)ethyl, 2-(ethylamino)ethyl, 3-(methylamino)-butyl, 3-(ethylamino)butyl; di-lower alkylamino-lower alkyl such as 2-(dimethylamino)ethyl. 2-(diethylamino)ethyl, 11 1 6 8 1 - 6 - 3-(dimethylaraino)butyl. 3-(diethylamino)butyl; halogen-lowec alkyl such as 2-fluoroethyl. 3-fluoro-n-butyl; carboxy-lower alkyl such as carboxymethyl. 2-carboxyethyl; sulfo-lowec alkyl such as sulfomethyl. 2-sulfoethyl and the like. 7 The aralkyl radical R which may be substituted is e.g. benzyl and can be substituted by one or more amino, nitro. lower alkylamino. di-lower alkylamino. halogen and/or lower alkoxy group(s) such as 4-aminobenzyl. 4-nitrobenzyl, 4-(dimethylamino)benzyl. 4-fluorobenzyl. 4-chlorobenzyl. 3-methoxybenzyl, 4-methoxybenzyl. 3.4-dimethoxybenzyl and the like. 0 The amino radical R may be unsubstituted or substituted by e.g. lower alkyl such as methylamino. dimethylamino. or by lover cycloalkyl such as cyclopropylamino. 0 A lower alkyl radical R may likewise be unsubstituted or substituted. The substituted alkyl radical represented by g R is e.g. carrying a carboxy or lower alkoxycarbonyl radical such as in 2-carboxyethyl, 3-carboxy-n-propyl. 2-methoxycarbonylethyl. 2-ethoxycarbonylethyl, 3-methoxycar-bonyl-n-propyl and the like. 0 The aryl radical represented by R is preferably phenyl: substituted aryl is preferably carrying one or more halogen, lower alkoxy. hydroxy, nitro and/or amino group(s) such as in 4-fluorophenyl. 4-chlorophenyl. 4-bromophenyl. 4-methoxyphenyl, 2-carboxyphenyl. 4-hydroxyphenyl, 4-nitro-phenyl. 4-aminophenyl and the like. 7 Especially preferable radicals represented by R are hydrogen, methyl, ethyl, n-propyl, iso-propyl, 2-hydroxy-ethyl, 2-methoxyethyl, 2-aminoethyl, 3-amino-n-butyl, 2-(methylamino)ethyl, 2-(ethylamino)ethyl. 2-fluoroethyl. carboxymethyl. sulfomethyl, allyl, 4-aminobenzyl. 4-fluorobenzyl, formyl. acetyl, propionyl, benzoyl, 4-aminobenzoyl. 22 1 6 8 1 - 7 - 2-oxo-n-propyl» 2-oxo-n-butyl. 3-oxo-n-butyl. 3-oxo-n--pentyl. 3-carboxypropionyl, 3-ethoxycarbonylpropionyl, 4-carboxy-n-butyryl. phenacyl, 41-aminophenacyl. ethoxycar-bonyl, methoxycarbonyl. carbamoyl and the like. Especially preferable radicals represented by 5 6. , R R N- in the formula (I) are l-piperazmyl. 4-methyl-l- -piperazinyl, 3-methyl-l-piperazinyl, 3-phenyl-l-pipera- zinyl. 3,4-dimethyl-l-piperazinyl. 4-ethyl-l-piperazinyl, 3-(4-aminophenyl)-l-piperazinyl. 4-n-propyl-l-piperazinyl. 4-(2-fluoroethyl)-l-piperazinyl. 4-allyl-l-piperazinyl. 4-(2-oxo-n-propyl)-l-piperazinyl. 4-(carboxymethyl)-l--piperazinyl, 4-(3-oxo-n-butyl)-l-piperazinyl. 4-(sulfo-methyl)-l-piperazinyl. 4-(4-aminobenzyl)-l-piperazinyl. 4-(2-hydroxyethyl)-l-piperazinyl. 3-oxo-l-piperazinyl. 4-phenacyl-l-piperazinyl. 4-(3-carboxypropionyl)-1-pipera-zinyl, 4-acetyl-l-piperazinyl. 4-(4-nitrobenzyl)-l-pipera-zinyl. morpholino. 2-methyl-4-morpholinyl. 2.6-dimethyl-4--morpholinyl, 4-thiomorpholinyl. l-oxide-4-thiomorpholinyl, 1.l-dioxide-4-thiomorpholinyl. 4-(aminomethyl)-l-piperidyl, 4-[(methylamino)methyl]-l-piperidyl. 4-methoxy-l-piperidyl. 4-hydroxy-l-piperidyl. 4-(l-pyrrolyl)-l-piperidyl, 4-amino--1-piperidyl, 4-(methylamino)-l-piperidyl. 4-(ethylamino)-l--piperidyl. 1-homopiperazinyl. 4-methyl-l-homopiperazinyl. 3-amino-l-pyrrolidinyl. 3-(methylamino)-l-pyrrolidinyl, 3-(ethylamino)-l-pyrrolidinyl. 3-(benzyloxycarbonylamino)-l--pyrrolidinyl. 3-(aminomethyl)-l-pyrrolidinyl. 3-amino-4--phenyl-l-pyrrolidinyl, 3-amino-3-methyl-l-pyrrolidinyl. 3-amino-4-methyl-l-pyrrolidinyl. 3-(4-aminobenzylamino)-1--pyrrolidinyl. 3-(4-methyl-l-piperazinyl)-1-pyrrolidinyl. 3-[(dimethylamino)methyleneamino]-l-pyrrolidinyl, 3-[(methylamino)methyl]-l-pyrrolidinyl. 3-[(methylamino)-methyl]-4-phenyl-l-pyrrolidinyl. 3-methyl-3-[(methylamino)-methyl]-l-pyrrolidinyl. 3-[(ethylamino)methyl]-l-pyrroli-dinyl, 3-(acetylaminomethyl)-1-pyrrolidinyl. 3-[(dimethyl-amino)methyl]-1-pyrrolidinyl. 3-[(ethylmethylamino)-methyl]-1-pyrrolidinyl. 3-amino-4-methoxy-l-pyrrolidinyl. \ ' 22 1 6 8 1 - 8 - 3-methoxy-4-(methylamino)-1-pyrrolidinyl. 3-(ethylamino)-4-methoxy-1-pyrrolidinyl. 3-amino-4-chloro-l--pyrrolidinyl. 3-chloro-4-(methylamino)-1-pyrrolidinyl. 0b 3-chloro-4-(ethylamino)-l-pyrrolidinyl. 3-amino-4-fluoro-1- 5 -pyrrolidinyl. 3-fluoro-4-(methylamino)-1-pyrrolidinyl. 3-(ethylamino)-4-fluoro-l-pyrrolidinyl. 3-(aminomethyl)-4--chloro-1-pyrrolidinyl. 3-chloro-4-[(methylamino)methy1]-1--pyrrolidinyl. 3-chloro-4-[(ethylamino)methyl]-1-pyrroli-dinyl, 3-(aminomethyl)-4-fluoro-l-pyrrolidinyl. 3-fluoro-4-10 -[(methylamino)methyl]-l-pyrrolidinyl. 3-[(ethylamino)- methyl]-4-fluoro-l-pyrrolidinyl. 3-(aminomethyl)-4-methyl-l--pyrrolidinyl, 3-methyl-4-[(methylaraino)methyl]-l-pyrroli-dinyl. 3-[(ethylamino)methyl]-4-methyl-l-pyrrolidinyl. 3-hydroxy-l-pyrrolidinyl. 3-methoxy-l-pyrrolidinyl. 15 3-chloro-l-pyrrolidinyl. 3-fluoro-l-pyrrolidinyl. 3-hydroxy--4-methoxy-l-pyrrolidinyl. l-imidazolyl. 4-methyl-l-imi-dazolyl. 3-amino-4-hydroxy-l-pyrrolidinyl. 3-(methylamino)--4-hydroxy-l-pyrrolidinyl. 3-(ethylamino)-4-hydroxy-l--pyrrolidinyl. 3-(dimethylamino)-4-hydroxy-l-pyrrolidinyl. 20 [2-(dimethylamino)ethylJmethylamino. and the like. c Explanation of X: X is a halogen atom such as fluorine, chlorine or 25 bromine, preferably fluorine or chlorine. The novel pyrido[3.2.1-ij]-1.3.4-benzoxadiazine derivatives of the formula (I) and their pharmaceutically acceptable salts and hydrates or solvates thereof and of these 30 salts are manufactured in accordance with the present invention by a process which comprises (a) reacting a compound represented by the general formula 35 < . mr . > ' - V' - 9 - 22 1 6 8 1 r ! O 25 30 ::xxY-' (in) R °yNvR;2 >A3 12 3 4 10 wherein R . R , R . R and X are the same as defined above, and X' is a halogen atom; and amino, hydroxy and/or carboxy groups present may be protected, with an amine represented by the general formula 15 HN - R5 (IV) I R6 5 6 wherein R and R are the same as defined above. 20 followed, if necessary by removal of a protecting radical, or (b) reacting a compound represented by the general focmula (V) H AHR^ 12 5 6 wherein R . R , R . R and X are the same as defined above; and amino, hydroxy and/or carboxy groups present may be protected. 35 with a carbonyl compound represented by the general formula i o ^ 221681 - 10 - R3 ^c-o (VI) 3 4 5 whecein R and R ace the same as defined above. or a polymer, acetal. ketal or enol ether thereof, followed, if necessary, by removal of a protecting radical, or (c) for the manufacture of a compound of formula I in which 7 L0 R is other than hydrogen,reacting a compound of formula I 7 in which R is hydrogen with an agent yielding the group R70 where R70 is as R7 but not hydrogen, or O (d) for the manufacture of a compound of formula I wherein 5 6 R and/or R are lower alkyl (or contain a di-lower alkylamino or lower alkoxy group) lower alkylating a compound of formula I wherein R5 and/or R6 are hydrogen or contain an amino, lower alkylamino or hydroxy group, or 20 (®) for the manufacture of a compound of formula I in which R5R6N- is a 5 to 7 membered heterocyclic ring with -S0-or -S02~ subjecting a corresponding compound wherein the ^ heterocyclic ring contains -S- to oxidation, or 25 (f) for the manufacture of a compound of formula I having a free amino, hydroxy and/or carboxy group,splitting off the protecting group(s) from a corresponding compound of formula I having (a) protected amino, hydroxy and/or carboxy group(s). or 30 (g) for the manufacture of a compound of formula I containing a halogen atom,halogenating a correspondingly hydroxy-substituted compound of formula I in which R1 is a carboxy-protecting radical and. if desired, splitting 35 said protecting radical R1. or It (h) for the manufacture of a compound of formula I V v containing an amino group, reducing the nitro gcpup of a^/ y E Q. 221681 - 11 - correspondingly nitro-substituted compound of formula I, or C (i) for the manufacture of a compound of formula I containing a group of the formula R50 •N-CH-N-. R 51. 10 where R50 and R5^" are lower alkyl or together with the nitrogen atom represent a 5 to 8 membered saturated N-heterocycle, reacting the amino group of a correspondingly amino-substituted compound of formula I with a reactive derivative of a formamide derivative of the general formula 15 N-CHO (VII) • «50 . _51 wherein R and R are as above. or C o 20 (j) for the manufacture of a compound of formula I in which R is a carboxy-protecting radical,subjecting a carboxylic acid of formula I to a corresponding esterification, or (k) for the manufacture of pharmaceutically acceptable 25 salts, hydrates or solvates of a compound of formula I or hydrates or solvates of said salts,converting a compound of formula I into a salt, hydrate or solvate or into a hydrate or solvate of said salt. 30 Process A: As stated above, the desired compounds can be obtained by reacting a compound represented by tfie"-geiieral formula 35 V ' ' •• • " o c 22 1 6 8 1 - 12 - (HI) 12 3 4 10 wherein R . R , R . R and X are the same as defined above, and X1 is a halogen atom, and amino, hydroxy and/or carboxy groups present may be protected, with an amine represented by the general formula 15 HN - R5 I (IV) R6 wherein R5 and R6 are the same as defined above, 20 followed, if necessary, by removal of a protecting radical. In Process A, the compound represented by the formula (III) which is used as starting compound is a novel compound, and this can be prepared, for example, according 25 to the following reaction scheme a) or b). 30 35 s "CAw > 22 1 6 8 1 - 13 - a) 0^ no2 reduction "XX* oh h5c2och-c(cooc2h5)2 h 2 5" (A) (B) o c h5c200c 'Xxy ooc2h5 Orf-protection yt' V' "Pi" > v * t H X OH H5C2OOC, ^ ^ ^cooc2h5 cyclization (C) cooc2h5 Xv^v^V^0002"5 amination ^ ,J^JL» J N-protection or' nh2 (E) (F) O 0 xv?vaVCOOC2H5 x x,-^sJLnJ' alkylation^ x, OR' NHR" (G) 00C2H5 V r* n C b) (c) 22 1 6 8 1 - 14 - X^!^°CV/COOC2H5 cyclization H X X' ,COOC2H5 OH-protect ion > oh (J) :^5' or' cooc2h5 amination (e) X. x" 0 Y^Y^V00002"5 N-protectioji 6w NH2 (F) c c ; ^Y&Y000 C2H5 alkylation or' nhr" (G) X X' N- COOC2H5 deprotection I 2 OR' N-R 4-' (hj ■iteawv • "V. r 22 1 6 - 15 - 2 3 4 wherein R , R . R , X and X1 are the same as defined above; R1 is a protecting radical, such as benzyl, methoxybenzyl, methoxymethyl, methoxyethoxy-methyl, tetrahydropyranyl. allyl, t-butyl, t-butyldi-5 methylsilyl, acetyl, benzoyl and the like; R" is a protecting radical, such as forrayl, acetyl, trifluoro-acetyl, benzoyl, ethoxycarbonyl. 2.2.2-trichloroethoxy-carbonyl, phenoxycarbonyl, benzyloxycarbonyl. t-butoxy-carbonyl and the like and H"1 is a hydrogen atom or an 10 ethyl radical. If the compound of the formula (IV) contains an amino or monoalkylamino substituent, said substituent may, if desired, be protected by an amino protecting radical such as 15 formyl. acetyl, trifluoroacetyl. benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl. phenoxycarbonyl. benzyloxycarbonyl. t-butoxycarbonyl and the like. The reaction between the compound of the formula (III) 20 and the amine of the formula (IV) or the suitably protected amine, if necessary, may be performed with or without a solvent, preferably at elevated temperature for a sufficient ^ time so that the reaction can be substantially completed. The convenient reaction temperature is in the range of about 25 30°C to about 200°C, preferably from 80°C to 150°C in order to obtain sufficiently fast reaction rate. The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine. 30 picoline. N.N-dimethylaniline. 1.8-diazabicyclo[5.4.0]undec--7-ene. 1.4-diazabicyclo[2.2.2]octane. alkali metal hydroxides, alkali metal carbonates, and the like. Alternatively an excess of the amine of the formula (IV) may be utilized as the acid acceptor. 35 The convenient solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsul- foxide. dimethylformamide, dimethylacetamide. pyridine. 221681 >4" n c - 16 picoline. lutidine, N,N'-diirethylpropyleneurea, and the like. Mixtures of two oc more solvents may also be used. The protecting cadical may, if desiced. be removed aftec the ceaction by pcoceduces known to those skilled in the act. For example, the formyl cadical may be cemoved by acid oc base hydcolysis pceferably base hydcolysis and the benzyloxycacbonyl cadical may be cemoved by hydcogenolysis. The stacting matecials represented by the focmula (III) may be exemplified as follows: 9,10-difluoco-3-methy1-7-oxo-2.3-dihydco-7H-pycido[3,2.1-ij]-1.3.4-benzoxadiazine-6-carboxylic acid, 9.10-dichloco-3-methyl-7-oxo-2,3-dihydco-7H-pyrido[3,2.1-ij]-1.3,4-benzoxadiazine-6-carboxylic acid. 9-chloro-10-fluoco-3-methyl-7-oxo-2,3-dihydco-7H-pycido-[3,2,1-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, ethyl 9,10-difluoco-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-l.3.4-benzoxadiazine-6-carboxylate. benzyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pycido-[3,2.1-ij]-l,3,4-benzoxadiazine-6-cacboxylate, 9.10-difluoco-3-(2-fluocoethyl)-7-0X0-2.3-dihydco-7H-pycido-[3,2,l-ij]-l,3,4-benzoxadiazine-6-cacboxylic acid, 9,10-difluoco-2.3-dimethyl-7-oxo-2,3-dihydco-7H-pycido-[3,2,1-ij]-l,3.4-benzoxadiazine-6-cacboxylic acid. 9.10-difluoco-2-(hydcoxymethyl)-3-methyl-7-oxo-2.3-dihydco-7H-pycido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylie acid. 22 1 6 8 1 - 17 - 9,10-dif luoro-2-[ (dimetliylamino)methyl ] -3-methyl-7-oxo-2. 3-dihydro-7H-pyrido[3,2.1-ij]-l.3.4-benzoxadiazine-6-carboxylic acid. 9,10-difluoro-2.2.3-trimethyl-7-oxo-2.3-dihydro-7H-pyrido-[3.2.1-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, and the like. The amine of the formula (IV) used in the above reaction is. for instance, piperazine. 4-methylpiperazine. 3-methylpiperazine, 3-phenylpipecazine. 3-(4-aminophenyl)-piperazine, 3-(4-nitrophenyl)piperazine. 4-(2-hydroxyethyl)-piperazine, morpholine. 2-methylmorpholine, 2,6-dimethylmor-pholine. thiomorpholine, 4-(aminomethyl)piperidine. 4-[(methylamino)methyl]piperidine, 4-[(ethylamino)methyl]-piperidine, 4-aminopiperidine, 4-(methylamino)piperidine, 4-(ethylamino)piperidine. 4-(benzyloxycarbonylamino)piperi-dine, 4-(benzyloxycarbonylmethylamino)piperidine, 4-(benzyl-oxycarbonylethylamino)piperidine, 4-hydroxypiperidine, 4-methoxypiperidine, 4-(l-pyrrolyl)piperidine, homopipera-zine, 3-[(methylamino)methyl]pyrrolidine, 3-[(ethylamino)-methyl]pyrrolidine. 3-(acetylaminomethyl)pyrrolidine, 3-hydroxypyrrolidine. 3-methoxypyrrolidine, 3-aminopyrroli-dine. 3-(benzyloxycarbonylamino)pyrrolidine. 3-(methylamino) pyrrol id ine. 3-(benzyloxycarbonyImethylamino)pyrrolidine. 3-amino-4-phenylpyrrolidine. 3-amino-3-methylpyrroli-dine. 3-amino-4-methylpyrrolidine, 3-(4-aminobenzylamino)-pyrrolidine. 3-(4-methyl-l-piperazinyl)pyrrolidine. 3-[(dimethylamino)methyleneamino]pyrrolidine. 3-[(methyl-amino)methyl]-4-phenylpyrrolidine, 3-methyl-3-[(methylamino )methyl]pyrrolidine. 3-(ethylamino)pyrrolidine. 3-(benzyloxycarbonylethylamino)pyrrolidine, 3-[(dimethyl-amino)methyl]pyrrolidine. 3-[(ethylmethylamino)methyl]-pyrrolidine, 3-azido-4-methoxypyrrolidine, 3-araino-4--methoxypyrrolidine, 3-methoxy-4-(methylamino)pyrrolidine. 3-(ethylamino)-4-methoxypyrrolidine. 3-azido-4-hydroxy-pyrrolidine. 3-amino-4-hydroxypyrrolidine. 3-(methylamino)- e 22 1 6 8 1 L - 18 - -4-hydcoxypyccolidine, 3-(ethylamino)-4-hydcoxypyccolidine, 3-(aminomethyl)-4-methylpyrrolidine, 3-methyl-4-[(methy1-amino)methyl]pyrrolidine, 3-[(ethylamino)methyl]-4-methyl-O pyrrolidine. 3-hydroxy-4-methoxypyrrolidine. 3-(acetylamino- S methyl)-4-hydroxypycrolidine. imidazole. 