AU602534B2 - Tricyclic compounds - Google Patents

Description

APPUCATION ACCEPTED AND AMENDMENTS ALLOW ED 5 s 8 4 12 a -i :1 S F Ref: 35646 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION (ORIGINAL) 6 2 5 3 FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: docuneinis the 'i doments made under Scti 49 ad iscorrectfor printing.

a

I

Name and Address of Applicant: F Hoffmann-La Roche Co Aktiengesellschaft Grenzacherstrasse 124-184 CH-4002 Basle

SWITZERLAND

it Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Tricyclic Compounds The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3 1h, qw V- RAN 4440/163

ABSTRACT

The invention is concerned with tricyclic compounds of the general formula S XCOOR'

X

R

15 K)R 2 31 wherein R 1 is a hydrogen atom or a carboxy-protecting 20 radical; 2 is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom;

R

3 and R 4 independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or a substituted or unsubstituted amino 25 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 6 taken together with the S 30 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 ring may further contain -NR 7

-SO-,

-S 2- or -NR7-CO-, [R 7 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 i i -i Ir~ C1-

-(CH

2 )nCOR 8

(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)], as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula I or their salts.

Also included is a process for the manufacture of these compounds, pharmaceutical preparations containing them and intermediates useful in said process. The end products have antimicrobial antivity.

0*e 00000* o i ft j. r c~ c, r 1B The present invention relates to novel tricyclic compounds, more particularly to pyrido [3,2,l-ij]-1,3,4-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 [3,2,1-1j]-1,3,4-benzoxadiazine derivatives represented by the general formula 0 1 x A COOR 6 R -N 0 O 2 wherein R is a hydrogen atom or a carboxy-protecting radical; R 2 JD is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom; R 3 and R 4 independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or with an unsubstituted amino acid radical or an amino acid radical substituted with di-lower alkyl, lower alkyl or lower cycloalkyl; X is a halogen atom; and

R

5 and R 6 are independently a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical, a lower alkoxy radical or 99: an unsubstituted amino acid radical or an amino acid radical substituted 5 6 S with di-lower alkyl, lower alkyl or lower cycloalkyl; or R 5 and R 6 taken together with the adjacent nitrogen atom, may form a 5 to 7 membered "Y0 heterocyclic ring which may be substituted at the carbon atom(s) with one or more substituents selected from hydroxy, lower alkoxy, amino, lower alkylamino, lower cycloalkylamino, di-lower alkylamino, lower e alkanoylamino, benzyloxycarbonyl-amino, halogen, lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower cycloalkylamino-lower alkyl, di-lower-alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, hydroxy-lower alkyl, phenyl (optionally substituted by amino, halogen, hydroxy and/or lower alkoxy) and a heterocyclic ring; or the heterocyclic ring formed by R 5 and R 6 may be substituted at the carbon atom(s) with one or more substituents selected from benzylamino (optionally substituted by nitro, amino, halogen, hydroxy and/or lower alkoxy) and a group of the general formula -o i 2

R

50

N-CH=N-

R

51 where R 50 and R 51 are lower alkyl or together with the nitrogen atom represent a 5 to 8 membered saturated N-heterocyclic ring; or the heterocyclic ring formed by R 5 and R 6 may be substituted as defined above and the hetero-cyclic ring may further contain -NR 7

-SO

2 or -NR 7

ER

7 is a hydrogen atom; a lower alkenyl radical; a lower alkyl radical which may be substituted by hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, halogen, carboxy and/or sulfo; an aralkyl radical which may be substituted with one or more 10 amino, nitro, lower alkylamino, di-lower alkylamino, halogen and/or lower 1 alkoxy group(s); or a radical represented by the general formula *4 4 4 4.

-(CH

2 nCOR 8

(II)

(in which n is 0 to 4 and R is a hydrogen atom; a lower alkoxy radial; an amino radical, which may be substituted by lower alkyl and/or lower cycloalkyl; a lower alkyl radical which may be substituted by carboxy and/or lower alkoxycarbonyl; or an aryl radical which may be substituted by S one or more halogen, lower alkoxy, hydroxy, nitro and/or amino group(s))]; as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula I or their salts.

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 preferably containing up to and including 7 carbon atoms, unless otherwise indicated.

4 1 Explanation of R 1

R

1 is a hydrogen atom or a carboxy-protecting radical.

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 acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and l-pivaloyloxyethyl); lower alkoxycarbonyloxyalkyl (e.g.

methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl); lactonyl phythalidyl and 'LL: thiophthalidyl); lower alkoxymethyl methoxymethyl); benzyloxymethyl; ,"(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl; or GSA 59 Z 3 3 lower alkanoylaminomethyl acetamidomethyl). Other ester groups e.g. benzyl, cyanomethyl, phenacyi, phenyl and the like can also be used.

2 Explanation of R

R

2 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.

3 4 Explanation of R 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 25 dimethylamino, diethylamino; lower alkylamino such as methylamino, ethylamino, lower cyclo alkylamino such as cyclopropylamino and the like.

Explanation of R 5 and R 6 3 R 5 6 30 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 unsub- 6 stituted amino 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 more substituents at the carbon atom(s), and the heterocyclic ring may further contain -NR 7 -SO or L i F. 4 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 -(CH 2 nCOR (II) 0 .0

C.

O

C

S.

0

OC

(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 1 to 4 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-propoxy, 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; lower cycloalkylamino such as cyclopropylamino and the like.

The 5 to 7 membered heterocyclic ring formed by R 5 and 25 R 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, 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 substituted by nitro, amiro, halogen, hydroxy and/or lower alkoxy, e.g. (4-aminobenzyl)amino; a group of the general formula h Ii -5 9 9

CH=N-

R

where R 50and R 51are lower alkyl or together with the nitrogen atom represent a 5 to 8 membered saturated N-heterocycle such as (dimethylamino)methyleneamino, (hexahydro-lH-azepin-1-yl)methyleleamino; benzyloxycarbonylamino; halogen, such as fluoro, chloro, bromo; lower alkyl such as methyl, ethyl, n-propyl, iso-propyl; amino-lower alkyl, lower alkylamino-lower alkyl, lower cycloalkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkanoylamino- -lower alkyl, examples of these substituents being: aminomethyl, (methylamino)methyl, (ethylamino)methyl, (n-propylamino)methyl, (iso-propylamino)methyl, (cyclopropylamino)methyl, (dimethylamino)methyl, (diethylamino)methyl, (ethylmethylamino)methyl, acetylaminomethyl, 2-aminoethyl, 2- (methylamino) ethyl, 2-(ethylamino )ethyl, 2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-(ethylrnethylamino)ethyl; hydroxy-(lower alkyl) such as hydroxymethyl, 2-hydroxy- 20 ethyl; phenyl, optionally substituted by amino, halogen, hydroxy and/or lower alkoxy such as 4-aminophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl; a heterocyclic ring such as pyrrolyl, 4-methyl-l- -piperazinyl and the like.

The lower alkenyl radical represented by R 7is e.g.

allyl, 3-methyl-2-butenyl, 2-butenyl, l-methyl-2-propenyl, 3-butenyl and the like.

30 The substituted alkyl radical represented by R 7is e.g. hydroxy-(lower alkyl) such as 2-hydroxyethyl, 3-hydroxybutyl; lower alkoxy-lows~er alkyl such as 2-methoxyethyl, 2-ethoxyethyl; amino-lower alkyl such as 2-aminoethyl, 3-aminobutyl; lower alkylamino-lower alkyl such as 2-(methylamino)ethyl, 2-(ethylamirio)ethyl, 3-(methylamino)butyl, 3-(ethylamino)butyl; di-lower alkylamino-lower alkyl such as 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 9**

I

-6- 3-(dimethylamilo) butyl, 3- (diethylamino) butyl; halogen-lower alkyl such as 2-fluoroethyl. 3-fluoro-n--butyl; carboxy-lower alkyl such as carboxymetiyl, 2-carboxyethyl; sulfo-lower alkyl such as sulfomethyl, 2-sulfoethyl and the like.

57 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.

8 The amino radical R may be unsubstituted or substituted by e.g. lower alkyl such as methylamino. dimethylamino, or by lower cycloalkyl such as cyclopropylamino.

A lower alkyl radical R may likewise be unsubstituted or substituted. The substituted alkyl radical represented by *8.

20 R is e.g. carrying a carboxy or lower alkoxycarbonyl radicaY' such as in 2-carboxyethyl, 3-carboxy-n-propyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonyl-n-propyl and the like. 8 25 The aryl radical represented by R 8is 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-nitrophenyl, 4-aminophenyl and the like.

Especially preferable radicals reprosented by R 7are hydrogen. methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 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, '4' -7- 2-oxo-n-propyl, 2-oxo-fl-butyl, 3-oxo-n-butyl, 3-oxo-n- -pentyl, 3-carboxypropionyl, 3-ethoxycarbonylpropionyl, 4-carboxy-n-butyryl, phenacyl, 41-aminophenacyl, ethoxycarbonyl, methoxycarbonyl, carbamoyl and the like.

Eseial preferable radicals represented by R R N- in the formula are 1-piperazinyl, 4-methyl-l- -piperazinyl, 3-met'hyl-l-piperazinyl, 3-phenyl--1-piperazinyl, 3.4-dimethyl--l-piperazinyl, 4-ethyl-l-piperazinyl, 3-(4-aminophenyl)-l-.piperazilyl, 4-n-propyl -1-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) -1-piperazinyl, 4- (sulfomethyl) -1-piperazinyl, 4- (4-aminobenzyl )-1-piperazinyl, 4-(2-hydroxyethyl)-l-piperazinyl, 3-oxo-l-piperazinyl, 4-phenacyl-l-piperazinyl, 4-(3-carboxypropionyl)-l-pipera- 0000 zinyl, 4-acetyl-l-piperazinyl, 4-(4-nitrobenzyl)-l-piperazinyl, morpholino, 2-methyl-4-morpholinyl, 2,6-dimethyl-4- 0 -morpholinyl, 4-thiomorpholinyl, I-oxide-4-thiomorpholinyl, l,l-dioxide-4-thiomorpholinyl, 4-(aminomethyl)-l-piperidyl, 0 4-[(methylamino)methyl]-l-piperidyl, 4-methoxy-l-piperidyl, 0.e.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-pyrroli 'dinyl, 3-(methylamino)-l-pyrrolidinyl, 00 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)-l- -pyrrolidinyl, 3-(4-methyl-l-piperazinyl)-l-pyrrolidinyl, 3-[(dimethylamino)methyleneamino]-l-pyrrolidinyl, 3-E (methylamino)methyl3-l-pyrrolidinyl, (methylamino)methylll-4-phenyl-l-pyrrolidinyl, 3-methyl-3-[(methylamino)methyl]-l-pyrrolidinyl, (ethylarino)methyl]-l-pyrrolidinyl, 3-(acetylaminomethyl)-l-gyrrolidinyl, 3-[(dimethylamino)methyl]-l-pyrrolidinyl, Cethylmethylamino)methyl)-l-pyrrolidinyl, 3-amino-4-methoxy-l-pyrrolidilyl, 8- 3-methoxy-4- (methylamino )-1-pyrrolidinyl, 3-(ethylamino)-4--methoxy-l-pyrrolidill 3-amino-4-chloro-l- -pyrrolidinyl, 3-chloro-4-(methylamino)-l-pyrrolidinyl, 3-chloro-4-(ethylamilo)-l-pyrrolidilyl, 3-amino-4--fluoro-l- -pyrrolidinyl, 3-fluoro-4-(methylamino)-l-pyrrolidinyl, 3- (ethylamino)-4-fluoro-l-pyrrolidilyl. 3- (aminomethyl) -4- -chloro-l-pyrrolidinyl, 3-chloro-4-[(methylaminao)methyl]-l- -pyrrolidinyl, 3-clloro-4-f(ethylamino)methyl]-l,-pyrrolidinyl, 3-(aminomethyl)-4-fluoro-l-pyrrolidilyl, 3-f luoro-4jo -[(methylamino)methyl]-l-pyrrolidinyl, 3-[(ethylamino)methyl]-4-fluoro--l-pyrrolidinyl, 3-(aminomethyl)-4-methyl-l- -pyrrolidinyl. 3-methyl-4-[(methylamino)methyl]-l-pyrrolidinyl, 3-f (ethylamino)methylll-4-methyl-l-pyrrolidinyl, 3-hydroxy-l-pyrrolidinyl, 3-methoxy-l-pyrrolidinyl, 3-chloro-l-pyrrolidinyl, 3-fluoro-l-pyrrolidinyl, 3-hydroxy- -4-methoxy-l-pyrrolidinyl, I-imidazolyl, 4-methyl-l-imidazolyl, 3-amino-4--hydroxy-l-pyrrolidinyl, 3-(methylamino)- -4-bydroxy-l-pyrrolidinyl, 3-(ethylamino)-4-hydroxy-l- 9-pyrrolidinyl. 3-(dimethylamino)-4-hydroxy-l-pyrrolidinyl, [2-(dimetbylamino)ethyllmethylamino, and the like.

Explanation of X: X is a halogen atom such as fluorine, chlorine or 25 bromine, preferably fluorine or chlorine.

99.. The novel pyrido[3,2,l-ij]-l,3,4-benzoxadiazine derivatives of the formula and their pharmaceutically acceptable salts and hydrates or solvates thereof and of these salts are manufactured in accordance with the present invention by a process which comprises reacting a compound represented by the general formula Ohl I_ I -9

(III)

1 2 3 4 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 HN R (IV)

S

S.

59

S

S.

6

R

wherein R and R are the same as defined above, 20 followed, if necessary by removal of a protecting radical, or reacting a compound represented by the general formula

(V)

4* S.

NHR

2 t& t 00 1 2 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, with a carbonyl compound represented by the general formula 1,

I

Ma OPEN-- OA I I UIIzUMJa L I LU L IV UIII I 1W I W I UU with di-lower alkyl, lower alkyl or lower cycloalkyl; or R 5 and R 6 taken together with the adjacent nitrogen atom, may form a 5 to 7 membered /2 cI j

T

10 C=O (VI) S S r a

-S

'a A.,r A

S

.4

S

wherein R 3 and R are the same as defined above, or its polymer, acetal, ketal or enol ether, followed, if necessary, by removal of a protecting radical, or for the manufacture of a compound of formula I in which 7.

R is other than hydrogen reacting a compound of formula I R7 6S'VX OC\\ in which R is hydrogen hich -ar-,agent yielding the group 70 7

R

70 where R 70 is as R 7 but not hydrogen, or for the manufacture of a compound of formula I wherein 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 R and/or R are hydrogen or contain an amino, lower alkylamino or hydroxy group, or 20 for the manufacture of a compound of formula I in which R5 6N- is a 5 to 7 membered heterocyclic ring with -SOor -SO subjecting a corresponding compound wherein the heterocyclic ring contains to oxidation, or 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 protected amino, hydroxy and/or carboxy group(s), or for the manufacture of a compound of formula I containing a halogen atom halogenating a correspondingly hydroxy-substituted compound of formula I in which R 1 is a carboxy-protecting radical and, if desired, splitting off said protecting radical R, or said protecting radical R or

AL

9 /6 I for the manufacture of a compound of formula I containing an amino group reducing the nitro group of a r L -r solvater of the compounds of the formula I or their salts.

11 correspondingly nitro-substituted compound of formula I, or for the manufacture of a compound of formula I containing a group of the formula R

-N-CH=N-,

R

5 51 where R and R 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

R

50 N-CHO (VII)

R

wherein R 50 and R 51 are as above, or 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 S 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 Sor solvate of said salt.

30 Process A: 'As stated above, the desired compounds can be obtained by reacting a compound represented by the general formula 5845/3 i u- i ICII~ 12

(III)

1 2 3 4 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 HN R I (IV)

SS

0

S

0 0 5* S. So

S

S.

5 6 wherein R and R are the same as defined above, 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).

general formula 13 k.

reduction -X1

H

5

C

2 OCH=C (COOC 2

H

5 )2

(A)

(C)

ON4-protection Xto 100C 2

H

5 aminat ion

X

:OOC

2

H

5

X

alkylation x

(D)

.COOC

2

H

cyclizatio

COOC

2

H

N-protection (E) (F)

!OOC

2

,H

deprotection I I OR' NHR"

(H)

c yc liz atio n (Va (Va) (ila)

I

14

:OOC

2

H

cyclization OH-protection

(C)

am inat ion N-protection

S.