4-methylimidazole, N.N.N'-trimethylethylenediamine and the like. Process B: The desired compound can be obtained by reacting a 10 compound represented by the formula 15 (V) I 2 H NHR L 2 5 6 20 wherein R . R . R . R and X are the same as defined above; and amino, hydroxy and/or carboxy groups present may be protected. with a carbonyl compounds represented by the general formula 25 R3 ^ C=0 (VI) 3 4 wherein R and R ace the same as defined above, and 30 amino groups present may be protected. or its polymer, acetal, ketal oc enol ethec. followed, if necessacy, by cemoval of a protecting cadical. In Pcocess B, the compound cepcesented by the focmula V 35 as stacting compound is a novel compound, and this compound can be pcoduced accocding to the above ceaction scheme a) oc b), oc ceacting a compound (H) ocfyajwith an amine of the - 19 - 221681 formula (IV). If the carbonyl compound of formula (VI) or its polymer, acetal. ketal or enol ether contains an amino or monoalkyl-amino substituent. said substituent may. if desired, be protected by a radical such as described above under R" in formulas (G) and (H). The reaction may. if desired, be carried out in a solvent, such as dioxane. tetrahydrofuran. acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, N,N1 -dirrethylpropyleneurea, acetic acid and the like. Mixture of two or more solvents may also be used. The reaction may, if necessary, be carried out in the presence of an acid catalyst such as acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfoaic acid, pyridinium p-toluenesulfonate, ferric chloride, zinc chloride, chlorotrimethylsilane. Nafion-H (perfluorinated resin-sulfonic acid ; Aldrich Chemical Co., Inc.). Amberlyst-15 (strongly acidic, macroreticular resin ; Aldrich Chemical Co.. Inc.), and the like. The reaction temperature may be varied within a relatively wide range. In general, the reaction is carried out at a temperature between 20°C and 150°C. In a preferred embodiment of the process provided according to the present invention, about 1 mole or excess moles of the carbonyl compound of the formula (VI), or its polymer, acetal. ketal or enol ether per mole of the compound of the formula (V) is employed. The amino or monoaIkylamino protecting radical may, if desired, be removed after the reaction by the procedures known to those skilled in the art. For example, the formyl adical may be removed by acid or base hydrolysis preferably V 22 1 6 8 t - 20 - base hydrolysis and the benzyloxycarbonyl radical may be removed by hydrogenolysis. o The starting materials represented by the formula (V) 5 may be exemplified as follows: 6.7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-l.4-dihydro-3-quinolinecarboxylic acid, c 10 ethyl 6.7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-1.4-dihydro-3-quinolinecarboxylate. benzyl 6.7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-l.4-dihydro-3-quinolinecarboxylate. 15 6,7-dichloro-8-hydroxy-1-(methylamino)-4-oxo-l.4-dihydro- 3-quinolinecarboxylic acid. 6-chloro-7-fluoro-8-hydroxy-1-(methylamino)-4-oxo-l.4-20 dihydro-3-quinolinecarboxylic acid. 6.7-difluoro-l-[(2-fluoroethyl)amino]-8-hydroxy-4-oxo-1.4-dihydro-3-quinolinecarboxylie acid. 25 6-fluoro-8-hydroxy-7-(1-imidazolyl)-l-(methylamino)-4-oxp-1.4-dihydro-3-quinolinecarboxylic acid. ethyl 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-(methylamino)-4-oxo-1.4-dihydro-3-quinolinecarboxylate. 30 benzyl 6-fluoro-8-hydroxy-7-(1-imidazolyl)-l-(methylamino)- 4-oxo-l.4-dihydro-3-quinolinecarboxylate. 6-fluoro-l-[(2-fluoroethyl)amino]-8-hydroxy-7-(1-imidazolyl)-35 4-oxo-l.4-dihydro-3-quinolinecarboxylic acid. L 221681 a - 21 - 6-chlor0-8-hydroxy-7-(1-imidazolyl )-l- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid. 6-f luoro-8-hydroxy-l-(methylamino)-7-(4-methyl-l-pipera-5 zinyl)-4-oxo-l.4-dihydro-3-quinolinecarboxylic acid, 7-(3.4-d ime thy 1-1-piperazinyl)-6-f luor o-8-hydroxy-l-(methylamino )-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid. O 10 7-[ 3-[ (benzyloxycar bony lethy lamino) methyl]-1-pyrrol idinyl]-6-fluoro-8-hydroxy-l-(methylamino)-4-oxo-1.4-dihydro-3-quinoline carboxylic acid, 7-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-6-fluoro-8-15 hydroxy-1-(methylamino)-4-oxo-l, 4-dihydro-3-quinolinecar-boxylic acid, 7 — [ 3 — [ (benzyloxycar bony Imethy lamino) me thyl]-4-methy 1-1-pyrrolidinyl]-6-fluoro-8-hydroxy-1-(methylamino)-4-oxo-l.4-20 dihydro-3-quinolinecarboxylic acid. 7—[3—[(benzyloxycar bony lamino) methyl ]-4-chlor o-l-pyrro li-^ dinyl]-6-f luor o-8-hydroxy-1-(methy lamino)-4-oxo-l. 4-dihydr o- 3-quinolinecarboxylic acid, and the like. 25 Examples of compounds which can be reacted with a compound of the formula (V) are carbonyl compounds of formula (VI) such as formaldehyde, acetaldehyde. acetone, methyl ethyl ketone, and the like ; polymers thereof such as para-30 formaldehyde, paracetaldehyde. trioxane. and the like ; acetals thereof such as dimethoxymethane, 1,1-dimethoxyethane, 1.3-dioxolane. glycolaldehyde dimethylacetal. dimethylamino-acetaldehyde dimethylacetal. and the like ; ketals -thereof such as 2.2-dimethoxypropane. and the like and^enol ethers thereof 35 such as 2-methoxypropene. 2-triroethylsilyloxyj like. ■- *»!*.■• v" ' \\ ' " '''V&Z+ A- , 22 1 6 8 1 - 22 - Process C: When it is desired to manufacture compounds of formula I 5 6 wherein the radical R R N- is a 5 to 7 membered rj 7 heterocyclic ring containing a group -NR - where R is 5 other than hydrogen, such as in r?°-n vtt- (VIII) \ / /"> wherein the piperazinyl radical may be substituted at 70 . 10 carbon atom(s). and R is a lower alkenyl radical, a lower alkyl or aralkyl radical which may be substituted, or a radical represented by the general formula -(CH2)qCOR8 (II) g (in which n is 0 to 4 and R is a hydrogen atom, a 15 lower alkoxy radical or an amino, lower alkyl or aryl radical which may be substituted). the desired compound can be prepared by reacting a compound 7 20 of formula I in which R is hydrogen with an agent 70 yielding the group R . This reaction, an N-alkylation (or an N-acylation). can be accomplished e.g. as follows: N-alkylation: 25 A compound of the general formula 30 HN^ O 2 .COOP^ (IX) , N, 4^;-^ 3- 35 ..V- - ' ' ' ■ J.. •. 22 1 6 8 1 - 23 - 12 3 4 wherein R . R . R , R and X are the same as defined above, the piperazinyl radical may be substituted at carbon atom(s), and amino, hydroxy and/or carboxy c groups present may be protected. 5 can be reacted (i) with a compound represented by the general formula 70 p R -Y (X) 10 70 wherein Y is a leaving group and R is the same as defined above. 7 or (for obtaining compounds where r is the group r9co-ch2ch2-) 15 (ii) with a Michael acceptor of the general formula R9-CO-CH-CH2 (XI) 9 20 wherein R is a lower alkyl radical or a lower alkoxy radical. 7 or (for obtaining compounds where R is methyl or sulfo-methyl) 25 (iii) with formaldehyde and formic acid or an alkalimetal bisulfite. N-Acylation: 3Q A compound of the above formula (IX) can be reacted with an anhydride of the general formula /^C0\ <XII> Z 0 35 VSSs"CO/// 221681 - 24 - wherein Z is an optionally substituted alkylene chain having 2 or 3 carbon atoms, or arylene radical, is to fo O HOOC-Z-CO-. 7 so as to form a compound of formula I wherein R is All these reactions are followed, if necessary, by removal of a protecting radical, if present. f"*1 Thus, the desired compound can be prepared by reacting a compound represented by the formula (IX) with a compound represented by the formula (X). As leaving group Y there may be mentioned e.g. halogen atoms such as chloro. bromo, iodo, acyloxy radicals such as acetoxy. lower alkanesulfonyloxy radicals such as methanesulfonyloxy, arylsulfonyloxy radicals such as p-toluenesulfonyloxy; optionally nitrated phenoxy radicals such as phenoxy, 4-nitrophenoxy; or succinimidooxy or phthalimidooxy. If the compound of the formula (X) contains an amino or monoalkylamino substituent, said substituent may. if desired, be protected by a radical such as described above under R" in formulas (G) and (H). C The reaction may, if necessary, be carried out in a solvent such as dimethylformamide, dimethylacetamide. dimethylsulfoxide, N,N'-dimetliylpropyleneurea, dioxane, tetra-hydrofuran, pyridine and the like. Mixtures of two or more w solvents may also be used. The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, N,N-dimethylaniline. 1,4-diazabicyclo[2.2.2]octane. l,8-diazabicyclo[5.4.0]undec-7-ene. sodium hydride, alkali metal hydroxides, alkali metal carbonates and the like. The reaction temperature may be varied within a relatively wide range. In general, the reaction is carried out at a temperature between about 0°C and 180°C. preferably bet- 22 1 6 8 1 - 25 - ween 0°C and 110°C. In carrying out the process provided according to the present invention. 1 to 4 moles, preferably 1 to 2 moles of the compound of the formula (X) is employed, based on one mole of the compound of the formula (IX). 5 The compound of the formula (X) used in the present invention can be iodomethane, iodoethane. bromoethane, 1-iodobutane. 1-bcomobutane. 1-iodopropane, 2-iodopropane, 1-fluoro-2-iodoethane, l-iodo-2-methoxyethane. N-(2-iodo-10 ethyl)acetamide. N-(2-iodoethyl)-N-methylacetamide. bromo-acetic acid, allyl bromide. 4-fluorobenzyl bromide, acetic formic anhydride, acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, benzoic anhydride, benzoyl chloride. 4-[(trifluoroacetyl)amino]benzoic 15 anhydride, chloroacetone, l-chloro-2-butanone. phenacyl chloride. 4-acetylaminophenyl chloromethyl ketone, ethyl chloroformate. methyl chloroformate, chloromethyl 4-nitro-phenyl ketone. 4-nitrobenzyl bromide, dimethylcarbamoyl chloride and the like. 20 Alternatively, the desired compound can be prepared by reacting a compound of the formula (IX) with a Michael acceptor of the formula (XI). 25 This reaction may, if desired, be carried out in a solvent such as dimethylformamide. dimethylacetamide. dimethylsulfoxide, dioxane, tetrahydrofuran. methanol, ethanol. propanol, glycol monomethyl ether and the like. Mixtures of two or more solvents may also be used. Vw 30 The reaction temperature may be varied within a relatively wide range. In general, the reaction is carried out at a temperature between about 30°C and about 170°C, preferably between 50°C and 140°C. 35 Jj-N - "v r „ . ,- "ifr—WT? - 22 1 6 8 1 - 26 - la carrying out the process provided according to the present invention preferably 1 to 5 moles, more preferably 1 to 2 moles, of the compound of the formula (XI) is employed, based on one mole of the compound of the formula (IX). 5 The Michael acceptor used in the present invention is e.g. methyl vinyl ketone, ethyl vinyl ketone and the like. The reaction of compounds (IX) with formaldehyde and 10 formic acid or an alkalimetal bisulfite (whereby compounds of formula I in which R7 is methyl or sulfomethyl are obtained) is normally carried out at slightly elevated temperature, e.g. at about +50°C to +100°C. 15 Moreover, the desired compound can be produced by reacting a compound of the formula (IX) with an anhydride of the formula (XII). The reaction may. if necessary, be carried out in a 20 solvent such as pyridine, dimethylformamide. dioxane. tetra-hydrofuran and the like. Mixtures of two or more solvents may also be used. The reaction is preferably carried out in the presence 25 of an acid acceptor such as triethylamine. pyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, alkali metal hydroxides, alkali metal carbonates and the like. The reaction temperature may be varied within a relati-30 vely wide range. In general, the reaction is carried out at a temperature between about 0°C and 120°C. preferably between 0°C and 100°C. In carrying out the process provided according to the 35 present invention, preferably 1 mole or excess moles of the compound of the formula (XII) per mole of the compound of the formula (IX) is employed. ^IKIHIWWI - m 22 1 6 8 1 27 The anhydride used in the present invention is e.g. succinic anhydride, glutaric anhydride. N-benzyloxycarbonyl-aspartic anhydride, N-benzyloxycarbonylglutamic anhydride, o phthalic anhydride and the like. 5 The protecting radical may, if desired, be removed after the reaction by the procedures known to those skilled in the art. For example, the formyl radical may be removed by acid or base hydrolysis preferably base hydrolysis and the 10 benzyloxycarbonyl radical may be removed by hydrogenolysis. The removal of a protecting radical may be accomplished either before or after isolating the product. 15 Process D: 25 c When it is desired to manufacture a compound of formula 5 6 I in which R and/or R are lower alkyl (or contain a di-lower alkylamino or lower alkoxy group) these compounds 20 can be manufactured by lower alkylating the corresponding non-alkylated compound viz. a compound of formula I wherein R5 and/or El6 are hydrogen or contain an amino, lower alkylamino or hydroxy group. The N-alkylation can be effected by reaction with a compound of the general formula R10Y (XIII) 10 . . wherein R is lower alkyl and Y is a leaving group. The leaving group is of the same type as that employed in 30 the compounds of formula (X). Also, the reaction can be carried out in the same manner as the alkylation reaction of the compounds (IX) with (X) described above. The O-alkyla-tion is effected as the N-alkylation; however, expediently a proton acceptor such as an alkali metal hydride e.g. sodium 35 hydride is added. * s, - ■ \ 22 1 6 8 1 - 28 - Process E: When it is desired co manufacture a compound of formula /-v 5 6 f , I in which R R N- is a 5 to 7 membered heterocyclic ring g with an -SO- or ~so2- member these compounds can be manufactured by oxidizing the corresponding desoxy-compounds of formula I viz. with an -S- member in the heterocycle. The oxidation is carried out by treatment with an 10 organic or inorganic oxidizing agent. Various compounds which readily yield oxygen can be used as the oxidizing agent; for example, organic peroxides such as monosubstitu-ted organic peroxides (e.g. C^-C^-alkyl- or alkanoyl-hydroperoxides such as t-butylhydroperoxide). performic acid 15 and peracetic acid, as well as phenyl-substituted derivatives of these hydroperoxides such as cumenehydroperoxide and perbenzoic acid. The phenyl substituent can, if desired, carry a further lower group (e.g. a C^-C^ alkyl or alkoxy group), a halogen atom or a carboxy group (e.g. 20 4-methylperbenzoic acid, 4-methoxy-perbenzoic, 3-chloroper-benzoic acid and monoperphthalic acid). Various inorganic oxidizing agents can also be used as the oxidizing agent; for example, hydrogen peroxide, ozone, permanganates such as potassium or sodium permanganate, hypochlorites such as 25 sodium, potassium oc ammonium hypochlorite, peroxymonosul-phuric and peroxydisulphuric acid. The use of 3-chloroper-benzoic acid is preferred. The oxidation is advantageously carried out in an inert solvent, for example, in an aprotic inert solvent such as tetrahydrofuran, dioxan, methylene 30 chloride, chloroform or ethyl acetate. The oxidation is generally carried out at a temperature in the range of -20°C to +50°C. When the oxidizing agent is used in equimolar amounts or 35 in slight excess in relation to the starting material there is mainly obtained the corresponding sulfoxide, i.e. a compound of formula I in which the heterocycle contains an "V ' NW 22 1 6 8 1 - 29 - -SO- member. When thtj amount of oxidizing agent is increased to double the stoichiometric ratio or more, there is obtained the corresponding sulfone, i.e. a compound of r formula I in which the heterocycle contains an -SO.- 5 member. It is also possible to obtain the sulfone from the corresponding sulfoxide by treatment with an eguimolar or greater amount of the oxidizing agent. Process F: 10 When it is desired to manufacture a compound of formula I having a free amino, hydroxy and/or carboxy group these compounds can be manufactured from the corresponding compounds of formula I having one or more of any amino. 15 hydroxy and carboxy groups present in protected form. Amino-protecting groups are e.g. lower alkanoyl such as acetyl; benzoyl; an alkoxycarbonyl group, e.g.. t-butoxycar-bonyl or ethoxycarbonyl; a substituted alkoxycarbonyl group, 20 e.g. trichloroethoxycarbonyl; phenoxycarbonyl; benzyloxy- carbonyl; p-nitrobenzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl; or a halogen-alkanoyl group such as ^ trifluoroacetyl. 25 The amino protecting groups may be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonyl or trityl group) or by basic hydrolysis (e.g. the trifluoroacetyl group). Benzyl-oxycarbonyl and p-nitrobenzyloxycarbonyl are removed by hydrogenolysis. 30 Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid 35 hydrolysis is generally carried out at room temperature. - 30 - 221681 although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about 0°C to +40°C). Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C. Carboxy-protecting groups are e.g. the carboxy-protecting radicals discussed under R above. The removal of these protecting groups can be effected in a manner known per se. e.g. by hydrogenation (benzyl) or by acidic or basic hydrolysis. The reaction is preferably effected in an inert solvent at a temperature between about 0°C and room temperature. Specific methods are also useful e.g: p-nitrobenzyl removed by hydrolysis in the presence of sodium sulfide at about or below 0°C to room temperature in a solvent, such as, dimethylformamide (aqueous); t-butyl removed by reaction with trifluoroacetic acid in the presence of anisole at about 0°C to room temperature with or without a co-solvent, such as methylene chloride; or allyl removed by a palladium (0) catalyzed transallylation reaction in the presence of sodium or potassium salt of 2-ethyl hexanoic acid, see for example J. Org. Chem. 1982, 42. 587. Process G: When it is desired to manufacture a compound of formula I containing a halogen atom, such as a compound where R5R6N- is CI- O this compound can be manufactured by halogenating a correspondingly hydroxy-substituted compound (e.g. where R5R6N- is HO-^Jn-). The halogenating agent is preferably a thionyl halide. especially thionyl chloride; or phosphorous trichloride, phosphorous oxychloride or phosphorous pentachloride. The reaction temperature is 221681 - 31 - preferably between about 0°C and 80°C. Carboxy groups present are preferably protected, e.g. benzylated. and subsequently, if desired, again set free e.g. by hydrogena-tion (removal of benzyl). Process H: When it is desired to manufacture a compound of formula I containing an amino group such as a compound where r5rV is h2n-Q-ch2-n_ji-. this compound can be manufactured by reducing the nitro groups of a correspondingly nitro-substituted compound of formula I. The reduction can be effected by hydrogenation in the presence of a noble metal catalyst such as palladium on charcoal. The reaction is suitably effected in water or a lower alkanol e.g. methanol or ethanol. if desired in admixture with other solvents soluble therein. The reaction temperature normally lies between about 10°C and about 40°C. preferably at about room temperature. Process I: When it is desired to manufacture a compound of formula I containing a group of the formula R50 N-CH-N- (wherein R50 and R R ,51 51. where R5R6N- is (CH3)2N-CH= are as above) such as a compound Q' -. this compound can be manufactured by reacting the amino group of a correspondingly amino substituted compound of formula I (e.g. where R5R6n- is with a reactive derivative of a formamide derivative of the general formula A v ' 22 1 68 1 & n 32 - N-CHO (VII) 50 51 whecein R and R ace as above. As reactive derivative of a compound of the focmula VII can be employed the corresponding di-(lowec alkyl)acetals such as the dimethyl acetals. The ceaction is pcefecably pecformed in an inect solvent such as diethyl ether. 10 dimethylfocmamide or dimethylsulfoxide. The temperature is pcefecably about coom temperature but can lie well below or above, e.g. in the range of about 0°C and 100°C. Process J: 15 Manufacture of esters of formula I i.e. where R1 is a carboxy-protecting group can be effected by reacting a carboxylic acid of formula I with a corresponding halide. pcefecably an iodide oc bcomide. containing the desiced 20 ester gcoup. The ceactions can be accelecated with the aid of a base such as an alkali metal hydcoxide. an alkali metal cacbonate oc an organic amine such as triethylamine. The esterification is preferably carried out in an inect ocganic solvent such as dimethylacetamide. hexamethylphosphocic acid 25 tciamide. dimethyl sulfoxide oc. especially, dimethyl-focmamide. The ceaction is pcefecably carried out at a tempecatuce in the cange of about 0°C-40°C. Pcocess K: 30 The manufacture of the pharmaceutically acceptable salts of the compounds of formula I or the hydcates or solvates of said salts can be carried out in a manner known per se; for example, by reacting a carboxylic acid of focmula I with an 35 equivalent amount of the desiced base or convecsely. a fcee base of focmula I with an ocganic or inorganic acid. The reaction is conveniently cacried out in a solvent such -•Ar" * •««, 221681 - 33 - n as water or an organic solvent (e.g. ethanol, methanol, acetone and the like). The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of o°C to +50°C. C Examples of pharmaceutically ' acceptable acids useful in the above process are hydrochloric, hydrobcomic. sulfuric, phosphoric, nitric, formic, acetic, propionic, succinic, glycolic. lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic. phenylacetic. benzoic. 4-aminobenzoic. anthranilic. 4-hydroxybenzoic, salicylic, aminosalicylic, nicotinic, methanesulfonic. ethanesulfonic, hydroxyethane-sulfonic, benzenesulfonic. p-toluenesulfonic, gluconic, glucuronic, galacturonic. aspartic and glutamic acid ; methionine, tryptophan, lysine, arginine, and the like. The acid addition salts can be converted into a free form by treatment with a base, such as a metal hydroxide, ammonia and the like. The base salts of the compounds of the formula (I) can be prepared by reacting a compound of the formula (I) with a metal base or amine such as an alkali or alkaline earth metal hydroxide, or an organic amine. Examples of the metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of amines are diethanol-amine. N,N'-dibenzylethylenediamine, choline, ethylenediamine and the like. ? 5 I** The acid addition salts or base salts of the compounds of the formula (I) differ from the corresponding free form n certain physical properties such as solubility in water. The compounds of the formula (I) and their pharmaceutically acceptable salts can exist in unsolvated as well as ~.iv - "H..- ' \ ' ' «• jV 22 1 6 8 1 a o C - 34 - solvated forms, including hydrated forms. The hydration can be effected automatically in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product. For the 5 controlled manufacture of a hydrate a completely or partially anhydrous product can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C). Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained during e.g. crystallization. 10 15 Certain compounds provided by the present invention have asymmetric centers. The pure D isomer, pure L isomer as well as mixtures thereof, including racemic mixtures, are also contemplated by the present invention. The compounds provided according to the present invention exhibit a broad antibacterial activity against gram-positive and gram-negative organisms and Mycoplasma and can be used as agents for treatment and prophylaxis of 20 infectious diseases. The in vitro and in vivo antibacterial activities of the compounds of the present invention are shown as follows: 1. In vitro antibacterial activities 25 The in vitro antibacterial activities of the represen tative pyrido[3,2,l-ij]-1.3.4-benzoxadiazine derivatives of the present invention were assayed by the standard agar dilution method [see: Chemotherapy. 22.. 1126 (1974)]. Their minimum inhibitory concentrations (MIC. in ug/ml) are 30 shown in Table 1 and Table 2. The compounds used here were produced by respective Examples as mentioned below. 35 TABLE 1 Antibacterial spectrum 1 MIC tug/ml) Co*pound 1 Example tlo.) Aerobic *1croorganisms S 6 7 6 9 12 13 15 16 17 16 19 21 Gram-positive bacteria Bacillus atibti lis PCI 219 o.os 0.10 0.10 0.025 <0.0009 0.10 <0.0006 0.05 0.20 0.01 3 0.013 0.05 O.OS Staphylococcus aureus FOA 209P JC-1 0.39 0.39 0.39 0.39 0.20 0.10 0.10 0.76 0.39 0.05 O.OS 0.39 0.39 Staphylococcus aureus MR 2855 0.20 3.13 1.5$ 0.39 0.006S 0.76 0.05 0.76 6.25 0.20 0.10 0.39 0.20 Staphylococcus aurous Smith 0.20 0.39 0.20 0.20 0.0033 0.10 0.025 0.39 0.39 0.025 0.025 0.20 0.39 Staphylococcus epidermidls IFO 12993 0.39 1 .56 0.76 0.39 0.20 0.39 0.10 0.76 ' 1.56 0.20 0.10 0.39 0.39 Staphylococcus epidermidls NR 2942 0.39 1.56 0.76 0.39 0.0065 0.39 0.05 0.76 1 .56 0.10 0.10 0.39 0.39 Enterococcus (aecalls MR 2943 3.13 12.5 12.5 6.25 12.5 3.13 3.13 6.25 25 1.56 1.56 6.25 3.11 Gran-negative bacteria Alcallgenns fnecalls IFO llltl 0.39 3.1) 6.25 0.76 6.25 50 1.1) 1.13 so 6.2S 6.2S 6.25 0.76 Cltrobactor tround11 IFO 12681 0.013 0.013 O.OS 0.02S 0.39 0.76 0.39 O.OS 0.10 0.20 0.10 1.56 0.76 Enterobactar aeroqanes MR 2945 0.013 0.013 0.05 0.025 0.0065 0.20 0.20 0.05 0.05 O.OS O.OS 1.56 0.20 Cnterobacti>r clrmcno IIR 2946 0.025 0.025 0.10 0.05 0.013 0.76 0.39 0.10 0.10 0.10 O.OS 1.56 0.76 Escherichia coll tllllj JC-2 0.02S 0.025 0.10 O.OS 0.10 0.20 0.39 0.10 0.20 0.10 O.OS I.S6 0.39 Escherichia coll (III 2630 0.013 0.025 0.02S 0.013 <0.0006 0.10 - - - 0.025 0.013 0.39 0.20 Klebsiella pneumoniae FOA PCI 602 0.10 0.10 0.39 0.20 3.13 3.13 0.76 0.39 1.36 0.76 0.39 6.25 0.76 Bordetella bronchiseptica ATCC 4617 0.20 6.25 3.13 0.39 1.56 6.25 0.76 0.76 25 6.25 3.13 6.25 0.76 Proteus rettgerl ATCC 14505 0.20 0.10 0.76 0.39 1.56 12.5 0.76 0.76 1.56 1.56 0.39 3.13 0.78 Proteus vulgaris 0X19 ATCC 6696 0.013 0.01 3 0.025 0.025 <0.0006 0.10 0.05 0.02S 0.10 0.025 0.025 0.39 O.OS Fseudoaonas aeruginosa A3 0.20 0.10 0.20 0.39 6.25 0.76 1.56 0.76 0.39 0.39 0.76 6.25 1 .56 Pseudoaonas aeruginosa NR 2950 0.76 0.70 3.13 3.13 12.5 12.5 6.25 1.13 6.25 6.25 6.2S 25 1.11 .Pseudononas stutzerl IFO I269S 0.025 0.025 O.OS 0.025 <0.0006 - 0.10 O.OS 0.05 0.025 0.025 0.39 0.20 Sercatla marcescens IFO 12646 0.10 o.to 0.20 0.10 0.76 3.13 0.39 0.39 0.39 0.76 0.39 1.11 0.19 Salmonella typliimurium (TO 12S29 0.025 0.013 0.05 0.025 0.0033 o.:o o.to O.OS 0.10 0.05 0.025 1.56 0.19 Al. ( ) o o o TAOLE 1 - continued Antibacterial spectrum HIC lug/al) Compound (Exaaple Ho.I Aerobic mlcroorqanlsms 22 24 25 26 27 10 11 32 13 34 35 16 Gram-positive bacteria Bacillus subtllls FCI 219 0.05 0.39 0.76 0.76 0.39 0.025 0.05 0.05 0.20 O.OS O.OS 0.02S Staphylococcus aureus FOA 209P JC-I 0.20 t.S6 6.25 3.13 1.56 O.OS 0.19 0.20 0.20 0.20 0.39 0.39 Staphylococcus aureus IIR 28SS 0.39 6.25 12.5 1.S6 12.S 0.39 0.76 0.39 1.56 1.56 1.56 0.10. Staphylococcus aureus Salth 0.20 1.S6 1.56 3.13 1.S6 O.OS 0.20 0.10 0.20 0.20 0.19 0.10 Staphylococcus epideraldls IfO 12993 0.39 3.13 6.2S 3.13 6.2S 0.20 0.39 0.39 0.78 0.78 0.78 0.20 Staphylococcus epidermidls NR 2942 0.20 3.1] 6.25 3.13 6.25 0.20 0.39 0.39 0.78 0.76 0.76 0.20 Enterococcus faecalis IIR 2943 3.13 2S 100 25 SO 3.13 12.5 6.25 3.13 6. 25 6.2S 3.13 Cran-neq.it 1 ve bacteria Alcaligam»s fnecalls ITO 13111 3.13 25 so 12.5 SO 1.56 3.13 1.56 50 50 25 3.13 Cltrabactor (rcundll IFO 12661 0.10 1.56 0.70 0.76 0.20 0.013 O.OS 0.10 0.20 0.20 0.20 0.20 Cnterobactor aerogenes IIR 294S 0.10 0.76 0.39 0.20 0.20 0.0033 0.025 0.025 O.OS 0.10 0.10 0.05 Enterobactor cloacae IIR 2946 0.10 3.13 0.76 0.76 0.78 0.01 3 O.OS 0.10 0.20 0.20 0.39 0.10 Escherichia coll tllllj JC-2 0.10 1.56 0.76 0.76 0.78 0.013 O.OS 0.10 0.20 0.20 0.10 0.10 Escherichia coll IIR 2630 0.02S 0.76 0.39 0.20 - 0.006S 0.02S 0.025 0.10 0.10 0.10 O.OS Klebsiella pneumoniae TOA PCI 602 0.39 6. 25 3.13 3.13 3.13 0.10 0.20 0.39 0.78 0.78 1.56 0.39 Bordetelln bronchlseptica ATCC 4617 I.SG SO too 12. 5 25 1.56 3.13 1 • 56 25 2S 12.S 0.39 Proteus rottqerl ATCC I450S 0.76 12.5 25 6.25 12.5 0.10 0.39 1 .56 1.56 3.13 3.13 0.78 Proteus vnlqaris OX19 ATCC 6B96 0.0(165 0.39 0.10 0.39 0.20 O.OOfiS 0.025 0.025 0.05 O.OS 0.05 0.02S Pseudononas aeruginosa A3 1.S6 3.13 3.13 6.2S 3.13 O.OS 0.20 0.39 0.39 0.78 1.56 0.78 Pssudomonns aeruginosa IIR 29S0 6.25 25 50 50 25 0.20 1.56 3.13 6.25 6.25 12.5 6.2S Pseudoaonns stutzerl IFO 12695 0.10 - 0.39 0.78 0.20 0.0031 0.025 0.10 - - . 0.10 Serratia mnrcescnns IFO 12646 0.76 6.25 3.13 1.56 3.13 O.OS 0.20 0.39 0.78 0.78 1.56 0.39 Salmonella typliiraurium IFO I2S29 0.10 n.m 0.20 0.76 0.39 0.006S 0.025 0.025 0.10 0.10 0.10 0.10 u> o> to JO M-03 00 o ) o TABLE 1 - continued Aerobic mlcroorqanlsms 37 38 39 Antibacterial spectrum HIC (ug/mi) Compound (Exiapla No.) 40 41 42 43 44 45 46 46 Cran-posltlve bacteria Bacillus suhtllls PCI 219 <0.0008 jO.OOOS 0.025 0.10 3.13 0.05 0.10 O.OS 0.39 O.OS O.OS 3.13 Staphylococcus aureus FDA 209P JC-1 0.0016 0.39 0.39 1.56 6.25 0.39 0.78 0.78 1 .56 0.78 0.39 6.25 Staphylococcus aureus IIR 285S <0.0008 0.20 0.78 0.78 6.25 0.39 0.78 0.39 3.13 0.39 0.39 12.5 Staphylococcus aureus Smith ^<0.0008 0.10 0.39 0.78 6.25 0.39 0.39 0.39 0.78 0.39 0.20 6.25 Staphylococcus epidermidls IFO 1299} 0.025 0.39 0.39 1.56 6.25 0.39 0.39 0.78 3.13 0.78 0.39 12.5 Stnphylocnrciii npitlormldls IIR 2942 <o.aoon 0.39 0.39 0.78 12.5 0.39 0.39 0.39 3.13 0.39 0.78 12.5 Enterococcus fancalls MR 2943 3.13 12.5 12.5 12.5 100 6.25 6.25 12.5 50 6.25 6.25 100 Cram-npontiun hacterla Alcallgenas faecalis IFO 13111 12.5 6.25 6.25 6.25 50 1.56 0.78 1.56 12.5 1.56 3.13 100 Cltrobacter frmindll IFO 12681 0.78 6.25 0.78 0.20 0.39 0.05 0.10 0.20 0.10 0.10 0.39 0.39 Enterobactor aerognnos HR 2945 0.10 3.13 O.OS 0.10 0.10 0.025 0.10 0.10 0.05 0.10 0.39 0.39 Enterobacmr cloacae IIR 2946 0.20 6.25 0.78 0.39 0.78 0.05 0.10 0.20 0.20 0.20 0.39 0.78 Escherichia rnli MI 11,1 JC-2 0.10 6.25 0.78 0.39 0.78 O.OS 0.10 0.20 0.20 0.10 0.39 1.56 Escherlchln coll MR 26)0 ^0.0000 0. J9 0.025 0.20 0.39 0.025 O.OS 0.05 0.10 O.OS 0.10 0.39 Klebsiella pneumoniae FDA PCI 602 3.13 25 1.56 1.56 3.13 0.39 0.39 0.39 0.39 0.78 1 .56 1 .56 ftordetell.i hronclilsoptlca ATCC 4617 1.56 6.25 0.78 1 .56 25 0.39 0.39 0.39 12.5 0.39 6.25 50 Proteus rnl-tqcrl ATCC 14S05 6.25 25 3.13 3.13 3.13 0.39 0.78 1.56 0.78 1.56 3.13 3.13 Proteus vulgaris 0X19 ATCC 689B ^0.0000 3.13 O.OS 0.20 1.56 0.02S 0.10 0.10 0.10 0.05 0.39 0.78 PseudomoiMft aeruginosa A3 6.25 25 3.13 1.56 3.13 0.39 0.78 0.78 0.78 1.56 3.13 3.1) Pseudononas aeruginosa IIR 2950 25 50 12.5 12.5 12.5 J.I3 6.25 6.25 6.25 6.25 f SO 50 Pseudononas stutzerl IFO 12695 0.013 6.25 - - - 0.10 - 0.20 0.05 1.56 - Serratla marcescons IFO 12648 0.78 12.5 1.56 1.56 3.13 0.10 0.20 0.39 0.7B 0.39 1.56 3.13 Salmonella typliimurium IFO 12529 0.20 6.25 0.20 0.39 0.78 0.025 0.10 0.30 0.10 0.10 0.39 0.39 o o O ) TAQLB I - continued Antibacterial spectrua HIC (119/iil) Compound 1 (Example Ho.) Aerobic microorganisms 50 51 *2 S3 54 56 59 63 69 Gram-positive bacteria Bacillus subtills PCX 219 0.0065 0.10 0.20 0.025 0.025 0.20 0.0065 0.78 0.20 Staphylococcus aureus FOA 209P JC-t 0.39 0.20 0.39 0.10 0.013 0.39 0.39 0.78 1.56 Staphylococcus aureus NR 2855 0.39 1.56 3.13 0.10 0.20 0.78 0.10 3.13 1.56 Staphylococcus auraua Smith 0.10 0.39 0.39 0.05 0.025 0.39 O.OS 0.39 0.78 Staphylococcus epidarmldis IFO 1299] 0.J9 0.78 1.56 0.10 0.10 0.39 0.39 1.56 1.56 Staphylococcus epidermidls lift 2942 0.20 0.78 1.56 0.10 0.10 0.39 0.20 0.78 1.56 Enterococcus faecalls tin 294] ].l) 12.5 25 1.56 1.56 12.5 3.13 25 12.5 Gram-negativo bacteria Alcallganes faecalls IFO 131*1 12.5 3.1] 12.5 3.13 6.25 3.13 6.25 100 3.13 Cltrobacter Creundll IFO 12681 3.1 J 0.025 0.025 0.10 0.10 0.10 1.56 0.78 0.10 Cntsrobactar aarogenas IIR 294S 0.78 0.025 0.025 0.10 0.025 0.10 0.78 0.39 0.10 Enterobactar cloacae IIR 2946 1.56 0.05 O.OS 0.20 0.10 0.05 0.78 1.56 0.20 Escherichia coll HIIU JC-2 1.56 0.10 0.05 0.20 0.10 0.10 1.56 1.S6 0.20 Escherichia coll MR 2630 0.20 0.025 0.02S 0.05 0.025 0.006S 0.39 0.78 0.10 Klebsialla pneumoniae FOA PCI 602 6.25 0.20 0.20 0.39 0.78 0.39 3.13 6.25 0.39 Bordetella bronchiseptlca ATCC 4617 3.1] 1.56 6.25 0.78 3.13 3.13 3.13 50 0.78 Protous rnttqori ATCC 14505 6.25 0.20 0.20 1.56 0.78 1.S6 3.13 6.25 0.78 Proteus vulgaris 0X19 ATCC 6098 0.39 0.025 0.025 0.10 0.013 0.013 0.20 0.39 O.OS Pseudononas aeruginosa A] 6.25 0.10 0.20 0.78 0.20 3.13 3.13 3.13 0.78 Pseudomonas aeruginosa MR 2950 2S 1.56 1.56 12.5 1.56 6.2S 25 25 6.25 Pseudononas stutzerl IFO 1269S - O.OS 0.05 0.20 0.013 0.0033 1.56 0.39 0.20 Serratia marcescons IFO I2C4B 3.13 0.10 0.20 0.78 0.39 0.78 3.13 3.13 0.20 Salmonella typhlmurlum iro I2S29 0.70 0.025 0.025 0.10 0.02S O.OS 1.56 0.78 0.10 ■Av. f n n 221681 - 39 -TABLE 2 Antibacterial spectrum MIC (y.g/ml) Compound (Example No. Anaerobic microorganisms 5 30 Bacteroides fragil Bacteroides fragil Bacteroides fragil S ATCC 23745 0.78 0.20 S NR 2579 3.13 1.56 s NR 2582 0.78 0.39 Bacteroides fragilis NR 2583 0.39 0.10 Bacteroides fragilis NR 2584 0.78 0.78 Bacteroides distasonis NR 2578 0.78 0.78 Bacteroides thetaiotaomicron NR 2588 1.56 0.78 Bifidobacterium adolescentis ATCC 15703 0.39 0.10 Clostridium botulinum NR 2611 0.10 0.013 Clostridium perfringens NR 2612 0.39 0.10 Clostridium moniliforme ATCC 25546 0.78 0.10 Fusobacterium varium ATCC 8501 12.5 Peptococcus prevotii ATCC 9321 1.56 0.39 Peptococcus variabilis ATCC 14955 0.78 0.20 Peptostreptococcus anaerobius NR 2743 0.39 0.013 Propionibacterium acnes ATCC 11828 0.78 0.78 Mycoplasma Mycoplasma hominis NR 2952 0.10 0.10 ' ' 22 1 6 8 1 - 40 - r^- i-y 10 2. In vivo therapeutic efficacy The in vivo antibacterial activities of pyrido[3,2,1-ij]-1,3.4-benzoxadiazine derivatives prepared by Example 5. Example 30, Example 65 and Example 66 as mentioned below were tested against lethal infection of Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICR mice weighing about 20 g were infected by intraperitoneal injection of a corresponding bacterial suspension. The test compounds were administered orally or subcutaneously at the time of injection. The mortality was observed for 5 days. The respective 50% effective dose (ED&0. mg/lcg) which protects 50* of the animals from death caused by infection, is shown in Table 3. 