*5* (E) (F) deprotection alkylation

NHR"

f11 2 OR' N-R

(G)

cyclization.0 (va) (Va) (IIla) -II- r 15 2 3 4 wherein R R R X and X' are the same as defined above; R' is a protecting radical, such as benzyl, methoxybenzyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, t-butyl, t-butyldimethylsilyl, acetyl, benzoyl and the like; R" is a protecting radical, such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl and the like and is a hydrogen atom or an 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 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) 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 0 C, preferably from 80 0 C to 150 0 C in order to obtain sufficiently fast reaction rate.

S. The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, 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.

The convenient solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, pyridine, -16 Py picoline, lutidine, lmtYrpcri\and the like.

Mixtures of two or more solvents may also be used.

The protecting radical may. if desired, be removed after the reaction by 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 benzyloxycarbonyl radical may be removed by hydrogenolysis.

The starting materials represented by the formula (III) may be exemplified as follows: 9,l0-difluoro-3-methyl-7-oxo--2,3-dihydro--7H-pyrido[3,2,-ij- 1,3,4-benzoxadiazine-6-carboxylic acid, 9,10-dichloro-3-methyl-7--oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]l,3,4-benzoxadiazine-6-carboxylic acid, 9-chloro--lO-fluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido- [3,2,l-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, ethyl 9,10-d."fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido- [3,2,1-ij]-l,3,4-benzoxadiazine-6-carboxylate, 9,lO-difluoro-3-methyl-7-oxo-2,3-dihydro-H-pyrido- 13,2, l-ij 4-benzoxadiazine-6-carboxylate, 9,10-difluoro-3-(2--fluoroethyl)-7-oxo-2,3-dihydrc-7H-pyrido- [3,2,l-ij]-l,3,4--benzoxadiazine-6--carboxylic acid, 9, l0-difluoro-2, 3-dimethyl-7-oxo-2, 3-dihydro-7H-pyrido- [3,2,l-ij]-l,3,4-benzoxadiazine-6-carboxylic acid, 9, l0-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2, 3-dihydro- 7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, -17 9,10-difluoro-2-[(dimethylamino)methyl]-3-methyl-7-oxo-2.3dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, 9,l0-difluoro-2,2,3-trimethyl-7-oxo-2,3-dihydro-7H-pyrido- (3,2,2-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, and the like.

The amine of the formula (IV) used in the above reaction is, for instance, piperazine, 4-methylpipLerazine, 3-methylpiperazine, 3-phenylpiperazirie. 3-(4-aminophenyl)piperazine, 3-(4-nitrophenyl)piperazine, 4- (2-hydroxyethyl)piperazine, morpholine. 2-methylmorpholine, 2,6-dimethylmor- 0:00 pholine. thiomorpholine. 4-(aminomethyl)piperidine, 4-[(methylamino)methyl~piperidine- 4-[(ethylamino)methyl]piperidine. 4-aminopiperidine. 4-(methylamino)piperidine, 4- (ethylamino)piperidine, 4- (benzyloxycarbonylamino )piperidine, 4-(benzy'l~xycarbonylmethylamino)piperidine. 4-(benzyloxycarbonylethylamino)piperidine, 4-hydroxypiperidine, 4-methoxypiperidine. 4-(l-pyrrolyl)piperidine, homopiperazine,23-[(methylamino)methyllpyrrolidine, 3-[(ethylami)o')methyl]pyrrolidine, 3-(acetylaminomethyl)pyrrolidine, 3-hydroxypyrrolidine, 3-methoxypyrrolidine, 3-aminogyrralidine, 3- (benzyloxycarbonylamino)pyrrolidine, 3- (methyl- 25 amino)pyrrolidine, 3-( 1 enzyloxycarbonylmethylamino)pyrrolidine, 3-amino-4-phenylpyrrolidine, 3-amino-3-methylpyrrolidine. 3-amino-4-methylpyrrolidine. 3-(4-aminobenzylamino)pyrrolidine, 3-(4-methyl-l-piperazinyl)pyrrolidine, 3-[(dimethylamino)methyleneamino]pyrrolidine, 3-LI(methylamino)methyl]-4-phenylpyrrolidine, 3-methyl-3-[(methylamino)methylllpyrrolidine, 3-C ethylamino) pyrrolidine, 3-(benzyloxycarbonylethylamino)pyrrolidiie, 3.-4(dimethylamino)methyl]pyrrolidine. 3-[(ethylmethylamino)methyl]pyrrolidine. 3-azido-4-methoxypyrrolidine. 3-amino-4- -methoxypyrrolidine, 3-methoxy-4-(methylamino)pyrrolidine, 3-(ethylamino)-4-methoxypyrrolidine. 3-azido-4-hydroxypyrrolidine, 3-amino--4-hydroxypyrrolidine, 3-(methylamino)pi 18 -4-hydroxypyrrolidine, 3-(ethylamino)-4-hydroxypyrrolidine, 3-(aminomethyl)-4-methylpyrrolidine, 3-methyl-4-[(methylamino)methyl]pyrrolidine, 3-[(ethylamino)methyl]-4-methylpyrrolidine, 3-hydroxy-4-methoxypyrrolidine, 3-(acetylaminomethyl)-4-hydroxypyrrolidine, imidazole, 4-methylimidazole, N,N,N'-trimethylethylenediamine and the like.

Process B: The desired compound can be obtained by reacting a compound represented by the formula

OOR

t*o* 15 N

V

i 1 R N 2 15 OH NHR 1 2 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, with a carbonyl compounds represented by the general formula R3 i 25

R

C=o (vI)

R

o. '3 4 wherein R and R are the same as defined above, and amino groups present may be protected, or its polymer, acetal, ketal or enol ether, followed, if necessary, by removal of a protecting radical.

In Process B, the compound represented by the formula V as starting compound is a novel compound, and this compound can be produced according to the above reaction scheme a) or or reacting a compound or(Va)with an amine of the i I- 19 formula (IV).

i If the carbonyl compound of formula (VI) or its polymer, acetal, ketal or enol ether contains an amino or monoalkylamino substituent, said substituent may, if desired, be protected by a radical such as described above under R" in formulas and The reaction may, if desired, be carried out in a solvent, such as dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, 4Aimthyl S"r a L 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 15 presence of an acid catalyst such as acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic 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 S. like.

S The reaction temperature may be varied within a relati- 25 vely wide range. In general, the reaction is carried out at a temperature between 20 0 C and 150 0

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 or its polymer, acetal, ketal or enol ether per mole of the compound of the formula is employed.

The amino or monoalkylamino protecting radical may, if desired, be removed after the reaction by the procedures known to those skilled in the art. For example, the formyl l\ radical may be removed by acid or base hydrolysis preferably r- 1 -e 20 base hydrolysis and the benzyloxycarbonyl radical may be removed by hydrogenolysis., The starting materials represented by the formula (V) may be exemplified as follows: 6, 7-difluoro-8-hydroxy--(methylamino )-4-oxo-1, 4-dihydro- 3-quinolinecarboxylic acid, ethyl 6,7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-1,4dihydro-3--quinolinecarboxylate, benzyl 6,7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-1,4dihydro.-3-quinolinecarboxylate, 6, 7-dichloro-8-hydroxy-1- (methylamino) -4-oxo-1, 4-dihydro- 3-quinolinecarboxylic acid, 6-chloro--7-fluoro-8-hydroxy-l- (methylamino)-4-oxo-1, 4- 20 dihydro-3-quinolinecarboxylic acid, 6,7-difluoro--[I(2-fluoroethyl)amino]-8-hydroxy-4-oxo-1, 4dihydro-3-quinolinecarboxylic acid, 6-fluoro-8-hydroxy-7-(1--imidazolyl)-1--(methylamino)-4-oxo- ~4 -dihydro-3-quinolinecarboxylic acid, ethyl 6-fluoro--8-hydroxy-7-(-midazolyl)-1-(methylamino)-4oxo-1, 4-dihydro-3-quinolinecarboxylate, benzyl 6-fluoro-8-hydroxy-7-(l-imidazolyl)-l-(methylamino)- 4-oxo-l, 4-dihydro-3--quinolinecarboxylate, 6-fluoro-1-[(2-fluoroethyl)amino]-8-hydroxy-7-(l-imidazolyl)- 4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 21. 6-chloro-8-hydroxy-7- (l2-imidazolyl) -1-(me thylamino )-4-oxo- 1,.4-dihydro-3-quinolinecarboxylic acid, 6-f luoro-8-hydroxy-l- Cmethylamino)-7-(4-methyl-l-piperazinyl)-4-oxo-1,4--dihydro-3-quinolinecarboxylic acid, 7- (3.4-dimethyl-l-piperazinyl) -6-f luoro-8--hydroxy-l- (methylamino )-4-oxo-2.,4-d'ihydro-3-quinolinecarboxylic acid, lo0 7-[3-[(benzyloxycarbonylethylamino)methyl]--pyrrolidinyl..6fluoro-8-hydroxy-1-(metbylamino)-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid, 7-[3-(benzyloxycarbonylamino)--pyrrolidinyl]6.fluoro.8 hydroxy-l-methylamino)-4-oxo1,4dihydr3-quinolinecarboxylic acid, 7-t3-[(benzyloxycarbonylmethylamino)methyl]-4-methyl-l- 5 0 pyrrolidinyl]-6-fluoro-8-hydroxy-l-(methylamino)4oxo-1,4- 20 dihydro-3-quinolinecarboxylic acid, 7 3 -[Cbenzyloxycarbonylamino)methyl1-4-chloro-l-pyrrolidinyl]-6-fluoro-8-hydroxyl(methylamino)4oxo14-dihydro- 3-quinolinecarboxylic acid, and the like.

Examples of compounds which can be reacted with a compound of the formula are carbonyl compounds of formula (VI) such as formaldehyde, acetaldehyde, acetone, methyl J ethyl ketone, and the like their polymers such as paraformaldehyde, paracetaldehyde, trioxane, and the like their acetals such as dimethoxymethane, l.1-dimethoxyethane.

1,3-dioxolane, glycolaldehyde dimethylacetal, dimethylaminoacetaldehyde dimethylacetal, and the like their ketal such as 2,2-dimethoxypropane, and the like and their enol ether such as 2-methoxypropene, 2-trimethylsilyloxypropene and the like.

I j 22 Process C: When it is desired to manufacture compounds of formula I wherein the radical R R 6N- is a 5 to 7 membered 7 7.

heterocyclic ring containing a group -NR where R is other than hydrogen, such as in 70 R -N N-

(VIII)

wherein the piperazinyl radical may be substituted at 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)nCOR 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), the desired compound can be prepared by reacting a compound S 20 of formula I in which R 7 is hydrogen with an agent yielding the group R 70 This reaction, an N-alkylation (or an N-acylation), can be accomplished e.g. as follows: N-alkylation: A compound of the general formula oo II

(IX)

R.

R.

;l iilrii~-LC-- :.d i I; 23 1 2 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 groups present may be protected, can be reacted with a compound represented by the general formula 70 R -Y (X) wherein Y is a leaving group and R 7 0 is the same as defined above, 7 or (for obtaining compounds where R is the group R CO-CH 2

CH

2 (ii) with a Michael acceptor of the general formula 9 SR -CO-CH=CH 2

(XI)

20 wherein R is a lower alkyl radical or a lower alkoxy radical, 7 or (for obtaining compounds where R' is methyl or sulfomethyl) (iii) with formaldehyde and formic acid or an alkalimetal bisulfite.

N-Acylation: A compound of the above formula (IX) can be reacted with an anhydride of the general formula C O

(XII)

z 0

\CO/

C L. r I j -1 _1 i 24 wherein Z is an optionally substituted alkylene chain having 2 or 3 carbon atoms, or arylene radical, 7 so as to form a compound of formula I wherein R is

HOOC-Z-CO-.

All these reactions are followed, if necessary, by removal of a protecting radical, if present.

Thus, the desired compound can be prepared by reacting a compound represented by the formula (IX) with a compound represented by the formula 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 radi- 15 cals such as p-toluenesulfonyloxy; optionally nitrated phenoxy radicals suchXphenoxy, 4-nitrophenoxy; or succinimidooxy or phthalimidooxy.

If the compound of the formula contains an amino or 20 monoalkylamino substituent, said substituent may, if desired, be protected by a radical such as described above under R" in formulas and The reaction may, if necessary, be carried out in a 25 solvent such as dimethylformamide, dimethylacetamide, Nt c<uner pyrops\ elabre dimethylsulfoxide, dimthyl a pr"-rt A dioxane, tetrahydrofuran, pyridine and the like. Mixtures of two or more solvents may also be used.

S.

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, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydride, alkali metal hydroxides, alkali metal carbonates and the like.

APUi 1 ?4 The reaction temperature may be varied within a relati- S vely wide range. In general, the reaction is carried out at a temperature between about 0 0 C and 180 0 C, preferably betr -I i ween 0 C and 110 0 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 is employed, based on one mole of the compound of the formula (IX).

The compound of the formula used in the present invention can be iodomethane, iodoethane, bromoethane, 1-iodobutane, 1-bromobutane, l-iodopropane, 2-iodopropane, 1-fluoro-2-iodoethane, l-iodo-2-methoxyethane, N-(2-iodoethyl)acetamide, N-(2-iodoethyl)-N-methylacetamide, bromoacetic 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-nitrophenyl ketone, 4-nitrobenzyl bromide, dimethylcarbamoyl chloride and the like.

I Alternatively, the desired compound can be prepared by reacting a compound of the formula (IX) with a Michael acceptor of the formula (XI).

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.

The reaction temperature may be varied within a relatively wide range. In general, the reaction is carried out at a temperature between about 30 0 C and about 170 0 C, preferably between 50 0 C and 140 0

C.

r i 26 In 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).

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 formic acid or an alkalimetal bisulfite (whereby compounds of formula I in which R 7 is methyl or sulfomethyl are obtained) is normally carried out at slightly elevated temperature, e.g. at about +50°C to +100 0

C.

15 Moreover, the desired compound can be produced by reacting a compound of the formula (IX) with an anhydride of Sthe formula (XII).

4 The reaction may, if necessary, be carried out in a 20 solvent such as pyridine, dimethylformamide, dioxane, tetrahydrofuran and the like. Mixtures of two or more solvents m;ay 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, 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 OOC and 120 0 C, preferably between 0°C and 100 0

C.

In carrying out the process provided according to the 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.

r i- 27 The anhydride used in the present invention is e.g.

succinic anhydride, glutaric anhydride, N-benzyloxycarbonylaspartic anhydride, N-benzyloxycarbonylglutamic anhydride, phthalic anhydride and the like.

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 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:

i SWhen it is desired to manufacture a compound of formula 6 I in which R and/or R are lower alkyl (or contain a di-lower alkylamino or lower alkoxy group) these compounds can be manufactured by lower alkylating the corresponding non-alkylated compound viz. a compound of formula I wherein 5 6 R and/or R 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 10 R Y (XIII) S wherein R is lower alkyl and Y is a leaving group.

The leaving group is of the same type as that employed in the compounds of formula Also, the reaction can be carried out in the same manner as the alkylation reaction of the compounds (IX) with described above. The O-alkylation is effected as the N-alkylation; however, expediently a proton acceptor such as an alkali metal hydride e.g. sodium hydride is added.

L 28 Process E: When it is desired to manufacture a compound of formula 6 I in which R R N- is a 5 to 7 membered heterocyclic ring with an -SO- or -SO member these compounds can be manu- 2 factured by oxidizing the corresponding desoxy-compounds of formula I viz, with an member in the heterocycle.

The oxidation is carried out by treatment with an organic or inorganic oxidizing agent. Various compounds which readily yield oxygen can be used as the oxidizing agent; for example, organic peroxides such as monosubstituted organic peroxides C -C 4 -alkyl- or alkanoylhydroperoxides 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 a C -C 4 alkyl or alkoxy group), a halogen atom or a carboxy group (e.g.

20 4-methylperbenzoic acid, 4-methoxy-perbenzoic, 3-chloroperbenz'oic 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 sodium, potassium or ammonium hypochlorite, peroxymonosulphuric and peroxydisulphuric acid. The use of 3-chloroperbenzoic 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 chloride, chloroform or ethyl acetate. The oxidation is generally carried out at a temperature in the range of -20 0

C

to +50 0

C.

When the oxidizing agent is used in equimolar amounts or in slight excess in relation to the starting material there is mainly obtained the corresponding sulfoTide, i.e. a compound of formula I in which the heterocycle contains an i 1 29 -SO- member. When the amount of oxidizing agent is increased to double the stoichiometric ratio or more, there is obtained the corresponding sulfone, i.e. a compound of formula I in which the heterocycle contains an -SO 2 member. It is also possible to obtain the sulfone from the corresponding sulfoxide by treatment with an equimolar or greater amount of the oxidizing agent.