15 Table 3 A 1 In vivo Antibacterial Activities Against Systemic Infection in Mice (ED&0, rag/kg) 20 -1 \ r. 25 30 Bacterium Escherichia Pseudomonas Streptococcus Compound coli aeruginosa pneumoniae ML4707 4au542 6-001 SaC* P . 0 . p.o. p.o. Example 5 0.06 0.11 13.4 10. 3 Example 30 0.10 0.62 57.0 65.9 Example 65 1. 12 - - Example 66 0. 51 — — 3. Acute toxicity The respective values of the compounds obtained 35 in Examples 5, 6, 7, 16, 17, 18, 30, 36 and 56 as mentioned below are more than 2000 mg/lcg. The acute toxicity of these compounds was examined by oral administration in ICR mice. i 22 1 6 8 1 - 41 - The compounds provided according to the present invention exhibit a broad antimicrobial spectrum against gram-positive, gram-negative bacteria and Mycoplasma, in particular against those which are resistant to various antibiotics, such as penicillins, cephalosporins, aminoglycosides, tetracyclins, and the like. Moreover, the compounds provided according to the present invention have low toxicity, and a potent and broad 10 antimicrobial efficacy. The protective effects of the compounds of the present invention on systemic bacterial infections in mice are greater than those of synthetic antibacterial agents which are commercially available. Therefore. the compounds of the present invention can be effecti-15 vely utilized for the prevention or treatment of diseases caused by gram-positive and gram-negative bacteria, and bacterioid microorganisms in human beings or animals. For example, diseases caused by the following micro-20 organisms, or by mixtures of the following microorganisms can be treated and/or prevented: Staphylococcus, Streptococcus. Aerococcus. Enterococcus. Micrococcus. Lactobacillus. Bifidobacterium. Clostridium. Eubacterium. Peptococcus. Peptostreptococcus, Propionibacterium, Escherichia, 25 Citrobacter, Campylobacter. Enterobacter. Klebsiella. Proteus. Pseudomonas. Serratia. Salmonella, Shigella. Vibrio. Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes. Bordetella. Bacteroides, Fusobacterium, Mycoplasma and other microorganisms. 30 The present invention further relates to the pharmaceutical compositions containing one or more compounds of the present invention. 35 The compounds of the present invention can be administrated orally or non-orally to human beings or animals by various conventional administration methods. 22 1 6 8 1 - 42 - Moreover, the compounds according to the present invention are used singly or formulated with auxiliaries, liquid diluents, binders, lubricants, humectants. etc.. for example, in the form of general medicinal compositions such as tablets, granulars, sugar coating tablets, powder, capsules, gels, dry syrup, syrup, ampules, suspension, liquid, emulsion, ointments, paste, cream, suppositories, and the like. Furthermore, dissolution delaying agents, absorption accelerating agents, surface active agents, and the like can be used as other additives for formulation, i.e.. any forms which are pharmaceutically acceptable can be employed. The compounds according to the present invention can be used as alone or mixture of two or more different kinds of compounds and the amount of the compounds is about 0.1 to 99.5 *. preferably 0.5 to 95* based on the weight of the all medicinal composition. The medical composition according to the present invention may be formulated in a combination of the compound of the present invention or the mixture thereof with other conventional compounds which are pharmaceutically active. A dosage per day to a patient of the novel compound according to the present invention may be varied depending upon an individual man, kinds of animals, weights thereof and a state to be remedied, but generally is in the range of 0.5 to 500 rag per 1 kg of weight, preferably about 1 to 300 mg. The following examples illustrate the preferred methods for the preparation of the compounds of the present invention. 22 1 6 8 1 - 43 - Preparation of starting materials Reference example Preparation of diethyl N-(3.4-difluoro-2-hvdroxv-5 phenyl)aminomethv1enemalonate (a) A solution of 2.3-difluoro-6-nitrophenol (500 rag) in methanol (7 ml) was hydrogenated over 5X Pd/C (60 rag) for 6 O hours. The reaction mixture was filtered under nitrogen ( 10 stream and the filtrate was evaporated under reduced | pressure to give 414 mg of crude 2-amino-5,6-difluorophenol, i (b) A mixture of the above amine (414 mg) and diethyl ethoxymethylenemalonate (618 mg) was heated at 130°C under 15 nitrogen atomosphere for 5 minutes. The resulting crystalline residue was triturated with ethanol and filtered to give 590 mg of diethyl N-(3,4-difluoro-2-hydroxyphenyl)-• aminomethylenemalonate. rap 178-180°C: MS ra/z 315 (M+). Additional 59 rag of the crystals were obtained after silica 20 gel column chromatography of the mother liquid using t CHCl3/acetone (20:1) as the eluent. 4 Preparation of ethyl 8-benzvloxv-6.7-difluoro-4-hvdroxy-3- quinolinecarboxylate (Route 1) 25 (c) To a mixture of diethyl N-(3.4-difluoro-2-hydroxy-phenyl)arainomethylenemalonate (80 rag) and anhydrous potassium carbonate (70 mg) in dry dimethylformamide (1.5 ml) was added benzyl bromide (30 ul). The mixture was 30 stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline 35 residue was washed with n-hexane and recrystallized from methanol to give diethyl N-(2-benzyloxy-3,4-difluorophenyl)-aminomethylenemalonate (90 mg), mp 87°C; MS m/z 405 (M+). 3 ■s r n 22 1 6 8 1 - 44 - (d) A solution of the above malonate (280 mg) in diphenyl ether (2.8 ml) was heated at 250°C for 30 minutes under nitrogen atmosphere. After cooling the reaction mixture, the ethanol generated in reaction medium was removed under 5 reduced pressure. The dark brown solution was applied onto a column of silica gel (10 g) followed by successive elution with benzene, dichloromethane and dichloromethane/acetone (30:1). The pure fractions were combined and the solvent was removed under reduced pressure to give the crystalline 10 residue. The residue was washed with a mixture of n-hexane and ethyl acetate to give 90 mg of ethyl 8-benzyloxy-6.7--difluoro-4-hydroxy-3-quinolinecarboxylate. An analytical sample, mp 200-201°C: MS m/z 359 (M+), was prepared by recrystallization from methanol. 15 Preparation of ethvl 8-benzyloxv-6.7-difluoro-4-hvdroxv-3-quinolinecarboxvlate (Route 2) To a stirred solution of ethyl 6.7-difluoro-4,8-20 -dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethyl-formamide (6 ml), was added anhydrous potassium carbonate (308 mg) and then benzyl chloride (145 ul). The mixture was stirred at 55-65°C for 11 hours. The reaction mixture was diluted with water (30 ml) and extracted with chloro-25 form. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (7 g) using acetone/chloroform (1:20) as an eluent to give 113 mg of ethyl 8-benzyloxy-6.7--difluoro-4-hydroxy-3-quinolinecarboxylate. mp 200-20l°C; MS 30 m/z 359 (M+), after recrystallization from methanol. Preparation of ethvl 8-benzyloxv-6.7-difluoro-1-(formvl-methvlamino)-4-oxo-l.4-dihvdro-3-ouinolinecarboxylate 35 (e) After a mixture of ethyl 8-benzyloxy-6,7-difluoro-4--hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformaraide (10 V-"V v.. 22 1 6 8 - 45 ml) was stirred at room temperature for 3 hours. 0-(2.4-di-nitrophenyl)hydroxylaraine (260 mg) was added. The mixture was stirred at room temperature for further 6.5 hours. After removal of the solvent under reduced pressure, water 5 (12 ml) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with cold water and then with ether to give 405 mg of ethyl l-amino-8-benzyloxy-C -6,7-difluoro-4-oxo-l.4-dihydro -3-quinolinecarboxylate. An 10 analytical sample, mp 143-144°C; MS m/z 374 (M+). was prepared by recrystallization from methanol. (f) 98* Formic acid (0.60 ml) was added to acetic anhydride (1.51 ml) at 0°C. The mixture was stirred at o°c for 15 15 minutes, at 50°C for 15 minutes, and then cooled to 0°C. To this solution was added dropwise a solution of the above amine (400 mg) in 98* formic acid (2.1 ml). The mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure to give the 20 crystalline residue, which was recrystallized from ethanol to give 410 mg of ethyl 8-benzyloxy-6.7-difluoro-1-(formyl-amino)-4-oxo -1.4-dihydro-3-quinolinecarboxylate, mp ^ 188-190°C: MS m/Z 402 (M+). 25 (g) A mixture of the above formamide (400 mg). anhydrous potassium carbonate (275 mg) and anhydrous dimethylformamide (17 ml) was stirred at room temperature for 1.5 hours. Methyl iodide (0.19 ml) was added to the mixture and stirring was continued for 2.5 hours. The solvent was 30 removed under reduced pressure and the residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 335 mg of ethyl 8-benzyloxy-6,7-35 -difluoro-1-(formylmethylamino)-4-oxo-l.4 -dihydro-3-quino-linecarboxylate. mp 180-181°C; MS m/z 416 (M+). *v O e 22 1 6 8 1 - 46 - Preparation of 6.7-difluoro-8-hydroxv-l-(methylamino)-4-oxo-l.4-dihydro-3-guinolinecarboxylie acid ' (h) Ethyl 8-benzyloxy-6,7-difluoro-l-(formylmethylamino)-4- 5 -oxo-1,4 -dihydro-3-quinolinecarboxylate (330 mg) was hydro-genated over 5* Pd/C (50 mg) in chloroform (14 ml) for 4 hours. The reaction mixture was diluted with methanol (14 ml) and filtered. The filtered cake was washed with chloro-form/methanol (1:1). The combined filtrate was evaporated 10 and the residue was recrystallized from ethanol to give 239 mg of ethyl 6,7-difluoro-1-(formylmethylamino)-8-hydroxy-4--oxo-1,4 -dihydro-3-quinolinecarboxylate, mp 221-225 °C (dec.); MS m/z 326 (M+). 15 (i) A mixture of the above ester (210 mg) and 0.5N sodium hydroxide (5.2 ml) was heated at 100°C for 2 hours under nitrogen atmosphere. The reaction mixture was acidified with acetic acid (0.16 ml). The precipitate which separated out was filtered, washed with water and dried under reduced 20 pressure to give 168 mg of 6,7-difluoro-8-hydroxy-l-(methyl-amino)-4-oxo-l.4-dihydro -3-quinolinecarboxylic acid. An analytical sample, mp 248-250°C (dec.); MS m/z 270 (M+), was prepared by recrystallization from ethanol. 25 Example 1 Preparation of 9.10-difluoro-3-methyl-7-oxo-2. 3-dihvdro-7H-pyridof3.2.1-ii1-1.3.4-benzoxadiazine-6-carboxylie acid 30 A mixture of 6,7-difluoro-8-hydroxy-l-(methylamino)-4- -oxo-1,4-dihydro -3-quinolinecarboxylic acid (105 rag) obtained in Reference example (i). paraformaldehyde (150 mg) and dry dioxane (5 ml) was heated at 100°C for 3 hours under nitrogen atmosphere. After removal of the solvent under 35 reduced pressure dimethylformamide (20 ml) was added to the residue and the mixture was stirred for 20 minutes and then filtered. The filtered cake was washed with dimethyl- v.- v 22 1 68 1 47 formamide and the combined filtrate was evaporated under reduced pressure. The residue was triturated with water and filtered to give 97 mg of 9.10-difluoro-3-methyl-7-oxo-2.3-0^ -dihydro -7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine-6- 5 -carboxylic acid. An analytical sample, mp 290-292°C (dec.); MS m/z 282 (M+) was prepared by recrystallization from dimethylformamide. Example 2 10 Preparation of 9.10-difluoro-2.3-dimethvl-7-oxo-2.3-dihvdro-7H-pyrido r3.2.1-111-1.3.4-benzoxadiazine-6-carboxvlic acid 15 A mixture of 6,7-difluoro-8-hydroxy-l-(methylamino)-4- -oxo-1,4-dihydro -3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i), 90* acetaldehyde (1 ml) and dioxane (5 ml) was heated at 100°C for 3 hours under nitrogen atmosphere. The reaction mixture was evaporated 20 under reduced pressure to give 52 mg of 9,10-difluoro-2.3--8imethyl-7-oxo-2.3-dihydro -7H-pyrido[3,2.1-ij]-l,3,4--benzoxadiazine-6-carboxylic acid, mp 285-289°C; MS m/z 296 C (M+)- 25 Example 3 Preparation of 9.10-difluoro-2-(hvdroxymethvl)-3-methvl-7-0X0-2.3-dihvdro-7H-pvridoT3. 2.1-i i1-1.3.4-benzoxadiazine-6-carboxvlic acid 30 A suspension of 6,7-difluoro-8-hydroxy-l-(methylamino)--4-oxo-l.4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i), glycolaldehyde diethyl-acetal (45 ill) and pyridinium p-toluenesufonate (7 mg) in 35 dry dioxane (2 ml) was heated at 110°C for 5 hours under nitrogen atmosphere. After the solvent was removed under reduced pressure, the crystalline residue was washed with V >»> 22 1 6 8 1 - 48 water and methanol to give 52 mg of 9,10-difluoro-2--(hydroxymethyl)- 3-methyl-7-oxo-2.3-dihydro-7H-pyrido-[3.2,1-ij]-l.3.4- benzoxadiazine-6-carboxylic acid, mp O 254-258°C (dec.); MS m/z 312 (M+). 5 Example 4 Preparation of 9.10-difluoro-2-f(dimethvlamino)methyll-3-methvl-7-oxo-2.3-dihydro-7H-pvridof3.2.1-i11-1.3.4-benzoxa-10 diazine-6-carboxvlic acid p-toluenesulfonate A suspension of 6,7-difluoro-8-hydroxy-l-(methylamino)--4-oxo-l.4-dihydro -3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i), dimethylaminoacetaldehyde 15 dimethylacetal (37 mg) and p-toluenesulfonic acid mono-hydrate (53 mg) in dry dioxane (2 ml) was heated at 110°C for 17 hours under nitrogen atmosphere. After the solvent was removed under reduced pressure, the residue was recrystallized from methanol to give 61 mg of 9.10-difluoro-20 -2-[(dimethylamino)methyl]-3-methyl-7-oxo-2,3 -dihydro-7H--pyrido[3,2,1-ij]-1.3.4-benzoxadiazine-6-carboxylic acid p-toluenesulfonate, mp 232-236°C (dec.); FAB-MS m/z 340 (MH+). 25 Example 5 Preparation of 9-fluoro-3-methvl-10-(4-methvl-l-pipera-zinyl)-7-0x0-2.3-dihvdro-7H-pvridor 3.2.1-i11-1.3.4-benzoxa-diazine-6-carboxvlic acid 30 A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido[3.2,1-ij]-l.3,4-benzoxadiazine-6-carboxylic acid (30 mg) obtained in Example 1. N-methylpiperazine (47 ul) and dry pyridine (3 ml) was heated at 100-110°C for 9 hours 35 under nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 23 mg of 9-fluoro-3-methyl-10-(4-methyl-l- , \ '<j> * ' •<"><*,... .. . . .... . . 22 1 - 49 - -piperazinyl)-7-oxo -2,3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4--benzoxadiazine -6-carboxylic acid, mp 268-269°C (dec.); MS m/z 362 (M+). g The followiag compounds wece obtained according to a manner analogous to that of Example 5: 10 15 20 25 30 35 22 1 6 8 1 - 50 - i^.ikcH3 Example No. r5r6n- Meltlng point °C Recrystallization ^5 my2 solvent 6 7 8 9 10 11 12 13 14 15 16 17 18 19 0 240*245 (dec.) MeOH 237*239 (dec.) MeOH/CHCl3 r-\ HN Jr Ph 256*259 (dec.) DMF O- >300 EtOH/CHCI3 CHq b- CH3>^ >300 DMF 0- >300 (dec.) DMF H2»-VXO" 238*242 (dec.) MeOH H0-O" 256*258 MeOH/CHCl3 D-O 272*274 (dec.) EtOH 270*275 h2o O 243*246 MeOH/CHCl3 242*244 (dec.) DMF C2H5KJ> 251*252 (dec.) EtOH 239*241 (dec.) EtOH 349 (MH+)* 362 (M*) 425 (MH+)» 349 (M+) 377 (M+) 365 (M+) 377 (MH+)* 363 (M*) 413 (MH+)* 393 (MH+)* 362 (M+) 377 (MH+)* 391 (MH+)* 405 (MH+)* * FAB-MS 22 1 6 8 1 continued Example No. r5r6n- Melting point °C Recrystal1ization solvent MS m/z 20 CH>vJ-3 CH3-^ 266*268 (dec.) EtOH 365 (MH+)* 21 £>-HO'^ 284*286 (dec.) DMF 350 (MH+)» 22 ch3-j=\ p- 280*284 (dec.) Me0H/CHCl3/Et20 345 (MH+)* 23 ch3irt> ch3-' 220*222 (dec.) EtOH 391 (MH+)» ♦ fab-ms Example 24 20 Preparation of 9-fluoro-3-methyl-7-oxo-10-(3-oxo-l-pipera-2invl)-2.3-dihvdro-7H-pyridor3.2.1-ii1-1.3.4-benzoxadiazine-6-carboxvlic acid 25 A mixture of 9.10-difluoro-3-methyl-7-oxo-2.3-dihydro -7H-pyrido[3.2.1-i j]-l.3.4-benzoxadiazine-6-carboxylie acid (40 mg) obtained in Example 1, 2-piperazinone (31.1 mg). 