Process F: 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, t-butoxycarbonyl or ethoxycarbonyl; a substituted alkoxycarbonyl group, 20 e.g. trichloroethoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl; or a halogen-alkanoyl group such as trifluoroacetyl.

The amino protecting groups may be cleaved off by acid hydrolysis the t-butoxycarbonyl or trityl group) or by basic hydrolysis the trifluoroacetyl group). Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl are removed by Shydrogenolysis.

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 hydrolysis is generally carried out at room temperature, i. i. i 30 although it can be carried out at a slightly higher or slightly lower temperature a temperature in the range of about 0 0 C to +40 0 Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30 0

C.

Carboxy-protecting groups are e.g. the carboxy-protec- 1 ting radicals discussed under R above.

I0 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 15 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 O°C to room temperature with or without a co-solvent, such as methylene chloride; or allyl removed by a palladium catalyzed transallylation reaction in the presence of sodium or potassium salt of 2-ethyl Shexanoic acid, see for example J. Org. Chem. 1982, 47, 587.

Process

G:

When it is desired to manufacture a compound of formula I containing a halogen atom, such as a compound where R R6N- is Cl- this compound can be manufactured by halogenating a correcespondifly hyd-roxy-substituted compound where R 5

R

6 N- is HO- The halogenating agent is preferably a thionyl halide, especially thionyl chloride; or phosphorous trichloride, phosphorous oxychloride or phosphorous pentachloride. The reaction temperature is 31 preferably between about 0 0 C and 80 0 C. Carboxy groups present are preferably protected, e.g. benzylated, and subsequently, if desired, again set free e.g. by hydrogenation (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 R5RN- is H N- -CH 2 -N this compound can be manufacturc- 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 15 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 0 C and about 40 0 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

R

N-CH=N-

R

5 1 (wherein R 5 0 and R 5 1 are as above) such as a compound where R 5

R

6 N- is (CH 3 2 N-CH=N- this compound can be manufactured by reacting the amino group of a correspondingly amino substituted compound of formula I where R 5

R

6 N- is H 2 N- with a reactive derivative of a formamide derivative of the general formula I -32- N-CHO (VII)

R

5 1 51 wherein R and R are as above.

As reactive derivative of a compound of the formula VII can be employed the corresponding di-(lower alkyl)acetals such as the dimethyl acetals. The reaction is preferably performed in an inert solvent such as diethyl ether, dimethylformamide or dimethylsulfoxide. The temperature is preferably about room temperature but can lie well below or above, e.g. in the range of about 0OC and 100 0

C.

Process J: Manufacture of esters of formula I i.e. where R is a carboxy-protecting group can be effected by reacting a carboxylic acid of formula I with a corresponding halide, preferably an iodide or bromide, containing the desired ester group. The reactions can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide or, especially, dimethyl- 'formamide. The reaction is preferably carried out at a temperature in the range of about 0 C-40 0

C.

U Process K: The manufacture of the pharmaceutically acceptable salts of the compounds of formula I or the hydrates or solvates of said salts can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base or conversely, a free base of formula I with an organic or inorganic acid. The reaction is conveniently carried out in a solvent such i 33 as water or an organic solvent 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 0 0 C to +50 0

C.

Examples of -rayacceptable acids useful in the above process are hydrochloric, hydrobromic, 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, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, gluconic, glucuronic, galacturonic, aspartic and glutamic acid methionine, tryptophan, lysine, arginine, and the like.

0* 0 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 can be prepared by reacting a compound of the formula with a 25 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 diethanolamine, dibenzylethylenediamine, choline, ethylenediamine and the like.

The acid addition salts or base salts of the compounds of the formula differ from the corresponding free form in certain physical properties such as solubility in water.

The compounds of the formula and their pharmaceuti- Scally acceptable salts can exist in unsolvated as well as L i 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 controlled manufacture of a hydrate a completely or partially anhydrous product can be exposed to a moist atmosphere at about +10°C to +40 0 Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained during e.g. crystallization.

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 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 representative pyrido[3,2,1-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 jLg/ml) are shown in Table 1 and Table 2. The compounds used here were produced by respective Examples as mentioned below.

S

.04 5** S. S S *SS S S *0* S S 550 S TABLE 1 Antibacterial spectrum MIC (Ucj/ml I Compound (Example No.) Aerobic microorganisms 5 6 7 8 9 12 13 15 16 17- 18 19 21 Gram-positive bacteria Bacillus subtilis PCI 219 0.05 0.10 0.10 0.025 <0.0008 0.10 <0.0008 0.05 0.20 0.013 0.013 0.05 0.05 Staphylococcus aureus FDA 209P ,JC-1 0.39 Staphylococcus aureus NR 2855 0.20 Staphylococcus aureus Smith 0.20 Staphyl ococcus epidermidis IFO 12993 0.39 0.39 0.39 0.39 0.20 0.10 0.10 0.78 0.39 0.05 0.05 0.39 0.39 0.78 6.25 0.20 0.10 0.29 0.20 0.39 0.39 0.025 0.025 0.20 0.39 3.13 1.56 0.39 0.0065 0.78 0.05 0.39 0.20 0.20 0.0033 0.10 0.025 1.56 0.78 0.39 0.20 0.39 0.10 0.8 15 020 .0 039 .9 0.78 1.56 0.20 0.10 0.39 0.39 ML ,L TABLE 1 -continued Antibacterial spectrum MIC (Uq/ml) Compound (Example No.) Aerobic microorganisms 5 6 7 8 9 12 13 15 16 17 18 19 21 Staphylococcus epidermidis NR 2942 0.39 1.56 Enterococcus Eaecalis NR 2943 3.13 12.5 Gram-negative bacteria Alcaligenes faecalis IFO 13111 0.39 3.13 Zitrobacter freundii IFO 12681 0.013 0.013 0.78 0.39 0.0065 0.39 0.05 0.78 1.56 0.10 0.10 0.39 0.39 12.5 6.25 12.5 3.13 3.13 6.25 25 3.13 50 1.56 1.56 6.25 3.13 6.25 6.25 6.25 0.78 6.25 0.78 6.25 s0 3.13 0.05 0.025 0.39 0.78 0.39 0.5 0.2 .3 .8 .9 0.05 0.10 0.20 0.10 1.56 0.78 S 555 S *5 S S S S 55 55 S S S S S S S **S S S S S S S S S TABLE 1 continued Antibacterial spectrum MIC (Ug/mi) Compound (Example No.) Aerobic microorganisms 5 6 7 8 9 12 13 15 16 17 18 19 21 Enterobacter aerogenes NR 294.5 Enterobacter cloacae NR 2946 Escheri chia coli NIHJ JC-2 Escherichia.

coli NR 2630 Klebsiella, pneumoni ae FDA PCI 602 0.013 0.013 0.05 0.025 0.0065 0.20 0.20 0.05 0.05 0.05 0.05 1.56 0.20 0.025 0.025 0.10 0.05 0.013 0.78 0.39 0.10 0.10 0.10 0.20 o 0.05 1.56 0.78 0 .025 0'.013 0.025 0.025 0.10 0.02S 0.05 0.10 0.013 <0.0008 0.20 0. 10 0.39 0.10 0.025 0.05 0.013 1 .56 0.39 0.39 0.20 0.10 00 0.10 0.39 0.20 3.13 3.13 0.78 39 15 078 .9 625 .8 -3.39 1.56 O 78 0.39 6.25 0.78 a a a a a a a a a a a a a a a a. a a a a a a a a a TABLE 1 continued Antibacterial spectrum HIC (Luo/1 1 Compound (Example No.) Aerobic microorganisms 5 6 7 8 9 12 13 i5 1G 17 18 19 2'l Bordetel la bronchi septica. ATCC 4617 0.20 6.25 3.13 0.39 1.56 Proteus rettgeri ATCC 14505 0.20 0.10 0.78 0.39 1.56 Proteus vulgaris OX19 ATCC 6898 0.013 0.013 0.025 0.025 <0.0008 Pseudomonas aeruginosa A3 0.20 0.10 0.20 0.39 6.25 Pseudomonas aerugi nosa, NR 2950 0.78 0.78 3.13 3.13 12.5 6.25 0.78 12.5 0.78 0.10 0.05 0.78 1.56 12.5 6.25 0.78 25 6.25 3.13 6.25 0.78 0.78 1.56 1.56 0.39 3.13 0.78 0.025 0.10 0.025 0.025 0.39 0.05 0.78 0.39 0.39 0.78 6.25 1.56 3.13 6.25 6.25 6.25 25 3.13

I

p I p p p p p **p p p p p p ppp p TABLE continued Antibacterial spectrum MIC 1 ig/ml) Compound (Example No.) Aerobic microorganisms 5 6 7 8 9 12 13 15 16 17 18 19 21 Pseudomonas stutzeri IFO 12695 0.025 0.025 0.05 0.025 <0.0008 0.10 0.05 0.05 0.025 0.025 0.39 0.20 Serrati a marcescens IFO 126418 0.10 0.10 0.20 0.10 0.78 3.13 0.39 0.39 0.39 0.78 0.39 3.13 0.39 Salmonella typhimuri um IFO 12529 0.25 0.013 0.05 0.025 0.0033 0.20 0.10 0.05 0.10 0.05 0.025 1.556 0.39 0

S

S S S S S *S S S S S **C S*C S TABLE 1 continued Anti bacterial spectrum MIC (iLli/111 Compound (Example No.) Aerobic microorganisms 22 24 25 26 27 30 31 32 33 M~ 35 36 Gram-positive bacteria Bacillus subtilis PCI 219 0.05 0.39 0.78 0.78 0.39 0.025 0.05 0.05 0.20 0.05 0.05 0.025 Staphylococcus aureus FDA 209P JC-l 0.20 Staphylococcus aureus NR 2855 0.39 Staphylococcus aureus Smi th 0.20 Staphyl ococcc:.

epidermidis IFO 12993 0.39 1.56 6.25 3.13 1.56 0.05 0.39 6.25 12.5 1.56 12.5 0.39 0.78 0.20 0.20 0.20 0.39 0.39 0.39 1.56 1.56 1.56 0.10 0.10 0.20 0.20 0.39 0.10 0.39 0.78 0.78 0.78 0.20 1.56 1.56 3.13 1.56 0.05 0.20 3.13 6.25 3.13 6.25 0.20 0.39 S. SO

**S

0 0 0*.

S

0S 0S *50 0 0 0 S 0 0 0 0 5 5 5 *0* S S 0 S 050 005 0 TABLE 1 continued Antibacterial soectrum MIC (tni) Compound (Example No.) Aerobic microorganisms 22 24 25 26 27 30 311 32 33 34 35 36 Staphyl ococus epi dermidis NR 2942 0.20 Enterococcus faecalis NR 2943 3.13 2 Gram-negative bacteri Al cal igenes faecalis IFO 13111 3.13 2 Citrobacter freUndii IFO 12681 0.10 3.13 6.25 3.13 6.25 0.20 0.39 .5 100 25 50 3.13 12.5 a .5 50 12.5 50 1.56 3.13 1.56 0.78 0.78 0.20 0.013 0.05 0.39 0.78 0.78 0.78 0.20 6.25 3.13 6.25 6.25 3.13 1 .56 50 50 25 3.13 0.10 0.20 0.20 0.20 0.20

L

a 0* a* *0 O* .C r S 0 TABLE 1I continued Antibacterial spectrum MIC (jig/nil) Compound (Example No.) Aerobic microorganisms 22 24 25 26 27 30 31 32 33 34 35 36 Enterobacter aerogenes NR 2945 0.10 0.78 Enterobac ter cloacae NR 2946 0.10 3.13 Escheri chia coli NIHJ JC-2 0.10 1.56 Escheri chi a coli NR 2630 0.025 0.78 Kiebsiella pneumoni ae FDA PCI 602 0.39 6.25 0.39 0.20 0.20 0.0033 0.25 0.25 0.05 0.10 0.10 0.05 0.78 0.78 0.78 0.013 0.05 0.10 0.20 0.20 0.39 0.10 0.78 0.39 0. 78 0.20 0.78 0.013 0.0065 0.05 0.025 0. 10 0.25 0.20 0.10 0.20 0.10 0. 10 0. 10 0.10 0.05 3.13 3.13 3.13 0.10 0.20 03 .8 07 .6 03 0.39 0.78 0.78 1.56 0.39 L- 4. 4* a C. C

C

*CG

*9 C

C

a C C C* a a a .a* a a a C CCC C TABLE 1 continued Antibacteriajl soectrum11 MIC (tIci/Ml) Compound (Example No.) Aerobic microorganisms 22 24- 25 26 27 30 31 32 33 34 35 36 Bordetella bronchiseptica ATCC 4617 1.56 Proteus rettgeri ATCC 14505 0.78 .Proteus vulgaris 0X19 ATCC 6898 0.001 Pseudomonas aeruginosa A3 1.56 Pseudomonas aerugi nosa NR 2950 6.25 50 12.5 100 12.5 25 1.56 3.13 0.39 .*1.56 25 25 12.5 .0.39 6.25 12.5 0.10 1.56 1.56 3.13 3.13 0.78 65 0.39 0.10 0.39 0.20 0.0065 0.025 0.025 0.05 0.05 0.05 0.025 3.13 3.13 6.25 3.13 0.05 0.20 0.39 0.39 0.78 1.56 0.78 25 550 50 25 0.20 1.56 31 .5 62 25 62 3.13 6.25 6.25 12.5 6.25 0:6 0% TABLE 1 -continued Antibacterial spectrum MIC hio/ml) Compound (Example No.) Aerobic microorganisms 22 24 25 26 27 30 31 32 33 34 35 36 Pseudomonas stutzeri IFO 12695 0.10 0.39 0.78 0.20 0.0033 0.025 0.10 0.10 Serrati a marcescens IFO 12648 0.78 6.25 3.13 1.56 3.13 0.05 0.20 0.39 0.78 0.78 1.56 0.39 Salmonel ia typhimuri um IFO 12529 0.10 0.78 0.20 0.78 0.39 0.0065 0.025 0.025 0.10 0.10 0.10 0.10 L- r %qI

S

S

*SS *5S 9 S S S S S S TABLE 1 continued Anti bacteria(l spectrUm MIC (jig/nil) Compound (Example No.) Aerobic microorganisms 37 38 39 40 41 42 43 44 45 46 48 49 Gram-positive bacteria Bacillus subtilis PCI 219 <0.0008 Staphylococcus aureus FDA 209P JC-l 0.0016 Staphylococcus aureus NR 2855 <0.0008 Staphylococcus aureus Smith <0.0008 Staphyl ococcs epi dermidis IFO 12993 0.025 <0.0008 0.025 0.10 3.13 0.05 0.10 0.05 0.39 0.05 0.05 3.13 0.78 1.56 0.78 0.39 6.25 0.39 0.39 1.56 6.25 0.39 0.78 0.20 0.10 0.78 0.78 6.25 0.39 0.78 0.39 3 .13 0.39 0. .9 12.5 0.39 0.78 6.25 0.39 0.39 0.39 0.78 0.39 0.20 6.25 0.39 0.39 1.56 6.25 0.39 0.39 07 .3 07 .9 1. 0.78 3.13 0.78 0.39 12.5 L_ O.L. 9 S 59 S S S S S S S S S S S TABLE 1 continued Anti bacteria- l spectrumil I (Iln/mi) Compound (Example No.) Aerobic microorganisms 37 38 39 40 41 42 43 441 45 46 48 49 Staphylococcus epidermidis NR 2942 <0.0008 Enterococcus faecalis NR 2943 3.13 12 Gram-negative bacteria Al cal i genes faecalis IFO 13111 12.5 0.39 0.39 0.78 12.5 2.5 12.5 12.5 100 6.25 6.25 6. 25 s0 0.39 0.39 6.25 6.25 1.56 0.78 0.39 3.13 0.39 0.78 12.5 12.5 50 6.25 6.25 100 1 .56 12.5 1 .56 3.13 100 Ci trobacter freundii IFO 12681 0.78 6.25 0.78 0.20 0.39 00 .0 02 .0 01 .9 03 0.05 0.10 0.20 0.10 0.10 0.39 0.39 a.