1.4-diazabicyclo[2.2.2]octane (31.8 mg) and dry dimethylsul-foxide (1 ml) was heated at 130°C for 28.5 hours under 30 nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (Silica gel: CHCl3/MeOH. 10:1.5) and recrystallized from a mixture of dichloromethane and methanol to give 6.3 mg of 9-fluoro-3-methyl-7-oxo-10-(3-oxo-l-piperazinyl)-2,3-dihydro 35 -7H-pyrido[3,2.1-ij]-l,3.4-benzoxadiazine-6-carboxylic acid, mp >300°C: FAB-MS m/z 363 (MH+). 22 1 6 8 1 - 52 - The following compounds wece pcepaced from the compounds desccibed in Example 2, 3 and 4 according to a manner analogous to that of Example 5: :ocV x1"' Example R5^- . Melting point Recrystalli- R3 oq zatlon MS m/z solvent 25 HfGX~ ch3 240*242 (dec.) MeOH 362 (M+) 26 CH3fQ<- CH3 203*206 EtOH 376 (M+) 27 cHaO CH20H 229*231 (dec.) MeOH 393 (MH+)# • 28 CH3(Q<— CH2N(CH3)2 210*212 MeOH 420 (MH+)* ♦ FAB-MS Example 29 Pceparation of 10-r3-fbenzvloxvcacbonvlamino)-l-Pvccoli-dinyll-9-fluoco-3-methvl-7-oxo-2.3-dihydco-7H-pvcido-30 f3.2.1-ii1-1.3.4-benzoxadiazine-6-carboxylic acid A mixtuce of 9,10-difluoro-3-raethyl-7-oxo-2.3-dihydro--7H-pyrido[3.2,l-ij] -1.3,4-benzoxadiazine-6-cacboxylic acid (28 mg) obtained in Example 1. 3-(benzyloxycarbonylamino)-35 pyccolidine (94 mg) and dcy pycidine (3 ml) was heated at 100°C foe 3 houcs under nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was ^ ... 22 1 6 8 1 53 - recrystallized from methanol to give 36 mg of 10-[3-(benzyl-oxycarbonylamino)-1-pyrrolidinyl]-9-fluoro -3-methyl-7-oxo--2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4 -benzoxadiazine-6-(P) -carboxylic acid, mp 227-230°C; MS m/z 482 (M+). 5 Example 30 preparation of 10-f3-amino-l-pvrrolidinvl)-9-fluoro-3-C methvl-7-oxo-2.3-dihydro-7H-pvridor3.2.l-i i1-1.3,4-benzoxa- 10 dia2ine-6-carboxvlic acid 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro -3-methy1-7-0x0-2.3-dihydro-7H-pyr ido[3.2.l-ij]-l.3,4 -benzoxadiazine-6-carboxylic acid (30 mg) obtained in 15 Example 29 was hydrogenated over 5* Pd/C (10 mg) in dimethylformamide (2 ml) for 4.5 hours. After removal of the catalyst by filtration the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give 16 mg of l0-(3-amino-l-pyrrolidinyl)-9-20 -fluoro-3-methyl-7-oxo-2.3 -dihydro-7H-pyrido[3.2.1-ij]--1,3,4-benzoxadiazine-6-carboxylic acid, mp 230-234°C (dec.); MS m/z 348 (M+). The following compounds were obtained according to a 25 manner analogous to that of Examples 29 and 30: 30 35 m Z2 1 6 8 - 54 - r5r6n Example r5r6n- Melting point Recrystallization Mc _/_ No. °C solvent 31 r>- 286*288 (dec.) HgO 363 (MH+)» CH3ir 32 PV- 269*273 (dec.) MeOH 377 (MH+)» 33 34 H2<>- 240*245 (dec.) MeOH 363 (MH+)* CHsN-^^N— 262*265 (dec.) MeOH 377 (MH+)* H \ 35 C2H5N-^JN- 252x256 (dec.) EtOH 390 (M+) * FAB-MS 30 Example 36 Preparation of 10-(3.4-dimethvl-l-piperazinvl)-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-pvridof3.2.1-i i1-1.3.4-benzoxa-35 diazine-6-carboxvlic acid A mixture of 9-fluoro-3-raethyl-10-(3-methyl-l-pipera- r 22 1 6 8 1 - 55 - zinyl)-7-oxo-2.3 -dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid (60 mg) obtained in Example 7, 98* formic acid (1 ml) and 35* formalin (1 ml) was stirred at * 100-110°C. After heating for 2 hours, the mixture was 5 evaporated under reduced pressure. The residue was dissolved in water, neutralized with IN sodium hydroxide and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure the crystalline 10 residue was recrystallized from methanol to give 43 mg of 10-(3,4-dimethy1-1-piperazinyl)-9-fluoro-3-methy1-7-oxo -2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxadiazine -6-carboxylic acid, mp 257-259°C; FAB-MS m/z 377 (MH+). 15 Example 37 Preparation of 9-fluoro-10-(3-methoxv-l-pvrrolidinvl^-3-me thvl-7-0x0-2. 3-dlhvdro-7H-pvridor 3.2.1-111-1.3.4-benzoxa-diazine-6-carboxvlic acid 20 To a suspension of 9-fluoro-10-(3-hydroxy-l-pyrroll-dinyl)-3-methy1-7-oxo -2.3-dihydro-7H-pyrido[3.2.1-ij J--1.3.4-benzoxadiazine -6-carboxylic acid (100 mg) obtained in Example 21 in dry dimethylformamide (10 ml) was added 60* 25 sodium hydride in oil (30 mg) and methyl iodide (40 ul). After stirring the mixture at room temperature for 2 hours, additional 60* sodium hydride (30 mg) and methyl iodide (40 ul) were added, and the mixture was stirred at 45°C for 3 hours. The solvent was then removed under reduced 30 pressure. To the residue was added cold water (2 ml) and O.SN sodium hydroxide (2.3 ml) and the resulting suspension was heated at 100°C for 2 hours. The reaction mixture was then cooled to room temperature, neutralized with acetic acid and diluted with water. The mixture was extracted with 35 chloroform, and the extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crystalline residue, which was chroma- \ •>» 22 1 6 8 1 - 56 - tographed on silica gel using acetone/chloroform (1:9) as an eluent. 42 mg of 9-fluoro-10-(3-methoxy-l-pyrrolidinyl)-3--methyl-7-oxo -2.3-dihydco-7H-pyrido[3,2,1-ij]-l.3.4--benzoxadiazine -6-carboxylic acid, mp 233-234°C; FAB-MS m/z 5 364 (MH+). was obtained after recrystallization from methanol. Example 38 10 Preparation of 9-fluoro-10-(4-methoxy-l-piperidvl)-3-methvl-7-oxo-2.3-dlhydro-7H-pyridof3. 2.1-111-1.3.4-benzoxadiazine-6-carboxvlic acid 9-Fluoro-10-(4-methoxy-l-piperidyl)-3-methyl-7-oxo -15 -2, 3-dihydro-7H-pyrido[3. 2.1-i j ]-1. 3 . 4-benzoxadiazine -6-carboxylic acid was prepared from 9-fluoro-10-(4-hydroxy-l--piperidyl)-3-methyl-7-0x0-2,3 -dihydro-7H-pyrido[3.2.1-ij]--1.3.4-benzoxadiazine-6-carboxylic acid obtained in Example 13 analogously to Example 37. and was obtained as crystals. 20 mp. 229-233°C (dec.): MS m/z 377 (M+), after recrystallization from chloroform/n-hexane. Example 39 25 Preparation of 10-(1.l-dioxide-4-thiomorpholinyl)-9-fluoro-3-methy1-7-oxo-2.3-dihvdro-7H-pyrido T3.2.l-iil-1.3.4-benzoxa-diazine-6-carboxylic acid To a suspension of 9-fluoro-3-methyl-7-oxo-10-(4-thio-30 morpholinyl)-2.3-dihydro -7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid (50 mg) obtained in Example 11 in dichloromethane (5 ml) was added m-chloroperbenzoic acid (70* purity. 74 mg). The mixture was stirred at room temperature for 18 hours. The solvent was then removed 35 under reduced pressure. The residue was washed with ether, dichloromethane and a mixture of chloroform and methanol, and recrystallized from diraethylformamide to give 22 mg of I S : v^. ... , ■ ' 22 1 6 8 1 10 57 - 10-(1.1-dioxide-4-thiomocpholinyl)-9-fluoro-3-methy1-7-oxo -2.3-dihydro-7H-pyrido[3.2,1-ij]-1,3.4-benzoxadiazine -6-carboxylic acid, mp >300°C; MS m/z 397 (M+). Example 40 Preparation of 9-fluoro-3-methvl-7-oxo-10-r4-(2-oxo-n-oropvl)-1-piperazinvl1-2.3-dihvdro-7H-pvridoT 3,2.l-ii1-l.3.4-benzoxadiazine-6-carboxvlic acid A mixture of 9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)--2.3-dihydro -7H-pyrido[3,2.1-ij]-l.3,4-benzoxadiazine-6--carboxylic acid (50 mg) obtained in Example 6, chloro-acetone (17 ul). triethylamine (40 ul) and dry dimethyl-15 formamide (1 ml) was heated at 80°C for 3.5 hours. The volatile components were then removed under reduced pressure and the residue was suspended in water. The precipitate was collected by filtration and recrystallized from a mixture of dichloromethane and methanol to give 32 mg of 9-fluoro-3-20 -methy1-7-oxo-lO-[4-(2-oxo-n-propyl)-1-piperazinyl] -2.3-dihydro-7H-pyrido[3,2.1-ijJ-1.3.4-benzoxadiazine -6-carboxylic acid, rap 225-229°C (dec.), FAB-MS m/z 405 (MH+). 25 The following compounds were obtained according to a manner analogous to that of Example 40. 30 35 A'rr s 22 1 6 8 1 n, 5 Example No. R70 Meltlng point 9c Recrystal11-zatlon solvent fab-ms m/z 41 O~C0CH2-' »» 223*226 (dec.) DMF 467 (mh+) 42 ch3ch2- 273*275 (dec.) EtOH 377 (mh+) 43 ch3ch2ch2- 255*257 (dec.) EtOH 391 (mh+) 44 fch2ch2- 257*259 (dec.) EtOH 395 (mh+) 45 ho2cch2- 256x259 (dec.) h2o 407 (mh+) 46 ch2-chch2- 236x238 (dec.) MeOH 389 (mh+) 47 °2n~^^"ch2- 275*276 (dec.) EtOH 484 (mh+) Example 4 8 25 Preparation of 10~r3~r (ethylmethylamino)methvn-l-pyrroli-dinvl1-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-pyrido-r3.2.1-111-1.3.4-benzoxadiazine-6-carboxvlie acid 30 10-[3-[(ethylmethylamino)methyl]-1-pyrrolidinyl] -9-fluoro-3-methy1-7-oxo-2,3-dihydro -7H-pyrido[3,2,1-ij]--1.3.4-benzoxadiazine-6-carboxylic acid was prepared from 9-fluoro-3-methy1-10-[3-[(methylamino)methyl] -1-pyrrolidinyl] -7 -oxo-2 .3-dihydro-7H-pyrido[3,2.l-ij]-l,3,4 -benzoxa- 35 diazine-6-carboxylic acid obtained in Example 17 and ethyl iodide analogously to Example 40. and was obtained as crystals, mp 210-225°C (dec.); FAB-MS m/z 405 (MH+) after a 22 1 6 8 1 - 59 - recrystallization from a mixture of chloroform, methanol and n-hexane. n Example 49 5 Preparation of 10-r4-(3-carboxvpropionvl)-l-piperazinvl1-9-fluoro-3-methyl-7-oxo-2.3-dihvdro-7H-pvridor3.2.1-i i1-1.3.4-benzoxadiazine-6-carboxvlic acid P 10 A mixture of 9-fluoro-3-methyl-7-oxo-10-(1-pipera zinyl )-2,3-dihydro -7H-pyridoI3,2.1-ij]-l.3,4-benzoxadia-zine-6-carboxylic acid (50 mg) obtained in Example 6, succinic anhydride (21.6 mg), triethylamine (40 ul) and dry dimethylformamide (4 ml) was heated at 80°C for 2 15 hours. The solvent was then removed under reduced pressure and the residue was suspended in water. The precipitate was collected by filtration and recrystallized from a mixture of dichloromethane and methanol to give 50 mg of 10-[4-(3-car-boxypropionyl)-1-piperazinyl]-9-fluoro-3-methyl -7-oxo-2,3-20 -dihydro-7H-pyrido[3.2.l-ij]-l.3,4-benzoxadiazine -6-car-boxylic acid, mp 257-259°C (dec.); FAB-MS m/z 449 (MH+). Example 50 25 Preparation of 10-(4-acetyl-l-pjperazinvl)-9-fluoro-3- methvl-7-oxo-2.3-dihydro-7H-pyridor 3.2.1-iil-1.3.4-benzoxa-diazine-6-carboxvlic acid 10-(4-Acetyl-1-piperazinyl)-9-fluoro-3-methyl-7-oxo 30 -2.3-dihydro-7H-pyrido[3,2.1-ij]-l.3.4-benzoxadiazine -6-carboxylic acid was prepared from 9-fluoro-3-methyl-7--oxo-10-(1-piperazinyl)-2,3-dihydro -7H-pyrido[3.2.1-ij]--1.3.4-benzoxadiazine-6-carboxylic acid obtained in Example 6 and acetic anhydride, analogously to Example 49, and was 35 obtained as crystals, mp 294-296°C (dec.); FAB-MS m/z 391 (MH+), after recrystallization from dichloromethane/ methanol. f 22 1 6 8 1 - 60 -Example 51 Preparation of 9-fluoro-3-methvl-7-oxo-10-f4-(3-oxo-n-butvl')-l-piperazinvll-2.3-dihvdro-7H-pyridor3.2.1-iil-1.3.4-benzoxa-5 diazine-6-carboxvlic acid A mixture of 9-fluoro-3-methyl-7-oxo-l0-(1-pipera-zinyl)-2.3-dihydro -7H-pyrido[3.2,1-ij]-1,3,4-benzoxadia-zine-6-carboxylic acid (30 mg) obtained in Example 6. methyl 10 vinyl ketone (36 ul) and ethanol (1 ml) was refluxed for 12 hours, and then cooled to room temperature. The precipitate which separated out was collected by filtration and crystallized from ethanol to give 28 mg of 9-fluoro-3--methyl-7-oxo-lO-[4-(3-oxo-n-butyl)-1-piperazinyl] 15 -2.3-dihydro-7H-pyr ido[3.2,1-i j]-l.3,4-benzoxadiazine -6-carboxylic acid, mp 187-189°C (dec.); FAB-MS m/z 419 (MH+). Example 52 20 Preparation of disodium 9-fluoro-3-methvl-7-oxo-10-T4-(sulfonatomethvl)-l-piperazinvll-2.3-dihvdro-7H-pvrido-r 3.2.1-i11-1.3.4-benzoxadiazine-6-carboxvlate 25 A mixture of 35\ formalin (26 mg). sodium hydrogen sulfite (32 mg) and water (0.5 ml) was heated at 75°C for 30 minutes and then cooled to room temperature. To this solution was added 9-fluoro-3-methyl-7-oxo-10-(1-pipera-zinyl)-2.3-dihydro -7H-pyrido[3,2.1-i)]-l,3,4-benzoxadia-30 zine-6-carboxylic acid (100 mg) obtained in Example 6 and sodium hydroxide (15 mg). After the mixture was heated at 75°C for 1 hour, ethanol (2 ml) was added. The mixture was then cooled to room temperature. The precipitate which separated out was collected by filtration and recrystallized 35 from water/ethanol (1:2) to give disodium 9-fluoro-3-methyl--7-oxo-10-[4-(sulfonatomethyl)-1-piperazinyl] -2.3-dihydro--7H-pyrido[3.2.l-ij]-l.3.4-benzoxadiazine -6-carboxylate. mp 22 1 68 f - 61 - ! 260-263°C (dec.): XH NMR (D20) 6: 2.98 (3H.S). 3.05 (4H.m), 3.39 (4H,ra). 3.84 (2H.S), 5.18 (2H.S). 7.55 (1H.d, J = 13.4 HZ), 8.34 (1H.S). . 5 Example 53 Preparation of 10-r4-(4-aminobenzvl)-l-piperazinvl1-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-pvridor3.2.l-iil-l.3.4-benzoxadiazine-6-carboxylic acid 10 9-Fluoro-3-methy1-10-[4-(4-nitrobenzyl)-1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido[3,2.1-ij]-l,3,4-benzoxadiazine -6-carboxylic acid (100 mg) obtained in Example 47 was hydrogenated over 5* Pd/C (10 mg) in dichloromethane/metha- ■J5 nol (1:1) for 2 hours. After removal of the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from - ethanol to give 69 mg of l0-[4-(4-aminobenzyl)-l-pipera- ■w ziny1]-9-fluoro-3-methy1-7-oxo -2.3-dihydro-7H-pyrido- 20 [3.2,l-ij]-l,3.4-benzoxadiazine -6-carboxylic acid, mp 237-238°C (dec.); FAB-MS m/z 454 (MH+). " Example 54 25 Preparation of 10-T3-(aminomethvl)-1-pvrrolidinvl1-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-Pvridof3.2.1-iil-1.3.4-benzoxa-diazine-6-carboxvlic acid The mixture of lo-[3-(acetylaminomethyl)-l-pyrroli- 30 dinyl]-9-fluoro-3-methyl -7-oxo-2.3-dihydro-7H-pyrido- [3.2,1-ij]-l,3.4-benzoxadiazine -6-carboxylic acid (40 mg) obtained in Example 19 and IN sodium hydroxide (2.5 ml) was heated at 100°C for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with acetic acid. 35 and the precipitate which separated out was collected by filtration and recrystallized from methanol to give 15 mg of 10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-3-methy1-7-oxo "iV x ' , ' 22 1 68 1 - 62 - -2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine -6-carboxylic acid, mp 177-1B0°C (dec.); FAB-MS m/z 363 (MH+). I n i 5 Example 55 Preparation of 6-£luoro-8-hvdroxv-7-(l-imidazolvl)-l-(methvlamino)-4-oxo-l.4-dihvdro-3-quinolinecarboxvlic acid % a 10 Carbonyldiimidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-l-(methylamino)-4-oxo--1.4-dihydro -3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i) in dry dimethylformamide (2 ml). Stirring was continued at room temperature for 2 hours and 15 Chen at 80°C for 5 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH was adjusted to pH 5 with acetic acid. The precipitate which separated out was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7-(l-imida-20 zolyl)-l-(methylamino)-4-oxo -1.4-dihydro-3-quinolinecar-boxylic acid as pale yellow powder. FAB-MS m/z 319 (MH+); LH-NMR (dg-DMSO) 6: 2.82 (3H.s). 7.10 (1H. d. J-10.7 HZ). 7.61 (1H. d). 7.75 (1H. d). 8.62 (1H.s). 8.92 (1H.s), 15.33 (1H. br.s) 25 Example 56 Preparation of 9-fluoro-lO-(l-imidazolvl)-3-methvl-7-oxo-2.3-dihvdro-7H-pyrido f3.2.1-ii1-1.3.4-benzoxadiazine-6-30 carboxylic acid A suspension of 6-fluoro-8-hydroxy-7-(l-imidazolyl)-l--(methylamino)-4-oxo-l.4 -dihydro-3-quinolinecarboxylic acid (15 mg) obtained in Example 55 in a mixture of 35% formalin 35 (1 ml) and dioxane (1 ml) was heated at 100-110°C for 1.5 hours under nitrogen atmosphere. The solvent was removed under reduced pressure and the crystalline residue was r'^ ?! 22 1 6 8 t - 63 - washed with methanol to give 15 mg of 9-fluoro-10-(l-imida-zolyl)-3-methy1-7-oxo-2.3-dihydro -7H-pyrido[3.2,1-ij]--1.3.4-benzoxadiazine-6-carboxylic acid as pale pink f*) powder. An analytical sample, mp >300°C; FAB-MS m/z 331 5 (MH+) was prepared by recrystallization from dimethyl-formamide and ether. 9-Fluoro-10-(1-imidazolyl)-3-methy1-7-oxo-2.3-dihydro c -7H-pyrido[3.2.1-i j]-l,3.4-benzoxadiazine-6-carboxylic acid 10 was also prepared from 9.10-difluoro-3-methyl-7-oxo-2.3--dihydro-7H-pyrido[3,2,1-ij] -1.3.4-benzoxadiazine-6-car-boxylic acid and imidazole in dimethylsulfoxide analogously to Example 5. 15 Example 57 Preparation of benzyl 9-fluoro-10-(3-hvdroxv-l-ovrrolidinvl)-3-methyl-7-oxo-2.3-dihydro-7H-pyrido\3.2.1-i i1-1.3. 