S

5*9

S

S S a S 55 .5 S S S S .55 TABLE 1 continued Antibacterial soectrum MIC W g/ml) Compound (Example No.) Aerobic microorganisms 37 38 39 40 41 42 413 44 4-5 46 48 49 Enterobacter aerogenes NR 2945 Enterobacter cloacae NR 2946 Escheri chi a coli NIHJ JC-2 Escherichia.

coli NR 2630 Klebsiella pneumoni ae FDA PCI 602 0.10 3.13 0.05 0.10 0.10 0.025 0.10 0.20 6.25 0.78 0.39 0.78 0.05 0.10 0.10 6.25 0.78 0.39 0.78 0.05 0.10 0.10 0.05 0.10 0.39 0.39 0.20 0.20 0.20 0.39 0.78 0.20 0.20 0.10 0.39 1.56 0.05 0.10 0.05 0.10 0.39 0.39 0.39 0.78 1.5G 1.56 <0 .0008 0.39 0.025 0.20 0.39 0.025 0.05 3.13 25 1.56 1.56 3.13 0.39 0.39 I

A

4

I

p S S S S S S S S S S S S S S S S S S S *CS S TABLE 1 continued t f Antibacterial spectrum MIC (Ugq/111) Compound (Example No.) Aerobic microorganisms 37 38 39 40 41 4-2 '13 44 45 46 48 49 Bordetell1a bronchiseptica. ATCC 4617 1.56 6.25 Proteus rettgeri ATCC 14505 6.25 25 Proteus vulgari~l fX19 ATCC 6898 0.0008 3.13 Pseudomonas aeruginosa A3 6.25 25 Pseudomonas aerugi nosa NR 2950 25 50 0.78 1.56 25 3.13 3.13 3.13 0.05 0.20 1-56 0.39 0.39 0.39 12.5 0.39 6. 25 0.39 0.78 1.56 0.78 1.56 3.13 3.13 0.025 0.10 0.10 0.10 0.05 0.39 0.78 0.39 0.78 0.78 0.78 1.56 3.13 3.13 3.13 .56 3. 13 12.5 12.5 12.5 125 1. 253.13 6.25 6.25 6.25 6.25 S. *S

S

*5 S

S

5*U S S S *5 *S S S S S S S S S S*S TABLE 1 continued Antibacterial spectrum MIC (1;Q/ml) Compound (Example No.) Aerobic microorganisms 37 38 39 40 41 12 4-3 4-4 4-5 46 48 49 Pseudomonas stutzeri IFO 12695 0.013 6.25 C.10 0.20 0.05 1.56 Serrati a marcescens IFO 12648 0.78 12.5 1.56 1.56 3.13 0.10 0.20 0.39 0.78 0.39 1.56 3.13 Salmonella typhimuri um IFO 12529 0.20 6.25 0.20 0.39 0.78 0.025 0.10 0.20 0.10 0.10 0.39 0.39 L- Mg. MMMMMUk___ a. a a a a a S a a a a a a TABLE 1 continued Antibacterial spectrum MIC (pjq/ml) Compound (Example No.) Aerobic microorc-anisms 50 51 52 53 54 56 59 63 69 Gram-positive bacteria Bacillus subtilis PCI 219 0.0065 Staphylococcus aureus FDA 209P JC-l 0.39 Staphylococcus aureUs NR 2855 0.39 Staphylococcus aureus Smith 0.10 Staphylococcus epi dermi di s IFO 12993 0.39 00 0.10 0.20 0.025 0.025 0.20 0.0065 0.78 0.20 0.20 0.39 0.10 0.013 0.39 0.39 0.78 1.56 1.56 3.13 0.10 0.20 0.78 0.10 3.13 1.56 0.39 0.39 0.05 0.025 0.39 0.05 0.39 0.78 0.78 1.56 0.10 0.10 0.9 .3 56 16 0.39 0.39 1.56 1.56

UMMMMEL

A

S S S S S S S S S S S S

S

S. 55 5 S

S..

S

TABLE 1 continued Antibacterial spectrum MIC (Upq/mi) Compound (Example No.) Aerobic microorganisms 50 51 52 53 54 56 59 63 69 Staphylococcus epidermidis NR 2942 0.20 0.78 Enterococcus faecalis NR 2943 3.13 12.5 Gram-negative bacteria Al cal i enes faecalis IFO 13111 12.5 3.13 Citrobacter freundii IFO 12681 3.13 0.025 1.56 0.10 0.10 0.39 0.20 0.78 1.56 1.56 1.5G 12.5 3.13 25 12.5 12.5 3.13 6.25 3.13 6.25 100 3.13 0.025 0.10 0.10 0.10 1.56 0.8 01 0.78 0.10 r p p

S

S

asp ep. p p p S P* PP S P S p p p p p p p p 9 P p 0 p TABLE continued Anti bacterial soectt-Rum MIC (ugq/mi) Compound (Example No.) Aerobic microorganisms 50 51 52 53- 54 56 59 63 69 Enterobacter aerogenes NR 2945 Enterobacter cloacae NR 2946 0.78 0.025 0.025 0.10 0.025 0.10 a.78 0.39 0.10 1.56 0.05 0.05 0.20 0.10 0.05 0.78 1.56 0.20 Escheri chi a coli NIHJ JC-2 Escherichia coli NR 2630 Klebsiella pneumoni ae FDA PCI 602 1.56 0.10 0.05 0.20 0.10 0.10 1-56 1.56 0.20 6.25 0.025 0.025 0.05 0.025 0.0065 0.39 0.78 0.10 0.20 0.20 0.39 0.78 0.39 3.13 6.25 0.39 4 4. 4.

4 0

*R*

0 .4 0 4 4 4 *04 .40 *1:

SO

9 9 0 B 44 S 4 4 0 *44 4 4 4 4 404 444 4 TABLE continued Antibacterial soectrun MIC (J.Ig/ml) Compound (Exanmple No.) Aerobic microorganisms 50 51 52 53 54 56 59 63 69 Bordetella bronchi septica ATCC 4617 Proteus rettgeri ATCC 14505 Proteus vulgaris 0X19 ATCC 6898 Pseudomonas aeruginosa A3 Ps eud omonas aerug inosa NR 2950 2 3.13 1.56 6.25 0.78 3.13 6.25 0.20 0.20 1.56 0.78 0.39 0.025 0.025 0.10 0.13 6.25 0.10 0.20 0.78 0.20 3.13 3.13 1 .56 3.13 0.013 0.20 13 3.13 50 0.78 6.25 0.78 0.39 0.05 3.13 0.78 5 1.56 1.56 12.5 1.56 6.25 25256 25 6.25

'U

0

U

0* U

U

U

**U

U..

U S S U S U U SO U U U U U U U C 550 S U U U

U

TABLE 1 continued Antibacterial spectrumn MIC (jig/nil) Compound (Example No.) AerGbi c microorganisms 50 51 52 53 54 56 59 63 69 Pseudomonas Stutzeri IFO 12695 0.05 0.05 0.20 0.013 0.0033 1.56 0.39 0.20 Serrati a marcescens IFO 12648 3.13 0.10 0.20 0.78 0.39 0.78 3.13 3.13 0.20 Salnmonel la typhimuriurn IFO 12529 0.78 0.025 '3.025 0.10 0.025 0.05 1.56 0.78 0.10 39 TABLE 2

S

*9 *9 *59.

S

*5

C..

Antibacterial spectrum MIC (-itg/ml) Compound (Example No.) Bacteroides fragilis ATCC 23745 0.78 0.20 Bacteroides fragilis NR 2579 3.3 1.56 Bacteroides fragilis 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 gsALL 40 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 g were infected by intraperitoneal injection of a corresponding bac:terial suspension. The test compounds were administered orally or subcutaneously at the time of injection.

The mortality was observed for 5 days. The respective 1 effective dose (ED 50 mg/kg) which protects 50% of the animals from death caused by infection, is shown in Table 3.

15 Table 3 '*Ii In vivo Antibacterial Activities Against Systemic Infection in Mice (EDS. mg/kg) e S 25 Bacterium Escherichia Pseudomonas Streptococcus Compound coli aeruginosa pneumoniae ML4707 4au542 6-001 s.c. p.o. 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 LD50 values of the compounds obtained in Examples 5, 6, 7, 16, 17, 18, 30, 36 and 56 as mentioned below are more than 2000 mg/kg. The acute toxicity of these compounds was examined by oral administration in ICR mice.

i i- -I 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 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.

SFor 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, Pepto- Scoccus, Peptostreptococcus, Propionibacterium, Escherichia, 25 Citrobacter, Campylobacter, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bacteroides, Fusobacterium, Myco- J plasma and other microorganisms.

The present invention further relates to the pharmaceutical compositions containing one or more compounds of the present invention.

The compounds of the present invention can be administrated orally or non-orally to human beings or animals by various conventional administration methods.

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, any forms which are pharmaceutically acceptable can be employed.

o. 15 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.

too The medical composition according to the present t'o invention may be formulated in a combination of the compound t 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 mg 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.

I L -43 Preparation of starting materials Reference example Preparation of diethyl N-(3,4-difluoro-2-hydroxyphenyl)aminomethylenemalonate A solution of 2,3-difluoro-6-nitrophenol (500 mg) in methanol (7 ml) was hydrogenated over 5% Pd/C (60 mg) for 6 hours. The reaction mixture was filtered under nitrogen stream and the filtrate was evaporated under reduced pressure to give 414 mg of crude 2-amino-5,6-difluoropheLlol.

A mixture of the above amine (414 mg) and diethyl ethoxymethylenemalonate (618 mg) was heated at 130 0 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, mp 178-180°C; MS m/z 315 Additional 59 mg of the crystals were obtained after silica I 20 gel column chromatography of the mother liquid using CHC1 /acetone (20:1) as the eluent.

3 Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3quinolinecarboxylate (Route 1) To a mixture of diethyl N-(3,4-difluoro-2-hydroxyphenyl)aminomethylenemalonate (80 mg) and anhydrous S. potassium carbonate (70 mg) in dry dimethylformamide ml) was added benzyl bromide (30 il). The mixture was 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 residue was washed with n-hexane and recrystallized from methanol to give diethyl N-(2-benzyloxy-3,4-difluorophenyl)aminomethylenemalonate (90 mg), mp 87 0 C; MS m/z 405 r i F- 1 p.- ~I -44 A solution of the above malonate (280 mg) in diphenyl ether (2.8 ml) was heated at 250 0 C for 30 minutes under nitrogen atmosphere. After cooling the reaction mixture, the ethanol generated in reaction medium was removed under 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 The pure fractions were combined and the solvent was removed under reduced pressure to give the crystalline 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 0 C; MS m/z 359 (M was prepared by recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3quinolinecarboxylate (Route 2) To a stirred solution of ethyl 6,7-difluoro-4,8- 20 -dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 ml), was added anhydrous potassium carbonate (308 mg) and then benzyl chloride (145 1l). The mixture S. was stirred at 55-65 0 C for 11 hours. The reaction mixture was diluted with water (30 ml) and extracted with chloroi 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 200-201OC; MS m/z 359 after recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-l-(formylmethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate After a mixture of ethyl 8-benzyloxy-6,7-difluoro-4- -hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide r- i 45 ml) was stirred at room temperature for 3 hours, 0-(2,4-dinitrophenyl)hydroxylamine (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 (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 1-amino-8-benzyloxy- -6,7-difluoro-4-oxo-1,4-dihydro -3-quinolinecarboxylate. An analytical sample, mp 143-144C; MS m/z 374 (M was 'i prepared by recrystallization from methanol.

I 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 It 4 S. 15 minutes, at 50 0 C for 15 minutes, and then cooled to o0C. To .this solution was added dropwise a solution of the above I 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 crystalline residue, which was recrystallized from ethanol to give 410 mg of ethyl 8-benzyloxy-6,7-difluoro-l-(formyl- Fl amino)-4-oxo -1,4-dihydro-3-quinolinocarboxylate, mp \188-190°C; MS m/z 402 (M 25 A mixture of the above formamide (400 mg), anhydrous Spotassium 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 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- -difluoro-l-(formylmethylamino)-4-oxo-l,4 -dihydro-3-quinolinecarboxylate, mp 180-181C; MS m/z 416 (M i I i 46 Preparation of 6,7-difluoro-8-hydroxy-1-(methylamino)-4oxo-1,4-dihvdro-3-quinolinecarboxylic acid Ethyl 8-benzyloxy-6,7-difluoro-1-(formylmethylamino)-4- -oxo-1,4 -dihydro-3-quinolinecarboxylate (330 mg) was hydrogenated 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 chloroform/methanol The combined filtrate was evaporated 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 OC MS m/z 326 (M A mixture of the above ester (210 mg) and 0.5N sodium 4 hydroxide (5.2 ml) was heated at 100 0 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 bit 20 pressure to give 168 mg of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro -3-quinolinecarboxylic acid. An analytical sample, mp 248-250 0 C MS m/z 270 (M was prepared by recrystallization from ethanol.

Example 1 Preparation of 9,10-difluoro-3-methl-7-oxo-2,3-dihydro-7Hpyridof3,2,1-ifi-1,3,4-benzoxadiazine-6-carboxylic acid A mixture of 6,7-difluoro-8-hydroxy-1-(methylamino)-4- -oxo-1,4-dihydro -3-quinolinecarboxylic acid (105 mg) obtained in Reference example paraformaldehyde (150 mg) and dry dioxane (5 ml) was heated at 100 0 C for 3 hours under nitrogen atmosphere. After removal of the solvent under 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- 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- -dihydro -7H-pyridol3,2,1-ij]-1,3,4--benzoxadiazine-6- -carboxylic acid. An analytical sample, mp 290-292 0

C

MS m/z 282 was prepared by recrystallization from dimethylformamide.

Example 2 Preparation of 9,10-difluoro-2 -dimethyl-7-oxo-2 .3dihydro-7H-pyridor3,2,1-iil-1,3,4-benzoxadiazine-6-carboxylic acid A mixture of 6,7-difluoro-8-hydroxy-l--(methylamino)-4- -oxo-1.4-dihydro -3-quinolinecarboxylic acid (50 mg) obtained in Reference example 90% acetaldehyde (1 ml) and dioxane (5 ml) was heated at 100 0 C for 3 hours under nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure to give 52 mg of 9,10-difluoro-23- -di- d i me t hy l- 7 oxo hyd o -7H--pyd-2,2. 3- ,3,4- -benzoxadiazine-6-carboxylic acid. mp 285-289 0 C; MS m/z 296 Example 3 Preparation of 9,10-difluoro-2-(hydroxymethyl)-3-methyl- 7-oxo-2,3-dihydro-7H-pyridor3,2,1-ii1-1.3,4-benzoxadiazine-6carboxylic acid A suspension of 6.7-difluoro-8-hydroxy-l-(methylamino)- -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference example Ci), glycolaldehyde diethylacetal (45 i.l) and pyridinium p-toluenesufonate (7 mg) in dry dioxane (2 ml) was heated at 1100C for 5 hours under nitrogen atmosphere. After the solvent was removed under reduced pressure, the crystalline residue was washed with 1.8 ~0680917M, 111 zAxMA n~sibdou Wjj!! q E1 ap:)q o 11112 111.4 .6zAXMAnisOdoNW1)IIHOdAQA()V 'Id 011.5 -48 water and methanol to give 52 mg of 9,10-difluoro-2- -(hydroxymethyl)- 3-methyl-7-oxo-2.3-dihydro-7H-pyridobenzoxadiazine-6-carboxylic acid, mp 254-258 0 C MS m/z 312 Example 4 Preparation of 9,10Z-difluoro-2-f(dimethylamino)methyl1- 3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-iil-1,3,4-benzoxadiazine-6-carboxy lic 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 dimethylaminoacetaldehyde dimethylacetal (37 mg) and p-toluenesulfonic acid monohydrate (53 mg) in dry dioxane (2 ml) was heated at 110 0

C

for 17 hours under nitrogen atmosphere. After the solvent 1' was removed under reduced pressure, the residue was recrystallized from methanol to give 61 mg of 9,10-difluoro- -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 0 C FAB-MS m/z 340 (MHi).

Example Preparation of 9-fluoro-3-methyl-l0-(4-methyl--piperazinyl)-7-oxo-2,3-dihvdro-7H-pvridor3,2,1-iil-1,3,4-benzoxadiazine-6-carboxylic acid A mixture of 9. l0-difluoro-3-.-methyl-7-oxo-2. 3-dihydro -7H-pyiido[3.2,l-ij]-l.3.4-benzoxadiazine-6-carboxylic acid mg) obtained in Example 1, N-methylpiperazine (47 ugl) and dry pyridine (3 ml) was heated at 100-110 0 C for 9 hours under nitrogen atmosphere. Pyridinie was removed under reduced pressure and the residue was recrystallized from methanol to give 23 mg of 9-fluoro-3-methyl-10-(4-methyl-i- -49 -piperazinyl)-7-oxo -2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4- -benzoxadiazine -6-carboxylic acid, mp 268-269 0 C MS m/z 362 (M The following compounds were obtained according to a manner analogous to that of Example *Oe##t

I

I

S*f *tC It .4 c~ Ct C t~ 50

F.