4-benzoxa-diazine-6-carboxvlate 20 A mixture of 9-fluoro-io-(3-hydroxy-l-pyrrolidinyl)-3- • -methy1-7-0x0-2.3 -dihydro-7H-pyrido[3,2.l-ij]-1.3.4-(^2 -benzoxadiazine -6-carboxylic acid (10 mg) obtained in Example 21. anhydrous potassium carbonate (8 mg) and 25 dimethylformamide (0.5 ml) was stirred at room temperature for 1.5 hours and then benzylbromide (10.8 mg) was added. This mixture was stirred at room temperature for 3 hours and evaporated under reduced pressure. 30 The residue was suspended in water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure. The residue was triturated with ether to give 11 mg of benzyl 9-fluoro-10-(3-hydroxy-l-pyrroli-dinyl)-3-methyl-7-oxo-2.3 -dihydro-7H-pyrido[3.2.1-ij]-35 -1.3.4-benzoxadiazine -6-carboxylate. mp 196-198°C (dec.); FAB-MS m/Z 440 (MH+). I © 22 1 6 8 1' - 64 -Example 58 Preparation of benzvl 10-f3-chloro-l-pyrrolidinyl)-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-pyridoC3.2.1-iil-1.3.4-benzoxa-5 diazine-6-carboxvlate Benzyl 9-fluoro-lO-(3-hydroxy-1-pyrrolidinyl)-3-methy1--7-oxo-2.3 -dihydro-7H-pyrido[3,2.1-ij]-l,3.4-benzoxadiazine -6-carboxylate (8 mg) obtained in Example 57 was dissolved 10 °*2 of thionyl chloride and stirred at 60°C for 15 | minutes. The reaction mixture was diluted with water and j extracted with chloroform. The extract was concentrated under reduced pressure. 15 The residue was chromatographed on silica gel (2 g) with ) chloroform to give 2.8 mg of benzyl 10-(3-chloro-l-pyrroli- i dinyl)-9-fluoro-3-methyl-7-oxo-2.3 -dihydro-7H-pyrido- ^ [3.2,1-ij]-l.3.4-benzoxadiazine -6-carboxylate. mp >300°C; FAB-MS m/Z 458 (MH+), 460 (MH+2)*. 20 Example 59 (2) Preparation of 10-(3-chloro-l-pvrrolidinvl)-9-fluoro-3- methvl-7-oxo-2.3-dihvdro-7H-pvridor3.2.1-i11-1.3.4-benzoxa-25 diazine-6-carboxvlic acid Benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-methyl-7-(3 -oxo-2.3 -dihydro-7H-pyrido[3,2.l-ij]-l.3.4-benzoxadiazine -6-carboxylate (2.5 mg) obtained in Example 58 was hydro-30 genated over 5% Pd/C (1 mg) in chloroform. After removal of the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to 35 give 1.0 mg of 10-(3-chloro-l-pyrrolidinyl)-9-fluoro-3--methy1-7-oxo-2.3 -dihydro-7H-pyrido[3.2.1-ij]-1.3.4--benzoxadiazine -6-carboxylic acid, mp 269-272°C (dec.); ^ •■->v o 22 1 6 8 f - 65 - FAB-MS m/Z 368 (MH+). 370 (MH+2)+. Example 60 Ci 5 Preparation of 9-f luoro-3-methvl-10-(4-iaethvl-l-piperazinvl)-7-0X0-2.3-dihvdro-7H-pvridoT3.2.1-i11-1.3.4-benzoxadiazine-6-carboxylic acid via the fluoroborane intermediate r (a) A mixture of 9.10-difluoro-3-methyl-7-oxo-2.3-dihydro- 10 -7H-pyrido[3.2.1-ij] -1.3.4-benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 1 and 60* aqueous fluoboric acid (1 ml) was heated at 90°C for 12 hours. After the reaction mixture was cooled to room temperature the precipitate was collected by filtration, washed with methanol and 15 dried under reduced pressure to give 110 mg of crude 9.10-difluoro-6-[[(difluoroboryl)oxy]carbonyl]-3-methyl-2.3 -dihydro-7H-pyrido[3.2.1-ij]-1.3,4-benzoxadiazin-7-one: FAB-MS m/z 331 (MH+). 20 (b) To a stirred solution of the above borane intermediate (33 mg) in dimethylsulfoxide (1 ml) were added N-methyl-piperazine (15 ul) and triethylamine (20 ul). After , " stirring at room temperature for 3 hours the reaction mixture was lyophilized. The residue was crystallized from 25 methanol to give 28 mg of 6-[[(difluoroboryl)oxy]carbonyl]~ -9-fluoro-3-methy1-10 -(4-methyl-l-piperazinyl)-2.3-dihydro--7H-pyrido[3.2.1-ij] -1.3.4-benzoxadiazin-7-one as yellow crystals, mp 228-230°C (dec.); FAB-MS m/z 411 (MH+). 30 (c) To a solution of the above borane intermediate (5 mg) in 95* ethanol (1 ml) was added triethylamine (3 ul)- After heating under reflux for 4 hours, the reaction mixture was cooled to room temperature. The precipitate which separated out was collected by filtration to give 9-fluoro-3-methyl-35 -l0-(4-methyl-l-piperazinyl)-7-oxo-2.3 -dihydro-7H-pyrido-[3.2.1-ij]-1.3.4-benzoxadiazine-6 -carboxylic acid, mp 268-269°C (dec.). 7.1 1 6 8 1 n r- v - 66 -Example 61 Preparation of 9-fluoro-3-methvl-lO-M-methvl-l-pipera-zinvl)-7-oxo-2.3-dihvdro-7H-pvridor3.2.1-i i1-1.3.4-benzoxa-5 diazine-6-carboxvlic acid via the acetoxvborane intermediate (a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2.3-dihydro--7H-pyrido[3,2.1-ij] -1. 3. 4-benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 1. acetic anhydride (1 ml) and 10 triacetoxyborane (100 mg) was heated at 140°C for 15 minutes. The reaction mixture was evaporated under reduced pressure. The residue was triturated with acetone and filtered to give 138 mg of 6-[[(diacetoxyboryl)oxy]car-bonyl]-9.10-difluoro-3-methyl-2.3 -dihydro-7H-pyrido-15 [3,2.1-i j ] — 1. 3,4-benzoxadiazin-7-one; FAB-MS m/z 411 (MH-4"). (b) To a solution of the above borane intermediate (41 mg) ;j in dimethylsulfoxide (1 ml) were added N-methylpiperazine ' (15 ul) and triethylamine (20 ul). After the mixture 20 was stirred at room temperature for 2 hours, the reaction _j mixture was lyophilized. The residue was crystallized from ' methanol/ether to give 34 mg of 6-[[(diacetoxyboryl)oxy]car- bony1]-9-fluoro-3-methy1-10 -(4-methyl-l-piperazinyl)-2,3--dihydro-7H-pyrido[3,2,l-ij] -1.3.4-benzoxadiazin-7-one as 25 yellow crystals; mp 156-157°C (dec.); FAB-MS m/z 491 (MH+). (c) The above borane intermediate (5 mg) was suspended in acetone (0.1 ml) and added conc. HC1 (2.5 ul). The reaction mixture was stirred at room temperature for 30 30 minutes and cooled in ice bath. The precipitate which separated out was collected by filtration and the precipitate was dissolved in 95% ethanol (0.1 ml). To the solution was added triethylamine (2 ul) and the mixture was refluxed for 1 hour. After the solution was cooled to room 35 temperature, the precipitate which separated out was collected by filtration to give 9-fluoro-3-methyl-10-(4--methyl-l-piperazinyl)-7-oxo-2.3 -dihydro-7H-pyrido- 221681 - 67 - [3.2,1-ij]-l.3,4-benzoxadiazine -6-carboxylic acid, mp 268-269°C (dec.). Example 62 Preparation of pivalovloxvmethvl 10-f3-(benzvloxvcarbonvl-amino)-1-pyrrolidiny11-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-pvridof 3.2.1-i i1-1.3.4-benzoxadiazine-6-carboxvlate A mixture of 10-[3-(benzyloxycarbonylamino)-l-pyrroli-dinyl]-9-fluoro-3 -methyl-7-oxo-2.3-dihydro-7H-pyrido-[3.2.1-ij]-1.3,4 -benzoxadiazine-6-carboxylic acid (290 mg) obtained in Example 29. pivaloyloxymethyl chloride (130 ul). anhydrous potassium carbonate (166 mg) and dry dimethylformamide (10 ml) was stirred at 45°C for 8 hours. The solvent was then removed under reduced pressure. The residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was recrystallized from ethyl acetate to give 325 mg of pivaloyloxymethyl 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-l.3 .4 -benzoxadiazine-6-carboxylate; mp 185-188°C; FAB-MS m/z 597 (MH+). Example 63 Preparation of pivalovloxvmethvl 10-(3-amino-l-pvrrolidinvl)-9-fluoro-3-methvl-7-0x0-2.3-dihydro-7H-pvridor 3.2.1-i i1-1.3.4-benzoxadiazine-6-carboxvlate Pivaloyloxymethyl 10-(3-amino-l-pyrrolidinyl)-9-fluoro--3-methyl-7-oxo-2.3 -dihydro-7H-pyrido[3.2,l-ij]-l,3.4--benzoxadiazine -6-carboxylate was prepared from pivaloyloxymethyl 10-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]-9--fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido[ 3 . 2.1-ij]- a 3 16 8 1 68 - 10 -1.3.4 -benzoxadiazine-6-carboxylate (200 mg) obtained in Example 62. analogously to Example 30. and was obtained as pale brown powder after precipitation from a mixture of ethyl acetate and n-hexane; NMR (CDC13) 5: 1.22 (9H. s). 1.6-2.4 (2H. m). 2.99 (3H. s). 3.3-4.0 (5H. m). 4.98 (2H. s). 5.96 (2H. s). 7.64 (1H. d. J-14.4 H2). 8.37 (1H. s); FAB-MS m/z 463 (MH+). Example 64 Preparation of ethvl 10-r3-(benzvloxvcarbonvlamino)-l-pyrrolidinyl1-9-fluoro-3-methvl-7-oxo-2.3-dihvdro-7H-pyrido-f 3.2.1-i11-1.3.4-benzoxadiazine-6-carboxvlate 15 A mixture of 10-[3-(benzyloxycarbonylamino)-l-pyrroli- dinyl]-9-fluoro-3 -methyl-7-oxo-2.3-dihydro-7H-pyrido-[3.2,1-ij]-1.3.4 -benzoxadiazine-6-carboxylic acid (337 mg) obtained in Example 29. ethyl iodide (84 ul). anhydrous potassium carbonate (193 mg) and dry dimethylformamide (12 20 ml) was stirred at 45°C for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then applied 25 onto a column of silica gel and eluted with a mixture of chloroform and acetone (20:1). The pure fractions were combined, concentrated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate to give 271 mg of ethyl l0-[3-(benzyloxycarbonylamino)-l-pyrroli-30 dinyl]-9-fluoro -3-methyl-7-oxo-2.3-dihydro-7H-pyrido-[3,2,l-ij]-l,3,4 -benzoxadiazine-6-carboxylate. mp 204-207°C: FAB-MS m/z 511 (MH+). 35 " -K ' , - v 'W.r;_ a, ,, ■-■i-U&S'' ' '■''j\-( . i,. >v ■ " •■•' ,"V ' " -'J'-.'. 2? 1 6 81 - 69 -Example 65 Prepacation of ethvl 10-(3-amino-l-pyccolidinvl)-9-fluoro-3-a methyl-7-oxo-2.3-dihydco-7H-pycidor3.2.1-i i 1-1.3.4-benzoxa- 5 diazine-6-carboxvlate Ethyl 10-[3-(benzyloxycacbonylamino)-l-pyccolidinyl]-9--fluoco-3 -methyl-7-oxo-2.3-dihydco-7H-pyrido[3,2,1-ij]-O -1.3.4 -benzoxadiazine-6-cacboxylate (200 mg) obtained in 10 Example 64 was hydcogenated ovec 5% Pd/C (120 mg) in a mixtuce of chlocofocm (25 ml) and methanol (10 ml) foe 23 hours- Aftec cemoval of the catalyst by filtcation the filtcate was concentcated undec ceduced pcessuce. The cesidue was then applied onto a column of silica gel. and 15 eluted with a mixtuce of chlocofocm and methanol (4:1). The puce fcactions wece combined and concentcated to dcyness undec ceduced pcessuce. The cesidue was fucthec pucified by pcepacative TLC (silica gel; CHClj/MeOH, 3:1) and ceccystallized from ethanol to give 71 mg of ethyl 20 10-(3-amino-l-pyccolidinyl)-9-fluoco-3-methy1-7-0x0-2.3 -dihydco-7H-pycido[3.2,1-ij]-l.3.4-benzoxadiazine -6-cacboxylate. mp 187-192"C (dec.); FAB-MS m/z 377 (MH+). 25 Example 66 Pceoacation of 10-(3-amino-l-pvrcolidinvl)-9-fluoco-3-methvl-7-oxo-2.3-dihvdco-7H-pycidor3.2.1-111-1.3.4-benzoxadiazine-6-cacboxvlic acid hvdcochlocide 30 The pH of a solution of lo-(3-amino-l-pyccolidinyl)-9- -fluoco-3-methy1-7-oxo-2.3 -dihydco-7H-pycido[3.2,1-ij]--1.3.4-benzoxadiazine-6-cacboxylic acid (20 mg) obtained in Example 30 in watec (1 ml) was adjusted to 1.0 with 6N-HC1. The eleae solution was then lyophilized and the cesidue was 35 ccystallized fcom watec/ethanol (1:2) to give 19 rag of 10-(3-amino-l-pyccolidinyl)-9-fluoco-3-methyl-7-oxo-2.3 -dihydro-7H-pycido[3,2,l-ij]-1.3,4-benzoxadiazine-6-cacboxylic 22 1 6 8 1 - 70 - acid hydrochloride, mp 226-228°C (dec.). Example 67 Preparation of 9-fluoro-3-methvl-10-(4-methyl-l-pipera2inyl)-7-0x0-2.3-dihydro-7H-pyridof 3.2.1-i11-1.3.4-benzoxadiazine-6-carboxvlic acid hydrochloride 9-Fluoro-3-methy1-10-(4-methyl-1-piperazinyl)-7-oxo-2.3 -dihydro-7H-pyrido[3,2.1-ij]-l,3,4-benzoxadiazine -6-carboxylic acid hydrochloride was obtained analogously to Example 66. mp 264-266°C (dec.). Example 68 Preparation of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2.3-dihydro-7H-pyridor 3.2.1-i i1-1.3.4-benzoxadiazine-6-car-boxvlate 9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H -pyrido[3.2.1-ij]-1.3,4-benzoxadiazine-6-carboxylic acid (14 mg) obtained in Example 9 was suspended in water (0.4 ml), and IN sodium hydroxide (40 ul) was added with stirring. The clear solution was lyophilized and the residue was crystallized from water/ethanol (1:4) to give 12 mg of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H -pyrido[3.2.1-ij]-l,3,4-benzoxadiazine-6-carboxylate, mp >300°C. Example 69 Preparation of 9-fluoro-3-(2-fluoroethyl)-l0-(4-methvl-l-pjperazinyl)-7-0x0-2.3-dihydro-7H-pyridof3.2.1-i11-1.3.4-ben2Qxadiazine-6-carboxvlic acid 9-Fluoro-3-(2-fluoroethyl)-10-(4-methyl-l-piperazinyl)-7 -oxo-2.3-dihydro-7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine 22 1 6 8 1 - 71 - -6-carboxylic acid was prepared from ethyl 8-benzyloxy-6.7--difluoro-1-(formylamino)-4-oxo-l.4-dihydro -3-quinolinecar-boxylate obtained in Reference example (f). following a series of procedures of Reference example (g. h and i) (using l-bromo-2-fluoroethane instead of methyl iodide). Example 1 and Example 5. and was obtained as crystals, mp 220-224°C; MS ra/z 394 (M+) after recrystallization from methanol. 10 Examples 70-77 There were obtained the following compounds starting from the compound obtained in Example 1 by using a manner analogous to the one described in Example 5 or Examples 15 29/30. 02H 20 CH, Exaopla 25 Ho. R5R6N- Meltlng point Recry»talli*ation FAB-MS a/Z C tolvant 30 35 70 71 72 73 74 oi> "'Vv h»h *~l-j k,n ph H»K ch, h|n D- 1> 2$2 (dec.) 240-241 MeOH 221-230 (dec.) EtOH/hex&n* 240-245 (dec.) EtOH/htxane 253-255 (dec.) MeOH/ethec MeOH ' 432 (MH+) 379 (MH+) 363 (MH+) 425 (MB+) 363 (MH+) - 72 - 22 1 6 8 f Exampla r5_6n_ Halting point Racryatalllsatlon FAB-MS m/Z Ro* *.C aolvant 73 ^ JJ1" >300 (dac.) EtOH/CHClj/baxana 363 (MH+) utn *\ 78 cm,kJ3~ 220-223 (dac.) EtOH 433 (MH+) 77 aj$>- *ll"2U <dec*> EtOH/CHClj 391 (MH+) (n 22 1 6 8 1 - 73 - The following compounds starting from the compound obtained in Example 1 are also obtained according to a manner analogous to that of Example 5 or Examples 29/30. 5 10-[3-(aminomethyl)-4-methyl-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2.1-ij]-1.3.4-benzoxa-diazine-6-carboxylic acid. 10-[3-[(ethylaminoJmethylJ-4-methyl-l-pyrrolidinyl]-9-fluoro-10 3-methy 1-7-oxo-2.3-dihydro-7H-pyrido[3,2.1-ij]-i,3,4-benzoxadiazine-6-carboxylic acid. 10-[3-(aminomethyl)-4-chloro-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-15 diazine-6-carboxylic acid. 10-(3-(aminomethyl)-4-fluoro-l-pyrrolidinyl]-9-fluoro-3-methy1-7-0x0-2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxa-diazine-6-carboxylic acid. 20 10-[3-chloro-4-[(methylamino)methyl]-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3,4-benzoxa-diazine-6-carboxylic acid. 25 9-fluoro-10-[3-fluoro-4-[(methylamino)methyl]-l-pyr rolidinyl]-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid. 10-[3-chloro-4-[(ethylamino) methyl]-l-pyrrolidiny1]-9-fluoro-30 3-methy1-7-0x0-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid. 35 10-[3-[(ethylamino)methyl]-4-fluoro-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid. 22 1 6 8 1 - 74 - 9-fluoro-10-[3-methoxy-4-(methylamino)-l-pyrrolidinyl]-3-methy 1-7-0x0-2,3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid, 10-[3-(ethylamino)-4-raethoxy-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid. 9-fluoro-10-(3-hydroxy-4-methoxy-l-pyrrolidinyl)-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3,2.1-ij]-l.3.4-benzoxadiazine-e-carboxylic acid. 10-(3-amino-4-chloro-l-pyrrolidinyl)-9-fluoro-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3,2.1-ij]-1.3,4-benzoxadiazine-6-carboxylic acid, 10-(3-amino-4-fluoro-l-pyrrolidinyl)-9-fluoro-3-methy1-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij J-l,3.4-benzoxadiazine-e-carboxylic acid, 10-[3-chloro-4-(methylamino)-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid. 9-fluoro-10-[3-fluoro-4-(methylamino)-1-pyrrolidinyl]-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l. 3,4-benzoxa-diazine-6-carboxylic acid. 9-fluoro-3-methy1-10-(l-oxide-4-thiomorpholinyl)-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-i j]-1,3.4-benzoxadiazine-6-carboxylic acid. 9-fluoro-10-[3-hydroxy-4-(methylamino)-l-pyrrolidinyl]-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-i j]-1.3.4-benzoxa-diazine-6-carboxylic acid. •••Vso • Ax* a 22 1 6 8 1' - 75 Example 78 Preparation of 10-r3~r(4-aminobenzvl)amino1-l-pvrrolidinyll-9-fluoro-3-methy1-7-oxo-2.3-dihvdro-7H-pvridor 3.2.1-i i1-5 1.3.4 -benzoxadiazine-6-carboxvlic acid 10-C 3—[(4-Aminobenzy1)amino]-l-pyccolidinyl]-9-fluoco-3-methy1-7-0x0-2.3-dihydro-7H-pyrido[3,2,l-ij]-l,3.4-benzoxa-diazine-6-cacboxylic acid was prepared analogously to the 10 methods described in Example 47 and 53. starting from 10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methy1-7-oxo-2.3 -dihydro-7H-pyrido[3.2.1-i j]-l.3.4-benzoxadiazine-6-carboxylie acid which was obtained in Example 30; mp. 180-182°C (dec.), FAB-MS m/z 453 (MH+). 15 Example 79 Prepacation of 9-f luoco-10-f 3-TI" (dimethvlamino)methvlenel-amino1-1-pvccolidinyl1-3-methy1-7-oxo-2.3-dihvdco-7H-pycido-20 f3.2.1-111-1.3.4-benzoxadiazine-6-carboxylic acid A suspension of 10-(3-amino-l-pycrolidinyl)-9-fluoro-3--methy1-7-0x0-2.3 -dihydro-7H-pyrido[3.2.1-ij]-l.3.4--benzoxadiazine-6-carboxylic acid (14 mg) obtained in 25 Example 30 and N.N-dimethylfocmamide dimethylacetal (6 ul) in dcy DMF (0.5 ml) was sticced at coom tempecatuce foe 8.5 houcs. The pcecipitate was collected by filtcation. washed with DMF and ethec. and ceccystallized from DMF to give 8 mg of 9-fluoco-10-[3-[[(dimethylamino)methylene]amino]-l 30 -pyccolidinyl]-3-methyl-7-oxo-2.3-dihydro-7H-pycido[3,2.1-ij] -1.3.4-benzoxadiazine-6-cacboxylic acid as pale yellow ccystals; mp. 218-220°C (dec.). FAB-MS m/z 404 (MH+). 35 •• x-. ! 22 1 6 8 1 0 - 76 -Example 80 Prepacation oC sodium 9-fluoco-3-methvl-l0-(4-methyl-l-pjpecazinyl)-7-oxo-2. 3-dihydro-7H-pycidor3 . 2.1-i i 1-1.3.4-5 benzoxadiazine-6-cacboxylate 9-Fluoco-3-methyl-10-(4-methyl-l-pipecazinyl)-7-oxo-2.3-dihydco-7H-pycido[3,2.1-ij]-l,3,4-benzoxadiazine-6-cacboxylic acid (520 mg) was dissolved in 0.5N sodium hydcoxide (2.88 10 ml). The cleac solution was evapocated undec ceduced pcessuce to give 555 mg of pale yellow powdec. which was recrystallized from ethanol to give 475 mg of sodium 9-fluoro-3-methy1-10-(4-methy1-1-piperazinyl)-7-0X0-2,3--dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxadiazine-6-car-15 boxylate. after drying in vacuo at 80°C for 2 days; mp 252-254°C (dec.). FAB-MS m/Z 385. The following Examples illustrate pharmaceutical preparations containing a compound provided by the present 20 invention: Example A Interlocking gelatin capsules each containing the follo-25 wing ingredients were manufactured in the conventional manner per se: 9-Fluoro-3-methy1-10-(4-methy1-1-piperazinyl)-7-oxo-2,3-dihydro-7H-30 pycido[3,2,1-ij]-l,3,4-benzoxadiazine- 6-carboxylic acid 200mg Luviskol (water-soluble polyvinylpyrrolidone) 20mg Mannitol 20mg Talc 15mg 35 Magnesium stearate 2mq 257mg </div>

Claims

<div id="claims" class="application article clearfix printTableText"> 22 1 6 8 1 - 77 -Example B Tablets each containing the following ingredients were manufactured in the conventional manner per se: 9-Fluoro-3-methyl-io-(4-methyl-l-piperazinyl)-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-i j]-l,3,4-benzoxadiazine- 6-carboxylic acid 200mg Starch 44mg Carboxymethylcellulose calcium 30mg Crystalline cellulose 40mg Magnesium stearate 6mo 320mg - 78 - 22 1 6 8 1 n 35 What we claim is 1. Tricyclic compounds of the general formula 0 i x> _ 11 ^COOR O '"I* Jl2 10 JA3 wherein R1 is a hydrogen atom or a carboxy-protecting 15 radical; R2 is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom; 3 4 R and R independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or with a substituted or unsubstituted amino 5 A 20 radical; X is a halogen atom; and R and R are independently a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical, a lower alkoxy radical or a substituted or unsubstituted amino 5 6 radical; or R and R , taken together with the 25 adjacent nitrogen atom, may form a 5 to 7 membered heterocyclic ring which may be substituted with one or more substituents at the carbon atom(s), and the hetero-cyclic ring may further contain -NR7-, -0-, -S-, -SO-, -S02- or -NR7-CO-. [R7 is a hydrogen atom, a lower 30 alkenyl radical, a lower alkyl or aralkyl radical which may be substituted, or a radical represented by the general formula -(CH2)nCOR8 (II) 8 . (in which n is 0 to 4 and R is a hydrogen atom, a lower alkoxy radical, or an amino, lower alkyl or aryl - 79 - 221681 -s en? cadical which may be substituted}]. as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the focmula I oc theic salts. 3 4 2. Compounds as in claim 1, whecein R and/oc R when being a substituted amino-lowec alkyl cadical. is di-lowec alkylamino-lowee alkyl. lowec alkylamino-lowec alkyl oc lowec cycloalkylamino-lower alkyl. 3. Compounds as in claim 1 oc 2. whecein R5 and/oc R6 when being a substituted amino-lowec alkyl cadical. is di-lowec alkylamino-lowec alkyl. lower alkylamino-lower alkyl or lowec cycloalkylamino-lowec alkyl. 5 6 4. Compounds as in claim 1 oc 2, whecein R and R , when being (together with the adjacent nitrogen atom) a 5 to 7 membered hetecocycle substituted with one oc moce substituents at the cacbon atom(s), have the substi-tuent(s) on said carbon atom(s) selected from hydcoxy. lower alkoxy. amino, lower alkylamino. lower cycloalkylamino. di-lowec alkylamino, lower alkanoylamino, benzyloxycacbonyl-amino. halogen, lowec alkyl. amino-lowec alkyl, lowec alkylamino-lower alkyl. lower cycloalkylamino-lower alkyl, di-lowec-alkylamino-lower alkyl, lowec alkanoylamino-lower alkyl. hydcoxy-lowec alkyl. phenyl (optionally substituted by amino, halogen, hydcoxy and/oc lowec alkoxy) and a heterocyclic cing. 5. Compounds as in claim 1 or 2. whecein R5 and R6. when being (togethec with the adjacent nitcogen atom) a 5 to 7 membeced heterocycle substituted with one or more substituents at the carbon atom(s). have the substi-tuent(s) on said cacbon atom(s) selected fcom benzylamino optionally substituted by nitco. amino, halogen, hydcoxy and/oc lowec alkoxy: and a gcoup of the genecal focmula N-CH=N- SEP19897' 1 jSlf'w-v o 22 1 6 8 1 - 80 - 50 51 where R and R are lower alkyl or together with the nitrogen atom represent a 5 to 8 membered saturated N-heterocycle. s 7 5 6. Compounds as in any one of claims 1-5. wherein R when being a substituted lower alkyl radical is substituted by hydcoxy. lower alkoxy. amino, lower alkylamino. di-lower alkylamino. halogen, cacboxy and/oc sulfo. 7 10 7. Compounds as in any one of claims 1-5. whecein R when being a substituted acalkyl cadical is substituted by one oc moce amino, nitco. lowec alkylamino. di-lower alkylamino. halogen and/or lowec alkoxy gcoup(s). 15 8. Compounds as in claim 7. whecein the acalkyl cadical is benzyl optionally substituted as defined in claim 7. 7 9. Compounds as in any one of claims 1-5, wherein R when being a radical of the general formula (II) with a 20 substituted amino radical is one caccying an amino cadical substituted by lowec alkyl and/oc lowec cycloalkyl. 7 10. Compounds as in any one of claims 1-5, whecein R when being a cadical of the genecal formula (II) with a 25 substituted lower alkyl radical is one caccying a lowec alkyl cadical substituted by cacboxy and/oc lowec alkoxycacbonyl. 7 11. Compounds as in any one of claims 1-5, whecein R 30 when being a radical of the general formula (II) with a substituted acyl cadical is one caccying an acyl cadical substituted by one or more halogen, lower alkoxy, hydroxy, nitco and/oc amino group(s). 35 #"-■ n - 81 - 221681 12. Compounds as in claim 11 wherein the aryl radical is phenyl, optionally substituted as defined in claim 11. 13. Compounds as in any one of claims 1-12 wherein X is fluorine. 14. Compounds as in any one of claims 1-13 wherein R1 is hydrogen. 2 15. Compounds as in any one of claims 1-14 wherein R is methyl. 16. Compounds as in any one of claims l and 13-15 3 wherein R is hydrogen. 17. Compounds as in any one of claims 1 and 3-16 wherein 4 . R is hydrogen. 18. Compounds as in any one of claims 1. 2 and 13-17 wherein the group R5R6N- is CH^I^ JJ-. 19. Compounds as in any one of claims 1. 2 and 13-17 wherein the group R^R6N- is H^N Q- 20. A compound according to claim 1 which is 9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine-6-carboxylie acid , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 21. A compound according to claim 1 which is 9-fluoro-3-methy1-7-oxo-10-(1-piperazinyl)-2.3-dihydro-7H-pyrido-[3.2,1-ijJ-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvent of this compound or of said salt. 22. A compound according to claim 1 which is 9-fluoro-3-methyl-10-(3-methyl-1-piperazinyl)-7-oxo-2.3-dihydro-7H-pyrido[3,2,l-ij]-l,3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hvdrate or solvate of this compound or of said salt. ^ '3 E * * o^ 23. A compound according to claim 1 which is 9-fluoro-^^methyl-7-oxo-10-(3-phenyl-1-piperazinyl)-2.3-dihydro-7H- O ,1 14SEP 1989 pyrido[3.2.1-ij3 — 1.3.4-benzoxadiazine-6-carboxylic acid, c- ,or a ohannaceutically acceptable salt thereof or a iSp C I V * - hydrate or solvent of this compound or of said salt. 22 1 6 8 1 - 82 - 24. A compound according to claim 1 which is 9-fluoro- 3-methyl-lo-morpholino-7-oxo-2.3-dihydro-7H-pyrido[3,2,1-i j]- 1. 3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 25. A compound according to claim 1 which is 9-fluoro-3-raethyl-10-[3-[(methylamino)methyl]-l-pyrrolidinyl]-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 26. A compound according to claim 1 which is 10-[3-[(ethylamino)methyl]-l-pyrrolidinyl]-9-fluoro-3-methy1- 7-oxo-2.3-dihydro-7H-pycido[3.2,1-ij]-l.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 27. A compound according to claim 1 which is 10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H-pyrido[3.2,1-ij]-l.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 28. A compound according to claim 1 which is 9-fluoco-3-methyl-10-[3-(methylamino)-l-pyrrolidinyl]-7-oxo-2.3-dihydro-7H-pyrido[3,2,l-ij]-1.3,4-benzoxadiazine-6-carboxylic acid, or a oharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 29. A compound according to claim 1 which is l0-[3- (ethylamino)-l-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-i j]-l.3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 30. A compound according to claim 1 which is 10-(3.4-dimethy1-1-piperaziny1)-9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido[3.2,l-ij]-l,3.4-benzoxadiazine-6- carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 31. A compound according to claim 1 which is 9-fluoro-10-(3-methoxy-l-pyrrolidinyl)-3-methy1-7-oxo-2. 3-dihydro-7H-pyrido[3,2.1-ij]-l,3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 22 1 6 8 1 - 83 - 32. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10-[4-(3-oxo-n-butyl)-1-piperazinyl]-2.3-dihydro-7H-pyrido[3,2,l-ij]-l,3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 33. A compound according to claim 1 which is disodium 9-fluoro-3-methy1-7-oxo-10-[4-(sulfonatomethy1)-l-pipera-zinyl]-2,3-dihydro-7H-pyrido[3.2.1-ij]-i.3,4-benzoxadiazine-6-carboxylate, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 34. A compound according to claim 1 which is 10-[4-(4-aminobenzyl)-l-piperazinyl]-9-fluoro-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 35. A compound according to claim 1 which is l0-[3- (aminomethyl)-l-pyr rolidinyl]-9-fluoro-3-methy1-7-0x0-2.3-dihydro-7H-pyrido[3.2.1-ij)-l.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 36. A compound according to claim 1 which is 9-fluoro- 10-(l-imidazoly1)-3-methy 1-7-oxo-2,3-dihydco-7H-pyrido-[3.2,1-ij]-1, 3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 37. A compound according to claim 1 which is 10-(4-ethyl-l-piperazinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 38. A compound according to claim 1 which is 9-fluoco-10-[4-(2-hydroxyethyl)-l-piperazinyl]-3-methy1-7-0x0-2,3-dihydro-7H-pyrido[3,2,1-ij]-l.3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 39. A compound according to claim 1 which is 9-fluoro-3-methy1-10-(4-methy1-1-imidazoly1)-7-0x0-2,3-dihydro-7H-pyrido[3,2,1-i j]-1,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 22 1 6 8 f - 84 - 40. A compound according to claim 1 which is 9-fluoro-3-methyl-10-[3-methy1-4-[(methylamino)methyl]-1-pyccoli-dinyl]-7-oxo-2.3-dihydco-7H-pycido[3.2,1-ij]-l.3,4-benzoxa-diazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this ccmpound or of said salt. 41. A compound according to claim 1 which is lo-[3- (aminomethyl)-4-methyl-l-pyrrolidinyl]-9-fluoro-3-methy1-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-i,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 42. A compound according to claim 1 which is 10-[3- [(ethylamino)methyl]-4-methyl-l-pyrrolidinyl]-9-fluoro-3-me thy1-7-0x0-2.3-dihydro-7H-pyrido[3,2.1-ij]-l,3.4-benzoxa-diazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 43. A compound accocding to claim 1 which is 10-[3-(aminomethyl)-4-chloro-l-pyrrolidinyl]-9-fluoro-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 44. A compound accocding to claim 1 which is 10-[3- (aminomethyl)-4-fluoro-l-pyrrolidinyl]-9-fluoco-3-methy1-7-oxo-2,3-dihydco-7H-pycido[3.2.1-ij]-l.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 45. A compound according to claim 1 which is 10-[3- chloro-4-[(methylamino)methy1]-1-pyrrolidinyl]-9-fluoro-3- methyl-7-oxo-2.3-dihydro-7H-pycido[3.2,1-ij]-l,3,4-benzoxa- diazine-6-cacboxylic acid , or a pharmaceutical^ acceptable salt thereof or a hydrate or solvate of this ccrpound or of said salt. 46. A compound accocding to claim 1 which is 9-fluoro-10-[3-fluoco-4-[(methylamino)methyl]-l-pyccolidinyl]-3-methyl-7-oxo-2.3-dihydco-7H-pycido[3.2.1-ij]-l.3.4-benzoxa-diazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 47. A compound accocding to claim 1 which is 10-[3-chloco-4-[(ethylamino)methyl]-l-pyccolidinyl]-9-fluoco-3- 22 1 68 1 - 85 - methyl-7-oxo-2.3-dihydro-7H-pyrido[3,2,1-ij]-l.3,4-benzoxa- diazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 48. A compound according to claim 1 which is 10-[3-5 [(ethylamino)methy13-4-fluoro-l-pyrrolidinyl3-9-fluoro-3- methy1-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3 . 4-benzoxa-diazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 49. A compound according to claim 1 which is 10-(3- 10 amino-4-raethoxy-l-pyrrolidinyl)-9-£luoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,l-ij]-1.3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 50. A compound according to claim 1 which is 9-fluoro-15 10-[3-methoxy-4-(methylamino)-1-pyrrolidinyl]-3-raethyl-7-oxo- 2.3~dihydro-7H-pyrido[3,2,1-ij]~1,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 51. A compound according to claim 1 which is 10-[3- 20 (ethylamino)-4-raethoxy-l-pyrrolidinyl]-9-fluoro-3-methy1-7-oxo -2,3-dihydro-7H-pyrido[3,2.1-ij]-l,3,4-benzoxadiazine-6- carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 52. A compound according to claim 1 which is 9-fluoro-25 10-(3-hydroxy-4-methoxy-l-pyrrolidinyl)-3-methy1-7-oxo-2.3- dihydro-7H-pyrido[3,2.1-ij3-l<3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 53. A compound according to claim 1 which is 10-(3- 30 amino-4-chloro-l-pyrrolidinyl)-9-fluoro-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3,2,1-ij 3-1.3,4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 54. A compound according to claim 1 which is 10-(3- 3 5 amino-4-fluoro-l-pyrrolidinyl)-9-fluoro-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3,2,l-ij3-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. ^ J.. 22 1 6 8 55. A compound accocding to claim 1 which is 10-[3-chloco-4-(methylamino)-1-pycrolidinyl]-9-Cluoco-3-methy1-7-oxo- 2 . 3-dihydco-7H-pycido[3.2,l-ij]-l,3.4-benzoxadiazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a 5 hydrate or solvate of this compound or of said salt. 56. A compound accocding to claim 1 which is 9-fluoco-fs 10-[3-fluoco-4-(methylamino)-l-pyrcolidinyl]-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido[3.2.1-ij]-l,3,4-benzoxadiaz ine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a 1q hydrate or solvate of this compound or of said salt. 57. A compound accocding to claim 1 which is l0-[4-(aminomethyl)-l-piperidyl]-9-fluoco-3-methyl-7-oxo-2.3-dihydco-7H-pycido[3.2,1-i j]-1,3,4-benzoxadiazine-6-cacboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate 15 or solvate of this compound or of said salt. 58. A compound accocding to claim 1 which is 9-fluoco-10-(4-hydroxy-l-piperidyl)-3-methyl-7-oxo-2.3-dihydco-7H-pycido[3.2.1-ij]-1.3,4-benzoxadiazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 59. A compound according to claim 1 which is 9-fluoco-3-methyl-7-oxo-10-[4-(l-pyccolyl)-l-pipecidyl]-2.3-dihydco-7H-pycido[3.2.1-ij]-l.3.4-benzoxadiazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. C 60' A compound according to claim 1 which is 9-fluoco- 10-(1-homopipecazinyl)-3-methyl-7-oxo-2.3-dihydco-7H-pyrido[3.2.l-ij]-i,3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 61. A compound according to claim 1 which is 9-fluoco-10-(3-hydcoxy-l-pyccolidinyl)-3-methyl-7-oxo-2. 