R 5R 6N ,0 2

H

Example 5 6 Melting point Exo.l R 5R 6N- 76H0 7HQ-

C

3 *041IPh I 9

CH

CH

3 0 411 14 CN1 17 H 18

H

C 2

H

5 19 Hf- A c NN,_L, 240-,,245 (dec.) 237" 239 (dec.) 256--259 (dec.) >300 >300 >300 (dec.) 238N'242 (dec.) 2 58 272'-'274 (dec.) 2 70,-275 24 3--246 242N'244 (dec.) 251--252 (dec.) 239, 241 (dec.) Recrystallization sol vent MeOH MeOH/CHC1 3

DMF

EtQH /CHC1 3

DMF

DMF

MeOH MeOH/CHC1 3 EtOH

H

2 0 MeOH/CHC13 E tOH E tOH MS M/z 349 362 425 349 377 365 377 363 413 393 362 377 391 405

FAB-MS

*4*a 0 4i *r 4i i I 4 £T 4 4B -51continued Example 5 6 Melting point Recrystallization MS m/z No. ROC solvent

CH

3 H3 266-268 (dec.) EtOH 365 (MH+)

CH

3 21 284"'286 (dec.) IMF 350 22 cH rj- 280"'284 (dec.) MeOH /CHC1 3 /Et 2 O 345 23 CH)N'r-D 220"222 (dec.) EtOH 391

CH

3

FAB-MS

Example 24 Preparation of 9-fluoro-3-methYl-7-oo-10-(3-oxo-l-piperaziny 3-dihydro-7H-pyridor32.1-i i1-1.3.4-benzoxadiazine- 6-carboxylic acid A mixture of 9.10-difluoro-3-methyl-7-oXo-2,3-dihydro 7R-pyrido[3,,1-ijl- ,34-benZox ad eb acid (40 mg) obtained in Example 1, 2-piperazinone (31.1 mg), 1.4-diazabicyclo[ 2.2.2]octafe (31.8 mg) and dry dimethylsulfoxide (1 ml) was heated at 130 0 C for 28.5 hours under nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (Silica gel: CHCI 3/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-1-piperazinyl) 3-dihydro -7H-pyrido[3.2.1-ij]-1,3.4-benzoxadiazine-6-carboxylic acid.

mp >300 0 C; FAB-MS m/z 363 (MHI).

52 The following compounds were prepared from the compounds described in Example 2. 3 and 4 according to a manner analogous to that of Example -C0 2

H

5 6 R R N.' Example R N Melting point Recrystalli- No 3 Czation MS m/z No. R 3 solvent HN CH 3 2110,-242 (dec.) MeOH 362 (M4i) 26 CHN CH 3 203-'206 EtOH 376 27 CH3CN- CH 2 0H 229N~231 (dec.) MeOH 393 28 CHAD CH 2

N(CH

3 2 21O"N212 MeOH 420 2

FAB-MS

Example 29 Preparation of 10-r3-(benzyloxcarbonylamino)--pyrrolidinyll-9-fluoro-3-methyl-7--oxo-2. 3-dihydro-7H-pyrido- [3,2,1-iil-1,3,4-benzoxadiazine-6-carboxylic acid A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro- -7H-pyrido[3.2,l-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (28 Mg) obtained in Example 1, 3-(benzyloxycarbonylamino)pyrrolidine (94 mg) and dry pyridine (3 ml) was heated at 1000C for 3 hours under nitrogen atmosphere. Pyridine was removed under reduced pressure a nd the residue was -53 recrystallized from methanol. to give 36 mg of 10-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]-9-fluoro -3--nethyl-7-oxo- -2,3-dihydro--7H-pyrido[3,2,l--ij]-1,3,4 -benzoxadiazine-6- -carboxylic acid, mp 227-230 0 C; MS m/z 482 (M Example Preparation of 10-C,3-amino-l-pyrrolidinyl)-9-fluoro-3methvl-7-oxo-2,3-dihydro-7H-pyridor3,2,1-ijl-l.3,4-benzoxadiazine-6-carboxylic acid l0-[3- (benzyloxycarbonvlamino) -l-pyrrolidinyl]-9-fluoro -3-methyl-7-oxo-2. 3-dihydro-7H-pyrido 1-ij]-l,3 .4 -benzoxadiazine-6-carboxylic acid (30 mg) obtained 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 10-(3-amino-l--pyrrolidinyl)-9- -fluoro--3-methyl-7--oxo-2,3 -dihydro-7H-pyrido[3,2,l-ij]- -1,3,4-benzoxadiazine-6-carboxylic acid, mp 230-234 0

C

MS m/z -48 The following compounds were obtained according to a manner analogous to that of Examples 29 and i.

p~

V

I;

54- C0 2

H

Example R 5 R 6 N- Melting point Recrystallization M No. ccsolvent M 31 C3D286-,288 (dec.) H 2 0 363 32 CA j- 269,-273 (dec.) MeOH 377

H

33 H 2 N-05- 24O'N'245 (dec.) MeOH 363 34H262, "265 (dec.) MeOH 37; 35 C 2 H5N-CN- 252".256 (dec.) EtOH 390

FAB-MS

Example 36 Preparation of 1O-(3,4-Qimethvl-l-piperazinyl)-9-flUOO-3methyl-7-oxo-2. 3-dihydro-7H-pyrido i 4-benzoxadiazine-6-carboxylic acid A mixture of 9-fluoro-3-methyl-l0-(3-methyl-1-pipera- 55 zinyl)-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-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 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 residue was recrystallized from methanol to give 43 mg of 10-(3,4-dimethyl-l-piperazinyl)-9-fluoro-3-methyl-7-oxo 2 3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp 257-259 0 C; FAB-MS m/z 377 Example 37 Preparation of 9-fluoro-10-(3-methoxy-l-pyrrolidinyl)- 3 -methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ii-1,3,4-benzoxadiazine-6-carboxylic acid To a suspension of 9-fluoro-10-(3-hydroxy-l-pyrrolidinyl)-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 21 in dry dimethylformamide (10 ml) was added sodium hydride in oil (30 mg) and methyl iodide (40 1j).

After stirring the mixture at room temperature for 2 hours, additional 60% sodium hydride (30 mg) and methyl iodide S1) were added, and the mixture was stirred at 45 0 C for 3 hours. The solvent was then removed under reduced pressure. To the residue was added cold water (2 ml) and sodium hydroxide (2.3 ml) and the resulting suspension was heated at 100 0 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 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- 56 tographed on silica gel using acetone/chloroform as an eluent. 42 mg of 9-fluoro-10-(3-methoxy-l-pyrrolaidinyl)-3.

-methyl-7-oxo -2,3-dihydro-7H-pyrido[3,2,1.ij]yl,3,4- -benzoxadiazine -6-carboxylic acid, mp 233-234 0 C; FAB-MS m/z 364 (MN was obtained after recrystallization from methanol.

Example 38 Preparation of 9-fluoro-lo0-(4-methoxy-l-piperidyl-3methyl- 7-oxo-2, 3-dihydro-.7H-pyrido F3,2,1-i ii-1,3, 4-benzoxadiazine-6carboxylic acid 9-Fluoro-1O- (4-methoxy-l-piperidyl)-3-methyl-7-oxo -2,3-dihydro-7H-pyrido[3,2,l-ijp.,l.3,4-benzoxadiazine -6carboxylic acid was prepared from 9-fluoro-l0-(4-hydroxy-l- -piperidyl)-3-methyl-7-oxo-2,3 -dihydro-7H-Ipyrido(3,2,1-ij..

-l.3,4-benzoxadiazine-6-carboxylic acid obtained in Example 13 analogously to Example 37, and was obtained as crystals, mp,, 229-233 0 C MS m/z 377 after recrystallization from chloroform/n-hexane.

Example 39 Preparation of 10-(1,l-dioxide-4-thiomorpholinyl)-9-fluoro.3.

methyl-7-oxo-2, 3-dihydro-7H-pyridorF3,2,1-i i 4-benzoxadiazine-6-cazboxylic acid To a suspension of 9-fluoro-3-methyl-7-oxo-lo-C4-thiomorpholinyl)-2,3-dihydro -7H-pyrido[3,2,-ij-,3,4benzoxa.

diazine-6-carboxylic acid (50 mg) obtained in Example 11 in dichloromethane (5 ml) was added m-chloroperbenzoic acid purity, 74 mg). The mixture was stirred at room temperature for 18 hours. The solvent was then removed under reduced pressure. The residue was washed with ether, dichloromethane and a mixture of chloroform and methanol.

and recrystallized from dimethylformamide to give 22 mg of -57 l-dioxide-4-thiomorphol inyl) -9-f luoro-3 -methyl-7-oxo 3-dihydro-7H-pyridor 3,2,*1-i j 4-benzoxadiazine -6-carboxylic acid, mp >300 0 C; MS m/z 397 Example Preparation of 9-f luoro-3-methyl-7-oxo-10-[4- (2-oxo-npropyl)-l-piperazinvrll-2,3-dihydro-7H-pyrido[3,2,1-iij-1,3,4benzoxadiazine-6-carboxylic acid A mixture of 9-fluoro-3-methyl-7-oxo-10-(l-piperazinyl)- -2.3-dihydro -7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine-6- -carboxylic acid (50 mg) obtained in Example 6, chloroacetone (17 triethylamine (40 i~l) and dry dimethyli formamide (I ml) was heated at 80%C for 3.5 hours. The volatile components wete 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- -methyl-7-oxo-l0-[4-(2-oxo-n-propyl)-1-piperazinyl] 3-dihydro-7H-pyridoC3.2, 1-ui-1, 3,4-benzoxadiazine -6-carboxylic acid, mp 225-2290C FAB-MS m/z 405 The following compounds were obtained according to a manner analogous to that of Example 58 F CO 2

H

Example R 7 0 Melting paint Recrystallji- No. cczation FAB-MS mlz solvent 41 Q CCH 2 -1 22Nx226 (dec.) DMF 467 (MH+) 42 CH 3

CH

2 273,,,275 (dec.) EtOH 377 (MH+) 43 CH 3

CH

2

CH

2 2551\257 (dec.) EtOH 391 (MH+) 44 FCH 2

CH

2 257,,,259 (dec.) ttOH 395 (MH+) 45 HO 2

CCH

2 256--259 (dec.) H 2 0 407 (MH+) 46 CH 2

=CHCH

2 23.6,L238 (dec.) MeOH 389 (MH+) 4 H- 275,1,276 (dec.) EtOH 484 (MH+) Oee* a ease 0 COCa,,

S

cease o C *e a.

000 0*

C,.

00 0 t CC eta 0

C.

0 *Ce Example 48 Preparation of ).Q-r3-r(ethvlmethvlamino)methvl]-l-pyrrolidinvll-9-fluioro-3-methyl-7-oxo-2. 3-dihydr'o-7H-pyrido- [3,2,1-iil-1,3,4-benzoxadiazine-6-carboxylic acid 10-E3-( (ethylmethylamino)methyl]-l-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3--dihydro -7H-pyrido[3,2,1-ij]- -134bnoaizie6croyi acid was prepared from 9-fluoro-3-methyl-10-[3-[(methylamino)methyl] -1-pyrrolidinyl]-7-oxo-2,3-dihydro--7H-pyrido(3,2,1-ij]-1,3,4 -benzoxadiazine-6-carboxylic acid obtained in Example 17 and ethyl iodide analogously to Example 40, and was obtained as crystals, mp 210-225 0 C FAB-MS m/z 405 (MH after lx ft 59 recrystallization from a mixture of chloroform, methanol and n-hexane.

Example 49 4 Preparation of 10-[4-(3-carboxvpropionyl)-l-piperazi1ivil-9- U fluoro-3-methvl-7-oxo-2,3-dihdro-7Hpyridof3,2,1.-iip-134 benzoxadiazine-6-ca-rboxylic acid A mixture of 9-fluoro-3-methyl-7-oxo-10-(l-piperaziny:3)-2.3-dihydro -7H-pyrido[3,2,1--ij]-l,3,4-benzoxadia- V zine-6-carboxylic acid (50 mg) obtained in Example 6, succinic anhydride (21.6 mg), triethylamine (40 j±l) and dry dimethylformamide (4 ml) was heated at 80 0 C for 2 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 l0-[4-(3-carboxypropionyl)-l-piperazinyl9fluoro.3-.methyl -7-oxo-2,3- 1 20 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4.benzoxadiazine -6-carboxylic acid, mp 257-259 0 C FAB-MS m/z 449 ExaMvle Preparation of l0-(4-acetyl-l-piperazinyl)-9-fluoro-3 methyl-7-oxo-2. 3-dihydro-7H--pyrido f3,2,1-i l1-,3. 4-benzoxadiazine-6-carboxylic acid (4-Acetyl--1-piperazinyl luoro-3-methyl-7-oxo -2,3-dihydro-7H-pyrido[3,2,1-ijJ-1,3,4-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 obtained as crystals, mp 294-296 0 C FAB-MS M/z 391 (MHl) after recrystallization from dichloromethane/ methanol.

Example 51 Preparation of 9-fluoro-3-methyl-7--oxo-l0-r4-(3-oxo-n-butyl)- .1-piperazinyll-2.3-dihydro-7H--pyrido[3,2,1-ijl1,3,4-benzoxa- 5diazine-6-carboxylic acid A mixture of 9-fluoro-3-methyl-7-oxo-10-(l-piperazinyl)-2,3-dihydro '-7H-pyrido[3,2,1-ij]-lJ,3,4-benzoxadiazine-6-carboxylic acid (30 mg) obtained in Example 6, methyl 1o vinyl ketone (36 jil) 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-10-[4- (3-oxo-n-butyl)-l-piperazinyl] -2,3-dihydro-7H--pyrido[3,2,l-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp 187-189 0 C FAB-MS m/z 419 Example 52 ~Prearation of disodium 9-fluoro-3-methyl-7-oxo-10-r4- .(sulfonatomethyl)-l-piperazinyll-2,3-dihydro-7H-pridor3 ,2,1-iii 4-benzioxadiazine--6-carboxylate A mixture of 35% formalin (26 mg), sodium hydrogen sulfite (32 mg) and water (0.5 ml) was heated at 75 0 C for minutes and then cooled to room Zemperature. To this solution wa's added 9-fluoro--3-methyl-7-oxo-10-(-piperazinyl)-2,3-dihydro -7H-pyrido[3,2-ij]-l,3,4-benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 6 and sodium hydroxide (15 mg). After the mixture was heated at 0 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 from water/ethanol to give disodium 9-fluoro-3-methyl- -7-oxo-l0-E4-(sulfonatomethyl)-l-piperazinyl] -2,3--dihydro- -7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine -6-carboxylate, mp ai~zogeu a~mospnere. arter tne solvent was removed under reduced pressure. the crystalline residue was washed with 16 260-263 0 C 1H NMR (D 0) 8: 2.98 3.05 3.39 3.84 5.18 (2HS), 7.55 (lH,d,J=13;4 Hz), 8.34 (1H.S).

Example 53 Preparation of 10-[4-(4-aminobenzyl)-l-piperazinyl-9.

fluoro-3-methyl-7-&xo-2,3-dihydro-7H-pyrido[3,2,1.il-.l,3,4.

benzoxadiazine-6-carboxylic acid 9-Fluoro-3-methyl-10-[4-C4-nitrobenzyl)-l-piperaziny.] -7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ijl-l,3,4-benzoxadiazine -6-carboxylic acid (100 mg) obtained in Example 47 was hydrogenated over 5% Pd/C (10 mg) in dichloromethane/methafor 2 hours. After removal of the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from eathanol to give 69 mg of 10-[4-(4-aminobenzyl)--l-piperazinyl]-9-fluoro-3-methyl-7-oxo -2,3-dihydro-7H--pyrido- [3,2,l-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp 237-238 0 C FAB-MS m/z 454 (MH~) Example 54 Preparation of l0-[3-(aminomethyl)-l-pyrrolidinyl]-9-fluoro- 3-methyl-7-oxo-2. 3-dihydro-7H-pvrido [3,2.1-i i 4-benzoxadiazine-6-carboxylic acid The mixture of 10-[3-(acetylaminomethyl)-1-pyrrolidinyl]-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 1N sodium hydroxide (2.5 ml) was heated at 100 0 C for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with acetic acid, and the precipitate which separated out was collected by filtration and recrystallized from methanol to give 15 mg of l0-[3- (aminomethyl)-1-pyrrolidinyl]-9-fluoro-3-methyl.7-oxo reduced Dressure and the residue was recrystallized from methanol to give 23 mg of 9-fluoro--3--methyl-l-O-4-methyl-l- -62 -2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp 177-180 0 C FAB-MS m/z 363

(MH)

Example Preparation of 6-fluoro--8-hydroxy-7-(l-imidazolyl)-..

(methylamino)-4-oxo-1.4-dihydro-3-puinolinec.arboxylic acid Carbonyldiimidazole (32 mg) was added to a stirred j soluition of 6,7-difluoro-8-hydroxy-l-(methylamino)-4oxo- -1.4-dihydro -3-quinolinecarboxylic acidi (50 mg) obtained in Reference example in dry dimethylformamide (2 ml).

Stirring was continued at room temperature for 2 hours and then at 80 0 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 to give 35 mg of 6-fluoro-8-hydroxy-7-(I-imidaboxylic acid as pale yellow powder, FAB-MS m/z 319 supnino1-loo8hdrx--1iiaoy)..

Eaml mg5bandi6xape5 namxur f3%frai m) oandione (n Exml was heaediatur of35% hours under nitrogen atmosphere. The solvent was removed under reduced pressure and the crystalline residue was -63 washed with methanol to give 15 mg of 9-luoro-10-(1-imidazolyl)-3-methyl-7-oxo-2,3-dihydro -7H-pyrido[3,2,1-ij]- -l,3,4-benzoxadiazine-6-carboxylic acid as pale pink powder. An analytical sample, mp >300 0 C;.FAB-MS m/z 331 (MH )was prepared by recrystallization from dimethylformamide and ether.

9-Fluoro-l0-(l-'imidazolyl)-3-methyl-7-oxo-2,3-dihydro -7H-pyridoC3,2,1--ijj-1,3,4--benzoxadiazine-6-carboxyliL acid was also prepared from 9,10-difluoro-3-methyl-7-oxo-2,3- -dihydro--7H-.pyrido[3,2,l-ij] -l,3,4-benzoxadiazine-6-carbcxylic acid and imidazole in dimethylsulfoxide analogously to Example Example 57 Preparation of benzyl 9-fluoro-10-(3-hydroxy--prrolidinyl)- 3-methyl-7-oxo-2. 3-dihydro--7H-pvrido 11-1,3, 4-benzoxad ia zi ne-6 -car b oxylate A mixture of 9-fluoro-10-(3-hydroxy-l-pyrrolidinyl)-3- -methyl-7-oxo-2,3 -dihydro-7H-pyrido[3.2,l-ij]-1,3,4- -benzoxadiazine -6-carboxylic acid (10 mg) obtained in Example 21, anhydrous potassium carbonate (8 mg) and 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.

The residue was suspended in water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure. The residue was tritura~ted with ether to give 11 mg of benzyl 9-fluoro-l0--(3-hydroxy-l-pyrrolidinyl)-3-methyl-7-oxo-2,3 -dihydro-7H--pyrido[3,2,l-ij]- -1.3,4-benzoxadiazine -6-carboxylate, mp 196-198 0 C (dec.); FAB-MS m/z 440 (MH FiC

*FAB-MS

-64 Example 58 Preparation of benzyi 10- (3-chloro-l-pyrrolid inyl )-9-fluoro- 3-methyl-7-oxo-2,3 dihydro-7H-pyrido[3,2,1-ii]-1,3,4-benzoxadiazine-6-carboxylate Benzyl 9-fluoro-10-C3-hydroxy-1-pyrrolidinyl)-3-methyl- -7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-i.,3,4-benzoxadiazine -6--carboxylate (8 mg) obtained in Example 57 was dissolved in 0.2 ml of thionyl chloride and stirred at 60 0 C for j minutes. The reaction mixture was diluted with water and extracted with chloroform.

The extract was concentrated under reduced pressure.

SThe residue was chromatographed on silica gel (2 g) with chloroform to give 2.8 mg of benzyl l0-(3--chloro-1--pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3 -dihydro--7H-pyrido- [3,2,l-ij]-l,3,4-benzoxadiazine -6-carboxylate, mp >300 0

C;

FAB-MS mlz 458 (MH 460 (MH+2).

Example 59 Preparation of 10-(3-chloro-l-pyrrolidinyl)-9-fluoro-3methyl-7-oxo-2,3-dihydro-7H-pyridor3,2,1-ii1-1,3,4-benzoxadiazine-6-carboxylic acid -oxo-2,3 -dihydro-7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine -6-carboxylate (2.5 mg) obtained in Example 58 was hydrogenated 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 give 1.0 mg of 10-(3-chloro-l-pyrrolidinyl)-9-fluoro-3- -methyl-7-oxo-2.3 -dihydro-7H-pyrido[3,2,l-ij]-1,3,4- -benzoxadiazine -6-carboxylic acid, mp 269-272 0 C (dec.); mp >300 0 fr'AI3-Mb m/Z ibij tir± 65 FAB-MS m/z 368 (MH 370 (MH+2)+ Example Preparation of 9-fluoro-3-methvl-10-(4--methvl-l-piperazinyl)- 7-oxo-2,3-.dihydro-7H-pyridof3,2,l-iil1,3,4-benzoxadiazile-6carboxylic acid via the fluoroborane intermediate A mixture of 9,10-difluoro--3-methyl-7-oxo-2,3-dihydro- -7H-pyrido[3,2,l-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 0 C for 12 hours. After the reaction mixture was cooled to room temperature the precipitate was collected by filtration, washed with methanol and dried under reduced pressure to give 110 mg of crude 9,10-difluoro-6-[[(difluoroboryl)oxyIjcarbonyl]-3-methyl-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazin-7-one; FAB-MS m/ 331 ±Z JM+ To a stirred solution of the above borane intermediate (33 mg) in dimethylsulfoxide (1 ml) were added N-methylpiperazine (15 vil) and triethylamine (20 i tl) After stirring at room temperature for 3 hours the reaction mixture was lyophilized. The residue was crystallized from methanol to give 28 mg of 6-[[(difluoroboryl)oxy]carbonyl]- -9-fluoro-3-methyl-l0 -(4-methyl-l-piperazinyl)-2,3-dihydro- -7H-pyrido(3.2,1-ij] -l,3,4-benzoxadiazin-7-one as yellow crystals, mp 228-230 0 C FAB-MS m/z 411 (MII -7 30 To a solution of the above borane intermediate (5 mg) in ethanol (1 ml) was added triethylamine (3 1±1l). 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- -10-(4-methyl-l-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyridof3,2.1-ij]-1,3,4-benzoxadiazine-6 -ca rboxylic acid, mp 268-269 0 C (dec.).

removed under reduced pressure and the residue was L I- 66 Example 61 Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperaziny1)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-i1-1, 3,4-benzoxadiazine-6-carboxylic acid via the acetoxyborane intermediate A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro- -7H-pyrido[3,2,1-ijJ -1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) Obtained in Example 1, acetic anhydride (1 ml) and triacetoxyborane (100 mg) was heated at 140 0 C for 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]carbonyl]-9,10-difluoro-3-methyl-2,3 -dihydro-7H-pyrido- £3.2.1-ij]-1,3,4-benzoxadiazin-7-one; FAB-MS m/z 411 To a solution of the above borane intermediate (41 mg) in dimethylsulfoxide (1 ml) were added N-methylpiperazine 1.l) and triethylamine (20 il). After the mixture was stirred at room temperature for 2 hours, the reaction mixture was lyophilized. The residue was crystallized from methanol/ether to give 34 mg of 6-[[(diacetoxyboryl)oxy]carbonyl]-9-fluoro-3-methyl-10 -(4-methyl-1-piperazinyl)-2,3- -dihydro-7H-pyrido[3,2,1-ij] -1.,3,4-benzoxadiazin-7-one as yellow crystals; mp 156-157 0 C FAB-MS m/z 491 The above borane intermediate (5 mg) was suspended in acetone (0.1 ml) and added conc. HC1 (2.5 il). The reaction mixture was stirred at room tempetrature for 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 il) and the mixture was refluxed for 1 hour. After the solution was cooled to room temperature, the precipitate which separated out was collected by filtration to give 9-fluoro-3-methyl-10-(4- -methyl-1-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido- -67 E3.2,l-ij]-l.3,4--benzoxadiazine -6-carboxylic acid, mp 268-269 0 C (dec.).

Example 62 Preparation of Pivaloyloxymethyl 10-f3-(benzyloxycarbonylamino)-l-pyrrolidinyll-9-fluoro-3-methyl-7-oxo-2, 3-dihydro- 7H-pyridofr3,2. 1-i l' 13, 4-benzoxadiazine-6-carboxylate A mixture of 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido- -benzoxadiazine-6-carboxylic acid (290 mg) obtained in Example 29, pivaloyloxymethyl chloride (130 jil), anhydrous potassium carbonate (166 mg) and dry (10 ml) was stirred at 45 0 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)-l-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 0 C; FAB-MS m/7, 597 Example 63 Preparation of pivaloyloxymethyl 10-(3-amino-l-pyrrolidinyl)- 9-fluoro-3-methyl-7-oxo-2.3-dihvdro-7H-pyrido3,2,l1-iil- 1.3.4-benzoxadiazine-6-carbo.,,ilate Pivaloyloxymethyl l0-(3-amino-l--pyrrolidinyl)-9-fluoro- -3-methyl-7-oxo-2,3 -dihydro-7Bi-pyrido[3,2,1-ij)-1,3,4- -benzoxadiazine -6-carboxylate was prepared from pivaloyloxymethyl 10-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]-9- -fluoro-3 -methyl-7-oxo-2.3-dihydro-7H-pyrido32,l-ij- A mixture of 9 -fluoro-3-methyl-lo-(3-methyl-l-pipera- 68 -benzoxadiazine-6-carboxylate (200 mg) obtained in J Example 62, analogously to Example 30, and was obtained as pale brown powder after precipitation from a mixture of ethyl acetate and n-hexane; 1H NMR (CDCl 3 6: 1.22 5(9H, 1.6-2.4 (2H, in), 2.99 O3H, 3.3-4.0 (5H, mn), 4.98 (2H, 5.96 (2H, 7.64 (1H, d, J=14.4 Hz), 8.37 (1H, FAfl-MS m/z 463 (MH I).

Example 64 Preparation of ethyl 10-[3-(benzyloxycarbonylainino)-l- -pyrrolidinyll-9-fluoro-3-nethyl-7-oxo-2, 3-dihydro-7H-pyrido- LL2_ i-1,3, 4-benzoxadiazine-6--carboxylate A mixture of l0-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]-9-fluoro-3 -iethyl-7-oxo-23-dihydro-7H-pyrido- -benzoxadiazine-6-carboxylic acid (337 mg) obtained in Example 29, ethyl iodide (84 i ii), anhydrous potassium carbonate (193 mg) and dry dimethylfornaiide (12 ml) was stirred at 45 0 C for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloroinethane. The dichloroinethane solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then applied onto a column of silica gel and eluted with a mixture of chloroform and acetone 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 10-[3-(benzyloxycarbonylainino)-l-pyrrolidinyl]-9-fluoro -3-methyl-7-oxo-2,3-dihydro-7H-pyrido- (3,2,1-ijl-1,3,4 -benzoxadiazine-6-carboxylate, mp 204-207 0 C; FAB-MS m/z 511 (MIH r--L LUL'Uvub buuouiu buLc~ ana coricenrtrar-ea undier reduced pressure to give the crystalline residue, which was chroma- 69 Example Prepartion of ethyl 10-(3-amino-i-pyrrolidinyl) -9--fluoro-3methyl-7-oxo-2. 3-dihydro-7H-pyrido F3,*2.1-i il-i*3, 4-benzoxadiazine-6-carboxylate Ethyl l0-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9- -fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,l-ijj- -1.3,4 -benzoxadiazine-6-carboxylate (200 mg) obtained in Example 64 was hydrogenated over 5% Pd/C (120 mg) in a mixture of chloroform (25 ml) and methanol (10 ml) for 23 hours. After removal of the catalyst by filtration the filtrate was concentrated under reduced pressure. The residue was then applied onto a column of silica gel, and eluted with a mixture of chloroform and methanol The pure fractions were combined and concentrated to *dryness under reduced pressure. The residue was further purified by preparative TLC (silica gel; CHC1 /MeOH, 3:1) and 3 recrystallized from ethanol to give 71 mg of ethyl 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2, 3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine- -6-carboxylate. mp 187-192 0 C FAB-MS m/z 377 (MH i{ Example 66 Preparation of 10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl- 7-oxo-2. 3-dihydro-711-pyridor3,2. 1-ii1-l. 3.4-benzoxadiazine-6carboxylic acid hydrochloride The pH of a solution of 10-(3-anwino-l-pyrrolidinyl)-9- -fluoro-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]- -1.3,4-benzoxadiazine-6-carboxylic acid (20 mg) obtained in Example 30 in water (1 ml) was adjusted to 1.0 with 61'-HCl.

The clear solution was then lyophilized and the residue was crystallized from water/ethanol to give 19 mg of 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2. 3 -dihydro-7H-pyrido[3,2.l-ijJ-1,3,4-benzoxadiazine-6-carboxylic 1 11 '4A I 1 A A L LL CtIJU ILL t L .ld 11U I and recrystallized from dimethylformamide to give 22 mg of No-U- 70 acid hydrochloride. mp 226-228 0 C (dec.).

Example 67 Preparation of 9-fluoro-3-methvl-10-(4-methyl-l-piperazilyl)- 7-oxo-2.3-dihvdro-7H-pyrido[3,2,1-il1,3,4-belzoxaciazile-6carboxylic acid hydrochloride 9-Fluoro-3-methyl-lO-(4-methyl-1-piperazinyl)-7-oxo-2,3 -dihydro-7H-Ipyrido(3,2,1-ij]-1,3,4-benzoxadiazile -6-carboxylic acid hydrochloride was obtained analogously to Example 66. mp 264-266 0 C (dec.).

Example 68 Preparation of sodium 9-fluoro-3-meth l-10-morpholino-7-oxo- 2. 3-dihydro-7H-pyridorF3, 2.1-i i 1-1,3. 4-benzoxadiazine--6-carboxy late lit t 2 9-loo3mty-0mrhoio7oo23dhdo7 -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 jil) was added with stirring.

The clear solution was lyophilized and the residue was crystallized from water/ethanol to give 12 mg of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2, 3-dihydro-7HI -pyridoI3,2,l-ij]-1,3,4-benzoxadiazine-6-carboxylate, mp >300 0

C.

Example 69 Preparation of 9-fluoro-3-(2-fluoroethyl)-10-(4-methyl-lpiperaziny1 -7-oxo-2,3-dihydro-7H- yridor3,2,1-iV -1,3,4benzoxadiazine-6-carboxylic acid 9-Fluoro-3- (2-f luoroethyl (4-methyl-1-piperazinyl) -7 -oxo-2. 3-dihydro-7H-pyrido[E3 1-i j -1,*3.4-benazoxadiazine -'Is 71 -6-carboxylic acid was prepared from ethyl 8-benzyloxy-6,7- -difluoro-l-(formylamino)-4-oxo-1,4-dihydro -3-quinolinecarboxylate obtained in Reference example following a series of procedures of Reference example h and i) (using 1-bromo-2-fluoroethane instead of methyl iodide), Example 1 and Example 5. and was obtained as crystals, mp 220-224 0 C; MS m/z 394 after recrystallization from methanol.

Examples 70-77 There were obtained the following compounds starting from the compound obtained in Example i by using a manner analogous to the one described in Example 5 or Examples sa 29/30.

F

R

5

R

6

N

t ii 8 r i e

I.

'c IC c ,5O ,I C ,,30 C I 6 St ar

I

V

N'CH

Example R5R6N Meltin$ point Recrystallization PA3-MS m/Z No. C solvent 70 Cx, exlo..

71 HaN OH 72 HN Ph, 73

H&ND

292 (dee.) 221-230 (dec.) 240-245 (dec.) 253-255 (dec.) MeOHl 'cCC'.'i

C

EtOH/hexane EtlO/hexane Me8/ether 432 (li+) 379 (Ms 365 425 (Mi 363 (M cHI.