3-dihydco-7H-pycido[3.2.1-ij]-1.3,4-benzoxadiazine-6-cacboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 62. A compound accocding to claim 1 which is 9-fluoco-3-methy1-7-oxo-10-(4-n-pcopyl-l-pipecazinyl)-2.3-dihydco-7H-pycido[3,2,1-ij]-1,3,4-benzoxadiazine-6-cacboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 63. A compound according to claim 1 which is 9-fluoco-10-[4-(2-fluoroethyl)-l-pipecazinyl]-3-methyl-7-oxo-2.3- 11 1 6 8 f - 87 - dihydro-7H-pyrido[3,2.1-ij]-l.3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 64. A compound according to claim 1 which is 10-[4- (carboxymethyl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3,2.1—i 3 3 — 1.3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 65. A compound according to claim 1 which is 10-(4-allyl-l-piperaziny1)-9-fluoro-3-methy1-7-oxo-2, 3-dihydro-7H-pyrido[3,2.1-ij]-1.3.4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 66. A compound according to claim 1 which is 10-(1,1-dioxide-4-thiomorpholinyl)-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 67. A compound according to claim 1 which is 9-fluoro-3-methyl-10-(l-oxide-4-thiomorpholinyl)-7-0x0-2,3-dihydro-7H-pyrido[3.2.1-ij]-1.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 68. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10-[4-(2-oxo-n-propyl)-l-piperazinyl]-2,3-dihydro-7H-pyrido[3,2,l-ij]-i,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrat; or solvate of this compound or of said salt. 69. A compound according to claim 1 which is 10-(3-chloro-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine-6-carboxylie acid , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 70. A compound according to claim 1 which is 9-fluoro-3-(2-fluoroethyl)-10-(4-methy1-1-piperazinyl)-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-i,3.4-benzoxadiazine-6-carboxylie acid , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 71. A compound according to claim 1 which is 10-(4-amino-l-piperidyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H- - 88 - 221681 pyrido[3.2,1-ij]-1.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 72. A compound according to claim 1 which is 9-fluoro-3-methyl-10-[4-(methylamino)-1-piperidyl]-7-oxo-2.3-dihydro-7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 73. A compound according to claim 1 which is l0-[4-(ethylamino)-1-piperidyl]-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2,1-ij]-i.3.4-benzoxadiazine-6-car-boxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 74. A compound according to claim 1 which is 10-[3- [(ethyImethylamino)methy1]-l-pyrrolidinyl]-9-fluoro-3-methyl-7- oxo-2.3-dihydro-7H-pyrido[3,2.1-i j]-l.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 75. A compound according to claim 1 which is 10-(3-amino-4-hydroxy-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-1.3.4-benzoxadiazine-6-carboxylic acid,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 76. A compound according to claim 1 which is 9-fluoro- 10-[3-hydroxy-4-(methylamino)-l-pyrrolidinyl]-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2,l-ij]-1.3,4-benzoxadiazine-6-carboxylic acid,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 77. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-2,3-dihydro-7H-pyrido-[3.2.l-ij]-l,3.4-benzoxadiazine-6-carboxylic acid,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 78. A compound according to claim 1 which is 10-(2.6- dimethyl-4-morpholinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2.1-ij]-1.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 79. A compound according to claim 1 which is 10-[3-acetylaminomethyl)-l-pyrrolidinyl]-9-fluoro-3-methy1-7-oxo-3-dihydro-7H-pyrido[3.2.1-ij]-1.3,4-benzoxadiazine-6-car- - 89 - 22 1 6 8 boxylic acid, or a pharmaceuticallv acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 80. A compound accocding to claims 1 which is 10-C[2-(dimethylamino)ethyl]methylamino]-9-fluoro-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3.2,l-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 81. A compound according to claim 1 which is 9-fluoro-3-methy1-7-oxo-10-(3-oxo-l-piperaziayl)-2.3-dihydro-7H-pyrido[3.2.1-ij]-1.3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 82. A compound according to claim 1 which is 9-fluoro- 2-(hydroxymethyl)-3-methyl-10-(4-raethyl-l-piperazinyl)-7-0x0-2.3-dihydro-7H-pyrido[3,2.1-i j]-1,3.4-benzoxadiazine-6-carboxylic acid,or a pharmaceutically acceptable salt tnereof or a hydrate or solvate of this compound or of said salt. 83. A compound according to claim 1 which is 2-[(dime-thylamino)methyl]-9-fluoro-3-methy1-10-(4-methy1-1-piperazinyl )-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxa-diazine-6-carboxylic acid , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 84. A compound according to claim 1 which is 10-[3- (benzyloxycarbonylamino)-l-pyrrolidinyl]-9-fluoro-3-methy1-7-oxo- 2. 3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxadiazine-6-car boxy lie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this ccnpound or of said salt. 85. A compound according to claim 1 which is 9-fluoro- 3-methyl-7-oxo-10-(4-phenacyl-l-piperazinyl)-2.3-dihydro-7H-pyrido[3,2.1-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 86. A compound according to claim 1 which is 9-fluoro-3-methyl-10-[4-(4-nitrobenzyl)-l-piperazinyl]-7-oxo-2,3-dihydro-7H-pyrido[3,2,l-ij]-1.3.4-benzoxadiazine-6-carboxylic acid,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 87. A compound according to claim 1 which is l0-[4-(3-carboxypropionyl)-1-piperazinyl]-9-fluoro-3-methy1-7-oxo- ?2 16 8T 2.3-dihydro-7H-pyr ido[3,2,l-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 88. A compound according to claim 1 which is 10-(4-acetyl-1-piperazinyl)-9—fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine-6-carboxylic acid , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 89. A compound according to claim 1 which is 9-fluoro-10-(4-methoxy-1-piperidyl)-3-methy1-7-oxo-2. 3-dihydro-7H-pyrido[3.2,l-ij]-1.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 90. A compound according to claim 1 which is 9-fluoro- 2,3-dimethy1-10-(4-methyl-l-piperazinyl)-7-oxo-2, 3-dihydro-7H-pyrido[3.2.1-ij]-l.3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 91. A compound according to claim 1 which is 9-fluoro- 2.3-dimethy1-7-oxo-10-(1-piperazinyl)-2.3-dihydro-7H-pyridols,2.l-ij]-l.3.4-benzoxadiazine-6-carboxylic acid , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 92. A compound according to claim 1 which is ethyl 10-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]-9-fluoro-3-methy1-7-0X0-2.3-dihydro-7H-pyrido[3.2,1-ij]-1.3, 4-benzoxa-diazine-6-carboxylate , or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 93. A compound according to claim 1 which is ethyl 10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2,1-ij]-l,3.4-benzoxadiazine-6-car-boxylate ,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this ccmpound or of said salt. 94. A compound according to claim 1 which is benzyl 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3,2.1-ij]-l,3.4-benzoxadiazine.-6-car-boxylate, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 95. A compound according to claim 1 which is benzyl 10-(3-chloro-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-l,3.4-benzoxadiazine-6- "'- " . -i' r " ' ' SI 22 1 6 8 f 91 - < carboxylate,or a pharmaceutically acceptable salt thereof or j a hydrate or solvate of this compound or of said salt, i ^ 96. A compound according to claim 1 which is pivaloyl- j oxymethyl 10-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]- 5 9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ij ] - 1. 3.4-benzoxadiazine-6-carboxylate, or a phaimaceutically acceptable salt thereof or a hydrate or solvate of this cotpound or of said salt. ^ 97. A compound according to claim 1 which is pivaloyl oxymethyl 10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl-7-10 oxo-2.3-dihydro-7H-pyrido[3.2,l-ij]-1,3,4-benzoxadiazine-6-carboxylate, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 98. A compound according to claim 1 which is 10-[3-[(4-aminobenzy1)amino]-1-pyrrolidinyl]-9-fluoco-3-methyl-7-oxo- 15 2,3-dihydro-7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiaz ine-6- cacboxylic acid,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 99. A compound according to claim 1 which is 9-fluoro-10-[3-[[(dimethylamino)methylene]amino]-l-pycro1idinyl]-3- 20 methy1-7-0X0-2.3-dihydco-7H-pyrido[3.2,1-ij]-l,3.4-benzoxa- diazine-6-cacboxylic acid, or a pharmaceutically acceptable salt thereof J or a hydrate or solvate of this compound or of said salt. • 100. A compound accocding to claim 1 which is 9-fluoro- 3-methyl-10-[3-(4-methyl-1-piperazinyl)-l-pyrrolidinyl]-7-25 oxo-2.3-dihydro-7H-pyrido[3,2.1-i j]-l.3.4-benzoxadiazine-6-carboxylic acid,or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 101. A compound according to claim 1 which is 10-(3-amino-3-methy1-l-pyrrolidinyl)-9-fluoro-3-methy1-7-oxo-2.3- 30 dihydro-7H-pyrido[3,2.1-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 102. A compound according to claim 1 which is 10-(trans-3-amino-4-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2.3- 35 dihydro-7H-pyrido[3,2.l-ij]-l,3,4-benzoxadiazine-6-carboxylie acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. Q 10 c c 22 1 6 8 1 - 92 - 103. A compound according to claim 1 which is 10-(trans-3-araino-4-phenyl-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3,2,1-ij]-l,3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 104. A compound according to claim 1 which is 9-fluoro-3-methyl-l0-[3-raethyl-3-[(methylamino) methyl]-l-pyrrolidinyl]-7-0x0-2.3-dihydro-7H-pyrido[3.2.1-ij]-l,3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt. 105. A compound according to claim 1 which is 9-fluoro-3-raethyl-10-[trans-3-[(methylamino)methyl]-4-phenyl-l-pyrrolidinyl ]-7-0x0-2.3-dihydro-7H-pyrido[3.2,1-ij]-l.3.4-benzoxa-diazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof is or a hydrate or solvent of this compound or of said salt. 106. A compound according to claim 1 which is l0-(trans-3-amino-4-methoxy-l-pyrrolidinyl)-9-fluono-3-methy1-7-oxo-2.3-dihydro-7H-pyrido[3.2,1-ij]-1.3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof 20 or a hydrate or solvate of this compound or of said salt. 107. A compound according to claim 1 which is 10-(trans-3-amino-4-hydroxy-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo- 2.3-dihydro-7H-pyrido[3,2,l-ij]-i,3.4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a 25 hydrate or solvate of this compound or of said salt. 108. Compounds represented by the general formula: 30 ,"3p6^ 35 1 . wherein R is a hydrogen atom oc a carboxy-protecting 2 radical ; R is a hydrogen atom or a lower alkyl -*V- . , o 4?. f* 2Zli>bl - 93 - cadical which may be substituted with a halogen atom; 3 4 R and R independently are a hydrogen atom or a lowec alkyl cadical which may be substituted with a hydroxy radical or with.a substituted or unsubstituted amino cadical ; and X and X1, which ace the same or different, ace halogen atoms. 109. Compounds as set focth in any one of claims 1-107 for use as pharmaceutically active substances. 110. Compounds as set focth in any one of claims 1-107 as phacmaceutically active substances foe use in the treatment and J prophylaxis of infectious diseases. Tf i o 111. a pcocess foe the manufactuce of the compounds accocding to any one of claims 1-107 which process comprises (a) ceacting a compound cepresented by the genecal formula 1 12 3 4 wherein R . R , R . R and X are the same as defined in claim 1. and X' is a halogen atom; and amino. hydroxy and/or carboxy groups present may be protected, with ,-an amine represented by the general formula HN - R5 (IV) 28SEPI989 Is R wherein R^ and R^ are the same as defined in claim 1, followed, if necessary by removal of a protecting radical, or (b) ceacting a compound represented by the general formula "* vW _ - 94 - 221G81 o (V) I 2 H NHR 12 5 6 wherein R . R . R . R and X are the same as defined in claim 1; and amino, hydroxy and/or cacboxy I groups pcesent may be pcotected, | with a carbonyl compound represented by the general formula ^ 3 i R 3 / c=o (VI) ■j 3 4 3 wherein R and R are the same as defined in claim 1. | or a polymer, acetal, ketal or enol ether thereof, followed, if i necessary, by removal of a protecting radical, or 1 i O (c) foc the manufacture of a compound of formula I, as defined : in claim 1, in which R7 is other than hydrogen, reacting a compound of formula I in which R is hydrogen with an agent yielding the group R70 where R70 is as R7 but not hydrogen, or (d) for the manufactuce of a compound of formula I, as defined in claim i, wherein IT* and/or are lower alkyl (or contain a di-lower alkylamino oc lowec alkoxy gcoup) lowec alkylating a compound of focmula I wherein R5 and/or R6 ace hydcogen oc contain an amino, lowec alkylamino oc hydcoxy gcoup, or (e) foc the manufactuce of a compound of focmula I , as defined in claim 1, in which R^R^N- is a 5 to 7 membered heterocyclic ring with -S0-oc -S02~ subjecting a corresponding i minimi!nil i tin it i n the hetecocyclic cing contains -S- to oxidation, r 221681 O o - 95 - (f) for the manufacture of a compound of formula I , as defined in claim 1, having a free amino, hydroxy and/or carboxy group, splitting off the protecting group(s) from a corresponding compound of formula I having (a) protected amino, hydroxy and/or carboxy group(s). or (g) for the manufacture of a compound of formula I, as defined in claim l, containing a halogen atom, halogenating a correspondingly hydroxy-substituted compound of formula I in which R1 is a carboxy-protecting radical and. if desired, splitting off said protecting radical R1. or (h) for the manufacture of a compound of formula I, as defined in claim 1, containing an amino group ^educing the nitro group of a correspondingly nitro-substituted compound of formula I, oc (i) foc the manufacture of a compound of formula I, as defined in 50 claim 1, containing a group of the formula R p N-CH=N-. R5l/ where R50 and R51 are lower alkyl or together with the nitrogen atom represent a 5 to 8 membered saturated N-heterocycle,reacting the amino group of a correspondingly amino-substituted compound of formula I with a reactive derivative of a formamide derivative of the general formula (VII) wherein R50 and R51 ace as above. or (j) for the manufacture of a compound of focmula I, as defined in claim 1, in which R* is a carboxy-protecting radical, subjecting a carboxylic acid of focmula I to a coccesponding estferirraaraon. or 221681 - 96 - (k) for the manufacture of pharmaceutically acceptable salts, hydrates or solvates of a compound of formula I, as defined iii claim 1, or hydrates or solvates of said salts t converting a ccnpound of formula I into a salt, hydrate or solvate or into a hydrate or solvate of said salt. 112. Process according to Claim 111, wherein one of process alternatives (a) - (h). (j) and (k) is carried out. 113. A pharmaceutical preparation containing a compound according to any one of claims 1-107. 114. A pharmaceutical preparation for use in the treatment and prophylaxis of infectious diseases containing a compound according to any one of claims 1-107. 115. The use of the compounds accocding to any one of claims 1-107 in the treatment and prophylaxis of illnesses other than in the treatment of humans. 116. The use of the compounds according to any one of-claims 1-107 in the treatment and prophylaxis of infectious diseases other than in the treatment of humans. 117. The use of the compounds according to any one of claims 1-107 for the manufacture of medicaments for use in the treatment and prophylaxis of infectious diseases. 113. compounds according to any one of claims 1-107 whenever prepaced according to the process claimed in claim 111. 119. A process for the manufacture of compounds of formula I, as defined in claim 1, substantially as here-inbefore described with reference to any one "of Examples K> , • - V , _ 221681 - 97 - 120. A pharmaceutical preparation containing a compound of formula I, as defined in claim 1, substantially as hereinbefore described with reference to Example A or Example B. to,-/ *• «*. •y bfe/thelr authorised Arentti A. J. ^ per: c t </div>