H&M7- 240-241 MeOH 72 Example R 5 R 6 N- Meltinf point Recrystallization JA3-MS m/Z No* C solvent ,D300 (does) EtOH/CRCl /hexane 363 (B) 76 H220-223 (dec.) EtOH 453 (MH C N.Z '211-214 (dec.) EtOH/di 3 '3 91 0e~f)

LI

methanol.

-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.

1O-(3-(aminomethyl)-4-methyl--pyrrolidinyl-9-fluoro-3methyl-7--oxo-2,3-dihydro-7H-pyrido[3..2,1-ij]-1,3,4-benzoxadiazine-6--carboxylic acid, 10-[3-[(ethylamino)methylll-4-methyl-l-pyrrolidinyl]-9-fluoro- 1o 3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2.1-ij]-1,3,4-benzoxadiazine-.6-carboxylic acid, 10-[3- (aminomethyl )-4-chloro-l-pyrrolidinyl ]-9-fluoro-3methyl-7-oxo-2,3-dihydro-71-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid.

10-[3-(aminomethyl)-4-fluoro-l-pyrrolidinyl]-9-fluoro-3methyl-7-oxo--2,3-dihydro-7H-pyridor3,2,1-ij]-l,3,4-benzoxa- 20diazine-6-carboxylic acid.

10-[3-chloro-4-[(methylamino)methyl]ll--pyrrolidinyl]-9-fluoro- 3-methyl-7-oxo-2,3-dihydro-7H-pyido32,1-ij--1,3,4-benzoxadiazine-6-carboxylic acid.

9-fluoro-10-E3-fluoro-4-[(methylamino)methyl]-l-pyrrolidinyl]- 3-methyl-7-oxo--2,3-dihydro-7H-pyrido[3.2.1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, 10-[3-chloro-4-[(ethylamino)methyl]-l-pyrrolidinyl]-9-fluoro- 3-methyl--7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,34-benzoxadiazine-6--carboxylic acid.

10-[3-[(ethylamino)methyl]-4-fluoro-l-pyrrolidinyl]-9-fluoro- 3-methyl-7--oxo-2.3-dihydro-7H-pyrido23,2,1-ijj-1,3,4-benzoxadiazine-6-.carboxylic acid.

-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylate, mp -74 9-fluoro-10-[3-methoxy-4-(methylamino)-l-pyrrolidinyl]-3 methyl-7-oxo-2, 3-dihydro-7H-.pyrido 1-i j] 4-benzoxadiazine-6-carboxylic acid, 10-[3-(ethylamino)-4-methoxy-l-pyrrolidinyl]>9.fluoro-3metilyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]l,3,4-benzoxa.

diazifte-6-carboxylic acid, 9-fluoro-1O-(3-hydroxy-4-methoxy-l-pyrrolidinyl)3methyl.7oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6 carboxylic acid, 10-(3-amino-4-chloro-l-pyrrolidinyl)-9-fluoro3methyl.>-oxo.

2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine.6 carboxylic acid, 1O-(3-amino-4-fluoro-l-pyrrolidinyl)-9-fluoro3methy7...oxo 2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6 ii carboxylic acid, 3-chloro-4-(methylamino)-l-pyrrolidinyl]-9-fluoro-3methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1ij]-l,3,4.benzoxadiazine-6-carboxylic acid, 9-f luoro-1O-[3-fl)uoro-4- (methylamino)-l-pyrrolidinyl]-3methyl-7-oxo-2. 3-dihydro-7H-pyrido [3,2,1-i j 4-benzoxa- 35diazine-6-carboxylic acid.

filtration and recrystallized from methanol to give 15 mg of 10-[3-(aminomethyl)-1-pyrrolidiflyl1-9-flUOro-3-methyl-7-oxo Example 78 Preparation of 10-[3-F(4-aminobenzyljamino1-l-pyrrolidinyll- 9-fluoro-3-methyl-7-oxo-2,3-dihYdro--7H-pyridor3,2,1-ii]- .1.3.4 -benzoxadiazine-6-carboxylic acid 10-13-C (4-Aminobenzyl)amino]-l-pyrrolidinyl]-9-fluoro-3-.

methyl-7-oxo-2. 3-dihydro-7H-pyrido [3.2.1-i j 4-benzoxadiazine-6-carboxylic acid was prepared analogously to the methods described in Example 47 and 53, starting from 10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido[3,2. 1- 3,4-benzoxadiazine-6-carboxylic acid which was obtained in Example 30; mp. 180-162 0

C

FAB-MS m/z 453 Example 79 Preparation of 9-fluoro-10-[3-[F(dimethylamino)methylenelaminol-1-pyrrolidinyll-3-methyl-7-oxo-2,3-dihydro-7H-pyridor3,2,1-ifl-1,3,4-b>enzoxadiazine-6-carboxylic acid A suspension of 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3- -methyl-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-l.3,4- -benzoxadiazine-6-carboxylic acid (14 mg) obtained in Example 30 and NN-dimethylformamide dimethylacetal (6 111) in dry DMF (0.5 ml) was stirred at room temperature for hours. The precipitate was collected by filtration, washed with DMF and ether, and recrystallized from DMF to give 8 mg Jll of 9-fluoro-10--(3-rC(dimethylamino)methylenejamino]-1 -pyrrolidinyl '-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij] -1.3.4-benizoxadliazine-6-carboxylic acid as pale yellow crystals: mp. 218-220 0 C FAB-MS m/z 404 nours unaer nitrogen atMOspnere. Tne solvent was removed under reduced pressure and the crystalline residue was -76 Example Preparation of sodium 9-fluoro-3-methvl-10-(4-methyl-l1ilperazinyl)-7-oxo-2 ,3-dihydro-7H--pyridoF3 .2.1-i i -1,3,4benzoxadiazine-6-carboxylate 9-Fluoro-3-methyl--l0-(4-methyl-l-piperazinyl)-7-oxo-2.3dihydro-7H-pyrido[3*,2,1-ijj--l,3,4-benzoxadiazine-6-carboxylic acid (520 mg) was dissolved in 0.5N sodium hydroxide (2.88 ml). The clear solution was evaporated under reduced pressure to give 555 mg of pale yellow powder, which was recrystallized from ethanol to give 475 mg of sodium 9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2. 3- -dihydro-7H-pyrido 3,2.1-ij]-1,3,4-benzoxadiazine-6-carboxylate, after drying in vacuo at 80 0 C for 2 days; mp 252-254 0 C FAB-MS m/z 385.

The following Examples illustrate pharmaceutical A preparations containing a compound provided by the present invention: Example A Interlocking gelatin capsules each containing the following ingredients were manufactured in the conventional manner per se: 9-Fluoro--3-methyl-l0- (4-methyl-lpiperazinyl )-7-oxo-2. 3-dihydro-7Hpyrido[3.2,,l-ij]-l,3,4-benzoxadiazine- 6-carboxylic acid 200mg Luviskol (water-soluble polyvinylpyrrolidone) Mannitol Talc Magnesium stearate 2mg 2 57mg FAB-MS m/z 440 -77 Example B Tablets each containing the following ingredients were manufactured in the conventional manner per se: 9-Fluoro-3-methyl-10- (4-methyl-ipiperazinyl )-7-oxo-2, 3-dihydro-7Hpyrido(3,2,1-ij']-1,3,4-benzoxadiazine- 6-carboxylic acid 200mg Starch 44mg Carboxymethylcellulose calcium Crystalline cellulose Magnesium stearate 6mg 3

Claims (3)

1. 268-269 0 C (dec.). 78 The claims defining the invention are as follows: 1. Tricyclic compounds of the general formula 0 1 x COOR R6_N R '2 wherein R 1 is a hydrogen atom or a carboxy-protecting radical; R is a hydrogen atom or a lower alkyl radical which may be substituted with a halogen atom; R 3 and R4 independently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or with an unsubstituted amino acid radical or an amino acid radical substituted with ~di-lower alkyl, lower alkyl or lower cycloalkyl; X is a halogen atom; and S R 5 and R 6 are independently a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical, a lower alkoxy radical or an unsubstituted amino acid radical or an amino acid radical substituted 6 with di-lower alkyl, lower alkyl or lower cycloalkyl; or R and R taken together with the adjacent nitrogen atom, may form a 5 to 7 membered heterocyclic ring which may be substituted at the carbon atom(s) with one or more substituents selected from hydroxy, lower alkoxy, amino, lower alkylamino, lower cycloalkylamino, di-lower alkylamino, lower alkanoylamino, benzyloxycarbonyl-amino, halogen, lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower cycloalkylamino-lower alkyl, S. di-lower-alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, hydroxy-lower alkyl, phenyl (optionally substituted by amino, halogen, hydroxy and/or lower alkoxy) and a heterocyclic ring; or said heterocyclic o ring formed by R and R may be substituted at the carbon atom(s) with one or more substituents selected from benzylamino (optionally substituted by nitro, amino, halogen, hydroxy and/or lower alkoxy) and a group of the general formula R 50 R R 5 1 SA 9Z A? 0 ~oiecuLea Uy tiIradtion to give y-riuoro-j-metnyl-iu-(4- -methyl-l-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido- 79 where R 50 and R 5 are lower alkyl or together with the nitrogen atom represent a 5 to 8 membered saturated N-heterocyclic ring; or said heterocyclic ring formed by R and R may be substituted as defined above and said hetero-cyclic ring may further contain -NR 7 -SO 2 or -NR 7 [R 7 is a hydrogen atom; a lower alkenyl radical; a lower alkyl radical which may be substituted by hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, halogen, carboxy and/or sulfo; an aralkyl radical which may be substituted with one or more amino, nitro, lower alkylamino, di-lower alkylamino, halogen and/or lower alkoxy group(s); or a radical represented by the general formula -(CH 2 )nCOR 8 (II) (in which n is 0 to 4 and R 8 is a hydrogen atom; a lower alkoxy radial; an amino radical, which may be substituted by lower alkyl and/or lower cycloalkyl; a lower alkyl radical which may be substituted by carboxy and/or lower alkoxycarbonyl; or an aryl radical which may be substituted by one or more halogen, lower alkoxy, hydroxy, nitro and/or amino group(s))]; as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula I or their salts. 2. Compounds as in claim 1, wherein R 7 when being an aralkyl radical is benzyl optionally substituted as defined in claim 1. Compounds as in claim 1, wherein R 8 when being an aryl radical is phenyl, optionally substituted as defined in claim 1. 4. Compounds as in any one of claims 1 to 3, wherein X is fluorine. Compounds as in any one of claims 1 to 4 wherein R 1 is hydrogen. 6. Compounds as in any one of claims 1 to 5 wherein R 2 is methyl. 7. Compounds as in any one of claims 1 to 6 wherein R 3 is hydrogen. 8. Compounds as in any one of claims 1 to 7 wherein R 4 is hydrogen. 9. Compounds as in any one of claims 1 and 4 to 8 wherein the group R 5 R 6 N- is CH 3 N N- 3 oxymethyl 10-13-(benzyloxycarbonylamino)-i-pyrroildlnyl]-9- -fluoro-3 -methyl-7-OXO-2,3-dihydro-7H-pyrido[3,2,1-ij]- Compounds as in any one of claims 1 and 4 to 8 wherein the group R R N- is H N-N- 11. A compound according to claim 1 which is 9-fluoro-3-methyl-lO- (4-methyl-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 said compound or of said salt. 12. A compound according to claim 1 which is 9-fluoro-3-methyl- 7-oxo-10-(l-piperazinyl)-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 said compound or of said salt. 13. A compound according to claim 1 which is 9-fluoro-3-methyl-l0- benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of said compound or of said salt. 14. A compound according to claim 1 which is 9-fluoro-3-methyl-7- oxo-l0-(3-phenyl-l-piperazinyl)-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 said compound or of said salt. A compound according to claim 1 which is l0-[3-[(ethylamino)- methyl )-l-pyrrol idinyl J-9-fluoro-3-methyl-7-oxo-2,3-dihydro-.7H-pyrido- I E[3,2,l-ij-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of said compound or of said salt. 16. A compound according to claim 1 which is l0-(3-amino-l- pyrrolidinyl )-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido3,,ij.. 1 ,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of said compound or of said salt. 17. A compound according to claim 1 which is 9-fluoro-3-methyl-l0- [3(ehlmn)lproiiyl7oo23dhdo7-yio321il l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of said compound or of said salt. 18. A compound according to claim 1 which is l0-[4-(4-aminobenzyl)- .1pprznl--loo3mty--xo23dhdo7-yio321ill3 4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt 7>'.thereof or a hydrate or solvate of said compound or of said salt. A -81- 19. A compound according to claim 1 which is l0-(trans-3-amino--4- methyl-l-pyrrolidinyl )-9-fluoro-3-methy1-7-oxo-2,3-dihydro-71,-pyido3,2,. ij)-l,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of said compound or of said salt. A compound according to claim 1 which is l0-(trans-3-amino-4- methoxy-l.-pyrrol idinyl )-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido- E3,2,l-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof or a hydrate or solvate of said compound or of said 9 21. A compound according to claim 1 which is selected from 9fluoro-3-methyl-0-or,3ldihydro..7H,3ridoE3,2,l..ij).l ,3,benzoxadiazine bezxaie6-carboxylic acid, l0-(3,4-di-methyl-l-ieaznl-9-lo3-methyl7..o) mty-lproiiy-7oxo-2,3-dihydro-7H-pyrido[3,2,l-ijj-l ,3,4-bezxdaie6croyi aciod, 9-luor-l0-(-meoxycai,1-3(tyaio-l-pyrrolidinyl )3mty--xo.,-iyr- fur--ehl7oo23dhdo 7 H-pyrido[3,2,1-ijJ-l,3,4-benzoxadiazine-6croyi cd 9-fluro-3-methyacid, o0-4-(3-xo-t byl -l-piperazinyl ]lur-3- dhyd-7- pyrido[3,2hydrij7Hlp3r4dobenzoxadiazine ,4-barboxliacid, disoium9floo 7Hpyrido3,2,1-ij-l,3,4-benzoxadiazine6 carboxyle ac[3i nohy, pyio32il134-benzoxadiazine-6-carboxylic acid, dsdu 9-fluoro-l--idacy)3 3me thyl-7-oxo- -ihydrlonaprioeh--p ii >1,3 4.-e 3odiazi e..-7 ayrboic aid, O -(34-enyoxadieazi ny-.-furbo aethy.-.-(m oo..2,3 c )roiiyl--fur-3-methyl-7-oxo-2,3-dihydro-7H-prd-321i dihydro-7H-pyrido3,2,.-ij].-,3,4-benzoxadiazine..6-carboxylic acid, LU GqA/ 15,92 -dihydro- 7 HI-pyrido[321i)]1,3,4-benzoxadiazine- 6 carboxylic acid, 9-fluoro-3-methyl-1O-(4-methyl-l-imidazolyl)-7-oxo-2,3-dilydro-7H- pyridoE3,2,l-ijJ-1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-3- methyl-1O-E3-methyl-4-[(methylamino)methyl)-1-pyrrolidinylj-7-oxo-2,3- dihydro-7H-pyrido3,2,-ij-1 ,3,4-benzoxadiazine--6-carboxylic acid, 1O-E3- (aminomethyl)-4-methyl-1-pyrrolidinyl )-9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido[3,2,1-ij)-l ,3,4-benzoxadlazine-6-carboxylic acid, lO-E3- [(ethylamino)methyl)-4-methyl-l-pyrrolidinylC--9-fluoro-3-methyl-7-oxo-2,3- dlhydro-7H-pyrido(3,2,l-ijJ-l,3,4-benzoxadiazine-6-carboxylic acid, 1O-[3- (aminomethyl)-4-chloro-1-pyrrolidinyl J-9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido[3,2,1-ij-1l,3,4-benzoxadiazine-6-carboxylic acid, 10-43- (aminomethyl )-4-fluoro--1-pyrrolidinyl )-9-fluoro-3-mrethyl-7-oxo-2,3-dihydro- 7H-pyrido[3,2,1-ij)-1 ,3,4-benzoxadiazine-6--carboxylic acid, 10-[3-chloro- 4- methyl ami no) me thyl 2-l-pyrrolidinyl )-9-fluoro-3-me thyl-7-oxo-2 ,3- dihydro-7H-pyrido[3,2,l-ij--1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10-C3-fluoro--4-[(methylamino)methyl]-l-.pyrrolidinyl)-3-methyl-7- oxo-2,3-dihydro--7H-pyrido[3,2,1-ijl-1 ,3,4-benzoxadiazine--6-carboxylic acid, 10-[3-chloro-4--C(ethylamino)methyl]-l-pyrrolidlnylj--9-fluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyridoC3,2,1-ijJ-l ,3,4-benzoxadiazine-6- caroxyicacid, l0-[3-C(ethylamino)methyl)-4-fluoro--l-pyrrolidinyl-9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ijJ-1 ,3,4-benzoxadiazine- 6-carboxylic acid, 10-(3-amino-4-methoxy-l-pyrrolidinyl)-9-fluoro-3- methyl-7--oxo-2,3-dihydro-7H--pyrido[3,2,l-ijj-1 ,3,4-benzoxadiazine-6- j carboxylic acid, 9-fluoro-10-[3-methoxy-4-methoxy--4-(methylamino)-l- pyrrolidinylh-3-methy]-7-oxo-2,3-dihydro-7H-pyridoC3,2,1-ij)-1,3,4- benzoxadiazine-6-carboxylic acid, l0-.3-(ethylamino)-4-methoxy-l- j pyrrolidinylJ-9-fluoro-3--methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,-ij]- 1 ,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10-(3-hydroxy-4--methoxy- l-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido3,2,-ij)-,3,4- benoxaiazne--caboxlicacid, l0-(3-amina-4-chloro-l-pyrrolidinyl)-9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij-1,3,4-benzoxadiazine- 6-carboxylic acid, 10-(3-amino-4-fluoro-1-pyrrolidinyl)-9--fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyridoE3,2,l-ij)-l ,3,4-benzoxadiazine-6-carboxylic acid, l0-[3-chloro-4-(methylamino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido[3,2,l-ijJ-1 ,3,4-benzoxadiazine-6-car'boxylic acid, 9-fluoro-10-[3-fluoro-4-(methylamino)-l-pyrrolidinyl]-3-methyl-7- oxo-2,3-.dihydro-7H-pyrido3,2,1-ijJ-l,3,4-benzoxadiazine-6-carboxylic acid, l0-[4-(amlnomethyl)-1-piperidyl-9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H-pyridof3,2,1-ij)-l,3,4-benzoxadiazine-6-carboxylic acid, 4 &~~LIV9-f Iuoro-1O-(4-hydroxy-l -pi peri dyl )-3-methyl -7-oxo-2 ,3-di hydro-7H-pyri doC3, ~yJTA:173F 0* 2,1-lJ)-1,3,4-benzoxadlazlne-6-carboxyllc acid, 9-fluoro-3-methyl-7-oxo- 1O-(4-1-pyrrolyl)-.1-piperidylJ-2,3-dihydro-7H-pyridoE3,2,1-ij)-1 ,3,4- t benzoxadiazine-6-carboxylic acid, 9-fluoro-1o-(1-hornopiperazinyl)-3- methyl-.7-oxo-2,3-dihydro-7H-pyridoE3,2,1-ijJ-1 ,3,4-benzoxadiazlne-6- .1 carboxylic acid, 9-fluoro-1O-(3--hydroxy-l-pyrrolidinyl)-3-methyl-7-oxo- 2,3-dlhydro.-7H-pyrido3,2,1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-3-methyl-7-oxo-O-(4-n-propyl--piperazinyl)-2,3-dihydro-7H- pyridot3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-1O- E4-(2-fluoroethyl)-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido- [3,2,1-ij)-1 ,3,4-benzoxadiazine-6-carboxylic acid, 1O-E4-(carboxymethyl).- I-piperazinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij 1- 1 ,3,4-benzoxadiazine-6-carboxyllc acid, 1O-(4-allyl-1-piperazinyl)-9- fluoro-3-methyl-7--oxo-2,3-dihydro-7H.-pyrido[3,2,1-ijC-1,3,4- j benzoxadiazine-6-carboxylic acid, 1O-(1 ,1-dioxide-4--thiomorpholinyl)-9- fluoro-.3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1--ij)-1,3,4-benzoxadiazine- 6-carboxylic acid, 9-fluoro-3-methyl-1O-(1-oxide-4-thiomorpholinyl)-7-oxo- t f e 2,3-dihydro-7H-pyridoE3,2,1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-3-methyl-7-oxo-1O-[4-C2-oxo-n-propyl)-l-piperazinyl)-2,3- dihydro-7H-pyrido[3,2,1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, 1O-(3- chloro-1-pyrrolidinyl )-9-fluoro-3-methyl-7--oxo-2,3-dihydro-7H-pyrido[3,2,1- ij]-1 ,3,4-benzoxadiazine-6--carboxylic acid, 9-fluoro-3-(2-fluoroethyl)-1O- (4-methyl-l-piperazinyl)-7-oxo-2,3--dihydro-7H-pyrido[3,2,1-ij]-1,3,4- benzoxadiazine-6-carboxylic acid, 1Q-(4-amino-l-piperidyl)-9-fluoro-3- methyl-7--oxo-2,3-dihydro-7H-pyrido[3,2,1-ijJ-1,3,4-benzoxadiazine-6-darboxy lic acid, 9-fluoro-3-methyl-1O-E4-(methylamino)-l-piperidyU!-7-oxo-2,3- dihydro-7H-pyridoE3,2,1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, 1O-[4-(ethylamino)-1-piperidylJ-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H- pyrido[3,2,1-ij)-1,3,4-benzoxadiazi'ie-6-carboxylic acid, 1O-[3- [(ethylmethylamino)methyl)-l-.pyrrolidinylj-9-fluoro-3-methyl-7-oxo-2,3- IJ dihydro-7H-pyrido[3,2,1-ijJ-1,3,4-benzoxadiazine-6-carboxylic acid, OW171O-(3-amino-4-hydroxy-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyridoE3,2,1-ijJ-1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-lO- [3-hydroxy-4-Cmethylamino)-l-pyrrolidinyl )-3-methyl-7-oxo-2,3-dihydro-7H- pyrido[3,2,1-ij)-1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-3- methy1-7-oxo-1O-(4-thiomorpholinyl)-2,3-dihydro-7H-pyrido-r3,2,1-ij]-1,3,4- benzoxadiazine-6-carboxylic acid, 1Q-(2,6-dimethyl-4-morpholinyl)-9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido3,2,1-ij-1,3,4-benzoxadiazine- 6-carboxylic acid, 1O-[3-Cacetylaminoniethyl)-1--pyrrolidinyl]-9-flhioro-3- methyl-7--oxo-2,3-dihydro-71I-pyrido[3,2,1-ij)-1,3,4-benzoxadiazine- JTA:173F 84-- Ni0F
2. 74240-24L MeCK 363(M) carboxylic acid, 10-1 12-(d imethyl amino) ethyl Imethyl ami no--9-flIuoro- 3 -methyl-7-oxo-2,3-dhydro-7H-pyrido[3,2, 1-ij 1-1 ,3,4-benzoxadiazine-6- carboxylic acid, 9-fluoro-3-methyl-7-oxo-1O-(3-.oxo-l-piperazinyl)-2,3- dlhydro-7H-pyrido3,2,l-ij-l ,3,4-benzoxadiazine-6--carboxyllc acid, 9-flIuoro-2-(hydroxymethyl )-3-methyl -1-(4-methy] 1-pi peraz inyl )-7--oxo-2,3- dlhydro-7H-pyridot3,2,1-ij1-l ,3,4-benzoxadiazine-6-carboxylic acid, 2-C(dimethylamino)nlethylJ-9-fluoro-3-methyl-1O-(4-methyl-l-piperazinyl)-7- oxo-2,3-di hydro-7H-pyri do[3,2, I-ij]1-1 3,4-benzoxadi azi ne-6-carboxyl ic acid, lO-C3-(benzyloxycarbonylamino)-l-pyrrolidinylj-9-fluoro-3-methyl-7- oxo.-2,3-di hydro-7H--pyri do[3,2 ,lI-i j 1 3,4-benzoxadi azi ne-6-carboxyl ic acid, 9-fluoro-3-methyl-7-oxo-lQ--(4-phenacyl-1-.piperazinyl)-2,3-dihydro- 7H-pyridoC3,2,l--ij 1-1 3,4-benzoxadi azi ne-6-carboxyl ic acid, 9-f Iuoro-3-methyl itrobenzyl -pi perazi nylJ1-7-oxo-2,3-d ihydro- 7H-pyrldo[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, 1O-[4-(3-carboxypropi onyl -1-p iperaz inyl J-9-fl1uoro--3-methyl -7--oxo-2,3- dihydro-7H-pyrido3,2,l-ij]-1 3,4-benzoxadiazine--6-carboxylic acid, 1O-(4-acetyl -1 -pi perazi nyl )-9-flIuoro-3-methyl -7-oxo-2,3-di hydro-7H- pyridoE3,2,1-ijJ-1,3,4-.benzoxadiazine-6-carboxylic acid, 9-fluoro-lO-(4- methoxy-1-pi peridyl )-3-methyl-7-oxo-2, 3-di hydro-7H-pyrido[3,2, 1-ijJ1-1 ,3,4- benzoxadiazine-6-carboxylic acid, 9-fluoro-2,3-dimethyl-lO-(4-methyl- 1-piperazinyl)-7-oxo-2,3--dihydro-7H-pyrido[3,2,l-ij]-l,3,4-benzoxadiazine- V 6-carboxylic acid, 9-fluoro-2,3-dimethyl-7-oxo-1O-(l-piperazinyl)-2,3- dihydro-7H-pyrido-[3,2,l-ij)-l,3,4-benzoxadiazine-6-carboxylic acid, ethyl lO-[3-(benzyloxycarbonylamino)-l-pyrrolidinyl]-9-fluoro-3-methyl- 7-oxo-2,3-di hydro-7H-pyri do[3,2,lI-.ijJ-1 3,4-benzoxadiazi ne-6-carboxyl ate, ethyl lO-(3-amino-l-pyrrol idinyl )-9-fluoro-3-methyl-7-oxo-2,3--dihydro-7H- pyri do[3,2, 1-i j]-1 3,4-benzoxadi azi ne-6-carboxyl ate, benzyl 9-fluoro-O.- (3-hydroxy-l-pyrrolidinyl)--3-methyl-7-oxo--2,3-dihydro-7H-pyrido[3,2,1-ij)- l,3,4-benzoxadiazine-6-carboxylate, benzyl lO-(3-chloro-l-pyrrolidinyl)-9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido3,2,-ij)- 3,4- benzoxadiazine-6-carboxylate, pivaloyl-oxymethyl 10-43- (benzyloxycarbonylamino)-l-pyrrol idinyl]-9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H-pyrido[3,2,1-ij1-l ,3,4-benzoxadi azi ne-6-carboxyl ate, pivaloyl- oxymethyl lO-(3-amino-l-pyrrol idiny)-9-fluoro-3-methyl--7-oxo-2,3-dihydro- 7H-pyridoE3,2,1-ij)-l ,3,4-benzoxadi azi ne-6-carboxyl ate, lO-[3-E(4- ami nobenzyl )ami no)-1-pyrrol idi nyl J-9-fl uoro-3-methyl-7-oxo-2 ,3-di hydro-7H- pyrido[3,2,1-ijJ,)-l ,3,4-benzodaxiazine-6-carboxylic acid, 9-fluoro-10-C3- (((dimethylamrino)methyleneJamino-l-pyrrolidinyl]-3-methyl-7-oxo-2,3- dihydro-7H-pyridoZ3,2,1-ij]-I ,3,4-benzoxadiazine-6-carboxyiic acid, 3 TA:1I73 F 9-fluoro-3-methyl-1O-[l-(4-methyl--l-piperazinyl)-l-pyrrolidinyl)-7-oxo-2,3- dihydro-7H-pyrldo[3,2,l-ij3.-l,3,4-benzoxadlazine-6-carboxylic acid, 1O-(3-amlno-3-methyl-l-pyrrol idinyl )-9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrldo[3,2,l-il-l,3,4-benzoxadiazine-6-carboxylic acid, lO-(trans-3- amlno-4-phenyl-l-pyrrolidlnyl )-9-fluoro-3-rnethyl-7-oxo-2,3-dihydro-7H- pyrido[3,2,l-l-1,3,4-benzoxadiazine-6-carboxyllc acid, 9-fluoro-3- methyl-lO-[3-methyl-3-E(methylamino)methylj-l-pyrrolidinyl*-7-oxo-2,3- dihydro-7H-pyridoE3,2,1-ij-,3,4-benzoxadazine-6-carboxylic acid, 9-fluoro-3-methyl-lO-[trans-3-[(methylamino)methylJ-4-phenyl-l-pyrroli- dinyl3-7-oxo--2,3-dihydro-7H-pyridoE3,2,l-ij)-1 ,3,4-benzoxadiazine-6- carboxylic acid, lO-(trans-3-3-amino-4-hydroxy-l-pyrrolidinyl)-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 said compound or of said salt.
3. 609422. Compounds represented by the general formula: 0 N 2 wherein R is a hydrogen atom or a carboxy-protecting radical: R 2is a hydrogen atom or a lower alkyl radical which may be substituted with a 2halogen atom;, and Rindependently are a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or an unsubstituted amino acid radical or an amino acid radical substituted with di-lower alkyl, lower alkyl or lower cycloalkyl; and X and X1, which are the same or different, are halogen atoms. 23. A process for the manufacture of the compounds according to any one of claims 1 to 22 which process comprises reacting a compound represented by the general formula 0 X QOR XI 0 N(III) SAl E I I I 86 wherein R R 2 R 3 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 R 5 (IV) R 6 wherein R 5 and R 6 are the same as defined in claim 1, followed, if necessary, by removal of a protecting radical, or reacting a compound represented by the general formula C OOR 6 N (V) R -N 2. SOH NHR 725 wherein R, R 2 R 5 R and X are the same as defined in claim 1; and amino, hydroxy and/or carboxy groups present may be protected, with a carbonyl compound represented by the general formula :4 3 SC=O (VI) r( 4 wherein R 3 and R 4 are the same as defined in claim 1, or its polymer, acetal, ketal or enol ether, followed, if necessary, by removal of a protecting radical, or for the manufacture of a compound of formula I in which R is other than hydrogen reacting a compound of formula I in which R is hydrogen with an agent yielding the group R where R is as R but not hydrogen, or for the manufacture of a compound of formula I wherein 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 R 5 and/or R 6 are hydrogen or contain an amino, lower alkylamino or hydroxy group, 87 or for the manufacture of a compound of formula I in which R 5 R 6 N- is a 5 to 7 membered heterocyclic ring with -SO- or -SO 2 subjecting a corresponding compound wherein the heterocyclic ring contains to oxidation, or for the manufacture of a compound of formula I having a free amino, hydroxy and/or carboxy group splitting o protecting group(s) from a corresponding compound of formula I having protected amino, hydroxy and/or carboxy group(s), or for the manufcture of a compound of formula I containing a halogen atom halogenating a correspondingly hydroxy-substituted compound of formula I in which R 1 is a carboxy-protecting radial and, if desired, splitting off said protecting radical R or for the manufacture of a compound of formula I containing an S' amino group reducing the nitro group of a correspondingly nitro-substituted compound of formula I, or for the manufacture of a compound of formula I containing a I' group of the formula SR I where R 50 and R 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 I reactive derivative of a formamide derivative of the general formula .j R N-CHO (VII) R wherein R 50 and R 51 are as above, or 88 for the manufacture of a compound of formula I in which R 1 is a carboxy-protecting radical subjecting a carboxylic acid of formula I to a corresponding esterification, or for the manufacture of pharmaceutically acceptable 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. 24. Process according to claim 23 wherein one of process alternatives and is carried out. A pharmaceutical preparation containing a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 26. A method of treatment and prophylaxis of infectious diseases in a patient requiring such treatment and prophylaxis which method comprises administering to said patient an effective amount of a compound as defined in any one of claims 1 to 21 and/or a pharmaceutical preparation as defined in claim 27. Compounds according to any one of claims 1 to 21 whenever prepared according to the process claimed in claim 23 or by an obvious chemical equivalent thereof. 28. A tricylic compound substantially as hereinbefore described with Sreference to any one of Examples 1 to 29. A process for preparing a tricylic compound, which process is substantially as hereinbefore described with reference to any one of Examples 1 to 30. A pharmaceutical preparation substantially as hereinbefore described with reference to Example A or Example B. DATED this SIXTEENTH day of JULY 1990 F Hoffmann-La Roche Co Aktiengesellschaft Patent Attorneys for the Applicant SPRUSON FERGUSON S Z 6 Amto f ramn adpohlai fifetosdsessi0